Adverse Covid-19 Vaccines Reactions in General Medicine: A Clinical-Epidemiological Case Series Reporting of 73 Patients in Toledo’s (Spain) from February to July 2021

Design and Emplacement

An observational, longitudinal and prospective case series study of patients with adverse COVID-19 vaccines reactions (ACVRs), based on a cohort of patients was carried out from February 1, 2021 to July 31, 2021, in a family medicine office, in the Health Center Santa Maria de Benquerencia, Toledo (Spain), which has a list of 2,000 patients>14 years of age (in Spain, the general practitioners [GPs] care for people >14 years of age, except for exceptions requested by the child’s family and accepted by the GP).

Events of Interest

The events of interest in this study were the spontaneous communications of the patients in consultation with the GP in general medicine.

Diagnosis of ACVRs

Reports of ACVRs that were reason for consultation with the GP by vaccinated patients were included. An adverse reaction was defined as any response to a vaccine that is harmful and unintended, and that occurs in doses that are normally applied in humans for the prophylaxis of COVID-19 [10].

Collected Variables

1. Data were extracted from the medical records of the general medicine practice under study. The following variables were collected:
2. Age and sex
3. Symptoms of ACVRs and chronic diseases (defined as “any alteration or deviation from normal that has one or more of the following characteristics: is permanent, leaves residual impairment, is caused by a non- reversible pathological alteration, requires special training of the patient for rehabilitation, and/or can be expected to require a long period of control, observation or treatment” [18], both classified according to the International Statistical Classification of Diseases and Health-Related Problems, CD-10 Version: 2019 [19].
4. Social-occupancy class (according to the Registrar General’s classification of occupations and social status code) [20, 21].
5. Complex family and low income household based on the genogram and in the experience of the general practitioner about continuity of care and knowledge of the family (genogram was a schematic model of the structure and processes of a family, which included the family structure, life cycle and family relational patterns.

It was understood that “complex” genogram identified complex families with psychosocial problems) [22, 23, 24, 25]. 6. Ethnic minority 7. Sick leave due to ACVRs 8. Symptomatic/asymptomatic prior COVID (the diagnosis was performed with reverse transcriptase polymerase chain reaction (PCR) oropharyngeal swab tests or antigen testing or antibody test. Spain had not initially devised an intensive testing strategy for suspected cases of COVID-19 infections [26]; since the beginning of the pandemic in mid-March 2020, PCR tests were only performed in the hospital context until mid-May 2020, when they began to be performed in general medicine as well. In mid-December 2020, rapid antigen tests began to be carried out for symptomatic patients with less than 5 days of evolution. The PCR tests were performed both in symptomatic patients and in asymptomatic contacts. A symptomatic confirmed case with active infection was considered to be any person with a clinical picture of sudden onset acute respiratory infection of any severity that occurs, among others, with fever, cough or feeling of shortness of breath. Other symptoms such as odynophagia, anosmia, ageusia, musc le pain, diarrhea, chest pain or headache, among others, were also considered symptoms of suspected SARS-CoV-2 infection according to clinical criteria; and a positive PCR or rapid antigen test positive [27]. 9. Severity of COVID-19 in the cases that had passed it (mild cases: clinical symptoms are mild and no manifestation of pneumonia could not be found on images; moderate cases: with symptoms such as fever and respiratory tract symptoms, and the manifestation of pneumonia can be seen on the imaging tests; and severe cases: respiratory distress, respiratory rate ≥ 30 breaths/min., pulse oxygen saturation ≤ 93% with room air at rest, arterial partial pressure of oxygen/oxygen concentration ≤ 300 mmHg.) [28]. To simplify comparison, moderate and severe cases were counted together. 10. Vaccine type: Comirnaty (Pfizer-BioNTech-BNT162b2 mRNA; Pfizer/BioNTech), Moderna-mRNA-1273 mRNA, Vaxzevria (AstraZeneca), and Janssen/Johnson & Johnson vaccine (Currently, the European Commission has licensed four vaccines: Comirnaty, Pfizer/BioNTech, licensed December 21, 2020; Moderna vaccine, licensed January 6; AstraZeneca vaccine, licensed 29 December and the Janssen/Johnson & Johnson vaccine, authorized on March 11. In Spain, these four vaccines are currently available, all of which have been approved by the European Medicines Agency) [29]. 11. Criteria for the causality of ACVR, classified as [30, 31, 32]:

