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PubMed2005

The role of rhinovirus in asthma exacerbations.

Rhinoviruses are a major cause of asthma exacerbations in children and adults. With the use of sensitive RT-PCR methods, respiratory viruses are found in approximately 80% of wheezing episodes in children and in approximately one half of such episodes in adults. Rhinovirus is a member of the family Picornaviridae, and acute rhinovirus infections occur predominantly in the upper airway. This virus has also been identified in the lower airway, and it might cause acute wheezing through the production of proinflammatory mediators with a resulting neutrophilic inflammatory response. Precisely how this process leads to increases in airway hyperresponsiveness and airway obstruction is not fully established. However, risk factors for wheezing with colds include asthma and atopy, extremes in age, and perhaps having a deficient TH1 response to rhinovirus. With the use of in vitro models and experimental inoculation studies, significant advances have led to a better understanding of the mechanisms by which rhinovirus infections cause asthma exacerbations. Advances in our understanding of this interaction might provide knowledge that could ultimately lead to specific treatment modalities to prevent and/or treat this significant burden of asthma exacerbations.

Adult↗
PubMed2006

6. Asthma: Factors underlying inception, exacerbation, and disease progression.

Asthma is a heterogeneous disorder that is characterized by variable airflow obstruction, airway inflammation and hyperresponsiveness, and reversibility either spontaneously or as a result of treatment. Multiple causes no doubt exist for both its inception and symptom exacerbation once the disease is established. Factors underlying inception can range from viral respiratory tract infections in infancy to occupational exposures in adults. Factors underlying asthma exacerbations include allergen exposure in sensitized individuals, viral infections, exercise, irritants, and ingestion of nonsteroidal anti-inflammatory agents among others. Exacerbating factors might include one or all of these exposures and vary both among and within patients. Asthma treatment is determined to a large extent after an assessment of severity, which can be variable over time and assessed in 2 domains: impairment (current) and risk (long-term consequences). Unfortunately, despite the availability of effective therapies, suboptimal asthma control exists in many patients on a worldwide basis. The future development of novel therapies and treatment paradigms should address these disparities.

Allergens↗
PubMed2004

beta-agonists through metered-dose inhaler with valved holding chamber versus nebulizer for acute exacerbation of wheezing or asthma in children under 5 years of age: a systematic review with meta-analysis.

OBJECTIVE: To compare the efficacy of beta-agonists given by metered-dose inhaler with a valved holding chamber (MDI+VHC) or nebulizer in children under 5 years of age with acute exacerbations of wheezing or asthma in the emergency department setting. STUDY DESIGN: Published (1966 to 2003) randomized, prospective, controlled trials were retrieved through several different databases. The primary outcome measure was hospital admission. RESULTS: Six trials (n=491) met criteria for inclusion. Patients who received beta-agonists by MDI+VHC showed a significant decrease in the admission rate compared with those by nebulizer (OR, 0.42; 95% CI, 0.24-0.72; P=.002); this decrease was even more significant among children with moderate to severe exacerbations (OR, 0.27; 95% CI, 0.13-0.54; P=.0003). Finally, measure of severity (eg, clinical score) significantly improved in the group who received beta-agonists by MDI+VHC in comparison to those who received nebulizer treatment (standardized mean difference, -0.44; 95% CI, -0.68 to -0.20; P=.0003). CONCLUSIONS: The use of an MDI+VHC was more effective in terms of decreasing hospitalization and improving clinical score than the use of a nebulizer in the delivery of beta-agonists to children under 5 years of age with moderate to severe acute exacerbations of wheezing or asthma.

Acute Disease↗
PubMed2005

Neuronal TGF-beta1 mediates IL-9/mast cell interaction and exacerbates excitotoxicity in newborn mice.

