Tracheal stenosis and airway complications in the Coronavirus Disease-19 era

BACKGROUND Severe Coronavirus Disease 2019 (COVID-19) infection is associated with prolonged intubation and its complications. Tracheal stenosis is one such complication that may require specialized surgical management. We aimed to describe the surgical management of post-COVID-19 tracheal stenosis. METHODS This case series describes consecutive patients with tracheal stenosis from intubation for severe COVID-19 infection at our single, tertiary academic medical center between January 1st, 2021, and December 31st, 2021. Patients were included if they underwent surgical management with tracheal resection and reconstruction, or bronchoscopic intervention. Operative through six-month, symptom-free survival and histopathological analysis of resected trachea were reviewed. RESULTS Eight patients are included in this case series. All patients are female, and most (87.5%) are obese. Five patients (62.5%) underwent tracheal resection and reconstruction (TRR), while three patients (38.5%) underwent non-resection-based management. Among patients who underwent TRR, six-month symptom free survival is 80%;one patient (20%) required tracheostomy after TRR due to recurrent symptoms. Two of the three (66.7%) of patients who underwent non-resection-based management experienced durable relief from symptoms of tracheal stenosis with tracheal balloon dilation, and the remaining patient required laser excision of tracheal tissue prior to experiencing symptomatic relief. CONCLUSIONS The incidence of tracheal stenosis may increase as patients recover from severe COVID-19 infection requiring intubation. Management of tracheal stenosis with TRR is safe and effective, with comparable rates of success to TRR for non-COVID-19 tracheal stenosis. Non-resection-based management is an option to manage tracheal stenosis in patients with less severe stenosis or in poor surgical candidates.

Hyperactivity of the CD155 immune checkpoint suppresses anti-viral immunity in patients with coronary artery disease.

Pre-existent cardiovascular disease is a risk factor for weak anti-viral immunity, but underlying mechanisms remain undefined. Here, we report that patients with coronary artery disease (CAD) have macrophages (Mϕ) that actively suppress the induction of helper T cells reactive to two viral antigens: the SARS-CoV2 Spike protein and the Epstein-Barr virus (EBV) glycoprotein 350. CAD Mϕ overexpressed the methyltransferase METTL3, promoting the accumulation of N6-methyladenosine (m6A) in Poliovirus receptor (CD155) mRNA. m6A modifications of positions 1635 and 3103 in the 3'UTR of CD155 mRNA stabilized the transcript and enhanced CD155 surface expression. As a result, the patients' Mϕ abundantly expressed the immunoinhibitory ligand CD155 and delivered negative signals to CD4+ T cells expressing CD96 and/or TIGIT receptors. Compromised antigen-presenting function of METTL3hi CD155hi Mϕ diminished anti-viral T cell responses in vitro and in vivo. LDL and its oxidized form induced the immunosuppressive Mϕ phenotype. Undifferentiated CAD monocytes had hypermethylated CD155 mRNA, implicating post-transcriptional RNA modifications in the bone-marrow in shaping anti-viral immunity in CAD.

Transplant of organs from donors with positive SARS-CoV-2 nucleic acid testing: A report from the organ procurement and transplantation network ad hoc disease transmission advisory committee.

BACKGROUND: Decisions to transplant organs from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid test-positive (NAT+) donors must balance risk of donor-derived transmission events (DDTE) with the scarcity of available organs. METHODS: Organ Procurement and Transplantation Network (OPTN) data were used to compare organ utilization and recipient outcomes between SARS-CoV-2 NAT+ and NAT- donors. NAT+ was defined by either a positive upper or lower respiratory tract (LRT) sample within 21 days of procurement. Potential DDTE were adjudicated by OPTN Disease Transmission Advisory Committee. RESULTS: From May 27, 2021 (date of OTPN policy for required LRT testing of lung donors) to January 31, 2022, organs were recovered from 617 NAT+ donors from all OPTN regions and 53 of 57 (93%) organ procurement organizations. NAT+ donors were younger and had higher organ quality scores for kidney and liver. Organ utilization was lower for NAT+ donors compared to NAT- donors. A total of 1241 organs (776 kidneys, 316 livers, 106 hearts, 22 lungs, and 21 other) were transplanted from 514 NAT+ donors compared to 21 946 organs from 8853 NAT- donors. Medical urgency was lower for recipients of NAT+ liver and heart transplants. The median waitlist time was longer for liver recipients of NAT+ donors. The match run sequence number for final acceptor was higher for NAT+ donors for all organ types. Outcomes for hospital length of stay, 30-day mortality, and 30-day graft loss were similar for all organ types. No SARS-CoV-2 DDTE occurred in this interval. CONCLUSIONS: Transplantation of SARS-CoV-2 NAT+ donor organs appears safe for short-term outcomes of death and graft loss and ameliorates the organ shortage. Further study is required to assure comparable longer term outcomes.

