New insights into the paradox between smoking and the risk of SARS-CoV-2 infection (COVID-19): Insufficient evidence for a causal association.

AIMS: Previous studies have reported a 'smoker's paradox', where people who smoke appear to be protected against Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) infection (COVID-19). This conflicts with well-established evidence that people who smoke are generally more vulnerable to respiratory infections. In this study, we aimed to validate the association between smoking and SARS-CoV-2 infection in a general Dutch population, and to evaluate the evidence underlying the possible causal relationship between smoking and SARS-CoV-2 infection by applying a modern adaptation of the Bradford Hill criteria. METHODS: In total, 57,833 participants from the Lifelines Cohort Study were included in the analysis. Smoking status, including never smoker, current smoker, and former smoker, was derived from the Lifelines general assessment between 2014 and 2017, while SARS-CoV-2 infection status was derived from an additional COVID-19 questionnaire from 2021 to 2022. Logistic regressions were used for the association between smoking status and infection status. The adapted Bradford Hill's criteria, including the strength of association (including an analysis of plausible confounding), plausibility, temporality and study design suitability, were applied to evaluate the existing literature. RESULTS: We found, compared with never smokers, an increased risk of SARS-CoV-2 infection for former smokers (odds ratio (OR)=1.07, 95% confidence interval (CI)=1.01-1.13), but a reduced risk for current smokers (OR=0.85, 95% CI=0.79-0.92), after adjusting for several relevant covariates. However, we discerned a possible explanation of the smoker's paradox since we observed that current smokers were more likely to be non-responders to the COVID-19 questions and, more importantly, these non-responders were more likely to have other established risk factors for SARS-CoV-2 infection. CONCLUSIONS: There is insufficient evidence to suggest that smoking protects against SARS-CoV-2 infection. According to the adapted Bradford Hill's criteria, we observed a high inconsistency between study results, a high possibility for residual confounding and no clear evidence for biological plausibility. Future studies should include linkage with the confirmed testing results from national healthcare registries to mitigate avoidable bias.

Piperacillin-Tazobactam Added to Vancomycin Increases Risk for Acute Kidney Injury: Fact or Fiction?

Vancomycin and piperacillin-tazobactam are 2 of the most commonly prescribed antibiotics in hospitals. Recent data from multiple meta-analyses suggest that the combination increases the risk for vancomycin-induced kidney injury when compared to alternative viable options. However, these studies are unable to prove biologic plausibility and causality as randomized controlled trials have not been performed. Furthermore, these studies define acute kidney injury according to thresholds of serum creatinine rise. Serum creatinine is not a direct indicator of renal injury, rather a surrogate of glomerular function. More reliable, specific, and sensitive biomarkers are needed to truly define if there is a causal relationship with increased toxicity when piperacillin-tazobactam is added to vancomycin. This viewpoint will explore the available evidence for and against increased acute kidney injury in the setting of vancomycin and piperacillin-tazobactam coadministration.

The association between acute flaccid myelitis (AFM) and Enterovirus D68 (EV-D68) - what is the evidence for causation?

BackgroundEnterovirus D68 (EV-D68) has historically been a sporadic disease, causing occasional small outbreaks of generally mild infection. In recent years, there has been evidence of an increase in EV-D68 infections globally. Large outbreaks of EV-D68, with thousands of cases, occurred in the United States, Canada and Europe in 2014. The outbreaks were associated temporally and geographically with an increase in clusters of acute flaccid myelitis (AFM).Aims: We aimed to evaluate a causal association between EV-D68 and AFM. Methods: Using data from the published and grey literature, we applied the Bradford Hill criteria, a set of nine principles applied to examine causality, to evaluate the relationship between EV-D68 and AFM. Based on available evidence, we defined the Bradford Hill Criteria as being not met, or met minimally, partially or fully. Results: Available evidence applied to EV-D68 and AFM showed that six of the Bradford Hill criteria were fully met and two were partially met. The criterion of biological gradient was minimally met. The incidence of EV-D68 infections is increasing world-wide. Phylogenetic epidemiology showed diversification from the original Fermon and Rhyne strains since the year 2000, with evolution of a genetically distinct outbreak strain, clade B1. Clade B1, but not older strains, is associated with AFM and is neuropathic in animal models. Conclusion: While more research is needed on dose-response relationship, application of the Bradford Hill criteria supported a causal relationship between EV-D68 and AFM.

