Changes in incidence of PCP, groups at risk for PCP, and possible trends in the disease are discussed.

Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express β -1,3-D-glucan synthetase and contain abundant β -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of β -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased β -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens.

Mortality risk factors for PCP were identifiable at or soon after hospitalization. The trend towards improved outcome after June 1996 occurred in the absence of highly active antiretroviral therapy.

During the past 30 years, major advances have been made in our understanding of HIV/AIDS and Pneumocystis pneumonia (PCP), but significant gaps remain. Pneumocystis is classified as a fungus and is host-species specific, but an understanding of its reservoir, mode of transmission, and pathogenesis is incomplete. PCP remains a frequent AIDS-defining diagnosis and is a frequent opportunistic pneumonia in the United States and in Europe, but comparable epidemiologic data from other areas of the world that are burdened with HIV/AIDS are limited. Pneumocystis cannot be cultured, and bronchoscopy with bronchoalveolar lavage is the gold standard procedure to diagnose PCP, but noninvasive diagnostic tests and biomarkers show promise that must be validated. Trimethoprim-sulfamethoxazole is the recommended first-line treatment and prophylaxis regimen, but putative trimethoprim-sulfamethoxazole drug resistance is an emerging concern. The International HIV-associated Opportunistic Pneumonias (IHOP) study was established to address these knowledge gaps. This review describes recent advances in the pathogenesis, epidemiology, diagnosis, and management of HIV-associated PCP and ongoing areas of clinical and translational research that are part of the IHOP study and the Longitudinal Studies of HIV-associated Lung Infections and Complications (Lung HIV).

Serum antibodies to human Pneumocystis carinii antigens were measured in greater than 400 specimens from different population groups by the immunoblotting technique. Serologic responses varied during the first 2 years of life, but in children greater than or equal to 2 1/2 years and in adults antibodies to a 40-kDa band were found in greater than 85% of the specimens; antigens to bands of 66, 92, and 116 kDa were also detected frequently. The prevalence of serum antibodies in immunosuppressed patients varied at different institutions and was usually lower than that of healthy controls. Seven (41%) of 17 patients with single episodes of pneumocystosis and 13 (93%) of 14 patients with recurrent episodes followed sequentially developed active serum IgM and/or IgG antibody responses to the 40-kDa antigen. Serologic responses to P. carinii were also detected, though less frequently, by immunofluorescence. These data suggest that the 40-kDa antigen is a major marker of P. carinii infection and that immunoblotting is useful in measuring serum antibody responses to the organism in both normal and immunocompromised hosts.

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Pulsed-field gel electrophoresis techniques were used to examine the chromosomes of Pneumocystis carinii isolated from laboratory rats and two human subjects. P. carinii organisms isolated from each of four rat colonies and from two patients each produced a distinct band pattern, but in all cases the bands ranged in size from 300 to 700 kilobase pairs. P. carinùi from three rat colonies produced patterns containing 15 prominent bands. Of these 15 bands, 2 stained more intensely than would be expected of bands of their size, suggesting that the P. carinii haploid genome contains 17 to 19 chromosomes. Summing the molecular sizes of the bands and accounting for staining intensities suggested that the haploid genome of rat-derived P. carinii contains on the order of 107 base pairs. Human-derived P. carinii produced patterns containing 10 to 12 bands which appeared to be similar to the 15-band patterns seen in rat-derived P. caring with respect to the size range of the bands. P. carinii from the fourth rat colony produced a more complex band pattern containing approximately 22 bands, most of which appeared to comigrate with the bands present in one of the 15-band P. carinii patterns, suggesting that these animals were simultaneously infected by two different varieties of P. carinii. Hybridization experiments using oligonucleotide probes specific for the P. carinu 18S rRNA gene supported this possibility. The band pattern of P. carinii derived from a given rat colony was generally stable over time. P. carinii band patterns were not strictly rat strain specific and appeared to be transferable between animals housed in the same room.

Seroepidemiologic studies of Pneumocystis pneumonia (PCP) in humans have been limited by inadequate reagents. We have developed an enzyme-linked immunosorbent assay (ELISA) using three overlapping recombinant fragments of the human Pneumocystis major surface glycoprotein (MsgA, MsgB, and MsgC) for analysis of antibody responses in HIV-positive patients and healthy blood donors. HIV-positive patients had significantly higher antibody levels to all Msg fragments. Furthermore, HIV-positive patients who experienced a previous episode of PCP (PCP-positive) had higher level of antibodies to MsgC than patients who never had PCP. A significant association was found between ELISA antibody level and reactivity by Western blot in HIV-positive patients, especially those who were PCP-positive. Thus, this ELISA will be useful in studying serum antibody responses to Pneumocystis in different human populations.