Tafenoquine for Relapsing Babesiosis: A Case Series.

BACKGROUND: Relapsing babesiosis often occurs in highly immunocompromised patients and has been attributed to the acquisition of resistance against drugs commonly used for treatment such as atovaquone, azithromycin, and clindamycin. Tafenoquine, which is approved for malaria prophylaxis and presumptive antirelapse treatment of Plasmodium vivax malaria, has shown activity against Babesia microti in several animal models of acute infection and in a single human case of relapsing babesiosis. Here, we report 5 cases of relapsing babesiosis treated with tafenoquine, including the previous case, and begin to define the conditions for optimal use of tafenoquine in relapsing babesiosis. METHODS: A definitive diagnosis of babesiosis was made by microscopic examination of Giemsa-stained thin blood smears or a real-time polymerase chain reaction (PCR) that targets the parasite 18S rRNA gene. Clearance of B. microti infection was ascertained by use of blood smear and real-time PCR. RESULTS: Tafenoquine was initiated with a loading dose of 600 mg. A weekly maintenance dose consisted of 200 mg or 300 mg; the lower dose was associated with a delayed clearance of B. microti. In 2 cases, all antimicrobial agents but tafenoquine were discontinued prior to clearance of infection. In 2 other cases, clearance was achieved while tafenoquine was administered along with other antimicrobial agents. In 3 of these 4 cases, tafenoquine was used in combination with atovaquone-proguanil. Other agents included atovaquone, azithromycin, and/or clindamycin. In 1 case, tafenoquine was administered alone and failed to prevent relapse. CONCLUSIONS: Tafenoquine can be a useful adjunct for the treatment of highly immunocompromised patients experiencing relapsing babesiosis caused by B. microti.

Broad Antimicrobial Resistance in a Case of Relapsing Babesiosis Successfully Treated With Tafenoquine.

We describe a case of relapsing babesiosis in an immunocompromised patient. A point mutation in the Babesia microti 23S rRNA gene predicted resistance to azithromycin and clindamycin, whereas an amino acid change in the parasite cytochrome b predicted resistance to atovaquone. Following initiation of tafenoquine, symptoms and parasitemia resolved.

Evaluation of Performance Characteristics of the Aptima CMV Quant Assay for the Detection and Quantitation of CMV DNA in Plasma Samples.

Quantification of Cytomegalovirus (CMV) DNA has become the standard of care in the diagnosis and management of CMV infection in transplant recipients. The objective of the study was to evaluate performance characteristics of the Aptima CMV Quant assay in comparison to Abbott RealTime CMV assay, Qiagen Artus CMV RGQ MDx assay, and Roche cobas CMV test using plasma samples. The performance of the Aptima assay was evaluated by comparing the Exact Diagnostics CMV verification panel and positive controls, Hologic CMV internal reproducibility panel, and SeraCare CMV DNA qualification panel to the RealTime assay. Clinical agreement was evaluated using 389 clinical plasma samples comparing the Aptima assay to three comparator assays. The Aptima assay demonstrated good linearity and strong linear correlation between the assays (R2 = 0.99); the intra- and interassay reproducibility was excellent overall (SD = 0.09 to 0.14 and SD = 0.04 to 0.14, respectively); 95% limit of detection (LOD) is 32 IU/mL and LOQ is 45 IU/mL. The SeraCare qualification panel yielded a strong linear correlation (R2 = 0.99). A total of 262 positive samples were analyzed to compare Aptima and Realtime assays using Deming regression and Bland-Altman analysis and demonstrated a mean bias of 0.092 Log10 IU/mL. Artus (85) and cobas (159) positive samples were compared to the Aptima assay using Deming regression and Bland-Altman analyses and showed mean bias of 0.184 and -0.208 Log10 IU/mL, respectively. The findings demonstrate that the Aptima assay is sensitive and accurate in quantifying CMV in plasma specimens on the fully automated Panther system and that the results were comparable to the other FDA-approved CMV assays.

