CLINICAL
AND
LABORATORY OBSERVATIONS
Ceftriaxone-induced Hemolytic Anemia: Case Report and Review of Literature Michael S. Northrop, MD and Hemant S. Agarwal, MBBS, FAAP
Summary: Ceftriaxone is a frequently used empiric antibiotic in children. Acute hemolysis is a rare side effect of ceftriaxone therapy associated with a high mortality rate. A 14-year-old boy suffering from Crohn disease developed bacterial pneumonia that was treated with ceftriaxone. We report successful management of ceftriaxone-induced hemolytic anemia (CIHA) in this patient and review the CIHA literature in pediatric patients. Early recognition of CIHA with prompt discontinuation of ceftriaxone therapy may have a beneficial role in reduction of high mortality seen in these patients. Key Words: ceftriaxone, immune hemolytic anemia, acute renal failure, multiple organ failure, drug induced
(J Pediatr Hematol Oncol 2015;37:e63–e66)
C
eftriaxone, a third-generation cephalosporin has been in use since 1982.1 It is widely used in pediatric patients because it provides a broad spectrum of activity against gram-positive and gram-negative bacteria. The prolonged half-life and once a day administration represent its added advantages. It is generally well tolerated, and uncommon adverse effects include diarrhea, skin rash, eosinophilia, elevation in serum hepatic enzymes, and biliary sludging.2 CIHA in children is a rare and often fatal complication.3,4 Previous reported cases of cardiovascular decompensation and renal failure in pediatric CIHA patients have been associated with a high mortality rate.4–7 We report successful management of CIHA with multiorgan failure in a 14-year-old boy suffering from Crohn disease by timely diagnosis of CIHA, immediate discontinuation of ceftriaxone therapy along with aggressive cardiorespiratory support. We also review CIHA literature in children.
CASE REPORT A 14-year-old boy with Crohn disease was admitted to the hospital for treatment of pneumonia. He was on stable medications of mesalamine and methotrexate for Crohn disease management. He developed worsening cough and fever up to 1031C over a 4-day period that was unresponsive to azithromycin and ceftriaxone therapy. The rapid influenza and streptococcal antigen tests were negative and his chest x-ray revealed left lingular pneumonia. There was no abdominal pain or diarrhea. He was admitted to the hospital and continued on ceftriaxone therapy for the next 3 days without any significant improvement. He underwent bronchoscopy Received for publication December 17, 2013; accepted April 30, 2014. From the Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN. The authors declare no conflict of interest. Reprints: Hemant S. Agarwal, MBBS, FAAP, Department of Pediatrics, Vanderbilt University Medical Center, 5121 Doctor’s Office Tower, 2200 Children’s Way, Nashville, TN 37232-9075 (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
and esophagogastroduodenoscopy with colonoscopy for further evaluation of his daily high-grade fevers. Bronchoscopy demonstrated mild erythema of the tracheobronchial tree and bronchoalveolar lavage fluid was negative for bacterial or fungal growth. The esophagogastroduodenoscopy and colonoscopy did not reveal new lesions except for an anal fissure. He tolerated the procedures well and he received his intravenous ceftriaxone dose the same night. He complained of abdominal pain, back pain, headache, and had 1 episode of nonbloody vomiting within half an hour of receiving ceftriaxone on day 7 of his antibiotic therapy. His clinical examination revealed a pulse rate of 162/min, fever of 102.31C, and significant pallor. His abdomen was mildly distended but soft. He was quickly transferred to the pediatric intensive care unit since he continued to remain tachycardic, tachypneic, and diaphoretic. He was emergently intubated and fluid resuscitated. His laboratory tests revealed hemoglobin of 2.6 g/dL (hemoglobin before the procedure: 9 g/dL) and serum lactate level of 11.3 mmol/L. He was urgently transfused with 2 U of packed red blood cells (RBCs) followed by another 2 U to give posttransfusion hemoglobin of 10 g/dL. There was no obvious clinical source of acute bleeding. Studies for evaluation of acute blood loss including computed tomography scan of his abdomen, chest, and brain and tagged RBC study of his gastrointestinal tract were negative. His haptaglobin level tested within 6 hours of suspected hemolysis was normal (80 mg/dL); however, the direct antibody test (DAT) was strongly positive (4 +) for complement and negative for immunoglobulin G (IgG). His plasma was tested against untreated and enzyme (ficin)-treated RBCs in the presence of ceftriaxone for suspicion of hemolytic anemia. The untreated RBCs agglutinated (3 +) in the presence of ceftriaxone; the saline control was nonreactive. The enzyme-treated RBCs strongly agglutinated (4 +) in the presence of ceftriaxone. No tests were reactive with anti-IgG. He developed acute tubular necrosis in the next 2 days with cola-colored urine, urinalysis was positive for blood but negative for RBCs on microscopy, serum creatinine rose from 0.65 mg/dL before his deterioration to peak level of 2.17 mg/dL, and renal ultrasound revealed normal corticomedullary differentiation. He also developed acute liver insufficiency in the next 2 days with peak levels of aspartate aminotransferase of 3978 IU/L, alanine aminotransferase of 1623 IU/L, and total bilirubin level of 4.2 mg/dL. He also developed coagulopathy with peak prothrombin time of 18.9 seconds and partial thrombin time of 35 seconds; although he never developed clinical signs of bleeding. Ceftriaxone was immediately discontinued after the acute episode of hemolysis and his antibiotic therapy was changed to vancomycin and piperacillin/tazobactam. His blood, urine, and endotracheal tube secretion cultures were negative and his antibiotic regimen was discontinued following negative culture results. He was extubated within 24 hours of his acute illness. His renal and liver insufficiency and coagulopathy gradually improved with supportive care. The patient was transferred from the intensive care unit in 3 days and discharged home after 4 days.
