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Review

Is the COVID-19 Pandemic Over? The Current Status of Boosters, Immunosenescence, Long Haul COVID, and Systemic Complications

by
Miriam Ting
1,* and
Jon B. Suzuki
2,3,4,5
1
Think Dental Learning Institute, Paoli, PA 19301, USA
2
University of Maryland, Baltimore, MD 20742, USA
3
University of Washington, Seattle, WA 98195, USA
4
Nova Southeastern University, Fort Lauderdale, FL 33314, USA
5
Temple University, Philadelphia, PA 19140, USA
*
Author to whom correspondence should be addressed.
Int. J. Transl. Med. 2022, 2(2), 230-241; https://doi.org/10.3390/ijtm2020021
Submission received: 24 April 2022 / Revised: 30 May 2022 / Accepted: 9 June 2022 / Published: 16 June 2022
(This article belongs to the Special Issue Translational Medicine Approach against the COVID-19 Pandemic)
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Abstract

:
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appears to be diminishing in infectivity and hospitalizations in the United States and many parts of the world. This review will provide current information on the pathogenesis of SARS-CoV-2 and long haul COVID, emerging research on systemic complications, and antibody responses of vaccines and boosters.

1. Introduction

Coronavirus disease 2019 (COVID-19) was first reported on 31st December 2019, and by 11th March 2020, it was declared a global pandemic by the WHO. COVID-19 started in Wuhan (China) and is caused by the highly contagious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This single stranded RNA virus has cell-surface spike glycoproteins which penetrate and adhere to host cells [1]. Entry into the host cell is via the angiotensin-converting enzyme 2 (ACE-2) receptor, which is found in the heart, lungs, kidneys, tongue, and salivary glands [1]. SARS-CoV-2 can easily colonize oral, nasal, and pharyngeal mucosa [2]. Transmission of SARS-CoV-2 occurs via aerosol, droplet, oral–fecal routes [3], and contaminated body fluids and surfaces [4].
Clinical COVID-19 symptoms included fever, dry cough, sore throat, myalgia, fatigue, diarrhea [5,6], and loss of taste [7]. These symptoms may appear 5.2 days after infection [8]. The majority of the time, COVID-19 infected patients may be asymptomatic or have mild symptoms. The report of acute respiratory distress syndrome (ARDS) or multi-organ failure was less than 5% [8]. SARS-CoV-2 can be highly contagious; asymptomatic patient may also transmit the virus. A study reported that COVID-19 transmission in asymptomatic patients and symptomatic patients were statistically similar [9]. The risk factors for COVID-19 include advanced age, diabetes, hypertension, obesity, and heart disease [10,11,12].
Healthcare facilities, including medical and dental offices, are at risk for cross infection between healthcare professionals and patients [13]. This risk of spread can be mitigated by the use of personal protective equipment (PPE) including masks, face shields, and gowns, and by preventive strategies including hand washing and pre-procedural mouth rinsing [14].

2. Pathogenesis and Immunosenescence

COVID-19 progression includes: (1) innate immunity activation; (2) adaptive immunity activation; (3) cytokine release syndrome (“cytokine storm”) [15]. Cytokine storms (Figure 1) are the result of a hyper-responsive host producing exaggerated cytokine release [16,17]. Cytokine storms increase vascular permeability and effector cell infiltration, resulting in excessive monocyte proliferation, lymphocyte apoptosis, and immunodeficiency states [18]. The clinical outcomes include shock, multiple organ dysfunction, hypercoagulation, acute lung injury [15], and multi-organ failure, including the kidneys and heart [19,20,21].
The COVID-19 proinflammatory factors involved in the cytokine storm included IFN-γ, IFN-γ-induced protein 10, IL-1, IL-6, IL-12, and monocyte chemoattractant protein [22]. COVID-19 non-survivors present with higher IL-6 levels than survivors [17]. IL-6 has been linked to increased severity [23,24,25,26,27] and deaths in the elderly and immunocompromised [28]. This increased inflammatory cytokine activation can cause long-lasting damage to the immune system [29]. The formation of microthrombi to larger blood clots in the vessels of major organs, including the lungs, may be responsible for the debilitating systemic effects of COVID-19 on the body [29].
Oral health and systemic health may influence COVID-19 susceptibility. The antibody response to SARS-CoV-2 peaks at 14–21 days after COVID-19 exposure [30]. SARS-CoV-2 can also stimulate neutralizing secretory antibodies, Immunoglobulin A (IgA), which can dominate the initial mucosal immune response in the oral cavity [31]. Patients with periodontal inflammation or other chronic inflammatory diseases, with an incipient heightened proinflammatory response, may have an increased risk of SARS-CoV-2 susceptibility and complications. In the oral cavity, the periodontal response to bacterial were designated as “high”, “low”, and “slow” [32]. High IL-1β levels were detected in the inflamed tissues of the “high” group. These differences of inflammatory response may contribute to COVID-19 patients, having different levels of disease severity from mild infections, hospitalizations, or morbidity [32].
COVID-19 infected older adults aged 70 and above presented with multiple complications and mortality [33]. Severe complications of COVID-19 were septic shock, blood clots, sepsis, pneumonia, and ARDS [34]. The cause of death was not usually the initial viral infection, but post-viral complications like ARDS. Headaches, encephalitis, and strokes have been reported complications in patients with COVID-19 [35]. Cardiac signs and symptoms include heart damage, arrhythmias, and heart failure. Myocarditis and cardiac muscle inflammation have been reported complications of COVID-19 [35].
Age-related compromised immunity (immunosenescence) may be the cause of increased mortality from COVID-19 in the elderly. Immunosenescence affects innate and adaptive immunity; it may cause increased cytokine production [36], lymphocyte blastogenesis impairment [37], ineffective antibody production, failed T-cell response, and severe inflammatory organ dysfunction [38]. Thus, immunosenescence may increase the susceptibility and the severity of COVID-19, as well as diminish the responses to the vaccine. This may result in higher COVID-19 vaccine breakthrough infections [39]. In August 2021, the Centers for Disease Control and Prevention (CDC) reported COVID-19 breakthrough infections, which could be due to waning vaccine antibody reaction or emerging SARS-CoV-2 variants [40].

