Davidson H. Hamer

Etiology of Bacteremia in Young Infants in Six Countries

Background: Neonatal illness is a leading cause of death worldwide; sepsis is one of the main contributors. The etiologies of community-acquired neonatal bacteremia in developing countries have not been well characterized. Methods: Infants <2 months of age brought with illness to selected health facilities in Bangladesh, Bolivia, Ghana, India, Pakistan and South Africa were evaluated, and blood cultures taken if they were considered ill enough to be admitted to hospital. Organisms were isolated using standard culture techniques. Results: Eight thousand eight hundred and eighty-nine infants were recruited, including 3177 0–6 days of age and 5712 7–59 days of age; 10.7% (947/8889) had a blood culture performed. Of those requiring hospital management, 782 (54%) had blood cultures performed. Probable or definite pathogens were identified in 10.6% including 10.4% of newborns 0–6 days of age (44/424) and 10.9% of infants 7–59 days of age (39/358). Staphylococcus aureus was the most commonly isolated species (36/83, 43.4%) followed by various species of Gram-negative bacilli (39/83, 46.9%; Acinetobacter spp., Escherichia coli and Klebsiella spp. were the most common organisms). Resistance to second and third generation cephalosporins was present in more than half of isolates and 44% of the Gram-negative isolates were gentamicin-resistant. Mortality rates were similar in hospitalized infants with positive (5/71, 7.0%) and negative blood cultures (42/557, 7.5%). Conclusions: This large study of young infants aged 0–59 days demonstrated a broad array of Gram-positive and Gram-negative pathogens responsible for community-acquired bacteremia and substantial levels of antimicrobial resistance. The role of S. aureus as a pathogen is unclear and merits further investigation.

Malian children with moderate acute malnutrition who are treated with lipid-based dietary supplements have greater weight gains and recovery rates than those treated with locally produced cereal-legume products: a community-based, cluster-randomized trial

BACKGROUNDnModerate acute malnutrition (MAM), defined as weight-for-length z score between -3 and -2 or midupper arm circumference between 11.5 and 12.5 cm, affects ∼33 million children aged <5 y worldwide.nnnOBJECTIVEnThe objective was to compare the effects of 4 dietary supplements for the treatment of MAM.nnnDESIGNnTwelve community health centers in rural Mali were randomly assigned to provide to 1264 MAM children aged 6-35 mo one of 4 dietary supplements containing ∼500 kcal/d for 12 wk: 1) ready-to-use, lipid-based supplementary food (RUSF); 2) special corn-soy blend (CSB++); 3) locally processed, fortified flour (Misola); or 4) locally milled flours plus oil, sugar, and micronutrient powder (LMF).nnnRESULTSnIn total, 1178 children (93.2%) completed the study. The adjusted mean (95% CI) change in weight (kg) from baseline was greater with RUSF than with the locally processed blends and was intermediate with CSB++ [1.16 (1.08, 1.24) for RUSF, 1.04 (0.96, 1.13) for CSB++, 0.91 (0.82, 0.99) for Misola, and 0.83 (0.74, 0.92) for LMF; P < 0.001]. For length change, RUSF and CSB++ differed significantly from LMF. Sustained recovery rates were higher with RUSF (73%) than with Misola (61%) and LMF (58%), P < 0.0001; CSB++ recovery rates (68%) did not differ from any of the other groups.nnnCONCLUSIONSnRUSF was more effective, but more costly, than other dietary supplements for the treatment of MAM; CSB++ yielded intermediate results. The benefits of treatment should be considered in relation to product costs and availability.

Setting global research priorities for integrated community case management (iCCM): Results from a CHNRI (Child Health and Nutrition Research Initiative) exercise.

