ABSTRACT
Introduction: Acquired hemophilia A (AHA) is a rare autoimmune hemorragic condition (1-2 cases/million person/year)1. Several cases of AHA diagnosed following the administration of the COVID19 vaccines were described. Incidence of AHA diagnoses possibly higher than expected was also reported2,3. Indeed, higher attention to, and/or screening for, coagulation disorders during the vaccination campaign (i.e. notoriety/detection bias) might have increased the probability of AHA diagnosis and reporting compared to the past. Objective(s): To observe the utilization of AHA laboratory tests and incidence of AHA cases in Tuscany region during 2017-2021 and compare the rate of AHA in patients tested for AHA during COVID19 immunization campaign (2021) with that observed in 2019-2017. Method(s): A retrospective cohort study was performed using population- based administrative data from Tuscany region (3.7million inhab), Italy. Per each year between 2017 and 2021, patients active into the database at 1st January, with >= 5 years of age and 2 years of look-back were included. Subjects with >= 1 laboratory tests used for diagnosing AHA1 were identified. Due to the absence of a AHA ICD9CM codes, possible AHA cases were identified combining information from different databanks. Cumulative annual incidence of both patients tested for AHA and possible AHA cases was respectively calculated. The rates of incident AHA cases on patients tested for AHA observed in 2021 and in 2017-2019 were calculated. All estimates were standardized by age and sex (std.). 95% confidence intervals (95% CIs) were estimated with Poissons method (statistical difference = no 95% CIs overlap). Result(s): A total of 126 possible AHA cases and 1.081.878 incident patients with >= 1 laboratory test for AHA were identified between 2017 and 2021. Calendar year 2020 was clearly non-representative of the pre-immunizazion campaign period due to pandemic waves, thus it was excluded from the analyses. In 2021, std. incidence of tested patients (6067/million inhab/year;95% CI 60412-60913) and std. Incidence of possible AHA cases (5.6/million inhab/year;95% CI 3.4-8.7) showed the lowest point estimates, though only the former was statistically significant compared to any other year of the observation period. The std. rate of possible AHA cases on patients tested for AHA in 2021 was 5,6/100milion (95% CI 3.4-8.7) was not statistically different from that observed in 2017-2019 (7.6/100milion;95% CI 5-11). Conclusion(s): No increased incidence of possible AHA cases during the COVID19 immunization campaign was observed in Tuscany. Findings from this study do not suggest neither a possible detection bias nor a possible safety signal. Notority of other known vaccineinduced coagulation disorders may explain the increased reporting of AHA following COVID19 vaccines.
ABSTRACT
Introduction: Acquired haemophilia A (AHA) is a rare, haematological disorder characterized by the development of autoantibodies to Anti-Factor VIII (FVIII), which can cause spontaneous hemorrhage 1. During 2021, some authors reported an unusual and unexpected number of AHA diagnoses that were temporally related to COVID-19 vaccination2,3 Objective: To explore a possible signal of risk of AHA associated with COVID-19 immunization. Method(s): We performed a disproportionality analysis on the World Health Organization (WHO) database (VigiBase-) to investigate the presence of a signal of risk for AHA associated with COVID-19 vaccines. We calculated the information component (IC) for all the COVID-19 vaccines and for single COVID-19 vaccine product using the entire database as reference. Reports of AHA have been systematically reviewed all the selected cases to check for clinical plausibility Results: In Vigibase, we identified 150 cases of suspected AHA associated with COVID-19 vaccines (146 included the PT ''acquired haemophilia''). Only three vaccine products have been reported as suspected causative agents for AHA. The disproportionality analysis showed a significant IC for the Preferred term ''Acquired haemophilia'' associated with all COVID-19 vaccines (IC: 1.3;IC025: 1.1) and with the vaccine product BNT162b2 (IC: 1.9;IC025: 1.6). After the integration with data available on VAERS and on the medical literature, and after the elimination of duplicates, 96 unique cases of AHA following COVID-19 vaccines (mostly mRNA vaccines) have been reviewed. Overall, about 22% of cases occurred in patients B 65 and no case associated with pregnancy was reported. Patients with at least one pre-existing condition that can be considered a risk factor for AHA (history of AHA, cancer, autoimmune disorder) were 20 (21%). A pre-existing condition predisposing to AHA was excluded in 57 (59%) of cases and not reported in 19 (20%) cases. The outcome was death in 10 (11%) patients and complete resolution or recovering in 39 (41%) patients with a single resolution without specific AHA treatment. Median time from last vaccine dose to diagnosis was 18 days and 40% of cases documented the occurrence after the second dose. Conclusion(s): Our disproportionality analysis confirmed a reporting risk for AHA associated with COVID-19 vaccines. The case review analysis identified several good-quality reports of AHA for which no alternative causes other than COVID-19 immunization can be considered. Although detection bias should be considered to explain the unexpected frequency of AHA in the population, the signal identified is robust and deserves further investigation.
