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CASE REPORT
Year : 2015  |  Volume : 33  |  Issue : 3  |  Page : 432-434
 

Prolonged remission in a child with chronic myeloid leukemia following Parvo virus B19 (B19V) infection


1 Department of Pediatrics, Division of Pediatric Hematology-Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India
2 Department of Microbiology, Division of Virology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Hematopathology, King George's Medical University, Lucknow, Uttar Pradesh, India
4 Department of Microbiology, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Submission30-Jun-2014
Date of Acceptance28-Jan-2015
Date of Web Publication12-Jun-2015

Correspondence Address:
A Kumar
Department of Pediatrics, Division of Pediatric Hematology-Oncology, King George's Medical University, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0255-0857.158580

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 ~ Abstract 

Parvovirus B19 (B19V) has been associated with a wide spectrum of clinico-pathological disorders in human beings depending upon the host immunity. The present report describes a child with chronic myeloid leukemia ( CML) on hydroxyurea in haematological remission, who developed profound erythroid suppression following B19V infection requiring multiple transfusions and withdrawal of hydroxyurea. Despite being off-therapy the child remained in complete clinical and haematological remission till anti B19V antibodies appeared. This case illustrates the ability of B19V infection in suppressing neoplastic myeloid clone, a phenomenon not described earlier.


Keywords: Chronic myeloid leukemia, hematological remission, Parvo virus B19


How to cite this article:
Kumar A, Moulik N R, Kishore J, Kumar A, Jain A. Prolonged remission in a child with chronic myeloid leukemia following Parvo virus B19 (B19V) infection. Indian J Med Microbiol 2015;33:432-4

How to cite this URL:
Kumar A, Moulik N R, Kishore J, Kumar A, Jain A. Prolonged remission in a child with chronic myeloid leukemia following Parvo virus B19 (B19V) infection. Indian J Med Microbiol [serial online] 2015 [cited 2019 Nov 17];33:432-4. Available from: http://www.ijmm.org/text.asp?2015/33/3/432/158580



 ~ Introduction Top


From a mild exanthema in the healthy host to severe hemolytic crisis in individuals with underlying disorders of RBC and lethal cytopenias in the immunocompromised B19V has been associated with an ever broadening spectrum of diseases in humans. [1],[2] B19V predominantly replicates in human erythroid progenitor cells inhibiting erythropoiesis. Tropism of B19V is due to restrictive distribution of the P blood group antigen globoside (Gb4) primarily on the cells of the erythroid lineage, though other cell lines are also variably infected. [3],[4] We report a child with chronic myeloid leukemia (CML) in haematological remission who developed profound anemia following infection with B19V.


 ~ Case Report Top


A 7-year-old boy presented with irregular fever and abdominal distension for 6 months. Clinical examination, counts and bone marrow were suggestive of CML. Bcr-abl translocation was documented on fluorescent in situ hybridisation (FISH). He attained complete clinical and haematological remission within 3 months of starting hydroxyurea and continued to be in haematological remission for subsequent 3 years. In the fourth year, while on the same treatment he developed progressive anaemia with an otherwise unremarkable clinical examination. Haemogram revealed low haemoglobin and RBC count, with normal leucocytes and platelets, without any peripheral immature myeloid cells, corrected reticulocyte count was 1% [Table 1]. Bone marrow aspiration revealed isolated erythroid hypoplasia with megaloblastoid changes and giant pronormoblasts [Figure 1] suggesting a possible B19V infection. Tests for B19V detected B19V DNA by PCR but IgM and IgG anti B19V antibodies were negative [Figure 2]. A repeat FISH did not show presence of bcr-abl translocation. Other viral markers including human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and Epstein-Barr virus (EBV) were negative.
Figure 1: Photomicrograph showing a giant pronormoblast with; "dog ear projections"; in the bone marrow (Leishman stain). The arrow points towards an intranuclear inclusion

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Figure 2: Trend of hemoglobin levels, transfusion requirement and B19V related markers in our patient

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Table 1: Serial clinico - haematological parameters in our patient


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Hydroxyurea was discontinued due to severe anaemia. Specific treatment could not be given as IV immunoglobulin could not be afforded. He remained off hydroxyurea and in complete haematological remission but required 10 units of packed red cell transfusion over a span of 18 months for persistent anaemia [Figure 2]. B19V markers repeated after 3 months showed persistent DNA positivity and undetectable antibodies. Antibodies became detectable after 6 months of onset of anaemia with disappearance of B19V DNA. Both IgM and IgG antibodies and only IgG antibodies were detectable after 12 and 18 months respectively [Figure 2]. Haemoglobin levels gradually improved and transfusion requirement ceased after 18 months, coinciding with the reappearance of myeloid precursors in the peripheral blood. Repeat bone marrow revealed features of relapsed CML with bcr-abl positivity in FISH.

Hydroxyurea was restarted and complete remission was attained within 2 months. Imatinib was later introduced (following its free availability in our hospital) and hydroxyurea gradually withdrawn. Currently the child is on imatinib monotherapy, in complete clinical and haematological remission for the last 3 years.


 ~ Discussion Top


Prolonged cytopenias leading to interruption in chemotherapy and increased chemotherapy related complications have been documented with B19V infection in children with ALL. [5] Dysplastic transformation of myeloid cells due to B19V infection leading to myelodysplastic syndrome- like entity and [6] aplastic anaemia is well documented. [1],[7] However to the best of our knowledge the effect of B19V infection on CML has not been previously reported.

