Current and Emerging Therapies for COVID-19 in Lung Transplantation.

Purpose of Review: The landscape of the coronavirus disease 2019 (COVID-19) pandemic has rapidly changed over the past 3 years. Paralleling this evolution, the scientific and medical communities have reported many novel findings relating to the infection's epidemiology, transmission, diagnosis, and treatment. We review pertinent studies of COVID-19 therapeutics with an emphasis on their application to lung transplant recipients. Recent Findings: Agents that have been well-studied for treating COVID-19 include antivirals (remdesivir, nirmatrelvir/ritonavir, molnupiravir), monoclonal antibodies, and immunomodulators (for example, corticosteroids and tocilizumab). Summary: Remdesivir remains an essential therapy for managing mild-moderate COVID-19. Though highly efficacious for mild-moderate COVID-19 for outpatient therapy, ritonavir-boosted nirmatrelvir has limited use in lung transplant recipients due to significant drug-drug interactions. Monoclonal antibodies, though useful, are the most affected by the emergence of new viral variants.

Possible Predictors of Coinfection in COVID-19: Making a Difficult Diagnosis

Background Coinfection with COVID-19 and a secondary pathogen contributes to morbidity and mortality. Despite its contribution to outcomes, diagnosing coinfection is challenging and no predictive tools have been established. To better assess risk factors for coinfection, we performed a review of all patients hospitalized for COVID-19 in our institution and evaluated them for candidate predictors of coinfection. Methods Medical records were reviewed in all patients admitted with COVID-19 at University of Chicago Medical Center between March 1, 2020 and April 18, 2020. Those identified as having coinfection were compared to those without coinfection. Secondary review was performed for characteristics of the coinfection, including diagnosis, microbiology, drug resistance, and nosocomial acquisition. Results 401 patients were included in the study, the mean age was 60 years (SD-17), 29% had severe disease, and 13% died. At least one test for coinfection was performed in 99% of patients. Coinfection was identified in 15% (72/401) of patients. Coinfection was associated with older age, disease severity, and hospital complications, such as DVT/PE, AKI, and delirium. [Table 1] No symptom, non-microbiologic test, radiograph, or preexisting condition was associated with coinfection. Dyspnea, chest pain, and obesity were more common in those without coinfection. 74% received antibiotics. The most common sites for coinfection were urinary 33%, lower respiratory 26%, and blood 24%. [Table2] Bacteria were most frequently recovered (82%). The most commonly recovered pathogens were Enterobacterales (42%), Staphylococcus aureus (12%), and Pseudomonas (4%). 42% of the infections were hospital acquired, 16% caused by MDRO, and 13% were catheter or ventilator associated. Table 1. Clinical Characteristics Associated with Coinfection Abbreviations: sd, standard deviation;WBC, white blood cell count;CRP, C-reactive protein;COPD, chronic obstructive pulmonary disease;ARDS, acute respiratory distress syndrome;DVT, deep venous thrombosis;PE, pulmonary embolism;MI, myocardial infarction;AKI, acute kidney injury Table 2. Characteristics of Coinfection Abbreviations: Cath, catheter;Vent, ventilator;Assoc, Associated;MDRO, Multiple Drug Resistant Organism Conclusion Coinfection in COVID-19 was most closely associated with age, COVID-19 disease severity, and complicated hospitalization. No presenting symptoms, non-microbiologic test, or radiograph was associated with coinfection, underscoring the challenge in diagnosing coinfection. A remarkable number of infections were hospital acquired, MDRO, and catheter/ventilator associated. Further prospective study on coinfection in COVID-19 is needed to guide diagnosis and treatment. Disclosures Renslow Sherer, MD, Gilead Sciences, Inc (Grant/Research Support)

Reducing the use of empiric antibiotic therapy in COVID-19 on hospital admission.

