HIV opportunistic infection pneumocystis pneumonia: prevention and treatment guidelines

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief:, Ujjwal Rastogi, MBBS [2]

Overview

Pneumocystis pneumonia (PCP) is a form of pneumonia caused by the yeast-like fungal Pneumocystis jirovecii (Jirovecii is pronounced "yee row vet zee eye"). The causal agent was originally described as a protozoan and spelled P. jiroveci and prior to then was classified as a form of Pneumocystis carinii, a name still in common usage.[1][2] These names are discussed below. As a result, Pneumocystis pneumonia (PCP) has also been known as Pneumocystis jiroveci[i] pneumonia and as Pneumocystis carinii pneumonia, as is also explained below.[3][4][5]

It is relatively rare in people with normal immune systems but common among people with weakened immune systems, such as premature or severely malnourished children, the elderly, and especially AIDS patients, in whom it is most commonly observed today.[6] PCP can also develop in patients who are taking immunosuppressant medications (e.g. patients who have undergone solid organ transplantation) and in patients who have undergone bone marrow transplantation.

The organism is distributed worldwide[7][3].

Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents

Outline of the Guideline:

Preventing Exposure

Certain authorities might recommend that persons who are at risk for PCP not share a hospital room with a patient who has PCP, a recommendations based on animal studies and anecdotal human experience. Data are insufficient to support this recommendation as standard practice (CIII).

Preventing Disease

Initiating Primary Prophylaxis

  • HIV-infected adults and adolescents, including pregnant women and those on ART, should receive chemoprophylaxis against PCP if they have a CD4+ count of <200 cells/µL (AI) or a history of oropharyngeal candidiasis (AII).[8][9]
  • Persons who have a CD4+ cell percentage of <14% or a history of an AIDS-defining illness, but do not otherwise qualify, should be considered for prophylaxis (BII). [8][9]
  • When monitoring CD4+ counts frequently (e.g., every 1--3 months) is not possible, initiating chemoprophylaxis at a CD4+ count of >200, but <250 cells/µL, also should be considered (BII). [9]
  • TMP-SMX is the recommended prophylactic agent (AI).[10][11][12]One double-strength tablet daily is the preferred regimen (AI). However, one single-strength tablet daily also is effective and might be better tolerated than one double-strength tablet daily (AI).[12] One double-strength tablet three times weekly also is effective (BI)[13]. TMP-SMX at a dose of one double-strength tablet daily confers cross-protection against toxoplasmosis[14] and selected common respiratory bacterial infections.[10][15]Lower doses of TMP-SMX also likely confer such protection. For patients who have an adverse reaction that is not life threatening, chemoprophylaxis with TMP-SMX should be continued if clinically feasible; for those who have discontinued such therapy because of an adverse reaction, reinstituting TMP-SMX should be strongly considered after the adverse event has resolved (AII). Patients who have experienced adverse events, including fever and rash, might better tolerate reintroduction of the drug with a gradual increase in dose (i.e., desensitization), according to published regimens (BI) [16][17] or reintroduction of TMP-SMX at a reduced dose or frequency (CIII); as many as 70% of patients can tolerate such reinstitution of therapy.[15]
  • If TMP-SMX cannot be tolerated, alternative prophylactic regimens include dapsone (BI)[10], dapsone plus pyrimethamineplus leucovorin (BI)[18][19][20],erosolized pentamidine administered by the Respirgard II nebulizer (manufactured by Marquest, Englewood, Colorado) (BI)[11], and atovaquone (BI)[21][22] Atovaquone is as effective as aerosolized pentamidine[21] or dapsone (BI) [22]but is substantially more expensive than the other regimens. For patients seropositive for Toxoplasma gondii who cannot tolerate TMP-SMX, recommended alternatives to TMP-SMX for prophylaxis against both PCP and toxoplasmosis include dapsone plus pyrimethamine plus leucovorin (BI)[18][19][20], erosolized pentamidine administered by the Respirgard II nebulizer (manufactured by Marquest, Englewood, Colorado) (BI)[11], and atovaquone (BI)[21][22]or atovaquone with or without pyrimethamine plus leucovorin (CIII).
  • Oral pyrimethamine plus sulfadoxine also has activity in preventing PCP (CIII)[23][24][25] This combination should not be used in patients with hypersensitivity to sulfonamides. Pyrimethamine plus sulfadoxine has an increased risk for severe cutaneous reactions, including Stevens-Johnson syndrome[26], and the long half-life of both pyrimethamine and sulfadoxine will result in a delayed clearance when the drug is stopped. Largely because TMP-SMX has superior safety, widespread availability, and is low cost, oral pyrimethamine plus sulfadoxine should be used rarely in the United States (CIII).
  • The following regimens cannot be recommended as alternatives because data regarding their efficacy for PCP prophylaxis are insufficient:
    • Aerosolized pentamidine administered by other nebulization devices.
    • Intermittently administered parenteral pentamidine.
    • Oral clindamycin plus primaquine.