DISCUSSION Drug-induced immune hemolytic anemia (DIIHA) is a serious but rare adverse reaction with an estimated incidence of 1 to 2 per million individuals per year.8 The median age of patients for DIIHA is 65 years, 58% are
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females and usually there is no direct relationship between the dose of a drug and the reaction.9,10 Medications implicated in DIIHA have substantially grown and changed in the past 50 years.10 In the recent years, anti-infective drugs (30% of cases) followed by musculoskeletal drugs (22% of cases) and cardiovascular drugs (20% of cases) have been associated with DIIHA.9 Drugs can induce hemolytic anemia either by drug adsorption, red cell membrane modification, immune complex formation, or positive antibody formation.11 Ceftriaxone causes hemolytic anemia by immune complex mechanism.12 It is thought that ceftriaxone or its degradation product binds to antibodies in the plasma forming immune complexes.5 Detectable antibodies to ceftriaxone are necessary but not sufficient to cause hemolysis in CIHA.13 Quillen and colleagues found a prevalence of anticeftriaxone antibodies in 8 of 64 (12.5%) pediatric patients with human immunodeficiency virus infection and sickle cell disease exposed to ceftriaxone. Only 2 of these 8 patients with the antibody experienced hemolysis.13 It has been proposed that the ability of ceftriaxone antibody to fix complement is an important variable that predicts the occurrence or severity of hemolysis.14 The immune complexes bind nonspecifically (without antigenic determination) to red cell membranes and activate complement that destroy the RBCs.12 The hemolysis due to complement activation by these antibodies is usually intravascular in nature. It is often acute, severe, and associated with hemoglobinemia, hemoglobulinuria, and in serious cases; there is dramatic drop of hemoglobin following drug exposure. The resulting hemoglobinuria is nephrotoxic particularly when intratubular obstruction facilitates
proximal tubular heme uptake.15 Patients can present with clinical signs and symptoms of jaundice, cardiopulmonary decompensation, renal failure, and shock. CIHA has been reported in 23 pediatric patients (including our case) since 1995 (PubMed online search; limits: English; terms: ceftriaxone and hemolysis; ceftriaxone and renal failure)3–7,16–31 (Table 1). CIHA occurs much more commonly in children as compared with adults.3,32 Children manifesting CIHA commonly have underlying chronic hematologic or immunological disorders or chronic/recurrent infections (Table 1). Eighteen of these patients, including our patient had previous exposure to ceftriaxone.4,6,7,16–23,25,28–31 There was no information reported in the remaining 5 patients.3,5,24,26,27 It is unclear whether the underlying disease processes contribute to the development of anticeftriaxone antibodies and hemolysis, or if repeated exposure to the drug is important, or both.13 Hemolysis in pediatric patients with CIHA usually occurs within 30 minutes (range, 5 to 120 min) of ceftriaxone administration.4–7,16–19,21,23,28 The hemolysis is often dramatic and the hemoglobin can acutely drop to 2.5 g/dL (range, 0.4 to 8.4 g/dL) (Table 1). In adults, the fall in hemoglobin is much less and occurs over a period of hours to days.33 Initial symptoms including chills, fever, vomiting, headache, lumbar and/or abdominal pain, tachycardia, and dyspnea are nonspecific. In serious cases of CIHA, severe anemia results in cardiopulmonary decompensation, and/or shock (Table 1). The massive intravascular hemolysis and hemoglobinuria may progress to acute tubular necrosis. Acute renal failure has been reported in at least 40% of pediatric CIHA patients with an associated mortality rate of 55% (Table 1). The acute drop in hemoglobin along with
Volume 37, Number 1, January 2015
TABLE 1. Ceftriaxone-induced Hemolytic Anemia in Pediatric Patients
References
Age/ Sex
Nadir Hb DAT DAT CVS Renal (g/dL) (IgG) (C3) Compromise Failure Outcome
Primary Diagnosis
Bernini et al6 Lascari and Amyot16 Borgna-Pignatti et al17 Scimeca et al7 Moallem et al18 Meyer et al5 Viner et al19 Citak et al20 Eastlund et al21 Mattis et al22 Kakaiya et al23 Corso and Ravindranath24 Bell et al25 Demirkaya et al26 Kapur et al27 Schuettpelz et al28 Doratotaj et al29 Tobian et al30
2/M 5/M 8/M 3/F 14/F 16/F 6/M 5/F 8/M 9/M 10/M 10/M
Sickle cell anemia Chronic myelocytic leukemia HIV Hypereosinophilic syndrome HIV Recurrent meningitis Sickle cell anemia Recurrent urinary tract infection Peter anomaly Crohn disease Sickle cell anemia Sickle cell anemia
0.9 1.4 4.1 NR 4.9 2.4 2.8 NR 4.5 2.3 NR 2
17/F 5/F 10/M 6/F 4/F 7/M
Hemoglobin SC
5 5.1 8.4 0.4 2.4 4.4
Reis Boto et al31 Goyal et al4 Goyal et al4 Boggs et al3 This case
2/M 2/M 10/F 11/F 14/M
— Craniosynostosis Sickle cell anemia Infantile astrocytoma Hemophagocytic Lymphohistocystosis Congenital nephrotic syndrome Hemoglobin SC Hemoglobin SC Lyme disease Crohn disease
2.8 NR 4 5.9 2.4
+ NR ? NR +
+ NR ? NR + + +
+ +
+ +
+
+ + +
+
+ + + + +
+
+
+ + +
+ +
NR ?
