No significant increase in Guillain-Barré syndrome after COVID-19 vaccination in adults: A vaccine adverse event reporting system study.

OBJECTIVE: To investigate the association between Guillain-Barré syndrome (GBS) and COVID-19 vaccination. BACKGROUND: On July 13, 2021, the US Food and Drug Administration (FDA) released a new warning that Johnson & Johnson COVID-19 vaccine could increase the risk of developing GBS. METHODS: The reporting rate of adult GBS after COVID-19 vaccination, ascertained with Brighton criteria, was compared with the reporting rate after other vaccinations during the same time period, and also compared with the reporting rate during control periods. Statistical methods such as proportion tests, and Pearson's chi-squared test were utilized to identify significant relationships. Self-controlled and case centered analyses were conducted. A machine learning model was utilized to identify the factors associated with a worse outcome defined as emergency room (ER) or doctor visits, hospitalizations, and deaths. RESULTS: The reporting rate of GBS after COVID-19 vaccination was significantly higher than after influenza and other vaccinations (49.7, 0.19, 0.16 per 10 million, p < 0.0001). However, the reporting rate was within the incidence range of GBS in the general population. Using self-controlled and case centered analyses, there was a significant difference in the reporting rate of GBS after COVID-19 vaccination between the risk period and control period (p < 0.0001). There was an estimated 0.7-1.7 per million excess reports of GBS within 6 weeks of COVID-19 vaccination. Machine learning model demonstrated that female gender and age between 18 and 44 are associated with worse outcome. No association was found between the onset interval of GBS and its prognosis. CONCLUSIONS: Although the reporting rate of GBS after COVID-19 vaccination was not statistically different than that of the general population, the increased reporting of GBS within the first 6 weeks after COVID-19 vaccination, more so than with other vaccinations, suggests that some cases of GBS are temporally associated with COVID-19 vaccination. However, there is a reduction in the reporting rate of GBS after other vaccines, compared to reporting rates pre-COVID-19, highlighting limitations inherent in any passive surveillance system. These findings warrant continuous analysis of GBS after COVID-19 vaccination. Further improvement of the machine learning model is needed for clinical use.

Are Elevated Interleukin-6 Serum Levels Associated with Increased Encephalopathy and In-hospital Mortality rates in SARS-CoV2 Patients

Objective: To identify whether elevated serum IL-6 levels are associated with increased occurrence of encephalopathy in hospitalized patients with SARS-CoV-2 infection. Background: SARS-CoV-2 induced cytokine storm may cause encephalopathy, which has been associated with poor prognosis. Design/Methods: IL-6 was measured in 201 PCR-confirmed COVID-19 patients who were hospitalized between Mar 1st and Apr 30th, 2020. Patients who did or did not develop encephalopathy with 24 hours after IL-6 collection were identified as encephalopathy and control group respectively. The Rest group included patients who developed encephalopathy during their hospitalization more than 24 hours after IL-6 collection. Mann-Whitney and non-paired t-test were used to compare demographics, outcomes, and IL-6 distribution. Results: 78, 85 and 38 encephalopathy, control and rest patients were identified respectively. The mean age, mean IL-6 level, in hospital mortality and comorbid conditions were significantly higher in the encephalopathy group compared to the control group (63.7 vs 54.8 year;96.7 pg/mL vs 68.5 pg/mL;53%vs 1%;73.1% vs 43.5% p<0.01). The need for invasive ventilation, acute respiratory distress syndrome, acute renal failure and multiorgan failure was significantly higher in the encephalopathy compared to the control group (56% vs 1%;68%vs 20%;52% vs 17%;86% vs 45.2% p<0.01). There was no significant difference in serum IL-6 distribution or mortality between the encephalopathy and rest group. Conclusions: Encephalopathy in patients with SARS-CoV2 infection is associated with significantly higher in-hospital mortality, serum IL-6 levels, comorbid conditions, and respiratory and multiorgan failure. The distribution of serum IL-6 concentration and mortality were not different between the encephalopathy group, and the rest group. Work is in progress to investigate whether IL-6 level can predict the occurrence of encephalopathy in patients hospitalized with SARS-CoV2 and whether the combination of encephalopathy and serum IL-6 level is a better predictor for in-hospital mortality than each of the markers alone.

