[Multidimensional geriatric assessment before transcatheter aortic valve implantation in frail elderly patients with one-year follow-up. Cardio-geriatrician collaboration benefits?]. / Évaluation gériatrique avant décision de remplacement valvulaire aortique par voie percutanée chez des patients âgés fragiles et suivi à un an : intérêt d'une collaboration cardio-gériatrique ?

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is a treatment for high-risk patients with symptomatic severe aortic stenosis. The aim of the study is to assess results of comprehensive geriatric assessment before TAVI and geriatrician advices about TAVI procedure feasibility. We report one-year outcomes after TAVI procedure. METHODS: All patients who underwent comprehensive geriatric assessment in geriatric day hospital before TAVI were prospectively included in Grenoble. We report characteristics of the patients, geriatrician advices about TAVI procedure feasibility and risks, and one year follow-up. RESULTS: Twenty-one frail elderly patients underwent geriatric assessment. The mean age was 85.4; demographics included cognitive impairment (76%), renal dysfunction (81%), NYHA functional class III or IV (48%). Eighteen patients were suitable for TAVI according to geriatric assessment, 8 underwent TAVI. None of the 3 patients who were not candidate for TAVI according to geriatricians were implanted. Cardiologists followed geriatrician advices for 56% of cases. Intensive care unit and cardiology stay were prolonged at 3.5 and 7.9days, respectively. Six out of the 8 patients stayed in rehabilitation unit after TAVI. None of the implanted patients died at one-year follow up, despite of the common periprocedural complications: acute kidney injury, ischemic stroke, delirium, pacemaker, hemorrhage. CONCLUSIONS: Cardiologists follow geriatrician advices about TAVI feasibility in frail elderly patients. Comprehensive geriatric assessment also helps preventing complications and providing quick assessment of occurring periprocedural and postprocedural complications. Optimal management of frail elderly patients undergoing TAVI is a multidisciplinary task involving cardiologists, anaesthetists and geriatricians.

Prevalence of protein-energy malnutrition in hospital patients over 75 years of age admitted for hip fracture.

INTRODUCTION: One percent of falls in over-75 years old cause hip fracture (HF). Protein-energy malnutrition (PEM) is associated with falls and fracture. PEM screening and perioperative nutritional management are recommended by the European Society of Parenteral and Enteral Nutrition, yet data on nutritional status in elderly HF patients are sparse. The Mini Nutritional Assessment (MNA) score is presently the most effective screening tool for PEM in over-75 years old. OBJECTIVE: The principal objective of the present study was to determine the prevalence on MNA of PEM in patients aged over 75 years admitted for HF. Secondary objectives were to identify factors associated with PEM and its role as a factor of evolution. MATERIALS AND METHODS: A prospective observational epidemiological study included 50 patients aged over 75 years admitted for HF in an 8-bed orthopedic surgery department with a geriatric follow-up unit. PEM was defined by MNA<17/30. Assessment systematically comprised associated comorbidity (Cumulative Illness Rating Scale-Geriatric [CIRS-G]), cognitive status on the Mini Mental State Examination (MMSE), functional status on activities of daily life (ADL), and mean hospital stay (MHS). Scores were compared on quantitative tests (Student t) with the significance threshold set at P<0.05. RESULTS: Mean age for the 50 patients was 86.1 years (range, 77-94 years). Prevalence of PEM was 28%; a further 58% of patients were at risk for PEM. PEM was associated with elevated CIRS-G (P<0.006), greater numbers of severe comorbidities (P=0.006), more severe cognitive disorder (P=0.005) and functional dependence (P=0.002), and 8 days' longer MHS (P=0.012). DISCUSSION: The present study confirmed the high prevalence of PEM in HF patients aged over 75 years, supporting longer hospital stay. MNA is a diagnostic gold standard, not to be replaced by albuminemia or body-mass index in this perioperative clinical situation. Given the present economic stakes relating to geriatric trauma patients' hospital stay, it is essential to prevent, diagnose and treat PEM in elderly subjects. LEVEL OF EVIDENCE: Level IV; prospective cohort study.

[Platypnea-orthodeoxia syndrome: a rare cause of severe hypoxemia]. / Syndrome de platypnée-orthodéoxie: une cause rare d'hypoxémie sévère.