A weight of evidence assessment approach for adverse outcome pathways.

The adverse outcome pathway (AOP) is a framework to mechanistically link molecular initiating events to adverse biological outcomes. From a regulatory perspective, it is of crucial importance to determine the confidence for the AOP in question as well as the quality of data available in supporting this evaluation. A weight of evidence approach has been proposed for this task, but many of the existing frameworks for weight of evidence evaluation are qualitative and there is not clear guidance regarding how weight of evidence should be calculated for an AOP. In this paper we advocate the use of a subject matter expertise driven approach for weight of evidence evaluation based on criteria and metrics related to data quality and the strength of causal linkages between key events. As a demonstration, we notionally determine weight of evidence scores for two AOPs: Non-competitive ionotropic GABA receptor antagonism leading to epileptic seizures, and Antagonist-binding and stabilization of a co-repressor to the peroxisome proliferator-activated receptor α (PPARα) signaling complex ultimately causing starvation-like weight loss.

From Correlation to Causation: What Do We Need in the Historical Sciences?

Changes in the methodology of the historical sciences make them more vulnerable to unjustifiable speculations being passed off as scientific results. The integrity of historical science is in peril due the way speculative and often unexamined causal assumptions are being used to generate data and underpin the identification of correlations in such data. A step toward a solution is to distinguish between plausible and speculative assumptions that facilitate the inference from measured and observed data to causal claims. One way to do that is by comparing these assumptions against a well-attested set of aspects of causation, such as the so-called "Bradford Hill Criteria" (BHC). The BHC do not provide a test for causation or necessary and sufficient conditions for causation but do indicate grounds for further investigation. By revising the BHC to reflect the needs and focus of historical sciences, it will be possible to assess the cogency of methods of investigation. These will be the Historical Sciences Bradford Hill Criteria (HSBHC). An application to one area in historical science is used to demonstrate the effectiveness of the HSBHC, namely biogeography. Four methods are assessed in order to show how the HSBHC can be used to examine the assumptions between our data and the causal biogeographical processes we infer.

Is chronic rhinosinusitis related to allergic rhinitis in adults and children? Applying epidemiological guidelines for causation.

The relationship between allergic rhinitis and chronic rhinosinusitis has been assessed in a number of observational and experimental studies. In this review, we attempt their synthesis and evaluation using the modified Bradford Hill guidelines for causation. Although there is no proof of causation, especially in the pediatric literature, an evaluation of underlying allergies is recommended at least as an initial measure of symptoms relief.

Evaluating weight of evidence in the mystery of Balkan endemic nephropathy.

Balkan endemic nephropathy (BEN) is a chronic, progressive wasting disease of the kidneys, endemic in certain rural regions of the Balkan nations Croatia, Serbia, Bulgaria, and Romania. It is irreversible and ultimately fatal. Though this disease was first described in the 1950s, its causes have been a mystery and a source of much academic and clinical contention. Possible etiologic agents that have been explored include exposure to metals and metalloids, viruses and bacteria, and the dietary toxins aristolochic acid (AA) and ochratoxin A (OTA). AA is a toxin produced by weeds of the genus Aristolochia, common in Balkan wheat fields. Aristolochia seeds may intermingle with harvested grains and thus inadvertently enter human diets. OTA is a mycotoxin (fungal toxin) common in many foods, including cereal grains. In this study, we analyzed the weight of evidence for each of the suspected causes of BEN using the Bradford Hill criteria (BHC): nine conditions that determine weight of evidence for a causal relationship between an agent and a disease. Each agent postulated to cause BEN was evaluated using the nine criteria, and for each criterion was given a rating based on the strength of the association between exposure to the substance and BEN. From the overall available scientific evidence for each of these suspected risk factors, AA is the agent with the greatest weight of evidence in causing BEN. We describe other methods for testing causality from epidemiological studies, which support this conclusion of AA causing BEN.

