KEY POINTS
Current knowledge:
• COVID 19 has generated multiple sequelae, with an impact on quality of life and return to work. A particularly affected sector has been health workers, with a high rate of infections, mortality and sequelae.
Article contribution:
• It analyzes in comparative ways the different definitions of prolonged COVID to make its interpretation more precise. It provides a survey of a large number of health workers in Latin America, with an analysis by symptom and syndrome, its severity and duration, which can support policies for its prevention and containment.
The acute phase of COVID-19 can evolve in a wide variety of ways, from asymptomatic to severe multiorgan involvement. Symptoms can persist for variable periods interfering with return to work and quality of life, with an addi tional burden on the health care system1-3. Sev eral designations for persistent symptoms after the acute stage and different criteria regarding the time of persistence for diagnosis have been postulated. Initially, the National Institutes of Health (NIH) proposed to study cases that per sisted with symptoms for more than one month after the initial infection4.The UK National Insti tute for Health and Care Excellence (NICE) uses the term Long COVID to define symptoms that continue beyond the first month or appears after the initial infection, in the absence of alternative diagnoses5. It considers an acute phase up to the first month, persistence of evolving symptoms from 4 to 12 weeks, and post COVID syndrome after 12 weeks from the initial episode. In turn, the World Health Organization (WHO) has defined post-COVID-19 condition as persistence of symptoms beyond three months, continuing for at least two more months and not explained by other pre-existing illness6. Reported symp toms involve various systems and domains, with a higher prevalence of functional mobility problems, respiratory abnormalities and men tal health disorders, an incidence of more than 50% in some series, and variable duration, which may extend to more than one year7-9. In an anal ysis of large administrative databases of US Vet erans, patients who experienced COVID-19, even without hospitalization compared with a simi lar control group, had a marked excess of mul tiple pathologies and medication use during the subsequent six months10.
The pandemic had a major impact on health care personnel, who were under great strain at work and had a high rate of infection. According to WHO data, infection rates among health care workers exceed those of the general popula tion11. Fourteen percent of the positive tests be long to workers in this sector, and in some coun tries, the figure rises to 35%. Several studies have reported the prevalence of post-COVID-19 syn drome in health care workers and its occupa tional repercussions in different regions of the world, which are summarized in the Appendix, but we lack information on Latin America. The aim of our study was to evaluate the severity and duration of different post-COVID-19 symp tomatology through a survey carried out in a social network of Latin-American health profes sionals who had suffered a confirmed episode of COVID-19. By obtaining 4673 valid responses, we believe that our study provides relevant in formation for the interpretation of post-COVID sequelae.
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.
Analysis of prevalence according to definitions
Some participants reported that the symptoms had not actually lasted more than one month since the CO VID-19 episode, and therefore did not meet the defined long-COVID criteria. For a better interpretation, we sum marized in a table the prevalence initially reported by the respondents and then the corrected prevalence, ex cluding cases that reported symptom duration of less than one month. In a post-hoc analysis, we explored the prevalence of each symptom according to the different definitions described in the introduction (more than one month, more than three months, and more than three months with persistence of at least two months) in a sub group of 3642 patients with more than 5 months since the episode of COVID-195-7.
Ethical considerations
Participants gave their consent by answering the questionnaire. The Hospital El Cruce IRB (resolution 0117) granted ethical approval. Survey responses were anonymous. All study procedures were carried out in accordance with international ethical norms and stan dards through defined operating procedures to respect the rights of the participants and protect confidentiality. Before starting the questionnaire, the participants were given information about the objectives of the study and the voluntary and anonymous nature of the survey. No records were generated that would allow the personal identification of the participants.
Statistical analysis
Quantitative variables were reported as mean/stan dard deviation or median/interquartile ranges (IQR) ac cording to their distribution. Discrete variables were reported as number and percentage, with their 95% con fidence intervals (95% CI). The analysis of the association between discrete variables was performed with contin gency tables, and their p level, odds ratio and confidence intervals were established. The comparative analysis of quantitative variables was performed with parametric or nonparametric methods according to their distribution. For the analysis of variables related to the lack of return to work, a logistic regression analysis was performed selecting those with a significant association in the univariate analysis, with a p level < 0.05. The association of symptoms corrected for age and gender was evaluated in multivariate models. A second multivariate analysis adjusted for symptom severity was performed; for this analysis, level 3-4 of each symptom was considered as severe, and for headaches, an intensity of 6 or more. The R (version 4.2.1)15 program and R Studio (version R Studio- 2022.07.1-554)16 were used for the analysis.
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%).
Need to modify the working area and return to work
Post-COVID-19, 738 respondents out of 4618 (16%) reported requiring a modification of the work area. This change was related to the severity of the initial symp toms: in asymptomatic or with mild symptom cases it was 12% and 11.5% respectively, in moderate cases with out hospitalization 18%, and in hospitalized patients 25% (p < 0.0001). Total recovery of activity was reported by 3537 patients (76.6%), almost total by 720 (15.6%), only partial by 263 (5.7%) and not recovered by 97 (2.1%), out of a total of 4617 valid responses. We grouped responses indicat ing no recovery or partial recovery as dichotomous data of lack of recovery, and performed a logistic regression analysis including gender, age, number of symptoms, and severity of the initial episode. Variables independently as sociated with lack of recovery from work were age with odds ratio (OR) 1.03 (95% CI 1.02-1.04; p < 0.001) per year, number of symptoms (OR 1.22, 95% CI 1.19-1.25; p < 0.001) per additional symptom, overall hospitalization (OR 1.9, 95% CI 1.1-3.6; p = 0.025), and hospitalization with re quirement of mechanical ventilation (OR 3.2, 95% CI 1.4-7; p < 0.001). Sex was not significantly associated (female OR 0.97; 95% CI 0.74-1.25; p = 0.802)).
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).
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.
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.
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).
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.
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.
Relationship with age
In the univariate analysis of the 21 symptoms ex plored, 7 had no differences by age, 6 were associated with younger ages and 8 with older ages. Although in 15 symptoms the differences by age were statistically signif icant, the difference between the presence and absence of the symptom was not greater than 2.5 years between the groups. In the multivariate analysis corrected for gen der and symptom severity, four symptoms were associat ed with younger age and none with older age: headache, OR per year of age 0.97 (95% CI 0.96-0.98); insomnia, OR 0.97 (0.96-0.98); anosmia, OR 0.98 (0.97-0.99) and depres sion 0.98 (0.96-0.99).
Relationship with gender
The majority of the survey participants were female, 64%. In the univariate analysis, female gender was as sociated with higher reporting of 19 of the 21 symptoms questioned, with two exceptions: appetite impairment and diarrhea, which were similar in both genders. Age was higher in the male group (51.6 ± 13) than in females (46 ± 11.5), p < 0.001.
Requirement for complementary studies
The reported frequency of use of 11 complementary studies was: chest x-ray 860 (18.4%), laboratory tests 1265 (27%), echocardiogram 695 (14.9%), chest CT 622 (13.3%), spirometry 423 (9.1%), ambulatory electrocardiographic monitoring 268 (5.7%), stress evaluations 296 (6.3%), car diac catheterization 14 (0.3%), digestive endoscopies 88 (1.9%), cognitive studies 126 (2.7%) and neurological stud ies 214 (4.6%).
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.
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 der9,17,18. 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 series8,9 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 fection28,29. 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.