Queen Elizabeth Central Hospital

BACKGROUND: Antiretroviral medications that are used as prophylaxis can prevent acquisition of human immunodeficiency virus type 1 (HIV-1) infection. However, in clinical trials among African women, the incidence of HIV-1 infection was not reduced, probably because of low adherence. Longer-acting methods of drug delivery, such as vaginal rings, may simplify use of antiretroviral medications and provide HIV-1 protection. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial of a monthly vaginal ring containing dapivirine, a non-nucleoside HIV-1 reverse-transcriptase inhibitor, involving women between the ages of 18 and 45 years in Malawi, South Africa, Uganda, and Zimbabwe. RESULTS: Among the 2629 women who were enrolled, 168 HIV-1 infections occurred: 71 in the dapivirine group and 97 in the placebo group (incidence, 3.3 and 4.5 per 100 person-years, respectively). The incidence of HIV-1 infection in the dapivirine group was lower by 27% (95% confidence interval [CI], 1 to 46; P=0.046) than that in the placebo group. In an analysis that excluded data from two sites that had reduced rates of retention and adherence, the incidence of HIV-1 infection in the dapivirine group was lower by 37% (95% CI, 12 to 56; P=0.007) than that in the placebo group. In a post hoc analysis, higher rates of HIV-1 protection were observed among women over the age of 21 years (56%; 95% CI, 31 to 71; P<0.001) but not among those 21 years of age or younger (-27%; 95% CI, -133 to 31; P=0.45), a difference that was correlated with reduced adherence. The rates of adverse medical events and antiretroviral resistance among women who acquired HIV-1 infection were similar in the two groups. CONCLUSIONS: A monthly vaginal ring containing dapivirine reduced the risk of HIV-1 infection among African women, with increased efficacy in subgroups with evidence of increased adherence. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01617096 .).

We studied the relationship between presenting features and outcome in 131 Malawian children admitted with cerebral malaria (P. falciparum malaria and unrousable coma). A method was devised for the measurement of depth of coma in children too young to speak. Twenty patients (15 per cent) died and 12 (9 per cent) recovered with residual neurological sequelae. Presenting clinical signs significantly associated with adverse outcome (death or sequelae) were profound coma, signs of decerebration, absence of corneal reflexes, convulsions at the time of admission and age under three years. Laboratory findings of prognostic significance were hypoglycaemia, leucocytosis, hyperparasitaemia, elevated plasma concentrations of alanine and 5'-nucleotidase, and elevated plasma or cerebrospinal fluid lactate. A prognostic index based on eight of these risk factors that can readily be ascertained at the bedside or in a ward sideroom, was more accurately predictive of outcome than any single feature. Such an index may be valuable as a measure of severity of illness for establishing the comparability of study groups, and for evaluating the role of other factors in the pathogenesis of cerebral malaria.

BACKGROUND: Case fatality rates among African children with cerebral malaria remain in the range of 15 to 25%. The key pathogenetic processes and causes of death are unknown, but a combination of clinical observations and pathological findings suggests that increased brain volume leading to raised intracranial pressure may play a role. Magnetic resonance imaging (MRI) became available in Malawi in 2009, and we used it to investigate the role of brain swelling in the pathogenesis of fatal cerebral malaria in African children. METHODS: We enrolled children who met a stringent definition of cerebral malaria (one that included the presence of retinopathy), characterized them in detail clinically, and obtained MRI scans on admission and daily thereafter while coma persisted. RESULTS: Of 348 children admitted with cerebral malaria (as defined by the World Health Organization), 168 met the inclusion criteria, underwent all investigations, and were included in the analysis. A total of 25 children (15%) died, 21 of whom (84%) had evidence of severe brain swelling on MRI at admission. In contrast, evidence of severe brain swelling was seen on MRI in 39 of 143 survivors (27%). Serial MRI scans showed evidence of decreasing brain volume in the survivors who had had brain swelling initially. CONCLUSIONS: Increased brain volume was seen in children who died from cerebral malaria but was uncommon in those who did not die from the disease, a finding that suggests that raised intracranial pressure may contribute to a fatal outcome. The natural history indicates that increased intracranial pressure is transient in survivors. (Funded by the National Institutes of Health and Wellcome Trust U.K.).

