J Clin Immunol (2015) 35:745–753 DOI 10.1007/s10875-015-0206-9
ORIGINAL ARTICLE
Report of the Tunisian Registry of Primary Immunodeficiencies: 25-Years of Experience (1988–2012) Fethi Mellouli 1,2 & Imen Ben Mustapha 2,3 & Monia Ben Khaled 1,2 & Habib Besbes 1,2 & Monia Ouederni 1,2 & Najla Mekki 2,3 & Meriem Ben Ali 2,3 & Beya Larguèche 2,3 & Mongia Hachicha 4 & Tahar Sfar 5 & Neji Gueddiche 6 & Siheme Barsaoui 7 & Azza Sammoud 8 & Khadija Boussetta 9 & Saida Ben Becher 10 & Ahmed Meherzi 11 & Najoua Guandoura 12 & Lamia Boughammoura 13 & Abdelaziz Harbi 14 & Fethi Amri 15 & Fethi Bayoudh 16 & Najla Ben Jaballah 17 & Neji Tebib 18 & Asma Bouaziz 19 & Abdelmajid Mahfoudh 4 & Hajer Aloulou 4 & Lamia Ben Mansour 4 & Imen Chabchoub 4 & Raoudha Boussoffara 5 & Jalel Chemli 14 & Jihène Bouguila 13 & Saida Hassayoun 14 & Saber Hammami 6 & Zakia Habboul 6 & Agnès Hamzaoui 20 & Jamel Ammar 20 & Mohamed-Ridha Barbouche 2,3 & Mohamed Bejaoui 1,2
Received: 16 July 2015 / Accepted: 5 October 2015 / Published online: 13 October 2015 # Springer Science+Business Media New York 2015
Abstract Purpose Primary immunodeficiencies (PIDs) are a large group of diseases characterized by susceptibility to not only recurrent infections but also autoimmune diseases and malignancies. The aim of this study was to describe and analyze the distribution,
clinical features and eventual outcome of PID among Tunisian patients. Methods We reviewed the record of 710 patients diagnosed with Primary Immunodeficiency Diseases (PIDs) from the registry of the Tunisian Referral Centre for PIDs over a 25-year period.
Fethi Mellouli, Imen Ben Mustapha, Mohamed-Ridha Barbouche and Mohamed Bejaoui contributed equally to this work. * Fethi Mellouli
[email protected] 1
Service d’immuno hématologie pédiatriques, Centre National de Greffe de Moelle Osseuse de Tunis, 13 Rue du Djebel Lakhdhar, 1006 Tunis, Tunisia
2
Faculté de medicine de Tunis, Université El Manar II, Tunis, Tunisia
3
Laboratoire d’immunologie, Institut Pasteur de Tunis, Tunis, Tunisia
4
Service de pédiatrie, hôpital de Sfax, Sfax, Tunisia
5
10
Service de pédiatrie PUC, hôpital Bechir Hamza de Tunis, Tunis, Tunisia
11
Service de pédiatrie, hôpital Mongi Slim La Marsa, La Marsa, Tunisia
12
Service de pédiatrie, hôpital de Bizerte, Bizerte, Tunisia
13
Service de pédiatrie, hôpital Farhat Hached de Sousse, Sousse, Tunisia
14
Service de pédiatrie, hôpital Sahloul de Sousse, Sousse, Tunisia
15
Service de pédiatrie, hôpital de Kairouan, Kairouan, Tunisia
16
Service de pédiatrie, hôpital Militaire de Tunis, Tunis, Tunisia
Service de pédiatrie, hôpital de Mehdia, Mehdia, Tunisa
6
Service de pédiatrie, hôpital de Monastir, Monastir, Tunisia
7
Service de pédiatrie A, hôpital Bechir Hamza de Tunis, Tunis, Tunisia
17
Service de réanimation pédiatrique, hôpital Bechir Hamza de Tunis, Tunis, Tunisia
8
Service de pédiatrie B, hôpital Bechir Hamza de Tunis, Tunis, Tunisia
18
Service de pédiatrie, hôpital La Rabta de Tunis, Tunis, Tunisia
19
9
Service de pédiatrie C, hôpital Bechir Hamza de Tunis, Tunis, Tunisia
Service de pédiatrie, hôpital de Nabeul, Nabeul, Tunisia
20
Service de pneumologie, hôpital l’Ariana de Tunis, Tunis, Tunisia
746
Results The male-to-female ratio was 1.4. The median age at the onset of symptoms was 6 months and at the time of diagnosis 2 years. The estimated prevalence was 4.3 per 100,000 populations. The consanguinity rate was found in 58.2 % of families. According to the International Union of Immunological Societies classification, spectrums of PIDs were as follows: combined T-cell and B-cell immunodeficiency disorders account for the most common category (28.6 %), followed by congenital defects of phagocyte (25.4 %), other well-defined immunodeficiency syndromes (22.7 %), predominant antibody deficiency diseases (17.7 %), diseases of immune dysregulation (4.8 %), defect of innate immunity (0.4 %) and complement deficiencies (0.4 %). Recurrent infections, particularly lower airway infections (62.3 %), presented the most common manifestation of PID patients. The overall mortality rate was 34.5 %, mainly observed with combined immunodeficiencies. Conclusion The distribution of PIDs was different from that reported in Western countries, with a particularly high proportion of Combined Immunodeficiencies and phagocyte defects in number and/or function. More is needed to improve PID diagnosis and treatment in our country. Keywords Primary immunodeficiencies . diagnosis . management . treatments . Tunisia
