Nahid Bhadelia, MD, MALD

A second study answered a question I am often asked about neurological sequalae such as Guillain Barre syndrome among patients with COVID-19 infection, compared to risk of the same from vaccines. Patone et al linked country wide data from English National Immunisation (NIMS) Database of COVID-19 vaccinations with patient level data to examine incidence of neurological adverse events such acute central nervous system (CNS) demyelinating events, encephalitis meningitis and myelitis, Guillain–Barré syndrome, Bell’s palsy, myasthenic disorders, hemorrhagic stroke and subarachnoid hemorrhage in the 28 days following either having a positive SARS-CoV-2 test, or neither ChAdOx1nCoV-19 or BNT162b2 vaccines. The study reported increased incidence risk ratios (IRR) of hospitalization or death related to all of the aforementioned neurological events in patients with SARS-CoV-2 infection, particularly in the time right after diagnosis. There was a small increase in IRR for Guillain-Barre syndrome (IRR, 2.90; 95% confidence interval (CI): 2.15–3.92 at 15–21 days after vaccination) and Bell’s palsy (IRR, 1.29; 95% CI: 1.08–1.56 at 15–21 days) with ChAdOx1nCoV-19. However, this was lower than what was seen after a positive SARS-CoV-2 test (Guillain–Barré syndrome (IRR, 5.25; 95% CI: 3.00–9.18) and Bell’s Palsy, (IRR, 1.34; 95% CI: 0.91–1.97). There was a slightly increased association seen between hemorrhagic stroke and the first dose of BNT162b2, with IRR at 1–7 days (IRR, 1.27; 95% CI: 1.02–1.59) and 15–21 days (IRR, 1.38; 95% CI: 1.12–1.71). However, this risk was dwarfed compared to risk for hemorrhagic stroke seen up to 7 days after a positive SARS-CoV-2 test (IRR, 12.42; 95% CI: 7.73–19.95 at day 0; IRR, 2.01; 95% CI: 1.29–3.15 at 1–7 days). The results highlight immense increase of neurological events after SARS-CoV-2 infection.

Lastly, the RECOVERY trial reported out results of colchicine treatment arm, where 5,610 patients were assigned to standard of care (SOC) with colchicine compared to 5,730 who just received standard of care. The ongoing RECOVERY trial has been an incredibly power tool in helping identify both some effective treatments as well as shedding light on the limited utility of others. No significant differences were seen between the treatment and SOC only arms in all-cause mortality (rate ratio [RR], 1.01; P = .77),  the probability of being discharged alive within 28 days (RR, 0.98; P = .44), or the risk of progressing to invasive mechanical ventilation or death (RR, 1.02; P = .47). The large sample size as well as the well-controlled design provides good evidence that colchicine will not make the COVID-19 treatment arsenal.

A second study answered a question I am often asked about neurological sequalae such as Guillain Barre syndrome among patients with COVID-19 infection, compared to risk of the same from vaccines. Patone et al linked country wide data from English National Immunisation (NIMS) Database of COVID-19 vaccinations with patient level data to examine incidence of neurological adverse events such acute central nervous system (CNS) demyelinating events, encephalitis meningitis and myelitis, Guillain–Barré syndrome, Bell’s palsy, myasthenic disorders, hemorrhagic stroke and subarachnoid hemorrhage in the 28 days following either having a positive SARS-CoV-2 test, or neither ChAdOx1nCoV-19 or BNT162b2 vaccines. The study reported increased incidence risk ratios (IRR) of hospitalization or death related to all of the aforementioned neurological events in patients with SARS-CoV-2 infection, particularly in the time right after diagnosis. There was a small increase in IRR for Guillain-Barre syndrome (IRR, 2.90; 95% confidence interval (CI): 2.15–3.92 at 15–21 days after vaccination) and Bell’s palsy (IRR, 1.29; 95% CI: 1.08–1.56 at 15–21 days) with ChAdOx1nCoV-19. However, this was lower than what was seen after a positive SARS-CoV-2 test (Guillain–Barré syndrome (IRR, 5.25; 95% CI: 3.00–9.18) and Bell’s Palsy, (IRR, 1.34; 95% CI: 0.91–1.97). There was a slightly increased association seen between hemorrhagic stroke and the first dose of BNT162b2, with IRR at 1–7 days (IRR, 1.27; 95% CI: 1.02–1.59) and 15–21 days (IRR, 1.38; 95% CI: 1.12–1.71). However, this risk was dwarfed compared to risk for hemorrhagic stroke seen up to 7 days after a positive SARS-CoV-2 test (IRR, 12.42; 95% CI: 7.73–19.95 at day 0; IRR, 2.01; 95% CI: 1.29–3.15 at 1–7 days). The results highlight immense increase of neurological events after SARS-CoV-2 infection.

