Pneumocystis pneumonia (PCP) remains an important opportunistic infection among HIV-infected persons who have advanced immunosuppression. The causative agent, Pneumocystis jiroveci (formerly Pneumocystis carinii), was renamed in honor of Otto Jirovec, the Czech pathologist, who first identified this organism as the cause of outbreaks of interstitial pneumonia in premature and malnourished infants in Europe in the 1930s and 1940s.[,] Based on DNA sequence analysis, P. jiroveci is now classified as a fungus, although unlike other fungi, it lacks ergosterol and is extraordinarily difficult to grow in culture. This organism shares some biologic characteristics with protozoa.
Transmission of Pneumocystis jiroveci
Airborne transmission of P. jiroveci has been demonstrated in animal studies and transmission in humans most likely also occurs via the airborne route. Based on serologic testing, nearly 100% of children acquire infection with P. jiroveci by age 2. Earlier expert opinion suggested Pneumocystis pneumonia was due to reactivation of latent infection, but subsequent reports identified clustered cases of Pneumocystis pneumonia among immunocompromised groups, suggesting that acute disease can develop due to person-to-person spread of P. jiroveci. In addition, in recent studies, investigators detected P. jiroveci in air samples surrounding hospitalized patients with Pneumocystis pneumonia and they documented regional clustering of drug-resistant strains, thus suggesting inter-human transmission. Furthermore, molecular analyses of P. jiroveci strains refute the hypothesis that disease predominantly results from reactivation of dormant organisms acquired in childhood.
Risk of Developing Pneumocystis Pneumonia
Among HIV-infected patients in the pre-HAART era, the risk of ever developing Pneumocystis pneumonia without preventive therapy was approximately 80%, and the likelihood of relapse without secondary prophylaxis was 70 to 80%. Formerly, Pneumocystis pneumonia was the most common AIDS-defining opportunistic infection and was responsible for almost 30% of all cases of community-acquired pneumonia in HIV-infected patients. The incidence of HIV-associated Pneumocystis pneumonia in the United States peaked in 1990 (20,000 cases/year) and then initially declined due to widespread use of Pneumocystis pneumonia prophylaxis. More dramatic reductions in the incidence of Pneumocystis pneumonia resulted from the introduction and widespread use of effective antiretroviral therapy (Figure 1) and (Figure 2).[,,] In well-resourced settings, Pneumocystis pneumonia is now an usual infection, predominantly occuring among individuals who are unaware of their HIV infection or disengaged from medical care.[,]
Recommendations for Preventing Exposure to P. jiroveci
According to the 2014 Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, published by the CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America (IDSA), no specific measures are recommended as standard practice for preventing exposure to P. jiroveci. Some experts recommend that HIV-infected persons at risk for Pneumocystis pneumonia should not share a hospital room with another patient with Pneumocystis pneumonia, but insufficient data exist to routinely recommend this practice.
Indications for Initiating Primary Prophylaxis
Prophylaxis for Pneumocystis pneumonia is classified as either primary prophylaxis (preventing first episode of Pneumocystis pneumonia) or secondary prophylaxis (preventing recurrence of Pneumocystis pneumonia). Among asymptomatic HIV-infected patients, a CD4 count less than 200 cells/mm3 is the strongest identified risk factor for developing Pneumocystis pneumonia (RR 4.9 compared with patients who have a CD4 count greater than 200 cells/mm3). Other independent risk factors for developing Pneumocystis pneumonia include a history of oral candidiasis, a CD4 percentage less than 14, or a history of an AIDS-defining illness.[,] The 2014 U.S. opportunistic infections guidelines strongly recommend initiating primary prophylaxis for Pneumocystis pneumonia for patients who have an absolute CD4 count less than 200 cells/mm3 or a history of oral candidiasis; in patients who do not meet those criteria, prophylaxis for Pneumocystis pneumonia should be considered if the CD4 percentage is less than 14, there is a history of an AIDS-defining illness, or the CD4 count is between 200 and 250 cells/mm3 and regular monitoring of the CD4 cell count is not possible (Figure 3). Patients receiving pyrimethamine plus sulfadiazine for the treatment or suppression of Toxoplasma encephalitis do not need additional medications for Pneumocystis pneumonia prophylaxis.
Recommended Primary Prophylaxis Regimens
Trimethoprim-sulfamethoxazole (Bactrim, Septra
) provides the most effective primary and secondary prophylaxis against Pneumocystis
Use of trimethoprim-sulfamethoxazole has the added benefit of providing protection against Toxoplasma
encephalitis, isosporiasis, and some community-acquired bacterial pathogens.[,,]
The 2014 opportunistic infection guidelines recommends trimethoprim-sulfamethoxazole at a dose of one double-strength or one single strength tablet daily as the preferred prophylaxis regimen (Figure 4
Common adverse effects due to trimethoprim-sulfamethoxazole include rash and fever; less common side effects include leukopenia, hepatitis, hyperkalemia, nephritis and, rarely, aseptic meningitis. Trimethoprim-sulfamethoxazole dosed at one double-strength tablet three times weekly is associated with fewer adverse effects than with daily dosing).
