Immunology - Immune Deficiences Flashcards by Natasha Hadfield

What are the major hallmarks of immune deficiency?

Serious Infections

Persistent Infections

Unusual Infections

Recurrent Infections

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What is a feature of Serious Infection?

Unresponsive to antibiotics

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What are features of persistent infections?

Early structural damage

Chronic infection

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What are features of unusual infections?

Unusual organisms

Unusual sites

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How are recurrent infections defined?

Two major

One major and recurrent minor infections in one year

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What other features may be suggestive of primary immune deficiency?

Weight loss/failure to thrive

Severe skin rash

Chronic diarrhoea

Mouth ulceration

Unusual autoimmune disease

Family history

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How are immunodeficiencies classified?

Primary

rare 1:10,000 live births

> 100 now described

Secondary

common

often subtle

often involves more than one component of immune system

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What are clinical features of phagocyte deficiency?

Recurrent infections at both common and unusual sites

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Which organisms are associated with phagocyte deficiency?

Common bacteria, e.g. Staph Aureus

Unusual bacteria, e.g. Burkholderia cepacia

Mycobacteria (both TB and atypical)

Fungi - candida, aspergillus

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Why may treatment for leukaemia cause serious bacterial infection?

Neutrophils numbers fall to very low levels - neutropaenia

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Where can things go wrong in the life cycle of a neutrophil?

Mobilisation from bone marrow or within tissues

Adhesion and migration into tissue

Phagocytosis

Activation of other immune components

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What are examples of failure to produce neutrophils?

Failure of stem cells to differentiate along myeloid lineage:

Recticular dysgenesis - primary defect

After stem cell transplantation - secondary defect

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Give examples of the failure of neutrophil maturation.

Kostmann syndrome - severe congenital neutropaenia, autosomal recessive

Cyclic neutropaenia - episodic neutropaenia every 4-6 weeks

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What is the clinical presentation of Kostmann syndrome?

Infections usually within 2 weeks after birth

Recurrent bacterial infection, may be systemic or localized

Fever

Irritability

Oral ulceration

Failure to thrive

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What is the management of Kostmann syndrome?

Prophylactic antibiotics

Prophylactic antifungals

Stem cell transplantation

Granulocyte colony stimulating factor (G-CSF) to assist maturation of neutrophils

WIthout definitive treatment 70% mortality in first year.

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What is the clinical picture of Leukocyte adhesion deficiency?

Marked leukocytosis

Localised bacterial infections that are difficult to detect

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What is leukocyte adhesion deficiency?

Rare primary immunodeficiency caused by genetic defect in leucocyte integrins (CD18) resulting in failure of neutrophil adhesion and migration

What is chronic granulomatous disease?

Deficiency of intracellular killing mechanisms of phagocytes:

inability to generate oxygen free radicals

impaired kiling of intracellular microorganisms

Commonest form is X-linked (NADPH oxidase)

Why are granulomas formed in Chronic Granulomatous Disease?

Inability to clear organisms leads to persistant accumulation of neutrophils, activated macrophages and lymphocytes resulting in granuloma formation.

What are the features of chronic granulomatous disease?

Recurrent deep bacterial infections

Staph, Aspergillus, pseudomonas, mycobacteria

Recurrent fungal infections

Failure to thrive

Lymphadenopathy

Hepatosplenomegaly

Granuloma formation

How is chronic granulomatous disease investigated?

NBT (nitroblue tetrazolium) test

Dye changes colour if neutrophils produce H₂O₂.

What is the management for chronic granulomatous disease?

prophylactic antibiotics

prophylactic antifungals

Stem cell transplantation

(gene therapy)

Which organisms tend to hide from immune system within cells?

Salmonella

Chlamydia

Ricksettia

Mycobacteria (within macrophages)

Defects in which axis are associated with susceptibility to intracellular bacteria?

IL12-gIFN axis

What is involved in the IL12-gIFN axis?

IL12 secreted by macrophage induces T cells to secrete gIFN gIFN stimulates production of TNF TNF activates NADPH oxidase stimulating oxidative pathways killing intracellular bacteria

What is an important side effect of anti-TNF drugs?

Reactivation of latent TB

What is severe combined immunodeficiency?

Failure of production of lymphocytes from stem cells

What is the clinical presentation of severe combined immunodeficiency?

Unwell by 3 months age Persistant diarrhoea Failure to thrive Infections of all types including vaccine associated diseases Unusual skin disease - Graft vs host Family history of early infant death

Why does severe combined immunodeficieny present around 3 months of age?

Because the neonate is protected by maternal IgG for the first 3 months of life.

What is transient hypogammaglobulinaemia?

Slow maturation of immune system in normal babies presenting with infection at around 3-4 months

What is the commonest form of Severe Combined Immunodeficiency?

X-Linked SCID Mutation of component of IL2 receptor resulting in inability to respond to cytokines Failure of T cell and NK cell development Production of immature B cells

What is the clinical phenotype of X-linked SCID?

Very low or absent T cells Normal or increased B cells Poorly developed lymphoid tissue and thymus

What is the treatment for SCID?

Prophylactic Antibiotics Prophylactic Antifungals No Vaccines Aggressive treatment of infection Antibody replacement - IV Ig **Stem cell transplant** (HLA identical sibling if possible)

What is DiGeorge syndrome?

Deletion of chromosome 22q11 Developmental defect of 3rd/4th pharyngeal pouch Low set, abnormally folded ears High forehead, cleft palate, small mouth and jaw Hypocalcaemia (secondard to hypoparathyroidism) Oesophageal Atrasia T cell lymphoma Complex congenital heart disease

What kind of infections is a child with DiGeorge syndrome susceptible to?

viral (CD8 T cells) bacterial (CD4 T cells) fungal infections

What laboratory results would point to DiGeorge syndrome?

Absent/decreased T cells Normal or increased B cells Low IgG, IgA, IgE Poor antibody response to specific pathogens Normal NK cell numbers

What is the management of DiGeorge syndrome?

Correct metabolic/cardiac anomalies Prophylactic antibiotics Aggressive treatment of infection Immunoglobulin replacement T cell function improves with age

What are the clinical features of T cell deficiencies?

Recurrent viral, bacterial, fungal, intracellular pathogen infections Opportunistic infections Malignancies at young age Autoimmune disease

What is the presentation of antibody deficiences?

Recurrent bacterial infections, often common organisms - LRTI, URTI, GI Viral infections are less common but may occur Antibody mediated autoimmune disease: Idiopathic thrombocytopaenia Autoimmune haemolytic anaemia

What is Bruton's X-linked hypogammaglobulinaemia?

Failure to produce mature B cells, resulting in no circulating B cells no plasma cells no circulating antibody after the first 6 months

What is common variable immune deficiency?

Low IgG, IgA and IgE Recurrent bacterial infections - severe end organ damage, bronchiectasis, persistent sinusitis, recurrent GI infection Often associated with autoimmune disease Granulomatous disease

How are B cell deficiencies managed?

Aggressive treatment of infection Immunoglobulin replacement, IV every 3-4 weeks Stem cell transplantation in some situations