Overview
1. What is long COVID?
2. What do reports on patients with post-COVID-19 syndrome point out?
3. What is MIS-A?
4. Inflammation of the heart caused by COVID-19: refer patients for examination;
5. What else should be paid attention to?
6. Is it a new phenomenon? About the consequences of the first SARS coronavirus, 2003;
7. Can lung capacity be improved?
8. How should post-COVID / long COVID be treated?
9. To be investigated further: hyperferritinaemia (iron overload), fat metabolism, EGFR and mitochondrial health
1. What is long COVID?
Long COVID was introduced by people who have had COVID-19 and are still dealing with health problems after weeks or months. These may include fatigue, exhaustion with moderate exertion, decrease in lung capacity, a persistent cough, chest pain, recurrent fever, and other symptoms. The official term is "Post acute COVID-19" or "Post-COVID-19 syndrome". The Long Alliance Netherlands uses the term "COVID-19 Associated Syndrome", CAS.
Long COVID is not specific. In some cases, persistent symptoms may be the result of pneumonia (Persistent Symptoms in Patients After Acute COVID-19, JAMA 2020; 324 (6): 603-605).
COVID-19 poses all grades of the disease (mild to severe) at risk of damage to the heart, lungs, kidneys and brain. Because COVID is a microthrombotic disease, small "clumps" can form in the fine vessels. Psychological and motor problems that arise during and after COVID-19 can be the result of neurological damage from the virus. Strokes, epilepsy and Guillain-Barré syndrome (a neurological disease) can also occur in young people. COVID-19 increases the risk of developing Parkinson's and Alzheimer's in the long term (COVID-19 (coronavirus): Long-term effects, Mayo Clinic, November 17, 2020).
Long COVID is used as a collective term for systemic diseases, immune disorders and inflammatory reactions resulting from COVID-19. Long COVID also includes post-IC syndrome and post-viral syndrome. An specific example of an inflammatory disease that can result from COVID is MIS-A (Multisystem Inflammatory Syndrome in Adults).
2. What do reports on patients with Post-COVID-19 syndrome point out?
In a follow-up study in 150 people who have had non-critical COVID-19, 30% report respiratory difficulties (dyspnoea) on day 60 after the first symptoms; 40% report general weakness (asthenia) on day 60. Half of this patient group works in the medical sector and half of this study population has at least one underlying disease (Follow-up of adults with noncritical COVID-19 two months after symptom onset, Clinical Microbiology and Infection, October 5, 2020).
A similar picture is painted in an evaluation of patients hospitalized in 2020 for COVID-19 (IC and non-IC patients). The disadvantage of these and other recent evaluations is that the details are lacking, that patients themselves report, that no control takes place, and that no control group is involved in the study for comparison. The comorbidities in this group are high blood pressure (46.7%), high BMI (47.5%) and diabetes (21.7%) (Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID -19, Journal of Infection Vol. 81, Issue 6, December 1, 2020). In a group of 143 patients previously admitted for COVID, 35% of whom have high blood pressure, 18% thyroid disease, 11% immune disease, 9% COPD, and 7% diabetes, fatigue (53%), breathing problems (43%) and joint pain (arthralgia, 27%) have been reported. Also in this study, the necessary details are lacking, the study itself reports that the pneumonia resulting from COVID-19 can cause the persistent symptoms (Persistent Symptoms in Patients After Acute COVID-19, JAMA 2020; 324 (6): 603 -605).
More specific is a follow-up of 384 former COVID between day 47 and day 59 after hospital discharge. 7.3% of 247 patients have a persistently low level of white blood cells, 30.1% of 229 patients have an elevated D-dimer value (D-dimer elevation indicates the breakdown of blood clots in the body) and 9.5% of 190 patients have an increase in the C-reactive protein (CRP, a protein produced by the liver in inflammation). Of 244 patients who received a chest X-ray during the evaluation, 9% had deteriorated lung tissue and 14.8% needed further investigation (Long-COVID: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalization for COVID-19, Thorax, November 10, 2020).
In a follow-up study in 150 people who have had non-critical COVID-19, 30% report respiratory difficulties (dyspnoea) on day 60 after the first symptoms; 40% report general weakness (asthenia) on day 60. Half of this patient group works in the medical sector and half of this study population has at least one underlying disease (Follow-up of adults with noncritical COVID-19 two months after symptom onset, Clinical Microbiology and Infection, October 5, 2020).
