Frequently Asked Questions on Long-COVID and Autoimmunity

About 10% to 30% of patients who experienced severe or mild symptoms of COVID-19 develop Long-COVID syndrome (aka post-acute sequelae of SARS-CoV-2 infection (PASC)). The persistent symptoms of fatigue, brain fog, weakness, heart palpitations, vision changes, headaches, tinnitus, pain, sleep disturbances, gastrointestinal abnormalities, pain, anxiety and depression are among some of the most common Long-COVID symptoms and may either continue to linger after the acute COVID-19 illness or occur within weeks of recovery from the acute COVID-19^1,2. The symptoms of Long-COVID may continue for months for some patients Research is currently ongoing to define specific blood and imaging biomarkers of Long-COVID that could help to improve diagnosis and treatment of this emerging condition which can affect multiple body systems. Patients experiencing persistent or new symptoms post-acute COVID-19 illness, should talk with their primary care physician about the possible diagnosis of Long-COVID and consider an evaluation at a Long-COVID center.

While many symptoms are associated with Long-COVID, some of these symptoms may be more suggestive of an emerging autoimmune disorder^3-7. Patients who experience new onset and persistent positional dizziness, heart palpitations, sweat dysregulation, gastrointestinal symptoms, neuropathic pain, unusual rashes, new one sided weakness or numbness, should seek a prompt evaluation for an autoimmune etiology of their symptoms.

There currently is not one test (laboratory, imaging, or physical exam findings) that could diagnose Long-COVID. While developing a test for Long-COVID is a priority for researchers, at this time all workup is focused on identifying other conditions that could be causing or contributing to the symptoms. Therefore, it is recommended that all patients get an initial general medical screening exam and be evaluated for cardiovascular, gastrointestinal, or neurological diseases, and to make sure co-occurring conditions such as diabetes, high blood pressure and other chronic conditions are well-controlled and that age-appropriate medical screenings are up to date.

For individuals who were hospitalized with COVID-19 during their initial illness, they may be at risk for damage to their organs including lung scarring, decreased kidney function, or heart damage^8-10. Therefore, if symptoms persist beyond 12 weeks, it is recommended to get initial tests of these organs. For individuals who recovered at home from their COVID-19 infection and did not require hospitalization, persistent lung or heart damage is rare^11-14. Generally, this means laboratory or imaging tests for Long-COVID should be limited for people who recovered at home and were previously healthy, unless there is concern for other illnesses based on the clinical evaluation. It is still reasonable to get these tests for persistent symptoms for individuals who were not hospitalized, but they are not always necessary and in most cases may be normal.

Care for Long-COVID can start with evaluation by the primary care provider to rule out other conditions that may be contributing to symptoms. If symptoms are persistent, patients should ask to be referred to a clinic specializing in Long-COVID as well as specific specialists for the active symptoms (eg cardiology, pulmonology, PM&R, neurology, neuroimmunology, rheumatology, neuro-otology, ENT, social work). Physical therapy and occupational therapy remain cornerstones of treating Long-COVID.
In general, care for Long-COVID should involve a multidisciplinary team given multiple organ involvement in this syndrome.

The course of Long-COVID is highly variable between individuals, and since it is such a new disease, not enough time has gone by to accurately estimate how long the recovery process will be. Many patients with symptoms lasting more than 6 months are reporting slow but persistent recovery, although some patients are reporting symptoms lasting longer than this.

Research shows that most patients recover from their initial COVID-19 infection within 4 weeks, and symptoms continue to decrease between 4 to 12 weeks. Improvement slows around 12 weeks after the infection. Men and women have a similar recovery pattern, although women tend to experience and report more symptoms¹⁵.

Individuals whose symptoms are lasting more than 12 weeks also continue to improve even though the recovery process may be slower. Some individuals describe a “relapsing and remitting” course where they have periods of improvement followed by a recurrence of symptoms, with or without a trigger. Pushing through fatigue or overexertion (on either physical, cognitive, or emotional tasks), is a common trigger of “relapses.” This is called post-exertional malaise, where activities that were not normally tiring can make Long-COVID symptoms worse. Research shows that when individuals with Long-COVID no longer have post-exertional malaise, that most of their other symptoms also improve¹⁶.

