ORIGINAL RESEARCH
First Report on the Moroccan Registry of Primary
Immunodeficiencies: 15 Years of Experience (1998 – 2012)
A. A. Bousfiha
&L. Jeddane
&N. El Hafidi
&N. Benajiba
&N. Rada
&J. El Bakkouri
&A. Kili
&S. Benmiloud
&I. Benhsaien
&I. Faiz
&O. Maataoui
&Z. Aadam
&A. Aglaguel
&L. Ait Baba
&Z. Jouhadi
&R. Abilkassem
&M. Bouskraoui
&M. Hida
&J. Najib
&H. Salih Alj
&F. Ailal
&For the Moroccan Society for Primary Immunodeficiencies (MSPID)
Received: 31 July 2013 / Accepted: 17 February 2014
#Springer Science+Business Media New York 2014
Abstract
Purpose
Primary immunodeficiencies (PIDs) are a large group of diseases characterized by susceptibility to infections.
We provide the first comprehensive report on PIDs in Moroc- co, the epidemiological, clinical, etiological and outcome features which have never before been described.
Methods
A national registry was established in 2008, group- ing together data for PID patients diagnosed since 1998.
Results
In total, 421 patients were diagnosed between 1998 and 2012. Parental consanguinity was common (recorded for 43.2 % of patients) and the median time to diagnosis was
2.0 years. Overall, 27.4 % of patients were considered to have well defined syndromes with immunodeficiency (48 cases of hyper-IgE syndrome and 40 of ataxia-telangiectasia); 22.7 % had predominantly antibody deficiencies (29 cases of agam- maglobulinemia and 24 of CVID); 20.6 % had combined immunodeficiencies (37 cases of SCID and 26 of MHC II deficiencies) and 17.5 % had phagocyte disorders (14 cases of SCN and 10 of CGD). The principal clinical signs were lower respiratory tract infections (60.8 %), skin infections (33.5 %) and candidiasis (26.1 %). Mortality reached 28.8 %, and only ten patients underwent bone marrow transplantation. We
A. A. Bousfiha (*)
:
L. Jeddane:
I. Benhsaien:
I. Faiz:
Z. Aadam
:
A. Aglaguel:
L. A. Baba:
Z. Jouhadi:
J. Najib:
F. Ailal Clinical Immunology Unit, Department of Pediatric Infectious Diseases, Averroes University Hospital, King Hassan II University—Aïn Chok, Casablanca, Morocco e-mail: profbousfiha@gmail.comN. El Hafidi
Department of Pediatric Infectious Diseases, Avicennes University Hospital, Rabat, Morocco
N. Benajiba
Department of Pediatrics, Al Farabi Hospital, Mohamed VI University Hospital, Oujda, Morocco
N. Rada
:
M. BouskraouiDepartment of Pediatrics, Mohamed VI University Hospital, Marrakech, Morocco
J. El Bakkouri
:
O. MaataouiImmunology Laboratory, Averroes University Hospital, University King Hassan II-Aïn Chok, Casablanca, Morocco
A. Kili
Pediatric Hematology and Oncology Center, Avicennes University Hospital, Rabat, Morocco
S. Benmiloud
:
M. HidaDepartment of Pediatrics, Hassan II University Hospital, Fez, Morocco
Z. Aadam
:
L. A. Baba:
H. S. AljLaboratory of Biology and Health URAC34—Metabolic and Immunologic pathology Research Team, Faculty of Science of Ben M’sik, King Hassan II University—Mohammedia, Casablanca, Morocco
A. Aglaguel
Laboratory of Immunology, Faculty of Sciences and Technology, King Hassan II University—Mohammedia, Mohammedia, Morocco
R. Abilkassem
Department of Pediatrics, Mohamed V Military Hospital, Rabat, Morocco
Moroccan Society for Primary Immunodeficiencies (MSPID) Casablanca, Morocco
URL:www.pid-moroccansociety.org DOI 10.1007/s10875-014-0005-8
analyzed the impact on mortality of residence, family history, parental consanguinity, date of diagnosis and time to diagno- sis, but only date of diagnosis had a significant effect.
Conclusions
The observed prevalence of PID was 0.81/
100,000 inhabitants, suggesting considerable underdiagnosis and a need to increase awareness of these conditions in Mo- rocco. The distribution of PIDs was different from that report- ed in Western countries, with a particularly high proportion of SCID, MHC II deficiencies, hyper-IgE syndrome and autoso- mal recessive agammaglobulinemia. However, we have now organized a national network, which should improve diagno- sis rates in remote regions.
Keywords Primary immunodeficiency . Morocco . registry . epidemiology
Introduction
Primary immunodeficiencies (PIDs) are a large group of dis- eases characterized by a dysfunction of the immune system.