Efficacy and Safety of Ensovibep for Adults Hospitalized With COVID-19 : A Randomized Controlled Trial.

BACKGROUND: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection. OBJECTIVE: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone. DESIGN: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978). SETTING: Multinational, multicenter trial. PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: Intravenous ensovibep, 600 mg, or placebo. MEASUREMENTS: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90. RESULTS: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep (n = 247) or placebo (n = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep). LIMITATION: The trial was prematurely stopped because of futility, limiting power for the primary outcome. CONCLUSION: Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified. PRIMARY FUNDING SOURCE: National Institutes of Health.

Seroconversion and outcomes after initial and booster COVID-19 vaccination in adults with hematologic malignancies.

BACKGROUND: Patients with hematologic malignancies have impaired humoral immunity secondary to their malignancy and its treatment, placing them at risk of severe coronavirus disease-19 (COVID-19) infection and reduced response to vaccination. METHODS: The authors retrospectively analyzed serologic responses to initial and booster COVID-19 vaccination in 378 patients with hematologic malignancy and subsequently tracked COVID-19-related outcomes. RESULTS: Seroconversion occurred in 181 patients (48%) after initial vaccination; patients who had active malignancy or those who were recently treated with a B-cell-depleting monoclonal antibody had the lowest rates of seroconversion. For initial nonresponders to vaccination, seroconversion after a booster dose occurred in 48 of 85 patients (56%). The seroconversion rate after the booster was similar for patients on (53%) and off (58%) active therapy (p = .82). Thirty-three patients (8.8%) developed a COVID-19 infection, and there were three COVID-19-related deaths (0.8%). Although no significant association was observed between postvaccination seroconversion and the incidence of COVID-19 infection, no patient with seroconversion died from COVID-19, and no patient who received tixagevimab/cilgavimab (N = 25) was diagnosed with a COVID-19 infection. CONCLUSIONS: Booster vaccinations can promote seroconversion in a significant proportion of patients who are seronegative after the initial vaccination course regardless of the specific vaccine or on/off treatment status at the time of revaccination. Although postvaccination seroconversion may not be associated with a decrease in any (including asymptomatic) COVID-19 infection, the authors' experience suggested that effective vaccination (including a booster), supplemented by passive immunization using tixagevimab/cilgavimab in case of lack of seroconversion, effectively eliminated the risk of COVID-19 death in the otherwise high-risk population. LAY SUMMARY: Patients with hematologic malignancy, especially lymphoma, have an impaired response to coronavirus disease 2019 (COVID-19) vaccination. In this single-institution review, less than one half of the patients studied made detectable antibodies. For those who did not make detectable antibodies after initial vaccination, over one half (65%) were able to produce antibodies after booster vaccination. By the end of February 2022, 33 of the original 378 patients had a documented COVID-19 infection. The only deaths from COVID-19 were in those who had undetectable antibodies, and no patient who received prophylactic antibody therapy developed a COVID-19 infection.

Elevated Tacrolimus Levels at Time of Diagnosis of COVID-19 Compared to Baseline Among Hospitalized Organ Transplant Recipients.

BACKGROUND: The effect of COVID-19 on immunosuppressant drug levels in organ transplant recipients (OTRs) has not been adequately studied. OBJECTIVE: To study the effect of COVID-19 on tacrolimus trough levels (primary outcome) in OTRs and the association of the later with acute kidney injury, bacterial infection, and oxygen requirements. METHODS: We studied adult (>18-year-old) hospitalized OTRs with COVID-19, who were receiving tacrolimus between 3/1 and 12/16/2020. RESULTS: Among 30 OTRs, 67% were men, 90% had a kidney transplant. Median age was 60.5 (interquartile range [IQR]: 45-68) years, median time from transplant 36 (IQR: 20-84) months. Tacrolimus troughs were higher on admission for COVID-19 than baseline (average over 6 months prior) (P = .001). Eighteen patients (60%) had admission tacrolimus trough >10, 5 (17%) >20 ng/mL. Patients with diarrhea had borderline higher tacrolimus troughs, compared to those without diarrhea (P = .09). Organ transplant recipients with a tacrolimus trough >10 ng/mL were more likely to have elevated aspartate aminotransferase on admission (P = .01) and require supplemental oxygen. (P = .026). CONCLUSION AND RELEVANCE: Tacrolimus trough levels were elevated in most OTRs with COVID-19 at the time of hospital admission, compared to baseline. Potential mechanisms are diarrhea and hepatic involvement in COVID-19. In OTRs with COVID-19, including outpatients, immunosuppressant drug levels should be closely followed; management of immunosuppression should be individualized.

