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Rifampicin-induced pure red cell aplasia
Rifampicin-lnduced Pure Red Cell Aplasia XAVIERMARIE'I-rE,M.D.Creteil, France MARIETHI~RI~SEMITJAVILA,M.D.Paris, France JEAN PIERREMOULINIE,M.D., ANNETTE BUSSEL,M.D., JEANCLAUDEBROUET,M.D., Ph.D.Cretei/, FranceWlLLIAM VAINCHENKER,M.D.Paris, France JEAN PAULFERMAND, M.D. Creteil, France
p
ure red cell aplasia (PRCA) is characterized by increased, and the hemoglobin level reached normal severe anemia with reticulocytopenia in the ab- values. Several months later, the hematologic survey sence of neutropenia or thrombocytopenia, and isolat- remained normal. ed erythroblastopenia in the bone marrow. It can occur as an idiopathic hematologic disorder or it may be IN VITRO STUDIES Serum samples were collected at the time of diagnoassociated with diverse conditions, including thymorea, lymphoid diseases, autoimmunity, and viral sis (acute-phase serum) and four weeks after the reinfections [1]. In addition, PRCA may develop after mission of PRCA. In vitro cultures of erythroid progenexposure to drugs and has been attributed to antibiot- itors from normal bone marrow were obtained; ics, especially izoniazide [2,3]. We report herein the colony-forming unit-erythroids (CFU-E) and burstcase of a patient treated with pefloxacin and rifampi- forming unit-erythroids (BFU-E) were assayed by the cin in which in vitro studies suggested that rifampicin methylcellulose technique, as previously described [4]. induced PRCA through a drug-dependent serum in- There was a reproducible 30% growth inhibition of normal donor's CFU-E when rifampicin (1 ~g/mL) hibitor of erythroid colony formation. was introduced into the culture medium along with CASE REPORT the acute-phase serum (10%); under the same condiSeven months after surgery for a post-traumatic tions, there was no effect on the growth of colonyfracture, a 30-year-old woman was found to have a forming unit-granulocyte macrophages (CFU-GM) humoral pseudarthrosis caused by staphylococcal in- (Table I). In addition, the effect of the patient's acutefection. She was treated daily with rifampicin (600 mg) phase serum samples and rifampicin on in vitro growth and pefloxacin (800 rag) and did not take any concur- of normal donor's BFU-E was studied in three differrent medication. At that time, the hemoglobin level ent experiments; in one, there was 54% growth inhibiwas 127 g/L, the hematocrit 38%, platelet and white tion and, on the whole, the mean percentage of inhibicell counts were 296 × 109/L and 9.2 × 109/L, respec- tion was 33%. The patient's serum samples did not tively, and the differential count was normal. Six induce any suppression when added to cultures alone weeks after the onset of the treatment, she complained or in combination with pefloxacin (and/or its main ' of increasing weakness, exertional dyspnea, and nau- metabolite, norfloxacin, 1 #g/ml each). Rifampicin per. sea; she stopped rifampicin but sought medical atten- se also had no effect at the concentrations used in the tion only several days later. Physical examination dis- experiments. Of note, no suppression of erythroid colclosed skin pallor but was otherwise normal. The ony formation could be detected in the presence of following laboratory values were obtained: hemoglo- rifampicin when added with a serum sample of the bin 35 g/L; hematocrit 28%; white blood cell count 4.5 patient obtained after remission of PRCA or when X 109/L, with a normal differential; platelets 137 × added with a normal serum sample. Finally, when pe109/L; and reticulocyte count, less than 0.1%. Exami- floxacin and norfloxacin were added together with an nation of a bone marrow specimen revealed normal acute-phase serum sample from the patient and rifammyeloid, lymphoid, and megakaryocytic lineages and a picin, the growth inhibition of erythroid progenitor selective decrease (9%) of erythroid precursors with no cells remained approximately 30% to 50%. mature erythroblasts. Serum electrophoresis and results ofother routine COMMENTS Several cases of PRCA have been induced by varilaboratory tests were normal. No antibodies to B19 parvovirus, hepatitis B virus, human immunodeficien- ous drugs. The drugs mainly held responsible for this cy virus 1 and 2, Epstein-Barr virus, or cytomegalovi- condition include isoniazid [2,3] and phenytoin [5], rus were detected. Anti-immunoglobulin and antinu- although alpha-methyldopa [6], procainamide [7], sulclear antibodies were absent, and Coombs' test was famides [8,9], gold salts [10], D-penicillamine [11], negative, even