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  Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 36  |  Issue : 1  |  Page : 49-53
 

Cytomegalovirus reactivation and disease amongst patients with allogeneic haematopoietic stem cell transplantation in Eastern India: Epidemiology, outcome and healthcare cost


1 Department of Clinical Hematology, Tata Medical Center, Kolkata, West Bengal, India
2 Department of Microbiology, Tata Medical Center, Kolkata, West Bengal, India
3 Department of Statistics, Tata Medical Center, Kolkata, West Bengal, India

Date of Web Publication2-May-2018

Correspondence Address:
Dr. Mammen Chandy
Tata Medical Center, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_17_269

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 ~ Abstract 

Purpose: Data from developing countries about incidence, prognosis and healthcare cost of cytomegalovirus (CMV) reactivation amongst patients with allogeneic hematopoietic stem cell transplantation (AHSCT) remain scarce. The purpose of the study was to describe the epidemiology, outcome and cost implications of CMV reactivation and CMV disease amongst patients with AHSCT in cancer hospital in Eastern India. Materials and Methods: The study design was a retrospective audit of clinical records. Results: Ninety-nine per cent of patients and 94% of the donors were found to be CMV seropositive. CMV reactivation rate was 43.8% amongst patients with AHSCT (n = 130 patients). CMV reactivation occurred 118 days after AHSCT (median; range: 28–943 days). Patients with any grade of graft-versus-host disease (GVHD) had higher CMV reactivation rate than patients without GVHD. Patients with CMV reactivation had more frequent GVHD than patients without CMV reactivation. Use of steroids was associated with CMV reactivation. We found no differences in overall survival of patients with or without CMV reactivation. The cost of in-house CMV-polymerase chain reaction at our centre was USD $57 (Rs. 3650), cost for intravenous ganciclovir was USD $26 (Rs. 1665) per infusion and oral valganciclovir USD $8 (Rs. 512)/900 mg tablet. The median duration of anti-CMV therapy was 14 days (interquartile range: 14–28 days) and the average cost per patient per month directed towards CMV management ranged between USD $800 and USD $1,300 (Rs. 51,238–Rs. 83,264). Three patients (2.3%) in this series had CMV disease, all of whom died. Conclusion: In an increasingly globalised world, where medical tourism is common, data from developing countries regarding cost and outcome of CMV infections in AHSCT patients are of relevance.


Keywords: Cytomegalovirus, disease, hematopoietic stem cell transplantation, reactivation, surveillance


How to cite this article:
Kumar M, Roychowdhury M, Kumar J, Harishankar A, Sinha S, Bhave SJ, Chakrapani A, Radhakrishnan V, Nair R, Bhattacharya S, Chandy M. Cytomegalovirus reactivation and disease amongst patients with allogeneic haematopoietic stem cell transplantation in Eastern India: Epidemiology, outcome and healthcare cost. Indian J Med Microbiol 2018;36:49-53

How to cite this URL:
Kumar M, Roychowdhury M, Kumar J, Harishankar A, Sinha S, Bhave SJ, Chakrapani A, Radhakrishnan V, Nair R, Bhattacharya S, Chandy M. Cytomegalovirus reactivation and disease amongst patients with allogeneic haematopoietic stem cell transplantation in Eastern India: Epidemiology, outcome and healthcare cost. Indian J Med Microbiol [serial online] 2018 [cited 2018 Nov 15];36:49-53. Available from: http://www.ijmm.org/text.asp?2018/36/1/49/231664



 ~ Introduction Top


Cytomegalovirus (CMV) reactivation is associated with significant clinical and financial burden in patients undergoing allogeneic haematopoietic stem cell transplantation (AHSCT).[1] The progress in the management of CMV infection over the past 25 years has been slow, with a lot of institutional variation in CMV management with regard to diagnostic methods, cut-offs used for therapy initiation and preference of anti-CMV drugs.[2] Although preliminary data with the use of recently available alternatives including the newer antiviral agents (maribavir, letermovir and brincidofovir) and adoptive cellular therapy (using cytotoxic lymphocytes and CMV vaccines) appear to be promising, these are not yet widely available outside of clinical trials.[3] Hence, most of the patients undergoing AHSCT in developing countries still rely on conventional anti-CMV drugs including ganciclovir, foscarnet, cidofovir and valganciclovir. The magnitude of CMV burden is expected to be more in countries with high CMV seroprevalence due to increased CMV reactivation rates. In the current article, we present our experience with CMV management in post-transplant setting from a single centre in Eastern India with high CMV seroprevalence including financial implications for the same.