However, clinicians might consider using these agents in unusual situations in which the recommended agents cannot be administered (CIII).

Discontinuing Primary Prophylaxis

  • Primary pneumocystis prophylaxis should be discontinued for adult and adolescent patients who have responded to ART with an increase in CD4+ counts to >200 cells/µL for >3 months (AI). In observational and randomized studies supporting this recommendation, the majority of patients were taking antiretroviral regimens that included a protease inhibitor (PI), and the majority had a CD4+ count of >200 cells/µL for >3 months before discontinuing PCP prophylaxis.[27][28] The median CD4+ count at the time prophylaxis was discontinued was >300 cells/µL, most had a CD4+ cell percentage of >14 %, and many patients had a sustained suppression of HIV plasma RNA levels below detection limits of the assay employed. Median follow-up was 6 - 19 months.
  • Discontinuing primary prophylaxis among these patients is recommended because prophylaxis adds limited disease prevention (i.e., for PCP, toxoplasmosis, or bacterial infections).[28][29]
  • Prophylaxis should be reintroduced if the CD4+ count decreases to <200 cells/µL (AIII).

Treatment of Disease

  • TMP-SMX is the treatment of choice (AI).[30]The dose must be adjusted for abnormal renal function. Multiple randomized clinical trials indicate that TMP-SMX is as effective as parenteral pentamidine and more effective than other regimens. Adding leucovorin to prevent myelosuppression during acute treatment is not recommended because of questionable efficacy and some evidence for a higher failure rate (DII). Oral outpatient therapy of TMP-SMX is highly effective among patients with mild-to-moderate disease (AI).
  • Mutations associated with resistance to sulfa drugs have been documented, but their effect on clinical outcome is uncertain. Patients who have PCP despite TMP-SMX prophylaxis are usually effectively treated with standard doses of TMP-SMX (BIII).
  • Patients with documented or suspected PCP and moderate-to-severe disease, as defined by room air pO2 <70 mm Hg or arterial-alveolar O2 gradient >35 mm Hg, should receive adjunctive corticosteroids as early as possible, and certainly within 72 hours after starting specific PCP therapy (AI).[31][32][33][34][35] If steroids are started at a later time, their benefits are unclear, although the majority of clinicians would use them in such circumstances for patients with moderate-to-severe disease (BIII). Methylprednisolone at 75% of the respectiveprednisone dose can be used if parenteral administration is necessary.
  • Alternative therapeutic regimens for mild-to-moderate disease include :
    • Dapsone and TMP (BI) (this regimen might have similar efficacy and fewer side effects than TMP-SMX but is less convenient because of the number of pills).[36][37]
    • Primaquine plus clindamycin (BI) (the clindamycin component can be administered intravenously for more severe cases.[38]
    • Atovaquone suspension (BI) (this is less effective than TMP-SMX for mild-to-moderate disease but has fewer side effects).
  • Patients should be tested for G6PD deficiency whenever possible before administration of primaquine.
  • Alternative therapeutic regimens for patients with moderate-to-severe disease include clindamycin-primaquine or intravenous (IV) pentamidine (AI) (usually the drug of second choice for severe disease). Certain clinicians prefer IV pentamidine because of convincing data regarding its high degree of efficacy. Other clinicians prefer clindamycin-primaquine because this combination is better tolerated than pentamidine, although data regarding efficacy are not as robust as the data supporting pentamidine. Aerosolized pentamidine should not be used for the treatment of PCP because of limited efficacy and more frequent relapse (DI). Trimetrexate is no longer available commercially.
  • The recommended duration of therapy for PCP is 21 days (AII).[39] The probability and rate of response to therapy depend on:
    • The agent used.
    • Number of previous PCP episodes.
    • Severity of illness.
    • Degree of immunodeficiency.
    • Timing of initiation of therapy.
  • Although the overall prognosis of patients whose degree of hypoxemia requires intensive care unit (ICU) admission or mechanical ventilation remains poor, survival in up to 50% of patients requiring ventilatory support has been reported in recent years.[40][41]Because long-term survival is possible for patients in whom ART is effective, certain patients with AIDS and severe PCP should be offered intensive care unit (ICU) admission or mechanical ventilation when appropriate (e.g., when they have reasonable functional status) (AII).
  • Because of the potential for additive or synergistic toxicities associated with anti-PCP and antiretroviral therapies, certain health-care providers delay initiation of ART until after the completion of anti-PCP therapy, or until at least 2 weeks after initiating anti-PCP therapy, despite some suggestion of potential benefit of early ART in the treatment of PCP (CIII). [41][42]

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

Careful monitoring during therapy is important to evaluate response to treatment and to detect toxicity as soon as possible. Follow-up after therapy includes assessment for early relapse, especially when therapy has been with an agent other than TMP-SMX or was shortened for toxicity. PCP prophylaxis should be initiated immediately upon completion of therapy and maintained until the CD4+ count is >200 cells/µL.

