Centrum für Chronische Immundefizienz - CCI

Inclusion of patients into P-CID Study

Due to lack of data on the natural history, there are no clear treatment concepts for patients with P-CID, in particular with respect to the appropriate indication and time point for HSCT. This P-CID cohort will include patients with “atypical” SCID (mutation in a SCID causing gene, but manifestation after 1 year of age), patients with a range of rare defined primary immunodeficiencies, but also patients with so far genetically undefined combined immunodeficiencies. At study entry, the local center decides and carefully documents, whether and why the patient undergoes HSCT or not. Patients who are not transplanted are followed up yearly and severe events related to the PID as well as decisions for secondary HSCT are documented. Patients undergoing HSCT also have standardized follow-up evaluation schedules. All three groups (1° HSCT, 2° HSCT, no HSCT within the 5 year follow-up period) will be analyzed with respect to survival, frequency of severe events (infections, immune dysregulation, HSCT related complications) and quality of life. A concomitant genetic and immunological study will aim at a better phenotypic characterization and elucidation of new genetic causes for P-CID. This first prospective outcome study on P-CID will provide important information on prognosis and treatment decisions in this potentially life-threatening disease.

The following molecularly defined diseases are eligible for inclusion, provided they fulfil the entry criteria. Some of these diseases will only fulfil the entry criteria in rare variants. The rationale for choosing such a broad approach is that the clinical problem concerning the decision for indication and time point of HSCT is similar in all of these patient groups. In all patients the clinical consequences of T cell deficiency is a major factor limiting survival. It is acknowledged that for some subgroups (e.g. radiosensitive disorders), additional specific risk factors such as malignancies have an important impact on survival. Similarly, neurodevelopmental problems associated with some forms of P-CID can have a significant impact on quality of life. Therefore, subgroup analysis should be performed for some diseases which will be limited by patient numbers. Overall, however, a significant number of core diseases will remain. Moreover, the value of a common standardized documentation platform for the study of the natural history of this poorly studied group of combined immunodeficiencies is rated higher than these limitations.

Group 1: Combined immunodeficiencies

Group 2: Combined immunodeficiencies with radiosensitivity

Group 3: Immunodeficiencies associated with a CID phenotype in some cases

Patients with WAS, CD40L deficiency or Ataxia teleangiectasia may fulfill the entry criteria, but in these disorders, sufficiently large cohorts are available to generate disease-specific information on treatment decisions.

Definition of Major Criteria for study inclusion

Major Infection Criteria

• Opportunistic infection (pneumocystis, invasive NTM, invasive fungal infection, oesophageal candidiasis, persistent cryptosporidiosis, other)
• Severe bacterial infection (necessitating PICU)
• Invasive bacterial infection (sepsis, meningitis, OM, septic arthritis, purulent pericarditis, mastoiditis, complicated pneumonia, abscess except skin/gut)
• Severe viral infection (requiring PICU)
• Persistent viremia (CMV, EBV, Adeno)
• Persistent severe viral skin lesions

Major manifestations of immune dysregulation:

• Biopsy proven granulomatous disease
• Inflammatory bowel disease
• Unexplained interstitial lung disease
• Autoimmune cytopenia or autoimmune endocrinopathy
• Lymphoproliferation (persistent splenomegaly or lymphadenopathy)
• Systemic Vasculitis (more than skin involvement)

Other Major manifestations:

• Malignant disease
• Chronic lung disease

Inclusion

Clinical and immunological criteria determine inclusion irrespective of the genetic diagnosis

• T cell criteria: (2 out of 4)

- Reduced T cell counts (CD4 : <700, if <2y ; <500, if 2-4y ; <300 if >4y ; CD8: <350, if <2y ; <250, if 2-4y ; <150, if >4y)

- Reduced thymic function (CD45RA+CD62L+ or CD45RA+CD31+ of CD4+ <30% <2y, <25% 2-6y, <20% >6y)

- Impaired T cell proliferation (PHA or anti CD3 response <30% of lower limit of normal)

- Elevated fraction of gamma/delta T cells (>15% of total CD3+ T cells)

AND

• At least one major infection criteria (viral, bacterial, opportunistic) OR
• At least one major immune dysregulation criteria (granulomas, lymphoproliferative disease, unexplained interstitial lung disease, inflammatory bowel disease, autoantibody mediated disease, vasculitis) OR
• At least one malignancy criteria (lymphoid malignancies and virally induced malignancies) AND
• Age >= 1year and <= 16years at study inclusion

Exclusion

• No written informed consent of patient or parents in case of minors available or no assent of minor if applicable
• Patients with a clinical diagnosis of SCID or Omenn syndrome within the first year of life
• P-CID Patients for whom decision for HSCT is taken at age < 1yr
• Patients with Wiskott-Aldrich syndrome, CD40 Ligand Deficiency and Ataxia teleangiectatica, because disease-specific prognosis and treatment data are available
• Patients undergoing gene therapy or ADA enzyme replacement will be followed using the same parameters, but will not be included in the analysis
• HSCT prior to study entry

• Study Synopsis (PDF)
• Flow Diagram (PDF)
• First Steps (PDF)

In case you are interested to participate as a centre, please contact Stephan Ehl for further information.

Combined immunodeficiencies are a hetergenous group of diseases with a similar clinical presentation. Immunologic and genetic diagnosis is difficult and often costly. To provide an orientation, we propose a diagnostic algorithm based on laboratory abnormalities, features of immune dysregulation and syndromal features. Since knowledge in this field is growing rapidly, this is a provisional algorithm and we would be happy about feedback (Stephan Ehl and Capucine Picard).

1 - Laboratory abnormalities in the differential diagnosis of CID

2 - Features of immune dysregulation in the differential diagnosis of CID

3 - Syndromal features in the differential diagnosis of CID

We are happy to provide advice for immunologic and genetic diagnosis and for treatment decisions for patients with all forms of combined immunodeficiency. Please use the provided case discussion form for a structured case presentation. It can be sent to Stephan Ehl and Carsten Speckmann.

Speckmann C, Doerken S, Aiuti A, Albert MH, Al-Herz W, Allende LM, Scarselli A, Avcin T, Perez-Becker R, Cancrini C, Cant A, Di Cesare S, Finocchi A, Fischer A, Gaspar HB, Ghosh S, Gennery A, Gilmour K, González-Granado LI, Martinez-Gallo M, Hambleton S, Hauck F, Hoenig M, Moshous D, Neven B, Niehues T, Notarangelo L, Picard C, Rieber N, Schulz A, Schwarz K, Seidel MG, Soler-Palacin P, Stepensky P, Strahm B, Vraetz T, Warnatz K, Winterhalter C, Worth A, Fuchs S, Uhlmann A, Ehl S; P-CID study of the Inborn Errors Working Party of the EBMT. A prospective study on the natural history of patients with profound combined immunodeficiency: An interim analysis. J Allergy Clin Immunol. 2017 Apr, Pubmed ID: 27658761