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New Insights Into Transmission, Diagnosis, and Drug Treatment of Pneumocystis carinii Pneumonia

Joseph A. Kovacs, MD; Vee J. Gill, PhD; Steven Meshnick, MD, PhD; Henry Masur, MD
JAMA. 2001;286(19):2450-2460. doi:10.1001/jama.286.19.2450.
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Pneumocystis carinii has been recognized as a human pathogen for nearly 50 years. We present a case of P carinii infection that typifies clinical presentation in the era of the acquired immunodeficiency syndrome epidemic. The high incidence of P carinii pneumonia in persons infected with human immunodeficiency virus (HIV) has served to focus laboratory and clinical research efforts on better understanding the biology of the organism and on improving diagnosis, treatment, and prevention of this disease. Although inability to culture P carinii has hampered research efforts, molecular and immunologic approaches have led to the recognition that the organism represents a family of fungi with a very restricted host range and have allowed characterization of clinically relevant antigens and enzymes. Molecular epidemiologic studies have identified more than 50 strains of human-derived P carinii and have suggested that recently acquired infection, as opposed to reactivation of latent infection, may account for many cases of clinical disease. Diagnosis has been improved by the development of organism-specific monoclonal antibodies and, more recently, by polymerase chain reaction using multicopy gene targets, together with induced sputum or oral wash samples. Chemotherapeutic prophylaxis is very effective in preventing P carinii pneumonia; the combination of trimethoprim-sulfamethoxazole remains the first-line agent for both therapy and prophylaxis. Prophylaxis needs to be administered only during periods of high risk; in HIV-infected patients responding to effective antiretroviral therapies, prophylaxis no longer needs to be lifelong. Molecular studies have identified mutations in the target of sulfa drugs that appear to represent emerging resistance in P carinii. Resistance to atovaquone, a second-line agent, may also be developing.

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Figure 1.Pneumocystis carinii Infecting a Rat Lung
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Electron micrograph illustrates both cysts (white arrowheads) and trophozoites (black arrowheads).
Figure 2. Incidence of Pneumocystis carinii Pneumonia (PCP): Impact of the Acquired Immunodeficiency Syndrome (AIDS) Epidemic and of Highly Active Antiretroviral Therapy (HAART)
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A, Cases of PCP reported to the Centers for Disease Control and Prevention (CDC) in the pre-AIDS era compared with the AIDS era. Horizontal bars at the top indicate the period during which prophylaxis to prevent PCP (prophylaxis) and HAART were available. The arrow indicates the time of publication of guidelines by the US Public Health Service for prevention of PCP in human immunodeficiency virus (HIV)–infected patients.8 B, Change in incidence of PCP in the pre-HAART and HAART era, demonstrating the marked decline in incidence that occurred following the introduction of HAART. In the immediate pre-HAART era (1992 to 1995), there was a 3.4% per year decline in incidence of PCP. During the HAART era, the incidence of PCP decreased by 21.5% per year. Data are from the Adult and Adolescent Spectrum of Disease Study.9
Figure 3. Clinical Findings of Patients With Pneumocystis carinii Pneumonia (PCP)
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A, Chest radiograph of a patient with PCP demonstrating diffuse bilateral infiltrates. B, Detection of human-derived P carinii by immunofluorescence using monoclonal antibodies. C, Hematoxylin-eosin–stained section of lung from an HIV-infected patient with PCP. An acellular eosinophilic exudate characteristic of PCP can be seen filling the alveoli.
Figure 4. National Institutes of Health Experience in the Diagnosis of Pneumocystis carinii Pneumonia (PCP), 1987-1999
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HIV indicates human immunodeficiency virus. Both the number of episodes of pulmonary symptoms evaluated for PCP (A) and the number of cases of PCP diagnosed (B) showed a decrease over time in patients with HIV infection (black circles) in contrast to patients without HIV (gray circles).
Figure 5. Algorithm for Evaluation of Patients With Suspected Pneumocystis carinii Pneumonia (PCP)
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PPD indicates purified protein derivative.
Figure 6. Mutations at the Dihydropteroate Synthase (DHPS) Active Site
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Diagram of the Pneumocystis carinii DHPS enzyme shows position of key amino acids involved in binding 7,8-dihydropterin-pyrophosphate (DHPPP), para-aminobenzoic acid (pABA), and sulfonamides (sulfa) based on homology to the known crystal structure of the Escherichia coli enzyme.82 Two commonly seen mutations that may be associated with resistance are Thr55Ala and Pro57Ser.



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