Adverse reaction rates among patients with AIDS are high for TMP-SMX (20%--85%).[30][31][37]Common adverse effects are rash (30%--55%) (including Stevens-Johnson syndrome), fever (30%--40%),leukopenia (30%--40%), thrombocytopenia (15%), azotemia (1%--5%), hepatitis (20%), andhyperkalemia. Supportive care for common adverse effects should be attempted before discontinuing TMP-SMX (AIII). Rashes can often be "treated through" with antihistamines, nausea can be controlled withantiemetics, and fever can be managed with antipyretics.

The most common adverse effects of alternative therapies include methemoglobinemia and hemolysis withdapsone or primaquine (especially in those with G6PD deficiency); rash and fever with dapsone;azotemia, pancreatitis, hypo- or hyperglycemia, leukopenia, electrolyte abnormalities, andcardiac dysrhythmia with pentamidine; anemia, rash, fever, and diarrhea with primaquine and clindamycin; and headache, nausea, diarrhea, rash, and transaminase elevations with atovaquone.

IRIS has been reported following PCP. Most cases have occurred within weeks of the episode of PCP. Reported cases are not sufficient to provide guidance on the optimal time to start ART following a mild or severe case of PCP.[43][44]

Management of Treatment Failure

Switching to another regimen is the appropriate management for treatment-related toxicity (BII). Failure attributed to lack of drug efficacy occurs in approximately 10% of those with mild-to-moderate disease. No convincing clinical trials exist on which to base recommendations for the management of treatment failure attributed to lack of drug efficacy. Clinicians should wait at least 4--8 days before switching therapy for lack of clinical improvement (BIII) In the absence of corticosteroid therapy, early and reversible deterioration within the first 3--5 days of therapy is typical, probably because of the inflammatory response caused by antibiotic-induced lysis of organisms in the lung. Other concomitant infections must be excluded as a cause for clinical failure ;[45][46] bronchoscopy with bronchoalveolar lavage should be strongly considered to evaluate for this possibility, even if it was conducted before initiating therapy.

If TMP-SMX has failed or must be avoided for toxicity in moderate-to-severe disease, the common practice is to use parenteral pentamidine or primaquine combined with clindamycin (BII).[47][48][49] For mild disease, atovaquone is a reasonable alternative (BII). Although one meta-analysis concluded that the combination of clindamycin and primaquine might be the most effective regimen for salvage therapy, no prospective clinical trials have evaluated the optimal approach to patients who experience a therapy failure with TMP-SMX.[50]

Preventing Recurrence

Patients who have a history of PCP should be administered chemoprophylaxis for life (i.e.,secondary prophylaxis or chronic maintenance therapy) with TMP-SMX unless immune reconstitution occurs as a result of ART (AI).[51] For patients who are intolerant of TMP-SMX, alternatives are dapsone, dapsone combined with pyrimethamine, atovaquone, or aerosolized pentamidine.

Discontinuing Secondary Prophylaxis (Chronic Maintenance Therapy)

Secondary prophylaxis should be discontinued for adult and adolescent patients whose CD4+ count has increased from<200 cells/µL to >200 cells/µL for >3 months as a result of ART (BII). Reports from observational studies[27][52][53][54] and from two randomized trials [55][29]and a combined analysis of eight European cohorts being followed prospectively[56] support this recommendation.

In these studies, patients had responded to ART with an increase in CD4+ counts to >200 cells/µL for >3 months. The majority of patients were taking PI-containing regimens. The median CD4+ count at the time prophylaxis was discontinued was >300 cells/µL and most had a CD4+ cell percentage of >14%. The majority of patients had sustained suppression of plasma HIV RNA levels below the detection limits of the assay employed; the longest follow-up was 40 months. If the episode of PCP occurred at a CD4+ count of >200 cells/µL, continuing PCP prophylaxis for life, regardless of how high the CD4+ count rises as a consequence of ART, would be prudent (CIII); however, data regarding the most appropriate approach in this setting are limited.

Discontinuing secondary prophylaxis for patients is recommended because prophylaxis adds limited disease prevention (i.e., for PCP, toxoplasmosis, or bacterial infections) and because discontinuing drugs reduces pill burden, potential for drug toxicity, drug interactions, selection of drug-resistant pathogens, and cost.

Prophylaxis should be reintroduced if the CD4+ count decreases to <200 cells/µL (AIII). If PCP recurs at a CD4+ count of >200 cells/µL, lifelong prophylaxis should be administered (CIII).

