E. J. A. Gerritsen

Bone marrow transplantation for autosomal recessive osteopetrosis A report from the Working Party on Inborn Errors of the European Bone Marrow Transplantation Group

The outcomes of 69 patients who received allogeneic bone marrow grafts for autosomal recessive osteopetrosis in the period between 1976 and 1994 were analyzed retrospectively. Four patients received bone marrow transplants (BMT) without prior myeloablative conditioning; transient osteoclast function was demonstrated in one of them. Sixty-five patients received myeloablative pretreatment. Recipients of a genotypically human leukocyte antigen (HLA)-identical BMT had an actuarial probability for 5-year survival, with osteoclast function, of 79%; recipients of a phenotypically HLA-identical bone marrow graft from a related or unrelated donor, or one HLA-mismatched graft from a related donor, had an actuarial probability for 5-year survival, with osteoclast function, of 38%; patients who received a graft from an HLA-haplotype mismatched related donor had a probability for 5-year survival of only 13%. The main problems in haplotype-nonidentical BMT were graft failure and BMT-related complications such as sepsis, bleeding, and interstitial pneumonia. Osteoclast function developed in all patients with full engraftment. Recovery of osteoclast function was associated with severe hypercalcemia in 24% of the patients with engraftment, especially those older than 2 years of age. At the time of BMT, severe visual impairment was present in 35% of the patients; of the 15 patients who had visual impairment at the time that a successful BMT was performed, two had improvement after BMT (13%). Within the total group, one patient had neurodegeneration. Engraftment of healthy donor cells had no influence on the progression of that abnormality and BMT thus had no beneficial effect on this phenotype of osteopetrosis. In general, however, early BMT remains the only curative treatment for autosomal recessive osteopetrosis.

Prevention of infection and graft-versus-host disease by suppression of intestinal microflora in children treated with allogeneic bone marrow transplantation

The effect of suppression with antimicrobial agents of the intestinal microflora of paediatric bone marrow graft recipients on severe bacterial and fungal infections and on moderate to severe acute graft-versus-host disease was studied retrospectively. Data on 65 cases of bone marrow transplantation for either severe bone marrow failure or leukaemia, performed in a strict protective environment with either complete or selective gastrointestinal decontamination, were evaluated. All bone marrow grafts were from HLA-identical siblings and were not depleted of T-lymphocytes. Twenty percent of the recipients had one or more episodes of septicaemia during the granulocytopenic period after transplantation, mostly due to gram-positive bacteria. Only five children died due to infection, in each case caused by a microorganism originating from the endogenous flora. Complete gastrointestinal decontamination was superior to selective gastrointestinal decontamination in preventing infectious complications (p<0.001). The same was the case for the prevention of acute graft-versus-host disease of grade II or higher, which was observed in 7 of 40 (17.5 %) completely decontaminated children versus 9 of 18 (50 %) selectively decontaminated children evaluable for graft-versus-host disease (p<0.01). It is concluded that complete gastrointestinal decontamination in a strict protective environment is a feasible and very effective method for preventing severe infections and acute graft-versus-host disease after allogeneic bone marrow transplantation in children and adolescents; it resulted in a low transplantation-related mortality of 26 % and a good quality of survival in 69 % of the graft recipients.

Monoclonal gammopathies in children

Over a 10-year period sera of 4000 pediatric patients were subjected to agar gel electrophoresis and immunoelectrophoresis. Retrospective examination of the electrophoresis patterns indicated that single or multiple homogeneous immunoglobulin components were present in sera of 155 children (3.9%). They were most frequently found in patients suffering from primary and secondary immuno-deficiency diseases, hematological malignancies, autoimmune diseases, and severe aplastic anemia. Follow-up analysis revealed that most of these monoclonal gammopathies were transient. The monoclonal gammopathies in the serum of 79 patients were identified by immunoblotting for class and light-chain isotypes. A marked absence of IgA monoclonal gammopathies and a predominance of monoclonal gammopathies of the lambda light-chain isotype were found. Most of the B-cell mono- or oligoclonal proliferations in children can probably develop due to a disturbance in the regulatory T-cell function.

C-reactive protein in the management of children with fever after allogeneic bone marrow transplantation

SummaryThe value of C-reactive protein (CRP) determinations in the analysis of fever after allogeneic bone marrow transplantation (BMT) was studied prospectively by serial measurements of serum CRP levels during 30 BMT episodes in 28 children and adolescents. The treatments and procedures accompanying BMT did not elicit a significant CRP response. Fourty-three febrile episodes were registered and analyzed, without previous knowledge of the results of CRP determinations. The incidence of bacterial infection and acute graft-versus-host disease (GvHD) was low, 8/30 and 5/30, respectively. Raised CRP levels occurred only once in association with GvHD. A CRP level higher than 50 mg/l was not sensitive as an indicator of bacterial infection (4/8). A CRP level below 50 mg/l in the presence of fever, however, excluded bacterial infection with a specificity of 86% and a negative predictive value of 88%. When timed properly and interpreted together with clinical and microbiological findings, CRP measurements can be a valuable aid in the management of fever after BMT, especially as a negative predictor.ZusammenfassungIn einer prospektiven Studie wurde durch Serien-Messungen der Spiegel von C-reaktivem Protein (CRP) im Serum während 30 Knochenmarktransplantationen bei 28 Kindern und Jugendlichen der Wert der CRP-Spiegel-Bestimmung für die Beurteilung von Fieber nach allogener Knochenmarktransplantation ermittelt. Therapien und Maßnahmen im Rahmen der Knochenmarktransplantation lösten keinen signifikanten CRP-Anstieg aus. Ohne Vorkenntnis der CRP-Spiegel wurden 43 Fieberepisoden analysiert. Bakterielle Infektionen und Graft-versus-Host-Disease traten nur in 8/30 beziehungsweise 5/30 Fällen auf. Nur einmal stieg das CRP im Zusammenhang mit einer Graft-versus-host-disease an. Ein Antieg des CRP-Spiegels über 50 mg/l war kein sensitiver Parameter für eine bakterielle Infektion (4/8). Dagegen war eine bakterielle Infektion mit einer Spezifizität von 86% und einem negativen prädiktiven Wert von 88% ausgeschlossen, wenn bei Fieber ein CRP-Serumspiegel von weniger als 50 mg/l vorlag. Bei entsprechender Koordination der Spiegelmessungen und Interpretation im Kontext klinischer und mikrobiologischer Befunde können die CRP-Spiegel eine Hilfe im therapeutischen Management von Fieber nach Knochenmarktransplantation darstellen, wobei ein negativer CRP-Wert vor allem ein wertvoller Parameter für den Ausschluß einer bakteriellen Infektion ist.

