LETTERS
Aplastic Crisis Secondary to Parvovirus B19 Infection as the First Manifestation of an Undiagnosed Hereditary Spherocytosis: Report of a Pediatric Series of Spanish Patients To the Editor: Human Parvovirus-B19 (HPV-B19) infection is a well-known cause of aplastic crisis in patients with chronic hemolytic anemia, such as hereditary spherocytosis (HS).1–5 In the pediatric population HS may have not been diagnosed when HPV-B19 infection occurs; therefore, it might be difficult to suspect hemolysis when the presenting symptom is a severe aregenerative anemia.6 We describe 8 pediatric patients in whom the first manifestation of an undiagnosed HS was an aplastic crisis due to HPV-B19. We performed a retrospective study between January 2008 and June 2015 in a Pediatric University Hospital in Barcelona. Table 1 shows patients characteristics. In brief, there were 5 women. The median age at diagnosis was 9.5 years (range, 4 to 12 y). Presenting symptoms in most cases were fever, abdominal pain, and vomiting. Only 1 patient developed an exanthema. All patients presented moderate to severe microcytic/normocytic anemia (median hemoglobin, 58 g/L; range, 31 to 86) with low reticulocyte count in 7 of them. One patient had leukopenia. Direct antiglobulin test was negative in all cases. Although corrected reticulocyte count was low, other signs of hemolysis, such as mild unconjugated hyperbilirubinemia, increased lactate dehydrogenase, or decreased haptoglobin were present.
TO THE
EDITOR
Serologic assay (anti-HPV-B19 IgM) was positive in all cases. HPV-B19 is the cause of erythema infectiosum, which is a common and self-limited exanthematous illness of childhood. The prodromal phase consists of fever, headache, and flu-like symptoms. The hallmark is a characteristic rash that appears after this phase. In healthy children, this virus is frequently associated to mild aregenerative anemia and in some cases to leukopenia and/or thrombocytopenia.4 Patients with hematologic diseases may not present the characteristic typical course. As described in pediatric patients with HS7 the characteristic rash was not observed in our series of pediatric patients except for 1 case.8 All patients presented with fever and most of them had abdominal pain and severe aregenerative anemia.1,7 In mild forms of HS, hemolysis is compensated and some children may not be diagnosed until a viral infection may trigger an aplastic crisis and uncover the underlying defect.1 Thus, in a patient presenting with unexplained acute moderate to severe aregenerative anemia, the possibility of an aplastic crisis secondary to HPV-B19 infection in an undiagnosed mild HS has to be considered, even in patients without a known family history. To confirm this diagnosis, other clinical and laboratory signs of hemolysis should be sought and an expert should evaluate a blood smear. As not always a hematopathologist is available, it is important to keep a blood smear for further evaluation, before transfusion. In our series, spherocytes could be observed in all cases. In addition, should these patients require hospital admission, the suspicion of HPV-B19 infection is important, as it will prompt to avoid their admission in a hemato-oncology ward to prevent an infectious outbreak in susceptible patients. Special precaution should be taken to avoid contact of the patient with pregnant women because HPV-B19 can cause severe intrauterine infections. In conclusion, severe aregenerative anemia by HPV-B19 infection may be the presenting symptom of HS in children.