More than 250 diseases have been classified as PIDs and more than 240 morbid genes have been identified [1,
2]. Studies ofPID patients have already improved our understanding of immunological pathways in humans, but we still have much to learn from patients in regions in which PIDs have never been studied or such investigations have only recently begun.
Indeed, particular features have been observed in series of PID patients from emerging countries or regions, such as a particularly high prevalence [3] or high frequency of some diseases, or even the description of new diseases or the detec- tion of founder effects [4]. These discoveries are emerging not only from appropriate immunological explorations of PIDs, but also from clinical observations.
The actual frequency of PIDs remains unknown. Recent epidemiologic studies have estimated the incidence of PIDs at 10.3/100,000 person-years [5], and the prevalence of PIDs at 86.3/100,000 inhabitants [6]. However, prevalence estimates based on registry data are much lower, at up to 5.63/100,000 [7
–13].We provide here the first comprehensive evaluation of PIDs in Morocco, highlighting social, epidemiological, clini- cal and etiological factors, and factors relating to disease progression.
Materials and Methods
The MSPID Network
The first center specializing in PID diagnosis and management in Morocco was the Clinical Immunology Unit of Averroes University Hospital, Casablanca. Since its creation in 1998,
this center has established collaborations with other university medical centers. This informal network was formalized in 2009, with the creation of the Moroccan Society for Primary Immunodeficiencies (MSPID,
www.pid-moroccansociety.org). This society brings together specialists from the
various departments of university medical centers (mostly pediatricians, but also specialists in immunology, hematology, pneumo-allergology, infectious diseases, neurol- ogy and/or internal medicine), and biologists specializing in PID exploration.
Data Collection
The medical records of all PID patients have been stored since the foundation of the Clinical Immunology Unit in 1998. Data collection activities have expanded with the growth of the network and now encompass the whole of Morocco. A data form was developed in collaboration with our PID specialists.
This form is completed by the physician or student responsible for patient management and then validated by PID specialists.
Data include personal information, the results of immunolog- ical analyses and clinical signs, such as failure to thrive, respiratory infections and cutaneous signs.
A computerized database was designed in 2008, based on the data collected, with the Rapid Application Development (RAD) tool of Microsoft Access 2003, with Visual Basic for Application (VBA) code, and OLE control extension (OCX) component technology. The database was designed with Re- lational Database Management System (RDMS) techniques.
Forms and dialogs were designed in Microsoft Access. The registry program allows the data for the patient to be entered from the data form and can also be used for basic statistical analysis. The registry data can also be loaded into Microsoft Excel.
Diagnosis and Classification of Patients
The patients were diagnosed on identification and were clas-
sified according to the most recent update of the IUIS PID
Expert Committee classification [1]. Two PID specialists
reviewed the medical records of each patient before registra-
tion, checking the clinical and laboratory criteria. The immu-
nological tests carried out for our patients were performed by
standard techniques and included serological testing for HIV,
complete blood formula determinations with peripheral blood
smear evaluation, serum immunoglobulin determinations (in-
cluding IgG subclasses and anti-pneumococcal antibody
levels), lymphocyte counts (T, B, NK cells and HLA-DR
expression) by flow cytometry, nitroblue tetrazolium dye tests,
and assessments of complement hemolytic activity (CH50),
with specific complement component when required. Genetic
testing was carried out for only a small number of patients.
Evaluation of Factors Affecting Mortality
We evaluated the impact of various factors on the time be- tween disease onset and diagnosis (time to diagnosis) and mortality. The factors evaluated included residence within or outside Casablanca, family history, parental consanguinity, date of diagnosis. We also assessed the impact of time to diagnosis on mortality.
Statistical Analysis
The registry database program can carry out basic statistical analysis in Microsoft Excel. We carried out Student’s
ttests and
χ2tests to evaluate the impact of the factors considered on time to diagnosis and mortality, respectively.
Results
Patient Characteristics
About 50 to 150 patients per year are referred to our institution for suspected PID, corresponding to about 2,100 patients over the observation period. Explorations led to a total of 421 patients with PID being registered from 1998 to December 2012. The characteristics of all patients are shown, by catego- ry, in Table
I. Mean age at diagnosis was 6.21 years (0–59 years), and mean age at onset was 1.40 years. However, 5.9 % of the patients were diagnosed during adulthood (over the age of 15 years). The sex ratio was 1.17 (228 male patients and195 female patients). Parental consanguinity was noted in 43.2 % of cases and a positive family history of PID was recorded for 81 patients (19.1 %). The number of patients diagnosed increased over time, as shown by an analysis of date of diagnosis (Fig.
1), particularly after the first nationalPID congress in 2008.
