Respiratory syncytial virus infection--risk factors for hospital admission: a case-control study.

UNLABELLED: Most infants are infected with respiratory syncytial virus (RSV) during the first 2 y of life. The majority have only a mild upper respiratory tract infection, but 1-2% develop a more severe illness and are admitted to hospital. AIM: To carry out a study of risk factors for hospital admission because of RSV infection in Denmark in children aged less than 2 y of age. METHODS: The study population included all 1252 children admitted to hospital with verified RSV infection in two Danish counties during the 5-y period 1990-1994. The investigation comprised a retrospective case-control study with five matched controls per case. In a multivariate analysis the risk factors included medical and demographic variables, and in infants <3 mo of age at hospitalization, two aspects of innate immunity: mannose-binding lectin (MBL) concentration and maternal RSV serum antibody titre, measured on eluates from stored dried blood from the infants' 4th day of life. The effect of each risk factor is expressed as an odds ratio, corresponding to the relative risk of being a case rather than a control if the risk factor is present. RESULTS: The following independent risk factors were identified: age, sex, month of birth, gestational age, birthweight, presence of a sibling, up to 5 y older than the case, and maternal smoking during pregnancy. There was a marginal effect of maternal RSV antibody levels, but no effect of neonatal serum MBL concentration or of crowding in the household. CONCLUSIONS: Ninety percent of cases and 80% of controls had one or more risk factors. Even though several factors were found to increase the risk for hospitalization for RSV disease, all the effects were small and no single specific factor could be identified to explain the hospitalization of the minority of children with RSV infection.

Presence of platelet antibodies in idiopathic thrombocytopenic purpura may discriminate acute from chronic disease.

UNLABELLED: This study estimated the prevalence of serum antibodies against thrombocyte glycoproteins, at disease onset (54 patients) and later on during the course of the disease (71 patients), in sera from children with idiopathic thrombocytopenic purpura (ITP). Only a minority had serum antibodies at disease onset, with a significantly higher frequency in those who developed the acute form of the disease than in those who developed the chronic form. Serum antibodies may persist after spontaneous cure of acute disease. There was no switch from immunoglobulin M (IgM) to IgG antibodies over time. CONCLUSION: The pathogenesis of the acute and chronic forms of ITP may be different.

Diagnostic assessment of haemorrhagic rash and fever.

AIMS: To establish criteria for early distinction between meningococcal disease and other conditions with similar clinical features, and to identify other causes for haemorrhagic rashes accompanied by fever. METHODS: In a prospective study, 264 infants and children hospitalised with fever and skin haemorrhages were studied. RESULTS: We identified an aetiological agent in 28%: 15% had meningococcal disease, 2% another invasive bacterial infection, 7% enterovirus infection, and 4% adenovirus infection. Five clinical variables distinguished between meningococcal disease and other conditions on admission: (1) skin haemorrhages of characteristic appearance; (2) universal distribution of skin haemorrhages; (3) maximum diameter of one or more skin haemorrhages greater than 2 mm; (4) poor general condition (using a standardised observation scheme); and (5) nuchal rigidity. If any two or more of these clinical variables were present, the probability of identifying a patient with meningococcal disease was 97% and the false positive rate was only 12%. This diagnostic algorithm did not identify children in whom septicaemia was caused by other bacterial species.

[Prednisolone treatment of respiratory syncytial virus infection. A randomized, controlled trial of 147 children]. / Prednisolonbehandling af respiratorisk syncytial virusinfektion. En randomiseret, kontrolleret undersøgelse af 147 børn.

OBJECTS: Our objective was to evaluate the effect of systemic prednisolone as an adjunct to conventional treatment with beta 2-agonist, fluid replacement and respiratory support in hospitalized infants younger than 24 months with respiratory syncytial virus (RSV) infection. METHODS: The study was randomized, double-blind and placebo-controlled. During the winter of 1995-96, 147 infants less than two years of age hospitalized with RSV infection were allocated to treatment with either systemic prednisolone mixture 2 mg/kg daily or placebo for 5 days. RESULTS: Our main outcome measures were: 1. Acute effect variables: duration of stay in hospital, use of medicine and supportive measures while in hospital. 2. At follow-up one month after discharge: duration of illness, start in day care center, morbidity and use of medicine. 3. At follow-up one year after discharge: morbidity, use of medicine and skin prick tests with allergens. CONCLUSION: Prednisolone treatment had no effect on any of the outcome measures. We find our results in agreement with the largest studies reported earlier; therefore, corticosteroid, whether by systemic route or by inhalation, should not be prescribed to infants with RSV infection.

