Background: Pneumocystis carinii pneumonia (PCP) is caused by the ubiquitous unicellular eukaryote, P carinii. It is a rare cause of infection in the general population, but it is a frequent cause of morbidity and mortality in persons who are immunocompromised, especially patients with acquired immunodeficiency syndrome (AIDS).

Patients without AIDS but who are immunocompromised and at risk for PCP include individuals with hematologic malignancies; organ transplant recipients; and those receiving long-term steroid or cytotoxic therapy, including patients with systemic vasculitis or other autoimmune deficiency. Other patients with immune deficiency disorders who are at particular risk for PCP include those with thymic dysplasia, those with severe combined immunodeficiency, and those with hypogammaglobulinemia. Severe malnutrition may predispose patients to PCP.

Pathophysiology: P carinii has a controversial taxonomy. However, on the basis of findings from ultrastructural and molecular analysis of its mitochondrial DNA and its affinity for fungal stain, the organism currently is recognized as a fungus. P carinii organisms consist of small cysts, each of which produces as many as 8 intracystic sporozoites. Upon maturity, the cysts rupture and release the sporozoites, which in turn differentiate into trophozoites. These subsequently develop into cysts and repeat the cycle. The mode of transmission is believed to be via the inhalation of air-borne cysts.

Almost all children acquire antibodies to P carinii by the age of 2 years. Disease develops only in individuals who are immunocompromised, probably as a result of reactivation of latent infection. Trophozoites attach to the cell membrane of type 1 alveolar pneumocytes, with subsequent cell death and leakage of proteinaceous fluid into the alveolar spaces. Histologically, the alveolar spaces are filled with an amphophilic, foamy, amorphous material composed of the parasites and cell debris; this material resembles proteinaceous edema fluid. Trophozoites are visible on electron microscopy and on smears or sections stained with toluidine blue or polychrome, but they are not visible by using routine histologic techniques.

No reliable antigen detection methods are available yet. The organism cannot be grown in culture; therefore, diagnosis relies on morphologic identification of the organism. The standard method of diagnosis is via cytologic examination of induced sputum specimens or bronchoalveolar lavage (BAL) washings. BAL has a sensitivity of as high as 90% and a specificity of 82%. In a minority of patients, transbronchial, percutaneous, or open lung biopsy may be necessary. Alternatively, patients who present with typical clinical and radiographic manifestations may be treated empirically, with invasive procedures reserved for patients who have atypical presentations or who fail to respond to empiric therapy.

Frequency:

• In the US: PCP was exceptionally rare prior to the AIDS epidemic, with a reported incidence of 0.3 cases per 1,000,000 persons per year. The AIDS epidemic led to an initial dramatic increase in incidence, although this subsequently declined significantly following the introduction of trimethoprim-sulfamethoxazole PCP prophylaxis. PCP is no longer the most common pulmonary complication or infection in patients with AIDS, having been supplanted by bacterial infection. However, PCP remains the most common pulmonary opportunistic infection, and it still affects 60% of patients during the course of the illness.

  PCP remains a common AIDS-defining illness, although its incidence as an index disease has declined. The reduction is partly due to a true reduction in incidence, attributed mainly to the widespread use of effective PCP prophylaxis, and partly a relative reduction due to a broadening of diagnostic criteria for AIDS. Currently, PCP accounts for approximately 40% of index diagnoses compared with approximately 60% at the start of the AIDS epidemic.

  Effective PCP prophylaxis not only reduces the incidence of PCP but also lengthens disease-free intervals between episodes.

  In patients without AIDS who are immunocompromised, the incidence of PCP prior to prophylactic therapy is 10-20% and decreases to 0-10% with prophylactic therapy.

• Internationally: In the African population, the incidence of PCP in patients with AIDS is lower than that of other groups, and only 9% of patients are affected.

   

Mortality/Morbidity: Although PCP is less common than bacterial respiratory tract infection in patients with AIDS, it accounts for more deaths. Initially, 50% of deaths due to respiratory failure in patients with AIDS were attributed to P carinii; the organism was identified in two thirds of cases. However, with a declining incidence, wider recognition, and more effective treatment, the mortality rate has decreased to approximately 5% overall.

• Slowly progressive forms, atypical features, and complications such as pneumothorax are associated with significantly higher mortality rates. Mortality rates increase to 75-100% in patients whose condition fails to respond to therapy during the first 5-10 days.

• The mortality rate in patients without AIDS and who are immunocompromised is 40%.

Race: PCP is 3 times more common in white patients compared with black patients, despite a higher use of prophylactic therapy in the former.

Sex: Rates of infection in homosexual and bisexual males are more than twice those in females.

Age: Individuals of any age can be affected, particularly when their immune system is compromised.

Clinical Details: PCP can occur at any level of immunocompromise, but it is more common in patients who are not receiving PCP prophylaxis and who have CD4 levels less than 200 cells per cubic millimeter. PCP is most common in persons with profound levels of immunodeficiency, that is, those with CD4 levels less than 100 cells per cubic millimeter.

PCP usually appears with insidious onset of malaise, weight loss, and low-grade fever (79-100%) associated with a dry cough (59-91%). However, the symptoms may be more severe, and dyspnea (29-95%), cyanosis, and respiratory failure (5-30%) may be present. Immunocompromised patients without AIDS but with PCP tend to present more acutely and have more fulminant disease. Chest pain (14-23%) and productive cough (23-30%) are reported. Patients classically demonstrate marked desaturation with exercise. An elevated serum lactate dehydrogenase level is sensitive for PCP, but this finding is nonspecific and has limited diagnostic value.

