Pneumocystis carinii and Geographic Clustering
Evidence for Transmission of Infection

James M. Beck

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, and Department of Veterans Affairs Medical Center, Ann Arbor, Michigan

	ARTICLE

TOP ARTICLE REFERENCES

Pneumocystis carinii is a continued cause of opportunistic infection, but our understanding of its transmission and epidemiology is rudimentary (1). Definitive information would be useful to predict individuals at risk for infection, to determine the need for respiratory isolation, and to guide long-term prophylaxis. Two studies in this issue of the Journal shed new light on this field (2, 3). For many years, P. carinii pneumonia was considered to represent reactivation of latent infection. Most children have serum antibodies against P. carinii, indicating early exposure to the organism. However, an autopsy study demonstrates that the lungs of immunocompetent individuals do not contain residual P. carinii organisms (4), suggesting that eradication of organisms is virtually complete.

The studies reported in this issue of the Journal demonstrate geographic clustering of P. carinii pneumonia cases in San Francisco and Cincinnati. Morris and coworkers used a retrospective, case-control design and compared human immunodeficiency virus (HIV)-infected individuals with a confirmed diagnosis of P. carinii pneumonia with symptomatic, HIV-infected individuals whose bronchoscopies did not yield P. carinii (2). Individuals living in a specific ZIP code area were significantly less likely to have a microbiologic diagnosis of P. carinii, despite the presence of a compatible clinical presentation, than were individuals living elsewhere in San Francisco. Dohn and coworkers retrospectively analyzed a database in Cincinnati to calculate rates of confirmed P. carinii pneumonia per number of HIV-infected individuals living in specific ZIP code areas (3). The rates of P. carinii pneumonia were significantly higher in four ZIP code areas in western Cincinnati compared with all ZIP codes in the metropolitan area. Although the first study was drawn from data collected in the 1990s, and the latter from data collected in the 1980s, the results are comparable and point toward acquisition of infection, rather than reactivation.

Both studies were retrospective analyses and, as the authors acknowledge, the causes of clustering are speculative. First, a common environmental reservoir could account for geographic clustering of the cases. The design of the present studies precluded sampling of the environment. However, P. carinii DNA has been identified in air samples, suggesting an environmental source that has not been identified (5). Although it is tempting to extend observations made in other fungi to P. carinii, a soil reservoir has not been documented. It also seems unlikely that animals serve as reservoirs of human infection. While P. carinii infections are ubiquitous in mammals, experimental evidence demonstrates that P. carinii organisms infecting different species are genetically and antigenically diverse (6), and organisms obtained from one species are unable to infect other hosts.

Alternatively, P. carinii could be transmitted from person to person. Experimental data strongly support transmission between infected and uninfected immunosuppressed animals by an airborne route (7). Using polymerase chain reaction (PCR) amplification of P. carinii DNA in hospital air samples, the presence of P. carinii in air was geographically related to the areas in which individuals with clinical infections wait and receive care, although DNA was also detected in other hospital locations (8). Furthermore, identification of distinct genetic isolates obtained during recurrent infections in small numbers of individuals suggests that recurrences represent acquisition of new populations of organisms (9), although the frequency of identification of different strains has been questioned (10). If P. carinii is transmissible, such transmission probably originates with an individual who is clinically ill, as it is unlikely that a carrier state exists (11). Regarding the current studies, however, the retrospective design precluded collection of information about living arrangements or contacts with other HIV-infected individuals.

Other data strongly support the theory that most clinical cases of P. carinii pneumonia occur by acquisition rather than by reactivation. Because P. carinii cannot be cultured reliably, these investigations depend on detection of the marked genetic and molecular differences among populations of P. carinii organisms (6). A major effort to characterize human- derived P. carinii isolates by sequence variation in the internal transcribed spacer regions of ribosomal RNA genes shows wide variation in samples from different countries (12). Genotypic analysis of organisms obtained from different cities showed that sequence patterns are determined by place of diagnosis, rather than by place of birth, of the patient (13). These data further support acquisition over reactivation as a cause of clinical infection.

