Acute Respiratory Failure in Exacerbations of Bronchial Asthma

Abstract

Asthma is defined as a chronic inflammatory disease of the respiratory tract in which various cells and inflammatory mediators are involved. It is characterized by remodeling of the airway wall. Multiple inflammatory mediators may be involved, including interleukins. Physiologically, acute asthma has an early component, with an acute bronchospastic aspect marked by smooth muscle bronchoconstriction and a later inflammatory component, resulting in airway swelling and edema. In the early stages of asthma, hypoxemic respiratory failure occurs. If the asthmatic crisis is maintained over time, it will produce a status of severe acute asthma (ASA), which is characterized by hypercapnic respiratory failure.

1. Introduction

From a pragmatic point of view, asthma could be defined as a chronic inflammatory disease of the airways in which various cells and inflammatory mediators are involved, conditioned in part by genetic factors, which occurs with bronchial hyperreactivity (BHR). Acute asthma attacks can cause great variability in gas exchange, as can be seen by measuring both the pressures of oxygen and carbon dioxide (PaO₂ and PaCO₂) on an arterial blood gas analysis, the same which may remain within normal values or experience a slight variation up to values that reflect severe hypoxemia, accompanied or not by hypercapnia.

2. Concept

Asthma is a chronic inflammatory disease in the airways. This state of chronic inflammation causes bronchial hyperresponsiveness, which leads to the narrowing of the conductive airways with airflow obstruction, which can be reversible spontaneously or with treatment. Asthma is a syndrome that includes various clinical phenotypes that share similar clinical manifestations but of probably different etiologies. From a pragmatic point of view, it could be defined as a chronic inflammatory disease of the respiratory tract, in the pathogenesis of which various cells and inflammatory mediators are involved, conditioned in part by genetic factors and which occurs with bronchial hyperresponsiveness (BHR). In patients with asthma, during acute attacks, arterial oxygen and carbon dioxide (PaO₂ and PaCO₂) values can range from nearly normal or slightly abnormal to extremely altered, ultimately resulting in profound hypoxemia with or without hypercapnia [1, 2].

3. Pathogenesis

One of the main triggers for an acute asthma attack is exposure to an allergen, which in susceptible people causes inflammation of the respiratory airways. The inflammation is generally predominantly eosinophilic, although the involvement of other cells, such as T cells, neutrophils, and mast cells, has also been identified. Many inflammatory mediators are involved in this process, including interleukins (IL)-3, IL-4, IL-5, IL-6, IL-8, IL-10, and IL-13, leukotrienes, and granulocyte-macrophage colony-stimulating factors (GM-CSF). In cases of sudden-onset, as is often with near fatal asthma, the infiltration is usually predominantly neutrophilic.

From the physiological point of view, acute asthma has two components: an early acute aspect marked by bronchoconstriction that occurs at the smooth muscle level; this, bronchoconstriction is usually episodic (asthmatic crisis or exacerbation); and an inflammatory component that develops later and causes edema of the airways [3, 4].

3.1 Early bronchospastic response

This response develops within minutes after exposure to a certain allergen and is characterized by the degranulation of mast cells or mast cells. This degranulation causes the release of immunoreactive mediators, such as histamine, prostaglandins, leukotrienes, and proinflammatory cytokines. These mediators produce smooth muscle bronchoconstriction and can compromise any level of the tracheobronchial tree, mainly compromising the peripheral airway (less than 2 mm in diameter in an adult). Other alterations that are observed are increased capillary permeability, mucus secretion, and activation of neural reflexes. This early response is characterized by a good response to inhalation therapy with beta 2-agonists [5].

3.2 Later inflammatory response

It is currently known that the airway epithelium is not only a passive barrier but an essential part of the local immune response in the airways, bridging innate and adaptive immunity against various environmental insults [2]. The release of inflammatory mediators primes adhesion molecules on the airway epithelium and capillary endothelium, allowing inflammatory cells, such as eosinophils, neutrophils, and basophils, to adhere to the epithelium and endothelium, and subsequently migrate to the tissues of the respiratory tract. A key inflammatory cell in asthma is the eosinophil of which there are increased numbers both locally and systemically in individuals with asthma. Eosinophils release eosinophil cationic protein (ECP) and major basic protein (MBP), and both ECP and MBP can cause desquamation of the airway epithelium and expose nerve endings. This interaction promotes increased airway hyperresponsiveness in asthma. This inflammatory component can even manifest in individuals with a mild exacerbation of asthma.

