In acute tracheitis/bronchitis, the mucosa is red; hemorrhage can be present especially in viral infections (Fig. 6.1). Later on, in bacterial infections, purulent exudate can be seen and necrosis of the mucosa can develop (Fig. 6.2).

In acute bronchitis and tracheitis, the mucosa is infiltrated by numerous neutrophils and will show epithelial damage with/without disruption of the basal lamina (Fig. 6.3). In chronic bronchitis, lymphocytes and plasma cells dominate (Fig. 6.4), and in addition hyperplasia of smooth muscle cells is seen. In recurrent bronchitis, the basal lamina might be thickened, and smooth muscle cells are gradually replaced by fibrocytes depositing collagen, resulting in scarring of the mucosa. Hyperplasia of goblet cells of the mucosa and within bronchial glands is usually a sign of recurrent chronic bronchitis. Hyperplasia of bronchial glands does occur in those cases where the large bronchi are dominantly involved (Figs. 6.5 and 6.6). In some cases, the morphologic picture might be almost indistinguishable from asthma bronchitis. However, there are differences: squamous metaplasia and hyperplasia of bronchial glands and smooth muscle layer are quite characteristic in chronic bronchitis and chronic obstructive lung disease (COPD) and much less pronounced in asthma bronchitis, where a dense eosinophilic infiltration in the mucosa and submucosa is pronounced. However, in the course of the diseases, this might overlap [1].

In chronic recurrent bronchitis, some additional changes can occur: bronchiectasis can develop, which might pave the way for bacterial colonization and repeated bacterial infections, resulting finally in purulent bronchiectasis (Figs. 6.7 and 6.8). Another but rare finding is thickening and degeneration of nerves (Fig. 6.9). If this phenomenon is associated with a special form of chronic bronchitis and is accompanied by a characteristic type of cough, it needs to be explored.

Acute bronchitis is most often caused by bacterial or viral infection, in rare instances by inhalation of noxious gases. By far the most common cause of chronic bronchitis is tobacco smoke, followed by air pollution and occupational exposure to noxious substances (will be discussed in the chapters on pneumonia, pneumoconiosis, and environmentally induced diseases). Many of the constituents of tobacco smoke are toxic to the respiratory epithelium, especially to the ciliated cells [2]. In addition heat slows down the beating frequency of the cilia. Loss of ciliated cells and lowered beating frequency together result in prolonged contact of the toxic substances to the epithelium, followed by toxic injury of increasing numbers of cells. Air pollution now very common in megacities of the developing countries is composed of gaseous substances and particulate matter. The gaseous phase is composed of combinations of sulfuric and nitric oxides, but also low amounts of ozone and polyaromatic hydrocarbons can be found [3–5]. Within the particle fraction, many different substances can be found: coal ash particles from combustion, metal oxides from industrial waste and automobile exhaust, and silica and silicates [6–10].

Bronchial asthma is a chronic inflammatory disease of the conducting airways, in which the epithelium and cells of the innate and adaptive immune system are involved. Asthma affects approximately 300 million people worldwide, and its incidence is increasing especially in developed countries. The leading symptom is hyperreactivity of the airway smooth muscle cells. Clinically it is characterized by shortness of breath, wheezing, and chest tightness. Traditionally asthma was separated into allergic (intrinsic) and nonallergic (extrinsic) asthma, but in recent years within nonallergic asthma, several so-called endotypes have been identified. So asthma is no longer regarded as a single disease but rather a syndrome [11]. These endotypes differ with respect to genetic susceptibility, environmental risk factors, age of onset, clinical presentation, prognosis, and response to treatment [12].

A huge amount of literature has accumulated on different immune mechanisms involved in asthma. It is impossible to discuss these data in this book; therefore, the reader is directed to several relevant reviews on the subject [11–20]. Here we will try to summarize the most relevant aspects.

Allergic asthma is a Th₂-driven disease, however, in patients Th₂ ^high and Th₂ ^low clusters have been identified [21], characterized by high IL4, IL5, and IL13 and eosinophilia in blood and tissues. In Th₂ ^high clusters, there is also high IgE, which characterizes these asthma patients as driven by IL4-induced class switching of immunoglobulins synthesized by B cells – these patients will also present with a history of atopy [22]. These patients are sensitized against a wide array of allergens, such as house dust mite, tree pollen, animal dander, and fungal spores [23]. Children in a family with atopy have a higher propensity to develop asthma. These children can present with allergic eczema already within the first year of life and in a high proportion will develop asthma later in their life. A good marker for this asthma endotype is a high serum level of IL25 and periostin, which also correlates well with tissue eosinophilia [24]. In these patients, new treatment options have been opened, such as blockade of IL4 and IL5 receptors. In addition to a specific allergen-oriented immune reaction by primed lymphocytes, also cells of the innate immune system are involved: in asthma innate lymphoid cell 2 (ILC2) plays a major role. ILC2 do not have antigen-specific receptors, but they similarly produce IL13, IL5, and IL9 as Th₂ cells when stimulated by epithelial-derived IL25, IL33, and thymic stromal lymphopoietin (TSLP) [12, 25, 26]. ILC2 are activated early on after allergen exposure, but can also respond to viral infection: in influenza infection, they produce IL5 and elicit an eosinophil infiltration. A recently detected player in asthma is Th₉ cells; they secrete IL9 which is a survival factor for ILC2 and a proliferation factor for mast cells; IL9 also promotes IL4-driven antibody production by B cells.