Frequency and Distribution of PIDs
The distribution of the Moroccan PID patients between the categories of the 2011 IUIS classification is shown in Table
I.Well defined syndromes with immunodeficiency predominat- ed, followed by predominantly antibody deficiencies, and T- and B-cell combined immunodeficiencies. The distribution of patients by disease is presented in Fig.
2. The most commonlyreported diseases were hyper-IgE syndrome (11.3 %), ataxia- telangiectasia (9.45 %) and severe combined immunodefi- ciencies (8.74 %). The most common condition identified in the predominantly antibody deficiencies category was agam- maglobulinemia (X-linked and autosomal recessive). The least represented category was complement deficiencies, and the 11 patients diagnosed with C1 inhibitor deficiency all belonged to the same family.
Clinical Signs
The clinical signs observed are listed in Table
II. The mostfrequently detected clinical signs were lower respiratory tract infections (60.8 %), followed by skin infections (33.5 %) and candidiasis (26.1 %). However, the frequency of these signs depended on the group of PIDs considered. For example, chronic diarrhea (73.6 %) and failure to thrive (60.9 %) were particularly frequent in combined immunodeficiencies. Simi- larly, bronchiectasis was found to be a common complication of antibody deficiencies (58.3 %).
Genetic Testing and Management
Until recently, no facilities for genetic testing for PIDs were available in Morocco. Tests were performed overseas, through international collaborations, for the following genes:
RAG1,
Jak3,
ELANE, MFEV, IL12RB1and
STAT1. Some research projects have recently been established for the molecular diagnosis of common PIDs in Morocco: MHCII deficiency [4], RAG1/2 deficiency, ataxia-telangiectasia [14], X-linked agammaglobulinemia, chronic granulomatous disease, con- genital neutropenia and Wiskott-Aldrich syndrome.
The management of PID patients in Morocco remains challenging. Only 18 % of our patients have health insurance.
Almost all our patients receive prophylaxis with cotrimoxazole, and CGD patients receive prophylaxis with itraconazole. Thanks to the Hajar Association (www.hajar-
maroc.org), all patients who require immunoglobulins cannow receive them. Subcutaneous immunoglobulins have been available only since 2012, and even then, only for a few patients. In total, 10 PID patients have undergone bone marrow transplantation, including two in Morocco.
Mortality
Global mortality was 28.8 %, and the deaths recorded resulted essentially from infections and their complications. Mortality rates reached 52.9 % for the combined immunodeficiencies category, but did not exceed 8.3 % in the defects of innate immunity category and no deaths were reported in the com- plement deficiencies category. However, 34 patients (8.0 %) have been lost to follow-up since the beginning of this study.
Evaluation of the Selected Factors
We used the data in our database to evaluate the impact on
mortality and time to diagnosis of certain factors, such as
proximity to the reference center, positive family history and
date of diagnosis, together with the impact of time to diagnosis
on mortality (Table
III). As the reference center is located inCasablanca, we suspected that residents of Casablanca were
more likely to be diagnosed and treated than individuals from
TableIPatientcharacteristics CategoryDiagnosisNumber ofpatientsSex- ratio(M/F)Ageat diagnosis (years) Ageat onset (years)
Parental consanguinityFamily historyMortality%over15years ofageat diagnosis I.Combined immunodeficiencies871.261.460.7744.8%19.5%52.9%0.0% SCID371.640.9735.1%18.9%75.7% MHCIIdeficiency281.151.3346.4%28.6%50.0% Omennsyndrome2Bothfemale0.33100.0%0.0%100.0% CD8αdeficiency320.9466.7%0.0%33.3% Others191.112.5757.8%10.5%21.1% II.Welldefinedsyndromes withimmunodeficiency1160.936.651.4945.7%25.9%24.1%4.3% HyperIgEsyndrome481.296.2537.5%18.8%8.3% Ataxia-telangiectasia400.747.1270.0%50.0%42.0% DiGeorgesyndrome150.53.7113.3%0.0%20.0% Wiskott-Aldrichsyndrome3Allmale9.060.0%0.0%0.0% Bloomsyndrome4Allfemale6.1725.0%0.0%25.0% Others6211.2766.7%16.7%33.3% III.Predominantantibody deficiencies961.346.082.0340.6%10.4%25.0%6.3% SeverereductioninallserumIg isotypeswithprofoundly decreasedorabsentBcells
2945.2424.1%17.2%17.2% Severereductioninatleast2serum Igisotypes,withnormalorlow numbersofBcells 241.188.7862.5%12.5%16.7% SeverereductioninserumIgGand IgA,withincreasedIgMand normalnumberofBcells
