Pneumocystis pneumonia in HIV-negative adults: missed opportunities for prevention
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Pneumocystis pneumonia (PCP), caused by the opportunistic fungus Pneumocystis jirovecii, is almost exclusively a disease of the immunocompromised.1 While PCP is most recognised as an AIDS-defining condition, it also occurs in HIV-negative immunocompromised patients. In this population, PCP is associated with poorer outcomes compared to HIV-positive patients, with a higher rate of fulminant respiratory failure and mortality of approximately 30%.2
Given the potential severity of PCP in HIV-negative immunocompromised patients, antimicrobial prophylaxis is crucial for those at highest risk. Trimethoprim-sulfamethoxazole (TMP-SMX) reduces the incidence of PCP by 85% and PCP-related mortality by 83% in this population, and is usually well tolerated.3 For patients with hypersensitivity to TMP-SMX, desensitisation or a graded challenge to this drug can be attempted in many instances.4 Alternatively, a second-line drug such as dapsone, atovaquone or nebulised pentamidine can be used, although their efficacy is inferior to TMP-SMX.1
For HIV-negative adults, the benefits of TMP-SMX prophylaxis outweigh the risks of adverse events when the risk of PCP exceeds 3.5% for the period of the patient’s immunocompromise.5 For patients with malignancy, stem cell transplantation (SCT) and solid organ transplantation, guidelines for PCP prophylaxis have been published by several authoritative bodies.6–9 Guidelines have not been published for patients with rheumatologic diseases and other diseases requiring immunosuppressive drugs, although some authors have proposed indications for PCP prophylaxis for these patients.3,10–14 A summary of commonly proposed indications for PCP prophylaxis are presented in Table 1.
Table 1: Commonly proposed indications for PCP prophylaxis in HIV-negative adult patients.
Polymerase chain reaction (PCR) is an important diagnostic tool for PCP in HIV-negative patients. PCR detects small amounts of Pneumocystis DNA in lower respiratory tract specimens and has far greater sensitivity in HIV-negative patients than immunofluorescent staining.1 However, PCR also detects asymptomatic airway colonisation with Pneumocystis; this is common in patients with chronic lung diseases but has not been definitively linked with risk of developing PCP.15 In the Auckland region, clinicians can request an Atypical Pneumonia PCR Panel16 on lower respiratory tract specimens that indiscriminately tests for multiple pathogens including Pneumocystis, and therefore a positive Pneumocystis result may be obtained in a patient who clinically does not have PCP. Consequently, a diagnosis of PCP requires a consistent clinical syndrome in addition to a positive PCR.1
Cases of PCP have been described among patients who were not prescribed prophylaxis despite having a commonly proposed indication for this.17,18 For these patients, it is very likely that PCP would have been prevented if prophylaxis was prescribed. In our hospitals, there are no general policies for PCP prophylaxis outside of solid organ and stem cell transplantation and for specific chemotherapy regimens, and we therefore hypothesised that potentially preventable cases of PCP may be occurring. Our study aimed to determine the incidence of PCP among HIV-negative patients from three hospitals in Auckland, New Zealand that would have been potentially preventable if prophylaxis had been prescribed according to the commonly proposed indications in Table 1.
Methods
We conducted a retrospective observational study of all HIV-negative patients aged >16 years old who were admitted to Middlemore Hospital (MMH), North Shore Hospital (NSH) or Waitakere Hospital (WTH) between January 2011 and June 2017 and had a positive Pneumocystis PCR on lower respiratory tract specimens. Patients were identified by searching the laboratory database at MMH, where PCR testing for all study sites was performed using an 8-plex Atypical Pneumonia PCR panel (AusDiagnostics, Mascot NSW, Australia).16 Curves with a cycle threshold of <32 in step 2 of the AusDiagnostics assay were reported as positive.
Patients with a positive PCR were classified clinically into two groups: those with probable PCP, and those with probable asymptomatic Pneumocystis colonisation. This classification was determined by reviewing clinical records to ascertain the impression of the clinicians caring for the patient at the time. Patients were classified as probable PCP if their clinicians thought their presentation was consistent with PCP or if they were given PCP treatment. Patients were classified as probable asymptomatic colonisation if their clinicians thought their presentation was not consistent with PCP.We collected data from clinical records on patient demographics and diagnoses of immunosuppressive conditions and chronic lung diseases (defined as bronchiectasis, chronic obstructive pulmonary disease, interstitial lung disease and lung cancer). We also collected laboratory data for immunofluorescent staining (with >5 cysts seen defined as positive). Dispensing records were reviewed for immunosuppressive drugs; for corticosteroids, we classified courses as either short (<4 weeks) or long (>4 weeks). For long courses of corticosteroids, we calculated the average daily dose of prednisone during the month prior to the positive PCR; for patients receiving dexamethasone, we converted this to an equivalent prednisone dose using a ratio of 0.75mg of dexamethasone to 5mg of prednisone.19 Dispensing records were also reviewed for TMP-SMX, dapsone and atovaquone, and we assumed that these were prescribed for PCP prophylaxis if dispensed for >4 weeks. Medication charts were reviewed to identify patients receiving nebulised pentamidine.
For patients with PCP, we classified their infection as potentially preventable if they had a commonly proposed indication for prophylaxis in Table 1 but had not been prescribed this. For patients receiving chemotherapy regimens not listed in Table 1, we classified PCP as potentially preventable if the treating hospital’s protocol for that chemotherapy regimen recommended PCP prophylaxis but this had not been prescribed.
Ethical approval was obtained from the research offices of the involved hospitals. Informed consent was not deemed necessary because our study was retrospective and no identifying characteristics were reported in our findings that could deanonymise patients. Fisher’s exact test was used for analysis of 2x2 contingency tables and a two-tailed t-test was used for comparison of means; a p-value <0.05 was deemed significant.
Results
A total of 217 patients with a positive Pneumocystis PCR were identified (Table 2). Of these, 108 patients (49.8%) had probable PCP and 109 patients (50.2%) had probable asymptomatic Pneumocystis colonisation. Those with probable PCP had a higher overall 30-day mortality than those classified as colonised (32.4% vs 16.5%, p=0.007). No patients classified as colonised subsequently developed PCP during the study period.
Table 2: Characteristics of patients with PCP and patients with Pneumocystis colonisation.
Of the 108 patients with PCP, 33/108 (30.6%) had a commonly proposed indication for prophylaxis as described in Table 1. No patient in this group had been prescribed prophylaxis, therefore all had potentially preventable infection. Of the patients with potentially preventable infection, 14/33 (42.4%) died within 30 days of the diagnosis of PCP. For no patient was it documented in the clinical record that prophylaxis was not prescribed due to a contraindication or concern about adverse effects.
The category of medical condition causing immunosuppression and/or requiring immunosuppressive drugs is shown in Table 3. Of the patients with solid organ malignancy, 17/26 (65.4%) had a commonly proposed indication for prophylaxis. This sub-group accounted for the majority of those with potentially preventable PCP (17/33, 51.5%). There were 22/26 patients (84.6%) with solid organ malignancy who had been prescribed long-course corticosteroids (average prednisone dose 42mg/day). In the three months prior to diagnosis of PCP, 8/26 patients (30.8%) had received chemotherapy and 12/26 patients (46.2%) had received radiotherapy.
Table 3: Condition causing immunosuppression and/or requiring immunosuppressive drugs in patients with PCP.
Of the 24 patients with haematologic malignancy and/or SCT, 10/24 (41.7%) had a commonly proposed indication for prophylaxis. This sub-group accounted for the second largest group with potentially preventable PCP (10/33, 30.3%). There were 14/24 patients (58.3%) with haematologic malignancy and/or SCT who had been prescribed long-course corticosteroids (average prednisone dose 23mg/day), and 3/24 (12.5%) who had undergone SCT. One patient with hematologic malignancy developed PCP despite prophylaxis; this patient was receiving nebulised pentamidine but did not have a commonly proposed indication for prophylaxis.
Of the 108 patients with PCP, 75/108 (69.4%) did not have a commonly proposed indication for prophylaxis. Patients with rheumatologic disease were the largest contributor to this group (27/75, 36%), followed by patients with haematologic malignancy and/or SCT (14/75, 18.7%) and respiratory disease (12/75, 16%). Of those with rheumatologic disease, 12/30 (40%) had rheumatoid arthritis (RA). No patient with RA had a commonly proposed indication for prophylaxis and only 5/12 (41.7%) had been prescribed long-course corticosteroids (average prednisone dose 9mg/day). All patients with RA were prescribed non-corticosteroid immunosuppressive drugs, with a median of three drugs. Among those with respiratory disease, most had interstitial lung disease (9/12, 75%), and most (8/12, 66.7%) had been prescribed long-course corticosteroids (average prednisone dose 23mg/day).
