Clin J Gastroenterol (2011) 4:313–317 DOI 10.1007/s12328-011-0235-8
CASE REPORT
Pure red cell aplasia caused by ribavirin and interferon treatment Andrew J. Skabelund • Timothy R. Hauser Kevin J. Goist
•
Received: 14 October 2010 / Accepted: 12 May 2011 / Published online: 30 July 2011 Ó Springer 2011
Abstract Anemia is a common complication of hepatitis C (HCV), and antiviral treatment can further increase this risk. We present the case of a 59-year-old man with HCV treated with ribavirin and pegylated interferon alpha (INF-a) who presented with severe anemia. Two months after initiating treatment his hemoglobin dropped from 14.2 to 5.0 g/dL. There was no evidence of bleeding or hemolysis, and a bone marrow biopsy revealed pure red cell aplasia (PRCA). Evaluations for acute cytomegalovirus and parvovirus B19 were negative. There was no evidence of malignancy or thymoma. The INF-a and ribavirin treatment were determined to have caused the PRCA, and withdrawal of the medications led to PRCA remission. INF-a and ribavirin have become the standard treatment for HCV. While these medications offer a potential cure, they are often poorly tolerated due to frequent side effects including anemia. Patients who are receiving treatment with ribavirin and INF-a warrant close monitoring for development of anemia, and PRCA should be considered in all patients in whom reticulocytopenic anemia develops.
Introduction Anemia is a common complication of infection with hepatitis C (HCV) [1]. The anemia can stem from direct effects of the virus, underlying liver disease, or even from treatment of the infection. The combination antiviral therapy of interferon, most commonly pegylated interferon alpha-2a (INF-a), and ribavirin (RIB) has revolutionized the treatment and outcomes for many patients with HCV. This combination therapy commonly causes dose-limiting hemolytic anemia. Pure red cell aplasia (PRCA) is a rare disorder associated with bone marrow erythroid hypoplasia that results in severe and often transfusion-dependent anemia [2]. PRCA is classically associated with thymomas, parvovirus B19 infection, and hematologic malignancies; however, numerous other etiologies have been described. We describe a unique case of PRCA caused by INF-a/RIB dual therapy in a patient being treated for HCV.
Case presentation Keywords Pure red cell aplasia Interferon Ribavirin Hepatitis C The views and opinions expressed in this article/presentation are those of the author(s) and do not reflect official policy or position of the United States Air Force, Department of Defense, or US Government. A. J. Skabelund (&) T. R. Hauser K. J. Goist 88th Medical Group, Department of Internal Medicine, Wright-Patterson Medical Center, 88th MDOS/SGOMI, 4881 Sugar Maple Drive, Wright-Patterson Air Force Base, OH 45433, USA e-mail: [email protected] T. R. Hauser e-mail: [email protected]
A 59-year-old male with chronic HCV presented with progressive weakness, fatigue, and decreased exercise capacity. Dual antiviral therapy for HCV with RIB and INF-a was initiated 2 months prior to presentation. He was presumed to have contracted HCV in the late 1980s when he received a blood transfusion during a surgical procedure. At baseline, he had mildly elevated liver enzymes and a liver biopsy had revealed fibrosis without cirrhosis. He presented with hemoglobin (Hg) of 5.0 g/dL. He had no previous history of anemia, and he denied any mucosal, gastrointestinal, cutaneous or urogenital bleeding. He also had history of hypertension, peripheral arterial disease, depression, and hyperlipidemia. He had been on a stable
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regimen of beclomethasone, spironolactone, enalapril, esomeprazole, gabapentin, nystatin, and megestrol for over a year prior to initiation of RIB and INF-a. One year prior to the initiation of treatment, his hg was 14.2 and was near that same value when treatment was initiated. Table 1 shows laboratory values prior to, during, and following his treatment. Over the course of treatment the patient’s hemoglobin was monitored and after 1 month the dose of RIB was reduced. His liver enzymes normalized, and there had been a 2 log drop in his viral load. At 2 months his Hg was noted to be 5.5; all treatment was discontinued and he subsequently presented to the hospital. The patient was pleasant and in no acute distress. He was normotensive with normal vital signs. He was pale, thin, and cachectic. He was without jaundice or scleral icterus. His cardiopulmonary, abdominal, and rectal examinations were unremarkable. His stool was repeatedly hemoccult negative. He was admitted to the hospital for severe anemia. He was transfused five units of packed red blood cells and demonstrated an appropriate increase in Hg (9.4 g/dL). Admission laboratory values and subsequent laboratory results are presented in Table 2. There was no evidence of Table 1 Laboratory data related to treatment course Hb hemoglobin, AST aspartate aminotransferase, ALT alanine aminotransferase, PCR hepatitis C polymerase chain reaction, quantitative real time
hemolysis, nutritional deficiencies, active bleeding or coagulopathy. Peripheral blood smear showed a paucity of red blood cells and the absence of reticulocytes. Serologies for parvovirus B19 and cytomegalovirus were negative for acute infection. Computed tomography (CT) of the chest revealed no masses or abnormalities. A bone marrow biopsy showed a hypocellular bone marrow with pure red cell aplasia, no proerythroblasts, adequate development of other cell lines, and no evidence of acute leukemia. Staining of the bone marrow for Hg can be seen in Fig. 1. PRCA was diagnosed based on the serologic and bone marrow findings. After ruling out other known causes of PRCA, the antiviral treatment of RIB and INF-a were determined to be the causative agents. Antiviral therapy was discontinued, and the patient’s Hg remained stable. He required no other transfusions, and 3 months following discontinuation of treatment his Hg was 13.6 g/dL.
