Post-COVID Care

Literature Review (Post-COVID Patient Care): Gallery View, Grid View

Post-Acute COVID Syndrome (PACS)Copy Link!

Updated Date: May 24, 2021

Course of RecoveryCopy Link!

Data on COVID-19 recovery are still emerging. However, it is clear that the course of recovery is highly variable among patients, may be prolonged over months, and is dependent on severity and particular manifestations of the initial illness. Anecdotal evidence suggests that recovery can be highly dynamic, with periods of improvement followed by periods of apparent acute worsening. Generally, recovery is thought to occur within about 2 weeks for mild infections and 2-3 months in severe infections (WHO).

Long term symptoms after COVID are often called "Long-COVID" in the popular media, but generally called post-acute COVID-19 syndrome (PACS), chronic COVID-19, post-COVID syndrome (PCS), or post-acute sequelae of SARS-CoV-2 infection (PASC) by the medical community. Various definitions for each of these exist, though increasingly they refer to symptoms occurring >4 weeks after COVID infection, without active viral activity or reinfection.

A recent Nature summary (Nalbandian et al) proposes two separate categories of PACS quoted here:

1. Subacute or ongoing symptomatic COVID-19, which includes symptoms and abnormalities present from 4–12 weeks beyond acute COVID-19
2. Chronic or post-COVID-19 syndrome, which includes symptoms and abnormalities persisting or present beyond 12 weeks of the onset of acute COVID-19 and not attributable to alternative diagnoses

Prevalence of PACSCopy Link!

In one study of 4,182 cases, 13.3% reported symptoms lasting ≥28 days, 4.5% for ≥8 weeks, and 2.3% for ≥12 weeks (Sudre et al). Amongst patients with prior hospitalization these are much higher: Patients were seen a mean of 60 days days after onset of symptoms. Only 12.6% of patients reported being asymptomatic, with particularly high rates of ongoing fatigue (53.1%), dyspnea (43.4%), joint pain (27.3%), and chest pain (21.7%) (Carfi et al). PACS is more common in people displaying a wider array of initial symptoms (>5 symptoms at time of diagnosis) (Sudre et al). It also appears to be more common in breakthrough cases (19% experience symptoms >6wks) (Bergwerk et al).

Demographics:

Longer term effects have been seen in persons of all demographic groups, though appear to be more common in women (14.9%) compared with men (9.5%), and older populations (ranging from 9.9% in 18–49 year olds to 21.9% in ≥70 year olds) (Sudre et al).

Tool: Table of Reported Prevalence of PACS (Nature Article, as of March 2021)

Symptom PatternsCopy Link!

Common reported symptoms are fatigue and dyspnea, joint pain, and chest pain (Carfi et al) In one survey of over 5000 patients with symptoms lasting >21 days, the most common symptoms were fatigue (79.0%), headache (55.3%), shortness of breath (55.3%), difficulty concentrating (53.6%), cough (49.0%), changed sense of taste (44.9%), diarrhea (43.9%), and muscle or body aches (43.5%). The timing of symptom onset varied and was best described as happening in waves. (Lambert et al)

One study found two different patterns of symptomatology (Sudre et al):

1. Exclusively fatigue, headache and upper respiratory complaints
2. Multisystem complaints (including fever and gastroenterological symptoms)

PathophysiologyCopy Link!

The causes of post-covid syndrome remain unknown at this time and are an area of active research. They include virus-specific pathophysiologic changes, immunologic aberrations and inflammatory damage and expected post-critical illness consequences. (Nalbandian et al)

1. Virus-specific pathophysiologic changes. The virus is known to infect and harm multiple organs, as described in each subsection here. Further, the endothelial damage and pro-coagulability seen in COVID may cause microangiopathic changes that cause longer-term damage (Lerner et al).
2. Immune and Inflammatory changes. Immune responses may have a role in the etiology of persistent symptoms. One analysis indicated that B-Cell responses may be similar to those described in autoimmune processes (activation of extrafollicular pathways) (Woodruf et al). T cell dysregulation may also be involved, given their role in acute disease. One study showed that coordinated CD4+ and CD8+ T-cell and antibody responses were associated with milder acute disease (Moderbacher et al). The relationship between antibody titers and viral load and post-COVID syndrome is unknown. In one study there was no statistically significant difference between initial viral titres or serial antibody levels between those who did and did not develop long term symptoms (Pereira et al).
3. Expected Post-Critical Illness. Post ICU syndrome is a constellation of symptoms and sequelae that is common for many people who have been critically ill.

Outpatient WorkupCopy Link!

Updated Date: April 19, 2021

Post-COVID Clinic VisitsCopy Link!

In some locations there are dedicated post-COVID care clinics specializing in care for PACS. However, most patients are still seen by primary care clinicians as well as an array of subspecialists such as pulmonologists, cardiologists, neurologists, and psychiatrists. Generally subspecialty care is not needed, except in patients who have known complications.

1. Frequency of Visits: Acute phase followup is discussed here. Visit frequency depends on many things, including severity of patient symptoms and initial disease, but generally for priorly hospitalized patients out of the acute phase and for those with ongoing symptoms we recommend a virtual check-in at 3 days after discharge, and again at 4-6 weeks. They should be seen in person at 12 weeks where possible. (Nalbandian et al)
2. Infection control: Patients who are seen in a clinic should be cleared based on infection control practices at the institution before an appointment is made. Generally time-based clearance criteria are acceptable, though those at risk for persistent infection or reinfection may need retesting.

Work-UpCopy Link!

Clinical testing is not always needed. If performed, testing should target evaluation for non-COVID etiologies as well as serious sequelae of disease. Clinicians need to distinguish between non-life-threatening symptoms such as persistent dyspnea, fatigue, and neurocognitive issues and serious sequelae such as VTE and heart failure (Greenhaigh et al).

