Fatigue and headaches top the list of common lingering symptoms four months after COVID infection


Fatigue and headache were the most common symptoms reported by individuals an average of more than four months out from having COVID-19, investigators report.

Muscle aches, cough, changes in smell and taste, fever, chills and nasal congestion were next in the long line of lingering symptoms.

“Our results support the growing evidence that there are chronic neuropsychiatric symptoms following COVID-19 infections,” Medical College of Georgia investigators write in the journal ScienceDirect.

“There are a lot of symptoms that we did not know early on in the pandemic what to make of them, but now it’s clear there is a long COVID syndrome and that a lot of people are affected,” says Dr. Elizabeth Rutkowski, MCG neurologist and the study’s corresponding author.

The published study reports on preliminary findings from the first visit of the first 200 patients enrolled in the COVID-19 Neurological and Molecular Prospective Cohort Study in Georgia, or CONGA, who were recruited on average about 125 days after testing positive for the COVID-19 virus.

CONGA was established at MCG early in the pandemic in 2020 to examine the severity and longevity of neurological problems and began enrolling participants in March 2020 with the ultimate goal of recruiting 500 over five years.

Eighty percent of the first 200 participants reported neurological symptoms with fatigue, the most common symptom, reported by 68.5%, and headache close behind at 66.5%. Just over half reported changes in smell (54.5%) and taste (54%) and nearly half the participants (47%) met the criteria for mild cognitive impairment, with 30% demonstrating impaired vocabulary and 32% having impaired working memory.

Twenty-one percent reported confusion, and hypertension was the most common medical condition reported by participants in addition to their bout with COVID-19.

No participants reported having a stroke, weakness or inability to control muscles involved with speaking, and coordination problems were some of the less frequently reported symptoms.

Twenty-five percent met the criteria for depression, and diabetes, obesity, sleep apnea and a history of depression were associated with those who met the criteria. Anemia and a history of depression were associated with the 18% who met the objective criteria for anxiety.

While the findings to date are not surprising and are consistent with what other investigators are finding, Rutkowski says the fact that symptoms reported by participants often didn’t match what objective testing indicated, was surprising. And, it was bidirectional.

For example, the majority of participants reported taste and smell changes, but objective testing of both these senses did not always line up with what they reported. In fact, a higher percentage of those who did not report the changes actually had evidence of impaired function based on objective measures, the investigators write.

While the reasons are not certain, part of the discrepancy may be a change in the quality of their taste and smell rather than pure impaired ability, Rutkowski says.

“They eat a chicken sandwich and it tastes like smoke or candles or some weird other thing but our taste strips are trying to depict specific tastes like salty and sweet,” Rutkowski says. Others, for example, may rely on these senses more, even when they are preparing the food, and may be apt to notice even a slight change, she says.

Either way, their data and others suggest a persistent loss of taste and smell following COVID-19, Rutkowski and her colleagues write.

Many earlier reports have been based on these kinds of self-reports, and the discrepancies they are finding indicate that approach may not reflect objective dysfunction, the investigators write.

On the other hand, cognitive testing may overestimate impairment in disadvantaged populations, they report.

The first enrollees were largely female, 35.5% were male. They were an average of 44.6 years old, nearly 40% were Black and 7% had been hospitalized because of COVID-19. Black participants were generally disproportionately affected, the investigators say.

Seventy-five percent of Black participants and 23.4% of white participants met criteria for mild cognitive impairment. The findings likely indicate that cognitive tests assess different ethnic groups differently. And, socioeconomic, psychosocial (issues like family problems, depression and sexual abuse) and physical health factors generally may disproportionately affect Black individuals, the investigators write.

It also could mean that cognitive testing may overestimate clinical impairment in disadvantaged populations, they write.

Black and Hispanic individuals are considered twice as likely to be hospitalized by COVID-19 and ethnic and racial minorities are more likely to live in areas with higher rates of infection. Genetics also is a likely factor for their increased risk for increased impact from COVID, much like being at higher risk for hypertension and heart disease early and more severely in life.

A focus of CONGA is to try to better understand how increased risk and effects from COVID-19 impact Blacks, who comprise about 33% of the state’s population.

A reason fatigue appears to be such a major factor among those who had COVID-19 is potentially because of levels of inflammation, the body’s natural response to an infection, remain elevated in some individuals. For example, blood samples taken at the initial visit and again on follow up showed some inflammatory markers were up and stayed up in some individuals.

These findings and others indicate that even though the antibodies to the virus itself may wain, persistent inflammation is contributing to some of the symptoms like fatigue, she says. She notes patients with conditions like multiple sclerosis and rheumatoid arthritis, both considered autoimmune conditions that consequently also have high levels of inflammation, also include fatigue as a top symptom.