Discussion
Our study demonstrates that there is a substantial burden of potentially preventable PCP and PCP-related mortality among HIV-negative patients in the Auckland region. In our cohort, 33/108 patients (30.6%) had a commonly proposed indication for prophylaxis but had not been prescribed this, and 14/33 (42.4%) of these patients died within 30 days of their PCP diagnosis. Assuming that TMP-SMX prophylaxis reduces the incidence of PCP by 85% and PCP-related mortality by 83%,3 we estimate that 28 cases of PCP and 12 deaths could have been prevented over the 78-month duration of our study if TMP-SMX was prescribed according to the commonly proposed indications in Table 1.
For patients with solid organ or haematologic malignancies, consensus guidelines provide unambiguous indications for PCP prophylaxis.6,7,9 Despite this, the vast majority of potentially preventable PCP in our cohort occurred in patients with solid organ or haematologic malignancy (27/33, 81.8%). This finding suggests that suboptimal guideline adherence is a cause of poor outcomes among these patients. To improve outcomes, we firstly recommend that clinicians who care for patients with solid organ or haematologic malignancies familiarise themselves with guidelines for PCP prophylaxis, particularly if prescribing prolonged corticosteroid courses to these high-risk patients. Secondly, we recommend that clinicians should be aware of options for PCP prophylaxis in patients with hypersensitivity or other contraindications to TMP-SMX, including desensitisation or graded challenge to TMP-SMX or the use of second-line drugs such as dapsone, atovaquone and nebulised pentamidine.1,4 Thirdly, we recommend that departments develop local policies to assist clinicians in prescribing PCP prophylaxis and to raise awareness of potentially preventable PCP. This applies not only to oncology and haematology, but also to specialities such as general medicine, respiratory medicine and neurosurgery, who are often the first to diagnose malignancy and initiate corticosteroids prior to cancer specialists taking over care of the patient. Finally, when cases of potentially preventable PCP occur, we recommend that these events are critically reviewed for the purposes of clinician education and to identify changes that can be implemented to reduce risk to future patients.
Although we identified many cases of PCP in patients with rheumatologic disease, only 3/30 (10%) had a commonly proposed indication for prophylaxis. Assessing PCP risk in patients with rheumatologic disease is challenging, due to a complex interaction of risk factors including the specific rheumatologic disease, disease activity, age, lymphopaenia, current and past corticosteroid use and the use of non-corticosteroid immunosuppressive drugs, some of which pose a greater risk of PCP compared to others.14,20,21 While some authors have proposed approaches to PCP prophylaxis in patients with rheumatologic diseases,13,14 there is a pressing need for evidence-based guidelines to clearly define which patients with rheumatologic and other autoimmune diseases will benefit from prophylaxis.
To the best of our knowledge, this is the largest study of HIV-negative patients with PCP in New Zealand.23,24 However, our study has several limitations. Firstly, we did not have a control group of patients who had indications for PCP prophylaxis but did not develop PCP; therefore, we were unable to estimate the overall incidence of PCP in this population. This would have been helpful to confirm whether the indications in Table 1 accurately predict the threshold at which the benefits of prophylaxis outweigh the harms. Secondly, no specific diagnostic criteria were used to classify patients as having PCP or asymptomatic colonisation. While none of the colonised group developed PCP, it is possible that some colonised patients were incorrectly classified as having PCP. Finally, because we only identified patients with a positive PCR, we were not able to include those who were diagnosed with PCP on clinical grounds alone or those who died before diagnostic testing.
In conclusion, the incidence of potentially preventable PCP and PCP-related mortality in the Auckland region is considerable. These events are mostly occurring among patients with solid organ and haematologic malignancies receiving high-dose corticosteroids for >4 weeks, and could be substantially reduced by prescribing prophylaxis to these patients according to guidelines. Patients with rheumatologic diseases also account for a significant proportion of those with PCP in the Auckland region, but reducing the occurrence of PCP in this group will remain challenging until publication of rheumatology-specific guidelines for PCP prophylaxis.
Summary
Abstract
Aim
Pneumocystis pneumonia (PCP) has a high mortality rate in HIV-negative immunocompromised patients, but is preventable with antimicrobial prophylaxis. We aimed to determine the incidence of PCP in three hospitals in Auckland, New Zealand that would have been potentially preventable if patients had been prescribed prophylaxis according to commonly proposed indications.
Method
We conducted a retrospective study of HIV-negative adults with PCP who were admitted to Middlemore, North Shore or Waitakere Hospitals between January 2011 and June 2017. We classified their PCP as potentially preventable if they had not been prescribed prophylaxis despite having a commonly proposed indication for this.
Results
Of the 108 patients with PCP, 33/108 (30.6%) had potentially preventable infection. Of these, 14/33 (42.4%) died within 30 days of diagnosis of PCP. Most potentially preventable infections occurred in patients with solid organ or haematologic malignancies who were receiving high-dose corticosteroids for >4 weeks. We estimate that 28 cases of PCP and 12 deaths could have been prevented over the study duration if prophylaxis was prescribed to those with commonly proposed indications.
Conclusion
There is a substantial incidence of potentially preventable PCP and PCP-related mortality in the Auckland region. This could be reduced by greater clinician familiarity with commonly proposed indications for PCP prophylaxis, particularly for clinicians prescribing prolonged corticosteroid courses to patients with malignancies.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1. Carmona EM, Limper AH. Update on the diagnosis and treatment of Pneumocystis pneumonia. Ther Adv Respir Dis. 2011; 5(1):41–59.
2. Liu Y, Su L, Jiang S, Qu H. Risk factors for mortality from Pneumocystis carinii pneumonia (PCP) in non-HIV patients: a meta-analysis. Oncotarget. 2017; 8(35):59729–39.
3. Stern A, Green H, Paul M, et al. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev. 2014(10):CD005590.
4. Gluckstein D, Ruskin J. Rapid oral desensitization to trimethoprim-sulfamethoxazole (TMP-SMZ): use in prophylaxis for Pneumocystis carinii pneumonia in patients with AIDS who were previously intolerant to TMP-SMZ. Clin Infect Dis. 1995; 20(4):849–53.
5. Green H, Paul M, Vidal L, Leibovici L. Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc. 2007; 82(9):1052–9.
6. Cooley L, Dendle C, Wolf J, et al. Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014. Intern Med J. 2014; 44(12b):1350–63.
7. Maertens J, Cesaro S, Maschmeyer G, et al. ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother. 2016; 71(9):2397–404.
8. Martin SI, Fishman JA, AST Infectious Diseases Community of Practice. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant. 2013; 13 Suppl 4:272–9.
9. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009; 15(10):1143–238.
10. Limper AH, Knox KS, Sarosi GA, 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(1):96–128.
11. Sepkowitz KA. Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome: who should receive prophylaxis? Mayo Clin Proc. 1996; 71(1):102–3.
12. Carmona EM, Limper AH. Update on the diagnosis and treatment of Pneumocystis pneumonia. Ther Adv Respir Dis. 2010; 5(1):41–59.
13. Winthrop KL, Baddley JW. Pneumocystis and glucocorticoid use: to prophylax or not to prophylax (and when?); that is the question. Ann Rheum Dis. 2018; 77(5):631–3.
14. Wolfe RM, Peacock JE, Jr. Pneumocystis pneumonia and the rheumatologist: which patients are at risk and how can PCP be prevented? Curr Rheumatol Rep. 2017; 19(6):35.
15. Morris A, Norris KA. Colonization by Pneumocystis jirovecii and its role in disease. Clin Microbiol Rev. 2012; 25(2):297–317.
16. AusDiagnostics Pty Ltd [homepage on the Internet]. Respiratory pathogens [cited 2020 22 Mar]. Available from: http://www.ausdiagnostics.com/respiratory-pathogens.html
17. Plakke MJ, Jalota L, Lloyd BJ. Pneumocystis pneumonia in a non-HIV patient on chronic corticosteroid therapy: a question of prophylaxis. BMJ Case Rep. 2013; 2013:bcr2012007912.
18. Yamaguchi T, Nagai Y, Morita T, et al. Pneumocystis pneumonia in patients treated with long-term steroid therapy for symptom palliation: a neglected infection in palliative care. Am J Hosp Palliat Care. 2014; 31(8):857–61.
19. Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet. 2005; 44(1):61–98.
20. Park JW, Curtis JR, Moon J, et al. 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.
21. Hashimoto A, Suto S, Horie K, et al. Incidence and risk factors for infections requiring hospitalization, including Pneumocystis pneumonia, in Japanese patients with rheumatoid arthritis. Int J Rheumatol. 2017; 2017:6730812-.
