The number of risk factors for persistent disease determines the clinical course of early arthritis.

OBJECTIVES: Management of early arthritis is based upon early recognition of individuals at high risk of developing persistent arthritis. Therefore, this study investigates whether the number of risk factors for persistent disease or treatment determines the clinical course of early arthritis by comparing the chance at (sustained) DMARD-free remission ((S)DFR) after 2 years follow-up. METHODS: Data from the tREACH trial, a stratified single-blinded multicentre strategy trial with a treat-to-target approach were used. We selected all patients with ≥1 swollen joint who did not fulfil 1987 and/or 2010 criteria for RA. The number of risk factors present; autoantibody-positivity, polyarthritis (>4), erosive disease and elevated acute phase reactants, determined risk group stratification. Multivariate logistic regression analyses were performed with (S)DFR as dependent variables and baseline disease activity score (DAS), treatment, symptom duration and number of risk factors present as independent variables. RESULTS: In total, 130 early arthritis patients were included and respectively 31, 66 and 33 had 0, 1 and ≥2 risk factors present. DFR rates were respectively 74%, 48% and 45% for early arthritis patients with 0, 1 and ≥2 risk factors present. In accordance SDFR rates were 61%, 32% and 30%. In our logistic model (S)DFR was not influenced by the initial treatment strategies when stratified for risk groups. CONCLUSION: The chance at (S)DFR in early arthritis diminishes when more risk factors are present, which is irrespective of the given initial treatment. Our data point out to a stratified management approach in early arthritis based on their risk profile, but validation is needed. TRIAL REGISTRATION: ISRCTN registry: ISRCTN26791028 (http://www.isrctn.com/ISRCTN26791028).

Pregnant women at increased risk of adverse perinatal outcomes: A combination of less healthy behaviors and adverse psychosocial and socio-economic circumstances.

Smoking during pregnancy is associated with a multitude of health behaviors and with the psychosocial and socio-economic circumstances of pregnant women. Limited research has so far been conducted on the clustering of these characteristics and on their effect on pregnancy outcomes. This study aimed to identify different groups of pregnant women based on their behavioral, psychosocial and socio-economic characteristics and their pregnancy outcomes. In total, 2455 women who were 12 weeks pregnant completed a questionnaire on smoking behavior, health behaviors and psychosocial and socio-economic characteristics. Neonatal and maternal outcomes were extracted from the Dutch perinatal registration. Subgroups were identified with latent class analysis and adverse pregnancy outcomes were compared between subgroups with logistic regression. Women were classified into four latent classes. Two classes represented the healthy higher-educated pregnant women who did not smoke: one group of multigravida women and one of primigravida women, also characterized by less pregnancy-specific knowledge and more pregnancy-related stress. The remaining women were grouped into two less healthy groups. One group frequently quit smoking, reported less healthy eating, less physical activity and comparable stress levels as the healthy higher-educated groups. The last group contained the most smokers, had the highest scores on psychosocial and pregnancy-related stress and the most adverse socio-economic circumstances. This group had an increased risk of adverse maternal outcomes, in particular developing diabetes during pregnancy. A comprehensive and integrated approach is needed to improve outcomes in pregnancies with a combination of adverse health, psychosocial, and socio-economic conditions.

Humoral immune response to influenza vaccination in patients with primary immunoglobulin A nephropathy. An analysis of isotype distribution and size of the influenza-specific antibodies.

Primary IgA nephropathy (IgAN) is characterized by mesangial deposits of IgA1, increased serum IgA1 levels, and circulating immune complexes containing predominantly IgA1. It has previously been found that patients with IgAN have a higher than normal IgA response to vaccination, but the IgA subclasses have not been studied. To investigate whether the IgA hyperresponsiveness is limited to the subclass IgA1, which is involved in the pathogenesis of IgAN, we compared the immune responses of 18 patients with 22 healthy controls after intramuscular vaccination with inactivated influenza virus. Antibody titers were significantly higher (P less than 0.0001) for the IgA1 subclass in patients versus controls, but not for the other isotypes. A substantial portion of the IgA and IgA1 antiinfluenza immune response comprised polymers in both patients and controls. There was no preferential response of polymers in patients. Patients produced significantly more monomeric IgA1 antibodies than controls. These results show that patients with IgAN have a hyperresponsiveness limited to the subclass IgA1 and mainly expressed by an excess of monomers.

Optimized basal-bolus therapy using a fixed mixture of 75% lispro and 25% NPL insulin in type 1 diabetes patients: no favorable effects on glycemic control, physiological responses to hypoglycemia, well-being, or treatment satisfaction.