ABSTRACT
Introduction: Hypertension is a serious disease that occurs when blood pressure is persistently elevated over time1. During the COVID- 19 vaccination campaign, several reports of hypertension occurred in plausible temporal relationship with immunization have been reported. Objective(s): To explore a possible signal of risk of hypertension associated with COVID-19 immunization using VigiBase the World Health Organization (WHO) pharmacovigilance database and to review the evidence available from real world. Method(s): We performed a disproportionality analysis using data on spontaneous reports recorded in VigiBase-. Data have been extract on May 8th, 2022. We calculated reporting odds ratio (ROR) as a measure of disproportionality for hypertension defined by the Standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) narrow. ROR was estimated for all reports including the MedDRA preferred term (PT) ''hypertension'', ''blood pressure increased'' and ''hypertensive crisis'' (cases). All other reports have been defined as non-cases. All reports in which the suspected causative agent was a COVID-19 vaccine were used as index reports and all other reports as reference. A signal was defined by at least three reports of the PT of interest and ROR025>1. We reviewed the medical literature using MEDLINE from January 2021 to May 2022 using ''COVID-19 vaccines'' AND ''hypertension'' as a search terms to check for evidence from observational studies. Result(s): As of May 8th, 2022, VigiBase included 3,746,090 reports of adverse events following immunization for COVID-19 vaccines and 87,653 de-duplicated reports of hypertension define by the SMQ. We identified 34,955 reports of ''hypertension'' (ROR:1.3;ROR025:1.2), 47,733 reports of ''blood pressure increased'' (ROR:2.6;ROR025:2.6) and 3,741 reports of ''hypertensive crisis'' (ROR:4.0;ROR025:3.8) in which a COVID-19 vaccine was indicated as suspected causative agent. Most frequently co-reported symptoms (>9%) included headache (n = 16.817;19.2%), dizziness (n = 12,892;14.7%), fatigue (n = 8,406;9.6%). Overall, 75% of cases (n = 65,761) have been classified as not serious. A meta-analysis of observational studies that includes 357,387 individuals reported 13,444 events of blood pressure abnormal or increased2. These events have been often described as short periods of hypertensive response and often observed in patients with risk factors. Conclusion(s): Our results confirmed a signal of risk of events of elevated blood pressure following immunization with COVID-19 vaccines. However, there is no evidence that these episodes could result in serious complication typically associated with hypertension, such as stroke, aneurysms, heart failure, myocardial infarction and chronic kidney disease.
