Most patients with suspected PID should be referred to a clinical immunologist with access to modern immunological tests. For severely affected patients, a combination of immunoglobulin replacement and periodic or prophylactic antibiotics (e.g. ciprofloxacin or a rotating regimen of amoxycillin, doxycycline and a quinolone) are required, but mild cases can often be managed with antibiotics alone. Most severely affected patients are given monthly intravenous immunoglobulin (400 mg/kg) or weekly subcutaneous infusions (100 mg/kg), the latter being recommended for infants and young children with difficult venous access. Morbidity and life expectancy depend on the type of immunodeficiency and the degree of organ damage at diagnosis; for example patients with XLA diagnosed early before there is lung damage will have an excellent prognosis if they are compliant with treatment. In contrast, CVID patients frequently develop chronic inflammation with granulomas in their lungs and livers, and a minority may have severe unexplained enteritis or autoimmune thrombocytopenia that can severely affect their quality of life. Other rarer PADs are associated with special complications, such as cholangitis and liver cancer in patients with CD40 ligand deficiency, and EBV-induced lymphoma in those with XLP. Protocols for management and follow-up therefore need to be tailored to the genetic defect.
In secondary antibody deficiency, prognosis depends on the primary disorder, but there is often recovery of antibody production if the offending drug is discontinued or the underlying disease remits. There is no consensus on the use of prophylactic immunoglobulin in CLL or myeloma, with many centres preferring to use prophylactic antibiotics for those prone to infection. Nevertheless, there are patients who benefit from prophylactic immunoglobulin therapy, particularly in the winter months.
Experimental mouse models have clearly demonstrated the importance of IL-12 and IFN-y and their corresponding receptors in protection against infection with intracellular pathogens, particularly mycobacteria. This work led to a search for defects in these proteins in rare cases of infants and young children presenting with chronic mycobacterial disease, including persistent local disseminated BCG infection following vaccination. Families have been reported with autosomal inherited defects involving the IFN-y receptor, STAT-1, which is critical in the signalling pathway for this receptor, and in IL-12 and its receptor. Affected patients usually present with chronic atypical mycobacterial infection at an early age and are also prone to chronic Salmonella infection. A defect in NEMO (NFkB modulator) causes a rare X-linked severe immunodeficiency with ectodermal dysplasia. Defects in IRAK-4 (interleukin-1 receptor-associated kinase 4) have been found in patients prone to recurrent pneumococcal pneumonia.
Patients with IFN-y receptor (R) defects either fail to express the R1 chain or partially express either the R1 or R2 chain. Partial expression allows signalling by high concentrations of IFN-y, and affected patients may respond to IFN-y therapy. The heterozygous dominant form of partial expression is the most common, the abnormal chains interfering with the signalling via Jak-1 and STAT-1 following binding of IFN-y to the receptor complex (so-called 'dominant negative' effect). Patients with complete deficiency of the p40 chain shared by both IL-12 and IL-23, and of the IL-12P1 receptor can be helped by IFN-y therapy, but the few patients described with STAT-1 deficiency do not respond.
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