More than half of all people who have been diagnosed with COVID-19 will experience post-COVID symptoms

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More than half of the 236 million people who have been diagnosed with COVID-19 worldwide since December 2019 will experience post-COVID symptoms – more commonly known as “long COVID” – up to six months after recovering, according to Penn State College of Medicine researchers.

The research team said that governments, health care organizations and public health professionals should prepare for the large number of COVID-19 survivors who will need care for a variety of psychological and physical symptoms.

During their illnesses, many patients with COVID-19 experience symptoms, such as tiredness, difficulty breathing, chest pain, sore joints and loss of taste or smell.

Until recently, few studies have evaluated patients’ health after recovering from the coronavirus. To better understand the short- and long-term health effects of the virus, the researchers examined worldwide studies involving unvaccinated patients who recovered from COVID-19.

According to the findings, adults, as well as children, can experience several adverse health issues for six months or longer after recovering from COVID-19.

The researchers conducted a systematic review of 57 reports that included data from 250,351 unvaccinated adults and children who were diagnosed with COVID-19 from December 2019 through March 2021.

Among those studied, 79% were hospitalized, and most patients (79%) lived in high-income countries. Patients’ median age was 54, and the majority of individuals (56%) were male.

The researchers analyzed patients’ health post-COVID during three intervals at one month (short-term), two to five months (intermediate-term) and six or more months (long-term).

According to the findings, survivors experienced an array of residual health issues associated with COVID-19. Generally, these complications affected a patient’s general well-being, their mobility or organ systems. Overall, one in two survivors experienced long-term COVID manifestations. The rates remained largely constant from one month through six or more months after their initial illness. 

The investigators noted several trends among survivors, such as:

  • General well-being: More than half of all patients reported weight loss, fatigue, fever or pain.
  • Mobility: Roughly one in five survivors experienced a decrease in mobility.
  • Neurologic concerns: Nearly one in four survivors experienced difficulty concentrating.
  • Mental health disorders: Nearly one in three patients were diagnosed with generalized anxiety disorders.
  • Lung abnormalities: Six in ten survivors had chest imaging abnormality and more than a quarter of patients had difficulty breathing.
  • Cardiovascular issues: Chest pain and palpitations were among the commonly reported conditions.
  • Skin conditions: Nearly one in five patients experienced hair loss or rashes.
  • Digestive issues: Stomach pain, lack of appetite, diarrhea and vomiting were among the commonly reported conditions.

“These findings confirm what many health care workers and COVID-19 survivors have been claiming, namely, that adverse health effects from COVID-19 can linger,” said co-lead investigator Vernon Chinchilli, chair of the Department of Public Health Sciences.

“Although previous studies have examined the prevalence of long COVID symptoms among patients, this study examined a larger population, including people in high-, middle- and low-income countries, and examined many more symptoms. Therefore, we believe our findings are quite robust given the available data.”

“The burden of poor health in COVID-19 survivors is overwhelming,” said co-lead investigator Dr. Paddy Ssentongo, assistant professor at the Penn State Center for Neural Engineering. “Among these are the mental health disorders. One’s battle with COVID doesn’t end with recovery from the acute infection.

Vaccination is our best ally to prevent getting sick from COVID-19 and to reduce the chance of long-COVID even in the presence of a breakthrough infection.”

The mechanisms by which COVID-19 causes lingering symptoms in survivors are not fully understood. These symptoms could result from immune-system overdrive triggered by the virus, lingering infection, reinfection or an increased production of autoantibodies (antibodies directed at their own tissues).

The SARS-CoV-2 virus, the agent that causes COVID-19, can access, enter and live in the nervous system. As a result, nervous system symptoms such as taste or smell disorders, memory impairment and decreased attention and concentration commonly occur in survivors. 

“Our study was not designed to confirm COVID-19 as the sole cause of these symptoms. It is plausible that symptoms reported by patients in some of the studies examined were due to some other causes,” said Ssentongo.

According to the researchers, early intervention will be critical for improving the quality of life for many COVID-19 survivors. They said that in the years ahead, health care providers will likely see an influx of patients with psychiatric and cognitive problems, such as depression, anxiety or post-traumatic stress disorder, who were otherwise healthy before their COVID-19 infection.

Based on these findings, health care providers should plan and allocate resources accordingly in order to effectively monitor and treat these conditions.

