Comparative efficacy and safety of Pneumocystis jirovecii pneumonia prophylaxis regimens for people living with HIV: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Pneumocystis jirovecii pneumonia (PCP) is a common opportunistic infection among people living with HIV (PWH), particularly among new and untreated cases. Several regimens are available for the prophylaxis of PCP, including trimethoprim-sulfamethoxazole (TMP-SMX), dapsone-based regimens (DBRs), aerosolized pentamidine (AP), and atovaquone. OBJECTIVES: To compare the efficacy and safety of PCP prophylaxis regimens in PWH by network meta-analysis. METHODS: DATA SOURCES: Embase, MEDLINE, and CENTRAL from inception to June 21, 2023. STUDY ELIGIBILITY CRITERIA: Comparative randomized controlled trials (RCTs). PARTICIPANTS: PWH. INTERVENTIONS: Regimens for PCP prophylaxis either compared head-to-head or versus no treatment/placebo. ASSESSMENT OF RISK OF BIAS: Cochrane risk-of-bias tool for RCTs 2. METHODS OF DATA SYNTHESIS: Title or abstract and full-text screening and data extraction were performed in duplicate by two independent reviewers. Data on PCP incidence, all-cause mortality, and discontinuation due to toxicity were pooled and ranked by network meta-analysis. Subgroup analyses of primary versus secondary prophylaxis, by year, and by dosage were performed. RESULTS: A total of 26 RCTs, comprising 55 treatment arms involving 7516 PWH were included. For the prevention of PCP, TMP-SMX was ranked the most favourable agent and was superior to DBRs (risk ratio [RR] = 0.54; 95% CI, 0.36-0.83) and AP (RR = 0.53; 95% CI, 0.36-0.77). TMP-SMX was also the only agent with a mortality benefit compared with no treatment/placebo (RR = 0.79; 95% CI, 0.64-0.98). However, TMP-SMX was also ranked as the most toxic agent with a greater risk of discontinuation than DBRs (RR = 1.25; 95% CI, 1.01-1.54) and AP (7.20; 95% CI, 5.37-9.66). No significant differences in PCP prevention or mortality were detected among the other regimens. The findings remained consistent within subgroups. CONCLUSIONS: TMP-SMX is the most effective agent for PCP prophylaxis in PWH and the only agent to confer a mortality benefit; consequently, it should continue to be recommended as the first-line agent. Further studies are necessary to determine the optimal dosing of TMP-SMX to maximize efficacy and minimize toxicity.

Nebulised pentamidine prophylaxis of pneumocystis pneumonia in adults accessing HIV services at royal free hospital, London.

Receipt of nebulised pentamidine in people with HIV was audited to identify if individuals were appropriately receiving nebulised pentamidine, and whether national guidelines were being followed when prophylaxis was commenced and discontinued. Of 76 people with who received nebulised pentamidine, the main indication for starting nebulised pentamidine was a co-trimoxazole adverse drug reaction. Co-trimoxazole desensitization was not attempted before starting nebulised pentamidine. The main indication for stopping nebulised pentamidine prophylaxis was when immune reconstitution occurred. This single centre audit revealed that national guidelines were being followed in most cases. The lack of information regarding the reason for starting or stopping nebulised pentamidine prophylaxis, or detail of the clinician's concerns about potential poor adherence with oral regimens of prophylaxis as a reason for choosing nebulised pentamidine prophylaxis, identifies a need for improved documentation of clinicians' decision-making. Introduction of pharmacist-led interventions/alerts using patients' electronic records, similar to those used in primary care, would enable the specialist pharmacy team to identify when and if co-trimoxazole desensitization has been offered and discussed/declined before a clinician prescribes nebulised pentamidine as well as enabling identification of those in who pentamidine prophylaxis has been continued, despite "immune reconstitution".

AIDS cases in Ottawa: A review of simultaneous HIV and AIDS diagnoses.

