Diseases of the Respiratory System

Infectious Respiratory Disease

Pneumonia

Pneumonia is an infection of the lung parenchyma, in which the alveoli become inflamed and flooded with fluid. Pneumonia can result from a variety of organisms or causes, including bacteria, viruses, fungi, parasites, chemical- or physical injury. The disease may be classified by where it was acquired: community, hospital, or ventilator-associated. Pneumonia occurs in all age groups and is the leading cause of death in elderly and the immunocompromised. Risk for pneumonia development is elevated in individuals with other lung diseases, such as cystic fibrosis, bronchiectasis, COPD and asthma, or in cases of pre-existing diabetes or heart failure. A history of smoking, a poor ability to cough such as following a stroke, or a weak immune system may predispose development of pneumonia. Older age may be a significant risk factor, as small-volume aspiration is common during sleep within older populations. 

Community-Acquired Pneumonia

Key points

• Community-acquired pneumonia (CAP) is defined as a pneumonia contracted in the community and may be of viral or bacterial origin.
• CAP often starts with cold or flu-like symptoms and patients may also have a (productive) cough, dyspnea, fever or febrility.
• If hospitalization is required plain chest radiography and investigations to elucidate the underlying pathogen are warranted (for example a sputum culture).
• Prior to treatment it should be determined whether a patient is treated as an out or in-patient. To do so, several risk scores exist like the pneumonia severity index (PSI).
• Treatment consists of empirical antibiotic treatment. There is no need to identify the pathogen in mild cases that resolve with antibiotics.

General

Community-acquired pneumonia (CAP) is defined as pneumonia that is contracted in the community, outside of health-care facilities or in the first 48 hours after admission Around a quarter of all CAP cases are treated as inpatients and require hospitalization. Mortality is less than 5% in outpatient cases, but ranges from 10-40% in a hospitalized setting. Vaccination against the most common pneumococcal serotypes has decreased the incidence of invasive pneumococcal infections.

Epidemiology

CAP has a seasonal distribution and is seen more often in the colder season (winter or rain season).

Symptoms 

A classic CAP starts as an infection of the upper airways with cold or flu-like symptoms after which the infection spreads to the lower respiratory tract creating a rich environment for bacterial growth. Cough (productive in 75%), chest pain, fever, febrility, and difficulty in breathing (dyspnea) are all associated with CAP infection. Sputum may or may not be produced in excess. Physical exam often reveals tachypnea, tachycardia, and arterial oxygen desaturation. Elderly patients may present with confusion and muscle weakness and are easily mislabeled as a neurologic case.

Auscultation findings typically demonstrate the presence of crepitations or crackling and bronchial breath sounds. Pleural effusion or lobar consolidation may cause dullness on percussion.

Risk factors

The risk of infection is increased in patients with obstructed lungs (for example due to a foreign object), underlying lung disease, and the immunocompromised.

Cause

In more than half of the cases, the causative agent cannot be determined with certainty, partly because many patients have already started prescribed antibiotics by the time they are assessed in hospital. Streptococcus pneumoniae accounts for up to 30% of adult community-acquired pneumonie. Other commonly-isolated bacteria include Haemophilus influenzae, Legionella pneumophila, Chlamydia pneumoniae and Chlamydia psittaci, Mycoplasma pneumoniae, Staphylococcus aureus, Enterobacteriaceae en Pseudomonas aeruginosa. 

Viral cases may be mediated by the influenza virus, respiratory syncytial virus (RSV), parainfluenza virus, coronaviruses including SARS-CoV-2, human metapneumovirus and bocavirus.

Diagnosis

A pulmonary opacity on chest radiography or CT scan demonstrating airspace opacities, lobar consolidation, or alveolar and interstitial opacities are diagnostic (figure 1). 

The instigating organism can be identified in sputum culture or urinary antigen assays in about half of all cases. However, there is no evidence that identification of the organism improves treatment outcomes. Patients who require hospitalization should be subjected to further testing; a chemistry panel of serum glucose, electrolytes, urea nitrogen, bilirubin, and liver enzymes and a complete blood count. Arterial blood gasses should be investigated in patients with hypoxemia or patients with tachypnoea and a low-normal saturation of peripheral O2. 

Figure 1. Opacity (or infiltrate) on chest radiography indicative of pneumonia. Adapted from NTVG ‘Belang van de alveolaire-arteriële-zuurstofgradiënt’ 2012.

Treatment

Whether the patient is treated as an inpatient or outpatient must first be established. To this end, severity and risk of complication can be assessed with the Pneumonia Severity Index (PSI) and the CURB-65 criteria. 

Antibiotics, rest, and if needed fluids are standard for the resolution of most pneumonias. Identification of the infectious agent is not necessary in outpatient cases that resolve with empiric antibiotic therapy. Abnormal presentation and patients who require hospitalization should undergo investigative testing to find the responsible organism; identification of the organism allows for more targeted antibiotic therapy. 

However, those with other medical conditions, the elderly, or those with significant trouble breathing may require more advanced care. 

Evidence of pleural effusion may indicate the presence of pleural empyema or complicated pleural effusion which warrants chest drainage. For patients with small uncomplicated parapneumonic effusion drainage is usually not needed. Neuraminidase inhibitors may be used to treat viral pneumonia caused by influenza viruses.

Prognosis

With treatment, most types of bacterial pneumonia will stabilize in 3–6 days. It often takes a few weeks before most symptoms resolve. Chest radiography findings typically improve or clear within four weeks. Mortality is low, especially in outpatient settings (< 5%). Worsening opacities following antibiotic therapy is a poor prognostic sign and may suggest a more extensive infection (for example pulmonary abscess).

Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia

Key points

• Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are defined as lung infections that arise 48 hours after admittance to hospital or endotracheal intubation, respectively.
• HAP and VAP are quite common, and present with fever, purulent sputum and flu-like symptoms. Patients are generally quite ill.
• HAP and VAP are thought to be caused by (micro)aspiration from the oropharynx. The oropharyngeal flora may change due to drug use making it more pathogenic when it reaches the lungs.
• The golden standard for diagnosis is bronchoalveolar lavage (BAL), but this may be risky especially in non-intubated patients.
• Treatment depends on the offending organism. VAP has a very poor prognosis.

General

Hospital-acquired pneumonia (HAP) is defined as a pulmonary infection that arises more than 48 hours after admission to the hospital and excludes any previous condition or infection. Pneumonia in patients treated with intravenous antibiotics outside the hospital, receiving hemodialysis, or staying in a healthcare facility are called healthcare-associated pneumonias (HCAP). Lastly, pneumonia that develops more than 48 hours after endotracheal intubation and ventilation, is called ventilator-associated pneumonia (VAP). Because pneumonia is acquired in a hospital setting, HAP or VAP patients often face more resistant flora of bacteria than community acquired pneumonia (CAP) patients. Complications and treatment success may differ based on the original complaint of the patient.

Epidemiology

Incidence of VAP is relatively high among ventilated patients; an estimated 6-52 cases per 100 patients arise each year. HAP is thought to occur in 15% of hospitalized patients.

Symptoms

Presence of a fever, cough, and purulent sputum, accompanied by nonspecific cold/flu symptoms suggest pneumonia. Auscultation typically demonstrates the presence of crepitations or crackling and bronchial breath sounds. Pleural effusion or lobar consolidation may cause dullness on percussion.

Note that positive radiographic findings (like lung opacities) are required to rule out other infections.

Risk factors 

Endotracheal intubation poses a high risk for the development of pneumonia due to several processes. Firstly, the endotracheal tube can damage the tracheal mucosa, allowing for the colonization of bacteria. Secondly, glycocalyx biofilms are known to grow inside the tube and can become dislodged and infect the lower or upper airways. Lastly, although intubation prevents aspiration, which is the accidental inhalation of foreign materials like reflux or food, nearly all patients on ventilation experience microaspiration. 

