Demographic characteristics
A total of 184 patients with IEI were enrolled in our study (120 males and 64 females). We enrolled patients who presented and were followed in our hospital since 2014 till now. There was a male predominance in each of the IEI categories. One hundred and fifteen patients (62.5%) were born to consanguineous parents and family history was positive in 59 patients (32.1%). Immunodeficiencies affecting cellular and humoral immunity had the highest rate of consanguinity at 75.3%, followed by defects of intrinsic and innate immunity at 62.5%, and the lowest rate of consanguinity was recorded for CID with associated or syndromic features at 47.1%. Death of a previous sibling was reported in 32 cases (17.4%) especially in predominantly antibody deficiency category (26.3%) (Table 1).
Table 1
Features of Egyptian patients with Inborn Error of Immunity (IEIs) according to final classification 2022 of International Union of Immunology Societies (IUIS)
Category
|
Patients with IEIs
(n = 184)
|
Total
N (%)
|
Gender M/F
|
Consanguinity
N (%)
|
Family history
N (%)
|
Death of previous sibling
N (%)
|
Case fatality rate
(%)
|
Overall total n (%)
|
184
|
120/64
|
115 (62.5)
|
59 (32.1)
|
32 (17.4)
|
26.1
|
Table 1: Immunodeficiencies affecting cellular and humoral immunity
|
77 (41.8)
|
46/31
|
58 (75.3) #
|
24 (31.2) #
|
18 (23.4)
|
36.4
|
Table 2: CID with associated or syndromic features
|
17 (9.2)
|
13/4
|
8 (47.1)
|
6 (35.3)
|
2(11.8)
|
29.4
|
Table 3: Predominantly Antibody deficiency
|
19 (10.3)
|
11/8
|
9 (47.4)
|
6 (31.6)
|
5 (26.3)
|
0.0
|
Table 4: Disease of immune dysregulation
|
22 (12.0)
|
18/4
|
12 (54.5)
|
3 (13.6)
|
2 (9.1)
|
31.8
|
Table 5: Congenital defects of phagocyte number or function
|
28 (15.2)
|
18/10
|
15(53.6)
|
13 (46.4)
|
3 (10.7)
|
17.9
|
Table 6: Defects in intrinsic and innate immunity
|
8 (4.4)
|
4/4
|
5(62.5)
|
3 (37.5)
|
1 (12.5)
|
12.5
|
Table 7: Autoinflammatory disorders
|
13 (7.1)
|
10/3
|
8 (61.5)
|
4 (30.8)
|
1 (7.7)
|
15.4
|
#: percent within IUIS 2022 categories |
Distribution of IEIs categories and subclasses
The 184 patients with IEI were distributed according to the IUIS 2022 classification as the followings:
Seventy-seven patients (41.8) had immunodeficiencies affecting cellular and humoral immunity. Among these 24 cases (31.2%) were diagnosed as severe combined immunodeficiency (SCID) and 53 cases (68.8%) were diagnosed with CID generally less profound combined immunodeficiency (CID) (66.2%).
Seventeen patients had CID with associated or syndromic features (9.2%); Hyper IgE syndromes was the most common subclass reported in this category with 7 patients (41.2% of them).
Nineteen patients (10.3%) had predominantly antibody deficiency; 9 cases in this category were diagnosed with severe reduction in at least two serum immunoglobulin isotypes with normal or low B cells, common variable immunodeficiency (CVID) phenotype.
Twenty-two patients (12%) had disease of immune dysregulation, 28 patients (15.2%) had congenital defects of phagocyte number or function; 16 of them had defects of respiratory burst. Eight patients (4.4%) had defects in intrinsic and innate immunity, and 13 (7.1%) had autoinflammatory disorders (Table 2) (Fig. 1).