BACKGROUND: Improved diagnostic tests for tuberculosis in children are needed. We hypothesized that transcriptional signatures of host blood could be used to distinguish tuberculosis from other diseases in African children who either were or were not infected with the human immunodeficiency virus (HIV). METHODS: The study population comprised prospective cohorts of children who were undergoing evaluation for suspected tuberculosis in South Africa (655 children), Malawi (701 children), and Kenya (1599 children). Patients were assigned to groups according to whether the diagnosis was culture-confirmed tuberculosis, culture-negative tuberculosis, diseases other than tuberculosis, or latent tuberculosis infection. Diagnostic signatures distinguishing tuberculosis from other diseases and from latent tuberculosis infection were identified from genomewide analysis of RNA expression in host blood. RESULTS: We identified a 51-transcript signature distinguishing tuberculosis from other diseases in the South African and Malawian children (the discovery cohort). In the Kenyan children (the validation cohort), a risk score based on the signature for tuberculosis and for diseases other than tuberculosis showed a sensitivity of 82.9% (95% confidence interval [CI], 68.6 to 94.3) and a specificity of 83.6% (95% CI, 74.6 to 92.7) for the diagnosis of culture-confirmed tuberculosis. Among patients with cultures negative for Mycobacterium tuberculosis who were treated for tuberculosis (those with highly probable, probable, or possible cases of tuberculosis), the estimated sensitivity was 62.5 to 82.3%, 42.1 to 80.8%, and 35.3 to 79.6%, respectively, for different estimates of actual tuberculosis in the groups. In comparison, the sensitivity of the Xpert MTB/RIF assay for molecular detection of M. tuberculosis DNA in cases of culture-confirmed tuberculosis was 54.3% (95% CI, 37.1 to 68.6), and the sensitivity in highly probable, probable, or possible cases was an estimated 25.0 to 35.7%, 5.3 to 13.3%, and 0%, respectively; the specificity of the assay was 100%. CONCLUSIONS: RNA expression signatures provided data that helped distinguish tuberculosis from other diseases in African children with and those without HIV infection. (Funded by the European Union Action for Diseases of Poverty Program and others).

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Severe malaria is commonly misdiagnosed in Africa, leading to a failure to treat other life-threatening illnesses. In malaria-endemic areas, parasitemia does not ensure a diagnosis of severe malaria because parasitemia can be incidental to other concurrent disease. The detection of malarial retinopathy is a candidate diagnostic test for cerebral malaria. Malarial retinopathy consists of a set of retinal abnormalities that is unique to severe malaria and common in children with cerebral malaria. Its presence and severity are related to risk of death and length of coma in survivors. A large, prospective autopsy study of children dying with cerebral malaria in Malawi found that malarial retinopathy was better than any other clinical or laboratory feature in distinguishing malarial from non-malarial coma. However, visualization has to date relied on specialist examination techniques. Further studies are planned to evaluate the usefulness of funduscopy by general clinicians in a variety of settings across Africa. Studies of the retina and retinal blood vessels provide an unparalleled opportunity to visualize an infected microvasculature and its effect on neural tissue in vivo. This report reviews current knowledge of malarial retinopathy, including its use as a diagnostic test in the comatose child, and its value as a tool for research into the pathophysiology of cerebral malaria.