Special considerations during pregnancy

PCP diagnostic considerations for pregnant women are the same as for nonpregnant women. Indications for therapy are the same as for nonpregnant women. The preferred initial therapy during pregnancy is TMP-SMX, although alternate therapies can be used if patients are unable to tolerate or are unresponsive to TMP-SMX (AI).[57] In case-control studies, trimethoprim has been associated with an increased risk for neural tube defects and cardiovascular, urinary tract, and multiple anomalies after first-trimester exposure.[58][59][60] Epidemiologic data suggest that folic acid supplementation might reduce this risk,[59][60] but no controlled studies have been done. In a small study, an increased risk for birth defects among infants born to women receiving antiretrovirals and folate antagonists, primarily trimethoprim, was reported, whereas no increase was observed among those with either antiretroviral or folate antagonist exposure alone.[61] Although first-trimester exposure to trimethoprim might be related to a small increased risk for birth defects, pregnant women in their first trimester with PCP should be treated with TMP-SMX (AIII). Although folic acid supplementation of 0.4 mg/day is routinely recommended for all pregnant women, data do not indicate if higher levels of supplementation, such as the 4 mg/day recommended for pregnant women with a previous infant with a neural tube defect, would provide added benefit in this situation. Follow-up ultrasound to assess fetal anatomy at 18--20 weeks is recommended (BIII).

Neonatal-care providers should be informed of maternal sulfa or dapsone therapy if used near the delivery date because of the theoretical increased risk for hyperbilirubinemia and kernicterus.

Pentamidine is embryotoxic but not teratogenic among rats and rabbits.[62]Adjunctive corticosteroid therapy should be used as indicated in nonpregnant adults (AIII).[63][64][65][66] Maternal fasting and postprandial glucose levels should be monitored closely when corticosteroids are used in the third trimester because the risk for glucose intolerance is increased.

Rates of preterm labor and preterm delivery are increased with pneumonia during pregnancy. Pregnant women with pneumonia after 20 weeks of gestation should be monitored for evidence of contractions(BII).

Chemoprophylaxis for PCP should be administered to pregnant women the same as for other adults and adolescents (AIII). TMP-SMX is the recommended prophylactic agent; dapsone is an alternative. Because of theoretical concerns regarding possible teratogenicity associated with drug exposures during the first trimester, health-care providers might withhold prophylaxis during the first trimester. In such cases, aerosolized pentamidine can be considered because of its lack of systemic absorption and the resultant lack of exposure of the developing embryo to the drug (CIII).

