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National Comprehensive Guidelines For Management Of Post-COVID Sequelae [for Doctors]

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Background

As we enter the second year of pandemic, patients with ongoing symptoms after recovery from COVID-19 are increasingly recognized as a growing population in need of attention. It has been found that many patients have been experiencing short to long-term sequelae of the disease. Some patients have residual sequelae/symptoms which may or may not be causally linked to COVID-19. In the absence of universally accepted definition, Post-COVID Syndrome by consensus is defined as signs and symptoms that develop during or after an infection consistent with COVID-19 which continue for more than 12 weeks and are not explained by alternative diagnosis. Recent literature also divides post-COVID patients into subacute or ongoing symptomatic COVID (4-12 weeks beyond acute COVID-19) and chronic COVID or Post-COVID syndrome (symptoms persisting beyond 12 weeks of onset of acute COVID-19). Another terminology which is in vogue is the ‘Long COVID’ that is defined by National Institute for Health and Care Excellence as symptoms that continue or develop after acute COVID-19. The timeline of COVID-19 phases and their definitions are shown in figure 1.

 

Figure 1: Terminology and Definition of Long COVID

 

Scope of the document

The purpose of this document is to guide doctors on managing post-COVID complications affecting cardiovascular, gastrointestinal, nephrological, neurological and respiratory systems.

 

Contents

Background

A.         Guidelines on Post-COVID Cardiovascular Sequel

• Cardiovascular sequelae Post-COVID
• Clinical features: Signs and symptoms
• Investigations
• Management
• Conclusion

B.         Guidelines on Post-COVID Gastrointestinal Sequelae

• Background
• Risk factors for developing post-COVID-19 GI and Liver manifestations
• Classification of GI symptoms
• Management of Post-COVID gastrointestinal manifestations
• Gastrointestinal checklist for long COVID syndrome
• Symptoms
• Investigations

C.         Guidelines for Screening and Management of Post-COVID-19 Nephrological sequelae

• Background: Common kidney diseases can be grouped into following major groups
• Common Post-COVID Nephrology related conditions
• What are the symptoms and signs to suspect Post-COVID nephrological related complications? When do we suspect Post-COVID nephrological complications/ sequelae?
• What are the minimum facilities required for treating these conditions?

D.         Guidelines for Management of Post-COVID Neurological Sequelae

• Background
• Common Post-acute COVID-19 Neurological Symptoms:
• Diagnosis and management of Post-COVID sequelae
• Investigations for Post-COVID patients with neurological sequelae
• Care and follow-up of Post-COVID patients:
• Annexure 1
• Annexure 2: IV Antiepileptics for management of SE

E.         Guidelines for the Management of Long-Term Respiratory Effects of COVID-19

• When do we suspect that the patient is having long term respiratory effects of COVID-19?
• What should be the initial evaluation of a patient with suspected long-term respiratory effects of COVID-19?
• Initial treatment offered to patients with Post-COVID respiratory sequelae?
• Management of specific Post-COVID pulmonary conditions

 

A. Guidelines on Post-COVID Cardiovascular Sequel

 

Cardiovascular sequelae Post-COVID

Cardiovascular sequelae not only occur in symptomatic COVID-19 patients but have also been reported in asymptomatic patients. Up to 20%–30% of patients hospitalized with severe COVID-19 have evidence of myocardial involvement manifested by elevated troponin levels, venous thromboembolism, heart failure and arrhythmias. Elevated troponins in acute symptomatic patients have been associated with poor outcomes and higher in hospital mortality rates. There are multiple mechanisms proposed to explain cardiovascular complications of COVID-19. Direct cardiomyocyte damage or damage secondary to hypoxia, microvascular dysfunction, thrombosis, and cytokine storm have been implicated. Given the high prevalence of cardiac injury, it is reasonable to expect a spectrum of heart disease with some residual post myocarditis abnormalities in severe cases. Myocardial involvement is presumed to be the initiator of inflammatory process and subsequent fibrosis (detectable on cardiac magnetic resonance imaging) and long-term sequelae too. The long-term sequelae include increased cardio-metabolic demands, myocardial fibrosis or myocardial scar, persistent left ventricular dysfunction, heart failure, arrhythmias, inappropriate sinus tachycardia and autonomic dysfunctions.

