Clinical Characterization of the Persistent COVID-19 Symptoms: A Descriptive Observational Study in Primary Care

Abstract

Introduction:

Evidence and clinical experience suggest that there are a range of signs of health issues that affect patients who have recovered from acute COVID-19 infection. This condition is commonly referred to as “persistent COVID-19,” which is not connected with the severity of the disease. We have identified the prevalence and clinical-epidemiological characteristics of patients with COVID-19 and persistent symptoms treated in primary care centers. This is a descriptive observational study conducted between December 2020 and May 2022, the data were collected from digitized medical records and interviewing 1542 individuals with laboratory-confirmed SARS-CoV-2 infection. These patients were clinically followed for up to 1 year, based on the prevalence of symptoms. When stratifying by the risk of developing persistent COVID-19, 37.09% of the patients exhibited risk factors, with age (over 60 years) and cardiovascular risk factors predominating. The obtained prevalence of persistent COVID-19 at 90 days was 12.39%, with a slight predominance in females (55%) and a mean age of 45.8 years. The most affected systems were the cardiovascular, respiratory, and psychoneurological systems, with predominant symptoms of fatigue (41.88%), dyspnea (32.46%), and headache (14.66%), among others. The average duration of persistent symptoms was 178 days, equivalent to 6 months. In conclusion, over 10% of patients who recover from acute SARS-CoV-2 infection developed long-term consequences.

Objective:

To measure the prevalence and clinical-epidemiological characteristics of individuals diagnosed with COVID-19 and persistent symptoms treated in primary care centers in Área Sanitaria Sur de Córdoba (Spain) between December 2020 and May 2022.

Methods:

A retrospective observational study of the population of Área Sanitaria Sur de Córdoba was developed between December 2020 and May 2022. The scope of the study was 1542 individuals, and the prevalence of patients diagnosed with COVID-19 and persistent symptoms was determined based on laboratory-confirmed cases, randomly selected from adults who had progressed beyond the acute phase of the disease. All data were managed by the Área Sanitaria Sur de Córdoba (Spain).

Results:

The risk factor of exhibiting one or more risk factors associated with developing persistent COVID-19 is 37.09%. The obtained prevalence of persistent COVID-19 at 90 days is 12.39%, it is higher in females (55%) than males and the mean age was 45.8 years. The most affected systems were the cardiovascular, respiratory, and psychoneurological systems, with predominant symptoms of fatigue (41.88%), dyspnea (32.46%), and headache (14.66%), among others.

Conclusions:

Results confirm that more than 10% of individuals recovering from acute SARS-CoV-2 infection showed long-term consequences and the observed persistent symptom duration was 178 days on average.

Introduction

Some patients infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) remain with persistent symptoms and had lower health-related quality of life (HRQoL) after an acute coronavirus disease 2019 (COVID-19). ¹ Long-term effects of COVID-19 as symptoms, signs, and abnormal laboratory parameters (D-dimer, NT-proBNP, serum levels of C-reactive protein, ferritin, procalcitonin) have been identified,^2,3 which are comparable with experienced during the acute phase of COVID-19. These symptoms can persist for months, even among non-hospitalized individuals with less severe clinical disease during the acute phase. ⁴ The most common symptoms in patients with coronavirus are dyspnea, fatigue, hair loss, headache and psychosocial distress, among others.^{2,5 -9}

Large number of evidence and clinical studies support the existence of persistent COVID-19, also known as post-COVID syndrome or long-COVID, which is refers to a collection of signs and health issues that affect patients following acute COVID-19 infection.^{5,7,10 -12} According to the World Health Organization, persistent COVID-19 is defined as a state at 3 months post the development of COVID-19, with symptoms remaining for at least 2 months and which cannot be explained by an alternative diagnostic. ¹³

