Pneumocystis Pneumonia During Combined Therapy of Infliximab, Corticosteroid, and Azathioprine in a Patient with Crohn’s Disease

Itaba, Soichi; Iwasa, Tsutomu; Sadamoto, Yojiro; Nasu, Toshifumi; Misawa, Tadashi; Inoue, Koji; Shimokawa, Hidehiko; Nakamura, Kazuhiko; Takayanagi, Ryoichi

doi:10.1007/s10620-006-9575-5

Cited by 17 publications

(16 citation statements)

References 27 publications

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“…Case reports have been sprinkled in the literature, showing that treatment of patients with rituximab, anti-CD20, as a part of chemotherapy for B cell lymphoma can result in severe PCP (46,47), confirming the importance of B cell function in controlling Pneumocystis infection. There have also been reports that TNF blockers (infliximab, adalimumab, and etanercept) used as therapy for Crohn's disease or rheumatoid arthritis have resulted in PCP in some individuals (26,27,48). This confirms the strong animal data demonstrating an important role of TNF in mediating the immune response to Pneumocystis.…”

Section: Discussionsupporting

confidence: 59%

“…Neutralization of TNF with monoclonal Abs (MAbs) resulted in persistent P. murina pneumonia in infected SCID mice that were reconstituted with splenocytes (22). Recently, it was reported that some individuals on monoclonal antibody therapy targeting TNF have developed PCP (26,27). It is well documented that TNF can be produced by a number of cell types, including B cells and T cells (24)(25)(26)(28)(29)(30).…”

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confidence: 99%

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B Cell Production of Tumor Necrosis Factor in Response to Pneumocystis murina Infection in Mice

Opata

Hollifield

et al. 2013

Infect Immun

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Pneumocystis species are opportunistic fungal pathogens that induce tumor necrosis factor (TNF) production by alveolar macrophages. Here we report that B cells from the draining lymph nodes as well as lung CD4 ؉ T cells are important producers of TNF upon Pneumocystis murina infection. To determine the importance of B cell-derived TNF in the primary response to P. murina, we generated bone marrow chimeras whose B cells were unable to produce TNF. The lung P. murina burden at 10 days postinfection in TNF knockout (TNFKO) chimeras was significantly higher than that in wild-type (WT) chimeras, which corresponded to reduced numbers of activated CD4 ؉ T cells in the lungs at this early time point. Furthermore, CD4 ؉ T cells isolated from P. murina-infected TNFKO chimeras were unable to stimulate clearance of P. murina upon adoptive transfer to recombinase-deficient (RAG1KO) hosts. Together, these data indicate that B cell-derived TNF plays an important function in promoting CD4 ؉ T cell expansion and production of TNF and facilitating protection against P. murina infection.

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Section: Discussionsupporting

confidence: 59%

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confidence: 99%

B Cell Production of Tumor Necrosis Factor in Response to Pneumocystis murina Infection in Mice

Opata

Hollifield

et al. 2013

Infect Immun

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“…Although the incidence has not been clearly defined, multiple cases of PJP in patients with IBD have been reported, associated with the use of IS alone and in combination, including cyclosporine, 15, 16 azathioprine, 17, 18 high dose CS 19 (a systemically delivered corticosteroid in a dose equivalent to prednisone >20 mg daily), 6-mercaptopurine, 20 and infliximab. 21–25 In an analysis of the Federal Drug Administration (FDA) database for the Adverse Event Reporting System, 84 cases of PJP were reported between 1998 and 2003 in patients receiving infliximab with or without concomitant IS. 26 Of these, 14 were receiving infliximab for Crohn’s disease (CD) and 2 for ulcerative colitis (UC).…”

Section: Introductionmentioning

confidence: 99%

Low Risk of Pneumonia From Pneumocystis jirovecii Infection in Patients With Inflammatory Bowel Disease Receiving Immune Suppression

