Immunodeficiencies Flashcards
PERIODIC FEVER SYNDROMES
PFAPPA, FMF
PFAPPA- Periodic Fever Apthous
FMF- Famillial Mediterranean Fever Syndrome
Antibody deficiencies- Selective IgA deficincy
Selective IGA deficiency
- Most common/benign
- Onset 6mo (after maternal)
- Low IgA, other immunoglobulins normal
Low IgA (<7mg/dL), normal IgG/D/M – less protection against resp/GI infection (mucous membranes)
Features:
- Most asymptomatic, recurrent sinopulmonary/GI infections
- Asthma/atopy
- Increased autoimmune disorders, anaphylaxis to blood containing IgA
Combined immunodeficiency
WISKOTT-ALDRICH SYNDROME
Define, outline features & inheritance pattern, natural history, investigations & treatment
Wiskott Aldrich Syndrome: combined immunodeficiency syndrome
TIME: Thrombocytopoenia, Immunodeficiency, Malignancy risk, Eczema
Genetics:
X-Linked inheritance
Xp11.22-23 → gene codes for WASP protein which controls actin filaments involved in protein kinase C/tyrosine kinase signaling
Leads to impaired humoral responses to polysaccharide antigens/diminished isohaemagglutinins (poor/absent antibody response following polysaccharide containing vaccinations)
- *Clinical features**
- *Immune deficiency**
- Infections due to encapsulated bacteria, commensal fungi,
- Otitis media, pneumonia meningitis and sepsis – polysaccharide capsules eg. strep pnuemo
- PJP
- Herpesviruses - EBV/CMV
- *Bleeding diathesis**
- Thrombocytopenic purpura, with normal appearing megakarocytes but small defective platelets
- Prolonged bleeding from circumcision or bloody diarrhoea
- *Malignancy- leukemia & lymphoma**
- *Eczema**
- *Prone to autoimmune conditions- ITP**
- *Natural history**
- Presents first year of life, survival beyond adolescence rare
- Bleeding, infections & malignancy common cause of mortality
- *Investigations:**
- FBE: Thrombopenia
- Immunoglobulins: IgG2 normal, variable levels of other Igs- (A,G,M)- high IgA/M
- Subsets: Reduced % T cells
- Depressed lymphocyte mitogen response
- WASP protein flow cytometry/ gene sequencing
- *Treatment**
- Prophylactic ABx
- Monthly IVIG
- Platelet infusions
- Splenectomy (maintains platelet count)
- HSCT if severe
Phagocyte disorders
CGD
What are some common infection sites/organisms involved for patients with CGD
Sites of infection — the most common sites of infection are lung, skin, lymph nodes, and liver. The types of infections most often seen (in descending order of frequency) include:
- Pneumonia
- Abscesses (skin, tissue, organs)
- Suppurative adenitis
- Osteomyelitis
- Bacteremia/fungemia
- Superficial skin infections (cellulitis/impetigo)
Pneumonia is the most common pulmonary infection, but patients may also have lung abscesses, empyema, and hilar lymphadenopathy. In contrast to what occurs in neutropenic patients, fungal pneumonias do not generally cavitate in CGD, whereas Nocardia infections do.
The most common sites for abscesses are perianal/perirectal and the liver. Gingivitis, stomatitis, gastroenteritis, and otitis are also common.
Organisms
In general, the organisms that infect patients with CGD are catalase-producing and include Staphylococcus aureus and Aspergillus species.
Catalase is an enzyme that inactivates the hydrogen peroxide normally produced by some bacteria and fungi during growth. However, the majority of pathogens are catalase-positive, and only a few cause infections in CGD, suggesting that catalase production alone is insufficient for pathogenicity.
i.e. Microbial catalase is not a significant virulence factor for CGD infections.
The overwhelming majority of infections in North America are due to five organisms:
- Staphylococcus aureus
- Burkholderia (Pseudomonas) cepacia
- Serratia marcescens
- Nocardia
- Aspergillus
Outside of North America, Salmonella and BCG are frequent infections and should suggest the diagnosis.
‘CATs have BeeN PLACESS’
- Burkholderia
- Nocardia
- Pseudomonas
- Listeria
- Ecoli
- Staphylococcus
- Serratia
XMEN
XMEN disease is also associated with EBV related lymphoma but patients have chronic infection rather than an acute episode. It is caused by a mutation of the gene encoding magnesium transporter 1
Nijmegen breakage syndrome (NBS)
NBS is caused by mutations in the nibrin (NBN) gene on 8q21 that encodes the protein nibrin. Patients have progressive, severe microcephaly. They also have intrauterine growth retardation and short stature, immunodeficiency with recurrent sinopulmonary infections and are susceptible to developing lymphomas.