Reference

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  12. ↑ 12.0 12.1 Schneider MM, Nielsen TL, Nelsing S, Hoepelman AI, Eeftinck Schattenkerk JK, van der Graaf Y, Kolsters AF, Borleffs JC (1995). "Efficacy and toxicity of two doses of trimethoprim-sulfamethoxazole as primary prophylaxis against Pneumocystis carinii pneumonia in patients with human immunodeficiency virus. Dutch AIDS Treatment Group". J. Infect. Dis. 171 (6): 1632–6. PMID 7769306. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  13. ↑ El-Sadr WM, Luskin-Hawk R, Yurik TM, Walker J, Abrams D, John SL, Sherer R, Crane L, Labriola A, Caras S, Pulling C, Hafner R (1999). "A randomized trial of daily and thrice-weekly trimethoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA)". Clin. Infect. Dis. 29 (4): 775–83. doi:10.1086/520433. PMID 10589887. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  14. ↑ Carr A, Tindall B, Brew BJ, Marriott DJ, Harkness JL, Penny R, Cooper DA (1992). "Low-dose trimethoprim-sulfamethoxazole prophylaxis for toxoplasmic encephalitis in patients with AIDS". Ann. Intern. Med. 117 (2): 106–11. PMID 1351371. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  15. ↑ 15.0 15.1 Hardy WD, Feinberg J, Finkelstein DM, Power ME, He W, Kaczka C, Frame PT, Holmes M, Waskin H, Fass RJ (1992). "A controlled trial of trimethoprim-sulfamethoxazole or aerosolized pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. AIDS Clinical Trials Group Protocol 021". N. Engl. J. Med. 327 (26): 1842–8. doi:10.1056/NEJM199212243272604. PMID 1448121. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  16. ↑ Para MF, Finkelstein D, Becker S, Dohn M, Walawander A, Black JR (2000). "Reduced toxicity with gradual initiation of trimethoprim-sulfamethoxazole as primary prophylaxis for Pneumocystis carinii pneumonia: AIDS Clinical Trials Group 268". J. Acquir. Immune Defic. Syndr. 24 (4): 337–43. PMID 11015150. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  17. ↑ Leoung GS, Stanford JF, Giordano MF, Stein A, Torres RA, Giffen CA, Wesley M, Sarracco T, Cooper EC, Dratter V, Smith JJ, Frost KR (2001). "Trimethoprim-sulfamethoxazole (TMP-SMZ) dose escalation versus direct rechallenge for Pneumocystis Carinii pneumonia prophylaxis in human immunodeficiency virus-infected patients with previous adverse reaction to TMP-SMZ". J. Infect. Dis. 184 (8): 992–7. doi:10.1086/323353. PMID 11574913. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  18. ↑ 18.0 18.1 Podzamczer D, Salazar A, Jiménez J, Consiglio E, Santín M, Casanova A, Rufí G, Gudiol F (1995). "Intermittent trimethoprim-sulfamethoxazole compared with dapsone-pyrimethamine for the simultaneous primary prophylaxis of Pneumocystis pneumonia and toxoplasmosis in patients infected with HIV". Ann. Intern. Med. 122 (10): 755–61. PMID 7717598. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  19. ↑ 19.0 19.1 Opravil M, Hirschel B, Lazzarin A, Heald A, Pechère M, Rüttimann S, Iten A, von Overbeck J, Oertle D, Praz G (1995). "Once-weekly administration of dapsone/pyrimethamine vs. aerosolized pentamidine as combined prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus-infected patients". Clin. Infect. Dis. 20 (3): 531–41. PMID 7756472. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  20. ↑ 20.0 20.1 Girard PM, Landman R, Gaudebout C, Olivares R, Saimot AG, Jelazko P, Gaudebout C, Certain A, Boué F, Bouvet E (1993). "Dapsone-pyrimethamine compared with aerosolized pentamidine as primary prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis in HIV infection. The PRIO Study Group". N. Engl. J. Med. 328 (21): 1514–20. doi:10.1056/NEJM199305273282102. PMID 8479488. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  21. ↑ 21.0 21.1 21.2 Chan C, Montaner J, Lefebvre EA, Morey G, Dohn M, McIvor RA, Scott J, Marina R, Caldwell P (1999). "Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides". J. Infect. Dis. 180 (2): 369–76. doi:10.1086/314893. PMID 10395851. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  22. ↑ 22.0 22.1 22.2 El-Sadr WM, Murphy RL, Yurik TM, Luskin-Hawk R, Cheung TW, Balfour HH, Eng R, Hooton TM, Kerkering TM, Schutz M, van der Horst C, Hafner R (1998). "Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group". N. Engl. J. Med. 339 (26): 1889–95. doi:10.1056/NEJM199812243392604. PMID 9862944. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  23. ↑ Schürmann D, Bergmann F, Albrecht H, Padberg J, Wünsche T, Grünewald T, Schürmann M, Grobusch M, Vallée M, Ruf B, Suttorp N (2002). "Effectiveness of twice-weekly pyrimethamine-sulfadoxine as primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmic encephalitis in patients with advanced HIV infection". Eur. J. Clin. Microbiol. Infect. Dis. 21 (5): 353–61. doi:10.1007/s10096-002-0723-3. PMID 12072919. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  24. ↑ Payen MC, De Wit S, Sommereijns B, Clumeck N (1997). "A controlled trial of dapsone versus pyrimethamine-sulfadoxine for primary prophylaxis of Pneumocystis carinii pneumonia and toxoplasmosis in patients with AIDS". Biomed. Pharmacother. 51 (10): 439–45. PMID 9863502. Retrieved 2012-04-06.