Table 2
The frequency of each IEIs subclasses and diseases according to the International Union of Immunology Societies (IUIS) subclass classification 2022
IUIS Category classification 2022
|
IUIS subclass classification 2022
|
N (%)
|
Disease
|
N (%)
|
Table 1: Immunodeficiencies affecting cellular and humoral immunity
(N = 77)
|
1.T-B + severe combined immunodeficiency (SCID)
|
6 (7.8)
|
Common Gama Gene Defeciency CD132 Defeciency
|
4 (66.7)
|
JAK Defeciency
|
1 (16.7)
|
Undefined
|
1 (16.7)
|
2.T-B-SCID
|
18 (23.4)
|
Adenosine Deaminase Defeciency
|
4 (22.2)
|
DCLRE1 C (Artemis) Defeciency
|
1 (5.6)
|
DNA ligase IV Defeciency
|
1 (5.6)
|
Cernunnos/XLF Defeciency
|
3 (16.7)
|
RAG Defeciency
|
2 (11.1)
|
Undefined
|
7 (38.9)
|
3. CID generally less profound than SCID
|
51 (66.2)
|
CD40 Ligand Defeciency
|
5 (9.8)
|
MHC Class II Defeciency
|
2 (3.9)
|
ZAP-70 Defeciency
|
4 (7.8)
|
DOC2 Defeciency
|
2 (3.9)
|
DOC 8 Defeciency
|
16 (31.4)
|
ITPKB Defeciency
|
1 (2.0)
|
STK4 Defeciency
|
1(2.0)
|
Undefined
|
20 (39.2)
|
3. Combined Immunodefeciency (CID), generally less profound than SCID
|
2 (2.6)
|
Undefined
|
2 (100.0)
|
Table 2: CID with associated or syndromic features
(N = 17)
|
1.Immunodefeciency with congenital thrombocytopenia
|
4 (23.5)
|
Wiskott Aldrish Syndrome (WAS LOF)
|
4 (100.0)
|
2.DNA repair defects other than listed in Table 1
|
2 (11.8)
|
Ataxia Telangiectasias
|
2 (100.0)
|
3.Thymic defects with additional congenital anomalies
|
1 (5.9)
|
Digeorge Nelocardio Facial syndrome Chromosome 22q11.2 Deletion Syndrome
|
1(100.0)
|
5.Hyper IgE syndromes
|
7 (41.2)
|
PGM3 Defeciency
|
1 (14.3)
|
AD-HIGE STAT3 Defeciency (Job syndrome)
|
6 (85.7)
|
7.Anhydrotic ectodermodysplasia with immunodeficiency (EDA-ID)
|
1 (5.9)
|
EDA-due to NEMO/IKBKG Defeciency
|
1 (100.0)
|
9.Other defects
|
2 (11.8)
|
EPG5 (VICI syndrome)
|
1 (50.0)
|
Purine Nucleoside Phosphorylase (PNP) Defeciency
|
1 (50.0)
|
Table 3: Predominantly Antibody deficiency
(N = 19)
|
1.Severe reduction in all serum immunoglobulin isotypes with profound decrease or absent B cells, agammaglobulinemia
|
8 (42.1)
|
BTK Defeciency, XLA
|
4 (50.0)
|
Undefined
|
4 (50.0)
|
2. Severe reduction in at least serum immunoglobulin isotypes with profound normal or low B cells, CVID phenotype
|
9 (47.3)
|
SEC61A1 Defeciency
|
1 (14.3)
|
NFKB1 Defeciency
|
1 (14.3)
|
Undefined
|
7 (77.8)
|
4. Isotope light chain, or functional deficiencies with generally normal numbers of B cells
|
2 (10.5)
|
CARD11Defeciency
|
1 (50.0)
|
Selective IgA Defeciency
|
1 (50.0)
|
Table 4: Disease of immune dysregulation
(N = 22)
|
1.Familial hemophagocytic histiocytosis (FHL)
|
1 (4.5)
|
RHOG Defeciency
|
1 (100.0)
|
2.FHL syndromes with hypopigmentation
|
2 (9.1)
|
Undefined
|
2 (100.0)
|
3.Regulatory T cell defects
|
2 (9.1)
|
LRBA Defeciency
|
2 (100.0)
|
4.Autoimmunity with or without lymphoproliferation
|
9 (40.9)
|
Undefined
|
9 (100.0)
|
5.Imune dysregulation with colitis
|
5 (22.7)
|
IL-10 RA DEfeciency
|
1 (20.0)
|
Undefined
|
4 (80.0)
|
6.Autoimmune lymphoproliferative syndrome (ALPS, Canate Smith syndrome)
|
1 (4.5)
|
Undefined
|
1 (100.0)
|
7.Susceptibilty to EBV and Lymphoproliferative conditions
