Diagnostic Criteria for Immunodeficiencies
Mary Ellen Conley, Luigi D. Notarangelo and Amos Etzioni
Representing PAGID (Pan- American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies)1
Clin. Immunol. 1999 93(3):190-197

Primary Immunodeficiencies (16 ESID guidelines)

The identification of many genes responsible for primary immunodeficiencies has provided us with a new perspective to evaluate these disorders. It has 1) clarified the clinical and laboratory findings that are most consistently associated with a specific gene; 2) demonstrated the spectrum of clinical severity seen in a particular disorder; and, 3) shown that not all of the patients with identical clinical and laboratory findings have mutations in the same gene. This new information allows us to re-evaluate the criteria that we use to make diagnoses.

The diagnostic criteria are meant to establish simple, objective and clear guidelines that ensure that different physicians and scientists are using the same definitions when they include patients in research studies. They may also help physicians formulate a diagnosis in patients with abnormalities of the immune system. The diagnostic criteria are divided into three categories: definitive, probable and possible. To guard against the inclusion of patients who have polymorphic variants in the genes associated with immunodeficiency, and to specify the clinical or laboratory finding that is most consistently abnormal in a particular disorder, the patient must fulfil an inclusion criterion which is characteristic of the disorder.

The patients with a definitive diagnosis are assumed to have a greater than 98% probability that in 20 years they would still be given the same diagnosis. Mutation detection is the most reliable method of making a diagnosis. In some disorders the absence of the specific mRNA or protein is diagnostic. In others, the mRNA and/or protein may be only transiently expressed, may be produced at very low levels, or clinically useful assays may not yet have been developed. The clinical and laboratory findings in several of the X-linked immunodeficiencies are sufficiently distinctive that these findings, when coupled with a family history of disease that is specific to X-linked inheritance, can be used to make a definitive diagnosis. In families with a known mutation in a particular gene, mutation detection can be used to provide a definitive diagnosis in a newborn or fetus.

Patients with a probable diagnosis are those with all of the clinical and laboratory characteristics of a particular disorder but they do not have a documented abnormality in the gene, the mRNA or the protein that is known to be abnormal in the disorder. They are assumed to have a greater than 85% probability that in 20 years they will be given the same diagnosis. Patients with a possible diagnosis are those that have some but not all of the characteristic clinical or laboratory findings of a particular disorder.

Not all of the patients with mutations in a specific gene will fulfil the criteria for a probable or even a possible diagnosis of the disorder associated with that gene. To indicate the range of findings in patients with mutations in a specific gene or who are diagnosed as having a particular syndrome, a short description of the spectrum of disease has been included for each disorder. However, the description is not meant to be all-inclusive.

Information about the family history can be useful in making a diagnosis of immunodeficiency; however, caution should be used. Approximately 50% of patients with an X-linked immunodeficiency, documented by mutation detection, do not have a family history of immunodeficiency because they are the first manifestation of a new mutation. The presence of consanguinity increases the possibility that a patient has a rare autosomal recessive immunodeficiency, but many patients with rare disorders are compound heterozygotes (have different mutations on the maternal and paternal alleles). In a patient with atypical clinical or laboratory findings, the presence of a sibling with more typical disease can suggest a diagnosis, but does not permit a definitive diagnosis in the absence of mutation detection.

A differential diagnosis is provided for many disorders. For some disorders, exclusion criteria are included. Phenotypic criteria are used to describe patients who have all of the typical findings of a particular disorder but they do not have a mutation in the gene associated with the disorder and they have normal protein for the gene associated with the disorder.

Other sources for clinical guidelines for primary immunodeficiencies:

IDdiagnostics Directory of Immunodeficiency Diagnostic Laboratories
PIDexpert, decision support system for primary immunodeficiencies
The Immune Deficiency Foundation Diagnostic & Clinical Care Guidelines for Primary Immunodeficiency Diseases
AAAAI/ACAAI Practice Parameters

USIDNET, disease registries
UK PIN Primary immunodeficiency network, guidelines
A multi-stage designed protocol for non-immunologists, de Vries E., for the Clinical Working Party of the European Society for Immunodeficiencies.