Research from post-viral illnesses prior to COVID-19 also demonstrates a gradual but persistent recovery. For example, data for patients who have postural orthostatic tachycardia syndrome (POTS) from a viral cause indicates that most patients have a meaningful recovery within 1-5 years of their initial illness^17,18.
It is uncertain at this time whether there will be permanent effects from Long-COVID, or if it will place individuals at a higher risk of developing other illnesses.

This is an area of active research, but the risks of developing Long-COVID generally fall under two categories: the severity of the initial COVID-19 illness, and the underlying immune response of individuals.

The sicker a individual is during their initial COVID-19 illness, the more likely they are to develop persistent symptoms. One study showed that 37% of patients admitted to an intensive care unit (ICU) had symptoms 6 months after their illness, compared to 4% of individuals who were never hospitalized¹⁹. Individuals with a higher number of symptoms during the first week of their infection and higher levels of the virus in their blood are more likely to develop Long-COVID. Similarly, the patients at highest risk of developing severe initial infections, for example obesity, diabetes, or older age, are more likely to experience lingering symptoms^20,21.

Most cases of COVID-19 do not require hospitalization, and it has been well-reported that many individuals develop Long-COVID who had mild or asymptomatic initial illness. Individuals who were not hospitalized make up to 75% of cases of Long-COVID²². These risks may be related to individual’s underlying immune response which can make them susceptible to Long-COVID, although the exact factors and mechanisms are unclear at this time. Research shows that individuals with pre-existing autoimmune antibodies in their blood or asthma are at risk of Long-COVID.

Approximately 80% of all individuals diagnosed with autoimmune disorders are women²³, and interestingly it has been shown that women are more likely to develop Long-COVID than men. This illustrates the possible autoimmune cause of Long-COVID, which is being studied^21,24. Lastly, one study found that individuals who have reactivation of Epstein-Barr Virus (EBV, the virus that caused mononucleosis) in their blood when they were infected with COVID-19 were more likely to develop Long-COVID. Interestingly, on follow up blood samples 3 months after the initial infection, no patients in that study had persistent EBV reactivation, so it is unclear if EBV is directly related to the symptoms, or is more of a sign of a dysregulated immune response²⁴.

Scientists and physicians are still learning about how past and emerging strains of SARS-CoV-2 may contribute to Long-COVID. Earlier SARS-CoV-2 variants, such as delta, appear to contribute to higher frequency of severe/persistent Long-COVID symptoms, though more recent strains such as omicron still lead to Long-COVID. Studies are underway to determine whether different viral strains may contribute to different types of Long-COVID symptoms²⁵.

Vaccination clearly reduces the risk of developing Long-COVID. Research of large populations in Britain and Israel show that the risk is reduced by at least 50%, and in some studies up to 80%. COVID-19 vaccines reduce the risk of severe illness, which is the greatest risk factor of having persistent symptoms, so it is the best tool at preventing Long-COVID currently. Unfortunately, vaccines do not fully eliminate the risk of developing Long-COVID, and there are many reports of persistent symptoms following breakthrough infections^25–29.

The use of COVID-19 vaccines to treat Long-COVID is an area of active research. Initial studies show that some patients with Long-COVID have significant improvement in their symptoms following the vaccination series, although most patients have no change in their symptoms. In these same studies, there was a small portion of patients who had worsening Long-COVID symptoms following vaccination^29,30. It is unclear which specific patients will have improvement in their symptoms with the vaccine.

Overall, most experts recommend vaccination and boosters for patients with Long-COVID as the risk of worsening symptoms from reinfection is higher than the risk of adverse effects from the vaccine. For patients who experience worsening of their symptoms or severe side effects from the vaccine, long-acting monoclonal antibodies like Evusheld are available and highly effective at preventing reinfection.

Depending on the Long-COVID symptoms experienced by patients, different treatment modalities ranging from: changes to daily routines, starting exercise regimens, improving diet, optimizing sleep, and considering symptomatic or disease modifying therapies that are targeted to the organ systems affected in the individual patients. For patients with emerging or worsening autoimmune disorders, immunomodulatory treatments are being evaluated.

While different etiologies have been proposed to explain Long-COVID, emergence of autoimmunity is thought to be an important driving factor of the Long-COVID syndrome^4,31–36. Research studies on Long-COVID autoimmunity are focusing on understanding i) what are the different autoantibodies that can contribute to Long-COVID and whether these autoantibodies may be transient or persistent over time, ii) how do types of different immune cells, such as T and B cells, neutrophils and monocytes change in response to SARS-CoV-2 infection, iii) is there re-activation of chronic viruses post-SARS-CoV-2 infection, such as Epstein Bar Virus, iv) how does the balance between our commensal and pathogenic gut microbiome species change in response to SARS-CoV-2 infection and how do these gut microbiome constituents influence the rest of the body.

