Verena Wiegering

Immune function in children under chemotherapy for standard risk acute lymphoblastic leukaemia – a prospective study of 20 paediatric patients

Multidrug chemotherapy is a highly effective treatment for paediatric acute lymphoblastic leukaemia (ALL), but at the same time compromises immunity of patients. Immune function in a homogenous cohort of 20 children with standard‐ and intermediate‐risk ALL was analysed by immunophenotyping, intracellular cytokine staining, assessment of serum cytokine concentrations, T‐cell receptor (TCR) repertoire diversity and thymic function. B‐cells were most severely affected by chemotherapy, rapidly declined under induction and did not recover until the cessation of maintenance therapy. This recovery was paralleled by a relative increase in naive IgM+IgD+CD27− B‐cells, indicating de novo B‐cell generation as the major pathway for B‐cell reconstitution. T‐ and Natural Killer‐cells were less severely affected. Although numerically diminished by chemotherapy, they had partially recovered at the end of induction. Interestingly, CD4:CD8 ratio, distribution of naive versus memory T‐cells, cytokine production, TCR‐repertoire complexity and thymic function were all only marginally affected by chemotherapy. Patients receiving dexamethasone had significantly less IFNγ+ T‐cells than those receiving prednisone. Our data show that during chemotherapy in standard‐ and intermediate‐risk paediatric ALL patients the T‐cell system remains relatively well preserved. Future studies will show if this effect can be exploited for inclusion of immunotherapy in standard ALL treatment protocols.

Crohn?s disease during etanercept therapy in juvenile idiopathic arthritis: a case report and review of the literature

Tumor necrosis factor alpha (TNFα) has broad effects on the immune system including lymphoid organ development as well as growth, survival und function of immune cells. TNFα has two main functions: regulatory effects and proinflammatory activities. In several diseases such as juvenile and adult “rheumatoid” arthritis, psoriasis and chronic inflammatory bowel disease, the application of TNFα-blocking medications has been beneficial. However, induction of inflammation in several organs including the eye, CNS, skin and gastrointestinal tract has been reported. We report on an 11-year-old girl with juvenile idiopathic arthritis, who developed Crohn’s disease (CD) while taking etanercept for her arthritis. Etanercept was discontinued and an antibody-based anti-TNF treatment using adalimumab was started, which induced remission of the gastrointestinal symptoms promptly. This case indicates that immunodysregulatory and even proinflammatory effects of etanercept are of relevance in the clinical practice. Furthermore, TNFα as a part of its function seems to downregulate mucosal inflammation in CD.

Activated memory B cells may function as antigen‐presenting cells in the joints of children with juvenile idiopathic arthritis

OBJECTIVE B cells impact the perpetuation of chronic inflammatory or autoimmune diseases in multiple ways. A role of B cells as antigen-presenting cells (APCs) in the pathogenesis of chronic arthritis in humans has been suggested; however, as of yet the presence of such B cells at the site of inflammation has not been demonstrated. This study was undertaken to investigate whether synovial B cells in patients with juvenile idiopathic arthritis (JIA) might display features of APCs. METHODS The frequency, phenotype, and immunoglobulin repertoire of synovial B cells were studied by flow cytometry and single-cell polymerase chain reaction (PCR). Cytokine expression by B cells was analyzed by real-time PCR, and interaction between B cells and T cells was investigated in a mixed lymphocyte culture. RESULTS CD27+IgD- and CD27-IgD- B cells accumulated in the joints of JIA patients and displayed an activated phenotype. Both B cell subsets expressed hypermutated and class-switched immunoglobulins, indicators of memory B cells. The accumulating memory B cells expressed the costimulatory molecules CD80/CD86 and showed a higher capacity to activate allogeneic T cells and prime a Th1 phenotype than their peripheral blood counterparts. CONCLUSION Activated immunoglobulin class-switched CD27- and CD27+ memory B cells, indicating a phenotype of APCs with expression of costimulatory molecules, accumulate in the joints of patients with JIA and might be involved in the amplification of pathogenic T cell activation. These findings provide evidence that B cells play an antibody-independent immunopathologic role in human chronic inflammatory arthritis of childhood.

