European Review for Medical and Pharmacological Sciences 2004; 8: 135-138 Brittle

E. GRAZIANI, A. PETROIANNI, C. TERZANO

Respiratory Diseases Unit, “La Sapienza” University – Rome (Italy)

Abstract. – Brittle asthma is a rare form Asthma causes recurrent episodes of cough- of severe asthma characterized by a wide varia- ing, wheezing, chest tightness and breathlessness. tion of Peak Expiratory Flow (PEF), in spite of In the year 2000 in USA than 11 milion heavy doses of steroides. Brittle asthmatic patients had very serious peoples had an asthma attack. and often, life threatening, attacks. In the year 1999, 478.000 people had been Type 1 brittle asthma is characterized by a admitted in hospital for acute asthma and mantained PEF variability despite therapy, and 4426 people died for asthma1. it affected mostly female, aged between 15 and Asthma is characterized by variable airflow 55 years. obstruction, reversible either spontaneously Type 1 is associated to skin prick tests posi- tivity and food intolerance. Several studies or with treatment. have referred a correlation with personality dis- The chronic inflammation of airways caus- orders. The patients affected with type 1 have es an increase of bronchial hyperresponsive- high morbidity, and frequently they have hospi- ness, that is inherited, to a variety of stimuli. tal admission for assessment and stabilitation Many cells are implicated in pathogenesis their asthmatic condition. of asthma: eosinophils, mast celles, T lym- Type 2 brittle asthma is characterized by phocites, neutrophils that infiltrated airways. acute attacks that are very severe and could led to death or mechanical ventilation for respi- Moreover in bronchial walls of asthmatic ratory insufficiency. people there is a deposition of collagen in the Brittle asthma is very difficult to recognize subbasament membrane, hyperplasia and hy- and to treat. In type 1 brittle asthma, the thera- pertrophy of the bronchial smooth muscle, py is based on inhaled and/or oral steroids, and with remodelling . β 2-agonists, used with an inhaler or with subcu- The major risk factor that causes asthma is taneous infusion. The patients affected with type 1 had to be atopy, that is the ability of syntethesize IGE nearly monitered and treated. antibodies to allergens. Patients affected with type 2 brittle asthma, In the development of asthma recent stud- are mostly free by simptoms, but they have se- ies established that airway inflammation is vere attacks that led them to emergency treat- due also to the loss of normal balance ment. beetween Th1-Th2 lymphocytes. Brittle asthma is a rare form of severe asth- According to the recent guidelines1 there is ma, that the clinicians may recognize and treat very strictly, because of high morbidity and a gradually approach to asthma. mortality. Asthma is classified in four steps: intermit- tent, mild, moderate, severe and will be treat- Key Words: ed according to the steps. Asthma, Airflow obstruction, Inhaled corticos- Brittle asthma is a rare form of severe asth- teroids, β -agonist. 2 ma characterized by a wide variation in peak expiratory flow (PEF), despite high doses of inhaled steroids, which could lead to death from an acute severe attack. The term Brittle Asthma was first used in Introduction 1977 by Turner-Warwick to describe another pattern of airflow obstruction in chronic asth- Asthma is a chronic inflammatory disease ma2. of the airways that is an important cause of The brittle asthmatic PEF pattern is a very mortality and morbidity. chaotic, so different from the morning dip