91.255.6344.4%11.1%66.7% Isotypeorlightchaindeficiencies withnormalnumbersofBcells330.575.2939.4%3.0%27.3% Transienthypogamma- globulinemiaofinfancy1Male0.830.0%0.0%0.0% IV.Diseasesofimmune dysregulation983.810.8344.4%22.2%44.4%0.0% V.Congenitaldefectsof phagocytes741.245.521.2941.9%12.2%16.2%2.7% Severecongenitalneutropenia142.52.6442.9%0.0%28.6% MSMD100.677.4540.0%10.0%40.0% Chronicgranulomatousdisease11Allmale3.2954.5%27.3%18.2% Others390.77.0438.5%12.8%7.7% VI.Defectsofinnateimmunity1218.631.0725.0%0.0%8.3%16.7% VII.Autoinflammatorydisorders121.48.573.0116.7%0.0%16.7%0.0% VIII.Complementdeficiencies130.4433.381.8884.6%100.0%0.0%69.2% Unclassified435.831.1325.0%0.0%0.0%0.0% Total4211.176.211.443.2%19.1%28.8%5.9% Ffemale,Mmale,MHCIImajorhistocompatibilitycomplextypeIId,MSMDMendeliansusceptibilitytomycobacterialdisease,SCIDseverecombinedimmunodeficiency
elsewhere. Likewise, we hypothesized that patients with a positive family history would be more likely to consult a physician more rapidly and would therefore also be at an advantage. However, none of these factors had a significant impact on time to diagnosis or mortality in our series.
Parental consanguinity also had no effect on time to diagnosis or mortality.
By contrast, date of diagnosis had a significant impact on time to diagnosis and mortality, demonstrating a marked im- provement in our practices over time. However, too little time has passed as yet for any firm conclusions to be drawn about the significance of the recent decrease in mortality. We also evaluated the impact of early and late diagnosis on mortality, but no significant impact was observed for the series as a whole, probably because our evaluation included both very severe and more moderate phenotypes.
Discussion
Biases
Our series was subject to several sources of bias. First, not all the tests were available throughout the 15-year period consid- ered. Indeed, the exploration process changed over time (e.g.
the NBT test was introduced in 2009, and CH50 was intro- duced only recently). Similarly, IgE levels were initially checked only in cases of a phenotype clearly suggestive of hyper-IgE syndrome (facial features, pneumatocele, etc.). This exploration was subsequently extended to patients with other clinical signs of hyper-IgE syndrome.
Even now, not all the tests required are available. This lack of resources limits diagnosis. For example, we do not have the facilities to perform lymphocyte proliferation tests, and we
therefore classify patients with hypogammaglobulinemia and normal T- and B-cell levels as having common variable im- munodeficiency. This may result in some functional T-cell defects being missed. This lack of precision in some of our diagnoses may account for certain unexpected or unusual clinical presentations in our patients (e.g. candidiasis in pa- tients with antibody deficiencies). Furthermore, previously unknown diseases may be concealed in our series, as genetic confirmation has been carried out for only a few patients.
The rate of diagnosis has increased with time (Fig.
1),thanks to awareness campaigns carried out throughout Mo- rocco, particularly since the 1st international meeting of the African Society for Immunodeficiencies (ASID) in 2008.
Another bias was introduced because particular attention was paid to awareness of certain diseases in recruitment for research projects. This was the case for hyper-IgE syndromes, ataxia-telangiectasia, agammaglobulinemia and congenital neutropenia.
Characteristics of Morocco
Morocco differs from its neighbors in terms of its history and geographic situation. Indeed, this country, which is bordered by the Mediterranean Sea to the north, the Atlantic Ocean to the west, the Sahara to the south and the Atlas Mountains to the east, has long been essentially isolated from its neighbors.
However, these natural frontiers are not insurmountable, and cultural and economic exchanges did take place, leading to the current Moroccan population displaying considerable ethnic diversity, combining Arabian, Berber, black African and Cau- casian groups. This particular history is reflected in the diver- sity of population genetics in Morocco.
Even now, geographic constraints still prevent patients from being diagnosed. Indeed, although there was one
13 15 13 10 12 1634 20
28 29
32 37
68 46
39
0 50 100 150 200 250 300 350 400 450
New Baseline Fig. 1 Changes in the rate of PID
diagnosis in Morocco
physician per 1,630 inhabitants in Morocco in 2011, this indicator ranged from 1/713 in the region of Rabat-Sale- Zemmour-Zaër to 1/4,867 in the southern region of Oued Eddahab-Lagouira. Moreover, only 16 of the 311 specialists in Morocco practice in rural areas [15]. Patients may therefore encounter difficulties gaining access to care, and awareness of PIDs must be raised in remote areas.
