Gout Is A Risk Factor For SARS-CoV-2 infections

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Researchers from the University of Otago-New Zealand, University of Alabama at Birmingham-USA, University of Queensland-Australia and the University of Auckland-New Zealand have in a new study found that gout is a risk factor for SARS-CoV-2 infections and COVID-19 mortality.

The study findings also showed that women with gout have higher COVID-19 death risk than men.

The international study team used data from the UK Biobank that included 15,560 people with gout. Multivariable-adjusted logistic regression was employed in the following analyses using a case-control study design: Analysis A, to test for association between gout and COVID-19 diagnosis (n=459,837); Analysis B, to test for association between gout and death related to COVID-19 in a case-control cohort of individuals who died or survived with COVID-19 (n=16,336); Analysis C, to test for association between gout and death related to COVID-19 in the entire UK Biobank cohort (n=459,837); Analysis D, to stratify by prescription of urate-lowering therapy (ULT) and colchicine on the risk of death related to COVID-19 in a subset of the UK Biobank cohort with medication data (n=341,398).

The study findings showed that gout was associated with diagnosis of COVID-19 in analysis A (OR=1.2 [1.1 ; 1.3]) but not with risk of death in the COVID-19-diagnosed group in analysis B. In analysis C gout associated with risk of death related to COVID-19 in the unadjusted model (OR=3.9 [3.3 ; 4.7]), in Model 1 adjusted for demographic factors (OR=1.8 [1.5 ; 2.1]) and in the fully adjusted Model 2 (OR=1.3 [1.1 ; 1.6]). In Analysis C risk was higher in women than men in Model 1 adjusted for demographic factors (OR=3.5 [2.4 ; 5.0] and OR=1.5 [1.2 ; 1.8], respectively) with the difference maintained after additional adjustment for eight metabolic co-morbidities (OR

The study findings were published on a preprint server and are currently being peer reviewed.

reference link : https://www.medrxiv.org/content/10.1101/2021.09.28.21264270v1

Discussion

Gout is a very prevalent arthropathy (for example 3.9% in the US population14 and 14% in people of Pacific ethnicity15) yet has received extremely limited attention with respect to outcomes of COVID-19.16

Here, for the first time, we report association of gout (OR=1.3) with death related to COVID-19 in a multivariable-adjusted population-based study. Statistical support, however, is relatively weak meaning that replication in larger cohorts is necessary.

The majority of the risk of death related to COVID-19 was accounted for by eight metabolic co-morbidities in men, but not women, despite the higher risk of metabolic co-morbidity in women with gout.9 This is evidence for the presence of additional risk factors for death related to COVID-19 in women.

What these risk factors could be was not revealed from our analysis but could be related to factors underlying the known higher risk of metabolic co-morbidity in women with gout.

When we investigated the influence of colchicine we found no difference in risk of death related to COVID-19 in the gout cohort.

The COLCORONA placebo-controlled randomized clinical trial provided, as yet un-replicated, evidence that colchicine reduces the risk of death or hospital admission in PCR-proven COVID-19.17

The highly statistically significant unadjusted risk estimate for death related to COVID-19 in the general population was OR=3.9 for gout and was particularly high for women with gout (OR=9.4). These raw estimates can be used in clinician-patient discussions regarding patient decisions to get vaccinated against SARS-Cov-2.

Little is currently known about vaccine hesitancy in people with rheumatic disease. In the Italian population vaccine hesitancy is higher in people with rheumatic disease.18,19 The possibility of vaccine hesitancy in people with gout is of concern in the context of our data of increased risk of death related to COVID-19.

While we are unable to generalize our findings to non-UK populations, in the absence of evidence to the contrary the safer approach is to assume that risks for death related to COVID-19 in other population groups are at least equivalent. For example, the prevalence of gout in the Māori population of Aotearoa New Zealand is 8% and 14% in the Pacific population, compared to 4% in the non-Māori non-Pacific population.15 These figures justify a targeted strategy for vaccination of Māori and Pacific people with gout in all healthcare settings.

We have identified nine limitations to our analyses. One, these analyses pertain to the population from which the UK Biobank was derived, predominantly the white European middle-aged ethnic group of the United Kingdom, and are not necessarily generalisable to other ethnic groups or other white European ethnic groups.

Two, there is also no available information on recovery status so there is the possibility of additional unidentified deaths in the COVID-19 diagnosed group in Analysis B. In addition to this COVID-19 outcomes will have been influenced over the time period of this study (March 2020-April 2021) as clinical treatments evolved. We were able to account for this only in Analysis B.

Limited testing outside of the hospital setting means that the full extent of SARS-CoV-2 infection is not known in this population. Thus, it is not possible to accurately compare asymptomatic or mild COVID-19 to those with more severe disease.

Three, the UK Biobank dataset is also limited to those aged 49 to 86 as of 2020, a demographic with a higher case fatality ratio.20 This will have contributed to the inflated infection fatality ratio in the UK Biobank cohort of 6.6%, well above general population estimates of 0.5 to 1.5% (e.g. ref21).

Therefore our findings cannot be generalised to those under 50 years of age. Four, there is the potential in Analysis B for index event (collider) bias resulting from conditioning the sample set on COVID-19 diagnosis which would serve to bias towards the null.22 However these limitations were addressed using the entire cohort-based approach in Analysis C. Five, the potential effect of severity in gout could not be assessed (e.g. presence / absence of tophus, flare frequency).

Six, in the context of reports of a U-shaped relationship of serum urate levels and COVID-19,23-25 we were unable to investigate any influence of current serum urate levels on death with COVID-19 as these data are unavailable in the UK Biobank.

Seven, the medicine prescription data were single script from General Practitioners only, there was no way of ascertaining adherence or whether participants were taking the medication during the COVID-19 pandemic although we attempted to account for this by only using prescription information from 2019 and 2020.

Eight, we were unable to account for the effect of individual behaviour modification on outcomes. For example people with rheumatic disease in the Netherlands have been reported to be twice as likely to adhere to strict isolation measures than healthy controls26 and, in the UK, people with risk factors for poor outcomes from COVID-19 exhibit greater risk-mitigating behaviour.27

A final point is that we included co-morbidities for gout as variables in Model 2 – there is not consensus as to whether this should be done in epidemiologic studies of COVID-19 outcomes in the rheumatic diseases.28 Therefore we also included models with fewer adjustors (unadjusted, and adjusted by BMI and demographic factors).

In summary, we provide evidence for an increased risk of gout for death related to COVID-19. Understanding the driver(s) for the increased risk in women with gout needs to be further explored in larger datasets.

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