+
+ + +
+ + +
+ NR ? + +
+ + + +
+ + +
Death Death Death Death Death Death Survival Survival Survival Survival Survival Survival Death Survival Survival Survival* Survival Survival Survival Survival Death Survival Survival
*Patient had severe neurological deficit. ? indicates antiglobulin test positive—not specified for IgG and/or C3; CVS, cardiovascular; DAT (C3), direct antibody test for complement; DAT (IgG), direct antibody test for immunoglobuln G; Hb, hemoglobin levels; NR, not reported.
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2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
Volume 37, Number 1, January 2015
Ceftriaxone Induced Hemolytic Anemia
cardiovascular decompensation and acute renal failure has been previously reported to have high mortality.4–7 The rapid progression of hemolysis leading to death in a few hours makes early diagnosis difficult. A high index of DIIHA suspicion is required to promptly diagnose CIHA with serological tests. Normal haptaglobin levels soon after the event may be misleading as in our patient. The DAT is used to determine whether patient’s RBCs have surfacebound IgG and/or complement. The DAT was positive in 18 of 23 reported cases of CIHA in children (Table 1). A positive DAT, however, can be found in 1 in 1000 to 14,000 healthy blood donors without hemolysis.34 The significance of a positive DAT therefore, requires clinical correlation. In the largest reported series of 25 pediatric and adult DIIHA cases caused by ceftriaxone, DAT detected RBC-bound IgG in half of the cases and the DAT was positive for complement in all the cases suggestive of antibody being predominantly immunoglobulin M (IgM) in nature.32 In the laboratory, IgM and/or IgG antibodies almost always activate complement and cause in vitro hemolysis, agglutination, and sensitization of test RBCs in the presence of ceftriaxone, and enzyme-treated RBCs react more strongly than untreated RBCs.8,32 Successful treatment of CIHA as in our patient warrants urgent cardiopulmonary support, correction of severe anemia with blood transfusion, identification of the druginduced hemolysis and most importantly, immediate cessation of ceftriaxone therapy. Blood transfusion can usually be safely administered because the antibodies are drug dependent.24 Steroid therapy is of questionable efficacy in treatment of CIHA.19,26 Plasmapheresis has been attempted as a therapeutic option in few patients with equivocal outcomes.4,28,29 Immediate discontinuation of ceftriaxone therapy after evidence of hemolysis seems to be beneficial in pediatric CIHA patients. In the review of 23 CIHA pediatric patients, 9 patients including our patient did not receive any further ceftriaxone after hemolysis and 8 (89%) of these patients survived.19,21–24,26,30,31 Ceftriaxone therapy was continued in 8 CIHA patients. Four of these 8 patients died, 1 patient had repeated cardiorespiratory arrests with subsequent ceftriaxone doses, 1 patient developed severe renal failure requiring 14 days of hemodialysis, and 1 patient survived with severe neurological deficit.3,5,6,17,20,25,28 In conclusion, physicians treating pediatric patients with chronic hematologic or immunologic disorders or chronic infections should be aware that repeated treatments with ceftriaxone can lead to erythrocyte sensitization associated with sudden and unpredictable hemolysis, which may be fatal. Careful observation is thus required for pediatric patients receiving ceftriaxone because the risk factors, if any, for this dramatic complication have not been clarified, and there is no way to predict its occurrence.