ABSTRACT
Introduction: During large-scale vaccination campaign against COVID-19, the Italian Medicines Agency (AIFA) in collaboration with the Regional Centres of Pharmacovigilance have carried out a closely monitoring of Individual Case Safety Reports (ICSRs) about Adverse Event Following Immunisation (AEFIs) related to COVID- 19 vaccines and have assured a constant communication through public monthly reports1. During the first months of the vaccination campaign, a signal of rare events of thrombosis associated with thrombocytopenia2, particularly in young women, was detected by health authorities associated with the viral vector vaccines ChAdOx1- S and Ad26.COV2-S. Objective(s): To present a comprehensive assessment of thrombotic and thromboembolic events associated with thrombocytopenia following COVID-19 immunisation with viral vector vaccines recorded in the Italian National Pharmacovigilance Network database Methods: We selected all ICSRs reported from 27 December 2020 to 26 December 2021 containing Preferred Terms (PT) related to platelet count reduction associated with PT related to thrombotic and thromboembolic events (clinical symptoms and/or diagnostic tests). All cases of thrombotic and thromboembolic events reporting thrombocytopenia in the narrative description of the report were also reviewed. The selected ICRSs were submitted to the independent evaluation of three pharmacovigilance experts who blindly classified into 5 levels of diagnostic certainty, according to the definition provided by the Brighton Collaboration Group (BCG)3. Disagreement were resolved by plenary discussion. Result(s): 12,166,236 doses of ChAdOx1-S and 1,500,746 of Ad26.COV2-S have been administered in Italy during the considered interval with overall 23,358/117,947 ICSRs related to ChAdOx1-S (19.8 %) and 1,580/117,947 related to Ad26.COV2-S (1.3 %). A total of 134 reports after vaccination with adenoviral vaccines were identified according to the inclusion criteria, of which 107 cases were defined as thrombotic thrombocytopenia (95 following ChAdOx1-S and 12 after Ad26.COV2-S). 27 reports were defined as ''not case'' (level 5, Brighton) on the basis of clinical examination or investigation, or because of the presence of heparin as a concomitant drug. Furthermore, 3 reports were excluded because of a hereditary thrombophilia or a previous history of other thrombotic episodes. Seventy-seven cases were classifiable as BCG levels 1, 2, and 3 (definite, probable and possible cases, respectively) with an overall reporting rate at about 1 case per approximately 200,000 doses administered. Women aged 30 to 49 years showed the highest reporting rates. Conclusion(s): In Italy, the rates of thrombotic thrombocytopenia following COVID-19 immunisation with viral vector vaccines are in line with those reported in other Countries.
ABSTRACT
Introduction: Acquired hemophilia A (AHA) is a rare autoimmune hemorragic condition (1-2 cases/million person/year)1. Several cases of AHA diagnosed following the administration of the COVID19 vaccines were described. Incidence of AHA diagnoses possibly higher than expected was also reported2,3. Indeed, higher attention to, and/or screening for, coagulation disorders during the vaccination campaign (i.e. notoriety/detection bias) might have increased the probability of AHA diagnosis and reporting compared to the past. Objective: To observe the utilization of AHA laboratory tests and incidence of AHA cases in Tuscany region during 2017-2021 and compare the rate of AHA in patients tested for AHA during COVID19 immunization campaign (2021) with that observed in 2019-2017. Methods: A retrospective cohort study was performed using population-based administrative data from Tuscany region (3.7million inhab), Italy. Per each year between 2017 and 2021, patients active into the database at 1st January, with > 5 years of age and 2 years of look-back were included. Subjects with > 1 laboratory tests used for diagnosing AHA1 were identified. Due to the absence of a AHA ICD9CM codes, possible AHA cases were identified combining information from different databanks. Cumulative annual incidence of both patients tested for AHA and possible AHA cases was respectively calculated. The rates of incident AHA cases on patients tested for AHA observed in 2021 and in 2017-2019 were calculated. All estimates were standardized by age and sex (std.). 95% confidence intervals (95% CIs) were estimated with Poissons method (statistical difference = no 95% CIs overlap). Results: A total of 126 possible AHA cases and 1.081.878 incident patients with > 1 laboratory test for AHA were identified between 2017 and 2021. Calendar year 2020 was clearly non-representative of the pre-immunizazion campaign period due to pandemic waves, thus it was excluded from the analyses. In 2021, std. incidence of tested patients (6067/million inhab/year;95% CI 60412-60913) and std. Incidence of possible AHA cases (5.6/million inhab/year;95% CI 3.4-8.7) showed the lowest point estimates, though only the former was statistically significant compared to any other year of the observation period. The std. rate of possible AHA cases on patients tested for AHA in 2021 was 5,6/100milion (95% CI 3.4-8.7) was not statistically different from that observed in 2017-2019 (7.6/100milion;95% CI 5-11). Conclusion: No increased incidence of possible AHA cases during the COVID19 immunization campaign was observed in Tuscany. Findings from this study do not suggest neither a possible detection bias nor a possible safety signal. Notority of other known vaccineinduced coagulation disorders may explain the increased reporting of AHA following COVID19 vaccines.
