Dihydropteroate synthase mutations in Pneumocystis pneumonia: impact of applying different definitions of prophylaxis, mortality endpoints and mutant in a single cohort

Pneumocystis jirovecii dihydropteroate synthase (DHPS) gene mutations are well-reported. Although sulfa prophylaxis generally is associated with DHPS mutant infection, whether mutant infection is associated with poorer clinical outcomes is less clear. The differing definitions of sulfa prophylaxis and the different mortality endpoints used in these studies may be one explanation for the conflicting study results. Applying different definitions of prophylaxis, mortality endpoints and DHPS mutant to 301 HIV-infected patients with Pneumocystis pneumonia, we demonstrate that prophylaxis, irrespective of definition, increased the risk of infection with pure mutant (any prophylaxis: AOR 4.00, 95% CI: 1.83–8.76, p0.05). Future studies should standardize key variables associated with DHPS mutant infection as well as examine DHPS mutant subtypes (pure mutant vs. mixed infections) – perhaps even individual DHPS mutant genotypes – so that data can be pooled to better address this issue

Healthcare Worker Occupation and Immune Response to Pneumocystis jirovecii

Humans may be a reservoir for this pathogen and transmit it from person to person

Predicting mortality from HIV-associated Pneumocystis pneumonia at illness presentation: an observational cohort study

BACKGROUND: Although the use of antiretroviral therapy has led to dramatic declines in AIDS-associated mortality, Pneumocystis pneumonia (PCP) remains a leading cause of death in HIV-infected patients. OBJECTIVES: To measure mortality, identify predictors of mortality at time of illness presentation, and derive a PCP mortality prediction rule that stratifies patients by risk for mortality. METHODS: Observational cohort study with case note review of all HIV-infected persons with a laboratory diagnosis of PCP at San Francisco General Hospital from 1997–2006. RESULTS: 451 patients were diagnosed with PCP on 524 occasions. In-hospital mortality was 10.3%. Multivariate analysis identified five significant predictors of mortality: age (adjusted odds ratio [AOR] per 10-year increase, 1.69; 95% confidence interval [CI] 1.08–2.65; p=0.02); recent injection drug use (AOR 2.86; 95% CI 1.28–6.42; p=0.01); total bilirubin >0.6 mg/dL (AOR 2.59; 95% CI 1.19–5.62; p=0.02); serum albumin <3 g/dL (AOR 3.63; 95% CI 1.72–7.66; p=0.001); and alveolar-arterial oxygen gradient ≥50 mm Hg (AOR 3.02; 95% CI 1.41–6.47; p=0.004). Using these five predictors, we derived a six point PCP mortality prediction rule that stratifies patients according to increasing risk of mortality: score 0–1, 4%; score 2–3, 12%; score 4–5, 48%. CONCLUSIONS: Our PCP mortality prediction rule stratifies patients by mortality risk at the time of illness presentation and should be validated as a clinical tool

Healthcare worker occupation and immune response to Pneumocystis jirovecii.

The reservoir and mode of transmission of Pneumocystis jirovecii remain uncertain. We conducted a cross-sectional study of 126 San Francisco General Hospital staff in clinical (n = 103) and nonclinical (n = 23) occupations to assess whether occupational exposure was associated with immune responses to P. jirovecii. We examined antibody levels by ELISA for 3 overlapping fragments that span the P. jirovecii major surface glycoprotein (Msg): MsgA, MsgB, and MsgC1. Clinical occupation participants had higher geometric mean antibody levels to MsgC1 than did nonclinical occupation participants (21.1 vs. 8.2, p = 0.004); clinical occupation was an independent predictor of higher MsgC1 antibody levels (parameter estimate = 0.89, 95% confidence interval 0.29-1.48, p = 0.003). In contrast, occupation was not significantly associated with antibody responses to either MsgA or MsgB. Healthcare workers may have occupational exposure to P. jirovecii. Humans may be a reservoir for P. jirovecii and may transmit it from person to person

Antibody responses against Pneumocystis jirovecii in health care workers over time.

In a previous cross-sectional study, we showed that clinical staff working in a hospital had significantly higher antibody levels than nonclinical staff to Pneumocystis jirovecii. We conducted a longitudinal study, described here, to determine whether occupation and self-reported exposure to a patient with P. jirovecii pneumonia were associated with antibody levels to P. jirovecii over time. Baseline and quarterly serum specimens were collected and analyzed by using an ELISA that targeted different variants of the Pneumocystis major surface glycoprotein (MsgA, MsgB, MsgC1, MsgC3, MsgC8, and MsgC9). Clinical staff had significantly higher estimated geometric mean antibody levels against MsgC1 and MsgC8 than did nonclinical staff over time. Significant differences were observed when we compared the change in antibody levels to the different MsgC variants for staff who were and were not exposed to P. jirovecii pneumonia-infected patients. MsgC variants may serve as indicators of exposure to P. jirovecii in immunocompetent persons

Antibody Responses against Pneumocystis jirovecii in Health Care Workers Over Time

In a previous cross-sectional study, we showed that clinical staff working in a hospital had significantly higher antibody levels than nonclinical staff to Pneumocystis jirovecii. We conducted a longitudinal study, described here, to determine whether occupation and self-reported exposure to a patient with P. jirovecii pneumonia were associated with antibody levels to P. jirovecii over time. Baseline and quarterly serum specimens were collected and analyzed by using an ELISA that targeted different variants of the Pneumocystis major surface glycoprotein (MsgA, MsgB, MsgC1, MsgC3, MsgC8, and MsgC9). Clinical staff had significantly higher estimated geometric mean antibody levels against MsgC1 and MsgC8 than did nonclinical staff over time. Significant differences were observed when we compared the change in antibody levels to the different MsgC variants for staff who were and were not exposed to P. jirovecii pneumonia–infected patients. MsgC variants may serve as indicators of exposure to P. jirovecii in immunocompetent persons

Dihydropteroate synthase mutations in Pneumocystis pneumonia: impact of applying different definitions of prophylaxis, mortality endpoints and mutant in a single cohort.

Pneumocystis jirovecii dihydropteroate synthase (DHPS) gene mutations are well-reported. Although sulfa prophylaxis generally is associated with DHPS mutant infection, whether mutant infection is associated with poorer clinical outcomes is less clear. The differing definitions of sulfa prophylaxis and the different mortality endpoints used in these studies may be one explanation for the conflicting study results. Applying different definitions of prophylaxis, mortality endpoints and DHPS mutant to 301 HIV-infected patients with Pneumocystis pneumonia, we demonstrate that prophylaxis, irrespective of definition, increased the risk of infection with pure mutant (any prophylaxis: AOR 4.00, 95% CI: 1.83-8.76, P &lt; 0.001) but not mixed genotypes (any prophylaxis: AOR 0.78, 95% CI: 0.26-2.36, P = 0.65). However, infection with mutant DHPS, irrespective of definition, was not associated with increased mortality (all-cause or PCP death) at the three time-intervals examined (all P &gt; 0.05). Future studies should standardize key variables associated with DHPS mutant infection as well as examine DHPS mutant subtypes (pure mutant vs. mixed infections) - perhaps even individual DHPS mutant genotypes - so that data can be pooled to better address this issue