Search

Polymerase chain reaction (PCR) is increasingly used in the diagnosis of soil-transmitted helminth infections. Despite this, few studies have evaluated the impact of different fecal fixatives on the outcome of fecal helminth qPCR analysis, and none have evaluated the effect of commercial parasitology fixatives commonly used in diagnostic laboratories. We fixed dog feces containing Ancylostoma spp. hookworm eggs in zinc polyvinyl alcohol (Zn-PVA) and Total-Fix, and with 70% ethanol (EtOH) as a control. DNA was extracted at timepoints 11, 33, 64, and 94 days and subjected to Ancylostoma spp. quantitative PCR (qPCR). A linear regression model was created to assess the effect of preservative types on the temporal change of qPCR quantification cycle number (Cq) values, accounting for variances among individual animals. Fixation in 70% EtOH least affected Cq values over 94 days. Total-Fix preservation yielded a higher Cq overall, but there was no significant difference compared with 70% EtOH fixation. Fixation in Zn-PVA resulted in significantly (P < 0.001) higher Cq values than 70% EtOH after only 33 days and loss of amplification at 64 days. Consistent with other helminth fixation studies, 70% EtOH performed well in preserving hookworm DNA over 94 days. Total-Fix provided a comparable alternative for qPCR analysis for hookworm. Fixation in Zn-PVA resulted in loss of detectable hookworm DNA at 64 days, as determined by qPCR.

Background Strongyloides stercoralis is considered to be historically endemic in Appalachia and the American South, but recent surveillance data, especially data evaluating strongyloidiasis associated with hospitalization, are lacking in most parts of the United States. Methods We performed a population-based retrospective analysis on strongyloidiasis using the National Inpatient Sample from 2003 to 2018. Geographic distribution of strongyloidiasis associated hospitalization was assessed. Logistic regression was used to identify risk factors associated with strongyloidiasis. Results We identified 6931 hospitalizations associated with strongyloidiasis during the study period (11.8 per million hospitalizations). The rate of strongyloidiasis was highest in the Northeast US region, including the Middle Atlantic division (47.1 cases per million population; adjusted odds ratio, 2.00 [95% confidence interval: 1.58–2.53]), and the East South Central division (27.5 cases per million; adjusted odds ratio, 2.77 [2.02–3.80]). Older age, male sex, nonwhite race/ethnicity (particularly Hispanic and Asian), nonprivate insurance, and residence in neighborhoods with low median income were also associated with strongyloidiasis. Immunocompromising conditions, particularly human immunodeficiency virus infection, were present in 41.3% of hospitalizations with strongyloidiasis. In-hospital death occurred in 7.8% of patients with strongyloidiasis-associated hospitalization. Conclusions Strongyloidiasis-associated hospitalization is rare in the United States but can be associated with increased mortality rate/mortality risk . It occurs more frequently in poor and marginalized populations. Immunocompromised conditions were common among hospitalized patients with strongyloidiasis. Enhanced surveillance efforts are needed to inform health policies for improving the health of at-risk populations.

BackgroundCommunity-onset bacterial coinfection in adults hospitalized with coronavirus disease 2019 (COVID-19) is reportedly uncommon, though empiric antibiotic use has been high. However, data regarding empiric antibiotic use and bacterial coinfection in children with critical illness from COVID-19 are scarce.MethodsWe evaluated children and adolescents aged ResultsOf the 532 patients, 63.3% received empiric antibiotics, but only 7.1% had bacterial coinfection, and only 3.0% had respiratory bacterial coinfection. In multivariable analyses, empiric antibiotics were more likely to be prescribed for immunocompromised patients (adjusted relative risk [aRR], 1.34 [95% confidence interval {CI}, 1.01–1.79]), those requiring any respiratory support except mechanical ventilation (aRR, 1.41 [95% CI, 1.05–1.90]), or those requiring invasive mechanical ventilation (aRR, 1.83 [95% CI, 1.36–2.47]) (compared with no respiratory support). The presence of a pulmonary comorbidity other than asthma (aRR, 2.31 [95% CI, 1.15–4.62]) was associated with bacterial coinfection.ConclusionsCommunity-onset bacterial coinfection in children with critical COVID-19 is infrequent, but empiric antibiotics are commonly prescribed. These findings inform antimicrobial use and support rapid de-escalation when evaluation shows coinfection is unlikely.

Previous studies of severe acute respiratory syndrome coronavirus 2 infection in infants have incompletely characterized factors associated with severe illness or focused on infants born to mothers with coronavirus disease 2019 (COVID-19). Here we highlight demographics, clinical characteristics and laboratory values that differ between infants with and without severe acute COVID-19.Active surveillance was performed by the Overcoming COVID-19 network to identify children and adolescents with severe acute respiratory syndrome coronavirus 2-related illness hospitalized at 62 sites in 31 states from March 15 to December 27, 2020. We analyzed patients7 days to1 year old hospitalized with symptomatic acute COVID-19.We report 232 infants7 days to1 year of age hospitalized with acute symptomatic COVID-19 from 37 US hospitals in our cohort from March 15 to December 27, 2020. Among 630 cases of severe COVID-19 in patients7 days to18 years old, 128 (20.3%) were infants. In infants with severe illness from the entire study period, the median age was 2 months, 66% were from racial and ethnic minority groups, 66% were previously healthy, 73% had respiratory complications, 13% received mechanical ventilation and1% died.Infants accounted for over a fifth of children18 years of age hospitalized for severe acute COVID-19, commonly manifesting with respiratory symptoms and complications. Although most infants hospitalized with COVID-19 did not suffer significant complications, longer term outcomes remain unclear. Notably, 75% of infants with severe disease were6 months of age in this cohort study period, which predated maternal COVID-19 vaccination, underscoring the importance of maternal vaccination for COVID-19 in protecting the mother and infant.

