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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2014  |  Volume : 25  |  Issue : 3  |  Page : 610-614
BK virus-associated hemophagocytic syndrome in a renal transplant recipient


1 Department of Nephrology, Hedi Chaker Hospital, Sfax, Tunisia
2 Department of Anatomo Pathology, Habib Bourguiba Hospital, Sfax, Tunisia

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Date of Web Publication9-May-2014
 

   Abstract 

Hemophagocytic syndrome (HPS) is a life-threatening hematological disorder in immunocompromised patients. Reactive HPS is observed in patients with systemic infection, neoplasia or auto-immune diseases. It is a rare hematological disorder after renal transplantation and must be suspected when fever and pancytopenia are seen in association with viral infections. HPS is usually associated with infection with the Cytomegalovirus and Epstein-Barr viruses. We report here a case of BK-virus-associated HPS.

How to cite this article:
Yaich S, Charfeddine K, Hsairi D, Zaghdane S, Kammoun K, Makni S, Boudawara T, Hachicha J. BK virus-associated hemophagocytic syndrome in a renal transplant recipient. Saudi J Kidney Dis Transpl 2014;25:610-4

How to cite this URL:
Yaich S, Charfeddine K, Hsairi D, Zaghdane S, Kammoun K, Makni S, Boudawara T, Hachicha J. BK virus-associated hemophagocytic syndrome in a renal transplant recipient. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2021 Dec 4];25:610-4. Available from: https://www.sjkdt.org/text.asp?2014/25/3/610/132205

   Introduction Top


Hemophagocytic syndrome (HPS) is a life-threatening hematological disorder, characterized by impaired or absent natural killer (NK) cells and increased activity of cytotoxic T cells, responsible for dysregulation of production of cytokines and proliferation and activation of histiocytes. [1] It is a clinico-pathologic entity characterized by high-grade fever, organomegaly, pancytopenia, high ferritin level and increased proliferation and activation of benign macrophages with hemophagocytosis throughout the reticuloendothelial system. [2] Reactive HPS is observed in patients with systemic infection, neoplasia or auto-immune disease. Various infectious agents have been associated with the development of HPS, including viruses. [3] It is rarely observed after renal transplantation and must be suspected when fever and pancytopenia are seen in association with immune-suppressed patients. We report herein a case of BK virus (BKV)-associated HPS.


   Case Report Top


A 29-year-old male patient with end-stage renal disease secondary to chronic glomerulonephritis received a kidney allograft from a living unrelated donor. His immunosuppression consisted of mycophenolate mofetil (MMF), tacrolimus and corticosteroids without induction therapy. The graft functioned immediately and the serum creatinine at discharge was 101 μmol/L (on day15), which remained stable on regular follow-up visits.

Eleven months after transplantation, the patient presented with fever up to 40°C, pancytopenia and an elevated serum creatinine of 398 μmol/L. There was no clinical evidence of infection and the urine and blood cultures were negative. The pulmonary radiograph was normal. Cytomegalovirus (CMV) PP-65 antigen was positive at 250 cells. Hence, intravenous gancyclovir treatment was instituted. Graft Doppler ultrasound showed no abnormality. A graft biopsy performed on day-seven of the fever showed features of acute rejection with viral inclusions [Figure 1]. Gancyclovir was continued and corticosteroid pulses were instituted. Ten days later, the CMV antigenemia was negative but the pancytopenia was worsening [white blood cells (WBC) of 500/mm 3 , platelet count of 62,000/mm 3 and hemoglobin of 7 g/dL). Biopsy marrow aspiration showed normal trilineage hematopoiesis [Figure 2]. The patient was prescribed granulocyte growth factor, which resulted in an increase in the WBC count to 3900/mm 3 . The serum creatinine came down to 150 μmol/L at discharge.
Figure 1: Graft biopsy on day 7 showing viral inclusions (HE magnification ×1000).

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Figure 2: Bone marrow biopsy showing normal trilineage with numerous macrophages filled with erythrocytes (HE magnification ×400).

