Evidence that inflammation was a component of asthma was initially derived from findings at autopsy in patients with fatal asthma. Their airways showed infiltration by neutrophils and eosinophils, degranulated mast cells, sub-basement-membrane thickening, loss of epithelial-cell integrity, and occlusion of the bronchial lumen by mucus. Hyperplasia and hypertrophy of bronchial smooth muscle and hyperplasia of goblet cells were also present. These findings were considered to be characteristic of fatal asthma, but not necessarily of other forms of the disease.
More recent studies have found substantial inflammation in bronchial-biopsy specimens from patients with asthma, even those with mild disease. These inflammatory changes can occur throughout the central and peripheral airways and often vary with the severity of the disease. Although not observed uniformly, denudation of the airway epithelium, deposition of collagen beneath the basement membrane, mast-cell degranulation, and infiltration of the airway by lymphocytes and eosinophils have been found in patients with mild-to-moderate asthma Many of the cells in the airway appear to be activated, implying that by releasing preformed or newly synthesized mediators, they have a direct role in asthma.
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Further evidence of an inflammatory response in asthma is the presence of cytokines that mediate inflammation and chemotactic chemokines in bronchoalveolar-lavage fluid or pulmonary secretions. Since these cytokines and chemokines are elaborated by resident and inflammatory cells in airways and have many effects on these cells, a variety of autocrine, paracrine, and endocrine networks could participate in asthma (Table 1). Some cytokines initiate inflammatory responses by activating transcription factors, which are proteins that bind to the promoter region of genes. Transcription factors involved in asthmatic inflammation include nuclear factor-B, activator protein-1, nuclear factor of activated T cells, cyclic AMP response-element binding protein, and various members of the family of signal transduction-activated transcription (STAT) factors. These transcription factors act on genes that encode inflammatory cytokines, chemokines, adhesion molecules, and other proteins that induce and perpetuate inflammation. Corticosteroids modulate immunoinflammatory responses in asthma by inhibiting these transcription factors.
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The ability of cytokines to induce the expression of adhesion molecules such as intercellular adhesion molecule 1, vascular-cell adhesion molecule 1, and endothelial-leukocyte adhesion molecule provides a mechanism for the adhesion of inflammatory cells to the endothelium and the migration of these cells from the circulation into the lamina propria, the epithelium, and in many cases, the airway lumen itself.
Allergic Inflammation in Asthma
Epidemiologic and clinical observations have linked IgE antibodies to the severity of asthma and the initial and sustained responses of the airway to allergens. To initiate the synthesis of IgE, inhaled allergens must encounter dendritic cells that line the airway. These dendritic cells then migrate to draining lymph nodes, where they present processed antigen to T and B cells. Interactions among these cells elicit responses that are influenced by cytokines and the presence or absence of costimulatory molecules. For example, a switch by B cells to the production of a particular immunoglobulin isotype requires two signals. For a switch to the synthesis of IgE, the first signal is delivered by interleukin-4 or interleukin-13 when these cytokines bind to receptors on B cells; the receptors for interleukin-4 and interleukin-13 share a common chain and use the same signal-transduction pathway (STAT-6). The second signal is delivered when CD40 on B cells binds to its ligand on T cells. Additional interactions between other pairs of ligands and receptors (between CD28 and B7 and between L 2 integrin and intercellular adhesion molecule 1) may complement or up-regulate the T cell–dependent activation of B cells that follows the binding of CD40 to its ligand
Once synthesized and released by B cells, IgE antibodies briefly circulate in the blood before binding to high-affinity IgE receptors (FcepsilonRI) on the surface of mast cells in tissue or peripheral-blood basophils, and low-affinity IgE receptors (FcRII, or CD23) on the surface of lymphocytes, eosinophils, platelets, and macrophages. Whether the binding of IgE to its low-affinity receptors activates cells and contributes to inflammation is unclear. Soluble FcepsilonRII receptors, however, appear to be important in regulating IgE synthesis.1Molecular bridging of FcRI receptors, which occurs when allergen interacts with receptor-bound IgE molecules, causes activation of the cell and the release of preformed and newly generated mediators. Interestingly, basophils and mast cells can secrete interleukin-4 and interleukin-13 and express the CD40 ligand; however, since the release of cytokines depends on cross-linking of IgE by allergen, these cells most likely amplify rather than induce the synthesis of IgE.