Discussion Anemia is a common complication of HCV [1]. Any drastic drop in hemoglobin in a patient with chronic liver
Test
13 months prior to therapy
Therapy initiation
Therapy month 1
Therapy month 2
3 months following therapy cessation
Hb (g/dL)
14.2
13.7
9.3
5.5
13.6
AST (U/L)
41
118
31
19
24
ALT (U/L)
44
73
34
17
28
PCR (IU/mL)
–
6170000
234000
47000
–
Table 2 Admission laboratory data Test
Results
Hematology
Test
Result
Test
Biochemistry
Result
Virology
WBC
2,400/lL
AST
17 U/L
CMV PCR
Negative
Hb Platelets
5.0 g/dL 91000/lL
ALT Alk Phos
15 U/L 125 U/L
CMV IgG CMV IgM
Positive Negative
MCV
101.6 fL
Tot Bili
0.1 mg/dL
PV B19 IgG
Positive
Retic
0.40%
Protein
7.2 g/dL
PV B19 IgM
Negative
Haptoglobin
408 mg/dL
Albumin
3.3 g/dL
Cryoglobulin
Negative
HIV
Negative
Vitamin B12
939 pg/mL
Folate
[24 ng/mL
Coagulation
Bone marrow
PT
9.4
Adenovirus Cx
PTT
24.3
CMV Cx
Negative Negative
INR
0.9
Fungal Cx
Negative
WBC white blood cells, Hb hemoglobin, MCV mean corpuscular volume, Retic reticulocyte, PT prothrombin time, PTT partial thromboplastin time, INR international normalized ratio, AST aspartate aminotransferase, ALT alanine aminotransferase, Alk Phos alkaline phosphatase, Cx culture, CMV cytomegalovirus, PCR polymerase chain reaction, IgG immunoglobulin G, IgM immunoglobulin M, PV parvovirus, HIV human immunodeficiency virus
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Fig. 1 a Patient bone marrow stained for hemoglobin by immunoprecipitation (IP). b Control bone marrow stained for hemoglobin by IP
disease is concerning for acute hemorrhage; however, extreme decreases in hemoglobin in patients with HCV can also be associated with hemolytic anemia [3] and bone marrow suppression [4]. Well-established pharmacological treatments of HCV are also associated with severe anemia [5]. The combination antiviral therapy of RIB/INF-a has revolutionized the treatment of HCV. This therapy produces a sustained viral response in approximately 50% of treated patients [6]. RIB is often associated with dose-dependent hemolytic anemia [7], and up to 25% of patients require dose reduction for treatment continuation [8]. INF-a can also suppress bone marrow and lead to significant hemoglobin reduction or even aplastic anemia [9–11]. INF-a has also very rarely been associated with hemolytic anemia in patients being treated for viral hepatitis [12]. PRCA is a rare disorder characterized by normochromic, normocytic or slightly macrocytic anemia with reticulocytopenia and near-complete absence of erythroblasts in the bone marrow [13–15]. Diamond–Blackfan anemia is a rare congenital form of PRCA associated with hypoplastic anemia and a variety of cardiac, neurological, and craniofacial defects [15]. More commonly, PRCA manifests in the adult population and can be classified as primary (idiopathic) or secondary [14]. Thymomas are classically associated with PRCA, and initial reports indicated that nearly 50% of cases of PRCA were associated with thymomas [16]; however, more recent literature reviews suggest that thymomas account for \10% of all cases of PRCA [17]. One of the best described associations with PRCA is parvovirus B19. The virus infects erythroid precursors in the bone marrow, resulting in arrest of the development of erythroid lineage at the pronormoblast stage. The bone marrow of afflicted individuals has numerous giant pronormoblasts and few mature erythroid progenitors. The result is a transient period of asymptomatic aplasia in the majority of infected individuals, but immunosuppressed patients and those with chronic hemolytic anemia may develop life-threatening aplastic crises [18]. Various other infections including
HCV, hepatitis A and B, HIV, CMV, and disseminated tuberculosis have been associated with development of PRCA [19–25]. Successful treatment of HCV has been associated with sustained hematologic remission of PRCA [20]. Other rare causes of PRCA include myelodysplastic syndrome, ABO-incompatible bone marrow transplantation, and rheumatologic disorders such as Sjo¨gren’s syndrome, systemic lupus erythematosus, and rheumatoid arthritis [14, 26–29]. Over 30 medications have been associated with PRCA [13]. The mechanism for erythroid suppression is generally unknown, but unique antibodies that retard development of progenitor cells when in the presence of certain medications have been identified [30]. Recently, numerous patients on chronic erythropoietin therapy for various forms of longstanding anemia developed PRCA. Subsequent evaluations revealed the development of neutralizing anti-EPO antibodies resulting in bone marrow erythroid hypoplasia [31]. Anemia is common in patients treated with RIB/INF-a dual therapy [32], and recombinant erythropoietin agents have been demonstrated to decrease the therapy-associated anemia [33]. These agents are commonly given to symptomatic patients being treated for HCV and have been associated with the development of erythropoietin antibody-associated PRCA [34]. Isolated INF-a therapy