Rishi Bolia

Prevalence, Natural History, and Outcome of Acute Fluid Collection and Pseudocyst in Children With Acute Pancreatitis.

Objective: Recent years have witnessed an increase in acute pancreatitis (AP) in children; however, the natural history of acute fluid collection (AFC) and pseudocyst is largely unknown. We evaluated the frequency, clinical characteristics, and natural history of pseudocysts in children with AP. Methods: Children with AP admitted at Sanjay Gandhi Postgraduate Institute of Medical Sciences from 2001 to 2011 were enrolled and studied until complete resolution. Subjects with inadequate follow-up, recurrent AP, and chronic pancreatitis were excluded. Results: Of the 58 children (43 boys, median age 14 [1–18] years) with AP, 34 (58.6%) and 22 (38%) developed AFC and pseudocyst, respectively. No difference in age (12 [4–18] vs 13 [1–16] years), etiology (idiopathic 64% vs 47% and traumatic 27.2% vs 22.2%), and systemic complications (pulmonary [18% vs 11%], renal [22.7% vs 11%], and shock [13.6% vs 10%]) was observed between children with and without pseudocyst. A total of 11 of the 22 subjects with pseudocyst underwent drainage, the commonest symptom requiring drainage being gastric outlet obstruction [n = 5] and infection [n = 2]. The 11 of the 22 children with AP and pseudocyst (size 6.4 [3–14.4] cm) showed spontaneous resolution (disappearance [n = 9] and significant reduction in size [n = 2]) during 110 (25–425) days. Symptomatic pseudocysts requiring drainage were more often secondary to traumatic AP (6/6 vs 2/14 [idiopathic], P = 0.0007) than asymptomatic pseudocysts resolving spontaneously. Overall, only 26.4% (9/34) children with AFC required drainage because of symptomatic pseudocyst. Conclusions: Among children with AP, 58.6% developed AFC and 38% developed pseudocysts. Only patients with symptomatic pseudocyst need drainage, and asymptomatic pseudocyst can be safely observed irrespective of size and duration of collection.

Role of Procalcitonin and C-reactive Protein As Biomarkers of Infection in Children With Liver Disease.

Objectives: Early and accurate identification of infection in patients with liver disease is challenging. The present study evaluated the role of procalcitonin (PCT) and C-reactive protein (CRP) as biomarkers of bacterial infection in children with liver disease. Methods: Demographic and clinical data of consecutive children admitted with acute liver failure (ALF) or decompensated chronic liver disease (DCLD) were collected. PCT and CRP were measured within 24 hours of admission. Blood and urine culture, chest x-ray, and ascitic fluid analysis were done. Results: One hundred sixty-four children (113 boys, age 76 [0.5–204] months, ALF 69, DCLD 95) were enrolled. Seventy-seven (47%) had infection. Most common site was ascitic fluid (n = 35), followed by urinary tract (n = 26), pneumonia (n = 22), and blood stream infection (n = 16). Twenty-one children had multiple-site infections, 18 had severe sepsis, and 36 had systemic inflammatory response syndrome. PCT and CRP correlated with infection severity, higher in severe sepsis (8.3 [3.5–38] ng/mL and 4.1 [0.3–13.8] mg/dL) than only infection (0.89 [0.1–8] ng/mL and 1.7 [0.32–24] mg/dL) and no infection (0.3 [0.1–6.75] ng/mL and 0.3 [0.1–4.16 mg/dL]). Systemic inflammatory response syndrome was more common in patients with infection (31/77 vs 5/87, P = 0.00). PCT (>0.5 ng/mL) and CRP (>0.6 mg/dL) performed better in DCLD (AUC of 0.90 and 0.83) compared with patients with ALF (AUC of 0.73 and 0.69). Conclusions : PCT and CRP are reliable markers of infection and correlate with infection severity in children with liver disease. Their diagnostic accuracy is better in DCLD than ALF cases.