Background Readmission rate is an important quality measure and can inform patient care. However, readmission of S. aureus bacteremia in children requires further research. Methods We performed a population-based longitudinal observational study using the State Inpatient Database from New York, Florida, and Washington, 2009-2015. Children aged 18 years or younger hospitalized with S. aureus bacteremia were included. The outcome of non-elective readmission was assessed by developing Cox proportional hazards regression models. Results Of 1240 children with S. aureus bacteremia, 223 (18.0%) and 351 (28.3%) had non-elective readmission within 30 days and 90 days after discharge, respectively. On multivariable analysis, catheter related infection (hazard ratio, HR: 1.79, 95% confidence interval, CI: 1.31-2.45) was associated with 30-day readmission. The median cost of the original hospitalization for S. aureus bacteremia was $29 914 (interquartile range, IQR: $13 276-$71 284), and that of 30 day readmission was $10 956 (IQR: $5765-$24 753). Conclusions S. aureus bacteremia is associated with a high rate of readmission in children, particularly in those with catheter related infection. Hospitalization with S. aureus bacteremia and readmission are costly. Future research should seek interventions to improve outcomes of S. aureus bacteremia in children, and the results of this study can serve as a benchmark.

Background Strongyloides stercoralis is considered to be historically endemic in Appalachia and the American South, but recent surveillance data, especially data evaluating strongyloidiasis associated with hospitalization, are lacking in most parts of the US. Methods We performed a population-based retrospective analysis on strongyloidiasis using the National Inpatient Sample from 2003-2018. Geographic distribution of strongyloidiasis associated hospitalization was assessed. Logistic regression was used to identify risk factors associated with strongyloidiasis. Results We identified 6931 hospitalizations associated with strongyloidiasis during the study period (11.8 per million hospitalizations). The rate of strongyloidiasis was highest in the US Northeast region including the Middle Atlantic division (47.1 cases per million population, adjusted odds ratio, aOR: 2.00 [95% confidence interval, CI: 1.58-2.53]), and the East South Central division (27.5 cases per million population, adjusted odds ratio, aOR: 2.77 [95% confidence interval, CI: 2.02-3.80]) (Figure 1, Figure 2). Older age, male sex, non-white race/ethnicity particularly Hispanic and Asian, non-private insurance, and residence in neighborhoods with low median income were also associated with strongyloidiasis (Table, Figure 2). Immunocompromising conditions, particularly human immunodeficiency virus infection, were present in 41.3% of hospitalizations with strongyloidiasis (Table). In-hospital death was seen in 7.8% of cases with strongyloidiasis-associated hospitalization. Conclusion Strongyloidiasis-associated hospitalization is rare in the U.S. but can be associated with mortality. It occurs more frequently in poor and marginalized populations. Immunocompromised conditions were common among hospitalized patients with strongyloidiasis. Enhanced surveillance efforts are needed to inform health policies for improving the health of at-risk populations. Disclosures Charlotte V. Hobbs, MD, Biofire (Biomerieux): Advisor/Consultant.

Background Risk factors for MIS-C, a rare but serious hyperinflammatory syndrome associated with SARS-CoV-2 infection, remain unclear. We evaluated household, clinical, and environmental risk factors potentially associated with MIS-C. Methods This investigation included MIS-C cases hospitalized in 14 US pediatric hospitals in 2021. Outpatient controls were frequency-matched to case-patients by age group and site and had a positive SARS-CoV-2 viral test within 3 months of the admission of their matched MIS-C case (Figure 1). We conducted telephone surveys with caregivers and evaluated potential risk factors using mixed effects multivariable logistic regression, including site as a random effect. We queried regarding exposures within the month before hospitalization for MIS-C cases or the month after a positive COVID-19 test for controls. Figure.Patient enrollment timeline. Enrollment scheme for MIS-C case-patients and SARS-CoV-2-positive outpatient controls. MIS-C case-patients were identified through hospital electronic medical records, while two outpatient controls per case were identified through registries of outpatient SARS-CoV-2 testing logs at facilities affiliated with that medical center. Caregivers of outpatient controls were interviewed at least four weeks after their positive test to ensure they did not develop MIS-C after their infection. Results We compared 275 MIS-C case-patients with 494 outpatient SARS-CoV-2-positive controls. Race, ethnicity and social vulnerability indices were similar. MIS-C was more likely among persons who resided in households with >1 resident per room (aOR=1.6, 95% CI: 1.1–2.2), attended a large (≥10 people) event with little to no mask-wearing (aOR=2.2, 95% CI: 1.4–3.5), used public transportation (aOR=1.6, 95% CI: 1.2–2.1), attended school >2 days per week with little to no mask wearing (aOR=2.1, 95% CI: 1.0–4.4), or had a household member test positive for COVID-19 (aOR=2.1, 95% CI: 1.3–3.3). MIS-C was less likely among children with comorbidities (aOR=0.5, 95% CI: 0.3–0.9) and in those who had >1 positive SARS-CoV-2 test at least 1 month apart (aOR=0.4, 95% CI: 0.2–0.6). MIS-C was not associated with a medical history of recurrent infections or family history of underlying rheumatologic disease. Conclusion Household crowding, limited masking at large indoor events or schools and use of public transportation were associated with increased likelihood of developing MIS-C after SARS-CoV-2 infection. In contrast, decreased likelihood of MIS-C was associated with having >1 SARS-CoV-2 positive test separated by at least a month. Our data suggest that additional studies are needed to determine if viral load, and/or recurrent infections in the month prior to MIS-C contribute to MIS-C risk. Medical and family history were not associated with MIS-C in our analysis. Disclosures Natasha B. Halasa, MD, Quidel: Grant/Research Support|Quidel: equipment donation|Sanofi: Grant/Research Support|Sanofi: HAI testing and vaccine donation Mark Hall, MD, Abbvie: Service on a Data Safety Monitoring Board|Kiadis: Licensing income unrelated to the current submission Mary A. Staat, MD, MPH, Centers for Disease Control and Prevention: Grant/Research Support|Cepheid: Grant/Research Support|National Institute of Health: Grant/Research Support|Uptodate: Royalties Pia S. Pannaraj, MD, MPH, AstraZeneca: Grant/Research Support|Pfizer: Grant/Research Support|Sanofi-Pasteur: Advisor/Consultant|Seqirus: Advisor/Consultant Charlotte V. Hobbs, MD, Biofire (Biomerieux): Advisor/Consultant.