The epidemiological date reported by Huang et al showed that 80% of infected persons with SARS-CoV-2 were mild or asymptomatic cases, 15% severe, and 5% critical. ¹⁴ For a mild cases, the symptoms reverted after 2 weeks, while in severe forms, the symptoms may persist for 3 to 6 weeks. ¹⁵ Persistent COVID-19 have been mainly reported in survivors with severe and critical illnesses courses, however long-lasting effects also occur in individuals with mild to moderate infection who did not require hospitalization. ⁸ Thus, a few studies have shown that individuals with mild to moderate infection, who showed persistent COVID-19, required longer recovery times to return to their normal life.^9,16,17 Consequently, currently there is no evidence of a relationship between the severity of the disease and the possibility of developing persistent COVID-19.^{18 -20}

In the pandemic and post-pandemic periods, numerous studies have reported the persistence of symptoms in COVID-19 patients. However, a limited number of these studies focused on non-hospitalized patients that indicate persistent COVID-19,^4,21 furthermore, the sample sizes studied have generally been small, and monitoring of patients has been short-term, in most cases.^6,7,14,22,23 Due to a significant number of individuals with COVID-19 do not require hospitalization and they receive ambulatory care, we consider it important quantify and characterize persistent COVID-19 in this population, to achieve a full understanding of the public health implications consequences of the pandemic.

The main goal of this study is to describe the prevalence and clinical-epidemiological characteristics of patients with persistent symptoms of COVID-19 treated in Primary Care in the Área Sanitaria Sur de Córdoba (Spain). To improve our knowledge about the natural history of the disease, we documented post-COVID symptoms, categorized patients according to the characteristics of their manifestations, and established risk factors associated with the development of persistent COVID-19. Furthermore, we evaluated the functional status of patients before and after their COVID-19 experience.

Materials and Methods

Design and Participants

The present research was a descriptive observational study, based on clinical practice and follow-up of a patient cohort, using routine clinical data collection and in-person visits patient or telephone interviews (at 1, 3, 6, 9, and 12 months) from onset of symptoms (data collection notebook can be consulted in the Supplemental Material).

The study population was selected from individuals with laboratory-confirmed SARS-CoV-2 infection in the Área Sanitaria Sur de Córdoba (Spain), between December 2020 and May 2022 both included. We selected 1542 participants in a random manner from laboratory confirmation reports, with the inclusion criterion of adults who had passed the acute phase of the illness. Invitation for study participation was extended to eligible individuals, and those who declined or were unable to be followed up were excluded from the study. We estimated a minimum of 1157 individuals need to be screened to achieve a persistence rate of 3%, with a 95% confidence level and a precision of 1%, assuming a 10% loss to follow-up ²⁴ (calculations performed using the Ene 3.0 program).

Finally, authorization was obtained from the management service of the Southern Health Area of Córdoba, and approval was granted by the Research Ethics Committee of the Reina Sofía Hospital in Córdoba (committee reference: 5051). Verbal informed consent was mandatory for participation. Data handling adhered to the European Regulation and Organic Law 3/2018 on Data Protection.

Clinical Parameters in the Prospective Studies

Standardized data, including demographic information, were collected from patient medical records. Follow-up visits were conducted between 1 and 5 times, based on the prevalence of symptoms. Symptom evaluation was performed using a validated standardized assessment through patient interviews.

Clinical data of the acute phase were collected at the first visit and post-COVID patients were stratified according to their risk of complications, differentiating between those who required hospitalization and those who did not. In addition, presence or absence of associated risk factors of persistent symptoms was considered to categorize the patient as “low, moderate or high risk” (Figure 1). ¹⁰ Subsequently to post-COVID-19 risk classification, subjects were categorized into symptomatic groups based on their manifestations: asymptomatic, for subjects who were symptom-free during the acute phase of COVID-19; acute symptoms for individuals with symptoms during the acute phase only; pre-existing manifestations for people who showed aggravation of pre-existing symptoms due to previous chronic diseases (such as migraine headaches for patients with a history of migraines); paradoxical manifestations to label those individuals who developed symptoms different from the acute phase during the follow-up; sequelae, which includes the patients with symptoms derived from acute COVID-19 infection disease; Persistent COVID-19 label was assigned to patients that experience symptoms in the acute stage of the disease and that persisted over time according to the WHO definition (28/03/23). ¹³ Subsequently, we measured the restrictions in daily life of the subjects after COVID-19, using a functional status scale of 0 to 4; where grade 0 represents no functional limitation, grade 1 indicates negligible limitation, grade 2 represents mild limitation, 3 indicates moderate limitation, and 4 represents severe functional limitation (Figure 2) (pre-COVID functional status was determined on the first visit). ²⁵