Indication for allogeneic stem cell transplantation in Glanzmann’s thrombasthenia

Glanzmanns thrombasthenia (GT) is an autosomal recessive disorder characterized by a lack of thrombocyte aggregation due to the absence of thrombocyte glycoproteins IIb and αIIbβ3. The role of haematopoietic stem cell transplantation (HSCT) in GT remains controversial. However, HSCT offers the only curative approach for patients with a severe clinical phenotype. In this review, we will discuss the limitation of current status evidence and the specific risk of GT, in particular the alloimmunization and refractoriness to thrombocyte infusions. 19 successful HSCT in 18 GT type I patients have been reported. Mean age at transplantation was 5 years. All patients are still alive. The majority received sibling bone marrow transplant with busulfan and cyclophosphamid conditioning. GvHD incidence was within the normal range, but 10 patients showed alloimmunization of thrombocytes. Median follow up is 25 months.

B-Cell Pathology in Juvenile Idiopathic Arthritis

Juvenile Idiopathic Arthritis (JIA) is the most common cause of chronic arthritis in childhood and adolescents and encompasses a heterogeneous group of different diseases. Due to the promising results of B-cell depleting therapies in rheumatoid arthritis the role of B-cells in autoimmune diseases has to be discussed in a new context. Additionally, experiments in mouse models have shed new light on the antibody-independent role of B-cells in the development of autoimmune diseases. In this review we will discuss the importance of B-cells in the pathogenesis of JIA appraising the question for an immunological basis of B-cell targeted therapy in JIA.

TGFβ and IL10 have an impact on risk group and prognosis in childhood ALL

Cytokines and their genes have been described to have an influence on incidence and prognosis in malignant, infectious and autoimmune disease. We previously described the impact of cytokine production on prognosis in paediatric standard‐risk acute lymphoblastic leukaemia (ALL).

A novel two‐nucleotide deletion in HPS6 affects mepacrine uptake and platelet dense granule secretion in a family with Hermansky–Pudlak syndrome

Hermansky–Pudlak syndrome (HPS) is a rare autosomal recessive disease characterized by oculocutaneous albinism and platelet dysfunction. We report on a novel HPS6 homozygous frameshift variant (c.1919_1920delTC; p.Val640Glyfs*29) in a nonconsanguineous Caucasian family with two affected siblings (index patients) who presented with oculocutaneous albinism at birth and a mild bleeding phenotype during childhood and adolescence.

Haemophilia in extreme immature preterm infants: increased risk for intracranial haemorrhage?

Abstract Haemophiliacs and extremely premature infants are both at an increased risk for intracranial haemorrhage; both conditions might be further elevating the risk. We report a case of a very immature preterm-infant of 26 gestational weeks (birth weight 635 g) with severe haemophilia A. Furthermore, we provide an overview of the published literature on this subject matter. Until now, deficiency of factor VIII or IX as a potential risk factor for ICH in preterm infants remains controversial. However, prophylactic substitution of factor VIII or IX in preterm infants with haemophilia may minimize the risk of bleeding complications and neurologic sequelae.

Varicella in pediatric oncology patients in the post-vaccine era—Analysis of routine hospital data from Bavaria (Germany), 2005–2011

