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Acute parvovirus B19 infection during anti-retroviral therapy
J Infect Chemother (2001) 7:110–112
© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2001
CASE REPORT Hitomi Taguchi · Takashi Takahashi · Mieko Goto Tetsuya Nakamura · Aikichi Iwamoto
Acute parvovirus B19 infection during anti-retroviral therapy
Received: April 7, 2000 / Accepted: March 6, 2001
Abstract Human parvovirus B19 (B19) has been described as a causative agent of chronic anemia in human immunodeficiency virus type-1 (HIV-1)-infected patients. We report an HIV-1 infected patient who had been receiving anti-retroviral therapy who showed sudden pancytopenia. Primary B19 infection was confirmed by the detection of plasma viremia and seroconversion. Although clearance required a prolonged period of time, the patient eventually cleared the B19 viral DNA from the plasma. More than likely, highly active anti-retroviral therapy (HAART), including a protease inhibitor, played a role in clearing the virus. Key words Human immunodeficiency virus type-1 · Acute anemia · Human parvovirus B19 · Anti-retroviral therapy
Introduction Human parvovirus B19 (B19) infects erythroid progenitor cells and thereby causes acute red-cell aplasia in patients with hematopoietic stress, such as hemolytic anemia.1 B19 may persistently infect and cause chronic anemia in human immunodeficiency virus type 1 (HIV-1)-positive patients who are undergoing treatment with anti-retroviral drugs, including zidovudine (ZDV).2–7 We report a patient with B19-induced acute anemia during anti-retroviral therapy that included ZDV.
H. Taguchi · T. Takahashi · M. Goto · A. Iwamoto Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan T. Nakamura · A. Iwamoto (*) Department of Infectious Diseases and Applied Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan Tel. 181-3-5449-5359; Fax 181-3-5449-5427 e-mail: [email protected]
Case report In 1995, a 39-year-old man was admitted to hospital because of acute anemia. He was found to be HIV-1-positive, the risk factor for HIV-1 infection being homosexual sexual practices. His initial CD41 cell count was 309 cells/µl, and plasma HIV-1 RNA level was 18 000 copies/ml. From November 1995, he was treated with ZDV/didanosine (ddI), and this was switched to ZDV/zalcitabine (ddC) in May, 1996, because of ddI-induced gastrointestinal problems. Although the anti-retroviral therapy including ZDV gradually decreased his hemoglobin level, the level stabilized 1 year after the start of the therapy. At the beginning of October, 1997, the patient noticed erythema on his trunk; the erythema disappeared in a few days. On November 6, 1997, acute normocytic anemia was shown (157 3 104 red blood cells/µl; hemoglobin, 6.2 g/dl; hematocrit, 16.3%). The ZDV/ddC therapy was withdrawn. His CD41 cell count on the same day was 195 cells/µl. On November 10, his hemoglobin level had deteriorated to 5.4 g/dl. Hematocrit was 14.2%, mean corpuscular volume was 102.9 fl, white-cell count was 1640, and platelet count was 9.7 3 104 cells/µl (Table 1). His serum haptoglobin level was 141 mg/dl (normal range, 55–324 mg/dl), and serum lactate dehydrogenase level was 422 IU/ml (normal range, 240–430 IU/ml). Both direct and indirect Coombs antiglobulin tests were negative. The patient was given a transfusion of four units of packed red blood cells. His clinical course, together with his serological and viral DNA status, is summarized in Fig. 1. In September 1996, frozen plasma from the patient had been negative for both anti-B19 IgM and -IgG antibodies (Parvo IgG enzyme immunoassay [EIA] and Parvo IgM-EIA; Denka Seiken, Tokyo, Japan), and B19 DNA. On November 6, 1997, when the patient suddenly became anemic, both anti-B19 IgM and anti-IgG antibodies were positive. At this time grossly positive B19 DNA was detected in his plasma by first polymerase chain reaction (PCR); however, after several months, B19 DNA levels could be detected only by nested PCR. He was treated with triple combination
