HIV-uninfected Children Research Articles

Impact of Respiratory Syncytial Virus and Severe Acute Respiratory Syndrome Coronavirus 2 Coinfection on Clinical Severity and Outcomes Among Children Hospitalized With Lower Respiratory Tract Infections in Soweto, South Africa

Background: No data are available regarding the interplay and clinical manifestations of respiratory syncytial virus (RSV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) coinfection in African children. We compared clinical characteristics and outcomes between RSV-only, SARS-CoV-2–only and RSV/SARS-CoV-2 coinfection lower respiratory tract infections (LRTI) in hospitalized African children. Methods: Prospective surveillance of children (0–59 months) hospitalized with severe LRTI was undertaken between March 1, 2020, and March 31, 2023, in Johannesburg, South Africa. Nasopharyngeal swabs for respiratory viruses and clinical data were collected, and clinical characteristics and outcomes were described and compared. Respiratory index of severity in children (RISC) scores were calculated for HIV-uninfected children, and covariates associated with high RISC scores (≥5) were evaluated. Results: Seven thousand four hundred fifty-six children [6.1 months (interquartile range, 14.4–18.6); 57.7% male] were enrolled, 1372 (18.4%) testing RSV+/SARS-CoV-2– (RSV only), 223 (3.0%) RSV−/SARS-CoV-2+ (SARS-CoV-2–only) and 28 (0.4%) RSV+/SARS-CoV-2+ (RSV/SARS-CoV-2 coinfection). Children with RSV only and RSV/SARS-CoV-2 coinfection were more likely to present with bronchiolitis than those with SARS-CoV-2–only (673/1372 and 15/28 vs. 46/223; P < 0.001). Children with RSV/SARS-CoV-2 coinfection had more severe disease than those with RSV or SARS-CoV-2–only, as well as a higher RISC score than SARS-CoV-2–only. Weight-for-age Z scores [adjusted risk ratio (aRR): 0.92], room air saturations (aRR: 0.988) and RSV+ status (aRR: 1.40) were independently associated with severe disease. Conclusions: Although both RSV and SARS-CoV-2 LRTI occurred commonly, coinfection did not. Children with RSV/SARS-CoV-2 coinfection had a higher prevalence of severe LRTI than those with RSV or SARS-CoV-2–only. These findings reinforce the urgent need for safe and effective RSV and SARS-CoV-2 vaccines, especially in children in low- and middle-income countries, where the burden of disease is the highest and the access to medical resources the lowest.

Longitudinal controlled attenuation parameter and liver stiffness in children with and without perinatal HIV infection in South Africa.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging cause of liver disease in HIV. Transient elastography (TE) with controlled attenuation parameter (CAP) measures liver stiffness as a marker of liver fibrosis and CAP as a measure of hepatic steatosis. Our aim was to evaluate longitudinal CAP and liver stiffness in children with perinatally acquired HIV (PHIV) on antiretroviral therapy (ART) from early life compared to children without HIV (HU). Prospective cohort study. PHIV and HU were followed annually for two years. During the study, 60% of PHIV switched from older ART regimens to tenofovir disoproxil, lamivudine and dolutegravir (TLD). Longitudinal evolution of CAP and liver stiffness were investigated in two PHIV groups - on older ART and on TLD - compared to HU children using linear mixed effects models. 263 children and adolescents (112 PHIV, 151 HU) aged 7-20 years were followed. PHIV on older ART had CAP 8.61% (95% CI 4.42-12.97, P < 0.001) greater than HU and no significant difference in CAP between PHIV on TLD and HU. No significant difference in liver stiffness was found between PHIV on older ART regimens and PHIV on TLD compared to HU. PHIV on older ART had higher CAP than HU, whereas in PHIV switched to TLD there was no difference in CAP compared to HU. There was no difference in liver stiffness between either PHIV group and HU. This suggests starting ART early in life might protect PHIV from developing hepatic fibrosis.

Perinatal HIV infection is associated with deficits in muscle function in children and adolescents in Zimbabwe.

