Treatment with replacement therapies can lead to a near-normal life if diagnosis is made early enough to avoid infectious sequelae.
Primary immunodeficiency diseases (PID) are a group of more than 120 different disorders of the immune system resulting from genetic defects of different molecules involved in the immune response.[1] Clinical and immunological manifestations and the severity of each disease vary widely.
However, the common features are lack of or poor quality of the response against infections and increased incidence of autoimmune manifestations. The possibility of treating most of them with replacement therapies renders early diagnosis essential to avoid infectious sequelae. Knowledge of the aetiology, genetics, clinical aspects and management have greatly improved the outcome of PID patients in recent years.
A simplified version of the IUIS classification:[2]
- Antibody production deficiencies, including X-linked agammaglobulinemia, hyper-IgM, common variable immunodeficiency (CVID)
- Combined immunodeficiency diseases with different degrees of T- and B-cell defects, including all variants of the severe combined immunodeficiency diseases (SCID), Wiskott-Aldrich syndrome, and so on
- Defects of the innate immune response, such as the phagocytic cell defects in chronic granulomatous disease (CGD). Therapy differs for the cases in each group.
Replacement therapy with gammaglobulin
Following the description by Dr Bruton of the benefit of gammaglobulin therapy in a boy with agammaglobulinaemia, therapy with intramuscular Ig (IMIg) was the standard treatment up to the beginning of the 1980s. In vitro, it has been demonstrated that IMIg produces aggregates of IgG with high molecular weight that activate the complement system and are responsible for the systemic reactions. Furthermore, the low levels obtained (there is a local proteolysis) with painful
administration currently limits its use to the prevention of certain infections (eg, HAV, HBV, tetanus, rabies).
Intravenous immunoglobulin (IVIg)
IVIg is the most widely used treatment for PID.[3] It has significant advantages, including easy administration of large doses and rapid onset of action. Furthermore, all the available preparations approved by the FDA and EMEA have a half-life of 18-25 days, contain all IgG subclasses, have minimal anti-complement activity, have a broad spectrum of antibodies and are free of hepatitis B, C, HIV and other viruses. Recent implementation of virus inactivation methods makes these products, which are available in our setting, very safe. The recommended dose to avoid infections or hospitalisations and improve lung function is 400-600 mg/kg, with the aim of maintaining an IgG level over 600 mg/dl just before a new administration.
The adverse effects of IV infusion of Ig such as headache, nausea, vomiting, joint pain and/or abdominal pain may occur in 5-15% of patients and can be minimised by slowing the infusion rate and by pretreatment with oral paracetamol or antihistamines.
Subcutaneous immunoglobulin (SCIg)
SCIg products, used for years in north Europe, are an alternative to IVIg and allow at-home therapy.[4] As the technique for inserting a small perfusion needle subcutaneously is simple, the medication can be self-administered into the abdominal wall or thighs. The injections are well tolerated. Local reactions are minimal and include erythema and/or pain; systemic reactions are rare. The monthly dose used is the same but is divided over four weeks. The concentration of the SCIg is 16%, to be infused with the aid of a small, battery-powered perfusion pump.
The standard doses used are 100-150 mg/kg/week, corresponding to a dose of 45-60 ml of a 16% solution. Comparative studies on the efficacy and safety of IVIg and SCIg for replacement therapy found no significant differences with respect to the number of infections or adverse reactions, and recent studies have shown that SCIg administered at home is associated with better quality of life than IVIg administered in the hospital; it also gives patients and their families greater independence and greater control over aspects of their treatment and daily life.
Main PID treated with SCIg or IVIg
Antibody deficiencies:
- X-linked agammaglobulinaemia.
- Common variable immunodeficiency.
- Hyper-I gM syndrome.
- Functional antibody deficiencies with or without I gG2/I gA deficiency
Combined deficiencies (before and during haematopoietic precursors [HP] or those with repeated bacterial infections):
- Severe combined immunodeficiencies.
- Wiskott-Aldrich syndrome.
- Ataxia-telangiectasia.
- X-linked lymphoproliferative syndrome.
Replacement of T and B cells with HPT[5]
Replacement of T and B cells with HPT is used in PIDs of T lymphocytes, combined T and B defects and defects of phagocytes, which would otherwise almost certainly be fatal, to restore the number and/or function of lymphocytes or phagocytes. For severe combined immunodeficiencies, of different types, it is the only therapy that can “cure” the disease. In such cases, the diagnosis is urgent in paediatrics to avoid infections that would limit their outcome.
Donor selection
Syngenic identical related (homozygotic twin) or HLAcompatible allogeneic donors (siblings) are the most commonly used. Matched unrelated allogeneic donors, such as blood-matched donors and cord blood, are also used when siblings are not available. For HPT in PID, haploidentical donors (parents) are rarely used owing to the high risk of severe graft-versus-host disease (GVHD). The choice is based on availability, condition of the patient and urgency, as well as on the underlying disease.
