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Boletín Médico del

EDITORIAL

249 Thoracoscopy using ultrasonic scalpel: importance in the etiologic study of interstitial lung disease in childrenLuis Jasso Gutiérrez

REVIEW ARTICLE

251 Efficacyandsafetyofomega3andomega6fattyacidsupplementationindevelopmentalneurologicaldisorders:systematicreviewAntonio Calderón-Moore, Mariel Pizarro-Castellanos, Antonio Rizzoli-Córdoba

RESEARCH ARTICLES

257 UseofultrasonicscalpelforpulmonarybiopsythroughthoracoscopyinpediatricpatientswithinterstitiallungdiseaseRicardo Villalpando Canchola, Esmeralda Piedra Buena Muñoz, Isis Beatriz Medel Morales, Edgar Morales Juvera, Gabriel Reyes García, Fortino Solórzano Santos

262 RiskfactorsassociatedwithretinopathyofprematurityinpreterminfantstreatedatatertiarylevelhospitalYolanda Vázquez Lara, Juan Carlos Bravo Ortiz, Claudia Hernández Galván, Narlly del Carmen Ruíz Quintero, Carlos Augusto Soriano Beltrán

268 AssociationofsteroidusewithweightgaininpediatricpatientswithrheumaticdiseaseSonia González-Muñiz, Donají Miranda-González, Miguel Ángel Villasís-Keever, Vicente Baca-Ruíz, Teresa Catalán-Sánchez, Patricia Yañez-Sánchez

275 Analysisofsociodemographicfeaturesofpatientswithend-stagechronicrenaldisease:differencesina6-yearperiodGuillermo Cantú, Graciela Rodríguez, Mercedes Luque-Coqui, Benjamín Romero, Saúl Valverde, Silvia Vargas, Alfonso Reyes-López, Mara Medeiros

CASE REPORTS

280 Bronchialmucoepidermoidcarcinoma:araretumorinchildrenLuis Hernández-Motiño, Yarisa Brizuela, Verónica Vizcarra, Rubén Cruz, Lourdes Jamaica, José Karam

284 Hermansky-Pudlaksyndrome:variableclinicalexpressionintwocases Rogelio Paredes Aguilera, Norma López Santiago, Angélica Monsiváis Orozco, Daniel Carrasco Daza, José Luis Salazar-Bailón

CLINICOPATHOLOGICAL CASE

291 NewbornwithhypoplasticleftheartsyndromeLuis Alexis Arévalo-Salas, Sandrino José Fuentes Alfaro, Jorge Omar Osorio Díaz, Begoña Segura Stanford, Mario Perezpeña Diazconti

Boletín Médico delHospital Infantil de México

BIMONTHLY PUBLICATIONVol. 69 July-August, 2012 No.4

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Boletín Médico del Hospital Infantil de México

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TOPICS IN PEDIATRICS

298 ShapinganewstrategyagainstB. pertussis:apublichealthprobleminMexicoLorena Suárez Idueta, Ilse Herbas-Rocha, César Misael Gómez Altamirano, Vesta Richardson López-Collada

VITAL STATISTICS

305 Mortalityduetodrowninginchildrenlessthan15yearsofageinMexico,1998-2010Sonia B. Fernández-Cantón, Ana María Hernández Martínez, Ricardo Viguri Uribe

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HEALTHEDUCATIONANDCLINICALETHICSJaime nieto zermeño2

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JoSé luiS arredondo García inStituto nacional de pediatría méxico d.F., méxico

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EDITORIALBOARD

249Vol. 69, July-August 2012

Departamento de Evaluación y Análisis de Medicamentos, Hospital Infantil de México Federico Gómez, México, D.F., México

Correspondence to:Dr. Luis Jasso GutiérrezJefe del Departamento de Evaluación y Análisis de MedicamentosHospital Infantil de México Federico GómezMéxico, D.F., MéxicoE-mail: [email protected]

Received for publication: 8-27-12Accepted for publication: 8-28-12

Thoracoscopy using ultrasonic scalpel: importance in the etiologic

study of interstitial lung disease in children

editorial

Bol Med Hosp Infant Mex 2012;69(4):249-250

Dr. Luis Jasso Gutiérrez

Interstitial lung disease (ILD) may present itself in children of any age. However, it is most frequent during the first 2 years of life and has a mortality

rate of ∼30%. The principal causes are lung injuries or problems in lung development which, in good measure, explains its frequency at this age and does not occur in children of other ages. In past years, identifying a patient and establishing a specific diagnosis has been a challenge for pulmonologists, radiologists and pediatric pathologists as well as for neonatologists and internists.1 Among the principal and most frequent causes are diffuse developmental anomalies such as the case of congenital alveolar dysplasia, disorders of lung growth as well as chronic pulmonary disease of prematurity, pulmonary interstitial glycogenosis, hyperplasia of neuroendocrine cells of infancy, dysfunction of the alveolar surfactant T and E, host disorders (such as infections, hypersensitiv-ity or aspiration), systemic diseases such as metabolic disorders, and collagen or autoimmune disorders, among others. Independent of the causes, ILD can affect, in ad-

dition to the interstitium, different compartments of the lung such as airways, alveolar space, lymphatic channels and pleura. For this reason, the term diffuse parenchymal lung disease was coined.2

From the clinical viewpoint, its common manifesta-tions are tachypnea, exercise intolerance, growth delay, cyanosis, resting dyspnea and, dependent on the time of evolution, Hippocratic fingers. After clinical suspicion and according to each case, it is necessary to perform chest x-ray, high-resolution computed tomography, bronchoscopy (that may include bronchial washings for investigation of microorganisms or for genetic analysis of its content), pulmonary function tests and, when required, lung biopsy.

With respect to lung biopsy, in the article published in the present number of Boletin Medico del Hospital Infantil de Mexico (BMHIM) by Villalpando et al., five cases are described in a retrospective series of children subjected to lung biopsies using thoracoscopy with three working ports and ultrasonic scalpel during a 12-month period.3 According to the authors' description, at least in these five cases the result was satisfactory. For this reason we believe that this innovation with respect to other techniques used in thoracoscopy is the safest due to scant bleeding and to the effect of aerostasia (absence of air leak). Although the results were satisfactory, it would be appropriate to increase the size of the sample to verify the findings. Also, the results could be compared with experiences of thora-coscopies performed in children using other methods.4

It should be mentioned that, for the general pediatrician, minimally invasive thoracoscopy is not only useful for lung biopsies but also for aortopexies, repair of congenital diaphragmatic hernias, excision of bronchogenic cysts,

250 Bol Med Hosp Infant Mex

Luis Jasso Gutiérrez

and exploratory thoracotomy or ligatures of the ductus arteriosus, among other important procedures.5,6

REFERENCES

1. Deutsch GH, Young LR, Deterding RR, Fan LL, Dell SD, Bean JA, et al. Diffuse lung disease in young children: application of a novel classification scheme. Am J Respir Crit Care Med 2007;176:1120-1128.

2. Deterding RR. Infants and young children with children’s interstitial lung disease. Pediatr Allergy Immunol Pulmonol 2010;23:25-31.

3. Villalpando CR, Piedra BME, Medel MIB, Morales JE, Reyes GG, Solórzano SF. Uso del bisturí ultrasónico para la toma de

biopsias pulmonares por toracoscopia en pacientes pediátricos con enfermedad pulmonar intersticial. Bol Med Hosp Infant Mex 2012;69:257-261

4. Ponsky TA, Rothenberg SS. Thoracoscopic lung biopsy in infants and children with endoloops allows smaller trocar sites and discreet biopsies. J Laparoendosc Adv Surg Tech A 2008;18:120-122.

5. Ponsky TD, Rothenberg S, Tsao KJ, Ostlie DJ, St Peter SD, Holcomb GW. Thoracoscopy in children: is a chest tube necessary? J Laparoendosc Adv Surg Tech A 2009;19(suppl 1):S23-S25.

6. Glüer S, Schwerk N, Reismann M, Metzelder ML, Nustede R, Ure BM, et al. Thoracoscopic biopsy in children with diffuse parenchymal lung disease. Pediatr Pulmonol 2008;43:992-996. doi: 10.1002/ppul.20896.


Efficacy and safety of omega 3 and omega 6 fatty acid supplementation

in developmental neurological disorders: systematic review

review article


Antonio Calderón-Moore1, Mariel Pizarro-Castellanos2, Antonio Rizzoli-Córdoba3

AbSTRACT

background. Available information on clinical guidelines and review articles is controversial and is insufficient to determine the clinical efficacy of supplementation with omega 3 and omega 6 fatty acids in neurodevelopmental disorders. Additional treatment may be effective for treatment of these disorders. methods. We conducted a systematic review based on the guidelines of the Cochrane group by searching for clinical trials in MEDLINE, COCHRANE DATABASE in the time interval 1990 to 2011, in English and Spanish, and in pediatric patients that comply with the informa-tion required by the CONSORT group. One hundred and two articles were obtained; 97 articles were excluded choosing five randomized, double-blind, placebo-controlled trials to perform the review. Results. In the trials analyzed we found no significant difference in the improvement of ADHD symptoms between placebo group and the intervention, but there was clear clinical improvement. No serious adverse events were reported. There are no similar characteristics in the reviewed articles to carry out a meta-analysis and accurate assessment of the effectiveness of supplementation. Conclusions. With the results of this systematic review, we cannot state categorically that the use of this supplementation is significantly effective due to the different characteristics of the studies described above. However, due to clinical improvement and adequate safety profile, it may be useful without replacing pharmacological treatment.Key words: essential fatty acids, omega 3, omega 6, attention deficit disorder.

1 Departamento de Pediatría, 2 Departamento de Neurología Pediátrica, 3 Dirección de Investigación, Hospital Infantil de México Federico

Gómez, México, D.F., México

Correspondence: Dr. Antonio Rizzoli-CórdobaDirección de InvestigaciónHospital Infantil de México Federico Gómez México, D.F., México E-mail: [email protected]


INTRODuCTION

According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), neurodevelopmental disorders are classified in Axis I, which are the clini-cal disorders that do not involve a syndrome. Among these are the Attention Deficit Hyperactivity Disorder (ADHD) and Developmental Coordination Disorder (DCD).1 Characteristics of attention deficit disorders are mismatching, inattention and impulsivity–hyperactivity.

The recommended treatment options for ADHD include pharmacological therapy with and without stimulant medications, and nonpharmacological treatment, mainly behavioral therapy.2 The base treatment for DCD consists of the acquisition of skills and problem solving, although there is no established pharmacological treatment for this disorder. Essential long-chain fatty acids are those that the body cannot synthesize or are synthesized in small amounts, so there is a need for dietary supplementation to meet the metabolic functions that they perform such as forming an important part of the cell membrane.

At present, according to the French Agency for Food Sanitary Safety (AFSSA), the diet in developed countries provides sufficient concentrations of omega 6 and very low omega 3, with an omega 6/omega 3 ratio insufficient for the proper functioning of neuroconduction.3

Long-chain polyunsatured fatty acids (LC-PUFAs) are metabolically very active. The highest concentrations of these are found in the central nervous system (CNS), predominantly in the neuronal membranes. The most abundant is docosahexaenoic acid (DHA), which mainly participates in neuronal synapses where it intervenes in


Antonio Calderón-Moore, Mariel Pizarro-Castellanos, Antonio Rizzoli-Córdoba

neuronal signaling and formation of neurotransmitters, increasing neuronal permeability through the activation of sodium channels, and eicosapentaenoic acid (EPA), which is the precursor of DHA and an important activator of me-tabolism in the CNS. In addition, it favors the generation of eicosanoids and cytokines.4 The relationship between LC-PUFA deficiency and hyperactivity was initially pro-posed by Colquhoun and Bunday.5 In 1995, Stevens et al. suggested a link between the deficiency of omega 3 and omega 6 and ADHD, learning disabilities, reading disor-ders, dyspraxia and ADHD-related symptoms.6,7

In most neurodevelopmental disorders, first-line treat-ment is pharmacological. However, up to 20% of the patients with ADHD with pharmacological therapy have side effects that hinder its effects, causing distrust in parents over their use and resulting in treatment discon-tinuation. As mentioned previously, DCD patients have no established drug treatment.

It has been suggested that supplementation with omega 3 and omega 6 can function as an additional treatment to those treatments already established, for improvement of the clinical status of patients with ADHD and DCD.

Some authors have suggested that children with ADHD, with and without a learning problem, respond differently to fatty acid supplementation. A higher response was ob-served in those children with learning disabilities.8 It has even been suggested that some combinations of omega 3, omega 6, zinc and magnesium may be beneficial for these patients. Huss et al. suggested that these combinations have beneficial effects on attention and on behavioral and emotional problems in children and adolescents with this type of disorder.9 There are research groups who have reported that there is no hard evidence to justify this type of supplement; therefore, they do not recommend omega 3 and omega 6 as adjuvant treatment options for ADHD.10

Information available in clinical guidelines and review articles are controversial and insufficient. Therefore, the objective of this review was to assess the available infor-mation on the efficacy and safety of supplementation with omega 3 and omega 6 for neurodevelopmental disorders using a systematic review of the literature.

mATERIALS AND mETHODS

A systematic review was conducted based on the guide-lines of the Cochrane systematic reviews,11 in Medline/

PubMed database, Cochrane Database and Artemis, and references of retrieved articles published between 1990 and 2011. The search was limited to clinical trials con-ducted in English and Spanish by a pediatric group. Studies were randomized and double-blind comparison was made between administration of essential fatty acids and placebo administration, which evaluate the clinical efficacy as well as safety of the intervention described. We sought clinical trials that complied with the required information in the articles of clinical trials, developed by the CONSORT Group (Consolidated Standards of Reporting Trials) in 2010.12 From the research done by two reviewers, 102 articles were obtained. Of these, we selected five clinical trials that met the requirements established initially to perform the review.

RESuLTS

The design of the five articles analyzed was randomized, double-blind, placebo-controlled clinical trials (Table 1).3,7,13-15 In four of the five articles, the effect of fatty acid supplementation in children with ADHD and symptoms related to it was analyzed, whereas one study examined the effect on children diagnosed with DCD. Interventions performed, supplement given, doses and time of admin-istration were different in all studies, ranging from 2–6 months (Table 1).

To evaluate the effectiveness of the supplement, the methods and scales used in the articles were diverse. No significant difference was found in improving ADHD symptoms between the placebo group and interventional group (Table 2). However, when assessing the clinical response in the intervention group, significant clinical improvement was found. Because this improvement was so significant, parents decided to continue with the PU-EFAs supplement after study completion.

In the study conducted by Sinn et al. where a com-bination of EPA, DHA, γ-linolenic acid and vitamin E (558 mg of EPA + 174 mg of DHA + 60 mg γ-LA + 10.8 mg of vitamin E daily, for 15 weeks) was administered, a statistically significant difference was demonstrated between groups (supplement and placebo) in the Con-ners test for parents, with improvement of more than one standard deviation (SD) in 30 to 40% of children. In the second phase, the same intervention was performed in both groups and clinical improvement was found in Conners


Efficacy and safety of omega 3 and omega 6 fatty acid supplementation in developmental neurological disorders: systematic review

test in all groups with supplement, with a decrease of >1 SD in 40 to 50% of the children. However, no significant difference was observed in the Conners test given to the teachers.7 Likewise, Johnson et al. found a favorable clinical response (not statistically significant) in the sub-group of patients with predominantly inattentive ADHD (26%). This group showed a reduction in symptoms of <25% in the ADHD-RS (Attention Deficit Hyperactiv-ity Disorder-Rating Scale). Within the same group, 12% showed a 50% reduction of symptoms after 3 months of treatment. At the end of the study, after 6 months of treat-ment, symptoms were reduced by 47% of the participants. Of these, seven (12%) had a reduction of >50% in their symptoms.13 Upon analyzing the safety of administration of the supplementation, no adverse effects were reported. Adverse effects were observed only in the gastrointestinal system (diarrhea and dyspepsia) in three patients, with no clinical compromise.

DISCuSSION

As discussed above, there are no similar features in the ana-lyzed studies to perform a meta-analysis and an accurate assessment of the effectiveness of supplementation with LC-EPAs, omega 3 and omega 6 in neurodevelopmental disorders.

The articles reviewed showed a wide age range (6–18 years). The supplement with which the intervention was made, its dose and time of administration ranged from 2 to 6 months. Methods of evaluation of the efficacy were diverse. This does not allow us to compare results between studies or to measure the effectiveness of the supplement used.

Although no statistically significant differences were found in the articles that evaluated the effectiveness of the supplement in ADHD patients, between the intervention group and the placebo group, there was obvious clinical improvement, mainly in the areas of hyperactivity/impul-sivity, inattention and coordination disorders.

The combination most used and recommended for improvement of symptoms of ADHD is essential polyun-saturated fatty acids omega 3 (EPA, DHA) and omega 6 (arachidonic acid and γ-LA). The most commonly used dose is 558 mg of EPA + 174 mg of DHA + 60 mg γ-LA + 10.8 mg vitamin E/day.

Clinical improvement observed in the areas of hyperac-tivity/impulsivity, inattention and coordination disorders, although not statistically significant, was sufficient to encourage parents to continue with the treatment of supplemental essential long-chain fatty acids, omega-3 and omega 6, even after completion of studies. This is coupled with its safety and no significant adverse effects.

Based on the results of this systematic review, we can-not categorically state that supplementation with essential long-chain fatty acids of omega 3 and omega 6 in neuro-developmental disorders present significant efficacy due to the different characteristics of the previously described studies. Although only statistically significant differences were shown in reading and spelling skills in the placebo group and the supplement group, it is suggested, for clini-cal improvement in other aspects such as hyperactivity/impulsivity and inattention, the possibility of supple-menting with omega 3 essential fatty acids and omega 6 when these symptoms predominate in the patient. For this reason, and an appropriate safety profile, the treatment may be useful in children with ADHD and DCD with the

Table 1. Differences between type of supplement, dose and time of administration

Author (year) Intervention Dose (per day) Time of administration

Sinn, et al (2007)7 EPA + DHA + GLA + Vit E 558 mg EPA + 174 mg DHA + 60 mg GLA + 10.8mg Vit E

Two periods, one of 15 and another of 30 weeks

Jonhson, et al (2008)13 EPA + DHA + GLA + Vit E 558 mg EPA + 174 mg DHA + 60 mg GLA + 10.8 mg Vit E

Two periods, each of 3 months

Hirayama, et al (2004)14 DHA + EPA 100 mg EPA + 514 mg DHA

One period of 2 months

Voigt, et al (2001)15 DHA 345 mg DHA One period of 4 months

Richardson, et al (2005)3

(en DCD)EPA + DHA + GLA + Vit E 558 mg EPA + 174 mg DHA +

60 mg GLA + 9.6 mg Vit ETwo periods, each of 3 months

EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; GLA, gamma-linoleic acid; Vit E, vitamin E; DCD, developmental coordination disorder.



Table 2. Description of analyzed studies

Author (year) Population Groups Intervention Evaluation Results

Sinn (2007)7

ADHD

First stage (15 weeks)

n=104

PUFA + MVM n=41

558 mg EPA + 174 mg DHA + 60 mg

GLA + 10.8 mg vit E/day + MVM

Conners scale, parentsImprovement in inattention, impulsivity,

and hyperactivity in >1 SD in 30-40% of children

Conners scale, teachers Without significant improvement

PUFAn=36

558 mg EPA + 174 mg DHA + 60 mg GLA + 10.8 mg vit

E/day

Conners scale, parentsImprovement in inattention, impulsivity

and hyperactivity in >1 SD in 30-40% of children

Conners scale, teachers Without significant improvement

Placebon=27

Placebo Conners scale Without significant improvement

Second stage (30 weeks)

n=87PUFA +

MVM

558 mg EPA + 174 mg DHA + 60 mg

GLA + 10.8 mg vit E/day +MVM

Conners scale, parentsImprovement of 40-50% of patients in regard to symptoms of inattention and

hyperactivity/impulsivity

Voigt (2001)15

ADHDn= 54

DHAn=27

345 mg/day DHA for 4 months

TOVA (omission/

commission)

Increase of 3 SD in errors of omission, decrease of 1 SD in errors of commis-

sion, time of response with increase of 2 SD (NS)

CCTTDecrease of time of carrying out test 1 of

2 SD and of 3 SD in test 2 (NS)

Placebon=27

PlaceboCBCL

Decrease in internalization of 2 SD, outside behavior of 2 SD, socialization of 3 SD, thought processes of 2 SD,

inattention 1.5 SD (NS)

Conners No results shown (NS)

Hirayama (2004)14

ADHD n=40

DHAn=20

3,600 mg DHA+700 mg EPA/week for 2

months

Attention No results shown (NS)

Auditory and visual memory

Without increase in number of remembered objects

Visuomotor integration Increase of 9 points in regard to normal age

Placebon=20

Olive oilContinuity

Without changes in errors of omission or commission

Impatient Decrease of number of errors in 1

Johnson (2008)13

ADHD

First stage (3 months)

n=75PUFAn=37

558 mg EPA + 174 mg DHA/day, 60 mg GLA, 10.8 mg Vit E

ADHD-RS-IV26% presented >25% reduction in score and 12% presented >50% reduction in

score

Placebon=38

Olive oilADHD-RS-IV 7% presented >25% improvement in

score

Second stage (3 months)

n=59 AGPI558 mg EPA + 174

mg DHA/day, 60 mg GLA, 10.8 mg Vit E

TDAH-RS-IV 47% improved their score and of these, 12% improved in >50% of symptoms


Efficacy and safety of omega 3 and omega 6 fatty acid supplementation in developmental neurological disorders: systematic review

Richardson (2005)3

DCD

First stage (3 months)

n= 117PUFAn=60

558 mg EPA + 174 mg DHA + 60 mg

GLA + 9.6 mg Vit E

Motor function (MABC)Increase of score from 6th to 12th per-

centile (NS)

Reading and spelling(WORD)

Increase in 1 SD in writing (z = 2.87, p <0.004) and 0.5 SD in spelling (z =3.36,

p <0.001)

ADH symptoms teachersCTRS-L

Decrease of >0.5 SD (z =5.48, p <0.0001)

Placebon=57

Olive oil

Motor function (MABC) Without changes

Reading and Spelling(WORD)

Slight improvement (<0.5 SD)

ADH symptoms teachersCTRS-L

Without changes

second stage (3 months)

n=100558 mg EPA + 174 mg DHA + 60 mg

GLA + 9.6 mg Vit E

Motor function (MABC) Without changes

Reading and spelling(WORD)

Increase in 0.5 SD in writing and spelling

ADH symptoms (teachers)CTRS-L

Decrease of <0.5 SD

ADHD, attention deficit-hyperactivity disorder; DCD, developmental coordination disorder; PUFA, polyunsaturated fatty acid; MVM, multivi-tamins/minerals; vit E, vitamin E; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; GLA, gamma-linoleic acid; MABC, movement assessment battery of children; SD, standard deviation; TOVA, test of variables of attention; CCTT, children’s color trails test; CBCL, child behavior check list; NS, results not shown.

Table 2. Description of analyzed studies

Author (year) Population Groups Intervention Evaluation Results

predominant symptoms mentioned, without replacing the first-line medical treatment.

Further studies should be conducted to evaluate the efficacy of essential fatty acids omega 3 and omega 6 in ADHD and DCD, following clinical characteristics, inter-vention models, and the type and timing of interventional studies undertaken in order to achieve a proper analysis of the results and to make them comparable to each other.

REFERENCES

1. López-Ibor AJ, Valdés MM, Flores I FT. DSM-IV-TR. Manual Di-agnóstico y Estadístico de los Trastornos Mentales. Barcelona: Masson Elsevier; 2003. Available at: http://148.228.156.172/DSMIV/DSMIV/CREDITOS.PDF

2. Floet AM, Scheiner C, Grossman L. Attention-deficit/hyperac-tivity disorder. Pediatr Rev 2010;31:56-69.

3. Richardson AJ, Montgomery P. The Oxford-Durham Study: a randomized, controlled trial of dietary supplementation with

fatty acids in children with developmental coordination disorder. Pediatrics 2005;115:1360-1366.

4. Das UN. Long-chain polyunsaturated fatty acids in the growth and development of the brain and memory. Nutrition 2003;19:62-65.

5. Colquhoun I, Bunday S. A lack of essential fatty acids as a possible cause of hyperactivity in children. Med Hypothesis 1981;7:673-679.

6. Stevens LJ, Zentall SS, Deck JL, Abate ML, Watkins BA, Lipp SR, et al. Essential fatty acid metabolism in boys with attetion-deficit hyperactivity disorder. Am J Clin Nutr 1995;62:761-768.

7. Sinn N, Bryan J. Effect of supplementation with polyunsatu-rated fatty acids and micronutrients on learning and behavior problems associated with child ADHD. J Dev Behav Pediatr 2007;28:82-91.

8. Milte CM, Sinn N, Buckley JD, Coates AM, Young RM, Howe PR. Polyunsaturated fatty acids, cognition and literacy in chil-dren with ADHD with and without learning difficulties. J Child Health Care 2011;15:299-311.

9. Huss M, Völp A, Stauss-Grabo M. Supplementation of polyun-saturated fatty acids, magnesium and zinc in children seeking medical advice for attention-deficit/hyperactivity problems—an observational cohort study. Lipids Health Dis 2010;9:105.



10. Aben A, Danckaerts M. Omega-3 and omega-6 fatty acids in the treatment of children and adolescents with ADHD. Tijdschr Psychiatr 2010;52:89-97.

11. Davey J, Turner RM, Clarke MJ, Higgins JP. Characteristics of meta-analyses and their component studies in the Co-chrane Database of Systematic Reviews: a cross-sectional, descriptive analysis. BMC Med Res Methodol 2011;11:160. doi:10.1186/1471-2288-11-160.

12. Schulz K, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. PLoS Med 2010;7:e1000251. doi:10.1371/journal.pmed.1000251.