can cause bone marrow suppression and rarely has been associated with development of PRCA [35–38]. Three of these cases were in patients who had underlying hematologic malignancies associated with development of PRCA. The fourth case, however, was in a patient with HCV on immunosuppressant therapy following orthotopic liver transplant (OLT). This patient was treated with INF-a and subsequently developed PRCA. The anemia in this patient did not resolve with discontinuation of the INF-a, and the patient required multiple transfusions over a 5-month period. IVIG was eventually administered, and the patient required no further transfusions. The protracted disease course following discontinuation of the INF-a and the need for IVIG therapy suggest a
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disease mechanism dissimilar to that of our patient. Additionally, that patient had multiple other possible unique contributing factors including transplant rejection and immunosuppression that were not shared by our patient. There are three previous cases where the combination therapy of INF-a and RIB has been associated with development of PRCA [39–41]. One case included a patient treated for longstanding HCV. Similar to our patient he experienced greater than a 2 log drop in his HCV viral load and all studies were suggestive of PRCA. Additionally, after complete discontinuation of therapy, his hematologic indices normalized without further intervention. However, in this patient INF-a therapy was restarted and there was no recurrence of his HCV or PRCA [39]. Another patient was also an OLT recipient who had been on mycophenolate mofetil and tacrolimus when he was started on dual therapy for recurrent HCV [40]. His anemia was noted after 2 weeks, and the INF-a/RIB therapy was discontinued but his Hg did not improved until the mycophenolate mofetil was stopped. The patient suffered an episode of graft rejection and eventually tolerated reinitiation of the mycophenolate mofetil and even the INFa/RIB therapy. This suggests a multifactorial cause of the PRCA that is difficult to attribute to the INF-a/RIB therapy. The final patient developed PRCA following combination therapy [41]. The RIB was discontinued and the patient remained transfusion dependent for an additional 11 weeks. At that time a bone marrow biopsy was performed and the patient was then determined to have PRCA. This patient did not recover spontaneously, and a 12-week course of cyclosporine and metenolone acetate was administered before his blood counts normalized. Analysis of these cases suggests two distinct mechanisms. One mechanism appears to be immunogenic and does not remit when the offending agent has been withdrawn. These cases require additional immunosuppression or immunomodulation before the bone marrow will recover. In these cases the INF-a appears to be more likely to be the causative agent. The other mechanism suggests direct bone marrow suppression. Once the offending agent is withdrawn, the bone marrow recovers function and the patient requires no further therapy. This was seen appears to be what occurred with our patient. This mechanism appears to be more likely to be attributed to the RIB therapy. The myelosuppressive effects of RIB have been demonstrated in animal studies [42]. In these studies the bone marrow biopsies of the animals demonstrated erythroid precursor aplasia. Elucidating the exact etiology of PRCA is often difficult. In our patient, common causes such as thymoma, leukemia, recombinant erythropoietin administration, and parvovirus B19 infection were ruled out. He had no
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evidence of other infections, and there was a temporal relationship between the drop in Hg and development of symptoms. He additionally exhibited complete recovery once the INF-a/RIB was discontinued. Thousands of individuals around the world are treated annually for HCV. Anemia is a well-established complication of HCV therapy but is generally associated with hemolytic anemia attributed to RIB use. Our case is only the 3rd case of PRCA that can readily be attributed to INFa/RIB therapy for HCV. When a patient being treated with INF-a and/or RIB develops anemia we would urge clinicians to consider the development of treatment-induced PRCA. In addition to monitoring labs designated to identify hemolytic anemia, vigilant monitoring of reticulocytes would detect any bone marrow hyporesponsiveness. Our patient presented with PRCA several months after initiation of INF-a and RIB dual therapy for chronic hepatitis C. The offending agents were removed, and the patient had a complete hematologic response. HCV is a common disease that is generally treated with INF-a and RIB antiviral therapy. Although anemia is common during the course of treatment, periodic monitoring of reticulocytes in anemic patients could help detect those patients with a hyporesponsive bone marrow and possible early PRCA. Conflict of interest
None.