OBJECTIVES: In Canada, HIV diagnoses continue unabated, with many of these cases being identified at a late stage of infection. While current public health surveillance data does not capture timing of diagnoses, locally, we identified a number of patients concurrently diagnosed with AIDS and HIV. DESIGN: To understand the key characteristics, presenting symptoms, and risk factors associated with an AIDS diagnosis, we undertook a prospective chart review of HIV and AIDS diagnoses in Ottawa, Canada. SAMPLE: Sixty seven charts of persons diagnosed with HIV and AIDS between 2015 and 2021 were reviewed. MEASUREMENTS: Data were analyzed using descriptive statistics. RESULTS: Results show some inconsistencies regarding HIV risk factors identified in published literature compared to those for persons diagnosed with AIDS in this study. Namely, patients in this review were more likely to be male, Black (from HIV-endemic regions), and heterosexual, and were diagnosed at critical stage in infection (total average CD4+ count of 92.9 cells/mm3 ) with 44.8% of patients concurrently diagnosed with one or more AIDS-related opportunistic infections. CONCLUSIONS: The findings can be applied to strengthen HIV screening efforts in primary care settings, particularly among patients who present with persistent symptoms or illnesses related to chronic HIV infection. Additional considerations should be made for public health nurses to provide counseling and linkage to HIV testing/prevention services for patients at the time of an STI or Tuberculosis diagnosis and to increase AIDS-specific data collection.

HIV/AIDS-Pneumonia Codynamics Model Analysis with Vaccination and Treatment.

In this paper, we proposed and analyzed a realistic compartmental mathematical model on the spread and control of HIV/AIDS-pneumonia coepidemic incorporating pneumonia vaccination and treatment for both infections at each infection stage in a population. The model exhibits six equilibriums: HIV/AIDS only disease-free, pneumonia only disease-free, HIV/AIDS-pneumonia coepidemic disease-free, HIV/AIDS only endemic, pneumonia only endemic, and HIV/AIDS-pneumonia coepidemic endemic equilibriums. The HIV/AIDS only submodel has a globally asymptotically stable disease-free equilibrium if ℛ 1 < 1. Using center manifold theory, we have verified that both the pneumonia only submodel and the HIV/AIDS-pneumonia coepidemic model undergo backward bifurcations whenever ℛ 2 < 1 and ℛ 3 = max{ℛ 1, ℛ 2} < 1, respectively. Thus, for pneumonia infection and HIV/AIDS-pneumonia coinfection, the requirement of the basic reproduction numbers to be less than one, even though necessary, may not be sufficient to completely eliminate the disease. Our sensitivity analysis results demonstrate that the pneumonia disease transmission rate ß 2 and the HIV/AIDS transmission rate ß 1 play an important role to change the qualitative dynamics of HIV/AIDS and pneumonia coinfection. The pneumonia infection transmission rate ß 2 gives rises to the possibility of backward bifurcation for HIV/AIDS and pneumonia coinfection if ℛ 3 = max{ℛ 1, ℛ 2} < 1, and hence, the existence of multiple endemic equilibria some of which are stable and others are unstable. Using standard data from different literatures, our results show that the complete HIV/AIDS and pneumonia coinfection model reproduction number is ℛ 3 = max{ℛ 1, ℛ 2} = max{1.386, 9.69 } = 9.69 at ß 1 = 2 and ß 2 = 0.2 which shows that the disease spreads throughout the community. Finally, our numerical simulations show that pneumonia vaccination and treatment against disease have the effect of decreasing pneumonia and coepidemic disease expansion and reducing the progression rate of HIV infection to the AIDS stage.

Cost-Effectiveness Analysis of the Implementation of Cryptococcal Antigen Lateral Flow Assay for the Diagnosis of Cryptococcal Meningitis in Symptomatic People Living With Human Immunodeficiency Virus in Brazil.

