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Agranulocytosis associated with parvovirus B19 infection in otherwise healthy patients
European Journal of Internal Medicine 15 (2004) 531 – 533 www.elsevier.com/locate/ejim
Brief report
Agranulocytosis associated with parvovirus B19 infection in otherwise healthy patients Valery Istomina, Ester Sadea, Zahava Grossmanb, Hagit Rudichb, Orit Soferc, David Hassina,d,* a
Department of Internal Medicine C, Hillel Yaffe Medical Center, Hadera, Israel b Central Virology Laboratory, Ramat Gan, Israel c Hematology unit, Hillel Yaffe Medical Center, Hadera, Israel d B. Rappaport Medical Faculty, Technion, Haifa, Israel
Received 24 June 2004; received in revised form 3 August 2004; accepted 1 November 2004
Abstract In the course of 6 years, 23 otherwise healthy patients with acute febrile illness and leukopenia were diagnosed as having acute parvovirus B19 infection. Five of these patients had agranulocytosis associated with acute parvovirus B19 infection and one had chronic agranulocytosis due to persistent parvovirus B19 infection. The diagnosis was made after positive anti-parvovirus B19 IgM antibodies were found in all of the patients and viral DNA was detected by PCR in four patients. Neutropenia and agranulocytosis appear to be much more frequently associated with parvovirus B19 infection than previously reported. D 2004 Elsevier B.V. All rights reserved. Keywords: Agranulocytosis; Neutropenia; Human parvovirus B19 infection; PCR; Immunocompetent patients
1. Introduction
2. Case reports
Parvovirus B19 has been found to cause a wide variety of hematological disorders, such as transient red cell aplasia and aplastic crisis, chronic anemia, leukopenia, neutropenia, and thrombocytopenia [1]. These presentations are typical of patients with underlying hematological and immunosuppressive disorders. Neutropenia in a normal host has only been reported in individual case reports in the English language literature [1,2]. Healthy volunteers with experimental parvovirus B19 infection demonstrated asymptomatic reticulocytopenia, mild leukopenia, and thrombocytopenia [3]. Five patients with agranulocytosis associated with acute parvovirus B19 infection in healthy hosts and one case of chronic agranulocytosis due to persistent parvovirus B19 infection are described here.
2.1. Patient 1
* Corresponding author. Internal Medicine Department C and Infectious Disease Unit, Hillel Yaffe Medical Center, Hadera, Israel. Tel.: +972 6 630 4678; fax: +972 6 630 4681. 0953-6205/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2004.11.002
A previously healthy 76-year-old man was admitted with a 5-day history of high temperature, an aphthous lesion on his tongue, and an echtyma gangrenosum skin lesion on his right leg. On admission the patient looked ill. His blood cell count showed agranulocytosis with 1.14109/l total white blood cells (WBC) and only 0.004109/l neutrophils. Hemoglobin was 11.4 gr% and platelets were within the normal range. Bone marrow aspiration showed infiltration by mature lymphocytes. The patient was treated with piperacillin-tazobactam, gentamycin, and granulocyte colony stimulating factor (G-CSF). On day 4, when fever relapsed, amphotericin B was started. On day 5, the WBC count started to rise, the fever and skin lesions disappeared promptly, and hemoglobin dropped to 9.5 gr%. At discharge, 11 days after admission, the total WBC count was 10.4109/ l (5.2109/l neutrophils), hemoglobin 11.8 gr%, and platelets 546,000/Al. Parvovirus B19 IgM antibodies were
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V. Istomin et al. / European Journal of Internal Medicine 15 (2004) 531–533
strongly positive and IgG was positive. Parvovirus B19 DNA was found in the serum by PCR. The patient recovered completely. A recurrent bone marrow biopsy was normal and the patient was followed for 3 years uneventfully. 2.2. Patient 2 A previously healthy 35-year-old woman was admitted because of fever and severe headache 4 days before admission. Her physical examination was normal. Blood count revealed leukopenia (2.26109/l) with agranulocytosis (0.474109/l neutrophils). Specific parvovirus B19 IgM antibodies and viral DNA were found in the serum. The patient recovered spontaneously within 5 days. WBC and neutrophils on discharge were 5.22109/l and 2.65109/l, respectively. 2.3. Patient 3 A 24-year-old juvenile diabetic patient was admitted with a 5-day history of acute febrile illness. Her physical examination was normal, apart from mild pharyngitis. Her blood count revealed a WBC of 2.26109/l and 0.4109/l neutrophils. Parvovirus B19 IgM and IgG antibodies were positive, and viral DNA was found in the serum. She recovered spontaneously and was discharged with a WBC of 3.54109/l and 0.881109/l neutrophils. 