Prevalence, Clinical Profile, and Outcome of Ascitic Fluid Infection in Children With Liver Disease

Objectives: Pediatric literature on spontaneous bacterial peritonitis (SBP) is limited. We evaluated the prevalence, subtypes, clinical profile, and effect on outcome of ascitic fluid infection (AFI) in children with liver disease. Methods: Children with liver disease-related ascites and subjected to paracentesis were classified as no-AFI and AFI (SBP, culture-negative neutrocytic ascites [CNNA], and monomicrobial non-neutrocytic bacterascites). Clinical and laboratory parameters, in-hospital mortality, and outcome in follow-up were noted. Results: Two hundred sixty-two children (163 boys; age 84 [1–240] months, chronic liver disease [CLD, n = 173], non-CLD [n = 89]) were enrolled. A total of 28.6% (n = 75) had SBP/CNNA, more common in CLD than non-CLD (55/173 [31.7%] vs 20/89 [22.4%]; P = 0.1). A total of 50.6% SBP/CNNA cases were symptomatic for AFI. Gram-negative bacilli were isolated from 70% SBP cases. Twenty-five percent (18/72) CLD children with AFI had a poor hospital outcome, with INR, Child-Pugh score and gastrointestinal bleeding predicting outcome on multivariate analysis. Patients with CLD with SBP had higher in-hospital mortality (10/20 vs 5/35; P = 0.01) than those with CNNA, but similar Child-Pugh score (12[7–15] vs 11[7–14]; P = 0.1), recurrence of AFI (3/9 vs 6/24; P = 0.6) and mortality in follow-up (22.2% vs 25%; P = 0.1). Patients with CLD with SBP/CNNA had higher mortality over 1 year follow-up than no-AFI (24.2% [8/33] vs 12.2% [7/57]; P = 0.1) but the difference was not significant. Conclusions: A total of 28.6% children with liver disease-related ascites have SBP/CNNA; 50% are symptomatic. Patients with CLD with SBP/CNNA have a mortality of 24% over 1year follow-up. CLD with SBP is similar to CNNA except for higher in-hospital mortality.

Pediatric CLIF-SOFA score is the best predictor of 28-day mortality in children with decompensated chronic liver disease

BACKGROUND & AIMS Early identification of children with decompensated chronic liver disease (DCLD) at risk of short-term mortality helps improve outcome. We aimed to evaluate the predictors of outcome and role of Child-Pugh, pediatric end-stage liver disease (PELD) and pediatric chronic liver failure sequential organ failure assessment (pCLIF-SOFA) score for prognosticating 28-day mortality in children with DCLD. METHODS DCLD children were prospectively evaluated with a clinico-laboratory proforma and followed for 28 days to determine outcome. Child-Pugh, PELD and pCLIF-SOFA were calculated at admission. Univariate and multivariate analysis was performed to identify the best predictors of outcome. RESULTS A total of 110 children (74 boys, 96 [4-204] months) were enrolled and 37 (33.6%) died at 28 days. Significant risk factors for mortality were a higher international normalized ratio (hazard ratio [HR] 1.17; 95% CI 1.04-1.31; p <0.001) and bilirubin (HR 1.04; 95% CI 1.01-1.08; p <0.001), lower albumin (HR 0.46; 95% CI 0.27-0.77; p = 0.03) and sodium (HR 0.93; 95% CI 0.89-0.98; p = 0.01), absence of treatable etiology (HR 2.00; 95% CI 1.40-2.87; p = 0.001) and presence of organ failure (HR 3.22; 95% CI 1.98-10.58; p <0.001). Organ failure and serum sodium were independent predictors of poor outcome on multivariate analysis. pCLIF-SOFA (16 [9-22] vs. 9 [5-15]), Child-Pugh (11 [9-15] vs. 10 [8-14]) and PELD (22.2 [7.5-45.3] vs. 15.3 [4.5-23.9]) scores were significantly higher in non-survivors. The area under the curve was 0.977 for pCLIF-SOFA, 0.815 for Child-Pugh score, and 0.741 for PELD score. A pCLIF-SOFA score of ≥11 identified 28-day mortality with a sensitivity and specificity of 94.9% and 91.5%, respectively. CONCLUSION Thirty-four percent of children with DCLD have a poor short-term outcome. Organ failure and low serum sodium are independent predictors of outcome. pCLIF-SOFA performs better than Child-Pugh and PELD in prognostication of 28-day mortality. Our study supports the use of scores based on organ failure in prognosticating children with DCLD. LAY SUMMARY The ability to predict the course of a disease is an important part of the assessment, enabling timely interventions that improve outcomes. We evaluated the outcome (death vs. survival) and compared three different scoring systems for their ability to predict mortality within 28 days in children with decompensated chronic liver disease (DCLD). One-third of children with DCLD died within 28 days and the pediatric chronic liver failure sequential organ failure assessment score, which considers the main organ systems of the body (lungs, liver, brain, kidney, blood and cardiac) fared better for identification of children with a poor outcome than the Child-Pugh and pediatric end-stage liver disease score which comprise of only liver-related parameters. Our study supports the use of scores based on organ failure in prognosticating children with DCLD.

