Convalescent Plasma for Immunocompromised Patients.

COVID-19 convalescent plasma (CCP) is an important therapeutic option for immunocompromised patients with COVID-19. Such patients are at increased risk for serious complications of infection and may also develop a unique syndrome of persistent infection. This article reviews the rationale for CCP utilization in immunocompromised patients and the evidence for its value in immunosuppressed patients with both acute and persistent COVID-19. Both historical precedence and understanding of the mechanisms of action of antibody treatment support this use, as do several lines of evidence derived from case series, comparative studies, randomized trials, and systematic reviews of the literature. A summary of recommendations from multiple practice guidelines is also provided.

Single monoclonal antibodies should not be used for COVID-19 therapy: a call for antiviral stewardship.

The COVID-19 pandemic saw the largest deployment of monoclonal antibodies (mAbs) for an infectious disease in history. mAbs to SARS-CoV-2 spike protein proved safe and were initially effective for COVID-19 therapy, but each was defeated by continued SARS-CoV-2 evolution, leading to their withdrawal. This was a setback for people with impaired immunity who cannot mount an effective antibody response to SARS-CoV-2 and often cannot clear the virus. New mAbs have now been developed for pre-exposure prophylaxis (PreEP) in immunosuppressed people. Here we argue that while mAb use for PreEP is justified, single mAbs should not be used for COVID-19 therapy. In contrast to PreEP where the viral inoculum is small, immunosuppressed people with COVID-19 have large viral burden that can harbor mAb-escape variants that single-agent mAb treatments can rapidly select for resistance. Selection of mAb-escape variants has potential risks for patients, society and the feasibility of mAb therapy itself.

Minimizing risk while maximizing opportunity: The infectious disease organ offer process survey.

BACKGROUND: The purpose of this study was to understand how transplant infectious disease (TID) physicians assess a potential donor with known or suspected infection and describe posttransplant management. METHODS: We designed a survey of 10 organ offer scenarios and asked questions pertaining to organ acceptability for transplantation and management posttransplant. The survey was distributed to TID clinicians via transplant society listservs and email. Responses were recorded in REDCap, and descriptive statistics were employed. RESULTS: One hundred thirteen infectious disease physicians responded to the survey, of whom 85 completed all cases. Respondents were generally in agreement regarding organ acceptability, although some divergence was seen when evaluating lungs from donors with influenza, tuberculosis, or multidrug-resistant Acinetobacter infection. Posttransplant management showed more variation. Areas of optimization were identified: (1) Further understanding of where risk-mitigation strategies within the donor offer process may improve donor acceptability and therefore organ utilization; (2) importance of recipient considerations in assessing degree of infectious risk; and (3) gaps in evidenced-based data regarding optimal posttransplant management of recipients. CONCLUSION: Evaluation of donor offers by TID clinicians is a complex process. Although the survey does not itself serve to make recommendations regarding best practices, it highlights areas where generation of data to inform acceptance and management practices may allow for improved organ utilization and recipient management.

Convalescent plasma and predictors of mortality among hospitalized patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Plasma collected from recovered patients with COVID-19 (COVID-19 convalescent plasma [CCP]) was the first antibody-based therapy employed to fight the COVID-19 pandemic. While the therapeutic effect of early administration of CCP in COVID-19 outpatients has been recognized, conflicting data exist regarding the efficacy of CCP administration in hospitalized patients. OBJECTIVES: To examine the effect of CCP compared to placebo or standard treatment, and to evaluate whether time from onset of symptoms to treatment initiation influenced the effect. DATA SOURCES: Electronic databases were searched for studies published from January 2020 to January 2024. STUDY ELIGIBILITY CRITERIA: Randomized clinical trials (RCTs) investigating the effect of CCP on COVID-19 mortality in hospitalized patients with COVID-19. PARTICIPANTS: Hospitalized patients with COVID-19. INTERVENTIONS: CCP versus no CCP. ASSESSMENT OF RISK OF BIAS: Cochrane risk of bias tool for RCTs. METHODS OF DATA SYNTHESIS: The random-effects model was used to calculate the pooled risk ratio (RR) with 95% CI for the pooled effect estimates of CCP treatment. The Grading of Recommendations Assessment, Development and Evaluation was used to evaluate the certainty of evidence. RESULTS: Twenty-seven RCTs were included, representing 18,877 hospitalized patients with COVID-19. When transfused within 7 days from symptom onset, CCP significantly reduced the risk of death compared to standard therapy or placebo (RR, 0.76; 95% CI, 0.61-0.95), while later CCP administration was not associated with a mortality benefit (RR, 0.98; 95% CI, 0.90-1.06). The certainty of the evidence was graded as moderate. Meta-regression analysis demonstrated increasing mortality effects for longer interval to transfusion or worse initial clinical severity. CONCLUSIONS: In-hospital transfusion of CCP within 7 days from symptom onset conferred a mortality benefit.

