Multilocus Genotyping of Pneumocystis jirovecii in Patients Developing Diverse Forms of Parasitism: Implication for a Wide Human Reservoir for the Fungus

ABSTRACT. Pneumocystis jirovecii ITS and DHPS genotypes were identified in 3 patient groups developing diverse forms of P. jirovecii infections: 13 patients with Pneumocystis pneumonia, 8 patients merely colonized by the fungus, and 19 immunocompetent infants with bronchiolitis developing mild P. jirovecii infection. Common P. jirovecii genotypes were found in the 3 patient groups, suggesting that common sources of P. jirovecii were involved in the fungus acquisition, and that transmission cycles of P. jirovecii infections in these patient groups are not independent. Parasitized patients, whatever the form of parasitism they present, may he part of a common reservoir for P. jirovecii.     

Outbreak-Causing Fungi: Pneumocystis jirovecii

Mycopathologia - Pneumocystis jirovecii pneumonia (PCP) is an important cause of morbidity in immunocompromised patients, with a higher mortality in non-HIV than in HIV patients. P. jirovecii is...     

Pneumocystis Pneumonia: Epidemiology and Options for Prophylaxis in Non-HIV Immunocompromised Pediatric Patients

The pediatric population of non-HIV immunocompromised patients at risk for Pneumocystis pneumonia (PCP) continues to increase. While prophylactic therapy can be highly effective in preventing this opportunistic pathogen, identifying the at-risk populations appropriate for use of prophylaxis and navigating the risks and benefits of each therapeutic option can be challenging. In this article, the available epidemiology for baseline rates of PCP is presented for a variety of non-HIV immunocompromised pediatric populations. Additionally, the comparative effectiveness and side effect profiles for trimethoprim/sulfamethoxazole, dapsone, atovaquone, and pentamidine are discussed. Institutions are encouraged to review the data and to establish and implement a local practice guideline for PCP prophylaxis that can be monitored for effectiveness over time. An example of a standardized practice guideline is suggested.     

Pneumocystis jirovecii pneumonia in developing countries

Pneumocystis pneumonia (PcP) is a serious fungal infection among immunocompromised patients. In developed countries, the epidemiology and clinical spectrum of PcP have been clearly defined and well documented. However, in most developing countries, relatively little is known about the prevalence of pneumocystosis. Several articles covering African, Asian and American countries were reviewed in the present study. PcP was identified as a frequent opportunistic infection in AIDS patients from different geographic regions. A trend to an increasing rate of PcP was apparent in developing countries from 2002 to 2010.     

Epidemiology of Pneumocystis jirovecii Pneumonia in Venezuela

Current Fungal Infection Reports - The aim of this work is to contribute to the knowledge of the epidemiology of pneumocystosis or Pneumocystis jirovecii pneumonia (PCP) in Venezuela, by an updated...     

Pneumocystis jirovecii colonization in chronic pulmonary disease

Pneumocystis jirovecii causes pneumonia in immunosuppressed individuals. However, it has been reported the detection of low levels of Pneumocystis DNA in patients without signs and symptoms of pneumonia, which likely represents colonization. Several studies performed in animals models and in humans have demonstrated that Pneumocystis induces a local and a systemic response in the host. Since P jirovecii colonization has been found in patients with chronic pulmonary diseases it has been suggested that P jirovecii may play a role in the physiopathology and progression of those diseases. In this report we revise P. jirovecii colonization in different chronic pulmonary diseases such us, chronic obstructive pulmonary disease, interstitial lung diseases, cystic fibrosis and lung cancer.     

Pneumocystis Pneumonia in HIV-Infected and Immunocompromised Non-HIV Infected Patients: A Retrospective Study of Two Centers in China

Background

Pneumocystis pneumonia (PCP) is an emerging infectious disease in immunocompromised hosts. However, the clinical characteristics of these patients are poorly understood in mainland China.

Methods

We performed a retrospective study of PCP from 2008 to 2012. Information was collected regarding clinical manifestations, hospitalization, and outcome. A prognostic analysis was performed using a Cox regression model.