Much research has also been done evaluating the role of regulatory T cells (Treg). Treg are decreased and functionally impaired in asthma; experimentally it has been shown that they can suppress asthma by secretion of IL10 and suppress IL17-induced bronchial hyperreactivity. However, their role is not entirely clear, probably because there are different populations of Treg acting such as ICOS1⁺Treg, which are probably the important population capable of counteracting asthma [17, 27].

One of the most important cells in asthma are dendritic cells (DCs). In the bronchial mucosa, three different types have been identified: common DC expressing CD11b⁺CD172⁺(SIRP1alpha) sufficient to induce allergic sensitization and DC expressing CD103⁺XCR1⁺ which will need additional IRF8 and BATF3 stimulation for sensitization; in contrast plasmacytoid DC counteract by inducing tolerance via FOXP3⁺ Treg [17, 18, 28]. However, DCs always interact with epithelial cells from the mucosa.

Epithelia among other functions are responsible to maintain an intact epithelial barrier. Many allergens possess a protease activity; for example, papain decreases epithelial barrier by cleaving tight junction proteins and stimulating innate cytokine response. Aspergillus fumigatus spore protease leads to fibrinogen cleavage, and these metabolites activate Toll-receptor 4 on epithelia; airway cells in response secrete IL33 and TSLP and GM-CSF, which in turn activates DC-CD11b⁺ and also ILC2. This again induces a Th₂ polarization, thus orchestrating the allergic response [16, 17, 29–31]. Some allergen also can contain an endotoxin fraction. In this case an additional Th₁ reaction is mounted. This links to so-called neutrophil asthma. An example has been shown in high exposure to diesel exhaust. This type of asthma is associated with Th₁₇ cells; secretion of IL17 is also found in exacerbation in asthmatic children, which again can be stimulated by polluted air. This simultaneous activation of Th₂ and Th₁₇ profile producing CD4⁺ cells (CD4⁺IL4⁺IL17⁺ cells) has been termed overlap syndrome [12, 32–34]. It could also be produced in experimental models.

A reduced barrier function has been shown recently by genetic studies. In atopic children, a single nucleotide polymorphism has been found for filaggrin, a protein functioning in tight junction stability; filaggrin controls the production of TSLP and IL1RL1 (the receptor for IL33); this modified protein does not function properly. In this context, nonallergic asthma caused by smoking, viral infection, and air pollution acts similarly on downregulation of the epithelial barrier function and subsequently epithelial-DC interaction.

Recently also an overlap of asthma and COPD has been described [35, 36]. Probably this again refers to a combination of Th₂ and Th17 polarization of the adaptive immune system and epithelial barrier disruption induced by cigarette smoke. However, much more has to be learned until this phenomenon is really understood. Initially mast cells were regarded as important in asthma. Recently the role of mast cells has been mainly attributed to Th₂ ^high, IgE^high, and atopy-associated asthma. But more likely basophils within the epithelia play a more prominent role. Both cells interact with eosinophils in promoting the release of cytotoxic eosinophilic granules [37]. Thus they are responsible for some of the morphologic changes seen in asthma biopsies.

The main finding of lung specimen of patients dying of asthma usually asthma attacks is hyperinsufflation of both lungs. Usually both lungs completely overlap the heart. Alveoli are visible at the surface. The pleura is normal unaffected. On cut surface, the only important finding is mucus impaction in the bronchi and bronchioles. If the lung is left for an hour, the trapped air vanishes and the lung shrinks to normal.

Biopsies or autopsy lung specimen of patients with bronchial asthma will show infiltration by eosinophils within the bronchial mucosa, spissated mucus with masses of eosinophils, Curshmann’s spirals (Figs. 6.10, 6.11, and 6.12), and different amounts of lymphocytes (depending to the disease activity). Mast cells and more important basophils highlighted by immunostains for tryptase and chymotryptase are seen in IgE^high atopic asthma. Goblet cells within the mucosa and the bronchial glands are increased; smooth muscle cells are hyperplastic in early stages, but may be replaced by fibrosis in long-standing asthma. Epithelial disruption is another characteristic feature of asthma bronchitis: the epithelial layer shows shedding of columnar cells; only basal cells remain firmly attached to the basal membrane. The basal lamina is typically thickened and on electron microscopy will show several layers, each newly formed after repair of an acute asthma attack and induced by TGF-β (also called airway remodeling; Fig. 6.13).

The major differential diagnosis is chronic bronchitis in COPD. There is no single feature which allows a certain distinction of both diseases; however, a combination of features can most likely be of help: eosinophilia, epithelial shedding, hyperplasia of smooth muscle cells, and extreme thickening of the basal membrane are together in favor of asthma bronchitis [1].