Approaches and Challenges in the Current Management of Cytomegalovirus in Transplant Recipients: Highlighting the Role of Advanced Practice Providers (Nurse Practitioners and Physician Assistants).

Cytomegalovirus (CMV) infection is associated with increased morbidity and mortality in hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients, with traditional anti-CMV therapies limited by their associated toxicities and the development of resistance. Clinical providers are often faced with challenging and complicated CMV infections that require multiple courses of antiviral therapies. Increasingly, advanced practice providers (APPs) are playing an important role in the day-to-day management of transplant recipients with CMV infection, including resistant/refractory CMV and other complex CMV syndromes. Here, we provide an overview of current preventative and treatment strategies for CMV infection in HCT and SOT recipients, highlighting the challenging aspects of current management and the potential utility of newer antiviral agents. This article also focuses on how a multidisciplinary team, orchestrated by APPs, can improve CMV-associated patient outcomes. Protocols using antiviral agents for the prevention or treatment of CMV infections require carefully designed and meticulously implemented strategies to ensure the best clinical outcomes for patients. APPs, who have increasingly become the frontline providers of outpatient care for transplant recipients, are ideally positioned to design and carry out these protocols.

Presentation, anagement, and outcomes of norovirus in adult and pediatric solid organ and hematopoietic stem cell transplant recipients: A multicenter, retrospective study.

BACKGROUND: Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients.  Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients. METHODS: A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated. RESULTS: A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a median of 36 months post-Tx (IQR [15.0, 90.0]). Most NoV cases had >3 diarrheal episodes daily (66.0%), nausea and vomiting (60.1%). Duration of diarrhea varied greatly (median = 10 days, mean = 85.9 days, range (1, 2100)). 71.3% were hospitalized. Adjustment of immunosuppression, including reduction and discontinuation of mToR inhibitor, CNI, and/or MMF, was the most common management intervention for NoV. Other therapies resulted only in temporary improvement. Four patients died within 30 days and three others died by 180 days postdiagnosis. Clinically significant renal dysfunction was observed in 12.5% by 30 days and 21.4% by 180 days post-NoV diagnosis. CONCLUSION: In HSCT and SOT patients, NoV frequently resulted in severe symptoms, prolonged diarrhea (30% persistent with diarrhea for >30 days), and clinically significant renal dysfunction (up to 21% of patients). Utilized therapies did not reliably result in the resolution of infection demonstrating the need for more effective treatment.

A Multicenter Assessment of the Outcomes and Toxicities of Foscarnet for Treatment of Acyclovir-Resistant Mucocutaneous Herpes Simplex in Immunocompromised Patients.

Background: Acyclovir-resistant mucocutaneous herpes simplex virus (HSV) infection is an uncommon problem typically seen in immunocompromised hosts. Systemic treatment options are limited. The performance of foscarnet and its toxicities in this population are poorly characterized. Methods: This was a multicenter retrospective study of adults treated with foscarnet for HSV infection between January 2012 and December 2017. Relevant data were collected including demographics, baseline conditions, previous anti-HSV medications, concomitant medications, HSV outcomes, and adverse events. Acyclovir-resistant HSV infection was defined based on genotypic or phenotypic testing results; refractory infection was defined as infection not improving after 5 days of treatment-dosed antiviral therapy in those not tested for resistance. Results: Twenty-nine patients had 31 episodes of HSV (15/18 resistant; among episodes without resistance testing, 7/10 refractory; 3 not evaluable) treated with foscarnet. All patients were immunocompromised including 19 (66%) with hematologic malignancy and 9 (31%) with HIV. Median duration of foscarnet was 16 days (range, 6-85 days). Fifteen episodes (48%) healed by the end of or after foscarnet. Median time to healing among those with resolution was 38 days (range, 9-1088 days). At least 1 adverse event during therapy was reported in 26 (84%) treatment episodes including 23 (74%) that were considered drug related. Common adverse events were electrolyte disturbance (20 [65%]) and kidney dysfunction (13 [42%]). Foscarnet was discontinued in 10 episodes (32%) due to an adverse event, including 6 due to kidney dysfunction. Conclusions: Among 31 episodes of HSV treated with foscarnet, only half resolved with treatment, and adverse events were common.

