Clinical characteristics of influenza virus infection in juvenile idiopathic arthritis patients treated with tocilizumab

Background

Inhibition of interleukin-6 (IL-6) signaling by tocilizumab is highly effective for treatment of refractory juvenile idiopathic arthritis (JIA). It appears that IL-6 plays an important role in the immune response to the influenza virus, but it is not clear whether treatment with tocilizumab affects the severity of influenza.

Methods

We retrospectively collected clinical and laboratory data from JIA patients (n = 33) treated with tocilizumab. Ten patients who developed influenza (tocilizumab group; 10.1 %, 10/99 patient-years) were analyzed. Eleven JIA patients who experienced influenza during conventional treatments, without tocilizumab (control group), were compared with the tocilizumab group.

Results

Of the 10 patients in the tocilizumab group, 6 patients did not have high fever (>38 °C), and the other 4 febrile patients recovered from fever in 1 day. White blood cell counts and lymphocyte counts were significantly lower at the acute phase of infection compared with data from before influenza infection. The degree of fever and level of C-reactive protein in the tocilizumab group were significantly reduced compared with the control group.

Conclusions

IL-6 inhibition by tocilizumab reduced inflammation associated with infection and resulted in mild symptoms during influenza. Leukopenia might be a useful indicator of viral infection, including influenza, during tocilizumab treatment.     

Hip fracture incidence in the elderly in Austria: An epidemiological study covering the years 1994 to 2006

Background

Previous studies have shown influenza vaccine uptake in UK nursing home residents to be low. Very little information exists regarding the uptake of pneumococcal vaccine in this population. The formulation of policies relating to the vaccination of residents has been proposed as a simple step that may help improve vaccine uptake in care homes.

Methods

A postal questionnaire was sent to matrons of all care homes with nursing within the Greater Nottingham area in January 2006. Non respondents were followed up with up to 3 phone calls.

Results

30% (16/53) of respondents reported having a policy addressing influenza vaccination and 15% (8/53) had a policy addressing pneumococcal vaccination. Seasonal influenza vaccine coverage in care homes with a vaccination policy was 87% compared with 84% in care homes without a policy (p = 0.47). The uptake of pneumococcal vaccination was found to be low, particularly in care homes with no vaccination policy. Coverage was 60% and 32% in care homes with and without a vaccination policy respectively (p = 0.06). This result was found to be statistically significant on multivariate analysis (p = 0.03, R = 0.46)

Conclusion

The uptake of influenza vaccine among care home residents in the Nottingham region is relatively high, although pneumococcal vaccine uptake is low. This study shows that there is an association between pneumococcal vaccine uptake and the existence of a vaccination policy in care homes, and highlights that few care homes have vaccination policies in place.     

Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab

Objective

For patients with rheumatoid arthritis (RA), yearly influenza vaccination is recommended. However, its efficacy in patients treated with rituximab is unknown. The objectives of this study were to investigate the efficacy of influenza vaccination in RA patients treated with rituximab and to investigate the duration of the possible suppression of the humoral immune response following rituximab treatment. We also undertook to assess the safety of influenza vaccination and the effects of previous influenza vaccination.

Methods

Trivalent influenza subunit vaccine was administered to 23 RA patients who had received rituximab (4–8 weeks after rituximab for 11 patients [the early rituximab subgroup] and 6–10 months after rituximab for 12 patients [the late rituximab subgroup]), 20 RA patients receiving methotrexate (MTX), and 29 healthy controls. Levels of antibodies against the 3 vaccine strains were measured before and 28 days after vaccination using hemagglutination inhibition assay. The Disease Activity Score in 28 joints (DAS28) was used to assess RA activity.

Results

Following vaccination, geometric mean titers (GMTs) of antiinfluenza antibodies significantly increased for all influenza strains in the MTX‐treated group and in healthy controls, but for no strains in the rituximab‐treated group. However, in the late rituximab subgroup, a rise in GMT for the A/H3N2 and A/H1N1 strains was demonstrated, in the absence of a repopulation of CD19+ cells at the time of vaccination. Seroconversion and seroprotection occurred less often in the rituximab‐treated group than in the MTX‐treated group for the A/H3N2 and A/H1N1 strains, while seroprotection occurred less often in the rituximab‐treated group than in the healthy controls for the A/H1N1 strain. Compared with unvaccinated patients in the rituximab‐treated group, previously vaccinated patients in the rituximab‐treated group had higher pre‐ and postvaccination GMTs for the A/H1N1 strain. The DAS28 did not change after vaccination.