13. Johnson M, Ostlund S, Fransson G, Kadesjo B, Gillberg C. Omega-3/omega-6 fatty acids for attention deficit hyperactivity disorder: a randomized placebo-controlled trial in children and adolescents. J Atten Disord 2009;12:394-401.

14. Hirayama S, Hamazaki T, Terasawa K. Effect of docosahexae-noic acid-containing food administration on symptoms of attention-deficit/hyperactivity-disorder—a placebo-controlled double-blind study. Eur J Clin Nutr 2004;58:467-473.

15. Voigt RG, Llorente AM, Jensen CL, Fraley JK, Berreta MC, Heird WC. A randomized, double-blind, placebo-controlled trial of docosahexanoic acid supplementation in children with atten-tion-deficit/hyperactivity disorder. J Pediatr 2001;139:189-196.


use of ultrasonic scalpel for pulmonary biopsy through thoracoscopy in

pediatric patients with interstitial lung disease

research article


Ricardo Villalpando Canchola,1 Esmeralda Piedra Buena Muñoz,2 Isis Beatriz Medel Morales,2 Edgar Morales Juvera,3 Gabriel Reyes García,4 Fortino Solórzano Santos5

AbSTRACT

background. Diagnosis of interstitial lung disease (ILD) in children is challenging. Open lung biopsy was long considered to be the best procedure to obtain lung tissue in children. Thoracoscopic biopsy may be equally effective and less aggressive. In this report we analyze the results of the use of ultrasonic scalpel with the placement of three 5-mm trocars (one for thoracoscope and two working ports) for lung biopsy through thoracoscopy.methods. We present a retrospective case series of children undergoing lung biopsy through thoracoscopy using three working ports and ultrasonic scalpel. The study was carried out from January 2011 to January 2012 in a third-level pediatric hospital.Results. A total of five patients aged 1 to 13 years were included. There were no complications in the five cases analyzed. The sample ob-tained was sufficient in all cases for histopathological study. During surgery, bleeding was reported on average of 4.3 ml (range: 0.5–10 ml). Operative time ranged from 2 to 3 h. Two cases required chest tube placement. These were removed 2 to 3 days after the surgical event, and patients were discharged without complications.Conclusions. Feasibility is confirmed of a technique for lung biopsy using an ultrasonic scalpel, which is easily reproducible in any hos-pital with the necessary resources to perform thoracoscopy. In this series there were no complications, bleeding was low and there was opportune placement of transpleural chest tube. Key words: lung biopsy, ultrasonic scalpel, interstitial lung disease.

1 Cirugía de Tórax, 2 Residente de Cirugía Pediátrica, 3 Servicio de Urología, 4 Servicio de Gastrocirugía, 5 Pediatría Médica, Unidad Médica de Alta Especialidad Hospital

de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexi-cano del Seguro Social, México D.F., México

Correspondence: Dr. Ricardo Villalpando CancholaCirugía de Tórax, Unidad Médica de Alta EspecialidadHospital de Pediatría, Centro Médico Nacional Siglo XXIInstituto Mexicano del Seguro SocialMéxico D.F., MéxicoE-mail: [email protected]


INTRODuCTION

Diagnosis of interstitial lung disease (ILD) in infancy constitutes a real challenge for the pediatrician.1 Within the term ILD, a very heterogeneous group of subacute and chronic lung diseases are grouped that share in common the production of chronic inflammatory process with a diffuse

lesion of the lung parenchyma, affecting the interstitium, epithelium, alveolar spaces and capillary endothelium. Because the interstitium is not affected alone, and the term pulmonary interstitial disease can cause some confusion, some authors prefer to refer to these groups as diffuse parenchymatous lung disease.2 The clinical picture is predominantly characterized by tachypnea, hypoxia and diffuse pulmonary infiltrates. Other pathologies also are taken into consideration for the differential diagnosis such as some infections, chronic aspiration, some cardiac dis-eases and pulmonary vascular disease.3 ILD is less frequent in children than in adults, but with higher comorbidities and mortality.4,5 By the time of development, it can be defined as either acute or chronic (lasting >6 months), and of known cause, unknown (idiopathic) or associated with other processes.

From the histopathological point of view, the most widely used classification is based on the predominant cell type involved in thickening of the alveolar wall, so it can be usual interstitial pneumonia, desquamative interstitial pneumonia, giant cell interstitial pneumonia, plasma cell interstitial pneumonia, interstitial lymphoid pneumonia or


Ricardo Villalpando Canchola, Esmeralda Piedra Buena Muñoz, Isis Beatriz Medel Morales, Edgar Morales Juvera, Gabriel Reyes García, Fortino Solórzano Santos

bronchiolitis obliterans with interstitial pneumonia. The histological appearance of usual interstitial pneumonia is large heterogeneous lesions from alveolar inflammation to diffuse interstitial fibrosis. During lung biopsy (LB), lesions may be seen in various stages of development with other areas of apparently healthy lung. It is very rare in children; therefore, many of the cases would be diagnosed today as nonspecific interstitial pneumonitis.7, 8 Desquamative interstitial pneumonitis is characterized by an inflammatory process, initially homogeneous, and with abundant intraalveolar macrophage. This disease, although rare, is well characterized in children. Most cases have been reported in children <1 year of age, and no association has been found with smoking (typical of the adult type). The mortality rate of this disease is high. There have been familial cases of desquamative interstitial pneumonia described during lactation, with a generally fatal outcome, but which respond to treatment with chlo-roquine.9 Lymphoid interstitial pneumonitis is closely related to HIV infection and connective tissue diseases. This disease is characterized by interstitial infiltration of a group of polyclonal lymphocytes and plasma cells.10 More recently, the term chronic pneumonitis of infancy has been introduced to refer to a specific histological pattern that appears in some infants with ILD. In these patients, LB is characterized by a marked thickening of the alveolar septa, significant hyperplasia of alveolar pneumocytes and alveolar exudate containing numerous foci of macrophages and eosinophilic waste.11

With regard to its etiology, there are multiple agents and diseases that can cause ILD. It may be of infectious, metabolic, toxic, or degenerative origin, among others.6 Therefore, different diagnostic methods are required to attempt to define the cause associated with the ILD such as imaging studies, nuclear medicine, non-invasive or invasive microbiological studies, endoscopic studies and pulmonary function tests.12–18

Treatment decisions involving ILD justify obtaining an accurate diagnosis using histological studies. Therefore, it is considered that LB is the technique of choice for diag-nosis of this entity. LB was widely considered for a long time as the best procedure to obtain lung tissue in children even when compared with transbronchial biopsy whose usefulness in children is controversial because of the small sample size obtained, which is sometimes insufficient to establish a diagnosis. Thoracoscopic biopsy can be equally

effective and less aggresive.19-23 Although minimally invasive surgery has more than 10 years at the forefront, the experience with obtaining biopsies thoracoscopically in pediatric patients is limited. The aim of this study was to present the results of the experience with a modified technique using the ultrasonic scalpel in performing the procedure.

mATERIALS AND mETHODS

We retrospectively analyzed cases in which LB was done through thoracoscopy using three working ports and ultrasonic scalpel during the period from January 2011 to January 2012. Sociodemographic characteristics were recorded for patients, length of hospital stay and compli-cations that occurred during surgical events. In all cases we obtained written informed consent and authorization for surgery and anesthesia prior to initiation of the surgi-cal approach.

Technique for Thoracoscopic biopsy

The procedure was performed under general anesthesia with endotracheal intubation. The patient was placed in lateral decubitus position. A 5-mm port was placed at the mid-axillary line in the fifth intercostal space to access the pleural cavity and CO2 gas was insufflated at low flow and pressure to help collapse the lung. A 30◦ lens was intro-duced, the site of the lung parenchyma where the biopsy was to be obtained was identified and the site of insertion of the two 5-mm working ports was determined to opti-mize the approach. Through one of the working ports a thoracoscopy grasper was introduced and an extreme of the pulmonary parenchyma was grasped (Figure 1). Through a third 5-mm working port, the ultrasonic scalpel was introduced and a cut of the parenchyma was done (Figure 2). The parenchyma was able to be extracted with the same forceps through the trocar orifice. Where there was any bleeding present, cauterization was performed with the ultrasonic scalpel. If there was any residual bleeding, the scalpel was removed so as to introduce a needle holder and place a transfixing suture of 3-0 polypropylene. In the case of major bleeding that warranted the placement of sutures, a chest tube was left in place due to the risk of postopera-tive bleeding. Subsequent evolution was monitored. In the absence of bleeding or air leak data, the chest tube was removed during the following 48-72 h after surgery.


Use of ultrasonic scalpel for pulmonary biopsy through thoracoscopy in pediatric patients with interstitial lung disease

RESuLTS

Included in the analysis were five patients with a median age of 9 years (1–13 years). No cases presented intra- or postoperative complications. The material obtained from the biopsy was considered sufficient in all cases by the pathology department (Figure 3). Perioperative bleeding was at minimum 0.5 ml and at maximum 10 ml. Median operative time was 2 h 15 min (range: 2–3 h). In two of the cases, placement of a chest tube was required, which was removed after 2 days in one patient and 3 days after surgery in the other patient. In all cases, therapeutic behav-ior was modified in accordance with the histopathological report of the LB (Table 1). One case presented neoplastic disease. The remaining four were of infectious etiology.

Figure 1. Tissue obtained with thorascopic grasper.

Figure 2. Cut with ultrasonic scalpel.

Figure 3. Final sampling of the biopsied pulmonary tissue without evidence of residual bleeding.

DISCuSSION

Obtaining an LB was a procedure that was considered to be invasive for many years and remained as a last resort. However, it is recognized that with LB the etiology, extent, severity and aggressiveness of disease can be verified.24 LB is carried out at the end of a sequence of decisions and diagnostic procedures, not as the first choice. However, in many instances, this has as a consequence a delayed diagnosis and treatment, which may further deteriorate the patient’s prognosis.25

It is believed that in order to have a useful biopsy, the tissue must be representative of the problem it seeks to explore. The ideal situation is a biopsy performed by an experienced thoracic surgeon who is familiar with the patient and is aware of the diagnostic possibilities. Hence, the surgeon’s experience during intraoperative lung evalu-ation and of the possible pathological processes involved will permit the surgeon to obtain tissue representative in quality and quantity, without incipient or advanced al-terations that result in being nonspecific. This will allow for an appropriate diagnosis to be made from the tissue obtained. Also, it will be able to be determined at which time tissue can be provided for cultures or special studies. LB does not tend to be a procedure that allows for repeti-tions. Therefore, perhaps more than other tissues obtained for biopsy, it is of particular importance that the tissues be managed carefully and appropriate measures used to optimize their informative value.26

For a long time, open LB was considered to be a major procedure to obtain lung tissue in children. Contraindica-


Ricardo Villalpando Canchola, Esmeralda Piedra Buena Muñoz, Isis Beatriz Medel Morales, Edgar Morales Juvera, Gabriel Reyes García, Fortino Solórzano Santos

Thus, the present study confirms the feasibility of a technique for sampling using the ultrasonic scalpel. This technique is easily reproducible in any hospital that has the resource. Through the thoracoscopic technique and three-port technique with the ultrasonic scalpel, sufficient samples can be obtained without major invasion or dete-rioration of the patient with ILD. Although there were only five cases reported, there were very few complications, bleeding was low and the effect of aerostasia was managed in a timely manner.

It is recommended that the skills and ability to practice this technique be acquired, and its use encouraged in other hospitals in Mexico.

REFERENCES

1. Barbato A, Panizzolo C, Cracco A, de Blic J, Dinwiddie R, Zach M. Interstitial lung disease in children: a multicentre survey on diagnostic approach. Eur Respir J 2000;16:509-513.

2. Glaspole I, Conron M, Du Bois RM. Clinical features of diffuse parenchymal lung disease. Eur Respir Mon 2000;14:1-14.

3. Sondheimer HM, Lung MC, Brugman SM, Ikle DN, Fan LL, White CW. Pulmonary vascular disorders masquerading as interstitial lung disease. Pediatr Pulmonol 1995;20:284-288.

4. Fan LL, Deterding RR, Langston C. Pediatric interstitial lung disease revisited. Pediatr Pulmonol 2004;38:369-378.

5. Fan LL, Kozinetz CA. Factors influencing survival in children with chronic interstitial lung disease. Am J Respir Crit Care Med 1997;156:939-942.

6. Hilman BC. Interstitial lung disease in children. In: Hilman BC, ed. Pediatric Respiratory Disease: Diagnosis and Treatment. Philadelphia: WB Saunders; 1993.

7. Villa Asensi JR. Diagnóstico de la enfermedad pulmonar inter-sticial en la infancia. An Pediatr (Barc) 2001;54(suppl 2):9-13.

8. Wert SE, Whitsett JA, Nogee LM. Genetic disorders of surfac-tant dysfunction. Pediatr Dev Pathol 2009;12:253-274.

9. Balasubramanyan N, Murphy A, O’Sullivan J, O’Connell EJ. Familial interstitial lung disease in children: response to chlo-roquine treatment in one sibling with desquamative interstitial pneumonitis. Pediatr Pulmonol 1997;23:55-61.

tions for open LB via thoracotomy are essentially surgical. The patient must be in optimal clinical and laboratory condition to be able to cope with the surgical procedure with the least possible risk.20 Transbronchial LB is a procedure that, up to a certain point, is considered blind and with a greater risk of complications. Indication for a transbronchial biopsy is geared for the most part towards infectious and acute processes and is contraindicated in chronic interstitial diseases as its discriminatory value in these situations is limited. The usefulness of a trans-bronchial biopsy in young children is debatable due to the reduced size of the sample obtained because, in most cases, it is insufficient to establish a diagnosis. In a study in which percutaneous needle biopsies with an 18-gauge needle guided by high-resolution CT were used, histologi-cal diagnosis was achieved in only 58% of the cases.23,27

In pediatrics, LB is a standard diagnostic method for ILD. At present there is the possibility of offering the patient the thoracoscopic procedure, which carries the basic principles and benefits that endoscopic surgery has demonstrated during the last decades. With respect to surgical technique, the current reports encourage the practice of obtaining biopsies by means of pre-knotted loops (Endoloop) or mechanical sutures (stapler) with the disadvantage of displacement of the pre-knotted loop when the lung is re-expanded or the size of the stapler, which makes it inadequate for pediatric patients.28

Based on the results of the five cases reported, it is considered that the technique described in this study is the safest because of the small amount of bleeding and the effect of the aerostasia (no air leak) with the use of the described instrument. In these cases, placement of chest tube is optional. If placed, it should always be removed within <72 h. This indicates lower morbidity for the pa-tient, ensuring a speedy postoperative recovery.

Table 1. General characteristics of pediatric patients subjected to pulmonary biopsy with thorascopy using ultrasonic scalpel

Case Age(years)

Complications Sufficientsample

Bleeding(ml)

Surgical time(h)

Pleural tube

Removal of tube (days)

Modification of postsurgical therapy

1 1 No Yes 0.5 2.25 No — Yes

2 13 No Yes 1 2 No — Yes

3 9 No Yes 5 2.5 No — Yes

4 1 No Yes 10 3 Yes 3 Yes

5 12 No Yes 5 2 Yes 2 Yes


Use of ultrasonic scalpel for pulmonary biopsy through thoracoscopy in pediatric patients with interstitial lung disease

20. Coren ME, Nicholson AG, Goldstraw P, Rosenthal M, Bush A. Open lung biopsy for diffuse interstitial lung disease in children. Eur Respir J 1999;14:817-821.

21. Hilman BC, Amaro-Galvez R. Diagnosis of interstitial lung disease in children. Paediatr Respir Rev 2004;5:101-107.

22. Rothenberg SS, Wagner JS, Chang JH, Fan LL. The safety and efficacy of thoracoscopic lung biopsy for diagnosis and treatment in infants and children. J Pediatr Surg 1996;31:100-103; discussion: 103-104.

23. Spencer DA, Alton HM, Raafat F, Weller PH. Combined percu-taneous lung biopsy and high-resolution computed tomography in the diagnosis and management of lung disease in children. Pediatr Pulmonol 1996;22:111-116.

24. Katzenstein AL, Fiorelli RF. Nonspecific interstitial pneumonia/fibrosis. Histologic features and clinical significance. Am J Surg Pathol 1994;18:136-147.

25. Dishop MK, Askin FB, Galambos C, White FV, Deterding RR, Young LR, et al, for the chILD Network. Classification of dif-fuse lung disease in older children and adolescents: a multi-institutional study of the Children’s Interstitial Lung Disease (chILD) pathology working group. Mod Pathol 2007;2:2878.

26. Leslie KO, Viggiano RW, Trastek VF. Optimal processing of diagnostic lung specimens. In: Leslie KO, Wick MR, eds. Practi-cal Pulmonary Pathology. A Diagnostic Approach. Philadelphia: Churchill Livingstone; 2005. pp. 19-32.

27. Langston D, Patterson K, Dishop MK, chILD Pathology Co-op-erative Group. A protocol for the handling of tissue obtained by operative lung biopsy: recommendations of the chILD pathol-ogy co-operative group. Pediatr Dev Pathol 2006;9:173-180.

28. Ponsky TA, Rothenberg SS. Thoracoscopic lung biopsy in infants and children with endoloops allows smaller trocar sites and discreet biopsies. J Laparoendosc Adv Surg Tech A 2008;18:120-122.

10. Whitsett JA, Wert SE, Weaver TE. Alveolar surfactant homeo-stasis and the pathogenesis of pulmonary disease. Annu Rev Med 2010;61:105-119.

11. Katzenstein AL, Gordon LP, Oliphant M, Swender PT. Chronic pneumonitis of infancy. A unique form of interstitial lung disease occurring in early childhood. Am J Surg Pathol 1995;19:439-447.

12. Copley SJ, Coren M, Nicholson AG, Rubens MB, Bush A, Hansell DM. Diagnostic accuracy of thin-section CT and chest radiography of pediatric interstitial lung disease. AJR Am J Roentgenol 2000;174:549-554.

13. Koh DM, Hansell DM. Computed tomography of diffuse inter-stitial lung disease in children. Clin Radiol 2000;55:659-667.

14. Bokulic RE, Hilman BC. Interstitial lung disease in children. Pediatr Clin North Am 1994;41:543-567.

15. Redding GJ, Fan LL. Idiopathic pulmonary fibrosis and lym-phocytic interstitial pneumonia. In: Taussig LM, Landau LI, eds. Pediatric Respiratory Medicine. St. Louis: Mosby; 1999. pp. 794-804.

16. Chollet S, Soler P, Dournovo P, Richard MS, Ferrans VJ, Bas-set F. Diagnosis of pulmonary histiocytosis X by immunodetec-tion of Langerhans cells in bronchoalveolar lavage fluid. Am J Pathol 1984;115:225-232.

17. Martin RJ, Coalson JJ, Rogers RM, Horton FO, Manous LE. Pulmonary alveolar proteinosis: the diagnosis by segmental lavage. Am Rev Respir Dis 1980;121:819-825.

18. Fan LL, Lung MC, Wagener JS. The diagnostic value of bronchoalveolar lavage in immunocompetent children with chronic diffuse pulmonary infiltrates. Pediatr Pulmonol 1997;23:8-13.

19. Fan LL, Kozinetz CA, Deterding RR, Brugman SM. Evaluation of a diagnostic approach to pediatric interstitial lung disease. Pediatrics 1998;101:82-85.


Risk factors associated with retinopathy of prematurity in preterm

infants treated at a tertiary level hospital

research article


Yolanda Vázquez Lara,1 Juan Carlos Bravo Ortiz,1 Claudia Hernández Galván,1 Narlly del Carmen Ruíz Quintero,2 Carlos Augusto Soriano Beltrán1

AbSTRACT

background. Retinopathy of prematurity (ROP) is defined as a peripheral proliferative vitreoretinopathy in which immaturity (determined by gestational age and birth weight) and oxygen are more decisive factors. We undertook this study to analyze the relative risk for develop-ment of ROP in relation to gestational age and birth weight in infants.methods. We carried out a retrospective, analytical, cross-sectional, single center trial in preterm infants with a gestational age <37 weeks and a birth weight <2,000 g. We performed fundus examination with binocular indirect ophthalmoscopy at different times according to gestational age. Injuries are accounted for using the international classification. Results. We included two groups: I) healthy individuals and II) those with ROP. Group I included 217 healthy subjects (91 females and 126 males) with a mean gestational age of 30.95 ± 2.7 weeks and a weight of 1291.98 ± 255.93 g (range: 620-2035 g). Group II was comprised of 127 patients (65 females and 62 males) with a mean gestational age of 29.37 ± 1.77 weeks (range: 26-34 weeks) and a weight of 1089.31 ± 194.74 g (range: 630-1650 g). Stage 1 retinopathy predominated (70.1%) followed by stage 2 (21.3%) and stage 3 (7.1%); 9.4% of patients presented a type 1 prethreshold retinopathy and 4.7% threshold type. The group of 28-29 weeks showed a factor of 2.37 times more risk of developing ROP and was the group with the highest incidence with 64.13% at 30-31 weeks, after which the risk begins to decrease. Conclusions. Preterm infants with gestational age between 28 and 29 weeks are at increased risk for developing ROP. Key words: retinopathy of prematurity, ophthalmoscopy, oxygen.

1 Servicio de Oftalmología, Unidad Médica de Alta Especialidad, Hospital de Pediatría, Centro Médico Nacional SXXI, Instituto Mexicano del Seguro Social, Mexico, D.F., Mexico

2 Asociación para Evitar la Ceguera, Hospital Dr. Luis Sánchez Bulnes, México D.F., México

Correspondence: Dra. Yolanda Vázquez LaraServicio de Oftalmología, Unidad Médica de Alta EspecialidadHospital de Pediatría, Centro Médico Nacional SXXI Instituto Mexicano del Seguro Social Mexico, D.F., MexicoE-mail: [email protected]


INTRODuCTION

Retrolental fibroplasia, now known as retinopathy of pre-maturity (ROP), was first described in 1942 by Terry.1 In 1951, Campbell suggested that ROP could be temporally related to the introduction of oxygen therapy in surgery of premature infants.2 It was Heath, in 1952, who named it retinopathy of prematurity.3 In the 1950s, Kinsey and

Hemphill reported the first epidemic of blind children due to ROP.4 In the 1980s, there was a second epidemic, and in the last two decades, despite knowledge of the disease and of technological advances, we faced the third epidemic of blindness due to ROP.5

Currently, it is estimated that there are ~60,000 blind children worldwide as a result of ROP. Half of these children live in Latin America.6-10 In the U.S. it is the leading cause of childhood blindness.11 The current concept of ROP is defined as a peripheral proliferative vitreoretinopathy that develops in premature children and has a multifactorial etiology. Immaturity (determined by gestational age and birth weight)12 and oxygen are the most common factors implicated in the pathology.13,14 Early diagnosis and prompt treatment, as well as knowl-edge of the risk factors, allow prevention of blindness in >50% of these patients.15,16

According to the literature, in Mexico there is no information regarding the relative risk for the devel-opment of ROP in relation to gestational age and birth weight in infants, the reason for which this study was undertaken.


Risk factors associated with retinopathy of prematurity in preterm infants treated at a tertiary level hospital

PATIENTS AND mETHODS

We conducted a retrospective, observational, descriptive, cross-sectional, unicentric and open study of premature newborns with a gestational age <37 weeks and a birth weight of <2035 g. Patients were referred to the Gynecol-ogy–Pediatric Hospital #4 (IMSS) or referred from other centers to the neonatal intensive care unit (NICU) of the Pediatric Hospital, Centro Medico Nacional XXI (CMN XXI) of the Instituto Mexicano del Seguro Social (IMSS). Patients were treated at the Pediatric Ophthalmology Ser-vice of the same hospital between November 1, 2008 and December 31, 2009.

The first examination of the fundus was performed between the fourth and sixth week of life in those patients with a gestational age of ≥28 weeks and at <28 weeks after completing 32 weeks of corrected gestational age and after every 2 or 3 weeks until the vascularization of the retina was complete. In those patients who developed some degree of ROP, they were examined at 1 or 2 weeks following according to the stage, until signs of regression were observed or without progression of the retinopathy in the following two examinations or until the retinopathy progressed to a prethreshold type 1 or threshold, which required treatment with laser or cryotherapy.

Routine retinal examination was performed in the Out-patient Department of the Pediatric Hospital with indirect binocular ophthalmoscopy after dilating the pupil with a commercial mixture of tropicamide and phenylephrine diluted to 50%, one drop in each eye every 10 min on three occasions. Tetracaine was used as a local anesthetic, a pediatric speculum and indentation of the peripheral retina. The support of a pediatrician or neonatologist and nurse was always available for patient monitoring, and examinations in the NICU was carried out under the same conditions. Injuries were recorded following the interna-tional classification (Table 1, Figure 1).

In cases where ROP developed, the stage and gesta-tional age at the time of appearance of the retinopathy was assessed. For patients with type 1 prethreshold stage or threshold stage, ablation of the avascular retina was car-ried out with argon laser or cryotherapy in the operating room under general anesthesia

The influence of the following variables on the devel-opment of ROP was analyzed: weight, gestational age at birth, gender, use of oxygen, sepsis, bronchopulmonary

dysplasia, respiratory history (which included respiratory distress syndrome, pneumonia, or atelectasis), history of cardiovascular disease (mainly persistent PDA), anemia and gastrointestinal history (such as necrotizing entero-colitis or jaundice).

Statistical analysis was performed using SPSS for Windows. Descriptive statistics of all variables and linear regression was done. Statistical significance was calcu-lated using the maximum likelihood method; p <0.05 was considered statistically significant.

RESuLTS

We included all preterm infants <37 weeks and weighing <2030 g born at the Hospital of Gynecology and Pediatrics, November 2008 to December 2009. Infants were divided into two groups: healthy individuals and those with some degree of ROP.

