Case 17- Immunodeficiency Flashcards
Primary immunodeficiency
Due to an inherited genetic mutation, for example; severe combined immunodeficiency disorder (SCID). Rare, intrinsic, usually inherited immune disorders usually present at birth and diagnosed in childhood. Potentially life threatening. Its more common in males
Secondary immunodeficiencies
Acquired immunodeficiencies as a result of disease or environmental factors i.e. HIV. More common then primary, manifests at any age
Treatment of secondary immunodeficiencies
Treatment of primary condition usually leads to resolution of the immunodeficiency
Causes of secondary immunodeficiency
Malnutrition is the biggest cause, other causes:
• Drug effects- chemotherapy, immunosuppressive drugs
• Chronic infections- HIV/AIDs, Malaria, Measles
• Malignancy- Leukaemia, Lymphoma and Myeloma
• Radiation exposure
• Extremes of age- prematurity
Immunodeficiency disorder
Partial or full impairment of the immune system which leaves patients unable to resolve infections. Can lead to infections or cancer
The clinical features of immunodeficiency
SPURR:
• Severe – increased severity of infection and unexpected complications
• Persistent – increased duration of infection
• Unusual - unusual manifestations of infection and non-infectious manifestations
• Recurrent – increased frequency
• Runs in the family (PIDs)
Symptoms of immunodeficiency
1) _ Increased frequency, severity and duration of infection
2) Infections with organisms of low pathogenicity (opportunistic infections)
3) You get non-infectious manifestations in gastrointestinal, endocrinological and haematological organ systems. Such as auto-immunity, inflammatory disorders, fevers, rashes, bowel problems and swollen joints
Clinical findings of immunodefiency in children
- > 4 ear infections in 1 year
- > 2 sinus infections in 1 year
- > 2 months on antibiotics
- > 2 pneumonias in 1 year
- Failure to thrive
- Recurrent Abscesses
- Persistent fungal infections
- IV antibiotics needed
- > 2 deep seated infections
- Family history
Immunodeficiency diagnosis
• History- infections, other symptoms of immunodeficiency, Family history
• Physical examination
• Baseline blood tests
Once diagnosed you would perform a complete blood count and Immunoglobulin levels to determine the type of immunodeficiency. You’d want to rule out a severe cause like antibody deficiency, neutropenia, SCID and AID’s.
Further tests for immunodeficiency
• Lymphocyte proliferation • B cell maturation • Phagocyte function • Complement components Where possible do genetic testing so you can definitively diagnose the immunodeficiency disorder.
Autobody immunodeficiencies
1) Most common cause of Primary immunodeficiency (PID). 2) Can occur in SID due to a T cell deficiency
3) Antibodies are part of the humoral response and protect our extracellular space
4) Commonly causes bacterial infections such as Otitis, Pneumonia, Sinusitis, GI tract disturbances and Autoimmunity i.e. coeliac disease.
5) Infectious organisms include Pneumococcus and H.influenzae.
6) Diagnosed with low immunoglobulins and B cell abnormalities. Untreated patients can develop bronchiectasis.
Treatment for antibody immunodeficiencies
Immunoglobulin replacement (IgG)
Examples of antibody immunodeficiencies
1) Transient physiological agammaglobulinaemia of the neonate
2) X-linked agammaglobulinemia of Bruton (Bruton’s disease)
3) Common variable hypogammaglobulinemia (CVID)
4) Selective IgA deficiency
Transient physiological agammaglobulinemia of the neonate
Neonates dont have a fully developed immune system at birth but rely on maternal transfer in utero. There is delayed IgG production till 3 months. If the baby is premature then this condition is exaggerated as the mother produced more IgG in the last trimester
X-linked agammaglobulinemia of Bruton (Bruton’s disease)
X linked recessive disorder which causes defective B cell maturation. Causing an antibody deficit, more common in males. Recurrent pyogenic infections i.e. streptococci and staphylococci, seen at 6 months
Common variable hypogammaglobulinaemia
Heterogeneous group of conditions with normal B cell numbers but abnormal function. Deficit in IgG and at least one other immunoglobulin. Late onset 15-35 years, presents with recurrent pyogenic infections i.e. streptococci and staphylococci
Selective IgA deficiency
Deficiency in just IgA, most common tyoe. More common in caucasians. Can be asymptomatic or cause recurrent infections of the respiratory and gastrointestinal tract. IgA is mostly found in mucosal secretions i.e. tears, saliva or secretions. In mucosal secretions its known as secretory IgA. Affects 1 in 400-1000, unknown genetic cause but often familial.
Example of secondary antibody deficiencies
Chronic Lymphocytic Leukaemia (CLL)- affects the ability of B cells to differentiate into plasma cells.
