Advancing cytomegalovirus prevention in solid organ transplant recipients: The promise of cell-mediated immune assays.

Cytomegalovirus (CMV) infections are a major source of morbidity and mortality in solid organ transplant recipients. Prophylactic, preemptive, and hybrid prevention strategies have traditionally been the mainstay of CMV prevention but there is growing interest in the use of CMV cell-mediated immune assays to inform novel approaches to risk stratification. Recent evidence suggests that CMV interferon-gamma release assays can offer predictive insights into the risk for CMV-related illnesses, raising the potential for tailored CMV prevention strategies anchored to each individual's unique CMV immune profile. However, the predictive capacity of these assays for CMV-related illnesses can be profoundly influenced by when they are performed relative to transplant, and the induction immunosuppressive regimen the patient has received. In this review, we explore the relevant literature shaping our understanding of the optimal use of these assays. Furthermore, we also highlight the benefits of quantifying the CD4+ and CD8+ T-Cell responses to CMV, which is offered by some interferon-gamma release assays utilizing intracellular cytokine staining, for providing a holistic assessment of the recovery of cell-mediated immunity post-induction immunosuppression.

Safety and Immunogenicity of a Delayed Heterologous Avian Influenza A(H7N9) Vaccine Boost Following Different Priming Regimens: A Randomized Clinical Trial.

BACKGROUND: Influenza A (H7N9) has caused multiple disease waves with evidence of strain diversification. Optimal influenza A (H7N9) prime-boost vaccine strategies are unknown. METHODS: We recruited participants who had received monovalent inactivated A/Shanghai/2/2013 (H7N9) vaccine (MIV) approximately 5 years earlier, as follows: MIV with MF59 (MF59 × 2 group), MIV with AS03 (AS03 × 2 group), unadjuvanted MIV (No Adj group), MIV with MF59 or AS03 followed by unadjuvanted MIV (Adjx1 group), and A/H7-naive (unprimed group). Participants were randomized to receive 1 dose of AS03-adjuvanted or unadjuvanted A/Hong Kong/125/2017 (H7N9) MIV and were followed for safety and immunogenicity using hemagglutination inhibition (HAI) and neutralizing antibody assays. RESULTS: We enrolled 304 participants: 153 received the adjuvanted boost and 151 received the unadjuvanted boost. At 21 days postvaccination, the proportion of participants with HAI antibody titers against the boosting vaccine strain of ≥40 in the adjuvanted and unadjuvanted arms, respectively, were 88% and 49% in MF59 × 2 group, 89% and 75% in AS03 × 2 group, 59% and 20% in No Adj group, 94% and 55% in Adjx1group, and 9% and 11% in unprimed group. CONCLUSIONS: Serologic responses to a heterologous A(H7N9) MIV boost were highest in participants primed and boosted with adjuvant-containing regimens. CLINICAL TRIALS REGISTRATION: NCT03738241.

Impact of an ultrasensitive Cytomegalovirus quantitative nucleic acid test on Cytomegalovirus detection and therapy in renal transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection has broad implications for morbidity and mortality in renal transplant recipients (RTR). Routine surveillance for CMV replication with PCR-based quantitative nucleic acid testing (qNAT) assays is standard practice in most transplant centers, but the impact of assay sensitivity on antiviral decision-making and virologic outcomes has not been studied. We investigated the effects of an ultrasensitive CMV qNAT assay on multiple clinical outcomes, including time to detection and duration of CMV DNAemia. METHODS: We conducted a single-center cohort study contrasting RTRs monitored with a qNAT with a higher lower limit of quantification (LLOQ >300 IU/mL) with those monitored with a more sensitive qNAT (LLOQ >35 IU/mL). Patients were stratified by donor (D)/recipient (R) CMV serostatus (D+/R-: high risk; any R+: moderate risk). CMV viral load monitoring was performed monthly post transplantation, with the primary outcomes being time to CMV DNAemia and its duration. RESULTS: Total 1382 patients were analyzed from 2014 to 2016 and 2019 to 2021. Moderate-risk RTRs monitored with the more sensitive assay experienced a greater hazard for the development of a first episode of CMV DNAemia (aHR: 1.95, 95% confidence interval [CI]: 1.55-2.46) and an average of 24 (95% CI: 16.40-31.98) additional days of DNAemia. There was no difference in CMV end-organ disease or 1-year all-cause mortality between moderate-risk RTRs. CONCLUSIONS: The more sensitive assay was associated with earlier detection and extended durations of CMV DNAemia in moderate-risk RTRs, without altering clinical outcomes. These findings inform optimal use of these assays and antiviral stewardship in RTRs. KEY SUMMARY: The use of ultrasensitive CMV qNAT assays in moderate-risk CMV renal transplant recipients is associated with earlier detection and longer durations of CMV DNAemia without impacting CMV end-organ disease or 1-year mortality.

