Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients

Pneumocystis carinii has taken on new importance with the emergence of the human immunodeficiency virus. It is the most common life-threatening opportunistic infection in the acquired immunodeficiency syndrome and eventually develops in 80% or more of those not receiving primary prophylaxis. This review focuses on the clinical presentation, diagnosis, treatment, and prophylaxis of P carinii pneumonia in patients with human immunodeficiency virus infection.     

Experimental Pneumocystis carinii pneumonia in simian immunodeficiency virus-infected rhesus macaques

To establish experimental Pneumocystis carinii infection in simian immunodeficiency virus (SIV)-infected macaques as a model of acquired immunodeficiency syndrome (AIDS)-associated P. carinii pneumonia (PCP), SIV-infected macaques were inoculated intrabronchially with macaque-derived P. carinii, and P. carinii-specific polymerase chain reaction (PCR) and flow cytometric analysis of bronchoalveolar lavage fluid were done biweekly for up to 44 weeks after inoculation. All inoculated animals had a P. carinii-specific PCR product after infection. CD8(+) T cells in lung lavage samples from SIV- and P. carinii-coinfected animals increased to >90% of total CD3(+) cells, a pattern associated with naturally acquired P. carinii infection. Progression of disease also was correlated with increased neutrophil infiltration to the lungs. The animals had a protracted period of asymptomatic colonization with P. carinii before progression to PCP. The development of a model of PCP in SIV-infected rhesus macaques provides the means to study AIDS-associated PCP.     

Diagnosis of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients with polymerase chain reaction: a blinded comparison to standard methods.

Pneumocystis carinii pneumonia (PCP) is an important cause of morbidity and death among persons with human immunodeficiency virus (HIV) infection. Polymerase chain reaction (PCR) analysis of respiratory specimens has been investigated as a rapid diagnostic method. We have previously reported on the utility of this technique for diagnosing PCP in HIV-infected patients. In this report we evaluate PCR used in a blinded study design to avoid biases inherent to retrospective and nonblinded studies. The diagnosis of PCP was established on the basis of clinical findings and morphological studies of bronchoalveolar lavage (BAL) and/or lung biopsy specimens before PCR testing. PCR was performed without knowledge of the diagnosis. PCR results were graded from "negative" to 3+ on the basis of intensity of the banding pattern. Forty-seven patients were enrolled in the study, including 18 with proven PCP and 29 with other conditions. PCR was positive at grade 1 or higher for all 18 patients with PCP (100% sensitivity), at grade 2 or higher for 13 patients (72.2% sensitivity), and at grade 1 or higher for 4 of the 29 control patients (specificity of 86.2%). If a grade 2 or higher was required for diagnosis, the specificity improved to 100%. Results were reproducible with testing of a second aliquot for 46 of 47 patients (97.8%). Our findings confirm that PCR is a sensitive and reproducible test for detection of P. carinii in BAL specimens. Problems with false-positive results for control patients, however, limit the applicability of this method.     

Prophylaxis for Pneumocystis carinii pneumonia in patients infected with human immunodeficiency virus.

Following the initial observation by Dr. Margaret Fischl that trimethoprim-sulfamethoxazole can prevent Pneumocystis carinii infection in patients with Kaposi's sarcoma, initiating prophylaxis for pneumocystic infection in all patients with less than 200 CD4+ cells/mm3 has become accepted practice. This prophylactic intervention has been found not only to reduce the development of pneumonia due to P. carinii but also to prolong life. Drs. Henry Masur and Joseph A. Kovacs first reviewed prophylaxis for P. carinii pneumonia in patients infected with the human immunodeficiency virus for the AIDS Commentary 3 years ago. They have updated that initial review for this AIDS Commentary, placing currently available information into concise clinical perspective and detailing a rational plan for the clinician to follow based on results of recent studies.     