Introduction Primary immunodeficiencies (PIDs) are heterogeneous and rare inherited disorders resulting from the dysfunction of the immune system manifesting itself not only in increased susceptibility to infections but also in the frequent occurrence of allergy, autoimmune diseases and malignancies. In recent years, important and rapid advances have been made in the diagnosis and management of patients with PIDs. They have reduced the morbidity and mortality associated with these diseases. Unlike most developed countries which established national registries for PIDs, a few developing countries in Africa, particularly in North Africa, provided epidemiological data on PID. The high rate of consanguinity in those countries would increase the incidence and prevalence of these diseases since most PIDs are autosomal recessive disorders. In Tunisia, a national registry did not exist in a practical way until 1988 when a working group studying PIDs has been created and almost all diagnosed patients in Tunisian territory have been indexed in a local database shared by the Pediatric Immuno-hematology department of the National Centre for Bone Marrow Transplantation of Tunis (NCBMT) and the Laboratory of Immunology at Pasteur Institute of Tunis (PIT). In this study, we analyzed the registry data from 1988 to 2012. The purpose was to characterize the spectrum of PIDs in
J Clin Immunol (2015) 35:745–753
Tunisia and describe the epidemiological, clinical and outcome features of patients and compare them to other international registries. This study will improve and deepen Tunisian physicians’ knowledge and awareness of PIDs, make more strategic decisions and ultimately improve survival rates.
Materials and Methods General Information on Tunisia Tunisia is a country in the north of Africa. It has a population of 10,776,400 inhabitants in 2012, subdivided into 24 governorates. Tunisia has a homogeneous population, almost entirely of Arab and Berber descent. The healthcare system is mainly public with four levels of care. Primary health care is the first level of contact between patients and structured care services. The secondary and tertiary levels (specialized and hyper-specialized care) play a support role for primary care with specialized diagnostic and therapeutic functions. A fourth level can be designated for interventions to improve the patients’ quality of life also for training and research activities. Data Collection The Pediatric immune-hematology department in the NCBMT is a tertiary referral center for consultation, investigation, and management, including stem cell transplantation of patients with PIDs. Specific and advanced immunological investigations are centralized in the national reference Laboratory of Immunology at PIT. A registry for patients who are diagnosed with PID has been established by a working group of PID specialists from both the NCBMT and PIT since 1988 with the development of a specific and standardized data sheet form to PID patients. Two categories of PID patients were included in the registry: – –
Patients from different regions of the country whatever their age (children or adults) who were referred to NCBMT for clinical and biological investigation Patients whose blood samples were directly addressed to PIT with duly completed form by the referring physician. Some patients were called when data were missing.
Data from the two centers were combined and computerized in 2010 using Microsoft excel. Database Content and Items The following information were recorded in the database : a detailed identification of the patient, the geographical origin of parents, parental consanguinity, personal history (the neonatal
J Clin Immunol (2015) 35:745–753
747
period, the stump cord falling off, vaccination and vaccine accidents, recurrent infections …) or family history suggestive of PID, the age at onset of the disease, the patient’s age at diagnosis, the main clinical manifestations that led to consultation or found in clinical examination, treatment and outcome. Basic tests, immunological findings were included. The content of the database was constant through years.
anonymity. The consent of the patients or their guardians was not requested for integration in the database because the management and access to the database was reserved to physicians. However, consent was required in case of genetic study.
PID Diagnoses and Classification
Registry data were exported to a Statistical Package SPSS Version 18.0 (SPSS Inc). Qualitative variables were quoted as numbers and percentages, and continuous variables as means and standard deviations or as the median and inter quartile range (IQR). The Student’s t-test or Wilcoxon test was used to compare means. For the comparison of percentages, we used the χ2 (Chi-squared) test with Yates’ continuity correction or the Fisher exact test.