Complications include spontaneous pneumothorax and hypoxemia secondary to an adult respiratory distress–like syndrome. Intubation may be needed, and this complication has a significantly worse prognosis.

Extrapulmonary disease occurs in 1% of patients due to hematogenous spread of the organism. In particular, this is associated with nebulized pentamidine, which once was used as a prophylactic agent; however, this has been superseded by oral antibiotics. With nebulized drug administration, less than 10% of the dose enters the systemic circulation, potentially allowing the organism to cause systemic disease or lie dormant in extrapulmonary sites, acting as a source of recurrent infection. The bone marrow, spleen, liver, lymph nodes, small bowel, and eyes can be affected. Less commonly involved areas include the adrenal glands, kidneys, pituitary gland, skin, thyroid gland, and gastrointestinal tract.

A subset of patients presents with atypical clinical and radiographic features termed chronic PCP. The patients have a prolonged clinical course over months or years, with persistent stable symptoms and radiographic abnormalities corresponding to pathologic findings of interstitial fibrosis, traction bronchiectasis, and honeycombing.

Preferred Examination: Chest radiographs should be included in the initial evaluation. Frequently, these are the only images required. High-resolution computed tomography (HRCT) and, occasionally, gallium-67 scanning are useful in symptomatic patients in whom chest x-ray findings are normal or equivocal.

Limitations of Techniques: Chest radiographic findings may be normal in 10-39% of patients. With both CT and ⁶⁷Ga scanning, the appearances of PCP are nonspecific.

DIFFERENTIALS

Bronchiolitis Obliterans Organizing Pneumonia
Extrinsic Allergic Alveolitis (Hypersensitivity Pneumonitis)
Kaposi Sarcoma, Thoracic
Lung, Drug-induced Disease

Other Problems to be Considered:

Other opportunistic infections
AIDS-related lymphoma
Kaposi sarcoma
Bronchiolitis obliterans with organizing pneumonia
Pulmonary edema
Pulmonary hemorrhage

X-RAY

Findings:

• In patients with PCP, chest radiographs classically demonstrate bilateral, diffuse, often perihilar, fine, reticular interstitial opacification, which may appear somewhat granular. This opacification progresses to airspace consolidation over 3-4 days. This appearance may be followed by coarse reticulation as the infection resolves.

   

• Chest x-ray findings may be normal in 10-39% of patients, or radiographic changes may lag behind the clinical symptoms.

   

• Trends are changing in the radiographic manifestations of PCP; features that previously were considered unusual are currently seen with increasing frequency.

   

• Atypical radiographic patterns are reported to occur in 5% of patients and include cystic lung disease, spontaneous pneumothorax, and isolated lobar or focal consolidation, particularly with an upper-lobe predominance.

   

• Pulmonary nodules, which may be cavitated, have been described but are rare in PCP. Pulmonary nodules have been shown histologically to represent granulomas. Usually, these are encountered early in the course of HIV infection when the patient is still capable of mounting a granulomatous response.

   

• Miliary nodularity, bronchiectasis, endobronchial lesions, and mediastinal lymphadenopathy (18%), which may show calcification, have been reported.

   

• Pleural effusions and hilar lymphadenopathy are uncommon. Indeed, the presence of an effusion should prompt the search for a different pathogen.

   

• Cysts are visible on chest radiographs in 10% of patients, although they are appreciated far more commonly on HRCT scans (33%).

   

• Cysts may occur in the acute or postinfective period and range in number, size, shape, and distribution.

   

• Cysts are commonly multiple, with a predilection for the upper lobes.

   

• The etiology of cysts is unclear, but several hypotheses have been proposed, including the release of elastase from alveolar macrophages, which causes tissue necrosis and cavitation; vascular invasion with subsequent infarction; and cavitation obstruction of small airways leading to a ball-valve effect.

   

• Radiologic-pathologic correlation has shown persistent infection in some of the cyst walls.

   

• Spontaneous pneumothorax may be a feature of PCP infection, with a reported incidence of approximately 6% rising to approximately 35% in patients with cysts. Development of a spontaneous pneumothorax has important implications for treatment and prognosis of patients, since it tends to be refractory to conventional tube drainage, frequently requiring pleurodesis or surgical intervention. In addition, spontaneous pneumothorax is associated with a significantly higher mortality rate, particularly in patients on ventilation. Pneumothoraces are frequently bilateral.

   

• Chest radiographic findings are usually resolved within 2-4 weeks with successful treatment. This resolution may be accelerated by the use of steroids. Occasionally, radiographic findings remain abnormal, and the images demonstrate reticular opacities, interstitial fibrosis, or focal scarring and/or nodularity.

Degree of Confidence: Despite the presence of overlapping radiographic features, chest x-ray findings are often of diagnostic value. Usually, chest radiography is the only imaging required. The overall accuracy of chest radiographs for the diagnosis of PCP is approximately 75%.

False Positives/Negatives: Chest x-ray findings may be normal in 5-30% of patients with PCP.

The literature reports a false-negative rate for the diagnosis of PCP by using chest radiography of 35-40%. Adult respiratory distress syndrome, pulmonary edema, other opportunistic lung infections, lymphoma, and Kaposi sarcoma may mimic PCP.