Post-COVID-19 Program Case Conference Summaries

Case Conference Summaries

UT Health Austin’s Post-COVID-19 Program aims to create an educational community in which healthcare professionals can come together to learn more about post-acute sequelae of COVID-19 (PASC) infection, an increasingly recognized syndrome in which patients continue to experience symptoms of COVID-19 months after initial infection.

The Dell Medical School at The University of Texas at Austin hosts case conferences, which are a part of a series known as the Austin PASC Collaborative. During these case conferences, community healthcare professionals present cases to and receive feedback on diagnosis, management, and the emerging science of post-acute sequelae of COVID-19 (PASC) infection from an expert panel consisting of specialists across internal medicine, neurology, pulmonology, and rheumatology as well as behavioral and mental health. See below for a list of case summaries presented at past conferences hosted through the Post-COVID-19 Program.

July 8, 2021

Written July 28, 2021 by: Matthew Seghers, MS4, Faith Noah, MS4, and W. Michael Brode, MD

Expert Panel: Esther Melamed, MD, Michael Shapiro, MD, George Rodgers, MD, Kevin Hackshaw, MD, Robin Hilsabeck, PhD, ABPP, David Ring, MD, PhD, Christopher Garrison, MD, Arlyn Thobaben, DPT, OCS,
Rama Thyagarajan, MD, Aaron Braverman, LCSW-S

Endocrine abnormalities are common in COVID-19, with previous history of T2DM associated with increased mortality in COVID-19. It is hypothesized that COVID-19 infection in patients with T2DM elevates secretion of glucocorticoids and catecholamines. Additionally, hyperglycemia and new onset diabetes is a predictor of worse outcomes in COVID-19.

Additional endocrine abnormalities, including hypothyroidism and hypoadrenalism, occur due to disruption of the hypothalamic-pituitary-adrenal (HPA) axis.

It has been shown that SARS-CoV-2 infection causes injury to thyroid epithelial cells, resulting in thyroid dysfunction. Patients have been shown to have lower TSH and T3. Additionally, lower level of T3 have been shown to correlate with disease severity. In PASC patients, thyroid abnormalities may persist for months after disease, with ~7% of patients presenting with hypothyroidism.

COVID-19 has also been shown to impact the adrenal gland, with infiltration by monocytes and lymphocytes resulting in disruptions to the HPA axis that can cause lethargy, malaise, fatigue, weakness, and dizziness. Many patients present with hypocortisolism months after recovery, though the majority recover within a year.1 The role of screening for hormone deficiencies in all PASC patients is unclear, but should be guided by symptoms and physical exam.

Regarding PCOS, the overlap between risk factors for PCOS and risk factors for COVID-19, including T2DM and hyperglycemia, suggests that individuals with PCOS may be at higher risk of developing severe COVID-19 infection and persistent symptoms. Hyperandrogenic states and hyper-inflammatory states that predispose individuals for developing cytokine storm have been proposed as risk factors for COVID-19, with both of these metabolic states demonstrated in patients with PCOS as well.2

Brain fog is a debilitating cognitive side effect of PASC, with some studies showing upwards of 80% of patients with PASC experience some degree of brain fog. Brain fog is characterized by a range of symptoms, including issues with memory, lack of concentration, headaches, confusion, and decreased mental clarity. One study showed that PASC patients with neurocognitive dysfunction have an average loss of 7 IQ points compared to their peers.3 While the pathophysiologic mechanism of how COVID-19 causes brain fog is not well understood, researchers have demonstrated high levels of inflammatory cytokines surrounding the brains of patients weeks after their primary infection.4

Treatment of brain fog focuses on lifestyle interventions aimed at addressing symptoms. Current recommendations include: decreasing screen time, improving sleep hygiene habits (~8 hours per night, no screens prior to bed), regular exercise, avoiding alcohol and coffee. Patients are encouraged to go on a daily walk, and brain games, including crosswords and puzzles, can help re-focus the brain. Patients should be aware that intentional cognitive activities, such as cross words or sudoku, are likely sufficient as long as the activity is enjoyable. There is no evidence that commercial brain training products, including Luminosity, are superior to these activities.5

Neural retraining is a program focused on using elements of cognitive behavioral therapy, mindfulness practices, behavior modification, and emotional therapy. While it is unlikely that neural retraining would “cure” PASC, as there are currently no FDA-approved treatments for PASC, many of the tenets of neural retraining could help to address mental health symptoms and cognitive dysfunction commonly associated with PASC. Additionally, addressing comorbid conditions in a multimodal manner is an important part of the recovery process.

One of the most important principles to follow during reconditioning and recovery from COVID-19 is the importance of patients knowing their limitations and not over-exerting themselves during recovery. Nearly 75% of patients suffering from PASC experience post-exertional malaise in which exhaustion and fatigue are greater than would be expected for the effort exerted. Consequently, it is recommended that clinicians promote the message “Stop. Rest. Pace.” This approach emphasizes avoiding cycles of overexertion, prioritizing rest even before patients feel symptoms of fatigue, and pacing individuals’ daily cognitive and physical activities. Similar advice from occupational therapist recommends the 4Ps: Prioritizing, Pacing, Posture, and Planning to manage fatigue.

