Scandinavian Journal of Infectious Diseases
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Pneumocystis jirovecii pneumonia in HIV-negative patients: A prospective study with focus on immunosuppressive drugs and markers of immune impairment France Roblot, Gwenael Le Moal, Catherine Kauffmann-Lacroix, Frederic Bastides, David Boutoille, Renaud Verdon, Cendrine Godet, Pierre Tattevin & on behalf of the Groupe d’etudes et de Recherche en Infectiologie Clinique du Centre Ouest (GERICCO) To cite this article: France Roblot, Gwenael Le Moal, Catherine Kauffmann-Lacroix, Frederic Bastides, David Boutoille, Renaud Verdon, Cendrine Godet, Pierre Tattevin & on behalf of the Groupe d’etudes et de Recherche en Infectiologie Clinique du Centre Ouest (GERICCO) (2014) Pneumocystis jirovecii pneumonia in HIV-negative patients: A prospective study with focus on immunosuppressive drugs and markers of immune impairment, Scandinavian Journal of Infectious Diseases, 46:3, 210-214, DOI: 10.3109/00365548.2013.865142 To link to this article: http://dx.doi.org/10.3109/00365548.2013.865142
Published online: 23 Jan 2014.
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Scandinavian Journal of Infectious Diseases, 2014; 46: 210–214
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Pneumocystis jirovecii pneumonia in HIV-negative patients: A prospective study with focus on immunosuppressive drugs and markers of immune impairment
FRANCE ROBLOT1, GWENAEL LE MOAL1, CATHERINE KAUFFMANN-LACROIX2, FREDERIC BASTIDES3, DAVID BOUTOILLE4, RENAUD VERDON5, CENDRINE GODET1, PIERRE TATTEVIN6 & ON BEHALF OF THE GROUPE D’ETUDES ET DE RECHERCHE EN INFECTIOLOGIE CLINIQUE DU CENTRE OUEST (GERICCO) From the 1Infectious Diseases Unit, Department of Internal Medicine, University Hospital, Poitiers, 2Mycology Laboratory, University Hospital, Poitiers, 3Infectious Diseases Unit, University Hospital, Tours, 4Infectious Diseases Unit, University Hospital, Nantes, 5Infectious Diseases Unit, University Hospital, Caen, and 6Intensive Care Unit and Infectious Diseases Department, University Hospital, Rennes, France
Abstract Pneumocystis jirovecii pneumonia (PCP) is emerging in HIV-negative patients, for whom the prognosis is significantly worse than in HIV-infected patients and risk factors are poorly characterized. We performed an observational, multicentre, prospective study of 56 consecutive cases of documented PCP in HIV-negative patients, and found that: (1) the main underlying conditions were haematological malignancies (43%), solid tumours (25%), inflammatory diseases (20%), and solid organ transplantation (7%); (2) most patients (80%) had received prolonged corticosteroids, with a mean daily dose of 47.3 ⫾ 32.8 mg equivalent prednisone when PCP was diagnosed, and a mean cumulative dose of 5807 ⫾ 5048 mg over the last 12 months; and (3) the median CD4 cell count was 0.12 ⫻ 109/l (range 0.0–1.42), with a median CD4/ CD8 ratio of 1.32 (0.0–6.4). These findings may be used to better target PCP prophylaxis according to the level of risk and contribute to decrease the burden of PCP in HIV-negative patients.
Keywords: Pneumocystis jirovecii, immunocompromised patients, corticosteroids, haematological malignancies, solid tumours
Introduction Pneumocystis jirovecii pneumonia (PCP) is a severe complication of various immunocompromised conditions [1]. Although during the y 1980–2000 most cases were reported in AIDS patients, over the last decade PCP has become more commonly diagnosed in non-HIV-infected patients than in HIV-infected patients, due to the combined effects of better control of HIV-related immunosuppression, with major progress achieved in antiretroviral treatment, and the emergence of various immunosuppressed states, poorly characterized, often as a consequence of medical progress (e.g. the use of novel therapeutic agents for the control of malignancies and inflammatory diseases; extension of transplant programs) [2,3].