Conclusion

Rituximab reduces humoral responses following influenza vaccination in RA patients, with a modestly restored response 6–10 months after rituximab administration. Previous influenza vaccination in rituximab‐treated patients increases pre‐ and postvaccination titers. RA activity was not influenced.

     

Improvement of health status evaluated by Arthritis Impact Measurement Scale 2 (AIMS-2) and Short Form-36 (SF-36) in patients with rheumatoid arthritis treated with tocilizumab

Objective

To evaluate the improvement of health status in patients with rheumatoid arthritis (RA) treated with tocilizumab.

Methods

Thirty-nine patients were treated with 8 mg/kg tocilizumab every 4 weeks for 24 weeks. Disease activity was assessed by Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI). Improvement of health status was assessed by Arthritis Impact Measurement Scale 2 (AIMS-2) and Short Form-36 (SF-36).

Results

Tocilizumab improved CDAI and SDAI significantly at week 4 compared with at baseline. In the components of AIMS-2, “physical score”, “symptom” and “affect” improved significantly at week 4 compared with at baseline, while “social interaction” did not improve significantly during 24 weeks of tocilizumab therapy. Similarly in SF-36, “bodily pain”, “general health”, “vitality” and “mental health” improved significantly at week 4. The most correlative component of AIMS-2 with CDAI was “symptom”, while “social interaction” did not correlate with CDAI during tocilizumab treatment.

Conclusion

The time-course diversity in improvement of health status should be considered to provide proper healthcare when treated with tocilizumab.     

Safety and tolerability of intradermal influenza vaccination in patients with cardiovascular disease

Background It is well-established that influenza vaccination reduces adverse cardiovascular outcomes in patients with cardiovascular diseases （CVD）, however, the vaccine coverage rate in most countries remains low. The concern about the local adverse effects of intramus-cular injection, particularly in CVD patients receiving antithrombotic therapy, is one of the important impediments. This study was con-ducted to assess the safety, side effects and tolerability of intradermal influenza vaccine in CVD patients. Methods This was an observa-tional study in adult CVD patients who had undergone vaccination against seasonal influenza by intradermal vaccination between May 16th and May 30th, 2012 at Maharaj Nakorn Chiang Mai Hospital. The medical history, patients＇ acceptability and adverse effects were collected using a written questionnaire completed by the patient immediately following vaccination and by a telephone survey eight days later. Results Among 169 patients, 52.1%were women and the mean age was 63 ＆#177; 12 years. Coronary artery disease, valvular heart disease and dilated cardiomyopathy were present in 121 （71.6%）, 40 （23.7%） and 8 （4.7%）, respectively. Antithrombotics were used in 89.3%. After vaccination, the pain score was 0, 1 or 2 （out of 10） in 44.4%, 15.1%, and 27.6%of the patients, respectively. Eight days after vaccination, the common adverse reactions were itching 19 （11.9%）, swelling 9 （5.7%） and fatigue （4.7%）. No hematoma or bruising was reported. Conclusions The intradermal influenza vaccination is safe and well tolerates with high rates of satisfaction in CVD patients. This technique should be useful in expanding influenza vaccine coverage.     

Analysis of perioperative clinical features and complications after orthopaedic surgery in rheumatoid arthritis patients treated with tocilizumab in a real-world setting: results from the multicentre TOcilizumab in Perioperative Period (TOPP) study

Objective

To evaluate perioperative changes in rheumatoid arthritis (RA) patients treated with tocilizumab.

Methods

We collected RA cases with tocilizumab and orthopaedic surgery from 1999 to 2010. Incidences of postoperative infections, delayed wound healing, and RA symptom flare-ups were extracted from the data for comparison with patients without these postoperative events. We also evaluated the changes in C-reactive protein (CRP) and body temperature in patients without postoperative complications with normal CRP before surgery, i.e., patients without postoperative events in whom the tocilizumab level was maintained, for each duration to discontinuation before surgery.