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One month later, the allograft function had worsened with the serum creatinine reaching 828 μmol/L, requiring hemodialysis. Graft Doppler ultrasound was repeated and showed no abnormality. Concomitant to the rise of serum creatinine, the patient developed fever again up to 41°C with pancytopenia (WBC: 400/mm 3 , platelets: 18,000/mm 3 , hemoglobin: 3 g/dL). Clinical examination was negative with no obvious features of infection other than splenomegaly. CMV PP-65 antigenemia was negative and liver enzyme levels were normal. The serum ferritin level was 3890 ng/mL and the triglyceride level was 2.9 mmol/L. The coagulation parameters were normal. Urine analysis and repeated blood cultures were negative. The patient's serum was tested for viruses [Epstein-Barr virus (EBV), hepatitis B and C, herpes simplex virus, human herpes virus 8 (HHV8), HHV6, parvo B19, human immunodeficiency virus (HIV)], fungi and parasites (toxoplasma, leishmania, candida, aspergillus, pneumocystis) and bacteria (chlamydia,  Brucella More Details, rickettsia, mycoplasma). Serology against all these organisms was negative. The test for Mycobacterium tuberculosis in the sputum on three consecutive days was negative. Anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies were negative. Total body computed tomography was normal except for splenomegaly. The patient underwent a second graft biopsy that showed lesions suggestive of BKV nephropathy. The urine sample was positive for decoy cells and BKV polymerase chain reaction was positive (5.1 log 10 copies/mL). Bone marrow biopsy was suggestive of hemophagocytosis without malignant cells [Figure 2]. Culture with Giemsa staining of the bone marrow aspirate was negative for leishmania; intracellular amastigotes were negative and marrow culture was negative.

We reduced the dose of MMF and tacrolimus by half and increased the dose of cortico-steroids. Methylprednisolone (500 mg/d) was administered for three consecutive days followed by oral prednisolone at a dose of 1 mg/kg/day. This resulted in the disappearance of fever, an improvement of general health and normalization of blood counts. Unfortunately, the allograft function continued to worsen and the patient had to return to dialysis. Three years later, the patient is still alive on regular hemodialysis.


   Discussion Top


HPS is a clinico-pathologic entity caused by systemic proliferation of benign hemophagocytic cells of the monocyte-macrophage-histiocyte lineage. [4] Diagnosis of HPS relies on specific clinical, laboratory and histopathological findings proposed by the Histiocyte Society in 1991 and updated in 2004. [1],[5] Five out of the following criteria need to be met: Fever, splenomegaly, cytopenia (affecting greater than two cell lineages, hemoglobin ≤9 g/dL, platelets <100,000/μL, neutrophils <1000/μL), elevated triglyceride levels (≥265 mg/L) and/or low fibrinogen levels (≤150 mg/dL), elevated ferritin levels (≥500 ng/ mL), histopathology showing hemophagocytosis without evidence of malignancy, low or absent NK cell cytotoxicity and elevated soluble CD25 (IL-2Rα chain ≥2400 IU/mL). [1] Two forms of HPS have been described: Primary HPS and secondary or reactive HPS. [2],[3]

The primary or familial HPS is a genetically inherited disorder affecting young children. Reactive HPS may develop at any age and can be related to malignancies, metabolic diseases, auto-immune diseases or infections. [2],[3] HPS secondary to infections is mainly observed after viral infections, especially CMV and EBV. [6],[7] However, infections due to intracellular bacteria, parasites and fungi may also be associated with HPS. [6],[7]

The pathophysiology is poorly understood. Clinical and biological manifestations result from the secretion of cytokines by activated T cells and macrophages. Cooperation between histiocytes, macrophages and cytotoxic lymphocytes T CD8 (CLT) and NK play a crucial role in HPS. Macrophages phagocytose and present pathogenic agents to CLT, in association with the antigen HLA DR. Following this, the CLT response is initiated, which is amplified by tumor necrosis factor alfa (TNFα) and IL-12, produced by macrophages. Subsequently, CLT and NK produce cytokines such as interferon-α (INFα), TNFα and soluble IL-2 receptor (S-IL-2) until a complete elimination of the pathogenic agent occurs. [8] In HPS, a high amount of these cytokines has been observed with a tendency to peripheral lymphopenia, suggesting an imbalance in Th1-Th2 response. INF-γ is the prominent Th1 cytokine and a well-known activator of macrophages. In fact, over-production of Th1 cytokines leads to macrophage activation and proliferation, escaping control of NK cell cytotoxicity activation. [9],[10]

Organomegaly can be explained by tissue infiltration by activated lymphocytes and histiocytes. Fever and high serum ferritin levels are induced by IL-1, IL-6 and TNFα. Pancytopenia is the consequence of bone marrow infiltration by activated macrophages and high levels of TNFα and INF-γ. [2],[8] These cytokines inhibit the enzyme hepatic lipoprotein lipase that results in elevated serum triglyceride levels.

