Pneumocystispneumonia (PCP) was historically one of the most common AIDS-defining illnesses among children, adolescents, and adults in high-income countries.[1]Palella FJ, Delaney KM, Moorman FC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998 Mar 26;338(13):853-60.
https://www.nejm.org/doi/10.1056/NEJM199803263381301?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
http://www.ncbi.nlm.nih.gov/pubmed/9516219?tool=bestpractice.com
In the era of combination antiretroviral therapy (ART), the incidence of opportunistic infections (including PCP) has declined.[2]Kaplan JE, Hanson D, Dworkin MS, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the US in the era of highly active antiretroviral therapy. Clin Infect Dis. 2000 Apr;30(suppl 1):S5-14.
https://academic.oup.com/cid/article/30/Supplement_1/S5/393485
http://www.ncbi.nlm.nih.gov/pubmed/10770911?tool=bestpractice.com
[3]Morris A, Lundgren JD, Masur H, et al. Current epidemiology of Pneumocystis pneumonia. Emerg Infect Dis. 2004 Oct;10(10):1713-20.
http://www.ncbi.nlm.nih.gov/pubmed/15504255?tool=bestpractice.com
[4]Low A, Gavriilidis G, Larke N, et al. Incidence of Opportunistic Infections and the Impact of Antiretroviral Therapy Among HIV-Infected Adults in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis. Clin Infect Dis. 2016 Jun 15;62(12):1595-1603.
https://www.doi.org/10.1093/cid/ciw125
http://www.ncbi.nlm.nih.gov/pubmed/26951573?tool=bestpractice.com
[5]Limper AH, Adenis A, Le T, et al. Fungal infections in HIV/AIDS. Lancet Infect Dis. 2017 Nov;17(11):e334-43.
https://www.doi.org/10.1016/S1473-3099(17)30303-1
http://www.ncbi.nlm.nih.gov/pubmed/28774701?tool=bestpractice.com
[6]Kolbrink B, Scheikholeslami-Sabzewari J, Borzikowsky C, et al. Evolving epidemiology of pneumocystis pneumonia: Findings from a longitudinal population-based study and a retrospective multi-center study in Germany. Lancet Reg Health Eur. 2022 Jul;18:100400.
https://www.doi.org/10.1016/j.lanepe.2022.100400
http://www.ncbi.nlm.nih.gov/pubmed/35814339?tool=bestpractice.com
The EuroSIDA study followed a cohort of more than 8500 HIV-positive patients in Europe, finding that incidence of PCP fell from 4.9 cases per 100 person-years before March 1995 to 0.3 cases per 100 person-years after March 1998.[7]Weverling GJ, Mocroft A, Ledergerber B, et al. Discontinuation of Pneumocystis carinii pneumonia prophylaxis after start of highly active antiretroviral therapy in HIV-1 infection. EuroSIDA Study Group. Lancet. 1999 Apr 17;353(9161):1293-8.
http://www.ncbi.nlm.nih.gov/pubmed/10218526?tool=bestpractice.com
Similarly, the NA-ACCORD study, which followed 16 cohorts of more than 80,000 HIV-positive patients from the US and Canada, observed a decrease in the incidence of PCP from 0.92 cases per 100 person-years in 2000 to 2003 to 0.39 in 2008 to 2010.[8]Buchacz K, Lau B, Jing Y, et al. Incidence of AIDS-defining opportunistic infections in a multicohort analysis of HIV-infected persons in the United States and Canada, 2000-2010. J Infect Dis. 2016 Sep 15;214(6):862-72.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996145
http://www.ncbi.nlm.nih.gov/pubmed/27559122?tool=bestpractice.com
However, PCP infection remains a common diagnosis in patients with HIV infection admitted to intensive care.[9]Turvey SL, Bagshaw SM, Eurich DT, et al. Epidemiology and Outcomes in Critically Ill Patients with Human Immunodeficiency Virus Infection in the Era of Combination Antiretroviral Therapy. Can J Infect Dis Med Microbiol. 2017;2017:7868954.
https://www.doi.org/10.1155/2017/7868954
http://www.ncbi.nlm.nih.gov/pubmed/28348607?tool=bestpractice.com
In an acute tertiary hospital in New York City (with a comprehensive outpatient HIV care programme), 4.8% of AIDS-related deaths between 2004 and 2008 were due to PCP.[10]Kim JH, Psevdos G Jr, Gonzalez E, et al. All-cause mortality in hospitalized HIV-infected patients at an acute tertiary care hospital with a comprehensive outpatient HIV care program in New York City in the era of highly active antiretroviral therapy (HAART). Infection. 2013 Apr;41(2):545-51.