Cause 

HAP is most probably caused by aspiration of bacteria from the oropharynx. Aspiration is common, even in healthy people who mostly do it in their sleep. However, healthy people can usually clear those bacteria with cilia of the airway epithelial cells and cough. Due to antibiotic and antacid use and malfunction of the cilia in the airway epithelial cells the bacterial flora of the oropharynx can become similar to the gut flora (more enterobacteriaceae and non-fermenters). Those microorganisms are more pathogenic for the lung than the normal flora of the oropharynx. Organisms responsible for HAP may include S. aureus (both methicillin-sensitive S. aureus and MRSA), P. aeruginosa, gram-negative rods, Enterobacter species, K. pneumoniae, and Escherichia coli species. Colonization with anaerobic species is common in HAP. VAP is associated with Acinetobacter species and Stenotrophomonas. Maltophilia.

Diagnosis

Diagnostic measures are identical to community acquired pneumonia. Clinical chemistry examinations and blood count (which may show leukocytosis) are crucial to evaluate the overall health status of the patient. However, these do not aid the identification of the organism. Sputum and gram stain cultures of respiratory tract secretions are unfortunately not always specific enough to identify the inflicting nosocomial organism and could indicate colonization or tracheobronchitis only. The golden standard for the diagnosis is bronchoalveolar lavage (BAL), which is usually not without risk, especially in patients who are not intubated. In this procedure sterile saline is instilled into a subsegment of the lung. The saline is then collected for cytological analysis and culture. Without accurate culture data, it is difficult to make antibiotic modifications.

Imaging, like plain chest radiography, may show lung opacities (see figure 1 in community acquired pneumonia). However, as HAP and VAP patients are admitted to hospital for some other illness prior to developing pneumonia, these preexisting conditions may confound imaging results.

Treatment

Each hospital should give empiric treatment according to epidemiological resistance data. Physicians should carefully assess risk for MRSA and other drug-resistant organisms and conduct an antibiogram to find antibiotic treatment the cultured bacteria are sensitive to. The species of pathogen, severity of pneumonia, and existence of other conditions are used to individualize the length of antibiotic treatments. Treatment with antibiotics for 5-7 days is usually enough. Certain bacteria, such as Pseudomonas aeruginosa, S. aureus and certain other bacteria causing atypical pneumonia (Coxiella burnetii, Mycoplasma pneumonia, Chlamydophilia, etc.) which warrants a longer course of antibiotics.

Prognosis

Prognostic outlook for patients with VAP is generally poor, with mortality rates as high as 70% of patients. Given that intubation is the largest risk for the development of pneumonia, avoidance of endotracheal intubation or reducing the duration are heavily advised. The prognosis of HAP (and HCAP) are much better but worse than in community acquired pneumonia.

Aspiration Pneumonia

Key points

• Aspiration pneumonia is an infectious complication of the inhalation of foreign materials into the lungs. 
• Aspiration pneumonitis is the lungs’ reaction to the aspiration of sterile foreign material (often gastric acid).
• Symptoms of aspiration pneumonia are similar to that of regular pneumonia: sudden onset dyspnea, a productive cough, and fever.
• Plain chest radiography may reveal a “whiteout” in chemical pneumonitis as rapidly as 6-24 hours after aspiration and consolidation in aspiration pneumonia.
• Treatment and prognosis depend on the exact underlying etiology as well as general health status and comorbidities of the patient.

General 

Aspiration pneumonia occurs as a complication to pulmonary aspiration, when foreign materials are inhaled into the respiratory tract. The aspirated material can be formed from oropharyngeal secretions, particulate matter, or gastric acids. The latter are sterile and only causes chemical pneumonitis, but the use of antacids causes greater risk of infectious pneumonia. Microorganisms that are responsible for aspiration pneumonia include S. aureus, S. pneumoniae, Enteric bacilli, Haemophilus species, Neisseria species, M. catarrhalis, and P. aeruginosa. 

Epidemiology

Due to the lack of biomarkers and similarities between etiologically distinct pneumonias, it is difficult to estimate the prevalence of aspiration pneumonia.

Symptoms 

Patients with bacterial aspiration pneumonia might present clinically with a productive cough, fever, fatigue, and dyspnea. Sputum that is discolored, with blood, or has a foul odor may be expelled during coughing. More advanced cases of pneumonia may demonstrate cyanosis of the skin, bronchopneumonia, or lung abscess. In later stages of chronic aspirations bronchiectasis can develop. Signs and symptoms of bacterial-induced disease develop over the course of days and weeks. Auscultation may reveal crackles.

In contrast, chemical pneumonitis, a consequence of the aspiration of gastric acids, presents rapidly with signs of tachypneic, tachycardic, and hypoxic without a fever.

Risk factors 

The failure of the natural defense mechanisms such as the closure of the epiglottis and impaired cough reflex. Altered mental status, neurologic disorders, esophageal motility disorders, protracted vomiting and gastro-esophageal reflux disease (GERD) may all affect the functioning of the epiglottis.

Cause 

In normal healthy adults, the mucociliary mechanism and alveolar macrophages act as defenses in clearing microaspirations from the oropharyngeal secretions. The pathological process of aspiration pneumonia occurs when the normal defenses mechanisms fail in a predisposed individual. 

The entry of fluid into the bronchi and alveolar space triggers an anti-inflammatory reaction with the release of proinflammatory cytokines, tumor necrosis factor alpha, and Interleukins. Inoculation of organisms of common flora from the oropharynx and esophagus results in the infectious process.

Diagnosis

A history suggestive of aspiration of sterile gastric acid should prompt investigations to ascertain chemical pneumonitis. On plain chest radiography chemical pneumonitis becomes apparent 6 to 24 hours after the aspiration of gastric fluids as a “whiteout.”

However, if there are clinical signs of pneumonia – i.e. sudden onset dyspnea, fever, hypoxemia, and crackles on auscultation – should raise suspicion for aspiration pneumonia. Radiological findings may reveal a consolidation, which is usually on the right side as shown in figure 2. This is the result of the normal bronchus anatomy and gravity which, if the patient is in an upright position, more easily allows for aspiration into the right lung as the foreign material “falls down”. However, patients most at risk of aspiration pneumonia are often elderly and frail and may be bedridden. In these cases, due to the supine position of the patient, aspiration pneumonia may occur anywhere in the lung.

In these patients imaging should be followed with sputum culture, complete blood count (CBC), arterial blood gas, and blood culture. 

Figure 2. Chest radiography showing aspiration pneumonia in the lower right lobe (red circle & arrow). The anatomy of the bronchial tree predisposes the lower right lobe is more often affected by aspiration than the left. Aspirated substances will more easily go down the right main bronchus as it travels almost straight down from the trachea (black arrow). The left main bronchus, on the other hand, bends off around the heart, making it more difficult for foreign substances to “fall down” it. Note that this is only the case for patients who aspirate while in an upright position. Adapted from Wikimedia Commons: chest radiography, diagram.

Treatment

Prior to treatment it should be clear whether the patient has bacterial aspiration pneumonia, food aspiration or obstruction, and/or chemical pneumonitis. A course of antibiotics is standard for bacterial pneumonia, but duration will differ based on the extent of pulmonary injury. Foreign body aspiration and mechanical obstruction usually requires bronchoscopy to remove the obstructive material.  Supportive measures, such as oxygen and fluids may also be necessary. 

Prognosis

Prognosis depends on treatment outcomes, existence of other comorbidities, and overall health status. 

Pulmonary Abscess

Key points

• Pulmonary abscess refers to necrosis of pulmonary tissue which forms cavities due to microbial infection.
• Patients may present with (bloody) and purulent cough, fever, and pleuritic chest pain. Work up should include imaging and taking blood and sputum cultures.
• Treatment consists of empiric antibiotic treatment and, if necessary, drainage or even surgery. The latter two carry considerable risk and should only be performed if absolutely necessary.
• Prognosis is good if the abscess is treated appropriately. Long-term outcomes depend on comorbidities.