Results

A total of 161 cases (n = 122) were collected. The patients had mean age of 56.9 years, and mean disease duration of 12.8 years at operation. Joint replacement surgery was performed in 89 cases. Three patients had postoperative infections (two superficial and one organ/space surgical-site infection), 20 had delayed wound healing, and 36 had RA symptom flare-ups. Delayed wound healing occurred most commonly in patients who underwent spinal surgery (P = 0.0061, versus patients without delayed wound healing). CRP levels were high when tocilizumab was restarted in patients with RA symptom flare-ups (P = 0.0010, versus patients without RA symptom flare-ups). Increased postoperative CRP was observed in patients without postoperative events when the duration from final tocilizumab infusion to surgery was long. The changes in body temperature showed a similar trend to CRP.

Conclusions

Although it has been demonstrated that infection rates in patients treated with tocilizumab are by no means high, incidence of delayed wound healing was significantly higher in cases with surgical interventions such as foot and spinal surgeries. Many patients treated with tocilizumab remained in a normal range of CRP even during the perioperative period. For prevention of perioperative complications, observation of postoperative conditions and surgical wounds, and subjective symptoms of patients are considered important.     

Development of universal influenza vaccines based on influenza virus M and NP genes

Purpose

Vaccination is the safest and most effective measure against influenza virus infections. However, traditional influenza vaccines cannot respond effectively to an unforeseen epidemic or pandemic caused by a virus with antigenic drifts or antigenic shifts. Therefore, developing a universal influenza vaccine (UIV) that induces broad-spectrum and long-term immunity has become a major trend in influenza vaccine research and development.

Methods

This article reviews the development of UIVs based on these conserved influenza virus proteins.

Results and Conclusion

The matrix protein (M1, M2) and nucleoprotein (NP) of influenza viruses have highly conserved sequences, and they become the major target antigens of current UIV studies.     

Exploring the effect of previous inactivated influenza vaccination on seasonal influenza vaccine effectiveness against medically attended influenza: Results of the European I‐MOVE multicentre test‐negative case‐control study, 2011/2012‐2016/2017

Background

Results of previous influenza vaccination effects on current season influenza vaccine effectiveness (VE) are inconsistent.

Objectives

To explore previous influenza vaccination effects on current season VE among population targeted for vaccination.

Methods

We used 2011/2012 to 2016/2017 I‐MOVE primary care multicentre test‐negative data. For each season, we compared current season adjusted VE (aVE) between individuals vaccinated and unvaccinated in previous season. Using unvaccinated in both seasons as a reference, we then compared aVE between vaccinated in both seasons, current only, and previous only.

Results

We included 941, 2645 and 959 influenza‐like illness patients positive for influenza A(H1N1)pdm09, A(H3N2) and B, respectively, and 5532 controls. In 2011/2012, 2014/2015 and 2016/2017, A(H3N2) aVE point estimates among those vaccinated in previous season were ?68%, ?21% and ?19%, respectively; among unvaccinated in previous season, these were 33%, 48% and 46%, respectively (aVE not computable for influenza A(H1N1)pdm09 and B). Compared to current season vaccination only, VE for both seasons' vaccination was (i) similar in two of four seasons for A(H3N2) (absolute difference [ad] 6% and 8%); (ii) lower in three of four seasons for influenza A(H1N1)pdm09 (ad 18%, 26% and 29%), in two seasons for influenza A(H3N2) (ad 27% and 39%) and in two of three seasons for influenza B (ad 26% and 37%); (iii) higher in one season for influenza A(H1N1)pdm09 (ad 20%) and influenza B (ad 24%).

Conclusions

We did not identify any pattern of previous influenza vaccination effect. Prospective cohort studies documenting influenza infections, vaccinations and vaccine types are needed to understand previous influenza vaccinations' effects.

     

Studies of cell‐mediated immune responses to influenza vaccination in systemic lupus erythematosus

Objective

Both antibody and cell‐mediated responses are involved in the defense against influenza. In patients with systemic lupus erythematosus (SLE), a decreased antibody response to subunit influenza vaccine has been demonstrated, but cell‐mediated responses have not yet been assessed. This study was therefore undertaken to assess cell‐mediated responses to influenza vaccination in patients with SLE.

