Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
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Recent Advances in the Diagnosis and Management of Pneumocystis Pneumonia

  • Tasaka, Sadatomo (Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine)
  • Received : 2020.02.19
  • Accepted : 2020.02.21
  • Published : 2020.04.30
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Abstract

In human immunodeficiency virus (HIV)-infected patients, Pneumocystis jirovecii pneumonia (PCP) is a well-known opportunistic infection and its management has been established. However, PCP is an emerging threat to immunocompromised patients without HIV infection, such as those receiving novel immunosuppressive therapeutics for malignancy, organ transplantation, or connective tissue diseases. Clinical manifestations of PCP are quite different between patients with and without HIV infections. In patients without HIV infection, PCP rapidly progresses, is difficult to diagnose correctly, and causes severe respiratory failure with a poor prognosis. High-resolution computed tomography findings are different between PCP patients with HIV infection and those without. These differences in clinical and radiological features are due to severe or dysregulated inflammatory responses that are evoked by a relatively small number of Pneumocystis organisms in patients without HIV infection. In recent years, the usefulness of polymerase chain reaction and serum β-D-glucan assay for rapid and non-invasive diagnosis of PCP has been revealed. Although corticosteroid adjunctive to anti-Pneumocystis agents has been shown to be beneficial in some populations, the optimal dose and duration remain to be determined. Recent investigations revealed that Pneumocystis colonization is prevalent and that asymptomatic carriers are at risk for developing PCP and can serve as the reservoir for the spread of Pneumocystis by airborne transmission. These findings suggest the need for chemoprophylaxis in immunocompromised patients as well as infection control measures, although the indications remain controversial. Because a variety of novel immunosuppressive therapeutics have been emerging in medical practice, further innovations in the diagnosis and treatment of PCP are needed.

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References

  1. Kovacs JA, Masur H. Evolving health effects of Pneumocystis : one hundred years of progress in diagnosis and treatment. JAMA 2009;301:2578-85. https://doi.org/10.1001/jama.2009.880
  2. Catherinot E, Lanternier F, Bougnoux ME, Lecuit M, Couderc LJ, Lortholary O. Pneumocystis jirovecii Pneumonia. Infect Dis Clin North Am 2010;24:107-38. https://doi.org/10.1016/j.idc.2009.10.010
  3. Maini R, Henderson KL, Sheridan EA, Lamagni T, Nichols G, Delpech V, et al. Increasing Pneumocystis pneumonia, England, UK, 2000-2010. Emerg Infect Dis 2013;19:386-92.
  4. Reid AB, Chen SC, Worth LJ. Pneumocystis jirovecii pneumonia in non-HIV-infected patients: new risks and diagnostic tools. Curr Opin Infect Dis 2011;24:534-44. https://doi.org/10.1097/QCO.0b013e32834cac17
  5. Tasaka S, Tokuda H. Pneumocystis jirovecii pneumonia in non-HIV-infected patients in the era of novel immunosuppressive therapies. J Infect Chemother 2012;18:793-806. https://doi.org/10.1007/s10156-012-0453-0
  6. Enomoto T, Azuma A, Kohno A, Kaneko K, Saito H, Kametaka M, et al. Differences in the clinical characteristics of Pneumocystis jirovecii pneumonia in immunocompromized patients with and without HIV infection. Respirology 2010;15:126-31. https://doi.org/10.1111/j.1440-1843.2009.01660.x
  7. Kovacs JA, Hiemenz JW, Macher AM, Stover D, Murray HW, Shelhamer J, et al. Pneumocystis carinii pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med 1984;100:663-71. https://doi.org/10.7326/0003-4819-100-5-663
  8. Limper AH, Offord KP, Smith TF, Martin WJ 2nd. Pneumocystis carinii pneumonia: differences in lung parasite number and inflammation in patients with and without AIDS. Am Rev Respir Dis 1989;140:1204-9. https://doi.org/10.1164/ajrccm/140.5.1204
  9. Tasaka S, Kobayashi S, Kamata H, Kimizuka Y, Fujiwara H, Funatsu Y, et al. Cytokine profiles of bronchoalveolar lavage fluid in patients with pneumocystis pneumonia. Microbiol Immunol 2010;54:425-33. https://doi.org/10.1111/j.1348-0421.2010.00229.x
  10. Thomas CF Jr, Limper AH. Pneumocystis pneumonia. N Engl J Med 2004;350:2487-98. https://doi.org/10.1056/NEJMra032588