Lastly, the RECOVERY trial reported out results of colchicine treatment arm, where 5,610 patients were assigned to standard of care (SOC) with colchicine compared to 5,730 who just received standard of care. The ongoing RECOVERY trial has been an incredibly power tool in helping identify both some effective treatments as well as shedding light on the limited utility of others. No significant differences were seen between the treatment and SOC only arms in all-cause mortality (rate ratio [RR], 1.01; P = .77),  the probability of being discharged alive within 28 days (RR, 0.98; P = .44), or the risk of progressing to invasive mechanical ventilation or death (RR, 1.02; P = .47). The large sample size as well as the well-controlled design provides good evidence that colchicine will not make the COVID-19 treatment arsenal.

A second study answered a question I am often asked about neurological sequalae such as Guillain Barre syndrome among patients with COVID-19 infection, compared to risk of the same from vaccines. Patone et al linked country wide data from English National Immunisation (NIMS) Database of COVID-19 vaccinations with patient level data to examine incidence of neurological adverse events such acute central nervous system (CNS) demyelinating events, encephalitis meningitis and myelitis, Guillain–Barré syndrome, Bell’s palsy, myasthenic disorders, hemorrhagic stroke and subarachnoid hemorrhage in the 28 days following either having a positive SARS-CoV-2 test, or neither ChAdOx1nCoV-19 or BNT162b2 vaccines. The study reported increased incidence risk ratios (IRR) of hospitalization or death related to all of the aforementioned neurological events in patients with SARS-CoV-2 infection, particularly in the time right after diagnosis. There was a small increase in IRR for Guillain-Barre syndrome (IRR, 2.90; 95% confidence interval (CI): 2.15–3.92 at 15–21 days after vaccination) and Bell’s palsy (IRR, 1.29; 95% CI: 1.08–1.56 at 15–21 days) with ChAdOx1nCoV-19. However, this was lower than what was seen after a positive SARS-CoV-2 test (Guillain–Barré syndrome (IRR, 5.25; 95% CI: 3.00–9.18) and Bell’s Palsy, (IRR, 1.34; 95% CI: 0.91–1.97). There was a slightly increased association seen between hemorrhagic stroke and the first dose of BNT162b2, with IRR at 1–7 days (IRR, 1.27; 95% CI: 1.02–1.59) and 15–21 days (IRR, 1.38; 95% CI: 1.12–1.71). However, this risk was dwarfed compared to risk for hemorrhagic stroke seen up to 7 days after a positive SARS-CoV-2 test (IRR, 12.42; 95% CI: 7.73–19.95 at day 0; IRR, 2.01; 95% CI: 1.29–3.15 at 1–7 days). The results highlight immense increase of neurological events after SARS-CoV-2 infection.

Lastly, the RECOVERY trial reported out results of colchicine treatment arm, where 5,610 patients were assigned to standard of care (SOC) with colchicine compared to 5,730 who just received standard of care. The ongoing RECOVERY trial has been an incredibly power tool in helping identify both some effective treatments as well as shedding light on the limited utility of others. No significant differences were seen between the treatment and SOC only arms in all-cause mortality (rate ratio [RR], 1.01; P = .77),  the probability of being discharged alive within 28 days (RR, 0.98; P = .44), or the risk of progressing to invasive mechanical ventilation or death (RR, 1.02; P = .47). The large sample size as well as the well-controlled design provides good evidence that colchicine will not make the COVID-19 treatment arsenal.

Similarly, Lin et al report the results of an international study of adults from 99 countries, which utilized longitudinal mobile based surveys to examine risk factors associated with SARS-CoV-2 infection. The mobile surveys captured baseline characteristics and behaviors of participants, and data was reported out for the study period of March to October 2020 (before vaccines were available). Adjusting for demographics, education level, a proxy for occupational risk, as well as medical comorbidities, authors found that greater number of non-household contacts, attending events with 10 or more individuals and restaurant visits predicted higher risk of SARS-CoV-2. Alternatively, older age was associated with lower risk, likely because of the protective behaviors undertaken by many in the older age group.