Methods

Fifty‐four patients with SLE and 54 healthy control subjects received subunit influenza vaccine. Peripheral blood mononuclear cells and sera were obtained before and 1 month after vaccination. Cell‐mediated responses to A/H1N1 and A/H3N2 vaccines were evaluated using an interferon‐γ (IFNγ) enzyme‐linked immunospot assay and flow cytometry. Antibody responses were measured using a hemagglutination inhibition test.

Results

Prior to vaccination, patients with SLE had fewer IFNγ spot‐forming cells against A/H1N1 compared with control subjects and a lower frequency of IFNγ‐positive CD8+ T cells. After vaccination, the number of IFNγ spot‐forming cells increased in both patients and control subjects, although the number remained lower in patients. In addition, the frequencies of CD4+ T cells producing tumor necrosis factor and interleukin‐2 were lower in patients after vaccination compared with healthy control subjects. As expected for a subunit vaccine, vaccination did not induce a CD8+ T cell response. For A/H3N2‐specific responses, results were comparable. Diminished cell‐mediated responses to influenza vaccination were associated with the use of prednisone and/or azathioprine. The increase in A/H1N1‐specific and A/H3N2‐specific antibody titers after vaccination was lower in patients compared with control subjects.

Conclusion

In addition to a decreased antibody response, cell‐mediated responses to influenza vaccination are diminished in patients with SLE, which may reflect the effects of the concomitant use of immunosuppressive drugs. This may render these patients more susceptible to (complicated) influenza infections.

     

Impact of synthetic and biologic disease‐modifying antirheumatic drugs on antibody responses to the AS03‐adjuvanted pandemic influenza vaccine: A prospective,open‐label,parallel‐cohort,single‐center study

Objective

To identify the determinants of antibody responses to adjuvanted split influenza A (H1N1) vaccines in patients with inflammatory rheumatic diseases.

Methods

One hundred seventy‐three patients (82 with rheumatoid arthritis, 45 with spondylarthritis, and 46 with other inflammatory rheumatic diseases) and 138 control subjects were enrolled in this prospective single‐center study. Controls received 1 dose of adjuvanted influenza A/09/H1N1 vaccine, and patients received 2 doses of the vaccine. Antibody responses were measured by hemagglutination inhibition assay before and 3–4 weeks after each dose. Geometric mean titers (GMTs) and rates of seroprotection (GMT ≥40) were calculated. A comprehensive medical questionnaire was used to identify the determinants of vaccine responses and adverse events.

Results

Baseline influenza A/09/H1N1 antibody levels were low in patients and controls (seroprotection rates 14.8% and 14.2%, respectively). A significant response to dose 1 was observed in both groups. However, the GMT and the seroprotection rate remained significantly lower in patients (GMT 146 versus 340, seroprotection rate 74.6% versus 87%; both P < 0.001). The second dose markedly increased antibody titers in patients, with achievement of a similar GMT and seroprotection rate as elicited with a single dose in healthy controls. By multivariate regression analysis, increasing age, use of disease‐modifying antirheumatic drugs (DMARDs) (except hydroxychloroquine and sulfasalazine), and recent (within 3 months) B cell depletion treatment were identified as the main determinants of vaccine responses; tumor necrosis factor α antagonist treatment was not identified as a major determinant. Immunization was well tolerated, without any adverse effect on disease activity.

Conclusion

DMARDs exert distinct influences on influenza vaccine responses in patients with inflammatory rheumatic diseases. Two doses of adjuvanted vaccine were necessary and sufficient to elicit responses in patients similar to those achieved with 1 dose in healthy controls.

     

Effect of simultaneous vaccination with H1N1 and GAD-alum on GAD<Subscript>65</Subscript>-induced immune response

Aims/hypothesis

A European Phase III trial of GAD formulated with aluminium hydroxide (GAD-alum) failed to reach its primary endpoint (preservation of stimulated C-peptide secretion from baseline to 15 months in type 1 diabetes patients), but subgroup analysis showed a clinical effect when participants from Nordic countries were excluded, raising concern as to whether the mass vaccination of the Swedish and Finnish populations with the Pandemrix influenza vaccine could have influenced the study outcomes. In the current study, we aimed to assess whether Pandemrix vaccination affects the specific immune responses induced by GAD-alum and the C-peptide response.

