Evaluation criteria for the interpretation of the oral glucose tolerance test (OGTT) in The National Mother-Child Teaching Hospital “San Bartolome” Combined Therapy in Diabetic Macular Edema History and progress of antiviral drugs: from acyclovir to direct-acting antiviral agents (DAAs) for Hepatitis C Chikungunya Virus: a general overview
Anaphylaxis: Practical aspects of diagnosis and treatment
EDITORIAL COMMITTEE General Director Editor in Chief
Santos Guzmán López
Ariel Ernesto Arias Ramírez
Félix Ramón Cedillo Salazar
David Gómez Almaguer
Norbert W. Brattig
Francisco Javier Bosques Padilla
María de los Ángeles Castro Corona
Carlos Alberto Acosta Olivo
Ricardo Cerda Flores
Beatriz Elizabeth De la Fuente Cortez
Salvador Cruz Flores
St. Louis, EEUU
Alfredo Arias Cruz
José Carlos Jaime Pérez
José A. González González
Oscar González Llano
Patricia de Gortari
EDITORIAL BOARD Hugo Alberto Barrera Saldaña
René Raúl Drucker Colín
Rubén Lisker Y.
Ruy Pérez Tamayo
Guillermo J. Ruiz Argüelles Ralph Weissleder Oliverio Welsh Lozano
Puebla, México Boston, EEUU Monterrey, México
Alejandra García Quintanilla
Elvira Garza González Pali Hungin
Stockton-on-Tees, Reino Unido Monterrey, México
Patricia Ileana Joseph Bravo
Susana Kofman Alfaro
David Kershenobich Stalnikowitz
Francisco López Jiménez
Xavier López Karpovitch
Nahum Méndez Sánchez
Monterrey, México DF, México
Claudia Elizalde Molina
Guillermo I. Pérez Pérez
Nueva York, EEUU
Mario Henry Rodríguez
Isaías Rodríguez Balderrama
Alejandro Ruiz Argüelles
Guillermo J. Ruiz Delgado
José Javier Sánchez
Josep María Segur Vilalta Gregorio A. Sicard
Eloy Cárdenas Estrada
Rolando Tijerina Menchaca
Antonio Costilla Esquivel
Lyuba Varticovski Joseph Varon
English translation and style:
José Luis Iglesias Benavides
Laura E. Martínez de Villarreal
Francisco Forriol Campos
Jordi Sierra Gil
Barcelona, España St. Louis, EEUU Monterrey, México Maryland, EEUU Houston, EEUU Barcelona, España
Emma Bertha García Quintanilla Juan Pablo Figueroa Delgado
Medicina Universitaria, Volumen 17, número 68, julio-septiembre 2015, es una publicación trimestral de la Revista de Investigación y Ciencia de la Facultad de Medicina y Hospital Universitario Dr. José E. González de la U.A.N.L. ISSN 1665-5796. Editada por: Masson Doyma México, S.A. Av. Insurgentes Sur 1388, Piso 8, Col. Actipan Del. Benito Juárez, CP 03230, México, D.F. Tels.: 5524-1069, 5524-4920, Fax: 5524-0468. Reservados todos los derechos. El contenido de la presente publicación no puede ser reproducido, ni transmitido por ningún procedimiento electrónico o mecánico, incluyendo fotocopia, grabación magnética, ni registrado por ningún sistema de recuperación de información, en ninguna forma, ni por ningún medio, sin la previa autorización por escrito del titular de los derechos de explotación de la misma. Cualquier forma de reproducción, distribución, comunicación pública o transformación de esta obra sólo puede ser realizada con la autorización de sus titulares, salvo excepción prevista por la ley. Impresa por Editorial de Impresos y Revistas S. A. de C. V. Emilio Carranza No. 100 Col. Zacahuizco C.P. 03550. Delegación Benito Juárez, México D.F. Este número se terminó de imprimir en septiembre de 2014 con un tiraje de 1,200 ejemplares. Índices en los que aparece esta revista: ARTEMISA (Artículos Editados en México sobre información en Salud). En Internet, compilada en el Índice Mexicano de Revistas Biomédicas (IMBIOMED) y LATINDEX.
Volume 17 Issue 68 July-September 2015
Some observations on the publication of articles in Medicine D. Gómez-Almaguer
ORIGINAL ARTICLES 133
Prevalence of sensorineural hearing loss in children and adolescents with diabetes mellitus J.L. Treviño-González, D.I. Campuzano-Bustamante, O. Flores-Caloca, R. Santos-Lartigue, M.J. Villegas-González Jr.
Tendencies in medical publications H.E. Tamez-Pérez, E. Delgadillo-Esteban, S.L. Proskauer-Peña, V. Arenas-Fabbri, A.M. Carranza-Trejo, J.G. González-González, A.L. Tamez-Peña
Efficacy of antiemetic therapy in patients undergoing laparoscopic cholecystectomy H.A. Llanes-Garza, N.G. López-Cabrera, R. Cacho-De la Vega, D. Palacios-Rios, A.L. Millan-Corrales, M. Pacheco-Juárez, E. Cárdenas-Estrada
Evaluation of the criteria for the interpretation of the oral glucose tolerance test in the National Mother-Child Teaching Hospital “San Bartolome” J.J. Moya-Salazar, L. Pio-Dávila
Combined therapy in diabetic macular edema J.H. González-Cortés, J.J. Toledo-Negrete, K. Butrón-Valdez, V. Zapata-Elizondo, B.O. Martínez-Gamero, E.E. Treviño-Cavazos, J.D. Guerra-Leal, J. Mohamed-Hamsho
SCIENTIFIC LETTERS 158
Spectrum of hemifacial microsomia in a pre-term newborn. Case presentation and literature review A.Y. Medina-de la Cruz, I. Rodríguez-Balderrama, C.H. Burciaga-Flores, M.E. de la O-Cavazos
Prostatic cyst: An unusual cause of hemospermia F. Hernández-Galván, R. Jaime-Dávila, L.S. Gómez-Guerra, A. Gutiérrez-González, J.F. Lozano-Salinas, J.G. Arrambide-Gutiérrez
REVIEW ARTICLES 165
History and progress of antiviral drugs: From acyclovir to direct-acting antiviral agents (DAAs) for Hepatitis C O.L. Bryan-Marrugo, J. Ramos-Jiménez, H. Barrera-Saldaña, A. Rojas-Martínez, R. Vidaltamayo, A.M. Rivas-Estilla
Chikungunya virus: A general overview K.A. Galán-Huerta, A.M. Rivas-Estilla, I. Fernández-Salas, J.A. Farfan-Ale, J. Ramos-Jiménez
SPECIAL ARTICLE 184
Perspective on stroke in Mexico F. Góngora-Rivera
EXPERT’S CORNER: A PERSONAL APPROACH 188
Anaphylaxis: Practical aspects of diagnosis and treatment A. Arias-Cruz
Fecal microbiota transplantation J. González-Altamirano, H.J. Maldonado-Garza, E. Garza-González, F.J. Bosques-Padilla
Medicina Universitaria. 2015;17(68):131---132
Some observations on the publication of articles in Medicine
The University is not only a school for adults, but it plays a major role in the search of new knowledge, in other words, research. In addition to assisting patients, teaching colleagues and students --- undergraduates as well as postgraduates --- it is important to highlight the need and duty of doctors to be involved in research. This does not necessarily require a great set of skills or special knowledge; it can be as simple as to cooperate in a workgroup that searches for new knowledge of a speciﬁc disease, or more complex activities, like designing and implementing a prospective/comparative study in search of new evidence and different paths than those previously established. In order to broadcast knowledge locally, domestically or internationally, it is necessary to publish the conducted research. Activity at a convention, like a conference, or a poster displaying the results of research, are far from ideal broadcasting and, in the scientiﬁc world, these are considered to be preliminary or simplistic. Final publication is essential in order to transcend and make a difference. To publish implies ﬁnding a magazine interested in the work submitted for publication. In this sense quality, originality and signiﬁcance are factors which would make its acceptance and spreading possible, which is part of the ﬁnal process of quality research, thus the popular saying ‘‘publish or perish’’; this stresses, in an exaggerated way, the importance of having a research work ﬁnally published. In this issue of ‘‘Medicina Universitaria’’ Tamez-Pérez et al. analyze the publication trends in a series of highimpact publications. This is measured by the number of references a magazine has versus the number of articles published in a speciﬁc period of time. These magazines include The New England Journal of Medicine, Lancet and JAMA, among others, hence the high quality of the articles and studies --- comparative, randomized and prospective --- accepted in these publications. This is the base of their relevance, hence their acceptance and acknowledgement in the community. In the aforementioned journals, we rarely ﬁnd articles from ‘‘developing countries’’, a group to which
Mexico belongs. Studies of major clinical signiﬁcance require a large number of patients, years of follow-up and money for their elaboration/culmination, and are supported or originate within the pharmaceutical industry or by a society or group in the US or Western Europe. This occurs and will continue to occur until our organization and ability to develop studies with a higher evidence level materializes. Until then, Mexico will remain in the background in the ﬁeld of innovation, ideas and contributions to the world of science. However, we must recognize those researchers who strive on a daily basis to show their abilities to innovate despite how complicated working in a developing country may be. Personally, the presence of high-quality articles in high-impact publications, articles which are the product of the resourcefulness, invention and perseverance of invariably optimistic Mexican doctors, never ceases to amaze. In the medical world we have the advantage of being able to search for valuable information in different types of studies, from an outstanding clinical case, to retrospective observational studies and case-control, among others. Everything is of value. On the other hand, in this day and age, the publication of articles in these high-proﬁle journals is not necessarily that important. The spreading of knowledge through the internet nowadays is such that ‘‘information democracy’’ has reached science, it just takes the touch of a button to access information of any publication indexed in Pubmed or any other entries. This allows for studies and papers of supposedly less signiﬁcance, published in low-impact journals, to be easily seen, eventually referenced and obviously transcending and having an impact in the scientiﬁc world, thus in the beneﬁt of patients and their surroundings. The one must is language: English, whether we like it or not, is the language of modern science, therefore ‘‘Medicina Universitaria’’ has decided to take this step forward towards internationalization. We are on the right track, the speed can be improved and we will continue trying, eventually getting us closer to the major journals in the scientiﬁc world.
D. Gómez-Almaguer ∗ Hematology Service at the ‘‘Dr. José E. González’’ University Hospital of the UANL, Monterrey, N.L., Mexico ∗
Corresponding author at: Servicio de Hematología, Hospital Universitario ‘‘Dr. José Eleuterio González’’ de la
UANL, Av. Madero y Gonzalitos s/n, Colonia Mitras Centro Monterrey, C.P. 64460, Monterrey, N.L., Mexico. Tel.: +52 81 83488510. E-mail address: [email protected]
Medicina Universitaria. 2015;17(68):133---137
Prevalence of sensorineural hearing loss in children and adolescents with diabetes mellitus J.L. Trevi˜ no-González a,∗ , D.I. Campuzano-Bustamante a , O. Flores-Caloca b , R. Santos-Lartigue a , M.J. Villegas-González Jr. a a
Department of Otolaryngology and Head and Neck Surgery of the ‘‘Dr. José Eleuterio González’’ University Hospital of the Autonomous University of Nuevo León, Mexico b Department of Endocrino-Pediatrics of the ‘‘Dr. José Eleuterio González’’ University Hospital of the Autonomous University of Nuevo León, Mexico Received 23 June 2015; accepted 23 June 2015 Available online 17 August 2015
KEYWORDS Diabetes mellitus type I; Insulin-dependent diabetes; Sensorineural hearing loss; Deafness; Children
Abstract Objective: To establish the prevalence of sensorineural hearing loss (SNHL), as well as the predisposing risk factors, in children and adolescents with type 1 diabetes mellitus (T1DM) attending the Service of Endocrino-Pediatrics and Otolaryngology Department of the ‘‘Dr. José Eleuterio González’’ University Hospital and the Materno-Infantil Hospital, from January 2011 to December 2012. Material and methods: A total of 84 children with T1DM, with ages between 6 and 18 years old, were studied. Values of glycated hemoglobin (HbA1c) were assessed and Tonal audiometry and Speech audiometry tests were performed. Results: A total of 84 patients with a diagnosis of T1DM were studied, out of which 12 (14.3%) presented SNHL. Fifty percent of patients with hearing loss were in the age range of 10---13 years old. Regarding time of evolution with the disease (T1DM), 33% of patients with more than 5 years with T1DM presented SNHL, and nearly 88.9% of the patients with less than 5 years with T1DM presented normal hearing (p = 0.011). Moreover, 65.47% of the patients presented complications due to poor glycemic control at some point in the evolution of their disease. All (100%) diabetic patients with SNHL and 91% of the patients without SNHL had HbA1c values greater than 6%. In patients with hearing impairments, 83.3% suffered mild and 16.4% suffered moderate hearing loss. Most presented bilateral hearing loss, with the right ear dominating. Acute frequencies, mainly 8000 kHz, were the most affected.
∗ Corresponding author at: Servicio de Otorrinolaringología del Hospital Universitario ‘‘Dr. José Eleuterio González’’ de la Universidad Autónoma de Nuevo León, Ave. Madero y Gonzalitos s/n Colonia Mitras Centro, C.P. 64460, Monterrey, N.L., Mexico. Tel.: +52 81 83 334299; fax: +52 81 83 3329 17. E-mail address: [email protected] (J.L. Trevi˜ no-González).
Introduction The World Health Organization (WHO) deﬁnes diabetes mellitus (DM) as a multiple-etiology metabolic disorder, characterized by chronic hyperglycemia and other metabolic abnormalities, which result in absolute or relative insulin deﬁciency. It is the most frequent endocrine-metabolic disorder in children and adolescents, and has remained the main type of diabetes in children.1---4 Type 1 diabetes mellitus (T1DM) is a disease with an etiology of intervening environmental factors which interact with a genetic-predisposition component; it is considered a chronic autoimmune disease which causes the destruction of the pancreatic ␤ cells which produce insulin.5 The average age of the onset of the disease is between 7 and 15 years of age; however, it may occur at any age.6 Values of the HbA1c > 6% higher than the normal range (5---6%) have been considered a risk of developing micro- and macroangiopatic complications. The affection of the blood vessels which supply the inner ear and the vascular stria have been reported by different authors as a physiopathological cause of SNHL in T1DM patients.3,7 Treatment with insulin, maintaining on average HbA1c of 7.2%, reduces the onset and progression of microangiopatic complications, atrophy, and demyelination of the spiral ganglion by up to 76%.8,9,13 Sensorineural hearing loss (SNHL) is a loss of hearing at any frequency more than 25 dB, with conductive and sensorineural gaps lower that 20 dB, and affecting the patient’s ability to communicate, his or her education, job prospects and social relationships, and also causes stigmatization.11,12 The reported prevalence of SNHL is up to 33% in children with T1DM versus 0.3---0.5% in healthy children. In Mexico there is a lack of sufﬁcient epidemiologic information which deﬁnes the hearing condition prevailing in our population.12
Materials and methods A prospective longitudinal, analytic, comparative study was conducted on a total of 87 patients of both sexes, ages 6---18, with a T1DM diagnosis, from the Service of EndocrinoPediatrics and Otolaryngology Department of the ‘‘Dr. José Eleuterio González’’ University Hospital and the MaternoInfantil Hospital, from January 2011 to December 2012. We included patients who agreed to participate in the protocol through a signed informed consent, signed by their parents and/or guardians and/or the patient. We excluded patients with noise exposure, a family history of deafness, use of ototoxic medications, otitis media, a history of
previous ear surgery (except ventilation tube insertion) and DM type 2. All subjects in this study were given a questionnaire, which included family, prenatal, natal and personal pathological and non-pathological history. Patients underwent basic otorhinolaryngological exploration, tone audiometry and oral audiometry using an audiometer AUDIOTEST 259b, manufactured for Interacustics, Type 2 Tone Audiometer, Type B-E-T speech audiometer in a soundproof cabin Acoustics Systems, Model RE-142, Serial #21413a , made in USA. The study was approved by the Ethics and Research Committee of the School of Medicine of the Universidad Autónoma de Nuevo León (UANL by its Spanish acronym) with the registration key OT12-002. The information obtained was gathered in a database using Excel, performing statistical analysis using SPSS 20.0. We obtained the traditional statistics in the quantitative and qualitative variables, looking to establish differences between both groups through hypothesis tests for means and proportions, to establish the absence or presence of association and correlation using chi square, Pearson or Spearman, with a conﬁdence and reliability of 95%.
Results Out of the 87 recruited patients with a T1DM diagnosis, we excluded a patient with a history of chronic otitis media of the right ear, one with otitis media with bilateral effusion and a patient with a ﬁnal diagnosis of T2DM. The remaining 84 patients were divided into 3 groups based on age: 6---9, 10---13, and 14---18 years old. We observed that 72 patients with a T1DM diagnosis showed normal hearing while 12 T1DM patients showed sensorineural hearing loss (Fig. 1).
14.3 Normal Hearing Sensorineural hearing loss 85.7
Figure 1 Average of patients with type 1 diabetes with normal hearing and sensorineural hearing loss.
1 4 5
14 to 18 years
135 8000 Hz
Prevalence of sensorineural hearing loss
10 to 13 years
6 to 9 years
0 1 1
5 years or less with T1DM
T1DM = diabetes mellitus type 1; SNH = sensorineural hearing loss
Comparison of both groups by T1DM evolution time.
12/84 78/84 6/84 55/84 = 65.47% 13/84 71/84
1 4 7 18 29 31 2 1 3 10 18 27 0 1 12 20 29 22
>6 <6 >5 years <5 years
Ketoacidosis, hyper/hypo glycemia
HbA1c HbA1c Previous complications Evolution Time Male
More than 5 years with T1DM
11 17 14
9 13 20
6---9 years 10---13 years 14---18 years
33.30% T1DM + SNH
11.10% T1DM + normal hearing
Result of variables studied, by age group.
The 6---9 group included 20 patients (9 girls and 11 boys) with diabetes with an evolution time of less than 5 years; 10 (50%) subjects presented a history of previous complications like ketoacidosis, hyperglycemia or hypoglycemia, 2 (10%) patients had HbA1c < 6 and 18 HbA1c > 6, and 1 (5%) subject presented mild SNHL for 8000 kHz thresholds. The 10---13 group included a total of 30 patients (13 girls and 17 boys); 29 (34.5%) had had diabetes mellitus for less than 5 years and 1 (1.21%) for over 5 years, 18 (21.4%) patients presented a history of ketoacidosis, hypo- or hyperglycemia, 29 (34.52%) presented HbA1c > 6 and 1 (1.19%) HbA1c < 6; mild SNHL was displayed in 3 (3.57%) subjects and 1 (1.19%) patient displayed moderate SNHL, and all 4 patients were in hearing thresholds of 8000 kHz. The 14---18 group consisted of 34 patients (40.47%) (20 girls and 14 boys), 22 (64.70%) with an evolution time of less than 5 years and 12 (35.29%) for more than 5 years; complications like ketoacidosis, hypoor hyperglycemia were reported by 27 of them; 3 (8.82%) subjects showed an HbA1c < 6 and 31 (91.17%) an HbA1c > 6; SNHL occurred within this group in 7 individuals (mild in 6 and moderate in 1). In all patients, SNHL was observed in thresholds of 8000 kHz (See Table 1). In our study, we were able to observe a percentage prevalence of SNHL of 14.3% (12 out of 84 patients). Also, 64 patients (76.19%) with T1DM were older than 10 years of age, as opposed to a small group of 20 patients (23.80%) between the ages of 6 and 9 (Fig. 2). There were no differences in gender, each representing 50%. In regard to time of evolution of T1DM, 15.47% (13 patients) with over 5 years with T1DM presented SNHL, and 84.52% (71 patients) with less than 5 years with T1DM presented normal hearing, this being a statistically signiﬁcant value (p = 0.011) (Fig. 3).
Sensorineural hearing loss
Comparison of both groups by age range.
T1DM + SNH
T1DM = siabetes sellitus type 1; SNH = sensorineural hearing loss
1 3 6
T1DM + normal hearing
0.00% 10.00% 20.00% 30.00% 40.00% 50.00% 60.00%
J.L. Trevi˜ no-González et al.
60% 50% 40%
30% 20% 10% 0%
Previous complications (ketoacidosis, hyper/hypo glycemia) No 29/84
Figure 4 Previous complications from uncontrolled blood glucose in both groups.
Profound more than 80 DB
Severe 61 to 80 DB
Moderate 41 to 60 DB
Light 20 to 40 DB
0.00% 20.00% 40.00% 60.00% 80.00% 100.00%
T1DM + SNH T1DM = diabetes mellitus type 1; SNH = sensorineural hearing loss
Degrees of sensorineural hearing loss.
Out of the 84 patients, 55 (64.47%) presented complications at some point during the evolution of their disease due to glycemic irregularities; the most frequent complication was ketoacidosis and the least prevalent was hypoglycemia (Fig. 4). In the present study, 100% of diabetic patients with SNHL (12 patients) and 91% of patients with normal hearing presented HbA1c values greater than 6%, showing an average value of 7.5% in the general population studied. According to age groups, the group consisting of children between 6 and 12 years presented, on average, an HbA1c value of 7.24%, while the group consisting of children between 13 and 19 years of age presented, on average, an HbA1c value of 7.67%. Of all the SNHL patients, 83.30% (10 patients) presented mild hearing loss and 16.70% (2 patients) moderate hearing loss (Fig. 5). Most patients presented bilateral hearing loss, predominately on the right ear. The 8000 kHz thresholds were the most affected. (Table 1)
Discussion An SNHL prevalence of up to 33% in children with T1DM has been considered, versus 0.3---0.5% in healthy children. In Mexico, there is a lack of epidemiologic information that can deﬁne the hearing condition which prevails among our population.12 The observed prevalence in our studied group was 14.3%, contrary to the rate reported in different publications.
However, we must keep in mind that most of the studied population is American or European. It is important to stress the fact that there are still many T1DM cases that have not been diagnosed, but with the obtained results at this point, we are able to infer that up to a sixth of the diabetic population in our society will develop SNHL. Regarding age, the obtained information matches the one found in the bibliography. Most children are in the mentioned peak ranges, especially above 10 years of age, beginning with hormone changes that are a normal part of puberty and adolescence. Nevertheless, based on the obtained results we are able to see that the patient’s age does not represent a risk factor for the presence of SNHL. According to the American Diabetes Association (ADA) and the Diabetes medical attention standards of 2014, the goal for HbA1c in type 1 diabetic patients varies depending on age. Concerning values <8% in the 6---12 years-of-age range, because it is not possible to have more strict goals due to the risk of developing hypoglycemia, even in this age range we can demand goals of <7.5% in speciﬁc cases where patients do not present severe hypoglycemia. In the 13---19 years-of-age range, values of <7.5% are considered and in speciﬁc cases even <7%. In children under 6 years of age, goals of <8% are too strict, so up to <8.5% is acceptable, because these children have a greater vulnerability for hypoglycemia, a greater sensitivity to insulin, and are unpredictable in their intake and physical activity.10 The average population showed HbA1c values of 7.5% and taking the results by age group into account, we are able to say that our patients, under 13 years of age with an HbA1c average of 7.24%, are within an adequate glycemic control, because they are inside the accepted range by the ADA 2014 (6---12 years = <8%); and patients older than 13 years of age with an average of 7.67% show a control barely above that expected for their age group (13---19 years = <7.5%). It is important to maintain HbA1c values as close to normal as possible, thus reducing by almost 80% the risk of presenting microangiopatic complications; however, we must not be very strict with our population, especially with children under 13 years of age, because of the risks of presenting severe or belated hypoglycemia cases, and hence the importance of following the standards established by the ADA 2014. Regarding time of evolution with T1DM, it was the only statistically signiﬁcant risk factor (p = 0.011) for a period greater than 5 years and the presence of hearing loss. However, when we looked for the correlation between both factors, we did not ﬁnd it. The present study showed a greater prevalence of hearing loss in patients with more than 5 years of evolution of T1DM, without it being associated or related. This could be due to the lack of potency in the studied population who presented T1DM and SNHL, requiring a greater number of patients and further research. Nevertheless, it is important that 5 years after a T1DM diagnosis, as there is an already established protocol in search of microangiopatic complications like retinopathy, we establish the application of hearing studies which allow us to detect hearing problems in a timely manner. Out of all of our patients with SNHL, 83.3% presented a mild hearing loss, bilaterally, in acute frequencies, predominately 8000 Hz, which agrees with the rate obtained in previous studies. The type of hearing loss presented
Prevalence of sensorineural hearing loss in these patients is similar to the one that patients with presbycusis would present, but at an earlier age compared to the population without T1DM. This research provided valuable data to lead the way for new researches in these types of patients, and establish a timely and protocol-led assessment for their glycemic control as well as their hearing, thus avoiding hearing complications which patients with a T1DM of long duration present, like SNHL and sudden hearing loss. Also, later studies are recommended where a long-term follow-up is given to these patients in order to determine the causation degree of the studied risk factors on the base pathology.
Conﬂicts of interest The authors have no conﬂicts of interest to declare.
Funding No ﬁnancial support was provided.
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137 3. LisowskaG, Namysłowski G, MorawskiK, Strojek K. Early identiﬁcation of hearing impairment in patients with type 1 diabetes mellitus. Otol Neurotol. 2001;22:316---20. 4. Kuzuya T, Nakagawa S, Satoh J, et al. Report of the Committee on the classiﬁcation and diagnostic criteria of diabetes mellitus. Diabetes Res Clin Pract. 2002;55:65---85. 5. Steele C, Hagopian WA, Gitelman S, et al. Insulin secretion in type 1 diabetes. Diabetes. 2004;53:426---33. 6. Mark AS, Stuart AW, William VT. Diabetic mellitus. Pediatric endocrinology, vol. 10, 3rd ed. Saunders Elsevier; 2008. p. 374---7. 7. Pi˜ nón PAL, Luis REJ. Valor diagnóstico de la Hemoglobina Glucosilada en el estado prediabético. Hospital Universitario Cdte. Faustina Pérez Hernández; 2008. 8. Lachin S, Genuth S, Nathan DM, Zinman B, Rutledge BN. Effectof glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial-revisited. Diabetes. 2008;57:995---1001. 9. DCCT (The Diabetes Control and Complications Trial Research Group). The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14). Massachusetts. 10. ADA --- American Diabetes Association. Standards of medical care in diabetes 2014. Diabetes Care. 2014;37 Suppl. 1. 11. Elamin A, Fadlallah M, Tuvemo T. Hearing loss in children with type 1 diabetes. Indian Pediatr. 2004;42:15---21. 12. Secretaria de Salud Guía de Práctica Clínica. Evidencias y recomendaciones. Hipoacusia Neurosensorial Bilateral e Implante Coclear. México, D.F.; 2010. 13. Maia CAS, Campos AC. Diabetes mellitus as etiological factor of hearing loss. Rev Bras Otorrinolaringol. 2005;2:208---14.
