Effect of COVID Vaccine on Long COVID: An Observational Study on Hospitalised Patients in North India

Discussion

Effect of vaccine on COVID severity

Effectiveness of vaccination in reducing the severity of COVID-19 disease, including the need for hospitalisation and death from COVID-19, is now well established by various studies.[14,15] Our study was conducted in patients admitted over the three waves and, in these patients also, the vaccinated group had a shorter average length of stay compared to the unvaccinated group (5.0 vs 7.4 days) (P < 0.001). More patients had mild COVID-19 at the time of admission in the vaccinated group (61.6%) compared to the unvaccinated group (53.4%) (P < 0.001) and moderate cases were lesser. It seems that vaccination helped in modifying severity from moderate to mild in some cases. Being tertiary care hospitals, ICU occupancy was higher due to direct referrals of sicker patients and ICU admissions were not different in the two groups.

Effect of vaccine on occurrence of long-COVID

There is no universally accepted definition of long-COVID. The National Institute for Health and Care Excellence (NICE)[1] defined long-COVID as signs and symptoms that continue or develop after acute COVID-19, including both ongoing symptomatic COVID-19 (from 4 to12 weeks) and post-COVID-19 syndrome (>12 weeks). The Centres for Disease Control and Prevention (CDC) defined long-COVID as a post-COVID condition with a wide range of new, returning or ongoing health problems people experience four or more weeks after first being infected with the virus that causes COVID-19.16 WHO,7 in Oct 2021, defined long-COVID as a condition that occurs in individuals with a history of probable or confirmed (SARS-COV-2) infection, usually three months from the onset of COVID-19, with symptoms that last for at least two months and cannot be explained by an alternative diagnosis.[17] Most of the studies included in the review by UK Health Security Agency used different definitions of long-COVID[18]. In the present study, we have taken symptoms persisting or developing after discharge from the hospital as long-COVID.

Castanares-Zapatero et al.[11] have proposed several reasons for long-COVID. The incidence was widely different in different studies, from 5% to 87% in hospitalised patients.[19-23] An Indian study on 773 patients by Senjam et al.[7] reported overall incidence of 33% with short-term long-COVID symptoms (4 to 12 weeks) and 13% with long-term long-COVID symptoms (≥ 12 weeks). Kuodi et al.[6] reported 35% of their patients in Israel experienced long-COVID. The incidence 90% in our cases is higher. This could be because we have not restricted to the criteria of > 4 weeks from the time of COVID-19 diagnosis and our duration is from the discharge and not diagnosis. If the patients with symptoms of duration 4 weeks or less are excluded, the incidence in our cases too steeply declines to 15%.

UK Health Security Agency[18] published rapid evidence briefing on the effectiveness of vaccination against long-COVID.

In their analysis, six of the 8 studies suggested that vaccinated cases were less likely to develop symptoms of long-COVID in the short term (within four weeks after infection), medium term (12 to 20 weeks after infection) and long term (6 months after infection). Antonelli et al.[24] found that fully vaccinated patients were almost half as likely to have symptoms lasting ≥ 28 days than unvaccinated patient (OR = 0.51; 95% CI: 0.32–0.82, P = 0.005). Al–Aly et al.[4] reported that vaccinated cases were less likely to have at least one post-acute sequelae of COVID-19 at 6 months compared with the unvaccinated cases (HR = 0.87; 95% CI: 0.83–0.92). A retrospective cohort study by Herman et al.5 observed that fully vaccinated patients were less likely to develop olfactory dysfunction after infection than unvaccinated patients (OR = 0.31; 95% CI: 0.10–0.94) but found little evidence for an association between full vaccination and olfactory dysfunction at 4 weeks after the end of infection (P = 0.59). An Israeli study by Koudi et al.[6] reported that those with 2 or 3 doses of vaccine were 54% to 83% less likely to report 7 of the 10 most commonly reported symptoms than the unvaccinated. Senjam et al.[7] from India reported that fully vaccinated patients were less likely to have long-COVID symptoms than unvaccinated patients (OR = 0.55; 95% CI: 0.37–0.85). A retrospective study by Simon et al.8 revealed that patients who received at least one dose of any of the three COVID vaccines in the USA prior to their diagnosis with COVID-19 were 7–10 times less likely to report two or more long-COVID symptoms compared to the unvaccinated patients.

