Andrea M. Rehman

Protective Effect of Natural Rotavirus Infection in an Indian Birth Cohort

BACKGROUND More than 500,000 deaths are attributed to rotavirus gastroenteritis annually worldwide, with the highest mortality in India. Two successive, naturally occurring rotavirus infections have been shown to confer complete protection against moderate or severe gastroenteritis during subsequent infections in a birth cohort in Mexico. We studied the protective effect of rotavirus infection on subsequent infection and disease in a birth cohort in India (where the efficacy of oral vaccines in general has been lower than expected). METHODS We recruited children at birth in urban slums in Vellore; they were followed for 3 years after birth, with home visits twice weekly. Stool samples were collected every 2 weeks, as well as on alternate days during diarrheal episodes, and were tested by means of enzyme-linked immunosorbent assay and polymerase-chain-reaction assay. Serum samples were obtained every 6 months and evaluated for seroconversion, defined as an increase in the IgG antibody level by a factor of 4 or in the IgA antibody level by a factor of 3. RESULTS Of 452 recruited children, 373 completed 3 years of follow-up. Rotavirus infection generally occurred early in life, with 56% of children infected by 6 months of age. Levels of reinfection were high, with only approximately 30% of all infections identified being primary. Protection against moderate or severe disease increased with the order of infection but was only 79% after three infections. With G1P[8], the most common viral strain, there was no evidence of homotypic protection. CONCLUSIONS Early infection and frequent reinfection in a locale with high viral diversity resulted in lower protection than has been reported elsewhere, providing a possible explanation why rotavirus vaccines have had lower-than-expected efficacy in Asia and Africa. (Funded by the Wellcome Trust.).

Insecticide resistance and the future of malaria control in Zambia.

Background In line with the Global trend to improve malaria control efforts a major campaign of insecticide treated net distribution was initiated in 1999 and indoor residual spraying with DDT or pyrethroids was reintroduced in 2000 in Zambia. In 2006, these efforts were strengthened by the Presidents Malaria Initiative. This manuscript reports on the monitoring and evaluation of these activities and the potential impact of emerging insecticide resistance on disease transmission. Methods Mosquitoes were captured daily through a series of 108 window exit traps located at 18 sentinel sites. Specimens were identified to species and analyzed for sporozoites. Adult Anopheles mosquitoes were collected resting indoors and larva collected in breeding sites were reared to F1 and F0 generations in the lab and tested for insecticide resistance following the standard WHO susceptibility assay protocol. Annual cross sectional household parasite surveys were carried out to monitor the impact of the control programme on prevalence of Plasmodium falciparum in children aged 1 to 14 years. Results A total of 619 Anopheles gambiae s.l. and 228 Anopheles funestus s.l. were captured from window exit traps throughout the period, of which 203 were An. gambiae malaria vectors and 14 An. funestus s.s.. In 2010 resistance to DDT and the pyrethroids deltamethrin, lambda-cyhalothrin and permethrin was detected in both An. gambiae s.s. and An. funestus s.s.. No sporozoites were detected in either species. Prevalence of P. falciparum in the sentinel sites remained below 10% throughout the study period. Conclusion Both An. gambiae s.s. and An. funestus s.s. were controlled effectively with the ITN and IRS programme in Zambia, maintaining a reduced disease transmission and burden. However, the discovery of DDT and pyrethroid resistance in the country threatens the sustainability of the vector control programme.

