Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Open Access

Peer-reviewed

Research Article

Global prevalence, mortality, and main characteristics of HIV-associated pneumocystosis: A systematic review and meta-analysis

  • Ehsan Ahmadpour,

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – review & editing

    Affiliations Infectious and Tropical Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran, Department of Medical Mycology and Parasitology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    ⨯
  • Sevda Valilou,

    Roles Data curation, Formal analysis, Investigation

    Affiliation Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    ⨯
  • Mohammad Ali Ghanizadegan,

    Roles Data curation, Formal analysis, Investigation

    Affiliation Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    ⨯
  • Rouhollah Seyfi,

    Roles Data curation, Formal analysis, Investigation

    Affiliation Infectious and Tropical Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    ⨯
  • Seyed Abdollah Hosseini,

    Roles Data curation, Formal analysis, Investigation

    Affiliation Department of Parasitology and Mycology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran

    ⨯
  • Kareem Hatam-Nahavandi,

    Roles Data curation, Formal analysis, Investigation

    Affiliation Iranshahr University of Medical Sciences, Iranshahr, Iran

    ⨯
  • Hanieh Hosseini,

    Roles Data curation, Formal analysis, Writing – original draft

    Affiliation Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    ⨯
  • Mahsa Behravan,

    Roles Data curation, Formal analysis, Writing – original draft

    Affiliation Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

    ⨯
  • Aleksandra Barac,

    Roles Formal analysis, Investigation, Writing – review & editing

    Affiliation Clinic for Infectious and Tropical Diseases, University Clinical Center of Serbia, Belgrade, Serbia

    ⨯
  • Hamid Morovati

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

    morovatihamid1989@gmail.com

    Affiliations Department of Medical Mycology and Parasitology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran, Department of Parasitology and Mycology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    ⨯

Abstract

The epidemiology of Human Immunodeficiency Virus (HIV)-associated pneumocystosis (HAP) is poorly described on a worldwide scale. We searched related databases between January 2000 and December 2022 for studies reporting HAP. Meta-analysis was performed using StatsDirect (version 2.7.9) and STATA (version 17) according to the random-effects model for DerSimonian and Laird method and metan and metaprop commands, respectively. Twenty-nine studies with 38554 HIV-positive, 79893 HIV-negative, and 4044 HAP populations were included. The pooled prevalence of HAP was 35.4% (95% CI 23.8 to 47.9). In contrast, the pooled prevalence of PCP among HIV-negative patients was 10.16% (95% CI 2 to 25.3). HIV-positive patients are almost 12 times more susceptible to PCP than the HIV-negative population (OR: 11.710; 95% CI: 5.420 to 25.297). The mortality among HAP patients was 52% higher than non-PCP patients (OR 1.522; 95% CI 0.959 to 2.416). HIV-positive men had a 7% higher chance rate for PCP than women (OR 1.073; 95% CI 0.674 to 1.706). Prophylactic (OR: 6.191; 95% CI: 0.945 to 40.545) and antiretroviral therapy (OR 3.356; 95% CI 0.785 to 14.349) were used in HAP patients six and three times more than HIV-positive PCP-negatives, respectively. The control and management strategies should revise and updated by health policy-makers on a worldwide scale. Finally, for better management and understanding of the epidemiology and characteristics of this coinfection, designing further studies is recommended.

Citation: Ahmadpour E, Valilou S, Ghanizadegan MA, Seyfi R, Hosseini SA, Hatam-Nahavandi K, et al. (2024) Global prevalence, mortality, and main characteristics of HIV-associated pneumocystosis: A systematic review and meta-analysis. PLoS ONE 19(3): e0297619. https://doi.org/10.1371/journal.pone.0297619

Editor: Benjamin M. Liu, Children’s National Hospital, George Washington University, UNITED STATES

Received: November 29, 2023; Accepted: January 9, 2024; Published: March 25, 2024

Copyright: © 2024 Ahmadpour et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting information files.

Funding: The author(s) received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Pneumocystis pneumonia (PCP) is a serious pulmonary infection caused by a ubiquitous opportunistic fungal pathogen, Pneumocystis jirovecii [1]. Humans are the main reservoir of P jirovecii, and inhalation of air-borne particles is the main transmission route [2]. PCP is extremely rare in healthy people, and P.jirovecii can live in the lungs without causing symptoms [3]. Exposure to this pathogen is very high [4]. More than 80% of children in developed countries commonly show antibodies against P.jirovecii [5, 6]. Up to 20% of adults might carry this fungus at any given time, although the immune system removes the fungus after several months [7]. In 1980 PCP was introduced as a substantial public health problem [8].

The prevalence of PCP escalated following the Human Immunodeficiency Virus (HIV) epidemic in the 1980swhen HIV was diagnosed in a group of homosexual men, hemophilia patients, and recipients of blood products. Although, genetic analysis revealed that the virus was first transmitted to humans around 1908 from chimpanzees polluted SIV virus, probably through the wounds of African people who slaughtered chimpanzees for food. The emergence and increase of the risk factors between 1908 and 1980 led to the HIV epidemic in 1980 [9]. PCP is almost exclusively seen in individuals with compromised immune systems by HIV/(Acquired Immunodeficiency Syndrome) AIDS. In addition, other immunocompromising statuses include cancer chemotherapy, organ transplantation, long-term corticosteroid therapy, chronic lung diseases, and inflammatory or autoimmune diseases (for example, lupus or rheumatoid arthritis) from PCP leading factors [4, 10, 11]. Also, it causes life-threatening pneumonic disorders in neonates [12]. HIV/AIDS is the main risk factor for 30–40% of PCP cases around the world [13]. PCP is usually a terminal event in HIV/AIDS patients, and much of the information we have about this infection comes from caring for patients with HIV/AIDS [14].

Recognition of at-risk patients is based on the severity of clinical symptoms(fever, cough, difficulty breathing, chest pain, and tiredness) in high-risk populations [15]. However, radiological examination and specific polymerase chain reaction (PCR) assay in sputum, bronchoalveolar lavage (BAL), tissue biopsies, and serum β-D-glucan levels (a part of the cell wall of many different types of fungi)should support the diagnosis of PCP [16–18]. Liu et al. [19] investigated the technical advantages of molecular methods, especially PCR-based methods, for the detection of P. jirovecii among BAL fluid specimens.

Without treatment, PCP can lead to severe uncontrolled consequences in the health status [8]. Trimethoprim/sulfamethoxazole(TMP/SMX), also known as co-trimoxazole, is used for PCP treatment and prophylaxis in HIV and non-HIV populations [20–22]. Recently, progressive achievements in designing antiretrovirals have decreased the prevalence of HIV-associated PCP (HAP) [23]. The mortality rate of PCP is elevated due to the abrupt occurrence of respiratory failure and delay in diagnosis [24, 25].

Here, we designed this analysis to provide accurate statistics of AIDS-defining PCP. The results of our study will be suitable for researchers and health policy-makers to manage and develop preventative strategies for infection control.

Methods

Search strategy

The present study is conducted and reported according to PRISMA 2020 guideline [26] (S1 Checklist). We developed a broad search strategy to identify studies that reported PCP among HIV/AIDS population. In our systematic review, the search terms "HIV/AIDS,""HIV,""AIDS,""Pneumocystis,""Pneumocystis jirovecii,""pneumocystosis,""Human Immunodeficiency Virus,"and related terms and words for relevant studies published in PubMed, Web of Science, Scopus, Google Scholar, and ProQuest between January 2000and December 2022 were used. No linguistic or geographical limits were applied. We hand-searched bibliographies of all recovered articles for potentially eligible studies and contacted corresponding authors for published or unpublished data if needed. January 2000 was chosen as the cut-off because we aimed to assay studies published during the past 22 years.