Reactive HPS can occur even in immune-competent patients, but immune-compromised individuals are more prone to this syndrome. In fact, following organ transplantation, the immune response is inadequate and unable to eliminate infectious agents, which results in abnormal stimulation of lymphocytes and macrophages. The lack of cytotoxicity caused by immunosuppression and the high amount of cytokines (TNFα and INF-γ) due to severe opportunistic infections may explain the excessive Th1 and macrophage activation. [4]

Although HPS has been described in immune-compromised patients, few studies have been published. [11],[12] Rare cases of HPS have been reported among renal transplant recipients, with an estimated incidence of about 0.4%. [13] The largest study of HPS after renal transplantation was reported by Karras et al and included 17 patients. [13]

The most common cause of HPS after renal transplantation is viral infections. However, any infectious agent can trigger HPS. In fact, reactive HPS has been described in association with bacterial, fungal or parasitic infections. [6] Another emerging cause is immunosuppressive medications. Recently, Raffray et al published a case of HPS in a renal transplant recipient, probably caused by MMF. [14]

In all reported series on HPS, the most frequently encountered viruses are CMV and EBV. Thus, the presence of CMV, EBV, HHV6 and HHV8 infection must be ruled out before other causes are investigated. Other agents such as toxoplasma, leishmania, M. tuberculosis and histoplasma have also been reported to cause HPS. [15],[16],[17]

BKV is an emerging problem in renal transplantation with the advent of newer, more potent immunosuppressive regimens. It is observed mainly in patients receiving a combination of tacrolimus and MMF. Additionally, BKV is increasingly emerging as a cause of acute renal failure and graft loss. Recently, a case of HPS-associated BKV nephropathy was first described. [18]

We report here the second case of BKV-associated HPS in a young renal transplant recipient. The clinical presentation was erroneous because there were no liver enzyme abnormalities and the ferritin as well as triglyceride levels were mildly elevated.

The treatment of HPS is not well established and there are no controlled clinical therapeutic trials, except for familial HPS. Treatment of reactive HPS is usually supportive and includes treatment of the underlying disease, which is effective with a recovery rate of 60-70%. [19] Anti-infectious agents are prescribed in HPS associated with infection; the drugs used depend on the microorganism identified. Intra-venous immunoglobulin (IVIg) was successfully tested in infection-associated HPS. Indeed, IVIg may have an anti-infectious effect and an immuno-modulatory effect, and can also interfere with macrophage activity. [4] Laroche et al in a multi-center study reported on 17 patients, nine of whom had infection-associated HPS. [20] These patients were treated with high doses of IVIg, with a mean dose of 1.6 mg/kg, for one or two cycles. This treatment was successful in 78% of the cases. A recent study reported the efficacy of high-dose immunoglobulin therapy in renal transplant recipients with hemophagocytic histiocytic syndrome. Six of the 13 patients with HPS were treated with high-dose immunoglobulin; all of them recovered completely. [21]

Other medical management includes reduction of immunosuppressive drugs to improve defence against infectious agents. Minimizing the dose of calcineurin inhibitors while giving high doses of intravenous steroids can be effective. [4] Increased inflammation caused by high levels of cytokines is life-threatening. Thereby, corticosteroids that are cytotoxic to lymphocytes and inhibit expression of cytokines and differentiation of dendritic cells are used, with the rationale being disrupting the activation of macrophages and cytokine production while protecting the allograft from rejection. [22]

Considering the pathophysiology of HPS, anti-TNFα compounds might be effective in the treatment. In fact, etanercept, a monoclonal anti-TNFα antibody, was successfully used in a case of reactive HPS. [23] In some cases resistant to steroids and IVIg, especially life-threatening ones with neurological dysfunction, plamapheresis may be attempted as a rescue therapy giving good results in anecdotal cases. [24]

Anti-CD52 monoclonal antibody (alemtuzumab), largely approved in the treatment of B-cell chronic lympocytic leukemia, is another rational therapeutic option for HPS. CD52 is strongly expressed on T cells and histiocytes, the main actors of HPS. [25] Mathew et al reported a case of atypical HPS in a non-transplant patient successfully treated with alemtuzumab before allogenic stem cell transplantation. [25]


   Conclusion Top


Reactive HPS is rare after renal transplantation and must be suspected when fever and pancytopenia are seen in association with viral infections. Early diagnosis, supportive therapy and specific treatment are crucial to improve the prognosis and can be life-saving. HPS is usually associated with CMV infections, but all the pathogenic infectious agents should be ruled out, particularly the new emerging ones.

 
   References Top

1.Maakaroun RN, Moanna A, Jacob JT, Albrecht H. Viral infections associated with haemophagocytic syndrome. Rev Med Virol 2010;20: 93-105.  Back to cited text no. 1
    
2.Janka GE. Hemophagocytic syndromes. Blood Rev 2007;21:245-53.  Back to cited text no. 2
    
3.Larroche C, Mouthon L. Pathogenesis of hemophagocytic syndrome (HPS). Autoimmun Rev 2004;3:69-75.  Back to cited text no. 3
    
4.Ponticelli C, Alberighi OD. Haemophagocytic syndrome-a life-threatening complication of renal transplantation. Nephrol Dial Transplant 2009;24: 2623-7.  Back to cited text no. 4
    