The mechanisms behind B19V mediated involvement of erythroid cells is mediated by its affinity towards the P blood group antigen globoside (Gb4) distributed mainly in cells of erythroid lineage [3] whereas the involvement of non erythroid cells may be due to direct virus induced cytotoxicity as well as by an indirect immune-modulation induced by the virus leading to upregulation of cytokines like interferon gamma (IFN-gamma). [1],[7]

The neoplastic myeloid proliferation in CML induced by bcr-abl fusion protein mediated aberrant tyrosine kinase activity leading to uncontrolled cell proliferation is amenable to suppression by myelosuppressive agents like hydroxyurea or recently molecular targeted therapy with tyrosine kinase inhibitors. Prolonged remission following B19V infection in our patient despite discontinuation of hydroxyurea for nearly 18 months suggests a possible role of B19V in suppressing neoplastic proliferation, at least transiently, a fact hitherto unreported in medical literature. With clearance of viremia and appearance of anti B19V antibodies the suppressed myeloid lineage sprung back to its pre-infection state leading to relapse of CML, which was controlled again after reinstituting therapy with hydroxyurea.

The mechanism behind prolonged suppression of neoplastic clone in our patient in absence of antineoplastic agents remains uncertain and may be attributed to direct virus induced cytotoxicity as well as B19V induced upregulation of IFN-gamma akin to its mechanism of involvement of the non-erythroid lineages. In vitro studies have demonstrated IFN-gamma to suppress the colony forming and blast forming units of hematopoietic progenitors derived from CML patients and it also mediates the action of imatinib (tyrosine kinase inhibitor) in treatment of CML [8] and gastrointestinal stromal tumours (GIST). [9] Given the antineoplastic role of IFN-gamma on the bone marrow progenitors of CML the mechanism mediated by IFN-gamma seems to be more plausible.

In the healthy host anti-B19V antibodies appear as early as the second week of infection and IgM antibodies usually persist in the serum for 3-6 months while IgG antibodies may last for life. [2] In our patient IgM antibodies appeared nearly 6 months after B19V-DNA was first detected and IgG antibodies were negative till very late in the course of infection and were detected at 18 months, a phenomenon typical of immunocompromised hosts. [1] Therefore, PCR based diagnostic techniques should be used when B19V infection is suspected in immunocompromised hosts. Clues to diagnosis may be provided by typical bone marrow findings showing giant pronormoblasts, where PCR based diagnosis is not readily available. [10]

The molecular remission in our patient was based on FISH alone and not by more sensitive PCR based techniques. Also, our hypothesis regarding the IFN-gamma mediated suppression of the neoplastic clones remains unsupported in the absence of IFN-gamma assays and in vitro studies on the bone marrow progenitors of our patient. Despite these limitations our case illustrates the ability B19V to suppress the myeloid lineage in addition to erythroid precursors and also its ability to suppress the proliferation of neoplastic myeloid progenitors, a unique phenomenon not reported earlier.

 
 ~ References Top

1.
Quian XH, Zhang GC, Jiao XY, Zheng YJ, Cao YH, Xu DL, et al. Aplastic anemia associated with parvovirus B19 infection. Arch Dis Child 2002;87:436-7.  Back to cited text no. 1
    
2.
Kishore J, Sen M, Kumar A, Kumar A. A pilot study on parvovirus B19 infection in paediatric haematological malignancies. Indian J Med Res 2011;133:407-13.  Back to cited text no. 2
[PUBMED]  Medknow Journal  
3.
Servant-Delmas A, Lefrère JJ, Morinet F, Pillet S. Advances in human B19 erythrovirus biology. J Virol 2010;84:9658-65.  Back to cited text no. 3
    
4.
Mortimer PP, Humphries RK, Moore JG, Purcell RH, Young NS. A human parvovirus-like virus inhibits haematopoietic colony formation in vitro. Nature 1983;302:426-9.  Back to cited text no. 4
[PUBMED]    
5.
Lindblom A, Heyman M, Gustafsson I, Norbeck O, Kaldensjö T, Vernby A, et al. Parvovirus B19 infection in children with acute Lymphoblastic leukemia is associated with cytopenia resulting in prolonged interruptions of chemotherapy. Clin Infect Dis 2008;46:528-36.  Back to cited text no. 5
    
6.
Yarali N, Duru F, Sipahi T, Kara A, Teziç T. Parvovirus B19 infection reminiscent of myelodysplastic syndrome in three children with chronic haemolytic anemia. Pediatr Hematol Oncol 2000;17:475-82.  Back to cited text no. 6
    
7.
Osaki M, Matsubara K, Iwasaki T, Kurata T, Nigami H, Harigaya H, et al. Severe aplastic anemia associated with human parvovirus B19 infection in a patient without underlying disease. Ann Hematol 1999;78:83-6.  Back to cited text no. 7
    
8.
Aswald JM, Lipton JH, Aswald S, Messner HA. Increased IFN-gamma synthesis by T cells from patients on imatinib therapy for chronic myeloid leukemia. Cytokines Cell Mol Ther 2002;7:143-9.  Back to cited text no. 8
    
9.
Zitvogel L, Kroemer G. Anticancer effects of imatinib via immunostimulation. Nat Med 2011;17:1050-1.  Back to cited text no. 9
[PUBMED]    
10.
McNall RY, Head DR, Pui CH, Razzouk BI. Parvovirus B19 infection in a child with acute lymphoblastic leukemia during induction therapy. J Pediatr Hematol Oncol 2001;23:309-11.  Back to cited text no. 10
    


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