Sex: U
Vaccine: VARZOS
Symptoms: Guillain-Barre syndrome, Respiratory failure
Clinical narrative: Guillain-Barre Syndrome; Respiratory failure; This case was reported in a literature article and described the occurrence of guillain barre syndrome in a elderly patient who received Herpes zoster (Shingrix) for prophylaxis.   On an unknown date, the patient received Shingrix. On an unknown date, less than 2 months after receiving Shingrix, the patient experienced guillain barre syndrome (serious criteria hospitalization and GSK medically significant) and respiratory failure (serious criteria GSK medically significant). On an unknown date, the outcome of the guillain barre syndrome and respiratory failure were unknown.   The reporter considered the guillain barre syndrome and respiratory failure to be related to Shingrix.  Additional information was provided as follows: This case was reported in a literature article and described the occurrence of Guillain-Barre Syndrome in a patient aged 65 years or older of unspecified gender, who was vaccinated with Shingrix (GlaxoSmithKline) for prophylaxis. This case belongs to eTable-8 in supplemental content reported in the literature article. The patient was a part of the cohort study that objective was to use Insurance claims data to evaluate risk of developing Guillain-Barre syndrome following vaccination with zoster vaccine. [This case series cohort study included 849397 recombinant zoster vaccine (RZV or Shingrix) vaccinated and 1817099 zoster vaccine live (ZVL or Zostavax)-vaccinated beneficiaries aged 65 years or older. Self-controlled analyses included events identified from 2113758 eligible RZV-vaccinated beneficiaries 65 years or older. The authors compared the relative risk of Guillain-Barre syndrome after RZV vs ZVL, followed by claims-based and medical record-based self-controlled case series analyses to assess risk of Guillain-Barre syndrome during a post-vaccination risk window (days 1-42) compared with a control window (days 43-183). In self-controlled analyses, RZV vaccinees were observed from 1st October 2017, to 29th February 2020. Study Population included participant RZV and zoster vaccine live (ZVL) vaccinations were identified. To ensure complete capture of RZV vaccinations, authors required continuous Insurance Fee-for-Service. From 1st October 2017, through 6 months after the last RZV vaccination, the end of the study period or death, whichever occurred earlier. Beneficiaries must have aged into Insurance, be aged 65 years or older on 1st October 2017. To reduce potential confounding from specific frail Insurance populations that could have a different association between vaccination and GBS, beneficiaries could not be undergoing long-term dialysis therapy, or admitted to a nursing home, skilled nursing facility, or in hospice at any point during the study period. In addition, the authors excluded any beneficiaries with a historical GBS diagnosis in any diagnosis position from any provider within 6 months prior to the first RZV vaccination, and any beneficiaries receiving RZV administration inconsistent with recommended dosing in the package insert (that was received more than 2 administrations of RZV; or received the second administration within 42 days of the first). The author collected GBS diagnoses from inpatient (IP), outpatient (OP), and carrier (PB) (that was office) claims. Generally, OP claims arise from outpatient procedural and emergency department settings, whereas the PB, or carrier, claims are submitted by professional clinicians in office settings. An incident GBS case was defined as either (1) the first occurrence of a primary discharge diagnosis of GBS in the IP setting post vaccination, or (2) the first occurrence of a GBS diagnosis in any setting and any position followed by a hospitalization within the subsequent 7 days where GBS was the primary discharge diagnosis. In the latter case, the case's onset date was the date of the earlier GBS claim in the 7 days prior. The author used a risk window of 42 days after vaccination because this was generally recommended by the Brighton Collaboration GBS case definition. The author requested medical records for all inpatient GBS cases identified during the original study period (1st October 2017, to 31st March 2019) and conducted medical record review (MRR) for all returned records. Trained abstractors extracted specific information from the medical records, and 2 independent neurologists independently adjudicated the abstracted data using the Brighton Collaboration's case definition for GBS. Abstractors and neurologists were blinded to vaccination histories. Cases identified by this process as Brighton Level 1, 2 or 3 were medical record confirmed GBS cases and were included in a medical record confirmed Agency analysis. The author also collected information on preceding illnesses potentially associated with GBS, such as respiratory and gastrointestinal illness, to investigate potential confounding. The cohort analysis compared the postvaccination GBS rate for RZV (1st October 2017, to 31st December 2018) to the rate for ZVL when it was predominantly administered (1st October 2012 to 30th September 2017) within the 42-day postvaccination window. Only eligible RZV vaccines with an incident GBS outcome in the risk or control windows were included in the analysis. The risk window was days 1 to 42 postvaccination after the first or second dose of RZV, whereas the control window was days 43 to 183 after a