In the group of healthy subjects there were 217 eyes studied (91 females and 126 males) with a mean gestational age of 30.95 ± 2.7 weeks (range: 25-37 weeks) and weight of 1291.98 ± 255.93 g (range: 620-2035 g) and corrected gestational age at the time of diagnosis of 36.22 ± 2.51 weeks (range: 30-42 weeks). In the group of patients who developed ROP there were 217 eyes studied (65 females and 62 males) with a mean gestational age of 29.37 ± 1.77 weeks (range: 26-34 weeks) and weight of 1089.31 ± 194.74 g (range: 630-1.650 g) and corrected gestational age of 35.52 ± 2.01 weeks (range: 32-42 weeks).

The degree of retinopathy that predominated was stage I (70.1%), stage 2 (21.3%), stage 3 (7.1%). No patients corresponded to stage 4 and 1.6% of the study patients were classified as stage 5; 9.4% of our popula-tion had type 1 prethreshold retinopathy and 4.6% had threshold type that warranted treatment with laser or cryotherapy.

With respect to gestational age at birth, it was found that the group of 28-29 weeks of age had a risk factor 2.37 times more of developing ROB and was also the group with the greatest incidence (64.13%). The 26-27 gestation weeks group also had a risk 1.65 times greater of developing ROP. Both resulted in being significant and from 30-31 weeks the risk began to decrease (Table 2). With regard to birth weight, it was found that weight from 751-1,000 g may represent a risk factor 1.85 times greater of developing ROP (Table 3).


Yolanda Vázquez Lara, Juan Carlos Bravo Ortiz, Claudia Hernández Galván, Narlly del Carmen Ruíz Quintero, Carlos Augusto Soriano Beltrán

DISCuSSION

ROP is a peripheral proliferative vitreoretinopathy that develops in premature children and in its most serious forms can cause blindness. Survival of premature infants has increased in the last decade; however, despite this it appears that the prevalence of ROP has decreased.17,18 It is essential to use screening systems to detect all of cases of severe newborn ROP and adapt them to the changes that are present in the epidemiology of the disease.

It is difficult to try to unify the criteria regarding the incidence of ROP among different populations because different variables can influence the results such as im-maturity and the survival rate as well as the race of the patients studied.17,19,20

The incidence of ROP in this study was 36.9%, simi-lar to that observed by Bossi and Koerner21 and Pallás et al.22 who found an incidence between 25 and 35%. In a comparative study, Blair et al.23 reported an incidence of 36.1% and in the UK an incidence of ROP was reported in general as 31.2%.12

However, our study showed an incidence less than that found in the studies by Holmström et al., Palmer et al. and Párraga et al. who reported incidences of between 40 and 60%.24-26

In the study performed between 2000 and 2002 by the Early Treatment for Retinopathy of Prematurity Coopera-

In our population, 59.09% of all premature NB weigh-ing from 751-1,000 g developed ROP. The rest of the sample population, depending on weight, had a relatively lower risk of developing ROP as birth weight increased. The factors that were related with a greater risk of devel-oping ROP were oxygen with a 1.30 times greater risk of developing ROP, mechanical ventilation with 1.65 times greater risk, pulmonary bronchodysplasia with a 1.60 times greater risk and sepsis with 1.27 times greater risk of developing ROP. All these values were statistically significant. The remaining factors analyzed did not present a significant risk but should be followed up.

Table 1. International classification of PROP

Stage• Stage 1. Line of demarcation: a fine white line that separates the vascular from the avascular retina• Stage 2. Elevated ridge: line of demarcation that appears in stage I increases in volume and extends outside the plane of

the retina• Stage 3.Increase in vascular tissue towards the vitreous space • Stage 4. Subtotal retinal detachment—subdivided into 4A if the macula is attached and 4B if the macula is detached• Stage 5. Total retinal detachment • Disease “plus”. Refers to dilatation and tortuosity of the vessels of the posterior pole and indicates that there is activity—can

present in any stage of retinopathy• Baseline retinopathy. Five continuous or 8 total clock hours of disease with a stage 3 “plus” in zone 1 or 2

Localization• Zone 1. Circle whose radius is two times the distance between the papila and the fovea• Zone 2. Comprises a band of retina from the limits of zone 1 up to the ora serrate nasally in the horizontal meridian• Zone 3. The remaining semilunar space, outside zone 2

Extension

Extension of the retinopathy is described in clock sectors

ROP, retinopathy of prematurity.

Figure 1. Representation of the retina in hourly sectors and divided according to zones.



tive Group (ETROP), an incidence of 68% was reported, which was similar to that reported by the CRYO-ROP group in 1986 and 1987.25,27 The number of patients studied and the screening parameters are different between the dif-ferent studies analyzed, which make comparisons difficult.

Screening for ROP should not only take into account gestational age and weight at birth, but should be enlarged to include other patients whose perinatal disease predispos-es them to an elevated risk for developing ROP. Efficient care now requires that children at high risk receive retinal

exams carefully synchronized by an experienced ophthal-mologist with experience in examinations of premature NB with risk of retinopathy, and that all pediatricians who care for these patients in risk situations be aware of the need for early examination.28

In developed countries such as the U.S. and UK, guide-lines for screening of these children have been established. However, it must be kept in mind that each region could have different parameters for screening due to the charac-teristics of the patients and that management is different in each region. These guidelines recommend screening for children born <32 weeks of gestation and weighing <1500 g. The national guidelines in Mexico recommend screening in premature children with gestational age ≤34 weeks and birth weight of ≤1750 g.29

Our study found an incidence of 7.6% retinopathy in those patients who were >33 weeks of gestation at birth; however, this percentage corresponded to stage I, whose prognosis is tendency towards remission in up to 90%.25 With regard to birth weight, the incidence of retinopathy in patients >1500 g was only 4.76%, although it resulted to be statistically significant even when compared with 22.32% corresponding to those patients who weighed <1500 g. Moreover, it was a stage 3 retinopathy at high risk of developing threshold retinopathy. Therefore, we agree with the new screening criteria described in the tech-nical guideline for the management of ROP.29 Screening criteria should be reviewed periodically according to the observed changes in the epidemiology of the disease or in the potential preventive treatments that may be developed.

In our population we found that the group of newborns weighing 501-750 g had a relative risk of developing ROP of 1.65 times, although the published risk is higher for this group. In our study, the highest risk was presented by the group weigh-ing 751 to 1,000 g, probably because in our population patients with a lower birth weight have a higher mortality.

The group with the highest risk of developing ROP and increased incidence corresponded to the group 28 to 29 weeks of gestational age. Also, we would expect to see these results in newborns <28 weeks, but below that age implies a high mortality rate.

We note that the percentage of patients who met the criteria for treatment, including prethreshold type 1 retinopathy and threshold, was low, but these results are sufficient to consider an alternative treatment that may prevent blindness in these patients.

Table 2. Evaluation of risk of ROP in accordance with gestational age

Gestationalage (weeks)

Without ROP

With ROP Total RR (p) Incidence (%)

24-25 2 0 2 — —

26-27 10 14 24 1.65(0.008)*

58.33

28-29 33 59 92 2.37(0.0005)*

64.13

30-31 71 29 100 0.72(0.063)

29.00

32-33 75 23 98 0.55(0.003)*

23.46

34-35 24 2 26 0.196(0.017)*

7.6

≥36 2 0 2 — —

Total 217 127 344 — —

ROP: retinopathy of prematurity; RR: risk factor.*p value statistically significant

Table 3. Evaluation of ROP risk with regard to weight

Weight (g) Without ROP

With ROP RR Incidence (%)

501-750 4 6 1.65(0.0600)

60

751-1,000 27 39 1.86(0.0005)*

59.09

1,001-1,250 57 55 1.58(0.001)*

49.10

1,251-1,500 87 25 0.508(0.0005)*

22.32

1,501-1,750 40 2 0.115(0.002)*

4.76

1,751-2,000 0 0 — —

>2,000 2 0 — —

Total 217 127 — —

ROP, retinopathy of prematurity; RR, relative risk.*p value statistically significant.


Yolanda Vázquez Lara, Juan Carlos Bravo Ortiz, Claudia Hernández Galván, Narlly del Carmen Ruíz Quintero, Carlos Augusto Soriano Beltrán

ROP continues to be a leading cause of blindness in children worldwide. A significant number of children who develop ROP will have serious visual problems (14.5%) and unfavorable structural problems (9.1%) despite abla-tive treatment with laser or cryotherapy.30,31

It is important to emphasize that ophthalmological control of these patients should not be limited to the diagnosis and management of retinopathy until it pro-gresses or until treatment is indicated. We must control these children in the early years due to the greater in-cidence of late refractive errors, strabismus and retinal detachments.32-35 Based on the results, we can conclude that preterm infants with gestational age between 28 and 29 weeks have a risk of up to 2.37 greater of developing ROP. In infants with birth weights of 751 to 1,000 g, the risk is up to 1.6 times of developing ROP. Supplemental oxygen, mechanical ventilation and sepsis are risk fac-tors of up to 1.6 times for the development of ROP in premature NB.

REFERENCES

1. Terry T. Extreme prematurity and fibroblastic overgrowth of persistent vascular sheath behind each crystalline lens. I. Preliminary report. Am J Ophthalmol 1942;25:203-204.

2. Campbell K. Intensive oxygen therapy as a possible cause for retrolental fibroplasia. A clinical approach. Med J Aust 1951;2:48-50.

3. Heath P. Pathology of the retinopathy of prematurity: retrolental fibroplasia. Am J Ophthalmol 1951;34:1249-1259.

4. Kinsey VE, Hemphill FM. Etiology of retrolental fibroplasia and preliminary report of cooperative study of retrolental fibroplasia. Trans Am Acad Ophthalmol Otolaryngol 1955;59:15-24.

5. Gibson DL, Sheps SB, Uh SH, Schechter MT, McCormick AQ. Retinopathy of prematurity-induced blindness: birth weight-specific survival and the new epidemic. Pediatrics 1990;86:405-412.

6. Gilbert C, Fielder F, Gordillo L, Quinn G, Semiglia R, Visintin P, et al; for the International NO-ROP Group. Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs. Pediatrics 2005;115:e518-e525.

7. Gilbert CE, Foster A. Childhood blindness in the context of VISION 2020—the right to sight. Bull WHO 2001;79:227-232.

8. Gilbert C, Rahi J, Eckstein M, O´Sullivan J, Foster A. Reti-nopathy of prematurity in middle-income countries. Lancet 1997;350:12-14.

9. Zimmermann CJ, Fortes FJB, Tartarella MB, Zin A, Dorneles JI Jr. Prevalence of retinopathy of prematurity in Latin America. Clin Ophthalmol 2011:5 1687-1695.

10. Zepeda RLC, Gutiérrez PJA, De la Fuente TMA, Angulo CE, Ramos PE, Quinn GE. Detection and treatment for retinopathy

of prematurity in Mexico: need for effective programs. J AAPOS 2008;12:225-226.

11. Steinkuller PG, Du L, Gilbert C, Foster A, Collins ML, Coats DK. Childhood blindness. J AAPOS 1999;3:26-32.

12. Mathew MR, Fern AI, Hill R. Retinopathy of prematurity: are we screening too many babies? Eye (Lond) 2002;16:538-542.

13. Holmström G, Broberger U, Thomassen P. Neonatal risk fac-tors for retinopathy of prematurity —a population-based study. Acta Ophthalmol Scand 1998;76:204-207.

14. Olea JL, Corretger FJ, Salvat M, Frau E, Galiana C, Fiol M. Factores de riesgo en la retinopatía del prematuro. An Esp Pediatr 1997;47:172-176.

15. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicentre trial of cryotherapy for retinopathy of prematurity. Preliminary results. Arch Ophthalmol 1988;106:471-479.

16. Early Treatment for Retinopathy of Prematurity Cooperative Group. Revised indications for the treatment of retinopathy of prematurity: results of the early treatment for retinopathy of prematurity randomized trial. Arch Ophthalmol 2003;121:1684-1694.

17. Lim J, Fong DS, Dang Y. Decreased prevalence of retinopathy of prematurity in an inner-city hospital. Ophtalmic Sur Lasers 1999;30:12-16.

18. Termote J, Schalij-Delfos NE, Brouwers HAA, Donders ART, Cats BP. New developments in neonatology: less severe retinopathy of prematurity? J Pediatr Ophthalmol Strabismus 2000;37:142-148.

19. Ng YK, Fielder AR, Shaw DE, Levene MI. Epidemiology of retinopathy of prematurity. Lancet 1988;2:1235-1238.

20. Hameed B, Shyamanur K, Kotecha S, Manktelow B, Woodruff G, Draper ES, et al. Trends in the incidence of severe retinopa-thy of prematurity in a geographically defined population over a 10-year period. Pediatrics 2004;113:1653-1657.

21. Bossi E, Koerner F. Retinopathy of prematurity. Intensive Care Med 1995;21:241-246.

22. Pallás CR, Tejada P, Medina MC, Martín MJ, Orbea C, Barrios MC. Retinopatía del prematuro: nuestra experiencia. An Esp Pediatr 1995;42:52-56.

23. Blair BM, O'Halloran HS, Pauly TH, Stevens JL. Decreased incidence of retinopathy of prematurity, 1995-1997. JAAPOS 2001;5:118-122.

24. Holmström G, El Azazi M, Jacobson L, Lennerstrand G. A population-based, prospective study of the development of ROP in prematurely born children in the Stockholm area of Sweden. Br J Ophthalmol 1993;77:417-423.

25. Palmer EA, Flynn JT, Hardy RJ, Phelps DL, Phillips CL, Schaf-fer DB, et al. Incidence and early course of retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology 1991;98:1628-1640.

26. Párraga QMJ, Sánchez PR, Barreiro LJC, Cañete ER, Fernández GF, Zapatero MM, et al. Retinopatía del prema-turo. Resultados tras un año de seguimiento. An Esp Pediatr 1996;44:482-484.

27. Good WV, Hardy RJ, Dobson V, Palmer EA, Phelps DL, Quitos M, et al; for the Early Treatment for Retinopathy of Prematurity Cooperative Group. The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study. Pediatrics 2005;116:15-23.

28. American Academy of Pediatrics, Section on Ophthalmology; American Academy of Ophthalmology; American Association



for Pediatric Ophthalmology and Strabismus. Screening ex-amination of premature infants for retinopathy of prematurity. Pediatrics 2006;117:572-576.

29. Secretaría de Salud. Manejo de la retinopatía del recién nacido prematuro. Lineamiento técnico. Available at: http://saludmaternamedicos.blogspot.mx/2011/09/lineamiento-tecnico-manejo-de-la.html#!/2011/09/lineamiento-tecnico-manejo-de-la.html

30. Smith LE. Pathogenesis of retinopathy of prematurity. Growth Horm IGF Res 2004;14(suppl A):S140-S144.

31. Msall ME, Phelps DL, Hardy RJ, Dobson V, Quinn GE, Sum-mers CG, et al. Educational and social competencies at 8 years in children with threshold retinopathy of prematurity in the CRYO-ROP multicenter study. Pediatrics 2004;113:790-799.

32. Holmström G, El Azazi M, Kugelberg U. Ophthalmological long term follow up of preterm infants: a population based, prospective study of the refraction and its development. Br J Ophthalmol 1998;82:1265-1271.

33. Ricci B. Refractive errors and ocular motility disorders in preterm babies with and without retinopathy of prematurity. Ophthalmologica 1999;213:295-299.

34. Good WV. Early treatment for Retinopathy of Prematurity Cooperative Group. The Early Treatment for Retinopathy of Prematurity Study: structural findings at age 2 years. Br J Ophthalmol 2006;90:1378-1382.

35. Larsson EK, Holmström GE. Development of astigmatism and anisometropia in preterm children during the first 10 years of life: a population based study. Arch Ophthalmol 2006;124:1608-1614.


Association of steroid use with weight gain in pediatric patients with

rheumatic disease

research article


Sonia González-Muñiz,1 Donají Miranda-González,2 Miguel Ángel Villasis-Keever,3 Vicente Baca-Ruíz,4 Teresa Catalán-Sánchez,4 Patricia Yañez-Sánchez4

AbSTRACT

background: Prevalence of obesity in pediatric patients with rheumatic disease (RD) receiving steroids can be as high as 43%. The aim of this study was to determine the association between low dose of prednisone and weight gain among children with RD.methods: We carried out a prospective cohort study. One cohort was comprised of patients exposed to steroids (group B) and the other group was comprised of patients not exposed to steroids (group A). After standardization, all patients were followed for 24 weeks and weight, height, waist circumference, arm circumference and body fat percentage were assessed.Results: There were 20 patients in group A and 32 in group B. In the first group, juvenile rheumatoid arthritis was the main diagnosis (40%) and systemic lupus erythematosus (56%) in the second group. Between groups, from the beginning and during the entire study period there was no difference in the averages of each anthropometric variable, but there were four (12.5%) new cases of obesity in group B and none in group A. Eleven (55%) patients in group A and 18 (56%) patients of group B showed an increase in fat percentage. Of these, only in group B patients was there was a statistically significant gain (p <0.01) in all anthropometric variables studied.Conclusions: Among pediatric patients with RD, receiving low-doses of prednisone seems to be a factor in weight increase.Key words: steroids, obesity, rheumatic disease, children.

1 Departamento de Pediatría, UMAE Hospital de Pediatría CMN Siglo XXI, Instituto Mexicano del Seguro Social, Mexico, D.F., Mexico

2 Departamento Pediatría e Investigación, Hospital Ángeles de Querétaro, Querétaro, Mexico

3 Unidad de Investigación en Epidemiología Clínica, 4Departa-mento de Reumatología, UMAE Hospital de Pediatría CMN Siglo XXI, Instituto Mexicano del Seguro Social, México, D.F., Mexico

Correspondence: Dr. Miguel Ángel Villasís Keever Unidad de Investigación en Epidemiología Clínica UMAE Hospital de Pediatría, CMN Siglo XXI, IMSS México, D.F., MexicoE-mail: [email protected]


INTRODuCTION

Glucocorticoids (GCs) are the most potent anti-inflamma-tory agents in the treatment of rheumatic diseases (RD). The first reports of its use in children, especially in those with rheumatic fever, juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE), appeared in 1950 and 1960.1 Some studies have been carried out to assess

the effect of steroids on the nutritional status of children. For example, in a study published in 1986, steroid therapy was assessed as causing obesity in children according to a retrospective study of 23 children diagnosed with ne-phrotic syndrome (1–14 years of age) and who required >60 days with prednisone. It was concluded that the risk of obesity was low among children who were at their normal weight at baseline as a result of continuous use of steroids.2 In 1988, a study in Kuwait evaluated the effects of chronic therapy with low-doses of prednisone on stature and obesity of 37 patients aged 2–15 years with nephrotic syndrome who had frequent relapses. Serial measurements of height and weight showed the persistence of obesity in only 2/13 of the children who were initially obese.3 In 2006, a Canadian study reported in a group of patients with nephrotic syndrome that the incidence of obesity was 35 to 43% during GC treatment and found that the weight decreased when the GC dose was reduced or suspended.4

Obesity is defined as a chronic metabolic disorder characterized by excessive body fat. A child is consid-ered obese when his/her weight is >20% of the ideal.5 According to the growth charts published in 2000 by the Centers for Disease Control and Prevention (CDC) in the


Association of steroid use with weight gain in pediatric patients with rheumatic disease

U.S., obesity is defined as body mass index (BMI) ≥95th percentile for age and gender and overweight is defined when the percentile is ≥85 and ≤94.6-8 Worldwide, obesity and overweight are considered a public health problem. In Mexico, beginning with the National Health Survey in 2000, it was determined that this was a problem that also occurs in the pediatric population. Prevalence of overweight was documented in children between 10 and 17 years of age: 10.8–16.1% in males and 14.3–19.1% in females. Prevalence of obesity was 9.2–14.7% in males and 6.8–10.6 % in females.9-11

In clinical practice, the most frequently used indicator for diagnosis of obesity is the BMI. However, when the BMI is high, it is not distinguished whether the increase in weight with respect to height is a function of fat mass or fat-free mass.8 Therefore, other measurement methods should be used to assess the total body composition such as biompedance.4,12

The aim of this study was to determine whether there is a relationship between low-dose steroid use and changes in nutritional status in children with RD during the first months after establishing the diagnosis.


We conducted an observational, longitudinal, prospec-tive and analytical cohort study with patients between 2 and 16 years of age who were recruited in the Service of Rheumatology of the Pediatric Hospital, Centro Medico Nacional Siglo XXI. Patients who were included had to have a certain initial diagnosis of RD. Patients were di-vided into two groups: group A patients who did not require steroids for a minimum of 24 weeks and group B included patients with RD who initiated treatment with steroids (prednisone) and in whom it was necessary to continue treatment for at least 24 weeks. The decision of whether or not to administer prednisone was made by the physician in charge of each patient. We excluded patients who received additional doses of steroids (such as methylprednisolone) as a result of complications of the disease itself during the monitoring period. The protocol was approved by the Local Committee for Health Research of the hospital. For admission to the study, parents signed an informed consent and patients >8 years provided informed assent.

Prior to the initiation of the study, one of the inves-tigators (SGM) conducted a standardization process for

assessment of weight, height, waist circumference (WC), arm circumference and electrical bioimpedance to deter-mine total body composition, in particular the percentage of fat mass. Weight was determined using a mechanical scale (BAME, Puebla, Mexico) with 140-kg maximum range and minimum weight of 1 kg. Height was measured using a stadiometer and a maximum range of 194 cm. Waist circumference (WC) and mid-upper arm circumference (MUAC) were measured with a fiberglass tape measure with a maximum length of 150 cm. Electrical bioimped-ance was assessed with a four derivation model (325F, Omron Healthcare, Bannockburn, IL). All measurements were performed at the time of confirmation of diagnosis and were repeated four times every 6 weeks during the 24 weeks of surveillance. We defined overweight when BMI was between the 85th and 94th percentile and as obese when it was ≥95th percentile.

Statistical Analysis

Information was captured in a database. Subsequently, statistical analysis was performed using SPSS v.13. For descriptive analysis, we used measures of central tendency according to the scale of measurement vari-ables. Qualitative variables were presented as modes and simple frequencies, whereas quantitative variables such as average and standard deviation (SD) showed a normal distribution after making a logarithmic conversion. For inferential analysis, we used the χ2 test. For independent and dependent samples, t test was performed as well as one- and two-way analyses of variance (ANOVA). Further-more, Pearson r correlation test was conducted; p <0.05 was considered statistically significant.

RESuLTS

The study consisted of 52 patients (Table 1). Except for the type of disease, between group variables were similar: there were 14 female patients from group A (70%) and 22 from group B (68.8%); group A patients were from 4 to 16 years of age (average 11 years 7 months) and in group B the range was from 5–16 years of age (average 12 years). As far as type of disease, SLE was more frequent in group B (56.2%) than in group A (20%). The opposite occurred with JIA because in group A (without steroid) the frequency was higher (40%) than in group B (12.5%).


Sonia González-Muñiz, Donají Miranda-González, Miguel Ángel Villasis-Keever, Vicente Baca-Ruíz, Teresa Catalán-Sánchez, Patricia Yañez-Sánchez

With respect to the amount of steroid prescribed in group B, there was little difference observed during the study period. The average dose at baseline was 0.32 mg/kg/day (range: 0.05–1.4 mg/kg/day), whereas for the fourth measurement, the average was 0.25 mg/kg/day (variation of 0.05–1.2 mg/kg/day).

Table 2 compares the anthropometric measurements in the two groups: at baseline and at the end of the 24-week monitoring period. As noted, there were no differences between groups with respect to baseline and final mea-surements. However, it is worth noting that in both groups there was a slight increase in weight, WC, MUAC and fat percentage, which was a little higher in the steroid group. Figure 1 shows the behavior of the latter four variables. The remaining did not show changes of the four measure-ments at any given time. In terms of weight, compared with group A (which remained unchanged), group B had progressive increases. This was also observed in the WC and MUAC. Regarding the percentage of fat, group B

Table 1. Comparison of the characteristics of patient with rheumatic disease with or without steroid exposure

Characteristics Group A (without steroids)

n = 20

Group B (with steroids)

n = 32

p

Age (years) Average ± SD 11.6 (± 3.3) 12.0 (± 3.2) 0.7

Pediatric stage (n) • Preschool 1 1 • School age 4 5

• Adolescents 15 26

Gender n (%) • Female • Male

14 (70)6 (30)

22 (68.8)10 (31.2)

0.9

Type of RD n (%) • SLE 4 (20) 18 (56.2)

0.03

• JIA 8 (40) 4 (12.5)

• Vasculitis 1 (5) 4 (12.5)

• Dermatomyositis 2 (10) 2 (6.2)

• DEL 3 (15) —

• APS 1 (5) 1 (3.1)

• Progressive systemic sclerosis

— 1 (3.1)

• Overlap syndrome — 1 (3.1)

• Scleroderma 1 (5) —

SD, standard deviation; SLE, systemic lupus erythematosus; JIA, juvenile idiopathic arthritis; APS, antiphospholipid syndrome; DLE, discoid lupus erythematosus; RD, rheumatic disease.

had a lower percentage at the beginning, but in the end it nearly equaled the other group. According to ANOVA, the behavior of these variables between groups over time was not statistically significant (p >0.05).

The average weight gain was higher in group B (0.3 kg vs. 1.3 kg) but was not statistically significant (p = 0.2); however, during the observation period, one patient from group A (5%) and five patients from group B (15%) showed an increase in weight much more than the average for the rest of the group (Figure 2). In the latter group, two patients increased their weight almost 15 kg as compared with the patient in group A who only showed an increase of 4.1 kg.