Selection criteria

Titles and abstracts of references were screened, and the full texts of potentially relevant articles were independently assessed. Studies assessing a clearly defined population of HIV/AIDS and PCP in any clinical setting were included if they had specific diagnostic criteria for PCP. These were predefined using clinical case definitions [27] or confirmation with laboratory testing using molecular assays, such as PCR, sequencing, and matrix-assisted laser desorption-ionization time of flight mass spectrometry (MALDI-TOF MS) [16–18]. Inclusion criteria were as follows; patients with HIV/AIDS and PCP, all types of studies encompassing data about patients with HIV/AIDS and PCP infected simultaneously, including clinical trials, retrospective, prospective, and cohort studies, gray literature including conference reports, etc. Exclusion criteria were as follows; patients with HIV/AIDS and without PCP or patients who have other fungal infections than pneumocystosis, all review type studies (e.g., narrative, critical, systematic, and meta-analysis, and mini-reviews) case reports and case series, all studies including letters to the editor, and editorials, without patient data.

Data extraction

Three authors independently extracted data and compared it for consistency. Discussion and consensus resolved disagreements on final inclusions. The key variable was the proportion of PCP coinfection among the HIV/AIDS population. Prevalence was defined as the number of PCP cases (nominator) among patients with established HIV/AIDS(denominator). The following information was captured where available; PCP among HIV-negative patients, underlying risk factors, PCP prophylaxis, antiretroviral therapy, age and gender of the target population, laboratory parameters (e.g., serum levels of CD4+ T cells, β-D-glucan, and lactate dehydrogenase), and the outcome of patients (death or survival).

Risk of bias (quality) assessment

This research involved studies concerning a minimum of three participants to minimize the small-study effect. Authors independently assessed the quality according to the Hoy et al. checklist previously described [28, 29]. This checklist explored the various dimensions of empirical proof and methodological assumptions. If required, a consensus was voted by other coauthors to settle the disputes between the investigators. Moreover, the regression-based Egger, Begg’s-Mazumdar, and Harbord tests for small-study effects will apply to analyze publication bias for our search [30].

Data analysis

Meta-analysis was performed according to the DerSimonian and Laird method [31, 32], applying the random-effects model [33] in case of considerable heterogeneity, defined as I2>75%. We evaluated heterogeneity using the chi-square (χ2-based Q statistic, significant for Pvalue0<0.5) and the I2 statistic. StatsDirect version 2.7.9 (StatsDirect Ltd, Wirral-UK)and STATA version 17 (STATA corporation, USA) were used to perform calculations and the meta-analysis [34, 35]. Analysis via STATA was performed using the metan and metaprop commands [36, 37] for standard mean difference (SMD) calculation. Odds ratio (OR) analysis was performed for related data if their case(s) and control(s) details were available. Point estimates and 95% confidence intervals were derived using prevalence data from included studies for all outcomes. Where standard errors (SE) were not provided, we incorporated confidence intervals into the formula, SE = (upper limit–lower limit)/3.92. Subgroup analysisand meta-regression were used to determine the source of heterogeneity based on certain putative moderator factors, and sensitivity analysis was used to assess the reliability of our pooling results.

Results

After searches in the databases and removing duplicate and irrelevant records, our meta-analysis included fifty-five eligible studies (_((((xxx))))_)[38–92] (Table 1; Fig 1). The results of the quality assessment were added to Table 1. The overall score of 4.378 was reached for quality assessment, which means analyzed studies had a moderate risk of bias (Table 1). A total of38,554HIV/AIDS patients were included, and PCP was found in 2,880of them. Also, 4,044 PCP cases were reported among 79,893 HIV/AIDS-negative patients.

thumbnail
Download:
Fig 1. The flowchart of study identification and selection process.

https://doi.org/10.1371/journal.pone.0297619.g001

thumbnail
Download:
Table 1. Notice: Some of the studies in this table were not included in the odds-ratio analysis due to heterogeneity and bias assessment problems [110–117].

However, they were included in other analyses. YOP: year of publish, HIV: human immunodeficiency virus, PCP: pneumocystosis, HAP: HIV-associated pneumocystis, -: negative, +: positive, LDH: lactate dehydrogenase, BDG: β-D-glucan, ART: antiretroviral therapy, PFX: prophylaxis, QA: quality assessment, ND: not defined, L: low, M: moderate, H: high.

https://doi.org/10.1371/journal.pone.0297619.t001

Five studies were conducted from the USA [50–52, 68, 73]; three studies, each were conducted in South Africa [67, 72, 90], Japan [81, 84, 85], and Thailand [61, 78, 86]; two studies, each were conducted in Iran [75, 80], France [45, 66], and Mexico [40, 47]; one study each was conducted in Ethiopia [39], Tanzania [60], Malawi [57], Spain [38], Cameroon [76], India [54], Taiwan [89], Zambia [79], and a study was from five European countries (France, Austria, Belgium, Croatia, Germany) [70].

Almost all analyzed studies targeted respiratory tract samples to detect PCP among HIV/AIDS patients. In some cases, serum specimen was targeted. Different diagnostic methods, e.g., conventional and real-time PCR, targeting mitochondrial small and large subunits (mtSSU and mtLSU), fast-track diagnostic (FTD) methods capturing β-D-glucan, and microscopical diagnosis were applied.

The pooled prevalence of HIV-associated PCP

Our random-effects model showed that in twenty-nine eligible studies [38–40, 45, 47, 50–52, 54, 57, 60, 61, 66–68, 70, 72, 73, 75, 76, 78–81, 84–86, 89, 90], the pooled prevalence of HAP was 35.4% (95% CI:23.8 to 47.9; I2: 99.4%) (Table 2). There is a negligible publication bias between studies (intercept: 6.946; 95% CI:-24.750 to 38.642; P = 0.6566). The percent rates of HAP by country in twenty-nine eligible studies were as follows: USA5.16% (1854/35885), South Africa22.8% (128/559), Thailand64.66% (97/150), Japan 97.79% (443/453), Iran 12.35% (21/170), France 27.93% (69/247), Mexico 42.27%(52/110), Ethiopia 22.79% (49/215), Tanzania 0.469% (1/213), 11.19% (15/134), Spain 37.5% (3/8), Cameroon 42.85% (54/126), Taiwan 82.35% (14/17), Zambia 25% (47/188), India 33.33%(22/66), and a study in the five European countries 84.61% (11/13).

thumbnail
Download:
Table 2. HIV: human immunodeficiency virus, PCP: pneumocystosis, PRP: proportion, OR: odds ratio, SMD: standard mean difference, AM: America, AF: Africa, AS: Asia, EU: Europe, M: men, W: women, P: positive, N: negative, LDH: lactate dehydrogenase, BDG: β-D-glucan, ART: antiretroviral therapy, TB: tuberculosis.

https://doi.org/10.1371/journal.pone.0297619.t002

The pooled prevalence of PCP among the HIV-negative population

The results of the random-effect model showed that in twenty-nine eligible studies [38–40, 45, 47, 50–52, 54, 57, 60, 61, 66–68, 70, 72, 73, 75, 76, 78–81, 84–86, 89, 90], the pooled prevalence of PCP among the HIV-negative population was 10.158% (95% CI:2 to 25.3; I2: 99.9%). Also, analysis of publication bias using the Egger test model indicated an intercept rate of 14.326% (95% CI: -2.023 to 30.675; P = 0.0834)(Table 2). By country percent rates are as follows: USA 0% (0/70418), Zambia 0% (0/1115), Tanzania 0% (0/279), South Africa 4.40% (25/567), Thailand 9.83% (36/366), Japan 84.73% (3631/4285), Iran 6.52% (21/322), Ethiopia 3.55% (6/169), Malawi 3.07% (4/130), Spain 2.32% (1/43), Cameroon 18.9% (21/111), Taiwan 86.29% (107/124), India 16.59% (37/223), and a study in the five European countries 77.61% (104/134).