Lastly, the RECoVERED Study (Wynberg, at al), based in Netherlands, followed recently diagnosed laboratory confirmed SARS-CoV-2 patients for a year, initially with three in person visits (where disease severity was determined based on vital signs and level of care needed) within the first month of illness and then monthly online surveys. Authors utilized a survey examining severity of 18 symptoms based on the World Health Organization Case Report Form. Authors found 86.7% of those with initial severe disease [95% confidence interval {CI} = 76.5–92.7%]), 63.8%  of those moderate disease 63.8% [95% CI = 54.8–71.5%], and 30.7% of those with mild disease [95% CI = 21.1–40.9%] had at least one persistent symptom at 12 weeks.  Fatigue was the most common symptom reported at 12 weeks overall, but among those with moderate and severe disease, dyspnea and myalgia also persisted frequently. After one years of follow up, about one-fifth still had one persistent symptom. Over half of those with initial severe disease reported symptom persistence (52.5% [95% CI = 38.0–65.1%]). In a multivariable Cox proportional hazard model, female sex and higher BMI were associated with slower recovery. One limitation of the study was that was no control group recruited.

Similarly, Lin et al report the results of an international study of adults from 99 countries, which utilized longitudinal mobile based surveys to examine risk factors associated with SARS-CoV-2 infection. The mobile surveys captured baseline characteristics and behaviors of participants, and data was reported out for the study period of March to October 2020 (before vaccines were available). Adjusting for demographics, education level, a proxy for occupational risk, as well as medical comorbidities, authors found that greater number of non-household contacts, attending events with 10 or more individuals and restaurant visits predicted higher risk of SARS-CoV-2. Alternatively, older age was associated with lower risk, likely because of the protective behaviors undertaken by many in the older age group.

Lastly, the RECoVERED Study (Wynberg, at al), based in Netherlands, followed recently diagnosed laboratory confirmed SARS-CoV-2 patients for a year, initially with three in person visits (where disease severity was determined based on vital signs and level of care needed) within the first month of illness and then monthly online surveys. Authors utilized a survey examining severity of 18 symptoms based on the World Health Organization Case Report Form. Authors found 86.7% of those with initial severe disease [95% confidence interval {CI} = 76.5–92.7%]), 63.8%  of those moderate disease 63.8% [95% CI = 54.8–71.5%], and 30.7% of those with mild disease [95% CI = 21.1–40.9%] had at least one persistent symptom at 12 weeks.  Fatigue was the most common symptom reported at 12 weeks overall, but among those with moderate and severe disease, dyspnea and myalgia also persisted frequently. After one years of follow up, about one-fifth still had one persistent symptom. Over half of those with initial severe disease reported symptom persistence (52.5% [95% CI = 38.0–65.1%]). In a multivariable Cox proportional hazard model, female sex and higher BMI were associated with slower recovery. One limitation of the study was that was no control group recruited.

Similarly, Lin et al report the results of an international study of adults from 99 countries, which utilized longitudinal mobile based surveys to examine risk factors associated with SARS-CoV-2 infection. The mobile surveys captured baseline characteristics and behaviors of participants, and data was reported out for the study period of March to October 2020 (before vaccines were available). Adjusting for demographics, education level, a proxy for occupational risk, as well as medical comorbidities, authors found that greater number of non-household contacts, attending events with 10 or more individuals and restaurant visits predicted higher risk of SARS-CoV-2. Alternatively, older age was associated with lower risk, likely because of the protective behaviors undertaken by many in the older age group.