The objective of the present study was to (a) describe epidemiology of CMV reactivation in patients with AHSCT, (b) to evaluate the risk factors for CMV reactivation in these patient cohort, (c) determine the incidence of CMV diseases and CMV-related attributable mortality and (d) evaluate cost of CMV monitoring and treatment in resource-constrained settings.


 ~ Materials and Methods Top


We retrospectively reviewed the medical records of patients transplanted for various haematological disorders at the Tata Medical Center, Kolkata, India, between December 2011 and December 2015, to assess the incidence of post-AHSCT CMV reactivation and disease. Human leucocyte antigen typing for all patients was done using molecular methods.

CMV DNA was routinely monitored by quantitative real-time polymerase chain reaction (PCR) using a method developed and standardised in house.[4] The laboratory also participates regularly in the UK NEQAS programme for CMV DNA quantification [Figure 1] and uses the 1st World Health Organization International Standard for human CMV (HCMV) for Nucleic Acid Amplification Techniques NIBSC code: 09/162 (National Institute for Biological Standards and Control) to calibrate its assay (1 copy/ml is equivalent to 0.59 IU/ml of HCMV). CMV reactivation was defined as CMV DNA level above 1000 copies/mL, and CMV disease was defined as CMV DNA copy number >1000 with clinical signs and evidence of organ involvement (e.g., pneumonitis, colitis, hepatitis, retinitis and encephalitis).
Figure 1: UK NEQAS reports of cytomegalovirus DNA quantification with respect to the cytomegalovirus viral load testing laboratory at Tata Medical Center, Kolkata, India

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CMV viral load assessments on ethylenediaminetetraacetic acid whole blood were done routinely every 2 weeks after graft infusion in patients with haploidentical and matched unrelated donor (MUD) transplants and once every 4 weeks for matched related transplants. Sampling was done on a specific day of the week with results being available the same evening, and patients with positive results were started on appropriate therapy within 24 h of CMV viral load reports. CMV reactivation was treated with intravenous ganciclovir for 2 weeks, followed by maintenance valganciclovir for another 2 weeks, until negative PCR results were achieved.[5] For patients with laboratory-confirmed ganciclovir-resistant CMV, cidofovir or foscarnet was used. Acute graft-versus-host disease (GVHD) was graded according to standard criteria.[6] Conditioning regimens and GVHD prophylaxis were used as per institutional protocols.

Statistical analysis was done between the patients with and without CMV reactivation, using Chi-square test.


 ~ Results Top


The study population consisted of 130 consecutive patients (95 males and 35 females; male: female ratio 2.7:1) who received AHSCT for a variety of haematological conditions. Patients were followed for a median of 385 days after AHSCT (range 162–1469 days). The characteristics of the patients included in the study are given in [Table 1]. One hundred and twenty-nine patients and 122 donors were CMV-seropositive (distribution of CMV IgG D+/R+, D−/R+ and D−/R− were 93.8%, 5.4% and 0.8%, respectively) [Table 2].
Table 1: Characteristics of patients receiving allogeneic hematopoietic stem cell transplantation at Tata Medical Center, Kolkata, India

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Table 2: Patterns of cytomegalovirus reactivation in patients with allogeneic haematopoietic stem cell transplantation

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A total of 57 of the total 130 patients (43.8%) experienced CMV reactivation at a median of 118 days (range: 28–943 days) after AHSCT [Table 3]. Eighteen of the 57 patients (31.6%) developed recurrent reactivation episodes, with a total of 89 reactivation episodes. CMV disease developed in three patients with reactivation (5.3% of the reactivated cases and 2.3% of the entire cohort). Two of these three patients had pneumonitis and one patient had CMV colitis. All three of these recipients died because of CMV disease. One of the patients with CMV pneumonitis had laboratory-confirmed ganciclovir resistance, and cidofovir was used for that patient.
Table 3: Cytomegalovirus reactivation rates in various conditions

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The groups with and without CMV reactivation were similar with respect to gender, diagnosis, underlying disease, intensity and type of conditioning regimen and the use of T-cell-depleting agents. Patients with MUDs had significantly higher CMV reactivation (75% vs. 35%, P= 0.03). Seropositive patients with seronegative donors also had significantly more CMV reactivation (P = 0.04) [Table 2]. Patients with GVHD had more CMV reactivations than patients without GVHD. Of the total 60 (46.2%) patients with GVHD after transplantation, 41 had CMV reactivation (68.3%), whereas 19 of the seventy patients without GVHD developed CMV reactivation (27.1%) (P < 0.0001). The frequency of CMV reactivation increased with higher grades of GVHD [Table 2]. CMV reactivation did not have an impact on overall all-cause mortality (31.5% in patients without CMV reactivation vs 31.6% in patients with CMV reactivation, P = not significant) [Figure 2].
Figure 2: Kaplan–Meier plots showing no difference in overall survival amongst patients with cytomegalovirus reactivation and without cytomegalovirus reactivation (Brown line-No cytomegalovirus reactivation, Blue line-cytomegalovirus reactivation)

