Eradication of parvovirus B19 infection after renal transplantation requires reduction of immunosuppression and high-dose immunoglobulin therapy

Anaemia is a frequent problem after renal transplantation, which may appear as hypo‐regenerative anaemia (due to myelotoxic drugs or infectious agents and/or 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. The patient is a 38‐year‐old male with end‐stage renal failure secondary to Goodpasture's syndrome who was 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 U/week). 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 g/dl). 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at around 280 μmol/l. Because of intolerable diarrhoea, mycofenolate mofetil had to be reduced and was finally withdrawn.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 g/dl). 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 g/dl, 2 units of packed red cells were transfused. In addition, treatment with erythropoietin was re‐instituted temporarily. Haemoglobin concentration as well as reticulocyte count, however, remained very low (7.7 g/dl 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 g/kg 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 g/kg 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 g/dl 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 concentration was still increasing while viraemia remained undetectable by PCR. 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 g/kg for 3 days). (B) ‘High dose’ i.v.IG (0.5 g/kg for 5 days). Rectangles, reticulocyte count (%); diamonds, haemoglobin concentration (g/dl). Haematological laboratory and blood chemical values Haematological laboratory and blood chemical values 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 g/kg 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 g/kg for 5 days). Clinical success, but not necessarily virological responses to i.v.IG and/or 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. Treatment regimens of parvovirus infections in renal transplant recipients aAs assessed by HPV B19‐PCR. i.v.IG, intravenous immunoglobulin; MMF, mycofenolate mofetil; n.d., not determined; IS, immunosuppression; GN, glomerulonephritis. Treatment regimens of parvovirus infections in renal transplant recipients aAs assessed by HPV B19‐PCR. i.v.IG, intravenous immunoglobulin; MMF, mycofenolate mofetil; n.d., not determined; IS, immunosuppression; GN, glomerulonephritis. Correspondence and offprint requests to: Dr Lutz Liefeldt, Medizinische Klinik mit Schwerpunkt Nephrologie, Charité, Humboldt‐Universität Berlin, Schumannstr. 20/21, D‐10117 Berlin, Germany. Email: lutz.liefeldt@charite.de