Medicina Universitaria. 2015;17(68):138---142
Tendencies in medical publications H.E. Tamez-Pérez, E. Delgadillo-Esteban ∗ , S.L. Proskauer-Pe˜ na, V. Arenas-Fabbri, na A.M. Carranza-Trejo, J.G. González-González, A.L. Tamez-Pe˜ Ofﬁce of Research, School of Medicine of the Autonomous, University of Nuevo León, Mexico Received 10 June 2014; accepted 14 April 2015 Available online 19 August 2015
Introduction ∗ Corresponding author at: Subdirección de Investigación, Facultad de Medicina, Universidad Autónoma de Nuevo León, Ediﬁcio de la Biblioteca Central de la Facultad de Medicina, planta baja, Av. no, Col. Francisco I, Madero Pte. s/n y Dr. Eduardo Aguirre Peque˜ Mitras Centro, C.P. 64460, Monterrey, N.L., Mexico. E-mail address: [email protected] (E. Delgadillo-Esteban).
In the area of continuous medical education, in order to achieve the gold standard in medical attention, growth and current information, frequent review of medical literature is necessary. In modern medicine, healthcare excellence is combined with scientiﬁc rigor in the practice of evidencebased medicine (EBM). This new paradigm in medical education integrates the use of the best clinical evidence
Tendencies in medical publications and experience in the diagnostic and therapeutic decisionmaking process. Proposed in 1992,1 its implementation has been replacing the authoritarian management and the purely heuristic in medicine. Using competences such as search strategies, critical reading and the application of evidence to the context of the patient2,3 to create and base an intervention. Some of its objectives are: to promote critical thinking, to promote continuous learning, to reduce the impact of medical error and improve the patient’s prognosis. Nevertheless, despite having acceptance among some medical circles; critics point out the difﬁculty of integrating EBM into clinical practice.4---6 They question its epistemological value7,8 and comment regarding the resistance of its implementation in some health centers and universities.9 Regarding medical education, the integration of a dynamic learning model must deliver results and content. An adequate curriculum should categorize content according to its level of complexity and difﬁculty. In the evidence-based medicine scenario, the competences must prepare doctors to evaluate and integrate the best evidence in order to generate an answer to a clinical problem. But, taking this into consideration, what does it take to answer a clinical question? In the process of critical reading, a study can apply to clinical context if it complies with internal and external validity. Therefore, the search of studies with a high level of evidence is the ﬁrst step. This represents a fact in medical journals with a high impact factor. First, in the review-by-pairs process, reviewers included in the editorial committee publish in high impact journals.10 Concerning the researcher’s participation, they recruit a higher number of patients, evaluate major results and analyze subgroups.11 With the selection of publications, the ‘‘method’’ section is evaluated on the integrity of the statistical analysis,12 while in ‘‘results’’, the inclusion of a conﬁdence interval13 and clinical signiﬁcance range is common.14 Despite all of the above, research design may offer a replicable example of information with high clinical value. Thus, the objective of the present study is to examine the publication tendencies in the different research designs in high-impact medical journals.
Materials and methods A transversal descriptive study was conducted. We evaluated issues of the following journals published during 2011: The New England Journal of Medicine, Journal of the American Medical Association, Annals of Internal Medicine, The Lancet and BMJ. The impact factor was obtained from the Journals Citation Report.15 These publications were then classiﬁed as primary (originals) and secondary (revisions) studies according to their focus. The main studies section was sub-divided according to the type of study and experimental (randomized clinical trials) and observational designs (prevalence, control case and cohort). The secondary studies section included: narrative review and systematic review, with and without meta-analysis, excluding genomic studies of this category. Descriptive statistics were utilized for better data management and interpretation.
Results Out of the 1130 publications analyzed in 2011, the journals published an average of 3 main studies and 1 secondary study per issue (results shown in Table 1). 337 randomized clinical trials (30.4%) were published in the main studies category. On the other hand, observational studies 243 (21.9%), included 102 cohorts (9.02%), 59 case reports (5.2%) and 52 (4.6). Regarding the secondary studies, 226 publications were classiﬁed as narrative reviews (20%), 67 as systemic reviews (5.9%) and 33 as systemic reviews with meta-analysis (2.9%). The New England Journal of Medicine published 241 articles, divided as follows: 0 (0%) meta-analysis, 1 (0.5%) systematic review, 33 (15.55%) narrative reviews, 110 (51.4%) clinical essays, 17 (7.9%) cohorts, 6 (2.8%) control cases, 5 (2.3%) prevalence and 42 (19.6%) case reports. The Lancet published 337 articles, divided as follows: 6 (1.8%) meta-analysis, 3 (0.9%) systematic reviews, 120 (35.6%) narrative reviews, 110 (29.7%) randomized clinical trials, 46 (13.6%) cohorts, 4 (1.2%) control cases, 5 (1.2%) prevalence and 53 (15.7%) case reports. The Journal of the American Medical Association, for its part, published 202 studies, divided as follows: 18 (8.9%) meta-analysis, 2 (1%) systematic reviews, 14 (6.9%) narrative reviews, 42 (20.8%) randomized clinical trials, 81 (40.1%) cohorts, 32 (15.8%) control cases, 10 (5%) prevalence and 3 (1.5%) case reports. BMJ included 270 publications, divided as follows: 1 (0.4%) meta-analysis, 43 (15.9%) systematic reviews, 53 (19.6%) narrative reviews, 72 (26.7%) randomized clinical trials, 69 (25.6%) cohorts, 15 (5.6%) control cases, 17 (6.3%) prevalence and 0 (0%) case reports. Last but not least, Annals of Internal Medicine published 107 studies, divided as follows: 8 (7.5%) meta-analysis, 18 (16.8%) systematic reviews, 6 (5.6%) narrative reviews, 20 (18.7%) randomized clinical trials, 34 (31.8%) cohorts, 2 (1.9%) control cases, 15 (14%) prevalence and 4 (3.7%) case reports. Regarding original studies, NEJM published 180 (84.1%), The Lancet 208 (61.7%), JAMA 168 (83.2%), BMJ 173 (64.1%) and Annals of Internal Medicine 75 (70.1%). The tendencies for secondary studies were NEJM 34 (15.9%), The Lancet 129 (38.3%), JAMA 34 (16.8%), BMJ 97 (35.9%) and Annals of Internal Medicine 32 (39.9%).
Discussion In our frequency distribution analysis, publication distribution was linked to evidence levels. Randomized clinical trials were the most represented studies, followed by cohorts. Our results suggest that medical journals with a high-impact factor publish studies with a high evidence level (Fig. 1). A relevant ﬁnding signiﬁcantly documented in The New England Journal of Medicine and The Lancet was the high frequency with which case reports were published, representing up to 15% of the total of their publications. Another major ﬁnding is the tendencies the journals have according to their geographic location. European journals (The Lancet and BMJ) published secondary studies to a greater extent (Fig. 2). These ﬁndings raise a question: What implications
Data are shown as n (%); CR, case report; PR, prevalence report; CC, case---control; Co, cohort; CCT, controlled clinical trial; NR, narrative revision; RS, systematic revision; Me, meta-analysis; Or, original publication; Sc, secondary publication; IF, impact factor; Ob, observational study; Ex, experimental study.
Distribution of publications according to study type in 2011.
(6.9) (5.6) (35.6) (15.4) (19.6) (20)
(83.2) (70.1) (61.7) (84.1) (64.1) (71.2)
(16.8) (29.9) (38.3) (15.9) (35.9) (28.8)
(62.4) (51.4) (32) (32.7) (37.4) (40.7)
(20.8) (18.7) (29.7) (51.4) (26.7) (30.4)
H.E. Tamez-Pérez et al.
Figure 1 ies.
NEJM Secondary Studies
Distribution of observational and experimental stud-
can this have? In order to answer this question correctly, the limitations and advantages of each design were evaluated. Experimental studies represent a high degree of evidence since they allow a direct determination of the causal connection of two phenomena. Another signiﬁcant point is its ability to reduce the amount of systematic errors.16 With randomization, an equilibrium between the characteristics of the compared groups is established. Blinding, concealment and intention-to-treat analysis allow the reduction of skewing in any type of randomized clinical trial. Unfortunately, one of the biggest disadvantages of RCT is in the context of clinical practice. Paradoxically, internal factors such as the strict inclusion criteria, evaluation of efﬁciency and short-term follow-up17 limit the study’s ability to establish a general conclusion. The fact that signiﬁcant results are obtained does not necessarily mean that they can be applied in a ‘‘real life’’ scenario. In other words, the results at that moment only apply to the population being studied. Also external factors of the study like high costs, ethical considerations18 and low ﬁnancing in the case of rare diseases are also an important issue. 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 JAMA
Distribution of original and secondary studies.
Tendencies in medical publications Consequently, the difﬁculty in clinical trials relies more importantly on external validation. Observational studies represent the lowest level in the evidence hierarchy. They are useful in clinical scenarios like in evaluating disparity and load and determining risk factors which contribute to the development of a disease.19 In medical history, cohorts play an important role in documenting associations, like in the Framingham study, or the conclusive data of the effectiveness of insulin analogs for the treatment of patients with type 1 or 2 diabetes.20 Additionally, cohort studies help determine safety proﬁles of medications. For example, the SCOUT study assessed the effectiveness of sibutramine in 10,744 patients with obesity and high cardiovascular risk for a period of 6 years. Compared to placebos, the sibutramine group showed a noticeable increase in mortality rates and cardiovascular events despite the signiﬁcant weight loss.21 This inﬂuenced its recall by the FDA in 2009. In contrast with experimental studies, studies without intervention represent a clearer, uncontrolled and unadjusted model of the disease. Nevertheless, internal validation is an important issue. The highest difﬁculty in observational studies lies in interpretation, since there are some factors like bias in selection, confusion factors or recall bias and thus the results may lead to different conclusions. According to the information obtained, it is possible to conclude that there are different problems in research within primary studies. European and American magazines have different criteria concerning their publication’s guidelines; in other words, there is no standard in the level of evidence regarding article revision. Perhaps a major implication in relation to the impact factor lies more in the context of transnational medicine. That is to say, The New England Journal of Medicine published mostly randomized clinical trials, studies frequently cited and with a higher impact in medical practice. Hence, a dichotomy is formed between the management of concepts: validity versus generalization. Observational studies are not as valid; however they include concepts which are more applicable in populations. On the contrary, experimental studies have a great epistemological value, but only represent the set of the population being studied. Secondary studies represent the highest level of evidence. They offer a summary of the investigation question. In the context of evidence-based medicine, both validity and generalization are important. The ﬁndings in these studies have a greater approximation to the Bradford---Hill criteria; nevertheless, the limitation in secondary studies lies in the presence of publication bias. One of the strengths of this study was the analysis of a representative sample of the publications in different journals in the yearly period. A similar trend was reported in a study conducted in 2003, but with different objectives22 and a much smaller sample. A limitation of the study was the classiﬁcation of evidence according to the study design, without evaluating the existence of discrepancies in the methodology, like the presence of bias or the weight of confusion factors. In conclusion, the tendency of publications or journals with a high impact factor is oriented to a greater extent to the publication of primary and observational studies; however, European journals such as The Lancet and BMJ publish a good amount of secondary studies. Future studies are
141 necessary to determine not only the validity, but also the impact of an article. The amount of quotations correlated with the publication of studies with a high level of evidence.
Conﬂict of interest The authors have no conﬂicts of interest to declare.
Funding No ﬁnancial support was provided.
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H.E. Tamez-Pérez et al. 21. James WPT, Caterson ID, Coutinho W, et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med. 2010;363:905---17. 22. Taback N, Krzyzanowska MK. A survey of abstracts of high-impact clinical journals indicated most statistical methods presented are summary statistics. J Clin Epidemiol. 2008;61:277---81.
Medicina Universitaria. 2015;17(68):143---146
Efﬁcacy of antiemetic therapy in patients undergoing laparoscopic cholecystectomy H.A. Llanes-Garza a,∗ , N.G. López-Cabrera a , R. Cacho-De la Vega a , D. Palacios-Rios a , A.L. Millan-Corrales a , M. Pacheco-Juárez a , E. Cárdenas-Estrada b a
Anesthesiology Department at the ‘‘José Eleuterio González’’ University Hospital at the School of Medicine of the Autonomous University of Nuevo Leon, Mexico b Center of Research and Development in Health Sciences at the UANL (CIDICS) Received 23 April 2015; accepted 27 April 2015 Available online 19 August 2015
∗ Corresponding author at: Departamento de Anestesiología, Hospital Universitario ‘‘José Eleuterio González’’ Facultad de Medicina, Universidad Autónoma de Nuevo León, Av. Madero y Gonzalitos s/n, Colonia Mitras Centro, Monterrey, 64460 Nuevo León, Mexico. E-mail address: [email protected] (H.A. Llanes-Garza).
Introduction Laparoscopic cholecystectomy is the golden choice in the treatment of gallbladder disease and has been proven to be better in the cost-effectiveness-efﬁciency relation when compared to open surgery.1,2 Out of 100 laparoscopic cholecystectomies performed, between 20 and 42% present a complication, postoperative nausea and vomiting (PONV), which delays the patients’ discharge. It translates into greater postoperative discomfort and distress for patients, on top of the fact that they usually remain 50% longer in the recovery room, thus altering the patient ﬂow of the hospital and increasing internment costs. PONV can also increase suture tension and the risk of pulmonary aspiration, which could lead to pneumonia or pneumonitis and the increase of intracranial pressure. Its etiology includes dehydration by fasting, the use of opioids, nitrous oxide, inhaled anesthetics in general anesthesia, pneumoperitoneum, CO2 and handling of the parietal peritoneum with vagal stimulation. The risk of PONV ought to be stratiﬁed preoperatively and reduced, adapting anesthetic techniques or using the available pharmacological resources.3---5 There are different PONV predictive models that, if applied, can help prevent its presence. When ranked by sensitivity, the Apfel score is the most used in the reviewed bibliography (see Table 1).6 The different vomit stimuli are related to the dopaminergic, histaminergic, serotoninergic, muscarinic and opioid receptors located in the central pathways (reticular formation of the medulla) and peripheral pathways (gastrointestinal system), thus their blockage is a mechanism of antiemetic medications. There are different antiemetic families; H1 antihistamines, anticholinergic, steroids, phenothiazine, butyrophenones, dopamine antagonists and 5-HT3 receptor antagonists. These medications are currently being utilized in an isolated or combined form. Metoclopramide, an antiemetic from the benzamide group with antidopaminergic and central and peripheral antiemetics, acts in the upper gastrointestinal tracts for 2 h (10---20 mg for every 70 kg on average in adults). Ondansetron is an antagonist of the serotonin receptor (5-HT3 ). It has been used for some years to control nausea and vomiting induced by
Table 1 Apfel risk assessment scale for nausea and vomiting. Risk factors
Previous history of postoperative vomiting and/or motion sickness Use of postoperative opioids
I. Bel Marcoval. Estratiﬁcación del riesgo, proﬁlaxis y tratamiento de las náuseas y vómitos postoperatorios. Rev. Esp. Anestesiol. Reanim. 2006; 53: 301---311.
chemotherapy and radiotherapy. It has central and peripheral effects. Doses of 4 mg peak plasmatic concentrations are reached in approximately 7---11 min depending of the speed of administration.7---9 The objective of our study was to compare the clinical effectiveness of ondansetron with metoclopramide in a single dose and ondansetron in an isolated form in the control of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy.
Methods and materials The current study included patients who were programmed for elective laparoscopic cholecystectomies at the surgical ward from the ‘‘Dr. José E. Gonzalez’’ University hospital of the Autonomous University of Nuevo León, México. The study consisted of a comparative, prospective, experimental, longitudinal double blind study. Our institution’s Ethics Committee reviewed and authorized the project. The inclusion criteria were patients undergoing elective laparoscopic cholecystectomy, between 18 and 60 years old, who weighted between 50 and 90 kg. ASA I-II patients and both genders were included. The exclusion criteria were ASA IIIIV patients, under 18 years old, allergic to the medications included in this study, pregnant women, patients who were chronically taking prokinetics, patients with an Apfel score of 3---4 and patients who required any other medication during induction. Within exclusion criteria were patients who presented allergic reactions during the procedure, those with conversions to open surgery and those who required the use of other rescue antiemetic medications. The sample calculation was performed based on the article ‘‘Risk stratiﬁcation, nausea and vomiting prophylaxis’’ postoperative, published by Dr. I Bel Marcoval et al., in the Spanish magazine of Anesthesiology in 2006, using the following formula, ((2* 2 )/(− + d)2 )*(Z1 − ˛2 + Z1 − ˇ)2 . We obtained a sample size of 30 patients, via a non-inferiority trial and with a conﬁdence level of 5% (p < 0.05). The sample was divided into two groups of 15 patients each. Metoclopramide 10 mg and ondansetron 4 mg were administered in the ﬁrst Group (A), and ondansetron 4 mg in the second Group (B), after induction of anesthesia. The general objective of our study was to compare the clinical effectiveness of ondansetron with metoclopramide in a single dose and ondansetron in an isolated form in the control of postoperative nausea and vomiting in patients undergoing laparoscopic cholecystectomy. Within our secondary objectives were the application and comparison of the Apfel scale for the risk of nausea and vomiting in the preoperative of both groups, to assess the antiemetic efﬁcacy of both medications for their study groups, and the requirement of rescue medications. In the pre-surgical area, demographic data was collected, such as age, gender and body mass index (BMI). Their ASA was determined based on their pathological and non-pathological background. In addition, we obtained the signature of the patient (or tutor) for the informed consents. The patients were pre-medicated with ranitidine and midazolam, and were evaluated with the Apfel score. After the patient entered the operation room (OR), monitoring and the taking of basal vital signs were
Efﬁcacy antiemetic in laparoscopic cholecystectomy conducted. Anesthetic induction consisted of fentanyl 3 mcg/kg, etomidate 0.2 mg/kg and atracurium 0.4 mg/kg with isoﬂurane-based anesthetic maintenance. The ﬁrst group (A) received ondansetron 4 mg and metoclopramide 10 mg in a single dose in a slow infusion for 20 min after anesthetic induction and the second group (B) received ondansetron 4 mg in the same fashion. The degree of nausea and vomiting was evaluated with the Likert scale of 5 points (0 = none, 1 = preview, 2 = mild, 3 = moderate, 4 = high, 5 = intense retching and presence of vomit). Patients were evaluated immediately and 24 h after the postoperative period. Basal time measurements were conducted 4, 8, 12 and 24 h later. Statistical analysis was performed via a non-inferiority trial; qualitative and quantitative variables were used. An alpha value of 0.05 was also used and null hypothesis was rejected when the critical value was under 0.05. Nonparametric tests were used (x2 and parametric (t student)). The electronic data processing and statistical methods (descriptive and inferential) were performed using STATA-IC-10-2010 software.
Results In the period, a total number of 30 patients were obtained and divided into 2 groups; group A (metoclopramide and ondansetron) with 15 patients and group B (ondansetron) with 15 patients. Group A consisted of 2 male patients (13.3%), and 13 female (86.6%) patients, while group B consisted of 1 male (6.66%) and 14 females (93.3%). The difference between the two groups was not statistically signiﬁcant. Regarding age range, 11 patients were between the ages of 18 and 29, 8 of them were between 30 and 39, 5 were between 40 and 49 and 6 were between 50 and 59. Group A consisted of 4 patients between the ages of 18 and 29, 5 between 30 and 39, 3 between 40 and 49 and 3 were between 50 and 59. On the other hand, Group B consisted of 7 patients between the ages of 18 and 29, 3 were between 30 and 39, 2 were between 40 and 49 and 3 were between 50 and 59. A statistically signiﬁcant difference was not found in the mean age of the groups. Regarding BMI, 8 of the patients who participated in the study had a normal BMI (18.5---24.9), 15 were overweight (25---29.9) and 7 had grade I obesity (30---34.9). Within Group A, there were 4 patients with a normal BMI, 10 overweight and 1 with grade I obesity, whereas in Group B there were 4 patients with normal BMI, 5 overweight and 6 with obesity. Once again no signiﬁcant differences between Group A and Group B were observed. It was noted that 20 of the patients included in the study were cataloged as ASA I and 10 as ASA II. No statistically signiﬁcant difference was observed in this parameter. As for the Apfel score, of the 30 patients included in the study, 5 presented 1 risk factor out of the 4 of the evaluation, representing a risk of 20% of suffering PONV. 12 patients presented 2 factors (a risk of 40%); 12 patients presented 3 factors (a risk of 60%) and 1 presented 4 factors (a risk of 80%). It was also noted that out of the 30 individuals of the study, 27 were women, 20 were non-smokers, 11 did not have a PONV or motion sickness background and postoperative opioids were used in 11 patients. The patient
145 Table 2
Data obtained in relation to the Apfel scale.
Number of positive patients
1 point (20%) 2 points (40%) 3 points (60%) 4 points (80%) V. Female V. Non-smoker V. Previous history of postoperative vomiting and/or motion sickness V. Use of postoperative opioids Patient with vomiting Patient with nausea no. 1 Patient with nausea no. 2 Patient with nausea no. 3
5 12 12 1 27 20 11
11 1 1 1 1
2 1 2 3
who presented a vomiting episode had 2 positive variables in the Apfel score, and the 3 subjects of study who presented mild nausea had 1, 2 and 3 positive variables respectively (see Table 2). No statistically signiﬁcant differences were observed in this parameter either. Regarding the efﬁcacy of the antiemetic in study, 1 patient presented vomiting on a single occasion immediately after extubation. He was a part of Group B (ondansetron). 2 of the 3 patients who presented nausea (number 2 in the Likert scale) belonged to Group A (metoclopramide and ondansetron) and presented it in the basal hour and at 4 h. It ceased without rescue medication. The third of the 3 patients with nausea (number 2 in the Likert scale) belonged to Group B (ondansetron) and only presented it during the basal hour; it ceased without rescue medication. However, no differences were found in the severity of the nausea or the satisfaction of the patients between groups. Thus, the difference between both groups was not statistically significant.
Discussion PONV is among the most frequent complications following anesthesia in the postoperative of laparoscopic cholecystectomies; 42% of post-operated laparoscopic cholecystectomy patients present nausea and vomiting, which translates into a greater postoperative discomfort and distress for patients, on top of the fact that they usually remain 50% longer in the recovery room, thus altering the patient ﬂow of the hospital and increasing the internment costs of each patient. This is reduced using effective antiemetics in a single dose previous to its presentation. The origin of this complication is complex and depends on a wide variety of factors previously mentioned. In this study, the treatment groups are similar in relation to the demographic data (inter-group homogeneity), surgical procedure, and type of anesthesia and analgesia utilized in the postoperative. The Apfel score was used to assess the risk of presenting PONV, in order to observe its ability to forecast this event
146 and because it includes the predisposed factors which have been observed, most in different studies, such as the Lenka Doubravskaa in 2010, which included 1954 patients. Here, they noted the fact that being a woman increased the risk of presenting PONV, with an occurrence of 24.5% in females and 6.3% in males. On the other hand, smoking seemed to be a protective factor. The incidence of PONV in smokers was 8.7%, compared to non-smokers, which was 17.7%. Also, a high PONV incidence was observed in patients with obesity (BMI over 30), at 11.8%. In our study, we were able to observe that the 4 patients who did not present PONV were all women; 2 smokers and 2 non-smokers; 2 with a PONV or motion sickness background; and none were administered opioids in postoperative. The patient who presented vomiting in the postoperative had 2 positive variables in the Apfel score, and the 3 patients who presented mild nausea had 1---3 variables, which cast doubt on the efﬁcacy of the Apfel score as the most sensitive PONV predictor.10 Different studies have been conducted around the world, where different managements for PONV prevention are proposed. The use of combined therapies for a better management is recommended in many of them, stressing it in patients with high risk factors.11,12 In a study conducted in Saudi Arabia by Dr. Mohamed Naguib et al. they included 132 patients undergoing laparoscopic cholecystectomies, who were randomly administered ondansetron 4 mg, tropisetron 5 mg, granisetron 3 mg, metoclopramide 10 mg or a placebo 10 min before anesthetic induction. The percentages of patients free of vomiting were 65.5%, 52%, 48%, 29.2% and 27.6% in the ondansetron, granisetron, tropisetron, metoclopramide and placebo groups, respectively. Prophylactic antiemetic treatment with ondansetron resulted in a lower PONV incidence (p = 0.02) than with metoclopramide or placebos. In our study, we were able to observe that the antiemetic therapy with ondansetron with metoclopramide in a single dose is not superior to that of just ondansetron.13
Conclusions Antiemetic combined therapy has proven in some studies to be more effective than monotherapy in the control of PONV. In our study, a statistically signiﬁcant difference was not found in the efﬁcacy of polytherapy with ondansetron with metoclopramide (4 mg + 10 mg) in a single dose and monotherapy with ondansetron (4 mg) in patients undergoing laparoscopic cholecystectomies under general anesthesia. However, both groups of patients presented a good control of PONV without the need for rescue medications. Regarding the Apfel score to assess the risk of presenting PONV, in the present study we did not ﬁnd a correlation between the risk percentage stated by the score and the patients who presented PONV. Therefore, based on the results obtained in our study we accept the established hypothesis that the combination of
H.A. Llanes-Garza et al. ondansetron and metoclopramide in a single dose is as effective as just ondansetron for the control of postoperative nausea and vomiting.
Conﬂict of interest The authors have no conﬂicts of interest to declare.
Funding No ﬁnancial support was provided.