Superior Mediastinal Syndrome : A Rare Presenting Feature of Acute Myeloid Leukemia

Superior mediastinal syndrome (SMS) is an uncommon manifestation of malignant neoplastic disease in children. The commonest neoplastic cause of SMS is Non Hodgkin lymphoma. Acute myeloid leukemia (AML) as a cause of SMS is extremely uncommon in childhood. The authors hereby report a case of a child with AML who presented with SMS at their hospital. This report also highlights the importance of flowcytometry as a diagnostic modality in hematological malignancies.

Children with untreated coeliac disease have sub-clinical cardiac dysfunction: a longitudinal observational analysis

Abstract Introduction: We assessed cardiac function (CF) in celiac disease (CD) patients and the effect of gluten-free diet (GFD) on CF. Methods: Prospective evaluation of CF using conventional and tissue doppler echocardiography in 50 CD patients (age 4.2 ± 1.1 years) at diagnosis and after a year of GFD (group 1), 100 CD children (group 2; 47 compliant and 53 non-compliant) in follow-up and 25 healthy controls. Results: Untreated CD (n = 50) children had larger left ventricle end diastolic dimension (35.33 ± 0.87 vs. 32.90 ± 0.91 mm; p = .04), reduced (<55%) left ventricular ejection fraction (20% vs. 0%; p = .01) and a higher (>0.6) myocardial performance index (MPI, 66% vs. 0%; p ≤ .01) as compared to controls. Re-evaluation after one year with good dietary compliance showed changes in isovolumic relaxation time (72.5 ± 4.2 vs. 50.62 ± 2.69; p = .0001) and deceleration time (121.05 ± 10.1 vs. 99.87 ± 8.5; p = .02), reflecting improved cardiac diastolic function. GFD compliant patients had lower MPI than non-compliant (0.60 ± .03 vs. 0.66 ± .08; p = .04), reflecting improvement in load-independent echocardiographic parameters. Conclusions: Subclinical cardiac dysfunction is common in CD children at diagnosis. Improvement in echocardiographic parameters occurs with GFD and non-compliant children continue to have persistent cardiac dysfunction.