5. Meyer O, Hackstein H, Hoppe B, et al. Fatal immune haemolysis due to a degradation product of ceftriaxone. Br J Haematol. 1999;4:1084–1085. 6. Bernini JC, Mustafa MM, Sutor LJ, et al. Fatal hemolysis induced by ceftriaxone in a child with sickle cell anemia. J Pediatr. 1995;126:813–815. 7. Scimeca PG, Weinblatt ME, Boxer R. Hemolysis after treatment with ceftriaxone. J Pediatr. 1996;1:163. 8. Petz LD, Garratty G. Immune Hemolytic Anemias. 2nd ed. Philadelphia: Churchill Livingston Press; 2004. 9. Garbe E, Andersohn F, Bronder E, et al. Drug induced immune haemolytic anaemia in the Berlin case-control surveillance study. Br J Haematol. 2011;154:644–653. 10. Salama A. Drug-induced immune hemolytic anemia. Expert Opin Drug Saf. 2009;8:73–79. 11. Wright MS. Drug-induced hemolytic anemias: increasing complications to therapeutic interventions. Clin Lab Sci. 1999; 12:115–118. 12. Arndt PA, Leger RM, Garatty G. Serology of antibodies to second and third generation cephalosporins associated with immune hemolytic anemia and/or positive direct antiglobulin tests. Transfusion. 1999;39:1239–1246. 13. Quillen K, Lane C, Hu E, et al. Prevalence of ceftriaxoneinduced red blood cell antibodies in pediatric patients with sickle cell disease and human immunodeficiency virus infection. Pediatr Infect Dis J. 2008;27:357–358. 14. Castellino SM, Combs MR, Zimmerman SA, et al. Erythrocyte autoantibodies in pediatric patients with sickle cell disease receiving transfusion therapy: frequency, characteristics and significance. Br J Hematol. 1999;104:189–194. 15. Zagar RA, Gamelin LM. Pathogenic mechanisms in experimental hemoglobinuric acute renal failure. Am J Physiol. 1989;256:F446–F455. 16. Lascari AD, Amyot K. Fatal hemolysis caused by ceftriaxone. J Pediatr. 1995;126:816–817. 17. Borgna-Pignatti C, Bezzi TM, Reverberi R. Fatal ceftriaxoneinduced hemolysis in a child with acquired immunodeficiency syndrome. Pediatr Infect Dis J. 1995;12:1116–1117. 18. Moallem HJ, Garratty G, Wakeham M, et al. Ceftriaxonerelated fatal hemolysis in an adolescent with perinatally acquired human immunodeficiency virus infection. J Pediatr. 1998;133:279–281. 19. Viner Y, Hashkes PJ, Yakubova R, et al. Severe hemolysis induced by ceftriaxone in a child with sickle-cell anemia. Pediatr Infect Dis J. 2000;1:83–85. 20. Citak A, Garratty G, Ucsel R, et al. Ceftriaxone-induced haemolytic anaemia in a child with no immune deficiency or haematological disease. J Paediatr Child Health. 2002;2: 209–210. 21. Eastlund T, Mulrooney D, Neglia J, et al. Self-limited immune hemolysis in a child after six days of ceftriaxone therapy (abstract). Transfusion. 2002;42(suppl):96S. 22. Mattis LE, Saavedra JM, Shan H, et al. Life-threatening ceftriaxone-induced immune hemolytic anemia in a child with Crohn’s disease. Clin Pediatr (Phila). 2004;2:175–178. 23. Kakaiya R, Cseri J, Smith S, et al. A case of acute hemolysis after ceftriaxone: immune complex mechanism demonstrated by flow cytometry. Arch Pathol Lab Med. 2004; 128:905–907. 24. Corso M, Ravindranath TM. Albuterol-induced myocardial ischemia in sickle cell anemia after hemolysis from ceftriaxone administration. Pediatr Emerg Care. 2005;21:99–101. 25. Bell MJ, Stockwell DC, Luban NL, et al. Ceftriaxone-induced hemolytic anemia and hepatitis in an adolescent with hemoglobin SC disease. Pediatr Crit Care Med. 2005;3: 363–366. 26. Demirkaya E, Atay AA, Musabak U, et al. Ceftriaxone-related hemolysis and acute renal failure. Pediatr Nephrol. 2006;21: 733–736. 27. Kapur G, Valentini RP, Mattoo TK, et al. Ceftriaxone induced hemolysis complicated by acute renal failure. Pediatr Blood Cancer. 2008;50:139–142.
REFERENCES 1. Garratty G. Immune cytopenia associated with antibiotics. Transfus Med Rev. 1993;4:255–267. 2. Finch RG, Greenwood D, Norrby SR, et al. Antibiotic and Chemotherapy. 9th ed. Philadelphia, PA: Elsevier Press; 2010: 170–199. 3. Boggs SR, Cunnion KM, Raafat RH. Ceftriaxone-induced hemolysis in a child with Lyme arthritis: a case for antimicrobial stewardship. Pediatrics. 2011;128:e1289–e1292. 4. Goyal M, Donoghue A, Schwab S, et al. Severe hemolytic crisis after ceftriaxone administration. Pediatr Emerg Care. 2011;27:322–323.
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2014 Wolters Kluwer Health, Inc. All rights reserved.
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28. Schuettpelz LG, Behrens D, Goldsmith MI, et al. Severe ceftriaxone-induced hemolysis complicated by diffuse cerebral ischemia in a child with sickle cell disease. J Pediatr Hematol Oncol. 2009;31:870–872. 29. Doratotaj S, Recht M, Garratty G, et al. Successful treatment of life-threatening ceftriaxone-induced hemolysis by plasmapheresis in a 4-year old girl (abstract). Transfusion. 2009; 49(suppl):13A. 30. Tobian AA, Shirey RS, Savage WJ. Transfusion med illustrated: ceftriaxone-induced acute hemolytic anemia. Transfusion. 2010;50:1647–1648.