BACKGROUND: Empiric antibiotics for community acquired bacterial pneumonia (CABP) are often prescribed to patients with COVID-19, despite a low reported incidence of co-infections. Stewardship interventions targeted at facilitating appropriate antibiotic prescribing for CABP among COVID-19 patients are needed. We developed a guideline for antibiotic initiation and discontinuation for CABP in COVID-19 patients. The purpose of this study was to assess the impact of this intervention on the duration of empiric CABP antibiotic therapy among patients with COVID-19. METHODS: This was a single-center, retrospective, quasi-experimental study of adult patients admitted between 3/1/2020 to 4/25/2020 with COVID-19 pneumonia, who were initiated on empiric CABP antibiotics. Patients were excluded if they were initiated on antibiotics > 48 h following admission or if another source of infection was identified. The primary outcome was the duration of antibiotic therapy (DOT) prior to the guideline (March 1 to March27, 2020) and after guideline implementation (March 28 to April 25, 2020). We also evaluated the clinical outcomes (mortality, readmissions, length of stay) among those initiated on empiric CABP antibiotics. RESULTS: A total of 506 patients with COVID-19 were evaluated, 102 pre-intervention and 404 post-intervention. Prior to the intervention, 74.5% (n = 76) of patients with COVID-19 received empiric antibiotics compared to only 42% of patients post-intervention (n = 170), p < 0.001. The median DOT in the post-intervention group was 1.3 days shorter (p < 0.001) than the pre-intervention group, and antibiotics directed at atypical bacteria DOT was reduced by 2.8 days (p < 0.001). More patients in the post-intervention group were initiated on antibiotics based on criteria consistent with our guideline (68% versus 87%, p = 0.001). There were no differences between groups in terms of clinical outcomes. CONCLUSION: Following the implementation of a guideline outlining recommendations for initiating and discontinuing antibiotics for CABP among COVID-19 inpatients, we observed a reduction in antibiotic prescribing and DOT. The guideline also resulted in a significant increase in the rate of guideline-congruent empiric antibiotic initiation.

Community-acquired Coinfection in Coronavirus Disease 2019: A Retrospective Observational Experience.

Community-acquired coinfection in coronavirus disease 2019 (COVID-19) is not well defined. Current literature describes coinfection in 0-40% of COVID-19 patients. In this retrospective report, coinfection was identified in 3.7% of patients and 41% of patients admitted to intensive care (P < .005). Despite infrequent coinfection, antibiotics were used in 69% of patients.

Late onset infectious complications and safety of tocilizumab in the management of COVID-19.

BACKGROUND: Tocilizumab (TCZ) has been used in the management of COVID-19-related cytokine release syndrome (CRS). Concerns exist regarding the risk of infections and drug-related toxicities. We sought to evaluate the incidence of these TCZ complications among COVID-19 patients. METHODS: All adult inpatients with COVID-19 between 1 March and 25 April 2020 that received TCZ were included. We compared the rate of late-onset infections (>48 hours following admission) to a control group matched according to intensive care unit admission and mechanical ventilation requirement. Post-TCZ toxicities evaluated included: elevated liver function tests (LFTs), GI perforation, diverticulitis, neutropenia, hypertension, allergic reactions, and infusion-related reactions. RESULTS: Seventy-four patients were included in each group. Seventeen infections in the TCZ group (23%) and 6 (8%) infections in the control group occurred >48 hours after admission (P = .013). Most infections were bacterial with pneumonia being the most common manifestation. Among patients receiving TCZ, LFT elevations were observed in 51%, neutropenia in 1.4%, and hypertension in 8%. The mortality rate among those that received TCZ was greater than the control (39% versus 23%, P = .03). CONCLUSION: Late onset infections were significantly more common among those receiving TCZ. Combining infections and TCZ-related toxicities, 61% of patients had a possible post-TCZ complication. While awaiting clinical trial results to establish the efficacy of TCZ for COVID-19 related CRS, the potential for infections and TCZ related toxicities should be carefully weighed when considering use.

Remdesivir Use in the Setting of Severe Renal Impairment: A Theoretical Concern or Real Risk?