Patients should work with their primary care providers and physical therapists to develop graduated exercise plans in order to slowly build back function. Clinicians may use the validated DePaul Symptoms Questionnaire to establish the severity and frequency of post exertional malaise for patients.

We recommend this editorial from JOSPT that includes helpful links to patient education materials for managing fatigue and post-exertional malaise. Patients with dysautonomia or POTS can also follow the POTS Exercise Program developed at the Children’s Hospital of Philadelphia, focused on recumbent, gradual reconditioning.

Patients with PASC frequently present with cough, shortness of breath, and exertional dyspnea, and while they present with a range of pulmonary findings on PFTs, they most commonly present with a restrictive pattern with decreased DLCO on PFTs. Of note, many PASC patients present with dyspnea/cough but have normal PFTs, however.

For patients who were hospitalized with COVID-19 pneumonia or ARDS, reduction in diffusion capacity of the lungs (DLCO) is closely related to disease severity. Reduced DLCO at 6 months has been found in 29% of patients who required oxygen by nasal cannula, and 59% of patients who required high-flow nasal cannula (HFNC) or mechanical ventilation.6

For some PASC patients, especially those who have normal findings on CXR, they may present with an obstructive physiology. These patients will respond frequently to bronchodilators and will present similarly to asthma, COPD, or bronchiolitis obliterans.

Evaluation should focus on the history/severity of the acute COVID-19 illness and underlying comorbidities. Hospitalized patients with COVID-19 are at risk of pulmonary fibrosis, bronchiectasis, restrictive lung disease on pulmonary function tests (PFTs), or neuromuscular weakness from post-ICU syndrome. Development of organizing pneumonia has also been described as either sequelae of the initial COVID-19 infection or late phase complication, especially in those with underlying autoimmunity.7–9

Further guidance for workup of PASC pulmonary symptoms can be found on the UT Health Austin Post-COVID-19 Program website.

This question raises several important points regarding thrombotic effects of COVID-19. Concerning checking COVID-19 patients for antiphospholipid (aPL) antibodies, a large meta-analysis of 21 studies and 1,159 patients demonstrated a prevalence rate of 47% for one or more aPL antibodies (anticardiolipin, anti-B2 glycoprotein, prothrombin, or lupus anticoagulant) among patients hospitalized with COVID-19. There was no association between prevalence of antiphospholipid antibodies and mortality, intubation, or VTE rates.10

Consequently:

  • If a patient has no history of VTE, it is not recommended to check or follow aPL labs.
  • If a patient had a recent VTE, aPL labs should be checked because if positive, the patient may benefit from warfarin therapy rather than a DOAC. aPL labs can be rechecked in 3-6 months to see if they have resolved, and if so, anticoagulation may be stopped if the risk factors have also resolved.
  • If a patient had a remote VTE, it is not recommended to check or follow aPL labs.

In the case of a patient recovering from COVID-19 with antiphospholipid antibody syndrome but no history of a thrombotic event, we would not recommend any additional treatment for primary prophylaxis given the unclear benefit and overall low rate of VTE in this population. Some guidelines recommend low-dose aspirin for primary prophylaxis in this population, but its efficacy has not been demonstrated in randomized controlled trials.11

MCAS is an umbrella term to describe episodic symptoms, including urticaria, flushing, nasal congestion, wheezing, headaches, nausea, diarrhea, with constitutional symptoms, such as fatigue and neurocognitive difficulties. Mast cells can infiltrate tissues and release vasoactive mediators, such as tryptase and histamine, leading to signs/symptoms of an allergic response.

  • Given the similarity and overlapping symptoms of PASC and MCAS, scientists have hypothesized that inappropriate mast cell activation is part of the underlying pathophysiology of PASC, but this has not been definitively demonstrated in the available research.

Diagnosis of MCAS requires the following 3 criteria: episodic symptoms consistent with MCAS, elevated serum tryptase, and response to mast cell inhibitors such as antihistamines. This is a difficult diagnosis to make in primary care and would likely need confirmation by an allergist/immunologist, but it is reasonable to trial antihistamine or mast cell stabilizing medications for PASC patients with these symptoms given the low risk of these medications.

  • Cetirizine 10mg BID (can be purchased OTC), or other second-generation antihistamine, is first-line therapy. If the patient has a response but has persistent flushing or GI symptoms, may consider adding montelukast 10mg daily or famotidine 20mg BID.

POTS, dysautonomia, and MCAS all have overlapping symptoms with PASC, but it is unclear whether there is a shared underlying pathophysiologic mechanism or if PASC patients have discrete phenotypes of these syndromes. We are hopeful that evidence-based therapies for these syndromes will also be effective in PASC, so for now we recommend trialing existing interventions and medications for the syndrome that most closely matches the patient’s presentation.