Testing the validity of preventing chronic regional pain syndrome with vitamin C after distal radius fracture. [Corrected].

PURPOSE: The American Academy of Orthopaedic Surgeons recommends the use of vitamin C to prevent complex regional pain syndrome (CRPS) for patients with distal radius fractures (DRFs). We hypothesized that the evidence for supporting this recommendation is weak, based on epidemiological principles of association and causality. The specific aim of this project was to test the validity of this recommendation. METHODS: We conducted a literature review to retrieve articles reporting on the use of vitamin C to prevent CRPS. Data collected included sample size, study design type, dose of vitamin C used, and outcome measures of association expressed as relative risk (RR) and odds ratio. We then applied Hill criteria to evaluate the relationship between vitamin C and CRPS. RESULTS: We obtained 225 articles from the database search. After the exclusion of duplicates, unrelated articles, editorial letters, and commentaries, we found 4 articles and 1 systematic review relevant to our topic. Six of the 9 Hill criteria were met, and an earlier meta-analysis showed a quantified reduction in CRPS risk. However, criteria like biological plausibility, specificity, and coherence were not met. CONCLUSIONS: The number of causal/association criteria met was adequate to support the scientific premise of the effect of vitamin C in preventing CRPS after DRF. Furthermore, vitamin C administration is of relatively low cost and has few complications unless administered in large doses. Owing to sufficient epidemiological evidence availability, the American Academy of Orthopaedic Surgeons recommendation of vitamin C to prevent CRPS has practical merit. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

A quantitative weight-of-evidence method for confidence assessment of adverse outcome pathway networks: A case study on chemical-induced liver steatosis.

The field of chemical toxicity testing is undergoing a transition to overcome the limitations of in vivo experiments. This evolution involves implementing innovative non-animal approaches to improve predictability and provide a more precise understanding of toxicity mechanisms. Adverse outcome pathway (AOP) networks are pivotal in organizing existing mechanistic knowledge related to toxicological processes. However, these AOP networks are dynamic and require regular updates to incorporate the latest data. Regulatory challenges also persist due to concerns about the reliability of the information they offer. This study introduces a generic Weight-of-Evidence (WoE) scoring method, aligned with the tailored Bradford-Hill criteria, to quantitatively assess the confidence levels in key event relationships (KERs) within AOP networks. We use the previously published AOP network on chemical-induced liver steatosis, a prevalent form of human liver injury, as a case study. Initially, the existing AOP network is optimized with the latest scientific information extracted from PubMed using the free SysRev platform for artificial intelligence (AI)-based abstract inclusion and standardized data collection. The resulting optimized AOP network, constructed using Cytoscape, visually represents confidence levels through node size (key event, KE) and edge thickness (KERs). Additionally, a Shiny application is developed to facilitate user interaction with the dataset, promoting future updates. Our analysis of 173 research papers yielded 100 unique KEs and 221 KERs among which 72 KEs and 170 KERs, respectively, have not been previously documented in the prior AOP network or AOP-wiki. Notably, modifications in de novo lipogenesis, fatty acid uptake and mitochondrial beta-oxidation, leading to lipid accumulation and liver steatosis, garnered the highest KER confidence scores. In conclusion, our study delivers a generic methodology for developing and assessing AOP networks. The quantitative WoE scoring method facilitates in determining the level of support for KERs within the optimized AOP network, offering valuable insights into its utility in both scientific research and regulatory contexts. KERs supported by robust evidence represent promising candidates for inclusion in an in vitro test battery for reliably predicting chemical-induced liver steatosis within regulatory frameworks.

