Primary Immunodeficiency ✅ Flashcards
(160 cards)
1
Q
How serious are primary immunodeficiency disorders?
A
Range from common minor and often asymptomatic disorders to severe, rare disorders
2
Q
Give 2 examples of minor immunodeficiency disorders
A
- Mannan-binding lectin deficiency
- Selective IgA deficiency
3
Q
What is the incidence of mannan-binding lectin deficiency?
A
1 in 20
4
Q
What is the incidence of selective IgA deficiency?
A
1 in 500
5
Q
Give 2 examples of severe primary immunodeficiency disorders
A
- Severe combined immunodeficiency (SCID)
- Chronic granulomatous disease
6
Q
What is the incidence of SCID?
A
1 in 35,000
7
Q
What is the incidence of chronic granulomatous disease?
A
1 in 200,000
8
Q
What is the incidence of primary immunodeficiency disorders (PID) severe enough to require haematopoietic stem cell transplantation?
A
1 in 30,000-50,000
9
Q
What can result from a primary immunodeficiency?
A
- Increased susceptibility to infection
- Autoimmunity
- Immunodysregulation
- Malignancy
10
Q
What can primary immune deficiency be classified on the basis of?
A
- Defects in innate or adaptive immunity
- Clinical presentation
- Age of onset
- Spectrum of encountered pathogens
11
Q
What organisms are patients with antibody deficiency more susceptible to?
A
- Bacterial infection
- Enteroviruses
- Giardia lamblia
12
Q
What bacterial infections are patients with antibody deficiencies more susceptible to?
A
- Streptococcus pneumoniae
- Haemophilus influenza
- Pseudomonas aeruginosa
- Mycoplasma
13
Q
Give 4 antibody deficiencies
A
- X-linked agammaglobulinaemia
- Combined variable immunodeficiency
- IgA deficiency
- Ataxia telangiectasia
14
Q
What is X-linked agammaglobulinaemia also known as?
A
Bruton’s disease
15
Q
What is the pathological process in X-linked agammaglobulinaemia?
A
B cell development is blocked
16
Q
When does X-linked agammaglobulinaemia typically present?
A
6 months - 5 years
17
Q
How does X-linked agammaglobulinaemia present?
A
Recurrent bacterial infection
18
Q
What is found on laboratory testing in X-linked agammaglobulinaemia?
A
- Low IgG, IgM, and IgA
- Absent B cells
- Absent isohaemagglutinins
- BTK gene mutation
19
Q
What is the pathological process in combined variable immunodeficiency (CVID)?
A
Lack of IgG antibody production
20
Q
When does CVID typically present?
A
2nd-4th decade of life
21
Q
How does CVID present?
A
Recurrent bacterial, viral, fungal, and parasitic infection
22
Q
Other than infections, what may be associated with CVID?
A
Increased risk of autoimmune disease and malignancy
23
Q
What is found on labatory testing in CVID?
A
- Reduced IgG
- Occasionally reduced IgM/IgA
- Occasionally low/dysfunctional T or B cells
- Abnormal patterns of B cell phenotype
- Decreased vaccine responses
24
Q
What abnormal pattern of B cell phenotype may be found in CVID?
A
Absence of switched memory B cells
25
In what % of CVID patients is a genetic defect identified?
10%
26
When does IgA deficiency present?
>4 years
27
How does IgA deficiency present?
Recurrent upper respiratory tract infections
28
Other than infection, what may IgA deficiency be associated with?
Increased frequency of allergies and autoimmunity
29
Can IgA deficiency be asymptomatic?
Yes
30
What is found on laboratory testing in IgA deficiency?
- IgA absent
- Normal IgM and IgG
- Normal vaccine responses
31
When does ataxia telangiectasia present?
2nd year of life
32
How does ataxia telangiectasia present?
Recurrent respiratory infection
33
Other than infections, what is ataxia telangiectasia associated with?
- Ocular or facial telangiectasia
- Progressive cerebellar ataxia
- Increased risk of leukaemia and lymphoma
34
What is found on laboratory testing in ataxia telangiectasia?