OBJECTIVES: Cryptococcal meningitis constitutes a significant source of mortality in the developing world. Annually, approximately 625 000 deaths occur worldwide among patients with human immunodeficiency virus (HIV) infection. This study aims to assess the cost-effectiveness of implementing cryptococcal antigen lateral flow assay (CRAG-LFA) screening in Brazil compared with the current practice. METHODS: An economic evaluation using a Monte Carlo microsimulation was conducted, considering the perspective of the Brazilian Public Health System, to calculate the cost-effectiveness of 4 diagnosis tests: (1) CRAG-LFA, (2) the cryptococcal antigen latex agglutination (CRAG-LA) test, (3) India ink, and (4) nontracking as a baseline. The time horizon comprised 1 year for the intervention and 5 years for the budgetary impact analysis. Two primary effectiveness outcomes were considered: years of life and quality-adjusted life-years. RESULTS: CRAG-LFA has extended dominance vis à vis CRAG-LA and India ink. CRAG-LFA would cost $418.46 more than CRAG-LA for the treatment of each symptomatic patient living with HIV, with an incremental cost effectiveness ratio of $2478.75/quality-adjusted life year. The budgetary impact analysis estimated that the incorporation of CRAG-LFA would have an additional cost of $1 959 236.50 in 5 years. CONCLUSIONS: These findings suggest that, for patients living with HIV in the Brazilian Public Health System, the adoption of CRAG-LFA screening is cost-effective compared with the use of CRAG-LA and India ink. It represents an opportunity to prevent cryptococcal meningitis and its mortality in Brazil.

Low prevalence of isoniazid preventive therapy uptake among HIV-infected patients attending tertiary health facility in Lagos, Southwest Nigeria.

INTRODUCTION: the burden of HIV and tuberculosis co-infection is a global public health challenge. Despite the benefit of isoniazid preventive therapy (IPT) in reducing the rate of co-infection, the uptake is generally limited in developing countries. This study aimed to determine the prevalence of IPT use and the factors affecting the uptake among HIV-infected patients attending our Teaching Hospital. METHODS: this cross-sectional survey involved 300 HIV-infected individuals attending the AIDS prevention initiatives in Nigeria clinic of the Lagos University Teaching Hospital. A self-designed and well-structured questionnaire was used to document the demographic data, patients' exposure to tuberculosis, and IPT uptake. Clinical data of eligible patients were also extracted from their case notes. The main outcome measure was the prevalence of IPT use and non-use. RESULTS: out of the respondents evaluated, (72.7%, n = 218) were females. Tuberculosis was the predominant comorbidity (15.7%, n = 47) and majority (53.0%, n = 159) had a CD4 count of < 500 cells/ml. Overall prevalence of IPT uptake was very low (7.1%, n = 18) among HIV-infected patients. Major factors affecting uptake were lack of awareness of benefit (44.4%, n = 8) and lack of fear of contracting tuberculosis (22.2%, n = 4). However, lack of awareness of IPT benefit was the only independent factor associated with poor IPT uptake (adjusted odds 1168.75, 95% confidence interval: 85.05-16060.33; p = 0.001). CONCLUSION: isoniazid preventive therapy uptake was found to be very low in this study. Increased awareness and policy implementation of IPT by the healthcare provider is necessary.

Introduction to the Site-specific Etiologic Results From the Pneumonia Etiology Research for Child Health (PERCH) Study.

The Pneumonia Etiology Research for Child Health (PERCH) study evaluated the etiology of severe and very severe pneumonia in children hospitalized in 7 African and Asian countries. Here, we summarize the highlights of in-depth site-specific etiology analyses published separately in this issue, including how etiology varies by age, mortality status, malnutrition, severity, HIV status, and more. These site-specific results impart important lessons that can inform disease control policy implications.