22. Katsuyama T, Saito K, Kubo S, et al. Prophylaxis for Pneumocystis pneumonia in patients with rheumatoid arthritis treated with biologics, based on risk factors found in a retrospective study. Arthritis Res Ther. 2014; 16(1):R43–R.
23. Meuli K, Chapman P, O’Donnell J, et al. Audit of Pneumocystis pneumonia in patients seen by the Christchurch Hospital rheumatology service over a 5-year period. Intern Med J. 2007; 37(10):687–92.
24. Carter JM, Town GI, Fisher M, et al. Management of Pneumocystis carinii pneumonia in the immunocompromised host. N Z Med J. 1988; 101(850):471–5.
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Pneumocystis pneumonia in HIV-negative adults: missed opportunities for prevention
View Article PDF
Pneumocystis pneumonia (PCP), caused by the opportunistic fungus Pneumocystis jirovecii, is almost exclusively a disease of the immunocompromised.1 While PCP is most recognised as an AIDS-defining condition, it also occurs in HIV-negative immunocompromised patients. In this population, PCP is associated with poorer outcomes compared to HIV-positive patients, with a higher rate of fulminant respiratory failure and mortality of approximately 30%.2
Given the potential severity of PCP in HIV-negative immunocompromised patients, antimicrobial prophylaxis is crucial for those at highest risk. Trimethoprim-sulfamethoxazole (TMP-SMX) reduces the incidence of PCP by 85% and PCP-related mortality by 83% in this population, and is usually well tolerated.3 For patients with hypersensitivity to TMP-SMX, desensitisation or a graded challenge to this drug can be attempted in many instances.4 Alternatively, a second-line drug such as dapsone, atovaquone or nebulised pentamidine can be used, although their efficacy is inferior to TMP-SMX.1
For HIV-negative adults, the benefits of TMP-SMX prophylaxis outweigh the risks of adverse events when the risk of PCP exceeds 3.5% for the period of the patient’s immunocompromise.5 For patients with malignancy, stem cell transplantation (SCT) and solid organ transplantation, guidelines for PCP prophylaxis have been published by several authoritative bodies.6–9 Guidelines have not been published for patients with rheumatologic diseases and other diseases requiring immunosuppressive drugs, although some authors have proposed indications for PCP prophylaxis for these patients.3,10–14 A summary of commonly proposed indications for PCP prophylaxis are presented in Table 1.
Table 1: Commonly proposed indications for PCP prophylaxis in HIV-negative adult patients.
Polymerase chain reaction (PCR) is an important diagnostic tool for PCP in HIV-negative patients. PCR detects small amounts of Pneumocystis DNA in lower respiratory tract specimens and has far greater sensitivity in HIV-negative patients than immunofluorescent staining.1 However, PCR also detects asymptomatic airway colonisation with Pneumocystis; this is common in patients with chronic lung diseases but has not been definitively linked with risk of developing PCP.15 In the Auckland region, clinicians can request an Atypical Pneumonia PCR Panel16 on lower respiratory tract specimens that indiscriminately tests for multiple pathogens including Pneumocystis, and therefore a positive Pneumocystis result may be obtained in a patient who clinically does not have PCP. Consequently, a diagnosis of PCP requires a consistent clinical syndrome in addition to a positive PCR.1
Cases of PCP have been described among patients who were not prescribed prophylaxis despite having a commonly proposed indication for this.17,18 For these patients, it is very likely that PCP would have been prevented if prophylaxis was prescribed. In our hospitals, there are no general policies for PCP prophylaxis outside of solid organ and stem cell transplantation and for specific chemotherapy regimens, and we therefore hypothesised that potentially preventable cases of PCP may be occurring. Our study aimed to determine the incidence of PCP among HIV-negative patients from three hospitals in Auckland, New Zealand that would have been potentially preventable if prophylaxis had been prescribed according to the commonly proposed indications in Table 1.
Methods
We conducted a retrospective observational study of all HIV-negative patients aged >16 years old who were admitted to Middlemore Hospital (MMH), North Shore Hospital (NSH) or Waitakere Hospital (WTH) between January 2011 and June 2017 and had a positive Pneumocystis PCR on lower respiratory tract specimens. Patients were identified by searching the laboratory database at MMH, where PCR testing for all study sites was performed using an 8-plex Atypical Pneumonia PCR panel (AusDiagnostics, Mascot NSW, Australia).16 Curves with a cycle threshold of <32 in step 2 of the AusDiagnostics assay were reported as positive.
Patients with a positive PCR were classified clinically into two groups: those with probable PCP, and those with probable asymptomatic Pneumocystis colonisation. This classification was determined by reviewing clinical records to ascertain the impression of the clinicians caring for the patient at the time. Patients were classified as probable PCP if their clinicians thought their presentation was consistent with PCP or if they were given PCP treatment. Patients were classified as probable asymptomatic colonisation if their clinicians thought their presentation was not consistent with PCP.We collected data from clinical records on patient demographics and diagnoses of immunosuppressive conditions and chronic lung diseases (defined as bronchiectasis, chronic obstructive pulmonary disease, interstitial lung disease and lung cancer). We also collected laboratory data for immunofluorescent staining (with >5 cysts seen defined as positive). Dispensing records were reviewed for immunosuppressive drugs; for corticosteroids, we classified courses as either short (<4 weeks) or long (>4 weeks). For long courses of corticosteroids, we calculated the average daily dose of prednisone during the month prior to the positive PCR; for patients receiving dexamethasone, we converted this to an equivalent prednisone dose using a ratio of 0.75mg of dexamethasone to 5mg of prednisone.19 Dispensing records were also reviewed for TMP-SMX, dapsone and atovaquone, and we assumed that these were prescribed for PCP prophylaxis if dispensed for >4 weeks. Medication charts were reviewed to identify patients receiving nebulised pentamidine.
For patients with PCP, we classified their infection as potentially preventable if they had a commonly proposed indication for prophylaxis in Table 1 but had not been prescribed this. For patients receiving chemotherapy regimens not listed in Table 1, we classified PCP as potentially preventable if the treating hospital’s protocol for that chemotherapy regimen recommended PCP prophylaxis but this had not been prescribed.
Ethical approval was obtained from the research offices of the involved hospitals. Informed consent was not deemed necessary because our study was retrospective and no identifying characteristics were reported in our findings that could deanonymise patients. Fisher’s exact test was used for analysis of 2x2 contingency tables and a two-tailed t-test was used for comparison of means; a p-value <0.05 was deemed significant.
Results
A total of 217 patients with a positive Pneumocystis PCR were identified (Table 2). Of these, 108 patients (49.8%) had probable PCP and 109 patients (50.2%) had probable asymptomatic Pneumocystis colonisation. Those with probable PCP had a higher overall 30-day mortality than those classified as colonised (32.4% vs 16.5%, p=0.007). No patients classified as colonised subsequently developed PCP during the study period.
Table 2: Characteristics of patients with PCP and patients with Pneumocystis colonisation.
Of the 108 patients with PCP, 33/108 (30.6%) had a commonly proposed indication for prophylaxis as described in Table 1. No patient in this group had been prescribed prophylaxis, therefore all had potentially preventable infection. Of the patients with potentially preventable infection, 14/33 (42.4%) died within 30 days of the diagnosis of PCP. For no patient was it documented in the clinical record that prophylaxis was not prescribed due to a contraindication or concern about adverse effects.
The category of medical condition causing immunosuppression and/or requiring immunosuppressive drugs is shown in Table 3. Of the patients with solid organ malignancy, 17/26 (65.4%) had a commonly proposed indication for prophylaxis. This sub-group accounted for the majority of those with potentially preventable PCP (17/33, 51.5%). There were 22/26 patients (84.6%) with solid organ malignancy who had been prescribed long-course corticosteroids (average prednisone dose 42mg/day). In the three months prior to diagnosis of PCP, 8/26 patients (30.8%) had received chemotherapy and 12/26 patients (46.2%) had received radiotherapy.
Table 3: Condition causing immunosuppression and/or requiring immunosuppressive drugs in patients with PCP.
Of the 24 patients with haematologic malignancy and/or SCT, 10/24 (41.7%) had a commonly proposed indication for prophylaxis. This sub-group accounted for the second largest group with potentially preventable PCP (10/33, 30.3%). There were 14/24 patients (58.3%) with haematologic malignancy and/or SCT who had been prescribed long-course corticosteroids (average prednisone dose 23mg/day), and 3/24 (12.5%) who had undergone SCT. One patient with hematologic malignancy developed PCP despite prophylaxis; this patient was receiving nebulised pentamidine but did not have a commonly proposed indication for prophylaxis.