- Decreased IgA
- Increased radiation-induced chromosomal breakage in cultured cells
- Increased alpha-fetoprotein
- Mutations in ATM gene
35
What kind of infections do combined immunodeficiencies increase in the susceptibility to?
- Bacteria
- Viruses
- Fungi
36
What bacteria do combined immunodeficiencies increase the susceptibility to?
- Streptococcus pneumoniae
- Haemophilus influenzae
- Gram negative Enterobacteriae
- Intracellular pathogens
37
What intracellular bacteria to combined immunodeficiencies increase susceptibility to?
- Salmonella
- Mycobacteria
- Cryptosporidium
- Pneumocystis
38
Give 5 viruses that patients with combined immunodeficiencies are more susceptible to?
- Parainfluenza
- RSV
- Rotavirus
- CMV
- EBV
39
What fungi do combined immunodeficiency disorders increase susceptibility to?
Candida species
40
Give 6 causes of combined immunodeficiency
- Severe combined immunodeficiency (SCID)
- Omenn SCID
- DiGeorge syndrome
- Wiskott-Aldrich syndrome
- X-linked hyper-IgM syndrome
- X-linked lymphoproliferative syndrome
41
What is the problem in SCID?
The development of lymphocytes is blocked by genetic defects
42
When does SCID present?
In the first 6 months of life
43
How does SCID present?
- Faltering growth
- Persistent diarrhoea
- Recurrent mucocutaneous candidiasis
- Severe pneumonitis
44
What form of pneumonitis is seen in SCID?
Viral or PJP
45
What can happen if SCID is not recognised and managed early?
It is commonly fatal
46
What is found on investigation in SCID?
- Lymphopenia
- Hypogammaglobulinaemia
- Abnormal lymphocyte subsets
- Various genetic mutations
47
What does the lymphocyte subset seen in SCID depend on?
The type of SCID
48
What abnormalities may be seen in the lymphocyte subset in SCID?
Absent T-cells +/- B +/- NK cells
49
What genes may be mutated in SCID?
- GAMMA C
- JAK 3
- RAG1
- RAG2
- IL7-RA
- ADA
- MHC class II
50
What is Omenn SCID?
SCID complicated by expansion of a few clones of T cells
51
What molecular type of SCID can develop in Omenn SCID?
Any molecular type
52
How does Omenn SCID present?
- Severe inflammation of skin (generalised erythroderma) and gut
- Lymphadenopathy
- Hepatosplenomegaly
53
What is found on laboratory investigation in Omenn SCID?
- T cells present but oligoclonal
- B/NK present or absent depending on SCID type
- Proliferation of T cells usually impaired
54
How does DiGeorge syndrome cause immune deficiency?
Absent/hypoplastic thymus causes T-cell deficiency
55
How severe is the immune deficiency in DiGeorge syndrome?
Variable, from SCID-like (complete DiGeorge) to normal (via a partial deficiency)
56
When does immunodeficiency caused by DiGeorge syndrome present?
Any time from neonatal period
57
How does immune deficiency caused by DiGeorge syndrome present?
Viral and fungal infections 1
58
What are the other features of DiGeorge syndrome?
- Conotruncal cardiac defect
- Hypocalcaemia
- Facial dysmorphic features
59
What are the features of the hypocalcaemia seen in DiGeorge syndrome?
Lasts >3 weeks and requires therapy
60
What is found on laboratory investigation in immune deficiency caused by DiGeorge syndrome?
- Lymphopenia
- Lymphocyte subsets and proliferation variable
- Genetic defects
61
What genetic defects are associated with DiGeorge syndrome?
- Chromosome 22q11.2 deletion
| - CHARGE syndrome
62
When does Wiskott-Aldrich syndrome present?
Early in infancy
63
How does Wiskott-Aldrich syndrome present?
- Bleeding/bruising
- Recurrent respiratory infections
- HSV and EBV infections
64
What later clinical features are associated with Wiskott-Aldrich syndrome?
- Bloody diarrhoea
- Eczema in early infancy
- Autoimmune manifestations
- Malignancy
65
What autoimmune manifestations are associated with Wiskott-Aldrich syndrome?
