Materials and methods

An open survey was carried out among health profes sionals of the Spanish-speaking INTRAMED social net work¹². The survey was anonymous, and the inclusion criterion was to have suffered from COVID-19 confirmed by PCR. The invitation to participate was sent through the network’s usual e-mails promoting activities and through the web page. The survey was kept open for one week (October 22 to 29, 2021) and collected sociodemographic data (age, gender, profession, work environment, coun try), date and clinical course of COVID-19, its impact on work activity (leave, return to work), the persistence of different symptoms more than one month after the initial infection and their severity, the need for consultations, diagnostic studies and new hospitalizations. Questions on a list of 21 symptoms were included: fatigue, dyspnea, cough, chest pains, palpitations or tachycardia, memory impairment, slow reasoning, concentration difficulties, anxiety, depressive symptoms, headaches, insomnia or new sleep disturbances, numbness of limbs, nausea, di arrhea, decreased appetite, joint pain-muscle pain, tin nitus, dizziness-vertigo, loss of taste and/or smell, and skin rashes¹³. For each symptom, the severity, duration and eventual persistence were asked. A subjective scale from 1 to 4 (mild, moderate, severe, very severe) was used to define the severity of most symptoms. For dyspnea, the scheme proposed by the Medical Research Council of the United Kingdom (MRC) was applied¹⁴, and for head ache, a severity scale from 1 to 10 was established. The survey also questioned about the studies performed after COVID-19 through a list that included laboratory studies, chest X-ray, electrocardiogram, echocardiogram, Holter monitoring, stress evaluations, cardiac catheterization, functional respiratory study, chest computed tomog raphy, endoscopies, cognitive studies and neurological studies.

Results

The survey had 4673 participants from 25 countries with valid responses. Gender distribu tion was 2998 females (64.2%) and 1675 males (35.8%) and mean age was 47.8 ± 11.8. Most of the professionals were physicians (n = 3080, 67.5%) or nurses (n = 525, 11.5%). A total of 701 partici pants worked in critical areas (15.3%) and 1332 in emergency services (29%). The initial episode of COVID-19 was asymptomatic in 420 respon dents (9.1%), with mild symptoms in 1701 (36.8%), moderate symptoms without hospitalization in 1886 (40.8%), moderate/severe symptoms with hospitalization in 543 (11.7%) and severe symp toms requiring respiratory support in 74 (1.6%).

Frequency and severity of symptoms

Table 1 summarize the frequency of each symptom, its severity and duration in months The first column con tains the frequency of each symptom as reported by the respondents, and the last column contains the frequency excluding symptoms with less than one month’s duration. In the group that reported appetite disturbance, the weight reduction reported in 530 cases was 5 kg (3-7) (median and interquartile range-IQR). The intensity of headache on a scale from 1 to 10 was 6 (4-7) (median and IQR).

Table 1 Frequency and severity of the different symptoms. Corrected frequency: excluding symptoms with persistence of less than one month 

Considering only severe symptoms (3-4), the most prevalent were slowness (36.3%), impaired concentra tion (33%), anosmia (20.4%), fatigue (19.1%) and impaired memory (18.1%).

Frequency of Long-COVID syndrome adjusted to the different definitions

A sub-analysis was performed on 3642 participants who reported having suffered from COVID-19 more than five months prior to the survey. The incidence of long- COVID according to the three definitions discussed in the introduction were applied (NIH: more than one month, NICE more than three months, and WHO more than three months with persistence of at least two months). Table 2.

Table 2 Frequency of symptoms corrected according to different symptom persistence criteria*. N (%) 

Number of symptoms per patient and duration

Table 1 reports the duration of each symptom in months as median and interquartile range. Figure 1 sum marizes the month-to-month evolution for each symp tomatology.

Figure 1 Reported duration in months for each symptomatology 

The median number of symptoms reported was 7 (IIC 3-10). The number of symptoms in each of the Latin American countries was variable, with medians between 3 and 9, although most countries ranged from 6 to 8, p < 0.001 (Fig. 2).

Figure 2 Distribution of the number of symptoms according to countries (excluding countries with less than 10 participants) 

The number of symptoms was related to gender: fe male, median and IQR 7 (4-11) and male, 6 (2-9), p < 0.001, and to the severity of the initial symptoms: asymptom atic (420 patients), 4 (1-8); mild course (1701 patients), 5 (2- 8); moderate course without hospitalization (1886 pa tients), 8 (5, 12); hospitalized with (74 patients) or without (542 patients) mechanical respiratory assistance require ments, 9 (6-13), p<0.001

Associations between symptoms and other variables. Relationship between the different symptoms

In the univariate analysis, the relationship of each in dividual symptom with each of the others was statistical ly significant. The odds of association with its confidence interval are summarized in the Figure 3A.

