Influenza A H1N1/2009 vaccine in juvenile dermatomyositis: reduced immunogenicity in patients under immunosuppressive therapy

Objectives The aim of the present paper is to assess the influence of demographic, muscle enzymes, JDM scores and treatment on non-adjuvanted influenza A H1N1/2009 vaccine immunogenicity in juvenile dermatomyositis (JDM) patients. Methods Thirty JDM patients and 81 healthy age-matched controls were vaccinated. All participants were evaluated pre- and 21 days post-vaccination and serology for anti-HI NI was performed by haemagglutination inhibition assay. Muscle enzymes, JDM scores and treatment were evaluated before and after vaccination. Adverse events were reported. Results After immunisation seroconversion rates were significantly lower in JDM patients compared to age-matched controls (86.7 vs. 97.5%, p=0.044), whereas seropmtection (p=0.121), geometric mean titres (GMT) (p=0.992) and factor increase (FI) in GMT (p=0.827) were similar in both groups. Clinical and labomtorial evaluations revealed that JDM scores and muscle enzymes remained stable throughout the study (p>0.05). A higher frequency of chronic course was observed in non-seroconverted compared to seroconverted (100% vs. 27%, p=0.012). Regarding treatment, a lower rate of seroconversion was observed in patients under prednisone>20mg/day (50% vs. 4%, p=0.039), and in those treated with a combination of prednisone, methotrexate and cyclosporine (50% vs. 4%, p=0.039). Local and systemic vaccine adverse events were mild and similar in patients and controls (p>0.05). Conclusion This study identified that chronic course and immunosuppressive therapy are the major factors hampering seroconversion was JDM, suggesting that a specific protocol may be required for this subgroup of patients. In spite of that, a single dose of non-adjuvanted influenza A/H1N1 2009 vaccine was generally seroprotective in this disease with no evident deleterious effect in disease itself (ClinicalTrials.gov, no. NCT01151644).

Glucocorticoid: Major Factor for Reduced Immunogenicity of 2009 Influenza A (H1N1) Vaccine in Patients with Juvenile Autoimmune Rheumatic Disease

Objective. To assess the immunogenicity and safety of non-adjuvanted influenza A H1N1/2009 vaccine in patients with juvenile autoimmune rheumatic disease (ARD) and healthy controls, because data are limited to the adult rheumatologic population. Method's. A total of 237 patients with juvenile ARD [juvenile systemic lupus erythematosus (JSLE), juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM), juvenile scleroderma, and vasculitis] and 91 healthy controls were vaccinated. Serology for anti-H1N1 was performed by hemagglutination inhibition assay. Seroprotection rate, seroconversion rate, and factor-increase in geometric mean titer (GMT) were calculated. Adverse events were evaluated. Results. Age was comparable in patients and controls (14.8 +/- 3.0 vs 14.6 +/- 3.7 years, respectively; p = 0.47). Three weeks after immunization, seroprotection rate (81.4% vs 95.6%; p = 0.0007), seroconversion rate (74.3 vs 95.6%; p < 0.0001), and the factor-increase in GMT (12.9 vs 20.3; p = 0.012) were significantly lower in patients with juvenile ARD versus controls. Subgroup analysis revealed reduced seroconversion rates in JSLE (p < 0.0001), JIA (p = 0.008), JDM (p = 0.025), and vasculitis (p = 0.017). Seroprotection (p < 0.0001) and GMT (p < 0.0001) were decreased only in JSLE. Glucocorticoid use and lymphopenia were associated with lower seroconversion rates (60.4 vs 82.9%; p = 0.0001; and 55.6 vs 77.2%; p = 0.012). Multivariate logistic regression including diseases, lymphopenia, glucocorticoid, and immunosuppressants demonstrated that only glucocorticoid use (p = 0.012) remained significant. Conclusion. This is the largest study to demonstrate a reduced but adequate immune response to H1N1 vaccine in patients with juvenile ARD. It identified current glucocorticoid use as the major factor for decreased antibody production. The short-term safety results support its routine recommendation for patients with juvenile ARD. ClinicalTrials.gov; NCT01151644. (First Release Nov 15 2011; J Rheumatol 2012;39:167-73; doi:10.3899/jrheum.110721)