Enhanced in vivo human immunodeficiency virus-1 replication in the lungs of human immunodeficiency virus-infected persons with Pneumocystis carinii pneumonia

The relationship of serum human immunodeficiency virus-1 (HIV-1) RNA levels to HIV-1 RNA levels in other compartments, such as the lungs, is not well characterized. The purpose of this study was to determine the viral burden of HIV-1 in the lungs by comparing HIV-1 RNA in cell-free bronchoalveolar lavage fluid (BALF) with that in serum. Specimens were examined from 77 HIV-seropositive adults (CD4(+) cell counts: 0 to 700 cells/mm(3); 48% receiving prescribed antiretroviral agents), comprising 43 asymptomatic individuals who were compared with 34 persons with active lung disease caused by Pneumocystis carinii (n = 26), bacteria (n = 3), Mycobacterium avium complex (n = 2), Nocardia sp. (n = 1), Aspergillus sp. (n = 1), or pulmonary Kaposi's sarcoma (n = 1). For serum HIV-1 RNA, the proportion of subjects with detectable levels and the mean values were similar for asymptomatic individuals and persons with active lung disease (85% versus 86%, respectively) (6.64 x 10(4) versus 1. 81 x 10(5) HIV-1 RNA copies/ml; p = 0.13). In contrast, HIV-1 RNA in BALF was more often detected (16% versus 62%; p = 0.001), and mean values were higher (1.04 x 10(5) versus 3.31 x 10(6) HIV-1 RNA copies/ml; p = 0.032), in subjects with active lung disease than in asymptomatic subjects, independent of early or advanced clinical stages of HIV-related disease. For both study groups, HIV-1 RNA levels in BALF exceeded those in serum in 56% of cases by up to 66-fold, and did not correlate with local levels of tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, or interleukin-16. HIV-1 proviral DNA in cells from BALF was detected in up to 86% of subjects, more frequently in persons with advanced HIV disease (p = 0.0496), and often involved > 10% of BALF cells, but did not correlate with HIV-1 RNA detected in BALF. These data provide evidence for active HIV-1 replication in the lungs. HIV-1 replication is compartmentalized relative to serum, may be restricted, is independent of HIV-1 proviral DNA and clinical stage of HIV, and may be influenced by pulmonary disease such as P. carinii pneumonia or by other local or lung-specific factors. The lungs represent a large reservoir for HIV-1, and may present a source of persistent HIV-1 replication even during periods of apparent clinical latency of HIV-1 infection.     

Pneumocystis carinii pneumonia in a human immunodeficiency virus-uninfected patient with sickle cell crisis.

Pneumocystis carinii pneumonia (PCP) usually occurs in the setting of preexisting immunosuppression. We present a case of PCP that occurred in an HIV-negative woman with severe sickle cell disease.     

Pneumocystis carinii pneumonia in patients without HIV infection

Pneumocystis carinii is an important, but sporadic, opportunistic pulmonary pathogen in immunosuppressed HIV seronegative persons. Historically, patients at highest risk for P. carinii pneumonia are included infants with severe malnutrition, children with primary immunodeficiencies, patients with hematological malignancies, and recipients of solid organ or bone marrow transplants. Recently, solid tumor patients, in particular those receiving high-dose corticosteroids for brain neoplasms, and patients with inflammatory or collagen-vascular disorders, especially patients with Wegener granulomatosis receiving immunosuppressive therapy, have been identified as subgroups at increased risk for P. carinii pneumonia. Other factors associated with P. carinii pneumonia include the intensity of the immunosuppressive regimen and tapering doses of corticosteroids. Because P. carinii pneumonia is associated with significant morbidity and mortality, it is important to identify high-risk patient populations to administer effective chemoprophylactic agents, such as trimethoprim-sulfamethoxazole.     

Reduction of pulmonary surfactant in patients with human immunodeficiency virus infection and Pneumocystis carinii pneumonia.