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

BACKGROUND: We present findings from the Pneumonia Etiology Research for Child Health (PERCH) site in Bamako, Mali. METHODS: Cases were patients 28 days to 59 months of age, admitted to hospital with severe or very severe pneumonia (2005 World Health Organization definition). Community controls were frequency matched by age. Both provided nasopharyngeal and oropharyngeal swabs for multiplex polymerase chain reaction and Streptococcus pneumoniae culture. Cases underwent blood culture and induced sputum culture for Mycobacterium tuberculosis. A subset had pleural fluid and lung aspirates collected for culture and polymerase chain reaction. Primary analyses included participants with negative or unknown HIV status (HIV-) and cases with abnormal chest radiographs (CXR+). Cases and controls were compared using logistic regression adjusting for age. Etiologic fractions were calculated by a Bayesian nested partially latent class analysis, the PERCH integrated analysis. RESULTS: Between January 1, 2012, and January 14, 2014, we enrolled 241 CXR+/HIV- cases and 725 HIV- controls. Compared with controls, cases were more likely to have moderate-to-severe wasting (43.1% vs. 14.1%, P < 0.001) and stunting (26.6% vs. 9.4%, P < 0.001). Predominant etiologies were respiratory syncytial virus [24.0%; 95% credible interval (CrI): 18.3%-31.1%], S. pneumoniae (15.2%; 95% CrI: 9.5-21.6), human metapneumovirus (11.8%; 95% CrI: 8.3%-16.2%) and parainfluenza virus type 3 (9.0%; 95% CrI: 5.8%-13.3%). Case fatality was 13.3%, with Staphylococcus aureus, Pneumocystis jirovecii and Haemophilus influenzae type b predominating (40% of fatal cases). CONCLUSIONS: PERCH uncovered high case fatality among children with severe pneumonia in Mali, highlighting a role for new interventions (eg, respiratory syncytial virus vaccines) and a need to improve vaccine coverage and strengthen healthcare delivery.

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

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

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

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

Etiology and Clinical Characteristics of Severe Pneumonia Among Young Children in Thailand: Pneumonia Etiology Research for Child Health (PERCH) Case-Control Study Findings, 2012-2013.

BACKGROUND: Pneumonia remains the leading cause of death among children <5 years of age beyond the neonatal period in Thailand. Using data from the Pneumonia Etiology Research for Child Health (PERCH) Study, we provide a detailed description of pneumonia cases and etiology in Thailand to inform local treatment and prevention strategies in this age group. METHODS: PERCH, a multi-country case-control study, evaluated the etiology of hospitalized cases of severe and very severe pneumonia among children 1-59 months of age. The Thailand site enrolled children for 24 consecutive months during January 2012-February 2014 with staggered start dates in 2 provinces. Cases were children hospitalized with pre-2013 WHO-defined severe or very severe pneumonia. Community controls were randomly selected from health services registries in each province. Analyses were restricted to HIV-negative cases and controls. We calculated adjusted odds ratios (ORs) and 95% CIs comparing organism prevalence detected by nasopharyngeal/oropharyngeal (NP/OP) polymerase chain reaction between cases and controls. The PERCH Integrated Analysis (PIA) used Bayesian latent variable analysis to estimate pathogen-specific etiologic fractions and 95% credible intervals. RESULTS: Over 96% of both cases (n = 223) and controls (n = 659) had at least 1 organism detected; multiple organisms were detected in 86% of cases and 88% of controls. Among 98 chest Radiograph positive (CXR+) cases, respiratory syncytial virus (RSV) had the highest NP/OP prevalence (22.9%) and the strongest association with case status (OR 20.5; 95% CI: 10.2, 41.3) and accounted for 34.6% of the total etiologic fraction. Tuberculosis (TB) accounted for 10% (95% CrI: 1.6-26%) of the etiologic fraction among CXR+ cases. DISCUSSION: More than one-third of hospitalized cases of severe and very severe CXR+ pneumonia among children 1-59 months of age in Thailand were attributable to RSV. TB accounted for 10% of cases, supporting evaluation for TB among children hospitalized with pneumonia in high-burden settings. Similarities in pneumonia etiology in Thailand and other PERCH sites suggest that global control strategies based on PERCH study findings are relevant to Thailand and similar settings.

The Etiology of Pneumonia in HIV-1-infected South African Children in the Era of Antiretroviral Treatment: Findings From the Pneumonia Etiology Research for Child Health (PERCH) Study.