Aims To systematically identify global research gaps and resource priorities for integrated community case management (iCCM). Methods An iCCM Child Health and Nutrition Research Initiative (CHNRI) Advisory Group, in collaboration with the Community Case Management Operational Research Group (CCM ORG) identified experts to participate in a CHNRI research priority setting exercise. These experts generated and systematically ranked research questions for iCCM. Research questions were ranked using a “Research Priority Score” (RPS) and the “Average Expert Agreement” (AEA) was calculated for every question. Our groups of experts were comprised of both individuals working in Ministries of Health or Non Governmental Organizations (NGOs) in low– and middle–income countries (LMICs) and individuals working in high–income countries (HICs) in academia or NGO headquarters. A Spearman’s Rho was calculated to determine the correlation between the two groups’ research questions’ ranks. Results The overall RPS ranged from 64.58 to 89.31, with a median score of 81.43. AEA scores ranged from 0.54 to 0.86. Research questions involving increasing the uptake of iCCM services, research questions concerning the motivation, retention, training and supervision of Community Health Workers (CHWs) and concerning adding additional responsibilities including counselling for infant and young child feeding (IYCF) and treatment of severe acute malnutrition (SAM) ranked highly. There was weak to moderate, statistically significant, correlation between scores by representatives of high–income countries and those working in–country or regionally (Spearman’s ρu2009=u20090.35034, Pu2009<u20090.01). Conclusions Operational research to determine optimal training, supervision and modes of motivation and retention for the CHW is vital for improving iCCM, globally, as is research to motivate caregivers to take advantage of iCCM services. Experts working in–country or regionally in LMICs prioritized different research questions than those working in organization headquarters in HICs. Further exploration is needed to determine the nature of this divergence.

Guidelines for the prevention and treatment of travelers’ diarrhea: a graded expert panel report

Backgroundn: Travelers diarrhea causes significant morbidity including some sequelae, lost travel time and opportunity cost to both travelers and countries receiving travelers. Effective prevention and treatment are needed to reduce these negative impacts.nnnMethodsn: This critical appraisal of the literature and expert consensus guideline development effort asked several key questions related to antibiotic and non-antibiotic prophylaxis and treatment, utility of available diagnostics, impact of multi-drug resistant (MDR) colonization associated with travel and travelers diarrhea, and how our understanding of the gastrointestinal microbiome should influence current practice and future research. Studies related to these key clinical areas were assessed for relevance and quality. Based on this critical appraisal, guidelines were developed and voted on using current standards for clinical guideline development methodology.nnnResultsn: New definitions for severity of travelers diarrhea were developed. A total of 20 graded recommendations on the topics of prophylaxis, diagnosis, therapy and follow-up were developed. In addition, three non-graded consensus-based statements were adopted.nnnConclusionsn: Prevention and treatment of travelers diarrhea requires action at the provider, traveler and research community levels. Strong evidence supports the effectiveness of antimicrobial therapy in most cases of moderate to severe travelers diarrhea, while either increasing intake of fluids only or loperamide or bismuth subsalicylate may suffice for most cases of mild diarrhea. Further studies are needed to address knowledge gaps regarding optimal therapies, the individual, community and global health risks of MDR acquisition, manipulation of the microbiome in prevention and treatment and the utility of laboratory testing in returning travelers with persistent diarrhea.