As part of a supplement entitled "Born Too Soon", this paper focuses on care of the preterm newborn. An estimated 15 million babies are born preterm, and the survival gap between those born in high and low income countries is widening, with one million deaths a year due to direct complications of preterm birth, and around one million more where preterm birth is a risk factor, especially amongst those who are also growth restricted. Most premature babies (>80%) are between 32 and 37 weeks of gestation, and many die needlessly for lack of simple care. We outline a series of packages of care that build on essential care for every newborn comprising support for immediate and exclusive breastfeeding, thermal care, and hygienic cord and skin care. For babies who do not breathe at birth, rapid neonatal resuscitation is crucial. Extra care for small babies, including Kangaroo Mother Care, and feeding support, can halve mortality in babies weighing <2000 g. Case management of newborns with signs of infection, safe oxygen management and supportive care for those with respiratory complications, and care for those with significant jaundice are all critical, and are especially dependent on competent nursing care. Neonatal intensive care units in high income settings are de-intensifying care, for example increasing use of continuous positive airway pressure (CPAP) and this makes comprehensive preterm care more transferable. For health systems in low and middle income settings with increasing facility births, district hospitals are the key frontier for improving obstetric and neonatal care, and some large scale programmes now include specific newborn care strategies. However there are still around 50 million births outside facilities, hence home visits for mothers and newborns, as well as women's groups are crucial for reaching these families, often the poorest. A fundamental challenge is improving programmatic tracking data for coverage and quality, and measuring disability-free survival. The power of parent's voices has been important in high-income countries in bringing attention to preterm newborns, but is still missing from the most affected countries. This article is part of a supplement jointly funded by Save the Children's Saving Newborn Lives programme through a grant from The Bill & Melinda Gates Foundation and March of Dimes Foundation and published in collaboration with the Partnership for Maternal, Newborn and Child Health and the World Health Organization (WHO). The original article was published in PDF format in the WHO Report "Born Too Soon: the global action report on preterm birth" (ISBN 978 92 4 150343 30), which involved collaboration from more than 50 organizations. The article has been reformatted for journal publication and has undergone peer review according to Reproductive Health's standard process for supplements and may feature some variations in content when compared to the original report. This co-publication makes the article available to the community in a full-text format.

PROBLEM: Early assessment, prioritization for treatment and management of sick children attending a health service are critical to achieving good outcomes. Many hospitals in developing countries see large numbers of patients and have few staff, so patients often have to wait before being assessed and treated. APPROACH: We present the example of a busy Under-Fives Clinic that provided outpatient services, immunizations and treatment for medical emergencies. The clinic was providing an inadequate service resulting in some inappropriate admissions and a high case-fatality rate. We assessed the deficiencies and sought resources to improve services. LOCAL SETTING: A busy paediatric outpatient clinic in a public tertiary care hospital in Blantyre, Malawi. RELEVANT CHANGES: The main changes we made were to train staff in emergency care and triage, improve patient flow through the department and to develop close cooperation between inpatient and outpatient services. Training coincided with a restructuring of the physical layout of the department. The changes were put in place when the department reopened in January 2001. LESSONS LEARNED: Improvements in the process and delivery of care and the ability to prioritize clinical management are essential to good practice. Making the changes described above has streamlined the delivery of care and led to a reduction in inpatient mortality from 10-18% before the changes were made (before 2001) to 6-8% after.

OBJECTIVES: This study was undertaken to determine the relative effect of malaria infection on HIV concentration in blood plasma, and prospectively to monitor viral concentrations after antimalarial therapy. DESIGN: A prospective, double cohort study was designed to compare the blood HIV-1 RNA concentrations of HIV-positive individuals with and without acute malaria illness. Subjects were followed for 4 weeks after successful malaria therapy, or for 4 weeks from enrollment (controls). METHODS: Malawian adults with symptomatic Plasmodium falciparum parasitemia (malaria group) and asymptomatic, aparasitemic blood donors (control group) were tested for HIV-1 antibodies to identify appropriate study groups. The malaria group received antimalarial chemotherapy only and were followed with sequential blood films. In both groups, blood plasma HIV-1 RNA viral concentrations were determined at enrollment and again at 1, 2 and 4 weeks. RESULTS: Forty-seven malaria patients and 42 blood donors were enrolled. At enrollment blood plasma HIV-1 RNA concentrations were approximately sevenfold higher in patients with malaria than in blood donors (medians 15.1 x 10(4) and 2.24 x 10(4) copies/ml, respectively, P = 0.0001). No significant changes in median HIV-1 concentrations occurred in the 21 blood donors followed to week 4 (P = 0.68). In the 27 subjects successfully treated for malaria who were followed to week 4, a reduction in plasma HIV-1 RNA was observed from a median of 19.1 x 10(4) RNA copies/ml at enrollment, to 12.0 x 10(4) copies/ml at week 4, (P = 0.02). Plasma HIV-1 concentrations remained higher in malaria patients than controls (median 12.0 x 10(4) compared with 4.17 x 10(4) copies/ml, P = 0.086). CONCLUSIONS: HIV-1 blood viral burden is higher in patients with P. falciparum malaria than in controls and this viral burden can, in some patients, be partly reduced with antimalarial therapy.

