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ARTICLES
Year : 2013  |  Volume : 38  |  Issue : 3  |  Page : 115-121

The prevalence of human parvovirus B19 infection in children with a variety of hematological disorders


1 Department of aMedical Microbiology and Immunology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission19-Dec-2012
Date of Acceptance10-Apr-2013
Date of Web Publication19-Jun-2014

Correspondence Address:
Mohammed M. Abdel Salam
MD, Department of Pediatrics, Faculty of Medicine, Zagazig University, Zagazig 12345
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJH.0000430749.56529.5a

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  Abstract 

Background

Human parvovirus B19 is a global and common infectious pathogen in humans, particularly in children.

The aim of the study

The aim of the study was to compare the prevalence of human parvovirus B19 in children with a variety of hematological disorders with that in normal controls and to highlight the relationship between humoral immune response and the presence of viremia.

Methods

This study included 80 children with different hematological disorders. Ten healthy children matched for age and sex were also included as controls. The patients were classified into four groups: group I included 25 patients with chronic hemolytic anemia not in aplastic crisis; group II included 15 patients with hemolytic anemia in aplastic crisis; group III included 20 acute leukemia patients under chemotherapy; and group IV included 20 patients with newly diagnosed acute leukemia. B19-specific IgM and IgG antibodies were detected in patient sera by enzyme-linked immunosorbent assay, whereas B19 DNA was detected by nested PCR analysis.

Results

A higher prevalence of B19-specific markers was found in patients compared with controls. In groups I and III, IgG positivity was the highest (52 and 50%, respectively). In group II, the rate of IgM positivity and viremia was the same (46%), followed by IgG positivity (33.3%). However, in group IV IgM positivity was the highest (35%), followed by IgG positivity (30%) and viremia (15%). Groups II, III, and IV showed a higher prevalence of recent B19 infection (53.3, 40, and 45%, respectively) compared with prior and absent infections, whereas in group I prior infection was the most prevalent (40%). None of the groups showed a significant relationship between B19 DNA and immunoglobulin detection, except group II, in which a significant association between the detection of B19 DNA and IgM existed. All groups of patients with positive markers for recent B19 infection had lower hemoglobin levels and RBC counts compared with controls; they also had reticulocytopenia and lymphocytosis.

Conclusion

B19 infection is highly prevalent among children with hematological disorders. B19 must be suspected and screened for in the presence of anemia in those patients with neutropenia and lymphocytosis. The direct detection of DNA by PCR needs to be coupled with serological testing for a more reliable diagnosis of B19 infections.

Keywords: acute leukemia, hemolytic anemia, parvovirus B19


How to cite this article:
Azzazy EA, Shaheen AA, Mousaad AA, Abdel Salam MM, Ibrahim RA. The prevalence of human parvovirus B19 infection in children with a variety of hematological disorders. Egypt J Haematol 2013;38:115-21

How to cite this URL:
Azzazy EA, Shaheen AA, Mousaad AA, Abdel Salam MM, Ibrahim RA. The prevalence of human parvovirus B19 infection in children with a variety of hematological disorders. Egypt J Haematol [serial online] 2013 [cited 2019 Dec 10];38:115-21. Available from: http://www.ehj.eg.net/text.asp?2013/38/3/115/134788


  Introduction Top


Human parvovirus B19 (B19) is a small, nonenveloped DNA virus belonging to the genus Erythrovirus (Parvoviridae family) 1. Its capsid comprises 60 capsomeres surrounding a single-stranded (ss) DNA genome (5596 nucleotides) 2 whose terminal sequences are capable of assuming hairpin duplex configurations, serving as primers for the synthesis of the complementary strand 3. B19 has exceptional tropism to human erythroid progenitors, and fetal liver and umbilical blood erythroblasts because of the presence of blood group P antigen (globoside, Gb4) in erythroid cells, which is the main B19 receptor 4.

The pattern of clinical disease caused by B19 varies and is influenced by the hematological and immunological status of the infected individual. In healthy hosts, B19 generally causes self-limiting subclinical erythroid aplasia, followed by rash or arthralgia. However, in patients with diminished production or increased loss of erythrocytes, B19 infection results in a severe drop in hemoglobin levels and in anemia, which could be life-threatening 1. B19 has been recognized as a cause of cytopenia in immunocompromised patients, including organ transplant recipients, patients with congenital and acquired immunodeficiency, and cancer patients 5.

