Artur Fedorowski, Monika Fagevik Olsén, Frida Nikesjö, Christer Janson, Judith Bruchfeld, Maria Lerm, Kristofer Hedma: May 2023, Journal of Internal MedicineVolume 294, Issue 5 p. 548-562
Abstract
A significant proportion of COVID-19 patients experience debilitating symptoms for months after the acute infection. According to recent estimates, approximately 1 out of 10 COVID-19 convalescents reports persistent health issues more than 3 months after initial recovery. This ‘post-COVID-19 condition’ may include a large variety of symptoms from almost all domains and organs, and for some patients it may mean prolonged sick-leave, homestay and strongly limited activities of daily life. In this narrative review, we focus on the symptoms and signs of post-COVID-19 condition in adults – particularly those associated with cardiovascular and respiratory systems, such as postural orthostatic tachycardia syndrome or airway disorders – and explore the evidence for chronic autonomic dysfunction as a potential underlying mechanism. The most plausible hypotheses regarding cellular and molecular mechanisms behind the wide spectrum of observed symptoms – such as lingering viruses, persistent inflammation, impairment in oxygen sensing systems and circulating antibodies directed to blood pressure regulatory components – are discussed. In addition, an overview of currently available pharmacological and non-pharmacological treatment options is presented.
Graphical Abstract
Introduction
COVID-19 – a disease caused by a novel variant of Coronavirus, SARS-CoV-2 – has affected more than 765 million individuals (6.9 million deaths) worldwide as of May 17, 2023 [1]. Male patients with comorbidities, such as obesity, diabetes and cardiopulmonary diseases are at increased risk of severe disease and death [2]. In contrast, female sex along with age, asthma and previous hospitalization have all been associated with higher risk of long-term symptoms [3]. SARS-CoV-2 enters the cells via the angiotensin-converting enzyme 2 (ACE2) receptor, which is present in numerous cell types throughout the body and therefore facilitates acute multiple organ damage [2, 4]. Important advances have been made in the treatment of the acute phase of COVID-19. Meanwhile, a significant proportion of COVID-19 patients experience debilitating symptoms that linger for months after the acute infection. This has been termed ‘long COVID’ or ‘post-acute COVID-19 syndrome’ and, more recently, the World Health Organization (WHO) suggested ‘post-COVID-19 condition’ [5].
Post-COVID-19 condition
According to a consensus statement adopted by the WHO, post COVID-19 condition occurs in individuals with prior confirmed or probable COVID-19 and with remaining symptoms or new onset symptoms at least 3 months after the initial infection and with duration of at least 2 months [5]. The plethora of symptoms reported by patients is striking and includes symptoms from almost all domains (e.g. physiological, psychological and cognitive) and organs (e.g. heart, lungs, gastrointestinal and brain) [6–8]. Prolonged symptoms have been shown to affect formerly hospitalized patients but also those who suffered a milder acute infection without need for hospitalization. In some patients, there are profound effects on functional abilities, such as activities of daily life, work capacity and school/university attendance [2, 3].
A survey by the NHS, UK, reported a 9.9% prevalence of any symptom at 12-week follow-up (UK Office for National Statistics. 2020). A recent Dutch population-based study reported that one out of eight individuals with acute COVID-19 will develop long-term symptoms [7]. Recent data supports the fact that symptoms may persist for several years in a majority of patients with post COVID-19 condition following hospitalization [9]. However, it is problematic with only symptoms as a base for diagnosis [5], as patients suffering sequelae from severe pneumonia and intensive care are defined by the same terminology as those who suffered a milder initial COVID-19 infection but with a prolonged course of debilitating symptoms. In addition, symptoms described as part of post-COVID-19 condition are not classified according to severity, and the impact on individual function and quality of life is at present not properly addressed.
It is therefore fundamental to systemically characterize the various phenotypes of post-COVID-19 condition in order to better understand the long-term effects, underlying pathophysiology and immune mechanisms to enable identification of treatable traits [10, 11]. Patients with post-COVID-19 condition are typically multi-symptomatic, and a common feature is the fluctuating nature of symptom intensity, as well as onset of new conditions, such as neurological or psychiatric diagnosis, dementia, respiratory conditions and sleep disorder [2, 4, 12].
