Exploring the Interplay: COVID-19 Vaccination’s Influence on Long-term Symptoms and Quality of Life in Post-COVID Recovery

The pandemic caused by the new SARS-CoV-2 virus has been progressively controlled and has entered the endemic stage. More than the newly diagnosed COVID-19, healthcare systems are increasingly dealing with the complex long-term health consequences of individuals who have not entirely recovered from the SARS-CoV-2 infection.¹ Infected individuals present with persistent acute symptoms of COVID-19, despite the lack of detection of viral DNA by Polymerase Chain Reaction (PCR), which is considered a sign of long-term COVID.^1–3 The signs and symptoms of long-term COVID-19 can appear suddenly, they may linger beyond the initial illness, they may change over time, or they could return back.⁴ There is increasing evidence indicating that individuals who have recovered from COVID-19 may experience symptoms affecting multiple organ systems.^5,6

The prevalence of long-term COVID varies widely across studies, ranging from 4.7% to over 90%.^5–8 A higher risk of developing long-term COVID was observed among older individuals, who had a higher body mass index and were female.⁹ The burden of long-term COVID in India has received much less attention.¹⁰ There has been a scarcity of studies conducted on COVID-recovered individuals to ascertain the proportion of individuals who continue to experience symptoms post-recovery. Hence, this study was to evaluate the prevalence of long-term COVID and the health-related quality of life among recovered individuals with varying severity levels of COVID-19 in southern India. Additionally, the study aimed to explore the effect of COVID-19 vaccines on long-term COVID-19 and the quality of life in this population.

Receiving approval from the Adichunchinagiri Hospital and Research Centre’s (AH & RC) Institutional Ethical Committee and with the approval number IEC/AH & RC/AC/005/2021, a prospective cross-sectional study was conducted in the rural area of Mandya, India. Registration number CTRI/2021/08/035758 (dated 18/08/2021) has been assigned to the study by the Clinical Trials Registry of India (CTRI).

The study comprised participants aged 18 and above who had recovered from COVID-19 at least one month before. The reverse transcriptase polymerase chain reaction (RT-PCR) test was used to confirm the diagnosis of COVID-19. The discharge criteria were based on the standardised revised policy published by the Ministry of Health and Family Welfare, Government of India.^11,12 Individuals with pre-existing mental health disorders or chronic diseases such as arthritis, diabetes, asthma, or COPD were not eligible to participate.

The study stratified COVID-19-recovered individuals into two categories based on existing literature: the mild/moderate acute COVID-19 group and the severe/critical acute COVID-19 group. Long-term COVID prevalence was estimated at 20% for the mild/moderate group and 50% for the severe/critical group. To determine the necessary sample size, the formula n= Z²p(1-p)/ (dp)² was employed, with a relative precision of 20% and a 95% confidence interval. This calculation yielded a sample size of 400 for the mild/moderate group and 100 for the severe/critical group, resulting in a total sample size of 500 for the study.

The list of individuals diagnosed and discharged with COVID-19 was obtained from the virology laboratory and COVID ward at AH & RC from July 2021 to December 2021, until the list reached a total of 1000 individuals. Individuals who had been diagnosed with COVID-19 at least one month prior were communicated by telephone, provided with a detailed explanation of the study, and requested to participate. Those who showedinterest in participating in the study were requested to visit either the Department of Pharmacy Practice or the Adichunchanagiri Clinical Trial Centre at AH & RC. Upon arrival, they were requested to provide their consent to participate in the study and underwent a screening process to assess their eligibility. A physical examination was performed on all participants, including measurements of Blood Pressure (BP), body weight, Body Mass Index (BMI), and oxygen saturation. Demographic information such as gender, age, height, weight, habits, qualifications, occupation, and vaccination status were obtained through face-to-face interviews using a validated data collection form. Furthermore, the study used the same form to captured a wide range of clinical manifestations, including general symptoms like myalgia, fatigue, and alopecia; respiratory symptoms like cough and dyspnoea; cardiovascular symptoms like chest pain and palpitations; neurological symptoms like headache, cognitive impairment, insomnia, paraesthesia, anxiety, and depression; and gastrointestinal symptoms like anorexia and dyspepsia.

The EQ-5D-5L questionnaire (https://euroqol.org/) was administered to all participants to assess their quality of life.^13,14 Two follow-ups were scheduled every six months from the date of enrolment. The EQ-5D-5L questionnaire, physical examination, and clinical symptoms of the individuals were evaluated at each follow-up. Two chances to reschedule their follow-up were provided to participants.

