COVID-19 Vaccination Trends and Side Effects among Egyptian Hemodialysis Patients: A Multicenter Survey Study

(1) Background: Vaccination may be a key intervention to prevent infection in chronic hemodialysis (CHD) patients. This study aimed to determine the COVID-19 vaccination status in Egyptian CHD patients and to analyze the safety and detailed side effect profile of the COVID-19 vaccine among these patients. (2) Methods: This survey-based study was conducted on 670 end-stage renal disease (ESRD) patients on CHD from 3 December 2021 to 5 February 2022. Subjects were asked about sociodemographic characteristics, clinical and therapeutic data, in addition to their COVID-19 vaccination status. If the subject had been vaccinated, we inquired about the type of vaccine and the side effects that occurred within a few days after administration of the first and second dose of the COVID-19 vaccine. Additionally, subjects were asked about the onset of side effects (days from vaccination), timing of maximum symptoms, intensity of symptoms and their effect on activity and need for medical attention. (3) Results: The study included 670 CHD patients with a mean age of 50.79 years; 58.1% were females. The vast majority (614; 91.6%) of the studied patients received two doses of the vaccine. Side effects were more commonly reported after the first dose than the second dose. The main side effects reported were generalized weakness/fatigue (56%), headache (43.8%) and fever (40.4%), and sore arm/pain was also reported (29.3%). Adverse events mostly occurred within one day after vaccination and the maximum symptoms usually happened on the second day. The median duration of symptoms was 3 days with a maximum duration up to 5 days. The univariate logistic regression analysis showed that male gender (OR 1.848; (95% CI, 1.242–2.749), p = 0.002), age (OR 0.981; (95% CI, 0.969–0.993), p = 0.003), smoking (OR 6.067; (95% CI, 3.514–10.475), p < 0.001), duration since starting HD (OR 0.998; (95% CI, 0.998–0.999), p < 0.001), associated comorbidities (OR 2.202; (95% CI, 1.478–3.281), p < 0.001) and prior COVID-19 infection (OR 3.318; (95% CI, 1.952–5.642), p < 0.001) were the main determinants of adverse events related to COVID-19 vaccination. (4) Conclusions: our preliminary findings support the favorable short-term safety profile of the COVID-19 vaccine among CHD patients, and hence can reassure both clinicians and patients, as well as further promote COVID-19 vaccine administration among these patients.


Introduction
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease , is a major pandemic that is imposing a great burden on healthcare systems all around the world [1]. Patients on dialysis for end-stage kidney disease (ESKD) face unique circumstances that increase their risk of SARS-CoV-2 infection.
The study included ESRD patients on CHD for more than 6 months and aged >18 years, who either were vaccinated with the COVID-19 vaccine or not. Vaccinated participants must have received the most recent dosage of the vaccine, either the first or second dose, no more than thirty days before completing the questionnaire. The participants were recruited from different Egyptian HD units in the Dakahlia Mansoura Nephrology and Dialysis Unit (MNDU), Fayom (Fayoum General Hospital, Tamia Hospital, Fayoum Insurance Hospital) and Cairo (Rawas Hemodialysis Center). Patients aged less than 18 years or who had psychiatric or neurological disabilities were excluded from the start.
Patients were approached (in person) and provided complete questionnaire data, as well as examples of commercial names for generic pharmaceutical drugs. The questionnaires were given to patients at respective HD units by the researchers. The questionnaire was self-administered for people who could read and write, and it was delivered by a researcher for those who could not.

Calculation of Sample Size
The online sample size calculator RaoSoft ® was used to determine the appropriate sample size. Based on an estimated prevalence of patients on dialysis (264 pmp [11]), the 50% predicted response, 5% margin of error and 95% confidence level, the minimum sample size was 397 participants.

