An observational multi-centric COVID-19 sequelae study among health care workers

Summary

Background

India has seen more than 43 million confirmed cases of COVID-19 as of April 2022, with a recovery rate of 98.8%, resulting in a large section of the population including the healthcare workers (HCWs), susceptible to develop post COVID sequelae. This study was carried out to assess the nature and prevalence of medical sequelae following COVID-19 infection, and risk factors, if any.

Methods

This was an observational, multicenter cross-sectional study conducted at eight tertiary care centers. The consenting participants were HCWs between 12 and 52 weeks post discharge after COVID-19 infection. Data on demographics, medical history, clinical features of COVID-19 and various symptoms of COVID sequelae was collected through specific questionnaire.

Finding

Mean age of the 679 eligible participants was 31.49 ± 9.54 years. The overall prevalence of COVID sequelae was 30.34%, with fatigue (11.5%) being the most common followed by insomnia (8.5%), difficulty in breathing during activity (6%) and pain in joints (5%). The odds of having any sequelae were significantly higher among participants who had moderate to severe COVID-19 (OR 6.51; 95% CI 3.46–12.23) and lower among males (OR 0.55; 95% CI 0.39–0.76). Besides these, other predictors for having sequelae were age (≥45 years), presence of any comorbidity (especially hypertension and asthma), category of HCW (non-doctors vs doctors) and hospitalisation due to COVID-19.

Interpretation

Approximately one-third of the participants experienced COVID sequelae. Severity of COVID illness, female gender, advanced age, co-morbidity were significant risk factors for COVID sequelae.

Funding

This work is a part of Indian Council for Medical Research (ICMR)- Rational Use of Medicines network. No additional financial support was received from ICMR to carry out the work, for study materials, medical writing, and APC.

Research in context.

Evidence before this study

During the COVID-19 pandemic population of India was widely inflicted. These sections of population are susceptible to develop COVID-19 sequelae. Prior data on COVID sequelae in Indian population are limited. It has been observed that majority of the symptoms of the COVID sequelae are under-reported. High quality evidence for the duration of COVID sequelae are also lacking.

Added value of this study

The study highlights the prevalence of COVID sequelae in the specific subset of healthcare workers among the Indian population. The study describes sequelae among COVID survivors who have various categories of risk factors. The study highlights the pattern of symptoms most commonly seen as COVID sequelae including general symptoms and system wise presentations. It is also attempted to evaluate association of such symptoms with various demographic and medical characteristics of the participants.

Implications of all the available evidence

The study results will aid in conducting the screening programmes and specialized outpatient clinics for the assessment of COVID sequelae. These can be developed primarily to focus on the sub-section of the population having higher risk to have COVID sequelae. To combat under-reporting of the symptoms, these programmes and clinics can stress on eliciting the symptoms based on the common pattern of symptoms in COVID sequelae.

Introduction

On March 11, 2020, Coronavirus disease 19 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was declared a pandemic by World Health Organization (WHO).¹ A number of those affected continue to suffer from long term effects of COVID which have been termed variously as COVID sequelae, post COVID symptoms, or post COVID condition.2, 3, 4 In India alone, 43, 045, 527 confirmed cases have been discharged as on April 19, 2022 with a recovery percentage of 98.8%,⁵ indicating that a large section of the population is susceptible to develop COVID sequelae.

The Government of India has issued guidelines for the management of post COVID complications affecting different systems of the body,⁶ and outpatient department services are being provided in various parts of India.^7,8

A questionnaire-based study in China in 538 COVID-19 survivors reported general symptoms (49% of patients), symptoms related to the respiratory (39%), and cardiovascular system (13%), and psychosocial symptoms (22.7%) as the most frequent sequelae three months after discharge.² Many other studies in different settings have found the prevalence of post-COVID sequelae from 49% to 76%.9, 10, 11, 12, 13 However, while health care workers (HCWs) are most liable to get exposed to this infection, to the best of our knowledge, no study has been reported from India to assess COVID-19 sequelae among HCWs. The post COVID sequelae by their very nature could effect on job performance which is especially important for HCWs. The Indian Council Medical Research (ICMR) recommended hydroxychloroquine (HCQ) for prophylaxis among asymptomatic (HCWs) involved in the care of COVID-19 cases.¹⁴ The effect of HCQ prophylaxis on the incidence of COVID sequelae also remains to be assessed.