Bronchospasm, mucus secretion, and edema produced in the peripheral airways increase airway resistance and obstruction, by causing, in addition to airway closure, mucous plugging, and impaired mucociliary clearance. It has been determined that airway obstruction does not occur uniformly in the different lung areas. Air trapping will lead to lung hyperinflation, ventilation/perfusion (V/Q) mismatch, and increased dead space. The lung will then inflate near the end of the inspiration on the lung compliance curve and, consequently, can have a variable degree of increase in the work of breathing.

Lung obstruction and hyperinflation, resulting from increased pulmonary and pleural pressures, together with increased mechanical forces of alveolar distension, lead to decreased alveolar perfusion. The formation of atelectasis, together with decreased perfusion, causes a V/Q imbalance in the lung units with the consequent hypoxemia and an increase in minute ventilation [5].

In this sensitization phase, inhaled allergens are captured by dendritic cells (DCs) and presented to naïve CD4+ T cells in the presence of coactivators, including epithelium-derived cytokines, which promote T helper cell activation and polarization of 2 (Th2) that produce IL-4, IL-5, and IL-13. These T2 cytokines are also produced by type 2 innate lymphoid cells (ILC2) and are prominent orchestrators of the allergic inflammatory cascade that occurs in asthma. IL-4 drives B cell isotype switching and the production of IgE, which binds to the high-affinity IgE receptor on mast cells. Re-exposure to allergens results in allergen-mediated IgE cross-linking, causing rapid activation and degranulation of mast cells. IL-5 promotes airway eosinophilia, IL-4, and IL-13 act directly on the airway epithelium to induce goblet cell metaplasia and mucus hypersecretion, and IL-13 mediates airway eosinophilia. Airway hyperresponsiveness through effects on airway smooth muscle cells [5].

3.3 Airway remodeling phenomenon

Asthma is characterized by remodeling of the airway wall: epithelial cell loss, goblet cell hyperplasia, airway smooth muscle hyperplasia and hypertrophy, and thickening of the basement membrane, with increased collagen deposition and increased vascular density.

The lesion-repair processes cause structural changes in the bronchial wall (fibrosis, hyperplasia and hypertrophy, denudation of the epithelium) that are an expression of the remodeling experienced by the asthmatic patient’s airway and will be responsible for a particular phenotype that shows worse airway control of the clinical parameters and response to treatment [3, 6].

This remodeling begins in the early stages of asthma, and a correlation has been established between the thickness of the airway wall and the severity of the disease. The thickening, along with the effects of increased vasculature, favors airway narrowing, the main long-term complication of asthma [3, 6].

Below is the basement membrane, which can increase up to five times in some asthmatic patients. This thickening has an impact on the efficacy of treatment since it correlates with limited responsiveness to glucocorticoid treatment.

Further down, we enter the submucosa, which in asthmatic patients is characterized by a marked increase in the vasculature and an increased presence of eosinophils and mast cells. These vessels are more permeable, which leads to edema and inflammation of tissues. The vasculature may contribute to the pathology of asthma in several ways: First, this increased angiogenesis with more permeable vessels may cause tissue edema and thus narrow airways; second, the exudation of plasma can aggravate local inflammation and remodeling; and third, an increased blood supply provides the hyperplastic and hypertrophied smooth muscle cells with the nutrients and oxygen necessary for their maintenance [6].

Even further down, we find the smooth muscle cells, which are the effectors that determine the diameter of the airways, causing them to relax or constrict according to different stimuli. Bronchoconstriction is the most serious symptom of an asthma attack, and these cells are the main effectors. In asthma, these cells are characterized by hypersensitivity to low doses of stimuli and hyperreactivity that produce a bronchoconstrictor response. This increased smooth muscle mass is already present in asthmatic children and youth without any signs of eosinophilic inflammation, suggesting that it could be the cause, rather than the consequence, of disease progression [6].

3.4 Other factors: Microbiome, microbiota, and asthma

It is estimated that the intestinal microbiome (a community of microorganisms that occupies a particular environment and performs a function within a specific environment) contains 150 more genes than the human being and there is a constant interaction between the two that, under normal circumstances, can thrive via symbiosis. Circumstances such as the country of origin, the route of delivery (vaginal or by cesarean section), and the use of antibiotics or lactation (maternal or artificial) influence the establishment of the microbiota.

Although we have less knowledge about how infections by viruses or bacteria, which cause many of the exacerbations of chronic respiratory diseases, modify the respiratory microbiota, recent studies have revealed the relationship between infections by certain respiratory viruses in childhood and predisposition to asthma.

