RNA respiratory viruses

RNA respiratory viruses, including influenza virus, respiratory syncytial virus (RSV), parainfluenza virus (PIV), human metapneumovirus (hMPV), human rhinovirus (HRV), and coronavirus (CoV), are increasingly being recognized as causing significant morbidity, graft failure, and death among immunocompromised patient populations. Respiratory viral infections are associated with increased risk of death, development of viral pneumonia, and coinfections, particularly bacterial pneumonia and invasive aspergillosis. Respiratory viral infections are associated with both acute and chronic rejection. Antiviral resistance is an emerging issue among immunocompromised patients infected with influenza virus, although resistance testing is not yet widely available outside the research setting. Unlike the case for RSV and influenza virus, no rapid antigen test kits are available for detection of PIV. There are several monoclonal antibody (MAb) systems that allow for identification and differentiation of the different PIV serotypes in primary patient samples and in cell cultures. There are currently five clinically significant human coronaviruses recognized, namely, OC43, 229E, NL63, HKU1, and severe acute respiratory syndrome CoV (SARS-CoV). © 2009 ASM Press, Washington, DC. All rights reserved.

An Outbreak Investigation of Pulmonary Infections Caused by Mycobacterium abscessus in a Cardiothoracic Transplant Population

Background. Nontuberculous mycobacteria (NTM) are environmental organisms that can form biofilms in municipal water systems and as such are difficult to eliminate. Mycobacterium abscessus is a rapid-growing NTMthat can cause skin and soft tissue, disseminated, and pulmonary infections. M. abscessus is difficult to treat, often requiring prolonged therapy with several antibiotics due to its intrinsic drug resistance. In 2021, our institution identified a significant increase in pulmonary infections caused by M. abscessus in the cardiothoracic transplant population. Methods. All M. abscessus cases among inpatients at our institution were extracted from the electronic medical record (EMR) between January 2019 and September 2021. Clinical characteristics were determined through EMR review and included demographics, transplant status, specimen type, COVID-19 history, and patient care practices involving water. A multidisciplinary team conducted an investigation to identify possible variations in practice related to the source of water used for clinical care activities in this identified population. Results. Between January 2021 and September 2021, there were 12 cases of M. abscessus among inpatients at our institution compared to 6 cases in 2019 and 5 in 2020 (Figure 1). Between 2019 and 2020, post-heart and pre-/post-lung transplant patients comprised 9% of cases, 55% of cases were pulmonary infections, and none had a history of COVID-19 infection. In 2021, post-heart and pre-/post-lung transplant patients comprised 58% of cases, 83% of cases were pulmonary infections, and 33% of cases had a history of COVID-19 infection. There were varying sources of water utilized for the clinical care activities in this identified population (Table 1). Conclusion. To investigate the potential outbreak, we are actively collecting water samples and swabs from water fixtures in both patient and nourishment rooms for water culturing. To mitigate a potential water-borne source, we will use sterile water for all clinical care practices involving water and for all patient water drinking needs in the post-heart and pre-/post-lung transplant population impacted by the outbreak. The only use of tap water is hand hygiene and patient bathing.

Lung Transplantation for COVID-19-Associated Lung Injury (CALI): An International Registry

Background. SARS-CoV-2 can result in a range of infections from asymptomatic disease to progressive COVID-19 and death. In some pts with CALI, lung transplantation (LTx) may be lifesaving. Up to 10% of LTx in the US is currently for pts with CALI. Understanding the characteristics and outcomes of these pts is critical. Methods. A open-access electronic registry was established to collect deidentified data from pts who have undergone LTx for CALI from centers globally. The study was IRB approved at Northwestern with a wavier for consent (no PHI is collected sites could submit data about pre-Tx, peri-Tx and post-Tx course). Follow-up for 1-yr post-LTx was collected. Results. To date, 89 pts with complete day 30 post-LTx data have been entered into the registry. Pt demographics and pre-Tx status are shown in Table 1. 3 pts required oxygen prior to COVID-19. Most sites required neg PCR tests prior to listing (11 (12.4%) required no - PCRs, 11 (12.4%) required 1 and 61 (68.5%) required 2). LTx occurred 137 days post-infection and none developed COVID-19 in the first 30 d;4 were given monoclonal antibodies post-tx. Post-tx ICU LOS averaged 24.5 d with total post-tx hospitalization of 37.6 d (See Table 2). Most experienced infectious and noninfectious morbidity. Most (47.8%) required an additional 30 days of rehab. 2 pts died within 30 days due to sepsis and anoxia. 5 died between day 30 and 90 and an additional 12 died between day 90 and 365. Conclusion. The contribution of cases to this international registry is ongoing. While outcomes of LTx for CALI are generally good, patients experience prolonged post-transplant hospitalization, rehabilitation and significant morbidity and infections are common. (Table Presented).