It is tempting to speculate that socioeconomic factors interact with geography to produce the results contained in these reports. The Pulmonary AIDS Complications Study showed a significantly decreased risk of P. carinii infection in African-American individuals, which could reflect differences in genetic susceptibility or in socioeconomic status (14). Neither of the present studies demonstrated race or sex differences between the P. carinii-infected and uninfected groups. Morris and coworkers demonstrated that the ZIP code from which individuals were least likely to have a diagnosis of P. carinii represents the South of Market area, a socioeconomically disadvantaged section of San Francisco. Dohn and coworkers demonstrated that clustering of P. carinii rates occurred in more affluent ZIP code areas of Cincinnati. Although other studies have indicated that limited insurance and/or access to care adversely affect outcome (15), such differences do not appear to account for the geographic clustering documented in the present studies. In San Francisco, all patients were seen at a county hospital. In Cincinnati, patients were seen at an AIDS treatment center. Thus, it is unlikely that differences in access to care or insurance coverage biased the results.

How do these observations impact on clinical care? If an environmental source of P. carinii exists, further efforts are needed to identify it and to prevent exposure of susceptible individuals. If P. carinii is indeed transmissible from person to person, it may be reasonable to isolate susceptible individuals from known cases of infection (18). However, USPHS/IDSA guidelines deem current information insufficient to support this practice (19). Second, the importance of environmental exposure or person-to-person transmission is unclear for HIV-infected individuals with successful responses to highly active antiretroviral therapy (HAART). Current recommendations suggest that clinicians consider discontinuation of primary prophylaxis against P. carinii after sustained immunologic reconstitution, but support for discontinuation of secondary prophylaxis is not available (19). Because the duration of the effect of HAART is unknown, there may be significant risks of acquisition with long-term exposure to environmental sources of infection. The current studies provide additional evidence to suggest that P. carinii infections represent acquisition rather than reactivation, and additional prospective investigations will be needed to assess the clinical application of these findings.

Acknowledgments: Supported by grants HL57011 and HL59823 from the National Institutes of Health.

Supported by the Medical Research Council of Canada.

	References

TOP ARTICLE REFERENCES

1. Stansell JD. Pneumocystis carinii pneumonia. In: Rosen MJ, Beck JM, editors. Human immunodeficiency virus and the lung. New York: Marcel Dekker; 1998. p. 271-312.

2. Morris AM, Swanson M, Ha H, Huang L. Geographic distribution of HIV-associated Pneumocystis carinii pneumonia in San Francisco. Am J Respir Crit Care Med 2000; 162: 1622-1626 [Abstract/Free Full Text].

3. Dohn MN, White ML, Vigdorth EM, Buncher CR, Hertzbert VS, Baughman RP, Smulian AG, Walzer PD. Geographic clustering of Pneumocystis carinii pneumonia in patients with HIV infection. Am J Respir Crit Care Med 2000; 162: 1617-1621 [Abstract/Free Full Text].

4. Peters SE, Sinclair K, Millard PR, Hopkin JM. A search for Pneumocystis carinii in post-mortem lungs by DNA amplification. J Pathol 1992; 166: 195-198 [Medline].

5. Wakefield AE. DNA sequences identical to Pneumocystis carinii f. sp. carinii and Pneumocystis carinii f. sp. hominis in samples of air spora. J Clin Microbiol 1996; 34: 1754-1759 [Abstract].

6. Smulian AG, Keely SP, Sunkin SM, Stringer JR. Genetic and antigenic variation in Pneumocystis carinii organisms: tools for examining the epidemiology and pathogenesis of infection. J Lab Clin Med 1997; 130: 461-468 [Medline].