The Questionnaire
The study used a questionnaire with multiple-choice items. The questionnaire was prepared and then refined and revised. It was then provided to the patients in Arabic after being translated. Five nephrology staff members examined the translation, questionnaire design, substance, words, comprehension, and ease of completion in a pilot study to validate the questionnaire. The questionnaire was finalized through an iterative conversation. The questions were written to be as straightforward as possible. Answers were limited to yes/no questions (closed-ended questions). Later, the questionnaire's reliability was assessed by a group of twenty recently vaccinated HD patients, who completed the questionnaire twice with a minimum interval of two weeks. The provisional instrument's re-test resulted in significant reliability, with a mean Cohen's kappa coefficient of 0.84 ± 0.16. The following areas were covered in the survey: sociodemographic characteristics, clinical and therapeutic data, history of COVID-19 infection, associated symptoms and sequalae. Before moving on to the rest of the questions, participants were questioned about their COVID-19 vaccination status. If the subject had not been vaccinated, the study explored the barriers of not being vaccinated. If the subject had been vaccinated, we inquired about the type of vaccine and the side effects that were associated with the administration of the first and second dose of the COVID-19 vaccine.
Regarding post-vaccination side effects, the participants were asked to choose from symptoms that they experienced within a few days after vaccination. This section was designed to answer questions about general, localized, musculoskeletal, gastrointestinal, psychological, neurological, endocrine, cardiovascular, respiratory, urinary, and allergic symptoms.
The final part concerned the onset of side effects (days from vaccination), timing of maximum symptoms, intensity of symptoms and their effect on activity and need for medical attention. Intensity of symptoms was assessed using the visual analogue scale (VAS), which ranges from 0 (no symptoms at all) to 10 (very severe symptoms).
Patients were approached (in person) and provided complete questionnaire data, as well as examples of commercial names for generic pharmaceutical drugs. The questionnaire was self-administered for people who could read and write, and it was delivered by a researcher for those who could not.
In the final section, those who had not been vaccinated were asked about the barriers to receiving COVID-19 vaccination.

Outcome Measures
Our primary outcome was the determination of the vaccination rate among Egyptian HD patients by asking all participants if they had received the COVID-19 vaccine and the secondary outcomes included the identification of adverse events related to COVID-19 vaccination and factors related to these adverse events.

Ethical Consideration
Prior to commencing the study, ethical approval was obtained from the institutional review board of Mansoura University (approval no: R.21.12.1543). The work was carried out in line with the Declaration of Helsinki [12]. The survey was completely voluntary and entirely anonymous. When inviting the participants, the purpose of the study was clearly explained, and informed written consent was obtained.

Statistical Analysis
SPSS (Statistical Product for Social Science) version 20.0 program was used to process the data. Frequencies and relative percentages were used to present the qualitative data. Mean and standard deviation were employed to represent the quantitative data that were normally distributed, while the median, minimum, and maximum were used to represent the quantitative data that were abnormally distributed. Regression analysis was used to determine the factors and associated adverse events related to COVID-19 vaccination in the vaccinated CHD patients. Logistic regression was used because the dependent variable was binary. Two models were considered a univariate model for each covariate and a multivariate model, including gender, age, weight, BMI, smoking, duration of HD, Ca supplementation, associated comorbidities and prior COVID-19 infection.

Study Participants' Demographics and General Characteristics
The study included 700 ESRD patients on CHD (response rate of 76.5%), recruited from multiple HD centers in 3 Egyptian governorates. Out of these patients, 30 were excluded due to incomplete data, as shown in the study flow chart (Figure 1).

Statistical Analysis
SPSS (Statistical Product for Social Science) version 20.0 program was used to process the data. Frequencies and relative percentages were used to present the qualitative data. Mean and standard deviation were employed to represent the quantitative data that were normally distributed, while the median, minimum, and maximum were used to represent the quantitative data that were abnormally distributed. Regression analysis was used to determine the factors and associated adverse events related to COVID-19 vaccination in the vaccinated CHD patients. Logistic regression was used because the dependent variable was binary. Two models were considered a univariate model for each covariate and a multivariate model, including gender, age, weight, BMI, smoking, duration of HD, Ca supplementation, associated comorbidities and prior COVID-19 infection.