References 1. Wender HR. Do current antiemetic practices result in positive patient outcomes? Results of a new study. Am J Health-Syst Pharm. 2009;66:S3---10. 2. Moore JH, Rodríguez S, Roa A, et al. Ambulatory laparoscopic cholecystectomy: a cost-efﬁcient model of laparoscopic surgery. Rev Colomb Cir. 2004;19:43---53. 3. Goll V, Akc ¸a O, Greif R, et al. Ondansetron is no more effective than supplemental intraoperative oxygen for prevention of postoperative nausea and vomiting. Anesth Analg. 2001;92:112---7. 4. Apuy RN, Chaverri FJ, Monge AM, Zavaleta ME. Caracterización del uso de antieméticos en el postoperatorio en pacientes adultos sometidos a cirugía durante el periodo enero-mayo 2009, en el Hospital Clínica Bíblica de Costa Rica. Acta Méd Costarric. 2010;52:167---72. 5. Forrester CM, Benﬁeld DA Jr, Matern CE, Kelly JA, Pellegrini JE. Meclizine in combination with ondansetron for prevention of postoperative nausea and vomiting in a high-risk population. AANA J. 2007;75:27---33. 6. Bel MI, Gambús CP. Estratiﬁcación del riesgo, proﬁlaxis y tratamiento de las náuseas y vómitos postoperatorios. Rev Esp Anestesiol Reanim. 2006;53:301---11. 7. Sinclair DR, Chung F, Mezei G. Can postoperative nausea and vomiting be predicted. Anesthesiology. 1999;91:109---18. 8. Golembiewski J, Chernin E, Chopra T. Prevention and treatment of postoperative nausea and vomiting. Am J Health-Syst Pharm. 2005;62:1247---60. 9. Ho KY, Chiu JW. Multimodal antiemetic therapy and emetic risk proﬁling. Ann Acad Med Singapore. 2005;34:196---205. 10. Doubravska L, Dostalova K, Fritscherova S, Zapletalova J, Adamus M. Incidence of postoperative nausea and vomiting in patients at a university hospital. Where are we today? Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010;154:69---76. 11. Dabbous AS, Jabbour-Khoury SI, Nasr VG, et al. Dexamethasone with either granisetron or ondansetron for postoperative nausea and vomiting in laparoscopic surgery. MEJ Anesth. 2010;20:565---70. 12. Rüsch D, Eberhart LHJ, Wallenborn J, Kranke P. Nausea and vomiting after surgery under General Anestesia. Dtsch Arztebl Int. 2010;107:733---41. 13. Naguib M, Karim AE, Khoshim MH, et al. Prophylactic antiemetic therapy with ondansetron, tropisetron, granisetron and metoclopramide in patients undergoing laparoscopic cholecystectomy: a randomized. Can J Anaesth. 1996;43:226---31.
Medicina Universitaria. 2015;17(68):147---152
Evaluation of the criteria for the interpretation of the oral glucose tolerance test in the National Mother-Child Teaching Hospital ‘‘San Bartolome’’ J.J. Moya-Salazar a,∗ , L. Pio-Dávila b a b
Hospital Nacional Docente Madre-Ni˜ no ‘‘San Bartolomé’’, Lima, Peru Hospital Nacional Arzobispo Loayza, Lima, Peru
Received 9 March 2015; accepted 28 April 2015 Available online 18 August 2015
∗ Corresponding author at: Departamento de ayuda al diagnóstico, Hospital Nacional Docente Madre-Ni˜ no ‘‘San Bartolomé’’, Jr. Paciﬁco 957, Lima 07, Lima, Peru. Tel.: +51 1 986014954. E-mail address: [email protected] (J.J. Moya-Salazar).
Introduction Diabetes mellitus (DM) is a metabolic disorder that is a consequence of the deﬁciency in the secretion of insulin, in the effectiveness of its actions, or both. It is one of the most prevalent chronic diseases in the world. It constitutes a public health problem due to the progressive increase of its incidence, to the point where it is considered an epidemic.1 Chronic hyperglycemia with disturbances in the metabolism of carbohydrates, fats and proteins, and alterations in microcirculation are all consequences of this disorder. Current DM classiﬁcation according to the American Diabetes Association --- ADA --- is shown in Table 1. About 63% of the 57 million deaths in the world in 2008 were caused by a non-transmissible chronic disease, including diabetes mellitus; thus, 80% of these deaths occurred in low and medium-income countries.2 By the year 2000, about 171 million people suffered from DM around the world, and this number is estimated to go up to 336 million by the year 2030.3,4 On the other hand, approximately 197 million people worldwide suffer from glucose intolerance --- prediabetic patients, which usually leads to obesity. Around 90% of type II diabetes is attributable to overweightness and to the metabolic syndrome. This number is also expected to increase to 420 million by the year 2025.5 In addition, the human and ﬁnancial costs of DM are also on the rise.6 A similar situation occurs in Peru, where TIIDM prevalence (TIIDM) ranges from 1 to 8%, Lima and Piura being the most affected regions.7 In conclusion, DM is a health problem around the world, one that is threatening to reach pandemic levels by 2030, with alarming increases of TIIDM among children and with potentially devastating consequences.5 DM is associated with an increase in risk of premature death; thus, every year almost 4 million deaths are caused directly by this disease. 80% of these occur in underdeveloped countries, constituting 6.8% of overall mortality.8 DM diagnostic methods are: random glucose test >200 mg/dl over clinical symptoms, fasting plasma glucose test >126 mg/dl, oral glucose tolerance test (OGTT) after a fast, and glycosylated hemoglobin test A1c ≥ 6.5% (Table 2).9 The test most frequently used is the OGTT, used in clinical practice for glycemic and insulin diagnoses.10---12 Moreover,
Classiﬁcation of DM.9
I. Type 1 diabetes A. Immune-mediated B. Idiopathic II. Type 2 diabetes III. Other speciﬁc types A. Genetic defects of ␤-cell function B. Genetic defects in insulin action C. Diseases of the exocrine pancreas D. Endocrinopathies E. Drug- or chemical-induced F. Infections G. Uncommon forms of immune-mediated diabetes H. Other genetic syndromes sometimes associated with diabetes IV. GDM
Diagnostic criteria for DM.9
1. AlC ≥ 6.5%. The test should be performed in a laboratory using a method that is NGSP certiﬁed and standardized to the DCCT assay.a OR 2. FPG ≥ 126 mg/dl (7.0 mmol/l). Fasting is deﬁned as no caloric intake for at least 8 h.a OR 3. 2-h plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.a OR 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/dl (11.1 mmol/l). a In the ansence of unequivocal hyperglycemia, criteria 1---3 should be conﬁrmed by repeat testing.
it is the most sensitive method for the diagnosis of DM within the fasting glycemic test, although it requires characteristics for its implementation, such as fasting basal glycemia < 110 mg/dl, doses of 75 g anhydrous glucose in adults or 1.75 g/kg for children, performance in the morning after a 10---16 h fast, the duration of the test is 180 min, etc.13 One of the main disadvantages of OGTT is its reproducibility, thus it is recommended to have at least 2 pathological OGTTs when basal glycemia is under 110 mg/dl.14 Moreover, inter-individual variabilities have been described according to glucose metabolism, which generate slants in the interpretation of clinical criteria that ought to be estimated. According to Clinical Laboratory Standards Institute (CLSI), the resultant parameters of OGTT should be assessed as the area under the curve of glucose (AUCG) and insulin (AUCI) basal indexes, the maximum allowable error, among others, mainly to determine the sensitivity to peripheral insulin.9,15---18 After an oral glycemia overload, the increase in glycemia does not depend solely on glucose. There are also intestinal hormones involved, the speed of gastric emptying and the composition of the intake. Thus, tolerance to glucose and sensitivity to insulin are different concepts, making the indexes of correction and evaluation of glycemic sensitivity necessary to guarantee the quality of the results and explain the recurrence of these phenomena.18 Having said that, the objective of this study was to evaluate the criteria for interpretation of OGTT in the Hospital Nacional Docente Madre-Ni˜ no ‘‘San Bartolomé’’ (HONADOMANI SB) in Lima, Peru, and determine the percentages of pre-diabetic patients, those who should not have been included within the test (basal glucose > 110 mg/dl) and those who presented alterations in the curve of glucose during biochemical determinations.
Materials and method A non-experimental, prospective cross-sectional analytic study was conducted.
Evaluation of the criteria for the interpretation of the oral glucose tolerance test
Population and sample Population The population consisted of all ambulatory patients referred to us by agreement, at HONADOMANI SB. Sample Blood samples referred from outpatient clinics independently from the Department of Help to diagnosis at the Biochemistry Department for glycemia determination though OGTT, which complies with the quality criteria according to CLSI Guide POCT12-A3, the ADA’s guidelines and the recommendations for the laboratory analysis of DM diagnosis and management and the standardized operational procedures --- SOP --- of the health center.19,20 These are selected respecting the following previously established criteria of inclusion and exclusion. Inclusion criteria. Patients (male and female) in a fasting state of at least 10 h, ages ranging from 18 to 65 years of age, stable, without a stress condition, pharmaceutical consumption, or debilitating situations like surgery. Also, patients were required to complete the test (180 min, 3 blood collections) post-glycemic overload. The collection of samples must comply with the quality guidelines previously mentioned. Exclusion criteria. Patients who did not comply with the fasting state of at least 10 h. Patients outside the age range (19---65 years old). Patients who were suffering from a debilitating or oncological situation, or undergoing pharmacological therapies. Those patients who left the test or complicated blood collections. Those samples which were collected without following the quality and normativity criteria of CLSI or ADA, in addition to samples which were clearly contaminated.
Data collection techniques and sample processing Pre-analytic stage The collection was conducted in the Phlebotomy area of the HONADOMANI SB between 6 am and 9 am, using BD Vacutainer® (Franklin Lakes, New Jersey, USA) of 3 ml, with a red cap which was mixed by inversion of 8---10 times, according to the CLSI H03-A6 guide. In order to achieve this, patients must have remained fasting for at least 10 h prior
to the collection, with a payment slip from the previous day of the test, and with a lemon and a disposable cup.21 The ﬁrst sample (basal) was used to evaluate the admission of patients to the test, excluding those who were above 100 mg/dl. Subsequently, they were overloaded with oral glucose (anhydride preparation: ‘‘lemonade’’) using the following formula; 75 g of anhydride glucose for adults or 1.75 g/kg for children. The patient was monitored for the whole duration of the test (180 min). The samples were collected at 60 and 180 min after the glycemic overload. Conventional cohort values were used at >200 mg/dl for diabetics and those indicated by the World Health Organization (WHO) for the diagnosis of pre-diabetic patients of 100---199 mg/dl (impaired glucose tolerance).22---24 Analytic stage The processing in the clinical lab was conducted following the algorithm established by the hospital for OGTT. This includes the reception and registration of the sample through the standardized code and its processing within 120 min after the sample was drawn. The biochemical processing was conducted through the Biochemical Biosystems A25 auto-analyzer (Pennsylvania, USA), which has a daily and historic registry of biochemical analyses. The method employed for the determination of glucose was glucose oxidase-peroxidase through the glucose activity test Trinder.25 Post-analytic stage Undetermined results or those which were outside the linearity of the trial were repeated and/or diluted. The results validated by Medical Technologists were inputted into the integrated health system --- SIGOS --- to inform patients within the stipulated times. Data analysis technique Data analysis was performed in three basic processes: codiﬁcation, from the Biochemical Biosystems A25 autoanalyzer’s historical registries system; tabulation, statistical veriﬁcation and the creation of charts and tables using the statistical analyzer SPSS 20.0 and Microsoft Ofﬁce Excel 2010 for Windows. The evaluation of the distribution of variables was conducted using KMO and Bartlett’s test of sphericity, resulting in a matrix of correlations between adequate variables (p = <0.05).
Basal glucose >110 mg/dl
Figure 1 Results of 1271 samplings of glycemia in the HONADOMANI SB. Also, the proportion of diabetic (glycemia at 2 h >200 mg/dl) and pre-diabetic (glycemia at 2 h between 110 and 199 mg/dl) patients diagnosed through the OGTT.
J.J. Moya-Salazar, L. Pio-Dávila
Ethics Within the diabetic ethics framework, the safeguarding, reliability and irreplaceable value of the obtained information will only be used for the purposes of this study. This research has the approval of the Department of Teaching and Aid for Research and the Ethics and Research Commission of the HONADOMANI SB (Reg. 78-2015). Limitations Several limitations should be taking into account before interpreting the results. First, the biochemical auto-analyzer informatics registry does not have detailed registries or information of the selected patients, such as age, gender, attributable risk factors, physiological condition, diseases, demographic characteristics and family history, etc. Second, the determination of glycemia varies considerably between demographics and age groups. Thus, the pre-diabetic and diabetic prevalence rates encountered are not transposed toward the general population of Peru. Third, the OGTT results could not be compared to the standard reference tests like Hb1Ac, to determine its variability and inaccuracy.26 Lastly, the biochemical processing was performed under an internal and external quality control; however, without a quality responsible planning. Despite these limitations, our research is the ﬁrst to evaluate the resultant parameters of the OGTT.
Results From the conducted research, 1.97% of patients were diabetic, 13.85% were pre-diabetic, 6.45% produced the ‘‘LowJump’’ (LJ) glucose reduction-rise phenomenon (alteration of the glucose curve post-oral overload which tends to reduce the concentration of plasma glucose in its determination at 60 min and returns to relatively superior levels to the basal concentration at 180 min), and 5.19% of the patients should not have been included in the study due to the fact that they did not have over 110 mg/dl of basal glucose (p = <0.05) (Fig. 1).11,27
Discussion The evaluation of OGTT interpretation criteria exposes an elevated rate of pre-diabetic patients and a reduced rate of diabetics, which in conjunction constitute 15.8% of the prevalence (Fig. 2). The prevalence of diabetic patients determined in this research was half of that communicated in the last report of DM prevalence in Lima and Callao, Peru (3.9%).28 The prevalence rate discovered is somewhat similar to urban averages in populations over 3000 asl. (Huaraz --- 1.3%).23 DM is a chronic, degenerative, progressive but manageable disease. It has a great impact on the economy of the healthcare system. It requires serious control and a reasonable stratiﬁcation of its systemic complications. In the same way, the proportion of patients who were pre-diabetic or had a high risk of diabetes or glucose intolerance was 13.85%; prevalence within the regional average is between 5 and 15%.29 Glucose intolerance is a risk factor for the development of TIIDM and implies a
Figure 2 Percentages of pre-diabetic and diabetic patients. The radial distribution of patients wrongly included in the test is shown in Fig. 3, highlighting the values of the second glycemia sampling in comparison to the ﬁrst and the third.
high cardiovascular risk.30,31 In our country, the reported prevalence is up to 90.8% in patients who are 50 years and older, a highly elevated prevalence, suggesting the immediate prioritization of health care attention in order to avoid future complications.32 The progression from normoglycemia to diabetes may take several years, which involves intermediate stages of dysglycemia. This atero-thrombogenic alteration becomes evident with the alteration of glucose when fasting, emergence of glycated proteins and progressively cellular hypofunction, increasing the risk of morbidity in patients.33,34 Thus, diabetes indicates a decrease in the pancreatic reserve (up to 50% when there is no diabetic manifestation), this previous metabolic stage is evident by glycemia between 100 and 199 mg/dl by the OGTT, which serves as a red ﬂag to avoid its progression to DM.24 Intervention in pre-diabetic patients is an efﬁcient strategy, since it avoids or slows down the progressive deterioration of the pancreas. This strategy includes an efﬁcient diagnosis, modiﬁcation in lifestyles, body weight management, ranges from 45 to 65% of daily energetic intake, physical exercise, pharmacological treatment, detection algorithms, etc.18 In this manner, it is demonstrated and conﬁrmed that the control of glycemia is an effective measure to reduce the load of microvascular and cardiovascular complications, such as retinopathy, nephropathy and neuropathy in patients with TIDM as well as TIIDM.35---37 The main complication in the misguided selection of patients for OGTT is the dizzy feeling and loss of consciousness during the glycemic overload. We found that 5.19% of patients should not have been included in the test (Fig. 3). It may be a minimum ﬁnding, however, it is of relevance given the fact that the lab procedures
Evaluation of the criteria for the interpretation of the oral glucose tolerance test 64
55 150 54
51 0 50
Figure 3 Radial distribution of patients wrongly included in the OGTT. Observe the elevated values in the second sampling (red line/thicker line). Glycemic concentration is expressed in mg/dl. (For interpretation of the references to color in this ﬁgure legend, the reader is referred to the web version of this article.)
are standardized, and follow internationally established ﬂowcharts which rule under a quality control system. Moreover, the diagnosis of over half of these patients was dysglycemia (3.2%), 1.5% were diabetics and only 0.5% were healthy patients.9,11,12,15,16 Considering that, these mistakes in patient selection are a result of the generally poor knowledge of the personnel on these investigations, work overload, or the fact that there is no other diagnostic method. Thus, the modiﬁcation of inclusion criteria of patients in the OGTT, POE, should be considered and rely on the CLSI POCT12-A, Clinical Laboratory Improvement Amendments, (CLIA), ADA guidelines, etc. Also, the use of other diagnostic methods (i.e. the A1c Glycosylated Hemoglobin test), evaluating their sensitivity, disadvantages and costs. Lastly, we reafﬁrm the importance of the LJ phenomenon in the interpretation of the OGTT, because it could interfere in the ﬁnal results. From the ﬁnal reports of this phenomenon 1.2% were dysglycemic in ranges of 100---175 mg/dl (Fig. 1), which leads us to consider its involvement in the development of the trial and interferences with glycemia --- increasing it or reducing it --- generating undetermined results, or even worse, false results.24 This ﬁnding proves the importance of inter-individual biological variability, evident by the events through which it may occur, like different physiological conditions, metabolism of the saturation of glycemia, type of anhydride
glucose, population group, diabetics, physiological conditions where typologies of the individuals, pre-diabetics, or other non-clear situations occur. Thus, it is necessary to evaluate its reach in interference, to establish its total allowable error and understand the biochemistry and cellular behavior during the development of the test among individuals. Furthermore, a judicious monitoring is required in order to understand and know its physiology and the events through which it occurs, corresponding to the different metabolisms during the test and their diagnostic implications. We deﬁnitely suggest that other glycemia tests should be conducted in a patient where this phenomenon is discovered, (Hb1A1c, etc.) or repeat the OGTT twice.11 Diabetes mellitus is a metabolic disease which imposes a high economic and social cost around the world, hence its prevention and treatment should be considered imperative in health and a priority worldwide. The diagnosis should be thoroughly examined, from the selection of patients to the determined ranges of glucose in each collection, with the purpose of avoiding undetermined results or false negatives.
Funding This study was self-ﬁnanced by the authors.
Conﬂict of interest The authors state that there are no conﬂicts of interests.
References 1. Rodbard HW, Blonde L, Braithwaite SS, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007;13 Suppl. 1:1---68. 2. World Health Organization. Global status report on noncommunicable diseases 2010. Geneva: WHO; 2011. 3. International Diabetes Federation, IDF. Diabetes atlas 2012 update. 5th ed. Brussels: IDF; 2013. 4. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27:1047---53. 5. Hossain P, Kawar B, El Nahas M. Obesity and diabetes in the developing world: a growing challenge. N Engl J Med. 2007;356:213---5. 6. The world health report 2006: working together for health. Geneva: World Health Organization; 2006. 7. García F, Solís J, Calderón J, et al. Prevalencia de diabetes mellitus y factores de riesgo relacionados en una población urbana. Rev Soc Per Med Interna. 2007;20:90---4. 8. Rawal RB, Tapp RJ, Williams ED, Chan C, Yasin S, Oldenburg B. Prevention of type 2 diabetes and its complications in developing countries: a review. Int J Behav Med. 2012;19: 121---33. 9. American Diabetes Association. Diagnosis and classiﬁcation of diabetes mellitus. Diabetes Care. 2014;37 Suppl. 1:S81---90. 10. Matsuda M, De Fronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999;22:1462---70. 11. Stumvoll M, Mitrakou A, Pimenta W, et al. Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity. Diabetes Care. 2000;23:295---301. 12. Calvar CE, Bengolea SV, Hermes R, Loyato M. Critical evaluation of the oral glucose tolerance test for the diagnosis of insulin resistance in patients with polycystic ovary syndrome. Medicine (Baltimore). 2007;67:2---6. 13. Puig-Domingo M, Leiva Hidalgo A. Diabetes mellitus: concepto, clasiﬁcación y etiología. In: Casanueva Freijo F, Vázquez García JA, editors. Endocrinología clínica. Díaz De Santos Eds, vol. 14. 1995. p. 241---9. 14. McDonald GW, Fisher GF, Burnham C. Reproducibility of the oral glucose tolerance test. Diabetes. 1965;14:473---80. 15. Myllynen P, Koivisto V, Nikkila E. Glucose in tolerance and insulin resistance accompany immobilization. Acta Med Scand. 1987;222:75---81. 16. Matthews DR, Hosker JP, RudenskiAS, Naylor BA, Teacher DF, Turner RC. Homeostasis model assessment: insulin resistance and b-cell function from fasting plasma glucose and insulin concentration in man. Diabetología. 1985;28:412---9. 17. Avignon A, Búgner C, Mariano-Goulart D, Colette C, Monnier L. Assessment of insulin sensitivity from plasma insulin and glucose in the fasting or post oral glucose-load state. Int J Obes. 1999;23:512---7. 18. Girbés BJ. Methods for the determination of insulin sensitivity based on an oral glucose tolerance test. Av Diabetol. 2008;24:296---304.
J.J. Moya-Salazar, L. Pio-Dávila 19. Clinical Laboratory Standards Institute. Point-of-care blood glucose testing in acute and chronic care facilities. Approv Guidel. 2013;33:14---26. 20. American Diabetes Association Guidelines. Recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Diabetes Care. 2011;34:e62---84. 21. Clinical and Laboratory Standards Institute. H3-A6. Procedures for the collection of diagnosis blood specimens by venipuncture; 2007. p. 27. 22. American Diabetes Association. Screening for type 2 diabetes. Diabetes Care. 2004;27 Suppl. 1:S11---4. 23. Pan American Health Organization. Guías ALAD de diagnóstico control y tratamiento de la diabetes mellitus tipo 2, vol. 3; 2006. p. 12---7. 24. American Diabetes Association. Standards of medical care in diabetes --- 2014. Diabetes Care. 2014;37 Suppl. 1:S14---20. 25. Trinder P. Determination of blood glucose using an system with a non-carcinogenic oxidase---peroxidase chromogenic. J Clin Pathol. 1969;22:158---61. 26. American Diabetes Association. Translating the A1C assay into estimated average glucose values. Diabetes Care. 2008;31:1473---8. 27. Amatuzio DS, Stutzman LF, Vanderbilt JM, Nesbitt S. Interpretation of the rapid intravenous glucose tolerance test in normal individuals and in mild diabetes mellitus. J Clin Investig. 1953;32:428---35. 28. Revilla L, López T, Sánchez S, Yasuda M, Sanjinés G. Prevalence of hypertension and diabetes in residents from lima and Callao, Peru. Rev Peru Med Exp Salud Publica. 2014;31:437---44. 29. Qiao Q, Lindström J, Valle TT, Tuomilehto J. Progression to clinically diagnosed and treated diabetes from impaired glucose tolerance and impaired fasting glycaemia. Diabet Med. 2003;20:1027---33. 30. Levitzky YS, Pencina MJ, D’Agostino RB, et al. Impact of impaired fasting glucose on cardiovascular disease: the Framingham Heart Study. J Am Coll Cardiol. 2008;51:264---70. 31. Vargas-Ancona L. Epidemiologia de la diabetes mellitus, intolerancia a la glucosa y factores de riesgo aterogénico en Yucatán, México. Rev Biomed. 1994;5:151---9. 32. Figueroa ML. Diagnóstico de Intolerancia a la glucosa en nos, en el servicio de laboratorio pacientes mayores de 50 A˜ del Hospital Suárez Angamos II --- Es Salud Lima-Perú. Rev Méd. 2011;1:72---7. 33. Flores JA, Díaz A, Trevi˜ no S, Brambila EM. The effects of a hypercaloric diet on the development of dysglycemia and dyslipemia its impact on the kidney cytoarchitecture. Mensaje Bioquímico. 2014;61:165---74. 34. Clement S, Braithwaite SS, Magee MF, et al. Management of diabetes and hyperglycemia in hospitals, American Diabetes Association. Diabetes Care. 2004;27:553---91. 35. The DCCT Research Group. Diabetes control and complications trial (DCCT): results of feasibility study. Diabetes Care. 1987;10:1---19. 36. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet. 1998;352(9131):837---53. 37. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28:103---17.
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Medicina Universitaria. 2015;17(68):153---157
Combined therapy in diabetic macular edema J.H. González-Cortés a,∗ , J.J. Toledo-Negrete a , K. Butrón-Valdez a , V. Zapata-Elizondo a , no-Cavazos a , J.D. Guerra-Leal b , J. Mohamed-Hamsho a B.O. Martínez-Gamero a , E.E. Trevi˜ a
Ophthalmology Services at the ‘‘Dr. José E. González’’ University Hospital of the Autonomous University of Nuevo Leon, México Radiology and Imaging Department at the ‘‘Dr. José E. González’’ University Hospital of the Autonomous University of Nuevo Leon, México
Received 20 November 2014; accepted 12 May 2015 Available online 8 July 2015
Introduction Diabetic macular edema (DME) is the main cause of visual loss in patients with diabetic retinopathy (DR). It is
∗ Corresponding author at: Servicio de Oftalmología. Hospital Universitario ‘‘Dr. José Eleuterio González’’ de la UANL, Av. Madero y Gonzalitos S/N. Mitras Centro. Monterrey Nuevo León, Mexico. E-mail address: [email protected] (J.H. González-Cortés).
considered to be the number one cause of blindness at a productive age in developed countries.1---6 DME is the result of alterations of the inner and outer blood-retinal barriers (BRB) due to the imbalance between the inﬂammatory and angiogenic factors of the retinal pigment epithelium (PE) and the vitreoretinal interface. Among these, there is the vascular endothelial growth factor (VEGF), the hepatocyte growth factor and the interleukin 1B. The reduction in the pigment epithelium-derived anti-angiogenic factor, a potent anti-inﬂammatory, antioxidant and anti-angiogenic
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154 which regulates, among other things, VEGF levels, also plays an important role in DME pathophysiology.7---9 The treatment focuses on reestablishing BRB, modulating inﬂammatory and angiogenic factors. Among the current options to accomplish said effect, there are the thermal laser and intravitreal drug therapies (corticosteroids and anti-angiogenics). The laser stimulates the PE, acting as a substance modulator for PEDF and VEGF. Moreover, the thermal destruction of the outer layers of the retina reduces the metabolic demand and oxygen expenditure with the consequent VEGF reduction.10---18 Triamcinolone is the main intraocular corticosteroid in the treatment of RD, DME and other neovascular and inﬂammatory diseases because it inhibits overregulation of inﬂammatory molecules and VEGF. Part of this regulation was completed through the reduction of vascular permeability in the retina by reducing the liberation of arachidonic acid derivatives, such as prostaglandins.19---22 Bevacizumab is a recombinant humanized monoclonal antibody (lgG1) which uniﬁes all isoforms of VEGF-A. It was approved by the FDA in 2004 for metastatic colon cancer treatment. Since then, it has been successfully used in an unofﬁcial manner to treat different ocular neovascular illnesses, such as age-associated macular degeneration, proliferative DR, neovascular glaucoma, premature retinopathy, macular edema secondary to retinal venous obstruction and DME, among others. Even though, to this day, it has not been approved by the FDA nor the COFEPRIS for its ophthalmologic use, the injection of 1.25---2.5 mg in the vitreous cavity has been performed in a safe and effective manner.23---29 Different regimes in DME treatment have been described. The laser is recommended for its application in a selective manner and on a single occasion, and, if necessary, reapply it in intervals of no less than 12 weeks apart.18,30,31 Intravitreal pharmacological therapy has been proposed for the different ocular neovascular pathologies, from having one dose and repeating treatment as deemed appropriate by the examiner pro re nata (PRN), up to a monthly dose for 24 months, without regard to visual and anatomic changes.32---41 This study showed that the maximum visual and anatomical effect occurs during the ﬁrst three doses, and those following them only helped to maintain the inactivity of the pathology; thus, the decision in the selection of the scheme during this ‘‘loading stage’’ is fundamental. The ‘‘treat and observe’’ regime is currently being proposed. This is to apply three doses in a row with an interval of 4 weeks in between these ‘‘loading doses’’ until accomplishing the maximum visual and anatomic effect, repeating the same treatment PRN.42 Based on the possible synergy between the laser, the corticosteroids and the anti-angiogenics, the combination between these has been utilized with a dual intention; to accomplish a greater visual and anatomic effect, and to accomplish the minimum number of repetitions in long-term treatment of this chronic degenerative illness.35,36,43---49 In spite of all of this, the question about which combination may be the best option remains unanswered.