Rates of myocardial injury is dependent on the severity of the initial COVID-19 illness (see PASC Cardiac Symptoms for full summary). ~35% of patients who required hospitalization have myocardial injury, which in a smaller portion, has led to diastolic heart failure, RV dysfunction, and pulmonary hypertension.12,13 Patients with mild to moderate illness who recovered as outpatients very rarely have ongoing cardiac injury (less than 1%).14 A TTE with LV strain will rule out irreversible cardiac injury in most cases, although may not be necessary for patients who had mild to moderate disease and no cardiac risk factors.

Patients recovering from COVID-19 may have persistently increased cardiometabolic demand from immune dysregulation leading to a hyperadrenergic state. Autonomic dysfunction, including inappropriate sinus tachycardia and postural orthostatic tachycardia syndrome (POTS), have been widely reported after COVID-19 and other viral illnesses.15,16 Time, graduated exercise, and appropriate treatment for the dysautonomia (see PASC Dysautonomia for full summary) are the mainstays of treatment.

Studying treatments for PASC is a national priority, and Congress has already allocated $1.15 billion to support this research. Unfortunately, most medications for acute COVID-19 illness have proven ineffective and many other studies of promising treatments have been underpowered, have methodological issues, or failed to be replicated in larger trials. Given the public interest, though, every study is getting press and public attention, which would normally not be the case. It is also uncertain whether treatments for acute COVID-19 will be effective in PASC since the pathophysiology is different throughout the phases of the disease. There are currently no FDA-approved therapies for PASC, and developing treatment will require partnership between scientists, clinicians, patients, and funders. This research is still in the preliminary stages, and as it is released, clinicians must continue to scrutinize and evaluate any published studies in a vigorous scientific manner.

Leronlimab is monoclonal antibody that acts as a CCR5 receptor antagonist similar to the HIV medication maraviroc. CCR5 is a chemokine receptor on white blood cells. Blocking it has proven effective in preventing HIV viral entry and potentially has other immunomodulatory activity. CytoDyn, the developer of leronlimab, tested their medication in acute COVID-19 illness in two trials, both of which failed to show efficacy in primary or secondary outcomes. CytoDyn misrepresented these results as positive in press announcements and publicity engagements, which led to an unprecedented statement by the FDA, disputing their assertions as the FDA does not comment on confidential trial information about unapproved products.

CytoDyn has completed enrollment in a phase 2 trial of leronlimab for PASC and has announced plans for a phase 3 trial based on their preliminary results. The results of their studies have not been published or peer-reviewed, so while their press releases are cause for cautious optimism, it will be important for the FDA and clinicians to evaluate the results before advocating for its use in PASC.

First, there are no FDA-approved treatments for PASC, although many studies are ongoing. Current management consists of treating end-organ damage with evidence-based therapies for those specific organs (i.e., heart failure or chronic kidney disease), rehabilitation with PT, and management of symptoms. There are no interventions that specifically treat the underlying cause currently.

Ivermectin is a controversial medication. It has exclusively been studied for prophylaxis or treatment of acute COVID-19 illness with mixed results, although a recent metanalysis showed no benefit.17 Currently, the NIH, IDSA, and other major guidelines recommend against the use of ivermectin for acute illness due to incomplete data, methodological issues of available studies, and lack of clear benefit until more trials are completed.18

A search of clinicaltrials.gov did not reveal any ongoing studies of ivermectin for PASC. Furthermore, ivermectin is being studied for its supposed anti-viral activity, and in PASC, ongoing viral replication has not been detected and symptoms are thought to be from a dysregulated immune response. Therefore, it is unclear how its mechanism of action would be effective in this phase of the disease.

  • Ivermectin is currently being promoted by the Front Line COVID-19 Critical Care Alliance in their treatment protocols for “Long-Haul COVID-19 Syndrome” and acute COVID-19 illness. They do not cite specific evidence for its use in PASC despite claims of its efficacy. This group and its physician leaders have previously promoted regimens for sepsis based on initial single institution studies that did not show benefit when tested in larger, more vigorous clinical trials.19 Therefore, we recommend waiting for clinical trial evidence before using ivermectin in PASC patients.

Patients who have had COVID-19 illness should get vaccinated once they do not have a fever and their healthcare provider believes that they have recovered from the initial infection. This timing is usually 10-20 days from symptom onset for patients who were not hospitalized.

  • If a patient received monoclonal antibody or convalescent plasma treatment, they should wait 90 days after treatment completion to ensure that the body produces its own antibodies.

In a small case series of 36 patients with persistent COVID-19 symptoms following vaccination, ~25% had an improvement of their symptoms, ~5% had worsening of symptoms, and ~70% of patients had no change in their symptoms.20 We recommend vaccination in all eligible persons. It appears some PASC patients will get relief with the vaccine, but there is a small proportion that will get worse.

  • If a PASC patient experienced prolonged symptom exacerbation following the first dose of a mRNA vaccine, it should be noted that a single dose can raise antibody titers up to 1,000 fold after natural infection.21 Completing both doses will offer maximal protection, but these patients likely have good immunity following a single dose, which should help inform shared decision making about risks/benefits of receiving the second dose.