3. Long Haul COVID

The healing time for COVID-19 is approximately 2 weeks for mild disease, and 3–6 weeks for more severe infections [41]. COVID-19 may progress to long haul COVID when symptoms extend beyond 4 weeks. Approximately 25–40% of COVID-19 infected patients will progress to long haul COVID [42]. The prevalence of long haul COVID were reported as follow: USA 16–53% [43,44], UK 1.6–71% [45,46,47,48], Denmark 1% [49], Germany 35–77% [50,51], Italy 5–51% [52,53], China 49–76% [54,55], Africa 68% [56], Bangladesh 16–46% [57,58], and India 22% [59,60]. A retrospective study reported that 34% of COVID-19 patients had lingering psychiatric or neurological symptoms 6 months after COVID-19 [42]. Another study reported that 87.4% of hospitalized COVID-19 patients have persistent symptoms after 60 days [61]. A Danish survey of 152,000 people reported that almost one third of the people surveyed had at least one persistent symptom between 6 and 12 months after COVID-19 onset. This survey revealed that the most commonly reported long-term symptoms were fatigue and impairment of taste and smell. These symptoms related to long haul COVID can last for at least 12 weeks [62]. Hospitalized patients reported higher prevalence compared to community patients [63].
Long haul COVID differs from acute COVID-19. Long haul COVID patients are survivors of acute COVID who have developed persistent symptoms that last for at least 6 months [64]. Long haul COVID can affect COVID survivors of all severity and age. Long haul COVID can also affect survivors who are no longer SARS-CoV-2 positive [65]. Following acute COVID-19 infection, a possible mechanism for long haul COVID could be the chronic inflammatory responses to persistent viral reservoirs [66] or the delayed damage from the autoimmune response to host antigens via molecular mimicry [67].
Long haul COVID has a higher prevalence in women and in patients aged 24–36 years [68]. Risk factors reported for long haul COVID include age, smoking, asthma, obesity, poor health, autoimmune diseases, and chronic inflammatory diseases [14,69]. Pre-existing asthma is significantly associated with long haul COVID [45]. Obese patients are 25% more likely to progress to long haul COVID than patients that are not obese [70]. Long haul COVID symptoms may include fever, fatigue, brain fog, headaches, dyspnea, coughing, nausea, vomiting, anxiety, depression, muscle pain, chest pain, skin rash, palpitations, post-exertional malaise, and joint pain [71]. In a social media survey of COVID patients, 89% reported persistent cardiopulmonary symptoms [72]. Other symptoms may include anxiety, depression, psychosis, venous thromboembolism, as well as cardiac, hepatic, and renal impairment [73]. A UK study [48] of hospitalized patients at 5 months post-discharge reported 48% with persistent fatigue, 41% dyspnea, and 21–28% with chest pain and palpitations. A China study [54] of hospitalized patients at 6 months post-infection reported 63% with fatigue, 26% dyspnea, and 5–9% with chest pain and palpitations. This China study [55] at 12 months further reported improvements in this patient group to 30% with dyspnea, 7% with chest pain, and 20% with fatigue. Taste and smell impairment [20], gastrointestinal disturbances like nausea, and loss of appetite, diarrhea, and bowel blockages that were reported in acute COVID-19 were not consistently reported in long COVID. Systemic conditions arising from acute COVID-19 may persist during long haul COVID [74]. The increased inflammatory cytokines initiated by SARS-CoV-2 can result in prolonged immune system damage [29].
Coughing, dyspnea, and fatigue were consistently reported in long haul COVID. These symptoms may be related to the persistent cytokine production by pulmonary inflammatory cells. The elevated cytokines in long haul COVID include IL 1-β, TNF-α, IL-6, among others [29]. A prospective study evaluated the serum analytes from patients with long haul COVID for over 8 months and reported that these patients had highly activated innate immunity lacking in naïve T and B cells, and increased expression of type I and Type III interferon [62]. Persisting immune activation may be due to lingering antigens, autoimmunity, or impaired healing [62]. Patients with long haul COVID-19 also reported palpitations and angina [35]. This increased risk of headaches, encephalitis, and strokes in patients with long haul COVID may require constant monitoring [35].
Although children may have less severe COVID-19 than adults [75], long haul COVID and multisystem inflammatory syndrome has been reported as a long-term consequence of SARS-CoV-2 infection in children. Both long-term consequences can even affect asymptomatic COVID-19 infected children [76]. The prevalence of long haul COVID reported in a systematic review was 25.24% and the most common clinical manifestations were mood symptoms, fatigue, and sleep disorders [77].
The patient’s levels of D-dimer, C-reactive protein (CRP), and lymphocytes were potential inflammatory biomarkers of long haul COVID. Increased levels of D-dimer, CRP, and reduced lymphocytes were more common in patients with persistent symptoms than fully recovered patients [78]. These systemic inflammatory biomarkers were also associated with radiological abnormalities of the heart, liver, and kidney at 2–3 months following discharge of COVID-19 patients [79].
Healthcare professionals should be aware that long COVID is becoming increasingly more prevalent. Oral healthcare professionals should be prepared to treat these patients safely in an outpatient setting per CDC infection control guidelines [73]. Potential treatment for long haul COVID may include rehabilitation, behavioral modification, psychological support, or pharmacologic treatments. Rehabilitation may include light aerobic exercise that gradually increases in intensity until improvements are seen [80]. Behavioral modification and psychological support aim to improve wellness and mental health [80]. In elderly post-COVID patients, a randomized controlled trial reported that a 6 week rehabilitation program improved exercise tolerance, lung functions, quality of life, and anxiety [81]. However, rehabilitation may not be suitable for post-COVID patients with severe lung or cardiac damage, and in situations where exercise is contraindicated [82]. Presently, no pharmacologic medicine has been shown to have significant effects on long haul COVID. However, anti-inflammatory drugs may be used to manage long haul COVID-specific symptoms like fever and pain [83]. Shared pathophysiology of long haul COVID and postural orthostatic tachycardia syndrome (POTS) suggests potential drug repurposing. A study of 24 post-COVID patients with palpitations reported that a POTS medication (Ivabradine) effectively relieved palpitations [84]. Other pharmacologic therapies that are further investigated for repurposing are as follows: metabolic modulators (Niagen), immunomodulatory therapies (Steroids, laranilubmab, Tocilizumab, Atorvastatin, Colchicine), antifibrotic treatments (Pirfenidone, LYT-100), and anticoagulation (Apixaban) [63]. The use of these medications is preliminary and more research is needed to confirm efficacy.
Vaccines may provide significant protection against COVID-19 breakthrough infections and long haul COVID [85]. In a United Kingdom study [86], there was a reduced risk for long-haul COVID, serious complications, and breakthrough infections in fully vaccinated patients.