COVID-19 therapeutics.

SUMMARYSince the emergence of COVID-19 in 2020, an unprecedented range of therapeutic options has been studied and deployed. Healthcare providers have multiple treatment approaches to choose from, but efficacy of those approaches often remains controversial or compromised by viral evolution. Uncertainties still persist regarding the best therapies for high-risk patients, and the drug pipeline is suffering fatigue and shortage of funding. In this article, we review the antiviral activity, mechanism of action, pharmacokinetics, and safety of COVID-19 antiviral therapies. Additionally, we summarize the evidence from randomized controlled trials on efficacy and safety of the various COVID-19 antivirals and discuss unmet needs which should be addressed.

Applying lessons of COVID-19 and other emerging infectious diseases to future outbreaks.

Infectious diseases are emerging and re-emerging far more frequently than many appreciate. In the past two decades alone, there have been numerous outbreaks (e.g., Ebola, chikungunya, Zika, and Mpox) and pandemics (i.e., swine flu and coronavirus disease 2019) with profound effects to public health, the economy, and society at large. Rather than view these in isolation, there are important lessons pertaining to how best to contend with future outbreaks of emerging infectious diseases. Those lessons span definition (i.e., what constitutes a pandemic), through deficiencies in surveillance, data collection and reporting, the execution of research in a rapidly changing environment, the nuances of study design and hierarchy of clinical evidence, triage according to clinical need as supply chains become overwhelmed, and the challenges surrounding forecasting of outbreaks. Understanding those lessons and drawing on both the successes and failures of the past are imperative if we are to overcome the challenges of outbreak/pandemic responsiveness.

Safety and Efficacy of Convalescent Plasma Combined with Other Pharmaceutical Agents for Treatment of COVID-19 in Hospitalized Patients: A Systematic Review and Meta-Analysis.

Plasma collected from people recovered from COVID-19 (COVID-19 convalescent plasma, CCP) was the first antibody-based therapy employed to fight the pandemic. CCP was, however, often employed in combination with other drugs, such as the antiviral remdesivir and glucocorticoids. The possible effect of such interaction has never been investigated systematically. To assess the safety and efficacy of CCP combined with other agents for treatment of patients hospitalized for COVID-19, a systematic literature search using appropriate Medical Subject Heading (MeSH) terms was performed through PubMed, EMBASE, Cochrane central, medRxiv and bioRxiv. The main outcomes considered were mortality and safety of CCP combined with other treatments versus CCP alone. This review was carried out in accordance with Cochrane methodology including risk of bias assessment and grading of the quality of evidence. Measure of treatment effect was the risk ratio (RR) together with 95% confidence intervals (CIs). A total of 11 studies (8 randomized controlled trials [RCTs] and 3 observational) were included in the systematic review, 4 studies with CCP combined with remdesivir and 6 studies with CCP combined with corticosteroids, all involving hospitalized patients. One RCT reported information on both remdesivir and steroids use with CCP. The use of CCP combined with remdesivir was associated with a significantly reduced risk of death (RR 0.74; 95% CI 0.56-0.97; p = 0.03; moderate certainty of evidence), while the use of steroids with CCP did not modify the mortality risk (RR 0.72; 95% CI 0.34-1.51; p = 0.38; very low certainty of evidence). Not enough safety data were retrieved form the systematic literature analysis. The current evidence from the literature suggests a potential beneficial effect on mortality of combined CCP plus remdesivir compared to CCP alone in hospitalized COVID-19 patients. No significant clinical interaction was found between CCP and steroids.

