Eradication of parvovirus B19 infection after renal

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Eradication of parvovirus B19 infection after renal transplantation requires reduction of immunosuppression and high-dose immunoglobulin therapy.
Nephrol Dial Transplant (2002) 17: 1840–1842

Case Report

Eradication of parvovirus B19 infection after renal transplantation requires reduction of immunosuppression and high-dose immunoglobulin therapy Lutz Liefeldt1, Martin Buhl6, Britta Schweickert2, Elisabeth Engelmann4, Orhan Sezer3, Peter Laschinski6, Lothar Preuschof 5 and Hans-H. Neumayer1 1

Department of Nephrology, 2Department of Virology and 3Department of Haematology, Charite´, Humboldt-University Berlin, 4Department of Virology and 5Department of Nephrology, University Hospital Benjamin Franklin, Free University Berlin and 6Kuratorium fu¨r Dialyse und Nierentransplantation e. V., Berlin, Germany

Introduction Anaemia is a frequent problem after renal transplantation, which may appear as hypo-regenerative anaemia (due to myelotoxic drugs or infectious agents anduor poor graft function) or hyper-regenerative anaemia (haemolysis or bleeding). It, therefore, seems reasonable to distinguish between different underlying causes of anaemia according to reticulocyte counts. One of the presumably rather rare infectious agents causing transient hypo-regenerative anaemia is the human parvovirus B19 (HPV B19) that was discovered in human blood 25 years ago [1] and was found to be the cause of ‘fifth disease’ in children in the 1980s [2]. More recently, it became evident that this virus may also cause severe infections in immunocompromised adults [3–6]. Here, we report on virological monitoring and on attempts to eradicate HPV B19 in a renal transplant recipient suffering from pure red cell anaemia as a severe form of hypo-regenerative anaemia. Furthermore, we systematically review the literature with respect to treatment regimens.

on maintenance haemodialysis during the preceding 9 years. Before transplantation the patient felt well and was able to work. He received erythropoietin treatment subcutaneously (6000 Uuweek). In August 2001, the patient received a first cadaveric renal allograft. At this time he was free of an acute illness and his anaemia secondary to chronic renal failure was adequately controlled (haemoglobin 13.7 gudl). Initially, a standard triple immunosuppressive regimen was used (cyclosporine, mycofenolate mofetil, prednisolone). An early mild rejection episode (Banff Ia) was treated with prednisolone pulses and cyclosporine was replaced by tacrolimus. Serum creatinine levels dropped and stabilized at around 280 mmolul. Because of intolerable diarrhoea, mycofenolate mofetil had to be reduced and was finally withdrawn. At discharge 4 weeks after transplantation, anaemia was present (Hb 7.7 gudl). Ferritin and vitamin B12 levels were within the normal range, but the reticulocyte count was not determined. When the haemoglobin concentration dropped to 6.8 gudl, 2 units of packed red cells were transfused. In addition, treatment with erythropoietin was reinstituted temporarily. Haemoglobin concentration as Table 1. Haematological laboratory and blood chemical values Parameter

Value

Reference range

Haemoglobin Reticulocytes Vitamin B12 Folic acid Iron Ferritin Haptoglobin Creatinine Erythropoietin Erythropoietin antibodies

6.0 gudl 0 296 nguml 7.0 nguml 42.5 mmolul 1243 mgul 155 mgudl 2.3 mgudl 277.4 IUul Negative

14–18 gudl 0.8–2.5% 187–1059 nguml 3.5–16.1 nguml 7–28 mmolul 30–300 mgul 30–200 mgudl -1.2 mgudl 6.2–28.2 IUul Negative

Case The patient is a 38-year-old male with end-stage renal failure secondary to Goodpasture’s syndrome who was

Correspondence and offprint requests to: Dr Lutz Liefeldt, Medizinische Klinik mit Schwerpunkt Nephrologie, Charite´, Humboldt-Universita¨t Berlin, Schumannstr. 20u21, D-10117 Berlin, Germany. Email: [email protected] #

2002 European Renal Association–European Dialysis and Transplant Association

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Keywords: eradication; immunosuppression; i.v. immunoglobulin; parvovirus B19; pure red cell anaemia; renal transplantation

Eradication of parvovirus B19 infection

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A

B

Table 2. Treatment regimens of parvovirus infections in renal transplant recipients Referenceuno. of patients