In the present study, patients were classified according to the updated clinical and laboratory criteria of PID reported by International Union of Immunological Societies (IUIS) in 2011 [1]. However, it should be pointed out that most PID diagnoses were based on a clinical and immunological phenotype characterization rather than a genetic analysis since advanced molecular tests for gene mutations was not always available throughout the period of study. Confrontation between clinical and immunological findings was performed in each case. The diagnosis could be revised over time, but only the final diagnosis was included in the database. Also we have adopted the following definitions or classifications to conditions below: – –
–
–
–
Impaired T-cell function was defined by absence of lymphocyte proliferation cells in response to mitogens (e.g., PHA) and antigens, with normal lymphocyte T count. CD4 deficiency was defined as isolated absence of CD4 T-cell (or very low count) without evidence of HIV infection or other known immunodeficiency (normal expression of HLADR). CD8 deficiency was defined as isolated absence of CD8 T-cell (diagnosis tools for underlying causes like ZAP70related SCID gene or CD8 alpha Chain Defect were not available). Hyper IgM syndrome: was phenotypically classified in the CID category when the clinical expression is compatible with cellular immune deficiency (CMV reactivation, opportunistic infections such as pneumocystosis…). Required criteria for the CVID diagnosis were decreased serum IgG, IgM and/or IgA level, decreased response to vaccines, B cell number more then 1 % of total lymphocytes, 4 years old or more at the age of diagnosis, and exclusion of other causes of hypogammaglobulinemia.
Ethical Aspects In like manner to the medical record, the registry was created under the operative laws of medical deontology, respecting doctor-patient confidentiality and security of private data. The data were encoding in the computerized database with
Statistics
Results Demographic data Our registry included 710 patients from 615 different families distributed in different governorates of Tunisia with a prevalence rate of 4.3 /100,000 population. The consanguinity was found in 358 families (58.2 %). The Sex-ratio was 1.4 (414 male and 296 female). The average age at diagnosis was 5.3 years (1 day-58 years) with a median of 24 months. Only 29 patients (4 %) had an age older than 18 years at diagnosis. The average incidence of PID was 28 new cases per year. Over the years, the incidence curve has maintained an upward pace, and between 2009 and 2012 more than 60 new cases are diagnosed every year (Fig. 1). The geographical distribution was heterogeneous with a maximum prevalence in the governorate of Medenine with 9.5/100,000 inhabitants followed by the governorate of Kasserine 8.6/100,000 inhabitants and a minimum in the governorates of Ben Arous and Mennouba with 1.7/100,000 inhabitants for both of them (Fig. 2).
Distribution of PIDs The spectrum of PIDs was as follows: 203 patients had a combined immune deficiency (28.6 %), 180 patients had phagocytes defects in number and/or function (25.4 %), 161 patients had a well-defined immunodeficiency syndrome (22.7 %), 126 patients had a predominant antibody deficiency (17.7 %), 34 patients had immune dysregulation (4.8 %), three patients had abnormal innate immunity (0.4 %) and three others had a complement deficiency (0.4 %). No patients with auto-inflammatory diseases were diagnosed. Types and subtypes of PIDs in our study are detailed in Table 1.
748
J Clin Immunol (2015) 35:745–753
Fig. 1 Change of PIDs incidence in Tunisia
Clinical Features A history of infant death was noted in 160 families (26 %). Vaccine complication was found in 70 patients dominated by disseminated BCGitis. The age at onset of symptoms was 1.9 years on average (1 day-52 years) with a median of 6 months. The mean delay between onset of symptoms and diagnosis varied depending on the category of immune deficiency: 16 months for CID, 41 months for well-defined immunodeficiency syndromes, 47 months for congenital defects of phagocytes and 90 months for predominantly antibody deficiencies (Table 2). Clinical presentation of PID was dominated by recurrent infections in 647 cases (91 %): The lower airway infection in all PID categories was the most frequent observed in a total of 442 patients (62.3 %). The upper airway infections, skin and digestive were found at similar rates. Failure to thrive and growth retardation were observed in 192 patients (27 %). 48 patients (6.7 %) had auto-immune manifestations in decreasing order: 17 with predominantly antibody immunodeficiency among which 12 CVID, 12 CID, 8 with immune dysregulation (all of them had ALPS), the rest was divided into other categories of PIDs. The auto-immune cytopenia mainly thrombocytopenia was the most frequent feature found.
DNA Analysis Genetic confirmation of the disease was performed in 98 patients (13.8 % of PIDs) mainly in patients having recurrent mutations with founder effect.
Treatment and Management Management of PID patients included predominantly prophylactic antibiotic therapy in almost patients then Intravenous Immune globulin replacement therapy in 13.5 % of patients.
Allogeneic genoidentical hematopoietic stem cell transplantation (HSCT) of PID has been started since 2007 in our center. 25 patients (3.5 %) had undergone HSCT distributed as follows: HLA class II deficiency in 12 cases, Omenn Syndrome in 4 cases, LAD1 deficiency in 4 cases, Chediak Higashi in 2 cases, Griscelli in 1 case and SCID in 2 cases. The graft success was observed in 13 /25cases (52 %).