Mast Cells
Mast cells arise in the bone marrow, enter the circulation as CD34+ mononuclear cells that are positive for stem-cell factor and FcRI, travel to mucosal and submucosal sites in the airway, and undergo tissue-specific maturation. The cross-linking of mast-cell–bound IgE by allergen induces the activation of membrane and cytosolic pathways that cause the release of preformed mediators such as histamine and initiates the synthesis of arachidonic acid metabolites.
There are at least two subpopulations of mast cells: mast cells with tryptase and mast cells with both tryptase and chymase. Although the role of these enzymes is not fully defined, inhibitors of tryptase have been shown to modulate the response of the airway to allergen. Mast cells also contain proteoglycans with diverse biologic properties or functions, ranging from being supporting structures for various proteins (i.e., remodeling) to exerting effects on the differentiation and proliferation of cells, the adhesion and motility of cells, and tissue morphogenesis. Mast cells produce several cytokines, including interleukin-1, interleukin-2, interleukin-3, interleukin-4, interleukin-5, granulocyte–macrophage colony-stimulating factor, interferon-, and tumor necrosis factor .The potential for the extracellular release of these cytokines raises the possibility that mast cells contribute to both acute and chronic allergic inflammation.
The response of the airway to inhaled allergen provides insights into immunologic mechanisms that contribute to the pathogenesis of asthma.In patients with asthma, inhaled allergen precipitates acute obstruction of the airway by initiating the release from mast cells of histamine and leukotrienes, which cause constriction of smooth muscles. This early-phase reaction usually resolves within an hour. Four to six hours later, a prolonged late-phase reaction with obstruction of airflow may develop as a result of cytokines and chemokines generated by resident inflammatory cells (e.g., mast cells, macrophages, and epithelial cells) and recruited inflammatory cells (lymphocytes and eosinophils).
Eosinophils
Eosinophilopoiesis begins in the bone marrow and is regulated by interleukin-3, interleukin-5, and granulocyte–macrophage colony-stimulating factor; interleukin-5 induces terminal differentiation of immature eosinophils. The mature eosinophil has dense intracellular granules that are sources of inflammatory proteins, including major basic protein, eosinophil-derived neurotoxin, peroxidase, and cationic protein. Major basic protein, in particular, can directly damage airway epithelium, intensify bronchial responsiveness, and cause degranulation of basophils and mast cells. These effects increase the severity of asthma. The eosinophil is a rich source of leukotrienes, particularly the cysteinyl leukotriene C4, which contracts airway smooth muscle, increases vascular permeability, and may recruit more eosinophils to the airway.
A number of cytokines regulate the function of eosinophils and other cells in asthma . Interleukin-5 stimulates the release of eosinophils into the circulation and prolongs their survival. Challenge of the airway with allergen increases the local concentration of interleukin-5, which correlates directly with the degree of airway eosinophilia. In mice lacking the gene for interleukin-5, eosinophilia does not occur after challenge by an antigen. Direct administration of interleukin-5 to the airway in humans causes mucosal eosinophilia and an increase in bronchial responsiveness. Whether interleukin-5 alone is sufficient to cause eosinophilic inflammation is not established in humans; in mice, it is not sufficient to induce an asthma-like state. A recent study involving an antibody against interleukin-5 in humans has indicated a dissociation between the concentration of eosinophils in peripheral blood and sputum and the late asthmatic responses and bronchial hyperresponsiveness that follow challenge of the airway with allergen.
To participate in the allergic inflammatory response, the eosinophil must migrate from the circulation to the airway. The first step in this process is the phenomenon of cell rolling, which is mediated by P-selectin on the surface of eosinophils . Cell rolling activates eosinophils and requires the participation of the beta 1 and beta2 classes of integrins on the eosinophil surface. Eosinophils and lymphocytes express the beta1 integrin alpha4 beta1 integrin (also referred to as very late antigen 4, or VLA4), which binds to its ligand, vascular-cell adhesion molecule 1. Adhesion of the eosinophil to vascular-cell adhesion molecule 1 decreases the threshold for activation of the cell by mediators. The interactions between the beta2 integrins on eosinophils and intracellular adhesion molecule 1 on vascular tissue appear to be important for the transendothelial migration of eosinophils. The beta1 and beta2 integrins are constitutively expressed on the surface of eosinophils, but their state of activity is regulated by a variety of cytokines and chemokines.