When compared to that of healthy subjects, the microbiota of patients with asthma has a higher bacterial load, especially of the genus Proteobacteria, and less diversity in their lower airways. Instead, the Firmicutes and Actinobacteria genera are more common in healthy subjects. There is a relationship between the microbiota and certain characteristics of asthma, such as disease severity or resistance to treatment, as well as bronchial hyperreactivity. In fact, some of the bacteria could potentiate the allergic response of the airway. Other cohort studies, with various platforms, have shown that resistance to corticosteroids could be related to changes in the microbiome of patients. Thus, it has been shown that corticosteroid-resistant patients have a higher load of proteobacteria, including Neisseria and Hemophilus, while members of the Bradyrhizobium and Fusobacterium families predominate in corticosensitive patients [7, 8].

4. Pathophysiology of acute asthma

Various phenomena can be observed in acute asthma, the most characteristic functional alteration of asthma being increased airway resistance (Raw), particularly those located in the periphery (<2 mm in diameter). The main factors that cause a decrease in its lumen are smooth muscle contraction, mucus hypersecretion, and wall thickening due to inflammation and/or remodeling. There are also two important factors that also favor the closure of the airway in asthma: the alteration of the surfactant produced by the protein exudate of the inflammatory process, which can also undergo degradation by eosinophilic enzymes; and decreased transpulmonary pressure (TP), also called elastic recoil pressure. Under normal conditions, at the end of a passive expiration, there is a balance between the tendency of the lung to collapse and that of the ribcage to expand. The decrease in elastic recoil is important because when traction is lost in areas of the peripheral airway, they tend to close prematurely at the end of expiration, causing classic air entrapment. The classic airway changes in asthma (bronchospasm, mucus hypersecretion, inflammation, and remodeling) are added to this tendency to premature collapse. Air entrapment is manifested by an increase in residual volume at the expense of a decrease in vital capacity.

When an asthma exacerbation occurs, the lung loses elasticity, that is, the decrease in TP is accentuated, causing the equilibrium point between the lung and the rib cage to be reached at higher volumes (increased functional residual capacity [FRC]), which implies that the patient may breathe the same tidal volume, but with more inflated lungs. During forced expiration, the premature closure of the airways causes air entrapment, that is, an increase in the residual volume. If the asthmatic exacerbation is severe, regional abnormalities in ventilation may become unbalanced with respect to blood perfusion, causing hypoxemia, likewise, increased work of breathing can lead to muscle fatigue, hypoventilation, and hypercapnia [4, 9].

4.1 Bronchial obstruction

The basic functional impairment in asthma is airflow obstruction caused by a decrease in the caliber of the airway, especially during expiration. Bronchial obstruction is a diffuse and heterogeneous phenomenon, resulting from a mixture of spasm-inflammation and mucous plugs, which causes a significant reduction in airflow (peak expiratory flow, PEF, maximum expired volume in the first second of forced expiration, and FEV1). Sometimes it is found that there are no such mucous plugs, which suggests that bronchospasm alone can cause mortality asphyxia.

Although during an exacerbation, obstruction can occur at any level of the tracheobronchial tree, the peripheral airway (less than 2 mm in diameter in an adult) seems to be the main site of obstruction. Other functional abnormalities may arise from this alteration, such as increased work of breathing, alteration of lung mechanics and lung volumes, imbalance of the ventilation/perfusion (V/Q) ratio, and compromised gas exchange.

Although bronchospasm is the most important phenomenon, it would be simplistic to reduce the problem to obstruction since it underestimates the consequences that this causes on the distribution of ventilation [4, 9, 10].

4.2 Dynamic hyperinflation due to pulmonary overdistension

In acute severe asthma (ASA), the increase in airway resistance prevents the respiratory system from reaching its end-expiratory resting volume or functional residual capacity (FRC), because exhalation is incomplete, and alveolar pressure remains positive at the end of expiration. Lung hyperinflation places the diaphragm at a mechanical disadvantage, which causes the appearance of progressive pulmonary overdistension, which in turn causes an increase in end-expiratory intra-alveolar pressure (intrinsic PEEP or auto-PEEP), which is known as dynamic lung hyperinflation.

The respiratory pattern that the patient adopts in response to this is what contributes to the appearance of this phenomenon. Tachypnea and active expiration further limit expiratory flow by shortening expiratory time and dynamic airway collapse, respectively. Consequently, the balance point of the respiratory system moves to a greater volume than that of the FRC, which implies a greater workload for the inspiratory muscles, placing them in a position of mechanical disadvantage due to an unfavorable muscle length-tension relationship.