General

Lung abscess is characterized by necrosis of the pulmonary tissue and formation of cavities filled with necrotic debris. Deep microbial infection precipitates necrosis. There are two types of lung abscesses: 

• Primary: the abscess results from infection of the pulmonary parenchyma. This affects otherwise healthy individuals, and is often the result of aspiration.
• Secondary: the abscess arises as a complication to a post-obstructive or systemic disease, such as a vascular emboli, tumor, or immunocompromising disorder. 

Epidemiology

Incidence has decreased tremendously due to the increased use of antibiotics. Most lung abscesses are primary in etiology, and predominantly affect older males.

Symptoms 

Symptoms typically emerge within 10 days after aspiration of infected material and closely resemble the clinical manifestations of pneumonia. Patients with acute lung abscess may present with fever, cough with purulent sputum, pleuritic chest pain, and occasional episodes of coughing up blood (hemoptysis). Many lung abscess patients have poor dental health.

Risk factors 

Alcoholism and immunocompromising disorders predispose lung abscesses.

Cause 

Primary lung abscesses result from the aspiration of bacteria into the lung parenchyma. The aspirate develops into pneumonitis; within 1-2 weeks, pneumonitis evolves into necrosis and cavitation. 

Secondary lesions may arise due to an obstruction which inhibits the clearance of bacteria or immunocompromising disease, like human immunodeficiency virus (HIV).  Due to their compromised immune system HIV patients are less likely to clear an infection after aspiration and thus more likely to develop pneumonitis and an abscess.

Diagnosis

Diagnosis of lung abscess is made based on clinical symptoms, physical examination, radiographic studies, and bacterial culture. Chest CT, as shown in figure 3, provides for the visualization of the abscess and cavitation, and can help differentiate between primary and secondary etiologies. Foul-smelling sputum is indicative of anaerobic bacterial colonization. 

Sputum and blood cultures are recommended to determine the species of bacteria, virus, or fungi. Sometimes bronchoscopy with bronchoalveolar lavage (BAL) is needed if no microbiologic diagnosis was made after noninvasive testing. 

Figure 3. Anterior-posterior (a) and lateral (b) chest radiography of a patient with a round consolidation in the left hemithorax. CT chest (c) revealed this consolidation to be a fluid filled cavity. The patient was diagnosed with a lung abscess. Adapted from NTVG ‘Een slecht gebit als oorzaak van een longabces,’ 2017.

Treatment

The mainstay of treatment is based on prompt initiation of empiric intravenous antibiotics which also targets the anaerobes. After clinical and radiological improvement the antibiotics can be switched to oral treatment guided by the susceptibility results. The optimal duration is unknown, mostly treatment is given for 3-6 weeks until chest imaging is clear or shows a stable residual lesion. Transthoracic drainage is usually not performed, since there is a risk of infecting the pleural space, pneumothorax and hemorrhage. Surgery is considered the last resort therapy when both medical treatments fail to resolve symptoms and is rarely performed. In ill patients unable to tolerate surgery, transthoracic drainage can be considered. 

Prognosis

The prognosis of lung abscess is good following successful antibiotic treatment and or surgery/drainage. The long-term outcomes depend on the other associated conditions underlying lung abscess. Although mortality is low and uncommon in primary lung abscess, comorbidity due to underlying disease is high among patients with secondary disease. 

Pleural Empyema

Key points

• Pleural empyema refers to the bacterial infiltration of accumulated pleural fluid (known as infusion), which results in an infection of the intrapleural space.
• Pleural effusion occurs in 20-40% of patients with pneumonia, however, only in 5-10% of patients the fluid becomes infected and forms empyema.
• Patients present with symptoms very similar to pneumonia, empyema should be suspected when the symptoms do not clear up despite adequate therapy.
• Diagnosis is made with imaging and obtaining some fluid for composition analysis. 
• Patients are treated with empiric antibiotics and transthoracic drains. Intrapleural fibrinolysis may help dissolve adhesions that obstruct the drainage process.

General

The pleural space is usually filled with a very small amount of fluid, which serves as a coupling system between the outer lining of the lungs (visceral pleura) and the inner lining of the thoracic cavity (parietal pleura). As the thoracic cavity expands during inhalation the fluid in between these two linings allows them to move independently of one another but still pulls the lung lining outward to match the expanding chest. The resulting negative pressure inside the lungs draws breath inward. 

Parapneumonic effusion is defined as an excess quantity of fluid in the pleural space associated with the spread of infection to the pleura from the lung infection. When the effusion gets infected it is called pleural empyema.

Epidemiology

Parapneumonic effusion affects 20-40% of patients hospitalized with pneumonia. Of these patients, 5-10% progress to develop pleural empyema.

Symptoms

Symptoms are similar to those of pneumonia, so patients often present with fever, cough, and difficulty breathing (dyspnea). Compared to ‘normal’ pneumonia, patients with empyema usually have a longer course of complaints. If patients being treated for pneumonia do not show clinical response despite appropriate antibiotics, pleural empyema of lung abscess should be considered. Auscultation may reveal decreased breath sounds and dullness on percussion.

Risk factors

Among the most common risk factors for developing complicated parapneumonic effusion or empyema are malnutrition, poor dental hygiene, drug or alcohol abuse and immunosuppression.

Cause

A pleural effusion develops when pleural fluid formation exceeds pleural fluid absorption or exceeds the rate of removal by the lymphatic system. When pleura becomes infected, leakage of fluids, proteins and leukocytes into the pleural space occur, subsequently forming a sterile parapneumonic effusion. When bacterial organisms manage to invade the pleural space it is called pleural empyema. 

Streptococcus pneumoniae, anerobes, Staphylococcus aureus, streptococci and anaerobes that colonize the oropharynx are the most common causative organisms in pleural empyema.

Diagnosis

Pleural effusion may be visualized using plain chest radiography, as shown in figure 4. 

Figure 4. Progression of pleural effusion in the left lung on chest radiography. Adapted from Wikimedia Commons by Nevit Dilman, CC BY-SA 4.0.

When a patient has pleural effusion an effort should be made to determine the cause. The first step is to determine whether the effusion is a transudate or exudate, as this helps determine what triggered the effusion. Exudate is often caused by inflammatory processes like pneumonia, malignancy, or pulmonary embolisms. Transudate, on the other hand, is more like ‘regular’ lung fluid which is pushed out of the lungs at a disproportionate rate due to fluid overload processes like heart failure or liver cirrhosis. Due to the different mechanisms of disease, the composition of the fluid will be different. Light’s criteria uses these compositional differences and if one or more criteria are met, the effusion is considered to be exudate:

• Pleural fluid protein / serum protein ratio > 0.5
• Pleural fluid lactate dehydrogenase (LDH) / serum LDH > 0.6
• Pleural LDH > ⅔ of the upper limit of normal serum LDH

When a parapneumonic exudative effusion is found the presence of following criteria this indicates an infected pleural effusion (i.e. empyema) which warrants the need for tube thoracostomy drainage: 

• Loculated pleural fluid
• Pleural fluid pH < 7.20
• Pleural fluid glucose <  3.3mmol/L
• Positive Gram stain or culture of the pleural fluid and the presence of gross pus in the pleural space.

Treatment

In pleural empyema treatment with empiric intravenous antibiotics and tube thoracostomy drainage is indicated. Clinical and radiological status should be reassessed within 24 hours. If little response is achieved it should be evaluated if antibiotic coverage is sufficient and whether all locules are adequately draining and, if needed, the chest tube(s) should be replaced or added. Additionally, intrapleural fibrinolysis may be administered. These agents dissolve adhesions in an effort to improve drainage. If these interventions don’t lead to clinical and radiological improvement surgery should be considered promptly.

Prognosis

Studies report overall mortality range from 4-55%. 