Study Participants' Demographics and General Characteristics
The study included 700 ESRD patients on CHD (response rate of 76.5%), recruited from multiple HD centers in 3 Egyptian governorates. Out of these patients, 30 were excluded due to incomplete data, as shown in the study flow chart (Figure 1). The mean age of the study participants was 50.79 (SD = 15.9) years. More than half of the patients (58.1%) were females and most of them were married (78.1%). Three hundred and eighty-seven (57.8%) patients were illiterate, 416 (62.1%) were from urban areas, 540 (80.6%) were non-smokers and 417 (62.2%) had an average socioeconomic status. The median duration of HD was 5 years.  The mean age of the study participants was 50.79 (SD = 15.9) years. More than half of the patients (58.1%) were females and most of them were married (78.1%). Three hundred and eighty-seven (57.8%) patients were illiterate, 416 (62.1%) were from urban areas, 540 (80.6%) were non-smokers and 417 (62.2%) had an average socioeconomic status. The median duration of HD was 5 years. In terms of comorbidities, 430 (64.2%) patients were hypertensive, 64 (9.6%) were diabetic, and 178 (26.6%) had chronic anemia, as illustrated in Table 1.

COVID-19 Vaccine Related Anamnesis
After evaluating the advice from healthcare providers (HCP) about receiving the COVID-19 vaccine, 72.2% of patients reported that HCPs strongly endorsed it, 15.1% suggested it, 0.6% of HCPs were unsure, 0.1% advised against it, while only 11.9% reported that HCPs strongly discouraged it.

COVID-19 Vaccination Status
Among the studied 670 CHD patients, only 56 did not receive the COVID-19 vaccine. Fear of the vaccine side effects (28.6%) was the most common cause of not receiving the vaccine, as shown in Figure 2.
On the other hand, the vast majority (614; 91.6%) of the studied patients received two doses of the vaccine. AstraZeneca and Sinopharm were the most used vaccines (50.3% and 35.5%, respectively), as shown in Figure 3.

Adverse Events of COVID-19 Vaccination
The event rate of adverse events associated with COVID-19 vaccination in the vaccinated CHD patients is illustrated in Table 3 and includes the following adverse events.
The main general side effects that were reported after the first dose were generalized weakness/fatigue (56%), headache (43.8%) and fever (40.4%). These manifestations were rarely reported after the second dose. Sore arm/pain was reported in about one third (29.3%) of CHD patients after the first dose, in ten (1.6%) patients after the second dose and in one-hundred-and-three (16.8%) patients after both doses. Localized swelling at the Myalgia and generalized muscle pain were reported in 90 (14.7%) patients after the first dose and 9 (1.5%) after both doses. Arthritis/joint pains occurred in only 55 (9%), 2 (0.3%) and 3 (0.5%) patients following the first, second and both doses, respectively. Muscle stiffness/spasm was reported in only one patient following both doses. Decreased appetite was the most common reported gastrointestinal (GI) symptoms (25.1%) in CHD patients after the first dose, followed by abdominal pain (7.5%) and food intolerance. However, GI symptoms rarely occurred after the second dose. Duration of symptoms related to COVID-19 infection (days) 3 (2-7)

COVID-19 Vaccine Related Anamnesis
After evaluating the advice from healthcare providers (HCP) about receiving the COVID-19 vaccine, 72.2% of patients reported that HCPs strongly endorsed it, 15.1% suggested it, 0.6% of HCPs were unsure, 0.1% advised against it, while only 11.9% reported that HCPs strongly discouraged it.

COVID-19 Vaccination Status
Among the studied 670 CHD patients, only 56 did not receive the COVID-19 vaccine. Fear of the vaccine side effects (28.6%) was the most common cause of not receiving the vaccine, as shown in Figure 2.