Background Pfizer-BioNTech COVID-19 vaccine received emergency use authorization for persons ≥ 16 years in December 2020 and for adolescents 12–15 years in May 2021. Despite the clear benefits and favorable safety profile, vaccine uptake in adolescents has been suboptimal. We sought to assess factors associated with COVID-19 non-vaccination in adolescents 12–18 years of age. Methods Between June 1, 2021 and April 29, 2022, we assessed factors associated with COVID-19 non-vaccination in hospitalized adolescents ages 12–18 years enrolled in the Overcoming COVID-19 vaccine effectiveness network. Demographic characteristics and clinical information were captured through parent interviews and/or electronic medical record abstraction; COVID-19 vaccination was assessed through documented sources. We assessed associations between receipt of the COVID-19 vaccine and demographic and clinical factors using univariate and multivariable logistic regression and estimated adjusted odds ratios (aOR) for each factor associated with non-vaccination. Results Among 1665 hospitalized adolescents without COVID-19, 56% were unvaccinated. Unvaccinated adolescents were younger (median age 15.1 years vs. 15.4 years, p Conclusions Efforts to increase COVID-19 vaccination of adolescents should focus on persons with geographic, socioeconomic, and medical risk factors associated with non-vaccination.

HIV and malaria geographically overlap. Trimethoprim–sulfamethoxazole (TMP-SMX) is a drug widely used in HIV-exposed uninfected and infected children in malaria-endemic areas, and is known to have antimalarial effects. Further study in terms of antimalarial impact and effect on development of malaria-specific immunity is therefore essential. Using rodent malaria models, we previously showed that repeated Plasmodium exposure during TMP-SMX administration, or chemoprophylaxis vaccination (CVac), induces CD8 T-cell–dependent preerythrocytic immunity. However, humoral immune responses have been shown to be important in models of preerythrocytic immunity. Herein, we demonstrate that antibody-mediated responses contribute to protective immunity induced by CVac immune sera using TMP-SMX in models of homologous, but not heterologous, parasite species. Clinical studies must account for potential anti-Plasmodium antibody induced during TMP-SMX prophylaxis.

Background Race/ethnicity is currently not considered a risk factor for bronchiolitis, except for indigenous populations in Western countries. A better understanding of the potential impact of race/ethnicity can inform programs, policies, and practices related to bronchiolitis. Methods We performed a population-based, longitudinal, observational study using the State Inpatient Database from New York State in the United States. Infants born between 2009 and 2013 at term without comorbidities were followed for the first 2 years of life, up to 2015. We calculated the cumulative incidences among different race/ethnicity groups, and evaluated the risks by developing logistic regression models. Results Of 877 465 healthy, term infants, 10 356 infants were hospitalized with bronchiolitis. The overall cumulative incidence was 11.8 per 1000 births. The cumulative incidences in non-Hispanic White, non-Hispanic Black, Hispanic, and Asian infants were 8.6, 15.4, 19.1, and 6.5 per 1000 births, respectively. In a multivariable analysis adjusting for socioeconomic status, the risks remained substantially high among non-Hispanic Black (odds ratio, 1.42; 95% confidence interval [CI], 1.34–1.51) and Hispanic infants (odds ratio, 1.77; 95% CI, 1.67–1.87), whereas being of Asian race was protective (odds ratio, .62; 95% CI, .56–.69). Conclusions The risks of bronchiolitis hospitalization in the first 2 years of life were substantially different by race/ethnicity, with Hispanic and Black infants having the highest rates of hospitalization. Further research is needed to develop and implement culturally appropriate public health interventions to reduce racial and ethnic health disparities in bronchiolitis.

Neutralization capacity of antibodies against Omicron after a prior SARS-CoV-2 infection in children and adolescents is not well studied. Therefore, we evaluated virus-neutralizing capacity against SARS-CoV-2 Alpha, Beta, Gamma, Delta and Omicron variants by age-stratified analyses (5 years of age. As expected, convalescent pediatric COVID-19 and MIS-C cohorts demonstrate higher neutralization titers than hospitalized acute COVID-19 patients. Overall, children and adolescents show some loss of cross-neutralization against all variants, with the most pronounced loss against Omicron. In contrast to SARS-CoV-2 infection, children vaccinated twice demonstrated higher titers against Alpha, Beta, Gamma, Delta and Omicron. These findings can influence transmission, re-infection and the clinical disease outcome from emerging SARS-CoV-2 variants and supports the need for vaccination in children.

Ocular toxocariasis can be vision threatening, and is commonly reported from tropical or subtropical regions. Knowledge of clinical manifestations from the United States, particularly in underserved areas such as the American South, is lacking. We report three cases of ocular toxocariasis in individuals from the Mississippi Delta, a rural community with prevalent poverty. Visual acuity was severely affected in two of the three cases. Increased awareness of ocular toxocariasis, which may have under-recognized frequency, will contribute to prompt diagnosis and treatment, which will ultimately improve patient health in the region.