in the presence of rifampicin or pefloxa- cephalothin [12], and valproate sodium [13] have been cin. There was no radiologic evidence of thymoma. A implicated to a lesser degree. In most cases, discovery diagnosis of PRCA was made, and pefloxacin was dis- of the relationship between PRCA and the drug relied continued. The patient received transfusions with red upon recovery following discontinuation of the therablood cells. Shortly thereafter, the reticulocyte count py that preceded the increase in the reticulocyte count by four to 35 days. Challenges with the putative offending drug were attempted in one patient in whom From the H6pital Saint Louis, Paris, France, and INSERM U.91, HOpital diphenylhydantoin reinduced reversible erythroid hyHenri Mondor, Creteil, France. Requests for reprints should be addressed poplasias [14]. Results of in vitro studies were either to Jean Paul Fermand, M.D., H6pital Saint Louis, Service d'lmmunohdmanegative [2,7,11] or suggested a direct toxic effect of a tologie, 1, avenue Claude Vellefaux, 75475 Paris Cedex 10, France. Manuscript submitted January 20, 1989, and accepted in revised form June 1, drug and/or of a circulating factor [5,6,15,16]. A drug1989. dependent mechanism was demonstrated in only one October 1989 The American Journal of Medicine Volume87
459
RIFAMPICIN-INDUCED PURE RED CELL APLASIA/ MARIETTE ET AL
TABLE I Effects of Patient's Serum on in Vitro Growth of Myeloid and Erythroblastic Colonies DrugAdded Patient's serum (acute phase)
Normal serumt
None Norfloxacin (1 pg) Pefloxacin (1 pg) Rifampicin (1 pg) All three drugs None Norfloxacin (1 #g) Pefloxacin (1 #g) Rifampicin ( l #g) All three drugs
CFU-E*
CFU-GM*
102.6 :E 18
"1994- 9
102 ± ]0 102 -I- 20 72~-7 56 4- 4 86 + 18 84 + 12 90 =t=12 80 4- 9 77 :E 14
200 -I- 20 166 + 26 204:1:20 206 + 20 237 ± 9 ND ND ND ND
ND = not done. " Results are expressed per 1 x 10s cells plated and are the average of triplicate dishes. Similar results were obtained with the patient's serum obtained after remission of PRCA.
case in which the patient's serum IgG obtained at the time of diagnosis induced more than 50% suppression of growth of allogeneic marrow or autologous blood erythroid progenitors only in the presence of diphenylhydantoin [5]. Similarly, we observed a suppression of allogeneic marrow CFU-E and BFU-E in the presence of both rifampicin and the patient's serum sample obtained at diagnosis (but not four weeks later). Pefloxacin, the second drug that might have been incriminated in our case, had no inhibitory effect. The rifampicin and serum suppressive effect was not observed in any control experiments; it was only partial (30% to 50%), but the acute-phase serum we studied was collected several days after rifampicin was discontinued and presumably contained low titers of antibodies. Other side effects of rifampicin, such as hemolytic anemia and peripheral thrombocytopenic purpura (which might have been present at the onset in our patient), are due to the fixation on target cells of drug and antibody complexes [17]. In addition, a similar mechanism may be considered in some cases of rifampicin-induced leukopenia and agranulocytosis [18], with, as in PRCA, involvement of a bone marrow pre-
460
October1989 The American Journal of Medicine Volume 87
cursor. As already mentioned, several cases of PRCA have been attributed to isoniazid but, until now, none to rifampicin. Of note, PRCA has been described as a side effect of the combination of the two drugs [19,20]. Our data demonstrate that in such a setting, one must consider rifampicin as well as isonazid as the putative causative agent. REFERENCES 1. Krantz SB, Dessypris EN: Pure red cell aplasia. In: Golde DW, Takahu F, eds. Hematopoietic stem cells. New York: Marcel Dekker, 1985; 229-251. 2. Hoffman R, Mophedran P, Benz EJ, Duffy TP: Isoniazid-induced pure red cell aplasia, Am Med Sci 1983; 286: 2-9. 3. Claiborne RA, Dutt AK: Isoniazid-inducedpure red cell aplasia.Am Rev Respir Dis 1985; 131: 947-949. 4. Golde DW, Bersch N, Quan SG, Lusis AJ: Production of er'ythroid-potentiating activity by a human Tqymphoblast cetl line. Proc Nati Acad Sci USA 1980; 77: 593596. 5. DessyprisEN, RedlineS, Harris JW, Krantz SB: Diphenylhydantoin-induced pure red cell aplasia. Blood 1985; 65: 789-794. 6. Itoh K, Wong P, Asai T, Yoshida S, Fukuda T: Pure red cell aplasia induced by alpha-methyldopa, Am J Med 1988; 84: 1088-1089. 7. Giannone L, Kugler JW, Krantz SB: Pure red cell aplasia associated with administration of sustained-release procainamide. Arch Intern Med 1987; 147: 11791180.
