Laxman Shrestha

Designs of two randomized, community-based trials to assess the impact of influenza immunization during pregnancy on respiratory illness among pregnant women and their infants and reproductive outcomes in rural Nepal.

BackgroundAmong the most important causes of illness and death in both pregnant women and their newborn infants are respiratory infections including influenza. Pregnant women in North America have a 4 to 5 fold excess rate of hospitalization compared to non-pregnant women. Rates of infant hospitalization associated with influenza are much higher than in their mothers. Fully half of children hospitalized for influenza in the US are in the age group 0–5 months, a group where no vaccine is licensed. Data on influenza are much fewer in low income countries where the risks of serious morbidity and mortality are much higher. A recent trial in Bangladesh suggested that influenza immunization in pregnant women could have important protective effects against influenza in both mothers and their infants. These trials were designed to provide additional evidence about the effect of influenza vaccination in pregnancy in settings where influenza may circulate for up to ten months/year.Methods/DesignWe conducted a consecutive pair of community-based, placebo-controlled, randomized trials of influenza vaccination of pregnant women in a rural district in southern Nepal. Two trials were conducted to insure, as much as possible, the match of circulating strains with those included in the vaccine. Eligible women included all who were or became pregnant over a one year period. Each trial included a one year cohort of pregnant women who were individually randomized to the influenza vaccine available at the time of their enrollment or placebo. Exclusions included a history of allergy to vaccine components, prior influenza vaccine receipt, and for the second trial, participation in the first trial. Morbidity was assessed on a weekly basis for women throughout pregnancy and through 180 days post-partum. Infants were followed weekly through 180 days. Primary outcomes included: 1) incidence of influenza like illness in women, 2) incidence of laboratory confirmed influenza illness in infants, and 3) birthweight among newborn infants.DiscussionWe have presented the design and methods of two randomized trials of influenza immunization of pregnant women.Trial registrationClinicaltrials.gov: (NCT01034254).

Clinical Presentation and Birth Outcomes Associated with Respiratory Syncytial Virus Infection in Pregnancy

Background Respiratory syncytial virus (RSV) is the most important cause of viral pneumonia in children worldwide. A maternal vaccine may protect both the mother and infant from RSV illness. The epidemiology and clinical presentation of RSV in pregnant and postpartum women is not well-described. Methods Data were collected from a prospective, randomized trial of influenza immunization in pregnant women in rural southern Nepal. Women were enrolled in their second trimester of pregnancy and followed until six months postpartum. Active weekly home-based surveillance for febrile respiratory illness was performed. Mid-nasal swabs collected with episodes of respiratory illness were tested for RSV by real-time polymerase chain reaction. Results RSV was detected in 14 (0.4%) illness episodes in 3693 women over 3554 person-years of surveillance from 2011–2014. RSV incidence was 3.9/1000 person-years overall, and 11.8/1000 person-years between September and December. Seven (50%) women sought care for RSV illness; none died. Of the 7 (50%) illness episodes during pregnancy, all had live births with 2 (29%) preterm births and a median birthweight of 3060 grams. This compares to 469 (13%) preterm births and a median birthweight of 2790 grams in women without RSV during pregnancy. Of the 7 mothers with postpartum RSV infection, RSV was detected in 4 (57%) of their infants. Conclusions RSV was an uncommon cause of febrile respiratory illness in mothers during pregnancy in Nepal. These data will inform prevention and therapeutic strategies against RSV in resource-limited settings.

Infant vaccination timing: Beyond traditional coverage metrics for maximizing impact of vaccine programs, an example from southern Nepal

Highlights • We prospectively examined, via weekly recall, the timing of EPI immunizations in infants less than 6 months in rural Nepal.• The majority of infants less than 6 months received immunizations on a delayed schedule.• National immunization coverage estimates do not capture delay in the first 6 months of life.

The effect of diarrheal disease on bivalent oral polio vaccine (bOPV) immune response in infants in Nepal