This study was thus carried out to explore the COVID-19 sequelae and associated risk factors among HCWs. We planned to assess the nature and prevalence of medical sequelae following COVID-19 infection, as well as the association of COVID-19 manifestations and other risk factors with the COVID sequelae.

Methods

This multi-centric cross-sectional study was conducted at eight tertiary care hospitals associated with Indian Council of Medical Research (ICMR) Rational Use of Medicine Centers (RUMCs) across India between July and October 2021 with the primary objective of assessing the nature and prevalence of post-COVID-19 sequelae along with the associated risk factors 12–52 weeks post-recovery following COVID-19 infection amongst health care workers (HCWs). All the sites obtained approval from their Institutional Ethics Committees to conduct the study. The study was registered at The Clinical Trials Registry- India (CTRI) with CTRI no. CTRI/2021/06/034255.

Any newly occurring or remaining symptoms or signs in COVID-19 patients after 3 months (12 weeks) of discharge from the hospital (or declared discharged in case of non-hospitalized patients) were defined as sequelae in our study as reported by Xiong Q et al. from China.² In the guidelines issued by National Institute for Health and Clinical Excellence (NICE), in collaboration with the Scottish Intercollegiate Guidelines Network and the Royal College of General Practitioners, the post COVID-19 syndrome has been defined as symptoms and signs that develop during or after an infection with COVID-19 and continue for more than 12 weeks and cannot be explained by any other diagnosis.³ World Health Organization (WHO) has defined post COVID-19 condition as symptoms that occur after 3 months of onset of COVID-19 which persist for at least 2 months and cannot be explained by an alternative diagnosis.⁴ As this study was planned before the above guidelines were issued, we have adopted the available definition of COVID sequelae for the study as mentioned above.² By default any patient with COVID sequelae as defined in our study also fulfilled the post COVID-19 syndrome definition of NICE guidelines.

The consenting participants included doctors, nurses, paramedical and ancillary staff with COVID-19 (confirmed SARS-CoV-2 positivity on RT-PCR) along with asymptomatic cases, who recovered (were declared ‘discharged’) as per national guidelines between 12 and 52 weeks post COVID-19 infection.¹⁵ Eligible HCWs were identified from a previous study database of this research group for the assessment of HCQ prophylaxis among HCWs,¹⁶ as well as any other available institutional database. HCWs with any serious co-morbid medical or mental health condition and pregnant women were excluded as many of the sequelae under assessment are commonly seen as presentations of these conditions.

Eligible HCWs were approached telephonically initially by trained research staff which included doctors and non-doctors. Upon receiving written consent, a structured interview was administered and responses collected. In the case record form, the demographic details, medical history, COVID-19 treatment details, details of investigations, and information regarding the general and system-wise sequelae symptoms were collected by the researcher while the participants were encouraged to self-administer the Depression, Anxiety, and Stress Scale-21 (DASS21) questionnaire and the modified sleep disorders questionnaire.¹⁷ In case participants found it difficult to self-administer any of the questionnaire, they were assisted by the investigators.

The sample size to find the prevalence of COVID-19 sequelae with a 95 percent confidence interval and a precision of 2.5 percent was calculated to be 292, assuming a prevalence of the least prevalent medical sequelae of COVID-19 of 5%. The sample size for identifying an independent variable as the risk factor, with an anticipated odds ratio of 1.3, a conventional two-tailed test, with power and alpha at 80% and 5%, respectively, were found to be 557 at a probability of occurrence rate of 0.3 for the outcome variable. Hence the sample size of 557 was considered for the study.