Parental Consanguinity
Parental consanguinity rates in Morocco have been estimated at 21 % [16] in the general population. This relatively high rate of parental consanguinity probably results in a high incidence of autosomal recessive genetic disorders. Parental consan- guinity rates reached 43.2 % in our series of patients and the
0 10 20 30 40 50
SCID MHC II deficiency CD4 deficiency CD8 deficiency Ommen Unclassified
Hyper IgE Ataxia Telangiectasia DiGeorge Bloom WAS XL-DKC HCC PMS2 Netherton
CVID Selective IgA def XLA AR agammaglobulinemia Hyper IgM IgG sub-classes def IgA + IgG sub-classes def Transient hypogammaglobulinemia
Griscelli Chediak Higashi Hermansky-Pudlak ALPS
Cyclic neutropenia SCN CGD MSMD LAD I Glycogenose Ib Poïkilodermia
CMC IRAK 4 EDA
FMF HIDS
C1 inhibitor C5 Unclassified Fig. 2 Number of patients, by disease, in Morocco
available data for genetic disorders showed a relatively high abundance of conditions displaying autosomal recessive in- heritance. Indeed, an immunophenotyping study of 30 SCID patients showed a predominance of T
−B
−SCID (63.3 %), with T
−B
−NK
+being the most common subtype (46.7 %) [17], and this subtype is known to have an exclusively autosomal re- cessive mode of transmission. Moreover, two of the three patients with the T
−B
+NK
−phenotype, which is generally
associated with XL-SCID, were diagnosed with Jak-3 defi- ciency, which is autosomal recessive.
Furthermore, 19 of the 46 diagnoses registered in our series corresponded to PIDs displaying exclusively autosomal reces- sive inheritance (41.3 % of the diagnoses), accounting for 31.1 % of our patients. Eight other diagnoses related to po- tentially autosomal recessive PIDs, and these diagnoses accounted for 34.5 % of our patients. Finally, one of our patients presented with FMF and cyclic neutropenia, although only
MFEVdeficiency was confirmed and no mutation was found in
ELA2[18]. The simultaneous presentation of two rare immunodeficiencies has already been reported in one girl from Qatar with ataxia-telangiectasia and susceptibility to mycobacteria [19]. Such cases are likely to be rare, but the simultaneous occurrence of two rare PIDs is probably more common in ethnic groups with high parental consanguinity rates.
Late Diagnosis
A comparison of the median age at diagnosis for the patients in our registry with that for the French registry showed that diagnosis occurred later in Morocco (4 years vs. 0.9 years in France in the last decade) [8]. In Kuwait, mean age at diag- nosis was 43 months [20], or 3.58 years, whereas mean age at diagnosis was 6.27 years in Morocco. However, mean or median age at diagnosis is not a good indicator, because the high proportion of patients with adult-onset disease in some series tends to increase this value, as already observed in Japan (12.8 years) and Australia (31 years) [7,
12]. It is thereforeimportant to consider the time to diagnosis (the time between disease onset and diagnosis). The median time to diagnosis is 2.00 years in Morocco, but has been estimated at 1 year in France [8]. This late diagnosis can be accounted for by the lack of awareness of these diseases in the Moroccan medical
Table II Clinical spectrum for PID patients at the time of diagnosisMajor clinical features All PIDs (N=421)
Combined immunodeficiencies (N=87)
Well defined syndromes (N=116)
Antibody deficiencies (N=96)
Phagocyte disorders (N=74)
Failure to thrive 99 23.5 % 53 60.9 % 16 13.8 % 19 19.8 % 11 14.9 %
Upper respiratory tract infections 103 24.5 % 14 16.1 % 36 31.0 % 38 39.6 % 14 18.9 %
Lower respiratory tract infections 256 60.8 % 69 79.3 % 71 61.2 % 85 88.5 % 28 37.8 %
Bronchiectasis 104 24.7 % 12 13.8 % 34 29.3 % 56 58.3 % 2 2.7 %
Skin infections 141 33.5 % 24 27.6 % 46 39.7 % 20 20.8 % 46 62.2 %
Candidiasis 110 26.1 % 63 72.4 % 13 11.2 % 9 9.4 % 18 24.3 %
Chronic diarrhea 109 25.9 % 64 73.6 % 19 16.4 % 14 14.6 % 10 13.5 %
Septicemia 57 13.5 % 24 27.6 % 3 2.6 % 5 5.2 % 25 33.8 %
Meningitis 19 4.5 % 5 5.7 % 2 1.7 % 7 7.3 % 2 2.7 %
Urinary tract infections 27 6.4 % 9 10.3 % 8 6.9 % 6 6.3 % 3 4.1 %
Osteomyelitis / septic arthritis 26 6.2 % 2 2.3 % 3 2.6 % 10 10.4 % 6 8.1 %
Table III Impact of various factors on time to diagnosis and mortality
Factors Median age
at diagnosis (years)
Median time to diagnosis (years)
Mortality
Residence
Casablanca (N=63) 2.75 1.5 31.75 %
Elsewhere (N=120) 2.5 1.58 31.67 %
Family history
Positive (N=48) 2.67 2 33.33 %
Negative (N=134) 2.46 1.44 31.34 %
Parental consanguinity
Positive (N=104) 2.58 1.58 37.50 %
Negative (N=78) 2.46 1.48 24.36 %
Date of diagnosis
Before 2000 (N=17) 5.5 3.25* 58.82 %*
2001–2008 (N=52) 2 1* 48.07 %*
2008–2012 (N=113) 2.75 2* 20.35 %*
Time to diagnosis
<0.5 years (N=51) NA NA 37.25 %
>0.5 years and <2 years (N=49)
NA NA 28.57 %
>2 years (N=81) NA NA 28.40 %
*p<0.05
community, the lack of facilities in certain regions and diffi- culties gaining access to care.