Anna Alonso-Saladrigues, MD* Albert Catala`, MD* Rube´n Berrueco, MD, PhD* Mireia Camo´s, MD, PhDw Montserrat Torrebadell, MDw Susana Rives, MD, PhD* *Department of Pediatric Hematology and Oncology wLaboratory Department, Molecular Genetics, Hospital Sant Joan de De´u de Barcelona, University of Barcelona Barcelona, Spain
REFERENCES 1. Kamoun T, Chabchoub I, Aissa K, et al. E´rythroblastope´nie aigue¨ secondaire a` une infection par le Parvovirus B19 re´le´vant une sphe´rocytose he´re´ditaire chez 2 enfants de la meme famille. [Acute erythroblastopenia due to Parvovirus B19 revealing hereditary spherocytosis]. Arch Pediatr. 2011;9: 990–992. 2. Kobayashi Y, Hatta Y, Ishiwatari Y, et al. Human parvovirus B19-induced aplastic crisis in an adult patient with hereditary spherocytosis: a case report and review of the literature. BMC Res Notes. 2014;7:137–141. 3. Wolfromm A, Rodriguez C, Michel M, et al. Spectrum of adult Parvovirus B19 infection according to the underlying predisposing condition and proposals for clinical practice. Br J Haematol. 2015;2:192–199. 4. Cauff BE, Quinn CT. Transient parvovirus-associated hypoplasia of multiple peripheral blood cell lines in children with chronic hemolytic anemia. Pediatr Blood Cancer. 2008;4:861–864. 5. Zimmerman SA, Davis JS, Schultz WH, et al. Subclinical parvovirus B19 infection in children with sickle cell anemia. J Pediatr Hematol Oncol. 2003;5:387–389. 6. Forde DG, Cope A, Stone B. Acute parvovirus B19 infection in identical twins unmasking previously unidentified hereditary spherocytosis. BMJ Case Rep. 2014;29. 7. Kellermayer R, Faden H, Grossi M. Clinical presentation of parvovirus B19 infection in children with aplastic crisis. Pediatr Infect Dis J. 2003;12: 1100–1101. 8. Kataoka A, Doi S, Suemori S, et al. Varied clinical course of aplastic crisis in hereditary spherocytosis. Pediatr Int. 2014;1:100–102.
The authors declare no conflict of interest.
J Pediatr Hematol Oncol
Volume 38, Number 1, January 2016
www.jpho-online.com |
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
81
J Pediatr Hematol Oncol
Letters to the Editor
Volume 38, Number 1, January 2016
TABLE 1. Clinical Characteristics of 8 Patients With Human Parvovirus-B19 Infection and Undiagnosed Hereditary Spherocytosis
Age (y)
Sex
Initial Symptoms
9
Female
Fever*, abdominal pain
5 7 12 12 12 9 4
Male Male Female Female Female Female Male
Pallor, fatigue, hepatomegaly Fever, pallor, fatigue, abdominal pain Fever, vomiting Fever, abdominal pain, vomiting Fever, abdominal pain, vomiting Fever, abdominal pain, vomiting Fever, rash
Family History of HS Unknown (adopted) Yes No No No No No No
Hgb at Diagnosis/ Steady State (g/L)
Corrected Retic Count at Diagnosis/ MCV (fl) Steady State (%)
56/132
75
0.19/5.8
78/118 60/123 49/102 31/101 48/103 86/109 73/94
84 71 77 68 70 69 76
0.53/4.1 1.55/7.6 0/3.5 0.06/7.3 0.13/6.7 0.32/5.9 6.23/7.7
*Fever was defined by axillary temperature Z381C. ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; Hgb, hemoglobin; HPLC, high-performance liquid cromatography; HPV-B19, human Parvovirus-B19; HS, hereditary spherocytosis; LDH, lactate dehydrogenase; MCV, mean corpuscular volume; PCR, polymerase chain reaction; RBC, red blood cell; Retic count, reticulocyte count; TB, total bilirubin; UCB, unconjugated bilirubin; UNL, upper normal limit.
