Occurrence of Pneumocystis jiroveci pneumonia after ... - Nature

3 downloads 60 Views 116KB Size Report
Sep 5, 2005 - occurring after allogeneic HSCT, mainly as a late complication in ..... Trimethoprim-sulfamethoxazole. RSV pneumonia. Cured. 5. F ever, cough,.
Bone Marrow Transplantation (2005) 36, 879–883 & 2005 Nature Publishing Group All rights reserved 0268-3369/05 $30.00

www.nature.com/bmt

Occurrence of Pneumocystis jiroveci pneumonia after allogeneic stem cell transplantation: a 6-year retrospective study N De Castro1, S Neuville1, C Sarfati2, P Ribaud3, F Derouin2, E Gluckman3, G Socie´3 and JM Molina1 1 Department of Infectious Diseases, Saint-Louis Hospital, Assistance-Publique Hoˆpitaux de Paris, Paris, France; 2Department of Parasitology, Saint-Louis Hospital, Assistance-Publique Hoˆpitaux de Paris, Paris, France; and 3Department of Hematology-Stem Cell Transplantation, Saint-Louis Hospital, Assistance-Publique Hoˆpitaux de Paris, Paris, France

Summary: Pneumocystis jiroveci pneumonia (PCP) has become a rare opportunistic infection due to the efficacy of prophylactic regimens. We conducted a 6-year retrospective study at our institution. A total of 13 cases of PCP were diagnosed among 519 patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) (2.5%). In three patients, PCP occurred within the first 5 months following HSCT. These severely immunocompromised patients were receiving prophylaxis and had concomitant aspergillosis that caused rapid death in two of them. In 10 other patients, PCP occurred a median of 14.5 months after HSCT. In all these patients, PCP prophylaxis had been discontinued, mainly because of the suspected bone-marrow toxicity of the prophylactic regimen. Median CD4 þ T cell count was 131/ll at diagnosis. Seven of these 10 patients were receiving immunosuppressive therapy for chronic graft versus host disease and three had a relapse of their hematological malignancy. One patient died from PCP despite high doses of cotrimoxazole. We conclude that PCP is still occurring after allogeneic HSCT, mainly as a late complication in patients in whom PCP prophylaxis had been prematurely discontinued. Long-term PCP prophylaxis should be maintained in patients receiving immunosuppressive drugs, and in those with low CD4 þ T cell counts or a relapse of their hematological malignancy. Bone Marrow Transplantation (2005) 36, 879–883. doi:10.1038/sj.bmt.1705149; published online 5 September 2005 Keywords: Pneumocystis jiroveci; allogeneic stem-cell transplantation; chronic GVHD; CD4 þ T cell count; prophylaxis

Correspondence: Dr N De Castro, Service de Maladies Infectieuses et Tropicales, Hoˆpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France; E-mail: [email protected] This study was presented at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington DC, USA, October 30–November 2, 2004 (poster M-1055). Received 4 April 2005; accepted 15 July 2005; published online 5 September 2005

Pneumocystis jiroveci is an atypical fungus causing severe pneumonia in immunocompromised patients, particularly among allogeneic hematopoietic stem cell transplant (HSCT) recipients.1 Before the use of prophylaxis, 5–16% of patients who received allogeneic marrow transplants developed P. jiroveci pneumonia (PCP) with a median onset at 9 weeks post-transplantation and a mortality rate of up to 76%.2,3 Since the use of effective prophylaxis with trimethoprim-sulfamethoxazole, less than 5% of HSCT recipients still develop PCP.2,4,5 However, recent studies have reported the occurrence of late onset PCP in patients discontinuing prophylaxis after the first 6 months posttransplant.4,6 These reports gave rise to the recommendation of prescribing PCP prophylaxis throughout all periods of immunocompromise after engraftment.7 These recommendations, however, do not clearly define parameters that could be used to determine the best time for discontinuing prophylaxis in HSCT recipients, as recent studies have shown a long-lasting defect in CD4 þ T cells in these patients.8,9 Following the occurrence of PCP among three HSCT recipients in our center in 2002, we decided to undertake a retrospective study of all cases of PCP diagnosed among HSCT recipients within the last 6 years.