Invasive Fungal Infections in Inpatient Solid Organ Transplant Recipients With COVID-19: A Multicenter Retrospective Cohort.

BACKGROUND: The prevalence and outcomes of COVID-19-associated invasive fungal infections (CAIFIs) in solid organ transplant recipients (SOTRs) remain poorly understood. METHODS: A retrospective cohort study of SOTRs with COVID-19 admitted to 5 hospitals within Johns Hopkins Medicine was performed between March 2020 and March 2022. Cox regression multilevel mixed-effects ordinal logistic regression was used. RESULTS: In the cohort of 276 SOTRs, 22 (8%) developed IFIs. The prevalence of CAIFIs was highest in lung transplant recipients (20%), followed by recipients of heart (2/28; 7.1%), liver (3/46; 6.5%), and kidney (7/149; 4.7%) transplants. In the overall cohort, only 42 of 276 SOTRs (15.2%) required mechanical ventilation; these included 11 of 22 SOTRs (50%) of the CAIFI group and 31 of 254 SOTRs (12.2%) of the no-CAIFI group. Compared with those without IFIs, SOTs with IFIs had worse outcomes and required more advanced life support (high-flow oxygen, vasopressor, and dialysis). SOTRs with CAIFIs had higher 1-y death-censored allograft failure (hazard ratio 1.65.116.4, P = 0.006) and 1-y mortality adjusting for oxygen requirement (adjusted hazard ratio 1.12.45.1, P < 0.001), compared with SOTRs without CAIFIs. CONCLUSIONS: The prevalence of CAIFIs in inpatient SOTRs with COVID-19 is substantial. Clinicians should be alert to the possibility of CAIFIs in SOTRs with COVID-19, particularly those requiring supplemental oxygen, regardless of their intubation status.

Impact of recipient age on mortality among Cytomegalovirus (CMV)-seronegative lung transplant recipients with CMV-seropositive donors.

BACKGROUND: Cytomegalovirus (CMV)-seronegative lung transplant recipients (LTRs) with seropositive donors (CMV D+/R-) have the highest mortality of all CMV serostatuses. Due to immunosenescence and other factors, we hypothesized CMV D+/R- status might disproportionately impact older LTRs. Thus, we investigated whether recipient age modified the relationship between donor CMV status and mortality among CMV-seronegative LTRs. METHODS: Adult, CMV-seronegative first-time lung-only recipients were identified through the Scientific Registry of Transplant Recipients between May 2005 and December 2019. We used adjusted multivariable Cox regression to assess the relationship of donor CMV status and death. Interaction between recipient age and donor CMV was assessed via likelihood ratio testing of nested Cox models and by the relative excess risk due to interaction (RERI) and attributable proportion (AP) of joint effects. RESULTS: We identified 11,136 CMV-seronegative LTRs. The median age was 59 years; 65.2% were male, with leading transplant indication of idiopathic pulmonary fibrosis (35.6%); and 60.8% were CMV D+/R-. In multivariable modeling, CMV D+/R- status was associated with 27% increased hazard of death (adjusted hazard ratio: 1.27, 95% confidence interval: 1.21-1.34) compared to CMV D-/R-. Recipient age ≥60 years significantly modified the relationship between donor CMV-seropositive status and mortality on the additive scale, including RERI 0.24 and AP 11.4% (p = 0.001), that is, the interaction increased hazard of death by 0.24 and explained 11.4% of mortality in older CMV D+ recipients. CONCLUSIONS: Among CMV-seronegative LTRs, donor CMV-seropositive status confers higher risk of posttransplant mortality, which is amplified in older recipients. Future studies should define optimal strategies for CMV prevention and management in older D+/R- LTRs.

Treatment for First Cytomegalovirus Infection Post-Hematopoietic Cell Transplant in the AURORA Trial: A Multicenter, Double-Blind, Randomized, Phase 3 Trial Comparing Maribavir With Valganciclovir.