|
2 (9.1)
|
SAP Defeciency (XLP1)
|
1 (50.0)
|
XIAP Defeciency
|
1 (50.0)
|
Table 5: Congenital defects of phagocyte number or function
(N = 28)
|
1.Congenital neutropenia
|
8 (28.6)
|
GFI1 Defeciency
|
1 (12.5)
|
HAX1 Defeciency
(Kostman Diseases)
|
4 (50.0)
|
Undefined
|
3 (37.5)
|
2.Defects of motility
|
4 (14.3)
|
Leukocyte Adhesion Defeciency type 1
|
3 (75.0)
|
WDR1 Defeciency
|
1 (25.0)
|
3.Defects of respiratory burst
|
16 (57.1)
|
X-linked CGD, gp91 phox
|
16 (100.0)
|
Table 6: Defects in intrinsic and innate immunity
(N = 8)
|
1.Mendelian susceptibity mycobacterial disease (MSMD)
|
6 (75.0)
|
Il-12 and IL-23 Receptor B1 Chain Deficiency
|
4 (66.7)
|
IRF8 Defeciency
|
1 (16.7)
|
STAT1 Defeciency
|
1 (16.7)
|
3. Predisposition to severe viral infection
|
1 (12.5)
|
STAT1 Defeciency
|
1 (100.0)
|
3. Predisposition to mucocutaneous candidiasis
|
1 (12.5)
|
Undefined
|
1 (100.0)
|
Table 7: Autoinflammatory disorders
(N = 13)
|
1.type 1 interferonpathies
|
1 (7.7)
|
ADA2 Defeciency
|
1 (100.0)
|
2.Defects affecting the inflammasome
|
4 (30.8)
|
Familial Mediterranean Fever
|
1 (25.0)
|
NLRC4-MAS
|
1 (25.0)
|
Familial Cold Autoinflaa\mmatory Syndrome Type 2
|
1 (25.0)
|
Undefined
|
1 (25.0)
|
3. Non-inflammasome Related conditions
|
5 (38.5)
|
ADAM 17 Defeciency
|
1 (20.0)
|
DIRA
|
1 (20.0)
|
TNF receptor associated Periodic Syndrome
|
1 (20.0)
|
DITRA (Defeciency of IL-36 receptor anatagoinst)
|
1 (20.0)
|
Undefined
|
1 (20.0)
|
Unclassified autoinflammatory diseases
|
3 (23.1)
|
Undefined
|
3 (100.0)
|
No patients with complement deficiency, bone marrow failure, or phenocopies of IEI were reported.
Each of IEI subclasses and diseases according to the IUIS subclass classification 2022 was detailed in Table 2.
The age of onset of symptoms ranged between 2 and 24 months, while the median of the onset of first infectious and non-infectious manifestation was 6 and 12 months, respectively. The age at diagnosis ranged between 12 and 33.5 months with a diagnostic delay range of 0 to 213 months. 48 patients died at age ranged between 16 and 70.5 months (Table 3).
Table 3
Age of onset of first manifestations, age of Diagnosis, and age of death within patients with IEIs
|
patients with IEIs
(n = 184)
Median (range)
|
Age of onset of symptoms (months)
|
6 (0.5 to 108)
|
Age of onset of 1st infectious manifestation (months)
|
6 (1 to 120)
|
Age of onset of 1st non-infectious manifestation (months)
|
12 (1 to 108)
|
Age of diagnosis (months)
|
24 (1 to 216)
|
Delay in diagnosis (months)
|
12 (0 to 213)
|
Age of deaths (months)
|
30 (2 to 167)
|
The age at diagnosis, phenotype features, and outcomes between different IEIs categories are presented in Table 2. Immunodeficiencies affecting cellular and humoral immunity was the category with the earliest onset of symptoms (4 months) and youngest age of death (27.5 months), while the predominantly antibody deficiency had the latest onset of symptoms (18 months). Immunodeficiencies affecting cellular and humoral immunity were diagnosed at a median age of 21 months. In contrast to diseases of immune dysregulation that were diagnosed at a median age of 48.5 months.