Furthermore, according to the BMI, group A had four overweight patients (20%) and three obese patients (15%) from the first evaluation and who did not change their status during the study. In contrast, at baseline, group B had four overweight patients (12.5%) and seven obese patients (21.8%), but at the end there were six (18.7%) and eight (25%) patients, respectively. It should be noted that in these eight children with obesity, one patient had BMI within normal limits at the beginning of the surveillance period and another child was overweight, so the change in BMI percentile occurred during the steroid treatment period. Likewise, of the six patients who were detected with overweight at the end of the study, their BMI (in three cases) was normal at initiation of the monitoring period. At the beginning and at the end of the study, the prevalence of overweight and obesity increased from 34 to 43%, and the incidence was 20%. In other words, there were five new cases of overweight or obesity. In contrast, it was also observed that the BMI improved in two patients: a patient with obesity changed to overweight and another overweight patient lowered to normal status.

By analyzing the variation in fat percentage, we identi-fied 11 patients in group A (55%) and 18 in group B (56%) with some increase in the percentage of fat during the 24-week follow-up. Of these patients, only those from group B showed a statistically significant gain (p <0.01) in each of the four variables (weight, WC, arm circumference and fat percentage) when comparing the initial and final values, but no statistical difference was observed between groups (Table 3).

Finally, when comparing the average prednisone dose among patients who increased their weight (1.15 ± 1.1 mg/kg/day) and those without increased weight (1.08 ± 0.6 mg/kg/day), there was no statistical difference (p = 0.53). While



Table 2. Basal and final measurements of patients with generalized rheumatic disease according to steroid exposure

Basal Final*

Variable No steroidsn=20

With steroidsn=32

No steroidsn=20

With steroidsn=32

Average ± SD Average ± SD Average ± SD Average ± SD

Weght (kg) 45.4 (17.0) 46.8 (16.7) 45.7 (16.5) 48.1 (17.1)

Length (cm) 145.4 (18) 145.4 (16.8) 145.7 (17.7) 145.9 (16.5)

BMI 20.5 (3.1) 21.4 (3.2) 20.6 (2.3) 21.8 (0.6)

WC (cm) 72.6 (14.0) 74.2 (13.8) 72.7 (13.3) 75.6 (14.2)

Arm circumference (cm) 23.6 (4.7) 23.9 (4.9) 23.7 (4.4) 24.7 (5.2)

Fat (%) 31.7 (10.0) 30.0 (10.0) 32.3 (9.3) 30.8 (8.2)

*No statistical difference between groups or before or after in the same group.

Figure 1. Comparison of four variables during the study period according to each group. BPI, brachial perimeter index.



performing the correlation between cumulative steroid dose and weight change, fat, WC and arm circumference, we only obtained a low correlation between steroid dose with the fat percentage (r = 0.31, p = 0.08); the other three variables did not show any correlation.

DISCuSSION

With the results of this investigation we observed that there is a relationship between administration of steroids and weight gain in pediatric patients with RD receiving low doses of steroids. This observation was seen particularly in five patients (15.6%) because their weight increase was significant (5 kg–13 kg during a 6-month period). These findings were in spite of the fact that in the group exposed to steroid use since the beginning of the surveil-lance period, 11 patients were already overweight or obese (34%), whereas at the end of the study there were 14 patients (43%). The weight gain in these five patients was as significant from the clinical point of view. In four of these patients who initially had normal BMI, at the end of the follow-up period three were overweight and one was obese, whereas the fifth patient changed from being overweight to obesity.

The results of this study are similar to other studies such as the one by Merrit et al. where there was an increased incidence of obesity over a period of about 2 years, but in children with nephrotic syndrome; nevertheless, the steroid dose administered was not clearly specified.2 Likewise, it

has also been described that upon discontinuation of ste-roids, the opposite effect was observed. In other words, it decreases the frequency of overweight or obese patients.3 In particular, in the case of patients with RD information on the modification of nutritional status has not been previously published. The only related studies refer to the possible impact of steroids in terms of stature.13,14 How-ever, the results of this study cannot be compared because the patients included in this study had a minimal change in their height, which is related to the monitoring time of our study (6 months) compared to previous studies with a much longer surveillance period.

Another aspect used in this study that has not been described previously was the analysis of body composi-tion by measurement of the percentage of body fat using impedance. As described, averages obtained between groups did not differ because during the study week there were patients who increased and others who decreased the amount of fat. Therefore, we proceeded to analyze the 29 patients separately (n = 11, without steroids; n = 18, with steroids) in whom the amount of body fat increased. Although there was no difference in the rate of increase of fat between groups (55% vs. 56.2%), interestingly, it was determined that in this subgroup the patients who received steroids gained more weight and had a greater increase in WC and arm circumference compared to the group without steroid use (Table 3). This would support the fact that the weight gain in patients who use prednisone would be related to the higher fat deposition. Furthermore, it is worth mentioning the manner in which fat accumu-lates with steroid use. Based on data from this study, it is possible to assume that there is no preference for either central or peripheral fat accumulation when it is expected that the accumulation of fat would be predominantly central, as occurs in Cushing’s syndrome. However, it must be noted that this syndrome is associated with high doses of steroids. The findings on how fat accumulates in patients using steroids, which is described in this study, is consistent with those reported by other authors using other assessment tools such as DEXA.15-17

Although in this study we considered important aspects, it is appropriate to mention that the study had some weak-nesses. For example, although SLE patients who require high doses of steroids are not included, monitoring of patients who participated in this study took about 3 to 6 months to be initiated after the conclusive diagnosis. The

Figure 2. Comparison of the weight increment between groups.



greater proportion of patients with SLE required high doses of steroids at the beginning of treatment for disease control. Thereafter, the dose is progressively reduced. Thus, it is possible that, in some patients, the cause of overweight or obesity prior to the study was due to the use of high doses of steroids. Another important point is that during the time the study was conducted, there was no control of food intake or physical activity of the patients. Of these two confounding variables, physical activity is prob-ably the most important according to the type of disease because it is possible that the weight gain is due to lack of activities commonly carried out by children. In these patients, clinical manifestations can cause a decrease in physical activity due to pain or musculoskeletal disability or articulation. It is also possible that during the different phases of treatment, family members do not allow the child to perform physical activities, work, or go to school without specific medical advice. In this regard, it should be noted that there are studies in pediatric patients with chronic diseases that note that it is common for the patients to frequently miss school, which is not necessarily related to functional or organic problems.18 Finally, this study did not consider adherence to the treatment as a possible confounding variable, although it could support the find-ings. In view of the above, and in order to explore and determine the most clear relationship between low doses of steroids and weight gain, further studies are necessary that would take into account the nutritional status of children prior to the initiation of steroids, their growth rate, time of exposure to steroids, and therapeutic adherence as well as dietary habits and physical activity.

In conclusion, according to the results obtained in this study, it appears that there is a greater likelihood that chil-dren with RD receiving low dose steroids are exposed to a significant increase in weight. These findings should be an alert to healthcare workers caring for these patients in order to offer precautionary measures to prevent overweight and obesity as well as dietary guidelines.

REFERENCIAS

1. Bijlsma J, Saag K, Buttgereit F, da Silva JA. Developments in glucocorticoid therapy. Rheum Dis Clin North Am 2005;31:1-17.

2. Merritt RJ, Hack SL, Kalsch M, Olson D. Corticosteroid therapy-induced obesity in children. Clin Pediatr (Phila) 1986;25:149-152.

3. Elzouki AY, Jaiswal OP. Long-term, small dose prednisone therapy in frequently relapsing nephrotic syndrome of child-hood. Effect on remission, statural growth, obesity, and infec-tion rate. Clin Pediatr (Phila) 1988;27:387-392.

4. Lara-Lafarge A, Marañón-Cardonne M, Castillo-Bonne J, Morales-Larramendi R, Román-Montoya A, Nuñez-Bouron A. Bioimpedancia eléctrica en 50 KHZ, evidencias experimentales.1ra parte. Memorias V Congreso de la So-ciedad Cubana de Bioingeniería 2003:1-4.

5. Dorantes-Álvarez LM, García-Morales LM, Gloria-Quintero ME, Martínez-Alvarado R, Espinosa-Palencia RA, Amaro-Moreno L. Talla baja y obesidad. En: Academia Mexicana de Pediatría, eds. Programa de Actualización Continua en Pediatría. México D.F.: Ed. Intersistemas; 2006. pp. 39-47.

6. Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA 2002;288:1728-1732.

7. Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, Mei Z, et al. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11 2002;246:1-190.

8. Cole TJ, Flegal KM, Nicholls D, Jackson AA. Body mass

Table 3. Baseline and final anthropometric evaluation of patients with increase in the percentage of fat in accordance with steroid exposure

Basal Final*

Variable Without steroidsn = 11

With steroidsn = 18

Without steroidsn = 11

With steroids**n = 18

Average ± SD Average ± SD Average ± SD Average ± SD

Weight (kg) 39.9 (14.9) 45.7 (16.9) 41.23 (15.3) 48.7 (17.9)

WC (cm) 65.5 (9.2) 71.3 (13.4) 67.8 (9.6) 75.3 (14.8)

Arm circumference (cm) 23.8 (4.2) 23.6 (4.3) 23.7 (3.8) 25.4 (5.1)

Fat (%) 28.9 (9.4) 23.8 (8.4) 31.3 (9.1) 29.6 (7.1)

*No statistically significant differences between groups (p >0.05).**p <0.01 between before and after measurements in the group with steroids in each of the four variables.



index cut offs to define thinness in children and adolescents: international survey. BMJ 2007;335:194.

9. Rudolf MC. The obese child. Arch Dis Child Educ Pract Ed 2004;89:ep57-ep62.

10. del Río-Navarro BE, Velázquez-Monroy O, Sánchez-Castillo P, Lara-Esqueda A, Berber A, Fanghänel G, et al. The high prevalence of overweight and obesity in Mexican children. Obes Res 2004;2:217-223.

11. Centers for Disease Control and Prevention. About BMI for chil-dren and teens. Disponible en: http://www.cdc.gov/healthyweight/assessing/bmi/childrens_bmi/about_childrens_bmi.html

12. Pi-Sunyer FX. Obesity: criteria and classification. Proc Nutr Soc 2000;59:505-509.

13. Simon D, Lucidarme N, Prieur AM, Ruiz JC, Czemichow P. Linear growth in children suffering from juvenile idiopathic arthritis requiring steroid therapy: natural history and effects of growth hormone treatment on linear growth. J Pediatr En-drocrinol Metab 2001;14(suppl 6):1483-1486.

14. Simon D, Fernando C, Czernichow P, Prieur AM. Linear growth and final height in patients with systemic juvenile idiopathic arthritis treated with longterm glucocorticoids. J Rheumatol 2002;29:1296-1300.

15. Foster BJ, Shults J, Zemel BS, Leonard MB. Interactions between growth and body composition in children treated with high-dose chronic glucocorticoids. Am J Clin Nutr 2004;80:1334–1341.

16. Leonard MB, Feldman HI, Shults J, Zemel BS, Foster BJ, Stallings VA. Long-term, high-dose glucocorticoids and bone mineral content in childhood glucocorticoid-sensitive nephrotic syndrome. N Engl J Med 2004;351:868-875.

17. Czock D, Keller F, Rasche FM, Häussler U. Pharmacokinetics and pharmacodynamics of systemically administered gluco-corticoids. Clin Pharmacokinet 2005;44:61-98.

18. Lollar DJ, Hartzell MS, Evans MA. Functional difficulties and health conditions among children with special needs. Pediatrics 2012; 129: e714-e722.


Analysis of sociodemographic features of patients with end-stage chronic

renal disease: differences in a 6-year period

research article


Guillermo Cantú,1 Graciela Rodríguez,2 Mercedes Luque-Coqui,3 Benjamín Romero,3 Saúl Valverde,3 Silvia Vargas,4 Alfonso Reyes-López,4 Mara Medeiros3

AbSTRACT

background. Chronic renal disease (CRD) has a strong impact on the Mexican childhood population with short-range limiting and serious consequences. Poverty and a social environment devoid of social justice hinder timely medical attention and long-range rehabilitation. The aim of this study was to determine the differences regarding sociodemographic features in patients under treatment at Hospital Infantil de México Federico Gómez, with a 6-year difference: patients diagnosed in 2003 as compared to those diagnosed in 2009.methods. A retrospective comparative study was carried out with end-stage chronic renal disease (ESRD) patients with information ob-tained from the clinical files. Data were obtained on age, gender, renal insufficiency etiology, socioeconomic level, type of financing, place of origin, and whether patient entered a rehabilitation program (dialysis or transplant).Results. In 2003, 69 patients with ESRD were treated, whereas 50 patients were treated in 2009. There were no differences in age or gender between dates. Etiology of uremia was determined in 40% of the children in 2003 and 50% in 2009. Most patients in the assessed years belong to the lowest socioeconomic levels, coming from the State of Mexico and metropolitan Mexico City. There was a decreas-ing trend in the number of patients coming from other states of the country: 30% in 2003 and 16% in 2009. Twenty-three patients (33%) entered the rehabilitation program in 2003 and 29 patients (58%) in 2009 (p = 0.007).Conclusions. There was a 28% decrease between 2003 and 2009 in the number of cases being managed. Attention has been focused on the State of Mexico and metropolitan Mexico City area. In spite of socioeconomic level being apparently similar in the studied years, there was a significant increase in the proportion of children entering a long-range rehabilitation program (from 33% in 2003 to 58% in 2009).Key words: renal insufficiency, pediatrics, distributive justice, bioethics.

1 Escuela de Medicina, Universidad Panamericana, Mexico, D.F., Mexico

2 Facultad de Psicología, Universidad Nacional Autónoma de México, Mexico, D.F., Mexico

3 Departamento de Nefrología, 4Subdirección de Investigación, Hospital Infantil de México Federico Gómez,

México D.F., México

Correspondence: Dra. Mara Medeiros Domingo Departamento de Nefrología Hospital Infantil de México Federico GómezMéxico, D.F., MéxicoE-mail: [email protected]


INTRODuCTION

Chronic renal disease (CRD) is considered to be a public health problem in our country, in children as well as in adults.1,2 At a worldwide level it tends to increase. Ac-cording to international guidelines, CRD in pediatrics is defined as structural or functional damage to the kidneys

for a period of 3 months or more, which may decrease the glomerular filtration rate, and the presence of any of the following findings: 1) alteration in the composition of the blood or urine, 2) alteration in imaging studies and 3) impaired renal biopsy, or those patients who have a glomerular filtration rate <60 ml/min/1.73 m2 SC with or without other signs of damage described.3

In turn, five stages of the disease are described. Stage 5 (or end-stage renal disease, ESRD) is defined when the glomerular filtration rate (GFR) is <15 ml/min or the patient requires renal replacement therapy (dialysis, hemodialysis or renal transplantation). These treatments are highly specialized, very expensive and beyond the financial reach of many families. World-wide, there are about two million people requiring renal replacement therapy and this implies a high cost for health services.4

The incidence of stage 5 ESRD in children worldwide is ∼1–3 children per million. In Latin America a wide range from 2.8–15.8 new cases per million in children <15 years of age is reported, whereas in Italy 12.1 cases per million


Guillermo Cantú, Graciela Rodríguez, Mercedes Luque-Coqui, Benjamín Romero, Saúl Valverde, Silvia Vargas, Alfonso Reyes-López, Mara Medeiros

are reported and in Japan 16.6% of its population of <15 years is reported.5-7

In the Mexican adult population the main causes of ESRD are diabetes and hypertension,2,8 whereas in chil-dren, unfortunately in most cases, an accurate diagnosis of the cause that led to uremia cannot be made due to the delay in seeking medical care. However, the main causes are congenital malformations (dysplasia, hypoplasia, uri-nary malformations) followed by glomerulopathy.9

The term distributive justice refers to the proper distri-bution of goods or burden of a society, to compensate for inequalities in which one lives. Thus, resources, taxes and opportunities are distributed in an equitable manner.10, 11

We live in a highly unequal society. In our country there are people with great economic fortunes, others with suitable conditions for their development and, fi-nally, those who lack the basic necessities for a decent life. There are reports of limitations and inequalities in access to dialysis and transplantation worldwide, even in developed countries.12-14

In Mexico it is known that those states with the greatest marginalization are precisely those that have the greatest incidence and mortality due to CRD.15 In Jalisco, it has been documented that the poorest patients are those who come in more advanced stages of the dis-ease when it is no longer possible to halt the progression of renal disease.16 However, in the past years much has been invested in hospital infrastructure and the Seguro Popular program was created which, at the time of this article, does not cover the expenses incurred as a result of a chronic terminal disease.

The aim of this study was to compare the demographic situation of children with ESRD who were treated at the Hospital Infantil de Mexico Federico Gomez (HIMFG) in the years 2003 and 2009.


We reviewed the clinical records provided by the De-partment of Biostatistics and clinical archives of the HIMFG of patients registered in 2003 and in 2009 with ESRD. From the clinical files, we recorded data on age, gender, etiology of renal disease, socioeconomic level assigned by the social worker (based on the number of minimum wages), type of funding for the support and place of origin.

Patients were classified according to their scores on the socioeconomic evaluation at different levels re-lated to family income. The classification is as follows:

Level 1. One to one and a half times the minimum salary

Level 2. More than three minimum salaries Level 3. More than four and a half times the mini-

mum salary Level 4. More than six times the minimum salary Level 5. Over eight minimum salaries Level 6. More than ten times the minimum salary

or patients subrogated by other institutionsFor statistical analysis, we used Student t test or χ2.

RESuLTS

In 2003 there were 69 patients with ESRD, whereas in 2009 there were 50 patients, i.e., in 6 years there was a decrease of 28% in patients with ESRD treated at the HIMFG.

Table 1 shows the demographic characteristics of patients treated in 2003 and in 2009. There were no dif-ferences with regard to the average age or to gender; however, the number of patients with an unknown etiology was significantly reduced in 2009 (60% in 2003 vs. 46% in 2009, p <0.05, χ2).

With regard to socioeconomic level, according to the so-cial worker in 2003 there were 31 patients in level 1 (45%), eight patients from level 2 (12%) and 29 patients representing

Table 1. Demographic characteristics of children with CRD treated at the Hospital Infantil de México Federico Gómez (2003 and 2009)

2003n= 69

2009n=50

p*

Age 11 ± 4.39 11 ± 4.53 1.00

Gender (n, %) 0.17

• Male 36 (52%) 28 (56%)

• Female 33 (48%) 22 (44%)

Etiology of uremia (n, %) 0.01

• Unknown 41 (60%) 23 (46%)

• Structural 18 (26%) 7 (14%)

• Other 10 (14%) 20 (40%)

*p value obtained using Student t test or c2 test.CRD, chronic renal disease.


Analysis of sociodemographic features of patients with end-stage chronic renal disease: differences in a 6-year period

an unspecified level (42%), probably because they were not treated in the emergency department and were not admitted into a rehabilitation program. In 2009 there were 32 level 1 patients (64%), nine patients from level 2 (18%) and only one patient (2%) at an unspecified level (Table 2).

With regard to type of financial support, in 2003 (as well as in 2009) the father was the main provider. The most frequent trades were tradesman, businessman, driver and bricklayer. In regard to maternal financial support, the most frequently reported type of work was that of housekeeper (Table 2).

In the years evaluated, most patients came from the State of Mexico and from the Federal District. There was a downward trend in the number of patients from other states, with 30% in 2003 and 16% in 2009 (p = 0.06) (Table 2). In 2003, in addition to the 48 patients from the Fed-eral District and State of Mexico, there were six patients from the state of Guanajuato (7%), three from the state of Guerrero (4%) and 12 patients representing more than nine different states. Moreover, in 2009 there were only eight patients from seven different states.

Table 2. Socioeconomic level, type of financing, place of residence and admission to long-term rehabilitation program for children with CRI attended in 2003 and 2009

2003(n=69)

2009(n=50)

p*

Socioeconomic level (n,%) 0.01

• 1 31 (45%) 32 (64%)

• 2 8 (12%) 9 (18%)

• Other 0 8 (16%)

• Not specified 29 (42%) 1 (2%)

Type of financing (n,%) 0.28

• Paternal 56 (81.2%) 34 (68%)

• Maternal 10 (14.5%) 12 (24%)

• Not specified 3 (4.3%) 1 (2%)

Place of residence (n,%) 0.06

• State of México 44 (64%) 34 (68%)

• Federal District 4 (6%) 8 (16%)

• 34 Other states 21 (30%) 8 (16%)

Admission to long-term rehabilitation program (n,%)

23 (33%) 29 (58%) 0.007

*p value obtained using c2.CRD, chronic renal disease.

In 2003, only 33% of patients were able to enter a long-term rehabilitation program. This means that 46 patients returned home with ESRD due to lack of socioeconomic resources. Of the 23 patients who managed to enter the rehabilitation program, 16 were transplanted within 12 months. Admission into the rehabilitation program in-creased significantly in 2009 with 29 patients (58%). Of these, 13 patients were transplanted during a 12-month span (Table 2).

DISCuSSION

In accordance with theories of distributive justice in health care such as that provided in the HIMFG, one can conclude that liberal theory seeks to give every person according to his right and property. The criticism of this approach is that it benefits only patients whose families have the financial resources to receive medical care, which does not correspond to the reality of our environment.17,18

This report documents that the number of patients who presented to the HIMFG for ESRD was lower, with a decrease of 28% between 2003 and 2009. This may be because other highly specialized hospitals have been created in several states, along with the phenomenon of epidemiological inversion by reducing the number of births. Although most patients came from the State of Mexico, the percentage of patients from other states de-creased significantly (from 30% in 2003 to 16% in 2009).

There were no differences in age at diagnosis. The av-erage age was 11 years. This may indicate that there has been progress in the early diagnosis of the disease. There were no differences regarding gender.

Regarding the etiology of renal failure, in 2009 the primary cause in 54% of children was able to be achieved, whereas in 2003 it was only 40%. This is important because some conditions may recur in the transplanted kidney, and knowing the epidemiology of renal failure can allow for developing strategies for timely detection and treatment.6,19,20

In adults, early detection of risk groups (diabetic pa-tients, obese patients, hypertensive patients or relatives with kidney disease) has been implemented by the National Kidney Foundation program called KEEP (Kidney Early Evaluation Program). To date the program is the most ef-fective community screening to identify individuals >18 years of age with risk of renal disease.20, 21 In Mexico, us-


Guillermo Cantú, Graciela Rodríguez, Mercedes Luque-Coqui, Benjamín Romero, Saúl Valverde, Silvia Vargas, Alfonso Reyes-López, Mara Medeiros

ing this program we have detected a prevalence of chronic kidney disease of 22% in the Federal District and of 33% in the state of Jalisco. The high prevalence is highlighted, little known even in subjects with high risk factors.8 A similar program for the pediatric population does not exist, and given that the causes of uremia are different in children, one would have to select the specific risk factors for screening in this population. History of prematurity, acute renal insufficiency, urinary tract infections, congeni-tal malformations, type I diabetes mellitus, obesity, and hypertension, among others, are suggested.1

Regarding socioeconomic status, there was an increase in the level of poverty (socioeconomic levels 1 and 2) from 57 to 84% in patients who were treated at the hospital. It is noteworthy that in 2003 there was a high percentage of patients at an unspecified level, so the data are now more representative.

Although a greater number of patients with low so-cioeconomic status are seen, the number of patients who entered a long-term rehabilitation program (dialysis or transplantation) increased from 33% in 2003 to 58% in 2009.

It is gratifying to report that more than half of the children entering rehabilitation programs are transplanted during the 12 months following diagnosis. Kidney trans-plantation is the optimal treatment for these patients because it allows better growth and development and impacts on the quality of life.9 It is also noted as the best method for low-income countries because the cost of maintaining an immunosuppressed patient is less than maintaining them under dialysis.22

We hope that the Seguro Popular program in Mexico will soon include renal transplantation as the universal treatment for children with renal insufficiency as in other countries in Latin America and the Caribbean.17

REFERENCES

1. Medeiros M, Muñoz-Arizpe R. Enfermedad renal en niños. Un problema de salud pública. Bol Med Hosp Infant Mex 2011;68:259-261.

2. López-Cervantes M, Rojas-Russell M, Tirado-Gómez LL, Durán-Arenas L, Pacheco-Domínguez RL, Venado-Estrada AA, et al. Enfermedad renal crónica y su atención mediante tratamiento sustitutivo en México. Facultad de Medicina, Uni-versidad Nacional Autónoma de México, México D.F. México; 2009.

3. Hogg RJ, Furth S, Lemley KV, Portman R, Schwartz GJ, Coresh J, et al. National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification. Pediatrics 2003;111:1416-1421.

4. Klarenbach S, Manns B. Economic evaluation of dialysis therapies. Semin Nephrol 2009;29:524-532.

5. Harambat J, van Stralen KJ, Kim JJ, Tizard EJ. Epidemiol-ogy of chronic kidney disease in children. Pediatr Nephrol 2012;27:363-373.

6. Warady BA, Chadha V. Chronic kidney disease in children: the global perspective. Pediatr Nephrol 2007;22:1999-2009.

7. Ardissino G, Dacco V, Testa S, Bonaudo R, Claris-Appiani A, Taioli E, et al. Epidemiology of chronic renal failure in children: data from the ItalKid project. Pediatrics 2003;111:e382-e387.

8. Obrador GT, García-García G, Villa AR, Rubilar X, Olvera N, Ferreira E, et al. Prevalence of chronic kidney disease in the Kidney Early Evaluation Program (KEEP) México and com-parison with KEEP US. Kidney Int Suppl 2010:S2-S8.

9. Medeiros-Domingo M, Romero-Navarro B, Valverde-Rosas S, Delgadillo R, Varela-Fascinetto G, Muñoz-Arizpe R. [Renal transplantation in children]. Rev Invest Clin 2005;57:230-236.

10. Beauchamp TL. Methods and principles in biomedical ethics. J Med Ethics 2003;29:269-274.

11. Buchanan A. A health-care delivery and resource allocation. In: Veatch RM, ed. Medical Ethics. Boston: Jones and Bartlett Publishers; 1997. pp. 321-358.

12. Sakhuja V, Sud K. End-stage renal disease in India and Paki-stan: burden of disease and management issues. Kidney Int Suppl 2003:S115-S118.

