Makhdum Ahmed

Respiratory Viruses Associated Hospitalization among Children Aged <5 Years in Bangladesh: 2010-2014.

Background We combined hospital-based surveillance and health utilization survey data to estimate the incidence of respiratory viral infections associated hospitalization among children aged < 5 years in Bangladesh. Methods Surveillance physicians collected respiratory specimens from children aged <5 years hospitalized with respiratory illness and residing in the primary hospital catchment areas. We tested respiratory specimens for respiratory syncytial virus, parainfluenza viruses, human metapneumovirus, influenza, adenovirus and rhinoviruses using rRT-PCR. During 2013, we conducted a health utilization survey in the primary catchment areas of the hospitals to determine the proportion of all hospitalizations for respiratory illness among children aged <5 years at the surveillance hospitals during the preceding 12 months. We estimated the respiratory virus-specific incidence of hospitalization by dividing the estimated number of hospitalized children with a laboratory confirmed infection with a respiratory virus by the population aged <5 years of the catchment areas and adjusted for the proportion of children who were hospitalized at the surveillance hospitals. Results We estimated that the annual incidence per 1000 children (95% CI) of all cause associated respiratory hospitalization was 11.5 (10–12). The incidences per 1000 children (95% CI) per year for respiratory syncytial virus, parainfluenza, adenovirus, human metapneumovirus and influenza infections were 3(2–3), 0.5(0.4–0.8), 0.4 (0.3–0.6), 0.4 (0.3–0.6), and 0.4 (0.3–0.6) respectively. The incidences per 1000 children (95%CI) of rhinovirus-associated infections among hospitalized children were 5 (3–7), 2 (1–3), 1 (0.6–2), and 3 (2–4) in 2010, 2011, 2012 and 2013, respectively. Conclusion Our data suggest that respiratory viruses are associated with a substantial burden of hospitalization in children aged <5 years in Bangladesh.

Factors influencing outcome in advanced stage, low-grade follicular lymphoma treated at MD Anderson Cancer Center in the rituximab era

BACKGROUND The optimal initial therapy of follicular lymphoma (FL) remains unclear. The aims of this study were to compare primary treatment strategies and assess the impact of maintenance rituximab and patterns of treatment failure. PATIENTS AND METHODS We retrospectively analyzed patients with treatment-naive advanced stage, grade 1-2 FL treated at our center from 2004 to 2014. We included 356 patients treated on clinical trials or standard of care with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP, n = 119); R-CHOP with maintenance (R-CHOP + M, n = 65); bendamustine/rituximab (BR, n = 45); BR with maintenance (BR + M, n = 35); R(2) (n = 94). We compared baseline characteristics, progression-free survival (PFS), overall survival (OS) and analyzed prognostic factors using univariate and multivariate analysis adjusted for treatment. RESULTS After a median follow-up of 4 years (range 0.2-15.0), the 3-year PFS was 60% [95% confidence interval (CI) 51% to 69%] for R-CHOP, 72% (59% to 82%) for R-CHOP + M, 63% (42% to 78%) for BR, 97% (80% to 100%) for BR + M and 87% (78% to 93%) for R(2). Patients treated with R-chemotherapy had more high-risk features than patients treated with R(2) but, by adjusted multivariate analysis, treatment with R(2) [hazard ratio (HR) 0.39 (0.17-0.89), P = 0.02] was associated with a superior PFS. Eastern Cooperative Oncology Group Performance status of one or more predicted inferior OS. Among patients treated with R-chemotherapy, maintenance was associated with the superior PFS [HR 0.38 (95% CI 0.21-0.68)]. By adjusted multivariate analysis, disease progression within 2 years [HR 5.1 (95% CI 1.57-16.83)] and histologic transformation (HT) [HR 11.05 (95% CI 2.84-42.93)] increased risk of death. CONCLUSION Induction therapy with R(2) may result in disease control which is comparable with R-chemotherapy. Early disease progression and HT are predictive of inferior survival.

Impact of Intensive Handwashing Promotion on Secondary Household Influenza-Like Illness in Rural Bangladesh: Findings from a Randomized Controlled Trial.