Impact of pyrethroid resistance on operational malaria control in Malawi

The impact of insecticide resistance on insect-borne disease programs is difficult to quantify. The possibility of eliminating malaria in high-transmission settings is heavily dependent on effective vector control reducing disease transmission rates. Pyrethroids are the dominant insecticides used for malaria control, with few options for their replacement. Their failure will adversely affect our ability to control malaria. Pyrethroid resistance has been selected in Malawi over the last 3 y in the two major malaria vectors Anopheles gambiae and Anopheles funestus, with a higher frequency of resistance in the latter. The resistance in An. funestus is metabolically based and involves the up-regulation of two duplicated P450s. The same genes confer resistance in Mozambican An. funestus, although the levels of up-regulation differ. The selection of resistance over 3 y has not increased malaria transmission, as judged by annual point prevalence surveys in 1- to 4-y-old children. This is true in areas with long-lasting insecticide-treated nets (LLINs) alone or LLINs plus pyrethroid-based insecticide residual spraying (IRS). However, in districts where IRS was scaled up, it did not produce the expected decrease in malaria prevalence. As resistance increases in frequency from this low initial level, there is the potential for vector population numbers to increase with a concomitant negative impact on control efficacy. This should be monitored carefully as part of the operational activities in country.

How much does malaria vector control quality matter: the epidemiological impact of holed nets and inadequate indoor residual spraying.

Background Insecticide treated nets (ITN) and indoor residual spraying (IRS) are the two pillars of malaria vector control in Africa, but both interventions are beset by quality and coverage concerns. Data from three control programs were used to investigate the impact of: 1) the physical deterioration of ITNs, and 2) inadequate IRS spray coverage, on their respective protective effectiveness. Methods Malaria indicator surveys were carried out in 2009 and 2010 in Bioko Island, mainland Equatorial Guinea and Malawi to monitor infection with P.falciparum in children, mosquito net use, net condition and spray status of houses. Nets were classified by their condition. The association between infection and quality and coverage of interventions was investigated. Results There was reduced odds of infection with P.falciparum in children sleeping under ITNs that were intact (Odds ratio (OR): 0.65, 95% CI: 0.55–0.77 and OR: 0.81, 95% CI: 0.56–1.18 in Equatorial Guinea and in Malawi respectively), but the protective effect became less with increasingly worse condition of the net. There was evidence for a linear trend in infection per category increase in deterioration of nets. In Equatorial Guinea IRS offered protection to those in sprayed and unsprayed houses alike when neighbourhood spray coverage was high (≥80%) compared to those living in areas of low IRS coverage (<20%), regardless of whether the house they lived in was sprayed or not (adjusted OR = 0.54, 95% CI 0.33–0.89). ITNs provided only personal protection, offering no protection to non users. Although similar effects were seen in Malawi, the evidence was much weaker than in Equatorial Guinea. Conclusions Universal coverage strategies should consider policies for repair and replacement of holed nets and promote the care of nets by their owners. IRS programs should ensure high spray coverage since inadequate coverage gives little or no protection at all.

Effect of weekly vitamin D supplements on mortality, morbidity, and growth of low birthweight term infants in India up to age 6 months: randomised controlled trial

Objective To investigate whether vitamin D supplementation can decrease the mortality and morbidity of low birthweight infants in low income countries. Design Randomised controlled trial. Setting Large government hospital in New Delhi, India. Participants 2079 low birthweight infants born at term (>37 weeks’ gestation). Main outcome measures Primary outcome was admission to hospital or death during the first six months of life. Main secondary outcome was growth. Interventions Weekly vitamin D supplements for six months at a dose of one recommended nutrient intake per day (35 µg/week). Infants were visited weekly at home for observed supplementation and were brought to the clinic monthly for clinical examination and anthropometric measurements. Results Between group differences were not significant for death or hospital admissions (92 among 1039 infants in the vitamin D group v 99 among 1040 infants in the placebo group; adjusted rate ratio 0.93, 95% confidence interval 0.68 to 1.29; P=0.68), or referral to the outpatient clinic for moderate morbidity. Vitamin D supplementation resulted in better vitamin D status as assessed by plasma calcidiol levels at six months. In adjusted analyses, vitamin D treatment significantly increased standard deviation (z) scores at six months for weight, length, and arm circumference and decreased the proportion of children with stunted growth (length for age z score ≤2) or with arm circumference z scores of 2 or less. Conclusion A weekly dose of vitamin D resulted in better vitamin D status and benefited the classic vitamin D function of bone growth but did not decrease the incidence of severe morbidity or death among young low birthweight infants. Trial registration ClinicalTrials.gov NCT00415402.