• Definitive (Certain): Event or alteration of laboratory tests with plausible temporal sequence in relation to the administration of the suspected drug. It cannot be explained by the concurrent disease, or by other drugs or substances. It can be a clinical syndrome associated with the use of drugs; Recovery after drug withdrawal (positive withdrawal effect); Positive re-exposure effect.
• Probable (Likely): Event or alteration of laboratory tests with plausible temporal sequence in relation to the administration of the suspect drug. It is unlikely to be attributed to the concurrent disease to other drugs or substances. There is a clinically reasonable response to drug withdrawal. Re-exposure not analyzed.
• Possible: Event or alteration of laboratory tests with a plausible temporal sequence in relation to the administration of the suspected drug, but which can also be explained by the concurrent disease, or by other drugs or substances. No information is available regarding the effect of the withdrawal.
• Unlikely: Improbable time sequence. It can be more plausibly explained by the concurrent disease, or by other drugs or substances.
• Conditional / Unclassified: It is essential to obtain more data in order to make a proper evaluation, or the additional data is under analysis.
• Not evaluable/Unclassifiable: It cannot be judged because the information is insufficient or contradictory, and that it cannot be verified or completed in your data
• Severity or intensity of ACVR, classified as Mild, Moderate, Severe [33]:
• Mild: There are easily tolerated signs and symptoms. They do not require therapy or medical intervention.
• Moderate: Signs and symptoms that interfere with normal activities. They require intervention or medical treatment.
• Severe: Signs or symptoms that incapacitate and disable to carry out habitual activities. They require medical intervention or therapy. 12. Time of appearance of ACVR, classified as [34]:
• Immediate: Present within the first 60 minutes (includes urticaria, angioedema, and anaphylaxis)
• Expedited. They manifest 1-72 h. after starting treatment (correspond to urticaria, angioedema, pruritus, laryngeal edema and bronchospasm, etc.)
• Late: They appear 3 days or more after starting treatment (their most common manifestations are urticaria, angioedema, rash, other skin eruptions, reactions similar to those of serum sickness, interstitial nephritis, hemolytic anemia, neutropenia, thrombocytopenia, Stevens-Johnson syndrome, exfoliative dermatitis, drug fever, etc.).

Sample

All patients who consulted for COVID-19 vaccination adverse reaction from February 1, 2021 to July 31, 2021 were included, and that they were seen in the consultation object of the study and their medical documentation was available.

Vaccination Campaign against COVID-19 in Spain and Toledo (Castilla La Mancha, Spain)

Once the Pizfer/BioNTech vaccine was approved on December 21 by the European Medicines Agency, the vaccination campaign began in Spain on December 27, 2021. It was carried out in a staggered manner and prioritizing the groups of people most exposed to COVID-19. As of June 21,

2020, vaccination began in the age range of 30 to 39 years. Meanwhile, the 40 to 49-year-old group was still being vaccinated and second doses were inoculated to those over 50 and 60 years of age. Residents and staff of centers for the elderly and care for dependents, first-line health and social health personnel and non-institutionalized dependents have been vaccinated. By age group, 58% of those over 50 years of age already have the complete regimen and 42% of the 40-49 group already have at least one dose [36].

Drug-Related Problems are Common in General Medicine: The Role of the GP

COVID-19 vaccine is the hope for containment of disease outbreak. The post vaccination adverse effect is an important consideration [37, 38, 39]. In general, out of every 100 courses of drug treatment, there are 20 adverse drug reactions (ADRs), between 5 and 25 clinically observable drug interactions (DDIs) (of which 5 are due to ADRs) and between 15 and 50 potential DDIs, which reach to 100 in geriatric patients [40, 41]. Among the advantages of GP are the continuous care and the possibility of improving knowledge of ADRs avoiding the difficulties of interpreting symptoms or diseases that are not due to medicines but psychosocial effects. Among the methods aimed at identifying and quantifying the ACVRs, in the GP consultation, we used two of them in this study: 1) Data derived from pure clinical observation; 2) Voluntary spontaneous notification by the patient in the consultation or as a direct reason for the consultation [42].

Causation of Adverse Events After Vaccination

The clearest and most reliable way to determine whether an adverse event is causally related to a vaccine is to compare the incidence of the event in two groups, vaccinated and unvaccinated, in a randomized clinical trial. These trials, however, can never be large enough to assess very rare events and pharmacovigilance systems are needed to identify events possibly related to vaccination. We use the WHO criteria as causality categories [12, 31, 32]. Accordin these causality criteria, we find 16% were considered definitive and 44% probable.