INTRODUCTION: The platypnea-orthodeoxia syndrome (PO) includes: (i) a dyspnea increasing with orthostatism and decreasing in supine position, (ii) wide positional range in arterial oxygen saturation with tachycardia, (iii) and hypoxemia refractory to oxygen therapy. This syndrome is usually related to a cardiac right-left shunt, and rarely to a pulmonary shunt. OBSERVATION: We report a case of a patient presenting with a post-lung infection dyspnea associated with severe hypoxemia and shunt effect at blood gas. Contrast-enhanced CT-scan showed no pulmonary embolism. PO syndrome was suspected given the transcutaneous blood oxygen saturation variation from 90% in supine position to 60% in standing position, tachycardia, and absence of response to the intensive oxygen therapy. CONCLUSION: This syndrome should be known by physicians as a possible differential diagnose for refractory dyspnea to oxygen since effective treatment is available.

Cyclodextrin curcumin formulation improves outcome in a preclinical pig model of marginal kidney transplantation.

Decreasing organ quality is prompting research toward new methods to alleviate ischemia reperfusion injury (IRI). Oxidative stress and nuclear factor kappa beta (NF-κB) activation are well-described elements of IRI. We added cyclodextrin-complexed curcumin (CDC), a potent antioxidant and NF-κB inhibitor, to University of Wisconsin (UW) solution (Belzer's Solution, Viaspan), one of the most effective clinically approved preservative solutions. The effects of CDC were evaluated on pig endothelial cells and in an autologous donation after circulatory death (DCD) kidney transplantation model in large white pigs. CDC allowed rapid and lasting uptake of curcumin into cells. In vitro, CDC decreased mitochondrial loss of function, improved viability and lowered endothelial activation. In vivo, CDC improved function recovery, lowered histological injury and doubled animal survival (83.3% vs. 41.7%). At 3 months, immunohistochemical staining for epithelial-to-mesenchymal transition (EMT) and fibrosis markers was intense in UW grafts while it remained limited in the UW + CDC group. Transcriptional analysis showed that CDC treatment protected against up-regulation of several pathophysiological pathways leading to inflammation, EMT and fibrosis. Thus, use of CDC in a preclinical transplantation model with stringent IRI rescued kidney grafts from an unfavorable prognosis. As curcumin has proved well tolerated and nontoxic, this strategy shows promise for translation to the clinic.

Impact of functional status on the onset of nosocomial infections in an acute care for elders unit.

OBJECTIVE: To assess the role of functional status as a risk factor for nosocomial infections in the elderly. DESIGN: Prospective study. SETTING: Acute care for elders units of university hospital of Grenoble. PARTICIPANT: All patients over 75 years old consecutively hospitalized between January and April 2007. MEASUREMENT: The main judgement criteria was the rate of nosocomial infection during the hospital stay, defined according to the French technical comity against nosocomial infections. Other data included functional status at baseline and admission (Katz' ADL), usual risk factors for nosocomial infections, demographic and geriatric assessment data. RESULTS: The study included 223 patients. The mean age was 86.7±6.5 years. A nosocomial infection was diagnosed for 17.0% of the patients. In univariate analysis, the number of medicines, pressure sore, pneumonia diagnosis, illness severity, indwelling bladder catheter, IADL at baseline, and all disability parameters (ADL at baseline, ADL at admission, recent functional decline) were significantly associated with nosocomial infection (p<0.05). In multivariate analysis considering functional status at admission, indwelling bladder catheter (OR=4.43), severe disability at admission (OR=4.42) and illness severity (OR=2.68) were independently associated with nosocomial infection (p<0.05). In a second analysis considering functional status at baseline, only disability at baseline was independently associated with the onset of a nosocomial infection (OR=2.21). CONCLUSION: Our results suggest a significant impact of functional impairment on the incidence of nosocomial infections in hospitalized elderly population. Disability is a higher risk factor for nosocomial infections than the usual and well-known other parameters. Larger prospective studies are needed to examine the power of this relationship.

What are key factors influencing malnutrition screening in community-dwelling elderly populations by general practitioners? A large cross-sectional survey in two areas of France.