The emergence of insecticide resistance in central Mozambique and potential threat to the successful indoor residual spraying malaria control programme

BackgroundMalaria vector control by indoor residual spraying was reinitiated in 2006 with DDT in Zambézia province, Mozambique. In 2007, these efforts were strengthened by the Presidents Malaria Initiative. This manuscript reports on the monitoring and evaluation of this programme as carried out by the Malaria Decision Support Project.MethodsMosquitoes were captured daily through a series of 114 window exit traps located at 19 sentinel sites, identified to species and analysed for sporozoites. Anopheles mosquitoes were collected resting indoors and tested for insecticide resistance following the standard WHO protocol. Annual cross sectional household parasite surveys were carried out to monitor the impact of the control programme on prevalence of Plasmodium falciparum in children aged 1 to 15 years.ResultsA total of 3,769 and 2,853 Anopheles gambiae s.l. and Anopheles funestus, respectively, were captured from window exit traps throughout the period. In 2010 resistance to the pyrethroids lambda-cyhalothrin and permethrin and the carbamate, bendiocarb was detected in An. funestus. In 2006, the sporozoite rate in An. gambiae s.s. was 4% and this reduced to 1% over 4 rounds of spraying. The sporozoite rate for An. funestus was also reduced from 2% to 0 by 2008. Of the 437 Anopheles arabiensis identified, none were infectious. Overall prevalence of P. falciparum in the sentinel sites fell from 60% to 32% between October 2006 and October 2008.ConclusionBoth An. gambiae s.s. and An. funestus were controlled effectively with the DDT-based IRS programme in Zambézia, reducing disease transmission and burden. However, the discovery of pyrethroid resistance in the province and Mozambiques policy change away from DDT to pyrethroids for IRS threatens the gains made here.

Reduced Prevalence of Malaria Infection in Children Living in Houses with Window Screening or Closed Eaves on Bioko Island, Equatorial Guinea

Background Previous studies demonstrated that fewer mosquitoes enter houses which are screened or have closed eaves. There is little evidence about the effect on malaria infection in humans that changes in house construction may have. This study examines the impact of protective housing improvements on malaria infection on Bioko Island. Methodology/Principal Findings Data from the annual malaria indicator surveys between 2009 and 2012 were used to assess trends in housing characteristics and their effect on RDT confirmed malaria infection in household members. Odds ratios were adjusted for socio-economic status of the household.22726 children between the ages of 2 and 14 years were tested for P. falciparum. Prevalence of infection in those living in houses with open eaves was 23.0% compared to 18.8% for those living in houses with closed eaves (OR = 0.81, 95% CI 0.67 - 0.98). The prevalence of infection for children in screened houses was 9.1% versus 20.1% for those living in unscreened houses (OR = 0.44, 95% CI 0.27 - 0.71). The proportion of houses with closed eaves increased from 66.0% in 2009 to 74.3% in 2012 (test for trend p = 0.01). The proportion of screened houses remained unchanged over time at 1.3%. Conclusion/Significance As a malaria control intervention, house modification has the advantages that it is not affected by the growing threat of insecticide resistance; it protects all household members equally and at all times while indoors; and it offers protection against a number of vector borne diseases. The study provides evidence in support of efforts to regulate or encourage housing improvements which impede vector access into residences as part of an integrated vector control approach to complement existing measures which have been only partially successful in reducing malaria transmission in some parts of Bioko.

Determinants of bed net use in children under five and household bed net ownership on Bioko Island, Equatorial Guinea