The chemokines RANTES, macrophage inflammatory protein 1alpha, and the eotaxins are central to the delivery of eosinophils to the airway.These chemoattractants are produced by epithelium, macrophages, lymphocytes, and eosinophils. Chemokines have been detected on cells and in airway tissue from patients with asthma. Berkman et al. found that the constitutive expression of messenger RNA (mRNA) for RANTES was greater in the airway of patients with asthma than in normal subjects. Holgate et al. detected RANTES, macrophage inflammatory protein-1alpha, and monocyte chemotactic protein 1 in the airway of normal subjects and patients with asthma within four hours after airway challenge with allergen. At 4 hours, there was a positive correlation between RANTES concentrations and the number of eosinophils in the air space, and the concentrations of all three chemokines returned to base-line values within 24 hours. Ying et al. performed immunohistochemical studies of airway-biopsy specimens from normal subjects, allergic patients with asthma, and patients with nonallergic asthma and found that epithelial cells, endothelial cells, and macrophages were the primary sources of eotaxin, eotaxin-2, RANTES, and monocyte chemotactic proteins 3 and 4. Moreover, significant correlations were found between the degree of staining of eosinophils for EG2, a monoclonal antibody against the cleaved form of eosinophil cationic protein, and the concentrations of eotaxin. Collectively, the characteristics of many of the chemokines that act through the CCR3 receptor on the eosinophil, such as eotaxin, suggest that they are important in attracting eosinophils to the airway in asthma.
Lymphocytes
Mucosal-biopsy specimens obtained from patients during an episode of asthma after the inhalation of allergen contain lymphocytes, many of which express surface markers of activation. In mice, there are two types of helper CD4+ T cells. In simple terms, type 1 helper T (Th1) cells produce interleukin-2 and interferon-gamma, which are essential for cellular defense mechanisms. In contrast, type 2 helper T (Th2) cells produce cytokines (interleukin-4, 5, 6, 9, and 13) that mediate allergic inflammation. Furthermore, there is reciprocal inhibition, in that Th1-type cytokines inhibit the production of Th2-type cytokines and vice versa. CD8+ T cells may also be classified in a similar fashion according to their cytokine profiles (Tc1 and Tc2). These observations in rodents raise the possibility that allergic (asthmatic) inflammation results from a Th2-mediated mechanism.
A number of observations support this hypothesis. Recently, high concentrations of mRNA for GATA-3, a transcription factor that is confined to Th2 cells, were found in bronchial-biopsy specimens from patients with asthma. In patients with asthma, more of the cells from bronchoalveolar-lavage fluid contain mRNA for interleukin-3, interleukin-4, interleukin-5, and granulocyte–macrophage colony-stimulating factor than do cells from bronchoalveolar-lavage fluid obtained from normal subjects. The interleukin-4 and interleukin-5 were found predominantly in T cells.In contrast, the number of cells containing mRNA for interferon-gamma was similar in the two groups. The concentration of interleukin-5 protein is higher in bronchoalveolar-lavage fluid from patients with allergic or nonallergic asthma than in samples from patients who have other lung diseases such as hypersensitivity pneumonia and sarcoidosis.
Bronchial-biopsy specimens from patients with symptomatic allergic asthma or nonallergic asthma contain increased concentrations of mRNA for interleukin-4 and interleukin-5. Thus, it seems that the bronchial mucosa in patients with asthma contains an excess of activated Th2 cells irrespective of the allergic sensitization of the patient, but whether this means that the immunopathology of allergic and nonallergic asthma is similar is unknown. In evaluating these results, it is important to acknowledge that interleukin-4 can contribute to allergic inflammation by mechanisms other than the regulation of IgE synthesis.
