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Multidrug-resistant (MDR) cytomegalovirus (CMV) emerged after transient responses to ganciclovir, foscarnet, and cidofovir in a CMV-seropositive recipient who underwent allogeneic hematopoietic stem cell transplantation from a CMV-seronegative donor. Experimental treatments using leflunomide and artesunate failed. Re-transplantation from a CMV-seropositive donor supported by adoptive transfer of pp65-specific T cells and maribavir was followed by lasting suppression. This case illustrates that successful MDR CMV therapy may require individualized multidisciplinary approaches., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Programmed death receptor-1 (PD-1) compromises cytomegalovirus (CMV)-specific T-cell responses and has been linked to CMV viremia after transplantation. An impaired functional and proliferative capacity of PD-1-positive CMV-specific T cells may be reversed by the antibody-mediated blockade of PD-1 signaling. However, knowledge is limited on changes in "cytokinome" expression profiles associated with reversal of functional exhaustion., Methods: The "cytokinome" was analyzed by 27-plex Luminex technology comparing renal transplant recipients with low (n = 5) and high (n = 5) PD-1 expression on CMV-specific T cells. The effect of blocking PD-1 by PD-ligand (PD-L) antibodies on restoration of cytokine expression was examined., Results: CMV-specific cytokine release and proliferation was lower in patients with high PD-1 expression on CMV-specific T cells. Antibody-mediated blockade of PD-L in CMV-stimulated samples restored expression levels of interleukin (IL)-1β, IL-2, IL-6, IL-9, IL-10, granulocyte colony-stimulating factor, interferon-γ, macrophage inflammatory protein-1α, and tumor necrosis factor-α. By contrast, no profound effect was observed for controls or patients with low PD-1 expression, or in staphylococcal enterotoxin B-stimulated cells., Conclusion: Taken together, this pilot study provides evidence that a high PD-1 expression on CMV-specific T cells actively impairs proliferation and "cytokinome" responses in an antigen-specific manner. Importantly, blockade of PD-L restores CMV-specific T-cell proliferation and expression of a panel of different proinflammatory and/or type 1 cytokines, suggesting a common but as yet unknown regulatory principle. We conclude that PD-1 exhaustion is reversible and potentially amenable to therapeutic ex vivo and possibly in vivo manipulation. However, detailed knowledge of the differential effects on the "cytokinome" will be necessary to increase the safety and the efficacy of such manipulations., (© 2012 John Wiley & Sons A/S.)

Human adenovirus (HAdV) infections are increasingly recognized as important pathogens in immunocompromised hosts, especially in patients with severely suppressed T-cell function. The 4th European Conference of Infections in Leukemia (ECIL-4) has developed evidence-based guidelines for diagnosis and management of HAdV infections. The risk for HAdV-associated disease is increased in children, and risk factors for HAdV disease are T-cell depletion, unrelated and cord blood hematopoietic stem cell transplantation, graft-versus-host disease grades III-IV, and lymphopenia. The recommended technique for monitoring of high-risk patients is quantitative polymerase chain reaction. Cidofovir is the most used antiviral therapy, although no controlled study has been performed. HAdV-specific T-cell therapy is in development., (© 2012 John Wiley & Sons A/S.)

Background: Influenza can cause significant morbidity and mortality in patients after hematopoietic stem cell transplantation (HSCT). The diagnostic methods and antiviral treatment have scarcely been investigated., Methods: We retrospectively identified influenza-infected patients with upper or lower respiratory tract infection (RTI) diagnosed by culture and polymerase chain reaction (PCR) testing between November 2007 and April 2008. Treatment with oseltamivir 75 mg twice daily and serial nasal swabs were performed at the discretion of the treating physician., Results: We identified 21 influenza infections in 19 patients: 19 with upper RTI and 2 with lower RTI. At diagnosis, all 21 samples were positive for PCR with a median influenza load of 5.9 log(10) copies/mL. Culture was positive in 14 (67%) patients. Influenza A virus was diagnosed in 8 (38%) episodes and influenza B virus in 13 (62%) episodes. Two patients were sequentially infected by influenza A, followed by B after 38 and 47 days, respectively. Eighteen (86%) patients were treated with oseltamivir for 11 days (median, interquartile range [IQR]: 8-14). No progression to lower RTI or mortality occurred. Shedding persisted for 12 days (median, IQR: 8-13). Absolute lymphocyte count at diagnosis correlated inversely with shedding of the virus (P<0.001)., Conclusions: Oseltamivir is well tolerated and may reduce mortality of influenza virus-infected patients after HSCT. PCR may help to optimize diagnosis and to monitor treatment strategies.

