ICON: The Early Diagnosis of Congenital Immunodeficiencies

Primary immunodeficiencies are intrinsic defects in the immune system that result in a predisposition to infection and are frequently accompanied by a propensity to autoimmunity and/or immunedysregulation. Primary immunodeficiencies can be divided into innate immunodeficiencies, phagocytic deficiencies, complement deficiencies, disorders of T cells and B cells (combined immunodeficiencies), antibody deficiencies and immunodeficiencies associated with syndromes. Diseases of immune dysregulation and autoinflammatory disorder are many times also included although the immunodeficiency in these disorders are often secondary to the autoimmunity or immune dysregulation and/or secondary immunosuppression used to control these disorders. Congenital primary immunodeficiencies typically manifest early in life although delayed onset are increasingly recognized. The early diagnosis of congenital immunodeficiencies is essential for optimal management and improved outcomes. In this International Consensus (ICON) document, we provide the salient features of the most common congenital immunodeficiencies.     

Long-term follow-up and prognosis of chronic granulomatous disease in Yugoslavia: is there a role for early bone marrow transplantation?

We report the long-term follow-up of 12 pediatric-aged patients with chronic granulomatous disease (CGD). The mean age at the onset of infections was 5 months with a median delay in diagnosis of 2.5 years. Bacille Calmette–Guérin lymphadenitis was the most common presenting infection (6) followed by suppurative lymphadenitis (4), liver abscess (1), or Salmonella sepsis (1). Prophylaxis with cotrimoxazole was recommended to all patients. During the mean follow-up of 10 years (range, 4–23 years) pneumonitis was the most prevalent infection (91%) followed by lymphadenitis (83%), aphtous stomatitis (58%), and liver abscesses (25%). Seven (58%) patients developed chronic lung disease due to grossly delayed diagnosis (3) or poor compliance with antimicrobial prophylaxis (4). Five (41%) patients died during the second decade of life of aspergillosis (3) or chronic lung disease (2). Probability of survival into the third decade of life was estimated to be only 19%. We argue that HLA-identical bone marrow transplantation (BMT), if possible, should be attempted at early age because of significant morbidity and mortality in adolescence. BMT also should be considered in patients who suffer severe infections despite antimicrobial prophylaxis or patients with evidence of chronic lung disease. Possibility of elective BMT from unrelated donors remains to be carefully evaluated.     

Autoimmunity in human primary immunodeficiency diseases

Human primary immunodeficiency diseases are experiments of nature characterized by an increased susceptibility to infection. In many cases, they are also associated with troublesome and sometimes life-threatening autoimmune complications. In the past few years, great strides have been made in understanding the molecular basis of primary immunodeficiencies, and this had led to more focused and successful treatment. This review has 3 aims: (1) to highlight the variety of autoimmune phenomena associated with human primary immunodeficiency diseases; (2) to explore how primary immunodeficiencies predispose patients to autoimmune phenomena triggered by opportunistic infections; and (3) to consider the rationale for the current treatment strategies for autoimmune phenomena, specifically in relation to primary immunodeficiency diseases. Reviewing recent advances in our understanding of the small subgroup of patients with defined causes for their autoimmunity may lead to the development of more effective treatment strategies for idiopathic human autoimmune diseases.     

Comparative effects of two ventilatory modes on speech in tracheostomized patients with neuromuscular disease

