Defining childhood severe falciparum malaria for intervention studies.

Background Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no “gold standard” individual test for severe malaria, malaria-attributable fractions (MAFs) can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints. Methods and Findings A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor), lower respiratory tract infection (clinician's final diagnosis), meningitis (on cerebrospinal fluid [CSF] examination), and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%–86.1%) without excluding these conditions, 89% (95% CI 88.4%–90.2%) after exclusions, and 95% (95% CI 94.0%–95.5%) when a threshold of 2,500 parasites/μl was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%–83%). Conclusions The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis), bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition

Untargeted analysis of the airway proteomes of children with respiratory infections using mass spectrometry based proteomics

The upper airway – which consists mainly of the naso- and oro-pharynx - is the first point of contact between the respiratory system and microbial organisms that are ubiquitous in the environment. It has evolved highly specialised functions to address these constant threats whilst facilitating seamless respiratory exchange with the lower respiratory tract. Dysregulation of its critical homeostatic and defence functions can lead to ingress of pathogens into the lower respiratory tract, potentially leading to serious illness. Systems-wide proteomic tools may facilitate a better understanding of mechanisms in the upper airways in health and disease. In this study, we aimed to develop a mass spectrometry based proteomics method for characterizing the upper airways proteome. Naso- and oropharyngeal swab samples used in all our experiments had been eluted in the Universal Transport Media (UTM) containing significantly high levels of bovine serum albumin. Our proteomic experiments tested the optimal approach to characterize airway proteome on swab samples eluted in UTM based on the number of proteins identified without BSA depletion (Total proteome: Protocol A) and with its depletion using a commercial kit; Allprep, Qiagen (cellular proteome: Protocol B, Ci, and Cii). Observations and lessons drawn from protocol A, fed into the design and implementation of protocol B, and from B to protocol Ci and finally Cii. Label free proteome quantification was used in Protocol A (n = 6) and B (n = 4) while commercial TMT 10plex reagents were used for protocols Ci and ii (n = 83). Protocols Ci and ii were carried out under similar conditions except for the elution gradient: 3 h and 6 h respectively. Swab samples tested in this study were from infants and children with and without upper respiratory tract infections from Kilifi County Hospital on the Kenyan Coast. Protocol A had the least number of proteins identified (215) while B produced the highest number of protein identifications (2396). When Protocol B was modified through sample multiplexing with TMT to enable higher throughput (Protocol Ci), the number of protein identified reduced to 1432. Modification of protocol Ci by increasing the peptide elution time generated Protocol Cii that substantially increased the number of proteins identified to 1875. The coefficient of variation among the TMT runs in Protocol Cii was <20%. There was substantial overlap in the identity of proteins using the four protocols. Our method was were able to identify marker proteins characteristically expressed in the upper airway. We found high expression levels of signature nasopharyngeal and oral proteins, including BPIFA1/2 and AMY1A, as well as a high abundance of proteins related to innate and adaptive immune function in the upper airway. We have developed a sensitive systems-level proteomic assay for the systematic quantification of naso-oro-pharyngeal proteins. The assay will advance mechanistic studies of respiratory pathology, by providing an untargeted and hypothesis-free approach of examining the airway proteome

Maternal perception of malnutrition among infants using verbal and pictorial methods in Kenya.

OBJECTIVE: To compare mothers' perceptions of their own infants' nutritional status with anthropometric indicators of undernutrition. DESIGN: A qualitative study and cross-sectional quantitative survey. The qualitative study involved developing tools to assess mother's perception. Two methods of verbal description and a pictorial scale were developed. The quantitative survey involved measuring maternal perception and comparing it with the anthropometric measures of weight-for-age Z-score (WAZ) and mid-upper arm circumference-for-age Z-score (MUACZ). SETTING: A rural community setting in Kenya. SUBJECTS: Seventy-four infants aged between 4 and 6 months, and their mothers, living in rural Kenya were enrolled. RESULTS: Using verbal description, the positive and negative likelihood ratios were 3.57 (95 % CI 1.44, 9.98) and 0.69 (95 % CI 0.50, 0.96) respectively for MUACZ<-2; and 4.60 (95 % CI 1.60, 13.3) and 0.67 (95 % CI 0.49, 0.92) respectively for WAZ<-2. Using the pictorial scale, the positive and negative likelihood ratios were 8.30 (95 % CI 1.91, 36.3) and 0.69 (95 % CI 0.52, 0.93) respectively for MUACZ<-2; and 4.31 (95 % CI 1.22, 15.0) and 0.78 (95 % CI 0.61, 1.00) respectively for WAZ<-2. CONCLUSIONS: In a rural community, mothers better identify undernutrition in their infants using a pictorial scale than verbal description. However, neither can replace formal anthropometric assessment. Objective anthropometric tools should be validated for identification of severe acute malnutrition among infants aged less than 6 months

Management of acute malnutrition in infants aged under 6 months (MAMI): current issues and future directions in policy and research.

