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Back to Index. 1. Diagnosis of patients with immunodeficiency Infection does not usually equate with a defective immune system. We all suffer regular minor infections despite possessing a normal immune system. Pathogens can cause serious or even lethal infections in some individuals but not in others, the variation in individual susceptibility to the infection being attributable to genetic variation in immune response rather than immune defect. Some defects in immunity do not cause an obvious increase in either the number or severity of infections over and above that expected normally. This may be because the defect is minor, or because other components of immunity compensate for the defect. Immunodeficiency is more likely to become manifest clinically if more than one component of the immune system is defective; this is exemplified by malnutrition compounded on immunodeficiency. Severe defects in major components of the immune system are inevitably accompanied by an obviously abnormal susceptibility to infection. The pattern of infections is usually characterised by the component of the immune system that is defective. An immunodeficiency may be quantitative as seen when there is inadequate production of neutrophils. Alternatively immunodeficiency may be qualitative as seen when there are normal numbers of neutrophils but they are defective in function. Immunodeficiency may be inherited, in which case it is categorised as a 'primary immunodeficiency'. There are a series of wellcharacterised primary immunodeficiencies, attributable to recessive genes, that present in early life with severe or overwhelming infection. Less severe forms of primary immunodeficiency are increasingly being recognised; these may not cause problems until later in life. Immunodeficiency secondary to other diseases are much more common than primary immunodeficiency and can be the result of infection or other disease processes. The importance of specific immune defects is that they illustrate the function of different immune components. The broad categories of immunodeficency are listed below: (1) Neutrophil disorders (2) Antibody deficiency (3) Complement deficiency (4) T cell dysfunction 1. Neutrophil Disorders Large numbers of neutrophils are produced in the bone marrow each day (~1011 ). Via the blood stream, they get into tissues by adhering to endothelium and migrate via diapedesis through blood vessels. Their lifespan is short and they die by apoptosis. Apoptotic neutrophils get taken up by macrophages and antigen-presenting cells (Langerhans) which subsequently present foreign antigens (which have been phagocytosed by neutrophils) to T cells. When neutrophils die by necrosis in pathological conditions (abscess), they release enzymes which can cause local tissue damage, e.g. recurrent chest infections lead to bronchiectasis. 1. Clinical features of neutrophil dysfunction Neutrophils are the principal phagocytes for eradicating extracellular pathogens like bacteria and fungi. The types of infection seen are dependent on the extent of the neutrophil dysfunction. In severe neutropaenia overwhelming sepsis is the most important clinical presentation for which antifungals and antibiotics are the mainstay of treatment. Dental sepsis and mouth ulcers can be important clinical indications to investigate neutrophil numbers and function. Normal neutrophil function depends on normal numbers, normal migration (chemotaxis and adhesion molecules), and normal killing mechanisms (respiratory burst, enzymes). The table below illustrates examples of the above neutrophil defects, and the clinical syndromes with which they are associated. In clinical practice drugs are the commonest cause of neutropaenia, either as a consequence of chemotherapy with cytotoxic reagents for immunosuppression. leukaemia or cancer, or as a result of idiosyncratic drug reactions. 