Statistical analysis

Clinical and demographic data were categorized and expressed as mean (±standard deviation) and percentage, respectively. Medical sequelae prevalence was reported in percentages and proportions. Odds ratios with a 95% confidence interval were calculated, along with p values using chi-square test in order to measure the association of medical sequelae with risk factors. Simple logistic regression was done using IBM SPSS version 28. A comparison was done between HCWs who received HCQ prophylaxis and those who did not receive HCQ prophylaxis, in terms of the occurrence of medical sequelae following COVID-19 infection. A subgroup analysis was carried out between HCWs who recovered within 12–24 weeks and HCWs who recovered between >24 and 52 weeks.

Role of the funding source

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Results

Site and participant characteristics

Out of 1223 HCWs with confirmed COVID-19 who were contacted, 928 participated (75.88%), with similar response rate between centres. The reasons for not participating could not be ascertained individually, but the common reasons as reported by the sites were hectic work schedule, unwilling to participate, change in place of posting or lengthy case report form. Out of the 928 participating HCWs, 249 were excluded for not fulfilling the inclusion criteria (as per the protocol, HCWs who recovered from COVID between 12 and 52 weeks were to be recruited for the sequelae study. 34 participants were recruited <12 weeks post recovery and 215 participants were recruited >52 weeks post recovery from COVID-19 respectively. Thus, a total of 679 eligible HCWs from eight sites were included in the final analysis. Of them, there were 270 doctors (39.76%), 181 nurses (26.66%) and the rest were other categories (hospital staff: 103, lab attendant/technician: 39, administrative staff: 30, research staff: 18, hospital attendant & security: 13 each, housekeeping: 12).

Table 1 summarizes the demographic and clinical status of the participants. The mean age of the participants was 31.49 ± 9.54 years and almost an equal proportion of male and female HCWs participated. At least one comorbidity was reported by 90 HCWs (13.25%), among which hypertension was the most common (5.74%) followed by diabetes and asthma.

Table 1.

Baseline characteristics and co-morbidity status of study participants.

Characteristic	Category	Frequency (%) (N = 679)
Age	<45 years	596 (87.78)
	≥45 years	83 (12.22)
Gender	Male	334 (49.19)
	Female	345 (50.81)
Body mass index (BMI)	Overweight/obese (≥25 kg/m2)	235 (34.61)
	Non-obese (<25 kg/m2)	444 (65.39)
Designation	Doctors (including interns)	270 (39.76)
	Nursing staff	181 (26.66)
	Other staff	228 (33.58)
Smoking	Never smoked	615 (90.57)
	Current smoker	39 (5.74)
	Former smoker	25 (3.68)
Alcohol	Lifetime abstainer	545 (80.27)
	Current drinker	113 (16.64)
	Former drinker	21 (3.09)
Co-morbidity	Hypertension	39 (5.74)
	Diabetes	25 (3.68)
	Asthma	21 (3.09)
	Heart Failure	1 (0.15)
	Othersa	53 (7.81)
Presence of co-morbidities	Any 1 co-morbidity	90 (13.25)
	Any 2 co-morbidities	13 (1.91)
	Any ≥3 co-morbidities	7 (1.03)

^aOthers include Hypothyroidism: 16; thyroid: 8; cardiac diseases (CAD, bicuspid aortic valve, RHD): 5; migraine & tuberculosis: 3 each; ankylosing spondylitis, PCOS, hyperlipidaemia, migraine, sinusitis: 2 each; anemia, anxiety, arthritis, carcinoma colon, cholesterol, dermatitis, epilepsy, fatty liver, GERD, lichen plannus, pericarditis, pleural effusion, POLG (progressive external ophthalmoplegia-mutation in POLG gene), reactive arthritis, recurrent allergies, rheumatoid arthritis, right bundle branch block, sickle cell trait: 1 each.

COVID-19 and related characteristics

As shown in Table 2, ∼90% of the participants had received a dose of COVID-19 vaccine (74.82% received Covishield and 14.28% Covaxin), with more than 70% having taken two doses. Only a small proportion (11.2%) had taken chemoprophylaxis with HCQ. Majority of the participants reported suffering from mild COVID-19 (73.9%), whereas 18.4% had asymptomatic infection. A very small proportion (2.06%) reported to have had COVID-19 a second time.

