In the Czech Republic, a total of 558,650 unique patients were tested via nasopharyngeal swab during our study, and 19,004 (3%) were deemed COVID-19 positive with 1.3% mortality [29]. Initially, our study recruitment was very successful with significant participation. Enrollment dropped dramatically, however, as the first wave of infections subsided in the Czech Republic, and fewer medical students were available at mobile sampling points to explain study principles and advantages. Study involvement later accelerated in the second half of August 2020, when numbers of infected people notably increased. At the University Hospital, during the study period, SARS-CoV-2 positivity was detected in 5% (n=594) of 11,469 examined patients, and 87% (n=517) were COVID-19 positive outpatients. In total, 105 outpatients (20% of University Hospital’s COVID-19 positive outpatients) agreed to participate in our study. A total of 1223 phone interviews were conducted (mean 12; median 11; min 1, max 25).
Demography and Comorbidities
Among 105 cohort outpatients, the mean age was 40 years with slightly more women (52%). Eighty-four (80%) patients had some comorbidity with the following frequency breakdown: n=1, 37%; n= 2, 24%; n=3, 8%; n=4, 5%; n=5, 5%; n=6, 1%, with the most frequent being allergy (43%) and hypertension (24%), (Tables 1, and 2). No significant difference was recorded between the two negative test cohort (40 patients; 38%) and the new algorithm cohort (65 patients; 62%) with regard to baseline characteristics and comorbidities (Table 1).
Secondary Hospitalized Outpatients
A telephone interview conducted by a doctor was necessary for 10 (10%) outpatients, from which 7 (7%) required examination and six (6%) were eventually hospitalized with a 7 day median following diagnostic test and a 4 day median hospital stay (Table 3). The male majority (83%) of hospitalized patients were admitted to the hospital with a median age of 56 years and a median of 2 comorbidities. Symptom frequency and median duration were as follows: Fever (83%; 9 days), dyspnea (67%; 2 days), cough (67%; 6 days), and diarrhea (33%; 1 day). In relation to COVID-19, pneumonia mandated hospitalization in 2 patients, diarrhea in 2 patients, atypical thoracalgia in 1 patient, and dyspnea with fever in 1 patient. We evaluated the disease course as mild in 4 patients and moderate in 2 patients. One patient was treated with remdesivir and one patient with a combination of hydroxychloroquine and azithromycin. No patient died. Table 3 provides a detailed description of secondary hospitalized outpatients.
For suspected pneumonia, a fifty-year-old obese woman with dyspnea and cough from the two negative test cohort underwent chest computer tomography. There was no pulmonary pathological finding apart from solitary cervical lymphadenopathy. After symptoms persisted for 38 days and PCR test result was negative, further diagnostic procedures were performed. Eventually, Castleman disease turned out to be the reason for persistent clinical symptoms.
Covid-19 Outpatient Symptomatology
Among 99 (94%) of symptomatic outpatients, symptom median number was 7 (mean 7.0; min 0, max 17). During diagnostic test sampling, 14 (13%) patients were pre-symptomatic and developed some symptoms during disease progression. Only 6 (6%) of outpatients were completely asymptomatic throughout the episode. All evaluated symptoms are shown in Table 4. Time distribution of symptoms is detailed in Table 5.
COVID-19 Symptom Frequency
Regarding symptom incidence, most common reported symptoms were: General symptoms of respiratory tract infection (RTI) (71%), fatigue (65%), fever (60%) with a median of 37.6°C, anosmia (59%), headache (58%), musculoskeletal pain (55%), ageusia (47%), and dry cough (43%) (Table 4). Females reported a higher frequency of anosmia (66% vs. 52%; p = 0.172) as well as younger patients (median age of patients with anosmia vs. without anosmia was 34 vs. 47 years; p=0.016). Other less frequent symptoms were noted in Table 6.
Length of COVID-19 Symptoms
Evaluated only in the two negative tests cohort, the shortest duration of symptoms with a median of up to 5 days included fever, headache, musculoskeletal pain, diarrhea, anorexia, tachypnea, thoracalgia, and abdominal pain. Conversely, breathing difficulties, general RTI symptoms, dry and wet cough, dyspnea, shortness of breath, anosmia, and ageusia had a longer median duration exceeding 10 days (Table 4). During telemonitoring termination owing to double PCR negativity, certain symptoms still persisted in 41% of patients. Regarding comparison of the length of anosmia and ageusia between the two outpatient cohorts, we observed a longer median duration of both symptoms in the cohort with two negative tests (anosmia 26 days vs. 9 days; p=0.039; ageusia 26 days vs. 8 days; p=0.242, respectively) (Figure 2).