4. Vaccines and Boosters

The US Food and Drug Administration (FDA) guidance document stated that for a vaccine to be considered it should have at least 50% efficacy [87]. Vaccine effectiveness is proportional to the reduction of infection between the vaccinated and non-vaccinated subjects. The ideal vaccine would need to be effective after 1–2 doses, with at least 6 months of protection, and reduce transmission in the infected. It should prevent infection and disease transmission, as well as reduce mortality and disease severity. Randomized controlled vaccine trials evaluated reduction of clinical disease severity, infection, and infectivity duration [88]. However, socioeconomic conditions, geographical settings, age differences, and herd immunity may interfere with the data.
Vaccine development encompasses many methodologies, including targeted nucleic acid DNA or mRNA, adenovirus carrier (viral vector), spike proteins (protein subunits), and inactivated (whole) virus [89]. The objective of these vaccines is to neutralize the mRNA, spike protein, or the virus [90]. A robust Ig G response by B-lymphocytes and plasma cells initiated by these vaccines provides adequate immunological defense against invading SARS-CoV-2 (Figure 2).
Clinical trials for SARS-CoV-2 vaccines evaluated the antibody response for the following: adenoviral vector [91,92], mRNA [93,94], spike glycoprotein [95], and inactivated SARS-CoV-2 [96,97]. Some of the major vaccines are outlined in Table 1.
This UK report supports patients receiving both doses of the two-dose vaccine regimen, with 94% of patients remaining asymptomatic after both doses. Fourteen days after the first dose (Pfizer-BioNTech, Moderna, or AstraZeneca–Oxford vaccines), patients have a 0.5% risk of a breakthrough infection. This dropped to 0.2% of patients with COVID breakthrough infection after the second dose of these vaccines [86].
The diminishing immunologic memory of the patient (Figure 3) or the mutating antigenicity of SARS-CoV-2 may decrease in vaccine efficacy as time progresses. A study showed 64% vaccine effectiveness in long term care residents with a median age of 84, and 90% effectiveness in healthcare workers [98]. The vaccine effectiveness in older individuals that are on long term care are more muted compared to healthy older individuals [99]. Vaccine boosters may extend protection, and boosters comprising of multiple vaccinations or with multiple vaccine types may induce a more robust and persistent immunity [100,101]. The medically-compromised have lowered vaccine effectiveness and higher risks of COVID-19 breakthrough infections [39]. However, breakthrough infections have also been reported in fully vaccinated patients [40]. Despite that, vaccines can significantly reduce breakthrough infections. The United Kingdom data [86] reported reduced complications risk, breakthrough infections, and long haul COVID in fully vaccinated patients. However, the antibody levels in the vaccinated may decline faster than the those who have been infected with SARS-CoV-2. A study of 25,000 healthcare workers in United Kingdom reported that infection with SARS-CoV-2 reduced the risk of catching the virus again by 84% for 7 months [102]. For the uninfected but vaccinated individuals, the requirement for a booster would depend on the rate of antibody decline (immunosenescence).
The European Medicines Agency data in December 2021 suggests boosters following full vaccination of patients. However, currently there is no consensus among clinicians on recommendations for timing of a second booster [103]. Immunocompromised patients, aging patients, and patients with certain systemic diseases and conditions, BMI over 30, and immunosenescence play a role in longevity of antibody protection against SARS-CoV-2 [14]. Immunized individuals also appear to have high levels of neutralizing secretory IgA antibodies against SARS-CoV-2 [104].
Despite the success and safety of the COVID-19 vaccines, very rare but life-threatening cases of thrombosis were reported after ChAdOx1nCov-19 (AstraZeneca) vaccination [105]. This presented as unusual blood clots in unusual anatomical locations, mostly reported as sinus or cerebral thrombosis with thrombocytopenia, and is named Vaccine-associated Immune Thrombosis and Thrombocytopenia (VITT). Of vaccinated cases, VITT was reported between 1 in 125,000 and 1 in 1 million [106]. Onset of symptoms reported approximated 1–2 weeks after vaccination [107]. Treatment for it was mostly unfractionated heparin or sometimes immunomodulatory agents like immunoglobulin or steroids. Mortality rate from VITT was reported as 41.0% [108]. Based on the limited cases reported, females on contraceptives seem to be at the highest risk. However, this is ever-changing as more surveillance safety data becomes available for this and other COVID-19 vaccines. The benefits of the COVID-19 vaccinations outweigh the negative effects and incidence of adverse reactions [109].

5. Conclusions

The COVID-19 pandemic appears to be slowly diminishing with the passage of time with enhancement of preventive and therapeutic strategies, like social distancing, good hand washing, and use of antimicrobial mouth rinses. However, evolving clinical research and observations have resulted in additional recognized systemic manifestations, including but not necessarily limited to multiple organ dysfunction, hypercoagulation, acute lung injury, and multi-organ failure, including the kidneys and heart. These systemic complications associated with COVID-19 may have lingering effects with long haul COVID patients. Immunosenescense may limit the antibody response against SARS-CoV-2 and contribute to “breakthrough infections” despite vaccinations. Vaccines and boosters against SARS-CoV-2 and optimal systemic and oral health may prevent the spread of COVID-19 and increase survival. Current data for appropriate booster intervals is contingent on existing, recognized risk factors of vaccinated patients coupled with rate and extent of immunosenescense.

Author Contributions

M.T. participated in the design of the review, article selection and literature search, drafting revision of manuscript and figures, and final approval of submitted version. J.B.S. participated in the design of the review, article selection, drafting and revision of manuscript and figures, and final approval of submitted version. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data is contained within the article.

Conflicts of Interest

The authors declare no conflict of interest in the writing of this manuscript. J.B.S. is a U.S. Government Special Government Employee with the US Food and Drug Administration, Silver Spring, MD, USA.

