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  • br Third trimester crossing the threshold to

    2019-12-02


    Third trimester – crossing the threshold to immunocompetence
    Summary Regrettably, studies on the fetal immune system have yet to yield practical results. While it is becoming apparent that the fetal immune response plays a role in determining the outcome of congenital CMV infection, we still lack the ability to harness this response for better prevention, detection, monitoring, or treatment of congenital CMV infection. The studies reviewed here, however, do provide glimpses toward utilizing our knowledge of immune development to better care for congenitally infected children. For instance, the correlation between KREC counts in DBS and long-term CMV sequelae could guide clinicians on patient selection and need for treatment. Activation of fetal NK p97 by pro-inflammatory cytokines produces a surprisingly robust response. The finding of a CMV-specific, publically shared T cell clone could instruct future vaccine development. As treatment for congenital CMV, both in utero and postnatally, remains suboptimal, every avenue to improve outcomes should continue to be explored.
    Conflict of interest The authors declare no conflict of interest.
    Background Primary or reactivation of latent human cytomegalovirus (CMV) infection is a common complication within the first six months after solid-organ transplantation (SOT). SOT patients with a serological mismatch between the donor and the recipient (CMV donor (D) IgG +/recipient (R)−) are at high-risk for the development of CMV infection. In addition, CMV seropositive patients (D+/R+ and D−/R+) are considered intermediate risk, whilst the CMV D−/R− constellation is considered low risk [1,2]. Currently two strategies for prevention of CMV reactivation/infection are available: firstly, regular monitoring of CMV-DNA and administration of antiviral therapy as soon as viral loads reach a certain threshold (pre-emptive strategy). Secondly, antiviral prophylaxis is indicated in high-risk transplant patients (200 days) and may be preferred in patients receiving potent immunosuppression including antilymphocyte therapy and ABO-incompatible protocols (intermediate risk, 100 days) [[3], [4], [5]]. Although associated with a higher percentage of side effects, costs, antiviral resistance and risk of late onset disease [1], prophylaxis proved superior to pre-emptive monitoring in a recent study in CMV R+ kidney transplant (KTx) recipients [6]. Cell-mediated immunity (CMI) plays an important role in the defense against CMV, with CD8+ T cells being active during primary infection and early post-Tx and CD4+ T cells establishing a long-term control of CMV replication [7]. It was demonstrated that assays measuring the CMV-specific CD8+ and CD4+ T cell response could predict relevant events related to CMV reactivation/infection [[8], [9], [10]]. A positive CMV-specific CMI was associated with a lower risk of CMV recurrence at the end of prophylaxis/antiviral treatment or spontaneous clearance of low level viremia [10,11]. It was assumed that assays detecting CMV-specific CMI could recognize patients at high-risk of developing CMV complications and help restructure the antiviral management of CMV infection in SOT recipients. These assays determine IFN-γ production after stimulation of whole blood or peripheral blood mononuclear cells (PBMCs) with CMV-specific antigens, viral peptides or whole virus lysates [4]. The QuantiFERON® assay (Qiagen, Hilden, Germany) and the T-Track®-CMV ELISpot (Lophius, Regensburg, Germany) were standardized and approved for commercial use in clinical settings in Europe. Various reports have compared the performance of these assays in SOT recipients. While previous studies have shown that a higher CMV-specific CMI pre-Tx/end of prophylaxis is associated with a lower incidence of CMV reactivation/infection, they have not provided a cut-off of the CMV-specific CMI, which correlates with protection from CMV reactivation/infection [8,12,13].