EVIDENCE REVIEW:  Severe Combined Immunodeficiency (SCID)

VIII.  SUMMARY

Key findings:
Severe Combined Immunodeficiency (SCID) affects at least 1/100,000 newborns within the United States.  However, experts believe that with systematic case-finding the prevalence may be higher (perhaps as high as 1/40,000) due to earlier diagnosis of infants who would otherwise die prior to confirming a diagnosis of SCID.  Although several population-based screening trials are underway (Wisconsin) or planned (Massachusetts, Navajo Reservation in Arizona and New Mexico), to date no population-based screening trial has been completed.

Without curative treatment, newborns with SCID develop severe, often opportunistic, infections which lead to early death.  Studies indicate that treatment, most commonly with hematopoietic stem cell transplant, is effective in decreasing both the morbidity and mortality associated with SCID.  Given the seriousness of SCID, it does not lend itself to randomized controlled trials of treatment.  The current evidence supports the notion that earlier treatment leads to better outcomes. 

Regarding the key questions:

• Do current screening tests effectively and efficiently identify cases of SCID?

Various screening methods ranging from targeted use of lymphocyte counts in hospitalized children to population based newborn screening using IL-7, TREC or a combination have been studied.  Both IL-7 and TREC have been investigated using anonymized dried-blood spots.  These studies allow for estimations of sensitivity and specificity, but due to the anonymous nature there is no way to prove which test results are true.

The state of Wisconsin began a trial of population-based screening for SCID, using low TREC as the marker of SCID, in January 2008.  As of December 31, 2008, they had screened 70,397 newborns of which 118 (0.168%) had initially inconclusive results requiring a second newborn screening sample and 32 (0.045%) had abnormal results requiring either a second newborn screening sample or diagnostic testing.  The rates for both inconclusive and abnormal results are higher in premature than in full-term infants.  As of December 31, 2008, the investigators have not detected any cases of SCID.

• Does pre-symptomatic or early symptomatic intervention in newborns or infants with SCID improve health outcomes?

The most common, and well-studied, treatment modality for SCID is hematopoietic stem cell transplant which appears to be effective in significantly decreasing the morbidity and mortality associated with SCID.  Within HSCT there are numerous variables which may contribute to the effectiveness.  The most studied of these are the degree of haplotype matching between donor and recipient and the type of pre-conditioning the recipient receives.  There is no clear evidence as to the best method for HSCT.  However, despite the lack of randomized controlled trials of SCID treatment, the evidence from large case series indicates that HSCT is effective in treating SCID. 

Furthermore, there is evidence, primarily from the early detection of siblings of known SCID cases, that earlier treatment may be more effective. Specifically, the existing evidence indicates that undergoing HSCT prior to the onset of lung infection has higher likelihood of success.

In addition to HSCT, there is limited evidence that for children with ADA deficiency enzyme replacement may be effective in reconstituting their immune function.

• What is the cost-effectiveness of newborn screening for SCID?

The cost-effectiveness data reviewed were very limited and may not reflect current costs of treatment.

• What critical evidence appears lacking that may inform screening recommendations for SCID?

We identified several areas with deficient data:

• Prevalence of SCID
  There is limited evidence regarding the true prevalence of SCID.  A systematic method of case finding is needed in order to accurately determine the prevalence.  Of note, the new consortium of treatment centers (USIDNET) that has recently been established may serve as a method of more systematic case-finding.
• Accuracy of screening
  Initial pilot screening data from Wisconsin suggests that the false-positive rate will be relatively low.  However, these data are limited at this time.  Data regarding the accuracy of other screening methods, when applied in population-based protocols, are not available.
• Feasibility of screening
  Wisconsin and Massachusetts have been able to implement universal newborn screening for SCID, at least on a pilot basis.  Data are needed regarding the ability of other newborn screening laboratories to offer SCID screening
• Acceptability of screening
  There are no data available regarding consumer or physician acceptance of newborn screening for SCID.
• Cost-effectiveness
  Cost-effectiveness analyses utilizing measured costs and utilities, as well as applicable sensitivity analyses, are needed.
• Adequacy of available treatment centers
  There are no data addressing variation in treatment success between centers or the number of centers in the United States and their capacity to provide treatment for SCID.  Data from USIDNET and CIBMTR may, in the future, provide evidence on this topic.

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