Pneumocystis jirovecii

Etiology

P. jirovecii is a common extracellular parasite found worldwide in the lungs of mammals. The taxonomic placement of this organism has not been unequivocally established, but nucleic acid homologies place it closest to fungi despite sharing morphologic features and drug susceptibility with protozoa. Detailed studies of the basic biology of the organism are not possible because of the inability to maintain P. jirovecii in culture. Phenotypic and genotypic analyses demonstrate that each mammalian species is infected by a unique strain (or possibly species) of Pneumocystis. A biologic correlate of these differences is evidenced by animal experiments that have shown organisms are not transmissible from one mammalian species to another. These observations have led to the suggestion that organisms be renamed, with those infecting humans renamed P. jirovecii .

Epidemiology

Serologic surveys show that most humans are infected with P. jirovecii before 4 yr. of age. In the immunocompetent child, these infections are usually asymptomatic. P. jirovecii DNA can occasionally be detected in nasopharyngeal aspirates of normal infants. Pneumonia caused by P. jirovecii occurs almost exclusively in severely immunocompromised hosts, including those with congenital or acquired immunodeficiency disorders, malignancies, or transplanted organs. Patients with primary immunodeficiency diseases at risk for infection include severe combined immunodeficiency disease, X-linked CD40 ligand deficiency, major histocompatibility complex class II deficiency, nuclear factor kappa B essential modulator deficiency, dedicator of cytokinesis 8 deficiency, Wiskott-Aldrich syndrome, and caspase recruitment domain 11 deficiency. Small numbers of P. jirovecii can be found in the lungs of infants who have died with the diagnosis of sudden infant death syndrome. This observation could indicate a cause-and-effect relationship or simply that there is overlap in the timing of the primary infection with P. jirovecii and sudden infant death syndrome.

Without chemoprophylaxis, approximately 40% of infants and children with AIDS, 70% of adults with AIDS, 12% of children with leukemia, and 10% of patients with organ transplants experience P. jirovecii pneumonia. Epidemics that occurred among debilitated infants in Europe during and after World War II are attributed to malnutrition. The use of new biologic immunosuppressive agents has expanded at-risk populations. The addition of tumor necrosis factor-α inhibitors to the management of patients with inflammatory bowel disease has resulted in a demonstrable increase in P. jirovecii pneumonia in this patient population, as has the use of rituximab in patients with hematologic malignancies.

The natural habitat and mode of transmission to humans are unknown, but animal studies clearly demonstrate airborne transmission. Animal-to-human transmission is unlikely because of the host specificity of P. jirovecii . Thus person-to-person transmission is likely but has not been conclusively demonstrated.

Pathogenesis

Two forms of P. jirovecii are found in the alveolar spaces: cysts, which are 5-8 µm in diameter and contain up to 8 pleomorphic intracystic sporozoites (or intracystic bodies), and extracystic trophozoites (or trophic forms), which are 2-5 µm cells derived from excysted sporozoites. The terminology of sporozoite and trophozoite is based on the morphologic similarities to protozoa, because there are no exact correlates for these forms of the organism among the fungi. P. jirovecii attaches to type I alveolar epithelial cells, possibly by adhesive proteins such as fibronectin or mannose-dependent ligands.

Control of infection depends on intact cell-mediated immunity. Studies in patients with AIDS show an increased incidence of P. jirovecii pneumonia with markedly decreased CD4 ⁺ T-lymphocyte counts. The CD4 ⁺ cell count provides a useful indicator in both older children and adults of the need for prophylaxis for P. jirovecii pneumonia. Although normally functioning CD4 ⁺ T cells are central to controlling infection by P. jirovecii, the final effector pathway for destruction of P. jirovecii is poorly understood but likely depends on alveolar macrophages. A role for CD4 ⁺ T cells could be to provide help for the production of specific antibody that is then involved in the clearance of organisms through interaction with complement, phagocytes, or T cells or through direct activation of alveolar macrophages.

In the absence of an adaptive immune response, as can be modeled in severe combined immunodeficient mice, infection with P. murina produces little alteration in lung histology or function until late in the course of the disease. If functional lymphocytes are given to severe combined immunodeficient mice infected with P. murina, there is rapid onset of an inflammatory response that results in an intense cellular infiltrate, markedly reduced lung compliance, and significant hypoxia, mimicking the characteristic changes of P. jirovecii pneumonia in humans. These inflammatory changes are also associated with marked disruption of surfactant function. T-cell subset analysis has shown that CD4 ⁺ T cells produce an inflammatory response that clears the organisms but also results in lung injury. CD8 ⁺ T cells are ineffective in the eradication of P. jirovecii. CD8 ⁺ T cells do help to modulate the inflammation produced by CD4 ⁺ T cells, but in the absence of CD4 ⁺ T cells the ineffectual inflammatory response of CD8 ⁺ T cells contributes significantly to lung injury. These various T-cell effects are likely responsible for the variations in presentation and outcome of P. jirovecii pneumonia observed in different patient populations.

Pathology

The histopathologic features of P. jirovecii pneumonia are of 2 types. The 1st type is infantile interstitial plasma cell pneumonitis, which was seen in epidemic outbreaks in debilitated infants 3-6 mo of age. Extensive infiltration with thickening of the alveolar septum occurs, and plasma cells are prominent. The 2nd type is a diffuse desquamative alveolar pneumonitis found in immunocompromised children and adults. The alveoli contain large numbers of P. jirovecii in a foamy exudate with alveolar macrophages active in the phagocytosis of organisms. The alveolar septum is not infiltrated to the extent it is in the infantile type, and plasma cells are usually absent.