BACKGROUND/OBJECTIVES: Malnutrition is associated with a high morbi-mortality in elderly populations and their institutionalization at an early stage. The incidence is well known despite being often under-diagnosed in primary care. General practitioners (GPs) have a key role in home care. What are the factors affecting malnutrition-screening implementation by French GPs? SUBJECTS/METHODS: We conducted a cross-sectional survey in two areas in the southeast of France (Savoie and Isère). In May 2008, an anonymized survey was sent by e-mail and/or post to all GPs with a large clinical practice. Two months later, reminder letters were sent. Potential barriers were measured by dichotomous scale. On GPs' characteristics (socio-demographic, medical training, geriatric practice and knowledge), multiple regression logistic was performed to identify others factors affecting malnutrition screening. RESULTS: In all, 493 GPs (26.85%) answered and 72.2% felt that malnutrition screening was useful although only 26.6% implemented it each year and 11.9% every 2-5 years. The main barriers to the implementation were patient selection (60.4%) and forgetting to screen (26.6%). Minor barriers were lack of knowledge (19.5%) or time (15%). New factors were identified: unsuitable working conditions (19.1%), insufficient motivation (6.8%) or technical support (7.2%). The quality of malnutrition information received was found to be the only promoter of annual screening (odds ratio=1.44 (1.087-1.919); P=0.011). CONCLUSIONS: This survey is the first in France to reveal GPs' factors affecting malnutrition implementation. New obstacles were identified in this survey. The hope of implementing regular malnutrition screening by GPs seems to lie with the quality of malnutrition information received.

[Wernicke's encephalopathy associated with pellagra encephalopathy: rare and unusual complication in an elderly woman hospitalized for aspiration pneumonia]. / Encéphalopathie de Gayet Wernicke associée à une encéphalopathie pellagrique : complication rare et inhabituelle chez une femme âgée hospitalisée pour pneumopathie d'inhalation.

INTRODUCTION: Wernicke's encephalopathy caused by thiamine deficiency is typically characterised by a mental-status change, oculomotor dysfunction and an ataxia. Pellagra is the clinical presentation of niacin deficiency comprising cutaneous, gastrointestinal and neuropsychiatric manifestations. OBSERVATION: We report a case of encephalopathy due to dual vitamin deficiency of both thiamine (vitamin B1) and niacin (vitamin PP) in an 80-year-old women, hospitalized for severe sepsis caused by aspiration pneumonia. Severe malnutrition and alcohol consumption pointed to a diagnosis of vitamin deficiency. The clinical presentation and magnetic resonance imaging (MRI) were compatible with Wernicke's encephalopathy that remained irreversible despite vitamin B1 supplementation. Niacin supplementation allowed for complete regression of the observed symptoms compatible with niacin deficiency. CONCLUSION: Malnourished and alcoholic patients showing signs of encephalopathy should receive supplemental multivitamins including niacin.

Six-month outcome of elderly people hospitalized via the emergency department: the SAFES cohort.

BACKGROUND: The objective of the study was to identify factors predictive of 6-month institutionalization or mortality in frail elderly patients after acute hospitalization. METHODS: A prospective cohort of elderly subjects 75 years and older was set up in nine French teaching hospitals. Data obtained from a comprehensive geriatric assessment were used in a Cox model to predict 6-month institutionalization or mortality. Institutionalization was defined as incident admission either to a nursing home or other long-term care facility during the follow-up period. RESULTS: Crude institutionalization and death rates after 6 months of follow-up were 18% and 24%, respectively. Independent predictors of institutionalization were: living alone (HR=1.83; 95% CI=1.27-2.62) or a higher number of children (HR=0.86; 95% CI=0.78-0.96), balance problems (HR=1.72; 95% CI=1.19-2.47), malnutrition or risk thereof (HR=1.93; 95% CI=1.24-3.01), and dementia syndrome (HR=1.88; 95% CI=1.32-2.67). Factors found to be independently related to 6-month mortality were exclusively medical factors: malnutrition or risk thereof (HR=1.92; 95% CI=1.17-3.16), delirium (HR=1.80; 95% CI=1.24-2.62), and a high level of comorbidity (HR=1.62; 95% CI=1.09-2.40). Institutionalization (HR=1.92; 95% CI=1.37-2.71) and unplanned readmission (HR=4.47; 95% CI=3.16-2.71) within the follow-up period were also found as independent predictors. CONCLUSION: The main factors predictive of 6-month outcome identified in this study are modifiable by global and multidisciplinary interventions. Their early identification and management would make it possible to modify frail elderly subjects' prognosis favorably.

Rapid cognitive decline, one-year institutional admission and one-year mortality: analysis of the ability to predict and inter-tool agreement of four validated clinical frailty indexes in the SAFEs cohort.

