Risk of Immune Thrombocytopenia Induced By Influenza Vaccine. a Nationwide Population-Based Study in France

Introduction: Epidemiological studies suggest a risk of immune thrombocytopenia (ITP) following viral infections, particularly influenza. Conversely, an increased risk of ITP following vaccination has been proven for some vaccines like Measles-Mumps-Rubella vaccine. However, the risk of ITP induced by influenza vaccine is debated. Two case-controls studies has been conducted, with contradictory results: in the Berlin Case-Control Surveillance Study, an increased risk has been found (odds ratio - OR: 3.8 [95% confidence interval - CI: 1.5- 9.1]. Conversely, the French PGRx study suggested the absence of risk of ITP after influenza vaccination [OR: 0.9; 95% CI: 0.4-2.1]. These studies were limited by the number of ITP patients included (169 and 198, respectively) and other limitations. Therefore, we aimed to assess the risk of ITP induced by influenza vaccine in a nationwide cohort in France. Methods: We conducted a population-based study in France within the FAITH cohort (NCT03429660). This cohort is built within the National Health Database that links sociodemographic, hospital and out-hospital data. The FAITH cohort includes all adult patients with incident ITP in France since 2009. Patients are identified using a validated algorithm combining diagnosis codes and drug exposures (with very high positive predictive values). We included in the present study all patients with incident primary ITP aged ≥65 years at ITP diagnosis (indication of influenza vaccination in the general population in France) between July 2009 and June 2015. We assessed the link between influenza vaccine and ITP onset using two designs: a case-control and a self-controlled case series designs. In the case-control design, ITP cases were matched with four controls from the general population for age, sex and place of residency. Index dates for controls were similar to index dates of their matched cases. Cases and controls were compared for exposure to influenza vaccine in the 6 weeks before the index date using conditional logistic regression models adjusted for exposure to other drugs known as inducers of ITP. In the self-controlled case series study, only vaccinated ITP cases were included. The analysis compared the incidence of ITP within periods of risk (6 weeks following vaccination) to the incidence of ITP within other periods of time. We further excluded the 2 weeks prior to vaccine dispensing from the analysis to address selective survival bias (healthy vaccinee effect). Incidence rate ratios (IRRs) adjusted for seasonality were calculated. Results: We included 3,142 incident primary ITP patients aged ≥65 years matched with 12,528 controls in the case-control study. Overall, 147 cases (4.7%) and 579 controls (4.6%) were vaccinated with influenza vaccine during the 6 weeks prior to the index date (adjusted OR: 0.99; 95% CI: 0.80-1.23]). In the self-controlled case series study, 1,875 vaccinated ITP cases were included. Among them, 146 (7.8%) patients were diagnosed for ITP during one of the risk periods following vaccination. The adjusted IRR was 0.96 [95 CI%: 0.80-1.17]. Conclusion: This nationwide population-based study using two different designs showed no increased risk of ITP after influenza vaccination. Disclosures Moulis: Novartis pharma: Research Funding, Speakers Bureau; Amgen pharma: Research Funding, Speakers Bureau; CSL Behring: Research Funding.

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Association between methylphenidate treatment and risk of seizure: a population-based, self-controlled case-series study

The Lancet Child & Adolescent Health ◽

10.1016/s2352-4642(20)30100-0 ◽

2020 ◽

Vol 4 (6) ◽

pp. 435-443 ◽

Cited By ~ 3

Author(s):

Kenneth K C Man ◽

Wallis C Y Lau ◽

David Coghill ◽

Frank M C Besag ◽

J Helen Cross ◽

...

Keyword(s):

Case Series ◽

Population Based ◽

Case Series Study ◽

Series Study

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Peripheral Neuropathy in MGUS and Progression to Amyloid Light-Chain Amyloidosis: A Population-Based Study Including 15,351 MGUS Cases

Blood ◽

10.1182/blood-2019-131514 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5444-5444

Author(s):