Knowledge gaps regarding the underlying mechanisms of post-COVID-19 condition are still vast [13]. Various hypotheses have been proposed – among others, a state of chronic inflammation in the lungs with sustained production of pro-inflammatory cytokines and reactive oxygen species that are released into the surrounding tissues and bloodstream. Endothelial damage may trigger activation of fibroblasts, which deposit collagen and fibronectin, resulting in fibrotic changes in the lungs and other organs [2]. Other proposed mechanisms include viral persistence as well as immune dysregulation and induction of autoimmunity, the latter a possible explanation of autonomic dysfunction such as COVID-19-triggered postural orthostatic tachycardia syndrome (POTS) [14].
There have been multiple reports on autonomic dysfunction as an important contributing factor behind post-COVID-19 condition, in particular in patients experiencing POTS, inappropriate sinus tachycardia (IST) and microvascular dysfunction, as well as gastrointestinal and respiratory functional disorders [8, 15–20].
In this narrative review, we focus on the symptoms and signs of post-COVID-19 condition – particularly those associated with cardiovascular and respiratory disease – and examine the evidence for autonomic dysfunction as a potential underlying mechanism. We have limited the scope of this review to the discussion of current published research on adult subjects with post-COVID-19 condition.
Autonomic dysfunction
Dysautonomia, or autonomic dysfunction, is a group of disorders that arise from malfunction of the autonomic nervous system (ANS). Dysautonomia may involve either failure or inadequate activation of sympathetic and parasympathetic components of ANS. Different aetiologies of dysautonomia include neurodegenerative disorders such as Parkinson’s disease and pure autonomic failure; chronic diseases such as diabetes and renal failure; genetic diseases (e.g. familial dysautonomia, Ehlers-Danlos syndrome); poisoning; viral infections (e.g. AIDS); chronic inflammatory conditions (e.g. multiple sclerosis); and autoimmune diseases (e.g. autonomic autoimmune ganglionopathy, Sjögren’s disease and systemic lupus erythematosus) [21, 22].
Typical dysautonomia conditions are essential hypertension, orthostatic hypotension, POTS, IST, recurrent reflex syncope, low blood pressure phenotype, dysmotility and dysuria. Importantly, malfunction of ANS may coexist with primary structural or functional organ and system diseases, such as heart failure, ischaemic heart disease, cardiac arrhythmias, diabetes and respiratory and gastrointestinal tract diseases [23, 24]
Manifestations
Cardiovascular manifestations
The primary function of the cardiovascular system is to maintain homeostasis through adaptations of cardiac output and blood flow, in order to transport nutrients, oxygen, carbon dioxide, hormones and cells (e.g. immune cells). Hence, a strict regulation of cardiac output (i.e. heart rate and stroke volume) as well as blood flow (i.e. blood pressure, vascular tone and organ perfusion) is required to match demand and delivery, which is accomplished primarily by the ANS and organ-specific, local auto regulation [24]. The adaptive capacity of the cardiovascular system is well illustrated by the acute transition from rest to exercise (which is clinically evaluated during exercise testing) [25, 26], by a sudden change in body position [27] or by the effects of long-term exercise training [28].
In patients with post-COVID-19 condition, cardiovascular symptoms include heart rhythm abnormalities (palpitations or tachycardia), chest pain, dyspnea and exercise intolerance (Figure 1, central illustration) [17, 29, 30]. In a large study of hospitalized COVID-19 patients, 5% experienced chest pain and 9% experienced palpitations at 6 months follow-up [6].
Several forms of cardiovascular dysautonomia should be considered in patients with suspected post-COVID-19 condition. Tests such as active standing or tilt table testing with autonomic function tests, Holter ECG monitoring (mainly for diagnosing IST) [31], 24-h BP monitoring for detection of low-BP phenotype and hypotensive tendency [32], and cardiac imaging such as echocardiography and stress-perfusion magnetic resonance imaging [33] are all of great value in the diagnostic workup.