Convalescent Plasma for Patients With Severe Coronavirus Disease 2019 (COVID-19): A Matched Cohort Study.

BACKGROUND: The efficacy of convalescent plasma (CP) for the treatment of coronavirus disease 2019 (COVID-19) remains unclear. METHODS: In a matched cohort analysis of hospitalized patients with severe COVID-19, the impact of CP treatment on in-hospital mortality was evaluated using univariate and multivariate Cox proportional-hazards models, and the impact of CP treatment on time to hospital discharge was assessed using a stratified log-rank analysis. RESULTS: In total, 64 patients who received CP a median of 7 days after symptom onset were compared to a matched control group of 177 patients. The incidence of in-hospital mortality was 12.5% and 15.8% in the CP and control groups, respectively (P = .52). There was no significant difference in the risk of in-hospital mortality between the 2 groups (adjusted hazard ratio [aHR] 0.93, 95% confidence interval [CI] .39-2.20). The overall rate of hospital discharge was not significantly different between the 2 groups (rate ratio [RR] 1.28, 95% CI .91-1.81), although there was a significantly increased rate of hospital discharge among patients 65-years-old or greater who received CP (RR 1.86, 95% CI 1.03-3.36). There was a greater than expected frequency of transfusion reactions in the CP group (2.8% reaction rate observed per unit transfused). CONCLUSIONS: We did not demonstrate a significant difference in risk of mortality or rate of hospital discharge between the CP and control groups. There was a signal for improved outcomes among the elderly, and further adequately powered randomized studies should target this subgroup when assessing the efficacy of CP treatment.

Implementing a regional standardized BK polyomavirus screening protocol across eleven transplant centres.

BK polyomavirus (BKPyV) reactivation is regularly monitored after kidney transplant to prevent progression to BK associated nephropathy (BKAN). The New England BK Consortium, made up of 12 transplant centres in the northeastern United States, conducted a quality improvement project to examine adherence to an agreed upon protocol for BKPyV screening for kidney transplants performed in calendar years 2016-2017. In a total of 1047 kidney transplant recipients (KTR) from 11 transplant centres, 204 (19%) had BKPyV infection, defined as detection of BKPyV in plasma, with 41 (4%) KTR progressing to BKAN, defined by either evidence on biopsy tissues or as determined by treating nephrologists. BKPyV infection was treated with reduction of immune suppressants (RIS) in >70% of the patients in all but two centres. There was no graft loss because of BKAN during the two-year follow-up. There were nine cases of post-RIS acute rejection detected during this same period. Adherence to the protocol was low with 54% at 12 months and 38% at 24 months, reflecting challenges of managing transplant patients at all centres. The adherence rate was positively correlated to increased detection of BKPyV infection and was unexpectedly positively correlated to an increase in diagnosis of BKAN.

Successful recovery from COVID-19 in three kidney transplant recipients who received convalescent plasma therapy.

Novel coronavirus disease 2019 (COVID-19) is a highly infectious, rapidly spreading viral disease that typically presents with greater severity in patients with underlying medical conditions or those who are immunosuppressed. We present a novel case series of three kidney transplant recipients with COVID-19 who recovered after receiving COVID-19 convalescent plasma (CCP) therapy. Physicians should be aware of this potentially useful treatment option. Larger clinical registries and randomized clinical trials should be conducted to further explore the clinical and allograft outcomes associated with CCP use in this population.

