Of the 798 patients referred to our clinic for long COVID, 452 had complicating diseases. Among those with a complaint of fatigue, POTS was the most common complication, followed by PSWT, mood disorders, anxiety disorders, and thyroid diseases. Palpitations and dyspnea were also common in patients with POTS. Postinfectious cough and cough-variant asthma were the most common among cough symptoms, and migraine and tension-type headaches were the most common among headache symptoms. POTS was also commonly associated with dizziness, followed by PPPD, whereas musculoskeletal problems were commonly associated with arthralgia. Diarrhea was associated with IBS complications, while numbness was associated with SFN. Psychopsychiatric complaints were often complicated with mood and adjustment disorders.
Fatigue
POTS and PSWT were frequently associated with complaints of fatigue. POTS is a form of orthostatic intolerance caused by abnormal autonomic responses that lead to excessive tachycardia without hypotension upon standing. Orthostatic symptoms include lightheadedness, blurred vision, tunnel vision, palpitations, tremulousness, and weakness. Other symptoms included fatigue, exercise intolerance, hyperventilation, shortness of breath, anxiety, chest pain, nausea, acral coldness or pain, concentration difficulties, and headache [14]. These symptoms are similar to those of long COVID. POTS has been reported to occur after viral infections, and cases of POTS following COVID-19 have also been reported [15]. Factors contributing to the development of POTS after COVID-19 are hypovolemia, neurotropism, inflammation, and autoimmunity [16]. Treatment strategies for POTS include sufficient fluid and salt intake, wearing elastic stockings, and the use of beta-blockers and alpha-1 adrenergic receptor agonists [17, 18]. These treatments may relieve POTS symptoms. Consequently, patients can be informed that, in POTS pathology, standing alone raises the pulse rate, and physical activity causes tachycardia, which in turn causes fatigue; this would help them understand their condition and alleviate their anxiety. Ormiston et al. reported that 2–14% of survivors of COVID-19 develop POTS, 9–61% experience POTS-like symptoms, and long-term COVID patients should be evaluated for POTS [19]. Our previous study found that patients with fatigue and anxiety after COVID-19 often have limited employment and schoolwork [20]. Psychogenic assessment for mental illness as a factor in fatigue must also focus on underlying social factors.
Among those who complained of fatigue, six patients had hypothyroidism or hyperthyroidism. Yanachkova et al. reported persistent abnormal thyroid function and the development of subacute thyroiditis due to autoantibody production after COVID-19 infection [21]. Appropriate treatment for abnormal thyroid function may lead to symptomatic improvement, and it is necessary to evaluate thyroid function in patients with long COVID who complain of fatigue.
Palpitations and dyspnea
Complications observed with POTS included palpitations in 49 patients and dyspnea in 50 patients. The Shellong test should be performed for palpitations and dyspnea that newly appear after COVID-19, considering the possibility of POTS. Another common complication associated with palpitations is panic disorder, which is important for diagnosis and treatment because the symptoms interfere with daily life. In addition to POTS, asthma, COPD, and organizing pneumonia were observed among those with dyspnea. Lee et al. reported 6 cases of new-onset asthma among 394 patients after COVID-19 infection and stated that asthma should be considered a differential diagnosis when respiratory symptoms persist after infection [22]. In contrast, although there have been many reports of patients with COPD experiencing exacerbations triggered by COVID-19 infection [23], there have been no reports of new-onset COPD following coronary infection. This is thought to be because COPD is a chronic disease caused mainly by smoking, and COVID-19 infection is not a factor in its development. The newly diagnosed COPD at our hospital was thought to be an exacerbation of previously undiagnosed COPD triggered by coronary infection. In addition, persistent inflammation of the lungs due to severe coronavirus pneumonia is known to induce organizing pneumonia [24]. When a patient with severe pneumonia due to the novel coronavirus infection complains of dyspnea after physical activity, respiratory function tests and imaging studies should be performed to exclude the possibility of organizing pneumonia.
Cough
Chronic cough after COVID-19 is influenced by chronic inflammation and vagal reflexes, and, as with previous coughs after viral infections, it requires treatment with inhaled steroids and common antitussive agents [25, 26]. In this study, of 129 patients with complaints of chronic cough, 12 were diagnosed with postinfectious cough or cough-variant asthma. Chronic cough after COVID-19 is not a unique condition and should be examined and treated like a normal chronic cough.
Headache
Headache is the most common neurological symptom after COVID-19 and has been reported to present with a migraine or tension-headache-like phenotype [11]. The symptoms may be exacerbated when there is a pre-existing headache, whereas a new onset may occur and is thought to involve sustained activation of the immune system and trigeminal vessels. Headache due to COVID-19 is common among middle-aged women. The pain is moderate to severe and may be accompanied by fatigue, cognitive dysfunction, dizziness, insomnia, and olfactory dysfunction [11].
Migraine-like headaches during the acute phase are associated with symptomatic headaches after infection [27].
Of the 323 patients with headache complaints in this study, 31 were newly diagnosed with migraine and 18 with tension headaches. Rather than treating headache as a generalized symptom of postinfectious headache, an approach should be adopted to address the underlying primary headache.
