Immunodeficincies could be primary and acquired.
Primary immunodeficinecies are caused by genetic disturbances that disrupt normal differentiation and function of the immune system. Diagnosis of the primary immunodeficiency diseases (PID) is most commonly made in children less than 15 years old (80% are males), with the predominance of B cell defects. Combined B and T cell deficits, disorders of the innate immunity and complement components are less common.
Acquired immunodeficiencies are far more common, and are the result of negative influence of the various environmental and microbial factors on the immune system. The most prominent infective cause of the secondary immune deficiency is the HIV virus, while malnutrition, chemo/radiotherapy could be also significant.
Epidemiology of P.I.D.
Incidence of PID is significantly underestimated due to the lack of sufficient information or poor understanding of PID among health care practitioners.
Incidence of PID varies depending of the disease entity. Selective IgA deficit is the common with the incidence of 1:500 inhabitants, while Severe Combined Immunodeficiency –SCID and Isolated Complement Deficiencies are among the rarest (1: 1 000 000 inhabitants). The general incidence of PID is higher than Hemophilia (1:15 000) or Cystic fibrosis (1:30 000).1
Heterogenity in Clincal Presentation
Over 250 different gene mutations were found to be the cause in various PID entities while the list of newly discovered disrupted genes is continuously growing. Such diversity has strong impact on clinical and laboratory heterogeneity in the presentation of PID entities. This in turn could also contribute to delay in making the right diagnosis of PID. There are variations in clinical presentation within the same genotype as well as similar clinical picture in genetically different lesions.
Example of such similarity in clinical presentation among different lesions could be found in IFNγ receptor-1 defects and in patients with IFNγ receptor 2 or IL-12 receptor defect as well as in, IL-12 RB or STAT-1 pathway defects2
Delay in making the diagnosis of P.I.D.
Delay in making the diagnosis is present in almost every subtype of PID and was recorded in every country, including those with the most developed and the richest health care systems.4, 5 Data about the average 8, 5 years delay in diagnosis of angioedema Type I and II in 8 countries (Germany, Italy, Spain, France, Denmark, Great Britain, Israel and Sweden) provides the excellent illustration of this problem. It was found than those patients had an average of 4, 4 admissions to emergency room before the suspicion of angioedema was raised. Studies have shown that the diagnosis of the hardest form- SCID was made averagely on 97th day since the birth, while diagnosis before the day 90 is considered optimal for successful treatment outcome with stem cell transplantation.
Consequences of delay in making the P.I.D. diagnosis
Delay in diagnosis leads to development of numerous organ and tissue defects and complications that might compromise definite cure. Dutch study revealed that cure of SCID is impossible in case of delay in diagnosis beyond the 57th week.6
Significance of the awareness of PID existence was illustrated by the 7 week improvement of the delay in diagnosis if the health care practitioners had earlier suspicion of PID (in case of family burden)
When to suspect about PID?
European Society for Primary Immunodeficinencies (ESID) has published the warning signs if present in a patient, should rise the suspicion on PID. There are 10 signs defined for all ages while later a shorter variant, adjusted for adult patients, with 6 warning signs was published.
10 warning signs for the presence of PID 5
- Four or more new ear infections within 1 year (for babies)
- Two or more serious sinus infections within 1 year
- Two or more months on antibiotics with little effect
- Two or more pneumonias within 1 year
- Failure of an infant to gain weight or grow normally
- Recurrent, deep skin or organ abscesses
- Persistent thrush in mouth or fungal infection of the skin after first year of life
- Need for intravenous antibiotics to clear infections
- Two or more deep seated infections including septicemia: example ostemyelitis, meningitis, celullitis
- A family history of PID
Around 20% of patients with initial autoimmune manifestations whitin PID would not have those warning signs.
6 ESID warning signs for P.I.D. in adult patients8
- Four or more infections 4 that need antibiotics within 1 year (otitis, bronchitis, sinusitis, pneumonia)
- Recurrent infections and infections in need for prolonged antibiotic treatment
- Two or more severe bacterial infections (osteomyelitis, meningitis, septicemia, celullitis)
- Two or more radiology proven pneumonias within 3 years
- Infections in unusual locations and with uncommon pathogen
- A family history of PID
Great variability require the revision of criteria that relay predominately on clinical presentation within infective complications
Classification of PID according to the Intentional Union of Immunological Societies from 2015 7
- Updated classification recognize 9 groups of PID
- Immunodeficiencis of both cellular and humoral immunity
- Combined immunodeficiencis with associated or syndromic features
- Predominant antibody deficiencies
- Diseases of immunoregulation
- Inborn defects of number and/or fagocyte function
- Disorders of innate immunity
- Autoinflamatory diseases
- Coplement deficiencies
- Fenocopies of PID
Tretment of PID depends on the defect
Primary antibody defects are treated by intravenous and subcutaneous Immunoglobulin administration, complement deficits depend on the type of defect with supplementation where adequate medication is developed. The backbone of Severe Combined Immunodeficiency treatment is allogeni stem cell transplantation in order to substitute damaged host stem cells. In specialized centers there are experimental attempts for gene therapy aiming to insert missing or defective gene and restore immunopoesis
Prof dr Goran Marjanović
- De Vries E, Driessen :G Educational paper: Primary immunodeficiencies in children: a diagnostic challenge., Eur J Pediat 2011: 170; 169-177
- Stoddard JL, Niemela JE, Fleisher TA, Rosenzweig SD: Targeted NGS: A Cost-Effective Approach to Molecular Diagnosis of PIDs. Front in Immunol 2014(5) 531: doi: 10.3389/fimmu.2014.00531. eCollection 2014.
- Zanichelli A, Longhurst HJ, Maurer M, Bouillet L, Aberer W, Fabien V, Andresen I, Caballero T; IOS Study Group. Misdiagnosis trends in patients with hereditary angioedema from the real-world clinical setting. Ann Allergy Asthma Immunol. 2016;117(4):394-398. doi: 10.1016/j.anai.2016.08.014
- O’Keefe AW, Halbrich M, Ben-Shoshan M, McCusker C: Primary immunodeficiency for the primary care provider.Paediatr Child Health 2016, 21(2), e10-14
- de Pagter AP, Bredius RG, Kuijpers TW, Tramper J, van der Burg M, vanMontfrans J, Driessen GJ; Dutch Working Party for Immunodeficiencies. Overview of 15-year severe combined immunodeficiency in the Netherlands: towards newborn blood spot screening. Eur J Pediatr. 2015 Sep;174(9):1183-8. doi:10.1007/s00431-015-2518-4.
- Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME,Cunningham-Rundles C, Etzioni A, Holland SM, Klein C, Nonoyama S, Ochs HD,Oksenhendler E, Puck JM, Sullivan KE, Tang ML, Franco JL, Gaspar HB. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015 Nov;35(8):696-726. doi: 10.1007/s10875-015-0201-1.
- Arslan S, Ucar R, Caliskaner AZ, Reisli I, Guner SN, Sayar EH, Baloglu I. How effective are the 6 European Society of Immunodeficiency warning signs for primary immunodeficiency disease? Ann Allergy Asthma Immunol. 2016Feb;116(2):151-155.e1. doi: 10.1016/j.anai.2015.12.001