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Agranulocytosis after infectious mononucleosis
Journal of Clinical Virology 56 (2013) 271–273
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case report
Agranulocytosis after infectious mononucleosis Tadafumi Yokoyama a,∗ , Yuko Tokuhisa a , Akiko Toga a , Toshihiro Fujiki b , Yasuhisa Sakakibara b , Shintaro Mase b , Raita Araki b , Ryosei Nishimura b , Taizo Wada b , Tetsuya Fuseda c , Eiji Kato a , Akihiro Yachie b a
Department of Pediatrics, Fukuiken Saiseikai Hospital, Wadanaka-machi, 7-1 Funahashi, Fukui, Fukui 918-8503, Japan Department of Pediatrics, School of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan c Department of Pediatrics, Tan-nan Regional Medical Center, 2-311-Chome Sanroku-cho, Sabae, Fukui 916-8515, Japan b
a r t i c l e
i n f o
Article history: Received 9 November 2012 Accepted 19 November 2012 Keywords: Agranulocytosis Epstein–Barr virus Anti-human neutrophil-specific antigen antibodies
a b s t r a c t We report the case of a 5-year-old boy with agranulocytosis after infectious mononucleosis (IM). Antibodies against anti-human neutrophil-specific antigens (HNA)-1 were detected in his serum. A literature review on agranulocytosis after IM and our case suggest that anti-HNA-1 antibodies play important roles in agranulocytosis associated with IM. © 2012 Elsevier B.V. All rights reserved.
1. Why this case is important? Infectious mononucleosis (IM) is a common clinical manifestation of primary Epstein–Barr virus (EBV) infection in children. Mild neutropenia is well-known to occur concomitantly with IM in the first weeks of illness,1,2 but agranulocytosis or severe neutropenia after IM is very rare.2–4 The pathophysiology of agranulocytosis is thought to be maturation arrest of the myeloid series and/or immunological mechanisms.2–4 Here, we present a case of agranulocytosis after IM and discuss the pathophysiology of agranulocytosis associated with IM. 2. Case description A previously healthy 5-year-old boy had fever and general malaise for 9 days before admission. He visited a family doctor and was diagnosed with infectious mononucleosis because he had tonsillitis, cervical lymphoadenopathy and hepatosplenomegaly on clinical examination. The total white blood cell (WBC) count was 15,200/L with 32% neutrophils, 44% lymphocytes and
Abbreviations: IM, infectious mononucleosis; HNA, human neutrophil-specific antigens; EBV, Epstein–Barr virus; WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CRP, C-reactive protein; VCA, viral capsid antigen; Ig, immunoglobulin; EBNA, anti-EB nuclear antigen; GIIFT, granulocyte indirect immunofluorescence test; ANCA, anti-neutrophil cytoplasmic antibodies. ∗ Corresponding author. Tel.: +81 776 23 1111; fax: +81 776 28 8518. E-mail address: [email protected] (T. Yokoyama). 1386-6532/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcv.2012.11.016
19% atypical lymphocytes. The serum aspartate aminotransferase (AST) level was 86 IU/mL, the alanine aminotransferase (ALT) level was 90 IU/mL, and the C-reactive protein (CRP) level was 0.5 mg/dL. He was admitted to an affiliated hospital and treated with hydration and acetaminophen. His fever and general malaise gradually decreased and he was discharged on day 13. After discharge, he was afebrile and could go to nursery school. The patient developed a high fever and general malaise again 10 days after discharge (day 23) and visited the same affiliated hospital. He still had cervical lymphoadenopathy, but the sizes of the lymph nodes were smaller than those on day 13. He had no hepatosplenomegaly. The WBC count was 5100/L with 48% neutrophils, 33% lymphocytes and 0% atypical lymphocytes. The AST level was 28 IU/mL, the ALT level was 16 IU/mL, and the CRP level was 0.8 mg/dL. At that time, the pediatrician did not give any medication and continued with observation. On day 28, the patient visited and was admitted to our hospital because his fever still continued and general malaise had worsened. His cervical lymph nodes had become larger again and he also had hepatosplenomegaly. The WBC count was 1600/L with 0% neutrophils, 59% lymphocytes and 18% atypical lymphocytes. CD4-positive lymphocytes were 31% and CD8-positive lymphocytes were 51% of total lymphocytes. The red blood cell count was 440 × 104 /L, hemoglobin was 11.9 g/dL, and the platelet count was 26.5 × 104 /L. The AST level was 21 IU/mL, the ALT level was 10 IU/mL, the CRP level was 4.6 mg/dL, and the erythrocyte sedimentation rate was 58 mm/h. After collecting specimens for culture, administration of cefotaxime was started.
