Pneumocystis jirovecii Pneumonia: Epidemiology, Clinical Manifestation and Diagnosis
- 3 Downloads
Purpose of Review
The purpose of this study is to provide an understanding of the increased range of patient cohorts at risk of Pneumocystis jirovecii pneumonia (PCP) and describe typical clinical presentations together with advances in diagnostic assays and strategies.
The range of immuno-compromised patients at risk of PCP continues to expand. Apart from human immunodeficiency virus (HIV)-positive patients, those with solid tumours or suffering from haematological malignancy, solid organ transplant recipients or with autoimmune and inflammatory conditions receiving immuno-modulating therapies and patients diagnosed with primary immune deficiencies are all at increased risk of PCP. The clinical presentation of respiratory distress may be mild/moderate in the HIV-positive patient, but fulminant in HIV-negative. While typical clinical signs of PCP, along with underlying risk factors and the absence of alternative diagnoses, may be sufficient to commence therapy, every effort should be made to achieve a mycological diagnosis. With the advent of modern diagnostics techniques (real-time polymerase chain reaction (PCR) and (1-3)-β-D-Glucan), a laboratory-based diagnosis should always be attempted, although microscopic identification of Pneumocystis within respiratory samples remains the reference method. By combining different assays, it may be possible to both exclude and confirm PCP, without the need for invasive samples.
This review will summarize the epidemiology, clinical manifestations and diagnostic options for PCP, and also briefly cover therapeutic management, the emerging issue of resistance and PCP in paediatric age group.
KeywordsPneumocystis PCP Diagnosis Epidemiology Clinical presentation
Compliance with Ethical Standards
Conflict of Interest
P. Lewis White served on an advisory board for F2G and Gilead; received speakers’ honoraria from Gilead, MSD and BOPA; received funding for travel and meeting attendance from Gilead, Launch Diagnostics, BOPA and Bruker Diagnostics; received research funding from Bruker Diagnostics; received payment from F2G for providing diagnostic services and is a founding member of the European Aspergillus PCR initiative. Jessica Price and Matthijs Backx declare no conflicts of interest relevant to this manuscript.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 3.Pegorie M, Denning DW, Welfare W. Estimating the burden of invasive and serious fungal disease in the United Kingdom. J Inf Secur. 2016. https://doi.org/10.1016/j.jinf.2016.10.005.
- 8.Montesinos I, Delforge ML, Ajjaham F, Brancart F, Hites M, Jacobs F, et al. Evaluation of a new commercial real-time PCR assay for diagnosis of Pneumocystis jirovecii pneumonia and identification of dihydropteroate synthase (DHPS) mutations. Diagn Microbiol Infect Dis. 2017;87(1):32–6. https://doi.org/10.1016/j.diagmicrobio.2016.10.005.Google Scholar
- 9.Hay J, Osmond D, Jacobson M. Projecting the medical costs of AIDS and ARC in the United States. J Aquir Immune Defic Syndr. 1988;1(5):466–85.Google Scholar
- 10.Salzer HJF, Schäfer G, Hoenigl M, Günther G, Hoffmann C, Kalsdorf B, et al. Clinical, diagnostic, and treatment disparities between HIV-infected and non-HIV-infected immunocompromised patients with Pneumocystis jirovecii pneumonia. Respiration. 2018;96(1):52–65. https://doi.org/10.1159/000487713.Google Scholar
- 12.Lee HY, Choi SH, Kim T, Chang J, Kim SH, Lee SO, et al. Epidemiologic trends and clinical features of Pneumocystis jirovecii pneumonia in non-HIV patients in a tertiary-care hospital in Korea over a 15-year-period. Jpn J Infect Dis. 2019. https://doi.org/10.7883/yoken.JJID.2018.400.
- 15.Amber K, Lamberts A, Solimani F, Agnoletti A, Didona D, Euverman I, et al. Determining the incidence of Pneumocystis pneumonia in patients with autoimmune blistering diseases not receiving routine prophylaxis. JAMA Dermatol. 2017;153(11):1137. https://doi.org/10.1001/jamadermatol.2017.2808.Google Scholar
- 18.Redjoul R, Robin C, Foulet F, Leclerc M, Beckerich F, Cabanne L, et al. Pneumocystis jirovecii pneumonia prophylaxis in allogeneic hematopoietic cell transplant recipients: can we always follow the guidelines? Bone Marrow Transplant. 2018. https://doi.org/10.1038/s41409-018-0391-2.