Many of the lingering signs and symptoms in patients after recovery from COVID-19 especially fatigue, dyspnea and chest pain are non-specific. This may occur denovo in an asymptomatic COVID-19 patients or in symptomatic COVID-19 patients with no clinically apparent cardiac involvement during the acute phase. Patients who develop viral myocarditis, myocardial infarction, pulmonary embolism, stress induced myocardial injury and arrhythmias during the acute phase are at higher risk of developing long-term cardiovascular complications and poor outcomes. These subsets of patients typically have comorbidities such as diabetes, hypertension, obesity, dyslipidemia and chronic kidney disease which would complicate their recovery after the acute phase.

Chest pain has been reported in ~20% of COVID-19 survivors at sixty-day follow-up. Palpitations have reported in ~10% of COVID-19 survivors at sixty-day follow-up. Ongoing chest pain and palpitations have been reported in 5% and 9% respectively at six-month follow-up post-acute COVID-19. Stress cardiomyopathy is 4-5 times more common during the COVID-19 pandemic when compared to pre-pandemic periods (7.8% versus 1.5-1.8%). Myocardial inflammation detected on cardiac MRI was found in as many as 60% of affected people more than 2 months after a diagnosis in one study. However, such high prevalence of myocardial involvement has not been replicated in other studies and the clinical implications, if any, of these findings is not known. Retrospective studies have found the rate of venous thromboembolism in the post-acute COVID-19 setting to be <5%. However, the vast majority of patients who have asymptomatic/mild COVID-19 do not have any serious sequalae. Case control studies have shown no excess cardiac involvement in survivors of COVID-19 infection as compared to controls.

 

Clinical features: Signs and symptoms

Profound fatigue is the most common symptom in most people with Long COVID. Other symptoms such as chest pain, dyspnea and palpitations are well described symptoms in patients with cardiac sequelae. Chest pain consistent with typical angina should be differentiated from atypical or non-anginal chest pain on the basis of location, aggravating and relieving factors. Likewise, respiratory causes of dyspnea need to be differentiated from cardiac causes. Heightened suspicion of dyspnea of cardiac origin especially in the setting of acute coronary syndrome, pulmonary embolism, myocarditis and tachy-arrhythmias is the key for early diagnosis of worsening cardiac status and initiating appropriate treatment. Palpitations in Post-COVID syndrome could be due to inappropriate sinus tachycardia, postural orthostatic tachycardia syndrome consequent to hyper-adrenergic state or premature ventricular contractions or ventricular arrhythmias consequent to myocardial fibrosis and scarring. Syncope of neurological origin has to be differentiated from that of cardiogenic causes by detailed history, meticulous examination and pertinent investigations like ECG and Holter examination. Heart failure should be suspected in patients with heart disease (Pre-COVID or during acute infection) having tachycardia, neck vein distention, dyspnea, orthopnea, paroxysmal nocturnal dyspnea, pedal edema, hepatomegaly, a left ventricular third heart sound.

 

Investigations

Patients with cardiovascular complications during acute infection or those experiencing persistent cardiac symptoms may be monitored with serial clinical, electrocardiogram and echocardiogram evaluations during follow-up. An algorithm to identify patients with cardiac injury during acute and convalescent phase is shown in figure 2. Patients evaluated at Post-COVID clinics with persistent cardiac symptoms described above should undergo chest radiograph, ECG and cardiac biomarkers (Troponins/NT-pro-BNP) to assess cardiovascular involvement.

Additional diagnostic tests such as echocardiography, cardiac MRI, cardio-pulmonary exercise testing, rhythm monitoring by Holter, chest CT and lower extremity Doppler testing maybe indicated based on symptoms and screening investigations.