1. Screen for “red flag” symptoms:

1. New or worsening dyspnea
2. Unexplained chest pain
3. New confusion
4. Focal weakness
5. New or worsening lower extremity edema

2. Screen for common neurocognitive symptoms:

1. Anxiety
2. Depression
3. PTSD
4. Sleep disturbances
5. Cognitive impairment

3. COVID Testing: SARS-CoV-2 PCR is discouraged as it can be positive for months (Katz). Reinfection is rare and generally there is not an indication for repeat testing. However if the patient has new symptoms of COVID or a concern for reinfection, it may be indicated in select cases. See here for guidance on repeat testing. Generally there is not an indication for serology, unless the initial diagnosis was not clear.
4. Imaging and Pulmonary Testing. See Radiographic Abnormalities and Pulmonary Function Tests. Adapted from the British Thoracic Society’s followup algorithms (George et al).

1. Mild disease without known pneumonia: Generally followup radiograph is not performed in patients with a mild course of disease, no prior positive imaging, and no worsening symptoms.
2. Mild disease with persistent dyspnea, or history of mild to moderate pneumonia: Obtain a Chest Xray at 12 weeks.

1. If normal and symptoms are resolved, no further workup is needed.
2. If persistently abnormal or symptoms persist, obtain full PFTs and consider CTPE for pulmonary embolism.

1. If PFTs are normal and the patient is improving, repeat Chest Xray.
2. If PFTs are abnormal or the patient is not improving, consider high resolution CT (HRCT).

3. Severe, or ICU- level disease: Obtain a Chest Xray at 12 weeks. Consider full pulmonary function tests and CTPE as well on a case-by-case basis.

1. If Xray is normal and symptoms are resolved, no further workup is needed.
2. If abnormal, get PFTs and a high resolution CT. Consider Echocardiogram and CTPE as well.

5. Ambulatory saturations including exercise pulse oximetry can be very helpful in determining of a patient has tachycardia on exertion (suggestive of POTS or arrhythmia) or desaturations on exertion (suggestive of parenchymal or pulmonary vascular disease).

1. 6 minute walk tests may help differentiate etiology of dyspnea in some patients

6. General labs for patients with persistent symptoms >4 weeks after infection, a complete blood count, chemistry panel, and liver function tests are recommended.

1. Additional labs will depend on symptoms, but could include cardiac enzymes and BNP for cardiac symptoms or prior cardiac concerns; D-dimer for concern for pulmonary embolism (although D-dimer may remain elevated up to four months following acute COVID-19 infection); thyroid function tests for fatigue symptoms CPK and ANA for joint or skin concerns. Routine coagulation markers are not needed. (Townsend et al.)
2. EKGs are done on a case-by-case basis, and should be performed on patients with persistent cardiopulmonary symptoms.
3. Echocardiograms are not routine except if concerned for heart failure. Cardiac MRI is typically experimental and not indicated clinically except by specialists for select indications (typically prior myocarditis).

7. Other workup and treatment will depend on the presenting symptoms. See below for:

1. Dyspnea and cough
2. Interstitial lung disease or organizing pneumonia
3. Fever or joint pain
4. Anxiety and depression
5. Fatigue and brain fog
6. Anosmia and ageusia (difficulty smelling and tasting)
7. Lightheadedness, sweating, racing heart or other symptoms of dysautonomia or postural orthostatic tachycardic syndrome (POTS)
8. Chest pain or history of cardiac complications/ myocarditis
9. Deep vein thrombosis
10. Kidney dysfunction
11. Post-ICU syndrome

General ManagementCopy Link!

1. Optimize comorbidities and health behaviors including sleep hygiene, smoking cessation, and decreased alcohol intake.
2. If the patient has residual oxygen requirement, have them keep a daily pulse oximetry journal to monitor for recurrent COVID-19
3. Encourage gradual increase in exercise (Greenhaigh et al). Generally patients should exercise as much as tolerated with Sp02 >90%. If oximetry monitoring is not available, try using an oximeter in the office, and tell them to pay attention to symptoms. Transient desaturations are unlikely to have negative consequences, but persistent desaturation should be avoided.
4. Please see all the specific subsections below (also linked just above) for specific management recommendations for common specific complaints, as well as indications for subspecialty referral.
5. Consider early rehabilitation referral for the patient if it is available
6. Educate patient on the typical course of recovery.
7. Consider enrollment in patient studies if available and patient advocacy groups if desired.
8. Make sure the patient still gets vaccinated for COVID.
9. Generally we advise against extended thromboprophylaxis unless it would be otherwise indicated if the patient were hospitalized with an acute illness (see delayed thrombosis for risk calculators and a more extensive discussion), though this is an area of active research.

Vaccination after COVID InfectionCopy Link!

Vaccination is recommended for patients who have had COVID infection. Vaccine-based immunity may provide immunity against a more conserved part of the virus (e.g. the receptor binding domain) than native immunity, and thus may be more effective.

1. Timing of vaccination for already infected patients is not determined, but many institutions recommend waiting 90 days after infection, especially if treated with monoclonal antibodies or convalescent plasma (as these may reduce the effectiveness of vaccines).
2. Currently most institutions recommend giving both vaccinations for two-shot vaccines, though in the future this may change as there is some evidence that a single dose may provide adequate immunity (An NIH study showed that after a single dose of the Pfizer-BioNTech vaccine, people with prior infection had antibody levels similar to people receiving 2 doses. However we do not know how antibody levels correlate with immunity. (NIH)
3. Warn patients that the injections may create more robust immune responses in them than they would in a never-infected patient, and thus they may experience more fevers and fatigue in the days following the injection

Anecdotal reports in COVID survivor communities that 30-40% of people may feel improved after COVID vaccination have not yet been empirically studied.

