Rutgers COVID-19 Pathobiology Lecture 11 PDF

COVID-19 Pathobiology All populations got very sick very fast Wastewater Survey Map SARS-CoV-2 tracking via wastewater survey map. Sewage is pulled because virus is...

COVID-19 Pathobiology All populations got very sick very fast Wastewater Survey Map SARS-CoV-2 tracking via wastewater survey map. Sewage is pulled because virus is excreted by infected individuals. This allows for tracking per states in real time.  Significantly increased risk of death in COVID infected compared to seasonal influenza. Xie, et al. JAMA 2024 CLINICAL PRESENTATION OF SARS COV-2 INFECTION (COVID-19) – HISTORICAL  Original Clinical Presentations in naïve populations Severity of Illness Timing – 40% mild without PNA – Exposure -> Symptoms – 40% moderate with PNA 5-6 days 10-15% become severe Up to 14 days – 15% severe – Symptoms -> Recovery 15-20% become critical Mild = 2 weeks – 5% critical Severe = 3-6 weeks – Symptoms -> Death 2-8 weeks  COVID-19 Symptoms Most common symptoms are fever, dry cough, and shortness of breath Common symptoms in hospitalized patients include: – Fever (70%-90%) – Dry cough (60%-86%) – Shortness of breath (53%-80%) – Fatigue (38%) – Myalgias (15%-44%) – Nausea/vomiting or diarrhea (15%-39%) – Headache, weakness (25%), and rhinorrhea (7%) – Anosmia or ageusia may be the sole presenting symptom in approximately 3% of individuals with COVID-19 COVID-19 Complications Approximately 5% of patients with Prothrombotic coagulopathy resulting in venous COVID-19, and 20% of those and arterial thromboembolic events (10%-25%) hospitalized, experience severe AKI (9%) symptoms necessitating intensive care Neurologic manifestations Common complication among – Impaired consciousness (8%) – Acute cerebrovascular disease (3%) hospitalized patients: – Shock (6%) – Pneumonia (75%) Rare complications among critically ill patients – ARDS (15%) with COVID-19 include cytokine storm and – Acute liver injury (19%) macrophage activation syndrome – Cardiac injury Case-fatality rate for COVID-19 varies by age Troponin elevation (7%-17%) – 0.3 deaths per 1000 cases among patients aged 5 Acute heart failure to 17 years Dysrhythmias – 304.9 deaths per 1000 cases among patients Myocarditis aged 85 years or older in the US ICU case fatality is up to 40% Age and Mortality Age is the number one risk factor for mortality from SARS-CoV-2 is age. High Risk Conditions in USA Cancer Chronic kidney disease Chronic liver disease Chronic lung disease Dementia Diabetes Down Syndrome Heart disease Immunocompromised state / HIV Mental health conditions Obesity / overweight (body mass index [BMI] of 25 kg/m 2 or higher) Physical inactivity Pregnancy Sickle cell disease Smoking Stroke Substance use disorders Transplant Tuberculosis CDC.gov Accessed 10/1/2023  Health Disparities Communities of color disproportionally devastated – Most people in This population were essential workers likely unable to quarantine. New Orleans (Oschner) – 31% African American – 76.9% hospitalizations – 70.8% deaths Bronx – Increased mortality – Not fully explained by comorbidities or SES Multiple other reports COVID “Long Haulers” THESE DATA REFLECT INITIAL INFECTION IN A NAÏVE POPULATION Age is still the prime risk Vo, et al. JAMA Open 2022 PATHOPHYSIOLOGY Viral Dynamics and Transmissibility High level viral replication in upper airways Asymptomatic transmission: virus would be transmitted by asymptomatic patients. Pneumonia and lung damage – 5% severe ARDS: adult respiratory distress syndrome that would severely scar the lungs. Shock Lung damage – Hypoxia Silent hypoxia – Critically low oxygen while patient appears “normal”. – Silent killer – Minimal dyspnea – Tachypnea more common Infection of Cells Initially infected nasal epithelium – Spike (S) glycoprotein mediates viral entry by binding to ACE2 on the epithelial cell surface – ACE2 expression is high in the epithelial cells of the nasal cavity Can also infect a wider range of cells – Cardiac myocytes – Endothelial – Testicular – Bile duct cells Theories on dissemination to alveolar level – Aspiration of SARS-CoV-2 particles causes spread from the oropharynx to the lungs – Airborne microparticles are transported directly into the lower respiratory tract by airflow – Possible dose response relationship Lung Damage – ARDS and Fibrosis ARDS not typical – Maintain high level compliance in the lungs Controversial: steroids were the number one protective modality for ARDS. Steroids typically contraindicated for ARDS. – Poor oxygen exchange – Prone positioning may help increase perfusion Fibrosis – Pro-fibrotic reaction to ARDS – More long term – Permanent Coagulopathy and Coagulation Direct effect of the virus on patients: – Clotting in high circulation regions such as the brain and the heart. – Endothelial damage is common – High incidence of VTE – High D-dimer – Pathophysiology unclear Direct viral mediated endothelial inflammation DIC Host Immune Response Vast majority of cases do well Cytokine response – Endothelial injury – TLR3, TLR7-9 – Full response not characterized – Cytokine storm controversial Elevated inflammatory markers CRP and ferritin Characteristics, Diagnosis, and Management of Covid-19 According to Disease Stage or Severity. Timeline and severity scale: By the time people reached severe and critical infection there was low viral replication Increased infection severity was caused by inflammation. Antiviral therapy: targets viral replication. This may be used in mild to moderate illness. Antiinflammatory treatment needed for severe and