BACKGROUND: Globally, some 4.7 million infants aged under 6 months are moderately wasted and 3.8 million are severely wasted. Traditionally, they have been over-looked by clinicians, nutritionists, and policy makers. OBJECTIVE: To present evidence and arguments for why treating acute malnutrition in infants under 6 months of age is important and outline some of the key debates and research questions needed to advance their care. METHODS: Narrative review. RESULTS AND CONCLUSIONS: Treating malnourished infants under 6 months of age is important to avoid malnutrition-associated mortality in the short-term and adverse health and development outcomes in the long-term. Physiological and pathological differences demand a different approach from that in older children; key among these is a focus on exclusive breastfeeding wherever possible. New World Health Organization guidelines for the management of severe acute malnutrition (SAM) include this age group for the first time and are also applicable to management of moderate acute malnutrition (MAM). Community-based breastfeeding support is the core, but not the sole, treatment. The mother-infant dyad is at the heart of approaches, but wider family and community relationships are also important. An urgent priority is to develop better case definitions; criteria based on mid-upper-arm circumference (MUAC) are promising but need further research. To effectively move forward, clinical trials of assessment and treatment are needed to bolster the currently sparse evidence base. In the meantime, nutrition surveys and screening at health facilities should routinely include infants under 6 months of age in order to better define the burden and outcomes of acute malnutrition in this age group

Antimicrobial and micronutrient interventions for the management of infants under 6 months of age identified with severe malnutrition: a literature review.

BACKGROUND: Infants under 6 months (U6M) contribute a significant proportion of the burden and mortality of severe malnutrition globally. Evidence of underlying aetiology in this population is sparse, but it is known that the group includes ex-preterm and low birthweight (LBW) infants. They represent a unique population given their dependence on breastmilk or a safe, secure alternative. Nutrition agencies and health providers struggle to make programming decisions on which interventions should be provided to this group based upon the 2013 WHO Guidelines for the 'Management of Severe Acute Malnutrition in Infants and Young Children' since there are no published interventional trial data focussed on this population. Interim guidance for this group might be informed by evidence of safety and efficacy in adjacent population groups. METHODOLOGY: A narrative literature review was performed of systematic reviews, meta-analyses and randomised controlled trials of antimicrobial and micronutrient interventions (antibiotics, deworming, vitamin A, vitamin D, iron, zinc, folic acid and oral rehydration solution (ORS) for malnutrition) across the population groups of low birthweight/preterm infants, infants under 6 months, infants and children over 6 months with acute malnutrition or through supplementation to breastfeeding mothers. Outcomes of interest were safety and efficacy, in terms of mortality and morbidity. RESULTS: Ninety-four articles were identified for inclusion within this review. None of these studied interventions exclusively in severely malnourished infants U6M. 64% reported on the safety of studied interventions. Significant heterogeneity was identified in definitions of study populations, interventions provided, and outcomes studied. The evidence for efficacy and safety across population groups is reviewed and presented for the interventions listed. CONCLUSIONS: The direct evidence base for medical interventions for severely malnourished infants U6M is sparse. Our review identifies a specific need for accurate micronutrient profiling and interventional studies of micronutrients and oral fluid management of diarrhoea amongst infants U6M meeting anthropometric criteria for severe malnutrition. Indirect evidence presented in this review may help shape interim policy and programming decisions as well as the future research agenda for the management of infants U6M identified as malnourished

Influenza surveillance among children with pneumonia admitted to a district hospital in coastal Kenya, 2007-2010