2.4. Patient 4 A 14-year-old previously healthy boy presented with high fever, abdominal pain, headache, and pain in both legs. Examination revealed bilateral conjunctivitis, pharyngitis, and cervical lymphadenopathy. Blood count showed agranulocytosis (0.3109/l neutrophils). Parvovirus B19 IgM antibodies were positive. The patient recovered 3 days after admission. His brother was admitted at the same time with identical clinical manifestations and a neutrophil count of 0.710 9/l. The parvovirus B19 IgM antibodies were also positive. The serums were not tested for HPV B19 DNA. 2.5. Patient 5 A previously healthy 10-year-old girl presented with fever, cough, and vomiting that lasted for 5 days. Physical examination revealed an ill-looking girl. Laboratory investigations showed neutropenia on admission (3.3109/l leukocytes and 0.89109/l neutrophils); hemoglobin was 11.8 gr% and platelets were normal. On day 3 after admission, her temperature rose to 39.3 8C, she still looked ill, and her WBC count dropped to 1.6109/l (0.490109/l neutrophils). A bone marrow aspiration was normal. She was started on ceftazidime and G-CSF. By day 5 after admission, her WBC had risen to 15.6109/l (11.2109/l neutrophils) and the patient recovered. Parvovirus B19 IgM and IgG were positive. The serum was not tested for parvovirus B19 DNA.
2.6. Patient 6 This patient was a 28-year-old woman who was known to have been suffering from chronic neutropenia for the past 6 years. Three years before admission, she had been hospitalized due to severe sepsis. Since this last hospitalization, the patient had been taking G-CSF; however, that was stopped 28 weeks before admission because she was pregnant. The patient presented with throat pain, rhinitis, cough, and sub-febrile temperature 3 days before admission. Her physical examination was normal. Laboratory examination showed agranulocytosis with a WBC of 1.3109/l and only 0.050109/l neutrophils. Hemoglobin was 10.2 gr% and platelets were within the normal range. Bone marrow examination showed an absence of polymorphonuclear cells with maturation defect. Parvovirus B19 IgM antibodies were strongly positive and IgG was negative. Parvovirus DNA was found in her serum. The patient was treated with G-CSF. Her WBC rose to 3.5109/ l (0.390109/l neutrophils) and she recovered.
3. Discussion We report five cases of agranulocytosis and one of chronic agranulocytosis among 23 immunocompetent patients with acute febrile illness and leukopenia diagnosed as acute parvovirus B19 infection. The diagnosis was based on specific parvovirus B19 IgM antibodies in all of the patients and parvovirus DNA detected by PCR in four out of four serum samples examined. The special tropism of the human parvovirus B19 for erythrocyte precursors has been well-documented [1]. The mechanism of neutropenia is not clear. Parvovirus B19 has been associated with chronic neutropenia in childhood, a benign condition characterized by fewer than 1.5109/l neutrophils for more than 3 months, that usually affects young children [4]. This syndrome is thought to be caused by immune-mediated destruction of the neutrophils. Recurrent granulocytic aplasia has been described in a case of persistent parvovirus B19 infection that failed to mount IgG antibodies against parvovirus B19 similar to our patient (case 6) [5]. A case report of neutropenia associated with parvovirus B19 and a review of 12 individual cases of parvovirus-associated neutropenia in healthy adults have been reported in the English language literature [2]. Two patients suffered from persistent infection, and in six patients viral associated hemophagocytic syndrome was diagnosed. In 8 out of 12 patients, the diagnosis was based on the detection of viral DNA in addition to a serological study. The underlying mechanism by which the parvovirus B19 affects the granulopoietic line is not clear. Inhibition of myeloid precursor cells has not been demonstrated in vitro. B19 can replicate in peripheral blood, and B19 DNA has been found in the granulocytic fraction of circulating cells [6]. It is possible that parvovirus B19-specific cytotoxic T
V. Istomin et al. / European Journal of Internal Medicine 15 (2004) 531–533
lymphocytes recognize and destroy non-productively infected granulocyte precursor cells in the bone marrow. In conclusion, acute infection with parvovirus B19 is a more common cause of neutropenia and agranulocytosis in healthy individuals than previously reported. The diagnosis should be considered in acute febrile illness associated with neutropenia in otherwise healthy patients.
