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The malady lingers on

As the COVID-19 pandemic rages on, reports are starting to emerge which paint a fuller picture of short- and intermediate-term damage to COVID survivors. Long-term studies obviously are years away, but we may increasingly see a pattern of symptoms and signs that indicate that while the patient may be considered recovered, significant ongoing issues remain.

A recent Science article by Jennifer Couzin-Frankel, “From ‘brain fog’ to heart damage, COVID-19’s lingering problems alarm scientists,” reviews some of these effects. Persistent problems include dyspnea, fatigue, tachycardia, joint aches, cognitive difficulties, persistent anosmia and multiorgan dysfunction. There are no large multicenter peer-reviewed studies on survivors published yet, only small studies measuring various outcomes with relatively small numbers of subjects. However, the large studies are enrolling and starting. A study enrolling 10,000 COVID survivors and following them initially for one year and then long term for 25 years began in the UK last month, and several others will be starting. (

Real time studies

The COVID Symptom Study is an international multicenter effort created by Massachusetts General Hospital and King’s College, London, in conjunction with ZOE, a private company, and multiple collaborative study partners including the Nurses’ Health Study. More than 4 million COVID-infected people have self-enrolled to self-report symptoms via an app which can be downloaded on the Apple App Store or Google Play. Data gathered can provide real-time information and guidance as to locations of COVID hot spots, alerts to new symptoms, new outbreaks and quarantine/resource planning. Enrollees can check the website for real-time results and news. Personal data is protected by the European General Data Protection Regulation (GDPR), which is much more stringent than U.S. data privacy laws.

So far, the COVID Symptom study has shown that COVID patients seem to fall within one of six clinical subtypes of disease, called “clusters.” Significantly, cluster classification predicted risk of requiring hospitalization and ventilatory support with more accuracy than an existing risk model based solely on age, sex, BMI and pre-existing conditions alone, and could make that prediction five days from symptom onset.

The higher the cluster number, the greater the eventual disease severity.

COVID symptom study clusters

  1. Cluster 1 (‘flu-like’ with no fever): Headache, loss of smell, muscle pains, cough, sore throat, chest pain, no fever.

  2. Cluster 2 (‘flu-like’ with fever): Headache, loss of smell, cough, sore throat, hoarseness, fever, loss of appetite.

  3. Cluster 3 (gastrointestinal): Headache, loss of smell, loss of appetite, diarrhea, sore throat, chest pain, no cough.

  4. Cluster 4 (severe level one, fatigue): Headache, loss of smell, cough, fever, hoarseness, chest pain, fatigue.

  5. Cluster 5 (severe level two, confusion): Headache, loss of smell, loss of appetite, cough, fever, hoarseness, sore throat, chest pain, fatigue, confusion, muscle pain.

  6. Cluster 6 (severe level three, abdominal and respiratory): Headache, loss of smell, loss of appetite, cough, fever, hoarseness, sore throat, chest pain, fatigue, confusion, muscle pain, shortness of breath, diarrhea, abdominal pain.

Only 1.5% of people with cluster 1, 4.4% of people with cluster 2, and 3.3% of people with cluster 3 COVID-19 required ventilatory support. However, these figures were 8.6%, 9.9% and 19.8% for clusters 4, 5 and 6. Almost half of the patients in cluster 6 required hospitalization during the disease course, compared to only 16% of patients in cluster 1.

Generally, people with cluster 4, 5 or 6 COVID-19 symptoms tended to be older, more fragile, more likely to be overweight or obese and/or have comorbid conditions such as diabetes or lung disease than those with clusters 1, 2 or 3.

A model to predict severity of disease was developed which combined information about age, sex, BMI and pre-existing conditions along with symptoms gathered over just five days from the onset of the illness.

The availability of such a model at day five of symptom onset may be critical given that the average patient requiring ventilatory support presents to the hospital around day 13 after symptom onset. Cluster categorization can provide an early alert to physicians as to which patients are likely to require higher levels of care due to more severe disease and therefore might need early intervention.

If you have COVID patients or know anyone who would like to enroll in this effort, please refer them to or direct them to the COVID Symptom Study App.

Resources for recovering COVID patients

Navigating life after the acute phase of COVID can be difficult for patients both physically and psychologically. Patients may be too fatigued to return to work or even to move about their house and perform activities of daily living. They may face stigma from others who believe they are still contagious in the light of scarce and evolving knowledge of the disease. Survivors may be afraid that they are maimed for life or may suffer additional late complications. Many of these “COVID Long Haulers” are turning to online support groups. There may be some role here for physicians to witness and learn what patients are encountering and enduring as with any other chronic disease.

One such support group is Body Politic, aimed at persons ill or recovering from COVID-19 and their caretakers. The website is

Another such group is the Facebook group Survivor Corps, which is aimed at COVID-19 patients and survivors. Both groups were started by COVID survivors with persistent symptoms which their physicians were at a loss to explain, prognosticate or treat (as the average post-COVID course is still unknown). Some felt dismissed by their physicians. Sometimes just knowing that one is not alone in having strange symptoms is enough to calm anxiety and give hope in the face of a mysterious disease. These resources may prove to be valuable for post-COVID patients.

