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Case 2: Discussion - Pneumocystis Pneumonia

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 recently renamed in honor of the Czech pathologist Otto Jirovec[1]. The epidemiology and primary prevention of Pneumocystis pneumonia are discussed in Case 1 in the section Opportunistic Infections: Prophylaxis. 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[2] and are not reliably 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[2]. The physical examination of the lungs 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[3].

Non-Definitive Diagnostic Tests

In general, patients with suspected Pneumocystis pneumonia should undergo evaluation to confirm the diagnosis. A chest radiograph should be performed in all patients with suspected Pneumocystis pneumonia. Characteristic radiographic features include bilateral, perihilar, interstitial infiltrates that appear as finely granular, reticular, or ground glass opacities (Figure 1 and Figure 2). More than 20% of patients, however, will have a normal chest radiograph, particularly early in the course of their Pneumocystis pneumonia[4,5]. In addition, some patients may have atypical chest radiographic findings, such as upper lobe predominance, cystic lesions, or focal infiltrates (Figure 3 and Figure 4). Several studies have suggested that high-resolution CT scans may have some value in patients with suspected Pneumocystis pneumonia, particularly in excluding the diagnosis in those with normal or atypical chest radiographs[6]. 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, mainly to evaluate the severity of the disease and to determine whether corticosteroids are indicated. The blood gas values can be used to calculate the alveolar-arterial oxygen p(A-aO2) difference (Figure 5). Although serum lactate dehydrogenase (LDH) levels correlate with severity, they probably do not accurately differentiate Pneumocystis pneumonia from other pulmonary processes and thus have limited diagnostic value in evaluating persons with suspected Pneumocystis pneumonia[7]. 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

Among the definitive tests, most experts recommend first collecting an induced sputum sample using an ultrasonic saline nebulizer, assuming the medical facility has experience with performing this test[2]. Among centers with significant experience, the sensitivity of the test ranges from 50-90%. A patient with a negative induced sputum should undergo bronchoscopy with bronchoalveolar lavage (BAL), which has a sensitivity of approximately 90%[8]. 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 consider the monoclonal antibody stain as the procedure of choice for identifying P. jiroveci, mainly because it is fast, easy to perform, detects both trophozoites and cysts, and has excellent sensitivity and specificity. Other stains 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. Establishing a microbiologic diagnosis makes exposure to these potentially toxic agents more justifiable.

Therapy for Pneumocystis Pneumonia

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[2,9] (Figure 6). 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[10]. Patients who are intolerant to sulfamethoxazole but who can tolerate trimethoprim and dapsone, can receive trimethoprim plus dapsone as an alternative oral regimen[11,12]. Other oral alternatives include clindamycin (Cleocin) plus primaquine[12,13], or atovaquone (Mepron)[14].Although atovaquone is well tolerated, approximately 30% of patients fail to respond to this drug[14]. For patients with more 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)[15,16], or intravenous clindamycin plus oral primaquine. Second-line regimens should be limited to patients who cannot tolerate or have failed trimethoprim-sulfamethoxazole.

Salvage Therapy

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)[17]. Treatment with trimetrexate (Neutrexin) has also shown moderate efficacy[18,19], 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 (Figure 7) 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 failures[2].

Role of HAART in Initial Therapy

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[20]. In contrast with this study, case reports have described paradoxical worsening of Pneumocystis pneumonia with initiation of HAART. Thus, randomized prospective studies are needed to clarify the role of HAART in patients with acute Pneumocystis pneumonia.

Corticosteroids for Pneumocystis Pneumonia

Multiple studies have shown that adjunctive therapy with corticosteroids reduces the mortality from Pneumocystis pneumonia in HIV-infected patients[21]. 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[22]. 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 6). 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 to develop severe disease.

Secondary Prophylaxis to Prevent Recurrence of Disease

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 prophylactic regimens (Figure 8) are the same as those used for primary prophylaxis[23].

Discontinuing Secondary Prophylaxis

Prior to the HAART era, secondary prophylaxis to prevent recurrence of Pneumocystis pneumonia was recommended for life. In new recommendations contained in the 2002 USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections, patients who have responded to HAART and have well controlled HIV RNA levels should discontinue long-term secondary prophylaxis for Pneumocystis pneumonia if their CD4 count has increased to greater than 200 cells/mm3 for at least 3 months[23]. If, however, Pneumocystis pneumonia occurred at a CD4 count above 200 cells/mm3, the patient should probably take secondary prophylaxis for life, regardless of the subsequent CD4 count response. The recommendations regarding discontinuation of secondary prophylaxis arose from multiple studies that have shown extremely low rates of recurrence in the setting of a good immune response to HAART[24,25]. Patients who have discontinued secondary prophylaxis and have a CD4 count that subsequently decreases to less than 200 cells/mm3, should restart prophylaxis.

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    Figure 1. Characteristic <em>Pneumocystis</em> Pneumonia (PA)

    Chest PA radiograph showing diffuse bilateral lung parenchymal opacities and interstitial infiltrates in a patient with Pneumocystis pneumonia

    Figure 1
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    Figure 2. Characteristic <em>Pneumocystis</em> Pneumonia (Lateral)

    Lateral chest radiograph showing diffuse bilateral lung parenchymal opacities and interstitial infiltrates in a patient with Pneumocystis pneumonia.

    Figure 2
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    Figure 3. Upper Lobe and Cystic <em>Pneumocystis</em> Pneumonia

    This PA chest radiograph from a patient with Pneumocystis pneumonia shows bilateral perihilar opacities and interstitial prominence, as well as multiple hyperlucent cystic lesions, most prominent in the upper lobes.

    Figure 3
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    Figure 4. Chest CT Showing Cystic <em>Pneumocystis</em> Pneumonia

    This contrast chest CT from a patient with Pneumocystis pneumonia shows multiple cystic lesions and areas of ground-glass opacity, with these abnormal findings predominantly found in the upper lobes.

    Figure 4
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    Figure 5. Calculation of Alveolar-Arterial Oxygen Difference

    This simplified calculation applies only to blood gases obtained on room air at sea level.

    Figure 5
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    Figure 6. Initial Therapy for <em>Pneumocystis</em> Pneumonia

    Abbreviations: TMP-SMX = trimethoprim-sulfamethoxazole; DS = double strength

    Figure 6
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    Figure 7. Toxicities Associated with Drugs Used to Treat <em>Pneumocystis</em> Pneumonia

    Abbreviations: TMP-SMX = trimethoprim-sulfamethoxazole; G-6PD = glucose 6-phosphate dehydrogenase

    Figure 7
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    Figure 8. Prophylaxis to Prevent Recurrence of Pneumocystis   Pneumonia

    This table is adapted from Kaplan JE, Masur H, Holmes KK; USPHS; Infectious Disease Society of America. 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. MMWR Recomm Rep. 2002;51(RR-8):1-52.

    Figure 8