Increased Risk of Serious Bacterial Infections Due to Maternal Immunosuppression in HIV-Exposed Uninfected Infants in a European Country

Abstract Background Perinatal HIV transmission has dramatically decreased with combination antiretroviral (ARV) regimens, but complications among HIV-exposed uninfected (HEU) children, such as microcephaly, warrant ongoing surveillance. Methods We evaluated HEU children enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study, a prospective cohort study conducted by the PHACS network at 22 US sites. Microcephaly was defined using 2000 CDC Growth z-scores for head circumference (HC) measured at 6–36 months of age (z-score <−2) and using Nellhaus standards (<2nd percentile) after age 3 (“SMARTT” criteria), or using Nellhaus standards across all ages. Modified Poisson regression models were fit to obtain relative risks (RRs) for associations between in utero ARV exposure and microcephaly status, adjusted for potential confounders. Sensitivity analyses were conducted. Neurodevelopmental functioning was compared between HEU children with vs. without microcephaly. Results Among 3055 SMARTT participants enrolled as of April 2017 with a HC measurement over 5.1 years median follow-up (IQR = 3.0, 7.2), 159 (5.2%, 95% CI: 4.4–6.1%) had microcephaly identified by Nellhaus criteria and 70 (2.3%, 95% CI: 1.8–2.9%) by SMARTT criteria. In adjusted models, in utero exposure to efavirenz (4.7% exposed) was associated with increased risk of microcephaly by both Nellhaus standards (aRR=2.02, 95% CI: 1.16, 3.51) and SMARTT criteria (adjusted RR = 2.56, 95% CI: 1.22, 5.37). These associations were more pronounced among children exposed to combination regimens of efavirenz which included zidovudine+lamivudine than those including tenofovir+emtricitabine (Figure 1). Associations of microcephaly with efavirenz persisted in several sensitivity analyses (Figure 2). Protective associations were observed for darunavir exposure (aRR = 0.50; 95% CI: 0.24, 1.00). HEU children with microcephaly had lower mean scores on neurodevelopmental assessments at ages 1 and 5 years and higher prevalence of impairment than those without microcephaly. Conclusion Efavirenz exposure during pregnancy was associated with a higher risk of microcephaly in infancy and childhood. These findings may support identification of alternatives to efavirenz as part of first-line ARV therapy. Disclosures All authors: No reported disclosures.

Download Full-text

Defective monocyte enzymatic function and an inhibitory immune phenotype in HIV-exposed uninfected African infants in the era of highly active anti-retroviral therapy

10.1101/2021.07.26.21261143 ◽

2021 ◽

Author(s):

Louise Afran ◽

Kondwani C Jambo ◽

Wilfred Nedi ◽

David J.C Miles ◽

Anmol Kiran ◽

...

Keyword(s):

B Cell ◽

Sub Saharan Africa ◽

Haemophilus Influenzae Type ◽

Cell Phenotype ◽

Bacterial Disease ◽

Enzymatic Function ◽

Increased Risk ◽

Hiv Exposure ◽

Hiv Exposed ◽

Exposed Uninfected

HIV-Exposed Uninfected (HEU) infants are a rapidly expanding population in Sub Saharan Africa and are highly particularly susceptible to disease caused by encapsulated bacteria in the first year of life. The mechanism of this increased risk is still poorly understood and we therefore, investigated if HIV exposure dysregulates HEU infant immunity and if this is amplified by human herpes infection (HHV). Here, we compared monocyte enzymatic function, innate and adaptive immune cell phenotype, and vaccine-induced antibody responses between HEU and HUU infants. We demonstrate altered monocyte phagosomal function and B cell subset homeostasis, and lower vaccine-induced anti-Haemophilus influenzae type b (Hib) and anti-Tetanus Toxoid (TT) IgG titers in HEU compared to HUU infants. There was no difference in the prevalence of HHV infection between HEU and HUU infants. Our findings suggest that even in the era of ART-mediated viral suppression, HIV exposure dysregulates monocyte and B cell function during a vulnerable period of immune maturation in infancy. This may contribute to the high rates of bacterial disease and pneumonia in HEU infants.

