Contributing Authors:
Linus Kutup, Eric Hoffmeister, Benjamin Kersch, Niclas Samirae, Tobias Verdegem, Alexander Wolff, Lara Afaneh, Joana Strzlkowski, Nadine Fernandez, Katharina Weitzel
3. Inflammatory diseases of the airways – acute and chronic bronchitis, bronchiolitis.
General about lungs:
Larynx -> Trachea -> Left and right main bronchus -> these 2 bronchi enter into the lung tissue and further divide into secondary, then into tertiary bronchi -> then terminal bronchioles -> then, terminal bronchioles give rise to respiratory bronchioles which divide and give rise to alveolar ducts to which are attached many alveolar sacs with alveoli. The wall of the alveoli consists of type 1 and type 2 pneumocytes and also possesses macrophages. Close the alveoli are located the pulmonary capillaries which come from the pulmonary artery.
-> The region, that contains the alveoli, the pulmonary capillaries and the interstitial space between them is the region where the gas exchange takes place -> This region is called lung parenchyma (IMPORTANT!)
There are 2 possible diseases of the lungs:
a) obstructive lung diseases: in obstructive diseases, there is a problem somewhere above the lung parenchyma -> thus problem is somewhere in bronchioles, bronchi or trachea. Obstructive diseases often result in narrowing of the lumen of airways (mucosa swelling, increased mucus synthesis,) and thus an increased resistance to airflow results. Since inspiration is an active process, the increased resistance to airflow can be overcome by inhaling stronger. But expiration is more of a passive process, and the resistance cannot be overcome -> CO2 cannot be expired and accumulates in lungs -> more CO2 in lungs means that less CO2 leaves the blood (decreased pressure gradient for CO2 exchange) -> more CO2 in blood results in respiratory acidosis, etc.…
In individuals with diffuse obstructive disorders, pulmonary function tests show decreased maximal airflow rates during forced expiration, usually expressed as the
forced expiratory volume at 1 second (FEV1) over the forced ventilatory capacity (FVC). An FEV1/FVC ratio of less than 0.7 generally indicates airway obstruction.
Common obstructive lung diseases include emphysema, acute and chronic bronchitis, bronchiolitis, asthma, and bronchiectasis.
b) restrictive lung diseases: restrictive lung diseases are diseases of the lung parenchyma (alveoli + pulmonary capillaries + interstitial fluid). In this case, the air conduction in airways is totally normal but gas exchange in alveoli is impaired. What can impair the gas exchange in alveoli? Basically, every change in the following parameters can impair normal gas exchange:
-> change in the distance between capillary and alveoli (interstitial edema)
-> e.g., due to interstitial pneumonia
-> change in the amount of fluid in alveoli (alveolar edema)
-> e.g., due to alveolar pneumonia, left sided heart failure
-> change in the overall surface area for gas exchange:
-> atelectasis (alveoli collapse), emphysema (alveolar walls get degraded)
🡪 This will again cause abnormalities in gas exchange, and the persons will have symptoms (check pathophysiology summary for more details)
🡪 PNEUMONIA is a restrictive disease! We only call a lung infection pneumonia if the infection is in the lung parenchyma! An inflammation of e.g., bronchioles is NOT called pneumonia!!!
Emphysema can be seen as:
a) restrictive lung disease: alveolar septa get destroyed -> less membrane for gas exch.
b) obstructive lung disease: loss of recoil of lungs for expiration due to destroyed septa -> disturbance of airflow during expiration
Restrictive diseases are associated with proportionate decreases in both total lung capacity and FEV1, leading to normal FEV1/FVC ratio.
Normal histology of airways:
Starting from inside:
Lumen
Mucosa: pseudostratified columnar ciliated epithelium + goblet cells
Submucosa: many submucosal mucus glands and many capillaries
Media consists of smooth muscle cells (muscularis ?!)
Adventitia: Connective tissue, and cartilage (C-shaped) in trachea and bronchi -> at the 2 ends the C-shaped cartilage is connected with smooth muscles (posterior side of trachea) -> The cartilage cannot be found in the bronchioles anymore!!!