COVID-19 convalescent plasma therapy decreases inflammatory cytokines: a randomized controlled trial.

IMPORTANCE: This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

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.

Rates Among Hospitalized Patients With COVID-19 Treated With Convalescent Plasma: A Systematic Review and Meta-Analysis.

Objective: To examine the association of COVID-19 convalescent plasma transfusion with mortality and the differences between subgroups in hospitalized patients with COVID-19. Patients and Methods: On October 26, 2022, a systematic search was performed for clinical studies of COVID-19 convalescent plasma in the literature from January 1, 2020, to October 26, 2022. Randomized clinical trials and matched cohort studies investigating COVID-19 convalescent plasma transfusion compared with standard of care treatment or placebo among hospitalized patients with confirmed COVID-19 were included. The electronic search yielded 3841 unique records, of which 744 were considered for full-text screening. The selection process was performed independently by a panel of 5 reviewers. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data were extracted by 5 independent reviewers in duplicate and pooled using an inverse-variance random effects model. The prespecified end point was all-cause mortality during hospitalization. Results: Thirty-nine randomized clinical trials enrolling 21,529 participants and 70 matched cohort studies enrolling 50,160 participants were included in the systematic review. Separate meta-analyses reported that transfusion of COVID-19 convalescent plasma was associated with a decrease in mortality compared with the control cohort for both randomized clinical trials (odds ratio [OR], 0.87; 95% CI, 0.76-1.00) and matched cohort studies (OR, 0.76; 95% CI, 0.66-0.88). The meta-analysis of subgroups revealed 2 important findings. First, treatment with convalescent plasma containing high antibody levels was associated with a decrease in mortality compared with convalescent plasma containing low antibody levels (OR, 0.85; 95% CI, 0.73 to 0.99). Second, earlier treatment with COVID-19 convalescent plasma was associated with a decrease in mortality compared with the later treatment cohort (OR, 0.63; 95% CI, 0.48 to 0.82). Conclusion: During COVID-19 convalescent plasma use was associated with a 13% reduced risk of mortality, implying a mortality benefit for hospitalized patients with COVID-19, particularly those treated with convalescent plasma containing high antibody levels treated earlier in the disease course.

Early antibody treatment, inflammation, and risk of post-COVID conditions.

IMPORTANCE: Approximately 20% of individuals infected with SARS-CoV-2 experienced long-term health effects, as defined PCC. However, it is unknown if there are any early biomarkers associated with PCC or whether early intervention treatments may decrease the risk of PCC. In a secondary analysis of a randomized clinical trial, this study demonstrates that among outpatients with SARS-CoV-2, increased IL-6 at time of infection is associated with increased odds of PCC. In addition, among individuals treated early, within 5 days of symptom onset, with COVID-19 convalescent plasma, there was a trend for decreased odds of PCC after adjusting for other demographic and clinical characteristics. Future treatment studies should be considered to evaluate the effect of early treatment and anti-IL-6 therapies on PCC development.

Dynamics of inflammatory responses after SARS-CoV-2 infection by vaccination status in the USA: a prospective cohort study.

BACKGROUND: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection. METHODS: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta). FINDINGS: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log10 cytokine and chemokine concentrations decreased faster among participants in the unvaccinated group than in other groups, but their geometric mean concentrations were generally higher than fully vaccinated participants at 90 days. Days since full vaccination and type of vaccine received were not correlated with cytokine and chemokine concentrations. INTERPRETATION: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals. FUNDING: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation.

Convalescent plasma therapy in COVID-19: Unravelling the data using the principles of antibody therapy.