8. Dunn AM. Kerr GO: Pure red cett aplasia associated with suiphasatazine(letter). Lancet 1981; Ih 1288. 9. Planas AT, Kranwinkel RN, Soletsky HB, Pezzimenti JF: Chlorpropamide-induced pure RBC aplasia. Arch Intern Med 1980; 140: 707-708. 10. Reid D, Patterson AC: Pure red-cell aplasia after gold treatment (letter). Br Med J 1977; 7: 1457. 11. Gollan JL, Hussein S, Hoffbrand AV, Sherlock S: Red cell aplasia following prolonged D-penicillamine therapy. J Clin Pathol 1976; 29: 135-139. 12. MacCulloch D, Jackson JM, Venerys J: Drug-induced red cell aolasia. Br Med J 1974; I: 163-164. 13. Douchain F, Leborgne JM, Robin M, Macart M, Kremp L: Erythroblastop(~nie aiguE par intolOranceau dipropyl acOtatede sodium. Nouv Pr Med 1980; 9: 17151716. 14. Brittingham TE, Lutcher CL, Murphy DL: Reversibleerythroid aplasia induced by diphenylhydantoin. Arch Intern Med 1964; 113: 764-768. 15. Yunis hA, Arimura GK, Lutcher CL, BlasquezJ, Halloran M: Biochemical lesion in Dilantin-induced erythroid aplasia. Blood 1967; 30: 587-600. 16. Lee CM, Firkin FC, Grace CS, Rosenberg MC: Pure red ceil aplasia: a report of three cases with studies on circulating toxic factors against erythroid precursors. Aust NZ J Med 1978; 8: 75-79. 17. Pujet JC, Homberg JC, Decroix G: Sensitivity to rifampicin: incidence, mechanism, and prevention. (3r Med J 1974; 2: 415-418. 18. Van Assendelft AHW: Leucopenia caused by two rifampicin preparations. Eur J Respir Dis 1984; 65: 251-258. 19. Goodman SB, Block MH: A case of red cell aplasia occurring as a result of antituberculous therapy. Blood 1964; 24: 616-623. 20. Dutt AK, Moers D, Stead WW: Short-course chemotherapy for tuberculosis with mainly twice-weekly isoniazid and rifampin. Am J Med 1984; 77: 233-242.
p
ure red cell aplasia (PRCA) is characterized by increased, and the hemoglobin level reached normal severe anemia with reticulocytopenia in the ab- values. Several months later, the hematologic survey sence of neutropenia or thrombocytopenia, and isolat- remained normal. ed erythroblastopenia in the bone marrow. It can occur as an idiopathic hematologic disorder or it may be IN VITRO STUDIES Serum samples were collected at the time of diagnoassociated with diverse conditions, including thymorea, lymphoid diseases, autoimmunity, and viral sis (acute-phase serum) and four weeks after the reinfections [1]. In addition, PRCA may develop after mission of PRCA. In vitro cultures of erythroid progenexposure to drugs and has been attributed to antibiot- itors from normal bone marrow were obtained; ics, especially izoniazide [2,3]. We report herein the colony-forming unit-erythroids (CFU-E) and burstcase of a patient treated with pefloxacin and rifampi- forming unit-erythroids (BFU-E) were assayed by the cin in which in vitro studies suggested that rifampicin methylcellulose technique, as previously described [4]. induced PRCA through a drug-dependent serum in- There was a reproducible 30% growth inhibition of normal donor's CFU-E when rifampicin (1 ~g/mL) hibitor of erythroid colony formation. was introduced into the culture medium along with CASE REPORT the acute-phase serum (10%); under the same condiSeven months after surgery for a post-traumatic tions, there was no effect on the growth of colonyfracture, a 30-year-old woman was found to have a forming unit-granulocyte macrophages (CFU-GM) humoral pseudarthrosis caused by staphylococcal in- (Table I). In addition, the effect of the patient's acutefection. She was treated daily with rifampicin (600 mg) phase serum samples and rifampicin on in vitro growth and pefloxacin (800 rag) and did not take any concur- of normal donor's BFU-E was studied in three differrent medication. At that time, the hemoglobin level ent experiments; in one, there was 54% growth inhibiwas 127 g/L, the hematocrit 38%, platelet and white tion and, on the whole, the mean percentage of inhibicell counts were 296 × 109/L and 9.2 × 109/L, respec- tion was 33%. The patient's serum samples did not tively, and