References [1] Young NS, Brown KE. Parvovirus B19. Mechanisms of disease. NEJM 2004;350:586 – 97.
533
[2] Barlow GD, McKendrick MW. Parvovirus B19 causing leucopenia and neutropenia in a healthy adult. J Infect 2000 (Mar.);40(2):192 – 5. [3] Anderson MJ, Higgins PG, Davis LR, et al. Experimental parvoviral infection in humans. J Infect Dis 1985;152:257 – 65. [4] Mc Clain K, Estrov Z, Chen H, Mahoney DH. Chronic neutropenia of childhood: frequent association with parvovirus infection and correlations with bone marrow culture studies. Br J Haematol 1993;85:57 – 62. [5] Pont J, Puchhammer-Stocki E, Chott A, et al. Recurrent granulocytic aplasia as clinical presentation of a persistent parvovirus B19 infection. Br J Hematol 1992;80:160 – 5. [6] Kurtzman GJ, Gascon P, Caras M, Cohen B, Young NS. B19 parvovirus replicates in circulating cells of acutely infected patients. Blood 1988;71:1448 – 54.
Brief report
Agranulocytosis associated with parvovirus B19 infection in otherwise healthy patients Valery Istomina, Ester Sadea, Zahava Grossmanb, Hagit Rudichb, Orit Soferc, David Hassina,d,* a
Department of Internal Medicine C, Hillel Yaffe Medical Center, Hadera, Israel b Central Virology Laboratory, Ramat Gan, Israel c Hematology unit, Hillel Yaffe Medical Center, Hadera, Israel d B. Rappaport Medical Faculty, Technion, Haifa, Israel
Received 24 June 2004; received in revised form 3 August 2004; accepted 1 November 2004
Abstract In the course of 6 years, 23 otherwise healthy patients with acute febrile illness and leukopenia were diagnosed as having acute parvovirus B19 infection. Five of these patients had agranulocytosis associated with acute parvovirus B19 infection and one had chronic agranulocytosis due to persistent parvovirus B19 infection. The diagnosis was made after positive anti-parvovirus B19 IgM antibodies were found in all of the patients and viral DNA was detected by PCR in four patients. Neutropenia and agranulocytosis appear to be much more frequently associated with parvovirus B19 infection than previously reported. D 2004 Elsevier B.V. All rights reserved. Keywords: Agranulocytosis; Neutropenia; Human parvovirus B19 infection; PCR; Immunocompetent patients
1. Introduction
2. Case reports
Parvovirus B19 has been found to cause a wide variety of hematological disorders, such as transient red cell aplasia and aplastic crisis, chronic anemia, leukopenia, neutropenia, and thrombocytopenia [1]. These presentations are typical of patients with underlying hematological and immunosuppressive disorders. Neutropenia in a normal host has only been reported in individual case reports in the English language literature [1,2]. Healthy volunteers with experimental parvovirus B19 infection demonstrated asymptomatic reticulocytopenia, mild leukopenia, and thrombocytopenia [3]. Five patients with agranulocytosis associated with acute parvovirus B19 infection in healthy hosts and one case of chronic agranulocytosis due to persistent parvovirus B19 infection are described here.