Figure 1.

Risk stratification in post-COVID-19 patients, adapted from Ref. ¹⁰

Figure 2.

Functional status scale scheme, adapted from Klok et al. ²⁵

Patients identified to have paradoxical manifestations, sequelae, or persistent COVID-19 were assigned for monitoring in follow-up visits, during which they were asked about the prevalence of each symptom and in addition we assessed their functional status. The patient’s monitoring period ended once all symptoms had been completely resolved and the last visit was registered. Lastly, a review of patients’ electronic records was conducted to determine their correlation with the interview results.

Statistical Analysis

Categorical variables were analyzed using absolute and relative frequencies, and their comparison was performed using the Chi-squared test. We assessed the normal distribution of quantitative variables using the Kolmogorov-Smirnov test, and they were described using the mean and standard deviation. Then, we review differences between data calculated for both models, using Student’s t-test. Confidence intervals were reported at the 95% level. Variate logistic regression was used to adjust for potential confounding variables and a P-value less than .05 was considered statistically significant. All data analyses were conducted using the G-Stat 2.0 statistical package.

Results

Study Population

A total of 1542 individuals with confirmed SARS-CoV-2 infection were recruited, with a mean age of 45.8 years (CI 95% = 44.93-46.66), and 55.77% were female (CI 95% = 53.25-58.28). Amount the individuals sampled, 958 (62.13%) were classified as low risk, 534 (34.63%) as moderate risk and 50 subjects (3.24%) as high risk. The number of hospitalized patients due to COVID-19 was 61 (3.96%, CI 95% = 3.04-5.05). We observed a statistically significant association between the subjects who were classified as high risk at the initial visit and a longer symptom persistence (P < .001). Significant differences were found between hospitalization and age, as well as all risk factors for developing persistent COVID-19 (P < .0001), except for transplant recipients (P = .1606). A total of 572 of the subjects studied (37.09%, CI 95% = 34.68-39.56) exhibited one or more risk factors associated to develop persistent COVID-19. The analysis of the studied risk factors indicates that advanced age is a significant risk factor, with individuals aged 60 years or older accounting for 20.36% of the cases. Cardiovascular disease shows a clear association with an increased risk of persistent COVID-19, as it was present in 15.76% of the cases studied. Amount the patients, 8.63% presented a previously known lung disease, which suggests a higher susceptibility to experience persistent symptoms in people with these types of disorders. Other comorbidities were also observed, including neurological disorders, renal disease, hepatopathy, diabetes mellitus, obesity, immunodeficiency, oncological processes, and transplant recipients. These conditions were present in different proportions, indicating their potential role as risk factors for persistent COVID-19 (Table 1). The study revealed that a precarious functional state prior to SARS-CoV-2 infection increases the increases the risk to exhibit persistent COVID-19, at 90 days and at 1 year of monitoring. Furthermore, the study showed that longer periods with persistent COVID-19 increased the loss of functional status (Figure 3).

Table 1.

Clinical Variables of the Study Population.

