Patients diagnosed with primary immune deficiency disorder may show any one of several gene defects that cause the immune system to fail. Contrary to secondary immunodeficiencies, environmental factors triggering symptom onset cannot be identified.
Many PIDD patients have a family history of immunodeficiency or associated autoimmune disease, but may not even be aware of it. Pointed questioning may be required to reveal evidence of a hereditary disease. Moreover, patients may not report determined complaints if these are considered irrelevant [3].
As a rule of thumb, T cell deficiencies manifest shortly after birth, B cell and antibody deficiencies within the first year of life after cessation of protection by maternal antibodies. Complement disorders and other PIDD may manifest at any age [10]. The most common symptom of PIDD is an increased susceptibility to infection. Because cell populations and components of the immune system fulfill distinct functions regarding defense against pathogens, the predominance of determined infectious agents may imply the nature of the underlying disorder. Patients suffering from T cell disorders present with recurrent opportunistic infections (e.g., Mycobacterium spp., enterovirus, Candida albicans), while disturbances of humoral immunity - B cell and antibody deficiencies - result in proneness to infections with encapsulated bacteria like Haemophilus influenzae and Streptococcus pneumoniae. Infections with Neisseria spp. are characteristic of complement disorders. Any organ system may be compromised, but sinusitis, otitis media, upper respiratory infection and pneumonia are most commonly observed among patients with this disorder [11]. Gastrointestinal disorders, primarily manifesting in form of diarrhea, may bother up to 50% of PIDD patients [5]. While neither recurrent sinusitis nor diarrhea are likely to be triggered by PIDD, co-occurrence of frequent infections of more than one organ system and gastrointestinal discomfort are highly suspicious of an immunodeficiency. In many cases, PIDD take a progressive course and depletion of immune cells and other factors becomes more severe as the patients gets older [11].
Workup usually starts with routine analyses of blood samples, that may reveal abnormal leukocyte counts. Differential blood counts, assessment of serum levels of complement factors and individual types of immunoglobulins by immunoelectrophoresis are also indispensable. However, qualitative are more important than quantitative studies [3], and in this context, more or less specific tests like the ImmuKnow cell function assay (evaluates the activity of CD4+ T cells), the CH50 and AH50 assays (provide information about the activation of the classical and alternative complement pathway, respectively), and molecular biological procedures (e.g., to assess cytokine and receptor expression), among others, may be helpful [12] [13] [14]. The patient's ability to produce antibodies may be evaluated by measuring antibody titers after immunization. Many PIDD are confirmed by means of genetic screens, but the scope of potential differential diagnoses needs to be narrowed down before a target-oriented approach to gene analysis is possible.
Also, SIDD should be ruled out. Anamnestic data are of utmost importance to that end, but additional measures may be required to determine if the patient is infected with the human immunodeficiency virus, or if they lose immunoglobulins due to a protein-losing enteropathy or nephropathy. Also, susceptibility to infection may be the result of severe congenital neutropenia or cyclic neutropenia, diseases that may be diagnosed after bone marrow examinations.
Substitution of IgG is the most common therapeutic approach to PIDD, since this type of immunoglobulin protects against infection with a broad range of pathogens [8]. Furthermore, considerable shares of PIDD patients receive antibiotics, both in order to prevent infections and to treat pre-existing ones. However, continuous antimicrobial therapy is not without side effects and resistance development may severely restrict the choice of antibiotics in case of life-threatening infections. Immunosuppressive therapy aims at counteracting aberrant immune responses that either trigger PIDD (autoimmune disease) or result from PIDD. On the other hand, proliferation of depleted cell pools may be enhanced by application of growth factors. Such therapies may bear the risk of malignant degeneration. Hematopoietic stem cell transplantation is usually carried out in non-responders to alternative treatments and may indeed be the only curative approach to many hereditary immunodeficiencies.
Life expectancy of PIDD patients depends on the underlying disease, but has been stated to be 1 to 49 years [8]. However, PIDD are presumably underdiagnosed and it is to be expected that mild forms of the disease don't significantly reduce the patient's life expectancy. In fact, other studies report many PIDD patients to have a near-normal lifespan [9].
The overall poor prognosis associated with moderate to severe PIDD is due to them being caused by gene defects that often have no cure. Here, treatment comprises preventive and supportive measures, but most patients will eventually die from severe infections, sepsis or malignancies. However, improvements in hematopoietic stem cell transplantation render this procedure a treatment option that is more available for patients afflicted with PIDD. Hopefully, morbidity and mortality will continue to decrease due to this treatment modality.
It is beyond the scope of this article to address each disorder classified as PIDD and the interested reader is referred to the extensive list compiled by the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency [2]. The following list may merely give an impression of the heterogeneity of PIDD.
Of course, PIDD may fulfill several of the aforementioned criteria, e.g., a genetic predisposition for autoimmune-mediated PIDD has been shown for various diseases [4]. In fact, such a combined etiology is assumed for one of the most common PIDD, for common variable immunodeficiency (CVID). Despite considerable research efforts, the precise triggers of CVID remain largely unknown. This also applies to selective IgA immunodeficiency (SIgAD), an even more common type of PIDD. Although considered a genetic disorder, CVID may develop from SIgAD, suggesting partial overlaps in their etiology.