Your Outpatient has Coronavirus Disease 2019: What Are the Treatment Options in the Current Severe Acute Respiratory Syndrome Coronavirus 2 Variant Climate?

Mutations accumulated by novel Severe Acute Respiratory Syndrome Coronavirus 2 Omicron sublineages contribute to evasion of previously effective monoclonal antibodies for treatment or prevention of Coronavirus Disease 2019 (COVID-19). Other authorized or approved antiviral drugs such as nirmatrelvir/ritonavir, remdesivir, and molnupiravir are, however, predicted to maintain activity against these sublineages and are key tools to reduce severe COVID-19 outcomes in vulnerable populations. A stepwise approach may be taken to target the appropriate antiviral drug to the appropriate patient, beginning with identifying whether a patient is at high risk for hospitalization or other complications of COVID-19. Among higher risk individuals, patient profile (including factors such as age, organ function, and comedications) and antiviral drug access inform suitable antiviral drug selection. When applied in targeted fashion, these therapies serve as a complement to vital ongoing nonpharmaceutical interventions and vaccination strategies that reduce morbidity and maximize protection against COVID-19.

Nucleocapsid Antigenemia in Patients Receiving Anti-CD20 Therapy With Protracted COVID-19.

Immunocompromised patients with prolonged coronavirus disease 2019 symptoms present diagnostic and therapeutic challenges. We measured viral nucleocapsid antigenemia in 3 patients treated with anti-CD20 immunotherapy who acquired severe acute respiratory syndrome coronavirus 2 infection and experienced protracted symptoms. Our results support nucleocapsid antigenemia as a marker of persistent infection and therapeutic response.

Occupational risk factors for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection among healthcare personnel: A 6-month prospective analysis of the COVID-19 Prevention in Emory Healthcare Personnel (COPE) Study.

OBJECTIVES: To determine the incidence of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection among healthcare personnel (HCP) and to assess occupational risks for SARS-CoV-2 infection. DESIGN: Prospective cohort of healthcare personnel (HCP) followed for 6 months from May through December 2020. SETTING: Large academic healthcare system including 4 hospitals and affiliated clinics in Atlanta, Georgia. PARTICIPANTS: HCP, including those with and without direct patient-care activities, working during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: Incident SARS-CoV-2 infections were determined through serologic testing for SARS-CoV-2 IgG at enrollment, at 3 months, and at 6 months. HCP completed monthly surveys regarding occupational activities. Multivariable logistic regression was used to identify occupational factors that increased the risk of SARS-CoV-2 infection. RESULTS: Of the 304 evaluable HCP that were seronegative at enrollment, 26 (9%) seroconverted for SARS-CoV-2 IgG by 6 months. Overall, 219 participants (73%) self-identified as White race, 119 (40%) were nurses, and 121 (40%) worked on inpatient medical-surgical floors. In a multivariable analysis, HCP who identified as Black race were more likely to seroconvert than HCP who identified as White (odds ratio, 4.5; 95% confidence interval, 1.3-14.2). Increased risk for SARS-CoV-2 infection was not identified for any occupational activity, including spending >50% of a typical shift at a patient's bedside, working in a COVID-19 unit, or performing or being present for aerosol-generating procedures (AGPs). CONCLUSIONS: In our study cohort of HCP working in an academic healthcare system, <10% had evidence of SARS-CoV-2 infection over 6 months. No specific occupational activities were identified as increasing risk for SARS-CoV-2 infection.

Dose-Response of a Norovirus GII.2 Controlled Human Challenge Model Inoculum.

