Fatal familial hemophagocytic lymphohistiocytosis with perforin gene (PRF1) mutation and EBV-associated T-cell lymphoproliferative disorder of the thyroid

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare fatal autosomal recessive disorder of immune dysregulation. The disease presents most commonly in the first year of life; however, symptomatic presentation throughout childhood and adulthood has also been identified. Biallelic mutation in the perforin gene is present in 20%­50% of all cases of FHL. Secondary hemophagocytic lymphohistiocytosis (HLH) in association with hematological malignancies is known; however, whether mutations in HLH-associated genes can be associated with FHL and hematolymphoid neoplasms is not well documented. Also, Epstein­Barr-virus- (EBV) positive systemic T-cell lymphoproliferative disease (SE-LPD) in the setting of FHL is not clearly understood. Here, we present the case of a young boy who presented with typical features of childhood FHL harboring the perforin gene (PRF1) mutation, and had SE-LPD diagnosed on autopsy, along with evidence of recent EBV infection. The patient expired due to progressive disease. Five siblings died in the second or third decade of life with undiagnosed disease. Genetic counseling was provided to the two surviving siblings and parents, but they could not afford genetic testing. One surviving sibling has intermittent fever and is on close follow-up for possible bone marrow transplantation.

Aetiology, outcomes & predictors of mortality in acute respiratory distress syndrome from a tertiary care centre in north India.

Background & objectives: Acute respiratory distress syndrome (ARDS) is a common disorder in critically ill patients and is associated with high mortality. There is a paucity of literature on this condition from developing countries. This prospective observational study was designed to find out the aetiology, outcomes and predictors of mortality in ARDS. Methods: Sixty four consecutive patients who satisfied American-European Consensus Conference (AECC) definition of ARDS from medical Intensive Care Unit (ICU) of a tertiary care centre in New Delhi, India, were enrolled in the study. Demographic, biochemical and ventilatory variables were recorded for each patient. Baseline measurements of serum interleukin (IL)-1β, IL-6, tumour necrosis factor-alpha (TNF-α), procalcitonin (PCT) and high sensitivity C-reactive protein (hsCRP) were performed. Results: Common causes of ARDS included pneumonia [44/64 (68.7%)], malaria [9/64 (14.1%)] and sepsis [8/64 (12.5%]. Eight of the 64 (12.5%) patients had ARDS due to viral pneumonia. The 28-day mortality was 36/64 (56.2%).Independent predictors of mortality included non-pulmonary organ failure, [Hazard ratio (HR) 7.65; 95% CI 0.98-59.7, P=0.05], Simplified Acute Physiology Score (SAPS-II) [HR 2.36; 95% CI 1.14-4.85, P=0.02] and peak pressure (Ppeak) [HR 1.13; 95% CI 1.00-1.30, P = 0.04] at admission. Interpretation & conclusions: Bacterial and viral pneumonia, malaria and tuberculosis resulted in ARDS in a considerable number of patients. Independent predictors of mortality included non-pulmonary organ failure, SAPS II score and Ppeak at baseline. Elevated levels of biomarkers such as TNF-α, PCT and hsCRP at admission might help in identifying patients at a higher risk of mortality.

Malignancies in human immunodeficiency virus infected patients in India: Initial experience in the HAART era.

Background & objectives: Limited data are available on malignancies in human immunodeficiency virus (HIV)-infected patients from India. We undertook this study to assess the frequency and spectrum of malignancies in HIV-infected adult patients during the first eight years of highly active antiretroviral therapy (HAART) rollout under the National ART Programme at a tertiary care centre in New Delhi, India. Methods: Retrospective analysis of records of patients registered at the ART clinic between May 2005 and December 2013 was done. Results: The study included 2598 HIV-infected adult patients with 8315 person-years of follow up. Malignancies were diagnosed in 26 patients with a rate of 3.1 (IQR 2.1-4.5) cases per 1000 person-years. The median age for those diagnosed with malignancy was 45 (IQR 36-54) yr, which was significantly (P<0.01) higher compared with those not developing malignancies 35 (IQR 30-40) yr. The median baseline CD4+ T-cell count in patients with malignancy was 135 (IQR 68-269) cells/μl compared to 164 (IQR 86-243) cells/μl in those without malignancies. AIDS-defining cancers (ADCs) were seen in 19 (73%) patients, while non-AIDS-defining cancers (NADCs) were observed in seven (27%) patients. Malignancies diagnosed included non-Hodgkin’s lymphoma (16), carcinoma cervix (3), Hodgkin’s lymphoma (2), carcinoma lung (2), hepatocellular carcinoma (1), and urinary bladder carcinoma (1). One patient had primary central nervous system lymphoma. There was no case of Kaposi’s sarcoma. Interpretation & conclusions: Malignancies in HIV-infected adult patients were infrequent in patients attending the clinic. Majority of the patients presented with advanced immunosuppression and the ADCs, NHL in particular, were the commonest malignancies.

Clinical profile & predictors of poor outcome of adult HIV-tuberculosis patients in a tertiary care centre in north India.