Based on the signs and symptoms observed, the disease severity was classified as mild when there was no radiographic evidence of pneumonia, moderate when pneumonia was accompanied by fever and respiratory symptoms, severe when the respiratory rate was ≥ 30 breaths per minute, oxygen saturation was ≤ 93% on room air, or PaO2/FiO2 was ≤ 300mm Hg, and critical when respiratory failure required mechanical ventilation or needed intensive care.^15,16

The EuroQol Group created the EQ-5D-5L in 2011 as a tool to measure Quality of Life (QoL). It assesses five aspects of health: mobility, self-care, activities of daily living, pain/discomfort, and anxiety/depression. There are five response levels for each dimension, ranging from no problems to extreme problems. The sum of the coefficients allotted to the dimensions yields the total score, which represents the participant’s overall quality of life.^13,14

Long-COVID is an umbrella term that includes two distinct conditions: ongoing symptomatic COVID-19 and post-COVID syndrome. Ongoing symptomatic COVID-19 is characterized by persistent symptoms and signs that persist for 4 to 12 weeks after the initial acute COVID-19 symptoms. Meanwhile, “post-COVID syndrome” refers to symptoms and signs that last for more than 12 weeks and are not explained by any other diagnosis.^3,4

The SPSS version 26 software was utilized to conduct statistical analysis. Frequency and percentage were used to present categorical variables such as gender, habits, qualifications, occupation, vaccination status, clinical manifestations, and EQ-5D-5L assessment. On the other hand, mean and Standard Deviation (S.D) were used to present numerical variables including age, weight, height, and quality of life.

We assessed the data’s normality using the Shapiro-Wilk and Kolmogorov-Smirnov tests. Age, Body Mass Index (BMI), and quality of life were compared between the mild/moderate and severe/critical acute COVID-19 recovery groups using one-way ANOVA, independent samples t-test, or Mann-Whitney test, depending on the data distribution. Applying the Chi-square or Fisher’s exact test allowed for the examination of the relationship between several parameters and long-term COVID. The prevalence rates of post-COVID syndrome and continued symptomatic COVID-19 were compared using the McNemar test. Statistical significance was defined as a p-value of 0.05.

Out of the initial list of 1000 individuals, we were unable to contact 107 of them, 153 were excluded due to having co-morbidities, and 86 declined to participate in the study. Therefore, a total of 654 individuals were enrolled in the study. During the study, 18 individuals missed the first follow-up and 12 individuals missed the second follow-up. Thus, a total of 624 individuals completed both the first and second follow-ups (Figure 1). Table 1 described the demographic characteristics of the study participants.

Figure 1:
Flow chart of enrolment of study participant.

In the study, 87.3% (545) of participants who recovered from COVID-19 reported experiencing at least one persistent symptom. The most frequently reported symptom was cough, affecting 64.3% of participants, followed by fatigue at 59.6%, myalgia at 52.6%, and headache at 31.9%. Other symptoms included lack of concentration (24.7%), insomnia (24.2%), hair loss (20.8%), chest pain (18.1%), anxiety (16.5%), indigestion (13%), anorexia (11.7%), depression (11.5%), dyspnoea (10.6%), and palpitations and paraesthesia, each reported by 5.4% of participants. Headaches, lack of concentration, and anorexia were statistically significantly more prevalent in severe to critical COVID-19-recovered individuals (p<0.001) (Table 2 and Figure 2).

Figure 2:
Long-term COVID prevalence at one month, six months, and twelve months after COVID-19 recovery.

After a six-month recovery period from COVID-19, 72.1% (450) of participants reported experiencing one or more long-COVID-19 symptoms. Fatigue was the most frequently reported symptom, affecting 18.6% of participants, followed by headaches at 15.5%, insomnia at 15.1%, hair loss at 14.1%, and cough at 13.6%. Fatigue, myalgia, hair loss, and insomnia were statistically more prevalent in those recovering from severe to critical COVID-19 (p< 0.05) (Table 2).

After a twelve-month recovery period from COVID-19, 73.9% (461 individuals) of the participants experienced one or more long-COVID-19 manifestations. Headaches were the most frequently reported ailment, affecting 20.8% of participants. It was followed by fatigue (19.6%), lack of concentration (18.4%), hair loss (16.7%), insomnia (15.7%). Myalgia and hair loss were statistically more prevalent in those recovering from severe to critical COVID-19 (p< 0.05) (Table 2 and Figure 2).

