Angarone, Michael P. DO*; Reddy, Pavani MD*; Berggruen, Senta MD†; Noskin, Gary A. MD*
*Division of Infectious Diseases, Departments of Medicine, and †Radiology, Northwestern Feinberg School of Medicine, Chicago, IL.
Address correspondence and reprint requests to Michael P. Angarone, DO, Division of Infectious Diseases, 676 N St Clair Ave, Suite 200, Chicago, IL 60611, 312-695-5088. E-mail: firstname.lastname@example.org.
A 29-year-old man with no medical history was admitted to the hospital with increasing fatigue, weakness, and dyspnea on exertion. He had been doing well until 1 week before admission when he developed weakness and fatigue. He started to notice dyspnea with walking the 2 flights of stairs to his apartment. Two days before admission, he developed a nonproductive cough. He denied any fever, chills, rhinorrhea, headache, or chest pain. There was no recent travel or sick contacts, and he does not have any pets. He is a homosexual man; he was last tested for human immunodeficiency virus (HIV) 2 years ago and was found to be negative. His last unprotected sexual encounter was reported 5 months ago. He denied injection drug use; he has never been incarcerated, and he was skin test negative for tuberculous approximately 1 year ago. He stated that he does not have his usual amount of energy, and he just "wants to sit down."
On physical examination, he was a febrile and with temperature of 97.1°F, respirations of 14 per minute, heart rate of 92 beats per minute, and blood pressure of 117/69 mm Hg; oxygen saturation was 94% on room air. The patient looked comfortable sitting in a chair in no respiratory distress. Decreased air movement was detected in the upper lung fields bilaterally, and crackles were present in both lower lobes. The rest of the examination was unremarkable.
A complete blood cell count revealed a white blood cell count of 5200 cells/μL, with an absolute lymphocyte count of 800 cells/μL and hemoglobin level of 12.3 g/dL. The lactate dehydrogenase was elevated at 275 U/L; otherwise the remainder of his chemistries was normal. Chest radiograph demonstrated bilateral patchy opacities with associated cystic changes (Fig. 1). Multiple areas of ground glass attenuation with scattered cavitary lesions were identified on computed tomography (CT) (Fig. 2). The largest cavity, measuring 9.2 × 4.1 cm, was located in the left upper lobe (Fig. 2).
A bronchoscopy with lavage was performed. Direct florescent antibody test for Pneumocystis jirovecii (formerly carinii) was performed and was positive. An HIV enzyme-linked immunosorbent assay and Western blot were positive with a CD4 count of 10 cells/μL (1%). The patient was started on trimethoprim-sulfamethoxazole (TMP/SMX) with prednisone for treatment of the Pneumocystis carinii pneumonia (PCP). He responded to therapy and was discharged with improvement in his pulmonary status.
He was readmitted to the hospital 1 week after discharge with worsening dyspnea and right-sided chest pain. Chest radiography revealed a right-sided tension pneumothorax (Fig. 3). A chest tube was placed, and the patient underwent video-assisted thoracoscopic surgery with biopsies of the lung. Again, histological examination of the biopsy specimen identified Pneumocystis organisms, confirming the diagnosis of PCP.