Time Distribution of COVID-19 Symptoms
In terms of symptom time distribution related to disease onset, fever, headache and musculoskeletal pain, practically appeared at median day zero from disease onset. Subsequent symptoms comprising dry and wet cough, general RTI symptoms, diarrhea, anorexia, breathing difficulties, and tachypnea were later reported with a median of 1-2 days following disease onset. Finally, late symptoms with a median onset of more than 2 days involved anosmia, ageusia, abdominal pain, dyspnea, and shortness of breath (Table 5). Symptom termination time also varied. Certain symptoms disappeared median 10 days after disease onset (fever, headache, musculoskeletal pain, diarrhea, anorexia, tachypnea), while most symptoms lasted more than median 11 days following disease onset (anosmia, ageusia, dry and wet cough, general RTI symptoms, abdominal pain, dyspnea, breathing difficulties, and shortness of breath).
Co-occurrence of Clinical Symptoms
We recognized a statistically significant (p<0.001) link between anosmia and ageusia, fever and wet cough, musculoskeletal pain and wet cough, general RTI symptoms and ageusia, diarrhea and abdominal pain, and breathing difficulties with dyspnea. The co-occurrence of clinical signs is recorded in Figures 3 and 4.
Association Between Symptoms and Comorbidities
We analyzed the relationship between patients' characteristics and comorbidities with the number of symptoms. In general, a linear relationship appeared between a higher number of comorbidities and a higher number of symptoms (p=0.209) (Figure 5). However, neither an older age (p=0.077), female gender (p=0.254), diabetes mellitus (p=0.129), cancer (p=0.699), nor allergies (p=0.171) were determined statistically significantly correlated with the number of disease symptoms. Patients exhibiting fewer symptoms were those with a higher BMI (p=0.370) and, surprisingly, smokers (p=0.096), although this relationship was statistically insignificant. Hypertension didn’t affect the symptom number (p=0.548), but anosmia incidence was higher in patients without arterial hypertension compared to patients having this comorbidity (40% vs. 65%; p=0.036). There was no link between hypertension and ageusia presence. Neither anosmia nor ageusia were influenced by diabetes mellitus presence.
Sensory Disorders with Extended Follow-Up
By October 31, 2020, we had completed a detailed reassessment of sensory disorder incidence over time in our two negative test cohort with a median follow-up of 181 days (Table 7). Total median for anosmia and ageusia length was 32 days and 21 days, with persisting symptoms in 26% and 5% of outpatients, respectively.
SARS-CoV-2 Viral Load
A total of 105 diagnostic (i.e. the first positive specimen in a unique patient) nasopharyngeal swabs were analyzed. Among the two negative tests cohort, a total of 148 follow up samples were examined (median 3; mean 3.7; min 2, max 9). Median diagnostic viral load was 25.1 Ct (mean 25.6; min 9.8, max 45.5) with viral load similar in both patient cohorts. In the group of 6 asymptomatic patients, median diagnostic viral load was 32.9 Ct (mean-32.4; min-18.9, max-41.7).
Correlation of Viral Load with Symptoms at the Time of Diagnosis
We evaluated the correlation between diagnostic Ct value in relation to the time between sampling and first symptom onset (six patients with completely asymptomatic disease course were excluded from the analysis; furthermore, another four patients with unknown absolute positive Ct value were marginalized), see Figure 6. Fourteen patients were affirmed as contacts up to 5 days before symptoms’ onset (i.e symptoms appeared after sampling -- the graph’s right portion). The remaining 81 patients, with known Ct value, were symptomatic at the time of their first positive PCR test, and they had already been symptomatic for average 6 days (i.e symptoms appearing before sampling, left side of the graph). The maximum sampling time was 36 days after symptoms’ onset. Correlation curve plotted U-shape between diagnostic Ct values and sampling time in relation to the symptoms’ onset. Highest viral load was detected in diagnostic samples analyzed 0 to 2 days after initial symptom onset. Albeit not precisely recorded in numbers, patients rationalized during telemonitoring that delays between the symptom onset and sampling resulted from either being scared of COVID-19 positive diagnosis or by an insufficient testing capacity.
SARS-CoV-2 Elimination Course
Among 40 patients from the two negative test cohort, median time from diagnostic sample to the first and the second negativity was 19 days (mean 21.9; min 5, max 53), and 26 days (mean 25.3; min 7, max 56), respectively. Median time from first to second negative sample was 2 days (mean 3.4; min 1, max 18). The virus elimination curve was steadily increasing (57%) or fluctuating (43%), see Figure 7.
With this patient cohort, a total of 44% and 31% still exhibited symptoms at the time of the first and the second negative test, respectively. Yet, in the new algorithm cohort, only 21% of patients reported any symptom 11 days after the first positive test.