- Vasculitis
| - Haemolytic anaemia
66
What malignancies are associated with Wiskott-Aldrich syndrome?
- Leukaemia
- Lymphoma
- EBV-driven brain tumours
67
What is found on laboratory investigation in Wiskott-Aldrich syndrome?
- Thrombocytopenia with small platelets
- Abnormal polysaccharide vaccine respones
- Abnormalities in immunoglobulins
- T-cell number and function progressively declining
- Genetic mutations
68
What is found when measuring immunoglobulins in Wiskott-Aldrich syndrome?
- Raised IgE and IgA
| - Low IgM
69
What genetic mutation is associated with Wiskott-Aldrich syndrome?
Mutation in WASP gene
70
What is X-linked hyper-IgM syndrome also known as?
CD40 ligand deficiency
71
When does X-linked hyper-IgM syndrome present?
In infancy
72
How does X-linked hyper-IgM syndrome present?
- Recurrent bacterial infections
- Pneumocystitis jiroveci pneumonia
- Cryptosporidium diarrhoea
- Sclerosing cholangitis
- Parvovirus induced anaemia
- Faltering growth
- Oral ulcers
73
What is found on laboratory investigation in X-linked hyper-IgM syndrome?
- Abnormalities in immunoglobulins
- Lymphocyte subsets and proliferation normal
- No CD40 ligand expression on activated T cells
- Genetic mutations
74
What abnormalities in immunoglobulins are seen in X-linked hyper-IgM syndrome?
- Decreased IgG
| - IgM normal or raised
75
What genetic mutation is associated with X-linked hyper-IgM syndrome?
CD40 ligand gene mutation
76
What are the types of X-linked lymphoproliferative syndrome?
- XLP1
| - XLP2
77
What is the classical presentation of XLP1?
Overwhelming EBV infection (but many other triggers) results in haemophagocytic lymphohistiocytosis (HLH)
78
How can XLP1 occasionally present?
- Hypogammaglobulin anaemia
| - Aplastic anaemia
79
What is the classical presentation of XLP2?
Like XLP1
80
How can XLP2 sometimes present?
- Enteropathy
- Arthritis
- Other immune dysregulatory features
81
What is found on laboratory testing in X-linked lymphoproliferative syndrome?
Immunological function tests variable, but usually low NK-cell function and often hypogammaglobulinaemia
82
What genetic mutation caused XLP1?
Mutation in SH2D1 coding for SAP protein
83
What genetic mutation is found in XLP2?
Mutation in XIAP (X-linked activator of apoptosis) gene
84
What kind of organisms are patients with neutrophil defects more susceptible to?
- Bacteria
| - Fungi
85
What bacteria are patients with neutrophil defects more susceptible to?
- Staphylococcus
- Pseudomonas
- Other gram negative Enterobacteriae
86
What fungi are patients with neutrophil defects more susceptible to?
- Candida
| - Aspergillus
87
Give 3 neutrophil defects
- Chronic granulomatous disease
- Leukocyte adhesion deficiency type 1
- Severe congenital neutropenia
88
What is the defect in chronic granulomatous disease?
Defect of pathogen killing within macrophage
89
When does chronic granulomatous disease present?
Usually before 5 years of age
90
How does chronic granulomatous disease present?
Recurrent, deep-seat infections
91
What infections may be seen in chronic granulomatous disease?
- Liver abscess
- Perirectal abscess
- Lung abscecss
- Adenitis
- Osteomyelitis
92
What other features may be present in chronic granulomatous disease?
- Diffuse granulomata in respiratory/gastrointestinal/urogenital tract
- Failure to thrive
- Hepatosplenomegaly
- Lymphadenopathy
93
What is found on laboratory testing in chronic granulomatous disease?
- Neutrophil oxidative burst absent
| - Nitro blue-tetrazolium test negative
94
What is the inheritance pattern of chronic granulomatous disease?
- X linked in 2/3
| - Autosomal recessive in 1/3
95
What is the problem in leukocyte adhesion deficiency type 1?
Leukocyte are unable to attach to vascular endothelium and leave circulation
96
When does leukocyte adhesion deficiency type 1 present?