the differential count was normal. Six induce any suppression when added to cultures alone weeks after the onset of the treatment, she complained or in combination with pefloxacin (and/or its main ' of increasing weakness, exertional dyspnea, and nau- metabolite, norfloxacin, 1 #g/ml each). Rifampicin per. sea; she stopped rifampicin but sought medical atten- se also had no effect at the concentrations used in the tion only several days later. Physical examination dis- experiments. Of note, no suppression of erythroid colclosed skin pallor but was otherwise normal. The ony formation could be detected in the presence of following laboratory values were obtained: hemoglo- rifampicin when added with a serum sample of the bin 35 g/L; hematocrit 28%; white blood cell count 4.5 patient obtained after remission of PRCA or when X 109/L, with a normal differential; platelets 137 × added with a normal serum sample. Finally, when pe109/L; and reticulocyte count, less than 0.1%. Exami- floxacin and norfloxacin were added together with an nation of a bone marrow specimen revealed normal acute-phase serum sample from the patient and rifammyeloid, lymphoid, and megakaryocytic lineages and a picin, the growth inhibition of erythroid progenitor selective decrease (9%) of erythroid precursors with no cells remained approximately 30% to 50%. mature erythroblasts. Serum electrophoresis and results ofother routine COMMENTS Several cases of PRCA have been induced by varilaboratory tests were normal. No antibodies to B19 parvovirus, hepatitis B virus, human immunodeficien- ous drugs. The drugs mainly held responsible for this cy virus 1 and 2, Epstein-Barr virus, or cytomegalovi- condition include isoniazid [2,3] and phenytoin [5], rus were detected. Anti-immunoglobulin and antinu- although alpha-methyldopa [6], procainamide [7], sulclear antibodies were absent, and Coombs' test was famides [8,9], gold salts [10], D-penicillamine [11], negative, even in the presence of rifampicin or pefloxa- cephalothin [12], and valproate sodium [13] have been cin. There was no radiologic evidence of thymoma. A implicated to a lesser degree. In most cases, discovery diagnosis of PRCA was made, and pefloxacin was dis- of the relationship between PRCA and the drug relied continued. The patient received transfusions with red upon recovery following discontinuation of the therablood cells. Shortly thereafter, the reticulocyte count py that preceded the increase in the reticulocyte count by four to 35 days. Challenges with the putative offending drug were attempted in one patient in whom From the H6pital Saint Louis, Paris, France, and INSERM U.91, HOpital diphenylhydantoin reinduced reversible erythroid hyHenri Mondor, Creteil, France. Requests for reprints should be addressed poplasias [14]. Results of in vitro studies were either to Jean Paul Fermand, M.D., H6pital Saint Louis, Service d'lmmunohdmanegative [2,7,11] or suggested a direct toxic effect of a tologie, 1, avenue Claude Vellefaux, 75475 Paris Cedex 10, France. Manuscript submitted January 20, 1989, and accepted in revised form June 1, drug and/or of a circulating factor [5,6,15,16]. A drug1989. dependent mechanism was demonstrated in only one October 1989 The American Journal of Medicine Volume87
459
RIFAMPICIN-INDUCED PURE RED CELL APLASIA/ MARIETTE ET AL
TABLE I Effects of Patient's Serum on in Vitro Growth of Myeloid and Erythroblastic Colonies DrugAdded Patient's serum (acute phase)
Normal serumt
None Norfloxacin (1 pg) Pefloxacin (1 pg) Rifampicin (1 pg) All three drugs None Norfloxacin (1 #g) Pefloxacin (1 #g) Rifampicin ( l #g) All three drugs
CFU-E*
CFU-GM*
102.6 :E 18
"1994- 9
102 ± ]0 102 -I- 20 72~-7 56 4- 4 86 + 18 84 + 12 90 =t=12 80 4- 9 77 :E 14
200 -I- 20 166 + 26 204:1:20 206 + 20 237 ± 9 ND ND ND ND
ND = not done. " Results are expressed per 1 x 10s cells plated and are the average of triplicate dishes. Similar results were obtained with the patient's serum obtained after remission of PRCA.