“They have body fatigue where they feel short of breath, they go to get the dishes done and they are feeling palpitations, they immediately have to sit down and they feel muscle soreness like they just ran a mile or more,” Rutkowski says.

“There is probably some degree of neurologic fatigue as well because patients also have brain fog, they say it hurts to think, to read even a single email and that their brain is just wiped out,” she says. Some studies have even shown shrinkage of brain volume as a result of even mild to moderate disease.

These multisystem, ongoing concerns are why some health care facilities have established long COVID clinics where physicians with expertise in the myriad of problems they are experiencing gather to see each patient.

CONGA participants who reported more symptoms and problems tended to have depression and anxiety.

Problems like these as well as mild cognitive impairment and even impaired vocabulary may also reflect the long-term isolation COVID-19 produced for many individuals, Rutkowski says.

“You are not doing what you would normally do, like hanging out with your friends, the things that bring most people joy,” Rutkowski says. “On top of that, you may be dealing with physical ailments, lost friends and family members and loss of your job.”

For CONGA, participants self-report symptoms and answer questions about their general state of health like whether they smoked, drank alcohol, exercised, and any known preexisting medical conditions. But they also receive an extensive neurological exam that looks at fundamentals like mental status, reflexes and motor function.

They also take established tests to assess cognitive function with results being age adjusted. They also do at-home extensive testing where they are asked to identify odors and the ability to taste sweet, sour, bitter, salty, brothy or no taste. They also have blood analysis done to look for indicators of lingering infection like those inflammatory markers and oxidative stress.

Neuropsychiatric symptoms are observed in the acute phase of infection, but there is a need for accurate characterization of how symptoms evolve over time, the investigators write.

And particularly for some individuals, symptoms definitely linger. Even some previously high-functioning individuals, who normally worked 80 hours a week and exercised daily, may find themselves only able to function about an hour a day and be in the bed the remainder, Rutkowski says.

The investigators are searching for answers to why and how, and while Rutkowski says she cannot yet answer all their questions, she can tell them with certainty that they are not alone or “crazy.”

One of the best things everyone can do moving forward is to remain diligent about avoiding infection, including getting vaccinated or boosted to help protect your brain and body from long COVID symptoms and help protect others from infection, Rutkowski says. There is evidence that the more times you are infected, the higher the risk of ongoing problems.

Rutkowski notes that their study findings may be somewhat biased toward high percentages of ongoing symptoms because the study likely is attracting a high percentage of individuals with concerns about ongoing problems.

SARS-CoV-2 is thought to have first infected people in late 2019 and is a member of the larger group of coronaviruses, which have been a source of upper respiratory tract infections, like the common cold, in people for years.

At least part of the reason SARS-CoV-2 is believed to have such a wide-ranging impact is that the virus is known to attach to angiotensin-converting enzyme-2, or ACE2, which is pervasive in the body.

ACE2 has a key role in functions like regulating blood pressure and inflammation. It’s found on neurons, cells lining the nose, mouth, lungs and blood vessels, as well as the heart, kidneys and gastrointestinal tract. The virus attaches directly to the ACE2 receptor on the surface of cells, which functions much like a door to let the virus inside.

Experience and study since COVID-19 started both indicate immediate neurological impact can include loss of taste and smell, brain infection, headaches and, less commonly, seizures, stroke and damage or death of nerves.

As time has passed, there is increasing evidence that problems like loss of taste and smell, can become chronic, as well as problems like brain fog, extreme fatigue, depression, anxiety and insomnia, the investigators write. Persistent conditions including these and others are now referenced as “long Covid.”

Funding: The research was supported by funding from the National Institute of Neurological Disorders and Stroke and philanthropic support from the TR Reddy Family Fund.

Long-lasting Testicular Pain

There is growing evidence that a rare long-term complication of SARS-CoV-2 infection is testicular pain. Case reports by Marca et al. and Kim et al. document instances of atypical abdominal and long-term testicular pain in patients following infection with SARS-CoV-2 [5, 6]. It has been proposed that the presence of high concentrations of angiotensin converting enzyme 2 (ACE2) in kidney and testicular tissue may help to explain the prevalence of long-term testicular pain in COVID-19 patients. SARS-CoV-2 appears to have a strong affinity for ACE2 receptors, serving as a pathway for viral entrance into human cells [6]. Given high expression of ACE2 in spermatogonia, Sertoli cells, and Leydig cells, it is possible that SARS-CoV-2 binding to ACE2 receptors in testis may induce inflammation and facilitate testicular damage and orchitis in infected patients [6, 7].