111 Table 1. Hematologic findings Date (Year/Month/Day)
White blood cell count (cells/µl)
Hemoglobin (g/dl)
Mean corpuscular volume (fl)
Reticulocyte count (%)
Platelet count (3104 cells/µl)
1995/10/27 1996/06/27 1997/01/20 1997/03/31 1997/07/07 1997/09/04 1997/11/06 1997/11/10 1997/11/17 1997/11/20 1997/11/28 1997/12/11 1998/02/26 1998/08/06
3910 3200 3120 3300 2950 2330 1870 1640 1750 2000 2270 2400 4230 3740
13.6 11.4 10.1 10.8 10.9 10.4 6.2 5.4 5.4 6.7 7.6 10.0 12.5 13.4
92.1 112.4 118.5 117.1 112.6 113.2 103.6 102.9 96.0 94.6 104.5 105.8 89.2 101.5
ND ND ND ND ND ND ND ND ND 1.78 4.91 2.54 0.41 1.92
20.7 19.5 17.0 21.4 20.7 16.6 11.1 9.7 10.7 12.3 17.8 19.5 15.0 20.3
ND, Not determined
Fig. 1. Patient’s clinical course, with B19 IgG, IgM, and polymerase chain reaction (PCR) products from the patient’s serum samples. Oligonucleotide primers for the initial PCR were 59CTTTAGGTATAGCCAACTGG-39 (nucleotide position 29052924) and 59-ACACTGAGTTTACTAGTGGC-39 (nucleotide position 4016-3997). Primers for the nested PCR were 59CAAAAGCATGTGGAGTGAGG-39 (nucleotide position 31873206) and 59-CCTTATAATGGTTGCTCTGGG-39 (nucleotide
position 3290-3271). The products of the initial and nested PCRs were 1112 and 104 base pairs (bp), respectively.11 Lane 1, DNA molecular weight marker; lane 2, DNA extracted from serum in September, 1996; lane 3, serum DNA in November, 1997; lane 4, serum DNA in March, 1998; lane 5, serum DNA in August, 1998; lane 6, serum of B19-negative volunteer. ZDV, Zidovudine; ddI, didanosine; ddC, zalcitabine; NFV, nelfinavir; d4T, sanilvudine; 3TC, lamivudine; Plt, platelets; PCR, polymerase chain reaction; Hb, hemoglobin
chemotherapy (sanilvudine [d4T]/lamivudine [3TC]/ nelfinavir) beginning in May 1998. Anti-B19 IgM antibody tested negative in August 1998. In February 1999, the initial CD41 cell count was 422 cells/µl, and plasma HIV-1 RNA
level was less then 400 copies/ml. His plasma became negative for B19 DNA even by nested PCR (data not shown). Based on these data, we concluded that the patient had primary B19 infection with pancytopenia.
112
Discussion We have reported here a patient with primary B19 infection that occurred while he was receiving anti-retroviral therapy. He was treated with highly active anti-retroviral therapy (HAART), including a protease inhibitor, and the B19 viral DNA was eventually cleared from his plasma. It has been reported that, in immunodeficient patients, failure to clear B19 virus may produce persistent infections, which lead to chronic anemia.3–6,8 Thus, the eradication of B19 in this HIV-infected patient may be attributed to an increase in cellular immunity brought about by HAART (CD4 cell counts: November, 1997, 195 cells/µl; February, 1999, 422 cells/µl). Although B19 is generally spread by a respiratory route of transmission, blood products that were not checked for B19 contamination could be the source of transmission.3,9,10,13 Consequently, the seroprevalence of B19 is higher in HIV-1-positive hemophiliacs (96%) than in HIV1-positive non-hemophiliacs (50%).13,14 Antibodies against B19 are protective against the virus; therefore, patients with HIV-1 infection transmitted by sexual intercourse may be vulnerable to B19-induced anemia, which leads to the discontinuance of anti-retroviral therapy. The morbidity of B19 infection in the general population in Japan increases every 4 or 5 years.15 The findings of this study could aid in the assessment of HIV-1-positive patients with acute episodes of pancytopenia. Acknowledgments We thank David Chao for his discussion and his kind correction of the English. The work was supported by grants from The Organization for Pharmaceutical Safety and Research (OPSR), The Ministry of Health and Welfare of Japan, and the Japan Health Sciences Foundation.