Association Between COVID-19 Vaccination and Rhabdomyolysis in Adults: A Vaccine Adverse Event Reporting System (VAERS) Study

Objective: To investigate whether there is an association between rhabdomyolysis and COVID-19 vaccination. Background: Rhabdomyolysis was reported after COVID-19 infection. Design/Methods: The reporting rate of rhabdomyolysis after COVID-19 vaccination was compared to the reporting rate of rhabdomyolysis after all other vaccinations in 3 periods: the vaccine period (December 2020-July 2021);the pre-vaccine period (April 2020-November 2020) and the pre-COVID-19 period (January 2019-August 2019). Self-controlled case series analysis and case-centered analysis was used. Six weeks after vaccination was defined as the risk period of probable cause-effect relationship between vaccination and rhabdomyolysis. Results: 169 and 8 cases of rhabdomyolysis after COVID-19 vaccination and all other vaccinations respectively. During COVID-19 vaccine period, the reporting rate of rhabdomyolysis after COVID-19 vaccination was significantly higher compared to the reporting rate of rhabdomyolysis after all other vaccinations (8.75 vs 0.34 per 10 million p<0.0001). However, it is within the incidence range reported in the general population. Only 4 and 8 cases of rhabdomyolysis after vaccination were reported during pre-vaccine and pre-COVID-19 period respectively. Using self-controlled and case centered analyses, there is a significant difference in the reporting rate of rhabdomyolysis after COVID-19 vaccination between the risk period and control period (98.22% vs 0.06% p<0.0001). The reporting rate of rhabdomyolysis after Johnson and Johnson was not significantly different from the reporting rate after Moderna and Pfizer vaccinations. Conclusions: There is no significant increase in cases of rhabdomyolysis with COVID-19 vaccinations. However, the unbalanced distribution of rhabdomyolysis within the first 12 weeks, with a significant increase in reporting rate, suggests that some rhabdomyolysis cases are temporally associated with COVID-19 vaccination. This supports an autoimmune-mediated muscle injury mechanism rather than direct viral muscle invasion for cases of rhabdomyolysis occurring after COVID-19 infections. Due to limitations in passive surveillance, nonreported or undiagnosed concomitant COVID-19 infections cannot be excluded. Controlled studies are needed for further investigation.

Machine Learning Analysis of Anosmia and Ageusia after COVID-19 Vaccination: A Vaccine Adverse Event Reporting System (VAERS) Study

Objective: To investigate whether there is an association between Anosmia and Ageusia (A/A) and COVID-19 vaccination in adults. Background: A/A was reported after COVID-19 vaccination in adults. Design/Methods: The reporting rate of A/A cases after COVID-19 vaccination was compared to the rate of cases after other vaccinations in three periods: the vaccine period (December 2020- July 2021);the pre-COVID-19 vaccine period (April 2020-November 2020) and the preCOVID-19 period (January 2019-August 2019). Self-controlled case series analysis and casecentered analysis was used. The risk period of probable association was defined as six weeks after vaccination. Machine Learning was performed using the random forest method with ROC curve validation. Results: 1852 and 5 patients with A/A were reported after COVID-19 vaccination and other vaccinations during the vaccine period, respectively. The reporting rate of A/A after COVID-19 vaccination, was significantly higher compared to A/A after other vaccinations (9.5 vs 0.021 per 1 million p<0.0001), however, the rate was still within the range of incidence of A/A in the general population. Only 20 and 14 cases of A/A were reported during the pre-vaccine and preCOVID-19 period, respectively. Using self-controlled and case centered analyses, there was a significant difference in the reporting rate of A/A between risk period and control period (89% vs 4-6% p < 0.00001). The reporting rate of A/A was not different between manufacturers. Preliminary data from Machine Learning/Confusion Matrix showed 94.97% accuracy to classify prediction of hospitalization using a binary category. Conclusions: There is no significant increase in the reporting rate of A/A after COVID-19 vaccination compared to the incidence in the general population. Although the reporting rate of A/A after COVID-19 vaccination was significantly higher during the risk period it was in the expected incidence range. Machine learning techniques found that patient age and time between vaccinations and reporting of A/A are important predictive factors of hospitalization.

