Pneumocystis Pneumonia Associated with Human Immunodeficiency Virus

Miller, R F; Huang, Laurence; Walzer, Peter D.

doi:10.1016/j.ccm.2013.02.001

Cited by 51 publications

(57 citation statements)

References 62 publications

(42 reference statements)

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“…Fungal infections in CD4 + T cell lymphopenic patients have risen at alarming rates due to the HIV pandemic, and despite antifungal therapy, they can carry a mortality rate of 5%–70% depending on the type of fungal infection [23–25]. In a recent survey, cryptococcosis in sub-Saharan Africa produced mortality rates of 50–70%, even surpassing deaths caused by tuberculosis, another major opportunistic infection associated with AIDS [24].…”

Section: Introductionmentioning

confidence: 99%

Vaccine immunity against fungal infections

Nanjappa

Klein

2014

Current Opinion in Immunology

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Only a handful of the many fungal species on our planet cause infections in humans. Despite many medical advances, invasive fungal infections have skyrocketed in recent years and pose a growing health problem in both immune-competent and -deficient hosts. Recent strides in our understanding of fungal immunity have raised the prospect that vaccines against fungi can be developed that are effective, safe and able to elicit lasting immunity even in immune deficient individuals. We discuss progress in vaccine development and understanding mechanisms of protection against fungi including in patients with impaired CD4+ T-cell immunity.

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Section: Introductionmentioning

confidence: 99%

Vaccine immunity against fungal infections

Nanjappa

Klein

2014

Current Opinion in Immunology

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“…The mortality rate of P. jirovecii pneumonia is approximately 10% to 12% in the HIV-infected patients [3]. While trimethoprim/sulfamethoxazole (TMP/SMX) has been the recommended treatment of choice for P. jirovecii pneumonia in HIV-infected patients, TMP/SMX administered at therapeutic doses may cause several adverse effects such as allergy, hepatotoxicity, bone marrow suppression, hyperkalemia, and nephrotoxicity [4], [5].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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“…Pneumocystis jirovecii is the species known to infect humans, while Pneumocystis carinii represents the parallel species studied widely in rodents (2). Pneumocystis pneumonia remains a significant cause of mortality during AIDS, despite highly active antiretroviral therapy (3)(4)(5). Severe Pneumocystis pneumonia is characterized by intense lung inflammation involving CD8 ϩ cells and neutrophils, impairing gas exchange (6)(7)(8)(9).…”

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Evidence for Proinflammatory β-1,6 Glucans in the Pneumocystis carinii Cell Wall

et al. 2015

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Inflammation is a major cause of respiratory impairment during Pneumocystis pneumonia. Studies support a significant role for cell wall ␤-glucans in stimulating inflammatory responses. Fungal ␤-glucans are comprised of D-glucose homopolymers containing ␤-1,3-linked glucose backbones with ␤-1,6-linked glucose side chains. Prior studies in Pneumocystis carinii have characterized ␤-1,3 glucan components of the organism. However, recent investigations in other organisms support important roles for ␤-1,6 glucans, predominantly in mediating host cellular activation. Accordingly, we sought to characterize ␤-1,6 glucans in the cell wall of Pneumocystis and to establish their activity in lung cell inflammation. Immune staining revealed specific ␤-1,6 localization in P. carinii cyst walls. Homology-based cloning facilitated characterization of a functional P. carinii kre6 (Pckre6) ␤-1,6 glucan synthase in Pneumocystis that, when expressed in kre6-deficient Saccharomyces cerevisiae, restored cell wall stability. Recently synthesized ␤-1,6 glucan synthase inhibitors decreased the ability of isolated P. carinii preparations to generate ␤-1,6 carbohydrate. In addition, isolated ␤-1,6 glucan fractions from Pneumocystis elicited vigorous tumor necrosis factor alpha (TNF-␣) responses from macrophages. These inflammatory responses were significantly dampened by inhibition of host cell plasma membrane microdomain function. Together, these studies indicate that ␤-1,6 glucans are present in the P. carinii cell wall and contribute to lung cell inflammatory activation during infection. P neumocystis organisms are opportunistic fungi that produce significant morbidity and mortality in immunocompromised hosts, with infection-related fatalities ranging between 10% and 45% (1). Pneumocystis jirovecii is the species known to infect humans, while Pneumocystis carinii represents the parallel species studied widely in rodents (2). Pneumocystis pneumonia remains a significant cause of mortality during AIDS, despite highly active antiretroviral therapy (3-5). Severe Pneumocystis pneumonia is characterized by intense lung inflammation involving CD8 ϩ cells and neutrophils, impairing gas exchange (6-9).The P. carinii cell walls contain abundant ␤-glucan molecules (10). Fungal cell wall ␤-glucans are homopolymers of D-glucose consisting of ␤-1,3 core chains with variable numbers of ␤-1,6 glucose side chains. The variable inflammatory activities of different glucan preparations have been postulated to be related to the relative amounts and configurations of these two major structures (␤-1,3 versus ␤-1,6) (11). Almost all of the initial studies in fungi have largely focused on unfractionated glucans (10). In fact, all prior studies in P. carinii previously utilized only unfractionated ␤-1,3/␤-1,6 glucans. Interestingly, recent investigations in Saccharomyces cerevisiae indicate major roles for ␤-1,6 glucans in strongly mediating cellular activation and inflammation (11). Our investigations of unfractionated P. carinii ␤-glucans indicate that innate ...

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Pneumocystis Pneumonia Associated with Human Immunodeficiency Virus

Cited by 51 publications

References 62 publications

Vaccine immunity against fungal infections

Vaccine immunity against fungal infections

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

Evidence for Proinflammatory β-1,6 Glucans in the Pneumocystis carinii Cell Wall

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