Pneumocystis jirovecii Pneumonia

Pneumocystis jirovecii (formerly Pneumocystis carinii sp. f. hominis) is an unusual fungus exhibiting pulmonary tropism and a highly defined host specificity. It is generally regarded as an opportunistic microorganism causing severe and often fatal pneumonia in AIDS patients. However, with the currently rising number of patients receiving immunosuppressive therapies for malignancies, allogeneic organ transplantations and autoimmune diseases, Pneumocystis pneumonia is becoming more and more recognized in non-HIV immunosuppressed individuals. The clinical presentation in HIV-infected patients may differ from that in other immunocompromised patients and its diagnosis continues to be challenging because no combination of symptoms, signs, blood chemistries, or radiographic findings is specific of Pneumocystis pneumonia. In addition, as P. jirovecii cannot be grown in culture from clinical specimens, the diagnosis of Pneumocystis pneumonia continues to rely on the microscopic demonstration of the characteristic organisms using conventional cytochemical or immunofluorescence staining in respiratory samples. These methods are useful when the organism burden is relatively high but they are insufficient for reliable detection when there is a small parasite load. Therefore, in an attempt to improve diagnosis of Pneumocystis pneumonia, more sensitive molecular techniques such as conventional and quantitative PCR have been developed. Using molecular technique mutations in both the gene encoding dihydropteroate synthetase, the target enzyme of sulfonamides, and the gene encoding cytochrome B, conferring potential atovaquone resistance, have been demonstrated. The exclusive license for this PDF is limited to personal website use only. No part of this digital document may be reproduced, stored in a retrieval system or transmitted commercially in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services. Enrique J. Calderón, José Manuel Varela, Isabelle Durand-Joly et al. 2 However, their clinical relevance on treatment failure has not yet been determined. Cotrimoxazole, an association of trimethoprim and sulfamethoxazole, pentamidine isethionate or atovaquone has been extensively prescribed for the prophylaxis and therapy of Pneumocystis pneumonia. Nevertheless, co-trimoxazole is currently regarded as the drug of choice for prophylaxis and therapy of any form or severity of Pneumocystis pneumonia. Looming on the horizon is the specter of resistance to co-trimoxazole and atovaquone, but there are few options for other alternative treatments. A prompt appropriate therapy is probably the most crucial factor in improving the prognosis of this devastating pneumonia for which care providers must continue to maintain a high index of suspicion in immunocompromised patients at risk. The management of Pneumocystis pneumonia remains a major challenge for all physicians caring for immunosuppressed patients. Introduction and Historical Perspective Pneumocystis jirovecii, previously known as Pneumocystis carinii sp. f. hominis [1], is an atypical fungus exhibiting pulmonary tropism and a highly defined host specificity. This microorganism causes opportunistic infection, particularly pneumonia, in patients who have impaired immunity. The general term for clinical disease caused by Pneumocystis is pneumocystosis. Pneumocytsis was originally identified in 1909 by Carlos Chagas in the lungs of guinea pigs that were inoculated with the blood of trypanomiasis patients. Therefore, he erroneously thought that this organism was part of the life cycle of Trypanosoma cruzi. One year later, Antonio Carini made a similar description in the lungs of rats infected by Trypanosoma lewisi. It was not until 1912 that the Delanoës working at the Pasteur Institute in Paris recognized that Pneumocystis in rats represented a unique species and suggested naming the new microorganism P. carinii in honor of Antonio Carinii [2]. For seven decades, most investigators thought Pneumocystis organisms to be protozoans because they do not look much like fungi base on the histological characteristics of its trophozoite and cyst life forms, fail to grow much in culture, and are not eliminated from patients by treatment with the usual antifungal agents. By contrast, drugs, such as trimethoprim-sulfamethoxazole and pentamidine, which are often useful in treating protozoan infections, are also active against Pneumocystis. Throughout this time P. carinii has been regarded as a single protozoan organism capable of infecting a wide variety of animal species [3]. This idea lasted until 1988 when DNA studies were able to identify it as an atypical fungus close to the family of Aschomycetos [4]. Subsequent studies using molecular techniques allowed knowing other aspects, as it is a ubiquitous fungus with pulmonary tropism, which colonizes only mammals and that have a high specificity for the host (stenoxenism). In this way, it has been shown in cross-infection experiments that the species of Pneumocystis is specific to each type of mammal, with no transmission among mammals of different species [5]. Therefore, human pneumocystosis is not a zoonotic disease, and this notion has important implications for the epidemiology of human-derived Pneumocystis. These findings have recently determined the modification of the nomenclature of Pneumocystis that colonize and cause infection in humans, formerly known as P. carinii sp. f. hominis, and has now been renamed P. jirovecii [6], leaving the end of P. carinii to the cause of infection in rats. Pneumocystis jirovecii Pneumonia 3 Pneumocystis is generally regarded as an opportunistic microorganism causing serious pneumonia in immunocompromised patients, especially in those with AIDS. However, Pneumocystis was first identified as a human-pathogen in premature or malnourished infants suffering from interstitial plasma cell pneumonia in European countries around World War II, occasionally occurring in epidemics [2,3]. Since then Pneumocystis pneumonia (PcP) had only been reported infrequently in individuals with malignancies and solid organ transplantations until the human immunodeficiency virus (HIV) pandemia turned PcP into a major medical and public health problem in the 1980s [2]. During the 1990s, the introduction of highly active antiretroviral therapy (HAART) for HIV infection and Pneumocystis chemoprophylaxis reduced the frequency of PcP. Although at the beginning of this century, the incidence of pneumonia caused by this microorganism among subjects with HIV infection has decreased in developed countries, the prevalence of AIDS-related PcP in developing countries remains high and poorly controlled. AIDS-related PcP continues to be a devastating illness among subjects unaware of their HIV infection, persons without access to antiretroviral therapy, among patients who are intolerant or non-adherent, and in occasional cases of failure of prophylaxis [4]. For theses reasons, PcP still remains considered as a principal AIDS-defining illness [7]. Presently, interest in P. jirovecii infection goes beyond AIDS patients since with the rising number of patients receiving immunosuppressive therapies for autoimmune diseases, malignancies, allogeneic bone marrow or solid organ transplantations, PcP is more and more recognized in non-HIV immunosuppressed patients [5,6,8]. Underlying conditions associated with PcP in HIV-negative patients include hematologic or solid malignancies, allograft transplantation, autoimmune inflammatory disorders (mainly Wegener granulomatosis and systemic lupus erythematosus), inflammatory bowel disease, protein-calorie malnutrition, and congenital immunodeficiency disorders [5,6,8-12]. Lately, PcP has been reported in patients undergone treatment with new biological tumor necrosis factor-alpha antagonist agents (adalimumab, infliximab, etanercept) and anti-CD20 monoclonal antibody, rituximab [13-16]. However, despite advances in laboratory technology, the diagnosis of PcP continues to be challenging [17]. PcP may be difficult to diagnose owing to nonspecific symptoms and signs, the use of chemoprophylaxis and simultaneous infection with multiple organisms in an immunocompromised individual [18]. On the other hand, few treatment options exist for patients with PcP. Thus, management of PcP remains a major challenge to all physicians caring for these patients.