Although the epidemiology of immunocompromising condition in children has evolved over time, updated epidemiology of pediatric pneumocystis infection in the United States is not available.We performed a retrospective analysis using the Kids' Inpatient Database, a nationally representative sample of US pediatric hospital discharges collected in 1997, 2000, 2003, 2006, 2009 and 2012. Pneumocystis cases were identified using International Classification of Diseases, Ninth Revision, Clinical Modification, code 136.3 among children 0-18 years of age. Demographic data of cases with and without mortality were compared.We identified 1902 [standard error (SE): 95] pneumocystis cases during the study period. The pneumocystis hospitalization rate decreased from 7.5 (SE: 0.91) to 2.7 (SE: 0.31) per a million US children from 1997 to 2012 (63.2% decrease). Cases with HIV infection decreased from 285 (SE: 56) cases in 1997 to 29 (SE: 7) cases in 2012, whereas hematologic malignancy and primary immunodeficiency became more prominent. Infants were the most commonly affected [510 cases (SE: 40)]. All-cause in-hospital mortality was 11.7% (SE: 1.3%) and was particularly high among cases with hematopoietic stem cell transplant [32.4%(SE: 7.1%); P0.001].Pneumocystis infection in children showed a marked decrease from 1997 to 2012 in the United States, largely driven by the reduction in HIV-associated cases, and cases with non-HIV illnesses became more prominent. Hematopoietic stem cell transplant-associated cases had particularly high mortality. Clinicians should be aware of high-risk groups that may benefit from chemoprophylaxis, particularly in infancy.

Surveillance for soil-transmitted helminths, strongyloidiasis, cryptosporidiosis, and giardiasis was conducted in Mississippi, USA. PCR performed on 224 fecal samples for all soil-transmitted helminths and on 370 samples for only Necator americanus and Strongyloides stercoralis identified 1 S. stercoralis infection. Seroprevalences were 8.8% for Toxocara, 27.4% for Cryptosporidium, 5.7% for Giardia, and 0.2% for Strongyloides parasites.

Background It is unclear how acute coronavirus disease 2019 (COVID-19)-directed therapies are used in children with life-threatening COVID-19 in US hospitals. We described characteristics of children hospitalized in the intensive care unit or step-down unit (ICU/SDU) who received COVID-19-directed therapies and the specific therapies administered. Methods Between March 15, 2020 and December 27, 2020, children, No therapies for acute coronavirus disease 2019 (COVID-19) have been tested in children to establish effectiveness. Despite this, across 48 hospitals, 235/424 children (55%) admitted to the intensive care or step-down unit with COVID-19 received directed therapies. Systemic steroids and remdesivir were most commonly administered, with use rising from March 2020 to December 2020.

Background COVID-19 testing data in children from different backgrounds such as race/ethnicity can guide the strategies for controlling the pandemic. In this study, we aimed to characterize the percent positivity of real time reverse transcriptase polymerase chain reaction (RT-PCR) testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) among children with different race/ethnicity in Mississippi, a state with historic racial health disparity. Methods We performed a retrospective study using a deidentified COVID-19 registry abstracted from the electronic health record at the University of Mississippi Medical Center, the only academic institution in the state encompassing the main university hospitals and ambulatory sites statewide. Children aged 18 years or younger who underwent RT-PCR for SARS-CoV-2 between 11 March 2020 and 31 May 2020 were included in the study. The primary outcome of interest was positive SARS-CoV-2 RT-PCR test, and the primary exposure of interest was race/ethnicity. Multivariable analysis was performed by developing a logistic regression model. Results Of 1838 children who underwent SARS-CoV-2 RT-PCR testing, 162 tested positive, corresponding to percent positivity of 8.8%. Non-Hispanic white children had percent positivity of 2.4%, which was substantially lower than that of non-white children (9.7%, 28.6%, and 11.5% for non-Hispanic black, Hispanic, and other race/ethnicity children, respectively) (Table). Older children (particularly those aged 10–18 years) also had higher percent positivity (Table, Figure). The risks associated with non-white race/ethnicity remained substantial after adjusting for insurance status, which was used as a surrogate for socioeconomic status (Figure). Table Figure Conclusion We found a striking difference in percent positivity by race/ethnicity among children, suggesting inadequate allocation of testing resources to this population. Higher percent positivity among school age children may also have particular public health implications, considering their school attendance. We argue that minority children should not be left behind in data analysis, research, targeted testing and transmission reduction measures. Disclosures All Authors: No reported disclosures

Laboratory data and prior pediatric reports indicate that HIV protease inhibitor (PI)–based antiretroviral therapy (ARV) kills gametocytes and reduces rates of gametocytemia, but not asymptomatic parasitemia, in a high malaria-transmission area. To determine whether ARV regimen impacts these rates in areas with less-intense malaria transmission, we compared asymptomatic parasitemia and gametocytemia rates in HIV-infected children by ARV regimen in Lilongwe, Malawi, an area of low-to-moderate transmission intensity. HIV PI lopinavir–ritonavir (LPV–rtv) ARV– or non-nucleoside reverse transcriptase inhibitor nevirapine ARV–treated children did not differ in the rates of polymerase chain reaction-detected asymptomatic parasitemia (relative risk [RR] 0.43 95% confidence interval [CI] [0.16, 1.18], P value 0.10) or microscopically detected gametocytemia with LPV–rtv ARV during symptomatic malaria (RR 0.48 95% CI [0.22,1.04] P value 0.06). LPV–rtv ARV was not associated with reduced rates of asymptomatic parasitemia, or gametocytemia on days of symptomatic malaria episodes, in HIV-infected children. Larger studies should evaluate whether ARV impacts transmission.