135 E. Graziani, A. Petroianni, C. Terzano and the double dip pattern of morning and Epidemiology evening, described for asthma3-4. Different physicians and British Thoracic Brittle asthma is a rare disease, with a Society used the term brittle asthma only to prevalence of 0.05% of all asthmatic patients. describe a severe attack of asthma, without The type 1 affected mostly female (2.5 F:1 M), regard to PEF patterns5. aged between 15 and 55 years, while type 2 The importance to recognize the typical brittle asthma seems to be no prevalence in PEF patterns of brittle asthma is related to be sex and age (Table I). a risk factor for death. In 1998, Ayres et al. defined Brittle asthma as a specific asthma phenotype, suggested a classification based on magnitude of diurnal Morbidity and Mortality PEF variability, describing two subclasses: type 1 and type 2, with different characteris- Type 1 brittle asthma has high morbidity in tics6-7. terms of frequent hospital admissions, for as- Many authors considered the possibility sessment and stabilitation of asthma. The pa- that the patients with a chaotic pattern of tients with type 1 brittle asthma are taking a PEF, were only non-compliant with the treat- considerable amounts of medications, as in- ment, and so they could lead to death for in- haled steroid and bronchodilator, or oral adeguate treatment. steroids, with many adverse effects. Another important question was to define Consequently, they suffer from oseophageal the disease asthma with precision, to avoid reflux, osteoporosis, weight gain, that con- to include in Brittle asthma the patients with duct them frequently to hospital admissions. severe symptoms despite the treatment, that Type 2 brittle asthma is correlated with an suffer with other diseases such as vocal cord high hospital admission for acute severe at- dysfunction, gastro-oesophageal reflux, im- tack, and is associated with a most higher munodeficiencies, , cystic fi- mortality. The patients are well controlled for brosis, and so on, that have the same symp- a long period, but when they have an attack, it toms or coexist with asthma8. So it was nec- is very severe, and may require ventilation6-9. essary a correct definition of Brittle asthma that could based on a specific pattern of PEF variability, as well as a correct diagnosis of asthma. Risk Factors

Type 1 brittle asthma is associated with atopy, demonstrated by a skin prick test posi- Definition tivity for cat, horse, wheat and chocolate10. The reaction to Dermatophagoides pteronyssinus is Brittle asthma is a distinct form of asthma, greater in type 1, but no statistically significa- characterized by a diurnal PEF variability, tive6. Many patients in this group report a food despite maximal medical treatment (high intolerance, for example peanuts, fish, wheat. doses of inhaled or oral , high doses of inhaled bronchodilator)6. Brittle asthma is classified in two types: Table I. Patients’ characteristics with brittle asthma. type 1 characterized by a maintained wide PEF variability (> 40% diurnal variation for Type 1 Type 2 > 50% of the time over a period of at least Sex F/M 2.5 F: 1 M 1F:1M 150 days) despite maximal medical therapy Age yr 15-55 *– including at least 1500 µg/day of inhaled be- Atopy Yes No clomethasone or equivalent. Food intolerance Yes No Type 2 is characterized by acute attacks oc- Psychological factors Yes No Morbidity High – curing within minutes, that coul lead to Mortality – High death, with a background of well controlled asthma6. *No prevalence.

136 Brittle asthma

Type 2 brittle asthma may worse after ex- Treatment posure to fungal spores such as Alternaria10. Type 1 is correlated with a personality dis- Brittle asthma is very difficult to treat. The order, as depression or psychological instabil- patients with brittle asthma have poor adher- ity11. ence to the treatment and have to be moni- All severe asthmatic patients have psycho- tored firmly. logical problems correlated with the state of The standard guidelines for asthma are not the disease, so that is difficult to define if brit- applyble, because the brittle asthmatic pa- tle asthma is associated with personality dis- tients are taking high doses of inhaled order (Table I). steroides and bronchodilators, so when their Both patients with type 1 and 2 brittle asth- conditions are worsening, they have to take ma have a reduced perception of worsening oral steroids. airways obstruction, and a reduced hypoxic The treatment of type 1 brittle asthma be- drive12-13. gins with reduced allergen exposure, and with avoid foods for which the patients are intoler- ance. Some authors have demonstrated that in type 1 brittle asthma is very important a good Possible Hypothesis Regarding the diet supported with minerals such as seleni- Pathology of Brittle Asthma um, magnesium and anti-oxidant vitamins A, C, B, that are deficiency19-20. An important mechanism in brittle asthma The therapy is essentially based on high is airway smooth muscle contraction, that is doses of inhaled , and when the activated rapidly by a cholinergic reflex, and patients have an acute attack it is necessary by local release of tachykinins, substance P, to prescribe oral steroids and increase the use β broncoconstrictor and inflammatory pep- of 2-agonist use. tides. Many allergens might induce fastly this There is a possibility to treat the patients 6 β mechanism . with continuous subcutaneous infusion of 2- Another important factor is the edema of agonist, such as terbutaline, needed doses the airways due to acute vasodilatation, plas- ranges between 6 and 15 mg a day, that may ma exudation that produce the acute airway be given trough a battery-powered syringe narrowing in brittle asthma14. driver (CSIT). It is important to maintaine The smooth muscle is also remodeled in se- the therapeutical range for terbutaline, to vere asthma and so much increased in avoid adverse effects as changes in serum bronchial walls of patients who dying for potassium or glucose concentrations in asthma attack. Bronchial biopsy demonstred blood21. β the thickening of the subbasement mem- The use of long-acting inhaled 2-agonists brane, the irreversible changes in smooth may have advantages to stabilizing the air- muscle, and the changes of glandular compo- ways; in several studies salmeterol has disap- nents, that conduced to stable and irre- pointed by the patients, whether formoterol versible obstruction of airways15. has improved lung function and has reduced Moreover in patients dying of acute asth- symptoms22. ma, an infiltration of neutrophils rather than The treatment of patients with type 2 brit- eosinophils have been seen, which suggest tle asthma, that are relatively symptom free, that neutrophils are the predominant cells consists to avoid allergen exposure, to identi- which appear earlier16-17. fy the triggers, self management, and to treat In type 1 brittle asthma the treatment the acute attacks with injection af adrenaline with high doses of inhaled or oral steroids with preloaded syringes. may often not controlled asthma, probably These patients have unexpected attacks, due to a steroid resistance. Several studies that request emergency hospital admission, try to explain the steroid resistance in asth- for acute respiratory insufficiency and they ma, and in brittle asthma it has been better may underwent to mechanical ventilation. defined as an “altered” steroid responsive- New therapy such as leukotriene receptor ness18. antagonists and 5-lipoxygenase inhibitors,