  11. Carmona EM, Limper AH. Update on the diagnosis and treatment of Pneumocystis pneumonia. Ther Adv Respir Dis 2011;5:41-59. https://doi.org/10.1177/1753465810380102
  12. Flori P, Bellete B, Durand F, Raberin H, Cazorla C, Hafid J, et al. Comparison between real-time PCR, conventional PCR and different staining techniques for diagnosing Pneumocystis jiroveci pneumonia from bronchoalveolar lavage specimens. J Med Microbiol 2004;53:603-7. https://doi.org/10.1099/jmm.0.45528-0
  13. Caliendo AM, Hewitt PL, Allega JM, Keen A, Ruoff KL, Ferraro MJ. Performance of a PCR assay for detection of Pneumocystis carinii from respiratory specimens. J Clin Microbiol 1998;36:979-82. https://doi.org/10.1128/JCM.36.4.979-982.1998
  14. Alvarez-Martinez MJ, Miro JM, Valls ME, Moreno A, Rivas PV, Sole M, et al. Sensitivity and specificity of nested and realtime PCR for the detection of Pneumocystis jiroveci in clinical specimens. Diagn Microbiol Infect Dis 2006;56:153-60. https://doi.org/10.1016/j.diagmicrobio.2006.03.010
  15. Ribes JA, Limper AH, Espy MJ, Smith TF. PCR detection of Pneumocystis carinii in bronchoalveolar lavage specimens: analysis of sensitivity and specificity. J Clin Microbiol 1997;35:830-5. https://doi.org/10.1128/JCM.35.4.830-835.1997
  16. Fan LC, Lu HW, Cheng KB, Li HP, Xu JF. Evaluation of PCR in bronchoalveolar lavage fluid for diagnosis of Pneumocystis jirovecii pneumonia: a bivariate meta-analysis and systematic review. PLoS One 2013;8:e73099. https://doi.org/10.1371/journal.pone.0073099
  17. Nakashima K, Aoshima M, Ohkuni Y, Hoshino E, Hashimoto K, Otsuka Y. Loop-mediated isothermal amplification method for diagnosing Pneumocystis pneumonia in HIV-uninfected immunocompromised patients with pulmonary infiltrates. J Infect Chemother 2014;20:757-61. https://doi.org/10.1016/j.jiac.2014.08.005
  18. Obayashi T, Negishi K, Suzuki T, Funata N. Reappraisal of the serum (1-->3)-beta-D-glucan assay for the diagnosis of invasive fungal infections: a study based on autopsy cases from 6 years. Clin Infect Dis 2008;46:1864-70. https://doi.org/10.1086/588295
  19. Onishi A, Sugiyama D, Kogata Y, Saegusa J, Sugimoto T, Kawano S, et al. Diagnostic accuracy of serum 1,3-beta-Dglucan for pneumocystis jiroveci pneumonia, invasive candidiasis, and invasive aspergillosis: systematic review and metaanalysis. J Clin Microbiol 2012;50:7-15. https://doi.org/10.1128/JCM.05267-11
  20. Tasaka S, Hasegawa N, Kobayashi S, Yamada W, Nishimura T, Takeuchi T, et al. Serum indicators for the diagnosis of pneumocystis pneumonia. Chest 2007;131:1173-80. https://doi.org/10.1378/chest.06-1467
  21. Watanabe T, Yasuoka A, Tanuma J, Yazaki H, Honda H, Tsukada K, et al. Serum (1-->3) beta-D-glucan as a noninvasive adjunct marker for the diagnosis of Pneumocystis pneumonia in patients with AIDS. Clin Infect Dis 2009;49:1128-31. https://doi.org/10.1086/605579
  22. de Boer MG, Gelinck LB, van Zelst BD, van de Sande WW, Willems LN, van Dissel JT, et al. beta-D-glucan and S-adenosylmethionine serum levels for the diagnosis of Pneumocystis pneumonia in HIV-negative patients: a prospective study. J Infect 2011;62:93-100. https://doi.org/10.1016/j.jinf.2010.10.007
  23. Tasaka S, Kobayashi S, Yagi K, Asami T, Namkoong H, Yamasawa W, et al. Serum (1 --> 3) beta-D-glucan assay for discrimination between Pneumocystis jirovecii pneumonia and colonization. J Infect Chemother 2014;20:678-81. https://doi.org/10.1016/j.jiac.2014.07.001
  24. Koga M, Koibuchi T, Kikuchi T, Nakamura H, Miura T, Iwamoto A, et al. Kinetics of serum beta-D-glucan after Pneumocystis pneumonia treatment in patients with AIDS. Intern Med 2011;50:1397-401. https://doi.org/10.2169/internalmedicine.50.5296
  25. Roblot F, Godet C, Le Moal G, Garo B, Faouzi Souala M, Dary M, et al. Analysis of underlying diseases and prognosis factors associated with Pneumocystis carinii pneumonia in immunocompromised HIV-negative patients. Eur J Clin Microbiol Infect Dis 2002;21:523-31. https://doi.org/10.1007/s10096-002-0758-5
  26. Quist J, Hill AR. Serum lactate dehydrogenase (LDH) in Pneumocystis carinii pneumonia, tuberculosis, and bacterial pneumonia. Chest 1995;108:415-8. https://doi.org/10.1378/chest.108.2.415
  27. Kuhlman JE, Kavuru M, Fishman EK, Siegelman SS. Pneumocystis carinii pneumonia: spectrum of parenchymal CT findings. Radiology 1990;175:711-4. https://doi.org/10.1148/radiology.175.3.2343118
  28. Fujii T, Nakamura T, Iwamoto A. Pneumocystis pneumonia in patients with HIV infection: clinical manifestations, laboratory findings, and radiological features. J Infect Chemother 2007;13:1-7. https://doi.org/10.1007/s10156-006-0484-5