BACKGROUND: HIV-1 infection predisposes to an increased burden of pneumonia caused by community-acquired and opportunistic pathogens. METHODS: Within the context of the Pneumonia Etiology Research for Child Health case-control study of under 5 pneumonia, we investigated the etiology of World Health Organization-defined severe/very severe pneumonia requiring hospitalization in South African HIV-infected children. Nasopharyngeal-oropharyngeal swabs and blood, collected from cases and age- and season-matched HIV-infected controls attending outpatient antiretroviral therapy (ART) clinics, were analyzed using molecular diagnostic methods. Cases were also investigated for tuberculosis. Etiologic fractions among cases with radiologically confirmed pneumonia were derived using Bayesian analytic techniques. RESULTS: Of 115 HIV-infected cases, 89 (77.4%) had radiologically confirmed pneumonia. Severe immunosuppression (adjusted odds ratio, 32.60; 95% confidence interval, 7.25-146.64) was significantly associated with radiologically confirmed pneumonia. Cotrimoxazole prophylaxis (46.4% vs. 77.4%) and ART (28.2% vs. 83.1%) coverage were significantly lower in cases compared with ART-clinic controls. An etiologic agent was identified in 99.0% of the radiologically confirmed cases. The 'top 4' pathogens associated with radiologically confirmed pneumonia were Pneumocystis jirovecii [23.0%; 95% credible interval (CrI), 12.4%-31.5%], Staphylococcus aureus (10.6%; 95% CrI, 2.2%-20.2%), pneumococcus (9.5%; 95% CrI, 2.2%-18.0%) and respiratory syncytial virus (9.3%; 95% CrI, 2.2%-14.6%). Bacteremia (6.7%) and in-hospital death (10.1%) were frequent among those with radiologically confirmed disease. CONCLUSIONS: Pneumocystis jirovecii, S. aureus, pneumococcus and respiratory syncytial virus contribute a considerable burden of radiologically confirmed pneumonia in South African HIV-infected children under 5 years. Expediting access to ART and cotrimoxazole prophylaxis would decrease the burden of pneumonia in these children.

Impact of HIV-1 Infection and Antigen Class on T Follicular Helper Cell Responses to Pneumococcal Polysaccharide-Protein Conjugate Vaccine-13.

Pneumococcal infections are common and serious complications of HIV-1 disease. Prevention has been compromised by the limited magnitude and quality of Ab responses to T cell-independent type 2 pneumococcal capsular polysaccharides (PPS). The pneumococcal polysaccharide-protein conjugate vaccine-13 (PCV-13) contains PPS conjugated to the T cell-dependent protein (diphtheria toxoid [DT] [CRM197]). We investigated the differential response to PPS and DT by human Ab-secreting B cells (ASC) after immunization with PCV-13 in newly diagnosed healthy HIV+ and control adults. The numbers of PPS-specific IgG ASC increased significantly and similarly in HIV+ and controls. However, DT-specific IgG ASC increased in controls but not HIV+ subjects. To determine the cellular basis of these disparate responses to DT and PPS, we characterized the frequency and activation of T follicular helper (Tfh) cells, the predominant T cell subset providing B cell help. Expression of inducible T cell costimulator (ICOS), which sustains Tfh function and phenotype, increased significantly among controls, when compared with the HIV+ group. Increases in ICOS+ Tfh correlated with changes in T-dependent, DT-specific IgG ASC in controls but not in HIV+ In contrast, ICOS expression did not correlate with T cell-independent type 2 PPS-specific ASC in either group. Of note, upon optimized ex vivo stimulation, CD4 T cells from HIV+ subjects differentiated into Tfh cells and formed synapses with Raji B cells at frequencies similar to that of controls. In summary, PCV-13-induced increase in ICOS expression on Tfh was associated with responses to DT, which was compromised in recently diagnosed healthy HIV+ adults and can be restored ex vivo by providing effective Tfh-differentiating signals.

HIV Infection in Adults: Initial Management.