Outcomes and Mortality The overall mortality rate was 245 patients (34.5 %) and 122 patients were lost to follow up (17.2 %). Patients with SCID had the most severe prognosis. In this group, 46/58 (79 %) patients died in the average age of 14 months (8 day48 months). The major causes of death were severe sepsis in all groups. Eight patients (1.1 %) had cancers: six patients had lymphoma (3 CVID, 1 HIGM syndrome, 1 CD4 deficiency and 1 Ataxia atelangiectsia), one patient had Kaposi sarcoma (Wiscott Aldrish) and one patient had pancreatic carcinoma (Ataxia atelangiectsia).
Discussion Since patients were enrolled from PID referral centers, our study provides relevant epidemiological information about PIDs in Tunisia. In our registry, the integrated data were those of 556 patients (78,3 %) referred to NCBMT, and 154 patients (21,7 %) from PIT (Non physically referred patients). The observed prevalence was estimated at 4.3/100,000 inhabitants. This frequency is probably under estimated for several reasons: the existence of severe forms causing rapid death, the presence of asymptomatic or pauci symptomatic forms of PIDs as IgA or subclasses of IgG deficiency, the lack of doctor’s awareness and knowledge of these diseases and the existence of atypical adult presentations that mislead the diagnosis of PID like granulomas, lymphomas and autoimmune diseases.
J Clin Immunol (2015) 35:745–753
749
Fig. 2 Prevalence rate of PIDs in Tunisia per 100,000 inhabitants by governorate
It would be quite difficult to give an absolute number of unregistered PID patients. However, if we consider an average
incidence of 60 new cases per year, the expected PID number would be 1500 cases over 25 years. In this case, the estimated
750 Table 1
J Clin Immunol (2015) 35:745–753 Distribution of patients according categories and subtypes of PIDs in Tunisia
PIDscategories and subtypes
Number of patients
Percentage
Median age at onset (months)
Median age at diagnosis (months)
Sex-Ratio (M/F)
Mortality rate
Combined immunodeficiencies (CID)
203
28,6 %
11 (1 m-26 m) 11
1,7
56 %
* HLA class II Deficiency
56
7.9 %
4 (1d-18 m) 4,5
1,1
35,70 %
* SCID
58
8,2 %
2
5
3,3
90,20 %
* Hyper IgM Syndrome * Omenn Syndrome
30 22
4,2 % 3,1 %
24 1,33
45 4
1,4 1,2
6,50 % 54,50 %
* CD4+Deficiency * CD8+Deficiency
7 3
1% 0.4 %
4 1
23 7
2,5 All female
28,6 % 66,7 %
* PNP deficiency
1
0,1 %
24
24
Female
100,00 %
* Impaired T-Cell function Congenital defects of phagocytes (AP)
26 180
3.7 % 25,4 %
29 22 (1d-58 y) 32
1,2 1,4
69,2 % 32,3 %
* Chronic granulomatous disease
86
12,1 %
7 4,5 (1d-18 y) 5
1,97
16,30 %
* MSMD * LAD1
32 30
4,5 % 4,2 %
4 0,5
12 3
1,3 2,1
15,60 % 74 %
* Neutropenia (Cyclic neutropenia, Severe congenital neutropenia and Other types) Well-defined immunodeficiency syndromes
32
4,5 %
40
54
0,5
23 %
161
22.7 %
60 (3y-18 y) 72
1.4
82 %
* Ataxia-Telangiectasia+Ataxia-Telangiectasia like
112
15.8 %
25 (1d-20y) 24
1
63 %
* Buckley Syndome * Wiskott Aldrich * DiGeorge Syndrome
34 6 5
4.8 % 0.8 % 0.7 %
12 0.9 0.04
36 17 10
2.4 All male All male
0% 66.6 % 100 %
* Netherton Syndrome Predominantly antibody deficiencies
4 126
0.6 % 17.7 %
100 % 4%
49
6.9 %
21 132 (4 m-53 y) 192
1 1.2
* CVID
1 36 (20 d - 52 y) 72
1
2%
* Agammaglobulinemia * IgA deficiency * Subtypes IgG deficiencies Diseases of Immune dysregulation
40 32 5 34
5.6 % 4.5 % 0.7 % 4,80 %
10 % 0% 0% 38,1 %
12 8 6 1 6 1 3 3 3 1 2
1,70 1,10 0,85 0,14 0,85 0,14 0,40 0,40 0,40 0,14 0,28
25 36 60 16 (15 d-14 y) 4,25 24 9,5 108 4,25 84 32
3 0,5 1,5 2,7
* ALPS * Chediak Higashi * Griscelli Syndrome * HermenskyPudlak Syndrome * Familial LymphohistiocyticHemophagocytosis * X-linked Lymphoproliferative syndrome Complement deficiencies * C1 inhibitor deficiency Defects of innate immunity * WHIM syndrome * NFkBsignaling pathway
6.5 12 34 9 (15 d-13 y) 3 20 2 10 3 82 6
5 3 1 Female 2 Male All male
0,00 % 12,50 % 33,30 % 0,00 % 83,30 % 100,00 % 0%
12
25
2
0%
% % % % % % % % % % %
