Clinical utility of a cytomegalovirus-specific T cell assay in assessing the risk of post-prophylaxis cytomegalovirus infection and post-treatment relapse.

INTRODUCTION: Cytomegalovirus (CMV) causes significant morbidity in solid organ transplant recipients (SOTR). Measuring cell-mediated immunity (CMI) may inform the risk of CMV infection after antiviral prophylaxis and predict relapse after CMV treatment. METHODS: We serially assessed CMV CMI using the QuantiFERON-CMV assay (QF-CMV; Qiagen, Germantown, MD) in two cohorts of SOTRs: during valganciclovir prophylaxis and during treatment of CMV viremia. Results of CMI were correlated with post-prophylaxis CMV infection and post-treatment relapse, respectively. RESULTS: Only one (4.2%) of 24 CMV D+/R- patients demonstrated positive QF-CMV by the end of valganciclovir prophylaxis. Four (16.6%) patients developed post-prophylaxis CMV infection; all four had undetectable QF-CMV at end of prophylaxis. Among 20 patients treated for CMV infection, 18 (90%) developed QF-CMV levels >.2 IU/mL by end of antiviral treatment and none developed CMV relapse. In contrast, the single patient who relapsed after completing treatment had a CMV CMI <.2 IU/ml (p = .0036). CONCLUSION: Since CMV D+/R- SOTRs are unlikely to develop adequate CMV CMI while receiving valganciclovir prophylaxis, the utility of CMV CMI monitoring for risk stratification during time of prophylaxis had limited value. Conversely, CMV CMI testing may be a useful marker of the risk of CMV relapse after antiviral treatment.

Hematopoietic stem cell transplantation and the noncytomegalovirus herpesviruses.

Although hematopoietic stem cell transplantation (HSCT) and other cellular therapies have significantly improved outcomes in the management of multiple hematological and nonhematological malignancies, the resulting impairment in humoral and cellular response increases the risk for opportunistic infection as an undesirable side effect. With their ability to establish latent infection and reactivate when the host immune system is at its weakest point, the Herpesviridae family constitutes a significant proportion of these opportunistic pathogens. Despite recent advancements in preventing and managing herpesvirus infections, they continue to be a common cause of significant morbidity and mortality in transplanted patients. Herein, we aim to provide and update on herpesvirus other than cytomegalovirus (CMV) affecting recipients of HSCT and other cellular therapies.

Evaluation of a Genus- and Group-Specific Rapid PCR Assay Panel on Synovial Fluid for Diagnosis of Prosthetic Knee Infection.

We evaluated a genus- and group-specific PCR assay panel using 284 prosthetic knee synovial fluid samples collected from patients presenting to our institution with implant failure. Using the Musculoskeletal Infection Society diagnostic criteria, 88 and 196 samples were classified as showing prosthetic joint infection (PJI) and aseptic failure (AF), respectively. Sensitivities of the synovial fluid PCR panel and culture were 55.6% and 76.1% (P ≤ 0.001), respectively, and specificities were 91.8% and 97.4% (P = 0.016), respectively. Among the 70 subjects who had received antibiotics within the month preceding synovial fluid aspiration (48 of whom had PJI), PCR panel and synovial fluid culture sensitivities were 64.5% and 85.4%, respectively (P < 0.0001). In this group, the PCR panel detected Staphylococcus aureus in two culture-negative PJI cases. Overall, the evaluated molecular diagnostic tool had low sensitivity when applied to synovial fluid.

Detection of prosthetic joint infection by use of PCR-electrospray ionization mass spectrometry applied to synovial fluid.

PCR coupled with electrospray ionization mass spectrometry applied to synovial fluid specimens had an 81% sensitivity and a 95% specificity for the diagnosis of prosthetic joint infection.

Mucormycosis in Hematopoietic Cell Transplant Recipients and in Patients With Hematological Malignancies in the Era of New Antifungal Agents.

BACKGROUND: The survival benefit of combination antifungal therapy for invasive mucormycosis (IM) in patients with hematologic malignancy (HM) and hematopoietic cell transplant (HCT) is not well defined. METHODS: This multicenter, retrospective study included HM and HCT recipients with proven or probable IM between January 1, 2007 and December 31, 2017 from 10 transplant centers across North America. RESULTS: Sixty-four patients with proven (n = 47) or probable (n = 17) IM defined by 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) consensus definitions were included. Thirty-nine (61%) were HCT recipients (95% allogeneic). Sites of infection included rhino-orbital-cerebral (33), pulmonary (30%), disseminated (19%), gastrointestinal (3%), and cutaneous (3%). Surgical debridement was performed in 66%. Initial antifungal treatment consisted of the following: lipid formulation of amphotericin B (AmB) alone (44%), AmB + posaconazole (25%), AmB + echinocandin (13%), AmB + isavuconazole (8%), posaconazole alone (5%), and isavuconazole alone (3%). All-cause mortality at 30 days and 1 year were 38% and 66%, respectively. Initial treatment with AmB plus posaconazole or isavuconazole (n = 28) was associated with a trend toward lower treatment failure compared with AmB (n = 21) (42% vs 64%, P = .136). CONCLUSIONS: Long-term survival with IM among HM and HCT populations remains poor. However, initial use of AmB + azole in conjunction with surgery may result in less treatment failure. More evidence from prospective controlled studies is needed to confirm this observation.

Management of nontuberculous mycobacterial infections of the eye and orbit: A retrospective case series.

PURPOSE: To provide an update on different management approaches for Nontuberculous Mycobacterial (NTM) infections of the eye and orbit. OBSERVATIONS: A total of 9 eyes from 8 patients were found to meet study criteria. Of these 9 eyes, 6 eyes (66%) involved Mycobacterium abscessus, 2 (22%) involved M. chelonae, and 1 (11%) involved M. fortuitum. In 8 (88%) eyes, NTM infection was treated with a combination of antibiotics and removal of involved foreign body or tissue (e.g. scleral buckle, intraocular lens, orbital implant, or granuloma). One case was observed on topical therapy alone due to low suspicion for clinically significant infection. In 1 patient, a second culture-positive infection was found in the contralateral eye requiring treatment. CONCLUSIONS AND IMPORTANCE: Depending on the clinical presentation, optimal treatment of ocular and orbital NTM infections may require combination anti-mycobacterial antibiotics (topical and systemic), surgical removal of implanted material or tissue, or both.

Letermovir and inhibitors of the terminase complex: a promising new class of investigational antiviral drugs against human cytomegalovirus.

Infection with cytomegalovirus is prevalent in immunosuppressed patients. In solid organ transplant and hematopoietic stem cell transplant recipients, cytomegalovirus infection is associated with high morbidity and preventable mortality. Prevention and treatment of cytomegalovirus with currently approved antiviral drugs is often associated with side effects that sometimes preclude their use. Moreover, cytomegalovirus has developed mutations that confer resistance to standard antiviral drugs. During the last decade, there have been calls to develop novel antiviral drugs that could provide better options for prevention and treatment of cytomegalovirus. Letermovir (AIC246) is a highly specific antiviral drug that is currently undergoing clinical development for the management of cytomegalovirus infection. It acts by inhibiting the viral terminase complex. Letermovir is highly potent in vitro and in vivo against cytomegalovirus. Because of a distinct mechanism of action, it does not exhibit cross-resistance with other antiviral drugs. It is predicted to be active against strains that are resistant to ganciclovir, foscarnet, and cidofovir. To date, early-phase clinical trials suggest a very low incidence of adverse effects. Herein, we present a comprehensive review on letermovir, from its postulated novel mechanism of action to the results of most recent clinical studies.