BACKGROUND A globally-coordinated phase out of all type 2 containing oral polio vaccine (OPV) is planned for April 2016 during which bivalent 1+3 OPV (bOPV) will replace trivalent OPV (tOPV) in routine immunization schedules and campaigns. Diarrhea impairs the immune response to tOPV, but the effect of diarrhea on bOPV is unknown. METHODS Infants aged 6 weeks to 11 months, who had received <3 doses of OPV and had mild-moderate diarrhea or no diarrhea, were recruited at five health facilities in Nepal. Neutralizing antibody titers to poliovirus types 1 and 3 were measured before and 28 days after bOPV administration. The effect of diarrhea and other factors on seroconversion or boosting in antibody titers to poliovirus was assessed by multivariable analysis. RESULTS Infants with diarrhea, versus those without diarrhea, had reduced response for poliovirus types 1 (56% [87/156] vs 66% [109/164]) and 3 (34% [70/209] vs 52% [122/236]). After adjusting for other factors, infants with diarrhea had significantly reduced response for type 3 (odds ratio [OR]=0.44, 95% CI 0.29-0.68), as did infants with >5 loose stools per day (OR=0.36, 95% CI 0.21-0.62). CONCLUSIONS Diarrhea reduced the immune response to bOPV. Provision of additional doses of polio vaccine is necessary to maintain high population immunity in areas with high prevalence of diarrheal disease. CLINICAL TRIAL REGISTRY This study is registered at clinicaltrials.gov as NCT01559636.

Transplacental transfer of maternal respiratory syncytial virus (RSV) antibody and protection against RSV disease in infants in rural Nepal

Highlights • Transplacental transfer of RSV antibody was highly efficient in Nepal.• Cord blood RSV antibody concentrations were not associated with age at RSV illness.• Estimated RSV antibody concentrations did not correlate with disease severity.

Effect of an improved biomass stove on acute lower respiratory infections in young children in rural Nepal: a cluster-randomised, step-wedge trial

www.thelancet.com/lancetgh 19 Published Online April 8, 2016 George Washington University Milken Institute School of Public Health, Washington, DC, USA (J M Tielsch); Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA (J Katz, P Breysse, S Zeger, L C Mullany, N Kozuki, S C LeClerq); Nepal Nutrition Intervention Project – Sarlahi, Kathmandu, Nepal (S K Khatry); Institute of Medicine, Tribhuvan University, Kathmandu, Nepal (L Shrestha); Johns Hopkins School of Medicine, Baltimore, MD, USA (W Checkley); Kathmandu Medical College, Kathmandu, Nepal (R Adhikari) Correspondence to: James Tielsch, Department of Global Health, Milken Institute School of Public Health, George Washington University, 950 New Hampshire Avenue, NW, Suite 400, Washington, DC 20052, USA jtielsch@gwu.edu Eff ect of an improved biomass stove on acute lower respiratory infections in young children in rural Nepal: a cluster-randomised, step-wedge trial James M Tielsch, Joanne Katz, Subarna K Khatry, Laxman Shrestha, Patrick Breysse, Scott Zeger, William Checkley, Luke C Mullany, Naoko Kozuki, Steven C LeClerq, Ramesh Adhikari Abstract Background Acute lower respiratory infections (ALRI) are an important cause of death in young children in lowincome countries. High concentrations of fi ne particulate matter (PM2.5) indoors caused by open burning of biomass are associated with risk of ALRI. However, improved biomass stoves reduce emissions and might reduce the incidence of lower respiratory illness. A cluster-randomised, step-wedge, community-based trial was conducted to estimate the eff ect that a change from open burning of biomass to improved biomass stoves could have on rates of ALRI in children younger than 36 months in a rural area of southern Nepal.Background Acute lower respiratory infections (ALRI) are an important cause of death in young children in lowincome countries. High concentrations of fi ne particulate matter (PM2.5) indoors caused by open burning of biomass are associated with risk of ALRI. However, improved biomass stoves reduce emissions and might reduce the incidence of lower respiratory illness. A cluster-randomised, step-wedge, community-based trial was conducted to estimate the eff ect that a change from open burning of biomass to improved biomass stoves could have on rates of ALRI in children younger than 36 months in a rural area of southern Nepal. Methods Households were enrolled in Sarlahi district that had at least one child aged younger than 36 months or a married woman aged 15–30 years. Respiratory morbidity data were collected for 6 months prior to the introduction of improved biomass stoves between March, 2010, and December, 2010. Mothers were asked about respiratory signs and symptoms (cough, diffi cult or rapid breathing, wheeze, ear discharge, fever) in their participating children in the past 7 days during weekly visits from local study staff . A 12-month stepped-wedge introduction of an improved biomass stove with chimney to participating households followed the 6-month run-in period (Envirofi t Corp. Colorado Springs, CO, USA). Weekly morbidity assessments continued during the step-wedge period (from January, 2011, to February, 2012) and for 6 months after stove introduction (from March, 2012, to December, 2012). Children were discharged at age 36 months. The primary outco me was ALRI, defi ned as a maternal report of 2 or more consecutive days of fast or diffi cult breathing accompanied by fever. Episodes were separated by a minimum of 7 symptom-free days. An environmental assessment was done in households once before and once after the improved stove was installed. The trial is registered at clinicaltrials.gov (NCT00786877). Findings 5254 children from 3376 households were enrolled either at baseline or during the trial period. Mean 20-h kitchen concentration of PM2.5 was reduced from 1386 μg/m to 930 μg/m There was a strong secular decline in the incidence of ALRI over the period of the study. The intervention was associated with a 13% decline in the incidence of ALRI but the strength of evidence was weak (0·87, 95% CI 0·67–1·13). There were statistically signifi cant reductions in persistent cough (0·91, 0·85–0·97), wheeze (0·87, 0·78–0·97) and burn injury (0·68, 0·48–0·95) but not for fever, severe ALRI, or ear discharge. Interpretation There was weak evidence for a modest decline in the incidence of ALRI. Post-installation PM2.5 concentrations remained well above current indoor air standards of 25 μg/m. Better performing biomass stoves or cleaner fuels such as liquid petroleum gas or ethanol are needed to reduce concentrations enough to estimate the impact on ALRI incidence. Funding National Institutes of Health, Thrasher Research Fund. Copyright