Table 2.

Prophylaxis, vaccination, and COVID-19 status of study participants.

Characteristic	Category	Frequency (%) (N = 679)
HCQ prophylaxis taken	Yes	76 (11.19)
	No	603 (88.81)
Duration of HCQ prophylaxis	<1–2 weeks	15 (2.21)
	3–6 weeks	26 (3.83)
	≥7 weeks	35 (5.15)
Vaccination (irrespective whether the participant had COVID-19 exposure or not)	One dose taken	118 (17.38)
	Both the dose taken	487 (71.72)
	No vaccine dose taken	74 (10.90)
Name of vaccine taken	Covishield	508 (74.82)
	Covaxin	97 (14.28)
COVID-19 status	Symptomatic	554 (81.59)
	Asymptomatic	125 (19.41)
Severity of COVID-1918	Mild	502 (73.93)
	Moderate	48 (7.07)
	Severe	4 (0.59)
2nd episode of COVID-19	Yes	14 (2.06)
	No	665 (97.94)
Hospitalisation due to COVID-19	Yes	310 (45.66)
	No	369 (54.34)
Hospitalisation duration	≥10 days	139 (20.47)
	<10 days	171 (25.18)

Prevalence and pattern of COVID-19 sequelae

Out of the 679 participants, 206 HCWs reported having suffered from at least one of the assessed medical sequelae giving an overall prevalence of 30.34%. Out of these, 7.51% participants had 2 sequelae and 9.72% had 3 or more sequelae. The detailed pattern of COVID-19 sequelae reported by participants, with their prevalence, is displayed in Table 3.

Table 3.

Prevalence of COVID-19 sequelae among study participants.

Characteristic	Symptom/sequelae	Prevalence n (%)
HCWs with any sequelae (one or more)		206 (30.34)
HCWs with one sequelae		89 (13.11)
HCWs with two sequelae		51 (7.51)
HCWs with three or more sequelae		66 (9.72)
General symptoms	Has any of the symptoms	174 (25.63)
	Fatigue	78 (11.49)
	Pain in joints	34 (5.01)
	Soreness in muscles	30 (4.42)
	Fever	19 (2.80)
Cardiovascular-Respiratory symptoms	Has any of the symptoms	120 (17.67)
	Difficulty in breathing while doing any physical activity	41 (6.04)
	Cough	31 (4.57)
	Tightness in chest	15 (2.21)
	Throat Pain	14 (2.06)
	Difficulty in breathing while at rest	11 (1.62)
	Sensation of irregular or fast heartbeat	8 (1.18)
Gastrointestinal symptoms	Has any of the symptoms	26 (3.83)
	Reduced Appetite	9 (1.33)
	Nausea	7 (1.03)
	Diarrhoea	6 (0.88)
	Abdominal pain	4 (0.59)
ENT symptoms	Has any of the symptoms	18 (2.65)
	Sore throat	13 (1.91)
	Pain in the ear	3 (0.44)
	Ringing sensation in ears	2 (0.29)
Neuro-psychiatric symptoms	Has any of the symptoms	228 (33.57)
	Headache	31 (4.57)
	Loss of smell	31 (4.57)
	Loss of taste	27 (3.98)
	Difficulty in concentrating	14 (2.06)
	Difficulty to focus on the usual things	12 (1.77)
	Forgetting things easily	11 (1.62)
	Pins & needles sensation or numbness in hands or feet	7 (1.03)
	Difficulty in thinking clearly or getting anything done	5 (0.74)
	Sleep disorder (Insomnia)	58 (8.54)
	Depression	9 (1.33)
	Stress	7 (1.03)
	Anxiety	1 (0.15)
Dermatological symptoms	Skin rash	7 (1.03)

Fatigue (11.5%) and sleep disorder (insomnia) (8.5%) were the most common sequelae suffered by the participants. Difficulty in breathing while doing any physical activity (6%) and pain in joints (5%) were the next most commonly reported sequelae. Other relatively common general sequelae were soreness in muscles (4.4%) and fever (2.8%). Among system-wise sequelae, the most common were cough, headache, loss of smell (4.6% each respectively), loss of taste (4%), sore throat (1.91%), reduced appetite (1.33%) and skin rash (1%) in the different systems. It was also seen that depression and stress were seen in 1.3% and 1% HCWs respectively.