critical illness. NIH Final Treatment Guidelines 2024  Dexamethasone: RECOVERY Trail Dexmethasone is a corticosteroid with anti inflammatory and immunosuppressive properties. – dampens the immune response in severe infection. Open label trial vs. usual care – Dexamethasone 6mg daily for up to 10 days – Dexmethasone given to patients hospitalized with COVID-19 Overall mortality within 28 days – 482 patients (22.9%) in the dexamethasone group – 1110 patients (25.7%) in the usual care – Age-adjusted rate ratio: 0.83; 95% confidence interval [CI], 0.75 to 0.93; P50 – Most (81%) vaccine efficacy or effectiveness estimates against severe disease remained greater than 70% over time Multiple Variables Vaccines – Communities should be vaccinated Severe disease annually to decrease amount of infected and symptomatic individuals walking around. – T-cell Product Timing – Memory Infection Boosters Infection – Incident – Repeat infection – Antibody Virus – Variants Current COVID-19 Vaccine Recommendations Pfizer or Moderna that mRNA vaccines target current KP.2 variant. – Concurrent administration of COVID-19 and Flu vaccines enhance spike-specific antibody responses. Novavax (protein subunit vaccine) JN.1 variant LONG COVID NYC “Real World” Data on COVID-19 Survivorship 1190 patients with COVID-19 at New Symptoms 3 months after discharge York City academic medical center in the – Cardiac or pulmonary symptoms (35.7%) spring of 2020 – Dyspnea (22.1%) Followed at 3 and 6 months after – Cough (16%) discharge – Fatigue (9%) Mortality rate of 21.9% Symptoms 6 Months after discharge 929 survivors – Cardiopulmonary (28%) – 570 had follow-up appointments – Dyspnea (16%) – 33 (3.5%) died during the follow-up period – Fatigue (10.4%) – “Generalized” symptoms (26.4%) – Neuropsychiatric symptoms (24.2%) Long covid theoretical timeline Typically considered long covid after 3 weeks since onset of infection. Patients with long covid have negative COVID-19 PCR test, but symptoms persist. Long covid seen all over Asia and Europe Potential Mechanisms of Post-Acute COVID-19 Virus-specific pathophysiologic changes Immunologic aberrations and inflammatory Expected sequelae of post-critical illness – New or worsening abnormalities in physical, cognitive and psychiatric domains after critical illness Microvascular ischemia and injury Immobility Metabolic alterations during critical illness  ORGAN SYSTEM DYSFUNCTION AND CARE A clinic dedicated to long COVID would consist of: Hematology Consider extended thromboprophylaxis for high risk survivors. Renal function Follow up with nephrologists Primary care Early rehab, patient education, clinical study enrollment, patient advocacy groups Neuropsychiatry Screening for anxiety, depression, ptsd, sleep disturbances and cognitive impairment. Pulmonary/cardiovascular and dyspnea/persistent oxygen requirement Symptom assessment 4-6 weeks and 12 weeks after discharge Pulmonary system assessment via X-rays, EKG, etc. Pulmonary Complications and Pathophysiology Alveolar damage – Viral toxicity – Immunologic damage – All phases of diffuse alveolar damage reported in autopsy series Pulmonary vascular thrombosis – 20–30% of patients with COVID-19 have blood clots. Higher than in other critically ill patient populations (1–10%) – Severity of endothelial injury and widespread thrombosis greater than seen in ARDS from influenza – Conflicting data on anticoagulation and antiplatelet therapy in acute phase Treatment Considerations for Pulmonary Damage Persistent dyspnea; patients developed asthma. Treatment with corticosteroids may be beneficial in post- COVID inflammatory lung disease Steroid use in acute COVID-19 may be somewhat protective Hematologic Concerns Retrospective data suggest the rate of venous thromboembolism in the post-acute COVID-19 setting is 30 days after acute infection with SARS-CoV-2 – New diagnosis 166% and 31% more likely to among patients with COVID-19 than among those without COVID-19  Vaccine Effects Fifteen studies on vaccinating to prevent long covid. – Preventing infection from becoming severe enough to become long covid. 7 studies - vaccination before infection reduced the symptoms or incidence of long COVID The effectiveness of vaccination 7 studies - vaccination of people with long COVID reduced or against long COVID cleared the symptoms of long COVID A rapid evidence briefing 1 study examined both Prevention of Long COVID Less likely to develop Fully vaccinated cases were symptoms of long COVID less likely to have the following infection following symptoms in the Likely underestimated medium or long term than because the prevention of unvaccinated cases incident infection was not – Fatigue, headache, factored weakness in arms and legs, persistent muscle pain, hair loss, dizziness, shortness of breath, anosmia, interstitial lung disease, myalgia, and other pain. Treatment of Long COVID 4 studies compared long COVID symptoms before and after vaccination – More cases reported an improvement in symptoms after vaccination, either immediately or over several weeks in 3 studies – Some cases in all studies who reported a worsening in symptoms after vaccination. 3 studies focused on long COVID in unvaccinated Compared subsequently vaccinated to those who remained unvaccinated – All suggested people with long-COVID were less likely to report symptoms shortly after vaccination and over longer periods – One study suggested cases who were vaccinated sooner rather than later after diagnosis were much less likely to report symptoms of long COVID than cases who remained unvaccinated