The patient in this case was diagnosed with Pneumocystis pneumonia by analysis of an induced sputum specimen, and she was successfully treated with trimethoprim-sulfamethoxazole (Bactrim, Septra) and corticosteroids. Pneumocystis pneumonia remains the most important life-threatening opportunistic infection in HIV-infected persons. The causative agent, Pneumocystis jiroveci (formerly Pneumocystis carinii), was renamed in honor of the Czech pathologist Otto Jirovec. The epidemiology and primary prevention of Pneumocystis pneumonia is discussed in detail in the case Prophylaxis for Pneumocystis Pneumonia. The following discussion will focus on the clinical manifestations, diagnosis, and treatment of Pneumocystis pneumonia.
Clinical Manifestations of Pneumocystis Pneumonia
In general, HIV-infected patients who develop Pneumocystis pneumonia have a CD4 count less than 200 cells/mm3 and are not taking effective Pneumocystis pneumonia prophylaxis. Patients with Pneumocystis pneumonia typically experience the gradual onset of nonspecific systemic manifestations, such as fever, fatigue, and weight loss, followed by respiratory symptoms that consist of a nonproductive cough, dyspnea on exertion, and shortness of breath. The pulmonary physical examination is typically normal, but in more advanced disease, rales may be present on auscultation. With progressive disease, patients may develop pronounced dyspnea and in some instances may present with respiratory failure. Rarely, patients may develop extrapulmonary disease, with these cases most often involving patients who have had previous episodes of Pneumocystis pneumonia, or have received aerosolized pentamidine for prophylaxis.
Non-Definitive Diagnostic Tests
All patients with suspected Pneumocystis pneumonia should undergo evaluation to confirm the diagnosis. In this situation, a chest radiograph is typically the first diagnostic test obtained and characteristic radiographic features include bilateral, perihilar, symmetrical interstitial infiltrates that appear as finely granular, reticular, or ground glass opacities (Figure 1) and (Figure 2). Some patients, however, will have a normal chest radiograph, particularly early in the course of Pneumocystis pneumonia.[,] Less commonly patients may have atypical chest radiographic findings, such as upper lobe predominance, cystic lesions, or focal infiltrates (Figure 3) and (Figure 4). In general, it is useful to obtain a resting O2 saturation test and O2 saturation before and during exercise. The suspicion for Pneumocystis pneumonia increases in patients who have significant desaturation with exertion. An arterial blood gas test should also be performed to evaluate both the severity of the disease and to determine whether corticosteroids are indicated. The arterial blood gas values can be used to calculate the alveolar-arterial oxygen p(A-aO2) difference (Figure 5). Patients with Pneumocystis pneumonia who undergo pulmonary function testing will usually have a significant decrease in single-breath diffusing capacity (DLCO), but this test is not specific for the diagnosis.
Definitive Diagnostic Tests
An induced sputum sample using an ultrasonic saline nebulizer has a sensitivity for diagnosing Pneumocystis pneumonia that ranges from 50 to 90%, assuming the medical facility has experience with performing this test. A patient with a negative induced sputum should undergo bronchoscopy with bronchoalveolar lavage (BAL), which has a sensitivity of approximately 95%. Some centers perform BAL as the initial procedure to expedite the diagnosis. A transbronchial biopsy or open lung biopsy can further increase the yield, but is rarely required because of the high yield with BAL. Many laboratories now consider the the direct immunofluorescent stain as the procedure of choice for identifying P. jiroveci; other tests that can detect P. jiroveci include methenamine silver, Giemsa silver, and toluidine blue-O. Newer molecular based assays such as PCR show promise, but are still considered experimental. The yield of induced sputum or bronchoscopy is not significantly reduced after several days of antimicrobial therapy for Pneumocystis pneumonia. Prolonged empiric therapy without a definitive diagnosis should be discouraged for several reasons: (1) a number of other conditions can mimic Pneumocystis pneumonia, including tuberculosis, Toxoplasma pneumonitis, and cryptococcal pneumonitis; (2) the use of corticosteroids without specific antimicrobial therapy could exacerbate other conditions, especially pneumonitis caused by mycobacteria or fungi; and (3) drug toxicity caused by anti-Pneumocystis agent frequently occurs during the 21-day course of therapy for Pneumocystis pneumonia.