POTS
According to recent estimates, between 20% and 30% of highly symptomatic post-COVID-19 condition patients (with palpitations, orthostatic intolerance, chest pain and dyspnoea) may meet the diagnostic criteria of POTS, while some also display IST [17, 18].
The definition of POTS endorsed by major autonomic, neurological and cardiological societies is (1) a sustained HR increment of not less than 30 beats/min within 10 min of standing or head-up tilt (for individuals 12–19 years of age, the required HR increment is at least 40 beats/min); and (2) an absence of orthostatic hypotension (i.e. no sustained systolic BP drop of 20 mm Hg or more); and (3) frequent symptoms of orthostatic intolerance (lightheadedness, palpitations, tremulousness, generalized weakness, blurred vision and fatigue) during standing, with rapid improvement upon return to a supine position; and (4) duration of symptoms for at least 3 months; and (5) absence of other conditions explaining sinus tachycardia, such as anorexia nervosa, primary anxiety disorders, hyperventilation, anaemia, fever, pain, infection, dehydration, hyperthyroidism, pheochromocytoma, use of cardioactive drugs (e.g. sympathomimetics and anticholinergics) or severe deconditioning caused by prolonged bed rest.
POTS was first defined in the 1990s by a group from the Mayo clinic [34]. Since then, it has been increasingly recognized as a specific form of cardiovascular dysautonomia, often appearing after viral infection and affecting mainly women of child-bearing age (15–45 years) [23, 34].
POTS is a complex disorder of the ANS characterized by orthostatic intolerance with excessive heart rate increase and symptoms upon standing while blood pressure is usually maintained, although some abnormal blood pressure variability may be observed [23, 35] (Figure 2). Apart from the impaired circulatory response to standing, patients with POTS may experience a variety of other persistent symptoms – such as low energy, headache, cognitive impairment, muscle fatigue, chest pain and non-specific generalized weakness – along with numerous gastrointestinal symptoms, to name a few typical POTS correlates [36].
Respiratory manifestations
Dyspnea and cough are common after a COVID-19 infection [37, 38], and studies evaluating patients after discharge from hospital care report new or aggravated dyspnea in 40%–48% of subjects [39, 40]. Although these problems resolve with time in most patients, a significant proportion of patients have remaining symptoms at medium term follow-up, especially in subjects with more severe acute disease [6]. In a follow-up of approximately 2000 patients who had been discharged from hospital after COVID-19 (of which around 4% had been admitted to intensive care units), the proportion with some level of dyspnea (mMRC ≥1) decreased from 26% 6 months after discharge to 14% after 2 years [6]. In another study, the prevalence of chronic cough after 1 year was only 2.5% [41].
Lung function impairment with low total lung capacity, low forced vital capacity and lung diffusion impairment is common after severe COVID-19 requiring hospitalization [37, 42]. Similarly, radiological findings have been found in a significant proportion of patients previously hospitalized [43–46]. Three months after confirmed COVID-19-related pneumonia, ground glass opacities were found in 75% of patients, reticulations in 30% and residual subpleural infiltration in 13% [47]. In another study with ∼200 hospitalized patients, 25% still had CT chest abnormalities after 12 months, the most common being residual linear opacities and multifocal reticular or cystic lesions [43, 48].
Respiratory muscle strength and dysfunctional breathing
Already early in the pandemic, decreased respiratory muscle strength was found in some patients [49]. A reduced respiratory muscle strength is to be expected after a severe chest infection and immobilization, but reported levels after COVID-19 that did not require hospitalization are not in parity of what could be expected. Both inspiratory and expiratory muscles seem to be affected, and muscle strength may not recover spontaneously [50, 51]. Apart from respiratory muscular impairment following severe pneumonia, a dysfunctional or abnormal breathing pattern has also been reported in patients with post-COVID-19 condition, both at rest and during exercise testing [51–54]. At rest, some patients have been found to have a breathing pattern involving accessory respiratory muscles in the upper part of the chest, increasing the effort of breathing, which may lead to respiratory muscle fatigue and ultimately a sensation of dyspnea [55]. During exercise testing with analysis of breathing gases and/or arterial blood gas sampling, a subset of patients has been found to have an atypical breathing pattern, including disproportionate fluctuations in ventilation and signs of ineffective ventilation [52, 54, 56]. Of note, in most cases, typical signs of alveolar hyperventilation (low pCO2 or low end-tidal CO2 pressure) are not present, and lung function testing including diffusion capacity for carbon dioxide is normal [52].
