Immunodeficiency Flashcards
primary immunodeficiency
more than 250
caused by an inherited defect of either nonspecific innate or specific adaptive immune defences
increased susceptibility to infection
- humoral immune deficiency (B cells) (e.g. primary humoral, multiple myeloma, CLL, AIDS)
- chronic granulomatous disease (granulocyte deficiency)
- SCID
generally grouped lymphocytes or granulocytes
chronic granulomatous disease (CGD)
defect in NADPH oxidase system of phagocytic cells including neutrophils and macrophages which prevents production of superoxide radicals in phagolysosomes so cannot phagocytose.
infections therefore persist longer and lead to a chronic local infection called a granuloma
common microorganisms associated wtih CGD:
- aspergillus spp
- staph aureus
- chrombacterium violaceum
primary immunodeficiency B cell:
X linked agammaglobulinaemia
(Bruton’s agammaglobulinaemia)
lack of a specific antibody known as X linked recessive agammaglobulinaemia
defective gene BTK in XLA. unable to produce Btk therefore b cell maturation and differentiation halts so no immunoglobulins are produced. there is abnormal b cell development an deficiency in all classess of immunoglobulins.
*onset usually 4 months of age (after maternal IgG has decreased)
recurrent infections almost exclusively to extracellular pathogens:
- haemophilus influenza
- streptococcus pneumoniae
- s pyogens
- s aureus
hypoplasia of lymphoid tissues (tonsils, lymph nodes)
ix: absent or low B cells, normal t cells, low immunoglobulins of all classes
(cell mediated is not impaired so not as vulnerable to virus or intracellular pathogens)
primary immunodeficiency
selective IgA deficiency
most common inherited form of immunoglobulin deficiency 1 in 800 people.
normal levels of IgG and IgM but cannot produce IgA.
predisposed to lung and GI infections (IgA is normally an important defence mechanism- it is present in mucous membranes suh as saliva, resp tract secretions, GI secretions, tears and sweat)
- mild and often not diagnosed
- likely to come across when testing for ceoliac. IgA anti TTG and anti EMA so important to test IgA as you could have negative test if the IgA is low.
H influenzae, S pnueoniae, Moraxella catarrhalis, S aureus, Giardia lamblia, E coli
common variable immunodeficiency
genetic mutation in genes coding for components of B cells. body is unable to make antibodies (hypogamaglobulinaemia)
deficiency in IgG and IgA with or without deficiency in IgM (despite a normal number of B cells)
symptoms:
recurrent respiratory tract infections, chronic lung disease over time. sinusitis, pneumonia, bronchitis, otitis, conjunctivitis, GI infection, GI disease. prone to RA, cancers such as non-hodgkins lymphoma
mx: immunoglobulin infusions and treat infections
Ix: low IgG, IgA and IgM. low plasma cells. normal b cells / t cells. poor response to immunizations
the decreased ability of the immune system to clear infections in patients may be responsible for causing autoimmunity. CVID- mltiple autoimmune dsieases are seen (IBS, autoimmune thromboyctopenia, thyroid)
SCID - severe combined immunodeficiency (pathophysiology)
(combined immunodeficiency)
B cell and T cell defects which impairs the T cell dependent antibody response as well as cell mediated response
cannot develop immunological memory
most common form is X linked. mutation in the common gamma chain that odes for interlukin receptor on T and B cells. other gene mutations include JAC3 gene or mutations leading to adenosine deaminase deficiency
diagnosed in first few months of life.
