What Should We Do after the COVID-19 Vaccination? Vaccine-Associated Diseases and Precautionary Measures against Adverse Reactions

COVID-19 vaccines have been used to counteract the global COVID-19 pandemic. While these are effective, adverse reactions have been reported, such as injection-site pain, muscle ache, fever, palpitation, and chest discomfort. The release of inflammatory cytokines, such as interleukin (IL)-6 and IL-1β, is a potential mechanism for post-vaccine side-effects. Chest discomfort after the vaccination, including myocarditis and acute coronary syndrome, is a particularly serious adverse reaction. It is important to be familiar with the differential diagnoses of chest discomfort and organ-specific diseases associated with COVID-19 vaccines as the preparation for booster shots and vaccinations among children aged 5–11 years begins. High-intensity exercise, alcohol, tobacco smoking, and baths promote inflammatory cytokines, such as IL-6, which may exacerbate the adverse reactions after vaccination. Japanese data show that deaths during baths are the most common for several days after mRNA vaccination. Additionally, alcohol and tobacco smoking were identified as predictive factors of lower antibody titers after vaccination. In this review, we aimed to provide a few recommendations to prevent vaccine-associated disease.

High-intensity exercise promotes the release of inflammatory cytokines [29]. Drinking alcohol, smoking tobacco, and baths can also increase inflammatory cytokines release [30][31][32]. In Singapore, individuals are advised against strenuous exercise after vaccination [33]. In Japan, deaths while taking a bath have been reported to occur within one week after mRNA vaccination [34,35] (Figure 1). In this review, we summarized the diseases associated with the COVID-19 vaccines (Table 1) and recommended several precautions to be taken post-vaccination, including limiting high-intensity exercise, alcohol use, tobacco smoking, and baths. In this review, we summarized the diseases associated with the COVID-19 vaccines (Table 1) and recommended several precautions to be taken post-vaccination, including limiting high-intensity exercise, alcohol use, tobacco smoking, and baths.
of chest discomfort and palpitation after COVID-19 vaccination ( Figure 2). Myocarditi and pericarditis are reported to be more common in young males after the second vac cination. In male patients aged 12-15 and 16-17 years, the reported incidence is 162.2/mil lion and 93.0/million, respectively [40]. Patients with myocarditis/pericarditis usually pre sent 24-72 h post-vaccination [38]. In contrast, patients with ACS tend to be older in ag and typically present 24 h post-vaccination [36]. Oster et al. reported that 98% of post vaccine myocarditis cases showed an elevated troponin level [38]. Troponin is useful fo screening post-vaccine myocarditis, but false negatives are possible, especially within 1 h of the vaccine or a few days later [46]. Electrocardiography and transthoracic echocar diography (TTE) have detected 72% and 17% of the abnormalities associated with post vaccine myocarditis, respectively [46]. Therefore, diagnosis by multi-modality imaging including cardiac magnetic resonance imaging and longitudinal strain measured by TTE is important [37,41]. In cases where a definitive diagnosis is difficult due to the inability to perform multi-modality imaging, detailed follow-up is critical in any cases of suspected myocarditis/pericarditis. NSAIDs, colchicine, and steroid therapy are the standard treat ments for myocarditis/pericarditis [27]. In severe cases, steroids may be effective in pre venting cytokine release, autoimmunity, and eosinophilic myocarditis [20]. Colchicine which has an inhibitory effect on the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, which is associated with IL-1β (inflammatory cytokine) secre tion [47], may be also effective for vaccine-associated inflammation [48].

Respiratory Diseases
Asthma attacks [49], diffuse alveolar hemorrhages [50], eosinophilic pneumonia [21] interstitial lung disease [51], and sarcoidosis [52] following COVID-19 vaccination hav been reported (Table 1). Although the relationship between the COVID-19 vaccines and asthma attacks and interstitial lung disease is unknown, there have been reports of cardia arrest after vaccination [34,35,49]. The deaths associated with respiratory disease are th third most common after cardiovascular and cerebrovascular disease [5]. Differentiating these cases from heart failure is important, especially in individuals who exhibit coughing and dyspnea.