Pulmonary ConcernsCopy Link!

Dyspnea or CoughCopy Link!

Updated Date: April 19, 2021

Dyspnea is the most common persistent symptom beyond acute COVID-19, ranging from 42–66% prevalence at 60–100 d follow-up (Nalbandian et al). The need for supplemental oxygen due to persistent hypoxemia at 60 days was reported in 6.6 of patients in one US study (Chopra et al).

Differential: The differential for persistent dyspnea after COVID infection includes:

1. Neuromuscular weakness associated with deconditioning, protein calorie malnutrition, or Post Intensive Care Syndrome including myopathy from corticosteroid or neuromuscular blockade
2. Post-ARDS pulmonary fibrosis (see below on PFT and imaging findings)
3. Pulmonary embolism. Pro-thrombotic effects of COVID infection and hospitalization may increase risk of pulmonary embolism. We do not yet know how long these effects last.
4. Bacterial superinfection. As with other viral pneumonias, there is a theoretical increased risk of subsequent bacterial superinfection. About 3% of patients with COVID-19 who are admitted have a community acquired bacterial infection (Garcia-Vidal et al). Patients previously admitted may be at risk for drug-resistance bacterial infections in the future.
5. Dysautonomia or neurologically-caused dyspnea.
6. Cardiac dyspnea including myocarditis and arrhythmias.

Workup:

1. In addition to a full history for cardiac and pulmonary symptoms, ascertain the patient’s tolerance for exertion and whether symptoms are worsening. Persistent or worsening symptoms should prompt workup for non-COVID causes.

1. For fever, infectious workup should be performed (see fever)
2. For signs of heart failure or tachyarrhythmia, see cardiac.
3. For tachycardia, pleuritic chest pain, or other signs of PE consider EKG, D-Dimer, Echocardiogram, or contrast CT.
4. If features of dysautonomia (orthostatic hypotension, rapid pulse fluctuations, temperature dysregulation, sweating changes, gastrointestinal concerns), workup and treat as below.

2. Vitals signs for patients that have dyspnea should include:

1. Ambulatory saturations
2. Orthostatic vitals signs (which could indicate dysautonomia)

3. Chest imaging indications are described here. Generally with persistent or worsening symptoms after 3 months imaging is merited.
4. Pulmonary Function Tests are indicated as described here. Generally full PFTs should be considered at 3-6 months for persistent dyspnea.
5. 6 minute walk tests may help differentiate etiology of COVID in some patients
6. If despite this workup dyspnea remains unexplained, we recommend a gentle exercise routine as described below. For very complex or ill patients with multiple possible etiologies (e.g. cardiac, pulmonary, and/or dysautonomic), referral to pulmonary for consideration of cardiopulmonary exercise testing may be indicated to help differentiate between these causes, but generally these do not often elucidate a cause of ongoing dyspnea in otherwise well patients and should not be routine.

Treatment:

1. Treatment consists of treating the underlying etiology

1. Treatment of pulmonary embolism, secondary infection, post-ARDS ILD, etc are as they would be for any non-COVID patient
2. Treatment of breathing concerns related to chest pain on deep inspiration after COVID is covered here.
3. If the patient has features of dysautonomia, see here.

2. If workup is normal and the patient had mild COVID we typically focus on physical therapy, breathing exercises, and reassurance. Many of these patients seem anecdotally to improve with time.

1. Some specialized breathing-related therapy programs exist, and more are starting to treat post-COVID symptoms. Some online programs are also available for this purpose, such as Stasis Performance. More will no doubt become available as demand increases.
2. Symptomatic treatment of dyspnea is described here
3. Symptomatic treatment of cough is described here

3. Unexplained persistent dyspnea may merit referral to pulmonary or dysautonomia treatment providers

Tool: Information on Six Minute Walk Tests from the American Thoracic Society

Pulmonary Function TestsCopy Link!

Updated Date: April 19, 2021
Literature Review (Pulmonary Function Tests): Gallery View, Grid View

Testing options:

Generally full PFT (spirometry, lung volumes, and DLCO) are not indicated for all patients, but should be performed 3-6 months after infection if there are persistent pulmonary symptoms or persistent radiographic abnormalities after 12 weeks from infection. MIP/MEP in patients who have been ventilated or who have concern for steroid myopathy may help differentiate neuromuscular etiologies, especially in patients with restrictive disease.

PFT abnormalities:

Abnormalities in PFTs, specifically diffusion capacity (DLCO) and TLC, at time of hospital discharge appear to be common and correspond with severity of illness (Mo X et al). It is unclear how long reductions in pulmonary function persist, though DLCO reductions remain common at 30 days after symptom onset (Frija-Masson et al).

• In one study of 57 patients 30 days after hospitalization: “Six (10.5%), 5(8.7%), 25(43.8%) 7(12.3%), and 30 (52.6%) patients had FVC, FEV1, FEV1/FVC ratio, TLC, and DLCO values less than 80% of predicted values, respectively… Compared with non-severe cases, severe patients showed higher incidence of DLCO impairment (75.6%vs42.5%, p = 0.019)” (Huang et al)
• The median 6-min walking distance is low in approximately 1/4 of patients at 6 months. (Huang et al)

Radiographic AbnormalitiesCopy Link!

Updated Date: April 19, 2021

Timing of radiographs is described in the general workup section above.