Infectious Complications of Lung Transplant for COVID-Associated Lung Injury (CALI)

Background. More than 200 orthotopic lung transplants (OLT) have been performed in the United States for patients (pts) with severe CALI. While some outcomes have been reported to generally be good, we conducted this study to describe the infectious outcomes. Methods. After IRB approval, a retrospective case review was conducted of pts at Northwestern Memorial Hospital who had undergone OLT for CALI between June 1, 2020 and January 31, 2022. Data was collected from our Enterprise Data Warehouse and primary chart review to describe pts demographics and epidemiology of infectious complications. Results. 35 OLTs were included (33 bilateral, 2 single lung;see Table 1). In the two weeks prior to transplant, 65.7% of pts were treated for bacterial, fungal, or mycobacterial infections (Table 2). Post-transplant, 32 (91.4%) of OLTs developed infections (Table 2), with most (28, 80%) developing pneumonia within 30 days of transplant. Five (14.3%) pts had airway complications, 7 (20%) pts required hemodialysis, and 3 (8.6%) pts died within one year of follow-up. Conclusion. Infections remain a significant cause ofmorbidity post-OLT forCALI. Enhanced immunosuppression, long ICU stays post-tx, high rates of primary graft dysfunction and deconditioning likely contributed to this high rate of infection. A matched control group is being collected to compare these outcomes to other OLT pts. (Figure Presented).

Lung Transplantation for COVID-19: An International Registry

Purpose: SARS-CoV-2 can result in a range of infections from asymptomatic disease to progressive COVID-19 and death. In some patients with COVID-19 Lung Disease (C19LD), lung transplantation (LTx) may be lifesaving. Up to 10% of LTx in the US is currently for patients with C19LD. Understanding the characteristics and outcomes of these patients is critical. Method(s): A open-access electronic registry was established to collect de-identified data from pts who have undergone LTx for C19LD from centers globally. The study was IRB approved at Northwestern with a wavier for consent (no PHI is collected sites could submit data about pre-Tx, peri-Tx and post-Tx course). Follow-up for 1-yr post-LTx was collected. Result(s): To date, 23 patients with complete day 30 post-LTx data have been entered into the registry. Patient demographics and pre-Tx status are shown in Table 1. 3 patients required oxygen prior to COVID-19 infection. All sites required neg PCR tests prior to listing (22 (95.7%) require 2 neg PCRs). LTx occurred 150 days post-infection and none developed COVID-19 in the first 30 days. Post-Tx ICU LOS averaged 18.6 days with total post-tx hospitalization of 36.3 days (See Table 2). Most LTx experienced infectious and non-infectious morbidity. Most (47.8%) required an additional 36.8 days of rehab. 1 patient died within 30 days due to sepsis. Conclusion(s): The contribution of cases to this international registry is ongoing. While outcomes of LTx for C19LD are generally good, patients experience prolonged post-transplant hospitalization, rehabilitation and significant morbidity.

