[Acute splenic sequestration in children with sickle cell disease--an overview]. / Mjältsekvestrering hos barn med sicklecellanemi - Akut livshotande komplikation, snabb behandling är avgörande.

Acute splenic sequestration in children with sickle cell disease - an overview Acute splenic sequestration (ASS) is a life-threatening complication of sickle cell disease (SCD). The condition is important to recognize due to the fact that it can occur with previously unknown disease. ASS is one of the most common causes of death in children with SCD and is the result of blood suddenly getting congested in the spleen, resulting in splenomegaly, acute anemia, and hypovolemic shock. Timely and appropriate treatment is essential in preventing death. Episodes of ASS before one year of age are associated with a higher risk of recurrence. There is no established effective treatment for recurrent ASS; however, there is evidence that all children with SCD should be treated with hydroxyurea. In Sweden, our recommendation is to evaluate the indications for splenectomy after the first episode of ASS. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment, and all children with SCD should be evaluated with regard to the potential success of HSCT. This article presents an overview of the condition with Swedish recommendations.

Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Human C1q Deficiency: The Karolinska Experience.

BACKGROUND: Human C1q deficiency is associated with systemic lupus erythematosus (SLE) and increased susceptibility to severe bacterial infections. These patients require extensive medical therapy and some develop treatment-resistant disease. Because C1q is produced by monocytes, it has been speculated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) may cure this disorder. METHODS: We have so far treated 5 patients with C1q deficiency. In 3 cases, SLE symptoms remained relatively mild after the start of medical therapy, but 2 patients developed treatment-resistant SLE, and we decided to pursue treatment with allo-HSCT. For this purpose, we chose a conditioning regimen composed of treosulfan (14 g/m) and fludarabine (30 mg/m) started on day -6 and given for 3 and 5 consecutive days, respectively. Thymoglobulin was given at a cumulative dose of 8 mg/kg, and graft-versus-host disease prophylaxis was composed of cyclosporine and methotrexate. RESULTS: A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms. The boy developed posttransplant lymphoproliferative disease, which resolved after treatment with rituximab and donor lymphocyte infusion. Unfortunately, donor lymphocyte infusion induced severe cortisone-resistant gastrointestinal graft-versus-host disease, and the patient died from multiple organ failure 4 months after transplantation. The girl is doing well 33 months after transplantation, and clinically, all signs of SLE have resolved. CONCLUSIONS: Allo-HSCT can cure SLE in human C1q deficiency and should be considered early in subjects resistant to medical therapy.

Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency.

OBJECTIVE: Globally approximately 60 cases of C1q deficiency have been described with a high prevalence of Systemic Lupus Erythematosus (SLE). So far treatment has been guided by the clinical presentation rather than the underlying C1q deficiency. Recently, it was shown that C1q production can be restored by allogeneic hematopoietic stem cell transplantation. Current literature lacks information on disease progression and quality of life of C1q deficient persons which is of major importance to guide clinicians taking care of patients with this rare disease. METHODS: We performed an international survey, of clinicians treating C1q deficient patients. A high response rate of >70% of the contacted clinicians yielded information on 45 patients with C1q deficiency of which 25 are published. RESULTS: Follow-up data of 45 patients from 31 families was obtained for a median of 11 years after diagnosis. Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms. In total 9 (20%) of the C1q deficient individuals had died. All except for one died before the age of 20 years. Estimated survival times suggest 20% case-fatality before the age of 20, and at least 50% of patients are expected to reach their middle ages. CONCLUSION: Here we report the largest phenotypic data set on C1q deficiency to date, revealing high variance; with high mortality but also a subset of patients with an excellent prognosis. Management of C1q deficiency requires a personalized approach.

Chronic granulomatous disease - conventional treatment vs. hematopoietic stem cell transplantation: an update.

PURPOSE OF REVIEW: We update and summarize the recent findings in conventional treatment and hematopoietic stem cell transplantation in chronic granulomatous disease (CGD). We also summarize the contemporary view on when hematopoietic stem cell transplantation should be the preferred treatment of choice in CGD. RECENT FINDINGS: Azole antifungal treatment in CGD has improved survival. With prolonged survival, inflammatory complications are an emerging problem in CGD. Several studies now present excellent results with stem cell transplantation in severe CGD, also with reduced intensity conditioning. SUMMARY: Several lines of evidence now suggest that stem cell transplantation should be the preferred treatment of choice in severe CGD, if there is an available donor. This should be performed as soon as possible to avoid severe sequelae from infection and inflammation.

Chronic granulomatous disease-haematopoietic stem cell transplantation versus conventional treatment.