Intraneocortical injection of ibotenate, a glutamate analog, in newborn mice produces damage mimicking lesions observed in human infants with cerebral palsy. Previous research using this model has demonstrated that pretreatment with IL-9, a Th2 cytokine, significantly exacerbated excitotoxic brain lesions. The goal of this study is to identify the underlying pathophysiological mechanism of lesion formation. Pretreatment with TGF-beta1 produced the same effects as IL-9 on ibotenate-induced lesions. IL-9 effects were abolished when a specific TGF-beta1 neutralizing antibody is administered at the same time. Real-time PCR, Western blot, and immunohistochemistry showed that pretreatment with IL-9 increased TGF-beta1 neocortical expression. In vitro studies using real-time PCR and immunocytochemistry demonstrated that neurons were a major contributor in IL-9-induced increase of TGF-beta1. In c-Kit mast cell-deficient mice, TGF-beta1 failed to exacerbate excitotoxic brain lesions, suggesting a key role of mast cells in TGF-beta1 effects. A specific inhibitor of mast cell degranulation and histamine receptor blockers abrogated TGF-beta1 effects on excitotoxic lesions, providing further evidence of mast cell involvement and the role of mast cell-derived histamine. Finally, in vitro studies using a mast cell line showed that TGF-beta1 increased histamine in the supernatant. In aggregate, these data support the notion that neuronal TGF-beta1 plays a key role in the IL-9/mast cell interaction, which leads to an exacerbation of neonatal excitotoxic damage through an increased extracellular histamine concentration. The identification of this pathway, if confirmed in human neonates, might have important implications for understanding and preventing cerebral palsy.

Animals↗
PubMed2004

Striatal dopaminergic D2 receptor occupancy and clinical efficacy in psychosis exacerbation: a 123I-IBZM study with ziprasidone and haloperidol.

OBJECTIVE: The aim of this study was to compare striatal dopaminergic D2 receptor occupancy (D2 RO) induced by ziprasidone and haloperidol and its relationship with clinical response and extrapyramidal side effects (EPS) in patients with acute psychosis exacerbation. METHOD: Twenty patients hospitalized with an acute psychosis exacerbation were randomised in a single-blind study to receive either ziprasidone (80-120 mg/day) or haloperidol (5-20 mg/day) for more than 2 weeks. When stable doses were achieved, data on 123I-IBZM single-photon emission computed tomography (SPECT), as well as data on clinical efficacy (positive and negative symptoms scale [PANSS]) and EPS (Simpson Angus scale [SAS]), were compared between the two groups of patients. Clinical response was defined as a percentage of change of >30% in PANSS. Striatal D2 RO and clinical data were also compared between responders and nonresponders on each treatment group. RESULTS: All patients on haloperidol and four patients on ziprasidone showed EPS. Mean D2 RO was significantly higher in the haloperidol (74.7+/-3.5) than in the ziprasidone (60.2+/-14.4) group (Mann Whitney U-test [M-W U-test] 8.50; p=0.002). Five patients were responders, and five were nonresponders on each group of treatment. Haloperidol responders and nonresponders did not differ in D2 RO, duration of treatment, doses or EPS. Ziprasidone responders were on higher doses than nonresponders and showed higher D2 RO although below 74%. A positive correlation of ziprasidone D2 RO was found with dose (r Spearman 0.87; p=0.001) and with SAS scores (r Spearman 0.88; p=0.001). CONCLUSIONS: Ziprasidone induces lower D2 RO and EPS than haloperidol, which is consistent with an atypical antipsychotic profile. A direct relationship of ziprasidone D2 RO with dose, clinical efficacy and EPS has been found in this study. These data suggest that high ziprasidone doses might be more beneficial in patients with psychosis exacerbation and claim for caution regarding EPS appearance with such high dosages.

Adult↗
PubMed2005

Single inhaler budesonide/formoterol in exacerbations of chronic obstructive pulmonary disease.

Inhaled bronchodilators, particularly short-acting inhaled beta(2)-agonists, and systemic glucocorticosteroids are effective treatments for acute exacerbations of chronic obstructive pulmonary disease (COPD). However, in the treatment of these episodes there may be some advantages to the longer-acting agents in that there will be prolonged bronchodilation. Moreover, high doses of systemic glucocorticosteroids are associated with a significant risk of side effects. In the last few years, evidence is mounting that nebulized budesonide and inhaled formoterol might be an alternative to oral prednisolone and short-acting beta(2)-agonists, respectively, in the treatment of acute exacerbations of COPD. Interestingly, some new data suggest that a combination therapy with single inhaler containing budesonide and formoterol may be an alternative to traditional therapy in the treatment of acute exacerbations of this disorder. However, since individual studies are typically statistically underpowered and are remarkably heterogeneous with regard to their conclusions, larger studies are needed to confirm these preliminary findings and determine conclusively any impact of budesonide/formoterol combination in acutely ill COPD patients.