31. Reis Boto ML, Sandes AR, Brites A, et al. Severe immune haemolytic anaemia due to ceftriaxone in a patient with congenital nephrotic syndrome. Acta Paediatr. 2011;100:e191–e193. 32. Arndt PA, Leger RM, Garratty G. Serologic characteristics of ceftriaxone antibodies in 25 patients with drug-induced immune hemolytic anemia. Transfusion. 2012;3:602–612. 33. Garratty G. Drug-induced immune hemolytic anemia. Hematol Am Soc Hematol Educ Program. 2009;73–79. 34. Gorst DW, Rawlinson VI, Merry AH, et al. Positive direct antiglobulin test in normal individuals. Vox Sang. 1980;38: 99–105.
e66 | www.jpho-online.com
Copyright
r
Volume 37, Number 1, January 2015
2014 Wolters Kluwer Health, Inc. All rights reserved.
AND
LABORATORY OBSERVATIONS
Ceftriaxone-induced Hemolytic Anemia: Case Report and Review of Literature Michael S. Northrop, MD and Hemant S. Agarwal, MBBS, FAAP
Summary: Ceftriaxone is a frequently used empiric antibiotic in children. Acute hemolysis is a rare side effect of ceftriaxone therapy associated with a high mortality rate. A 14-year-old boy suffering from Crohn disease developed bacterial pneumonia that was treated with ceftriaxone. We report successful management of ceftriaxone-induced hemolytic anemia (CIHA) in this patient and review the CIHA literature in pediatric patients. Early recognition of CIHA with prompt discontinuation of ceftriaxone therapy may have a beneficial role in reduction of high mortality seen in these patients. Key Words: ceftriaxone, immune hemolytic anemia, acute renal failure, multiple organ failure, drug induced
(J Pediatr Hematol Oncol 2015;37:e63–e66)
C
eftriaxone, a third-generation cephalosporin has been in use since 1982.1 It is widely used in pediatric patients because it provides a broad spectrum of activity against gram-positive and gram-negative bacteria. The prolonged half-life and once a day administration represent its added advantages. It is generally well tolerated, and uncommon adverse effects include diarrhea, skin rash, eosinophilia, elevation in serum hepatic enzymes, and biliary sludging.2 CIHA in children is a rare and often fatal complication.3,4 Previous reported cases of cardiovascular decompensation and renal failure in pediatric CIHA patients have been associated with a high mortality rate.4–7 We report successful management of CIHA with multiorgan failure in a 14-year-old boy suffering from Crohn disease by timely diagnosis of CIHA, immediate discontinuation of ceftriaxone therapy along with aggressive cardiorespiratory support. We also review CIHA literature in children.
CASE REPORT A 14-year-old boy with Crohn disease was admitted to the hospital for treatment of pneumonia. He was on stable medications of mesalamine and methotrexate for Crohn disease management. He developed worsening cough and fever up to 1031C over a 4-day period that was unresponsive to azithromycin and ceftriaxone therapy. The rapid influenza and streptococcal antigen tests were negative and his chest x-ray revealed left lingular pneumonia. There was no abdominal pain or diarrhea. He was admitted to the hospital and continued on ceftriaxone therapy for the next 3 days without any significant improvement. He underwent bronchoscopy Received for publication December 17, 2013; accepted April 30, 2014. From the Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN. The authors declare no conflict of interest. Reprints: Hemant S. Agarwal, MBBS, FAAP, Department of Pediatrics, Vanderbilt University Medical Center, 5121 Doctor’s Office Tower, 2200 Children’s Way, Nashville, TN 37232-9075 (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved.
J Pediatr Hematol Oncol
and esophagogastroduodenoscopy with colonoscopy for further evaluation of his daily high-grade fevers. Bronchoscopy demonstrated mild erythema of the tracheobronchial tree and bronchoalveolar lavage fluid was negative for bacterial or fungal growth. The esophagogastroduodenoscopy and colonoscopy did not reveal new lesions except for an anal fissure. He tolerated the procedures well and he received his intravenous ceftriaxone dose the same night. He complained of abdominal pain, back pain, headache, and had 1 episode of nonbloody vomiting within half an hour of receiving ceftriaxone on day 7 of his antibiotic therapy. His clinical examination revealed a pulse rate of 162/min, fever of 102.31C, and significant pallor. His abdomen was mildly distended but soft. He was quickly transferred to the pediatric intensive care unit since he continued to remain tachycardic, tachypneic, and diaphoretic. He was emergently intubated and fluid resuscitated. His laboratory tests revealed hemoglobin of 2.6 g/dL (hemoglobin before the procedure: 9 g/dL) and serum lactate level of 11.3 mmol/L. He was urgently transfused with 2 U of packed red blood cells (RBCs) followed by another 2 U to give posttransfusion hemoglobin of 10 g/dL. There was no obvious clinical source of acute bleeding. Studies for evaluation of acute blood loss including computed tomography scan of his abdomen, chest, and brain and tagged RBC study of his gastrointestinal tract were negative. His haptaglobin level tested within 6 hours of suspected hemolysis was normal (80 mg/dL); however, the direct antibody test (DAT) was strongly positive (4 +) for complement and negative for immunoglobulin G (IgG). His plasma was tested against untreated and enzyme (ficin)-treated RBCs in the presence of ceftriaxone for suspicion of hemolytic anemia. The untreated RBCs agglutinated (3 +) in the presence of ceftriaxone; the saline control was nonreactive. The enzyme-treated RBCs strongly agglutinated (4 +) in the presence of ceftriaxone. No tests were reactive with anti-IgG. He developed acute tubular necrosis in the next 2 days with cola-colored urine, urinalysis was positive for blood but negative for RBCs on microscopy, serum creatinine rose from 0.65 mg/dL before his deterioration to peak level of 2.17 mg/dL, and renal ultrasound revealed normal corticomedullary differentiation. He also developed acute liver insufficiency in the next 2 days with peak levels of aspartate aminotransferase of 3978 IU/L, alanine aminotransferase of 1623 IU/L, and total bilirubin level of 4.2 mg/dL. He also developed coagulopathy with peak prothrombin time of 18.9 seconds and partial thrombin time of 35 seconds; although he never developed clinical signs of bleeding. Ceftriaxone was immediately discontinued after the acute episode of hemolysis and his antibiotic therapy was changed to vancomycin and piperacillin/tazobactam. His blood, urine, and endotracheal tube secretion cultures were negative and his antibiotic regimen was discontinued following negative culture results. He was extubated within 24 hours of his acute illness. His renal and liver insufficiency and coagulopathy gradually improved with supportive care. The patient was transferred from the intensive care unit in 3 days and discharged home after 4 days.