References 1. Young N. Hematologic and hematopoietic consequences of B19 parvovirus infection. Semin Hematol 1988;25:159–72.
2. Frickhofen N, Abkowitz JL, Safford M, Berry JM, Antunez-deMayolo J, Astrow A, et al. Persistent B19 parvovirus infection in patients positive for human immunodeficiency virus type 1 (HIV1): a treatable cause of anemia in AIDS. Ann Int Med 1990;113: 926–33. 3. Schwartz TF, Hottentrager B, Roggendorf M. Prevalence of antibodies to parvovirus B19 in selected groups of patients and healthy individuals. Int J Med Microbiol Virol Parasitol Infect Dis 1992;276:437–42. 4. Zuckerman MA, Williams I, Bremner J, Cohen B, Miller RF. Persistent anaemia in HIV-infected individuals due to parvovirus B19 infection. AIDS 1994;8:1191–2. 5. Gyllensten K, Sonnerborg A, Jorup-Ronstrom C, Halvarsson M, Yun Z. Parvovirus B19 infection in HIV-1 infected patients with anemia. Infection 1994;22:356–8. 6. Naides SJ, Howard EJ, Swack NS, True CA, Stapleton JT. Parvovirus B19 infection in human immunodeficiency virus type 1-infected persons failing or intolerant to zidovudine therapy. J Infect Dis 1993;168:101–5. 7. Griffin TC, Squires JE, Timmons CF, Buchanan GR. Chronic human parvovirus B19-induced erythroid hypoplasia as the initial manifestation of human immunodeficiency virus infection. J Pediatr 1991;118:899–901. 8. Kerr JR, Kane D, Crowley B, Leonard N, O’Brian S, Coyle PV, Mulcahy F. Parvovirus B19 infection in AIDS patients. Int J STD AIDS 1997;8:184–6. 9. Musiani M, Zerbini M, Gentilomi G, Rodorigo G, De Rosa V, Gibellini D, et al. Persistent B19 parvovirus infections in haemophilic HIV-1 infected patients. J Med Virol 1995;46:103– 8. 10. Yee TT, Cohen BJ, Pasi KJ, Lee CA. Transmission of symptomatic parvovirus B19 infection by clotting factor concentrate. Br J Haematol 1996;93:457–9. 11. Musiani M, Azzi A, Zerbini M, Gibellini D, Venturoli S, Zakrzewska K, et al. Nested polymerase chain reaction assay for the detection of B19 parvovirus DNA in human immunodeficiency virus patients. J Med Virol 1993;40:157–60. 12. Matsunaga Y, Takeda N, Yamazaki S, Kamata K, Kurosawa D. Seroepidemiology of human parvovirus B19 using recombinant VP1 1 VP2 particle antigen. J Jpn Assoc Infect Dis 1995;69:1371– 5. 13. Taguchi H, Yamada T, Takahashi T, Gotoh M, Nakamura T, Iwamoto A. Seroprevalence of parvovirus B19 among HIV-1positive population in Japan. Jpn J Infect Dis 2000;53:21. 14. Fukushima Y, Okuyama K, Komuro K, Ueda M, Fukutake K, Fujimaki M. Elevated Clq-bearing immune complex in hemophiliacs with viral infections (in Japanese). Rinsho Ketsueki (Jap J Clin Hematol) 1991;32:1540–6. 15. National Institute of Infectious Diseases and Infectious Diseases Control Division, Ministry of Health and Welfare of Japan. Infectious Agents Surveillance Report 1998;19:50–3.
© Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases 2001
CASE REPORT Hitomi Taguchi · Takashi Takahashi · Mieko Goto Tetsuya Nakamura · Aikichi Iwamoto
Acute parvovirus B19 infection during anti-retroviral therapy
Received: April 7, 2000 / Accepted: March 6, 2001
Abstract Human parvovirus B19 (B19) has been described as a causative agent of chronic anemia in human immunodeficiency virus type-1 (HIV-1)-infected patients. We report an HIV-1 infected patient who had been receiving anti-retroviral therapy who showed sudden pancytopenia. Primary B19 infection was confirmed by the detection of plasma viremia and seroconversion. Although clearance required a prolonged period of time, the patient eventually cleared the B19 viral DNA from the plasma. More than likely, highly active anti-retroviral therapy (HAART), including a protease inhibitor, played a role in clearing the virus. Key words Human immunodeficiency virus type-1 · Acute anemia · Human parvovirus B19 · Anti-retroviral therapy
Introduction Human parvovirus B19 (B19) infects erythroid progenitor cells and thereby causes acute red-cell aplasia in patients with hematopoietic stress, such as hemolytic anemia.1 B19 may persistently infect and cause chronic anemia in human immunodeficiency virus type 1 (HIV-1)-positive patients who are undergoing treatment with anti-retroviral drugs, including zidovudine (ZDV).2–7 We report a patient with B19-induced acute anemia during anti-retroviral therapy that included ZDV.
H. Taguchi · T. Takahashi · M. Goto · A. Iwamoto Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan T. Nakamura · A. Iwamoto (*) Department of Infectious Diseases and Applied Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan Tel. 181-3-5449-5359; Fax 181-3-5449-5427 e-mail: [email protected]
Case report In 1995, a 39-year-old man was admitted to hospital because of acute anemia. He was found to be HIV-1-positive, the risk factor for HIV-1 infection being homosexual sexual practices. His initial CD41 cell count was 309 cells/µl, and plasma HIV-1 RNA level was 18 000 copies/ml. From November 1995, he was treated with ZDV/didanosine (ddI), and this was switched to ZDV/zalcitabine (ddC) in May, 1996, because of ddI-induced gastrointestinal problems. Although the anti-retroviral therapy including ZDV gradually decreased his hemoglobin level, the level stabilized 1 year after the start of the therapy. At the beginning of October, 1997, the patient noticed erythema on his trunk; the erythema disappeared in a few days. On November 6, 1997, acute normocytic anemia was shown (157 3 104 red blood cells/µl; hemoglobin, 6.2 g/dl; hematocrit, 16.3%). The ZDV/ddC therapy was withdrawn. His CD41 cell count on the same day was 195 cells/µl. On November 10, his hemoglobin level had deteriorated to 5.4 g/dl. Hematocrit was 14.2%, mean corpuscular volume was 102.9 fl, white-cell count was 1640, and platelet count was 9.7 3 104 cells/µl (Table 1). His serum haptoglobin level was 141 mg/dl (normal range, 55–324 mg/dl), and serum lactate dehydrogenase level was 422 IU/ml (normal range, 240–430 IU/ml). Both direct and indirect Coombs antiglobulin tests were negative. The patient was given a transfusion of four units of packed red blood cells. His clinical course, together with his serological and viral DNA status, is summarized in Fig. 1. In September 1996, frozen plasma from the patient had been negative for both anti-B19 IgM and -IgG antibodies (Parvo IgG enzyme immunoassay [EIA] and Parvo IgM-EIA; Denka Seiken, Tokyo, Japan), and B19 DNA. On November 6, 1997, when the patient suddenly became anemic, both anti-B19 IgM and anti-IgG antibodies were positive. At this time grossly positive B19 DNA was detected in his plasma by first polymerase chain reaction (PCR); however, after several months, B19 DNA levels could be detected only by nested PCR. He was treated with triple combination