BACKGROUND: Genogroup II noroviruses are the most common cause of acute infectious gastroenteritis. We evaluated the use of a new GII.2 inoculum in a human challenge. METHODS: Forty-four healthy adults (36 secretor-positive and 8 secretor-negative for histo-blood group antigens) were challenged with ascending doses of a new safety-tested Snow Mountain virus (SMV) GII.2 norovirus inoculum (1.2 × 104 to 1.2 × 107 genome equivalent copies [GEC]; n = 38) or placebo (n = 6). Illness was defined as diarrhea and/or vomiting postchallenge in subjects with evidence of infection (defined as GII.2 norovirus RNA detection in stool and/or anti-SMV immunoglobulin G [IgG] seroconversion). RESULTS: The highest dose was associated with SMV infection in 90%, and illness in 70% of subjects with 10 of 12 secretor-positive (83%) and 4 of 8 secretor-negative (50%) becoming ill. There was no association between prechallenge anti-SMV serum IgG concentration, carbohydrate-binding blockade antibody, or salivary immunoglobulin A and infection. The median infectious dose (ID50) was 5.1 × 105 GEC. CONCLUSIONS: High rates of infection and illness were observed in both secretor-positive and secretor-negative subjects in this challenge study. However, a high dose will be required to achieve the target of 75% illness to make this an efficient model for evaluating potential norovirus vaccines and therapeutics. CLINICAL TRIALS REGISTRATION: NCT02473224.

Occupational risk factors for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) infection among healthcare personnel: A cross-sectional analysis of subjects enrolled in the COVID-19 Prevention in Emory Healthcare Personnel (COPE) study.

Among 353 healthcare personnel in a longitudinal cohort in 4 hospitals in Atlanta, Georgia (May-June 2020), 23 (6.5%) had severe acute respiratory coronavirus virus 2 (SARS-CoV-2) antibodies. Spending >50% of a typical shift at the bedside (OR, 3.4; 95% CI, 1.2-10.5) and black race (OR, 8.4; 95% CI, 2.7-27.4) were associated with SARS-CoV-2 seropositivity.

A 42-Year-Old Man with Back Pain and Lower Extremity Weakness.

Back Pain and Lower-Extremity WeaknessA 42-year-old man with HIV presented for evaluation of acute-onset back pain and lower-extremity weakness. How do you approach the evaluation, and what is the diagnosis?

Clinical characteristics and outcomes of toxoplasmosis among transplant recipients at two US academic medical centers.

Toxoplasma gondii can cause severe opportunistic infection in immunocompromised individuals, but diagnosis is often delayed. We conducted a retrospective review of solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients with toxoplasmosis between 2002 and 2018 at two large US academic transplant centers. Patients were identified by ICD-9 or ICD-10 toxoplasmosis codes, positive Toxoplasma polymerase chain reaction test result, or pathologic diagnosis. Data were collected regarding transplant type, time from transplant to toxoplasmosis diagnosis, clinical and radiographic features, and mortality at 30 and 90 days. Twenty patients were identified: 10 HSCT recipients (80% allogeneic HSCT) and 10 SOT recipients (60% deceased donor renal transplants). Rejection among SOT recipients (70%) and graft-versus-host disease (GVHD) prophylaxis among HSCT recipients (50%) were frequent. Median time from transplant to toxoplasmosis diagnosis was longer for SOT than HSCT (1385 vs. 5 days, P-value .002). Clinical manifestations most commonly were encephalitis (65%), respiratory failure (40%), renal failure (40%), and distributive shock (40%). Cohort 30-day mortality was 45%, and 90-day mortality was 55%. Diagnosis was postmortem in 25% of the cohort. Further evaluation of toxoplasmosis screening is needed for noncardiac SOT recipients, HSCT recipients with GVHD, and periods of increased net immunosuppression.

Immune Responses to SARS-CoV-2 in Solid Organ Transplant Recipients.