Characterisation of Novel Angiogenic and Potent Anti-Inflammatory Effects of Micro-Fragmented Adipose Tissue.

Adipose tissue and more specifically micro-fragmented adipose tissue (MFAT) obtained from liposuction has recently been shown to possess interesting medicinal properties whereby its application supports pain reduction and may enhance tissue regeneration particularly in osteoarthritis. Here we have characterised samples of MFAT produced using the Lipogems® International Spa system from eight volunteer individuals in order to understand the critical biological mechanisms through which they act. A variation was found in the MFAT cluster size between individual samples and this translated into a similar variation in the ability of purified mesenchymal stem cells (MSCs) to form colony-forming units. Almost all of the isolated cells were CD105/CD90/CD45+ indicating stemness. An analysis of the secretions of cytokines from MFAT samples in a culture using targeted arrays and an enzyme-linked immunosorbent assay (ELISA) showed a long-term specific and significant expression of proteins associated with anti-inflammation (e.g., interleukin-1 receptor alpha (Il-1Rα) antagonist), pro-regeneration (e.g., hepatocyte growth factor), anti-scarring and pro-angiogenesis (e.g., transforming growth factor beta 1 and 2 (TGFß1/2) and anti-bacterial (e.g., chemokine C-X-C motif ligand-9 (CXCL-9). Angiogenesis and angiogenic signalling were notably increased in primary bovine aortic endothelial cells (BAEC) to a different extent in each individual sample of the conditioned medium whilst a direct capacity of the conditioned medium to block inflammation induced by lipopolysaccharides was shown. This work characterises the biological mechanisms through which a strong, long-lasting, and potentially beneficial effect can be observed regarding pain reduction, protection and regeneration in osteoarthritic joints treated with MFAT.

The COVID-19 Diagnostic Dilemma: a Clinician's Perspective.

In this commentary, we provide a broad overview of how the rapidly evolving coronavirus disease 2019 (COVID-19) diagnostic landscape has impacted clinical care during the COVID-19 pandemic. We review aspects of both molecular and serologic testing and discuss the logistical challenges faced with each. We also highlight the progress that has been made in the development and implementation of these assays as well as the need for ongoing improvement in diagnostic testing capabilities.

Correction to: Clinical experience with a novel assay measuring cytomegalovirus (CMV)-specific CD4+ and CD8+ T-cell immunity by flow cytometry and intracellular cytokine staining to predict clinically significant CMV events.

After publication of the original article [1], we were notified that an author's family name has been erroneously spelled. Aditya Chandrokar should be replaced with Aditya Chandorkar.

Clinical experience with a novel assay measuring cytomegalovirus (CMV)-specific CD4+ and CD8+ T-cell immunity by flow cytometry and intracellular cytokine staining to predict clinically significant CMV events.

BACKGROUND: Cytomegalovirus (CMV) infection is one of the most common opportunistic infections following organ transplantation, despite administration of CMV prophylaxis. CMV-specific T-cell immunity (TCI) has been associated with reduced rates of CMV infection. We describe for the first time clinical experience using the CMV T-Cell Immunity Panel (CMV-TCIP), a commercially available assay which measures CMV-specific CD4+ and CD8+ T-cell responses, to predict clinically significant CMV events. METHODS: Adult (> 18-year-old) patients with CMV-TCIP results and ≥ 1 subsequent assessment for CMV DNAemia were included at Brown University and the University of Maryland Medical Center-affiliated hospitals between 4/2017 and 5/2019. A clinically significant CMV event was defined as CMV DNAemia prompting initiation of treatment. We excluded indeterminate results, mostly due to background positivity, allogeneic hematopoetic cell transplant (HCT) recipients, or patients who were continued on antiviral therapy against CMV irrespective of the CMV-TCIP result, because ongoing antiviral therapy could prevent a CMV event. RESULTS: We analyzed 44 samples from 37 patients: 31 were solid organ transplant recipients, 4 had hematologic malignancies, 2 had autoimmune disorders. The CMV-protection receiver operating characteristic (ROC) area under the curve (AUC) was significant for %CMV-specific CD4+ (AUC: 0.78, P < 0.001) and borderline for CD8+ (AUC: 0.66, P = 0.064) T-cells. At a cut-off value of 0.22% CMV-specific CD4+ T-cells, positive predictive value (PPV) for protection against CMV was 85% (95%CI 65-96%), and negative predictive value (NPV) was 67% (95%CI 41-87%). CONCLUSIONS: The CMV-TCIP, in particular %CMV-specific CD4+ T-cells, showed good diagnostic performance to predict CMV events. The CMV-TCIP may be a useful test in clinical practice, and merits further validation in larger prospective studies.