Background Staphylococcus aureus bacteremia is associated with substantial mortality and morbidity. Readmission is becoming increasingly recognized as an important quality measure and can inform optimal patient care. We previously reported readmission analyses in the setting of S. aureus bacteremia in the adult population. However, readmission has not been characterized in children. Methods We performed a population-based longitudinal observational study using the State Inpatient Database from New York, Florida, and Washington states, 2009–2015. Children aged 18 years or younger hospitalized with S. aureus bacteremia were included. The outcome of unplanned readmission within 30 days and 90 days of discharge was assessed by developing Cox proportional hazards regression models. Results Of 1240 children that were included in the analysis, 18% (223 children) had unplanned readmission within 30 days after discharge, and 28.3% were readmitted within 90 days. On multivariable analysis, children with underlying conditions of hematologic malignancy (hazard ratio, HR: 1.67, 95% confidence interval, CI: 1.09–2.56) and catheter related infection (HR: 1.79, 95%CI: 1.31–2.45) had higher hazards of readmission, whereas coexisting skin and soft tissue infection (HR: 0.42, 95%CI: 0.24–0.71) was associated with a lower rate of readmission (Table, Figure). In addition to these, solid tumor malignancy and longer length of stay during the original hospitalization were associated with higher hazards of 90-day readmission. The median cost of the original hospitalization for S. aureus bacteremia was $29914 (interquartile range, IQR: $13276-$71284), and that of 30-day readmission was $10956 (interquartile range, IQR: $5765-$24753). Table Figure Conclusion Unplanned readmission is common and costly among children who survived S. aureus bacteremia, occurring in 18% and 28.3% within 30 and 90 days after discharge, respectively. Those with malignancies and catheter related infection had higher hazards of unplanned readmission. Further research is needed to identify optimal interventions to reduce readmission rates associate with S. aureus bacteremia in children. Disclosures All Authors: No reported disclosures

Background Chemoprophylaxis vaccination with sporozoites (CVac) with chloroquine induces protection against a homologous Plasmodium falciparum sporozoite (PfSPZ) challenge, but whether blood-stage parasite exposure is required for protection remains unclear. Chloroquine suppresses and clears blood-stage parasitemia, while other antimalarial drugs, such as primaquine, act against liver-stage parasites. Here, we evaluated CVac regimens using primaquine and/or chloroquine as the partner drug to discern whether blood-stage parasite exposure impacts protection against homologous controlled human malaria infection. Methods In a Phase I, randomized, partial double-blind, placebo-controlled study of 36 malaria-naive adults, all CVac subjects received chloroquine prophylaxis and bites from 12–15 P. falciparum–infected mosquitoes (CVac-chloroquine arm) at 3 monthly iterations, and some received postexposure primaquine (CVac-primaquine/chloroquine arm). Drug control subjects received primaquine, chloroquine, and uninfected mosquito bites. After a chloroquine washout, subjects, including treatment-naive infectivity controls, underwent homologous, PfSPZ controlled human malaria infection and were monitored for parasitemia for 21 days. Results No serious adverse events occurred. During CVac, all but 1 subject in the study remained blood-smear negative, while only 1 subject (primaquine/chloroquine arm) remained polymerase chain reaction–negative. Upon challenge, compared to infectivity controls, 3/3 chloroquine arm subjects displayed delayed patent parasitemia (P = .01) but not sterile protection, while 3/11 primaquine/chloroquine subjects remained blood-smear negative. Conclusions CVac-primaquine/chloroquine is safe and induces sterile immunity to P. falciparum in some recipients, but a single 45 mg dose of primaquine postexposure does not completely prevent blood-stage parasitemia. Unlike previous studies, CVac-chloroquine did not produce sterile immunity. Clinical Trials Registration NCT01500980.

BACKGROUND. We previously used mathematical modeling to predict reduced malaria incidence in children with protease inhibitor- (PI), compared with non-nucleoside reverse transcriptase inhibitor (NNRTI-), based highly-active antiretroviral therapy (HAART), in moderate to high malaria transmission areas. These effects were accounted for, in part, by pharmacokinetic (PK) interactions between PIs and artemether-lumefantrine (AL). OBJECTIVE: Because of potentially reduced malaria transmission reservoirs in HIV-infected children due to PI/AL PK interactions impacting non-HIV-infected children, we estimate the antimalarial benefit of PI-based HAART in all children, and in HIV-infected children only residing in low to moderate malaria transmission areas. DESIGN: A dynamic model of malaria transmission was developed to evaluate the pharmacokinetic interaction of PI-based HAART with the antimalarial, artemether-lumefantrine (AL) for preventing malaria. METHODS. To evaluate the benefit of HIV PI-based HAART on malaria incidence, a malaria transmission model with varying degrees of HIV newborn prevalence was developed using recent pediatric clinical trial data in Lilongwe Malawi. RESULTS. Comparing situations of low to high HIV newborn prevalence, and low to moderate malaria transmission intensities, our model predicts the combination of PI-based HAART with AL-treated malaria prevents 0.04-24.8, and 0.05-34.5 annual incidences of malaria overall per 1000 children, and saves 0.003-1.66, and 0.003-2.30 DALYs per 1000 children, respectively. When incorporating seasonality, 0.01-7.3, and 0.01-5.9 annual incidences of malaria overall per 1000 children, and 0.0-0.5, and 0.001-0.41 DALYs per 100 children, are prevented, respectively. CONCLUSIONS. In low to moderate malaria transmission intensity areas, PI-based HAART may reduce malaria events in children when AL is used.

Trimethoprim–sulfamethoxazole (TMP–SMX) prophylaxis in HIV-uninfected, exposed (HUE) children variably reduces clinical malaria burden despite antifolate resistance, but data regarding achieved serum levels and adherence are lacking. Serum samples from 70 HUE children aged 3–12 months from Rakai, Uganda, enrolled in an observational study were assayed for random SMX levels using a colorimetric assay. Adherence with TMP–SMX prophylaxis data (yes/no) was also collected. Of 148 visits with concurrent SMX levels available, 56% had self-reported adherence with TMP–SMX therapy. Among these 82 visits, mean (standard deviation) level was 19.78 (19.22) µg/mL, but 33% had SMX levels below half maximal inhibitory concentrations (IC50) for Plasmodium falciparum with some, but not all, of the reported antifolate resistance mutations reported in Uganda. With TMP–SMX prophylaxis, suboptimal adherence is concerning. Sulfamethoxazole levels below IC50s required to overcome malaria parasites with multiple antifolate resistance mutations may be significant. Further study of TMP–SMX in this context is needed.