About the syllabus point: Acute and chronic bronchitis, bronchiolitis.
1) Acute and chronic bronchitis:
Both describe an inflammation of the Bronchi (No matter if primary, secondary or tertiary (or all together)). These 2 conditions belong to the group of obstructive lung disorders. Toxins from smoking, microorganisms, etc. cause an inflammatory response in the bronchi. The release of inflammatory mediators causes:
-> edema in mucosa -> mucosa swells and lumen become smaller
-> hypersecretion of mucus to thicken the protective mucus layer -> lumen becomes even smaller
-> contraction of muscles in the walls of bronchi -> bronchi constrict in order to get a greater chance to catch the invader/toxins -> lumen becomes even smaller
- The flow of air is heavily impaired by the narrowing of the lumen -> obstructive disease!
a) Acute bronchitis:
-> is not as important as chronic bronchitis
-> in most cases it is a viral infection, that starts with a rhinitis and that spreads down to trachea and bronchi. May lead to bacterial superinfection
-> Mucus hypersecretion, mucosal swelling and bronchoconstriction may impair respiration -> obstruction of airways
-> patient will show symptoms like productive cough (maybe with pus if bacterial superinfection occurred), fever, malaise, etc.
-> you can hear wheezes during auscultation due to obstruction of airways, if you hear crackles a few days after wheezes, this shows that the bronchitis has progressed to pneumonia
b) Chronic bronchitis:
Chronic bronchitis is defined clinically as persistent cough with sputum production for at least 3 months in at least 2 consecutive years, in the absence of any other identifiable cause.
It is very common in smokers and people who live in smog-laden cities.
Furthermore, Chronic bronchitis is one spectrum of COPD, with emphysema being the
other. Most patients lie somewhere in between the 2 spectra, having features of both.
When chronic bronchitis persists for years, it may lead to:
a) cor pulmonale and heart failure -> why? Alveoli are not ventilated well -> less oxygen in an alveolus causes reflex constriction of the supplying capillaries -> when many capillaries constrict, blood pressure in the remaining capillaries increased because more blood flows through them -> higher blood pressure in pulmonary circulation means more work for right heart -> right heart undergoes hypertrophy,etc -> this is the general mechanism how lung diseases can cause heart failure 😉
b) atypical metaplasia and dysplasia of the respiratory epithelium, providing a rich soil for cancerous transformation.
Pathogenesis of (chronic) bronchitis:
The primary or initiating factor in the genesis of chronic bronchitis is exposure to noxious or irritating inhaled substances such as tobacco smoke (90% of patients are smokers) and dust from grain, cotton, etc. Inflammation results and the inflammatory mediators cause mucus hypersecretion, which is the earliest feature of chronic bronchitis, and which is associated with hypertrophy of the submucosal
glands in the trachea and bronchi. We also see edema in mucosa and contraction of the muscles in the walls.
About infection: Infection by a microorganism does usually not initiate chronic bronchitis but is significant in maintaining it and may be critical in producing acute exacerbations. It should be recognized that cigarette smoke predisposes to chronic bronchitis in several ways. Not only does it damage airway lining cells, leading to chronic inflammation, but it also interferes with the ciliary action of the
respiratory epithelium, preventing the clearance of mucus and increasing the risk of infection.
Clinical Features of chronic bronchitis
The cardinal symptom of chronic bronchitis is a persistent cough productive of sparse sputum. For many years no other respiratory functional impairment is present, but eventually dyspnea on exertion develops. With the passage of time, and usually with continued smoking, other elements of COPD may appear, including hypercapnia, hypoxemia, and mild cyanosis (“blue bloaters”). Death may also result from further impairment of respiratory function due to superimposed acute infections.
Reid index
- Describes the ratio of the thickness of the mucous gland layer (submucosa and mucosa) to the thickness of the wall between the epithelium and the cartilage (norm 0.4)
- Is increased in conditions like chronic bronchitis, squamous metaplasia and dysplasia -> marked narrowing of bronchioles due to goblet cell metaplasia, inflammation, mucus plugging, and fibrosis
2) Bronchiolitis:
Is pretty similar to bronchitis, only that the inflammation is closer to the alveoli. There was nothing in the book and nothing in the lecture.