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Clin J Gastroenterol (2011) 4:313–317 10. Ganser A, Carlo-Stella C, Greher J, Vo¨lkers B, Hoelzer D. Effect of interferon recombinants alpha and gamma on human bone marrow-derived megakaryocytic progenitor cells. Blood. 1987;70:1173–9. 11. Ioannou S, Hatzis G, Vlahadami I, Voulgarelis M. Aplastic anemia associated with interferon alpha 2a in a patient with chronic hepatitis C virus infection: a case report. J Med Case Rep. 2010;4:268. 12. Fattovich G, Giustina G, Favarato S, Ruol A. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with alfa interferon. J Hepatol. 1996;24(1):38–47. 13. Erslev AJ, Soltan A. Pure red-cell aplasia: a review. Blood Rev. 1996;10(1):20–8. 14. Lipton JM, Ellis SR. Diagnosis and management of acquired pure red cell aplasia. Hematol Oncol Clin North Am. 2009;23(2): 249–59. 15. Krantz SB. Annotation: pure red cell aplasia. Br J Haematol. 1973;25:1–6. 16. Charles RJ, Sabo KM, Kidd PG, Abkowitz JL. The pathophysiology of pure red cell aplasia: implications for therapy. Blood. 1996;87:4831-4838. 17. Heggard ED, Brown KE. Parvovirus B19. Clin Micro Rev. 2002;15(3):485–505. 18. Davidovitz Y, Halpern Z, Vardi J, Ballin A, Meytes D. Pure red cell aplasia responsive to interferon-alpha in a patient with hepatitis C virus iection. Acta Haematol. 1998;100(4):213–5. 19. al-Awami Y, Sears DA, Carrum G, Udden MM, Alter BP, Conlon CL. Pure red cell aplasia associated with hepatitis C infection. Am J Med Sci. 1997;314(2):113–7. 20. Dessypris EN, Redline S, Harris JW, Krantz SB. Diphenylhydantoin-induced pure red cell aplasia. Blood. 1985;65(4):789–94. 21. Majluf-Cruz A, Luna-Castan´os G, Nieto-Cisneros L. AIDS-related pure red cell aplasia. Am J Hematol. 1996;51(2):171. 22. Koiso H, Kobayashi S, Ueki K, Hamada T, Tsukamoto N, Karasawa M, et al. Pure red cell aplasia accompanied by autoimmune hemolytic anemia in a patient with type A viral hepatitis. Rinsho Ketsueki. 2009;50(5):424–9. 23. Ide T, Sata M, Nouno R, Yamashita F, Nakano H, Tanikawa K. Clinical evaluation of four cases of acute viral hepatitis complicated by pure red cell aplasia. Am J Gastroenterol. 1994;89(2): 257–62. 24. Kumar V, Gupta S, Singh S, Goyal VK, Yadav M. Pure red cell aplasia associated with cytomegalovirus infection. J Pediatr Hematol Oncol. 2010;32(4):315–6. 25. Dutta S, Mohta R, Pati HP. Tuberculosis pure red cell aplasia. Int J Tuberc Lung Dis. 1999;3(4):361–2. 26. Djaldetti M, Blay A, Bergman M, Salman H, Bessler H. Pure red cell aplasia—a rare disease with multiple causes. Biomed Pharmacother. 2003;57(8):326–32. 27. Assimakopoulos SF, Michalopoulou S, Melachrinou M, Giannakoulas N, Papakonstantinou C, Lekkou A, et al. Primary
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Sjo¨gren syndrome complicated by autoimmune hemolytic anemia and pure red cell aplasia. Am J Med Sci. 2007;334(6):493–6. Habib GS, Saliba WR, Froom P. Pure red cell aplasia and lupus. Semin Arthritis Rheum. 2002;31(4):279–83. Ustu¨n C, Karaveliog˘lu D, Ilhan O, Aydintug˘ O, Beksac¸ M. A case report of a patient who has pure red cell aplasia and rheumatoid arthritis. Int J Hematol. 1997;66(4):505–12. Lim LC. Acquired red cell aplasia in association with the use of recombinant erythropoietin in chronic renal failure. Hematology. 2005;10(3):255–9. Lim LC. Acquired red cell aplasia in association with the use of recombinant erythropoietin in chronic renal failure. Hematology. 