BACKGROUND: Neutropenia may limit the use of valganciclovir treatment for cytomegalovirus (CMV) infection following hematopoietic cell transplant (HCT). A phase 2 study indicated efficacy of maribavir with fewer treatment-limiting toxicities than valganciclovir. METHODS: In this multicenter, double-blind, phase 3 study, patients with first asymptomatic CMV infection post-HCT were stratified and randomized 1:1 to maribavir 400 mg twice daily or valganciclovir (dose-adjusted for renal clearance) for 8 weeks with 12 weeks of follow-up. The primary endpoint was confirmed CMV viremia clearance at week 8 (primary hypothesis of noninferiority margin of 7.0%). The key secondary endpoint was a composite of the primary endpoint with no findings of CMV tissue-invasive disease at week 8 through week 16. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: Among patients treated (273 maribavir; 274 valganciclovir), the primary endpoint of noninferiority of maribavir was not met (maribavir, 69.6%; valganciclovir, 77.4%; adjusted difference: -7.7%; 95% confidence interval [CI]: -14.98, -.36; lower limit of 95% CI of treatment difference exceeded -7.0%). At week 16, 52.7% and 48.5% of patients treated (maribavir and valganciclovir, respectively) maintained CMV viremia clearance without tissue-invasive disease (adjusted difference: 4.4%; 95% CI: -3.91, 12.76). With maribavir (vs valganciclovir), fewer patients experienced neutropenia (16.1% and 52.9%) or discontinued due to TEAEs (27.8% and 41.2%). Discontinuations were mostly due to neutropenia (maribavir, 4.0%; valganciclovir, 17.5%). CONCLUSIONS: Although noninferiority of maribavir to valganciclovir for the primary endpoint was not achieved based on the prespecified noninferiority margin, maribavir demonstrated comparable CMV viremia clearance during post-treatment follow-up, with fewer discontinuations due to neutropenia. Clinical Trials Registration. NCT02927067 [AURORA].

Teaching Everyone Everywhere All at Once: Leveraging Social Media to Implement a Multisite Fungal Diagnostics Curriculum.

Background: Environmental fungi are threats to personal and public health. Fungal in vitro diagnostics help diagnose invasive fungal infections (IFIs), but clinicians remain underinformed about their use and interpretation. Given the increasing use of social media to share infectious diseases-related content, we designed and implemented a multisite Twitter-based curriculum focused on IFIs and related diagnostics. Methods: Questions were posted through a dedicated Twitter account twice weekly over 8 weeks. We surveyed clinicians at 3 US academic centers before and after completion of the curriculum and interviewed a subset of participants. We undertook quantitative and qualitative evaluations and reviewed Twitter analytics. Results: We surveyed 450 participants. One hundred twenty-one participants (27%) completed the knowledge assessment precurriculum, 68 (15%) postcurriculum, and 53 (12%) pre- and postcurriculum. We found a significant increase (72% vs 80%, P = .005) in the percentage of correct answers in the pre- versus postcurriculum knowledge assessments. Perceived benefits included a well-executed curriculum that facilitated engagement with appropriately detailed tweetorials from a dedicated Twitter account. Perceived barriers included lack of awareness of tweetorial posts and timing, competing priorities, and the coronavirus disease 2019 pandemic. The Twitter account accrued 1400 followers from 65 countries during the 8-week period. Tweets with multiple-choice questions had a median of 14 904 impressions (interquartile range [IQR], 12 818-16 963), 798 engagements (IQR, 626-1041), and an engagement rate of 6.1% (IQR, 4.2%-6.6%). Conclusions: Educators can leverage social media to share content with a large audience and improve knowledge while being mindful of the barriers associated with implementing a curriculum on social media.

Progressive disseminated histoplasmosis: The experience in one non-endemic medical center.

Histoplasmosis, the most common endemic mycosis in North America, presents in a myriad of ways, spanning the spectrum from self-limiting pneumonia to progressive disseminated histoplasmosis (PDH). Toward better describing contemporary histoplasmosis syndromes, risks, and outcomes, this single-center retrospective cohort study was performed (2009-2019). The population who developed PDH was similar to that with other forms of histoplasmosis (OFH) except for higher rates of preexisting immunocompromising conditions (91.3% vs. 40%, P < .001) and a trend toward receiving more chronic immunosuppression (65.2% vs. 33.3%, P = .054) compared to those with OFH. Diagnosis was most frequently achieved by urinary or serum antigen positivity. People with PDH more frequently tested positive compared to those with OFH, but negative tests did not rule out histoplasmosis. Median time to diagnosis was prolonged among people with both PDH and OFH (32 vs. 31 days, respectively). Following diagnosis, people with PDH received more liposomal amphotericin (78.3% vs. 20%, P < .001). Subsequent survival at 90 and 365 days and treatment response were similar in both groups. Patients with PDH were more often hospitalized (95.7% vs. 60%, P = .006); however, once admitted, there were no differences in hospital length of stay or intensive care unit admission rate. The challenges of diagnosing histoplasmosis based on clinical presentation alone highlight the need for heightened awareness of these entities especially given the recent reports on expanded endemicity and delays in diagnosis.