To determine how muscle strength, power, mass, and density (i.e. quality) differ between children living with HIV (CWH) and those uninfected, and whether antiretroviral therapy (ART) regime is associated with muscle quality. A cross-sectional study in Harare, Zimbabwe. The study recruited CWH aged 8-16 years, taking ART for at least 2 years, from HIV clinics, and HIV-uninfected children from local schools. Muscle outcomes comprised grip strength measured by hand-held Jamar dynamometer, lower limb power measured by standing long-jump distance, lean mass measured by dual-energy X-ray absorptiometry, and muscle density (reflecting intramuscular fat) by peripheral quantitative computed tomography. Linear regression calculated adjusted mean differences (aMD) by HIV status. Overall, 303 CWH and 306 without HIV, had mean (SD) age 12.5 (2.5) years, BMI 17.5 (2.8), with 50% girls. Height and fat mass were lower in CWH, mean differences (SE) 7.4 (1.1) cm and 2.7 (0.4)kgs, respectively. Male CWH had lower grip strength [aMD 2.5 (1.1-3.9) kg, P < 0.001], long-jump distance [7.1 (1.8-12.5) cm, P = 0.006], muscle density [0.58 (0.12-1.05) mg/cm 3 , P = 0.018, but not lean mass 0.06 (-1.08 to 1.21) kg, P = 0.891) versus boys without HIV; differences were consistent but smaller in girls. Mediation analysis suggested the negative effect of HIV on jumping power in boys was partially mediated by muscle density ( P = 0.032). CWH taking tenofovir disoproxil fumarate (TDF) had lower muscle density [0.56 (0.00-1.13)mg/cm 3 , P = 0.049] independent of fat mass, than CWH on other ART. Perinatally acquired HIV is associated, particularly in male individuals, with reduced upper and lower limb muscle function, not mass. Intra-muscular fat (poorer muscle quality) partially explained reductions in lower limb function. TDF is a novel risk factor for impaired muscle quality.

Diagnosis and Management of Tuberculous Meningitis in Children- an Update

UPDATE ON THE DIAGNOSIS AND MANAGEMENT OF TUBERCULOUS MENINGITIS IN CHILDREN: Ronald van Toorn, Regan Solomons Seminars in Pediatric Neurology Volume 21, Issue 1, March 2014, Pages 12-18 Tuberculous meningitis (TBM), the most devastating manifestation of tuberculosis, is often missed or overlooked because of nonspecific symptoms and difficulties in diagnosis. It continues to be an important cause of neurologic handicap in resource-poor countries. Owing to the suboptimal performance of diagnostic tests of TBM, diagnosis relies on thorough history, clinical examination, and relevant investigations. The development of affordable, accurate diagnostic tests for TBM in resource-poor settings remains a priority. Short intensified treatment is safe and effective in both human immunodeficiency virus (HIV)-infected and HIV-uninfected children. Treatment of tuberculous hydrocephalus depends on the level of the cerebrospinal fluid obstruction. Corticosteroids reduce risk of neurodisability and death in HIV-uninfected children. Thalidomide should be considered in children compromised by tuberculosis abscesses and tuberculous-related optochiasmic arachnoiditis. In resource-poor countries, home-based TBM treatment after initial in-hospital stabilization is feasible in carefully selected patients. Early diagnosis and treatment of TBM is the single most important factor determining outcome.

Measles immunity gaps among children and adolescents with HIV in Zambia despite high measles vaccination and antiretroviral therapy coverage.

The study objective was to identify measles and rubella immunity gaps among people with HIV (PWH) in Zambia despite high measles vaccine coverage and widespread access to antiretroviral therapy. Nationally representative cross-sectional serosurvey using biorepository specimens. Blood specimens collected in the Zambia Population HIV Impact Assessment survey (ZAMPHIA) of 2016 were tested for measles and rubella immunoglobulin G (IgG) antibodies by enzyme immunoassay. Hierarchical generalized additive models were fit to characterize age-specific measles and rubella seroprevalence profiles by HIV infection status. Log-binomial regression was performed to identify factors associated with seronegativity. Of the 25 383 specimens, a subsample of 11 500 were selected and 9852 (85%) were successfully tested. Measles seroprevalence was lower among PWH compared with HIV-uninfected individuals until approximately 30 years of age. Among children younger than the age of 10 years, measles seroprevalence was 47.2% [95% confidence interval (CI): 32.7, 61.7] in PWH and 76.4% (95% CI: 74.9, 78.0) in HIV-uninfected children in same age category. In contrast, rubella seroprevalence was higher among PWH than HIV-uninfected individuals, particularly for children younger than 10 years (68.6% vs. 44.3%, P < 0.001). Having a detectable viral load was associated with being measles seronegative (adjusted prevalence ratio 0.15, 95% CI: 0.06, 0.38). These results from a nationally representative serosurvey demonstrate persistence of measles immunity gaps among PWH younger than 30 years of age. There is need to implement the World Health Organization's recommendation to revaccinate children living with HIV against measles following immune reconstitution with antiretroviral therapy to protect these children and prevent measles outbreaks.