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T. Yokoyama et al. / Journal of Clinical Virology 56 (2013) 271–273
Fig. 1. (a) Fluorescence intensities of IgG-type homo HNA-1a (blue) and HNA-1b (red) from the patient’s serum on day 31, and negative control (black). (b) Peripheral neutrophil count and fluorescence intensities of anti-HNA-1a and anti-HNA-1b antibodies. The arrow indicates the day of bone marrow examination. Fluorescence intensities are shown for IgG-type anti-HNA-1a (blue), IgM-type anti-HNA-1a (light blue), IgG-type anti-HNA-1b (red), and IgM-type anti-HNA-1b (light red) antibodies. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
On day 31, a bone marrow examination revealed a normocellular marrow without hemophagocytes or malignant cells. The marrow showed a normal myeloid/erythroid ratio, but there were no segmented cells, stab cells or metamyelocytes and many myeloid cells were myelocytes (so-called maturation arrest of myeloid series). Six days after admission (day 34), the neutrophil count increased to 714/L and his clinical symptoms improved. On day 39, he was discharged from hospital without any complications. No pathogenic bacteria were detected in the blood, urine, nasal cavity, and stool. Subsequently, agranulocytosis has not recurred for 8 months. Anti-EBV antibodies showed an antiviral capsid antigen (VCA) immunoglobulin (Ig) M titer of 1:10, an anti-VCA-IgG titer of 1:160, and an anti-EB nuclear antigen (EBNA) titer of 1:<10 on day 28. At 8 months after discharge, these respective titers were 1:<10, 1:320, and 1:40. These data confirmed EBV infection. We tried to detect anti-neutrophil antibodies in the patient’s serum using a granulocyte indirect immunofluorescence test (GIIFT).5–7 At first, the patient’s serum was incubated with neutrophils from three donors typed for homo human neutrophilspecific antigens (HNA)-1a and four donors typed for homo HNA-1b. Pooled sera from normal volunteers were also incubated as negative controls. Membrane-bound anti-neutrophil antibodies were detected using fluorescence-conjugated anti-human IgG antibodies or anti-human IgM antibodies. The fluorescence intensity was expressed as MFI, which was calculated by subtraction of the geometric mean intensities of the patient from those of negative controls. Anti-neutrophil antibodies were detected in the patient’s serum (Fig. 1(a)). The fluorescence intensity of IgG-type anti-HNA-1a antibodies (blue) was elevated compared with negative controls on day 23 and was strongest on day 31, before decreasing to a standard level on day 39 (Fig. 1(b)). Similarly, the fluorescence intensity of IgG-type anti-HNA-1b antibodies (red) was higher than negative controls on day 23 and strongest on day 31, but had a standard level on days 34, 39, and 51. In contrast, the fluorescence intensity of IgM-type anti-HNA-1a antibodies (light blue) was strongest on day 23, before gradually decreasing to a standard level from day 34 to day 51. Similar behavior was observed for the fluorescence intensity of IgM-type anti-HNA-1b antibodies (light red).
Cytoplasmic anti-neutrophil cytoplasmic antibodies (ANCA) and myeloperoxidase ANCA were under the detection limit. An indirect Coombs test was negative and anti-platelet antibodies were not detected in the patient’s serum. 3. Other similar and contrasting cases in the literature Agranulocytosis or profound neutropenia after IM is very rare, with only 29 cases of agranulocytosis after IM reported in the English-language literature since 1925 (search on PubMed Central). In these cases, agranulocytosis after IM had underlying characteristics of (1) occurrence about 1 month after onset of IM, (2) recurrent or persistent fever, (3) redevelopment of cervical lymphadenopathy, (4) no predominance of age or sex, (5) improvement spontaneously within 5–7 days, (6) complication with severe bacterial infection is sometimes critical, and (7) bone marrow examination commonly shows disappearance of mature neutrophil precursors in the myelocytic series.2–6,8,9 4. Discussion The pathophysiology of agranulocytosis after IM remains uncertain, but may involve hypoproduction or maturation arrest of myeloid cells in the marrow due to the direct effect of EBV2–4 or antibody-mediated peripheral destruction of myeloid cells.5 The mechanism of maturation arrest of myeloid cells has been suggested because mature myeloid cells disappear in the patient’s bone marrow. In support of this hypothesis, Sumimoto et al. were unable to detect anti-neutrophil antibodies in a case of agranulocytosis after IM associated with maturation arrest in the myeloid series.4 The mechanism of antibody-mediated peripheral destruction of myeloid cells5,10 is consistent with a case of agranulocytosis without maturation arrest and transitional anti-neutrophil opsonic activity in the serum reported by Stevens et al.10 In this case, it was suggested that the opsonic activity could be explained by IgG in the serum, although these antibodies were not identified.10 Auvin et al. reported a patient with agranulocytosis after IM with IgG-typed anti-HNA-1a antibodies in serum.5 Thus, in agranulocytosis after IM, involvement of anti-neutrophil autoantibodies is suspected,5,7,10 but details of these autoantibodies is lacking in previous reports.
