Post-COVID19perspectives for primary careRenée Janssen MD FRCPCGeneral Internal Medicine

No disclosures / Conflicts of interest

Objectives

• Understand an approach to evaluation of patients with prolonged symptoms following SARS CoV2 infection• Identify who requires additional evaluation • Discuss approach to investigation of focal symptoms • Identify patients who require referral to subspecialists• (Treatment of post-COVID sequelae will not be discussed)

• Discussion of cases – mine and yours

Pathophysiology of SARS-CoV-2REVIEW ARTICLE NATURE MEDICINE

of SARS-CoV13. Recent studies have demonstrated higher affin-ity of binding of SARS-CoV-2 to ACE2 than of SARS-CoV to ACE2, which may partially explain the increased transmissibility of SARS-CoV-214–16.

Key mechanisms that may have a role in the pathophysiology of multi-organ injury secondary to infection with SARS-CoV-2 include direct viral toxicity, endothelial cell damage and throm-boinflammation, dysregulation of the immune response, and dys-regulation of the renin–angiotensin–aldosterone system (RAAS) (Fig. 1). The relative importance of these mechanisms in the patho-physiology of COVID-19 is currently not fully understood. While some of these mechanisms, including ACE2-mediated viral entry and tissue damage, and dysregulation of the RAAS, may be unique to COVID-19, the immune pathogenesis caused by the systemic release of cytokines and the microcirculation dysfunctions may also occur secondary to sepsis17.

Direct viral toxicity. SARS-CoV-2 is transmitted mainly through direct or indirect respiratory-tract exposure. It has tropism for the respiratory tract, given the high expression of ACE2, its entry recep-tor, in multiple epithelial cell types of the airway, including alveolar epithelial type II cells in the lung parenchyma18,19. Live SARS-CoV-2 virus and viral subgenomic mRNA isolated from the upper airway can successfully be detected by RT-PCR. Later in the disease course, viral replication may occur in the lower respiratory tract20, which manifests in severe cases as pneumonia and ARDS.

Studies evaluating body-site-specific viral replication of SARS-CoV-2 have isolated viral RNA from fecal samples at high titers2,20 and, less commonly, from urine and blood21,22. Histopathological studies have reported organotropism of SARS- CoV-2 beyond the respiratory tract, including tropism to renal21,23, myocardial21,24, neurologic21, pharyngeal21, and gastrointestinal25 tissues. In addition, single-cell RNA-sequencing studies have con-firmed expression of ACE2 and TMPRSS2 in lung alveolar epithelial type II cells, nasal goblet secretory cells, cholangiocytes, colono-cytes, esophageal keratinocytes, gastrointestinal epithelial cells, pancreatic β-cells, and renal proximal tubules and podocytes21,26–28. These findings suggest that multiple-organ injury may occur at least in part due to direct viral tissue damage. The mechanism

of extrapulmonary spread of SARS-CoV-2, whether hematogenous or otherwise, remains elusive.

Endothelial cell damage and thromboinflammation. Endothelial cell damage by virtue of ACE2-mediated entry of SARS-CoV-2 and subsequent inflammation and the generation of a prothrom-botic milieu are other proposed pathophysiological mechanisms of COVID-1929–31. ACE2 expression has been demonstrated in arte-rial and venous endothelium of several organs29,32, and histopatho-logical studies have found microscopic evidence of SARS-CoV-2 viral particles in endothelial cells of the kidneys31 and lungs29. Infection-mediated endothelial injury (characterized by elevated levels of von Willebrand factor) and endothelialitis (marked by the presence of activated neutrophils and macrophages), found in mul-tiple vascular beds (including the lungs, kidney, heart, small intes-tine, and liver) in patients with COVID-19, can trigger excessive thrombin production, inhibit fibrinolysis, and activate complement pathways, initiating thromboinflammation and ultimately leading to microthrombi deposition and microvascular dysfunction31,33–36. Platelet–neutrophil cross-communication and activation of mac-rophages in this setting can facilitate a variety of proinflammatory effects, such as cytokine release, the formation of neutrophil extracel-lular traps (NETs), and fibrin and/or microthrombus formation37–40. NETs further damage the endothelium and activate both extrinsic coagulation pathways and intrinsic coagulation pathways. They were detected at higher levels in patients hospitalized with COVID-19 in a study from a large academic center in the USA (50 patients and 30 control participants), with a ‘pro-NETotic state’ positively correlating with severe illness41. Hypoxia-mediated hyperviscosity and upregulation of the HIF-1 (hypoxia-inducible factor 1) signal-ing pathway subsequent to acute lung injury may also contribute to the prothrombotic state42. Finally, direct coronavirus-mediated effects may also lead to an imbalance of pro- and anti-coagulant pathways43,44. Small case reports and case series have demonstrated the presence of fibrinous exudates and microthrombi in histopatho-logical examinations in patients with COVID-1944–48.

