Download 1. Diagnosis of patients with immunodeficiency

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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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