Single-Center Study of 72 Patients with Severe Combined Immunodeficiency: Clinical and Laboratory Features and Outcomes.

Severe combined immunodeficiency is an inborn error of immunity characterized by impairments in the numbers and functions of T and B lymphocytes due to various genetic causes, and if it remains untreated, patients succumb to infections during the first 2 years of life. PURPOSE AND METHODS: This study reported retrospective data from 72 infants diagnosed with SCID including their major clinical features, HSCT characteristics, and outcomes over a 20-year period (1997-2017). RESULTS: Sixty-one of 72 SCID patients in the study underwent HSCT from 1997 to 2017. Median ages at the time of diagnosis and transplantation were 3.5 months and 5 months, respectively. Consanguinity was present in 68% of the patients, and T - B - NK + phenotype was predominantly identified. The overall survival was 80.3% over a 20-year period. However, the patients transplanted during an active infection had a lower survival rate of 73.9% compared to 100% for patients transplanted infection-free or with a previous infection that had resolved. The survival rate was significantly higher among recipients of HLA-identical transplants (92.9%), compared to recipients of mismatched related transplants (70%). The overall survival increased from 50 (1997-2006) to 85% (2007-2017) during the last 10 years. CONCLUSIONS: This is one of the largest single-center studies in Turkey with extensive experience about SCID patients. Early diagnosis of SCID patients before the onset of an infection and early transplantation are shown to be extremely important factors affecting the outcome and increasing the survival regardless of the donor type based on the results of this study.

IL-4 impairs wound healing potential in the skin by repressing fibronectin expression.

BACKGROUND: Atopic dermatitis (AD) is characterized by intense pruritis and is a common childhood inflammatory disease. Many factors are known to affect AD development, including the pleiotropic cytokine IL-4. Yet little is known regarding the direct effects of IL-4 on keratinocyte function. OBJECTIVE AND METHODS: In this report RNA sequencing and functional assays were used to define the effect of the allergic environment on primary keratinocyte function and wound repair in mice. RESULTS: Acute or chronic stimulation by IL-4 modified expression of more than 1000 genes expressed in human keratinocytes that are involved in a broad spectrum of nonoverlapping functions. Among the IL-4-induced changes, repression of fibronectin critically impaired the human keratinocyte wound response. Moreover, in mouse models of spontaneous and induced AD-like lesions, there was delayed re-epithelialization. Importantly, topical treatment with fibronectin restored the epidermal repair response. CONCLUSION: Keratinocyte gene expression is critically shaped by IL-4, altering cell fate decisions, which are likely important for the clinical manifestations and pathology of allergic skin disease.

Use of urinalysis as a screening tool for asymptomatic infants.

AIM: The utility of screening urinalysis in asymptomatic children has been questioned based on studies done in school-age children or adolescents. The American Academy of Pediatrics (AAP) recommended to abandon this screening in 2007 but many paediatricians perform it at some point during childhood. Thus, we aimed to investigate usefulness of screening urinalysis during infancy. METHODS: We retrospectively reviewed results of screening urinalysis done in infants at 6-18 months of age who had regular care since birth at our centre. Infants with an ICD-10 (International Classification of Diseases, Tenth Revision) diagnostic code for routine child health exam (Z00.1) and a urinalysis requested with this code on the same date were included. RESULTS: A total of 683 infants met the inclusion criteria. 44 (6%) had an abnormal urinalysis. The most common abnormality (n = 39, 5,7%) was pyuria. Of these 39 babies, 5 had a repeat urinalysis only, 18 had a repeat urinalysis with urine culture, and 16 had a urine culture alone. Six patients had positive culture results and were given antibiotic treatment. All six babies who received treatment had normal ultrasound and two patients had a voiding cystourethrography, which were also normal. The other abnormalities (n = 5) detected were microscopic hematuria and proteinuria. Repeat urinalyses of these patients were normal. CONCLUSION: Screening urinalysis results were abnormal in 6% of the babies, but in 86% of those, abnormalities were transient. Only <1% had positive culture results. These data add to the evidence that screening urinalysis during infancy is unjustified supporting the AAP 2007 recommendations.