The relationship between HIV/AIDS and susceptibility to PCP

The results of the random effect model in twenty-nine included studies [38–40, 45, 47, 50–52, 54, 57, 60, 61, 66–68, 70, 72, 73, 75, 76, 78–81, 84–86, 89, 90] indicated that the prevalence of PCP among the HIV-positive population is almost 12 times higher than HIV-negative population (OR: 11.710; 95% CI:5.420 to 25.297;I2: 93.1%; P<0.0001) (Table 2; Fig 2). Also, the Egger test assay result indicated a negligible publication bias among analyzed studies (intercept: 1.416; 95% CI: 0.133 to 2.966; P = 0.1437) (Table 2; S1 Fig).

thumbnail
Download:
Fig 2. Forest plot of the prevalence OR of HAP.

https://doi.org/10.1371/journal.pone.0297619.g002

The intercontinental distribution of HIV-associated PCP

Our random-effects model showed that the pooled prevalence of HAP in four continents is as follows: America13% (95% CI:10 to 17; I2: 99.2%), Africa 24%(95% CI: 12 to 35; I2: 98.61%), Asia 52% (95% CI: 32 to 73; I2: 96.11%), and Europe 43% (95% CI: 22 to 64; I2: 90.05%) (Tables 2 and 3).

thumbnail
Download:
Table 3. The intercontinental distribution of HIV-associated PCP.

https://doi.org/10.1371/journal.pone.0297619.t003

Relationship between mortality and PCP among HIV-positive patients

In eleventen studies [54, 55, 57, 60, 61, 65, 87, 88, 90, 91], including 670 PCP cases among 1272 HIV-positive patients, death events were recorded in 124 and 210 cases, respectively. The results of our OR analysis indicated that the mortality rate increased by 52% in HAP patients (OR:1.522; 95% CI:0.959 to 2.416;I2: 53.8%; P = 0.022)(Table 2).

Relationship between PCP prophylaxis and HIV ART and PCP occurrence among HIV-positive patients

Related data were captured from twelve (for PCP prophylaxis) [46, 48, 56, 57, 60, 62, 71, 73, 79, 82, 83, 90] and eleven (for ART) [42, 51, 57, 60, 62, 63, 67, 69, 71, 76, 82] studies. The OR analysis results indicated that PCP prophylaxis in HIV/PCP-positive patients was used six times more than in HIV-positive PCP-negative patients (OR: 6.191; 95% CI:0.945 to 40.545; I2: 90.4%; P = 0.0472)(Table 2). Also, ART in HIV/PCP-positive patients was used three times more than in HIV-positive PCP-negative patients (OR: 3.356; 95% CI: 0.785 to 14.349;I2: 89.7%; P = 0.0012) (Table 2).

Relationship between age and sex with PCP occurrence among HIV-positive patients

The results of the OR analysis of patient gender captured from six studies [48, 60, 62, 74, 76, 82] indicated that HIV-positive men had a 7% higher chance rate for PCP compared to women (OR:1.073; 95% CI:0.674 to 1.706;I2: 0%; P = 0.959)(Table 2). The results of standard mean difference (SMD) analysis of patient’s age captured from twenty-one studies [40, 41, 44, 48, 49, 53, 55, 56, 58, 59, 61–65, 74, 77, 82, 88, 91, 92], including 1583 PCP patients among 2044 HIV-positive cases, indicated that there is no significant difference between HIV/AIDS patients with PCP and without PCP (SMD: -0.140; 95% CI:-0.315 to -0.034;I2: 78.6%;P = 0.000).

Variation of serological factors and/or BAL levels between HIV-positive patients with and without PCP

Our random effect models for SMD analysis of serum levels of CD4+ T cells [43, 49, 55, 56, 58–62, 74, 88, 91, 92], LDH [48, 55, 64, 65, 88], and BDG [45, 55, 59, 64, 92] in 12, 5, and 5 studies (respectively), indicated that serum levels of CD4+ T cells (SMD: -0.617; 95% CI:-1.122 to -0.111; I2: 95.1%;P = 0.000) and LDH (SMD: -0.089; 95% CI:-0.089 to 0.267; I2: 8.2%;P = 0.36) did not differ statistically between HIV/PCP-positive and HIV-positive PCP-negative patients. However, the mean serum and/or BAL levels of BDG of HIV/PCP-positive patients were higher than HIV-positive PCP-negatives (SMD: 2.664; 95% CI:1.110 to 4.217; I2: 97.7%;P = 0.000)(Table 2).

Risk factors for PCP

The random effect model for OR analysis indicated that smokers [56, 64, 76] (OR: 2.25; 95% CI 0.578 to 8.753) and patients with tuberculosis [39, 48, 76] (OR: 2.15; 95% CI 0.311 to 14.879) had a higher chance for PCP.

Discussion

Before the beginning of the HIV/AIDS epidemic in the 1980s, PCP was uncommon. But soon became one of the major AIDS-defining illnesses in the world. Also, during the COVID-19 pandemic, PCP, known as a COVID mimic, caused major health problems alongside superinfection [93, 94]. Liu et al. performed two valuable studies about the host immune responses to COVID superinfection [95, 96]. These studies indicated that immunity triggered by SARS-CoV-2 may restrict the pathogenicity of the second post-COVID infection, such as PCP. Also, several cytokine biomarkers may be the same in these two infections, alongside the clinical sign & symptoms. In the late 1980s, 75% of people living with AIDS developed PCP [97]. A study estimated the prevalence of HIV/AIDS in the U.S. and Canada, PCP was the most common opportunistic infection during 2008–2010 [98]. There were 10,590 hospitalizations due to PCP in the U.S. in 2017 [99]. Moreover, PCP is also a common opportunistic infection among people living with HIV/AIDS in developing countries [99]. Although the prevalence of HAP has significantly decreased due to ART and prophylactic therapy with TMP/SMX, it remains a public health concern [98, 100].

In this study, a total of 38,554 HIV/AIDS patients were included, and PCP was found in 2880 of them. However, 4,044 PCP cases were reported among 79,893 HIV-negative patients(Table 2). We resulted a pooled prevalence rate of 35.4% (95% CI: 23.8 to 47.9) for HAP and 10.16% (95% CI: 2 to 25.3) for PCP among the HIV-negative population(Table 2). Also, HIV-positive patients were susceptible to PCP 12 times more than the HIV-negative population (OR: 11.710;95% CI:5.420 to 25.297)(Table 2; Fig 2; S1 Fig). Here, we indicated the worldwide distribution of the HAP; patients were reported from four continents and distributed in eighteen countries(Tables 1 and 2). Asia had the highest prevalence rate (52%), followed by Europe (43%), Africa (24%), and America had the lowest prevalence rate, 13%. The prevalence percent rate by country indicated that Japan is the highest (97.79%; 443/453), followed by Taiwan (82.35%; 14/17) and Thailand (64.66%; 97/150). The lowest rate was reported for Tanzania (0.47%; 1/213). However, in HIV-negative population prevalence percent rate of PCP was highest in Taiwan 86.29% (107/124), followed by Japan 84.73% (3631/4285), Cameroon 18.9% (21/111), and India 16.59% (37/223). These rates were zero for USA 0% (0/70418), Zambia 0% (0/1115), and Tanzania 0% (0/279).

Unfortunately, we did not find a meta-analysis study that reports the global prevalence of HAP to compare with our results. However, two meta-analysis studies investigated the prevalence of PCP among HIV-positive adults in Africa [101, 102]. Wasserman et al. [101] studied 6,884 individuals from 18 countries in sub-Saharan Africa. The pooled prevalence of PCP among 6,018 patients from all clinical settings was 15.4% (95% CI: 12.9 to 18.0) and was highest amongst inpatients, 22.4% (95% CI: 17.2 to 27.7). They resulted that there was a trend of decreasing PCP prevalence amongst inpatients over time, from 28% (95% CI: 21 to 34) in the 1990s to 9% (95% CI: 8 to 10) after 2005. Another study by Wills et al. [102] conducted a systematic review and meta-analysis to evaluate P. jirovecii prevalence in African HIV-positive adults with or without respiratory symptoms. They reported a prevalence rate of 19% (95% CI: 12 to 27) among 3,583 symptomatic and a 9% [95% CI: 0 to 45] prevalence rate among 140 asymptomatic adults. They concluded that despite increased access to local HIV services, P. jirovecii remains common in Africa.