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Cost calculations

We calculated costs for CMV management per patient per month that included costs for CMV monitoring, supportive blood tests, costs for anti-CMV drug therapy and hospital admission charges and excluded costs for managing concomitant GVHD or other infections. As a hospital policy to deal with hospital bed crises, patients with CMV reactivation after discharge from hospital were readmitted only if they had CMV disease, required care for concomitant GVHD or other infections or were sick for other medical issues. Patients with isolated, asymptomatic CMV viraemia were managed as outpatients, and they constituted 60% of patients with CMV reactivation. The in-house CMV-PCR at our centre costs USD $57 (Rs. 3650), costs for ganciclovir was USD $26 (Rs. 1665) per infusion (5 mg/kg body weight) and valganciclovir USD $ 8 (Rs. 512)/900 mg tablet. As per the above criteria, the average cost per patient per month directed towards CMV management was USD $800–USD $1300 (Rs. 51,238–Rs. 83,264).


 ~ Discussion Top


CMV management in post-AHSCT setting is known to have significant clinical and financial burden on the healthcare system in developed countries despite having lower CMV seroprevalence rates.[6] There is limited literature regarding the impact of CMV in AHSCT from developing countries with high CMV seroprevalence rates. We retrospectively evaluated the risk factors for CMV reactivation in a cohort of patients undergoing AHSCT in a centre in Eastern India, with a reported CMV seroprevalence of 90%–100%.[7]

In the present study, 99% patients and 94% of the donors were seropositive. Although CMV is an endemic virus throughout the world, its prevalence varies widely from 45% to 100%, being higher in Asian and African countries and lower in Western Europe and the United States.[6] We observed CMV reactivation rates of 43.8%. Data from other Asian and non-Asian countries with high CMV seroprevalence have reported varying CMV reactivation rates in the range of 24.9%–70.1%.[6],[8],[9] Progression to CMV disease based on clinical findings with the presence of organ involvement has been reported to range from 7.5% to 21%, and this was seen in three patients (2.3%) in this series, all of whom died.[6],[8],[9] This low CMV-related mortality despite sizable CMV reactivation rates in our patient cohort is notable, and we presume that it is partly attributable to strict implementation of CMV monitoring and prompt intervention. Training of staff, patient education and awareness regarding consequences of delay in therapy play an important part in the prevention of progression to CMV disease.

We observed D−R+ status as a risk factor for CMV reactivation post-AHSCT as reported previously.[10],[11] Presence of GVHD is a risk factor for CMV reactivation. In the present study, patients with any grade of GVHD had higher CMV reactivation than patients without GVHD. This applied to all grades of GVHD (64% vs. 33%, P < 0.001), Grade II–IV acute GVHD (76.3% vs. 28.9%, P < 0.001) and chronic extensive GVHD (64% vs. 33%, P= NS). Furthermore, patients with CMV reactivation had more frequent GVHD than patients without CMV reactivation (68.3% patients with CMV reactivation had any grade GVHD, with 27.1% patients having no GVHD [P < 0.001]). This highlights close association between the appearance of GVHD and CMV reactivation, as reported previously.[12] Use of steroids was also associated with CMV reactivation in the present study.

Impact of CMV reactivation on overall survival is debatable. Some studies have shown CMV reactivation to be associated with improved survival, whereas others have failed to show such benefit.[13],[14],[15] Although recent Center for International Blood and Marrow Transplant Research analysis has shown an association between CMV reactivation and lower overall survival in myeloid and lymphoid malignancies, we found no differences in overall survival outcomes of the patients with or without CMV reactivation.[16]

Cost impact of strict cytomegalovirus monitoring policy

The average costs per patient per month directed towards CMV management was USD $800–USD $1300 (Rs. 51,238–Rs. 83,264) as discussed above. This contrasts with the cost estimates for similar management administered in developed countries approximating USD $10,000 (Rs. 640,500)/patient/month.[1]

This study documents that, despite high CMV seroprevalence and reactivation rates post-AHSCT in developing countries like ours, the burden of CMV can still be managed effectively at a lower cost with a protocol of strict surveillance and prompt institution of appropriate therapy.