Patients and methods In order to describe the clinical characteristics of recent cases of PCP, we retrospectively reviewed the charts of all patients who underwent an allogeneic HSCT and who developed PCP between January 1997 and December 2002 at our institution. Patients were identified through the computerized records of the laboratory of parasitology, by the identification of P. jiroveci trophozoites or cysts with Giemsa staining and/or immunofluorescence with human monoclonal anti-Pneumocystis cysts antibodies in bronchoalveolar lavage (BAL).10 A semiquantitative assessment of parasitic burden was performed on BAL samples, with slides with less than three cysts scored as ( þ ) or presence of rare parasites, slides with 3–20 cysts scored as ( þ þ ) or presence of parasites, and slides with more than 20 cysts scored as ( þ þ þ ) or presence of numerous parasites. Patients infected with the human immunodeficiency virus (HIV) were excluded from this study.

Pneumocystis pneumonia after allogeneic stem cell transplantation N De Castro et al

Bone Marrow Transplantation

AML ¼ acute myeloid leukemia; CML ¼ chronic myeloid leukemia; NHL ¼ non-Hodgkin lymphoma; CMML ¼ chronic myelogenous leukemia; ALL ¼ acute lymphoblastic leukemia; HD ¼ Hodgkin’s disease; MDS ¼ myelodysplasic syndrome; HSCT ¼ hematopoietic stem cell transplantation; GVHD ¼ graft-versus-host disease; IS ¼ immunosuppressive drugs; PCP ¼ Pneumocystis jiroveci pneumonia. ATG ¼ antithymocyte globulin; TBI ¼ total body irradiation; NA ¼ not available.

2.5 months 5 months 4 months 15 months 18.5 months NA 16 months 9 months 13 months 19 months 8 months 44 months 7.5 months — — — 6 months 8.5 months NA 4.5 months NA 3 months 5 months 3 months 5 months 3.5 months No No No Yes Yes Yes Yes NA Yes Yes Yes Yes Yes Cyclosporine 0 Cyclosporine Cyclosporine Hydroxyurea NA 0 Cyclosporine 0 0 0 Cyclosporine Cyclosporine 110 mg/day (1.2 mg/kg) 90 mg/day (2.1 mg/kg) 40 mg/day (0.85 mg/kg) 0 10 mg/day (0.2 mg/kg) Yes 0 50 mg/day (0.9 mg/kg) 5 mg/day (0.1 mg/kg) 0 0 25 mg/day 0 No No No No Yes NA Yes Yes No No NA No No Acute Acute Acute Chronic Chronic Chronic Resolved Chronic Chronic Resolved No Chronic Chronic Busulfan, melphalan Busulfan, cyclophosphamide, ATG TBI, cyclophosphamide, melphalan TBI, Thiothepa, cyclophosphamide, ATG TBI, Thiothepa, cyclophosphamide, ATG TBI, Thiothepa, cyclophosphamide, ATG TBI, cyclophosphamide, ATG Fludarabine, Busulfan TBI, cyclophosphamide, ATG TBI, cyclophosphamide, ATG Busulfan, fludarabine, ATG TBI, Vepeside, cyclophosphamide Busulfan, cyclophosphamide AML 2 AML 4 CMML CML CML CML CML NHL AML 4 T ALL HD ALL/MDS CML

Steroids dose Hematological relapse GVHD Conditioning regimen Sex, age Indication (years) for HSCT n

In three patients, PCP occurred within 5 months following HSCT (patients 1, 2, and 3). All three patients were receiving high doses steroids for GVHD and two of them were also receiving cyclosporine. All were receiving PCP prophylaxis at the time of PCP diagnosis. Patient 1 (Table 2) developed respiratory failure and died 2 days after admission. Bronchial and pulmonary invasive aspergillosis was supposed to be the cause of death, although the role of PCP could not be ruled out. Patient 2 had both pulmonary and cerebral aspergillosis and died from neurological failure 3 weeks after the identification of rare cysts of P. jiroveci in the BAL. This patient did not receive anti-PCP therapy because the diagnosis of PCP was considered unlikely. The third patient (patient 3) was successfully treated for aspergillosis with voriconazole, and for unknown reasons, the result of the detection of P. jiroveci in BAL was only seen 2 months later, a time at which the patient had no pulmonary symptom. Of note, the parasitic burden in BAL was low in these three patients, as no trophozoı¨ te was seen, and only rare cysts (less than three cysts per slide) were detected using immunofluorescence staining.

