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Long Coronavirus 2019 (COVID-19)

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Practice Essentials

A small number of individuals develop long term clinical residua following acute coronavirus 2019 (COVID-19) infection, sometimes persisting for months; this is termed “Long COVID,”(LC).
 Adults who have received the complete vaccination series but experienced breakthrough infection are 50% less likely to develop LC or chronic 1-3 month COVID-19 residua. The virus can damage the lungs, heart, and brain, which increases the risk for long-term health problems, particularly in patients with preexisting organ dysfunction.

The most commonly reported sequela is persistent fatigue, very similar to the medical illness referred to as chronic fatigue syndrome (CFS) or more recently termed myalgic encephalomyelitis (ME). Some aspects of our understanding and management of CFS/ME have already been applied to LC and the overlap should direct clinicians to consider a diagnosis of CFS/ME in patients who have documented evidence of COVID-19 infection and subsequent clinical symptoms without the more unusual features of LC. It is the unique features of each that help differentiate them (eg, loss of taste and smell, cardiac dysrhythmia, shortness of breath or difficulty breathing, and loss of memory for LC vs. orthostatic intolerance and information processing for CFS/ME).

Long COVID-19

The entity now referred to as LC has not been officially defined, but published cases offer some background for identifying this entity. Such cases have not been followed beyond 2 years as the pandemic has only been in existence since April 2020. A study of 28,118 people in the Kaiser Permanente program who tested positive for SARS-CoV-2 by PCR before the omicron wave were evaluated and presented at the Conference on Retroviruses and Opportunistic Infections 2022.
 These data may be used to help guide diagnoses of LC. CDC continues to work to identify how common post-COVID-19 conditions are, who is most likely to get them, and why some symptoms eventually improve for some people and last longer for others. Rapid and multi-year studies are underway to further investigate post-COVID-19 conditions in more detail.
These studies will help us better understand the long term effects of COVID-19 infection and how to treat patients with these long-term clinical changes.

Observations in the United States and elsewhere indicate there is a higher percentage of females, predominantly middle-aged females, as compared with males who are more likely to develop LC; this difference is also seen in most countries in Europe and Asia, and similar trends are being seen in other countries.
 

Also ongoing is a nationwide clinical trial called Researching COVID to Enhance Recovery (RECOVER) being conducted by the National Institutes of Health.
 No data are yet available from this study.

For purposes of this review of the literature, LC will be defined as an illness lasting longer than 3 months, although some experts use the term for symptoms lasting as short as 3 weeks. 

Fatigue is the most common symptom, and it may continue for 3 months to 2 years. Symptoms in order of frequency are as follows
:

Fatigue

Cough

Loss of taste and smell (the most unique feature of LC)

Insomnia

Headache

Shortness of breath or difficulty breathing (a unique feature)

Joint pain

Muscle pain

Difficulty concentrating

Loss of memory (a unique feature)

Chest pain

Palpitations

Fluid and electrolyte disorders (a unique feature)

Cardiac dysrhythmia (a unique feature)

Dysuria (a unique feature)

Chronic COVID-19

COVID-19: Long-term effects

Most people who have coronavirus disease 2019 (COVID-19) completely recover within a few weeks, but some, even those who had mild disease, continue to experience symptoms for 2-12 weeks after their initial recovery.

Terminology in the lay press has been variable, further confusing the issue. People are sometimes described as “long haulers” and the conditions have been called post-COVID-19 syndrome or COVID-19 conditions rather than LC. They are generally lumped together as effects of COVID-19 that persist for 2-12 weeks after documentation of COVID-19 virus infection without separating the categories as described below.