The transmission of B19 occurs through respiratory droplets, contaminated blood, and organ transplants, as well as by vertical transmission from the mother to the fetus 1. B19 is easily transmitted through blood transfusion and therapy using plasma-derived products. The small size of the B19 virus makes its removal by filtration using virus-removal membranes impossible 6. B19 can therefore contaminate minipools, coagulation factors, and packed red cell concentrates, and there are at present no strict protocols for determining B19 contamination of pooled plasma or blood products before product use and transfusion to those at risk 7.

The aim of this study was to compare the prevalence of human parvovirus B19 in children with a variety of hematological disorders with that in normal controls and to highlight the relationship between humoral immune response and the presence of viremia.


  Patients and methods Top


Patients

This study was conducted on peripheral blood samples obtained from 80 children selected from the Hematology outpatient clinic and inpatient unit of the Pediatric Department at Zagazig University Hospitals from March 2010 to March 2011. The patients included 56 boys and 24 girls with ages ranging from 4 to 12 years. Age-matched and sex-matched healthy children were also enrolled.

Informed consent was obtained from the participants’ guardians, according to requirements of the Ethical Committee of the Zagazig University Hospitals.

Patients were classified into four groups as follows:

Group I included 25 patients with chronic hemolytic anemia who were not in aplastic crisis [15 patients with β thalassemia, three with sickle cell disease (SCD), two with hereditary spherocytosis, and five with glucose 6-phosphate dehydrogenase (G6PD) deficiency].

Group II included 15 patients with chronic hemolytic anemia who were in aplastic crisis (10 patients with β thalassemia, one with sickle cell disease, one with hereditary spherocytosis, and three with G6PD deficiency).

Group III included 20 patients with acute leukemia who were on maintenance chemotherapy [16 patients with acute lymphoblastic leukemia (ALL) and four with acute myeloid leukemia].

Group IV included 20 patients with recently diagnosed acute leukemia who were not on chemotherapy (18 patients with ALL and two with acute myeloid leukemia).


  Methods Top


All patients had already been diagnosed for various hematological conditions in the Pediatric Department by the following investigations:

  1. Full history taking including age and sex.
  2. Full clinical examination.
  3. Routine laboratory investigations including complete blood picture and bone marrow aspiration and smear.
  4. Special laboratory investigations to diagnose patients with hemolytic anemia, including estimation of G6PD activity, osmotic fragility test for diagnosis of hereditary spherocytosis, and screening for sickle cell anemia by demonstrating sickling of red blood cells (RBCs) under reduced conditions. Hemoglobin electrophoresis was also performed to confirm the presence of HbS in sickle cell anemia and for the diagnosis of thalassemia 8.
  5. Diagnosis and classification of acute myeloid leukemia and acute lymphoblastic leukemia based on morphologic criteria, cytochemical staining patterns, and immunophenotyping by flow cytometry 9.


Parvovirus B19 assays were performed as follows

  1. A volume of 2–3 ml of venous blood was obtained from the studied patients and controls. Sera were separated and stored at −20˚C in two aliquots: one for B19-specific immunoglobulin testing by enzyme-linked immunosorbent assay (ELISA) and the other for B19 DNA assay by PCR analysis 10.
  2. Detection of B19-specific IgM and IgG antibodies: B19-specific IgM and IgG antibodies in serum samples were tested for by ELISA using an AxyPrep Body Fluid Viral DNA Miniprep Kit (R-Biopharm, Darmstadt, Germany). Values of more than 5 IU/ml for IgG and 12 IU/ml for IgM were considered positive.
  3. Nested PCR for parvovirus B19 DNA detection: viral DNA extraction was performed using an AxyPrep Body Fluid Viral DNA Miniprep Kit (Axygen, California, USA).


Amplification was performed using ready-to-use PCR master mix beads (Bioron, Ludwigshafen, Germany), and two pairs of primers designed to bracket a well-conserved region in parvovirus B19 DAN were used for two rounds of amplification.

The primer pairs (from The Midland Reagent Co., Germany) were as follows: for B19SI and B19ASI – 5′-CCTTTTCTGTGCTAACCTGC-3′ and 5′-CCCAGGCTTGTGTAAGTCTT-3′, respectively; forB19SII and B19ASII – 5′-AAAGCTTTGTAGATTATGAG-3′ and 5′-GGTTCTGCATGACTGCTATGG-3′, respectively 11.