T. Yokoyama et al. / Journal of Clinical Virology 56 (2013) 271–273
GIIFT results for our patient suggested that anti-HNA-1a and anti-HNA-1b antibodies are both associated with the pathophysiology in agranulocytosis after IM, although the association with anti-HNA-1a antibodies may be stronger. Both IgM and IgG were also associated with the pathophysiology. These findings lead us to hypothesize that agranulocytosis is caused by anti-neutrophil antibodies. The period of production of anti-neutrophil antibodies might be short and transient because the GIIFT results in our study and many previous case reports of transient agranulocytosis indicate spontaneous recovery. In our case, the bone marrow showed disappearance of metamyelocytes, stab cells, and segmented cells. We speculate that these changes may be due to mature myeloid cell destruction because the HNA-1 antigen appears in the metamyelocyte stage.5 Thus, some cases of maturation arrest in the bone marrow may actually be due to disappearance of mature neutrophils. Furthermore, a detailed analysis of the correlation of findings on the day of bone marrow aspiration and that of onset of peripheral agranulocytosis has not been performed. Therefore, previous reports of normal bone marrow in agranulocytosis after IM might have been due to recovery of the bone marrow because the examination was performed slightly too late to detect abnormalities. It is unknown whether anti-neutrophil antibodies are produced in EBV-infected B cells. Agranulocytosis after IM is a very rare complication and clarification of the detailed pathophysiology will require accumulation of cases and detailed analysis. The results in our case suggest that anti-HNA-1 antibodies have an important role in agranulocytosis associated with IM. Funding None.
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Competing interests None declared. Ethical approval Not required. References 1. Husain EH, Mullah-Ali A, Al-Sharidah A, Azab AF, Adekile A. Infectious etiologies of transient neutropenia in previously healthy children. Pediatr Infect Dis J 2012;31:575–7. 2. Koziner B, Hadler N, Parrillo J, Ellman L. Agranulocytosis following infectious mononucleosis. JAMA 1973;225:1235–6. 3. Hammond WP, Harlan JM, Steinberg SE. Severe neutropenia in infectious mononucleosis. West J Med 1979;131:92–7. 4. Sumimoto S, Kasajima Y, Hamamoto T, Miyanomae T, Iwai Y, Mayumi M, et al. Agranulocytosis following infectious mononucleosis. Eur J Pediatr 1990;149:961–4. 5. Auvin S, Dalle JH, Ganga-Zandzou PS, Ythier H. Is agranulocytosis following infectious mononucleosis caused by autoimmunity? Pediatr Hematol Oncol 2003;20:611–5. 6. Audrain M, Martin J, Fromont P, Prie N, Thomas C, Muller JV. Autoimmune neutropenia in children: analysis of 116 cases. Pediatr Allergy Immunol 2011;22:494–6. 7. Kagoya Y, Hangaishi A, Takahashi T, Imai Y, Kurokawa M. High-dose dexamethasone therapy for severe thrombocytopenia and neutropenia induced by EBV infectious mononucleosis. Int J Hematol 2010;91: 326–7. 8. Schooley RT, Densen P, Harmon D, Felsenstein D, Hirsch MS, Henle W, et al. Antineutrophil antibodies in infectious mononucleosis. Am J Med 1984;76: 85–9. 9. Neel EU. Infectious mononucleosis. Death due to agranulocytosis and pneumonia. JAMA 1976;225:1493–4. 10. Stevens MDL, Everett ED, Boxer LA, Landefeld MRA. Infectious mononucleosis with severe neutropenia and opsonic antineutrophil activity. South Med J 1979;72:519–21.