PTSD is common following COVID-19, with 6% of survivors receiving their first psychiatric diagnosis within 90 days of illness and up to 30% of ICU survivors experiencing PTSD.22, 23

PTSD should be screened for using the PC-PTSD-5 or IES-6. Symptoms include flashbacks, nightmares, hypervigilance, avoidance, irritability, anxiety, and depression. Patients should be referred to a mental health provider for further evaluation and therapy. Evidence-based treatments include trauma-focused CBTp, cognitive processing therapy, EMDR (eye movement desensitization and reprocessing), and exposure therapy.

Initial evaluation will depend on the initial COVID-19 illness severity and persistent symptoms (full evaluation by chief complaint is detailed here). Hospitalized patients are at high risk for end-organ damage and should be worked up aggressively, whereas patients with mild to moderate illness who recovered at home rarely have evidence of organ dysfunction.

All patients should receive orthostatic vital signs and measure SpO2. They should also be screened for mental health comorbidities with a PHQ-9, GAD-7, and PC-PTSD-5:

  • Cough or dyspnea: Recommend a CXR, CBC, CMP, D-dimer, and TSH. If normal PFTs, an ambulatory saturation test should be pursued.
  • Neurocognitive dysfunction: Recommend MoCA or MMSE screening in office, along with Vitamin B12, methylmalonic acid, TSH, CBC, CMP, Vitamin D, and HIV/RPR if risk factors.
  • In select cases, if the history or exam is worrisome for autoimmune disorder, may consider obtaining an ESR, CRP, ANA with reflex panel, and anti-neutrophil antibodies.

NADH is not part of the standard treatment regimen in PASC, although it is widely available as a nutritional supplement in pharmacies and vitamin stores.

There is little potential harm in moderate NADH supplementation as it is well-tolerated; however, evidence does not demonstrate any definitive benefit for chronic fatigue syndrome.

  • Data shows that NADH may lead to small benefit in symptom improvement (e.g., reduction in anxiety) in chronic fatigue syndrome, though studies cite small sample sizes.24–26 NADH has not been studied for PASC specifically.

Tremors and sensations of total body vibration can be attributed to various neurological causes. Helpful history to ascertain includes assessment of:

  • Type of tremor
  • Timing/duration of symptoms
  • Variation with sleep, time of day, stress levels.
  • Nutritional status
  • Exposure to medications with extrapyramidal side effects

Depending on the patient’s history/physical exam findings, evaluation could include: B vitamins, heavy metals, organophosphate screen, TSH, HIV, RPR, ANA panel, and consideration of electromyogram/nerve conduction studies for assessment of peripheral neuropathy.

If the patient endorses tinnitus, helpful history to ascertain includes assessment of:

  • Type of tinnitus
  • Timing of the start of symptoms
  • Exposure to medications with ototoxic side effects
  • Association with hearing loss

Tinnitus can be evaluated using a variety of approaches:

  • Dix Hallpike maneuver to evaluate for BPPV
  • ENT and audiology referral for inner ear evaluation for abnormalities of auditory canal, tympanic membrane, bone ossification, fluid level, cerumen impaction, associated hearing loss, and ruling out medication toxicities
  • MRI of the brain if clinical suspicion for acoustic neuroma
  • Vascular evaluation with CTA or MRA if objective findings on exam (e.g., arterial bruit)

Tinnitus can be exacerbated by/associated with thyroid/B vitamin deficiencies, high stress levels, or post-infectious states.

Cardiac rehabilitation aims to reduce cardiovascular risk factors in patients, focusing on lowering blood pressure, improving control of lipid levels and comorbid diabetes, tobacco cessation counseling, behavioral counseling, and graded physical activity, typically 36 sessions of monitored exercise over the course of 12 weeks.27

We recommend a graduated and supervised exercise plan for improvement of post-COVID-19 symptoms in almost all patients. Most patients utilize physical therapy for this rehabilitation, although patients with coronary artery disease or other cardiac diagnoses may be excellent candidates for cardiac rehabilitation instead. There is no evidence comparing cardiac rehab to physical therapy rehab for PASC.

The consensus of the medical community is that ABO blood type is not associated with COVID-19 disease susceptibility or severity. This is supported by an April 2021 JAMA study of over 11,000 individuals.28

Some researchers hypothesize that PASC symptoms are the result of reactivation of dormant EBV, which they define as an increase in EBV antibodies. A June 2021 study showed significantly higher rates of EBV reactivation in PASC patients compared with control; however, the sample sizes of these groups were small (30 individuals in Long-COVID-19 group and 20 in control),29 and current literature lacks further data to more robustly assess this question. It should be noted that EBV, CMV, and HSV viruses have been found to be reactivated in other acute illnesses, such as burns and sepsis, with unclear clinical significance and no improvement with antiviral treatment.30

Despite uncertainty in the aforementioned topics, the risk factors that have been consistently demonstrated to be associated with the development of PASC include:31,32

  • Older age
  • Number of symptoms in the first week of infection
  • Higher BMI
  • Female sex
  • History of asthma

Risk factors for severe COVID-19 in the acute initial illness are the same risk factors for development of PASC.