Background: Influenza data gaps in sub-Saharan Africa include incidence, case fatality, seasonal patterns, and associations with prevalent disorders. Methods: Nasopharyngeal samples from children aged <12 years who were admitted to Kilifi District Hospital during 2007–2010 with severe or very severe pneumonia and resided in the local demographic surveillance system were screened for influenza A, B, and C viruses by molecular methods. Outpatient children provided comparative data. Results: Of 2002 admissions, influenza A virus infection was diagnosed in 3.5% (71), influenza B virus infection, in 0.9% (19); and influenza C virus infection, in 0.8% (11 of 1404 tested). Four patients with influenza died. Among outpatients, 13 of 331 (3.9%) with acute respiratory infection and 1 of 196 without acute respiratory infection were influenza positive. The annual incidence of severe or very severe pneumonia, of influenza (any type), and of influenza A, was 1321, 60, and 43 cases per 100 000 <5 years of age, respectively. Peak occurrence was in quarters 3–4 each year, and approximately 50% of cases involved infants: temporal association with bacteremia was absent. Hypoxia was more frequent among pneumonia cases involving influenza (odds ratio, 1.78; 95% confidence interval, 1.04–1.96). Influenza A virus subtypes were seasonal H3N2 (57%), seasonal H1N1 (12%), and 2009 pandemic H1N1 (7%). Conclusions: The burden of influenza was small during 2007–2010 in this pediatric hospital in Kenya. Influenza A virus subtype H3N2 predominated, and 2009 pandemic influenza A virus subtype H1N1 had little impact

Effect of HIV infection on the acute antibody response to malaria antigens in children: an observational study

<p>Abstract</p> <p>Background</p> <p>In sub-Saharan Africa, the distributions of malaria and HIV widely overlap. Among pregnant and non-pregnant adults, HIV affects susceptibility to malaria, its clinical course and impairs antibody responses to malaria antigens. However, the relationship between the two diseases in childhood, when most deaths from malaria occur, is less clear. It was previously reported that HIV is associated with admission to hospital in rural Kenya with severe malaria among children, except in infancy. HIV-infected children with severe malaria were older, had higher parasite density and increased mortality, raising a hypothesis that HIV interferes with naturally acquired immunity to malaria, hence with little effect at younger ages (a shorter history of exposure). To test this hypothesis, levels of anti-merozoite and schizont extract antibodies were compared between HIV-infected and uninfected children who participated in the original study.</p> <p>Methods</p> <p>IgG responses to malaria antigens that are potential targets for immunity to malaria (AMA1, MSP2, MSP3 and schizont extract) were compared between 115 HIV-infected and 115 age-matched, HIV-uninfected children who presented with severe malaria. The children were classified as high and low responders for each antigen and assigned antibody-response breadth scores according to the number of antigens to which they were responsive. A predictive logistic regression model was used to test if HIV was an effect modifier on the age-related acquisition of antibody responses, with age as a continuous variable.</p> <p>Results</p> <p>Point estimates of the responses to all antigens were lower amongst HIV-infected children, but this was only statistically significant for AMA1 (P = 0.028). HIV-infected children were less likely to be high responders to AMA1 [OR 0.44 (95%CI, 0.2-0.90) P = 0.024]. HIV was associated with a reduced breadth of responses to individual merozoite antigens (P = 0.02). HIV strongly modified the acquisition of antibodies against schizont extract with increasing age (P < 0.0001), but did not modify the rate of age-related acquisition of responses to individual merozoite antigens.</p> <p>Conclusions</p> <p>In children with severe malaria, HIV infection is associated with a lower magnitude and narrower breadth of IgG responses to merozoite antigens and stunting of age-related acquisition of the IgG antibody response to schizont extract.</p

Age patterns of severe paediatric malaria and their relationship to Plasmodium falciparum transmission intensity

BACKGROUND: The understanding of the epidemiology of severe malaria in African children remains incomplete across the spectrum of Plasmodium falciparum transmission intensities through which communities might expect to transition, as intervention coverage expands. METHODS: Paediatric admission data were assembled from 13 hospitals serving 17 communities between 1990 and 2007. Estimates of Plasmodium falciparum transmission intensity in these communities were assembled to be spatially and temporally congruent to the clinical admission data. The analysis focused on the relationships between community derived parasite prevalence and the age and clinical presentation of paediatric malaria in children aged 0-9 years admitted to hospital. RESULTS: As transmission intensity declined a greater proportion of malaria admissions were in older children. There was a strong linear relationship between increasing transmission intensity and the proportion of paediatric malaria admissions that were infants (R2 = 0.73, p < 0.001). Cerebral malaria was reported among 4% and severe malaria anaemia among 17% of all malaria admissions. At higher transmission intensity cerebral malaria was a less common presentation compared to lower transmission sites. There was no obvious relationship between the proportions of children with severe malaria anaemia and transmission intensity. CONCLUSION: As the intensity of malaria transmission declines in Africa through the scaling up of insecticide-treated nets and other vector control measures a focus of disease prevention among very young children becomes less appropriate. The understanding of the relationship between parasite exposure and patterns of disease risk should be used to adapt malaria control strategies in different epidemiological settings