Of the 108 patients with PCP, 75/108 (69.4%) did not have a commonly proposed indication for prophylaxis. Patients with rheumatologic disease were the largest contributor to this group (27/75, 36%), followed by patients with haematologic malignancy and/or SCT (14/75, 18.7%) and respiratory disease (12/75, 16%). Of those with rheumatologic disease, 12/30 (40%) had rheumatoid arthritis (RA). No patient with RA had a commonly proposed indication for prophylaxis and only 5/12 (41.7%) had been prescribed long-course corticosteroids (average prednisone dose 9mg/day). All patients with RA were prescribed non-corticosteroid immunosuppressive drugs, with a median of three drugs. Among those with respiratory disease, most had interstitial lung disease (9/12, 75%), and most (8/12, 66.7%) had been prescribed long-course corticosteroids (average prednisone dose 23mg/day).
Discussion
Our study demonstrates that there is a substantial burden of potentially preventable PCP and PCP-related mortality among HIV-negative patients in the Auckland region. In our cohort, 33/108 patients (30.6%) had a commonly proposed indication for prophylaxis but had not been prescribed this, and 14/33 (42.4%) of these patients died within 30 days of their PCP diagnosis. Assuming that TMP-SMX prophylaxis reduces the incidence of PCP by 85% and PCP-related mortality by 83%,3 we estimate that 28 cases of PCP and 12 deaths could have been prevented over the 78-month duration of our study if TMP-SMX was prescribed according to the commonly proposed indications in Table 1.
For patients with solid organ or haematologic malignancies, consensus guidelines provide unambiguous indications for PCP prophylaxis.6,7,9 Despite this, the vast majority of potentially preventable PCP in our cohort occurred in patients with solid organ or haematologic malignancy (27/33, 81.8%). This finding suggests that suboptimal guideline adherence is a cause of poor outcomes among these patients. To improve outcomes, we firstly recommend that clinicians who care for patients with solid organ or haematologic malignancies familiarise themselves with guidelines for PCP prophylaxis, particularly if prescribing prolonged corticosteroid courses to these high-risk patients. Secondly, we recommend that clinicians should be aware of options for PCP prophylaxis in patients with hypersensitivity or other contraindications to TMP-SMX, including desensitisation or graded challenge to TMP-SMX or the use of second-line drugs such as dapsone, atovaquone and nebulised pentamidine.1,4 Thirdly, we recommend that departments develop local policies to assist clinicians in prescribing PCP prophylaxis and to raise awareness of potentially preventable PCP. This applies not only to oncology and haematology, but also to specialities such as general medicine, respiratory medicine and neurosurgery, who are often the first to diagnose malignancy and initiate corticosteroids prior to cancer specialists taking over care of the patient. Finally, when cases of potentially preventable PCP occur, we recommend that these events are critically reviewed for the purposes of clinician education and to identify changes that can be implemented to reduce risk to future patients.
Although we identified many cases of PCP in patients with rheumatologic disease, only 3/30 (10%) had a commonly proposed indication for prophylaxis. Assessing PCP risk in patients with rheumatologic disease is challenging, due to a complex interaction of risk factors including the specific rheumatologic disease, disease activity, age, lymphopaenia, current and past corticosteroid use and the use of non-corticosteroid immunosuppressive drugs, some of which pose a greater risk of PCP compared to others.14,20,21 While some authors have proposed approaches to PCP prophylaxis in patients with rheumatologic diseases,13,14 there is a pressing need for evidence-based guidelines to clearly define which patients with rheumatologic and other autoimmune diseases will benefit from prophylaxis.
To the best of our knowledge, this is the largest study of HIV-negative patients with PCP in New Zealand.23,24 However, our study has several limitations. Firstly, we did not have a control group of patients who had indications for PCP prophylaxis but did not develop PCP; therefore, we were unable to estimate the overall incidence of PCP in this population. This would have been helpful to confirm whether the indications in Table 1 accurately predict the threshold at which the benefits of prophylaxis outweigh the harms. Secondly, no specific diagnostic criteria were used to classify patients as having PCP or asymptomatic colonisation. While none of the colonised group developed PCP, it is possible that some colonised patients were incorrectly classified as having PCP. Finally, because we only identified patients with a positive PCR, we were not able to include those who were diagnosed with PCP on clinical grounds alone or those who died before diagnostic testing.
In conclusion, the incidence of potentially preventable PCP and PCP-related mortality in the Auckland region is considerable. These events are mostly occurring among patients with solid organ and haematologic malignancies receiving high-dose corticosteroids for >4 weeks, and could be substantially reduced by prescribing prophylaxis to these patients according to guidelines. Patients with rheumatologic diseases also account for a significant proportion of those with PCP in the Auckland region, but reducing the occurrence of PCP in this group will remain challenging until publication of rheumatology-specific guidelines for PCP prophylaxis.
Summary
Abstract
Aim
Pneumocystis pneumonia (PCP) has a high mortality rate in HIV-negative immunocompromised patients, but is preventable with antimicrobial prophylaxis. We aimed to determine the incidence of PCP in three hospitals in Auckland, New Zealand that would have been potentially preventable if patients had been prescribed prophylaxis according to commonly proposed indications.
Method
We conducted a retrospective study of HIV-negative adults with PCP who were admitted to Middlemore, North Shore or Waitakere Hospitals between January 2011 and June 2017. We classified their PCP as potentially preventable if they had not been prescribed prophylaxis despite having a commonly proposed indication for this.
Results
Of the 108 patients with PCP, 33/108 (30.6%) had potentially preventable infection. Of these, 14/33 (42.4%) died within 30 days of diagnosis of PCP. Most potentially preventable infections occurred in patients with solid organ or haematologic malignancies who were receiving high-dose corticosteroids for >4 weeks. We estimate that 28 cases of PCP and 12 deaths could have been prevented over the study duration if prophylaxis was prescribed to those with commonly proposed indications.
Conclusion
There is a substantial incidence of potentially preventable PCP and PCP-related mortality in the Auckland region. This could be reduced by greater clinician familiarity with commonly proposed indications for PCP prophylaxis, particularly for clinicians prescribing prolonged corticosteroid courses to patients with malignancies.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1. Carmona EM, Limper AH. Update on the diagnosis and treatment of Pneumocystis pneumonia. Ther Adv Respir Dis. 2011; 5(1):41–59.
2. Liu Y, Su L, Jiang S, Qu H. Risk factors for mortality from Pneumocystis carinii pneumonia (PCP) in non-HIV patients: a meta-analysis. Oncotarget. 2017; 8(35):59729–39.
3. Stern A, Green H, Paul M, et al. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev. 2014(10):CD005590.
4. Gluckstein D, Ruskin J. Rapid oral desensitization to trimethoprim-sulfamethoxazole (TMP-SMZ): use in prophylaxis for Pneumocystis carinii pneumonia in patients with AIDS who were previously intolerant to TMP-SMZ. Clin Infect Dis. 1995; 20(4):849–53.
5. Green H, Paul M, Vidal L, Leibovici L. Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc. 2007; 82(9):1052–9.
6. Cooley L, Dendle C, Wolf J, et al. Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014. Intern Med J. 2014; 44(12b):1350–63.
7. Maertens J, Cesaro S, Maschmeyer G, et al. ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother. 2016; 71(9):2397–404.
8. Martin SI, Fishman JA, AST Infectious Diseases Community of Practice. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant. 2013; 13 Suppl 4:272–9.
9. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009; 15(10):1143–238.
10. Limper AH, Knox KS, Sarosi GA, 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(1):96–128.
11. Sepkowitz KA. Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome: who should receive prophylaxis? Mayo Clin Proc. 1996; 71(1):102–3.
12. Carmona EM, Limper AH. Update on the diagnosis and treatment of Pneumocystis pneumonia. Ther Adv Respir Dis. 2010; 5(1):41–59.
13. Winthrop KL, Baddley JW. Pneumocystis and glucocorticoid use: to prophylax or not to prophylax (and when?); that is the question. Ann Rheum Dis. 2018; 77(5):631–3.
14. Wolfe RM, Peacock JE, Jr. Pneumocystis pneumonia and the rheumatologist: which patients are at risk and how can PCP be prevented? Curr Rheumatol Rep. 2017; 19(6):35.
15. Morris A, Norris KA. Colonization by Pneumocystis jirovecii and its role in disease. Clin Microbiol Rev. 2012; 25(2):297–317.