We resulted that the mortality rate increased by 52% in HAP patients compared to the HIV-positive PCP-negative population (OR: 1.522; 95% CI:0.959 to 2.416) (Table 2). Wasserman et al. [101] resulted an 18.8% (95% CI: 11.0 to 26.5)case fatality rate that PCP accounted for 6.5% (95% CI: 3.7 to 9.3) of their study deaths. Sonego et al. [103] designed a meta-analysis to evaluate risk factors for death from acute lower respiratory infections (ALRI) in 19,8359 children in low- and middle-income countries. Although they didn’t target HAP patients, they indicated that diagnosis of P. Carinii and HIV/AIDS increased the risk of death (OR: 4.79; 95% CI: 2.67 to 8.61) and (OR: 4.68; 95% CI: 3.72 to 5.90), respectively. Also, they indicated that personal factors, such as age below two months (OR: 5.22; 95% CI:1.70 to 16.03), chronic underlying diseases (OR: 4.76; 95% CI: 3.27 to 6.93), severe malnutrition (OR: 4.27; 95% CI: 3.47 to 5.25) increased that risk of death. Moreover, socioeconomic and environmental factors, such as maternal age (OR:1.84; 95% CI: 1.03 to 3.31); low maternal education (OR: 1.43; 95% CI: 1.13 to 1.82); low socioeconomic status (OR: 1.62; 1.32 to 2.00), indoor air pollution (OR: 3.02; 95% CI: 2.11 to 4.31) are significantly associated with increased death rates. However, immunization (OR: 0.46; 95% CI: 0.36 to 0.58) and good antenatal practices (OR: 0.50; 0.31 to 0.81) were associated with decreased odds of death. National-scale strategies seem needed to reduce mortality rates mediated by pulmonary infections, chiefly PCP, among HIV-positive populations.

We resulted that HIV/PCP-positive patients received PCP prophylaxis six times more than HIV-positive PCP-negative cases (Table 2). The main prophylactic agent in our analyzed studies was TMP/SMX. Although there was a lack of meta-analysis studies about the status of prophylactic agents’ consumption in HAP patients [104], we found three meta-analysis [105–107] of adjunctive corticosteroid therapy in these patients; however, we excluded one [105] due to the same authors’ list and published study. Bucher et al. [104] reported the suitable outcomes of TMP/SMX on 1,448 HIV/PCP-positive patients and indicated that TMP/SMX decreased the risk ratio (RR) of PCP (versus aerosolized pentamidine: RR:0.59; 95% CI: 0.45 to 0.76&versus dapsone/pyrimethamine: RR:0.4995% CI: 0.26 to 0.92). Briel et al. [106] resulted that RR for overall mortality for adjunctive corticosteroids was 0.56 (95% CI: 0.32 to 0.98) at one month and 0.68 (95% CI: 0.50 to 0.94) at 3 to 4 months of follow-up. In 2015 Ewald et al. [107], which have the same authors list with Briel et al., indicated that RR for overall mortality for adjunctive corticosteroids were 0.56 (95% CI: 0.32 to 0.98) at one month and 0.59 (95% CI: 0.41 to 0.85) at three to four months of follow-up. However, the number and size of trials of two recent studies were small (six eligible studies). Also, we found that ART in HIV/PCP-positive patients was used three times more than in HIV-positive PCP-negative patients (OR: 3.356; 95% CI:0.785 to 14.349)(Table 2). Bucher et al. [104] reported that 80.5% of their studied patients had received ART.

Here we indicated that HIV-positive men had a 7% higher chance rate for PCP than women (OR:1.073; 95% CI:0.674 to 1.706)(Table 2). Therefore, gender is not a potent risk factor for PCP among HIV-positive patients. However, Wasserman et al. [101] indicated that 39.6% of their study population were men. Also, SMD analysis of 1,583 PCP patients among 2,044 HIV-positive cases revealed no significant difference between HIV/AIDS patients with PCP and without PCP (SMD: -0.140; 95% CI:-0.315 to -0.034). Our SMD analysis showed that BDG serum mean levels in HIV/PCP patients were higher than in HIV-positive PCP-negative cases. Despite CD4+ T cells and LDH, no difference was observed in mean serum levels among the two groups. Bucher et al. [104] found that their studied patients’ mean CD4+ T cell counts ranged from 51 to 200 cells/mm3 (group mean, 115 cells/mm3). We found that HIV-positive smokers and tuberculosis patients are twice more susceptible to PCP. De et al. [108] investigated the influence of smoking cessation on PCP incidence in HIV patients. They indicated no evidence to support that smoking increased the incidence of PCP. However, they reported that current smokers were at higher risk of bacterial pneumonia than current non-smokers (HR: 1.73; 95%CI: 1.44 to 2.06).

During a valuable study, Elango et al. [109] investigated the epidemiology of PCP among HIV-positive patients in the U.S. Due to the publication bias and heterogeneity problems, we could not include this study in our final analysis; however, we read carefully and analyzed the OR of PCP-associated risk factors that were assayed in this study. They studied 148,624 HAP and 2,863,099 HIV-positive PCP-negative patients. The most associated risk factors for PCP are as follows; peripheral vascular diseases (OR: 3.467; 95% CI: 3.217 to 3.737), metastatic cancer (OR: 3.129; 95% CI: 2.865 to 3.417), paralysis (OR: 2.533; 95% CI: 2.387 to 2.687), and followed by solid tumor without metastasis (OR: 2.209; 95% CI: 2.076 to 2.350), rheumatoid arthritis (OR: 1.985; 95% CI: 1.816 to 2.165), diabetes mellitus (OR: 1.904; 95% CI: 1.866 to 1.943), Obesity (OR: 1.854; 95% CI: 1.785 to 1.926), renal failure (OR: 1.845; 95% CI: 1.816 to 1.893), hypertension (OR: 1.822; 95% CI: 1.797 to 1.846), chronic blood loss anemia (OR: 1.814; 95% CI: 1.705 to 1.929), hypothyroidism (OR: 1.716; 95% CI: 1.647 to 1.787), neurological disorders (OR: 1.552; 95% CI:1.516 to 1.589), chronic liver diseases (OR: 1.529; 95% CI: 1.500 to 1.559), lymphoma (OR: 1.531; 95% CI: 1.470 to 1.594), psychosis (OR: 1.502; 95% CI: 1.469 to 1.537), depression (OR: 1.360; 95% CI: 1.334 to 1.386), drug abuse (OR: 1.249; 95% CI: 1.232 to 1.266), valvular diseases (OR: 1.201; 95% CI: 1.149 to 1.257), congestive heart failure (OR: 1.147; 95% CI: 1.117 to 1.177). Moreover, peptic ulcer diseases (OR: 1.030; 95% CI: 0.854 to 1.241) and coagulopathy (OR: 0.967; 95% CI: 0.949 to 0.986) have not differed between PCP- positive and negatives. Moreover, the following underlying diseases are not considered a risk factor for PCP among HIV patients: chronic lung diseases (OR: 0.052; 95% CI: 0.051 to 0.053), weight loss (OR: 0.411; 95% CI: 0.406 to 0.417), fluid and electrolyte disorders (OR: 0.616; 0.610 to 0.622), deficiency anemias (OR: 0.668; 0.661 to 0.675), and pulmonary circulation disorders (OR: 0.681; 0.655 to 0.707).

Conclusion

Now, PCP is still a serious health concern for people living with HIV/AIDS or other conditions with a weakened immune system. The exact number of HAP cases is challenging to estimate because there is no national surveillance program in different countries. We reported a high prevalence, risk, and mortality rates of PCP among the HIV-positive population. We concluded that, despite ART and prophylactic therapy, prevalence and mortality rates of HAP remained high. Therefore, the control and management strategies should be revised and updated by health policy-makers on a worldwide scale. For better management and understanding of the epidemiology and characteristics of this coinfection, designing a large-scale meta-analysis is recommended every three years.

Supporting information

S1 Checklist. PRISMA guideline.

https://doi.org/10.1371/journal.pone.0297619.s001

(DOCX)

S1 Fig. L’Abbe and funnel plots for prevalence OR of HAP patients.

https://doi.org/10.1371/journal.pone.0297619.s002

(DOCX)

Acknowledgments

The authors are grateful to the Departments of Medical Mycology and Parasitology, Schools of Medicine, Tabriz and Shiraz Universities of Medical Sciences; also, Infectious and Tropical Disease Research Center, Tabriz University of Medical Sciences for their excellent supports.