DISCUSSION Drug-induced immune hemolytic anemia (DIIHA) is a serious but rare adverse reaction with an estimated incidence of 1 to 2 per million individuals per year.8 The median age of patients for DIIHA is 65 years, 58% are
Volume 37, Number 1, January 2015
www.jpho-online.com |
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J Pediatr Hematol Oncol
females and usually there is no direct relationship between the dose of a drug and the reaction.9,10 Medications implicated in DIIHA have substantially grown and changed in the past 50 years.10 In the recent years, anti-infective drugs (30% of cases) followed by musculoskeletal drugs (22% of cases) and cardiovascular drugs (20% of cases) have been associated with DIIHA.9 Drugs can induce hemolytic anemia either by drug adsorption, red cell membrane modification, immune complex formation, or positive antibody formation.11 Ceftriaxone causes hemolytic anemia by immune complex mechanism.12 It is thought that ceftriaxone or its degradation product binds to antibodies in the plasma forming immune complexes.5 Detectable antibodies to ceftriaxone are necessary but not sufficient to cause hemolysis in CIHA.13 Quillen and colleagues found a prevalence of anticeftriaxone antibodies in 8 of 64 (12.5%) pediatric patients with human immunodeficiency virus infection and sickle cell disease exposed to ceftriaxone. Only 2 of these 8 patients with the antibody experienced hemolysis.13 It has been proposed that the ability of ceftriaxone antibody to fix complement is an important variable that predicts the occurrence or severity of hemolysis.14 The immune complexes bind nonspecifically (without antigenic determination) to red cell membranes and activate complement that destroy the RBCs.12 The hemolysis due to complement activation by these antibodies is usually intravascular in nature. It is often acute, severe, and associated with hemoglobinemia, hemoglobulinuria, and in serious cases; there is dramatic drop of hemoglobin following drug exposure. The resulting hemoglobinuria is nephrotoxic particularly when intratubular obstruction facilitates
proximal tubular heme uptake.15 Patients can present with clinical signs and symptoms of jaundice, cardiopulmonary decompensation, renal failure, and shock. CIHA has been reported in 23 pediatric patients (including our case) since 1995 (PubMed online search; limits: English; terms: ceftriaxone and hemolysis; ceftriaxone and renal failure)3–7,16–31 (Table 1). CIHA occurs much more commonly in children as compared with adults.3,32 Children manifesting CIHA commonly have underlying chronic hematologic or immunological disorders or chronic/recurrent infections (Table 1). Eighteen of these patients, including our patient had previous exposure to ceftriaxone.4,6,7,16–23,25,28–31 There was no information reported in the remaining 5 patients.3,5,24,26,27 It is unclear whether the underlying disease processes contribute to the development of anticeftriaxone antibodies and hemolysis, or if repeated exposure to the drug is important, or both.13 Hemolysis in pediatric patients with CIHA usually occurs within 30 minutes (range, 5 to 120 min) of ceftriaxone administration.4–7,16–19,21,23,28 The hemolysis is often dramatic and the hemoglobin can acutely drop to 2.5 g/dL (range, 0.4 to 8.4 g/dL) (Table 1). In adults, the fall in hemoglobin is much less and occurs over a period of hours to days.33 Initial symptoms including chills, fever, vomiting, headache, lumbar and/or abdominal pain, tachycardia, and dyspnea are nonspecific. In serious cases of CIHA, severe anemia results in cardiopulmonary decompensation, and/or shock (Table 1). The massive intravascular hemolysis and hemoglobinuria may progress to acute tubular necrosis. Acute renal failure has been reported in at least 40% of pediatric CIHA patients with an associated mortality rate of 55% (Table 1). The acute drop in hemoglobin along with
Volume 37, Number 1, January 2015
TABLE 1. Ceftriaxone-induced Hemolytic Anemia in Pediatric Patients
References
Age/ Sex
Nadir Hb DAT DAT CVS Renal (g/dL) (IgG) (C3) Compromise Failure Outcome
Primary Diagnosis
Bernini et al6 Lascari and Amyot16 Borgna-Pignatti et al17 Scimeca et al7 Moallem et al18 Meyer et al5 Viner et al19 Citak et al20 Eastlund et al21 Mattis et al22 Kakaiya et al23 Corso and Ravindranath24 Bell et al25 Demirkaya et al26 Kapur et al27 Schuettpelz et al28 Doratotaj et al29 Tobian et al30
2/M 5/M 8/M 3/F 14/F 16/F 6/M 5/F 8/M 9/M 10/M 10/M
Sickle cell anemia Chronic myelocytic leukemia HIV Hypereosinophilic syndrome HIV Recurrent meningitis Sickle cell anemia Recurrent urinary tract infection Peter anomaly Crohn disease Sickle cell anemia Sickle cell anemia
0.9 1.4 4.1 NR 4.9 2.4 2.8 NR 4.5 2.3 NR 2
17/F 5/F 10/M 6/F 4/F 7/M
Hemoglobin SC
5 5.1 8.4 0.4 2.4 4.4
Reis Boto et al31 Goyal et al4 Goyal et al4 Boggs et al3 This case
2/M 2/M 10/F 11/F 14/M
— Craniosynostosis Sickle cell anemia Infantile astrocytoma Hemophagocytic Lymphohistocystosis Congenital nephrotic syndrome Hemoglobin SC Hemoglobin SC Lyme disease Crohn disease
2.8 NR 4 5.9 2.4
+ NR ? NR +
+ NR ? NR + + +
+ +
+ +
+
+ + +
+
+ + + + +
+
+
+ + +
+ +
NR ?