Many patients with respiratory failure related to neuromuscular disease receive chronic invasive ventilation through a tracheostomy. Improving quality of life, of which speech is an important component, is a major goal in these patients. We compared the effects on breathing and speech production of assist-control ventilation (ACV) and bilevel positive-pressure ventilation (BPPV) in nine patients with neuromuscular disease. Ventilator-delivered flow was measured using a pneumotachograph, and respiratory rate, inspiratory time, and ventilator-delivered volume were measured on this flow signal. Gas exchange was assessed using oxygen saturation and end-tidal carbon dioxide measurement. Microphone speech recordings were subjected to quantitative analysis. At rest, ventilatory parameters were similar with both modes. Speech induced an increase in inspiratory time during BPPV, with a greater increase in the volume released by the ventilator during speech as compared with ACV (172 +/- 194 versus 26 +/- 31 ml). Consequently, speech duration was longer during inspiration with BPPV. Moreover, BPPV allowed speech production to extend into expiration, and three patients could speak continuously during several respiratory cycles while receiving BPPV. Blood gas exchange was not modified by speech with BPPV or ACV. This study shows that BPPV provides better speech duration than ACV with no detectable short-term deleterious effects.     

Successful umbilical cord blood stem cell transplantation for chronic granulomatous disease

Chronic granulomatous disease (CGD) causes growth failure, inflammatory lung damage and often early death. Prophylactic cotrimoxazole improves medium-term survival, but cannot prevent inflammatory sequelae. We report the first patient with CGD who underwent successful HLA identical sibling umbilical cord stem cell transplantation (UCSCT) after myeloablative conditioning. The patient presented with colitis, confirmed as CGD at 2 years of age. Following BU16/CY200 conditioning, he had UCSCT from his unaffected HLA identical sister. A year post-transplant, his colitis had resolved clinically and on radioisotope scan growth has improved. Neutrophil oxidative burst was 92% normal with full donor lymphocyte reconstitution.     

Rapid protein-based assays for the diagnosis of T-B+ severe combined immunodeficiency

The severe combined immunodeficiencies (SCID) are a heterogeneous group of conditions arising from a variety of molecular defects. The X-linked form of SCID (X-SCID) is caused by defects in the common gamma chain (gammac), and is characterized by a T-B+NK- immunophenotype. This lymphocyte profile is seen in an autosomal recessive form of SCID caused by mutations in the JAK3 molecule. Thus, X-SCID and JAK3-deficient SCID are clinically and immunologically indistinguishable. Knowledge of the precise molecular defect is essential for antenatal diagnosis, carrier testing and for treatment using somatic gene therapy. To identify the molecular defect in children presenting with a T-B+NK- form of SCID, we have developed rapid assays based on flow cytometric analysis of gammac, immunoblotting for JAK3 and gammac, and detection of interleukin-2 (IL-2)-induced tyrosine phosphorylation of JAK3. Sixteen T-B+NK- SCID patients from 15 families were examined. Nine had no detectable gammac, four had abnormal gammac expression and no IL-2-induced JAK3 tyrosine phosphorylation, and one had normal gammac expression but no IL-2-induced JAK3 tyrosine phosphorylation, although JAK3 was present. All these patients had mutations identified in their gammac gene. Two patients exhibited normal gammac expression, but JAK3 was not detected by immunoblotting and these patients were confirmed as having JAK3 gene mutations. Thus, these protein-based assays have led to rapid molecular diagnoses in T-B+ SCID that have subsequently been confirmed by genetic analysis.     

N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains

Omenn's syndrome is an autosomal recessive primary immunodeficiency characterized by variable numbers of T lymphocytes of limited clonality, hypereosinophilia, and high IgE levels with a paradoxical absence of circulating B lymphocytes. We have previously attributed this disorder to missense mutations that render the RAG1/RAG2 recombinase only partially active. Here we report seven Omenn's patients with a novel class of genetic lesions: frameshift mutations within the 5' coding region of RAG1. Interestingly, we demonstrate in transient expression experiments that these frameshift deletion alleles remain partially functional for both deletional and inversional recombination and can hence explain the partial rearrangement phenotype observed in these patients. The rearrangement activity is mediated by truncated RAG1 proteins that are generated by alternative ATG usage 3' to the frameshift deletion and that demonstrate improper cellular localization. Taken together, our results suggest a novel mechanism for the development of immunodeficiency in a subset of Omenn's syndrome patients.