The idea that allergic inflammation in asthma arises from an imbalance between Th1 and Th2 cells has focused attention on the Th1-type cytokine interferon-gamma. Since interferon-gamma inhibits the synthesis of IgE and the differentiation of precursor cells to Th2 cells, a lack of interferon-gamma would induce the Th2-type cytokine pathway to promote allergic inflammation. The evidence from in vivo studies of asthma, however, conflicts with this hypothesis. For example, the amount of interferon-gamma is elevated in the serum of patients with severe asthma during the acute phase of an attack, in supernatants from cultures of unstimulated and stimulated bronchoalveolar-lavage-fluid cells, and in the lavage fluid itself after challenge with an allergen. Furthermore, interferon-gamma increases not only the expression of CD69, HLA-DR, and intercellular adhesion molecule 1 (all of which are markers of cell activation) on eosinophils but also the viability of eosinophils. These and other data suggest that interferon-gamma contributes to the activation of eosinophils and thus is likely to augment inflammation. For these reasons, the classification of allergic inflammation in asthma as a Th2-mediated disease is too simplistic.
An Imbalance between Th1 and Th2 Cells and the Origins of Asthma
Although we question the importance of an imbalance between Th1 cells and Th2 cells in patients with established asthma, the possibility that this imbalance contributes to the cause and evolution of atopic diseases, including asthma, is intriguing. Largely as a result of Th2-trophic factors from the placenta, the population of T cells in the cord blood of newborn infants is skewed toward a Th2 phenotype. The extent of the imbalance between Th1 cells and Th2 cells (as indicated by diminished production of interferon-gamma) during the neonatal phase may be useful in predicting the subsequent development of allergic disease, asthma, or both. To reduce the risk of asthma and allergies in childhood, some have suggested that infants at high risk for these conditions should be exposed to stimuli that up-regulate Th1-mediated responses, so as to restore the balance during a critical time in the development of the immune system and the lung.
The increasing prevalence of asthma in Western countries has led to the “hygiene hypothesis. The basic tenet of this hypothesis is that the immune system of the newborn infant is skewed toward Th2 cells and needs timely and appropriate environmental stimuli to create a balanced immune response . Factors that enhance Th1-mediated responses and that are associated with a reduced incidence of allergy, asthma, or both include infection with Mycobacterium tuberculosis, measles virus and hepatitis A virus; increased exposure to infections through contact with older siblings; attendance at a day-care facility during the first six months of life; and a reduction in the production of interferon-gtamma as a result of decreased exposure to environmental endotoxin or to polymorphisms of the major endotoxin receptor (CD14) that diminish the response to endotoxin. Restoration of the balance between Th1 cells and Th2 cells may be impeded by frequent administration of oral antibiotics, with concomitant alterations in gastrointestinal flora. mune “imprinting” may actually begin in utero through the transplacental transfer of allergens and cytokines. Although these observations have generated intense interest, conflicting results have prevented researchers from drawing firm conclusions about the validity of the hygiene hypothesis.
The relevance to asthma of allergic sensitization is supported by the evolution of the disease in later childhood. Indeed, many children with asthma have positive skin-prick tests to extracts of protein from house-dust mites, cockroaches, pets (especially cat dander), and the fungi alternaria. n 6-year-old children with asthma, sensitization to alternaria was associated with a significantly reduced frequency of remission of asthma by the age of 11 years (9 percent in those who were sensitized vs. 39 percent in those who were not sensitized) Thus, it appears that the genetic background sets the stage for a cytokine imbalance that promotes the formation of IgE and that the allergens in the local environment dictate the specificity of the antibody response. Finally, sensitization to certain allergens, such as cockroach and alternaria allergens, may increase the risk of asthma-related morbidity, respiratory arrest during exacerbations of asthma, nd, perhaps, of the development of asthma.
Airway Remodeling in Asthma
The rate of decline in lung function with age is greater in adults with asthma than in those without asthma,and the ability to reverse the impairment in pulmonary function in many patients with asthma depends on the early recognition and treatment of the condition.Remodeling entails thickening of the airway walls, with increases in submucosal tissue, the adventitia, and smooth muscle. These features differ in asthma and chronic obstructive pulmonary diseases, in allergic and nonallergic asthma, and with the severity of asthma. The precise mechanisms underlying the remodeling process are under intense study. Recent observations in children with asthma (age, 5 to 12 years) suggest that preventing the progressive loss of lung function in childhood may require recognition and treatment of the disease during the first five years of life.Whether there is a mechanistic link between this loss of airway function and structural remodeling of the airway in early life is not yet known.