16. AusDiagnostics Pty Ltd [homepage on the Internet]. Respiratory pathogens [cited 2020 22 Mar]. Available from: http://www.ausdiagnostics.com/respiratory-pathogens.html
17. Plakke MJ, Jalota L, Lloyd BJ. Pneumocystis pneumonia in a non-HIV patient on chronic corticosteroid therapy: a question of prophylaxis. BMJ Case Rep. 2013; 2013:bcr2012007912.
18. Yamaguchi T, Nagai Y, Morita T, et al. Pneumocystis pneumonia in patients treated with long-term steroid therapy for symptom palliation: a neglected infection in palliative care. Am J Hosp Palliat Care. 2014; 31(8):857–61.
19. Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet. 2005; 44(1):61–98.
20. Park JW, Curtis JR, Moon J, et al. 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.
21. Hashimoto A, Suto S, Horie K, et al. Incidence and risk factors for infections requiring hospitalization, including Pneumocystis pneumonia, in Japanese patients with rheumatoid arthritis. Int J Rheumatol. 2017; 2017:6730812-.
22. Katsuyama T, Saito K, Kubo S, et al. Prophylaxis for Pneumocystis pneumonia in patients with rheumatoid arthritis treated with biologics, based on risk factors found in a retrospective study. Arthritis Res Ther. 2014; 16(1):R43–R.
23. Meuli K, Chapman P, O’Donnell J, et al. Audit of Pneumocystis pneumonia in patients seen by the Christchurch Hospital rheumatology service over a 5-year period. Intern Med J. 2007; 37(10):687–92.
24. Carter JM, Town GI, Fisher M, et al. Management of Pneumocystis carinii pneumonia in the immunocompromised host. N Z Med J. 1988; 101(850):471–5.
For the PDF of this article,
contact nzmj@nzma.org.nz
Pneumocystis pneumonia in HIV-negative adults: missed opportunities for prevention
View Article PDF
Pneumocystis pneumonia (PCP), caused by the opportunistic fungus Pneumocystis jirovecii, is almost exclusively a disease of the immunocompromised.1 While PCP is most recognised as an AIDS-defining condition, it also occurs in HIV-negative immunocompromised patients. In this population, PCP is associated with poorer outcomes compared to HIV-positive patients, with a higher rate of fulminant respiratory failure and mortality of approximately 30%.2
Given the potential severity of PCP in HIV-negative immunocompromised patients, antimicrobial prophylaxis is crucial for those at highest risk. Trimethoprim-sulfamethoxazole (TMP-SMX) reduces the incidence of PCP by 85% and PCP-related mortality by 83% in this population, and is usually well tolerated.3 For patients with hypersensitivity to TMP-SMX, desensitisation or a graded challenge to this drug can be attempted in many instances.4 Alternatively, a second-line drug such as dapsone, atovaquone or nebulised pentamidine can be used, although their efficacy is inferior to TMP-SMX.1
For HIV-negative adults, the benefits of TMP-SMX prophylaxis outweigh the risks of adverse events when the risk of PCP exceeds 3.5% for the period of the patient’s immunocompromise.5 For patients with malignancy, stem cell transplantation (SCT) and solid organ transplantation, guidelines for PCP prophylaxis have been published by several authoritative bodies.6–9 Guidelines have not been published for patients with rheumatologic diseases and other diseases requiring immunosuppressive drugs, although some authors have proposed indications for PCP prophylaxis for these patients.3,10–14 A summary of commonly proposed indications for PCP prophylaxis are presented in Table 1.
Table 1: Commonly proposed indications for PCP prophylaxis in HIV-negative adult patients.
Polymerase chain reaction (PCR) is an important diagnostic tool for PCP in HIV-negative patients. PCR detects small amounts of Pneumocystis DNA in lower respiratory tract specimens and has far greater sensitivity in HIV-negative patients than immunofluorescent staining.1 However, PCR also detects asymptomatic airway colonisation with Pneumocystis; this is common in patients with chronic lung diseases but has not been definitively linked with risk of developing PCP.15 In the Auckland region, clinicians can request an Atypical Pneumonia PCR Panel16 on lower respiratory tract specimens that indiscriminately tests for multiple pathogens including Pneumocystis, and therefore a positive Pneumocystis result may be obtained in a patient who clinically does not have PCP. Consequently, a diagnosis of PCP requires a consistent clinical syndrome in addition to a positive PCR.1
Cases of PCP have been described among patients who were not prescribed prophylaxis despite having a commonly proposed indication for this.17,18 For these patients, it is very likely that PCP would have been prevented if prophylaxis was prescribed. In our hospitals, there are no general policies for PCP prophylaxis outside of solid organ and stem cell transplantation and for specific chemotherapy regimens, and we therefore hypothesised that potentially preventable cases of PCP may be occurring. Our study aimed to determine the incidence of PCP among HIV-negative patients from three hospitals in Auckland, New Zealand that would have been potentially preventable if prophylaxis had been prescribed according to the commonly proposed indications in Table 1.
Methods
We conducted a retrospective observational study of all HIV-negative patients aged >16 years old who were admitted to Middlemore Hospital (MMH), North Shore Hospital (NSH) or Waitakere Hospital (WTH) between January 2011 and June 2017 and had a positive Pneumocystis PCR on lower respiratory tract specimens. Patients were identified by searching the laboratory database at MMH, where PCR testing for all study sites was performed using an 8-plex Atypical Pneumonia PCR panel (AusDiagnostics, Mascot NSW, Australia).16 Curves with a cycle threshold of <32 in step 2 of the AusDiagnostics assay were reported as positive.
Patients with a positive PCR were classified clinically into two groups: those with probable PCP, and those with probable asymptomatic Pneumocystis colonisation. This classification was determined by reviewing clinical records to ascertain the impression of the clinicians caring for the patient at the time. Patients were classified as probable PCP if their clinicians thought their presentation was consistent with PCP or if they were given PCP treatment. Patients were classified as probable asymptomatic colonisation if their clinicians thought their presentation was not consistent with PCP.We collected data from clinical records on patient demographics and diagnoses of immunosuppressive conditions and chronic lung diseases (defined as bronchiectasis, chronic obstructive pulmonary disease, interstitial lung disease and lung cancer). We also collected laboratory data for immunofluorescent staining (with >5 cysts seen defined as positive). Dispensing records were reviewed for immunosuppressive drugs; for corticosteroids, we classified courses as either short (<4 weeks) or long (>4 weeks). For long courses of corticosteroids, we calculated the average daily dose of prednisone during the month prior to the positive PCR; for patients receiving dexamethasone, we converted this to an equivalent prednisone dose using a ratio of 0.75mg of dexamethasone to 5mg of prednisone.19 Dispensing records were also reviewed for TMP-SMX, dapsone and atovaquone, and we assumed that these were prescribed for PCP prophylaxis if dispensed for >4 weeks. Medication charts were reviewed to identify patients receiving nebulised pentamidine.
For patients with PCP, we classified their infection as potentially preventable if they had a commonly proposed indication for prophylaxis in Table 1 but had not been prescribed this. For patients receiving chemotherapy regimens not listed in Table 1, we classified PCP as potentially preventable if the treating hospital’s protocol for that chemotherapy regimen recommended PCP prophylaxis but this had not been prescribed.
Ethical approval was obtained from the research offices of the involved hospitals. Informed consent was not deemed necessary because our study was retrospective and no identifying characteristics were reported in our findings that could deanonymise patients. Fisher’s exact test was used for analysis of 2x2 contingency tables and a two-tailed t-test was used for comparison of means; a p-value <0.05 was deemed significant.
Results
A total of 217 patients with a positive Pneumocystis PCR were identified (Table 2). Of these, 108 patients (49.8%) had probable PCP and 109 patients (50.2%) had probable asymptomatic Pneumocystis colonisation. Those with probable PCP had a higher overall 30-day mortality than those classified as colonised (32.4% vs 16.5%, p=0.007). No patients classified as colonised subsequently developed PCP during the study period.
Table 2: Characteristics of patients with PCP and patients with Pneumocystis colonisation.
Of the 108 patients with PCP, 33/108 (30.6%) had a commonly proposed indication for prophylaxis as described in Table 1. No patient in this group had been prescribed prophylaxis, therefore all had potentially preventable infection. Of the patients with potentially preventable infection, 14/33 (42.4%) died within 30 days of the diagnosis of PCP. For no patient was it documented in the clinical record that prophylaxis was not prescribed due to a contraindication or concern about adverse effects.
The category of medical condition causing immunosuppression and/or requiring immunosuppressive drugs is shown in Table 3. Of the patients with solid organ malignancy, 17/26 (65.4%) had a commonly proposed indication for prophylaxis. This sub-group accounted for the majority of those with potentially preventable PCP (17/33, 51.5%). There were 22/26 patients (84.6%) with solid organ malignancy who had been prescribed long-course corticosteroids (average prednisone dose 42mg/day). In the three months prior to diagnosis of PCP, 8/26 patients (30.8%) had received chemotherapy and 12/26 patients (46.2%) had received radiotherapy.