Epidemiological characteristics of the patients with Pneumocystis jiroveci pneumonia

Early onset PCP

Table 1

From January 1997 to December 2002, 519 patients underwent allogeneic HSCT at our institution. During that period, 14 cases of PCP were diagnosed, with one to three cases each year without temporal clustering. One patient was excluded from the study because he was infected with HIV. Finally, 13 patients were eligible for this study. The demographics of these patients, as well as their clinical and radiological presentation and outcome are presented in Tables 1 and 2. There were six male and seven female subjects, aged 19–50 years (median age: 42 years). A total of 10 patients underwent myeloablative conditioning regimen, two patients a nonmyeloablative conditioning regimen and one patient received a cord-blood HSCT.

Other IS

Results

F, 41 F, 44 F, 40 M, 19 M, 36 F, 42 M, 50 M, 42 F, 38 M, 49 M, 43 M, 45 F, 28

Discontinuation of PCP prophylaxis

Time between prophylaxis interruption and PCP

The following parameters were then collected retrospectively by the same investigator: age, sex, underlying hematological disease, immunosuppressive regimens, presence of graft-versus-host disease (GVHD), PCP-prophylactic regimens, clinical features, treatment and outcome of PCP, total lymphocyte counts, CD4 þ T cell counts, and g-globulin levels at the time of PCP. PCP was considered to have an early onset if occurring within the first 6 months following HSCT, and to have a late onset if occurring more than 6 months after HSCT. In our department, prophylactic regimens are started 2 weeks before engraftment, and are maintained for at least 6 months thereafter. Sulfadoxine-pyrimethamine once weekly and trimethoprim-sulfamethoxazole thrice weekly are the preferred regimens.11

1 2 3 4 5 6 7 8 9 10 11 12 13

Time between HSCT and PCP

880

Pneumocystis pneumonia after allogeneic stem cell transplantation N De Castro et al

NA ¼ not available; OI ¼ opportunistic infections. a IF staining: rare cysts, o3 cysts (+); few cysts, 3–20 cysts (++); many cysts, 420 cysts (+++). b The patients were treated for aspergillosis either with voriconazole or amphotericine B. None received caspofungin that is active on Pneumocystis. c The date of CD4+ T cell counts measurement may be different from the date of total lymphocytes counts measurement: 1, 5 months before for patient 3; 4 months before for patient 6; 4 months before for patient 13.

+++ +++ +/++ +/++ ++ + +/++ + ++ +/++ 4 5 6 7 8 9 10 11 12 13

Fever, cough, dyspnoea Fever, cough, dyspnoea Fever, cough, dyspnoea Fever, cough Fever, cough, chest pain Fever, cough, dyspnoea Fever, cough Cough, dyspnoea Fever, dyspnoea Fever, cough, dyspnoea

Interstitial Alveolar Interstitial Interstitial NA Interstitial Alveolar Interstitial Alveolar Interstitial

+ +        +

160 276 970 980 870 1400 980 3700 NA 1210

1 67 145 140

(1%) (24%) (15%)c (25%) NA 173 (13%) 123 (18%) 368 (10%) NA 101 (21%)c

Delayed Trimethoprimsulfamethoxazole Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole Pentamidine isethionate Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole + None 3

Alveolar



222

17 (7%)c

RSV pneumonia Invasive aspergillosis None Zoster Invasive aspergillosis None None None None None

Died of pulmonary aspergillosis Died of cerebral and pulmonary aspergillosis Died of unrelated sepsis 3 months later Cured Cured Cured Cured Died of PCP Cured Cured Cured Cured Cured Invasive aspergillosisb Invasive aspergillosisb Trimethoprim-sulfamethoxazole 0 + + Fever, dyspnoea None 1 2