References

  1. 1. Nevez G, Hauser PM, Le Gal S. Pneumocystis jirovecii. Trends in Microbiology. 2020;28(12):1034–5. pmid:33171104
  2. 2. Weyant RB, Kabbani D, Doucette K, Lau C, Cervera C. Pneumocystis jirovecii: a review with a focus on prevention and treatment. Expert Opinion on Pharmacotherapy. 2021;22(12):1579–92. pmid:33870843
  3. 3. Dellière S, Gits-Muselli M, Bretagne S, Alanio A. Outbreak-causing fungi: Pneumocystis jirovecii. Mycopathologia. 2020;185(5):783–800. pmid:31782069
  4. 4. Cillóniz C, Dominedò C, Álvarez-Martínez MJ, Moreno A, García F, Torres A, et al. Pneumocystis pneumonia in the twenty-first century: HIV-infected versus HIV-uninfected patients. Expert Review of Anti-Infective Therapy. 2019;17(10):787–801. pmid:31550942
  5. 5. Rodríguez YDA, Wissmann G, Müller A, Pederiva M, Brum M, Brackmann R, et al. Pneumocystis jirovecii pneumonia in developing countries. Parasite: journal de la Société Française de Parasitologie. 2011;18(3):219.
  6. 6. Vargas SL, Hughes WT, Santolaya ME, Ulloa AV, Ponce CA, Cabrera CE, et al. Search for primary infection by Pneumocystis carinii in a cohort of normal, healthy infants. Clinical infectious diseases. 2001;32(6):855–61. pmid:11247708
  7. 7. Medrano FJ, Montes-Cano M, Conde M, De La Horra C, Respaldiza N, Gasch A, et al. Pneumocystis jirovecii in general population. Emerging infectious diseases. 2005;11(2):245. pmid:15752442
  8. 8. Harris JR, Balajee SA, Park BJ. Pneumocystis jirovecii pneumonia: current knowledge and outstanding public health issues. Current Fungal Infection Reports. 2010;4(4):229–37.
  9. 9. Agarwal-Jans S. Timeline: HIV. Cell. 2020;183(2):550. pmid:33064990
  10. 10. Ghembaza A, Vautier M, Cacoub P, Pourcher V, Saadoun D. Risk factors and prevention of Pneumocystis jirovecii pneumonia in patients with autoimmune and inflammatory diseases. Chest. 2020;158(6):2323–32. pmid:32502592
  11. 11. Rekhtman S, Strunk A, Garg A. Incidence of pneumocystosis among patients exposed to immunosuppression. Journal of the American Academy of Dermatology. 2019;80(6):1602–7. pmid:30639289
  12. 12. Zakrzewska M, Roszkowska R, Zakrzewski M, Maciorkowska E. Pneumonia: Still a serious disease in children. Journal of Mother and Child. 2019;23(3):159–62.
  13. 13. Gold JA, Jackson BR, Benedict K, editors. Possible diagnostic delays and missed prevention opportunities in pneumocystis pneumonia patients without hiv: analysis of commercial insurance claims data—United States, 2011–2015. Open forum infectious diseases; 2020: Oxford University Press US.
    • 14. Greene WC. A history of AIDS: looking back to see ahead. European journal of immunology. 2007;37(S1):S94–S102. pmid:17972351
    • 15. Salzer HJ, Schäfer G, Hoenigl M, Günther G, Hoffmann C, Kalsdorf B, et al. Clinical, diagnostic, and treatment disparities between HIV-infected and non-HIV-infected immunocompromised patients with Pneumocystis jirovecii pneumonia. Respiration. 2018;96(1):52–65. pmid:29635251
    • 16. Bateman M, Oladele R, Kolls JK. Diagnosing Pneumocystis jirovecii pneumonia: A review of current methods and novel approaches. Medical Mycology. 2020;58(8):1015–28. pmid:32400869
    • 17. Guegan H, Robert-Gangneux F. Molecular diagnosis of Pneumocystis pneumonia in immunocompromised patients. Current Opinion in Infectious Diseases. 2019;32(4):314–21. pmid:31107250
    • 18. Issa N, Gabriel F, Baulier G, Mourissoux G, Accoceberry I, Guisset O, et al. Pneumocystosis and quantitative PCR. Medecine et maladies infectieuses. 2018;48(7):474–80. pmid:29789160
    • 19. Liu B, Totten M, Nematollahi S, Datta K, Memon W, Marimuthu S, et al. Development and evaluation of a fully automated molecular assay targeting the mitochondrial small subunit rRNA gene for the detection of Pneumocystis jirovecii in bronchoalveolar lavage fluid specimens. The Journal of Molecular Diagnostics. 2020;22(12):1482–93. pmid:33069878
    • 20. Braga BP, Prieto-González S, Hernández-Rodríguez J. Pneumocystis jirovecii pneumonia prophylaxis in immunocompromised patients with systemic autoimmune diseases. Medicina Clínica (English Edition). 2019;152(12):502–7. pmid:30853123
    • 21. Brakemeier S, Pfau A, Zukunft B, Budde K, Nickel P. Prophylaxis and treatment of Pneumocystis Jirovecii pneumonia after solid organ transplantation. Pharmacological research. 2018;134:61–7. pmid:29890253
    • 22. Park JW, Curtis JR, Moon J, Song YW, Kim S, Lee EB. Prophylactic effect of trimethoprim-sulfamethoxazole for pneumocystis pneumonia in patients with rheumatic diseases exposed to prolonged high-dose glucocorticoids. Annals of the rheumatic diseases. 2018;77(5):644–9. pmid:29092853
    • 23. Tasaka S. Recent advances in the diagnosis and management of Pneumocystis pneumonia. Tuberculosis and Respiratory Diseases. 2020;83(2):132. pmid:32185915
    • 24. Pereira-Díaz E, Moreno-Verdejo F, De la Horra C, Guerrero JA, Calderón EJ, Medrano FJ. Changing trends in the epidemiology and risk factors of Pneumocystis pneumonia in Spain. Frontiers in public health. 2019;7:275. pmid:31637227
    • 25. Wang Y, Zhou X, Saimi M, Huang X, Sun T, Fan G, et al. Risk factors of mortality from Pneumocystis pneumonia in non-HIV patients: a meta-analysis. Frontiers in Public Health. 2021;9:680108. pmid:34222179
    • 26. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Systematic reviews. 2021;10(1):1–11.
    • 27. White PL, Backx M, Barnes RA. Diagnosis and management of Pneumocystis jirovecii infection. Expert review of anti-infective therapy. 2017;15(5):435–47. pmid:28287010
    • 28. Munn Z, Moola S, Riitano D, Lisy K. The development of a critical appraisal tool for use in systematic reviews addressing questions of prevalence. International journal of health policy and management. 2014;3(3):123. pmid:25197676
    • 29. Hoy D, Brooks P, Woolf A, Blyth F, March L, Bain C, et al. Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement. Journal of clinical epidemiology. 2012;65(9):934–9. pmid:22742910
    • 30. Lin L, Chu H. Quantifying publication bias in meta-analysis. Biometrics. 2018;74(3):785–94. pmid:29141096
    • 31. Jackson D, Bowden J, Baker R. How does the DerSimonian and Laird procedure for random effects meta-analysis compare with its more efficient but harder to compute counterparts? Journal of Statistical Planning and Inference. 2010;140(4):961–70.
    • 32. Jackson D, White IR, Thompson SG. Extending DerSimonian and Laird’s methodology to perform multivariate random effects meta-analyses. Statistics in medicine. 2010;29(12):1282–97. pmid:19408255
    • 33. DerSimonian R, Kacker R. Random-effects model for meta-analysis of clinical trials: an update. Contemporary clinical trials. 2007;28(2):105–14. pmid:16807131
    • 34. Freemantle N. StatsDirect—statistical software for medical research in the 21st century. Bmj. 2000;321(7275):1536.
    • 35. Fisher DJ, Zwahlen M, Egger M, Higgins JP. Meta-Analysis in Stata. Systematic Reviews in Health Research: Meta-Analysis in Context. 2022:481–509.
    • 36. Harris RJ, Deeks JJ, Altman DG, Bradburn MJ, Harbord RM, Sterne JA. Metan: fixed-and random-effects meta-analysis. The Stata Journal. 2008;8(1):3–28.