Variables	Number of cases (n)	Percentage %	CI 95%
Age (over 60 years)	314	20.36	18.38-22.46
Cardiovascular disease	243	15.76	13.97-17.67
Lung disease	133	8.63	7.27-10.14
Neuropsychological disorder	36	2.33	1.64-3.22
Renal disease	32	2.08	1.42-2.92
Liver disease	21	1.36	0.84-2.07
Diabetes mellitus	103	6.68	5.48-8.04
Obesity a	115	7.46	6.20-8.88
Underweigh b	1	0.06	0.02-0.36
Immunodeficiency	24	1.56	1.00-2.31
Oncological process	28	1.82	1.21-2.61
Transplant	2	0.13	0.02-0.47
Pregnancy	16	1.04	0.59-1.68
Radiological alterations	36	2.33	1.64-3.22
Respiratory insufficiency	18	1.17	0.69-1.84
Severe neurological sequelae	5	0.32	0.11-0.76
Intensive Care Unit admission	10	0.65	0.31-1.19
Invasive ventilation	4	0.26	0.07-0.66
High-flow nasal ventilation	12	0.78	0.40-1.36

Abbreviation: CI, confidence intervals.

^aObesity is defined as a body mass index ≥30.

^bUnderweigh is defined as a body mass index <18.

Figure 3.

Functional status of patients with persistent COVID-19.

*X = 90, 180, 270 and 365 periods. *Y = Quantitative average of functional status scale.

Additionally, the risk stratification study of persistent COVID-19 showed that 3.96% (CI 95% = 3.04-5.05) of the studied cases required hospitalization due to persistent COVID-19. Thus, the most cases (62.13%) were classified as low risk, followed by moderate risk (34.63%) and a reduced number classified as high risk (3.24%).

Furthermore, 236 individuals (15.30%) were still symptomatic at 28 days after the initiation of acute infection. The study of patients with persistent symptoms at the 90, 180, 270 and 365 periods was categorized into groups of asymptomatic, paradoxical, pre-existing symptoms, sequelae. Thus 191 subjects (12.39%, 95% CI 10.78-14.14), experienced persisting complaints after 90 days. In addition, 16 subjects (1.04%) experienced a paradoxical effect, 18 subjects (1.17%) developed pre-existing symptoms, and 2 subjects (0.13%) experienced sequelae (patient was mainly monitored at primary care level).

From 28 to 90 days, 85.26% of patients were asymptomatic, while 12.39% had persistent symptoms. The remaining percentages represent patients with paradoxical, pre-existing, or sequelae symptoms. At 90 to 180 days, the number of asymptomatic patients increased to 90.08%, and the ratio of patients with persistent symptoms was 8.69%. Finally, the analysis of the date between from 180 to 270 days and 270 to 365 days, showed that the ratio of patients with persistent symptoms remained relatively stable at 6.81% and 6.29%, respectively (Table 2).

Table 2.

Duration of the Persistent COVID-19 Symptoms.

Duration (in days)	Asintomático n (%)	Symptomatic group					Monitoring
		Paradoxical n (%)	Pre-existing n (%)	Sequelae n (%)	Persistent		PC n (%)	H n (%)	PC and H n (%)	Total (CI 95%)
					n (%)	(CI 95%)
28-90	1315 (85.26)	16 (1.04)	18 (1.17)	2 (0.13)	191 (12.39)	12.39 (10.78-14.14)	143 (9.27)	54 (3.50)	4 (0.26)	201 (13.03)
90-180	1389 (90.08)	12 (0.78)	6 (0.39)	1 (0.06)	134 (8.69)	8.69 (7.33-10.21)	90 (5.84)	44 (2.85)	4 (0.26)	138 (8.95)
180-270	1423 (92.28)	8 (0.52)	6 (0.39)	0 (0.00)	105 (6.81)	6.81 (5.60-8.18)	69 (4.47)	39 (2.53)	3 (0.19)	111 (7.19)
270-365	1433 (92.93)	7 (0.45)	5 (0.32)	0 (0.00)	97 (6.29)	6.29 (5.13-7.62)	64 (4.15)	32 (2.08)	1 (0.06)	97 (6.29)

Abbreviations: n, number of patients; PC, primary care; H, hospitalized patient; CI, confidence intervals.