CID Combined immunodeficiencies, CVID common variable immunodeficiency, SCID severe combined immune deficiency, HLA class II Human Leukocyte Antigen class II, PNP Purine Nucleoside Phosphorylase, CD cluster differentiation, MSMD Mendelian Susceptibility to Mycobacterial Diseases, LFA Leukocyte Adhesion Molecule type 1, ALPS Autoimmune lymphoproliferative syndrome, WHIM Warts, Hypogammaglobulinemia, Infections, Myelokathexis, NFkB Nuclear Factor Kappa B d: day, m: month, y: year
J Clin Immunol (2015) 35:745–753 Table 2
751
Clinical presentations and complications of PIDs observed in Tunisian patients Well-defined ID syndromes
Predominantly antibody deficiencies
Immune dysregulation anomalies
Other PIDs
78 (11,0 %)
96 (13,5 %)
103 (14,5 %)
12 (1,7 %)
5 (0,7 %)
106 (14,9 %)
49 (6,9 %)
26 (3,7 %)
11 (1,5 %)
0 (0,0 %)
46 (6,5 %) 56 (7,9 %)
24 (3,4 %) 45 (6,3 %)
44 (6,2 %) 61 (8,6 %)
7 (1,0 %) 7 (1,0 %)
2 (0,28 %) 1 (0,14 %)
39 (5,5 %) 30 (4,2 %)
23 (3,2 %) 24 (3,4 %)
37 (5,2 %) 27 (3,8 %)
7 (1,0 %) 4 (0,56 %)
0 (0,0 %) 0 (0,0 %)
126 (17,7 %)
0 (0,0 %)
21 (3,0 %)
0 (0,0 %)
45 (6,3 %) 29 (4,1 %)
43 (6,1 %) 44 (6,2 %)
6 (0,8 %) 7 (1,0 %)
26 (3,7 %) 26 (3,7 %)
21 (3,0 %) 24 (3,4 %)
0 (0,0 %) 0 (0,0 %)
41 (5,8 %)
Clinical presentation
All PIDs
CID
Lower airway infections
442 (62,3 %)
148 (20,8 %)
Skin infections
275 (38,7 %)
83 (11,7 %)
Digestive infections Upper airway infections
265 (37,3 %) 233 (32,8 %)
142 (20,0 %) 63 (8,9 %)
Failure to thrive Growth retardation
200 (28,2 %) 158 (22,2 %)
94 (13,2 %) 73 (10,3 %)
Candidiase Infections
153 (21,5 %)
Hepatomegaly Splenomegaly
141 (19,9 %) 130 (18,3 %)
Septicaemia
Congenital defects of phagocytes (AP)
105 (14,8 %)
43 (6,1 %)
Bronchectasies
96 (13,5 %)
16 (2,3 %)
2 (0,28 %)
BCGitis Hypersensibility Autoimmunity Osteoarticular infections
64 (9,0 %) 50 (7,0 %) 48 (6, 8 %) 46 (6, 5 %)
21 (3,0 %) 13 (1,8 %) 12 (1, 7 %) 7 (1, 0 %)
Meningitis Urinary tract infection Mallignancies
43 (6, 1 %) 8 (1,1 %) 8 (1,1 %)
12 (1, 7 %) 0 (0,0 %) 2 (0,28 %)
6 (0,85 %)
0 (0,0 %)
7 (1,0 %)
9 (1,3 %)
5 (0,7 %)
0 (0,0 %)
31 (4,4 %)
46 (6,5 %)
0 (0,0 %)
1 (0,14 %)
40 (5,6 %) 11 (1,5 %) 5 (0, 7 %) 21 (3, 0 %)
3 (0,42 %) 16 (2,3 %) 6 (0, 8 %) 3 (0, 42 %)
0 (0,0 10 (1,4 17 (2,4 13 (1,8
0 (0,0 %) 0 (0,0 %) 8 (1,1 %) 1 (0,14 %)
0 (0,0 %) 0 (0,0 %) 0 (0,0 %) 1 (0,14 %)
10 (1,4 %) 0 (0,0 %) 0 (0,0 %)
4 (0,56 %) 0 (0,0 %) 3 (0,42 %)
4 (0,56 %) 0 (0,0 %) 0 (0,0 %)
1 (0,14 %) 0 (0,0 %) 0 (0,0 %)
number of unregistered patients would be slightly higher than the registered one (790 patients). Nonetheless, there were only 710 registered cases. The observed prevalence was more frequent in Tunisia than in the following countries of Africa: Egypt 0.08/100,000 Inhabitants [2], Morocco: 0.81 /100,000 Inhabitants [3] and South Africa 0.32/100,000 Inhabitants [4]. It was close to what was found in Norway 5.03/100,000 inhabitants [5], in France 4,4/100,000 inhabitants [6], the in USA 5.01/100,000 inhabitants [7] and in Australia 4.67/100,000 inhabitants [8]. But it was less frequent than in Canada 9.78/100,000 inhabitants [7]. These differences may be related not only to ethnic and geographic variations as described in several epidemiological studies [9–11] but also for the differences in data collection methods with the variable degrees of expertise in the diagnosis and management of PIDs between countries [6]. The incidence of PIDs in our country is rising every year. It was less than 10 patients per year in 1988 while exceeding 60 patients per year in the last 4 years. This increasing incidence reflects a major and active effort to improve the field of immunopathology in our country by organizing a working group studying PIDs since 1988 [12], the creation of the hematoimmunology department with a specialized consultation for almost all patients (children and adults) suspected of immunodeficiency, the existence of a national laboratory specialized in the investigation of PIDs at PIT and the organization of
%) %) %) %)
12 (1,7 %) 8 (1,1 %) 3 (0,42 %)