A phase I randomized, double-blind, controlled trial of 2009 influenza A (H1N1) inactivated monovalent vaccines with different adjuvant systems

Methods We conducted a phase I, multicenter, randomized, double-blind, placebo-controlled, multi-arm (10) parallel study involving healthy adults to evaluate the safety and immunogenicity of influenza A (H1N1) 2009 non-adjuvanted and adjuvanted candidate vaccines. Subjects received two intramuscular injections of one of the candidate vaccines administered 21 days apart. Antibody responses were measured by means of hemagglutination-inhibition assay before and 21 days after each vaccination. The three co-primary immunogenicity end points were the proportion of seroprotection >70%, seroconversion >40%, and the factor increase in the geometric mean titer >2.5. Results A total of 266 participants were enrolled into the study. No deaths or serious adverse events were reported. The most commonly solicited local and systemic adverse events were injection-site pain and headache, respectively. Only three subjects (1.1%) reported severe injection-site pain. Four 2009 influenza A (H1N1) inactivated monovalent candidate vaccines that met the three requirements to evaluate influenza protection, after a single dose, were identified: 15 μg of hemagglutinin antigen without adjuvant; 7.5 μg of hemagglutinin antigen with aluminum hydroxide, MPL and squalene; 3.75 μg of hemagglutinin antigen with aluminum hydroxide and MPL; and 3.75 μg of hemagglutinin antigen with aluminum hydroxide and squalene. Conclusions Adjuvant systems can be safely used in influenza vaccines, including the adjuvant monophosphoryl lipid A (MPL) derived from Bordetella pertussis with squalene and aluminum hydroxide, MPL with aluminum hydroxide, and squalene and aluminum hydroxide.

Immunogenicity and Reactogenicity of 2009 Influenza A (H1N1) Inactivated Monovalent Non-Adjuvanted Vaccine in Elderly and Immunocompromised Patients

Background Immunosuppressed individuals present serious morbidity and mortality from influenza, therefore it is important to understand the safety and immunogenicity of influenza vaccination among them. Methods This multicenter cohort study evaluated the immunogenicity and reactogenicity of an inactivated, monovalent, non-adjuvanted pandemic (H1N1) 2009 vaccine among the elderly, HIV-infected, rheumatoid arthritis (RA), cancer, kidney transplant, and juvenile idiopathic arthritis (JIA) patients. Participants were included during routine clinical visits, and vaccinated according to conventional influenza vaccination schedules. Antibody response was measured by the hemagglutination-inhibition assay, before and 21 days after vaccination. Results 319 patients with cancer, 260 with RA, 256 HIV-infected, 149 elderly individuals, 85 kidney transplant recipients, and 83 with JIA were included. The proportions of seroprotection, seroconversion, and the geometric mean titer ratios postvaccination were, respectively: 37.6%, 31.8%, and 3.2 among kidney transplant recipients, 61.5%, 53.1%, and 7.5 among RA patients, 63.1%, 55.7%, and 5.7 among the elderly, 59.0%, 54.7%, and 5.9 among HIV-infected patients, 52.4%, 49.2%, and 5.3 among cancer patients, 85.5%, 78.3%, and 16.5 among JIA patients. The vaccine was well tolerated, with no reported severe adverse events. Conclusions The vaccine was safe among all groups, with an acceptable immunogenicity among the elderly and JIA patients, however new vaccination strategies should be explored to improve the immune response of immunocompromised adult patients. (ClinicalTrials.gov, NCT01218685)

Influenza A(H1N1) infection and severe cardiac dysfunction in adults: A case series