We assessed qualitative and quantitative differences in surfactant lipid composition of bronchoalveolar lavage (BAL) fluid in patients with acquired immune deficiency syndrome (AIDS) and Pneumocystis carinii (PC) pneumonia. Five normal volunteers and 27 patients with human immunodeficiency virus (HIV) infection underwent BAL for evaluation of possible pulmonary infection. Bronchoalveolar lavage studies in eight patients were negative for PC organisms, and 19 were positive. Pneumocystis carinii pneumonia was graded (mild vs moderate to severe) by initial alveolar-arterial oxygen gradient. Bronchoalveolar lavage fluid was centrifuged, the lipids were extracted from the supernatant, and total lipid profiles of dephosphorylated glycerolipids were analyzed as trimethylsilylether derivatives by high temperature gas-liquid chromatography. Phospholipase A2 levels were determined using a radiolabeled E coli membrane method. Compared to the normal volunteers (109 +/- 13 micrograms/5 ml) and the PC negative group (107 +/- 13 micrograms/5 ml), total BAL lipid was reduced for both the mild PC pneumonia group (73 +/- 10 micrograms/5 ml) and the moderate to severe PC pneumonia group (46 +/- 4 micrograms/5 ml). There was a parallel reduction of diacylglycerol lipids: normal volunteers, 52 +/- 7 micrograms/5 ml; PC negative, 52 +/- 9 micrograms/5 ml; mild PC pneumonia, 35 +/- 7 micrograms/5 ml; and moderate to severe PC pneumonia, 15 +/- 2 micrograms/5 ml. Phospholipase A2 activity in moderate to severe PC pneumonia was twice that of the PC negative patients, and 30 times that for normals. The data demonstrate a marked diminution in surfactant glycerophospholipid in patients with AIDS and PC pneumonia and suggest a potential role for surfactant abnormality in the pathophysiology of this disease.     

A comparison of the effectiveness of three regimens in the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected patients.

BACKGROUND--Pneumocystis carinii pneumonia (PCP) is a major cause of morbidity and the leading cause of death in patients with the acquired immunodeficiency syndrome. The prevention of the occurrence and recurrence of PCP is a cornerstone in the treatment of patients infected with the human immunodeficiency virus. There are few studies comparing PCP prophylactic regimens. METHODS--The efficacy of three regimens for prophylaxis against PCP was assessed in a retrospective chart review of 211 human immunodeficiency virus-infected patients at risk for the disease. Over the course of the 2-year study period, 133 patients were prescribed trimethoprim-sulfamethoxazole (one double-strength tablet twice a day, thrice weekly) for a mean of 7.4 months (range, 1 to 25 months). Seventy-seven patients received dapsone (50 mg daily) for a mean of 5.7 months (range, 1 to 23 months), and 125 patients received aerosolized pentamidine (300 mg via nebulizer once monthly) for a mean of 9.3 months (range, 1 to 21 months). The majority of patients (62%) received primary prophylaxis; 38% had one or more previous episodes of PCP; and 73% were receiving concomitant antiretroviral therapy. RESULTS--Pneumocystis carinii pneumonia did not develop in any patient receiving trimethoprim-sulfamethoxazole in 981 patient-months. Five patients receiving dapsone for 437 patient-months and 17 patients receiving aerosolized pentamidine for 1166 patient-months developed PCP. Fifty-six percent of the trimethoprim-sulfamethoxazole group and 55% of the dapsone group changed drug due to adverse reactions, while only 2% in the aerosolized pentamidine group required drug change. CONCLUSION--Despite its adverse reaction profile, trimethoprim-sulfamethoxazole is the most effective agent to prevent the occurrence and recurrence of PCP.     

