The risk of delayed acute complications after non-hospitalized SARS-CoV-2 infection is low

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A new study published in The Lancet Infectious Diseases journal has found that the risk of delayed acute complications after non-hospitalized SARS-CoV-2 infection is low, but persistent symptoms in this group could lead to increased visits to general practitioners or outpatient clinics in the six months following infection. The study assessed only those complications that led to contact with hospitals.

Researchers assessed the risk of initiating medication and receiving a hospital diagnosis for a new condition by comparing individuals who tested positive via a PCR test for SARS-CoV-2 with individuals who had a negative test during the first wave of the pandemic in Denmark.

Results found SARS-CoV-2 positive individuals were at a slightly increased risk of initiating medications to help improve breathing and alleviate migraines, and had a slightly increased risk of receiving a first diagnosis for breathing problems and blood clots in the veins.

Senior author, Professor Anton Pottegård from the University of Southern Denmark says: “Until now, most research investigating long-term complications from COVID-19 has been focused on hospitalized patients. But the reality is that the majority of people with COVID-19 are not admitted to the hospital.

Our study finds a very low risk of severe delayed effects from COVID-19 in people who didn’t require hospitalization for the infection. However, our research provided evidence for some long-term effects that did not require hospitalization or the use of new medicines, which we found reflected in higher use of primary health-care services after infection. This highlights the need to ensure clinicians have the resources and support to manage any potential long-term conditions.”

The researchers used data from the Danish health registries on all individuals who were tested for SARS-CoV-2 between Feb 27, 2020, and May 31, 2020. The study followed up 8,983 non-hospitalized SARS-CoV-2 positive people and 80,894 SARS-CoV-2-negative people during the period from two weeks to six months after the test. By comparing data from the two groups, researchers assessed the relative risk of starting new medications and of receiving a diagnosis of a new health condition during this time.

The analysis took into account variables that could be associated with having a positive versus negative test and with the risk of a more severe course of COVID-19, such as obesity, cancer, and kidney disease.

The cohorts had a median age of 43 years and 64% were female. Among SARS-CoV-2 positive individuals, 31% had initiated new medication treatments during the follow up period. A more detailed analysis found that compared with those with a negative SARS-CoV-2 test those with a positive test were at an increased risk of initiating medications to widen the airways (1.8% compared with 1.5%), and medications to treat migraines (0.4% compared with 0.3%). As such, observed differences were generally small.

The risks of receiving a hospital diagnosis for a new health condition during follow up were similar in the two groups (around 26%). Compared with individuals who tested negative, those with a positive SARS-CoV-2 test were at an increased risk of receiving a first diagnosis of breathing difficulties (1.2% compared with 0.7%) and blood clots in the veins (0.2 % compared with 0.1%).

No increased risk of serious complications identified by previous research conducted among individuals hospitalized for COVID-19, such as stroke, encephalitis, and psychosis, was identified among individuals who did not require hospitalization.

The research also analyzed the use of health services in the follow-up period and found that those with a positive SARS-CoV-2 test visited their general practitioners around 20% (1.2 times) more often than those that tested negative, and visited outpatient clinics 10% (1.1 times) more often. However, there was no difference in the visits to emergency department or being hospitalized.

The follow-up of the study was limited to six months after the positive test, which means the data may not have captured the longer-term complications and symptoms of COVID-19 that could occur after this time. In addition, due to the limited resources during the pandemic, some individuals with complications may have been referred to hospitals but not actually attended clinics before the end of the follow-up. This may have affected the numbers of hospital diagnoses recorded.

Commenting on the limitations of the study, co-author Stine Hasling Mogensen, Ph.D., from the Danish Medicines Agency adds: “Our analysis only captures specific symptoms leading to contact with hospitals, so it is likely that the study underestimates symptoms which do not require this level of care, like fatigue and breathing difficulties which are not severe enough for hospitalization or require initiation of new medical treatment.

Previous research has found a high level of these symptoms reported by patients, so the differences between patient reports and healthcare encounters could be important to investigate in regards to potential unmet healthcare needs and the need for new medications for treatment.”