    • 37. Nyaga VN, Arbyn M, Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Archives of Public Health. 2014;72(1):1–10.
    • 38. Acosta J, Catalan M, del Palacio-Peréz-Medel A, Lora D, Montejo J-C, Cuetara M-S, et al. A prospective comparison of galactomannan in bronchoalveolar lavage fluid for the diagnosis of pulmonary invasive aspergillosis in medical patients under intensive care: comparison with the diagnostic performance of galactomannan and of (1→ 3)–β–d-glucan chromogenic assay in serum samples. Clinical Microbiology and Infection. 2011;17(7):1053–60.
    • 39. Aderaye G, Bruchfeld J, Olsson M, Lindquist L. Occurrence of Pneumocystis carinii in HIV-positive patients with suspected pulmonary tuberculosis in Ethiopia. Aids. 2003;17(3):435–40. pmid:12556698
    • 40. Alcántara-Mojica A, Delhaes L, Ramírez-Corona F, Sánchez-Paredes E, Córdova-Martínez É, Morales-Villarreal FR, et al. Pneumocystis jirovecii detection and genotyping from HIV-positive and HIV-negative Mexican patient samples. Gac Med Mex. 2019;155:348–55.
    • 41. Almaghrabi RS, Alfuraih S, Alohaly R, Mohammed S, Alrajhi AA, Omrani AS. Pneumocystis jiroveci pneumonia in HIV-positive and HIV-negative patients: A single-center retrospective study. Tanaffos. 2019;18(3):238. pmid:32411264
    • 42. Azimi S, Sabokbar A, Bairami A, Gharavi MJ. Evaluation of three different laboratory methods for identification of pneumocystis jirovecii pneumonia (PCP) among HIV positive asymptomatic prisoners. Iranian Journal of Parasitology. 2019;14(2):280. pmid:31543916
    • 43. Azovtseva OV, Viktorova EA. Visceral Mycoses as a Cause of Severe HIV Infection and Death. International Archives of Allergy and Immunology. 2021;182(9):888–94. pmid:33882486
    • 44. Bienvenu A-L, Traore K, Plekhanova I, Bouchrik M, Bossard C, Picot S. Pneumocystis pneumonia suspected cases in 604 non-HIV and HIV patients. International Journal of Infectious Diseases. 2016;46:11–7. pmid:27021532
    • 45. Bigot J, Vellaissamy S, Senghor Y, Hennequin C, Guitard J. Usefulness of ß-d-Glucan Assay for the First-Line Diagnosis of Pneumocystis Pneumonia and for Discriminating between Pneumocystis Colonization and Pneumocystis Pneumonia. Journal of Fungi. 2022;8(7):663.
    • 46. Bozorgomid A, Hamzavi Y, H Khayat S, Mahdavian B, Bashiri H. Pneumocystis jirovecii pneumonia and human immunodeficiency virus co-infection in western iran. Iranian Journal of Public Health. 2019;48(11):2065. pmid:31970106
    • 47. Carreto-Binaghi LE, Morales-Villarreal FR, García-de la Torre G, Vite-Garín T, Ramirez J-A, Aliouat E-M, et al. Histoplasma capsulatum and Pneumocystis jirovecii coinfection in hospitalized HIV and non-HIV patients from a tertiary care hospital in Mexico. International Journal of Infectious Diseases. 2019;86:65–72. pmid:31207386
    • 48. Chagas OJ, Nagatomo PP, Pereira-Chioccola VL, Gava R, Buccheri R, Del Negro GMB, et al. Performance of a Real Time PCR for Pneumocystis jirovecii Identification in Induced Sputum of AIDS Patients: Differentiation between Pneumonia and Colonization. Journal of Fungi. 2022;8(3):222. pmid:35330224
    • 49. Christe A, Walti L, Charimo J, Rauch A, Furrer H, Meyer A, et al. Imaging patterns of Pneumocystis jirovecii pneumonia in HIV-positive and renal transplant patients-a multicentre study. Swiss medical weekly. 2019;149. pmid:31580472
    • 50. Crothers K, Daly KR, Rimland D, Goetz MB, Gibert CL, Butt AA, et al. Decreased serum antibody responses to recombinant Pneumocystis antigens in HIV-infected and uninfected current smokers. Clinical and Vaccine Immunology. 2011;18(3):380–6. pmid:21191078
    • 51. Crothers K, Huang L, Goulet JL, Goetz MB, Brown ST, Rodriguez-Barradas MC, et al. HIV infection and risk for incident pulmonary diseases in the combination antiretroviral therapy era. American journal of respiratory and critical care medicine. 2011;183(3):388–95. pmid:20851926
    • 52. Daly KR, Fichtenbaum CJ, Tanaka R, Linke MJ, O’Bert R, Thullen TD, et al. Serologic responses to epitopes of the major surface glycoprotein of Pneumocystis jiroveci differ in human immunodeficiency virus–infected and uninfected persons. The Journal of infectious diseases. 2002;186(5):644–51. pmid:12195351
    • 53. de Figueiredo IR, Alves RV, Borges DD, Torres M, Lourenço F, Antunes A, et al. Pneumocystosis pneumonia: a comparison study between HIV and non-HIV immunocompromised patients. Pulmonology. 2019;25(5):271–4. pmid:31076291
    • 54. Dhanalakshmi S, Gupta R, Varughese S, Varghese GM, George B, Michael JS. Effectiveness of a real-time PCR for diagnosis of Pneumocystis pneumonia in immunocompromised patients–Experience from a tertiary care center, India. Journal of Medical Mycology. 2022;32(2):101241. pmid:34999296
    • 55. Feng Q, Hao J, Li A, Tong Z. Nomograms for Death from Pneumocystis jirovecii Pneumonia in HIV-Uninfected and HIV-Infected Patients. International Journal of General Medicine. 2022;15:3055. pmid:35313548
    • 56. Fraczek M, Ahmad S, Richardson M, Kirwan M, Bowyer P, Denning D, et al. Detection of Pneumocystis jirovecii by quantitative real-time PCR in oral rinses from Pneumocystis pneumonia asymptomatic human immunodeficiency virus patients. Journal de Mycologie Médicale. 2019;29(2):107–11. pmid:31047784
    • 57. Graham SM, Mankhambo L, Phiri A, Kaunda S, Chikaonda T, Mukaka M, et al. Impact of human immunodeficiency virus infection on the etiology and outcome of severe pneumonia in Malawian children. The Pediatric infectious disease journal. 2011;30(1):33–8. pmid:21173674
    • 58. Hammarström H, Grankvist A, Broman I, Kondori N, Wennerås C, Gisslen M, et al. Serum-based diagnosis of Pneumocystis pneumonia by detection of Pneumocystis jirovecii DNA and 1, 3-β-D-glucan in HIV-infected patients: a retrospective case control study. BMC Infectious Diseases. 2019;19(1):1–10.
    • 59. Huang Y, He X, Chen H, Harypursat V, Lu Y, Yuan J, et al. No Statistically Apparent Difference in Antifungal Effectiveness Observed Among Trimethoprim/Sulfamethoxazole Plus Clindamycin or Caspofungin, and Trimethoprim/Sulfamethoxazole Monotherapy in HIV-Infected Patients with Moderate to Severe Pneumocystis Pneumonia: Results of an Observational Multicenter Cohort Study. Infectious diseases and therapy. 2022;11(1):543–57. pmid:35050490
    • 60. Jensen L, Jensen AV, Praygod G, Kidola J, Faurholt-Jepsen D, Changalucha J, et al. Infrequent detection of Pneumocystis jirovecii by PCR in oral wash specimens from TB patients with or without HIV and healthy contacts in Tanzania. BMC infectious diseases. 2010;10(1):1–7. pmid:20509902
    • 61. Jitmuang A, Nititammaluk A, Boonsong T, Sarasombath PT, Sompradeekul S, Chayakulkeeree M. A novel droplet digital polymerase chain reaction for diagnosis of Pneumocystis pneumonia (PCP)-a clinical performance study and survey of sulfamethoxazole-trimethoprim resistant mutations. Journal of Infection. 2021;83(6):701–8. pmid:34562541
    • 62. Juniper T, Eades CP, Gil E, Fodder H, Quinn K, Morris-Jones S, et al. Use of β-D-glucan in diagnosis of suspected Pneumocystis jirovecii pneumonia in adults with HIV infection. International journal of STD & AIDS. 2021;32(11):1074–7.