13. Yeates K. Health disparities in renal disease in Canada. Semin Nephrol 2010;30:12-18.

14. Xue JL, Eggers PW, Agodoa LY, Foley RN, Collins AJ. Lon-gitudinal study of racial and ethnic differences in developing end-stage renal disease among aged medicare beneficiaries. J Am Soc Nephrol 2007;18:1299-1306.

15. Franco-Marina F, Tirado-Gómez LL, Venado-Estrada A, Moreno-López JA, Pacheco-Domínguez RL, Durán-Arenas L, et al. Una estimación indirecta de las desigualdades actuales y futuras de la frecuencia de enfermedad renal crónica terminal en México. Salud Publica Mex 2011;53(suppl 4):506-515.

16. García-García G, Renoirte-López K, Márquez-Magaña I. Disparities in renal care in Jalisco, Mexico. Semin Nephrol 2010;30:3-7.

17. Cantú-Quintanilla G, Orta-Sibú N, Romero-Navarro B, Luque-Coqui M, Medeiros-Domingo M, Grimoldi I, et al. Patrones de suficiencia y prioridad de la justicia distributiva en atención de los pacientes pediátricos con enfermedad renal crónica terminal en América Latina y el Caribe. Arch Latin Nefr Ped 2010;10:25-33.

18. Cantú-Quintanilla G, Orta-Sibu N, Romero-Navarro B, Luque-Coqui M, Rodríguez-Ortega EG, Reyes-López A, et al. Acceso a trasplante renal de donante fallecido en pacientes pediátricos de América Latina y el Caribe. Pers Bioét 2010;14:151-162.

19. Staples A, Wong C. Risk factors for progression of chronic kidney disease. Curr Opin Pediatr 2010;22:161-169.

20. Whaley-Connell AT, Vassalotti JA, Collins AJ, Chen SC, McCullough PA. National Kidney Foundation's Kidney Early


Analysis of sociodemographic features of patients with end-stage chronic renal disease: differences in a 6-year period

Evaluation Program (KEEP) annual data report 2011: executive summary. Am J Kidney Dis 2012;59(suppl 2):S1-S4.

21. Obrador GT, Mahdavi-Mazdeh M, Collins AJ; Global Kidney Disease Prevention Network. Establishing the Global Kidney Disease Prevention Network (KDPN): a position statement

from the National Kidney Foundation. Am J Kidney Dis 2011;57:361-370.

22. Garcia GG, Harden P, Chapman J; for the World Kidney Day Steering Committee. The global role of kidney transplantation. Transplantation 2012;93:337-341.


bronchial mucoepidermoid carcinoma: a rare tumor in children

clinical case


Luis Hernández-Motiño, Yarisa Brizuela, Verónica Vizcarra, Rubén Cruz, Lourdes Jamaica, José Karam

Servicio de Neumología Pediátrica, Hospital Infantil de México Federico Gómez, México D.F., México

Correspondence: Dr. Luis Carlos Hernández MotiñoServicio de Neumología Pediátrica Hospital Infantil de México Federico Gómez México D.F., MéxicoE-mail: [email protected]; [email protected]


INTRODuCTION

Primary pulmonary neoplasms are rare in children.1 Because symptoms are nonspecific, diagnosis and management may be delayed, thus worsening the prog-nosis. These tumors should be suspected when there are persistent or recurrent respiratory symptoms. Initially, common causes should be ruled out such as infectious, immunodeficiencies, and cystic fibrosis, among others. Diagnostic approach should include imaging studies such as plain chest x-rays and, if necessary, other studies such as chest computed tomography (CT) or bronchoscopy, which determine the nature of the process.2 Among the bronchial tumors, the most frequent are carcinoid tumors

AbSTRACT

background. Lung neoplasms are rare in children. Mucous and serous glands from trachea and upper airway contain cells similar to those of the major salivary glands. Of these glands there is a group of very rare tumors including adenoid cystic carcinoma, mucoepidermoid carcinoma, pleomorphic adenoma, acinic cell carcinoma and oncocytoma. Mucoepidermoid carcinomas (MEC) represent 0.2% of cases of lung cancer at any age, and slightly more than 100 children have been reported with this entity in the international literature. Formerly classified as bronchial adenoma, this term is inappropriate for a slow-growing neoplasm and may be locally invasive. These tumors present a relatively benign course when they correspond to tumors of low-grade malignancy and may be manifested as recurrent pneumonia or slow resolution. Children with these clinical manifestations should be thoroughly evaluated including endoscopic and tomographic studies. Surgical resection of the affected lung lobe with the respective lobar hilar lymph nodes is the most accepted treatment.Case Report. We report the case of a 10-year-old female with a history of recurrent airway infection and two left lung pneumonias. Chest tomography showed a left bronchus stenosis confirmed by endoscopy. Following pneumonectomy, histopathological and immunohisto-chemical findings reported a low-grade MEC. Conclusions. MEC of low-grade malignancy has a good prognosis with complete tumor excision that requires a comprehensive approach that includes bronchoscopy.Key words: mucoepidermoid carcinoma, cancer, lung.

(in 80–90% of the cases). The remaining tumors (10–20%) are those described as carcinomas of the salivary glands (adenocystic and mucoepidermal carcinomas).3 Pulmonary mucoepidermoid carcinoma (MEC) is a rare malignant tumor (0.2%). It may originate in the trachea, main bron-chus, or in the lobes or segmental bronchi. Despite its low malignant potential, it has a benign behavior. Therefore, in the majority of the cases conservative pulmonary resection is an adequate and sufficient treatment with an eventual good prognosis.1,3-5

CLINICAL CASE

We present the case of a 10-year-old previously healthy female student who from 2008 presented with recurrent airway infections (RAI) and was hospitalized twice for left lung pneumonia. She has been treated at our service since June 2011. She was referred due to RAI with oc-casional episodes of hemoptysis. An approach to rule out common causes of RAI was begun, e.g., sinusitis, immunodeficiencies, cystic fibrosis, among others. Chest x-ray was done and demonstrated total left atelectasis with an area of consolidation at the left base (Figure 1). The patient was initially managed with antibiotics, steroids and


Bronchial mucoepidermoid carcinoma: a rare tumor in children

bronchodilators with no improvement and with persistence of total atelectasis. High-resolution chest CT reported left bronchial stenosis, left pulmonary necrosis, areas of bron-chiectasis and fibrosis (Figure 2). The diagnostic approach was later complemented with bronchoscopy. The findings in the left bronchus were as follows: ill-defined reddish-colored, solid granulomatous mass completely occluding the lumen of the left bronchus without allowing passage of the bronchoscope (Figure 3). Biopsy of the lesion reported left bronchial granuloma. A ventilation/perfusion scan of the lung was done that showed functional absence of the left lung and the right lung with normal perfusion and ventilation. Total pneumonectomy was performed. The pathology report was as follows:

1. Left bronchial tumor. Low-grade MEC with vascu-lar permeation and lesion on the surgical margins (pancytokeratin, EMA, CD 31, CD 34, FACTOR VIII positive, adequate controls).

2. Hypoplastic left lung. It was later decided, in conjunction with the Oncology

Service, to keep the patient under observation because of the low grade of malignancy of the tumor. During outpa-tient pulmonary follow-up there have been no episodes of pneumonia or RAI.

Figure 1. Posteroanterior chest x-ray where atelectasis of the left lower lobe is seen with overdistention of the right lung.

DISCuSSION

Primary lung tumors are rare in the pediatric population. The majority correspond to carcinoid tumors, adenocystic carcinoma and MEC.6,7 Of these, mucoepidermoid tumors are the least frequent. It has been proposed that the MEC originates in the mucosal and serosal glands of the cen-tral tracheobronchial tree. Other structures can develop MEC such as the salivary, mammary, thyroid gland or skin.2,3 Histologically, two types of MEC are character-ized according to the degree of malignancy as proposed by Heitmiller et al.8

Figure 2. Axial cut (A) and coronal cut (B) chest computed to-mography (CT). Total obstruction of the left bronchus with total left atelectasis is seen (black arrow) and areas of necrosis within the interior (arrowhead).

A

b


Luis Hernández-Motiño, Yarisa Brizuela, Verónica Vizcarra, Rubén Cruz, Lourdes Jamaica, José Karam

lapse of the left lung. This prolonged evolution of almost 2 years was due to lack of an adequate diagnostic approach before arrival at our hospital and delayed the diagnosis 18 months, resulting in pneumonectomy.

The most common radiological manifestation is the presence of an intraluminal mass in the tracheobronchial tree, although it is difficult to predict its endobronchial situation when it is found in the segmental bronchus. Pulmonary lesion secondary to obstruction such as the atelectasis presented by our patient is found in one third of the cases.13,14 On chest CT it may appear as an oval or lobulated mass with well-defined borders with puntiform calcifications in half of the cases, and slight reinforce-ment with contrast media. The greatest diameter of the tumor is parallel to the direction of the branches of the airway in which it is found.1,2 In this case, no well-defined mass was seen, only stenosis of the left main bronchus, total left atelectasis and left pulmonary necrosis second-ary to the prior events of pneumonia. For this reason, it was decided to do an exploratory endoscopy, which corroborated the presence of a mass that occluded the entire left bronchus.

A biopsy was carried out followed by scheduling of pneumonectomy. This reinforces the importance of car-rying out endoscopic study for the diagnostic approach of these patients.4,11 For a low-grade malignant pulmonary MEC, lobectomy or segmentectomy is sufficient for cure. Bronchoscopic laser resection may be indicated in the case of small tumors where there is no question of compromise of the parenchyma.7,15-18 The prognosis for mucoepider-moid bronchial tumors is closely related with tumor grade and extension at the time of diagnosis. Unlike high-grade MECs, progression of low-grade MECs predominantly in children is slow, which allows for a good prognosis at the time of diagnosis (if established at the beginning of the diagnostic process). Diagnosis can be made more rapidly with the early search of these tumors in patients with chronic cough or RAI, improving the prognosis.5,7,14

In conclusion, primary lung neoplasms, although rare in children, should be included in the differential diagnosis of patients with chronic lung disease. With the presentation of persistent respiratory symptoms, chest x-ray should be done. Diagnosis of lung atelectasis that does not improve with conservative treatment warrants diagnostic bronchos-copy. Among the list of endobronchial lesions, one must consider MEC and confirm its diagnosis with endoscopic

Figure 3. Fiberoptic bronchoscopy where tumor is observed oc-cluding the left main bronchus (arrow).

1) Low gradepresent macroscopically as well-delin-eated endobronchial polypoid tumors covered with a thin mucosa. Microscopically they are heterogeneous with pre-dominance of glandular elements with muocoid content. Benign tumors represent the majority of pediatric cases. In the international literature only one case that developed metastasis to peribronchial nodes has been reported.

2) High-grade macroscopically infiltrating. Micro-scopic study reveals a predominance of epidermoid elements, atypias, hyperchromatism and elevated mitotic activity. This type of MEC is less common and with a poor prognosis and almost always presents in adults. Only two cases of this type have been reported in the pediatric age.

Symptoms produced by endobronchial tumors are irritation (cough and hemoptysis) or bronchial obstruc-tion.9,10 The insidious evolution with nonspecific clinical manifestations are generally suggestive of other diagnoses such as asthma, obstructive pneumonia or foreign body.11 They can present as pulmonary phenomena in the zones distal to the bronchial obstruction, as recurrent pneumonia, bronchiectasis, pulmonary hyperinsufflation (in case of partial obstruction) and atelectasis (if there is total bron-chial obstruction).11,12 Prolonged evolution of the patient resulted in total obstruction of the bronchus and total col-


Bronchial mucoepidermoid carcinoma: a rare tumor in children

biopsy. During pediatric age, with complete excision, MEC has a good prognosis.

REFERENCES

1. Alves dos Santos JW, Licks da Silveira M, Tonello C, Du-bermann M. Carcinoma mucoepidermoide de bajo grado: una causa rara de neumonía recurrente. Rev Am Med Resp 2005;1:52-54.

2. Sánchez RI, Arce QM. Carcinoma mucoepidermoide bronquial. Diagnóstico diferencial de neumonía recurrente. Rev Med Costa Rica Centroamérica 2007;64:113-117.

3. Reyes-Kattar J, Gómez M, Gómez L, Mota D, Giménez C, Arcamone G, et al. Carcinoma mucoepidermoide de pulmón en la infancia. Reporte de caso, revisión de la literatura. Rev Venez Oncol 2007;19:344-348.

4. Oura H, Ishida I, Niikawa H, Mori Y, Ube K, Sasajima T, et al. Sleeve resection of the left main bronchus for broncho-genic carcinoid for preserving lung parenchyma. Kyobu Geka 2010;63:795-799.

5. El Mezni F, Ben Salha I, Ismaïl O, Braham E, Zeddini A, Ayadi-Kaddour A, et al. Mucoepidermoid carcinoma of the lung. A series of 10 cases. Rev Pneumol Clin 2005;61:78-82.

6. Fujita K. Mucoepidermoid carcinoma in a 13-year-old girl; report of a case. Kyobu Geka 2009;62:423-426.

7. Ghraïri H, Kartas S, Ammar J, Abid H, Ayadi A, Kilani T, et al. Prognosis of mucoepidermoid carcinoma of the bronchi. Rev Pneumol Clin 2007;63:29-34.

8. Heitmiller RF, Mathisen DJ, Ferry JA, Mark EJ, Grillo HC. Mucoepidermoid lung tumors. Ann Thorac Surg 1989;47:394-399.

9. Wu M, Wang Q, Xu XF, Xiang JJ. Bronchial mucoepidermoid carcinoma in children. Thorac Cardiovasc Surg 2011;59:443-445.

10. Vogelberg C, Mohr B, Fitze G, Friedrich K, Hahn G, Roesner D, et al. Mucoepidermoid carcinoma as an unusual cause for recurrent respiratory infections in a child. J Pediatr Hematol Oncol 2005;27:162-165.

11. Andersen JB, Mortensen J, Damgaard K, Skov M, Sparup J, Petersen BL, et al. Fourteen-year-old girl with endobronchial carcinoid tumour presenting with asthma and lobar emphy-sema. Clin Respir J 2010;4:120-124.

12. Yu CH, Li J, Yu JQ, Wang B, Wang T, Wang DJ. Clinicopatho-logical features and prognosis of bronchial mucoepidermoid carcinoma: analysis of 21 cases. Zhonghua Yi Xue Za Zhi 2007;87:41-43.

13. Firinci F, Ates O, Karaman O, Tekin A, Ozer E, Cakmakci H, et al. A 7-year-old girl with cough, fever, pneumonia. Diagnosis: mucoepidermoid carcinoma (MEC). Pediatr Ann 2011;40:124-127.

14. Sogut A, Yilmaz O, Yuksel H. A rare cause of persistent atelec-tasis in childhood: mucoepidermoid carcinoma. Tuberk Toraks 2008;56:325-328.

15. Lei J. Successful treatment of bronchial mucoepidermoid carcinoma in a longstanding collapsed lung. Ann Thorac Surg 2010;90:655-657.

16. Fauroux B, Aynie V, Larroquet M, Boccon-Gibod L, Ducau le Pointe H, Tamalet A, et al. Carcinoid and mucoepidermoid bronchial tumours in children. Eur J Pediatr 2005;164:748-752.

17. Roby BB, Drehner D, Sidman JD. Pediatric tracheal and endo-bronchial tumors: an institutional experience. Arch Otolaryngol Head Neck Surg 2011;137:925-929.

18. Al-Qahtani AR, Di Lorenzo M, Yazbeck S. Endobronchial tu-mors in children: institutional experience and literature review. J Pediatr Surg 2003;38:733-736.


Hermansky-Pudlak syndrome: variable clinical expression in two cases

clinical case


Rogelio Paredes Aguilera,1 Norma López Santiago,1 Angélica Monsiváis Orozco,2 Daniel Carrasco Daza,2 José Luis Salazar-Bailón1

1 Servicio de Hematología Pediátrica, 2Servicio de Patología Clínica, Instituto Nacional de Pediatría, México, D.F., México

Correspondencia: Dr. José Luis Salazar BailónServicio de Hematología Pediátrica, Instituto Nacional de Pediatría México, D.F., MéxicoE-mail: [email protected]


AbSTRACT

background. Hermansky-Pudlak syndrome is a genetic disorder characterized by albinism and bleeding of varying degrees due to altera-tion in the structure of the platelets. The disorder may be accompanied by pulmonary, intestinal or kidney involvement. Identification of several genetic alterations in this syndrome has been reported.Case reports. We present two cases: the first of an adolescent male with mucocutaneous albinism and renal involvement. Bleeding epi-sodes started after being subjected to invasive studies and venipunctures, developing a perinephric hematoma. After severe sepsis, the patient developed hemoperitoneum and pulmonary hemorrhage, which precipitated the patient’s death. Diagnosis was made postmortem. In the second case, a female patient was diagnosed during infancy due to albinism and bleeding episodes, with progressive pulmonary fibrosis that to date has limited her vital lung capacity.Conclusions. Early diagnosis of the syndrome as well as the correct approach may prevent the development of complications or limit the evolution. It is still under debate whether the genetic alterations described are associated with the expression of any particular clinical manifestation.Key words: Hermansky-Pudlak syndrome, albinism, hemorrhage, pulmonary fibrosis, renal failure.

INTRODuCTION

Hermansky-Pudlak Syndrome (HPS) is a multisystemic disorder characterized by the presence of tyrosinase-pos-itive oculocutaneous albinism, hemorrhagic disease with impaired platelet structure and, in some cases, pulmonary fibrosis, colitis granulomatous or enteropathic granuloma-tous renal disease secondary to disease due to lysosomal storage of ceroid lipofuscin. HPS was first described in 1959. Initially, it was believed to be a single disease; however, it is now considered to be a heterogeneous group of at least eight autosomal recessive linked disorders that share a common genetic pathway.

A diverse number of experimental studies have rec-ognized the association of HPS1, AP3B1, HPS3, HPS4,

HPS5, HPS6, DTNBP1 and BLOC1S3 genes with HPS. However, to date there is a debate about whether any particular expression is directly related to a determined clinical picture. We are presenting two clinical cases of patients with this syndrome in which classic clinical signs were observed, but seriously affected two different organs.

CLINICAL CASES

Case 1

We present the case of a 13-year-old male who was the second child in his family and a descendant of Mexican origin. His parents are healthy and a natural birth was recorded with weight and height in the 50th percentile for age. The patient experienced normal growth and devel-opment with an albino phenotype, for which no specific diagnosis was made. His clinical condition initiated with a high fever without predominance of occurrence, general malaise, fatigue, weakness, nonproductive cough, sore throat and ascending and rapidly progressive lower limb edema. He was prescribed intramuscular gentamicin treat-ment for 4 consecutive days, furosemide (20 mg/12 h for 8 days), trimethoprim with sulfamethoxazole (unspecified dose for 5 days) and prednisone (10 mg/24 h for 8 days).



The patient experienced a torpid evolution that progressed insidiously. One month after the onset of fever, the parents brought the patient to the emergency room of the National Institute of Pediatrics in Mexico City (INP) because of shortness of breath and orthopnea. Physical examination documented widespread lack of skin pigment, widespread poliosis, high-speed horizontal nystagmus, iris atrophy with gray/blue coloring, positive transillumination, and retina with macular bilateral hypoplasia without pigment in the right eye. They also corroborated further clinical data such as acute renal illness, anasarca, nephritis, congestive heart failure due to hypervolemia, arterial hypertension, pulmonary edema, and ascites.

Laboratory analysis showed the following results: 7.0 Hg, Hct 21%, MCV 90, MCH 28, 11,700 leukocytes, neu-trophils 83%, bands 2%, lymphocytes 15%, and platelets 265,000. Blood chemistry results were as follows: serum creatinine 9.96, BUN 190, glucose 153, sodium 131, potassium 6.1, and chloride 106. Urinalysis was cloudy yellow, urine specific gravity 1.020, pH 5, protein 75, blood 250, leukocytes 5, erythrocytes 75. Venous blood gases were pH 7.26, pCO2 20.0, pO2 39, HCO3 8.9, base excess -16.9, lactate 6.

With the above, the following diagnoses were integrated: normochromic normocytic anemia, uremia, proteinuria, hematuria, compensated metabolic acidosis and symptom-atic hyperkalaemia. The patient received medical treatment based on loop diuretics, acute peritoneal dialysis, and prazo-sin for arterial tension management. The patient exhibited a successful evolution over a 3-week period.

To achieve stabilization of the patient, ultrasound-guided percutaneous renal biopsy was performed. During the immediate postoperative period, the patient developed a left perirenal hematoma of 5 x 4 x 2 cm with 38 mL fluid. This was corroborated with an ultrasound and involved the renal capsule, fascia and adjacent muscle (Figure 1). It was reabsorbed after 15 days of conservative treatment. The biopsy material obtained was insufficient or inconclusive to establish a diagnosis.

Based on the suspicion of a multisystemic disease (kidney, lung, hematologic) with decreased C4 and normal C3, the patient was initially treated for systemic lupus erythematosus (SLE) and consisted of boluses of methyl-prednisolone at 30 mg/kg of weight for 7 consecutive days.

When the patient was discharged due to improvement, primary and secondary outpatient coagulation tests were

conducted and normal clot retraction was found, positive tourniquet, normal bleeding time and aggregometry with a slight decrease in the ADP (adenosine diphosphate) curve and epinephrine. From the time of symptom onset, the patient showed normochromic normocytic anemia (chronic disease). Total neutrophils ranged from 1,800 to 2,600 and platelets between 146,000 and 334,000. Clotting times were always normal. Bone marrow presented data of red cell hyperplasia without evidence of blue histiocytes or alterations in megakaryocytes (Table 1).

One month after discharge, the patient was readmitted to the emergency room with symptoms of acute hyperten-sion secondary to renal failure. The event was controlled with prazosin and diuretics for 3 days, for which the patient had a favorable outcome.

As a consequence to the progressive decline in renal function, it was necessary to place a permanent cath-eter for dialysis. This became infected three times with Staphylococcus epidermidis, thus requiring treatment with vancomycin i.v. and i.p. for 10 days without complications.

Figure 1. Renal ultrasound showing the size and the relationship between the cortex and normal marrow.

Table 1. Results of patient aggregometry

Patient (%) Control (%)

ADP 62 84

Collagen 64 78

Epinephrine 60 86

Ristocetin 78 70

AA 70 70

ADP, adenosine diphosphate; AA, arachidonic acid.


Rogelio Paredes Aguilera, Norma López Santiago, Angélica Monsiváis Orozco, Daniel Carrasco Daza, José Luis Salazar-Bailón

During the third colonization, the patient developed bacterial peritonitis complicated with bilateral pneumonia. Despite treatment with specific antibiotics according to the culture and sensitivity, the patient experienced deteriora-tion in his condition and eventually led to septic shock. Deterioration of the patient’s general condition persisted despite supportive treatment. Disseminated intravascular coagulation (DIC) was presented with organ dysfunc-tion involving the heart, lung and liver. Peritonitis was documented due to Candida albicans and Enterococcus faecium, as well as a right lung abscess with empyema. Treatment included broad spectrum antibiotics (merope-nem and vancomycin) for 21 days, with doses adjusted for renal function. The patient demonstrated whitish, hyper-emic lesions on gums and cheeks, with a necrotic aspect on the nose, which led to suspicion of fungal infection. Nasal and oral aspergillosis secondary to DIC was confirmed by culture, and bleeding developed in venipuncture sites along with malignant hemoperitoneum.

The patient died as a result of massive pulmonary hemorrhage and cardiac arrest despite the treatment he received.

During postmortem study and conducting an intentional search, bone marrow and patient’s blood were analyzed by electronic microscopy. Platelets showed an irregular dis-coid shape, granulations, canalicular system, mitochondria and normal structure microtubules (Figure 2). Absence of dense granules in the platelet structure was noted as well as replacement by collagen fragments (Figure 3). These data, together with the clinical course of the patient, al-lowed us to establish the diagnosis of HPS in this patient.

Case 2

We present the case of a 5-year-old female who was ad-mitted without relevant perinatal history. The patient was of Mexican origin and descent. Her father had sequelae of neurocysticercosis and a paternal aunt was reported to have lupus erythematosus. The patient’s two brothers are apparently healthy.

Among her important clinical events, the patient pre-sented a Henoch-Schönlein blister at the age of 1 year and 3 months, for which she received unspecified hospital treatment. She was discharged at 2 weeks without appar-ent sequelae.

During her follow-up and while performing serial blood counts, mild transient neutropenic events were docu-

Figure 2. Electron microscopy showing granulations (1), canalicular system (2), mitochondria (3) and microtubules (4). Irregular collagen fragments replacing dense granules are also seen.

mented without cyclical pattern and with total neutrophil nadir between 1,500 and 1,800. For this reason, the patient was referred to the pediatric hematologist who initiated treatment with granulocyte-stimulating colony factor (GSCF) at a dose of 5 µg/kg/weight during alternating periods. With this treatment, the numbers of neutrophils rose to normal levels. No specific alterations were seen in the platelet counts. There was an intentionally search of structural alterations in the platelet number. Using electron microscopy, 32 platelets were studied of which 27 lacked dense granules, i.e., an average of 0.27 dense bodies per platelet, which is well below the normal values (Figure 4).

Again, during routine examination, hepatomegaly was found. An ultrasound determined the presence of a 3 x 4 x 3 cm liver mass. Liver biopsy was performed at the age of 2 years and 3 months. It was concluded that the mass was secondary to infection caused by Epstein-Barr virus. To date the patient receives monthly treatment with i.v. doses of immuomodulatory gammaglobulin.

At 3 years of age the patient demonstrated severe mucositis with sloughing of both cheeks and mucosal



detachment, compromising gums and tongue. She was treated with clindamycin and fluconazole for 10 days with favorable results.