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19) is caused by a complex interplay between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dynamics and host immune responses. Hosts with altered immunity, including solid organ transplant recipients, may be at increased risk of complications and death due to COVID-19. A synthesis of the available data on immune responses to SARS-CoV-2 infection is needed to inform therapeutic and preventative strategies in this special population. RECENT FINDINGS: Few studies have directly compared immune responses to SARS-CoV-2 between transplant recipients and the general population. Like non-transplant patients, transplant recipients mount an exuberant inflammatory response following initial SARS-CoV2 infection, with IL-6 levels correlating with disease severity in some, but not all studies. Transplant recipients display anti-SARS-CoV-2 antibodies and activated B cells in a time frame and magnitude similar to non-transplant patients-limited data suggest these antibodies can be detected within 15 days of symptom onset and may be durable for several months. CD4+ and CD8+ T lymphopenia, a hallmark of COVID-19, is more profound in transplant recipients, but SARS-CoV-2-reactive T cells can be detected among patients with both mild and severe disease. SUMMARY: The limited available data indicate that immune responses to SARS-CoV-2 are similar between transplant recipients and the general population, but no studies have been sufficiently comprehensive to understand nuances between organ types or level of immunosuppression to meaningfully inform individualized therapeutic decisions. The ongoing pandemic provides an opportunity to generate higher-quality data to support rational treatment and vaccination strategies in this population.

Adenovirus causing hepatic abscess formation and unexplained fever in adult liver transplant recipients.

Adenovirus infection is commonly associated with self-limited respiratory and gastrointestinal illnesses. However, infection in immunocompromised individuals, such as transplant recipients, can cause severe life-threatening illness including pneumonitis, hemorrhagic cystitis, nephritis, hepatitis, and enterocolitis. In orthotopic liver transplant recipients, adenovirus viremia can cause hepatitis leading to marked transaminitis, allograft loss, and death. Although hepatic abscesses mediated by adenovirus have been described in other immunosuppressed patient populations, it has very rarely been described in liver transplant recipients. Here, we report two adult cases of hepatic abscesses following liver transplantation secondary to adenovirus infection and describe the successful treatment of these patients. Adenovirus should be considered as an uncommon etiology of hepatic abscess and unexplained fevers in adults following liver transplantation.

Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults.

BACKGROUND: Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased incidences of illness and death from coronavirus disease 2019 (Covid-19) have been associated with an older age. METHODS: We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). All the participants were assigned sequentially to receive two doses of either 25 µg or 100 µg of vaccine administered 28 days apart. RESULTS: Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. Binding-antibody responses increased rapidly after the first immunization. By day 57, among the participants who received the 25-µg dose, the anti-S-2P geometric mean titer (GMT) was 323,945 among those between the ages of 56 and 70 years and 1,128,391 among those who were 71 years of age or older; among the participants who received the 100-µg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells. CONCLUSIONS: In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-µg dose induced higher binding- and neutralizing-antibody titers than the 25-µg dose, which supports the use of the 100-µg dose in a phase 3 vaccine trial. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study ClinicalTrials.gov number, NCT04283461.).

Contemporary Management Strategies in VAD Infection.

PURPOSE OF REVIEW: The use of durable ventricular assist devices (VAD) to manage end-stage heart failure is increasing, but infection remains a leading cause of morbidity and mortality among patients with VAD. In this review, we synthesize recent data pertaining to the epidemiology, diagnosis, management, and prevention of VAD infections, discuss transplant considerations in patients with VAD infections, and highlight remaining knowledge gaps. We also present a conceptual framework for treating clinicians to approach these infections that draws on the same principles that guide the treatment of analogous infections that occur in patients without VAD. RECENT FINDINGS: Despite advances in device design, surgical techniques, and preventative interventions, more than a third of VAD recipients still experience infection as an adverse outcome. Positron emission tomography has emerged as a promising modality for identifying and characterizing VAD infections. High-quality data to support many of the routine therapeutic strategies currently used for VAD infections-including suppressive antibiotic therapy, surgical debridement/device exchange, and novel antimicrobials for emerging multidrug-resistant organisms-remain limited. Although pre-transplant VAD infection may impact some early transplant outcomes, transplantation remains a viable option for patients with most types of VAD infection. Standardized definitions of VAD infection applied to large registry datasets have yielded key insights into the epidemiology of infectious complications among VAD recipients, but more prospective studies are needed to evaluate the effectiveness of existing and novel diagnostic and therapeutic strategies.

Relapsing Uveitis due to Human T-lymphotropic Virus Type 1 in a Patient Living With HIV Diagnosed by Metagenomic Deep Sequencing.