PIDs in Adults
In our series, only 5.9 % of the patients were diagnosed after the age of 15 years, and 17.6 % of our patients are now adults.
This proportion seems low, when compared to other series for which age data are available: 52.1 % in ESID [13], 42.8 % in Japan [12] and 40.7 % in Iran [10]. However, this is not surprising, given that most of our PID specialists are pediatri- cians. This suggests that efforts should be made to train adult physicians in the diagnosis of PIDs.
Etiology
Comparisons of the distribution of our patients between major categories with that of patients in other published registries (Fig.
3) revealed a difference between regions with low andhigh parental consanguinity rates. In Europe, Japan and South America, the predominant category of PIDs is antibody defi- ciencies. However, in the Arab world (represented here by Morocco and Tunisia), patients tend to be essentially equally distributed between combined immunodeficiencies, antibody deficiencies and well defined syndromes with immunodefi- ciency. This difference may be accounted for partly by the limits to PID exploration encountered in less developed
regions, leading to the overrepresentation of severe pheno- types. We also had fewer patients diagnosed with common variable immunodeficiency, which accounts for a large pro- portion of antibody deficiencies, than might have been ex- pected. Moreover, only symptomatic selective IgA deficien- cies were diagnosed in our series, whereas other registries generally include cases of asymptomatic IgA deficiency diag- nosed at transfusion centers.
Another difference is the large proportion of cases displaying MHC II deficiency in North African countries.
Indeed, a founder effect has already been identified in these countries [4,
21], and has been dated to 2,000 years ago,before the arrival of the Muslim groups, most of which are Arabian [21]. This was confirmed by the finding of another mutation in patients from the Middle East [22]. We also found a large proportion of patients with Mendelian susceptibility to mycobacterial disease (MSMD). Indeed, IL12RB1 deficien- cies were first reported in Moroccan patients [22].
The major differences between the Moroccan and Tunisian profiles are the higher proportions of LAD, AT, CVID and CGD patients in Tunisia and the higher proportions of hyper- IgE syndrome, cyclic neutropenia and auto-inflammatory dis- orders in our series. As mentioned above, this is due mostly to the bias introduced by particular interest being paid to certain topics. We specifically searched for leukocyte adhesion defi- ciency, but were unable to diagnose more than two patients.
Moreover, the founder effect detected in Tunisian patients [24]
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
Other complement deficiencies C1 inhibitor
Other autoinflammatory disorders FMF
Other defects in innate immunity CMC
Other phagocytic disorders MSMD
CGD SCN
Diseases of immune dysregulation Other antibody deficiencies CVID
Agammaglobulinemias Other well-defined syndromes HIES
Ataxia telangiectasia Other CIDs MHC II SCID
Fig. 3 Comparison of the distribution of the major categories of PID between series. I to VIII represent the eight major groups of the IUIS classification.CGDchronic granulomatous disease,CMCchronic muco- cutaneous candidiasis,CVIDcommon variable immunodeficiency,FMF
familial Mediterranean fever,HIEShyper-IgE syndrome,MHC IImajor histocompatibility complex type II deficiency,MSMDMendelian suscep- tibility to mycobacterial disease,SCIDsevere combined immunodefi- ciency,SCNsevere congenital neutropenia
was not found in our patients. However, most of the Tunisian patients originated from the same tribe, which has a high consanguinity coefficient. The high proportion of ataxia- telangiectasia cases observed in Tunisia was already apparent in the first data published for the Tunisian series, in which one third of the patients had been diagnosed with this condition [24]. However, this was explained by a recruitment bias, due to the large number of pediatric neurologists.