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A New Element in the Mechanism of Asthma
–>The telltale wheeze of asthma is the sound of an ill wind blowing through easily irritated, narrowed, and thickened airways. Underlying these changes is bronchial inflammation in which type 2 helper T (Th2) cells, a type of CD4 helper T cell, are prominent. Th2 cells secrete interleukins that promote allergic inflammation and stimulate B cells to produce IgE and other antibodies. In contrast, type 1 helper T (Th1) cells, another class of CD4 T cells, produce interferon-gamma and interleukin-2, which initiate the killing of viruses and other intracellular organisms by activating macrophages and cytotoxic T cells. These two subgroups of helper T cells arise in response to different immunogenic stimuli and cytokines, and they constitute an immunoregulatory loop: cytokines from Th1 cells inhibit Th2 cells, and vice versa . An imbalance in this reciprocal arrangement may be the key to asthma: there is credible evidence that, when freed from the restraining influence of interferon-gamma, Th2 cells can provoke airway inflammation.
Recent experiments by Finotto et al.2 support this concept. They focused on a newly discovered transcription factor, T-bet, which is necessary to induce helper T cells to differentiate into Th1 cells and for Th1 cells to produce interferon-gamma. For these reasons, T-bet is thought to be central to the feedback loops that regulate Th1 and Th2 cells, and in this way it could be important in asthma.
Finotto et al. performed immunohistochemical studies of samples of human lung tissue and found that T-bet was undetectable in lymphocytes within bronchi from patients with allergic asthma, but was present in lymphocytes from control lungs. The relevance of T-bet to asthma was also investigated in mice with deliberately disabled T-bet genes (T-bet –/– knockout mice). The findings were dramatic. Without any allergic sensitization of the animals, the bronchi in the T-bet–/– mice were infiltrated with eosinophils and lymphocytes and showed signs of the airway remodeling typical of allergic asthma. Moreover, these animals had airway hyperresponsiveness, and their bronchoalveolar-lavage fluid contained increased amounts of cytokines produced by the Th2 cells. These spontaneous changes in the T-bet–/– knockout mice were similar to those found in bronchi of wild-type mice that had been sensitized with a foreign protein and then challenged with an aerosol containing the allergen.
These findings constitute strong evidence of the modulating role of interferon-gamma in asthma and provide support for the hypothesis that an imbalance between Th1 and Th2 cells contributes to asthma. Nevertheless, we need to understand how the abnormalities of allergic asthma can arise spontaneously, without any need for an allergen, in T-bet–/– mice. Moreover, given the systemic deficiency of interferon-gamma and the global increase of Th2 cells in these mice, the specificity of the bronchial lesions must be established. If the airway is the sole target in these animals, we need to know why. Another point for further study is the difference between T-bet–/– mice and mice with disabled interferon-gamma genes, which are also devoid of interferon-gamma but do not seem to have bronchial lesions.
The work of Finotto et al. suggests that T-bet could be a therapeutic target in allergic asthma. Since interferon-gamma itself induces the expression of T-bet, it would be of considerable interest to determine whether this cytokine affects the expression of T-bet by Th1 cells from patients with allergic asthma. The cytokine networks that determine the fates of Th1 and Th2 cells are ripe targets for therapeutic intervention in asthma. Small, soluble molecules that can enter cells and specifically influence the production of T-bet could have considerable clinical value.
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The Role of Mast Cells in the Pathophysiology of Asthma
–>The mast cell has long been considered to be of paramount importance in the pathophysiology of asthma. Its key role in driving the IgE-mediated allergic reaction and thus the early asthmatic response is well documented. In addition, there is evidence that it responds to non-IgE stimuli in the airway — for example, changes in the osmotic cellular environment associated with such challenges as exercise, hypertonicity, and hypotonicity. The array of mediators released from the activated mast cell is diverse, including prostaglandins; leukotrienes; cytokines, such as interleukins 1, 2, 4, 10, and 13; growth factors, such as platelet-derived growth factor and transforming growth factor beta; and potent proteases, such as tryptase.1In contrast, the airway smooth-muscle cell has generally been considered less critical to the cascade of events that causes an asthma attack. This type of cell was initially thought to be primarily a resident structural cell that contracted in response to pharmacologic mediators and relaxed after stimulation of the beta-adrenergic receptors. During the past five years, however, it has become apparent that the airway smooth-muscle cell has the potential to play a more central part, by dint of its ability to secrete a large number of inflammatory cytokines, proliferate in response to a vast array of agents secreted by other cells in the airway, and express adhesion molecules on its surface and thereby attract inflammatory cells such as T lymphocytes. The result of these interactions among cells is increased cytokine secretion, increased proliferation of the muscle, and attraction of more inflammatory cells to the site. Moreover, the muscle cell sits in a bed of matrix proteins with which it interacts and to the composition of which it contributes by means of the secretion of matrix proteins, metalloproteinases, and their tissue inhibitors. The interactions between the matrix and muscle appear to be critical to the synthetic and proliferative functions of the muscle and to the composition of the matrix.