The HIV epidemic is an important public health priority. Transmissions continue to occur despite effective therapies that make HIV preventable and treatable. Approximately one-half of people with HIV are not receiving suppressive antiretroviral therapy (ART). Starting ART early, followed by continuous lifetime treatment, most effectively achieves durable virologic suppression and restoration of immune function that can improve clinical outcomes and prevent transmission to partners who are seronegative. National treatment guidelines include ART options that can be offered immediately after diagnosis, even before the results of baseline HIV drug-resistance testing are available. Initial ART selection should be guided by co-occurring conditions, including viral hepatitis, medications, and other factors such as pregnancy. Identifying and addressing psychosocial barriers to care is a key element of ensuring long-term adherence to treatment. The initial physical examination typically reveals no clinical manifestations of HIV in the absence of advanced disease. A comprehensive laboratory evaluation, including HIV viral load and CD4 lymphocyte monitoring, is necessary to guide decision-making for treatment, opportunistic infection prophylaxis, and vaccinations. The initial management of people with HIV presents a unique opportunity for family physicians to improve patients' long-term health care and reduce HIV transmissions.

Pneumocystis Pneumonia: Still a serious disease in children.

Pneumocystis carinii pneumonia is a common opportunistic respiratory infection among children with human immunodeficiency virus and a weakened immune system. The primary infection in immunocompetent patients may be asymptomatic, whereas fever, shortness of breath, night sweats, nonproductive (dry) cough, pneumonia, progressive respiratory distress and apnea are cardinal symptoms of full-blown pneumocystis pneumonia. The diagnosis can be confirmed by histochemical staining of biological specimens or, recently, by polymerase chain reaction. International recommendations indicate that the drug of choice is the intravenously administered trimethoprim-sulfamethoxazole combination. Early diagnosis and appropriate treatment reduce the mortality of the disease. This article briefly highlights the epidemiology of Pneumocystis pneumonia, its diagnosis and therapeutic options in the pediatric population.

Pulmonary tuberculosis screening in anti-retroviral treated adults living with HIV in Kenya.

BACKGROUND: People living with HIV (PLHIV) who reside in high tuberculosis burden settings remain at risk for tuberculosis disease despite treatment with anti-retroviral therapy and isoniazid preventive therapy (IPT). The performance of the World Health Organization (WHO) symptom screen for tuberculosis in PLHIV receiving anti-retroviral therapy is sub-optimal and alternative screening strategies are needed. METHODS: We enrolled HIV-positive adults into a prospective study in western Kenya. Individuals who were IPT-naïve or had completed IPT > 6 months prior to enrollment were eligible. We evaluated tuberculosis prevalence overall and by IPT status. We assessed the accuracy of the WHO symptom screen, GeneXpert MTB/RIF (Xpert), and candidate biomarkers including C-reactive protein (CRP), hemoglobin, erythrocyte sedimentation rate (ESR), and monocyte-to-lymphocyte ratio for identifying pulmonary tuberculosis. Some participants were evaluated at 6 months post-enrollment for tuberculosis. RESULTS: The study included 383 PLHIV, of whom > 99% were on antiretrovirals and 88% had received IPT, completed a median of 1.1 years (IQR 0.8-1.55) prior to enrollment. The prevalence of pulmonary tuberculosis at enrollment was 1.3% (n = 5, 95% CI 0.4-3.0%): 4.3% (0.5-14.5%) among IPT-naïve and 0.9% (0.2-2.6%) among IPT-treated participants. The sensitivity of the WHO symptom screen was 0% (0-52%) and specificity 87% (83-90%). Xpert and candidate biomarkers had poor to moderate sensitivity; the most accurate biomarker was CRP ≥ 3.3 mg/L (sensitivity 80% (28-100) and specificity 72% (67-77)). Six months after enrollment, the incidence rate of pulmonary tuberculosis following IPT completion was 0.84 per 100 person-years (95% CI, 0.31-2.23). CONCLUSIONS: In Kenyan PLHIV treated with IPT, tuberculosis prevalence was low at a median of 1.4 years after IPT completion. WHO symptoms screening, Xpert, and candidate biomarkers were insensitive for identifying pulmonary tuberculosis in antiretroviral-treated PLHIV.