ABSTRACT
Introduction: Acquired haemophilia A (AHA) is a rare, haematological disorder characterized by the development of autoantibodies to Anti-Factor VIII (FVIII), which can cause spontaneous hemorrhage 1. During 2021, some authors reported an unusual and unexpected number of AHA diagnoses that were temporally related to COVID-19 vaccination2,3 Objective: To explore a possible signal of risk of AHA associated with COVID-19 immunization. Methods: We performed a disproportionality analysis on the World Health Organization (WHO) database (VigiBase) to investigate the presence of a signal of risk for AHA associated with COVID-19 vaccines. We calculated the information component (IC) for all the COVID-19 vaccines and for single COVID-19 vaccine product using the entire database as reference. Reports of AHA have been systematically reviewed all the selected cases to check for clinical plausibility Results: In Vigibase, we identified 150 cases of suspected AHA associated with COVID-19 vaccines (146 included the PT "acquired haemophilia"). Only three vaccine products have been reported as suspected causative agents for AHA. The disproportionality analysis showed a significant IC for the Preferred term "Acquired haemophilia" associated with all COVID-19 vaccines (IC: 1.3;IC025: 1.1) and with the vaccine product BNT162b2 (IC: 1.9;IC025: 1.6). After the integration with data available on VAERS and on the medical literature, and after the elimination of duplicates, 96 unique cases of AHA following COVID-19 vaccines (mostly mRNA vaccines) have been reviewed. Overall, about 22% of cases occurred in patients B 65 and no case associated with pregnancy was reported. Patients with at least one pre-existing condition that can be considered a risk factor for AHA (history of AHA, cancer, autoimmune disorder) were 20 (21%). A pre-existing condition predisposing to AHA was excluded in 57 (59%) of cases and not reported in 19 (20%) cases. The outcome was death in 10 (11%) patients and complete resolution or recovering in 39 (41%) patients with a single resolution without specific AHA treatment. Median time from last vaccine dose to diagnosis was 18 days and 40% of cases documented the occurrence after the second dose. Conclusion: Our disproportionality analysis confirmed a reporting risk for AHA associated with COVID-19 vaccines. The case review analysis identified several good-quality reports of AHA for which no alternative causes other than COVID-19 immunization can be considered. Although detection bias should be considered to explain the unexpected frequency of AHA in the population, the signal identified is robust and deserves further investigation.