Patients older than 65 years and younger patients with serious medical conditions are the most likely to experience lingering COVID-19 symptoms, but even young, otherwise healthy people experience illness for weeks to months after infection.
 Common signs and symptoms that linger over time include:

Fatigue

Shortness of breath or difficulty breathing

Cough

Joint pain

Chest pain

Memory, concentration or insomnia

Muscle pain or headache

Palpitations

Loss of taste and smell (similar to LC)

Depression or anxiety

Fever

Dizziness when standing

Worsened symptoms after physical or mental activities

Organ damage caused by COVID-19

Both adults and children who have had COVID-19 can later develop a post-COVID-19 condition lasting fewer than 3 months as contrasted with LC that we have defined in the present review as more than 3 months.
 Although post-COVID-19 conditions appear to be less common in children and adolescents than in adults, long-term effects after COVID-19 do occur in the younger age groups.

Although COVID-19 is reported as a virus that primarily affects the lungs, it can also damage many other organs, including the heart, kidneys, and the brain, not apparent until weeks after infection. Organ damage may lead to health changes that linger after the COVID-19 acute illness, including long-term respiratory illness, heart complications, chronic kidney impairment, stroke, and Guillain-Barre syndrome.

Some adults and children are diagnosed with multisystem inflammatory syndrome during acute COVID-19 infection.
 In this condition, many organs and tissues become severely inflamed. This appears to be most consistent with an autoimmune process and therefore has led clinicians to consider treating these conditions with prolonged steroids and NSAIDs although the illness often resolves after initial treatment.

Information on post-COVID-19 conditions in children and adolescents is limited because young children often have trouble describing the problems they are experiencing. Studies have reported long-term symptoms in children with both mild and severe COVID-19, during or immediately after a COVID-19 infection and particularly in children who previously had multisystem inflammatory syndrome in children (MISC).
 MISC is a condition in which different organs become inflamed, particularly the heart, with laboratory and MRI findings compatible with myocarditis. MISC can lead to post-COVID-19 chronic residua if a person continues to experience multiorgan effects or other symptoms associated with LC. Similar to the changes seen in adults, the most common changes reported in children have been tiredness or fatigue, headache, trouble sleeping (insomnia), trouble concentrating, muscle and joint pain, and cough. 

Some younger patients experience new or ongoing symptoms that can last weeks but less than 3 months after first being infected with COVID-19 but then resolve spontaneously.

Non-specific changes related to hospitalization itself

Hospitalizations for any illness as well as for COVID-19 can cause health effects including severe weakness and exhaustion during the recovery period. Effects of hospitalization for LC can also result in post-intensive care syndrome (PICS), which refers to health effects that begin when a person is in an intensive care unit (ICU) and can remain after the patient is discharged.
 These effects include severe weakness, problems with thinking and judgment, and post-traumatic stress disorder (PTSD), which occurs as a long-term reaction to any very stressful event.

Some symptoms that can occur after hospitalization are similar to symptoms that people with initially mild or no symptoms may experience many weeks after COVID-19. It is therefore difficult to separate changes that are a consequence of hospitalization itself, the long-term effects of the virus, or a combination of both. These conditions might also be complicated by other effects related to the COVID-19 pandemic, including mental health effects from isolation, negative economic situations, and lack of access to healthcare for managing underlying conditions. These factors have affected both people who were infected with COVID-19 and those who have had many other illnesses.

Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis

It is important to define CFS/ME using the Institute of Medicine 2015 diagnostic criteria for adults and children,
 because of the considerable overlap with LC:

Three symptoms and at least one of two additional manifestations are required for diagnosis. The frequency and severity of these symptoms need to be carefully evaluated by the examining physician.

The three required symptoms are:

A reduction or impairment of greater than 50% in the ability to perform at pre-illness levels of essential activities such as work related, educational, social, and personal life. This impairment lasts for more than 6 months and it associated with or caused by fatigue that is severe, new onset, not the result of extreme exercise or activities requiring excessive exertion, and is not significantly alleviated by rest.

Post-exertional malaise (PEM)—worsening of symptoms after physical, mental, or emotional exertion that were not experienced prior to the onset of the current changes. This PEM often puts the patient in relapse that may last days, weeks, or even longer. For some patients, sensory overload (light and sound) can induce PEM. The symptoms typically get worse 12 to 48 hours after the activity or exposure and can last for days or even weeks.

