How effective are the 6 European Society of Immunodeficiency warning signs for primary immunodeficiency disease?

doi:10.1016/j.anai.2015.12.001

Annals of Allergy, Asthma & Immunology

Volume 116, Issue 2, February 2016, Pages 151-155.e1

https://doi.org/10.1016/j.anai.2015.12.001 Get rights and content

Abstract

Background

The European Society of Immunodeficiency (ESID) developed 6 warning signs to promote the awareness of adult primary immunodeficiency disease (PID).

Objective

To screen adult patients for the presence of PID using these 6 warning signs to determine the effectiveness of this protocol.

Methods

Questions related to the ESID warning signs for adult PID were added to the standard outpatient clinic file system and asked of 3,510 patients who were admitted to our clinic for any reason. Patients with signs and/or suspicion of PID based on their medical history underwent immunologic investigation.

Results

In total, 24 patients were diagnosed as having a PID. The most common reason that patients with PID were admitted was frequent infection (n=18 [75%]), and the most common PID subgroup was common variable immunodeficiency (n=12 [50%]). Twenty patients with PID had at least one positive finding according to the ESID warning signs. Two patients with gastrointestinal concerns and 2 with dermatologic symptoms were also diagnosed as having a PID, although they did not have any of the ESID warning signs.

Conclusion

The ESID warning signs do not specify the need for symptoms to diagnose a PIDs and do not include a comprehensive list of all signs and symptoms of PIDs. As a result, more than infection-centric questions are needed to identify adult patients with immunodeficiencies.

Introduction

Primary immunodeficiency diseases (PIDs) are rare diseases caused by defects of the immune system, and early diagnosis of PIDs is important for reducing morbidity and mortality. PIDs are characterized by recurrent and/or severe infections, autoimmunity, malignancy, and allergic disorders.[1], [2], [3] Diagnostic delays in adult patients with PID are problematic for clinicians worldwide, and most physicians are not familiar with rare disorders. Because of this lack of awareness, immunologic investigations are not commonly used for the diagnosis of PIDs.[1], [2], [3], [4] The European Society of Immunodeficiency (ESID) published the common designation for PIDs in 1999. Since then, a working party from the ESID established a European Patient and Research database for continuous long-term documentation of patients with the aim of improving the diagnosis, classification, prognosis, and therapy of PIDs.⁵

The ESID suggested 6 warning signs for the suspicion of PIDs (Table 1),⁶ and patients with these signs must undergo further evaluations for an underlying PID. However, the warning signs do not include comprehensive symptoms of PIDs, and the effectiveness of this screening protocol in clinical practice remains to be established.⁷ The warning signs suggested by the ESID for adult PIDs have been published and are clinically useful; however, this model has not been tested in a clinical trial. Moreover, the infection-based warning signs do not cover the broad clinical spectrum for PIDs.⁸ In adults, the clinical presentation of PIDs is usually based on the complications and comorbidities of immunodeficiencies, especially for common variable immunodeficiency (CVID).

This study had 2 major objectives. The first was to determine the prevalence of PIDs among patients who were admitted to our adult clinical immunology and allergy outpatient clinic, independent of their reason for admission. The second objective was to evaluate the effectiveness of the 6 ESID warning signs in the diagnosis of immunodeficiencies.

Section snippets

Methods

This prospective study was approved by the local ethics committee conducted in the Adult Clinical Immunology and Allergy Department, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey. Written informed consent was obtained from the all study participants. Questions regarding the 6 ESID warning signs for adult PIDs were added to the standard outpatient clinic patient file system and asked of 3,510 patients who were admitted to our clinic for any reason from November 2011 to

Results

Medical records for 3,510 patients were evaluated in this study. The mean (SD) age of the patients was 39.0 (13.5) years; 2,316 (66%) were female, and 1,194 (34%) were male. Twenty-four patients were diagnosed as having a PID. The most common reason for admission among patients with PID was frequent infection (n=18 [75%]). The number of patients with a final diagnosis of a PID and their reasons for admission are given in Table 3. The most common PID subgroup was CVID (n=12 [50%]) (Table 4). The

Discussion

PIDs are devastating disorders that typically result from monogenic defects of the human immune system. Many PIDs present early in life as an increase in susceptibility to recurrent infections.[11], [12] In adults, the largest problem with PIDs is poor awareness because the diseases are generally considered childhood disorders. PIDs are associated with severe morbidity and increased mortality if left untreated.¹³ Many PIDs are easily diagnosed, and effective treatment options are available;

References (22)

L. Notarangelo et al.
Primary immunodeficiency diseases: an update
J Allergy Clin Immunol
(2004)
M.E. Conley et al.
Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies)
Clin Immunol
(1999)
R.S. Geha et al.
Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee
J Allergy Clin Immunol
(2007)
M. Ballow
Primary immunodeficiency disorders: antibody deficiency
J Allergy Clin Immunol
(2002)
J.L. Casanova et al.
From idiopathic infectious diseases to novel primary immunodeficiencies
J Allergy Clin Immunol
(2005)
S. Agarwal et al.
Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency
Clin Gastroenterol Hepatol
(2013)
E. de Vries et al.
Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update
Clin Exp Immunol
(2012)
C. Samarghitean et al.
Systematic classification of primary immunodeficiencies based on clinical, pathological, and laboratory parameters
J Immunol
(2009)
W.A. Sewell et al.
Early indicators of immunodeficiency in adults and children: protocols for screening for primary immunological defects
Clin Exp Immunol
(2006)
http://esid.org/Working-Parties/Clinical/Resources/6-Warning-Signs-for-PID-in-Adults. Accessed September...

R. Ameratunga et al.

New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin

Clin Exp Immunol

(2013)

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: Disclosures: Authors have nothing to disclose.

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Original ArticleSystemic Immune DisordersHow effective are the 6 European Society of Immunodeficiency warning signs for primary immunodeficiency disease?

Abstract

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Methods

Results

Discussion

J Allergy Clin Immunol

Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Clin Gastroenterol Hepatol

Patient-centred screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update

Clin Exp Immunol

Systematic classification of primary immunodeficiencies based on clinical, pathological, and laboratory parameters

J Immunol

Early indicators of immunodeficiency in adults and children: protocols for screening for primary immunological defects

Clin Exp Immunol

New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin

Clin Exp Immunol

Original Article
Systemic Immune Disorders
How effective are the 6 European Society of Immunodeficiency warning signs for primary immunodeficiency disease?