- 19.Maschmeyer G, Helweg-Larsen J, Pagano L, Robin C, Cordonnier C, Schellongowski P. 6th European Conference on Infections in Leukemia (ECIL-6), a joint venture of The European Group for Blood and Marrow Transplantation (EBMT), The European Organization for Research and Treatment of Cancer (EORTC), the International Immunocompromised Host Society (ICHS) and The European LeukemiaNet (ELN). ECIL guidelines for treatment of Pneumocystis jirovecii pneumonia in non-HIV-infected haematology patients. J Antimicrob Chemother. 2016;71(9):2405–13. https://doi.org/10.1093/jac/dkw158.Google Scholar
- 20.Shimada K, Yokosuka K, Nunokawa T, Sugii S. Differences in clinical Pneumocystis pneumonia in rheumatoid arthritis and other connective tissue diseases suggesting a rheumatoid-specific interstitial lung injury spectrum. Clin Rheumatol. 2018;37(8):2269–74. https://doi.org/10.1007/s10067-018-4157-4.Google Scholar
- 26.Garg N, Jorgenson M, Descourouez J, Saddler C, Parajuli S, Astor B, et al. Pneumocystis jiroveci pneumonia in kidney and simultaneous pancreas kidney transplant recipients in the present era of routine post-transplant prophylaxis: risk factors and outcomes. BMC Nephrol. 2018;19(1):332. https://doi.org/10.1186/s12882-018-1142-8.Google Scholar
- 31.Vogel MN, Brodoefel H, Hierl T, Beck R, Bethge WA, Claussen CD, et al. Differences and similarities of cytomegalovirus and Pneumocystis pneumonia in HIV-negative immunocompromised patients thin section CT morphology in the early phase of the disease. Br J Radiol. 2007;80(955):516–23. https://doi.org/10.1259/bjr/39696316.Google Scholar
- 32.Hidalgo A, Falcó V, Mauleón S, Andreu J, Crespo M, Ribera E, et al. Accuracy of high-resolution CT in distinguishing between Pneumocystis carinii pneumonia and non-Pneumocystis carinii pneumonia in AIDS patients. Eur Radiol. 2003;13(5):1179–84. https://doi.org/10.1007/s00330-002-1641-6.Google Scholar
- 34.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(10):915–23. https://doi.org/10.2169/internalmedicine.47.0702.Google Scholar
- 35.Block B, Mehta T, Ortiz G, Ferris S, Vu T, Huang L, et al. Unusual radiographic presentation of Pneumocystis pneumonia in a patient with AIDS. Case Rep Infect Dis. 2017:3183525. https://doi.org/10.1155/2017/3183525.
- 36.• Cereser L, Dallorto A, Candoni A, Volpetti S, Righi E, Zuiani C, et al. Pneumocystis jirovecii pneumonia at chest high-resolution computed tomography (HRCT) in non-HIV immunocompromised patients: spectrum of findings and mimickers. Eur J Radiol. 2019;116:116–27. https://doi.org/10.1016/j.ejrad.2019.04.025 Excellent summary of the typical PcP chest radiology in HIV-negative, important given the increasing incidence of disease in this cohort. Google Scholar
- 39.Onishi A, Sugiyama D, Kogata Y, Saegusa J, Sugimoto T, Kawano S, et al. Diagnostic accuracy of serum 1,3-β-D-Glucan for Pneumocystis jiroveci pneumonia, invasive Candidiasis, and invasive Aspergillosis: systematic review and meta-Analysis. J Clin Microbiol. 2012;50(1):7–15. https://doi.org/10.1128/JCM.05267-11.Google Scholar
- 40.Li WJ, Guo YL, Liu TJ, Wang K, Kong JL. Diagnosis of pneumocystis pneumonia using serum (1-3)-β-D-Glucan:a bivariate meta-analysis and systematic review. Thorac Dis. 2015;7(12):2214–25. https://doi.org/10.3978/j.issn.2072-1439.2015.12.27.Google Scholar
- 41.Summah H, Zhu Y-G, Falagas ME, Vouloumanou EK, Qu J-M. Use of real-time polymerase chain reaction for the diagnosis of Pneumocystis pneumonia in immunocompromised patients: a meta-analysis. Chin Med J. 2013;126:1965–73.Google Scholar
- 46.Deng C, Li Y, Li Y. Systemic review: the accuracy of lactic dehydrogenase in the diagnosis of Pneumocystis pneumonia. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2018;30(4):322–6. https://doi.org/10.3760/cma.j.issn.2095-4352.2018.04.007.Google Scholar
- 47.Nyamande K, Lalloo UG. Serum procalcitonin distinguishes CAP due to bacteria, Mycobacterium tuberculosis and PJP. Int J Tuberc Lung Dis. 2006;10:510–5.Google Scholar