Background & objectives: There is a paucity of data from India on response to treatment of tuberculosis (TB) in patients with human immunodeficiency virus (HIV)-TB co-infection. This study was done to assess the frequency and pattern of TB, outcome of anti-tuberculosis treatment, and the factors related to poor outcome of TB treatment in adult patients with HIV infection. Methods: Retrospective review of case records of HIV-TB co-infected patients attending the antiretroviral therapy (ART) clinic in a tertiary care centre in north India was done. Results: Of the 1754 patients included in the study, 583 (33.2%) were diagnosed with active TB and 466 (79.9%) of them had CD4 count less than 200/μl at diagnosis. Extrapulmonary TB was diagnosed in 372 (63.8%) patients [76 (20.4%) had disseminated TB], and pulmonary TB in 211 (36.2%) patients. “Favourable outcome” (cure and completed treatment) was observed in 332 (77%) patients. Unfavourable outcome included default (8.1%), treatment failure (1.6%), and death (13.2%). At 1-year post-treatment follow up, 12 (3.6%) patients had disease relapse. CD4 count of less than 200/ μl at diagnosis [OR-2.32, CI (1.06-5.09)], and retreatment cases [OR-2.91, CI (1.22-6.89)] were independent predictors of unfavourable outcome. Interpretation & conclusions: There is an urgent need to strengthen the information, education, communication activities and expand the ART services to meet the requirement of early testing and treatment initiation in patients co-infected with HIV-TB. The findings highlight the need for performing drug susceptibility testing (DST) for patients starting retreatment regimen to improve treatment outcome.

Rare manifestations of sarcoidosis in modern era of new diagnostic tools.

Background & objectives: Growing body of literature on sarcoidosis in India has led to an increased awareness of the disease. With the advent of better imaging tools hitherto under-recognized manifestations of sarcoidosis are likely to be better recognized. We sought to study the rare clinical and radiological manifestations (<5%) in patients with sarcoidosis. Methods: Retrospective review of records of 164 patients with histopathologically proven sarcoidosis seen over six years in a tertiary care centre in north India, was done. Results: Fifty four rare manifestations were observed in 164 patients. Acute presentation in the form of Lofgren syndrome was seen in eight (4.9%) and Heerfordt's syndrome in two (1.2%) patients. Musculoskeletal manifestations included chronic sarcoid arthritis in three (1.8%), deforming arthritis and bone erosion in one (0.6%) each. Rare initial presentation with dilated cardiomyopathy in one (0.6%), complete heart block in two (1.2%), bilateral sequential facial nerve palsy in two (1.2%), and pyrexia of unknown origin was seen in one (0.6%) patient. Other rare manifestations included chronic respiratory failure in one (0.6%), dysphagia in one (0.6%), sicca syndrome in five (3%), massive splenomegaly in one (0.6%), portal hypertension in two (1.2%), hypersplenism, gastric sarcoidosis, ninth and tenth cranial nerve palsies, moderate pericardial effusion and nephrocalcinosis in one (0.6%) each, and pulmonary artery hypertension in two (1.2%) patients. Rare radiological manifestations included moderate pleural effusion in two (1.2%), pleural thickening in five (3%), calcification of intrathoracic lymph nodes in four (2.4%), alveolar (nodular) sarcoidosis in three (1.8%), and myocardial uptake of 18F-fluorodeoxyglucose (F-18 FDG) in two (1.2%) patients. Fourteen patients had airways obstruction and behaved typically like seasonal bronchial asthma with excellent response to corticosteroids. Interpretation & conclusions: Increased awareness of rare manifestations will facilitate better management of these patients. With increasing use of modern diagnostic tools, manifestations hitherto considered rare, are likely to be recognized more frequently in the future.

HIV & immune reconstitution inflammatory syndrome (IRIS).

Antiretroviral therapy (ART) initiation in HIV-infected patients leads to recovery of CD4+T cell numbers and restoration of protective immune responses against a wide variety of pathogens, resulting in reduction in the frequency of opportunistic infections and prolonged survival. However, in a subset of patients, dysregulated immune response after initiation of ART leads to the phenomenon of immune reconstitution inflammatory syndrome (IRIS). The hallmark of the syndrome is paradoxical worsening of an existing infection or disease process or appearance of a new infection/disease process soon after initiation of therapy. The overall incidence of IRIS is unknown, but is dependent on the population studied and the burden of underlying opportunistic infections. The immunopathogenesis of the syndrome is unclear and appears to be result of unbalanced reconstitution of effector and regulatory T-cells, leading to exuberant inflammatory response in patients receiving ART. Biomarkers, including interferon-γ (INF-γ), tumour necrosis factor-α (TNF-α), C-reactive protein (CRP) and inter leukin (IL)-2, 6 and 7, are subject of intense investigation at present. The commonest forms of IRIS are associated with mycobacterial infections, fungi and herpes viruses. Majority of patients with IRIS have a self-limiting disease course. ART is usually continued and treatment for the associated condition optimized. The overall mortality associated with IRIS is low; however, patients with central nervous system involvement with raised intracranial pressures in cryptococcal and tubercular meningitis, and respiratory failure due to acute respiratory distress syndrome (ARDS) have poor prognosis and require aggressive management including corticosteroids. Paradigm shifts in management of HIV with earlier initiation of ART is expected to decrease the burden of IRIS in developed countries; however, with enhanced rollout of ART in recent years and the enormous burden of opportunistic infections in developing countries like India, IRIS is likely to remain an area of major concern.