  25. ↑ Schürmann D, Bergmann F, Albrecht H, Padberg J, Grünewald T, Behnsch M, Grobusch M, Vallée M, Wünsche T, Ruf B, Suttorp N (2001). "Twice-weekly pyrimethamine-sulfadoxine effectively prevents Pneumocystis carinii pneumonia relapse and toxoplasmic encephalitis in patients with AIDS". J. Infect. 42 (1): 8–15. doi:10.1053/jinf.2000.0772. PMID 11243747. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  26. ↑ Navin TR, Miller KD, Satriale RF, Lobel HO (1985). "Adverse reactions associated with pyrimethamine-sulfadoxine prophylaxis for Pneumocystis carinii infections in AIDS". Lancet. 1 (8441): 1332. PMID 2860516. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  27. ↑ 27.0 27.1 Dworkin MS, Hanson DL, Kaplan JE, Jones JL, Ward JW (2000). "Risk for preventable opportunistic infections in persons with AIDS after antiretroviral therapy increases CD4+ T lymphocyte counts above prophylaxis thresholds". J. Infect. Dis. 182 (2): 611–5. doi:10.1086/315734. PMID 10915098. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  28. ↑ 28.0 28.1 Mussini C, Pezzotti P, Govoni A, Borghi V, Antinori A, d'Arminio Monforte A, De Luca A, Mongiardo N, Cerri MC, Chiodo F, Concia E, Bonazzi L, Moroni M, Ortona L, Esposito R, Cossarizza A, De Rienzo B (2000). "Discontinuation of primary prophylaxis for Pneumocystis carinii pneumonia and toxoplasmic encephalitis in human immunodeficiency virus type I-infected patients: the changes in opportunistic prophylaxis study". J. Infect. Dis. 181 (5): 1635–42. doi:10.1086/315471. PMID 10823763. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  29. ↑ 29.0 29.1 Lopez Bernaldo de Quiros JC, Miro JM, Peña JM, Podzamczer D, Alberdi JC, Martínez E, Cosin J, Claramonte X, Gonzalez J, Domingo P, Casado JL, Ribera E (2001). "A randomized trial of the discontinuation of primary and secondary prophylaxis against Pneumocystis carinii pneumonia after highly active antiretroviral therapy in patients with HIV infection. Grupo de Estudio del SIDA 04/98". N. Engl. J. Med. 344 (3): 159–67. doi:10.1056/NEJM200101183440301. PMID 11172138. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  30. ↑ 30.0 30.1 Hughes W, Leoung G, Kramer F, Bozzette SA, Safrin S, Frame P, Clumeck N, Masur H, Lancaster D, Chan C (1993). "Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS". N. Engl. J. Med. 328 (21): 1521–7. doi:10.1056/NEJM199305273282103. PMID 8479489. Retrieved 2012-04-06. Unknown parameter |month= ignored (help)
  31. ↑ 31.0 31.1 Nielsen TL, Eeftinck Schattenkerk JK, Jensen BN, Lundgren JD, Gerstoft J, van Steenwijk RP, Bentsen K, Frissen PH, Gaub J, Orholm M (1992). "Adjunctive corticosteroid therapy for Pneumocystis carinii pneumonia in AIDS: a randomized European multicenter open label study". J. Acquir. Immune Defic. Syndr. 5 (7): 726–31. PMID 1613673. |access-date= requires |url= (help)
  32. ↑ Bozzette SA, Sattler FR, Chiu J, Wu AW, Gluckstein D, Kemper C, Bartok A, Niosi J, Abramson I, Coffman J (1990). "A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group". N. Engl. J. Med. 323 (21): 1451–7. doi:10.1056/NEJM199011223232104. PMID 2233917. Retrieved 2012-04-07. Unknown parameter |month= ignored (help)
  33. ↑ Montaner JS, Lawson LM, Levitt N, Belzberg A, Schechter MT, Ruedy J (1990). "Corticosteroids prevent early deterioration in patients with moderately severe Pneumocystis carinii pneumonia and the acquired immunodeficiency syndrome (AIDS)". Ann. Intern. Med. 113 (1): 14–20. PMID 2190515. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
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  35. ↑ Briel M, Boscacci R, Furrer H, Bucher HC (2005). "Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV infection: a meta-analysis of randomised controlled trials". BMC Infect. Dis. 5: 101. doi:10.1186/1471-2334-5-101. PMC 1309617. PMID 16271157. Retrieved 2012-04-07.
