Early Clinical Experience with Nirmatrelvir/Ritonavir for Treatment of COVID-19 in Solid Organ Transplant Recipients

Purpose: Nirmatrelvir/ritonavir use has not yet been described in solid organ transplant recipients (SOTR) who become infected with COVID-19. The objective of our study was to evaluate outcomes among a heterogeneous population of SOTR and quantify the drug-drug interaction with commonly used immunosuppressive medications. Method(s): This is an IRB-approved, retrospective study of all adult SOTR on a calcineurin inhibitor or mammalian target of rapamycin inhibitor who were prescribed nirmatrelvir/ritonavir between 12/28/21 and 1/6/2022. Result(s): A total of 26 adult SOTR were included (n=20 tacrolimus, n=4 cyclosporine, n=3 everolimus, n=1 sirolimus). All patients were instructed to follow the following standardized protocol during treatment with 5 days of nirmatrelvir/ritonavir: hold tacrolimus, reduce cyclosporine dose to 20% of baseline daily dose, and/or hold everolimus/sirolimus. Two patients (7.7%) were hospitalized;one patient for symptoms related to COVID-19 and the other for infectious diarrhea. No patients died within 12 days of receipt of nirmatrelvir/ritonavir. Median time to first CNI trough from completion of nirmatrelvir/ritonavir was 2 days (IQR, 1 - 3). Median tacrolimus trough concentration pre- and post-nirmatrelvir/ritonavir were 7.7 ng/mL (IQR, 6.6 - 8.6) and 5.3 ng/mL (IQR, 3.6 - 8.5), respectively. One patient on cyclosporine had trough concentrations pre- and post- nirmatrelvir/ritonavir of 73 ng/mL and 45 ng/ mL (day 9), while the other patient had a trough of 75.9 ng/mL prior and 190 ng/mL and 80 ng/mL on days 6 and 9, respectively. Median everolimus trough concentration prior to receipt of nirmatrelvir/ritonavir was 4.8 ng/mL (IQR, 3 - 4.9). Everolimus trough concentrations post-nirmatrelvir/ritonavir were undetectable in two patients on day 7 and day 9, and 1.4 ng/mL on day 8 in the third patient. Conclusion(s): Our results suggest that nirmatrelvir/ritonavir may be an effective therapy to prevent COVID-19-related hospitalization and death in SOTR. Furthermore, the clinically significant interaction between nirmatrelvir/ritonavir and immunosuppressive agents can be reasonably managed with a standardized dosing protocol.

COMPUTERIZED TOMOGRAPHY OF CHEST AND ABSOLUTE LYMPHOCYTE COUNT AS PREDICTOR OF POSITIVE SARS-COV-2 POLYMERASE CHAIN REACTION

TOPIC: Chest Infections TYPE: Original Investigations PURPOSE: Severe acute respiratory syndrome coronavirus 2 (SARS-COV2) is the virus responsible for the coronavirus disease 2019 (COVID-19) which has caused a pandemic generating over half a million deaths in the United States. Lymphopenia is common at presentation in COVID-19 and has been associated with disease severity. Furthermore, patients with severe infection are more likely to have multifocal, bilateral, peripheral ground glass opacities on chest computerized tomography (CT). COVID-19 is diagnosed with a polymerase chain reaction (PCR) test using a nasopharyngeal swab (NPS) for SARS-COV2. The turnaround time for this test has improved;however, as the pandemic continues there have been shortages of reagents leading to continued challenges in timely testing. The aim of our study is to evaluate whether CT chest findings combined with absolute lymphocyte count (ALC) can predict positive COVID-19 PCR swab result. METHODS: We included 3544 patients who presented to the emergency department at a large, urban academic center between March and September 2020. All patients had a NPS for the presence of SARS-CoV-2 using the Luminex NxTAG CoV Extended Panel, a low-resolution chest CT scan without contrast, and a complete blood count with differential to determine ALC. CT scans were classified into three standardized categories by a board-certified chest radiologist based on features of multifocal pneumonia. Category 1 is consistent with multifocal pneumonia, category 2 is indeterminate for multifocal penumonia, and category 3 is inconsistent with multifocal pneumonia. In our analysis we combined categories 2 and 3 into one group. Using the Youden index (J) method, a joint test was performed on CT scan and lymphocyte count. Logistic regression was used determine the parameters of our model. RESULTS: We found that patients with category 1 CT scans and ALC < 1.6 K/mm