The recommended alternative regimens for patients unable to take daily trimethoprim-sulfamethoxazole include trimethoprim-sulfamethoxazole three times weekly, dapsone, dapsone plus pyrimethamine plus leucovorin, aerosolized pentamidine via Respirard II nebulizer (NebuPent
), atovaquone (Mepron
), or atovaquone plus pyrimethamine plus leucovorin. Dapsone (or dapsone plus pyrimethamine plus leucovorin) is an effective alternative, but some who are intolerant of trimethoprim-sulfamethoxazole will also be intolerant of dapsone. Moreover, dapsone can cause hemolytic anemia, particularly in glucose-6-phosphate dehydrogenase (G6PD)-deficient persons, and methemoglobinemia regardless of G6PD status. If dapsone is used for prophylaxis against Pneumocystis
pneumonia and Toxoplasma
encephalitis, pyrimethamine and leucovorin should be added to the dapsone. Monthly, aerosolized pentamidine is moderately effective, but inferior to trimethoprim-sulfamethoxazole.
Distribution of aerosolized pentamidine throughout the lung is not uniform, putting patients at risk for Pneumocystis
pneumonia in the lung periphery and upper lobes.
In addition, aerosolized pentamidine does not provide protect against extra-pulmonary P. jiroveci
infection. The major adverse effect of aerosolized pentamidine is bronchial airway constriction, which can be overcome or prevented with inhaled bronchodilators. Atovaquone causes few adverse effects and is equivalent to dapsone for the prevention of Pneumocystis
pneumonia, but it is very expensive.
If atovaquone is used, and the patient requires prophylaxis for Toxoplasma
encephalitiis, consider adding pyrimethamine and leucovorin.
Resistance to Trimethoprim-Sulfamethoxazole
The antimicrobial effect of trimethoprim-sulfamethoxazole results from its inhibition of enzymes that catalyze successive steps in folate synthesis: sulfamethoxazole (and dapsone) inhibit the enzyme dihydropteroate synthase (DHPS) and trimethoprim inhibits dihydrofolate reductase (DHFR) (Figure 5). Standard testing for bacterial resistance to trimethoprim-sulfamethoxazole is performed using in vitro susceptibility testing (growth of the bacteria in the presence of drug), but P. jiroveci cannot be easily grown in culture, P. jiroveci resistance testing requires sequence analysis of the genes for DHPS and DHFR. Several studies have investigated the prevalence of DHPS and DHFR mutations in patients with P. jiroveci and detected DHPS mutations in approximately 75% of patients who had received sulfamethoxazole prophylaxis versus approximately 20% of patients who had not received sulfamethoxazole prophylaxis.[,] However, the presence of mutations does not correlate well with treatment failure or decreased survival, making their clinical significance uncertain. Mutations in DHFR, the target of trimethoprim, have not been observed with P. jiroveci, suggesting that trimethoprim provides no selective pressure (and possibly no treatment effect) on P. jiroveci. A retrospective European study reported that interhuman spread of resistant strains, rather than on-treatment selective pressure, accounts for a significant proportion of the (DHPS) resistance found in HIV-infected patients.
Desensitization to Trimethoprim-Sulfamethoxazole
Adverse reactions to trimethoprim-sulfamethoxazole and dapsone are common among HIV-infected patients, with a mean onset at day 10 to 14. Unfortunately, patients who are intolerant of trimethoprim-sulfamethoxazole have approximately a 40% chance of having an adverse reaction to dapsone. For patients who develop a rash due to trimethoprim-sulfamethoxazole, desensitization to trimethoprim-sulfamethoxazole is ultimately successful in 37 to 70% (less success with longer follow-up) and should be attempted if the rash is not severe. Gradual desensitization to trimethoprim-sulfamethoxazole can be accomplished in the outpatient setting using a liquid suspension trimethoprim-sulfamethoxazole (Figure 6). The patient should not be rechallenged with trimethoprim-sulfamethoxazole if the prior reaction included hepatitis, aseptic meningitis, or a severe hypersensitivity reaction (marked by high fever, severe rash, or mucosal involvement suggestive of Stevens-Johnson syndrome).
Recommendations for Discontinuing Primary Prophylaxis
Multiple studies have shown that HIV-infected persons receiving effective antiretroviral therapy who have a CD4 count that increases above 200 cells/mm3 (for at least 3 months) have an extremely low risk of developing Pneumocystis pneumonia.[,,] In these studies, patients generally had sustained excellent responses to antiretroviral therapy. Accordingly, the 2013 opportunistic infections guidelines recommend that patients should discontinue primary Pneumocystis pneumonia prophylaxis if they have responded to effective combination antiretroviral therapy and their CD4 counts have increased to greater than 200 cells/mm3 for at least 3 months. Discontinuing prophylaxis can reduce pill burden, cost, the potential for drug toxicity, and the risk of developing resistant infectious pathogens. If a patient's CD4 count subsequently decreases to less than 200 cells/mm3, the patient should restart Pneumocystis prophylaxis. Notably, an analysis of 12 cohorts of more than 23,000 European patients on antiretroviral therapy with suppressed HIV (less than 400 copies/ml) and CD4 counts between 100 and 200 cells/mm3, who were not taking Pneumocystis pneumonia prophylaxis had low rates of Pneumocystis pneumonia, similar to those on prophylaxis, suggesting it may be safe to discontinue prophylaxis in these individuals. These findings, however, need to be confirmed in other studies before such a recommendation should be routinely adopted into practice.