    • 63. Kasahara T, Imahashi M, Hashiba C, Mori M, Kogure A, Yokomaku Y, et al. Retrospective Analysis of the Efficacy of Early Antiretroviral Therapy in HIV-1-Infected Patients Coinfected with Pneumocystis jirovecii. AIDS Research and Human Retroviruses. 2021;37(10):754–60. pmid:34235941
    • 64. Kato H, Samukawa S, Takahashi H, Nakajima H. Diagnosis and treatment of Pneumocystis jirovecii pneumonia in HIV-infected or non-HIV-infected patients—difficulties in diagnosis and adverse effects of trimethoprim-sulfamethoxazole. Journal of Infection and Chemotherapy. 2019;25(11):920–4. pmid:31300379
    • 65. Kim T-O, Lee J-K, Kwon Y-S, Kim Y-I, Lim S-C, Kim M-S, et al. Clinical characteristics and prognosis of patients with Pneumocystis jirovecii pneumonia without a compromised illness. Plos one. 2021;16(2):e0246296. pmid:33539407
    • 66. Louis M, Guitard J, Jodar M, Ancelle T, Magne D, Lascols O, et al. Impact of HIV infection status on interpretation of quantitative PCR for detection of Pneumocystis jirovecii. Journal of Clinical Microbiology. 2015;53(12):3870–5. pmid:26468505
    • 67. Maartens G, Griesel R, Dube F, Nicol M, Mendelson M. Etiology of Pulmonary Infections in Human Immunodeficiency Virus–infected Inpatients Using Sputum Multiplex Real-time Polymerase Chain Reaction. Clinical Infectious Diseases. 2020;70(6):1147–52. pmid:31286137
    • 68. Makinson A, Park LS, Stone K, Tate J, Rodriguez-Barradas MC, Brown ST, et al., editors. Risks of opportunistic infections in people with human immunodeficiency virus with cancers treated with chemotherapy. Open forum infectious diseases; 2021: Oxford University Press US.
      • 69. Marjani M, Moeinpour M, Moniri A, Khabiri S, Hashemian SM, Tabarsi P, et al. Etiology of Respiratory Complications among Iranian HIV Infected Patients. Tanaffos. 2019;18(2):96. pmid:32440296
      • 70. Mercier T, Aissaoui N, Gits-Muselli M, Hamane S, Prattes J, Kessler HH, et al. Variable correlation between bronchoalveolar lavage fluid fungal load and serum-(1, 3)-β-D-glucan in patients with pneumocystosis—A multicenter ECMM Excellence Center study. Journal of Fungi. 2020;6(4):327.
      • 71. Moore DP, Baillie VL, Mudau A, Wadula J, Adams T, Mangera S, et al. 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. The Pediatric infectious disease journal. 2021;40(9):S69. pmid:34448746
      • 72. Morrow BM, Samuel CM, Zampoli M, Whitelaw A, Zar HJ. Pneumocystis pneumonia in South African children diagnosed by molecular methods. BMC research notes. 2014;7(1):1–6. pmid:24410938
      • 73. Park DR, Sherbin VL, Goodman MS, Pacifico AD, Rubenfeld GD, Polissar NL, et al. The etiology of community-acquired pneumonia at an urban public hospital: influence of human immunodeficiency virus infection and initial severity of illness. The Journal of infectious diseases. 2001;184(3):268–77. pmid:11443551
      • 74. Qiao L, Cui X, Jia L, Gao Y, Wang W, Wei F, et al. Peripheral immune phenotypes and T cell receptor repertoire in pneumocystis pneumonia in HIV-1 infected patients. Clinical Immunology. 2022;237:108985. pmid:35346863
      • 75. Rafat Z, Ashrafi K, Hashemi SJ, Sasani E, Naserani A, Sarvestani HK, et al. The mycological and molecular study of Pneumocystis jiroveci pneumonia among HIV and non-HIV immunocompromised patients hospitalized in pulmonary units in Guilan, northern Iran. Iranian Journal of Microbiology. 2021;13(4):518. pmid:34557281
      • 76. Riebold D, Enoh D, Kinge T, Akam W, Bumah M, Russow K, et al. Pneumocystis jirovecii colonisation in HIV-positive and HIV-negative subjects in Cameroon. Tropical Medicine & International Health. 2014;19(6):643–55. pmid:24645978
      • 77. Rilinger J, Staudacher DL, Rieg S, Duerschmied D, Bode C, Wengenmayer T. Extracorporeal membrane oxygenation in Pneumocystis jirovecii pneumonia: outcome in HIV and non-HIV patients. Critical Care. 2019;23(1):1–3.
      • 78. Sarasombath PT, Thongpiya J, Chulanetra M, Wijit S, Chinabut P, Ongrotchanakun J, et al. Quantitative PCR to discriminate between pneumocystis pneumonia and colonization in HIV and Non-HIV immunocompromised patients. Frontiers in microbiology. 2021;12. pmid:34745031
      • 79. Seidenberg P, Mwananyanda L, Chipeta J, Kwenda G, Mulindwa JM, Mwansa J, et al. The etiology of pneumonia in HIV-infected Zambian children: findings from the Pneumonia Etiology Research for Child Health (PERCH) Study. The Pediatric infectious disease journal. 2021;40(9):S50. pmid:34448744
      • 80. Sheikholeslami M-F, Sadraei J, Farnia P, Forozandeh Moghadam M, Emadikochak H. Dihydropteroate synthase gene mutation rates in Pneumocystis jirovecii strains obtained from Iranian HIV-positive and non-HIV-positive patients. Medical mycology. 2015;53(4):361–8. pmid:25631478
      • 81. Shoji K, Michihata N, Miyairi I, Matsui H, Fushimi K, Yasunaga H. Recent epidemiology of Pneumocystis pneumonia in Japan. Journal of Infection and Chemotherapy. 2020;26(12):1260–4. pmid:32753118
      • 82. Singh Y, Mirdha BR, Guleria R, Kabra SK, Mohan A, Chaudhry R, et al. Novel dihydropteroate synthase gene mutation in Pneumocystis jirovecii among HIV-infected patients in India: Putative association with drug resistance and mortality. Journal of Global Antimicrobial Resistance. 2019;17:236–9. pmid:30658203
      • 83. Spottiswoode N, Bloomstein JD, Caldera S, Sessolo A, McCauley K, Byanyima P, et al. Pneumonia surveillance with culture-independent metatranscriptomics in HIV-positive adults in Uganda: a cross-sectional study. The Lancet Microbe. 2022;3(5):e357–e65. pmid:35544096
      • 84. Tasaka S, Hasegawa N, Kobayashi S, Yamada W, Nishimura T, Takeuchi T, et al. Serum indicators for the diagnosis of pneumocystis pneumonia. Chest. 2007;131(4):1173–80. pmid:17426225
      • 85. Tasaka S, Kobayashi S, Yagi K, Asami T, Namkoong H, Yamasawa W, et al. Serum (1→ 3) β-D-glucan assay for discrimination between Pneumocystis jirovecii pneumonia and colonization. Journal of Infection and Chemotherapy. 2014;20(11):678–81.
      • 86. Tia T, Putaporntip C, Kosuwin R, Kongpolprom N, Kawkitinarong K, Jongwutiwes S. A highly sensitive novel PCR assay for detection of Pneumocystis jirovecii DNA in bronchoalveloar lavage specimens from immunocompromised patients. Clinical microbiology and infection. 2012;18(6):598–603. pmid:21951463
      • 87. Ueckermann V, Janse van Rensburg L, Pannell N, Ehlers M. Characteristics and outcomes of patients admitted to a tertiary academic hospital in Pretoria with HIV and severe pneumonia: a retrospective cohort study. BMC Infectious Diseases. 2022;22(1):1–7.
      • 88. Xue T, Du W-Q, Dai W-J, Li Y-S, Wang S-F, Wang J-L, et al. Genetic Polymorphisms of in HIV-Positive and HIV-Negative Patients in Northern China. Polish Journal of Microbiology. 2022;71(1):27–34.
      • 89. Yang S-L, Wen Y-H, Wu Y-S, Wang M-C, Chang P-Y, Yang S, et al. Diagnosis of Pneumocystis pneumonia by real-time PCR in patients with various underlying diseases. Journal of Microbiology, Immunology and Infection. 2020;53(5):785–90. pmid:31635929