Prophylaxis of Pneumocystis carinii pneumonia in patients infected with the human immunodeficiency virus type 1

Immunosuppression due to human immunodeficiency virus type 1 (HIV) infection has led to a marked increase in Pneumocystis carinii pneumonia (PCP). Prophylaxis against PCP is standard practice in pediatric cancer patients but is associated with unique problems in HIV-infected patients, including the need for lifelong therapy, adverse reactions, and drug interactions. HIV-infected patients at highest risk for PCP are those with a prior episode of PCP and/or a CD4 lymphocyte count of less than 200 cells/microL. A combination of trimethoprim and sulfamethoxazole is effective prophylactically, although a significant rate of adverse reactions makes long-term prophylaxis difficult. Other oral medications such as dapsone and a combination of pyrimethamine and sulfadoxine are promising but not yet adequately tested. Inhalation of aerosolized pentamidine is an effective and safe means of prophylaxis if the proper dose and nebulizer are used. The only common adverse effects with the latter are airway irritation manifested by cough or wheezing. Zidovudine appears to have a synergistic benefit in further reducing the attack rate of PCP when used with aerosolized pentamidine.     

Pneumocystis carinii pneumonia in human immunodeficiency virus (HIV)-positive and HIV-negative immunocompromised patients.

For 89 human immunodeficiency virus (HIV)-positive and 32 HIV-negative immunocompromised patients who had 121 episodes of Pneumocystis carinii pneumonia (PCP), clinical features and changes over time were compared. HIV-infected patients characteristically had a longer duration of symptoms (23 vs. 13 days; P<.005); were younger (39 vs. 48 years; P<.001); had a higher frequency of sweating, weight loss, and thoracic pain; and had fewer admissions to the intensive care unit (16% vs. 31%; P<.05). In addition, they had significantly higher hemoglobin levels, lower thrombocyte counts, lower C-reactive protein values, and a higher proportion of eosinophils and lymphocytes in bronchoalveolar lavage fluid. After 1995, HIV-negative patients' mean length of stay dropped from 34 days to 16 days (P<.005), and their hospital mortality rate dropped from 29% to 7% (P<.001). HIV-positive patients with PCP differed in several aspects from those without HIV infection. Knowledge gained from experience with treatment of opportunistic infections in patients with AIDS has improved the management of PCP in patients with other immunodeficiencies.     

Aerosolised pentamidine for Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome

The goal of this study was to evaluate inhaled pentamidine for the treatment of patients with mild and moderate Pneumocystis carinii pneumonitis. Eight adults with AIDS and pneumocystis pneumonia (4 with a first episode and 4 with a repeat pneumocystosis) received daily inhalations of aerosol pentamidine isethionate for 21 days. Six patients were treated with doses of 300 mg of pentamidine and the remaining 2 received 600 mg every day. In the 300 mg treatment group, 2 individuals showed discrete and transient neutropenia. However, both subjects that received 600 mg of aerosol pentamidine daily developed leukopenia. One of them had major toxicity (overall severe intolerance of 12.5%) that required drug discontinuation and did not allow any analysis of the treatment efficacy. Of the 7 evaluable patients, 6 (88%) completed the treatment successfully. One subject of the 300 mg regimen experienced an early recurrence. In conclusion, inhaled pentamidine is an effective treatment for mild and moderate cases of P. carinii pneumonia. It is less toxic than standard anti-pneumocystis therapy and is suitable for outpatient use.     

Eflornithine treatment of refractory Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome.

Eflornithine was offered as compassionate treatment of 33 episodes of Pneumocystis carinii pneumonia in 31 patients with acquired immunodeficiency syndrome who were intolerant of and/or unresponsive to conventional trimethoprim-sulfamethoxazole or pentamidine therapy. A full course of eflornithine consisted of ten days at 400 mg/kg/d but no more than 30 g/d in four divided intravenous doses, four days at 300 mg/kg/d in four divided intravenous doses, and then up to six weeks at 300 mg/kg/d in four divided oral doses where tolerated. Of 33 patient-episodes, 15 patients were discharged from the hospital without need for supplemental oxygen after receiving ten or more days of parenteral therapy and were classified as responders. Of the 16 episodes classified as treatment failures, death occurred within the first 10 days of therapy in 12, and supplemental oxygen could not be withdrawn in 4. The other two patients left the hospital without need of oxygen after receiving one and six days of treatment with eflornithine and were not considered evaluable for efficacy. The most serious adverse effect was thrombocytopenia, which occurred in 12 of 19 patients treated for ten days or more. Serious bleeding associated with thrombocytopenia was observed in two patients. Other common adverse effects were anorexia, nausea, and diarrhea. Prior to receiving eflornithine, 13 of 15 responders had received ten or more days of conventional therapy without demonstrating clinical improvement. Two had improved while receiving conventional therapy but were switched to eflornithine because of a treatment-limiting adverse effect of standard therapy. These results suggest that eflornithine may be useful as an alternative therapeutic agent for Pneumocystis carinii pneumonia. Studies designed to determine proper dosage, duration of therapy, and efficacy as primary therapy are warranted.     

Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in non-human immunodeficiency virus-infected patients: retrospective study of 31 patients.

The aim of this retrospective study was to assess whether corticosteroid adjunctive therapy (CAT) could prevent death in immunocompromised patients with severe Pneumocystis carinii pneumonia (PCP) who do not have human immunodeficiency virus (HIV) infection, similarly to what has been demonstrated for HIV-infected patients. The charts of all non-HIV-infected patients who were admitted to two medical intensive care units between 1988 and 1996 because of severe PCP, defined by an arterial oxygen pressure (determined while the patient was breathing room air) of <70 mm Hg, and who were treated with trimethoprim-sulfamethoxazole were analyzed retrospectively. Thirty-one patients met the study criteria, of whom 23 received CAT (within 72 hours of antibiotic therapy) and eight did not receive CAT. The need for mechanical ventilation (10 [43%] of 23 vs. 4 [50%] of 8) and the mortality rate (9 [39%] of 23 vs. 4 [50%] of 8) were similar for the two groups. Although this small study does not have a statistical power high enough to rule out the possibility of a difference, the results suggest that CAT does not improve the survival of non-HIV-infected patients as has been described for HIV-infected patients with severe PCP.     

Tuberculosis in patients with human immunodeficiency virus infection. How often does it mimic Pneumocystis carinii pneumonia?

Adjunctive corticosteroid therapy is recommended for selected human immunodeficiency virus (HIV)-infected patients with presumed Pneumocystis carinii pneumonia. Because corticosteroids may exacerbate undiagnosed tuberculosis, we evaluated the frequency with which tuberculosis in HIV-infected patients mimics P carinii pneumonia. Over a 12-month period, we identified 105 HIV-infected patients with pleuropulmonary tuberculosis and 84 patients with P carinii pneumonia who were sufficiently hypoxemic to warrant corticosteroid therapy. Of the 105 patients with tuberculosis, acid-fast smears of clinical samples were positive in 49 cases, and chest roentgenographic findings suggested tuberculosis in an additional 44 cases. The 12 patients with negative acid-fast smears and nonspecific chest roentgenographic findings presented a potential diagnostic dilemma between tuberculosis and P carinii pneumonia. Pneumocystis carinii pneumonia should not have been a presumptive diagnosis of eight of these 12 patients because of absence of pulmonary symptoms and chest roentgenographic abnormalities (four cases), a CD4 count greater than 500/cu mm (three cases), or marked lymphadenopathy suggestive of tuberculosis (one case). Thus, only 4 percent (4/105) of HIV-infected patients with pleuropulmonary tuberculosis had clinical and chest roentgenographic features mimicking P carinii pneumonia. Two of these four patients were sufficiently hypoxemic to warrant corticosteroid therapy. Thus, if corticosteroids had been routinely used during the study period, 84 patients with P carinii pneumonia would have been treated, including two patients with undiagnosed tuberculosis. We conclude that the use of corticosteroids for presumed P carinii pneumonia carries a small but acceptable risk of inadvertent exacerbation of tuberculosis, provided clinical and chest roentgenographic features do not suggest tuberculosis.     

