Ajib Phiri

Severe Anemia in Malawian Children

BACKGROUND Severe anemia is a major cause of sickness and death in African children, yet the causes of anemia in this population have been inadequately studied. METHODS We conducted a case-control study of 381 preschool children with severe anemia (hemoglobin concentration, <5.0 g per deciliter) and 757 preschool children without severe anemia in urban and rural settings in Malawi. Causal factors previously associated with severe anemia were studied. The data were examined by multivariate analysis and structural equation modeling. RESULTS Bacteremia (adjusted odds ratio, 5.3; 95% confidence interval [CI], 2.6 to 10.9), malaria (adjusted odds ratio, 2.3; 95% CI, 1.6 to 3.3), hookworm (adjusted odds ratio, 4.8; 95% CI, 2.0 to 11.8), human immunodeficiency virus infection (adjusted odds ratio, 2.0; 95% CI, 1.0 to 3.8), the G6PD(-202/-376) genetic disorder (adjusted odds ratio, 2.4; 95% CI, 1.3 to 4.4), vitamin A deficiency (adjusted odds ratio, 2.8; 95% CI, 1.3 to 5.8), and vitamin B12 deficiency (adjusted odds ratio, 2.2; 95% CI, 1.4 to 3.6) were associated with severe anemia. Folate deficiency, sickle cell disease, and laboratory signs of an abnormal inflammatory response were uncommon. Iron deficiency was not prevalent in case patients (adjusted odds ratio, 0.37; 95% CI, 0.22 to 0.60) and was negatively associated with bacteremia. Malaria was associated with severe anemia in the urban site (with seasonal transmission) but not in the rural site (where malaria was holoendemic). Seventy-six percent of hookworm infections were found in children under 2 years of age. CONCLUSIONS There are multiple causes of severe anemia in Malawian preschool children, but folate and iron deficiencies are not prominent among them. Even in the presence of malaria parasites, additional or alternative causes of severe anemia should be considered.

The outcome of non-typhoidal salmonella meningitis in Malawian children, 1997–2006

Abstract Introduction: The clinical course and outcome of non-typhoidal salmonella (NTS) meningitis in Malawian children over a 10-year period (1997–2006) is described. Methods: Demographic, clinical and laboratory data were collected for all children over 2 months of age admitted with salmonella meningitis to Queen Elizabeth Central Hospital from 1997 to 2006. In the 1st year, salmonellae were susceptible to chloramphenicol, and children received 2 weeks of chloramphenicol treatment. When NTS resistance to chloramphenicol started to appear in 1998, treatment was changed to ceftriaxone. From 2002, the duration of antibiotic therapy was extended to 4-weeks which included 2 weeks of intravenous ceftriaxone and a further 2 weeks of oral ciprofloxacin. Results: The in-hospital case fatality rate (CFR) was 52.3% (48.2% until 2002 and 53.9% after prolonged antibiotic therapy was introduced). Of the survivors, one in 12 (8.3%) became completely well (sequelae-free) in the period 1997–2001 while 18 of 31 survivors (58.1%) made a complete recovery during 2002–2006 (p<0.01). After the 4-week course of antimicrobial therapy was introduced, the number of relapses or recurrences fell from nine in 15 (60%) survivors treated with chloramphenicol or ceftriaxone to three in 35 (8.7%) survivors who received 4 weeks of antibiotics (p<0.0001). Conclusion: In Malawi, salmonella meningitis has a CFR of ∼50%, which has remained constant over many years. Residual morbidity, however, has decreased over 10 years, despite rising numbers of multi-drug-resistant cases of NTS. This improvement might be owing to better treatment and management and/or reduced pathogenicity of the multi-drug-resistant bacteria.

Impact of human immunodeficiency virus infection on the etiology and outcome of severe pneumonia in Malawian children.

Background: HIV infection is a major risk factor for death in childhood pneumonia in HIV-endemic regions. Improved case management and preventive strategies require better understanding of the impact of HIV on causes, clinical presentation, and outcome. Methods: A prospective, clinical descriptive study of Malawian infants and children with severe pneumonia included blood culture and nasopharyngeal aspiration for diagnosis of pneumocystis pneumonia (PcP). A select group with consolidation on chest radiograph, and without severe hypoxia or hyperinflation, also had lung aspirate taken for culture and identification of bacterial deoxyribonucleic acid by real-time polymerase chain reaction (PCR). Results: There were 327 study patients with a median age of 11 months (range, 2 months–14 years). HIV prevalence was 51%. There were 58 cases of confirmed bacterial pneumonia, of which the most common bacterial isolates were Streptococcus pneumoniae and Salmonella typhimurium. Of the 54 lung aspirates, only 2 were positive on culture but 27 were positive for bacterial deoxyribonucleic acid by PCR. PcP was confirmed in 16 patients, and was associated with young age, severe hypoxia, HIV infection, and a very poor outcome. The overall case-fatality rate was 10% despite presumptive therapy for PcP and routine broad-spectrum antibiotic treatment appropriate for local antimicrobial susceptibility data. Most of the deaths occurred in infants of 2 to 6 months of age and PcP was associated with 57% of these deaths. Conclusions: PcP is a major barrier in reducing the case-fatality rate of severe pneumonia in infants of HIV-endemic communities. The use of PCR on lung aspirate specimens greatly increased the diagnostic yield.