Chikungunya: Establishing a New Home in the Western Hemisphere

Chikungunya, a mosquito-borne viral pathogen responsible for a febrile illness that is usually accompanied by a rash and severe, incapacitating arthralgias, emerged in the Caribbean in October 2013. Since its detection in Saint Martin, chikungunya virus has rapidly spread throughout the Caribbean and to Central and South America, where local transmission has now been documented in El Salvador, Costa Rica, Panama, Venezuela, Guyana, Suriname, French Guiana, Colombia, Brazil, and Paraguay. According to the Pan American Health Organization, as of 6 November 2014, there have been 874103 suspected cases, 14703 confirmed cases, and 153 deaths, with many afflicted patients in the Dominican Republic and El Salvador (1). In the continental United States, 1616 imported cases have been reported, with autochthonous transmission in southern Florida. Given the widespread presence of competent mosquito vectors (Aedes aegypti and A. albopictus), it may spread further within the United States. Epidemiology Chikungunya is an RNA virus in the Alphavirus genus of the Togaviridae family, initially described in an epidemic in Tanzania (formerly southern Tanganyika) among the Makonde tribe (2). The name originated from a Kimakonde word meaning that which bends up or to be contorted. Since the first description of chikungunya in the 1950s, outbreaks have occurred in West Africa, the Indian Ocean, India, and Southeast Asia. There are 3 major geographically defined viral lineages: West African; East, Central, and South African (ECSA); and Asian. In 2004, an epidemic began in East Africa, then spread in 2005 and 2006 to several islands in the Indian Ocean. La Runion, Comoros, Mayotte, and the Seychelles were especially hard-hit, and the virus subsequently traveled to Asian countries bordering the Indian Ocean; Southeast Asia; and the Pacific Islands and, most recently, American Samoa. This major epidemic was notable for a high attack rate, with one third of the population in La Runion infected (3). Travelers from India to Europe introduced chikungunya, resulting in local transmission in France and Italy. During this outbreak, the virus seems to have acquired mutations in glycoprotein E1, which is important for membrane fusion and virion assembly (4). This mutation resulted in the ECSA Indian Ocean lineage, which is adapted to and efficiently transmitted by A. albopictus. In October 2013, chikungunya virus was detected in Saint Martin and thereafter rapidly spread to Martinique and Guadeloupe. In the first half of 2014, this outbreak grew in magnitude, affecting nearly every island in the Caribbean. It also was introduced via travelers to several Central and South American countries, with resulting autochthonous transmission. The viral strain responsible for the growing epidemic in the Western hemisphere is the Asian rather than the ECSA Indian Ocean lineage, which is less efficiently transmitted by A. albopictus (5, 6); the preferred vector for the current outbreak seems to be A. aegypti. Nevertheless, the combination of 2 competent mosquito vectors (6), frequent travel between the Caribbean and Latin and North America (7), and an immunologically naive human population has set the stage for a continued epidemic with a high attack rate. Given the relatively widespread presence of both species of Aedes in the United States, risk for further spread in the Southeast is substantial, particularly for autochthonous transmission. However, in contrast to West Nile virus, a zoonotic pathogen that spreads in a birdmosquito cycle, transmission of chikungunya is limited to humanAedes species interactions. Clinical Manifestations and Diagnosis After an incubation period averaging 3 to 7 days (range, 2 to 12 days) (8), infected persons have abrupt onset of high fever, headache, back pain, myalgia, and polyarthralgia. The joint pain is typically symmetrical; can be severe; and usually affects the phalanges, ankles, and wrists, although large joints may also be involved. Rash occurs in approximately one half of patients and usually consists of a pruritic, erythematous, maculopapular eruption on the trunk. Although most symptoms resolve within 7 to 10 days, severe relapsing and debilitating arthralgia can persist for months and, in some patients, several years. Severe disease is relatively uncommon, and complications, including meningoencephalitis and death, have been rarely reported. During the large outbreak in La Runion between 2005 and 2006, motherchild transmission was documented in pregnant women infected close to delivery. Vertical transmission occurred predominantly in nearly full-term pregnancies and was associated with symptomatic neonatal infections a median of 4 days after parturition (9). Symptoms among patients infected with chikungunya and dengue viruses substantially overlap, and co-infection can occur. The severity and persistence of joint pain are clues to distinguish between these 2 viral infections. During the acute phase of infection (days 1 to 8 of symptoms), real-time polymerase chain reaction and IgM testing should be done, although IgM may not appear for 5 to 7 days after symptom onset (8). Acute and convalescent sera can be tested for IgG to confirm the diagnosis, with the acute sample obtained in the first 8 days of symptomatic infection and the convalescent sample obtained at least 2 to 3 weeks after symptom onset. Because of geographic and clinical overlap, serum testing for dengue should also be done. Treatment, Prevention, and Control No antiviral agents are licensed to treat chikungunya, so therapy is supportive with anti-inflammatory agents, such as acetaminophen and nonsteroidal anti-inflammatory drugs. Antivector measures, including use of diethyltoluamide- or picaridin-containing insect repellents during the daytime, help to reduce the risk for exposure from the daytime-biting Aedes species. Prevention campaigns include drainage of breeding sites, application of insecticides, and insecticide-treated bed nets for such populations as hospitalized patients who are immobilized during the day. No licensed vaccine is currently available, but efforts to develop live, attenuated, inactivated DNA and recombinant subunit vaccines are ongoing (10). Clinician Advisory The effect of chikungunya virus in travelers since its recent arrival in the Western hemisphere underscores the interconnectedness of the continental United States, the Caribbean, and Central and South America. Clinicians should advise patients to use antivector measures when traveling to regions with chikungunya transmission. Clinicians should consider chikungunya in the differential diagnosis of febrile travelers with arthralgia and rash after visiting regions with chikungunya transmission, including the Caribbean and Central and South America.