Decreased inspiratory muscle function and dysfunctional breathing pattern are closely connected to other frequently reported symptoms in post-COVID-19 condition, such as the feeling of breathing discomfort, inability to take deep breaths, chest tightness, cough and pain [40, 57, 58].
In summary, some of the respiratory symptoms reported in patients with post-COVID-19 condition seem to be related to radiologically confirmed sequelae following initially severe pneumonia and/or intensive care with mechanical ventilation [6]. In these cases, lung function testing is often at least slightly abnormal, with more advanced abnormalities related to initial severity of disease. In other cases – often following mild initial COVID-19 disease – respiratory symptoms may be severe, while lung function testing is normal. At least in some of these subjects, dysfunctional breathing and/or reduced respiratory muscle strength may play a role, in which autonomic dysfunction could be an important pathophysiological mechanism.
Potential cellular and molecular mechanisms of dysautonomia
The molecular aetiology of post-COVID-19 condition remains obscure. In this section, we will discuss some of the molecular mechanisms that could contribute to the dysautonomia associated with post-COVID-19 condition.
Lingering viruses and persisting inflammation
Several studies have identified evidence for persisting SARS-CoV-2 several months after the acute infection resolved. For example, one study found 5% of subjects to be positive for SARS-CoV-2 RNA in nasopharyngeal swabs 3 months after the infection [59]. Another study found SARS-CoV-2 RNA and protein in intestinal biopsies in a fraction of subjects 6 months after COVID-19 [60]. Post-mortem analysis in patients with worsened clinical status despite negative PCR testing for SARS-CoV-2 indicates that infection can persist much longer than suggested by PCR testing [61]. In fact, persistent replication of other coronaviruses has been demonstrated by numerous studies [62–64]. Proteomic analyses of a cohort of patients with symptoms remaining more than 1 month after confirmed COVID-19 revealed increased levels of circulating tumour necrosis factor α (TNFα) compared to healthy controls [65, 66]. In-line with this observation, a recent intervention study suggested that TNFα inhibitors relieved symptoms of post-COVID-19 condition [67]. A unique inflammatory response, characterized by interferon-γ and interleukin-2, has been identified using machine-learning approaches that can separate post-COVID-19 condition from acute COVID-19 [68]. This points towards an enhanced effector T cell activation in post-COVID-19 condition, which could be a protective response against the virus but at the same time be associated with a risk of autoimmune cell damage. However, although persisting replicating viruses are likely to drive a general immune activation and inflammatory responses, this does not explain the dysautonomia observed in post-COVID-19 condition.
Impairment of oxygen-sensing systems – Is there a connection to taste receptor dysfunction?
A very widely recognized feature of both acute COVID-19 and post COVID-19 condition is the impairment of smell and taste. Taste bud morphology and the mechanism of chemoreception is highly similar to the carotid artery chemoreceptors, which together with other chemosensory systems maintain oxygen homeostasis throughout the body. The pH of the blood is sensed by glomus cells, and this mechanism involves sensing by acid sensing ion channels. The pH sensing receptors in taste buds are similar to the pH sensing mechanism in the carotid body [69]. Peripherally in the lung, oxygen levels can be sensed via pulmonary neuroendocrine cells (PNECs). These cells form patches in the pulmonary epithelium and, like glomus cells, sense oxygen via a similar mechanism and connect to afferent neurons [70].
The glomus cells and the PNECs also have in common with taste cells that they express ACE2, which is the primary receptor of cell entry of SARS-CoV-2 [71, 72]. The tongue provides an easily accessible organ for biopsies, and it has been demonstrated in ex vivo experiments with COVID-19 patients that SARS-CoV-2 can in fact infect type 2 taste cells [72].