Clinical Features
As expected, Infections were the main presenting symptoms in about 90% of our cases followed by immune dysregulations, syndromic features, malignancy, and laboratory abnormalities only.
The most common infectious presentations were pneumonia in 122 cases (66.3%), followed by skin abscess in 63 cases (34.2%), and gastroenteritis in 60 patients (32.6%). Other infectious manifestations included sepsis, chronic cough, bronchiectasis, otitis media, septic arthritis, osteomyelitis, meningitis, oral thrush, lung, liver, lymph node abscesses, and mucocutaneous candidiasis with variable frequencies (2.7–26.1%). The least frequent infectious manifestations were omphalitis, splenic, brain, renal, muscle, and paraspinal abscesses (0.5–1.1%) (Table 4).
Table 4
Distribution of clinical manifestation and complications within patients with IEIs
Clinical manifestation and Complications
|
patients with IEIs
(n = 184)
|
N (%)
|
Infectious
|
Sepsis
|
26 (14.1)
|
Pneumonia
|
122 (66.3)
|
Chronic cough
|
15 (8.2)
|
Bronchiectasis
|
18 (9.8)
|
Gastroenteritis
|
60 (32.6)
|
Otitis media
|
48 (26.1)
|
Septic arthritis
|
9 (4.9)
|
Osteomyelitis
|
5 (2.7)
|
Meningitis
|
5 (2.7)
|
Omphalitis
|
2 (1.1)
|
Oral thrush
|
44 (23.9)
|
Skin abscesses
|
63 (34.2)
|
Lung abscesses
|
6 (3.3)
|
Liver abscesses
|
7 (3.8)
|
Splenic abscess
|
1 (0.5)
|
Lymph node abscesses
|
6 (3.3)
|
Brain abscesses
|
2 (1.1)
|
Renal abscesses
|
1 (0.5)
|
Muscle abscesses
|
2 (1.1)
|
Paraspinal abscesses
|
1 (0.5)
|
Mucocutaneous candidiasis
|
5 (2.7)
|
Non-infectious
|
Interstitial lung disease
|
7 (3.8)
|
Hepatomegaly
|
35 (19.0)
|
Splenomegaly
|
43 (23.4)
|
Lymphadenopathy
|
37 (20.1)
|
Malignancy
|
8 (4.3)
|
Sclerosing cholangitis
|
4 (2.2)
|
Autoimmune hepatitis
|
5 (2.7)
|
Autoimmune cytopenia
|
26 (14.1)
|
• Autoimmune hemolytic anemia
|
6 (3.3)
|
• Neutropenia
|
20 (10.9)
|
• ITP
|
20 (10.9)
|
Hypothyroidism
|
1 (0.5)
|
Inflammatory diarrhea
|
25 (13.6)
|
Asthma
|
9 (4.9)
|
Eczema
|
51 (27.7)
|
Vitiligo
|
5 (2.7)
|
Inflammatory arthritis
|
2 (1.1)
|
Alopecia
|
7 (3.8)
|
Clubbing
|
11 (6.0)
|
Vasculitis
|
2 (1.1)
|
The most recorded non-infectious manifestations were eczema, hepatosplenomegaly, lymphadenopathy, autoimmune cytopenia. Other less frequent non-infectious manifestations include interstitial lung disease, sclerosing cholangitis, hypothyroidism, inflammatory diarrhea, alopecia, clubbing, autoimmune hepatitis, vitiligo, and vasculitis. Malignancy was reported in 8 cases (4.3%) (Table 4).
Figure 2 describes the main initial clinical features of different IEI categories according to the IUIS 2022 classification, infectious events were most frequently reported in CID with associated or syndromic features (100%), immunodysregulatory manifestations were observed in 50% of patients categorized as defects in intrinsic and innate immunity. Notably, immunodeficiency affecting cellular and humoral immunity was the most common category with malignancy (7.8%) and the age at which malignancy was diagnosed ranged from 3 to 147 months.
The initial presenting symptoms in relation to the age groups revealed that the majority of manifestations were common in children less than 1 year and least noticed in patients older than 5 years.