- 48.Mendelson F, Griesel R, Tiffin N, Rangaka M, Boulle A, Mendelson M, et al. C-reactive protein and procalcitonin to discriminate between tuberculosis, Pneumocystis jirovecii pneumonia, and bacterial pneumonia in HIV-infected inpatients meeting WHO criteria for seriously ill: a prospective cohort study. BMC Infect Dis. 2018;18(1):399. https://doi.org/10.1186/s12879-018-3303-6.Google Scholar
- 51.• Alanio A, Hauser PM, Lagrou K, Melchers WJ, Helweg-Larsen J, Matos O, et al. ECIL guidelines for the diagnosis of Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother. 2016;71(9):2386–96. https://doi.org/10.1093/jac/dkw156 Provides a well thought diagnostic algorithm using both invasive and non-invasive samples that is applicable to all patient populations. Google Scholar
- 52.Cruciani M, Marcati P, Malena M, et al. Meta-analysis of diagnostic procedures for Pneumocystis carnii pneumonia in HIV-1-infected patients. Eur Respir J. 2002;20:982–9.Google Scholar
- 53.• Guegan H, Robert-Gangneux F. Molecular diagnosis of Pneumocystis pneumonia in immunocompromised patients. Curr Opin Infect Dis. 2019;32(4):314–21. https://doi.org/10.1097/QCO.0000000000000559 Excellent overview of the molecular diagnosis of PcP, the likely future reference method for diagnosis. Google Scholar
- 54.Fraczek M, Ahmad S, Richardson M, Kirwan M, Bowyer P, Denning D, et al. Detection of Pneumocystis jirovecii by quantitative real-time PCR in oral rinses from Pneumocystis pneumonia asymptomatic human immunodeficiency virus patients. J Mycol Méd. 2019;29(2):107–11. https://doi.org/10.1016/j.mycmed.2019.04.001.Google Scholar
- 55.Wang M, Dai X, Huang Y, Sun J, Dong X, Guo Y, et al. The presence of Pneumocystis jirovecii DNA in plasma is associated with a higher mortality rate in patients with AIDS-associated Pneumocystis pneumonia. Med Mycol. 2018. https://doi.org/10.1093/mmy/myy110.
- 57.Roger PM, Vandenbos F, Pugliese P, De Salvador F, Durant J, Le Fichoux Y, et al. Persistence of Pneumocystis carinii after effective treatment of P. carinii pneumonia is not related to relapse or survival among patients infected with human immunodeficiency virus infection. Clin Infect Dis. 1998;26(2):509–10. https://doi.org/10.1086/517099.Google Scholar
- 58.Matsumura Y, Tsuchido Y, Yamamoto M, Nakano S, Nagao M. Development of a fully automated PCR assay for the detection of Pneumocystis jirovecii using the GENECUBE system. Med Mycol. 2018. https://doi.org/10.1093/mmy/myy145.
- 60.Lee CH, Helweg-Larsen J, Tang X, Jin S, Li B, Bartlett MS, et al. Update on Pneumocystis carinii f. sp. hominis typing based on nucleotide sequence variations in internal transcribed spacer regions of rRNA genes. J Clin Microbiol. 1998;36(3):734–41.Google Scholar
- 63.Gits-Muselli M, Peraldi MN, de Castro N, Delcey V, Menotti J, Guigue N, et al. New short tandem repeat-based molecular typing method for Pneumocystis jirovecii reveals intrahospital transmission between patients from different wards. PLoS One. 2015;10(5):e0125763. https://doi.org/10.1371/journal.pone.0125763.Google Scholar
- 68.Damiani C, Le Gal S, Da Costa C, Virmaux M, Nevez G, Totet A. Combined quantification of pulmonary Pneumocystis jirovecii DNA and serum (1-3)-β-D-glucan for differential diagnosis of pneumocystis pneumonia and Pneumocystis colonisation. J Clin Microbiol. 2013;51:3380–8. https://doi.org/10.1128/JCM.01554-13.Google Scholar
- 69.de Boer MG, Gelinck LB, van Zelst BD, van de Sande WW, Willems LN, van Dissel JT, et al. β-D-glucan and S-adenosylmethionine serum levels for the diagnosis of Pneumocystis pneumonia in HIV-negative patients: a prospective study. J Inf Secur. 2011;62(1):93–100. https://doi.org/10.1016/j.jinf.2010.10.007.Google Scholar
- 72.Rautemaa V, Green HD, Jones AM, Rautemaa-Richardson R. High level of β-(1,3)-d-glucan antigenaemia in cystic fibrosis in the absence of invasive fungal disease. Diagn Microbiol Infect Dis. 2017;88(4):316–21. https://doi.org/10.1016/j.diagmicrobio.2017.05.010.Google Scholar
- 74.Esteves F, Lee CH, deSousa B, Badura R, Seringa M, Fernandes C, et al. (1-3)-beta-D-glucan in association with lactate dehydrogenase as biomarkers of Pneumocystis pneumonia (PcP) in HIV-infected patients. Eur J Clin Microbiol Infect Dis. 2014;33(7):1173–80. https://doi.org/10.1007/s10096-014-2054-6.Google Scholar