EPIDEMIOLOGY OF P. JIROVECII IN PATIENTS WITH HIV/ACQUIRED IMMUNE DEFICIENCY SYNDROME
During the first decade of the HIV epidemic, PCP was the AIDS-defining illness for as many as two thirds of patients.1 Since the introduction of highly active retroviral therapy (HAART), there has been a dramatic decrease in the incidence of PCP. The earliest cases of PCP were reported in orphanages in Europe in the 1940s. It was referred to as "plasma cell pneumonia" and was associated with malnutrition. The PCP was later recognized in immunocompromised patients.1 In the 1980s, clusters of PCP began to appear in the homosexual community.2 Early in the HIV epidemic, the rates of PCP were as high as 20 cases per 100 person-years in those with CD4 counts of less than 200 cells/μL, and an estimated 75% of HIV-infected persons developed PCP in their lifetime.3,4
The first decline in the incidence of PCP occurred in the late 1980s with the introduction of Pneumocystis prophylaxis.5 The percentage of AIDS patients with PCP declined from 53% in 1989 to 42% in 1992.1 With the introduction of HAART in 1996, there have been further declines in the rate of PCP and other opportunistic infections. There has been a 21.5% decline per year in the rate of PCP from 1996 to 1998.5 Opportunistic infection rates were evaluated by the Multicenter AIDS Cohort Study group in the pre-HAART era (1990-1992) and in the HAART era (1996-1998). The study found a relative hazards ratio of 0.06 for the development of PCP from seroconversion between the 2 groups.6 Even with this reduction, PCP still remains one of the most serious opportunistic infections in HIV-infected persons.5 Mortality rate in patients with AIDS and PCP remains 10% to 20% with initial infection.7
PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS
The Pneumocystis organisms were first identified in the early 20th century by Chagas8 and Carinii.9 Pneumocystis was initially classified as protozoan based on its morphological features. In 1988, ribosomal RNA analysis provided a linkage of Pneumocystis to the fungal kingdom.10 Pneumocystis has a unique tropism for the lung where it exists as an alveolar pathogen, rarely invading the host.11 Until recently, it was believed that PCP represented reactivation of latent disease. There is now growing evidence that person-to-person transmission and environmental acquisition are the most likely modes for acquiring infection.12 Recently, Rabodonirina et al13 reported 10 cases of PCP in renal transplant patients over a 3-year period. The analysis found an increase in PCP among transplant patients, which coincided with an increase in HIV-infected patients. Molecular genotyping of the Pneumocystis isolates suggested transmission of the same isolates in both the transplant and HIV patients. On further analysis, it was found that at least half of the 10 cases were hospital acquired, but the exact mechanism of transmission remains unknown.13
The most common symptoms of PCP include the subtle onset of dyspnea, nonproductive cough, and low-grade fever. Acute dyspnea or chest pain may indicate a pneumothorax. Examination may reveal tachycardia, tachypnea, and varied lung findings from normal to diffuse crackles.14 Rarely, P. jirovecii can also result in extrapulmonary infection. Although the actual incidence is very difficult to calculate, it is thought to be low. A 1991 review by Cohen and Stoeckle15 calculated an incidence of 0.06% based on less than 50 cases of extrapulmonary disease in more than 80,000 cases of Pneumocystis infection. Despite the uncommon nature of extrapulmonary disease, Pneumocystis can result in infection in virtually any organ. The most commonly affected, other than the lung, are the ear and eye, resulting in hearing loss, ear pain, "floaters," or visual field defects.16 Reports have also confirmed P. jirovecii in the central nervous system, bone marrow, thyroid gland, muscle, and gastrointestinal tract.16 Diagnosis requires consideration of extrapulmonary Pneumocystis and demonstration of the organism in the affected tissues.16
The chest roentgenograms (CXR) of PCP may have varying appearances, ranging from normal to diffuse interstitial infiltrates. DeLorenzo et al17 evaluated 104 CXR in patients with AIDS and PCP. They found that the most common finding on CXR was an interstitial pattern in 75% of the patients. Other common findings were alveolar pattern and an alveolar-interstitial pattern. Both peripheral and central infiltrates were seen, and 95% of the patients had bilateral involvement. The most common associated findings on CXR are cystlike structures, localized infiltrates, and hilar enlargement in approximately 10% of the cases. Spontaneous pneumothorax occurred in 6% of the cases reviewed.17
The CT of the chest has become more widely available and is frequently used to aid in the diagnosis of pulmonary processes in HIV-infected patients. When compared with CXR, CT scans can give a more detailed image of the lung parenchyma and mediastinum. In patients with HIV and an abnormal CXR finding, a chest CT can make an accurate diagnosis of PCP in 94% of the patients.18 In 1990, Kuhlman et al19 evaluated 39 CT scans from HIV-infected patients with a confirmed diagnosis of PCP. Infiltrates were bilateral (100%), asymmetrical (51%), patchy (59%), and mixed alveolar and interstitial (46%). A ground-glass pattern was seen in 26% of the scans evaluated. The most characteristic pattern was bilateral, asymmetrical, patchy parenchymal opacities (56% of the patients). Again, the most commonly found associated findings were cysts and bullae, with pneumothorax present in 13% of the patients.19 Lymphadenopathy and pleural effusions are not typically identified.
