lescents who received BMTs at The University of Texas litis. Keywords: dapsone; Pneumocystis carinii; children;. MD Anderson Cancer Center from July 1992 to ...
Bone Marrow Transplantation, (1997) 20, 879–881 1997 Stockton Press All rights reserved 0268–3369/97 $12.00
Dapsone for Pneumocystis carinii prophylaxis in children undergoing bone marrow transplantation HC Maltezou 1,2, D Petropoulos3 , M Choroszy3 , M Gardner3, EC Mantzouranis2, KVI Rolston1 and KW Chan3 Departments of 1Medical Specialties, and 3Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; and 2 Department of Pediatrics, University of Crete, Heraclion, Greece
Summary: Children who undergo bone marrow transplantation (BMT) are at risk for Pneumocystis carinii pneu- monia (PCP). Prophylaxis using trimethoprim/sulfamethoxazole (TMP/SMX) is highly effective but the incidence of adverse drug reactions is significant. We retrospectively reviewed 33 pediatric BMT (25 allogeneic and eight autologous) in whom dapsone was used for PCP prophylaxis because patients were unable to receive TMP/SMX. Dapsone was administered at 50 mg/m2 p.o. once a week from engraftment to 180 days post-autologous BMT, and to 1 year or throughout the duration of immunosuppressive treatment post-allogeneic BMT. With a total of 7268 patient days of dapsone prophylaxis and a median follow-up of 353 days post-BMT, no proven PCP was diagnosed. Sixteen cases of chest radiograph abnormalities were noted in this patient population but none was attributed to PCP. Dapsone was well tolerated by all children with no serious adverse effects; however, one patient developed Toxoplasma gondii encephalitis during dapsone prophylaxis. Dapsone warrants further evaluation as an alternative for PCP prophylaxis in pediatric BMT patients intolerant of TMP/SMX. Additional prophylaxis should be considered for patients at high risk for T. gondii encephalitis. Keywords: dapsone; Pneumocystis carinii; children; bone marrow transplantation
Without effective chemoprophylaxis, Pneumocystis carinii pneumonia (PCP) occurs in 5 to 15% of bone marrow transplant (BMT) recipients, and is associated with a mortality of approximately 60%.1–3 Trimethoprim/sulfamethoxazole (TMP/SMX) is effective for prevention of PCP in the immunocompromised host.1,4,5 Over the last decade, the institution of TMP/SMX prophylaxis has almost completely eliminated PCP in BMT recipients; documented infections were noted only after chemoprophylaxis had been interrupted because of intolerance to the drug, noncompliance or Correspondence: Dr KW Chan, Department of Pediatrics, Box 87, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA Received 4 April 1997; accepted 7 July 1997
when continual immunosuppressive treatment was required.1,6,7 Unfortunately, administration of TMP/SMX can be associated with adverse effects, including myelosuppression, renal toxicity, skin rash, nausea and fever.6–8 For patients undergoing BMT, myelosuppression is of major concern, especially if ganciclovir is required simultaneously. Renal dysfunction is problematic, particularly in patients already receiving potentially nephrotoxic drugs such as cyclosporine. Nausea, vomiting, and skin rash in the post-BMT period can be confused with acute graft-versus-host disease (GVHD). Oral dapsone has been used as an alternative to PCP prophylaxis in children with acquired immunodeficiency syndrome (AIDS) or cancer who are intolerant to TMP/SMX.4,5,9 However, the use of dapsone prophylaxis in BMT recipients (children or adults) has not been reported previously. We report here our experience of using dapsone for PCP prophylaxis in pediatric BMT recipients who were intolerant or allergic to TMP/SMX.
Materials and methods The medical records of 96 consecutive children and adolescents who received BMTs at The University of Texas MD Anderson Cancer Center from July 1992 to October 1996 were reviewed. Patients were followed from the day of admission for BMT to the most recent day of follow-up or death. The standard PCP prophylaxis regimen for BMT recipients in our center is TMP/SMX (5 mg/kg/day twice a week). Dapsone was used instead of TMP/SMX when (1) the patients had a history of allergy or were already on dapsone prior to BMT; (2) were intolerant of the standard regimen after BMT; or (3) their clinical condition such as slow hematologic recovery or skin rash rendered the use of TMP/SMX less desirable. Prophylactic dapsone was administered at a dose of 50 mg/m2 a week (rounded to the nearest 25 mg tablet) for 180 days to autologous BMT recipients for 1 year to allogeneic BMT recipients or for as long as immunosuppressive treatment for GVHD was administered. P. carinii was routinely evaluated in lung tissue or broncho alveolar lavage (BAL) specimen by Grocott methenamine silver stain and correlated with clinical and radiological signs compatible with pneumonia.
