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Pneumocystis is an opportunistic yeast-like fungus that is tropic to mammalian lung tissue and produces a clinical spectrum ranging from asymptomatic infection to subacute and acute interstitial pneumonia in susceptible hosts. The earliest descriptions of Pneumocystis jiroveci pneumonia (PCP) in humans came from reports of malnourished children and neonates with pneumonia in the 1940s, but the syndrome came into worldwide prominence during the HIV/AIDS pandemic in the 1980s where PCP accounted for more than one-fourth of community-acquired pneumonias in persons living with HIV/AIDS (PLWH). The subsequent introduction of combination antiretroviral therapy (ART) and institution of routine PCP prophylaxis for those at greatest risk of infection led to a decreased incidence of PCP among PLWH. In the developed world, HIV-negative patients with cell-mediated immune deficiencies have become the most common hosts for PCP, with 60% to 70% of new infections occurring in patients on prolonged high-dose corticosteroids and chemotherapeutic agents as well as those with autoimmune diseases or recipients of solid organ or hematopoietic stem cell transplantation.1–3 Although it produces a characteristic interstitial pneumonia for which effective treatments are available, Pneumocystis jiroveci has remained a problematic pathogen due to an enlarging population of at-risk individuals, a propensity to colonize hosts for short periods of time without necessarily causing infection, an ability to produce fulminant infection despite low pathogen burdens, intrinsic resistance to the most common antifungal classes, and the inability to sustain and thus study the organism in vitro.
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HISTORY AND BACKGROUND
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The fungus Pneumocystis, a unicellular, host-specific yeast-like organism, is unusual among fungi in many respects including its history. First described by Carlos Chagas in 1909, Pneumocystis was mistakenly interpreted as a developmental stage of the protozoan Trypanosoma cruzi and classified as a parasite until years later when genetic analyses revealed the organism to be more closely related to fungi.4 In 1912, the organism infecting rat lung tissue was understood by Delanoe and Delanoe to be separate from the trypanosome and named Pneumocystis carinii, but Pneumocystis was not recognized as a pathogen of humans until 1942 (Van der Meer and Brug).5,6 The first descriptions of a syndrome consistent with PCP came from orphanages in Europe in the 1930s and following World War II and the Vietnam War where clusters of “plasma cell interstitial pneumonitis” were reported among disadvantaged children and neonates.7 It was not until 1952 that a clear association with human disease was made by Vanek and Jírovec.7 In addition to severe malnutrition, prolonged corticosteroids and chemotherapeutic agents were recognized as risk factors for PCP.
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In the 1970s, the Centers for Disease Control and Prevention (CDC) undertook epidemiologic and therapeutic studies to better characterize the host–pathogen interaction and to broaden the antimicrobial armamentarium beyond pentamidine, which was the only available therapeutic option at the time. This investigation resulted in the development of pyrimethamine, sulfadoxine, trimethoprim (TMP), and sulfamethoxazole (SMX), agents that ...