The difficulty in radiological diagnosis of PCP in HIV-infected patients arises when the CXR finding is normal. Surprisingly, a normal CXR is seen in 2% to 21% of HIV patients with PCP.20 Hidalgo et al21 evaluated 30 patients with HIV, pulmonary symptoms, and a normal CXR. All 30 of the cases had CT scans of the lung to evaluate for any abnormalities missed by CXR. Nineteen were found to have PCP by bronchoscopy. Evaluation of the CT scans of the 19 patients with PCP revealed ground-glass opacities; none of the CT scans were considered normal. In 2 of the cases, the CT scan was considered consistent with PCP; however, an alternate diagnosis was made. The sensitivity of CT scan was 100%, and the specificity was 83.3%.21 These data suggest that in an HIV patient with pulmonary complaints or hypoxia and a normal CXR, a chest CT should be considered to guide the diagnostic workup or to confirm the clinical suspicion of PCP.
Patients with PCP have nonspecific physical examination findings, as there may be other infections present, and patients are routinely using prophylactic medications. These factors make the diagnosis of PCP difficult.14 Because P. jirovecii does not grow in culture, the diagnosis requires microscopic examination of respiratory specimens.22 Those with AIDS and PCP have more Pneumocystis organisms that allows for higher diagnostic yield with induced sputum and bronchoalveolar lavage (BAL) fluid.23 Sputum induction has a diagnostic yield of 50% to 90% and is the initial procedure of choice. If the induced sputum does not reveal the Pneumocystis organisms, then a BAL should be performed.24 Trophic and cyst forms can be detected with conventional stains, such as Wright-Giemsa, modified Papanicolaou, or methenamine silver stains.14 Monoclonal antibodies, which are used in the direct florescent antibody test, have higher sensitivity (67.1% vs. 43.1%) and equivocal specificity (96.5% vs. 96.2%) in induced sputum when compared with conventional staining.25,26 Another advantage to the monoclonal antibodies is the ability to stain both the trophic and cyst forms.14 Polymerase chain reaction to detect Pneumocystis nucleic acids has been shown to have better sensitivity and specificity in induced sputum and BAL specimens than conventional testing methods. There remains a management challenge in those patients with positive PCR and negative smears, making PCR not useful, at this time, in clinical practice.27 Elevated levels of serum lactate dehydrogenase may be seen in patients with PCP, but this is likely a marker of lung injury and not specific to the Pneumocystis organism.28
PROPHYLAXIS AND TREATMENT
The mainstay of prophylaxis and therapy for PCP is TMP/SMX. Prophylaxis is recommended for HIV patients with CD4+ counts of less than 200 cells/μL or in those who have a history of oral candidiasis.29 Lifelong secondary prophylaxis is recommended for those who have had a history of PCP. Both primary and secondary prophylaxis are continued until the CD4+ count is greater than 200 cells/μL for more than 3 consecutive months.14 The TMP/SMX is the preferred treatment for PCP and the most effective agent, usually administered for 21 days. Clindamycin plus primaquine, atovaquone, and pentamidine are alternative therapies in patients intolerant or allergic to TMP/SMX.14,30 In patients with PCP and hypoxemia, corticosteroids are indicated (Po2, <70 mm Hg on room air; or alveolar-arterial gradient, >35). These patients should receive a prednisone taper for 21 days according to the following schedule: 40 mg twice daily for 5 days, then 40 mg daily for 5 days, and then 20 mg daily for the remaining 11 days.31
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