Protocol for a magnetic resonance imaging study of participants in the fever RCT: Does fever control prevent brain injury in malaria?

BACKGROUND: Despite eradication efforts, ~135,000 African children sustained brain injuries as a result of central nervous system (CNS) malaria in 2021. Newer antimalarial medications rapidly clear peripheral parasitemia and improve survival, but mortality remains high with no associated decline in post-malaria neurologic injury. A randomized controlled trial of aggressive antipyretic therapy with acetaminophen and ibuprofen (Fever RCT) for malarial fevers being conducted in Malawi and Zambia began enrollment in 2019. We propose to use neuroimaging in the context of the RCT to further evaluate neuroprotective effects of aggressive antipyretic therapy. METHODS: This observational magnetic resonance imaging (MRI) ancillary study will obtain neuroimaging and neurodevelopmental and behavioral outcomes in children previously enrolled in the Fever RCT at 1- and 12-months post discharge. Analysis will compare the odds of any brain injury between the aggressive antipyretic therapy and usual care groups based upon MRI structural abnormalities. For children unable to undergo imaging without deep sedation, neurodevelopmental and behavioral outcomes will be used to identify brain injury. DISCUSSION: Neuroimaging is a well-established, valid proxy for neurological outcomes after brain injury in pediatric CNS malaria. This MRI ancillary study will add value to the Fever RCT by determining if treatment with aggressive antipyretic therapy is neuroprotective in CNS malaria. It may also help elucidate the underlying mechanism(s) of neuroprotection and expand upon FEVER RCT safety assessments.

The renal angina index accurately predicts low risk of developing severe acute kidney injury among children admitted to a low-resource pediatric intensive care unit.

BACKGROUND: Acute kidney injury (AKI) increases the risk of adverse outcomes. The renal angina index (RAI) has previously been used to predict patients at risk of developing severe AKI (sAKI). METHOD: This single-centre prospective observational study aimed to assess the prevalence of sAKI in PICU as the primary outcome and the duration of mechanical ventilation and PICU stay, RRT need, and mortality as secondary outcomes. The utility of the RAI in predicting day 3 sAKI was also assessed. We enrolled 122 patients aged 1 month to 16 years whose baseline characteristics were collected via questionnaire. RAI was calculated on day 0 with a score of ≥8 being considered positive. sAKI was defined as KDIGO stages 2 and 3. RESULTS: sAKI prevalence was 14.8% and its development was associated with longer duration of mechanical ventilation (p = 0.001) and higher mortality (p = 0.011). A positive Day 0 RAI predicted day 3 sAKI with sensitivity 55.6%, specificity 85.6%, PPV 40.0%, NPV 91.8%, and AUC of 0.77. Exclusion of children older than 5 years improved RAI performance (sensitivity 72.7%, specificity 88.0%, PPV 57.1%, NPV 93.6%, AUC 0.80). A modified RAI based on local AKI risk factors had equivalent performance to RAI (Z - score 0.78 (CI -0.077-0.033), p = 0.435) with sensitivity 72.2%, specificity 80.8%, PPV 39.4%, NPV 94.4% and AUC 0.80. CONCLUSION: The RAI can be an effective tool in ruling out sAKI in patients and a modification of RAI based on population-based risk factors improves the test's sensitivity and NPV.

Neuromuscular disease genetics in under-represented populations: increasing data diversity.

Neuromuscular diseases (NMDs) affect ∼15 million people globally. In high income settings DNA-based diagnosis has transformed care pathways and led to gene-specific therapies. However, most affected families are in low-to-middle income countries (LMICs) with limited access to DNA-based diagnosis. Most (86%) published genetic data is derived from European ancestry. This marked genetic data inequality hampers understanding of genetic diversity and hinders accurate genetic diagnosis in all income settings. We developed a cloud-based transcontinental partnership to build diverse, deeply-phenotyped and genetically characterized cohorts to improve genetic architecture knowledge, and potentially advance diagnosis and clinical management. We connected 18 centres in Brazil, India, South Africa, Turkey, Zambia, Netherlands and the UK. We co-developed a cloud-based data solution and trained 17 international neurology fellows in clinical genomic data interpretation. Single gene and whole exome data were analysed via a bespoke bioinformatics pipeline and reviewed alongside clinical and phenotypic data in global webinars to inform genetic outcome decisions. We recruited 6001 participants in the first 43 months. Initial genetic analyses 'solved' or 'possibly solved' ∼56% probands overall. In-depth genetic data review of the four commonest clinical categories (limb girdle muscular dystrophy, inherited peripheral neuropathies, congenital myopathy/muscular dystrophies and Duchenne/Becker muscular dystrophy) delivered a ∼59% 'solved' and ∼13% 'possibly solved' outcome. Almost 29% of disease causing variants were novel, increasing diverse pathogenic variant knowledge. Unsolved participants represent a new discovery cohort. The dataset provides a large resource from under-represented populations for genetic and translational research. In conclusion, we established a remote transcontinental partnership to assess genetic architecture of NMDs across diverse populations. It supported DNA-based diagnosis, potentially enabling genetic counselling, care pathways and eligibility for gene-specific trials. Similar virtual partnerships could be adopted by other areas of global genomic neurological practice to reduce genetic data inequality and benefit patients globally.