Association of full blood count findings with risk of mortality in children with Klebsiella pneumoniae bloodstream infection at a south african children’s hospital

BackgroundBloodstream infection (BSI) caused by Klebsiella pneumoniae (KP), is a leading cause of hospital-associated childhood mortality. There are limited data on how poor outcomes of KPBSI can be predicted in poorly resourced areas. This study aimed to assess if the profile of differential counts from full blood counts (FBC) taken at two time points in children with KPBSI could be used to predict the risk of death.MethodsWe conducted a retrospective study of a cohort of children admitted to hospital between 2006 and 2011 with KPBSI. FBC collected within 48 h (T1) of blood culture and 5–14 days later (T2), were reviewed. Differential counts were classified as abnormal if they were higher or lower than laboratory ranges for normal results. The risk of death was assessed for each category of differential counts. Risk ratios adjusted (aRR) for potential confounders were used to estimate the effect of cell counts on risk of death using multivariable analysis. Data were stratified by HIV status.ResultsOf 296 children, median age 5 (IQR:2–13) months, 82 were HIV -infected. Ninety-five (32%) children with KPBSI died. Mortality in HIV-infected and uninfected children was 39/82 (48%) and 56/214 (26%), respectively (p < 0.001). Independent associations with mortality were observed with leucopenia, neutropenia and thrombocytopenia. Risk of mortality in HIV-uninfected children with thrombocytopenia at T1 and T2 was aRR 2.5 (95% CI: 1.34–4.64) and 3.18 (95% CI: 1.31–7.73) respectively, whereas the mortality risk in the HIV-infected group with thrombocytopaenia at T1 and T2 was aRR 1.99 (95% CI: 0.94–4.19) and 2.01 (95% CI: 0.65–5.99) respectively. Neutropenia in the HIV-uninfected group at T1 and T2, showed aRR 2.17 (95% CI: 1.22–3.88) and aRR 3.70 (95% CI 1.30-10.51) respectively, while in the HIV-infected group, they were aRR 1.18 (95% CI 0.69–2.03) and aRR 2.05 (95% CI 0.87–4.85) at similar time points. Leucopenia at T2 was associated with mortality in HIV-uninfected and HIV-infected patients, aRR 3.22 (95%CI 1.22–8.51) and aRR 2.34 (95% CI 1.09–5.04) respectively. Persistent high band cell percentage at T2 in HIV-infected children indicated a risk of mortality of aRR 2.91 (95% CI 1.20–7.06).ConclusionAbnormal neutrophil counts and thrombocytopenia are independently associated with mortality in children with KPBSI. In resource-limited countries haematological markers have the potential to predict KPBSI mortality.

Serum vitamin E levels in children with human immunodeficiency virus infection in Lagos Nigeria

BackgroundVitamin E supplementation in many adult populations has been found to reduce the impact of oxidative stress from chronic diseases which include HIV infection. With paucity of data among the pediatric population, this study was conducted to determine the mean serum vitamin E levels and its associations with the immunologic status, the nutritional status and the use of highly active antiretroviral drugs (HAART) in children with HIV aged 6 weeks to 13 years.MethodsSeventy HIV-infected children (35 HIV-infected on HAART, 35 HIV-infected HAART-naïve) and seventy age- and sex-matched HIV-uninfected children were recruited to the study. Social class, anthropometric measures, results of serum vitamin E (using HPLC), CD4 counts, and cholesterol levels were inputted into a pretested questionnaire.ResultsThe median (IQR) serum vitamin E levels among the children with HIV was 2.54 (1.55–5.27) μmol/L which was higher than the controls 1.87 (1.63–2.88) μmol/L, p = 0.03.There was a positive correlation between serum vitamin E levels and immunological status using CD4% (r = + 0.141, p = 0.53) and CD4 counts (r = + 0.017, p = 0.91) among the children with HIV. There was no significant association between serum vitamin E levels and nutritional status. The vitamin E levels were higher in the HAART-exposed children compared to the HAART-naïve children but the difference was not significant p = 0.480 and p = 0.485 respectively.ConclusionThe children with HIV had higher serum vitamin E levels. Further research is needed to investigate possible reasons and implications for this including the role of the vitamin E carrier protein in HIV management.