The research team noted that these long-term health conditions may cause increased demand for medical care and could overwhelm health care systems, particularly in low- and middle-income countries. They said the findings from this study could help shape treatment plans to improve care for COVID-19 patients and establish integrated evidence-based clinical management for those affected.

“Since survivors may not have the energy or resources to go back and forth to their health care providers, one-stop clinics will be critical to effectively and efficiently manage patients with long COVID,” Ssentongo said. “Such clinics could reduce medical costs and optimize access to care, especially in populations with historically larger health care disparities.”


Acute COVID

Those infected with SARS-CoV-2 virus commonly develop symptoms 4–5 days after exposure. Acute COVID symptoms include fever, throat pain, cough, muscle or body aches, loss of taste or smell and diarrhea. A study from England, Wales and Scotland identified three clusters of symptoms during acute illness [2]. They are.

  • • respiratory symptom cluster: with cough, sputum, shortness of breath, and fever;
  • • musculoskeletal symptom cluster: with myalgia, joint pain, headache, and fatigue
  • • enteric symptom cluster: with abdominal pain, vomiting, and diarrhea

COVID Symptom Study group identified six clusters of symptoms [3]. They are:

  • • “Flu-like” with no fever – headache, loss of smell, muscle pains, cough, sore throat, chest pain, no fever
  • • “Flu-like” with fever – headache, loss of smell, cough, sore throat, hoarseness, fever, loss of appetite
  • • Gastrointestinal – headache, loss of smell, loss of appetite, diarrhea, sore throat, chest pain, no cough
  • • Severe level one, fatigue – headache, loss of smell, cough, fever, hoarseness, chest pain, fatigue
  • • Severe level two, confusion – headache, loss of smell, loss of appetite, cough, fever, hoarseness, sore throat, chest pain, fatigue, confusion, muscle pain
  • • 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

Recovery from mild SARS-CoV-2 infection commonly occurs within 7–10 days after the onset of symptoms in mild disease; it could take 3–6 weeks in severe/critical illness [4]. However, continued follow up of patients who recovered from COVID-19 showed that one or more symptoms persist in a substantial percentage of people, even weeks or months after COVID-19.

“Long COVID”

The term long COVID was first used by Perego in social media to denote persistence of symptoms weeks or months after initial SARS-CoV-2 infection and the term ‘long haulers’ was used by Watson and by Yong [[5], [6], [7]].

“Long COVID” is a term used to describe presence of various symptoms, even weeks or months after acquiring SARS-CoV-2 infection irrespective of the viral status [8]. It is also called “post-COVID syndrome”. It can be continuous or relapsing and remitting in nature [9]. There can be the persistence of one or more symptoms of acute COVID, or appearance of new symptoms.

Majority of people with post-COVID syndrome are PCR negative, indicating microbiological recovery. In other words, post COVID syndrome is the time lag between the microbiological recovery and clinical recovery [10]. Majority of those with long COVID show biochemical and radiological recovery. Depending upon the duration of symptoms, post COVID or Long COVID can be divided into two stages-post acute COVID where symptoms extend beyond 3 weeks, but less than 12 weeks, and chronic COVID where symptoms extend beyond 12 weeks [11]. (Fig. 1 ).

Fig. 1
Fig. 1 – Classification of long COVID.

Thus, among people infected with SARS-CoV-2 the presence of one or more symptoms (continuous or relapsing and remitting; new or same symptoms of acute COVID) even after the expected period of clinical recovery, irrespective of the underlying mechanism, is defined as post COVID syndrome or Long COVID.

There are several challenges in the diagnosis of long COVID. The time taken for the clinical recovery varies depending upon the severity of illness; while associated complications make it difficult to define the cut-off time for the diagnosis. A significant proportion of SARS-CoV-2 infected individuals are asymptomatic, and many individuals would not have undergone any test to confirm SARS-CoV-2 infection.

If these individuals develop multiple symptoms subsequently, making a diagnosis of long COVID without a preceding evidence of SARS-CoV-2 infection is challenging. The testing policy varies in different countries and it is a common practice during a pandemic to diagnose clinically based on symptoms without any confirmatory tests. Therefore, persistence of symptoms in those who had never checked for COVID is a challenge [12].

Similarly, residual symptoms in those checked negative for COVID (false negative as testing may be done too early or too late in the disease course) may also add to diagnostic dilemma [13]. Antibody response to infection also varies and about 20% does not seroconvert. Antibody level may decrease over time challenging the retrospective diagnosis of recent SARS-CoV-2 infection [14,15].