A similar picture is painted in an evaluation of patients hospitalized in 2020 for COVID-19 (IC and non-IC patients). The disadvantage of these and other recent evaluations is that the details are lacking, that patients themselves report, that no control takes place, and that no control group is involved in the study for comparison. The comorbidities in this group are high blood pressure (46.7%), high BMI (47.5%) and diabetes (21.7%) (Post-discharge persistent symptoms and health-related quality of life after hospitalization for COVID -19, Journal of Infection Vol. 81, Issue 6, December 1, 2020). In a group of 143 patients previously admitted for COVID, 35% of whom have high blood pressure, 18% thyroid disease, 11% immune disease, 9% COPD, and 7% diabetes, fatigue (53%), breathing problems (43%) and joint pain (arthralgia, 27%) have been reported. Also in this study, the necessary details are lacking, the study itself reports that the pneumonia resulting from COVID-19 can cause the persistent symptoms (Persistent Symptoms in Patients After Acute COVID-19, JAMA 2020; 324 (6): 603 -605).
More specific is a follow-up of 384 former COVID between day 47 and day 59 after hospital discharge. 7.3% of 247 patients have a persistently low level of white blood cells, 30.1% of 229 patients have an elevated D-dimer value (D-dimer elevation indicates the breakdown of blood clots in the body) and 9.5% of 190 patients have an increase in the C-reactive protein (CRP, a protein produced by the liver in inflammation). Of 244 patients who received a chest X-ray during the evaluation, 9% had deteriorated lung tissue and 14.8% needed further investigation (Long-COVID: a cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalization for COVID-19, Thorax, November 10, 2020).
3. What is MIS-A?
MIS-A stands for Multi Inflammatory Syndrome in Adults. Until recently it was known that children can develop this systemic syndrome after infectious diseases, in children it is called "MIS-Children". It means that the body remains in a state where it is trying to clear up an infection. This inflammatory response is different from inflammation and organ dysfunction due to hypoxia. A variety of symptoms are reported in the sparse literature on MIS-A.
Patients may present with persistent sore throat, fever, weakness, general malaise, stiffness, diarrhea, rash, shock, kidney failure, eating problems, pressure, palpitations of the heart ("fluttering"), ringing in the ears, haemophilia, a weak pulse, low blood pressure, nausea, very dark urine, pain when swallowing and burning when urinating. To determine if it is MIS-A, an RT-PCR and antigen test must be performed, supplemented with a measurement of the inflammatory and thrombotic markers CRP (C-reactive protein), ferritin, D-dimer, alanine aminotransferase (liver function), absolute lymphocyte count (ALC) and troponin (heart function). The examination is complemented by CT scans to assess the organs, a chest X-ray to detect any frosted glass spots on the lungs, an ultrasound scan of the heart (TTE), ECG of the heart and ejection fraction examination of the heart.
In the reported cases of MIS-A, inflammatory markers were markedly elevated and resulted in endothelial damage or coagulopathy from SARS-CoV-2 infection. In one case, particles of the complement system were found in the blood vessels. Treatment with corticosteroids, heparin, phenylephrine, dobutamine, Remdesivir, tocilizumab, midodrine, norepinephrine and vasopressin, among others, improved (Case Series of MIS-A Associated with SARS-CoV-2 Infection-- United Kingdom and United States, March-August 2020 , Morbidity and Mortality Weekly Report CDC, Oct 9, 2020; 69 (40): 1450-1456).
4. Inflammation of the heart caused by COVID-19: refer patients for examination
Inflammation of the heart muscle may develop in recovered COVID patients. An MRI study of 100 patients recovered from COVID showed that 78% had heart problems and 60% had persistent inflammation of the heart. In the patient group, the presence of LGE (Late Gadolinium Enhancement, a marker for fibrosis and edema due to inflammation of the pericardium) and a marked increase in troponin (Outcomes of Cardiovascular MRI in Patients Recently Recovered from COVID-19, JAMA Cardiology 2020; 5 ( 11): 1265-1273).