The stratified study of the symptoms revealed that 87 subjects reported general and cardiovascular symptoms, representing 45.55% of the full patients and 74 reported respiratory symptoms (38.74%). Neuropsychological symptoms were presented for 52 individuals, representing 27.23% of the total patients. Symptoms related to sensory organs were reported by 51 subjects, which represents the 26.70% of the total, while osteoarticular symptoms were informed by 41 subjects, and dermatological symptoms by 15, (representing the 21.47% and 7.85% respectively). Lastly, digestive symptoms were indicated by 3.66% (7 subjects) of the patients studied. The most frequent symptoms reported by the 191 patients with persistent COVID-19 were fatigue, which 41.88% of the patients reported, followed by dyspnea (32.46%), anosmia/dysgeusia (20.94%) and headache (14.66%). Furthermore, the data analysis revealed that the average duration of the cardiovascular and general symptoms were the longest, with an average of 217 days. In contrast, digestive problems were the least persistent, with a mean value of 124 days. Dermatological and neuropsychological symptoms showed a high prevalence, with average durations of 216 and 199 days, respectively. Finally, symptoms associated with sensory organ, osteoarticular, and respiratory disorders had mean prevalence values of 150, 171, and 172 days, respectively (Figure 4). Table 3 provides a comprehensive overview of the remaining persistent symptoms and their evolution over time.

Figure 4.

Prevalence of the symptom clusters.

Table 3.

Overview of the Remaining Persistent Symptoms and Their Evolution Over Time.