“Long COVID”-real world scenario

A report from Italy found that 87% of people recovered and discharged from hospitals showed persistence of at least one symptom even at 60 days [16]. Of these 32% had one or two symptoms, where as 55% had three or more. Fever or features of acute illness was not seen in these patients.

The commonly reported problems were fatigue (53.1%), worsened quality of life (44.1%), dyspnoea (43.4%), joint pain, (27.3%) and chest pain (21.7%). Cough, skin rashes, palpitations, headache, diarrhea, and ‘pins and needles’ sensation were the other symptoms reported. Patients also reported inability to do routine daily activities, in addition to mental health issues such as anxiety, depression and post-traumatic stress disorder.

Another study found that COVID-19 patients discharged from hospital experience breathlessness and excessive fatigue even at 3 months [17].

The prevalence of residual symptoms is about 35% in patients treated for COVID-19 on outpatient basis, but around 87% among cohorts of hospitalized patients [16,18].

The percentage of people, who failed to return to their job at 14–21 days after becoming COVID positive, was 35% according to one survey [18]. It is more common in older age groups (26% in 18–34 years, 32% in 35–49 years and 47% in 50 years and above), and among those with co morbidities (28% with nil or one co-morbidity, 46% with two and 57% with three or more co morbidities).

Obesity (BMI>30) and presence of psychiatric conditions (anxiety disorder, depression, posttraumatic stress disorder, paranoia, obsessive-compulsive disorder and schizophrenia) are associated with greater than two-fold odds of not returning to job by 14–21 days after a positive result [18]. Fever and chills present in the acute stage of infection resolved in 97% and 96% of individuals respectively.

But cough, fatigue and shortness of breath did not resolve in 43%, 35% and 29% of patients during interview. Loss of taste and loss of smell took longer duration for resolution (8 days). As per a recent meta analysis the 5 most common manifestations of Long COVID-19 were fatigue (58%), headache (44%), attention disorder (27%), hair loss (25%), dyspnea (24%) [19].

Among patients admitted to critical care unit who were on ventilator for a prolonged time, residual symptoms are common. However, COVID patients who had mild disease also report not regaining their pre-COVID health status, effectively questioning the terminology of “mild” disease.

Risk factors for long COVID

Follow up of patients recovered from COVID identified a few factors which are commonly associated with development of long COVID. The risk of long COVID is twice common in women compared to men [9]. Increasing age is also a risk factor and it is found that patients with long COVID are around four years older than those without [9].

Presence of more than 5 symptoms in the acute stage of illness is associated with increased risk of developing long COVID [20]. Symptoms most commonly associated with long COVID include fatigue, headache, dyspnea, hoarse voice and myalgia [20]. Presence of co morbidities also increases the risk of developing post COVID syndrome. Even those with mild symptoms at initial presentation were noted to develop long COVID.

Pathophysiology of “Long COVID”

The exact mechanism behind the persistence of symptoms has to be identified. Reason for the persistence of symptoms can be the sequelae of organ damage, varying extent of injury (organ damage) and varying time required for the recovery of each organ system, persistence of chronic inflammation (convalescent phase) or immune response/auto antibody generation, rare persistence of virus in the body, nonspecific effect of hospitalization, sequelae of critical illness, post-intensive care syndrome, complications related to corona infection or complications related to co morbidities or adverse effects of medications used [21,22].(Fig. 2 )

Persistence of infection can be due to persistent viremia in people with altered immunity, re-infection or relapse [[23], [24], [25]]. Deconditioning, psychological issues like post-traumatic stress also contribute to symptoms [[26], [27], [28]]. The social and financial impact of COVID-19 also contributes to post COVID issues including psychological issues. Differentiating residual symptoms from re-infection is important in the public health perspective. Persistently elevated inflammatory markers point towards chronic persistence of inflammation. It is helpful to remember that in any patient, multiple mechanisms may contribute to long COVID symptoms.

Fig. 2
Fig. 2 – Various pathophysiological mechanism of “Long COVID”.

reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056514/


More information: Destin Groff et al, Short-term and Long-term Rates of Postacute Sequelae of SARS-CoV-2 Infection: A Systematic Review,
JAMA Netw Open (2021). DOI: 10.1001/jamanetworkopen.2021.28568

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