There are several possible ways in which the chemoreceptor systems could be damaged by the virus. First of all, as described by Doyle et al., there is a measurable reduction in taste stem cells, indicating damage caused by viral replication and/or inflammation during the acute phase of COVID-19 [72]. Second, we have discovered that epigenetic alterations to pathways related to odor-sensing can be found in immune cells of healthy recoverees of COVID-19 and in individuals with post-COVID-19 condition months after the acute phase of COVID-19 has resolved [73]. Although highly speculative, the possible correlation between epigenetic modulation of chemoreceptor pathways and dysautonomia is appealing.
Circulating autoantibodies directed to BP regulatory components?
Previous clinical observations associating a recent viral infection with POTS onset – now strengthened by the emerging post-COVID-19 condition-linked POTS – suggest the possibility of an autoimmune etiology [34, 36]. Positive (though often non-specific) autoantibody tests are frequently seen among POTS patients, and about 20% report a history of an autoimmune disorder such as Hashimoto’s thyroiditis, lupus and rheumatoid arthritis or Sjögren’s syndrome [23, 35]. In recent years, a focus in POTS research has been on autoantibodies to cardiovascular G-protein coupled membrane receptors, such as adrenergic, muscarinic, angiotensin- and endothelin-related, although only cell-based functional assays have demonstrated positivity [74–76].
Although not yet demonstrated in post-COVID-19 condition, a recent report demonstrated that antibodies from COVID-19 patient sera directed towards the SARS-CoV-2 spike protein receptor-binding region (interacting with the ACE2 receptor) display cross-reactivity to angiotensin II, one of the major BP-regulating hormones of the body [77]. The authors demonstrated that the levels of the angiotensin II cross-reactive antibodies correlated with BP dysregulation. In our recent study, we were able to demonstrate that the angiotensin II signaling pathway was strongly enriched for epigenetic modifications in immune cells in subjects suffering from post-COVID-19 condition, thereby underpinning the possible epigenetic contribution to COVID-19-related disease manifestations [73].
Other possible mechanisms of dysautonomia
Other proposed pathophysiological mechanisms include abnormally increased sympathetic activity and circulating catecholamine excess, peripheral sympathetic noradrenergic denervation leading to venous pooling and relative central hypovolemia, and low blood volume [35]. Recent reports have suggested the presence of endothelial and microvascular dysfunction as possible contributors to the cardiovascular symptoms in post-COVID-19-condition [14], either in parallel to POTS or as a part of a broader concept of post-COVID-19 cardiovascular dysautonomia. Although this hypothesis is mechanistically very attractive, more studies on well-defined cardiovascular post-COVID phenotypes are needed.
Management
Post-COVID-19 condition is a poorly explored multisystem and multiorgan illness with a substantial subset of patients affected by cardiorespiratory autonomic dysfunction. Better diagnostic tests and treatment options are both currently under development, but in many instances circulatory and respiratory symptoms are treated with repurposed methods applied in the pre-COVID era (e.g. for conditions such as POTS and asthma). Although a causal therapy is still lacking, some efforts have been planned or are underway. The main targets in current research are elimination of persistent virus particles (e.g. nirmatrelvir and ritonavir [Paxlovid], ClinicalTrials.gov Identifier: NCT05576662 and NCT05823896), reduction of circulating autoantibodies (e.g. efgartigimod alfa-fcab, ClinicalTrials.gov Identifier: NCT05633407) or inhibition of inflammation (e.g. human immunoglobulin, ClinicalTrials.gov Identifier: NCT05350774) in hope to alleviate debilitating symptoms. The immunomodulating therapy has been long in focus based on the inflammatory and autoimmune hypotheses in post-COVID-19 condition [36, 78]. Although there is evidence of a beneficial effect of corticosteroids on symptoms and recovery during the acute phase in hospitalized patients [79–81], and specifically in patients with concomitant asthma [82–84], similar data on pharmacological treatment options for patients with post-COVID-19 