severe often life threatening opportunistic infections- candida, pneumocystis jirovecci, Ecoli
*bone marrow transplant
SCID and vaccines
vaccines cannot provide protection as they cannot develop immunological memory
live attenuate vaccines (varicella, measles, rotovirus, poliovirus) can actually cause the infection they are intended to prevent
Omenn syndrome and SCID
Omenn syndrome is a rare cause of SCID
caused by the mutation in the recombination activating gene (RAG1/RAG2) which is needed for coding important proteins in T and B cells. autosomal recessive inheritance
The syndrome is caused by abnormally functioning and deregulated T cells that attack the tissues in the fetus or neonate. This leads the classic features of Omenn syndrome:
A red, scaly, dry rash (erythroderma) Hair loss (alopecia) Diarrhoea Failure to thrive Lymphadenopathy Hepatosplenomegaly
SCID management
atal unless successfully treated.
specialist immunology centre. treating underlying infections, immunoglobulin therapy, minimising the risk of new infections with a sterile environment, avoiding live vaccines and performing haematopoietic stem cell transplantation.
secondary immunodeficiency
as a result of acquired impairment or function of B cells, T cells or both
can be caused by
1. systemic disorders e.g diabetes, malnutrition, HIV, hepatitis
- immunosuppressive treatment e.g. cytotoxic chemotherapy, bone marrow ablation before transplantation, or radiation therapy
- prolonged critical illness due to an infection, surgery, trauma in young/elderly/hospitalised patients
increased susceptibility to an otherwise benign infection by opportunistic pathogens such as Candida spp., P. jirovecii, and Cryptosporidium.
AIDS
T cell deficiency
acquired immunodeficiency syndrome
profound CD4 t cell lymphopenia
other T cell deficiencies- marrow and other transplant, AIDS, cancer, chemotherapy, lymphoma, glucocorticoid therapy.
complement disorders
disorders that affect the complement proteins to make up the complement system and destroy pathogenic cells
- haemophilus influenza B
- streptococcus pneumoniae
- nisseria meningitidis
vulnerable to certain infective organisms leading to recurrent infections. linked with immune complex disorders e.g. SLE as incomplete complement leads to immune complex build up in tissues.
important to vaccinate against encapsulated organisms
C1 esterate inhibitor deficiency
bradykinin is important part of inflammatory response (blood vessel dilation, increased vasuclar permeabiltiy= angiodema)
c1 esterase is responsibly for inhibiting bradykinin so in it’s absence there is intermittent agniodema (triggers= stress, vrial infection, random)
face, lips, resp, GI, larynx
treat with IV c1 esterase inhibitor prophylaxis
check c4 levels
mannose binding lectin deficiency
deficiency leads to inhibition of the alternative pathway.
if already susceptible to infection (CF) then can lead to more severe variant of the disease
T cell disorder
- DiGeorge syndrome
- Purine Nucloeside Phosphorylase Deficiency
- Wiskott-Aldrich syndrome
- Ataxic Telangiectasia
Di George syndrome
DiGeorge syndrome, also called 22q11.2 deletion syndrome, results from a microdeletion in a portion of chromosome 22 that leads to a developmental defect in the third pharyngeal pouch and third branchial cleft. One of the consequences of this is incomplete development of the thymus gland. An underdeveloped thymus gland results in an inability to create functional T cells.
Features of DiGeorge syndrome can be remembered with the CATCH-22 mnemonic:
C – Congenital heart disease
A – Abnormal facies (characteristic facial appearance)
T – Thymus gland incompletely developed
C – Cleft palate
H – Hypoparathyroidism and resulting Hypocalcaemia
22nd chromosome affected
Purine nucleoside phosphorylase deficiency
Purine nucleoside phosphorylase (PNP) deficiency is an autosomal recessive condition. PNPase is an enzyme that helps breakdown purines. Without this enzyme, a metabolite called dGTP builds up. This metabolite is exclusively toxic to T cells. Increased levels of dGTP causes low levels of T-lymphocytes. There are normal levels of B cells and immunoglobulins. Clinically, patients immunity to infection gradually gets worse. They become increasingly susceptible to infections, particularly viruses and live vaccines.