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Results A total of 32 children underwent 33 (25 allogeneic and eight autologous) BMTs and received dapsone for PCP prophylaxis (Table 1). Patients were followed for a median of 349 days (range, 55 to 1245) post-BMT. The indications for use of dapsone for PCP prevention were a history of allergic reaction to TMP/SMX (11 patients), concurrent skin rash (six patients), nausea and vomiting (seven patients), slowly recovering blood counts (eight patients), and intolerance to the taste of TMP/SMX (one patient). Dapsone was introduced at a median of 22 days (range, 11 to 55) post-BMT and was administered for a median of 230 days (range, 14 to 667) in allogeneic BMT recipients and a median of 164 days (range, 47 to 275) in autologous BMT recipients. A total of 7268 patient-days of dapsone prophylaxis were evaluated. Fourteen (56%) of the allogeneic BMTs were associated with grade II or greater acute GVHD and extensive chronic GHVD was diagnosed in nine (36%). Twenty-three (70%) of the patients received steroids for a median of 59 days (range, 5 to 518) for the treatment of GVHD, immune hemolytic anemia and recurrent leukemia. No episode of PCP or extrapulmonary P. carinii infection was diagnosed during the period of observation. There were 16 episodes of chest radiographic abnormalities; in 10 episodes an infectious etiology other than PCP was diagnosed by culture and/or response to antimicrobial therapy. Pulmonary hemorrhage was the cause in three other episodes. In the two remaining episodes, both BAL and autopsy showed no infectious etiology. In only one episode was the diagnosis uncertain (in a patient with hepatic GVHD and leukemia in relapse, whose family requested that no invasive diagnostic or therapeutic interventions be performed). This patient had been switched to aerosolized pentamidine (AP) prophylaxis 11 weeks earlier because of liver enzyme abnormalities. Dapsone was well tolerated. Two children had prolonged anorexia and nausea. While on dapsone four patients developed GVHD involving the liver. They were switched Table 1
Patient characteristics
Characteristic
Patients (n = 32)
Median age in years (range)
10 (1.5–21)
BMT total allogeneic, related (%) allogeneic, unrelated (%) autologous (%)
33 11 (33) 14 (43) 8 (24)
GVHD prophylaxis (%) cyclosporine + MTX FK 506 + MTX MTX alone
16 (64) 8 (32) 1 (4)
Relapse of underlying disease post-BMT (%) allogeneic autologous
7 (21) 4 3
BMT = bone marrow transplantation; GVHD = graft-versus-host disease; MTX = methotrexate
to AP prophylaxis but none showed improvement of their liver function tests. No vomiting, diarrhea, skin rash, hemolysis or unexplained myelosuppression was temporally attributed to dapsone administration. Transfusion requirements were similar between patients receiving dapsone and those on TMP/SMX (data not shown). One episode of Toxoplasma gondii encephalitis occurred 3 months postBMT during dapsone prophylaxis in a patient from an endemic area. Dapsone prophylaxis was discontinued in 25 cases: completion of prophylaxis schedule in 14 patients; death in five patients; hepatic GVHD in four patients and change to TMP/SMX prophylaxis in two patients (including one patient with T. gondii encephalitis and one patient by the decision of his primary physician). Eight patients are still receiving dapsone at the time of this report. No PCP was diagnosed in the remaining 64 patients who received TMP/SMX prophylaxis post-BMT during the same period of observation. Discussion Regular administration of TMP/SMX has been proven to be highly effective in the prevention of PCP in immunocompromised patients. Unfortunately, 9–20% of children with leukemia have to discontinue TMP/SMX, mostly as the result of myelosuppression or skin rash. 8,10 The incidence of intolerance is even higher in children with AIDS, probably as a result of the underlying disease and the number of drugs these patients are taking concomitantly. Patients recovering after BMT are also often receiving multiple medications and battling with GVHD and opportunistic infections. When adverse reactions results in interruption of TMP/SMX prophylaxis post-transplant, PCP often develops.7 An alternative to TMP/SMX for PCP prophylaxis is aerosolized pentamidine. The drawbacks of AP include a 5–9% incidence of bronchospasm,10,11 absence of activity against T. gondii and extrapulmonary P. carinii infection,5 and a significantly higher cost. From the current study, we found dapsone to be well tolerated in children intolerant or allergic to TMP/SMX. The once weekly schedule enhanced patient compliance. Despite the large number of medications these patients were receiving, we did not encounter any significant sideeffects related to dapsone. Our experience is similar to that of AIDS patients given low-dose dapsone, in whom only mild and reversible effects were noted.5,11–13 The observed safety of dapsone in