Laboratory evaluation
Lymphopenia was present in 88 cases (21.2%). Other cellular abnormalities recorded were anaemia (112, 60.9%), neutropenia (24 cases, 13%), thrombocytopenia (20, 10.9%). Numerous serum immunoglobulin abnormalities were observed, low serum IgG level (n = 34, 18.5%), IgA deficiency (n = 20, 10.9%), elevated IgM (n = 32, 17.4%), and elevated IgE (n = 73, 39.7%). Other reported immunological findings were abnormal percentage of CD3 + cells, CD4 + cells, CD8 + T cells, CD19 + cells, CD16 + 56+ (NK) cells, and double-negative (DN) CD3 + CD4-CD8- T cells 33.7%, 40.8%, 26.6%, 29.3%, 2.2%, 1.6%, respectively.
Documented bacterial infectious aetiology varied. Staphylococci coagulase positive (n = 26, 17.9%) and staphylococcus aureus (n = 25, 17.2%) infections predominated. The least isolated bacteria were streptococci, enterobacteria, proteus vulgaris, salmonella typhi (n = 2, 1.4%) for each. Fungal infections included candida (n = 19, 13.1%) and aspergillus (n = 1, 0.7%).
Genetic testing
Among 128-genetically studied patients a causative mutation was identified in 106 patients (57.6% of all cases) with a diagnostic yield of 82.6%, the genetic defects were not identified in 15 patients (Table 5). Homozygous mutations were dominant (44.5% of all genotypes) followed by heterozygous mutations (25%).
Table 5
Genetic diagnosis of patient with IEIs
|
Number of patients with IEIs underwent molecular diagnosis*
(n = 128)
N (%)
|
N
|
(%)
|
Hemizygous
|
16
|
12.5
|
Heterozygous
|
32
|
25
|
Homozygous
|
57
|
44.5
|
Double mutation
|
1
|
0.8
|
No mutation
|
15
|
11.7
|
Waiting
|
11
|
8.5
|
*Genetic diagnostic yield = 82.8 |
The most common mutated genes detected were dedicator of cytokinesis 8 (DOCK8) (16 patients) then STAT3 (6 patients). Adenosine deaminase deficiency (ADA), Bruton tyrosine kinase (BTK), HCLS-associated protein X-1(HAX-1), interleukin-12 receptor subunit beta-1 (IL-12RB1), Wiskott-Aldrich syndrome (WAS) gene mutations were detected in 4 patients for each. Interleukin-2 receptor subunit gamma (IL-2RG), non-homologous end joining factor1 (NHEJ1), Zeta-chain-associated protein kinase 70 (ZAP-70) mutations were identified in 3 patients, respectively. The association of the genotypes features, phenotypes, and outcomes of patients with various IEIs categories are detailed on Table 6.
Table 6
Genotype–phenotype association among patients with IEIs.
IUIS 2022 categories
|
Genetic analysis
|
Age of onset of symptoms
Median (range)
|
Diagnostic delay
Median (range)
|
Age of onset of infectious manifestation
Median (range)
|
Age of onset of noninfectious
Manifestation
Median (range)
|
Malignancy
Median (range)
|
Death
|
Table 1: Immunodeficiencies affecting cellular and humoral immunity
|
RFXANK
(n = 2)
|
1.5
(1 to 2)
|
18
(14 to 22)
|
2 (100.0)
|
0 (0.0)
|
0 (0.0)
|
1
|
ZAP70
(n = 4)
|
6.5
(2 to 8)
|
8
(7 to 154)
|
4 (100.0)
|
3 (75%)
|
0 (0.0)
|
3
|
ADA
(n = 4)
|
6.6
(0.5 to 24)
|
4.3
(3 to 27)
|
4 (100.0)
|
2 (50.0)
|
0 (0.0)
|
3
|
CD40L
(n = 2)