The patient has presented multiple cases of lower respiratory tract infection with varying severity. The first event was pneumonia was at 11 months of age with unspecified treatment. At 2 years of age, pneumonia was complicated by pleural effusion, which required hospital treatment for 6 weeks. The third case of pneumonia was 2 months after discharge from the hospital and required treatment with mechanical ventilation and 15 days of treatment with unspecified broad-spectrum antibiotics. The fourth event of pneumonia was presented at 2 years and 8 months of age, with a torpid evolution despite management with broad-spectrum antibiotics. Bronchos-copy was performed with bronchoalveolar lavage, and pulmonary candidiasis was reported. On this ocassion, the patient was treated with itraconazole (50 mg/kg of weight for 21 days) and subsequently with continuous prophylaxis. She persisted with a sporadic, productive

cough for >2 years, progressive wheezing with medium efforts and later with lower efforts. At 3 years of age the patient already showed signs of chronic hypoxia with clubbing fingers and pectus carinatum. She also had recurrent cases of bronchospasm necessitating hospital treatment with supplemental oxygen, bronchodilators and antibiotics. For this reason she was referred to the National Pediatric Institute (INP).

Physical examination of the patient revealed light tan skin color, silver-colored hair with dark brown eyebrows and eyelashes, coarse facies with bulbous nose, prominent forehead at the level of the metopic suture, bilateral epi-canthus, eyes with isochoric pupils and normal reflexes, fundus of the eye with 30 to 40% excavation of the papilla, macula with no foveolar brightness, gingival hyperplasia, no cardiovascular compromise, hepatomegaly of 4-4-1 cm below the costal margin and generalized hypotonia, pectus carinatum, normal inspiration and expiration, bilateral crepitant rales with “sail sign” and bilateral reticulonodular infiltrates on chest x-ray (Figure 5). At 5 years of age the

Figure 3. Replacement of missing collagen-dense granules is clearly shown.

Figure 4. Electron microscopy performed in blood. Normal platelet structures are observed as well as the absence of dense granules.



DISCuSSION

The classic form and description of diagnostic criteria of HPS are the presence of mucocutaneous albinism and bleeding diathesis of variable severity.1,2 It is of high di-agnostic value to document the decreased index of dense granular bodies in platelets using electron microscopy. This was carried out in both patients. In an optional and complementary form we can determine the presence of a complex amorphous lipid protein and ceroid-lipofuscin autofluorescence in urinary sediment and in parenchymal cells. However, this is not essential for diagnosis.1,3-9

Albinism in this syndrome is characterized with the skin having a white to olive color, but always in a lighter shade than the rest of the family. In addition, hair color is usually between white and light brown, with a tendency to become darker over the years.1,4-6 A constant is the presence of nystagmus from birth that, generally, is decreased alter-nating with visual acuity. It is fast moving with a tendency to decrease with age, and it is usually most severe when the patient is tired or under stress. The iris color is bluish and

Figure 6. Lateral chest x-ray confirming the presence of reticulo-nodular infiltrate.

Figure 5. AP chest x-ray showing bilateral reticulonodular infiltration and prominent pulmonary artery is demonstrated.

patient presented with a new case of pneumonia, which was treated with meropenem for 14 days.

Bilateral micronodular infiltrate was observed with chest CAT (with no apparent subpleural affection) and left-sided rounded pulmonary nodule (with well-defined edges) (Figure 6). Bronchoscopy was performed, demonstrating normal results. Bronchoalveolar lavage reported the pres-ence of abundant hemosiderophages and compatible data with lymphocytic interstitial pneumonia. Angioresonance reported vasculitis data with posterior bilateral basal con-solidation, suggestive of bronchiectasis.

Lung biopsy was performed where data were consis-tent with pulmonary fibrosis. To complement the data, echocardiogram was performed, which showed evidence of pulmonary hypertension with pulmonary artery pres-sure of 87 mmHg. The patient was was treated with sildenafil.

Respiratory function showed progressive deteriora-tion, increasing dyspnea with less stress, persistent rales, acrocyanosis, and clubbing. Treatment was initiated with supplemental oxygen when necessary, methotrexate 500 mg/kg monthly and 18 mg of deflazacort daily, nebuliza-tion with budesonide and salbutamol with ipratropium bromide as needed and i.v. gammaglobulin to 500 mg monthly. With this treatment, respiratory symptoms have decreased and the breathlessness improved as well as the overall status of the patient. In addition, the patient changed her residence to a location at sea level. Her other laboratory studies were normal except for mild persistent neutropenia and discreetly decreased NK cell cytotoxicity.



rarely does it turn blue or brown. Visual acuity is found between 20/50 and 20/400, but it is typically 20/200 and usually remains constant after early childhood.1

From the hematological viewpoint, bleeding is second-ary to the lack of dense granules in the platelets. In the normal structure, these granules contain calcium, sero-tonin, ADP, ATP, pyrophosphate and lysosomal membrane proteins. Once the platelets are activated, the granules fuse with the plasma membrane via the soluble receptor of the protein factor of the fixative sensitive to N-ethylmaleimide and undergo exocytosis, resulting in platelet recruitment. In the absence of this mechanism (secondary aggregation response), patients have prolonged bleeding time, absence of secondary wave in the ADP test and epinephrine in ag-gregometry results, as well as absence of ATP secretion in lumi-aggregometry. These studies are not suitable for diagnosis because they present a high rate of variation. However, demonstration of platelet hypogranulation in electron microscopy is considered, along with the clinical features, in the definitive diagnosis of HPS.1,3,8,9

Pulmonary fibrosis consists of a progressive lung dis-ease with a highly variable course, although symptoms generally worsen during the fourth decade of life due to the deposition of ceroid lipofuscin.1,10 Granulomatous colitis presents with clinical resemblance to Crohn’s disease due to widespread inflammation and is not infrequent to be seen in the entire digestive tract. Renal failure has been reported in cases with an isolated syndrome or even associated with lupus nephritis. However, renal dysfunction, colitis and pulmonary fibrosis have been associated with infiltration by lysosomal deposits of ceroid lipofuscin.1,11,12 Through genetic analysis we can sequence the genes involved in the origin of the syndrome, although it is still debated whether there is direct correlation with the clinical scenario of each patient. Therefore, it is only applied in experimental studies and not in daily clinical practice.1,3-9

HPS1-mutation is common among homozygous pa-tients from Puerto Rico. It is associated with pulmonary fibrosis; likewise, the HPS4 in European individuals confers a similar predisposition so it is suggested that the mutation of these genes may cause lung and hemorrhagic disease. The AP3B1 mutation is associated with persistent neutropenia and recurrent infectious conditions in the patient. Congenital neutropenia tends to be less severe than in patients with severe or cyclic chronic neutropenia and presents a tendency to develop syndromes of activa-

tion of macrophages and NK cell function. Patients with HPS3 usually have slightly marked symptoms. Albinism is characterized by minimal cutaneous hypopigmentation and even the only condition becomes ocular. Mutations of HP5, HP6, HPS7 and HPS8 have been sporadically reported.1,11-23

The patients described in this study met the diagnostic criteria of HPS and illustrated the heterogeneity of possible manifestations. Our data are consistent with those reported by Gamboa et al. which, due to the prominence of hema-tologic and pulmonary manifestations, can be considered as type 1. However, lack of purposeful approach causes a subdiagnosis and lacks most representative cases. We must always consider HPS in the differential diagnosis of newborns with oculocutaneous albinism so as to not overlook the determination of a deficiency in clotting that could lead to serious complications in the patient.

REFERENCES

1. Gahl WA. Hermansky Pudlak Syndrome. Gene Reviews. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1287

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5. Schachne JP, Glaser N, Lee SH, Kress Y, Fisher M. Her-mansky-Pudlak syndrome: case report and clinicopathologic review. J Am Acad Dermatol 1990;22:926-932.

6. Sánchez MR. Cutaneous diseases in Latinos. Dermatol Clin 2003;21:689-697.

7. El-Molfy MA, Esmat SM, Abdel-Halim MR. Pigmentary disor-ders in the Mediterranean area. Dermatol Clin 2007;25:401-417.

8. Neunert CE, Journeycake JM. Congenital platelet disorders. Hematol Oncol Clin North Am 2007;21:663-684.

9. Córdova A, Barrios NJ, Ortiz I, Rivera E, Cadilla C, Santiago-Borrero PJ. Poor response to desmopressin acetate (DDAVP) in children with Hermansky-Pudlak syndrome. Pediatr Blood Cancer 2005;44:51-54.

10. Brantly M, Avila NA, Shotelersuk V, Lucero C, Huizing M, Gahl WA. Pulmonary function and high-resolution CT find-ings in patients with an inherited form of pulmonary fibrosis, Hermansky-Pudlak syndrome, due to mutations in HPS-1. Chest 2000;117:129-136.

11. Sandrok K, Bartsch I, Rombach N, Schmidt K, Nakamura L, Hainmann I, et al. Compound heterozygous mutations in



siblings with Hermansky-Pudlak syndrome type 1 (HPS1). Klin Padriatr 2010;3:168-174.

12. Morra M, Geigenmuller U, Curran J, Rainville IR, Brennan T, Curtis J, et al. Genetic diagnosis of primary immune deficien-cies. Immunol Allergy Clin North Am 2008;28:387-412.

13. Dessinioti C, Stratigos AJ, Rigopoulus D, Katsambas AD. A re-view of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes. Exp Dermatol 2009;18:741-749.

14. Ciciotte S, Gwynn B, Moriyama K, Huizing M, Gahl WA, Boni-facino JS, et al. Cappuccino, a mouse model of Hermansky-Pudlak syndrome, encodes a novel protein that is part of the pallidin-muted complex (BLOC-1). Blood 2003;101:4402-4407.

15. Huizing M, Anikster Y, Gahl WA. Hermansky-Pudlak syn-drome and related disorders of organelle formation. Traffic 2000;1:823-835.

16. Jung J, Bohn G, Allroth A, Boztug K, Brandes G, Sandrock I, et al. Identification of a homozygous deletion in the AP3B1 gene causing Hermansky-Pudlak syndrome, type 2. Blood 2006;108:362-369.

17. Gerrard JM, Lint, D, Sims PJ, Wiedmer T, Fugate RD, McMillan E, et al. Identification of a platelet dense granule membrane protein that is deficient in a patient with the Hermansky Pudlak syndrome. Blood 1991;1:101-112.

18. Fontana S, Parolini S, Vermi W, Booth S, Gallo F, Donini M, et al. Innate immunity defects in Hermansky Pudlak type 2 syndrome. Blood 2006;107:4857-4864.

19. Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, et al. Lethal hemophagocytic lymphohis-tiocytosis in Hermansky-Pudlak syndrome type II. Blood 2006;108:81-87.

20. Gunay-Aygun M, Huizing M, Gahl WA. Molecular defects that affect platelet dense granules. Semin Thromb Hemost 2004;30:537-547.

21. White JG, Edson JR, Desnick SJ, Witkop CJ Jr. Studies of platelets in a variant of the Hermansky-Pudlak syndrome. Am J Pathol 1971;63:319-332.

22. Feng L, Novak EK, Hartnell LM, Bonifacino JS, Collinson LM, Swank RT. The Hermansky Pudlak syndrome 1 (HPS1) and HPS2 genes independently contribute to the production and function of platelet dense granules, melanosomes, and lysosomes. Blood 2002;99:1651-1658.

23. Carmona-Rivera C, Golas G, Hess R, Cardillo ND, Martin EH, O’Brien K, et al. Clinical, molecular, and cellular features of non-Puerto Rican Hermansky-Pudlak syndrome patients of Hispanic descent. J Invest Dermatol 2011;131:2394-2400. doi: 10.1038/jid.2011.228.


Newborn with hypoplastic left heart syndrome

clinicopathological case


Luis Alexis Arévalo Salas,1 Sandrino José Fuentes Alfaro,1 Jorge Omar Osorio Díaz,1 Begoña Segura Stanford,1 Mario Pérezpeña Díazconti2

1 Departamento de Cardiología, 2 Departamento de Patología Clínica y Experimental, Hospital

Infantil de México Federico Gómez, México, D.F., México

Correspondence: Dr. Luis Alexis Arévalo Salas Departamento de CardiologíaHospital Infantil de México Federico Gómez México, D.F., MéxicoE-mail: [email protected]


Summary of the Clinical History

We present the case of a male newborn (NB) 4 days of age who was referred to a tertiary hospital due to polypnea and cyanosis. The infant was the product of a first pregnancy of a 17-year-old mother who reported prenatal care from the second month of pregnancy. At 20 weeks an obstetric ultrasound noted a cardiac alteration. For this reason the mother was sent to a high specialty hospital where the condition was confirmed. Treatment based on folic acid and ferrous sulfate and two doses of anti-tetanus vac-cine was provided. At 38.6 weeks of gestation there was spontaneous rupture of membranes with onset of labor. The NB was born via eutocic labor with spontaneous cry and respiration: Apgar 9/9, weight 2515 g, height 47.5 cm. Cyanosis was noted and the newborn was transferred to the neonatal intensive care unit (NICU) where treatment with prostaglandin E1 (PGE1) was begun at an initial dose of 0.05 μg/kg/min until a maintenance dose of 0.01 μg/kg/min was reached. On the fourth day of life, the NB was transferred to the Hospital Infantil de Mexico Federico Gomez (HIMFG) for cardiac management.

On admission the NB was found to be active and reactive, without characteristic facies, perioral and nail cyanosis I/IV, and decreased pulses in all four extremities.

Blood pressure on the right arm was 72/36/48 and oxy-gen saturation was 85%. The infant was normocephalic, anterior fontanelle 2 x 2 cm, and normotensive. There was polypnea at rest, xiphoid retraction and intercostal retraction, intense left parasternal precordial hyperactiv-ity and palpable S2. On auscultation there were rhythmic heart sounds, intense and single second sound, and a 2/6 systolic murmur in the 4th left intercostal parasternal space. Pulmonary fields were clear. Abdomen was soft with mummified umbilical stump without evidence of infection. Liver was 3 cm below the right costal margin and of firm consistency. Spleen was nonpalpable. Normal male genitalia were reported.

X-ray on admission showed situs solitus, levocardia and grade III cardiomegaly with evidence of venocapillary congestion. Electrocardiogram (EKG) showed right atrial enlargement and right ventricular hypertrophy. Transfonta-nelle and renal ultrasound were done with normal results. Laboratory tests were considered within normal limits.

Two-dimensional Echocardiography with Doppler Color

Flow (Eco-bi)

In the subcostal axis there was situs solitus, levocar-dia, and normal systemic and pulmonary venous return. Atresia of the left A-V valve was documented as well as an interatrial septal defect of 4.8 mm in diameter with left to right shunt without gradient.

In the apical four-chamber cut a dominant right ven-tricular cavity was demonstrated with moderate tricuspid valve insufficiency with hypoplastic left ventricular cavity (Figure 1).

In the parasternal long axis, a hypoplastic left ventricu-lar cavity is seen from which emerges the aorta with severe hypoplasia with a 2-mm diameter (Z = -9.6). On color flow Doppler, no flow was observed through the aortic and


Luis Alexis Arévalo Salas, Sandrino José Fuentes Alfaro, Jorge Omar Osorio Díaz, Begoña Segura Stanford, Mario Pérezpeña Díazconti

mitral valves. In the parasternal short axis the diameter of the aortic ring was observed to be 2.8 mm (Z = -8.47) and pulmonary ring 12.3 mm (Z = +3.34) in anterior and left position. The ratio of the rings was 4.3:1 in favor of the pulmonary ring. The pulmonary branches were confluent. On color flow Doppler, systolic flow from a large patent ductus arteriosus (PDA) was observed. In the suprasternal axis was appreciated a suprasternal narrowing at the level of the aortic isthmus (Figure 2) suggesting juxtaductal aortic coarctation. There is a large PDA that showed a short circuit from right to left into the aorta, with retrograde flow to the aortic arch and ascending aorta.

On admission, management was begun by restricting parenteral fluids to 80 ml/kg/day, glucose 6 g/kg/min, sodium 3 mEq/kg day, 4% potassium, calcium 100 mEq/kg/ day, PGE1 0.01 μg/kg/min, furosemide 1 mg/kg/dose every 12 h, and captopril 0.2 mg/kg/dose every 8 h. During the second day of hospital stay, jaundice was detected with indirect bilirubin 12.68 mg dL, direct bilirubin 0.67 mg dL, albumin 3.2 g/dL, and globulin 2.6 g dL. Phototherapy was begun and was maintained for 3 days.

The case was discussed in a joint session with the Car-diovascular Surgery Service concluding that the patient was a candidate for total correction using the Norwood technique, which was done 10 days after admission. Operative report notes a perfusion of 1 h 55 min with a minimum temperature of 16-18°C. Surgery was without complications or incidents. However, on attempting to wean from the cardiopulmonary bypass pump, the patient showed persistent hypotension, bradycardia and desatu-ration without recovery and died in the operating room. During the surgical waiting period, the NB remained in good general condition without signs of acute heart failure and was under oral feeding until the surgical event.

Case Discussion

This was a NB who was the product of a first pregnancy of a healthy young mother who had satisfactory prenatal care. At 20 weeks of gestation (WG), congenital heart disease was detected by fetal echocardiography. For this reason the patient was sent to a tertiary level institution for management where the impression of cardiac dysfunction was confirmed. At 38 weeks there was spontaneous rupture of membranes and the NB was vaginally delivered with Apgar scores of 9/9.

The reason for admission to our service was the pres-ence of generalized cyanosis and resting polypnea with intercostal retractions, along with findings of intense pre-cordial hyperactivity and a second palpable tone, which are significant conditions for diagnosis of severe congenital heart disease. These alterations during the neonatal stage are characterized by the condition of relying on a PDA for survival because, upon closure, signs and symptoms that tend to be lethal appear. At this point three physio-pathological conditions should be mentioned in which this may occur: a) pulmonary flow is dependent on the PDA whose clinical manifestation is hypoxia, b) with an inap-propriate mixture of blood, a state of metabolic acidosis will develop when there is closure of the PDA and c) when the systemic flow depends on a PDA and when it closes there is cardiogenic shock.

In the condition mentioned, congenital heart disease is characterized by an obstruction present at the outflow tract of the right ventricle (stenosis or atresia) and a de-fect that allows mixing of intracardiac blood (ventricular septal defect, atrioseptal defect) or extracardiac (PDA). This group is characterized by reduced pulmonary flow,

Figure 1. (A) Four-chamber apical view where a dominant right ventricular cavity and a hypoplastic left ventricle chamber are seen. (B) Schematically, right atrium (RA), left atrium (LA), right ventricle (RV) and hypoplastic left ventricle (LV) are seen.

Figure 2. (A) Suprasternal projection with color Doppler where the anatomy of the aortic arch is observed as well as retrograde filling (red) of the isthmus, transverse portion and ascending portion of the aortic arch. (B) In the same suprasternal projection the posi-tion of the ascending aorta (AoA), the transverse portion and the isthmus of the aortic arch (Ao Arco), the relationship of the trunk of the pulmonary artery (TAP) with patent ductus arteriosus (PDA) and the descending aorta (AoD) are diagrammed. The area of aortic coarctation (CoA) is noted (arrow).

A b

A b



and clinical data in addition to cyanosis are tachypnea at rest and a second pulmonary sound that is inaudible or difficult to detect, which is occasionally associated with an ejection murmur specifically in the tetralogy of Fal-lot. Other abnormalities in this group such as pulmonary atresia or Ebstein’s disease may present without murmurs. This group can be ruled out by the respiratory pattern, auscultation and cardiomegaly, in addition to the fact that the clinical manifestation is the hypoxic crisis.

The second group mentioned are heart diseases in which there may be no intracardiac defects, but there is a ventric-ular arterial discordance in the case of D-transposition of the great vessels or double outlet of the right ventricle with subpulmonary interventricular communication (Taussig-Bing disease) in which the circulation is parallel. By force, a defect is needed so that the mixture can “oxygenate” the blood in the aorta. Symptoms are cyanosis and metabolic acidosis but usually the cardiomegaly is small or nonex-istent and associated with a narrow vascular pedicle, for which this group of symptoms can also be ruled out.

The third group includes those heart diseases in which some type of left obstruction predominates and is mani-fested by cardiac insufficiency, pulmonary edema and, under extreme conditions, by cardiogenic shock. In this group, the PDA allows a right to left shunt that retains systemic output to the extent possible with possible cardiac diseases such as critical aortic stenosis of the NB, Shone Syndrome, hypoplastic left heart syndrome (HLHS), and total anomalous connection of infradiaphragmatic pulmonary veins.1

Physical examination is a crucial weapon to establish the diagnosis of cardiac disorders. In the case in question, pulses were decreased in all four extremities; therefore, aortic coarctation can be ruled out because one would find intense pulses in the arms and neck and absent or diminished in the lower extremities with a pressure gra-dient between arm and leg. However, coarctation of the aorta may accompany other left-sided obstructions and the classic clinical picture may be modified, particularly in the presence of a PDA that allows improvement of cardiac systemic pulses, which may be felt even in the legs. Furthermore, in the case of critical aortic stenosis, whereas the pulses may be filiform in all four extremities and be accompanied by variable cardiomegaly, there is often an ejection murmur in the second right intercostal space, sometimes accompanied by an opening snap. This

is different from what was described for this patient whose auscultatory focus was the fourth left intercostal parasternal space (tricuspid), very possibly related to tricuspid regurgitation. Therefore, diagnosis of critical aortic stenosis can be eliminated.

In 1963 an anomaly called Shone syndrome2 was described and characterized by serial left obstructions (aortic coarctation, subaortic stenosis, parachute mitral valve and mitral supraventricular ring) that could imply a diagnostic complexity similar to that shown in extreme cases of left-side obstruction such as HLHS. Clinical data may be similar with regard to the magnitude of cardiac insufficiency, pulmonary edema or shock under great precordial hyperactivity and pulmonary hypertension, which is manifested by an intense second pulmonary sound. However, in Shone syndrome it is possible to detect murmurs due to aortic obstruction. In HLHS the clinical severity will be related to the size of the foramen ovale. If it is restricted or absent, symptoms will begin minutes after birth.3 In this case there was an interatrial communica-tion of 4.8 mm in diameter that allowed early treatment of PGE1 as well as demonstrating clinical stability for some days. Closure of PDA is crucial to the survival of these patients because it allows decongestion of the pulmonary vasculature by decreasing pulmonary edema. If the patient becomes lethargic, more dyspneic, with desaturation and increased heart failure, then the PDA has certainly started to close.4 In order to be able to establish the differential diagnosis between these conditions, imaging studies are mandatory. X-rays as well as EKG are nonspecific in both conditions because they show diverse degrees of cardiomegaly as well as right ventricular hypertrophy. Undoubtedly, accurate diagnosis is provided by an Eco-Bi because it reports extreme hypoplasia of the left ventricle associated with aortic and mitral atresia and it is the one examination that determines an ascending aorta of 2 mm in diameter, which is a relevant prognostic factor for post-operative survival.5 Interatrial communication of 4.8 mm in diameter possibly provided hemodynamic stability by allowing a free short circuit from left to right. In this way, there was decongestion of the lungs and tricuspid evidence that could eventually contraindicate a Fontan circulation.

It is relevant to mention that this case had a prenatal diagnosis and that from birth the patient received optimal treatment due to the infusion of PGE1,6 which allowed for transfer without incidence, maintaining hemodynamic



stability and acid-base equilibrium during the patient’s admission. It also allowed the surgical team, together with the family, to decide on the type of correction that was finally provided. When the available treatment op-tions were evaluated, hybrid palliation was ruled out because of the echographically demonstrated association with aortic coarctation which, at the same time, could impede a waiting period for heart transplant so that the only option was to perform a Norwood-type correction. This option had a poor prognosis due to the weight limits for this procedure (2515 g) and an ascending aorta of 2 mm in diameter, which are factors associated with a rate of mortality.5

At 16 days of life, a stage I Norwood procedure was performed that consisted of reconstructing the ascending aorta, creating an anastomosis with the trunk of the pul-monary artery including release of the coarctation, placing a bandage in each pulmonary branch with the goal of regulating pulmonary flow and placing a tube under Sano technique between the right ventricle and the pulmonary artery to provide pulmonary flow. At this time, a perfusion time of 1 h 55 min was reported with hypothermia of 16 to 18°. This is relevant because the complications related to circulatory failure are greater after 40 min and are inherent to a greater metabolic suppression. Although this scenario was predictable because of the anatomic characteristics of the case, this was possibly the reason why the patient could not be weaned from the pump. The final diagnoses were as follows:

1. Term NB with weight appropriate for gestational age

2. HLHS associated with mitral-aortic atresia and aortic coarctation

3. Norwood type surgery with Sano tube 4. Cardiogenic shock as cause of death.

Histopathological Description

Autopsy was performed on the NB in the Pathology De-partment with an incision over the sternal line of 10 cm in length. On opening the chest and abdominal cavity, there was 13 mL of bloody material coming from the left pleural cavity and 15 mL in the abdominal cavity. The heart was in levocardia with situs solitu, the cardiopulmonary block weighed 99 g (for an expected 66 g). This increase was at the expense of the heart that showed dilatation of the right ventricle as well as right atrium and vena cavas. The

external surface of the right ventricle showed hemorrhagic zones and a sutured surgical wound.

On atrial dissection there was atrioventricular concor-dance observed and a surgically widened foramen ovale of 1 cm in its greatest axis. When the right ventricle was opened, the right morphology in a very dilated and hypertrophic cavity was documented with a thickness of 0.6 mm as well as zones of different colors throughout the length of the myocardium in this ventricle. The tricuspid valve was redundant and its output had a pulmonary valve with a 1-cm diameter ring with normal-appearing valves. The trunk of the pulmonary artery was anastomosed to the aorta up to the level of the arch. There was no ductus arteriosus seen and the supraaortic trunk arose normally. There was a widened aortic arch and descending aorta seen. At the level of the infundibulum the exit of the polytetrafluoroethylene (Gore-Tex) tube was found, which connected with the proximal third of the left pulmonary branch without obstructions. Five right pulmonary veins were discovered: three right and two left, which connect to the left atrium. The mitral valve was atresic and com-municated with a small cavity that corresponded to the left ventricle without demonstrating permeability towards the aorta (Figure 3). The histological sections carried out in the right ventricular myocardium showed multiple areas of infarction of ∼4 h of evolution in which areas of hemorrhage, edema, erythrocytes between myofibrils and disruption of the fibers was seen, which correlate with findings of color changes described macroscopically. In addition to the above, there were myocytolysis cellular changes that translate into cardiogenic shock (Figure 4).