References

  1. Walls, A.C.; Park, Y.J.; Tortorici, M.A.; Wall, A.; McGuire, A.T.; Veesler, D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 2020, 183, 281–292.e6. [Google Scholar] [CrossRef] [PubMed]
  2. Wölfel, R.; Corman, V.M.; Guggemos, W.; Seilmaier, M.; Zange, S.; Müller, M.A.; Niemeyer, D.; Jones, T.C.; Vollmar, P.; Rothe, C.; et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020, 581, 465–469. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Khan, S.; Liu, J.; Xue, M. Transmission of SARS-CoV-2, Required Developments in Research and Associated Public Health Concerns. Front. Med. 2020, 7, 310. [Google Scholar] [CrossRef] [PubMed]
  4. Van Doremalen, N.; Bushmaker, T.; Morris, D.H.; Holbrook, M.G.; Gamble, A.; Williamson, B.N.; Tamin, A.; Harcourt, J.L.; Thornburg, N.J.; Gerber, S.I.; et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N. Engl. J. Med. 2020, 382, 1564–1567. [Google Scholar] [CrossRef] [PubMed]
  5. Rothan, H.A.; Byrareddy, S.N. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J. Autoimmun. 2020, 109, 102433. [Google Scholar] [CrossRef] [PubMed]
  6. Greenland, J.R.; Michelow, M.D.; Wang, L.; London, M.J. COVID-19 Infection: Implications for Perioperative and Critical Care Physicians. Anesthesiology 2020, 132, 1346–1361. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Chen, L.; Zhao, J.; Peng, J.; Li, X.; Deng, X.; Geng, Z.; Shen, Z.; Guo, F.; Zhang, Q.; Jin, Y.; et al. Detection of SARS-CoV-2 in saliva and characterization of oral symptoms in COVID-19 patients. Cell Prolif. 2020, 53, e12923. [Google Scholar] [CrossRef]
  8. Li, Q.; Guan, X.; Wu, P.; Wang, X.; Zhou, L.; Tong, Y.; Ren, R.; Leung, K.S.; Lau, E.H.; Wong, J.Y.; et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N. Engl. J. Med. 2020, 382, 1199–1207. [Google Scholar] [CrossRef]
  9. Chen, Y.; Wang, A.H.; Yi, B.; Ding, K.Q.; Wang, H.B.; Wang, J.M.; Shi, H.B.; Wang, S.J.; Xu, G.Z. Epidemiological characteristics of infection in COVID-19 close contacts in Ningbo city. Zhonghua Liu Xing Bing Xue Za Zhi 2020, 41, 667–671. [Google Scholar]
  10. Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382, 727–733. [Google Scholar] [CrossRef]
  11. Zhou, F.; Yu, T.; Du, R.; Fan, G.; Liu, Y.; Liu, Z.; Xiang, J.; Wang, Y.; Song, B.; Gu, X.; et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020, 395, 1054–1062. [Google Scholar] [CrossRef]
  12. Simonnet, A.; Chetboun, M.; Poissy, J.; Raverdy, V.; Noulette, J.; Duhamel, A.; Labreuche, J.; Mathieu, D.; Pattou, F.; Jourdain, M.; et al. High Prevalence of Obesity in Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Requiring Invasive Mechanical Ventilation. Obesity 2020, 28, 1195–1199. [Google Scholar] [CrossRef] [PubMed]
  13. Souza, R.C.C.; Costa, P.S.; Costa, L.R. Dental sedation precautions and recommendations during the COVID-19 pandemic. Braz. J. Dent. 2020, 77, e1788. [Google Scholar]
  14. Ting, M.; Suzuki, J.B. SARS-CoV-2: Overview and Its Impact on Oral Health. Biomedicines 2021, 9, 1690. [Google Scholar] [CrossRef] [PubMed]
  15. Calabrese, L.H.; Lenfant, T.; Calabrese, C. Interferon therapy for COVID-19 and emerging infections: Prospects and concerns. Clevel. Clin. J. Med. 2020; in press. [Google Scholar] [CrossRef] [PubMed]
  16. Siu, K.L.; Yuen, K.S.; Castano-Rodriguez, C.; Ye, Z.W.; Yeung, M.L.; Fung, S.Y.; Yuan, S.; Chan, C.P.; Yuen, K.Y.; Enjuanes, L.; et al. Severe acute respiratory syndrome Coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. FASEB J. 2019, 33, 8865–8877. [Google Scholar] [CrossRef]
  17. Tay, M.Z.; Poh, C.M.; Rénia, L.; Macary, P.A.; Ng, L.F.P. The trinity of COVID-19: Immunity, inflammation and intervention. Nat. Rev. Immunol. 2020, 20, 363–374. [Google Scholar] [CrossRef]
  18. Tisoncik, J.R.; Korth, M.J.; Simmons, C.P.; Farrar, J.; Martin, T.R.; Katze, M.G. Into the eye of the cytokine storm. Microbiol. Mol. Biol. Rev. 2012, 76, 16–32. [Google Scholar] [CrossRef] [Green Version]
  19. Jose, R.J.P.; Manuel, A. COVID-19 cytokine storm: The interplay between inflammation and coagulation. Lancet Respir. Med. 2020, 8, e46–e47. [Google Scholar] [CrossRef]
  20. Perico, L.; Benigni, A.; Remuzzi, G. Should COVID-19 Concern Nephrologists? Why and to What Extent? The Emerging Impasse of Angiotensin Blockade. Nephron 2020, 144, 213–221. [Google Scholar] [CrossRef]
  21. Yao, X.H.; Li, T.Y.; He, Z.C.; Ping, Y.F.; Liu, H.W.; Yu, S.C.; Mou, H.M.; Wang, L.H.; Zhang, H.R.; Fu, W.J.; et al. A pathological report of three COVID-19 cases by minimal invasive autopsies. Zhonghua Bing Li Xue Za Zhi 2020, 49, 411–417. [Google Scholar] [PubMed]
  22. Wong, C.K.; Lam, C.W.K.; Wu, A.K.L.; Ip, W.K.; Lee, N.L.S.; Chan, I.H.S.; Lit, L.C.W.; Hui, D.S.C.; Chan, M.H.M.; Chung, S.S.C.; et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin. Exp. Immunol. 2004, 136, 95–103. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Chen, L.; Liu, H.G.; Liu, W.; Liu, J.; Liu, K.; Shang, J.; Deng, Y.; Wei, S. Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 2020, 43, 203–208. [Google Scholar] [PubMed]
  24. McGonagle, D.; Sharif, K.; O’Regan, A.; Bridgewood, C. The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease. Autoimmun. Rev. 2020, 19, 102537. [Google Scholar] [CrossRef]
  25. Henry, B.M.; de Oliveira, M.H.S.; Benoit, S.; Plebani, M.; Lippi, G. Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): A meta-analysis. Clin. Chem. Lab. Med. 2020, 58, 1021–1028. [Google Scholar] [CrossRef] [Green Version]
  26. Ulhaq, Z.S.; Soraya, G.V. Interleukin-6 as a potential biomarker of COVID-19 progression. Med. Mal. Infect. 2020, 50, 382–383. [Google Scholar] [CrossRef]
  27. Zhang, C.; Wu, Z.; Li, J.W.; Zhao, H.; Wang, G.Q. Cytokine release syndrome in severe COVID-19: Interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int. J. Antimicrob. Agents 2020, 55, 105954. [Google Scholar] [CrossRef]
  28. Adriaensen, W.; Matheï, C.; Vaes, B.; Van Pottelbergh, G.; Wallemacq, P.; Degryse, J.M. Interleukin-6 as a first-rated serum inflammatory marker to predict mortality and hospitalization in the oldest old: A regression and CART approach in the BELFRAIL study. Exp. Gerontol. 2015, 69, 53–61. [Google Scholar] [CrossRef]
