Live rubella virus vaccine long-term persistence as an antigenic trigger of cutaneous granulomas in patients with primary immunodeficiency.

Granulomas may develop as a response to a local antigenic trigger, leading to the activation of macrophages and T-lymphocytes. Primary immunodeficiency (PID) is associated with the development of extensive cutaneous granulomas, whose aetiology remains unknown. We performed high-throughput sequencing of the transcriptome of cutaneous granuloma lesions on two consecutive index cases, and RT-PCR in a third consecutive patient. The RA27/3 vaccine strain of rubella virus-the core component of a universally used paediatric vaccine-was present in the cutaneous granuloma of these three consecutive PID patients. Controls included the healthy skin of two patients, non-granulomatous cutaneous lesions of patients with immunodeficiency, and skin biopsy samples of healthy individuals, and were negative. Expression of viral antigens was confirmed by immunofluorescence. Persistence of the rubella vaccine virus was also demonstrated in granuloma lesions sampled 4-5 years earlier. The persistence of the rubella virus vaccine strain in all three consecutive cutaneous granuloma patients with PID strongly suggests a causal relationship between rubella virus and granuloma in this setting.

Economic evaluation of immunoglobulin replacement in patients with primary antibody deficiencies.

Lifelong immunoglobulin replacement is the standard, expensive therapy for severe primary antibody deficiencies. This treatment can be administrated either by intravenous immunoglobulin (IVIG) or subcutaneous infusions (SCIG) and delivered at home or in an out-patient setting. This study aims to determine whether SCIG is cost-effective compared with IVIG from a French social insurance perspective. Because both methods of administration provide similar efficacies, a cost-minimization analysis was performed. First, costs were calculated through a simulation testing different hypothesis on costs drivers. Secondly, costs were estimated on the basis of field data collected by a questionnaire completed by a population of patients suffering from agammaglobulinaemia and hyper-immunoglobulin (Ig)M syndrome. Patients' satisfaction was also documented. Results of the simulation showed that direct medical costs ranged from 19 484 euro for home-based IVIG to 25 583 euro for hospital-based IVIG, with home-based SCIG in between at 24 952 euro per year. Estimations made from field data were found to be different, with significantly higher costs for IVIG. This result was explained mainly by a higher immunoglobulin mean dose prescribed for IVIG. While the theoretical model showed very little difference between SCIG and hospital-based IVIG costs, SCIG appears to be 25% less expensive with field data because of lower doses used in SCIG patients. The reality of the dose difference between both routes of administration needs to be confirmed by further and more specific studies.

[Feasibility of administering Tegeline at home. Retrospective study of efficacy, safety and tolerance]. / Faisabilité de la substitution à domicile par Tégéline. Etude rétrospective sur des données d'efficacité de sécurité et de tolérance.

OBJECTIVE: To demonstrate the feasibility of administration Tegeline at home from a point of view of efficacy, safety, tolerance, to validate the pertinence of the selection and the training of patients who could benefit from this type of administration and to assess the long term efficacy and safety. METHOD: This retrospective study was conducted in patients exhibiting primary immune deficiency and formerly treated with intravenous immunoglobulins at least six months in hospital settings, trained by the centre for the training of children in the home (Centre de formation au traitement à domicile de l'enfant--CFTDE) and having received at least one administration of Tegeline at home from January 1st 2000. Tegeline contains a mean of 97.6% of whole IgG (58.8% of IgG1, 34.1% of IgG2, 5.4% of IgG3 and 1.7% of IgG4). RESULTS: Two hundred and eighteen follow-up sheets were completed by 13 patients in whom all the eligibility criteria were fulfilled. The total number of infusions per patient ranged from 4 to 41. No difficulty in administration was reported in 10 patients, difficulties in placing the needle were encountered in 3 other patients and motivating their return to the hospital for treatment (after 6 and 10 months) in 2 cases. The infusion flow rate was usually of 2 to 3 ml/kg/h. During the follow-up period, no episode of infection was noted in 5 patients and 8 presented infections that were treated with antibiotics. Regarding safety, the security 'kits' (corticosteroids, adrenalin) that were supplied to each patient were never used. Over time, the median duration of the infusions at home was of 5 years and 6 months. CONCLUSION: In trained and selected patients, this study demonstrated the efficacy, safety and tolerance to the administration of Tegeline at home.

Highly active antiretroviral therapy started in infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug resistance outcome.