Regional Genotyping of Rotavirus: Role in Vaccine Development

Rotavirus is the most common cause of severe acute diarrhea in young children worldwide, resulting in >2 lac deaths annually [1]. Viral serotypes are defined on the basis of outer capsid proteins VP4 (P serotype) and VP7 (G serotype). Till date, at least 24 G and 33 P genotypes have been identified and 12 G and 15 P serotypes are known to infect humans. Development of a protective immune response after primary infection that reduces symptom severity on re-infection is the basis for oral rotavirus vaccine development. In this issue, Bulut et al. from Middle Black Sea region of Turkey, evaluated the prevalence and genotype of rotavirus in 111 fecal samples from children (<5 y) hospitalized with acute gastroenteritis and positive for rotavirus antigen by latex agglutination test [2]. They used semi-nested multiplex polymerase chain reaction (PCR) for genotyping. Rotavirus RNA was present in 83/111 (74.7%) samples positive by latex agglutination test. Enzyme linked immunoassay (ELISA) has better sensitivity and specificity than latex agglutination test [3]. Use of ELISA could have potentially reduced the 28 false positive results in the study. This study provides regional data about the genotype distribution of rotavirus. Such studies are informative but have limited global utility. Multicentric national studies with a uniform protocol for recruitment, data collection and testing serve as a better guide for policy makers. Three common G types (G1, G9, and G2) and two common P types (P [8], P [4]) accounted for 85.5% and 97.5% of the strains, respectively. No strain was untypeable. These results are in concordance with the Turkey Rotavirus Surveillance Network data, suggesting similarity to the rest of the country [4]. Globally, the most common types found are G (G1 – G4) and P ([4] and [8]) [4]. Most cases of rotavirus diarrhea in India are caused by G1 (most common), G2 and G untypeable strains and P [4], [6] and P untypeable strains with distinct regional variations [5]. Two rotavirus vaccines, RotaTeq® (pentavalent, bovine-human, reassortant G1–4, P [8]) and Rotarix® (monovalent human G1P [8]) are currently available and contain 92% and 86% genotypes respectively found in this study. These vaccines are expensive and have a lower efficacy in developing countries. Authors suggest that development of indigenous vaccines based on the local rotavirus strains may be more efficacious and cheaper. India has led the way in this direction. Rotavac® (116E strain) containing G9P [11] strain has an efficacy of 55% in preventing severe rotavirus diarrhea in the first year of life, similar to the efficacy of Rotateq and Rotarix in African and Asian countries [6]. Even with lower efficacy, rotavirus vaccination provides health and cost benefits due to the high disease burden and mortality. The authors suggest that rotavirus vaccines used in their region must include the genotypes identified there. But does this hold true? Recent evidence from clinical trials indicate Bheterotypic immunity^ i.e. protection against a wide range of circulating rotavirus strains, even those not included in the vaccine. It has been shown recently that heterotypic immunity is mediated through antibodies directed against VP5* (stalk region of the rotavirus attachment protein VP-4) [7]. This may open the field for development of third generation vaccines. In the developing world, a two pronged strategy of prevention and therapy has to be developed simultaneously as 1/3rd to 1/2 of the children remain unprotected despite vaccination and need management for severe diarrhea [8]. Treatment with anti rotaviral protein was found to have a promising role in severe rotaviral diarrhea across all genotypes [8]. To conclude, the jury is still out whether vaccines based on local strains or against VP5* would be the way in future. However, development of specific therapy against rotavirus should continue to be the target of research to have complete cure of rotavirus disease. * Anshu Srivastava avanianshu@yahoo.com

Relationship of Severity of Hepatitis A with Polymorphisms in Hepatitis A Virus Cellular Receptor 1 (HAVCR1) Gene

INTRODUCTION AND AIM HAVCR1 protein is the cellular receptor for hepatitis A virus (HAV). Genetic polymorphism in this gene may alter the outcome of HAV infection. In a previous study, a 6-amino acid insertion (157insMTTTVP) in HAVCR1 gene was associated with more severe disease. We decided to investigate this association further. MATERIAL AND METHODS We sequenced exon 4 of the HAVCR1 gene in patients with clinical hepatitis A attending our institution, and a group of healthy controls in a disease-endemic setting in India. Frequencies of different haplotypes of a genomic region with two overlapping insertion-deletion polymorphisms (indels; rs141023871 and rs139041445) were compared between patients and controls, as well as between patients with and without a severe form of disease (liver failure). RESULTS The gene had three haplotypes in the region of interest - a short form, an intermediate-form with a 5-amino acid 157insMTTVP insertion and a long-form with a 6-amino acid 157insMTTTVP insertion. The allele frequency (29/150 [19%] vs. 43/146 [29%]; p = ns) and haplotype frequency (29/75 [39%] vs. 39/73 [53%]; p = ns) of the 157insMTTTVP variant were similar in hepatitis A patients and healthy controls (30%). Further, the allele frequency (12/58 [21%] vs. 17/92 [18%]; p = ns) and haplotype frequency (12/29 [41%] vs.17/46 [37%]; p = ns) of the longest variant were also similar in patients with severe and mild disease. DISCUSSION In the study population, the 157insMTTTVP variant of HAVCR1 gene was not associated with more severe outcome of HAV infection. Further studies in other populations around the world are needed to assess the relation of this genetic variation with disease outcome.INTRODUCTION AND AIM HAVCR1 protein is the cellular receptor for hepatitis A virus (HAV). Genetic polymorphism in this gene may alter the outcome of HAV infection. In a previous study, a 6-amino acid insertion (157insMTTTVP) in HAVCR1 gene was associated with more severe disease. We decided to investigate this association further. MATERIAL AND METHODS We sequenced exon 4 of the HAVCR1 gene in patients with clinical hepatitis A attending our institution, and a group of healthy controls in a disease-endemic setting in India. Frequencies of different haplotypes of a genomic region with two overlapping insertion-deletion polymorphisms (indels; rs141023871 and rs139041445) were compared between patients and controls, as well as between patients with and without a severe form of disease (liver failure). RESULTS The gene had three haplotypes in the region of interest - a short form, an intermediate-form with a 5-amino acid 157insMTTVP insertion and a long-form with a 6-amino acid 157insMTTTVP insertion. The allele frequency (29/150 [19%] vs. 43/146 [29%]; p = ns) and haplotype frequency (29/75 [39%] vs. 39/73 [53%]; p = ns) of the 157insMTTTVP variant were similar in hepatitis A patients and healthy controls (30%). Further, the allele frequency (12/58 [21%] vs. 17/92 [18%]; p = ns) and haplotype frequency (12/29 [41%] vs.17/46 [37%]; p = ns) of the longest variant were also similar in patients with severe and mild disease. DISCUSSION In the study population, the 157insMTTTVP variant of HAVCR1 gene was not associated with more severe outcome of HAV infection. Further studies in other populations around the world are needed to assess the relation of this genetic variation with disease outcome.