2. Neutrophil Disorders Disease Clinical Functional Defect Pathogenesis Genetics Septicaemia with Bacteria, Fungi, Yeast No phagocytes Chemotherapy, acute leukaemia, autoimmune, primary bone marrow failure, increased consumption (Felty's) Acquired Coarse skin scarring, high IgE, mucocutaneous candida, lung and skin abscesses Defective chemotaxis Unknown Non-inherited Giant lysosomal granules, skin abscesses Defective chemotaxis and killing Microtubule disorder Autosomal recessive Abscesses with Staphylococci, Fungi, gram negative Decreased respiratory burst Enzymes do not digest micro-organisms Cytochromes deficient X-linked and autosomal recessive Deficient numbers Neutropaenia Abnormal Movement Hyper-IgE syndrome Chediak-Higashi Abscesses are "cold" Killing Chronic Granulomatous Disease Granuloma Adherence Leukocyte adhesion deficiency Skin, mouth, abscesses, osteomyelitis Decreased Adherence and Phagocytosis CD18 deficiency bchain of LFA-1 Autosomal recessive 2. Antibody deficiency 1. Clinical features associated with antibody deficiency Defective antibody production rarely causes clinical problems until levels of maternally-derived IgG have waned. This becomes critical 4-6 months after a full-term delivery but infants born before placental transfer of maternal IgG was complete are protected for a shorter period. The main manifestations of antibody deficiency are. (1) Recurrent infections with encapsulated pyogenic bacteria (e.g. S. pneumoniae) Sites involved - upper and lower respiratory tract, middle ear, meninges, skin, joints. (2) Viral infections unusual except for Enterovirus infection (e.g. ECHO virus infections of CNS; Paralytic poliomyelitis following oral polio vaccine). (3) Fungal infections or intracellular bacterial or parasitic infections are not usually a problem. (4) Diarrhoea and malabsorption -may be due to chronic infection with Giardia, campylobacter or cryptosporidia or due to bacterial overgrowth in the small intestine. (5) Arthritis - septic (H. influenzae, pneumococci, mycoplasma) - aseptic - resembles rheumatoid arthritis (6) Granulomatous lesions - in lungs can give a sarcoid like picture with impaired gas transfer. (7) Autoimmune diseases e.g. pernicious anaemia, Autoimmune thyroid disease, Thrombocytopenic purpura, and SLE can be seen with selective IgA and common variable antibody deficiency (8) Onset of symptoms in X-linked hypogammaglobulinaemia is after the fourth or fifth month of life - maternal Igs protect the baby before this. 2. Aetiology of antibody deficiency Most adult cases of antibody deficiency are acquired. The important causes in adults are B cell malignancy, particularly low grade chronic lymphocytic leukaemias and myelomatosis. Some patients develop antibody deficiency as a consequence of viral infection (EBV), drugs (Penicillamine, Gold) or for unknown reasons. These patients are labelled as having Common Variable Immunodeficiency (CVI). Congenital causes include X-linked agammaglobulinaemia where the B cell tyrosine kinase (Btk) is absent, resulting in failure of B cell development. Failure of T cells to help B cells can also lead to profound antibody deficiency. In the sex-linked disorder Hyper-IgM Syndrome, there is a failure of expression of CD40-ligand expression on activated T cells. 3. Investigation of Antibody Deficiency A number of simple tests can be performed to assess antibody function. (1) Measurement of total IgG, IgA and IgM together with a serum electrophoretic strip and assessment of urinary light chains. The latter is particularly relevant in myeloma patients (2) Measurement of functional antibody levels against polysaccharide and protein antigens, before and after immunisation. This can be particularly useful in patients with low serum albumin where you suspect that the IgG is spuriously low due to hyercatabolism (nephrotic syndrome and other protein losing states) (3) In infants, measurement of IgM isohaemagglutanins (ABO cross matching antigens) gives some idea of whether B cells can make antibody (4) Specialist in vitro tests can test B cell function (5) Cell marker studies to look for circulating B cells (deficient in Btk deficiency) Antibody deficiency disorders Disease Functional Defect Pathogenesis Genetics Transient Ig deficiency of infancy Presents at ~6/12 when maternal Ig wanes Normal Variant No B cells Presents ~6/12 Bruton's tyrosine kinase deficiency X-linked Low IgG and IgA. IgM high or normal Deficient T cell help for B cells. Pneumocystis Carinii and cryptosporidiosis CD40-ligand deficiency X-linked In some cases T help for B cells is poor Unknown, some secondary to drugs and Bruton's Disease Hyper-IgM syndrome Common Variable Immunodeficiency failure of B cell and macrophage activation viral infection like EBV Non-inherited Both sexes affected Low IgG secondary to protein loss Usually not associated with infection. Normal