Clinical Predictors of Primary Immunodeficiency Diseases in Children

Primary immunodeficiency (PID) diseases are a diverse group of rare genetic disorders that affect the development and/or function of the immune system. Affected individuals are predisposed to an increased rate and severity of infections, allergy, autoimmunity, and malignancy.1 With the exception of immunoglobulin A (IgA) deficiency, PID diseases are considered to be rare; the estimated prevalence of these disorders in the United States is approximately 1 in 1,200 live births. IgA deficiency is the most common PID, occurring in approximately 1 in 300 to 1 in 500 persons.2 Early detection of PID is important for timely intervention before serious infections compromise the patient's general condition.3, 4 However, failure to recognize these conditions remains a major challenge for clinicians worldwide. The problem is that general practitioners lack familiarity with these rare disorders and lack guidance regarding the appropriate use of immunological investigations.5 Moreover, considering that other diseases, including anatomic defect, allergy, and metabolic disorders, are primarily associated with recurrent infections, it is crucial for the general practitioner to determine which patient should be evaluated for PID.6-8 In an attempt to facilitate clinical reasoning concerning when to suspect PID in clinical practice, National Primary Immunodeficiency Resource Center9 developed a list of 10 warning signs of PID (Table 1). Physicians should consider PID if a patient encounters one or more of these warning signs, which basically focus on the site, severity, and frequency of infection. Because the scope of PID clinical presentations includes manifestations other than infection, Cunningham-Rundles and colleagues10 developed an immunodeficiency-related (IDR) score to identify the likelihood of finding immunodeficiency among patients undergoing immune evaluation. The score includes several medical conditions associated with PID (Table 2). An IDR score of ≥6 was considered by the authors to be a threshold indicating a significant number of illnesses with the likelihood of PID.10, 11

Table 1
The 10 warning signs of primary immunodeficiency in children

• Click for larger image
• Click for full table
• Download as Excel file

Table 2
Immunodeficiency diseases related (IDR) score

• Click for larger image
• Click for full table
• Download as Excel file

Egypt is a country with nearly 83 million inhabitants (according to the last national population census in 2009), of which 9 million are below the age of 5 years. The estimated mortality rate among children less than 5 years reached 21/1,000 live births, of which pneumonia and gastroenteritis accounted for 17% of all deaths.12 Unfortunately, no national registry of PID diseases exists in Egypt and currently only 160 Egyptian PID children are registered with the European Society for Immunodeficiencies (ESID).13 These patients are affiliated with two PID centers in the country: one at Ain Shams University (100 cases) and the other at Cairo University (60 patients). These figures clearly do not represent the actual burden of PID diseases in Egypt. We believe that many PID patients die before diagnosis probably because awareness of these diseases among clinicians is suboptimal. In a previous study, we found a significant delayed diagnosis, severe morbidity, and high mortality rates among patients with severe PID phenotypes,14 indicating that more effort is needed to implement educational campaigns that target general practitioners and pediatricians. Thus, in the present study, we aimed to test the validity of the 10 warning signs and IDR score as predictors of PID disease, and to identify the most significant warning signs that would help physicians to identify PID cases in clinical practice.

This study was approved by the ethical committee of the Pediatric department, Faculty of Medicine, Ain Shams University.

The medical records of 204 patients who presented with recurrent, severe, or unusual infection at Ain Shams University Children's Hospital during the last 7 years were reviewed. Based on the World Health Organization (WHO) diagnostic criteria of PID,15 a diagnosis of PID disease was established in 92 patients. In the remaining 112 patients, laboratory investigations failed to reveal underlying PID disease. For each patient, an evaluation sheet was designed to describe demographic data, including age at onset of symptoms, age at diagnosis, the diagnosis lag, which represents the time elapsed between onset of symptoms and diagnosis, sex, parental consanguinity, family history of PID, history of sibling death due to infections, as well as clinical and laboratory findings at the time of diagnosis. The performed laboratory work-up of these patients included measurement of the complete blood count with differential, C-reactive protein level, erythrocyte sedimentation rate, cultures from infection sites, serum immunoglobulins (IgA, IgG, IgM, and IgE), delayed cutaneous hypersensitivity (purified protein derivative, Candida skin test), peripheral blood lymphocyte subsets, including the basic panel of T-cell subsets (CD3, CD4, and CD8, B-cell [CD19], and natural killer cell [CD56/16]) by flow cytometry. Other laboratory investigations, including nitroblue tetrazolium dye testing, measurement of serum alpha fetoprotein, and assessment of CD18/CD11 on neutrophils by flow cytometry, were performed when indicated. Both complement hemolytic activity (CH50) and genetic testing were not available in our laboratories and hence were not evaluated. Imaging studies such as chest radiography, computed tomography (CT), echocardiography, and abdominal ultrasonography were employed in some cases. Additionally, each patient was evaluated for the frequency of each criterion of the current version of the 10 warning signs (Table 1) and given a score out of 10, representing the number of positive warning signs. Similarly, the IDR score (Table 2) was calculated and the score weight of each patient represented the sum of score descriptions acquired from the date of symptom onset to the date of diagnosis. Chronic conditions were counted only once in a 12-month period. The study was approved by the ethical committee of Ain Shams University. Informed consent was obtained from the legal guardian of every patient enrolled in the present study.

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 Iran,19 Kuwait,20 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. Fig. 2 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

Fig. 2
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.

• Click for larger image
• Download as PowerPoint slide

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.