Persistent symptoms	90 days n (%, CI 95%)	180 days n (%, CI 95%)	270 days n (%, CI 95%)	365 days n (%, CI 95%)
Cardiovascular and general symptoms
Total	87 (45.55, 38.34-52.90)	69 (36.13, 29.32-43.37)	53 (27.75, 21.53-34.67)	44 (23.04, 17.27-29.66)
Fatigue	80 (41.88, 34.80-49.22)	62 (32.46, 25.88-39.60)	49 (25.65, 19.62-32.46)	42 (21.99, 16.33-28.54)
Weight loss	8 (4.19, 1.83-8.09)	5 (2.62, 0.86-6)	1 (0.52, 0.01-2.88)	0 (0)
Other a	15 (7.85)	8 (4.19)	8 (4.19)	8 (4.19)
Respiratory symptoms
Total	74 (38.74, 31.80-46.05)	55 (28.80, 22.49-35.78)	40 (20.94, 15.40-27.41)	36 (18.45, 13.56-25.13)
Cough	31 (16.23, 11.30-22.24)	18 (9.42, 5.68-14.48)	15 (7.85, 4.46-12.62)	12 (6.28, 3.29-10.72)
Dyspnea	62 (32.46, 25.88-39.60)	49 (25.65, 19.62-32.46)	35 (18.32, 13.11-24.55)	32 (16.72, 11.75-22.82)
Wheezing	6 (3.14, 1.16-6.71)	0 (0)	0 (0)	0 0
Chest pain	8 (4.19, 1.83-8.09)	5 (2.62,0.86-6)	1 0.52 (0.01-2.88)	1 0.52 (0.01-2.88)
Other b	5 (2.62)	2 (1.05)	2 (1.05)	3 (1.57)
Sensory organ dysfunctions
Total	51 (26.70, 20.57-33.57)	41 (21.47, 15.87-27.97)	27 (14.14, 9.53-19.90)	22 (11.52, 7.36-16.92)
Odynophagia/Pharyngodynia	8 (4.19, 1.83-8.09)	5 (2.62, 0.86-6)	3 (1.57, 0.33-4.52)	1 (0.52, 0.01-2.88)
Congestion/Rhinorrhea	8 (4.19, 1.83-8.09)	10 (5.24, 2.54-9.42)	6 (3.14, 1.16-6.71)	4 (2.09, 0.57-5.28)
Anosmia/Dysgeusia	40 (20.94, 15.40-27.41)	31 (16.23, 11.30-22.24)	17 (8.90, 5.27-13.87)	15 (7.85, 4.46-12.62)
Red eye/conjunctivitis	2 (1.05, 0.13-3.73)	2 (1.05, 0.13-3.73)	2 (1.05, 0.13-3.73)	1 (0.52, 0.01-2.88)
Other c	4 (2.09)	6 (3.14)	6 (3.14)	5 (2.62)
Osteoarticular symptoms
Total	41 (21.47, 15.87-27.97)	33 (17.28, 12.20-23.40)	28 (14.66, 9.97-20.49)	24 (12.57, 8.22-18.12)
Arthralgia	27 (14.14, 9.53-19.90)	24 (12.57, 8.22-18.12)	18 (9.42, 5.68-14.48)	17 (8.90, 5.27-13.87)
Myalgia	23 (12.04, 7.79-17.52)	17 (8.90, 5.27-13.87)	13 (6.81, 3.67-11.36)	11 (5.76, 2.91-10.07)
Other d	4 (2.09)	2 (1.05)	3 (1.57)	2 (1.05)
Digestive disorders
Total	7 (3.66, 1.49-7.41)	7 (3.66, 1.49-7.41)	6 (3.14, 1.16-6.71)	5 (2.62, 0.86-6)
Abdominal pain	4 (2.09, 0.57-5.28)	3 (1.57, 0.33-4.52)	2 (1.05, 0.13-3.73)	2 (1.05, 0.13-3.73)
Nausea/vomiting,	4 (2.09, 0.57-5.28)	1 (0.52, 0.01-2.88)	1 (0.52, 0.01-2.88)	1 (0.52, 0.01-2.88)
Diarrhea	1 (0.52, 0.01-2.88)	1 (0.52, 0.01-2.88)	1 (0.52, 0.01-2.88)	0 (0)
Anorexia	1 (0.52, 0.01-2.88)	1 (0.52, 0.01-2.88)	1 (0.52, 0.01-2.88)	1 (0.52, 0.01-2.88)
Others e	5 (2.62)	4 (2.09)	4 (2.09)	3 (1.57)
Neuropsychological disorders
Total	52 (27.23, 21.05-34.12)	43 (22.51, 16.80-29.10)	36 (18.85, 13.56-25.13)	32 (16.72, 11.75-22.82)
Headache	28 (14.66, 9.97-20.49)	20 (10.47, 6.51-15.71)	18 (9.42, 5.68-14.48)	14 (7.33, 4.07-11.99)
Confusion/mental foggines	7 (3.66, 1.49-7.41)	8 (4.19, 1.83-8.09)	4 (2.09, 0.57-5.28)	4 (2.09, 0.57-5.28)
Memory loss	12 (6.28 (3.29-10.72)	11 (5.76, 2.91-10.07)	11 (5.76, 2.91-10.07)	11 (5.76, 2.91-10.07)
Loss of attention	6 (3.14, 1.16-6.71)	6 (3.14, 1.16-6.71)	5 (2.62, 0.86-6)	5 (2.62, 0.86-6)
Paresthesias	5 (2.62, 0.86-6)	2 (1.05, 0.13-3.73)	2 (1.05, 0.13-3.73)	1 (0.52, 0.01-2.88)
Dizziness	1 (0.52, 0.01-2.88)	1 (0.52, 0.01-2.88)	0 (0)	0 (0)
Sleep	8 (4.19, 1.83-8.09)	6 (3.14, 1.16-6.71)	5 (2.62, 0.86-6))	3 (1.57, 0.33-4.52)
Vertigo	0 (0)	0 (0)	0 (0)	0 (0)
Language difficulties	0 (0)	1 (0.52, 0.01-2.88)	0 (0)	0 (0)
Mood	4 (2.09, 0.57-5.28)	2 (1.05, 0.13-3.73)	3 (1.57, 0.33-4.52)	3 (1.57, 0.33-4.52)
Depression/Anxiety	13 (6.81, 3.67-11.36)	11 (5.76, 2.91-10.07)	7 (3.66, 1.49-7.41)	6 (3.14, 1.16-6.71)
Others f	3 (1.56)	1 (0.52)	1 (0.52)	1 (0.52)
Dermatological disorders
Total	15 (7.85, 4.46-12.62)	14 (7.33, 4.07-11.99)	6 (3.14, 1.16-6.71)	4 (2.09, 0.57-5.28)
Hair loss	13 (6.81, 3.67-11.36)	10 (5.24, 2.54-9.42)	4 (2.09, 0.57-5.28)	2 (1.05, 0.13-3.73)
Pruritus	1 (0.52, 0.01-2.88)	1 (0.52, 0.01-2.88)	0 (0)	0 (0)
Exanthema	2 (1.05, 0.13-3.73)	3 (1.57, 0.33-4.52)	1 (0.52, 0.01-2.88)	1 (0.52, 0.01-2.88)
Others g	2 (1.05)	2 (1.05)	2 (1.05)	2 (1.05)