OBJECTIVE: To assess the feasibility and impact of highly active antiretroviral therapy (HAART) started in vertically HIV-1-infected infants less than 3 months of age. DESIGN: A multicentre, phase I/II, non-randomized, open-label study (PENTA 7). METHODS: Adverse events, plasma HIV-1 RNA, CD4 cell counts, CD4 cell percentage (CD4%) and clinical progression were recorded at baseline and prospectively to 72 weeks in order to assess the toxicity, tolerability and efficacy of a combination of stavudine, didanosine and nelfinavir. Selection of genotypic resistance was also investigated. RESULTS: Twenty infants, of whom only three had Centers for Disease Control and Prevention stage B, initiated HAART at median age 2.5 months (range, 0.9-4.7) with median HIV-1 RNA concentration 5.5 log10 copies/ml (range, 3.2-6.8) and CD4% 33% (range, 11-66). Median follow-up was 96 weeks (range, 60-144). At week 72, 11 infants were still taking the original treatment. Few adverse events were reported related to treatment, all minor and causing treatment interruption in only three infants. No AIDS-defining events occurred; one child died of non-HIV-related causes (prematurity). All but two had CD4% > 25% at 72 weeks; however, 14 infants had virological failure and six acquired resistance mutations. CONCLUSIONS: Early treatment with stavudine, didanosine and nelfinavir was well tolerated and associated with good clinical and immunological outcomes at week 72. However, a high rate of virological failure with emergence of genotypic resistance is of great concern. More palatable drug combinations for infants and closer drug monitoring are required.

[Successful treatment of Echovirus 27 meningoencephalitis in agammaglobulinaemia with intraventricular injection of gammaglobulin. A case report]. / Guérison d'une méningo-encéphalite à Echovirus 27 par immunoglobulines intraventriculaires au cours d'une agammaglobulinémie. A propos d'un cas.

BACKGROUND: Meningoencephalitis due to enteroviruses is particularly serious when occurring in patients with agammaglobulinaemia. This disease is associated with a high mortality and a significant risk for neurological sequelae in such circumstances. We report here a new case treated with intraventricular immunoglobulin, whose evolution was favourable. CASE REPORT: A three-year-old boy with agammaglobulinaemia, while he was treated with gammaglobulin with an IgG residual concentration of 10 g/l, presented neurological symptoms related to Echovirus 27 meningo encephalitis. Under treatment with intraventricular gammaglobulin by means of an Ommaya reservoir, the patient recovered. CONCLUSION: Favourable evolution is rare in meningo encephalitis in agammaglobulinaemic patients. Prognosis depends on an early diagnosis and on the extent of dissemination of the infection. Intraventricular gammaglobulin administration may contribute to a favourable outcome.

Cancer risk in heterozygotes for ataxia-telangiectasia.

Epidemiological studies have suggested that ataxia-telangiectasia (AT) heterozygotes have a predisposition to cancer, especially breast cancer in women. Now, haplotyping can identify heterozygotes for AT mutation (ATM) in AT families, allowing the risk of cancer associated with ATM heterozygosity status to be better assessed. We report a family study of AT patients, in which we estimated the risk of cancer according to ATM heterozygosity status. We analyzed demographic characteristics and occurrence of cancer in 1,423 relatives of AT patients. Haplotyping was performed in living relatives. The probability of being heterozygotes for ATM was calculated for deceased relatives. The risk of developing cancer was estimated in the cohort of relatives, and expected numbers of cancer cases were calculated from French age period-specific incidence rates. The number of cancers at all sites in the total population of relatives was not higher than expected. However, significant heterogeneity was found according to ATM heterozygosity status. This is mainly due to the increased risk of breast cancer previously observed in obligate heterozygotes. In obligate heterozygotes, relative risk (RR) was non-significantly increased for thyroid cancer, leukemia and liver cancer. Risks of ovarian, lung, pancreatic, kidney, stomach and colorectal cancers were non-significantly increased in the group with 0.5 probability of being heterozygotes. The RR was not significantly increased for any site of cancer, except for breast. Therefore, there is no evidence that specific screening of relatives of AT patients would be justified at particular sites other than the breast. However, the amplitude of the risk of breast cancer estimated in heterozygous women does not appear to justify a separate screening program from that already available to women with a first-degree relative affected by breast cancer.