Prednisolone treatment of respiratory syncytial virus infection: a randomized controlled trial of 147 infants.

OBJECTIVE: To evaluate the effect of systemic prednisolone as an adjunct to conventional treatment with beta2-agonist, respiratory support, and fluid replacement in hospitalized infants <24 months of age with respiratory syncytial virus (RSV) infection. METHODS: The study was randomized, double-blind, and placebo-controlled. During the winter of 1995-1996, 147 infants <2 years of age, hospitalized with RSV infection, were allocated to treatment with either systemic prednisolone mixture 2 mg/kg daily or placebo for 5 days. MAIN OUTCOME MEASURES: The acute effect variables were duration of stay in hospital, use of medicine, and supportive measures while in hospital. At follow-up 1 month after discharge, the acute effect variables were duration of illness, start in day care center, morbidity, and use of medicine. At follow-up 1 year after discharge, the acute effect variables were morbidity, use of medicine, and skin prick tests with allergens. RESULTS: Prednisolone treatment had no effect on any of the outcome measures. CONCLUSIONS: Our randomized prospective study in infants hospitalized with acute RSV infection showed no effect of systemic prednisolone treatment either in the acute state of RSV infection, nor in the follow-up 1 month and 1 year after admission to hospital. We find our results in agreement with the largest studies reported earlier; therefore, corticosteroid, whether by the systemic route or by inhalation, should not be prescribed to infants with RSV infection.

Epidemiology of juvenile chronic arthritis: risk dependent on sibship, parental income, and housing.

OBJECTIVE: We studied the socioeconomic background of children with juvenile chronic arthritis (JCA) diagnosed during the years 1988-91 in Denmark. The working hypothesis is that JCA may be triggered by one or several different infectious agents and that the amount of exposure to infectious agents in infancy and childhood affects the risk of JCA. METHODS: In this case-control study, we investigated socioeconomic variables prior to disease onset from national registers, primarily the Fertility Database of Statistics Denmark, in a national cohort of all 220 known cases of JCA fulfilling the EULAR criteria incident during the years 1988-91, identified from national and local diagnosis registers. There were 4 controls per case, matched for sex, age, and county of residence. Socioeconomic variables as risk factors were quantified by odds ratios, which are equivalent to relative risks of contracting JCA if exposed to a risk factor. RESULTS: Three socioeconomic variables were significantly and mutually independently associated with the risk of developing JCA during the following year. An only child had a risk of JCA 1.6 times that of a child with siblings. Children whose parents had a high income had a relative risk of 1.9. Children living in an urban flat had a risk 2.7 times that of children living on a farm. We found no space-time clustering of cases and no cyclical variations of incidence rates. CONCLUSION: The absence of clustering and of seasonal variation does not support a theory of triggering by infection. The hitherto unreported effects of the socioeconomic variables on the risk of JCA are of the same order of magnitude as reported for certain HLA alleles. Our findings do not lend full support to either of the 2 mechanisms, that growing up under either hygienic or unhygienic conditions increases the risk of JCA, and lack an obvious biological explanation.

Feasibility of neonatal screening for toxoplasma infection in the absence of prenatal treatment. Danish Congenital Toxoplasmosis Study Group .