  36. ↑ Safrin S, Finkelstein DM, Feinberg J, Frame P, Simpson G, Wu A, Cheung T, Soeiro R, Hojczyk P, Black JR (1996). "Comparison of three regimens for treatment of mild to moderate Pneumocystis carinii pneumonia in patients with AIDS. A double-blind, randomized, trial of oral trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine. ACTG 108 Study Group". Ann. Intern. Med. 124 (9): 792–802. PMID 8610948. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  37. ↑ 37.0 37.1 Medina I, Mills J, Leoung G, Hopewell PC, Lee B, Modin G, Benowitz N, Wofsy CB (1990). "Oral therapy for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A controlled trial of trimethoprim-sulfamethoxazole versus trimethoprim-dapsone". N. Engl. J. Med. 323 (12): 776–82. doi:10.1056/NEJM199009203231202. PMID 2392131. Retrieved 2012-04-07. Unknown parameter |month= ignored (help)
  38. ↑ Black JR, Feinberg J, Murphy RL, Fass RJ, Finkelstein D, Akil B, Safrin S, Carey JT, Stansell J, Plouffe JF (1994). "Clindamycin and primaquine therapy for mild-to-moderate episodes of Pneumocystis carinii pneumonia in patients with AIDS: AIDS Clinical Trials Group 044". Clin. Infect. Dis. 18 (6): 905–13. PMID 8086551. Retrieved 2012-04-07. Unknown parameter |month= ignored (help)
  39. ↑ Kovacs JA, Hiemenz JW, Macher AM, Stover D, Murray HW, Shelhamer J, Lane HC, Urmacher C, Honig C, Longo DL (1984). "Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies". Ann. Intern. Med. 100 (5): 663–71. PMID 6231873. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  40. ↑ Curtis JR, Yarnold PR, Schwartz DN, Weinstein RA, Bennett CL (2000). "Improvements in outcomes of acute respiratory failure for patients with human immunodeficiency virus-related Pneumocystis carinii pneumonia". Am. J. Respir. Crit. Care Med. 162 (2 Pt 1): 393–8. PMID 10934059. Retrieved 2012-04-07. Unknown parameter |month= ignored (help)
  41. ↑ 41.0 41.1 Dworkin MS, Hanson DL, Navin TR (2001). "Survival of patients with AIDS, after diagnosis of Pneumocystis carinii pneumonia, in the United States". J. Infect. Dis. 183 (9): 1409–12. doi:10.1086/319866. PMID 11294675. Retrieved 2012-04-07. Unknown parameter |month= ignored (help)
  42. ↑ Huang L, Quartin A, Jones D, Havlir DV (2006). "Intensive care of patients with HIV infection". N. Engl. J. Med. 355 (2): 173–81. doi:10.1056/NEJMra050836. PMID 16837681. Retrieved 2012-04-07. Unknown parameter |month= ignored (help)
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  44. ↑ Koval CE, Gigliotti F, Nevins D, Demeter LM (2002). "Immune reconstitution syndrome after successful treatment of Pneumocystis carinii pneumonia in a man with human immunodeficiency virus type 1 infection". Clin. Infect. Dis. 35 (4): 491–3. doi:10.1086/341974. PMID 12145736. Retrieved 2012-04-07. Unknown parameter |month= ignored (help)
  45. ↑ Baughman RP, Dohn MN, Frame PT (1994). "The continuing utility of bronchoalveolar lavage to diagnose opportunistic infection in AIDS patients". Am. J. Med. 97 (6): 515–22. PMID 7985710. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  46. ↑ Stover DE, Zaman MB, Hajdu SI, Lange M, Gold J, Armstrong D (1984). "Bronchoalveolar lavage in the diagnosis of diffuse pulmonary infiltrates in the immunosuppressed host". Ann. Intern. Med. 101 (1): 1–7. PMID 6375497. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  47. ↑ Toma E, Thorne A, Singer J, Raboud J, Lemieux C, Trottier S, Bergeron MG, Tsoukas C, Falutz J, Lalonde R, Gaudreau C, Therrien R (1998). "Clindamycin with primaquine vs. Trimethoprim-sulfamethoxazole therapy for mild and moderately severe Pneumocystis carinii pneumonia in patients with AIDS: a multicenter, double-blind, randomized trial (CTN 004). CTN-PCP Study Group". Clin. Infect. Dis. 27 (3): 524–30. PMID 9770152. Retrieved 2012-04-08. Unknown parameter |month= ignored (help)
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  49. ↑ Sattler FR, Frame P, Davis R, Nichols L, Shelton B, Akil B, Baughman R, Hughlett C, Weiss W, Boylen CT (1994). "Trimetrexate with leucovorin versus trimethoprim-sulfamethoxazole for moderate to severe episodes of Pneumocystis carinii pneumonia in patients with AIDS: a prospective, controlled multicenter investigation of the AIDS Clinical Trials Group Protocol 029/031". J. Infect. Dis. 170 (1): 165–72. PMID 8014493. Retrieved 2012-04-08. Unknown parameter |month= ignored (help)
  50. ↑ Smego RA, Nagar S, Maloba B, Popara M (2001). "A meta-analysis of salvage therapy for Pneumocystis carinii pneumonia". Arch. Intern. Med. 161 (12): 1529–33. PMID 11427101. Retrieved 2012-04-08. Unknown parameter |month= ignored (help)
  51. ↑ Masur H, Kaplan JE, Holmes KK (2002). "Guidelines for preventing opportunistic infections among HIV-infected persons--2002. Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America". Ann. Intern. Med. 137 (5 Pt 2): 435–78. PMID 12617574. Retrieved 2012-04-08. Unknown parameter |month= ignored (help)