There are more than 150 PIDD and they vary widely with regards to incidence and prevalence, predilection for determined patient groups and age distribution. The most common PIDD is SIgAD, and its prevalence has been estimated to be about 1 in 600 inhabitants in the western world. Interestingly, prevalence rates in East Asia are much lower and may only amount to 1 in 18,000 persons [4]. In contrast, other PIDD, such as Job syndrome, affect less than 1 in 1,000,000 people.
PIDD is a general term that comprises a heterogenous group of disorders sharing the common feature of immunodeficiency. However, the underlying gene defects (or autoimmune responses) may induce further complaints, e.g., neurological deficits, cardiovascular and pulmonary disorders and cutaneous lesions, to name a few, and these are sometimes referred to as syndromic features. Gastrointestinal disorders are rather common, too, and may be observed both in CVID and SIgAD patients. Celiac disease and diarrhea is often associated with the former, inflammatory bowel disease-like lesions have been related to the latter [5]. The mucous membranes of the gastrointestinal tract are continuously exposed to bacterial, viral and fungal pathogens, to parasites, to non-pathogenic antigens, and to physical stimuli. Accordingly, this organ system has evolved to become one of the largest immune organs in the human body. It relies on innate mucosal immunity as well as adaptive immune responses mediated by lymphocytes, macrophages, and dendritic cells. In CVID and SIgAD, the adaptive immune system is disturbed. Pediatric chronic granulomatous disease shall serve as an example for malfunction of impairment of innate immunity [6].
Although an increased susceptibility to infection is the hallmark of many PIDD, the immune system's role in anti-mutagenesis and anti-carcinogenesis should not be underestimated. Indeed, PIDD patients may be prone to develop neoplasms. Ataxia telangiectasia shall serve as an example for PIDD predisposing for malignancies. This disease is inherited with an autosomal recessive trait and is provoked by mutations of the ATM (ataxia telangiectasia mutated) gene, whose gene product senses DNA double-strand breaks. Consequently, cell cycle arrest induction due to DNA damage is reduced and cells with nucleic acid anomalies may proliferate. Individuals affected by this disease are prone to acute lymphoblastic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma and carcinoma [7].
PIDD may develop due to gene defects or autoimmune responses against components of the immune system, and both pathophysiological events are of unknown etiology. Thus, no specific measures can be recommended to prevent PIDD. However, the mode of inheritance is known for many diseases associated with primary immunodeficiency and affected families may be advised to seek genetic counselling. Also, psychological support may be offered in counselling sessions. Prenatal diagnosis of PIDD by means of chorionic villus sampling or amniocentesis should be considered.
Primary immune deficiency disorder (PIDD) is a general term that refers to malfunctions of the immune system that are not triggered by an identifiable cause, e.g., by any other disease, drugs or environmental factors. Should that be the case, the respective patient would be diagnosed with secondary immune deficiency disorder (SIDD).
Most PIDD are congenital diseases, which differentiates them from SIDD. Still, PIDD comprise a very heterogeneous group of more than 150 diseases [1] [2]. PIDD may be difficult to be determined; single molecules that form part of the innate or adaptive immune system, such as a particular cytokine, or may affect large cell populations, e.g., all cells originating from lymphoid progenitor cells in the bone marrow. The precise defect underlying PIDD determines the severity of the disease and renders the patient susceptible to certain pathogens or noxious agents. Because exposure to those stimuli occurs early in life, PIDD-associated symptoms usually manifest shortly after birth or after cessation of protection by maternal antibodies. Autoimmune-mediated PIDD may be an exception to this rule. Here, components of the immune system are destroyed due to an autoimmune response against those structures, and this may occur at any age.
Besides an increased susceptibility to infection, many PIDD are associated with developmental defects, failure to thrive and growth retardation and development of malignancies. Symptoms of often non-specific and don't raise the suspicion of PIDD, that requires a detailed workup to identify both quantitative and functional alterations of a subpopulations of cells, antibodies and mediators [3]. Only then can the broad spectrum of differential diagnoses be narrowed down. Still, the etiology of many PIDD remains poorly understood and this fact further complicates their diagnosis.
Immunodeficiency refers to malfunctions of the immune system that render the patient susceptible to infections. Many diseases are associated with immunodeficiency, with acquired immunodeficiency syndrome (AIDS) due to infection with the human immunodeficiency virus (HIV) probably being the one best known. Because AIDS is the result of an infection with HIV, the corresponding immunodeficiency is classified as secondary immune deficiency disorder (SIDD). This also applies to defective immunity due to other infectious diseases, the intake of drugs, tumors of immune organs, etc. In contrast, if no trigger can be identified, immunodeficiencies are referred to as primary immune deficiency disorder (PIDD). PIDD are most commonly induced by gene defects and are thus present at birth. They don't necessarily manifest within the first year of life, but most PIDD do. Affected children suffer from recurrent sinusitis, otitis media, upper respiratory infection and pneumonia, but also from developmental defects and failure to thrive. Components of the immune system may also be the target of autoimmune responses, i.e., attacks of the patient's immune cells against their own tissues. In that case, PIDD may manifest at any age. Symptoms are similar to those mentioned before. There is a total of 150 PIDD known to date, and common variable immunodeficiency and selective IgA immunodeficiency are the most prevalent ones. PIDD is usually diagnosed through blood tests and clinical features. Treatment is generally directed at restoring the normal function of the immune system through immunoglobulin therapy, growth factor therapy or hematopoietic stem cell transplantation for refractory cases.