Diarrhoeal pathogens in the stools of children living with HIV in Ibadan, Nigeria.

Diarrhoea can be debilitating in young children. Few aetiological investigations in Africans living with human immunodeficiency virus (HIV) have been performed since antiretrovirals became widely available. Stool specimens from children with diarrhoea living with HIV, and HIV-uninfected controls, recruited at two hospitals in Ibadan, Nigeria, were screened for parasites and occult blood, and cultured for bacteria. Following biochemical identification of at least five colonies per specimen, diarrhoeagenic Escherichia coli and Salmonella were confirmed by PCR. Data were line-listed and comparisons were made using Fisher's Exact test. Only 10 children living with HIV could be enrolled during the 25-month study period and 55 HIV-uninfected children with diarrhoea were included for comparison. The most common pathogens overall were enteroaggregative E. coli (18/65, 27.7%), enteroinvasive E. coli (10/65, 15.4%), Cryptosporidium parvum (8/65, 12.3%) and Cyclospora cayetanensis (7/65, 10.8%). At least one pathogen was detected from seven of ten children living with HIV and 27 (49.1%) HIV-uninfected children. Parasite detection was associated with HIV positive status (p=0.03) with C. parvum specifically recovered more commonly from children living with HIV (p=0.01). Bacterial-parasite pathogen combinations were detected in specimens from four of ten children living with HIV but only 3(5.5%) HIV-uninfected children (p=0.009). Stools from five of ten children living with HIV and 7(12.7%) HIV-negative children (p = 0.014) contained occult blood. Even though children living with HIV present infrequently to Ibadan health facilities with diarrhoea, their greater propensity for mixed and potentially invasive infections justifies prioritizing laboratory diagnosis of their stools.

Fracture prevalence and its association with bone density among children living with HIV in Zimbabwe.

HIV infection impairs bone density in children living with HIV (CLWH). We aimed to determine the prevalence of self-reported fracture (past or current), associated risk factors and disability, by HIV status in Zimbabwean children. Cross-sectional study. We recruited CLWH aged 8-16 years taking antiretroviral therapy (ART) for ≥2 years from HIV clinics, and HIV-uninfected children from schools in Harare. Interviewer-administered questionnaires collected data on fracture site and management, sociodemographics, dietary calcium and vitamin D, physical activity and HIV history. Dual-energy X-ray absorptiometry (DXA) measured size-adjusted bone density. We recruited 303 CLWH [mean (SD) age 12.5 (2.5) years; 50% female] and 306 children without HIV [12.5 (2.5) years; 51% female]. Median age at HIV diagnosis in CLWH was 3.0 years [interquartile range (IQR) 1.2, 5.9], and median ART duration 8.1 years [IQR 6.2, 9.5]. 53.8% CLWH had self-reported disability and/or functional impairment, vs. 29.4% children without HIV. Fracture prevalence was 5.9% with no difference by HIV status [21/306 (6.9%) vs. 14/303 (4.6%), P = 0.24]. Male sex was associated with fractures. Low size-adjusted bone density ( Z -score < -2) was associated with prevalent fractures in CLWH {risk ratio [RR] 1.14 (95% confidence interval (CI) -0.02, 2.29]}, but not in children without HIV [RR -0.04 (-2.00, 1.91)], P -interaction = 0.27. All sought medical attention for their fracture(s), but CLWH were less often admitted to hospital [2/14 (14.3%) vs. 7/21 (33.3%)]. Prevalent fractures may be associated with low lumbar spine bone density in CLWH. Fracture surveillance and strategies to reduce future fracture risk are warranted as CLWH enter adulthood.

Maternal Socio-Demographic Factors and Mother-to-Child Transmission of HIV in the North Region of Cameroon.