1. Agarwal, S. & Agarwal, S. K. Endocrine changes in SARS-CoV-2 patients and lessons from SARS-CoV. Postgrad. Med. J. 96, 412–416 (2020).

2. Kyrou, I. et al. Polycystic ovary syndrome (PCOS) and COVID-19: an overlooked female patient population at potentially higher risk during the COVID-19 pandemic. BMC Med. 18, 220 (2020).

3. Hampshire, A. et al. Cognitive deficits in people who have recovered from COVID-19. EClinicalMedicine 101044 (2021) doi:10.1016/j.eclinm.2021.101044.

4. Graham, E. L. et al. Persistent neurologic symptoms and cognitive dysfunction in non-hospitalized Covid-19 “long haulers”. Ann. Clin. Transl. Neurol. 8, 1073–1085 (2021).

5. Gates, N. J. et al. Computerised cognitive training for 12 or more weeks for maintaining cognitive function in cognitively healthy people in late life. Cochrane Database Syst. Rev. 2020, CD012277 (2020).

6. Huang, C. et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. The Lancet 0, (2021).

7. George, P. M. et al. Respiratory follow-up of patients with COVID-19 pneumonia. Thorax 75, 1009–1016 (2020).

8. Lu, J. et al. Acute fibrinous and organizing pneumonia: two case reports and literature review. BMC Pulm. Med. 19, 141 (2019).

9. Wang, Y. et al. Organizing pneumonia of COVID-19: Time-dependent evolution and outcome in CT findings. PLoS ONE 15, (2020).

10. Taha, M. & Samavati, L. Antiphospholipid antibodies in COVID-19: a meta-analysis and systematic review. RMD Open 7, e001580 (2021).

11. Treatment of antiphospholipid syndrome - UpToDate. https://www.uptodate.com/contents/treatment-of-antiphospholipid-syndrome?search=antiphospholipid%20antibody%20syndrome&source=search_result&selectedTitle=2~150&usage_type=default&display_rank=2#references.

12. Lala, A. et al. Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection. J. Am. Coll. Cardiol. 76, 533–546 (2020).

13. Puntmann, V. O. et al. Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered From Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 5, 1265 (2020).

14. Moulson Nathaniel et al. SARS-CoV-2 Cardiac Involvement in Young Competitive Athletes. Circulation 0,.

15. Nalbandian, A. et al. Post-acute COVID-19 syndrome. Nat. Med. 27, 601–615 (2021).

16. Nishiga, M., Wang, D. W., Han, Y., Lewis, D. B. & Wu, J. C. COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives. Nat. Rev. Cardiol. 17, 543–558 (2020).

17. Roman, Y. M. et al. Ivermectin for the treatment of COVID-19: A systematic review and meta-analysis of randomized controlled trials. Clin. Infect. Dis. (2021) doi:10.1093/cid/ciab591.

18. Statement on Ivermectin. COVID-19 Treatment Guidelines https://www.covid19treatmentguidelines.nih.gov/statement-on-ivermectin/.

19. Vitamin Treatment For Sepsis Fails In Large Trial. NPR.org https://www.npr.org/sections/health-shots/2020/01/17/797058463/vitamin-treatment-for-sepsis-fails-in-large-trial.

20. Arnold, D. T. et al. Symptoms After COVID-19 Vaccination in Patients With Persistent Symptoms After Acute Infection: A Case Series. Ann. Intern. Med. (2021) doi:10.7326/M21-1976.

21. Stamatatos, L. et al. mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection. Science 372, 1413–1418 (2021).

22. Taquet, M., Geddes, J. R., Husain, M., Luciano, S. & Harrison, P. J. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry 0, (2021).

23. Hatch, R. et al. Anxiety, Depression and Post Traumatic Stress Disorder after critical illness: a UK-wide prospective cohort study. Crit. Care 22, 310 (2018).

24. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? - PubMed. https://pubmed.ncbi.nlm.nih.gov/25386668/.

25. Alegre, J. et al. Nicotinamida adenina dinucleótido (NADH) en pacientes con síndrome de fatiga crónica. Rev. Clin. Espanola - REV CLIN ESPAN 210, 284–288 (2010).

26. Forsyth, L. M. et al. Therapeutic effects of oral NADH on the symptoms of patients with chronic fatigue syndrome. Ann. Allergy Asthma Immunol. Off. Publ. Am. Coll. Allergy Asthma Immunol. 82, 185–191 (1999).

27. Servey, J. T. & Stephens, M. Cardiac Rehabilitation: Improving Function and Reducing Risk. Card. Rehabil. 94, 7 (2016).

28. Anderson, J. L. et al. Association of Sociodemographic Factors and Blood Group Type With Risk of COVID-19 in a US Population. JAMA Netw. Open 4, e217429 (2021).