This emergence of PCP in new populations raises unresolved issues. For example, the risk factors for PCP are poorly characterized in these populations, precluding evidence-based guidelines for the targeted use of prophylaxis in the populations most at risk [4]; also, several studies have demonstrated that the prognosis of PCP in HIV-negative patients is worse than that in HIV-infected patients, with in-hospital mortality rates as high as 50% [5]. Given that trimethoprim–sulfamethoxazole (TMP–SMX) is highly effective for the prevention of PCP, with a significant impact on mortality documented not only in HIV-infected patients [6], but also in transplant recipients and selected inflammatory diseases and malignancies [7,8], a
Correspondence: P. Tattevin, Service des Maladies Infectieuses et de Réanimation Médicale, CHU Pontchaillou, 2 rue Henri Le Guilloux, 35033 Rennes Cedex, France. Tel: ⫹33 299289564. Fax: ⫹33 299282452. E-mail:
[email protected] (Received 28 September 2013 ; accepted 4 November 2013) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2013.865142
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Pneumocystis jirovecii in HIV-negative patients better characterization of the risk factors for PCP in non-HIV-infected patients may dramatically reduce the burden of PCP. In HIV-infected patients, the CD4 cell count in peripheral blood provides a simple and accurate method to determine the risk of PCP; the recommendation is that TMP–SMX be initiated in any patient with a CD4 count ⬍ 200 cells/μ l (0.2 ⫻ 109/l), or 15%. For HIV-negative patients, the accuracy of this biomarker is poorly characterized. The level of immunosuppression results from both the impairment in immunity related to the underlying disease itself and from the immunosuppressive effect of most drugs used to control these diseases, particularly corticosteroids. In addition, the pathogenesis of PCP may be different in patients with AIDS as compared to other immunosuppressive states. We aimed to better characterize cases of PCP in nonHIV-infected patients through a prospective, multicentre study, with systematic collection of extensive data on the underlying diseases, the immunosuppressive agents received, and systematic investigations of selected immune system markers. Methods From 2004 to 2008, we prospectively included all cases of PCP in HIV-negative adults documented in 5 university hospitals of the central-western area of France (Poitiers, Tours, Nantes, Rennes, and Caen). These tertiary care hospitals serve as referral centres for an estimated population of 4 million inhabitants, with a mean of 20,000 new diagnoses of cancer per y, and a mean number of 280 solid organ transplants and 75 hematopoietic stem cell transplants (HSCT) performed each year during the study period. A case of PCP was defined by a positive microscopic examination (Gomori–Grocott staining or immunofluorescence) on bronchoalveolar lavage, associated with respiratory symptoms and suggestive chest X-ray or computed tomography scan abnormalities. PCP documented only by polymerase chain reaction was not included, to avoid over-estimation of the number of cases by including patients with mere colonization. Only patients who provided signed informed consent were included (in the case of incapacity, informed consent could be obtained from their relatives). The study was approved by the Poitiers University Hospital review board. In the case of multiple PCP episodes in a patient, we only collected data on the first episode. Demographic and clinical data were collected using a standardized questionnaire, with special attention to the underlying disease(s) and any drug with potential immunosuppressive effect received within the 2 y prior to PCP diagnosis. The daily
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dosage of glucocorticoids was expressed in terms of the prednisone equivalent (e.g. 1 mg of prednisone is equivalent to 0.8 mg of methylprednisolone is equivalent to 1 mg of prednisolone). The prolonged use of corticosteroids was defined as daily intake for more than 1 month. The following biological data were measured in peripheral blood within 3 days after PCP diagnosis: the white blood cell count, total lymphocyte count, CD4 cell count, and CD4/CD8 ratio. Quantitative variables were recorded as the mean (⫾ standard deviation) or as the median (range). Qualitative parameters were recorded as proportions (with percentages).
Results During the study period, 60 patients fulfilled the inclusion criteria. Four patients were excluded for the following reasons: no underlying condition (n ⫽ 1), close to death (n ⫽ 1), and refusal to participate (n ⫽ 2). Finally, 56 patients (38 men and 18 women), with a mean age of 64 ⫾ 14 y (range 23–82 y), were included (Table I). No significant trend was observed over time and there was no seasonal variation. Only 1 patient was supposedly receiving TMP–SMX as PCP prophylaxis when PCP occurred (adherence not evaluated) and 4 were on monthly aerosolized pentamidine.
