MAJOR ARTICLE Clinical Infectious Diseases HIV Exposure or Infection in Carriage of Streptococcus pneumoniae and Pneumocystis jiroveci • CID 2021:72 (15 March) • 1033 A Tale of 2 Pneumos: Te Impact of Human Immunodefciency Virus Exposure or Infection Status on Pediatric Nasopharyngeal Carriage of Streptococcus pneumoniae and Pneumocystis jiroveci: A Nested Case Control Analysis From the Pneumonia Etiology Research In Child Health Study Ingrid Y. Camelo, 1 Lawrence M. Mwananyanda, 2,3 Donald M. Thea, 2 Philip Seidenberg, 4 Christopher J. Gill, 2 and John R. Weinstein 5 1 Pediatric Infectious Diseases Department, Boston University Medical Center, Boston University School of Medicine, Boston, Massachusetts, USA, 2 Department of Global Health, Boston University School of Public Health, Boston, Massachusetts, USA, 3 Right to Care Zambia, Lusaka, Zambia, 4 Department of Emergency Medicine, University of New Mexico, Albuquerque, New Mexico, USA, and 5 Department of Medicine, Boston University Medical Center, Boston, Massachusetts, USA Background. Te majority of pediatric human immunodefciency virus (HIV) cases in Africa refect maternal-to-child trans- mission. HIV exposed but uninfected (HEU) children have increased rates of morbidity and mortality when compared to HIV un- exposed and uninfected (HUU) children. Te mechanisms behind these unexpected trends are only partially understood but could be explained by the diferences in the immune response to infections triggered by an altered immune system state. Methods. Using quantitative reverse transcription polymerase chain reaction, we compared the nasopharyngeal carriage prev- alence and density of Streptococcus pneumoniae (SP) and Pneumocystis jirovecii (PJ) between children living with HIV and HEU or HUU cases (pneumonia) and controls (without pneumonia). Results. Te cohort included 1154 children (555 cases and 599 matched controls). Te SP carriage prevalence rates were similar between cases and controls. Among SP carriers with pneumonia, carriage density was increased among children living with HIV, versus HEU or HUU children (15.8, 4.7, and 3.6 × 10 5 copies/mL, respectively). Te rate of PJ carriage was signifcantly higher among children living with HIV than among HEU and HUU children (31%, 15%, and 10%, respectively; P < .05), as was carriage density (63.9, 20.9, and 4.8 × 10 3 copies/mL, respectively; P < .05). Conclusions. Carriage prevalences and densities for SP and PJ show diferent kinetics in terms of their relationship with HIV ex- posure and clinical status, particularly for Pneumocystis jirovecii. Tis supports the theory that the increased morbidity and mortality observed among HEU children may refect defcits not just in humoral immunity but in cell-mediated immunity as well. Keywords. HIV exposure; Streptococcus pneumoniae; Pneumocystis jirovecii; Zambia; nasopharyngeal carriage. Interventions to prevent mother-to-child transmission sig- nificantly reduced vertical transmission between 2004 and 2012 [1]. Paradoxically, the persistently high seroprevalence of human immunodeficiency virus (HIV) in pregnant women has resulted in a high and expanding number of children who are HIV exposed but uninfected (HEU). As of 2018, there have been a cumulative estimated 14.8 million HEU children, with approximately 1.13 million born each year globally [2]. Despite being uninfected by HIV, emerging data suggest that HEU children sufer increased rates of morbidity and mortality, as compared to HIV unexposed and uninfected (HUU) chil- dren [3–9]. In 2 prior meta-analyses, our team documented the adverse health consequences experienced by HEU infants in terms of reduced survival generally and increased incidences of diarrhea and pneumonia specifcally [10, 11]. Such data sug- gest that HEU children experience some degree of immunosup- pression despite having evaded HIV infection per se. Some of this is clearly explained by changes in transplacental maternal antibodies [12, 13]. But accumulating evidence also implicates defcits in cell-mediated immunity [14]. Tis is surprising and harder to reconcile, given that lymphocytes do not cross the pla- centa. But it is plausible that intrauterine exposure to an acti- vated maternal infammatory state might directly or indirectly infuence the development of the infant’s cell-mediated immune function [15, 16]. Received 18 December 2019; editorial decision 7 February 2020; accepted 10 March 2020; published online February 15, 2020. Correspondence: C. J. Gill, Department of Global Health, Boston University School of Public Health, 801 Massachusettes Avenue, Boston, MA 02118 (cgill@bu.edu). Clinical Infectious Diseases ® 2021;72(6):1033–41 © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. DOI: 10.1093/cid/ciaa164