Clinical problem

i.v.IG treatment

Clinical response

Virological responsea

Shan [9]u1

Anaemia Hepatitis Anaemia Anaemia Anaemia Anaemia Anaemia Hepatitis, anaemia Anaemia Anaemia Anaemia Anaemia AnaemiaqGN Anaemia Anaemia Anaemia Anaemia

0.4 gukg 3 7 days

Temporarily No (patient died) No Yes Yes Yes Yes Yes Yes Yes Yes Yes Primarily Yes Yes Yes Yes

No No n.d. Yes Yes n.d. n.d. No n.d. n.d. n.d. n.d. No Yes No No No

Lui [10]u3 Shimmura [7]u3 So [11]u1 Lee [12]u1 Pamidi [13]u2 Moudgil [14]u3 Ahsan [15]u1 Bertoni [16]u4 Sturm [8]u1 Uemura [17]u1

(21 g 3 5 days) 3 2 (21 g 3 5 days) 3 2 No Withdrawal of MMF or azathioprine 0.5 gukg 3 5 days Reduced ISq0.4 gukg 3 7 days 50 g 3 5 days Withdrawal of MMFq25 g 3 5 days 0.4 gukg 3 10 days 0.4 gukg 3 10 days 1 gukg 3 2 days Reduced ISq0.4 gukg 3 5 days 0.4 gukg 3 15 days Reduced ISq0.4 gukg 3 4 days 5 g 3 7 days

a As assessed by HPV B19-PCR. i.v.IG, intravenous immunoglobulin; MMF, mycofenolate mofetil; n.d., not determined; IS, immunosuppression; GN, glomerulonephritis.

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Fig. 1. Response of pure red cell anaemia secondary to parvovirus B19 infection in a renal transplant recipient to i.v.IG. (A) ‘Low dose’ i.v.IG (0.25 gukg for 3 days). (B) ‘High dose’ i.v.IG (0.5 gukg for 5 days). Rectangles, reticulocyte count (%); diamonds, haemoglobin concentration (gudl).

well as reticulocyte count, however, remained very low (7.7 gudl and 0.1%, respectively). A bone marrow examination disclosed characteristic findings of pure red cell anaemia (depletion of all erythroid elements except a few ‘giant proerythroblasts’ with intranuclear inclusions). Laboratory tests were performed (Table 1). As suspected from the bone marrow smear, HPV B19 infection was confirmed by polymerase chain reaction (PCR). Serum samples were borderline for HPV B19 IgM but negative for IgG antibodies. PCR analyses of sera stored prior to transplantation and early after transplantation were negative for HPV B19 DNA and for both HPV B19 IgM and IgG antibodies. Analysis of donor serum did not reveal acute infection with HPV B19 (IgG positive, IgM and DNA negative). Therefore, a primary infection early after transplantation can be supposed. As i.v. immunoglobulin therapy (i.v.IG) is the only recommended treatment option for HPV B19 infection [7], doses of 0.25 gukg per day were administered i.v. for 3 days. This resulted in a prompt response, which was followed by an early relapse (Figure 1A). Serum HPV B19 DNA remained positive with negative results for IgG and IgM antibodies. During follow-up, the patient’s haemoglobin concentration fell again and reappearing severe reticulocytopenia as well as persistent positive results for HPV B19 DNA PCR led us to a second, more intense course of i.v.IG (0.5 gukg per day over a period of 5 days). At the end of this course the reticulocyte count increased to 3.1%. One month later the haemoglobin concentration reached approximately 10 gudl and the reticulocyte count remained elevated (Figure 1B). Serum HPV B19 DNA and IgM antibodies were tested negative, while IgG antibodies were positive. Four weeks after the disappearance of viral DNA from peripheral blood, the haemoglobin

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concentration was still increasing while viraemia remained undetectable by PCR.

Discussion

References 1. Cossart YE, Field AM, Cant B, Widdows D. Parvovirus-like particles in human sera. Lancet 1975; 1: 72–73

