|Year : 2018 | Volume
| Issue : 4 | Page : 247-250
Management of chronic parvovirus infection in postkidney transplant with prophylactic intravenous immunoglobulin therapy
Manmeet Singh Jhawar1, Pratish George1, Chepsy C Philips2, Kanwardeep Singh Kwatra3, Jasmin Das1, M Joseph John2
1 Department of Nephrology, Christian Medical College and Hospital, Ludhiana, Punjab, India
2 Department of Clinical Hematology Hemato-Oncology and Bone Marrow Transplantation, Christian Medical College and Hospital, Ludhiana, Punjab, India
3 Department of Pathology, Christian Medical College and Hospital, Ludhiana, Punjab, India
|Date of Web Publication||18-Dec-2018|
Dr. Manmeet Singh Jhawar
Department of Nephrology, Christian Medical College and Hospital, Ludhiana, Punjab
Source of Support: None, Conflict of Interest: None
Parvovirus (PV) infection is a rare cause of persistent anemia in kidney transplant recipients. The diagnosis of PV infection depends on a high index of suspicion, persistent anemia, red cell aplasia in the bone marrow, and positive polymerase chain reaction for PV B19. Treatment with intravenous immunoglobulin (IVIg) has shown to improve anemia but persistence of PV is common after treatment. This case report highlights a postkidney transplant recipient who had PV infection, treated with IVIg but had multiple relapses. He was managed with monthly IVIg prophylactic therapy for 6 months following which he had complete clearance of PV. PV B19 results in multiple relapses in postkidney transplant patients. Monthly prophylaxis therapy with higher dose delivery of IVIg can result in the clearance of PV and relapse-free response. Further studies may be required to determine the duration of prophylaxis therapy.
Keywords: Anemia, intravenous immunoglobulin, kidney transplant, parvovirus B19
|How to cite this article:|
Jhawar MS, George P, Philips CC, Kwatra KS, Das J, John M J. Management of chronic parvovirus infection in postkidney transplant with prophylactic intravenous immunoglobulin therapy. Indian J Transplant 2018;12:247-50
|How to cite this URL:|
Jhawar MS, George P, Philips CC, Kwatra KS, Das J, John M J. Management of chronic parvovirus infection in postkidney transplant with prophylactic intravenous immunoglobulin therapy. Indian J Transplant [serial online] 2018 [cited 2020 Mar 28];12:247-50. Available from: http://www.ijtonline.in/text.asp?2018/12/4/247/247793
| Introduction|| |
Infection remains one of the main concerns in postkidney transplant patients. Parvovirus (PV) B19 viremia is seen in 30% of organ transplant recipients and can present with anemia or with subclinical infection. We present the case of a postkidney transplant patient, who had recurrent episodes of PV disease requiring multiple blood transfusions and repeated intravenous immunoglobulin (IVIg) treatment. He was managed with prophylactic regimen of monthly IVIg with higher dose delivery for 6 months with documented clearance of PV and maintenance of remission. This case report highlights the difficulty in diagnosis and eradicating PV infection postkidney transplant. It also provides an insight into successful treatment of chronic recurrent PV infection with prophylactic IVIg monthly therapy.
| Case Report|| |
A 50-year-old male, postkidney transplant recipient, with wife as his donor (human leukocyte antigen 0/6, white blood cell tissue crossmatch negative), received basiliximab induction and was on triple immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone). His perioperative period was complicated by acinetobacter wound sepsis, leukopenia, and new-onset diabetes mellitus posttransplant, with a nadir creatinine of 1.4 mg/dl on day 26 posttransplant. He was diagnosed and treated for cytomegalovirus (CMV) infection (positive colonic biopsy for tissue polymerase chain reaction [PCR]) 2 months posttransplant.
Three months after the transplant, the patient had anemia and leukopenia. Bone marrow analysis revealed a hypocellular marrow with 20% cellularity. Aspiration smears showed erythroid hypoplasia with early maturation arrest. Several giant pronormoblasts containing multiple intranuclear inclusions were present [Figure 1]a, [Figure 1]b, [Figure 1]c. Granulopoiesis was normal with adequate megakaryocytes. The trephine biopsy also showed giant erythroid precursors containing multiple amphophilic intranuclear inclusions with chromatin clearing [Figure 1]d. PV PCR from blood was positive (2.5 × 103 copies/ml), suggestive of PV infection. His immunosuppression was reduced and IVIg therapy (400 mg/kg for 5 days) was initiated. Response in his blood parameters was noted over a period of 2 weeks and hemoglobin stabilized (Hb – 10.0 g/dl).