+
+ + +
+ + +
+ NR ? + +
+ + + +
+ + +
Death Death Death Death Death Death Survival Survival Survival Survival Survival Survival Death Survival Survival Survival* Survival Survival Survival Survival Death Survival Survival
*Patient had severe neurological deficit. ? indicates antiglobulin test positive—not specified for IgG and/or C3; CVS, cardiovascular; DAT (C3), direct antibody test for complement; DAT (IgG), direct antibody test for immunoglobuln G; Hb, hemoglobin levels; NR, not reported.
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J Pediatr Hematol Oncol
Volume 37, Number 1, January 2015
Ceftriaxone Induced Hemolytic Anemia
cardiovascular decompensation and acute renal failure has been previously reported to have high mortality.4–7 The rapid progression of hemolysis leading to death in a few hours makes early diagnosis difficult. A high index of DIIHA suspicion is required to promptly diagnose CIHA with serological tests. Normal haptaglobin levels soon after the event may be misleading as in our patient. The DAT is used to determine whether patient’s RBCs have surfacebound IgG and/or complement. The DAT was positive in 18 of 23 reported cases of CIHA in children (Table 1). A positive DAT, however, can be found in 1 in 1000 to 14,000 healthy blood donors without hemolysis.34 The significance of a positive DAT therefore, requires clinical correlation. In the largest reported series of 25 pediatric and adult DIIHA cases caused by ceftriaxone, DAT detected RBC-bound IgG in half of the cases and the DAT was positive for complement in all the cases suggestive of antibody being predominantly immunoglobulin M (IgM) in nature.32 In the laboratory, IgM and/or IgG antibodies almost always activate complement and cause in vitro hemolysis, agglutination, and sensitization of test RBCs in the presence of ceftriaxone, and enzyme-treated RBCs react more strongly than untreated RBCs.8,32 Successful treatment of CIHA as in our patient warrants urgent cardiopulmonary support, correction of severe anemia with blood transfusion, identification of the druginduced hemolysis and most importantly, immediate cessation of ceftriaxone therapy. Blood transfusion can usually be safely administered because the antibodies are drug dependent.24 Steroid therapy is of questionable efficacy in treatment of CIHA.19,26 Plasmapheresis has been attempted as a therapeutic option in few patients with equivocal outcomes.4,28,29 Immediate discontinuation of ceftriaxone therapy after evidence of hemolysis seems to be beneficial in pediatric CIHA patients. In the review of 23 CIHA pediatric patients, 9 patients including our patient did not receive any further ceftriaxone after hemolysis and 8 (89%) of these patients survived.19,21–24,26,30,31 Ceftriaxone therapy was continued in 8 CIHA patients. Four of these 8 patients died, 1 patient had repeated cardiorespiratory arrests with subsequent ceftriaxone doses, 1 patient developed severe renal failure requiring 14 days of hemodialysis, and 1 patient survived with severe neurological deficit.3,5,6,17,20,25,28 In conclusion, physicians treating pediatric patients with chronic hematologic or immunologic disorders or chronic infections should be aware that repeated treatments with ceftriaxone can lead to erythrocyte sensitization associated with sudden and unpredictable hemolysis, which may be fatal. Careful observation is thus required for pediatric patients receiving ceftriaxone because the risk factors, if any, for this dramatic complication have not been clarified, and there is no way to predict its occurrence.