Prevalence of post-COVID symptoms

An Italian study published as a letter in JAMA analyzed prevalence of COVID symptoms two months post-discharge in 143 post-hospitalization COVID patients with a mean age of 56.5; 71% had interstitial pneumonia, 21% were given noninvasive ventilation and 5% were ventilated. Mean hospital stay was 13.5 days. Of these patients, 87.4% had at least one significant persistent symptom and 55% had three or more (fatigue, dyspnea, joint pain, chest pain). Quality of life was decreased in 44.1%. (Persistent Symptoms in Patients After Acute COVID-19 Angelo Carfì, MD1; Roberto Bernabei, MD1; Francesco Landi, MD, PhD1; et al for the Gemelli Against COVID-19 Post-Acute Care Study Group. JAMA. Published online July 9, 2020.)

Neurologic symptoms

COVID-19 can cause a wide array of neurological symptoms ranging from encephalitis to cardiovascular accident to Guillain-Barre syndrome. These symptoms can be the reason for hospital admission and can persist months afterwards. A recent study accepted for publication in Brain and published online last month reviewed 43 COVID cases at one center with neurologic involvement and delineated five major categories: encephalopathies, inflammatory CNS syndromes, ischemic strokes due to pro-thrombotic states, peripheral neurologic disorders including Guillain-Barre, and miscellaneous disorders. Some responded to immunotherapies. The incidence of acute disseminated encephalomyelitis with hemorrhagic change was significant. Some COVID patients report persistent “brain fog” and cognitive dysfunction which will need to be studied. (The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Ross W Paterson, Rachel L Brown, Laura Benjamin, Ross Nortley, Sarah Wiethoff et al. Brain, Published:08 July 2020.)

Cardiac symptoms

As the pathophysiology of COVID-19 is better elucidated, it has emerged that inflammation and a pro-thrombotic state are characteristics of the disease as is multiorgan involvement. Cardiac involvement is particularly dangerous and may persist after the acute course of the disease has ended. Several recent studies have shown cardiac abnormalities in post-COVID survivors, regardless of whether their disease was severe enough to require hospitalization.

A June study in Heart Rhythm showed that up to 20-30% of hospitalized COVID patients showed elevated troponin levels indicative of myocardial involvement, which the authors suggest is attributable to the high prevalence of ACE-2 receptors in myocardial tissue. ACE-2 receptors are a known target of the COVID-19 virus’s spike protein. (COVID-19 cardiac injury: Implications for long-term surveillance and outcomes in survivors. Mitrani, Raul D., Dabas, Nitika, Goldberger, Jeffrey J. Heart Rhythm. Published June 26, 2020.)

A German study published last month in JAMA Cardiology showed mitral regurgitation (MR) abnormalities in an observational cohort of 100 COVID survivors from University Hospital Frankfurt when compared to risk factor matched patients and healthy volunteers. Among COVID survivors, MR showed cardiac involvement in 78% and active myocarditis in 60% independent of all other conditions, disease severity, course of illness and time from diagnosis to imaging. Most concerning was that only 33 of these patients had required hospitalization; the rest had recovered at home. This suggests that undiagnosed cardiac disease could be common among even so-called mild COVID cases. Elevated troponin levels were found in 71% of survivors while 5% had significantly elevated levels. Left ventricle ejection fraction (LVEF) also was compromised in survivors as were other indicators of cardiac function. Cardiac biopsy in those with serious findings revealed active myocarditis. It is possible that this could correlate with fatigue. (Outcomes of Cardiovascular Magnetic Resonance Imaging in Patients Recently Recovered from Coronavirus Disease 2019 (COVID-19). Puntmann VO, Carerj ML, Wieters I et al. JAMA Cardiology. Published online July 27, 2020.)

Pulmonary fibrosis

COVID-related acute respiratory distress syndrome (ARDS) can impact the old and the young as evidenced by the recent double-lung transplant in a 20-year-old COVID patient in Chicago. A recent article on the Massachusetts General Hospital research website states that up to 25% of ARDS survivors develop restrictive lung disease within six months of diagnosis including pulmonary fibrosis, and that proposals to study antifibrotic agents in COVID-related ARDS are emerging. Progressive fibrotic interstitial lung disease would severely impact the quality of life and decrease the life expectancy of survivors. Recently, 22 patients returned to King Edward Memorial Hospital in Mumbai, India, with pulmonary fibrosis a month after discharge after treatment for COVID-related pneumonia. More research needs to be done in this regard. The renal and hepatic impact of COVID disease also will need to be studied in the months ahead. (

In summary

We all will be seeing both acute COVID-19 and significant chronic post-COVID-19 signs and symptoms in our patients. It is important to stay informed, be prepared and be vigilant for late sequelae and to refer and/or investigate properly. Long-term survivor studies are starting for both symptoms and organ system involvement over time. Be supportive of your patients even when you don’t have all the answers; it’s OK to say so. Patient support groups may be helpful as patients share resources and bond. Counseling also may be indicated, and virtual counseling can be explored.

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