Among participants with multiple sequelae, fatigue and difficulty in breathing while doing physical activity or insomnia (3.4% each) were the sequelae most commonly seen together followed by fatigue and pain in joints (3%), and insomnia and headache (2.4%) (Supplementary Table S1).

Association of COVID-19 manifestations and other risk factors with sequelae

Upon calculation of odds ratio to assess association of various demographic, clinical and COVID-19 parameters, deemed as possible risk factors, with the occurrence of medical sequelae among the participants, it was found that the odds of having sequelae were most significantly higher if the participant had moderate—severe COVID-19 (OR 6.51; 95% CI 3.46–12.23).

As depicted in Table 4 (and Supplementary Table S2), in the univariate analysis, the odds of suffering from a post COVID sequelae were also significantly higher among HCWs ≥ 45 years of age (OR 2.03; 95% CI 1.27–3.25), those who had any comorbidity (OR 2.01); more specifically in those who had asthma (OR 2.61) and hypertension (OR 2.06). In contrast, the odds of having sequelae were found to be significantly lesser among males (OR 0.55) and among doctors as well as doctors and nursing staff as a combined group compared to other HCWs (OR 0.65 and 0.70 respectively).

Table 4.

Association of various risk factors with COVID-19 sequelae among study participants.

Risk factors	HCWs having any sequelae	HCWs not having any sequelae	Category wise prevalence of sequelae (%)	Odds ratio; (95% CI)	p-value
Gender
Male	80	254	23.95	0.55; (0.39–0.76)	0.00036
Female	126	219	36.52
Age (yrs)
Age ≥45	37	46	44.58	2.03; (1.27–3.25)	0.0025
Age <45	169	427	28.36
Obesity
Overweight/Obese (BMI ≥25 kg/m2)	78	157	33.19	1.23; (0.87–1.72)	0.239
Non-obese (BMI <25 kg/m2)	128	316	28.83
Occupation
Doctors	66	204	24.44	0.65; (0.44–0.88)	0.0069
Nurses & other HCWs	140	269	34.23
Doctors & Nurses	125	326	27.72	0.7; (0.49–0.98)	0.0037
Other HCWs	81	147	35.53
Co-morbidities
Any co-morbidity present	48	62	43.64	2.01; (1.32–3.06)	<0.0011
Any co-morbidity absent	158	411	27.77
Diabetes present	11	14	44.00	1.85; (0.82–4.15)	0.135
Diabetes absent	195	459	29.82
Asthma present	11	10	52.38	2.61; (1.09–6.25)	0.031
Asthma absent	195	463	29.64
Hypertension present	18	21	46.15	2.06; (1.07–3.96)	0.029
Hypertension absent	188	452	29.38
Prophylaxis and Vaccination
HCQ prophylaxis taken	22	54	28.95	0.93; (0.55–1.57)	0.779
HCQ prophylaxis not taken	184	419	30.51
Vaccinated with at least 1 dose	181	424	29.92	0.84; (0.50–1.40)	0.495
Not vaccinated with any dose	25	49	33.78
COVID-19 severity
Symptomatic COVID-19	175	379	31.59	1.4; (0.90–2.18)	0.137
Asymptomatic COVID-19	31	94	24.80
Moderate—severe COVID-19	37	15	71.15	6.51; (3.46–12.23)	<0.0001
Mild COVID-19	138	364	27.49

There was no significant change in the odds of having post COVID-19 sequelae due to preventive chemoprophylaxis with HCQ or vaccination (one or two doses) or due to hospitalisation for COVID-19 or having symptomatic infection. Similarly, other factors such as obesity, smoking or alcohol intake, presence of diabetes, or blood group also did not significantly increase the odds of having sequelae.