  29. Wu, Y.; Huang, X.; Sun, J.; Xie, T.; Lei, Y.; Muhammad, J.; Li, X.; Zeng, X.; Zhou, F.; Qin, H.; et al. Clinical Characteristics and Immune Injury Mechanisms in 71 Patients with COVID-19. mSphere 2020, 5, e00362-20. [Google Scholar] [CrossRef]
  30. Long, Q.X.; Liu, B.Z.; Deng, H.J.; Wu, G.C.; Deng, K.; Chen, Y.K.; Liao, P.; Qiu, J.F.; Lin, Y.; Cai, X.F.; et al. Antibody responses to SARS-CoV-2 in patients with COVID-19. Nat. Med. 2020, 26, 845–848. [Google Scholar] [CrossRef]
  31. Sterlin, D.; Fadlallah, J.; Adams, O.; Fieschi, C.; Parizot, C.; Dorgham, K.; Rajkumar, A.; Autaa, G.; El-Kafsi, H.; Charuel, J.-L.; et al. Human IgA binds a diverse array of commensal bacteria. J. Exp. Med. 2020, 217, e20181635. [Google Scholar] [CrossRef] [PubMed]
  32. Bamashmous, S.; Kotsakis, G.A.; Kerns, K.A.; Leroux, B.G.; Zenobia, C.; Chen, D.; Trivedi, H.M.; McLean, J.S.; Darveau, R.P. Human variation in gingival inflammation. Proc. Natl. Acad. Sci. USA 2021, 118, e2012578118. [Google Scholar] [CrossRef] [PubMed]
  33. Huang, C.; Wang, Y.; Li, X.; Ren, L.; Zhao, J.; Hu, Y.; Zhang, L.; Fan, G.; Xu, J.; Gu, X.; et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020, 395, 497–506. [Google Scholar] [CrossRef] [Green Version]
  34. World Health Organization. Clinical Management of Severe Acute Respiratory Infection When Novel Coronavirus (2019-nCoV) Infection is Suspected; World Health Organization: Geneva, Switzerland, 2020. [Google Scholar]
  35. Wadman, M.; Couzin-Frankel, J.; Kaiser, J.; Matacic, C. A rampage through the body. Science 2020, 368, 356–360. [Google Scholar] [CrossRef] [PubMed]
  36. Fulop, T.; Larbi, A.; Dupuis, G.; Le Page, A.; Frost, E.H.; Cohen, A.A.; Witkowski, J.M.; Franceschi, C. Immunosenescence and Inflamm-Aging as Two Sides of the Same Coin: Friends or Foes? Front. Immunol. 2017, 8, 1960. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  37. Kovtonyuk, L.V.; Fritsch, K.; Feng, X.; Manz, M.G.; Takizawa, H. Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment. Front. Immunol. 2016, 7, 502. [Google Scholar] [CrossRef] [Green Version]
  38. Cunha, L.L.; Perazzio, S.F.; Azzi, J.; Cravedi, P.; Riella, L.V. Remodeling of the Immune Response with Aging: Immunosenescence and Its Potential Impact on COVID-19 Immune Response. Front. Immunol. 2020, 11, 1748. [Google Scholar] [CrossRef]
  39. Tenforde, M.W.; Olson, S.M.; Self, W.H.; Talbot, H.K.; Lindsell, C.J.; Steingrub, J.S.; Shapiro, N.I.; Ginde, A.A.; Douin, D.J.; Prekker, M.E.; et al. Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Among Hospitalized Adults Aged >/=65 Years—United States, January-March 2021. MMWR Morb. Mortal. Wkly. Rep. 2021, 70, 674–679. [Google Scholar] [CrossRef]
  40. Brown, C.M.; Vostok, J.; Johnson, H.; Burns, M.; Gharpure, R.; Sami, S.; Sabo, R.T.; Hall, N.; Foreman, A.; Schubert, P.L.; et al. Outbreak of SARS-CoV-2 Infections, Including COVID-19 Vaccine Breakthrough Infections, Associated with Large Public Gatherings—Barnstable County, Massachusetts, July 2021. MMWR Morb. Mortal. Wkly. Rep. 2021, 70, 1059–1062. [Google Scholar] [CrossRef]
  41. World Health Organization. Coronavirus Disease 2019 (COVID-19) Situation Report—46; World Health Organization: Geneva, Switzerland, 2019. [Google Scholar]
  42. Taquet, M.; Geddes, J.R.; Husain, M.; Luciano, S.; Harrison, P.J. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: A retrospective cohort study using electronic health records. Lancet Psychiatry 2021, 8, 416–427. [Google Scholar] [CrossRef]
  43. Logue, J.K.; Franko, N.M.; McCulloch, D.J.; McDonald, D.; Magedson, A.; Wolf, C.R.; Chu, H.Y. Sequelae in Adults at 6 Months After COVID-19 Infection. JAMA Netw. Open 2021, 4, e210830. [Google Scholar] [CrossRef] [PubMed]
  44. Hirschtick, J.L.; Titus, A.R.; Slocum, E.; Power, L.E.; Hirschtick, R.E.; Elliott, M.R.; McKane, P.; Fleischer, N.L. Population-Based Estimates of Post-acute Sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection (PASC) Prevalence and Characteristics. Clin. Infect. Dis. 2021, 73, 2055–2064. [Google Scholar] [CrossRef] [PubMed]
  45. Sudre, C.H.; Murray, B.; Varsavsky, T.; Graham, M.S.; Penfold, R.S.; Bowyer, R.C.; Pujol, J.C.; Klaser, K.; Antonelli, M.; Canas, L.S.; et al. Attributes and predictors of long COVID. Nat. Med. 2021, 27, 626–631. [Google Scholar] [CrossRef] [PubMed]
  46. Whitaker, M.; Elliott, J.; Chadeau-Hyam, M.; Riley, S.; Darzi, A.; Cooke, G.; Ward, H.; Elliott, P. Persistent symptoms following SARS-CoV-2 infection in a random community sample of 508,707 people. MedRxiv, 2021; in press. [Google Scholar]
  47. Office for National Statistics. Prevalence of Ongoing Symptoms Following Coronavirus (COVID-19) Infection in the UK. Available online: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/conditionsanddiseases/bulletins/prevalenceofongoingsymptomsfollowingcoronaviruscovid19infectionintheuk/1april2021 (accessed on 23 April 2022).
  48. Evans, R.A.; McAuley, H.; Harrison, E.M.; Shikotra, A.; Singapuri, A.; Sereno, M.; Elneima, O.; Docherty, A.B.; Lone, N.I.; Leavy, O.C.; et al. Physical, cognitive, and mental health impacts of COVID-19 after hospitalisation (PHOSP-COVID): A UK multicentre, prospective cohort study. Lancet Respir. Med. 2021, 9, 1275–1287. [Google Scholar] [CrossRef]
  49. Lund, L.C.; Hallas, J.; Nielsen, H.; Koch, A.; Mogensen, S.H.; Brun, N.C.; Christiansen, C.F.; Thomsen, R.W.; Pottegård, A. Post-acute effects of SARS-CoV-2 infection in individuals not requiring hospital admission: A Danish population-based cohort study. Lancet Infect. Dis. 2021, 21, 1373–1382. [Google Scholar] [CrossRef]
  50. Augustin, M.; Schommers, P.; Stecher, M.; Dewald, F.; Gieselmann, L.; Gruell, H.; Horn, C.; Vanshylla, K.; Di Cristanziano, V.; Osebold, L.; et al. Post-COVID syndrome in non-hospitalised patients with COVID-19: A longitudinal prospective cohort study. Lancet Reg. Health Eur. 2021, 6, 100122. [Google Scholar] [CrossRef]
  51. Seeßle, J.; Waterboer, T.; Hippchen, T.; Simon, J.; Kirchner, M.; Lim, A.; Müller, B.; Merle, U. Persistent Symptoms in Adult Patients 1 Year After Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study. Clin. Infect. Dis. 2022, 74, 1191–1198. [Google Scholar] [CrossRef]