scientific events about PID (National congress of immunopathology, seminars, etc.…) and national campaigns for a better awareness and understanding of PID presentations. The positive impact of national programs in transforming PID epidemiology was well demonstrated in Latin American Society for Immunodeficiencies (LASID) programs and Physician Education and Public Awareness Campaign (PEPAC) program and Jeffrey Modell Centers Network leading to a continued increase in the number of patients with PID identified, diagnosed, and treated [13, 14]. The frequency of PIDs in our study was higher in the governorate of Medenine and the governorate of Kasserine with frequencies of 9.5 and 8.6/100,000 inhabitants respectively, whereas this frequency was the lowest in the governorate of Mennouba, Ariana and Ben Arous at around 2/100,000 inhabitants. This can be explained by the variation of the rate of consanguinity between these areas [15] and by the fact that many governorates such as Ariana and Mennouba had many internally displaced persons who were assigned to their original governorate. Other causes, such as easy access to medical care and cultural level, could play a less prominent part. The heterogeneity of the geographical distribution has been also described in many national registries [3, 5, 6, 9, 16]. Male predominance was also described in all consulted registries. But it was even more important in Taiwan [17], Korea [18] and Japan [19] with a sex ratio (M/F) more than 2 related to the relative preponderance of X-linked
752
J Clin Immunol (2015) 35:745–753
transmission. The median diagnostic delay between onset of symptoms and diagnosis in all PIDs was 18 months, a delay similar to that of Morocco (24 months) [3] and superior to France (1 year) [6]. But, same to all published registries, it was very variable according to the category of PIDs [3, 4, 6, 14, 16, 20–24]. It may also be explained by the delay in consultation particularly with pauci-symptomatic forms of PIDs [25]. In comparison to an early Tunisian PID study in 1996 [12], the distribution of the different categories of PIDs has undergone several changes : – – –
The decline in the frequency of well-defined immunodeficiency syndromes from 40 to 22.7 %. The increase in phagocytes defects from 11 to 25.4 % thus becoming the second frequent disorder. The identification of new entities: the syndrome of Mendelian susceptibility to mycobacterial disease, autoimmune lymphoproliferative syndrome, Comel Netherton syndrome, etc.…
Some features have remained constant over time such as: the preponderance of the combined deficiencies, the rare frequency of innate immunity defects as well as complement deficiency and stable rate of humoral immune deficiency. These constants have been a particularity in our population in which consanguinity has remained widespread and preserved the genetic heritage of these diseases [12]. Indeed, consanguinity was found in 58.2 % of families. This rate varied widely in the international registries ranging from 0 % in Singapore [26] to 77 % in Kuwait [24]. But in general and in most countries, the rate of consanguinity in PIDs is higher than in general population. Compared to other North African registries [3], the CID occupied the third place (23 %) in Morocco while they predominated in our study. Also, congenital phagocyte defects, 2nd PID in Tunisia, were ranked 4th in Morocco and fifth in Egyptian frequency. A lot of differences were noticed between the results of Tunisian and Moroccan patients despite similar ethnic, cultural and social characteristics. However, in North Africans countries, the emergence of autosomal recessive forms of PID is a common characteristic favored by endogamy and consanguinity [27]. In Eastern and Western Europe, predominantly antibody deficiencies occupy almost half of the PIDs dominated by IgA and IgG class deficiencies, whereas in our cohort humoral immune deficiencies occupy the fourth place [10]. In the French and Irish records [6, 22], we noticed a higher frequency of humoral immune deficiencies with predominance of CVID. Furthermore, Ireland is distinguished by the frequency of complement deficiencies (29 %) whereas these deficiencies were rare in our country (0.4 %).
