Persistent complaints after COVID-19 from the perspective of the population, patient, and health care

After recovery from the acute symptoms of COVID-19, a substantial proportion of people retain persistent symptoms of a physical, psychological and cognitive nature: long COVID. It is unclear what the causes and consequences of these symptoms are for the person and society and how healthcare can respond to them. Existing research on Long COVID has major limitations:
(1) it does not take into account for symptoms that were already present before infection;
(2) it often lacks a control group of people who have not had COVID-19;
(3) it relies largely on clinical cohorts, while the data suggest that the vast majority of people with Long COVID have never been hospitalized, the severity of symptoms differs little between hospitalized and non-hospitalized Long COVID patients and the impact on (work) performance is reported to be high in the latter (relatively younger group); and
(4) the patient's search for the right patient perspective is insufficiently involved in the search for appropriate care. In addition, existing research uses very different definitions of Long COVID, which makes comparison difficult. 

The aim of the proposed research is to arrive at a well-founded design for a care path, based on 3 work packages (WP).

WP1: Prevalence and course
Estimates of the prevalence of long COVID are highly variable, partly because studies use different
definitions of long COVID in which both symptoms, and duration and start of time period differ.
The course also remains unclear; the only available Dutch study recruited participants through
an online Long COVID support group. A very recently published review found a median prevalence of 72.5% (interquartile range [IQR], 55.0%-80.0%) of at least one persistent complaint one month after COVID-19. The major symptoms were shortness of breath (36.0%; IQR, 27.6%-50.0%) and
fatigue (40.0%; IQR, 31.0%-57.0%). However, the review also found that studies differed widely in
patient populations and Long COVID definition. The authors also noted a lack of data on the
pre-infection symptom level and that a control group without COVID-19 was missing. From this, a
number of recommendations that are being also applied in the current project, related to the study population (taking into account comorbidities, symptom levels for infection, severity of illness, and compare with a control cohort without COVID-19), follow-up (longitudinal measurement), and outcome measures (measure number and severity of symptoms, use validated scales). Previous studies have also shown that the prevalence and course of Long COVID differ based on demographic factors and medical characteristics. Higher prevalence was found with older age and female sex, although particularly in patients with milder disease. Relevant medical characteristics are the severity of the acute illness, which predicted Long COVID in some but not all studies, and medical history, specifically a diagnosis of anxiety or depression and somatic comorbidities.

WP2: Mechanisms and risk factors.
More knowledge about the mechanisms and risk factors is necessary for a proper diagnostic process and for the identification of known and novel treatable mechanisms. Large studies based on
registries have convincingly shown that going through COVID-19 confers an increased risk of both somatic and psychiatric problems in the months following recovery from acute illness, suggesting that COVID-19 may have long-term effects. However, it remains unclear how relevant these
observations are to the wider group with long COVID. Pathophysiological research on long COVID
suggests a number of possible explanations. A first explanation is persistent organ damage.
Indications for this are radiological abnormalities in lungs, heart, liver, and kidneys. A
impaired diffusion capacity was found particularly in more severe patients, and impaired
exercise tolerance also in a young previously fit group. Besides lung damage, impaired
exercise tolerance could also be a consequence of deconditioning by degradation of cardiac and skeletal muscle(s) during and after infection, exacerbated by inactivity due to corona measures.
Deconditioning could also explain the reported orthostatic intolerance after mild COVID-19. A second explanation for persistent symptoms after COVID-19 assumes persistent inflammation, manifested
in more subtle inflammatory and metabolic dysregulations. Clues to this explanation
comes from studies suggesting that SARS-CoV-2 is prolonged and gives immune activation.
The literature is inconsistent with regard to markers of inflammation. A number of studies find an elevation in markers of inflammation associated with radiological abnormalities. Two studies have compared Long COVID with fully recovered patients; the first found increased D-dimer and CRP in Long COVID 24 and the second lymphopenia and elevated troponin. Other studies found no difference between Long COVID and recovered patients in a range of pro-inflammatory markers (CRP, D-dimer, IL-6, CD25, and neutrophil and lymphocyte numbers). Clearly, both of these pathophysiological pathways do not fully explain the frequent occurrence of persistent symptoms that are part of long COVID, and new leads are needed. Meanwhile, genetic risk factors have also been identified that influence the risk of acquiring a COVID-19 infection and to develop severe COVID-19 infection. This makes it plausible that Long COVID also has a genetic basis, and research into this genetic basis has been identified as a research priority identified by a group of international stakeholders. Beyond these limited Long COVID studies, much knowledge about mechanisms and risk factors for persistent symptoms stems from research on functional syndromes, such as Chronic Fatigue Syndrome, Fibromyalgia, and Irritable Bowel Syndrome, which also involve persistent symptoms that often arise after infection. These studies suggest three types of risk factors: vulnerability factors, elicitation factors (including infections) and maintenance factors. A recent review of these factors in these syndromes suggests the involvement of childhood trauma, neuroticism, having a lot of stress, impaired cognitive functioning, health-related anxiety, excessive health care use lifestyle habits (alcohol, smoking, inactivity), and social support. These factors may offer clues for treatment in patients with persistent symptoms without objective pathology.

WP3: Impact and care needs
For good care, in addition to understanding causes, knowledge about the impact of persistent symptoms after COVID-19 and about the care needs of patients, is essential. However, studies of functioning in the months after COVID-19 are scarce and often limited to hospitalized patients or very select groups. One study in the general population showed a reduction in quality of life measured by the RAND-36, particularly in the domains of general health, social functioning, and fatigue, but no differences in physical functioning and pain. Substantiated information on the impact of Long COVID on functioning in work and the specific factors that lead to long-term disability is lacking. A large proportion of the patient population is in the middle of his/her working life and the first signals from the health care sector and from patients themselves indicate that the consequences of persistent symptoms after COVID-19 have a large impact on workload capacity,  which can have major consequences on the labor market position of this patient group.