Table 3. Overview of variables included in the unPAD study.

Variable	Definition
General (level 1)
Patient
Patient consent	Signed/Not applicable (only if deceased) For minors, parents or the legal guardian must give their written consent.
Date of birth	Year; Month (month only if <12 years of age)
Country of current residence	This should be the country where the patient has his permanent residence, i.e. where he/she lives for the majority of the year. If the patient stays in the current country for a longer period, but only temporarily (e.g. for specialized medical treatment or seasonal work), his/her country of origin should be selected.
Sex	Male/Female
Familial case	Defined as another patient with a diagnosed primary immunodeficiency in the genetic family (e.g. parents, siblings, grandparents).
Consanguinity of parents	Defined as genetically related parents or other ancestors (e.g. grandparents) of the patient.
Documenting Centre	Name of the center from which the data originate.
Way to Diagnosis
Date of first clinical diagnosis of IEI	Year; Month; Day The date when this patient was first diagnosed with a primary immunodeficiency based on clinical features and laboratory values.
First IEI-related symptom(s)	• Infection • Immune dysregulation (lymphoproliferation, granuloma formation, autoimmunity, inflammatory bowel disease, celiac disease, vasculitis, eczema, autoinflammatory disease) • Malignancy • Syndrome manifestations • Other • No IEI-related symptoms at all
Date of onset of symptoms	Year; Month The year and month when the first symptoms suggestive of an IEI (see above) appeared in this patient, based on the physician’s judgement.
IEI Diagnosis
Current IEI Diagnosis	Defined as the most recent IEI diagnosis.
Affected gene	The gene in which disease-causing mutation(s) have been found in this patient.
Status
Current status	• Alive • Deceased • Lost to follow-up • Discharged after complete recovery
Current Ig replacement	Yes/No
Did the patient ever receive immune modifying treatment?	Yes/No
Did the patient ever suffer from a malignancy?	Yes/No
HSCT	Yes/No
Splenectomy	Yes/No
Gene therapy	Yes/No
unPAD study (level 2)a first registration
Clinical presentations (multiple answer)	• Recurrent ENT and airway infections • Failure to thrive from early infancy • Recurrent pyogenic infections • Unusual infections or unusually severe course of infections • Recurrent infections with the same type of pathogen • Autoimmune or chronic inflammatory disease; lymphoproliferation
Clinically most important clinical presentation (single answer)	• Recurrent ENT and airway infections • Failure to thrive from early infancy • Recurrent pyogenic infections • Unusual infections or unusually severe course of infections • Recurrent infections with the same type of pathogen • Autoimmune or chronic inflammatory disease; lymphoproliferation
Bacterial infections	Any major bacterial infection (+ which micro-organism)? • Pneumonia • Meningitis • Osteomyelitis • Liver Abscess • Other major infection
Frequently recurring infections	• Upper respiratory tract • Lower respiratory tract • Gastrointestinal tract • Urinary tract • Skin • Other
Unusual infections	• Severe viral • Opportunistic • Parasitic
Inflammatory bowel disease/ allergic manifestations	Inflammatory bowel disease is subdivided in ‘biopsy-proven’ and ‘clinically suggestive, but not biopsy-proven’. Allergic manifestations are subdivided in ‘proven with sensitization’ and ‘clinically suggestive, but not proven by sensitization’.
Chronic organ pathology	• Hepatomegaly • Splenomegaly (splenectomy ever performed?) • Chronic liver disease • Bronchiectasis • Parenchymal lung disease • Hearing impairment (not congenital) • Other
Autoimmunity	• Auto-immune hemolytic anemia • Auto-immune granulocytopenia • Auto-immune thrombocytopenia • Other
Malignancy and other manifestations	The type of malignancy and/or of other manifestations has to be specifically defined.
Medication	Daily immunosuppressive drugs or drugs that may cause hypogammaglobulinemia as a side effect (currently in use or stopped less than three months before the diagnosis of hypogammaglobulinemia).
Diagnostic vaccination response measurements	• Tetanus • Pneumococcal polysaccharide • Other
Virological analysis	• HCV-RNA • HIV-DNA • EBV-DNA • CMV-DNA
Instrumental data	• Lung function; FEV1 • HRCT thorax • Gastroscopy
Blood counts/ Immunoglobulins/ sensitization	• Laboratory values at time point closest to the diagnosis (leukocytes, neutrophils, lymphocytes, eosinophils, basophils, monocytes) • Laboratory values at time point closest to diagnosis before start of Ig-replacement (IgG, IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, M-protein) • Sensitization (specific IgE, skin prick test)
Lymphocyte subsets/ auto-anti-bodies	• Laboratory values at time point closest to diagnosis (CD3+, CD3+CD4+, CD3+CD8+, CD19+CD20+, CD3-CD16/56+, CD20+CD27+IgD-, CD19+CD38++IgM++, CD19+CD27-IgM+IgD+, CD19+CD27+IgM+IgD+, CD19+CD27+IgM+IgD-, CD19+CD27+IgM-IgD-) • Auto-antibodies (ANA, TPO-antibodies)

^a Follow-up forms (shown in S1 Table) can be added indefinitely.

Abbreviations: ANA, antinuclear antibody; CD, cluster of differentiation; CMV, cytomegalovirus; DNA, deoxyribonucleic acid; EBV, Epstein-Barr Virus; e.g., exempli gratia; ENT, ear-nose-throat; IEI, inborn error of immunity; FEV1, forced expiratory volume in 1 second; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HRCT, high-resolution computed tomography; HSCT, hematopoietic stem cell transplantation; Ig, immunoglobulin; RNA, ribonucleic acid; TPO, thyroid peroxidase; unPAD, unclassified primary antibody deficiency.