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Virology journal homepage: www.elsevier.com/locate/jcv
Case report
Agranulocytosis after infectious mononucleosis Tadafumi Yokoyama a,∗ , Yuko Tokuhisa a , Akiko Toga a , Toshihiro Fujiki b , Yasuhisa Sakakibara b , Shintaro Mase b , Raita Araki b , Ryosei Nishimura b , Taizo Wada b , Tetsuya Fuseda c , Eiji Kato a , Akihiro Yachie b a
Department of Pediatrics, Fukuiken Saiseikai Hospital, Wadanaka-machi, 7-1 Funahashi, Fukui, Fukui 918-8503, Japan Department of Pediatrics, School of Medicine, Institute of Medical Pharmaceutical and Health Sciences, Kanazawa University, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan c Department of Pediatrics, Tan-nan Regional Medical Center, 2-311-Chome Sanroku-cho, Sabae, Fukui 916-8515, Japan b
a r t i c l e
i n f o
Article history: Received 9 November 2012 Accepted 19 November 2012 Keywords: Agranulocytosis Epstein–Barr virus Anti-human neutrophil-specific antigen antibodies
a b s t r a c t We report the case of a 5-year-old boy with agranulocytosis after infectious mononucleosis (IM). Antibodies against anti-human neutrophil-specific antigens (HNA)-1 were detected in his serum. A literature review on agranulocytosis after IM and our case suggest that anti-HNA-1 antibodies play important roles in agranulocytosis associated with IM. © 2012 Elsevier B.V. All rights reserved.
1. Why this case is important? Infectious mononucleosis (IM) is a common clinical manifestation of primary Epstein–Barr virus (EBV) infection in children. Mild neutropenia is well-known to occur concomitantly with IM in the first weeks of illness,1,2 but agranulocytosis or severe neutropenia after IM is very rare.2–4 The pathophysiology of agranulocytosis is thought to be maturation arrest of the myeloid series and/or immunological mechanisms.2–4 Here, we present a case of agranulocytosis after IM and discuss the pathophysiology of agranulocytosis associated with IM. 2. Case description A previously healthy 5-year-old boy had fever and general malaise for 9 days before admission. He visited a family doctor and was diagnosed with infectious mononucleosis because he had tonsillitis, cervical lymphoadenopathy and hepatosplenomegaly on clinical examination. The total white blood cell (WBC) count was 15,200/L with 32% neutrophils, 44% lymphocytes and
Abbreviations: IM, infectious mononucleosis; HNA, human neutrophil-specific antigens; EBV, Epstein–Barr virus; WBC, white blood cell; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CRP, C-reactive protein; VCA, viral capsid antigen; Ig, immunoglobulin; EBNA, anti-EB nuclear antigen; GIIFT, granulocyte indirect immunofluorescence test; ANCA, anti-neutrophil cytoplasmic antibodies. ∗ Corresponding author. Tel.: +81 776 23 1111; fax: +81 776 28 8518. E-mail address: [email protected] (T. Yokoyama). 1386-6532/$ – see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcv.2012.11.016
19% atypical lymphocytes. The serum aspartate aminotransferase (AST) level was 86 IU/mL, the alanine aminotransferase (ALT) level was 90 IU/mL, and the C-reactive protein (CRP) level was 0.5 mg/dL. He was admitted to an affiliated hospital and treated with hydration and acetaminophen. His fever and general malaise gradually decreased and he was discharged on day 13. After discharge, he was afebrile and could go to nursery school. The patient developed a high fever and general malaise again 10 days after discharge (day 23) and visited the same affiliated hospital. He still had cervical lymphoadenopathy, but the sizes of the lymph nodes were smaller than those on day 13. He had no hepatosplenomegaly. The WBC count was 5100/L with 48% neutrophils, 33% lymphocytes and 0% atypical lymphocytes. The AST level was 28 IU/mL, the ALT level was 16 IU/mL, and the CRP level was 0.8 mg/dL. At that time, the pediatrician did not give any medication and continued with observation. On day 28, the patient visited and was admitted to our hospital because his fever still continued and general malaise had worsened. His cervical lymph nodes had become larger again and he also had hepatosplenomegaly. The WBC count was 1600/L with 0% neutrophils, 59% lymphocytes and 18% atypical lymphocytes. CD4-positive lymphocytes were 31% and CD8-positive lymphocytes were 51% of total lymphocytes. The red blood cell count was 440 × 104 /L, hemoglobin was 11.9 g/dL, and the platelet count was 26.5 × 104 /L. The AST level was 21 IU/mL, the ALT level was 10 IU/mL, the CRP level was 4.6 mg/dL, and the erythrocyte sedimentation rate was 58 mm/h. After collecting specimens for culture, administration of cefotaxime was started.
