Disease course and risk factors for hospitalization in outpatients with SARS-CoV-2 infection

Characteristics of the surveyed population

Between May 2020 and February 2021, 3840 people who tested positive for SARS-CoV-2 were invited to study. These represent 69.7% of all infections from the Vorpommern-Greifswald district (total population 235,773) in northeastern Germany during the second wave of infection (supplementary figure). 1). The remaining 30.3% were not invited because they were under the age of 18, missing address data, or had a positive test result older than a week. 983 (25.6% of all invited) agreed to participate in the survey, and 710 completed both questionnaires and were included in the analysis.The table below shows the characteristics of the population and comorbidities. 1..

Frequency, duration, and passage of infection symptoms

We asked patients to monitor 16 infectious symptoms (table) 2). We received information about symptoms from 700 of the 710 participants.

Thirty-four (4.9%) self-reported to be completely asymptomatic throughout the observation period. Of the remaining participants, 622 reported the exact time of onset of symptoms associated with PCR confirmation of infection (Figure. 1: Top panel). Onset occurred on average 2.3 days before confirmation of infection by PCR. Of those who had symptoms before the test was positive, 18.2% experienced the first symptoms one day before the test.

The time of onset of symptoms and the number of symptoms on the day of onset. Top panel Sets the onset date of the symptom for the PCR infection confirmation date (day 0 is set as the day for sampling the PCR test) of all 622 participants who self-reported the exact time of onset of the symptom. is showing. No symptoms were reported by 91 people on the day of the PCR test. Bottom panel Shows the number of simultaneous symptoms on the day of onset of the first symptom.

At the onset of symptoms, participants ranged from 1 (134 participants) to 12 symptoms (1 participant, figure. 1, Bottom panel). Importantly, the initial symptoms reported were non-specific. For example, fatigue (60.3%), headache (48.6%), myalgia / arthralgia (46.1%), sore throat (29.3%, supplementary table) 1). More SARS-CoV-2 specific symptoms, such as odor loss or taste loss, were reported in only 15.4% and 13.7% on the day of onset of symptoms, respectively.

Fatigue is the most persistent symptom (mean duration 12.1 days), followed by odor loss, dyspnea, taste loss, and dry cough (each lasting an average of 10 days or more, table). 2).In contrast, the shortest-lasting symptoms were vomiting, fever, diarrhea, nausea, and abdominal pain (mean duration less than 5 days, respectively, table). 2). Almost half of the participants (n = 239; 44.3%) reported at least one infection-related symptom on the final day of observation (day 25). Fatigue was the most frequently reported symptom on day 25 (n = 98, 18.2%, figure. 2), Followed by anosmia (n = 83, 15.4%) and dry cough (n = 72, 13.4%; Figure. 2).

Comparison of the frequency of symptoms during the acute phase of infection (1st to 10th day) and the end of the observation period (25th day). Symptoms are categorized according to persistence on day 25. The analysis is based on 539 participants who reported symptoms over 25 days. Shown are the frequency of symptoms for female (n = 420, dark gray) and male (n = 280, white gray) participants. * p <0.05, ** p <0.01, *** p <0.001 (calculation of gender difference) Pearson χ² test.

The frequency and duration of symptoms depended on gender. Women more commonly reported fatigue, loss of odor, loss of taste, headache, sore throat, abdominal pain, and nausea in the first 10 days of infection, with 23% of women reporting 25. Even on the day, he reported fatigue. Infectious disease (figure). 2Supplementary table 2).

The frequency and duration of some symptoms were also age-dependent.Young participants (ages 18-39) had shorter durations of fatigue, fever, arthralgia / myalgia, all forms of cough, and skin lesions (Supplementary Table). Four).On the other hand, few participants over the age of 60 reported odor or taste loss, headache, or sore throat (Supplementary Table). Five), But when these symptoms occurred, their duration was age-independent (Supplementary Table) Four).

Course of symptoms

Two different patterns were observed over time of symptoms. The majority of symptoms were reported within the first 3 days of infection, and the proportion of individuals reporting them consistently decreased over time (Figure. 3, Top panel). Within this group, the most rapidly improving symptom was fever, with less than 2% of participants reporting fever after 12 days.

Course of SARS-CoV-2 symptoms within a 25-day observation period. Shown are 10 of the 16 symptoms analyzed stratified according to a particular pattern.Top panel) And it increases from the 7th day to the 9th day (Center panel). Common symptoms are gray, neurologically green, and lungs blue. Skin symptoms, conjunctivitis, abdominal pain, diarrhea, nausea and vomiting are not shown as less than 15% of participants reported these symptoms on any observation day. These figures show the frequency based on the original (not entered) data. Except for fever, the results using the input data are very similar, as participants record their temperature much less frequently.The Bottom panel Shows the correlation between the duration of taste loss and the sense of smell. Each individual is represented as a single dot. Participants who are in the hospital are filled with white circles and are shown as not in the hospital.