Effectiveness of 4% chlorhexidine umbilical cord care on neonatal mortality in Southern Province, Zambia (ZamCAT): a cluster-randomised controlled trial.

BACKGROUNDnChlorhexidine umbilical cord washes reduce neonatal mortality in south Asian populations with high neonatal mortality rates and predominantly home-based deliveries. No data exist for sub-Saharan African populations with lower neonatal mortality rates or mostly facility-based deliveries. We compared the effect of chlorhexidine with dry cord care on neonatal mortality rates in Zambia.nnnMETHODSnWe undertook a cluster-randomised controlled trial in Southern Province, Zambia, with 90 health facility-based clusters. We enrolled women who were in their second or third trimester of pregnancy, aged at least 15 years, and who would remain in the catchment area for follow-up of 28 days post-partum. Newborn babies received clean dry cord care (control) or topical application of 10 mL of a 4% chlorhexidine solution once per day until 3 days after cord drop (intervention), according to cluster assignment. We used stratified, restricted randomisation to divide clusters into urban or two rural groups (located <40 km or ≥40 km to referral facility), and randomly assigned clusters (1:1) to use intervention (n=45) or control treatment (n=45). Sites, participants, and field monitors were aware of their study assignment. The primary outcomes were all-cause neonatal mortality within 28 days post-partum and all-cause neonatal mortality within 28 days post-partum among babies who survived the first 24 h of life. Analysis was by intention to treat. Neonatal mortality rate was compared with generalised estimating equations. This study is registered at ClinicalTrials.gov (NCT01241318).nnnFINDINGSnFrom Feb 15, 2011, to Jan 30, 2013, we screened 42u2008356 pregnant women and enrolled 39u2008679 women (mean 436·2 per cluster [SD 65·3]), who had 37u2008856 livebirths and 723 stillbirths; 63·8% of deliveries were facility-based. Of livebirths, 18u2008450 (99·7%) newborn babies in the chlorhexidine group and 19u2008308 (99·8%) newborn babies in the dry cord care group were followed up to day 28 or death. 16u2008660 (90·0%) infants in the chlorhexidine group had chlorhexidine applied within 24 h of birth. We found no significant difference in neonatal mortality rate between the chlorhexidine group (15·2 deaths per 1000 livebirths) and the dry cord care group (13·6 deaths per 1000 livebirths; risk ratio [RR] 1·12, 95% CI 0·88-1·44). Eliminating day 0 deaths yielded similar findings (RR 1·12, 95% CI 0·86-1·47).nnnINTERPRETATIONnDespite substantial reductions previously reported in south Asia, chlorhexidine cord applications did not significantly reduce neonatal mortality rates in Zambia. Chlorhexidine cord applications do not seem to provide clear benefits for newborn babies in settings with predominantly facility-based deliveries and lower (<30 deaths per 1000 livebirths) neonatal mortality rates.nnnFUNDINGnBill & Melinda Gates Foundation.

Epidemiology, Prevention, and Potential Future Treatments of Sexually Transmitted Zika Virus Infection

Purpose of ReviewWhile mosquitoes have been primarily responsible for outbreaks of Zika virus worldwide, most prominently in the Americas during 2015 and 2016, there has been increased recognition of the importance of sexual transmission. We review human reports and animal model studies of Zika sexual transmission and summarize potential therapeutic candidates.Recent FindingsMale-to-female, male-to-male, and female-to-male transmission has been reported, among unprotected sexual contacts of returning travelers. Human studies have shown the potential importance of long-term persistence of Zika virus in semen while animal models have begun to yield important insights into pathogenesis of Zika infection of the genital tract.SummaryAdherence to federal and global guidelines for prevention of sexual transmission of Zika virus from travelers to their sexual partners represents the best strategy for reducing the risk of transmission outside of endemic areas. Active research on potential treatments may soon yield candidates for clinical trials.