 

 

Abbreviations: COVID-19: Coronavirus disease 2019; ICM: Ischemic cardiomyopathy; LGE-MRI: Late Gadolinium Enhancement- Magnetic Resonance Imaging; STEMI: ST-segment Elevation Myocardial Ischemia

Figure 2: Recommendations to identify patients with cardiac injury during acute and convalescent phase.

 

Management

The management of patients with Post-COVID cardiovascular complications depends on the status of pre-existing cardiac comorbidities and the cardiac condition developed during the acute phase (myocardial infarction, pulmonary embolism, tachy-arrhythmias, etc.) or during recovery. Common do’s and don’ts during post-COVID-19 period have been summarized in table 1.

Table 1: Common do’s and don’ts during Post-COVID period

Do’s during post-COVID-19 period

Don’ts during post-COVID-19 period

Frequent    hand    washing    and    social distancing Restructure routines at home Greater emphasis on healthy weight Healthy eating habits Moderate intensity exercise (30 minutes per day- 5 times a week) Avoid alcohol No smoking or tobacco products Avoid self-medication Arrange for telemedicine contacts for follow up with physician/cardiologist Vaccination after 3 months post recovery    if not vaccinated prior Important to control HT, DM and dyslipidemia. Follow guideline directed medical therapy for cardiovascular risk factors like HT, DM, dyslipidemia and cardiac conditions as prescribed by physician/ cardiologist Practice meditation, Yoga within your tolerance limits

Persistent symptoms (such as fatigue, cough, breathlessness, fever): limit activity to 60% of maximum heart rate (220- age in years) until 2-3 weeks after symptoms resolve Intense cardiovascular exercise in known cardiac patients and all cardiovascular training in case of athletes to be avoided for 3 months. Do not stop medications or take over the counter medications without consulting your cardiologist Do not ignore warning signs such as high grade fever, oxygen saturation< 93%, chest pain, dizziness, syncope or palpitations.

 

Impact of cardiopulmonary exercise in Post-COVID patients is not clearly known yet. However, general rules that are applicable to this subset of patients include one week of low level stretching and strengthening before exercise in patients with mild COVID-19 post recovery. In presence of mild Post-COVID symptoms, limiting exercise to slow walking and increasing rest period if symptoms worsen would be recommended. In patients with persistent symptoms (such as fatigue, cough, breathlessness, fever), limiting activity to 60% maximum heart rate (220-age in years) until 2-3 weeks after symptoms resolve. Intense cardiovascular exercise is to be avoided in all patients for 3 months. Athletes are advised to take three months of complete rest from cardiovascular training followed by specialist follow-up, with return to sport guided by functional status, biomarkers, absence of dysrhythmias, and evidence of normal left ventricular systolic function.

Patients with cardiac comorbidities/conditions such as diabetes mellitus, hypertension, obesity, atrial fibrillation and prior myocardial infarction and heart failure should be managed meticulously as per guideline directed medical therapy. Patients with cardiovascular diseases should be on statins, antiplatelet drugs in addition to the drugs for management of their risk factors including hypertension and diabetes. Adequate treatment of cardiac risk factors such as diabetes, hypertension, obesity and dyslipidemia in addition to the lifestyle modifications described above is the need of the hour in this ongoing pandemic to not only avoid development of new cardiac complications, but also preventing decompensation in those with pre-existing heart disease. Serial follow up of these patients biannually or annually is the key to ensure drug compliance and avoid further major adverse cardiac event.