Tuberculosis

Key points

• Tuberculosis (TB) is a granulomatous infection caused by the contagious M. tuberculosis bacteria. TB is disproportionately prevalent in developing countries.
• Primary TB infection is often asymptomatic and enters a state of latency (latent tuberculosis) Latent tuberculosis is capable of being reactivated after immunosuppression in the host, called secondary tuberculosis which is characterized by cough and constitutional symptoms.
• TB is diagnosed by demonstrating the presence of M. tuberculosis on culture or using acid fast staining (Auramine, Ziehl-Neelsen) nuclear Amplification and gene-based tests. Imaging is used to determine the extent of disease.
• Treatment of active disease consists of antibiotics, these same medications may also be used to prevent reactivation of latent disease.
• Prognosis depends on therapy adherence as well as the presence of comorbidities like human immunodeficiency virus (HIV).

General 

Tuberculosis (TB) is a granulomatous infection caused by the bacteria Mycobacterium tuberculosis. TB is a contagious disease which spreads through infected droplets expelled by patients with active pulmonary disease, through coughing, speaking, or sneezing. However, only 10% of infected individuals go on to actually develop active disease themselves. The other 90% is able to clear or halt replication of the bacteria. TB replicates inside of macrophages, and the first infection is often asymptomatic. However, weeks later the infection activates cell-mediated immune systems that will start to form the typical granulomas seen in TB.

TB primarily infects the lungs (pulmonary TB) but can disseminate via the blood to any organ in the body. Disseminated TB is also called miliary TB. When TB manifests in an organ that is not the lungs it is called extrapulmonary TB. When TB manifests specifically in the spine it may be called TB-spine or Pott disease.

Epidemiology

Although tuberculosis is present globally, developing countries carry a disproportionate share of tuberculosis disease burden. Worldwide, TB is the 13th leading cause of death and the second leading infectious cause of death after COVID-19. There are around 10 million cases per year. More than half of all cases are reported in males.

Symptoms 

Pulmonary tuberculosis is divided into primary and secondary disease/reactivation TB. 

Primary pulmonary TB

When first infected with tuberculosis, most patients are asymptomatic. A minority may experience mild flu-like symptoms and rarely pleuritic or retrosternal chest pain. The speed of the progression from latent primary disease to active secondary disease largely depends on the individual’s immunocompetency; rapid evolution to active disease is often seen in malnourished individuals and HIV patients.

Secondary/reactivation pulmonary TB

In secondary tuberculosis, also called reactivation or postprimary TB, constitutional symptoms (fever, chills, night sweats, low appetite, weight loss, fatigue) and cough (including hemoptysis) are common. Fever is usually low grade initially, but becomes worse as the disease progresses. As the disease progresses cough usually worsens and becomes more productive.

Other

Miliary (disseminated) tuberculosis refers to clinical disease resulting from hematogenous dissemination of TB and can affect any organ. Symptoms of miliary disease depend on the organ affected. Extrapulmonary TB can be found in any organ but most commonly resides in the lymph nodes, pleura, genitourinary tract, or bones. Manifestations of lymphatic disease, termed tuberculous lymphadenitis, often include painless swollen lymph nodes that develop into a matted mass. This is often present in the neck, near the collarbone.

Risk factors 

Human immunodeficiency virus (HIV) and TB coinfection accounts for nearly a quarter of HIV-related deaths worldwide. All TB patients have to be tested for HIV. Damaged immunocompetency, the hallmark of HIV, creates the foundation for the proliferation of the mycobacterium. Tuberculosis is also closely tied to overcrowding populations and malnutrition, making it one of the principal diseases of poverty. 

Cause 

Mycobacterium tuberculosis is responsible for tuberculosis. The bacteria is a curved shaped, aerobic, non-encapsulated, non-motile, acid-fast bacillus with a slow replication rate (visible growth takes up to 6 weeks).

The infection is transmitted through the inhalation of infected droplets from individuals with active pulmonary TB (eg. coughing, speaking, or sneezing, etc). Once infected, 90% of patient with normal immune system, control further replication by complete clearance or keeping the TB  latent and asymptomatic for years; only about 10% of latent cases evolve to active disease within one’s lifetime (usually in the first 2 years after infection or later due to immunosuppressive drugs, organ transplantations, HIV infections, etc).

The bacteria, once inhaled, is phagocytosed by alveolar macrophages, where it remains inside a phagosome by impeding the fusion of the phagosome with the lysosome. TB replicated inside the macrophage and this eventually causes the primary tuberculosis infection, which is usually asymptomatic. A couple of weeks after the primary infection, cell-mediated immune system is activated, which forms granuloma within infected areas in order to wall-off the infection. The tissue inside the granuloma dies off, a process called caseating necrosis and forms what is called a Ghon focus. Later, mediastinal or hilar lymph nodes get affected as well, and caseous necrosis in these lymph nodes form Ghon complexes. Figure 5 gives an overview of these processes. Once the tissue encapsulated by the granuloma undergoes fibrosis and calcification it is called a Ranke complex.

Figure 5. An overview of TB’s pathogenesis. Note that in 90% of individuals TB is cleared by macrophages or remains latent, i.e. there is no replication. These patients will never have active TB. This figure represents what happens in the other 10% where TB manages to proliferate. Created with Biorender.com

Diagnosis

A definitive diagnosis of TB is made by identifying M. tuberculosis in a clinical sample (e.g., sputum, pus, or a tissue biopsy). The bacteria can be visualized using the acid-fast staining (Ziehl-Neelson, auramine staining), which stains them red, but bacterial growth takes a lot of time. Amplification of mycobacterial nucleic acid has also become the gold standard diagnostic in recent years due to the speed and accuracy associated with this method. Xpert MTB/RIF assay is recommended, as it can detect TB and rifampin resistance with remarkable sensitivity. 

The Mantoux tuberculin skin test or tuberculin PPD is often used to screen people at high risk for TB and can detect latent infection; the skin test is often recommended for healthcare workers. However, this test cannot differentiate between active and latent TB. Additionally, the Mantoux test can be false positive in those previously immunized with the Bacillus Calmette–Guérin (BCG) vaccine against tuberculosis. An alternative in these people is the interferon gamma release assay (IGRA), which does not show false positive results in people who have received the BCG vaccination. 

The chest radiograph in primary tuberculosis is often normal, while most patients with post-primary TB have abnormalities. Common abnormalities are hilar or mediastinal lymphadenopathy, lung consolidation (up to 90% in upper lobes, see figure 6), cavitations and pleural effusion. As a sign of healed primary tuberculosis Ranke complexes (fibrosis and calcifications) can be seen.

Figure 6. (a) Chest radiography showing bilateral infiltrates (white triangles) and cavity formation (black arrows), which is often seen in late stage tuberculosis. However, identifying M. tuberculosis remains the golden standard. Image (b) shows M. tuberculosis (stained red using the Ziehl-Neelson method) in a sputum sample.

Treatment

Primary prevention involves the administration of the Bacillus Calmette–Guérin (BCG) vaccine, however immunity decreases after 10 years of initial injection. As TB is uncommon in most of Europe, the United States, and Canada, BCG is administered to only those people at high risk. Part of the reasoning against the use of the vaccine is that it makes the tuberculin skin test falsely positive, reducing the test’s usefulness as a screening tool

Active TB is managed with a combination of antibiotics to reduce the risk of antibiotic resistance: a two month course of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by a 4 month combination course of isoniazid and rifampin resolves infection in 90% of patients. 

To prevent development of active infection and prevent spread of the bacteria, latent TB is treated with 6 months of isoniazid (6H), 3 months of isoniazid and rifampicine (3HR) or 4 months of rifampicine (4R). If for some reason no preventive treatment is given or the treatment could not be finished it is advised to follow up the patient with chest radiography every 6 months for 2 years.

Tuberculosis Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndromes (IRIS) refer to a condition where an infectious disease flares up patients who regain immune cell response after being immunodeficient. IRIS is typically seen in patients infected with human immunodeficiency virus (HIV) who start antiretroviral treatment (ART). As HIV is often disproportionately seen in developing countries that often also see a lot of TB; TB-IRIS is not uncommon.