111 Table 1. Hematologic findings Date (Year/Month/Day)
White blood cell count (cells/µl)
Hemoglobin (g/dl)
Mean corpuscular volume (fl)
Reticulocyte count (%)
Platelet count (3104 cells/µl)
1995/10/27 1996/06/27 1997/01/20 1997/03/31 1997/07/07 1997/09/04 1997/11/06 1997/11/10 1997/11/17 1997/11/20 1997/11/28 1997/12/11 1998/02/26 1998/08/06
3910 3200 3120 3300 2950 2330 1870 1640 1750 2000 2270 2400 4230 3740
13.6 11.4 10.1 10.8 10.9 10.4 6.2 5.4 5.4 6.7 7.6 10.0 12.5 13.4
92.1 112.4 118.5 117.1 112.6 113.2 103.6 102.9 96.0 94.6 104.5 105.8 89.2 101.5
ND ND ND ND ND ND ND ND ND 1.78 4.91 2.54 0.41 1.92
20.7 19.5 17.0 21.4 20.7 16.6 11.1 9.7 10.7 12.3 17.8 19.5 15.0 20.3
ND, Not determined
Fig. 1. Patient’s clinical course, with B19 IgG, IgM, and polymerase chain reaction (PCR) products from the patient’s serum samples. Oligonucleotide primers for the initial PCR were 59CTTTAGGTATAGCCAACTGG-39 (nucleotide position 29052924) and 59-ACACTGAGTTTACTAGTGGC-39 (nucleotide position 4016-3997). Primers for the nested PCR were 59CAAAAGCATGTGGAGTGAGG-39 (nucleotide position 31873206) and 59-CCTTATAATGGTTGCTCTGGG-39 (nucleotide
position 3290-3271). The products of the initial and nested PCRs were 1112 and 104 base pairs (bp), respectively.11 Lane 1, DNA molecular weight marker; lane 2, DNA extracted from serum in September, 1996; lane 3, serum DNA in November, 1997; lane 4, serum DNA in March, 1998; lane 5, serum DNA in August, 1998; lane 6, serum of B19-negative volunteer. ZDV, Zidovudine; ddI, didanosine; ddC, zalcitabine; NFV, nelfinavir; d4T, sanilvudine; 3TC, lamivudine; Plt, platelets; PCR, polymerase chain reaction; Hb, hemoglobin
chemotherapy (sanilvudine [d4T]/lamivudine [3TC]/ nelfinavir) beginning in May 1998. Anti-B19 IgM antibody tested negative in August 1998. In February 1999, the initial CD41 cell count was 422 cells/µl, and plasma HIV-1 RNA
level was less then 400 copies/ml. His plasma became negative for B19 DNA even by nested PCR (data not shown). Based on these data, we concluded that the patient had primary B19 infection with pancytopenia.
112
Discussion We have reported here a patient with primary B19 infection that occurred while he was receiving anti-retroviral therapy. He was treated with highly active anti-retroviral therapy (HAART), including a protease inhibitor, and the B19 viral DNA was eventually cleared from his plasma. It has been reported that, in immunodeficient patients, failure to clear B19 virus may produce persistent infections, which lead to chronic anemia.3–6,8 Thus, the eradication of B19 in this HIV-infected patient may be attributed to an increase in cellular immunity brought about by HAART (CD4 cell counts: November, 1997, 195 cells/µl; February, 1999, 422 cells/µl). Although B19 is generally spread by a respiratory route of transmission, blood products that were not checked for B19 contamination could be the source of transmission.3,9,10,13 Consequently, the seroprevalence of B19 is higher in HIV-1-positive hemophiliacs (96%) than in HIV1-positive non-hemophiliacs (50%).13,14 Antibodies against B19 are protective against the virus; therefore, patients with HIV-1 infection transmitted by sexual intercourse may be vulnerable to B19-induced anemia, which leads to the discontinuance of anti-retroviral therapy. The morbidity of B19 infection in the general population in Japan increases every 4 or 5 years.15 The findings of this study could aid in the assessment of HIV-1-positive patients with acute episodes of pancytopenia. Acknowledgments We thank David Chao for his discussion and his kind correction of the English. The work was supported by grants from The Organization for Pharmaceutical Safety and Research (OPSR), The Ministry of Health and Welfare of Japan, and the Japan Health Sciences Foundation.