Childhood Ewing Sarcoma of Orbit: Is It So Fatal? To the Editor: Alfaar et al1 reported 3 cases of orbital Ewing sarcoma with dismal outcomes. One of the 3 patients survived at 2 years of follow-up. The authors concluded that the existing chemotherapy regimen and multimodality treatment schedule is ineffective, and should be revised. Before making such recommendation it would be prudent to know what chemotherapy dose and schedule they used as it could affect the outcome. It would also be helpful to know whether chemotherapy dose and intensity was maintained, and what was the treatment compliance used in their study? We would also like to know about the detailed metastatic workup as imaging of the thorax has not been mentioned in any of the reported cases. Were all patients adequately diagnosed with proper immunohistochemistry (not clear in case 2 and 3) to rule out
other close differential diagnosis such as rhabdomyosarcoma or non-Hodgkin lymphoma, as 2 of the 3 patients were fluorescence in situ hybridization negative for EWS gene rearrangement? In contrast to the outcome reported by Alfaar et al1 our own experience with orbital Ewing sarcoma was pretty good.2 We treated 5 patients of orbital Ewing sarcoma with POGCCG INT-0091 protocol3 incorporating vincristine, adriamycin, dactinomycin, and cyclophosphamide alternating with ifosfamide and etoposide similar to the chemotherapy drugs used by Alfaar and colleagues. Four patients had localized disease and 1 had metastases in bone marrow, with an overall age range of 1 to 20 years. One patient underwent primary neoadjuvant chemotherapy, and subsequently died after 3 months. Of the rest of the 4 patients, 1 patient had surgery of the primary mass followed by adjuvant radiotherapy, whereas other 3 received radical radiotherapy for local control at a dose of 55 Gy. All of the 4 patients after completion of treatment are alive without any evidence of recurrence at 92, 89, 71, and 51 months until last follow-up.
Therefore, the result published by Alfaar et al1 may not represent the true fact. We need more study to ascertain the true outcome pattern in this rare subgroup of Ewing sarcoma. Bivas Biswas, MD* Sameer Bakhshi, MD* Moushumi Sengupta, MDw *Department of Medical Oncology, AIIMS New Delhi wDepartment of Otorhinolarygology Medical College, Kolkata West Bengal, India
REFERENCES 1. Alfaar AS, Zamzam M, Abdalla B, et al. Childhood Ewing sarcoma of the orbit. J Pediatr Hematol Oncol. 2015;37:433–437. 2. Biswas B, Thakar A, Mohanti BK, et al. Prognostic factors in head and neck Ewing sarcoma family of tumors. Laryngoscope. 2015;125:E112–E117. 3. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348: 694–701.
The authors declare no conflict of interest.
82 | www.jpho-online.com
Copyright
r
2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Aplastic Crisis Secondary to Parvovirus B19 Infection as the First Manifestation of an Undiagnosed Hereditary Spherocytosis: Report of a Pediatric Series of Spanish Patients To the Editor: Human Parvovirus-B19 (HPV-B19) infection is a well-known cause of aplastic crisis in patients with chronic hemolytic anemia, such as hereditary spherocytosis (HS).1–5 In the pediatric population HS may have not been diagnosed when HPV-B19 infection occurs; therefore, it might be difficult to suspect hemolysis when the presenting symptom is a severe aregenerative anemia.6 We describe 8 pediatric patients in whom the first manifestation of an undiagnosed HS was an aplastic crisis due to HPV-B19. We performed a retrospective study between January 2008 and June 2015 in a Pediatric University Hospital in Barcelona. Table 1 shows patients characteristics. In brief, there were 5 women. The median age at diagnosis was 9.5 years (range, 4 to 12 y). Presenting symptoms in most cases were fever, abdominal pain, and vomiting. Only 1 patient developed an exanthema. All patients presented moderate to severe microcytic/normocytic anemia (median hemoglobin, 58 g/L; range, 31 to 86) with low reticulocyte count in 7 of them. One patient had leukopenia. Direct antiglobulin test was negative in all cases. Although corrected reticulocyte count was low, other signs of hemolysis, such as mild unconjugated hyperbilirubinemia, increased lactate dehydrogenase, or decreased haptoglobin were present.
