Hematopoietic stem cell transplantation in Omenn syndrome: a single-center experience.

We retrospectively analyzed the outcome of hematopoietic stem cell transplantations (HSCT) performed at our Center between 1991 and 2002 in 11 unselected patients with Omenn syndrome, a variant of severe combined immunodeficiency. The patients' mean age at the time of the first HSCT was 8.4 months. Two patients received two, and one patient three, HSCT procedures. The resulting 15 HSCT derived in seven cases from HLA-haploidentical parents, in four patients from matched unrelated donors, in three cases from an HLA phenotypically identical related donor, and in one case from an HLA genotypically identical family donor. Nine out of 11 patients are alive and immunoreconstituted 30-146 months after transplantation. At the time of the most recent evaluation, all of the nine survivors had normal T-cell function, and eight of them had developed normal antibody production. This study demonstrates an overall mortality of 18.2%, which is substantially lower than previously reported. Early recognition of OS, rapid initiation of adequate supportive treatment and HSCT lead to improved outcome for this otherwise fatal disease, regardless of the origin and matching of hematopoietic stem cells.

Impaired thymic output and restricted T-cell repertoire in two infants with immunodeficiency and early-onset generalized dermatitis.

We evaluated the T-cell repertoire and the thymic output in two infants, one with Omenn Syndrome (OS) and another with complete DiGeorge Syndrome (DGS), who developed generalized dermatitis. The patients shared common T-cell abnormalities, as demonstrated by the low response to mitogenic stimulation, by an unusual usage of specific T-cell receptor (TCR) segments, and by a reduction of TCR diversity in both alpha/beta and gamma/delta populations. Furthermore, they both showed an impaired thymic function, as assessed by the low number of TCR recombination excision circles, which are formed from excised DNA during the rearrangement of TCR genes. These data indicated that generalized erythrodermia may be present in different forms of T-cell immunodeficiency and may reflect intrinsic defects in either V(D)J recombination or in thymic development, leading to the peripheral expansion of T-cell clonotypes, that bear peculiar TCR chains.

Liposomal amphotericin (AmBisome) is safe in bone marrow transplantation for primary immunodeficiency.

The use of conventional amphotericin B is limited by toxicity, side-effects, drug interactions and the need for large infusion volumes, especially for infants. Use of liposomal amphotericin B (AmBisome) in 15 paediatric BMT patients with primary immunodeficiency (PID) was therefore studied. Adverse clinical reactions to AmBisome and biochemical profiles were monitored daily for 2 weeks before, during and after each treatment episode. Fungal cultures were obtained weekly and when patients were pyrexial. There were 18 treatment episodes. Mean daily dose was 5 mg/kg (2-6 mg/kg). Mean duration of treatment was 25 days (5-90 days). Clinical reactions to AmBisome were observed in one infant who had a pyrexia of 38 degrees C. One of the 15 infants had a significant increase in creatinine level while on concomitant nephrotoxic therapy. Four developed mild hypokalaemia on AmBisome which resolved with increased potassium supplementation. AmBisome was well tolerated and without significant renal or hepatic toxicity in severely ill immunodeficient infants receiving multiple nephrotoxic and hepatotoxic drugs such as cyclosporin, vancomycin and foscarnet.

The Serbian version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ).

We report herein the results of the cross-cultural adaptation and validation into the Serbian language of the parentís version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. The Serbian CHAQ-CHQ were fully validated with 3 forward and 1 backward translations. A total of 139 subjects were enrolled: 79 patients with JIA (30% systemic onset, 28% polyarticular onset, 6% extended oligoarticular subtype, and 36% persistent oligoarticular subtype) and 60 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Serbian version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

Novel H1N1 influenza in neonates: from mild to fatal disease.

Analysis of pediatric deaths associated with pandemic A H1N1 influenza shows that fatal outcome is more likely in young children, under the age of 5. Neonates, because of the immaturity of their immune system, could represent a high-risk group for severe disease and fatal outcome. We present a group of five neonates with confirmed novel influenza A H1N1 infection. This report indicates that the full spectrum of influenza A H1N1 infection ranging from mild febrile illness with spontaneous recovery to severe disease with fatal outcome may be expected even in neonates.

Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis in Wiskott-Aldrich syndrome.

UNLABELLED: A patient with Wiskott-Aldrich syndrome who developed Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis (EBV-HLH) is described in this study. At 4 mo of age the patient developed fever associated with bicytopenia and splenomegaly. Analysis of a bone marrow specimen revealed extensive haemophagocytosis, and in situ hybridization for EBV of the bone marrow specimen using an EBV-encoded RNA probe was positive. Diagnosis of EBV-HLH was established and immunotherapy with HLH-94 protocol was started. HLH has been described in patients with other well-defined primary immunodeficiencies such as X-linked lymphoproliferative syndrome, Chediak-Higashi syndrome and Griscelli disease. Also, HLH was reported recently in severe combined immunodeficiency and DiGeorge syndrome. CONCLUSION: The possibility of an underlying primary immunodeficiency should be considered in paediatric patients who present with HLH during infancy.