Risk factors for acute kidney injury at presentation among children with CNS malaria: a case control study.

BACKGROUND: Recent research has established that acute kidney injury (AKI) is a common problem in severe paediatric malaria. Limited access to kidney diagnostic studies in the low resources settings where malaria is common has constrained research on this important problem. METHODS: Enrolment data from an ongoing clinical trial of antipyretics in children with central nervous system (CNS) malaria, CNS malaria being malaria with seizures or coma, was used to identify risk factors for AKI at presentation. Children 2-11 years old with CNS malaria underwent screening and enrollment assessments which included demographic and anthropomorphic data, clinical details regarding the acute illness, and laboratory studies including creatinine (Cr), quantitative parasite count (qPC), quantitative histidine rich protein 2 (HRP2), lactate, and bilirubin levels. Children with a screening Cr > 106 µmol/l were excluded from the study due to the potential nephrotoxic effects of the study drug. To identify risk factors for AKI at the time of admission, children who were enrolled in the study were categorized as having AKI using estimates of their baseline (i.e. before this acute illness) kidney function and creatinine at enrollment applying the Kidney Disease: Improving Global Outcome (KDIGO) 2012 guidelines. Logistic regressions and a multivariate model were used to identify clinical and demographic risk factors for AKI at presentation among those children enrolled in the study. RESULTS: 465 children were screened, 377 were age-appropriate with CNS malaria, 22 (5.8%) were excluded due to Cr > 106 µmol/l, and 209 were enrolled. Among the 209, AKI using KDIGO criteria was observed in 134 (64.1%). One child required dialysis during recovery. Risk factors for AKI in both the logistic regression and multivariate models included: hyperpyrexia (OR 3.36; 95% CI 1.39-8.12) and age with older children being less likely to have AKI (OR 0.72; 95% CI 0.62-0.84). CONCLUSION: AKI is extremely common among children presenting with CNS malaria. Hyperpyrexia with associated dehydration may contribute to the AKI or may simply be a marker for a more inflammatory systemic response that is also affecting the kidney. Appropriate fluid management in children with CNS malaria and AKI may be challenging since generous hydration to support kidney recovery could worsen malaria-induced cerebral oedema in this critically ill population. Trial registration https://clinicaltrials.gov/ct2/show/NCT03399318.

The prevalence of primary headache disorders in children and adolescents in Zambia: a schools-based study.

BACKGROUND: The Global Campaign against Headache collects data from children (6-11 years) and adolescents (12-17) to inform health and education policies and contribute to the Global Burden of Disease (GBD) study. This survey in Zambia, part of this global enquiry, was the second from sub-Saharan Africa (SSA). METHODS: Following the generic protocol, this was a schools-based cross-sectional survey. We used the child and adolescent versions of the structured Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire, self-completed by pupils within classes, in a total of nine schools in Lusaka (urban) and Copperbelt (semi-rural). These two of Zambia's ten provinces were selected to represent the country's urban/rural divide. Headache diagnostic questions were based on ICHD-3 except for undifferentiated headache (UdH). RESULTS: Of 2,759 potential participants, 2,089 (615 children [29.4%], 1,474 adolescents [70.6%]) completed questionnaires (participating proportion 75.7%). Children were therefore under-represented (mean age 13.1 ± 2.8 years), while gender distribution (1,128 [54.0%] male, 961 [46.0%] female) was close to expectation. Observed lifetime prevalence of headache was 97.5%. Gender- and age-adjusted 1-year prevalence estimates were 85.8% for all headache, 53.2% for migraine (definite 17.5%, probable 35.7%), 12.1% for tension-type headache (TTH), 14.8% for UdH, 3.3% for all headache on ≥ 15 days/month and 0.9% for probable medication-overuse headache. Headache durations were short: only 28.6% of participants with any headache, and only 10.5% of those diagnosed as probable migraine, reported usual durations of > 2 h (the threshold for definite migraine). Of the latter, 36.6% reported < 1 h, the duration criterion for UdH. There were weak associations of migraine (definite + probable) with female gender, and of TTH and headache on ≥ 15 days/month with adolescence. Headache yesterday was reported by 22.2% of the sample, 25.5% of those with headache. CONCLUSIONS: Headache disorders among young people are prevalent in Zambia. Among them, migraine is the most common, with UdH also highly prevalent. In this study there were diagnostic uncertainties, which rested to a large extent on the distinction between migraine and UdH among the many participants reporting headache of < 2 h' duration. Similar uncertainties occurred in the first study in SSA, in Ethiopia. Because of these, we conclude only that migraine affects at least 17.5% of these age groups in Zambia, which is still a large proportion, adult prevalence in an earlier study being 22.9%. Supplementary estimates of attributed burden are needed to inform public-health and educational policies in Zambia.