2005;10(3):255–9. Kowdley KV. Hematologic side effects of INF-a and ribavirin therapy. J Clin Gastroenterol. 2005;39(1 Suppl):S3–8. Dieterich DT, Wasserman R, Bra¨u N, Hassanein TI, Bini EJ, Bowers PJ, et al. Once-weekly epoetin alfa improves anemia and facilitates maintenance of ribavirin dosing in hepatitis C virusinfected patients receiving ribavirin plus INF-a alfa. Am J Gastroenterol. 2003;98(11):2491–9. Stravitz RT, Chung H, Sterling RK, Luketic VA, Sanyal AJ, Price AS, et al. Antibody-mediated pure red cell aplasia due to epoetin alfa during antiviral therapy of chronic hepatitis C. Am J Gastroenterol. 2005;100(6):1415–9. Sacchi S, Kantarjian HM, Freireich EJ, et al. Unexpected high incidence of severe toxicities associated with alpha interferon, low-dose cytosine arabinoside and alltrans retinoic acid in patients with chronic myelogenous leukemia. Leuk Lymph. 1999;35:483–9. Hirri HM, Green PJ. Pure red cell aplasia in a patient with chronic granulocytic leukaemia treated with interferon-alpha. Clin Lab Haematol. 2000;22:53–4. Tomita N, Motomura S, Ishigatsubo Y. Interferon-alpha-induced pure red cell aplasia following chronic myelogenous leukemia. Anticancer Drugs. 2001;12:7–8. Arcasoy MO, Rockey DC, Heneghan MA. Pure red cell aplasia following pegylated interferon alpha treatment. Am J Med. 2004;117(8):619–20. Tanaka N, Ishida F, Tanaka E. Ribavirin -induced pure red-cell aplasia during treatment of chronic hepatitis C. N Engl J Med. 2004;350(12):1264–5. Miura Y, Kami M, Yotsuya R, Toda N, Komatsu T. Pure red-cell aplasia associated with pegylated interferon-alpha-2b plus ribavirin. Am J Hematol. 2008;83(9):758–9. Hodo Y, Tsuji K, Mizukoshi E, Yamashita T, Sakai A, Nakamoto Y, et al. Pure red cell aplasia associated with concomitant use of mycophenolate mofetil and ribavirin in post-transplant recurrent hepatitis C. Transpl Int. 2006;19(2):170–1. Canonico PG, Kastello MD, Cosgriff TM, et al. Hematological and bone marrow effects of ribavirin in rhesus monkeys. Toxicol Appl Pharmacol. 1984;74:163–72.
123
CASE REPORT
Pure red cell aplasia caused by ribavirin and interferon treatment Andrew J. Skabelund • Timothy R. Hauser Kevin J. Goist
•
Received: 14 October 2010 / Accepted: 12 May 2011 / Published online: 30 July 2011 Ó Springer 2011
Abstract Anemia is a common complication of hepatitis C (HCV), and antiviral treatment can further increase this risk. We present the case of a 59-year-old man with HCV treated with ribavirin and pegylated interferon alpha (INF-a) who presented with severe anemia. Two months after initiating treatment his hemoglobin dropped from 14.2 to 5.0 g/dL. There was no evidence of bleeding or hemolysis, and a bone marrow biopsy revealed pure red cell aplasia (PRCA). Evaluations for acute cytomegalovirus and parvovirus B19 were negative. There was no evidence of malignancy or thymoma. The INF-a and ribavirin treatment were determined to have caused the PRCA, and withdrawal of the medications led to PRCA remission. INF-a and ribavirin have become the standard treatment for HCV. While these medications offer a potential cure, they are often poorly tolerated due to frequent side effects including anemia. Patients who are receiving treatment with ribavirin and INF-a warrant close monitoring for development of anemia, and PRCA should be considered in all patients in whom reticulocytopenic anemia develops.