While viral interaction with ACE2 in the testicular tissue may explain the mechanism in atypical testicular pain in some cases [6, 7], it has been noted in other studies that the SAR-CoV-2 virus was not found to be present in the semen or testicular tissue [8]. A case study by Paoli et al. demonstrated that viral mRNA was not present in a patient’s semen or urine that had tested positive for the virus through a nasopharyngeal swab [9]. While there was not mRNA found in the urine, semen, or testicular tissue — a study by Holtmann and colleagues found there to be a decrease in quality of sperm with a moderate COVID infection [10]. Another study from Corona et al. suggests that COVID-19-associated orchitis-like syndrome could be the result of vasculitis due to abnormalities in coagulation and segmental vascularization of the testis [7].

Given these discrepancies in findings regarding a potential mechanism for pain, it is reasonable to assume that there may be a variety of mechanisms for long-lasting testicular pain in post-COVID patients and clinicians should focus on treating symptoms and identifying patients who are at risk for these post-COVID effects. Due to the increase in COVID-19-related testicular pain as a long-term consequence, there is a need to find a proper treatment plan for these patients. Generally, to treat testicular pain, it is recommended to use ice to reduce swelling or take acetaminophen/ibuprofen; however, further study should be conducted to assess and determine the best treatment plan for COVID-19-related testicular pain. Furthermore, risk factors should be identified for the development of testicular pain with COVID-19 to better prevent its occurrence.

At the University of Wisconsin-Madison Pain Clinic, there have been several cases of post-COVID testicular pain. These cases at UW Pain Clinics can be added to this emerging field of interest analyzing long-lasting long-term testicular pain in patients following infection with SARS-CoV-2.

Chronic Pain

Similar to long-term testicular pain, chronic pain is another atypical symptom following COVID-19 that should be investigated further. Chronic pain is of particular concern for COVID patients who have been admitted to the hospital, particularly the ICU, for their care. Investigations into risk factors for long-standing pain have identified potential risk factors and mechanisms to explain the phenomenon in patients who have been seen in a hospital setting for coronavirus disease [11]. Potential risk factors include acute pain, prolonged ventilation, prolonged immobility, neuromuscular blockade, repeating proning, and neurological insult [11]. Additionally, patient age and overall physical condition likely contribute to patient risk for chronic pain post-infection. Elderly patients and patients with more underlying disorders, particularly hypertension, have been shown to be at a greater risk for chronic pain following treatment for coronavirus [11, 12]. It has been proposed that patient weakness may contribute to rapid deconditioning and joint-related pain, which may help to explain why chronic shoulder pain has been particularly prevalent in patients who were seen in the ICU for coronavirus treatment [13].

While the exact mechanisms causing post-COVID pain in various parts of the body are unknown, a phenomenon of protracted immunosuppression, known as PICS (persistent inflammation, immunosuppression, and catabolism syndrome), has been presented as a potential major contributing factor for the presentation of post-COVID symptoms [14]. PICS facilitates inflammation, immunosuppression, and catabolism that may exacerbate or make patients more susceptible to the ACE2-mediated infiltration of testicular cells, instances of chronic pain, and other more common symptoms associated with post-COVID syndrome such as fatigue, headache, and dyspnea [14]. PICS typically occurs following an event which prompts a systemic inflammatory response. Following the acute inflammatory response and initial infection, patients experience a compensatory anti-inflammatory response [14]. It is when this compensatory response is disproportionally aggressive for the amount of initial inflammation that patients experience the phenomenon of immunosuppression, known as PICS [14, 15].

The treatment for chronic pain is extremely variable and beyond the scope of this narrative; however, the treatment for COVID-19-related chronic pain should be assessed. Further study should determine the most efficacious way to treat COVID-19-related chronic pain and if it differs from the usual course. While it is likely that a portion of the long-term pain experienced by patients can be explained by the effects of prolonged hospitalization, including intubation and immobility, the growing evidence of post-COVID pain syndromes indicates that infection with COVID-19 may independently contribute to patients’ lasting pain. Additional research should be conducted to evaluate the extent to which COVID-19 contributes to the chronic pain patients’ experience, independent of other contributing factors associated with prolonged hospital admissions.


