Curr Rheumatol Rep (2014) 16:445 DOI 10.1007/s11926-014-0445-4

INFECTIONS AND ARTHRITIS (K WINTHROP, SECTION EDITOR)

Pneumocystis jirovecii Pneumonia in Patients Receiving Tumor-Necrosis-Factor-Inhibitor Therapy: Implications for Chemoprophylaxis James A. Grubbs & John W. Baddley

Published online: 3 September 2014 # Springer Science+Business Media New York 2014

Abstract Pneumocystis jirovecii pneumonia (PJP) is an important opportunistic infection that has been increasingly reported in patients with rheumatic disease. Reported incidence among patients taking TNF inhibitors (TNFi) has varied, but has usually been low. Still, disease causes significant mortality among those affected and must be considered in patients with rheumatological disease presenting with dyspnea and cough. Diagnosis can be difficult in the non-HIV population, and our understanding of the epidemiology and natural history after exposure is changing. Trimethoprim–sulfamethoxazole is believed to be the most effective agent for treatment and prophylaxis, but is associated with significant adverse effects. Given the low incidence reported in most studies of patients on TNFi, prophylaxis is probably not beneficial for this patient population as a whole. Keywords Pneumocystis jirovecii . PJP . Autoimmune disease . Biologicals . TNF inhibitor . Prophylaxis . Trimethoprim-sulfamethoxazole

Introduction Pneumocystis jirovecii is an opportunistic fungal respiratory pathogen that was initially described as a cause of pneumonia in the malnourished in Europe during World War II [1]. This article is part of the Topical Collection on Infections and Arthritis J. A. Grubbs : J. W. Baddley (*) Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, 1900 University Boulevard, 229 Tinsley Harrison Tower, Birmingham, AL 35294-0006, USA e-mail: [email protected] J. W. Baddley Birmingham Veterans Affairs Medical Center, 700 19th Street South, Birmingham, Alabama 35233, USA

Afterwards it was recognized as a cause of disease in other immunocompromised hosts, particularly premature infants, children with primary deficiencies in cell-mediated immunity, and those receiving chemotherapy for hematological malignancies [2–4]. In 1981 the report of Pneumocystis jirovecii pneumonia (PJP) in homosexual men and intravenous drug users was an early indicator of the AIDS epidemic [5]. Since that time PJP has remained the most common AIDS-defining illness in the United States, although the incidence has fallen significantly with the advent of antiretroviral therapy. PJP was described in patients with rheumatoid arthritis (RA) as early as the 1960s, but was more widely recognized after the onset of the AIDS epidemic [6]. The importance of PJP in connective tissue diseases other than RA was also increasingly recognized. The diagnosis was made more readily in hospitals with more experience of PJP in the HIVinfected population [7]. Of concern in these early reports of PJP in patients with rheumatological disease was a mortality of almost 50 %, higher than that seen in HIV-infected patients. The risk was also noted to vary among patients with different diseases, being highest (approximately 6 %) among those with granulomatosis with polyangiitis [8]. With the advent of TNF inhibitors (TNFi), PJP has been reported more frequently in patients with rheumatological disease. These effective disease-modifying agents have improved response rates to clinical treatment but are also associated with increased risk of infection. Those on TNFi have a 1–3 case per 100 person-years increased incidence of serious infection compared with those on non-biological DMARDs, with pneumonia and soft-tissue infections being most common [9•]. Initial clinical trials that led to the approval of TNFi did not identify cases of PJP [10]. In post-marketing surveillance of TNFi, increased risk of PJP has been suggested to be associated with these agents. This observation has prompted the question of whether primary chemoprophylaxis against this disease is advisable for patients on TNFi.