Histoplasmosis is the most common endemic mycosis in North America. This article summarizes the clinical features, risk factors, and outcomes in patients who developed disseminated disease compared to more localized forms of histoplasmosis.

Genomic Markers Associated with Cytomegalovirus DNAemia in Kidney Transplant Recipients.

Human cytomegalovirus (CMV) is a major pathogen after solid organ transplantation, leading to high morbidity and mortality. Transplantation from a CMV-seropositive donor to a CMV-seronegative recipient (D+/R-) is associated with high risk of CMV disease. However, that risk is not uniform, suggesting a role for host factors in immune control of CMV. To identify host genetic factors that control CMV DNAemia post transplantation, we performed a whole-exome association study in two cohorts of D+/R- kidney transplant recipients. Quantitative CMV DNA was measured for at least one year following transplantation. Several CMV-protective single-nucleotide polymorphisms (SNPs) were identified in the first cohort (72 patients) but were not reproducible in the second cohort (126 patients). A meta-analysis of both cohorts revealed several SNPs that were significantly associated with protection from CMV DNAemia. The copy number variation of several genes was significantly different between recipients with and without CMV DNAemia. Amongst patients with CMV DNAemia in the second cohort, several variants of interest (p < 5 × 10-5), the most common of which was NLRC5, were associated with peak viral load. We provide new predictive genetic markers for protection of CMV DNAemia. These markers should be validated in larger cohorts.

New Treatment Options for Refractory/Resistant CMV Infection.

Despite advances in monitoring and treatment, cytomegalovirus (CMV) infections remain one of the most common complications after solid organ transplantation (SOT). CMV infection may fail to respond to standard first- and second-line antiviral therapies with or without the presence of antiviral resistance to these therapies. This failure to respond after 14 days of appropriate treatment is referred to as "resistant/refractory CMV." Limited data on refractory CMV without antiviral resistance are available. Reported rates of resistant CMV are up to 18% in SOT recipients treated for CMV. Therapeutic options for treating these infections are limited due to the toxicity of the agent used or transplant-related complications. This is often the challenge with conventional agents such as ganciclovir, foscarnet and cidofovir. Recent introduction of new CMV agents including maribavir and letermovir as well as the use of adoptive T cell therapy may improve the outcome of these difficult-to-treat infections in SOT recipients. In this expert review, we focus on new treatment options for resistant/refractory CMV infection and disease in SOT recipients, with an emphasis on maribavir, letermovir, and adoptive T cell therapy.

Impact of Baseline and Week 2 and Week 4 Posttransplant CMV Cell-Mediated Immunity on Risk of CMV Infections and Mortality in Recipients of Allogeneic Hematopoietic Cell Transplant.

Background: Cytomegalovirus (CMV) infection is a common opportunistic infection after allogeneic hematopoietic cell transplant (alloHCT). We explored whether a change in CMV cell-mediated immunity during the first month after transplant predicts the risk of development of CMV infection and all-cause mortality. Methods: This follow-up analysis is based on data from the REACT study, a multicenter prospective observational study of recipients of alloHCT who were CMV-seropositive. Production of interferon γ following ex vivo stimulation with CMV antigens IE1 (immediate early 1) and pp65 (phosphoprotein 65) was assessed by CMV ELISPOT assay at baseline and 2 and 4 weeks after transplant. Clinically significant CMV infection (CS-CMVi) was defined as CMV viremia and/or disease necessitating antiviral therapy. We evaluated the impact of CMV CMI changes on the risk of CS-CMVi and post transplant mortality. Results: The analysis included 226 recipients of alloHCT with CMV cell-mediated immunity data at baseline and 2 and/or 4 weeks after transplant. CS-CMVi occurred in 64 patients (28%). On Cox regression analyses, independent predictors of CS-CMVi included a negative Δ change from baseline to week 2 of pp65 spot counts (hazard ratio, 3.65 [95% CI, 1.65-8.04]; P = .001) to week 4 of IE1 spot counts (hazard ratio, 2.79 [95% CI, 1.46-5.35]; P = .002), anti-thymocyte globulin conditioning regimen, type of transplant, female sex, and corticosteroid use. Kaplan-Meir analysis showed a significant association of a negative IE1 change from baseline to week 4 and increased all-cause mortality after transplant (log rank test = 0.041). Conclusions: A decrease in CMV-specific T-cell responses during the first month after transplant may predict CS-CMVi and is associated with all-cause mortality in recipients of alloHCT.