Methods

In this secondary analysis, we analysed data acquired from the Swedish participants in the Phase III GAD-alum trial who received subcutaneous GAD-alum vaccination (two doses, n = 43; four doses, n = 46) or placebo (n = 48). GAD autoantibodies (GADA) and H1N1 autoantibodies, GAD₆₅-induced cytokine secretion and change in fasting and stimulated C-peptide levels from baseline to 15 months were analysed with respect to the relative time between H1N1 vaccination and the first injection of GAD-alum.

Results

GADA levels at 15 months were associated with the relative time between GAD-alum and Pandemrix administration in participants who received two doses of the GAD-alum vaccine (p = 0.015, r = 0.4). Both in participants treated with two doses and four doses of GAD-alum, GADA levels were higher when the relative time between vaccines was ≥210 days (p < 0.05). In the group that received two doses of GAD-alum, levels of several GAD₆₅-induced cytokines were higher in participants who received the H1N1 vaccination and the first GAD-alum injection at least 150 days apart, and the change in fasting and stimulated C-peptide at 15 months was associated with the relative time between vaccines. Neither of these effects were observed in individuals who received four doses of GAD-alum.

Conclusions/interpretation

In individuals who received two doses of GAD-alum, receiving the Pandemrix vaccine closer to the first GAD-alum injection, i.e. <150 days, seemed to affect both GAD₆₅-induced immune response and C-peptide preservation.

Trial registration:

ClinicalTrials.gov NCT00723411.

     

Predictors of seasonal influenza vaccination in chronic asthma

Background

Guidelines advise annual influenza vaccination in chronic asthma. The aim of this study was to determine uptake of the influenza vaccine in a group of patients (n?=?146) with moderate to severe chronic asthma and establish the main predictors of vaccination.

Method

Patients attending a hospital asthma clinic were asked to complete a questionnaire in February 2012 (n?=?146). These same patients were contacted a year later via telephone (n?=?109 responded), and they were asked to complete the same questionnaire.

Results

Vaccination rate was 50.3% in winter 2011/12, and 57.8% in 2012/13. Using binary logistic regression, the predictors for vaccination in 2012 were patient advice (Odds ratio [OR] 15.37 p?=?0.001), female gender (OR 2.75, p?=?0.028), past side effects (OR 0.21, p?=?0.001) and comorbidity (OR 0.39, p?=?0.013). Stepwise regression resulted in age as predictor (T value?=?3.99, p?=?0.001). On analyzing the responses from the second questionnaire at one year after attendance to asthma clinic, predictors changed to compliance to medication (OR 9.52, p= 0.001) and previous exacerbations (OR 4.19, p?=?0.026). Out of the 56 patients vaccinated in 2011/12, 33 reported asthma exacerbations before 2012, and 29 reported asthma exacerbations after receiving the influenza vaccine. Out of the 46 unvaccinated patients in 2012, 27 had asthma exacerbations before 2012 and 19 patients had exacerbations in 2013. Patients vaccinated in 2011/12 needed 0.59 courses of steroid/patient/year, and 1.23 visits for nebulizer/patient/year while non-vaccinated patients needed 0.18 courses of steroids/patient/year (p?=?0.048), and 0.65 visits for nebulized/patient/year (p?=?0.012). Patients’ subjective statements broadly confirmed the predictors. 16/69 (23.1%) received the vaccine in winter 2012/13 despite reporting previous side effects.

Conclusions

Advice to patient, female gender and patients’ age predicted vaccination, while past side effects to the influenza vaccine, and presence of comorbidities predicted non vaccination. Symptomatic asthma patients are more likely to be vaccinated. One year after the first contact, treatment compliance and previous asthma exacerbations gained statistical significance as predictors of vaccination.