Is COVID-19 Vaccination Associated with an Increased Reporting Rate of MyastheniaGravis? A Vaccine Adverse Event Reporting System (VAERS) Study

Objective: To investigate whether there is an association between Myasthenia Gravis (MG) and COVID-19 vaccination. Background: New onset or exacerbation of MG after vaccination was previously reported. Design/Methods: The reporting rate of MG cases after COVID-19 vaccination was compared to that of MG after all other vaccinations in 3 time periods: the vaccine period (December 2020- July 2021);the pre-vaccine pandemic period (April 2020-November 2020) and pre-pandemic period (January 2019-August 2019). Self-controlled case series analysis and case-centered analysis were used. Six weeks after vaccination was defined as the risk period for possible causeeffect relationship. For self-controlled case analysis, the risk period was followed by one month of washout and another six weeks of control monitoring. Results: 77 and 3 cases with MG after COVID-19 vaccination and all other vaccinations were reported during the vaccine period respectively. The reporting rate of MG after COVID-19 vaccination was significantly higher than the reporting rate of MG after other vaccines (4 vs 0.1 per 10 million p< 0.00001). However, the reporting rate was within the incidence range expected in the general population. Two cases of MG after vaccination were reported during pandemic period and none in the pre-pandemic period. Using self-controlled and case centered analyses, there is a significant difference in the reporting rate of MG after COVID-19 vaccination between the risk period and control period (92.2% vs 2.6-3.9% p<0.00001). The reporting rate of MG after COVID-19 vaccination was not significantly different between Johnson and Johnson, Moderna and Pfizer vaccines. Conclusions: There is no significant increase in reporting rate of MG after COVID-19 vaccination. Although the reporting rate of MG after COVID-19 vaccination was significantly higher during the risk period compared to the control period, a non-reported or undiagnosed concomitant COVID-19 infection, other triggering factors or non-adherence to medications cannot be excluded;this could account for the observed increase.

Investigating the relationship of Miller Fisher Syndrome and COVID-19 Vaccination: A Vaccine Adverse Event Reporting (VAERS) Study

Objective: To investigate whether there is an relationship between Miller Fisher Syndrome (MFS) and COVID-19 vaccination Background: MFS was rarely reported after COVID-19 vaccination. Design/Methods: The reporting rate of MFS cases after COVID-19 vaccination was compared to the rate after all other vaccinations in 3 time periods: COVID-19 vaccination (December 2020 - July 2021);COVID-19 pandemic outside the vaccination time period (April 2020-November 2020) and the time outside of COVID-19 vaccination and the pandemic (January 2019-August 2019). Self-controlled case series analysis and case-centered analysis was used. Six weeks after vaccination was defined as the risk period of possible association. Results: 12 cases after COVID-19 vaccination and 1 case from all other vaccinations were reported during the vaccine period. The reporting rate of MFS after COVID-19 vaccination (0.62 per 10 million vaccinations) was significantly higher than the rate after other vaccinations (0.04 per 10 million vaccinations) p<0.05. Both reporting rates are within the incidence range expected in the general population. No cases of MFS were reported during the pandemic period and 2 cases of MFS were reported outside the pandemic period. Using self-controlled and case centered analyses, there was a significant difference in the reporting rate of MFS after COVID-19 vaccination between the risk period and control period (91.6% vs 0-8,3% p<0.00001). The reporting rate of MFS after each vaccine used in USA (Johnson & Johnson, Pfizer and Moderna) was within the expected incidence range and there was no significant difference between them. Conclusions: There is no association between MFS and COVID-19 vaccination. Although the reporting rate MFS after COVID-19 was significantly higher during the risk period compared to control period, and compared to the rate of other vaccines, the number of reported cases was low and within the expected incidence range. Furthermore, cases of MFS related to COVID-19 infection or other triggering factors cannot be excluded.