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Taxonomy P jirovecii’s taxonomic assignment to the fungal kingdom was a subject of debate for many years, but there is now general consensus regarding this classification. Unlike other fungi, however, it lacks the cell membrane sterol ergosterol and is thus not susceptible to amphotericin B. Also, again unlike other fungi, it is not possible to grow it in sustained culture, hindering research on the organism and clinical diagnosis of the pneumonia it causes. It grows as trophic and cystic forms during its life cycle, with the trophic form being predominant in lungs during pneumonia at a ratio of 10:1 to cystic forms. P. jirovecii was previously known as P. carinii, but the name was changed in 1999 as a result of the recognition that Pneumocystis organisms found in different mammals differ extensively at the sequence level [11]. P. jirovecii DNA has been found only in human samples, also suggesting it to be a unique species. This finding is consistent for other Pneumocystis species; Pneumocystis organisms isolated from one species are incapable of causing disease in other species.

Acquisition and Colonization P. jirovecii exposure is believed to occur early in life, and infants perinatally infected with HIV often present early with disease. Serology data for healthy children also indicate early exposure, with anti-Pneumocystis antibodies developing in 85 % of infants by 20 months of age [12]. In a Spanish study 52 %, 66 %, and 80 % of children at 6, 10, and 13 years of age, respectively, were found to be seropositive, indicating that exposure also continues over time [13]. Recent data indicate that new exposure has an important function in disease acquisition and is perhaps the mechanism behind most cases of PJP. For instance, nosocomial clusters of PJP are caused by organisms of similar genotype [14, 15]. Different genotypes are most often responsible for recurrent episodes of PJP in the same individual [15]. Infecting Pneumocystis genotypes tend to cluster on the basis of the region in which a patient is currently living rather than their place of birth [16]. All these observations support recent acquisition, as opposed to reactivation from latency, as the route of disease in a significant number of patients. No environmental reservoir has been identified for P. jirovecii, but in animal models of infection asymptomatic immunocompetent carriers of the organism are able to transmit the fungus to immunocompromised animals that then develop disease [17]. Use of polymerase chain reaction (PCR) for the detection of P. jirovecii DNA in respiratory samples has provided a tool to assess colonization by the organism and to potentially aid in clinical diagnosis. Studies using PCR on respiratory specimens have suggested that healthcare workers may carry

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P. jirovecii after exposure to HIV-infected patients with P. jirovecii pneumonia (PJP) [18]. A serology study of healthcare workers also revealed correlation between levels of antibodies to some major surface glycoproteins of P. jirovecii and repeated exposure to patients with PJP [19]. A study using multi-locus sequence typing of DNA sequences from clinical isolates of P. jirovecii from a case cluster revealed genetically similar strains, suggesting nosocomial person-to-person transmission [20]. This study, however, did not investigate the presence of P. jirovecii DNA in healthcare workers as a possible vector of transmission. Given evidence of a colonization state, there has been further investigation into the prevalence of colonization in different populations. In a Spanish study of asymptomatic patients with RA, psoriatic arthritis, and ankylosing spondylitis, 26 % of patients were found to have P. jirovecii DNA present in their oral wash, with corticosteroid use, methotrexate use, and infliximab use of >3 years all associated with higher risk of colonization [21•]. Similar findings were reported in a German study [22]. A Japanese study evaluated the natural history of PJP-DNA positivity in RA by use of PCR [23]. Nine of 82 asymptomatic patients had induced sputum that was PCR positive for P. jirovecii at enrollment. Six patients were given antimicrobial treatment while asymptomatic, with resolution of their PCR positivity. The remaining three were reported to have developed PJP. Their reported clinical symptoms were very mild: minimal hypoxemia, interstitial infiltrates on HRCT, and elevated serum β-D-glucan. All were treated as outpatients, with resolution of their symptoms. Given the small numbers in the trial and the number of asymptomatic individuals that were treated, the trial did not address the natural history of P. jirovecii PCR positivity in the RA population. It is uncertain from the data presented whether any of those with asymptomatic colonization, or even some of those classified as having mild disease, may have cleared their PCR positivity and recovered without disease progression.

Clinical Presentation and Diagnosis In HIV-infected patients PJP typically presents with cough, fever, and dyspnea, with symptoms present for >4 weeks on average. Presentation is different in non-HIV-infected immunocompromised patients, who tend to have a shorter duration of symptoms and lower arterial-oxygen pressures [24]. Consistent with these prior observations, a Japanese study comparing presentation of PJP between patients with HIV and those with RA found that HIV-infected patients had symptoms for 37.8 days on average before diagnosis, in contrast with 7.6 days for patients with RA [25]. These RA patients with PJP also had higher CRP and lower β-D-glucan levels than those with HIV [26].