Wiskott Aldrich syndrome
Wiskott-Aldrich syndrome (WAS) is an X-linked recessive condition with a mutation on the WAS gene. It causes abnormal functioning of T cells. Other features include:
Thrombocytopenia Immunodeficiency Neutropenia Eczema Recurrent infections Chronic bloody diarrhoea
Ataxic telangiectasia
Ataxic telangiectasia is an autosomal recessive condition affecting the gene coding for the ATM serine/threonine kinase protein on chromosome 11. This protein is important in several functions of DNA coding, meaning that a mutation in this gene leads to problems coding for many other genes.
There are various features of the condition:
Low numbers of T-cells and immunoglobulins, causing immunodeficiency and recurrent infections.
Ataxia: problems with coordination due to cerebellar impairment
Telangiectasia, particularly in the sclera and damaged areas of skin
Predisposition to cancers, particularly haematological cancers
Slow growth and delayed puberty
Accelerated ageing
Liver failure
SCID investigations
PCR- low TRECs
absent T cells, b cells and NK cells
CXR absent thymic shadow
lymph node biopsy- absent germinal centres
criteria for CVI
- hypogammaglobulinaemia with IgG leveles 2 SD below mean
- impaired vaccien response / absent isohaemagglutinins
- exclusion of other causes of hypogammaglobulinaemia
decrease IgG, IgA or IgG, Ig A and IgM or t-cell defects (variable)
investigations for CVI
- Bedside
- Temperature
- Sputum – if productive cough present for MC&S
- Stool – If persistent diarrhoea/GI infections Giardia Lambia, salmonella, shigella and campylobacter. - Bloods
- FBC Serum IgA and IgG levels (decreased not absent)
- Serum IgM (can be decreased)
- Circulating T and B lymphocytes by flow cytometry
Imaging
- CXR
- High-resolution CT of chest – pulmonary abnormalities.
Special Functional response to killed polysaccharide vaccines (serum levels of Ab to vaccine antigens).
Genetics/Mutations
ICOS (inducible co-stimulatory)
TACI (mutations in cell receptor)
Lymph Node/ Other Biopsy – Histology may show: - - Granulomatous - Inflammation, - Atypical Hyperplasia. - Reactive follicular hyperplasia.
Bronchoscopy/Endoscopy – specific lesions or infective processes
management of CVI
MDT
Review (low threshold for treating with abx)
support group (PID UK)
education
*avoid attenuated / live and inactive vaccine
influenza vaccine to be given annually
elevating care if low IgG, development of pesistet infections despite therapy.
medical: abx, corticosteroids, three weekly IgG replacement >7.8g/L aim
SCID signs and symptoms
Chronic diarrhoea
Failure to thrive
Recurrent severe infections
Recurrent fevers -
Persistent mucocutaneous candidiasis -
Infections with common viruses often fatal
Opportunistic infections with usually non pathogenic organisms such as PCP
Attenuated vaccines (oral polio, rotavirus, varicella, BCG) may cause fatal infection
EXAMINATION FINDINGS Diagnosis is often delayed, as infants look normal. Peripheral lymphoid tissue (tonsils, adenoids, LNs) may be absent. Absence of thymic shadow on CXR.