Late effects of total body irradiation and cytostatic preparative regimen for bone marrow transplantation in children with hematological malignancies

Twenty-seven children, surviving disease-free for more than 1 year after allogeneic bone marrow transplantation (BMT) for hematological malignancy were evaluated for the long-term effects on endocrine function, sexual development, physical growth, appearance of ocular cataract and psychological sequelae. The growth rate was not decelerated in the prepubertal period in children not affected by chronic graft-versus-host (GVH) disease and without previous cranial irradiation. Development of sexual characteristics was delayed in 4 relevant cases. Thyroid function was not adversely affected, gonadal function was impaired in girls, transplanted after menarche, ocular cataract developed in all cases, irradiated without shielding of the eyes after 4 years. Psychologically, children after BMT had an advantageous social development.

Major complications of the central nervous system after bone marrow transplantation in children with acute lymphoblastic leukemia

After the first ten bone marrow transplantations for acute lymphoblastic leukemia in children, we evaluated the cerebral outcome as severe cerebral complications had occurred in these patients. From these data we deduced a score of risk factors (SRF) encompassing the facts known to cause cerebral damage in leukemia treatment. In the following 13 patients, we lowered, in the individual patient, the SRF. The number of patients with cerebral damage was lower and no cerebral death occurred.

Kinderen met recidiverende infecties

SummaryAntibody deficiencies are by far the most common primary immunodeficiency in pediatrics. Complement deficiency is rare. Most children present with recurrent respiratory tract infections. Because the presence of immunodeficiency is difficult to exclude from clinical presentation, a low threshold should be used to perform laboratory evaluation, even with the knowledge that in many cases the results will be normal. This because early recognition of immunodeficiency may have great impact on the quality of life and because early intervention prevents serious complications.SamenvattingAntistofdeficiënties zijn verreweg de meest voorkomende primaire immuundeficiënties bij kinderen, complementdeficiënties zijn zeldzaam. De kinderen presenteren zich meestal met recidiverende luchtweginfecties. Omdat het bestaan van een antistofdeficiëntie of complementdeficiëntie op basis van de klinische presentatie niet altijd uit te sluiten is, dient laagdrempelig laboratoriumonderzoek ingezet te worden, ondanks de wetenschap dat dit vaak niet afwijkend is. Onderkennen van een immuundeficiëntie heeft namelijk grote invloed op de kwaliteit van leven van het kind. Gericht beleid voorkomt bovendien ernstige complicaties op de langere termijn.

SEVERE COMPLICATIONS DUE TO REACTIVATION OF DNA-VIRUSES POST-BMT: RELATIONSHIP WITH IMMUNE STATUS OF THE HOST AND PERSPECTIVES FOR THERAPY 7

Infants and children suffering from some congenital diseases, SAA and haematological malignancies with a poor prognosis are being treated with an allogeneic bone marrow transplantation (BMT), including a graft from another donor than an HLA-identical sibling. In order to obtain engraftment and to circumvent graft-vs-host disease the pretreatment of the host has to be more immunosuppressive and the graft may have to be processed by either T-cell depletion or stem-cell (CD34) enrichment. One or other may result in graft rejection and severe delay of immunological recovery, giving rise to reactivation of DNA-viruses. Most dangerous in this respect are herpesviruses, especially CMV and EBV, and adenoviruses. Studies in the severely compromised BMT-recipients may throw some light on viral pathogenesis and anti-viral immunity. Between January 1985 and January 1997 90 infants and children were grafted with another than an HLA-identical sibling donor in the BMT-centre for children of the Leiden University Hospital. EBV-B-cell lymphoproliferative disease (BLPD) occurred in 10 and severe c.q. systemic adenovirus reactivation in 8 graft recipients, leading to death in 8, respectively 4 of them. Most important variables associated with an increased risk for lethal reactivations were T-cell depletion of the graft and severe delay of haematological and T-cellular recovery after BMT. Whereas anti-viral chemotherapy is efficacious against CMV-reactivations, if administered pre-emptively, this is not the case against BLPD or systemic adenovirus reactivations. The best option for suppression of the latter reactivations is the prophylactic administration of virus-specific cytotoxic T cells, generated from the donor ex vivo.