TO THE
EDITOR
Serologic assay (anti-HPV-B19 IgM) was positive in all cases. HPV-B19 is the cause of erythema infectiosum, which is a common and self-limited exanthematous illness of childhood. The prodromal phase consists of fever, headache, and flu-like symptoms. The hallmark is a characteristic rash that appears after this phase. In healthy children, this virus is frequently associated to mild aregenerative anemia and in some cases to leukopenia and/or thrombocytopenia.4 Patients with hematologic diseases may not present the characteristic typical course. As described in pediatric patients with HS7 the characteristic rash was not observed in our series of pediatric patients except for 1 case.8 All patients presented with fever and most of them had abdominal pain and severe aregenerative anemia.1,7 In mild forms of HS, hemolysis is compensated and some children may not be diagnosed until a viral infection may trigger an aplastic crisis and uncover the underlying defect.1 Thus, in a patient presenting with unexplained acute moderate to severe aregenerative anemia, the possibility of an aplastic crisis secondary to HPV-B19 infection in an undiagnosed mild HS has to be considered, even in patients without a known family history. To confirm this diagnosis, other clinical and laboratory signs of hemolysis should be sought and an expert should evaluate a blood smear. As not always a hematopathologist is available, it is important to keep a blood smear for further evaluation, before transfusion. In our series, spherocytes could be observed in all cases. In addition, should these patients require hospital admission, the suspicion of HPV-B19 infection is important, as it will prompt to avoid their admission in a hemato-oncology ward to prevent an infectious outbreak in susceptible patients. Special precaution should be taken to avoid contact of the patient with pregnant women because HPV-B19 can cause severe intrauterine infections. In conclusion, severe aregenerative anemia by HPV-B19 infection may be the presenting symptom of HS in children.
Anna Alonso-Saladrigues, MD* Albert Catala`, MD* Rube´n Berrueco, MD, PhD* Mireia Camo´s, MD, PhDw Montserrat Torrebadell, MDw Susana Rives, MD, PhD* *Department of Pediatric Hematology and Oncology wLaboratory Department, Molecular Genetics, Hospital Sant Joan de De´u de Barcelona, University of Barcelona Barcelona, Spain
REFERENCES 1. Kamoun T, Chabchoub I, Aissa K, et al. E´rythroblastope´nie aigue¨ secondaire a` une infection par le Parvovirus B19 re´le´vant une sphe´rocytose he´re´ditaire chez 2 enfants de la meme famille. [Acute erythroblastopenia due to Parvovirus B19 revealing hereditary spherocytosis]. Arch Pediatr. 2011;9: 990–992. 2. Kobayashi Y, Hatta Y, Ishiwatari Y, et al. Human parvovirus B19-induced aplastic crisis in an adult patient with hereditary spherocytosis: a case report and review of the literature. BMC Res Notes. 2014;7:137–141. 3. Wolfromm A, Rodriguez C, Michel M, et al. Spectrum of adult Parvovirus B19 infection according to the underlying predisposing condition and proposals for clinical practice. Br J Haematol. 2015;2:192–199. 4. Cauff BE, Quinn CT. Transient parvovirus-associated hypoplasia of multiple peripheral blood cell lines in children with chronic hemolytic anemia. Pediatr Blood Cancer. 2008;4:861–864. 5. Zimmerman SA, Davis JS, Schultz WH, et al. Subclinical parvovirus B19 infection in children with sickle cell anemia. J Pediatr Hematol Oncol. 2003;5:387–389. 6. Forde DG, Cope A, Stone B. Acute parvovirus B19 infection in identical twins unmasking previously unidentified hereditary spherocytosis. BMJ Case Rep. 2014;29. 7. Kellermayer R, Faden H, Grossi M. Clinical presentation of parvovirus B19 infection in children with aplastic crisis. Pediatr Infect Dis J. 2003;12: 1100–1101. 8. Kataoka A, Doi S, Suemori S, et al. Varied clinical course of aplastic crisis in hereditary spherocytosis. Pediatr Int. 2014;1:100–102.
The authors declare no conflict of interest.
