Pathogenesis of PCP

Today the term 'plasma cell pneumonia' is replaced by Pneumocystis pneumonia (PCP), which reflects not only the recognition of the etiological agent, but also the histopathologically different appearance of the lung tissue in AIDS-associated PCP and the severe interstitial reaction seen in infected small children.

Infection with P. carinii typically results in a pneumonia which is histologically seen to consist of an eosinophilic foamy alveolar exudate associated with a mild plasma cell interstitial infiltrate. Special stains show that cysts of P. carinii lie within the alveolar exudate. Atypical histological appearances may occasionally be seen, including a granulomatous pneumonia and diffuse alveolar damage (Robillard et al. 1965; Foley et al. 1993).

Cells of the macrophage lineage mediate extremely important normal functions of the immune system. The CD4 glycoprotein is the major cellular receptor for HIV. Macrophages mediate the elimination of P. carinii from the living host. The uptake and degradation of 35S-labelled P. carinii by cultured macrophages has been quantified, demonstrating significant degradation of P. carinii over 6h (Limper et al. 1997). Quantitative differences have been observed in phagocytosis and degradation of P. carinii by alveolar macrophages in AIDS and non-HIV patients in vivo (Wehle et al. 1993). CD4, although expressed at low levels on the surface of alveolar macrophages, appears to be critical in the HIV-1 infection of these cells. (Lewin et al. 1996). Extrapulmonary infection with P. carinii is an uncommon event involving the skin of the external auditory canal, the mastoid area, and the glabrous skin (Hennessey et al. 1991; Litwin and Williams 1992).

The classical model for the study of P. carinii exposed to PC, is corticosteroid-immunosuppressed rats developing PCP when exposed to the parasite (Frenkel et al. 1966; Sukura et al. 1991a). PCP also occurs spontaneously in other rodents such as SCID mice, athymic mice, and voles. Furthermore a subclinical PCP occurs in young rabbits at the end of their first month of life (Dei Cas et al. 1998). Impaired cellular immunity has been shown to be more important than impaired humoral immunity (Frenkel et al. 1966; Walzer et al. 1989). In mice the disease can be cleared by adoptive transfer of CD4 cells but not of CD8 cells (Harmsen and Stankiewicz, 1990). In HIV-infected individuals a low CD4+ cell count is the single most important risk factor for PCP (Masur et al. 1989; Lidman et al. 1992; Lundgren et al. 1994). Treatment with immunosuppressive drugs involves a risk for developing PCP, which is time and dose dependent. The combined effect of immunosuppression and drug-dependant differences in the effects on different host cell types apparently accounts for the differences seen among immunosuppressive drugs with respect to their capacity to induce PCP. In addition to corticosteroids, cyclosporin A, a highly specific inhibitor of T-cell activation, used in treatment of transplant recipients, is associated with a risk for developing PCP. The pathogenic effect of corticosteroids is not fully known, but apart from affecting the immune system, for example, depressing the production of TNF-a and IL-6 (Perenboom et al. 1996), they induce a decrease in the alveolar cell surface glycocalyx, an effect which might enhance organism attachment.

In severe cases of PCP, interstitial fibrosis, granulomatous inflammations, pulmonary cavitations, and pneumothorax can develop (Travis et al. 1991). Using sensitive immunocytochemical techniques, P. carinii has been found in the interstitial compartment, pleura, and vessel walls during autopsy and in open lung biopsy specimens (Murry and Schmidt 1992). Extrapulmonary P. carinii was previously rarely seen. With the use of local treatment with Penthamidine aerosol a number of cases have been reported. Various authors have estimated the risk of extrapulmonary P. carinii as 0.5-3% in AIDS patients (Raviglione 1990; Telzak et al. 1990). These are probably underestimations since the clinical picture is very variable and adequate sensitive staining is not routinely performed on material outside the lung during an autopsy.

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