In TB-IRIS, symptoms of adequately treated TB either worsen with the start of ART (paradoxical TB-IRIS) or a thus far undiagnosed TB suddenly becomes symptomatic with the start of ART (unmasking TB-IRIS). Very rarely TB-IRIS affects patients who have not been infected with HIV.

To prevent TB-IRIS, ART should ideally be initiated by 8 to 12 weeks after TB treatment initiation for patients with CD4 count ≥ 50/mm3 and within the first 2 weeks of TB treatment for patients with CD4 < 50/mm3.

Prognosis

Recurrence of a more resistant form of TB may arise if the bacteria is not fully eliminated. Impediments to treatment often involve non-adherence to the antibiotic regimen. Patients should be closely followed with social support services and medical intervention to ensure that the treatment is followed consistently.

Non-Tuberculous Mycobacteria

Nontuberculous mycobacteria (NTM) are mycobacterial species other than Mycobacterium tuberculosis and Mycobacterium leprae. These patients usually present with a productive cough and dyspnea. B symptoms like night sweats, fever, weight loss, and fatigue may also be present but are less common.

For diagnosis to be made patients are required to have pulmonary or systemic symptoms with nodular, cavitary opacities or bronchiectasis on imaging. Additionally, there should be positive culture results from at least two separate sputum samples or at least one positive culture result from a bronchial wash or lavage (BAL).

Pulmonary disease is caused mostly by Mycobacterium avium complex, Mycobacterium abscessus and Mycobacterium kansasii. Pulmonary NTM infections are treated until sputum cultures are negative for at least 12 consecutive months. Since this treatment course is long and difficult to tolerate, only patients who meet the clinical, radiographic and microbiologic criteria should be treated. Figure 7 below ranks NTM according to their clinical relevance: i.e. bacteria on the right end of the spectrum are very clinically relevant and warrant treatment while those on the left rarely cause disease.

Figure 7. Clinical relevance of species of NTM. The percentage bar on the horizontal axis represents the percentage of cases who met diagnostic criteria for NTM pulmonary disease. Credit: adaption form Ingen et al. (Thorax 2009) by Vande Weygaerde et al. (BMC Infectious Diseases, CC BY 4.), reproduced with permission.

Fungal Infection

Key points

• Fungi are opportunistic organisms and generally do not become pathogenic unless the immune system is compromised.
• Pulmonary fungal infection may lead to non-specific symptoms like fever, chills, fatigue, and cough. However, some fungal species also cause systemic manifestations of the skin, joints, nervous system, or affect coagulation.
• Pneumocystis pneumonia (PCP) is commonly seen in the immunocompromised and caused by Pneumocystis Jirovecii. In many immunocompetent patients the fungus is present but does not cause any symptoms.
• Most findings in PCP are non-specific, however, detection of round cysts (6 to 8mm) in biopsy, brushing or lavage is diagnostic.
• PCP can be treated with trimethoprim-cotrimoxazole, and by ways of prevention most immunocompromised individuals receive these antibiotics prophylactically. 

Fungal infection of the lungs can be caused by different fungal species. Species like Coccidioides immitis, Blastomyces dermatitidis, and Histoplasma capsulatum are implicated in disseminated fungal pulmonary disease. Fungi are opportunistic organisms, and normally only become pathogenic when changes in the host immune function, such as radiotherapy, corticosteroids, or antineoplastic drugs, permit colonization.

Nonspecific symptoms of fever, chills, fatigue, or cough are commonly observed. Extrapulmonary manifestations are notable in coccidioimycosis; bones and joint pain, cranial neuropathies, and dysuria may also be evident. Skin lesions are pronounced in disseminated blastomycosis and represent late stages of disease. Disseminated histoplasmosis presents with features of sepsis, acute respiratory distress syndrome and intravascular coagulation. 

Diagnosis requires the identification of the fungal organism through isolation in respiratory secretions, pus, or lung tissue. Chest radiography typically depicts hilar adenopathy. 

Fungal respiratory infections can be treated swiftly with a course of antifungal medication. However, surgical debridement may be necessary if fungi colonize other organ systems. 

Figure 8. Bone marrow biopsy showing a macrophage infiltrated with Histoplasma spp. Image adapted from NTVG ‘Histoplasmose bij een patient met sarcoidose, ‘2022. 

Pneumocystis Pneumonia

Pneumocystis pneumonia (PCP) is a fungal infection caused by Pneumocystis Jirovecii that most commonly affects immunocompromised individuals, such as those with human immunodeficiency virus (HIV), cancer, or transplant recipients. Pneumocystis is thought to be transmitted from person to person via inhalation of the organism; and immunocompetent individuals normally remain asymptomatic for years until the infection is reactivated. Early stages of disease are characteristic of nonspecific pulmonary illness. Fever, tachypnea, dyspnea, and an unproductive cough are the most common manifestations and progressively worsen throughout the course of disease. No classic exam findings point directly to a Pneumocystis infection; the exam may reveal crackles and rhonchi on auscultation, but many cases will have normal and clear lung sounds. Other common physical exam findings include associated dyspnea, tachypnea, and tachycardia. Hypoxemia is a hallmark sign in immunocompromised children. Respiratory failure will ensue if sufficient treatment is not provided. 

Laboratory findings can be nonspecific for PCP; most notable is an elevated serum lactate dehydrogenase (LDH), which indicates general pulmonary injury. A chest radiograph will typically reveal diffuse bilateral perihilar interstitial infiltrates in advanced disease, but is normal in early stages. A definitive diagnosis requires detection of 6-8 mm round cysts in lung biopsy, bronchial brushings, alveolar washings, induced sputum, or tracheal aspirates (figure 9). 

Figure 9. Microscopic imaging of the round cysts found in PCP. Adapted from NTVG: Pneumocystis-pneumonie tijdens behandeling met infliximab voor actieve Crohn-colitis, 2005.

The first-line treatment choice for both HIV-infected and uninfected patients is trimethoprim-sulfamethoxazole. Two to three days after starting antiPJP treatment, hypoxemia of patients often worsens because of increased inflammation in the lungs as a reaction to pneumocystis particles from killed organisms. Therefore patients with hypoxemia are also started with corticosteroids to help control the increased inflammation. Prophylactic therapies can also be employed in at-risk populations; a course of trimethoprim-sulfamethoxazole is advised in children receiving chemotherapy, high-dose corticosteroids, organ transplants, and those with active HIV infection.

SARS-CoV-2

Key points

• SARS-CoV-2 is a respiratory virus that caused a global pandemic in 2019/2020 that was declared a public health emergency of international concern.
• The virus enters the body through the angiotensin converting enzyme 2 (ACE 2) receptors on epithelial cells. In the cell it replicates and spreads through the body.
• It may cause a range of (typical viral) symptoms, commonly loss of taste and smell, muscle pain, dyspnea, cough, headaches and/or fatigue. However, some patients experience more severe disease with hypoxemia and respiratory distress.
• Roughly one fifth of patients experience disease severe enough to warrant hospitalization, and a minority will need invasive ventilation.
• Recovery rates are good in those with mild disease, however, in severe disease SARS-CoV-2 can lead to death. A subgroup of infected individuals report long covid complaints (like fatigue, dyspnea, or sensory overload) that persists after the initial infection has cleared.

General

Coronaviruses are prevalent worldwide and were, prior to 2019, regarded as ‘regular’ flu viruses. In 2019/2020 the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain of coronavirus (sometimes dubbed Covid-19 or simply corona) caused a global pandemic which resulted in an excess mortality of 3 million in 2020 alone. This led to the world health organization to mark it as a public health emergency of international concern. People suddenly had to conform to strict isolation measures and global travel was halted by rigorous travel regulations. Additionally, the pandemic brought about massive shortages in personal protective equipment (PPE), as demand grew when millions of potential SARS-CoV-2 patients needed to be assessed while protecting healthcare workers from contracting the virus.