Coronavirus Disease 2019-Associated Pulmonary Aspergillosis: A Noninvasive Screening Model for Additional Diagnostics.

Background: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is likely underdiagnosed, and current diagnostic tools are either invasive or insensitive. Methods: A retrospective study of mechanically ventilated patients with COVID-19 admitted to 5 Johns Hopkins hospitals between March 2020 and June 2021 was performed. Multivariable logistic regression was used for the CAPA prediction model building. Performance of the model was assessed using the area under the receiver operating characteristic curve (AUC). Results: In the cohort of 832 patients, 98 (11.8%) met criteria for CAPA. Age, time since intubation, dexamethasone for COVID-19 treatment, underlying pulmonary circulatory diseases, human immunodeficiency virus, multiple myeloma, cancer, or hematologic malignancies were statistically significantly associated with CAPA and were included in the CAPA prediction model, which showed an AUC of 0.75 (95% confidence interval, .70-.80). At a screening cutoff of ≥0.085, it had a sensitivity of 82%, a specificity of 51%, a positive predictive value of 18.6%, and a negative predictive value of 95.3%. (The CAPA screening score calculator is available at www.transplantmodels.com). Conclusions: We developed a CAPA risk score as a noninvasive tool to aid in CAPA screening for patients with severe COVID-19. Our score will also identify a group of patients who are unlikely to have CAPA and who therefore need not undergo additional diagnostics and/or empiric antifungal therapy.

Ribavirin treatment for respiratory syncytial virus infection in patients with haematologic malignancy and haematopoietic stem cell transplant recipients: a systematic review and meta-analysis.

BACKGROUND: Ribavirin use for respiratory syncytial virus (RSV) infection in patients with haematologic malignancies (HM) and haematopoietic stem cell transplant (HSCT) recipients remains controversial. OBJECTIVES: To summarize the current evidence of ribavirin treatment in association with mortality and progression to lower respiratory tract infection (LRTI) among patients with HM/HSCT with RSV infection. DATA SOURCES: MEDLINE, Embase, and the Institute for Scientific Information Web of Science. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials and observational studies investigating the effects of ribavirin, compared with treatment without ribavirin, for RSV infection. PARTICIPANTS: Patients with HM/HSCT. INTERVENTIONS: Ribavirin versus no ribavirin. ASSESSMENT OF RISK OF BIAS: The risk of bias in non-randomized studies of exposure (ROBIN-E). METHODS OF DATA SYNTHESIS: The random-effects model was used to calculate the pooled OR (pOR) with 95% CI for the pooled effect estimates of ribavirin benefits. Grading of recommendation assessment, development, and evaluation was used to evaluate the certainty of evidence. RESULTS: One randomized controlled trial and 14 observational studies were included, representing 1125 patients with HM/HSCT. Ribavirin use was not associated with lower all-cause or RSV-associated mortality with pORs [95% CI] of 0.81 [0.40, 1.66], I2 = 55% (low certainty of evidence) and 0.48 [0.11, 2.15], I2 = 64% (very low certainty of evidence), respectively. In subgroup analyses, ribavirin use was associated with lower mortality in patients with HM/HSCT with LRTI with pOR [95% CI] of 0.19 [0.07, 0.51], I2 = 0% (moderate certainty of evidence). In subgroup analyses among studies providing adjusted OR, ribavirin use was associated with lower all-cause mortality with pOR of 0.41 [0.23, 0.74], I2 = 0% (moderate certainty of evidence). In addition, aerosolized ribavirin was associated with lower progression to LRTI with pOR [95% CI] of 0.27 [0.09, 0.80], I2 = 71% (low certainty of evidence). CONCLUSIONS: Ribavirin may be a reasonable option to treat RSV in patients with HM/HSCT in the absence of other effective antiviral agents.