http://www.ncbi.nlm.nih.gov/pubmed/23264096?tool=bestpractice.com
In HIV-positive adults, the greatest risk factor for developing PCP is a CD4 cell count <200 cells/microlitre, with risk increasing the lower the CD4 cell count falls below this level.[11]Phair J, Munoz A, Detels R, et al. The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. Multicenter AIDS Cohort Study Group. N Engl J Med. 1990 Jan 18;322(3):161-5.
http://www.ncbi.nlm.nih.gov/pubmed/1967190?tool=bestpractice.com
[12]Stansell JD, Osmond DH, Charlebois E, et al. Predictors of Pneumocystis carinii pneumonia in HIV-infected persons. Pulmonary Complications of HIV Infection Study Group. Am J Respir Crit Care Med. 1997 Jan;155(1):60-6.
http://www.ncbi.nlm.nih.gov/pubmed/9001290?tool=bestpractice.com
The risk of PCP is decreased if patients sustain increases in their CD4 cell count to more than 200 cells/microlitre with the use of ART. Thus, nowadays most cases of PCP occur in patients who are unaware of their HIV infection, those who do not seek medical care for HIV or do not use ART or PCP prophylaxis owing to nonadherence or intolerance, and those with advanced immunosuppression (i.e., CD4 counts <100 cells/microlitrr).[2]Kaplan JE, Hanson D, Dworkin MS, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the US in the era of highly active antiretroviral therapy. Clin Infect Dis. 2000 Apr;30(suppl 1):S5-14.
https://academic.oup.com/cid/article/30/Supplement_1/S5/393485
http://www.ncbi.nlm.nih.gov/pubmed/10770911?tool=bestpractice.com
[5]Limper AH, Adenis A, Le T, et al. Fungal infections in HIV/AIDS. Lancet Infect Dis. 2017 Nov;17(11):e334-43.
https://www.doi.org/10.1016/S1473-3099(17)30303-1
http://www.ncbi.nlm.nih.gov/pubmed/28774701?tool=bestpractice.com
[13]Pulvirenti J, Herrera P, Venkataraman P, et al. Pneumocystis carinii pneumonia in HIV-infected patients in the HAART era. AIDS Patient Care STDS. 2003 Jun;17(6):261-5.
http://www.ncbi.nlm.nih.gov/pubmed/12880489?tool=bestpractice.com
[14]Lundberg BE, Davidson AJ, Burman WJ. Epidemiology of Pneumocystis carinii pneumonia in an era of effective prophylaxis: the relative contribution of non-adherence and drug failure. AIDS. 2000 Nov 10;14(16):2559-66.
http://www.ncbi.nlm.nih.gov/pubmed/11101068?tool=bestpractice.com
[15]Huang L, Hecht FM. Why does Pneumocystis carinii pneumonia still occur? AIDS. 2000 Nov 10;14(16):2611-2.
http://www.ncbi.nlm.nih.gov/pubmed/11101076?tool=bestpractice.com
Between 2000 and 2013, a European study reported an increase in the age and proportion of patients in which an episode of PCP preceded HIV diagnosis (from 34 to 44 years, and from 48% to 67%, respectively).[16]López-Sánchez C, Falcó V, Burgos J, et al. Epidemiology and long-term survival in HIV-infected patients with Pneumocystis jirovecii pneumonia in the HAART era:experience in a university hospital and review of the literature. Medicine (Baltimore). 2015 Mar;94(12):e681.
http://journals.lww.com/md-journal/Fulltext/2015/03040/Epidemiology_and_Long_Term_Survival_in.14.aspx
http://www.ncbi.nlm.nih.gov/pubmed/25816039?tool=bestpractice.com
In the US, the prevalence of HIV infection may be under-estimated and, therefore, the incidence of the first episode of PCP may also be under-estimated, particularly in groups with poor access to health care.[17]Centers for Disease Control and Prevention (CDC). HIV prevalence estimates: United States, 2006. MMWR Morb Mortal Wkly Rep. 2008 Oct 3;57(39):1073-6.