Lastly, the RECoVERED Study (Wynberg, at al), based in Netherlands, followed recently diagnosed laboratory confirmed SARS-CoV-2 patients for a year, initially with three in person visits (where disease severity was determined based on vital signs and level of care needed) within the first month of illness and then monthly online surveys. Authors utilized a survey examining severity of 18 symptoms based on the World Health Organization Case Report Form. Authors found 86.7% of those with initial severe disease [95% confidence interval {CI} = 76.5–92.7%]), 63.8%  of those moderate disease 63.8% [95% CI = 54.8–71.5%], and 30.7% of those with mild disease [95% CI = 21.1–40.9%] had at least one persistent symptom at 12 weeks.  Fatigue was the most common symptom reported at 12 weeks overall, but among those with moderate and severe disease, dyspnea and myalgia also persisted frequently. After one years of follow up, about one-fifth still had one persistent symptom. Over half of those with initial severe disease reported symptom persistence (52.5% [95% CI = 38.0–65.1%]). In a multivariable Cox proportional hazard model, female sex and higher BMI were associated with slower recovery. One limitation of the study was that was no control group recruited.

Marconi et al report out the results of the COV-Barrier study, a phase 3 randomized placebo controlled (RCT) trial with baricitinib, a JAK-STAT pathway inhibitor generally used to suppress proinflammatory cytokine production and systemic inflammation in rheumatoid arthritis, in hospitalized COVID-19 patients. The 1525 participants equally divided between placebo and baricitinib in an intention to treat analysis, were recruited from 12 countries, and most were on systemic corticosteroids (79.3%) and about one fifth received the antiviral, remdesivir. The study did not show a difference in the primary outcome (a composite of progression to more severe disease including need for high flow oxygen, non-invasive or invasive mechanical ventilation or death by 28 days), but did note a 5% absolute reduction in mortality at 28 days. Based on this results, Baricitinib may have a role similar role in the care of COVID-19 patients as tocilizumab (an IL-6 inhibitor) when given in combination with steroids, but may be used in the care of patients earlier in their disease including those on high flow or noninvasive oxygen as well as those requiring invasive mechanical ventilation, compared to tocilizumab, which is currently preferred by many clinicians in those on more intensive respiratory support and within 24-48 hours of ICU admission.  Like other immunomodulators, there is a concern for increased secondary infections with the use of this therapy, but JAK inhibitors also carry a risk for increase in venous thromboembolic events. Interestingly, in this trial, there was no difference in the incidence of either of these adverse effects between the placebo and treatment groups.

The results of a phase 3 RCT with Canakinumab, an anti-interleukin-1B monoclonal antibody, on the other hand, did not show a benefit in primary outcome of survival without need for mechanical ventilation day 3 to day 29, or recovery time, in hospitalized patients who had elevated C-reactive protein and ferritin but were not yet intubated. Canakinumab was evaluated because IL-1B has been identified as one of the signature elevated cytokines in a maladaptive immune response to SARS-CoV-2 infection and because had shown some promise in small and retrospective studies. 

Lastly, on the prevention side, a study of Regeneron’s anti-SARS-CoV-2 monoclonal antibody cocktail (casirivimab and imdevimab) was evaluated in a double blind placebo controlled RCT in prevention of development of symptomatic SARS-CoV-2 infection within 28 days among household contacts who did not have prior immunity. In the study, 1.5% of those who received the monoclonal therapy subcutaneously versus 7.8% of those who received placebo met the primary endpoint. Additionally, those who received the therapy and were symptomatic, resolved their symptoms two weeks earlier. The real-world utility of the results, however, maybe limited to specific groups, given that need for early identification of contacts, the need to access medical facility for administration, as well as the cost of the drug. There may be a role in high risk and immunocompromised contacts who do not develop adequate immune response to vaccination.

Marconi et al report out the results of the COV-Barrier study, a phase 3 randomized placebo controlled (RCT) trial with baricitinib, a JAK-STAT pathway inhibitor generally used to suppress proinflammatory cytokine production and systemic inflammation in rheumatoid arthritis, in hospitalized COVID-19 patients. The 1525 participants equally divided between placebo and baricitinib in an intention to treat analysis, were recruited from 12 countries, and most were on systemic corticosteroids (79.3%) and about one fifth received the antiviral, remdesivir. The study did not show a difference in the primary outcome (a composite of progression to more severe disease including need for high flow oxygen, non-invasive or invasive mechanical ventilation or death by 28 days), but did note a 5% absolute reduction in mortality at 28 days. Based on this results, Baricitinib may have a role similar role in the care of COVID-19 patients as tocilizumab (an IL-6 inhibitor) when given in combination with steroids, but may be used in the care of patients earlier in their disease including those on high flow or noninvasive oxygen as well as those requiring invasive mechanical ventilation, compared to tocilizumab, which is currently preferred by many clinicians in those on more intensive respiratory support and within 24-48 hours of ICU admission.  Like other immunomodulators, there is a concern for increased secondary infections with the use of this therapy, but JAK inhibitors also carry a risk for increase in venous thromboembolic events. Interestingly, in this trial, there was no difference in the incidence of either of these adverse effects between the placebo and treatment groups.