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T. Yokoyama et al. / Journal of Clinical Virology 56 (2013) 271–273
Fig. 1. (a) Fluorescence intensities of IgG-type homo HNA-1a (blue) and HNA-1b (red) from the patient’s serum on day 31, and negative control (black). (b) Peripheral neutrophil count and fluorescence intensities of anti-HNA-1a and anti-HNA-1b antibodies. The arrow indicates the day of bone marrow examination. Fluorescence intensities are shown for IgG-type anti-HNA-1a (blue), IgM-type anti-HNA-1a (light blue), IgG-type anti-HNA-1b (red), and IgM-type anti-HNA-1b (light red) antibodies. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
On day 31, a bone marrow examination revealed a normocellular marrow without hemophagocytes or malignant cells. The marrow showed a normal myeloid/erythroid ratio, but there were no segmented cells, stab cells or metamyelocytes and many myeloid cells were myelocytes (so-called maturation arrest of myeloid series). Six days after admission (day 34), the neutrophil count increased to 714/L and his clinical symptoms improved. On day 39, he was discharged from hospital without any complications. No pathogenic bacteria were detected in the blood, urine, nasal cavity, and stool. Subsequently, agranulocytosis has not recurred for 8 months. Anti-EBV antibodies showed an antiviral capsid antigen (VCA) immunoglobulin (Ig) M titer of 1:10, an anti-VCA-IgG titer of 1:160, and an anti-EB nuclear antigen (EBNA) titer of 1:<10 on day 28. At 8 months after discharge, these respective titers were 1:<10, 1:320, and 1:40. These data confirmed EBV infection. We tried to detect anti-neutrophil antibodies in the patient’s serum using a granulocyte indirect immunofluorescence test (GIIFT).5–7 At first, the patient’s serum was incubated with neutrophils from three donors typed for homo human neutrophilspecific antigens (HNA)-1a and four donors typed for homo HNA-1b. Pooled sera from normal volunteers were also incubated as negative controls. Membrane-bound anti-neutrophil antibodies were detected using fluorescence-conjugated anti-human IgG antibodies or anti-human IgM antibodies. The fluorescence intensity was expressed as MFI, which was calculated by subtraction of the geometric mean intensities of the patient from those of negative controls. Anti-neutrophil antibodies were detected in the patient’s serum (Fig. 1(a)). The fluorescence intensity of IgG-type anti-HNA-1a antibodies (blue) was elevated compared with negative controls on day 23 and was strongest on day 31, before decreasing to a standard level on day 39 (Fig. 1(b)). Similarly, the fluorescence intensity of IgG-type anti-HNA-1b antibodies (red) was higher than negative controls on day 23 and strongest on day 31, but had a standard level on days 34, 39, and 51. In contrast, the fluorescence intensity of IgM-type anti-HNA-1a antibodies (light blue) was strongest on day 23, before gradually decreasing to a standard level from day 34 to day 51. Similar behavior was observed for the fluorescence intensity of IgM-type anti-HNA-1b antibodies (light red).
Cytoplasmic anti-neutrophil cytoplasmic antibodies (ANCA) and myeloperoxidase ANCA were under the detection limit. An indirect Coombs test was negative and anti-platelet antibodies were not detected in the patient’s serum. 3. Other similar and contrasting cases in the literature Agranulocytosis or profound neutropenia after IM is very rare, with only 29 cases of agranulocytosis after IM reported in the English-language literature since 1925 (search on PubMed Central). In these cases, agranulocytosis after IM had underlying characteristics of (1) occurrence about 1 month after onset of IM, (2) recurrent or persistent fever, (3) redevelopment of cervical lymphadenopathy, (4) no predominance of age or sex, (5) improvement spontaneously within 5–7 days, (6) complication with severe bacterial infection is sometimes critical, and (7) bone marrow examination commonly shows disappearance of mature neutrophil precursors in the myelocytic series.2–6,8,9 4. Discussion The pathophysiology of agranulocytosis after IM remains uncertain, but may involve hypoproduction or maturation arrest of myeloid cells in the marrow due to the direct effect of EBV2–4 or antibody-mediated peripheral destruction of myeloid cells.5 The mechanism of maturation arrest of myeloid cells has been suggested because mature myeloid cells disappear in the patient’s bone marrow. In support of this hypothesis, Sumimoto et al. were unable to detect anti-neutrophil antibodies in a case of agranulocytosis after IM associated with maturation arrest in the myeloid series.4 The mechanism of antibody-mediated peripheral destruction of myeloid cells5,10 is consistent with a case of agranulocytosis without maturation arrest and transitional anti-neutrophil opsonic activity in the serum reported by Stevens et al.10 In this case, it was suggested that the opsonic activity could be explained by IgG in the serum, although these antibodies were not identified.10 Auvin et al. reported a patient with agranulocytosis after IM with IgG-typed anti-HNA-1a antibodies in serum.5 Thus, in agranulocytosis after IM, involvement of anti-neutrophil autoantibodies is suspected,5,7,10 but details of these autoantibodies is lacking in previous reports.