condition is scarce [84]. The selection of an appropriate therapeutic approach to possible inflammatory and autoimmune disorders underlying post-COVID-19 condition is hampered by the fact that positive laboratory findings are unspecific or very limited. For instance, elevated levels of proinflammatory cytokines have been found in some, but not in all, patients [36, 78]. Thus, laboratory tests specifically designed for post-COVID-19 condition are currently not available. In a recently published study on a small patient series who were found to have lower immunoglobulin levels and received empirical long-term intravenous human immunoglobulin therapy, some success was reported [85]. Importantly, that study was non-randomized and without placebo control. Consequently, as there are no established immunological tests for post-COVID-19 condition – including those for antibodies to G-protein coupled receptors – and as randomized controlled trials are underway, no specific immunomodulatory therapy can be currently recommended. If there are strong humanitarian reasons and high clinical suspicion of autoimmune involvement, an experimental ex juvantibus approach might be considered, but a cautious attitude is advised. Another important aspect of disease management is prevention of post-COVID-19 condition by large-scale vaccination programs. Every episode of COVID-19, both de novo and re-infection, increases the risk of post-COVID-19 condition [86, 87]. Prevention of further episodes is therefore important [86]. In a recent publication, 12 studies reported data on vaccination before infection with the SARS-CoV-2 virus, and 10 showed a significant reduction in the incidence of post-COVID-19 condition; the odds ratio of developing post-COVID-19 condition with one dose of vaccine ranged from 0.22 to 1.03; with two doses, odds ratios were 0.25–1; with three doses, 0.16; and with any dose, 0.48–1.01. However, the high heterogeneity between studies precluded any meta-analysis [87, 88]. In summary, there is an urgent need for novel and specific diagnostic assays able to identify the pathophysiological mechanisms of post-COVID-19 condition and its treatable targets.
Management of cardiovascular symptoms
Following proper diagnostic work-up to rule out other underlying cardiovascular diseases, there may be several available treatments, primarily directed at symptom relief. Considering the wide range of cardiovascular symptoms of patients with post-COVID-19 condition, specific treatment will be highly individualized. As there is a considerable overlap with POTS in this group of patients, currently recommended strategies for treatment of POTS are listed in Table 1 [23, 35].Table 1. Treatments for postural orthostatic tachycardia syndrome.
| Drug | Dosing information | Side effects | Precautions |
|---|---|---|---|
| Non-pharmacological treatments | |||
| Withdraw exacerbating medications | Stop drugs that decrease blood volume or directly increase heart rate such as diuretics or vasoselective calcium channel blockers | The coexisting condition may require treatment with drugs that may worsen POTS symptoms. In such setting, the decision to withdraw medication should be carefully considered and discussed with an appropriate expert | |
| Increased oral water intake | Target 2–3 L/day | Frequent urination | |
| Increased oral NaCl intake | Target 8–10 g/day | Hypertension, peripheral oedema | Buffered NaCl tablets/solutions if cannot be done with diet alone |
| Lower body compression garments | 20–40 mm Hg compression; focus on abdomen ± legs | Can be hot, tight and itchy | |
| Exercise training | Aerobic: 30+ min 4 days/week with some leg resistance training | Will initially feel poorly/worse for up to 6 weeks | Initial recumbent exercise (rowing, recumbent cycle or swimming) |
| Pharmacological treatments | |||
| Blood volume expanders | |||
| Fludrocortisone | 0.1–0.2 mg daily | Hypokalemia, oedema and headache | Electrolytes must be monitored, especially potassium |
| Desmopressin (DDAVP) | 0.1–0.2 mg as needed | Hyponatremia, oedema | Monitor electrolytes |
| Acute IV Saline | 2 L intravenous over 2–3 h | Venous thrombosis, infection | Acute saline infusion offers short-term relief only |
| Chronic IV saline | 2 L given intravenously once weekly | Infection/thrombosis risk of central venous catheters | Avoid long-term use; avoid placement of central catheters |