Epidemiology

–

Symptoms

Since its appearance, different strains of the SARS-CoV-2 virus have been identified. Each strain had its own characteristics, but in general would lead to symptoms ranging from the common cold to severe respiratory distress necessitating invasive ventilation. Roughly 80% of patients only experience mild disease which ranges from asymptomatic to experiencing symptoms like cough, nasal congestion, muscle pain, headaches, fatigue, and typically loss of taste (ageusia) and smell (partial loss is termed hyposmia and a total loss anosmia). Although most patients present with these respiratory (upper) airway infection symptoms, some patients experience more gastro-intestinal complaints like diarrhea. 

The remaining 20% of patients have more severe disease. They may experience dyspnea (though in the first wave of SARS-CoV-2 the dyspnea sensation was notably absent in spite of hypoxia) and respiratory distress. A quarter of these patients become critically ill and require treatment in an intensive care setting.

Different strains of SARS-CoV-2 also led to increased thrombogenicity (in varying degrees), which meant that some patients experienced dyspnea not only from infiltrative changes in the lungs but also as a result of pulmonary embolisms. 

Risk factors

Although anyone can contract the SARS-CoV-2 virus, smoking, obesity, and/or pre-existing heart or lung disease increase the risk of severe disease.

Causes

SARS-CoV-2 originated in Wuhan China, and the virus mainly spreads through inhalation of airborne particles or infected droplets. Once ingested the viral particles can bind to oral and/or respiratory cells of the ciliated epithelium utilizing the angiotensin-converting enzyme 2 (ACE2) receptor. This allows for entry into the cell, where the viral particle releases its RNA and stimulates formation of new viral proteins. These are then packaged up again and released into the body.

The virus may directly damage cells (like respiratory pneumocytes, hepatic cholangiocytes, or cardiac cardiomyocytes) through inflammation or damage. Lymphocyte or leukocyte infiltration in response to inflammation may cause further damage and in extreme cases even organ failure. In terms of organ systems SARS-CoV-2 may affect different types of organs as shown in figure 10.
Figure 10. Potential effects of SARS-CoV-2 on different organ systems. Source: Wikimedia Commons by Grégorie Lebeau, Damien Vagner, Étienne Frumence, Xavier Guillot, Estelle Nobécourt, Loïc Raffray, and Philippe Gasque – Lebeau, G.; Vagner, D.; Frumence, É.; Ah-Pine, F.; Guillot, X.; Nobécourt, E.; Raffray, L.; Gasque, P. Deciphering SARS-CoV-2 Virologic and Immunologic Features. Int. J. Mol. Sci. 2020, 21, 5932.

Diagnosis

Patients with SARS-CoV-2 may present with a wide-range of symptoms. A nasopharyngeal swab may be used to demonstrate viral particles utilizing a polymerase chain reaction (PCR). The more viral particles are present at the time of testing, the fewer cycle times (Ct) are necessary to establish SARS-CoV-2’s presence. However, there is evidence that patients who have been through (mild) coronavirus infection may still test positive despite no longer being infectious. However, while they are clearing the virus the particles may still be detected.

Other parameters that may indicate a SARS-CoV-2 infection are elevated inflammation parameters like leukocytosis and C-reactive protein (CRP). The white blood cell differential may reveal lymphocytopenia.

Imaging studies like chest CT scans may also be used to diagnose SARS-CoV-2 infection, and infection looks different throughout the course of disease. In early infection bilateral multilobular, asymmetric, peripheral or posterior ground-glass opacities may be seen. When combined with thickened inter- or intralobular lines this ground glass pattern forms a pattern called crazy paving. Subpleural involvement, traction bronchiectasis and pleural thickening are less common and can occur in later stages. It should be noted that these findings can also be found in other respiratory viral infections, so imaging alone is not sufficient to diagnose SARS-CoV-2.

Treatment

Paxlovid, a combination of the antiviral drugs nirmatrelvir/ritonavir, can be used in patients who do not need to be hospitalized. This treatment strategy is generally reserved for immunocompromised patients as they are at risk of severe SARS-CoV-2. 

Dysregulation of the immun eresponse plays an important role in the pathophysiology of COVID-19. Hospitalized patients that need oxygen therapy are treated with (intravenous) dexamethasone to mitigate risk of death. This treatment strategy relies on the fact that dysregulation of the immune response plays an important role in the pathophysiology of SARS-Cov-2. If patients need a lot of supplemental oxygen or worsen within 24 hours after starting dexamethasone therapy, interleukin (IL)-6 antagonists (like tocilizumab or sarilumab) may be used. Before starting IL-6 antagonists other reasons for respiratory deterioration should be excluded (for example bacterial superinfection or pulmonary embolism). 

Immunocompromised patients may benefit from monoclonal antibodies even when they are not severely ill.

Prognosis

Since severity of SARS-CoV-2 infection varies, prognosis also ranges from complete recovery in a few weeks to death. The risk of death is greatest in elderly patients or those with significant comorbidities like pre existing heart or lung disease, obesity, or those who are immunocompromised.

Long covid

A subset of patients experience symptoms after the initial infection has waned, appropriately dubbed long covid. These symptoms range from (extreme) fatigue, exercise intolerance, dyspnea, and/or sensory overload. It should be noted that these wide-ranging symptoms may affect anyone, even those who had mild disease during the initial infection. Little is known about long covid and while some patients recover or experience some alleviation of symptoms, others have suffered from debilitating fatigue or dyspnea for months to years. The mechanisms behind the syndrome have not yet been elucidated, despite global research efforts. This makes it difficult to devise treatment strategies for those suffering from long covid. 

Bronchiectasis

Key points

• Bronchiectasis refers to irreversible dilation of the bronchial airways as a result of chronic inflammation. This may be due to various causes including (bacterial) infection, cystic fibrosis, or airway obstruction.
• The dilation leads to impaired mucus transport and leads to patients presenting with purulent cough and sometimes chest pain.
• Diagnosis is made primarily on CT which may yield characteristic findings.
• Treatment consists of addressing the primary cause of the bronchiectasis as well as interventions that aim to clear mucus like chest physiotherapy and mucolytics.

General 

Bronchiectasis is a chronic condition characterized by the irreversible dilation of the bronchial airways and impairment of mucociliary transport mechanism due to repeated inflammation of the bronchial tree. It is often seen in patients with recurrent infections, as is common in the immunocompromised, or with underlying lung pathology like cystic fibrosis.

Epidemiology

Bronchiectasis is found in every age group, but prevalence does increase with age. Recent evidence shows that bronchiectasis disproportionately affects female patients and older individuals.

Symptoms 

History of a long-standing cough with purulence, coughing up blood (hemoptysis), and pleuritic chest pain are typical of bronchiectasis. Patients may report recurrent pulmonary infections that require antibiotics. Progressive dyspnea, intermittent wheezing, and associated fatigue and weight loss are common. 

In acute exacerbation of bronchiectasis patients could have fever, increased cough, dyspnea, and changes in sputum production.

Auscultation typically reveals crackling at the base of the lungs with diffuse rhonchi.

Risk factors 

Diseases that predispose to recurrent respiratory infections are risk factors. These include tuberculosis, cystic fibrosis as well as disease affecting immunocompetency.

Cause 

Chronic dilation of bronchi in bronchiectasis is caused by chronic inflammation, which has many different etiologies. They include lung infections (childhood infections or recurrent infections), defective host defense (human immunodeficiency virus (HIV), common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), etc), cystic fibrosis, allergic bronchopulmonary aspergillosis (ABPA), auto-immune disease, gastro-esophageal reflux, aspirations, airway obstruction (eg foreign body aspiration or endobronchial tumor), alpha-1 antitrypsin deficiency. Chronic inflammation causes impaired mucociliary clearance, leading to mucus hypersecretion and obstruction. Bacteria can get trapped in the mucus clogged in the airways and cause pneumonia, which can cause further destruction and dilatation of the airways which in turn worsens the bronchiectasis (figure 11).  Bronchiectasis is instigated by a bacterial infection within the bronchi that causes chronic inflammation and coughing. Colonization and infection, step 3 in figure 11, are often caused by H influenzae, P aeruginosa, S pneumoniae, and Staphylococcus aureus organisms. 