Organophosphate insecticide poisoning with monocrotophos-induced fabricated illness in a 7-year-old girl with refractory seizures over a 4-year period.

Munchausen syndrome by proxy is a form of abuse in which an adult, usually the mother, deceives health workers by exaggerating, falsifying or directly inducing psychological or physical symptoms in the child victim for psychological gratification. In 2013, the American Academy of Pediatrics coined the term 'caregiver-fabricated illness in a child' to describe this form of child abuse. A 7-year-old girl had many encounters with health workers over a period of 4 years and presented with evolving clinical features including refractory seizures and red urine for which she was followed up as a case of acute intermittent porphyria. She was later discovered to be the victim of chronic monocrotophos organophosphate poisoning by her mother. If all medical staff who manage children are to avoid becoming inadvertent participants in medical child abuse, this case report is an important reminder that a high index of suspicion is warranted in cases which present a diagnostic dilemma and who respond unexpectedly to treatment.Abbreviations AIP: Acute intermittent porphyria; APSAC: American Professional Society on the Abuse of Children; ASM: anti-seizure medication; CFIC: caregiver-fabricated illness in a child; CT: computed tomography: DVT: deep vein thrombosis; EEG: electroencephalogram: ESR: erythrocyte sedimentation rate; HDW: high-dependency ward; ICU: intensive care unit; LFT: liver function test; MBP: Munchausen syndrome by proxy; NICU: neonatal intensive care unit; RFT: renal function test; TB: Tuberculosis; UTH-CH: University Teaching Hospitals Children's Hospital.

The Etiology of Pneumonia in Zambian Children: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

BACKGROUND: Childhood pneumonia in developing countries is the foremost cause of morbidity and death. Fresh information on etiology is needed, considering the changing epidemiology of pneumonia in the setting of greater availability of effective vaccines, changing antibiotic use and improved access to care. We report here the Zambia site results of the Pneumonia Etiology Research for Child Health study on the etiology of pneumonia among HIV-uninfected children in Lusaka, Zambia. METHODS: We conducted a case-control study of HIV-uninfected children age 1-59 months admitted with World Health Organization-defined severe or very severe pneumonia to a large tertiary care hospital in Lusaka. History, physical examination, chest radiographs (CXRs), blood cultures and nasopharyngeal/oropharyngeal swabs were obtained and tested by polymerase chain reaction and routine microbiology for the presence of 30 bacteria and viruses. From age and seasonally matched controls, we tested blood and nasopharyngeal/oropharyngeal samples. We used the Pneumonia Etiology Research for Child Health integrated analysis to determine the individual and population etiologic fraction for individual pathogens as the cause of pneumonia. RESULTS: Among the 514 HIV-uninfected case children, 208 (40.5%) had abnormal CXRs (61 of 514 children were missing CXR), 8 (3.8%) of which had positive blood cultures. The overall mortality was 16.0% (82 deaths). The etiologic fraction was highest for respiratory syncytial virus [26.1%, 95% credible interval (CrI): 17.0-37.7], Mycobacterium tuberculosis (12.8%, 95% CrI: 4.3-25.3) and human metapneumovirus (12.8%, CrI: 6.1-21.8). CONCLUSIONS: Childhood pneumonia in Zambia among HIV-uninfected children is most frequently caused by respiratory syncytial virus, M. tuberculosis and human metapneumovirus, and the mortality remains high.