Association Between COVID-19 Vaccination and Cerebrovascular Accidentsin Adults: A Vaccine Adverse Event Reporting System (VAERS) Study

Objective: To investigate whether there is an association between cerebrovascular accidents (CVA's) and COVID-19 vaccination Background: CVA's have been reported in severe COVID-19 infections and are attributed to infection-related hypercoagulability and inflammation. Design/Methods: The reporting rate of CVA cases after COVID-19 vaccination was compared to the reporting rate of CVA after all other vaccinations in three periods: pre-COVID period (January 2019-August 2019), pre-COVID-19 vaccine period (April 2020-November 2020), and vaccine period (December 2020-July 2021). Results: 812 and 17 cases of CVA were reported after COVID-19 vaccination and all other vaccinations, respectively, during the COVID-19 vaccination period. The reporting rate of CVA after COVID-19 vaccination was significantly higher than the rate after all other vaccines (4.2 vs 0.07 per million p<0.00001). However, it was within the incidence range expected in the general population. Only 2 cases of CVA were reported after vaccination during the pandemic period and no cases outside the pandemic period. Based upon self-controlled and case-centered analyses, there is a significant difference in the reporting rate of CVA after COVID vaccination between the risk period (six weeks after vaccination was defined as the risk period of probable association) and control period (93.97% vs 1.97-2.96% p< 0.0001). The reporting rate of CVA after Pfizer was significantly higher compared to CVA after Moderna and Johnson and Johnson vaccinations (5.9 vs 2.8 vs 3.2 per million p<0.0001). However, all reporting rates were within the expected incidence range reported in the general population. Conclusions: There is no association between CVA and COVID-19 vaccination. Furthermore, this work is based on passive surveillance where several limitations exist, which include under-reporting, differential reporting and nonreported or undiagnosed concomitant COVID-19 infection. These factors preclude establishing a cause-effect relationship. Controlled studies are needed for further investigation.

Anosmia and Ageusia after COVID-19 vaccination in Pediatrics Population: A Vaccine Adverse Event Reporting System (VAERS) Study

Objective: To investigate whether there is an association between COVID vaccination in children and anosmia and ageusia Background: Anosmia and ageusia were reported after COVID-19 infection. Design/Methods: The reporting rate of pediatric anosmia and ageusia (age between 12-17 years) after COVID-19 vaccination was compared to the reporting rate after HPV and meningococcal vaccinations (vaccines given chiefly to the pediatric population) and influenza vaccinations in three periods: pre-COVID period (January 2019-August 2019), pre-COVID-19 vaccine period (April 2020-November 2020), and vaccine period (December 2020-July 2021). Six weeks after vaccination was defined as the risk period of probable association. Results: 32, 0, 0, and 1 cases with anosmia and ageusia were reported after COVID-19, HPV, meningococcal and influenza vaccinations during the COVID-19 vaccination period respectively. The reporting rate of anosmia and ageusia after COVID-19 vaccination is 3.3 per million vaccinations which is significantly higher compared to cases after HPV, meningococcal and Influenza vaccinations during the COVID-19 vaccine period p<0.0001. Only one case of anosmia and ageusia was reported after meningococcal and Influenza vaccinations and no cases were reported after HPV vaccinations during the pandemic period. No cases were reported outside the pandemic and vaccination periods. Using self-controlled and case centered analyses, there is a significant difference in the reporting rate of anosmia and ageusia after COVID-19 vaccination between the risk period and control period (81.3% vs 3.1-12.5% p<0.0001). However, the reporting rate is within the incidence range expected in the general population. Conclusions: There is no significant increase in the reporting rate of Anosmia and Ageusia after COVID-19 vaccination. Although the reporting rate of Anosmia and Ageusia after COVID-19 vaccination was significantly higher during the risk period compared to the control period, a non-reported or undiagnosed concomitant COVID-19 infection explanation cannot be excluded.