BACKGROUND: While viral myocarditis and heart failure are recognized and feared complications of seasonal influenza A infection, only limited information is available for 2009 influenza A(H1N1)-induced heart failure. METHODS AND MAIN FINDINGS: This case series summarizes the disease course of four patients with 2009 influenza A(H1N1) infection who were treated at our institution from November 2009 until September 2010. All patients presented with severe cardiac dysfunction (acute heart failure, cardiogenic shock or cardiac arrest due to ventricular fibrillation) as the leading symptom of influenza A(H1N1) infection. Two patients most likely had pre-existent cardiac pathologies, and three required catecholamine therapy to maintain hemodynamic function. Except for one patient who died before influenza A(H1N1) infection had been diagnosed, all patients received antiviral therapy with oseltamivir and supportive critical care. Acute respiratory distress syndrome due to influenza A(H1N1) infection developed in one patient. Heart function normalized in two of the three surviving patients but remained impaired in the other one at hospital discharge. CONCLUSIONS: Influenza A(H1N1) infection may be associated with severe cardiac dysfunction which can even be the leading clinical symptom at presentation. During an influenza pandemic, a thorough history may reveal flu-like symptoms and should indicate testing for H1N1 infection also in critically ill patients with acute heart failure.

The relationship between extravascular lung water and oxygenation in three patients with influenza A (H1N1)-induced respiratory failure

This case series reports the correlation between extravascular lung water (EVLW) and the partial arterial oxygen pressure/fractional inspiratory oxygen (PaO(2)/FiO(2)) ratio in three patients with severe influenza A (H1N1)-induced respiratory failure. All patients suffered from grave hypoxia (PaO(2), 26-42 mmHg) and were mechanically ventilated using biphasic airway pressure (PEEP, 12-15 mmHg; FiO(2), 0.8-1) in combination with prone positioning at 12 hourly intervals. All patients were monitored using the PICCO system for 8-11 days. During mechanical ventilation, a total of 62 simultaneous determinations of the PaO(2)/FiO(2) ratio and EVLW were performed. A significant correlation between EVLW and the PaO(2)/FiO(2) ratio (Spearman-rho correlation coefficient, -0.852; p < 0.001) was observed. In all patients, a decrease in EVLW was accompanied by an improvement in oxygenation. Serum lactate dehydrogenase levels were elevated in all patients and significantly correlated with EVLW during the intensive care unit stay (Spearman-rho correlation coefficient, 0.786; p < 0.001). In conclusion, EVLW seems increased in patients with severe H1N1-induced respiratory failure and appears to be closely correlated with impairments of oxygenatory function.

Immunogenicity and safety of seasonal and 2009 pandemic A/H1N1 influenza vaccines for patients with autoimmune diseases: a prospective, monocentre trial on 199 patients

The 2009 pandemic A/H1N1 influenza outbreak represented a theoretical risk for patients with autoimmune diseases (AID), especially those immunosuppressed. This study was undertaken to evaluate immunogenicity and tolerance of seasonal (SFV) and A/H1N1 flu vaccines (HFV) in AID patients.

Severity assessment tools in ICU patients with 2009 influenza A (H1N1) pneumonia.

The aim of this study was to determine if severity assessment tools (general severity of illness and community-acquired pneumonia specific scores) can be used to guide decisions for patients admitted to the intensive care unit (ICU) due to pandemic influenza A pneumonia. A prospective, observational, multicentre study included 265 patients with a mean age of 42 (±16.1) years and an ICU mortality of 31.7%. On admission to the ICU, the mean pneumonia severity index (PSI) score was 103.2 ± 43.2 points, the CURB-65 score was 1.7 ± 1.1 points and the PIRO-CAP score was 3.2 ± 1.5 points. None of the scores had a good predictive ability: area under the ROC for PSI, 0.72 (95% CI, 0.65-0.78); CURB-65, 0.67 (95% CI, 0.59-0.74); and PIRO-CAP, 0.64 (95% CI, 0.56-0.71). The PSI score (OR, 1.022 (1.009-1.034), p 0.001) was independently associated with ICU mortality; however, none of the three scores, when used at ICU admission, were able to reliably detect a low-risk group of patients. Low risk for mortality was identified in 27.5% of patients using PIRO-CAP, but above 40% when using PSI (I-III) or CURB65 (<2). Observed mortality was 13.7%, 13.5% and 19.4%, respectively. Pneumonia-specific scores undervalued severity and should not be used as instruments to guide decisions in the ICU.