Acute Disease↗
PubMed2005

New treatment regimes for virus-induced exacerbations of asthma.

This review will focus on the role of viruses as causes of asthma exacerbations. The article will briefly review the current literature supporting this view, with a special focus on human rhinovirus (RV), the main virus associated with exacerbations of asthma. The review will then refer to possible strategies for treatment, and will include discussion on treatment with specific anti-viral therapy and type I interferon as a treatment for RV. The review will also include a discussion on current therapies for asthma, such as glucocorticosteroid and beta(2) agonist therapy alone and in combination and why this may be relevant to virus-induced exacerbations of asthma. Finally, the potential for future anti-inflammatory/immunomodulatory therapies with a focus on NF-kappaB inhibition will be discussed.

Adrenergic beta-Agonists↗
PubMed2004

COPD exacerbations: the importance of a standard definition.

Efforts to assess the efficacy of new therapies in the treatment of acute exacerbations of chronic obstructive pulmonary disease (COPD) have been hampered by the lack of a widely agreed and consistently used definition. A variety of definitions have been used in clinical studies, based on changes in patient symptoms or the requirement for antibiotic therapy, oral steroids or hospitalisation. To date, none of these definitions have been assessed in detail for their reliability, responsiveness and validity determined. Considerable heterogeneity in the aetiology and manifestation of COPD exacerbations makes identification and quantification of defining symptoms extremely difficult. New approaches are therefore being sought with a view to identifying a serum or tissue marker that can be used as a valuable diagnostic tool. Improvements in data recording will also contribute to the accuracy of data retrieval and assessment. If we are to progress to a level of sophistication seen in the diagnosis and management of other diseases, it is evident that considerable research efforts will be required to improve our understanding of COPD exacerbations and develop a standard definition for these events, thereby facilitating the assessment of therapeutic approaches.

Ambulatory Care↗
PubMed2005

Markers of inflammation and oxidative stress in exacerbated chronic obstructive pulmonary disease patients.

COPD is characterised by damage to small airways due to an inflammatory process as well as an imbalance between oxidants and antioxidants. Several cytokines and cell adhesion molecules enhancing a mainly neutrophilic inflammation have been associated with COPD. The aim of the study was to investigate whether inflammation or oxidative markers gave an indication of the course of COPD during an exacerbation. Fourteen patients with moderate to severe COPD admitted to the St. Antonius Hospital because of an exacerbation have been monitored during treatment with prednisolone 50 mg intravenously during 24 h at admission, reduced to 25 mg at day 3 and tapered off with oral prednisolone at day 7. On three separate occasions, day 1, 3 and 7, H2O2 in exhaled air, IL-8 and the soluble cell adhesion molecule sICAM and sE-selectin in serum were measured. We compared the patients at day 1 with healthy controls (in both non-smokers and smokers). Furthermore, we examined the changes from the study group in time during therapy. At admission all the markers were raised in comparison with the control groups. During treatment H2O2 concentrations in breath condensate declined significantly (P<0.001) as well as IL-8 and sICAM in serum (P=0.002, respectively, P<0.001). There was no significant change in sE-selectin (P=0.132). No significant improvement has been found in spirometry. These data suggest that the markers H2O2 in exhaled air, IL-8 and sICAM in serum are suitable markers in monitoring exacerbated COPD.

Aged↗
PubMed2004

The relationship between the quality of prescribing and practice appointment rates with asthma management data in those admitted to hospital due to an acute exacerbation.

Specific targeting of patients with a previous asthma hospitalisation could be more focused if predictors could be identified. This study was an observational retrospective analysis using ridge and linear multivariate regression analysis. Patient asthma management data were extracted from the hospital and general practice notes of those that had been admitted with an acute exacerbation of their asthma over a 5-year period. From the prescribing data, the annual doses of preventer (P) and reliever (R) medication were converted to defined daily doses then divided to give a P:R ratio. Preliminary statistical analysis was used to identify any association between either the P:R ratio or for the number of general practitioner (GP) practice appointments (PA) and their asthma management data. Multivariate regression analysis was applied to the P:R ratio and to PA to determine a model between each of these and asthma management data/events. GPs gave consent to access the data of 115 (out of 440) asthmatics, age >5 years, admitted to a district general hospital for asthma exacerbations between 1994 and 1998. The multivariate analysis revealed that PA was associated with oral prednisolone rescue courses (PRCs) and age whilst the P:R ratio was associated to PRCs and more reliever usage but not preventers. Patients with low preventer usage with respect to their reliever medication should be targeted for medication review as these were the patients prescribed more prednisolone courses and their increased PAs reflect this. This could decrease visits to the doctor and acute exacerbations.

