Asymptomatic persistent pulmonary infiltrates in an immunocompetent boy with cat-scratch disease.

We describe here an immunocompetent boy with fever, regional adenopathy, multifocal hepatosplenic granulomas, and high and increasing serum antibody titers for Bartonella henselae in whom diffuse bilateral reticulonodular pulmonary infiltrates developed in the absence of respiratory symptoms.

Tolerance and hematopoietic stem cell transplantation 50 years after Burnet's theory.

OBJECTIVE: In 1949, the original formulation of Burnet's theory on the mechanisms responsible for the capacity of the immune system to discriminate between foreign antigens (i.e., the "non-self") and the cells of its own body (i.e., the "self") was published. Since then, further refinements and reconsiderations of the basic concepts underlying the achievement of a state of tolerance toward a certain antigen have been reported. Here, we attempt to analyze critically new clinical and experimental strategies aimed at inducing alloantigen-specific unresponsiveness. DATA SOURCES: The data discussed in this review are drawn from articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF THE ART: Induction of tolerance toward alloantigens still remains one of the most elusive goals of clinical immunology. Until now, nonspecific immunosuppressive drugs have been used to successfully perform both solid organ and hematopoietic stem cell transplantation. However, using this approach, patients given an allograft are exposed to the threat of infections, tumors, and other side effects. Moreover, in solid organ transplant recipients, permanent tolerance toward the graft's alloantigens is never achieved. Recently, considerable progress has been made in expanding our knowledge of transplant tolerance. The traditional model of central tolerance, derived from Burnet's concept, has been complemented by knowledge of mechanisms of peripheral tolerance. CONCLUSIONS: New experimental and therapeutic trials based on the blockade of costimulatory molecules, as well as on generation and infusion of either regulatory or nonimmunogenic cells, have been recently proposed for inducing alloantigen-specific tolerance.The achievements obtained in understanding the mechanisms of unresponsiveness toward non-self antigens are fundamental prerequisites for successful allogeneic transplants, and they could open a new exciting era of specific, immunosuppressive therapies.

Alternative therapies and the Di Bella affair in pediatrics. A questionnaire submitted to Italian pediatric oncologists and hematologists.

BACKGROUND AND OBJECTIVE: Over the last 2-3 years in particular, the so-called Di Bella therapy (DBT) become the most famous of alternative treatments applied to pediatric oncology and hematology in Italy. Many Italian oncologists and hematologists had to cope with the problems that it introduced and the treatment also elicited heated reactions all over Europe. We attempted to evaluate the impact of this treatment on children with cancer. DESIGN AND METHODS: A questionnaire prepared with the aim of addressing the use of alternative therapies in pediatric hematology and oncology was circulated to the 48 centers (or divisions) belonging to AIEOP (Associazione Italiana di Oncoematologia Pediatrica) [Italian Pediatric Oncology and Hematology Association] and FONOP (Forza Operativa Nazionale di Oncologia Pediatrica) [National Pediatric Oncology Task Force]. The questionnaire consisted of 9 questions elaborated to give credit to the case-related and professional experiences of the colleagues we contacted. RESULTS: Forty-three centers replied to the questionnaire. Request to switch to DBT represented a considerable problem, involving the vast majority of centers participating into this study; however, case quantification varied greatly from center to center. One of the most significant aspects is that children switched to DBT, abandoning conventional therapies, were often relapsing or had had multiple relapses (from solid tumor or leukemia), but some children abandoned conventional therapies at an early stage and/or without fully exploiting the curative potential of these therapies. INTERPRETATION AND CONCLUSIONS: This study allowed us to obtain an evaluation of the impact of DBT in children with oncologic or hematologic disorders. It also highlights the importance of cultivating physician-parent dialogue and provides an opportunity for a few pedagogic thoughts on the attitude and opinions of pediatricians on this problem.

Tolerance and auto-immunity: 50 years after Burnet.