Breast implant illness: Is it causally related to breast implants?

Once believed to be completely inert implants, Silicon Breast Implants (SBIs) have been shown to be able to induce a chronic inflammatory response in the body which can lead to a variety of possible manifestations ranging from the most common capsular contraction to rarer conditions such as malignancies and autoimmune diseases. Among the latter, new syndromes have been consistently recognized: Breast Implant Illness (BII) and autoimmunity/autoinflammatory syndrome induced by adjuvants (ASIA syndrome/Shoenfeld's Syndrome). The pathophysiological mechanisms underlying such syndromes are not yet clear and the overlap they show with other common conditions have sparked an important debate in the scientific community regarding their existence and their cause-effect relationship with SBIs. In this article Professor Cohen Tervaert and Professor Bassetto, leading experts in the field, are going to present arguments in favor and against such causal relationship according to the latest scientific evidence. Professor Cohen Tervaert is going to demonstrate how the evidence available is enough to prove a causal relationship as defined by the Bradford Hill's criteria. Professor Bassetto is going to highlight how the many biases that afflict the available evidence prevent us from drawing such conclusions. Professor Shoenfeld is going to moderate the discussion with its insightful conclusions.

Assigning cause for emerging diseases of aquatic organisms.

Resolving the cause of disease (= aetiology) in aquatic organisms is a challenging but essential goal, heightened by increasing disease prevalence in a changing climate and an interconnected world of anthropogenic pathogen spread. Emerging diseases play important roles in evolutionary ecology, wildlife conservation, the seafood industry, recreation, cultural practices, and human health. As we emerge from a global pandemic of zoonotic origin, we must focus on timely diagnosis to confirm aetiology and enable response to diseases in aquatic ecosystems. Those systems' resilience, and our own sustainable use of seafood, depend on it. Synchronising traditional and recent advances in microbiology that span ecological, veterinary, and medical fields will enable definitive assignment of risk factors and causal agents for better biosecurity management and healthier aquatic ecosystems.

Causation in different scientific disciplines: A comparison of standards in occupational medicine and particle physics.

Occupational medical research involves the collection and analysis of data to draw conclusions about the causes and prevention of workplace injuries and diseases. However, there has been criticism that some studies lack rigour in determining causation. This article examines the similarities and differences between occupational medical research and particle physics in terms of their approach to hypothesis testing, statistical methods, and confounder control. The article also explores the use of criteria such as the Bradford Hill criteria to determine causation in occupational medical research. While particle physics is often viewed as a highly rigorous science, occupational medical research also employs rigorous scientific methods to ensure findings are accurate and reliable. However, there is room for improvement in determining causation in occupational medical research, particularly in the use of criteria such as the Bradford Hill criteria to guide the development of more robust studies. It is essential for occupational medical research to adhere to rigorous scientific methods to deliver findings that can help reduce workplace injuries and diseases. The use of criteria such as the Bradford Hill criteria can ensure that the conclusions drawn. Med Pr Work Health Saf. 2023;74(4):333-9.

Spinal injury rates and specific causation in motor vehicle collisions.