The researchers call for large population-based studies of patient-reported symptoms and healthcare visits to fully evaluate the duration and range of any persisting symptoms after SARS-CoV-2 infection.


Weeks and months after the onset of acute COVID-19, people continue to suffer. Paul Garner, a professor of epidemiology at Liverpool School of Tropical Medicine, UK, wrote on the 95th day after the onset of symptoms that “I am unable to be out of bed for more than three hours at a stretch, my arms and legs are permanently fizzing as if injected with Szechuan peppercorns, I have ringing in the ears, intermittent brain fog, palpitations, and dramatic mood swings.”1

Other people also describe similar complaints.2, 3 78 of 100 patients in an observational cohort study who had recovered from COVID-19 had abnormal findings on cardiovascular MRI (median of 71 days after diagnosis) and 36 of those reported dyspnoea and unusual fatigue.4

We are seeing patients in clinics dedicated to COVID-19 convalescents, and for some of these patients the return to their former health trajectory is slow and painful. These patients are not only those recovering from the severe form of the acute disease (ie, post intensive care syndrome), but also those who had mild and moderate disease. A summary of the most common complaints, based on our clinical impressions, is shown in the appendix (p 1).

Rare long-term sequelae can result after other viral infections – eg, infectious mononucleosis, measles, and hepatitis B. Long-term sequelae of COVID-19 are unknown (as are many aspects of the acute disease). Long-term consequences were observed in survivors of severe acute respiratory syndrome (SARS)5, 6 but it is unknown whether lessons from SARS are applicable to COVID-19. Other concerns are rising: does acute COVID-19 cause diabetes?7

Or other metabolic disorders? Will patients develop interstitial lung disease?

We are still in the first months of the pandemic and we do not know what to tell our patients when they are asking about the course and prognosis of their ongoing complaints.

The number of people affected by COVID-19 is unprecedented. We owe good answers on the long-term consequences of the disease to our patients and health-care providers. The obvious answer is in research. In the appendix (p 2) we have compiled a list of questions we think should be answered.

This list is based on the authors’ views and experience rather than on the literature, which is scant. For efficient research and for research that our patients (and we) can trust, some common problems in the description and research of acute COVID-19 should be avoided.

The main problem is fragmentation. For example, Wynants and colleagues8 described 47 models for predicting COVID-19 infection and 16 prognostic models for COVID-19 patients. Most of these models had a high risk of bias and most of them did not have external validation.

Additionally, randomised controlled trials on interventions to treat the acute disease were stopped before enlisting the planned sample size. Although much effort was invested in these studies, we have learned little. Fragmentation also happens by discipline,6, 7 and the follow-up (for clinical and research purposes) should be multinational, multidisciplinary, comprehensive, and homogenous.

Careful recording of symptoms and patient examination should allow understanding of which part of the sequelae is common to all severe infections, which symptoms might be explained by the anxiety caused by a new disease and by the isolation,9 and which symptoms are secondary to a complicated form of COVID-19 (eg, pulmonary involvement during the acute disease).

If indeed COVID-19 is causing long-term sequelae then are the mechanisms underlying the long-term consequences immunological?

Or caused by new or relapsing inflammation, ongoing infection, or side-effects of immunomodulatory treatment? Such data can serve to point at candidate management strategies to be tested in trials.

Support for research is needed on the trajectory of people recovering from COVID-19. To avoid the problems we have witnessed in the research of the acute phase of the disease, a clear definition of patient inclusion criteria, a common protocol, and uniform definitions of outcomes and ways to measure them are required.

Additionally, data should be collected in real time and computational tools are needed to be able to do this  (appendix p 3).

reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462626/#sec1


More information: Lars Christian Lund et al. Post-acute effects of SARS-CoV-2 infection in individuals not requiring hospital admission: a Danish population-based cohort study, The Lancet Infectious Diseases (2021). DOI: 10.1016/S1473-3099(21)00211-5

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