Omicron breakthrough infections in patients with immune-mediated inflammatory diseases

Breakthrough SARS-CoV-2 infection after vaccination is an ongoing concern for people on specific immunosuppressive medications known to reduce immunogenicity, and thus protection, against severe COVID-19 outcomes. Improved understanding of COVID-19 risks for these individuals in the context of the circulating omicron (B.1.1.529) variant and its lineages and future potential variants of concern is needed.

Data on delta (B.1.617.2) variant breakthrough infections among people with immune dysfunction have suggested a protective impact of vaccination.1, 2 Although Sun and colleagues¹ found an increased risk of breakthrough infections among individuals with immune dysfunction (including those with rheumatoid arthritis or HIV, and solid-organ transplant recipients) versus the general population in the US-based N3C database, they also found that vaccination was associated with reduced risk of infection. In a previous study of a Dutch prospective cohort, which has been used to study vaccine efficacy and immunogenicity in patients with immune-mediated inflammatory diseases versus healthy controls, Laura Boekel and colleagues found the incidence and severity of delta breakthrough infections was similar in both groups.²

In a Comment by Boekel and colleagues³ in The Lancet Rheumatology, the group again used data from the same Dutch prospective cohort to study breakthrough infections at the time the omicron variant was the dominant variant in circulation. In their analysis of 1882 individuals with immune-mediated inflammatory diseases (1518 [81%] on any immunosuppressive treatment; 48 [3%] on anti-CD20 therapy) and 708 age-matched and sex-matched healthy controls found roughly similar frequencies of breakthrough infections (431 [23%] of 1882 patients with immune-mediate inflammatory diseases vs 210 [30%] of 708 healthy controls). Their primary outcome of hospitalisations due to breakthrough infection during the omicron dominant period was low (five [1%] of 431 vs one [<1%] of 210); thus, their main multivariable analysis for the odds of hospitalisation comparing patients with immune-mediated inflammatory diseases with healthy controls was null (adjusted OR 1·48 [95% CI 0·16–13·28]).

In their secondary analyses among patients with immune-mediate inflammatory diseases, they found that omicron breakthrough infections were associated with lower risk of hospitalisation versus either delta breakthrough infections or infections with wild-type or alpha (B.1.1.7) variants of SARS-CoV-2 among unvaccinated individuals.³ The results, shown in the figure of the Comment, are also informative: when the proportions of hospitalised individuals were stratified by the different periods in which each variant has been dominant, further grouped by healthy control versus patient with immune-mediated inflammatory disease, and by immunosuppressive therapy, the proportion requiring hospitalisation was highest among those on anti-CD20 therapy.

These data³ provide further reassurance for most individuals with immune-mediated inflammatory diseases regarding the currently circulating omicron subvariants, provided that they are up to date on recommended vaccinations. However, those who are treated with B-cell depleting therapies like anti-CD20 therapy (eg, rituximab) remain at high risk. Consistent with other studies, in the large UK OpenSAFELY study, MacKenna and colleagues⁴ also found an association between rituximab use and an increased risk of severe COVID-19 outcomes, including death.

In addition to vaccination, early treatment interventions including antivirals and anti-spike monoclonal antibodies can improve COVID-19 outcomes in high-risk patients.⁵ Use of pre-exposure prophylaxis (PrEP) with anti-spike monoclonal antibodies in high-risk patients, such as those on B-cell depleting therapies, has also been shown to decrease rate of infections and severe illness including during the recent omicron wave.6, 7 Although the armamentarium of therapeutics that are effective for preventing hospitalisation and death among high-risk individuals has grown in size, barriers to distribution, access, and use still exist. For example, in a US study by Gold and colleagues,⁸ although the number of dispensed oral antivirals increased over time, dispensing rates lagged in neighbourhoods with high-social-vulnerability zip codes versus those with medium-social-vulnerability or low-social-vulnerability zip codes. These results were seen despite the number of dispensing sites being higher in high-vulnerability zip codes.⁸ Similarly, notwithstanding the effectiveness of PrEP with anti-spike monoclonal antibodies, distribution of these therapies has also met with barriers,⁹ and concern regarding disparities in the use of PrEP among high-risk patients eligible for this treatment has been highlighted.¹⁰

Previous efforts with vaccine dissemination and education need to be replicated for these interventions that will continue to be important mitigation strategies for high-risk patients with existing and future SARS-CoV-2 variants. When considering populations that remain at highest risk for severe COVID-19 outcomes despite vaccination, those receiving B-cell depleting therapies should be prioritised. Although findings like those of Boekel and colleagues are reassuring for most individuals who are immunosuppressed, they also continue to highlight the need for earlier identification of those at high risk and the use and equitable distribution of existing mitigation strategies to adequately protect all patients.

JWL reports research grant from Pfizer, unrelated to this work, completed in 2021. SES reports research support from AstraZeneca, unrelated to this work.