Cotter

Gathaiya

Catania

et al. 2017

Clinical Gastroenterology and Hepatology

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Background & Aims Use of immunosuppressants and inflammatory bowel disease (IBD) may increase the risk of pneumonia caused by Pneumocystis jirovecii (PJP). We assessed the risk of PJP in a population-based cohort of patients with IBD treated with corticosteroids, immune-suppressive medications, and biologics. Methods We performed a population-based cohort study of residents of Olmsted County, Minnesota, diagnosed with Crohn’s disease (n=427) or ulcerative colitis (n=510) from 1970 through 2011. Records of patients were reviewed to identify all episodes of immunosuppressive therapies and concomitant PJP prophylaxis through February 2016. We reviewed charts to identify cases of PJP, cross-referenced with the Rochester Epidemiology Project database (using diagnostic codes for PJP) and the Mayo Clinic and Olmsted Medical Center databases. The primary outcome was risk of PJP and associated with use corticosteroids, immune-suppressive medications, and biologics by patients with IBD. Results Our analysis included 937 patients and 6066 patient-yrs (p-y) of follow up (median, 14.8 yrs per patient). Medications used included corticosteroids (520 patients; 55.5%; 555.4 p-y of exposure), immunosuppressants (304 patients; 32.4%; 1555.7 p-y of exposure), and biologics (193 patients; 20.5%; 670 p-y of exposure). Double therapy (corticosteroids and either immunosuppressants and biologics) was used by 236 patients (25.2%), with 173 p-y of exposure. Triple therapy (corticosteroids, immunosuppressants, and biologics) was used by 70 patients (7.5%) with 18.9 p-y of exposure. There were 3 cases of PJP, conferring a risk of 0.2 (95% CI, 0.01–1.0) to corticosteroids, 0.1 (95% CI, 0.02–0.5) cases per 100 p-y of exposure to immunosuppressants, 0.3 (95% CI, 0.04–1.1) cases per 100 p-y of exposure to biologics, 0.6 (95% CI, 0.01–3.2) cases per 100 p-y of exposure to double therapy, and 0 (95% CI, 0.0–19.5) cases per 100 p-y of exposure to triple therapy. Primary prophylaxis for PJP was prescribed to 37 patients, for a total of 24.9 p-y of exposure. Conclusion In a population-based cohort of patients with IBD patients treated with corticosteroids, immunosuppressants, and biologics, there were only 3 cases of PJP, despite the uncommon use of PJP prophylaxis. Routine administration of PJP prophylaxis in these patients may not be warranted, although it should be considered for high-risk groups, such patients receiving triple therapy.

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“…The presence of P. jirovecii in patients with underlying chronic diseases such as chronic obstructive pulmonary disease has been suggested to be a comorbidity factor (42-44). A series of recent case reports have identified P. jirovecii as a significant cause of infection in patients being treated with tumor necrosis factor alpha inhibitors for rheumatoid arthritis and other chronic diseases (22,25,28,54). Other studies in animals and humans suggest that Pneumocystis organisms are also present in the lungs of nonimmunocompromised hosts (24, 60).…”

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confidence: 99%

Biofilm Formation by Pneumocystis spp

2009

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Pneumocystis spp. can cause a lethal pneumonia in hosts with debilitated immune systems. The manner in which these fungal infections spread throughout the lung, the life cycles of the organisms, and their strategies used for survival within the mammalian host are largely unknown, due in part to the lack of a continuous cultivation method. Biofilm formation is one strategy used by microbes for protection against environmental assaults, for communication and differentiation, and as foci for dissemination. We posited that the attachment and growth of Pneumocystis within the lung alveoli is akin to biofilm formation. An in vitro system comprised of insert wells suspended in multiwell plates containing supplemented RPMI 1640 medium supported biofilm formation by P. carinii (from rat) and P. murina (from mouse).Dramatic morphological changes accompanied the transition to a biofilm. Cyst and trophic forms became highly refractile and produced branching formations that anastomosed into large macroscopic clusters that spread across the insert. Confocal microscopy revealed stacking of viable organisms enmeshed in concanavalin A-staining extracellular matrix. Biofilms matured over a 3-week time period and could be passaged. These passaged organisms were able to cause infection in immunosuppressed rodents. Biofilm formation was inhibited by farnesol, a quorum-sensing molecule in Candida spp., suggesting that a similar communication system may be operational in the Pneumocystis biofilms. Intense staining with a monoclonal antibody to the major surface glycoproteins and an increase in (1,3)-␤-Dglucan content suggest that these components contributed to the refractile properties. Identification of this biofilm process provides a tractable in vitro system that should fundamentally advance the study of Pneumocystis.Organisms in the fungal genus Pneumocystis cause an oftenlethal pneumonia in mammals with a compromised immune status. To date, there have been five formally described species, although all mammalian species examined to date appear to host at least one Pneumocystis species. Those that have been described are P. jirovecii from humans (20), P. carinii (53) and P. wakefieldiae (10, 11) from rats, P. murina (30) from mice, and P. oryctolagi (16) from rabbits.Limited progress has been made in understanding the life cycle, transmission, and natural history of any Pneumocystis species, due in large part to the absence of a continuous in vitro culture system. Although the incidence of frank pneumonia caused by these organisms has decreased in developed countries such as the United States and European countries, mounting evidence points to new niches being exploited by these fungi. The presence of P. jirovecii in patients with underlying chronic diseases such as chronic obstructive pulmonary disease has been suggested to be a comorbidity factor (42-44). A series of recent case reports have identified P. jirovecii as a significant cause of infection in patients being treated with tumor necrosis factor alpha inhibitors for rheum...

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Pneumocystis Pneumonia During Combined Therapy of Infliximab, Corticosteroid, and Azathioprine in a Patient with Crohn’s Disease

Cited by 17 publications

References 27 publications

B Cell Production of Tumor Necrosis Factor in Response to Pneumocystis murina Infection in Mice

B Cell Production of Tumor Necrosis Factor in Response to Pneumocystis murina Infection in Mice

Low Risk of Pneumonia From Pneumocystis jirovecii Infection in Patients With Inflammatory Bowel Disease Receiving Immune Suppression

Biofilm Formation by Pneumocystis spp

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