Results

151 cases of PCP were included; 46 non-HIV and 105 HIV cases. All-cause mortality (15.2% vs. 12.4%, p = 0.64) and the results of time-to-event analysis (log-rank test, p = 0.62) were similar between non-HIV and HIV infected cases, respectively. From 2008 to 2012, time from admission to initial treatment in non-HIV infected PCP patients showed declining trend [median (range) 20 (9–44) vs. 12 (4–24) vs. 9 (2–23) vs. 7 (2–22) vs. 7 (1–14) days]. A similar trend was observed for all-cause mortality (33.3% vs. 20.0% vs.14.3% vs. 14.3% vs. 6.7%). Patients with four or more of the following clinical manifestations (cough, dyspnea, fever, chest pain, and weight loss) [adjusted HR (AHR) 29.06, 95% CI 2.13–396.36, P = 0.01] and admission to intensive care unit (ICU) [AHR 22.55, 95% CI 1.36–375.06, P = 0.03] were independently associated with all-cause mortality in non-HIV infected PCP patients. Variables associated with mortality in HIV infected PCP patients were admission to ICU (AHR 72.26, 95% CI 11.76–443.87, P<0.001) and albumin ≤30 g/L (AHR 9.93 95% CI 1.69–58.30, P = 0.01).

Conclusions

Upon admission comprehensive clinical assessment including assessment of four or more clinical manifestations (cough, dyspnea, fever, chest pain, and weight loss) in non-HIV infected PCP patients and albumin ≤30 g/L in HIV infected patients might improve prognosis.     

Ambient Air Pollution Associated with Suppressed Serologic Responses to Pneumocystis jirovecii in a Prospective Cohort of HIV-Infected Patients with Pneumocystis Pneumonia

Background

Ambient air pollution (AAP) may be associated with increased risk for Pneumocystis pneumonia (PCP). The mechanisms underlying this association remain uncertain.

Objectives

To determine if real-life exposures to AAP are associated with suppressed IgM antibody responses to P. jirovecii in HIV-infected (HIV+) patients with active PCP, and to determine if AAP, mediated by suppressed serologic responses to Pneumocystis, is associated with adverse clinical outcomes.

Methods

We conducted a prospective cohort study in HIV+ patients residing in San Francisco and admitted to San Francisco General Hospital with microscopically confirmed PCP. Our AAP predictors were ambient air concentrations of particulate matter of < 10 µm in diameter (PM₁₀) and < 2.5 µm in diameter (PM_2.5), nitrogen dioxide (NO₂), ozone (O₃), and sulfur dioxide (SO₂) measured immediately prior to hospital admission and 2 weeks prior to admission. Our primary outcomes were the IgM serologic responses to four recombinant P. jirovecii major surface glycoprotein (Msg) constructs: MsgC1, MsgC3, MsgC8, and MsgC9.

Results

Elevated PM₁₀ and NO₂ exposures immediately prior to and two weeks prior to hospital admission were associated with decreased IgM antibody responses to P. jirovecii Msg. For exposures immediately prior to admission, every 10 µg/m³ increase in PM₁₀ was associated with a 25 to 35% decrease in IgM responses to Msg (statistically significant for all the Msg constructs), and every 10 ppb increase in NO₂ was associated with a 19-45% decrease in IgM responses to Msg (statistically significant for MsgC8 and MsgC9). Similar findings were seen with exposures two weeks prior to admission, but for fewer of the Msg constructs.

Conclusions

Real life exposures to PM₁₀ and NO₂ were associated with suppressed IgM responses to P. jirovecii Msg in HIV+ patients admitted with PCP, suggesting a mechanism of immunotoxicity by which AAP increases host susceptibility to pulmonary infection.     

Serologic Responses to Recombinant Pneumocystis jirovecii Major Surface Glycoprotein among Ugandan Patients with Respiratory Symptoms

Background

Little is known about the serologic responses to Pneumocystis jirovecii major surface glycoprotein (Msg) antigen in African cohorts, or the IgM responses to Msg in HIV-positive and HIV-negative persons with respiratory symptoms.