Practitioners are advised to include COVID-19 suspicion in new cardiological complaints are reported (Myocardial injury and COVID-19: Possible mechanisms, Life Sciences 2020, July 15, 2020; 253). In a study among competitive and endurance athletes, 15% showed abnormalities on the Cardio-MR, which indicate myocarditis, while LGE is present in 30.8%. Also in this group, fibrosis and edema due to inflammation of the heart tissue as a result of COVID (Cardiovascular Magnetic Resonance Findings in Competitive Athletes Recovering from COVID-19 Infection, JAMA Cardiology, September 11, 2020). There is currently no guideline regulating a return to competitive and endurance sports after COVID-19. The collection of troponin, ECG and ultrasound is recommended in all cases (from asymptomatic COVID-19 to COVID with severe complaints).
At least 2 weeks of rest after infection is recommended. In case of myocarditis (inflammation of the heart muscle), 3 to 6 months rest may be recommended. If there has been "mild" COVID-19 infection, exercise can be resumed according to the "50/30/20/10 principle": in the first week, the normal intensity and duration are halved, until the fourth week. only 10% of the intensity and duration of sports activities is reduced (Considerations for Return to Exercise Following Mild-to-Moderate COVID-19 in the Recreational Athlete, Muscoskeletal Journal of Hospital for Special Surgery 2020 Nov; 16 (Suppl 1): 102 -107).
5. What else should be paid attention to?
Muscle pain occurs in 15% of COVID patients. In most cases this will pass. If the muscle pain persists due to inflammatory mechanisms after COVID, heat, ice cooling, optional topical non-steroidal anti-inflammatory drugs (NSAIDs) and stretching exercises are applied. Because COVID-19 is a disease with an increased risk of thromboembolic disease, physicians should be alert to athletes reporting fibula pain and consider investigating VTE (venous thromboembolism) (Considerations for Return to Exercise Following Mild -to-Moderate COVID-19 in the Recreational Athlete, Muscoskeletal Journal of Hospital for Special Surgery 2020 Nov; 16 (Suppl 1): 102-107).
Persistent fatigue could be due to Autoimmune Hemolytic Anemia (AIHA) (Autoimmune haemolytic anemia associated with COVID-19 infection, British Journal of Haematology Vol. 190, Issue 1, July 2020, p. 29-31). Hemoglobin must be checked to rule out anemia.
6. Is it a new phenomenon? About the consequences of the first SARS coronavirus, 2003
No, long term effects of coronavirus disease are not new. The virus that causes COVID-19 (Coronavirus Disease-2019) is SARS-CoV-2, a relative of SARS-CoV-1. In 2003 Asia and Canada were badly hit by the SARS-1 epidemic. In 2006 and 2010, international studies were conducted among people who had recovered from SARS-1. A 2005 evaluation reports that a decline in gas transmission in the lungs was observed in 15.5% of SARS survivors (Impact of SARS on pulmonary function, functional capacity and quality of life in survivors, Thorax May 2005; 60 (5 ): 401-409).
In a group of 37 patients, stability of deterioration was reported in 20-30% of cases 3 years after SARS-CoV-1 infection (the functions FVC, VC and especially FEF showed no improvement after 3 years), ( Changes in pulmonary function in SARS patients during the three-year convalescent period, Zhongguo Wei Zhong, September 2007; 19 (9): 536-8). This means that, while pulmonary performance had deteriorated, the clinical picture had not become worse.
In a 2010 study, 52% of SARS survivors found a deterioration in the diffusion capacity of the lungs (DLCO). In ARDS, 76% of patients have a limitation in DLCO after 5 years. On the CT scans, ground glass opacities, ground glass spots between the lungs and disruption of the pressure in the lungs (air trapping) were seen (Pulmonary sequelae in convalescent patients after SARS: evaluation with thin-section CT, Radiology , September 1, 2005). Epithelial tissue damage and pulmonary fibrosis explain these persistent limitations in lung capacity, while lack of fitness training aggravates the condition. Average performance on the 6-minute walk test (6MWT) remains below par (The long-term impact of SARS on pulmonary function, exercise and health status, Respirology April 2010; 15 (3): 543-550).