BackgroundAs part of comprehensive malaria control strategies, the Bioko Island Malaria Control Project (BIMCP) distributed 110,000 long-lasting insecticide-treated nets (LLIN) in late 2007 with the aim of providing one net for each sleeping area. Despite attaining initially very high levels of net coverage and net use, many children under five years of age did not sleep under a net by 2009, according to annual malaria indicator surveys. The aim of this study was to assess the determinants of bed net use in children under five and bed net ownership of the households in which they live.MethodsUsing data from annual cross-sectional household surveys of 2008 and 2009, we investigated factors associated with sleeping under a mosquito net the night prior to the survey, and a households owning at least one net, in all households which had at least one child under five years. Amongst others, caregivers knowledge of malaria and household characteristics including a socio-economic score (SES), based on ownership of household assets, were analysed for their effect on net ownership and use.ResultsThere was a decline of around 32% in the proportion of households that owned at least one net between 2008 and 2009. Higher household bed net ownership was associated with knowing how malaria was prevented and transmitted, having the house sprayed in the previous 12 months, having fewer children under five in the household, and children being sick at some point in the previous 14 days. Higher bed net use in children < 5 was associated with being sick at some point in the last 14 days prior to the survey, living in an urban area, more years of education of the head of the household, household ownership of at least one ITN (as opposed to an untreated net) and the year in which the survey took place.ConclusionsThe big fall in bed net use from 2008 to 2009 was attributable to the striking decline in ownership. Although ownership was similar in rural and urban areas, rural households were less likely to protect their children with bed nets. Knowledge about malaria was an important determinant of bed net ownership. Further research is needed to elucidate the decline in bed net ownership between 2008 and 2009.

Burden of Illness in the First 3 Years of Life in an Indian Slum

The morbidity and mortality in a cohort of 452 children followed up from birth up to 3 years of age, in an urban slum in India, is described. These children were recruited and followed from March 2002 to September 2006. A prospective morbidity survey was established. There were 1162 child-years of follow-up. The average morbidity rate was 11.26 episodes/child-year. Respiratory infections caused 58.3 and diarrheal disease 18.4% of the illnesses. Respiratory illnesses resulted in 48, 67.5 and 50 days of illnesses, and there were 3.6, 1.64 and 1.16 diarrheal episodes per child in the 3 years, respectively. There were five deaths in the cohort in the 3 years of follow-up. Of the 77 drop-outs 44 were contacted for mortality data. The morbidity in the area is high, comparable to other studies. The mortality is low, and is attributed to the facilitated access to care.

Five years of malaria control in the continental region, Equatorial Guinea

BackgroundA successful malaria control programme began in 2004 on Bioko Island, Equatorial Guinea. From 2007, the same multiple malaria interventions, though reduced in scope for funding reasons, were introduced to the four mainland provinces of Equatorial Guinea (the continental region) aiming to recreate Bioko’s success. Two provinces received long-lasting insecticidal nets (LLINs) and two provinces received biannual indoor residual spraying (IRS). Enhanced case management and communications were introduced throughout.MethodsEstimates of intervention coverage and indicators of malaria transmission for 2007 to 2011 were derived from annual malaria indicator surveys (MIS). Results were complemented by health information system (HIS) and entomological data. The personal protection offered by LLINs and IRS against Plasmodium falciparum infection was estimated with logistic regression.ResultsThe estimated proportion of children aged 1–4 using either an LLIN the previous night or living in a house sprayed in the last six months was 23% in 2007 and 42% in 2011. The estimated prevalence of P. falciparum in children aged 1–4 was 68% (N=1,770; 95% confidence interval [CI]: 58-76%) in 2007 and 52% (N=1,602; 95% CI: 44-61%) in 2011. Children 1–4 years had lower prevalence if they used an LLIN the previous night (N=1,124, 56%; adjusted odds ratio [aOR] 0.64, 95% CI: 0.55-0.74) or if they lived in a sprayed house (N=1,150, 57%; aOR 0.80, 95% CI: 0.62-1.03) compared to children with neither intervention (N=4,131, 66%, reference group). The minority of children who both used an LLIN and lived in a sprayed house had the lowest prevalence of infection (N=171, 45%; aOR 0.52, 95% CI: 0.35-0.78). High site-level intervention coverage did not always correlate with lower site-level P. falciparum prevalence. The malaria season peaked in either June or July, not necessarily coinciding with MIS data collection.ConclusionsThough moderate impact was achieved after five years of vector control, case management, and communications, prevalence remained high due to an inability to sufficiently scale-up coverage with either IRS or LLINs. Both LLINs and IRS provided individual protection, but greater protection was afforded to children who benefitted from both.