Respiratory syncytial virus infection in infants in rural Nepal

Summary Objectives Respiratory syncytial virus (RSV) pneumonia is a leading cause of infant mortality worldwide. The risk of RSV infection associated with preterm birth is not well-characterized in resource-limited settings. We aimed to obtain precise estimates of risk factors and disease burden of RSV in infants in rural southern Nepal. Methods Pregnant women were enrolled, and along with their infants, followed to six months after birth with active weekly home-based surveillance for acute respiratory illness (ARI). Mid-nasal swabs were obtained and tested for RSV by PCR for all illness episodes. Birth outcomes were assessed at a postpartum home visit. Results 311 (9%) of 3509 infants had an RSV ARI. RSV ARI incidence decreased from 551/1000 person-years in infants born between 28 and 31 weeks to 195/1000 person-years in infants born full-term (p = 0.017). Of 220 infants (71%) evaluated in the health system, 41 (19%) visited a hospital or physician. Of 287 infants with an assessment performed, 203 (71%) had a lower respiratory tract infection. Conclusions In a rural south Asian setting with intensive home-based surveillance, RSV caused a significant burden of respiratory illness. Preterm infants had the highest incidence of RSV ARI, and should be considered a priority group for RSV preventive interventions in resource-limited settings.

Febrile rhinovirus illness during pregnancy is associated with low birth weight in Nepal

Abstract Background Adverse birth outcomes, including low birth weight (LBW), defined as <2500 grams, small-for-gestational-age (SGA), and prematurity, contribute to 60%–80% of infant mortality worldwide and may be related to infections during pregnancy. The aim of this study was to assess whether febrile human rhinovirus (HRV) illness is associated with adverse birth outcomes. Methods Active household-based weekly surveillance was performed for respiratory illness episodes in pregnant women as part of a community-based, prospective, randomized trial of maternal influenza immunization in rural Nepal. Rhinovirus (HRV) febrile illness episodes were defined as fever plus cough, sore throat, runny nose, and/or myalgia with HRV detected on mid-nasal swab. Multivariate regression analysis evaluated the association between febrile HRV respiratory illness and adverse birth outcomes. Results Overall, 96 (3%) of 3693 pregnant women had HRV-positive febrile respiratory illnesses. Infants born to pregnant women with HRV febrile illness had a 1.6-fold increased risk of being LBW compared with those with non-HRV febrile illness (28 of 96 [38%] vs 109 of 458 [24%]; relative risk [RR], 1.6; 95% confidence interval [CI], 1.1–2.3). No difference in risk of LBW was observed between infants born to mothers with non-HRV febrile respiratory illness and those without respiratory illness during pregnancy (109 of 458 [24%] vs 552 of 2220 [25%], respectively; RR, 1.0; 95% CI, 0.8–1.2). Conclusions Febrile illness due to rhinovirus during pregnancy was associated with increased risk of LBW in a rural South Asian population. Interventions to reduce the burden of febrile respiratory illness due to rhinovirus during pregnancy may have a significant impact on LBW and subsequent infant mortality.

Impact of maternal vaccination timing and influenza virus circulation on birth outcomes in rural Nepal

To describe the effect of maternal vaccination on birth outcomes in rural Nepal, modified by timing of vaccination in pregnancy and influenza virus activity.

Human Metapneumovirus and Other Respiratory Viral Infections during Pregnancy and Birth, Nepal.

Women infected with human metapneumovirus during pregnancy had an increased risk of delivering infants who were small for gestational age.