Figure 3A Association between symptoms expressed as odds ratio (colored boxes) and 95% confidence intervals (boxes below). The colors mark the intensity of the association in red, yellow to green grading. All associations were significant 

A multivariate analysis was performed for each symp tom as a dichotomous dependent variable, including each of the other symptoms, age and gender. In this analysis the symptoms tended to group into distinct syndromes (Fig. 3B). As examples: lack of appetite was associated with diarrhea, tinnitus, dizziness, anosmia and cough; depres sion was associated with anxiety and insomnia, slowness, memory problems, younger age and tinnitus; chest pain with palpitations, cough, headache, myalgia; fatigue, the most prevalent symptom, was associated with dyspnea, anxiety, depression, myalgia, memory problems and in somnia, and concentration problems were associated with slowness, memory problems and insomnia.

Figure 3B Association between symptoms in multivariate analysis. The colored boxes indicate the odds ratio and the boxes below its confidence interval. The color grading is as in the previous figure. Only significant odds ratios were included 

Requirement for consultations, new medications, leave of absence and rehabilitation

The relationship between each symptom and the requirement for consultations, new medications, reha bilitation, new hospitalizations and the initial COVID-19 course was analyzed. Each symptom was associated with a higher severity course of the initial COVID-19 episode, with the requirement for new consultations, rehabilita tion, psychotherapy and new hospitalizations, with the use of new medications and tranquilizers in particular. Table 3 summarizes as an example the relationship be tween dyspnea and the variables discussed.

Table 3 Persistent dyspnea and its relationship to initial COVID course, duration of leave, re-interventions and new medications. N(%) 

Discussion

The perception of post-COVID-19 sequelae has implications for quality of life, work capacity and demand on the health care system. In this survey of health professionals in Latin America, the frequency of the different conditions re ported was high, with frequent overlapping of symptoms (median of 7). In a survey of 6504 pa tients with confirmed or suspected COVID-19, 203 different symptoms were reported and the number of symptoms per patient was 55.9 ± 2517. Although without an exact reference to the number of symptoms, other series have had sim ilar results¹⁸. In our series, the prevalence of the number of symptoms per country was variable, which could be expected due to the epidemio logical differences by region and their multiple conditioning factors¹⁹. Although this variability was statistically significant, most countries re ported 6 to 8 symptoms per participant. As in other series, this multiplicity of symptoms was statistically associated with greater severity of the initial episode of COVID-19 and female gen der^9,17,18. Post-COVID-19 sequelae decrease with evolution, so that the prevalence of “Long- CO VID” will vary according to the adopted cut-off point in months.