Objective To evaluate effectiveness with three different treatment combinations in the ‘‘loading phase’’ of diabetic macular
J.H. González-Cortés et al. edema (DME); using bevacizumab (BVZ), triamcinolone (TCL) and subthreshold macular photocoagulation (SMPC).
Method and materials Controlled clinical, experimental, prospective, longitudinal, comparative and blind essay, including those patients from the Department of Ophthalmology at the ‘‘Dr. José Eleuterio González’’ University Hospital using the following inclusion criteria: male and female with diabetes (type I or II), 18 years of age or older, with a clinical and tomographic DME diagnosis, best corrected visual acuity (BCVA) higher than 20/400. Patients who did not present any of the exclusion criteria; presence of signiﬁcant cataract (according to the researcher’s criteria), diagnosis of glaucoma, vitreous hemorrhage, previous intraocular surgery, macular laser treatment and/or intravitreal drug therapy in the three months previous to the study. Patients who for any reason did not complete treatment or developed complications during treatment were eliminated. The protocol was evaluated and approved by our institution’s Ethics Committee and registered under the code OF11-010. The study was conducted following the guidelines established in the Helsinki Declaration and the International Conference on Harmonization Guidelines for Good Clinical Practices. All patients signed an informed consent form respecting the Ofﬁcial Mexican Standards on the patients’ right to know everything about their illness and its possible treatment options. Clinical diagnosis was made through fundoscopy, using a magnifying glass of 90 diopters and a Goldman contact lens and DME was considered as the central thickening of at least a diameter of 1500 microns, situating the center of this circle in the umbo foveolar. Tomographic diagnosis was performed whenever there was a central macular thickness (CMT) greater than 230 microns using the ‘‘Macular Thickness Map’’ scanning modality of the optical coherence tomography (OCT) using Stratus OCTTM by Carl Zeiss. Baseline BCVA measurements were taken by means of distant subjective refraction with a Snellen primer. IOP was taken by means of an applanation tonometry from Goldmann and clinical and OCT ﬁndings were recorded. Later, the randomized selection of the study groups was made, using the six-sided die technique: numbers 1 or 4 to group 1 (BVZ + SMPC), numbers 2 or 5 to group 2 (BVZ + TCL + SMPC), and 3 or 6 to group 3 (BVZ + TCL). In this study, the principal investigator, who evaluated the study at the beginning and ﬁnalized the treatment regimen during the ‘‘loading phase’’, did not know which group each patient belonged to. The laser was only applied at the beginning of treatment (week 0), with the aim of avoiding possible complications from the laser threshold. The shots were made on subthreshold (invisible) mode,50 using VISULASTM 532s laser equipment (Carl Zeiss Meditec AG. Jena, Germany). The pharmacological treatment was performed on week 0, repeating at weeks 4 and 8. A dose of 1.25 mg in 0.05 ml of BVZ, commercial name AvastinTM (Genentech Inc., South San Francisco, CA, USA/Roche Mexico) was applied each session. The TCL utilized was ATLCTM (conservative-free), distributed by GRIN laboratories, Mexico, at a rate of 2 mg in 0.05 ml every injection. The procedure was performed
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Combined therapy in diabetic macular edema Table 1
Description of the studied population.
Age Initial VA Initial IOP Initial CMT Final IOP Final VA Final CMT
in the ‘‘cure room,’’ with prior asepsis and antisepsis of the eyelids and ocular surface with a solution of povidone-iodine at 5% (BetadineMR Alcon Laboratories Inc., Fort Worth, TX) for 3 min and posterior irrigation with a balanced saline solution. The topical anesthesia applied was tetracaine (PontiTM Laboratorios Sophia, S.A. de C.V., Guadalajara, Mexico). The injection was made via pars plana in the superotemporal quadrant (4 mm from the corneal limbo in phakic eyes and 3.5 mm in pseudo-phakic eyes). A drop of moxiﬂoxacin (VigamoxiTM , Alcon Laboratories Inc., Fort Worth, TX) was applied as a wide-spectrum antibiotic at the end of the procedure, which was used prophylactically at a rate of one drop every 6 h for three consecutive days. The IOP, BCVA, clinical ﬁndings and CMT were documented on week 12 after the beginning of treatment, and these results were compared with the baseline measurements. A statistical analysis was made by the IBM SPSS Statistics software, with a descriptive analysis of the data, which was compared to the average through the Student’s t-test for related samples. p < .05 was determined to be a statistically signiﬁcant difference.
Results Our study included 30 eyes from 30 patients, with ages between 48 and 71 years old, an initial BCVA of .2 Logmar (20/30) to 1.3 Logmar (20/400), an initial CMT average of 396.93 m and an initial average IOP of 14.16 mmHg (Table 1). The global BCVA change was from .6933 to .6133 Logmar (p = .24), a statistically insigniﬁcant difference. The global CMT change was from 396.93 m to 308.03 m (p = .01), a statistically signiﬁcant difference. There were no signiﬁcant differences between the initial and ﬁnal IOP, which was from 14.16 mmHg to 14.77 mmHg (p = .176) (Table 1). In the group analysis, we found that the average change in BCVA in group 1 (12 eyes, BVZ + SMPC) was from .64 to .46 Logmar (p = .01), a statistically signiﬁcant difference compared to group 2 (7 eyes, SPMC + BVZ + TCL) which was from .74 to .67 (p = .28) and group 3 (11 eyes, BVZ + TCL) which was from .71 to .73 (p = .67). In the same way, the decrease of CMT in group 1 was from 456.5 m to 319.41 m (p = .019), a statistically signiﬁcant value in comparison to group 2, which showed a decrease of 385.28 m to 290.57 m (p = .110), and group 3, which showed a decrease of 339.36 m to 306.72 m (p = .110). There were no signiﬁcant differences in IOP change in any of the 3 groups (Table 2). Two patients from group 3 (BVZ + TCL)
and one from group 2 (SPMC + BVZ + TCL) showed cataract progression which required surgery more than IOL placement.
Discussion Since the ﬁrst results of ETDRS were published in 1985, macular laser became, and still is, the ‘‘gold standard’’ for the treatment of DME.18 Despite this, laser offers suboptimal results, never mind the possible complications due to the burning of the external retina.In 2008, Faghihi et al.36 demonstrated that a single dose of BVZ or BVZ + TCL showed superiority in diminishing CMT with patients with DME in comparison to the laser alone. Regardless, the effect of BVZ on monotherapy was short, and the decrease of CMT with an improvement of BCVA only correlated the BVZ + TCL group.36 In 2010, Solaiman et al. compared laser and BVZ treatment against the monotherapy of either one, and his results indicated an improvement in the BCVA and CMT in the groups that were treated with BVZ in combination with laser as a starting therapy.48 In 2011, DRCR.net published results comparing combined therapy using macular lasers and BVZ or TCL. After receiving panphotocoagulation laser treatment, the visual improvement was greater in groups that received BVZ or TCL, although there were no differences in muscular thickness, suggesting that combined therapies utilizing laser + BVZ or laser + TCL were superior to laser monotherapy.51 The same year, Wang et al. demonstrated the beneﬁcial effects of BVZ as a monotherapy or in combination with TCL in the treatment of DMC, without there being a difference between the two groups. In 2012, Soheilian et al.52 published results comparing BVZ monotherapy, BVZ + TCL and macular laser monotherapy. The group with the laser did not obtain a signiﬁcant improvement on BCVA, but although the BCVA improvement in the BVZ group was signiﬁcant during the ﬁrst 6 months, there was no signiﬁcant difference between the BVZ group and the combined treatment group (BVZ + TCL) at the end of the treatment. Although the CMT reduction was greater in the BVZ group, there were also no signiﬁcant differences between the 3 groups.52 To our knowledge upon the printing of this publication, the only study to utilize a BVZ + TCL + macular laser combined triple therapy was published by Chan et al. in 2012,53 who compared the triple therapy to laser monotherapy. Regardless, unlike our study, TCL administration was subtenonian. They reported an important decrease and sustained CMT in the combined therapy group, when compared to laser monotherapy.53
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The majority of the reports which include combined therapies in DME demonstrate the superiority of any one of them over laser monotherapy,25,33,36,40,41,43,47---49,52,53 and the small impact when using TCL.26,36,45---47,51---53 Our results indicate that the BVZ + laser combined therapy during the ‘‘loading phase’’ is signiﬁcantly superior to therapies that included TCL, in achieving an BCVA improvement and a CMT decrease, and we suggest that this combination be repeated PRN in long-term follow-up. One possible limitation, owing to the methodological design of our study (which did not include monotherapies) is that we could not conclude, as previous publications have, if the combination of anti-angiogenic + laser is equal to or superior than monotherapy with anti-angiogenics. Regardless, this was not the object of our study. Another of the limitations of our study is that we only evaluated the therapy during the ‘‘loading phase.’’ It would be interesting to follow-up on these patients in the long term, with the aim of determining if this therapeutic combination could additionally be effective in prolonging the intervals of the retreats in the long term.
Conclusion Our study shows that out of the combined therapies during the ‘‘loading phase’’ in DME treatment, the combination of BVZ and SMPC was the best option. However, further studies are necessary, with a longer follow-up period and a larger number of participants, to establish this alternative as a ﬁrst treatment option.
Conﬂict of interest The authors have no conﬂicts of interest to declare.
Funding No ﬁnancial support was provided.
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macular laser photocoagulation in diabetic macular edema. Eur J Ophthalmol. 2008;18:941---8. Group CR, Martin DF, Maguire MG, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364:1897---908. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology. 2010;117:2146---51. Massin P, Bandello F, Garweg JG, et al. Safety and efﬁcacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010;33:2399---405. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615---25. Schmidt-Erfurth U, Lang GE, Holz FG, et al. Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. Ophthalmology. 2014;12:1045---53. Treatment for CI-DME in eyes with very good VA study (Protocol V). ClinicalTrials.gov. clinicaltrials.gov/ct2/ show/NCT01909791. Updated November 20, 2013 [accessed 15.01.14]. Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127:245---51. Bandello F, Cunha-Vaz J, Chong NV, et al. New approaches for the treatment of diabetic macular oedema: recommendations by an expert panel. Eye. 2012;26:485---93. Kreutzer TC, Al Saeidi R, Kook D, et al. Comparison of intravitreal bevacizumab versus triamcinolone for the treatment of diffuse diabetic macular edema. Ophthalmologica. 2010;224:258---64. Marey HM, Ellakwa AF. Intravitreal bevacizumab alone or combined with triamcinolone acetonide as the primary treatment for diabetic macular edema. Clin Ophthalmol. 2011;5:1011---6. Forte R, Cennamo GL, Finelli M, et al. Intravitreal bevacizumab vs intravitreal triamcinolone combined with macular laser grid for diffuse diabetic macular oedema. Eye. 2010;24:1325---30. Solaiman KA, Diab MM, Abo-Elenin M. Intravitreal bevacizumab and/or macular photocoagulation as a primary treatment for diffuse diabetic macular edema. Retina. 2010;30:1638---45. Arevalo JF, Lasave AF, Wu L, et al. Intravitreal bevacizumab plus grid laser photocoagulation or intravitreal bevacizumab or grid laser photocoagulation for diffuse diabetic macular edema: results of the Pan-american Collaborative Retina Study Group at 24 months. Retina. 2013;33:403---13. González CJH, Trevi˜ no CEE, Cuervo LEE, et al. Tratamiento del nicamente signiﬁcativo con láser edema macular diabético cli´ Nd:Yag subumbral de doble frecuencia. Medicina Universitaria. 2008;10:190---9. Googe J, Brucker AJ, Bressler NM, et al. Randomized trial evaluating short-term effects of intravitreal ranibizumab or triamcinolone acetonide on macular edema after focal/grid laser for diabetic macular edema in eyes also receiving panretinal photocoagulation. Retina. 2011;31:1009---27. Soheilian M, Garfami KH, Ramezani A, et al. Two-year results of a randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus laser in diabetic macular edema. Retina. 2012;32:314---21. Chan CK, Lai TY, Mohamed S, et al. Combined high-dose sub-tenon triamcinolone, intravitreal bevacizumab, and laser photocoagulation for refractory diabetic macular edema: a pilot study. Retina. 2012;32:672---8.
Medicina Universitaria. 2015;17(68):158---161
Spectrum of hemifacial microsomia in a pre-term newborn. Case presentation and literature review A.Y. Medina-de la Cruz a , I. Rodríguez-Balderrama a,∗ , C.H. Burciaga-Flores b , M.E. de la O-Cavazos c a
Neonatology Service of the ‘‘Dr. José Eleuterio González’’ University Hospital, Autonomous University of Nuevo Leon, Mexico Genetics Service of the ‘‘Dr. José Eleuterio González’’ University Hospital, Autonomous University of Nuevo Leon, Mexico c Pediatrics Department of the ‘‘Dr. José Eleuterio González’’ University Hospital, Autonomous University of Nuevo Leon, Mexico b
Received 12 August 2014; accepted 21 January 2015 Available online 5 May 2015
∗ Corresponding author at: Servicio de Neonatología, Departamento de Pediatría, Hospital Universitario ‘‘Dr. José Eleuterio González’’, Universidad Autónoma de Nuevo León. Av. Madero y Gonzalitos s/n, Colonia Mitras Centro, C.P. 64460 Monterrey, NL, Mexico. Tel.: +52 8183872460. E-mail address: [email protected] (I. Rodríguez-Balderrama).
Spectrum of hemifacial microsomia in a pre-term newborn. Case presentation and literature review
Introduction The spectrum of hemifacial microsomia, or facio-auriculovertebral spectrum, is a complex of craniofacial and vertebral anomalies ﬁrst described by Goldenhar in 1952.1 Axis malformation is microtia, and it may even be the only manifestation. Nevertheless, it can be found linked to mandibular hypoplasia and vertebral malformations.1 Microtia is a malformation characterized by the absence of some parts of the outer ear, and in some cases the entire ear. It can include the external hearing conduct and may be unilateral or bilateral.1 The unilateral form occurs in between 79 and 93% of cases.1 It has an incidence of 1:500 to 1:3000 live births, is more frequent in males at a 3:2 ratio, and has a dominant autosomal inheritance in 1---2% and a sporadic inheritance in 98%.1,2 It is the result of a defect in blastogenesis involving the ﬁrst and the second pharyngeal arch, at approximately 30---45 days of gestation, with the formation of the ﬁrst arch, which contributes to the formations of the structure of the face, both mandibular and maxillary portions, as well as the auricular pavilions.1---3 From the dysmorphologic point of view it is classiﬁed as a disruption. Among prenatal risk factors, there are: multiple pregnancies, anemia, advanced maternal age, threatened miscarriage, diabetes mellitus type 1 and 2 and medications such as isotretinoin. Twin pregnancy increases the risk of congenital malformations 2.47 times.4 Among the milder cases, preauricular appendices or isolated microtia may occur, whereas in the most severe cases, macrostomia and epibulbar dermoid, also known as the Goldenhar syndrome, occur.1,2 Hemifacial microsomia appears with a frequency of 20---65%. Regarding microtia, the right side is the most frequently affected, with a 3:2 ratio. Auricular malformations have a frequency of 65---99%, including preauricular appendices (with 40%).1,2,4,5 Axial skeleton alteration is limited to the cervical region and occasionally to the thoracic vertebrae, including hemivertebrae in 30%, renal malformations in 1---10% and cardiac malformations in 14---47%.6,7 There are known malformations associated with the spectrum, such as cleft palate, tracheoesophageal ﬁstula, ﬁnger and hand anomalies and pulmonary hypoplasia.8---10
Case presentation A male, newborn, preterm of 29.5 weeks of gestational age, twin product, twin number 2, the mother 23 and the father 24 years old, non-blood relatives, without exposure to teratogens, product of a third gestation. It was a dichorionic and diamniotic spontaneous twin pregnancy, with proper prenatal care, and went through the ﬁrst trimester with threatened miscarriage. There is a premature rupture of membranes at week 29.4 of gestational age, a dosage of pulmonary maturation inductors and the patient is granted conservative management after not presenting preterm labor. However, 7 h after rupture there is fetal distress caused by type 2 decelerations of twin number 2, thus interrupting the pregnancy via C-section. The product is obtained with an Apgar score 5/8, a weight of 1110 g, size 39 cm, and a 27-cm head circumference, requiring admittance to the Neonatal Intensive Care Unit. Twin number 1, male born with
Photograph of the front. (1.1) Proﬁle photograph.
a weight of 1290 g, size 39 cm, a 27.5 cm head circumference and an Apgar score of 8/9, had no dysmorphias detected during physical examination and no bone defects in imaging studies, thus, no genetic studies are performed. He dies after 5 days of life outside the womb due to prematurityrelated complications; hyaline membrane disease grade 2, pulmonary hemorrhage and late sepsis, we requested an autopsy from the parents; however, they declined. During twin no. 2’s physical examination, a wide anterior fontanelle is detected, broad nasal bridge, hemifacial microsomia, anteverted nares, left microtia Tanzer 3, low implantation of right auricular pavilion with backwards rotation, bilobed left preauricular appendices, bilateral ﬁfth ﬁnger clinodactyly, bilateral cryptorchid, macrostomia, pointed palate, micrognathia without evidence of epibulbar dermoid (Fig. 1). A thoracoabdominal X-ray is taken, observing hemivertebrae in cervical and dorsal areas, in addition to hyaline membrane disease grade 2 (Fig. 2) requiring 3 doses of pulmonary surfactant and mechanical ventilation, accomplishing continuous positive nasal airway pressure and
A.Y. Medina-de la Cruz et al. a karyotype is performed, where a chromosomal complement of 46, XY is found corresponding to a male without major numeric or structural alterations in addition to performing follow-up during internment, giving a diagnosis of spectrum of hemifacial microsomia. A renal ultrasound is performed, as well as a transfontanellar ultrasound and an echocardiogram without pathological ﬁndings, an assessment by ophthalmology is requested without ﬁnding the presence of epibulbar dermoid or any other pathological ﬁnding during examination. The newborn is admitted to the Neonatal Intermediate Care Unit for growth and development, maternal training and attachment through the ‘‘kangaroo technique’’. An ear CAT scan is performed, which reports a lack of development of the right ear and pneumatization of mastoid air cells, external hearing canal, tympanic membrane and ossicular chain without alterations, normal internal ear structures; at a left-ear level, atresia of the left ear canal without evidence of tympanic membrane and dysplastic ossicular chain attached to the attic’s lateral wall (Fig. 3). The internal ear structures were normal. There is a lack of development and pneumatization of mastoid air cells. He was discharged at 78 days of chronological age, 6 days corrected age, with a weight of 1570 g with follow-up in high risk neonatal consultation in order to continue with the monitoring of neurological growth and development.
successful extubation. Given the ﬁndings observed during physical and radiological examinations the Genetic Service is brought in. They obtain the parents’ genetic clinical history, and as a part of the approach of a dysmorphic patient
It is described in the literature that the risk of congenital malformations increases 2.47 times in twin pregnancies; the spectrum of hemifacial microsomia is more frequent in dichorionic and diamniotic twin pregnancies, according to a study conducted at the National Institute of Perinatology on discordance of congenital defects in newborns of multiple pregnancies, this being our patient’s case. Some of the risk factors found in this case include being male, a twin product and having a background of threatened miscarriage in the ﬁrst trimester of pregnancy.11,12 We are talking about discordant dichorionic and diamniotic twins, which we assume are dizygotic because only one of them was
CAT scan of the ear. (3.1) Left ear. (3.2) Right ear.
Spectrum of hemifacial microsomia in a pre-term newborn. Case presentation and literature review affected; nevertheless we do not have the proper evaluation to deﬁne a dizygotic or monozygotic origin of the twins, which was not performed when twin number 1 died. It is also described in the literature that monochorial twins show a higher discordance frequency regarding congenital anomalies; in fact they are considered to be concordant only in 9---18% of the cases.13,14 However, the risk of congenital defects in monozygotic twins is 10 times greater in comparison to the general population and dizygotic twins.15 As of 1988, with the high amount of published cases worldwide, a concordance for this spectrum of 20% was considered for monozygotic twins and much lower for dizygotic, also weighing in environmental factors, a situation that has been conﬁrmed due to alterations found such as vascular disruptions occurring in the stapedial and internal carotid arteries in monozygotic twins.16,17 Because most cases of spectrum of hemifacial microsomia occur as an isolated case (where the occurrence is in just one individual in the family), its low penetrance and unknown etiology, the risk of recurrence given is an empiric 2---3%. The presence of hemifacial microsomia, macrostomy and microtia without the presence of an external hearing canal stands out in this case, because it turns out to be a relevant defect since it is commonly found in this spectrum. Different from what is described in the literature, the microtia found in the patient was on the left side, without ﬁnding any cardiac, renal and at-brain-level malformations which are common cause of morbimortality. Within the external follow-up of these patients, special attention must be placed on the affection in speech development, the presence of pharyngeal and/or laryngeal anomalies and velopalatal insufﬁciency, and a dental assessment must be performed in addition to craniofacial defects which require surgical correction prior to conducting an imaging study or esthetic corrections during the assessment of appendices and microtia and the evaluation of visual and hearing acuity. These measures do not help nor strengthen the diagnosis; nevertheless, they are evaluations conducted with the purpose of assessing the patient’s capability at a sensorial and functional level. There are few reported cases of the spectrum of hemifacial microsomia in preterm newborns who accomplish a successful evolution, because of the conditions related to prematurity or alterations caused by the spectrum. Thus it is important to highlight the state of prematurity of 29.5 weeks of gestational age and being a product of a twin pregnancy in our case.
Conﬂict of interest The authors have no conﬂicts of interest to declare.
References 1. Mu˜ noz LA, Arenas ML. Manifestaciones clínicas de 149 pacientes con espectro facio-aurículo-vertebral. Acta Otorrinolaringol Esp. 2013;64:359---62. 2. Quintana ME, Canún S. Espectro facio-aurículo-vertebral y frecuencia de malformaciones asociadas. Rev Hosp Gral Dr M Gea González. 2006;7:6---12. 3. López A, Aguinaga M. Discordancia de defectos congénitos en recién nacidos de embarazos múltiples en el Instituto Nacional de Perinatología. Perinatol Reprod Hum. 2012;26:8---16. 4. Alasti F, Van Camp G. Genetics of microtia and associated syndromes. J Med Genet. 2009;46:361---9. 5. Heike CL, Hing AV. Craniofacial microsomia overview. Seattle. Gene Reviews® . Seattle (WA): University of Washington, Seattle; 1993---2014 [Internet] Available from: http://www.ncbi. nlm.nih.gov/books/NBK1116/ 6. Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® . Seattle, WA: University of Washington; 1993---2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1116/ 7. Cammarata F, Zerpa R, Stock F, et al. Diagnóstico oportuno del espectro oculo-auriculo-vertebral (síndrome de Goldenhar). A propósito de un caso. Can Pediatr. 2012;36:25---9. 8. Barisic I, Odak L, Loane M, et al. Prevalence, prenatal diagnosis and clinical features of oculo-auriculo-vertebral spectrum: a registry-based study in Europe. Eur J Hum Genet. 2014;22:1026---33. 9. Rooryck C, Souakri N, Calley D, et al. Array-CGH analysis of a cohort of 86 patients with oculoauriculovertebral spectrum. Am J Med Genet A. 2010;152A:1984---9. 10. Agredo F, Cuello G, Blanco P. Síndrome de Goldenhar Reporte de un caso. Acta Otorrinolaringol Cir Cabeza Cuello. 2009;37:215---9. 11. De la Barca M, Paz A, Oca˜ na M, Atienza L. Displasia Oculoauriculovertebral o Síndrome de Goldenhar. Estudio multidisciplinario de un caso clínico. Rev Cubana Oftalmol. 2001;14:42---6. 12. Pachajoa H, Saldarriaga W, Isaza C. Un caso de espectro oculoauriculovertebral con meningocele occipital. medUNAB. 2006;9:164---7. 13. Yokochi K1, Terasawa S, Kono C, Fujishima I. Dysphagia in children with oculo-auriculo-vertebral spectrum. Dysphagia. 1997;12:222---5. 14. Singh SM, Murphy B, O’Reilly R. Epigenetic contributors to the discordance of monozygotic twins. Clin Genet. 2002;62:97---103. 15. Zwijnenburg PJG, Meijers-Heijboer HEJ, Boomsma DI. Identical but not the same: the value of discordant monozygotic twins in genetic research. Am J Med Genet Part B. 2010;153B: 1134---49. 16. Ryan A, Finer N, Ives E. Discordance of signs in monozygotic twins concordant for the Goldenhar anomaly. Am J Med Genet. 2005;29:755---61. 17. Dagmar W, Ludwig M, Boehringer S, Jongbloet PH, GillessenKaesbach G, Horsthemke B. Reproduction abnormalities and twin pregnancies in parents of sporadic patients with oculoauriculo-vertebral spectrum/Goldenhar syndrome. Hum Genet. 2007;121:369---76.
Medicina Universitaria. 2015;17(68):162---164
Prostatic cyst: An unusual cause of hemospermia F. Hernández-Galván ∗ , R. Jaime-Dávila, L.S. Gómez-Guerra, A. Gutiérrez-González, J.F. Lozano-Salinas, J.G. Arrambide-Gutiérrez Urology Service at the ‘‘Dr. José Eleuterio González’’ University Hospital and School of Medicine of the Autonomous University of Nuevo León, Mexico Received 27 March 2015; accepted 12 May 2015 Available online 2 July 2015
Introduction Prostatic cysts, although an infrequent diagnosis in men, are usually asymptomatic and mostly detected incidentally during abdominal or transrectal ultrasonography. Etiological factors include chronic prostatitis as a cause of lateral ∗
Corresponding author at: Servicio de Urología del Hospital Universitario ‘‘Dr. José Eleuterio González’’ de la Universidad Autónoma de Nuevo León, Av. Francisco I. Madero s/n, Col. Mitras Centro, Monterrey, NL CP 64460, Mexico. Tel.: +52 81 83331713. E-mail address: [email protected] (F. Hernández-Galván).
prostatic cysts and congenital disease as a cause of midline cysts. Existent scientiﬁc publications on prostatic cysts are mostly isolated case reports, which highlights their uncommon occurrence and even lower propensity for causing symptoms.1 We report a case of a benign prostatic cyst with hemospermia.
