CME INDIA Presentation by Dr. T. B. Uma Devi, MD, FICP. Professor, Institute of Internal Medicine, Madras Medical College, Chennai.

Post COVID Sequelae: Non-Neurological & Non-Respiratory

Based on presentation at APICON 2022,Jaipur

Post COVID conditions

• CDC definition: Broad range of symptoms that develop during or after COVID-19, continue for ≥4 weeks and are not explained by an alternative diagnosis

Synonyms: This generally consists of a wide range of symptoms, often alternatively termed as

• Long Covid
• Post-acute sequelae of SARS-CoV-2 (PASC)
• Post-acute COVID-19
• Chronic COVID-19
• Post COVID syndrome

Timeline of LONG COVID

Predisposing conditions

• Survivors of all severity from mild to severe Covid can develop post COVID sequelae
• Some identified risk factors are
  • More than five symptoms during acute Covid
  • Female sex
  • Age >70 years
  • Comorbidities
  • Increased inflammatory markers

Clinical features

• MC Clinical manifestation – Fatigue & Dyspnoea
• Another common C/F s-
  • Persistent fever
  • Cough
  • Dysosmia
  • Rhinitis
  • Tinnitus
  • Hearing loss
  • Sore throat

Pathophysiology

1. Long term tissue damage: –
   • Pulmonary fibrosis
   • Cardiac myocyte injury
2. Pathological inflammation: –
   • T cell dysfunction resulting in activation of autoreactive T cells
   • Antiphospholipid antibodies causing neutrophil hyperactivity
   • Autoantibodies against interferon, neutrophils, connective tissues
3. Gut dysbiosis: – Causes altered neurotransmitter circuitries
4. Abnormal Mast cell activations: –

Multi-system Inflammatory Syndrome

Clinical features: –

• Average interval b/w preceding infection and MIS: 2-5 weeks
• Mimics Kawasaki disease & Macrophage Activation Syndrome

• Patients more than 21 years of age
• Hospitalized for more than 24 hours or
• With an illness resulting in death
• Meet the following clinical and laboratory criteria
• Without an alternative diagnosis for illness

Multi-system Inflammatory Syndrome – CDC – Lab Criteria

Diagnosis of MIS: –

• Subjective fever or temperature >38°C for ≥24 hours +
• at least three of above criteria with one being primary clinical criteria
• Common laboratory findings: –
  • Cytopenia’s with relative neutrophilia
  • Elevated CRP, ESR, D-dimer, ferritin, IL-6, and procalcitonin
  • Hypertriglyceridemia
  • Elevated liver enzymes
  • Elevated cardiac biomarkers
  • Hypoalbuminemia
  • Echocardiography- LV Dysfunction

Multisystem Inflammatory Syndrome- Rx

• Resuscitation of shock.
• IV steroids
• Plasmapheresis- Mainstay of treatment

Haematological sequelae

• Increased risk of arterial and venous thromboembolism.
• Higher risk during acute infection.

Predisposing Factors

What about Thromboprophylaxis

1. Thromboprophylaxis to all COVID positive hospitalized patients.
2. Post discharge prophylaxis: Based on individual risk factors.

Routine use of antiplatelet and anticoagulants post discharge- not recommended.

Endocrine sequelae

Risk factors

• Age – proportionally related
• Severe Covid-19 with ARDS
• Prolonged steroid therapy
• Known T1 & T2DM patients with increased risk of worsened hyperglycaemia

Endocrine sequelae other than Diabetes:

• Subacute thyroiditis – usually self-limiting
• Exacerbation of Graves’ disease
• Loss of bone density – particularly in elderly patients
• Stress induced pituitary adrenal axis changes
• Hot flushes, amenorrhea

Post Covid Infections

• Mucor mycosis
  • Risk Factors:  Prolonged use of corticosteroids.
    • Uncontrolled Diabetes
    • Immunocompromised states- Malignancy, CKD
  • Presentation:  MC – Rhino orbital symptoms
    • Pulmonary/ GI Involvement
• Increased incidence of invasive aspergillosis and strongyloides hyper infection have also been reported.

Mucor mycosis: Management

Extensive surgical debridement:

1.  Functional Endoscopic Sinus Surgery.
2. Orbital exenteration.

Antifungal therapy

A -LAMB 5–10 mg/kg for 4–6 weeks f/b T. Posaconazole 300 mg OD for 6-12 months.