Adverse Events of COVID-19 Vaccination
The event rate of adverse events associated with COVID-19 vaccination in the vaccinated CHD patients is illustrated in Table 3 and includes the following adverse events.
The main general side effects that were reported after the first dose were generalized weakness/fatigue (56%), headache (43.8%) and fever (40.4%). These manifestations were rarely reported after the second dose. Sore arm/pain was reported in about one third (29.3%) of CHD patients after the first dose, in ten (1.6%) patients after the second dose and in one-hundred-and-three (16.8%) patients after both doses. Localized swelling at the injection site occurred in 32 (5.2%) patients after the first dose. However, localized bleeding was reported in 62 (10.1%) patients after both first and second doses.   Anxiety (25.4%), psychological stress (12.9%), increase in sleep (9.3%), depression (2.8%) and decrease in memory (2%) were reported among recipients after the first dose and rarely reported after the second one. Tingling at the limb of the injection site (17.1%), sense of incoordination (10.4%), vertigo-like symptoms (8.6%), extremity weakness (3.9%) and reactivation of shingles (0.5%) occurred after the first dose and were seldom reported after the second dose. Of note, no patient reported loss of consciousness/fainting, seizures nor facial weakness following COVID-19 vaccination.
Chest pain, blood pressure changes and palpitations were reported in 14.3%, 12.2% and 7.7% of patients, respectively, following the first dose and rarely reported after the second one. Of note, no patient reported syncope after COVID-19 vaccination. Among the respiratory symptoms, shortness of breath occurred in 14.8% of recipients after the first dose, 0.3% after the second one and 0.7% after both doses. Coughing was reported in 1% and 0.5% of patients after the first and second dose. Only one patient reported wheezing after the first dose.

Other Data about the Adverse Events of COVID-19 Vaccine
As shown in Table 4, adverse events occurred within one day after vaccination. The maximum symptoms usually happened on the second day. The median duration of symptoms was 3 days, with a maximum duration up to 5 days. The median score of VAS used to determine the intensity of symptoms was 3, with a maximum score of 5. About two thirds of vaccinated CHD patients (64.5%) reported some temporary trouble when performing regular daily activities following COVID-19 vaccination. Only 4.2% of patients required transient time off from work. One patient sought help from an emergency department provider and two patients needed hospitalization following COVID-19 vaccination.

Determinants of Adverse Events Related to COVID-19 Vaccination
The univariate logistic regression analysis showed that male gender ( Table 5.