Motor vehicle collisions (MVCs) are a leading cause of acute spinal injuries. Chronic spinal pathologies are common in the population. Thus, determining the incidence of different types of spinal injuries due to MVCs and understanding biomechanical mechanism of these injuries is important for distinguishing acute injuries from chronic degenerative disease. This paper describes methods for determining causation of spinal pathologies from MVCs based on rates of injury and analysis of the biomechanics require to produce these injuries. Rates of spinal injuries in MVCs were determined using two distinct methodologies and interpreted using a focused review of salient biomechanical literature. One methodology used incidence data from the Nationwide Emergency Department Sample and exposure data from the Crash Report Sample System supplemented with a telephone survey to estimate total national exposure to MVC. The other used incidence and exposure data from the Crash Investigation Sampling System. Linking the clinical and biomechanical findings yielded several conclusions. First, spinal injuries caused by an MVC are relatively rare (511 injured occupants per 10,000 exposed to an MVC), which is consistent with the biomechanical forces required to generate injury. Second, spinal injury rates increase as impact severity increases, and fractures are more common in higher-severity exposures. Third, the rate of sprain/strain in the cervical spine is greater than in the lumbar spine. Fourth, spinal disc injuries are extremely rare in MVCs (0.01 occupants per 10,000 exposed) and typically occur with concomitant trauma, which is consistent with the biomechanical findings 1) that disc herniations are fatigue injuries caused by cyclic loading, 2) the disc is almost never the first structure to be injured in impact loading unless it is highly flexed and compressed, and 3) that most crashes involve predominantly tensile loading in the spine, which does not cause isolated disc herniations. These biomechanical findings illustrate that determining causation when an MVC occupant presents with disc pathology must be based on the specifics of that presentation and the crash circumstances and, more broadly, that any causation determination must be informed by competent biomechanical analysis.

Vulval Aphthous Ulcers in Adolescents Following COVID-19 Vaccination-Analysis of an International Case Series.

STUDY OBJECTIVE: To review and characterize reports of vulval aphthous ulcers (VAUs) following COVID-19 vaccination in VigiBase, the World Health Organization global database of reported potential adverse effects of medicinal products, to demonstrate the importance and power of case reports for rare suspected adverse reactions and to investigate whether they suggest a potential for COVID-19 vaccination to be a trigger METHODS: Cases reporting the Medical Dictionary for Regulatory Activities' (MedDRA) preferred term "Vulvovaginal ulceration" and related preferred terms in adolescent patients aged 12-17 years in association with any COVID-19 vaccine were extracted from VigiBase. The cases were clinically reviewed, and causality was assessed by applying the Bradford Hill criteria to the obtained case series. RESULTS: As of June 30th, 2022, there were 444 reports for the selected Medical Dictionary for Regulatory Activities preferred terms following COVID-19 vaccination in VigiBase. Ninety-four de-duplicated reports concerned adolescent female patients. Thirty-seven cases were clinically consistent with the diagnosis of VAU. On causality assessment, the analyzed case series fulfilled 6 of the 9 Austen Bradford Hill criteria supporting a potential causal relationship. CONCLUSION: VAUs can be perceived as a traumatic experience, especially in adolescent patients. There is, furthermore, a risk that the ulcers will be misdiagnosed, resulting in avoidable investigation and treatment burdens for patients. We communicate our findings to support the small number of published case reports and raise awareness of VAUs occurring in a temporal association with COVID-19 vaccination. Furthermore, our analysis supports observations about the value of case reports for the recognition and assessment of rare adverse events.

Tamsulosin and risk of priapism: A causality assessment using Austin Bradford Hill Criteria.

Tamsulosin hydrochloride, a selective alpha-adrenergic blocking agent has been previously associated with priapism. Priapism is a medically serious condition that, if not intervened, can cause permanent erectile dysfunction. This study was conducted to investigate whether the association of tamsulosin and priapism is causal. All currently available evidence such as experimental, biological, toxicological, published studies, and safety data mined from the WHO global pharmacovigilance database was systematically organized into the Austin Bradford Hill causality assessment framework. In the international pharmacovigilance database, a strong association between tamsulosin and priapism (IC025  = 4.1; PRR025  = 19.9; ROR025  = 20) was observed. There were 122 cases of priapism associated with tamsulosin submitted to the database from 23 countries. In 87.7% of the cases, tamsulosin was reported as a 'sole suspect,' and in 50.8%, it was the only drug administered. In several patients, priapism resolved following discontinuation of tamsulosin and recurred after its reintroduction. Both in the published and unpublished data, for majority of the cases, the time to onset of priapism was within few days following the first intake of tamsulosin. Cases of priapism, particularly those published, were consistent in their clinical features with patients experiencing prolonged painful erection that required aspiration of cavernosal blood, irrigation of the corpora cavernosa, and treatment with vasopressors. Other alpha-adrenergic blocking agents that are structurally analogous with tamsulosin have also been associated with priapism. In several cases, tamsulosin was used off-label, for the treatment of ureteral calculi expulsion. Eight patients experienced priapism that ended up with serious complications such as ejaculation disorders and erectile dysfunction. The currently available totality of evidence suggests that the association of tamsulosin and priapism is causal. Healthcare professionals are therefore recommended to cautiously prescribe tamsulosin and ensure that consumers are aware of the potential risk of priapism.