BACKGROUND: Remdesivir (RDV) is US FDA approved for coronavirus disease 2019 (COVID-19) but not recommended in severe renal impairment (SRI, Creatinine clearance <30mL/min or requiring renal replacement therapy). Few studies have evaluated RDV in patients with SRI. METHODS: Hospitalized patients who received RDV between 1 May 2020 and 31 October 2020 were analyzed in a retrospective chart review. We compared incident adverse events (AEs) in patients with and without SRI, including hepatotoxicity, nephrotoxicity, any reported AE, mortality, and length of stay. RESULTS: Of a total of 135 patients, 20 had SRI. Patients with SRI were significantly older (70 vs 54 years, P = .0001). The incidence of possible AEs was 30% among those with SRI vs 11% without (P = .06). Liver function test (LFT) elevations occurred in 10% vs 4% (P = .28), and serum creatinine (SCr) elevations in 27% vs 6% (P = .02) of patients with SRI vs without, respectively. LFT and SCr elevations were not attributed to RDV in either group. Mortality and length of stay were consistent with historical controls. CONCLUSIONS: RDV AEs occurred infrequently and overall were not significantly different between those with and without SRI. While more of patients with SRI experienced SCr elevations, 3 (75%) patients had acute kidney injury prior to RDV. The use of RDV in this small series of patients with SRI appeared to be relatively safe, and the potential benefit outweighed the theoretical risk of liver or renal toxicity. Additional studies are needed to confirm this finding.

COVIDOSE: A Phase II Clinical Trial of Low-Dose Tocilizumab in the Treatment of Noncritical COVID-19 Pneumonia.

Interleukin-6 (IL-6)-mediated hyperinflammation may contribute to the mortality of coronavirus disease 2019 (COVID-19). The IL-6 receptor-blocking monoclonal antibody tocilizumab has been repurposed for COVID-19, but prospective trials and dose-finding studies in COVID-19 have not yet fully reported. We conducted a single-arm phase II trial of low-dose tocilizumab in nonintubated hospitalized adult patients with COVID-19, radiographic pulmonary infiltrate, fever, and C-reactive protein (CRP) ≥ 40 mg/L. We hypothesized that doses significantly lower than the emerging standards of 400 mg or 8 mg/kg would resolve clinical and laboratory indicators of hyperinflammation. A dose range from 40 to 200 mg was evaluated, with allowance for one repeat dose at 24 to 48 hours. The primary objective was to assess the relationship of dose to fever resolution and CRP response. Thirty-two patients received low-dose tocilizumab, with the majority experiencing fever resolution (75%) and CRP decline consistent with IL-6 pathway abrogation (86%) in the 24-48 hours following drug administration. There was no evidence of a relationship between dose and fever resolution or CRP decline over the dose range of 40-200 mg. Within the 28-day follow-up, 5 (16%) patients died. For patients who recovered, median time to clinical recovery was 3 days (interquartile range, 2-5). Clinically presumed and/or cultured bacterial superinfections were reported in 5 (16%) patients. Low-dose tocilizumab was associated with rapid improvement in clinical and laboratory measures of hyperinflammation in hospitalized patients with COVID-19. Results of this trial provide rationale for a randomized, controlled trial of low-dose tocilizumab in COVID-19.

IL-6 Inhibition in Critically Ill COVID-19 Patients Is Associated With Increased Secondary Infections.

Background: Anti-inflammatory therapies such as IL-6 inhibition have been proposed for COVID-19 in a vacuum of evidence-based treatment. However, abrogating the inflammatory response in infectious diseases may impair a desired host response and pre-dispose to secondary infections. Methods: We retrospectively reviewed the medical record of critically ill COVID-19 patients during an 8-week span and compared the prevalence of secondary infection and outcomes in patients who did and did not receive tocilizumab. Additionally, we included representative histopathologic post-mortem findings from several COVID-19 cases that underwent autopsy at our institution. Results: One hundred eleven patients were identified, of which 54 had received tocilizumab while 57 had not. Receiving tocilizumab was associated with a higher risk of secondary bacterial (48.1 vs. 28.1%; p = 0.029 and fungal (5.6 vs. 0%; p = 0.112) infections. Consistent with higher number of infections, patients who received tocilizumab had higher mortality (35.2 vs. 19.3%; p = 0.020). Seven cases underwent autopsy. In three cases who received tocilizumab, there was evidence of pneumonia on pathology. Of the four cases that had not been given tocilizumab, two showed evidence of aspiration pneumonia and two exhibited diffuse alveolar damage. Conclusions: Experimental therapies are currently being applied to COVID-19 outside of clinical trials. Anti-inflammatory therapies such as anti-IL-6 therapy have the potential to impair viral clearance, pre-dispose to secondary infection, and cause harm. We seek to raise physician awareness of these issues and highlight the need to better understand the immune response in COVID-19.