The second pattern is characterized by a steadily increasing frequency of participants in the first week, peaking on days 7-9 (figure). 3, Center panel).Interestingly, it is considered a characteristic symptom of the disease, such as loss of smell and taste.^{15,16 16} In our study, we followed this alternative pattern. On day 1, only 17.1% of participants reported odor loss or taste loss, while 48.8% of participants suffered odor loss on day 7 (Figure. 3Center panel).

Correlation between symptoms

The strongest correlation was observed between the duration of sensory loss and taste loss (r = 0.83, p <0.001, supplementary figure. 2). However, the duration of these two symptoms is different. Smell loss was reported over a longer period (mean 11.6 days, median 10 days) compared to taste loss (mean 10.6 days, median 9 days, p = 1.2 × 10).^–8 Paired t-test). Importantly, 50 reported that they lost their sense of smell without losing their sense of taste, and 26 reported that they lost their sense of taste without losing their odor (figure). 3Bottom panel).

A strong correlation was also observed between the duration of common symptoms (r = 0.56 fatigue and joint pain / myalgia and r = 0.51 fatigue and headache). Supplementary figure. 2).

Not only within a group of specific symptoms (eg, between nausea and abdominal pain, and between diarrhea and vomiting), but also between specific and non-specific symptoms, especially with common symptoms such as dyspnea and malaise. Correlation was also observed between lung symptoms (r = 0.43, p <0.001, supplementary figure. 2). Interestingly, the day with fever was only moderately correlated with any of the other recorded symptoms (r <0.3, supplementary figure). 2).

Relationship between symptoms and hospitalization

Next, we analyzed whether the symptoms of outpatients could predict the risk of hospitalization. Data on infection symptoms and hospitalization were available from 685 study participants, of whom 36 (5.3%) were hospitalized. The median time from onset of symptoms to hospitalization was 6 days (range 1 to 23 days).

Five symptoms were individually associated with hospitalization (figure). Four, Top panel). Vomiting, dyspnea, and fever were associated with an increased risk of hospitalization, and loss of odor and sore throat were associated with a reduced risk (Figure. FourTop panel).

The relationship between symptoms and the risk of hospitalization. Shown are age, gender, BMI unadjusted (upper panel) or adjusted odds ratio and 95% confidence interval (lower panel). Statistically significant associations are highlighted in bold and the significance level is reported (* p <0.05, ** p <0.01, *** p <0.001). Pearson χ² The test was used to calculate the significance of each pair on both sides. Adjustments for age, gender, and BMI were performed using binary logistic regression with hospitalization as the dependent variable and three adjustment parameters and each symptom as the dependent variable separately.

Importantly, individuals (n = 26) who reported loss of taste without losing their sense of smell were nearly seven times more at risk of hospitalization (Figure. Four, Top panel). Relevance remained significant after adjusting for age, gender, and BMI (Figure. Four, Bottom panel). In addition, individuals who reported loss of taste without losing odor more commonly experienced dyspnea and nausea (figure). Five).

The association between loss of taste without losing odor and symptoms of other infectious diseases. Shown are the odds ratio and 95% confidence interval for experiencing one of the other infectious symptoms when the patient suffers from taste loss without losing odor. Statistically significant associations are highlighted in bold and the significance level is reported (** p <0.01). Pearson χ² The test was used to calculate the significance of each pair on both sides.

Relationship between baseline risk factors and hospitalization

We also analyzed potential risk factors (demographic factors, comorbidities, and baseline medications) in relation to hospitalization.To enrich the participants in our study (36 participants admitted due to infection), we analyzed 143 individuals admitted to COVID-19 at Greifswald University Hospital (Supplementary Table). 6), Major tertiary hospitals in the area (ViP Research, DRKS-ID: DRKS00023770). The resulting total population included 838 people infected with SARS-CoV-2, of which 179 (21.4%) of the participants were hospitalized for infection.

Age and BMI were very significantly associated with the risk of hospitalization (p <10).^–26 And p = 0.004, Mann-Whitney U test, respectively.Supplementary figure 3).

In addition to ages 60 and older, cardiovascular disease, hypertension, true diabetes, lung disease (both general lung disease and COPD), neurological disease (both general neurological disease and stroke) coexisting with male gender ), And the risk of hospitalization associated with kidney disease (Table) 3).Of these, age, neurological disorder, COPD, heart disease, and diabetes were independent predictors of hospitalization (Table). 3). Liver disease, joint disease, allergies and neoplasms were not significantly associated with the risk of hospitalization.

Drugs used to treat hypertension were also associated with the risk of hospitalization. ACE inhibitors and AT1 receptor blockers were associated with similar increased risk (Table) 3), But none of them was an independent predictor of hospitalization risk.

In particular, all grades of disability were associated with a 3.1-fold increased risk of hospitalization (Table). 3). Only 3.9% of non-disabled participants were hospitalized, compared to 11.1% of disabled participants. However, because the ViP study did not document the grade of disability, these analyzes were based on only 36 inpatients from the outpatient study.