MUTATIONS in PERSISTENT SARS-CoV-2 CASES

Background: The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with decreased susceptibility to neutralizing antibodies are of clinical importance. While several demographic and clinical correlates of Coronavirus Disease 2019 (COVID-19) outcome have been identified, their relationship to virological and immunological parameters remain poorly defined. Here, we evaluate viral diversity and the accumulation of intra-host mutations over time in a population of hospitalized adults positive for SARS-CoV-2. Methods: We performed longitudinal collection of nasopharyngeal swabs and blood samples from a small cohort of hospitalized adults with COVID-19. Clinical information regarding study subject's immunocompromised status was collected. Samples were assessed for SARS-CoV-2 viral load, viral genotype, viral diversity, and antibody titer. Results: Intra-host viral genetic diversity remained constant through disease course in study subjects that were non-immunocompromised and resulted in changes in viral genotype in some participants. We report the de novo emergence of Spike mutations that have been previously associated with circulating variants of concern in two immunosuppressed patients with persistent SARS-CoV-2 infection. Conclusion: Constant rates of viral evolution suggest the emergence of variants as a function of time, emphasizing the need for effective antivirals to control viral load over long disease courses.

Therapeutic Effect of Regdanvimab in Patients with Mild to Moderate COVID-19: Day 28 Results from a Multicentre, Randomised, Controlled Pivotal Trial

Background. Regdanvimab is a monoclonal antibody with activity against SARSCoV-2. A Phase 2/3 study with two parts is currently ongoing and data up to Day 28 of Part 1 is available while the data from 1315 patients enrolled in Part 2 are expected in June 2021. Methods. This phase 2/3, randomized, parallel-group, placebo-controlled, double-blind study with 2 parts is aimed to assess the therapeutic efficacy of regdanvimab in outpatients with mild to moderate COVID-19, not requiring supplemental oxygen therapy. Patients aged >18 with the onset of symptoms within 7 days were eligible to be enrolled. Results. In Part 1, 307 patients (101, 103, and 103 patients in the regdanvimab 40 mg/kg, regdanvimab 80 mg/kg, and placebo groups, respectively) were confirmed to have COIVD-19 by RT-qPCR at Day 1 (or Day 2). Regdanvimab significantly reduced the proportion of patients who required hospitalization or supplemental oxygen therapy compared to placebo (8.7% in the placebo vs. 4.0% in the regdanvimab 40 mg/kg). The difference in events rate was even larger in patients who met the high-risk criteria and confirmed a 66.1% reduction in patients receiving regdanvimab 40 mg/kg (Table 1). The median time to clinical recovery was shortened by 2.9 days (7.18 days for regdanvimab 40 mg/kg and 10.03 days for placebo;high-risk). Also, greater reductions from baseline viral load were shown in regdanvimab groups (Figure 1). The safety results confirmed that the regdanvimab was safe and well-tolerated. Occurrence of adverse events (Table 2) and results of other safety assessments were generally comparable among the 3 groups. The overall rate of infusion-related reaction was low and no serious adverse events or deaths were reported. The anti-drug antibody positive rate was low in the regdanvimab groups (1.4% in regdanvimab vs. 4.5% in placebo), and no antibody-dependent enhancement was reported. Conclusion. Results from the first part of the study indicate that regdanvimab may lower the rate of hospitalisation or requirement of oxygen supplementation, with the greatest benefit noted in patients at high-risk of progressing to severe COVID-19. The second part of the study remains ongoing and blinded. Therefore, results for the primary endpoint are forthcoming and will be presented at IDWeek.

COVID Vaccine and Cardiovascular Risks: A Natural Language Analysis of Vaccine Adverse Event Reports

Adverse events (AEs) following COVID vaccination have been intensely monitored. In our study, we developed a natural language processing system to analyze data from a spontaneous reporting system - Vaccine Adverse Event Reporting System and detect signals of AEs following administration of COVID vaccines. Our system included several components to magnify novel and rare AEs, including 1) excluding COVID positive patients, 2) excluding sentences discussing disease history or family history, 3) standardizing symptom concepts into 30 major AEs, 4) using influenza vaccine recipients as control group when calculating reporting odds ratio. We identified several cardiovascular and inflammatory-related AEs that demonstrated high odds ratio. We demonstrated our system can serve as a complementary system to identify and monitor AEs outside of pre-defined outcomes routinely monitored by existing databases or projects. © 2021 IEEE.