Cowpox to COVID: History of vaccination in the immunocompromised host.

BACKGROUND: The use of vaccination to prevent infection has a long history, starting in the 1700s with Jenner. New innovations have led to improvements in the safety and efficacy of vaccines, from live attenuated viruses to subunit vaccines, to RNA-based vaccination for SARS-CoV-2. Despite this progress, however, solid organ transplant (SOT) recipients on immunosuppression demonstrate an impaired vaccine response compared with healthy controls. This issue is important given the increased vulnerability to infection in immunocompromised patients, especially in the setting of the Coronavirus Disease 2019 (COVID-19) pandemic. METHODS: We reviewed the literature on key topics in vaccination with significant clinical impact on SOT patients. RESULTS: Prior to COVID-19, a large amount of data has been published demonstrating impaired humoral and T-cell responses to multiple vaccinations targeting influenza, hepatitis B, VZV, and Pneumococcus. Poor immunogenicity can be addressed through the use of adjuvants to boost the immune response, even in the setting of senescence related to age or immunosuppression. New vaccines provide hope for preventing infection due to hepatitis C and Cytomegalovirus, and to the emerging infection, monkeypox. The data on the impact of the COVID-19 vaccine in SOT patients is reviewed, with a focus on seroconversion, antibody titer, and antigen-specific T cells. Factors associated with impaired response, including mycophenolate, are described. CONCLUSION: The history of vaccination demonstrates how scientific breakthroughs can be applied to clinical challenges. New approaches using adjuvants, strategic antigen selection, and RNA-based vaccines offer the potential to improve immune response in SOT recipients. Future innovations are needed to better protect the vulnerable immunocompromised host.

Persistent SARS-CoV-2-specific immune defects in kidney transplant recipients following third mRNA vaccine dose.

Kidney transplant recipients (KTRs) show poorer response to SARS-CoV-2 mRNA vaccination, yet response patterns and mechanistic drivers following third doses are ill-defined. We administered third monovalent mRNA vaccines to n = 81 KTRs with negative or low-titer anti-receptor binding domain (RBD) antibody (n = 39 anti-RBDNEG; n = 42 anti-RBDLO), compared with healthy controls (HCs, n = 19), measuring anti-RBD, Omicron neutralization, spike-specific CD8+%, and SARS-CoV-2-reactive T cell receptor (TCR) repertoires. By day 30, 44% anti-RBDNEG remained seronegative; 5% KTRs developed BA.5 neutralization (vs 68% HCs, P < .001). Day 30 spike-specific CD8+% was negative in 91% KTRs (vs 20% HCs; P = .07), without correlation to anti-RBD (rs = 0.17). Day 30 SARS-CoV-2-reactive TCR repertoires were detected in 52% KTRs vs 74% HCs (P = .11). Spike-specific CD4+ TCR expansion was similar between KTRs and HCs, yet KTR CD8+ TCR depth was 7.6-fold lower (P = .001). Global negative response was seen in 7% KTRs, associated with high-dose MMF (P = .037); 44% showed global positive response. Of the KTRs, 16% experienced breakthrough infections, with 2 hospitalizations; prebreakthrough variant neutralization was poor. Absent neutralizing and CD8+ responses in KTRs indicate vulnerability to COVID-19 despite 3-dose mRNA vaccination. Lack of neutralization despite CD4+ expansion suggests B cell dysfunction and/or ineffective T cell help. Development of more effective KTR vaccine strategies is critical. (NCT04969263).

Invasive fungal infections after respiratory viral infections in lung transplant recipients are associated with lung allograft failure and chronic lung allograft dysfunction within 1 year.