Most Frequently Reported Adverse Events

Reporting of incidence of adverse events to official surveillance systems after COVID-19 vaccination varies between countries: from 0.43% in the UK, 0.41% in Australia, 0.31% in Italy and 0.24 % in Argentina to 0.12% in Spain, 0.10% in Brazil and 0.07% in Mexico. In all cases, the sensitivity is higher for serious adverse events [13]. A Center of Disease Control (CDC) analysis of adverse event data during the first month of COVID-19 vaccination in the US offered reassurance on the use of the two licensed mRNA vaccines: Between December 14, 2020 and December 13 January 2021, for 14,000,000 vaccine doses and approximately 7,000 adverse events were reported. Of these, 91% were considered not serious. The most common were headache, fatigue, and dizziness [43].

The two messenger RNA (mRNA) vaccines, made by Moderna and Pfizer-BioNTech, appear to cause similar reactions. A significant portion of people experience non- serious reactions, such as arm pain or headache. That ratio is higher than that of the annual flu vaccine, perhaps because COVID-19 mRNA vaccines elicit a particularly strong immune response. Compared to Moderna, the most common adverse reactions included injection site pain, fatigue, headache, muscle pain, joint pain, and chills; these were generally short-lived. It has been reported that compared to the Pfizer-BioNTech vaccine, Moderna’s was more likely to cause headaches, arm pain, and related side effects [44]. Until April 25, 2021, 14,290,507 doses of vaccines against COVID-19 had been administered in Spain, with 17,297 notifications of adverse events having been registered. The most frequently reported events are still general disorders (fever, pain in the vaccination area), of the nervous system (headache, dizziness) and of the musculoskeletal system (myalgia and arthralgia) [45].

After reviewing the available safety data, the following has been established:

• Comirnaty (BioNTech/Pfizer): rash and pruritus (rare) and urticaria (rare) have been incorporated into the technical data sheet and package leaflet as possible adverse reactions. The possible occurrence of localized inflammation after vaccination in people who had previously received filler injections in the face will also be incorporated [45]. Likewise, it is considered probable Link Between Pfizer Vaccine and Myocarditis Cases [46, 47, 48].
• Vaxzevria (AstraZeneca): the appearance of thrombosis accompanied by thrombocytopenia in unusual places such as the cerebral venous sinuses and splanchnic veins, is a possible adverse reaction of the vaccine. Its frequency of occurrence is very rare and the majority of cases reported at the time of evaluation occurred within 14-27 days of vaccination and under 60 years of age. This information has been incorporated into the technical sheet with recommendations for healthcare professionals and citizens. The possible appearance of isolated thrombocytopenia has also been incorporated into the technical data sheet and the package leaflet. The estimated frequency was 1.13 cases per 100,000 first dose vaccinations [49, 50, 51, 52, 53]. Of the approximately 10,000 healthcare professionals who received the first dose of the Oxford/AstraZeneca vaccine in France between February 6 and 10, the drug regulatory agency received

149 reports of pharmacovigilance for influenza-like signs and symptoms, often severe, with an average temperature of 39°C. Effects occurred within 24 hours in 127 cases, and most cases were seen in people with an average age of 34 years (range: 20 to 63) [54]. Likewise, the possible association with the appearance of capillary leak syndrome is under study after some isolated cases have been reported [44]. • COVID-19 Vaccine Janssen: The development of thrombosis accompanied by thrombocytopenia in unusual places such as the cerebral venous sinuses and splanchnic veins is a possible adverse reaction of the vaccine. Its frequency of appearance is very rare. At the time of evaluation, the cases reported with this vaccine occurred within 21 days of vaccination and, mostly, in women under 60 years of age. This possible adverse reaction is described in the technical data sheet and the package insert for this vaccine, with recommendations for healthcare professionals and citizens [45, 55].

In our study, the reported symptoms were mostly labelled in the group of Symptoms and Signs: Injection site pain, arm pain, fever, chills, dizziness, headache, asthenia, paraesthesia in limbs, lymphadenopathy, edema in feet, etc.

Each new vaccine has potential adverse events of special concern (AESI) that warrant a focused evaluation, based on what is known about previous vaccines and vaccine development. In relation to the so-called events of interest (non-hemorrhagic and hemorrhagic stroke, acute myocardial infarction, deep vein thrombosis, pulmonary embolism, anaphylaxis, Bell’s palsy, myocarditis or pericarditis, narcolepsy, appendicitis, immune thrombocytopenia, disseminated encephalomyelitis), syndrome Guillain-Barré and transverse myelitis) [56], in our series none were found any of them within the categories of certain, probable and possible.