Curr Rheumatol Rep (2014) 16:445

Multiple radiography presentations have been reported for PJP, but diffuse bilateral interstitial infiltrates are most common [27]. Normal chest radiographs are not unusual, upper lobe disease is reported more often in those who have received pentamidine prophylaxis, and nodular lesions are also described [28]. Those with normal chest radiographs are often found to have abnormalities on high-resolution computed tomography (CT), with diffuse ground-glass opacity being most common [28]. Diagnosis of PJP can be difficult because of its relative rarity and non-specific presentation (particularly in HIVnegative individuals), complicating studies on epidemiology and transmission. Even when disease is suspected, diagnosis is not always straightforward. As mentioned above, P jirovecii cannot be cultured. Definitive diagnosis is made by visualization of the organisms. For HIV-infected individuals, microscopy of respiratory specimens stained with either a silver stain or an immunofluorescent stain for the organism has reasonable sensitivity and has been the standard basis of diagnosis. However, sensitivity can vary depending upon the type of respiratory specimen obtained and the center at which the test is performed [29, 30]. Overall, the sensitivity and specificity of induced sputum for the diagnosis of PJP in the HIVinfected population are 43 and 96 %, respectively, using cytochemical staining and 67 and 97 %, respectively, using immunofluorescence staining [31, 32]. In the non-HIVinfected population with PJP, lower numbers of P. jirovecii organisms and increased neutrophils are reported in bronchoalveolar lavage (BAL) samples as compared with those from the HIV-infected population [33]. Given this difference in pathogen burden, the sensitivity of staining techniques for the diagnosis of PJP in non-HIV-infected patients is believed to be lower even when using BAL specimens, on the order of 67 % or less [24]. Use of PCR testing for the diagnosis of PJP is becoming more widespread. Results of studies indicate that PCR testing for PJP is a sensitive diagnostic test, but discrimination of colonization from disease has been difficult. As mentioned above, the risk of colonization is high for immunocompromised hosts, up to 26 % in those with rheumatological disease who may be on TNFi [21•, 22]. Quantitative PCR (qPCR) has been suggested as a means of differentiating colonization and disease [34]. Using this method, the natural history qPCR positivity was studied [35•]. DNA was extracted from BAL specimens of patients with pneumonia and/or fever in the course of routine clinical care for qPCR (treating team blinded to the result), and immunofluorescence microscopy was used for clinical diagnosis. Patients with systemic inflammatory disease who were qPCR positive and independent fluorescent antibody (IFA) negative (and thus not treated for PJP) had a reduced one-year survival compared with those who were qPCR negative and IFA negative. The authors report that this group of patients was on “high dose steroids” but offer no