A 15-year review was published in February 2020, covering former SARS patients treated between 2003 and 2005. Lung function (total lung capacity, TLC and carbon monoxide diffusion, DCLO) has not significantly improved over the past 15 years in SARS patients with pulmonary fibrosis. Direct treatment of pneumonia can prevent the lung function of SARS / COVID survivors from deteriorating. In 15 of the 71 patients evaluated, hip necrosis (femoral head necrosis) has occurred on a bump course of corticosteroids, but remarkably (favorably) this hip necrosis may be reduced. With controlled dosing of corticosteroids, this risk can be reduced (Long-term bone and lung consequences associated with hospital-acquired SARS: a 15-year follow-up from a prospective cohort study. Bone Research 2020; 8: 8).
Inflammation of the heart muscle may develop in recovered COVID patients. An MRI study of 100 patients recovered from COVID showed that 78% had heart problems and 60% had persistent inflammation of the heart. In the patient group, the presence of LGE (Late Gadolinium Enhancement, a marker for fibrosis and edema due to inflammation of the pericardium) and a marked increase in troponin (Outcomes of Cardiovascular MRI in Patients Recently Recovered from COVID-19, JAMA Cardiology 2020; 5 ( 11): 1265-1273).
Practitioners are advised to include COVID-19 suspicion in new cardiological complaints are reported (Myocardial injury and COVID-19: Possible mechanisms, Life Sciences 2020, July 15, 2020; 253). In a study among competitive and endurance athletes, 15% showed abnormalities on the Cardio-MR, which indicate myocarditis, while LGE is present in 30.8%. Also in this group, fibrosis and edema due to inflammation of the heart tissue as a result of COVID (Cardiovascular Magnetic Resonance Findings in Competitive Athletes Recovering from COVID-19 Infection, JAMA Cardiology, September 11, 2020). There is currently no guideline regulating a return to competitive and endurance sports after COVID-19. The collection of troponin, ECG and ultrasound is recommended in all cases (from asymptomatic COVID-19 to COVID with severe complaints).
At least 2 weeks of rest after infection is recommended. In case of myocarditis (inflammation of the heart muscle), 3 to 6 months rest may be recommended. If there has been "mild" COVID-19 infection, exercise can be resumed according to the "50/30/20/10 principle": in the first week, the normal intensity and duration are halved, until the fourth week. only 10% of the intensity and duration of sports activities is reduced (Considerations for Return to Exercise Following Mild-to-Moderate COVID-19 in the Recreational Athlete, Muscoskeletal Journal of Hospital for Special Surgery 2020 Nov; 16 (Suppl 1): 102 -107).
5. What else should be paid attention to?
Muscle pain occurs in 15% of COVID patients. In most cases this will pass. If the muscle pain persists due to inflammatory mechanisms after COVID, heat, ice cooling, optional topical non-steroidal anti-inflammatory drugs (NSAIDs) and stretching exercises are applied. Because COVID-19 is a disease with an increased risk of thromboembolic disease, physicians should be alert to athletes reporting fibula pain and consider investigating VTE (venous thromboembolism) (Considerations for Return to Exercise Following Mild -to-Moderate COVID-19 in the Recreational Athlete, Muscoskeletal Journal of Hospital for Special Surgery 2020 Nov; 16 (Suppl 1): 102-107).
Persistent fatigue could be due to Autoimmune Hemolytic Anemia (AIHA) (Autoimmune haemolytic anemia associated with COVID-19 infection, British Journal of Haematology Vol. 190, Issue 1, July 2020, p. 29-31). Hemoglobin must be checked to rule out anemia.
6. Is it a new phenomenon? About the consequences of the first SARS coronavirus, 2003
No, long term effects of coronavirus disease are not new. The virus that causes COVID-19 (Coronavirus Disease-2019) is SARS-CoV-2, a relative of SARS-CoV-1. In 2003 Asia and Canada were badly hit by the SARS-1 epidemic. In 2006 and 2010, international studies were conducted among people who had recovered from SARS-1. A 2005 evaluation reports that a decline in gas transmission in the lungs was observed in 15.5% of SARS survivors (Impact of SARS on pulmonary function, functional capacity and quality of life in survivors, Thorax May 2005; 60 (5 ): 401-409).