Upon assessing association of the various factors with the commonly seen COVID sequelae individually (Supplementary Table S3), it was found that moderate-severe COVID-19 remained a risk factor for most of the common sequelae other than loss of taste and smell, whereas presence of any comorbidity, hypertension and being doctors did not remain significant predictors for most of the sequelae. Age ≥45 years and female gender remained significant predictors for some sequelae but not for others like sleep disorder, soreness in muscles.

Similarly, assessment of association of COVID sequelae with multiple comorbidities and other risk factors showed that the odds of having sequelae were higher in participants who had multiple comorbidities together, significantly among those with both hypertension and diabetes (Supplementary Table S4). Number of participants with concurrent multiple comorbidities and risk factors such as drinking and smoking were however quite low, making the analysis non-conclusive.

Logistic regression analysis

Taking into account the odds ratios obtained for various factors, a multivariate logistic regression analysis was performed to assess the strength of association of significant risk factors with the occurrence of sequelae. A forward stepwise approach was used and a regression model was developed that showed overall significance (p < 0.001). Table 5 displays the variables in the final regression model with the adjusted odds ratio. Moderate—Severe COVID remained an independent predictor for risk of having COVID sequelae (adjusted OR 5.83; 95% CI 3.05–11.14) and male gender was a protective factor (adjusted OR 0.56; 95% CI 0.4–0.8).

Table 5.

Multivariate logistic regression analysis for associated risk factors.

Variable	Adjusted odds ratio; p value	95% CI for adjusted odds ratio
Age	1.362; 0.278	0.780–2.377
Gender (Male vs Female)	0.560; 0.001	0.395–0.795
Doctors vs Other HCWs	0.745; 0.115	0.516–1.074
Presence any co-morbidity (Yes vs No)	1.447; 0.136	0.890–2.351
COVID Severity (Moderate-Severe vs Mild)	5.832; <0.001	3.054–11.139
Constant	0.000; <0.001	−

The regression equation obtained was: Log (p/1-p) odds of COVID sequelae = −0.695 + 1.763∗COVID severity − 0.580∗Male gender.

Subgroup analysis according to time of participation post COVID-19

A pre-specified subgroup analysis was conducted by categorising the participants according to the time of their participation in the study as 12–24 weeks and >24–52 weeks post recovery from COVID-19 (See Supplementary Tables).

There were no significant differences in the subgroups in demographic characteristics except for drinking status—lifetime abstainer/former drinker, but some differences were seen in the proportion of participants having taken HCQ prophylaxis or both doses of vaccine (higher in the >24–52 weeks’ subgroup), as well as type of vaccine taken - covishield or covaxin. (Supplementary Tables S5 and S6).

In terms of the post COVID-19 sequelae suffered, there were some significant differences in the prevalence of symptoms such as soreness in muscles, fever, headache, loss of taste which were all seen to be more prevalent in the participants who participated between 12 and 24 weeks of COVID-19 recovery. Prevalence of other symptoms was not significantly different in the two subgroups (Supplementary Table S7).

Moderate-severe COVID-19 remained a significant risk factor for occurrence of sequelae in both subgroups. Results showed that odds of having a COVID-19 sequelae remained lower with male gender and higher with age ≥45 respectively in both the subgroups of participants but statistical significance was retained for the >24–52 weeks' subgroup only whereas odds of sequelae were significantly reduced for doctors with/out nursing staff for the 12–24 weeks' subgroup only. In case of comorbidities, the odds with presence of any comorbidity and asthma remained significantly elevated for the >24–52 weeks' subgroup, but hypertension did not remain a significant predictor for occurrence of sequelae in either of the subgroups. Rest of the results remained in congruence with those obtained in the overall analysis (Supplementary Table S8).

Ancillary analysis

The drugs most commonly used for management of COVID-19 among the participants were vitamin supplements (in all prescriptions), paracetamol (69.66%), azithromycin (44.18%), levocetirizine (14.14%), ivermectin (11.93%) and doxycycline (10.16%) (Supplementary Table S9). The symptoms most commonly reported by participants at the time of having COVID were cough (15.76%), myalgia (13.99%), headache (11.49%), fatigue/weakness (9.87%) and sore throat (8.1%) (Supplementary Table S10).