Rationale There is little evidence for the efficacy of handwashing for prevention of influenza transmission in resource-poor settings. We tested the impact of intensive handwashing promotion on household transmission of influenza-like illness and influenza in rural Bangladesh. Methods In 2009–10, we identified index case-patients with influenza-like illness (fever with cough or sore throat) who were the only symptomatic person in their household. Household compounds of index case-patients were randomized to control or intervention (soap and daily handwashing promotion). We conducted daily surveillance and collected oropharyngeal specimens. Secondary attack ratios (SAR) were calculated for influenza and ILI in each arm. Among controls, we investigated individual risk factors for ILI among household contacts of index case-patients. Results Among 377 index case-patients, the mean number of days between fever onset and study enrollment was 2.1 (SD 1.7) among the 184 controls and 2.6 (SD 2.9) among 193 intervention case-patients. Influenza infection was confirmed in 20% of controls and 12% of intervention index case-patients. The SAR for influenza-like illness among household contacts was 9.5% among intervention (158/1661) and 7.7% among control households (115/1498) (SAR ratio 1.24, 95% CI 0.92–1.65). The SAR ratio for influenza was 2.40 (95% CI 0.68–8.47). In the control arm, susceptible contacts <2 years old (RRadj 5.51, 95% CI 3.43–8.85), those living with an index case-patient enrolled ≤24 hours after symptom onset (RRadj 1.91, 95% CI 1.18–3.10), and those who reported multiple daily interactions with the index case-patient (RRadj 1.94, 95% CI 1.71–3.26) were at increased risk of influenza-like illness. Discussion Handwashing promotion initiated after illness onset in a household member did not protect against influenza-like illness or influenza. Behavior may not have changed rapidly enough to curb transmission between household members. A reactive approach to reduce household influenza transmission through handwashing promotion may be ineffective in the context of rural Bangladesh. Trial Registration ClinicalTrials.gov NCT00880659

B-Cell Lymphoma Patient-Derived Xenograft Models Enable Drug Discovery and Are a Platform for Personalized Therapy

Purpose: Patients with B-cell lymphomas often relapse after frontline therapy, and novel therapies are urgently needed to provide long-term remission. We established B-cell lymphoma patient-derived xenograft (PDX) models to assess their ability to mimic tumor biology and to identify B-cell lymphoma patient treatment options. Experimental Design: We established the PDX models from 16 patients with diffuse large B-cell lymphoma, mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, or Burkitt lymphoma by inoculating the patient tumor cells into a human bone chip implanted into mice. We subjected the PDX models to histopathologic and phenotypical examination, sequencing, and drug efficacy analysis. Primary and acquired resistance to ibrutinib, an oral covalent inhibitor of Bruton tyrosine kinase, were investigated to elucidate the mechanisms underlying ibrutinib resistance and to identify drug treatments to overcome resistance. Results: The PDXs maintained the same biological, histopathologic, and immunophenotypical features, retained similar genetic mutations, and produced comparable drug responses with the original patient tumors. In the acquired ibrutinib-resistant PDXs, PLC-γ2, p65, and Src were downregulated; however, a PI3K signaling pathway member was upregulated. Inactivation of the PI3K pathway with the inhibitor idelalisib in combination with ibrutinib significantly inhibited the growth of the ibrutinib-resistant tumors. Furthermore, we used a PDX model derived from a clinically ibrutinib-relapsed patient to evaluate various therapeutic choices, ultimately eliminating the tumor cells in the patients peripheral blood. Conclusions: Our results demonstrate that the B-cell lymphoma PDX model is an effective system to predict and personalize therapies and address therapeutic resistance in B-cell lymphoma patients. Clin Cancer Res; 23(15); 4212–23. ©2017 AACR.

ATM mutation and radiosensitivity: An opportunity in the therapy of mantle cell lymphoma

ATM (ataxia telangiectasia mutated) is a DNA damage signaling-initiation kinase which has diverse function in responding to genotoxic stress to maintain its genomic integrity. Cells harboring loss-of-function ATM deficiencies demonstrate extreme radiosensitivity. The scope of radiotherapy has been considered very limited among patients with biallelic mutations or deletions of ATM due to its toxic effect on normal tissue. Mantle cell lymphoma (MCL) is a highly chemo-refractory tumor with generally poor outcome, especially if the patients develop resistance to frontline drugs. ATM is the most frequently mutated gene in MCL and recent experimental evidence demonstrated that this mutational status can be taken advantage of using radiotherapy. Radiotherapy should be considered in the treatment of mantle cell lymphoma with a curative intent.

Gene mutations and actionable genetic lesions in mantle cell lymphoma

Mutations and epigenetic alterations are key events in transforming normal cells to cancer cells. Mantle cell lymphoma (MCL), a non-Hodgkins lymphoma of the B-cell, is an aggressive malignancy with poor prognosis especially for those patients who are resistant to the frontline drugs. There is a great need to describe the molecular basis and mechanism of drug resistance in MCL to develop new strategies for treatment. We reviewed frequent somatic mutations and mutations involving the B-cell pathways in MCL and discussed clinical trials that attempted to disrupt these gene pathways and/or epigenetic events. Recurrent gene mutations were discussed in the light of prognostic and therapeutic opportunity and also the challenges of targeting these lesions. Mutations in the ATM, CCND1, TP53, MLL2, TRAF2 and NOTCH1 were most frequently encountered in mantle cell lymphoma. Translational models should be built that would assess mutations longitudinally to identify important compensatory, pro-survival and anti-apoptic pathways and actionable genetic targets.

Estimates of seasonal influenza-associated mortality in Bangladesh, 2010-2012

Seasonal influenza‐associated mortality estimates help identify the burden of disease and assess the value of public health interventions such as annual influenza immunization. Vital registration is limited in Bangladesh making it difficult to estimate seasonal influenza mortality.