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5739a2.htm
http://www.ncbi.nlm.nih.gov/pubmed/18830210?tool=bestpractice.com
Another group of patients at risk for PCP are HIV-positive refugees from low- and middle-income countries in whom it may be difficult to differentiate PCP from pulmonary tuberculosis infection or dual infection.[18]Fisk DT, Meshnick, S, Kazanjian PH. Pneumocystis carinii pneumonia in patients in the developing world who have acquired immunodeficiency syndrome. Clin Infect Dis. 2003 Jan 1;36(1):70-8.
http://www.ncbi.nlm.nih.gov/pubmed/12491205?tool=bestpractice.com
In children, the overall incidence of PCP has declined since the beginning of the HIV era, partly owing to improved antenatal HIV testing and use of HIV treatment to prevent vertical transmission of the virus, but also due to ART.[2]Kaplan JE, Hanson D, Dworkin MS, et al. Epidemiology of human immunodeficiency virus-associated opportunistic infections in the US in the era of highly active antiretroviral therapy. Clin Infect Dis. 2000 Apr;30(suppl 1):S5-14.
https://academic.oup.com/cid/article/30/Supplement_1/S5/393485
http://www.ncbi.nlm.nih.gov/pubmed/10770911?tool=bestpractice.com
[19]B-Lajoie MR, Drouin O, Bartlett G, et al. Incidence and Prevalence of Opportunistic and Other Infections and the Impact of Antiretroviral Therapy Among HIV-infected Children in Low- and Middle-income Countries: A Systematic Review and Meta-analysis. Clin Infect Dis. 2016 Jun 15;62(12):1586-1594.
https://www.doi.org/10.1093/cid/ciw139
http://www.ncbi.nlm.nih.gov/pubmed/27001796?tool=bestpractice.com
In the Perinatal AIDS Collaborative Transmission Study, the incidence of PCP in HIV-positive children dropped from 5.2 cases per 100 person-years during the pre-ART era to 0.3 cases per 100 person-years in the post-ART era.[20]Nesheim SR Kopogiannis BG, Soe SM, et al. Trends in opportunistic infections in the pre- and post-highly active antiretroviral therapy eras among HIV-infected children in the Perinatal AIDS Collaborative Transmission Study, 1986-2004. Pediatrics. 2007 Jul;120(1):100-9.
http://www.ncbi.nlm.nih.gov/pubmed/17606567?tool=bestpractice.com
In HIV-positive children, the highest rates of PCP occur in infants 3 to 6 months old. The risk of PCP is not related to CD4 cell counts in those under 6 years of age but rather relates to CD4 percentage. In children over 6 years old, CD4 cell count is related to PCP risk, similar to adults.[3]Morris A, Lundgren JD, Masur H, et al. Current epidemiology of Pneumocystis pneumonia. Emerg Infect Dis. 2004 Oct;10(10):1713-20.
http://www.ncbi.nlm.nih.gov/pubmed/15504255?tool=bestpractice.com
[21]Kovacs A, Frederick T, Church J, et al. CD4 T-lymphocyte counts and Pneumocystis carinii pneumonia in pediatric HIV infection. JAMA. 1991 Apr 3;265(13):1698-703.
http://www.ncbi.nlm.nih.gov/pubmed/1672169?tool=bestpractice.com
[22]National Institutes of Health, Centers for Disease Control and Prevention, HIV Medicine Association of the Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and American Academy of Pediatrics. Panel on Opportunistic Infections in Children with and Exposed to HIV. Guidelines for the prevention and treatment of opportunistic infections in children with and exposed to HIV: Pneumocystis jirovecii pneumonia. Nov 2013 [internet publication].
https://clinicalinfo.hiv.gov/en/guidelines/pediatric-opportunistic-infection/pneumocystis-jirovecii-pneumonia?view=full
PCP is an important opportunistic infection in HIV-positive children and adults in low- and middle-income countries although definitive pathogen identification may be challenging due to limited resources.[23]Lowe DM, Rangaka MX, Gordon F, et al. Pneumocystis jirovecii pneumonia in tropical and low and middle income countries: a systematic review and meta-regression. PLoS One. 2013;8(8):e69969.
https://www.doi.org/10.1371/journal.pone.0069969
http://www.ncbi.nlm.nih.gov/pubmed/23936365?tool=bestpractice.com
In HIV-negative patients, the overall incidence of PCP is low and occurs almost exclusively in patients who have other causes of immunocompromise.[24]Falagas ME, Manta KG, Betsi GI, et al. Infection-related morbidity and mortality in patients with connective tissue diseases: a systematic review. Clin Rheumatol. 2007 May;26(5):663-70.
http://www.ncbi.nlm.nih.gov/pubmed/17186117?tool=bestpractice.com
[25]Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc. 1996 Jan;71(1):5-13.
http://www.ncbi.nlm.nih.gov/pubmed/8538233?tool=bestpractice.com
[26]Fillatre P, Decaux O, Jouneau S, et al. Incidence of Pneumocystis jiroveci pneumonia among groups at risk in HIV-negative patients. Am J Med. 2014 Dec;127(12):1242.e11-7.