29. Gold, J. E., Okyay, R. A., Licht, W. E. & Hurley, D. J. Investigation of Long COVID Prevalence and Its Relationship to Epstein-Barr Virus Reactivation. Pathogens 10, 763 (2021).

30. Clinical manifestations and treatment of Epstein-Barr virus infection - UpToDate. https://www.uptodate.com/contents/clinical-manifestations-and-treatment-of-epstein-barr-virus-infection?search=ebv&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1.

31. Sudre, C. H. et al. Attributes and predictors of long COVID. Nat. Med. (2021) doi:10.1038/s41591-021-01292-y.

32. Blomberg, B. et al. Long COVID in a prospective cohort of home-isolated patients. Nat. Med. 1–7 (2021) doi:10.1038/s41591-021-01433-3.

June 3, 2021

Written June 11, 2021 by: Faith Noah, MS4, Matthew Seghers, MS4, and W. Michael Brode, MD

Expert Panel: Esther Melamed, MD, Michael Shapiro, MD, George Rodgers, MD, Kevin Hackshaw, MD, Robin Hilsabeck, PhD, ABPP, David Ring, MD, PhD, Christopher Garrison, MD, Arlyn Thobaben, DPT, OCS

Summary

44-year-old man with history of ocular migraines presenting with anosmia and worsening anxiety after COVID-19. Patient was diagnosed with COVID-19 in June 2020 after presumed work exposure as a first responder, initial symptoms were headache and anosmia without respiratory symptoms and he recovered at home. He presents to workers compensation clinic with short-term memory difficulties and headaches. He had seen a neurologist noted a normal neuro exam and recommended a trial of mirtazapine, but patient was hesitant given stigma of mental illness at his job.

  • His labs show a normal CBC, CMP, CRP, TSH, vitamin B12, zinc, iron studies, homocysteine, folic acid, and methylmalonic acid. ANA with reflex panel was negative.
  • Total and free testosterone were also normal, Vitamin D level 25.
  • Imaging: MRI - minimal nonspecific white matter disease. EEG - normal.
  • Psychiatric screenings: MMSE 29/30, PHQ-9 (score 7 out of 27), GAD-7 (score 7 out of 21).
  • Current medications: Sildenafil. Testosterone. Nicotine patch 28 mg/day. Vitamin B12. Vitamin D. Fish oil. Mirtazapine (patient declines to start).

Teaching Points From Expert Panel

Headaches are common in patients with PASC and may be managed similarly to headaches in the primary care setting. No specific headache phenotype has been described in PASC, although patients have reported new daily persistent headaches and concomitant tinnitus.

  • Evaluation should focus on classifying the most similar headache type (migraine, cluster, tension, drug-related headache) and treating with existing evidence-based therapeutics for the type.
  • Many patients with PASC report difficulties with sleep which can exacerbate headaches, and primary care providers should screen for sleep hygiene issues.

PASC patients are at high risk for PTSD, providers may incorporate evidence-based psychiatric screenings including the PHQ9, GAD-7, and PC-PTSD-5. Patients who screen positive may be considered for treatment with psychotherapy and/or referral to psychiatry.

As individuals return to work, there is increasing understanding that some occupations may place employees at greater risk of acquiring COVID-19. Consequently, individuals may seek care for PASC under a worker’s compensation claim, which poses distinct challenges to the treatment process.

  • Providers should be prepared to assist patients in the claims process, as some employers may require documentation of pathologic sequelae of COVID-19 to cover treatment. The CDC recommends using the ICD-10 code B94.8 or B94.9 (Sequelae of unspecified infectious and parasitic disease), although a specific code for PASC is expected to be forthcoming.
  • Treatment of comorbid psychiatric disorders including anxiety and depression presents a challenge under worker’s compensation, as some patients may prefer not to disclose psychiatric diagnoses to employers through worker’s compensation.
  • For patients seeking treatment under worker’s compensation, early documentation of functional status and capacity to return to work is important to the claims process.

Physical therapy can play an important role in neurocognitive complaints in PASC, especially with a complaint of headache, and primary care providers should consider referral for a full evaluation of functional status.

Written June 11, 2021 by: Faith Noah, MS4, Matthew Seghers, MS4, and W. Michael Brode, MD

Expert Panel: Esther Melamed, MD, Michael Shapiro, MD, George Rodgers, MD, Kevin Hackshaw, MD, Robin Hilsabeck, PhD, ABPP, David Ring, MD, PhD, Christopher Garrison, MD, Arlyn Thobaben, DPT, OCS

Summary

69-year-old man with a history of chronic lower back pain and obesity hospitalized for 10 days with COVID-19. He presented to the ER in November 2020 with fatigue, malaise, fever, and was admitted for hypoxemia. He received 5 days of remdesivir and 10 days of dexamethasone during admission. He experienced a 20 lb. weight loss during his hospital stay and was discharged on oxygen which he required through January 2021. He began experiencing poor recall and memory during this hospitalization, which progressively worsened in the following months. In February, he experienced severe, unprovoked spastic lower back pain.