Underlying conditions Underlying conditions included haematological malignancies (n ⫽ 24, 43%), solid tumours (n ⫽ 14, 25%), inflammatory diseases (n ⫽ 11, 20%), and solid organ transplantation (n ⫽ 4, 7%). Among the 24 haematological malignancies, 11 (46%) were active, while 8 (33%) were in remission when the PCP occurred. Twenty (83%) of these 24 haematological malignancies were non-Hodgkin lymphoma or chronic lymphocytic leukaemia. Three patients had received an autologous bone marrow transplant, at respectively 1 month, 21 months, and 9 y before PCP was diagnosed. One patient had received an allogeneic bone marrow transplant 9 months before PCP. In the group of 14 patients with solid tumours who developed PCP, 10 (71%) were considered as active cancers when the PCP occurred. These were brain (n ⫽ 2), breast (n ⫽ 3), kidney (n ⫽ 2), and uterus, colon, pancreas, sarcoma, molar pregnancy, hepatocellular carcinoma, and oesophagus cancer (1 patient each). Eleven patients had inflammatory diseases: vasculitis (n ⫽ 4), polymyalgia rheumatica (n ⫽ 2), and dermatopolymyositis, rheumatoid arthritis, myasthenia, immune thrombocytopenic purpura, and extramembranous glomerulonephritis (1 patient
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Table I. Patient characteristics (N ⫽ 56). Age y, mean ⫾ SD (range) Male gender, n (%) Underlying condition, n (%) Haematological malignancy Solid tumour Inflammatory disease Solid organ transplant Hematopoietic stem cell transplant Immunosuppressive therapy before PCP diagnosis Corticosteroids, n (%) Steroids, average daily dose (mg), mean ⫾ SD (range) Steroids, mean cumulative dose over the previous y (mg), mean ⫾ SD Cytotoxic chemotherapy, n (%) Biological investigations WBC count (109/l), mean ⫾ SD; median (range) Total lymphocyte count (109/l), mean ⫾ SD; median (range) CD4 cells counta (109/l), median (range) CD4/CD8 ratioa, median (range) CD4 (percentage of total lymphocytes)a, median (range)
64 ⫾ 14 (23–82) 38 (68%) 24 (43%) 14 (23%) 11 (20%) 4 (7%) 4 (7%) 45 (80%) 47.3 ⫾ 32.8 (5–120) 5807 ⫾ 5048 37 (66%) 11.37 ⫾ 12.5; 8.25 (2.4–80.8) 3.18 ⫾ 11.5; 0.49 (0.02–73.8) 0.12 (0.0–1.42) 1.32 (0.0–6.4) 35.0 (0.0–75.4)
SD, standard deviation; PCP, Pneumocystis jirovecii pneumonia; WBC, white blood cell. available for 37 patients only.
aData
each). The 4 solid organ transplant recipients who developed PCP had received a kidney transplant at respectively 4, 8, 11 months, and 10 y before PCP diagnosis. Of note, the latter was on cytotoxic chemotherapy for non-Hodgkin lymphoma when PCP was diagnosed. Immunosuppressive agents Overall, 45 patients (80%) had received corticosteroids during the year before PCP diagnosis, of whom 40 (71%) had received prolonged corticosteroid therapy. On the day of PCP diagnosis, corticosteroid therapy was ongoing in 34 patients (61%), with a mean daily dose of 47.3 ⫾ 32.8 mg equivalent prednisone (range 5–120 mg) and a mean cumulative dose of 5807 ⫾ 5048 mg over the last 12 months. In addition, 37 patients (66%) had received cytotoxic drugs within the 2 y before PCP diagnosis, mostly cyclophosphamide (n ⫽ 22, including 18 intravenous and 4 oral) and vincristine (n ⫽ 11). Regarding monoclonal antibody use, 12 patients (21%) had received rituximab during the year preceding PCP diagnosis, and 2 had received tumour necrosis factor alpha inhibitors. Biological investigations The mean white blood cell count was 11.37 ⫾ 12.5 ⫻ 109/l, with a median of 8.25 ⫻ 109/l (range 2.4–80.8), and the mean total lymphocyte count was 3.18 ⫾ 11.5 ⫻ 109/l, with a median of 0.49 ⫻ 109/l (range 0.02–73.8). CD4 cell counts were available for only 37 patients; the median count was
0.12 ⫻ 109/l (range 0.0–1.42) and the median CD4/ CD8 ratio was 1.32 (0.0–6.4).