The Etiology of Pneumonia in HIV-infected Zambian Children: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

BACKGROUND: Despite recent declines in new pediatric HIV infections and childhood HIV-related deaths, pneumonia remains the leading cause of death in HIV-infected children under 5. We describe the patient population, etiology and outcomes of childhood pneumonia in Zambian HIV-infected children. METHODS: As one of the 9 sites for the Pneumonia Etiology Research for Child Health study, we enrolled children 1-59 months of age presenting to University Teaching Hospital in Lusaka, Zambia, with World Health Organization-defined severe and very severe pneumonia. Controls frequency-matched on age group and HIV infection status were enrolled from the Lusaka Pediatric HIV Clinics as well as from the surrounding communities. Clinical assessments, chest radiographs (CXR; cases) and microbiologic samples (nasopharyngeal/oropharyngeal swabs, blood, urine, induced sputum) were obtained under highly standardized procedures. Etiology was estimated using Bayesian methods and accounted for imperfect sensitivity and specificity of measurements. RESULTS: Of the 617 cases and 686 controls enrolled in Zambia over a 24-month period, 103 cases (16.7%) and 85 controls (12.4%) were HIV infected and included in this analysis. Among the HIV-infected cases, 75% were <1 year of age, 35% received prophylactic trimethoprim-sulfamethoxazole, 13.6% received antiretroviral therapy and 36.9% of caregivers reported knowing their children's HIV status at time of enrollment. A total of 35% of cases had very severe pneumonia and 56.3% had infiltrates on CXR. Bacterial pathogens [50.6%, credible interval (CrI): 32.8-67.2], Pneumocystis jirovecii (24.9%, CrI: 15.5-36.2) and Mycobacterium tuberculosis (4.5%, CrI: 1.7-12.1) accounted for over 75% of the etiologic fraction among CXR-positive cases. Streptococcus pneumoniae (19.8%, CrI: 8.6-36.2) was the most common bacterial pathogen, followed by Staphylococcus aureus (12.7%, CrI: 0.0-25.9). Outcomes were poor, with 41 cases (39.8%) dying in hospital. CONCLUSIONS: HIV-infected children in Zambia with severe and very severe pneumonia have poor outcomes, with continued limited access to care, and the predominant etiologies are bacterial pathogens, P. jirovecii and M. tuberculosis.

Chest Radiograph Findings in Childhood Pneumonia Cases From the Multisite PERCH Study.

BACKGROUND.: Chest radiographs (CXRs) are frequently used to assess pneumonia cases. Variations in CXR appearances between epidemiological settings and their correlation with clinical signs are not well documented. METHODS.: The Pneumonia Etiology Research for Child Health project enrolled 4232 cases of hospitalized World Health Organization (WHO)-defined severe and very severe pneumonia from 9 sites in 7 countries (Bangladesh, the Gambia, Kenya, Mali, South Africa, Thailand, and Zambia). At admission, each case underwent a standardized assessment of clinical signs and pneumonia risk factors by trained health personnel, and a CXR was taken that was interpreted using the standardized WHO methodology. CXRs were categorized as abnormal (consolidation and/or other infiltrate), normal, or uninterpretable. RESULTS.: CXRs were interpretable in 3587 (85%) cases, of which 1935 (54%) were abnormal (site range, 35%-64%). Cases with abnormal CXRs were more likely than those with normal CXRs to have hypoxemia (45% vs 26%), crackles (69% vs 62%), tachypnea (85% vs 80%), or fever (20% vs 16%) and less likely to have wheeze (30% vs 38%; all P < .05). CXR consolidation was associated with a higher case fatality ratio at 30-day follow-up (13.5%) compared to other infiltrate (4.7%) or normal (4.9%) CXRs. CONCLUSIONS.: Clinically diagnosed pneumonia cases with abnormal CXRs were more likely to have signs typically associated with pneumonia. However, CXR-normal cases were common, and clinical signs considered indicative of pneumonia were present in substantial proportions of these cases. CXR-consolidation cases represent a group with an increased likelihood of death at 30 days post-discharge.

Knowledge and perceptions of asthma in Zambia: a cross-sectional survey.