5.Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol 1991;18:29-33.  Back to cited text no. 5
    
6.Fisman DN. Hemophagocytic syndromes and infections. Emerg Infect Dis 2000;6:601-8.  Back to cited text no. 6
    
7.Karras A, Hermine. O. Syndrome d'activation macrophagique. Rev Med Interne 2002;23:768-78.  Back to cited text no. 7
    
8.Créput C, Galicier L, Oksenhendler E, et al. Syndrome d'activation lymphohistiocytaire: Revue de la literature, implications en réanimation. Réanimation 2005;14:604-13.  Back to cited text no. 8
    
9.Verbsky JW, Grossman WJ. Hemophagocytic lymphohistiocytosis: Diagnosis, pathophysiology, treatment, and future perspectives. Ann Med 2006;38:20-31.  Back to cited text no. 9
    
10.Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohisticytosis: Clinical features, pathogenesis and therapy. Expert Rev Clin Immunol 2010;6:137-54.  Back to cited text no. 10
    
11.Karasu Z, Kilic M, Cagirgan S, et al. Hemophagocytic syndrome after living-related liver transplantation. Transplant Proc 2003;35:1482-4.  Back to cited text no. 11
    
12.Kürsat S, Cagirgan S, Ok E, et al. Haemophagocytic-histiocytic syndrome in renal transplantation. Nephrol Dial Transplant 1997;12: 1058-60.  Back to cited text no. 12
    
13.Karras A, Thervet E, Legendre C. Hemophagocytic syndrome in renal transplant recipients: Report of 17 cases and review of literature. Transplantation 2004;77:238-43.  Back to cited text no. 13
    
14.Raffray L, Couzi L, Viallard JF, et al. Mycophenolate mofetil: A possible cause of hemophagocytic syndrome following renal transplantation? Am J Transplant 2010;10:2378-9.  Back to cited text no. 14
    
15.Segall L, Moal MC, Doucet L, Kergoat N, Bourbigot B. Toxoplasmosis-associated hemophagocytic syndrome in renal transplantation. Transplant Int 2006;19:78-80.  Back to cited text no. 15
    
16.Rostaing L, Fillola G, Baron E, Cisterne JM, Durand D. Course of hemophagocytic syndrome in renal transplant patients. Transplantation 1995; 60:506-9.  Back to cited text no. 16
    
17.Lo MM, Mo JQ, Dixon BP, Czech KA. Disseminatated histoplasmosis associated with hemophagocytic lymphohistiocytosis in kidney transplant recipients. Am J Transplant 2010;-10:687-91.  Back to cited text no. 17
    
18.Esposito L, Hirsh H, Basse G, Fillola G, Kamar N, Rostaing L. BK Virus-Related Hemophagocytic syndrome in a renal Transplant Patient. Transplantation 2007;83:365.  Back to cited text no. 18
    
19.Freeman B, Rathore MH, Salman E, Joyce MJ, Pitel P. Intravenously administered immune globulin for the treatment of infection-associated hemophagocytic syndrome. J Pediatr 1993;123 :479-81.  Back to cited text no. 19
    
20.Larroche C, Bruneel F, André MH, et al. Les immunoglobulines intraveineuses dans les syndromes d'activation macrophagique secondaires. Ann Med Interne 2000;151:533-9.  Back to cited text no. 20
    
21.Asci G, Toz H, Ozkahya M, et al. High-dose immunoglobulin therapy in renal transplant recipients with hemophagocytic histiocytic syndrome. J Nephrol 2006;19:322-6.  Back to cited text no. 21
    
22.Wong PK, Cuello C, Bertouch JV, et al. Effects of pulse methylprednisolone on macrophage chemotactic protein-1 and macrophage inflammatory protein-1 alpha in rheumatoid synovium. J Rheumatol 2001;28:2634-6.  Back to cited text no. 22
    
23.Prahalad S, Bove KE, Dickens D, Lovell DJ, Grom AA. Etanercept in the treatment of macro-phage activation syndrome. J Rheumatol 2001; 28:2120-4.  Back to cited text no. 23
    
24.Matsumoto Y, Naniwa D, Banno S, Sugiura Y. The efficacy of therapeutic plasmapheresis for the treatment of fatal hemophagocytic syndrome: Two case reports. Ter Apher 1998;2:300-4.  Back to cited text no. 24
    
25.Machaczka M, Vaktnäs J, Chiang SC, Bryceson YT. Alemtuzumab treatment for hemophagocytic lymphohistiocytosis. Nat rev Clin Oncol 2010;7: 415-20.  Back to cited text no. 25
    

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Correspondence Address:
Dr. S Yaich
Department of Nephrology, Hedi Chaker Hospital, Sfax
Tunisia
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DOI: 10.4103/1319-2442.132205

PMID: 24821160

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