Discussion PCP can complicate the course of various immunosuppressive conditions, including HIV infection, organ transplant, malignancies, and inflammatory diseases [1,9]. Guidelines for primary prophylaxis of PCP have been well established in only a few groups of patients, including HIV-infected patients [6], HSCT recipients, those with malignancies [10,11], solid organ transplant recipients [12,13], and patients with granulomatosis with polyangiitis (formerly known as Wegener’s granulomatosis). In addition, the American Thoracic Society (ATS) advises prophylaxis to be considered during the time period when the prednisone dose exceeds 20 mg/day for longer than 1 month, but acknowledges that this is based on a low level of evidence [14]. Our prospective, observational, multi-centre study investigated in depth the main underlying conditions and immunosuppressive therapies associated with PCP in non-HIV-infected patients in the modern era. Haematological malignancies remain, by far, the conditions most at risk, especially nonHodgkin lymphoma and chronic lymphocytic leukaemia. Two other groups of underlying conditions are reported in most series, at a lower level: (1) solid cancer (brain cancer being top of this list, probably due to the prolonged use of high doses of corticosteroids to relieve tumour-related brain oedema) [15], and (2) inflammatory diseases [16]. Among all these conditions, the use of cytotoxic drugs and
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Pneumocystis jirovecii in HIV-negative patients glucocorticoids is a common observation, and probably a powerful cofactor. Primary PCP prophylaxis should be targeted at the populations most at risk, taking into account these findings. The distribution of the main underlying conditions identified in this observational study of PCP in HIV-negative patients should be interpreted in the light of the practices regarding PCP prophylaxis during the study period. For example, some of the immunosuppressive states at higher risk had been recognized before this study took place and this led to the routine use of daily or three times weekly TMP–SMX in any patient with granulomatosis with polyangiitis, and during the early phase after HSCT or solid organ transplantation [17]. Given the high efficacy of these prophylactic regimens, PCP has become a rare event in these conditions, occurring only in patients not receiving TMP–SMX (because of adherence issues, intolerance, or medical error). This study confirms most of the epidemiological data previously available on the risk factors for PCP in non-HIV-infected patients. In addition, prospective collection of extensive information on the immunosuppressive drugs used during the 2 y prior to PCP diagnosis provides detailed data on the broad spectrum of immunosuppressive agents received by these patients, often in combination. Glucocorticoids have long been reported as a common and major risk factor for PCP, as documented in our study, with a mean daily dose of 47.3 ⫾ 32.8 mg equivalent prednisone by the time PCP was diagnosed. Of note, most patients also received cytotoxic drugs, cyclophosphamide being the most frequent, as reported previously. Although 12 of our patients (21%) had received rituximab during the previous 2 y, the association of this drug with the risk of PCP is not certain, because of the multiplicity of potential cofactors (underlying diseases, other immunosuppressive agents). The same applies for low-dose methotrexate. Whether or not HIV-infected, most patients who develop PCP present with low total lymphocyte and CD4 cell counts; medians of 0.49 and 0.12 ⫻ 109/l, respectively, were found in the study presented here. In a prospective observational study, Mansharamani et al. found that a cut-off of 300 CD4 cells/μl (0.3 ⫻ 109/l) would capture 91% of cases of PCP in HIV-negative patients [18]; however this cut-off would also capture 39.1% of patients on corticosteroids and 46.7% of persons receiving corticosteroids in combination with at least one other agent, most of whom would be unaffected by PCP. Administering prophylaxis to such large numbers of patients would unnecessarily expose patients to drug-related adverse events. Indeed, among all patients administered TMP–SMX prophylaxis in a meta-analysis, the
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rate of discontinuation due to adverse events was 15.2%, with a 3.1% rate of severe adverse events. A risk–benefit analysis suggested that only patients with an estimated risk of PCP ⬎ 3.5% should be initiated on TMP–SMX prophylaxis [18]. This study has limitations. Its observational design, with only 5 participating sites in the centralwestern part of France, means that findings may not be applicable in other settings, especially given the heterogeneity of practices regarding PCP prophylaxis in non-HIV patients and the variability in PCP epidemiology worldwide. In addition, due to the limited sample size, we were not powered to identify underlying conditions at low risk of PCP. Despite these limitations, our findings may be used to better target PCP prophylaxis according to the level of risk and contribute to decrease the burden of PCP in HIV-negative patients.
Acknowledgements We are indebted to all of the patients who participated in the study and the healthcare workers who took care of them. Declaration of interest: FR has received grants from Aventis, Novartis, Pfizer, and ViiV Healthcare for workshops or travel to meetings and accommodation. PT has received grants from Astellas, Astra-Zeneca, Aventis, Bristol-Myers Squibb, Galderma, Gilead Sciences, Janssen-Cilag, MSD, Novartis, Pfizer, and ViiV Healthcare for consultancy, workshops, or travel to meetings and accommodation. RV has received grants for travel and workshops from Bristol-Myers Squibb, Gilead Sciences, MSD, and ViiV Healthcare. This study was supported by the French Ministry of Health (Programme Hospitalier de Recherche Clinique).
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