  52. Venturelli, S.; Benatti, S.V.; Casati, M.; Binda, F.; Zuglian, G.; Imeri, G.; Conti, C.; Biffi, A.M.; Spada, M.S.; Bondi, E.; et al. Surviving COVID-19 in Bergamo province: A post-acute outpatient re-evaluation. Epidemiol. Infect. 2021, 149, e32. [Google Scholar] [CrossRef]
  53. Bellan, M.; Soddu, D.; Balbo, P.E.; Baricich, A.; Zeppegno, P.; Avanzi, G.C.; Baldon, G.; Bartolomei, G.; Battaglia, M.; Battistini, S.; et al. Respiratory and Psychophysical Sequelae Among Patients With COVID-19 Four Months after Hospital Discharge. JAMA Netw. Open 2021, 4, e2036142. [Google Scholar] [CrossRef]
  54. Huang, C.; Huang, L.; Wang, Y.; Li, X.; Ren, L.; Gu, X.; Kang, L.; Guo, L.; Liu, M.; Zhou, X.; et al. 6-month consequences of COVID-19 in patients discharged from hospital: A cohort study. Lancet 2021, 397, 220–232. [Google Scholar] [CrossRef]
  55. Huang, L.; Yao, Q.; Gu, X.; Wang, Q.; Ren, L.; Wang, Y.; Hu, P.; Guo, L.; Liu, M.; Xu, J.; et al. 1-year outcomes in hospital survivors with COVID-19: A longitudinal cohort study. Lancet 2021, 398, 747–758. [Google Scholar] [CrossRef]
  56. Dryden, M.; Vika, C. Post Acute Sequelae of SARS-CoV-2 Infection (PASC)—Formally Long COVID. Available online: https://www.nioh.ac.za/wp-content/uploads/2021/04/NIOH-Webinar-Invitation_-COVID-19-_Long-Covid-and-the-workplace_22-April-2021-Dr-Dryden.pdf (accessed on 23 April 2022).
  57. Mahmud, R.; Rahman, M.M.; Rassel, M.A.; Monayem, F.B.; Sayeed, S.J.B.; Islam, M.S.; Islam, M.M. Post-COVID-19 syndrome among symptomatic COVID-19 patients: A prospective cohort study in a tertiary care center of Bangladesh. PLoS ONE 2021, 16, e0249644. [Google Scholar] [CrossRef]
  58. Hossain, M.A.; Hossain, K.M.A.; Saunders, K.; Uddin, Z.; Walton, L.M.; Raigangar, V.; Sakel, M.; Shafin, R.; Kabir, F.; Faruqui, R.; et al. Prevalence of Long COVID symptoms in Bangladesh: A prospective Inception Cohort Study of COVID-19 survivors. BMJ Glob. Health 2021, 6, e006838. [Google Scholar] [CrossRef] [PubMed]
  59. Naik, S.; Haldar, S.N.; Soneja, M.; Mundadan, N.G.; Garg, P.; Mittal, A.; Desai, D.; Trilangi, P.K.; Chakraborty, S.; Begam, N.N.; et al. Post COVID-19 sequelae: A prospective observational study from Northern India. Drug Discov. Ther. 2021, 15, 254–260. [Google Scholar] [CrossRef] [PubMed]
  60. Chopra, N.; Chowdhury, M.; Singh, A.K.; Ma, K.; Kumar, A.; Ranjan, P.; Desai, D.; Wig, N. Clinical predictors of long COVID-19 and phenotypes of mild COVID-19 at a tertiary care centre in India. Drug Discov. Ther. 2021, 15, 156–161. [Google Scholar] [CrossRef] [PubMed]
  61. Carfì, A.; Bernabei, R.; Landi, F. Persistent Symptoms in Patients After Acute COVID-19. JAMA 2020, 324, 603–605. [Google Scholar] [CrossRef]
  62. Phetsouphanh, C.; Darley, D.R.; Wilson, D.B.; Howe, A.; Munier, C.; Patel, S.K.; Juno, J.A.; Burrell, L.M.; Kent, S.J.; Dore, G.J.; et al. Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection. Nat. Immunol. 2022, 23, 210–216. [Google Scholar] [CrossRef]
  63. Raman, B.; Bluemke, D.A.; Lüscher, T.F.; Neubauer, S. Long COVID: Post-acute sequelae of COVID-19 with a cardiovascular focus. Eur. Heart J. 2022, 43, 1157–1172. [Google Scholar] [CrossRef]
  64. Yong, S.J. Long COVID or post-COVID-19 syndrome: Putative pathophysiology, risk factors, and treatments. Infect. Dis. 2021, 53, 737–754. [Google Scholar] [CrossRef]
  65. Davis, H.E.; Assaf, G.S.; McCorkell, L.; Wei, H.; Low, R.J.; Re’Em, Y.; Redfield, S.; Austin, J.P.; Akrami, A. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. eClinicalMedicine 2021, 38, 101019. [Google Scholar] [CrossRef] [PubMed]
  66. Pollack, A.; Kontorovich, A.R.; Fuster, V.; Dec, G.W. Viral myocarditis—Diagnosis, treatment options, and current controversies. Nat. Rev. Cardiol. 2015, 12, 670–680. [Google Scholar] [CrossRef] [PubMed]
  67. Blagova, O.; Varionchik, N.; Zaidenov, V.; Savina, P.; Sarkisova, N. Anti-heart antibodies levels and their correlation with clinical symptoms and outcomes in patients with confirmed or suspected diagnosis COVID-19. Eur. J. Immunol. 2021, 51, 893–902. [Google Scholar] [CrossRef]
  68. UK Office for National Statistics. Prevalence of Long COVID Symptoms and COVID-19 Complications. 2020. Available online: https://www.ons.gov.uk/news/statementsandletters/theprevalenceoflongcovidsymptomsandcovid19complications (accessed on 23 April 2022).
  69. Ting, M.; Suzuki, J.B. COVID-19: Current overview on SARS-CoV-2 and the dental implications. Oral Health 2022, in press. [Google Scholar]
  70. Thompson, E.J.; Williams, D.M.; Walker, A.J.; Mitchell, R.E.; Niedzwiedz, C.L.; Yang, T.C.; Huggins, C.; Kwong, A.S.; Silverwood, R.; Di Gessa, G.; et al. Risk factors for long COVID: Analyses of 10 longitudinal studies and electronic health records in the UK. MedRxiv, 2021; in press. [Google Scholar]
  71. Couzin-Frankel, J. The long haul. Science 2020, 369, 614–617. [Google Scholar] [CrossRef]
  72. Ziauddeen, N.; Gurdasani, D.; O’Hara, M.E.; Hastie, C.; Roderick, P.; Yao, G.; Alwan, N.A. Characteristics and impact of Long Covid: Findings from an online survey. PLoS ONE 2022, 17, e0264331. [Google Scholar] [CrossRef]
  73. France, K.; Glick, M. Long COVID and oral health care considerations. J. Am. Dent. Assoc. 2022, 153, 167–174. [Google Scholar] [CrossRef]
  74. Temgoua, M.N.; Endomba, F.T.; Nkeck, J.R.; Kenfack, G.U.; Tochie, J.N.; Essouma, M. Coronavirus Disease 2019 (COVID-19) as a Multi-Systemic Disease and its Impact in Low- and Middle-Income Countries (LMICs). SN Compr. Clin. Med. 2020, 2, 1377–1387. [Google Scholar] [CrossRef]
  75. Chua, P.E.Y.; Shah, S.U.; Gui, H.; Koh, J.; Somani, J.; Pang, J. Epidemiological and clinical characteristics of non-severe and severe pediatric and adult COVID-19 patients across different geographical regions in the early phase of pandemic: A systematic review and meta-analysis of observational studies. J. Investig. Med. 2021, 69, 1287–1296. [Google Scholar] [CrossRef]