Bronchiolitis obliterans – in the most severe cases, obliteration of lumen due to fibrosis.
Bronchioles do not possess cartilage in their wall!!!
4. Tumors of the larynx and trachea. Laryngeal cancer
Carcinoma of the Larynx
- occurs after age 40 years and is more common in men than in women
- laryngeal cancers are typical squamous cell carcinomas
- The tumor develops directly on the vocal cords in 60% to 75% of cases but it may arise above the cords (supraglottic; 25% to 40%) or below the cords (subglottic; less than 5%)
- The glottic tumors are usually keratinizing, well- to moderately differentiated squamous cell carcinomas, although nonkeratinizing, poorly differentiated carcinomas may also be seen
- Carcinoma of the larynx manifests itself clinically with persistent hoarseness.
- The location of the tumor within the larynx has a significant bearing on prognosis
- The subglottic tumors tend to remain clinically quiescent, usually manifesting as advanced disease
- With surgery, radiation therapy, or combination treatment, many patients can be cured, but about one third die of the disease.
- The usual cause of death is infection of the distal respiratory passages or widespread metastases and cachex
5. Pneumonias – classification. Viral pneumonias – types, special morphological features.
Pneumonia: can be defined as an inflammation of the parenchyma of the lungs. Remember: parenchyma = alveoli, pulmonary capillaries and interstitial space between them.
Pneumonia (just like any other inflammation) can be caused by:
a) microorganisms (bacteria, viruses, fungi, parasites) -> usually inhaled or spreading to lungs from other site of infection in body
b) toxins (from smoking, dirty air, bacterial toxins, gastric acid in case of aspiration)
c) necrosis of cells (due to killing by bacterial toxins, viruses, etc.)
What can predispose people to pneumonia?
-> impaired function of cilli (e.g., due to toxins from smoking and due to metaplasia from smoking) -> mucus (with all the toxins and microorganisms that it ‘caught’) cannot be transported away
-> Cold -> cold air in lungs causes constriction of blood vessels -> less blood flow to lung tissue and thus less antibodies, white blood cells etc. are transported to the lung tissue -> decreased immunity in lungs and thus microorganisms can do damage easily
-> Malfunction of alveolar macrophages (caused by toxins from smoking and also alcohol)
-> Accumulation of mucus due to cystic fibrosis or due to bronchial obstruction (mucus cannot be transported away because airway lumen is obstructed)
Classification of pneumonia:
1) By the causing agent:
a) viral pneumonia,
b) bacterial pneumonia,
c) aseptic pneumonia (e.g. due to aspired gastric acid,)
2) By the exact location of the inflammation:
a) lobar/croupous pneumonia (affects the parenchyma of
one or few whole lobes)
b) bronchopneumonia (affects small patches of
parenchyma)
-> a) and b) are caused by bacteria and the inflammatory
Process (edema etc.) is inside the alveoli and the mucosa.
c) Interstitial pneumonia: mostly viral infections -> viruses
are so small, they can even enter into interstitial space
and cause inflammation there.
3) Classification by the clinical setting (most important):
This classification includes 7 different types of pneumonias! The 7 different classes are also called the 7 different pneumonia syndromes.
According to the syllabus point, we should now concentrate on viral pneumonias.
If you check the classification from above, you will see that viruses are the causative agents only for the community- acquired atypical pneumonia.
Common viral infections of the airways are caused by:
– Influenza virus types A and B (GRIPPE – Viren),
– the respiratory syncytial viruses,
– human metapneumovirus, adenovirus, rhinoviruses, rubeola, and varicella viruses.
Pathogenesis of viral pneumonia:
Any of the above-mentioned viruses can either cause an upper respiratory tract infection, recognized as the common cold, or they can cause a more severe infection of the lung parenchyma (especially the interstitial space)-> pneumonia!