Persistent radiographic abnormalities from COVID pneumonia may be present. These are likely to improve gradually over several months, but some dysfunction may persist, particularly in patients with ARDS. In a small study of 55 patients 3 months after discharge (64%) had persistent symptoms and 39 (71%) had radiologic abnormalities (interstitial changes or fibrosis) (Zhao et al) In a study of 114 patients with severe COVID pneumonia, fibrotic-like changes were found in 35% of patients on 6 month CT scans. The remainder had either complete radiological resolution (38%) or residual ground-glass opacification or interstitial thickening (27%) (Han et al).

Interstitial Lung DiseaseCopy Link!

There are case reports of COVID causing organizing pneumonia and interstitial lung disease, some of which appears to be independent of ARDS or mechanical ventilation (see radiographic abnormalities and pulmonary function tests above). The pathophysiology is likely a viral invasion of epithelial and endothelial cells, as well as immunologic damage, that cause endothelial/epithelial breakdown similar to other forms of ARDS. In history studies and autopsy studies, diffuse alveolar damage in multiple stages is seen, as are myofibroblasts, mural fibrosis, and honeycombing (Carsana et al). Fibrosis may be provoked by cytokines such as IL-6 and TGF-β, which have been found in non-COVID studies to contribute to pulmonary fibrosis.

There is not yet any consensus about whether treating patients who appear to have an inflammatory ILD or organizing pneumonia with corticosteroids is beneficial. At present, we recommend that clinicians weigh the risks and benefits of protracted corticosteroid treatment for each individualized patient case. There is early evidence to suggest it may help in a subset of cases: One study reviewed 837 patients with ongoing symptoms six weeks after infection. 35 patients were found to have persistent interstitial lung changes, predominantly organizing pneumonia (as reviewed by multidisciplinary specialists). Of these, 30 were offered corticosteroid therapy, resulting in a mean relative increase in transfer factor (DLCO) of 31.6% and forced vital capacity of 9.6% with significant symptomatic and radiological improvement (Myall et al).

Rheumatologic ConcernsCopy Link!

FeverCopy Link!

Updated Date: April 19, 2021

Persistent fevers can be seen in COVID infection, however fevers after 14 days (or new or severe fevers after improvement) should always prompt an infectious workup as these can be caused by secondary bacterial infections.

• Infectious workup should include (where available) a CBC with differential, LFT, UA, blood culture, procalcitonin, Chest Xray, and sputum culture.

Joint PainCopy Link!

Updated Date: April 19, 2021

While there are case reports of reactive arthritis (Jali, Ono) and rheumatoid arthritis (Derksen) triggered by COVID infection, frank arthritis (inflammation of the joints) is very rare after infection with COVID-19. However, persistent polyarthralgias (i.e. joints that are achy but not inflamed on exam or on imaging) are common, as is myalgic encephalitis/ chronic fatigue syndrome. Clinicians should work up joint pain depending on the severity and chronicity, similar to other clinical contexts.

1. Patients with signs of inflammation (swelling, erythema, effusion, etc) in one or more joints should be referred to a rheumatologist for work-up of alternate etiologies, such as septic arthritis, Lyme disease, gout, and rheumatoid arthritis. A joint aspiration can be helpful. If there is any suspicion for septic arthritis (e.g. sudden swelling and effusion, often with fever), joint aspiration should be performed emergently.
2. Patients with symptoms of less than 3 months’ duration can be managed conservatively with NSAIDS (if not otherwise contraindicated).
3. In patients with persistent joint pain after 3 months, or particularly debilitating joint pain or red flags such as visibly swollen joints, joint effusions, rashes, or daily fevers or drenching night sweats, we recommend workup with ESR, CRP, appropriate rheumatologic serologies (e.g. ANA, rheumatoid factor, CCP antibodies), a CBC with differential, complete metabolic panel, and urinalysis with sediment (to screen for protein or blood in urine). Patients should be referred to a rheumatologist for consultation.

Neurologic and Neuropsychiatric ConcernsCopy Link!

Updated Date: April 19, 2021
Literature Review (Post-COVID Neuropsychiatric Effects): Gallery View, Grid View

IncidenceCopy Link!

Patients may have sequelae of direct neurologic effects of COVID infection, including encephalitis or stroke. Prolonged hospitalization, particularly ICU admission, can lead to cognitive deficits (see post-ICU syndrome). In addition, prolonged illness can manifest different psychiatric and neurologic sequelae. In a study of over 200,000 patients, the estimated incidence of a neurological or psychiatric diagnosis in the 6 months following a COVID diagnosis was 33.62%, for 12.84% it was their first such diagnosis. These effects were more common in COVID-19 than in those who had influenza (hazard ratio [HR] 1.44, 1.78 for first diagnosis. (Taquet et al). The incidence of several neuropsychiatric complications are provided below. Please see ‘Fatigue’ for discussion of chronic fatigue syndrome.

• 0.56% for intracranial haemorrhage and 2.10% for ischaemic stroke (these are covered here)
• 0.11% for parkinsonism and 0.67% for dementia
• Mood disorder 13.66%; first diagnosis 4.22%
• Anxiety disorder 17.39%; first diagnosis 7.11%
• Psychotic disorder 1.40%; first diagnosis 0.42%
• Substance use disorder 6.58%; first diagnosis 1.92%

Workup and treatment: Patients with known neurologic and/or psychiatric complications of COVID-19 should be followed by a neurologist and/or psychiatrist where available. Management of these complications following COVID-19 should be the same as it is in patients who have these disorders independent of COVID19.

Fatigue and “Brain Fog”Copy Link!