OBJECTIVE: To investigate the effects of a multiple injection regimen with a mixture of 75% lispro and 25% intermediate-acting insulin (lispro high mixture [HM]) before meals on glycemic control, physiological responses to hypoglycemia, well-being, and treatment satisfaction. RESEARCH DESIGN AND METHODS: We studied 35 type 1 diabetes patients. After an 8- to 10-week lead-in period, patients were randomized to HM or human regular insulin therapy for 12-14 weeks. During the lead-in and treatment periods, HbA1c levels and hypoglycemic frequencies were measured, and patients completed the Well-Being Questionnaire and the Diabetes Treatment Satisfaction Questionnaire. In 19 patients, responses to hypoglycemia were tested during stepped euglycemic-hypoglycemic clamps. RESULTS: HM treatment improved postprandial glycemia but had no effect on HbA1c, frequency of hypoglycemia, well-being, or treatment satisfaction. During experimental hypoglycemia, HM therapy was associated with a slightly lower total adrenaline response and a higher autonomic symptom threshold (i.e., the autonomic symptom response occurred at a lower blood glucose level) than human regular insulin therapy. We speculate that this effect resulted from an accumulation of insulin during the night. CONCLUSIONS: Multiple injection therapy with HM rather than human regular insulin before meals does not offer advantages regarding glycemic control, frequency of hypoglycemia, well-being, or treatment satisfaction. In addition, this regimen causes an attenuation of the adrenaline and autonomic symptom responses to hypoglycemia.

Impairment of the immune response to influenza vaccination in renal transplant recipients by cyclosporine, but not azathioprine.

Influenza vaccination has been strongly recommended for immunosuppressed renal transplant recipients. However, immunosuppression may lead to impaired antibody responses. We studied the antibody response to an inactivated trivalent influenza vaccine in 59 renal transplant recipients with life-sustaining kidney function: 21 were on cyclosporine and prednisone, 38 on azathioprine and prednisone. Healthy volunteers (n = 29) and patients on hemodialysis (n = 28) served as controls. Despite comparable renal allograft function, cyclosporine-treated patients had a significantly lower immune response against influenza A viruses than azathioprine-treated patients, whether mean antibody levels, fourfold titer rise, or seroconversion to protective titers was analyzed. No significant differences in antibody responses were found between healthy controls and patients on azathioprine. The patients on hemodialysis showed an impaired response to vaccination. However, in contrast to the cyclosporine-treated patients, booster immunization proved valuable in this group.

Dose-dependent antibody response to influenza H1N1 vaccine component in elderly nursing home patients.

The effects of an increased antigen dose on HI, IgG, IgA, and IgM antibody responses to influenza A/Taiwan/1/86 (H1N1) were investigated in 92 elderly nursing-home residents (mean age 81 years) and 104 young subjects (mean age 20 years). At a standard 10-microg dose, HI and IgG titer rises were lower in the elderly. HI titers did not improve at higher vaccine dosages. By contrast, influenza-specific IgG and IgA antibody responses were dose dependent in elderly subjects, but not in young. In the young subjects, IgM antibody responses were dose dependent. The improved antibody responses in the elderly as observed in IgG and IgA were not reflected in the HI response. Therefore, the evaluation of antibody production by HI only may lead to an underestimate of the immune response in elderly people.

Influenza: relation of mortality to morbidity parameters--Netherlands, 1970-1989.

The purpose of this study is to investigate the relationship between the number of influenza-like illness (ILI), weekly registered by the general practitioners (sentinel stations), and the monthly overall influenza mortality in people over 60 years of age, provided by the Dutch Statistical Bureau during the period July 1970 to June 1989. The quantitative impact of influenza-morbidity is expressed by three summary parameters, calculated from the 52 (53) weekly ILI-figures per season-year, (i) their sum (i.e. global extent of an epidemic), (ii) their standard deviation, and (iii) their maximum (i.e. peak number of ILI during an epidemic). In the analysis influenza A subtype is also included. These four parameters are mutually compared with respect to their predictability for yearly total influenza mortality in the 19 season-years available. In most cases, the standard deviation and the peak number of ILI are more powerful for prediction of mortality, than the global extent of the epidemic. The peak number of ILI is of special interest. It is particularly useful for estimating the effect on current influenza mortality during an ongoing epidemic. From the model it is possible to calculate a threshold (of weekly ILI) beyond which mortality increases proportionately more than the number of illness episodes. By using the peak value of morbidity it is possible to calculate the minimal impact of epidemic mortality. This study indicates that the weekly number of influenza-like illnesses has a certain prognostic value for the real impact of influenza. An electronic surveillance system could detect immediately the threshold above which influenza mortality increases more than proportionally.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of influenza on mortality in relation to age and underlying disease, 1967-1989.