  76. Kundu, A.; Maji, S.; Kumar, S.; Bhattacharya, S.; Chakraborty, P.; Sarkar, J. Clinical aspects and presumed etiology of multisystem inflammatory syndrome in children (MIS-C): A review. Clin. Epidemiol. Glob. Health 2022, 14, 100966. [Google Scholar] [CrossRef] [PubMed]
  77. Lopez-Leon, S.; Wegman-Ostrosky, T.; del Valle, C.A.; Perelman, C.; Sepulveda, R.; Rebolledo, P.A.; Cuapio, A.; Villapol, S. Long COVID in Children and Adolescents: A Systematic Review and Meta-analyses. medrxiv, 2022; in press. [Google Scholar]
  78. Mandal, S.; Barnett, J.; Brill, S.E.; Brown, J.S.; Denneny, E.K.; Hare, S.S.; Heightman, M.; Hillman, T.E.; Jacob, J.; Jarvis, H.C.; et al. ‘Long-COVID’: A cross-sectional study of persisting symptoms, biomarker and imaging abnormalities following hospitalisation for COVID-19. Thorax 2021, 76, 396–398. [Google Scholar] [CrossRef] [PubMed]
  79. Raman, B.; Cassar, M.P.; Tunnicliffe, E.M.; Filippini, N.; Griffanti, L.; Alfaro-Almagro, F.; Okell, T.; Sheerin, F.; Xie, C.; Mahmod, M.; et al. Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge. EClinicalMedicine 2021, 31, 100683. [Google Scholar] [CrossRef]
  80. Wang, T.J.; Chau, B.; Lui, M.; Lam, G.-T.; Lin, N.; Humbert, S. Physical Medicine and Rehabilitation and Pulmonary Rehabilitation for COVID-19. Am. J. Phys. Med. Rehabil. 2020, 99, 769–774. [Google Scholar] [CrossRef]
  81. Liu, K.; Zhang, W.; Yang, Y.; Zhang, J.; Li, Y.; Chen, Y. Respiratory rehabilitation in elderly patients with COVID-19: A randomized controlled study. Complement. Ther. Clin. Pract. 2020, 39, 101166. [Google Scholar] [CrossRef]
  82. Demeco, A.; Marotta, N.; Barletta, M.; Pino, I.; Marinaro, C.; Petraroli, A.; Moggio, L.; Ammendolia, A. Rehabilitation of patients post-COVID-19 infection: A literature review. J. Int. Med Res. 2020, 48, 300060520948382. [Google Scholar] [CrossRef]
  83. Greenhalgh, T.; Knight, M.; A’Court, C.; Buxton, M.; Husain, L. Management of post-acute covid-19 in primary care. BMJ 2020, 370, m3026. [Google Scholar] [CrossRef]
  84. Jadhav, K.; Jariwala, P. ‘Ivabradin’ versus ‘Carvedilol’ in the management of Post-COVID-19 palpitation with sinus tachycardia. Indian Heart J. 2020, 72, S33. [Google Scholar] [CrossRef]
  85. The Effectiveness of Vaccination against Long COVID: A Rapid Evidence Briefing: UK Health Security Agency. Available online: https://ukhsa.koha-ptfs.co.uk/cgi-bin/koha/opac-retrieve-file.pl?id=fe4f10cd3cd509fe045ad4f72ae0dfff (accessed on 10 June 2022).
  86. Antonelli, M.; Penfold, R.S.; Merino, J.; Sudre, C.H.; Molteni, E.; Berry, S.; Canas, L.S.; Graham, M.S.; Klaser, K.; Modat, M.; et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: A prospective, community-based, nested, case-control study. Lancet Infect. Dis. 2021, 22, 43–55. [Google Scholar] [CrossRef]
  87. U.S. Food and Drug Administration. Development and Licensure of Vaccines to Prevent COVID-19: Guidance for Industry; U.S. Food and Drug Administration: Rockville, MD, USA, 2020. [Google Scholar]
  88. Weinberg, G.A.; Szilagyi, P.G. Vaccine Epidemiology: Efficacy, Effectiveness, and the Translational Research Roadmap. J. Infect. Dis. 2010, 201, 1607–1610. [Google Scholar] [CrossRef] [PubMed]
  89. Wang, J.; Peng, Y.; Xu, H.; Cui, Z.; Williams, R.O., 3rd. The COVID-19 Vaccine Race: Challenges and Opportunities in Vaccine Formulation. AAPS PharmSciTech 2020, 21, 225. [Google Scholar] [CrossRef] [PubMed]
  90. Thanh Le, T.; Andreadakis, Z.; Kumar, A.; Gómez Román, R.; Tollefsen, S.; Saville, M.; Mayhew, S. The COVID-19 vaccine development landscape. Nat. Rev. Drug Discov. 2020, 19, 305–306. [Google Scholar] [CrossRef] [PubMed]
  91. Zhu, F.-C.; Guan, X.-H.; Li, Y.-H.; Huang, J.-Y.; Jiang, T.; Hou, L.-H.; Li, J.-X.; Yang, B.-F.; Wang, L.; Wang, W.-J.; et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2020, 396, 479–488. [Google Scholar] [CrossRef]
  92. Logunov, D.Y.; Dolzhikova, I.V.; Zubkova, O.V.; Tukhvatulin, A.I.; Shcheblyakov, D.V.; Dzharullaeva, A.S.; Kovyrshina, A.V.; Lubenets, N.L.; Grousova, D.M.; Erokhova, A.S.; et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: Two open, non-randomised phase 1/2 studies from Russia. Lancet 2020, 396, 887–897. [Google Scholar] [CrossRef]
  93. Anderson, E.J.; Rouphael, N.G.; Widge, A.T.; Jackson, L.A.; Roberts, P.C.; Makhene, M.; Chappell, J.D.; Denison, M.R.; Stevens, L.J.; Pruijssers, A.J.; et al. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. N. Engl. J. Med. 2020, 383, 2427–2438. [Google Scholar] [CrossRef]
  94. Walsh, E.E.; Frenck, R.W., Jr.; Falsey, A.R.; Kitchin, N.; Absalon, J.; Gurtman, A.; Lockhart, S.; Neuzil, K.; Mulligan, M.J.; Bailey, R.; et al. Safety and Immunogenicity of Two RNA-Based COVID-19 Vaccine Candidates. N. Engl. J. Med. 2020, 383, 2439–2450. [Google Scholar] [CrossRef]
  95. Keech, C.; Albert, G.; Cho, I.; Robertson, A.; Reed, P.; Neal, S.; Plested, J.S.; Zhu, M.; Cloney-Clark, S.; Zhou, H.; et al. Phase 1–2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine. N. Engl. J. Med. 2020, 383, 2320–2332. [Google Scholar] [CrossRef]
  96. Xia, S.; Duan, K.; Zhang, Y.; Zhao, D.; Zhang, H.; Xie, Z.; Li, X.; Peng, C.; Zhang, Y.; Zhang, W.; et al. Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA 2020, 324, 951–960. [Google Scholar] [CrossRef] [PubMed]
  97. Xia, S.; Zhang, Y.; Wang, Y.; Wang, H.; Yang, Y.; Gao, G.F.; Tan, W.; Wu, G.; Xu, M.; Lou, Z.; et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: A randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect. Dis. 2021, 21, 39–51. [Google Scholar] [CrossRef]
  98. Moustsen-Helms, I.R.; Emborg, H.D.; Nielsen, J.; Nielsen, K.F.; Krause, T.G.; Molbak, K.; Møller, K.L.; Berthelsen, A.S.N.; Valentiner-Branth, P. Vaccine effectiveness after 1stand 2nd dose of the BNT162b2 mRNA Covid-19 Vaccine in long-term care facility residents and healthcare workers—A Danish cohort study. medrxiv, 2021; in press. [Google Scholar]
  99. Haas, E.J.; Angulo, F.J.; McLaughlin, J.M.; Anis, E.; Singer, S.R.; Khan, F.; Brooks, N.; Smaja, M.; Mircus, G.; Pan, K.; et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: An observational study using national surveillance data. Lancet 2021, 397, 1819–1829. [Google Scholar] [CrossRef]