All of the viruses that cause pneumonia produce disease through similar general mechanisms. These viruses have the ability to attach to and enter the cells that line the respiratory lumen.
Intracellular viral replication leads to cytopathic changes, inducing cell death and secondary inflammation. The resulting damage and impairment of local pulmonary defenses, such as mucociliary clearance, may predispose to bacterial superinfections, which are often more serious than the viral infection itself.
It is important to know that thanks to their small size, the viruses can leave the alveoli and enter into the interstitial space, where they will then enter into the pneumocytes. This means that the inflammatory process will take place entirely in the interstitial space (edema etc.) -> there will be no fluid in the alveoli -> no crackles to hear during auscultation,…
Because the viruses can also enter into the septa, and there enter into pneumocytes and cause inflammation with edema, we will see enlarged septa between alveoli.
Summary: Must-knows about viral pneumonia
Viral pneumonia presents as patchy (flecking) inflammation of lung parenchyma, especially in the septa and the interstitium.
The term “atypical” in the name ‘community acquired atypical pneumonia’ denotes:
– only moderate amount of sputum (in typical= bacterial pneumonia there is a lot of sputum)
– no physical findings of consolidation
– only moderate elevation of white cell count
– lack of alveolar exudate
Special morphological features:
1) interstitial inflammation within alveoli walls:
a) septa and interstitial space: widened and edematous, with lymphocytes -> viral infections always with lymphocytes because viruses are intracellular pathogens!
b) alveoli:
free from exudate, but may contain protein material, and the typical pink hyaline membranes
🡪 Eradication of the infection is followed by reconstruction of NORMAL lung architecture.
🡪 These changes above reflect alveolar damage similar to the alveolar damage seen DIFFUSELY in ARDS (explained at another syllabus point)
2) Superimposed bacterial infection
-> modifies the picture by causing ulcerative bronchitis and bronchiolitis
Types of viral pneumonia
-> I do not know what he means by this… in the book and in the lecture some of the viruses are explained in more detail:
About influenza:
The influenza genome encodes a number of proteins, but the most important from the
vantage point of viral virulence is the hemagglutinin and neuraminidase proteins. Hemagglutinin has three major subtypes (H1-H3), while neuraminidase has two (N1, N2). Both proteins are components of the influenza virus envelope, which consists of a lipid bilayer. Hemagglutinin is particularly important, as it serves to attach the virus to its cellular target via sialic acid residues on surface polysaccharides.
Following uptake of the virus into endosomal vesicles, acidification of the endosome triggers a conformation change in hemagglutinin that allows the viral envelope
to fuse with the host cell membrane, releasing the viral genomic RNAs into the cytoplasm of the cell. Neuraminidase in turn facilitates the release of newly formed virions that are budding from infected cells by cleaving sialic acid residues.
Neutralizing host antibodies against viral hemagglutinin and neuraminidase prevent and ameliorate, respectively, infection with the influenza virus by interfering
with these functions.
The viral genome is composed of eight single stranded RNAs, each encoding one or more proteins. The RNAs are packaged into helices by nucleoproteins that determine the influenza virus type (A, B, or C). A single subtype of influenza virus A predominates throughout the world at a given time. Epidemics of influenza are caused by spontaneous mutations that alter antigenic epitopes on the viral hemagglutinin and neuraminidase proteins. These antigenic changes (antigenic drift) result in new viral strains that are sufficiently different to elude, at least in part, antiinfluenza antibodies produced in members of the population in response to prior exposures to other flu strains. Usually, however, these new strains bear sufficient resemblance to prior strains that some members of the population are at least partially resistant to infection. By contrast, pandemics, which are longer and more widespread than
epidemics, occur when both the hemagglutinin and the neuraminidase genes are replaced through recombination with animal influenza viruses (antigenic shift). In this
instance, essentially all individuals are susceptible to the new influenza virus. Viral assembly involves packaging of each of the 8 viral RNAs into single virions, and it is easy to see how infection of an animal by two different flu types could lead to swapping of genetic material within coinfected cells, creating a completely new viral strain. Thus, the unusual genome of influenza virus ensures that antigenic shifts leading to pandemics are inevitable.