Focusing on patients with heart failure with reduced ejection fraction, the non-pharmacological treatment in people with congestive heart failure include educating people about self-management, limiting dietary sodium to < 2g/day and fluid intake to < 2 L/day (1.5 L for severe CHF), explaining the symptoms of dyspnea, edema and bloating and smoking cessation. They are advised to report or reach through telemedicine to their cardiologist for worsening symptoms and for regular follow-up. Prior experience suggests higher risk of cardiovascular events after severe viral infections in patients with cardiovascular disease. Data from the ongoing pandemic is scarce as of now and it is encouraged to get vaccinated for COVID-19 and pneumococcal disease. Guideline directed medical therapy for heart failure includes beta blockers, Angiotensin Converting Enzyme Inhibitors (ACE inhibitors)/Angiotensin Receptor-Neprilysin Inhibitor (ARNi)/ Angiotensin Receptor Blockers (ARB), mineralocorticoid receptor blockers and diuretics. Patients with atrial fibrillation will require anticoagulation for stroke prevention as dictated by CHA2DS2Vasc score. Patients with confirmed DVT/pulmonary embolism require anticoagulation prophylaxis preferable with novel oral anticoagulants or warfarin to maintain the INR (International normalized ratio) in the range of 2-3.

 

Conclusion

COVID-19 impacts cardiovascular system in the recovery phase and is part of the overall Post- COVID syndrome. Physicians managing Post-COVID clinics should be aware of these symptoms and cardiovascular implications of COVID-19 sequelae. Discrete screening, appropriate investigations and evidence-based treatment of cardiovascular Long COVID is mandated to reduce long term impact of COVID-19.

 

B. Guidelines on Post-COVID Gastrointestinal Sequelae

Background

Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2). The virus has air borne transmission, but SARS-CoV-2 could also be isolated from the stool samples of COVID-19 patients indicating the possibility of faeco-oral

transmission. Beside the common respiratory symptoms, some COVID-19 patients experience gastrointestinal symptoms such as ageusia, lack of appetite, nausea, vomiting, dyspepsia, diarrhea, abdominal pain and hepatitis. Most symptoms pertaining to GI tract are mild and self-limiting. Presence of angiotensin converting enzyme 2 (ACE 2) receptors in the epithelium of gastrointestinal (GI) tract facilitates the entry and replication of the virus in the GI system resulting in GI manifestations. In some patient GI symptoms may appear before the onset of fever and respiratory symptoms. Numerous studies have been published on the prevalence of GI and liver manifestations during active COVID-19, the prevalence of post-COVID-19 GI and live manifestations is not known.

 

Risk factors for developing post-COVID-19 GI and Liver manifestations       

• Severe disease
• Older age
• Admission to intensive care
• Respiratory tract infection
• Gut dysbiosis due to antivirals and antibiotic use during hospitalization
• Liver injury due to COVID-19, drugs or alternative medication intake
• Polypharmacy

 

Prevalence of GI and liver manifestations during COVID-19

Symptom	Prevalence	Remarks
Diarrhea	8%	May be presenting symptom More common in hospitalized patients Rule out drugs or infectious cause of diarrhea
Nausea/Vomiting	8%	Avoid Polypharmacy
Abdominal pain	4%	May be the presenting symptom rule out other causes
Elevated OT/PT	15%	Seen in patients with severe disease, Exclude drug induced liver injury Compare with the baseline values if available

 

Classification of GI symptoms

 

 

Differences between COVID-19 induced and drug induced liver injury

Parameters	COVID-19 induced	Drug induced
AST, ALT	AST>ALT	ALT>AST
ALP	Normal / ↑	↑ / Normal
Serum bilirubin	Normal / ↑	↑ / Normal
Degree of enzyme elevation	< 5 times ULN	> 5 times ULN
Temporal association with drug	No	Yes
Abnormal LFT at presentation	Yes	No

 

Drugs used in COVID-19 management and GI side effects

Drug	Class	GI side effects
Azithromycin	Antibiotic	Diarrhea, Cholestatic hepatitis, Nausea, Pain abdomen
Hydroxychloroquine	Antimalarial	Abdominal pain, anorexia, diarrhoea, nausea, vomiting
Lopinavir	Antiviral	Dysgeusia, nausea, vomiting, pain abdomen, diarrhea, elevated amylase and lipase
Remdesivir	Antiviral	Nausea, transaminitis
Favipiravir	Antiviral	Nausea, vomiting, diarrhea, transaminitis
Tocilizumab	IL6 inhibitor	Transaminitis

 

Management of Post-COVID gastrointestinal manifestations

 

 