Underdiagnosis
It is widely accepted that PIDs are underdiagnosed worldwide, but particularly in low-income countries. In our series, the observed prevalence of PID was 0.81/100,000 inhabitants, which is considerably lower than the values reported for France (5.56/100,000) or Australia (5.6/100,000) [7,
8]. In arecent study, we estimated that 27,852 patients would be expected to harbor a PID in Morocco in 2011, and that about 3,300 new cases should be diagnosed each year [26]. Even if the first of these estimates appears high, the gap between these estimates and those for France remain large, even without taking into account the effect of parental consanguinity. We have tried to improve diagnosis rates in our country, by raising public awareness of PIDs through the actions of the HAJAR Association (http://www.hajar-maroc.org) and participation in World PI Week [26]. We have also tried to increase the awareness of the medical community, through publications at the national and regional (North Africa) levels [28,
29]. Wehave also recently published a phenotypic version of the IUIS classification, which should help physicians to recognize and diagnose PID at the patient’s bedside [30].
Conclusion
The establishment of a registry by our network made it pos- sible to take a snapshot of PID epidemiology in Morocco. The observed prevalence of PIDs (0.81/100,000 inhabitants) was considerably lower than the expected value and the distribu- tion of patients between the different types of PID differed from that in Western countries. Time to diagnosis was also longer in Morocco. These findings suggest that we should continue our efforts to raise awareness of these diseases.
We have highlighted the effect of high parental consan- guinity rates on the emergence of autosomal recessive dis- eases, and the overrepresentation of severe phenotypes, which are easier to diagnose. We also observed unexpected clinical features in our series, suggesting that further investigations are required in these patients, potentially leading to the identifi- cation of new diseases or pathways.
These data should help stakeholders (authorities, NGOs, MSPID) to develop strategies for improving the care and quality of life of patients with PIDs in Morocco. However,
coverage of the patients diagnosed in this country could be improved by a better recruitment strategy, to increase our understanding of the epidemiology of PIDs in Morocco.
The position of Morocco at the crossroads between Europe and Africa has prompted us to try to establish a center of excellence for PID diagnosis and management in our country, which should be of benefit to West African countries in general.
Acknowledgement We would like to thank the HAJAR Association (www.hajar-maroc.com), for the funding and support allocated to this project.
Conflict of Interest The authors have no conflict of interest to declare.
References
1. 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.
2. RAPID: Resource of Asian Primary Immunodeficiency Diseases:
http://rapid.rcai.riken.jp/RAPID. Accessed 28 Jul 2013.
3. Ehlayel MS, Bener A, Laban MA. Primary immunodeficiency dis- eases in children: 15 year experience in a tertiary care medical center in Qatar. J Clin Immunol. 2013;33:317–24.
4. Naamane H, El Maataoui O, Ailal F, Barakat A, Bennani S, Najib J, et al. The 752delG26 mutation in the RFXANK gene associated with major histocompatibility complex class II deficiency: evidence for a founder effect in the Moroccan population. Eur J Pediatr.
2010;169(9):1069–74.
5. Joshi AY, Iyer VN, Hagan JB, Sauver JLS, Boyce TG.
Incidence and temporal trends of primary immunodeficiency:
a population-based cohort study. Mayo Clin Proc. 2009;84(1):
16–22.
6. Boyle JM, Buckley RH. Population prevalence of diagnosed primary immunodeficiency diseases in the United States. J Clin Immunol.
2007;27:497–502.
7. Kirkpatrick P, Riminton S. Primary immunodeficiency diseases in Australia and New Zealand. J Clin Immunol. 2007;27:517–24.
8. CEREDIH. The French PID study group. The French national regis- try of primary immunodeficiency diseases. Clin Immunol. 2010;135:
264–72.
9. Leiva LE, Zelazco M, Oleastro M, Carneiro-Sampaio M, Condino- Neto A, Tavares Costa-Carvalho B, et al. Primary immunodeficiency diseases in Latin America: the second report of the LAGID Registry.
J Clin Immunol. 2007;27(1):101–8.
10. Rezaei N, Aghamohammadi A, Moin M, Pourpak Z, Movahedi M, Gharagozlou M, et al. Frequency and clinical manifestations of patients with primary immunodeficiency disorders in Iran: update from the Iranian Primary Immunodeficiency Registry. J Clin Immunol. 2006;26(6):519–32.
11. Barbouche MR, Galal N, Ben Mustapha I, Jeddane L, Mellouli F, Ailal F, et al. Primary immunodeficiencies in highly consan- guineous North African populations. Ann N Y Acad Sci.
2011;1238:42–52.