Dizziness
According to the self-reports of 1082 patients in Germany, 60% complained of dizziness and 30% of tinnitus after COVID-19 infection, of whom 10% were severe [28].
Of the 168 patients who reported dizziness in our initial questionnaire, 38 had POTS, and nine had PPPD. PPPD is characterized by floating, unstable, and non-rotational vertigo that persists for > 3 months. Symptoms are exacerbated by a standing posture and walking, active or passive body movements, and viewing moving objects or complex visual patterns, which is secondary to some equilibrium disorders, mainly vestibular disease. Organic vestibular or psychiatric disorders may complicate these symptoms but do not explain them [29]. An increase in PPPD in older adult patients with stress since the COVID-19 pandemic in 2020 has been reported [30], and PPPD and POTS should be included in the differential diagnosis as factors for dizziness in long COVID.
Arthralgia and myalgia
Arthralgia and myalgia are reportedly present in 25% and 20%, respectively, of post-illness symptoms [31].
In our study, 141 and 150 patients exhibited arthralgia and myalgia, respectively, during the initial interview. Of the patients who reported arthralgia, two were diagnosed with reactive arthritis, and 13 had musculoskeletal problems. In their review of arthritis after COVID-19 infection, Jacopo et al. suggested that inflammatory arthritis may be a new entity of musculoskeletal disease temporarily associated with post-infection, and the course of the disease and its response to treatment needs to be determined in prospective studies [32].
Diarrhea
Although persistent gastrointestinal symptoms after COVID-19 have not been well documented, Joseph et al. reported that 21 of 48 hospitalized patients (43.8%) still had IBS-like abdominal pain and indigestion 6 months later [33]. Other reports have shown an increase in gastrointestinal disorders, such as reflux esophagitis, peptic ulcers, acute pancreatitis/cholecystitis, and functional dyspepsia after COVID-19 [34]. IBS was present in six patients in this study who complained of diarrhea. Proper diagnosis of IBS is important because treatment can lead to early improvement of symptoms.
Numbness
Sensory symptoms in patients with long COVID are described as burning, tingling, numbness, itching, crawling pain, electric shock, and tightness. These symptoms tend to be symmetrical and length-dependent, with a polyneuropathic pattern, often more symptomatic in the hands and feet, with diffuse sensory abnormalities. However, nerve conduction studies are usually not abnormal in many patients. SFN is suspected in such cases and has been reported after the novel coronavirus infection [35, 36].
A skin biopsy is necessary to diagnose SFN, but we were unable to perform skin biopsies. Therefore, we diagnosed SFN in patients with complaints of numbness in the absence of abnormalities in nerve conduction velocity, magnetic resonance imaging of the head and spine, and blood tests. SFN should be listed as a differential diagnosis in cases of limb numbness after COVID-19.
Complications of psychogenic psychiatric disorders
In this study, psychogenic psychiatric disorders such as mood, adjustment, generalized anxiety, and panic disorders were common.
Gasnier et al. reported that psychiatrists diagnosed 177 patients with posthospitalization or sequelae coronary infection. A total of 115 (65%) patients had at least one psychiatric disorder. New-onset psychiatric disorders were observed in 29 patients (16.4%), including 24 (13.6%) with major depressive episodes, 20 (11.3%) with anxiety disorders, 20 (11.3%) with PTSD7, 20 (11.3%) with anxiety disorders, seven (3.9%) with PTSD, and nine (5.1%) at risk for suicide [11].
Early intervention for psychiatric symptoms in patients with long COVID, including selective serotonin reuptake inhibitor prescription, improves prognosis; however, in case of treatment resistance, patients should be promptly referred to a psychiatrist for systematic evaluation of psychoneurotic disorders and suicide risk [37].
It is important to always keep in mind the possibility of psychogenic psychiatric disorders, as well as to administer the usual medical care. Further, prompt collaboration with a psychiatrist is encouraged when the likelihood of psychogenic psychiatric disorder is high or when the patient is refractory to treatment.
When caring for patients who complain of various symptoms that appear after COVID-19, it is necessary to list possible differential diagnoses based on symptoms and to accurately diagnose complications as usually performed for patients who are not infected with COVID-19.
Limitations
First, this cross-sectional single-center study was conducted at a university hospital. In Japan, there are few university hospitals specializing in long COVID; this may have caused a selection bias. Second, our outpatient clinic required face-to-face consultations, and we were unable to evaluate patients with severe long COVID who were unable to leave their homes. Further patient studies are required to confirm the generalizability of our findings. Diagnostic bias may also factor into these findings because the method of diagnosing complications was based solely on the judgment of one person who reviewed the medical records. The symptoms identified in this study were those reported at the time of initial consultation, and some patients subsequently developed new symptoms that led to the discovery of complications. Therefore, it is possible that the symptoms and complications did not match. In the future, it will be necessary to investigate the chronological changes in complications further by dividing them into those that were present from the beginning and those that emerged during the course of the disease. Additional research is planned to determine whether treatment of complications improves the course of symptoms after the disease.