Respiratory Diseases
Asthma attacks [49], diffuse alveolar hemorrhages [50], eosinophilic pneumonia [21], interstitial lung disease [51], and sarcoidosis [52] following COVID-19 vaccination have been reported (Table 1). Although the relationship between the COVID-19 vaccines and asthma attacks and interstitial lung disease is unknown, there have been reports of cardiac arrest after vaccination [34,35,49]. The deaths associated with respiratory disease are the third most common after cardiovascular and cerebrovascular disease [5]. Differentiating these cases from heart failure is important, especially in individuals who exhibit coughing and dyspnea.

Others
Abnormal menstrual cycles (delayed menstruation or increased bleeding or pain) [106], anaphylaxis [44], gout flares [48], lymphadenopathy [107,108], rhabdomyolysis [109], shoulder injuries related to vaccine administration (SIRVA) [109,110], and Vogt-Koyanagi-Harada syndrome [19] have also been reported following COVID-19 vaccination (Table 1). SIRVA is an acute inflammation of the shoulder that causes substantial shoulder pain and a limited range of motion [109,110]. FDG uptake with positron emission tomography imaging, which suggests the inflammation of the deltoid muscle and axillary lymph nodes at the inoculation site, has been reported [107,108].

Inflammatory Cytokines
One of the most plausible causes of post-vaccine adverse reactions is the increased release of inflammatory cytokines [7][8][9][10]. Inflammatory cytokines, such as IL-6, IL-1β, etc., are released due to the LNP component of the mRNA vaccines [9]. LNPs are also components of the small interfering RNA therapeutics (Patisiran) [111]. Patisiran increases IL-6 and interferon-inducible protein 10 (IP10) levels after infusion [112]. In practice, patisiran requires premedication before infusion, including dexamethasone, an H1/H2 blocker, and acetaminophen, preventing cytokine release and injection-site reaction [112]. The spike protein produced by the COVID-19 mRNA vaccine or by SARS-CoV-2 itself induces IL-1β secretion in macrophages [28]. NLRP3 inflammasome is associated with IL-1β secretion. Colchicine has the effect of suppressing the formation of NLRP3 inflammasome [47], which may be useful for vaccine-associated inflammation [48]. The mRNA vaccines increase both immunostimulatory cytokines release and inflammatory cytokines release, especially after the second vaccination and in patients infected by SARS-CoV-2 [10]. The number of deaths after vaccination is higher after the second vaccination (60.6%) than after the first (39.4%) [6]. These similarities may suggest the association in the overproduction of inflammatory cytokines.

ACE2 Downregulation
Post-vaccine adverse reactions may also be the result of the downregulation of ACE2 [26,27]. ACE2 converts angiotensin II (Ang II) to Ang1-7, leading to vasodilation and cardioprotection [26]. The SARS-CoV-2 spike protein in a COVID-19 mRNA vaccine binds to ACE2 and induces ACE2 downregulation. ACE2 downregulation causes an increased level of Ang II and decreases Ang1-7, leading to vasoconstriction and cardiovascular events. The increase in Ang II and the decrease in Ang1-7 trigger the NF-kB pathway, which further promotes the release of inflammatory cytokines, including IL-6, IL-1β, etc. [116]. Myopericarditis is more common in young men than in women, which may be related to the increased level of ACE2 in the latter due to estrogen [117].

Avoid Strenuous Exercise
High-intensity exercise increases the expression of the NLRP3 gene and inflammatory cytokines (IL-1β and IL-18) compared to moderate-intensity exercise [29]. Moderate-tolow-intensity training is recommended for athletes instead of high-intensity at the time of vaccination [118]. As a precautionary measure against post-vaccination myocarditis in Singapore, young individuals, including children and adolescents, are advised to avoid strenuous physical activities such as running, weightlifting, competitive sports, or playing ball games for two weeks after receiving a COVID-19 vaccination [33]. High school-aged male students tend to exercise more than adult men [119], and because myocarditis occurs predominantly in male adolescents, exercise restriction is recommended. Regarding infection prevention, lymphocytes decrease on the second day following the mRNA vaccination [120], and 3 to 72 h after the vaccination, high-intensity exercise increases the risk of opportunistic infections, according to the open window theory [118].