Download Full-text

Faculty Opinions recommendation of Severe Infections in HIV-Exposed Uninfected Infants Born in a European Country.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725726158.793509247 ◽

2015 ◽

Author(s):

Lynne Mofenson

Keyword(s):

European Country ◽

Severe Infections ◽

Hiv Exposed ◽

Exposed Uninfected

Download Full-text

No Increased Risk For Invasive Bacterial Infection Found Following Diphtheria-Tetanus-Pertussis Immunization

PEDIATRICS ◽

10.1542/peds.89.4.640 ◽

1992 ◽

Vol 89 (4) ◽

pp. 640-642

Author(s):

Marie R. Griffin ◽

Jo A. Taylor ◽

James R. Daugherty ◽

Wayne A. Ray

Keyword(s):

Bacterial Infections ◽

Vaccine Trial ◽

Adjusted Relative Risk ◽

Relative Risks ◽

Health Clinics ◽

Increased Risk ◽

Serious Infections ◽

Invasive Bacterial Infection ◽

Serious Bacterial Infections

During the acellular pertussis vaccine trial in Sweden, 4 children who were randomly assigned to receive the vaccine died of suspected or confirmed bacterial infections compared to 1 expected. There were no deaths in the placebo arm. This raised concern about the role of pertussis immunization in the development of serious infections. Through linking computerized immunization records with an active surveillance system for serious bacterial infections in children, the authors studied a cohort of 64 591 children immunized through Tennessee county health clinics who had a total of 158 episodes of invasive bacterial infections after a diphtheria and tetanus toxoids and pertussis (DTP) immunization. There were 8 invasive bacterial infections that occurred within the first 7 days following DTP immunization,yielding an age-adjusted relative risk (95% confidence interval) of 1.0 (0.5 to 2.0), compared to the interval 29 or more days following immunization. There were 7 and 20 infections in the 8- through 14- and 15-through 28-day intervals following DTP immunization, giving relative risks of 0.8 (0.4 to 1.7) and 1.2 (0.7 to 1.9), respectively. These data provide reassurance that the use of DTP vaccine is not followed by a large increased risk of serious bacterial infections.

Download Full-text

Rule out Sepsis in Infant

Acute Care Casebook ◽

10.1093/med/9780190865412.003.0052 ◽

2018 ◽

pp. 257-262

Author(s):

Temima Waltuch

Keyword(s):

Risk Stratification ◽

Lumbar Puncture ◽

Antibiotic Treatment ◽

Bacterial Infections ◽

Individual Risk ◽

Immune Systems ◽

Increased Risk ◽

Empiric Antibiotic ◽

Empiric Antibiotic Treatment ◽

Serious Bacterial Infections

This case reviews the workup and management of febrile infants less than 3 months of age. These infants are a unique population as their immune systems are immature, placing them at increased risk for serious bacterial infections. Most febrile infants have self-limited viral illnesses; however, it is important to identify those that have a coexisting or isolated bacterial illness. Febrile infants <28 days require a full sepsis workup and admission to the hospital for monitoring and parenteral empiric antibiotic treatment. Workup and management of febrile infants between 29 and 90 days present more of a controversy in the literature. At minimum, infants 1 to 2 months of age will have blood and urine cultures performed, while the lumbar puncture is dependent on their individual risk stratification. Workup for infants 2 to 3 months of age will be completely dependent on risk stratification.

Download Full-text

Maternal Diarrhea and Antibiotic Use are Associated with Increased Risk of Diarrhea among HIV-Exposed, Uninfected Infants in Kenya

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.19-0705 ◽

2020 ◽

Vol 102 (5) ◽

pp. 1001-1008

Author(s):

Emily L. Deichsel ◽

Patricia B. Pavlinac ◽

Dorothy Mbori-Ngacha ◽

Judd L. Walson ◽

Elizabeth Maleche-Obimbo ◽

...

Keyword(s):

Antibiotic Use ◽

Increased Risk ◽

Hiv Exposed ◽

Exposed Uninfected

Download Full-text

Measles Immunity at 4.5 Years of Age Following Vaccination at 9 and 15–18 Months of Age Among Human Immunodeficiency Virus (HIV)–infected, HIV-exposed–uninfected, and HIV-unexposed Children

Clinical Infectious Diseases ◽

10.1093/cid/ciy964 ◽

2018 ◽

Vol 69 (4) ◽

pp. 687-696 ◽

Cited By ~ 1

Author(s):

Eleonora A M L Mutsaerts ◽

Marta C Nunes ◽

Martijn N van Rijswijk ◽

Kerstin Klipstein-Grobusch ◽

Kennedy Otwombe ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Geometric Mean ◽

