After COVID-19: PASC

After COVID-19: PASC

(Post-Acute Sequalae of COVID-19)

Long COVID Other Subtypes

Marjan Islam, MD Assistant Professor of Medicine Division of Pulmonary Medicine Department of Medicine Montefiore Medical Center Albert Einstein College of Medicine

Naming the Syndrome Categories proposed by the CDC: Acute COVID-19 – Symptoms of COVID-19, up to four weeks following the onset of illness Post-COVID Conditions – Broad range of symptoms (physical and mental) that develop during or after COVID-19, continue for ≥4 weeks, and are not explained by an alternative diagnosis ▪ Long COVID/Long Haulers ▪ Chronic COVID-19 ▪ Post-COVID Syndrome ▪ Post-Acute COVID-19 ▪ Post-Acute Sequelae of SARS-CoV-2 Infection Evaluating and Caring for Patients with Post-COVID Conditions: Interim Guidance https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-index.html

JACC Basic Transl Sci. Sep-Oct 2021;6(9):786-811

PASC

Non-Severe COVID-19 MultiOrgan Sequelae

Pulmonary Fibrosis Sequelae

Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome

Postural Orthostatic Tachycardia Syndrome

Rev Med Virol. 2021 Dec 9;e2315

PASC

https://covid.cdc.gov/covid-data-tracker Accessed May 5th 2022

Variants (time of onset): • Original (24%) • Alpha (15%) • Delta (27%) • Omicron (19%)

Predominant Symptom: • Fatigue (51%) • Shortness of Breath (34%) • Loss of Smell (28%) • Body Aches (24%)

Magnitude of Impact: • Limited 1.1 million (67%) • Significant 322,000 • (19%)

Vanichkachorn G et al.

Mayo Clin Proc.

July 2021;96(7):1782-1791

Davis H, Assaf G et al. EClinicalMedicine; July 14, 2021

Davis H, Assaf G et al. EClinicalMedicine; July 14, 2021

Davis H, Assaf G et al. EClinicalMedicine; July 14, 2021

• Viral URI • GI

• Cardiac • Pulmonary • Neuropsychiatric

• Dermatologic • Ocular, Otologic • Neuropsychiatric

▪ Prevalence of post COVID-19 symptoms via Long COVID Symptom Tool assessing for 53 symptoms

Tran V et al. Nat Commun. 2022 Apr 5;13(1):1812

Tran V et al. Nat Commun.

2022 Apr 5;13(1):1812

Day-by-Day Prevalence of Symptoms

Impact on Patient Lives

Lancet Respir Med 2022 May 11

▪ Survivors of severe COVID-19 had significantly more symptoms at 2 years compared to matched controls ▪ Group with long COVID symptoms: o o o o

Lower QoL Worse Exercise Capacity Increased Mental Health Symptoms More Health Care Utilization PostDischarge

J Neurol Sci. 2022 Mar 15; 434: 120162.

Patients hospitalized for COVID-19 had >50% reduction in neuropsychiatric symptoms J Neurol Sci. 2022 Mar 15; 434: 120162.

PLoS Med. 2021 Sep 28;18(9):e1003773

• Longitudinal multiomics associate PASC with autoantibodies, viremia, and comorbidities • Reactivation of latent viruses during initial infection may contribute • Subclinical autoantibodies negatively correlate with antiSARS-CoV-2 antibodies • GI symptoms present with post-acute expansion of cytotoxic Tcells Cell 2022 Mar 3;185(5):881-895.e20.

▪ 41% of PoTS linked to preceding viral infection ▪ Multisystem condition with a preponderance of younger female patients ▪ Several mechanisms at play: hypovolemia, autonomic dysfunction, autoimmunity Diagnostic Criteria: • Symptoms of orthostatic intolerance with or without systemic symptoms • Symptoms with increase in upright heart rate by >30 beats/minute within 10 minutes of standing, without hypotension Br J Gen Pract 2021 Dec 31;72(714):8-9

Clinical Autonomic Research (2021) 31:385–394

• N=27 patients with PASC with autonomic symptoms • 59% Female, Median Age 30

• 63% had abnormalities on autonomic function testing, ranging from symptomatic orthostatic tachycardia to POTS

▪ ME/CFS patients (<4 years vs >10 years since diagnosis) demonstrated: o Significantly higher Heart Rate with standing o Abnormally narrowed Pulse Pressure ▪ Findings suggest inadequate ventricular filling and low venous return pressures

▪ N=100 with PASC, expiratory CT chest showed air-trapping: o Ambulatory (25.4%) o Hospitalized (34.6%) o ICU (27.3%) o Controls (7.2%) ▪ Air-Trapping Correlated with RV/TLC, not Spirometry ▪ ACE-2 is expressed throughout the small airways, thus obstruction may occur through direct viral infection or post-infectious constrictive bronchiolitis Radiology. 2022 Mar 15;212170

CHEST 2022; 161(1):54-63

▪ N=10 healthy patients with PASC underwent iCPET ▪ None with pre-existing cardiopulmonary disease ▪ Average interval between COVID-19 and iCPET: 11 months ▪ Significant reduction in peak exercise capacity (VO2) in PASC group, associated with impaired systemic oxygen extraction

▪ No cardiac limitation ▪ No pulmonary limitation ▪ Limitation to exercise occurred due to reduced peripheral systemic oxygen extraction ▪ Suspected Pathogenesis: microcirculatory dysfunction due to small fiber/autonomic neuropathy CHEST 2022; 161(1):54-63

▪ N=17 patients with mild COVID-19 ▪ Mean Age: 43.3 years, 69% Female ▪ N=10 diagnosed with small-fiber neuropathy (smalldiameter unmyelinated autonomic fibers) ▪ Potential Treatment: Corticosteroids or IVIG, immunotherapy

Neurol Neuroimmunol Neuroinflamm. 2022 Mar 1;9(3):e1146

▪ Mast cells harbor histamine and specific cytokines and are activated by SARS-CoV-2 ▪ COVID-19 associated hyperinflammation may be driven by Mast Cell activation, both in the acute and post-acute phase ▪ Mast Cell Activation Syndrome is a chronic multisystem disorder with inflammatory symptoms that overlap with Long COVID Front. Pharmacol, 23 March 2021

Int J Infect Dis 2021 Nov;112:217-226.

J Investig Med. 2022 Jan;70(1):61-67.

Trends Mol Med . 2021 Sep;27(9):895-906

Medicina. 2021 May; 57(5): 418

Mayo Clin Proc. 2021 Aug 23;S0025-6196(21)00513-9.

PASC

Consider the Differential Diagnosis

Identify Potential Co-Morbidities

Pathophysiology Persistent Viral Reservoir?

• COVID-19 Vaccination and Booster • Anti-viral Therapy • Monoclonal Antibodies Autoimmunity?

• Immunosuppressants • Intravenous Immunoglobulin • Immune Modulators

Treatment Mast Cell Activation?

• H1 Antihistamine • H2 Antihistamine • Cromolyn Sodium Reactivation of Latent Virus?

• EBV, HSV, CMV, HHV • Anti-viral Therapy Small Fiber Neuropathy?

• IVIG (if autoimmune)

Pharmacotherapy: ▪ POTS: fludrocortisone, midodrine, beta-blockers ▪ Fatigue and Cognitive Impairment: methylphenidate, modafinil ▪ Pain: low-dose naltrexone, SSRIs, gabapentin, baclofen ▪ Insomnia: trazodone, TCAs, gabapentin, pregabalin No FDA approved drugs.

Therapies aimed to mitigate symptom severity.