Challenges in the Management of HIV-Infected Malnourished Children in Sub-Saharan Africa

Infection with HIV, and oftentimes coinfection with TB, complicates the care of severely malnourished children in sub-Saharan Africa. These superimposed infections challenge clinicians faced with a population of malnourished children for whose care evidence-based guidelines have not kept up. Even as the care of HIV-uninfected malnourished children has improved dramatically with the advent of community-based care and even as there are hopeful signs that the HIV epidemic may be stabilizing or ameliorating, significant gaps remain in the care of malnourished children with HIV. Here we summarize what is currently known, what remains unknown, and what remains challenging about how to treat severely malnourished children with HIV and TB.

Glycerol and acetaminophen as adjuvant therapy did not affect the outcome of bacterial meningitis in Malawian children.

We investigated the benefit of 2 candidate adjunctive therapies in bacterial meningitis: glycerol, which has shown promise in earlier studies, and acetaminophen, which is reportedly beneficial in adult septicemia. In a hospital in Blantyre, Malawi, we enrolled 360 children aged ≥ 2 months with proven bacterial meningitis (36% HIV infected) in a double-blind, randomized, placebo-controlled trial of glycerol and acetaminophen in a 2 × 2 factorial design. Of 4 groups, first group received oral glycerol, second received rectal acetaminophen, third received both therapies and the fourth received placebos only. Adjuvant therapies were given for the first 48 hours of antibiotic therapy. Endpoints were mortality and neurological sequelae. Baseline findings were similar across all groups, except that many children had prior antibiotics in the acetaminophen group and many were anemic in the acetaminophen and glycerol group. Outcomes were similar for all groups. We found no benefit from oral glycerol or rectal acetaminophen in, mostly pneumococcal, meningitis in Malawian children.

Risk Factors for Death and Severe Sequelae in Malawian Children with Bacterial Meningitis, 1997--2010

Background: Acute bacterial meningitis (ABM) causes significant death and disability in children worldwide, with HIV recognized as an established risk factor for infection and negative outcomes. However, additional major risk factors for death and disability in pediatric ABM remain unclear. Methods: We conducted a retrospective analysis of case data from 3 departmental studies of ABM involving 1784 children <15 years old who attended Queen Elizabeth Central Hospital in Blantyre, Malawi during 1997 to 2010. Univariate and multivariate logistic regression models were used to estimate the effects of HIV seropositivity, impaired consciousness and causative organism on death and severe sequelae. Results: Impaired consciousness or coma at the time of admission was strongly associated with death (coma: odds ratio [OR] = 14.4, 95% confidence interval [CI]: 9.42, 22.1) and severe sequelae (Coma: OR = 3.27, 95% CI: 2.02, 5.29) in multivariate logistic regression models. HIV seropositivity was significantly associated with increased odds of death (OR = 1.65, 95% CI: 1.20, 2.26) but not with developing severe sequelae (OR = 0.88, 95% CI: 0.56, 1.38). After adjustment, infection with Salmonella spp. was associated with increased odds of death (OR = 2.11, 95% CI: 1.06, 4.08) and pneumococcal meningitis was associated with increased odds of severe sequelae (OR = 1.84, 95% CI: 1.03, 3.29). Conclusions: Impaired consciousness and HIV infection increased the odds of death from ABM in Malawian children. Use of pneumococcal conjugate vaccine could greatly reduce the burden of ABM in Malawi.

Lactate as a predictor of mortality in Malawian children with WHO-defined pneumonia