first dose (or until second dose receipt) and days 43 to 183 after a second dose (or until end of study period, disenrollment, or death). The control window was bound at 6 months because additional control time would increase enrollment requirements, thus decreasing the size of eligible population and reducing the power of analyses. Owing to influenza vaccinations' known association with GBS, the authors produced descriptive statistics for influenza vaccinations occurring 42 days before or after RZV vaccination and that were associated with an identified GBS case. Both claims identified and medical record confirmed analyses of hospitalized GBS cases were conducted after all doses. For the secondary analyses, GBS risk was assessed following the first and second RZV doses independently. The author also investigated changes in postvaccination GBS risk over time and patterns of GBS case severity]. The patient was from risk window. No information on patient's medical history or family history or concurrent condition or concomitant medication was provided. On an unspecified date, the patient received Shingrix vaccine (Route and site of administration unknown; batch number not provided, dosage unknown). The age at vaccination was not reported. On an unspecified date between 1st October 2017 to 29th February 2020, 1 to 42 days after the vaccination, the patient had Guillain-Barre syndrome (GBS). The patient occurred respiratory failure during the hospital on day 21 post GBS onset. [A total of 1318004 were identified eligible RZV vaccinations (849397 beneficiaries) and 1817099 eligible ZVL vaccinations (1817099 beneficiaries). Amongst the RZV vaccinees, the mean age was 74.8 years at first dose, and 58% were female, whereas among those who received the ZVL vaccine, the mean age was 74.3 years, and 60% were female. After adjusting for age and sex, GBS risk after RZV compared with ZVL was elevated with an RR of 2.34. Out of all eligible RZV vaccinees, 13 claims based GBS cases during the risk period and 8 during the control period were observed. The primary analysis identified an increased risk of GBS in the risk window compared with the control window. The authors found that there were 6.47 excess cases of GBS in the risk window compared with the control window per million vaccinations. The PPV-adjusted AR calculation showed 5.08 excess cases per million vaccinations. Only 2 of the 21 observed claims based GBS cases received an influenza vaccination in the 42 days prior to RZV vaccination; both cases occurred in the control window, so no GBS cases identified in the risk window were preceded by influenza vaccination. In the extended analysis, of the 44 claims based GBS cases, 6 received an influenza vaccination in the 42 days prior to RZV vaccination; 3 cases each in the risk and control windows. The authors' secondary analysis included 950797 first RZV doses and identified an increased risk of GBS. There were 9.50 excess cases for every million vaccinations administered, adjusted for PPV. Seasonality-adjusted analyses produced similar results. Of the 36 total cases requested for MRR across both the cohort and AGENCY studies, 28 were returned and reviewed, 22 of which were MRR confirmed by neurologists as a GBS case, resulting in a return rate of 77.78% and a medical record confirmed PPV of 78.57%. Of the confirmed Agency cases, 7 were in the risk window and 4 were in the control window. The authors found an increased risk of GBS when comparing incidence in the risk and control windows, resulting in a PPV adjusted AR of 5.17 per million doses. The authors' analysis of infectious illnesses preceding GBS onset did not diminish study findings as preceding infection occurred more frequently among cases in the control window. The extended study period Agency analysis confirmed earlier results by including additional data, which decreased the observed risk from an RR of 4.30 to 2.84; PPV-adjusted AR became 3.13. Initially, the authors did not have sufficient power to conduct second dose only analyses (0 cases were identified). However, after extending the study period for the claims based Agency analysis, the author identified 15 GBS events occurring after the second dose; this resulted in an RR of 0.22. The authors used two metrics to measure the severity of GBS cases occurring after Shingrix vaccination: (i) occurrence of respiratory failure or mechanical intubation, and (ii) length of hospital stay. The authors produced descriptive statistics determining the number of cases with a claim for respiratory failure or intubation during a hospitalization with a primary GBS diagnosis. The authors used the codes to search for intubation and respiratory failure occurring during the same hospital stay as the primary GBS diagnosis. Cases were additionally assessed for severity based upon the length of stay during a hospitalization with a primary GBS diagnosis]. This case has been considered as serious due to hospitalization. Treatment was unknown. The outcome of the event was not reported. The authors commented, "The CDC VSD signal suggested an association of GBS with RZV. Clinical trial data was not powered to detect a statistical association between the rare event, GBS, and vaccination, and the trials observed an imbalance with more cases occurring after placebo. Our current findings confirm an increased risk of GBS following RZV vaccination in the Insurance population aged 65 years and older. The Insurance cohort analysis showed a statistically