Socio-demographic factors are important risk factors for HIV infection. Maternal socio-demographic factors associated with HIV transmission from mother to child are not well elucidated to our knowledge. This study aimed to assess the maternal socio-demographic factors associated with HIV vertical transmission. A matched case-control study was conducted among children under 15 years of age born to HIV-infected mothers; using a structured questionnaire. The study was conducted in four health facilities in the North Region of Cameroon from July 2015 to October 2016. HIV- infected children were the cases, and HIV-uninfected children were the controls. One case was matched to nearly 4 controls according to age and sex. A total of 113 HIV-infected mothers of children under 15 years of age were purposively enrolled in the study. A questionnaire was administered to mothers and socio-demographic characteristics were collected. Blood samples were collected from the mother and her child for the determination or confirmation of HIV status. Univariate and multiple logistic regressions were used to assess associations between socio-demographic variables and HIV transmission from mother to child. A total of 113 HIV-infected mothers and 113 children under 15 years of age were enrolled in this study. The majority of the mothers were between the age ranges of 25 years to 34 years. Of the 113 HIV-infected mothers, 69 (61%) were Muslims, 33 (32.1%) were not educated, 88 (77.8%) were unemployed, 80 (70.9%) were married, out of which 49 (61.6%) were engaged in a monogamous union. Of the 113 children (49.6%) were female, 25 (22.1%) were HIV-infected and 88 (77.9%) were HIV-exposed uninfected. At the univariate level, mothers who achieved a primary level of education were less likely to transmit HIV to infants compared to uneducated mothers [OR=0.28; CI (0.08-0.95); p=0.04]; and widows had a higher likelihood of HIV transmission to infants compared to married mothers [OR=4.65; CI (1.26-17.20); p=0.02]. Using multiple logistic regression, the maternal primary education level [aOR=0.32; CI (0.08-0.90); p=0.03] and widowerhood [aOR=7.05; CI (1.49-33.24); p=0.01] remained highly associated with the likelihood of HIV transmission to infants. Uneducated mothers and widows had a higher likelihood of mother-to-child transmission of HIV. Our findings should prompt reinforcement of prevention strategies targeting uneducated women and widows.

Electrocardiographic Abnormalities in Children with Human Immunodeficiency Virus Infection Presenting to the Federal Medical Centre, Umuahia, South-east Nigeria

Background: With the availability of highly active anti-retroviral therapy and attendant increased lifespan of human immunodeficiency virus (HIV)-infected children, late complications of the disease, especially cardiovascular complications have become a growing problem for them. The cardiovascular complications of HIV infection start early in the course of the disease, although may remain asymptomatic until later in life, when they manifest with life-threatening symptoms. The electrocardiogram (ECG) is an invaluable tool in the early diagnosis of these abnormalities. Aim: This study assessed the prevalence and types of ECG abnormalities among HIV-infected children. Patients, Materials and Methods: It was a hospital-based, comparative, cross-sectional study involving randomly selected HIV-infected children (subjects) and age- and gender-matched HIV-uninfected children (controls). Relevant information was obtained through questionnaires, medical records, and physical examination. All participants underwent a 12-lead ECG assessment. Results: Electrocardiographic abnormalities were observed in 42.9% of subjects compared to 17.9% of controls (χ 2 = 8.28; P = 0.004). The participants were about three times more likely to have ECG abnormalities than controls (odds ratio = 3.45, 95% confidence interval = 1.45–8.19). Left ventricular hypertrophy (LVH) was the most common abnormality in the subjects (14.3%), and compared to controls (1.8%), this was significant (χ 2 = 0.032; P = 0.032). Other ECG abnormalities such as right ventricular hypertrophy, T-wave changes, and T-axis abnormalities were more prevalent among subjects (10.7%, 5.4%, and 10.7%, respectively) than controls (1.8%, 3.6%, and 14%, respectively), although not significant. Conclusion: Electrocardiographic abnormalities are quite prevalent among HIV-infected children, with LVH being predominant. It is recommended that routine ECG evaluations be done on HIV-infected children to enable the early detection and prompt management of these problems.

Impact of Drug Exposure on Resistance Selection Following Artemether-Lumefantrine Treatment for Malaria in Children With and Without HIV in Uganda.

Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria. It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK/PD model using data from our previous study of artemether-lumefantrine in HIV-uninfected and HIV-infected children living in a high-transmission region of Uganda. HIV-infected children were on efavirenz-, nevirapine-, or lopinavir-ritonavir-based antiretroviral regimens, with daily trimethoprim-sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42-day follow-up and incorporated genotyping into a time-to-event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy-seven children contributed 364 episodes to the model (186 HIV-uninfected and 178 HIV-infected), with recurrent microscopy-detectable parasitemia detected in 176 episodes by day 42. The final model was a two-compartment model with first-order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir-ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV-uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5-fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV-infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa.