Beliefs, Behaviors, and Perceptions of Community-Led Total Sanitation and Their Relation to Improved Sanitation in Rural Zambia.

Inadequate hygiene and sanitation remain leading global contributors to morbidity and mortality in children and adults. One strategy for improving sanitation access is community-led total sanitation (CLTS), in which participants are guided into self-realization of the importance of sanitation through activities called triggering. This qualitative study explored community members and stakeholders sanitation, knowledge, perceptions, and behaviors during early CLTS implementation in Zambia. We conducted 67 in-depth interviews and 24 focus group discussions in six districts in Zambia 12-18 months after CLTS implementation. Triggering activities elicited strong emotions, including shame, disgust, and peer pressure, which persuaded individuals and families to build and use latrines and handwashing stations. New sanitation behaviors were also encouraged by the hierarchical influences of traditional leaders and sanitation action groups and by childrens opinions. Poor soil conditions were identified as barriers to latrine construction. Taboos, including prohibition of different generations of family members, in-laws, and opposite genders from using the same toilet, were barriers for using sanitation facilities. CLTS, through community empowerment and ownership, produced powerful responses that encouraged construction and use of latrines and handwashing practices. These qualitative data suggest that CLTS is effective for improving sanitation beliefs and behaviors in Zambia.

Engagement of the Community, Traditional Leaders, and Public Health System in the Design and Implementation of a Large Community-Based, Cluster-Randomized Trial of Umbilical Cord Care in Zambia

Conducting research in areas with diverse cultures requires attention to community sensitization and involvement. The process of community engagement is described for a large community-based, cluster-randomized, controlled trial comparing daily 4% chlorhexidine umbilical cord wash to dry cord care for neonatal mortality prevention in Southern Province, Zambia. Study preparations required baseline formative ethnographic research, substantial community sensitization, and engagement with three levels of stakeholders, each necessitating different strategies. Cluster-specific birth notification systems developed with traditional leadership and community members using community-selected data collectors resulted in a post-natal home visit within 48 hours of birth in 96% of births. Of 39,679 pregnant women enrolled (93% of the target of 42,570), only 3.7% were lost to follow-up or withdrew antenatally; 0.2% live-born neonates were lost by day 28 of follow-up. Conducting this trial in close collaboration with traditional, administrative, political, and community stakeholders facilitated excellent study participation, despite structural and sociocultural challenges.

What is the burden of submicroscopic malaria in pregnancy in central India

Abstract Background: Conventional microscopy underestimates the burden of malarial infection when compared with molecular diagnosis using polymerase chain reaction (PCR)-based methods. Lower density parasitemias serve as a reservoir for infection. We evaluated the prevalence of submicroscopic infections in an area of unstable malarial transmission in India and determined whether these infections negatively impacted maternal or fetal outcomes. Methods: This cross-sectional study (2007–2008) was undertaken in two districts of Chhattisgarh, recruiting women from both antenatal clinics (ANCs) and delivery units (DUs). For ANC/DU subjects, peripheral/placental blood, respectively, was obtained for conventional microscopy and collected onto filter paper for PCR analysis. Results: There were 3425 pregnant women, including 2477 ANC subjects and 948 DU subjects who had both microscopic and PCR samples available. Polymerase chain reaction detected significantly more Plasmodium infections than traditional light microscopy both from peripheral (3·4 vs 1·2%; OR 2·9, 95% confidence intervals (CIs) 1·9–4·5) and placental (4·2 vs 1·7%; OR 2·5, 95% CIs 1·4–4·8) blood samples. Submicroscopic infections were not associated with anemia or severe maternal anemia among ANC or DU participants and were not associated with low birth weight (LBW) among DU participants. In contrast, microscopically detected infections were associated with severe anemia and LBW. Conclusions: In this area of unstable malarial transmission from India, submicroscopic infections did not identify a set of pregnant women at increased risk for anemia or LBW. Until PCR techniques become much less expensive and available as a point of care test for the field setting, its use will be limited for malarial detection.