5. Meyer O, Hackstein H, Hoppe B, et al. Fatal immune haemolysis due to a degradation product of ceftriaxone. Br J Haematol. 1999;4:1084–1085. 6. Bernini JC, Mustafa MM, Sutor LJ, et al. Fatal hemolysis induced by ceftriaxone in a child with sickle cell anemia. J Pediatr. 1995;126:813–815. 7. Scimeca PG, Weinblatt ME, Boxer R. Hemolysis after treatment with ceftriaxone. J Pediatr. 1996;1:163. 8. Petz LD, Garratty G. Immune Hemolytic Anemias. 2nd ed. Philadelphia: Churchill Livingston Press; 2004. 9. Garbe E, Andersohn F, Bronder E, et al. Drug induced immune haemolytic anaemia in the Berlin case-control surveillance study. Br J Haematol. 2011;154:644–653. 10. Salama A. Drug-induced immune hemolytic anemia. Expert Opin Drug Saf. 2009;8:73–79. 11. Wright MS. Drug-induced hemolytic anemias: increasing complications to therapeutic interventions. Clin Lab Sci. 1999; 12:115–118. 12. Arndt PA, Leger RM, Garatty G. Serology of antibodies to second and third generation cephalosporins associated with immune hemolytic anemia and/or positive direct antiglobulin tests. Transfusion. 1999;39:1239–1246. 13. Quillen K, Lane C, Hu E, et al. Prevalence of ceftriaxoneinduced red blood cell antibodies in pediatric patients with sickle cell disease and human immunodeficiency virus infection. Pediatr Infect Dis J. 2008;27:357–358. 14. Castellino SM, Combs MR, Zimmerman SA, et al. Erythrocyte autoantibodies in pediatric patients with sickle cell disease receiving transfusion therapy: frequency, characteristics and significance. Br J Hematol. 1999;104:189–194. 15. Zagar RA, Gamelin LM. Pathogenic mechanisms in experimental hemoglobinuric acute renal failure. Am J Physiol. 1989;256:F446–F455. 16. Lascari AD, Amyot K. Fatal hemolysis caused by ceftriaxone. J Pediatr. 1995;126:816–817. 17. Borgna-Pignatti C, Bezzi TM, Reverberi R. Fatal ceftriaxoneinduced hemolysis in a child with acquired immunodeficiency syndrome. Pediatr Infect Dis J. 1995;12:1116–1117. 18. Moallem HJ, Garratty G, Wakeham M, et al. Ceftriaxonerelated fatal hemolysis in an adolescent with perinatally acquired human immunodeficiency virus infection. J Pediatr. 1998;133:279–281. 19. Viner Y, Hashkes PJ, Yakubova R, et al. Severe hemolysis induced by ceftriaxone in a child with sickle-cell anemia. Pediatr Infect Dis J. 2000;1:83–85. 20. Citak A, Garratty G, Ucsel R, et al. Ceftriaxone-induced haemolytic anaemia in a child with no immune deficiency or haematological disease. J Paediatr Child Health. 2002;2: 209–210. 21. Eastlund T, Mulrooney D, Neglia J, et al. Self-limited immune hemolysis in a child after six days of ceftriaxone therapy (abstract). Transfusion. 2002;42(suppl):96S. 22. Mattis LE, Saavedra JM, Shan H, et al. Life-threatening ceftriaxone-induced immune hemolytic anemia in a child with Crohn’s disease. Clin Pediatr (Phila). 2004;2:175–178. 23. Kakaiya R, Cseri J, Smith S, et al. A case of acute hemolysis after ceftriaxone: immune complex mechanism demonstrated by flow cytometry. Arch Pathol Lab Med. 2004; 128:905–907. 24. Corso M, Ravindranath TM. Albuterol-induced myocardial ischemia in sickle cell anemia after hemolysis from ceftriaxone administration. Pediatr Emerg Care. 2005;21:99–101. 25. Bell MJ, Stockwell DC, Luban NL, et al. Ceftriaxone-induced hemolytic anemia and hepatitis in an adolescent with hemoglobin SC disease. Pediatr Crit Care Med. 2005;3: 363–366. 26. Demirkaya E, Atay AA, Musabak U, et al. Ceftriaxone-related hemolysis and acute renal failure. Pediatr Nephrol. 2006;21: 733–736. 27. Kapur G, Valentini RP, Mattoo TK, et al. Ceftriaxone induced hemolysis complicated by acute renal failure. Pediatr Blood Cancer. 2008;50:139–142.
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28. Schuettpelz LG, Behrens D, Goldsmith MI, et al. Severe ceftriaxone-induced hemolysis complicated by diffuse cerebral ischemia in a child with sickle cell disease. J Pediatr Hematol Oncol. 2009;31:870–872. 29. Doratotaj S, Recht M, Garratty G, et al. Successful treatment of life-threatening ceftriaxone-induced hemolysis by plasmapheresis in a 4-year old girl (abstract). Transfusion. 2009; 49(suppl):13A. 30. Tobian AA, Shirey RS, Savage WJ. Transfusion med illustrated: ceftriaxone-induced acute hemolytic anemia. Transfusion. 2010;50:1647–1648.
31. Reis Boto ML, Sandes AR, Brites A, et al. Severe immune haemolytic anaemia due to ceftriaxone in a patient with congenital nephrotic syndrome. Acta Paediatr. 2011;100:e191–e193. 32. Arndt PA, Leger RM, Garratty G. Serologic characteristics of ceftriaxone antibodies in 25 patients with drug-induced immune hemolytic anemia. Transfusion. 2012;3:602–612. 33. Garratty G. Drug-induced immune hemolytic anemia. Hematol Am Soc Hematol Educ Program. 2009;73–79. 34. Gorst DW, Rawlinson VI, Merry AH, et al. Positive direct antiglobulin test in normal individuals. Vox Sang. 1980;38: 99–105.
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