Sæmundur Rögnvaldsson ◽

Ingemar Turesson ◽

Magnus Björkholm ◽

Ola Landgren ◽

Sigurður Yngvi Kristinsson

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Large Population ◽

Diagnostic Delay ◽

Population Based ◽

Lymphoproliferative Disorders ◽

First Year ◽

Advisory Committees ◽

Population Based Study ◽

Increased Risk

Introduction Peripheral neuropathy (PN) is a common disorder that can be caused by amyloid light-chain amyloidosis (AL). AL is a rare disorder caused by the deposition of amyloid fibers, originating from malignant plasma cells. Amyloid deposition in peripheral nerves causes PN and is present in 35% of patients with newly diagnosed AL. Diagnosis of AL can be difficult, leading to under-recognition, diagnostic delay, and delayed treatment. Virtually all instances of AL are preceded by monoclonal gammopathy of undetermined significance (MGUS). MGUS is relatively common with a reported prevalence of 4.2% in the general Caucasian population over the age of 50 years. Although MGUS is usually considered asymptomatic, a significant proportion of affected individuals develop PN. However, we are not aware of any studies assessing how PN affects risk of MGUS progression to AL. We were therefore motivated to conduct a large population-based study including 15,351 Swedish individuals with MGUS diagnosed 1986-2013. Methods Participants diagnosed with MGUS between 1986-2013 were recruited from a registry of a nationwide network of hematology- and oncology centers and the Swedish Patient Registry. We then cross-linked data on recorded diagnoses of AL and PN from the Swedish Patient Registry, diagnoses of lymphoproliferative disorders form the Swedish Cancer Registry, and dates of death from the Cause of Death Registry to our study cohort. Individuals with a previous history of other lymphoproliferative disorders were excluded from the study. A multi-state survival model was created. At inclusion, participants started providing person time into the PN or the non-PN states depending on whether they had a previous diagnosis of PN. Those with MGUS who developed PN after inclusion were included into the PN state at the time of PN diagnosis and provided person time in the PN state after that. We then created a Cox proportional hazard regression model with AL as the endpoint. Participants were censored at diagnosis of other lymphoproliferative disorders. We adjusted for sex, age, and year of MGUS diagnosis. Results We included 15,351 participants with MGUS. Of those, 996 participants provided person-time with PN (6.5%). About half of those had PN at MGUS diagnosis (55%). A total of 174 cases of AL were recorded, with AL being more common among those who had PN (2.1% vs 1.0% p=0.002). Those who had PN had a 2.3-fold increased risk of AL as compared to those who did not have PN (hazard ratio (HR): 2.3; 95% confidence interval (95% CI): 1.5-3.7; p<0.001). The results were similar for those who had PN at MGUS diagnosis and those who did not. More than half of AL cases (53%) were diagnosed within one year after MGUS diagnosis. The rate was even higher among those with PN, with 82% of AL cases among those who presented with PN being diagnosed within one year after MGUS diagnosis. In the first year after inclusion, the incidence of AL was 15.2 and 6.1 per 1000 person-years for participants with and without PN respectively (HR: 1.8; 95% CI:1.0-3.4; p=0.04). Participants with PN continued to have an increased risk of progression to AL after the first year with an incidence of AL of 2.6 per 1000 person-years as compared to 1.1 per 1000 person-years among participants who did not have PN (HR:2.4; 95% CI: 1.1-5.0; p=0.02) (Figure). Discussion In this large population-based study, including 15,351 individuals with MGUS, we found that individuals with MGUS who develop PN have an increased risk of progression to AL. In fact, individuals with MGUS who have PN at MGUS diagnosis might already have AL. This risk of AL was highest during the first year after MGUS diagnosis with participants with PN having a higher risk than those who did not have PN. PN continued to be associated with a higher risk of MGUS progression to AL throughout the study period. This is the largest study that we are aware of assessing the association of PN and MGUS progression to AL. Since this is a registry-based study based on recorded diagnoses, some clinical data, including MGUS isotype, is not available. These findings suggest that increased awareness of PN as a feature of MGUS might decrease diagnostic delay and improve outcomes for patients with AL. Figure Disclosures Landgren: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Risk of presentation to hospital with epileptic seizures after vaccination with monovalent AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine (Pandemrix): self controlled case series study

BMJ ◽

10.1136/bmj.e7594 ◽

2012 ◽

Vol 345 (dec18 3) ◽

pp. e7594-e7594 ◽

Cited By ~ 14

Author(s):

L. Arnheim-Dahlstrom ◽

J. Hallgren ◽

C. E. Weibull ◽

P. Sparen

Keyword(s):

Influenza Vaccine ◽

Case Series ◽

Epileptic Seizures ◽

Case Series Study ◽

Series Study

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Association between Ophthalmic Timolol and Hospitalisation for Bradycardia

Journal of Ophthalmology ◽

10.1155/2015/567387 ◽

2015 ◽

Vol 2015 ◽

pp. 1-6 ◽

Cited By ~ 8

Author(s):