  • Prior to his illness, medications included omeprazole 40mg, and testosterone cypionate 100mg/ml IM.
  • Prior medical conditions included GERD, bronchitis, spinal surgery with chronic back pain, hypotestosteronism, and obesity. He has a 20-pack year tobacco history, quitting >10 years ago.

He presented in late February to his primary care office for “brain fog,” shortness of breath, and severe fatigue. Physical exam was unremarkable at this visit. There was a small pleural effusion at the base of the left lung found on POCUS.

  • Labs from his initial visit showed normal CBC, CMP, ESR, TSH, Free T4, and Creatinine. He had a mildly elevated CPK and ALT.
  • Imaging ordered includes L-spine series and CPAP monitoring by ENT, referred due to obese body habitus. He was diagnosed with sleep apnea and began treatment.
  • Referred to PT for back pain, with significant improvement.

In April, he noted improvement of shortness of breath, but not yet returned to baseline, and persistent “brain fog” despite better sleep hygiene. Physical exam was normal and peripheral SpO2 was normal.

Teaching Points From Expert Panel

The experience of clinicians in the panel is that neurocognitive symptoms do not improve with treatment of sleep apnea by CPAP, despite the improvement in fatigue with treatment.

Exudative effusions have been documented in the literature as likely related to COVID-19 infection, confirmed effusions should be worked up with thoracentesis with strong consideration to refer to a pulmonologist.

There is no single test for evaluation of “brain fog,” but the Montreal Cognitive Assessment (MoCA) could prove useful in older patients, although this may not pick up subtle deficits in younger patients. Patients should also be evaluated for comorbid mental health issues (PTSD, anxiety, depression), especially since energy deficits and concentration difficulties are included in diagnostic criteria for depression (the 9 criteria can be remembered with the SIGECAPS mnemonic).

SNRIs (duloxetine, venlafaxine) or TCAs that target norepinephrine reuptake (preferably nortriptyline) can be used treat chronic fatigue syndrome, coupled with graduated exercise. SSRIs can be used in case of comorbid depression, with agents like fluoxetine or bupropion having a more energizing effect (whereas paroxetine and citalopram can be more sedating).

  • The expert panel recommends nortriptyline as the “go to” agent for a therapeutic trial for chronic fatigue or symptoms resembling fibromyalgia. The consensus was that stimulant medications (e.g., modafinil, dextroamphetamine) should only be used in refractory cases after trialing TCAs or SNRIs/SSRIs and patient has not improved with PT or graduated exercise.

Neurocognitive Functioning Post-COVID-19

Key Teaching Points from Robin C. Hilsabeck, PhD, ABPP, Director of UT Health Austin’s Comprehensive Memory Center

  • Please see Neurocognitive Dysfunction and “Brain Fog” for a detailed description of workup and treatment, this will be updated to reflect the key teaching points from Dr. Hilsabeck here.
  • “Brian fog” is a subjective complaint of trouble focusing, forming thoughts, thinking clearly, and remembering. It is presenting in approximately 2/3 of patients with PASC symptoms and is correlated with the degree of fatigue, isolation, depression, acute stress, and sleep deprivation.
  • Most patients perform well on neurocognitive testing, except in patients who had prolonged hospitalization with neurological complications (and are more similar to post-ICU syndrome). For the small proportion of patients who had mild to moderate disease and have persistent deficits, they are primarily in attention and working memory.
  • Therapy consists primarily of psychoeducation (reassurance in many cases), promotion of healthy lifestyle, and cognitive rehab/training. Mental health screening and psychotherapy are recommended to treat comorbid mood disorders.
  • There are no specific tests for “brain fog,” existing dementia screenings like MoCA are most useful in older adults but will not pick up subtle deficits. Subtle deficits can best be elicited by assessing impact of cognitive difficulties on ability to perform usual activities.

May 6, 2021

Written May 16, 2021 by: Matthew Seghers, MS3, Faith Noah, MS3, and W. Michael Brode, MD

Expert Panel: Esther Melamed, MD, Michael Shapiro, MD, Robin Hilsabeck, PhD, ABPP, David Ring, MD, PhD, Christopher Garrison, MD, Arlyn Thobaben, DPT, OCS

Summary

34-year-old man with no past medical history who had mild COVID-19 in December 2020 and recovered at home. He was then hospitalized January 2021 with presumed Guillain-Barré Syndrome and treated with corticosteroids.

  • Following discharge, he presented to his PCP with persistent fatigue, malaise, tinnitus, brain fog, and exercise intolerance. Prior to his COVID-19 infection, his baseline labs were normal at an annual physical. Medications include only over the counter antihistamines for seasonal allergies. Prior to illness, he was very active, and had no history of tobacco, alcohol, or illicit drug use.
  • His labs show a mild normocytic anemia. During hospitalization, his ferritin was elevated and LFTs were 4x upper limit of normal, but both have now normalized 2 months post-hospitalization. He has an ANA positive at 1:160 titer, but the reflex panel was negative.
  • On imaging, MRI brain was normal as part of a workup for “brain fog”, and TTE and EKG were normal to evaluate his fatigue and exertional malaise.

