Translational and clinical immunology
Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations

https://doi.org/10.1016/j.jaci.2021.04.015Get rights and content

Background

Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.

Objective

We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.

Methods

We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.

Results

Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.

Conclusions

An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.

Section snippets

Patients

As of March 2019, 21,485 patients of 68 nationalities were documented by 29 countries participating in the ESID Registry based on informed consent (No. 493/14 of the Ethical Committee Freiburg). From these, the following were excluded: 161 patients without an IEI diagnosis and 304 patients with “unclassified immunodeficiency,” because there was concern whether these patients indeed represent patients with IEI, or rather secondary immunodeficiencies or other diseases. Another 3362 patients were

Infection is the most frequent initial presenting manifestation of IEI

Of 16,486 patients with IEI documented in the ESID Registry and eligible for this study, 12,741 (77%) initially presented with infection, 2,955 (18%) with immune dysregulation, 1,983 (12%) with syndromic features, and 137 (0.8%) with malignancy (Fig 2). A total of 1292 (8%) presented with “other” symptoms (including, eg, aphthae, asthma, alopecia, fatigue, and ataxia), with 254 of them (1.5% of all patients) as the only initial manifestation. Abnormal laboratory test results (eg,

Discussion

Here, we report the age-related presenting manifestations of IEI in general and in different IEI disease groups across a cohort of 16,574 patients documented in the ESID Registry. Our results emphasize the importance of both immune dysregulation and syndromic features (18% and 12% of all patients, respectively) in addition to infections as the initial manifestation of IEI. A third of patients (33%) showed initial manifestation of their IEI within the first year of life and another third (30%)

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    The European Society for Immunodeficiencies Registry was supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung [BMBF] grant nos. 01GM0896, 01GM1111B, 01GM1517C, 01EO1303, and 01ZZ1801B), the European Union (grant no. HEALTH-F2-2008-201549 [EURO-PADnet]), the pharmaceutical companies Novartis, GlaxoSmithKline, LFB, UCB UK, and Pharming, the Plasma Protein Therapeutics Association, the Care-for-Rare Foundation, PROimmune e.V., ERN RITA, and the European Society for Immunodeficiencies (www.ESID.org).

    Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

    Data sharing: Deidentified patient data collected for this study are available to others with publication of this article according to the European Society for Immunodeficiencies Registry data access and publication rules (https://esid.org/Education/Call-for-studies/Data-access-and-Publication-rules-Research-Proposal-Form).

    These authors contributed equally to this work.

    For a complete list of European Society for Immunodeficiencies Registry Working Party collaborators, please see the Acknowledgment section at the end of the article.

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