Differentiation of Langerhans cells in Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) consists of lesions composed of cells with a dendritic Langerhans cell (LC) phenotype. The clinical course of LCH ranges from spontaneous resolution to a chronic and sometimes lethal disease. We studied 25 patients with various clinical forms of the disease. In bone and chronic lesions, LCH cells had immature phenotype and function. They coexpressed LC antigens CD1a and Langerin together with monocyte antigens CD68 and CD14. Class II antigens were intracellular and LCH cells almost never expressed CD83 or CD86 or dendritic cell (DC)-Lamp, despite their CD40 expression. Consistently, LCH cells sorted from bone lesions (eosinophilic granuloma) poorly stimulated allogeneic T-cell proliferation in vitro. Strikingly, however, in vitro treatment with CD40L induced the expression of membrane class II and CD86 and strongly increased LCH cell allostimulatory activity to a level similar to that of mature DCs. Numerous interleukin-10-positive (IL-10(+)), Langerin(-), and CD68(+) macrophages were found within bone and lymph node lesions. In patients with self-healing and/or isolated cutaneous disease, LCH cells had a more mature phenotype. LCH cells were frequently CD14(-) and CD86(+), and macrophages were rare or absent, as were IL-10-expressing cells. We conclude that LCH cells in the bone and/or chronic forms of the disease accumulate within the tissues in an immature state and that most probably result from extrinsic signals and may be induced to differentiate toward mature DCs after CD40 triggering. Drugs that enhance the in vivo maturation of these immature DCs, or that induce their death, may be of therapeutic benefit.

Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families.

Epidemiological studies in ataxia telangiectasia (AT) families have suggested that AT heterozygotes could have an increased cancer risk, especially breast cancer (BC) in women. It has also been suggested that an increased sensibility of AT heterozygotes to the effect of ionizing radiation could be responsible for the increased BC risk. BC relative risk (RR) estimation in AT heterozygotes within families ascertained through AT children is presented here. Family data collected included demographic characteristics, occurrence of cancers, past radiation exposures and blood samples. DNA samples were studied using seven ATM linked microsatellites markers allowing AT haplotypes reconstitution. The relative risk of BC was assessed using French estimated incidence rates. A significant increase risk of BC is found among obligate ATM heterozygotes with a point estimate of 3.32 (P = 0.002). BC relative risk calculated according to age is significantly increased among the obligate ATM heterozygotes female relatives with an age < or = 44 years (RR = 4.55, P = 0.005). The BC relative risk is statistically borderline among the obligate ATM heterozygote female relatives with an age > or = 45 years (RR = 2.48, P = 0.08). The estimated BC relative risk among ATM heterozygotes is consistent with previously published data. However, the increased risk is only a little higher than classical reproductive risk factors and similar to the risk associated with a first-degree relative affected by BC.

Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients.

OBJECTIVE: To evaluate the outcome of children who received prolonged intravenous immunoglobulin (IVIg) replacement therapy early in life for X-linked agammaglobulinemia (XLA). STUDY DESIGN: We performed a retrospective study of the clinical features and outcome of patients with genetic and/or immunologic results consistent with XLA. Patients receiving IVIg replacement therapy within 3 months of the diagnosis and for at least 4 years between 1982 and 1997 were included. RESULTS: Thirty-one patients began receiving IVIg replacement therapy at a median age of 24 months and were followed up for a median time of 123 months. IVIg was given at doses >0.25 g/kg every 3 weeks, and mean individual residual IgG levels ranged from 500 to 1140 mg/dL (median, 700 mg/dL). During IVIg replacement, the incidence of bacterial infections requiring hospitalization fell from 0.40 to 0.06 per patient per year (P <. 001). However, viral or unidentified infections still developed, including enteroviral meningoencephalitis (n = 3) causing death in one patient, exudative enteropathy (n = 3), and aseptic arthritis (n = 1). At last follow-up, 30 patients were alive at a median age of 144 months (range, 58 to 253 months). Among 23 patients who were evaluated by respiratory function tests and computed tomography, 3 had an obstructive syndrome, 6 had bronchiectasis, and 20 had chronic sinusitis. CONCLUSION: Early IVIg replacement therapy achieving residual IgG levels >500 mg/dL is effective in preventing severe acute bacterial infections and pulmonary insufficiency. More intensive therapy may be required to fully prevent the onset of bronchiectasis, chronic sinusitis, and nonbacterial infections, particularly enteroviral infections, in all cases.

Normal CD40-mediated activation of monocytes and dendritic cells from patients with hyper-IgM syndrome due to a CD40 pathway defect in B cells.

Patients with X-linked hyper-IgM syndrome [CD40 ligand (CD40L) deficiency] are prone to infections by intracellular parasites. It has been suggested that this susceptibility is caused by defective macrophage activation through the CD40L-CD40 pathway. We studied the CD40-mediated activation of monocytes and dendritic cells from patients affected with a CD40L+ hyper-IgM syndrome characterized by a defect of B lymphocyte responses to CD40 agonists. We show that the CD40-induced production of IL-6, IL-8 and TNF-alpha by monocytes, and IL-12 by dendritic cells, and expression of the activation markers CD83, the costimulatory molecules CD86 and CD80, and HLA-DR antigens were all similar in patient and control cells. This observation is consistent with the clinical characteristics of the syndrome: a defect of immunoglobulin switch but no susceptibility to opportunistic infections, as observed in CD40L-deficient patients. These observations suggest that CD40-mediated activation pathways could be, at least in part, different in B and monocytic/dendritic cell lineages.