Our survey was designed considering the persistence of symptomatology beyond the first month and we reported additionally the preva lence according to different cut point’s criteria. From this analysis it can be inferred that: a) half of the reported symptoms disappear within the first five months and b) a significant percent age of the surveyed population persists with symptoms, whose reported duration can also be very long, in many cases over one year, which is in agreement with other series^8,9 In the uni variate analysis each symptom was statistical ly linked to each of the other 21, but in the multivariate analysis corrected for gender and age, symptomatic “clusters” emerged: diges tive, cognitive, cardiorespiratory and neuropsy chiatric, which in turn implied differentiated complementary studies. In the referenced sur vey by Davis et al.¹⁷ which contemplated 203 symptoms, three clusters of symptom grouping were defined, although without a clear cut-off point by organic systems as those observed in our study. The most prevalent symptom in our series is fatigue, coincident with reports avail able in the literature. This symptom has been associated with that of chronic fatigue syn drome²⁰. In this condition, also called myalgic encephalomyelitis²¹, a distinct clinical feature is the so-called PEM (post-exertional malaise), an intense malaise of exhaustion after activity, a post-COVID aspect that has not been thorough ly addressed. Chronic fatigue syndrome has no clear etiopathogenesis, and a randomized study has reported that both psychotherapy and exer cise have an influence on the improvement of symptomatology²², although the validity of their results is still questioned²³. Nevertheless, reha bilitation has been proposed as a strategy for the improvement of post-COVID syndrome²⁴. The prevalence of symptoms that could be grouped as neuropsychiatric in our series was high. For reference, we compared the reported incidence of at least three-month duration with a recent meta-analysis that explored this domain in 10 530 patients²⁵. Five of the symptoms considered in our series had percentages above the 95% confidence interval of the meta-analysis (mem ory disturbances, headache, myalgia, depression and fatigue) and three were somewhat higher but within the 95% CI: (concentration-attention, anosmia and insomnia). This higher incidence in our population is more striking considering that 55% of the patients included in the meta-analy sis were hospitalized during the acute phase vs. only 12.3% in our series, and the severity of the initial condition is related to a higher incidence of all symptoms both in the meta-analysis as in our experience. It is difficult to infer whether this greater involvement is associated with the condition of health professionals in our popu lation and their particular vulnerability in this pandemic, given that there are multiple biases and confounders that we cannot rule out. Pre vious studies have reported the frequency of psychological involvement in health care work ers and its relationship with multiple symp toms²⁶, which coincides with the frequency re ported in our survey. In a study of patients who reported having suffered from COVID-19 and a control group, it was observed that the symptomatology was not related to the plasma con firmation of having had the disease, but to the belief of having suffered from it²⁷. This observa tion is more related to a subjective-emotional explanation than to an “organic” sequela. Return to work has been a major challenge during the pandemic, and has required specific policies to improve the safety of workers and prevent in fection^28,29. In Huang et al.¹⁸, it is reported that 12% of those who were employed before the dis ease had not returned to work after 12 months. The difficulty in returning to work in our series was conditioned by the greater severity of the initial symptoms, age and higher number of symptoms. This is only a modest approxima tion to the evaluation of the problem, since we lacked a personal history of other pathologies and other relevant subjective dimensions³⁰. Dif ferent reviews have discussed the complexity of the etiological interpretation of symptoms. In the case of cardiorespiratory symptoms (dys pnea, fatigue, precordial pain, palpitations), they may imply persistent pulmonary involvement, myocardial aggression³¹, autonomic dysfunc tion³², classic or microvascular angina pectoris³³, or peripheral detraining³⁴. In our series-although multiple studies were used (chest computed to mography, electrocardiogram, chest x-ray, am bulatory electrocardiographic monitoring, stress tests, and even cardiac catheterization) their application was restricted, indicating that the population that responded to the survey pos sibly did not consider that they needed supple mentary evaluations. Women participated more frequently than men in this survey and reported greater symptomatology. In an analysis of a co hort of 1969 patients, female gender was asso ciated in an adjusted manner with many more symptoms than in our series³⁵, although the population differed from ours, since they were 15 years older and in all cases had been dis charged from hospital. We do not have thorough studies on gender perspective in this syndrome.

This study is a survey performed through a social network, where the participating health professionals decide whether to answer or not. Frequently, in this type of survey, those who have symptomatology are more likely to answer, which biases towards a higher prevalence. The INTRAMED network has registered hundreds of thousands of members distributed in differ ent countries, so that although we have a large number of responses it implies an important bias and limits the possibility of establishing the real prevalence of the syndrome. Even so, the detailed report has allowed us to analyze its severity and evolution. Although COVID-19 af fects both genders indistinctly, two-thirds of the survey participants were women. The duration of symptoms may not be accurate since many participants had suffered from COVID-19 more than a year earlier. Vaccination status was not asked in order to simplify the otherwise rather lengthy questionnaire. During 2020, no vaccines were available, but in 2021, most countries in the region developed mass vaccination projects starting with the groups at greater risk, priori tizing health personnel. Although there is agree ment on the ability of vaccination to prevent infections and their serious complications, the data on the prevention of post-COVID-19 syn drome are not yet consistent.

In conclusion, our study shows the evolution of symptoms compatible with post-COVID-19 syndrome among health personnel in our region, which in many cases reached enough severity to interfere with quality of life, implying a change of job or the impossibility of recovering it. The prev alence of symptoms decreases over the months but in many cases it persists for more than a year and has required complementary studies, new medication, psychotherapy, rehabilitation and new hospitalizations. In the multivariate exami nation, symptoms could be grouped by “clusters”, which allowed discriminating cognitive, neuro psychiatric, cardiorespiratory, digestive and other conditions, which required differentiated studies and may have specific pathogenesis. Health care workers have been exposed to an extraordinary demand from the community in this pandemic, with very significant personal repercussions on their health- related quality of life and their abil ity to work, which require long-term care and protection strategies in both medical and occu pational aspects.