Treatment Interruption ◽

Enzyme Linked Immunosorbent Assay ◽

Increased Risk ◽

Immunodeficiency Virus ◽

Antibody Titers ◽

Measles Vaccination ◽

Hiv Exposed ◽

Exposed Uninfected

AbstractBackgroundHuman immunodeficiency virus (HIV)–infected and HIV-exposed–uninfected (HEU) children may be at increased risk of measles infection due to waning of immunity following vaccination. We evaluated persistence of antibodies to measles vaccination at 4.5 years of age in HIV-unexposed, HEU, and HIV-infected children with CD4+ ≥25% previously randomized to immediate antiretroviral therapy (ART) interrupted at 12 months (HIV/Immed-ART-12), 24 months (HIV/Immed-ART-24), or when clinically/immunologically indicated (HIV/Def-ART). The HIV/Def-ART group initiated ART by median 5.8 (interquartile range, 4.4–10.3) months of age.MethodsIn this study, HIV-unexposed (n = 95), HEU (n = 84), HIV/Immed-ART-12 (n = 70), HIV/Immed-ART-24 (n = 70), and HIV/Def-ART (n = 62) children were scheduled to receive measles vaccination at age 9 and 15–18 months. Antimeasles serum immunoglobulin G titers were quantified using enzyme-linked immunosorbent assay at 4.5 years.ResultsCompared with HIV-unexposed children (2860 mIU/mL), measles antibody geometric mean titers (GMTs) were significantly lower in both HIV/Immed-ART-12 (571; P < .001) and HIV/Immed-ART-24 (1136; P < .001) but similar in the HIV/Def-ART (2777) and HEU (3242) groups. Furthermore, compared with HIV-unexposed, antibody titers ≥330 mIU/mL (ie, presumed serocorrelate for protection; 99%) were also significantly lower in HIV/Immed-ART-12 (70%; P < .001) and HIV/Immed-ART-24 (83%; P < .001) but similar in the HIV/Def-ART (90%) and HEU (98%) groups.ConclusionsHIV-infected children in whom ART was interrupted at either 12 or 24 months had lower GMTs and lower proportions with seroprotective titers than HIV-unexposed children, indicating a potential downside of ART treatment interruption.Clinical Trials RegistrationNCT00099658 and NCT00102960.

Download Full-text

Peripheral blood mononuclear cell transcriptomes reveal an over-representation of down-regulated genes associated with immunity in HIV-exposed uninfected infants

Scientific Reports ◽

10.1038/s41598-019-54083-4 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Zaneta D. Musimbi ◽

Martin K. Rono ◽

James R. Otieno ◽

Nelson Kibinge ◽

Lynette Isabella Ochola-Oyier ◽

...

Keyword(s):

Peripheral Blood ◽

Bacterial Infections ◽

Mononuclear Cells ◽

Enrichment Analysis ◽

Functional Enrichment ◽

Morbidity And Mortality ◽

High Mobility Group Protein ◽

Peripheral Blood Mononuclear ◽

Hiv Exposed ◽

Exposed Uninfected

AbstractHIV-exposed uninfected (HEU) infants are disproportionately at a higher risk of morbidity and mortality, as compared to HIV-unexposed uninfected (HUU) infants. Here, we used transcriptional profiling of peripheral blood mononuclear cells to determine immunological signatures of in utero HIV exposure. We identified 262 differentially expressed genes (DEGs) in HEU compared to HUU infants. Weighted gene co-expression network analysis (WGCNA) identified six modules that had significant associations with clinical traits. Functional enrichment analysis on both DEGs and the six significantly associated modules revealed an enrichment of G-protein coupled receptors and the immune system, specifically affecting neutrophil function and antibacterial responses. Additionally, malaria pathogenicity genes (thrombospondin 1-(THBS 1), interleukin 6 (IL6), and arginine decarboxylase 2 (ADC2)) were down-regulated. Of interest, the down-regulated immunity genes were positively correlated to the expression of epigenetic factors of the histone family and high-mobility group protein B2 (HMGB2), suggesting their role in the dysregulation of the HEU transcriptional landscape. Overall, we show that genes primarily associated with neutrophil mediated immunity were repressed in the HEU infants. Our results suggest that this could be a contributing factor to the increased susceptibility to bacterial infections associated with higher morbidity and mortality commonly reported in HEU infants.

Download Full-text