Based on data from the Dutch Central Bureau of Statistics, the impact of influenza on mortality in The Netherlands was estimated for a 22.5-year period (1967-1989) in four age groups and three entities of disease, using Poisson regression techniques. Our analysis suggests that, on average, more than 2000 people died from influenza in The Netherlands each year, but in only a fraction of these deaths was influenza recognized as the cause of death. For each case of death registered as caused by influenza (registered influenza mortality), 2.6 additional cases of death registered as due to causes other than influenza, nevertheless, were influenza-related (non-registered influenza mortality). Therefore, the overall impact of influenza on mortality is estimated to be greater than registered influenza mortality by a factor of 3.6. Those under 60 years of age accounted for 5% of all non-registered influenza deaths, whereas people aged 60-69, 70-79 years and > 80 years accounted for 12%, 29% and 54% of such deaths, respectively. When extrapolating the figures for the Dutch population of 1989, we could attribute, on average per season-year, 82 deaths per 100,000 people > 60 years, 143 in people > 70 years, and 280 in people > 80 years. Of all non-registered influenza cases of death, 47% were estimated to occur in people with heart disease as a primarily reported cause of death, 23% in those with lung disease, and 30% in those with other diseases. This study stresses the serious effects of influenza, mainly in the elderly (95% of non-registered influenza mortality).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of two techniques for detecting antibody to HBsAg during a hepatitis B vaccine study.

Two assays for the detection of antibody against hepatitis B surface antigen (anti-HBs) were compared. The first was a direct sandwich radioimmunoassay (RIA) which detects, in principle, antibody against any epitope of hepatitis B surface antigen (HBsAg). The second assay was an inhibition enzyme-linked immunosorbent assay (ELISA). In this assay a fixed amount of HBsAg which can be blocked by anti-HBs is measured in a direct sandwich test. Prevaccination screening sera (n = 191) and follow-up sera obtained from high risk groups (n1 = 85; n2 = 41) during two hepatitis B vaccine studies were compared in RIA and ELISA. In prevaccination sera either HBsAg or anti-HBs were detected by ELISA. Full agreement between the results of RIA and ELISA for anti-HBs was obtained in sera containing more than 10 IU/l anti-HBs. Both tests showed variable results at low titres. Experiments with monoclonal anti-HBs indicated that ELISA is less sensitive for subtype specific antibodies (anti-d, anti-y), which may explain that there were consistent differences between RIA and ELISA in a minority of cases.

Type-specific identification of influenza viruses A, B and C by the polymerase chain reaction.

The aim of this study was to develop a polymerase chain reaction for specific detection of influenza A, B, and C RNA genomes. Three primer sets were selected from conserved regions of the genome coding for the non-structural proteins and were tested on 61 influenza A (22 H1N1, 9 H2N2, and 30 H3N2), 11 influenza B, and three influenza C isolates. Specific amplified products were obtained with all these strains after electrophoresis on a 2% agarose gel. The specificity of the reaction was increased by hybridization with oligonucleotide probes. When nucleic acids from a variety of micro-organisms from the respiratory tract were subjected to the PCR with these primers, no specific amplified products were generated. The sensitivity of the technique was found to be at the subpicogram level. The RNA-PCR was applied to 21 clinical specimens from patients with a culture/IF proven influenza infection. Six influenza A positive patients and 13 influenza B positive patients could be confirmed in the RNA-PCR. In two cases, influenza B positive IF specimens were found negative by the PCR. No virus could be isolated on eggs or tissue culture from these samples. RNA-PCR is a specific and sensitive technique for the detection of influenza virus genomes.

Influenza A and B antibody status in Tanzania.

Sera from 200 babies and young children and from 205 mother-newborn pairs were tested for haemagglutination inhibiting antibody against three A-H1N1, one A-H2N2, four A-H3N2, and two influenza B viruses. The results indicated that a higher concentration of antibody against all influenza A and B viruses tested was found more frequently in maternal sera than in neonatal sera. High prevalences of antibody and high geometric mean titres against the A-H2N2-1957 and A-H3N2-1968 viruses from the eras 1957-1968 and 1968-now, respectively, were found in the age groups above 15 years. The antibodies against former and recent epidemic influenza viruses of the A-H3N2 subtype, found among different adult age groups in Mwanza, Tanzania, showed a pattern similar to that in the population of The Netherlands.

Measles in Tanzania: antibody response in children after vaccination and antibody state of mothers and newborns.

