Introduction Pneumocystis Disclaimer: This lecture slide presentation is intended solely for educational purposes. Many of the images contained herein are the property of the original owner, as indicated within the figure itself or within the figure legend. These images are used only for illustrative purposes within the context of this lecture material. Use of these images outside the purpose of this presentation may violate the rights of the original owner. Dr. Cooper and Youngstown State University assume no responsibility for the unauthorized use of the material contained herein. Pneumocystis pneumonia (PCP) [original acronym for Pneumocystis carinii pneumonia] is a life-threatening lung infection of immunocompromised individuals Most prominent in HIV-infected persons Historical perspective 1909: organism first recognized as a protozoan 1914: microbe given the name Pneumocystis carinii Introduction (cont.) Historical perspective (cont.) 1950s: controversy regarding exact nature of microbe protozoan or fungus? 1940s-1960s: disease associated with debilitated patients or those being treated for other diseases 1980s: associated with AIDS Introduction (cont.) Less than 500 cases reported in U.S. 1967-1970. Late 1980 s numbers increased to 20-60,000 new cases Mycology Until 1976, it was thought that there was only a single species of Pneumocystis, P. carinii 1988: phylogenetic studies of rrna sequences indicated that Pneumocystis was a member of the fungal kingdom whose closest relative is Schizosaccharomyces pombe, the fission yeast Suggested classification: Phylum Ascomycota, Family Pneumocystidiaceae 1
Once thought to be a single species, P. carinii actually is a complex of species, each unique for each mammal studied Four distinct species described in detail to date: P. carinii: rats P. wakefieldiae: rats P. murina: mice P. jiroveci: humans Taxonomy is still very controversial, however Pneumocystis has a unique tropism for lung tissue Exists in alveoli, but does not invade host cells Rare dissemination beyond lung Morphology Trophic form: unicellular and ameboid, possessing 1-2 nuclei Sporocyte form: cell walled form with 2-8 nuclei that have not yet become conidia like Cyst form: diagnostic form; ascus-like Cyst form Easily stained with GMS Spherical or cupped shaped (latter are collapsed forms of cyst) Contains 8 conidia Wall is tri-layered comprised of glucan, chitin, and melanin No ergosterol Life cycle of Pneumocystis Cannot be cultured in vitro Presumptive life cycle derived from observations of specimens from humans or rats Possibly, the cells mate in vivo as mating type genes have been identified in this fungus Fungus is ubiquitous in nature PCP: Incidence in HIV+ Pneumocystis carinii is the most common opportunistic infection in AIDS in the U.S. 65% of these cases are the AIDS-defining illness. (1991 - down to 25%) 80-90% of patients with HIV+ will develop PCP if not given prophylaxis. Only 15% of patients compliant with prophylaxis will develop disease. Pneumocystis life cycle 2
PCP: Transmission Airborne via human-to-human transmission or environmental. Possibly, exposed almost universally as children and then have reactivation later as immunity decreases. Results in interstitial inflammation with lymphocytes and macrophages. Patients at Risk AIDS at CD4 < 200. Congenital and acquired defects in cellular immunity. Organ transplantation recipients. Chemotherapy. Corticosteroids. Malnutrition. Premature birth. PCP: Clinical Features PCP: Clinical Features (cont.) Cough - 60-91% Usually nonproductive, occasionally whitish sputum. Only productive in 23-30% of patients. Dyspnea - 29-95% May be present only on exertion at first. Fever - 79-100% May be accompanied by night sweats, but not rigors. Chest pain - 14-23% If a pneumothorax accompanies the infection. Tachypnea and tachycardia Occasionally, severe respiratory distress. Rales May be present, but are often absent. Aspergillus as a Pathogen Aspergillus fumigatus and related species are highly-significant opportunistic pathogens No classical virulence factors have been discovered Mutations in 20+ genes have been demonstrated to reduce virulence All these genes have primary roles in basic fungal biology, e.g., growth, metabolism, etc. Hence, their secondary roles are as virulence attributes that promote survival in vivo Histologic Diagnosis Sputum (induced if necessary): Diagnostic in 60-80% of AIDS, but a negative predictive value of 54%. Only 5-10% of non-hiv patients are diagnostic. Flexible Bronchoscopy with Bronchoalveolar lavage: 80-90% diagnostic. Safe. 3
Pneumocystis BIOL 4849 - Summer 2010 Histologic Diagnosis (cont.) Transbronchial biopsy: Histologic Diagnosis (cont.) Stains: 85-95% diagnostic. 1-5% morbidity. Percutaneous Lung aspiration: 91% diagnostic. 44% complications. Gram and Giemsa stain both cyst and trophozoites. Gomori s silver and Toluidine stains for cysts. Future techniques: Serum PCR? Open lung biopsy: Only in rapidly deteriorating patients with a negative bronchoscopy. Pneumocystis fluorescent antibody stain Pneumocystis infection of the lung: interstitial pneumonia Pneumocystis infection of the lung Pneumocystis cysts in the lung 4
Pneumocystis trophic forms Pneumocystis cyst forms PCP Treatment: Goals Treating the acute infection. Antipneumocystis chemotherapy. Decreasing the inflammatory response. Improving the immunologic status of the patient. Supportive care with oxygen, nutrition, chest tubes etc. Preventing infection Antipneumocystis Therapy Effectively inhibit dihydrofolate reductase with a greater affinity towards Pneumocystis than host enzyme Drugs used Trimethoprim-Sulfamethoxazole Trimethoprim Dapsone Trimetrexate Other therapies include (mechanism of action unknown) pentamadine, atovaquone, and clindamycin-primaquine PCP: Prophylaxis Shown to decrease infection rates and recurrences. HIV+ and one of the following: Previous PCP infection (Risk of recurrence 50%). CD4 < 200. Oral thrush. Persistent fevers > 2 weeks. PCP: Prophylaxis Immunocompromised hosts: Allogeneic organ or bone marrow transplant recipient. Children with severe combined immunodeficiency. Children with ALL. Patients on chronic steroids 5
PCP: Survival Mortality: 6-12% of HIV+ 39% of non-hiv+ Nearly 100% fatal if untreated in HIV. Some patients may develop resistance lowering chance of survival. 50-60% mortality if require mechanical ventilation. PCP: Recurrence 50-75% of patients with AIDS and PCP will relapse in a year if no prophylaxis is offered. 10-20% relapse in other immunocompromised patients. 6