Acute Disease↗
PubMed2005

Treatment of acute exacerbation of severe-to-very severe COPD with azithromycin in patients vaccinated against Streptococcus pneumoniae.

Sixty-five consecutive eligible adult patients, who were treated as outpatients for stable severe-to-very severe COPD, were enrolled in the study. All of them received 23-valent pneumococcal capsular polysaccharide vaccine intramuscularly. Patients were seen monthly, as well as whenever they had symptoms suggestive of an exacerbation, at our outpatient clinic. Eighteen out of 65 patients suffered from acute exacerbation (AECOPD). Three of these patients presented two episodes of AECOPD. Patients with an acute exacerbation of COPD received azithromycin 500 mg/day once daily for 3 days and a short course of oral prednisolone 25 mg/die. In 16 cases, a single species was isolated, while in the remaining 5 cases at least two species were recovered. Clinical cure or improvement at the end of therapy (3-5 days post-therapy) was reported in 17 episodes of AECOPD with no relapse at the late post-therapy (10-14 days after the completion of treatment). Bacteriologic eradication or presumptive eradication rates at the end of therapy were 86% (24 out of 28 isolates). Azithromycin eradicated all isolates of Haemophilus influenzae, Moraxella catarrhalis, H. parainfluenzae, Klebsiella pneumoniae, and Klebsiella spp. isolated at baseline. Eradication of Sta aureus occurred in 1 of 3 isolates whereas azithromycin was unable to eradicate Pseudomonas aeruginosa isolates. Our data seem to indicate that pneumococcal vaccination reduces the possibility that an AECOPD is caused by Streptococcus pneumoniae. This finding allows the use of antibiotics such as azithromycin, which, otherwise, should be avoided because of resistances.

Acute Disease↗
PubMed2005

Capillary blood gases in acute exacerbations of COPD.

OBJECTIVES: To assess the correlation and agreement between measurements of PO(2), PCO(2), H(+) and HCO(3)(-) in arterial and capillary blood in patients with acute exacerbations of COPD. To assess the repeatability of capillary measurements. DESIGN: Method comparison study. SETTING: Accident and emergency department in a university teaching hospital. MAIN OUTCOME MEASURES: Measurements of PO(2), PCO(2), H(+) and HCO(3)(-) in one arterial and two capillary samples taken from consecutive patients with acute exacerbations of COPD. RESULTS: The agreement between measurements of PCO(2), H(+) and HCO(3)(-) in arterial and capillary blood was good with mean differences of 0.087 kPa, 1.044 nmol/l and 0.513 mmol/l, respectively. The corresponding 95% limits of agreement were narrow. The agreement between measurements of PO(2) was poor with a mean difference of 1.256 kPa and wide 95% limits of agreement. There was good repeatability between capillary samples with mean differences of 0.094 kPa, 0.674 nmol/l and 0.028 mmol/l for measurements of PCO(2), H(+) and HCO(3) respectively and narrow coefficients of repeatability. CONCLUSIONS: Capillary blood gas measurements provide an accurate assessment of PCO(2), H(+) and HCO(3)(-) and can be used to reliably measure the ventilatory status of patients. Combined with continuous pulse oximetry they can be used as an alternative to arterial blood gas measurements in patients with acute exacerbations of COPD.

Acute Disease↗
PubMed2006

Oral bacterial vaccines for the prevention of acute exacerbations in chronic obstructive pulmonary disease and chronic bronchitis.