In Asian registries, congenital defects of phagocyte were in second place of PIDs in Korea [18] consistent with our results. Although in the last Iranian report [23] predominantly antibody deficiencies were the most common subcategory of PID, SCID was the most common disorder similarly to our results. In contrast with Latin American countries of LAGID [28] and north American countries (USA and Canada) [14], our study is distinguished by the important frequency of combined deficiencies and phagocyte defects while humoral immune deficiencies were the most common in those countries. Besides, the proportion of patients with a well-defined immunodeficiency syndrome is similar to that found in Latin America and the USA with some differences in the subgroups. In our cohort, the Ataxia Telangiectasia syndrome was the predominating group while in Latin America the DiGeorge syndrome was the most common disorder. The complement deficiency and defects of innate immunity were also rare in our study. In comparison with all previously mentioned nationwide registries, the predominance of combined immunodeficiencies as subcategory remains a particular pattern in the present study. This distribution is partly explained by recruitment biases since mainly pediatric clinics were enrolled. The overall mortality rate was 34.5 % in our study. This rate is similar to what was reported in Egypt [2], it is much higher than to what was observed in Asian countries such as Taiwan (19 %) [17], Singapore (10 %) [26] and Hong Kong (11 %) [18]. This difference is explained by the preponderance of SCID in our study. The low frequency of grafted SCID was due to the relatively recent activity of HSCT in our center with restriction to genoidentical graft and also because death occurs rapidly before graft for programmed one.
Conclusion This registry provides the minimal prevalence of PIDs in Tunisia, since the majority of adult patients and probably a large number of children were not included in the database. Nevertheless, this policy will provide better support to Tunisian doctors and researchers to be more familiar with these diseases. It will also be of a great help to the authorities to develop a national strategy for PIDs that involves means of improving the healthcare system for an optimal management of PIDs, of initiating newborn screening programs especially for the identification of infants with SCID and a better and deeper development of the molecular analysis. The poor adult representation (4 %) was an obstacle to get more realistic prevalence. This further underlines a major necessity for awareness programs and additional efforts in adults’ recruitment.
J Clin Immunol (2015) 35:745–753
753
References 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Al-Herz W, Bousfiha A, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2011;2:54. doi:10.3389/fimmu.2011. 00054. Reda SM, Afifi HM, Amine MM. Primary immunodeficiency diseases in Egyptian children: a single-center study. J Clin Immunol. 2009;29(3):343–51. doi:10.1007/s10875-008-9260-x. Bousfiha AA, Jeddane L, El Hafidi N, Benajiba N, Rada N, El Bakkouri J, et al. First report on the Moroccan registry of primary immunodeficiencies: 15 years of experience (1998–2012). J Clin Immunol. 2014;34(4):459–68. doi:10.1007/s10875-014-0005-8. Naidoo R, Ungerer L, Cooper M, Pienaar S, Eley BS. Primary immunodeficiencies: a 27-year review at a tertiary paediatric hospital in cape Town, South Africa. J Clin Immunol. 2011;31(1):99– 105. doi:10.1007/s10875-010-9465-7. Stray-Pedersen A, Abrahamsen TG, Froland SS. Primary immunodeficiency diseases in Norway. J Clin Immunol. 2000;20(6):477– 85. CEREDIH. The French national registry of primary immunodeficiency diseases. Clin Immunol. 2010;135(2):264–72. doi:10.1016/ j.clim.2010.02.021. Modell V, Gee B, Lewis DB, Orange JS, Roifman CM, Routes JM, et al. Global study of primary immunodeficiency diseases (PI)– diagnosis, treatment, and economic impact: an updated report from the Jeffrey Modell Foundation. Immunol Res. 2011;51(1):61–70. doi:10.1007/s12026-011-8241-y. Kirkpatrick P, Riminton S. Primary immunodeficiency diseases in Australia and New Zealand. J Clin Immunol. 2007;27(5):517–24. doi:10.1007/s10875-007-9105-z. Shabestari MS, Maljaei SH, Baradaran R, Barzegar M, Hashemi F, Mesri A, et al. Distribution of primary immunodeficiency diseases in the Turk ethnic group, living in the northwestern Iran. J Clin Immunol. 