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other information as to the immunomodulatory regimens with which they were treated. Of this group of patients who were qPCR positive and IFA negative, 42.9 % had diffuse pulmonary infiltrates on chest imaging. Most of the deaths occurred in the first 100 days after samples were obtained; however, the authors were unable to determine cause of death for these patients. Steroid treatment is known to be a risk factor for PJP and could have been an important predisposing factor for patients irrespective of their exposure to TNFi [36]. It is also not clear whether qPCR positivity indicated PJP disease or only acted as a proxy identifying patients with worse underlying lung disease [37, 38]. qPCR did not predict outcomes among those with hematological disease or transplants as risk factors for PJP. Use of concomitant serum β-D-glucan and respiratorysample PCR has been suggested as another means of diagnosing PJP [39]. With quantitative PCR used as an initial screen to divide patients into negative, positive, and indeterminate groups and β-D-glucan then used to classify those in the indeterminate group, the authors of this small study report accurate assignment of patients into those with disease or colonization. The standard by which this diagnostic method was evaluated was the clinical diagnosis of PJP or P. jirovecii colonization. In support of this assignment, the 17 patients deemed to have PJP had interstitial infiltrates, dyspnea or cough, hypoxemia, and no evidence of bacterial pneumonia. P. jirovecii was seen on BAL microscopy for 10 of these patients, and the other seven had P. jirovecii DNA detected only by qualitative PCR. All improved with treatment for PJP, but no mention is made of treatment for other possible conditions. Colonized patients were all BAL-microscopy negative but qualitative-PCR positive. They all had respiratory disease attributed to another etiology, all improved without therapy for PJP, and none had a recurrent episode of respiratory disease attributed to PJP in at least the following two months. The classification of the seven patients as having PJP on the basis of qualitative-PCR positivity and clinical characteristics may have been erroneous if these patients instead had a similar disease that improved either without treatment or with treatment that was given concomitantly. With this imperfect standard for defining disease, the true performance of this diagnostic method is unclear. β-D-glucan is a polysaccharide component of most fungal cell walls. An assay detecting this antigen is approved by the FDA as an aid in the diagnosis of invasive fungal infections, and its use in the diagnosis of PJP has been studied [40–42]. A recent meta-analysis revealed the test to have a sensitivity and specificity for PJP diagnosis of 96 % and 84 %, respectively, with comparable performance for HIV-infected and non-HIVinfected individuals [43]. Again, determination of a sensitivity higher than that of the prior method of choice (microscopy of BAL samples) has relied upon surrogate diagnostic criteria in studies included in the meta-analysis. β-D-glucan testing can

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be problematic in that it does not distinguish which among many fungal infections a patient may have. Most reports on its use are regarding diagnosis of invasive aspergillosis and candidiasis, but the antigen is present at high levels in the cell walls of most fungi. There are also multiple causes of false positives, including receipt of some antibiotics (notably some cephalosporins), bacteremia (particularly with Alcaligenes faecalis and Pseudomonas aeruginosa), receipt of some blood products, and use of hemodialysis [44–47].

Treatment The drug of choice for treatment of PJP is trimethoprim– sulfamethoxazole (TMP–SMX) [48, 49]. Multiple trials found equivalent efficacy for TMP–SMX and pentamidine (both IV) [50, 51]. One smaller non-crossover study obtained better efficacy for TMP–SMX than pentamidine IV [52]. Consistent with current recommendations, a cohort study investigating outcomes for HIV-infected patients on different treatment regimens for PJP found that most patients received TMP– SMX [53]. Patients treated with intravenous pentamidine were found to have higher three-month mortality than those on other treatments, with a hazard ratio of 2 (95 % confidence interval 1.2–3.4). Of note, prior prophylaxis with TMP–SMX does not seem to be associated with clinical failure when this agent is used to treat disease. Studies have revealed mutations in the dihydropteroate-synthase gene of infecting P. jirovecii in those who have been on TMP–SMX prophylaxis, but these patients do not seem to have a clear increase in mortality even if TMP–SMX is used as treatment [54, 55]. Meta-analyses of second-line therapy have favored clindamycin plus primaquine over pentamidine [56, 57]. In one study, patients receiving second-line therapy with pentamidine for treatment failure with their first-line agent had higher mortality than those on second-line therapy with TMP– SMX or clindamycin plus primaquine [53]. In patients who were started on TMP–SMX first line but changed because of toxicity, those changed to clindamycin and primaquine had a lower mortality than those changed to pentamidine. For patients with mild disease, atovaquone is a treatment option that seems as effective as pentamidine, but less effective than TMP–SMX, although it is better tolerated [58, 59]. Treatment and prophylaxis options are summarized in Table 1.

Prophylaxis Early in the HIV epidemic, prophylaxis for PJP was found to reduce the incidence of this important AIDS-defining illness [60]. A meta-analysis comparing different agents for chemoprophylaxis in the HIV-infected population found that TMP– SMX was more efficacious in preventing PJP in patients with

Curr Rheumatol Rep (2014) 16:445

CD4 counts

Pneumocystis jirovecii pneumonia in patients receiving tumor-necrosis-factor-inhibitor therapy: implications for chemoprophylaxis.

Pneumocystis jirovecii pneumonia (PJP) is an important opportunistic infection that has been increasingly reported in patients with rheumatic disease...
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