OBJECTIVES: To evaluate the predictive ability of four clinical frailty indexes as regards one-year rapid cognitive decline (RCD - defined as the loss of at least 3 points on the MMSE score), and one-year institutional admission (IA) and mortality respectively; and to measure their agreement for identifying groups at risk of these severe outcomes. DESIGN: One-year follow-up and multicentre study of old patients participating in the SAFEs cohort study. SETTING: Nine university hospitals in France. PARTICIPANTS: 1,306 patients aged 75 or older (mean age 85±6 years; 65% female) hospitalized in medical divisions through an Emergency department. MEASUREMENTS: Four frailty indexes (Winograd; Rockwood; Donini; and Schoevaerdts) reflecting the multidimensionality of the frailty concept, using an ordinal scoring system able to discriminate different grades of frailty, and constructed based on the accumulation of identified deficits after comprehensive geriatric assessment conducted during the first week of hospital stay, were used to categorize participants into three different grades of frailty: G1 - not frail; G2 - moderately frail; and G3 - severely frail. Comparisons between groups were performed using Fisher's exact test. Agreement between indexes was evaluated using Cohen's Kappa coefficient. RESULTS: All patients were classified as frail by at least one of the four indexes. The Winograd and Rockwood indexes mainly classified subjects as G2 (85% and 96%), and the Donini and Schoevaerdts indexes mainly as G3 (71% and 67%). Among the SAFEs cohort population, 250, 1047 and 1,306 subjects were eligible for analyses of predictability for RCD, 1-year IA and 1-year mortality respectively. At 1 year, 84 subjects (34%) experienced RCD, 377 (36%) were admitted into an institutional setting, and 445 (34%) had died. With the Rockwood index, all subjects who experienced RCD were classified in G2; and in G2 and G3 when the Donini and Schoevaerdts indexes were used. No significant difference was found between frailty grade and RCD, whereas frailty grade was significantly associated with an increased risk of IA and death, whatever the frailty index considered. Agreement between the different indexes of frailty was poor with Kappa coefficients ranging from -0.02 to 0.15. CONCLUSION: These findings confirm the poor clinimetric properties of these current indexes to measure frailty, underlining the fact that further work is needed to develop a better and more widely-accepted definition of frailty and therefore a better understanding of its pathophysiology.

Predictors of institution admission in the year following acute hospitalisation of elderly people.

OBJECTIVES: The aim of the study was to identify factors related to institutionalisation within one-year follow up of subjects aged 75 or over, hospitalised via the emergency department (ED). DESIGN: Prospective multicentre cohort. SETTING: Nine French university teaching hospitals. PARTICIPANTS: One thousand and forty seven (1 047) non institutionalised subjects aged 75 or over, hospitalised via ED. A sub-group analysis was performed on the 894 subjects with a caregiver. MEASUREMENTS: Patients were assessed using Comprehensive Geriatric Assessment (CGA) tools. Cox survival analysis was performed to identify predictors of institutionalisation at one year. RESULTS: Within one year after hospital admission, 210 (20.1%) subjects were institutionalised. For the overall study population, age >85 years (HR 1.6; 95%CI 1.1-2.1; p=0.005), inability to use the toilet (HR 1.6; 95%CI 1.1-2.4; p=0.007), balance disorders (HR 1.6; 95%CI 1.1-2.1; p=0.005) and presence of dementia syndrome (HR 1.9; 95%CI 1.4-2.6; p<0.001) proved to be independent predictors of institutionalisation; while a greater number of children was inversely linked to institutionalisation (HR 0.8; 95%CI 0.7-0.9; p<0.001). Bathing was of borderline significance (p=.09). For subjects with a caregiver, initial caregiver burden was significantly linked to institutionalisation within one year, in addition to the predictors observed in the overall study population. CONCLUSIONS: CGA performed at the beginning of hospitalisation in acute medical wards is useful to predict institutionalisation. Most of the predictors identified can lead to targeted therapeutic options with a view to preventing or delaying institution admission.

The geriatric patient: use of acute geriatrics units in the emergency care of elderly patients in France.