Avoid Consuming Alcohol and Smoking
Alcohol intake and tobacco smoking cause an increased release of inflammatory cytokines [30,31], coronary spasms [121], and arrhythmia [122]. Alcohol intake and tobacco smoking have also been identified as predictive factors for lower antibody titers after vaccination [123,124]. Alcohol intake increases atrial fibrillation (AF) [122]. On the contrary, limiting alcohol reduces the incidence of AF [122]. Therefore, avoiding alcohol consumption and tobacco smoking is important for increasing antibody titers and preventing adverse reactions, such as coronary spasms and arrhythmia.

Take a Shower Instead of Sitting in a Hot Bath
Taking a bath improves sleep quality, vascular functions, and insulin sensitivity. In contrast, sudden deaths have been associated more frequently with bathing [125]. Inflammatory cytokines, especially IL-6, also increase immediately after bathing [32]. The exact relationship between bathing and COVID-19 vaccination is unknown. However, there have been many sudden deaths while bathing after vaccination in Japan (50 cases; 29 females, 58% and 21 males, 42%; median age 80 (IQR 73-86) years) [34,35] (Figure 1). On the contrary, there have been no reported deaths related to bathing after the influenza vaccine in 2019-2020 [126]. Taking a bath is uniquely customary in Japan. Hot baths are less popular outside of Japan. As such, this issue must be addressed locally. The majority of deaths  (Figure 1). Based on these reported cases, we suggest that, immediately after COVID-19 vaccination and for several days afterwards, individuals should be advised to take showers rather than baths

Discussion
Deaths after COVID-19 vaccination usually occur within several days. According to the US surveillance data, the most common cause of death after vaccination is cardiovascular events, followed by cerebrovascular events [5]. Similarly, the Japanese data have shown that deaths during baths are the most common for several days after mRNA vaccination [34,35] ( Figure 1). The COVID-19 vaccines promote inflammatory cytokine release [7][8][9][10], and the overproduction of inflammatory cytokines and thrombosis has been documented in cardiovascular pathology [45].
High-intensity exercise, alcohol intake, tobacco smoking, and taking a bath also increase inflammatory cytokine release [29][30][31][32], which may promote cardiovascular events after vaccination. Based on the current evidence, we recommend refraining from highintensity exercise, alcohol intake, tobacco smoking, and baths immediately after COVID-19 vaccination and for several days afterwards for the prevention of severe adverse reactions, including death. In Singapore, adolescents and younger persons are advised to avoid strenuous physical activities for two weeks after COVID-19 mRNA vaccination [33]. Most postvaccination deaths have occurred among the elderly (median age: 76 (IQR 66-86) years) [5]. As such, we propose that high-intensity exercise restriction should be recommended for all individuals after COVID-19 vaccination, regardless of age. Alcohol intake and tobacco smoking interfere with the increase in antibody titers after vaccination. Likewise, corticosteroids and immunosuppressive drugs interfere with vaccine efficacy [123,124]. To increase the vaccine's effectiveness against COVID-19, we recommend refraining from drinking alcohol and smoking immediately after vaccination.
In patients who take corticosteroid and immunosuppressive medication, there is a high risk of aggravation due to COVID-19 infection [127]. In particular, pre-existing respiratory disorder cases, including MG, may take advantage of the vaccination to avoid COVID-19 pneumonia [66]. On the other hand, although reports are limited, vaccines are also known to relapse autoimmune diseases such as MG, GBS, Graves' disease, and RA [64,66,89,128]. Therefore, autoimmune diseases require careful observation before and after vaccination.
For patients with a history of COVID-19 infection, vaccination may further increase both inflammatory and immunostimulatory cytokines, including IL-6, compared to patients who have not had the infection [10]. Therefore, receiving a COVID-19 vaccine shortly after COVID-19 infection is likely to cause more pronounced inflammation [10] and autoimmunity due to IL-6 overproduction [113]. In Japan, vaccination is recommended about three months after COVID-19 infection for the healthy population [129].

Conclusions
After COVID-19 vaccination, inflammatory cytokines, autoimmune involvement, eosinophilia, and the downregulation of ACE2 have been reported in relation to various symptoms and diseases. We should recognize these adverse effects and recommend the following precautions immediately after vaccination: limit strenuous exercise, alcohol intake, tobacco smoking, and taking baths.