De Novo Diagnosis of Lymphocytic Colitis After SARS-CoV-2 Vaccination.

SARS-CoV-2 mRNA vaccines are safe and effective for most patients. Gastrointestinal complications reported after vaccination have included gastroparesis and inflammatory bowel disease flares. In this study, we present a unique case of lymphocytic colitis that occurred in a healthy middle-aged man after Moderna SARS-CoV-2 mRNA vaccination. This reveals an unexpected complication of a mRNA vaccine that presented as worsening diarrhea after vaccination in a dose-dependent pattern. Caregivers should be aware of lymphocytic colitis as a possible complication of the Moderna vaccine and monitor those patients closely for symptom resolution.

SARS-CoV-2 Brain Regional Detection, Histopathology, Gene Expression, and Immunomodulatory Changes in Decedents with COVID-19.

Brains of 42 COVID-19 decedents and 107 non-COVID-19 controls were studied. RT-PCR screening of 16 regions from 20 COVID-19 autopsies found SARS-CoV-2 E gene viral sequences in 7 regions (2.5% of 320 samples), concentrated in 4/20 subjects (20%). Additional screening of olfactory bulb (OB), amygdala (AMY) and entorhinal area for E, N1, N2, RNA-dependent RNA polymerase, and S gene sequences detected one or more of these in OB in 8/21 subjects (38%). It is uncertain whether these RNA sequences represent viable virus. Significant histopathology was limited to 2/42 cases (4.8%), one with a large acute cerebral infarct and one with hemorrhagic encephalitis. Case-control RNAseq in OB and AMY found more than 5000 and 700 differentially expressed genes, respectively, unrelated to RT-PCR results; these involved immune response, neuronal constituents, and olfactory/taste receptor genes. Olfactory marker protein-1 reduction indicated COVID-19-related loss of OB olfactory mucosa afferents. Iba-1-immunoreactive microglia had reduced area fractions in cerebellar cortex and AMY, and cytokine arrays showed generalized downregulation in AMY and upregulation in blood serum in COVID-19 cases. Although OB is a major brain portal for SARS-CoV-2, COVID-19 brain changes are more likely due to blood-borne immune mediators and trans-synaptic gene expression changes arising from OB deafferentation.

First lung and kidney multi-organ transplant following COVID-19 Infection.

As the world responds to the global crisis of the COVID-19 pandemic an increasing number of patients are experiencing increased morbidity as a result of multi-organ involvement. Of these, a small proportion will progress to end-stage lung disease, become dialysis dependent, or both. Herein, we describe the first reported case of a successful combined lung and kidney transplantation in a patient with COVID-19. Lung transplantation, isolated or combined with other organs, is feasible and should be considered for select patients impacted by this deadly disease.

Angiotensin-converting enzyme 2 (ACE2) expression increases with age in patients requiring mechanical ventilation.

Mortality due to Covid-19 is highly associated with advanced age, owing in large part to severe lower respiratory tract infection. SARS-CoV-2 utilizes the host ACE2 receptor for infection. Whether ACE2 abundance in the lung contributes to age-associated vulnerability is currently unknown. We set out to characterize the RNA and protein expression profiles of ACE2 in aging human lung in the context of phenotypic parameters likely to affect lung physiology. Examining publicly available RNA sequencing data, we discovered that mechanical ventilation is a critical variable affecting lung ACE2 levels. Therefore, we investigated ACE2 protein abundance in patients either requiring mechanical ventilation or spontaneously breathing. ACE2 distribution and expression were determined in archival lung samples by immunohistochemistry (IHC). Tissues were selected from the specimen inventory at a large teaching hospital collected between 2010-2020. Twelve samples were chosen from patients receiving mechanical ventilation for acute hypoxic respiratory failure (AHRF). Twenty samples were selected from patients not requiring ventilation. We compared samples across age, ranging from 40-83 years old in the ventilated cohort and 14-80 years old in the non-ventilated cohort. Within the alveolated parenchyma, ACE2 expression is predominantly observed in type II pneumocytes (or alveolar type II / AT2 cells) and alveolar macrophages. All 12 samples from our ventilated cohort showed histologic features of diffuse alveolar damage including reactive, proliferating AT2 cells. In these cases, ACE2 was strongly upregulated with age when normalized to lung area (p = 0.004) or cellularity (p = 0.003), associated with prominent expression in AT2 cells. In non-ventilated individuals, AT2 cell reactive changes were not observed and ACE2 expression did not change with age when normalized to lung area (p = 0.231) or cellularity (p = 0.349). In summary, ACE2 expression increases with age in the setting of alveolar damage observed in patients on mechanical ventilation, providing a potential mechanism for higher Covid-19 mortality in the elderly.