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

Serum Antibody Levels to the Pneumocystis jirovecii Major Surface Glycoprotein in the Diagnosis of P. jirovecii Pneumonia in HIV+ Patients

infection has never been developed. major surface glycoprotein recombinant fragment C1 (MsgC1) in 110 HIV+ patients with active PcP (cases) and 63 HIV+ patients with pneumonia due to other causes (controls) by an enzyme-linked immunosorbent assay (ELISA). The cases had significantly higher IgG and IgM antibody levels to MsgC1 than the controls at hospital admission (week 0) and intervals up to at least 1 month thereafter. The sensitivity, specificity and positive predictive value (PPV) of IgG antibody levels increased from 57.2%, 61.7% and 71.5% at week 0 to 63.4%, 100%, and 100%, respectively, at weeks 3–4. The sensitivity, specificity and PPV of IgM antibody levels rose from 59.7%, 61.3%, and 79.3% at week 0 to 74.6%, 73.7%, and 89.8%, respectively, at weeks 3–4. Multivariate analysis revealed that a diagnosis of PcP was the only independent predictor of high IgG and IgM antibody levels to MsgC1. A high LDH level, a nonspecific marker of lung damage, was an independent predictor of low IgG antibody levels to MsgC1.The results suggest that the ELISA shows promise as an aid to the diagnosis of PCP in situations where diagnostic procedures cannot be performed. Further studies in other patient populations are needed to better define the usefulness of this serologic test

Effects of Environmental Exposures on: Pneumocystis jirovecii Pneumonia (PcP) Hospital Admissions; and Antibody Levels to Major Surface Glycoprotein among HIV-infected Patients from San Francisco

Pneumocystis is an opportunistic pathogen for subjects with a compromised immune system, including patients with HIV+ infection, post organ-transplant patients, malignancy cancer patients and those receiving immunosuppressive drugs. Previous studies showed that about 85% of HIV-infected patients developed PcP at some time during their illness. However, with the introduction of HAART and the use of PcP prophylaxis, the frequency of PcP has decreased over time. In spite of this reduction in incidence, PcP currently is the second leading cause of morbidity among HIV-infected patients in the U.S. Although PcP causes serious outcomes in immunocompromised patients, some epidemiologic features are still puzzling scientists. Researchers are still struggling to agree on the mode of transmission and the effects of environmental factors. The Major Surface Glycoprotein (Msg) is a crucial protein complex in Pneumocystis pathogenicity and is involved in host-organism interaction. This protein is encoded by a multicopy gene family and is capable of antigenic variation to allow Pneumocystis to evade the host immune response. However, the immunologic study of this organism has been hindered because Pneumocystis is difficult to grow, making it difficult to obtain native Msg in a large amount for Seroepidemiology studies. Recently, studies have used Msg as the main antigen to develop different recombinant fragments. Although studies showed that there are geographic variations and seasonal variation in antibody responses to Msg, no study has analyzed the effects of environmental factors on antibody levels to Msg fragments. In the first aim of the study, the case-crossover design was used to identify environmental factors associated with PcP hospital admissions in San Francisco General Hospital (SFGH). Environmental data were collected from the National Air Quality database. Data from 457 HIV+ patients with advanced stages of HIV+ disease were analyzed. A significant seasonal variation of PcP hospital admissions was found (p levels was significantly associated with PcP hospital admissions (p were modified by the presence of CO. In the second aim of the study, the influence of environmental factors on antibody levels to Msg fragments was determined. One hundred and thirty nine serum specimens sampled at the time of PcP admissions were analyzed. The levels of environmental factors at admission and two weeks before admission were measured, and Tobit regression models were used to determine the association between the environmental factors and antibody levels. It was found that after controlling for other environmental parameters, temperature measured at the time of admission was significantly associated with IgG antibody responses to both MsgC and MsgA. However, temperature measured two weeks before hospital admission was only significantly associated with IgG antibody levels to MsgA. There was a significant seasonal variation in antibody levels to MsgA, but not to MsgC. In conclusion, this study shows that among environmental factors, temperature and SO2 are independent risk factors for hospital admissions for HIV+ patients with PcP infection in San Francisco. It also shows that temperature fluctuations have significant effects on antibody levels to Pneumocystis infection

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 (PM2.5), 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/m(3) 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

Descriptive Characteristics of the Children at Enrollment.

<p>Continuous and Discrete Data Were Expressed as Median (IQR) and Count (% N), Respectively.</p><p>Note: Bolded values are significantly different. * Proportion of HIV-infected patients on ART = antiretroviral therapy. LDH = serum lactate dehydrogenase. HIV+ = HIV-infected. HIV- = HIV-uninfected </p

Estimated 75^th and 90^th Percentiles [SE] of IgG Antibody Responses to MsgC Fragments by PcP Diagnosis among HIV+ and HIV- Children at Enrolment.

<p>^* The groups are significantly different. SE = Standard error. HIV+ = HIV-infected. HIV- = HIV-uninfected</p

Estimated 75^th and 90^th Percentiles [SE] of IgM Antibody Responses to MsgC Fragments by PcP Diagnosis among HIV+ and HIV- Children at Enrolment.

<p>^* The groups are significantly different. SE = Standard error. HIV+ = HIV-infected. HIV- = HIV-uninfected SE: </p