In the lungs there was emphysema with rupture of alveolar walls and enlargement of the air spaces. No in-flammation, edema or hemorrhage was noted; however, small- and medium-caliber vessels showed changes in the arterial media by muscularization secondary to pul-monary hypertension. When these cells were stained with Masson trichrome, there was fibrosis around the vessel and decreased lumen. Elastic fiber disorganization and rupture of the muscle were demonstrated by staining that corresponded to changes due to grade A pulmonary arterial hypertension according to the Rabinovitch classification (Figure 5).7

The enlarged liver was congested microscopically, with extramedullary hematopoiesis and steatosis. Portal spaces were normal and liver and kidneys showed an increase



Figure 5. (A) Pulmonary parenchyma cuts show rupture of al-veolar walls forming large air spaces, which represent areas of emphysema. (B) In this Masson trichrome stain, small and mid-size vessels demonstrate perivascular fibrosis and muscularization of the median.

Figure 3. (A) Cardiopulmonary block weighing 99 g (expected weight 66 g) due to the increased size and weight of the heart. Changes in the color of the cardiac surface are observed, which correlate with histological changes of extensive infarction. (B) Pulmonary veins, three right and two left, show no alterations. (C) Gore-Tex tube extends from the middle third ventricle into the pulmonary artery on the left side. (D) At the opening of the heart chambers, the atrium and right ventricle are of right morphology. The first is very dilated, and there is ventricular wall hypertrophy. There is interatrial communication (blue arrow) that is enlarged during surgery and measures 1 cm on the long axis. Wall thickness demonstrates changes in coloration.

Figure 4. (A) Histological sections of the left ventricular wall show changes of acute infarction of ∼4 h. Changes are extensive and are observed in all studied sections. There is disorganization of the myo-fibrils, recent hemorrhage, edema and shock changes represented by myocytolysis. (B) Intense edema is shown in this field (arrows).

in size and weight due to intense congestion. All these changes were secondary to cardiac insufficiency. The brain showed a normal weight and development with conges-tion of the blood vessels. Two zones of hemorrhage were detected in the brain, possibly secondary to congestion. The digestive tract showed bands of contraction caused by the shock status (Table 1).

Comment

This case reported here is of particular interest according to two aspects. The first, because the diagnosis of congenital heart disease was made at 20 weeks of gestation with fetal echocardiography, and second because the patient was treated immediately with PGE1 from the time of birth. Re-ferring to the echocardiography, it is important to note that

Table 1. Final anatomic diagnoses

PRINCIPAL DISEASE

HLHS

CONCOmITANT ALTERATIONS

Status postsurgery of Norwood/Sano

Mitral atresia

Aortic atresia

Widened foramen ovale 1 cm

Left hemithorax 15 ml

Recent hemorrhage in visceral and parietal pericardium

RVH

Recent hemorrhage in myocardium of right atrium and ventricle

Pulmonary arterial hypertension (grade A Rabinovitch)

Acute extensive infarct to myocardium (~4 h of evolution)

Serosanguineous ascitic fluid 13 ml

Recent sutured surgical wound in the anterior chest of 10 cm in lengthPartial surgical absence of the thymus

Hemorrhagic areas in the brain

Panlobular steatosis affecting 30% of the hepatic parenchyma

Anatomic data of shock

Ischemic visceral hypoxic myopathy affecting the esophagus, stomach, colon and bladderDecrease in the lymphoid tissue of the thymus

Recent subarachnoid cerebellar hematoma

HLHS, hypoplastic left heart syndrome: RVH, right ventricular hypertrophy.

A b

C D

A b

A b



Upon acceptance to a particular therapeutic program, the best option then needs to be considered according to the anatomy of the lesion. In the present case, moderate tricuspid regurgitation, ascending aortic diameter of 2 mm and juxtaductal aortic coarctation are described. There are elements to consider when determining a therapeutic approach. To plan a corrective Norwood-type surgery has the disadvantage that when tricuspid regurgitation is severe, it practically contraindicates the second stage (cavopulmonary connection).

The hybrid treatment option (surgical/interventional) aims to first control pulmonary flow by performing a cer-clage of each pulmonary branch, ensuring systemic flow by means of stent implantation in the ductus arteriosus and freeing the obstruction of pulmonary flow by performing a medical or surgical atrial septostomy. This option was considered to be contraindicated due to the fact of having an ascending aorta of 2 mm in diameter as well as an aortic coarctation because these inhibit retrograde circulation towards the ascending and coronary aorta, thereby ruling out this procedure.10.11

When discussing the anatomic conditions of this case that has several adverse factors for success in any type of surgery, the obligation to treat or not treat these patients should be considered. This discussion is not new and there are literature reports that support or do not support intervention12 with the conclusion that it is not necessarily the disease that leads to death and that the options depend on the experience of the responsible physicians13 to the point that extreme cases are offered only palliative care.

It is without a doubt an obligation to clearly inform parents of the surgical and medical possibilities of long-term results that may include psychomotor retardation, high mortality in each of the three surgeries that make up the Norwood program and the almost nil donation of neonatal heart, so jointly parents as well as the physicians, social worker and psychologists make a consensus decision to accept or reject the therapeutic option. It is a medical obligation to act with a deep sense of ethics to address cases such as the one presented to offer the best action in the face of conflicting decisions. Ethical principles should not be ignored, such as autonomy as well as the right to self-determination and the benefit to provide truthful information of the medical group’s surgical experience.14

Finally, from the medical point of view, it is extremely important to formalize the treatment of these cases by

from 20028 there have been high percentages reported of high diagnostic accuracy in fetal echocardiography. It has been mentioned that among the most frequently diagnosed heart diseases, HLHS is the most notable.9 However, there are diagnostic failures related to the skill and experience of the radiologist and even to the quality of the equipment. In the second aspect, it is of utmost importance to provide adequate treatment from the time of birth that leads to maintaining stable conditions in these children, decreasing as much as possible development of cardiac insufficiency. For this reason, we must emphasize that multidisciplinary management is required that involves obstetricians, neona-tologists, nurses, cardiologists, surgeons and intensivists trained in severe congenital heart disease.

The priority is the PGE1 infusion at doses of 0.01 to 0.05 μg/kg/min. This is used to maintain PDA with the intention of allowing a proper systemic output and to reduce, as far as possible, heart failure and underlying pulmonary edema. On occasions, orotracheal intubation is necessary in which case it is fundamental to keep these patients in hypercarbia trying to maintain a pCO2 between 35 and 45 mmHg and a PaO2 between 30 and 40 mmHg in order to safeguard the high pulmonary vascular resistance and prevent the pulmonary vasodilator effect of oxygen. As secondary effects, an improved cerebral perfusion is obtained (ben-eficial) and the possibility of developing metabolic acidosis that can be treated by administering sodium bicarbonate at conventional doses of 1 to 2 mEq/kg/dose. It is noteworthy that parenteral fluids should be restricted and rapid boluses avoided. When there is need of providing inotropic support, it is recommended that it be a combination of dobutamine and dopamine, with the latter a dopaminergic dose with the goal of favoring renal circulation. On the other hand, higher doses of these inotropes (>5 μg/kg/min) tend to increase the systemic vascular resistence with deleterious effects on the systemic flow and tissue perfusion.3

In this case, once the fetal diagnosis was made, thera-peutic options can be presented to the parents: interruption of pregnancy, carry pregnancy to term and offer only com-passionate support, plan a surgical intervention (Norwood) or the possibility of heart transplantation. It is essential to clearly explain the options to parents, emphasizing the high mortality rate of the Norwood procedure, the shortage of donor hearts and the high possibility of neurological sequelae, even if patient survival is achieved. With this information a joint decision can be made.



taking into consideration the best possibilities. We must remember that this particular surgery has a long learning curve. Diagnosis should be made as early as possible, and a transfer system should be established to ensure the use of PGE1 and to maintain metabolic constants in order to achieve a better prognosis.

REFERENCES

1. Lees MH. Cyanosis of the newborn infant. Recognition and clinical evaluation. J Pediatr 1970;77:484-498.

2. Shone JD, Sellers RD, Anderson RC, Adams P, Lillehei C, Edwards JE. The developmental complex of “parachute mitral valve”, supravalvular ring of left atrium, subaortic stenosis, and coarctation of the aorta. Am J Cardiol 1963;11:714-725.

3. Rudolph A. Aortic atresia, mitral atresia, and hypoplastic left ventricle. In: Rudolph A, ed. Congenital Diseases of the Heart. Clinical-Physiological Considerations. West Sussex: Wiley-Blackwell; 2009. pp. 257-288.

4. Marino BS, Bird GL, Wernovsky G. Diagnosis and management of the newborn with suspected congenital heart disease. Clin Perinatol 2001;28:91-136.

5. Jenkins KJ. Risk adjustment for congenital heart surgery: the RACHS-1 method. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2004;7:180-184.

6. Browning Carmo KJ, Barr P, West M, Hopper NW, White JP, Badawi N. Transporting newborn infants with suspected duct dependent congenital heart disease on low-dose prostaglandin E1 without routine mechanical ventilation. Arch Dis Child Fetal Neonatal Ed 2007;92:F117-F119.

7. Rabinovitch M. Pathobiology of pulmonary hypertension: impact on clinical management. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2000;3:63-81.

8. Haak MC, Twisk JW, Van Vugt JM. How successful is fetal echocardiographic examination in the first trimester of preg-nancy? Ultrasound Obstet Gynecol 2002;20:9-13.

9. Marantz P, García-Guevara C. Ecocardiografía fetal. Rev Argent Cardiol 2008;76:392-398.

10. Bacha E. Hybrid therapy for hypoplastic left heart syndrome: system-wide approach is vital. Pediatr Cardiol 2008;29:479-480.

11. Hoffman J. Hypoplastic left heart syndrome. In: Hoffman J, ed. The Natural and Unnatural History of Congenital Heart Disease. West Sussex: Wiley-Blackwell; 2009. pp. 531-545.

12. Osiovich H, Phillipos E, Byrne P, Robertson M. Hypoplastic left heart syndrome: “to treat or not to treat”. J Perinatol 2000;20:363-365.

13. Feinstein JA, Benson DW, Dubin AM, Cohen MS, Maxey DM, Mahle WT, et al. Hypoplastic left heart syndrome: current con-siderations and expectations. J Am Coll Cardiol 2012;59(suppl 1):S1-S42.

14. Zeigler VL. Ethical principles and parental choice: treatment options for neonates with hypoplastic left heart syndrome. Pediatr Nurs 2003;29:65-69.


Shaping a new strategy against B. pertussis: a public health problem in

mexico

pediatric theMe


Lorena Suárez-Idueta,1 Ilse Herbas-Rocha,2 César Misael Gómez-Altamirano,3 Vesta Richardson-López Collada4

1 Especialista en Pediatría, 2 Especialista en Salud Pública, Supervisor Médico en Área

Normativa, 3 Especialista en Infectología Pediátrica, Subdirector de Coordi-

nación y Operación del CONAVA, Mexico, D.F., Mexico4 Especialista en Pediatría, Dirección General del Centro Nacio-

nal para la Salud de la Infancia y la Adolescencia, México, D.F., México

Correspondence: Dra. Lorena Suárez IduetaEspecialista en Pediatría, Subdirector de Coordinación y Operación

del CONAVAMexico, D.F., MexicoE-mail: [email protected]


AbSTRACT

Despite vaccination against pertussis, there are still a large number of pertussis deaths worldwide. Waning vaccine-induced immunity and the gradual increase in reported incidence among adolescents and adults have supported the role of these age groups in the transmission. Several countries have implemented a booster vaccination in order to reduce transmission and clinical significance. Pertussis is a current public health problem in Mexico. The clinical suspicion in toddlers, adolescents and adults, delayed or incomplete vaccination series and diagnostic confirmation are the most important challenges for pertussis control. The introduction of new vaccination strategies in adults and adolescents as well as pregnant women should improve disease control.Key words: Pertussis, whooping cough, B. pertussis, immunization, vaccines.

INTRODuCTION

Pertussis is a disease of worldwide distribution1 that continues to cause a large number of deaths despite the existence of a vaccination against Bordetella pertussis that has been in existence for >50 years. In 2008, the World Health Organization (WHO) estimated 195,000 annual deaths attributed to the disease. In relation to other vaccine-preventable diseases, it ranks as the fifth leading cause of death in children <5 years old, preceded only by pneumococcal disease, measles, rotavirus and invasive disease caused by type B Haemophilus influenzae.2-4

Pertussis is considered a reemerging disease because its incidence has increased worldwide, even in countries with adequate vaccination coverage.5-8 Advances in the reporting and diagnosis, loss of acquired immunity due to the vaccination and changes in the genome of B. pertussis are some of the factors attributed to the increase in cases. The adolescent age group has been the most affected, especially in industrialized countries.8-11

Diagnostic Difficulty

In Mexico, pertussis and coqueluchoide syndrome are immediately notifiable diseases through the system of surveillance and epidemiological monitoring of immuno-preventable diseases. The fundamental aim of this system is to detect and passively study probable cases and follow them to establish their etiological diagnosis. Patients who meet the operational definitions enter the system through an immediate notification (local, municipal, federal) (Table 1).12 The final diagnosis of pertussis is made by clinical, laboratory and epidemiological association. The mortality surveillance is conducted through the Epidemiological System and Statistical Mortality (SEED).12,13

The disease follows epidemic cycles every 3 to 4 years. The average baseline incidence (nonepidemic years) is reported to be between 1 and 2 confirmed cases per mil-lion inhabitants. The periods with higher incidence in the last 10 years have been the year 2005 (three cases/million


Shaping a new strategy against B. pertussis: a public health problem in Mexico

inhabitants) and the year 2009 (five cases/million popula-tion) (Figure 1).14 The most affected region during the last epidemic year (2009) was the northern border. During that year, 1,959 suspected cases or coqueluchoide syndrome were documented, confirming 579 cases of pertussis. The states of Nuevo Leon, Sonora and Tamaulipas had the high-est incidence rates: 44.5, 42.6 and 16.6/million inhabitants, respectively, corresponding to 62% of all confirmed cases during that year for the country.14

The real burden of disease is underestimated both by the low diagnostic suspicion as well as the low percentage of confirmation. In Mexico, we diagnosed two cases of pertussis per every 10 cases of coqueluchoide syndrome that are studied. In the last 10 years, the percentage of confirmation was maintained uniform (~20%) (Figure 1). Difficulties of laboratory diagnosis through culture include inadequate sample collection, collection of the sample after starting antibiotics and late sample collection (third week after the onset of cough). Despite the heterogeneity in epidemiological surveillance of pertussis worldwide, different operational definitions and diagnostic methods used,15 the percentages of confirmation from countries like Australia,16 U.S.,6 Canada,17 Spain18 and Switzerland19 are reported in 90%, 55%, 25.6%, 57.6% and 24.3%, respectively.

The age group most affected was that of <1 year of age.14 In 2009, this group accounted for 70.4% of all the reported cases. In the case of adolescents and adults, low clinical suspicion and underreporting seem to explain the low incidence (Figure 2).14 There is evidence that adoles-cents in Mexico are an important reservoir of the disease. The seroepidemiological survey conducted in 1987 shows that the seroprevalence of antibodies against B. pertussis decreases with age.20 Tome et al. isolated B. pertussis in

32.8% of the 61 adolescents studied with chronic cough.21 Ruiz Palacios et al. found a higher prevalence of pertussis in adolescents with chronic cough (5.4/1,000) than that passively reported by our epidemiological surveillance system.22

Vaccination Strategies in mexico

In 1954, implementation of a vaccine against diphtheria, pertussis and tetanus (DPT) was initiated, which was massively used until 1973. In 1999, the pentavalent whole cell vaccine (DPT + HB + Hib) was introduced, and since 2007, it was replaced by the pentavalent acellular vaccine (DPaT/VIP + Hib). The current vaccination schedule is only intended for infants and toddlers and includes the application of pentavalent acellular vaccine (DPaT/VIP + Hib) at 2, 4, 6 and 18 months of age with a DPT booster at 4 years of age.23 Beginning in 2009, after the outbreak in the northern border states of our country and for the benefit of reducing missed opportunities for vaccination, the National Immunization Council (CONAVA), a coordi-nating body of public policies on vaccination, approved a temporary application of accelerated vaccination schedule at 6 weeks, 3, 4 and 18 months with pentavalent acellular vaccine and a DPT reinforcement in preschool children at 4 years of age, with the goal of protecting as early as possible children <6 months old, especially in states with recent outbreaks.

Vaccination coverage against B. pertussis in the 1-year-old group has increased in Mexico through the years. According to the National Immunization Survey in 1990, national vaccination coverage with DPT3 in the 1-year-old group was 53% and, by 2008, the estimated coverage was reported to be 96%, representing an increase of 46% from 1990.24,25

Table 1. Operational definitions, coqueluchoide syndrome and pertussis12

Probable case Person of any age with cough of 14 days or more and with two or more of the following characteristics: shortness of breath, in addition to spasmodic or struggling laryngeal inspiration and one or more of the fo-llowing data: cyanosis, hemorrhage (conjunctival, petechiae, epistaxis), laboratory analysis with leukocytosis with predominance of lymphocytes or being in contact with similar cases during the past 2-4 weeks prior to treatment initiation (children <3 months may manifest only as episodes of apnea or cyanosis)

Confirmed case All probable cases that isolated B. pertussis according to culture or PCR or in contact, living with a person who was epidemiologically associated with isolation of B. pertussis

Clinical case of pertussis All probable cases without simple, independently of their five contacts

Asymptomatic carrier All persons without signs or symptoms of respiratory disease and who show samples for having AE (spell out) with a probable or confirmed case and positive results to B. pertussis


Lorena Suárez-Idueta, Ilse Herbas-Rocha, César Misael Gómez-Altamirano, Vesta Richardson-López Collada

Since 1991, national coverage with these immunogens has remained close to 90% at 1 year of age;24,25 neverthe-less, the main difficulty was the late implementation of the series of immunogens. According to the National Immunization Coverage Survey (ENCOVA) carried out between April and June, 2010 by the National Public Health Institute, among children <2 years of age with a vaccination card, coverage with pentavalent acellular vaccine in the group of ≤2 years of age was 90.8%; how-ever, it decreased to 70% in the group of <1 year old and 65% in groups of 2 and 4 months,26 which represents a delayed vaccination. Vaccine effectiveness (VE) against B. pertussis gradually increases as the infants complete the initial set of immunogens. Bisgard et al.27 reported a VE to prevent the disease from just 50.5% (95% CI 71.1-86.3) after the first dose of vaccine, which increases to 80% (95% CI 41.3-93.2), 93.3% (95% CI 83.1-97.4) and 95.1% (95% CI 85.1-98.4) with two, three and four doses, respectively (Figure 3). Similarly, Juretzo et al.28 described a VE to prevent hospitalizations due to disease by 68.7% (95% CI 46.3-81.7), 91.8% (95% CI 84.7-95.7) and 99.8% (95% CI 98.3-100) after one scheme, two and three doses, respectively. In this sense, infants <3 months old who were timely vaccinated with a biological dose (VE 50.5%), those with late or incomplete schemes (vac-cinated late) and <6 weeks of age who are not eligible to

start vaccination (programmatically not preventable) are the most vulnerable populations to acquire the disease, its complications and die.22,23 In 2009, 32 deaths were confirmed due to pertussis and 44 were associated (coque-luchoide syndrome). The total number of deaths occurred in children <1 year of age and 85% were concentrated in those <3 months old.

The duration of posterior immunity with a complete scheme against B. pertussis decreases gradually over the years. It has been reported to last between 4 and 12 years,29-36 without apparent significant differences between the whole cell vaccine and the acellular vaccine.31 Theoreti-cally, in Mexico, vaccination has kept cohorts of infants, preschoolers and children immune through immunization since 1973. However, adolescents and adults who lose immunity are the carriers. They contract the disease4,11 or are carriers of the disease to infants,37,38 in addition to the disease not being suspected or diagnosed in them. In the study of ill infants <6 months of age, contacts have been identified as family members being the source of transmis-sion in 43-80% of the cases.38-42

Current Strategies for Prevention

In 2005, the biological tetanus, diphtheria and acellular pertussis (Tdap) was regulated in the U.S. for use in adolescents and adults; the composition is similar to the

Figure 1. Probable and confirmed cases and incidence of pertussis (México, 1995-2011).14



pediatric DTaP vaccine, but with a lower concentration of antigen.43 Ward et al. described it as a safe vaccine with an efficacy of 92% (95% CI 32-99%).44 A 5-year follow-up of post-adolescents after a Tdap reinforcement has shown an adequate response in both humoral as well as cell-mediated immunity.45

Both the Global Pertussis Initiative15,46 as well as the Advisory Committee on Immunization of the United States of America (ACIP)47 have recommended a booster of Tdap in adolescents and adults, as well as a vaccination of healthcare staff and pregnant women, based on the loss of acquired immunity through vaccination in these specific

age groups, the increase in incidence,10,12,31 their role in the transmission of the disease37,38 and as a potential measure to reduce morbidity and mortality, especially in infants.48 Countries like the U.S., Canada, Australia, France, Costa Rica, and Argentina have recognized and implemented these new vaccination strategies into their schemes.8,49

The introduction of Tdap as a booster in the adoles-cent population has proven effective in reducing the incidence of pertussis in this age group. Kandola et al. evaluated the impact of the introduction of Tdap in ado-lescents of 14–16 years of age and found an incidence of pertussis before the introduction of the vaccine in

Figure 2. Age distribution of confirmed cases of pertussis (México, 2000-2010).14

Figure 3. Vaccination coverage with pentavalent acellular vaccine in Mexico and vaccine effectivity.26,27



18/100,000 of the population compared to 0.2/100,000 of the population after its introduction.50 Quinn et al. demonstrated the impact of vaccination with Tdap in the adolescent population in the reduction of reported cases of pertussis in the group of adolescents and in children <6 months of age.16

Meanwhile, vaccination in pregnancy is aimed at pro-viding specific protection to susceptible infants before the regular vaccination schedule51 with the biological applica-tion to pregnant women, considered to be the most captive population during their prenatal care visit. The serological survey reported that only 14 to 34% of pregnant women have antibodies against B. pertussis.51,52 Several studies have substantiated the passage of maternal IgG antibodies through the placenta53-55 as well as the increase of specific antibodies in cord blood from vaccinated mothers with re-spect to those not vaccinated.53,54 The half-life of maternal antibodies has been estimated to be 6 weeks55 and do not seem to interfere with the immune response to the primary vaccination against pertussis when administering acellular vaccine to infants.55 The effectiveness of the vaccination with Tdap during pregnancy to prevent disease in infants has not been well established; however, maternal antibod-ies against B. pertussis confer protection and modify the severity of the disease in infants.56,57

At the National Center for Health of Children and Adolescents (CeNSIA), the importance for federal states to maintain >95% coverage with pentavalent acellular vaccine is recognized, as well as to ensure timely vaccination of the first dose of biological to the population <6 months of age through an accelerated vaccination scheme. In order to strengthen the ongoing vaccination campaign and invite the population to promptly arrive at the nearest healthcare unit and request vaccination, from 2010 the CeNSIA launched an original, interactive and efficient major mass social me-dia campaign through mobile marketing, linking with the private sector and NGOs. Thanks to the diaper manufactur-ers, they distributed >36 million diapers with the logo of "vaccinate on time," and they produced 1 million collars to adhere to baby products. They trained over 400 hospitals with a range of >7,000 nurses as well as dissemination through leaflets and posters in the hospital. However, it is clear that effective vaccination for infants and toddlers will not be a sufficient measure to control the disease. There is a need to implement new strategies for vaccination in the adolescent and adult population, such as a strategy to reduce

transmission to the group of infants <6 months old and disease morbidity and mortality in this age group.

In Mexico, pertussis is still a major public health prob-lem, which is also presented in other countries despite having good vaccination coverage. The main obstacles for its control have been an underestimation of the true burden of the disease, the low percentage of confirmation, the poor suspected diagnosis in adolescents and adults, the low effectiveness of the antigen, late or incomplete vaccination schedules and loss of acquired immunity from the vaccination through the years. At the present time there are still major outbreaks in our country, and its main significance lies in the impact to those <1 year of age who are likely to die or to have neurological sequelae.

Strategies for disease control should be designed to improve diagnostic methods as well as awareness among clinicians of the diagnosis in infants, adolescents and adults. Maintaining vaccination coverage >95% in the popula-tion <5 years of age will result in immunity of school-age children and will prevent transmission by this age group. Dissemination and awareness of parents to come to the healthcare units to obtain the biological vaccine beginning at 6 weeks of life will be a cornerstone for disease control.

However, in addition to using the accelerated scheme for early vaccination, it is necessary to protect infants <6 months of age in reducing the source of infection of B. pertussis from a close relative, carrier or an infected person. The only way to prevent carriers or cases among adolescents and adults is through the administration of a booster vaccine.

REFERENCES

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2. World Health Organization. Centers for Disease Control and Prevention. Vaccine preventable deaths and the global immu-nization vision and strategy, 2006-2015. MMWR 2006;55:511-515. Available at: http://www.cdc.gov/mmwr/preview/mmwrht-ml/mm5518a4.htm

3. Plotkin S. Aims, scope and findings of the global pertussis initiative. Pediatr Infect Dis J 2005;24(suppl 5):S5-S6.

4. World Health Organization. Pertussis vaccines: WHO position paper. Wkly Epidemiol Rec 2010;85:385-400. Available at: http://www.who.int/wer/2010/wer8540.pdf

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6. Tanaka M, Vitek CR, Pascual FB, Bisgard KM, Tate JE, Murphy TV. Trends in pertussis among infants in the United States, 1980-1999. JAMA 2003;290:2968-2975.

