Symptom-based screening has been very important in the efficient utilization of testing for infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the agent responsible for the coronavirus disease 2019 (COVID-19). A new paper published on the preprint server medRxiv* compares changes in the symptoms due to COVID-19 over the course of the pandemic to elicit their evolution with the change in variants and with vaccination status.
Study: Symptoms and SARS-CoV-2 positivity in the general population in the UK. Image Credit: simona pillola 2 / Shutterstock.com
A majority of people infected with COVID-19 are asymptomatic, with symptoms being more typical of those with higher viral loads who, in turn, drive higher rates of transmission. Universal testing is generally ruled out because of limited resources. Instead, contact tracing and testing with isolation strategies are preferred, usually including those with symptoms that have the highest positive predictive value.
There are four symptoms used at present for screening in the United Kingdom, which include a change in or loss of taste and smell, fever with or without a new persistent cough. Comparatively, in the United States, the Centers for Disease Control and Prevention (CDC) has a wider set of symptoms that are used for their COVID-19 screening protocols. These symptoms instead include fever or chills, cough, shortness of breath/difficulty breathing, the new loss of taste/smell, fatigue, muscle or body aches, headache, sore throat, congestion/runny nose, nausea/vomiting, or diarrhea.
The UK REACT study suggests that age plays a role in defining the symptom set, such as adding some combination of headache, muscle aches, chills, and appetite loss. Another UK study, ZOE, suggests that besides age, the patient’s sex, body mass index, and healthcare occupation are involved in defining the need for testing. The VirusWatch adds feverish feelings, headache, myalgia, loss of appetite, or chills, though this leads to 2-3 times increased numbers of tests and a seven-fold rise in the numbers of tests per positive result.
These studies were conducted when the SARS-CoV-2 Alpha variant was the dominant circulating variant throughout the U.K. and preceded the large-scale deployment of the vaccine. Therefore, further refinements are required to track the evolution of symptoms with the change in dominant variant from Alpha to Delta.
The ZOE study demonstrated that with the Delta variant, headache was the most frequently observed symptom with a breakthrough infection in a fully vaccinated person. Comparatively, sore throat with and runny nose/sneezing were primarily observed in partially vaccinated and unvaccinated, individuals, respectively.
About the study
Using test results from over five million polymerase chain reaction (PCR) results obtained between April 26, 2020, to August 7, 2021, of which 0.67% were positive, the researchers of the current study identified approximately 28,000 symptomatic positive episodes in about 27,000 women. The authors then compared these symptoms with a similar group of symptomatic negative visits.
The positive episodes were most frequently associated with tiredness, weakness, cough, and headache, which occurred in over half the cases. Notably, headache and cough were also found, along with sore throat, in almost a quarter of negative symptomatic visits.
The specificity of symptoms was highest for anosmia and ageusia, which occurred in around a third of positive cases, each, but only 2% of negative visits. These symptoms usually occurred together. Headache, myalgia, and tiredness were also reported together.
The viral load, variant, vaccination status, and age did not appear to affect the co-occurrence of these symptoms. However, muscle pain fell a little behind headache and fatigue with the Delta variant in individuals between the ages of 6-15 years and in breakthrough infections. In the group of negative COVID-19 results, the same clusters of symptoms were observed.
Conversely, individual symptoms showed differing patterns by variants, with anosmia/ageusia being reported by 28% and 31% of those with positive symptomatic episodes caused by the Alpha variant. In contrast, wild-type or Delta variants were linked to these symptoms in approximately 38% of the episodes.
These symptoms were mostly reported among patients in their twenties and reduced with age, with a slight increase in older people.
Fever and sore throat occurred in 37% of Alpha-related episodes, whereas headache occurred in 56% of individuals infected with the Delta strain. Cough or tiredness was reported in half of the wild-type-related cases, but in just over 61% and 64% of Alpha and Delta cases, respectively. For individuals over the age of 20, cough was reported by twice as many positive symptomatic people than negative, along with breathlessness, tiredness, and diarrhea.
The frequency of symptoms among positive cases did not show many alterations from August 2020, except for an increase in September 2020 and May 2021, both probably due to school reopenings. The onset of the spread of both the Alpha and Delta variants in November 2020 and May 2021 was also marked by fluctuations.
As people became more aware of specific symptoms, positive symptomatic episodes were marked by a higher percentage of reporting of each of these symptoms. The Alpha peak in January 2021 coincided with peak symptoms except for anosmia and ageusia.
The decline in symptoms remained constant until May 2021, which is when the Delta virus hit and causing symptoms to rise again. Reports of headache, cough, and fever increased significantly as the Delta variant became dominant.
School reopening in September 2020, as well as school closures in both January and April 2021, were linked to a higher reporting of cough and sore throat that were attributed to other respiratory viruses. Winter was marked by increased gut symptoms, tiredness, muscle pain, and headache among symptomatic negative episodes, again due to other endemic seasonal microbes.
Women reported more symptoms in positive episodes than negative for anosmia, ageusia, diarrhea, and breathlessness, though fever was less common. Whites had fewer complaints of fever and more headache, nausea, vomiting, and breathlessness, relative to non-whites. Anosmia and ageusia were less common during positive episodes for non-whites.
Positive episodes occurring 21 or more days from the first vaccine shot were less likely to report 10 of 12 symptoms than negative visitors. When the viral load was high (cycle thresholds Ct at 20 or below), symptoms such as cough, fatigue, and headache with myalgia, were reported at least half the time, declining from a Ct of 27.5 and above.
Anosmia and ageusia increased significantly from 30% to 45% for Ct 15-45%, as did breathlessness, though less markedly.
The study shows that specific symptoms are few, with a symptom-related positive-predictive value (PPV) of less than 10%. Sensitivity went up to 90% if any of the 12 selected symptoms were included; however, this was at the cost of specificity compared to the use of the four classic symptoms.
Including fatigue or weakness boosted sensitivity of detection from 74% to 81%, but at the cost of more tests per case detected. In young people, the addition of headache into the list of potential COVID-19 symptoms led to the highest sensitivity without sacrificing specificity, especially for those less than 10 years of age.
Early infection in positive cases included symptoms of fatigue, headache, cough, anosmia, and ageusia, and myalgia, all less than 10%. The highest Ct values were associated with asymptomatic cases, while the lowest had symptoms being reported at the earliest and subsequent visits.
The researchers found that as different variants became dominant and with higher viral loads, the reporting pattern for symptoms changed over time. The four classic symptoms of cough, fever, anosmia, and ageusia all appeared to be optimal for screening by symptoms in low-resource settings.
With the possibility of somewhat greater testing, the inclusion of fatigue or weakness led to the greatest increase in screening sensitivity. Unlike the large array of symptoms promoted by the CDC for testing, it can lead to much higher numbers of tests per positive diagnosis and may reduce the overall accuracy.
“Currently, we therefore have limited evidence for expanding the case definition beyond the classic four symptoms where universal testing is not practical/affordable, with fatigue/weakness the most promising candidate. However, this requires ongoing monitoring as other respiratory viruses increasingly circulate following lifting of restrictions with vaccine roll-out.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.