Updated Date: May 9, 2021

Fatigue is by far one of the most common PACS symptoms. Half of patients in one study reported ongoing fatigue, a median of 10 weeks after infection, with 32% reporting symptoms >12 weeks after (Townsend et al). Most patients' symptoms resolve on their own, though it may take many months. If symptoms last more than six months, some of these patients may meet criteria for Myalgic encephalitis/chronic fatigue syndrome (ME/CFS), which has been documented with many severe viral syndromes including COVID. More information about diagnosis of ME/CFS is available in the Institute of Medicine Clinician’s Report. There is some relationship between ME/CFS symptoms and dysautonomia/ POTS. For ME/CFS specifically:

1. Diagnosis requires the following three symptoms Frequency and severity of symptoms should be assessed. The diagnosis of ME/CFS (SEID) should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity. :

1. A substantial reduction or impairment in the ability to engage in pre-illness levels of occupational, educational, social, or personal activities, that persists for more than 6 months and is accompanied by fatigue, which is often profound, is of new or definite onset (not lifelong), is not the result of ongoing excessive exertion, and is not substantially alleviated by rest and
2. Post-exertional malaise, and
3. Unrefreshing sleep

2. At least one of the two following manifestations is also required:

1. Cognitive impairment or
2. Orthostatic intolerance

Management:

There is no cure or medical treatment for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Some patients, but not all, achieve some degree of relief with symptom management. There is some overlap between ME/CFS and dysautonomia (treatment is covered here).

• Post-exertional malaise can be managed by pacing training (or activity management). Many patients describe a push/crash cycle where they feel exhausted after physical or mental exertion, and take a long time to recover and thus avoid exercise. However, gentle exercise anecdotal improves patients tolerance over time and improves quality of life. Pacing management is generally targeted at increasing mental and physical exertion slowly, but staying within an “exertion envelope” to avoid exceeding personal limits. See this tool.

• Rehabilitation specialists or exercise physiologists with experience with ME/CFS can help develop strategies.

• For treating insomnia, good sleep habits and medications are helpful
• Pain should be managed with over the counter medications (generally NSAIDs and acetaminophen), gentle movement, gentle massage and other supportive treatments.
• Memory and concentration problems can be hard to treat. Some patients may benefit from stimulant medications such as those used to treat ADHD. However, not all patients derive benefit from these, and they often can worsen the push/crash cycles described above. Medications such as those used for Alzheimer's Disease are not recommended.
• Depression and anxiety are covered here.
• Lightheadedness and orthostasis are covered here.
• Disability from ME/CFS is complicated. In the USA, more information is available from the CDC website.

Tool: Institute of Medicine Clinician’s Report for ME/CFS diagnosis and treatment

Tool: Pacing Tutorial

Anxiety and DepressionCopy Link!

Updated Date: May 9, 2021

Recovered COVID patients are at increased risk of mood disorders including depression and anxiety, as well as consequences of isolation and social stigma. It is unclear as yet whether mood changes arise from increased stress, isolation, and trauma or whether there is an additional direct neurocognitive effect of the virus.

• In a study of analyzing health records of more than 236,000 patients with COVID-19 found that six months after being diagnosed with COVID-19, 1 in 3 patients had experienced a psychiatric or neurological illness (Taquet et al). While anxiety, mood, and substance use disorders were most common, concern was raised about rates of serious neurological complications, especially in patients who had been severely ill with Covid-19. The data also indicated that compared to control groups of people who had the flu or other non-Covid respiratory infections, first-ever neuropsychiatric diagnoses were almost twice as high.
• The presence of a mood disorder prior to admission is associated with greater likelihood of discharge to a skilled nursing facility or other rehabilitation facility rather than home (Castro et al).
• Hospitalized individuals with a history of mood disorder may be at risk for greater COVID-19 morbidity and mortality and are at increased risk of need for postacute care. Further studies should investigate the mechanism by which these disorders may confer elevated risk.
• ICU patients are at particular risk of post-traumatic stress disorder. See Post-ICU syndrome
• ME/CFS can also be associated with mood changes.

Management:

In general, these are not treated differently than patients suffering with anxiety or depression from other etiologies (see here for treatment recommendations).

Prolonged Anosmia and AgeusiaCopy Link!

Updated Date: April 19, 2021

Loss of smell and taste have been observed to be prolonged, often many months. See anosmia and ageusia for a review of this topic. Some patients have phantom smells (parosmia). Overall, the loss of smell persists for more than 4 weeks in about 10% of patients (Walker et al).

Management:

• Confirm that the olfactory disturbance is COVID-19 related. People with progressive smell loss/disturbance that does not line up chronologically with COVID-19 infection need to go through the typical workup for olfactory disturbance so that nothing is missed (typically nasal endoscopy and MRI if endoscopy is normal). Similarly, patients with anosmia associated with other neurological findings should be worked up for alternate causes.
• There is currently no definitive recommendation for medical treatment of these effects. A synthesis of ENTUK and BRS expert guidance and recommends (Walker et al, Hopkins et al):

• Olfactory (smell) training for patients with symptoms over 2 weeks. Training is available at AbScent and Fifth Sense.
• Topical corticosteroid nasal drops (fluticasone or betamethasone typically) can be tried in patients with symptoms lasting more than 2 weeks. These tend to be low-risk, but efficacy is not yet proven, and they likely help mostly with nasal obstruction.
• Oral steroids have minimal data, except some case reports (Le Bon et al). Do not offer oral corticosteroids within 2 weeks of infection unless otherwise indicated as the chance of spontaneous recovery is high, and they may cause delayed viral clearance. We do not recommend using these in patients who are still symptomatic. They are optional in patients with no other symptoms more than 2 weeks after infection.