response to test immunisation Nephrotic syndrome, Non-inherited Neoplastic cells suppress normal B cell activation Myeloma, B cell Chronic lymphocytic Leukaemia Non-inherited Patients with total IgA def can get Autoimmune disease Patients with infections often have associated functional antibody defects(see below) Other Igs mainly IgA is a non-inflammatory Ig. absence predisposes to AI phenomena ? Normal total IgG-subclasses especially IgG2 and IgA may be reduced Functional impaired capacity to respond to thymus-independent polysaccharide antigens Non-inherited Protein losing enteropathy Low IgG secondary to B cell malignancy IgA deficiency (Commonest immunoglobulin deficiency 1/700). IgM can usually compensate for selective IgA deficiency Functional Antibody Deficiency 3. Disorders of Complement 1. The main features of defects in complement Inherited defects of the complement system are very rare. If you refer to your second MB course in immunology you will recall that the central component of complement is C3, which is present in serum at a concentration of about 1g/L. C3 lies at the pivotal point in both the classical and alternative activation pathways. The alternate pathway is activated directly by some yeasts, bacteria and fungi., and also IgA immune complexes. The classical pathway is mainly activated by IgM and IgG immune complexes. Inherited deficiency of C3 is very rare, but is associated with severe, recurrent bacterial infections in infancy and is usually lethal. This is because their is failure to opsonise efficiently through C3 receptors on phagocytes. Also release of proinflammatory mediators like C3a and C5a is absent. The early components (C1,4,2) of the classical pathway can be associated with infection, but more commonly are associated with systemic lupus erythematosus like diseases due to deficiency in clearing immune complexes and perhaps apoptotic cells. The late components of complement (C5-C9) which are homologous to the pore forming protein perforin, are associated with recurrent meningococcal infections, in particular meningococcal meningitis.. There is case for screening all patients with this disorder for late complement component deficiency. The complement system is a system of enzymes that act in a cascade manner by which a small initial event is greatly amplified. There are a number of complement control proteins which moderate complement activation. C1 esterase inhibitor is one of these control proteins. Unlike most proteins, the 1 normal functional allele is not enough to prevent disease which presents as an autosomal dominant disorder. Patients develop spontaneous angioedema which can be lethal if it involves the respiratory tract or present as abdominal pain due to oedema of the gut and obstruction. In contrast to angioedema due to mast cell degranulation, itching is not a feature. 2. Investigation of suspected complement deficiency Gross defects in complement can be assessed by the capacity of patient's serum to lyse heterologous blood cells. Depending on the red cells used, defects in the alternate and classical pathway may be detected. If abnormal, it is then possible to screen for individual components and do functional tests on discrete aspects of the complement cascade. 4. T cell deficiency CD4 T cells play a central role in orchestrating immune responses. Antigen-primed cells provide help for: (1) B cell responses to protein antigens (2) Inflammatory responses by release of Th1 cytokines IFNg , IL2 and TNF. (3) Priming of cytotoxic CD8 T cells which are helped by IL2. Because CD4 T cells play such a complex role in immunity, the spectrum of illness is also quite broad. It also depends on the age of the patient. Adults who acquire CD4 deficiency as a consequence of HIV infection have a different spectrum of disease young children with inherited or acquired CD4 deficiency. This is partly due to the fact that adults are protected by their immunoglobulin and have memory cells whereas infants do not. The table below shows infections associated with CD4 T cell deficiency. 