Measuring cellular immunity to predict CMV infection post-transplantation

CMV infection still remains one of the most common and unpredictable complications in transplant recipients, and the negative consequences in terms of graft lost and recipient survival are well known. In this setting, I would like to present a remarkable kidney transplant case from our institution: an unsensitized 40 y/o female, IgG seropositive for CMV was transplanted from a seropositive deceased donor. She had taken the standard immunosuppressive therapy, and after 2 months was diagnosed with CMV-disease. Considering the situation above, one may question why this happened and how could it have been possible to predict this outcome.

Currently, the immune-risk stratification before transplant is based only on CMV-specific antibody (IgG+) of donor and recipient. However, the cellular immunity is crucial in controlling the viral replication and conferring long-lasting protection. The proportion of both CD4+ and CD8+ T cells committed to the anti Human CMV (HCMV) response is large, ranging from 10 to 40% in peripheral blood.

In this scenario, novel immune assays may play a mainstay role. They consist in evaluating physiological response of HCMV specific T cells (cell activation, cytokine expression or proliferation) through antigen stimulation in vitro (virus-infected cells lysates or virus-like particles). As depicted in Table 1, these tests have different characteristics; therefore a physician must know how to choose the best test for a specific situation.

Similar cases have already been described and one may conclude that these patients lack cellular-immunity. On the other hand, seronegative recipients who have low rate of specific T cell have also been described. In this scenario, these new tests could give information on how to predict the ability to control viral replication. Hence, T cells analysis can justify a whole new perspective of prophylaxis indications. Also, in posttransplant situations (Figure 1), serial evaluation of viral load and T cell test are important to guide therapy and foresee relapse after its cessation.

Low levels of CMV-specific T cell response correlates well with reactivation of CMV-infection and late-onset disease; immediate treatment or prolonged prophylaxis would hold back these outcomes. Therefore, an individualized approach with measurement of CMV specific cellular and antibody response will be crucial in the improvement of transplant outcomes, in particular in centers that do not routinely use CMV prophylaxis.

Abel Portela

References:

1-     Sester M; Lebooeuf, C; Schmidt T, Hirsch HH. The “ABC” of virus-specific Tcell immunity in solic organ transplantation. Am J Transplant 2016; 16(6):1697-1706.

1-     Lucia M, Crespo E, Cruzado JM, Grinyo JM, Bestard O. Human CMV-specificT-cel reponses in kidney transplantation; toward changing currentrisk-stratification paradigm. Transplant Int 2014;  27(2): 643-656.

1-     Kotton CN, Kumar D, Caliendo AM et al. Updated International ConsensusGuidelines on the management of cytomegalovirus in solid-organ transplation.Transplantation 2013; 96: 333-360.

Management of CMV after transplantation

Pre-transplant:

All the donors and recipients of kidney transplants (both living and deceased) should be tested for status of CMV by CMV IgG in the blood. If there is history of recent transfusion, pre-transfusion status should be regarded as the true status of CMV. The status of both donor and recipient for a given pair. should be documented in the record post-transplant

Post-transplant:

Prophylaxis:

• CMV related illness is common in the KTRs and the risk is highest in D+/R- group and the least in D-/R-. 
• We do prophylaxis KTRs with Valganciclovir (Valcyte) 900 mg daily (adjusted for renal function) for 6 months in D+/R- group, and 450 mg daily for 3 months for R+ group regardless of the donor status. No CMV prophylaxis is required for the D-/R- group (this group receives acyclovir for prophylaxis of other opportunistic viruses like HSV and HZV).
• Leukopenia is a side effect of Valcyte and the anti-metabolites. If leukopenia is encountered, valcyte dose or dose of the anti-metabolite (eg MPA derivative, azathioprine, or TOR inhibitor) or both be adjusted based on the physician’s discretion (consider checking for CMV pcr). Consider use of G-CSF if the absolute neutrophil count is less than 500. If Valcyte dose must reduced or discontinued for more than one week, weekly monitoring of CMV Quantitative (blood PCR) could be considered for a total of 3-4 months from the time of transplant.
• Routine CMV PCR testing is NOT recommended in patients receiving full doses of prophylactic therapy unless there is some other clinical suspicion for breakthrough CMV infection.

Treatment - CMV related illness is divided into:

1. CMV infection:

Active viral replication (based on blood PCR) without any symptoms attributable to CMV. It is recommended to start treatment even at a low level of viral load. It should be noted that a change of viral load less than or greater than three times the previous value (0.5 times log 10) does not mean a true change in the viral load. 

Valcyte at treatment dose (900 mg BID), adjusted for renal function) is recommended for treatment. Weekly Quantitative PCR in plasma is recommended while on treatment and duration of treatment to continue at least for two consecutive negative Quantitative PCRs, and not less than a total of 2 weeks. Secondary prophylaxis at the end of treatment (at prophylaxis dose of Valcyte) for a month or two after finishing treatment can be considered if suspicion for relapse is high.

2. CMV disease:

Active viral replication plus symptoms: Either 1) a flu-like illness with fever and general malaise,  often associated with leukopenia or 2) tissue invasive disease (commonly GI but also including hepatitis, pulmonary and rarely uveitis and encephalitis).

Treatment either with Valcyte at treatment dose or IV Ganciclovir at treatment dose (for life threatening illness and GI disease). IV Ganciclovir can be switched to corresponding dose of Valcyte at any time during the therapy if considered appropriate. Monitoring for response and duration of treatment are similar to CMV infection treatment. Please note that tissue invasive disease can rarely occur with negative quantitative PCR in blood (especially when disease is limited to the GI tract). In that situation, duration of therapy should consist of at least two weeks of the antiviral or longer as guided by clinical response. Secondary prophylaxis at the end of treatment with Valcyte for a month or two (at prophylaxis dose of valcyte) can be considered if suspicion for relapse is high. 

Lowering of immunosuppression should be considered starting with the anti-metabolite (definitely for life threatening illness) at the discretion of physician. If leukopenia is encountered, it is recommended to lower anti-metabolite rather than lowering valcyte dose to avoid failure of therapy and resistance of CMV to valcyte.

CMV resistance, although rare, should be suspected if no response to therapy even after a total duration of 5 weeks with Valcyte. If CMV resistance is confirmed, consider foscarnet for treatment, the dose of which should be also adjusted based on renal function

CrCl (ml/min)	Maintenance/Prophylaxis	Treatment
Valcyte
>60	900 mg q day	900 mg bid
40-59	450 mg q day	450 mg bid
25-39	450 mg q 2 days	450 mg q day
10-24	450 mg twice weekly	450 mg q 2 days
<10	100 mg 3 times a week, after HD	200 mg 3 times a week, after HD
IV Ganciclovir
>70		5 mg/kg q 12 hr
50-69		2.5 mg/kg q 12 hr
25-49		2.5 mg/kg q 24 hr
10-24		1.25 mg/kg q 24 hr
<10		1.25 mg/kg 3 times a week after HD

 

Posted by Raj Sabaru