Whole exome sequencing finds inborn errors of immunity in children with sepsis

Key takeaways:

• 85% of the patients with diagnosed or suspected community-acquired sepsis had undiagnosed genetic diseases.
• Recurrent infections and family histories of inborn errors of immunity were risk factors.

Whole-exome sequencing helped physicians identify undiagnosed primary immunodeficiency diseases in children with community-acquired sepsis, according to a study published in Pediatric Allergy and Immunology.

Family histories of primary immunodeficiencies and patient histories of recurrent infections were leading indicators of which children should get this testing, Elham Rayzan, MD, postdoctoral research fellow, division of pediatric hematology/oncology, Boston Children’s Hospital, and colleagues wrote.

The study comprised 34 children aged 1 month to 14 years (mean age, 46.5 months; 18 girls) admitted to the ICU at Children’s Medical Center in Tehran with suspected community-acquired sepsis (CAS) and symptoms or signs that suggested inborn errors of immunity (IEI), but without an IEI diagnosis.

Common clinical manifestations that suggested IEI in the cohort included recurrent respiratory infections (35%), chronic or recurrent diarrhea and gastroenteritis (32%), failure to thrive (23.5%), recurrent skin or perianal abscesses (15%), recurrent oral aphthous (12%) and candidiasis (6%).

The cohort also included 22 (65%) patients with a family history of consanguinity and 10 (29%) with a family history of IEI.

Two of the patients were diagnosed with hemophagocytic lymphohistiocytosis instead of community-acquired sepsis but remained in the cohort due to their personal histories of recurrent infections and family histories of IEI.

Whole-exome sequencing identified causative gene variants in 29 (85%) of the patients. Overall, the researchers said, 28 had primary immunodeficiencies, and one had interstitial lung and liver disease.

Seven (21%) patients had afflicted cellular and humoral immunity, including two (6%) with severe combined immunodeficiency (SCID) and four (15%) with combined immunodeficiencies (CIDs). Additional diagnoses included:

1. CIDs with associated or syndromic features: six (18%) patients;
2. congenital defects of phagocyte number or function: four (12%) patients;
3. defects in intrinsic and innate immunity: four (12%) patients;
4. immune dysregulation: six (18%) patients;
5. autoinflammatory disorders: 1 patient; and
6. predominantly antibody deficiency: 1 patient.

Five patients did not have any IEI. Average ages of admission included 43.6 months overall, 41.6 months for patients with an IEI and 55 months for patients who did not have an IEI. Other average ages of admission included:

1. CID: 36.8 months;
2. SCID: 4.5 months;
3. CIDs with associated or syndromic features: 60.3 months;
4. predominantly antibody deficiency: 120 months;
5. disease of immune dysregulation: 38.7 months;
6. congenital defects of phagocyte: 51.5 months;
7. defects in intrinsic and innate immunity: 10.5 months; and
8. autoinflammatory disorders: 29 months.

Further, the researchers identified pathogenic variants in 26 different genes, including 25 genes associated with IEI in the International Union of Immunological Societies 2022 classification. The remaining gene was not associated with IEI.

Based on these findings, the researchers concluded that whole-exome sequencing had high diagnostic value for detecting IEI in children with a history of recurrent infections or a family history of IEI who were admitted to the ICU for community-acquired sepsis.

The researchers noted that the high proportion of patients from consanguineous marriages, which are more prevalent in Iran than in Western countries, may have contributed to the high rates of IEI diagnosis in this cohort.

Although whole-exome sequencing is a costly first-line screening tool and is not routinely used, the researchers continued, it may be cost-effective for severely symptomatic patients with risk factors in their histories because it may guide physicians in preventing further recurrent serious infections and in more effective disease management.

The researchers called for additional studies with larger, multicentric patient populations to confirm these findings, with an emphasis on cost-effectiveness to support its use in low-resource settings, along with other genetic testing approaches including whole-genome sequencing and targeted gene panel testing.