Typically in the neonatal period
97
How does leukocyte adhesion deficiency type 1 typically present?
- Delayed umbilical cord separation
| - Sepsis
98
What are the other features of leukocyte adhesion deficiency type 1?
- Recurrent/persistent bacterial or fungal infections with absence of pus
- Defective wound healing
- Periodonitis
99
What is found on laboratory investigation in leukocyte adhesion deficiency type 1?
- Neutrophil counts persistently above normal range
- Leukocyte CD18 and CD15a expression <5%
- Lack of beta-2 integrin expression
100
What is the problem in severe congenital neutropenia?
Failure of neutrophil maturation
101
When does severe congenital neutropenia present?
Typically in neonatal period or early infancy
102
How does severe congenital neutropenia present?
- Recurrent superficial or invasive bacterial and fungal infections
- Delayed umbilical cord spseration
- Periodonitis
103
What is found on laboratory testing in severe congenital neutropenia?
- Neutrophil counts persistently low
- Bone marrow shows maturational arrest in myeloid series
- Genetic defects
104
What genetic defects may be found in severe congenital neutropenia?
- ELANE
- HAX1
- GFI1
- G6PC3
- WASP
105
What does the ELANE gene code for?
Neutrophil elastase
106
What is the inheritance pattern of severe congenital neutropenia caused by mutations in the ELANE gene?
Autosomal dominant
107
What pathogens do innate immune deficiencies increase the susceptibility to?
Depends on specific defect
108
Give 4 innate immune defects
- Complement deficiency
- Hyper-IgE syndrome type 1
- Autosomal recessive hyper-IgE syndrome
- Mendelian susceptibility to mycobacterial disease
109
What are patients with complement deficiency more susceptible to?
Severe bacterial infections with Neisseria species
110
What are patients with early classical forms of complement deficiencies more susceptible to, as well as Neisseria?
Encapsulated bacteria
111
How do classical pathway complement deficiencies present?
Lupus-like disease
112
When do complement deficiencies present?
Can present at any age
113
What can C1 esterase inhibitor deficiency lead to?
Hereditary angioedema (HAE)
114
When does HAE present?
Mid-childhood (5-10 years)
115
What laboratory tests should be done in suspected complement deficiency?
- Complement function tests
| - Mannose-binding lectin
116
What is found on complement function tests in HAE?
C4 level is low
117
How is HAE confirmed?
C1 inhibitor protein and function tests
118
What is hyper-IgE syndrome type 1 also known as?
Job syndrome
119
When does hyper-IgE syndrome type 1 present?
Usually before 5 years of age, but may present later
120
How might hyper-IgE syndrome type 1 present?
- Mucocutaneous candidiasis in infancy
- Recurrent or persistent respiratory infections
- Pneumatocoele formation pathological feactures
- Scoliosis
- Increased malignancy risk
121
What are the laboratory features of hyper-IgE syndrome type 1?
- Raised IgE
| - Lymphocyte subsets and proliferations usually normal
122
What genetic mutations cause hyper-IgE syndrome type 1?
Mutations in gene encoding STAT3
123
What is autosomal recessive hyper-IgE syndrome also known as?
DOCK8 deficiency
124
When does autosomal recessive hyper-IgE syndrome present?
Usually before 5 years, but variable
125
How does autosomal recessive hyper-IgE syndrome present?
- Eczema
- Severe superficial viral infections
- Recurrent bacterial and opportunistic infections
126
What superficial viral infections may autosomal recessive hyper-IgE syndrome present with?
- Papilloma virus
- Molluscum contagiosum
- Herpes simplex
127
How is autosomal recessive hyper-IgE syndrome associated with cancer?
There is a high risk of squamous cell cancer
128
What is found on laboratory testing in autosomal recessive hyper-IgE syndrome?
- Raised IgE
| - Lymphocyte studies show variably low T-cell numbers and proliferation
129
What is the inheritance pattern of mutations causing hyper-IgE syndrome type 1?
Autosomal dominant
130
What genetic abnormality causes autosomal recessive hyper-IgE syndrome?