• Monitor patients’ weight, as smelling and tasting changes can trigger weight loss
• Ensure loss-of smell safety measures: smoke detectors should be functional, if there is natural gas in the household then it should be removed or detectors obtained, and food safety should be assured with adequate refrigerator/freezer temperatures and expiration date checks
• For patients with symptoms persisting after 3 months, consider referral to ear, nose, and throat physician.

HeadacheCopy Link!

Migraine-like headaches are relatively common, and late-onset headaches may be do to high cytokine levels. Many times these headaches are refractory to typical analgesics. About 38% of patients in one study had ongoing headaches after 6 weeks (Pozo-Rosich et al). Management of headache is the same as for non-COVID patients, and is covered in BWH’s COVID guidelines.

Dysautonomia and POTSCopy Link!

Updated Date: March 15, 2021

After COVID, some patients develop disorders of the autonomic nervous system, which most commonly include orthostatic hypotension, postural tachycardia of either CNS or peripheral etiology, gastrointestinal disorders, and sweating abnormalities, as well as other rarer symptoms. Evidence-based treatments exist for autonomic dysfunction, particularly for the cardiovascular manifestations.

• Autonomic dysfunction has been associated with post-infectious syndromes in the past, and is thought to occur most likely either through direct viral sequelae or through autoimmune mechanisms (Dani et al).
• In a retrospective study of all 841 COVID patients admitted to two Spanish hospitals in March 2020 (the ALBACOVID registry), 2.5% developed dysautonomia (Romero-Sanchez et al).
• The literature includes multiple case reports and small case series of patients developing autonomic intolerance (most commonly postural orthostatic tachycardia syndrome (POTS), but also orthostatic hypotension, hyperhidrosis, nausea/constipation/dyspepsia, and pupillary abnormalities such as accommodation defects) after COVID infection (see e.g. Umapathi et al).

DiagnosisCopy Link!

• Vitals: Initial steps include orthostatic vital signs, thorough cardiopulmonary and neurologic exams, and EKG.

• POTS is diagnosed by an increase in HR by at least 30 bpm from supine to standing or by an increase to a HR of >120 within ten minutes of standing. Further testing can help distinguish a central etiology, which is generally accompanied by a hyperadrenergic state, from a peripheral autonomic neuropathy.
• Orthostatic hypotension is diagnosed by a drop in blood pressure by >20 mmHg systolic or 10 mmHg diastolic within three minutes of standing.

• Differential: Autonomic symptoms can overlap with other pathologies. For instance, patients can have shortness or breath (often orthostatic), palpitations, and poor exercise tolerance. Thus, investigating other etiologies with targeted testing such as outpatient rhythm monitoring, echocardiogram, chest imaging, pulmonary function tests, etc. is often warranted.
• Laboratory tests to consider (Benarroch et al, Zadourian et al).

• CBC to rule out significant anemia, chemistry panel for electrolyte disturbances, TSH, Early morning cortisol, Hemoglobin A1c, ANA, with subserologies if elevated
• Supine/seated/standing plasma catecholamine levels (marked increases can point towards a central hyperadrenergic state as a cause of POTS, rather than peripheral nerve pathology)
• Urinary catecholamines and metanephrines
• If available, serum paraneoplastic antibody panel (Through Mayo Clinic in the U.S.)

• Additional diagnostic tests to consider in select patients (most of these are not widely available outside of select centers, and often do not change management)

• Skin biopsy for epidermal axonal density, as evidence for small fiber autonomic neuropathy
• Non invasive and invasive cardiopulmonary exercise testing
• Tilt table testing
• 24-hour blood pressure monitoring
• Formal autonomic testing (including cardiovagal and sudomotor testing, sometimes thermoregulatory testing as well)
• Urodynamic testing, gastrointestinal motility testing, or ophthalmologic exam if indicated by symptoms

Treatment:Copy Link!

Common treatment options for postural orthostatic tachycardia and orthostatic hypotension include the following:

• Lifestyle measures (Mar et al):

• Elevation of head of bed
• Avoiding prolonged recumbent position
• Copious fluid intake (2-3 L daily)
• Plenty of salt intake (10-12g daily)
• Graded exercise regimen - can start with recumbent exercise such as seated bike/rowing machine)
• Compression pants such as running compression pants, and/or abdominal binders
• Small frequent meals
• Avoid exacerbating factors such as dehydration, overheating, alcohol, prolonged standing

• Pharmacologic therapy (most common therapies; others exist as well) (Zadourian et al, Fedorowski):

• Salt tablets - e.g. 1g TID, though dietary salt preferable
• Beta blockers - best evidence for propranolol, 10-40 mg three times daily, start at lower end of dosage range
• Fludrocortisone - For volume expansion. Start with 0.1 mg PO daily, then increase up to 0.2 mg PO daily, monitoring after initiation and titration for hypokalemia
• Pyridostigmine - Acetylcholinesterase inhibitor to facilitate cholinergic ganglionic nerve transmission and increase sympathetic vascular tone, particularly in patients suspected of autonomic neuropathy as primary etiology. 30-60 mg two to three times daily. Start at 30 mg twice daily.
• Midodrine - For orthostatic hypotension. 2.5-10 mg three times daily, start at 2.5 mg three times daily during daytime hours. Note that some patients with POTS may have hypertension, and that midodrine can cause severe supine hypertension, so use in select patients, avoid <4 hours before bedtime, and monitor blood pressure after initiation/titration.
• Clonidine - As a sympatholytic, especially in patients with elevated standing catecholamines. 0.1-0.4 mg PO twice daily, start at 0.1 mg at night and can titrate up by 0.1 mg each week
• Ivabradine, a negative chronotropic, may be indicated in patients with hyperadrenergic POTS (plasma NE >600 pg/ml and abnormal tilt table test). (Taub et al)

• Some data, particularly for small fiber autonomic neuropathy, exists for IVIG (Oaklander) and/or immunosuppression in cases with strong suspicion for autoimmune etiology. This should be pursued only in consultation with neurology.
• Appropriate referrals include cardiology and neurology. Specialist autonomic neurologists exist as well.
• There is inadequate data at present to assess the course of post-COVID autonomic dysfunction, though some patients have shown recovery (see e.g. Umpathi et al).