|
7
(6 to 8)
|
45
(8 to 82)
|
2 (100.0)
|
2 (100.0)
|
0 (0.0)
|
2
|
DCLRE1C
(n = 1)
|
2
(2 to 2)
|
2
(2 to 2)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
LF
|
DOC2
(n = 1)
|
6
(6 to 6)
|
6
(6 to 6)
|
1 (100.0)
|
1 (100.0)
|
1 (100.0)
|
0
|
DOC8
(n = 16)
|
30
(4 to 78)
|
21
(6 to 90)
|
16 (100.0)
|
14 (87.5)
|
2 (12.5)
|
4
|
DOCK2
(n = 1)
|
4
(4 to 4)
|
4
(4 to 4)
|
1 (100.0)
|
0 (0.0)
|
0 (0.0)
|
0
|
IL2 RG
(n = 4)
|
3
(1 to 6)
|
4.5
(2 to 14)
|
4 (100.0)
|
1 (25.0)
|
0 (0.0)
|
3
|
ITPKB
(n = 1)
|
1
(1 to 1)
|
5
(5 to 5)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
1
|
JAK3
(n = 1)
|
18
(18 to 18)
|
37
(37 to 37)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
LIG4
(n = 1)
|
2
(2 to 2)
|
3
(3 to 3)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
LF
|
NHEJ1
(n = 3)
|
12
(4 to 25)
|
48
(4 to 80)
|
3 (100.0)
|
3 (100.0)
|
1 (33.3)
|
2
|
RAG1
(n = 1)
|
1
(1 to 1)
|
9
(9 to 9)
|
1 (100.0)
|
0 (0.0)
|
0 (0.0)
|
1
|
RAG2
(n = 1)
|
1
(1 to 1)
|
8
(8 to 8)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
1
|
STK4
(n = 1)
|
1
(1 to 1)
|
23
(23 to 23)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
1
|
No mutation
(n = 4)
|
15.5
(6 to 60)
|
20.5
(12 to 24)
|
4 (100.0)
|
2 (50.0)
|
0 (0.0)
|
0
|
Waiting
(n = 3)
|
24
(24 to 24)
|
12
(12 to 12)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
1
|
Table 2: CID with associated or syndromic features
|
ATM
(n = 2)
|
21
(18 to 24)
|
14
(6 to 22)
|
2 (100.0)
|
2 (100.0)
|
1 (50.0)
|
1
|
EPG5
(n = 1)
|
1
(1 to 1)
|
8
(8 to 8)
|
1 (100.0)
|
0 (0.0)
|
0 (0.0)
|
1
|
IKBKG
(n = 1)
|
2
(2 to 2)
|
5
(5 to 5)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
PGM
(n = 1)
|
6
(6 to 6)
|
18
(18 to 18)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
PNP
(n = 1)
|
18
(18 to 18)
|
6
(6 to 6)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
1
|
STAT3
(n = 6)
|
12
(1 to 36)
|
48
(6 to 71)
|
6 (100.0)
|
6 (100.0)
|
0 (0.0)
|
0
|
WAS
(n = 4)
|
4.5
(4 to 5)
|
23
(3 to 43)
|
4 (100.0)
|
4 (100.0)
|
0 (0.0)
|
2
|
Table 3: Predominantly Antibody deficiency
|
BTK
(n = 4)
|
24
(6 to 54)
|
33
(6 to 84)
|
4 (100.0)
|
3 (75.0)
|
0 (0.0)
|
0
|
CARD11
(n = 1)
|
24
(24 to 24)
|
12
(12 to 12)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
IL-36RA and SEC61A1
(n = 1)
|
2
(2 to 2)
|
106
(106 to 106)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
NFKB1
(n = 1)
|
48
(48 to 48)
|
48
(48 to 48)
|
1 (100.0)
|
0 (0.0)
|
0 (0.0)
|
0
|
No mutation
(n = 1)
|
18
(18 to 18)
|
6
(6 to 6)
|
1 (100.0)
|
0 (0.0)
|
0 (0.0)
|
0
|
Waiting
(n = 3)
|
18
(7 to 48)
|
15
(4 to 36)
|
3 (100.0)
|
2 (66.7)
|
0 (0.0)
|
0
|
Table 4: Disease of immune dysregulation
|
ARHGAP5
(n = 1)
|
108
(108 to 108)
|
2
(2 to 2)
|
0 (0.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
HIVEP1
(n = 1)
|
NA
|
NA
|
0 (0.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
HPS6
(n = 1)
|
91
(91 to 91)
|
16
(16 to 16)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
IL-10RA
(n = 1)
|
1
(1 to 1)
|
10