BACKGROUND: Cervical cancer is the second most common cancer and the leading cause of cancer death in women in sub-Saharan Africa (SSA). METHODS: Trends in the incidence of cervical cancer are examined for a period of 10-25 years in 10 population-based cancer registries across eight SSA countries (Gambia, Kenya, Malawi, Mauritius, Seychelles, South Africa, Uganda and Zimbabwe). A total of 21,990 cases of cervical cancer were included in the analyses. RESULTS: Incidence rates had increased in all registries for some or all of the periods studied, except for Mauritius with a constant annual 2.5% decline. Eastern Cape and Blantyre (Malawi) registries showed significant increases over time, with the most rapid being in Blantyre (7.9% annually). In Kampala (Uganda), a significant increase was noted (2.2%) until 2006, followed by a non-significant decline. In Eldoret, a decrease (1998-2002) was followed by a significant increase (9.5%) from 2002 to 2016. CONCLUSION: Overall, cervical cancer incidence has been increasing in SSA. The current high-level advocacy to reduce the burden of cervical cancer in SSA needs to be translated into support for prevention (vaccination against human papillomavirus and population-wide screening), with careful monitoring of results through population-based registries.

Pulmonary macrophages with a key role in defence against respiratory infection are a heterogeneous family of cells with phagocytic, antigen processing and immunomodulatory functions. Macrophages are important in both innate and acquired immunity in the respiratory tract, and have a role in lung defence against viruses, bacteria, mycobacteria and fungi. Interactions of pathogens with lung macrophages is strongly influenced by soluble immune components including complement, collectins and immunoglobulins. Macrophage function can be modulated by cytokines, environmental exposures, recent and chronic infection including HIV infection, drug therapy and gene transfer.

BACKGROUND: Perinatal transmission of human immunodeficiency virus (HIV) type 1 contributes significantly to infant mortality. Exposure in the birth canal may account for some transmission. We examined the efficacy of a birth canal washing procedure in reducing perinatal transmission in Malawi. METHODS: The infection status of infants of 3327 control women (conventional delivery procedures) was compared with that of 3637 infants of intervention-delivered women. The infants' HIV status was determined by polymerase chain reaction on dried blood spots collected at 6 and 12 weeks of age. The intervention consisted of manual cleansing of the birth canal with a cotton pad soaked in 0.25% chlorhexidine, which was done on admission in labour and every 4 h until delivery. FINDINGS: No adverse reactions to the intervention procedure were seen. 2094 (30%) of the enrolled women were HIV-infected, and 59% of their infants were seen in follow-up. Among 982 vaginal vertex singleton deliveries to HIV-infected women, 269 (27%) infants were infected. The intervention had no significant impact on HIV transmission rates (27% in 505 intervention women compared with 28% in 477 control women), except when membranes were ruptured more than 4 h before delivery (transmission 25% in the intervention group vs 39% in the control group). INTERPRETATION: If birth canal exposure is an important risk factor, different or additional methods to reduce the risk of perinatal HIV transmission should be tested. Alternatively, perhaps birth canal exposure is not a major contributor to perinatal infection risk.