significant increased risk of GBS among RZV recipients compared with ZVL recipients. The Agency medical record confirmed sensitivity analyses, which used the set of GBS cases for which we had the highest degree of certainty, showed an increased risk of GBS following RZV vaccination, with an AR of 5.17 excess GBS cases per million doses during the 42-day risk window following vaccination. The increased risk of GBS following RZV should be considered in the context of the benefits of the vaccine. Herpes zoster is associated with substantial morbidity, including possible persistent pain, and disseminated disease. In clinical trials, RZV reduced the incidence of HZ by 97% in participants aged 50 years and older, and efficacy appeared durable through 4 years after vaccination. Comparatively, clinical trials for ZVL reduced incidence of HZ by 51% in participants aged 60 years and older. If HZ reactivation also triggers cases of GBS, then RZV vaccine could potentially prevent these cases of GBS, and the vaccine could be protective against the outcome. Our study examined the risk of GBS in the 42 days following vaccination, which may not account for potential changes in GBS risk over time owing to wild type HZ reactivation. Recent presentations to Agency estimated the risk of GBS after HZ reactivation as an RR of 4.0 an AR of 12.8 cases per million HZ episodes. This is statistically similar to the most precise estimates of GBS after RZV identified herein: RR, 2.84 and an AR of 3.13. Using this AR, and the vaccine efficacy of 97%, one would expect 6.26 cases of GBS among a million fully vaccinated individuals (2 doses per individual), whereas one would expect to prevent approximately 7070 HZ reactivations in the same population according to the trial data for those aged 60 to 69 years in the Shingrix Package Insert. Taking into account risk of GBS after HZ reactivation and RZV, it estimated 6.3 excess GBS cases after RZV vaccination in those aged 60 to 69 years compared with 61600 HZ cases averted (including 62 potential deaths, 5500 cases of HZ ocular complications, and 9350 cases of postherpetic neuralgia). These data convey that the risk-benefit balance for RZV remains favorable, and clinicians should continue to offer and discuss RZV vaccination with their patients. This study had several major strengths. First, this is the largest post-market study evaluating GBS risk following RZV vaccination. Further, we use a study population well suited to the analyses being conducted because the Insurance  population is the largest cohort of beneficiaries aged 65 years or older with individually linked data (eg, demographic, diagnostic, and vaccination information). We also completed confirmatory Agency analyses after the initial cohort analyses to reduce the risk of confounding by time-fixed covariates (eg, sex), which potentially provided more precise estimates of increased GBS risk after RZV vaccination. Finally, we completed an MRR and conducted an analysis of medical record confirmed cases to increase the reliability of our results; this also helped increase precision of onset dates and case classification. There are several limitations of this study. First, the cohort and Agency analyses did not explicitly adjust for preceding illness or other time-varying confounders. However, the potential influence of preceding illnesses was not found to diminish results. Second, using Insurance claims creates the possibility for under-ascertainment of vaccine administration because nontraditional clinical settings may not submit vaccination claims to Insurance, which limits sample size. Third, the risk window for GBS following RZV vaccination is not as well defined as the risk window following influenza vaccination, and we lacked sufficient data to empirically determine the ideal risk window using scanning statistics. Finally, although RZV is approved for individuals aged 50 years or older, our study population only included individuals aged 65 years or older. This study relied on a rather specific GBS case identification algorithm, which provides additional confidence in identification, but may have limited the number of cases included; we only included cases with hospital discharge diagnoses of GBS in the primary position, which may have excluded some GBS cases. However, GBS is a well-defined acute disease that usually requires hospitalization and defining cases as claims with a primary GBS hospitalization results in a higher PPV". The authors concluded, "This collaborative effort between the FDA, CMS and CDC to examine an early VSD statistical signal illustrates the value of multiagency efforts to conduct GBS surveillance in a timely manner. Despite the elevated risk of GBS observed herein, patients and clinicians should be aware of the risk of GBS and consider the benefits of avoiding zoster with an efficacious vaccine. Findings of this case series cohort study indicate a slightly increased risk of Guillain-Barre syndrome during the 42 days following RZV vaccination in the Insurance population, with approximately 3 excess Guillain-Barre syndrome cases per million vaccinations. Clinicians and patients should be aware of this risk, while considering the benefit of decreasing the risk of herpes zoster and its complications through an efficacious vaccine, as risk-benefit balance remains in favor of vaccination". This is 1 of the 2 valid cases reported in the same literature article.; Sender's Comments:  US-GLAXOSMITHKLINE-US2021GSK231698:Same reporter