Psychiatric disorders in perinatally HIV-exposed, uninfected children: a systematic review

ABSTRACT The population of perinatally HIV-exposed but uninfected (HEU) children is growing rapidly globally. However, perinatal HIV and antiretroviral (ARV) medicine exposure in HIV-uninfected children has raised concerns about HEU children’s mental well-being. The objective of this study was to systematically review the literature on psychiatric disorders in HEU children. The PRISMA guideline was used as a methodical frame of reference. A systematic search was conducted in 5 databases. Data from the included studies were extracted, and the results were summarized qualitatively. The search identified 1,976 articles of which 105 were eligible for full-text analysis. 13 studies met the inclusion criteria. Eight studies compared psychiatric disorder prevalence in perinatally HIV-infected children with HEU children, and only one study found a difference between the two groups. Three studies found that HEU children had a higher prevalence of psychiatric disorders compared with HIV-unexposed, uninfected (HUU) children. These findings indicate that factors such as psychosocial stress, socioeconomic status, and stigma contribute to the increased risk of mental disorders in HEU children. More research is needed comparing HEU children with HUU children adjusting for potential confounders that might partially explain the higher rates seen in the HIV-exposed population. Prospero ID: CRD42020212420.

Mental health and adaptive functioning among school-aged children living with HIV in Zambia.

BackgroundThe number of children living with HIV (CLWHIV) has been increasing, reflected by lower mortality. However, this change is coupled with higher rates of morbidity, where CLWHIV face considerable challenges, including neurocognitive delays and mental health and behavioral functioning challenges. Despite Sub-Sahara accounting for the highest number of CLWHIV, there is still limited research on the effects of HIV on child mental health and adaptive functioning.MethodMental health and adaptive functioning were assessed in 120 children. The sample included 62 CLWHIV and 58 demographically-matched HIV-uninfected children aged 6–12 years. Mental health was assessed using the Connors, while adaptive functioning was assessed using the Vineland Adaptive Behavioral Scale (VABS).ResultsScores obtained were within average ranges for mental health (T-score 40–59) and adaptive functioning standard scores (70–115). However, CLWHIV had significantly higher mental health problems than uninfected children in executive functioning and aggressiveness (p < 0.05). CLWHIV had lower adaptive functioning scores on the VABS Communication domain although these differences were not significant. In the Daily Living Skills domain, CLWHIV had significantly higher scores than the HIV-uninfected children (p < 0.05). There were no significant differences in the Socialization subdomain. Furthermore, CLWHIV had significantly higher scores on the Maladaptive Behavior scales of the VABS' internalizing and externalizing subdomains.ConclusionChallenges to mental health and adaptive functioning are still pervasive among CLWHIV. These findings support the need to develop support mechanisms for CLWHIV to help address mental health and adaptive functioning problems, especially as they progress into adolescence.

Acute Malaria in Malawian Children and Adults is Characterized by Thrombocytopenia That Normalizes in Convalescence.

BackgroundPlasmodium falciparum malaria has been linked with significant perturbations of the peripheral cell-mediated immune system during acute phase. Some of these changes include lower than normal platelet counts. Although the exact mechanisms that drive thrombocytopenia in P. falciparum malaria are not fully known, a number of hypotheses have been proposed. We conducted two sets of studies with one aimed at determining platelet counts in Malawian children, and the other in adults during acute P. falciparum malaria and a month post treatment.Materials and MethodsWe recruited a total of 113 HIV-uninfected children with acute malaria [n=54 with uncomplicated malaria (UCM), n=30 with severe malarial anemia (SMA), n=29 presenting with cerebral malaria (CM)]. We also recruited 42 HIV-uninfected healthy controls. Out of the 113 participants with malaria, 73 (65%) [n=34 (63%) UCM, n=21 (70%) SMA and n=18 (62%) CM] were successfully followed-up one month after treatment. A 5mL peripheral blood sample was collected for platelet count using HMX Haematological Analyzer analysis both at baseline (acute malaria) and at follow-up a month later. Platelet counts were also determined in blood samples of 106 HIV-uninfected adults, 47 of whom presented with UCM and 29 with severe malaria (SM) and these counts were compared to those of 30 healthy controls. Of the malaria cases, platelet counts for 44 UCM and 21 SM were determined again during follow-up a month after treatment.ResultsIn both children and adults, platelet counts were significantly lower during acute disease compared to the levels in the healthy controls with the lowest levels observed in CM (children) or SM (adults). These lower than normal levels increased close to normal levels a month post treatment.ConclusionP. falciparum malaria in Malawian children and adults was characterized by profound thrombocytopenia which recovered during convalescence.