Unrefreshing sleep—patients with ME/CFS may not feel better or less tired even after a full night of sleep despite the absence of specific objective sleep alterations.

At least one of the following two additional manifestations must be present:

Cognitive impairment—patients have problems with thinking, memory, executive function, and information processing, as well as attention deficit and impaired psychomotor functions. All can be exacerbated by exertion, effort, prolonged upright posture, stress, or time pressure, and may have serious consequences on a patient’s ability to maintain a job or attend school full time.

Orthostatic intolerance (a unique feature)—patients develop a worsening of symptoms upon assuming and maintaining upright posture as measured by objective heart rate and blood pressure abnormalities during standing, bedside orthostatic vital signs, or head-up tilt testing. Orthostatic symptoms including lightheadedness, fainting, increased fatigue, cognitive worsening, headaches, or nausea are worsened with quiet upright posture (either standing or sitting) during day-to-day life and are improved (though not necessarily fully resolved) with lying down. Orthostatic intolerance is often the most bothersome manifestation of CFS/ME among adolescents.

The IOM committee specified that “ The diagnosis of CFS/ME should be questioned if patients do not have these symptoms at least half of the time with moderate, substantial, or severe intensity.”

Other Common Symptoms of CFS/ME

Many people with CFS/ME also have other symptoms, including the following:

Muscle pain

Pain in the joints without swelling or redness

Headaches of a new type, pattern, or severity

Swollen or tender lymph nodes in the neck or armpit

A sore throat that is frequent or recurring

Chills and night sweats

Visual disturbances

Sensitivity to light and sound

Nausea

Allergies or sensitivities to foods, odors, chemicals, or medications

Treatment

There are no basic nor clinical research studies to support any treatment for the few months of lingering symptoms after COVID-19 nor for LC but healthcare providers may be able to help reduce or manage symptoms through simpler measures of rehabilitation services, symptomatic medications, and coordinated care. Mild disease is more likely to resolve without aggressive therapy. Particularly with milder illness it is important to consider other possible diagnoses masquerading as LC. Conventional interventions can be used to address issues such as pain, poor appetite, headache, nausea, and diarrhea. Specialists are needed for patients with chronic kidney disease who may need long-term dialysis after COVID-19 infection. Clotting abnormalities have been reported that require consultation and treatment by hematologists.

There is an absence of research on self-management practices among individuals with LC. Patients and patient advocacy groups have reported an absence of timely support and poor recognition and definition of LC, partly attributable to insufficient understanding of LC infection and overwhelmed healthcare systems. The lack of support for these patients has led to loss of faith and disappointment in healthcare service delivery, leading people with LC to seek alternative sources of support and treatment.

Uncontrolled studies and case reports have suggested a wide range of self-prescribed medications employed for the prevention and management of acute LC, including steroids, ivermectin, anti-retrovirals, montelukast, hyperbaric oxygen, penicillin, vitamin C, traditional medicines, chloroquine and hydroxychloroquine.
 Self-prescribing practices are unsurprising given the concern of LC patients based on the well reported high incidence of morbidity and mortality from acute COVID-19 infection, restricted access to healthcare during lockdowns, and few treatments and preventive therapies for COVID-19 infection itself.

Unfortunately medicines are being used off label, in unsafe doses, and are sometimes purchased in an unregulated manner overseas. Harmful drug–drug interactions are enhanced due to the complexity and multiple symptoms of LC, leading to the sequential addition of multiple treatments when earlier ones fail.

People with LC have sought advice from social media platforms, such as Facebook, where individuals share their self-management experiences, regardless of the outcome, and online resources, including medical blogs and journals. Due to the small evidence base, these platforms are a potential source of conflicting information and unfortunately, misinformation.

Self-management of symptoms in the long term is often costly, with some individuals using a substantial proportion of their income, which threatens to increase existing health costs. Further inequalities include geographical disparities in access to clinics for LC, access to private healthcare, and health literacy.