our population may be secondary to the dosage and schedule used. Much of the information about the use of dapsone as PCP prophylaxis is reported in AIDS patients. However, the optimal dosage and schedule has not been firmly established.4,5,14 Various studies have demonstrated the efficacy of daily, twice weekly and weekly dapsone in the prevention of PCP. The incidence of adverse reactions to dapsone appears to be related to the dose and frequency of administration.12,14,15 In the present study, we chose a lower dapsone dose of 50 mg/m2 once a week, one successfully used by our leukemia service for over 10 years. Weekly administration of dapsone is feasible because of its prolonged plasma half-life and the long incubation period and repli-
Dapsone for PCP prophylaxis post-BMT HC Maltezou et al
cation cycle of P. carinii. 12,13 We believe that the progressive recovery of the immune system and the relative short duration of immunosuppressive therapy post-BMT allow the use of a less intensive regimen for PCP prophylaxis.6,7,14 It is noteworthy that BMT recipients are customarily given TMP/SMX twice weekly for PCP prophylaxis, whereas leukemia or AIDS patients frequently receive a three times per week regimen.2,4,8 One of our patients developed T. gondii encephalitis while on dapsone prophylaxis. Dapsone possesses activity against T. gondii and can achieve cerebrospinal fluid concentration inhibitory to this organism.16,17 In these reports, dapsone was either administered with pyrimethamine or at doses higher than those used in our patients. We suggest that in patients susceptible to reactivation of T. gondii, pyrimethamine should be incorporated in the current dapsone prophylaxis regimen. None of the patients on dapsone developed PCP after a median observation time of 1 year. Similarly, no patients given TMP/SMX during the same period had PCP infection. Because PCP occurs in less than 1% of BMT patients when effective prophylaxis is prescribed, it requires a very large sample size to detect a difference in regimen efficacy. The result of this retrospective study should therefore be considered preliminary and further studies are warranted to determine the efficacy of dapsone prophylaxis in BMT recipients. References 1 Tuan IZ, Dennison D, Weisdorf DJ. Pneumocystis carinii pneumonitis following bone marrow transplantation. Bone Marrow Transplant 1992; 10: 267–272. 2 Walters EA, Bowden RA. Infection in the bone marrow transplant recipient. Infect Dis Clin N Am 1995; 9: 823–847. 3 Meyers JD, Atkinson K. Infection in bone marrow transplantation. Clin Haematol 1983; 12: 791–811. 4 Ioannidis JP, Cappelleri JC, Skolnik PR et al. A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylaxis regimens. Arch Intern Med 1996; 156: 177–187.
5 Masur H. Prevention and treatment of pneumocystis pneumonia. New Engl J Med 1992; 327: 1853–1860. 6 Hoyle C, Goldman JM. Life threatening infections occurring more than 3 months after BMT. Bone Marrow Transplant 1994; 14: 247–252. 7 Lyytikainen O, Ruutu T, Volin L et al. Late onset Pneumocystis carinii pneumonia following allogeneic bone marrow transplantation. Bone Marrow Transplant 1996; 17: 1057– 1059. 8 Hughes WT, Rivera GK, Schell MJ et al. Successful intermittent chemoprophylaxis for Pneumocystis carinii pneumonitis. New Engl J Med 1987; 316: 1627–1632. 9 Stavola JJ, Noel GJ. Efficacy and safety of dapsone prophylaxis against Pneumocystis carinii pneumonia in human immunodeficiency virus infected children. Pediatr Infect Dis J 1993; 12: 644–647. 10 Mustafa MM, Pappo A, Cash J et al. Aerosolized pentamidine for the prevention of Pneumocystis carinii pneumonia in children with cancer intolerant or allergic to trimethoprim/sulfamethoxazole. J Clin Oncol 1994; 12: 258– 261. 11 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. 12 Hughes WT. Comparison of dosages, intervals and drugs in the prevention of Pneumocystis carinii pneumonia. Antimicrob Agents Chemother 1988; 32: 623–625. 13 Opravil M, Joos B, Luthy R. Levels of dapsone and pyrimethamine in serum during once weekly dosing for prophylaxis of Pneumocystis pneumonia and toxoplasmic encephalitis. Antimicrob Agents Chemother 1994; 38: 1197–1199. 14 Hughes WT, Kennedy W, Dugdale M et al. Prevention of Pneumocystis carinii pneumonitis in AIDS patients with weekly dapsone. Lancet 1990; 36: 1066. 15 Falloon JD, Lavelle J, Ogata-Arakaki D et al. Pharmacokinetics and safety of weekly dapsone and dapsone plus pyrimethamine for the prevention of Pneumocystis pneumonia. Antimicrob Agents Chemother 1994; 38: 1580–1587. 16 Rich JD, Mirochnick M. Dapsone penetrates cerebrospinal fluid during Pneumocystis carinii pneumonia prophylaxis. Diagn Microbiol Infect Dis 1996; 24: 77–79. 17 Derouin F, Piketty C, Chastang C et al. Anti-Toxoplasma effects of dapsone alone and combined with pyrimethamine. Antimicrob Agents Chemother 1991; 35: 252–255.
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