In a group of 37 patients, stability of deterioration was reported in 20-30% of cases 3 years after SARS-CoV-1 infection (the functions FVC, VC and especially FEF showed no improvement after 3 years), ( Changes in pulmonary function in SARS patients during the three-year convalescent period, Zhongguo Wei Zhong, September 2007; 19 (9): 536-8). This means that, while pulmonary performance had deteriorated, the clinical picture had not become worse.
In a 2010 study, 52% of SARS survivors found a deterioration in the diffusion capacity of the lungs (DLCO). In ARDS, 76% of patients have a limitation in DLCO after 5 years. On the CT scans, ground glass opacities, ground glass spots between the lungs and disruption of the pressure in the lungs (air trapping) were seen (Pulmonary sequelae in convalescent patients after SARS: evaluation with thin-section CT, Radiology , September 1, 2005). Epithelial tissue damage and pulmonary fibrosis explain these persistent limitations in lung capacity, while lack of fitness training aggravates the condition. Average performance on the 6-minute walk test (6MWT) remains below par (The long-term impact of SARS on pulmonary function, exercise and health status, Respirology April 2010; 15 (3): 543-550).
A 15-year review was published in February 2020, covering former SARS patients treated between 2003 and 2005. Lung function (total lung capacity, TLC and carbon monoxide diffusion, DCLO) has not significantly improved over the past 15 years in SARS patients with pulmonary fibrosis. Direct treatment of pneumonia can prevent the lung function of SARS / COVID survivors from deteriorating. In 15 of the 71 patients evaluated, hip necrosis (femoral head necrosis) has occurred on a bump course of corticosteroids, but remarkably (favorably) this hip necrosis may be reduced. With controlled dosing of corticosteroids, this risk can be reduced (Long-term bone and lung consequences associated with hospital-acquired SARS: a 15-year follow-up from a prospective cohort study. Bone Research 2020; 8: 8).
7. Can lung capacity be improved?
Patients that have been mechanically ventilated for any disease may present with post-IC syndrome. Post-IC syndrome (PICS) may also occur in patients admitted to the ICU for COVID-19. It is recommended that a special rehabilitation center be set up to see patients after discharge from the ICU. Ventilated patients should be examined for barotrauma and lactic acid deposition from respiratory exhaustion.
It is a common view that COVID patients discharged from the ICU score below average on the 6-minute walk test (6MWT). Rehabilitation specialists should monitor for neuropathy, myopathy (inflammation of the muscles), cognitive and neurological functions, respiration, heart function, and musculoskeletal functions. Neuromotor exercises should be performed to prevent disease and deterioration of body functions due to inactivity (Early Rehabilitation in post-acute COVID-19 patients: data from an Italian COVID-19 Rehabilitation Unit and proposal of a treatment protocol, Edizioni Minerva Medica 2020 October; 56 (6): 633-41).
A recent evaluation of 145 COVID-19 patients after 100 days concluded that the cardiopulmonary damage (damage to lungs and heart) has decreased and is no longer an obstacle. Although the CT scans seem to indicate no pulmonary fibrosis, it is difficult to distinguish between inflammation in the lung tissue and incipient pulmonary fibrosis (Cardiopulmonary recovery after COVID-19 - an observational prospective multi-center trial, European Respiratory Journal. 2020 December 10).
8. How should post-COVID / long COVID be treated?
Patients who have had "mild" or no COVID complaints have usually not had an examination. Fibrosis, thrombotic activity and any neurological consequences can be overlooked.
To avoid misdiagnoses, investigations for inflammation markers (inflammatory markers), thrombotic activity / pulmonary thromboembolism (D-dimer and C-reactive protein), neurological examination and imaging (CT / MRI) of lungs can be conclusive. If the symptoms persist 3 weeks after the first COVID-19 symptoms, the blood can be checked for the total picture, electrolytes, liver and kidney function, troponin, D-dimer, brain natriuretic peptides (BNP), CRP and ferritin to reduce inflammation and assess thrombosis activity. In addition, chest X-rays, urinalysis and an EKG can be performed, as well as tests of thyroid function. Patients should not be excluded from referral on the grounds that an RT-PCR gives a negative result (National Institute for Health and Care Excellence, COVID-19 Guideline: Managing the long-term effects of COVID-19, NICE Guideline 188).