|Figure 1: (a-c) Bone marrow aspiration smear showing giant pronormoblasts with multiple intanuclear inclusions (arrows, MGG ×1000), (d) Trephine biopsy also showing multiple intranuclear amphophilic inclusions with chromatin clearing in giant erythroid precursors (arrows, H and E, ×400).|
Click here to view
Six months later, the patient had breathlessness, generalized weakness, anemia, and transaminitis [Table 1]. Bone marrow aspiration biopsy revealed 40% cellularity with erythroid hypoplasia and few giant pronormoblasts showing intranuclear inclusions, similar to the initial bone marrow; blood PV PCR was positive (4 × 104 copies/ml) and he received IVIg therapy (400 mg/kg for 5 days) following which his hemoglobin improved (Hb – 9.7 g/dl). His immunosuppressive medication dose was reduced to maintain tacrolimus trough of 3–5 ng/ml, mycophenolate mofetil was reduced to half the initial dose, and steroid was continued at the same dose. He was lost to follow-up and presented 4 months later, with symptoms of angina, anemia, and leukopenia [Table 1], requiring transfusion of seven units of packed cells and underwent percutaneous angioplasty for coronary artery disease (CAD). PV PCR was positive (3 × 103 copies/ml) and he received one dose of IVIg 400 mg/kg.
He got readmitted 1 month later with giddiness, dyspnea on exertion, anemia, and leukopenia [Table 1] with positive PV PCR (1 × 103 copies/ml), and was treated with IVIg (1 g/kg/day for 2 days) keeping a possibility of PV relapse.
In view of anemia requiring repeated blood transfusion and persistently positive PV PCR, he was treated with a prophylaxis regimen of IVIg (1 g/kg for 2 days) – monthly doses for 6 months [Table 2]. An improvement in anemia was observed and the bone marrow repeated after the second dose of monthly prophylactic IVIg revealed normocellular marrow with normoblastic erythroid hyperplasia, normal granulopoiesis, and adequate megakaryocytes with no inclusion bodies. One month after completion of six prophylactic doses of IVIg, the PV PCR was undetectable and hemoglobin was 15.8 g/dl, with tacrolimus trough level at 4.14 ng/ml [Table 2]. His hemoglobin has been stable for the last 26 months with no requirement of blood transfusion and a negative PV PCR.
|Table 2: Investigation during intravenous immunoglobulin monthly prophylaxis|
Click here to view
| Discussion|| |
PV B19 is a self-limiting disease with increased severity in individuals with immune or hematological disorders and can result in severe anemia due to its propensity to infect erythroid progenitor cells. Up to 30% of organ transplant recipients develop PV B19 viremia and may present with clinical or subclinical infection. In these subset of patients, classical PV B19 symptoms such as rash and arthritis are lacking, hence a diagnosis of anemia due to PV B19 can be challenging; considering other differentials for anemia in postkidney transplant period (blood loss, generalized bone marrow suppression, antiviral medications, and other viral infections such as CMV).
Use of serology can lead to missed diagnosis of PV B19 in immunosuppressed postorgan transplant patients due to lack of adequate antibody response. In a review of posttransplant PV, serological tests done in 98 cases were found to be negative in 29%. In this setting, use of viral PCR DNA (deoxyribonucleic acid) can be helpful in diagnosis and instituting therapy, but a positive PCR should be carefully interpreted in the context of clinical setting and laboratory data as it can be detected long after acute phase of infection in some patients. Positive PCR has a high positive predictive value in the setting of red cell aplasia in an immune compromised host. In the setting where serology and blood PCR are negative, a bone marrow examination (showing typical findings of hypocellularity, giant pronormoblasts with finely granular cytoplasm, and glassy intranuclear inclusion with a clear central halo [lantern cells] and absence of late normoblasts) supported with in situ hybridization or immunohistochemical staining is helpful in diagnosis.
In our patient, the persistence of anemia, negative CMV PCR, and presence of inclusion bodies in bone marrow with erythroid hypoplasia, proerythroblasts, and intranuclear inclusion bodies led to the suspicion of PV B19 infection, which was confirmed by DNA PCR. The typical symptoms of PV B19 such as rash and arthritis were lacking in our patient. He was treated for PV B19 with IVIg along with reduction in his immunosuppressive medications.
Optimal dosage and duration for IVIg therapy for PV B19 infection have not been established. Rate of relapse is not different in those receiving ≤2 g/kg or >2 g/kg with most patients treated with 400 mg/kg/day for 5 days, and complete eradication, especially in transplant patients, may not occur, with 28% patients experiencing relapse. Persistent viremia and relapses can occur up to several months after completion of treatment and require repeated administration of IVIg. This was seen in our patient who had multiple relapses of PV requiring repeated therapy with IVIg.