Hematologic ConcernsCopy Link!

Delayed ThrombosisCopy Link!

Updated Date: May 9, 2021

The pro-thrombotic state of acute COVID is well-described, but the duration of this state is unclear. Retrospective studies to date suggest that the rates of VTE following hospitalization for COVID-19 are similar to rates for other acute medical illnesses (Patell et al and Roberts et al). One study of 163 patients suggested a 2.5% incidence of thrombosis by 30 days, with mean occurrence at 23 days. However, there was a 3.7% incidence of bleeding, mostly due to fall (Patell et al). One registry study of COVID patients indicated that the 90 day post-discharge venous and arterial thromboembolism and all-cause mortality rates were 1.55%, 1.71%, and 4.83% respectively (Giannis et al). Delayed VTE events, even in patients who were never hospitalized, have been reported.

Extended thromboprophylaxis. Generally we do not recommend extended thromboprophylaxis past hospitalization for COVID patients, unless it would otherwise be indicated for non-COVID factors related to acute illness (such as protracted immobility). We recommend the IMPROVEDD score (Spyropoulous et al) to assess 42- and 77-day VTE risk, and to weigh this risk against bleeding risk when determining if extended prophylaxis is indicated. Some centers do recommend extended prophylaxis (generally up to 6 weeks after discharge). This remains an area of active investigation, and shared decision-making is appropriate.

Acute COVID-related VTE treatment after hospitalization. For thromboses associated with acute COVID infection, these are considered “provoked” thromboses and are treated with the same duration of anticoagulation as for non-COVID associated clots of a similar type (typically 3-6 months depending on resolution of the initial provocation, residual vein thrombosis, elevated inflammatory markers, other VTE risks including obesity, known inherited thrombophilia, or past VTE).

Delayed VTE. The duration of the hypercoagulable state from COVID is unknown. For patients who present later than 8-12 weeks after an COVID infection with a new VTE we would recommend considering this “unprovoked” and working up accordingly for hypercoagulable states. There is no data behind this specific time cutoff for post-COVID syndrome, this recommendation is based on the analogy of delayed VTE after surgery and may change in the future as more is learned. There is some evidence that antiphospholipid autoantibodies may be found in some cases (Zuo et al).

Arterial Thrombosis. For arterial clots without obvious structural abnormalities, cardioembolic source, or catheter-associated thromboses, hypercoagulability workup is generally warranted, regardless of COVID status or timing (for arterial clot workup and treatment see May et al).

Cardiac ConcernsCopy Link!

Chest Tightness and DiscomfortCopy Link!

Updated Date: April 19, 2021

Persistent chest discomfort following recovery is common (21.7%, Carfi et al) and can take quite some time to abate. The etiology is unknown but is hypothesized to be a combination of pleuritic or pericardial inflammation, costochondritis, musculoskeletal pain from coughing, or microvascular cardiac injury. Of course, more serious causes of chest pain are also possible, including myocarditis, myocardial infarction, spontaneous coronary artery dissection (Cannata et al), pulmonary embolism, new bacterial pneumonia, pleural effusion, and pneumothorax. Palpitations are also reported in about 9% of patients. These can be due to arrhythmias, but are often due to a debilitating but challenging to diagnose condition called Postural Orthostatic Tachycardia Syndrome (POTS) (which is addressed under dysautonomia). Frustrating for the provider and the patient is that standard testing, encompassing ECG, ECHO, stress test, heart rate monitors, and cardiac magnetic resonance imaging, tend to be normal in the majority of patients.

Management:

1. New and worsening chest pain should always prompt workup for the above etiologies according to the nature and timeline of the pain. An exhaustive summary of the workup of chest pain is beyond the scope of this site, but generally include ECG, Echocardiogram, stress testing, Holter or event monitors, and cardiac MR depending on the indication.
2. Ongoing but improving chest pain after concerning etiologies have been ruled out generally does not require treatment if it is not interfering with life. However, NSAIDs may be considered in the absence of contraindications. Colchicine (in half dose) can be used NSAIDs are ineffective. We do not recommend opiates.
3. For Postural Orthostatic Tachycardia Syndrome see Dysautonomia and POTS.

Cardiac DysfunctionCopy Link!

Updated Date: April 19, 2021

Many patients who have recovered from COVID infection have signs of cardiac damage (see myocarditis). In individuals with no known cardiac involvement or specific complaints, studies of recovered COVID patients have documented changes in systolic function and elevated troponin (Puntmann et al; Huang et al). The long term implications of documented inflammation remain unknown. Patients with viral myocarditis will likely have some recovery over time, as is seen in other forms of virally-induced inflammation, but the extent of recovery is not yet known

• In one study of 100 patients undergoing cardiac MRI 69-92 days after diagnosis, 78% of patients who had recovered had some signs of cardiac damage, and 60% had ongoing myocardial inflammation. Troponins were elevated in 76% of these patients, but cardiac function was preserved. This was independent of severity, pre-existing conditions, and the time of diagnosis (Puntmann et al).
• This is true even among patients without prior cardiac disease. In one study of 26 college athletes diagnosed with COVID (none hospitalized, most asymptomatic), 46% showed evidence of myocarditis or prior myocardial injury by cardiac MRI ranging 12-53 days after diagnosis. (Rajpal et al)

Management:

1. Whether screenings to detect cardiovascular damage should become a routine part of follow-up care for COVID-19 patients remains unclear.