Oral vaccines using killed bacterial extracts have been used to prevent acute exacerbations of chronic obstructive pulmonary disease (COPD); however, they are not recommended by current clinical guidelines. Two systematic reviews have been published on the efficacy of oral vaccines. The first, on the effects of an oral whole-cell nontypeable Haemophilus influenzae vaccine (NTHi) found a significant decrease in the incidence of acute episodes of chronic bronchitis (Poisson rate ratio 0.666; 95% confidence interval (CI) 0.500, 0.887; P = 0.005), and a 58% reduction in the prescription of antibiotics 3 months after vaccination. The second review evaluated studies that used multicomponent vaccines. It found that the duration of exacerbations was significantly shorter in the treatment group (weighted mean difference -2.7 days, 95% CI -3.5 to -1.8). These reviews suggest that oral vaccines reduce the number, severity, duration, or both, of acute exacerbations. However, many of the primary trials on which they are based are small and methodologically flawed. Further trials are needed before the use of oral vaccines could be considered as part of the routine clinical management of patients with COPD or chronic bronchitis.

Administration, Oral↗
PubMed2006

Inhaled budesonide in the management of acute worsenings and exacerbations of asthma: a review of the evidence.

The use of systemic corticosteroids, together with bronchodilators and oxygen therapy, has become established for the management of acute asthma. These agents are undoubtedly effective, but are also associated with problems such as metabolic adverse effects. Inhaled corticosteroids (ICS) offer potential benefit in the acute setting because they are delivered directly to the airways. They are also likely to reduce systemic exposure, which would lead in turn to reductions in rates of unwanted systemic effects. In order to evaluate the role of budesonide in the management of acute asthma exacerbations we conducted a review of the literature and critically evaluated the rationale for the use of ICS in general in this setting. Trials in adults and children requiring treatment for acute exacerbation of asthma have shown clinical and/or spirometric benefit for budesonide when delivered via nebulizer, dry powder inhaler, or aerosol in the emergency department, hospital and follow-up settings. The efficacy seems to benefit from high doses given repeatedly during the initial phase of an acute exacerbation. These acute effects are likely to be linked to the drug's distinctive pharmacokinetic and pharmacodynamic profile. The current evidence base revealed encouraging results regarding the efficacy of the ICS budesonide in patients with wheeze and acute worsening of asthma. Future studies should focus on the efficacy of these agents in more severe asthma worsenings.

Acute Disease↗
PubMed2006

A double-blind comparison of risperidone, quetiapine and placebo in patients with schizophrenia experiencing an acute exacerbation requiring hospitalization.

OBJECTIVE: This study compared the effects of atypical antipsychotics (risperidone or quetiapine) with placebo and with each other in recently exacerbated patients with schizophrenia requiring hospitalization. METHODS: This international, randomized, double-blind study included a 2-week monotherapy phase followed by a 4-week additive therapy phase. Recently exacerbated patients with schizophrenia or schizoaffective disorder (DSM-IV) were randomized (2:2:1) to risperidone (n = 153), quetiapine (n = 156), or placebo (n = 73). Target doses were 4 or 6 mg/day of risperidone and 400 or 600 mg/day of quetiapine by day 5, with the ability to increase to 600 or 800 mg/day of quetiapine on day 8. The main outcome measures were the total Positive and Negative Syndrome Scale (PANSS) and need for additional psychotropic medications. RESULTS: Monotherapy Phase: The combined atypical antipsychotic group (n = 308) reached borderline superiority to placebo (n = 71) at the 2-week endpoint on mean change in total PANSS score (-24.1 +/- 1.2 and -20.2 +/- 2.0, respectively; p = 0.067). The change in the atypical group was driven by the improvement with risperidone (-27.7 +/- 1.5 vs. -20.2 +/- 2.0 with placebo, p < 0.01; and vs. -20.5 +/- 1.5 with quetiapine, p < 0.01); the improvement with quetiapine was similar to placebo, p = 0.879. Results were similar on other efficacy endpoints. Additive Therapy Phase: Additional psychotropics were prescribed to fewer (p < 0.01) risperidone (36%) than quetiapine (53%) or placebo patients (59%). The overall discontinuation rate was 18%, 26%, and 38%, respectively. Risperidone, compared with placebo, was associated with more parkinsonism, akathisia, plasma prolactin changes, and weight gain; while quetiapine was associated with more somnolence, sedation, dizziness, constipation, tachycardia, thyroid dysregulation, and weight gain. CONCLUSION: While the combined atypical antipsychotic group did not experience greater improvements than the placebo group, risperidone, but not quetiapine, was significantly superior in all measured domains to placebo in the management of recently exacerbated hospitalized patients with schizophrenia or schizoaffective disorder, with no unexpected tolerability findings.