BACKGROUND: The best method for prevention and control of congenital toxoplasma infection is uncertain. Prenatal screening is done in Austria and France, but the effect of treatment during pregnancy is not well documented. The aim of our study was to find out the maternofetal transmission rate and outcome in infants born to mothers who were not treated during pregnancy. METHODS: We analysed 89873 eluates from phenylketonuria (PKU) cards from neonates and paired first-trimester serum samples from the mothers for specific IgG antibodies to Toxoplasma gondii. Children born to mothers who seroconverted during pregnancy were followed-up clinically and serologically to 12 months of age. In addition, 21144 PKU cards were analysed for toxoplasma-specific IgM antibodies during the last 12 months of the study. FINDINGS: In 24989 (27.8%) cases both the PKU eluate and the first-trimester samples were IgG positive, which indicates previous maternal infection. 139 of the 64884 seronegative women acquired toxoplasma infection during pregnancy and gave birth to 141 infants (two sets of twins). 27 of these children were diagnosed with congenital toxoplasma infection. The transmission rate was 19.4% (95% CI 13.2-27.0). Clinical signs and symptoms were found in four (15%) of the 27 children. The additional analysis for toxoplasma-specific IgM antibodies from the PKU card identified seven of nine children with congenital toxoplasma infection. The false-positive rate for the IgM test was 0.19 per 1000, and no false-negatives were found. INTERPRETATION: The risks of transmission of infection and of disease in the infant are low in an area with a low risk of toxoplasma infection. A neonatal screening programme based on detection of toxoplasma-specific IgM antibodies alone will identify between 70% and 80% of cases of congenital toxoplasmosis.

Childhood sarcoidosis presenting with hypercalcaemic crisis.

We report a case of hypercalcaemic crisis due to sarcoidosis in a 15-year-old boy. The clinical suspicion of sarcoidosis was confirmed by a liver biopsy. At admission serum calcium, 1,25(OH)2 and ACE were elevated and iPTH was suppressed. The levels of serum total and ionized calcium, iPTH, ACE, 1,25(OH)2 and 25-OH were followed and chest X-ray and pulmonary function tests were performed during systemic steroid treatment. The clinical condition improved during treatment and the paraclinical measurements normalised within 5 weeks. The mechanism whereby hypercalcaemia occurs in childhood sarcoidosis is clarified.

Partial complement deficiencies in idiopathic thrombocytopenia of childhood.

We have examined the classical complement activation pathway in 36 children with idiopathic thrombocytopenia (ITP) in a retrospective study. An increased prevalence of congenital, partial complement deficiencies is found in ITP. Homozygous C4A deficiency was found in 5 patients (p < 0.05) and heterozygous C2 deficiency in 2 other patients (p = 0.05). We suggest that some cases of childhood ITP belong to the immune complex mediated diseases, such as systemic lupus erythematosus and that abnormal immune complex formation and clearance may lead to ITP.

Rate-limiting components and reaction steps in complement-mediated haemolysis.

The aims of this study were to identify the rate-limiting components and reaction steps in the integrated activation sequence of the alternative (AP) and classical (CP) pathways of the complement (C) system. In an initial correlation analysis we found that the haemolysis rate in AP was correlated with the concentrations of C5 and IgM. In CP, the haemolysis rate was correlated with the concentrations of C2-C6, factors I and B, and IgM. In order to identify the rate-limiting components, we added single, purified C components and IgM to pooled, normal human serum and measured the resultant change in the haemolysis rate. We found that a large number of different components, rather than a single one, were rate-limiting in AP and CP. In reconstitution experiments we found that in CP the rate-limiting reaction steps are the activation of C4 and C2. In AP we cannot identify the rate-limiting step precisely, but can only state that it is at the C3 activation step or earlier.

Immunoglobulin and complement studies in children with Schönlein-Henoch Syndrome and other vasculitic diseases.

In 35 children with Schönlein-Henoch Syndrome (SHS) serum IgG, IgM, and IgA concentrations were increased in 15%, 21%, and 44% of cases, respectively. Seven children with other vasculitic syndromes (VS) had normal serum Ig concentrations. Serum concentration of IgG subclass IgG1 was increased in 72% of children with SHS and 57% with VS. In SHS this was related to the presence of arthritis, but inversely related to nephritic symptoms. Only a few children had IgG subclasses IgG2, IgG3, or IgG4 concentrations outside the normal ranges. Platelet associated Ig (PAIg) was found in 75% of children with SHS or VS. In SHS the identification of increased amounts of PAIgG was related to the presence of nephritis. The serum concentration of properdin, a component of the alternative complement system, was reduced in 21% of children with SHS. This was related to the presence of abdominal symptoms or nephritis. No cases of retinal vasculitis was observed, but 4 of 22 children with SHS had punctuate retinal haemorrhages. SHS and VS may be clinical variations of the same syndrome. The immunological aspects indicate a close relationship with autoimmune diseases.