2007;27(5):510–6. doi:10.1007/s10875-007-9101-3. Gathmann B, Binder N, Ehl S, Kindle G. The European internetbased patient and research database for primary immunodeficiencies: update 2011. Clin Exp Immunol. 2012;167(3):479–91. doi:10.1111/j.1365-2249.2011.04542.x. Aghamohammadi A, Moein M, Farhoudi A, Pourpak Z, Rezaei N, Abolmaali K, et al. Primary immunodeficiency in Iran: first report of the national registry of PID in children and adults. J Clin Immunol. 2002;22(6):375–80. Bejaoui M, Barbouche MR, Sassi A, Larguche B, Miladi N, Bouguerra A, et al. Primary immunodeficiency in Tunisia: study of 152 cases. Archives de Pedia Organe Officiel de la Soc francaise de Pediat. 1997;4(9):827–31. Condino-Neto A, Sorensen RU, Gomez Raccio AC, King A, Espinosa-Rosales FJ, Franco JL. Current state and future perspectives of the Latin american Society for immunodeficiencies (LASID). Allergol Immunopathol. 2014. doi:10.1016/j.aller.2014. 05.007. Modell V, Knaus M, Modell F, Roifman C, Orange J, Notarangelo LD. Global overview of primary immunodeficiencies: a report from Jeffrey Modell Centers worldwide focused on diagnosis, treatment,
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
and discovery. Immunol Res. 2014;60(1):132–44. doi:10.1007/ s12026-014-8498-z. Lamia S, Aloulou H, Kamoun T, Chabchoub I, Ben Moustapha I, Barbouch R, et al. Primary immunodeficiency disorders in 51 cases. La Tunisie medicale. 2013;91(1):38–43. Matamoros Flori N, Mila Llambi J, Espanol Boren T, Raga Borja S, Fontan CG. Primary immunodeficiency syndrome in Spain: first report of the national registry in children and adults. J Clin Immunol. 1997;17(4):333–9. Lee WI, Kuo ML, Huang JL, Lin SJ, Wu CJ. Distribution and clinical aspects of primary immunodeficiencies in a Taiwan pediatric tertiary hospital during a 20-year period. J Clin Immunol. 2005;25(2):162–73. doi:10.1007/s10875-005-2822-2. Rhim JW, Kim KH, Kim DS, Kim BS, Kim JS, Kim CH, et al. Prevalence of primary immunodeficiency in Korea. J Korean Med Sci. 2012;27(7):788–93. doi:10.3346/jkms.2012.27.7.788. Takada H. Primary immunodeficiency in Japan; epidemiology, diagnosis, and pathogenesis. Pediat Int Off J Japan Pediat Soc. 2013;55(6):671–4. doi:10.1111/ped.12224. Gathmann B, Goldacker S, Klima M, Belohradsky BH, Notheis G, Ehl S, et al. The German national registry for primary immunodeficiencies (PID). Clin Exp Immunol. 2013;173(2):372–80. doi:10. 1111/cei.12105. Edgar JD, Buckland M, Guzman D, Conlon NP, Knerr V, Bangs C, et al. The united kingdom primary immune deficiency (UKPID) registry: report of the first 4 years’ activity 2008–2012. Clin Exp Immunol. 2014;175(1):68–78. doi:10.1111/cei.12172. Abuzakouk M, Feighery C. Primary immunodeficiency disorders in the republic of Ireland: first report of the national registry in children and adults. J Clin Immunol. 2005;25(1):73–7. doi:10.1007/s10875005-0360-9. Aghamohammadi A, Mohammadinejad P, Abolhassani H, Mirminachi B, Movahedi M, Gharagozlou M, et al. Primary immunodeficiency disorders in Iran: update and New insights from the third report of the national registry. J Clin Immunol. 2014;34(4):478–90. doi:10.1007/s10875-014-0001-z. Al-Herz W. Primary immunodeficiency disorders in Kuwait: first report from Kuwait national primary immunodeficiency registry (2004–2006). J Clin Immunol. 2008;28(2):186–93. doi:10.1007/ s10875-007-9144-5. Garcia JM, Gamboa P, de la Calle A, Hernandez MD, Caballero MT, Garcia BE, et al. Diagnosis and management of immunodeficiencies in adults by allergologists. J investig Allergol Clin Immunol. 2010;20(3):185–94. Lim DL, Thong BY, Ho SY, Shek LP, Lou J, Leong KP, et al. Primary immunodeficiency diseases in Singapore–the last 11 years. Singap Med J. 2003;44(11):579–86. Barbouche MR, Galal N, Ben-Mustapha I, Jeddane L, Mellouli F, Ailal F, et al. Primary immunodeficiencies in highly consanguineous North African populations. Ann N Y Acad Sci. 2011;1238:42– 52. doi:10.1111/j.1749-6632.2011.06260.x. Leiva LE, Zelazco M, Oleastro M, Carneiro-Sampaio M, Condino-Neto A, Costa-Carvalho BT, et al. Primary immunodeficiency diseases in Latin america: the second report of the LAGID registry. J Clin Immunol. 2007;27(1):101–8. doi: 10.1007/s10875-006-9052-0.