High adenosine deaminase level among healthy probands of Diamond Blackfan anemia (DBA) cosegregates with the DBA gene region on chromosome 19q13. The DBA Working Group of Société d'Immunologie Pédiatrique (SHIP).

Phenotypic characterization of Diamond Blackfan Anemia (DBA) patients and their relatives was performed in 54 families. Complete blood count, fetal hemoglobin level, erythrocyte i antigen expression, and erythrocyte adenosine deaminase (eADA) activities were quantitated in patients and relatives. eADA was elevated in 28 of 34 transfusion-independent DBA patients, whereas persistence of erythrocyte i antigen was noticed in only 10 of 20 DBA patients. High eADA activities were also found in 14 of 149 healthy family members, allowing us to identify an isolated high eADA phenotype in these families. In contrast, increase in erythrocyte i antigen expression, elevated fetal hemoglobin levels, and macrocytosis were much less frequently noted in nonaffected members of the DBA families studied. Importantly, isolated high eADA phenotype was found to be significantly associated with genetic markers on chromosome 19 that segregate with the DBA phenotype. Isolated high eADA phenotype thus seems to reflect a silent phenotype of DBA in affected families. These findings suggest that elevated eADA activity in unaffected individuals needs to be taken into account during genetic assessment of DBA families and could be used for accurate assessment of mode of inheritance.

Is there a role for interleukin-3 in Diamond-Blackfan anaemia? Results of a European multicentre study.

Forty patients (nine adults aged 20-54; 31 children aged 1-17) with Diamond-Blackfan anaemia (DBA) were treated with recombinant human interleukin-3 (IL-3) in a European multicentre compassionate-need study. IL-3 was given as a daily subcutaneous injection at a starting dose of 2.5 micrograms/kg, escalating at day 21 to 5 micrograms/kg, and then to 10 micrograms/kg if there was no response, for a total duration of 12 weeks. Three children achieved a significant response, achieving sustained remissions off all therapy. At the time of entry, one was steroid-responsive and transfusion-independent, and two were transfusion-dependent. Two adults had a transient reduction in transfusion requirements, but could not tolerate the complete course of therapy. Eosinophilia was common; neutrophil and platelet counts were unaffected except in three patients in whom previously noted mild thrombocytopenia was transiently exacerbated. Clinical response to IL-3 did not correlate with in vitro culture results. A comparison of individual patient characteristics of our study with previously reported series confirms earlier impressions that patients who have never achieved significant in vivo erythropoiesis in response to steroids or during a spontaneous remission are highly unlikely to respond to IL-3. In contrast, there may be a 50% chance of a sustained remission, off steroids, in children who are steroid-dependent and transfusion-independent at the time of IL-3 therapy, suggesting a possible role for a short course of IL-3 earlier in the treatment of children with steroid-responsive DBA.

[Chronic septic granulomatosis revealed by neonatal pulmonary aspergillosis]. / Granulomatose septique chronique révélée par une aspergillose pulmonaire néonatale.

BACKGROUND: Pulmonary aspergillosis is now the main cause of death in chronic granulomatous disease (CGD); it may occur before the age of one year and then often reveals CGD. CASE REPORT: A male newborn was referred to hospital at 27 days of age for fever (39 degrees C), hemodynamic failure and biological inflammation syndrome caused by pulmonary infection. Chest CT scan revealed multiple and bilateral intraparenchymatous nodules. An open lung biopsy showed histiocystic granuloma with multinucleated giant cells. Culture of tracheal, bronchoalveolar lavage samples and lung biopsy grew positive for Aspergillus fumigatus. Impaired chemiluminescence production by neutrophils was detected, enabling the diagnosis of CGD. It was later confirmed by the study of neutrophils functions. The child recovered after 12 months of parenteral amphotericin B therapy. CONCLUSION: A febrile multifocal pneumopathy occurring in infancy should lead to consider the possibility of CGD which may be confirmed by the chemiluminescence test.

Hepatic toxicity associated with 2'-3' dideoxyinosine in children with AIDS.