Sources of haematopoietic precursor (HP) cells
- Bone marrow.
- Cord blood: this is a rich source and produces hundreds of times more CD34/CD38 precursor cells[6] than bone marrow or peripheral blood, and these cells usually cause less GVHD. There are more than 150,000 cord donations stored in different bone marrow banks throughout the world.
- Peripheral blood (mobilisation of CD34 precursorcells to the periphery using G-CSF, with leukapheresis on day 5-7) from compatible donors. HP preparation includes a laminar-flow room, good nutrition (if necessary, use total parenteral or enteral nutrition), antibiotic prophylaxis and irradiation of blood products, if required.
Graft-versus-host-disease (GVHD)[7]
This is due to the recognition of the host tissues by the donor T lymphocytes (“reverse rejection”). If an HLA class II mismatch exists, the disorder is usually very severe or even fatal. The minor histocompatibility antigens give rise to a greater or lesser degree of GVHD despite the matching (even if ‘complete’) in the majority of patients transplanted for PID. It is more common and/or intense with unrelated donors. The results are better the earlier the HPT is performed, in the absence of previous infections and with the optimum degree of matching.
Therapy for defects of the innate immune response
This group of PIDs includes a very wide range of immunological abnormalities with different therapies. Severe cases can also be treated with HPT, but, as for CGD, a defect of the phagocytic function, only with a good compatible donor (sibling) owing to the risk of GVHD. In the majority of these patients, prophylactic antibiotics and antifungal drugs are the standard therapeutic protocol. The use of cytokines, such as IFNγ,[8] is also well accepted in CGD and some cases of IL12/IFNγ pathway defects.
Most probably, new therapy protocols will be developed for the defects of the innate immune response and other different types of PID still to be described.
Gene therapy (GT)
Patients with PID are ideal candidates for GT because they have monogenic defects of haematopoietic cells.[9] Transfection of the stem cells of the patient’s bone marrow with vectors carrying the wild gene and reintroduction of the transduced cells as a transfusion are well-known techniques. Different vectors (mostly virus, such as retrovirus) could be used. Encouraging results have been obtained in X-linked SCID, and even better in ADA-deficient patients. A number of patients are considered “cured”, although neoplastic processes have been diagnosed in a few of those of the first group.
Different protocols are being tested in various European centres (Paris, Milan and London) and the USA. Despite the difficulties encountered, the reconstitution of immunological normality has been demonstrated in several cases (with normalised lymphocyte function), and many studies are being conducted on the different regimens and indications in very diverse diseases, which will lead to better protocols and outcome in the near future.
Other therapeutic considerations
Antibiotics are widely used in PID and need to be clearly indicated following culture results (serologies are not useful in the majority of patients). Anti-inflammatories, or even immunosuppressors, have to be used in specific circumstances. Nutrition protocols and physiotherapy are to be taken into account.
Conclusion
PID therapy has changed greatly in the last 15-20 years, and a near-normal life is obtained in most patients if diagnosis is made correctly and therapeutic measures are established early; in addition, we can expect more advances in the coming years that will probably improve the prognosis of PID patients even more.
Author
Teresa Espanol MD PhD
Immunology Unit University Hospital Vall d’Hebron, Barcelona, Spain
References
1. Ochs HD, et al. Primary immunodeficiency diseases. A molecular and genetic approach.2nd ed. New York: Oxford University Press; 2007.
2. Geha RS, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol 2007;120(4):776-94.
3. Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. Allergy Clin Immunol 2006;117:S525-53.
4. Gardulf A, et al. Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J Allergy Clin Immunol 2004;114:936-42.
5. O’Reilly RJ, Small TN, Friedrich W. Hematopoietic cell transplant for immunodeficiency diseases. In: Thomas ED, Blume KG, Forman SJ, editors. Hematopoietic cell transplantation. 2nd ed. Malden: Blackwell Science; 2004. p. 1430-42.
6. Barker JN, Davies SM, DeFor T, Ramsay NK, Weisdorf DJ, Wagner JE, et al. Survival after transplantation of unrelated donor umbilical cord blood is comparable to that of human leukocyte antigenmatched unrelated donor bone marrow: results of a matched-pair analysis. Blood 2001;97:2957-61.
7. Sale GE. Pathogenesis of graft-versus-host disease. Biol Blood Marrow Transplant 2005;11:21-3.
8. Weening RS, Leitz GJ, Seger RA. Recombinant human interferon-gamma in patients with chronic granulomatous disease. European follow-up study. Eur J Pediatr 1995;154:295-6.
9. Chinen J, Puck J. Successes and risks of gene therapy in primary immunodeficiencies. J Allergy Clin Immunol 2004;113:595-603.