Discussion
The COVID-19 pandemic has had a significant negative impact on the dialysis population. SARS-CoV-2 infection and mortality are more common among these patients [13]. These patients are at a higher risk of opportunistic infections, serious sequelae, admission to the ICU, or possibly death due to their old age, uremic status, high comorbidity burden, and poor nutrition [14]. Preventive measures, such as hand hygiene, respiratory hygiene and self-isolation, are applied in HD units to prevent and control the spread of COVID-19 infection [15]. Given the high morbidity and mortality associated with COVID-19, the development of a safe and effective vaccine is critical. The COVID-19 vaccine is a vital milestone in the fight against the virus pandemic [16] and revolutionary in the control of disease among CHD patients [17]. However, safety data on the COVID-19 vaccine in these patients are lacking. This study aimed to determine the vaccination status in Egyptian CHD patients and analyze the safety and detailed side effect profile of the COVID-19 vaccine among these patients. To the best of our knowledge, this is the first study to address this topic in Egyptian CHD patients.
Based on the results of the current study, about one fourth of CHD patients reported previous infection with COVID-19. Most of the patients (84.4%) did not need hospitalization nor oxygen supply, while only 3.5% were admitted to ICU during infection with COVID-19. In a retrospective single center study from China, the incidence of COVID-19 infection among CHD patients was 11% [18]. In a recent meta-analysis of 29 international studies, the incidence of COVID-19 infection in CHD patients was 7.7% and the overall mortality was 22.7% [19]. Variations in viral screening criteria and COVID-19 infection confirmation methods could potentially explain the differences in incidence observed between the studies.
Most of the study patients (91.6%) have received the COVID-19 vaccine. This percentage is a result of the high COVID-19 vaccine acceptance rate in Egypt (90.50%) [20]. Of note, about three fourths of our sample reported that HCPs strongly endorsed it. In dialysis patients, the immune response after vaccination is comparable to that of controls [21]. So, COVID-19 vaccination is critical in this high-risk group in reducing mortality and hospitalization rates [22]. However, some individuals still have unwarranted fears about the vaccine [23], and this explains the percentage of 8.4% of our cohort who refrained from having the vaccination.
Despite the importance of vaccination, we still need more information on the side effects that accompany it, especially in some high-risk groups, including CHD patients. In this study, side effects were more commonly reported after the first dose than the second dose. This is in agreement with the findings of Hatmal and colleagues [24] findings, who showed that the side effects are more obvious after the first dose. On the other side, findings of previous studies [25,26] reported that adverse reactions are more common after administration of the second dose. It would be interesting to include a larger sample of people that received their second dose to compare their experience with side effects to those who received their first dose.
In this study, weakness, fatigue, headache, and fever were the most common reported general side effects of the COVID-19 vaccine. These results are in agreement with those obtained by Kadali and co-authors [27]. In the long term, fever may play a significant role in the immunological response following vaccination; chills and fever were found to have a significant relationship with an antibody response to the SARS-CoV-2 spike protein [28].
The most reported local reaction in our cohort was pain at the injection site. Similarly, in an observational study conducted on 50 vaccinated HD patients, the most prevalent local reaction was pain at the injection site within seven days following the injection, which occurred in 38 % of patients with mild degrees of pain after the first injection [29]. In addition, in a phase 3 trial conducted on 30,420 volunteers to determine the efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine, 86% reported pain at the injection site. Atypical, very delayed large injection site reactions to RNA COVID-19 vaccines may also occur; they usually begin a week after vaccination, last for several days and are resolved without treatment [30].
Inflammatory musculoskeletal symptoms may occasionally occur in close temporal association with the administration of the COVID-19 vaccine [31]. In a recently published meta-analysis of 15 phase 1/2 clinical trials, myalgia was one of the most common manifestations of the newly licensed vaccines [32]. More than half of the participants reported myalgia after vaccination in a prospective, controlled multicenter study conducted on 159 participants on dialysis, who received 2 doses of the mRNA-1273 COVID-19 vaccine (Moderna) [21]. In the present study, myalgia and generalized muscle pain were found in 14.7% of CHD patients after the first dose and 1.5% after both doses, while arthritis/joint pains occurred in only 9%. There is great uncertainty about whether the COVID-19 vaccine could cause or exacerbate inflammatory arthritis [33,34].
Regarding gastrointestinal (GI) symptoms, about 25% of our cohort reported decreased appetite and 7.5% experienced abdominal pain after the first dose. GI symptoms were rarely reported (0.5%) after COVID-19 vaccine in cancer patients. In general, the majority of GI tract-related side effects observed after COVID-19 vaccination are non-life threatening and transient [35,36].