Geographical clusters of amyotrophic lateral sclerosis and the Bradford Hill criteria.

With the aim of shedding further light on the role of environmental factors in amyotrophic lateral sclerosis (ALS) etiology, we hereby conducted a historical narrative review to critically appraise the published reports on ALS geographical clusters using the modern interpretation of the Bradford Hill criteria for causation. Our research hypothesis was that the more criteria were met, the greater was the evidence supporting a causal association. We found that cluster studies that met the greatest number of Bradford's Hill criteria regarded the non-protein amino acid ß-N-methylamino-L-alanine (L-BMAA) and exposure to metals and minerals, but the evidence for causation was at best moderate and was poor for other environmental factors. This defective picture might be attributed not only to the methodological approach adopted by published studies, but also to the inherent difficulties in the application of Bradford Hill criteria, due to the complexity of the disease phenotype and the underlying pathogenic mechanisms.

Breast Cancer Risk and Human Papillomavirus Infection: A Bradford Hill Criteria Based Evaluation.

BACKGROUND: The association between human papillomavirus (HPV) and human breast cancer (BC) has already been thoroughly studied worldwide with contradictory findings. Although the researchers have tried to minimize the conflict using statistical meta-analysis because of its shortcomings, there is still a need to evaluate the correlation between HPV and BC using any additional method. OBJECTIVES: This study was launched to investigate the correlation between HPV and BC through the application of Bradford Hill criteria postulates. METHODS: Population-wide studies associating HPV with BC were searched using the PubMed database. Then, the information of HPV burden in BC, normal/benign samples was analyzed, and ultimately Bradford Hill criteria postulates were applied on the collected evidence to explore the relationship between HPV and BC. In addition, to make the outcomes more authentic, we also reviewed the methodologies of previous studies to address the propensity of false results. RESULTS: After a careful evaluation of the obtained data against major Bradford Hill criteria postulates, it was noted that all these postulates, including strength, consistency, biological gradient, temporality, plausibility, experiment, specificity, and analogy were not fulfilled. CONCLUSION: The results of the present study have failed to establish a causal association between HPV and BC, but they did suggest HPV as a cause-effective agent or at least a co-participant in the pathogenesis of BC. Because of the weakness of association, particularly the lack of consistency between studies and the lack of effect specificity, more research into Bradford Hill criteria postulates is required.

Breast implant illness: scientific evidence of its existence.

INTRODUCTION: More than one million breast augmentation procedures using silicone breast implants (SBI) have been performed worldwide. Adverse events of SBI include local complications such as pain, swelling, redness, infections, capsular contracture, implant rupture, and gel-bleed. Furthermore, patients experience systemic symptoms such as chronic fatigue, arthralgias, myalgias, pyrexia, sicca, and cognitive dysfunction. These symptoms received different names such as autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) due to silicone incompatibility syndrome and breast implant illness (BII). Because of chronic immune activation, BII/ASIA, allergies, autoimmune diseases, immune deficiencies, and finally lymphomas may develop in SBI patients. AREAS COVERED: Causality for SBI-related BII/ASIA is reviewed. To address the role of silicone implants in promoting causality, we utilized the Bradford Hill criteria, with results highlighted in this article. EXPERT OPINION: We conclude that there is a causal association between SBIs and BII/ASIA. Using data derived from patients with BII/ASIA and from other medically implanted devices, there appears to be clear pathogenic relationship between SBI and BII/ASIA. Breast implants cause characteristic systemic reactions in certain women, leading to symptoms of sufficient severity to warrant device removal. The morbidity suffered is variable. SBI removal resolves the symptoms in most women, and removal is the most effective treatment.