BLOOM SYNDROME
Outline inheritance, characteristic features and common populations affected
Bloom syndrome, an autosomal recessive disorder which has increased risk of malignancy. Children have recurrent infections, short stature & a characteristic appearance and develop an erythematous photosensitive rash in the first two years of life. Bloom syndrome is a rare disorder but especially prevalent among the Ashkenazi Jewish population. Although it is rare, it is common in exams.
SCHIMKE IMMUNEOSSEOUS DYSPLASIA
Outline inheritance & features
Schimke immuneouseous dysplasia is an autosomal recessive disorder (SMARCAL1- chromatin remodelling) which presents with short stature, spondyloepiphyseal dysplasia, IUGR, immunodeficiency and progressive renal failure. Children may also have skin and eye abnormalities. Any child who presents with short stature and recurrent infections should have renal function tested. Children with Schimke immuneouseous dysplasia develop nephrotic syndrome secondary to focal segmental glomerulosclerosis and will progress to renal failure.
Antibody deficiencies- Hyper IgM
Hyper IgM
- X-linked recessive disorder
- Defect in CD40L on T lymphocytes– prevents class switching
- IgM only, unable to make other (low G,A,E)
- Onset >6mo age
Features:
- Commensal infections (PJP, cryptosporidium, CMV, encapsulated bacteria)
- Chronic infections can lead to cholangiocarcinoma
- Predisposition to neuroectodermal tumours
Diagnosis:
Elevated IgM, reduce IgG,A,E
Deficient CD40L expression on CD4+ T cells
Treatment:
- Lifelong IVIG
Antibody deficiencies- X-linked agammaglobulinemia
- *X-Linked Agammaglobulinemia**
- 85% of congenital agammaglobulinemia’s
- 2-3million kids in UK affected
- BTK gene (Colonel Bruton) - also on myeloid/erythrocytes
- 157 identifiable mutations, less common monogenic/autosomal (if female/normal BTK)
- On long arm of X chromosome
- Promoted B cell proliferation/differentiation
- Failure of B-cell maturation, normal T cells but reduced repertoire
Presentation
Present 4-6mo after waning of maternal IgG
Absent tonsils/adenoids
Male patient
Low mature CD19+ B cells - low in blood & lymphoid tissue (), plasma cells absent
Defective immunoglobulin production- IgG, A & M
Lack of mucosal IgA/M leads to ongoing impaired function despite IVIG
Predisposed to recurrent infections
- Encapsulated- Strep Pneumonia, Haemophillus Influnza, Giardia, Salmonella, Campylobacter, Enterovirus (polio, coxsackie), HSV, low incidence of PJP (usually neutralised by IgA in gut)
- Pneumonia 40%, ENT infections 35%, gastro/chronic diarrhoea 30%, skin infections 30%, CNS infections 5-10%, ho
Diagnosis
<2% CD19+ B cells in male patient
Low serum IgGs (<200mg/dl), IgG,A,M (<400mg/dl), absence of IgM/A after infancy
Positive FHx
BTK gene
Vaccine responses
Natural history
Infection 1% per year (prev. up to 25%, now)
Majority of patients survive until adulthood
Leading cause of mortality → bronchiectasis 10% 5-8yrs, 30% at 13yrs (pseudomonas/lung infections, functional impact)
Increased incidence of malignancy compared to population, however overall low rates
Treatment
- IVIG (IgG)- lacks IgA & IgM → impaired mucosal immunity
- Aim trough level >8g/L (higher if bronchiectasis)
- Can be screened for in pre-natal period (no standard)- similar to SCID, KRECs (kappa deleting recombination excision circles)
-
X-linked lymphoproliferative disease (XLP)
Outline epidemiology, pathophysiology
X-linked lymphoproliferative disease (XLP) XLP is caused by mutations in the signalling lymphocyte activation molecule (SLAM)-associated protein (SAP) gene. Children appear well until they are infected with EBV – they most commonly present with fulminant infectious mononucleosis during the preschool years but can also present with lymphoma or dysgammaglobulinaemia.