Alveolar Alveolar

 

480 610

80 (27%) NA

Invasive aspergillosisb

Outcome CD4+ T cells count (/ml) P. jiroveci in BAL Total lymphocytes Giemsa/IF staininga count (/ml) Radiologic features Symptoms n

Table 2

Clinical, radiological and biological results, and outcome of P. jiroveci pneumonia

Treatment

Concomitant OI (30 days)

881

Late onset PCP In total, 10 of the 13 cases (77%) of PCP were diagnosed more than 6 months after HSCT, and the median time between allogeneic HSCT and PCP was 14.5 months (range, 7.5–44). None of these 10 patients was receiving PCP prophylaxis at the time of diagnosis. The median time between the discontinuation of prophylaxis and PCP was 4.8 months (range, 3–8.5). The decision to discontinue PCP prophylaxis was related to poor graft function attributed to the toxicity of the prophylactic regimen in six patients, intolerance to trimethoprim-sulfamethoxazole in one case, discontinuation of immunosuppressive drugs in one patient, and a duration of more than 1 year of prophylaxis after engraftment in another patient. However, seven of these patients (70%) were receiving immunosuppressive drugs for chronic GVHD at the time of discontinuation of PCP prophylaxis (steroids and cyclosporine, alone or in combination), and three had a relapse of their hematological malignancy. Nine of the 10 assessable patients had lymphopenia with a median lymphocyte count of 970/ml (range, 160–1400). Median CD4 T cell count, available for eight patients, was 131 cells/ml (range, 1–368). Only one patient had a CD4 þ T cell count of more than 200/ml but his CD4 þ T cells represented only 10% of the total T cells. Median g-globulin level, available for eight patients, was 2.4 g/l. Clinical and radiological features of PCP in our patients were typical, with most patients having bilateral pneumonia with a recent onset of fever, cough, and dyspnoea (Table 2). The results of BAL examination are reported in Table 2. As compared to patients with an early onset of PCP, most of these patients with a late onset of PCP had a high parastic burden with trophozoı¨ tes seen on Giemsa stain in three patients. Treatment of PCP included high doses trimethoprimsulfamethoxazole in nine patients, and pentamidine-isethionate in one patient. Seven patients fully recovered from PCP with normal respiratory function, one died from PCP with an acute respiratory distress syndrome, and two developed chronic respiratory failure (restrictive ventilatory defect in one, worsening of an obstructive airway disease due to pulmonary GVHD in the other).

Discussion In our retrospective study, the incidence of PCP among patients with allogeneic HSCT was 2.5%. Among the 13 cases of PCP reported in our study, we were able to distinguish two different situations. The first three patients developed PCP with an early onset of less than 6 months after bone marrow transplantation despite the use of PCP prophylaxis. All patients had invasive aspergillosis and the role of P. jiroveci in the clinical and radiological symptoms of these patients is unclear. We cannot exclude that P. jiroveci was only responsible for colonization and not infection at least in the third case, as recent studies have reported that patients with chronic lung disease or bacterial pneumonia as well as immunocompromised HIV-infected Bone Marrow Transplantation

Pneumocystis pneumonia after allogeneic stem cell transplantation N De Castro et al