      • 90. Zar H, Hanslo D, Tannenbaum E, Klein M, Argent A, Eley B, et al. Aetiology and outcome of pneumonia in human immunodeficiency virus-infected children hospitalized in South Africa. Acta Paediatrica. 2001;90(2):119–25. pmid:11236037
      • 91. Zeng Y-M, Li Y, Lu Y-Q, Liu M, Nie J-M, Yuan J, et al. Initiating antiretroviral therapy within 2 weeks of anti-Pneumocystis treatment does not increase mortality or AIDS-defining events in patients with HIV-associated moderate to severe Pneumocystis pneumonia: results of a prospective observational multicenter study. BMC Pulmonary Medicine. 2022;22(1):1–9.
      • 92. Zhu M, Ye N, Xu J. Clinical characteristics and prevalence of dihydropteroate synthase gene mutations in Pneumocystis jirovecii-infected AIDS patients from low endemic areas of China. Plos one. 2020;15(9):e0238184. pmid:32911508
      • 93. Bretagne S, Sitbon K, Botterel F, Dellière S, Letscher-Bru V, Chouaki T, et al. COVID-19-associated pulmonary aspergillosis, fungemia, and pneumocystosis in the intensive care unit: a retrospective multicenter observational cohort during the first French pandemic wave. Microbiology spectrum. 2021;9(2):e01138–21. pmid:34668768
      • 94. Khodadadi H, Ahmadpour E, Nami S, Mohammadi R, Hosseini H, Behravan M, et al. Global prevalence, mortality, and main risk factors for COVID-19 associated pneumocystosis: A systematic review and meta-analysis. Asian Pacific Journal of Tropical Medicine. 2022;15(10):431.
      • 95. Liu BM, Hill HR. Role of host immune and inflammatory responses in COVID-19 cases with underlying primary immunodeficiency: a review. Journal of Interferon & Cytokine Research. 2020;40(12):549–54. pmid:33337932
      • 96. Liu BM, Martins TB, Peterson LK, Hill HR. Clinical significance of measuring serum cytokine levels as inflammatory biomarkers in adult and pediatric COVID-19 cases: A review. Cytokine. 2021;142:155478. pmid:33667962
      • 97. Hay JW, Osmond DH, Jacobson MA. Projecting the medical costs of AIDS and ARC in the United States. JAIDS Journal of Acquired Immune Deficiency Syndromes. 1988;1(5):466–85. pmid:3065476
      • 98. Buchacz K, Baker RK, Palella FJ Jr, Chmiel JS, Lichtenstein KA, Novak RM, et al. AIDS-defining opportunistic illnesses in US patients, 1994–2007: a cohort study. Aids. 2010;24(10):1549–59. pmid:20502317
      • 99. Benedict K, Jackson BR, Chiller T, Beer KD. Estimation of direct healthcare costs of fungal diseases in the United States. Clinical Infectious Diseases. 2019;68(11):1791–7. pmid:30204844
      • 100. Kelley CF, Checkley W, Mannino DM, Franco-Paredes C, Del Rio C, Holguin F. Trends in hospitalizations for AIDS-associated Pneumocystis jirovecii pneumonia in the United States (1986 to 2005). Chest. 2009;136(1):190–7. pmid:19255292
      • 101. Wasserman S, Engel ME, Griesel R, Mendelson M. Burden of pneumocystis pneumonia in HIV-infected adults in sub-Saharan Africa: a systematic review and meta-analysis. BMC infectious diseases. 2016;16(1):1–9. pmid:27612639
      • 102. Wills NK, Lawrence DS, Botsile E, Tenforde MW, Jarvis JN. The prevalence of laboratory-confirmed Pneumocystis jirovecii in HIV-infected adults in Africa: A systematic review and meta-analysis. Medical mycology. 2021;59(8):802–12. pmid:33578417
      • 103. Sonego M, Pellegrin MC, Becker G, Lazzerini M. Risk factors for mortality from acute lower respiratory infections (ALRI) in children under five years of age in low and middle-income countries: a systematic review and meta-analysis of observational studies. PloS one. 2015;10(1):e0116380. pmid:25635911
      • 104. Bucher HC, Griffith L, Guyatt GH, Opravil M. Meta-analysis of prophylactic treatments against Pneumocystis carinii pneumonia and toxoplasma encephalitis in HIV-infected patients. JAIDS Journal of Acquired Immune Deficiency Syndromes. 1997;15(2):104–14. pmid:9241108
      • 105. Briel M, Boscacci R, Furrer H, Bucher HC. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV infection: a meta-analysis of randomised controlled trials. BMC infectious diseases. 2005;5(1):1–8. pmid:16271157
      • 106. Briel M, Bucher H, Boscacci R, Furrer H. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV-infection. Cochrane database of systematic reviews. 2006;(3). pmid:16856118
      • 107. Ewald H, Raatz H, Boscacci R, Furrer H, Bucher HC, Briel M. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV infection. Cochrane database of systematic reviews. 2015;(4). pmid:25835432
      • 108. De P, Farley A, Lindson N, Aveyard P. Systematic review and meta-analysis: influence of smoking cessation on incidence of pneumonia in HIV. BMC medicine. 2013;11(1):1–12. pmid:23339513
      • 109. Elango K, Mudgal M, Murthi S, Yella PR, Nagrecha S, Srinivasan V, et al. Trends in the Epidemiology and Outcomes of Pneumocystis Pneumonia among Human Immunodeficiency Virus (HIV) Hospitalizations. International Journal of Environmental Research and Public Health. 2022;19(5):2768. pmid:35270461
      • 110. Ali M, Razok A, Gassim M, Elmaki N, Goravey W, Alkhal A, et al. HIV and AIDS-defining opportunistic illnesses in the state of Qatar: A cohort population-based retrospective study covering 17 years (2000–2016). Annals of Medicine and Surgery. 2022;78. pmid:35734645
      • 111. de Armas Y, Capó V, Bornay-Linares FJ, Del Águila C, Matos O, Calderón EJ. Pneumocystis jirovecii and microsporidia: An unusual coinfection in HIV patients? Medical Mycology. 2020;58(8):1191–4. pmid:32497173
      • 112. Pansu N, Le Moing V, Poizot-Martin I, Joly V, Allavena C, Hocqueloux L, et al., editors. Pneumocystis jirovecii Pneumonia and Toxoplasmosis in PWH With HIV-Controlled Disease Treated for Solid Malignancies: A DAT’AIDS Study. Open Forum Infectious Diseases; 2022: Oxford University Press US.
        • 113. Schäfer G, Hoffmann C, Arasteh K, Schürmann D, Stephan C, Jensen B, et al. Immediate versus deferred antiretroviral therapy in HIV-infected patients presenting with acute AIDS-defining events (toxoplasmosis, Pneumocystis jirovecii-pneumonia): a prospective, randomized, open-label multicenter study (IDEAL-study). AIDS research and therapy. 2019;16:1–8.
        • 114. Tang Y-F, Wang Y, Xue T-J, Liu G, Chen Q, Zhao W, et al. Clinical Characteristics of HIV-Infected Patients with Venous Thromboembolism and Different CD4+ T Lymphocyte Levels. Journal of inflammation research. 2022:613–20. pmid:35115809
        • 115. Wójtowicz A, Bibert S, Taffé P, Bernasconi E, Furrer H, Günthard HF, et al. IL-4 polymorphism influences susceptibility to Pneumocystis jirovecii pneumonia in HIV-positive patients. Aids. 2019;33(11):1719–27. pmid:31225812
        • 116. Yanagisawa K, Wichukchinda N, Tsuchiya N, Yasunami M, Rojanawiwat A, Tanaka H, et al. Deficiency of mannose-binding lectin is a risk of Pneumocystis jirovecii pneumonia in a natural history cohort of people living with HIV/AIDS in Northern Thailand. Plos one. 2020;15(12):e0242438. pmid:33362211
        • 117. Zar HJ, Nduru P, Stadler JA, Gray D, Barnett W, Lesosky M, et al. Early-life respiratory syncytial virus lower respiratory tract infection in a South African birth cohort: epidemiology and effect on lung health. The Lancet Global health. 2020;8(10):e1316–e25. pmid:32971054