References 1. Young N. Hematologic and hematopoietic consequences of B19 parvovirus infection. Semin Hematol 1988;25:159–72.
2. Frickhofen N, Abkowitz JL, Safford M, Berry JM, Antunez-deMayolo J, Astrow A, et al. Persistent B19 parvovirus infection in patients positive for human immunodeficiency virus type 1 (HIV1): a treatable cause of anemia in AIDS. Ann Int Med 1990;113: 926–33. 3. Schwartz TF, Hottentrager B, Roggendorf M. Prevalence of antibodies to parvovirus B19 in selected groups of patients and healthy individuals. Int J Med Microbiol Virol Parasitol Infect Dis 1992;276:437–42. 4. Zuckerman MA, Williams I, Bremner J, Cohen B, Miller RF. Persistent anaemia in HIV-infected individuals due to parvovirus B19 infection. AIDS 1994;8:1191–2. 5. Gyllensten K, Sonnerborg A, Jorup-Ronstrom C, Halvarsson M, Yun Z. Parvovirus B19 infection in HIV-1 infected patients with anemia. Infection 1994;22:356–8. 6. Naides SJ, Howard EJ, Swack NS, True CA, Stapleton JT. Parvovirus B19 infection in human immunodeficiency virus type 1-infected persons failing or intolerant to zidovudine therapy. J Infect Dis 1993;168:101–5. 7. Griffin TC, Squires JE, Timmons CF, Buchanan GR. Chronic human parvovirus B19-induced erythroid hypoplasia as the initial manifestation of human immunodeficiency virus infection. J Pediatr 1991;118:899–901. 8. Kerr JR, Kane D, Crowley B, Leonard N, O’Brian S, Coyle PV, Mulcahy F. Parvovirus B19 infection in AIDS patients. Int J STD AIDS 1997;8:184–6. 9. Musiani M, Zerbini M, Gentilomi G, Rodorigo G, De Rosa V, Gibellini D, et al. Persistent B19 parvovirus infections in haemophilic HIV-1 infected patients. J Med Virol 1995;46:103– 8. 10. Yee TT, Cohen BJ, Pasi KJ, Lee CA. Transmission of symptomatic parvovirus B19 infection by clotting factor concentrate. Br J Haematol 1996;93:457–9. 11. Musiani M, Azzi A, Zerbini M, Gibellini D, Venturoli S, Zakrzewska K, et al. Nested polymerase chain reaction assay for the detection of B19 parvovirus DNA in human immunodeficiency virus patients. J Med Virol 1993;40:157–60. 12. Matsunaga Y, Takeda N, Yamazaki S, Kamata K, Kurosawa D. Seroepidemiology of human parvovirus B19 using recombinant VP1 1 VP2 particle antigen. J Jpn Assoc Infect Dis 1995;69:1371– 5. 13. Taguchi H, Yamada T, Takahashi T, Gotoh M, Nakamura T, Iwamoto A. Seroprevalence of parvovirus B19 among HIV-1positive population in Japan. Jpn J Infect Dis 2000;53:21. 14. Fukushima Y, Okuyama K, Komuro K, Ueda M, Fukutake K, Fujimaki M. Elevated Clq-bearing immune complex in hemophiliacs with viral infections (in Japanese). Rinsho Ketsueki (Jap J Clin Hematol) 1991;32:1540–6. 15. National Institute of Infectious Diseases and Infectious Diseases Control Division, Ministry of Health and Welfare of Japan. Infectious Agents Surveillance Report 1998;19:50–3.