Another matched case-control study by Taquet et al.[9] from the USA included 9,479 vaccinated and a similar number of unvaccinated cases who were followed up for 6 months after infection and studied a composite long-COVID outcome. The study found no association between vaccination and composite long-COVID outcome in 6 months after infection with hazard ratio (HR = 1.00; 95% CI: 0.95–1.06). In their study, 64.9% and 65.5% of vaccinated and unvaccinated patients had longCOVID, respectively. There was no significant difference in the overall reporting of long-COVID between the vaccinated and the unvaccinated in our study and no effect could be detected of the covariates (except comorbidities) but there was significant difference in the specific symptoms as discussed in a short while. In our series, 8.5% of vaccinated and 10.1% of unvaccinated cases reported no symptoms; this difference was not statistically significant (P = 0.161). However, in the mild COVID-19 group, slightly higher number of unvaccinated patients had no long-COVID symptoms (5.6%) compared to the vaccinated group (4.3%) (P = 0.010).

The results of logistic regression showed in our study that hypertension and diabetes were more common in those who reported long-COVID symptoms (P <0.001). The study by Senjam et al.[7] also indicated a strong association between the pre-existing comorbidity and the presence of post COVID sequelae. Pre-existing co-morbidity such as hypertension, chronic respiratory diseases, diabetes mellitus were shown to be associated with the prolonged COVID-19 symptoms in other studies also.[25-27]

Effect of vaccine on duration of long-COVID

Groff et al.[2] identified 57 studies with 250,351 survivors of COVID-19, of which 197,777 (79%) were hospitalised during acute COVID-19. More than half of these were experiencing long-COVID 6 months after recovery. They divided patients into 3 categories of symptom duration, Short term: up to 1 month (median – IQR 54% – 45% to 69%; 13 studies); intermediate term: 2-5 months (median – IQR 55% – 34.8% to 65.5%; 38 studies), long-term: ≥ 6 months (median – IQR 54% – 31% to 67%; 9 studies).

In our study, 74.7% of the vaccinated patients in wave-3 versus 60.0% of the unvaccinated patients reported symptoms that lasted 1-4 weeks after discharge from the hospital (P = 0.009). Although a similar trend was observed during wave-2, the difference was not statistically significant. A retrospective cohort study by Arjun et al.[10] from India, involving 487 patients, also reported reverse finding that fully vaccinated participants were more likely to have long-COVID symptoms 4 weeks from the date of diagnosis compared to the unvaccinated patients (OR = 2.32; 95% CI: 1.17 - 4.58, P = 0.01).

We did not find any difference in the occurrence of intermediate and long term PASC between vaccinated and unvaccinated groups. More than 11% of the patients during the first two waves continued to have long-COVID symptoms 52 weeks or more and there was no significant difference between the vaccinated and the unvaccinated groups.

Effect of vaccine on occurrence of specific symptoms of long-COVID

When the effect of wave, age, gender, length of hospital stays, severity of COVID-19 and comorbidities is eliminated through multivariate logistic regression, the adjusted odds ratio (aOR = 1.27; 95% CI: 0.58–2.77) for reporting of symptoms was statistically not significant between vaccinated and unvaccinated groups in our cases. When all three waves and both groups (vaccinated and unvaccinated) are combined, the most commonly reported long-COVID symptoms in our study were fatigue (17.0%), followed by insomnia (15.1%) and myalgia (15.0%). In a study by Senjam et al.[7], the most commonly reported long-COVID symptoms were fatigue, pain in the joints and muscle, hair loss, headache, cough, breathlessness, sleep disorders, sore throat and decrease in smell and taste. These are somewhat different from what we observed.

In the vaccinated group, we found particularly higher odds of reporting eyesight issues (aOR = 7.54; 95% CI: 4.25–13.38; P < 0.001) and fever (aOR=4.79; 95% CI : 3.24–4.07; P < 0.001). In a study by Senjam et al.[7], some patients experienced both near and distance visual impairment and dry eyes. They surmised these eye symptoms could be side effects of medication such as hydroxychloroquine, which was commonly used during their acute management. Since the post-COVID assessment was done by them four or more weeks after recovery, symptoms like red and painful eyes could be due to immunological mechanisms.

Kuodi et al.[6] compared participants with 2 or 3 doses of vaccine with the unvaccinated participants and observed that the vaccinated had less of fatigue, headache, weakness in arms and legs, persistent muscle pain, loss of concentration, hair loss, sleeping problems, dizziness, persistent cough, shortness of breath and more feeling fully recovered from COVID-19. Taquet et al.9 found no association between vaccination and composite long-COVID. Patients with 2 doses of vaccine were found to be less likely to be diagnosed with anosmia, fatigue, hair loss, intestinal lung disease, myalgia and any other pain. Our findings suggest that vaccinated group had higher odds of reporting eyesight issues, fever, weight loss, headache, memory loss, dyspnoea, cold and a lower odds of reporting insomnia, cough, myalgia, and anxiety.