The antibody response to attenuated live measles vaccines was studied in two groups of 29 (A) and 53 (B) African children. In group A 22 sera and in group B 34 sera showed no pre-immunization haemagglutination inhibition (HI) titres. Vaccination resulted in seroconversion in 64 and 85% of groups A and B, respectively. The difference in antibody response between the two groups could be traced to children in the age group seven to eight months, where seroconversion was absent in 67% of group A children and in 0% of group B children. Antibody levels were studied in 234 mothers and their newborns. In 131 serum pairs the antibody levels of mother and child were similar. 78 (33%) of mothers showed a higher titre and 25 (11%) a lower titre than their babies. All newborns except one and all mothers except one possessed antibody titres above 10. Children in the age groups seven to eight months and nine to ten months showed antibody in 12 and 7%, respectively. Over 90% of these children had not been infected in the first ten months of life.

Effect of epidemic influenza on ketoacidosis, pneumonia and death in diabetes mellitus: a hospital register survey of 1976-1979 in The Netherlands.

The influence of epidemic influenza on hospitalizations because of influenza, pneumonia and diabetic acidosis in patients with diabetes mellitus was investigated. Data on the weekly incidence of influenza-like illness were obtained from the Continuous Morbidity Registration and the cumulative data on hospitalizations in short-stay hospitals were obtained from the National Medical Registration. Patients with duodenal ulcer were used as a control population. Epidemic elevations of influenza infections were observed in 1976 and 1978. The estimated relative risk for hospitalization because of influenza infection was 1.1 and 1.0 for the two non-epidemic years 1977 and 1979, respectively. For the epidemic years 1976 and 1978 this risk was calculated to be 5.7 and 6.2, respectively. An increased relative risk was also noted for pneumonia; being 25.6 for both epidemic years. The estimated relative risk of dying during hospitalization rose from 30.9 in 1977 to 91.8 in 1978. The number of hospitalizations for ketoacidosis was 50% higher in 1978 than in the other three years. During the epidemic years, 25.7% of patients hospitalized for pneumonia died, while this percentage was 14.6% in the non-epidemic years (P less than 0.05). Differences in mortality due to diabetic acidosis were similar: 25.4% in epidemic and 14.7% in non-epidemic years (P less than 0.01). During the 1978 epidemic, one out of every 1300 patients with diabetes mellitus was hospitalized because of pneumonia. It is estimated that 1 of every 260 patients with IDDM was hospitalized for diabetic acidosis. It is concluded that patients with diabetes mellitus have indeed a very high influenza-associated morbidity.

Prevalence of influenza viruses A-H1N1 and A-H3N2 in swine in the Netherlands.

In the period December 1979-May 1980 a respiratory disease spread rapidly through pig herds in The Netherlands. Surveillance of 12 pig farms resulted in isolation of 22 influenza A-Swine-H1N1 (Hsw1N1) strains from 9 pig herds. The morbidity rate was high but the mortality rate was nil. Retardation in growth was observed. Sera collected from affected pig herds showed a fourfold increase in haemagglutination inhibition (HI) titre against A-Swine-H1N1 virus. Sera collected on five farms showed a geometric mean HI titre against the A-H3N2 virus above 100. A significant HI titre increase against this virus was found in sera collected on three farms. These findings indicated a recent infection by this virus. A-H3N2 virus was not isolated. The Dutch Swine-1980 isolates showed in the cross-HI test a distant antigenic relationship with the classical A/Swine/Iowa/30 (H1N1) virus and one-sided close antigenic relationship with A/New Jersey/76 (H1N1) virus. HI antibody to A/Swine/Nederland/80 (H1N1) virus was found in 4, 0, and 44%, to A/New Jersey/76 (H1N1) virus in 0.5, 0.4, and 42%, and to A/Swine/Iowa/30 (H1N1) virus in 0.5, 1, and 30% of pig sera collected in 1976, 1977, and 1980, respectively. HI antibody to A/Hong Kong/68 (H3N2) virus was detected in 36, 56, and 68%, and to A/Victoria/75 (H3N2) virus in 38, 73, and 68% of these sera, respectively. The results of this study indicate that pigs in The Netherlands, like those in North America, Southeast Asia, Japan, and Western Europe harbour A-Swine-H1N1 and A-H3N2 influenza viruses and are thus potential reservoirs for future human pandemics.

Cytotoxic T-cell response to influenza A subunit vaccine in patients with type 1 diabetes mellitus.