Case report A young 31-year-old male was presented to us with hemospermia with a duration of more than 4 years. Consecutive hemospermia was present in each ejaculation with abundant
blood clots. There were no others symptoms like perineal pain, fever, dysuria, nocturia or urgency. No urinary tract infection or prostatic infection was reported. Initial evaluation included a urine microscopic analysis, semen culture, and a screening abdominal ultrasonography, which documented the presence of a prostatic cyst. A CT scan was performed to evaluate the seminal vesicles and a small calciﬁcation was found in the right seminal vesicle (not shown). His sperm count was 36 × 106 sperm per milliliter (normal 15 × 106 ) with 109 × 106 sperm in the total count (normal 39 × 106 ), the progressive motility was 55% (normal 32%), white blood cells was 1 × 106 (normal 1 × 106 ) and red blood cells were abundant (normal 0 × 106 ). After the surgery, the semen analysis parameters were sperm count 33 × 106 sperm per milliliter, with 99 × 106 sperm in the total count, the progressive motility was 54%, white blood cells was 1 × 106 , and red blood cells 0 × 106 . The patient was initially managed with antibiotic therapy. A retrograde urethrogram did not reveal any communication with the prostatic cyst. The patient underwent cystoscopy and transurethral resection of the prostatic cyst (Fig. 1). Back pressure
changes were noted in this case. The roof of the cyst was resected with minimal coagulation under direct vision with a wire loop to marsupialize the cyst. Care was taken to spare the bladder neck and verumontanum to prevent retrograde ejaculation (Fig. 2). The resection resulted in drainage of a clear ﬂuid. Cold-cup biopsies taken from the cyst wall revealed non-urothelial epithelium with no preneoplastic changes. A 16 F Foley catheter was placed overnight and the patient was discharged the next morning. Follow-up at one, three and six months demonstrated unobstructed urinary ﬂow and normal ejaculation.
Discussion Prostatic cysts include the utricle cyst, the Müllerian duct cyst, the hemorrhagic prostatic cyst, the hydatid cyst, and cysts associated with prostatitis. Our patient had a lateral cyst near the bladder neck in the right side and another small cyst in the left side. He was concerned about his hemospermia, because there was more than before in each event and this was the reason he came to the hospital. The patient
164 never referred to pelvic pain, dysuria or perineal pain; his only symptom was hemospermia. He had no infertility problem (he had 2 children, aged 6 and 4). After the surgery and to date, he has never presented hemospermia again, and his sperm count parameters are normal. Some cysts are primarily prostatic glandular in origin and are acquired later in life. Most lateral prostatic cysts are related to chronic prostatitis.2,3 Symptomatic prostatic cysts are a cause of chronic pelvic pain, upper or lower urinary tract infection (UTI), infertility, hemospermia and, rarely, malignancy.4---6 In our case the only symptom was hemospermia, no infertility and no pelvic or perineal pain were present. Some therapeutic options for managing prostatic cysts include transrectal aspiration with or without sclerotherapy, transurethral marsupialization, and open surgery. Some authors report durable recurrence-free results in a series of patients with medial prostatic cysts treated with transurethral incision.4,7 We treated this patient by means of a transurethral marsupialization and fulguration of the vessels. This lead to full recuperation, and the patient was discharged the next day without pain and he had an uneventful recovery. Valuable information was obtained by performing a cistourethroscopy, demonstrating that the vessels ran over the cyst, which is by itself an unusual ﬁnding. This was important because hemospermia is usually treated only with antibiotics. In our case, the solution was marsupialization of the cyst and fulguration of the dilated vessels.
F. Hernández-Galván et al.
Conﬂicts of interest The authors have no conﬂicts of interest to declare.
Funding No ﬁnancial support was provided.
References 1. Saha B, Sinha RK, Mukherjee S, et al. Midline prostatic cyst in a young man with lower urinary tract symptoms. BMJ Case Rep. 2014, http://dx.doi.org/10.1136/bcr-2014-207816. 2. Issa MM, Kalish J, Petros JA. Clinical features and management of anterior intraurethral prostatic cyst. Urology. 1999;54:923. 3. Tamaki M, Isogawa Y, Ohmori K. A case of prostatic cyst. Hinyokika Kiyo. 1994;40:537---40. 4. Dik P, Lock TM, Schrier BP, et al. Transurethral marsupialization of a medial prostatic cyst in patients with prostatitis-like symptoms. J Urol. 1996;155:1301---4. 5. Xing JP, Dang JG, Wu D, et al. Papillary cystadenoma in a mullerian duct cyst: report of a case with review of literature. Zhonghua Nan Ke Xue. 2006;12:218---21. 6. Etherington RJ, Clements R, Grifﬁths GJ, et al. Transrectal ultrasound in the investigation of hematospermia. Clin Radiol. 1990;41:175---7. 7. Jarow JP. Diagnosis and management of ejaculatory duct obstruction. Tech Urol. 1996;2:79---85.
Medicina Universitaria. 2015;17(68):165---174
History and progress of antiviral drugs: From acyclovir to direct-acting antiviral agents (DAAs) for Hepatitis C O.L. Bryan-Marrugo a , J. Ramos-Jiménez b , H. Barrera-Salda˜ na a , A. Rojas-Martínez a , c a,∗ R. Vidaltamayo , A.M. Rivas-Estilla a
Department of Biochemistry and Molecular Medicine, School of Medicine, ‘‘Dr. José Eleuterio González’’, University Hospital, Universidad Autónoma de Nuevo León, Monterrey, N.L., Mexico b Department of Internal Medicine, School of Medicine, ‘‘Dr. José Eleuterio González’’, University Hospital, Universidad Autónoma de Nuevo León, Monterrey, N.L., Mexico c Universidad de Monterrey, Monterrey, N.L., Mexico Received 17 December 2014; accepted 12 May 2015 Available online 3 July 2015
KEYWORDS Hepatitis C virus; Antiviral drugs; Direct-acting antiviral agents (DAAs)
Introduction From 1972 to date, more than 50 new viruses have been identiﬁed as etiologic agents of human disease.1 These new viral diseases have required more sophisticated therapeutic agents, but the development process of these strategies to this point has been slow and full of hurdles. Antiviral chemotherapy has advanced at snail-like pace, unlike antibiotics, which in 30 years achieved an advanced therapeutic stage. 34 years elapsed from the description of the antibacterial molecule salvarsan, ‘‘the magic bullet’’, by Ehlrich in 1910,2 to the discovery of penicillin by Fleming in 1929,3 to Domagk’s description of prontosil, the precursor of sulfonamides in 19354 and the isolation of streptomycin, chloramphenicol, erythromycin and tetracycline by Waksman in 1944.5 However, it took almost 60 years for antiviral development to reach its current status of effectiveness. The evolution of the treatment for Hepatitis C is a good example of how complex antiviral development can be and how a combined and speciﬁc targeted antiviral therapy has proved to be the best approach to follow for viral disease treatment. The Hepatitis C virus (HCV) affects over 170 million individuals worldwide, 80% of which are chronically infected.6 This is four times the number of people infected with HIV and about half the number of persons infected with the Hepatitis B virus (HBV). 7 HCV is caused by a hepatotropic virus, which belongs to the Flaviviridae family, genus Hepacivirus. HCV was discovered in 1989 and its viral genome is a 9.6 kb-long positive single-stranded RNA. It encodes a single polyprotein precursor of 3010 amino acids and has an internal ribosome entry site at the 5 untranslated region. This polyprotein precursor is co-translationally processed by cellular and viral proteases into three structural proteins (core, E1 and E2) and seven non-structural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B).8 The structural proteins associate with the genomic RNA and a viral particle is assembled inside a lipidic envelope. Treatment for HCV infection has come a long way. Between 2001 and 2011, a standard of care (SOC) for chronic HCV infection was established worldwide. It consisted of a combination of pegylated interferon (PEG-IFN) and ribavirin (RBV). Nowadays, new speciﬁc antiviral agents have been approved. In May 2011, boceprevir and telaprevir, two ﬁrst-generation NS3/4A protease inhibitors, were authorized for their use in combination with PEG-IFN and RBV for a 24-to-48-week course of treatment in HCV-genotype 1 infections. Two years later (December 2013), Simeprevir (a second-generation NS3/4A protease inhibitor) was approved for use with PEG-IFN and RBV for a 12-week course of treatment in HCV-genotype 1, while sofosbuvir (a NS5B nucleotide polymerase inhibitor) was approved for use with PEG-IFN and/or RBV for a 12/24-week course of treatment in HCV-genotypes 1 to 4. IFN-free regimens have been shown to give better results, because sofosbuvir, combined with simeprevir or an NS5A replication complex inhibitor (ledipasvir or daclatasvir), with or without RBV for a 12-week treatment in genotype 1, resulted in a sustained virological response (SVR) >90%. In addition, ABT-450/r (ritonavir-boosted NS3/4A protease inhibitor)based regimens, in combination with other direct-acting antiviral agent(s) with or without RBV for 12 weeks in
O.L. Bryan-Marrugo et al. genotype 1, have demonstrated similar results regarding SVR.9
Roadblocks for antiviral drug development As we see in the text above, therapy for HCV infection remained almost the same from 2001 to 2011. After a decade of poorly effective HCV therapy, the development of speciﬁc compounds against this virus ramped up HCV treatment on a pace that nearly matched antiretroviral therapy for HIV. ‘‘Why did it take such a long time?’’ is an important question whose answer could help on the approaches towards drug development against untreated diseases. The ﬁrst complication when studying a virus is the limitations regarding in vitro systems and animal models for experimentation; second, is the low rate of discovery for efﬁcient candidate molecules, and third, the delicate balance between efﬁcacy, toxicity and resistance towards the selected antiviral drug. Additional economical aspects must also be considered. Here we have analysed each of these aspects under the light of the promises and pitfalls related to Hepatitis C research and treatment.
HCV study tools Viruses are intracellular organisms which depend on cellular machinery for replication. Therefore, a huge breakthrough in this ﬁeld was achieved by Enders, Robbins and Weller in 1951, when they developed an in vitro virus propagation system in cell culture.10 Since then, many in vitro and in vivo systems have been implemented for the study of several viruses, such as polio and HIV. Cell assays systems were recently developed for HCV infection and propagation. In the early beginnings of HCV studies, no small animal model existed to study HCV infections, and Chimpanzees, the only animals capable of being infected with HCV, were precluded by both ethical and functional difﬁculties. The in vitro development for HCV research began with the sub-genomic replicon cell culture system that replicates autonomously in the human hepatoma cell line Huh-7 generated by Bartenschlager et al., in 2001.11,12 This sub-genomic replicon model was further improved by the identiﬁcation and introduction of adaptive mutations, which enhanced virus replication capacity and lead to the establishment of the full-length replicon system using the highly permissive cell line Huh-7.5.1 in 2003, by Blight and Bartenschlager et al., separately.13---15 These developments allowed the study of HCV infection mechanisms, such as packaging, budding and a more accurate evaluation of potential antiviral molecules. On the other hand, the development of a small animal model that can be infected with HCV became a reality with the T- and B-cell deﬁcient mice with severe combined immunodeﬁciency (SCID), grafted with human hepatocytes. The ﬁrst HCV infection studies in this model were performed by Mercer et al. in 2001. In recent years the development of transgenic mice with a chimeric mousehuman liver revolutionized HCV infection research, allowing the assessment of pathological and immunological proﬁles of the disease.16 Today, scientists rely on a combination of antiviral activity assessment in the HCV replicon cell culture system, cell-based infection systems, and pharmacokinetic
History and progress of antiviral drugs
proﬁling in animals as proxy indicators of antiviral drugs’ efﬁcacy, before attempting clinical trials.17
Screening process for antiviral drug discovery Another aspect that made antiviral drug discovery a difﬁcult endeavor was the lack of a structured and systematic method for antiviral drug development. Three decades ago most of the ﬁrst discoveries of antiviral compounds were fortuitous, since molecules originally developed for other purposes were selected as antiviral candidates, based on their success in other medical disciplines. These methods for antiviral discovery were empirical, and most of the time, the biological mechanism behind the observed antiviral effect remained unclear. For instance, the use of thio-semicarbazones against the vaccinia virus, described in 1950 by Hamre et al., and used later as an antibacterial drug against tuberculosis.18 In 1959, the 5-iodo-2-deoxyuridine (IDU), which was originally designed for cancer treatment, proved to exhibit antiviral activity against the Herpes Virus, but due to its high cytotoxicity, its use was limited to topical application. IDU boosted antiviral development, and from its discovery many antiviral molecules were proposed for the treatment of various viral diseases.19 In Fig. 1, a time line of the milestones in the development of antiviral agents shows the early years of this discipline and how it evolved to become a structured and methodic science.20 At the time of IDU discovery, only a handful of viruses were known to cause diseases in humans. The ﬁrst antiviral drugs were directed to treat herpes, polio, smallpox and inﬂuenza, as they were the most relevant viral diseases of that time. Some of them
that we can mention are the following: triﬂouro-thymidine (TFT), a nucleoside analogue used to treat herpes; adenine arabinoside (Ara-A) a nucleoside analogue against the herpes simplex virus21 ; 2-(␣-hydroxybenzyl) benzimidazole for the treatment of poliomyelitis; Marboran for the treatment of smallpox and amantadine and rimantadine to treat inﬂuenza, which were identiﬁed by traditional biological screening assays in the early 1960s and was shown to be inhibitory for inﬂuenza A viruses in cell culture and animal models. In the last two decades, medicinal chemistry has developed into a recognized discipline, in which a lead compound was usually identiﬁed by screening a large collection of molecules. This method was improved with the introduction of combinatorial chemistry and highthroughput screening.22 Today, more structured rationales are implemented when looking for new antiviral drugs; simple screening, blind screening and programmed screening have become more sophisticated, as the tools to analyze structure, protein interaction and viral behavior have evolved. For HCV therapy development, many attempts to treat the infection were implemented, with rather poor results.23 Due to the lack of a serological test, systematic treatment protocols could not be performed, and so several ‘‘informal’’ studies were reported, evaluating many kinds of molecules. But it was not until 1986 that Hoofnagle reported the beneﬁcial effect of Interferon Alpha in a pilot study to treat Non-A/Non-B hepatitis.24 This report primed a boom in HCV therapeutics and many randomized controlled clinical trials were performed to improve HCV treatment. In 1990 Ribavirin was ﬁrst proposed to treat HCV infection and the ﬁrst clinical trial for the assessment of its efﬁcacy began in 1991.25,26 After the efﬁcacy of the combined antiviral
HCV Potential targets for antiviral chemotherapy. Many targets for antiviral action can be found along HCV’s life cycle.
therapy of Pegylated Interferon-␣ (PEG-IFN-␣) and ribavirin against HCV infection was proven, it became the standard of care (SOC) for this disease, and despite its shortcomings (50% response rate and 50% relapse rate on patients infected with genotype 1b, and unwanted side effects), it remained as such for more than 15 years.27,28 During this time, using blind screening approaches, some molecules were found to reduce HCV-RNA levels in vitro, but none of them were signiﬁcant enough to be implemented clinically. It was not until May, 2011 that the improved understanding of the HCV life cycle led to the discovery, assessment and FDA approval of the HCV protease inhibitors Telaprevir and Boceprevir, that effectively reduce viral load on chronic HCV infected patients, in treatment of naïve patients and in prior relapsers and non-responders. 29,30 Telaprevir and boceprevir were the ﬁrst direct-acting antiviral agents (DAAs) that selectively target HCV. However, new DDAs have been recently added to this list: simeprevir (protease inhibitor), sofosbuvir (NS5b polymerase inhibitor), daclatasvir (NS5A protein inhibitor), and faldaprevir (second-wave NS3/4A protease inhibitor), all of them showing very promising results and some have even been proposed as the treatment backbone for Interferonfree HCV therapies.31,32 With these selective HCV protease inhibitors, the establishment of STAT-C therapy became a reality. Today, several DAAs (including HCV protease inhibitors, polymerase inhibitors, and NS5A inhibitors) are in various stages of clinical development. Current research is attempting to improve the pharmacokinetics and tolerability of these agents, deﬁne the best regimens, and determine treatment strategies that produce the best outcomes. Some of these DAAs will reach the market simultaneously, and resources will be needed to guide the use of these drugs. It is also worth mentioning that different lines of research are currently evaluating other ways to improve HCV chemotherapy. For example, taribavirin, a prodrug for the long-known nucleoside analogue ribavirin, is at 3rd phase clinical trials and has shown promising results.33 This new antiviral would further boost HCV therapy in the coming years.
Fig. 2 shows the major HCV potential targets for antiviral chemotherapy.
Efﬁcacy and toxicity on the development of an efﬁcient antiviral drug Since the discovery of IDU 50 years ago, only a few molecules have proven to be effective and safe when used for selective antiviral therapy. A huge breakthrough that came from the better understanding of virus-host interaction was the inception of 9-(2-hydroxyethoxymethyl) guanine (Acyclovir). It was the ﬁrst highly selective antiviral drug, being a substrate for the Herpes Simplex Virus-encoded thymidinekinase. It displayed a direct inhibitory effect against viral replication and practically no adverse effects on the host. The achievement of selective viral toxicity by Acyclovir and other similar molecules were thought of as the beginning of a new therapeutic age for a well-established, effective and safe antiviral therapy. Acyclovir is a pro-drug, which means it has to be further metabolized in vivo before entering the infected cell wherein further metabolism may or may not be required to yield the active inhibitor. The key to Acyclovir’s speciﬁcity is the selective phosphorylation of the acyclic guanosine nucleoside by the Herpes virusencoded pyrimidine deoxynucleoside kinase, which means it would only be active on Herpes-infected cells.34 After Acyclovir’s discovery and study, several nucleoside analog pro-drugs have been developed, all of them with relatively high speciﬁcity (Table 1 shows a list of the most important antiviral drugs, including their mode of action). Sadly, new challenges arose for antiviral treatment. Several resistant mutants have been identiﬁed, making it more difﬁcult to achieve a complete viral eradication and therefore demands for a successful antiviral therapy became more complex, involving many aspects that were previously not considered. One undeniable fact is that most of our current knowledge on viral and antiviral science comes from the study of
History and progress of antiviral drugs Table 1
Major antiviral compounds developed and approved for use in humans.
IMINE DERIVATIVE CYTOKINE (Immunomodulator) NA UD UD NA UD NA NA NA NA PA NA NA NARTI NARTI NARTI NARTI NA NA NNRTI NNRTI NARTI PI FI NI NNRTI PI NA NNRTI PI PI FI NI PI NA NI NARTI PI PI NA PI RA II PI II
BROAD SPECTRUM BROAD SPECTRUM HERPES SIMPLEX BROAD SPECTRUM DNA VIRUSES HERPES SIMPLEX INFLUENZA HERPES SIMPLEX HERPES BROAD SPECTRUM BROAD SPECTRUM HERPES, CYTOMEGALOVRUS HERPES HERPES, CYTOMEGALOVRUS HIV HIV HIV HIV CMV HERPES SIMPLEX HIV HIV HIV HIV HERPES, SINCYTIAL VIRUS INFLUENZA HIV HIV HIV HIV HIV HIV HIV INFLUENZA HIV HEPATITIS B INFLUENZA HBV HIV HIV BROAD SPECTRUM HCV HIV HIV HCV HIV
HIV. The science of antiviral research was well established when HIV/AIDS appeared as a major viral disease in early 1980s. An increase of antiviral therapy studies with no equal took place when the ﬁrst cases of HIV were reported. Azidothymidine (AZT), among other antiviral molecules already in existence, proved to have selective toxicity against HIV.
However, it was during the treatment of HIV that medicine confronted new obstacles. The concept of resistant strains was long known in the microbiological world, but for the young and developing antiviral terrene, it was an issue of little importance until then. HIV was one of the ﬁrst chronic viral diseases discovered to have a considerable impact
Non-responders to traditional IFN-RBV therapy
Combination of Ledispavir 90 mg/sofosbuvir 400 mg for 12 wks
Combination of Ledispavir 90 mg/sofosbuvir 400 mg for 12 wks
Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/twice daily dose of dasabuvir 250 mg and RBVa for 12 wks
Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/twice daily dose of dasabuvir 250 mg and RBVa for 12 wks
Sofosbuvir 400 mg/Simeprevir 150 mg/RBVa for 12 wks
Sofosbuvir 400 mg/Simeprevir 150 mg/RBVa for 12 wks
Ledipasvir 90 mg/sofosbuvir 400 mg for 12 wks
Ledipasvir 90 mg/sofosbuvir 400 mg for 12 wks
Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/twice daily dose of dasabuvir 250 mg for 12 wks
Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/twice daily dose of dasabuvir 250 mg for 12 wks
Sofosbuvir 400 mg/Simeprevir 150 mg for 12 wks
Sofosbuvir 400 mg/Simeprevir 150 mg plus RBVa for 12 wks
Extend treatment for 24 wks
Sofosbuvir 400 mg and RBVa for 12 wks
Sofosbuvir 400 mg and RBVa for 12 wks
Extend treatment for 16 wks
Sofosbuvir 400 mg and RBVa plus weekly PEG-IFN for 12 wks 3
Sofosbuvir 400 mg/RBVa
Sofosbuvir 400 mg and RBVa for 12 wks
Resistant to traditional therapy and 1st generation protease inhibitors
Patients with Cirrhosisb
Combination of Ledispavir 90 mg/sofosbuvir 400 mg for 12 wks Combination Of Ledispavir 90 mg/sofosbuvir 400 mg plus RBVa for 12 wks.
Extend treatment for 24 wks
Extend treatment for 24 wks
Extend treatment for 24 wks Ledispavir 90 mg/sofosbuvir 400 mg plus RBVa
Combination Of Ledispavir 90 mg/sofosbuvir 400 mg for 12 wks Combination Of Ledispavir 90 mg/sofosbuvir 400 mg plus RBVa for 12 wks.
Extend treatment to 24 wks
O.L. Bryan-Marrugo et al.
Resistant to Sofosbuvir
Table 2 Summary of the recent treatment guidelines for HCV infection therapy [described by the American Association for the Study of Liver Diseases (AASLD), Infectious Disease Society of America (IDSA) and the International Antiviral Society (IASUSA)].
Non-responders to traditional IFN-RBV therapy
Sofosbuvir 400 mg/RBVa plus Weekly PEG-IFN for 12 wks
Sofosbuvir 400 mg and RBVa plus weekly PEG-IFN for 12 wks
Ledipasvir 90 mg/Sofosbuvir 400 mg for 12 wks Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/and RBVa for 12 wks Sofosbuvir 400 mg/RBVa for 24 wks
Ledipasvir 90 mg/Sofosbuvir 400 mg for 12 wks Paritaprevir 150 mg/ritonavir 100 mg/ombitasvir 25 mg/and RBVa for 12 wks Sofosbuvir 400 mg plus RBVa plus Weekly PEG-IFN for 12 wks Sofosbuvir 400 mg plus RBVa for 24 wks
Sofosbuvir 400 mg plus RBVa plus Weekly PEG-IFN for 12 wks 5
Sofosbuvir 400 mg plus RBVa plus Weekly PEG-IFN for 12 wks Weekly PEG-IFN plus RBVa for 48 wks
Sofosbuvir 400 mg plus RBVa plus Weekly PEG-IFN for 12 wks Weekly PEG-IFN plus RBVa for 48 wks
Ledispavir 90 mg/Sofosbuvir 400 mg for 12 wks Sofosbuvir 400 mg plus RBVa plus weekly PEG-IFN for 12 wks
Ledispavir 90 mg/Sofosbuvir 400 mg for 12 wks Sofosbuvir 400 mg plus RBVa plus weekly PEG-IFN for 12 wks
Resistant to Sofosbuvir
Resistant to traditional therapy and 1st generation protease inhibitors
Patients with Cirrhosisb
History and progress of antiviral drugs
a RBV (Ribavirin) dosage is weight based (1000 mg [<75 kg] and 1200 mg [>75 kg]). All indications refer to daily doses unless is otherwise clariﬁed in the text. b Deﬁnitions for treatment criteria.42,43 (Treatment) Naïve patient: A person who has never undergone any HCV therapy. --- Rapid Virologic Response (RVR): It is deﬁned as an undetectable HCV RNA at week 4 of treatment. --- Sustained Virological Response (SVR): It is deﬁned as undetectable HCV RNA 12 weeks (SVR12) or 24 weeks (SVR24) after treatment completion. --- Non-response: Refers to a patient who do not achieve undetectable HCV RNA during the ﬁrst 24 weeks of treatment. There are two forms of non-responders: Partial responders and null responders. --- Partial response: It is a sub-category of non-response and describes a decrease in HCV RNA levels by at least 2 Log10 at week 12 of treatment but detectable levels at week 24. --- Null response: Is a sub-category of non-response and refers to the situation when a patient does not suppress their HCV RNA levels by at least 2 Log10 by week 12 of treatment. --- Drug resistant: A patient who is Partial or Null responder to a speciﬁc treatment for which a HCV ‘‘resistant’’ mutant remains immune making necessary to change the therapeutical approach. --- Liver Cirrhosis: Liver disease severity should be assessed prior to therapy. Identifying patients with cirrhosis is of particular importance as their prognosis is altered and their treatment regimen may be adapted. Liver biopsy remains the reference method for grading the activity and histological progression (staging) of the disease (ﬁbrosis and cirrhosis). Some non-invasive methods can also be used: Assessment for Liver stiffness, muscle atrophy, patient skin, sclera and mucous; skin turgor, jaundice, spider angiomas and palmar erythema along with elevation of liver enzymes (AST, ALT and LDH). Patients with liver cirrhosis must also be assessed for Hepatocellular Carcinoma.
172 on public health. Although antiviral research and development were ignited by the HIV threat, many HIV patients were not responsive to the treatment. The discovery of AZT was followed by several other dideoxynucleoside (ddN) analogues (ddI, ddC, d4T, 3TC, ABC, FTC) (Fig. 2). All these NRTIs act in a similar fashion; after their phosphorylation to triphosphates, they interact as ‘chain terminators’ of the HIV-reverse transcriptase, thus preventing the formation of the proviral DNA. Even though they had great success, drug resistance forced HIV treatment to evolve. Today, it is known that two inevitable and important consequences of antiviral therapy have to be taken into account when planning a treatment strategy for viral chronic diseases. The ﬁrst is that, given its nature, long-term antiviral therapy automatically selects resistant mutants that will survive and become dominant strains. Resistant mutants are even more frequent in viral than in bacterial infection, and this becomes more evident when treating chronic viral infections such as HIV and HCV.35---37 For viral infections, any attempt to attack the virus’ metabolism could have an effect on host cells. It is evident then, that modiﬁcations of these two aspects of antiviral therapy, could improve the results of treatment for chronic patients. This barrier was overcome in part through the use of combinatorial therapy. In addition to that, the concept of a broad spectrum or at least a ‘‘pangenotypic’’ antiviral molecule that could be effective on a wide range of viral pathogens is paradoxically selfdefeating if we think that speciﬁcity is required to avoid cell toxicity and the opposite is needed to broaden the spectrum of a given antiviral molecule. With our current knowledge on viral metabolism and host interaction, three aspects of viral infection can be targeted for antiviral treatment: inhibition of viral genes and proteins, blocking of host genes and enzymes that interact with viral counterparts, and modulation of host metabolic pathways involved in the virus life cycle.