Linking Human Betaretrovirus with Autoimmunity and Liver Disease in Patients with Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the production of diagnostic antimitochondrial antibodies (AMA) reactive to the pyruvate dehydrogenase complex. A human betaretrovirus (HBRV) resembling mouse mammary tumor virus has been characterized in patients with PBC. However, linking the viral infection with the disease is not a straight-forward process because PBC is a complex multifactorial disease influenced by genetic, hormonal, autoimmune, environmental, and other factors. Currently, PBC is assumed to have an autoimmune etiology, but the evidence is lacking to support this conjecture. In this review, we describe different approaches connecting HBRV with PBC. Initially, we used co-cultivation of HBRV with biliary epithelial cells to trigger the PBC-specific phenotype with cell surface expression of cryptic mitochondrial autoantigens linked with antimitochondrial antibody expression. Subsequently, we have derived layers of proof to support the role of betaretrovirus infection in mouse models of autoimmune biliary disease with spontaneous AMA production and in patients with PBC. Using Hill's criteria, we provide an overview of how betaretrovirus infection may trigger autoimmunity and propagate biliary disease. Ultimately, the demonstration that disease can be cured with antiviral therapy may sway the argument toward an infectious disease etiology in an analogous fashion that was used to link H. pylori with peptic ulcer disease.

Title: Understanding a Low Vitamin D State in the Context of COVID-19.

While a low vitamin D state has been associated with an increased risk of infection by SARS-CoV-2 in addition to an increased severity of COVID-19 disease, a causal role is not yet established. Here, we review the evidence relating to i) vitamin D and its role in SARS-CoV-2 infection and COVID-19 disease ii) the vitamin D status in the Irish adult population iii) the use of supplemental vitamin D to treat a deficient status and iv) the application of the Bradford-Hill causation criteria. We conclude that reverse causality probably makes a minimal contribution to the presence of low vitamin D states in the setting of COVID-19. Applying the Bradford-Hill criteria, however, the collective literature supports a causal association between low vitamin D status, SARS-CoV-2 infection, and severe COVID-19 (respiratory failure, requirement for ventilation and mortality). A biologically plausible rationale exists for these findings, given vitamin D's role in immune regulation. The thresholds which define low, deficient, and replete vitamin D states vary according to the disease studied, underscoring the complexities for determining the goals for supplementation. All are currently unknown in the setting of COVID-19. The design of vitamin D randomised controlled trials is notoriously problematic and these trials commonly fail for a number of behavioural and methodological reasons. In Ireland, as in most other countries, low vitamin D status is common in older adults, adults in institutions, and with obesity, dark skin, low UVB exposure, diabetes and low socio-economic status. Physiological vitamin D levels for optimal immune function are considerably higher than those that can be achieved from food and sunlight exposure alone in Ireland. A window exists in which a significant number of adults could benefit from vitamin D supplementation, not least because of recent data demonstrating an association between vitamin D status and COVID-19. During the COVID pandemic, we believe that supplementation with 20-25ug (800-1000 IU)/day or more may be required for adults with apparently normal immune systems to improve immunity against SARS-CoV-2. We expect that higher monitored doses of 37.5-50 ug (1,500-2,000)/day may be needed for vulnerable groups (e.g., those with obesity, darker skin, diabetes mellitus and older adults). Such doses are within the safe daily intakes cited by international advisory agencies.