Hyperammonemia syndrome due to Ureaplasma urealyticum in a kidney transplant recipient: A case of disseminated disease from a fluoroquinolone-resistant isolate.

Ureaplasma species (spp.) are common colonizers of the urogenital tract but may cause systemic infection in immunocompromised patients. They release significant amounts of ammonia via urea hydrolysis and have been recently implicated in the pathogenesis of hyperammonemia syndrome after organ transplantation. We describe a unique case of hyperammonemia syndrome after kidney transplant caused by U urealyticum infection, and the first, to our knowledge, case of a fluoroquinolone-resistant Ureaplasma strain causing hyperammonemia syndrome. A 17-year-old female developed intermittent fevers, rising creatinine, sterile pyuria and debilitating polyarthritis approximately 1 year after kidney transplant. Serum ammonia level was elevated, and urine PCR was positive for U urealyticum. Near the end of treatment with levofloxacin, she had rebound hyperammonemia, which preceded clinical relapse of polyarthritis and encephalopathy. Blood and urine PCR and synovial fluid culture were positive for U urealyticum. Susceptibility testing showed fluoroquinolone resistance, but she responded well to azithromycin and doxycycline. The frequency of Ureaplasma spp. infection in immunocompromised patients is probably underestimated due to diagnostic challenges. Ammonia levels were helpful biomarkers of response to antimicrobial therapy in our case. Susceptibility testing of clinical isolates should be pursued. In serious Ureaplasma spp. infections, particularly in immunocompromised patients, two empiric antibiotics may be indicated given the potential for antimicrobial resistance.

Urothelial cell carcinoma after BK polyomavirus infection in kidney transplant recipients: A cohort study of veterans.

BACKGROUND: BK polyomavirus (BKPyV) reactivation is a common clinical occurrence in kidney transplant recipients (KTR). Several other polyomaviruses have been implicated as pathogens with a direct role in the development of malignancies, raising the question of whether BKPyV might also be oncogenic. METHODS: This study is the first retrospective, multicenter cohort study evaluating the relative risk for urothelial cell carcinoma (UCC) associated with BKPyV infection among KTR, and was conducted among veterans who underwent transplantation between 2000 and 2009. BKPyV cases were defined as those veterans with any clinical evidence of BKPyV infection, including positive polymerase chain reaction testing of urine and/or serum for BKPyV or kidney biopsy showing BKPyV-associated nephropathy. RESULTS: Among the 646 veterans who met inclusion criteria for the study, 103 had clinical evidence of BKPyV infection (16%). The overall relative risk for developing any malignancy after BKPyV infection was 1.13 (95% confidence interval [CI] 0.89-1.44). The adjusted relative risk for malignancy after BKPyV infection was greatest with UCC (8.21, 95% CI 0.75-89.7) and with metastatic disease of unknown etiology (8.21, 95% CI 0.75-89.7). The screening prevalence for BKPyV infection increased from 18% for those veterans who underwent transplantation in 2000 to 86% for those veterans who underwent transplantation in 2009, during which time the measured prevalence of BKPyV infection increased from 7% to 24%. CONCLUSION: In this cohort of KTR veterans, no overall increased or decreased relative risk for malignancy was associated with evidence of prior BKPyV infection. A >8-fold increased risk of developing UCC after BKPyV infection was seen, although this risk was not found to be statistically significant.