Figure 11. Changes seen in bronchiectasis. An initial bacterial infection triggers inflammation that starts off a vicious cycle in which changes in the airways predispose to further colonization and infection of the bronchus which causes further destruction. Adapted from: bronchiectasis toolbox, created with Biorender.com.

Diagnosis

Diagnosis is made by the presentation of a chronic cough and heightened sputum output, as well as characteristic imaging findings. Unremarkable chest radiography does not exclude clinically significant bronchiectasis, therefore CT with high resolution is the best imaging modality. Positive imaging studies feature dilated and enlarged bronchi that resemble train tracks or rings due to scattered areas of opacity (figure 12). The absence of bronchial tapering, thickening of the bronchial wall, and a tree-in-bud pattern also hint to bronchiectasis. 

Figure 12. High-resolution CT images of different types of bronchiectasis. Image (a) shows cylindrical bronchiectasis, image (b) varicose bronchiectasis, and image (c) shows cystic bronchiectasis which often have air-fluid levels. Credit: CT images and interpretation adapted from NTVG ‘ Diagnostiek en behandeling van bronchiëctasieën,’ 2004. Drawn interpretation of bronchiectasis types courtesy of Frank Gaillard, Radiopaedia, the case.

After finding bronchiectasis it is important to search for underlying etiology with laboratory tests  (complete blood count with differential, excluding auto-immune diseases and immune deficiencies, testing for cystic fibrosis, etc.). Sputum smear and culture for bacteria, mycobacteria and fungi should also be performed. Pulmonary function test can show decreased forced expiratory volume (FEV1), maximum vital capacity (VCmax), and reduced diffusion capacity of the lungs for carbon monoxide (DLCO).

Treatment

The first step in treatment of bronchiectasis is addressing the underlying etiology. Bacterial-induced bronchiectasis should be treated with a course of aggressive antibiotics guided by sputum culture. Patients with cystic fibrosis-induced bronchiectasis may be treated with mucolytic dornase (DNase).

These treatments should be followed closely with interventions that optimize mucus clearance. This includes inhaled bronchodilators as well as inhaled 3% NaCl of mucolytics. The latter hydrates the mucosa and lowers the viscosity of the mucus. Additionally, chest physiotherapy is key. Interventions like postural drainage and chest percussion help clear mucus and are of great value in reducing the frequency of cough and amount of sputum.

Bronchiectasis exacerbations caused by bacterial infections are similarly treated with antibiotics. In patients with frequent and serious exacerbations and maximal conservative therapy, long-term macrolides treatment may be considered in an effort to prevent infection. Advanced cases may be considered for surgery where focal areas of affected lung may be resected. Very severe cases may warrant lung transplantation.

A course of aggressive antibiotics guided by sputum culture is the gold standard treatment of bacterial-induced bronchiectasis. Antibiotics should be followed closely by inhaled bronchodilators with daily chest physiotherapy with postural drainage and chest percussion. These mucus clearance interventions are of great value in reducing the frequency of cough and amount of sputum. Chest physiotherapy may be replaced with a handheld flutter valve device to eliminate sputum. Inhalation of 3% NaCl of mucolytics can be used to hydrate the mucosa and lower the viscosity of the mucus. 

Medical treatment with mucolytic dornase (DNase) is advised in cystic fibrosis (CF) related cases, however should not be given to patients without CF. Infection with nontuberculous mycobacterium make the treatment difficult, as the bacterium resists antibiotic therapy. A course of antibiotics guided by sputum culture is the standard treatment of bacterial-induced exacerbation of bronchiectasis. Antibiotics should be followed closely with daily chest physiotherapy with postural drainage and chest percussion, and inhaled bronchodilators. In patients with frequent and serious exacerbations and maximal conservative therapy treatment with long term macrolides treatment can be considered. 

Surgery to resect focal areas and lung transplantation are reserved for advanced cases. 

Obstructive Lung Disease

Asthma

Key points

• Asthma is reversible airway inflammation often as a result of an environmental trigger. Most patients are diagnosed before the age of 14.
• The inflammation narrows the airways resulting in characteristic findings like wheezing, dyspnea, and chest tightness.
• A clinical diagnosis is made when asthmatic symptoms rapidly respond to the use of bronchodilator therapy. The diagnosis requires a history or current presence of respiratory signs and symptoms consistent with asthma, combined with the demonstration of variable airflow obstruction.  
• Treatment follows a stepwise approach starting with inhaled corticosteroids combined with long-acting bronchodilators or inhaled corticosteroids only. The more severe the disease is, the more tailored the approach becomes.

General 

Asthma is defined as a condition of reversible airway obstruction (bronchial hyperreactivity), often following exposure to an environmental trigger. Common stimulants may include dust, cold air, mold, pollen, animal hair, exercise, or stress. Asthma can be induced by occupational irritants and air pollution as well. Disease is characterized by the history of respiratory symptoms (such as wheeze, shortness of breath, chest tightness and cough) that vary over time and intensity, together with variable expiratory airflow limitation.

Epidemiology

Approximately 8-12% of the population have some degree of asthma, with a majority diagnosed in those younger than 14 years of age. In childhood there is 2:1 male/female predominance, but this equalizes by age 30. Mortality from asthma has decreased substantially since the use of inhaled corticosteroids.

Symptoms

Classic symptoms include prolonged expiratory wheeze, which is the result of air being forced out through the narrowed airways (the force causes the wheeze). As this takes longer than normal the expiration is said to be prolonged. Wheezing may be audible without a stethoscope. Additionally, cough and shortness of breath, may also be present. Symptoms often follow a circadian rhythm and worsen in the night and early morning. The patient’s posture may also reveal an asthmatic episode; the use of accessory muscles to aid chest expansion and ventilation is often observed in patients.

A rapid reduction of symptoms in response to bronchodilator therapy is enough to make a positive clinical diagnosis of bronchial hyperreactivity. If there is no response to medication, other respiratory diseases should be evaluated. It should be noted that although most diagnoses of asthma are made in a pediatric population, the diagnosis is difficult to make in children under the age of 4. Asthmatic symptoms in this population may respond to bronchodilators but are diagnosed as viral induced wheezing. Often, children outgrow these asthmatic ‘attacks’ and do not develop asthma. Some other children with viral induced wheezing will develop asthma. A genetic predisposition to allergic symptoms (known as atopy, which includes eczema, allergies to pollen; or a positive family history of atopy) are poor prognostic factors in the risk of developing asthma at a later age.

Frequency of asthma attacks vary in each individual; some remain asymptomatic between episodes, while others have mild continuous symptoms.

Severe asthma (status asthmaticus) attacks are often accompanied with reduced breath sounds evident on auscultation and absent wheezing. When nothing can be heard on auscultation this may be described as a silent chest, which is a medical emergency. Accessory muscles may become visible and a paradoxical pulse may develop. Acute attacks may be life threatening and respond poorly to inhalers. Cyanosis and breathlessness may be evident.

Risk factors 

Numerous risk factors, such as exercise, atopy and/or irritant exposure, obesity and certain medications have been identified to play a role in the development of asthma. Besides environmental factors, a variety of infectious and genetic factors also determine whether individuals progress to asthma.

Cause 

Asthma onset may be due to atopic or non-atopic factors. Exposure to different triggers elicits inflammation and mucosa production, thickening or occluding the airway. The cells that play an important role in the inflammatory response are mast cells, eosinophils, lymphocytes and airway epithelial cells. These cells can induce mediators and cytokines leading to inflammtory reaction involving bronchoconstriction, increased mucus production, impaired mucociliary transport, vascular congestion and oedema. As a result, the (smallest) airways narrow creating the classic symptoms of asthma, as shown in figure 13.
Figure 13. Effects of asthma on the small airways (bronchioles). Adapted from Wikimedia Commons.