HLA-haploidentical transplantations for primary immunodeficiencies: a single-center experience.

SCID is characterized by profound deficiencies of T and B lymphocytes. HSCT is the only curative treatment for children with SCID. The clinical characteristics and outcome of 30 HLA-haploidentical transplantations in 18 patients (15 SCID, two Omenn syndrome, and one MHC Class II deficiency) are reported here. The age of patients at diagnosis ranged from one and half to nine months (median: four months). The median time was one month between the diagnosis and the time of the initial transplantation. Infused CD34+ stem cell dose was ranged between 7 and 94.2 × 10(6) /kg. Nine of 18 patients were found to be positive for CMV antigenemia at diagnosis; therefore, none of them received a conditioning regimen. The most common complication was graft failure (61%), so repeated transplantations (two to four) were performed in seven patients. The mean time of lymphoid engraftment was 17.5 days (median: 16, range: 11-29 days). Ten of 15 SCID (67%) patients survived with a stable complete donor chimerism. However, all three non-SCID patients died. In conclusion, in the absence of a matched family donor, HLA-haploidentical transplantation from parental donors represents a readily available treatment option especially for patients with SCID, offering a high chance of cure.

Late onset hemorrhagic cystitis in a hematopoietic stem cell recipient: treatment with intravesical hyaluronic acid.

HC is a common complication following HSCT. Risk factors include viral infections, cyclophosphamide and busulfan usage, pelvic irradiation, older age at transplantation, allogeneic HSCT and GvHD. The severity of HC ranges from mild hematuria to life-threatening bleeding. Here, we present a seven-and-a-half-yr-old boy with Wiskott-Aldrich syndrome who experienced a late onset Grade III hemorrhagic cystitis following HSCT from his fully matched sibling. A Grade I GvHD localized to skin developed on day +11 and prednisolone therapy was given between the 11th and 22nd d. Myeloid and platelet engraftments were achieved +13 and +16 d, respectively. A gross hematuria began on the 21st post-transplant day. The urine cultures for bacterial or fungal organisms were negative. Urine analysis by PCR revealed a CMV viruria. Following systemic ganciclovir treatment, urinary CMV became negative but hemorrhagic cystitis did not improve. Due to the probability of existing BK virus or adenovirus, two doses of cidofovir were administered intravesically. As he continued to have painful hematuria with large clot formations, two doses of intravesical hyaluronic acid were applied. Macroscopic hematuria resolved within four d after the second dose. Complete remission was achieved on day +77. Finally, intravesical administration of hyaluronic acid seems to be effective and safe and can be a promising treatment in patients suffering from severe and late onset HC.

The role of Treg cells and FoxP3 expression in immunity of ß-thalassemia major AND ß-thalassemia trait patients.

There is increased susceptibility to infections in ß-thalassemia. Changes in T- and B-lymphocyte subsets and functions, defective chemotaxis, and phagocytosis of neutrophils and macrophages have been described in these patients. Regulatory T cells (Treg cells) play a crucial role in the maintenance of immunological self-tolerance. The FOXP3 gene is specifically expressed on Treg cells. Increased antigenic stimuli due to repeated blood transfusions might change the Treg cells and FOXP3 percentage in ß-thalassemia. Immune functions of peripheral blood lymphocytes, percentage of Treg cells (defined as CD4(+)CD25(+)FoxP3(+)) were evaluated in 30 ß-thalassemia major, 30 ß-thalassemia trait, and 20 healthy children. Percentage of CD4(+)CD45RA(+) cells were increased in ß-thalassemia trait compared to both ß-thalassemia major and controls, whereas percentage of CD4(+)CD45RO(+) cells were higher in ß-thalassemia major and trait patient compared to controls. Percentages of CD4(+)CD25(bright) and CD4(+)CD25(+)FoxP3(+) Treg cells were increased only in ß-thalassemia major patients compared to controls (P = .001 and P = .0001, respectively). T lymphocytes express activated phenotype both in ß-thalassemia major and trait patients. However, only in ß-thalassemia major patients who were exposed to chronic antigenic stimulus as a result of repeated blood transfusions was an increase observed in Treg cells, which might suppress immune activation status.