Prolonged viral shedding of SARS-CoV-2 in solid organ transplant recipients

Background: Solid organ transplant (SOT) recipients are more susceptible to viral infection and present with differing viral kinetics when compared to non-immunocompromised cohorts. The duration of viral shedding in SOT recipients with SARS-CoV-2 infection is unknown. Methods: All SOT recipients with a diagnosed of SARS-CoV-2 by nasopharyngeal of bronchoalveolar lavage RT-qPCR from March 06, 2020 to May 31, 2020 were identified. Viral shedding duration was obtained by evaluating all subsequent SARS-CoV-2 PCR results following initial positivity over time. Severity classification was defined as mild (outpatient), moderate (hospitalized), and severe (ICU level care). Data were obtained from electronic medical record case review and analyzed with Stata 16. Results: 71 patients with a positive SARS-CoV-2 PCR test were identified. 50 (70.4%) were classified as mild/moderate disease, while 21 (29.5%) had severe disease. Median age was 56.5 (IQR 45 - 61.3) years, and 56.9% (n = 41) were male. Older age was significantly associated with severe disease. A disproportionate number of patients were African American/Black or Hispanic at 72.2% (n=52). Interestingly, Caucasian race was significantly associated with less severe outcomes (p=0.038). The majority of patients were kidney transplant recipients (46, 63.9%), followed by liver (13, 18.1%), heart (6, 8.3%), lung (3, 4.2%), and pancreas (9, 12.5%) with a median duration from transplantation at 5 (IQR 3 - 17) years. Overall mortality was 5.6% (n=4), with all deaths occurring only in those with severe disease (19.1%, n=4). Prolonged viral shedding was observed in few patients, with median duration of SARS-CoV-2 PCR positivity at 32 (IQR 18.5 - 41.0) days. One kidney recipient was observed with up to 64 days of positive SARS-CoV-2 RT-PCR from initial diagnosis despite not developing severe disease. Demographics and Outcomes Duration of Viral Shedding in SOT Patients with COVID-19 Conclusion: COVID-19 can lead to significant outcomes in SOT with increased mortality in those with severe disease, as well as prolonged viral shedding. Further studies are needed to elucidate the full duration of viral shedding in this population.

Longitudinal analysis of SARS-CoV-2 viruses in hospitalized adults

Background: The rapid spread of SARS-CoV-2, the causative agent of Coronavirus disease 2019 (COVID-19), has been accompanied by the emergence of viral mutations, some of which may have distinct virological and clinical consequences. While whole genome sequencing efforts have worked to map this viral diversity at the population level, little is known about how SARS-CoV-2 may diversify within a host over time. This is particularly important for understanding the emergence of viral resistance to therapeutic interventions and immune pressure. The goal of this study was to assess the change in viral load and viral genome sequence within patients over time and determine if these changes correlate with clinical and/or demographic parameters. Methods: Hospitalized patients admitted to Northwestern Memorial Hospital with a positive SARS-CoV-2 test were enrolled in a longitudinal study for the serial collection of nasopharyngeal specimens. Swabs were administered to patients by hospital staff every 4 ± 1 days for up to 32 days or until the patients were discharged. RNA was extracted from each specimen and viral loads were calculated by quantitative reverse transcriptase PCR (qRT-PCR). Specimens with qRT-PCR cycle threshold values less than or equal to 30 were subject to whole viral genome sequencing by reverse transcription, multiplex PCR, and deep sequencing. Variant populations sizes were estimated and subject to phylogenetic analysis relative to publicly available SARS-CoV-2 sequences. Sequence and viral load data were subsequently correlated to available demographic and clinical data. Results: 60 patients were enrolled from March 26th to June 20th, 2020. We observed an overall decrease in nasopharyngeal viral load over time across all patients. However, the temporal dynamics of viral load differed on a patient-by-patient basis. Several mutations were also observed to have emerged within patients over time. Distribution of SARS-CoV-2 viral loads in serially collected nasopharyngeal swabs in hospitalized adults as determined by qRT-PCR. Samples were collected every 4 ± 1 days (T#1-8) and viral load is displayed by log(copy number). Conclusion: These data indicate that SARS-CoV-2 viral loads in the nasopharynx decrease over time and that the virus can accumulate mutations during replication within individual patients. Future studies will examine if some of these mutations may provide fitness advantages in the presence of therapeutic and/or immune selective pressures.

SARS-CoV-2 exhibits clade-specific differences in nasopharyngeal viral loads

Background: The rapid spread of SARS-CoV-2, the causative agent of Coronavirus disease 2019 (COVID-19), has been accompanied by the emergence of distinct viral clades, although their clinical significance has yet to be fully elucidated. While whole genome sequencing efforts have identified viral diversity over time, less is known about the clinical significance of this diversity. This study assessed the nasopharyngeal viral loads within patients over time to determine if these changes affect clinical parameters. Methods: Samples were collected from patients presenting to Northwestern Memorial Hospital in Chicago, IL with a positive SARS-CoV-2 RT-PCR from nasopharyngeal swabs. Cycle threshold (Ct) values less than 35 were considered positive, and whole genome sequencing was performed by reverse transcription, multiplex PCR, and Nanopore sequencing. Phylogenetic analysis was conducted on sequenced isolates and compared with publicly available global sequences. Sequence characteristics and viral loads were correlated with each clade. Results: 177 samples were analyzed from March 14, 2020, through May 1, 2020. Most of the sequences (92.6%) clustered in three main clades [Figure 1]. Clade IDs were ordered by relative abundance as Clades 1 (n=122, 68.9%), 2 (n=34, 19.2%), and 3 (n=8, 4.5%). Over this time, Clade 1 viruses have been increasing in incidence across the USA and globally while Clade 2 viruses were uniquely predominant in Illinois with limited global distribution. Ct values were compared across clades [Figure 2]. Significantly lower average Ct values (higher viral loads) were observed in Clade 1 relative to both Clade 2 (p=0.0002) and Clade 3 (p=0.0011). These findings were independent of time from symptom onset to specimen collection. Phylogenetic Analysis of SARS-CoV-2 Isolates with Number of Clades and Clade Distribution Conclusion: These data suggest that SARS-CoV-2 genotype may impact viral load in the upper airways. It remains to be determined whether this difference in clades may impact transmission potential and overall viral spread. Further longitudinal studies with more specimens and associated clinical data are needed.

A Multicenter Prospective Registry Study of Lung Transplant Recipients Hospitalized with COVID-19

Purpose Outcomes of lung transplant recipients (LTR) hospitalized for COVID-19 and comparisons to non-lung solid organ transplant recipients (SOTR) are incompletely described. Methods Using a multicenter prospective registry of SOTR, we examined 28-day outcomes (mortality [primary outcome], intensive care unit (ICU) admission, mechanical ventilation, and bacterial pneumonia) among both LTR and non-lung SOTR hospitalized with laboratory-confirmed COVID-19 diagnosed between March 1, 2020 and September 21, 2020. Data were analyzed using Stata (StataCorp, College Station, TX);chi-square tests were used to compare categorical variables and multivariable logistic regression was used to assess risk factors for mortality. Results The cohort included 72 LTR and 392 non-lung SOTR (Table 1). Overall, 28-day mortality trended higher in LTR vs. non-lung SOTR (27.8% vs. 19.9%, P=0.136). Other 28-day outcomes were similar between LTR and non-lung SOTR: ICU admission (45.8% vs. 39.1%, P=0.28), mechanical ventilation (32.9% vs. 31.1%, P=0.78), and bacterial pneumonia (15.3% vs. 8.2%, P=0.063). Congestive heart failure, diabetes, age >65 years, and obesity (BMI >= 30) were independently associated with mortality in non-lung SOTR, but not in LTR (Table 2). Conclusion In this large prospective cohort comparing lung and non-lung SOTR hospitalized for COVID-19, there were high but not significantly different rates of short-term morbidity and mortality. Baseline comorbidities appeared to drive mortality in non-lung SOTR but not LTR. Further studies are needed to identify risk factors for mortality among LTR.