Introduction Anemia is a common complication of infection with hepatitis C (HCV) [1]. The anemia can stem from direct effects of the virus, underlying liver disease, or even from treatment of the infection. The combination antiviral therapy of interferon, most commonly pegylated interferon alpha-2a (INF-a), and ribavirin (RIB) has revolutionized the treatment and outcomes for many patients with HCV. This combination therapy commonly causes dose-limiting hemolytic anemia. Pure red cell aplasia (PRCA) is a rare disorder associated with bone marrow erythroid hypoplasia that results in severe and often transfusion-dependent anemia [2]. PRCA is classically associated with thymomas, parvovirus B19 infection, and hematologic malignancies; however, numerous other etiologies have been described. We describe a unique case of PRCA caused by INF-a/RIB dual therapy in a patient being treated for HCV.
Case presentation Keywords Pure red cell aplasia Interferon Ribavirin Hepatitis C The views and opinions expressed in this article/presentation are those of the author(s) and do not reflect official policy or position of the United States Air Force, Department of Defense, or US Government. A. J. Skabelund (&) T. R. Hauser K. J. Goist 88th Medical Group, Department of Internal Medicine, Wright-Patterson Medical Center, 88th MDOS/SGOMI, 4881 Sugar Maple Drive, Wright-Patterson Air Force Base, OH 45433, USA e-mail: [email protected] T. R. Hauser e-mail: [email protected]
A 59-year-old male with chronic HCV presented with progressive weakness, fatigue, and decreased exercise capacity. Dual antiviral therapy for HCV with RIB and INF-a was initiated 2 months prior to presentation. He was presumed to have contracted HCV in the late 1980s when he received a blood transfusion during a surgical procedure. At baseline, he had mildly elevated liver enzymes and a liver biopsy had revealed fibrosis without cirrhosis. He presented with hemoglobin (Hg) of 5.0 g/dL. He had no previous history of anemia, and he denied any mucosal, gastrointestinal, cutaneous or urogenital bleeding. He also had history of hypertension, peripheral arterial disease, depression, and hyperlipidemia. He had been on a stable
123
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regimen of beclomethasone, spironolactone, enalapril, esomeprazole, gabapentin, nystatin, and megestrol for over a year prior to initiation of RIB and INF-a. One year prior to the initiation of treatment, his hg was 14.2 and was near that same value when treatment was initiated. Table 1 shows laboratory values prior to, during, and following his treatment. Over the course of treatment the patient’s hemoglobin was monitored and after 1 month the dose of RIB was reduced. His liver enzymes normalized, and there had been a 2 log drop in his viral load. At 2 months his Hg was noted to be 5.5; all treatment was discontinued and he subsequently presented to the hospital. The patient was pleasant and in no acute distress. He was normotensive with normal vital signs. He was pale, thin, and cachectic. He was without jaundice or scleral icterus. His cardiopulmonary, abdominal, and rectal examinations were unremarkable. His stool was repeatedly hemoccult negative. He was admitted to the hospital for severe anemia. He was transfused five units of packed red blood cells and demonstrated an appropriate increase in Hg (9.4 g/dL). Admission laboratory values and subsequent laboratory results are presented in Table 2. There was no evidence of Table 1 Laboratory data related to treatment course Hb hemoglobin, AST aspartate aminotransferase, ALT alanine aminotransferase, PCR hepatitis C polymerase chain reaction, quantitative real time
hemolysis, nutritional deficiencies, active bleeding or coagulopathy. Peripheral blood smear showed a paucity of red blood cells and the absence of reticulocytes. Serologies for parvovirus B19 and cytomegalovirus were negative for acute infection. Computed tomography (CT) of the chest revealed no masses or abnormalities. A bone marrow biopsy showed a hypocellular bone marrow with pure red cell aplasia, no proerythroblasts, adequate development of other cell lines, and no evidence of acute leukemia. Staining of the bone marrow for Hg can be seen in Fig. 1. PRCA was diagnosed based on the serologic and bone marrow findings. After ruling out other known causes of PRCA, the antiviral treatment of RIB and INF-a were determined to be the causative agents. Antiviral therapy was discontinued, and the patient’s Hg remained stable. He required no other transfusions, and 3 months following discontinuation of treatment his Hg was 13.6 g/dL.