Nicole L. Pratt ◽

Emmae N. Ramsay ◽

Lisa M. Kalisch Ellett ◽

Tuan A. Nguyen ◽

Elizabeth E. Roughead

Keyword(s):

Beta Blocker ◽

Case Series ◽

Cardiovascular Effects ◽

Eye Drops ◽

Continuous Exposure ◽

Case Series Study ◽

Increased Risk ◽

Risk Period ◽

Series Study ◽

Remaining Time

Introduction. Ophthalmic timolol, a topical nonselective beta-blocker, has the potential to be absorbed systemically which may cause adverse cardiovascular effects. This study was conducted to determine whether initiation of ophthalmic timolol was associated with an increased risk of hospitalisation for bradycardia.Materials and Methods. A self-controlled case-series study was undertaken in patients who were hospitalised for bradycardia and were exposed to timolol. Person-time after timolol initiation was partitioned into risk periods: 1–30 days, 31–180 days, and >180 days. A 30-day risk period prior to initiating timolol was also included. All remaining time was considered unexposed.Results. There were 6,373 patients with at least one hospitalisation for bradycardia during the study period; 267 were exposed to timolol. Risk of bradycardia was significantly increased in the 31–180 days after timolol initiation (incidence rate ratio (IRR) = 1.93; 95% confidence interval (CI) 1.00–1.87). No increased risk was observed in the first 30 days or beyond 180 days of continuous exposure (IRR = 1.40; 95% CI 0.87–2.26 and IRR = 1.21; 95% CI 0.64–2.31, resp.).Conclusion. Bradycardia is a potential adverse event following timolol initiation. Practitioners should consider patient history before choosing a glaucoma regime and closely monitor patients after treatment initiation with topical nonselective beta-blocker eye drops.

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No increased risk of Guillain-Barré syndrome after human papilloma virus vaccine: A self-controlled case-series study in England

Vaccine ◽

10.1016/j.vaccine.2017.01.076 ◽

2017 ◽

Vol 35 (13) ◽

pp. 1729-1732 ◽

Cited By ~ 32

Author(s):

Nick Andrews ◽

Julia Stowe ◽

Elizabeth Miller

Keyword(s):

Human Papilloma Virus ◽

Virus Vaccine ◽

Case Series ◽

Guillain Barre Syndrome ◽

Human Papilloma Virus Vaccine ◽

Papilloma Virus ◽

Case Series Study ◽

Increased Risk ◽

Guillain Barré ◽

Series Study

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The Impact of Fractures on Survival in Multiple Myeloma: Results from a Population-Based Study

Blood ◽

10.1182/blood-2018-99-115403 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4490-4490

Author(s):

Sigrun Thorsteinsdottir ◽

Ingigerdur S Sverrisdottir ◽

Gauti Gislason ◽

Ola Landgren ◽

Ingemar Turesson ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Population Based ◽