(10 to 10)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
1
|
LRBA
(n = 2)
|
42
(36 to 48)
|
24
(0 to 48)
|
1 (50.0)
|
2 (100.0)
|
0 (0.0)
|
2
|
SH2D1A
(n = 1)
|
6
(6 to 6)
|
102
(102 to 102)
|
1 (100.0)
|
0 (0.0)
|
0 (0.0)
|
0
|
XIAP
(n = 1)
|
6
(6 to 6)
|
102
(102 to 102)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
1
|
No mutation
(n = 6)
|
11.5
(2 to 95)
|
9
(3 to 70)
|
4 (66.7)
|
6 (100.0)
|
1 (16.7)
|
2
|
Waiting
(n = 4)
|
13.5
(6 to 96)
|
21
(0 to 72)
|
4 (100.0)
|
4 (100.0)
|
0 (0.0)
|
0
|
Table 5: Congenital defects of phagocyte number or function
|
ITGB2
(n = 3)
|
3
(1 to 3)
|
14
(9 to 17)
|
3 (100.0)
|
2 (66.7)
|
0 (0.0)
|
1
|
GFI1
(n = 1)
|
5
(5 to 5)
|
31
(31 to 31)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
HAX
(n = 4)
|
10.5
(9 to 12)
|
39
(18 to 86)
|
3 (75.0)
|
4 (100.0)
|
0 (0.0)
|
0
|
WDR1
(n = 1)
|
1
(1 to 1)
|
47
(47 to 47)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
No mutation
(n = 2)
|
2.5
(1 to 4)
|
9.5
(8 to 11)
|
2 (100.0)
|
2 (100.0)
|
0 (0.0)
|
0
|
Table 6: Defects in intrinsic and innate immunity
|
IL2RB1
(n = 4)
|
5
(3 to 12)
|
19.5
( 4 to 34)
|
2 (50.0)
|
3 (75.0)
|
0 (0.0)
|
0
|
IRF8
(n = 1)
|
108
(108 to 108)
|
36
(36 to 36)
|
1 (100.0)
|
0 (0.0)
|
0 (0.0)
|
0
|
STAT
(n = 2)
|
4.5
(2 to 7)
|
11.5
(11 to 12)
|
2 (100.0)
|
2 (100.0)
|
0 (0.0)
|
1
|
Waiting
(n = 1)
|
4
(4 to 4)
|
14
(14 to 14)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
Table 7: Autoinflammatory disorders
|
ADAM17
(n = 1)
|
1
(1 to 1)
|
3
(3 to 3)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
1
|
CARD8
(n = 1)
|
15
(15 to 15)
|
0
(0 to 0)
|
0 (0.0)
|
0 (0.0)
|
0 (0.0)
|
1
|
CECR1
(n = 1)
|
9
(9 to 9)
|
21
(21 to 21)
|
0 (0.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
IL1RN
(n = 1)
|
1
(1 to 1)
|
11
(11 to 11)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
IL36
(n = 1)
|
29
(29 to 29)
|
1
(1 to 1)
|
0 (0.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
MEFV
(n = 1)
|
60
(60 to 60)
|
12
(12 to 12)
|
0 (0.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
NLRC4
(n = 1)
|
1
(1 to 1)
|
11
(11 to 11)
|
0 (0.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
NLRP12
(n = 1)
|
1
(1 to 1)
|
35
(35 to 35)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
TRAPS
(n = 2)
|
3.5
(2 to 5)
|
20.5
(7 to 34)
|
0 (0.0)
|
2 (100.0)
|
0 (0.0)
|
0
|
WDR3
(n = 1)
|
60
(60 to 60)
|
84
(84 to 84)
|
1 (100.0)
|
1 (100.0)
|
0 (0.0)
|
0
|
No mutation
(n = 2)
|
12
(12 to 12)
|
6
(6 to 6)
|
2 (100.0)
|
2 (100.0)
|
0 (0.0)
|
0
|
Treatment and disease outcome
Treatment modalities varied between IEIs categories as shown in Table 7. The most frequently used treatment options were antimicrobial prophylaxis, intravenous immunoglobulin therapy, both were dispensed for 153 (83.1%), and 126 (68.4%) patients, respectively. The highest rate of prophylactic antibacterial medications use (100%) and IVIG (100%) was in immunodeficiencies affecting cellular and humoral immunity, CID with or associated syndromic features and predominantly antibody deficiency.