Discussion Anemia is a common complication of HCV [1]. Any drastic drop in hemoglobin in a patient with chronic liver
Test
13 months prior to therapy
Therapy initiation
Therapy month 1
Therapy month 2
3 months following therapy cessation
Hb (g/dL)
14.2
13.7
9.3
5.5
13.6
AST (U/L)
41
118
31
19
24
ALT (U/L)
44
73
34
17
28
PCR (IU/mL)
–
6170000
234000
47000
–
Table 2 Admission laboratory data Test
Results
Hematology
Test
Result
Test
Biochemistry
Result
Virology
WBC
2,400/lL
AST
17 U/L
CMV PCR
Negative
Hb Platelets
5.0 g/dL 91000/lL
ALT Alk Phos
15 U/L 125 U/L
CMV IgG CMV IgM
Positive Negative
MCV
101.6 fL
Tot Bili
0.1 mg/dL
PV B19 IgG
Positive
Retic
0.40%
Protein
7.2 g/dL
PV B19 IgM
Negative
Haptoglobin
408 mg/dL
Albumin
3.3 g/dL
Cryoglobulin
Negative
HIV
Negative
Vitamin B12
939 pg/mL
Folate
[24 ng/mL
Coagulation
Bone marrow
PT
9.4
Adenovirus Cx
PTT
24.3
CMV Cx
Negative Negative
INR
0.9
Fungal Cx
Negative
WBC white blood cells, Hb hemoglobin, MCV mean corpuscular volume, Retic reticulocyte, PT prothrombin time, PTT partial thromboplastin time, INR international normalized ratio, AST aspartate aminotransferase, ALT alanine aminotransferase, Alk Phos alkaline phosphatase, Cx culture, CMV cytomegalovirus, PCR polymerase chain reaction, IgG immunoglobulin G, IgM immunoglobulin M, PV parvovirus, HIV human immunodeficiency virus
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Fig. 1 a Patient bone marrow stained for hemoglobin by immunoprecipitation (IP). b Control bone marrow stained for hemoglobin by IP
disease is concerning for acute hemorrhage; however, extreme decreases in hemoglobin in patients with HCV can also be associated with hemolytic anemia [3] and bone marrow suppression [4]. Well-established pharmacological treatments of HCV are also associated with severe anemia [5]. The combination antiviral therapy of RIB/INF-a has revolutionized the treatment of HCV. This therapy produces a sustained viral response in approximately 50% of treated patients [6]. RIB is often associated with dose-dependent hemolytic anemia [7], and up to 25% of patients require dose reduction for treatment continuation [8]. INF-a can also suppress bone marrow and lead to significant hemoglobin reduction or even aplastic anemia [9–11]. INF-a has also very rarely been associated with hemolytic anemia in patients being treated for viral hepatitis [12]. PRCA is a rare disorder characterized by normochromic, normocytic or slightly macrocytic anemia with reticulocytopenia and near-complete absence of erythroblasts in the bone marrow [13–15]. Diamond–Blackfan anemia is a rare congenital form of PRCA associated with hypoplastic anemia and a variety of cardiac, neurological, and craniofacial defects [15]. More commonly, PRCA manifests in the adult population and can be classified as primary (idiopathic) or secondary [14]. Thymomas are classically associated with PRCA, and initial reports indicated that nearly 50% of cases of PRCA were associated with thymomas [16]; however, more recent literature reviews suggest that thymomas account for \10% of all cases of PRCA [17]. One of the best described associations with PRCA is parvovirus B19. The virus infects erythroid precursors in the bone marrow, resulting in arrest of the development of erythroid lineage at the pronormoblast stage. The bone marrow of afflicted individuals has numerous giant pronormoblasts and few mature erythroid progenitors. The result is a transient period of asymptomatic aplasia in the majority of infected individuals, but immunosuppressed patients and those with chronic hemolytic anemia may develop life-threatening aplastic crises [18]. Various other infections including
HCV, hepatitis A and B, HIV, CMV, and disseminated tuberculosis have been associated with development of PRCA [19–25]. Successful treatment of HCV has been associated with sustained hematologic remission of PRCA [20]. Other rare causes of PRCA include myelodysplastic syndrome, ABO-incompatible bone marrow transplantation, and rheumatologic disorders such as Sjo¨gren’s syndrome, systemic lupus erythematosus, and rheumatoid arthritis [14, 26–29]. Over 30 medications have been associated with PRCA [13]. The mechanism for erythroid suppression is generally unknown, but unique antibodies that retard development of progenitor cells when in the presence of certain medications have been identified [30]. Recently, numerous patients on chronic erythropoietin therapy for various forms of longstanding anemia developed PRCA. Subsequent evaluations revealed the development of neutralizing anti-EPO antibodies resulting in bone marrow erythroid hypoplasia [31]. Anemia is common in patients treated with RIB/INF-a dual therapy [32], and recombinant erythropoietin agents have been demonstrated to decrease the therapy-associated anemia [33]. These agents are commonly given to symptomatic patients being treated for HCV and have been associated with the development of erythropoietin antibody-associated PRCA [34]. Isolated INF-a therapy can cause bone marrow suppression and rarely has been associated with development of PRCA [35–38]. Three of these cases were in patients who had underlying hematologic malignancies associated with development of PRCA. The fourth case, however, was in a patient with HCV on immunosuppressant therapy following orthotopic liver transplant (OLT). This patient was treated with INF-a and subsequently developed PRCA. The anemia in this patient did not resolve with discontinuation of the INF-a, and the patient required multiple transfusions over a 5-month period. IVIG was eventually administered, and the patient required no further transfusions. The protracted disease course following discontinuation of the INF-a and the need for IVIG therapy suggest a