882

and uninfected patients could be asymptomatic carriers of P. jiroveci.12–14 Alternatively, acute GVHD and high-dose steroids and cyclosporine in these patients could have triggered PCP despite the use of prophylaxis, maybe because of low intestinal absorption of the prophylactic regimen or resistance of P. jiroveci to sulfonamides through the selection of mutations in the dihydropteroate synthase gene.15,16 The 10 other patients developed a late onset PCP, a median of 14.5 months after engraftment. All patients had discontinued PCP prophylaxis a median of 4.8 months earlier, mainly because of proven or suspected bone marrow toxicity of the prophylactic regimen. Also, seven patients were still receiving immunosuppressive drugs for active chronic GVHD, and three had a malignant relapse, situations which had not been appreciated as an indication for ongoing PCP prophylaxis. Two previous studies have also reported the occurrence of late onset PCP in patients who prematurely discontinued PCP prophylaxis.4,6 Lyytika¨inen et al,6 reported 14 cases of late onset PCP among 110 patients in whom PCP prophylaxis was routinely used only during the first 6 months following engrafment. However, 10 patients were receiving steroids and seven cyclosporine when they developed PCP. Also, seven patients had GVHD and five were in relapse of their hematological malignancy. Tuan et al 4 reported 10 patients with a late onset PCP, a mean of 27 months after marrow transplant. PCP prophylaxis had been discontinued in all patients at least 3 months earlier, although seven patients were receiving immunosuppressive drugs, two had active chronic GVHD and five a malignant relapse. All our patients had lymphopenia at the time of PCP with a low median CD4 cell count of 131 cells/ml. Persistent B- and T cell deficiency has now been documented more than 1 year after allogeneic HSCT and a low CD4 þ T cell count is predictive of infectious morbidity.17,18 A threshold of 200 CD4 T cells/ml has been identified in HIV-infected patients as the level below which the risk of PCP increases dramatically, and at which prophylaxis should be initiated as the activity of CD4 T cells is pivotal in the host’s defense against P. jiroveci.19 Similarly, Mansharamani et al 20 found a median CD4 þ T cell counts of 61/ml in 22 non-HIV-infected patients (mostly transplant recipients and patients with cancer) with PCP and suggest that CD4 þ T cell counts may be a useful marker. Based on these reports and following CDC recommendations, PCP prophylaxis should be given for at least 6 months after engraftment for all patients, but should be continued for patients still receiving immunosuppressive drugs, in case of chronic GVHD, relapse of hematological malignancy, or CD4 þ cell counts less than 200/ml.7 It should be interrupted only several weeks after the cessation of immunosuppressive therapy given the long-lasting T cell defects in patients with chronic GVHD.21 Trimethoprim-sulfamethoxazole or sulfadoxine-pyrimethamine are the preferred regimens because they are the most effective and also prevent Toxoplasma gondii reactivation.11,22 Aerosolized pentamidine, atovaquone, or disulone are acceptable alternatives in case of intolerance Bone Marrow Transplantation

but are probably less effective.23–26 It should also be remembered that bone marrow toxicity is rare with the low doses of trimethoprim-sulfamethoxazole or sulfadoxinepyrimethamine used in prophylaxis, even in bone marrow recipients.22,27 Following this study, we spread these recommendations among our team and only one case of PCP was observed during the following 2 years, as compared to 2–3 cases per year previously.

References 1 Thomas CF, Limper AH. Pneumocystis pneumonia. N Engl J Med 2004; 350: 2487–2498. 2 Meyers JD, Piffer LL, Sale GE, Thomas ED. The value of Pneumocystis carinii antibody and antigen detection for diagnosis of Pneumocystis carinii pneumonia after bone marrow transplantation. Am Rev Resp Dis 1979; 120: 1283–1287. 3 Meyers JD, Flournoy N, Thomas ED. Nonbacterial pneumonia after allogeneic marrow transplantation: a review of ten year’s experience. Rev Infect Dis 1982; 4: 1119–1132. 4 Tuan IZ, Dennison D, Weisdorf DJ. Pneumocystis carinii pneumonitis following bone marrow transplantation. Bone Marrow Tranplant 1992; 10: 267–272. 5 Wingard JR, Mellits ED, Sostrin MB et al. Interstitial pneumonitis after allogeneic bone marrow transplantation. Medicine 1988; 67: 175–186. 6 Lyytika¨inen O, Ruutu T, Volin L et al. Late onset Pneumocystis carinii pneumonia following allogeneic bone marrow transplantation. Bone Marrow Transplant 1996; 17: 1057–1059. 7 Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients: recommendations of the CDC, the Infectious Disease Society of America and the American Society of Blood and Marrow Transplantation. MMWR Recomm Rep 2000; 49: 1–125. 8 Lum LG. The kinetics of immune reconstitution after human marrow transplantation. Blood 1987; 69: 369–380. 9 Maury S, Mary JY, Rabian C et al. Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients. Br J Haematol 2001; 115: 630–641. 10 Beauvais B, Sarfati C, Gerber F et al. Comparative study of 2 classical techniques of coloration and an indirect immunofluorescent assay applied to research on Pneumocystis carinii in the bronchoalveolar lavage fluid and induced sputum in HIV+ patients. Ann Biol Clin (Paris) 1989; 47: 635–639. 11 Foot AB, Garin YJ, Ribaud P et al. Prophylaxis of toxoplasmosis infection with pyrimethamine/sulfadoxine (Fansidar) in bone marrow transplant recipients. Bone Marrow Transplant 1994; 14: 241–245. 12 Chabe´ M, Dei-Cas E, Creusy C et al. Immunocompetent hosts as a reservoir of Pneumocystis organisms: histological and RTPCR data demonstrate active replication. Eur J Clin Microbiol Infect Dis 2004; 23: 89–97. 13 Maskell NA, Waine DJ, Lindley A et al. Asymptomatic carriage of Pneumocystis jiroveci in subjects undergoing bronchoscopy: a prospective study. Thorax 2003; 58: 594–597. 14 Nevez G, Raccurt C, Jounieaux V et al. Pneumocystosis versus pulmonary Pneumocystis carinii colonization in HIV-negative and HIV-positive patients. AIDS 1999; 13: 535–536. 15 Helweg-Larsen J, Benfield TL, Eugen-Olsen J et al. Effects of mutations in Pneumocystis carinii dihydropteroate synthase