The results of a phase 3 RCT with Canakinumab, an anti-interleukin-1B monoclonal antibody, on the other hand, did not show a benefit in primary outcome of survival without need for mechanical ventilation day 3 to day 29, or recovery time, in hospitalized patients who had elevated C-reactive protein and ferritin but were not yet intubated. Canakinumab was evaluated because IL-1B has been identified as one of the signature elevated cytokines in a maladaptive immune response to SARS-CoV-2 infection and because had shown some promise in small and retrospective studies. 

Lastly, on the prevention side, a study of Regeneron’s anti-SARS-CoV-2 monoclonal antibody cocktail (casirivimab and imdevimab) was evaluated in a double blind placebo controlled RCT in prevention of development of symptomatic SARS-CoV-2 infection within 28 days among household contacts who did not have prior immunity. In the study, 1.5% of those who received the monoclonal therapy subcutaneously versus 7.8% of those who received placebo met the primary endpoint. Additionally, those who received the therapy and were symptomatic, resolved their symptoms two weeks earlier. The real-world utility of the results, however, maybe limited to specific groups, given that need for early identification of contacts, the need to access medical facility for administration, as well as the cost of the drug. There may be a role in high risk and immunocompromised contacts who do not develop adequate immune response to vaccination.

Marconi et al report out the results of the COV-Barrier study, a phase 3 randomized placebo controlled (RCT) trial with baricitinib, a JAK-STAT pathway inhibitor generally used to suppress proinflammatory cytokine production and systemic inflammation in rheumatoid arthritis, in hospitalized COVID-19 patients. The 1525 participants equally divided between placebo and baricitinib in an intention to treat analysis, were recruited from 12 countries, and most were on systemic corticosteroids (79.3%) and about one fifth received the antiviral, remdesivir. The study did not show a difference in the primary outcome (a composite of progression to more severe disease including need for high flow oxygen, non-invasive or invasive mechanical ventilation or death by 28 days), but did note a 5% absolute reduction in mortality at 28 days. Based on this results, Baricitinib may have a role similar role in the care of COVID-19 patients as tocilizumab (an IL-6 inhibitor) when given in combination with steroids, but may be used in the care of patients earlier in their disease including those on high flow or noninvasive oxygen as well as those requiring invasive mechanical ventilation, compared to tocilizumab, which is currently preferred by many clinicians in those on more intensive respiratory support and within 24-48 hours of ICU admission.  Like other immunomodulators, there is a concern for increased secondary infections with the use of this therapy, but JAK inhibitors also carry a risk for increase in venous thromboembolic events. Interestingly, in this trial, there was no difference in the incidence of either of these adverse effects between the placebo and treatment groups.

The results of a phase 3 RCT with Canakinumab, an anti-interleukin-1B monoclonal antibody, on the other hand, did not show a benefit in primary outcome of survival without need for mechanical ventilation day 3 to day 29, or recovery time, in hospitalized patients who had elevated C-reactive protein and ferritin but were not yet intubated. Canakinumab was evaluated because IL-1B has been identified as one of the signature elevated cytokines in a maladaptive immune response to SARS-CoV-2 infection and because had shown some promise in small and retrospective studies. 

Lastly, on the prevention side, a study of Regeneron’s anti-SARS-CoV-2 monoclonal antibody cocktail (casirivimab and imdevimab) was evaluated in a double blind placebo controlled RCT in prevention of development of symptomatic SARS-CoV-2 infection within 28 days among household contacts who did not have prior immunity. In the study, 1.5% of those who received the monoclonal therapy subcutaneously versus 7.8% of those who received placebo met the primary endpoint. Additionally, those who received the therapy and were symptomatic, resolved their symptoms two weeks earlier. The real-world utility of the results, however, maybe limited to specific groups, given that need for early identification of contacts, the need to access medical facility for administration, as well as the cost of the drug. There may be a role in high risk and immunocompromised contacts who do not develop adequate immune response to vaccination.