A cytomegalovirus (CMV) donor positive/recipient negative liver transplant recipient developed CMV syndrome with presumed colitis 2 weeks after discontinuing the standard 3 months of valganciclovir prophylaxis. Treatment with intravenous ganciclovir (GCV) reduced, but did not clear, CMV replication. A CMV UL97 mutation (M460V) conferring GCV resistance was identified. Reduction of immunosuppression was followed by rapidly rising lymphocyte counts as well as by clearance of CMV viremia and of clinical symptoms. However, bilateral chorioretinitis was diagnosed 2 weeks later and treated with foscarnet and cidofovir. Then, right eye vitritis occurred necessitating vitrectomy due to a partially rhegmatogeneous retinal detachment. Because chorioretinitis-vitritis after rising lymphocyte counts and clearance of CMV viremia was strongly suggestive of an immune reconstitution syndrome (IRS)-like disease, we investigated CMV-specific T-cells in the peripheral blood available during follow-up. We found strong CD8(+) but only low CD4(+) T-cell responses (4.77% vs.<0.1%) to the CMV immediate early pp72, while responses to CMV-lysate or CMV-pp65 (CD4(+) <0.01%; CD8(+)<0.01%) were low. Over 16 weeks of follow-up, pp72-specific CD8(+) responses declined, while responses to pp65 gradually increased (CD4(+) 0.16%; CD8(+) 0.76%) indicating a slowly adapting CMV-specific cellular T-cell response. Review of 12,653 published liver transplant patients identified only 14 (0.1%) reported cases of CMV-associated chorioretinitis at a median 41.7 weeks post transplant. CMV-associated opthalmologic complications late post transplantation may possibly involve 2 different entities of cytopathic retinitis and IRS-like chorioretinitis-vitritis.

Over the last decade, polyomavirus-associated nephropathy (PVAN) has occurred with increasing frequency after renal transplantation, leading to significant renal dysfunction and graft loss. More than 95% of all cases are caused by the human polyomavirus type 1 called the BK virus. The primary treatment for PVAN is immunosuppression reduction, which must be carefully balanced against increased risks of rejection. Although no validated protocols exist, a first step commonly involves reduction of calcineurin inhibitors with antiproliferative agents by more than one-third, e.g., reaching trough levels of tacrolimus <6 ng/mL, of cyclosporine <150 ng/mL, dosing of mycophenolate mofetil to <1 g/day, and azathioprine <75 mg/day. When rejection is diagnosed together with PVAN, a transient pulse treatment is recommended before subsequent reduction in immunosuppression. No antiviral treatments for PVAN have been approved by the United States Food and Drug Administration. The antiviral drug cidofovir has shown in vitro activity against murine polyomaviruses, and has been used in some patients in lower doses in an effort to minimize the nephrotoxic effects of cidofovir while treating PVAN. Small series of PVAN patients treated with leflunomide, intravenous immune globulin therapy, and fluoroquinolones have also been reported recently.

The human polyomavirus type 1, also called BK virus (BKV), causes polyomavirus-associated nephropathy (PVAN) in 1-10% of renal transplant recipients, with graft loss in over 50% of cases. The risk factors for PVAN are not conclusively defined and likely involve complementing determinants of recipient, graft, and virus. A central element seems to be the failing balance between BKV replication and BKV-specific immune control, which can result from intense triple immunosuppression, HLA-mismatches, prior rejection and anti-rejection treatment, or BKV-seropositive donor/seronegative recipient pairs. Consistent with this general hypothesis, the timely reduction of immunosuppression in kidney transplant recipients reduced graft loss to less than 10% of cases. However, the BKV-specific humoral and cellular immune response is not well characterized. Recent work from several groups suggest that changes in antibody titers and BKV-specific CD4+ and CD8+ T cells may help to better define the risk and the course of PVAN in renal transplant patients.