^aFever, tachyarrhythmia, AIT, peripheral circulatory disturbance, menstrual disturbance.

^bDysphonia, hemoptysis, respiratory failure.

^cHearing loss, vision changes, altered temperature sensitivity.

^dIntercostal neuropathies, gait disturbance, arthritis flare-up.

^eHypertransaminasemia, rectorrhagia, GERD.

^fDemyelinating neuropathy, altered self-perception and environment.

^gPhotodermatosis, ecchymosis.

The provided data represents an analysis of the variables, including their odds ratios (OR), 95% confidence intervals (CI), and P-values. The analysis is conducted for both the crude data and the stratified data. These results indicate the odds ratios, confidence intervals, and P-values for each variable in both the raw and stratified analyses. It revealed that persistence was statistically significantly associated with age, hospitalization, neurological disease, previous immunopathology, and radiographic abnormalities after admission for COVID-19 (Table 4). In contrast, there was an association but no statistical significance with lung disease, liver disease, obesity, neurological sequelae, and respiratory failure requiring oxygen therapy as a result of COVID-19.

Table 4.

Logistic Regression Model Prevalence of the Study Population.

Variables	Raw data			Stratified
	OR	CI 95%	P-values	OR	CI 95%	P-values
Age	1.0267	1.01-1.04	.0005	1.02	1.01-1.04	.0001
Hospitalization	4.7220	1.94-11.47	.0006	4.37	1.98-9.64	.0002
Neuropsychological disorders	2.9383	1.20-7.19	.0183	3.13	1.37-7.14	.0067
Immunopathology	3.8545	1.27-11.60	.0165	4.13	1.57-10.85	.0040
Radiographic abnormalities	3.9443	1.18-1.18	.0254	4.65	1.55-13.96	.0061

Abbreviations: OR, odds ratios; CI, confidence intervals.

Discussion

The purpose of our study was described the prevalence and clinical-epidemiological characteristics of the patients with persistent symptoms after acute episode of COVID-19, who were seen in primary care. The results obtained are compared to previously reported in the literature.

Summary

We determined that 15.3% of the subjects selected for the study presented symptomatic persistence after 28 days of acute infection. The prevalence of persistent COVID-19 at 90 days was 12.4%, and it was reduced to 6.3% for a 1 year after acute infection; these results are consistent with the previous report by Perlis et al, ²⁶ where 14.7% of adults experienced different symptoms after more than 2 months from the acute COVID-19. However, our results contrast with the meta-analysis developed by O’Mahoney et al. ²⁷ It showed a prevalence of persistent COVID-19 of 45.0% in SARS-CoV-2 survivors who experienced a range of unresolved symptoms at 126 days after an acute infection, which was independent of whether the individual was hospitalized or not.