Advisory Committees ◽

Population Based Study ◽

Risk Of Death ◽

Increased Risk ◽

The Impact

Abstract Introduction Multiple myeloma (MM) causes lytic bone lesions, osteopenia, and fractures, which increase the morbidity of MM patients. Results from small previous studies have indicated that fractures in MM have a negative effect on survival. Aims The aim of the study was to evaluate the impact of fractures on survival in MM patients diagnosed in Sweden in the years 1990-2013. Furthermore, to analyze the effect of bone fractures at MM diagnosis on subsequent survival. Methods Patients diagnosed with MM in 1990-2013 were identified from the Swedish Cancer Registry. Information on date of birth, diagnosis, and death were collected from the Registry of Total Population. Information on all fractures were retrieved from the Swedish Patient Registry. Cox regression model was used with fractures as time-dependent variables. The effect of fractures on survival was assessed for any fracture or a subtype of fracture (a specific bone fracture or ICD-coded pathologic fracture). Either first fracture or the first subtype of fracture was used in the analysis. The effect of a fracture at MM diagnosis (within 30 days before or 30 days after MM diagnosis) on survival was also estimated using a Cox regression model. All models were adjusted for age, sex, time of diagnosis, and previous fractures. Results A total of 14,008 patients were diagnosed with MM in the study period. A total of 4,141 (29.6%) patients developed a fracture including fractures that occurred within a year before MM diagnosis and thereafter. Hereof 2,893 (20.7%) patients developed a fracture after MM diagnosis. The risk of death was significantly increased for patients that developed a fracture after the time of MM diagnosis with a hazard ratio (HR) of 2.00 (95% confidence interval (CI) 1.91-2.10) for all fractures combined. The risk of death was significantly increased for patients that developed all subtypes of fractures after MM diagnosis except ankle fractures. The risk of death was significantly increased for patients that developed pathologic fractures (HR=2.17; 95% CI 2.03-2.32), vertebral fractures (HR=1.73; 95% CI 1.61-1.87), hip fractures (HR=1.99; 95% CI 1.82-2.18), femoral fractures (HR=2.62; 95% CI 2.32-2.98), humerus fractures (HR=2.57; 95% CI 2.32-2.86), forearm fractures (HR=1.24; 95% CI 1.05-1.46), and rib fractures (HR=1.52; 95% CI 1.31-1.77), but not for ankle fractures (HR 1.07; 95% CI 0.79-1.44). A total of 942 (6.7%) of all MM patients were diagnosed with a fracture within 30 days before or 30 days after MM diagnosis. The patients with a fracture at diagnosis were at a significantly increased risk of death compared to those without (HR 1.31; 95% CI 1.21-1.41; Figure) Conclusions Our large population-based study, including over 14,000 patients diagnosed with MM in Sweden in the years 1990-2013, showed that MM patients that developed a fracture after the time of diagnosis were at twofold increased risk of dying compared to MM patients without a fracture. Furthermore, MM patients with a fracture at diagnosis had a 30% higher risk of dying compared to patients without a fracture. Our results indicate that fractures in MM reflect a more advanced disease at diagnosis and stress the importance of managing MM bone disease in all MM patients. Figure. Figure. Disclosures Landgren: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

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Peripheral Neuropathy Is Associated with an Increased Risk of Fractures in Individuals with Monoclonal Gammopathy of Undetermined Significance: A Population-Based Study Including 15,351 MGUS Cases

Blood ◽

10.1182/blood-2018-99-116740 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1914-1914

Author(s):

Sæmundur Rögnvaldsson ◽

Sigrun Thorsteinsdottir ◽

Ingemar Turesson ◽

Magnus Björkholm ◽

Ola Landgren ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Board Of Directors ◽

Monoclonal Gammopathy ◽

Research Funding ◽

Large Population ◽

Population Based ◽

Advisory Committees ◽

Population Based Study ◽

Increased Risk ◽

Swedish Patient

Abstract Introduction: Monoclonal gammopathy of undetermined significane (MGUS) is the precursor of multiple myeloma (MM) and related disorders. MGUS is relatively common in the general population with a reported prevalence of 4.2% over the age of 50. Although MGUS is usually considered asymptomatic, affected individuals have been shown to have an increased risk of fractures. This is believed to be related to an early form of MM bone disease characterized by abnormal bone architecture. Peripheral neuropathy (PN) has also been shown to be associated with MGUS. Currently, the prevalence of PN in MGUS is unclear, with reports ranging from 3 to 70%. PN has been associated with an increased risk of falls and fractures, especially in diabetic neuropathy, the most common type of PN. However, we are not aware of any studies assessing how PN affects fracture risk in individuals with MGUS. Therefore, we were motivated to create a large population-based study to assess how PN affects the risk of fractures in MGUS. Methods: We included all MGUS cases diagnosed in Sweden between 1986 and 2013 and recorded in a registry of a nationwide network of hematology- and oncology centers or in the Swedish patient registry. We then cross-linked data from the Swedish Patient Registry, Cancer Registry, and Cause of Death Registry to our study cohort. Individuals with a previous history of other lymphoproliferative disorders were excluded from the study. We created a multi-state survival model. At inclusion participants started providing person time into the PN or the non PN states depending on whether they had a previous diagnosis of PN or not. Those with MGUS who developed PN after inclusion were included into the PN state at the time of PN diagnosis and provided person time into the PN state after that. We then created a Cox proportional hazard regression model with the endpoint defined as the first fracture of any type after inclusion with participants being censored at diagnosis of MM or related disorders. We adjusted for sex, age, year of MGUS diagnosis and previous fracture in the 2 years before inclusion. Results At total of 15,351 individuals with MGUS were enrolled and followed for a median of 3.2 years, providing a total of 76,141 years of person time. Of those, 951 individuals provided a total of 3,497 years of person time with PN, being followed for a median of 2.7 years. A total of 3,121 fractures were observed, 2,970 among those without PN and 151 among those with PN. Results from an adjusted Cox regression model showed that those who had PN had a higher risk of having a first fracture than did those who did not have PN (hazard ratio (HR): 1.21, 95% confidence interval (95%CI): 1.02-1.42, p=0.027). Discussion In this large population-based study including 15,351 individuals with MGUS we found that individuals with MGUS who also have PN have an increased risk of fractures as compared to those who only have MGUS. In a previous study, we have already showed that PN does not affect the risk of MGUS progression. Therefore, it is unlikely that these findings are attributed to fractures caused by active undiagnosed MM. These findings suggest that the increased fracture risk observed in individuals with MGUS can at least partly be attributed to concomitant PN. We are currently validating these results within the iStopMM trial, a large prospective MGUS screening study. Disclosures Landgren: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Pfizer: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees.