Meningitis is more common in the neonatal period than any other time in life and is an important cause of morbidity and mortality globally. Despite the majority of the burden occurring in the developing world, the majority of the existing literature originates from wealthy countries. Mortality from neonatal meningitis in developing countries is estimated to be 40-58%, against 10% in developed countries. Important differences exist in the spectrum of pathogens isolated from cerebrospinal fluid cultures in developed versus developing countries. Briefly, while studies in developed countries have generally found Group B streptococcus (GBS), Escherichia coli and Listeria monocytogenes as important organisms, we describe how in the developing world results have varied; particularly regarding GBS, other Gram negatives (excluding E. coli), Listeria and Gram-positive organisms. The choice of empiric antibiotics should take into consideration local epidemiology if known, early versus late disease, resistance patterns and availability within resource constraints. Gaps in knowledge, the role of adjuvant therapies and future directions for research are explored.

Background Post-tuberculosis lung damage (PTLD) is a recognised consequence of pulmonary TB (pTB). However, little is known about its prevalence, patterns and associated outcomes, especially in sub-Saharan Africa and HIV-positive adults. Methods Adult (≥15 years) survivors of a first episode of pTB in Blantyre, Malawi, completed the St George’s Respiratory Questionnaire, 6-minute walk test, spirometry and high-resolution CT (HRCT) chest imaging at TB treatment completion. Symptom, spirometry, health seeking, TB-retreatment and mortality data were collected prospectively to 1 year. Risk factors for persistent symptoms, pulmonary function decline and respiratory-related health-seeking were identified through multivariable regression modelling. Results Between February 2016 and April 2017, 405 participants were recruited. Median age was 35 years (IQR: 28 to 41), 77.3% (313/405) had had microbiologically proven pTB, and 60.3% (244/403) were HIV-positive. At pTB treatment completion, 60.7% (246/405) reported respiratory symptoms, 34.2% (125/365) had abnormal spirometry, 44.2% (170/385) had bronchiectasis ≥1 lobe and 9.4% (36/385) had ≥1 destroyed lobe on HRCT imaging. At 1 year, 30.7% (113/368) reported respiratory symptoms, 19.3% (59/305) and 14.1% (43/305) of patients had experienced declines in FEV 1 or FVC of ≥100 mL, 16.3% (62/380) had reported ≥1 acute respiratory event and 12.2% (45/368) had symptoms affecting their ability to work. Conclusions PTLD is a common and under-recognised consequence of pTB that is disabling for patients and associated with adverse outcomes beyond pTB treatment completion. Increased efforts to prevent PTLD and guidelines for management of established disease are urgently needed. Low-cost clinical interventions to improve patient outcomes must be evaluated.

hybrid genes, which encode a serologically distinct blood group antigen known as Dantu. This variant reduces the risk of severe malaria by 40% and has recently increased in frequency in parts of Kenya, yet it appears to be absent from west Africa. These findings link structural variation of red blood cell invasion receptors with natural resistance to severe malaria.

AIM: To determine the influence of placental malaria, maternal HIV infection, and maternal hypergammaglobulinaemia on transplacental IgG antibody transfer. METHODS: One hundred and eighty materno-neonatal pairs from a Malawian population were assessed. Cord and maternal serum samples were tested for total serum IgG antibody titres using nephelometry, and for specific IgG antibody titres to Streptococcus pneumoniae, measles, and tetanus toxoid antibodies using an enzyme linked immunosorbent assay (ELISA). RESULTS: Multiple regression analyses showed that placental malaria was associated with a decrease in placental IgG antibody transfer to S pneumoniae and measles to 82% and 81%, respectively. Maternal HIV infection was associated with a reduction in IgG antibody transfer to S pneumoniae to 79%; raised maternal total serum IgG titres were correlated with S pneumoniae and measles IgG antibody transfer reduction to 86% and 87%, respectively. No effect was seen with tetanus toxoid antibody transfer. CONCLUSION: The combined influence of placental malaria, maternal HIV infection, and maternal hypergammaglobulinaemia seems to be linked to the low transplacental antibody transfer observed in the Malawian population.