B- Salvage therapy: T. Posaconazole 200 mg QID or T. Isavuconazole 200mg TDS on Day 1 f/b 200 mg OD

Cardiovascular sequelae

Pathophysiology

1. Direct viral invasion
2. Cardiomyocyte death & scarring
3. Persistently high oxygen demand

Courtesy: Reference 1

Courtesy: Reference 2

Clinical events

• Asymptomatic heart disease
• Myocardial injury –
  • Stress cardiomyopathy
  • Myocarditis
  • Myocardial infarction
• LVSD
• Right heart failure
• Cardiogenic shock
• Cardiac arrhythmia

Chest pain & palpitations are most common symptoms experienced.

Renal sequelae – COVAN

Some established risk factors are:

1. Severe COVID 19 infections
2. AKI on admission or during acute phase
3. Prolonged mechanical ventilation
4. Male > Female
5. Higher IL-6 level
6. Deranged baseline eGFR
7. Comorbidities – SHTN, DM, CAD

Although data regarding COVAN leading to ESRD is lacking, decline in eGFR during 6 months follow up is higher compared to seronegative patients.

Gastrointestinal Sequelae

Pathophysiology

Gut dysbiosis secondary to inflammation and direct effect of SARS-CoV-2 on intestinal epithelium

Clinical features

• Loss of appetite
• Nausea
• Vomiting
• Diarrheal
• Heartburn
• Abdominal pain

Management

• Symptomatic

Otorhinolaryngeal sequelae

1. MC – Sore throat
2. 2nd MC – Headache
3. Pharyngeal erythema
4. Nasal congestion
5. Anosmia or Dysosmia
6. Upper respiratory tract infection
7. Hearing loss

Ophthalmological sequelae

1. Most common – Conjunctivitis
2. 2nd Most common – Dry eyes
3. Ischemic complications – Ischemic optic neuropathy, Central retinal venous occlusion.
4. Uveitis
5. Retinal micro vasculopathy – retinal haemorrhages, cotton wool spots
6. White dot syndrome – multiple whitish-yellow inflammatory lesions affecting the outer retina, retinal pigment epithelium, and choroid.

Obstetric sequelae

1. Preeclampsia
2. Stillbirth
3. Preterm birth
4. Compared with mild COVID-19, severe COVID-19 is strongly associated with
   • preeclampsia
   • gestational diabetes
   • preterm birth and low birth weight
   • increased incidence of caesarean delivery

Dermatological sequelae

• Livedo reticularis
• Vesicular eruptions
• Urticaria
• Telogen effluvium

Psychological sequelae

Common symptoms include

• Excessive worry
• Irritability
• Restlessness and fatigue
• Poor appetite and insomnia
• Sexual dysfunction
• Sleep disturbance
• Patients may present with symptoms consistent with   
  • Anxiety
  • Depression
  • PTSD

Vaccination & Long Covid

• Two dose vaccination can potentially reduce the incidence of Long Covid.
• Recently, a case control study in UK showed that there were lower odds of symptoms lasting 28 days or more in individuals who had received two vaccine doses with odds ratio 0·51

Final Points

References:

1. Gheblawi M, et al. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ Res. 2020;126(10):1456-1474. doi:

2. Raman B, Bluemke DA, Lüscher TF, Neubauer S. Long COVID: post-acute sequelae of COVID-19 with a cardiovascular focus. Eur Heart J. 2022 Mar 14;43(11):1157-1172. doi: 10.1093/eurheartj/ehac031. PMID: 35176758; PMCID: PMC8903393.:10.1161/CIRCRESAHA.120.317015

3. Kidney Outcomes in Long COVID.Benjamin Bowe,Yan Xie,Evan Xu and Ziyad Al-Aly 2021 nov issue 32

4. Shu Qin Wei, Marianne Bilodeau-Bertrand et al. The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis. CMAJ April 19, 2021 193 (16) E540-E548; DOI: https://doi.org/10.1503/cmaj.202604

5. Do vaccines protect from long COVID? Priya V. The Lancet Respiratory Medicine  VOLUME 10, ISSUE 3, E30, MARCH 01, 2022.

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