Two rounds of amplification were performed using a DNA thermal cycler (Cetus; Perkin Elmer, Emeryville, California, USA) as follows:

First round

In the first round, initial denaturation was performed for 5 min at 94°C, followed by 38 cycles of denaturation at 94°C for 45 s, annealing at 54°C for 45 s, and extension at 72°C for 1 min. A volume of 2 μl of the product was then added to another PCR tube with addition of the second pair of primers.

Second round

In the second round, 25 cycles of amplification were performed with the same parameters as those in the first round.

Negative controls containing all components except the DNA extract were included in each cycle to exclude nonspecific amplification.

The amplified PCR products were visualized as fluorescent bands on agarose gel electrophoresis. Products with to a molecular weight of 322 bp were recorded as being positive for parvovirus B19 DNA 11.

Statistical analysis

The data were tabulated and statistically analyzed using Epi-Info (2000; CDC, Atlanta, Georgia, USA) software packages 12. Quantitative data were expressed as mean±SD. The Kruskal–Wallis test was used to compare more than two groups. The Mann–Whitney U-test was used to compare two groups. Qualitative data were expressed as number and percentage. The χ2-test was used to analyze qualitative data. P-values less than 0.05 were considered significant.


  Results Top


The frequency of B19 infection among the studied groups has been summarized in [Table 1].

A statistically significant difference was detected in level of B19-specific IgM between groups I, II, and IV and the control group. In addition, a significant difference was detected as regards PCR results between group II and the control group [Table 1].

In the present study, parvovirus B19 infection was classified as recent infection in patients with positive results on IgM evaluation and/or PCR, whereas positive results only on IgG evaluation was considered as prior B19 infection. Absence of any of the B19 markers was considered as absent infection. In group I, the rate of prior B19 infection was the highest (40%), followed by absent and recent infection (36 and 24%, respectively). In groups II, III, and IV, rate of recent B19 infection was the highest (53.3, 40, and 45%, respectively). Statistically significant differences were observed in the rates of recent infection between groups II, III, and IV and controls, as well as between patient groups [Table 1].

No significant relation was found between the detection of B19-specific IgM and DNA or B19-specific IgG and DNA except for in group II patients, who showed a statistically significant positive relation between B19-specific IgM and B19 DNA in serum. Further, a statistically significant negative relation was observed between B19-specific IgG detection and B19 DNA [Table 2] and [Table 3].

There was a significant difference in B19 marker combinations among recently infected patients of all groups, of which group II showed the highest association between B19-specific IgM and B19 DNA on PCR (75%; [Table 4].

Age distribution of the studied patients as regards recent, prior, and absent infection revealed no statistically significant differences, except among patients of group IV, in which a statistically significant difference between patients with recent and absent infection was observed. The control group showed a significantly higher mean age for children with prior infection (P<0.05).

The effect of B19 infection on blood parameters during recent, prior, and absent infection for all studied patients was assessed through laboratory investigations. The results revealed that all patients with recent B19 infection had anemia (mean Hb=7.19 g/dl, P<0.001; RBC count=2.9×106/l, P<0.01). This was followed by the presence of reticulocytopenia (RC%=0.53, P<0.05) with a statistically significant difference in the mean hemoglobin concentration, RBC count, and reticulocytic counts between patients with recent and prior infection and between patients with recent and absent infection. Neutrophil counts and platelet counts were lower in recently infected patients but were not statistically significant. Relative lymphocytosis (mean=4.09×103/mm3) was observed in all recently infected patients but the occurrence was again not statistically significant [Table 5] and [Table 6].

The occurrence of unexplainedanemia was higher among leukemia patients on chemotherapy with recent parvovirus B19 infection than among those with prior or absent infection. Erythrocyte count, platelet transfusion requirement, and duration of hospital stay were higher in recently infected patients [Table 7].


  Discussion Top


Certain populations are vulnerable to complications from depressed erythropoiesis that arises with parvovirus B19 infection. These populations include patients with hematological disorders that cause an increase in erythrocyte destruction 1.

In the present study, a higher prevalence of B19-specific IgM and B19 DNA, indicative of recent infection, was found in the studied groups compared with controls; however, only the difference in the prevalence of parvovirus B19 DNA, detected by PCR, was statistically significant. In group I, the prevalence of parvovirus B19-specific IgG was the highest (52%; controls, 40%). This was followed by the prevalence of B19-specific IgM and B19 DNA (24 and 4%, respectively). Similar rates were reported by Badr 13 in a study conducted in Saudi Arabia and by Regaya et al. 14 in a study conducted on young Tunisian patients with chronic hemolytic anemia.