Methods

We conducted a prospective study of 550 patients, both HIV-positive (n = 467) and HIV-negative (n = 83), hospitalized with cough ≥2 weeks in Kampala, Uganda, to evaluate the association between HIV status, CD4 cell count, and other clinical predictors and antibody responses to P. jirovecii. We utilized ELISA to measure the IgM and IgG serologic responses to three overlapping recombinant fragments that span the P. jirovecii major surface glycoprotein: MsgA (amino terminus), MsgB (middle portion) and MsgC1 (carboxyl terminus), and to three variations of MsgC1 (MsgC3, MsgC8 and MsgC9).

Results

HIV-positive patients demonstrated significantly lower IgM antibody responses to MsgC1, MsgC3, MsgC8 and MsgC9 compared to HIV-negative patients. We found the same pattern of low IgM antibody responses to MsgC1, MsgC3, MsgC8 and MsgC9 among HIV-positive patients with a CD4 cell count <200 cells/µl compared to those with a CD4 cell count ≥200 cells/µl. HIV-positive patients on PCP prophylaxis had significantly lower IgM responses to MsgC3 and MsgC9, and lower IgG responses to MsgA, MsgC1, MsgC3, and MsgC8. In contrast, cigarette smoking was associated with increased IgM antibody responses to MsgC1 and MsgC3 but was not associated with IgG responses. We evaluated IgM and IgG as predictors of mortality. Lower IgM responses to MsgC3 and MsgC8 were both associated with increased in-hospital mortality.

Conclusions

HIV infection and degree of immunosuppression are associated with reduced IgM responses to Msg. In addition, low IgM responses to MsgC3 and MsgC8 are associated with increased mortality.     

Diagnosis,Burden and Mortality of Pneumocystis jirovecii Pneumonia in Venezuela

Current Fungal Infection Reports - The aim of this work is to contribute to the knowledge of diagnosis, burden, and mortality of pneumocystosis or Pneumocystis jirovecii pneumonia (PCP) in...     

Sterol composition of Pneumocystis jirovecii with blocked 14alpha-demethylase activity

Several drugs that interact with membrane sterols or inhibit their syntheses are effective in clearing a number of fungal infections. The AIDS-associated lung infection caused by Pneumocystis jirovecii is not cleared by many of these therapies. Pneumocystis normally synthesizes distinct C28 and C29 24-alkylsterols, but ergosterol, the major fungal sterol, is not among them. Two distinct sterol compositional phenotypes were previously observed in P. jirovecii. One was characterized by delta7 C28 and C29 24-alkylsterols with only low proportions of higher molecular mass components. In contrast, the other type was dominated by high C31 and C32 24-alkylsterols, especially pneumocysterol. In the present study, 28 molecular species were elucidated by nuclear magnetic resonance analysis of a human lung specimen containing P. jirovecii representing the latter sterol profile phenotype. Fifteen of the 28 had the methyl group at C-14 of the sterol nucleus and these represented 96% of the total sterol mass in the specimen (excluding cholesterol). These results strongly suggest that sterol 14alpha-demethylase was blocked in these organisms. Twenty-four of the 28 were 24-alkylsterols, indicating that methylation of the C-24 position of the sterol side chain by S-adenosyl-L-methionine:sterol C-24 methyl transferase was fully functional.     

Multicenter Study of Trimethoprim/Sulfamethoxazole-Related Hepatotoxicity: Incidence and Associated Factors among HIV-Infected Patients Treated for Pneumocystis jirovecii Pneumonia