Evidence from clinical studies and murine models supports a role for cytokines in the pathogenesis of human cerebral malaria (CM). In this study, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to investigate expression of mRNA for transforming growth factor (TGF)-beta, interleukin (IL)-1beta, and tumor necrosis factor (TNF)-alpha in human postmortem tissue. Immunohistochemistry was used to examine the distribution of cytokine protein. TGF-beta was expressed in normal brain, in CM, and in meningitis and encephalitis. IL-1beta was absent from normal brain but was detected in CM and other cerebral infections. TNF-alpha mRNA was expressed only in CM, although TNF-alpha protein was also seen in meningitis. Cytokine mRNA expression in the brain did not correlate with the density of parasitized erythrocytes detected using RT-PCR for major surface protein-2. This report of RT-PCR on postmortem human tissues infected with CM demonstrates induction of the proinflammatory cytokines TNF-alpha and IL-1beta in the brain.

PURPOSE OF REVIEW: This is part two of a two-part state of the art--hepatoblastoma. International hepatoblastoma specialists were brought together to highlight advances, controversies, and future challenges in the treatment of this rare pediatric tumor. RECENT FINDINGS: Pretreatment extent of disease (PRETEXT) is a grouping system introduced as part of the multicenter international childhood liver tumors strategy group, SIOPEL-1, study in 1990. The system has been refined over the ensuing years and has now come to be adopted for risk stratification by all of the major pediatric liver tumor multicenter trial groups. PRETEXT is being intensively studied in the current Children's Oncology Group (COG) AHEP-0731 trial in an attempt to validate interobserver reproducibility and ability to monitor response to neoadjuvant chemotherapy, and determine surgical resectability. PRETEXT is now used to identify those patients who are at risk for having an unresectable tumor and who should be referred to a liver specialty center with transplant capability early in their treatment schema. SUMMARY: International collaborative efforts in hepatoblastoma have led to increased refinements in the use of the PRETEXT and post-treatment extent to define prognosis and surgical resectability. PRETEXT criteria which suggest a possible need for liver transplantation are discussed in detail.

Although the accessibility of HIV treatment in developing nations has increased dramatically over the past decade, viral load testing to monitor the response of patients receiving therapy is often unavailable. Existing viral load technologies are often too expensive or resource-intensive for poor settings, and there is no appropriate HIV viral load test currently available at the point-of-care in low resource settings. Here, we present a lateral flow assay that employs gold nanoparticle probes and gold enhancement solution to detect amplified HIV RNA quantitatively. Preliminary results show that, when coupled with nucleic acid sequence based amplification (NASBA), this assay can detect concentrations of HIV RNA that match the clinically relevant range of viral loads found in HIV patients. The lateral flow test is inexpensive, simple and rapid to perform, and requires few resources. Our results suggest that the lateral flow assay may be integrated with amplification and sample preparation technologies to serve as an HIV viral load test for low-resource settings.

BACKGROUND: In patients with cerebral malaria (CM), retinal angiography allows the study of infected central nervous system microvasculature in vivo. We aimed to examine retinal perfusion in children with CM by use of fluorescein angiography to investigate the pathophysiology of CM. METHODS: We performed fluorescein angiography on children with CM admitted to Queen Elizabeth Central Hospital, Malawi. We related angiograms to funduscopic findings. RESULTS: Fluorescein angiography was performed for 34 patients with CM, and impaired perfusion was identified in 28 (82%). Areas of capillary nonperfusion (CNP) were seen in 26 patients (76%). Multiple, scattered areas of CNP were typical and topographically matched to retinal whitening. Larger retinal vessels were occluded in 9 patients (26%) who had associated ischemia. These vessels appeared white on ophthalmoscopy. Intravascular abnormalities were seen in 9 patients (26%), including filling defects and mottling of the blood column. Limited fluorescein leakage occurred in 15 patients (44%) and was not related to angiographic intravascular abnormalities or visible vessel discoloration. CONCLUSIONS: Impaired perfusion occurs in the retinal microvasculature of most children with CM. This is evidence for hypoxia and ischemia as important components in the pathogenesis of CM. Vessel occlusion and filling defects are likely to be due to sequestration of infected erythrocytes. Interventions which improve perfusion or limit hypoxic injury may be beneficial in CM.