BACKGROUND: Respiratory viral infections (RVI) are associated with chronic lung allograft dysfunction (CLAD) and mortality in lung transplant recipients (LTRs). However, the prevalence and impact of secondary invasive fungal infections (IFIs) post RVIs in LTRs have not been investigated. METHODS: We performed a single center retrospective study including LTRs diagnosed with 5 different respiratory viral pathogens between January 2010 to May 2021 and evaluated their clinical outcomes in 1 year. The risk factors of IFIs were evaluated by logistic regression. The impact of IFIs on CLAD stage progression/death was examined by Cox regression. RESULTS: A total of 202 RVI episodes (50 influenza, 31 severe acute respiratory syndrome coronavirus-2, 30 metapneumovirus, 44 parainfluenza, and 47 respiratory syncytial virus) in 132 patients was included for analysis. Thirty-one episodes (15%) were associated with secondary IFIs, and 27 occurred in LTRs with lower respiratory tract infection (LRTI; 28% from 96 LRTI episodes). Aspergillosis was the most common IFI (80%). LTRs with IFIs had higher disease severity during RVI episodes. In multivariable analysis, RVI with LTRI was associated with IFI (adjusted odds ratio [95% confidence interval (CI)] of 7.85 (2.48-24.9). Secondary IFIs were associated with CLAD stage progression/death after accounting for LRTI, pre-existing CLAD, intensive care unit admission, secondary bacterial pneumonia and underlying lung diseases pre-transplant with adjusted hazard ratio (95%CI) of 2.45 (1.29-4.64). CONCLUSIONS: This cohort demonstrated 15% secondary IFI prevalence in LTRs with RVIs. Importantly, secondary IFIs were associated with CLAD stage progression/death, underscoring the importance of screening for fungal infections in this setting.

Neutralizing activity and 3-month durability of tixagevimab and cilgavimab prophylaxis against Omicron sublineages in transplant recipients.

Neutralizing antibody (nAb) responses are attenuated in solid organ transplant recipients (SOTRs) despite severe acute respiratory syndrome-coronavirus-2 vaccination. Preexposure prophylaxis (PrEP) with the antibody combination tixagevimab and cilgavimab (T+C) might augment immunoprotection, yet in vitro activity and durability against Omicron sublineages BA.4/5 in fully vaccinated SOTRs have not been delineated. Vaccinated SOTRs, who received 300 + 300 mg T+C (ie, full dose), within a prospective observational cohort submitted pre and postinjection samples between January 31, 2022, and July 6, 2022. The peak live virus nAb was measured against Omicron sublineages (BA.1, BA.2, BA.2.12.1, and BA.4), and surrogate neutralization (percent inhibition of angiotensin-converting enzyme 2 receptor binding to full length spike, validated vs live virus) was measured out to 3 months against sublineages, including BA.4/5. With live virus testing, the proportion of SOTRs with any nAb increased against BA.2 (47%-100%; P < .01), BA.2.12.1 (27%-80%; P < .01), and BA.4 (27%-93%; P < .01), but not against BA.1 (40%-33%; P = .6). The proportion of SOTRs with surrogate neutralizing inhibition against BA.5, however, fell to 15% by 3 months. Two participants developed mild severe acute respiratory syndrome-coronavirus-2 infection during follow-up. The majority of fully vaccinated SOTRs receiving T+C PrEP achieved BA.4/5 neutralization, yet nAb activity commonly waned by 3 months postinjection. It is critical to assess the optimal dose and interval of T+C PrEP to maximize protection in a changing variant climate.

Guidance on the Use of Convalescent Plasma to Treat Immunocompromised Patients With Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) is a safe and effective treatment for COVID-19 in immunocompromised (IC) patients. IC patients have a higher risk of persistent infection, severe disease, and death from COVID-19. Despite the continued clinical use of CCP to treat IC patients, the optimal dose, frequency/schedule, and duration of CCP treatment has yet to be determined, and related best practices guidelines are lacking. A group of individuals with expertise spanning infectious diseases, virology and transfusion medicine was assembled to render an expert opinion statement pertaining to the use of CCP for IC patients. For optimal effect, CCP should be recently and locally collected to match circulating variant. CCP should be considered for the treatment of IC patients with acute and protracted COVID-19; dosage depends on clinical setting (acute vs protracted COVID-19). CCP containing high-titer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies, retains activity against circulating SARS-CoV-2 variants, which have otherwise rendered monoclonal antibodies ineffective.