2.1. Patient 1
* Corresponding author. Internal Medicine Department C and Infectious Disease Unit, Hillel Yaffe Medical Center, Hadera, Israel. Tel.: +972 6 630 4678; fax: +972 6 630 4681. 0953-6205/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2004.11.002
A previously healthy 76-year-old man was admitted with a 5-day history of high temperature, an aphthous lesion on his tongue, and an echtyma gangrenosum skin lesion on his right leg. On admission the patient looked ill. His blood cell count showed agranulocytosis with 1.14109/l total white blood cells (WBC) and only 0.004109/l neutrophils. Hemoglobin was 11.4 gr% and platelets were within the normal range. Bone marrow aspiration showed infiltration by mature lymphocytes. The patient was treated with piperacillin-tazobactam, gentamycin, and granulocyte colony stimulating factor (G-CSF). On day 4, when fever relapsed, amphotericin B was started. On day 5, the WBC count started to rise, the fever and skin lesions disappeared promptly, and hemoglobin dropped to 9.5 gr%. At discharge, 11 days after admission, the total WBC count was 10.4109/ l (5.2109/l neutrophils), hemoglobin 11.8 gr%, and platelets 546,000/Al. Parvovirus B19 IgM antibodies were
532
V. Istomin et al. / European Journal of Internal Medicine 15 (2004) 531–533
strongly positive and IgG was positive. Parvovirus B19 DNA was found in the serum by PCR. The patient recovered completely. A recurrent bone marrow biopsy was normal and the patient was followed for 3 years uneventfully. 2.2. Patient 2 A previously healthy 35-year-old woman was admitted because of fever and severe headache 4 days before admission. Her physical examination was normal. Blood count revealed leukopenia (2.26109/l) with agranulocytosis (0.474109/l neutrophils). Specific parvovirus B19 IgM antibodies and viral DNA were found in the serum. The patient recovered spontaneously within 5 days. WBC and neutrophils on discharge were 5.22109/l and 2.65109/l, respectively. 2.3. Patient 3 A 24-year-old juvenile diabetic patient was admitted with a 5-day history of acute febrile illness. Her physical examination was normal, apart from mild pharyngitis. Her blood count revealed a WBC of 2.26109/l and 0.4109/l neutrophils. Parvovirus B19 IgM and IgG antibodies were positive, and viral DNA was found in the serum. She recovered spontaneously and was discharged with a WBC of 3.54109/l and 0.881109/l neutrophils. 2.4. Patient 4 A 14-year-old previously healthy boy presented with high fever, abdominal pain, headache, and pain in both legs. Examination revealed bilateral conjunctivitis, pharyngitis, and cervical lymphadenopathy. Blood count showed agranulocytosis (0.3109/l neutrophils). Parvovirus B19 IgM antibodies were positive. The patient recovered 3 days after admission. His brother was admitted at the same time with identical clinical manifestations and a neutrophil count of 0.710 9/l. The parvovirus B19 IgM antibodies were also positive. The serums were not tested for HPV B19 DNA. 2.5. Patient 5 A previously healthy 10-year-old girl presented with fever, cough, and vomiting that lasted for 5 days. Physical examination revealed an ill-looking girl. Laboratory investigations showed neutropenia on admission (3.3109/l leukocytes and 0.89109/l neutrophils); hemoglobin was 11.8 gr% and platelets were normal. On day 3 after admission, her temperature rose to 39.3 8C, she still looked ill, and her WBC count dropped to 1.6109/l (0.490109/l neutrophils). A bone marrow aspiration was normal. She was started on ceftazidime and G-CSF. By day 5 after admission, her WBC had risen to 15.6109/l (11.2109/l neutrophils) and the patient recovered. Parvovirus B19 IgM and IgG were positive. The serum was not tested for parvovirus B19 DNA.