     

A review of tocilizumab treatment in 122 rheumatoid arthritis patients included in the Tsurumai Biologics Communication Registry (TBCR) Study

Objectives

Biologics have transformed the treatment of rheumatoid arthritis. Clinical remission is now the goal. We sought to verify whether the administration of tocilizumab—a biologic—can help to achieve current treatment goals.

Methods

Using data from the Tsurumai Biologics Communication Registry for 122 patients treated with tocilizumab, we evaluated changes in DAS28-ESR at 12 months after initiation, and also evaluated remission rates defined using conventional and new Boolean-based remission criteria. We divided 50 patients who had received tocilizumab as a first-line treatment into two groups [disease duration at baseline of 12 months or less (≤12 M) and more than 12 months (>12 M)].

Results

At 12 months after initiation, there was no difference in DAS28-ESR, and remission rates based on the conventional criterion were also comparable (50 % in both groups). However, under the new criterion, remission was 50.0 % in the ≤12 M group against 12.5 % in the >12 M group (p = 0.0181). Among the individual components of the new remission criterion, the small proportion of patients in the >12 M group with a patient global assessment (PtGA) of ≤1 had a particularly strong influence on the remission rate for that group, but this component was not as important for the ≤12 M group.

Conclusions

When used as a first-line biological drug for patients with early-stage RA (≤12 M), tocilizumab appears to provide high rates of remission under the Boolean-based remission criterion, which were strongly affected by the PtGA.     

Introducing seasonal influenza vaccine in low‐income countries: an adverse events following immunization survey in the Lao People's Democratic Republic

Objective

In 2012, Lao PDR introduced seasonal influenza vaccine in pregnant women, persons aged ≥50 years, persons with chronic diseases, and healthcare personnel. We assessed adverse events following immunization (AEFI).

Methods

We used a multistage randomized cluster sample design to interview vaccine recipients.

Findings

Between April and May 2012, 355 902 were vaccinated. Of 2089 persons interviewed, 261 (12·5%) reported one or more AEFI. The most commonly reported AEFIs were local reactions. No hospitalizations or deaths were reported; 16% sought medical care. Acceptance and awareness of vaccination were high.

Conclusions

Following the introduction of seasonal influenza vaccine in Lao PDR, self-reported adverse events were mild.     

An analysis of national target groups for monovalent 2009 pandemic influenza vaccine and trivalent seasonal influenza vaccines in 2009-10 and 2010-11

Background

Vaccination is generally considered to be the best primary prevention measure against influenza virus infection. Many countries encourage specific target groups of people to undertake vaccination, often with financial subsidies or a priority list. To understand differential patterns of national target groups for influenza vaccination before, during and after the 2009 influenza pandemic, we reviewed and analyzed the country-specific policies in the corresponding time periods.

Methods

Information on prioritized groups targeted to receive seasonal and pandemic influenza vaccines was derived from a multi-step internet search of official health department websites, press releases, media sources and academic journal articles. We assessed the frequency and consistency of targeting 20 different groups within populations which are associated with age, underlying medical conditions, role or occupations among different countries and vaccines. Information on subsidies provided to specific target groups was also extracted.

Results

We analyzed target groups for 33 (seasonal 2009 and 2009-10 vaccines), 72 (monovalent pandemic 2009-10 vaccine) and 34 (seasonal 2010 and 2010-11 vaccines) countries. In 2009-10, the elderly, those with chronic illness and health care workers were common targets for the seasonal vaccine. Comparatively, the elderly, care home residents and workers, animal contacts and close contacts were less frequently targeted to receive the pandemic vaccine. Pregnant women, obese persons, essential community workers and health care workers, however, were more commonly targeted. After the pandemic, pregnant women, obese persons, health care and care home workers, and close contacts were more commonly targeted to receive the seasonal vaccine compared to 2009-10, showing continued influence from the pandemic. Many of the countries provided free vaccines, partial subsidies, reimbursements or national health insurance coverage to specific target groups and over one-third of the countries offered universal subsidy regarding the pandemic vaccine. There was also some inconsistency between countries in target groups.

Conclusions

Differences in target groups between countries may reflect variable objectives as well as uncertainties regarding the transmission dynamics, severity and age-specific immunity against influenza viruses before and after vaccination. Clarification on these points is essential to elucidate optimal and object-oriented vaccination strategies.