Among the 504 HCWs who received 1st dose of Covishield vaccine, the most common adverse events (AEs) seen were fever (53.97%), body ache (43.06%), injection site tenderness/pain/warmth (35.91%), headache (23.02%) and myalgia (18.65%). Similar AEs were seen with the 2nd dose of the vaccine as well, but in much lesser proportions (Supplementary Table S11). Similarly, the common AEs reported by participants who received the 1st or 2nd doses of Covaxin were fever, injection site tenderness/pain/warmth, and general body ache; by proportionately fewer HCWs than those receiving Covishield.

Discussion

In this cross-sectional study in 679 confirmed COVID-19 (hospitalized and non-hospitalized) health care workers, the prevalence of COVID sequelae was found to be 30.34% after 12–52 weeks of their discharge. Other studies which included both hospitalized and non-hospitalized COVID-19 patients, reported prevalence rates of COVID sequelae between 30% and 64%^9,13,19,20 while studies that included hospitalized patients only, reported comparatively higher prevalence rates ranging from 49% to 87.4%.^2,21, 22, 23 Consistent with the findings of our study, the most common overall symptoms were general symptoms followed by neuropsychiatric and cardio-respiratory symptoms,^{2,19,21,23,24} while fatigue, sleep disorder, difficulty in breathing while doing any physical activity, pain in joints, and loss of smell, and headache were the most commonly reported individual symptoms.^2,9,19,22, 23, 24 All these symptoms have been included in the various guidelines for managing the long-term effects of COVID-19.^3,4,6 In a multinational online survey in 3762 participants, for more than 91% of the patients the recovery time was more than six months. The most common reported symptoms after six months were fatigue, post-exertional malaise, and cognitive dysfunction. There were 203 symptoms reported across ten organ systems. Patients had multisystem involvement for more than seven months.²⁵ The difference in the study results of this study from our study can be attributed to the different study populations and study settings.

Guidelines issued by the MOHFW (Ministry of Health and Family Welfare, Government of India) also mentioned fatigue as the most common COVID sequel. Cardiovascular, neurological, and nephrological components have been implicated for causing fatigue. Among symptoms due to cardiovascular system involvement in long COVID, myocardial involvement has been implicated in 20–30% of hospitalized patients who have been affected by severe COVID. Cardiomyocyte damage, thrombosis, microvascular dysfunction, and cytokine storm have been implicated as the cause of myocardial injury. Shortness of breath, dry cough, and chest pain are the most common respiratory sequelae among COVID-19 patients. Fatigue, changes in concentration, impaired memory, myalgias, headaches, sleep disorders, dizziness, anosmia, and ageusia are the most commonly reported neurological sequelae. Reactivation of latent SARS CoV-2 in the central nervous system has been suggested to be responsible for these neurological sequelae.⁶

The odds of having COVID sequelae were found significantly higher in females as compared to males, both in ours and several other studies.^2,24,26,27 A study in 180 COVID-19 patients found no association between COVID sequelae with gender or co-morbidity.⁹ This can be attributed to the smaller sample size of the study. In particular, fatigue, cough, loss of smell, loss of taste, and headache were found to be significantly more common in females than in males.^2,23,28 The odds of having COVID sequelae were found to be significantly higher in participants 45 years or older as compared to their younger counterparts. This is consistent with the finding of a longitudinal study in COVID-19 (both non-hospitalized & hospitalized) survivors, wherein sequelae of COVID-19 were found to be more prevalent with advanced age.^20,26,27

We also found an association between persistent COVID-19 symptoms with hospitalisation.

However, in adjusted models, this association was no longer statistically significant, implying that the association was related to a higher prevalence of co-morbidity, severe illness, and older age among hospitalized patient groups.

