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.

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.

Investigating Cerebral Sinus Venous Thrombosis after COVID-19 Vaccination in Adults

Objective: To investigate whether there is an association between Cerebral Sinus Venous Thrombosis (CSVT) and COVID-19 vaccination. Background: CSVT has been reported after COVID-19 infections. Design/Methods: Data from the Vaccine Adverse Event Reporting System (VAERS) was used. The reporting rate of CSVT cases after COVID-19 vaccination was compared to the reporting rate of CSVT after all other vaccinations in 3 time 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 and case-centered analysis were used. Six weeks after vaccination was defined as the risk period of probable association. Results: 217 cases with CSVT after COVID-19 vaccination were reported during COVID-19 vaccination period. The reporting rate of CSVT after COVID-19 vaccination was 1.12 per million vaccination, which is in the range of incidence within the general population. No cases of CSVT were reported after all other vaccinations in the vaccine period, pre-vaccine period and pre-COVID-19 period. Using self-controlled and case centered analyses, there was a significant difference in the reporting rate of CSVT after COVID vaccination between the risk and control period (88.9% vs 1.8-6.0% p<0.0001). The reporting rate of CSVT for each vaccine used in USA was significantly higher with Johnson & Johnson compared to Pfizer and Moderna vaccines (2.75 vs 1.3 vs 0.8 <0.0001). All reporting rates did not exceed the incidence of CSVT in the general population. Conclusions: There is no association between CSVT and COVID-19 vaccination. Although the reporting rate of CSVT after COVID-19 was significantly higher during the risk period compared to control period, it was within the expected incidence range in general population. In addition, cases of CSVT triggered by unreported or undiagnosed infection and inflammation cannot be excluded. Controlled studies are needed to assess the relationship between CSVT and COVID-19 vaccination.

Reporting Rates of Encephalopathy Post-COVID-19 Vaccination: A Vaccine Adverse Event Reporting System (VAERS)

Objective: To investigate whether there is an association between Encephalopathy and COVID-19 vaccination. Background: Encephalopathy has been reported in COVID-19 vaccinations. Design/Methods: The reporting rate of Encephalopathy cases after COVID-19 vaccination was compared to the reporting rate of Encephalopathy after all other vaccinations in 3 periods: COVID-19 vaccination (December 2020 - July 2021);COVID-19 pandemic outside the vaccination period (April 2020 - November 2020) and time outside both the 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 probable association between Encephalopathy and COVID-19 vaccination. Results: 371 and 4 cases of Encephalopathy were reported after COVID-19 vaccination and all other vaccinations respectively during the COVID-19 vaccination period. The reporting rate of Encephalopathy after COVID-19 vaccination was significantly higher than the reporting rate of Encephalopathy after all other vaccinations (1.9 vs 0.017 per million p<0.00001). However, the reporting rate of Encephalopathy after COVID-19 vaccination was within the incidence range expected in the general population. 12 and 23 cases of Encephalopathy were reported after vaccination during the pandemic period and outside the pandemic period. Using self-controlled and case centered analyses, there was a significant difference in the reporting rate of Encephalopathy after COVID-19 vaccination between the risk and control periods (94.33% vs 1.08-2.70% p< 0.0001). The reporting rate of Encephalopathy after Pfizer was significantly higher compared to that of Encephalopathy after Moderna and Johnson & Johnson vaccinations. However, all reporting rates were within the incidence range reported in the general population. Conclusions: There is no association between Encephalopathy 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.

Do Neurological Manifestations Following SARS-CoV-2 Infection Beget A Poor Prognosis?