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Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study

BMJ ◽

10.1136/bmj.n1931 ◽

2021 ◽

pp. n1931 ◽

Cited By ~ 6

Author(s):

Julia Hippisley-Cox ◽

Martina Patone ◽

Xue W Mei ◽

Defne Saatci ◽

Sharon Dixon ◽

...

Keyword(s):

Venous Thromboembolism ◽

Hospital Admission ◽

Ischaemic Stroke ◽

Case Series ◽

Positive Test ◽

Vascular Events ◽

Arterial Thromboembolism ◽

Case Series Study ◽

Increased Risk ◽

Series Study

Abstract Objective To assess the association between covid-19 vaccines and risk of thrombocytopenia and thromboembolic events in England among adults. Design Self-controlled case series study using national data on covid-19 vaccination and hospital admissions. Setting Patient level data were obtained for approximately 30 million people vaccinated in England between 1 December 2020 and 24 April 2021. Electronic health records were linked with death data from the Office for National Statistics, SARS-CoV-2 positive test data, and hospital admission data from the United Kingdom’s health service (NHS). Participants 29 121 633 people were vaccinated with first doses (19 608 008 with Oxford-AstraZeneca (ChAdOx1 nCoV-19) and 9 513 625 with Pfizer-BioNTech (BNT162b2 mRNA)) and 1 758 095 people had a positive SARS-CoV-2 test. People aged ≥16 years who had first doses of the ChAdOx1 nCoV-19 or BNT162b2 mRNA vaccines and any outcome of interest were included in the study. Main outcome measures The primary outcomes were hospital admission or death associated with thrombocytopenia, venous thromboembolism, and arterial thromboembolism within 28 days of three exposures: first dose of the ChAdOx1 nCoV-19 vaccine; first dose of the BNT162b2 mRNA vaccine; and a SARS-CoV-2 positive test. Secondary outcomes were subsets of the primary outcomes: cerebral venous sinus thrombosis (CVST), ischaemic stroke, myocardial infarction, and other rare arterial thrombotic events. Results The study found increased risk of thrombocytopenia after ChAdOx1 nCoV-19 vaccination (incidence rate ratio 1.33, 95% confidence interval 1.19 to 1.47 at 8-14 days) and after a positive SARS-CoV-2 test (5.27, 4.34 to 6.40 at 8-14 days); increased risk of venous thromboembolism after ChAdOx1 nCoV-19 vaccination (1.10, 1.02 to 1.18 at 8-14 days) and after SARS-CoV-2 infection (13.86, 12.76 to 15.05 at 8-14 days); and increased risk of arterial thromboembolism after BNT162b2 mRNA vaccination (1.06, 1.01 to 1.10 at 15-21 days) and after SARS-CoV-2 infection (2.02, 1.82 to 2.24 at 15-21 days). Secondary analyses found increased risk of CVST after ChAdOx1 nCoV-19 vaccination (4.01, 2.08 to 7.71 at 8-14 days), after BNT162b2 mRNA vaccination (3.58, 1.39 to 9.27 at 15-21 days), and after a positive SARS-CoV-2 test; increased risk of ischaemic stroke after BNT162b2 mRNA vaccination (1.12, 1.04 to 1.20 at 15-21 days) and after a positive SARS-CoV-2 test; and increased risk of other rare arterial thrombotic events after ChAdOx1 nCoV-19 vaccination (1.21, 1.02 to 1.43 at 8-14 days) and after a positive SARS-CoV-2 test. Conclusion Increased risks of haematological and vascular events that led to hospital admission or death were observed for short time intervals after first doses of the ChAdOx1 nCoV-19 and BNT162b2 mRNA vaccines. The risks of most of these events were substantially higher and more prolonged after SARS-CoV-2 infection than after vaccination in the same population.

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