1. Aetiology of CD4 deficiency and clinical presentation The most important cause nowadays is acquired infection with the Human Immunodeficiency Virus (HIV) which can present with any of the infections listed in the table below. Secondary lymphoma due to failure of T cells to control viruses such as EBV is also a problem. The second cause in adults is secondary to immunosuppressive therapy, e.g. after transplantation There are also a number of congenital defects such as Di George syndrome which results from abnormal embryogenesis of the branchial arches with defective thymic development. These condition present from the time of birth with infections and failure to thrive. Infections associated with CD4 deficiency Type of Infection Protozoan Infections - Organisms and Disease Reason Pneumocystis Carinii - Pneumonia IFNg secretion from primed Th1 CD4 cells is required to activate macrophages and other cells to eliminate intracellular organisms Toxoplasmosis - Multisystem disease, CNS Cryptosporidiosis - Diarrhoea Intracellular bacteria - Tuberculosis - Disseminated infection as above Atypical organisms - i.e. M. Avium Salmonella- Diarrhoea Fungal/Yeast Candida - Mucocutaneous infection Cryptococcus neoformans - lungs/meningitis Aspergillosis - lungs and systemic infection Not really known but T cell derived cytokines may be important in recruiting phagocytes like neutrophils to inflammatory sites Extracellular Bacteria Encapsulated Bacteria-Pneumonia This was an unexpected finding in African HIV patients. The reason is probably as above Viruses CMV - Pneumonia/CNS/Liver CD4 cells help in the priming of cytotoxic CD8 T cells. IL2 also expands NK cells important for killing Herpes Viruses which downregulate MHC EBV - lymphoma Herpes simplex/zoster Herpes virus Kaposi's Sarcoma 2. Investigation of suspected T cell deficiency A T cell CD4 and CD8 cell count in the blood remains an extremely useful tool for monitoring the progress of HIV infection and predicting progression to AIDS. Functional assessment of CD4 function can be performed by testing for delayed hypersensitivity to common antigens like mumps and candida by intradermal skin testing. Lymphocyte function can also be assessed in vitro and this is especially relevant in infants who may not have been immunised, where it is impossible to test recall antigens. For investigation of individual patients, the local Clinical Immunologist should be consulted and involved. USUAL PATTERNS OF ASSOCIATED INFECTIONS IN DEFECTS OF HOST DEFENSE PHYSIOLOGIC MECHANISM ABNORMALITY ORGANISMS* SITE: TYPES+ Integumental barrier Burns, eczema, skull fracture, sinus tract. Pyogenic and enteric bacteria occasionally fungi, especially candida Recurrent in same location Outflow Obstruction of Eustachian tube, urinary tract or bronchi. Vascular perfusion Oedema, angiopathy, infarction. Microbiologic flora Alteration by antibiotic therapy Skin & respiratory tract NON IMMUNE SYSTEM PHAGOCYTE FUNCTION Chemotaxis Defects of neutrophil migration. Staphylococci, enteric bacteria Phagocytosis Opsonin deficiency see Humoral systems below Neutropaenia Staphylococci, enteric bacteria Skin and respiratory tract stomatitis pseudomonas species Asplenia Pneumococcus, Haemophilus influenzae type b Septicaemia, meningitis Intrinsic cellular defects, Chronic granulomatous disease Staphylococci, enteric bacteria aspergillus species, candida Skin & respiratory tract, abscesses Circulating antibody Hypogammaglobulinaemia Pyogenic bacteria, less commonly enteric Bacteria, enteroviruses Any site/localised and bacteraemic Mucosal antibody IgA deficiency Pyogenic bacteria Respiratory tract; less commonly, diarrho urinary tract infections. Complement Congenital deficiency C3, Factor I Pyogenic bacteria, especially pneumococci Bacteraemia, meningitis, pyoderma Congenital deficiency C5,C6,C7,C8 Neisseria meningitidis or N.gonorrhoeae Meningitis, pyogenic arthritis C1 Inhibitor No infections Develop angioedema Primary T-lymphocyte defects Viruses, fungi, protozoa bacteria Any site/localised and systemic Killing HUMORAL SYSTEMS CELL MEDIATED IMMUNITY *Common infecting organisms are emphasised. 'Pyogenic bacteria' refers to pneumococci, Streptococcus pyogenes, Hemophilus influenzae, meningococci, and staphylococci. 'Enteric bacteria' refers to enterococci and the gram-negative bacilli common to the intestinal tract, especially Escherichia coli, Pseudomonas species, Klebsiella-Enterobacter species, and Proteus species. #Skin infections include furunculosis, subcutaneous abscesses, & cellulitis; respiratory-tract infections include recurrent pneumonia, otitis media and sinusitis. +Liver, lungs, lymph nodes & spleen. 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