The Front Line COVID-19 Critical Care Alliance (FLCCC) suggests more than 20 medications, vitamins, and therapies as part of its “i-recover” protocol for LC, with ivermectin at the top of the list.
 The group developed a sequential detailed protocol to support the large numbers of patients diagnosed with LC since specific recommendations from official sources do not exist. However, experts and physicians at many medical centers treating patients with documented LC have expressed concern for the FLCCC’s treatment plans, instead recommending patience until possible treatments have been more fully examined and confirmed.

Exercise is currently being evaluated as early management of these patients with encouraging results.
 Specific treatment for defined organ involvement should include specialists such as cardiologists, pulmonologists, gastroenterogists, psychologists, neurologists, and physical therapists, as well as specialists in other fields of medicine.

The various presentations of LC are accounted for by variations in the effect of the virus on the immune system and other organs and the extent of the host inflammatory response. This interaction is currently being evaluated.

There are now published series of LC in children, although treatment data are lacking.
 A major difference between LC in adults and children is that the percent of COVID-19 infected children developing LC is significantly lower and the duration of illness is shorter. Early symptoms appear to be similar to adults, with fatigue and difficulty concentrating being most common. Difficulty concentrating is of greatest concern because of the interference with optimal learning and school performance. One contrasting feature is that insomnia is much less common than in adults. Some series have suggested that in addition to the duration of illness being shorter, long-term outcome is better than for adults.

Some people with LC have symptoms of CFS/ME, postural orthostatic tachycardia syndrome (POTS), dysautonomia, fibromyalgia, autoimmune disease, mast cell activation syndrome (MCAS), and other health conditions that require management that has been shown to be effective in clinical trials. When someone suspected of having LC receives a new diagnosis of these other conditions, medical and rehabilitation specialists may then be able to apply the appropriate treatments and therapies.

Some patients may find that their LC symptoms improve over time. It is unclear which LC patients have symptoms that are likely to be permanent or are reversible with time.

In a retrospective study presented in March 2022 at the American College of Cardiology’s virtual Cardiovascular Summit, scientists from Cleveland Clinic reviewed their data that used enhanced external counterpulsation (EECP).
 This intervention compresses the blood vessels in the lower limbs to increase blood flow to the heart. EECP uses contracting and relaxing pneumatic cuffs on the calves, thighs, and lower hip area to provide oxygen-rich blood to the heart muscle, brain, and the rest of the body. Each session takes 1 hour, and patients may undergo as many as 35 sessions over 7 weeks. The researchers evaluated the effect of the therapy in 50 COVID-19 survivors. Twenty patients had coronary artery disease (CAD), whereas 30 did not; average age was 54 years.

All patients completed the Seattle Angina Questionnaire-7 (SAQ7), Duke Activity Status Index (DASI), PROMIS Fatigue Instrument, Rose Dyspnea Scale (RDS), and the 6-minute walk test (6MWT) before and after they completed 15 to 35 hours of EECP therapy.

The analysis showed statistically significant improvements in all areas assessed, including 25 more points for health status on the SAQ7 (range, 0 to 100), 20 more points for functional capacity on DASI (range, 0 to 58.2), six fewer points for fatigue on PROMIS (range, 4 to 20), 50% lower shortness of breath score on the RDS, and 178 more feet on the 6MWT.

The change from baseline among participants who had LC but not CAD was significant for all end points, but there was no difference between LC patients with or without CAD.

Finally as a warning: there are potential risks of self-prescription, such as harmful drug–drug interactions and use of inappropriate treatments. Research is needed to understand the self-management practices that are being used to manage LC symptoms; factors influencing their uptake; and the benefits, harms, and costs. There is also a need to assess the potential harmful effects of polypharmacy and drug–drug interactions in these individuals. The Therapies for LC study (ISRCTN15674970) will begin to explore self-management practices through a survey of people with LC.
 This study aims to be a first step towards understanding this important and under-researched public health issue.

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