The most common psychological symptoms reported among our CHD patients after the first dose were anxiety (25.4%), psychological stress (12.9%) and hypersomnolence (9.3%). Impaired sleep quality was reported in 10.65% of health care workers after COVID-19 vaccination [37]. In a survey study from Saudia Arabia conducted on 455 individuals, 3.2% reported a desire to sleep after the second dose compared to only 0.4% after the first dose [38]. In another survey study from Jordon conducted on 2213 participants, sleepiness and laziness were reported in 45.36% of participants [24]. In contrast, Abu-Hammad and coworkers found sleepiness in only 0.2% of a total 409 participants [39].
It is vital to know if COVID-19 vaccinations induce neurologic problems, such as demyelinating illnesses, seizures, or other possible deficits [40]. In real-world data, both vaccinated and unvaccinated people experienced a similar number of neurological events [41]. In the current study, tingling at the limb of the injection site (17.1%), sense of incoordination (10.4%), vertigo-like symptoms (8.6%) and extremity weakness (3.9%) were the most common neurological symptoms associated with the vaccine.
Regarding otolaryngology-related symptoms, sore throat was reported in 11.2% and nasal stuffiness in 8.8% of our patients. This is in agreement with the study by Avci and coauthors [42], in which rhinorrhea (4.4%), sore throat (3.2%), and nasal congestion (2.9%) were the most common otolaryngology-related complaints.
Subacute thyroiditis has been reported in association with COVID-19 vaccination. COVID-19 vaccine adjuvants may provoke an autoimmune/inflammatory condition [43]. Endocrinal symptoms related to COVID-19 vaccination have not been sufficiently highlighted and still need to be clarified.
Kaur and colleagues analyzed the cardiovascular (CV) adverse events reported after the COVID-19 vaccine in the WHO global database. Despite the fact that many CV adverse events were reported after COVID-19 vaccine administration, a causality evaluation is needed to validate the link because these CV adverse events are more common in particular age groups [44].
In the present study, manifestations of allergy, such as a rash, hives and atopic eczema, rarely occurred after the COVID-19 vaccine. Allergy was reported in about one fourth of those who received the COVID-19 vaccine [28]. However, only a few cases of severe allergic reactions have been reported after COVID-19 vaccination [45].
According to our results, the side effects after COVID-9 vaccination in CHD patients are mostly mild to moderate. Only one patient sought help from an emergency department provider and two patients needed hospitalization following COVID-19 vaccination. These findings are in line with earlier work, which found that the majority of the adverse events following COVID-19 vaccination were mild and were related to female sex and young age [46].
Using univariate regression analysis, male gender, age, smoking, duration since starting HD and prior COVID-19 infection were the main determinants of adverse events related to COVID-19 vaccination. In fact, females are more likely than males to experience side effects from vaccination [37]. In a cross-sectional survey study conducted in the United Arab Emirates to collect data on the effects of the COVID-19 vaccine on individuals, after the first dose of vaccination, 83% of females experienced adverse effects compared to 55% of men, and 98.5% of females versus 80% of males after the second dose [47]. The difference in side effects recorded for inactivated virus vaccinations, such as influenza, the measles, mumps and rubella combination vaccine, and attenuated dengue vaccines, across genders suggests that females have higher immune responses and side effects are more frequent [48]. Short-term experiments with Pfizer-BioNTech mRNA vaccines found that older adults had poorer immune responses [49]. In addition to lower post-vaccine responses, older people showed faster waning of antibodies following vaccinations [50]. However, we report in our study that older individuals were associated with more adverse events related to the COVID-19 vaccine.
To the best of our knowledge, this is the first study to investigate the side effects of the COVID-19 vaccine in CHD patients in Egypt. The strength of this study is the relatively large number of participants. However, certain limitations should be acknowledged. First, we employed self-reported data, which might lead to information bias, such as inconsistency in participants' reports. Second, this study only investigated the vaccine's short-term side effects (immediately after injection). The vaccine's medium and long-term effects are still unknown. Third, patients received different types of COVID-19 vaccine, which precludes conclusion about the side effect of a specific type. Multi-nation, larger sample size research, including a more diversified population, as well as assessing probable long-term side effects of various COVID-19 vaccinations, is recommended.

Conclusions
In conclusion, the side effects after COVID-9 vaccination in CHD patients are mostly mild to moderate. Male gender, age, smoking, duration since starting HD and prior COVID-19 infection were the main determinants of adverse events related to COVID-19 vaccination. Our preliminary findings support the favorable short-term safety profile of the COVID-19 vaccine among CHD patients, and hence can reassure both clinicians and patients, as well as further promote COVID-19 vaccine administration among these patients. Institutional Review Board Statement: Prior to commencing the study, ethical approval was obtained from the institutional review board of Mansoura University (approval no: R.21.12.1543). The work was carried out in line with the Declaration of Helsinki. The survey was completely voluntary and entirely anonymous. When inviting the participants, the purpose of the study was clearly explained, and informed written consent was obtained.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: All data generated or analyzed during this study are included in this published article.