Among 34 children with AIDS enrolled in a trial with 2'-3' dideoxyinosine (ddI), six (aged 1-6 years) developed liver abnormalities within 2-18 months after institution of ddI. Two children died of fulminant hepatic failure (one had also an adenovirus infection), and four had a striking elevation of alkaline phosphatases (AP: 1120-7000 IU/L). All of them received sulfa drugs and antifungic treatment with ketoconazole or fluconazole. Three had a serology positive for hepatitis C virus. The evolution of liver enzymes following withdrawal and rechallenge with ddI in the children with elevated AP was an indication of drug-induced toxicity in two patients. In both of the others, readministration of ddI did not cause any subsequent problems. Liver histology in the patients with fulminant hepatitis showed an extensive hepatic necrosis. Liver biopsy done in two other patients revealed a mild granulomatous hepatitis in one and nonspecific changes (i.e., steatosis and a mild inflammation) in the other. Hepatic toxicity has been described with ddI and other nucleoside analogs in adult patients. These six children had many potential causes of liver disease. It may be that ddI is not hepatotoxic per se but that it precipitates liver disease in predisposed patients. We recommend that liver functions be carefully monitored when using this drug.

Four new adenosine deaminase mutations, altering a zinc-binding histidine, two conserved alanines, and a 5' splice site.

Three new missense mutations (H15D, A83D, and A179D) and a new splicing defect (573 + IG-->A) in the 5' splice site of intron 5 were among six mutant adenosine deaminase (ADA) alleles found in three unrelated patients with severe combined immunodeficiency disease, the most common phenotype associated with ADA deficiency. When expressed in vitro, the H15D, A83D, and A179D proteins lacked detectable ADA activity. The splicing defect caused skipping of exon 5, resulting in premature termination of translation and a reduced level of mRNA. H15D is the first naturally occurring mutation of a residue that coordinates directly with the enzyme-associated zinc ion. Molecular modeling based on the atomic coordinates of murine ADA suggests that the D15 mutation would create a cavity or gap between the zinc ion and the side chain carboxylate of D15. This could alter the ability of zinc to activate a water molecule postulated to play a role in the catalytic mechanism. A83 and A179 are not directly involved in the active site, but are conserved residues located respectively in alpha helix 4 and beta strand 4 of the alpha/beta barrel. Replacement of these small hydrophobic Ala residues with the charged, more bulky Asp side chain may distort ADA structure and affect enzyme stability or folding.

Infusion of Fc gamma fragments for treatment of children with acute immune thrombocytopenic purpura.

Treatment of acute immune thrombocytopenic purpura (ITP) with intravenous immunoglobulin (IVIG) induces partial or complete responses, shown by transient or persistent increases in platelet count. The clinical benefit could be due to blockade of the Fc gamma receptor (Fc gamma R); platelets sensitised by IgG could not be cleared by cells of the reticuloendothelial system if Fc gamma R on these cells was blocked with IVIG. To find out whether this putative mechanism is correct, we treated twelve children who had acute ITP with intravenous infusions of Fc gamma fragments. Eleven children showed rapid increases in platelet counts to above the critical value of 50 x 10(9)/L, thereby avoiding major haemorrhagic risk. The response was stable in six patients and transient in five. No adverse reactions were observed. In responders who had detectable platelet-associated IgG before treatment (> 1500 IgG per platelet), platelet IgG fell substantially with treatment. Serum soluble CD16 (sCD16 or sFc gamma RIII) concentrations, measured in five children, showed transient or stable increases that correlated with the rise in platelet count. No sCD16 was detected in the Fc gamma preparation used. We conclude that the infusion of Fc gamma fragments is an efficient treatment of acute ITP in children. The efficacy of Fc gamma fragments strengthens the hypothesis that Fc gamma R blockade is the main mechanism of action of IVIG in ITP, although other immunoregulatory mechanisms triggered by the presence of increased sCD16 concentrations in serum could be involved in the clinical benefit observed.

Donor for BMT with haemoglobin H disease.

We report a successful allogeneic BMT for the treatment of juvenile chronic myelogenous leukemia (JCML) in a 9-month-old Laotian boy using an HLA-matched sibling donor with HbH disease (--SEA/aaCS). In addition, before BMT the recipient had a complex haemoglobinopathy associating heterozygous state AE along with HbH disease (--SEA/-a3,7) without haemoglobin Constant Spring (HbCS). Because various haemoglobinopathies are frequently encountered in southeast Asia, when BMT is performed in Asian families the results may be evaluated by the differing haemoglobin characteristics of recipient and donor. However, there is also a significant risk of transmitting a new haemoglobinopathy to the recipient. Because transplantation from HLA-identical siblings offers the only chance of cure for JCML, the presence of HbH disease with mild clinical expression in the donor should not be taken as a contra-indication to BMT.