The cytotoxic T-cell and humoral immune response to a commercially available influenza A-H1N1 subunit vaccine in 14 patients with type 1 diabetes mellitus was compared with the response in 13 healthy volunteers. Cytotoxic T-cell response to vaccination was poor in both patients and controls. At a calculated 50: 1 effector-target cell ratio, however, significantly more controls than patients showed an increase of over 5% cytotoxic T-cell mediated lysis after vaccination (P less than 0.05). In patients the cytotoxic T-cell response decreased with higher percentages of glycosylated haemoglobin (regression coefficient not equal to 0 with P less than 0.05). No significant difference was found between diabetic patients and control subjects with respect to antibody response after vaccination. Implications for vaccination strategy are discussed.

No evidence for the enhanced production of insulin autoantibodies after confrontation with common viral antigens in insulin dependent diabetes mellitus.

The production of insulin autoantibodies (IAA) was studied after common viral infections in 12 children with type 1 diabetes mellitus and in their 18 healthy siblings. In addition, the production of IAA was measured after influenza vaccination with booster in 39 patients with type 1 diabetes mellitus and in 39 healthy controls. In 7 of the 12 diabetic children 13 viral infections were serologically confirmed. Among the siblings 14 periods of infection were noted in 9 individuals. A significant rise in IAA antibody titre was demonstrated in patients twice (IgG both times) and in siblings 11 times (IgM 5x, IgG 6x, difference significant P less than 0.05). In only three cases the rise in antibody titres occurred 6-12 wk after documented infection. There was a significant inverse correlation with age in both patients (r = 0.89, P less than 0.0001) and siblings (r = 0.67, P less than 0.001) for IgM IAA. After influenza vaccination a significant increase in IAA was noted twice: IgM IAA in a patient with diabetes and IgG IAA in a healthy volunteer. A four-fold decrease in IgG IAA was demonstrated in one diabetic patient. From these results it is concluded that IAA formation is not a direct sequela of viral infection or vaccination.

Equine influenza in the Netherlands during the winter of 1978-1979; antigenic drift of the A-equi 2 virus.

Influenza virus A-equi 2(Heq2Neq2) caused an epizootic in the Netherlands in the winter of 1978-1979. Horses vaccinated with A/Equi/Praha/56 (HEq1Neq1) and A/Equi/Miami/63 (Heq2Neq2) were also infected and showed clinical signs. The virus involved showed a marked antigenic drift from the prototype and vaccine strain A/Equi/Miami/63 (Heq2Neq2). Infection of ferrets with the Dutch/79 isolates gave rise to high haemagglutination-inhibition antibody titres to a number of A-Equi 2-1963, 1968 and 1979 viruses. The incorporation of this virus into future influenza vaccines should be considered.

Adverse reactions to influenza vaccine in elderly people: randomised double blind placebo controlled trial.

OBJECTIVE: To assess the frequency and type of side effects after influenza vaccination in elderly people. DESIGN: Randomised double blind placebo controlled study. SETTING: 15 general practices in the southern Netherlands. SUBJECTS: 1806 patients aged 60 or older, of whom 904 received influenza vaccine and 902 placebo. MAIN OUTCOME MEASURES: Adverse reactions reported on postal questionnaire completed four weeks after vaccination. RESULTS: 210 (23%) patients given vaccine reported one or more adverse reactions compared with 127 (14%) given placebo. The frequency of local adverse reactions were 17.5% in the vaccine group and 7.3% in the placebo group (p < 0.001). There was no difference in systemic adverse reactions (11% v 9.4%; p = 0.34). In general, men reported fewer side effects than women. CONCLUSION: Only local side effects were more common in vaccinated patients and all side effects were mild.

[Influenza epidemic in a nursing home caused by a virus not included in the vaccine]. / Influenza-epidemie in een verpleeghuis door een virus dat niet in het vaccin was opgenomen.

In the autumn of 1992 two-thirds of the population of a nursing home in Amsterdam was vaccinated against influenza. However, in March 1993 an outbreak of an influenza like illness occurred with a morbidity rate of 49% and a mortality rate of 10%. There was sufficient serological evidence to show that the vaccine as such had induced adequate immunity. As the causative agent an influenza A/H3N2 virus was identified. The failing activity of the vaccine in this instance was apparently caused by the absence of sufficient antigen similarity between the A/H3N2 vaccine component and the epidemic virus ('vaccine mismatch').

[A fatal influenza infection in a 10-year-old boy]. / Een fatale influenza-infectie bij een 10-jarige jongen.

A previously healthy 10-year-old boy died a few days after onset of septicaemia with non-specific clinical symptoms. Influenza B virus was isolated post mortem from pulmonary tissue. The histopathological findings did not indicate a virus disease. Specimens were taken for virus culture from other people in contact with the patient and affected with influenza-like illnesses. One other strain of influenza B virus was isolated. The strains could not be distinguished either serologically or genetically from other influenza B isolates of the season 1992/'93.