Multiple Myeloma- cancer of plasma cells producing abnormal antibodies.
The different presentations of selective IgA deficiency
- Asymptomatic- majority, diagnosed incidentally. May have some IgM or IgG in the secretions which partially compensate. May go on to become symptomatic
- Recurrent infection of mucosal surfaces- about half of symptomatic patients. Infections in sinus, ear, lungs and GI tract. Can have partial IgG deficiency but will have normal blood levels
- Allergies- 10-15% of symptomatic patients. For example, allergic asthma or food allergies
- Autoimmunity- 25-33% of symptomatic patients. Get rheumatoid arthirits, lupus and coeliac disease
Diagnosis of selective IgA deficiency
Blood IgA <0.5-0.7 mg/L, other Ig levels normal. Normal B and T cell number and function. Can coexist with an IgG deficiency but changes diagnosis to CVID.
Treatment for selective IgA deficiency
No specific treatment, you treat infections as they arise and use long term prophylaxis. Patients with severe infections may be offered immunoglobulin (IgG) replacement therapy but doesn’t always work.
How common is Lymphocyte immunodeficiency
Most common type of SID, can cause some serious PID as lack of T lymphocytes can cause antibody deficiency.
Lymphocyte deficiency
Lymphocyte deficits commonly result in recurrent viral, fungal, protozoal and intracellular bacterial infections causing deep-seated infections i.e. tuberculosis, thrush, P.jirovecii pneumonia (PCP) and reactivation of latent viral infections. Children can be killed through opportunistic infections and live vaccines i.e. Rotavirus
Diagnosing Lymphocyte immunodeficiency
By looking at the lymphocyte subpopulation (ratio of CD4 and CD8 T cells) and proliferation tests which show the functionality of lymphocytes
Examples of primary lymphocyte deficiencies
Commonly caused by abnormal maturation of lymphocyte stem cells:
• DiGeorge syndrome (Thymic hypoplasia)
• Wiskott-Aldrich syndrome
• Severe combined immunodeficiency disorder (SCID)
DiGeorge syndrome (Thymic hypoplasia)
Deletion of a small part of chromosome 22, abnormal fetal development. Leads to an underdeveloped thymus affecting T cell number and function. Can cause developmental delays, cleft palate and congenital heart disease
Wiskott-Aldrich syndrome
A group of rare disorders that affect T cell function but not development. Caused by the WAS gene mutation, this encodes the WAS protein which activates Actin polymerisation. Affects the immune synapse. X-linked recessive condition characterised by normal serum IgG, low IgM and high IgA and IgE. Worsens as the patient ages. Get recurrent infections, eczema and thrombocytopenia
Examples of secondary lymphocyte deficiencies
- Malnutrition- causes atrophy of the thymus which is involved in production of T cells
- Hodgkin’s lymphoma- cancer of lymphocytes which leads to immunodeficiency
- Infections: Measles, Malaria, Leprosy and HIV- impair T cell function and sometimes B cells
- Drugs: glucocorticoids and cytotoxic chemokines- decrease circulating lymphocyte number as they decrease proliferation
Severe combined immunodeficiency
Rare but fatal if not treated before the age of 1. Can affect B cells, T cells and natural killer cells. Lymphocyte deficiency and failure of thymic development due to inherited abnormalities. Causes severe deficits in cellular and humoral immunity. Diverse genetic causes
Types of SCID:
1) Common gamma chain deficiency
2) Adenosine deaminase (ADA) deficiency
3) JAK3 kinase deficiency
4) MHC class 2 deficiency
5) Recombinase deficiency (RAG)
SCID- common gamma chain deficiency
Most common by far, X-linked inheritance, women can be carriers. Family history in 40% of cases. Defect in the gene that encodes the cytokine receptor which encodes the common gamma chain. Affects T and natural killer cells. Causes 60% of SCID cases. Phenotype- absence of T cells and natural killer cells and normal B cell numbers. Diagnosed through looking at gamma chain protein levels and gamma chain gene mutations
SCID- Adenosine deaminase (ADA) deficiency
Autosomal recessive pattern of inheritance, need both parents to have the gene. Mutation in the ADA gene which leads the absence or low levels of the ADA enzyme which is involved in purine metabolism. Without this enzyme there is a build up of toxic metabolic products causing abnormal immune cell development and non-immune symptoms like deafness, abnormal bone development and slow CSF. Causes about 15% of SCID cases.
Phenotype, diagnoses and treatment of ADA (SCID)
Phenotype- absence of T lymphocytes, Natural killer cells and B cells.
Diagnosed- look at enzyme levels of ADA.
Treatment: PEG-ADA (enzyme replacement therapy) weekly via intramuscular injection.