Use of early corticosteroid therapy on ICU admission in patients affected by severe pandemic (H1N1)v influenza A infection.

INTRODUCTION Early use of corticosteroids in patients affected by pandemic (H1N1)v influenza A infection, although relatively common, remains controversial. METHODS Prospective, observational, multicenter study from 23 June 2009 through 11 February 2010, reported in the European Society of Intensive Care Medicine (ESICM) H1N1 registry. RESULTS Two hundred twenty patients admitted to an intensive care unit (ICU) with completed outcome data were analyzed. Invasive mechanical ventilation was used in 155 (70.5%). Sixty-seven (30.5%) of the patients died in ICU and 75 (34.1%) whilst in hospital. One hundred twenty-six (57.3%) patients received corticosteroid therapy on admission to ICU. Patients who received corticosteroids were significantly older and were more likely to have coexisting asthma, chronic obstructive pulmonary disease (COPD), and chronic steroid use. These patients receiving corticosteroids had increased likelihood of developing hospital-acquired pneumonia (HAP) [26.2% versus 13.8%, p < 0.05; odds ratio (OR) 2.2, confidence interval (CI) 1.1-4.5]. Patients who received corticosteroids had significantly higher ICU mortality than patients who did not (46.0% versus 18.1%, p < 0.01; OR 3.8, CI 2.1-7.2). Cox regression analysis adjusted for severity and potential confounding factors identified that early use of corticosteroids was not significantly associated with mortality [hazard ratio (HR) 1.3, 95% CI 0.7-2.4, p = 0.4] but was still associated with an increased rate of HAP (OR 2.2, 95% CI 1.0-4.8, p < 0.05). When only patients developing acute respiratory distress syndrome (ARDS) were analyzed, similar results were observed. CONCLUSIONS Early use of corticosteroids in patients affected by pandemic (H1N1)v influenza A infection did not result in better outcomes and was associated with increased risk of superinfections.

Influenza A(H1N1)pdm09 and cystic fibrosis lung disease: a systematic meta-analysis.

BACKGROUND To systematically assess the literature published on the clinical impact of Influenza A(H1N1)pdm09 on cystic fibrosis (CF) patients. METHODS An online search in PUBMED database was conducted. Original articles on CF patients with Influenza A(H1N1)pdm09 infection were included. We analyzed incidence, symptoms, clinical course and treatment. RESULTS Four surveys with a total of 202 CF patients infected by Influenza A(H1N1)pdm09 were included. The meta-analysis showed that hospitalisation rates were higher in CF patients compared to the general population. While general disease symptoms were comparable, the clinical course was more severe and case fatality rate (CFR) was higher in CF patients compared to asthmatics and the general population. CONCLUSIONS Evidence so far suggests that CF patients infected with Influenza A(H1N1)pdm09 show increased morbidity and a higher CFR compared to patients with other chronic respiratory diseases and healthy controls. Particularly, CF patients with advanced stage disease seem to be more susceptible to severe lung disease. Accordingly, early antiviral and antibiotic treatment strategies are essential in CF patients. Preventive measures, including vaccination as well as hygiene measures during the influenza season, should be reinforced and improved in CF patients.