Table 3: Condition causing immunosuppression and/or requiring immunosuppressive drugs in patients with PCP.
Of the 24 patients with haematologic malignancy and/or SCT, 10/24 (41.7%) had a commonly proposed indication for prophylaxis. This sub-group accounted for the second largest group with potentially preventable PCP (10/33, 30.3%). There were 14/24 patients (58.3%) with haematologic malignancy and/or SCT who had been prescribed long-course corticosteroids (average prednisone dose 23mg/day), and 3/24 (12.5%) who had undergone SCT. One patient with hematologic malignancy developed PCP despite prophylaxis; this patient was receiving nebulised pentamidine but did not have a commonly proposed indication for prophylaxis.
Of the 108 patients with PCP, 75/108 (69.4%) did not have a commonly proposed indication for prophylaxis. Patients with rheumatologic disease were the largest contributor to this group (27/75, 36%), followed by patients with haematologic malignancy and/or SCT (14/75, 18.7%) and respiratory disease (12/75, 16%). Of those with rheumatologic disease, 12/30 (40%) had rheumatoid arthritis (RA). No patient with RA had a commonly proposed indication for prophylaxis and only 5/12 (41.7%) had been prescribed long-course corticosteroids (average prednisone dose 9mg/day). All patients with RA were prescribed non-corticosteroid immunosuppressive drugs, with a median of three drugs. Among those with respiratory disease, most had interstitial lung disease (9/12, 75%), and most (8/12, 66.7%) had been prescribed long-course corticosteroids (average prednisone dose 23mg/day).
Discussion
Our study demonstrates that there is a substantial burden of potentially preventable PCP and PCP-related mortality among HIV-negative patients in the Auckland region. In our cohort, 33/108 patients (30.6%) had a commonly proposed indication for prophylaxis but had not been prescribed this, and 14/33 (42.4%) of these patients died within 30 days of their PCP diagnosis. Assuming that TMP-SMX prophylaxis reduces the incidence of PCP by 85% and PCP-related mortality by 83%,3 we estimate that 28 cases of PCP and 12 deaths could have been prevented over the 78-month duration of our study if TMP-SMX was prescribed according to the commonly proposed indications in Table 1.
For patients with solid organ or haematologic malignancies, consensus guidelines provide unambiguous indications for PCP prophylaxis.6,7,9 Despite this, the vast majority of potentially preventable PCP in our cohort occurred in patients with solid organ or haematologic malignancy (27/33, 81.8%). This finding suggests that suboptimal guideline adherence is a cause of poor outcomes among these patients. To improve outcomes, we firstly recommend that clinicians who care for patients with solid organ or haematologic malignancies familiarise themselves with guidelines for PCP prophylaxis, particularly if prescribing prolonged corticosteroid courses to these high-risk patients. Secondly, we recommend that clinicians should be aware of options for PCP prophylaxis in patients with hypersensitivity or other contraindications to TMP-SMX, including desensitisation or graded challenge to TMP-SMX or the use of second-line drugs such as dapsone, atovaquone and nebulised pentamidine.1,4 Thirdly, we recommend that departments develop local policies to assist clinicians in prescribing PCP prophylaxis and to raise awareness of potentially preventable PCP. This applies not only to oncology and haematology, but also to specialities such as general medicine, respiratory medicine and neurosurgery, who are often the first to diagnose malignancy and initiate corticosteroids prior to cancer specialists taking over care of the patient. Finally, when cases of potentially preventable PCP occur, we recommend that these events are critically reviewed for the purposes of clinician education and to identify changes that can be implemented to reduce risk to future patients.
Although we identified many cases of PCP in patients with rheumatologic disease, only 3/30 (10%) had a commonly proposed indication for prophylaxis. Assessing PCP risk in patients with rheumatologic disease is challenging, due to a complex interaction of risk factors including the specific rheumatologic disease, disease activity, age, lymphopaenia, current and past corticosteroid use and the use of non-corticosteroid immunosuppressive drugs, some of which pose a greater risk of PCP compared to others.14,20,21 While some authors have proposed approaches to PCP prophylaxis in patients with rheumatologic diseases,13,14 there is a pressing need for evidence-based guidelines to clearly define which patients with rheumatologic and other autoimmune diseases will benefit from prophylaxis.
To the best of our knowledge, this is the largest study of HIV-negative patients with PCP in New Zealand.23,24 However, our study has several limitations. Firstly, we did not have a control group of patients who had indications for PCP prophylaxis but did not develop PCP; therefore, we were unable to estimate the overall incidence of PCP in this population. This would have been helpful to confirm whether the indications in Table 1 accurately predict the threshold at which the benefits of prophylaxis outweigh the harms. Secondly, no specific diagnostic criteria were used to classify patients as having PCP or asymptomatic colonisation. While none of the colonised group developed PCP, it is possible that some colonised patients were incorrectly classified as having PCP. Finally, because we only identified patients with a positive PCR, we were not able to include those who were diagnosed with PCP on clinical grounds alone or those who died before diagnostic testing.
In conclusion, the incidence of potentially preventable PCP and PCP-related mortality in the Auckland region is considerable. These events are mostly occurring among patients with solid organ and haematologic malignancies receiving high-dose corticosteroids for >4 weeks, and could be substantially reduced by prescribing prophylaxis to these patients according to guidelines. Patients with rheumatologic diseases also account for a significant proportion of those with PCP in the Auckland region, but reducing the occurrence of PCP in this group will remain challenging until publication of rheumatology-specific guidelines for PCP prophylaxis.
Summary
Abstract
Aim
Pneumocystis pneumonia (PCP) has a high mortality rate in HIV-negative immunocompromised patients, but is preventable with antimicrobial prophylaxis. We aimed to determine the incidence of PCP in three hospitals in Auckland, New Zealand that would have been potentially preventable if patients had been prescribed prophylaxis according to commonly proposed indications.
Method
We conducted a retrospective study of HIV-negative adults with PCP who were admitted to Middlemore, North Shore or Waitakere Hospitals between January 2011 and June 2017. We classified their PCP as potentially preventable if they had not been prescribed prophylaxis despite having a commonly proposed indication for this.
Results
Of the 108 patients with PCP, 33/108 (30.6%) had potentially preventable infection. Of these, 14/33 (42.4%) died within 30 days of diagnosis of PCP. Most potentially preventable infections occurred in patients with solid organ or haematologic malignancies who were receiving high-dose corticosteroids for >4 weeks. We estimate that 28 cases of PCP and 12 deaths could have been prevented over the study duration if prophylaxis was prescribed to those with commonly proposed indications.
Conclusion
There is a substantial incidence of potentially preventable PCP and PCP-related mortality in the Auckland region. This could be reduced by greater clinician familiarity with commonly proposed indications for PCP prophylaxis, particularly for clinicians prescribing prolonged corticosteroid courses to patients with malignancies.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1. Carmona EM, Limper AH. Update on the diagnosis and treatment of Pneumocystis pneumonia. Ther Adv Respir Dis. 2011; 5(1):41–59.
2. Liu Y, Su L, Jiang S, Qu H. Risk factors for mortality from Pneumocystis carinii pneumonia (PCP) in non-HIV patients: a meta-analysis. Oncotarget. 2017; 8(35):59729–39.
3. Stern A, Green H, Paul M, et al. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev. 2014(10):CD005590.
4. Gluckstein D, Ruskin J. Rapid oral desensitization to trimethoprim-sulfamethoxazole (TMP-SMZ): use in prophylaxis for Pneumocystis carinii pneumonia in patients with AIDS who were previously intolerant to TMP-SMZ. Clin Infect Dis. 1995; 20(4):849–53.
5. Green H, Paul M, Vidal L, Leibovici L. Prophylaxis of Pneumocystis pneumonia in immunocompromised non-HIV-infected patients: systematic review and meta-analysis of randomized controlled trials. Mayo Clin Proc. 2007; 82(9):1052–9.
6. Cooley L, Dendle C, Wolf J, et al. Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014. Intern Med J. 2014; 44(12b):1350–63.
7. Maertens J, Cesaro S, Maschmeyer G, et al. ECIL guidelines for preventing Pneumocystis jirovecii pneumonia in patients with haematological malignancies and stem cell transplant recipients. J Antimicrob Chemother. 2016; 71(9):2397–404.
8. Martin SI, Fishman JA, AST Infectious Diseases Community of Practice. Pneumocystis pneumonia in solid organ transplantation. Am J Transplant. 2013; 13 Suppl 4:272–9.
9. Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant. 2009; 15(10):1143–238.
10. Limper AH, Knox KS, Sarosi GA, 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(1):96–128.
11. Sepkowitz KA. Pneumocystis carinii pneumonia without acquired immunodeficiency syndrome: who should receive prophylaxis? Mayo Clin Proc. 1996; 71(1):102–3.
12. Carmona EM, Limper AH. Update on the diagnosis and treatment of Pneumocystis pneumonia. Ther Adv Respir Dis. 2010; 5(1):41–59.
13. Winthrop KL, Baddley JW. Pneumocystis and glucocorticoid use: to prophylax or not to prophylax (and when?); that is the question. Ann Rheum Dis. 2018; 77(5):631–3.
14. Wolfe RM, Peacock JE, Jr. Pneumocystis pneumonia and the rheumatologist: which patients are at risk and how can PCP be prevented? Curr Rheumatol Rep. 2017; 19(6):35.
15. Morris A, Norris KA. Colonization by Pneumocystis jirovecii and its role in disease. Clin Microbiol Rev. 2012; 25(2):297–317.
16. AusDiagnostics Pty Ltd [homepage on the Internet]. Respiratory pathogens [cited 2020 22 Mar]. Available from: http://www.ausdiagnostics.com/respiratory-pathogens.html
17. Plakke MJ, Jalota L, Lloyd BJ. Pneumocystis pneumonia in a non-HIV patient on chronic corticosteroid therapy: a question of prophylaxis. BMJ Case Rep. 2013; 2013:bcr2012007912.
18. Yamaguchi T, Nagai Y, Morita T, et al. Pneumocystis pneumonia in patients treated with long-term steroid therapy for symptom palliation: a neglected infection in palliative care. Am J Hosp Palliat Care. 2014; 31(8):857–61.
19. Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet. 2005; 44(1):61–98.
20. Park JW, Curtis JR, Moon J, et al. 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.
21. Hashimoto A, Suto S, Horie K, et al. Incidence and risk factors for infections requiring hospitalization, including Pneumocystis pneumonia, in Japanese patients with rheumatoid arthritis. Int J Rheumatol. 2017; 2017:6730812-.
22. Katsuyama T, Saito K, Kubo S, et al. Prophylaxis for Pneumocystis pneumonia in patients with rheumatoid arthritis treated with biologics, based on risk factors found in a retrospective study. Arthritis Res Ther. 2014; 16(1):R43–R.
23. Meuli K, Chapman P, O’Donnell J, et al. Audit of Pneumocystis pneumonia in patients seen by the Christchurch Hospital rheumatology service over a 5-year period. Intern Med J. 2007; 37(10):687–92.
24. Carter JM, Town GI, Fisher M, et al. Management of Pneumocystis carinii pneumonia in the immunocompromised host. N Z Med J. 1988; 101(850):471–5.
Contact diana@nzma.org.nz
for the PDF of this article
Pneumocystis pneumonia in HIV-negative adults: missed opportunities for prevention
View Article PDF
Pneumocystis pneumonia (PCP), caused by the opportunistic fungus Pneumocystis jirovecii, is almost exclusively a disease of the immunocompromised.1 While PCP is most recognised as an AIDS-defining condition, it also occurs in HIV-negative immunocompromised patients. In this population, PCP is associated with poorer outcomes compared to HIV-positive patients, with a higher rate of fulminant respiratory failure and mortality of approximately 30%.2
Given the potential severity of PCP in HIV-negative immunocompromised patients, antimicrobial prophylaxis is crucial for those at highest risk. Trimethoprim-sulfamethoxazole (TMP-SMX) reduces the incidence of PCP by 85% and PCP-related mortality by 83% in this population, and is usually well tolerated.3 For patients with hypersensitivity to TMP-SMX, desensitisation or a graded challenge to this drug can be attempted in many instances.4 Alternatively, a second-line drug such as dapsone, atovaquone or nebulised pentamidine can be used, although their efficacy is inferior to TMP-SMX.1
For HIV-negative adults, the benefits of TMP-SMX prophylaxis outweigh the risks of adverse events when the risk of PCP exceeds 3.5% for the period of the patient’s immunocompromise.5 For patients with malignancy, stem cell transplantation (SCT) and solid organ transplantation, guidelines for PCP prophylaxis have been published by several authoritative bodies.6–9 Guidelines have not been published for patients with rheumatologic diseases and other diseases requiring immunosuppressive drugs, although some authors have proposed indications for PCP prophylaxis for these patients.3,10–14 A summary of commonly proposed indications for PCP prophylaxis are presented in Table 1.
Table 1: Commonly proposed indications for PCP prophylaxis in HIV-negative adult patients.
Polymerase chain reaction (PCR) is an important diagnostic tool for PCP in HIV-negative patients. PCR detects small amounts of Pneumocystis DNA in lower respiratory tract specimens and has far greater sensitivity in HIV-negative patients than immunofluorescent staining.1 However, PCR also detects asymptomatic airway colonisation with Pneumocystis; this is common in patients with chronic lung diseases but has not been definitively linked with risk of developing PCP.15 In the Auckland region, clinicians can request an Atypical Pneumonia PCR Panel16 on lower respiratory tract specimens that indiscriminately tests for multiple pathogens including Pneumocystis, and therefore a positive Pneumocystis result may be obtained in a patient who clinically does not have PCP. Consequently, a diagnosis of PCP requires a consistent clinical syndrome in addition to a positive PCR.1
Cases of PCP have been described among patients who were not prescribed prophylaxis despite having a commonly proposed indication for this.17,18 For these patients, it is very likely that PCP would have been prevented if prophylaxis was prescribed. In our hospitals, there are no general policies for PCP prophylaxis outside of solid organ and stem cell transplantation and for specific chemotherapy regimens, and we therefore hypothesised that potentially preventable cases of PCP may be occurring. Our study aimed to determine the incidence of PCP among HIV-negative patients from three hospitals in Auckland, New Zealand that would have been potentially preventable if prophylaxis had been prescribed according to the commonly proposed indications in Table 1.
Methods
We conducted a retrospective observational study of all HIV-negative patients aged >16 years old who were admitted to Middlemore Hospital (MMH), North Shore Hospital (NSH) or Waitakere Hospital (WTH) between January 2011 and June 2017 and had a positive Pneumocystis PCR on lower respiratory tract specimens. Patients were identified by searching the laboratory database at MMH, where PCR testing for all study sites was performed using an 8-plex Atypical Pneumonia PCR panel (AusDiagnostics, Mascot NSW, Australia).16 Curves with a cycle threshold of <32 in step 2 of the AusDiagnostics assay were reported as positive.
Patients with a positive PCR were classified clinically into two groups: those with probable PCP, and those with probable asymptomatic Pneumocystis colonisation. This classification was determined by reviewing clinical records to ascertain the impression of the clinicians caring for the patient at the time. Patients were classified as probable PCP if their clinicians thought their presentation was consistent with PCP or if they were given PCP treatment. Patients were classified as probable asymptomatic colonisation if their clinicians thought their presentation was not consistent with PCP.We collected data from clinical records on patient demographics and diagnoses of immunosuppressive conditions and chronic lung diseases (defined as bronchiectasis, chronic obstructive pulmonary disease, interstitial lung disease and lung cancer). We also collected laboratory data for immunofluorescent staining (with >5 cysts seen defined as positive). Dispensing records were reviewed for immunosuppressive drugs; for corticosteroids, we classified courses as either short (<4 weeks) or long (>4 weeks). For long courses of corticosteroids, we calculated the average daily dose of prednisone during the month prior to the positive PCR; for patients receiving dexamethasone, we converted this to an equivalent prednisone dose using a ratio of 0.75mg of dexamethasone to 5mg of prednisone.19 Dispensing records were also reviewed for TMP-SMX, dapsone and atovaquone, and we assumed that these were prescribed for PCP prophylaxis if dispensed for >4 weeks. Medication charts were reviewed to identify patients receiving nebulised pentamidine.
For patients with PCP, we classified their infection as potentially preventable if they had a commonly proposed indication for prophylaxis in Table 1 but had not been prescribed this. For patients receiving chemotherapy regimens not listed in Table 1, we classified PCP as potentially preventable if the treating hospital’s protocol for that chemotherapy regimen recommended PCP prophylaxis but this had not been prescribed.
Ethical approval was obtained from the research offices of the involved hospitals. Informed consent was not deemed necessary because our study was retrospective and no identifying characteristics were reported in our findings that could deanonymise patients. Fisher’s exact test was used for analysis of 2x2 contingency tables and a two-tailed t-test was used for comparison of means; a p-value <0.05 was deemed significant.
