Clinical Features That Identify Children With Primary Immunodeficiency Diseases

DISCUSSION

Our results provide a simple evidence-based schema for identifying children with PID; until now, guidelines have relied largely on expert opinion.⁵ Because our data demonstrate that 95% of children with PID are referred by hospital pediatricians and 1 of the key warning signs is the need for intravenous antibiotics to treat sepsis, it seems logical to focus on educating physicians rather than the general public to ensure that children with PID are diagnosed in a timely fashion.⁷ Indeed, the success of a physician-focused awareness program in central and eastern Europe (J Project) is clearly illustrated by the exponential increase in the incidence of patients with PID followed up between 2004 and 2007 (from tens to thousands of patients).⁸

We also found that a positive family history is the key warning sign of PID. In addition to educating hospital-based pediatricians, families of children with PID should receive genetic counseling and understand the importance of screening all subsequent children soon after birth if unnecessary morbidity and mortality are to be avoided. Particularly in PID with an autosomal recessive basis, parental consanguinity is important. Countries with high rates of consanguinity—such as north and sub-Saharan Africa, the Middle East, and west, central, and south Asia—are likely to have a higher prevalence.⁹ For example, in Egypt,¹⁰ Kuwait,¹¹ and Iran,¹² where more than half of the parents are second cousins or even more closely related, studies have highlighted the link between consanguinity and PID. Regional variation in the prevalence of PID also occurs within countries. An example is the higher prevalence of PID in ethnic Turks living in northwestern Iran.¹³ A northwestern England PID database set up in 2002 and incorporating prospective information of all patients seen in the 2 tertiary PID centers, found a threefold higher prevalence of defined PID (1 per 3600 children) than in the United Kingdom as a whole (unpublished data). This northwest area is home to 25% of total Asians from the Indian Subcontinent living in England, and >50% of the parents from this ethic group are in first-cousin marriages.¹⁴

Pediatricians managing children with infectious diseases, particularly infants and young children needing intravenous antibiotics for sepsis, should inquire about a family history of PID. Physicians caring for infants who also have congenital anomalies or failure to thrive should specifically exclude T-lymphocyte PID.

Public awareness campaigns have undoubtedly had a major impact on the burden of some diseases,¹⁵ including relatively rare diseases such as sudden infant death syndrome.¹⁶ However, these public awareness campaigns regarding PID should not take priority over targeting general pediatricians and families with other children suffering from PID if the overall burden of PID is to be reduced.¹⁷

The simple schema in Fig 2 allows for the diagnosis of ∼90% of T lymphocyte, complement, and neutrophil or monocytic PID. Using clinical signs alone, patients with B-lymphocyte PID are more difficult to differentiate from those with normal immunity. Thus, a lower threshold is required to initiate laboratory investigations or referral to specialists where antibody immunodeficiencies are in the differential diagnosis. Laboratory screening tests for PID subtypes are listed in Table 5. If a diagnosis of PID is made, or where there is ongoing clinical concern about the possibility of such a diagnosis, the attending physician should refer the child to a pediatric immunologist for further assessment or shared care. Universal newborn screening programs using T-cell receptor excision circle for SCID have recently been developed^18,19 and implemented in pilot schemes in the United States.^20,–,22 Although newborn screening technology may detect children with SCID, it does not currently identify children with the remaining >120 PID that can also be life-threatening or life-limiting but are not associated with low T-cell receptor excision circle values.²³

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FIGURE 2

A simple schema for identifying primary immunodeficiency diseases in children with severe, unusual, or recurrent infections. Note that this flow diagram is not all-inclusive; if a clinician has concerns, he or she should refer the patient to a specialist in pediatric immunology. Igs indicates immunoglobulins; UTI, urinary tract infection.

No clinical guidelines can be all-inclusive. At least 4% of children with PID will be missed even if the recommendations made in this study are followed. Our knowledge of the spectrum of PID has expanded over the last 2 decades.²³ It is increasingly recognized that specific PID predispose to the development of not only infectious diseases but also inflammatory, autoimmune, allergic, and neoplastic conditions, particularly in infants and young children.^24,25 Severe, recurrent, or unusual infections are thus not the only clinical presentation in which PID needs to be considered in the differential diagnosis. Optimizing detection and management of children with PID requires that pediatricians, particularly those working in hospitals, remain vigilant to the possibility that children who present with these conditions may have an underlying immunodeficiency.