Evaluation of late disorders as possible long-COVID and/or vaccination consequences

doi:10.21203/rs.3.rs-3447623/v1

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Evaluation of late disorders as possible long-COVID and/or vaccination consequences

https://doi.org/10.21203/rs.3.rs-3447623/v1

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Background:Following SARS-CoV-2 outbreak, another crisis has been established by progress or persistence of COVID-19 symptoms, as post or long COVID, which is critical to be recognized according to increasing number of late symptoms reports. In this study, we investigated long-term disorders in vaccinated individuals who developed late adverse events/side effects post-vaccination and/or COVID-19 episode owing to the challenging differentiation between them.

Methods: The vaccinated individuals of four vaccine regimens including inactivated virus-based/prime-boost group, inactivated virus-based prime/subunit protein-based boost, adenovirus-based prime/boost and adenovirus-based prime/subunit protein-based boost were followed from the first dose of vaccination up to 6-month post the booster shot. All the vaccine adverse events were documented through in-depth interview using a researcher-made questionnaire as well as the COVID-19 history and demographics. The medical history of all the cases were also collected and the late disorders post-vaccination were investigated by Adverse Events Committee of Pasteur Institute of Iran.

Results: Totally 329 individuals who got 3 doses of vaccination were followed 6 months after the booster shots among whom 41 (12.4%) of investigated cases (including 31 females) with the mean age of 40.9±10.48 years had a type of disorder following vaccination. The late adverse events/side effects were captured in various forms among which gynecological and osteoarticular involvements were the most common ones. After evaluation of the medical background, age, vaccination and the date of disorder initiation, 39% of the documented complains have been found to be linked with long-COVID-19 as a trigger. Interestingly, the average time of symptoms persistence was 155±10.4 days and mostly continued up to the end of the study.

Conclusion: In this era in which the vast majority of the global population have developed COVID-19 and/or got vaccinated against it, identification of the late disorders as the vaccine side effect or long-COVID manifestation is difficult. Therefore, some complications though late ones, might be a possible consequence of any SARS-CoV-2 infection or vaccination. This study takes the advantage of long-term follow-up which presents various forms of late events in each episode of COVID-19 infection and vaccination. The rate of late-disorders in the present study also highlights the importance of long-term follow-up studies among population worldwide.

Health sciences/Diseases

Health sciences/Medical research

Health sciences/Risk factors

Late AEs

Long-COVID

Long-VAX

long-term disorders

As the world has overcome the recent COVID-19 pandemic, owing to the great effort on vaccine development, the struggle against the long-term effects of the infection has emerged as a pandemic post the other one called “long COVID” [1, 2]. According to the definition by the World Health Organization, long COVID is a condition occurring in individuals with a background of probable or confirmed SARS-CoV-2 infection in which the symptoms usually appears three months after the COVID-19 symptoms onset and continues at least for two months [3]. This condition can affect a wide range of organs in the body through various symptoms [4].

Although vaccination against COVID-19 has been a crucial step to manage the pandemic, uncertainties about the side effects of long COVID have brought concerns in the general population causing vaccine hesitancy which is potentially important for next probable new COVID-19 peaks and need of booster doses [5, 6]. There is no doubt that vaccinations have significantly decreased the severity of the illness and also the risk of hospitalization, however, the effect of vaccines on long-COVID has remained less discussed [7–9]. What is more, vaccinated individuals might be infected and be asymptomatic or even suffer from mild to moderate forms of COVID-19 [10–12]. Long-COVID can manifest after all types of severity. Hence, COVID-19 vaccines could possibly impact on long-COVID symptoms. There have been studies showing that vaccines might reduce the risk of long-COVID [13, 14]. A crucial factor to determine this issue is the time of infection and vaccination. It seems that vaccination before infection might limit long-COVID [15]. What is unknown is the re-infection impact which could give a rise to long-OVID persistence.

From another point of view, long term manifestations of vaccination has also came to attention by evidences and case reports worldwide [16, 17]. The late adverse events thought to be rare, however, they may cause seriously durable problems and influence the life quality as well. Furthermore, the majority of the global population have already been immunized and may still develop the infection in this era. To determine that a long-term symptom is the long COVID manifestation or the vaccination side effects seems a challenging puzzle to resolve [18]. Therefore, in addition to the current vaccine safety reports and long COVID studies, it is of high value to investigate the symptomology of SARS-CoV-2 infection before and after vaccination and also to estimate associations between long-COVID symptoms and vaccination consequences [19].

The long-term assessment of late disorders post COVID-19 vaccination has been previously investigated in our last report [16]. Some identified problems were not associated to the vaccinations according to the opinion of the Adverse Events Committee of Pasteur Institute of Iran. Hereby, we aimed to describe some late disorders in vaccinated individuals who mostly suffered from COVID-19 infection and tried to classify them as the incidences causing by the COVID-19 infection and/or vaccination against it.