  100. Tatsis, N.; Ertl, H.C. Adenoviruses as vaccine vectors. Mol. Ther. 2004, 10, 616–629. [Google Scholar] [CrossRef] [PubMed]
  101. Dolzhikova, I.V.; Zubkova, O.V.; Tukhvatulin, A.I.; Dzharullaeva, A.S.; Tukhvatulina, N.M.; Shcheblyakov, D.V.; Shmarov, M.M.; Tokarskaya, E.A.; Simakova, Y.V.; Egorova, D.A.; et al. Safety and immunogenicity of GamEvac-Combi, a heterologous VSV- and Ad5-vectored Ebola vaccine: An open phase I/II trial in healthy adults in Russia. Hum. Vaccin. Immunother. 2017, 13, 613–620. [Google Scholar] [CrossRef] [Green Version]
  102. Hall, V.J.; Foulkes, S.; Charlett, A.; Atti, A.; Monk, E.J.; Simmons, R.; Wellington, E.; Cole, M.J.; Saei, A.; Oguti, B.; et al. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: A large, multicentre, prospective cohort study (SIREN). Lancet 2021, 397, 1459–1469. [Google Scholar] [CrossRef]
  103. Ferdinands, J.M.; Rao, S.; Dixon, B.E.; Mitchell, P.K.; DeSilva, M.B.; Irving, S.A.; Lewis, N.; Natarajan, K.; Stenehjem, E.; Grannis, S.J.; et al. Waning 2-Dose and 3-Dose Effectiveness of mRNA Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalizations Among Adults During Periods of Delta and Omicron Variant Predominance—VISION Network, 10 States, August 2021-January 2022. MMWR Morb. Mortal. Wkly. Rep. 2022, 71, 255–263. [Google Scholar]
  104. Levine-Tiefenbrun, M.; Yelin, I.; Katz, R.; Herzel, E.; Golan, Z.; Schreiber, L.; Wolf, T.; Nadler, V.; Ben-Tov, A.; Kuint, J.; et al. Initial report of decreased SARS-CoV-2 viral load after inoculation with the BNT162b2 vaccine. Nat. Med. 2021, 27, 790–792. [Google Scholar] [CrossRef]
  105. European Medicine Agency (EMA). AstraZeneca’s COVID-19 Vaccine: EMA Finds Possible Link to Very Rare Cases of Unusual Blood Clots with Low Blood Platelets. Available online: https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood (accessed on 23 April 2022).
  106. Menaka, P.; Schull, M.; Razak, F.; Grill, A.; Ivers, N.; Maltsev, A.; Miller, K.J.; Schwartz, B.; Stall, N.M.; Steiner, R.; et al. Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) following AstraZeneca COVID-19 Vaccination: Interim Guidance for Healthcare Professionals in Emergency Department and Inpatient Settings. Infect. Dis. Clin. Care 2021, 1, 10-47326. [Google Scholar] [CrossRef]
  107. Oldenburg, J.; Klamroth, R.; Langer, F.; Albisetti, M.; von Auer, C.; Ay, C.; Korte, W.; Scharf, R.E.; Pötzsch, B.; Greinacher, A. Diagnosis and Management of Vaccine-Related Thrombosis following AstraZeneca COVID-19 Vaccination: Guidance Statement from the GTH. Hamostaseologie 2021, 41, 184–189. [Google Scholar] [CrossRef]
  108. Franchini, M.; Liumbruno, G.M.; Pezzo, M. COVID-19 vaccine-associated immune thrombosis and thrombocytopenia (VITT): Diagnostic and therapeutic recommendations for a new syndrome. Eur. J. Haematol. 2021, 107, 173–180. [Google Scholar] [CrossRef]
  109. European Medicine Agency (EMA). COVID-19 Vaccine AstraZeneca: Benefits Still Outweigh the Risks Despite Possible Link to Rare Blood Clots with Low Blood Platelets. Available online: https://www.ema.europa.eu/en/news/covid-19-vaccine-astrazeneca-benefits-still-outweigh-risks-despite-possible-link-rare-blood-clots (accessed on 23 April 2022).
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Figure 1. SARS-CoV-2 pathogenesis in an unvaccinated patient illustrating cytokine storm impact of damage to lungs and adjacent blood vessels.
Figure 1. SARS-CoV-2 pathogenesis in an unvaccinated patient illustrating cytokine storm impact of damage to lungs and adjacent blood vessels.
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Figure 2. Immune response and IgG antibodies against SARS-CoV-2 reduced in waning fully vaccinated patient or patient with immunosenescence.
Figure 2. Immune response and IgG antibodies against SARS-CoV-2 reduced in waning fully vaccinated patient or patient with immunosenescence.
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Figure 3. Immune response and IgG antibodies against SARS-CoV-2 reduced in waning fully vaccinated patient or patient with immunosenescence.
Figure 3. Immune response and IgG antibodies against SARS-CoV-2 reduced in waning fully vaccinated patient or patient with immunosenescence.
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Table
Table 1. Major SAR-CoV-2 vaccines available (updated April 2022).
Table 1. Major SAR-CoV-2 vaccines available (updated April 2022).
TypeVaccineAge GroupDosesBooster
mRNAPfizer-BioNTechAdults (>18 years)
Teens (12–18 years)
Children (5–11 years)		2
(30 ug/mL, 3 weeks apart)
(>12 years)
(10 ug/mL, 3 weeks apart) (5–11 years)		Yes
ModernaAdults (>18 years)
Teens (12–18 years)
Children (6–11 years)
Children (0.5–5 years)		2
(100 ug/mL, 4 weeks apart)
(>18 years)
TBD (6–18 years)
Pending approval		Yes
Viral vectorJanssen J & JAdults (>18 years)1
(0.5 mL)		Yes
AstraZeneca-Univ. of OxfordAdults (>18 years)2
(0.5 mL, 8–12 weeks apart)		TBD
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Ting, M.; Suzuki, J.B. Is the COVID-19 Pandemic Over? The Current Status of Boosters, Immunosenescence, Long Haul COVID, and Systemic Complications. Int. J. Transl. Med. 2022, 2, 230-241. https://doi.org/10.3390/ijtm2020021

AMA Style

Ting M, Suzuki JB. Is the COVID-19 Pandemic Over? The Current Status of Boosters, Immunosenescence, Long Haul COVID, and Systemic Complications. International Journal of Translational Medicine. 2022; 2(2):230-241. https://doi.org/10.3390/ijtm2020021

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Ting, Miriam, and Jon B. Suzuki. 2022. "Is the COVID-19 Pandemic Over? The Current Status of Boosters, Immunosenescence, Long Haul COVID, and Systemic Complications" International Journal of Translational Medicine 2, no. 2: 230-241. https://doi.org/10.3390/ijtm2020021

APA Style

Ting, M., & Suzuki, J. B. (2022). Is the COVID-19 Pandemic Over? The Current Status of Boosters, Immunosenescence, Long Haul COVID, and Systemic Complications. International Journal of Translational Medicine, 2(2), 230-241. https://doi.org/10.3390/ijtm2020021

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