The incidence of hepatotoxicity related to trimethoprim/sulfamethoxazole (TMP/SMX) administered at a therapeutic dose may vary among study populations of different ethnicities and hepatotoxic metabolites of TMP/SMX may be decreased by drug-drug interaction with fluconazole. We aimed to investigate the incidence of hepatotoxicity and the role of concomitant use of fluconazole in HIV-infected patients receiving TMP/SMX for Pneumocystis jirovecii pneumonia. We reviewed medical records to collect clinical characteristics and laboratory data of HIV-infected patients who received TMP/SMX for treatment of P. jirovecii pneumonia at 6 hospitals around Taiwan between September 2009 and February 2013. Hepatotoxicity was defined as 2-fold or greater increase of aminotransferase or total bilirubin level from baselines. Roussel UCLAF Causality Assessment Method (RUCAM) was used to analyze the causality of drug-induced liver injuries. NAT1 and NAT2 acetylator types were determined with the use of polymerase-chain-reaction (PCR) restriction fragment length polymorphism to differentiate common single-nucleotide polymorphisms (SNPs) predictive of the acetylator phenotypes in a subgroup of patients. During the study period, 286 courses of TMP/SMX treatment administered to 284 patients were analyzed. One hundred and fifty-two patients (53.1%) developed hepatotoxicity, and TMP/SMX was considered causative in 47 (16.4%) who had a RUCAM score of 6 or greater. In multivariate analysis, concomitant use of fluconazole for candidiasis was the only factor associated with reduced risk for hepatotoxicity (adjusted odds ratio, 0.372; 95% confidence interval, 0.145–0.957), while serostatus of hepatitis B or C virus, NAT1 and NAT2 acetylator types, or receipt of combination antiretroviral therapy was not. The incidence of hepatotoxicity decreased with an increasing daily dose of fluconazole up to 4.0 mg/kg. We conclude that the incidence of TMP/SMX-related hepatotoxicity was 16.4% in HIV-infected Taiwanese patients who received TMP/SMX for pneumocystosis. Concomitant use of fluconazole was associated with decreased risk for TMP/SMX-related hepatotoxicity.     

Humoral Immune Responses to Pneumocystis jirovecii Antigens in HIV-Infected and Uninfected Young Children with Pneumocystis Pneumonia

Background

Humoral immune responses in human immunodeficiency virus (HIV)-infected and uninfected children with Pneumocystis pneumonia (PcP) are poorly understood.

Methods

Consecutive children hospitalized with acute pneumonia, tachypnea, and hypoxia in South Africa were investigated for PcP, which was diagnosed by real-time polymerase chain reaction on lower respiratory tract specimens. Serum antibody responses to recombinant fragments of the carboxyl terminus of Pneumocystis jirovecii major surface glycoprotein (MsgC) were analyzed.

Results

149 children were enrolled of whom 96 (64%) were HIV-infected. PcP occurred in 69 (72%) of HIV-infected and 14 (26%) of HIV-uninfected children. HIV-infected children with PcP had significantly decreased IgG antibodies to MsgC compared to HIV-infected patients without PcP, but had similar IgM antibodies. In contrast, HIV-uninfected children with PcP showed no change in IgG antibodies to MsgC, but had significantly increased IgM antibodies compared to HIV-uninfected children without PCP. Age was an independent predictor of high IgG antibodies, whereas PcP was a predictor of low IgG antibodies and high IgM antibodies. IgG and IgM antibody levels to the most closely related MsgC fragments were predictors of survival from PcP.

Conclusions

Young HIV-infected children with PcP have significantly impaired humoral immune responses to MsgC, whereas HIV-uninfected children with PcP can develop active humoral immune responses. The children also exhibit a complex relationship between specific host factors and antibody levels to MsgC fragments that may be related to survival from PcP.     

Absence of dihydropteroate synthase mutations in Pneumocystis jirovecii from Brazilian AIDS patients

Several studies from developed countries have documented the association between trimethoprim-sulfamethoxazole prophylaxis failure and mutations in the Pneumocystis jirovecii gene coding for dihydropteroate synthase (DHPS). DNA was extracted from Giemsa-stained smears of 70 patients with P. jirovecii pneumonia seen in Porto Alegre, Brazil, from 1997 to 2004. Successful PCR amplification of the DHPS locus was obtained in 57 of 70 cases (81.4%), including five cases (8.7%) that had used sulfa prophylaxis. No DHPS gene mutations were seen. These results suggest that DHPS mutations are currently as rare in Brazil as in other developing countries.