SCID epidemiology
4 times as many men get it then femailes, it is classified by inheritance patterns and the lymphocytes present
SCID- clinical features
- Usually presents in 3-6 month olds
- Experience severe and life threatening infections
- Opportunistic infections
- Infections from live vaccines i.e. rotavirus
- Failure to thrive
- Chronic diarrhoea and thrush
Diagnosis of SCID
Decreased number of T cells, poor proliferation to mitogens (growth factors). Variable number of B cells, low immunoglobulins. You need further blood tests and a genetic test for diagnosis
Management of SCID
- Isolation until definitive treatment- in a specialised ward at hospital. Immediate treatment
- Prophylactic medication- antibiotics, antivirals and antifungal
- Immunoglobulin therapy
- Blood transfusions- must be heat treated and negative for Cytomegalovirus (CMV) which can cause severe infections in SCID. Can be transferred by breast milk so the mother must be tested.
- If they have ADA they can be given PEG-ADA
- Avoid live vaccinations- Rotavirus and MMR
Definitive treatment for SCID
Haematopoietic stem cell transplantations- should be given by direct relative if the match is not positive chemotherapy should be given but some patients may be too sick for that. Most effective if done straight after birth. Gene therapy- can be done in ADA.
Phagocyte immunodeficiencies
Commonly cause extracellular bacterial infections i.e. s.aureus and pseudomonas as well as fungal infections like Aspergillus. Commonly occur at the interface between host and environment. For example- skin (abscesses), respiratory tract (pneumonia), GI tract (diarrhoea), deep seated infections and Granulomatous inflammation.
Diagnosing phagocyte immunodeficiencies
Granulocyte function tests, measure the level of superoxide radical production by granulocytes to kill bacteria and fungi. Also looks at the ability of cells to phagocytose and move towards stimuli.
Treatment for phagocyte immunodeficiencies
Granulocyte- colony stimulating factor injection or can be treated definitively by a stem cell transplant
Examples of primary phagocyte immunodeficiencies
- Neutropenia
- Leukocyte adhesion deficiency (LAD)
- Chronic granulomatous disease (CGD)
Primary phagocyte immunodeficiencies- Neutropenia
Reduced production or accelerated removal of granulocytes. Can be a primary or secondary immunodeficiency. Can be caused by drugs, autoimmune disease or cancer
Primary phagocyte immunodeficiencies- Leukocyte adhesion deficiencies
Failure to mobilise WBC’s to tissues. Causes rapid spread of the infection systemically. Caused by pyogenic bacteria like S.aureus. Lack of beta2-integrin molecules causes impaired adhesion and extravasion of phagocytes
Primary phagcyte immunodeficiency- Chronic granulomatous disease
Failure to kill infectious organisms, lack of superoxide radical production. Results in localised infections and abscesses. Normally X linked, can be autosomal recessive. Lack of NADPH oxidase impairs killing of ingested pathogens. Is tested by impaired reduction of nitroblue tetrazolium by stimulated neutrophils
Examples of secondary phagocyte deficiencies
- Malnutrition- decrease in natural killer cells and abnormal phagocytosis
- Drugs: Corticosteroids and cytotoxic chemotherapy- decrease phagocytosis
Complement immunodeficiencies
When a protein in the complement system is absent or malfunctioning. Very rare, these disorders arent always diagnosed. Categorised based on the component of the complement system which is affected which can cause different symptoms
Symptoms of complement immunodeficiencies
- Recurrent and or serious bacterial infections which can be pyogenic i.e. streptococci and lead to sepsis
- Autoimmune disease
- Angioedema
Diagnosis of complement immunodeficiency
Total complement activity test (CH50) and specific complement activity test (AH50)
Treatment of complement immunodeficiencies
No specific treatment, clinical features are treated as they arise
Complement immunodeficiencies- defects in the classical pathway
Immune complex disease. Classical pathway is responsible for clearing immune complexes and dying cells. Can cause autoimmune disease like Lupus
Complement immunodeficiencies- defects in the alternate pathway and C3
Cause similar problems to an antibody deficit. Inability to clear extracellular polysaccharide, encapsulated and pyrogenic bacteria. As there is no compliment opsonisation of bacteria for phagocytosis. For example, Neisseria spp. Cause under activation of the compliment system, increasing susceptibility to infection.
Complement immunodeficiencies- C1 inhibitor deficiency
Causes overactivation of the compliment system (hereditary angiodema). Can be treated with a C1 inhibitor concentrate
Examples of secondary complement deficiencies
- Osteomyelitis- infection of the bone
- Endocarditis- infection of the lining of the heart
- Treatment with Eculizumab- a C5 inhibitor, used for the treatment of blood disorders