ABSTRACT Varicella in oncology patients can result in serious complications. We analyzed trends in hospitalization rates and characteristics of pediatric oncology and non-oncology patients hospitalized with varicella during the first 7 years after introduction of routine varicella vaccination. Our data included children <17 years of age with an International Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) main or secondary discharge diagnosis of varicella identified by annual database queries in 22–29 pediatric hospitals in Bavaria (Germany) in 2005–2011. Of a total of 1,245 varicella-associated hospitalizations, 42 children (median age 4 years, interquartile range 3–5) had an underlying malignancy (67% with acute lymphoblastic leukemia). Overall, additional diagnoses potentially associated with varicella were reported less often in oncology than in non-oncology varicella patients (62% vs. 77%, p = 0.041), suggesting earlier hospitalization of high-risk patients. Acute hematological diagnoses (29% vs. 3%, p < 0.001) and coinfections (invasive 12% vs. 2%, p = 0.001; noninvasive 19% vs. 8%, p = 0.019) were more frequent, whereas neurological (5% vs. 19%, p = 0.023) and upper respiratory tract diagnoses (2% vs. 16%, p = 0.014) were less frequent in oncology compared to non-oncology varicella patients. Oncology varicella patients showed a longer hospital stay (median 5 vs. 3 days, p < 0.001). Hospitalization rates in non-oncology varicella patients declined constantly since 2006, from 114.8 (2006) to 30.5 (2011) per 1,000 pediatric beds. The rates of varicella-associated hospitalizations in oncology patients indicated an overall decreasing trend (3.8, 1.9, 4.6, 3.5, 0.4, 2.1 and 0.6 cases per 1,000 pediatric beds in 2005–2011). Thus, pediatric oncology patients potentially profit from herd protection effects, resulting from increasing vaccine coverage in the general population.

Prevention of major infectious complications by pre-emptive enterostomy in patients awaiting allogeneic stem cell transplantation

Dear Editor: Allogeneic hematopoietic stem cell transplantation (aHSCT) is a well-established immunotherapy with curative potential for various hematological diseases. Reduced toxicity conditioning regimens, improved prophylaxis for graft-versus-host disease and optimized supportive have contributed to the overall success of this approach. Particularly, the introduction of novel antibiotic, antiviral, and antifungal drugs have helped to overcome infectious complications also resulting in lower nonrelapse mortality. In the case of aHSCT, it has been demonstrated that the existence of infectious foci before therapy initiation may lead to fatal complications in the following treatment period. Abdominal and perianal infectious foci may therefore represent a significant risk factor for infectious spreading in neutropenia and under immunosuppressive therapy after aHSCT. Even though abdominal and perianal infections can usually be well controlled by modern anti-infective agents, the situation is dramatically worse in patients with neutropenia and impaired immune response, such as in hematologic diseases. These patients suffer from a higher morbidity and mortality to infections and are more often colonized by multiresistant pathogens. Furthermore, these patients may often developmore and more severe complications due to their underlying disease. One surgical option in the management of infectious abdominal complications is the construction of an enterostomy. Today, on the one hand, ileostomy is an emergency operation in combination with resection of the small or large intestines. On the other hand, ileostomy is also a routine protective surgical procedure to minimize the complications of anastomosis leakage. Colostomy has its place in the treatment of severe anal infections and low rectal cancer under neoadjuvant radio-/chemotherapy, or as the so-called “Hartmann ́s procedure” in the case of severe sigmoid diverticulitis. Here, we describe our experiences with a case series of three patients scheduled for aHSCT in our hospital. They suffered from classical surgical problems, such as free abdominal air or complex perianal infectious situation before initiation of conditioning regimen. To minimize the patients’ risk in the periand post-transplant period, the patients received a coloor ileostomy and were subsequently included in the transplant process. The first patient was a 68-year-old male presenting with secondary acute myeloid leukemia (AML) and persistence of blasts after standard induction chemotherapy. On the route to aHSCT, the patient received a routine CT scan of the chest pretransplant where free abdominal air was observed. The patient was completely asymptomatic. Although a perforation of the right hemicolon was not confirmed by laparoscopy, a protective ileostomy in the terminal ileum was constructed before aHSCT. On the fourth day post-operation, aHSCTwas M. Kapp :G. U. Grigoleit :G. Stuhler :H. Einsele : S. Mielke Department of Internal Medicine II, University of Wuerzburg, Wuerzburg, Germany