CARTILAGE HAIR HYPOPLASIA
Outline inheritance, etiology, characteristic features
Cartilage-hair hypoplasia: combined immunodeficiency disorder
Genetics
Autosomal recessive
9q21-p13 → defectiv RNAse MRP gene (RMRP)
→ cleaves RNA into mitochondrial DNA
→ leads to decreased T cell counts and defective T cell proliferation
→ defective antibody mediated immunity
- *Features**
- Immunodeficiency (frequent infections, )
- Short limbed dwarfism - scalloping & sclerotic changes to bones
- Hypermobile joints
- Sparse, fine hair & redundant skin
- Children have increased risk of Hirschsprung disease, haematological malignancies and autoimmune disorders
T cell dysfunction: Di George
Di George
- 22q11 deletion
- Developmental midline defects
- Thymic hypoplasia (no mature T cells)
- CATCH22 (congenital heart defects, abnormal facies, thymic aplasia, cleft palate, hypocalcemia)
Thymic hypoplasia:
- Mild to mod (not fatal), complete = fatal within 1st year of life
Diagnosis:
- In vivo: delayed hypersensitivity
- In vitro: low lymphocytes (<1.5 at 5yrs), T cell function tests (mitogen proliferation test), genetics (FISH)
Combined immunodeficiency- SCID
- *SCID (Severe combined immunodeficiency)**
- Gene mutations- affect functional B & T cell development
- ABSENT adaptive immunity
- Presents in infancy
Features:
- Serious infections (including commensal pathogens)
- Poor growth,
- Diarrhoea
Investigations:
- Low absolute lymphocyte (<2.5), low T cells (<20%), low mitogen response (<10% compared to control)
- High mortality rate in 1st year
Treatment
- HSCT before 3mo
- Sterile environment, antibiotic (PJP- bactrim) /antifungal prophylaxis
- Monthly IVIG
Chronic Granulomatous Disease (CGD)
Define CGD, what is the pathophysiology, how is it diagnosed and where are common sites of infection?
Chronic granulomatous disease (CGD) is a genetically heterogeneous condition characterised by recurrent life-threatening bacterial and fungal infections and granuloma formation. CGD is caused by defects in the phagocyte NADPH oxidase (phox). These genetic defects result in the inability of phagocytes (neutrophils, monocytes, and macrophages) to destroy certain microbes.
The diagnosis is made by neutrophil function testing and then the exact defect is determined by genotyping.
Infections are generally caused by catalase-positive microorganisms (most bacterial and all fungal pathogens are catalase-positive). The frequent sites of infection are lung, skin, lymph nodes, and liver. The formation of granulomata is especially problematic in the gastrointestinal and genitourinary tracts. Other inflammatory manifestations are seen as well.
Infections
- Patients with CGD typically experience recurrent infections caused by bacterial and fungal pathogens. However, CGD patients may exhibit few clinical signs and symptoms, despite the presence of significant infection.
- Response to viral infections is normal in patients with CGD.
- Bacterial infections in CGD tend to be symptomatic and are associated with fever and mildly elevated leukocyte counts.
- In contrast, fungal infections are associated with less fever and lower leukocytosis and are therefore more difficult to diagnose.
- Fungal infections are often detected either at asymptomatic stages on routine screening for infections or at an advanced stage.
Combined immunodeficiency- ataxia-telangectasia
Ataxia-Telangectasia
- ATM protein mutation (autosomal recessive)
- Ususally repairs damaged DNA
Features:
- Ataxia by 2yrs, telangiectasia eyes by 5ys, skin 7rs, increased malignancy risk (lymphoma, leukemia)
- Sinopulmonary infection
Diagnosis
- Low IgG, IgA, IgE, T cell
- Low ATM protein on RBC culture
Treatment:
- IVIG, antibiotic prophylaxis
Phagocyte deficiencies- LAD
Leukocyte adhesion deficiency
- After birth
- Autosomal recessive genetic
- Lack adhesion molecules (CD18/integrim, Sialyl-Lewis X)- unable to pass BV wall to travel to site of infection
Features:
- Skin (cellulitis), bone & joint (OM/septic arthritis), respiratory (pneumonia)- no pus/abscesses
- Resistance to viral infection
- Delayed umbilical cord degeneration
- Bugs:
Diagnosis:
- Neutrophilia (WBCs trapped in circulation) 30-150
- Flow cytometry to CD18
Treatment:
- Prophylactic ABx
- HSCT
Phagocyte deficiencies
Chediak Higashi Syndrome
- Infancy/early childhood
- Autosomal recessive
- Mutation in lysosomal trafficking regulator protein – impairs neutrophil phagocytosis
Features:
- Recurrent severe bacterial & fungal infections
- Albinism
- Peripheral neuropathy (sensory)
Investigations:
- Low neutrophil (<1,1.5), BM smears show giant granules/inclusion bodies
Treatment:
- Antibiotic/antifungal prophylaxis, HSCT
Complement deficiencies
Classical pathway (Autosomal recessive)
- C1-4: autoimmune conditions (i.e SLE)
- C3 deficiency: recurrent bacterial infections - encapsulated (strep/Hib)
- C5-8: formation of MAC (late teenage) – recurrent Neisseria (meningitis, sepsis, arthritis)
- C9 asymptomatic
Alterntive pathway (X-linked)
- Properdin
- Lectin
Complement function (CH50/CH100)- then specific Treatment: antibiotics, vaccination- Hib/pneumococcal
Omenn Syndrome (variant of SCID)
Stem: A child with eczema, recurrent infections and recombinase activating gene 1 defect.
