|Year : 2014 | Volume
| Issue : 2 | Page : 181-183
Fatal missed case of hemophagocytic lymphohistiocytosis co-infected with parvovirus B19 and Epstein-Barr virus in an infant: Test hyperferritinaemia early
J Kishore1, D Kishore2
1 Department of Microbiology Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Pediatrics, Dr. Shyama Prasad Mukherjee (Civil) Hospital, Lucknow, Uttar Pradesh, India
|Date of Submission||26-Jul-2013|
|Date of Acceptance||28-Oct-2013|
|Date of Web Publication||2-Apr-2014|
Department of Microbiology Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Hemophagocytic lymphohistiocytosis (HLH) triggered by Parvovirus B19 and Epstein-Barr virus co-infection is rare and unknown in infants. A 2-month-old male infant with fever, rash, bicytopenia and hepato-splenomegaly died owing to diagnostic dilemmas. Hence simply testing for hyperferritinaemia and hypertriglyceridemia/hypofibrinogenemia could diagnose HLH early while robust treatment be life-saving.
Keywords: Anaemia, Epstein-Barr, hemophagocytic, hepato-splenomegaly, parvovirus B19, polymerase chain reaction, thrombocytopenia
|How to cite this article:|
Kishore J, Kishore D. Fatal missed case of hemophagocytic lymphohistiocytosis co-infected with parvovirus B19 and Epstein-Barr virus in an infant: Test hyperferritinaemia early. Indian J Med Microbiol 2014;32:181-3
|How to cite this URL:|
Kishore J, Kishore D. Fatal missed case of hemophagocytic lymphohistiocytosis co-infected with parvovirus B19 and Epstein-Barr virus in an infant: Test hyperferritinaemia early. Indian J Med Microbiol [serial online] 2014 [cited 2020 Jul 2];32:181-3. Available from: http://www.ijmm.org/text.asp?2014/32/2/181/129819
| ~ Introduction|| |
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening  clinical condition with activation and proliferation of lymphocytes and histiocytes with excessive cytokine release causing uncontrolled phagocytosis of erythrocytes and platelets. HLH can be primary (genetic) or secondary to infectious rheumatologic, malignant or metabolic conditions but is commonly acquired and triggered by viral infection. Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are usual but parvovirus B19 (B19)  infection or B19 and EBV co-infections are rare.  The main diagnostic difficulty of HLH is low specificity of symptoms, requirement of multiple criteria and many triggering agents with varied clinical presentation; posing a diagnostic dilemma. Hence clinical, virological and hematological features in an infant ending fatally are presented here.
| ~ Case Report|| |
A 2-month-old male infant weighing 5.4 kg delivered by Caesarean section presented with history of high grade fever for 2 weeks, rash, anaemia, thrombocytopenia and abnormal movements for 1 day and was admitted in a private hospital. Despite supportive and multiple anti-microbial therapy, the child continued with moderate fever for the next 2 weeks hence was referred for further investigations in the Virology division, Department of Microbiology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, a tertiary care institute. Father of the infant gave consent for its publication.
On examination, moderate pallor, few petechial rash on abdomen with hepato-splenomegaly (liver 5 cm and spleen 4 cm below the costal margin) were observed. Investigation revealed severe anaemic (haemoglobin 6 g/dL; 5.7 g/dL packed cell volume 19.4%), leucocytosis (17 × 10 9 /L; 26 × 10 9 /L) and lymphocytosis (89%) with 6% polymorphs and 4% monocytes and 1% eosinophils together with thrombocytopenia (42 × 10 9 /L, 12 × 10 9 /L; 6 × 10 9 /L). Liver functions were slightly deranged with raised alkaline phosphatase and lactate dehydrogenase (LDH) while renal functions were normal. Blood and urine cultures were sterile, malarial parasites were not seen, nor were dengue-specific IgM and IgG antibodies detected, while direct Coombs' test was negative. TORCH
(Toxoplasma gondii, rubella, CMV, herpes simplex virus) titres were negative for IgM antibodies by enzyme-linked immunosorbent assay (ELISA). Chest X-ray showed no abnormalities, computed tomography (CT) whole abdomen confirmed hepato-splenomegaly with minimal ascites. The infant was repeatedly treated with anti-microbial agent (ceftriaxone, later meropenem), packed red blood cell transfusion (2 units/2-3 weeks) platelet transfusions (1 unit/week) but the infant did not respond.
During the hospital stay the infant developed maculopapular rash on face resembling 'slapped cheek' [Figure 1], later became generalised and persisted for 3 weeks, hence a course of intravenous immunoglobulin (IVIG) was given. Serum was tested for human parvovirus B19 by ELISA and polymerase chain reaction (PCR) as described previously , and real-time PCR (Shanghai, China). Anti-B19 IgM, IgG were positive but no B19 DNA was detected. Further, CMV IgM antibodies and CMV real-time PCR were negative but EBV (VCA) IgM antibodies and EBV DNA (329.81 × 10 3 copies/ml) were positive.