http://www.ncbi.nlm.nih.gov/pubmed/25058862?tool=bestpractice.com
[27]Bienvenu AL, Traore K, Plekhanova I, et al. Pneumocystis pneumonia suspected cases in 604 non-HIV and HIV patients. Int J Infect Dis. 2016 May;46:11-7.
http://www.ncbi.nlm.nih.gov/pubmed/27021532?tool=bestpractice.com
[28]Ling C, Qian S, Wang Q, et al. Pneumocystis pneumonia in non-HIV children: a 10-year retrospective study. Clin Respir J. 2018 Jan;12(1):16-22.
http://www.ncbi.nlm.nih.gov/pubmed/26878193?tool=bestpractice.com
While the incidence of PCP in HIV-positive patients decreased in England between 2000 and 2010 and in France between 2005 and 2013, PCP in HIV-negative patients increased over the same period.[29]Maini R, Henderson KL, Sheridan EA, et al. Increasing Pneumocystis pneumonia, England, UK, 2000-2010. Emerg Infect Dis. 2013 Mar;19(3):386-92.
http://wwwnc.cdc.gov/eid/article/19/3/12-1151_article.htm
http://www.ncbi.nlm.nih.gov/pubmed/23622345?tool=bestpractice.com
In this population, PCP occurs mainly in organ transplant recipients (7% to 43%), people with haematological malignancies (23% to 39%), people with solid malignancies (18% to 27%), and people with inflammatory conditions (11% to 27%).[26]Fillatre P, Decaux O, Jouneau S, et al. Incidence of Pneumocystis jiroveci pneumonia among groups at risk in HIV-negative patients. Am J Med. 2014 Dec;127(12):1242.e11-7.
http://www.ncbi.nlm.nih.gov/pubmed/25058862?tool=bestpractice.com
[27]Bienvenu AL, Traore K, Plekhanova I, et al. Pneumocystis pneumonia suspected cases in 604 non-HIV and HIV patients. Int J Infect Dis. 2016 May;46:11-7.
http://www.ncbi.nlm.nih.gov/pubmed/27021532?tool=bestpractice.com
A retrospective longitudinal population-based study in Germany found that the overall incidence of PCP increased between 2014 and 2019 from 2.3 cases per 100,000 people to 2.6 cases per 100,000 people. More than 80% of PCP cases occurred in HIV-negative patients. Although the number of cases among patients with HIV, haematologic malignancies, and transplants decreased over time, patients with solid malignancies experienced an increase in the annual number of cases, indicating that the distribution of underlying immunosuppressive diseases among incident PCP cases changed over time. Similar trends were identified for PCP-related deaths.[6]Kolbrink B, Scheikholeslami-Sabzewari J, Borzikowsky C, et al. Evolving epidemiology of pneumocystis pneumonia: Findings from a longitudinal population-based study and a retrospective multi-center study in Germany. Lancet Reg Health Eur. 2022 Jul;18:100400.
https://www.doi.org/10.1016/j.lanepe.2022.100400
http://www.ncbi.nlm.nih.gov/pubmed/35814339?tool=bestpractice.com
PCP has been reported in patients using tumour necrosis factor-alpha antagonists or the anti-CD20 monoclonal antibody, rituximab.[30]Martin-Garrido I, Carmona EM, Specks U, et al. Pneumocystis pneumonia in patients treated with rituximab. 2013 Jul;144(1):258-65.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694106
http://www.ncbi.nlm.nih.gov/pubmed/23258406?tool=bestpractice.com
[31]Stern A, Green H, Paul M, et al. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev. 2014 Oct 1;(10):CD005590.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005590.pub3/full
http://www.ncbi.nlm.nih.gov/pubmed/25269391?tool=bestpractice.com
PCP in the HIV-negative population is a more fulminant process and is associated with greater morbidity and mortality than in HIV-positive patients.[6]Kolbrink B, Scheikholeslami-Sabzewari J, Borzikowsky C, et al. Evolving epidemiology of pneumocystis pneumonia: Findings from a longitudinal population-based study and a retrospective multi-center study in Germany. Lancet Reg Health Eur. 2022 Jul;18:100400.
https://www.doi.org/10.1016/j.lanepe.2022.100400
http://www.ncbi.nlm.nih.gov/pubmed/35814339?tool=bestpractice.com
[27]Bienvenu AL, Traore K, Plekhanova I, et al. Pneumocystis pneumonia suspected cases in 604 non-HIV and HIV patients. Int J Infect Dis. 2016 May;46:11-7.
http://www.ncbi.nlm.nih.gov/pubmed/27021532?tool=bestpractice.com