[Diagnostic problems of Stevens-Johnson syndrome. A case report]. / Stevens-Dzonsonov sindrom u decjem dobu. Znacaj imunoloskih parametara u dijagnostici i tumacenju patogeneze (prikaz bolesnika).

Stivens-Johnson Syndrome is a rare, severe, bullose form of erythema multiforme of unknown etiology. The role of immunological factors in its pathogenesis elucidates. A patients (Sh.V.), nine years of age, was admitted for reccurent streptococcal infections with skin and mucose membrane lesions. In June 1990 streptococcal pharyngitis, fever (38.8-39,9 degrees C) were registered. Penicillin was given. Next day bullous lesions on lips, left ear, trunk and lower extremities and vesiculose lesions with a wide, erythematose base ("iris") and then conjuctivitis were registered. Laboratory tests: SR70.; Leu - 11,0; anti-herpes Ab IgG 1/64, IgM 1/8. Stevens-Johnson was diagnosed. There was a recidivation two years after - oral lesions followed by necrosis and bleeding, after half a year a second recidivation with spreading of bullous and vesiculous lesions to penis gland with prepuce of the penis. Last recidivation in February 1993. Anamnesis: Viral meningitis in 1988. mother suffers from herpes labialis. Peripheral blood immunophenotiping lymphocite extremly indicated decreasing values of B Ly, NK and IL-2R+ cells. Bacteriological tests showed an increase of anti-Chlamidia Ab titer (IgG 1/128, IgA and IgM +). In virological testing there was no increase of titer of Abs against viral antigens (Herpes simplex virus, Varicella-Zoster virus, Citomegalovirus, Adenovirus). We conclude that Stevens-Johnson Sy to be diagnosed by characteristic clinical features, aspecialy by frequent reccurences. Immunological testing during the last recidivation showed that parameters of humoral immune reactivity were within normal ranges while revealed defects of cellular immune reactivity cannot elucidate the ethiopathogenesis of this disease.

Pneumocystis carinii pneumonitis in haemophagocytic lymphohistiocytosis.

UNLABELLED: We report on a 10-y-old boy who developed Pneumocystis carinii pneumonitis (PCP) as the dominant symptom at the onset of haemophagocytic lymphohistiocytosis (HLH). PCP is a common infection in patients with combined primary immunodeficiencies or acquired immunodeficiency syndrome but it has rarely been observed at the onset of HLH. Typically, HLH presents as a febrile syndrome associated with cytopenia and hepatosplenomegaly. Repeated bone marrow aspirates, spleen or lymph node biopsies are sometimes required to reveal haemophagocytosis. Because of the significant immunosuppression during treatment of HLH, prophylaxis of PCP with co-trimoxazole is recommended. However, de-arranged immune response in HLH renders the patients susceptible to opportunistic infections, even before the introduction of immunosuppressants. CONCLUSION: We suggest that in patients with unclear respiratory symptoms, it is worth considering a differential diagnosis of HLH.

Disseminated Bacillus Calmette-Guérin infection in a girl with hyperimmunoglobulin E syndrome.

Disseminated Bacillus Calmette-Guérin infection occurs in few well-defined immunodeficiencies, such as severe combined immunodeficiency, chronic granulomatous disease and paediatric acquired immunodeficiency syndrome. This severe complication of immunization against tuberculosis has been lethal in the majority of children who had primary immunodeficiency. Our patient, a 9-y-old girl with hyperimmunoglobulin E syndrome developed disseminated Bacillus Calmette-Guérin infection in infancy. Patients with hyperimmunoglobulin E syndrome (HIES) are susceptible to serious staphylococcal and fungal infections. Disseminated Bacillus Calmette-Guérin infection has not previously been reported in this rare immunodeficiency.

[C-reactive protein concentrations during initial (empiric) treatment of neonatal sepsis]. / Koncentracije C-reaktivnog proteina tokom pocetnog lecenja sepse kod novorodjenceta.