Low-dose intermittent trimethoprim-sulfamethoxazole for prevention of Pneumocystis carinii pneumonia in patients with human immunodeficiency virus infection

The important role of chemoprophylaxis for the prevention of Pneumocystis carinii pneumonia (PCP) in human immunodeficiency virus type 1 (HIV)-infected patients is undisputed. The most cost-effective regimen, however, is unknown. We reviewed our experience at two hospitals in the New York City area in which low-dose, intermittent therapy with the combination of trimethoprim and sulfamethoxazole was used to prevent PCP in HIV-infected patients. During a total of 202 months of primary prophylaxis in 32 patients and 319 months of secondary prophylaxis in 35 patients, PCP was diagnosed only once. More than 80% of patients were receiving zidovudine concomitantly. Adverse reactions to trimethoprim-sulfamethoxazole occurred in 31% and 52% of those receiving primary or secondary prophylaxis, respectively. When those patients who were considered ineligible to receive trimethoprim-sulfamethoxazole prophylaxis (principally based on a prior adverse drug reaction) are also factored in, then approximately 50% of HIV-infected patients are candidates for long-term trimethoprim-sulfamethoxazole prophylaxis. The projected cost savings of this prophylaxis regimen, compared with those currently recommended by the US Public Health Service, are enormous.     

Biomolecular techniques to detect Pneumocystis carinii f. sp. hominis pneumonia in patients with acquired immunodeficiency syndrome

Objectives: To verify the clinical value of two different polymerase chain reactions (PCBs) for noninvasive diagnosis and follow-up during Pneumocystis carinii f. sp. hominis pneumonia (PCP) and to analyze the P. carinii f. sp. hominis genotypes involved.Methods: Internal transcribed spacers (ITSs) nested PCR was applied to 630 samples (bronchoalveolar lavage, sera, peripheral blood mononuclear cells, and oropharyngeal samples) from 122 patients with acquired immunodeficiency syndrome and pneumonia and 40 control samples from 20 subjects sero-negative for human immunodeficiency virus. One hundred and eighty samples also were examined by mt-rRNA PCR. Bronchoalveolar lavage samples and 33 sera were analyzed by type-specific oligonucleotide hybridization.Results: On bronchoalveolar lavage samples, the two PCRs consistently confirmed the morphologic diagnosis of PCP. The sensitivity of ITSs nested PCR versus mt-rRNA PCR was 57.3% versus 14.3% on sera, 32.3% versus 22.8% on peripheral blood mononuclear cells, and 69.1% versus 48.6% on oropharyngeal samples (garglings). Both PCRs had 100% specificity. Type-specific oligonucleotide hybridization revealed in 72.2% of bronchoalveolar lavage samples a single P. carinii f. sp. hominis genotype, whereas in 27.8% co-infection with more than one strain was detected.Conclusion: On noninvasive samples, ITSs nested PCR was more sensitive than mt-rRNA PCR, and it confirmed the diagnosis in all patients with PCP. For each patient with PCP at least one noninvasive sample was positive for P. carinii. f. sp. hominis DNA.     

Atovaquone suspension compared with aerosolized pentamidine for prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected subjects intolerant of trimethoprim or sulfonamides.

Atovaquone suspensions (750 mg and 1500 mg once a day) were compared with aerosolized pentamidine (300 mg once a month) for the prevention of Pneumocystis carinii pneumonia (PCP) in subjects with human immunodeficiency virus (HIV) infection who were intolerant to trimethoprim or sulfonamides (or both). Median time using the assigned therapy was 6.6 months, and the median follow-up was 11.3 months. Intent-to-treat analyses (n=549) showed no statistically significant differences among subjects with regard to the incidence of PCP (26%, 22%, and 17%, respectively) or mortality (20%, 13%, and 18%, respectively). The incidence of treatment-limiting adverse events with atovaquone was significantly higher (P<.01). There was, however, no significant difference in the time using therapy. Incidences of PCP and death were higher in subjects receiving 750 mg of atovaquone than in subjects receiving 1500 mg. Atovaquone suspension at 1500 mg once a day has an efficacy similar to that of aerosolized pentamidine for prevention of PCP in HIV-infected subjects and is a safe, effective alternative in those who are intolerant to trimethoprim or sulfonamides.