Objectives To determine whether blood lactate measured at the time of presentation to hospital predicted outcome in children with pneumonia in Malawi, and to understand the factors associated with high blood lactate concentrations in pneumonia. Design Analysis of data from a prospective study of children presenting to Queen Elizabeth Central Hospital, Blantyre, with WHO-defined severe or very severe pneumonia. Results Among 233 children with pneumonia, the median serum lactate concentration was 2.7 mmol/l (IQR 1.8–4.4 mmol/l). 77 children (33%) had a lactate concentration of 2.1–4.0 mmol/l, and 72 children (31%) had a lactate concentration >4.0 mmol/l. 92% of children who died (23/25) had lactate >2.0 mmol/l at the time of admission to hospital. There were 10 deaths (13%) among 77 children who had a serum lactate concentration of 2.1–4.0 mmol/l; and 13 deaths (18%) in the 72 children who had lactate >4.0 mmol/l. The relative risk of death if the lactate level was above 2 mmol/l was 7.48 (1.72–32.6); sensitivity 0.92, specificity 0.39, positive predictive value 0.15, negative predictive value 0.98. Multivariable analysis showed that hypoxaemia, hyperlactataemia and age ≤12 months were independent risk factors for death from pneumonia. Conclusions Used in conjunction with clinical risk factors and pulse oximetry for measuring oxygen saturation, lactate could play an important role in identifying the sickest patients with pneumonia in developing countries.

Task sharing within a managed clinical network to improve child health in Malawi

BackgroundEighty per cent of Malawi’s 8 million children live in rural areas, and there is an extensive tiered health system infrastructure from village health clinics to district hospitals which refers patients to one of the four central hospitals. The clinics and district hospitals are staffed by nurses, non-physician clinicians and recently qualified doctors. There are 16 paediatric specialists working in two of the four central hospitals which serve the urban population as well as accepting referrals from district hospitals. In order to provide expert paediatric care as close to home as possible, we describe our plan to task share within a managed clinical network and our hypothesis that this will improve paediatric care and child health.Presentation of the hypothesisManaged clinical networks have been found to improve equity of care in rural districts and to ensure that the correct care is provided as close to home as possible. A network for paediatric care in Malawi with mentoring of non-physician clinicians based in a district hospital by paediatricians based at the central hospitals will establish and sustain clinical referral pathways in both directions. Ultimately, the plan envisages four managed paediatric clinical networks, each radiating from one of Malawi’s four central hospitals and covering the entire country. This model of task sharing within four hub-and-spoke networks may facilitate wider dissemination of scarce expertise and improve child healthcare in Malawi close to the child’s home.Testing the hypothesisFunding has been secured to train sufficient personnel to staff all central and district hospitals in Malawi with teams of paediatric specialists in the central hospitals and specialist non-physician clinicians in each government district hospital. The hypothesis will be tested using a natural experiment model. Data routinely collected by the Ministry of Health will be corroborated at the district. This will include case fatality rates for common childhood illness, perinatal mortality and process indicators. Data from different districts will be compared at baseline and annually until 2020 as the specialists of both cadres take up posts.Implications of the hypothesisIf a managed clinical network improves child healthcare in Malawi, it may be a potential model for the other countries in sub-Saharan Africa with similar cadres in their healthcare system and face similar challenges in terms of scarcity of specialists.

Growth and HIV-free survival of HIV-exposed infants in Malawi: a randomized trial of two complementary feeding interventions in the context of maternal antiretroviral therapy.

Objective:To compare the growth of HIV-exposed children receiving 1 of 2 complementary foods after prevention of mother-to-child HIV transmission through maternal lifelong antiretroviral therapy (ART). Methods:In rural Malawi, 280 HIV-infected pregnant women were consecutively identified and offered ART, without consideration of their CD4 counts. Mothers were supported to exclusively breast-feed and children tested for HIV status at 1.5 and 5.5 months of age. From this group, 248 HIV-exposed children were enrolled and randomized to receive micronutrients with either whole milk powder or a ready-to-use complementary food (RUF), until the child reached 12 months of age. Children were followed until 18 months of age. Results:HIV-free survival at 12 months was 90% (95% confidence interval: 87% to 94%). Exclusive breast-feeding for the first 6 months of life was practiced in 97% of the children. At 12 months of age, 89% of the children continued to be breast-fed. At 6 months of age, infants had a weight-for-height z score of 0.7 ± 1.1 (mean ± SD) and length-for-age z score of −1.3 ± 1.2. The decrease in length-for-age z score among children receiving RUF at 12 months of age was greater than that seen in those receiving milk powder (−0.3 ± 0.8 vs −0.1 ± 0.7, P = 0.04). Mean weight-for-height z score was >0 at 12 and 18 months of age in both groups. Conclusions:HIV-free survival ≥90% at 12 months was achieved with maternal ART while either milk powder or RUF as a complementary food preserved child anthropometry. Breast-feeding by mothers receiving ART was acceptable.

Establishing sickle cell diagnostics and characterizing a paediatric sickle cell disease cohort in Malawi

poor accrual. In summary, this study provides preliminary data on the efficacy of the combination of alisertib and bortezomib for relapsed MM. The duration of response varied widely with one patient staying on therapy for more than 3 years. Nevertheless, the contribution of alisertib to bortezomib activity cannot be determined without additional Phase II testing. Further studies looking at inhibition of Aurora kinase A alone or in combination with established or novel anti-MM therapies will be necessary.