Background Race/ethnicity is currently not considered a risk factor for bronchiolitis, except for indigenous populations in western countries. We sought to determine the incidence of hospitalization with bronchiolitis among different races/ethnicities, because such information can lead to more tailored preventive care. Methods We performed a population-based longitudinal observational study using the State Inpatient Database from New York state. Infants born between 2009 and 2013 at term without comorbidities were followed for the first 2 years of life, up to 2015. We calculated incidence among different race/ethnicity groups, and evaluated risks by developing Cox proportional hazards regression models. Results Of 877,465 healthy term infants, 10 356 infants were hospitalized with bronchiolitis. Overall, incidence was 11.8 per 1,000 births. Substantial difference in infants born in different seasons was observed (Figure 1). The incidence in non-Hispanic white, non-Hispanic black, Hispanic, and Asian infants was 8.6, 15.4, 19.1, and 6.5 per 1,000 births, respectively (table). On multivariable analysis adjusting for socioeconomic status, the risks remained substantially high among non-Hispanic black (hazard ratio [HR] 1.42, 95% confidence interval [CI]: 1.34–1.51) and Hispanic infants (HR 1.77, 95% CI: 1.67–1.87), particularly beyond 2–3 months of age, whereas Asian race was protective (HR 0.62, 95% CI: 0.56–0.69) (Figure 2, 3). Conclusion The risks of bronchiolitis hospitalization in the first 2 years of life was substantially higher among infants with non-Asian minority infants, particularly beyond 2–3 months of age. Further research efforts to identify effective public health interventions in each race/ethnic groups with varied socioeconomic status, such as improvement in access to care and anticipatory guidance, is warranted to overcome health disparity. Disclosures All authors: No reported disclosures.

Background Although epidemiology of immunocompromising condition in children has evolved over time, updated epidemiology of pediatric pneumocystis infection in the United States is not available. Methods We performed a retrospective analysis using the Kids’ Inpatient Database, a nationally representative sample of US pediatric hospital discharges collected in 1997, 2000, 2003, 2006, 2009, and 2012. Pneumocystis cases were identified using International Classification of Diseases, Ninth Revision, Clinical Modification code 136.3 among children aged 0–18 years. Demographic data of cases with and without mortality were compared. Results We identified 1,902 (standard error, SE: 95) pneumocystis cases during the study period. The pneumocystis hospitalization rate decreased from 7.5 (SE: 0.91) to 2.7 (SE: 0.31) per a million US children from 1997 to 2012 (63.2% decrease). Cases with human immunodeficiency virus (HIV) infection decreased from 285 (SE: 56) cases in 1997 to 29 (SE: 7) cases in 2012, although non-HIV-associated cases remained relatively stable. After 2009, HIV was the third common underlying disorder after hematologic malignancy and primary immunodeficiency. All-cause in-hospital mortality was 11.7% (SE: 1.3%) and was particularly high among cases with hematopoietic stem cell transplant (HSCT) (32.4% [SE: 7.1%]) (P < 0.001). Conclusion Pneumocystis infection in children showed a marked decrease from 1997 to 2012 in the United States, largely driven by the reduction in HIV-associated cases. Non-HIV illnesses including hematologic malignancy and primary immunodeficiency became prominent underlying conditions over time. HSCT-associated cases had particularly high mortality. Non-HIV conditions should be the target for primary and secondary prevention in reducing the disease burden. Disclosures All authors: No reported disclosures.

HIV and malaria overlap geographically, but the full impact of different antiretrovirals (ARVs) on malaria remains poorly understood. We examined the antimalarial activity of the HIV protease inhibitors (PI) lopinavir and saquinavir and the non-nucleoside reverse transcriptase inhibitor (NNRTIs) nevirapine on Plasmodium falciparum liver stages. Our results demonstrate that the HIV PI lopinavir inhibits liver stage parasites at clinically relevant concentrations, that is, at drug levels achieved in HIV-infected patients on standard dosing regimens. Because drugs that inhibit liver stages target parasites when they are present in lower numbers, these results might have implications for eradication efforts.

Background. Millions of individuals being treated for human immunodeficiency virus (HIV) live in malaria-endemic areas, but the effects of these treatments on malaria transmission are unknown. While drugs like HIV protease inhibitors (PIs) and trimethoprim-sulfamethoxazole (TMP-SMX) have known activity against parasites during liver or asexual blood stages, their effects on transmission stages require further study. Methods. The HIV PIs lopinavir and saquinavir, the nonnucleoside reverse-transcriptase inhibitor nevirapine, and the antibiotic TMP-SMX were assessed for activity against Plasmodium falciparum transmission stages. The alamarBlue assay was used to determine the effects of drugs on gametocyte viability, and exflagellation was assessed to determine the effects of drugs on gametocyte maturation. The effects of drug on transmission were assessed by calculating the mosquito oocyst count as a marker for infectivity, using standard membrane feeding assays. Results. Lopinavir and saquinavir have gametocytocidal and transmission blocking activities at or approaching clinically relevant treatment levels, while nevirapine does not. TMP-SMX is not gametocytocidal, but at prophylactic levels it blocks transmission. Conclusions. Specific HIV treatments have gametocyte killing and transmission-blocking effects. Clinical studies are warranted to evaluate these findings and their potential impact on eradication efforts.