Teaching Points From Expert Panel

Brain fog is a persistent cognitive symptom of PASC, and while screening tools such as the MoCA or MoCA-blind are helpful at detecting/diagnosing a gross cognitive impairment, they may not detect more subtle findings. Physicians should consider checking reaction time and testing individuals’ ability to process information quickly (although no standardized tool for primary care use is widely available).

  • Questions to ask on history for brain fog evaluation to identify more subtle deficits should focus on functional limitations, including: whether patients are able to work, whether they are making mistakes at work, whether others are noticing any deficits.
  • If the evaluation is indeterminate, and patients have persistent and debilitating cognitive symptoms that affects their daily functional abilities, full neuropsychological evaluation may be warranted.

Positive autoantibodies have been commonly identified in PASC patients, but it is unclear whether it represents a true autoimmune condition or post-infectious inflammation. Antibody panels should be ordered based on the presenting symptom and how common the autoimmune syndrome is (ANA with reflex panel is very reasonable). Antiphospholipid antibodies should be checked as some reports have found 50% positive in post-COVID-19 patients. Once again, the clinical significance is unclear, but will informed shared decision making about anticoagulation or antiplatelet therapy.

Patients in rehab may have both functional and psychosocial components to the limitations they are facing, and rehab should include a graded program with functional milestones, but also confidence building. Physical therapy is an excellent starting point to diagnose or problem solve these issues for patients with fatigue or deconditioning.

  • Pulmonary rehabilitation is excellent, goal-directed and evidence-based. Unfortunately, it requires specific pulmonary diagnoses and/or PFT abnormalities for insurance to cover, so it will only be available to PASC patients in very specific cases.

Written May 16, 2021 by: Matthew Seghers, MS3, Faith Noah, MS3, and W. Michael Brode, MD

Expert Panel: Esther Melamed, MD, Michael Shapiro, MD, Robin Hilsabeck, PhD, ABPP, David Ring, MD, PhD, Christopher Garrison, MD, Arlyn Thobaben, DPT, OCS

Summary

45-year-old man with a history of type 2 diabetes and obesity who was hospitalized with COVID-19 pneumonia in June of 2020. His hospital course was complicated by severe ARDS requiring prolonged mechanical ventilation and a tracheostomy. He received dexamethasone, convalescent plasma, remdesivir, and antibiotics before being discharged to a LTAC in August, with tracheostomy removal in October of 2020.

  • Prior to his illness, his medications included lisinopril and carvedilol. He had no history of drug, alcohol, or tobacco use.

He presented to his primary care clinic with PASC-related symptoms in November, noting a persistent dry cough, dyspnea, and new right foot drop with peripheral weakness. Throughout the proceeding months, dextromethorphan cough syrup, albuterol inhalers, and Tessalon Perles have not alleviated his cough, and he has also endorsed symptoms of orthopnea and persistent chest pain.

  • Labs from monthly follow-up visits revealed a normal CBC, BMP, BNP, and D-dimer. His CXR, TTE, and EKG were also normal, with PFTs and an EMG for the foot drop still pending.

Teaching Points From Expert Panel

For PASC patients presenting with dyspnea, pulmonary diagnostics should be limited to a CXR on the initial visit. If dyspnea persists, pulmonary function tests should be pursued in addition to baseline labs outlined in the algorithm below.

  • If the workup is normal and dyspnea or cough persist, check oxygen saturation at rest and upon ambulation in clinic. Hypoxemia even with normal CXR and PFTs merits referral to pulmonology.
  • If PFTs are normal, a trial of empiric corticosteroids is NOT recommended as it will likely have little benefit. Ruling out other causes of chronic cough (upper airway cough syndrome from allergies, GERD, etc) is recommended and continuing symptomatic treatment with OTC cough medications.
  • The utility of ordering D-dimer as a screening test In the outpatient setting is uncertain, but reasonable to many experts. Although much of the morbidity/mortality from acute COVID-19 illness is from diffuse microthrombosis and rates of VTE in the ICU are estimated at 24%, for patients with mild disease or who have recovered from acute illness, the preliminary literature suggests rates of VTE are similar to that of the general population (~0.5%).

The etiology of dyspnea in the PASC setting can be multi-factorial. For this patient, in particular:

  • Anxiety could lead to dyspnea and palpitations, especially after coping with a life-threatening hospitalization.
  • For patients who underwent tracheostomies, granulation tissue could lead to mild obstruction, which could be diagnosed by PFTs.
  • Obesity could lead to increased dyspnea in this patient, and providers should consider evaluating for sleep apnea or obesity hypoventilation syndrome.
  • Recovering from a long period of ventilation could lead to overall deconditioning, presenting as weakness in this patient. Although unilateral foot drop is likely from a peripheral nerve, may also consider critical illness myopathy (proximal weakness) or neuropathy (distal weakness) if symptoms are symmetric.
Dyspnea Workup PASC