12. Ishimura M, Takada H, Doi T, Imai K, Sasahara Y, Kanegane H, et al.
Nationwide survey of patients with primary immunodeficiency dis- eases in Japan. J Clin Immunol. 2011;31:968–76.
13. ESID database statistics. In: European Society for Immunodeficiencies.
2012.http://www.esid.org/statistics.php. Accessed 26 July 2013.
14. Jeddane L, Ailal F, Dubois-d’Enghien C, Abidi O, Benhsaien I, Kili A, et al. Molecular defects in Moroccan patients with ataxia-telangiectasia.
NeuroMolecular Med. 2013;15(2):288–94.
15. Health Ministry of Morocco. Healthcare indicators in 2011. In:http://
cartesanitaire.sante.gov.ma/offresoins/. Accessed 10 Sept 2013.
16. Haut-commissariat au Plan. Mariage et divorce de la femme marocaine: tendances d’évolution. In:http://www.hcp.ma/Mariage- et-divorce-de-la-femme-marocaine-Tendances-d-evolution_a1261.
htmlAccessed 17 Oct 2013.
17. El-Maataoui O, Ailal F, Naamane H, Benhsaien I, Jeddane L, Farouqi B, et al. Immunophenotyping of severe combined immunodeficiency in Morocco. Immunol Anal Biol Spécialisée. 2011. doi:10.1016/j.
immbio.2011.05.002.
18. Ganiou Tidjani K, Ailal F, Najib J, Bellanné-Chantelot C, Donadieu J, Bousfiha AA. Intermittent chronic neutropenia in a patient with fa- milial Mediterranean fever. Pediatr Blood Cancer. 2008;51(5):701–3.
19. Ehlayel M, de Beaucoudrey L, Fike F, Nahas SA, Feinberg J, Casanova JL, et al. Simultaneous presentation of 2 rare hereditary immunodeficiencies: IL-12 receptor beta1 deficiency and ataxia- telangiectasia. J Allergy Clin Immunol. 2008;122(6):1217–9.
20. 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.
21. Ouederni M, Vincent QB, Frange P, Touzot F, Scerra S, Bejaoui M, et al. Major histocompatibility complex class II expression deficiency caused by a RFXANK founder mutation: a survey of 35 patients.
Blood. 2011;118(19):5108–18.
22. Al-Herz W, Alsmadi O, Melhem M, Recher M, Frugoni F, Notarangelo LD. Major histocompatibility complex class II
deficiency in Kuwait: clinical manifestations, immunological find- ings and molecular profile. J Clin Immunol. 2013;33(3):513–9.
23. Altare F, Ensser A, Breiman A, Reichenbach J, Baghdadi JE, Fischer A, et al. Interleukin-12 receptor beta1 deficiency in a patient with abdominal tuberculosis. J Infect Dis. 2001;184(2):231–6.
24. Fathallah DM, Jamal T, Barbouche MR, Bejaoui M, Hariz MB, Dellagi K. Two novel frame shift, recurrent andde novomutations in the ITGB2 (CD18) genecausing leukocyte adhesion deficiency in a highly inbred North African population. J Biomed Biotechnol.
2001;1(3):114–21.
25. Bejaoui M, Barbouche MR, Sassi A, Larguche B, Miladi N, Bouguerra A, et al. Primary immunodeficiency in Tunisia: study of 152cases. Arch Pediatr. 1997;4(9):827–31.
26. Bousfiha AA, Jeddane L, Ailal F, Benhsaien I, Mahlaoui N, Casanova JL, et al. Primary immunodeficiency diseases worldwide:
more common than generally thought. J Clin Immunol. 2013;33(1):
1–7.
27. Sorensen R, Etzioni A, Bousfiha AA, Zeiger JB, Collaborating to improve quality of life in primary immunodeficiencies: World PI Week, 2013. J Clin Immunol. 2013. doi:10.1007/s10875-013-9921-2.
28. Ailal F, Benhsaien I, Amenzoui N, Kili A, Jeddane L, Najib J, et al.
Evoquer, explorer et diagnostiquer un déficit immunitaire primitif.
Rev Marocaine Mal l’Enfant. 2012;28:46–52.
29. Admou B, Haouach K, Ailal F, Benhsaine I, Barbouch MR, Bejaoui M, et al. Déficits immunitaires primitifs: approche diagnostique pour les pays émergents. Immunol Anal Biol Spécialisée. 2010. doi:10.
1016/j.immbio.2010.09.003.
30. Bousfiha AA, Jeddane L, Ailal F, Al Herz W, Conley ME, Cunningham-Rundles C, et al. A phenotypic approach for IUIS PID classification and diagnosis: guidelines for clinicians at the bedside. J Clin Immunol. 2013. doi:10.1007/s10875-013-9901-6.