The overall mean age of subjects with persistent symptoms was 45.8 years, which is lower than described in studies conducted at the beginning of the COVID-19 pandemic,^10,28 and is close to the age reported by studies carried out in later stages of the pandemic.^3,21 This provides evidence of increased immunization of the population due to the administration of vaccines. Furthermore, our results are consistent with the idea that older individuals are more susceptible to experience persistent symptoms, ⁴ which is disagrees whit others authors, such as Romero et al, ²¹ that described a inverse relationships between symptom prevalence and age. We consider that these differences may be due to data collection for the Romero study; It was compiled through an online questionnaire, which is a more accessible format for younger individuals while in our case, the data was recorded by face-to-face or by telephonic clinical interviews.

The prevalence of symptoms based on sex has been controversial since some studies suggest a higher prevalence in females,^17,29 while other authors have reported the opposite effect.^10,14,28 In our case, a higher prevalence of 55% was observed in females, which may be due to the fact that the study was conducted in non-hospitalized patients, and males have been reported to be at higher risk of severe COVID-19, requiring hospitalization. ³⁰ Our results are consistent with the reported by Vaes et al, ³¹ and showed that pre-infection functional status plays a crucial role in symptom persistence after the acute phase. Similar to their study, we observed a substantial increase of care dependency after COVID-19 infection, for the subjects with a poorer pre-infection functionality status. However, through the follow-up visits conducted in our study, we observed an improvement in the functional scale, which was previously described by Ayuso et al. ³² These results support the theory that individuals that have shown symptom persistence and poorer functional, need special care.

Of the individuals who showed persistent symptoms after 90 days of acute infection, representing 12.39% of the total, the symptoms most frequently reported were fatigue (41.88%), which is consistent with several studies COVID-19.^3,17,21 Dyspnea (32.46%), anosmia/dysgeusia (20.94%) and headache (14.66%) were the other symptoms that appeared more frequently. After 1 year of monitoring, these symptoms disappeared in approximately one-half of the cases.^3,17,21 Although other authors have reported the nervous system as the most commonly affected (with symptoms such as brain fog, headache, cognitive impairment, or sleep disturbances, among others), ³³ the study revealed that symptoms related to the cardiovascular and general systems were the most frequently reported, while neuropsychological symptoms were not priority in our study. However, it is noteworthy that sets of neuropsychological symptoms showed longer persistence over time in comparison with other variables.

Strengths and Limitations

To the best of our knowledge, we have not been able to find similar studies conducted in primary care with such a large sample size as ours. However, in general, our results are consistent with other studies conducted outside of primary care. Furthermore, in this study, we were able to examine a substantial population over an extended period of 1 year, which allowed us to draw interesting and statistically significant conclusions regarding the frequency and persistence of the variables under investigation. Thus, the average symptom persistence was 178 days (5.95 months), which agree with date reported by Rodríguez Ledo et al ³ who conducted an online survey over a period of 3 months. The primary limitation of our work is its observational design, which precludes establishing causal relationships. Another limitation is the lack of validation for the scale used to measure pre- and post-functional status.

Conclusion

The available data suggests that more than 10% of patients who presented acute SARS-CoV-2 infection will experience long-term consequences, defined as persistent COVID-19, which are independent of the severity of the acute infection and proved to be higher among women. Patients who are particularly vulnerable to develop persistent COVID-19 are more susceptible to require hospitalization due to the severity of the acute illness, with age (>60 years) and cardiovascular disease being the prevalent risk factors.

Patients with persistent COVID-19 may exhibit manifestations affecting any body system, and may exhibit single or multiple symptoms that impact to their functional status. General, cardiovascular, and respiratory symptoms were predominant, while fatigue, dyspnea, loss of smell/taste, and headache were less frequent. Overall, these findings suggest the existence of and a relationship between poorer functional status and increased risk of persistent COVID-19, although further studies are needed to continue characterizing this condition.

Immunization is one of the most effective public health interventions, and the development of vaccination in COVID-19 has led to a shift in disease transmission. Addressing the involvement of vaccines and persistent COVID-19 would be an interesting idea for future studies.