ABSTRACT
Introduction: Hypertension is a serious disease that occurs when blood pressure is persistently elevated over time1. During the COVID19 vaccination campaign, several reports of hypertension occurred in plausible temporal relationship with immunization have been reported. Objective: To explore a possible signal of risk of hypertension associated with COVID-19 immunization using VigiBase® the World Health Organization (WHO) pharmacovigilance database and to review the evidence available from real world. Methods: We performed a disproportionality analysis using data on spontaneous reports recorded in VigiBase®. Data have been extract on May 8th, 2022. We calculated reporting odds ratio (ROR) as a measure of disproportionality for hypertension defined by the Standardized Medical Dictionary for Regulatory Activities (MedDRA) query (SMQ) narrow. ROR was estimated for all reports including the MedDRA preferred term (PT) "hypertension", "blood pressure increased" and "hypertensive crisis" (cases). All other reports have been defined as non-cases. All reports in which the suspected causative agent was a COVID-19 vaccine were used as index reports and all other reports as reference. A signal was defined by at least three reports of the PT of interest and ROR025 > 1. We reviewed the medical literature using MEDLINE from January 2021 to May 2022 using "COVID-19 vaccines" AND "hypertension" as a search terms to check for evidence from observational studies. Results: As of May 8th, 2022, VigiBase® included 3,746,090 reports of adverse events following immunization for COVID-19 vaccines and 87,653 de-duplicated reports of hypertension define by the SMQ. We identified 34,955 reports of "hypertension" (ROR:1.3;ROR025:1.2), 47,733 reports of "blood pressure increased" (ROR:2.6;ROR025:2.6) and 3,741 reports of "hypertensive crisis" (ROR:4.0;ROR025:3.8) in which a COVID-19 vaccine was indicated as suspected causative agent. Most frequently co-reported symptoms (> 9%) included headache (n = 16.817;19.2%), dizziness (n = 12,892;14.7%), fatigue (n = 8,406;9.6%). Overall, 75% of cases (n = 65,761) have been classified as not serious. A meta-analysis of observational studies that includes 357,387 individuals reported 13,444 events of blood pressure abnormal or increased2. These events have been often described as short periods of hypertensive response and often observed in patients with risk factors. Conclusion: Our results confirmed a signal of risk of events of elevated blood pressure following immunization with COVID-19 vaccines. However, there is no evidence that these episodes could result in serious complication typically associated with hypertension, such as stroke, aneurysms, heart failure, myocardial infarction and chronic kidney disease.
ABSTRACT
Introduction: During large-scale vaccination campaign against COVID-19, the Italian Medicines Agency (AIFA) in collaboration with the Regional Centres of Pharmacovigilance have carried out a closely monitoring of Individual Case Safety Reports (ICSRs) about Adverse Event Following Immunisation (AEFIs) related to COVID19 vaccines and have assured a constant communication through public monthly reports1. During the first months of the vaccination campaign, a signal of rare events of thrombosis associated with thrombocytopenia2, particularly in young women, was detected by health authorities associated with the viral vector vaccines ChAdOx1S S Ad26.COV2-S. Objective: To present a comprehensive assessment of thrombotic and thromboembolic events associated with thrombocytopenia following COVID-19 immunisation with viral vector vaccines recorded in the Italian National Pharmacovigilance Network database Methods: We selected all ICSRs reported from 27 December 2020 to 26 December 2021 containing Preferred Terms (PT) related to platelet count reduction associated with PT related to thrombotic and thromboembolic events (clinical symptoms and/or diagnostic tests). All cases of thrombotic and thromboembolic events reporting thrombocytopenia in the narrative description of the report were also reviewed. The selected ICRSs were submitted to the independent evaluation of three pharmacovigilance experts who blindly classified into 5 levels of diagnostic certainty, according to the definition provided by the Brighton Collaboration Group (BCG)3. Disagreement were resolved by plenary discussion. Results: 12,166,236 doses of ChAdOx1-S and 1,500,746 of Ad26.COV2-S have been administered in Italy during the considered interval with overall 23,358/117,947 ICSRs related to ChAdOx1-S (19.8 %) and 1,580/117,947 related to Ad26.COV2-S (1.3 %). A total of 134 reports after vaccination with adenoviral vaccines were identified according to the inclusion criteria, of which 107 cases were defined as thrombotic thrombocytopenia (95 following ChAdOx1-S and 12 after Ad26.COV2-S). 27 reports were defined as "not case" (level 5, Brighton) on the basis of clinical examination or investigation, or because of the presence of heparin as a concomitant drug. Furthermore, 3 reports were excluded because of a hereditary thrombophilia or a previous history of other thrombotic episodes. Seventy-seven cases were classifiable as BCG levels 1, 2, and 3 (definite, probable and possible cases, respectively) with an overall reporting rate at about 1 case per approximately 200,000 doses administered. Women aged 30 to 49 years showed the highest reporting rates. Conclusion: In Italy, the rates of thrombotic thrombocytopenia following COVID-19 immunisation with viral vector vaccines are in line with those reported in other Countries.