The prevalence of at least one long-term COVID-19 symptom decreased from 87.3% during ongoing symptomatic COVID-19 to 72.1% at six months post-recovery (p < 0.001). This reduction was statistically significant for several symptoms: fatigue (59.6% to 18.6%), myalgia (52.6% to 13%), hair loss (20.8% to 14.1%), cough (64.3% to 13.6%), dyspnoea (10.6% to 6.1%), chest pain (18.1% to 9.5%), palpitations (5.4% to 2.7%), insomnia (24.2% to 15.1%), headache (31.9% to 15.5%), lack of concentration (24.7% to 9%), paraesthesia (5.4% to 3%), anxiety (16.5% to 8%), and indigestion (13% to 7.7%) (p < 0.05). However, there were no statistically significant differences in the prevalence of depression (11.5% to 9.6%) and anorexia (11.7% to 9.3%) from ongoing symptomatic COVID-19 to six months post-recovery (p > 0.05) (Table 2).

The prevalence of at least one long-COVID symptom decreased from 87.3% during ongoing symptomatic COVID-19 to 65.7% one-year post-recovery (p < 0.001). Significant reductions were observed in symptoms such as fatigue (59.6% to 19.6%), myalgia (52.6% to 12.7%), hair loss (20.8% to 16.7%), cough (64.3% to 15.4%), dyspnoea (10.6% to 9.1%), chest pain (18.1% to 10.6%), palpitations (5.4% to 3.7%), insomnia (24.2% to 15.5%), headache (31.9% to 21%), lack of concentration (24.7% to 18.6%), paraesthesia (5.4% to 2.6%), anxiety (16.5% to 9.6%), anorexia (11.7% to 10.3%), and indigestion (13% to 9.8%) (p < 0.05). However, there was a significant increase in the prevalence of depression, rising from 11.5% to 12.5% from ongoing symptomatic COVID-19 to the second follow-up after one year of recovery (p < 0.05) (Table 2).

One month after recovering from COVID-19, the average quality of life score for individuals stood at 0.90 ± 0.13. A statistically significant difference was observed between those who had mild to moderate cases and those who experienced severe to critical illness (p < 0.05). By the six-month mark, the average quality of life improved to 0.93 ± 0.11, with no significant differences noted between the two groups (p > 0.05). After one year of recovery, the quality of life further increased to 0.94 ± 0.10, with no statistically significant differences found between individuals based on the severity of their initial illness (p > 0.05) (Table 3).

While vaccinated individuals had a higher incidence of Long-COVID than unvaccinated individuals (74.5% vs. 69.6%), the difference was not statistically significant (p > 0.05). Long-COVID incidence was considerably greater among individuals who received a booster dose compared to those who only completed the initial immunisation series or were unvaccinated (p < 0.05). Vaccinated individuals had significantly lower quality of life compared to uninfected individuals (0.94 ± 0.10 vs. 0.96 ± 0.07, p < 0.005). Those who received a booster dose had an even lower quality of life (0.92 ± 0.11) (Table 4).

In this prospective cross-sectional study, our objective is to examine the prevalence and health-related quality of long-term COVID-19 symptoms over a 6- and 12-month period compared to the symptoms experienced within one-month post-COVID-19 recovery and the effect of COVID-19 vaccination on long-term COVID syndrome and health-related quality of life. One month after recovering from COVID-19, the prevalence of long-term symptoms declined from 87.3% (ongoing symptomatic COVID-19) to 72.1% (post-COVID-19 syndrome) and subsequently to 73.9% one-year post-recovery. Huang et al.,¹⁷ reported a higher prevalence, and Huang et al.¹⁸ reported a lower prevalence of at least one long-term COVID manifestation compared to this study at 6 months from COVID-19 recovery. Similarly, Huang et al.,¹⁸ and Fang et al.,¹⁹ reported a lower prevalence of at least one long-COVID manifestation than this study in a year from COVID-19 recovery. A potential factor contributing to the decrease in long-term COVID cases could be a reduction in the levels of natural neutralizing antibodies, which may have declined over time. The WHO highlighted the decline in naturally developed neutralizing antibodies after 7 months and urged them to go for COVID-19 vaccination after 6 months of COVID-19 recovery.^14,20,21 The study reveals an increase in the long-term COVID manifestation from six to twelve months after COVID-19 recovery (72.1% vs. 73.9%). All other long-term COVID manifestations significantly decreased, with the exception of depression and anorexia, which persisted from ongoing symptomatic COVID to 6-month post-COVID syndrome and depression, anorexia, and indigestion, which persisted from ongoing symptomatic COVID to 12-month post-COVID syndrome. In the study at 1 year of COVID-19 recovery, 87.33% (545) of the participants were vaccinated with a full or booster dose of the available COVID-19 vaccine. The long-term COVID prevalence appears to be higher in those who received the booster dose (79.4% vs. 69.9% vs. 69.6%) than in those who received the full dosage and were not vaccinated. The increase in neutralizing antibodies following COVID-19 vaccination might be associated with a higher incidence of long-term COVID. Previous studies by Peghin et al. and Tsuchida et al. have reported elevated immunogenicity, antibody titers, and reactogenicity in individuals with a history of COVID-19 infection.^22,23