The value of PCR in monitoring response to therapy is not known. Follow-up with serial hemoglobin values and PCR in case of recurrence of anemia is a good method for the diagnosis of relapse. Our patient had an evidence of significant triple-vessel disease requiring coronary stenting and it is important to note that a higher seropositive rate of chronic B19 infection is seen in patients with CAD, with localization of PV B19 DNA to the endothelial cells of thickened intima.
Our patient received three complete courses of treatment (2 g/kg) of IVIg, but still persisted to have recurrent PV infection despite optimal reduction of immunosuppressive therapy. There are no guidelines or recommendations available as to how to proceed in such a case. Given that the patient had recurrent episodes of anemia requiring repeated blood transfusions, persistently positive PV B19 PCR, and responding to treatment with IVIg, a plan was made for monthly prophylaxis of IVIg at a dose of 1 g/kg for 2 days every month for 6 months. The regimen was planned as a higher dose delivery but similar cumulative dose so as to clear viremia, keeping a possibility of persistence of PV. This dose was supported from a review of PV patients by Eid et al., wherein four of the six patients treated with IVIg had a relapse of disease and were retreated with IVIg. Our patient received monthly dosage of IVIg (1 g/kg for 2 days) for a period of 6 months following which there was complete eradication of parvo viremia with documented negative PCR. He had normalization of hemoglobin and has been free from requirement of blood transfusion for the last 26 months. The last documented hemoglobin is 15.8 g/dl, his PV PCR is not detectable, and he has stable graft function.
We presume that the recurrence of PV after treatment might be due to low levels of PV undetectable by currently available methods. Ongoing viral replication after completion of therapy may later on result in relapse. Using monthly prophylactic therapy of IVIg with higher deliver dose delivery, we may have been able to completely eradicate parvo viremia resulting in successful treatment and relapse-free response.
| Conclusion|| |
It is important to keep a possibility of PV B19 in postkidney transplant patients presenting with anemia, even if other typical clinical features of arthralgia and rash may not be present and the presence of other concomitant infections should not rule out the possibility of the underlying PV B19. Treatment with lowering of immunosuppressive medications and IVIg provides a good response; however, the disease is difficult to eradicate completely and may require repeated dosages of IVIg, depending on the viral load and symptomatology. Serial monitoring of hemoglobin and PCR can lead to early diagnosis of disease relapse. Prophylaxis therapy using higher dose delivery of monthly IVIg (1 g/kg for 2 days) can result in complete clearance of PV and the result is relapse-free response. However, further studies would be required to determine the frequency of viral DNA PCR testing in patients treated for PV with monthly IVIg and the duration of prophylaxis therapy required for eradication of PV load.
Being a case report, further studies are needed for prophylactic IVIg usage during chronic PV infection including the dosage used, duration of prophylaxis, cost–benefit comparison of low- versus high-dose IVIg, and frequency of monitoring.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
The authors would like to thank Dr. Naveen Kakkar, Department of Pathology, Christian Medical College and Hospital, Ludhiana, for his support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Ki CS, Kim IS, Kim JW, Lee NY, Kim SH, Lee KW, et al.
Incidence and clinical significance of human parvovirus B19 infection in kidney transplant recipients. Clin Transplant 2005;19:751-5.
Servey JT, Reamy BV, Hodge J. Clinical presentations of parvovirus B19 infection. Am Fam Physician 2007;75:373-6.
Serjeant GR, Topley JM, Mason K, Serjeant BE, Pattison JR, Jones SE, et al.
Outbreak of aplastic crises in sickle cell anaemia associated with parvovirus-like agent. Lancet 1981;2:595-7.
Marchand S, Tchernia G, Hiesse C, Tertian G, Cartron J, Kriaa F, et al.
Human parvovirus B19 infection in organ transplant recipients. Clin Transplant 1999;13:17-24.
Eid AJ, Brown RA, Patel R, Razonable RR. Parvovirus B19 infection after transplantation: A review of 98 cases. Clin Infect Dis 2006;43:40-8.
Alves MT, Vilaça SS, Carvalho MD, Fernandes AP, Dusse LM, Gomes KB, et al.
Human parvovirus B19 infection in a renal transplant recipient: A case report. BMC Res Notes 2013;6:28.
Cassinotti P, Siegl G. Quantitative evidence for persistence of human parvovirus B19 DNA in an immunocompetent individual. Eur J Clin Microbiol Infect Dis 2000;19:886-7.
Kumar J, Shaver MJ, Abul-Ezz S. Long-term remission of recurrent parvovirus-B associated anemia in a renal transplant recipient induced by treatment with immunoglobulin and positive seroconversion. Transpl Infect Dis 2005;7:30-3.
Liu SC, Tsai CT, Wu CK, Yu MF, Wu MZ, Lin LI, et al.
Human parvovirus b19 infection in patients with coronary atherosclerosis. Arch Med Res 2009;40:612-7.
[Table 1], [Table 2]