Although COVID-19 is primarily a respiratory illness, headache is an acute symptom during infection and also has been shown to be a potential long-term problem following the acute phase of the infection. A literature review from Rahman et al. found headache and dizziness to be the most common neurological manifestation in multiple studies [12, 16, 17]. To assess the neuro-invasion by a corona virus and influenza A, Lahiri and Ardil analyzed the current literature and found the general consensus to be that there is a hematogenous spread and retrograde axonal transport [18–22]. Other than this, Lahiri and Ardila also mentioned a few other potential mechanisms, such as a cytokine storm, of neuro-invasion proposed from a few other studies.

Since headaches lower a person’s quality of life and depending on the severity can affect daily living activities, it is important to determine patients who are at risk for headaches long-term after contracting COVID-19 to aid in prevention of this consequence. Once a patient is experiencing COVID-19-related headache, it may be difficult to distinguish the difference between a primary headache from a secondary headache disorder when COVID-19 is a factor, so a neurologist may be needed [23]. The guidelines for management for headache in adults in the primary care setting vary based on the type of headache present in the patient; however, one of the first general practice points for the management of a primary headache in adults is to rule out secondary headache [24]. Since there are currently no official guidelines for the treatment of headaches once they are determined to be associated as a long term post-COVID-19 complication, there are many patients suffering from these long-term headaches.

One case study assessing the treatment of refractory headache in the setting of COVID-19 pneumonia found that a patient who had controlled migraines did not respond to their usual effective acute therapy [24]. The study also mentioned that anti-convulsants may offer benefits with the lowest risk of side-effects and medication interactions [24]. This case however was when the patient acutely was affected with the coronavirus. One physician, Dr. Brain Plato, was quoted saying that “for those who have persistent symptoms, probably the thing we are finding to be most effective might be to put them on a course of steroids…” and mentions there being a use of other preventative and as needed medications [25]. Other physicians online mention the potential benefit of breathing exercises. While there are many proposed modalities for the treatment of long-term headaches associated with COVID-19, there are no official guidelines for doctors to follow. It is important for there to be further research into the treatment of headaches that are long-term consequences to COVID-19 to help these patients.

Chest Pain

A major concern in patients who present with long-term pain following infection with SARS-CoV-2 is chest pain, as there is evidence to suggest that persistent cardiac symptoms like chest pain, palpitations, and tachycardia for up to 6 months indicate underlying cardiac sequelae [26]. Previous radiologic investigation of patients who recovered from coronavirus found persistent cardiac abnormalities in 78% of patients and myocardial inflammation in 60% of patients [27]. This investigation also found no association between the incidence of cardiac sequela and severity of acute coronavirus illness [27]. A separate investigation of athletes who recovered from COVID-19 found similar instances of myocardial inflammation in 46% of patients, providing additional evidence for both the risk of long-term cardiac sequela and the independence of cardiac damage from illness severity and overall patient health [28]. While not all instances of post-COVID chest pain may be indicative of underlying cardiac abnormalities, it is important for clinicians to investigate all instances of post-COVID chest pain as it is both a prevalent and potentially concerning finding for patient cardiac health.

Persistent chest pain is one of the most common long-term symptoms in patients who have recovered from SARS-CoV-2. A clinical follow-up of 130 patients recovering from SARS-CoV-2 found that 13% of patients reported persistent chest pain at least 60 days after initial infection [29]. Additionally, a separate, retrospective study of 274 patients in Nigeria noted similar results, finding that 10% of patients enrolled in the study self-reported symptoms of chest pain following coronavirus infection [30]. There are a variety of proposed mechanisms for post-COVID chest pain, each of which should be investigated by clinicians in patients presenting with correlated symptoms. Chest pain may be secondary to cardiac damage, as previously discussed.

The ACE2 receptor, which SARS-CoV-2 displays a high affinity for, is highly expressed in myocardial cells, which offers a possible route of entry for the virus to cause long-term cardiac damage [31]. ACE2 receptors are also highly expressed in type II alveolar epithelial cells, which accounts for the lungs being the primary target of SARS-CoV-2 infection [31]. Underlying pulmonary embolism has also been proposed as a potential mechanism for post-COVID chest pain, particularly when accompanied by shortness of breath in patients [32]. Patients who present with long-term chest pain following coronavirus infection should be thoroughly investigated for pulmonary emboli, as this could present a life-threatening complication in high-risk patients. While post-COVID chest pain can be acutely managed with pain medication, it is critical for clinicians to investigate these patients for pulmonary emboli as well as underlying cardiac conditions such as pericarditis, myocarditis, and other cardiac abnormalities.

reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8907389/

Original Research: Open access.
Neuropsychiatric sequelae of long COVID-19: Pilot results from the COVID-19 neurological and molecular prospective cohort study in Georgia, USA” by Elizabeth Rutkowski et al. Brain, Behavior & Immunity: Health


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