case in which the patient's serum IgG obtained at the time of diagnosis induced more than 50% suppression of growth of allogeneic marrow or autologous blood erythroid progenitors only in the presence of diphenylhydantoin [5]. Similarly, we observed a suppression of allogeneic marrow CFU-E and BFU-E in the presence of both rifampicin and the patient's serum sample obtained at diagnosis (but not four weeks later). Pefloxacin, the second drug that might have been incriminated in our case, had no inhibitory effect. The rifampicin and serum suppressive effect was not observed in any control experiments; it was only partial (30% to 50%), but the acute-phase serum we studied was collected several days after rifampicin was discontinued and presumably contained low titers of antibodies. Other side effects of rifampicin, such as hemolytic anemia and peripheral thrombocytopenic purpura (which might have been present at the onset in our patient), are due to the fixation on target cells of drug and antibody complexes [17]. In addition, a similar mechanism may be considered in some cases of rifampicin-induced leukopenia and agranulocytosis [18], with, as in PRCA, involvement of a bone marrow pre-
460
October1989 The American Journal of Medicine Volume 87
cursor. As already mentioned, several cases of PRCA have been attributed to isoniazid but, until now, none to rifampicin. Of note, PRCA has been described as a side effect of the combination of the two drugs [19,20]. Our data demonstrate that in such a setting, one must consider rifampicin as well as isonazid as the putative causative agent. REFERENCES 1. Krantz SB, Dessypris EN: Pure red cell aplasia. In: Golde DW, Takahu F, eds. Hematopoietic stem cells. New York: Marcel Dekker, 1985; 229-251. 2. Hoffman R, Mophedran P, Benz EJ, Duffy TP: Isoniazid-induced pure red cell aplasia, Am Med Sci 1983; 286: 2-9. 3. Claiborne RA, Dutt AK: Isoniazid-inducedpure red cell aplasia.Am Rev Respir Dis 1985; 131: 947-949. 4. Golde DW, Bersch N, Quan SG, Lusis AJ: Production of er'ythroid-potentiating activity by a human Tqymphoblast cetl line. Proc Nati Acad Sci USA 1980; 77: 593596. 5. DessyprisEN, RedlineS, Harris JW, Krantz SB: Diphenylhydantoin-induced pure red cell aplasia. Blood 1985; 65: 789-794. 6. Itoh K, Wong P, Asai T, Yoshida S, Fukuda T: Pure red cell aplasia induced by alpha-methyldopa, Am J Med 1988; 84: 1088-1089. 7. Giannone L, Kugler JW, Krantz SB: Pure red cell aplasia associated with administration of sustained-release procainamide. Arch Intern Med 1987; 147: 11791180.
8. Dunn AM. Kerr GO: Pure red cett aplasia associated with suiphasatazine(letter). Lancet 1981; Ih 1288. 9. Planas AT, Kranwinkel RN, Soletsky HB, Pezzimenti JF: Chlorpropamide-induced pure RBC aplasia. Arch Intern Med 1980; 140: 707-708. 10. Reid D, Patterson AC: Pure red-cell aplasia after gold treatment (letter). Br Med J 1977; 7: 1457. 11. Gollan JL, Hussein S, Hoffbrand AV, Sherlock S: Red cell aplasia following prolonged D-penicillamine therapy. J Clin Pathol 1976; 29: 135-139. 12. MacCulloch D, Jackson JM, Venerys J: Drug-induced red cell aolasia. Br Med J 1974; I: 163-164. 13. Douchain F, Leborgne JM, Robin M, Macart M, Kremp L: Erythroblastop(~nie aiguE par intolOranceau dipropyl acOtatede sodium. Nouv Pr Med 1980; 9: 17151716. 14. Brittingham TE, Lutcher CL, Murphy DL: Reversibleerythroid aplasia induced by diphenylhydantoin. Arch Intern Med 1964; 113: 764-768. 15. Yunis hA, Arimura GK, Lutcher CL, BlasquezJ, Halloran M: Biochemical lesion in Dilantin-induced erythroid aplasia. Blood 1967; 30: 587-600. 16. Lee CM, Firkin FC, Grace CS, Rosenberg MC: Pure red ceil aplasia: a report of three cases with studies on circulating toxic factors against erythroid precursors. Aust NZ J Med 1978; 8: 75-79. 17. Pujet JC, Homberg JC, Decroix G: Sensitivity to rifampicin: incidence, mechanism, and prevention. (3r Med J 1974; 2: 415-418. 18. Van Assendelft AHW: Leucopenia caused by two rifampicin preparations. Eur J Respir Dis 1984; 65: 251-258. 19. Goodman SB, Block MH: A case of red cell aplasia occurring as a result of antituberculous therapy. Blood 1964; 24: 616-623. 20. Dutt AK, Moers D, Stead WW: Short-course chemotherapy for tuberculosis with mainly twice-weekly isoniazid and rifampin. Am J Med 1984; 77: 233-242.