invesitgations for SCID
investigate / suspect in children with unexplained lymphopenia, recurrent fevers, failure to thrive, chronic diarrhoea, recurrent severe thrush, mouth, ulcers, RSV, HSV, measels, influenza
bedside: height/weight decie
bloods: low lymphocyte, absent t cells, hypogammaglobulinaemia
imaging; CXR (Absent thymus)
special: newborn screening
SCID management
Conservative
MDT Paediatrics, immunology, microbiology, dietician
Review (when, by whom) Regular and managed by secondary care Lifestyle
Modification Protective isolation Medical
Acute Management (attack/complication) Protective isolation Immunoglobulin replacement treatment of acute infections
Long term Management Hematopoietic cell transplant Avoidance of live virus vaccines All blood products must be irradiated, leukodepleted and CMV negative
exampels of 2’ immunodeficiency
diabetes dialysis cirrhosis malnutrition disorders of protein loss environmental (DNA damage) trauma/burns normal life event- ageing, pregnancy, major life stress infection biologics and other immunosupressive drugs
secondary immunodeficiency
can result from a wide array of disease processes. increases susceptibility to infection, malingnacy and autoimmune disease
chronic imbalance in hormones, metabolism, nutrients or waste product
neutrophil dysfunction secondary to hyperglycaemia predisposes bacterial and fungal infection
poor peripheral circulation leads to impaired delivery of neutrophils
dialysis and uraemia in 2’ immunodeficiency
Haemodialysis: Impaired T cell function, reduced antibody production and altered neutrophil and dendritic cell function. Neutrophils may be partly impaired due to effects of dialysis membrane.
Peritoneal dialysis: Less effect on immune system however any immune cells within peritoneum washed out with dialysate. Indwelling foreign body increases risk of bacterial peritonitis.
cirrhosis: reduced hepatic metabolism leads to higher circualting glucocorticoids. shunting of portal blood- reduces avilality of kupffer cells to celar opsonised particles. less opsonisation occrus due to reduced complement
2’ immunodeficiency malnutrition
Protein energy malnutrition associated with; -Impaired epithelial barrier function of skin & gut -Reduced levels of IgA in saliva & tears -Fewer circulating cells and complement proteins -Lymphoid organ atrophy & lymphocyte hyporesponsiveness -Reduced vaccine responsiveness Zinc, iron, folate, pyridoxine & Vit A deficiency also associated with immune dysfunction.
disorders of protein loss:
nephrotic syndrome: hypogammaglobulinaemia from renal losses. Associated with recurrent LRTI, UTI, peritonitis & sepsis especially encapsulated bacteria. Protein-losing enteropathies: Coeliac, IBD. Measure stool alpha-1 antitrypsin Intestinal lymphangiectasia: Abnormal dilation of intestinal lymphatics
trauma and burns 2’ immunodeficiency
SIRS (widespread activation of monocytes and macrophages by products of cellular necrosis)- results in an immunosuppressed state CARS (compensatory anti-inflammatory response syndrome).
normal life events 2’ immunodeficiency
Aging: Immune dysfunction with aging Pregnancy: Multifactorial & not well understood but theorised immunosuppression helps inhibit rejection of fetus Major life stress: observational increase in reported infections. Lab studies showed reduced NK cell activity & lymphocyte responses
infection causing 2’ immunodeficiency
Radiation: DNA damage, induces apoptosis, B cells sensitive
HIV, Malaria, herpes virus Measles: global immune suppression leading to bacterial superinfection
drugs causing 2’ immunodeficiency
Rituximab: Targets B cells Abatacept: Targets T cells Anti TNF: infliximab, etanercept Azathioprine: Purine antimetabolite. Affects DNA replication in rapidly dividing cells (T cells, B cells- inducing apoptosis) Cyclophosphamide: Prevents cell division by cross linking DNA. Methotrexate: Folate antagonist. Corticosteroids: Reduce neutrophils ability to adhere to endothelium which is why you get a raised neutrophil count on steroids. Impairs neutrophil migration to sites of inflammation. Promotes eosinophil apoptosis. Suppress mast cells and cytokines. Inhibition of phagocytosis. Cyclosporin: blocks cytotoxic T cell activation
diabetes and 2’ immunodefiency
a Hba1c of >7% indicates poorly controlled diabetes and therefore immunosupressoin with susceptibility to infection
impaired neutrophil and macrophage function (chemotaxis, phagocytosis and intracellular killing)
Neutrophil dysfunction secondary to hyperglycaemia predisposes to bacterial and fungal infections. Poor peripheral circulation leads to impaired delivery of
neutrophils. Hyperglycaemia also impairs chemotaxis & phagocytosis.