Trimethoprim-sulfamethoxazole (TMP-SMX) is widely used in malaria-endemic areas in human immunodeficiency virus (HIV)-infected children and HIV-uninfected, HIV-exposed children as opportunistic infection prophylaxis. Despite the known effects that TMP-SMX has in reducing clinical malaria, its impact on development of malaria-specific immunity in these children remains poorly understood. Using rodent malaria models, we previously showed that TMP-SMX, at prophylactic doses, can arrest liver stage development of malaria parasites and speculated that TMP-SMX prophylaxis during repeated malaria exposures would induce protective long-lived sterile immunity targeting pre-erythrocytic stage parasites in mice. Using the same models, we now demonstrate that repeated exposures to malaria parasites during TMP-SMX administration induces stage-specific and long-lived pre-erythrocytic protective anti-malarial immunity, mediated primarily by CD8+ T-cells. Given the HIV infection and malaria coepidemic in sub-Saharan Africa, clinical studies aimed at determining the optimum duration of TMP-SMX prophylaxis in HIV-infected or HIV-exposed children must account for the potential anti-infection immunity effect of TMP-SMX prophylaxis.

Introduction: Using the data of a trial on cotrimoxazole (CTX) cessation, we investigated the effect of different antiretroviral therapy (ART) regimens on the incidence of clinical malaria. Methods: During the cotrimoxazole cessation trial (ISRCTN44723643), HIV-infected Ugandan adults with CD4+ at least 250 cells/μl were randomized to receive either CTX prophylaxis or placebo and were followed for a median of 2.5 years. Blood slides for malaria microscopy were examined at scheduled visits and at unscheduled visits when the participant felt unwell. CD4+ cell counts were done 6-monthly. Malaria was defined as fever with a positive blood slide. ART regimens were categorized as nucleoside reverse transcriptase inhibitor (NRTI) only, non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing or protease inhibitor containing. Malaria incidence was calculated using random effects Poisson regression to account for clustering of events. Results: Malaria incidence in the three ART regimen groups was 9.9 (3.6-27.4), 9.3 (8.3-10.4), and 3.5 (1.6-7.6) per 100 person-years, respectively. Incidence on protease inhibitors was lower than that on the other regimens with the results just reaching significance (adjusted rate ratio 0.4, 95% confidence interval = 0.2–1.0, comparing with NNRTI regimens). Stratification by CTX/placebo use gave similar results, without evidence of an interaction between the effects of CTX/placebo use and ART regimen. There was no evidence of an interaction between ART regimen and CD4+ cell count. Conclusion: There was some evidence that protease inhibitor-containing ART regimens may be associated with a lower clinical malaria incidence compared with other regimens. This effect was not modified by CTX use or CD4+ cell count. The antimalarial properties of protease inhibitors may have clinical and public health importance.

We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium liver stages in rodent malarias and in vitro in P. falciparum. Since clinically relevant levels are better achieved in the non-human-primate model, and since Plasmodium knowlesi is an accepted animal model for the study of liver stages of malaria as a surrogate for P. falciparum infection, we investigated the antimalarial activity of these drugs on Plasmodium knowlesi liver stages in rhesus macaques. We demonstrate that TMP-SMX and TMP-SMX+LPV-RTV (in combination), but not LPV-RTV alone, inhibit liver stage parasite development. Because drugs that inhibit the clinically silent liver stages target parasites when they are present in lower numbers, these results may have implications for eradication efforts.

Human immunodeficiency virus (HIV) infection and Plasmodium falciparum malaria overlap geographically, especially in sub-Saharan Africa. Studies suggest that, in coinfected patients, each disease exacerbates the other [1]. We have previously shown that HIV protease inhibitors (HIV PIs) inhibit Plasmodium liver stage development [2]. In contrast to HIV PIs, the effect of nonnucleoside reverse transcriptase inhibitors (NNRTIs) on Plasmodium liver stages remains uncharacterized. The World Health Organization (WHO) recommends HIV management with combination antiretroviral therapy (ART), generally including an NNRTI and 2 nucleoside reverse transcriptase inhibitors (NRTIs), or second-line therapy including an HIV PI and 2 NRTIs [3, 4]. Because these drugs are used in HIV-infected patients in malaria-endemic areas, effects of various ART components on Plasmodium requires further investigation. Separately, trimethoprim-sulfamethoxazole (TMP-SMX), when used for opportunistic infection prophylaxis in HIV-exposed infants and HIV-infected patients [5, 6], reduces clinical malaria [1]. However, the effect of TMP-SMX on Plasmodium liver stages requires further evaluation as it is unclear whether TMP-SMX liver stage effect contributes to the reduction of clinical malaria episodes observed in studies. This will have implications for eradication. Plasmodium parasites have a complex life cycle. The female Anopheles mosquito infects the mammalian host with sporozoites, the infective form of the parasite, which travel to the liver. There they invade hepatocytes and develop into liver stages, or exoerythrocytic forms (EEFs). These events constitute an asymptomatic period of infection and a time when parasite numbers are low. Infected hepatocytes release merozoites, which invade erythrocytes, initiating the phase of infection responsible for all clinical symptoms of malaria [7]. Most antimalarials target this symptomatic asexual blood stage. However, there is a need for drugs that target liver stages: preventing malaria infection by targeting liver stages will impact transmission and contribute to malaria eradication efforts. Here, we describe our investigations of NNRTIs (efavirenz, etravirine, and nevirapine) and TMP-SMX effects on liver stages of malaria parasites.