 ~ Conclusion Top


A recent Center for International Blood and Marrow Transplant Research (CIBMTR) report has shown that early cytomegalovirus reactivation remains associated with increased transplant-related mortality.[17] Our study documents that despite high CMV seroprevalence and reactivation rates post-AHSCT in developing countries like India, the burden of CMV can still be managed effectively at a lower cost with a protocol of strict surveillance and prompt institution of appropriate therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 ~ References Top

1.
Jain NA, Lu K, Ito S, Muranski P, Hourigan CS, Haggerty J, et al. The clinical and financial burden of pre-emptive management of cytomegalovirus disease after allogeneic stem cell transplantation-implications for preventative treatment approaches. Cytotherapy 2014;16:927-33.  Back to cited text no. 1
    
2.
de la Cámara R. CMV in hematopoietic stem cell transplantation. Mediterr J Hematol Infect Dis 2016;8:e2016031.  Back to cited text no. 2
    
3.
Maffini E, Giaccone L, Festuccia M, Brunello L, Busca A, Bruno B, et al. Treatment of CMV infection after allogeneic hematopoietic stem cell transplantation. Expert Rev Hematol 2016;9:585-96.  Back to cited text no. 3
    
4.
Harishankar A, Chandy M, Bhattacharya S. How to develop an in-house real-time quantitative cytomegalovirus polymerase chain reaction: Insights from a cancer centre in eastern india. Indian J Med Microbiol 2015;33:482-90.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Chandy M, Bhattacharya S, Chawla T. Antimicrobial Guidelines for Prophylaxis and Treatment of Infections in Bone Marrow Transplant settings. In: Treatment Guidelines for Antimicrobial Use in Common Syndromes. New Delhi, India: Indian Council of Medical Research Department of Health Research; 2017. Available from: http://www.icmr.nic.in/guidelines/treatment%20guidelines%20for%20antimicrobial.pdf. [Last accessed on 2017 Jun 15].  Back to cited text no. 5
    
6.
Yanada M, Yamamoto K, Emi N, Naoe T, Suzuki R, Taji H, et al. Cytomegalovirus antigenemia and outcome of patients treated with pre-emptive ganciclovir: Retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2003;32:801-7.  Back to cited text no. 6
    
7.
Kumar H, Gupta PK, Kumar S, Sarkar RS. Is seroprevalence of anti-IGM CMV among blood donors relevant in India? Indian J Pathol Microbiol 2008;51:351-2.  Back to cited text no. 7
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8.
George B, Mathews V, Viswabandya A, Srivastava A, Chandy M. Infections in children undergoing allogeneic bone marrow transplantation in India. Pediatr Transplant 2006;10:48-54.  Back to cited text no. 8
    
9.
Acar K, Akı SZ, Ozkurt ZN, Bozdayı G, Rota S, Türköz Sucak G, et al. Factors associated with cytomegalovirus reactivation following allogeneic hematopoietic stem cell transplantation: Human leukocyte antigens might be among the risk factors. Turk J Haematol 2014;31:276-85.  Back to cited text no. 9
    
10.
Jang JE, Hyun SY, Kim YD, Yoon SH, Hwang DY, Kim SJ, et al. Risk factors for progression from cytomegalovirus viremia to cytomegalovirus disease after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2012;18:881-6.  Back to cited text no. 10
    
11.
Boeckh M, Nichols WG. The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and pre-emptive therapy. Blood 2004;103:2003-8.  Back to cited text no. 11
    
12.
Pietersma FL, van Dorp S, Minnema MC, Kuball J, Meijer E, Schuurman R, et al. Influence of donor cytomegalovirus (CMV) status on severity of viral reactivation after allogeneic stem cell transplantation in CMV-seropositive recipients. Clin Infect Dis 2011;52:e144-8.  Back to cited text no. 12
    
13.
Cantoni N, Hirsch HH, Khanna N, Gerull S, Buser A, Bucher C, et al. Evidence for a bidirectional relationship between cytomegalovirus replication and acute graft-versus-host disease. Biol Blood Marrow Transplant 2010;16:1309-14.  Back to cited text no. 13
    
14.
Elmaagacli AH, Steckel NK, Koldehoff M, Hegerfeldt Y, Trenschel R, Ditschkowski M, et al. Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: Evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients. Blood 2011;118:1402-12.  Back to cited text no. 14
    
15.
Ito S, Pophali P, CO W, Koklanaris EK, Superata J, Fahle GA, et al. CMV reactivation is associated with a lower incidence of relapse after allo-SCT for CML. Bone Marrow Transplant 2013;48:1313-6.  Back to cited text no. 15
    
16.
Schmidt-Hieber M, Labopin M, Beelen D, Volin L, Ehninger G, Finke J, et al. CMV serostatus still has an important prognostic impact in de novo acute leukemia patients after allogeneic stem cell transplantation: A report from the acute leukemia working party of EBMT. Blood 2013;122:3359-64.  Back to cited text no. 16
    
17.
Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: A CIBMTR analysis. Blood 2016 19;127:2427-38.  Back to cited text no. 17
    


    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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