J Pediatr Hematol Oncol
Volume 38, Number 1, January 2016
www.jpho-online.com |
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
81
J Pediatr Hematol Oncol
Letters to the Editor
Volume 38, Number 1, January 2016
TABLE 1. Clinical Characteristics of 8 Patients With Human Parvovirus-B19 Infection and Undiagnosed Hereditary Spherocytosis
Age (y)
Sex
Initial Symptoms
9
Female
Fever*, abdominal pain
5 7 12 12 12 9 4
Male Male Female Female Female Female Male
Pallor, fatigue, hepatomegaly Fever, pallor, fatigue, abdominal pain Fever, vomiting Fever, abdominal pain, vomiting Fever, abdominal pain, vomiting Fever, abdominal pain, vomiting Fever, rash
Family History of HS Unknown (adopted) Yes No No No No No No
Hgb at Diagnosis/ Steady State (g/L)
Corrected Retic Count at Diagnosis/ MCV (fl) Steady State (%)
56/132
75
0.19/5.8
78/118 60/123 49/102 31/101 48/103 86/109 73/94
84 71 77 68 70 69 76
0.53/4.1 1.55/7.6 0/3.5 0.06/7.3 0.13/6.7 0.32/5.9 6.23/7.7
*Fever was defined by axillary temperature Z381C. ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; Hgb, hemoglobin; HPLC, high-performance liquid cromatography; HPV-B19, human Parvovirus-B19; HS, hereditary spherocytosis; LDH, lactate dehydrogenase; MCV, mean corpuscular volume; PCR, polymerase chain reaction; RBC, red blood cell; Retic count, reticulocyte count; TB, total bilirubin; UCB, unconjugated bilirubin; UNL, upper normal limit.
Childhood Ewing Sarcoma of Orbit: Is It So Fatal? To the Editor: Alfaar et al1 reported 3 cases of orbital Ewing sarcoma with dismal outcomes. One of the 3 patients survived at 2 years of follow-up. The authors concluded that the existing chemotherapy regimen and multimodality treatment schedule is ineffective, and should be revised. Before making such recommendation it would be prudent to know what chemotherapy dose and schedule they used as it could affect the outcome. It would also be helpful to know whether chemotherapy dose and intensity was maintained, and what was the treatment compliance used in their study? We would also like to know about the detailed metastatic workup as imaging of the thorax has not been mentioned in any of the reported cases. Were all patients adequately diagnosed with proper immunohistochemistry (not clear in case 2 and 3) to rule out
other close differential diagnosis such as rhabdomyosarcoma or non-Hodgkin lymphoma, as 2 of the 3 patients were fluorescence in situ hybridization negative for EWS gene rearrangement? In contrast to the outcome reported by Alfaar et al1 our own experience with orbital Ewing sarcoma was pretty good.2 We treated 5 patients of orbital Ewing sarcoma with POGCCG INT-0091 protocol3 incorporating vincristine, adriamycin, dactinomycin, and cyclophosphamide alternating with ifosfamide and etoposide similar to the chemotherapy drugs used by Alfaar and colleagues. Four patients had localized disease and 1 had metastases in bone marrow, with an overall age range of 1 to 20 years. One patient underwent primary neoadjuvant chemotherapy, and subsequently died after 3 months. Of the rest of the 4 patients, 1 patient had surgery of the primary mass followed by adjuvant radiotherapy, whereas other 3 received radical radiotherapy for local control at a dose of 55 Gy. All of the 4 patients after completion of treatment are alive without any evidence of recurrence at 92, 89, 71, and 51 months until last follow-up.
Therefore, the result published by Alfaar et al1 may not represent the true fact. We need more study to ascertain the true outcome pattern in this rare subgroup of Ewing sarcoma. Bivas Biswas, MD* Sameer Bakhshi, MD* Moushumi Sengupta, MDw *Department of Medical Oncology, AIIMS New Delhi wDepartment of Otorhinolarygology Medical College, Kolkata West Bengal, India
REFERENCES 1. Alfaar AS, Zamzam M, Abdalla B, et al. Childhood Ewing sarcoma of the orbit. J Pediatr Hematol Oncol. 2015;37:433–437. 2. Biswas B, Thakar A, Mohanti BK, et al. Prognostic factors in head and neck Ewing sarcoma family of tumors. Laryngoscope. 2015;125:E112–E117. 3. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone. N Engl J Med. 2003;348: 694–701.
The authors declare no conflict of interest.
82 | www.jpho-online.com
Copyright
r
2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