Results
A total of 217 patients with a positive Pneumocystis PCR were identified (Table 2). Of these, 108 patients (49.8%) had probable PCP and 109 patients (50.2%) had probable asymptomatic Pneumocystis colonisation. Those with probable PCP had a higher overall 30-day mortality than those classified as colonised (32.4% vs 16.5%, p=0.007). No patients classified as colonised subsequently developed PCP during the study period.
Table 2: Characteristics of patients with PCP and patients with Pneumocystis colonisation.
Of the 108 patients with PCP, 33/108 (30.6%) had a commonly proposed indication for prophylaxis as described in Table 1. No patient in this group had been prescribed prophylaxis, therefore all had potentially preventable infection. Of the patients with potentially preventable infection, 14/33 (42.4%) died within 30 days of the diagnosis of PCP. For no patient was it documented in the clinical record that prophylaxis was not prescribed due to a contraindication or concern about adverse effects.
The category of medical condition causing immunosuppression and/or requiring immunosuppressive drugs is shown in Table 3. Of the patients with solid organ malignancy, 17/26 (65.4%) had a commonly proposed indication for prophylaxis. This sub-group accounted for the majority of those with potentially preventable PCP (17/33, 51.5%). There were 22/26 patients (84.6%) with solid organ malignancy who had been prescribed long-course corticosteroids (average prednisone dose 42mg/day). In the three months prior to diagnosis of PCP, 8/26 patients (30.8%) had received chemotherapy and 12/26 patients (46.2%) had received radiotherapy.
Table 3: Condition causing immunosuppression and/or requiring immunosuppressive drugs in patients with PCP.
Of the 24 patients with haematologic malignancy and/or SCT, 10/24 (41.7%) had a commonly proposed indication for prophylaxis. This sub-group accounted for the second largest group with potentially preventable PCP (10/33, 30.3%). There were 14/24 patients (58.3%) with haematologic malignancy and/or SCT who had been prescribed long-course corticosteroids (average prednisone dose 23mg/day), and 3/24 (12.5%) who had undergone SCT. One patient with hematologic malignancy developed PCP despite prophylaxis; this patient was receiving nebulised pentamidine but did not have a commonly proposed indication for prophylaxis.
Of the 108 patients with PCP, 75/108 (69.4%) did not have a commonly proposed indication for prophylaxis. Patients with rheumatologic disease were the largest contributor to this group (27/75, 36%), followed by patients with haematologic malignancy and/or SCT (14/75, 18.7%) and respiratory disease (12/75, 16%). Of those with rheumatologic disease, 12/30 (40%) had rheumatoid arthritis (RA). No patient with RA had a commonly proposed indication for prophylaxis and only 5/12 (41.7%) had been prescribed long-course corticosteroids (average prednisone dose 9mg/day). All patients with RA were prescribed non-corticosteroid immunosuppressive drugs, with a median of three drugs. Among those with respiratory disease, most had interstitial lung disease (9/12, 75%), and most (8/12, 66.7%) had been prescribed long-course corticosteroids (average prednisone dose 23mg/day).
Discussion
Our study demonstrates that there is a substantial burden of potentially preventable PCP and PCP-related mortality among HIV-negative patients in the Auckland region. In our cohort, 33/108 patients (30.6%) had a commonly proposed indication for prophylaxis but had not been prescribed this, and 14/33 (42.4%) of these patients died within 30 days of their PCP diagnosis. Assuming that TMP-SMX prophylaxis reduces the incidence of PCP by 85% and PCP-related mortality by 83%,3 we estimate that 28 cases of PCP and 12 deaths could have been prevented over the 78-month duration of our study if TMP-SMX was prescribed according to the commonly proposed indications in Table 1.
For patients with solid organ or haematologic malignancies, consensus guidelines provide unambiguous indications for PCP prophylaxis.6,7,9 Despite this, the vast majority of potentially preventable PCP in our cohort occurred in patients with solid organ or haematologic malignancy (27/33, 81.8%). This finding suggests that suboptimal guideline adherence is a cause of poor outcomes among these patients. To improve outcomes, we firstly recommend that clinicians who care for patients with solid organ or haematologic malignancies familiarise themselves with guidelines for PCP prophylaxis, particularly if prescribing prolonged corticosteroid courses to these high-risk patients. Secondly, we recommend that clinicians should be aware of options for PCP prophylaxis in patients with hypersensitivity or other contraindications to TMP-SMX, including desensitisation or graded challenge to TMP-SMX or the use of second-line drugs such as dapsone, atovaquone and nebulised pentamidine.1,4 Thirdly, we recommend that departments develop local policies to assist clinicians in prescribing PCP prophylaxis and to raise awareness of potentially preventable PCP. This applies not only to oncology and haematology, but also to specialities such as general medicine, respiratory medicine and neurosurgery, who are often the first to diagnose malignancy and initiate corticosteroids prior to cancer specialists taking over care of the patient. Finally, when cases of potentially preventable PCP occur, we recommend that these events are critically reviewed for the purposes of clinician education and to identify changes that can be implemented to reduce risk to future patients.
Although we identified many cases of PCP in patients with rheumatologic disease, only 3/30 (10%) had a commonly proposed indication for prophylaxis. Assessing PCP risk in patients with rheumatologic disease is challenging, due to a complex interaction of risk factors including the specific rheumatologic disease, disease activity, age, lymphopaenia, current and past corticosteroid use and the use of non-corticosteroid immunosuppressive drugs, some of which pose a greater risk of PCP compared to others.14,20,21 While some authors have proposed approaches to PCP prophylaxis in patients with rheumatologic diseases,13,14 there is a pressing need for evidence-based guidelines to clearly define which patients with rheumatologic and other autoimmune diseases will benefit from prophylaxis.
To the best of our knowledge, this is the largest study of HIV-negative patients with PCP in New Zealand.23,24 However, our study has several limitations. Firstly, we did not have a control group of patients who had indications for PCP prophylaxis but did not develop PCP; therefore, we were unable to estimate the overall incidence of PCP in this population. This would have been helpful to confirm whether the indications in Table 1 accurately predict the threshold at which the benefits of prophylaxis outweigh the harms. Secondly, no specific diagnostic criteria were used to classify patients as having PCP or asymptomatic colonisation. While none of the colonised group developed PCP, it is possible that some colonised patients were incorrectly classified as having PCP. Finally, because we only identified patients with a positive PCR, we were not able to include those who were diagnosed with PCP on clinical grounds alone or those who died before diagnostic testing.
In conclusion, the incidence of potentially preventable PCP and PCP-related mortality in the Auckland region is considerable. These events are mostly occurring among patients with solid organ and haematologic malignancies receiving high-dose corticosteroids for >4 weeks, and could be substantially reduced by prescribing prophylaxis to these patients according to guidelines. Patients with rheumatologic diseases also account for a significant proportion of those with PCP in the Auckland region, but reducing the occurrence of PCP in this group will remain challenging until publication of rheumatology-specific guidelines for PCP prophylaxis.
Summary
Abstract
Aim
Pneumocystis pneumonia (PCP) has a high mortality rate in HIV-negative immunocompromised patients, but is preventable with antimicrobial prophylaxis. We aimed to determine the incidence of PCP in three hospitals in Auckland, New Zealand that would have been potentially preventable if patients had been prescribed prophylaxis according to commonly proposed indications.
Method
We conducted a retrospective study of HIV-negative adults with PCP who were admitted to Middlemore, North Shore or Waitakere Hospitals between January 2011 and June 2017. We classified their PCP as potentially preventable if they had not been prescribed prophylaxis despite having a commonly proposed indication for this.
Results
Of the 108 patients with PCP, 33/108 (30.6%) had potentially preventable infection. Of these, 14/33 (42.4%) died within 30 days of diagnosis of PCP. Most potentially preventable infections occurred in patients with solid organ or haematologic malignancies who were receiving high-dose corticosteroids for >4 weeks. We estimate that 28 cases of PCP and 12 deaths could have been prevented over the study duration if prophylaxis was prescribed to those with commonly proposed indications.
Conclusion
There is a substantial incidence of potentially preventable PCP and PCP-related mortality in the Auckland region. This could be reduced by greater clinician familiarity with commonly proposed indications for PCP prophylaxis, particularly for clinicians prescribing prolonged corticosteroid courses to patients with malignancies.
Author Information
Acknowledgements
Correspondence
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Competing Interests
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Pneumocystis pneumonia in HIV-negative adults: missed opportunities for prevention
Pneumocystis pneumonia (PCP), caused by the opportunistic fungus Pneumocystis jirovecii, is almost exclusively a disease of the immunocompromised.
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