[Occurrence of complement defects in meningococcal disease: who should be examined?]. / Forekomsten af komplementdefekter ved meningokoksygdom: Hvem skal undersøges?

Congenital complement deficiency states occur very rarely. These deficiencies are associated with a high risk of meningococcal disease (MD). We suggest that the following groups of individuals with MD are examined for complement deficiencies: 1. Individuals belonging to families, in which more than one case of MD has occurred with an interval exceeding one month. 2. Individuals infected with the low-virulent meningococcal serogroups W-135, 29E, X, Y, Z. 3. Individuals with recurrent MD. Since properdin deficiency probably is the most common deficiency associated with MD it is important that the screening includes the alternative complement pathway.

Complement and immunoglobulin studies in 15 cases of chronic meningococcemia: properdin deficiency and hypoimmunoglobulinemia.

The purpose of this study was to investigate whether patients with chronic meningococcemia have abnormalities in their humoral immune system. The alternative and classical complement system, the levels of IgA, IgG and IgM, as well as IgG subclasses were studied in 15 individuals who had recovered from chronic meningococcemia. We found one individual with complete deficiency of properdin, a component of the alternative complement pathway. In the other patients, the complement system was normal. The mean plasma IgG concentration was significantly below normal in the patient group, while the mean values of IgA, IgM and the IgG subclasses were normal. Two individuals, however, had low IgG2 and IgG4 levels. We conclude that properdin deficiency and reduced plasma IgG levels may predispose to chronic meningococcal disease, but that the majority of patients with chronic meningococcemia have a normal humoral immune system.

Hereditary, complete deficiency of complement factor H associated with recurrent meningococcal disease.

Complement factor H (beta-1H globulin) is an important regulatory protein which inhibits the spontaneous complement activation via the alternative pathway. We describe a 15-year-old girl without any detectable factor H in plasma. She has had two episodes of meningococcal disease, but is otherwise completely healthy. Secondary to the factor-H deficiency, the levels of factor B, properdin, C3, and C5-C9 were strongly reduced due to spontaneous in vivo activation of the alternative complement pathway. Plasma C3dg was strongly elevated in spite of the factor-H deficiency; apparently erythrocyte CR1 substitutes for factor H in C3 degradation. Neither C3 nor complement lesions were demonstrable on her erythrocytes which did, however, show increased, spontaneous haemolysis in vitro in citrate plasma, but not in serum. The patient is a single child and her parents, who are unrelated and healthy, had half-normal levels of factor H. This reduction of factor H is sufficient to cause increased, spontaneous activation of the alternative pathway.

Complement deficiencies in selected groups of patients with meningococcal disease.

We have examined 125 individuals who have earlier had meningococcal (mgc) disease. They belonged to one or more of the following groups: (1) 2 or more cases of mgc disease in the same family; (2) individuals with 2 episodes of mgc disease or with 1 episode of mgc disease and 1 or more episodes of purulent meningitis of another aetiology; and (3) infections with Neisseria meningitidis belonging to serogroups that are uncommon as causes of disease and presumably low-virulent (W-135, 29E, X, Y). Among these we found 15 complement (C)-deficient individuals (12%). The prevalence of C deficiency in the groups above was 7%, 41% and 19%, respectively. The first group (family cases), is very heterogeneous and may be further subdivided into 2 groups: families whose members fell ill within an interval of 30 days (in these the prevalence of C deficiency was 2%), and families in which the interval between mgc disease cases exceeded 30 days (in those the prevalence of C deficiency was 14%). We found a predominance of defects of the initiation pathways, with properdin deficiency being the most common.

Epidemiology of Schönlein-Henoch purpura.

The purpose of this study was to determine if Schönlein-Henoch purpura represents an abnormal host response to microorganisms. Among 1,222 cases, representing all new Danish cases in children during the years 1977-84, there was no tendency for the cases to cluster; this means that the disease is not caused by a single, contagious agent. In a smaller sample of 281 children examined in detail, a higher number than expected attended day nursery or nursery school and 17% had received antibiotic treatment during the week prior to admission. The latter findings, together with the seasonal variation of the incidence and the activation of the immune apparatus in many cases, suggest that Schönlein-Henoch purpura may be triggered by infection with several different microorganisms, but there is no evidence that a single one such as the streptococcus is the major offender.