2. Anderson MJ, Jones SE, Fisher-Hoch SP et al. Human parvovirus, the cause of erythema infectiosum (fifth disease)? Lancet 1983; 1: 1378 3. Taillan B, Heudier P, Ferrari E, Garnier G, Fuzibet JG, Dujardin P. Pure red-cell aplasia due to parvovirus B19 infection in a patient with AIDS-related complex. Ann Med 1992; 24: 137 4. Fisher D, Spencer D, Iland H, Brammah S, Cossart Y. Red cell aplasia caused by human parvovirus B19 in acute leukaemia. Aust N Z J Med 1992; 22: 303–304 5. Kamper AM, Malbrain M, Zachee P, Chew SL. Parvovirus infection causing red cell aplasia and leukopenia in rheumatoid arthritis. Clin Rheumatol 1994; 13: 129–131 6. Bertoni E, Rosati A, Zanazzi M et al. Severe aplastic anaemia due to B19 parvovirus infection in renal transplant recipient. Nephrol Dial Transplant 1995; 10: 1462–1463 7. Shimmura H, Tanabe K, Ishikawa N, Tokumoto T, Toda F, Toma H. Discontinuation of immunosuppressive antimetabolite for parvovirus B19-associated anemia in kidney transplant patients. Transplant Proc 2000; 32: 1967–1970 8. Sturm I, Watschinger B, Geissler K et al. Chronic parvovirus B19 infection-associated pure red cell anaemia in a kidney recipient. Nephrol Dial Transplant 1996; 11: 1367–1370 9. Shan YS, Lee PC, Wang JR, Teal HP, Sung CM, Jin YT. Fibrosing cholestatic hepatitis possibly related to persistent parvovirus B19 infection in a renal transplant recipient Nephrol Dial Transplant 2001; 16: 2420–2422 10. Lui SL, Luk WK, Cheung CY, Chan TM, Lai KN, Pelris JS. Nosocomlal outbreak of parvovirus B19 infection in a renal transplant unit. Transplantation 2001; 71: 59–64 11. So BJ, Chae KM, Lee KK, Lee YJ, Jeong BH. Pure red cell aplasia due to parvovirus B19 infection in a renal transplant patient; a case report. Transplant proc 2000; 32: 1954 –1958 12. Lee PC, Hung CJ, Lel HY, Chan TT, Wang JR, Jan MS. Parvovirus B19-related acute hepatitis in an Immunosuppressed kidney transplant. Nephrol Dial Transplant 2000; 15: 1486 –1488 13. Pamidi S, Friedman K, Kampalath B, Eshoa C, Hariharan S. Human parvovirus B19 Infection presenting as persistent anemia in renal transplant recipients. Transplantation 2000; 69: 2668–2669 14. Moudgil A, Shidban H, Nast CC et al. Parvovirus B19 infectionrelated complications in renal transplant recipients: treatment with Intravenous immunoglobulin. Transplantation 1987; 64: 1847–1850 15. Ahsan N, Holman MJ, Gocke CD, Groff JA, Yang HC. Pure red cell aplasia due to parvovirus B19 Infection in solid organ transplantation. Clin Transplant 1997; 11: 265–270 16. Bertonl E, Rosati A, Zanazzi M, Azzi A, Zakrewska K, Guidl S, Salvadori M. Unusual incidence of aplastic anaemia due to B-19 parvovirus infection in renal transplant recipients. Transplant Proc 1997; 29: 818–819 17. Uemura N, Ozawa K, Tani K et al. Pure red cell aplasia caused by parvovirus B19 Infection in a renal transplant recipient. Eur J Haematol 1995; 54: 668–69 Received for publication: 20.4.02 Accepted in revised form: 11.6.02

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This case of acute HPV B19 infection illustrates the burden of viral infections in patients after renal transplantation. Despite the early discontinuation of mycofenolate mofetil severe parvovirus-associated anaemia developed and persisted, which is clearly in contrast to a report by Shimmura et al. [7] suggesting that discontinuation of immunosuppressive antimetabolites alone is capable of resolving HPV B19-induced anaemia. Reduced immunosuppression (tacrolimus and steroids) and a first attempt to treat infection by low-dose i.v.IG (0.25 gukg for 3 days) failed to eradicate viraemia. In the first line a ‘low-dose’ regimen was used in order to prevent side effects related to the formation and deposition of immune complexes. These are known to induce the rash and even more severe symptoms of HPV B19 disease such as nephritis [8]. However, parvovirus disease was successfully resolved and viraemia was eradicated by using higher doses of i.v.IG (0.5 gukg for 5 days). Clinical success, but not necessarily virological responses to i.v.IG anduor reduction of immunosuppression have been reported using different treatment regimens (Table 2). We, therefore, conclude that high-dose immunoglobulin treatment in combination with a significant reduction of immunosuppression may be necessary to eradicate HPV B19 infection in immunocompromised patients.

L. Liefeldt et al.