INTRODUCTION: Neonatal septicaemia is characterized by high mortality so that intravenous antibiotics must be administered on clinical suspicion. Initial antibiotic therapy, before the results of microbiological evaluation, is based on empirical data in regard to sensitivity of prevalent bacterial strains. In the past years, aetiological causes of neonatal sepsis have been changed with an increased bacterial resistance to the usual combination of initial antibiotics. AIM: We compared changes of serum C-reactive protein (CRP) concentrations in neonates with proven neonatal sepsis in response to initial antibiotic therapy (inappropriate or appropriate). Our hypothesis was that changes of CRP levels during the first 48 hours of treatment and before microbiologic results could be useful in evaluation of effectiveness of empiric antibiotics. METHODS: Our prospective study included all neonates with suspected sepsis referred to our Intensive Care Unit from January 1992 to December 1996. Neonates received ampicillin and gentamycin/or amikacin (during the first week of life), while infants older than 7 days of life were given combination of cloxacillin and aminoglycozides. In patients with late neonatal sepsis who also had meninigitis, cloxacillin was substituted with ampicillin. Microbiological identification was performed with routine bacteriological methods. Susceptibility of isolated bacterial strains to antibiotics was performed by Kirby-Bauer disc-diffusion method. Serum concentration of CRP was measured by immunoturbidimetry (Turbox CRP, Orion Diagnostica) and CRP concentration higher than 20 mg/l was regarded as elevated. Blood sampling for CRP measurements were taken before the treatment (CRP0), and during the first (CRP1) and second (CRP2) day of empiric therapy. The interval between sampling was from 12 to 24 hours. RESULTS: A total of 1520 neonates were evaluated during this study period and 47 patients fulfilled criteria for final analysis. In 14 of 47 patients initial antibiotic treatment was inappropriate. The most frequent resistant strains was KI. pneumoniae (6) followed with St. aureus (4), E. coli (2) and Pseudomonas (2). During initial evaluation six patients had concomitant meningitis while two had concomitant septic arthritis and two necrotizing enterocolitis, respectively. Seven (50%) of 14 patients with non-adequate initial treatment died. In 33 cases of adequately treated septicaemia the course was uncomplicated and no lethal outcome was observed. In the first group of 14 patients who received inappropriate treatment serum CRP concentations (mg/L; mean and +/- SD) were: CRP0 = 107.5 +/- 65.6; CRP1 = 155.3 +/- 75.7; CRP2 = 209.1 +/- 67.0, while in 33 repeated samples of the 33 patients in the second group who received adequate treatment the following results were recorded: CRP0 = 124.0 +/- 78.1; CRP1 = 133.8 +/- 63.5; CRP2 = 94.6 +/- 46.4. Increase in serum CRP concentration in the first group during the first 48 hours of initial non-adequate therapy was significantly higher (p = 0.015, two way ANOVA) than in the second group with appropriate treatment. During the first 24 hours of treatment increase in serum concentration of CRP was registered in 12 (85.7%) of 14 measurements in patients with non-adequate therapy and in 19 (56.7%) of 33 measurements in patients with adequate therapy. In the first group during the second day of treatment, in 11 (78.6%) of 14 cases an increase in serum CRP concentration was recorded while in 3 (14.3%) cases CRP concentration decreased. In 31 (91.2%) of 34 measurements in patients with adequate treatment CRP concentration decreased during the second day of treatment and in only 3 (8.8%) cases CRP concentration increased. With an increase in serum concentration of CRP more than 10 mg/L in the second day of antibiotic treatment, probability of non-adequate antibiotic therapy (positive predictive value) was estimated to be 77.0%. Any recorded decrease of serum CRP concentration may confirm appropriate choice of antibiotics during the second day of treatment with probability of 93.3% (negative predictive value). DISCUSSION: Measurement of serum CRP concentration is useful for diagnosis of severe neonatal sepsis. In our study all isolated bacterial strains were comparable in their ability to activate systemic inflammatory response and CRP production. It is known that serial CRP measurements during neonatal sepsis are useful in making decision to cease antibiotic treatment. The highest serum CRP concentrations were detected during the first day of illness but, in some cases even with appropriate treatment, CRP peak levels due to sustained pro-inflammatory action of interleukin-6 production could be detected even 24 hours after treatment was started. Our study showed that in patients with non-adequate initial antibiotic therapy of neonatal sepsis serum CRP concentrations increase further during the second day of treatment. By contrast, the use of appropriate antibiotic therapy in the same time period followed the significant decrease of serum CRP levels in our patients. Therefore, increase of CRP level during initial treatment, especially during the second day of treatment of neonatal sepsis should be taken as indication for replacement of initial antibiotics, even before sensitivity of microbiological causes to given antibiotics is known.

Prenatal diagnosis of RAG-deficient Omenn syndrome.

Mutations in recombination activating genes (RAG) 1 and 2 have been found to cause Omenn syndrome (OS), a severe combined immunodeficiency (SCID) with a peculiar phenotype. Here we report the prenatal diagnosis performed in three OS patients. Mutations were detected in the probands as well as in their parents by genomic sequencing of the complete coding regions of both RAG 1 and RAG 2, which are contained in a single exon. All the three probands had RAG 1 mutations in both alleles, at least one of which was a missense substitution. Of the three fetuses tested, one had a wild type sequence on both alleles, while the other two had one mutated allele. None of the three patients were predicted to be affected and this was confirmed at birth. Detection of RAG genes mutations on fetal samples by direct sequencing is an easy and effective way to investigate fetuses from families affected with RAG-dependent SCID and OS families affected by RAG-dependent SCID and OS.