About Severe acute respiratory syndrome
Severe acute respiratory syndrome (SARS) first appeared in November 2002 in the Guangdong Province of China and subsequently spread to Hong Kong, Taiwan, Singapore, Vietnam, and Toronto, where large outbreaks also occurred.
The ease of travel between continents clearly contributed to this initial rapid spread. The epidemic went no further, however, perhaps in part because of public health measures, and the last cases of SARS were laboratory-associated infections reported in April 2004. The cause of SARS was a new coronavirus. Many upper respiratory infections are caused by coronaviruses, but the SARS virus differed from other coronaviruses because it also infected the lower respiratory tract (alveoli) and even spread throughout the body. SARS is a cardinal example of sudden emergence of a new infectious agent, but since 2004 the virus has completely disappeared
as mysteriously as its original debut. It is unknown if or when it will appear again.
There were more than 8000 cases, 774 people died.
After an incubation period of 2-10 days, the infection with this new virus begins with a dry cough, malaise, myalgias, fever and chills (mild form of SARS). Approximately 2/3 of the infected patients actually progress to SARS disease with dyspnea, tachypnea, and pleurisy and nearly 10% of patients die. 1/3 of infected patients stayed with symptoms like dry cough, fever, malaise (mild forms of SARS).
6. Acute bacterial focal pneumonias. Bronchopneumonias. Complications.
The last syllabus point was about viral pneumonia, this point now will be about bacterial pneumonia.
The bacterial pneumonia can present in 2 different forms:
a) Focal pneumonia = Bronchopneumonia -> patchy (fleckenartige) inflammation
b) Lobar/ Croupous pneumonia -> one or more entire lobes are affected
This classification may be difficult to apply in individual cases because the patterns of bronchopneumonia and lobar pneumonia may overlap. The patchy involvement of bronchopneumonia may become confluent, thus producing virtually total lobar consolidation (=solidification = hardening).
Moreover, the same organisms may produce either pattern depending on patient susceptibility. Actually, it is not so important to find out, whether the patient has bronchopneumonia or lobar pneumonia. Most important from the clinical standpoint are identification of the causative agent and determination of the extent of disease.
This syllabus point will concentrate on the focal pneumonia = bronchopneumonia.
The foci of bronchopneumonia are consolidated areas of acute suppurative (pyogenic) inflammation -> pyogenic because bacteria are the causing agents. The consolidation may be limited to one lobe but is more often multilobar and frequently bilateral. Very often, the basal parts of lungs are affected -> because of the tendency of secretions to gravitate to the lower lobes.
Macroscopically: Well-developed lesions are slightly elevated, dry, granular, gray red to yellow, and poorly delimited at their margins.
Microscopically: the reaction usually elicits a neutrophil-rich exudate that fills the bronchi, bronchioles, and adjacent alveolar spaces.
Causative agents of bronchopneumonia:
The causative agents of bronchopneumonia are the same ones as in lobar pneumonia. As explained above, it depends on the patient’s susceptibility, etc. whether the infection with a certain bacterium results in lobar pneum. or in bronchopneumonia.
Most common causative bacteria of pneumonia are:
1) Community acquired infections:
Community-acquired acute pneumonia refers to lung infection in otherwise healthy individuals that is acquired from the normal environment (in contrast to hospital
acquired pneumonia).
a) Streptococcus pneumoniae
Streptococcus pneumoniae, or pneumococcus, is the most common cause of community-acquired acute pneumonia. They are gram-positive, lancet-shaped diplococci.
Examination of Gram-stained sputum is an important step in the diagnosis of acute pneumonia. The presence of numerous neutrophils containing the typical gram-positive, lancet-shaped diplococci supports the diagnosis of pneumococcal
pneumonia, but it must be remembered that S. pneumoniae is a part of the endogenous flora in 20% of adults, and therefore false-positive results may be obtained. Isolation of pneumococci from blood cultures is more specific
but less sensitive (in the early phase of illness, only 20% to 30% of patients have positive blood cultures).
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