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disease mechanism dissimilar to that of our patient. Additionally, that patient had multiple other possible unique contributing factors including transplant rejection and immunosuppression that were not shared by our patient. There are three previous cases where the combination therapy of INF-a and RIB has been associated with development of PRCA [39–41]. One case included a patient treated for longstanding HCV. Similar to our patient he experienced greater than a 2 log drop in his HCV viral load and all studies were suggestive of PRCA. Additionally, after complete discontinuation of therapy, his hematologic indices normalized without further intervention. However, in this patient INF-a therapy was restarted and there was no recurrence of his HCV or PRCA [39]. Another patient was also an OLT recipient who had been on mycophenolate mofetil and tacrolimus when he was started on dual therapy for recurrent HCV [40]. His anemia was noted after 2 weeks, and the INF-a/RIB therapy was discontinued but his Hg did not improved until the mycophenolate mofetil was stopped. The patient suffered an episode of graft rejection and eventually tolerated reinitiation of the mycophenolate mofetil and even the INFa/RIB therapy. This suggests a multifactorial cause of the PRCA that is difficult to attribute to the INF-a/RIB therapy. The final patient developed PRCA following combination therapy [41]. The RIB was discontinued and the patient remained transfusion dependent for an additional 11 weeks. At that time a bone marrow biopsy was performed and the patient was then determined to have PRCA. This patient did not recover spontaneously, and a 12-week course of cyclosporine and metenolone acetate was administered before his blood counts normalized. Analysis of these cases suggests two distinct mechanisms. One mechanism appears to be immunogenic and does not remit when the offending agent has been withdrawn. These cases require additional immunosuppression or immunomodulation before the bone marrow will recover. In these cases the INF-a appears to be more likely to be the causative agent. The other mechanism suggests direct bone marrow suppression. Once the offending agent is withdrawn, the bone marrow recovers function and the patient requires no further therapy. This was seen appears to be what occurred with our patient. This mechanism appears to be more likely to be attributed to the RIB therapy. The myelosuppressive effects of RIB have been demonstrated in animal studies [42]. In these studies the bone marrow biopsies of the animals demonstrated erythroid precursor aplasia. Elucidating the exact etiology of PRCA is often difficult. In our patient, common causes such as thymoma, leukemia, recombinant erythropoietin administration, and parvovirus B19 infection were ruled out. He had no
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evidence of other infections, and there was a temporal relationship between the drop in Hg and development of symptoms. He additionally exhibited complete recovery once the INF-a/RIB was discontinued. Thousands of individuals around the world are treated annually for HCV. Anemia is a well-established complication of HCV therapy but is generally associated with hemolytic anemia attributed to RIB use. Our case is only the 3rd case of PRCA that can readily be attributed to INFa/RIB therapy for HCV. When a patient being treated with INF-a and/or RIB develops anemia we would urge clinicians to consider the development of treatment-induced PRCA. In addition to monitoring labs designated to identify hemolytic anemia, vigilant monitoring of reticulocytes would detect any bone marrow hyporesponsiveness. Our patient presented with PRCA several months after initiation of INF-a and RIB dual therapy for chronic hepatitis C. The offending agents were removed, and the patient had a complete hematologic response. HCV is a common disease that is generally treated with INF-a and RIB antiviral therapy. Although anemia is common during the course of treatment, periodic monitoring of reticulocytes in anemic patients could help detect those patients with a hyporesponsive bone marrow and possible early PRCA. Conflict of interest
None.
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