Recently, as airway smooth-muscle cells obtained from biopsy specimens from patients with asthma have become available for study, it has become clear that, at least in culture, airway smooth-muscle cells from such patients multiply at twice the rate of cells cultured from the lungs of subjects without asthma.2 Whether this accelerated rate of growth is responsible for the increased bulk of muscle observed in the airways of patients with asthma is not known, but the finding points to an intrinsic abnormality of the muscle cell. Is the muscle cell, then, the initiator of the asthmatic response — the basic abnormality that leads to all the other events?
In this issue of the Journal, Brightling et al.3 report that the comparison of immunohistochemical analyses of biopsy specimens from patients with asthma, patients with eosinophilic bronchitis, and normal control subjects revealed a striking increase in the number of mast cells in the bundles of smooth muscle from the patients with asthma. Furthermore, the number of mast cells was correlated with the hallmark of asthma — airway hyperresponsiveness, as measured by a methacholine inhalation test. Tissue from patients with eosinophilic bronchitis, like that from patients with asthma, contained increased numbers of eosinophils, but eosinophilic bronchitis was not associated with the airway hyperresponsiveness.
Carroll et al.4 studied the number of mast cells and their degranulation in tissue obtained on postmortem examination from persons who had died from asthma, persons who had had asthma but had died from other causes, and nonasthmatic controls. Like Brightling et al., they found that the largest proportion of mast cells was in the smooth muscle, and as would be expected, the number of degranulated mast cells was greatest in the persons who had died from asthma. It has also been reported that muscle from patients with allergies but not asthma contained greater numbers of mast cells than tissue from patients with neither allergies nor asthma, despite the fact that there were no differences between these groups in the populations of lymphocytes or eosinophils.
What could be the reason for the increased presence of mast cells in the airway smooth muscle in patients with asthma? Perhaps the attraction is caused by the secretion of stem-cell factor by the muscle. Stem-cell factor is a chemoattractant for mast cells and is responsible for regulating their growth, function, and survival. It exists in two forms — membrane-bound and soluble — and the former is expressed on the cell surface. The receptor for stem-cell factor, c-kit, is expressed on the surface of the mast cell, creating an opportunity for interplay between the two types of cells. Whether more stem-cell factor is released by the muscle in patients with asthma than in persons without asthma remains to be investigated. It is also possible that stem-cell factor is less readily metabolized in the airway in persons with asthma or that there is a deficiency of a mediator that negatively regulates the release of stem-cell factor.
What are the possible consequences of this close association between mast cells and the muscle? Obviously, when mast cells degranulate in response to any of the relevant stimuli, there will be smooth-muscle contraction. In addition, the cytokines that are released will bring more inflammatory cells into the airway. They will increase the expression of adhesion molecules on the surface of the muscle, resulting in adherence of inflammatory cells and increased proliferation. The growth factors and proteases such as tryptase cause proliferation of the smooth muscle, and tryptase may potentiate the contractile response to agonists such as histamine.
There are some caveats about the methods used by Brightling et al., and the authors draw attention to some of them. The association between mast cells and muscle could be a feature of all obstructive airway diseases rather than asthma in particular, given that the investigators did not study a control group of patients with forms of obstructive pulmonary disease other than asthma. Variability in sampling is always a problem and can occur at a number of levels. There is also variability in the interpretations of different observers. In this study, each tissue section was assessed by two investigators who were unaware of the disease status of the subject. However, there is no indication of the degree of variability between the findings of the two observers. Current thinking would suggest that the way to overcome variability is to increase the number of patients studied — “to do more less well
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