  29. Tokuda H, Sakai F, Yamada H, Johkoh T, Imamura A, Dohi M, et al. Clinical and radiological features of Pneumocystis pneumonia in patients with rheumatoid arthritis, in comparison with methotrexate pneumonitis and Pneumocystis pneumonia in acquired immunodeficiency syndrome: a multicenter study. Intern Med 2008;47:915-23. https://doi.org/10.2169/internalmedicine.47.0702
  30. Kameda H, Tokuda H, Sakai F, Johkoh T, Mori S, Yoshida Y, et al. Clinical and radiological features of acute-onset diffuse interstitial lung diseases in patients with rheumatoid arthritis receiving treatment with biological agents: importance of Pneumocystis pneumonia in Japan revealed by a multicenter study. Intern Med 2011;50:305-13. https://doi.org/10.2169/internalmedicine.50.4508
  31. Tasaka S, Tokuda H, Sakai F, Fujii T, Tateda K, Johkoh T, et al. Comparison of clinical and radiological features of pneumocystis pneumonia between malignancy cases and acquired immunodeficiency syndrome cases: a multicenter study. Intern Med 2010;49:273-81. https://doi.org/10.2169/internalmedicine.49.2871
  32. Hardak E, Brook O, Yigla M. Radiological features of Pneumocystis jirovecii pneumonia in immunocompromised patients with and without AIDS. Lung 2010;188:159-63. https://doi.org/10.1007/s00408-009-9214-y
  33. Kaplan JE, Benson C, Holmes KK, Brooks JT, Pau A, Masur H, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep 2009;58:1-207.
  34. Thomas M, Rupali P, Woodhouse A, Ellis-Pegler R. Good outcome with trimethoprim 10 mg/kg/day-sulfamethoxazole 50 mg/kg/day for Pneumocystis jirovecii pneumonia in HIV infected patients. Scand J Infect Dis 2009;41:862-8. https://doi.org/10.3109/00365540903214256
  35. Nakashima K, Aoshima M, Nakashita T, Hara M, Otsuki A, Noma S, et al. Low-dose trimethoprim-sulfamethoxazole treatment for pneumocystis pneumonia in non-human immunodeficiency virus-infected immunocompromised patients: a single-center retrospective observational cohort study. J Microbiol Immunol Infect 2018;51:810-20. https://doi.org/10.1016/j.jmii.2017.07.007
  36. Limper AH, Knox KS, Sarosi GA, Ampel NM, Bennett JE, Catanzaro A, et al. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-128. https://doi.org/10.1164/rccm.2008-740ST
  37. Helweg-Larsen J, Benfield T, Atzori C, Miller RF. Clinical efficacy of first- and second-line treatments for HIV-associated Pneumocystis jirovecii pneumonia: a tri-centre cohort study. J Antimicrob Chemother 2009;64:1282-90. https://doi.org/10.1093/jac/dkp372
  38. Nahimana A, Rabodonirina M, Bille J, Francioli P, Hauser PM. Mutations of Pneumocystis jirovecii dihydrofolate reductase associated with failure of prophylaxis. Antimicrob Agents Chemother 2004;48:4301-5. https://doi.org/10.1128/AAC.48.11.4301-4305.2004
  39. Huang L, Cattamanchi A, Davis JL, den Boon S, Kovacs J, Meshnick S, et al. HIV-associated Pneumocystis pneumonia . Proc Am Thorac Soc 2011;8:294-300. https://doi.org/10.1513/pats.201009-062WR
  40. Briel M, Boscacci R, Furrer H, Bucher HC. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV infection: a meta-analysis of randomised controlled trials. BMC Infect Dis 2005;5:101. https://doi.org/10.1186/1471-2334-5-101
  41. Pareja JG, Garland R, Koziel H. Use of adjunctive corticosteroids in severe adult non-HIV Pneumocystis carinii pneumonia. Chest 1998;113:1215-24. https://doi.org/10.1378/chest.113.5.1215
  42. Moon SM, Kim T, Sung H, Kim MN, Kim SH, Choi SH, et al. Outcomes of moderate-to-severe Pneumocystis pneumonia treated with adjunctive steroid in non-HIV-infected patients. Antimicrob Agents Chemother 2011;55:4613-8. https://doi.org/10.1128/AAC.00669-11
  43. Delclaux C, Zahar JR, Amraoui G, Leleu G, Lebargy F, Brochard L, et al. Corticosteroids as adjunctive therapy for severe Pneumocystis carinii pneumonia in non-human immunodeficiency virus-infected patients: retrospective study of 31 patients. Clin Infect Dis 1999;29:670-2. https://doi.org/10.1086/598651
  44. Segal BH, Freifeld AG, Baden LR, Brown AE, Casper C, Dubberke E, et al. Prevention and treatment of cancer-related infections. J Natl Compr Canc Netw 2008;6:122-74. https://doi.org/10.6004/jnccn.2008.0013
  45. Centers for Disease Control and Prevention; Infectious Disease Society of America; American Society of Blood and Marrow Transplantation. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep 2000;49:1-125.