Gastrointestinal checklist for long COVID syndrome

Symptoms

Sl No	Symptoms	During COVID-19 disease		Post-COVID disease recovery
		Yes / No	Severity (0-10)	Yes/ No	Severity (0-10)
1.	Nausea
2.	Vomiting
3.	Dysguesia
4.	Loss of appetite
5.	Abdominal pain
6.	Hematemesis /melena
7.	Dysphagia
8.	GERD
9.	Constipation
10.	Fatigue

 

Examination

Sl no	Examination Findings	During COVID-19 disease	Post-COVID disease recovery
1.	Pallor
2.	Icterus
3.	Pedal edema
4.	Hepatomegaly
5.	Splenomegaly
6.	Signs of vitamin deficiency

 

Investigations

Sl no	Investigations	During COVID-19 disease	Post-COVID disease recovery
1.	AST
2.	ALT
3.	ALP
4.	Deranged PT/aPTT
5.	aPTT
6.	Amylase
7.	Lipase

 

Do’s and Don’ts in COVID-19

Do’s	Don’ts
Get COVID-19 vaccine Sanitize hands frequently Follow social distancing norms Wear mask properly Use bleach agent (Sodium hypochlorite    0.5%) to disinfect toilets Adequate intake of water Take healthy diet rich in fruits Seek health professional through telemedicine facility for advice Ensure adequate physical activity and  exercise at home	Don’t eat junk food Avoid use of non-prescription drugs Avoid self-medication Consult the nearest COVID-19 facility Avoid overcrowding Don’t panic if you get infected Avoid unnecessary Google search Avoid unnecessary visits to the hospitals and clinics for minor illnesses

 

 

C. Guidelines for Screening and Management of Post-COVID-19 Nephrological sequelae

 

Background: Common kidney diseases can be grouped into following major groups

1. Acute Kidney Injury: acute kidney injury (AKI) is recent onset (In days to few weeks) of kidney dysfunction characterized by an increase in creatinine, therefore reduction in estimated glomerular filtration rate (eGFR) with or without oliguria and has potential of complete recovery in more than 80-90% cases. 10-20% cases of severe AKI are at risk of developing chronic kidney disease (CKD).
2. Chronic Kidney disease: Chronic kidney disease (CKD) is defined as evidence of kidney disease with or without eGFR < 60 ml/min/1.73 m2. Evidence of kidney disease can be in the form of abnormal urinary albumin excretion > 30 mg/day, urinary sediment abnormality and/or abnormal radiological kidney abnormality. Once CKD is correctly diagnosed, it does not recover and has tendency of progression to advanced kidney damage, called end stage kidney disease (ESKD), when patient needs renal replacement therapy (RRT); that is dialysis and/or kidney transplant.
3. Glomerular diseases: Many kidney diseases involve glomerulus and can be grouped under glomerular diseases. Considering degree of proteinuria, kidney dysfunction and rapidity of onset of disease, the glomerular diseases can be further classified into clinical syndromes like; acute glomerulonephritis (GN), nephrotic syndrome, acute nephritic syndrome, rapidly progressive GN and asymptomatic urinary abnormalities.
4. Hypertension: More than 90% cases of hypertension are primary hypertension but out of 10% cases of secondary hypertension, kidney is commonest cause resulting in secondary hypertension.

 

1. Common Post-COVID Nephrology related conditions

 

1.1. What are the usual Post-COVID related nephrological complications/sequelae?

“Sequelae” is a pathological condition resulting from a prior disease, therapy or other trauma. A typical sequela is a chronic complication of an acute condition: long term effect of a temporary disease or injury. The common kidney related complications following COVID are as follows:

• New onset Acute Kidney Injury (AKI) in native kidney or transplant kidney
• Rapid progression of pre-existing CKD in native kidney or transplant kidney
• Progression of CKD to End Stage Kidney Disease (ESKD) in native kidney or transplant kidney
• New onset glomerular disease – proteinuria, hematuria and renal dysfunction
• New onset hypertension or worsening of hypertension