The main ongoing symptomatic COVID-19 manifestations of individuals were cough, fatigue, myalgia, and headache. Fatigue, headaches, insomnia, and hair loss were the main post-COVID syndromes six months after recovery, and headache, fatigue, lack of concentration, and hair loss were the main post-COVID syndromes a year of COVID-19 recovery. Similar to the findings of this study, Indian researchers reported myalgia, fatigue, shortness of breath, and headache as the primary persistent symptoms.^2,24

The study found that the COVID-19 recovered individuals experienced a gradual improvement in their QoL between the baseline and the follow-up periods of six and twelve months (0.90 ± 0.13 vs. 0.93 ± 0.11 vs. 0.94 ± 0.1) (Table 2 and Figure 3). The QoL among mild to moderately COVID-19-recovered individuals was significantly higher than severe to critical at a month post-COVID-19 recovery (0.91 ± 0.13 vs. 0.88 ± 0.15, p <0.05) (Figure 3). There were no significant differences in QoL between illness severity at 6 and 12 months post-COVID-19 recovery (p >0.05). Arab-Zozani et al., reported a lower QoL compared to this study; however, it is important to note that they did not specify the timeframe of their study concerning COVID-19 recovery.^25,26 The analysis of the percentage of individuals reporting problems affecting their QoL in each EQ-5D-5L dimension revealed that pain or discomfort was the most frequent issue reported at one month, mobility at six months, and pain or discomfort again at twelve months after recovery. The findings reported in the study by Huang et al.¹⁸ were consistent with the findings of the present study. In each of the EQ-5D-5L dimensions, anxiety or depression emerged as the most often reported problem by Arab-Zozani et al. and Nguyen HC et al.,^25,26 The study found that individuals who had received the COVID-19 vaccination demonstrated a lower QoL in comparison to not vaccinated (0.94 ± 0.1 vs. 0.96 ± 0.07). Individuals who had received a booster dosage show this pattern even more (0.92 ± 0.11). This indicates that receiving the COVID-19 vaccination affects QoL.

Figure 3:
Impact of COVID-19 vaccination on quality of life.

The strength of our study is that individuals with comorbidities were excluded, reducing the chance of symptom overlap for long-term COVID manifestations. Additionally, we specifically evaluated the influence of COVID-19 vaccinations on long-term COVID symptoms and health-related quality of life among individuals who had previously recovered from COVID-19.

Our research has several limitations since it is single-centric which only covers a small portion of Southern India. The generalizability of our findings to larger groups may be limited as a result. Additionally, we did not specifically focus on acute COVID-19 symptoms or the persistence of these symptoms as ongoing manifestations in our study. We may have identified the persistent COVID-19 symptom from the newly emerging long-term COVID manifestation by looking at the acute COVID-19 symptoms.

The prevalence of long-term COVID-19 symptoms was notable, affecting 87.3% of patients after one month. However, it decreased to 72.1% after six months and remained relatively unchanged at 73.9% after one year. The main ongoing symptomatic COVID-19 manifestations of individuals were cough, fatigue, myalgia, and headache. Fatigue, headaches, insomnia, and hair loss were the main post-COVID syndromes six months after recovery, and headaches, fatigue, lack of concentration, and hair loss were the main post-COVID syndromes a year after COVID-19 recovery. Individuals who had recovered from COVID-19 experienced a gradual improvement in their health-related quality of life between the baseline and the follow-up periods of six and twelve months. The study also found that individuals who had received the COVID-19 vaccination demonstrated an increase in long-term COVID manifestation and a lower health-related quality of life in comparison to those who had not.

We express our gratitude to Dr. B Ramesh, Dean & Principal of Sri Adichunchanagiri College of Pharmacy, and Dr. M. G. Shivaramu, Principal of Adichunchanagiri Institute of Medical Sciences, for their support in creating an environment conducive to the successful completion of this study.