Dysregulation of the immune response. Dysregulated immune response and cytokine-release syndrome, due to overactivation of

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Fig. 1 | Pathophysiology of COVID-19. SARS-CoV-2 enters host cells through interaction of its spike protein with the entry receptor ACE2 in the presence of TMPRSS2 (far left). Proposed mechanisms for COVID-19 caused by infection with SARS-CoV-2 include (1) direct virus-mediated cell damage; (2) dysregulation of the RAAS as a consequence of downregulation of ACE2 related to viral entry, which leads to decreased cleavage of angiotensin I and angiotensin II; (3) endothelial cell damage and thromboinflammation; and (4) dysregulation of the immune response and hyperinflammation caused by inhibition of interferon signaling by the virus, T cell lymphodepletion, and the production of proinflammatory cytokines, particularly IL-6 and TNFα.

NATURE MEDICINE | VOL 26 | JULY 2020 | 1017–1032 | www.nature.com/naturemedicine1018

Gupta 2020

ACUTE COVID19

Nalbandian et al 2021

Symptom Reports

observed among 44.1% of patients. The Figure shows that ahigh proportion of individuals still reported fatigue (53.1%),dyspnea (43.4%), joint pain, (27.3%) and chest pain (21.7%).

Discussion | This study found that in patients who had recov-ered from COVID-19, 87.4% reported persistence of at least 1symptom, particularly fatigue and dyspnea. Limitations of thestudy include the lack of information on symptom history be-fore acute COVID-19 illness and the lack of details on symp-tom severity. Furthermore, this is a single-center study witha relatively small number of patients and without a controlgroup of patients discharged for other reasons. Patients withcommunity-acquired pneumonia can also have persistentsymptoms, suggesting that these findings may not be exclu-sive to COVID-19.6

Clinicians and researchers have focused on the acute phaseof COVID-19, but continued monitoring after discharge for long-lasting effects is needed.

Angelo Carfì, MDRoberto Bernabei, MDFrancesco Landi, MD, PhDfor the Gemelli Against COVID-19 Post-Acute CareStudy Group

Author Affiliations: Geriatrics Department, Fondazione PoliclinicoUniversitario Agostino Gemelli IRCCS, Rome, Italy.

Corresponding Author: Angelo Carfì, MD, Centro Medicinadell’Invecchiamento, Fondazione Policlinico Universitario AgostinoGemelli IRCCS, Largo Francesco Vito 1, 00168 Rome, Italy(angelo.carfi@policlinicogemelli.it).

Accepted for Publication: June 23, 2020.

Published Online: July 9, 2020. doi:10.1001/jama.2020.12603

Author Contributions: Drs Carfì and Landi had full access to all of the data inthe study and take responsibility for the integrity of the data and the accuracyof the data analysis.Concept and design: All authors.Drafting of the manuscript: Carfì, Landi.Critical revision of the manuscript for important intellectual content: Bernabei,Landi.Statistical analysis: Carfì.Supervision: Bernabei, Landi.

Conflict of Interest Disclosures: None reported.

Additional Information: The members of the Gemelli Against COVID-19Post-Acute Care Study Group are listed in reference 5.