There are many online resources for people with Long COVID. The CDC has a web pages dedicated to Post-Covid conditions and the related symptoms: https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Flong-term-effects.html

There are also resources created by Long COVID communities including:

• https://www.longcovid.org/resources/patients
• https://patientresearchcovid19.com/
• https://www.survivorcorps.com/

If you will be going to physical therapy, these handouts can be helpful to your therapist as they offer advice on how to resume activities at a pace that is safe and manageable.

• https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html
• CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Flong-term-effects.html

Your physician may want to see resources and guidance statements related to treatment of Long COVID:
https://www.aapmr.org/members-publications/covid-19

COVID-19 vaccines are safe and effective. Severe reactions after vaccination are rare, the most commonly identified are myocarditis in young men after receiving Pfizer-BioNTech or Moderna (mRNA COVID-19 vaccines), and most patients recover quickly without long-term complications. Serious clotting disorders (thrombosis with thrombocytopenia syndrome, or TTS) and Guillan-Barre Syndrome (GBS, a rare disorder where the body attacks nerve cells and causes paralysis) are extremely rare but have been linked to J&J and AstraZeneca (adenovirus vaccines). Adenovirus vaccines are no longer recommended, and those complications have not been identified in the mRNA vaccines ³⁷.

A review of clinical trials that included more than 45,000 participants showed the rate of any reported adverse effects was 46% with the vaccine, and 35% for participants who received placebo. The most common adverse effects for participants who received placebo were headache and fatigue³⁸.

Overall, as COVID-19 vaccination and boosters become more common, it is difficult to distinguish if common symptoms are related to the vaccine, or other causes. There are reports of patients developing similar symptoms to Long-COVID following vaccination, and the NIH is investigating these cases. Some researchers have hypothesized that the COVID-19 virus can induce autoimmunity, which theoretically the vaccine could do the same. This has not been definitively proven though, and reported cases remain extremely rare³⁹. Therefore, since the risk of developing Long-COVID from an infection is between 5%-30%, experts agree that the benefits of the vaccine heavily outweigh the risks.

If an individual is concerned that the vaccination has caused an adverse effect, it is highly recommended to report it to the Vaccine Adverse Event Reporting System (VAERS) so it can be investigated by the CDC or FDA. Individuals who have had adverse effects from the vaccine still have options available to protect themselves from COVID-19 infection, including long-acting monoclonal antibodies like Evusheld.

Re-infection is defined as an infection in the same individual across time with a new viral strain: within ≥ 45 days with highly suspicious symptoms or ≥ 90 days if asymptomatic or experiencing low suspicion symptoms⁴⁰. Re-infections appear to contribute to exacerbation in symptoms of Long-COVID for many patients and especially patients who may be immunocompromised^41–43, with duration of symptom exacerbation varying between individuals. Doctors and scientists are still learning about how individual variants contribute to disease severity of Long-COVID and whether re-infections are more likely to lead to autoimmunity post-COVID.

Long COVID is now a disability under Titles II and III of the Americans with Disabilities Act (ADA), Section 504 of the Rehabilitation Act of 1973 (Section 504), and Section 1557 of the Patient Protection and Affordable Care Act (Section 1557). Each of these federal laws protects people with disabilities from discrimination. Put simply, you are entitled to full and equal opportunities to participate in and enjoy all aspects of civic and commercial life.

People with Long COVID might also be eligible for disability benefits through Social Security (SSDI or SSI) if their disability is expected to prevent them from working for at least a year or result in death. This is a complicated process and can take months, so it is important to apply as early as possible. An initial application is filed with the Social Security Administration.

Many centers around the country are offering research study participation for patients with Long-COVID. Individuals interested to participate in a research study should contact their local Long-COVID clinical center or an academic center to learn more about how to participate in research.

Organizations for patient advocacy:

National Center for Health Research – https://www.center4research.org

AAPMR – https://www.aapmr.org/members-publications/member-news/member-news-details/2021/12/14/aapm-r-long-covid-consensus-guidance-statements-published-on-diagnosing-and-treating-long-covid-symptoms-of-breathing-discomfort-and-cognitive-symptoms

Body Politic – https://www.wearebodypolitic.com

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