The United Kingdom has recorded amongst the highest number of cases (8,918 per 100,000 population) and deaths (193.9 per 100,000 population) from COVID-19 in the world [14]. Despite public health measures to minimise the exposure of clinically extremely vulnerable individuals to SARS-CoV-2 [15], the pandemic has disproportionately affected patients with PID and SID. In this large nationwide study, we demonstrate an increased risk of mortality from COVID-19 in individuals with PID requiring antibody replacement therapy and individuals with CVID in all age groups above 20 years old compared to the UK general population. In patients with SID, an increased risk of mortality emerges beyond 40 years of age. Inpatient mortality in patients with immunodeficiency was higher than the general population (38.2% vs 26.0%) [1]. In comparison to the general population, where the median age of death from COVID-19 was 83.0 years, immunodeficiency patients died, on average, up to 26 years younger than the general population.
The risk factors for poor outcome from COVID-19 in patients with primary immunodeficiencies closely mirror those in the general population [16]; increasing age and common comorbidities were all associated with an increased risk of death in univariate analysis; chronic liver disease and diabetes mellitus (PID on IgRT) and receipt of prophylactic antibiotics (CVID) were independently associated with death in multivariate analysis of these cohorts. In SID, no additional independent risk factors were observed, but the overall CFR of 31.6% compared to 2.95% in the UK general population illustrates the vulnerability of individuals requiring long-term immunological support following treatment for other diseases. Furthermore, the CFR of 38.1% for patients with rheumatological disease in this study is markedly higher than the estimated CFR of 5.6% for unselected rheumatoid arthritis patients demonstrating the subgroup of patients with SID are at especially high risk of poor outcome [17]. Our data also highlights that those individuals with secondary immunodeficiency who continue to receive treatment with any daily dose of prednisolone also appear at increased risk of mortality. Reassuringly and concordant with other UK studies in immunocompromised children [7], we found no increased risk of mortality amongst in the 18 paediatric patients within this study, although 27.7% were hospitalised.
One striking observation from this study is that pre-existing lymphopenia is independently associated with mortality in all three groups with immunodeficiency. Previous studies have demonstrated that pre-existing lymphopenia is independently associated with an increased risk of developing pneumonia, skin infections, urinary tract infections, sepsis and endocarditis in the Danish general population [18] and an increased risk of mortality from pneumonia in the UK general population [19]. Peripheral CD4 and CD8 T cell lymphopenia and dysregulated T cell responses have also been associated with severe disease during acute COVID-19, although some studies suggest this observation is secondary to lymphocyte redistribution during acute illness [20, 21]. Characterising the nature of pre-existing lymphopenia and its impact on functional immunity with respect to outcomes from infectious disease, is an important research priority in both the general population and patients with immune deficiency.
There is a paucity of evidence regarding the efficacy of treatments for COVID-19 in patients with PID and SID [22]. In this case series, compared to an overall inpatient survival following COVID-19 of 61.8%, survival was improved in individuals who received dexamethasone (75.0%), remdesivir (84.6%) or antibody-based treatments (80.0%) as a monotherapy or in any combination. In contrast, only 20% of individuals receiving tocilizumab survived. These data require cautious interpretation; specific data on the timing of these pharmacological interventions in relation to disease onset and COVID-19 severity was not gathered as part of this study and the number of treated individuals is small. However, it is possible, or even likely, that modulation of the immune response in a patient with immunodeficiency is different to the general population. For example, although convalescent plasma demonstrated no benefit in healthy individuals during acute severe COVID-19 infection [23], antibody-based treatments appear effective herein and in case reports of antibody deficiency patients where ex vivo studies have confirmed viral neutralization [24]. Furthermore, polyclonal immunoglobulin replacement is the standard of care in the prevention of chronic sinopulmonary infection in individuals with antibody deficiency and hyperimmune serum may be used for post-exposure prophylaxis in seronegative individuals against certain infectious diseases, a concept supported by early data in anti-SARS-CoV-2 monoclonal antibody trials [25, 26]. Similarly, inhibition of the IL-6 axis in individuals already suffering from an existing immunodeficiency, may have unintended consequences despite success in randomised control trials in previously healthy individuals [27].
The major strength of this study is its size and comprehensive representation amongst UK PIN affiliated centres across the United Kingdom reducing the potential for bias seen in smaller case series and facilitating the enrolment of large numbers of patients with rare disease. The work confirms the increased risk of mortality from COVID-19 we observed in our original case series [5] and builds upon it by providing revised estimates of the magnitude of that risk in relation to the UK general population and the determinants of that risk in clinically relevant disease subgroups. However, this study remains a clinician-reported registry and we are unable to guarantee that all SARS-CoV-2 infections in patients with PID or SID have been captured by this study. Furthermore, bias may exist within the SID cohort described herein; by definition, these individuals have been referred to a Clinical Immunologist for immunological assessment which may enrich for more severe phenotypes of SID. Cases of SARS-CoV-2 in paediatric patients remain underrepresented by this study, but similar outcomes in a larger cohort of UK patients have been reported elsewhere [7]. Owing to the retrospective nature of this study, we are unable to characterize the nature or longevity of serological responses of individuals with PID or SID following natural infection; however, the COV-AD study, a national UK study studying the cellular and humoral response to SARS-CoV-2 natural infection and vaccination is in progress and will be able to inform upon these important immunological questions.
In summary, our study highlights the burden of morbidity and mortality in individuals with PID and SID following infection with SARS-CoV-2 and elucidates independent risk factors associated with poor outcome. The impact of the COVID-19 on individuals with PID and SID cannot be underestimated; these data must inform public health policy, including the urgent provision of anti-SARS-CoV-2 antibody-based therapies this population, to minimise the risk of poor outcome during future waves of the evolving pandemic.