Proinflammatory and cardiovascular biomarkers are associated with echocardiographic abnormalities in children with HIV taking antiretroviral therapy.

Children with perinatally acquired HIV (PHIV) and taking antiretroviral therapy (ART) have a high prevalence of subclinical cardiac disease. We hypothesized that cardiac disease may be a consequence of dysregulated systemic immune activation driven by HIV infection. We examined cardiovascular and proinflammatory biomarkers and their association with echocardiographic abnormalities in children with PHIV. Cross-sectional analysis of soluble biomarkers from a prospective cohort of children aged 6-16 years with PHIV and age-matched HIV-uninfected comparison group. Cryopreserved plasma samples were used to measure seven soluble biomarkers using multiplex bead assay (Luminex). Multivariable logistic regression assessed how biomarker levels related to cardiac abnormalities. A total of 406 children participated in this study (195 PHIV and 211 HIV-uninfected). Mean [standard deviation (SD)] ages of PHIV and HIV-uninfected participants were 10.7 (2.6) and 10.8 (2.8) years, respectively. Plasma levels of CRP, TNF-α, ST2, VCAM-1 and GDF-15 were significantly higher in the PHIV group compared with uninfected control ( P < 0.001). Among children with PHIV, with one-unit representing one SD in biomarker level, a one-unit increase in CRP and GDF-15, was associated with increased odds of having left ventricular (LV) diastolic dysfunction [adjusted odds ratio (aOR), 1.49 (1.02-2.18; P < 0.040)] and [aOR 1.71 (1.18-2.53; P = 0.006)], respectively. Each one unit increase in GDF-15 was associated with increased odds of LV hypertrophy [aOR 1.84 (95% CI 1.10-3.10; P < 0.021)]. Children with PHIV had higher levels of proinflammatory and cardiovascular biomarkers compared with HIV-uninfected children. Increased CRP and GDF-15 were associated with cardiac abnormalities in children with PHIV.

Intrauterine HIV exposure is associated with linear growth restriction among Ethiopian children in the first 18 months of life.

The role of HIV exposure in determining growth among HIV-uninfected children is debated. We determined whether intrauterine HIV exposure influences linear growth in a cohort of Ethiopian children followed up to 18 months of age in public health facilities in Adama city, Ethiopia. Participants were offspring of pregnant women enrolled in a prospective cohort study that included screening for HIV infection during antenatal care. Growth patterns of HIV-exposed and uninfected (HEU) and HIV-unexposed (HU) children were compared up to 18 months of age, with length-for-age z-score (LAZ) and proportion with stunting as primary outcomes. Multivariable linear and logistic regression models were constructed to investigate the associations between HIV exposure and linear growth, controlling for socio-demographic factors and breastfeeding status. Of 1705 included infants (164 HEU), 1276 remained in follow-up at 18 months. Among HIV-positive mothers, 132 (80.5%) were receiving antiretroviral therapy at enrolment. At the 18-month visit, mean LAZ was -1.08 among HEU children and -0.74 among HU children (p=0.052). Proportions of HEU and HU children with stunting at the 18-month visit were 27.8% and 18.7%, respectively (p=0.010). In multivariable models, HIV exposure was associated with lower LAZ at all follow-up visits, and with stunting at the 18-month visit (adjusted odds ratio 2.29, 95% confidence interval 1.40-3.71). HIV exposure was not associated with weight-related growth outcomes. HEU children in Ethiopia had inferior linear growth compared with HU children, implying that intrauterine HIV exposure impacts early childhood growth in this setting.

Prevalence and Risk Factors for Hepatic Steatosis in Children With Perinatal HIV on Early Antiretroviral Therapy Compared to HIV-Exposed Uninfected and HIV-Unexposed Children.