| Erythropoietin | 10,000 IU weekly | Increased risk of cardiovascular death | Monitor Haematocrit |
| Heart rate inhibitors | |||
| Propranolol | 10–20 mg orally up to four times daily | Hypotension, bradycardia and bronchospasm | Can worsen asthma or exercise tolerance |
| Ivabradine | 2.5–7.5 mg orally twice daily | headaches, palpitations, hypertension and visual disturbances | Can induce nocturnal bradycardia |
| Pyridostigmine | 30–60 mg orally up to three times daily | Abdominal cramps, diarrhoea | Can worsen asthma |
| Vasoconstrictors | |||
| Midodrine | 2.5–15 mg orally three times daily | Headache, scalp tingling and hypertension | |
| Droxidopa | 100–600 mg orally three times daily | Headache, nausea, diarrhoea and supine hypertension | Off-label use only; high cost |
| Methylphenidate | 10 mg orally two to three times a day. Last dose should be avoided before bed | Tachycardia, insomnia, nausea, headache and dizziness | |
| Sympatholytic drugs | |||
| Alpha-2 adrenergic agonists, such as clonidine | 0.1–0.2 mg orally two to three times daily or long-acting patch | Hypotension, fatigue and brain fog | For hyperadrenergic form only (pronounced tachycardia, orthostatic hypertension) |
| Methyldopa | 125–250 mg orally twice daily | Hypotension, fatigue and brain fog | As above |
| Other | |||
| Modafinil | 50–200 mg orally one to two times daily | Tachycardia | Used off-label as a drug counteracting ‘brain fog’ and fatigue |
Management of respiratory symptoms
There is no specific pharmacological treatment for respiratory symptoms in post-COVID-19 condition, but evidence is evolving for different rehabilitation strategies, as discussed below. These, and specific recommendations for patients with concomitant asthma, are summarized in Table 2.Table 2. Treatments for respiratory symptoms in post-COVID-19 condition
| Non-pharmacological treatments | ||
|---|---|---|
| Symptom | Treatment | Precautions |
| Hypoventilation | Mobilization, deep breathing exercises with or without breathing devices | Nocturnal symptoms |
| Hyperventilation | Regimen and instructions | Anxiety |
| Dysfunctional breathing pattern | Retraining of a normal breathing pattern | Neurological reasons |
| Decreased respiratory muscle strength/endurance | Inspiratory/expiratory muscle training | Neurological reasons |
| Productive cough | Forced expiration techniques | Haemorrhage |
| Non-productive cough | Regimen how to avoid coughing | Aspiration |
| Musculoskeletal pain in the ribcage and adjacent joints | Stretching, exercises to increase range of motion and circulation and manual treatment | Osteoporosis |
| Decreased thoracic expansion | Stretching, exercises to increase range of motion, manual treatment and retraining of a normal breathing pattern | |
| Chest tightness | Stretching, exercises to increase range of motion and circulation, manual treatment and retraining of a normal breathing pattern | Cardiac reasons |
| Low physical capacity | Physical training, preferably in intervals | Post exertion malaise POTS |
| Hypoxia | Depending on the cause, see above | |
| Dyspnoea | Depending on the cause, see above | |
| Obstructive sleep apnea | Continuous positive airway pressure (CPAP) | Nasal congestion, rhinorrhoea and pharyngeal irritation |
| Excessive dynamic airway collapse (EDAC) | Continuous positive airway pressure (CPAP) | Nasal congestion, rhinorrhoea and pharyngeal irritation |
| Pharmacological treatments | |||
|---|---|---|---|
| Drug | Dosing information | Indication | Side effects |
| Inhaled corticosteroids | |||
| Budesonide | 200–400 μg twice daily | Asthma | Oral and pharyngeal side effects |
| Ciclesonide | 160 μg once daily | Asthma | Oral and pharyngeal side effects |
| Mometasone | 200–400 μg once daily | Asthma | Oral and pharyngeal side effects |
| Fluticasone propionate | 125–250 μg twice daily | Asthma | Oral and pharyngeal side effects |
| Inhaled corticosteroids and long acting beta-2-agonists | |||
| Budesonide and formoterol | 160/4.5 μg twice daily and/or when needed | Asthma | Oral and pharyngeal side effects |
| Beclomethasone and formoterol | 100/6 or 200/6 μg 2 inhalations twice daily and/or when needed | Asthma | Oral and pharyngeal side effects |
| Fluticasone furoate and vilanterol | 92/22 or 184/22 μg once daily | Asthma | Oral and pharyngeal side effects |
| Inhaled corticosteroids, long acting beta-2-agonists and long acting muscarinic antagonist | |||