BACKGROUND: Zambia is currently experiencing an epidemiological transition, from communicable to non-communicable diseases. The annual rate of physician-diagnosed asthma is estimated at 3 %. However, the general public's knowledge of asthma symptoms and signs, and their perception of asthma remain unknown. A survey was conducted aiming to determine knowledge and perceptions of asthma among Zambians. METHODS: Adults and adolescents attending four clinics in the capital, Lusaka, were surveyed using a standardized questionnaire from July 2011 to March 2012. RESULTS: Data from 1,540 participants (mean age 30.7 years, 65% female) were collected. Most patients (74%) were living in low-cost housing. One hundred and sixteen (7.6%) participants reported either a medical diagnosis of asthma or currently taking asthma medications. The most frequent asthma symptoms reported were wheezing (88%), and waking up at night with either shortness of breath (85%), chest tightness (85%), or cough (67%). Medications used to treat asthma were mostly oral short-acting beta-agonists (SABA) (59%), inhaled SABA (30.2%) and antibiotics (29.8%). Inhaled steroids were only used by 16.4% while less than 1% were on long-acting beta-agonists (LABA). Many misconceptions were identified among the entire surveyed population with only 54.7% believing hospitalisations are not preventable, 54.7% believing asthma symptoms can be prevented with the right medications and 37% believing inhalers are addictive. Nearly 60% thought that people with asthma cannot exercise or play hard. Significantly more individuals with asthma compared to those without thought tablets are better than inhalers for the treatment of asthma (46% vs 30%). CONCLUSIONS: We conclude that knowledge on asthma is poor in Zambia, where there remains many misconceptions on asthma and its management.

Improving paediatric asthma care in Zambia.

PROBLEM: In 2008, the prevalence of paediatric asthma in Zambia was unknown and the national treatment guideline was outdated. APPROACH: We created an international partnership between Zambian clinicians, the Zambian Government and a pharmaceutical company to address shortcomings in asthma treatment. We did two studies, one to estimate prevalence in the capital of Lusaka and one to assess attitudes and practices of patients. Based on the information obtained, we educated health workers and the public. The information from the studies was also used to modernize government policy for paediatric asthma management. LOCAL SETTING: The health-care system in Zambia is primarily focused on acute care delivery with a focus on infectious diseases. Comprehensive services for noncommunicable diseases are lacking. Asthma management relies on treatment of acute exacerbations instead of disease control. RELEVANT CHANGES: Seven percent of children surveyed had asthma (255/3911). Of the 120 patients interviewed, most (82/120, 68%) used oral short-acting ß2-agonists for symptom control; almost half (59/120, 49%) did not think the symptoms were preventable and 43% (52/120) thought inhalers were addictive. These misconceptions informed broad-based educational programmes. We used a train-the-trainer model to educate health-care workers and ran public awareness campaigns. Access to inhalers was increased and the Zambian standard treatment guideline for paediatric asthma was revised to include steroid inhalers as a control treatment. LESSONS LEARNT: Joint activities were required to change paediatric asthma care in Zambia. Success will depend on local sustainability, and it may be necessary to shift resources to mirror the disease burden.

Clinical patterns of juvenile idiopathic arthritis in Zambia.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of disorders with different disease manifestations among various populations. There are few reports of JIA among indigenous Africans especially sub-Saharan Africa. We present herein the clinical patterns of JIA encountered at a tertiary hospital in Lusaka, Zambia. METHOD: Hospital records of patients with a diagnosis of chronic arthritis with onset at the age of 16 years or less presenting to University Teaching Hospital, Lusaka, Zambia for the periods 1994-98 and 2006-2010 were retrospectively reviewed and reclassified as Juvenile Idiopathic Arthritis (JIA) based on the International League of Associations for Rheumatology (ILA R) JIA diagnostic criteria. RESULTS: In total, 126 patients with chronic arthritis of onset at age 16 years or less were evaluated over these periods at the hospital. Of these, 85 could further be analyzed by ILAR JIA criteria but 7 (8.24%) were HIV seropositive and were assessed separately. The average age at disease onset among the 78 JIA patients was 8.70 years (range: 1-15 years) with average age at first visit to hospital being 11.3 years (range: 2 to 25 years) and with a female to male ratio of 1.2:1. Polyarticular rheumatoid factor negative JIA, at 34.62%, was the most frequent type of chronic arthritis encountered. Oligoarthritis was found in 32.05% while 11.54% and 14.10% were polyarticular rheumatoid factor positive and systemic JIA, respectively. Enthesitis-related arthritis was found in 6.41% and only 1.28% were determined to have psoriatic arthritis among this population. CONCLUSION: JIA is predominantly a polyarticular rheumatoid factor negative disease in Zambia. Late presentation is an issue with major implications for educational input and resource acquisition. There is need to elucidate the genetics and environmental factors of JIA in this region.