- 76.Maartens G, Stewart A, Griesel R, Kengne A, Dube F, Nicol M, et al. Development of a clinical prediction rule to diagnose Pneumocystis jirovecii pneumonia in the World Health Organization’s algorithm for seriously ill HIV-infected patients. S Afr J HIV Med. 2018;19(1):851. https://doi.org/10.4102/sajhivmed.v19i1.851.Google Scholar
- 77.Azoulay E, Roux A, Vincent F, Kouatchet A, Argaud L, Rabbat A, et al. A Multivariable prediction model for Pneumocystis jirovecii Pneumonia in hematology patients with acute respiratory failure. Am J Respir Crit Care Med. 2018;198(12):1519–26. https://doi.org/10.1164/rccm.201712-2452OC.Google Scholar
- 80.Baddley JW, Winthrop KL, Chen L, Liu L, Grijalva CG, Delzell E, et al. Non-viral opportunistic infections in new users of tumour necrosis factor inhibitor therapy: results of the SAfety Assessment of Biologic ThERapy (SABER) Study. Ann Rheum Dis. 2014;73:1942–8. https://doi.org/10.1136/annrheumdis-2013-203407.Google Scholar
- 81.Park JW, Curtis JR, Moon J, Song YW, Kim S, Lee EB. Prophylactic effect of trimethoprim-sulfamethoxazole for pneumocystis pneumonia in patients with rheumatic diseases exposed to prolonged high-dose glucocorticoids. Ann Rheum Dis. 2018;77(5):644–9. https://doi.org/10.1136/annrheumdis-2017-211796.Google Scholar
- 82.Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. Accessed 11/09/2018, Page numbers B-1 to B-16.Google Scholar
- 86.• Injean P, Eells SJ, Wu H, McElroy I, Gregson AL, McKinnell JA. A systematic review and meta-analysis of the data behind current recommendations for corticosteroids in non-HIV-related PCP: knowing when you are on shaky foundations. Transplant Direct. 2017;3(3):e137. https://doi.org/10.1097/TXD.0000000000000642 Provides up-to-date information on the limitations and risks of using corticosteroids in the HIV-negative patient with PcP. Google Scholar
- 87.•• Yiannakis EP, Boswell TC. Systematic review of outbreaks of Pneumocystis jirovecii pneumonia: evidence that P. jirovecii is a transmissible organism and the implications for healthcare infection control. J Hosp Infect. 2016;93(1):1–8. https://doi.org/10.1016/j.jhin.2016.01.018 Extensive review of PcP outbreaks, but also provides much needed infection control and outbreak advice. Google Scholar
- 91.Argy N, Le Gal S, Coppée R, Song Z, Vindrios W, Massias L, et al. Pneumocystis Cytochrome b mutants associated with atovaquone prophylaxis failure as the cause of Pneumocystis infection outbreak among heart transplant recipients. Clin Infect Dis. 2018;67(6):913–9. https://doi.org/10.1093/cid/ciy154.Google Scholar
- 93.Ponce CA, Chabé M, George C, Cárdenas A, Durán L, Guerrero J, et al. High prevalence of Pneumocystis jirovecii dihydropteroate synthase gene mutations in patients with a first episode of Pneumocystis pneumonia in Santiago, Chile, and clinical response to trimethoprim-sulfamethoxazole therapy. Antimicrob Agents Chemother. 2017;61(2):e01290–16. https://doi.org/10.1128/AAC.01290-16.Google Scholar
- 94.Hauser PM, Nahimana A, Taffe P, Weber R, Francioli P, Bille J, et al. Interhuman transmission as a potential key parameter for geographical variation in the prevalence of Pneumocystis jirovecii dihydropteroate synthase mutations. Clin Infect Dis. 2010;51(4):e28–33. https://doi.org/10.1086/655145.Google Scholar
- 96.Panel on Opportunistic Infections in HIV-exposed and HIV-Infected children. Guidelines for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-Infected children. Department of Health and Human Services. Accessed 11/10/2016, Page numbers W-1 to W-16.Google Scholar
- 97.Basiaga ML, Ross ME, Gerber JS, Ogdie A. Incidence of Pneumocystis jirovecii and adverse events associated With Pneumocystis prophylaxis in children receiving glucocorticoids. J Pediatr Infect Dis Soc. 2018, 7(4):283–9. https://doi.org/10.1093/jpids/pix052.
- 98.• Katragkou A, Fisher BT, Groll AH, Roilides E, Walsh TJ. Diagnostic imaging and invasive fungal diseases in children. J Pediatr Infect Dis Soc. 2017;1(6):S22–31. https://doi.org/10.1093/jpids/pix055 Good overview of typical paediatric radiology associated with invasive fungal disease. Google Scholar