1. Patients with ongoing chest pain, palpitations, or signs of heart failure should be worked up for active disease as above.
2. Completely asymptomatic patients with a history of mild disease likely do not need any post-COVID workup, though this may change as we learn more.
3. Completely asymptomatic patients with underlying cardiac conditions or a history of severe COVID infection, comparing a pre-COVID and a post-COVID EKG is reasonable, as is obtaining troponin/ Nt-proBNP. If any abnormalities, work up as above.

2. Patients who experienced a known cardiac injury (including MI, cardiac arrest, arrhythmia, or symptomatic myocarditis) due to COVID should be followed by a cardiologist.

1. Serial echocardiogram and electrocardiogram at weeks 4-12 is generally indicated (George et al).
2. Management of arrhythmia is covered in this article (Desai et al).
3. Competitive athletes with cardiac damage should abstain from competitive sports or aerobic activity for 3–6 months until resolution of myocardial inflammation (by MRI or troponin). (Maron et al)
4. Adhere to guideline-directed medical therapy. Despite initial concerns, RAAS inhibitors are considered safe to use in COVID patients.
5. Standard lifestyle modifications are always recommended including

1. Ensure daily physical activity, ideally following the American Heart Association Guidelines of at least 30 minutes of exercise per day for at least 6 days per week
2. Smoking and alcohol cessation
3. Lipid lowering medications if indicated
4. Weight loss management for obese patients

Renal ConcernsCopy Link!

Updated Date: March 15, 2021

Incidence: Up to 40% of the hospitalized COVID-19 patients develop acute kidney injury (AKI) and 6.6% require renal replacement therapy (RRT). (Ng et al) Interestingly, one study found that 13% of patients in a cohort of hospitalized patients from Wuhan had normal eGFR on admission and no AKI while in hospital had reduced eGFR at 6 month follow up, suggesting a longer-term insult. (Huang et al).

Pathophysiology: The mechanism of renal injury is generally acute tubular necrosis on renal biopsies and autopsies. Microthrombi may play a role as well. A new entity, COVID-19-associated nephropathy (COVAN), is also possible. COVAN is characterized by a collapsing variant of focal segmental glomerulosclerosis with involution of the glomerular tuft. COVAN likely emerges from interferon and chemokine activation, with APOL1 risk alleles as a risk factor (similar to HIV) (Velez et al).

Management

1. No known renal injury: Given the Huang et al study suggesting a possible late presentation of decreased eGFR, we recommend that where possible post-COVID patients who have not received a BMP get their eGFR tested prior to the prescription of renally-cleared medications. Similarly, patients with symptoms past 4 weeks or prior hospitalization may benefit from a basic metabolic panel on followup.
2. Known renal injury unresolved at the time of discharge: AKI patients who do not recover to baseline kidney function should be followed by nephrology where possible after their discharge from the hospital for potential residual CKD.
3. For patients on Renal Replacement Therapy (RRT): Although mortality is significantly higher in RRT requiring patients, 66% of the survivors have renal recovery to become RRT-independent (Ng et al) in the first month. Recovery rate rises to 92% with longer follow up at 150 days (Stockmann et al). Hence, these patients should be monitored closely by the dialysis units for signs of renal recovery such as lower pre-dialysis serum creatinine levels and increasing urine output. Hemodialysis patients should be directed into the dialysis units accepting COVID-19 patients until completion of COVID-19 quarantine period, whereupon they can return to their original units. These practices highly vary depending on location, available dialysis units and logistics.
4. Transplant patients who had reduction in their immunosuppression regimen during COVID-19 pneumonia should have close follow up after recovery. If the immunosuppression was reduced during the infection, it can be increased back to pre-infection level cautiously within weeks to months depending on their clinical course (Kataria et al). However, clear data and guidelines remain absent about how to manage the immunosuppression in patients with COVID-19.

Post-ICU SyndromeCopy Link!

Updated Date: April 19, 2021

Patients admitted to ICU are at risk of post-ICU syndrome, a diverse constellation of physical, cognitive, and psychiatric deficits. In one study of 45 patients in New York 91% met criteria for post-ICU syndrome (Martillo et al).

• 86.7 % had impairments in the physical domain

• 58% had some degree of mobility impairment

• 48% reported impairments in the psychiatric domain. 38% exhibited at least mild depression, and 18 % moderate to severe depression. 18% met criteria for PTSD.

• This is also supported by a much larger study where post-ICU patients had a six-month estimated incidence of a neurologic or psychiatric diagnosis of 46%. This was the first such diagnosis for 25%. (Taquet et al).

• 8% had impairments on cognitive screening.

Tracheostomy and Chronic ventilation: In a study of 1,800 patients requiring tracheostomies, only 52% were successfully weaned from mechanical ventilation after a month in a national cohort study from Spain (Martin-Villars et al).

Diagnostic Evaluation:

• Cognitive: Patients with suspected PICS can undergo an assessment in the clinic, with referral to neuropsychiatry – if available – for further testing depending on results. It is not known to what extent results on this testing following hospital discharge predicts long-term impairment.

• Montreal Cognitive Assessment (MOCA). This is a more sensitive test for cognitive impairment. Modified Mini-Mental State Examination (MMSE)
• Mini-Cog

• Mental health:

• Hospital Anxiety and Depression Scale (HADS)
• Impact of Events Scale-Revised (IES-R) for PTSD

Management:

Treatment for post-ICU syndrome is largely targeted at the specific physical and psychological needs of the individual. Some additional information is available at AfterTheICU.