AIM: Chronic granulomatous disease (CGD) is a rare X-linked or autosomal recessive primary immune deficiency characterized by recurrent, life-threatening bacterial and fungal infections. Mortality rates are high with conventional treatment. However, haematopoietic stem cell transplantation (HSCT) offers cure. Here, we compare the outcome of HSCT in 14 Swedish patients with CGD to that in 27 patients with CGD who were given conventional treatment. METHODS: Forty-one patients in Sweden were diagnosed with CGD between 1990 and 2012. From 1997 to 2012, 14 patients with CGD, aged 1-35 years, underwent HSCT and received grafts either from an HLA-matched sibling donor or a matched unrelated donor. RESULTS: Thirteen of the 14 transplanted patients are alive and well. Mean age at transplantation was 10.4 years, and the mean survival time was 7.7 years. In contrast, seven of 13 Swedish men or boys with X-linked CGD who were treated conventionally died from complications of CGD at a mean age of 19 years, while the remaining patients suffered life-threatening infections. CONCLUSION: The outcome of the patients who underwent HSCT supports HSCT as being the preferable treatment for severe CGD. Our results advocate early HSCT for all patients with X-linked CGD, using grafts from either a matched sibling donor or a matched unrelated donor.

Involvement of a functional NADPH oxidase in neutrophils and macrophages during programmed cell clearance: implications for chronic granulomatous disease.

Resolution of inflammation requires clearance of activated neutrophils by macrophages in a manner that prevents injury to adjacent tissues. Surface changes, including phosphatidylserine (PS) exposure, may target neutrophils for phagocytosis. In this study, we show that externalization of PS is defective in phorbol myristate acetate (PMA)-activated neutrophils obtained from chronic granulomatous disease (CGD) patients with mutations in components of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Moreover, activated neutrophils from CGD patients failed to undergo clearance upon cocultivation with macrophages from normal donors. In line with these results, treatment of donor neutrophils with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase, blocked PMA-induced PS oxidation and externalization and prevented their engulfment by macrophages. Furthermore, primary macrophages from CGD patients or human gp91(phox)-deficient PLB-985 cells differentiated into macrophage-like cells were defective for engulfment of apoptotic target cells. Pretreatment of normal macrophages with DPI also suppressed the subsequent ingestion of PS-positive target cells. Together, these data demonstrate that NADPH oxidase plays an important role in the process of macrophage disposal of target cells (programmed cell clearance). Thus we speculate that the lack of a functional NADPH oxidase results in impaired neutrophil clearance and the exaggerated inflammation that is characteristic for CGD.

Chronic granulomatous disease: the European experience.

CGD is an immunodeficiency caused by deletions or mutations in genes that encode subunits of the leukocyte NADPH oxidase complex. Normally, assembly of the NADPH oxidase complex in phagosomes of certain phagocytic cells leads to a "respiratory burst", essential for the clearance of phagocytosed micro-organisms. CGD patients lack this mechanism, which leads to life-threatening infections and granuloma formation. However, a clear picture of the clinical course of CGD is hampered by its low prevalence (approximately 1:250,000). Therefore, extensive clinical data from 429 European patients were collected and analyzed. Of these patients 351 were males and 78 were females. X-linked (XL) CGD (gp91(phox) deficient) accounted for 67% of the cases, autosomal recessive (AR) inheritance for 33%. AR-CGD was diagnosed later in life, and the mean survival time was significantly better in AR patients (49.6 years) than in XL CGD (37.8 years), suggesting a milder disease course in AR patients. The disease manifested itself most frequently in the lungs (66% of patients), skin (53%), lymph nodes (50%), gastrointestinal tract (48%) and liver (32%). The most frequently cultured micro-organisms per episode were Staphylococcus aureus (30%), Aspergillus spp. (26%), and Salmonella spp. (16%). Surprisingly, Pseudomonas spp. (2%) and Burkholderia cepacia (<1%) were found only sporadically. Lesions induced by inoculation with BCG occurred in 8% of the patients. Only 71% of the patients received antibiotic maintenance therapy, and 53% antifungal prophylaxis. 33% were treated with gamma-interferon. 24 patients (6%) had received a stem cell transplantation. The most prominent reason of death was pneumonia and pulmonary abscess (18/84 cases), septicemia (16/84) and brain abscess (4/84). These data provide further insight in the clinical course of CGD in Europe and hopefully can help to increase awareness and optimize the treatment of these patients.

Chronic granulomatous disease caused by mutations other than the common GT deletion in NCF1, the gene encoding the p47phox component of the phagocyte NADPH oxidase.