UNLABELLED: Fifty years ago Sir F. Macfarlane Burnet published his first fundamental contribution to the theory of immune tolerance he perfected 10 years later. Since then an impressive amount of new information on the function of the immune system has been gathered. As any original meaningful theory, Burnet's hypothesis on the development of immune tolerance has undergone extensive modifications to take into account all these new findings. An improved understanding of the mechanisms of tolerance has led to new possibilities for the treatment of auto-immune diseases. CONCLUSION: All new information in the field of immune function is rooted in Burnet's contribution which set the stage for the development of modern immunology.

Transplant of hematopoietic stem cells in childhood: where we are and where we are going.

Over the past decade, relevant improvements and refinements have significantly changed the indications, technique and results obtained with allogeneic transplantation of hematopoietic stem cells (HSC) in childhood. In this review the most important innovations that have characterized the practice of HSC transplantation in childhood during this decade will be discussed. We will analyze the clinical and biological advantages or disadvantages which characterize most typically HSC transplantation procedure in terms of the source of these cells (bone marrow, peripheral blood, placental blood). A fundamental turning point in the history of allogeneic transplantation of HSC is represented by the use of placental blood, which was first employed in 1988. Autologous, peripheral blood progenitor cells are increasingly being used as a source of HSC following high-dose therapy for malignant disease, because of the ease of collection and the markedly faster kinetics of engraftment in comparison with bone marrow. In particular, over the past decade, due to the much faster recovery of all hematopoietic lineages in comparison with bone marrow and due to the short duration of antibiotic therapy and hospitalization, also in pediatric patients, auto-transfusion of circulating hematopoietic progenitors is rapidly replacing autologous bone marrow transplantation after high-dose chemotherapy for lymphomas and solid tumors. On the contrary, due to concerns in pediatric patients related to the use of hematopoietic growth factors in a healthy donor, allograft of peripheral blood progenitor cells is not routinely used. Since indications for allogeneic HSC transplantation that had already been well established in the recent past have been complemented by others and a relevant number of disorders are no longer considered to be eligible for allograft, the evolution in the indications for allogeneic transplant of HSC in childhood will be discussed. Likewise, biotechnological, social and organizational refinements which have allowed the greatest advances of allogeneic HSC transplantation in this decade will be analyzed, as well as some still open bioethical question regarding this procedure.

Transplant of bone marrow and cord blood hematopoietic stem cells in pediatric practice, revisited according to the fundamental principles of bioethics.

The two most widely used sources of hematopoietic stem cells for allogeneic transplants in pediatric practice are bone marrow (BM) and cord blood (CB). While bone marrow transplantation (BMT) is reaching its 30th year of application, human umbilical cord blood transplantation (HUCBT) is approaching its 10th. Although these procedures have basically the same purpose, a number of biological differences distinguish them. In particular, the intrinsically limited quantity of CB stem cells and their immunological naiveté confer peculiar characteristics to these hematopoietic progenitors. From a bioethical point of view, the problems which have repeatedly been raised when the BM donor is a child are well-known. Different but no less important ethical problems are raised when one considers HUCBT; in this regard the most important issues are the easier propensity of programming a CB donor in comparison with a BM donor (clearly due to the shorter time interval needed to collect the hematopoietic progenitors); the in utero HLA-typing; the implication of employing 'blood belonging to a neonate' for a third party; the need to perform a number of investigations both on the CB of the donor and on the mother and the implications that the discovery of disease may have for them, but also the need to establish banks for storing CB, with the accompanying administration and management problems. All these different aspects of UCBT will be discussed in the light of the four fundamental and traditional principles of bioethics, namely autonomy, nonmaleficence, beneficence and justice.

Recurrent chest pain as the presenting manifestation of spinal meningioma.

We report the case of a 9-year-old boy with a spinal cord meningioma whose only manifestations were recurrent episodes of chest pain lasting for 2 years. This case shows that spinal cord meningioma should be considered among the possible causative factors of chronic chest pain in childhood.

Cyclosporine therapy for refractory Langerhans cell histiocytosis.