Association Between COVID-19 Vaccination and Optic Neuritisin Adults: A Vaccine Adverse Event Reporting System (VAERS) Study

Objective: To investigate whether there is an association between Optic Neuritis and COVID-19 vaccination. Background: Optic Neuritis has been reported after COVID-19 infections. Design/Methods: The reporting rate of Optic Neuritis cases after COVID-19 vaccination was compared to the reporting rate of Optic Neuritis after Influenza vaccination and after other vaccination in 3 time periods: the COVID-19 vaccine period (December 2020-July 2021);the pre-COVID-19 vaccine period (April 2020-November 2020) and the pre-COVID-19 period (January 2019-August 2019). Self-controlled case series and case-centered analyses were used. Six weeks after vaccination was defined as the risk period of probable association. Results: 89 cases with Optic Neuritis after COVID-19 vaccination and 3 cases after all other vaccinations were reported during COVID-19 vaccination period. The reporting rate of Optic Neuritis cases after COVID-19 vaccination is significantly higher compared to Optic Neuritis after other vaccinations (0.46 vs 0.012 per million vaccination p<0.0001). However, this is within the incidence range reported in the general population. Only 3 and 2 cases of Optic Neuritis were reported after vaccination during and outside the pandemic time period respectively. Using self-controlled and case centered analyses, there is a significant difference in the reporting rate of Optic Neuritis after COVID-19 vaccination between the risk and control period (97.8% vs 0-2.2% p<0.0001). The reporting rate of Optic Neuritis after each vaccine used in USA (Johnson & Johnson, Pfizer and Moderna) is within the expected incidence range and there was no significant difference between them. Conclusions: There is no association between Optic Neuritis and COVID-19 vaccination. Although the reporting rate of Optic Neuritis after COVID-19 is significantly higher during the risk period compared to control period and compared to the reporting rate after other vaccines, it is within the expected incidence range. In addition, cases of Optic Neuritis triggered by unreported or undiagnosed demyelination, autoimmunity, infection and neuroinflammation cannot be excluded.

No Significant Increase of Guillain-Barré Syndrome after COVID-19 Vaccination in Adults: A Vaccine Adverse Event Reporting System (VAERS) Study

Objective: To investigate whether there is an association between Guillain-Barré syndrome (GBS) and COVID-19 vaccination. Background: On July 12, 2021, the US Food and Drug Administration (FDA) released a new warning that Johnson & Johnson COVID-19 vaccine could increase the risk of developing GBS. Design/Methods: The reporting rate of adult GBS after COVID-19 vaccination, ascertained with Brighton criteria, was compared to the rate after Influenza and all other vaccinations: preCOVID (January 2019-August 2019), pre-vaccine (April 2020-November 2020);and the vaccine period (December 2020-July 2021). Results: 513, 2, and 13 patients reported GBS after COVID-19, Influenza and all other vaccinations during the COVID-19 vaccination time period, respectively. The reporting rate of GBS after COVID-19 vaccination was significantly higher than after Influenza and other vaccinations (26.5, 0.15, 1.21 per 10 million, p<0.0001). However, the rate is within the incidence range of GBS in the general population. Using self-controlled and case centered analysis, there is a significant difference in the reporting rate of GBS after COVID-19 vaccination between the risk period and control period (p<0.0001). The reporting rate of GBS after the Johnson and Johnson vaccine was significantly higher than after Moderna and Pfizer (p<0.0001). Similar results were obtained when all patients, regardless of Brighton criteria, were included. Conclusions: Although the incidence of GBS after COVID-19 vaccination was not statistically different than that of the general population, the increased reporting of GBS within the first 12 weeks after COVID-19 vaccination (more so than with other vaccinations) suggests that some cases of GBS are temporally associated with COVID-19 vaccination. However, there is a reduction in the reporting rate of GBS after other vaccines (compared to reporting rates preCOVID), highlighting limitations inherent in any passive surveillance system. These findings warrant continuous analysis of GBS after COVID-19 vaccination. Further controlled studies are needed to investigate the association of GBS after COVID-19 vaccination.