Objective: Investigate the effect of neurological manifestations on the prognosis of SARS-CoV-2 infection. Background: Mounting evidence suggests that neurological manifestations of SARS-CoV-2 infection are associated with a severe prognosis. Design/Methods: Using medical records from University Hospital, Newark NJ, we investigated the outcomes of patients regarding their COVID-19 and neurological status. The groups included patients with COVID-19 and with neurological manifestations (COVID-19N), without COVID-19 and with neurological manifestations (non COVID-19N), with COVID-19 and without neurological manifestations (COVID-19WN), and without COVID-19 or neurological diagnosis (NCOVID-19WN). Results: Among the 1,356 COVID-19 and 37,111 non COVID-19 patients, 25.3% vs 19.5% developed neurological complications, respectively. The average length of stay (LoS) in days and mortality were significantly higher in COVID-19N compared to non COVID-19N, COVID-19WN, and NCOVID-19WN respectively (12;45.2% vs 10;9.8% vs 7;13.2% vs 5;1.3% p<0.05). The proportion of patients admitted to the ICU was significantly highest in non COVID-19N compared to COVID-19N, COVID-19WN, and NCOVID-1WN respectively (36.4% vs. 31.5% vs. 10% vs. 16.6% p<0.05). The ICU LoS in days was significantly higher in COVID-19N compared to non COVID-19N, COVID-19WN, NCOVID-1WN respectively (11 vs. 5 vs. 7 vs. 3 p<0.05). The rate of home discharge was significantly lower in the COVID-19N compared to non-COVID-19N and to COVID-19WN and NCOVID-19WN respectively (41.5% vs. 48.8% vs. 75.1%, VS 78.6% p<0.001). The rate of discharge to hospice was significantly higher in the COVID-19N compared to non-COVID-19N and COVID-19WN and NCOVID-19WN (5.3% vs. 2.4% vs. 0.6% vs. 0.8% p<0.05). The rate of discharge to skilled nursing facilities was significantly higher in the COVID-19N compared to non-COVID-19N and COVID-19WN and NCOVD-19WN (34.0% vs 23.9% vs 9.8% vs 8.6% p<0.05). Conclusions: Our study demonstrated that neurological manifestations of SARS-CoV-2 infection are associated with significant increase in death rate, length of hospitalization including length of stay in ICU and hospice discharges.

Is Rhabdomyolysis after SARS-CoV-2 infection a Factor of Poor Prognosis?

Objective: Investigate whether rhabdomyolysis is a factor of a poor prognosis in COVID-19 patients. Background: Acute skeletal muscle injury including rhabdomyolysis was reported in COVID-19 patients. Design/Methods: Using medical records of patients admitted between March 2020 and March 2021 at University Hospital, Newark NJ, we identified patients with COVID-19 infection and rhabdomyolysis (COVID-19A). We compared outcomes of COVID-19A to: COVID-19 patients without rhabdomyolysis (COVID-19NA), non-COVID-19 patients with rhabdomyolysis (nonCOVID-19A) and non-COVID-19 patients without rhabdomyolysis (non-COVID-19NA). ICD10 codes were used to identify rhabdomyolysis and COVID-19 patients. Results: Among a total of 38,467 patients, 1,356 were diagnosed with COVID-19. The incidence of rhabdomyolysis was significantly higher in COVID-19 patients compared to non-COVID-19. (5.6% vs 1.7% p<0.001). The average length of hospitalization in days (LoS) and mortality rate were significantly higher in COVID-19A compared to COVID-19NA and non-COVID-19A as well as non-COVID-19NA, respectively 13, 61.8% vs. 8, 18.9% vs. 10, 11% vs. 6, 2.8% (p<0.01). Discharge rate to skilled nursing facilities (SNF) and to hospices were significantly higher in COVID-19A compared to COVID-19NA as well as non-COVID-19N, respectively 18.4% vs. 11.8% vs. 22.1% (p<0.01). However, discharge to these facilities was highest among non-COVID19A (22.2%). ICU admission rates were significantly higher in COVID-19A compared to COVID-19NA and non-COVID-19A as well as non-COVID-19N, respectively 39.5% vs. 14% vs. 34.3 vs. 20.2% (p<0.01). Conclusions: Our study demonstrated a significant increased incidence of rhabdomyolysis in COVID-19 patients which is associated with increased mortality rate, LoS, and a higher rate of discharge to SNF and to hospice. Work is in progress to investigate whether rhabdomyolysis is an independent risk factor of poor prognosis of COVID-19 patients.