[TGF-Beta1-915G/C and TNF-alpha-308G/A polymorphisms in children with asthma]. / Astimli çocuklarda TGF-Beta1-915G/C ve TNF-alpha-308G/A polimorfizmleri.

TGF-Beta1 is a pro and antiinflammatory cytokine and plays an important role in airway remodelling in asthma. TNF-alpha is a proinflammatory cytokine that involved in the pathogenesis of asthma. Cytokine production is under genetic control, and certain single nucleotide polymorphisms (SNPs), which lead to allelic variants of cytokine genes are associated with higher or lower cytokine production in vitro. In some studies TGF-Beta1-915G/C and TNF-alpha-308G/A polymorphisms are found to be more prevalent and associated with asthma. The aim of this study is to investigate the frequency of TGF-Beta1-915G/C and TNF-alpha-308G/A polymorphisms and to determine whether or not these polymorphisms are associated with the development of asthma in children. 46 asthmatic children and 67 healthy controls were investigated by LightCycler PCR analysis for TGF-Beta1-915G/C and TNF-alpha-308G/A polymorphisms. The frequency of TGF-Beta1-915G/C and TNF-alpha-308G/A polymorphisms in asthmatic children were 15.2% and 23.9% respectively while the corresponding figures were 8.9% and 23.8% in the control group (p> 0.05). The risk of asthma development was not associated for TGF-Beta1 915G/C (OR: 0.54, 95% CI: 0.17-1.75) and TNF-alpha-308G/A (OR: 0.99, 95% CI: 0.41-2.40) polymorphisms. These results indicated that, the frequency of TGF-Beta1 915G/C and TNF-alpha-308G/A polymorphisms did not show any difference in asthmatic children compared to healthy controls and these polymorphisms do not seem to influence suspectibilty to asthma.

A novel mutation for TAP deficiency and its possible association with Toxoplasmosis.

We describe two siblings (a male patient and his older sister) with a novel mutation in the peptide transporter associated to antigen processing (TAP). The index case presented with not only granulomatous skin lesions and recurrent sino-pulmonary infections, often associated with this deficiency, but also a severe pulmonary toxoplasmosis. His toxoplasmosis and skin lesions were successfully treated.

A case of Wiskott-Aldrich syndrome with de novo mutation at exon 4.

Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by thrombocytopenia, eczema and immunodeficiency. Clinical features of the disease are highly varied; therefore, the diagnosis is sometimes difficult, especially in solitary cases or cases with milder forms of the disease. However, the identification of the WASP gene has made possible a definite WAS diagnosis for these cases. In this report, we present a 26-month-old boy who had received several ineffective treatments for chronic immune thrombocytopenic purpura. He was then suspected to have WAS because of the early onset of thrombocytopenia and small platelets. The diagnosis became definite with the detection of a de novo mutation at exon 4 of the WASP gene, Arg138Pro, through mutation analysis.

Stable mixed chimerism after hematopoietic stem cell transplantation in Wiskott-Aldrich syndrome.

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disease characterized by thrombocytopenia, eczema, impaired cellular and humoral immunity, and increased susceptibility to malignancy and autoimmunity. The only curative treatment for WAS is hematopoietic stem cell transplantation, especially in the presence of a matched sibling donor or matched unrelated donor. Here, we report the case of a 2.5-yr-old boy with WAS that resulted in mixed chimerism after having received bone marrow from his phenotypically identical grandfather. Although the patient has persistent thrombocytopenia (platelet counts 50-80 x 10(9)/L), he is currently alive and doing well at 36 months post-transplant and is free of any bleeding episodes.