The present study clearly demonstrates that PID diseases are underdiagnosed in Egypt. In the present study, various PID diseases were identified in 45% of cases with recurrent infection observed at a single tertiary hospital. Delayed diagnosis was evident in all PID diseases, reflecting poor knowledge of PID among clinicians. The overall evaluation of the 10 warning signs revealed that at least two warning signs should be fulfilled to identify nearly two-thirds of PID cases. Similar to other studies,17,18
the need for intravenous antibiotics to clear infection was the most significant warning sign reported in PID patients, denoting that physicians and general practitioners should consider the diagnosis of PID in children when intravenous antibiotics are needed to clear infection. However, the strongest predictors of PID in our cohort were a positive family history of PID, parental consanguinity, and previous sibling death from infection. Indeed, high rates of parental consanguinity in PID patients were previously reported in Middle Eastern countries, including Egypt,14
and other North African countries.21
A positive family history of PID was also the strongest predictor of PID in two tertiary pediatric immunology hospitals in the north of England, although 30% of those cases were of Asian-Pakistani descent in whom parental consanguinity was high.17
Failure to thrive was a significant predictor of PID in the entire cohort. However, unlike the study of Subbarayan and associates,17
this sign was not a significant predictor of combined T- and B-cell immunodeficiencies, probably because one-third of non-PID patients exhibited failure to thrive. Although the only significant predictors of combined T- and B-cell immunodeficiencies in the present study were consanguinity and a history of repeated sibling death due to infection, it is possible that deceased siblings had unidentified PID. Thus, physicians must be vigilant to the likelihood of severe PID when a history of previous sibling death and/or parental consanguinity is identified in infants with infection. illustrates the most significant warning signs found in our study that would help general practitioners to suspect PID among children with one or more of these signs. If available, a neonatal screening test for severe life-threatening PID diseases, such as SCID, will provide timely diagnoses and improve the management and prognosis of such conditions.23
The most significant warning signs of primary immunodeficiencies in studied cases. *Neonatal screening is indicated for the timely diagnosis of severe PID diseases, such as severe combined immunodeficiency. PID, primary immunodeficiency.
Recently, the feasibility of promoting the use of the 10 warning signs as predictors of PID has been questioned. Specifically, if these signs are considered to be a screening tool for PID, many patients who manifest with atopy,24
autoimmunity, malignancy, or initially present with fulminant infections will be missed.25
In a recent publication, Modell and colleagues26
acknowledged the 10 warning signs to be a useful tool to promote awareness among PID families, the general public, and medical practitioners, but urged for the development of additional tools that facilitate identification of patients at high risk for PID.
Conversely, the cut-off value of the IDR score in predicting PID in our cohort was similar to that in other series,10,11,27
indicating that nearly 75-80% of PID cases could be identified at a score ≥6. However, our data showed that the IDR score did not help in the diagnosis of severe life-threatening PID diseases, because nearly one-fifth of PID patients had scores <6 and their diagnoses could have been missed if the IDR score was the only predictor of PID. Undoubtedly, appropriate clinical and laboratory assessments are required to confirm or exclude the suspicion of PID. Education regarding the various manifestations of PID diseases should target not only general practitioners and pediatricians, but also specialists in hematology, oncology, rheumatology, and neurology.25
To improve the recognition of PID diseases in children, ESID has recently developed a multistep diagnostic protocol for PID diseases28
that describes the various clinical presentations of PID disease and the essential laboratory tests required at the initial step of evaluation. Thus, early identification and timely referral of suspected cases to a specialized PID center may be achieved, allowing for more detailed investigations and genetic diagnoses,29
which are important to guide the treatment and follow-up of PID patients, as well as genetic counseling of families.
Finally, our study possessed some limitations. First, the study was conducted on a small number of patients who presented at a tertiary hospital, which made it difficult to evaluate the prevalence of different PID diseases in the entire country. Second, patients in the present cohort presented at a tertiary hospital because they either had critical acute illnesses or chronic difficult-to-treat conditions; thus, the cohort was biased towards the severe forms of PID diseases as well as severe and complicated non-PID conditions. Additionally, advanced molecular and genetic studies are not available in Egypt; hence, we could not confirm the diagnosis of many subtypes of PID diseases listed in the IUIS classification16
that require molecular analysis for diagnosis.
In conclusion, the present study represents an evidence-based analysis of the 10 warning signs and IDR score as predictors of PID. Our data showed that only 4 of 10 warning signs were significant in identifying PID, of which a family history of PID was the strongest predictor. Parental consanguinity and a history of sibling death were two additional significant warning signs in our community. A high index of suspicion is still the mainstay for detecting PID. Negative scoring of either the 10 warning signs or the IDR score must not exclude PID diagnosis if clinically suspected, and early referral to a specialized center should be considered. It is essential to encourage genetic counseling of affected or high-risk families, and to establish population-based neonatal screening of severe life-threatening PID diseases.