  46. Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int 2010;77:299-311. https://doi.org/10.1038/ki.2009.377
  47. Martin SI, Fishman JA; AST Infectious Diseases Community of Practice. Pneumocystis pneumonia in solid organ transplant recipients. Am J Transplant 2009;9 Suppl 4:S227-33. https://doi.org/10.1111/j.1600-6143.2009.02914.x
  48. Hughes WT, Rivera GK, Schell MJ, Thornton D, Lott L. Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med 1987;316:1627-32. https://doi.org/10.1056/NEJM198706253162604
  49. Utsunomiya M, Dobashi H, Odani T, Saito K, Yokogawa N, Nagasaka K, et al. Optimal regimens of sulfamethoxazoletrimethoprim for chemoprophylaxis of Pneumocystis pneumonia in patients with systemic rheumatic diseases: results from a non-blinded, randomized controlled trial. Arthritis Res Ther 2017;19:7. https://doi.org/10.1186/s13075-016-1206-8
  50. Mizushina K, Hirata A, Hayashi N, Takenaka S, Ito H, Ogura T, et al. Possible preventive effect of salazosulfapyridine against development of Pneumocystis pneumonia in methotrexatereceiving patients with rheumatoid arthritis. Mod Rheumatol 2016;26:976-8. https://doi.org/10.3109/14397595.2015.1118196
  51. Nunokawa T, Yokogawa N, Shimada K, Sugii S, Nishino J, Gosho M, et al. Prophylactic effect of sulfasalazine against Pneumocystis pneumonia in patients with rheumatoid arthritis: a nested case-control study. Semin Arthritis Rheum 2019;48:573-8. https://doi.org/10.1016/j.semarthrit.2018.05.013
  52. Wang J, Gigliotti F, Bhagwat SP, George TC, Wright TW. Immune modulation with sulfasalazine attenuates immunopathogenesis but enhances macrophage-mediated fungal clearance during Pneumocystis pneumonia. PLoS Pathog 2010;6:e1001058. https://doi.org/10.1371/journal.ppat.1001058
  53. Anand S, Samaniego M, Kaul DR. Pneumocystis jirovecii pneumonia is rare in renal transplant recipients receiving only one month of prophylaxis. Transpl Infect Dis 2011;13:570-4. https://doi.org/10.1111/j.1399-3062.2011.00692.x
  54. Le Gal S, Pougnet L, Damiani C, Frealle E, Gueguen P, Virmaux M, et al. Pneumocystis jirovecii in the air surrounding patients with Pneumocystis pulmonary colonization. Diagn Microbiol Infect Dis 2015;82:137-42. https://doi.org/10.1016/j.diagmicrobio.2015.01.004
  55. Yazaki H, Goto N, Uchida K, Kobayashi T, Gatanaga H, Oka S. Outbreak of Pneumocystis jiroveci pneumonia in renal transplant recipients: P. jiroveci is contagious to the susceptible host. Transplantation 2009;88:380-5. https://doi.org/10.1097/TP.0b013e3181aed389
  56. de Boer MG, de Fijter JW, Kroon FP. Outbreaks and clustering of Pneumocystis pneumonia in kidney transplant recipients: a systematic review. Med Mycol 2011;49:673-80. https://doi.org/10.3109/13693786.2011.571294
  57. Matsumura Y, Shindo Y, Iinuma Y, Yamamoto M, Shirano M, Matsushima A, et al. Clinical characteristics of Pneumocystis pneumonia in non-HIV patients and prognostic factors including microbiological genotypes. BMC Infect Dis 2011;11:76. https://doi.org/10.1186/1471-2334-11-76

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