While antiretroviral drugs (ARV) are generally considered safe, they have been associated with mitochondrial toxicity in experimental and clinical studies 1–4 and they have been linked to a wide range of clinical problems in children including lactic acidosis, acute liver injury and myopathy5. The focus of mitochondrial toxicity investigations has been on the effects of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) effects on oxidative phosphorylation (OXPHOS) through inhibition of the mitochondrial polymerase gamma6. In children, there is evidence that exposure to NRTIs in utero and in the newborn period causes lactic acidosis and abnormal mitochondria number and function7 and that dysfunction may persist after the exposure ends, potentially affecting growth and development8. Despite the fact that many pathways of intermediary metabolism (including fatty acid oxidation, organic acid metabolism and amino acid metabolism) are dependent on normal OXPHOS and dysfunction of these steps can lead to clinical problems such as those seen in ARV-exposed patients 9,10, there is little known in humans about whether these pathways are points of ARV toxicity. In the last decade, the number of metabolic disorders (or inborn errors of metabolism) included in newborn screening (NBS) panels in the United States has increased dramatically due to the implementation of tandem mass spectrometry (MS/MS) 11. MS/MS is a sensitive and specific method for the quantitation of the substrates and products of intermediary metabolism, including acylcarnitines and amino acids, abnormal levels of which indicate dysfunctional fatty acid oxidation/organic acid metabolism or amino acid metabolism, respectively12. Levels of acylcarnitines and amino acids can also be abnormal in patients with inherited mitochondrial diseases representing secondary dysfunction in metabolic pathways biochemically related to OXPHOS 13. We hypothesized that HIV/ARV-exposed children would have disruption of metabolic pathways that are normally dependant on functional OXPHOS leading to a greater incidence of positive newborn metabolic screens compared to the general newborn population. We then specifically assessed fatty acid oxidation/organic acid metabolism in a group of HIV/ARV-exposed infants and a group of HIV-exposed/ARV-unexposed infants by measuring acylcarnitine levels in plasma.

Antiretroviral therapy in children has expanded dramat- ically in low-income and middle-income countries. The World Health Organization revised its pediatric HIV guidelines to recom- mend initiation of antiretroviral therapy in all HIV-infected children younger than 2 years, regardless of CD4 count or clinical stage. The number of children starting life-long antiretroviral therapy should therefore expand dramatically over time. The early initiation of antiretroviral therapy has indisputable benefits for children, but there is a paucity of definitive information on the potential adverse effects. In this review, a comprehensive literature search was conducted to provide an overview of our knowledge about the complications of treating pediatric HIV. Antiretroviral therapy in children, as in adults, is associated with enhanced survival, reduction in opportunistic infections, improved growth and neurocognitive function, and better quality of life. Despite antiretroviral therapy, HIV-infected children may continue to lag behind their uninfected peers in growth and development. In addition, epidemic concurrent conditions, such as tuberculosis, malaria, and malnutrition, can combine with HIV to yield more rapid disease progression and poor treatment outcomes. Additional studies are required to evaluate the long-term effects of antiretroviral therapy in HIV-infected infants, children, and adolescents, particularly in resource-limited countries where concomitant infections and conditions may enhance the risk of adverse effects. There is an urgent need to evaluate drug-drug interactions in children to determine optimal treatment regimens for both HIV and coinfections.

Recent studies have demonstrated that human immunodeficiency virus (HIV) protease inhibitors (PIs) exert inhibitory effects on erythrocytic stages of the human-malaria parasite Plasmodium falciparum in vitro and on erythrocytic stages of the rodent-malaria parasite Plasmodium chabaudi in vivo. Although it remains unclear how HIV PIs inhibit the parasite, the effect seen on parasite development in the erythrocytic stages is potent. The effect on preerythrocytic stages has not yet been investigated. Using the rodent parasite Plasmodium berghei, we screened a panel of HIV PIs in vitro for effects on the preerythrocytic stages. Our data indicated that the HIV PIs lopinavir and saquinavir affect preerythrocytic-stage parasite development in vitro. We then evaluated the effect of HIV PIs on preerythrocytic stages in vivo using the rodent parasite Plasmodium yoelii. We found that lopinavir/ritonavir had a dose-dependent effect on liver-stage parasite development. Given that sub-Saharan Africa is where the HIV/AIDS pandemic intersects with malaria, these results merit analysis in clinical settings.

Plasmodium vivax malaria causes significant morbidity and mortality worldwide, and only one drug is in clinical use that can kill the hypnozoites that cause P. vivax relapses. HIV and P. vivax malaria geographically overlap in many areas of the world, including South America and Asia. Despite the increasing body of knowledge regarding HIV protease inhibitors (HIV PIs) on P. falciparum malaria, there are no data regarding the effects of these treatments on P. vivax's hypnozoite form and clinical relapses of malaria. We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium actively dividing liver stages in rodent malarias and in vitro in P. falciparum, but effect against Plasmodium dormant hypnozoite forms remains untested. Separately, although other antifolates have been tested against hypnozoites, the antibiotic trimethoprim sulfamethoxazole, commonly used in HIV infection and exposure management, has not been evaluated for hypnozoite-killing activity. Since Plasmodium cynomolgi is an established animal model for the study of liver stages of malaria as a surrogate for P. vivax infection, we investigated the antimalarial activity of these drugs on Plasmodium cynomolgi relapsing malaria in rhesus macaques. Herein, we demonstrate that neither TMP-SMX nor LPV-RTV kills hypnozoite parasite liver stage forms at the doses tested. Because HIV and malaria geographically overlap, and more patients are being managed for HIV infection and exposure, understanding HIV drug impact on malaria infection is important.

PURPOSE OF REVIEW: We review the current literature supporting adoption of higher CD4 thresholds for initiation of antiretroviral treatment and survey progress in adoption of early treatment policies in resource-limited settings. We highlight some of the challenges and opportunities implementation of early treatment will bring. RECENT FINDINGS: The initial success of combination antiretroviral treatment resulted in the recommendation to treat early all individuals with HIV. However the gradual realization that antiretroviral treatment was associated with toxicity led to a more tempered approach. Recent cohort studies and some clinical trials have shown that delaying treatment is associated with increased morbidity and mortality. SUMMARY: Early treatment is routinely practiced in developed countries. Now early treatment is being adopted as a strategy in many resource-limited settings. The implications of this policy shift are not known but we predict early treatment will have important consequences for the health system the individual and the community. Whereas these consequences will bring significant challenges the increased numbers of HIV-infected individuals on treatment will result in many new opportunities - antiretroviral treatment will become less expensive systems to deliver chronic care will be strengthened and the policy shift will focus greater attention on pregnant women and children. Finally some authors postulate that early treatment may impact HIV transmission.