We studied the factors influencing the choice of admission to Geriatrics units, instead of other acute hospital units after an emergency visit. We report the results from a cohort of 1283 randomly selected patients aged >75 years hospitalized in emergency and representative of the French University hospital system. All patients underwent geriatric assessment. Baseline characteristics of patients admitted to Geriatrics and other units were compared. A center effect influencing the use of Geriatrics units during emergencies was also investigated. Admission to a Geriatrics unit during the acute care episode occurred in 499 cases (40.3%). By multivariate analysis, 4 factors were related to admission to a Geriatrics unit: cognitive disorder: odds ratio (OR)=1.79 (1.38-2.32) (95% confidence interval=95% CI); "failure to thrive" syndrome OR=1.54 (1.01-2.35), depression: OR=1.42 (1.12-1.83) or loss of Activities of Daily Living (ADL): OR=1.35 (1.04-1.75). The emergency volume of the hospital was inversely related to the use of Geriatrics units, with high variation that could be explained by other unstudied factors. In the French University Emergency Healthcare system, the "geriatrics patient" is defined by the existence of cognitive disorder, psychological symptoms or installed loss of autonomy. Nevertheless, considerable nation-wide variation was observed underlining the need to clarify and reinforce this discipline in the emergency healthcare system.

Derivation and validation of a mortality-risk index from a cohort of frail elderly patients hospitalised in medical wards via emergencies: the SAFES study.

To identify predictive factors for 2-year mortality in frail elderly patients after acute hospitalisation, and from these to derive and validate a Mortality Risk Index (MRI). A prospective cohort of elderly patients was set up in nine teaching hospitals. This cohort was randomly split up into a derivation cohort (DC) of 870 subjects and a validation cohort (VC) of 436 subjects. Data obtained from a Comprehensive Geriatric Assessment were used in a Cox model to predict 2-year mortality and to identify risk groups for mortality. A ROC analysis was performed to explore the validity of the MRI. Five factors were identified and weighted using hazard ratios to construct the MRI: age 85 or over (1 point), dependence for the ADL (1 point), delirium (2 points), malnutrition risk (2 points), and co-morbidity level (2 points for medium level, 3 points for high level). Three risk groups were identified according to the MRI. Mortality rates increased significantly across risk groups in both cohorts. In the DC, mortality rates were: 20.8% in the low-risk group, 49.6% in the medium-risk group, and 62.1% in the high-risk group. In the VC, mortality rates were respectively 21.7, 48.5, and 65.4%. The area under the ROC curve for overall score was statistically the same in the DC (0.72) as in the VC (0.71). The proposed MRI appears as a simple and easy-to-use tool developed from relevant geriatric variables. Its accuracy is good and the validation procedure gives a good stability of results.

Predicting early mortality among elderly patients hospitalised in medical wards via emergency department: the SAFES cohort study.

OBJECTIVES: The aim of the study was, by early identification of deleterious prognostic factors that are open to remediation, to be in a position to assign elderly patients to different mortality risk groups to improve management. DESIGN: Prospective multicentre cohort. SETTING: Nine French teaching hospitals. PARTICIPANTS: One thousand three hundred and six (1 306) patients aged 75 and over, hospitalised after having passed through Emergency Department (ED). MEASUREMENTS: Patients were assessed using Comprehensive Geriatric Assessment (CGA) tools. A Cox survival analysis was performed to identify prognostic variables for six-week mortality. Receiver Operating Characteristics analysis was used to study the discriminant power of the model. A mortality risk score is proposed to define three risk groups for six-week mortality. RESULTS: Crude mortality rate after a six week follow-up was 10.6% (n=135). Prognostic factors identified were: malnutrition risk (HR=2.1; 95% CI: 1.1-3.8; p=.02), delirium (HR=1.7; 95% CI: 1.2-2.5; p=.006), and dependency: moderate dependency (HR=4.9; 95% CI: 1.5-16.5; p=.01) or severe dependency (HR=10.3; 95% CI: 3.2-33.1; p < .001). The discriminant power of the model was good: the c-statistic representing the area under the curve was 0.71 (95% IC: 0.67 - 0.75; p < .001). The six-week mortality rate increased significantly (p < .001) across the three risk groups: 1.1% (n=269; 95% CI=0.5-1.7) in the lowest risk group, 11.1% (n=854; 95% CI=9.4-12.9) in the intermediate risk group, and 22.4% (n=125; 95% CI=20.1-24.7) in the highest risk group. CONCLUSIONS: A simple score has been calculated (using only three variables from the CGA) and a practical schedule proposed to characterise patients according to the degree of mortality risk. Each of these three variables (malnutrition risk, delirium, and dependency) identified as independent prognostic factors can lead to a targeted therapeutic option to prevent early mortality.