Mutations in genes encoding DOCK8
131
When does mendelian susceptibility to mycobacterial present?
Usually before 5 years of age
132
How does the severity of an immune defect affect the presentation?
The more severe the immune defect, the earlier the child presents with features of opportunistic infections or immune dysregulation
133
Why might infants with severe immune defects appear well in the early newborn period?
Due to protection from maternal antibodies and from breastfeeding
134
What form of immune deficiency is an immunological emergency?
SCID
135
Why is SCID an immunological emergency?
Very high risk of life threatening infection
136
What kind of infections are children with SCID at particularly high risk of life-threatening infections?
- Viral infection
| - Pneumocystitis jiroveci
137
Why is SCID so severe?
Children have no adaptive immune response
138
Why can it be hard to distinguish healthy children from those with an immunodeficiency?
Frequent symptomatic infections are common in early childhood
139
What are the warning signs for primary immunodeficiency?
- 4 or more new ear infections within 12 months
- Two or more serious sinus infections or episodes of pneumonia within 1 year
- Infections that present atypically or with unusual severity
- Failure of an infant to gain weight or grow normally
- Prolonged/recurrent diarrhoea
- Recurrent deep skin or organ abscess
- Severe or long-lasting warts or molloscum
- Persistent mucocutaneous candidiasis after 1 year of age
- Episode of infection with an opportunistic pathogen
- Complication after live vaccination
- Need for IV antibiotics to clear infection
- Two or more invasive infections
- Unexplained autoimmune disease
- Positive family history suggestive of primary immunodeficiency
140
Give 4 complications that might occur after live vaccination in children with primary immune deficiency
- Disseminated BCG
- Varicella
- Paralytic polio
- Rotavirus
141
Give 4 examples of invasive infections
- Meningitis
- Osteomyelitis
- Pneumonia
- Sepsis
142
Give 4 examples of invasive infections
- Meningitis
- Osteomyelitis
- Pneumonia
- Sepsis
143
Give 4 examples of invasive infections
- Meningitis
- Osteomyelitis
- Pneumonia
- Sepsis
144
What family history might suggest primary immunodeficiency?
- Relatives with infections or immunodeficiency
- Infant deaths due to infections or unexplained
- Consanguinity
145
What is essential when evaluating a potential primary immunodeficiency?
- Detailed history and clinical examination
| - Family history
146
Why is family history particularly important in primary immunodeficiency?
As primary immune deficiencies have a genetic basis
147
What should examination focus on in potential primary immune deficiency?
- Assessment of growth and nutrition
- Skin
- Nails
- Teeth
- Hair
- ENT
- Respiraotry
- Lymphoid tissue
- Organomegaly
- Dysmorphism
- Neurodevelopment
148
What determines initial laboratory investigations in suspected immunodeficiency?
Clinical presentation and differential diagnosis based on the spectrum of infections suffered
149
What initial simple investigations may be useful in suspected PID?
- FBC
- Immunoglobulins
- Lymphocyte subsets
- Vaccine antibody responses
150
What are initial simple investigations useful for in suspected PID?
Confirm or rule out many forms of PID
151
What is required if there is strong clinical suspicion of PID?
Assessment by a paediatric immunologist
152
What does the specific management of primary immune deficiencies depend on?
The underlying syndrome
153
What do prophylactic measures include in children with PID?
- Avoidance of exposure to infection
- Prophylactic antimicrobials
- IV or SC immunoglobulin
154
What is the purpose of IV of SC immunoglobulin in PID?
To maintain normal levels of IgG
155
What is the role of immunisation in PID?
May be helpful in less severe immunodeficiencies, but live vaccines will be contraindicated in some conditions
156
How are infections in PID managed?
Prompt and aggressive treatment
157
What can immunodysregulatory problems in PID lead to?
- Autoimmune disease
| - Lymphoproliferation
158
How are immunodysregulatory problems in PID managed?
Immunomodulatory treatments
159
What immunomodulatory treatments may be used in immunodysregulatory problems in PID?
- Monoclonal antibodies
| - Immunosupressive drugs
160
How are severe primary immune deficiencies managed?
Curative approach using haematopoietic stem cell transplantation