Pneumococcal Conjugate Vaccine Protection against Coronavirus-Associated Pneumonia Hospitalization in Children Living with and without HIV.

In December 2019 a new coronavirus (CoV) emerged as a human pathogen, SARS-CoV-2. There are few data on human coronavirus infections among individuals living with HIV. In this study we probed the role of pneumococcal coinfections with seasonal CoVs among children living with and without HIV hospitalized for pneumonia. We also described the prevalence and clinical manifestations of these infections. A total of 39,836 children who participated in a randomized, double-blind, placebo-controlled clinical trial on the efficacy of a 9-valent pneumococcal conjugate vaccine (PCV9) were followed for lower respiratory tract infection hospitalizations until 2 years of age. Nasopharyngeal aspirates were collected at the time of hospitalization and were screened by PCR for four seasonal CoVs. The frequency of CoV-associated pneumonia was higher in children living with HIV (19.9%) than in those without HIV (7.6%, P < 0.001). Serial CoV infections were detected in children living with HIV. The case fatality risk among children with CoV-associated pneumonia was higher in those living with HIV (30.4%) than without HIV (2.9%, P = 0.001). C-reactive protein and procalcitonin levels were elevated in 36.8% (≥40 mg/liter) and 64.7% (≥0.5 ng/ml), respectively, of the fatal cases living with HIV. Among children without HIV, there was a 64.0% (95% CI: 22.9% to 83.2%) lower incidence of CoV-associated pneumonia hospitalizations among PCV9 recipients compared to placebo recipients. These data suggest that Streptococcus pneumoniae infections might have a role in the development of pneumonia associated with endemic CoVs, that PCV may prevent pediatric CoV-associated hospitalization, and that children living with HIV with CoV infections develop more severe outcomes.IMPORTANCE SARS-CoV-2 may cause severe hospitalization, but little is known about the role of secondary bacterial infection in these severe cases, beyond the observation of high levels of reported inflammatory markers, associated with bacterial infection, such as procalcitonin. We did a secondary analysis of a double-blind randomized trial of PCV to examine its impact on human CoV infections before the pandemic. We found that both children living with and without HIV randomized to receive PCV had evidence of less hospitalization due to seasonal CoV, suggesting that pneumococcal coinfection may play a role in severe hospitalized CoV infections.

Withholding Primary Pneumocystis Pneumonia Prophylaxis in Virologically Suppressed Patients With Human Immunodeficiency Virus: An Emulation of a Pragmatic Trial in COHERE.

BACKGROUND: Using data from the COHERE collaboration, we investigated whether primary prophylaxis for pneumocystis pneumonia (PcP) might be withheld in all patients on antiretroviral therapy (ART) with suppressed plasma human immunodeficiency virus (HIV) RNA (≤400 copies/mL), irrespective of CD4 count. METHODS: We implemented an established causal inference approach whereby observational data are used to emulate a randomized trial. Patients taking PcP prophylaxis were eligible for the emulated trial if their CD4 count was ≤200 cells/µL in line with existing recommendations. We compared the following 2 strategies for stopping prophylaxis: (1) when CD4 count was >200 cells/µL for >3 months or (2) when the patient was virologically suppressed (2 consecutive HIV RNA ≤400 copies/mL). Patients were artificially censored if they did not comply with these stopping rules. We estimated the risk of primary PcP in patients on ART, using the hazard ratio (HR) to compare the stopping strategies by fitting a pooled logistic model, including inverse probability weights to adjust for the selection bias introduced by the artificial censoring. RESULTS: A total of 4813 patients (10 324 person-years) complied with eligibility conditions for the emulated trial. With primary PcP diagnosis as an endpoint, the adjusted HR (aHR) indicated a slightly lower, but not statistically significant, different risk for the strategy based on viral suppression alone compared with the existing guidelines (aHR, .8; 95% confidence interval, .6-1.1; P = .2). CONCLUSIONS: This study suggests that primary PcP prophylaxis might be safely withheld in confirmed virologically suppressed patients on ART, regardless of their CD4 count.