2.6. Patient 6 This patient was a 28-year-old woman who was known to have been suffering from chronic neutropenia for the past 6 years. Three years before admission, she had been hospitalized due to severe sepsis. Since this last hospitalization, the patient had been taking G-CSF; however, that was stopped 28 weeks before admission because she was pregnant. The patient presented with throat pain, rhinitis, cough, and sub-febrile temperature 3 days before admission. Her physical examination was normal. Laboratory examination showed agranulocytosis with a WBC of 1.3109/l and only 0.050109/l neutrophils. Hemoglobin was 10.2 gr% and platelets were within the normal range. Bone marrow examination showed an absence of polymorphonuclear cells with maturation defect. Parvovirus B19 IgM antibodies were strongly positive and IgG was negative. Parvovirus DNA was found in her serum. The patient was treated with G-CSF. Her WBC rose to 3.5109/ l (0.390109/l neutrophils) and she recovered.
3. Discussion We report five cases of agranulocytosis and one of chronic agranulocytosis among 23 immunocompetent patients with acute febrile illness and leukopenia diagnosed as acute parvovirus B19 infection. The diagnosis was based on specific parvovirus B19 IgM antibodies in all of the patients and parvovirus DNA detected by PCR in four out of four serum samples examined. The special tropism of the human parvovirus B19 for erythrocyte precursors has been well-documented [1]. The mechanism of neutropenia is not clear. Parvovirus B19 has been associated with chronic neutropenia in childhood, a benign condition characterized by fewer than 1.5109/l neutrophils for more than 3 months, that usually affects young children [4]. This syndrome is thought to be caused by immune-mediated destruction of the neutrophils. Recurrent granulocytic aplasia has been described in a case of persistent parvovirus B19 infection that failed to mount IgG antibodies against parvovirus B19 similar to our patient (case 6) [5]. A case report of neutropenia associated with parvovirus B19 and a review of 12 individual cases of parvovirus-associated neutropenia in healthy adults have been reported in the English language literature [2]. Two patients suffered from persistent infection, and in six patients viral associated hemophagocytic syndrome was diagnosed. In 8 out of 12 patients, the diagnosis was based on the detection of viral DNA in addition to a serological study. The underlying mechanism by which the parvovirus B19 affects the granulopoietic line is not clear. Inhibition of myeloid precursor cells has not been demonstrated in vitro. B19 can replicate in peripheral blood, and B19 DNA has been found in the granulocytic fraction of circulating cells [6]. It is possible that parvovirus B19-specific cytotoxic T
V. Istomin et al. / European Journal of Internal Medicine 15 (2004) 531–533
lymphocytes recognize and destroy non-productively infected granulocyte precursor cells in the bone marrow. In conclusion, acute infection with parvovirus B19 is a more common cause of neutropenia and agranulocytosis in healthy individuals than previously reported. The diagnosis should be considered in acute febrile illness associated with neutropenia in otherwise healthy patients.
References [1] Young NS, Brown KE. Parvovirus B19. Mechanisms of disease. NEJM 2004;350:586 – 97.
533
[2] Barlow GD, McKendrick MW. Parvovirus B19 causing leucopenia and neutropenia in a healthy adult. J Infect 2000 (Mar.);40(2):192 – 5. [3] Anderson MJ, Higgins PG, Davis LR, et al. Experimental parvoviral infection in humans. J Infect Dis 1985;152:257 – 65. [4] Mc Clain K, Estrov Z, Chen H, Mahoney DH. Chronic neutropenia of childhood: frequent association with parvovirus infection and correlations with bone marrow culture studies. Br J Haematol 1993;85:57 – 62. [5] Pont J, Puchhammer-Stocki E, Chott A, et al. Recurrent granulocytic aplasia as clinical presentation of a persistent parvovirus B19 infection. Br J Hematol 1992;80:160 – 5. [6] Kurtzman GJ, Gascon P, Caras M, Cohen B, Young NS. B19 parvovirus replicates in circulating cells of acutely infected patients. Blood 1988;71:1448 – 54.