T. Yokoyama et al. / Journal of Clinical Virology 56 (2013) 271–273
GIIFT results for our patient suggested that anti-HNA-1a and anti-HNA-1b antibodies are both associated with the pathophysiology in agranulocytosis after IM, although the association with anti-HNA-1a antibodies may be stronger. Both IgM and IgG were also associated with the pathophysiology. These findings lead us to hypothesize that agranulocytosis is caused by anti-neutrophil antibodies. The period of production of anti-neutrophil antibodies might be short and transient because the GIIFT results in our study and many previous case reports of transient agranulocytosis indicate spontaneous recovery. In our case, the bone marrow showed disappearance of metamyelocytes, stab cells, and segmented cells. We speculate that these changes may be due to mature myeloid cell destruction because the HNA-1 antigen appears in the metamyelocyte stage.5 Thus, some cases of maturation arrest in the bone marrow may actually be due to disappearance of mature neutrophils. Furthermore, a detailed analysis of the correlation of findings on the day of bone marrow aspiration and that of onset of peripheral agranulocytosis has not been performed. Therefore, previous reports of normal bone marrow in agranulocytosis after IM might have been due to recovery of the bone marrow because the examination was performed slightly too late to detect abnormalities. It is unknown whether anti-neutrophil antibodies are produced in EBV-infected B cells. Agranulocytosis after IM is a very rare complication and clarification of the detailed pathophysiology will require accumulation of cases and detailed analysis. The results in our case suggest that anti-HNA-1 antibodies have an important role in agranulocytosis associated with IM. Funding None.
273
Competing interests None declared. Ethical approval Not required. References 1. Husain EH, Mullah-Ali A, Al-Sharidah A, Azab AF, Adekile A. Infectious etiologies of transient neutropenia in previously healthy children. Pediatr Infect Dis J 2012;31:575–7. 2. Koziner B, Hadler N, Parrillo J, Ellman L. Agranulocytosis following infectious mononucleosis. JAMA 1973;225:1235–6. 3. Hammond WP, Harlan JM, Steinberg SE. Severe neutropenia in infectious mononucleosis. West J Med 1979;131:92–7. 4. Sumimoto S, Kasajima Y, Hamamoto T, Miyanomae T, Iwai Y, Mayumi M, et al. Agranulocytosis following infectious mononucleosis. Eur J Pediatr 1990;149:961–4. 5. Auvin S, Dalle JH, Ganga-Zandzou PS, Ythier H. Is agranulocytosis following infectious mononucleosis caused by autoimmunity? Pediatr Hematol Oncol 2003;20:611–5. 6. Audrain M, Martin J, Fromont P, Prie N, Thomas C, Muller JV. Autoimmune neutropenia in children: analysis of 116 cases. Pediatr Allergy Immunol 2011;22:494–6. 7. Kagoya Y, Hangaishi A, Takahashi T, Imai Y, Kurokawa M. High-dose dexamethasone therapy for severe thrombocytopenia and neutropenia induced by EBV infectious mononucleosis. Int J Hematol 2010;91: 326–7. 8. Schooley RT, Densen P, Harmon D, Felsenstein D, Hirsch MS, Henle W, et al. Antineutrophil antibodies in infectious mononucleosis. Am J Med 1984;76: 85–9. 9. Neel EU. Infectious mononucleosis. Death due to agranulocytosis and pneumonia. JAMA 1976;225:1493–4. 10. Stevens MDL, Everett ED, Boxer LA, Landefeld MRA. Infectious mononucleosis with severe neutropenia and opsonic antineutrophil activity. South Med J 1979;72:519–21.