In this long-term follow-up study, we investigated vaccinated individuals from the first dose of COVID-19 vaccination up to at least 6-month post the booster shot. The participants were classified by the vaccine regimes including standard and combinational ones as:

The individuals who primed with Sinopharm and got a booster dose of PastoCovac or PastoCovac Plus (protein subunit vaccines)[20],

The individuals who primed with AstraZeneca and got a booster dose of PastoCovac Plus,

The individuals who got three doses of Sinopharm,

The individuals who got three doses of AstreaZeneca.

The full medical history of the participants were collected through face-to-face interview or on call including any underlying diseases, COVID-19 history, time of incidence, symptoms, vaccine doses, any kind of adverse events (AEs), medical care, hospitalization and symptoms persistence. The collected AEs during an 18-month period (6 months after the booster dose) were then evaluated by AEs assessment committee of Pasteur Institute of Iran, to associate any causal inference of AEs with the vaccine/COVID-19. Descriptive statistics are presented as means (SD) for quantitative variables and as frequency (percentage) for categorical variables. All statistical analyses were performed with an alpha level of 0.05 in Stata software (version 17).

All the participants were provided with informed consent prior to enrolment and the study was performed according to the Declaration of Helsinki (Fortaleza, 13 October 2013). The ethical approval was achieved from Pasteur Institute of Iran National Committee for Ethics (ethics code numbers: IR.PII.REC.1400.077 and IR.PII.REC.1400.076).

Participants

Totally, 329 individuals participated in the follow-up study (171 females, 158 males) with the mean age of 40.9 (SD: 13.2) and the mean BMI of 26.56 (SD: 4.58).

The medical history showed that the most common underlying disease were thyroid disorders (7.2%), hypertension (5.4%) and diabetes mellitus (4.5%), respectively. Of the total population, 75 ones got Sinopharm/Sinopharm, 110 individuals got Sinopharm/PastoCovac Plus, 54 participants got Sinopharm/PastoCovac, 70 persons got AstraZeneca/ PastoCovac Plus, and 20 individuals were AstraZeneca/ AstraZeneca recipients.

Long-term symptoms classification

During the retrospective follow-up all the reported disorders were collected into a researcher made form by trained experts according to the time of the incidence and duration. Only, the late AEs which started post-21-day after each dose of vaccination were considered in this study.

The collective data showed that in total, 41 individuals (12.46%) had at least one disorder following vaccination (31 females, 12 males) with a mean age of 40.9 ± 10.48, among whom menstrual problems (discussed in other under review data), hair loss, osteoarticular disorders, neuritis at the injection site, headache and skin manifestations were the most common, respectively (Table 1.).

18 individuals (nearly 44%) had an underlying diseases among whom hypothyroidism was the most frequent. Nevertheless, the compatible comorbidity with the AEs/side effect were only hyperlipidemia and joints inflammation in two cases who reported worsen pre-existing condition after the vaccination. In general, the identified symptoms were mostly persistent up to the end of the study with a mean duration of 155 days.

In order to find the probable cause of each complication, the medical background of each case was firstly noticed. What is more, the gap time between the symptoms initiation with COVID-19 infection and also vaccination was considered. Furthermore, the coincidence of the infection and vaccination was considered as a dual effect cause on the late symptoms.

By considering the role of COVID-19 in various types of late involvements and also the vaccine which could possibly trigger the previous impact of the infection, we found that in 17 (41.4%) of the cases, long-COVID could possibly manifest in which vaccination also gave a rise as a trigger, whereas 10 cases without any documented history of the infection which were then possibly affected by the vaccination. Moreover, by considering the duration between the late symptom/disorder presentation and vaccination and COVID-19, 24 whom were affected by the vaccine according to AEs committee members’ opinion (Fig. 1).