INTRODUCTION: When the COVID-19 pandemic struck no specific therapies were available and many turned to COVID-19 convalescent plasma (CCP), a form of antibody therapy. The literature provides mixed evidence for CCP efficacy. AREAS COVERED: PubMed was searched using the words COVID-19 and convalescent plasma and individual study designs were evaluated for adherence to the three principles of antibody therapy, i.e. that plasma 1) contain specific antibody; 2) have enough specific antibody to mediate a biological effect; and 3) be administered early in the course of disease. Using this approach, a diverse and seemingly contradictory collection of clinical findings was distilled into a consistent picture whereby CCP was effective when used according to the above principles of antibody therapy. In addition, CCP therapy in immunocompromised patients is useful at any time in the course of disease. EXPERT OPINION: CCP is safe and effective when used appropriately. Today, most of humanity has some immunity to SARS-CoV-2 from vaccines and infection, which has lessened the need for CCP in the general population. However, COVID-19 in immunocompromised patients is a major therapeutic challenge, and with the deauthorization of all SARS-CoV-2-spike protein-directed monoclonal antibodies, CCP is the only antibody therapy available for this population.

Vaccines and therapeutics for immunocompromised patients with COVID-19.

The COVID-19 pandemic has disproportionately impacted immunocompromised patients. This diverse group is at increased risk for impaired vaccine responses, progression to severe disease, prolonged hospitalizations and deaths. At particular risk are people with deficiencies in lymphocyte number or function such as transplant recipients and those with hematologic malignancies. Such patients' immune responses to vaccination and infection are frequently impaired leaving them more vulnerable to prolonged high viral loads and severe complications of COVID-19. Those in turn, have implications for disease progression and persistence, development of immune escape variants and transmission of infection. Data to guide vaccination and treatment approaches in immunocompromised people are generally lacking and extrapolated from other populations. The large clinical trials leading to authorisation and approval of SARS-CoV-2 vaccines and therapeutics included very few immunocompromised participants. While experience is accumulating, studies focused on the special circumstances of immunocompromised patients are needed to inform prevention and treatment approaches.

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.

Coronavirus Disease 2019 Convalescent Plasma Utilization in the United States: Data From the National Inpatient Sample.

Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) use between October and December 2020 was characterized using the National Inpatient Sample database. CCP was administered in 18.0% of COVID-19-associated hospitalizations and was strongly associated with older age and increased disease severity. There were disparities in the receipt of CCP by race and ethnicity, geography, and insurance.

Early Treatment, Inflammation and Post-COVID Conditions.

Background: Post-COVID conditions (PCC) are common and have significant morbidity. Risk factors for PCC include advancing age, female sex, obesity, and diabetes mellitus. Little is known about early treatment, inflammation, and PCC. Methods: Among 883 individuals with confirmed SARS-CoV-2 infection participating in a randomized trial of CCP vs. control plasma with available biospecimens and symptom data, the association between early COVID treatment, cytokine levels and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14 and day 90 using a multiplexed sandwich immuosassay (Mesoscale Discovery). Presence of any self-reported PCC symptoms was assessed at day 90. Associations between COVID treatment, cytokine levels and PCC were examined using multivariate logistic regression models. Results: One-third of the 882 participants had day 90 PCC symptoms, with fatigue (14.5%) and loss of smell (14.5%) being most common. Cytokine levels decreased from baseline to day 90. In a multivariable analysis including diabetes, body mass index, race, and vaccine status, female sex (adjusted odds ratio[AOR]=2.70[1.93-3.81]), older age (AOR=1.32[1.17-1.50]), and elevated baseline levels of IL-6 (AOR=1.59[1.02-2.47]) were associated with development of PCC.There was a trend for decreased PCC in those with early CCP treatment (≤5 days after symptom onset) compared to late CCP treatment. Conclusion: Increased IL-6 levels were associated with the development of PCC and there was a trend for decreased PCC with early CCP treatment in this predominately unvaccinated population. Future treatment studies should evaluate the effect of early treatment and anti-IL-6 therapies on PCC development.