7. Walzer PD, Schnelle V, Armstrong D, Rosen PP. Nude mouse: a new experimental model for Pneumocystis carinii infection. Science 1977; 197: 177-179 [Abstract/Free Full Text].

8. Bartlett MS, Vermund SH, Jacobs R, Durant PJ, Shaw MM, Smith JW, Tang X, Lu J, Li B, Jin S, et al . Detection of Pneumocystis carinii DNA in air samples: likely environmental risk to susceptible persons. J Clin Microbiol 1997; 35: 2511-2513 [Abstract].

9. Keely SP, Stringer JR, Baughman RP, Linke MJ, Walzer PD, Smulian AG. Genetic variation among Pneumocystis carinii hominis isolates in recurrent pneumocystosis. J Infect Dis 1995; 172: 595-598 [Medline].

10. Helweg-Larsen J, Tsolaki AG, Miller RF, Lundgren B, Wakefield AE. Clusters of Pneumocystis carinii pneumonia: analysis of person-to-person transmission by genotyping. QJM 1998; 91: 813-820 [Abstract/Free Full Text].

11. Lundgren B, Elvin K, Rothman LP, Ljungström I, Lidman C, Lundgren JD. Transmission of Pneumocystis carinii from patients to hospital staff. Thorax 1997; 52: 422-424 [Abstract].

12. Lee CH, Helweg-Larsen J, Tang X, Jin S, Li B, Bartlett MS, Lu JJ, Lundgren B, Lundgren JD, Olsson M, et al . Update on Pneumocystis carinii f. sp. hominis typing based on nucleotide sequence variations in internal transcribed spacer regions of rRNA genes. J Clin Microbiol 1998; 36: 734-741 [Abstract/Free Full Text].

13. Beard CB, Carter JL, Keely SP, Huang L, Pieniazek NJ, Moura INS, Roberts JM, Hightower AW, Bens MS, Freeman AR, et al . . Genetic variation in Pneumocystis carinii isolates from different geographic regions: implications for transmission. Emerg Infect Dis 2000; 6: 265-272 . [Medline]

14. Stansell JD, Osmond DH, Charlebois E, Lavange L, Wallace JM, Alexander BV, Glassroth J, Kvale PA, Rosen MJ, Reichman LB, et al . . Predictors of Pneumocystis carinii pneumonia in HIV-infected persons. Am J Respir Crit Care Med 1997; 155: 60-66 [Abstract].

15. Bennett CL, Horner RD, Weinstein RA, Dickinson GM, DeHovitz JA, Cohn SE, Kessler HA, Jacobson J, Goetz MB, Simberkoff M, et al . . Racial differences in care among hospitalized patients with Pneumocystis carinii pneumonia in Chicago, New York, Los Angeles, Miami, and Raleigh-Durham. Arch Intern Med 1995; 155: 1586-1592 [Abstract].

16. Bastian L, Bennett CL, Adams J, Waskin H, Divine G, Edlin BR. Differences between men and women with HIV-related Pneumocystis carinii pneumonia: experience from 3,070 cases in New York City in 1987.  J Acquir Immune Defic Syndr 1993; 6: 617-623 .

17. Horner RD, Bennett CL, Rodriguez D, Weinstein RA, Kessler HA, Dickinson GM, Johnson JL, Cohn SE, George WL, Gilman SC, et al . . Relationship between procedures and health insurance for critically ill patients with Pneumocystis carinii pneumonia. Am J Respir Crit Care Med 1995; 152: 1435-1442 [Abstract].

18. Kovacs JA, Masur H. Prophylaxis against opportunistic infections in patients with human immunodeficiency virus infection. N Engl J Med 2000; 19: 1416-1429 .

19. USPS/IDSA Prevention of Opportunistic Infections Working Group. 1999 USPS/IDSA guidelines for the prevention of opportunistic infections in persons infected with the human immunodeficiency virus. Ann Intern Med 1999;131:873-903.