7. Mooi FR, van Loo IH, King AJ. Adaptation of Bordetella pertus-sis to vaccination: a cause for its reemergence? Emerg Infect Dis 2001;7(3 suppl):526-528.

8. Tan T, Trindade E, Skowronski D. Epidemiology of pertussis. Pediatr Infect Dis J 2005;24(suppl 5):S10-S18.

9. Singh M, Lingappan K. Whooping cough: the current scene. Chest 2006;130:1547-1553.

10. Halperin SA. Pertussis immunization for adolescents: what are we waiting for? Can J Infect Dis 2001;12:74-76.

11. Edwards KM. Overview of pertussis: focus on epidemiology, sources of infection, and long term protection after infant vac-cination. Pediatr Infect Dis J 2005;24(suppl 6):S104-S108.

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16. Quinn HE, McIntyre PB. The impact of adolescent pertussis immunization, 2004-2009: lessons from Australia. Bull World Health Organ 2011;89:666-674.

17. Rivest P, Richer F, Bédard L. Difficulties associated with pertus-sis surveillance. Can Commun Dis Rep 2004;30:29-33,36.

18. Crespo I, Cardeñosa N, Godoy P, Carmona G, Sala MR, et al. Epidemiology of pertussis in a country with high vaccination coverage. Vaccine 2011;29:4244-4248.

19. Wymann MN, Richard JL, Vidondo B, Heininger U. Prospec-tive pertussis surveillance in Switzerland, 1991-2006. Vaccine 2011;29:2058-2065.

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21. Sandoval PT, Arreola L del P, Quechol GR, Gallardo HG. Bordetella pertussis in adolescent students in Mexico City. Rev Saude Publica 2008;42:679-683.

22. Ruiz Palacios, et al. A prospective cohort study of pertussis in adolescents attending middle school in Mexico City (ICAAC 2010) (unpublished data).

23. Centro Nacional para la Salud de la Infancia y la Adolescen-cia. Manual de Vacunación 2008-2009. Secretaria de Salud. México; 2008.

24. Organización Mundial de la Salud. Estadísticas Sanitarias Mundiales; 2010. Available at: http://www.who.int/whosis/whostat/ES_WHS10_Full.pdf

25. WHO/UNICEF. Regional Global Coverage; 2010. Available at: http://www.who.int/immunization_monitoring/routine/im-munization_coverage/en/index4.html

26. Instituto Nacional de Salud Pública. Encuesta Nacional de Cobertura de Vacunación. Informe Final de Resultados. México; 2010.

27. Bisgard KM, Rhodes P, Connelly BL, Bi D, Hahn C, Patrick S, et al. Pertussis vaccine effectiveness among children 6 to 59 months of age in the United States, 1998-2001. Pediatrics 2005;116:e285-e294.

28. Juretzko P, von Kries R, Hermann M, Wirsing von König CH, Weil J, Giani G. Effectiveness of acellular pertussis vaccine assessed by hospital-based active surveillance in Germany. Clin Infect Dis 2002;35:162-167.

29. Salmaso S, Mastrantonio P, Tozzi AE, Stefanelli P, Anemona A, Ciofidegliatti ML, et al. Sustained efficacy during the first 6 years of life of 3-component acellular pertussis vaccines administered in infancy: the Italian experience. Pediatrics 2001;108:e81.

30. Gustafsson L, Hessel L, Storsaeter J, Olin P. Long-term follow-up of Swedish children vaccinated with acellular pertussis vaccines at 3, 5, and 12 months of age indicates the need for a booster dose at 5 to 7 years of age. Pediatrics 2006;118:978-984.

31. Wendelboe AM, Van Rie A, Salmaso S, Englund JA. Duration of immunity against pertussis after natural infection or vac-cination. Pediatr Infect Dis J 2005;24(suppl 5):S58-S61.

32. Jenkinson D. Duration of effectiveness of pertussis vaccine: evidence from a 10 year community study. Br Med J (Clin Res Ed) 1988;296:612-614.

33. Ramsay ME, Farrington CP, Miller E. Age-specific efficacy of pertussis vaccine during epidemic and non-epidemic periods. Epidemiol Infect 1993;111:41-48.

34. Van Buynder PG, Owen D, Vurdien JE, Andrews NJ, Matthews RC, Miller E. Bordetella pertussis surveillance in England and Wales: 1995-7. Epidemiol Infect 1999;123:403-411.

35. Tindberg Y, Blennow M, Granström M. A ten year follow-up after immunization with a two component acellular pertussis vaccine. Pediatr Infect Dis J 1999;18:361-365.

36. Lugauer S, Heininger U, Cherry JD, Stehr K. Long-term clini-cal effectiveness of an acellular pertussis component vaccine and a whole cell pertussis component vaccine. Eur J Pediatr 2002;161:142-146.

37. Kowalzik F, Barbosa AP, Fernandes VR, Carvalho PR, Avila-Aguero ML, et al. Prospective multinational study of pertussis infection in hospitalized infants and their household contacts. Pediatr Infect Dis J 2007;26:238-242.

38. Wendelboe AM, Njamkepo E, Bourillon A, Floret DD, Gaudelus J, Gerber M, et al. Transmission of Bordetella pertussis to young infants. Pediatr Infect Dis J 2007;26:293-299.

39. Bisgard KM, Pascual FB, Ehresmann KR, Miller CA, Cianfrini C, Jennings CE, et al. Infant pertussis: who was the source? Pediatr Infect Dis J 2004;23:985-989.

40. Deen JL, Mink CA, Cherry JD, Christenson PD, Pineda EF, Lewis K, et al. Household contact study of Bordetella pertussis infections. Clin Infect Dis 1995;21:1211-1219.

41. Elliott E, McIntyre P, Ridley G, Morris A, Massie J, McEniery J, et al. National study of infants hospitalized with pertussis in the acellular vaccine era. Pediatr Infect Dis J 2004;23:246-252.

42. Perret C, Viviani T, Peña A, Abarca K, Ferrés M. Source of infection in young infants hospitalized with Bordetella pertus-sis. Rev Med Chil 2011;139:448-454.



43. Broder KR, Cortese MM, Iskander JK, Kretsinger K, Slade BA, Brown KH, et al. Preventing tetanus, diphtheria, and pertussis among adolescents: use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccines recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55(RR-3):1-34.

44. Ward JI, Cherry JD, Chang SJ, Partridge S, Lee H, Treanor J, et al. Efficacy of an acellular pertussis vaccine among ado-lescents and adults. N Engl J Med 2005;353:1555-1563.

45. Edelman K, He Q, Mäkinen J, Sahlberg A, Haanperä M, Schuerman L, et al. Immunity to pertussis 5 years after booster immunization during adolescence. Clin Infect Dis 2007;44:1271-1277.

46. Ulloa-Gutierrez R, Hozbor D, Avila-Aguero ML, Caro J, Wirs-ing von König CH, Tan T, et al. The global pertussis initiative: meeting report from the Regional Latin America Meeting, Costa Rica, 5-6 December, 2008. Hum Vaccin 2010;6:876-880.

47. Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap) in pregnant women and persons who have or anticipate having close contact with an infant aged <12 months. Ad-visory Committee on Immunization Practices (ACIP). CDC 2011;60:1424-1426. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6041a4.htm

48. Wood N, Quinn HE, McIntyre P, Elliott E. Pertussis in infants: preventing deaths and hospitalizations in the very young. J Paediatr Child Health 2008;44:161-165.

49. Ulloa-Gutiérrez R. Estrategias actuales de vacunación con-tra tos ferina en niños y adultos. Acta Pediátr Costarricense 2009;20:81-87.

50. Kandola K, Lea A, White W, Santos M. A comparison of pertus-sis rates in the Northwest Territories: pre- and postacellular pertussis vaccine introduction in children and adolescents. Can J Infect Dis Med Microbiol 2005;16:271-274.

51. Mooi FR, de Greeff SC. The case for maternal vaccination against pertussis. Lancet Infect Dis 2007;7:614-624.

52. Shakib JH, Ralston S, Raissy HH, Stoddard GJ, Edwards KM, Byington CL. Pertussis antibodies in postpartum women and their newborns. J Perinatol 2010;30:93-97.

53. Gall SA, Myers J, Pichichero M. Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels. Am J Obstet Gynecol 2011;204:334.e1-e5.

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mortality due to drowning in children less than 15 years of age in

mexico, 1998-2010

vital statistics


Sonia Fernández Cantón,1 Ana María Hernández Martínez,1 Ricardo Viguri Uribe2

1 Dirección de Información Epidemiológica, Secretaría de Salud, Mexico, D.F., Mexico

2 Departamento de Ediciones Médicas, Hospital Infantil de México Federico Gómez, México, D.F., México

Correspondence: Dra. Sonia B. Fernández CantónDirección de Información Epidemiológica Secretaría de Salud Mexico, D.F., MexicoE-mail: [email protected]; sonia_fernandez@

prodigy.net.mx


Nationally in Mexico, accidents are the fourth leading cause of death for the general population. When we refer to children <15 years of age, the

situation reflects an even more critical problem because accidental deaths tend to be the leading cause of death. On previous occasions, such behavior has been discussed in this journal. Therefore, on this occasion it was intended to disaggregate the analysis by more precisely describing one of the accidental causes affecting the population, mostly in childhood and adolescence: drowning by submersion.

According to the Pan American Health Organization (PAHO), drowning is defined as the process of experienc-ing respiratory difficulties by submersion or immersion in liquid, with resultant death, morbidity or disability. The pattern of deaths in the population <15 years of age was approached based on the official data generated by the National Institute of Statistics and Geography (INEGI) from death certificates issued by the Ministry of Health. The codes used were International Classification of Dis-ease (ICD) 10th revision for the period 1998-2010 during the last year with definitive figures comprised from W65 to W74 (Table 1).

The World Health Organization (WHO) estimates that, in 2004, drowning deaths worldwide accounted for 7% of deaths related to unintentional injuries. This figure is consistent with the situation observed in Mexico during the period from 1998-2010. Of 475,923 fatalities, there were 33,408 deaths due to drowning. This proportion doubled when only the group of <15 years of age was analyzed. The volume of accidental deaths during the same period was 65,236. Of this total, 9190 cases were drowning by submersion as the cause, i.e., 14.1% of these deaths (Table 2). Therefore, >25% of deaths due to drowning in Mexico (27.5%) occur in persons <15 years of age (Figure 1).

Notwithstanding this description, it is important to note that the analysis of behavioral trends from the national fig-ures recorded during the last 13 years shows a clear trend of declining mortality. The number of deaths in 2010 (567) accounted for only 61% of admissions in 1998 (923), i.e., a decrease of almost 39% (Table 3). During this period, the mortality rate decreased from 2.71 to 1.86 deaths/100,000 persons <15 years of age (Figure 2). This decline occurred in all age groups and in both genders. It is noteworthy that, in the group of children <1 year of age, the figures were reduced by 58%, from 48 deaths in 1998 to just 20 in 2010. On the other hand, the group of 1- to 4-years of age was the one that showed the lowest percentage decline because deaths were reduced by only 30%.

The age distribution indicates that age is a major risk fac-tor. Children between 1 and 4 years of age are those with the highest rates of death due to drowning, not only in Mexico but virtually in the entire world (Table 3). Half of the deaths during the study period (48%) corresponded to this age group, followed in importance by the group of 10- to 14-year-olds with 27% of deaths, whereas deaths in the group of 5- to 9-year-olds represent a fifth of all deaths (20.7%).


Sonia Fernández Cantón, Ana María Hernández Martínez, Ricardo Viguri Uribe

consistent with the approach of gender analysis, because males from early childhood are at higher risk of drowning because they have increased exposure to water-related activities and riskier practices. In this sense, new sports such as jet skiing and other water sports using inflatable devices may affect the increase of childhood injuries in-cluding drowning as well as musculoskeletal or long-bone injuries in certain population groups.

Regarding the specific breakdown for causes of submer-sion drowning, the International Classification of Diseases (ICD) indicates the distribution of deaths according to eight groups (ICD-10 three digits), which in turn are broken down into 68 subgroups (ICD-10 to four digits). It is notable that although >98% of deaths are certified by a physician (which gives certainty to the diagnosis), it is observed that there is a serious problem in the accuracy of the death certificate. In 58% of the records, the deaths are registered in the category for "unspecified drowning and submersion" (code W74). Of specified deaths (3877), the highest number of deaths (1100) occurred while the children were in natural waters (ditches, ponds, rivers, lakes or sometimes cataclysmic floods and other events), representing 28% compared to 10% of cases linked to swimming pools or bathtubs which, incidentally, represent the only water bodies specified by the ICD (Table 1).

In conclusion, according to the consensus of investiga-tors specializing on the subject, most drownings occur due to the negligence and carelessness of parents and children; 80% of deaths, as highlighted by the coordinator of the

Table 1. Deaths caused by drowning and accidental submersion in the population <15 years of age, Mexico, 1998-2010

Five-year age group

Classification of causes of death to 3 digits of the ICD-10 <1 year 1 - 4 years 5 - 9 years 10 - 14 years <15 years

W65 Drowning and submersion while in the bathtub 4 13 2 2 21

W66 Drowning and submersion consecutively by falling in the bathtub 5 32 1 1 39

W67 Drowning and submersion while in the swimming pool - 59 76 51 186

W68 Drowning and submersion consecutively due to falling in the swimming pool

- 89 39 15 143

W69 Drowning and submersion while in natural waters 5 181 299 615 1,100

W70 Drowning and submersion after falling in natural waters 14 166 113 134 427

W73 Other specified types of drowning and submersion 94 1,295 263 309 1,961

W74 Unspecified drowning and submersion 239 2,609 1,080 1,385 5,313

Total 361 4,444 1,873 2,512 9,190

Source: SINAIS/SSA/INEGI/system of deaths/Dynamic System of Information in Health Systems (Cubes), ICD causes: W65-W74.http://dgis.salud.gob.mx/cubos

Table 2. Relative weight of drowning due to accidental submersion in children <15 years, Mexico, 1998-2010

Year Drowning by acci-dental submersion

Accidental deaths

Relative weight (%)

1998 923 5,848 15.78

1999 871 6,022 14.46

2000 777 5,590 13.90

2001 763 5,667 13.46

2002 777 5,646 13.76

2003 707 5,186 13.63

2004 642 5,053 12.71

2005 645 4,762 13.54

2006 629 4,846 12.98

2007 645 4,483 14.39

2008 637 4,156 15.33

2009 607 4,161 14.59

2010 567 3,816 14.86

Total 9,190 65,236 14.09

Source: SINAIS/SSA/INEGI/system of deaths/Dynamic System of Information in Health Systems (Cubes), ICD Causes: W65-W74. http://dgis.salud.gob.mx/cubos

All children <1 year of age comprise the remaining 4% (Figure 3). Regarding gender distribution, males represent 68% of deaths, a percentage that varies relatively little over the years. This excess male mortality (213 male deaths per hundred females) is due, according to some studies


Mortality due to drowning in children less than 15 years of age in Mexico, 1998-2010

Table 3. Deaths caused by drowning and accidental submersion in children <15 years of age, Mexico, 1998-2010

Year reported < 1 year 1 - 4 years 5 - 9 years 10 - 14 years < 15 years Rate*

1998 48 414 200 261 923 2.75

1999 33 429 197 212 871 2.60

2000 32 366 157 222 777 2.31

2001 35 376 148 204 763 2.27

2002 26 367 171 213 777 2.32

2003 29 342 138 198 707 2.13

2004 15 335 124 168 642 1.95

2005 25 321 137 162 645 1.98

2006 23 309 131 166 629 1.96

2007 26 307 121 191 645 2.03

2008 28 292 120 197 637 2.03

2009 21 297 121 168 607 1.96

2010 20 289 108 150 567 1.86

Total 361 4,444 1,873 2,512 9,190 2.17

Source: SINAIS/SSA/INEGI/system of deaths/Dynamic Systems of Information in Health Systems (Cubes), ICD cause: W65-W74a W74. http://dgis.salud.gob.mx/cubos*Rate/100,000 persons <15 years of age.

Figure 1. Relative weight of deaths by drowning and accidental submersion in regard to the total deaths due to accidents in children <15 years of age, Mexico,1998-2010.


Sonia Fernández Cantón, Ana María Hernández Martínez, Ricardo Viguri Uribe

Figure 2. Mortality rate and deaths due to drowning and accidental submersion in children <15 years of age, Mexico,1998- 2010.

Figure 3. Percent distribution of deaths due to drowning and acci-dental submersion broken down by age groups, Mexico, 1998-2010.

Committee for the Prevention of Accidents and Injuries of the Spanish Association of Pediatrics, Dr. Jordi Pou, are avoidable. In that sense, it is essential to promote further research and public health initiatives, not only to widen the knowledge of the quality of information but also to more precisely determine the causes and contexts in which drowning deaths occur in Mexico, thus determining effec-tive preventive interventions.

Boletín Médico del Hospital Infantil de México is the official publication of the Hospital Infantil de México “Federico Gómez.” The journal has been continuously published on a bi-monthly basis since 1944 and publishes studies relating to pediatrics ac-cording to the following areas: biomedical, clinical, public health, clinical epidemiology, health education and clinical ethics. The following guidelines are in accordance with the “Uniform Re-quirements for Manuscripts Submitted to Biomedical Journals,” published by the International Committee of Medical Journal Editors (http://www.icmje.org).

Types of articlesTypes of articles published are as follows: Review Articles, Cli-nical Case Reports, Clinicopathological Cases, Pediatric Themes and Letters to the Editor. Published articles appear both in print and on-line in Spanish and on-line in English.

Submissions should be sent via electronic mail to: [email protected] with the following requirements:1. Letter addressed to Dr. Gonzalo Gutiérrez Trujillo, Editor,

Boletín Médico del Hospital Infantil de México, Departamen-to de Ediciones Médicas. The letter, signed by the correspon-ding author, should include the following information:a) The enclosed article is being submitted for evaluation

for eventual publication in Boletín Médico del Hospital Infantil de México.

b) The authors declare that the work has not been pre-viously published, has not been previously accepted for publication and has not been submitted simultaneously to another publication.

c) Type of study should be indicated along with the corres-ponding pertinent area of pediatrics.

d) Confirm that the Guidelines to Authors have been re-viewed and adhered to prior to submission.

e) If applicable, the authors should declare any conflict of interest or submit a statement that no conflict of interest exists. In the event of a conflict of interest, the authors must disclose any external financial or economic inter-est.

f) All external funding sources should be clearly indicated.g) All authors must affirm that they are in agreement with

the submission of the manuscript and that they have reviewed and approved the work.

Please be reminded that without the appropriately signed author letter, the initial editorial process will be delayed.

manuscript preparationAll manuscripts should be prepared with standard programs (Word 97 or higher) using the word processor function of your computer. Double space all sections of the manuscript including References, Tables and Figure Legends. Do not justify right mar-gins and use one-inch margins all around. Keep formatting to a minimum. Pages should be numbered consecutively beginning with the first page and numbers should appear in the lower right corner of the page.

AbbreviationsComplex terms used frequently in the manuscript may be ab-breviated. Abbreviations are placed in parentheses at first use in the abstract and again at first use in the text. Confirm that any

Guidelines to authors

abbreviations used in Tables are appropriately spelled-out in the Table legend underneath.

Organization of the manuscriptThe first page should include the following:

a) Title of the manuscript (Spanish and English) b) Type of manuscript: Original Article, Review Article,

Clinical Case Report, etc.c) Name(s) of all authors in their order of appearance in

relation to the publication d) Affiliation of each author (degrees and honors should

be omitted)e) Name, E-mail address, postal address and telephone

number of the corresponding author to whom any co-rrespondence can be directed during the review process of the manuscript.

The second page should contain the Abstract. Note that the Abstract is the most-often read part of the manuscript. For this reason, it must be clear, concise and contain information relevant to the article. Do not use references in the Abstract. In the case of Original Articles and Clinical Case Reports, the Abstract should be structured according to the following sections: Background, Methods, Results, Conclusions, or Background, Clinical Case and Conclusions. Abstracts for Review Articles and Pediatric Themes should be unstructured and include only one paragraph. The Abstract should be limited to 200 words and include only relevant aspects of each of the principal sections of the body of the manuscript. Authors should provide 3–6 keywords following the Abstract and use Medical Subject Headings (MeSH) terms as a guide. Visit: http://www.nlm.nih.gov/mesh/meshhome.html. The manuscript should include the following sections: 1) Original articles: Introduction, Methods, Results, Discus-

sion and References.2) Clinical case reports: Introduction, Clinical case, Discus-

sion and References.3) Clinicopathological cases: Clinical case, Discussion and

References.

An Acknowledgment section may be included directly following the Reference section. Granting institutions or other financial aid may be listed under Acknowledgments. If there are persons, other than the authors, who assisted with the study or preparation of the manuscript (i.e., technicians, nurses, ancillary health personnel, editorial assistance), they may be listed here.

ReferencesReferences should be numbered consecutively, double spaced, and listed in the order in which they appear in the text using ara-bic numbers (in the text, references are indicated by superscript arabic numbers after any punctuation). The Reference section should follow the last section of the manuscript. It is not neces-sary to begin the References on a separate page. The references should be formatted according to the instructions from the U.S. National Library of Medicine. Abbreviated journal names should reflect the style of Index Medicus (visit http://www.nlm.nih.gov/tsd/serials/lji.html) When a reference cites six or fewer authors, names should be included for all authors. When there are seven or more authors, use the first six names followed by et al. Authors are responsible for the accuracy of references. Please use the following examples for presentation of references:

Journals:• Klimo P, Rao G, Brockmeyer D. Congenital anomalies of

the cervical spine. Neurosurg Clin North Am 2007;18:463-478.

• Published book:• Bell RM. Holy Anorexia. Chicago: University of Chicago

Press; 1985.• Book chapter:• Hudson JI, Hudson RA, Pope HG. Psychiatric comorbidi-

ty and eating disorders. In: Wonderlich S, Mitchell J, eds. Eating Disorders Review. Part 1. Oxford: Radcliffe Publis-hing; 2005. pp. 43-58.

• Internet consult: • McKusick VA. Klippel Feil syndrome. Online. Mendelian

inheritance in man (accessed: March 26, 2008). Availa-ble at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=148900.

Tables and Figures All tables and figures including schemes, diagrams and table legends must be presented in an editable form. Do not “copy and paste” material from external sources.

TablesTables should be numbered using arabic numbers in the order in which they are cited in the text and include a short descriptive title. Tables should not reiterate information presented in the Results section. For preparation of Tables containing only data, use the “Table Editor” function of your word processing program. Do not insert any vertical lines. Use horizontal lines only for clarity of information under table headings. Confirm that infor-mation provided below each table heading is properly aligned and clearly identifiable. Tables containing schemes or diagrams should be prepared in PowerPoint; graphics with shading, bars, dispersions, etc. should be prepared using Excel. Each Table should be prepared on a separate page, following the Reference section. Table footnotes should include any abbreviations that need to be explained and notes relating to the Table should be presented alphabetically using superscript letters.

FiguresAuthors should number figures in the order in which they appear in the text. Figures include graphs, charts, photographs, and illustrations. Each figure should be accompanied by a self-explanatory legend. Digital images should be legible and printed with a resolution of not less than 300 dpi, using .jpg (jpeg) or .bmp extension. If photographs submitted correspond to actual patients, the anonymity of the patients should be protected or written per-mission from the patient and/or family/legal guardian to publish the photograph(s) should be submitted. Figure legends with corresponding figure numbers should be typed consecutively on a separate page following the last Table (or following the Acknowledgments if there are no Tables).

Permission to use previously published Tables or FiguresIf the manuscript contains Tables or Figures that have been pre-viously published, permission must be obtained from the original Publisher in order to reproduce the material. This applies to Ta-bles or Figures that have been modified, adapted or translated. A sample “permission” letter is available from the Editorial Office of Boletín Médico del Hospital Infantil de México. Appropriate credit must be written per the following example:

Reprinted (or Adapted, Modified, Translated) from Castilloux J, Noble AJ, Faure C. Risk factors for short- and long-term morbidity in children with esophageal atresia. J Pediatr 2010;156:755-760. With permission.

Ethical approval of studies and informed consentIn regard to possible ethical conflicts, the rights of patients of privacy and confidentiality shall be maintained. For studies involving human subjects, state the manner in which informed consent was obtained from the study participants (i.e., oral or written). All manuscripts reporting data from studies involving humans or animals are subject to formal review and approval by an appropriate institutional review board or ethics committee and should be described at the end of the Methods section. For investigators who do not have formal ethics review committees, the principles outlined in the Declaration of Helsinki as well as in the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, Commission on Life Sciences, National Research Council) should be followed. Review process The first review of the manuscript is performed by the Editor to assure that the manuscript corresponds to the theme of the journal and that all required information has been properly submitted in accordance with the Guidelines to Authors. The second review is carried out by two independent reviewers who have been assigned to the manuscript on the basis of their field of expertise. The identities of authors’ and reviewers’ are kept confidential.

CopyrightAll accepted manuscripts become the permanent property of the Boletín Médico del Hospital Infantil de México and may not be published elsewhere, in whole or in part, without prior written permission from the Editor and appropriate credit to the authors and to Boletín Médico del Hospital Infantil de México. Upon acceptance of an article for publication in Boletín Médico del Hospital Infantil de México, a letter signed by all authors shall be submitted transferring copyright of the published article to Boletín Médico del Hospital Infantil de México. If the author(s) wishes to reprint any of the material already published in Boletín Médico del Hospital Infantil de México, prior authorization is required from the Editor.

Note: For periodic up-to-dates of "Guidelines to Authors", please consult our internet page: www.himfg.edu.mx

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