137 E. Graziani, A. Petroianni, C. Terzano oral cyclosporin or methotrexate, or intra- 8) BALFOUR-LYNN JAN. Difficult asthma: beyond the venous immunoglobulin, may help the treat- guidelines. Arch Dis Child 1999; 80: 201-206. ment in brittle asthma6-22. 9) HETZEL MR. Brittle asthma: fiend or phantom? A good attention physicians may have for Thorax 1998; 53: 235-236. psychologicol aspects that in asthma, and es- 10) MILES JF, CAYTON RM, TUNNICLIFFE WS, et al. pecially in brittle asthma, could influence the Increased atopic sensitization in brittle asthma. disease. Clin Exp Allergy 1995; 25: 1074-1082. In conclusions, brittle asthma is a rare form 11) MILES JF, GARDEN GM, TUNNICLIFFE WS, et al. of asthma, which has a particularly pheno- Psychological morbidity and copyng skills in pa- tients with brittle and non-brittle asthma: a case- types, and a specific pattern regarding the control study. Clin Exp Allergy 1997; 27: 1151- PEF variability, that may have to identify and 1159. treat6. 12) KIKUCHI Y, O KABE S, TAMURA G, et al. Chemo- Patients with brittle asthma expecially type sensitivity and perception of dyspnea in patients 1 are in severe clinical conditions, and in a with a history of near-fatal asthma. N Engl J Med “stable state of instability”9. 1994; 330: 1319-1324.

These patients have several hospital admis- 13) BARNES PJ. Blunted perception and death from sions to establish their therapy, to treat the asthma. N Engl J Med 1994; 330: 1383-1384. worsening symptoms, and side effects of 14) KUWANO K, BOSKEV CH, PAR PD, et al. Small air- treatment, with high costs. ways dimensions in asthma and chronic obstruc- Patients with type 2 brittle asthma may tive pulmonary disease. Am Rev Respir Dis 1993; have a severe attack that bring to respiratory 148: 1220-1225. insufficiency, and needs ventilatory support. 15) AMERICAN THORACIC SOCIETY. Proceeding of the ATS Brittle asthma may have been considered Workshop on refractory asthma. Am J Respir Crit with a great attention, since it poses many Care Med 2000; 162: 2341-2351. difficult problems to management. 16) JATAKANON A, UASUF C, MAZIAK W, L IM S, CHUNG KF, BARNES PJ. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med 1999; 160: 1532-1539.

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