ObjectivesWe evaluated the prevalence and risk factors for hepatic steatosis in South African children with perinatally acquired HIV (PHIV) who started treatment early and remain on long-term antiretroviral therapy (ART) compared to HIV-uninfected children.DesignA cross-sectional study from April 2019 to October 2021. PHIV, HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children were enrolled from an ongoing cohort study.MethodsAll children had transient elastography (TE) with controlled attenuation parameter (CAP). Liver enzymes, lipogram, insulin and glucose were sent after an overnight fast. Multivariable linear regression analyses identified predictors of CAP. Hepatic steatosis was defined as CAP>248kPa.Results215 children (111 [52%] male; median age 14.1 years; IQR 12.7–14.9) participated in the study, 110 PHIV, 105 HIV-uninfected (36 HEU, 69 HU). PHIV initiated ART at a median age of 2.7 months (IQR 1.8–8.5). Hepatic steatosis prevalence was 9% in PHIV, 3% in HEU and 1% in HU children (p = 0.08). However, 8% of lean (body mass index z-score ≤ +1) PHIV had hepatic steatosis compared to zero lean HEU or HU children (p = 0.03). In multivariable linear regression analysis of all PHIV, body mass index (BMI) z-score was positively associated with CAP (p = 0.001) while CD4 count (p = 0.02) and duration of suppression of HIV viraemia (p = 0.009) were negatively associated with CAP, adjusting for age, sex and ethnicity.ConclusionsHepatic steatosis prevalence was higher in lean PHIV than lean HIV-uninfected South African children. Longer suppression of HIV viraemia and higher CD4 count were associated with lower CAP and might be protective factors for hepatic steatosis in PHIV children.

Immune surveillance for six vaccinable pathogens using paired plasma and dried blood spots in HIV infected and uninfected children in Kinshasa

Child vaccination reduces infant mortality rates. HIV-infected children present higher risk of diseases than non-infected. We report the protection coverage rates for 6 vaccine-preventable diseases in a paediatric population from the Democratic Republic of the Congo (DRC) and the impact of HIV infection, providing the first data on the validity of dried blood samples (DBS) to monitor the immune protection. During 2016–2018 DBS from 143 children/adolescents were collected in Kinshasa (DRC), being 52 HIV-infected. Forty-two had a paired plasma sample. Protective IgG was quantified (VirClia-IgG,VIRCELL) to obtain the optimal cut-off in IgG detection in DBS. ROC curves were generated with R software and statistical analyses with Stata. Protective IgG levels varied across pathogens, not reaching herd immunity. HIV-infected presented lower vaccine protection than uninfected for all analyzed pathogens, except rubella, with statistically significant differences for measles (30.8% vs. 53.8%; p = 0.008) and tetanus (3.8% vs. 22%; p = 0.0034). New cut-offs were calculated when using DBS to improve test performance. We reinforce the necessity to increase pediatric vaccination coverage in Kinshasa, especially in HIV seropositive, with less capacity to maintain adequate antibody levels. DBS were useful to monitor vaccination coverage in seroprevalence studies in resource-limited settings, after optimizing the cut-off value for each pathogen.

Differential CD4+ and CD8+ T cell recognition of mycobacteria antigens in pediatric versus adult TB

Abstract T cells from young children may be limited in capacity to mount pro-inflammatory responses to intracellular pathogens, thus contributing to vulnerability to TB disease. We compared CD4+ and CD8+ T cell cytokine production in response to mycobacterial antigens and mitogen SEB, between Ugandan children &amp;lt;5 yr (PedTB) and adults (ATB) with culture-confirmed pulmonary TB. HIV-uninfected children (n=12) and adults (n=41) had blood drawn for PBMC isolation prior to TB treatment. CD4+ and CD8+ T cell production of IFNγ, IL2, and TNFα in response to ESAT6/CFP10 (EC), ESXJ, PE12/13, PE3, PPE15, and PPE51 peptide pools, and SEB, were assessed by intracellular flow cytometry. Proportions and frequencies of CD4+ and CD8+ T cells producing cytokines were compared using Fisher’s Exact and Kruskal-Wallis tests, respectively, with adjusted p-values &amp;lt;0.05 significant. PedTB and ATB had equivalent CD4+ and CD8+ T cell production of IFNγ, IL2, and TNFα, including polyfunctional responses, to EC. T cell cytokine responses to ESXJ and PPE51 were equivalent; significant differences were noted in CD4+ T cell responses to PE3 and PPE15, and CD8+ T cell responses to PE12/13. Frequencies of CD4+ T cells producing IFNγ or IL2 in response to SEB were lower (p&amp;lt;0.0001) in PedTB versus ATB. Young children with PedTB exhibited adult-like capacity to generate Th-1 cytokines in response to EC, ESXJ, and PPE 51. Pediatric responses to PE3, PPE15, and PE12/13 were impaired, suggesting that the breath of antigen recognition differs between infants and adults with TB. Differential T cell recognition of mycobacterial antigens between adults and children should be considered in development of novel T cell based diagnostics and vaccines targeting pediatric TB. Supporting from grants by NIH: AI157807; HHSN272200900053C