Kishore et al. 15 reported much higher rates of B19-specific IgG and IgM (81 and 41.1%, respectively) in 90 patients with thalassemia major.

In contrast, Obeid 16 reported lower rates of 37.6, 2.9, and 2.9% for B19-specific IgG and IgM, and B19 DNA, respectively, in 138 patients with SCD. The higher prevalence of B19-specific IgG antibodies may be because of multiple blood transfusions, which play a significant role in the transmission of the virus 17; therefore, screening of blood for the presence of B19 may reduce the risk of transmission of the virus. In group II, B19-specific IgM and B19 DNA had the highest positive rate (46.7%), followed by B19-specific IgG (33.3%), which did not agree with the results of Zaki et al. 18, who found higher IgG positivity (45%) compared with IgM (5%) and DNA (0%) positivity in patients with aplastic crises. These differences may be primarily due to the transient aplastic crisis caused by parvovirus B19 and to a lesser extent due to folate deficiency and herpes zoster infection 19.

In group III, the rate of IgG positivity was the highest (50%), followed by IgM positivity and DNA prevalence (25 and 20%, respectively). Nearly similar findings were reported by El-Mahallawy et al. 20 in a study conducted on Egyptian children with acute leukemia, in which B19-specific IgM and IgG and B19 DNA rates were 26, 38, and 22%, respectively.

Lindblom 21 in a Swedish study on 117 children with ALL undergoing chemotherapy found B19 DNA in 15% of patients; Zaki and Ashry 22 also reported B19-specific IgG and IgM and B19 DNA rates of 40, 31.1, and 22.2%, respectively, in a study that involved 45 children with acute leukemia on maintenance chemotherapy. All the previously mentioned studies on children with acute leukemia on chemotherapy showed that the number of children with an immune response to B19 is higher than the number of children with B19 viremia. However, persistence and maintenance of B19 infection was reported in such patients on analysis of their serum and bone marrow samples 23, which led to the conclusion that there may be an aberrant immune response to B19 in patients with acute leukemia as the presence of neutralizing antibodies to B19 did not clear the virus, and in this case high levels of antibodies are associated with the persistence and not the clearance of the virus. In group IV, IgM positivity was the highest (35%), followed by IgG positivity (30%) and DNA prevalence (15%).

Zaki and Ashry 22 reported B19-specific IgM and IgG, and B19 DNA rates of 50, 40, and 45%, respectively, in 40 children recently diagnosed with acute leukemia.

Recently, Kishore et al. 24 in an Indian study that involved 18 recently diagnosed ALL patients reported B19-specific IgG and IgM, and B19 DNA rates of 34.3, 27.8, and 11.1%, respectively.

In the present study, parvovirus B19 infection was classified as recent infection in patients with IgM positivity and/or in those positive for B19 DNA on PCR, whereas only IgG positivity was considered to be indicative of prior B19 infection. Absence of any of the B19 markers was considered as absent infection. In group I, prior B19 infection (as diagnosed by the presence of IgG positivity only) had a higher prevalence (40%) compared with recent infection (24%).

Similarly, Smith-Whitley et al. 25 found that 30% of patients with SCD had evidence of prior B19 infection. Zaki et al. 18 also reported a 30% prevalence of prior B19 infection in children with various types of chronic hemolytic anemia but reported a lower rate of recent infection (5%). This difference in the rate of recent B19 infection may be attributed to different socioeconomic standards, frequency of blood transfusions, and possibility of nosocomial exposure. In group II, recent B19 infection showed a high rate of 53%, which is consistent with the findings of other studies that reported parvovirus B19 as the leading cause of transient aplastic crisis in patients with chronic hemolytic anemia, representing 65–80% of B19 infections 26.

In group III, recent infection had a higher prevalence rate (40%) compared with prior infection, which agrees with the results of El-Mahallawy et al. 20 and Zaki and Ashry 22, who reported prevalence rates of 40 and 50%, respectively, for recent B19 infection in leukemic patients on maintenance chemotherapy. There may be an association between acute leukemia and B19 infection, which may result from chemotherapy-induced immune suppression with activation of persistent infection or from repeated blood transfusions 27,28.

In group IV, 45% of patients had evidence of recent B19 infection, among whom 15% showed only positive PCR results for B19 DNA, whereas 30% had evidence of prior infection at the time of diagnosis.