Similar to our study, previous studies have reported higher odds of having COVID sequelae in participants with comorbidity.^20,29 Similarly, the odds of having COVID sequelae were found to be significantly higher in participants who had severe or moderately severe COVID as compared to the participants who had mild COVID. In a prospective cohort study in adult COVID-19 patients, vaccination was not found to improve symptoms of post-acute sequelae of COVID-19.³⁰ A retrospective cohort study in HCWs, high BMI and previous pulmonary disease was found to be a risk factor for 35-day long-COVID characteristics.³¹ A multicentric retrospective cohort study in HCWs found that higher antibody titres were associated with decreased risk of SARS-CoV-2 breakthrough infections.³²

Interestingly, we found that doctors and nursing staff were at lower risk for COVID sequelae than ancillary staff, although the reasons for this difference are not clear. On the other hand, no significant difference was found in the odds of having COVID sequelae with respect to HCQ prophylaxis.

There have been multiple potential mechanisms proposed for the development of COVID sequelae. These include direct viral invasion via ACE2 receptors, hidden viral reservoirs, immune and inflammatory disturbances, altered microbiome, imbalance in the renin-angiotensin system, and abnormal metabolism and mitochondrial dysfunction.³² Which of these particular mechanisms is responsible for the development of the specific sequelae remains to be explored. Abnormal immunometabolism and mitochondrial dysfunction could be responsible for fatigue³³ while residual reservoir of the virus may lead to loss of smell and taste.³⁴

The role of health care workers during the period of COVID-19 pandemic cannot be undermined. COVID-19 pandemic has not only exposed HCWs to unprecedented levels of risk but also to the higher levels of stress due to the increased work pressure. The incidence of COVID sequelae among HCWs will affect their performance on the long term and consequently will have impact on health care settings.

Due to the insufficient understanding and data on COVID sequelae, there is a lack of research on management, including self-management practices among patients having COVID sequelae.³⁵ The study results provide useful insight into the wide range of symptoms experienced by COVID-19 survivors. These symptoms will affect their quality of life as well as performance at workplace as compared to the pre-illness level. As millions of people have suffered from COVID-19, the prevalence of COVID-sequelae is going to be substantial. The planning for the management of the health care services can be devised based on the prevalence and risk factors of COVID sequelae.

This was an observational questionnaire-based study. No objective assessments like laboratory or radiographic investigations were carried out per se for the study. Being a cross-sectional study, there was no follow-up of the patients. The inclusion of health care workers only, limits the generalization of the results. As the participants were asked to report experienced symptoms within the designated periods, this could impact the reliability of symptom prevalence estimates leading to the possibility of both under-reporting and over-reporting of symptoms. The definition of WHO for post-COVID condition has recently introduced a newer criterion that symptoms should persist for at least two months to qualify for the post-COVID condition. In this cross-sectional study duration of presenting symptoms could not be accurately assessed. The subgroup analysis was relatively underpowered as one of the participant subgroups had comparatively lesser sample size.

Our findings highlight the prevalence and pattern of COVID sequelae along with the associated risk factors among a special subgroup of COVID-19 survivors—the health care workers. Approximately one-third of the participants experienced COVID sequelae. Female gender, advanced age, co-morbidity, and severity of COVID illness were risk factors for COVID sequelae. Considering the heterogeneity in symptoms of COVID sequelae, longitudinal studies with follow-up assessments and treatment interventions are further required. These studies will foster an understanding of the natural history of the disease and prediction of risk factors to devise evidence-based treatment guidelines for the management of long-term effects of COVID.

Contributors

NK and AS conceptualized the study while NK, AS, SA, RJ and BS were responsible for methodology. Data collection and curation was done by all authors. Data analysis was done by SA and AB. Validation of the study protocol was done by NK whilst final validation of the results was done by SA, AS, NK and AB. Visualizations, project supervision, and resource management were led by NK, AS, SA and JC. Original draft was prepared by AS, SA RJ and AB, whilst revisions and final editing were done by all authors. All authors have read and approved the final manuscript for publication.

Data sharing statement

Data supporting this study's findings are available from the corresponding author (AS: ajay.pharm@aiimsbhopal.edu.in) upon review of request by the Indian Council for Medical Research (ICMR)- Rational Use of Medicines network.

Declaration of interests

All other authors declare no competing interests.