| Beclomethasone, formoterol and glycopyrronium | 87/5/9 or 172/5/9 μg 2 inhalations twice daily | Asthma | Oral and pharyngeal side effects |
| Mometasone, indacaterol and glycopyrronium | 114/46/136 μg once daily | Asthma | Oral and pharyngeal side effects |
| Montelukast | 10 mg orally once daily. | Asthma | Sleep disturbances and depression |
| Short acting bronchodilators | |||
| Salbutamol | 0.2–1.5 mg given through a spacer | Asthma attack or acute bronchial obstruction | Tachycardia |
| Ipratropium | 20–120 μg given through a spacer | Asthma attack or acute bronchial obstruction | Mouth dryness |
| Oral corticosteroids | |||
| Prednisolone | 25–50 mg orally | Asthma attack or acute bronchial obstruction | Anxiety, sleep disturbances and hyperglycaemia |
| Betamethasone | 4–6 mg orally | Asthma attack or acute bronchial obstruction | Anxiety, sleep disturbances and hyperglycaemia |
Pulmonary rehabilitation strategies in post-COVID-19 condition
Several studies and systemic reviews have found that pulmonary rehabilitation after COVID-19 improves 6-min walking distance, health related quality of life, anxiety, depression and dyspnea [89–92].
Effects of treatment for persisting respiratory symptoms have been investigated in several studies. A combination of different breathing exercises for 5 weeks has been found to improve pulmonary function, quality of life and exercise capacity of patients with respiratory symptoms following COVID-19 [93]. A breathing and wellbeing program including singing techniques had minor effects on breathlessness [94].
The decreased respiratory muscle strength may be treated by inspiratory- and/or expiratory muscle training. This has been evaluated after intensive care and in patients with persisting symptoms [50, 95, 96]. These exercises have been shown to significantly improve respiratory muscle strength, dyspnoea, chest symptoms and quality of life, but their effect on pulmonary function and functional performance remains unclear.
Effects of structured pulmonary rehabilitation comprising a variety of combinations of breathing exercises including inspiratory muscle training, exercises to increase thoracic range of motion and general aerobic exercises have been evaluated in different settings [90, 97–101]. The rehabilitation programs were performed in outpatient clinics, were home based or via telemedicine. The results indicate that the interventions had an impact on pulmonary function, hyperventilation, dyspnoea and exercise capacity, even if it is not known which parts of the interventions were most efficient and in which combinations.
Knowledge gaps and future directions
During the last 2 years, much effort has been put into illuminating the prevalence, risk factors and underlying mechanisms for post-COVID-19 condition, generating several definitions [102] and hypotheses [36]. Although much has been learned about dysautonomia in post-COVID-19 condition, there are still important gaps in our understanding of mechanisms underlying observed cardiovascular and respiratory alterations. First, the overlap between dysautonomia and other debilitating chronic conditions (e.g. concurrence of POTS and myalgic encephalomyelitis/chronic fatigue syndrome) needs to be further elucidated in the search for what is common and what separates various post-COVID-19 phenotypes. Second, it is possible or even likely that different subtypes of cardiorespiratory dysautonomia may coexist (e.g. IST and microvascular dysfunction), requiring different therapeutic approaches and clinical follow-up, which needs to be systematically studied. Third, clinical trials are crucial in order to test the robustness of hypotheses explaining pathophysiological mechanisms of post-COVID-19 condition, such as viral persistence or autoimmune process. These trials should be carefully designed to include precise characterization of dysautonomia subtypes, which hitherto has been largely missing. Fourth, there is an obvious need for novel treatment options to relieve the most vexing symptoms of post-COVID-19 condition, such as brain fog or exercise intolerance. Although several studies are ongoing, as outlined above, more clinical trials are needed to improve symptom alleviation, perspectives for return to work, long-term prognosis and – in the best-case scenario – to offer a curative treatment. Such a goal may seem unattainable today, but a decisive breakthrough may not be far away.