Case No.	Gender	Age	BMI	Disorder type	COVID-19 vaccine regimen	Time of disorder initiation	Persistency of the disorder	Underlying medical conditions	Covid-19 history time	Vaccine outcome	Long –COVID-19 manifest
Case No.	Gender	Age	BMI	Disorder type	COVID-19 vaccine regimen	Time of disorder initiation	Persistency of the disorder	Underlying medical conditions	Covid-19 history time	Possibility
1	Female	44	22.5	Menstrual	Sinopharm/ PastoCovac plus	After each dose	30	-	9 months after the booster dose	^⎫	-
2	Female	31	25.1	Menstrual and hair loss	Sinopharm/ PastoCovac plus	Post the booster dose	180	-	2 weeks after the booster	^⎫	^⎫
3	Female	41	24	Joints involvement	Sinopharm/ PastoCovac plus	Post the booster dose	180	hypertension	3 months before vaccination	^⎫	^⎫
4	Male	51	25.7	Morphea	Sinopharm/ PastoCovac plus	Post the booster dose	180	-	6 months before vaccination	^⎫	-
5	Female	46	35.3	Skin rashes	Sinopharm/ PastoCovac plus	Post the booster dose	180	Endometriosis,polycystic ovary	1 month after the booster	^⎫	^⎫
6	Male	42	22.7	Skin rashes	Sinopharm/ PastoCovac plus	Post the booster dose	180	IBS	-	^⎫	-
7	Female	52	23.3	Hair loss	Sinopharm/ PastoCovac plus	Post the booster dose	90	-	-	^⎫	-
8	Female	42	30.9	Joints involvement	Sinopharm/ PastoCovac plus	Post the 1st dose	180	Asthma	2 months before vaccination and shortly after the 1st dose	^⎫	^⎫
9	Female	54	34.9	Joints inflammation worsening	Sinopharm/ PastoCovac plus	Post the booster dose	180	Joints inflammation	2 months before vaccination	^⎫	^⎫
10	Female	37	31.9	Hair loss	AstraZeneca/ PastoCovac plus	Post the booster dose	180	Hypothyroidism	6 months after the booster shot	^⎫	-
11	Female	50	26.5	Pain at the injection site	Sinopharm/ PastoCovac plus	Post the booster dose	180	-	-	^⎫	-
12	Female	37	25.2	Pain at the injection site	Sinopharm/ PastoCovac	Post the booster dose	30	-	-	^⎫	-
13	Male	38	32.7	Blurred vision	Sinopharm/ PastoCovac	Post the booster dose	180	-	1 year before vaccination	^⎫	⁻
14	Female	44	28.7	Menstrual and Hyper lipedema (worsening)	AstraZeneca/ PastoCovac plus	Post the booster dose	180	Hyper lipedema	8 months After 3rd dose	^⎫	-
15	Male	42	27.2	Joints inflammation	AstraZeneca/ PastoCovac plus	Post the booster dose	90	Hyper lipedema	2 months after the booster	^⎫	⁻
16	Female	66	25.9	Hair loss	AstraZeneca/ PastoCovac plus	Post the 1st dose	180	-	One year before vaccination	^⎫	⁻
17	Female	33	22.5	Menstrual	AstraZeneca/ PastoCovac plus	Post the 1st dose	180	-	1 month post the booster	^⎫	^⎫
18	Male	37	25	headache	AstraZeneca/ PastoCovac plus	Post the 2nd dose	180	-	7 months before vaccination and post each dose	^⎫	^⎫
19	Female	27	20.8	Hair loss	AstraZeneca/ PastoCovac plus	Post the booster dose	180	-	-	^⎫	-
20	Female	32	26	Menstrual	AstraZeneca/ PastoCovac plus	Post each dose	90	Hypothyroidism	2 months after the 1st dose and 2 months after the booster dose	^⎫	^⎫
21	Female	42	29.1	Menstrual	AstraZeneca/ PastoCovac plus	Post the 2nd dose	180	-	7 months before vaccination	^⎫	-
22	Female	45	23.6	Menstrual	AstraZeneca/ PastoCovac plus	Post the 1st dose	60	Hypothyroidism & hyperlipidemia	6 months post the booster dose	^⎫	-
23	Female	37	36.2	Joints inflammation/problem	Sinopharm/PastoCovac	Post the booster dose	180	-	10 months before vaccination	^⎫	-
24	Male	52	30.7	Joints involvement	Sinopharm/PastoCovac	Post the booster dose	180	Hypertension	3 months before vaccination	^⎫	^⎫
25	Female	22	29.8	Flu-like symptoms	Sinopharm/PastoCovac	Post the booster dose	180	-	1 month after the booster shot	⎫	⎫
26	Female	38	21.6	Hair loss	Sinopharm/PastoCovac	Post the booster dose	180	-	5 months post booster	⎫	-
27	Female	23	23.9	Hair loss	Sinopharm/PastoCovac	Post the booster dose	180	-	Shortly after the 2nd dose	⎫	⎫
28	Female	44	24.1	Hypothyroidism worsening	Sinopharm/PastoCovac	Post the booster dose	180	Hypothyroidism	6 months before vaccination	-	⎫
29	Female	42	19.4	Headache	Sinopharm/PastoCovac	Post the booster dose	180	Anemia	2 months before vaccination and 2 months after the 2nd dose	⎫	⎫
30	Female	24	23.2	Hair loss	Sinopharm/PastoCovac	Post the booster dose	180	-	2 months after the 2nd dose	⎫	⎫
31	Male	55	34.7	Hyperglycemia	Sinopharm/ Sinopharm	Post the booster dose	180	Hypertension	-	⎫	-
32	Male	42	34.5	Gastritis	Sinopharm/ Sinopharm	Post the booster dose	180	-	4 months before vaccination	⎫	⎫
33	Female	56	23	Muscles involvement	Sinopharm/ Sinopharm	Post the booster dose	180	Hypothyroidism	-	⎫	-
34	Male	22	22.5	Hypertension	Sinopharm/ Sinopharm	Post the booster dose	180	-	-	⎫	-
35	Female	21	23.7	Muscles involvement	Sinopharm/ Sinopharm	Post the booster dose	180	-	5 months before vaccination and 2months post the 2nd dose	⎫	⎫
36	Female	59	25.6	Pain at the injection site	Sinopharm/ Sinopharm	Post the booster dose	180	-	-	⎫	-
37	Female	44	29.4	Menstrual and headache	Sinopharm/ Sinopharm	Post the booster dose	180	-	1 month after the 1st dose	⎫	-
38	Female	42	23.7	Pain at the injection site	Sinopharm/ Sinopharm	Post the booster dose	180	Hypothyroidism	-	⎫	-
39	Female	37	25.7	headache	Sinopharm/ Sinopharm	Post the booster dose	14	Hypothyroidism	8 months before vaccination	⎫	-
40	Female	49	21.6	Hives and bruises	AstraZenca/AsraZeneca	Post the 1st dose	14	-	Shortly after the booster	⎫	-
41	Female	37	32.1	Menstrual	AstraZenca/AsraZeneca	Post 1st dose	180	Hypothyroidism	8 months before vaccination and 6 months post the booster	⎫	⎫