Clinical characteristics and outcomes in children hospitalised with pandemic influenza A/H1N1/09 virus infection – a nationwide survey by the Pediatric Infectious Diseases Group of Switzerland

OBJECTIVE To describe all patients admitted to children's hospitals in Switzerland with a diagnosis of influenza A/H1N1/09 virus infection during the 2009 influenza pandemic, and to analyse their characteristics, predictors of complications, and outcome. METHODS All patients ≤18-years-old hospitalised in eleven children's hospitals in Switzerland between June 2009 and January 2010 with a positive influenza A/H1N1/09 reverse transcriptase polymerase chain reaction (RT-PCR) from a nasopharyngeal specimen were included. RESULTS There were 326 PCR-confirmed patients of whom 189 (58%) were younger than 5 years of age, and 126 (38.7%) had one or more pre-existing medical condition. Fever (median 39.1 °C) was the most common sign (85.6% of all patients), while feeding problems (p = 0.003) and febrile seizures (p = 0.016) were significantly more frequent in children under 5 years. In 142 (43.6%) patients there was clinical suspicion of a concomitant bacterial infection, which was confirmed in 36 patients (11%). However, severe bacterial infection was observed in 4% of patients. One third (n = 108, 33.1%) of the patients were treated with oseltamivir, 64 (59.3%, or 20% overall) within 48 hours of onset of symptoms. Almost half of the patients (45.1%) received antibiotics for a median of 7 days. Twenty patients (6.1%) required intensive care, mostly for complicated pneumonia (50%) without an underlying medical condition. The median duration of hospitalisation was 2 days (range 0-39) for 304 patients. Two children (<15 months of age with underlying disease) died. CONCLUSIONS Although pandemic influenza A/H1N1/09 virus infection in children is mostly mild, it can be severe, regardless of past history or underlying disease.

A community-based assessment of the spatiotemporal distribution of influenza in a U.S.-Mexico border county during the spring 2009 novel H1N1 swine-origin influenza A pandemic

This study retrospectively evaluated the spatial and temporal disease patterns associated with influenza-like illness (ILI), positive rapid influenza antigen detection tests (RIDT), and confirmed H1N1 S-OIV cases reported to the Cameron County Department of Health and Human Services between April 26 and May 13, 2009 using the space-time permutation scan statistic software SaTScan in conjunction with geographical information system (GIS) software ArcGIS 9.3. The rate and age-adjusted relative risk of each influenza measure was calculated and a cluster analysis was conducted to determine the geographic regions with statistically higher incidence of disease. A Poisson distribution model was developed to identify the effect that socioeconomic status, population density, and certain population attributes of a census block-group had on that area's frequency of S-OIV confirmed cases over the entire outbreak. Predominant among the spatiotemporal analyses of ILI, RIDT and S-OIV cases in Cameron County is the consistent pattern of a high concentration of cases along the southern border with Mexico. These findings in conjunction with the slight northward space-time shifts of ILI and RIDT cluster centers highlight the southern border as the primary site for public health interventions. Finally, the community-based multiple regression model revealed that three factors—percentage of the population under age 15, average household size, and the number of high school graduates over age 25—were significantly associated with laboratory-confirmed S-OIV in the Lower Rio Grande Valley. Together, these findings underscore the need for community-based surveillance, improve our understanding of the distribution of the burden of influenza within the community, and have implications for vaccination and community outreach initiatives.^

Future pandemic influenza control (FPIC) related strategic management plan based on the 2009 H1N1 pandemic influenza review of health policy decisions, their practice and implications