SIGNIFICANT DYSPNEA IN POST-ACUTE COVID-19 IS ASSOCIATED WITH ABNORMAL PULMONARY VASCULATURE ON CT DURING THE ACUTE PHASE

TOPIC: Chest Infections TYPE: Original Investigations PURPOSE: SARS-CoV-2 is a highly contagious respiratory virus associated with significant morbidity and mortality in the acute phase. It is also associated with long-term morbidity in a subset of patients. It is not clear which patients will have persistent symptoms. SARS-CoV-2 affects the pulmonary vasculature. We hypothesize that differences in blood volume measurements on CT of the chest during the acute phase are associated with significant dyspnea after the acute phase. METHODS: We retrospectively studied subjects hospitalized for COVID-19 pneumonia who had an initial and follow-up CT chest, pulmonary function tests (PFTs), 6-minute walk test (6MWT), and a clinical assessment in our post-COVID-19 clinic. We excluded subjects with pre-existing lung disease based on prior PFTs. Serum inflammatory biomarkers, CT scan, and clinical characteristics were assessed during the hospitalization. CT images were evaluated by Functional Respiratory Imaging (deep learning trained) with automated tissue segmentation algorithms of the lungs and pulmonary vasculature. Volumes of the pulmonary vessels that were ≤5mm2 (BV5), 5-10mm2 (BV5_10), and ≥10mm2 (BV10) in cross-sectional area were analyzed. Additionally, the amount of opacification on CT (i.e., ground-glass opacities, crazy paving, reticular disease and edema) was quantified in each patient. PFTs were performed <3 months after discharge. We defined a modified Medical Research Council (mMRC) score≥2 as having significant dyspnea. We compared subjects with an mMRC score≥2 to those with an mMRC score<2. BV measures were also compared to a historical cohort of healthy controls. RESULTS: 50 subjects were included. 22 had mMRC score≥2. The groups had similar baseline characteristics. Admission hemoglobin, peak inflammatory biomarkers, and follow-up PFTs were similar between groups. On 6MWT, there were no differences between groups in resting SpO2, lowest SpO2, or walk distance. On admission CT, percent BV5 was lower, and percents BV5_10 and BV10 were higher in the mMRC≥2 group compared to the mMRC<2 group. All BV measures in both groups were different compared to healthy controls. At follow-up, BV5 measures in the mMRC≥2 group improved but remained abnormal compared to healthy controls, without a statistical difference compared to the mMRC<2 group. Opacification was similar between groups on admission and follow-up CTs. CONCLUSIONS: Despite similar baseline characteristics, lung function, degree of opacification and oxygenation, persistent dyspnea after COVID-19 pneumonia is related to pruning of the small pulmonary vessels (BV5) during the acute phase and not to differences in vascular abnormalities seen in short term follow-up. CLINICAL IMPLICATIONS: Identification of markers of persistent dyspnea in post-acute COVID-19 contributes to a better understanding of the natural course and prognosis of the disease. This will impact research and patient care in the near future. DISCLOSURES: No relevant relationships by Melinda Darnell, source=Web Response Owner/Founder relationship with Fluidda Please note: $20001 - $100000 by Jan De Backer, source=Web Response, value=Ownership interest No relevant relationships by Derlis Fleitas Sosa, source=Web Response No relevant relationships by Victor Kim, source=Web Response Employee relationship with FLUIDDA Please note: 02/01/2017 - Present Added 04/26/2021 by Maarten Lanclus, source=Web Response, value=Salary No relevant relationships by Ifeoma Oriaku, source=Web Response No relevant relationships by Daniel Salerno, source=Web Response

Association of Serum D-Dimer and Abnormal Pulmonary Vasculature on CT Scan during Hospitalization with Decreased Diffusion Capacity in Follow Up for COVID-19 Infection