ABSTRACT
Introduction: The Istituto Superiore di Sanita and the Agenzia Italiana del Farmaco coordinate the project TheShinISS-Vax, Flu, a post-marketing "active" surveillance of influenza vaccines. We report the results of the investigation using the Self- Controlled Case Series (SCCS) design on influenza vaccine and Guillain-Barre syndrome in vaccinated population aged over than 6 months, during the influenza vaccine campaign 2020-2021 in Italy. Materials and methods: A SCCS multi-regional study was carried out using linked data from Regional Health Care Registries of Valle d'Aosta, Friuli Venezia Giulia, Emilia-Romagna, Toscana, Lazio, Campania, and Puglia. Relative incidence of Guillain-Barre syndrome was estimated, comparing the exposure risk periods (0-41 days from the vaccination day, subdivided in six intervals) with the unexposed period.
ABSTRACT
Risk communication related to treatments was particularly challenging during the COVID-19 pandemic and became more complicated with the advent of vaccines. The miraculous speed with which the vaccines were developed and authorized was a key element in getting out of the emergency because it limited the circulation of the virus and consequently slowed down the onset of worrying variants. However, it was also the object of attack for all vaccine detractors, who considered development times too fast to guarantee safety. Cases of thrombotic syndrome with thrombocytopenia (TTS) generated a risk signal for the Vaxzevria vaccine, later confirmed by regulatory agencies, which fuelled the fear of the vaccine in the population and resulted in a rather widespread vaccination hesitancy. All this has been favoured by the large use of social media, where news (fake or not) circulates uncontrollably by the rampant populist and conspiracy sentiment in many Western countries and, in general, by the lack of trust in governments. In this context, the set up of a correct communication, which can effectively support a vaccination campaign that never before in history is a priority like in this moment, has become a particularly difficult challenge. To set up an effective communication strategy, it is first of all important to understand the mental shortcuts that underlie vaccination hesitancy. The population generally relies on heuristics to process risk information. These are mental processes that allow you to make quick decisions when dealing with large volumes of information. For example, people's overestimation of an unlikely outcome ('compression') can make it difficult to communicate the actual size of an extremely rare event like TTS. Likewise, a serious but rare event such as TTS can carry more weight in the decision when it is highly publicized ('availability'). Some people tend to anticipate negative emotions in the face of a decision and therefore avoid that path ('anticipated regret'), and this can limit the acceptance of the vaccine and impact on the desire of a healthcare professional to recommend the Vaxzevria vaccine. In relation to this, people may prefer to accept an outcome that comes from doing nothing (not getting vaccinated) rather than an outcome that comes from doing something (getting vaccinated) ('omission bias') or avoid taking risks when the outcome is uncertain ('aversion to ambiguity'). The heuristics is based on values that determine people's thinking, feelings and actions towards risk. The relevant values for the approximate hesitation can be self-determination, fairness, harm minimization and justice. With these principles in mind, an effective communication strategy that supports the vaccination campaign must have the support of health professionals and regulatory authorities. Communication must be written and verbal and where possible use graphic tools that help understanding in the less educated population groups. It must be frequent and transparent so that the population feels part of the decisions made and the reasons behind these decisions. Vaccination should be promoted but not be over-reassuring, always communicating elements of uncertainty. The channels through which information is conveyed must be as diversified as possible. False or misleading information must be identified early and debunked. Communication should be prioritized in certain key groups such as healthcare professionals. It is important that the messages are conveyed by vaccine experts rather than politicians. Finally, it is advisable to consider monitoring the effects of communication by identifying parameters that can detect changes in behaviour and that allow adjustments to be made in the strategy, when necessary.