The challenges of ﬁghting Hepatitis C As we mentioned before, a new era of therapeutics is currently emerging for Hepatitis C treatment, since several other direct-acting HCV antiviral drugs are being developed (Protease inhibitors: faldaprevir, asunaprevir, danoprevir, vaniprevir, ABT-450-ritonavir, MK5172, GS-9451; NS5A inhibitors: ledipasvir, ombitasvir, GS-5816, PPI-668, MK-8742 and daclatasvir; NS5b inhibitors: mericitabine, VX-135, dasabuvir, BMS-791325, GS-9669), which have been shown to reduce viral RNA levels, reaching SVR in up to 95% of the treated patients.38,39 However, there are several challenges to be addressed to combat HCV using new drugs. DAA’s directly attack the Hepatitis C virus and, similar to some of the drugs used to treat HIV, these new molecules target the enzymes needed for viral protein processing; the virus should counterpart this effect (Fig. 2). Based on that, HCV genetic variability and drug resistance are the bigger obstacles that DAAs must overcome. HCV has a high rate of replication, with 1012 virions produced daily, along with an equally high mutation rate, meaning that, for any given drug, there are already resistant mutants present on the infected subject that would ultimately render single drugs useless. However, Hepatitis C resistance may be delayed or
O.L. Bryan-Marrugo et al. prevented by using combinations of potent antiviral drugs without cross-resistance proﬁles and optimizing patient adherence to therapy.38 On the other hand, accessibility to the new and approved HCV therapies is a challenge in combating the Hepatitis C, mainly because of the high cost of the combined treatments (between 100,000 and 250,000 USD). Availability and accessibility of new protease inhibitors (PI), telaprevir, boceprevir, simeprevir, and the recently approved RNA polymerase inhibitor (RPI) sofosbuvir depends on the region where patients are located and their access to governmental health programs. In most countries, accessibility to these drugs is possible only for those patients who can afford treatment for themselves, as public health systems do not yet have policies for application of the new HCV therapy to the general population through insurance systems.40 This will likely require concerted public and political mobilization to pressure originator companies to reduce prices and stimulate generic competition. In addition, lower prices could make widespread access to HCV treatment possible in low and middle income countries.
Where we stand today After almost 20 years since HCV’s discovery, today we account for a solid-yet-not-completely effective treatment landscape to ﬁght hepatitis infection. First, modern biomolecular diagnostic tools are used to determine genotype and viral load as a base to design an accurate therapeutic regimen; second, viral load dynamics is monitored in order to determine drug resistance, and third the liver’s state and the presence of infection are assessed in patients who have completed the therapy. In an effort to provide a condensed set of treatment guidelines, the American Association of Liver Disease (AASL), Infectious Disease Society (IDSA) and the International Antiviral Society (IASUSA) generated the Guidelines for HCV infection treatment which are based on patient’s previous exposure to treatment, HCV genotype, relapsing proﬁle and hepatic status.41 In Table 2 we show a compendium of the recent treatment guidelines for HCV infection therapy. It is important for physicians to evaluate patient clinical history (naïve or not), HCV genotype, treatment effectiveness and HIV co-infection in order to avoid unwanted drug interactions.
Conclusions and perspectives Antiviral therapy is a well-established discipline with a promising future. Based on economic, scientiﬁc and medical interest, and a continuous need for new drugs to avoid resistance, it is most likely that the development of antiviral drugs over the next 20 years will be focused on HIV and HCV. Today, well-established diagnostic and study systems are available for HCV and other viruses. New targets against HCV, such as inhibitors for the scavenger receptor type B1 (SR-B1) and CD81, neutralizing antibodies against the viral glycoproteins and the NS5B polymerase, as well as the NS2/3 auto-protease, the NS3 helicase, and non-enzymatic targets such as NS4B and NS5A proteins are in development (Fig. 1). Other potential drugs targeting HCV replication include compounds active against the IRES element and antisense inhibition. As mentioned before,
History and progress of antiviral drugs virus factors are not the only potential targets for inhibition, but host targets are as well, including microRNAs, cellular receptors, adhesion molecules and cyclophilins. For the near future, a combination of host and viral inhibitors will provide a variety of drug regimes appropriate for different patients that could lead to interferon-free therapies that can consistently clear the infection. A new era of HCV treatment and the increasing knowledge about viruses and their mechanisms of infection, combined with the rapid discovery of novel antiviral strategies and techniques, will speed up the development of novel antiviral drugs.
Funding Financial support was provided by the CONACYT, grant number CB-2011-1-58781 to A.M.R.E.
Conﬂict of interest The authors have no conﬂicts of interest.
Acknowledgements We thank Sergio Lozano-Rodriguez, M.D. for his assistance in reviewing the manuscript.
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173 14. Wakita T, Pietschmann T, Kato T, et al. Production of infectious hepatitis C virus in tissue culture from a clone viral genome. Nat Med. 2005;7:791---6. 15. Bartenschlager R, Kaul A, Sparacio S. Replication of the hepatitis C virus in cell culture. Antivir Res. 2003;2:91---102. 16. Ernst E, Schönig K, Bugert JJ. Generation of inducible hepatitis C virus transgenic mouse lines. J Med Virol. 2007;8: 1103---12. 17. Lin C. HCV NS3-4A serine protease. Hepatit C Viruses Genomes Mol Biol. 2006;1:163---206. 18. Bauer D. Clinical experience with the antiviral drug Marboran (1-methyl.isatin 3-thiosemicarbazone). Ann N Y Acad Sci. 1965;130:110---7. 19. Field HJ, De Clerk E. Antiviral drugs --- a short history of their discovery and development. Microbiol Today. 2004;31: 60---2. 20. Pierrel J. An RNA phage lab: MS2 in Walter Fiers’ laboratory of molecular biology in Ghent from genetic code to gene and genome 1963---1976. J Hist Biol. 2012;1:109---38. 21. Nesburn AB, Robinson C, Dickmson R. Adenine arabinoside effect on experimental idoxiuridine-resistant herpes simplex infection. Invest Ophthalmol Vis Sci. 1974;4:302---4. 22. Xu H, Agraﬁotis DK. Retrospect and prospect of virtual screening in drug discovery. Curr Top Med Chem. 2002;12:1305---20. 23. Choo QL, Kuo G, Weiner A. A cDNA clone derived from a bloodborne non-A, non-B viral. Science. 1989;4902:359---62. 24. Hoofnagle JH, Mullen KD, Jones B, et al. Treatment of chronic non-A, non-B Hepatitis with recombinant human alfa interferon. A preliminary report. N Engl J Med. 1986;25:1575---8. 25. Reichard O, Andersson J. Ribavirin: a possible alternative for the treatment of chronic non-A, non-B hepatitis. Scand J Infect Dis. 1990;4:509. 26. Reichard O, Andersson J, Schvarcz R, et al. Ribavirin treatment for chronic hepatitis C. Lancet. 1991;337:1058---61. 27. Sherlock S. Antiviral therapy for chronic hepatitis infection. J Hepatol. 1995;23:3---7. 28. Reichard O, Schuarcz R, Weiland O. Therapy of hepatitis C: alpha interferon and ribavirin. Hepatology. 1997;3 Suppl. 1:108s---11s. 29. Traynor K. Two drugs approved for chronic hepatitis infection. Am J Health Syst Pharm. 2011;13(1176):2011. 30. Jesudian AB, Gambarin-Gelwan M, Jacobson IM. Advances in the treatment of hepatitis C virus infection. Gatroenterol Hepatol. 2012;8:91---101. 31. Yau AH, Yoshida EM. Hepatitis C drugs: the end of the pegylated interferon era and the emergence of all-oral interferon-free antiviral regimens. A concise review. Can J Gastroenterol Hepatol. 2014;28:445---51. 32. Kim DY, Ahn SH, Han KH. Emerging therapies for hepatitis C. Gut Liver. 2014;8:471---9. 33. Palmer M, Rubin R, Rustgi V. Randomised clinical trial: predosing with taribavirin before starting pegylated interferon vs standard combination regimen in treatment naïve patients with chronic hepatitis C genotype 1. Aliment Pharmacol Ther. 2012;36:370---8. 34. De Clercq E, Field HJ. Antiviral prodrugs-the development of successful prodrug strategies for antiviral chemotherapy. Br J Pharmacol. 2006;1:1---11. 35. Heim MH. Interferons and hepatitis C virus. Swiss Med Wkly. 2012;142:1---13. 36. Pfeiffer JK, Kirkegaard K. Bottleneck-mediated quasispecies restriction during spread of an RNA virus from inoculation site to brain. Proc Natl Acad Sci. 2007;14:5520---5. 37. Romano KP, Ali A, Aydin C, et al. The molecular basis of drug resistance against hepatitis C Virus NS3/4A protease inhibitors. PLoS Pathol. 2012;7:1---15. 38. Dhaliwal HS, Nampoothiri RV. Daclatasvir plus sofosbuvir for HCV infection. N Engl J Med. 2014;370:1560.
174 39. Malcom B, Liu R, Lahser F, et al. SCH 503034, a mechanismbased inhibitor of hepatitis C virus NS3 protease suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells. Antimicrobial Agents Chemother. 2006;3:1013---20. 40. Rehman S, Ashfaq UA, Javed T. Antiviral drugs against hepatitis C virus. Genet Vaccines Therapy. 2011;11:1---10. 41. Recommendations for testing, managing, and treating hepatitis C; 2014, December. http://www.hcvguidelines.org
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Medicina Universitaria. 2015;17(68):175---183
Chikungunya virus: A general overview K.A. Galán-Huerta a , A.M. Rivas-Estilla a , I. Fernández-Salas b , J.A. Farfan-Ale c , J. Ramos-Jiménez d,∗ a
Department of Biochemistry and Molecular Medicine, School of Medicine, ‘‘Dr. Jose E. Gonzalez’’ University Hospital, Universidad Autonoma de Nuevo Leon, Monterrey, N.L., Mexico b Centro Regional de Investigacion en Salud Publica, Tapachula, Chiapas, Mexico c Centro de Investigaciones Regionales ‘‘Dr. Hideyo Noguchi’’, Universidad Autonoma de Yucatan, Yucatan, Mexico d Infectious Diseases Service, Department of Internal Medicine, School of Medicine, ‘‘Dr. Jose E. Gonzalez’’ University Hospital, Universidad Autonoma de Nuevo Leon, Monterrey, N.L., Mexico Received 14 April 2015; accepted 16 June 2015 Available online 29 July 2015
Introduction ∗ Corresponding author at: Infectious Disease Service, Department of Internal Medicine, School of Medicine and Hospital Universitario ‘‘Dr. Jose E. Gonzalez’’, Universidad Autonoma de Nuevo Leon, Ave. Francisco I. Madero and Ave. Gonzalitos s/n, Col. Mitras Centro, 64460 Monterrey, Nuevo Leon, Mexico. Tel.: +52 81 83485013; fax: +52 81 83485013. E-mail address: [email protected] (J. Ramos-Jiménez).
Chikungunya fever is a viral disease transmitted through the bite of infected Aedes mosquitoes. The disease typically consists of an acute illness with fever, skin rash, and incapacitating arthralgia. The word chikungunya means, ‘‘to walk bent over’’ in the African dialect Makonde, and refers to the effect of the incapacitating arthralgia seen in the affected
176 patients.1 Chikungunya virus (CHIKV) is the etiological agent and a member of the Alphavirus genus in the Togaviridae family.2 Chikungunya cases occur in Africa, Asia and the Indian subcontinent. Human infections in Africa have been at relatively low levels for a number of years. In December 2013, France reported 2 laboratory-conﬁrmed autochthonous cases of in the French part of the Caribbean island of St Martin. Since then, local transmission has been conﬁrmed in over 43 countries and territories in the American region.3 This was the ﬁrst documented outbreak of CHIKV with autochthonous transmission in the Americas; therefore it is subject of big concern in our continent.
CHIKV genome, structure and replication Chikungunya virus is an enveloped plus-strand RNA virus with icosahedral symmetry. The virion is 70 nm in diameter and it is composed of repeating units of the E1 and E2 transmembrane glycoproteins (240 heterodimers of E2/E1 arranged as trimeric spikes on its surface), the capsid (C), a host-derived lipid bilayer, and a single molecule of genome RNA.4 The genome is approximately 12 kb in length and encodes the nonstructural proteins (nsPs) at the 5 end and the structural proteins at the 3 end. The nsPs are translated from genomic RNA and the structural proteins from a subgenomic RNA (Fig. 1).5 Alphaviruses enter target cells by endocytosis. A few receptors (DC-SIGN, L-SIGN, heparin sulphate, laminin and integrins) have been implicated in this process, but their precise roles have not been clearly proven.5 Recently, prohibitin was identiﬁed as CHIKV receptor protein.6 Following endocytosis, the acidic environment of the endosome triggers conformational changes in the viral envelope that expose the E1 peptide, which mediates virus---host cell membrane fusion. This allows cytoplasmic delivery of the core and release of the viral genome. Two precursors of nonstructural proteins are translated from the viral mRNA, and cleavage of these precursors generates nsP1---nsP4.7 These proteins assemble to form the viral replication complex, which synthesizes a full-length negative-strand RNA intermediate. This serves as the template for the synthesis of both subgenomic (26S) and genomic (49S) RNAs. The subgenomic RNA drives the expression of the C---pE2---6K---E1 polyprotein precursor, which is processed by autoprotolysis. The capsid is released, and further processing generates the pE2 and E1 glycoproteins. PreE2 and E1 associate in the Golgi and are exported to the plasma membrane, where pE2 is cleaved into E2 and E3. Binding of the viral nucleocapsid to the viral RNA and the recruitment of the membraneassociated envelope glycoproteins promote viral assembly. The assembled alphavirus particle, with an icosahedral core, buds at the cell membrane.5,7
Vectors, transmission and reservoirs Two distinct transmission cycles have been well documented: enzootic and urban. In Africa, an enzootic cycle occurs in forested habitats where arboreal mosquitoes, principally Aedes spp, serve as vectors. Evidence points to nonhuman primates as the principal reservoir and
K.A. Galán-Huerta et al. ampliﬁcation hosts in the enzootic cycle based on their high rates of seroprevalence, documented infection and viremia in nature, and viremia levels in response to experimental infection.8 The enzootic transmission cycle can spill over to infect people who live nearby, and enzootic mosquito vectors may be involved in interhuman transmission during small outbreaks. Epidemics also occur in Africa when CHIKV is introduced into urban areas where the more anthropophilic vectors, Aedes aegypti and Aedes albopictus, can initiate human---mosquito---human transmission. CHIKV is capable of initiating a sustained, urban transmission cycle that relies only on A. aegypti and/or A. albopictus and human ampliﬁcation hosts.9 This endemic/epidemic cycle results in high levels of human exposure to mosquito transmission, particularly because these vectors live in close proximity to people. The behavior and ecology of A. aegypti, in particular, are ideal for epidemic transmission because adult females prefer to feed on humans, often take several partial blood meals during a single gonotrophic cycle, oviposit in artiﬁcial containers as their preferred larval sites, and rest inside houses with ready access to human hosts.10 A. albopictus is both zoophilic and anthropophilic, aggressive, silent, active all-day long, and has a longer lifespan than other mosquitoes (up to 8 weeks). In recent decades it has expanded to several areas previously known to be Aedes-free.11,12 It seems that most new introductions of A. albopictus have been caused by vegetative eggs contained in timber and tires exported from Asia throughout the world.13 Although the infectivity of various CHIKV strains varies widely for both A. aegypti and A. albopictus, humans develop high-titer viremias that generally persist during the ﬁrst 4 days after the onset of symptoms, with the peak estimated on the day of onset at approximately 109 viral RNA copies/ml14 and infectious titers sometimes exceeding 107 PFU/ml.15 These titers generally exceed the oral infectious dose 50% levels for both epidemic vector species, permitting efﬁcient transmission among humans by mosquitoes.16 Human beings serve as the main CHIKV reservoir during epidemic periods. Outside these periods, monkeys, rodents, and birds constitute the virus reservoir sustaining virus circulation in the environment in the absence of human cases.17,18
Geographic distribution CHIKV is typically found being transmitted in Africa and Southeast Asia. Since its discovery in 1952, CHIKV has caused several epidemics in these places.19,20 The last huge outbreak started in Kenya in 2004 and spread through neighbor islands to La Réunion in 2005.21 After that, the virus spread to several islands in the Indian Ocean and India.1,22 From India it spread to Sri Lanka, Thailand, Malaysia and ﬁnally to Italy in 2007.23,24 In 2009 CHIKV transmission restarted in La Réunion and lead to CHIKV reimportation to Europe in May 2010.25 During 2011, CHIKV was transmitted in Oceania, Central Africa, Southern and Southeastern Asia, Europe and Western Indian Ocean Islands. In 2012, CHIKV was reported in:
Figure 1 Organization of the chikungunya virus genome. The ﬁgure shows the nonstructural and structural proteins the way they are organized throughout the genome as well as the non-translatable regions in 5 and 3 . The function and size in amino acids is showed for each protein. The ﬁgure is drawn to scale based on the CHIKV genome with GenBank access number: AM258990. The non-translatable regions sizes were obtained from Hyde et al.92 The ﬁgure was adapted from Weaver61 and Solignat.93 nsP, nonstructural protein; C, capsid; E, envelope; AA, amino acid.
Southeastern, Southern and Western Asia; Oceania; Central and Western Africa; and Western Indian Ocean Islands. During 2013, CHIKV was transmitted in Southeastern, Southern and Eastern Asia and Oceania.20 The current outbreak started in, the Caribbean Island, Saint Martin on December 6, 2013.26 During December 2013 and January 2014 it spread to the neighbor islands.27 In February, it continued spreading and reached French Guiana.28 In May, Guiana and almost all the Caribbean Islands reported autochthonous CHIKV infections.29 In June, the ﬁrst cases of El Salvador were reported.30 By July, autochthonous transmission was reported in Florida, USA, Costa Rica, Panama and Venezuela.31 By September, cases were reported in Guatemala, Colombia and Brazil.32 In October, Nicaragua and Paraguay reported cases for the ﬁrst time and Guatemalan cases rose.33 By the end of November, Mexico reported its ﬁrst autochthonous transmission in the southern state of Chiapas. Also by this month, Belize and Honduras reported cases.34 According to the Pan American Health Organization (PAHO), since the current outbreak started, there have been 1,280,953 suspected autochthonous transmission cases and more than 26,300 have been conﬁrmed in America.35 The recent reports obtained from Mexico reveals 405 conﬁrmed autochthonous transmissions.35 Nevertheless, this numbers does not include patients that did not look for medical aid.
Phylogeny There are four identiﬁed CHIKV lineages, each with distinct genotypic and antigenic characteristics. The ﬁrst phylogenetic study revealed that CHIKV spread from Africa where two major lineages circulated: West African and East/Central/South African (ECSA). Posteriorly the ECSA lineage spread to Asia and originated the Asian lineage.36,37 Until 2004, these were the only identiﬁed CHIKV lineages that were circulating. The source of the 2005 Indian Ocean epidemic was traced to the ECSA lineage.38 When the Indian Ocean epidemic started in Kenya 2004, the ﬁrst CHIKV isolates from La Réunion epidemic exhibited an alanine at E1 envelope protein residue 226, but later isolates showed an A226V substitution. This and additional substitutions gave rise to the fourth lineage, Indian Ocean lineage.38,39
Pathogenesis The pathogenesis of CHIKV infection in humans is still poorly understood, but recent outbreaks have helped providing insights into the cells and organs involved in viral replication. Following intradermal inoculation by infected mosquitoes, CHIKV directly enters the subcutaneous capillaries and infects susceptible cells in the skin: macrophages, ﬁbroblasts and endothelial cells, where limited replication occurs.40 Locally produced viruses are transported to secondary lymphoid organs, where it infects migratory cells and release viruses to the lymph circulation and proceed to blood.20 Once in the blood, the virus has access to various parts of the body, including the liver, muscle, joints and brain.41 In these tissues, the infection is associated with a marked inﬁltration of mononuclear cells. The mononuclear cell inﬁltration and viral replication in muscles and joints are associated with pain.42,43 CHIKV infection elicits strong systemic innate responses, principally involving the production of antiviral IFN-␣ as well as many pro-inﬂammatory cytokines, chemokines, and growth factors.44 This is followed by the activation of the adaptive immunity through activation and proliferation of CD8+ T cells in the early stages of the disease. A classical switch to CD4+ T-cell response and the production of antiinﬂammatory proteins IL-1RA and IL-2RA are characteristics of later stages of the acute phase.44 CHIKV infection induces a strong inﬂammatory response that is possibly orchestrated by the production of IL-16, IL-17, monocyte chemoattractant protein 1 (MCP-1), IP-10, and MIP-1␣. The end of the acute phase is characterized by the production of proinﬂammatory MIF, MIP-1␤, SDF1␣, and IL-6 and IL-8. CCL5 (RANTES) levels were also high in all patients during the ﬁrst week after symptom onset.44 CCL5, MCP-1, IP-10, MIP-1␤, and IL-8 are produced by activated macrophages that are susceptible to CHIKV infection.40 These chemokines play a major role in leukocyte recruit to sites of infection, coordinating the deployment of efﬁcient antiviral defenses. CHIKV infection also induces strong cellular immune response. High plasma levels of IFN-␥, IL-4, IL-7, and IL12p40, cytokines that promote the adaptive immunity, suggested the involvement of cellular responses.44 A key role for natural killer cells in the clearance of infected cells
178 and in the development of CHIKV arthralgia has also been suggested.45 The B cell-promoting cytokines IL-4 and in some cases IL-10, were also up regulated in the ﬁrst few days after symptom onset probably initiating the production of CHIKV-speciﬁc IgG. Additionally, CD4+ T lymphocytes, which are also involved in the promotion of humoral responses, were strongly activated toward the end of the acute phase.44 IgG antibodies are detected in the ﬁrst week after infection, indicating rapid seroconversion and high levels of antibody responses among CHIKV-infected individuals.46 Speciﬁc IgM lasts for 3---4 months from the onset of the disease, and that IgG lasts more than 6 months.47 However, their role in chronic arthralgia is not very well understood.
Clinical manifestations Chikungunya fever is characterized by an abrupt febrile illness, polyarthralgia and maculopapular rash. The incubation period lasts 2---4 days (rage 1---12 days) and asymptomatic infections occur in 5---15% of the cases.48 Studies conducted in infected patients during La Réunion outbreak indicated that arthralgia was bilateral and symmetrical in 78.4% of the patients. It affected mostly ankles, knees, hands, wrists, feet, shoulders, and elbows.49---52 Rash was present in 54% of the patients, predominantly on the trunk and arms. Periarticular edema was reported in 45% of the patients, affecting the ankles in a greater proportion. Myalgia and headache were present in 72 and 63% of the patients, respectively. Hemorrhagic signs such as gingivorrhagia and epistaxis were only present in 10.6% of the patients.49---52 Radiological ﬁndings are normal and biological markers of inﬂammation like erythrocyte sedimentation rate and C-reactive protein are moderately elevated.49,50,52---54 Iridocyclitis and retinitis are the most common ocular manifestations associated with CHIKV infection and have a benign course with complete resolution and preservation of vision.55 The acute signs and symptoms usually resolve in less than 2 weeks, but arthralgia may last for weeks, months or even years;56,57 this is a clinical symptom that may distinguish CHIKV from dengue virus infection. Also in a univariate analysis, CHIKV infected patients displayed fewer gastrointestinal symptoms compared to dengue-infected patients, and a higher proportion of myalgia and arthralgia.58 Chikungunya is not generally considered life threatening; nevertheless severe forms can also be present. Patients with severe chikungunya fever requiring hospitalization tend to be older and have comorbidities such as cardiovascular, neurologic, and respiratory disorders or diabetes, which are independent risk factors for severe disease.49,59 Severe chikungunya can manifest as encephalopathy and encephalitis, myocarditis, hepatitis, and multiorgan failure. These rare forms can be fatal and typically arise in patients with underlying medical conditions.60,61 Neonates are also at risk for severe infection associated with neurologic signs. The rate of infection of neonates born to viremic mothers and exposed to the virus during birth can reach 50%, leading to severe disease and encephalopathy, resulting in long-term neurological sequelae and poor outcome.62
K.A. Galán-Huerta et al. In general, CHIKV infection has a good prognosis. Nevertheless, older patients (<45 years old) are more likely to evolve toward relapsing and lingering chronic rheumatic musculoskeletal pain.63 A study showed that subjects who experienced severe initial rheumatic involvement (six or more painful sites with at least four other symptoms) at the acute stage of infection were more likely to exhibit chronic rheumatic musculoskeletal pain on follow up.63 Moreover, a positive association between high titers of CHIKV-speciﬁc IgG in the plateau phase and long-lasting arthralgia has been observed contemporaneously from a pilot study and in the Italian cohort.63,64 A possible mechanistic hypothesis may be that an imbalance toward B cell expansion and differentiation, in response to IL-6 secretion following the progression of both immunosenescence65 and chikungunya is triggered by viral persistence in host sanctuaries.66,67 Taking in consideration the clinical features mentioned above, the algorithm presented in Fig. 2 would guide the clinician throughout case deﬁnition, and management. This algorithm is an adaptation from Palacios-Martinez.68
Diagnosis Chikungunya infection is diagnosed on the basis of clinical, epidemiological and laboratory criteria. An acute onset of fever and severe arthralgia or arthritis that is not explained by other medical disorders is considered a possible CHIKV case.20 Three main types of laboratory tests are used for diagnosing CHIKV infection: virus isolation, reverse transcriptase-polymerase chain reaction (RT-PCR), and serology. Virus isolation can be performed on ﬁeld collected mosquitoes or acute serum specimens (≤8 days). Serum obtained from whole blood collected during the ﬁrst week of illness can be inoculated into a susceptible cell line or suckling mouse at a reference laboratory. This can be achieved if the sample is transported cold (between 2 ◦ C and 8 ◦ C or dry ice) and as soon as possible (within 48 h).69 Several RT-PCR assays for the detection of CHIKV RNA have been published. Real-time, closed system assays should be used, due to their increased sensitivity and lower risk of contamination. Taking into account the sensitivity, PAHO recommends the use of the CHIKV RT-PCR protocols from the Centers for Disease Control and Prevention and the Institute Pasteur.14,70 Serum from whole blood is used for PCR testing as well as virus isolation. For serological diagnosis, serum obtained from whole blood is used in enzyme-linked immunosorbent assay (ELISA). The serum (or blood) specimen should be transported at 2---8 ◦ C and should not be frozen. Serologic diagnosis can be made by demonstration of IgM antibodies speciﬁc for CHIKV or by a four-fold rise in IgG titer in acute and convalescent specimens.69 The determination of IgM can be made by different commercially available techniques. However, it should be taken into account that the best sensitivity is from techniques that use the complete virus as antigen compared to those that use recombinant proteins. Since the ﬁrst commercially available kits had poor results, it is recommended that in house techniques for IgM/IgG ELISA be implemented using the puriﬁed viral antigen and following the CDC protocols.60 Recent ELISA
Chikungunya Virus Overview
179 CHIKV fever clinical suspicion
Clinical criteria Acute onset of fever > 38,5°C and severe arthralgia/arthritis not explained by other medical conditions.