Pneumocystis pneumonia after allogeneic stem cell transplantation N De Castro et al

883

16

17

18

19

20

21

gene on outcome of AIDS-associated P. carinii pneumonia. Lancet 1999; 354: 1347–1351. Saito T, Seo S, Kanda Y et al. Early onset Pneumocystis carinii pneumonia after allogeneic peripheral blood stem cell transplantation. Am J Hematol 2001; 67: 206–209. Storek J, Gooley T, Witherspoon RP et al. Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol 1997; 54: 131–138. Nordoy T, Endresen P, Kolstad A et al. Persistent changes in the immune system 4–10 years after ABMT. Bone Marrow Transplant 1999; 24: 873–878. Phair J, Munoz A, Detels R et al. The risk of Pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. N Engl J Med 1990; 322: 161–165. Mansharamani NG, Balachandran D, Vernovsky I et al. Management and outcome patterns for adult Pneumocystis carinii pneumonia, 1985 to 1995. Chest 2000; 118: 704–711. Socie G, Salooja N, Cohen A et al. Late Effects Working Party of the European Study Group for Blood and Marrow Transplantation. Nonmalignant late effects after allogeneic stem cell transplantation. Blood 2003; 101: 3373– 3385.

22 Ioannidis JP, Cappelleri JC, Skolnik PR et al. A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regimens. Arch Intern Med 1996; 156: 177–188. 23 Colby C, McAfee S, Sackstein R et al. A prospective randomized trial comparing the toxicity and safety of atovaquone with trimethoprim/sulfamethoxale as Pneumocystis carinii pneumonia prophylaxis following autologous peripheral blood stem cell tranplantation. Bone Marrow Transplant 1999; 24: 897–902. 24 Link H, Vohringer HF, Wingen F et al. Pentamidine aerosol for prophylaxis of Pneumocystis carinii pneumonia after BMT. Bone Marrow Transplant 1993; 11: 403–406. 25 Marras TK, Sanders K, Lipton JH et al. Aerosolized pentamidine prophylaxis for Pneumocystis carinii pneumonia after allogeneic marrow transplantation. Transpl Infect Dis 2002; 4: 66–74. 26 Souza JP, Boeckh M, Gooley TA et al. High rates of Pneumocystis carinii pneumonia in allogeneic peripheral blood and marrow transplant recipients receiving dapsone prophylaxis. Clin Infect Dis 1999; 29: 1467–1471. 27 Lew MA, Kehoe K, Ritz J et al. Ciprofloxacin versus trimethoprim/sulfamethoxazole for prophylaxis of bacterial infections in bone marrow transplant recipients: a randomized, controlled trial. J Clin Oncol 1995; 13: 239–250.

Bone Marrow Transplantation