Rationale: Coronavirus Disease 2019 (COVID-19) is a highly contagious respiratory viral illness causing pneumonia and systemic disease. Abnormalities in pulmonary function after COVID-19 infection have been described. The determinants of these abnormalities are unclear. We hypothesized that inflammatory biomarkers and computed tomography (CT) scan parameters at the time of infection would be associated with abnormal gas exchange at short term follow-up.Methods: We studied subjects who were hospitalized for COVID-19 pneumonia and then discharged. Those with pre-existing lung disease (except asthma) or reduced diffusing capacity for carbon monoxide (DLCO) prior to COVID-19 infection were excluded. Information on serum inflammatory biomarkers, CT scan, and clinical characteristics were collected in the index hospitalization. Pulmonary function tests and 6-minute walk tests were assessed at 2-3 months after discharge. CT images at the time of hospitalization were evaluated by Functional Respiratory Imaging (FRI;FLUIDDA, Inc., Antwerp, Belgium) with 3D reconstruction of the lungs and pulmonary vasculature to analyze pulmonary blood volume. Blood volumes of the pulmonary vessels that were ≤5mm (BV5), 5-10mm (BV5-10), and ≥10mm (BV10) in cross-sectional area were analyzed. Additionally, the amount of inflammation on CT (ground-glass opacities) was quantified. We divided subjects into those with a DLCO <80% predicted and those with a DLCO ≥80% predicted based on follow-up pulmonary function tests. Results: 38 subjects were included in our cohort. Pulmonary function tests were performed 76.5±35.1 days after the first day of hospitalization. The results are summarized in the Table. 31 out of 38 (81.5%) subjects had a DLCO<80% predicted. The groups were similar in terms of demographics, body mass index, and smoking status. Peak D-dimer, LDH, and ferritin levels were greater in the DLCO<80% group. Spirometric measures and lung volumes were similar between groups. Inflammation was not different between groups, but BV5-10 and BV10 measures were higher in the DLCO<80% group. BV5-10 was associated with DLCO<80% in multivariable logistic regression with demographics, smoking status, lung volumes, and hemoglobin as covariates (OR 1.29, 95% CI 1.01, 1.64).Conclusions: Higher peak D-dimer levels at the time of hospitalization and abnormalities in pulmonary blood volumes are associated with a reduced DLCO at follow-up. These findings suggest that pulmonary vascular and coagulation abnormalities during hospitalization with COVID-19 might have long-lasting effects on pulmonary function. Further study regarding the influence of pulmonary blood volumes and measures of abnormal coagulation on short term COVID-19 outcomes is warranted.

Obesity outcomes in acute respiratory distress syndrome due to COVID-19: A retrospective single center experience

Introduction: The “obesity paradox” has been reported in critically ill patients with acute respiratory distress syndrome (ARDS). Obese patients with ARDS were shown to have more ventilator free days and lower mortality compared to non-obese patients. One proposed explanation was increased levels of pro-inflammatory cytokines creating a protective environment from acute inflammation. In COVID-19, BMI ≥ 30 increases risk of illness severity, need for critical care, respiratory failure requiring use of invasive mechanical ventilation (IMV), and mortality. It is unknown if the “obesity paradox” applies to patients with SARS-CoV2 who require IMV. We examined a cohort of patients with respiratory failure due to COVID-19 who required IMV and compared outcomes between obese and non-obese patients. Methods: Data was collected from patients treated in the COVID Intensive Care Unit (ICU) from March to June 2020. A total of 85 patients were identified. All patients were COVID nasopharyngeal swab positive. Results: There were 38 (44.7%) patients with BMI < 30, and 47 (55.3%) with BMI ≥ 30. The median BMI was 25.5 in the BMI < 30 group, and 37.5 in the BMI ≥ 30 group. In the BMI < 30 group, median age was 67 years, majority male (65.8%) and African American (50%). The BMI ≥ 30 group had a median age of 63.5, majority male (53.2%) and African American (63.8%). Median Sequential Organ Failure Assessment score on admission was higher in the BMI ≥ 30 group at 3 (1.5-4.5) vs. 2 (1.0-4.0). There was elevated creatinine on admission with higher percentage of diabetes, heart failure, and renal disease in the BMI ≥ 30 group. Inflammatory markers, such as CRP and IL-6 were lower in the higher BMI group at presentation. There was higher in-hospital mortality in the BMI ≥ 30 group at 57.5%, with longer ICU length of stay (12.35 vs. 7.6 days), longer days on ventilator (10.2 vs. 4 days), and lower PaO2/FiO2 ratio after intubation (146 vs 348). The higher BMI group had higher rates of prone ventilation, paralytic use, and extracorporeal membrane oxygenation support. Discussion: From our data, obesity did not appear to have better outcomes in ARDS due to COVID-19 infection. Higher BMI was associated with higher disease severity, severe respiratory failure, longer ventilator days, longer ICU length of stay, and higher mortality. Interestingly, inflammatory markers were initially lower in obese patients, suggesting a possible adaptive physiologic response to inflammation, but without effect on overall outcomes.