1. Istituto Superiore Sanità. Sorveglianza Integrata COVID-19 in Italia. Published2020. Accessed June 8, 2020. https://www.epicentro.iss.it/coronavirus/bollettino/Infografica_3giugno%20ITA.pdf

2. Docherty AB, Harrison EM, Green CA, et al; ISARIC4C Investigators. Featuresof 20 133 UK patients in hospital with COVID-19 using the ISARIC WHO ClinicalCharacterisation Protocol: prospective observational cohort study. BMJ. 2020;369:m1985. doi:10.1136/bmj.m1985

3. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patientswith 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA.2020;323(13):1239-1242. doi:10.1001/jama.2020.1585

4. Landi F, Barillaro C, Bellieni A, et al. The new challenge of geriatrics: savingfrail older people from the SARS-CoV-2 pandemic infection. J Nutr Health Aging.2020;24(5):466-470. doi:10.1007/s12603-020-1356-x

5. Gemelli Against COVID-19 Post-Acute Care Study Group. Post-COVID-19global health strategies: the need for an interdisciplinary approach. Aging ClinExp Res. Published online June 11, 2020. doi:10.1007/s40520-020-01616-x

6. Metlay JP, Fine MJ, Schulz R, et al. Measuring symptomatic and functionalrecovery in patients with community-acquired pneumonia. J Gen Intern Med.1997;12(7):423-430. doi:10.1046/j.1525-1497.1997.00074.x

Trends in Daily Use of Biotin SupplementsAmong US Adults, 1999-2016Over-the-counter biotin supplements, especially in high dos-ages (≥5 mg/d, or 166-fold greater than the dietary recom-mendation of 30 μg/d), are widely available and marketed ashaving health benefits such as stimulating growth of hair andnails. The US Food and Drug Administration (FDA) issued asafety communication in 2017 warning that high-dosage bio-tin supplement use may interfere with laboratory testaccuracy.1 To understand the potential clinical implicationsof high-dosage biotin supplement use, we characterized theprevalence and trends in use of 1 mg/d or greater and 5 mg/dor greater of biotin among US adults from 1999 to 2016.A biotin dosage of 1 mg/d or greater was chosen becauselower dosages (<1 mg/d) are unlikely to interfere with labora-tory tests; a dosage of 5 mg/d or greater was studied becausebiotin supplements for hair and nail growth often contain5 mg/d or more.

Methods | Repeated cross-sectional surveys from the nation-ally representative National Health and Nutrition Examina-tion Survey (NHANES) were used to assess trends in self-reported biotin supplement use of 1 mg/d or greater and5 mg/d or greater from 1999 to 2016 (9 survey cycles). In eachcycle, NHANES sampled noninstitutionalized US residentsthrough a complex, stratified, multistage probability sam-pling design with certain populations overrepresented (over-all response, 74%).2 Participants provided informed consent.2

Because the data are publicly available and anonymized, the

Figure. COVID-19–Related Symptoms

40 20 0 20 40 6060 80

Acute COVID-19 phase Post–COVID-19 follow-up

Patients with symptom, %

FatigueSymptoms

Dyspnea

Joint pain

Chest pain

Cough

Anosmia

Sicca syndrome

Rhinitis

Red eyes

Dysgeusia

Headache

Sputum production

Lack of appetite

Sore throat

Vertigo

Myalgia

Diarrhea

80

The figure shows percentages of patients presenting with specific coronavirusdisease 2019 (COVID-19)–related symptoms during the acute phase of thedisease (left) and at the time of the follow-up visit (right).

Letters

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Carfì et al 2020

10% of people infected with SARS-CoV-2 will develop long COVID, with persistent symptoms after 4 weeks

COVID19 – British Columbia numbers

Cases148,000

Recovered145,000

Deaths1,759

https://ourworldindata.org/coronavirus-data

14,800

What to call it?