|Figure 1: Photograph of infant with characteristic 'Slapped Cheek' maculopapular lacy rash on face, which spread later to entire body and which persisted over 2 weeks|
Click here to view
A repeat haemogram after 3 weeks showed haemoglobin level as 7.8 g/dL platelets 10 × 10 9 /L, total leucocyte count of 14 × 10 9 /L with lymphocytosis (98%) and atypical lymphocytes and. confirmed hypercholesterolaemia (triglyceride = 216 mg/dL) and hypertriglyceridemia (3290 mcg/L). Bone-marrow smears [Figure 2] showed hemophagocytosis, but no blast cells were seen. The infant continuously deteriorated with increasing demand for platelets and red blood cell transfusions and required oxygen inhalation; given methylprednisolone intravenously to suppress hemophagocytosis but of no avail and ultimately the infant died after 2 months of hospitalisation in intensive care unit (ICU) due to multi-organ involvement causing hypoxia, serous effusions, comatosed condition and congestive cardiac failure.
|Figure 2: Photomicrograph of bone-marrow smear stained with Giemsa showing activated macrophage with multiple red blood cell phagocytosed within it (in the centre) with myelosuppresion and erythroid hyperplasia. Inset shows another macrophage engulfi ng many red blood cells and platelets. (Magnifi cation = 10 × 100)|
Click here to view
| ~ Discussion|| |
HLH is severe uncontrolled hyperinflammatory disorders with dysfunction of cytotoxic T cells and NK cells due to defects in perforin-dependent cytotoxic function causing an aberrant cytokine release causing proliferation/activation of histiocytes with potentially fatal damage to organ systems including the bone-marrow, liver or brain. , HLH requires multiple diagnostic criteria  (fever, hepato-splenomegaly, bicytopenia, hypertriglyceridemia/ hypofibrinogenemia and hemophagocytosis) with three additional criteria added in 2004 namely low/absent NK-cell-activity, hyperferritinaemia and high-soluble interleukin-2-receptor levels. Altogether five of these eight criteria must be fulfilled, our case fulfilled six of eight criteria. Further superimposition of generalised rash added to diagnostic dilemma. Hence this syndrome is much difficult to diagnose early 7 so was the case of this infant.
Owing to prior IVIG infusions B19 viremia had cleared giving negative B19 real-time PCR but anti-B19 IgM antibodies were positive as it lasts longer. Since EBV real-time PCR as well as anti-EBV IgM antibodies were also positive, hence B19 and EBV co-infection occurred simultaneously. Further investigations were done late but it confirmed hypercholesteroleamia and hyperferritinaemia. Since induction of HLH by BCG vaccine has been reported  and symptoms ensued soon after DPT vaccination in this infant it raises a remote possibility of DPT-induced HLH; but the exact mechanism is unknown.
Non-improvement of fever, anaemia and/or thrombocytopenia and hyperferritinaemia (ferritin level >500 mcg/L) are risk known factors.  Therefore, all cases of fever with hepatosplenomegaly and bicytopenia be screened at least for hyperferritinaemia, which is reliable (93%) and cost-effective.  Early clinical suspicion, diagnosis of HLH combined with robust treatment  with chemotherapy, immunotherapy and stem cell transplantation only can reduce mortality. Further genetic studies are needed for future guidance and aetiological classification of HLH.
| ~ References|| |
|1.||Risma K, Jordan MB. Hemophagocytic lymphohistiocytosis: Updates and evolving concepts. Curr Opin Pediatr 2012;24:9-15. |
|2.||Janka G. Hemophagocytic lymphohistiocytosis: When the immune system runs amok. Klin Padiatr 2009;221:278-85. |
|3.||Qiang Q, Zhengde X, Shuang Y, Kunling S. Prevalence of coinfection in children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol 2012;34:e45-8. |
|4.||Kishore J, Srivastava M, Choudhary N. Standardization of B19 IgG ELISA to study the seroepidemiology of parvovirus B19 in North Indian voluntary blood donors. Asian J Transfus Sci 2010;4:86-90. |
|5.||Kishore J, Mukhopadhyay C. Persistence of parvovirus B19 IgM antibodies and DNA in pure red cell aplasia resulting in myelodysplasia: A case report. Indian J Pathol Microbiol 2004;47:78-81. |
|6.||Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31. |
|7.||Balwierz W, Czoga³a M, Pawiñska-Wasikowska K, Cwikliñska M, Walicka-Soja K. Hemophagocytic lymphohistiocytosis: Diagnostic problems in pediatrics. Przegl Lek 2010;67:417-24. |
|8.||Cwikliñska M, Czoga³a M, Balwierz W, Hnatko-Ko³acz M, Moryl-Bujakowska A, Malinowska I, et al . Hemophagocytic syndrome in children with different underlying conditions. Przegl Lek 2010;67:430-5. |
|9.||Trottestam H, Berglöf E, Horne A, Onelöv E, Beutel K, Lehmberg K, et al. Risk factors for early death in children with haemophagocytic lymphohistiocytosis. Acta Paediatr 2012;101:313-8. |
|10.||Switala JR, Hendricks M, Davidson A. Serum ferritin is a cost-effective laboratory marker for hemophagocytic lymphohistiocytosis in the developing world. J Pediatr Hematol Oncol 2012;34:e89-92. |
|11.||Marsh RA, Allen CE, McClain KL, Weinstein JL, Kanter J, Skiles J, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer 2013;60:101-9. |
[Figure 1], [Figure 2]