Allergic Reactions to COVID Vaccines

A small number of people have experienced severe allergic reactions to these vaccines. They are extremely rare and no one has died. Fewer than five people per million administered doses of Moderna or Pfizer - BioNTech experienced anaphylactic reactions. That’s based on self- reported data from healthcare workers and vaccinated people. For the Oxford-AstraZeneca vaccine, 30 cases of anaphylaxis have been confirmed so far, out of just over 3 million doses administered [57]. It has been communicad 2.1% acute allergic reactions. These included itching or a rash outside the injection site, respiratory symptoms, hives, and swelling; 16 confirmed cases of anaphylaxis (rate: 0.027% with Pfizer-BioNTech, 0.023% with Moderna). Of these, 94% were women, the mean age was 41 years, 63% had a history of allergy, and 31% had a history of anaphylaxis [58]. The CDC’s reports in late December 2020 and January 2021 indicated rates of 11.1 and 2.5 anaphylaxis cases per million vaccine doses of the Pfizer-BioNTech and Moderna vaccines, respectively, with no fatalities [59]. The rate of anaphylactic reactions to the application of messenger RNA vaccines against COVID-19 is only 7.9 cases per million inoculations [60], which, according to the researchers, is “within the range” of rates observed with other common vaccines. People that developed an allergic reaction after the first dose of a messenger RNA vaccine, including erythema, dizziness, tingling, shortness of breath, and even anaphylaxis, seem to tolerate the second dose better [61]. In our study, there were 4% of bronchial hypersensitivity reactions with cough, dyspnea or rhinitis, and 3% of urticaria.

Among Pfizer-BioNTech vaccine recipients enrolled in CDC’s “v-safe” program, a smartphone-based tool that enables automated health checks after COVID-19 vaccination, reactions were more common after vaccination. Second dose than after the first [62]. Both Moderna and Pfizer/BioNTech vaccines require two doses several weeks apart. Although reactogenicity is usually higher after a second dose, side effects seem to mean that the vaccine is working well [63]. In our case series, the majority of ADVRs were with the first dose (80%). It has been reported that in Moderna’s clinical trial, 10% of vaccine recipients developed axillary swelling or tenderness ipsilateral to the vaccination arm within 7 days of the first dose, and 14% within 7 days of the second dose. Rates in the Pfizer-BioNTech trial were lower, but probably an underestimate, they note [64]. In our series of cases, we found 2 cases of lymphadenopathy (3%).

Vaccination during Pregnancy

Regarding vaccination during pregnancy, local and systemic events after vaccination appear to be similar between pregnant and non-pregnant people. The miscarriage rate was 13% among the v-safe pregnancy registry participants with complete pregnancies, with the majority occurring before 13 weeks’ gestation. By comparison, published miscarriage rates range from 10% to 26% [65]. In our series of cases, 1 spontaneous abortion was found, but with an unlikely causality criterion.

Women Report More and Worse Acvrs

Men and women offer a responder differently to many types of vaccines. It is probably due to a combination of factors, including hormones, genes, and the dose of the injections. Researchers at the CDC analyzed safety data for 13.7 million Covid-19 vaccines and found that 79% of reported side effects came from women, although only 61% of vaccines were administered to women. In general, women have more reactions to a variety of vaccines. That includes flu vaccines given to adults, as well as some given in childhood, such as the hepatitis B and measles, mumps, and rubella (MMR) vaccines. But the side effects are usually mild and short-lived. And these physical reactions are a sign that a vaccine is working, that it is generating a very robust immune response [66]. In our case series, these data were repeated, with a majority of women (70%) reporting ACVRs.

Non-Pharmacological Effects of COVID-19 Vaccines

The mechanisms that produce ADRs are extraordinarily numerous and of very diverse origin, although they can be classified as dependent on the drug used or on the patient himself [67]. Some ADRs cannot strictly be ascribed to pharmacological effects, so other non-specific mechanisms, such as nocebo effects or cultural factors, also give rise to ADRs experienced by patients. It has been reported that the presence ofADRs is related to the greater presence of anxiety and depression and a predominance of the female sex. Likewise, a high level of anxiety has been reported during provocation tests in “false allergy” (“pseudo-allergy”) and may be related to the nocebo effect as a mechanism for producing ADR symptoms.