Optimal treatment for Langerhans Cell Histiocytosis (LCH) has not yet been established. Preliminary reports suggest some effect of cyclosporine (CSA), both alone or in combination with steroids and/or vinblastine, in untreated cases. Twelve children (6 females and 6 males, age at diagnosis 3 months to 4 years) with biopsy proven, systemic LCH received oral CSA (12 mg/kg/day in two divided doses given daily) as a second-line therapy following chemotherapy including vinblastine and/or etoposide (10 cases) or steroid alone (one case); one child was not pretreated. A total of 16 CSA courses were administered to the 12 patients: 8 were completed, 4 were interrupted as unsuccessful, and 4 are still ongoing. CSA related toxicity consisted of hypertrichosis and transient hypertension and was never limiting. Treatment was associated with a clinical response in 8/12 patients: 3 had a complete response and are off therapy, and 5 had a partial response; disease reactivation following first favorable response required additional CSA courses in 3 patients. Four patients failed to respond to CSA: two died of progressive disease, while two had a favorable response to CSA + VP16. Favorable response to CSA was not related to CSA trough and peak levels and was usually observed during the first 2 weeks of CSA therapy. CSA is effective for treatment of LCH also in pretreated children with progressive disease including life-threatening organ dysfunction. Long-lasting complete remission may be achieved after 6 to 12 months of CSA therapy. When disease reactivation occurs after treatment withdrawal, a second course may be followed by favorable response. As minimal or no adverse effects are observed during or after prolonged CSA therapy, this may also be safely used in young patients.

Immunological features of Down's syndrome: a review.

Young patients with Down's syndrome (DS) have high rates of infections, malignancies and autoimmune phenomena. Therefore, DS may be considered as a model of precocious, abnormal ageing of the thymus-dependent system in man. In DS children less than 6 years of age, the levels of serum immunoglobulins did not differ from healthy controls, but after that age, considerable hyper-IgG and -IgA were found. Furthermore, high levels of IgG1 and IgG3 have been found, whereas a progressive decline of IgG2 and IgG4 with age has been observed. The frequency of hepatitis B virus carriers even in the youngest age group is much higher among DS children. It has been reported that an IgG response was detectable in 75% of controls after HBsAg vaccination as compared to the 16.6% of DS patients. The presence of autoantibodies against human thyroglobulin did show a positive association with HB Virus Ag carriers, but only in the oldest DS subjects. Natural antibodies against intestinal antigens are low, while in the presence of cow's milk, abnormally high titres against casein and beta-lactoglobulin were present. High levels of IgG antibodies against gliadin have been observed. In spite of a normal percentage of CD3- and CD2-positive lymphocytes, a high proportion of cells express low-avidity receptors for sheep erythrocytes. Although the proportion of CD4+ T-lymphocyte helper-cells is normal, a marked imbalance in the CD4+ subpopulations has been documented. The percentage of suppressor-cytotoxic CD8+ lymphocytes is markedly increased. The responses to phytohemagglutinin and concanavalin A are within the normal range in the first decade of life and decline progressively thereafter. A recent study reported defective proliferative response to allo-mixed lymphocyte culture, with decreased expression of the membrane CD25, low secretion of interleukin 2 in the supernatant and depressed allo-specific cytotoxic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Recurrent juvenile dermatomyositis and cutaneous necrotizing arteritis with molecular mimicry between streptococcal type 5 M protein and human skeletal myosin.

An adult patient had a syndrome associating the features of juvenile dermatomyositis and cutaneous polyarteritis nodosa that followed a cyclic course from childhood; recurrences were always associated with a rise of serum antistreptococcal antibodies. Regions of homology between streptococcal type 5 M protein and skeletal myosin were found. These findings suggest that streptococcal infection, possibly through a molecular mimicry mechanism, played a role in the pathogenesis of the disease in our patient.

Prospective randomized comparison of toxicity of two prophylactic regimens of cotrimoxazole in leukemic children.