Acute Disease↗
PubMedDate not supplied

Paraparesis due to exacerbation of preexisting spinal pseudoarthrosis following infliximab therapy for advanced ankylosing spondylitis.

BACKGROUND CONTEXT: Recent reports have described the long-term efficacy and safety of infliximab as a treatment for ankylosing spondylitis (AS). The most important adverse effects of infliximab are infections, malignancies, autoimmunities, and hypersensitivity reactions. There has never been a reported case of paraparesis after infliximab therapy for AS. PURPOSE: To describe a case with paraparesis caused by rapid exacerbation of preexisting spinal pseudoarthrosis after infliximab therapy for advanced AS. STUDY DESIGN/SETTING: Case report/Osaka University Graduate School of Medicine, Suita, Japan. PATIENT SAMPLE: A 55-year-old man with a 27-year history of AS. OUTCOME MEASURES: Case report. METHODS: A 55-year-old man with a 27-year history of AS was treated with infliximab, which provided considerable pain relief and improvement of activities of daily living. However, as the patient resumed vigorous daily activity, he felt back pain and subsequently developed paraparesis. Radiographs showed rapid exacerbation of preexisting spinal pseudoarthrosis at the T11-T12 level after infliximab therapy. RESULTS: After laminectomy and posterolateral fusion, the back pain and paraparesis improved sufficiently to allow independent walking, but moderate bladder dysfunction persisted. CONCLUSIONS: Although this patient could have certainly become myelopathic over time without undergoing infliximab therapy, the patient's history and radiographic course suggest that suppression of inflammation by infliximab improved his activities of daily living, which paradoxically exacerbated preexisting spinal pseudoarthrosis and quickened the onset of subsequent myelopathy.

Antibodies, Monoclonal↗
PubMed2004

Does influenza vaccination exacerbate asthma in children?

BACKGROUND: The risks of influenza vaccination in asthmatic children are still being discussed. Especially, the risk that influenza vaccination may exacerbate asthma is an issue in this debate. METHODS: We conducted a randomised double-blind placebo-controlled trial in 696 children 6-18 years of age with asthma recruited in general practice during two influenza seasons, 1999-2000 and 2000-2001. Children participated for only one season. During the first week after vaccination, participants recorded local, influenza like and asthma symptoms as well as use of medication, health care use and absenteeism. RESULTS: Except for cough during the day in the first season, favouring placebo, there were no differences indicating that vaccination exacerbates asthma. CONCLUSIONS: Influenza vaccination does not seem to exacerbate asthma.

Adolescent↗
PubMed1995

Predicting mortality of patients hospitalized for acutely exacerbated chronic obstructive pulmonary disease.

PURPOSE: To identify factors affecting the short-term prognosis of patients with acutely exacerbated chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: The 590 patients having COPD as primary disease who were hospitalized in the pneumology unit of a university hospital from 1981 to 1990 were studied. A standardized protocol for the treatment of acutely exacerbated COPD was adopted for all the patients. The patient records were retrospectively analyzed by two observers, and 23 clinical and laboratory variables defining the patient status on admission were collected. Age and arterial gas data were also taken into account, and the outcome mortality was recorded. Interobserver reproducibility was tested by computing the kappa coefficient and Spearman's rho for dichotomous and continuous variables, respectively. The relationship of clinical and laboratory factors to the outcome was assessed first by univariate analysis and then by a logistic regression analysis assessing the independent predictive role of variables previously shown to be univariately correlated with mortality. RESULTS: The mortality rate was 14.4%. The logistic regression analysis identified four independent predictors of death: age (odds ratio [OR] 1.07; 95% confidence interval [CI] 1.04 to 1.11), alveolar-arterial oxygen gradient greater than 41 mm Hg (OR 2.33; 95% CI 1.39 to 3.90), ventricular arrhythmias (OR 1.91; 95% CI 1.10 to 3.31), and atrial fibrillation (OR 2.27; 95% CI 1.14 to 4.51). CONCLUSIONS: Patients with acutely exacerbated COPD having a high risk of death can be identified at the time of admission. Variables reflecting heart dysfunction are important determinants of this risk. Among pulmonary function data, only alveolar-arterial oxygen gradient contributes to the predictive model.

Acute Disease↗