  52. ↑ Kirk O, Lundgren JD, Pedersen C, Nielsen H, Gerstoft J (1999). "Can chemoprophylaxis against opportunistic infections be discontinued after an increase in CD4 cells induced by highly active antiretroviral therapy?". AIDS. 13 (13): 1647–51. PMID 10509565. Retrieved 2012-04-08. Unknown parameter |month= ignored (help)
  53. ↑ Soriano V, Dona C, Rodríguez-Rosado R, Barreiro P, González-Lahoz J (2000). "Discontinuation of secondary prophylaxis for opportunistic infections in HIV-infected patients receiving highly active antiretroviral therapy". AIDS. 14 (4): 383–6. PMID 10770540. Retrieved 2012-04-08. Unknown parameter |month= ignored (help)
  54. ↑ Zellweger C, Opravil M, Bernasconi E, Cavassini M, Bucher HC, Schiffer V, Wagels T, Flepp M, Rickenbach M, Furrer H (2004). "Long-term safety of discontinuation of secondary prophylaxis against Pneumocystis pneumonia: prospective multicentre study". AIDS. 18 (15): 2047–53. PMID 15577626. Retrieved 2012-04-08. Unknown parameter |month= ignored (help)
  55. ↑ Mussini C, Pezzotti P, Antinori A, Borghi V, Monforte A, Govoni A, De Luca A, Ammassari A, Mongiardo N, Cerri MC, Bedini A, Beltrami C, Ursitti MA, Bini T, Cossarizza A, Esposito R (2003). "Discontinuation of secondary prophylaxis for Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients: a randomized trial by the CIOP Study Group". Clin. Infect. Dis. 36 (5): 645–51. doi:10.1086/367659. PMID 12594647. Retrieved 2012-04-08. Unknown parameter |month= ignored (help)
  56. ↑ Ledergerber B, Mocroft A, Reiss P, Furrer H, Kirk O, Bickel M, Uberti-Foppa C, Pradier C, D'Arminio Monforte A, Schneider MM, Lundgren JD (2001). "Discontinuation of secondary prophylaxis against Pneumocystis carinii pneumonia in patients with HIV infection who have a response to antiretroviral therapy. Eight European Study Groups". N. Engl. J. Med. 344 (3): 168–74. doi:10.1056/NEJM200101183440302. PMID 11188837. Retrieved 2012-04-08. Unknown parameter |month= ignored (help)
  57. ↑ Connelly RT, Lourwood DL (1994). "Pneumocystis carinii pneumonia prophylaxis during pregnancy". Pharmacotherapy. 14 (4): 424–9. PMID 7937279. |access-date= requires |url= (help)
  58. ↑ Czeizel AE, Rockenbauer M, Sørensen HT, Olsen J (2001). "The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study". Reprod. Toxicol. 15 (6): 637–46. PMID 11738517. Retrieved 2012-04-09.
  59. ↑ 59.0 59.1 Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA (2000). "Folic acid antagonists during pregnancy and the risk of birth defects". N. Engl. J. Med. 343 (22): 1608–14. doi:10.1056/NEJM200011303432204. PMID 11096168. Retrieved 2012-04-09. Unknown parameter |month= ignored (help)
  60. ↑ 60.0 60.1 Hernández-Díaz S, Werler MM, Walker AM, Mitchell AA (2001). "Neural tube defects in relation to use of folic acid antagonists during pregnancy". Am. J. Epidemiol. 153 (10): 961–8. PMID 11384952. Retrieved 2012-04-09. Unknown parameter |month= ignored (help)
  61. ↑ Jungmann EM, Mercey D, DeRuiter A, Edwards S, Donoghue S, Booth T, Mohan D, Lyall H, Taylor GP (2001). "Is first trimester exposure to the combination of antiretroviral therapy and folate antagonists a risk factor for congenital abnormalities?". Sex Transm Infect. 77 (6): 441–3. PMC 1744398. PMID 11714944. Retrieved 2012-04-09. Unknown parameter |month= ignored (help)
  62. ↑ Harstad TW, Little BB, Bawdon RE, Knoll K, Roe D, Gilstrap LC (1990). "Embryofetal effects of pentamidine isethionate administered to pregnant Sprague-Dawley rats". Am. J. Obstet. Gynecol. 163 (3): 912–6. PMID 2403167. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  63. ↑ Albino JA, Shapiro JM (1994). "Respiratory failure in pregnancy due to Pneumocystis carinii: report of a successful outcome". Obstet Gynecol. 83 (5 Pt 2): 823–4. PMID 8159362. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  64. ↑ Madinger NE, Greenspoon JS, Ellrodt AG (1989). "Pneumonia during pregnancy: has modern technology improved maternal and fetal outcome?". Am. J. Obstet. Gynecol. 161 (3): 657–62. PMID 2782348. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  65. ↑ Koonin LM, Ellerbrock TV, Atrash HK, Rogers MF, Smith JC, Hogue CJ, Harris MA, Chavkin W, Parker AL, Halpin GJ (1989). "Pregnancy-associated deaths due to AIDS in the United States". JAMA. 261 (9): 1306–9. PMID 2783746. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
  66. ↑ Benedetti TJ, Valle R, Ledger WJ (1982). "Antepartum pneumonia in pregnancy". Am. J. Obstet. Gynecol. 144 (4): 413–7. PMID 7124859. Unknown parameter |month= ignored (help); |access-date= requires |url= (help)
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