Severe Liver Disease in Indian Children: Is Transplant the Only Option?

There have been major advances in the knowledge about presentation, diagnosis and management of liver diseases in children in the last 2–3 decades. However, liver transplantation (LT) is the final option for patients with acute liver failure (ALF), decompensated chronic liver disease, tumors and metabolic liver disease (MLD) who have failed other therapies. Biliary atresia (BA) and MLD are the most common indications for LT in children [1, 2]. In this volume of the Journal, two studies have addressed issues inmanagement of liver disease in young children. Alam et al. prospectively evaluated 30 young children with ALF [3]. MLD, hemophagocytic lymphohistiocytosis and acute viral hepatitis were the commonest etiologies (33, 17 and 17 % cases respectively), with only 10 % indeterminate cases. However, only 40 % children had a good outcome and LT could not be done in any of the children where it was indicated (8/30; 27 %). In the second article, Malhotra et al. have reported the results of living donor liver transplantation (LDLT) in 20 children with BA (18 post Kasai procedure and 2 primary) [4]. The authors evaluated 49 post Kasai BA cases: 21 (42.8%) had a poor outcome (18 refused and 3 died while awaiting LT), 10 were doing well and 18 were transplanted. Both these studies have shown what can be achieved with good medical care, in terms of high rate of etiological diagnosis in ALF and good post-transplant outcome in BA. However, they highlight multiple deficiencies in the management of children with liver disease in our country. The children withMLD had a delayed diagnosis, presented in a sick state with ALF and could not be salvagedwith dietary measures and supportive therapy [3]. This highlights the need of increasing awareness among pediatricians regarding presentation of MLD, initiation of neonatal screening programs, establishment of laboratories capable of diagnosing MLD and ensuring availability of specific formulae and diets required for their treatment. In the study by Alam et al., ~50 % of cases had a potentially treatable etiology [3]. Early appropriate therapy has the potential to improve the outcome and reduce need of LT in these children. Although there is no direct calculation, but ~30 % children with liver diseases from a referral centre in North India were found to be candidates for LT [5]. The need for pediatric LT is estimated to be 1–2 per million population in the West. Extrapolating it to India, about 2500 children will need LT per year [6]. Various factors contribute to non availability of LT, most important being cost and lack of donors. There has been very little progress in harvesting and sharing of deceased donor organs even after 17 y of the first pediatric LT due to various logistic and cultural reasons in India. This is in contrast to the US where majority are deceased donor liver transplant (DDLT). There is an urgent need for establishing the deceased donor LT program and utilizing all strategies like LDLT (living donor liver transplant) and DDLT (including split-liver grafts) to bridge the gap between requirement and organ availability. DDLT will help in multi-organ transplantation and appropriate use of scarce ICU resources including mechanical ventilation [7]. Having both LDLT and DDLT is useful for managing children who require urgent re-transplantation. The 2 deaths in the BA patients could have been avoided if a second organ was available [4]. Although the average cost of a transplant in India (12–15 lakh rupees) is only about 1/5–1/10th the cost in the West, but * Anshu Srivastava avanianshu@yahoo.com