Post acute sequelae of COVID19 (PASC) – research term

Long COVID

Long-haul COVID

Post-acute COVID syndrome

Chronic COVID

(Myalgic encephalomyelitis/chronic fatigue syndrome?)

Definitions: timeline

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

There is no agreed-upon definition, but here is one from the CDC

Most common symptoms

• Fatigue• Brain fog • Dyspnea • Cough• Painful joints or muscles• Chest pain

• Depression or anxiety• Headache• Fever• Palpitations• Dizziness on standing• Post-exertional malaise

Who gets long COVID?• SEX: more common in women• Eg 23% of women and 19% of men still had symptoms 5

weeks after infection• AGE: most common in younger to middle-aged adults• E.g. prevalence was 25.6% at 5 weeks for those between 35

and 49 years old• SEVERE COVID: Patients with more severe acute symptoms were

more likely; HOWEVER also seen in a large percentage of those with mild or even asymptomatic acute cases

FAIR health white paper

Medically unexplained symptoms

“Everything has come back negative”

“There is nothing wrong with you”

Persistent symptoms and loss of function despite normal labs, imaging, electrophysiology, and other

objective measures of organ function

NOT PSYCHOSOMATIC/SOMATIFORM

Pathophysiology of long COVID

• Organ damage resulting from acute phase infection?• Complications from a persistent

hyperinflammatory state?• Ongoing viral activity?• Inadequate antibody response?• Worsening of co-morbidities?• Extrinsic factors e.g. lockdown, isolation?

How to approach long-COVID patients

Complete review of systems,

screening for common

symptoms

Target investigations to

patient symptoms

Exhaustive investigations are

not required to rule out objective end-organ disease

Validate patient symptoms

Refer to subspecialty for

red flags or objective findings

of disease

Approach to symptoms – what we do

• Dyspnea, cough: PFT, CT chest, echocardiogram, 6 minute walk test

• Palpitations: Holter, ECG

• Chest pain: ECG, exercise treadmill test, CCTA

• Orthostasis: orthostatic vitals, screen for POTS, am cortisol

• Mood symptoms – refer to Psychiatry (I am GIM!), trial of e.g. SSRI

Approach to Fatigue

• Review of focal symptoms to direct investigations• Screening labs: • CBC + diff • Lytes, urea, creatinine • Mg, Phos, Ca • Fasting blood sugar • CRP Liver tests• CK TSH Ferritin Urinalysis • HIV HBV HCV FIT test

• >6 months fatigue, PEM, brain fog, unrefreshing sleep ?= ME/CFS?

How to approach long-COVID patients

Complete review of systems,

screening for common

symptoms

Target investigations to

patient symptoms

Exhaustive investigations are

not required to rule out objective end-organ disease

Validate patient symptoms

Refer to subspecialty for

red flags or objective findings

of disease

When to refer

• Referral to subspecialty will depend on your access in your community, and your comfort with post-COVID patients• NO referral: If a patient has normal investigations and symptoms are

typical for long COVID, and are slowly improving• We often refer to other specialists with objective findings of organ

dysfunction (cardiac, respiratory, mental health, neurologic, dermatologic, thrombosis, voice dysfunction)• I consider referral to the CCDP at BCWH in cases of severe fatigue,

inability to work who have plateaued wrt recovery after 6-9 mo

Post-COVID19: Key points (CDC)

• The term “Post-COVID Conditions” is an umbrella term for the wide range of physical and mental health consequences experienced by some patients • Objective laboratory or imaging findings should not be used as the

only measure or assessment of a patient’s well-being• Lack of laboratory or imaging abnormalities does not invalidate the

existence, severity, or importance of a patient’s symptoms or conditions• Approach treatment by focusing on specific symptoms • Understanding of post-COVID conditions remains incomplete

How to approach long-COVID patients

Complete review of systems,

screening for common

symptoms

Target investigations to

patient symptoms

Exhaustive investigations are

not required to rule out objective end-organ disease

Validate patient symptoms

Refer to subspecialty for

red flags or objective findings

of disease

Questions/discussion

• rjanssen3@providencehealth.bc.ca