     

Effect of passive immunization on immunogenicity and protective efficacy of vaccination against a Mexican low‐pathogenic avian H5N2 influenza virus

Background

Despite the use of vaccines, low‐pathogenic (LP) H5N2 influenza viruses have continued to circulate and evolve in chickens in Mexico since 1993, giving rise to multiple genetic variants. Antigenic drift is partially responsible for the failure to control H5N2 influenza by vaccination; the contribution of maternal antibodies to this problem has received less attention.

Methods

We investigated the effect of different antisera on the efficacy of vaccination and whether booster doses of vaccine can impact immune suppression.

Results

While single doses of inactivated oil emulsion vaccine to currently circulating H5N2 influenza viruses provide partial protection from homologous challenge, chickens that receive high‐titer homologous antisera intraperitoneally before vaccination showed effects ranging from added protection to immunosuppression. Post‐infection antisera were less immunosuppressive than antisera obtained from field‐vaccinated chickens. Homologous, post‐infection chicken antisera provided initial protection from virus challenge, but reduced the induction of detectable antibody responses. Homologous antisera from field‐vaccinated chickens were markedly immunosuppressive, annulling the efficacy of the vaccine and leaving the chickens as susceptible to infection as non‐vaccinated birds. Booster doses of vaccine reduced the immunosuppressive effects of the administered sera.

Conclusion

Vaccine efficacy against LP H5N2 in Mexico can be severely reduced by maternal antibodies. Source‐dependent antisera effects offer the possibility of further elucidation of the immunosuppressive components involved.     

Effect of Biologic Therapy on Clinical and Laboratory Features of Macrophage Activation Syndrome Associated With Systemic Juvenile Idiopathic Arthritis

Objective

To assess performance of the 2016 macrophage activation syndrome (MAS) classification criteria for patients with systemic juvenile idiopathic arthritis (JIA) who develop MAS while treated with biologic medications.

Methods

A systematic literature review was performed to identify patients with MAS while being treated with interleukin (IL)‐1 and IL‐6 blocking agents. Clinical and laboratory information was compared to a large previously compiled historical cohort.

Results

Eighteen publications were identified, and after removing duplicates, 35 patients treated with canakinumab and 49 patients with tocilizumab were available for analysis; 5 anakinra‐treated patients were excluded due to limited numbers. MAS classification criteria were less likely to classify tocilizumab‐treated patients as having MAS compared to the historical cohort or canakinumab‐treated patients (56.7%, 78.5%, and 84%, respectively; P < 0.01). Patients who developed MAS while treated with canakinumab trended towards lower ferritin at MAS onset than the historical cohort (4,050 versus 5,353 ng/ml; P = 0.18) but had no differences in other cardinal clinical or laboratory features. In comparison, patients who developed MAS while treated with tocilizumab were less likely febrile and had notably lower ferritin levels (1,152 versus 5,353 ng/ml; P < 0.001). Other features of MAS were more pronounced in patients treated with tocilizumab, including lower platelet counts, lower fibrinogen, and higher aspartate aminotransferase levels. Mortality rates for patients with MAS treated with tocilizumab or canakinumab were not significantly different from the historical cohort.

Conclusion

These findings show substantial alterations in MAS features that may limit utility of defined criteria for diagnosis of systemic JIA patients treated with biologic agents.

     

Adherence and factors associated with influenza vaccination among subjects with asthma in Spain

Purpose

Influenza has a high morbidity and mortality rate and an increased risk of complications in vulnerable individuals. Children and adults with asthma have a high risk of complications, hospitalisation and even death. The objectives of this study were as follows: to compare influenza vaccination coverage in Spain in a population of asthmatics aged ≥16 years with an equivalent population of non-asthmatics; to identify the factors that influence vaccination coverage among patients with asthma; and to compare coverage during the period 2006/2007 with that of 2009/2010.

Methods

We used data from the 2009 European Health Survey (EHS), which included a population of 22,188 individuals (≥16 years of age), of whom 1,669 [7.5 %; 95 % confidence interval (CI), 7.13–7.98] had asthma. The dependent variable was the answer (yes/no) to a question asking whether or not the interviewed person had been vaccinated against seasonal (not pandemic) influenza in the previous season. As independent variables, we analysed socio-demographic characteristics, health-related variables and the use of health care services.

Results

Vaccination coverage was 35.2 % (95 % CI, 32.5–37.9) among asthmatics and 22.1 % (95 % CI, 21.4–22.7) among non-asthmatics (p < 0.001). The probability of being vaccinated is almost twice as high for asthmatics as it is for non-asthmatics [odds ratio (OR), 1.92; 95 % CI, 1.69–2.17]. Among asthmatics, vaccination coverage increased with age, worse self-rated health status and not smoking. No significant change in coverage was observed between the study periods.

Conclusions

Seasonal influenza vaccination coverage among Spanish asthmatics is lower than desired and has not improved in recent years. Urgent strategies are necessary in order to increase vaccination coverage among asthmatics.     

Phase I clinical trial of vaccination with URLC10-derived peptide for patients with advanced esophageal cancer

Background

Up-regulated gene in lung cancer 10 (URLC10), confirmed to be lymphocyte antigen 6 complex locus K and defined as an oncoantigen, has been identified as a tumor-associated antigen by systematic analysis of expression levels of thousands of genes in lung cancer tissues and esophageal squamous cell carcinoma tissues, which were compared with those of normal human tissues by use of cDNA microarray analysis. Human leukocyte antigen (HLA)-A*2402-positive dendritic cells pulsed with URLC10-derived epitope peptide induced CD8⁺ cytotoxic T lymphocytes to exert specific cytotoxicity against the HLA-A*2402-positive URLC10-expressing esophageal carcinoma cell lines.

Methods

In a phase I clinical trial we evaluated the safety and immunogenicity of a URLC10-177 peptide vaccine emulsified with Montanide ISA51 for patients with unresectable advanced esophageal cancer. One milligram of URLC10-177 peptide in 1 mL sterile saline was emulsified with 1 mL incomplete Freund’s adjuvant and administered subcutaneously to the inguinal region or axilla of the patients. One course of treatment comprised four vaccinations, which were performed every week in the first and second treatment courses and subsequently every 2 weeks after the first vaccination in the third treatment course.

Results

Redness and induration of the skin were the only adverse events at the injection site and were believed to be a delayed-type hypersensitivity (DTH) reaction against the peptide vaccine. A URLC10-177-specific immune reaction in the enzyme-linked immunospot assay was detected in three of four DTH-positive patients (75 %) and in one of three DTH-negative patients (33 %). Furthermore, patients who had a DTH reaction seemed to survive longer than those who had no DTH reaction.

Conclusion

URLC10-177 peptide/Montanide vaccine therapy was well tolerated and induced a URLC10-177 peptide-specific immune response. Therapeutic URLC10-177 peptide vaccination is expected to have clinical benefit in prolonging the survival of patients with unresectable advanced esophageal cancer.     

Immunotherapy by autologous dendritic cell vaccine in patients with advanced HCC

Background

Dendritic cells (DCs) could be used as potential cellular adjuvant for the production of specific tumor vaccines.

Objectives

Our study was aimed to evaluate the safety and efficacy of autologous pulsed DC vaccine in advanced hepatocellular carcinoma (HCC) patients in comparison with supportive treatment.

Methods

Thirty patients with advanced HCC not suitable for radical or loco-regional therapies were enrolled. Patients were divided into 2 groups, group I consisted of 15 patients received I.D vaccination with mature autologous DCs pulsed ex vivo with a liver tumor cell line lysate. Group II (control group, no. 15) received supportive treatment. One hundred and 4 ml of venous blood were obtained from each patient to generate DCs. DCs were identified by CD80, CD83, CD86 and HLA-DR expressions using flow cytometry. Follow up at 3, and 6 months post injection by clinical, radiological and laboratory assessment was done.

Results

Improvement in overall survival was observed. Partial radiological response was obtained in 2 patients (13.3 %), stable course in 9 patients (60 %) and 4 patients (26.7 %) showed progressive disease (died at 4 months post-injection). Both CD8⁺ T cells and serum interferon gamma were elevated after DCs injection.

Conclusion

Autologous DC vaccination in advanced HCC patients is safe and well tolerate.