Incidence of acute diarrhea-associated death among children < 5 years of age in Bangladesh, 2010-12

Although acute diarrheal deaths have declined globally among children < 5 years, it may still contribute to childhood mortality as an underlying or contributing cause. The aim of this project was to estimate the incidence of acute diarrhea-associated deaths, regardless of primary cause, among children < 5 years in Bangladesh during 2010-12. We conducted a survey in 20 unions (administrative units) within the catchment areas of 10 tertiary hospitals in Bangladesh. Through social networks, our field team identified households where children < 5 years were reported to have died during 2010-12. Trained data collectors interviewed caregivers of the deceased children and recorded illness symptoms, health care seeking, and other information using an abbreviated international verbal autopsy questionnaire. We classified the deceased based upon the presence of diarrhea before death. We identified 880 deaths, of which 36 (4%) died after the development of acute diarrhea, 17 (2%) had diarrhea-only in the illness preceding death, and 19 (53%) had cough or difficulty breathing in addition to diarrhea. The estimated annual incidence of all-cause mortality in the unions < 13.6 km of the tertiary hospitals was 26 (95% confidence interval [CI] 16-37) per 1,000 live births compared with the mortality rate of 37 (95% CI 26-49) per 1,000 live births in the unions located ≥ 13.6 km. Diarrhea contributes to childhood death at a higher proportion than when considering it only as the sole underlying cause of death. These data support the use of interventions aimed at preventing acute diarrhea, especially available vaccinations for common etiologies, such as rotavirus.

Evaluating Hospital-Based Surveillance for Outbreak Detection in Bangladesh: Analysis of Healthcare Utilization Data.

Background The International Health Regulations outline core requirements to ensure the detection of public health threats of international concern. Assessing the capacity of surveillance systems to detect these threats is crucial for evaluating a country’s ability to meet these requirements. Methods and Findings We propose a framework to evaluate the sensitivity and representativeness of hospital-based surveillance and apply it to severe neurological infectious diseases and fatal respiratory infectious diseases in Bangladesh. We identified cases in selected communities within surveillance hospital catchment areas using key informant and house-to-house surveys and ascertained where cases had sought care. We estimated the probability of surveillance detecting different sized outbreaks by distance from the surveillance hospital and compared characteristics of cases identified in the community and cases attending surveillance hospitals. We estimated that surveillance detected 26% (95% CI 18%–33%) of severe neurological disease cases and 18% (95% CI 16%–21%) of fatal respiratory disease cases residing at 10 km distance from a surveillance hospital. Detection probabilities decreased markedly with distance. The probability of detecting small outbreaks (three cases) dropped below 50% at distances greater than 26 km for severe neurological disease and at distances greater than 7 km for fatal respiratory disease. Characteristics of cases attending surveillance hospitals were largely representative of all cases; however, neurological disease cases aged <5 y or from the lowest socioeconomic group and fatal respiratory disease cases aged ≥60 y were underrepresented. Our estimates of outbreak detection rely on suspected cases that attend a surveillance hospital receiving laboratory confirmation of disease and being reported to the surveillance system. The extent to which this occurs will depend on disease characteristics (e.g., severity and symptom specificity) and surveillance resources. Conclusion We present a new approach to evaluating the sensitivity and representativeness of hospital-based surveillance, making it possible to predict its ability to detect emerging threats.

Epidemiology of childhood intussusception in Bangladesh: Findings from an active national hospital based surveillance system, 2012–2016

Introduction Rotavirus vaccines have significantly decreased the burden of diarrheal diseases in countries that have introduced them into their immunization programs. In some studies, there has been a small association between rotavirus vaccines and intussusception in post-marketing surveillance, high-lighting the importance of tracking incidence before and after vaccine introduction. The objective of this study was to describe the epidemiology of intussusception among Bangladeshi children pre-vaccine introduction. Methods We conducted active, hospital-based surveillance for intussusception at 7 tertiary care hospitals with pediatric surgical facilities during July 2012 to September 2016. Hospitalized children under 2 years of age were identified according to Brighton Collaboration level 1 criteria for intussusception. The frequency and proportion of intussusception among overall surgical admissions, as well as the demographic and clinical information of the cases is described. Results Overall 153 cases of intussusception among children <2 years-old were identified at participating sites over the enrolment period, confirmed by Level 1 Brighton criteria. These cases represented 2% of all surgical admissions under 2 years of age. One hundred twelve cases (73%) were male; the median age was 7 months; and the median duration of hospitalization was 7 days. One hundred forty-six (95%) children with intussusception required surgery, and 11 (7%) died. Conclusions Confirmed cases of intussusception represented nearly 2% of pediatric surgical admissions at tertiary referral centers in Bangladesh during the study period and 7% of children with intussusception died. Given the high burden of rotavirus disease in Bangladesh, vaccine introduction is warranted, however, further studies after introduction of rotavirus vaccine are necessary to determine any association between vaccine and intussusception in this setting.