[Videophone assistance and home hospitalization: the ViSaDom program]. / Téléassistance en hospitalisation b domicile: le programme ViSaDom.

OBJECTIVE: The purpose of this project was to study the clinical feasibility of videophone-based communication between patients in their homes, and the care teams who work in the Home Hospitalization department (HH). METHODS: This pilot study of videophone users compared them with a group of control patients also in HH. They came from either the adult, maternity or pediatric departments. Patients who met the inclusion criteria and consented to participate in the study were randomly assigned to one of two groups: those who had a videophone installed in their homes (telemedicine group), and those who received the standard HH care (control group). Sixteen patients in the telemedicine group were matched with 16 from the control group, according to age, Karnofsky Index score, and the reason for HH admission. RESULTS: The mean videophone call lasted six minutes, and patients averaged 23 calls each over the study period (0.7 calls per patient per working day). The videophone enabled better follow-up of wounds: for example, the nurse could transmit photos from the patient's home for real-time coordination. It was also useful for following patients suffering from pain, for technical nursing care, and for educating patients and their caregivers. Anxiety (measured with the Hospital Anxiety and Depression Scale) diminished during the study period for the telemedicine patients, compared with the control group (p=0.048). Within the telemedicine group, all patients and their families were very satisfied or satisfied with their care and with the communication (15/15), although the staff's level of satisfaction was slightly lower (14/16); there were no significant differences between groups. CONCLUSION: The ViSaDom program indicates that videophone communication is feasible and acceptable and could be a useful tool for improving the quality, efficiency and effectiveness of care.

ACTIDOM--a microsystem based on MEMS for activity monitoring of the frail elderly in their daily life.

A "ambulatory activity recorder" was developed, with 3 accelerometers and 3 magnetometers, to detect and qualify the elementary activities of a person, such as walking and transfers. The signal processing is explained, along with the preliminary results obtained on young and older healthy subjects. This work open the way to continuous and automatic monitoring of the level of mobility.

Evaluation of postural stability by means of a single inertial sensor.

Human posture control during standing is a combination of many complicated control processes. Physical therapists perform different clinical balance tests to either assess postural control or identify balance disorders that can ultimately cause a patient to fall. In this article, several standardized clinical exercises for balance assessment are executed together with an orientation tracker strapped onto the volunteer's sternum. The tracker estimates the 3-D orientation of the trunk in real-time using an efficient attitude determination algorithm. The device is fully portable and sensitive to anteroposterior and mediolateral sways. Analysis of the resulting angles provides several parameters that are useful in assessing and quantifying balance function. This approach could be a valuable tool for a therapist for patient's follow-up and could be combined with existing procedures such as force platforms or optical motion analysis systems. Also, statistical analysis on these parameters could help to characterize normal and pathological performances in a population.

A double-blind placebo-controlled evaluation of sublingual immunotherapy with a standardized ragweed extract in patients with seasonal rhinitis. Evidence for a dose-response relationship.

BACKGROUND: There is a growing consensus on the benefits of sublingual-swallow immunotherapy in the treatment of allergic diseases. METHODS: This randomized, double-blind placebo-controlled study was undertaken to assess the efficacy and safety of sublingual immunotherapy with standardized ragweed pollen extract tablets, in patients with an allergic rhinitis. A total of 110 outpatients were randomized (immunotherapy [I]: 55; placebo [P]: 55), of whom 99 were analyzable for efficacy (I: 48; P: 51) and 106 analyzable for safety (I: 53; P: 53). After a 28-day progression phase, the patients received a maintenance treatment during 6.5 months. Efficacy variables included a global assessment of efficacy (patient/ investigator), symptoms and medication scores as well as the frequency of asthma attacks. RESULTS: In the active treatment group, 43 patients completed the study, versus 49 on placebo. During the whole period of pollination, the difference favoring immunotherapy was highly significant for the global assessment by the patient (p = 0.004) and by the investigator (p = 0.005). Adverse reactions were reported more often in the active treatment but mild or moderate, and they abated after dose adjustment. A subgroup analysis of those patients receiving the highest dose of immunotherapy (3 tablets 3 times a week) showed a highly significant response for rhinitis and conjunctivitis total scores by comparison to lower dosages. CONCLUSION: This study confirms the efficacy and safety of sublingual immunotherapy and strongly suggests a dose-response relationship.