This cross-sectional study is based on the qualitative and quantitative research design to review health policy decisions, their practice and implications during 2009 H1N1 influenza pandemic in the United States and globally. The “Future Pandemic Influenza Control (FPIC) related Strategic Management Plan” was developed based on the incorporation of the “National Strategy for Pandemic Influenza (2005)” for the United States from the U.S. Homeland Security Council and “The Canadian Pandemic Influenza Plan for the Health Sector (2006)” from the Canadian Pandemic Influenza Committee for use by the public health agencies in the United States as well as globally. The “global influenza experts’ survey” was primarily designed and administered via email through the “Survey Monkey” system to the 2009 H1N1 influenza pandemic experts as the study respondents. The effectiveness of this plan was confirmed and the approach of the study questionnaire was validated to be convenient and the excellent quality of the questions provided an efficient opportunity to the study respondents to evaluate the effectiveness of predefined strategies/interventions for future pandemic influenza control.^ The quantitative analysis of the responses to the Likert-scale based questions in the survey about predefined strategies/interventions, addressing five strategic issues to control future pandemic influenza. The effectiveness of strategies defined as pertinent interventions in this plan was evaluated by targeting five strategic issues regarding pandemic influenza control. For the first strategic issue pertaining influenza prevention and pre pandemic planning; the confirmed effectiveness (agreement) for strategy (1a) 87.5%, strategy (1b) 91.7% and strategy (1c) 83.3%. The assessment of the priority level for strategies to address the strategic issue no. (1); (1b (High Priority) > 1a (Medium Priority) > 1c (Low Priority) based on the available resources of the developing and developed countries. For the second Strategic Issue encompassing the preparedness and communication regarding pandemic influenza control; the confirmed effectiveness (agreement) for the strategy (2a) 95.6%, strategy (2b) 82.6%, strategy (2c) 91.3% and Strategy (2d) 87.0%. The assessment of the priority level for these strategies to address the strategic issue no. (2); (2a (highest priority) > 2c (high priority) >2d (medium priority) > 2b (low priority). For the third strategic issue encompassing the surveillance and detection of pandemic influenza; the confirmed effectiveness (agreement) for the strategy (3a) 90.9% and strategy (3b) 77.3%. The assessment of the priority level for theses strategies to address the strategic Issue No. (3) (3a (high priority) > 3b (medium/low priority). For the fourth strategic issue pertaining the response and containment of pandemic influenza; the confirmed effectiveness (agreement) for the strategy (4a) 63.6%, strategy (4b) 81.8%, strategy (4c) 86.3%, and strategy (4d) 86.4%. The assessment of the priority level for these strategies to address the strategic issue no. (4); (4d (highest priority) > 4c (high priority) > 4b (medium priority) > 4a (low priority). The fifth strategic issue about recovery from influenza and post pandemic planning; the confirmed effectiveness (agreement) for the strategy (5a) 68.2%, strategy (5b) 36.3% and strategy (5c) 40.9%. The assessment of the priority level for strategies to address the strategic issue no. (5); (5a (high priority) > 5c (medium priority) > 5b (low priority).^ The qualitative analysis of responses to the open-ended questions in the study questionnaire was performed by means of thematic content analysis. The following recurrent or common “themes” were determined for the future implementation of various predefined strategies to address five strategic issues from the “FPIC related Strategic Management Plan” to control future influenza pandemics. (1) Pre Pandemic Influenza Prevention, (2) Seasonal Influenza Control, (3) Cost Effectiveness of Non Pharmaceutical Interventions (NPI), (4) Raising Global Public Awareness, (5) Global Influenza Vaccination Campaigns, (6)Priority for High Risk Population, (7) Prompt Accessibility and Distribution of Influenza Vaccines and Antiviral Drugs, (8) The Vital Role of Private Sector, (9) School Based Influenza Containment, (10) Efficient Global Risk Communication, (11) Global Research Collaboration, (12) The Critical Role of Global Public Health Organizations, (13) Global Syndromic Surveillance and Surge Capacity and (14) Post Pandemic Recovery and Lessons Learned. The future implementation of these strategies with confirmed effectiveness to primarily “reduce the overall response time’ in the process of ‘early detection’, ‘strategies (interventions) formulation’ and their ‘implementation’ to eventually ensure the following health outcomes: (a) reduced influenza transmission, (b) prompt and effective influenza treatment and control, (c) reduced influenza related morbidity and mortality.^

Influenza Tipo A (H1N1)

Fil: Attorri, Silvia. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas