Aff ecting T cells and B cells (combined immunode \201 ciency disorders) Severe combined i mmunode \201 ciency \200\224SCID A mixed group of disorders that all have grossly impaired T- and B-cell function leading to death normally within the fi rst years of life. They can be broadly classifi ed into 5 groups depending on their clinical and patho- logical charac teristics. Reticular dysgenesis is generally considered to be a SCID variant, accounting fo r 3% of the total. Other types are: \200 Adenosine deaminase defi ciency (16%). \200 T \210\222 B \210\222 SCID (27%). \200 T \210\222 B+ SCID (44%). \200 T+ B+ SCID (9%). Adenosine deaminase defi ciency A recessively inherited enzyme defi ciency. ADA is rate lim iting in purine salvage metabolism and is essential for the synthesis of nucleotides in cel ls incapable of de novo purine synthesis \200\224including lymphocytes. The gene for ADA is on chromosome 20q12 \200\223q13.11, and many mutations have been defi ned. Gene deletion l eads to very low ADA activity and a pro- found T and B lymphopenia with early onset of clin ical symptoms. Other tissues are involved, and there may be bony defects and neurological d is- turbances. A similar rare syndrome is seen with defi ciency of the enzyme purine nucleo side phosphorylase. It is less severe and presents later. 547 CONGENITAL IMMUNODEFICIENCY SYNDROMES Other forms of SCID SCID with both T-cell and B-cell lymphopenia is a recessive disorder th at also occurs without the enzyme defi ciencies described above, but the commonest form of the disease is X-linked and shows a lack only of T cells. It appears to be due to a defect in the gene coding for the chain of the interleukin (IL)-2 receptor. There are other rare SCID variants where T cells are present but dys- functional, including MHC class II defi ciency, where lymphocytes fail to express MHC class II molecules; and Om enn syndrome which presents in early infancy with the clinical features of acute widespread GvHD (skin rash, hepatosplenomegaly, diarrhea, failure to thrive) coupled with per- sisten t infections. Omenn syndrome is due to mutations in recombination activating genes 1 or 2 ( RAG1/2) and is associated with absent B cells. In contrast to the more typical T-B-cell SCI D defects, patients with Omenn syndrome have normal/elevated numbers of T and B cells. Howe ver, these cells lack the normal diverse T-cell repertoire, being oligoclonal in nature and having poor/absent proliferative capacity in vitro with no/low antibody responses to immun izations. The fi ndings of activated T cells with i production of IL-4, IL-5, and IL-10 at least in part may explain some of the clinical and laboratory manifestations of this syndro me. Recently a subtype of X-linked dyskeratosis congenita has also been recognized to prese nt with SCID (T+ B \210\222 NK \210\222 phenotype). Treatment of SCID \200 Matched BMT is the treatment of choice for all varieties; a good outcome can be expected in >90%. No preconditioning needed for matched donors. \200 Mismatched BMT results improving but d onor marrow needs careful mature T-cell depletion and patients may need conditioning. ADA defi ciency can be treated with regular enzyme replacement using a polyethylene glycol-linked ADA preparation. ADA defi ciency has also been treated with gene replacement therapy, with so far only a tra nsient eff ect, but the technique shows promise. \200 X-linked SCID due to mutations in c ommon -chain has been treated with gene replacement therapy in 19 patients with long-term effi cacy. Wiskott \200\223Aldrich syndrome An X-linked congenital disorder with a triad of (i) eczema , (ii) throm- bocytopenia with characteristically small platelets, and (iii) T- and B-cell dysfunction with susceptibility to infections, particularly otitis media and pneumonia. Due to a mutation in the gene encoding the Wiskott \200\223 Aldrich syndrome protein (WASP), i mportant inter alia in regulating the cytoskeleton of haemopoietic cells. \200 Presents i n childhood. \200 Tendency to immune cytopenias \200\224compounding pre-existing thrombocytopenia and causing haemolytic anemia. Herpes simplex, EBV, varicella, and CMV may be severe and life- threatening. Greatly i risk of lymphoid malignancy in adulthood for survivors. \200 Splenectomy greatl y i risk of fatal infection. \200 Need prophylactic antibiotics and immunoglobulin replac ement therapy. \200 BMT now treatment of choice; early in childhood if possible. 548 CHAPTER 11 Immunode \201 ciency Ataxia telangiectasia A recessive disorder with i chromosome fragility and a single gene (A TM) defect on chromosome 11q22.3. This aff ects several systems. The fi rst is neuromotor d evelopment with cerebellar ataxia appearing around 18 months of age and progressing to incl ude dysarthria associated with degeneration of the Purkinje cells. Telangiectases appear be tween 2 \200\2238 years of age aff ecting the eyes, face, and ears. An immune defi ciency i s evident aff ecting both humoral and cellular immunity, though less severe than SCID. Aff ected children get: \200 Sinopulmonary infections. \200 Progressive failure of antibody production. \200 Hypogammaglobulinaemia. \200 CD4+ lymphopenia. \200 Small thymus. \200 i incidence of lymphoid malignancies. Aff ecting T cells DiGeorge syndrome Absence or hypoplasia of the thymus and parathyroid gl ands with aortic arch anomalies, contralateral cardiac abnormalities or other congenital he art defects. This congenital anomaly of the 3rd and 4th branchial arches usually presents w ith hypocalcaemic fi ts or problems with a heart defect. Total thymic aplasia occurs only i n a minority, with severe immunodefi - ciency and a high risk of transfusion-transmitted Gv HD. Most have some T-cell function, and relatively minor problems with impaired immunity fo r which treatment is supportive. Aff ecting B cells X-linked agammaglobulinaemia (Bruton tyrosine kinase de \201 ciency) Bo ys with this condition have mutations in the gene for Bruton tyrosine kinase (locus Xq22), resulting in a failure of B-cell development and lack of antibody production. Early infancy is not a problem because of mater- nally transmitted IgG, but by 2 years of age serious in fections become apparent. These include bacterial invasion of the respiratory system, the G IT, meninges, joints, and skin. Viruses, particularly coxsackie and echo viruses, are also a major threat. \200 Absent or very low numbers of B cells. \200 Absent or low levels o f all immunoglobulins. \200 Treatment is by regular antibody replacement with polyvalent IVIg. Hyper IgM syndrome An X-linked disorder with B-cell dysfunction due to defective T-cell CD4 0 ligand production and thus lack of signaling to B-cell CD40 receptors. B cells are normal , but receive no instructions to generate isotypes of Ig other than IgM. Low levels of IgG, IgA, and IgE result. There is also defi - cient function of some tissue macrophages and a tendency to develop Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneu- monia. Treatment is with IVIg replacement therapy and cotrimoxazole prophylaxis. 549 CONGENITAL IMMUNODEFICIENCY SYNDROMES IgA de \201 ciency A relatively benign and common disorder aff ecting 1:500 individuals. T hey may develop anti-IgA antibodies in serum which can cause urti- carial and anaphylactic reactions to blood product infusions. No replace- ment therapy is needed. Aff ecting neutrophils, monocytes, and macrophages Inherited disorders of neutrophil functi on mostly present in childhood and are described in the pediatric section on congenital neu tropenia (E p.600). 1 functional disorders of monocytes and macrophages are also describe d in the pediatric section under histiocytic syndromes (E p.628). Poorly characterized 1 immune de \201 ciency syndromes There are a number of syndromes w here susceptibility to certain types of infection is not associated with a clear pattern of inheritance and where the clinical picture is variable. Few are as severe as the spe- cifi c syndromes referred to earlier in this section. They include chronic mucocutaneous candid iasis, where there is persistent superfi cial skin and mucous membrane fungal infection, an d where there may be defective T-cell regulation or dendritic cell function. CMC is also as sociated with a wide variety of autoimmune phenomena, particularly thyroid and adrenal dise ase, and diff erent patterns of inheritance are seen in dif- ferent kindreds. There is also a heterogeneous group of disorders collectively referred to as common variabl e immunodefi ciency. Defi ned by the clinical suscep- tibility to infection and in the abse nce of any other apparent cause, this collectively named syndrome is usually a diagnosis of exclusion and pre- sents in adult life. Low rather than absent levels of several isotypes of Ig are usual, and the condition is rarely life-threatening. 550 CHAPTER 11 Immunode \201 ciency Acquired immune de \201 ciencies Clinically important defects in lymphocyte numbers and/or function can be seen as a complication of a variety of acquired diseases. They can also be due to drugs, both those given deliberately to suppress an auto- immune process and those given primarily for other reasons. Similarly neutrophils can be reduced by a large number o f acquired disorders and a long list of drugs and toxins. An acquired susceptibility to inf ection also arises in patients with absent or poorly functioning spleens. Acquired hypogammaglobulinaemia Causes \200 Malignant LPDs including CLL and myeloma. \200 Immunosuppressive therapy with, e.g. azathioprine. \200 Maintenance therapy for ALL . \200 Nephrotic syndrome. Clinical features Bacterial infections \200\224recurrent chest infections (may lead to bron chiec- tasis), sinus, skin, and urinary tract infections common. Fulminant viral infections , especially measles, varicella. Treatment \200 May improve with treatment of the underlying disease. \200 IVIg should n ot be used routinely as prophylaxis. \200 High titre specifi c antibody can be given for serious zoster/varicella infections if available; polyvalent for measles. Patients with severe hypogammaglobulinaemia and recurrent infections may be considered for IVIg replacement therapy every 4 weeks (400 \200\223600mg/ kg). Acquired T-lymphocyte abnormalities Reduced numbers \200 HIV infection (E see HIV infecti on and AIDS, p.552). \200 High-dose steroids. \200 ATG. \200 Purine analogs especiall y fl udarabine and cladribine. \200 Pentostatin (deoxycoformycin) (adenosine deaminase in hibitor). \200 After allogeneic STC. Reduced function LPDs, HL, immunosuppressive agents, e.g. ciclosporin and steroids, burns, uraemia. Clinical features i risk of viral, fungal, and atypical infections including HSV, HZV, CMV, EBV, Candida, Aspergillus, Mycoplasma, PCP, toxoplasmosis, TB, and atyp- ical mycobacteria . Treatment Treat specifi c infection where possible. Consider prophylaxis against HZV, CMV, PCP, and Candida in high-risk groups, e.g. post-allogeneic stem cell transplant.