Epidemiological criteria Residing or having visited epidemic areas, having reported transmission within 15 days prior to the onset of symptoms.
Confirmed case Clinical criteria: + Epidemiological criteria: +/Laboratory criteria: +
Immediate notification to ministry of health
Primary attention or ambulatory care
• Hemodynamic instability • Postural dizziness, cold extremities • Decreased urine output • Any bleeding under the skin or through any orifice • Incessant vomiting • Pregnancy • Patients above 60 years old or newborns
Symptomatic treatment: • Acetaminophen until other etiologies, like dengue, are ruled out.
• Non-steroidal anti-inflammatory drugs or narcotics can be used if acetaminophen does not provide relief.
• Observation • Asses evolution
Dengue or malaria warning signs
Hospital care Yes
Asses • Hemodynamic status and hydration • Renal failure, neurologic alterations, hepatic failure
Source: Modiﬁed and adapted from Blacksell.71,89---91 PPV, positive predictive value; NPV, negative predictive value; RT-PCR, reverse transcriptase-polymerase reaction; IgM, immunoglobulin M; IgG, Immunoglobulin G; ELISA, enzyme-linked immunosorbent assay.
180 assays have improved sensibility and speciﬁcity as shown in Table 1.71 The use of rapid tests is not recommended. The second sample for serological determination should be taken between 1 and 2 weeks after the ﬁrst sample. Seroconversion can also be detected as an increase in IgG by a factor of 4 or more between acute-phase and convalescent-phase serum samples.69
Treatment There is no speciﬁc antiviral drug treatment for CHIKV infection. Symptomatic treatment is recommended after excluding more serious conditions like malaria, dengue, and bacterial infections.20,21 In acute infection, treatment is symptomatic and supportive, comprised of rest and the use of acetaminophen to relieve fever (<4 g/day). The use of ibuprofen, naproxen, or another non-steroidal anti-inﬂammatory agent (NSAID) to relieve the arthritic component of the disease can be used when dengue infection is discarded.60 In patients with severe joint pains that are not relieved by NSAID, tramadol or narcotics (e.g., morphine) can be advised.60,61 Patients should be advised to drink plenty of ﬂuids to replenish ﬂuid lost from sweating, vomiting, and other insensible losses.60,72 While recovery from CHIK is the expected outcome, convalescence can be prolonged and persistent joint pain may require pain management, including long-term anti-inﬂammatory therapy. Speciﬁc treatment for diffuse post-CHIKV polyarthralgia in chronic stage consists of oral or topic NSAIDs plus a short course of oral corticotherapy or corticoid injection in affected joint. Neuropathic pain can treated with tricyclic antidepressants, antiepileptic drugs or tramadol.73 Although an older study suggested that hydroxychloroquine phosphate offered some beneﬁt in arthralgia,74 posterior studies failed to conﬁrm its efﬁcacy.73,75,76 In patients with refractory joint symptoms, alternative therapies such as methotrexate (MTX) can be evaluated. In a retrospective study made in La Réunion Island, 54 out of 72 patients had a positive clinical response when treated with MTX.73,77 When MTX is contraindicated or ineffective, immune-modulating biologic agents as etanercept, rituximab, or tocilizumab can be used.73 It has been shown that patients with rheumatoid arthritis have low vitamin D levels and a negative correlation with disease activity.78 Therefore, reposition of vitamin D could improve disease severity. In a study made in India, patients with chronic CHIKV-related arthritis were treated with vitamin D and calcium for ﬁve months which improved joint pain and fatigue.79 In addition to pharmacotherapy, cases with arthralgia and joint stiffness may beneﬁt from a program of graduated physiotherapy in acute and chronic stages of the disease. Movement and mild exercise tend to improve morning stiffness and pain, but heavy exercise may exacerbate symptoms.
Prevention Pending vaccine development, the only effective preventive measures consist of individual protection against mosquito
K.A. Galán-Huerta et al. bites and vector control. Control of both adult and larval mosquito populations uses the same model as for dengue and has been relatively effective in many countries and settings.80 Mosquito control is the best available method for preventing CHIKV infection. Breeding sites must be removed, destroyed, frequently emptied, and cleaned or treated with insecticides.3 For protection, clothing which minimizes skin exposure to the day-biting vectors is advised. Repellents can be applied to exposed skin or to clothing in strict accordance with product label instructions. Repellents should contain DEET (N,N-diethyl-3-methylbenzamide), IR3535 (3[N-acetyl-N-butyl]-aminopropionic acid ethyl ester) or icaridin (1-piperidinecarboxylic acid, 2-(2-hydroxyethyl)1-methylpropylester). Mosquito coils or other insecticide vaporizers may also reduce indoor biting.3
Vaccines There is currently no commercial vaccine for CHIKV, although some candidate vaccines have been tested in human beings.81,82 Several technologies have been used to develop CHIK vaccines, including inactivated viral vaccines, live-attenuated viruses, alphavirus chimeras, recombinant viral vaccines, consensus-based DNA vaccines, recombinant subunit vaccines and more recently, a virus-like particle (VLP) vaccine. Two vaccine candidates have ﬁnished phase I trials: a live recombinant measles-virus-based chikungunya vaccine and the VRC-CHKVLP059-00-VP, VLP vaccine. The live recombinant measles-virus-based chikungunya vaccine had good immunogenicity, even in the presence of measles immunity, was safe, and had a generally acceptable tolerability proﬁle.83 The VLP vaccine, VRC-CHKVLP059-00-VP was also immunogenic, safe, and well tolerated.84
Economic burden In India, the chikungunya epidemic in 2006 imposed heavy epidemiological burden and productivity loss to the community. National burden of chikungunya was estimated to be 25,588 DALYs lost during 2006 epidemic. Persistent arthralgia was found to impose heavy burden, accounting for 69% of the total DALYs. The productivity loss in terms of income foregone was estimated to be a minimum of 6 million USD.85 Other studies made in India reported that the burden for Andhra Pradesh was 6600 DALYs (cost: US$12,400,000). While the burden was moderate, costs were high and mostly out of pocket.86 A study made with military policemen at La Réunion in June 2006 reported that most symptomatic patients (93.7%) complained of a chronic stage of the disease, which is characterized by pains in joints or bones, or both, although the inquiry was made 6 months after the epidemic peak. Most working adults are disabled with loss of mobility, hand disability, and depressive reaction, which can each last for weeks to months and has negative consequences in health, social organization, and economy in epidemic areas.87,88 With these antecedents, if the outbreak spreads throughout Mexico, the infected working adults will be incapacitated, and will increase the economic burden.
Chikungunya Virus Overview
Conclusion The arrival of CHIKV to America will be a challenge to the public health system and a signiﬁcant economic burden. The probability of autochthonous transmission in the rest of Mexico and USA is high due to the vector ubiquity. Economic development does not protect countries from vector-borne diseases; modern lifestyles may amplify an epidemic through travel, population aging, and production of solid waste that can shelter Aedes mosquitoes.
Funding No ﬁnancial support was provided.
Conﬂict of interest The authors have no conﬂicts of interest to declare.
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Medicina Universitaria. 2015;17(68):184---187
Perspective on stroke in Mexico F. Góngora-Rivera ∗ Department of Neurology and Internal Medicine at the ‘‘Dr. José Eleuterio González’’ University Hospital of the Autonomous University of Nuevo León, Monterrey, N.L., Mexico Received 18 April 2015; accepted 20 April 2015 Available online 29 July 2015
According to the World Health Organization’s world health report 2004, cerebral-vascular disease --- stroke --- is the third leading cause of premature death in both genders.1 Its greatest impact is represented as the leading cause of disability in adults and the second leading cause of dementia. Over 15 million cases of stroke occur every year worldwide, one case every 6 s. The impact of the disease is greater in developing countries (2 out of 3 cases). In 2005, 87% of the 5.7 deaths by cerebral-vascular disease were in lower or middle socio-economic-level countries.2 This means that by the year 2020, over 52 million deaths will be caused by strokes in developing countries.3 In Mexico, according to the National Institute of Statistics and Geography (INEGI, by its Spanish acronym), strokes were the sixth leading cause of death in 2012, just after heart diseases, diabetes mellitus, malign tumors, accidents and liver diseases.4 The fact that it registered as number 6 may seem like in Mexico, death by cerebral-vascular disease is less frequent. However, it is possible that when it occurs in diabetic patients it becomes sub-registered. This can be explained in different ways. Approximately 30% of patients who suffer a stroke have comorbidities with other diseases of cardiovascular risk, such as diabetes, heart diseases, hypertension and other modiﬁable risk factors, which are registered as the main cause of death in the certiﬁcates
∗ Corresponding author at: Servicio de Neurología del Hospital Universitario ‘‘Dr. José Eleuterio González’’, Universidad Autónoma de Nuevo León, Av Francisco I. Madero S/N, Col. Mitras Centro, C.P. 64460 Monterrey, N.L., Mexico. E-mail address: [email protected]
in our country. Another explanation is the lack of a universal term that encompasses the whole spectrum of the disease. For example, in the US the word ‘‘stroke’’ includes ischemic vascular disease and hemorrhagic vascular disease, and it is clearly separated from heart disease. In Spain a single term is used: ‘‘ictus’’. This allows them to have global numbers of the disease. In Brazil, it is known as the second leading cause of death. On the other hand, in Mexico, like in many other countries in Latin America, there is no clear distinction between the diseases involving the cardiovascular system. The General population and healthcare personnel use many ‘‘similar’’ terms to refer to cerebral-vascular disease, or stroke, like embolism, apoplexy, brain attack, cerebral infarct, cerebral hemorrhage and cerebral-vascular accident; it is, in many cases, even generalized as ‘‘infarct’’, without specifying whether it was the heart or the brain. This causes a fragmentation in the registry of the disease, thus its incorrect representation in ofﬁcial health records. Cerebral-vascular disease is more frequent in adults and its frequency increases signiﬁcantly after the age of 60; however, it may occur at any age. The reason for this is the variety of etiologies, ranging from genetic causes, metabolic origin, hematological causes, cardio-embolic origin, atherosclerosis and even some caused by direct trauma like arterial dissection; thus, age does not represent a restriction to suffering from a cerebral-vascular disease. For example, children with sickle cell anemia may suffer a cerebral infarction during the ﬁrst years of their lives; a teenager may suffer a carotid artery trauma during a car accident, causing a carotid dissection resulting in cerebral infarction by occlusion of the neck vessels. A young adult with cardiovascular risk factors may suffer a cerebral infarction
Perspective on Stroke in Mexico secondary to a heart paroxysmal arrhythmia caused by a thyroid disorder, or even by a defect in the electric conduction to the myocardium; lastly, the elderly may suffer a cerebral infarct caused by an extra atherosclerotic or intracranial plaque which progressively occludes an artery that irrigates the brain. Therefore, it is a disease which affects all ages, with multiple etiologies, and one that should be contemplated by the Health Sector as catastrophic and a priority. The average age of onset of cerebral-vascular disease is 65 years of age, and the prevalence and incidence of the disease will hopelessly increase with the demographic change. In 2004, the base of the population pyramid is narrower than in 1990 due to the fact that the proportion of children and young people had been signiﬁcantly reduced, with an increase from 6.2 to 9.7% in the participation of the elderly. By 2050, this is expected to increase to 21.5%.5 The increase in the survival rate of the population has caused most deaths to occur at an advanced age. For example, in Mexico, out of the 602,000 deaths registered in 2012, 61.9% corresponded to people over 60 years of age and older, the higher percentage of mortality reported by the INEGI in 2012 was a result of chronic degenerative diseases, among which a few stand out: diabetes mellitus (16.9%), ischemic heart diseases (16.5%) and cerebral-vascular diseases (7%).4 Most of the healthcare information registered in the country is based on hospital reports and death certiﬁcates. There are few epidemiological studies based on communal studies designed to determine the prevalence and incidence of cerebral-vascular disease in Mexico.6 Information on cerebral-vascular disease incidence in Mexico results from a door-to-door study called BASID (The Brain Attack Surveillance in Durango),7 where the accumulated incidence was 232.3 per 100,000 inhabitants (IC 95% 27.8---436.9), with a mean sample of 51.5 years of age and 16% subjects over 65 years of age. In Latin America, the variation of cerebral-vascular disease prevalence is wide. In Mexico, estimations suggest 6.7 per 1000 inhabitants in urban areas and 6.5 per 1000 in rural areas.8 In the BASID study, cerebral-vascular disease prevalence was 7.7 per 1000 in all patients and 18.2 per 1000 in those 60 years old or older.7 Cerebral-vascular disease mortality rate has increased in Mexico, while the mortality rate has decreased in developed countries, like in the US, where it went from being the third leading cause of death to number 4,9 This was thanks to the education awareness of the population, early detection of risk factors, and the implementation of specialty hospital services, called Stroke Units. In Mexico, in the year 2000, 435,386 deaths by cerebral-vascular disease were registered, with an annual mortality rate of 25.21/100,000, while in the year 2008, 538,288 deaths were registered with an annual mortality rate of 28.3/100,000.10 In 2007, cerebral-vascular disease was the fourth cause of death in people 65 years of age and older,11 and in 2012, it is the third leading cause of death after diabetes and heart diseases.4 Global CVD mortality rates reported in some hospital records in the country range from 19.6% at 30 days up to 29% at one year. Cerebral hemorrhage reported a higher mortality rate than cerebral infarction.6 The most commonly associated risk factors of cerebralvascular disease in our country are high blood pressure (65---70%), diabetes mellitus (35---39%), obesity (50%),
185 frequent consumption of alcohol (16%), smoking (16---24%) and dyslipidemia (11%).7,12 Cerebral-vascular disease (CVD) includes ischemic and hemorrhagic CVD and cerebral venous thrombosis (CVT). At the same time, ischemic CVD includes transient ischemic attack (TIA) and cerebral infarction (CI); Hemorrhagic CVD includes different forms of intracranial hemorrhage (ICH), such as cerebral hemorrhage (CH) and subarachnoid hemorrhage (SAH), excluding those hemorrhages of traumatic etiology. The most common form of cerebral-vascular disease is ischemic, especially cerebral infarction (≈60---80%).13 The most frequent ischemic CVD etiology in Mexico cannot be precisely known, due to the fact that a uniform protocol of attention to the disease, including a diagnostic approach, does not exist among hospitals in this country. This is unfortunate because the secondary prevention treatment, which helps to avoid a recurrence, depends on the prompt etiological deﬁnition of the cerebral infarct. For example, in the PREMIER study, the etiological mechanism registered to cerebral infarct was: 8% by large artery atherosclerosis, 20% by lacunar infarction or by small vessel disease, 20% by cardioembolism, without specifying whether or not it was atrial ﬁbrillation, 5% by diverse causes and 41% by an undeﬁned etiology.13 It is evident that the etiology of cerebral infarction is deﬁned as the necessary laboratory and clinical studies are conducted. In the 2012 report of the neurovascular unit of the University Hospital of Monterrey, 39% were caused by large artery atherosclerosis, 17% by lacunar infarction or by small vessel disease, 13% by cardioembolism, 0.5% by arterial dissection and 24% by undetermined causes.14 These differences are due to the fact that the hospital has created a systematic form for the clinical and laboratory studies, such as MRIs (86%), echocardiograms (60%) and ultrasound studies of the arteries of the neck (75%), during the patient’s stay in the acute stage of the stroke, while in the PREMIER study (the ﬁrst multicenter study in Mexico) an MRI was performed on 24%, an echocardiogram on 15% and a carotid ultrasound study on 20% of the patients registered with a stroke. Despite the high percentage of cases without an etiological deﬁnition, the rate of recurrence of cerebral ischemia was 8% annually,12 and 50% occurred in the ﬁrst month after the initial event. The functional incapacity after an ictus for cerebral vascular event is a consequence of the extent of the cerebral damage. For example, in the evolution of a stroke, if the treatment is begun as early as possible and is able to reestablish cerebral circulation before the ﬁrst 3 h of the evolution, functional and neurological recuperation will be very satisfactory. In Mexico’s registers, between 24 and 59% of patients are left with moderate to severe functional dependency at 30 days of follow-up. The greater degree of functional damage is felt by patients in rural areas, as opposed to urban,8,15 possibly due to incomplete medical attention and the lesser exposure of new treatments in rural areas. Another reason why the health priority that CVD represents is underestimated is a lack of complete analysis of the costs. In Mexico, the hospital costs are less than those reported by other countries like the United States, Spain or Brazil. However, the true cause seems to be the greater mortality rate and the lack of diagnostic approach studies made in our hospitals, causing the lack of deﬁnition of the
186 etiology, thus the administration of a medication which is less-effective in avoiding recurrence. On the other hand, the indirect cost of a patient with neurological sequelae and functional dependence is enormous, especially if we consider long-term care, rehabilitation, the loss of productive capacity and the impact on the family economy. The ﬁrst step in the chain of events that lets us treat a patient with a cerebral-vascular event opportunely is the recognition of the alarm symptoms and the necessity of moving the patient to a hospital center immediately.2 The Mexican population does not know the alarm signs of a cerebral-vascular event. For example, in Mexico City it was found that 37% of the population recognized an alarm symptom such as weakness in an arm or leg, deviation of the mouth or difﬁculty speaking, but only 2.1% could name 3 or more clinical manifestations. This evidences the necessity of making massive education campaigns with the information that would permit the population to identify the manifestations of a cerebral-vascular event and permit the urgent transportation to a hospital.16,17 Current treatment has changed the panorama of CVD, especially cerebral infarcts. Since 1995, it has been known that the treatment called thrombolysis allows patients who immediately go to a hospital to receive an intravenous medication which recanalize the occluded artery and which can sometimes achieve a complete recovery in the neurological functions of the patient. The time in which this medication can be appiled is only 4-and-a-half hours from the onset of symptoms. Nevertheless, its use has changed the way we see ischemic CVD and opened the hope of medical recuperation for the patient. Because of this, it is a priority to annouce to the public that they must get to a hospital quickly if they notice signs of ischemic stroke, and ask the doctors and authorities to prepare to offer this alternative treatment in national hospitals. There have been some efforts made to improve the public’s knowledge of, and the hospitals’ attention to, this disease in Mexico. National and international scientiﬁc meetings have been organized, generating collaboration initiatives between national societies like the Mexican Neurological Academy and the Mexican Association of Cerebral-Vascular Disease, and other international associations like the Iberoamerican Society of Cerebrovascular Disease, the American Academy of Neurology and the World Federation of Neurology. In 2010 the ﬁrst Neurovascular Units were inaugurated in Mexico, although, to this day, the only one that has survived the passage of time has been the one at the University Hospital of the city of Monterrey, thanks to the aid of the local authorities. On October 29th, ‘‘World Cerebral-Vascular Disease Day’’ in 2012, the state of Nuevo Leon won ﬁrst place in the World Stroke Campaign of the World Stroke Organization with the Campaign of Education and Diffusion against Cerebral Attacks, made with the aid of the Secretary of Health. Other states of Mexico have added to the effort of working toward this proposal, highlighting the states of Querétaro, Sinaloa, Jalisco, Chiapas and the Federal District, with education programs and training for medical personnel and paramedics on prehospitalization attention. In the framework of the Annual Meeting of the Mexican Neurological Academy in November of 2013, the Merida Declaration was made, where a commitment was signed between medical societies to work together
F. Góngora-Rivera with the states of Mexico to improve the means of education, prevention and medical and paramedical attention, as well as the rehabilitation services of cerebral-vascular disease. However, in spite of all these efforts, the impact on the recovery of the patient with a cerebral-vascular event has been minimal. We believe that the only way to change and improve the prognosis of patients with a cerebral-vascular event or Stroke is to guarantee their management with national health coverage. We must develop a strategic plan for universal coverage of CVD through educational programs, organization of pre-hospitalization attention, and growth of the medical infrastructure with the support of authorities and the Goverment, which will allow us to access the treatments which have been scientiﬁcally demonstrated to change the functional prognosis of the patient.
Conﬂict of interest The authors have no conﬂicts of interest to declare.
Funding No ﬁnancial support was provided.
References 1. Estadísticas Sanitarias Mundiales. Una mina de información sobre Salud Publica Mundial. Geneva, Switzerland: Organización Mundial de la Salud, WHO Document Production Services; 2014. 2. WHO. Preventing chronic diseases: a vital investment. Geneva: World Health Organization; 2005. 3. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990---2020: global burden of disease study. Lancet. 1997;349:1498---504. 4. Instituto Nacional de Estadística y Geografía (INEGI). Estadísticas de mortalidad, 2012. Consulta interactiva de datos. México: INEGI; 2012. http://www3.inegi.org.mx/sistemas/sisept/ Default.aspx?t=mdemo107&s=est&c=23587 5. Consejo Nacional de Población. Proyecciones de la Población de México 2010---2050. México: CONAPO; 2013. 6. Marquez-Romero JM, Arauz A, Góngora-Rivera F, et al. The burden of stroke in México. Int J Stroke. 2013;10:251---2. 7. Cantú-Brito C, Majersik JJ, Sánchez BN, et al. Door-to-door capture of incident and prevalent stroke cases in Durango, Mexico: the Brain Attack Surveillance in Durango Study. Stroke. 2011;42:601---6. 8. Ferri CP, Schoenborn C, Kalra L, et al. Prevalence of stroke and related burden among older people living in Latin America, India and China. J Neurol Neurosurg Psychiatry. 2011;82:1074---82. 9. Lackland DT, Roccella EJ, Deutsch AF, et al. Factors inﬂuencing the decline in stroke mortality: a statement from the American Heart Association/American Stroke Association. Stroke. 2014;45:315---53. 10. Chiquete-Anaya E, Ruíz-Sandoval JL, Murillo-Bonilla LM, et al. Mortalidad por enfermedad vascular cerebral en México, 2000---2008: Una exhortación a la acción. Rev Mex Neuroci. 2011;12:235---41. 11. SINAIS. Estadísticas sobre mortalidad general. Mexico; 2008. Available from: http://sinais.salud.gob.mx [updated 2008, 01.07.11; cited 03.05.12]. 12. Cantú-Brito C, Ruiz-Sandoval JL, Murillo-Bonilla LM, et al. The ﬁrst Mexican multicenter register on ischaemic stroke (the PREMIER study): demographics, risk factors and outcome. Int J Stroke. 2011;6:93---4.
Perspective on Stroke in Mexico 13. Cantú-Brito C, Ruiz-Sandoval JL, Murillo-Bonilla LM, et al. Acute care and one-year outcome of Mexican patients with ﬁrstever acute ischemic stroke: the PREMIER study. Rev Neurol. 2010;51:641---9. 14. Huerta-Esquivel L, Gutiérrez-Herrera MA, Muruet W, et al. Características demográﬁcas y clínicas del registro neurovascular del Hospital Universitario: 400 pacientes. Rev Mex Neuroci. 2012;13(S1):S9. 15. Ruiz-Sandoval JL, Cantú C, Chiquete E, et al. Aneurysmal subarachnoid hemorrhage in a Mexican multicenter registry of
187 cerebrovascular disease: the RENAMEVASC study. J Stroke Cerebrovasc Dis. 2009;18:48---55. 16. Góngora-Rivera F, Gutiérrez-Jiménez E, Zenteno MA. Knowledge of ischemic stroke among a Mexico City population. J Stroke Cerebrovasc Dis. 2009;18:208---13. 17. Gutiérrez-Jiménez E, Góngora-Rivera F, Martínez HR, et al. Knowledge of ischemic stroke risk factors and warning signs after a health education program by medical students. Stroke. 2011;42:897---901.
