Search

A subgroup of patients with 22q11·2 microdeletion and partial DiGeorge syndrome (pDGS) appears to be susceptible to non-cardiac mortality (NCM) despite sufficient overall CD4+ T cells. To detect these patients, 20 newborns with 22q11·2 microdeletion and congenital heart disease were followed prospectively for 6 years. Besides detailed clinical assessment, longitudinal monitoring of naive CD4+ and cytotoxic CD3+CD8+ T cells (CTL) was performed. To monitor thymic activity, we analysed naive platelet endothelial cell adhesion molecule-1 (CD31+) expressing CD45RA+RO-CD4+ cells containing high numbers of T cell receptor excision circle (TREC)-bearing lymphocytes and compared them with normal values of healthy children ( n = 75). Comparing two age periods, low overall CD4+ and naive CD4+ T cell numbers were observed in 65%/75%, respectively, of patients in period A (< 1 year) declining to 22%/50%, respectively, of patients in period B (> 1/< 7 years). The percentage of patients with low CTLs (< P10) remained robust until school age (period A: 60%; period B: 50%). Low numbers of CTLs were associated with abnormally low naive CD45RA+RO-CD4+ T cells. A high-risk (HR) group ( n = 11) and a standard-risk (SR) ( n = 9) group were identified. HR patients were characterized by low numbers of both naive CD4+ and CTLs and were prone to lethal infectious and lymphoproliferative complications (NCM: four of 11; cardiac mortality: one of 11) while SR patients were not (NCM: none of nine; cardiac mortality: two of nine). Naive CD31+CD45RA+RO-CD4+, naive CD45RA+RO-CD4+ T cells as well as TRECs/106 mononuclear cells were abnormally low in HR and normal in SR patients. Longitudinal monitoring of naive CD4+ and cytotoxic T cells may help to discriminate pDGS patients at increased risk for NCM. [ABSTRACT FROM AUTHOR]

More than 11 genetic causes of severe combined immunodeficiency (SCID) have been identified, affecting development and/or function of T lymphocytes, and sometimes B lymphocytes and natural killer (NK) cells. Deletion of 22q11.2 is associated with immunodeficiency, although less than 1% of cases are associated with T–B + NK + SCID phenotype. Severe immunodeficiency with CHARGE syndrome has been noted only rarely Omenn syndrome is a rare autosomal recessive form of SCID with erythroderma, hepatosplenomegaly, lymphadenopathy and alopecia. Hypomorphic recombination activating genes 1 and 2 mutations were first described in patients with Omenn syndrome. More recently, defects in Artemis, RMRP, IL7Rα and common gamma chain genes have been described. We describe four patients with mutations in CHD7, who had clinical features of CHARGE syndrome and who had T–B + NK + SCID (two patients) or clinical features consistent with Omenn syndrome (two patients). Immunodeficiency in patients with DiGeorge syndrome is well recognized − CHARGE syndrome should now be added to the causes of T–B + NK + SCID, and mutations in the CHD7 gene may be associated with Omenn-like syndrome. [ABSTRACT FROM AUTHOR]

Background More than 350 genetic disorders cause immune deficiencies; given the rarity of these conditions, in-depth study of infections associated with primary immune deficiencies (PID) requires extremely large sample sizes from broad populations. Using a large electronic health record (EHR) dataset, we linked clinical and microbiologic data to develop digital phenotypes for PID. Methods Using the Cerner HealthFacts EHR dataset from 2009 to 2017 we extracted clinical and microbiologic data for hospitalizations from patients <18 years old with ICD9/10 PID diagnoses and ≥1 positive culture for infection. Machine learning models were used to identify key features to predict PID diagnosis. Features included patient and hospitalization characteristics; infectious agent and infection site; and selected comorbidities. Model validation was done using the area under the receiver operating characteristic (AUC) curve. Results Overall 1316 patients with a PID were identified (Table 1). The 10 most common pathogens identified by PID are listed in Table 2. The models classified DiGeorge syndrome (positive predictive value 49%), functional disorders of polymorphonuclear neutrophils (PMN) (PPV 43%), and common variable immunodeficiency (CVID) (PPV 47%) better than combined immunodeficiency (CID) (PPV 20%); the overall true positive rate was 47% with an AUC of 0.73. Predictive features for each PID were as follows: CVID—having enteritis, hypertension, and pneumonia (Figure 1a); PMN—having hypoxia and hypertension (Figure 1b); DiGeorge syndrome—having congenital deformities and not having hypertension (Figure 1c); CID—finding Staphylococcus aureus in a wound or Escherichia coli in the blood were predictive of CID (Figure 1d). Conclusion Early models demonstrate some discrimination, specifically for more common PIDs (CVID) and those with highly identifying factors (DiGeorge syndrome). These models can be improved by including a wider array of clinical data, and they provide a first look at a new methodology to digitally phenotype PIDs for future diagnostic use. Disclosures All authors: No reported disclosures. [ABSTRACT FROM AUTHOR]