Table 7
Treatment modalities within IEI categories
IEI Category 2022
|
Total
|
Treatment modalities
|
Anti-microbial prophylaxis
|
Immuno-globulin therapy
|
Steroids
|
Immuno-suppressant therapy
|
Biologics cytokines
|
Bone marrow transplantation
|
Others
|
Overall
N (%)
|
184
|
153 (83.1)
|
126 (68.4)
|
36 (19.6)
|
40 (21.7)
|
15 (8.2)
|
10 (5.4)
|
16 (8.7)
|
Table 1: Immunodeficiencies affecting cellular and humoral immunity
|
77
|
77 (100)
|
77 (100)
|
5 (6.5)
|
5 (6.5)
|
2 (2.6)
|
8 (10.4)
|
3 (3.9)
|
Table 2: CID with associated or syndromic features
|
17
|
17 (100)
|
17 (100)
|
3 (17.6)
|
3 (17.6)
|
0 (0.0)
|
1 (5.9)
|
0 (0.0)
|
Table 3: Predominantly Antibody deficiency
|
19
|
19 (100)
|
19 (100)
|
2 (10.5)
|
2 (10.5)
|
0 (0.0)
|
0 (0.0)
|
0 (0.0)
|
Table 4: Disease of immune dysregulation
|
22
|
6 (27.3)
|
9 (40.9)
|
19 (86.4)
|
19 (86.4)
|
8 (36.4)
|
1 (4.5)
|
2 (9.1)
|
Table 5: Congenital defects of phagocyte number or function
|
28
|
27 (96.4)
|
1 (3.6)
|
1 (3.6)
|
1 (3.6)
|
0 (0.0)
|
0 (0.0)
|
5 (17.9)
|
Table 6: Defects in intrinsic and innate immunity
|
8
|
6 (75.0)
|
2 (25.0)
|
4 (50.0)
|
4 (50.0)
|
0 (0.0)
|
0 (0.0)
|
1 (12.5)
|
Table 7: Autoinflammatory disorders
|
13
|
1 (7.7)
|
1 (7.7)
|
2 (15.4)
|
6 (46.2)
|
5 (38.5)
|
0 (0.0)
|
5 (38.5)
|
Categories are not mutually exclusive |
Prophylaxis include Azithromycin, Azithromycin and itraconzaol, TMP\SMX, TMP\SMX and itraconazole |
Immunosuppressive include methotrexate, MMF,, sulfasalazine, and sirolimus |
Biological include Etanarecpt, infiliximab, rituximab, tocilizumab |
Other drugs include antituberculous, colchicine, DDAVP, Impetigo treatment, recombinant human granulocyte colony-stimulating factor |
Corticosteroids were used in 36 cases (19.6%), of which 19 cases were diseases of immune dysregulation. Forty patients (21.7%) received immunosuppressive (methotrexate, mycophenolate mofetil, sulfasalazine, and sirolimus) agents especially in disease of immune dysregulation category (86.4%). Fifteen patients (8.2%) predominantly with autoinflammatory disorders (38.5%) received biological therapy, including etanerecpt, infiliximab, rituximab, tocilizumab.
Ten patients (5.4%) underwent bone marrow transplantation. Of those, 8 patients were diagnosed with immunodeficiencies affecting cellular and humoral immunity, 1 patient with CID with associated or syndromic features, and another patient with disease of immune dysregulation. Other lines of management include anti-tuberculous therapy, colchicine, 1-desamino-8-d-arginine vasopressin (DDAVP), impetigo treatment, recombinant human granulocyte colony-stimulating factor, which were used in 16 patients (8.7%).
The overall case fatality rate was 48 patients (26.1%); the age at death ranged from 16 to 70.5 months (Table 1). The highest fatality rate (36.4%) was in patients with immunodeficiencies affecting cellular and humoral immunity. This was followed by diseases of immune dysregulation (31.8%). The mortality within other categories was as follows: CID with associated or syndromic features (29.4%), congenital defects of phagocyte number or function (18%), defects in intrinsic and innate immunity (12.5%), and autoinflammatory disorders (15.4%). No deaths were reported in patients with predominantly antibody deficiency (Table 1).