Medicina Universitaria. 2015;17(68):188---191
EXPERT’S CORNER: A PERSONAL APPROACH
Anaphylaxis: Practical aspects of diagnosis and treatment A. Arias-Cruz ∗ Regional Center of Allergy and Clinical Immunology (CRAIC), ‘‘Dr. José Eleuterio González’’ University Hospital, Autonomous University of Nuevo León, Francisco I. Madero and Gonzalitos Avenue, Monterrey, N.L., Mexico Received 18 June 2015; accepted 18 June 2015 Available online 10 August 2015
Introduction Anaphylaxis is a severe systemic allergic reaction that is rapid in onset and is potentially fatal. Its severity varies in relation to the affected organs and the intensity of the damage to these. The more severe forms are associated with airway obstruction (laryngeal edema, severe bronchoconstriction) and/or vascular collapse (anaphylactic shock).1,2 The frequency of anaphylaxis ranges from 0.03% to 0.95%. Its lifetime can be of up to 2.6%. Although anaphylaxis occurs more frequently in children and adolescents, fatal cases are more common in adults. Even though mortality rates are sub-reported, it is estimated to occur in 0.65---2% of severe anaphylaxis cases. Laryngeal edema and cardiovascular complications are the main cause of death.2---6 Anaphylaxis can occur as a consequence of immunological and non-immunological mechanisms. In general, the most frequent form of anaphylaxis is associated with IgEmediated hypersensitivity reactions. Nevertheless, aside from the mechanism involved in the onset of response, a common pathophysiological characteristic of anaphylaxis is the degranulation of basophils and mast cells, with the
∗ Corresponding author at: Regional Center of Allergy and Clinical Immunology (CRAIC), ‘‘Dr. José Eleuterio González’’ University Hospital. Autonomous University of Nuevo León, Francisco I. Madero and Gonzalitos Avenue, Mitras Centro, C.P. 64460 Monterrey, N.L., Mexico. Tel.: +81 8346 2515; fax: +81 8347 6798. E-mail address: a[email protected]
consequent liberation of mediators of inﬂammation, including histamine, leukotrienes and prostaglandins. The action of these mediators in the skin, mucous membranes, airways, gastrointestinal tract, cardiovascular system, and other target organs, originates the signs and symptoms of anaphylaxis.2,4 The most common causes of anaphylaxis are medications, drugs and hymenoptera venoms. Other causes of anaphylaxis mediated by immunological mechanisms include allergen immunotherapy, latex, occupational allergens, seminal ﬂuid, aeroallergens and monoclonal antibodies. Exercise, some physical factors (cold, heat and radiation), ethanol, opioid medications and contrast media, may cause non-immunological anaphylaxis. Idiopathic anaphylaxis, where it is not possible to identify the cause, represents over 20% of all anaphylaxis cases.2---7 Anaphylaxis is characterized by a varied clinical presentation and its manifestations include skin, respiratory, ocular, cardiovascular and gastrointestinal symptoms. Vital functions are compromised in the most severe forms, and if this occurs during the ﬁrst minutes after the onset of the reaction, the risk of death is greater.1,2,8,9 Over 90% of the patients display skin symptoms. Most episodes begin with pruritus and ﬂushing and continue with the progressive development of hives and/or angioedema. Eyes and mucous membranes can acquire a congestive-like aspect, changes generally associated with intense itching, epiphora and rhinorrhea. Gastrointestinal symptoms include abdominal pain, nausea, vomiting, and diarrhea. At a respiratory level, the symptoms can include tightness in the throat, dysphagia, dysphonia, inspiratory stridor
Anaphylaxis: Practical aspects of diagnosis and treatment and even signs of asphyxia, which is caused by the generation of laryngeal edema. On the other hand, cough, dyspnea, wheezing, a feeling of tightness in the chest may onset as a consequence of bronchoconstriction, which can also cause hypoxemia and cyanosis. Cardiovascular manifestations may onset with tachycardia and a feeling of dizziness or instability, and progress until the loss of consciousness. Peripheral vasodilatation and the increase in vascular permeability, characteristics of anaphylaxis, lead to hypotension and shock, which increase heart rate and reduce coronary perfusion. These cardiovascular changes, in addition to hypoxemia related to the obstruction of the airways, reduce cardiac oxygenation and may lead to arrhythmias and myocardium necrosis, which are causes of cardiac arrest. In some cases, anaphylaxis onset can be abrupt, like syncope, or even cause sudden death. Other manifestations that may occur during anaphylaxis are; disorientation, anxiety, seizures and profuse sweating.1,2,8---11 Approximately 20% of patients presenting anaphylaxis may suffer biphasic reactions. In these cases, the late phase begins between 1 and 72 h after the initial phase, usually with similar clinical manifestations. No clinical data has been identiﬁed which allows the prediction of risk of late reactions in a trustworthy manner. However, the patients who present severe initial reactions may have a greater risk of suffering biphasic reactions.1,8,9
Diagnosis The diagnosis of anaphylaxis is fundamentally clinical. Clinical history constitutes the most important tool in the identiﬁcation of a patient who is suffering from anaphylaxis and it is also of great help to identify its cause. In addition to the detailed description of signs and symptoms present in the patient, it is important to obtain information about the moment of onset of the reaction, medication used to treat
189 it, the duration of the episode and exposure to allergens or potential triggers. Whenever possible, we ought to question the people who witnessed the event.9---13 Useful clinical criteria have been established for the diagnosis of anaphylaxis, which are listed in Table 1. With the proper use of these criteria, it is possible to identify over 95% of anaphylaxis cases.1 During the clinical evaluation of the patient, we should always consider other conditions which may occur with similar signs and symptoms to those of anaphylaxis. Differential diagnoses include: vasovagal reactions, anxiety, myocardial dysfunction, pulmonary embolism, foreign body aspiration, poisoning, hypoglycemia, convulsive disorders, urticaria and angioedema, hereditary angioedema and asthma. Although urticaria and angioedema may occur up to 90% of anaphylaxis episodes, when it occurs without affecting other organs or systems, it does not correspond to anaphylaxis cases.9---13 Serum tryptase, plasmatic histamine and histamine metabolites in urine (methyl-histamine) may be useful to conﬁrm an anaphylaxis diagnosis. The best time for its measurement after the onset of the anaphylaxis episode is between 1 and 6 h for serum tryptase, from 10 min to 1 h for histamine and during the ﬁrst 24 h for methyl-histamine. Nevertheless, these studies are not always available and the administration of the treatment should not be delayed.1,10---14 On the other hand, as a part of the attention in the emergency service, in moderate to severe anaphylaxis, it is convenient to perform a complete blood count, metabolic panel, arterial blood gas, and chest x-rays in order to assess the patient’s general condition as well as rule out other diagnoses.9,11---13,15
Treatment Timely treatment considerably reduces the risk of mortality in patients with anaphylaxis. Management ought to begin
Clinical criteria for anaphylaxis diagnosis.
The probability of anaphylaxis in a patient is high when at least one of the following three criteria are met: 1. Acute onset (from a few minutes to a few hours) of a condition characterized by affectation of the skin and/or mucous (ex. hives, itching or generalized ﬂushing/edema of the lips, tongue and/or uvula) AND AT LEAST ONE OF THE FOLLOWING a. Compromised breathing (ex. dyspnea, wheezing [bronchospasm], stridor, reduced PEF, hypoxemia) b. Arterial hypotension or symptoms associated with circulatory compromise (e.g. hypotonia [collapse], syncope, incontinence) 2. Two or more of the following situations which occur rapidly after exposure to a probable allergen (a few minutes to a few hours): a. Affectation of the skin and/or mucous (ex. hives, itching or generalized ﬂushing/edema of the lips, tongue and/or uvula) b. Compromised breathing (ex. dyspnea, wheezing [bronchospasm], stridor, reduced PEF, hypoxemia) c. Arterial hypotension or symptoms associated with circulatory compromise (e.g. hypotonia [collapse], syncope, incontinence) d. Persistent gastrointestinal symptoms (ex. crampy abdominal pain, vomiting) 3. Hypotension after exposure to a known allergen for this patient (a few minutes to a few hours) a. Children: low systolic BP (according to age) or a reduction greater than 30% in the systolic BP b. Adults: systolic BP less than 90 mm Hg or a decrease greater than 30% in the systolic BP Source: Adapted from Sampson H.A., et al. J Allergy Clin Immunol 2006;117: 391-7. PEF, peak expiratory ﬂow; BP, blood pressure. *Low systolic blood pressure in children is deﬁned as less than 70 mm Hg in children from 1 month to 1 year old; less than 70 mm. Hg + 2× years of age, in children from 1 to 10 years old, and less than 90 mm Hg in patients from 11 to 17 years old.
190 Table 2
A. Arias-Cruz Drugs indicated in the treatment of anaphylaxis.
Dose and administration
• Adults: 0.3---0.5 mg (0.3---0.5 mL of a 1:1000 solution) intramuscular. • Children: 0.01 mg/kg (0.01 mL/kg of a 1:1000 solution) intramuscular (maximum dosage 0.3 mg). • The dose can be repeated every 5---15 min if necessary (depending on response). • Intravenous administration: only if there is no response to epinephrine administered intramuscular. It should be administered slowly and diluted 1:10,000, through an infusion pump and only by trained medical personnel. • H1 Antagonists. Diphenhydramine: 25---50 mg in adults; 1 mg/kg (up to 50 mg) in children. Intravenous administration should be slow. Intramuscular administration is an alternative. Oral intake can be considered in less serious cases. • H2 antagonists. Ranitidine: 50 mg in adults and 1 mg/kg (up to 50 mg) in children. IV administered over 5 min, diluted in a glucose solution at 5%. • Methylprednisolone: 1---2 mg/kg/day or an equivalent dose of hydrocortisone (4---8 mg/kg). Intravenous administration every 6 h. Oral prednisone 0.5 mg/kg; useful in less serious cases. • Beta-2 agonist. Nebulized salbutamol, 2.5---5 mg in 3 mL of saline solution or 2---6 puffs of MDI. Repeat as necessary (every 20 min). • 0.9% saline solution. Adults: 0.5---1 L in the ﬁrst 5---10 min. Some cases may require administration of up to 7 L in total. Children may receive up to 30 mL/kg in the ﬁrst hour. • Dopamine: 400 mg in 500 mL of glucose solution at 5%; infuse at a dosage of 20 g/kg/min. Use only when there is no adequate response to treatment with epinephrine intramuscular and infusion with intravenous ﬂuids, or if the hypotension is severe. • Initial dosage: 1---5 mg in adults and 20---30 g/kg (maximum dosage of 1 mg) in children. Intravenous administration over 5 min. Maintenance dosage: intravenous infusion (5---15 g/min).
with an evaluation and the maintenance of airways, ventilation and circulation.1,9---15 If the patient meets clinical criteria for an anaphylaxis diagnosis, epinephrine should be administered immediately. The recommended dose is 0.01 mg/kg (maximum dose of 0.3 mg in children and 0.5 mg in adults) administered intramuscular in the antero-lateral area of the thigh, repeating every 5---15 min if necessary (Table 2). Intravenous administration is an option in patients with severe hypotension or cardiovascular collapse who do not respond to treatment with intramuscular epinephrine and intravenous ﬂuids. Nevertheless, due to the risks of lethal arrhythmia, the latter form of administration should be considered only when continuous cardiac monitoring is possible.1,2,4,8---16 The need for therapeutic procedures in addition to the administration of epinephrine in the patient with anaphylaxis should be individualized according to the present situation in each particular case and the response to treatment. 9---16 These measures include: • Monitoring of vital signs and surveillance of the level of consciousness. • Supine position with elevation of lower extremities in case of hypotension. • Canalization of the peripheral venous way. • Ventilatory assistance with a bag-valve-mask device. Consider endotracheal intubation or cricothyroidotomy if the severity of the episode requires it. • Administration of oxygen (6---8 L/min). Pulse oximetry is a guide to determine the oxygen requirements. • Fluid resuscitation. The use of crystalloid solutions (normal saline) is preferred (Table 2). Colloid volume expanders are an option, but they have not shown be
• • •
• • •
better than crystalloid solutions for the treatment of hypotension in anaphylaxis. Antihistamines. They are second line drugs in anaphylaxis. Antihistamines may be useful for the treatment of cutaneous and mucous membranes symptoms. In anaphylaxis, it is recommended the use of a combination of H1 and H2 antagonists (Table 2). Inhaled beta-2 adrenergic agonists, if there is bronchospasm resistant to epinephrine (Table 2). Corticosteroids. Although they are not useful in the early phase of anaphylaxis, they can potentially reduce the risk of late phase reactions (Table 2). In cases of hypotension refractory to treatment with intravenous ﬂuids and epinephrine, The administration of vasopressors should be considered, with the aim of maintaining arterial pressure above 90 mm Hg. Continuous hemodynamic monitoring is necessary (Table 2). Glucagon is an alternative in patients who are undergoing treatment with beta-adrenergic blockers and do not respond to treatment with epinephrine (Table 2). Vasopressors. If epinephrine injections and ﬂuid resuscitation fail to alleviate hypotension, vasopressors (such as dopamine) should be administered (Table 2). If the patient presents cardiopulmonary arrest, life support maneuvers should be applied and the patient should be transferred to an intensive care unit, if necessary.
Considering the possibility of late reactions, an observation period is recommended after the early phase, even though the symptoms may have disappeared with the initial attention. The observation periods should be personalized. In most cases, a 4---6 h observation period in emergency services is reasonable. However, in patients with severe
Anaphylaxis: Practical aspects of diagnosis and treatment symptoms or refractions to the treatment, the observation period should be longer. The need of hospitalization should be considered in cases of respiratory or cardiovascular compromise which puts the patient’s life at risk, anaphylaxis refractory to the initial treatment, late reactions, and patients with a signiﬁcant risk of severe complications due to pre-existing cardiac or pulmonary diseases.1,8---16
Discharge recommendations Discharge recommendations for a patient who has suffered an anaphylaxis episode should include: 1. A prescription of self-administered epinephrine in case of a new episode of anaphylaxis. The use of auto-injector devices is recommended whenever possible. 2. Provide a written emergency plan guiding the patient on the steps to take in case of onset of anaphylaxis symptoms. 3. Instructions and enough information on the nature of their problem should be provided, as well as how to avoid exposure to allergens or potential triggers. 4. Refer the patient to an allergist for his/her study and possible identiﬁcation of the speciﬁc cause of anaphylaxis, as well as to evaluate the possibility of a desensitization treatment or speciﬁc allergen immunotherapy.9---16
Conclusions Anaphylaxis is a systemic reaction, it is life-threatening and it has a rapid onset. The most frequent triggers are medications, foods and hymenoptera venom. Diagnosis is based on clinical criteria. Clinical manifestations include skin, respiratory, cardiovascular and gastrointestinal signs and symptoms. Epinephrine (intramuscular) is the ﬁrst choice of treatment and should be administered as soon as the anaphylaxis diagnosis is made. Treatment additional to the epinephrine will depend on the clinical manifestations of each case. The patient’s observation period after the attention of the early phase should be individualized according to the severity of the anaphylaxis. At the moment of hospital discharge, self-administration of epinephrine should always be prescribed for all patients who suffered anaphylaxis. It is essential to provide a written action plan in case of future events of anaphylaxis and to refer the patient to an allergist for long-term attention.
Conﬂict of interest The author has no conﬂicts of interest to declare.
Funding No ﬁnancial support was provided.
References 1. Sampson HA, Mu˜ noz-Furlong A, Campbell RL, et al. Second symposium on the deﬁnition and management of anaphylaxis: summary report-second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. J Allergy Clin Immunol. 2006;117:391---7. 2. Simons FE. Anaphylaxis. Allergy Clin Immunol. 2010;125: S161---81. 3. Lieberman P, Camargo CA Jr, Bohlke K, et al. Epidemiology of anaphylaxis: ﬁndings of the American College of Allergy Asthma and Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol. 2006;97:596---602. 4. Ben-Shoshan M, Clarke AE. Anaphylaxis: past, present and future. Allergy. 2011;66:1---14. 5. Sole D, Ivancevich JC, Borges MS, et al. Anaphylaxis in Latin America: a report of the online Latin American survey on anaphylaxis (OLASA). Clinics (Sao Paulo). 2011;66:943---7. 6. Moneret-Vautrin DA, Morisset M, Flabbee J, Beaudouin E, Kanny G. Epidemiology of life-threatening and lethal anaphylaxis: a review. Allergy. 2005;60:443---51. 7. Kuhlen JL, Virkud V. Pathogenesis, newly recognized etiologies, and management of idiopathic anaphylaxis. Discov Med. 2015;19:137---44. 8. Sampson HA, Mu˜ noz-Furlong A, Block SA, et al. Symposium on the deﬁnition and management of anaphylaxis: summary report. J Allergy Clin Immunol. 2005;115:584---91. 9. Lieberman P, Kemp SF, Oppenheimer J, et al. The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol. 2005;115:S483---523. 10. Simons FE. Anaphylaxis: recent advances in assessment and treatment. J Allergy Clin Immunol. 2009;124:625---36. 11. Lieberman P, Nicklas RA, Oppenheimer, et al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol. 2010;126:477---80. 12. Simons FER, Ardusso LRF, Bilò MB, et al. World Allergy Organization anaphylaxis guidelines: summary. J Allergy Clin Immunol. 2011;127:587---93. 13. Simons FER, Ardusso LRF, Bilò MB, et al. 2012 update: World Allergy Organization Guidelines for the assessment and management of anaphylaxis. Curr Opin Allergy Clin Immunol. 2012;12:389---99. 14. Simons FER, Ardusso LRF, Dimov V, et al. World Allergy Organization anaphylaxis guidelines: 2013 update of the evidence base. Int Arch Allergy Immunol. 2013;162:193---204. 15. Muraro A, Roberts G, Worm M, et al. Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. Allergy. 2014;69:1026---45. 16. Simons FER, Ardusso LR, Bilò MB, et al. World Allergy Organization Journal. 2014;7:9.
Medicina Universitaria. 2015;17(68):192---194
EXPERT’S CORNER: A PERSONAL APPROACH
Fecal microbiota transplantation J. González-Altamirano a , H.J. Maldonado-Garza a , E. Garza-González a,b , F.J. Bosques-Padilla a,∗ a
Gastroenterology Services at the ‘‘Dr. José Eleuterio González’’ University Hospital of the Autonomous University of Nuevo León, Monterrey, N.L., Mexico b Department of Clinical Pathology of the ‘‘Dr. José Eleuterio González’’ University Hospital of the Autonomous University of Nuevo León, Monterrey, N.L., Mexico Received 19 June 2015; accepted 19 June 2015 Available online 14 August 2015
Fecal microbiota transplantation (FMT) represents the most promising free-antibiotic therapy in the management of patients with infection by Clostridium difﬁcile, recurrent or refractory to treatment with antibiotics. FMT’s superiority over conventional treatment has been proven in multiple series of cases and recently in experimental prospective randomized clinical trials with a resolution of the infection in over 90% of patients.1 FMT occurs when intestinal microorganisms are infused with a suspension from a healthy donor into a sick patient for the purposes of restoring altered microbiota. The ﬁrst known description of the use of human feces as a therapeutic agent comes from China. During the IV century, Ge Hong prescribed --- in the emergency medicine pocket book --- the intake of feces for different diseases. The success of fecal microbiota transplantation in modern medicine was ﬁrst described by Eiseman et al. in 1958, administrating microbiota in enemas to patients with pseudomembranous colitis.2,3 C. difﬁcile is a Gram-positive spore-forming bacteria isolated in 1935 and described for the ﬁrst time as a cause of diarrhea and pseudomembranous colitis in a patient in 1978.
∗ Corresponding author at: Facultad de Medicina y Servicio de Gastroenterología, Hospital Universitario ‘‘Dr. José Eleuterio González’’ de la Universidad Autónoma de Nuevo León, Av. Francisco I. Madero y Gonzalitos s/n, Colonia Mitras Centro, C.P. 64460 Monterrey, N.L., Mexico. Tel.: +52 81 8333 3664; fax: +52 81 8333 3664. E-mail address: [email protected] (F.J. Bosques-Padilla).
In the last three decades we have witnessed the increase in the incidence and severity of infectious proﬁles by C. difﬁcile, making it a serious health issue, increasing morbidity and mortality in hospitalized patients as well as in outpatients. The incidence of infection by C. difﬁcile in the community has increased 5.3 times from 1991 to 2005 and in these outpatients the disease occurs in young adults without comorbidities who lack traditional risk factors like the exposure to antibiotics and recent hospitalization. This suggests new risk factors and new forms of transmission.3,4 One of the factors which has contributed to the increase in the number of cases of infection by C. difﬁcile is the presence of a new, more virulent, quinolone-resistant strain, which produces 16 times more toxin A and 23 times more toxin B, in addition to a third toxin, which has enterotoxigenic activity in vitro.5 Moreover, this new strain produces more spores, conditioning a greater pollution in the environment, thereby increasing the risk of spreading. This epidemic strain is associated with a higher incidence of complicated cases and a higher mortality rate. Initially identiﬁed by a restriction endonuclease analysis and denominated as BI (1980), it is currently referred to as Type 1 (NAP1) by pulsed ﬁelds analysis or ribotype 027 by ribotypiﬁcation. This NAP1 strain has spread widely in the US; nevertheless, very few clinics are aware of its presence due to its characteristics.1,4 Current recommendations to decide on a treatment for patients with infection by C. difﬁcile are based on clinical severity. Patients with mild infections may be treated with metronidazole 500 mg, administered orally 3 times a day, or vancomycin 125 mg, administered orally 4 times a day for
Fecal microbiota transplantation 10 days. Severe cases are treated with vancomycin 125 mg, administered orally 4 times a day for 10 days. Complicated severe cases are treated with a combination of vancomycin 500 mg, administered orally 4 times a day, plus metronidazole 500 mg IV every 8 h and rectal vancomycin (vancomycin 500 mg in 500 ml of saline solution in enema) 4 times a day in case of the presence of ileus.5 However, one of the challenging aspects in the management of patients with a C. difﬁcile infection is the recurrence of the disease after a successful treatment. It is considered a recurrence when symptoms restart within the ﬁrst 8 weeks after the end of treatment. Recurrence rates after treatment with metronidazole and vancomycin are similar (20.2% and 18.4%, respectively)6 . For the treatment of recurrences, we recommend the same treatment that was used during the initial episode, coupled with a suspension of any antibiotics the patient may be taking to allow the restoration of the intestinal microﬂora. If the new episode is severe, vancomycin should be utilized. Some experts recommend giving pulses of vancomycin in the case of a second recurrence. Other antibiotics, like rifaximin and ﬁdaxomicin, have been tested in cases of recurrence and obtained variable results and, overall, a greater cost7,8 . Neither of these is currently recommended for recurring cases. In the context of treating a recurrent C. difﬁcile infection, we are confronted with a grand paradigm; the recurring infection is secondary to a disruption of the colonic microﬂora started by the antibiotic therapy and perpetuated by metronidazole or vancomycin. The antibiotics destroy the bacteria, but also destroy the intestinal microbiota, which is vital to maintaining health, immunity and colonic metabolism. The risk of recurrence is greater in patients with a previous recurrence, increasing by 20% after the ﬁrst episode, up to 40% with the ﬁrst recurrence and up to more than 60% after 2 recurrences4,9 . There is a decrease in the diversity of fecal microbiota in patients with recurrent diarrhea due to a C. difﬁcile infection. This decrease can be observed, for the most part, in the concentration of the specie Bacteroides and Fermicutes. Because of this, a treatment without antibiotics, preserving and restoring microbiotic diversity, can represent a new strategy to achieve the prevention and treatment of recurring C. difﬁcile infections10 . FMT has been demonstrated to be an effective alternative in the treatment of refractory C. difﬁcile infections, and is the most radical and direct method to change the composition of the colon microbiota2 . To perform a FMT, a feces sample from a healthy person is required. In our hospital we performed a simple questionnaire looking for a person without comorbidities, with an adequate BMI, who did not have any antecedent of previous hospitalization or use of antibiotics within the last 3 months. We performed general examinations (blood count, blood chemistry) a viral proﬁle (HBVAgs, Antibodies against HCV and HIV), a coprological is conducted as well as a single stool specimen ova and parasite examination and toxins A and B for C. difﬁcile in feces. Upon deciding that the patient with a C. difﬁcile infection is a candidate for FMT, the use of antibiotics was suspended for 48---72 h and a nasojejunal probe was placed and its adequate placement veriﬁed by simple X-rays. One day before the transplant, 4 packets of Nulitely (109.6 g each) were administered, each one diluted in 4 L of water.
193 On the day of the transplant a fecal material sample is requested from the donor in the morning, and laboratory personnel homogenize the sample in a saline solution and ﬁlter it, obtaining approximately 50 ml of microbiotic solution. The FMT is administered by means of the nasojejunal probe. In case it does not advance to the small intestine, an endoscope is used to instill the FMT directly into the duodenum. The case can be used as an alternate method of administering a colonoscopy, as the situation warrants. The therapy is considered to be effective when the diarrhea disappears after the administration of the FMT. The superiority of the FMT over treatment with antibiotics has been demonstrated in multiple publications. The series of cases show favorable responses in more than 90% of cases11 . Recently, a controlled randomized study was performed, comparing the effectiveness of FMT (n = 16) against treatment with antibiotics, observing the resolution of the disease in 94% of cases (3 patients received a double FMT infusion)12 . Now, there are studies that show its utility in seriously ill patients or immunosuppressed patients with recurring or refracting C. difﬁcile infections, observing a recovery in 89% (n = 80). In our center, we have used the FMT in refractory as well as recurring cases. For the most part, the patients are hospitalized and suffering from multiple comorbidities. We have obtained a resolution of diarrhea of 87%, and were able to avoid surgical management and reduce morbi-mortality in these patients. Recently, methods have been developed to freeze the microbiota for the FMT in capsules at −80C◦ and study its effects in cases of refractory C. difﬁcile infections, with an observed effectiveness of 90%13 . None of the studies have reported signiﬁcant side effects. Other uses that the FMT has been used for have been in patients with a C. difﬁcile infection and inﬂammatory bowel disease (IBD), including a therapeutic proposal in cases of refractory IBD1 . By what has been documented, we can conclude that the FMT has shown its usefulness in patients with a recurrent or refractory C. difﬁcile infection, and as a medical treatment even for patients that are seriously ill or with some degree of immunosuppression. With the increase in the incidence and severity of C. difﬁcile infections, the FMT has a very important role to play in the combating of this disease. Our experience underlines the fact that treatment with FMT in Mexico is a reality. The requirements for its implementation and the technical process are simple, bringing the option of a cure to the majority of patients managed with this therapy, which is free of antibiotics and serious adverse effects.
Funding No ﬁnancial support was provided.
Conﬂict of interest The authors have no conﬂicts of interest to declare.
References 1. Oldﬁeld EC IV, Oldﬁeld EC III, Johnson DA. Clinical update for the diagnosis and treatment of Clostridium difﬁcile infection. World J Gastrointest Pharmacol Ther. 2014;5:1---26.
194 2. Petrof A, Khoruts A. From stool transplants to next-generation microbiota therapeutics. Gastroenterology. 2014;146:1573---82. 3. Smits LP, Bouter KEC, de Vos WM, et al. Therapeutic potential of fecal microbiota transplantation. Gastroenterology. 2013;145:946---53. 4. Kelly CP, LaMont JT. Clostridium difﬁcile----more difﬁcult than ever. N Engl J Med. 2008;359:1932---40. 5. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difﬁcile infections. Am J Gastroenterol. 2013;108:478---98. 6. Khanna S, Pardi DS. Clostridium difﬁcile infection: management strategies for a difﬁcult disease. Therap Adv Gastroenterol. 2014;7:72---86. 7. Lo Vecchio A, Zacur GM. Clostridium difﬁcile infection: an update on epidemiology, risk factors, and therapeutic options. Curr Opin Gastroenterol. 2012;28:1---9. 8. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difﬁcile infection. N Engl J Med. 2011;364:422---31.
J. González-Altamirano et al. 9. Austin M, Mellow M, Tierney WM. Fecal microbiota transplantation in the treatment of Clostridium difﬁcile infections. Am J Med. 2014;127:479---83. 10. Chang JY, Antonopoulos DA, Kalra A, et al. Decreased diversity of the fecal microbiome in recurrent Clostridium difﬁcile-associated diarrhea. J Infect Dis. 2008;197: 435---8. 11. Gough E, Shaikh H, Manges AR. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difﬁcile infection. Clin Infect Dis. 2011;53:994---1002. 12. Van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difﬁcile. N Engl J Med. 2013;368:407---15. 13. Youngster I, Russell GH, Pindar C, et al. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difﬁcile infection. JAMA. 2014;312:1772---8.
RMU OFC 17(68).indd - Facultad de Medicina UANL
Vol. 17 Num. 68 July-September 2015
Vol. 17 Num. 68 July-September 2015 ISSN 1665-5796
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