- Recombinase activating gene 1 defect and recombinase activating gene 2 defect (RAG1 and 2)
- Variant of SCID (severe combined immunodeficiency)
- Present with recurrent infections, exudative erythroderma, lymphadenopathy, hepatosplenomegaly, chronic persistent diarrhoea, and failure to thrive.
Netherton Syndrome
Stem: A child with eczema, recurrent infections, raised serum immunoglobulin E (IgE) and trichorrhexis invaginata.
Disorder of skin, hair & immune system
Bad icthyosis
Trichorrhexis invaginata of hair is also known as “bamboo hair” → pathognomonic of Netherton syndrome.
- Netherton syndrome is a severe disorder of cornification caused by (SPINK5) mutations.
- DDx Menkes disease is also known as ‘kinky hair disease’ but is not associated with eczema, recurrent infections or raised IgE.
- Children present with seizures and development delay due to genetic disorder leading to severe copper deficiency.
HLH
HLH -Haemophagocytic Lymphohistiocytosis
Syndrome of excess immune activation -> uncontrolled haemophagocytosis (RBC/WBC/platelets in macrophage cytoplasm) and cytokine release(IFN-g, TNF, IL-6,10,12, CD25), lack of down-regulation of macrophages/lymphocytes
Birth-18mo
Fever (>90%), petechial rash, lymphadenopathy/hepatosplenomegaly (7-100%), respiratory/CNS symptoms
Familial/primary: autosomal recessive
- Perforin mutation: lead to inability of perforin to bind with plasma membrane decreased killing
- Munc mutations: decreased monocyte killing
- Syntaxin mutation
- Associated Griscelli Syndrome, Chediak Higashi, Hermansy-Pudlak II, EBV driven in some immunodeficiencies
Secondary
- Viral: EBV, CMV, HSV, VZV, parvovirus, HHV6, measles, H1N1
- Bacterial: Gram negatives, TB, malaria, brucella
- Malignancy associated (leukemia, lymphoma)
MAS (JIA/rheumatoid)
Diagnosis:
- molecular diagnosis (i.e PRF/SAP mutation) OR
- 5 of
> fevers
> splenomegaly
> cytopenia in 2x cell lineages
> high trigs
> low fibrinogen
> high ferritin (>500)
> elevated CD25/IL-2R (>2500)
> evidence of haemophagocytosis on BMA/spleen/LN biopsy,
> low NK cell killing,
Treatment
- Variable
- Steroids + chemo (cytotoxicity impacts cytokine production)
Primary: etoposide, intrathecal MTX, transplant to cure
Secondary: treat infection- i.e aciclovir, antibiotics
LCH
LCH- Langerhan’s cell histiocytosis
- Abnormal clonal proliferation of Langerhan’s cells
- Rare 1 in 5million, children 1-3yrs
4 main subtypes
Letterer-Siwe disease: infancy-2yrs, rash- crusted papules to armpit/groin, bone/lung, liver lesions
Hand-Schuller-Christian: 2-6yrs, crusted papules, oral/genital ulcers, bone/skull lesions
Eosinophilic granuloma: single bone/skin lesion
Hashimoto-Pritzer disease: birth, widespread red-brown rash, nil other organs
Dx: skin biopsy
Treatment:topical steroids, NSAIDs, chemotherapy/radiotherapy if multisystem, BRAF-V600 inhibitors, vemurafenib and dabrafenib