HIV infection can result in vision loss from different causes, including HIV retinopathy and uveitis secondary to other infections, such as toxoplasmosis and viral retinitis. It is imperative to identify any infectious causes of uveitis to successfully treat the condition and prevent further vision loss. Metagenomic deep sequencing (MDS) is an emerging technology that presents an unbiased approach to the evaluation of clinical syndromes, including uveitis, that have not been diagnosed by pathogen-specific testing. Herein we present a case of a woman living with HIV with 11 years of relapsing bilateral uveitis refractory to systemic corticosteroid therapy who was diagnosed with human T-lymphotropic virus type 1 (HTLV-1)-associated uveitis by this technology. We also briefly review the literature of MDS as a diagnostic tool and the epidemiology, pathogenesis, and diagnosis of HTLV-1-associated uveitis.

Assessment and Validation of Syndromic Case Definitions for Respiratory Syncytial Virus Infections in Young Infants: A Latent Class Analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of pediatric morbidity and mortality worldwide. Standardized case definitions that are applicable to variety of populations are critical for robust surveillance systems to guide decision-making regarding RSV control strategies including vaccine evaluation. Limited data exist on performance of RSV syndromic case definitions among young infants or in high-resource settings. OBJECTIVE: The purpose of this study was to evaluate existing and potential syndromic case definitions for RSV among young infants in an urban, high-income setting using latent class analyses (LCA). METHODS: We used data collected on infants <6 months of age tested for RSV as part of routine clinical care at Children's Healthcare of Atlanta between January 2010 and December 2015. We computed the sensitivity, specificity, positive and negative predictive values of clinical features, existing syndromic case definitions used by the World Health Organization (WHO) and alternative definitions we constructed using LCA to detect RSV infection. RESULTS: Among 565 infants tested for RSV, 161 (28.5%) had laboratory-confirmed RSV infection. Among all case definitions evaluated, the definition developed through LCA (cough plus shortness of breath plus coryza plus wheeze plus poor feeding plus chest in-drawing) was the most specific (95.8%, 95% CI 93.8-97.8) and had the highest positive predictive value (51.4%, 95% CI, 34.9-68.0). WHO-acute respiratory infection (cough or sore throat or shortness of breath or coryza, plus a clinician's judgment that illness is due to infection) was the most sensitive (98.1%, 95% CI, 96.1-100.0; negative predictive value 96.3%, 95% CI 92.2-100.0). CONCLUSIONS: The WHO acute respiratory infection definition could be useful for initial screening for RSV among infants <6 months, whereas our alternative syndromic case definition may serve as the strongest confirmatory case definition in the same population. Appropriate case definitions will vary depending on the content and setting in which they are utilized.

Yogurt consumption during pregnancy and preterm delivery in Mexican women: A prospective analysis of interaction with maternal overweight status.

Preterm delivery is an important cause of perinatal morbidity and mortality, often precipitated by maternal infection or inflammation. Probiotic-containing foods, such as yogurt, may reduce systemic inflammatory responses. We sought to evaluate whether yogurt consumption during pregnancy is associated with decreased preterm delivery. We studied 965 women enrolled at midpregnancy into a clinical trial of prenatal docosahexaenoic acid supplementation in Mexico. Yogurt consumption during the previous 3 months was categorized as ≥5, 2-4, or <2 cups per week. Preterm delivery was defined as delivery of a live infant before 37 weeks gestation. We used logistic regression to evaluate the association between prenatal yogurt consumption and preterm delivery and examined interaction with maternal overweight status. In this population, 25.4%, 34.2%, and 40.4% of women reported consuming ≥5, 2-4, and <2 cups of yogurt per week, respectively. The prevalence of preterm delivery was 8.9%. Differences in preterm delivery were non-significant across maternal yogurt consumption groups; compared with women reporting <2 cups of yogurt per week, those reporting 2-4 cups of yogurt per week had adjusted odds ratio (aOR) for preterm delivery of 0.81 (95% confidence interval, CI [.46, 1.41]), and those reporting ≥5 cups of yogurt per week had aOR of 0.94 (95% CI [.51, 1.72]). The association between maternal yogurt consumption and preterm delivery differed significantly for nonoverweight women compared with overweight women (p for interaction = .01). Compared with nonoverweight women who consumed <2 cups of yogurt per week, nonoverweight women who consumed ≥5 cups of yogurt per week had aOR for preterm delivery of 0.24 (95% CI [.07, .89]). Among overweight women, there was no significant association. In this population, there was no overall association between prenatal yogurt consumption and preterm delivery. However, there was significant interaction with maternal overweight status; among nonoverweight women, higher prenatal yogurt consumption was associated with reduced preterm delivery.