Chronic granulomatous disease (CGD) is an inherited immunodeficiency caused by defects in any of four genes encoding components of the leukocyte nicotinamide dinucleotide phosphate, reduced (NADPH) oxidase. One of these is the autosomal neutrophil cytosolic factor 1 (NCF1) gene encoding the p47phox protein. Most (>97%) CGD patients without p47phox (A47 degrees CGD) are homozygotes for one particular mutation in NCF1, a GT deletion in exon 2. This is due to recombination events between NCF1 and its two pseudogenes (psiNCF1) that contain this GT deletion. We have previously set up a gene-scan method to establish the ratio of NCF1 genes and pseudogenes. With this method we now found, in three CGD families patients with the normal number of two intact NCF1 genes (and four psiNCF1 genes) and in six CGD families, patients with one intact NCF1 gene (and five psiNCF1 genes). All patients lacked p47phox protein expression. These results indicate that other mutations were present in their NCF1 gene than the GT deletion. To identify these mutations, we designed PCR primers to specifically amplify the cDNA or parts of the genomic DNA from NCF1 but not from the psiNCF1 genes. We found point mutations in NCF1 in eight families. In another family, we found a 2,860-bp deletion starting in intron 2 and ending in intron 5. In six families the patients were compound heterozygotes for the GT deletion and one of these other mutations; in two families the patients had a homozygous missense mutation; and in one family the patient was a compound heterozygote for a splice defect and a nonsense mutation. Family members with either the GT deletion or one of these other mutations were identified as carriers. This knowledge was used in one of the families for prenatal diagnosis.

[Chronic granulomatous disease--not only the lack of oxygen radicals]. / Kronisk granulomatös sjukdom--inte bara brist på syreradikaler.

Chronic granulomatous disease (CGD) is caused by mutations in the phox-family of superoxide ion generating enzymes. The clinical manifestations of CGD include increased infection susceptibility, a lupus like dermatitis and inflammatory bowel disease. The severe consequences of this rare disorder need to be handled by specialists, experienced in the care of CGD patients. Many CGD manifestations are due to the lack of superoxide ions, but some also to deficient pumping of protons to the extracellular space. An excessive inflammatory component, e.g. the granuloma formation in various organs, might be secondary to impaired superoxide ion dependent inactivation of inflammatory mediators. CGD can be successfully treated by hematopoietic stem cell transplantation, and gene therapy might become an alternative in the future.

Aberrant [correction of Abberant] cytosolic calcium ion mobilization in chronic granulomatous disease neutrophils.

Beside the inability to produce superoxide ions, neutrophils (PMN) from chronic granulomatous disease (CGD) patients show other functional defects, e.g. abnormal membrane potential reactions. We observed that PMN from a female CGD carrier, with a discrete mutation in one allele of the pg91(phox) gene and exhibiting extreme lyonization, showed a consistently and remarkably delayed PMN cytosolic calcium response to the tripeptide fMLP or leukotriene B4 (LTB4). In keeping with results from other CGD patients, membrane potential changes were abnormal, whereas chemotaxis and adherence was normal. Since phospholipase D-generated metabolites are important for calcium transients we examined the generation of phosphatidic acid, but found that to be normal. A male CGD patient with pg91(phox) deficiency exhibited a trend toward prolongation of this calcium response, whereas two other CGD patients (one with p47 and one with 67(phox) deficiencies) had normal calcium transients. Thus, our finding points to a defect of the stimulus response coupling for fMLP and LTB4, which is supposed to be characteristic for this patient or a subset of CGD patients.

Efficacy and safety of two different rG-CSF preparations in the treatment of patients with severe congenital neutropenia.

In patients with severe congenital neutropenia (SCN), the absolute neutrophil count (ANC) is raised during treatment with granulocyte colony-stimulating factor (G-CSF), resulting in a marked reduction of bacterial infection. Some patients, however, still have recurrent but less severe bacterial infections and severe periodontal infections. As it has been suggested that the biological activity of glycosylated recombinant human G-CSF (rHuG-CSF, i.e. lenograstim) is higher than the non-glycosylated form (i.e. filgrastim), we compared the two given in equimolar doses. Seven SCN patients participated in an open, randomized, double crossover study comprising 60 weeks, with four 12-week periods when the two drugs alternated after a 12-week run-in-period. The mean ANC values, sampled every second week, were 5.1 x 10(9)/l during filgrastim treatment and 4.2 x 10(9)/l during lenograstim treatment (P = 0.042). The ANC levels were also significantly higher during filgrastim treatment, when comparing each complementary pair of ANC measurements (P = 0.011) as well as the mean ANC values during each 12-week treatment period (P = 0.033). There were no differences regarding the frequency of infection, antibiotic treatment, gingival bleeding and the number of hospital admissions between the groups. We conclude that filgrastim and lenograstim displayed equal clinical efficacy, but that ANC levels were higher during filgrastim treatment, when administered in equimolar doses.