The Royal College of General Practitioners (RCGP), has a clear module for general practitioners and referrers (Course: Long COVID-19). The BMJ has also issued an advisory report for management of post-acute COVID-19 (Management of post-acute COVID-19 in primary care, BMJ 2020; 370). Immune-related disruption of the autonomic system should be considered when orthostatic intolerance (orthostatic hypotension, a drop in blood pressure), fainting and tachycardia occur (Autonomic dysfunction in 'long COVID': rationale, physiology and management strategies, Clinical Medicine Journal, November 28, 2020 ). If the patient has swallowing and speech problems due to COVID-19, it is suggested that a referral is made to the speech therapist. Physiotherapy is recommended for condition building under supervision (monitoring heart / lung function), twice a week (A proposal for multidisciplinary tele-rehabilitation in the assessment and rehabilitation of COVID-19 survivors, International Journal of Environmental Research and Public Health, July 2020; 17 (13): 4890).
9. To be investigated further: hyperferritinaemia (iron overload), fat metabolism, EGFR and mitochondrial health
Hyperferritinaemia and CoVILD (Interstitial Lung Disease)
Hyperferritinaemia can occur during and after infections, such as coronavirus infection. It means that there is an excess of iron in certain parts of the body. Hyperferritin, iron overload, is associated with persistent inflammation and persistent lung disease after infectious diseases (The Hyperferritenemic Syndrome: macrophage activation syndrome, Still's disease, septic shock and catastrophic antiphospholipid syndrome, BMC Medicine 2013; 11: 185). It is not yet entirely clear whether hyperferritin is a result of inflammation, or whether it has an inflammatory effect; hyperferritin is believed to contribute to the "cytokine storm" that occurs in severe COVID-19 (Severe COVID-19, Another Piece in the Puzzle of the Hyperferritinemic Syndrome. An Immunomodulatory Perspective to Alleviate the Storm, Frontiers in Immunology 2020; 11; 1130).
The influence of a SARS-CoV-2 disrupted iron balance on persistent lung problems / lung fibrosis is currently being investigated (Persisting alterations of iron homeostasis in COVID-19 are associated with non-resolving lung pathologies and poor patients' performance: a prospective cohort study , Respiratory Research 2020; 21: 276). The study is registered under the "Development of Interstitial Lung Disease (ILD) in Patients with Severe SARS-CoV-2 Infection (COVID-19) (CovILD)" trial.
Lipid metabolism
In patients who survived the first SARS coronavirus (2003), impaired lipid metabolism is observed 12 years after infection. Long-term treatment of SARS patients with Methylprednisolone is associated with changes in fat metabolism (Altered Lipid Metabolism in SARS Patients Twelve Years after Infection, Scientific Reports 2017; 7: 9110).
Fibrosis due to over-activation of the epidermal growth factor receptor
A 2017 study found that over-activation of the epidermal growth factor receptor (EGFR) after infection with the SARS coronavirus causes fibrosis. Modulating EGFR activity is a potential treatment option to prevent / mitigate COVID-19 fibrosis (Overactive Epidermal Growth Factor Receptor Signaling Leads to Increased Fibrosis after SARS Coronavirus Infection, Journal of Virology 2017 Jun 15; 91 (12 )).
Mitochondrial dysfunction and oxidative stress
Finally, it is clear that the health of mitochondria during and after COVID-19 is an important factor in the disease process and recovery. Mitochondria regulate the energy of the cell and are involved in immunity and inflammatory responses. The cells' waste product is oxidative stress or, more specifically, Reactive Oxygen Species (ROS). If the functioning of mitochondria is disrupted by an invader, such as the coronavirus, oxidative stress increases and mitochondria can die.
By disrupting the normal functioning of the mitochondria, these energy regulators are less able to fight the cells against inflammation and infections. Physical activity, the absorption of antioxidants, including melatonin, Vitamin C, the steroid Vitamin D3 and phenols are important for the maintenance of healthy mitochondria. The exact role of mitochondria in long COVID is under investigation.
Colchicine, an anti-inflammatory agent
The reappraisal of colchicine for the treatment of inflammation deserves mention. This medicine could be given to treat pericarditis and myocarditis (inflammation of the pericardium or inflammation of the heart muscle).