This was much lower than that reported by Zaki and Ashry 22, who detected recent B19 infection in 85% of children with recently diagnosed acute leukemia.

In contrast, Kerr et al. 29 found evidence of recent infection in four of 16 (25%) patients with ALL at the time of presentation.

In the present study, patients with acute hemolytic crisis showed a significant positive correlation between B19-specific IgM and B19 DNA in their serum; no relation was found in other patients. In recently infected patients, levels of B19 markers were seen to be increased, but there was disparity between ELISA and PCR results. Thus, depending solely on serology or PCR results for the diagnosis of recent B19 infections may lead to misdiagnosis in some cases. This disparity between PCR and ELISA results was also reported in similar studies but with different prevalence rates of B19 markers 11, 18, 22, 24, 30.

Further, the present study showed a comparison of the blood profile parameters between the recently infected group and the control group. We observed that the constant laboratory finding in patients with recent B19 infection in our studied groups was anemia, followed by reticulocytopenia. Similar findings were reported by Hegaard et al. 31, who investigated 43 patients with hematological disorders and revealed that those with recent B19 infection had hemoglobin levels of less than 9.7 g/dl with marked reticulocytopenia.

In addition, in agreement, Zaki et al. 18 reported anemia and reticulocytopenia as constant features in patients with hematologic disorders recently infected with B19, together with lymphocytosis. Among patients with acute leukemia on chemotherapy, those with recent B19 infection showed significant reduction in hemoglobin concentration, RBC count, platelet count, and neutrophil count.

In agreement, Lindblom 21 reported that six of seven children with ALL on maintenance chemotherapy experienced episodes of cytopenia or pancytopenia due to recent B19 infection, which was indistinguishable from that caused by chemotherapy or other causes.

In the present study, associated conditions were assessed in acute leukemic patients on chemotherapy with recent B19 infection and compared with those in other patients of the same group with prior or absent B19 infection. In all, 75% of recently infected patients suffered from unexplained anemia with different forms of cytopenia compared with 25% of patients with prior or no infection. Unexplained anemia, defined as an acute drop in hemoglobin levels by more than 2.5 g/dl compared with earlier follow-up hemogram records without attributable etiology such as acute and chronic blood loss, accelerated RBC destruction, iron deficiency, or renal insufficiency 32, or severe cytopenias in those patients, usually necessitate withdrawal of maintenance chemotherapy and multiple blood transfusions because cytopenias that may result from B19 infection are indistinguishable from those due to bone marrow toxicity by chemotherapy or due to a leukemic relapse. Thus, considering B19 as a possible factor would prevent unnecessary interruption of chemotherapy 21.

The frequency of blood transfusion was higher in B19-infected patients [median (range)=8(2–9)/patient] compared with B19-noninfected patients [1(0–3)/patient]. In addition, patients recently infected with B19 missed a significantly greater number of days of maintenance chemotherapy [median (range)=54(30–90) days compared with 15(7–30) days] compared with B19-noninfected patients. The total duration of hospital stay was also higher in B19-infected patients of group III, which, together with the frequency of blood transfusion, can be considered a possible risk factor for or a consequence of B19 infection. More or less similar results for these variables were reported by other studies 11, 21, 24.


  Conclusion Top


Finally, we concluded that B19 infection is highly prevalent among children with hematological disorders. B19 must be suspected and screened for when anemia is present in those patients with neutropenia and lymphocytosis. In patients with acute leukemia under chemotherapy who have unexpected anemia or cytopenia, B19 infection should be considered before a change in chemotherapy protocol. The direct detection of B19 DNA by PCR in sera needs to be coupled with serological testing for a more reliable diagnosis of B19 infections in those children. We recommend that measures to avoid iatrogenic and nosocomial transmission be implemented, including screening of donated blood for B19 DNA, especially blood given to patients with hematological disorders, and introduction of an approved B19 vaccine. Further studies involving serial bone marrow examination for B19 DNA and other genetic studies to establish or deny the association between B19 infection and acute leukemia are also recommended.[32]

 
  References Top

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32.Kuo SH, Lin LI, Chang CJ, Liu XR, Lin K, Cheng AL.increased risk of parvovirus b19 infection in young adult cancer patients receiving multiple courses of chemotherapy.J Clin Microbiol2002;40:3909–3912.  Back to cited text no. 32
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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