Therapy for Pneumocystis Pneumonia
The 2013 guidelines for the prevention and treatment of opportunistic infections separates recommendations for treatment of Pneumocystis pneumonia based on whether the patient has moderate-to-severe disease (Figure 6) or mild-to-moderate disease (Figure 7). For patients with moderate-to-severe pneumonia or those who cannot take or absorb oral medications, intravenous trimethoprim-sulfamethoxazole is the first-line regimen. Alternative intravenous regimens include intravenous pentamidine (Pentam 300), or intravenous clindamycin (Cleocin) plus oral primaquine.[,,] Second-line regimens should be limited to patients who cannot tolerate or have failed trimethoprim-sulfamethoxazole. In a patient with mild-to-moderate Pneumocystis pneumonia, treatment can be given on an outpatient basis, assuming the patient will reliably take the oral medications. Those treated as an outpatient should appear nontoxic, have a documented paO2 greater than 70 mm Hg, and a calculated p(A-a O2) gradient less than 35. Trimethoprim-sulfamethoxazole is the preferred first-line oral agent and duration of therapy is 21 days.[,] Treatment with trimethoprim-sulfamethoxazole is highly effective for Pneumocystis pneumonia, but is often complicated by adverse reactions. Cutaneous adverse reactions occur less frequently in patients taking adjunctive corticosteroids. Patients who are intolerant to sulfamethoxazole but who can tolerate trimethoprim and dapsone, can receive trimethoprim plus dapsone as an alternative oral regimen.[,] Other oral alternatives include clindamycin plus primaquine, or atovaquone (Mepron).[,,,]
Corticosteroids for Pneumocystis Pneumonia
Multiple studies have shown that adjunctive therapy with corticosteroids reduces the mortality from Pneumocystis pneumonia in HIV-infected patients. Corticosteroids are indicated in patients who have a paO2 less than 70 mm Hg or a calculated p(A-a O2) gradient greater than 35.[,] Patients with an indication for corticosteroids should receive a 21-day course of prednisone; those unable to take oral medications can receive intravenous prednisolone (Figure 8). Ideally, patients should begin corticosteroids at the time they start taking antimicrobial therapy for Pneumocystis pneumonia, even if the diagnosis has not been confirmed. If a diagnosis other than Pneumocystis pneumonia is made, the corticosteroids should be stopped. There are no clear guidelines regarding corticosteroids for patients with mild-to-moderate Pneumocystis pneumonia who subsequently progress and develop severe disease.
A meta-analysis found that clindamycin plus primaquine was the most effective salvage regimen among patients who failed to respond to initial Pneumocystis pneumonia therapy (most of the cases involving failure with trimethoprim-sulfamethoxazole). Treatment with trimetrexate (Neutrexin) has also shown moderate efficacy,[,] but the production of this drug was stopped in March 2007. There are no clear guidelines regarding the approach to patients who fail initial therapy for Pneumocystis pneumonia and it remains unclear whether patients do better if switched to a salvage regimen. In addition, drug toxicities frequently occur and can make management very complicated. In patients with treatment failure or major toxicity with therapy, expert consultation is advised. Although molecular studies have identified mutations in the P. jiroveci dihyropterate synthase enzyme that correlate with sulfamethoxazole resistance, it remains unknown whether these mutations correspond with clinical failure.
Timing of Intiating Antiretroviral Therapy in Patients with Pneumocystis Pneumonia
In a retrospective study of 58 patients with Pneumocystis pneumonia admitted to the intensive care unit, investigators reported a lower mortality in those patients who started on antiretroviral therapy either before or during hospitalization. A subsequent large study that addressed the issue of timing of antiretroviral therapy in 282 patients who had an acute opportunistic infection, patients had significantly better outcome with early (median 12 days) than deferred (median 45 days); approximately 60% of the patients in the study had Pneumocystis pneumonia. The concern for using early antiretroviral therapy arose from case reports that have described paradoxical worsening of Pneumocystis pneumonia with initiation of antiretroviral therapy (paradoxical immune reconstitution syndrome).[,] For patients not taking antiretroviral therapy who are newly diagnosed with Pneumocystis pnemonia, the opportunistic infections guidelines recommend starting antiretroviral therapy within 2 weeks of the diagnosis of Pneumocystis pneumonia.
Secondary Prophylaxis to Prevent Recurrence of Disease
The 2013 opportunistic infections guidelines recommend that all patients who complete the initial 21-day course of therapy for Pneumocystis pneumonia should receive secondary prophylaxis to prevent recurrence of disease. Before the widespread use of Pneumocystis prophylaxis, recurrence rates were very high. The recommended secondary prophylaxis regimens (Figure 9) are the same as those used for primary prophylaxis.
Discontinuing Secondary Prophylaxis
Prior to the era of highly effective antiretroviral therapy, secondary prophylaxis to prevent recurrence of Pneumocystis pneumonia was recommended for life. The opportunistic infections guidelines now recommend that patients can safely discontinue long-term Pneumocystis pneumonia secondary prophylaxis if they have suppressed HIV RNA levels in response to antiretroviral therapy and they achieved a sustained increase in CD4 count to greater than 200 cells/mm3 for at least 3 months. These recommendations are based on two randomized trials,[,] multiple observational studies, and a combined analysis of eight European cohort studies, all of which showed that discontinuation of Pneumocystis pneumonia prophylaxis was safe in patients who had a sustained CD4 count increase to above 200 cells/mm3 for at least 3 months in response to antiretroviral therapy. Patients who have discontinued secondary prophylaxis and have a CD4 count that subsequently decreases to less than 200 cells/mm3 should restart secondary prophylaxis.. If the episode of Pneumocystis pneumonia occurred at a CD4 count above 200 cells/mm3, the opportunistic infections guidelines recommend continuing secondary prophylaxis for life, irrespective of future CD4 cell count values.