Cotrimoxazole is currently used for Pneumocystis carinii pneumonia prophylaxis in leukemic children. The former regimen of continuous administration was recently replaced by intermittent administration. The antifolic activity of cotrimoxazole could theoretically enhance that of methotrexate, also administered to leukemic children. We report on a prospective, randomized study to compare two different regimens--continuous vs. 3 days a week--of cotrimoxazole prophylaxis. The aim of the study was to evaluate the toxicity, assuming that both regimens are equally effective to prevent P. carinii pneumonia. Seventy-seven leukemic children were enrolled; 67 were evaluable, 35 from arm A (continuous), 32 from arm B (intermittent cotrimoxazole administration). The conclusion was that long-term maintenance chemotherapy with antimetabolites produced lower levels of folate but normal levels of vitamin B12 in leukemic children. This pattern did not vary between the continuous and the 3-days-a-week administration of cotrimoxazole prophylaxis. Thus it seems hypothesizable that the antimetabolic activity of methotrexate alone exceeds that of cotrimoxazole.

From a historical outline of transplants to the concept of biological ego.

A chronology of the biological preliminaries of human transplantation science is proposed together with a chronological listing of the applications which transplants have had in clinical medicine in general and in pediatrics in particular. The most significantly immunological elements which surface from this assortment of experiences (in which those of pediatric interest have a considerable role) contribute easily to a more deeply perceived culture of man's biological individuality.

Clotting abnormalities in children during maintenance chemotherapy for acute lymphoblastic leukemia.

BACKGROUND: Many of the drugs used in the treatment of acute lymphoblastic leukemia in children may induce modifications in different organs and functions. Following the observation of a recurrent, mild delay in the prothrombin time in ALL children during maintenance chemotherapy, we explored the main parameters of the clotting function. METHODS: 17 children with acute lymphoblastic leukemia were studied during maintenance chemotherapy for clotting function screening evaluation; 15 healthy children, matched for age and sex, were used as controls. RESULTS: A uniform pattern of slight prolongation of the prothrombin time with significantly reduced levels of factors VII, IX, and a trend toward reduced activity of factor X was observed in the absence of any demonstrable anticoagulant factor. CONCLUSIONS: Antileukemic maintenance chemotherapy is associated with a subclinical modification of the clotting parameters that is not responsible for hemorrhagic diathesis. Long-term administration of anti-metabolites (6-mercaptopurine and methotrexate) could be responsible for this reversible impairment.

Correlation of serum interleukin-6 levels with joint involvement and thrombocytosis in systemic juvenile rheumatoid arthritis.

We measured interleukin-6 (IL-6) levels in 70 serum samples obtained from 25 patients with systemic-onset juvenile rheumatoid arthritis (JRA), using the hybridoma cell line B9. Patients with systemic-onset JRA had significantly elevated serum IL-6 levels during active disease (mean +/- SD 92.1 +/- 75.1 hybridoma growth factor units/ml; P less than 0.00001 versus healthy age-matched controls), but not during remission. Serum IL-6 levels correlated with the extent and severity of joint involvement (P less than 0.001) and with platelet counts (P less than 0.05). Our data suggest that IL-6 plays a significant role in the pathogenesis of systemic-onset JRA.

Kaposi's sarcoma in a child after autologous bone marrow transplantation for non-Hodgkin's lymphoma.

A case of Kaposi's sarcoma in a child with no serologic evidence of human immunodeficiency virus (HIV) infection is reported. A 7-year-old boy with Stage IV non-Hodgkin's lymphoma, after conventional chemotherapy, underwent autologous bone marrow transplantation (ABMT). Five months later he presented with supraclavicular mass and mediastinal enlargement. A bone marrow biopsy showed hypoplasia with no signs of the underlying disease, whereas the excised mass revealed a typical histologic pattern of Kaposi's sarcoma. The child is currently being treated with recombinant alpha-interferon (alpha-IFN) and regression of the disease has been achieved.