Automatic ID Consultation for Inpatients With COVID-19: Point, Counterpoint, and a Single-Center Experience.

There are many unknowns with regard to COVID-19 clinical management, including the role of Infectious Diseases Consultation (IDC). As hospitalizations for COVID-19 continue, hospitals are assessing how to optimally and efficiently manage COVID-19 inpatients. Typically, primary teams must determine when IDC is appropriate, and ID clinicians provide consultation upon request of the primary team. IDC has been shown to be beneficial for many conditions; however, the impact of IDC for COVID-19 is unknown. Herein, we discuss the potential benefits and pitfalls of automatic IDC for COVID-19 inpatients. Important considerations include the quality of care provided, allocation and optimization of resources, and clinician satisfaction. Finally, we describe how automatic IDC changed throughout the COVID-19 pandemic at a single academic medical center.

Obesity is Associated with Increased Risk for Mortality Among Hospitalized Patients with COVID-19.

OBJECTIVE: Obesity has been identified as a risk factor for severe coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 virus. This study sought to determine whether obesity is a risk factor for mortality among patients with COVID-19. METHODS: The study was a retrospective cohort that included patients with COVID-19 between March 1 and April 18, 2020. RESULTS: A total of 238 patients were included; 218 patients (91.6%) were African American, 113 (47.5%) were male, and the mean age was 58.5 years. Of the included patients, 146 (61.3%) had obesity (BMI > 30 kg/m2 ), of which 63 (26.5%), 29 (12.2%), and 54 (22.7%) had class 1, 2, and 3 obesity, respectively. Obesity was identified as a predictor for mortality (odds ratio [OR] 1.7 [1.1-2.8], P = 0.016), as was male gender (OR 5.2 [1.6-16.5], P = 0.01) and older age (OR 3.6 [2.0-6.3], P < 0.0005). Obesity (OR 1.7 [1.3-2.1], P < 0.0005) and older age (OR 1.3 [1.0-1.6], P = 0.03) were also risk factors for hypoxemia. CONCLUSIONS: Obesity was found to be a significant predictor for mortality among inpatients with COVID-19 after adjusting for age, gender, and other comorbidities. Patients with obesity were also more likely to present with hypoxemia.

A Case Series of Five People Living with HIV Hospitalized with COVID-19 in Chicago, Illinois.

The risk of COVID-19 among people living with HIV (PLWH) is largely unknown and there have been very few reported cases in the literature. We report a case series of five PLWH with COVID-19. We identified all patients with a diagnosis of HIV who tested positive for SARS-CoV-2 at University of Chicago Medicine between March 1, 2020, and April 7, 2020. We retrospectively collected data regarding demographics, comorbidities, medications, laboratory test results, radiology results, and outcomes associated with COVID-19. All five PLWH with COVID-19 were African American; 80% (4/5) were cisgender females. The mean age of patients was 48 years old (range 38-53). The majority of patients presented with cough, fever, and shortness of breath. Three patients had diarrhea. One patient presented with predominantly cardiac symptoms. All were taking antiretroviral therapy (ART) with CD4 count >200 cells/mm3 and suppressed HIV viral loads at the time of COVID-19 diagnosis. All five patients were hospitalized, two required supplemental oxygen, and none required mechanical ventilation. Four patients were treated with azithromycin and a cephalosporin and two were also treated with hydroxychloroquine. The median length of stay was 3 days (range 2-7). All patients recovered. More research is needed to understand the risks of COVID-19 among PLWH and the impact of ART on outcomes for patients with COVID-19.