In all acute states of bronchial asthma, the ventilation/perfusion ratio (V/Q) imbalance is the main mechanism of alteration of arterial gases, being the determining factor of the degree of hypoxemia. On the other hand, hypercapnia is attributable to V/Q imbalance, although alveolar hypoventilation due to fatigability and/or weakness of the respiratory muscles also play an important role [11, 12].

4.2.1 Dynamic hyperinflation: Predisposing factors

Factors that predispose to dynamic hyperinflation are reduced expiratory time and increased respiratory rate, tidal volume, or inspiratory time. The initial tachypnea achieves an increase in minute ventilation and hypocapnia. However, the increased minute ventilation in the setting of airflow obstruction leads to dynamic hyperinflation, that is, incomplete exhalation and air-trapping. If the exhalation is incomplete, the alveolar pressure remains positive at the end of expiration; this is termed auto-positive end-expiratory pressure (PEEP). Lung hyperinflation places the diaphragm at a mechanical disadvantage [12].

A randomized placebo-controlled trial, which included 32 asthma patients on inhaled glucocorticoid therapy, showing dynamic hyperinflation, defined by a ⩾10% reduction in inspiratory capacity measured by standardized metronome-paced tachypnea test, showed that treatment with systemic glucocorticoids partly reversed dynamic hyperinflation, suggesting that it is caused by inflammatory processes that affect the airway in asthmatic patients. It was also observed that this improvement was more marked within the group of patients who presented greater eosinophilia [11].

4.2.2 Hemodynamic impact

Dynamic hyperinflation leads to hemodynamic consequences that represent the deleterious effect that air trapping causes on intrathoracic blood volume and can lead to cardiac dynamics. Pulmonary hypertension, due to compression of the pulmonary vasculature, alters the compliance of the right ventricle and causes displacement of the septum toward the left ventricle (LV). This phenomenon, known as ventricular interdependence, adds to reduced venous return’s effect on LV end-diastolic volume and leads to a drop in cardiac output. The paradoxical pulse then appears as an expression of cardiorespiratory interactions in the severe exacerbation of asthma.

5. Acute respiratory failure

In the early stages of asthma, hypoxemic respiratory failure (type I) occurs, which can be observed on arterial blood gas examination as a blood pressure of oxygen (PaO₂) less than 60 mm Hg together with a blood pressure of carbon dioxide (PaCO₂) abnormal or low. This is the most common form of respiratory failure that accompanies most acute lung diseases and is generally due to fluid filling or collapse of the alveolar units. The disease process that causes progressive airway obstruction results in decreased oxygen available in the distal airways for uptake through the pulmonary capillaries. Through hypoxic pulmonary vasoconstriction, the blood flow of these lung units decreases, but this decrease is of less magnitude than that observed in the availability of oxygen.

If the asthmatic crisis is maintained over time, it will produce a status of acute severe asthma or Asthmatic Status (ASA), which is characterized by hypercapnic respiratory failure (type II) caused by excessive CO₂ production or decreased effective alveolar ventilation and characterized by a PaCO₂ higher than 50 mm Hg. The pH depends on the bicarbonate level, which, in turn, depends on the duration of hypercapnia.

All asthmatic patients are susceptible and at risk of developing status asthmaticus, which is a life-threatening episode of asthma that is refractory to usual therapy. Recent studies report an increase in the severity and mortality associated with asthma. In the airways, inflammatory cell infiltration and activation and cytokine generation produce airway injury and edema, bronchoconstriction, and mucus plugging. The key pathophysiological consequence of severe airflow obstruction is dynamic hyperinflation. The resulting hypoxemia, tachypnea, together with increased metabolic demands on the muscles of respiration, may lead to respiratory muscle failure [12]. If this state is maintained over time, it can inevitably lead to death.

6. Conclusions

• The airway epithelium is the first line of defense against pathogenic environmental factors. Therefore, the airway epithelium plays an important role in initiating host defense and controlling immune responses in asthmatic patients.

• The key pathophysiological consequence of severe airflow obstruction is dynamic hyperinflation. Dynamic hyperinflation in asthmatic patients with increased eosinophilia has a better response to anti-inflammatory therapy and eosinophilic biologics.

• Near-fatal or fatal asthma is a catastrophic, devastating clinical condition that occurs despite an increased understanding of its pathophysiology and pathogenesis.

• The intestinal microbiota plays an important role in bronchial asthma. Compared to that of healthy subjects, the microbiota of patients with asthma presents a higher bacterial load, especially of the genus Proteobacteria, and less diversity in their lower respiratory tracts.