Persistent symptoms of COVID-19, as the long-term effect of COVID-19 has evolved recently. It is stated that nearly two-thirds of COVID-19 experienced individuals report at least one residual symptom even after 3 months. [21]. More recently, some other reports on long-term AEs came to attention by COVID-19 vaccine implementation. This fact makes long-COVID incidence or vaccination consequences really undistinguishable. In addition to long-COVID, there is another condition which appears in a number of vaccinated individuals against COVID-19 called “Long Vax” due to the fact that symptoms have resembled long COVID. Therefore, it could be stated that the late and persistent symptoms which initiated after the vaccination might be considered as the long vaccine syndrome [22].

Although we attempted to associate the incidences to the COVID-19 infection and/or vaccination, it should not be neglected that the discussed disorders might be only spontaneous events as age, life style or other conditions.

In the present study, we tried to investigate individuals after full vaccine schedule with a kind of disorder. First of all, the impact of the applied vaccine was considered as the potential cause. Nevertheless, some cases had a coincidence of COVID-19 infection and a vaccine dose (shortly after the vaccine).

It has been claimed that vaccination could possibly reduce the rate of long COVID incidence in those who develop the infection after vaccination [23]. In the present study, we observed that 15 (36.5%) individuals had a COVID-19 history before vaccination (< 1 year) in whom vaccine could act as a trigger to set up the disorder and present the late symptoms. On the other side, are the cases 16 (39%) who developed a kind of irregularities without previous COVID-19 infection but post-vaccination. It is hypothesized that in this population, the vaccine was the main cause and the infection, Long VAX, could act as the trigger for late side effects of the vaccine. Furthermore, 15 individuals with a persistent symptom got infected after vaccination in whom the time of the disorder was mostly after the booster shots. Therefore, vaccination itself may lead to some sorts of persistent side effects.

The advantage of this study is the long-term follow-up of vaccinated individuals through different vaccine regimens. Long-COVID could be a situation caused by the infection itself which could be similar to Long VAX condition as they both result in similar symptoms. The difficulty of defining this issue stems from largely vaccinated people who had a previous infection, a post-exposure or reinfection. The present data evaluated some late disorders in vaccinated individuals as possible long-COVID, the vaccine side effects or the both.

We live in an era in which the vast majority of people have infected by SARS-CoV-2 and/or got vaccinated against it, differentiation of the late disorders as the vaccine side effect or long-COVID manifestation is difficult. Hence, some complications though late ones, might be a possible consequence of COVID-19 or its vaccination. The present data takes the advantage of long-term follow-up which presents various forms of late events in each episode of COVID-19 infection beside the vaccination. The rate of late symptoms in the present study also highlights the importance of long-term follow-up studies among population worldwide.

Funding

None.

Declaration of interest

The authors have no conflict of interest to declare.

Data availability

All data generated or analyzed during this study are included in this published article.

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No competing interests reported.

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Evaluation of late disorders as possible long-COVID and/or vaccination consequences

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Abstract

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Introduction

Methods

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Participants

Long-term symptoms classification

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Conclusion

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