Diagnosis

Asthma should be considered in those with (intermittent) asthmatic symptoms. Pulmonary function testing, also called spirometry, is important in making a diagnosis (figure 14).

Figure 14. Spirometry in different lung diseases. (a) shows spirometry as produced by a person with healthy lungs. Image (b) shows spirometry in obstructive lung diseases such as asthma where the expiration becomes concave (orange arrow). The respiration curve will normalize (i.e. more like (a)) after administering bronchodilators if the patient is asthmatic. Image (c) shows restrictive lung disease. PEF/MEF= peak or maximal expiratory flow, FEF= forced expiratory flow, FVC= forced vital capacity. Adapted from NTVG ‘COPD: denken in behandelbare kenmerken ’ 2021.

The following findings on pulmonary function test support an asthma diagnosis: 

• expiratory flow limitation which is defined as forced expiratory volume (FEV1)/ forced vital capacity (FVC) under the lower limit of normal (usually < 70) 
• excessive variability in lung function (positive bronchodilator responsiveness test, increase of > 12% and 200 ml or excessive variation in lung function after 4 weeks of anti-inflammatory treatment, in between visits or a positive histamine or methacholine provocation/challenge test.

Asthma severity is based on how difficult the disease is to treat, which will be discussed under ‘treatment.’ 

Imaging, like CT, may reveal structural changes related to the constricted airway, such as bronchial wall thickening and air trapping.

Laboratory work-up is not used to diagnose asthma but is used to determine different types of asthma and identify triggers for exacerbations or worsening asthma. Specific tests include the radioallergosorbent test (RAST) which may be used to determine if the patient has any allergies. Alternatively, a skin prick test may be used to determine environmental triggers. Additionally, arterial blood gas measurements may be used in acute exacerbations. These may show hypoxemia and/or respiratory acidosis. Respiratory acidosis or PaCO2 increase indicate imminent respiratory failure.

Treatment

There are several key types of medication in managing asthma. Beta-agonists work (primarily) on beta-2 receptors, which relax bronchial smooth muscle cells and thus dilate the bronchial airways when activated. There are short-acting beta-agonists (SABAs) and long-acting beta-agonists (LABAs).

The use of SABAs monotherapy in the management of asthma is no longer recommended, since even patients that rarely have symptoms can suddenly develop a severe asthma exacerbation. To reduce this risk, all patients should be treated with inhaled corticosteroids (ICS), preferably in combination with LABAs. The use and type of inhaled medication follows a stepwise approach as shown in figure 15. Disease severity is determined by which step of treatment is needed.

Reducing exposure to the allergen or environmental trigger is key to the decline of symptoms in chronic and intermittent conditions. Educating patients on the recognition of early symptoms and early intervention techniques is crucial to reducing the progression to acute exacerbations. In patients with allergies 

Figure 15. Stepwise approach to asthma management. Track 1 is preferred and does not use any short-acting beta-agonists (SABA). The degree of management that is needed to control a patient’s asthma also determines the severity of disease. ICS: inhaled corticosteroids, LABA: long-acting beta-agonist, **LAMA: long-acting muscarinic antagonist. Adapted from the GINA GUIDELINES 2022 with permission, created with Biorender.com

Depending on the inflammatory phenotype, severe asthma may be treated with other types of medication:

• Muscarinic antagonists have a localized relaxing effect on the bronchial smooth muscles. This results in bronchodilation. Long-acting muscarinic antagonists (LAMA) like tiotropium are used in asthmatic patients.
• Leukotriene receptor antagonists (LTRA) like montelukast inhibit antigen-triggered bronchoconstriction.
• Or low-dose azithromycin (antibiotic) and biologic agents (type 2 targeted agents: for example omalizumab for severe allergic asthma or mepolizumab for severe eosinophilic asthma).

High doses of SABA with a nebulized anticholinergic, oral corticosteroids and oxygen if needed are standard therapies of acute exacerbations. If asthma exacerbation is induced by a bacterial infection antibiotics are added. If respiratory failure nears, intubation may be necessary.

Prognosis

Asthma is manageable with proper medication and avoidance of triggers. Mortality is low, but is a risk in acute exacerbations.

Chronic Obstructive Pulmonary Disease

Key points

• Chronic obstructive pulmonary disease (COPD) is a form of obstructive lung disease most commonly caused by cigarette smoke.
• In COPD there is chronic airflow limitation and/or destruction of alveoli that may lead to chronic bronchitis, emphysema, and/or small airway disease.
• Patients may present as pink puffers: with chronic cough, pursed lip-breathing, and cachexia or as blue bloaters: with productive cough and progressive dyspnea.
• Diagnosis is made with spirometry, it shows obstructive lung disease with no reversibility after the administration of bronchodilators.
• Smoking cessation is the mainstay in treatment. Bronchodilators and anticholinergic inhalers are also used in COPD.

General

Chronic obstructive pulmonary disease (COPD) is a form of obstructive lung disease characterized by the chronic airflow limitation and/or alveolar destruction, usually caused by exposure to certain gasses and particles (most commonly cigarette smoke). Based on the underlying pathology, COPD may be classified into chronic bronchitis, emphysema, or small airway disease. However, most patients present with varying degrees of all three forms.

Hallmark features of chronic bronchitis are defined by hyperplasia and hypertrophy of the mucosal cells of the airway, inducing the abnormal secretion of mucus. Continual mucus secretion creates a chronic cough in an attempt to clear the airway.

Emphysema is marked by destruction of respiratory bronchioles, alveolar ducts, and alveoli, resulting in the expansion of air spaces. According to the areas affected it can be classified into centrilobular, panlobular, and paraseptal emphysema. 

In small airway disease-bronchiolitis, chronic inflammation in terminal bronchioles can lead to airway remodeling and eventually airway loss. However, this is not pathognomonic for COPD, small airway disease is seen in many different diseases including asthma, infections, and connective tissue diseases.

Epidemiology

COPD is one of the most common causes of respiratory failure and death and the third leading cause of death worldwide. Globally, COPD affects approximately 5% of the population in varying degrees. The disease indiscriminately affects males and females equally. 

Symptoms 

Symptoms normally emerge in middle-aged patients who have a history of cigarette smoking or living in a polluted environment. Patients generally complain of shortness of breath, wheezing, persistent cough and excess sputum production.

The different underlying etiologies can lead to distinct COPD phenotypes. Chronic bronchitis patients present with a productive cough, progressive dyspnea. On auscultation there may be crackles, wheezing and cyanosis. These patients are known as blue bloaters (figure 16). On the other hand, emphysema leads to dyspnea without coughing (or mild coughing), pursed lips-breathing, accessory muscle use, and cachexia. The pursed lips-breathing generates pressure on expiration that keeps the airways open and allows for more air to be exhaled. On auscultation there may be decreased breath sounds. These patients are commonly called pink puffers (figure 16).

Figure 16. COPD phenotypes: blue bloaters and pink puffers are specific presentations of COPD. Blue bloaters disease is predominantly caused by chronic bronchitis while pink puffers have a predominantly emphysematous lung. Created with Biorender.com

Risk factors 

Cigarette smoking or residing in areas with air pollution are the greatest determinants for disease.

Cause 

Tobacco smoking is the most common cause of COPD, with factors such as air pollution and genetics playing a smaller role in onset. Genetically-induced COPD is associated with a deficiency in alpha-1 antitrypsin. 

Diagnosis

Diagnosis requires lung function testing or spirometry (figure 17) for the identification of the airflow limitation/obstruction (forced expiratory volume (FEV1)/ forced vital capacity (FVC) less than 0.7 or less than lower limit of normal). Unlike airflow limitation in asthma, obstruction in COPD is irreversible on pre and post bronchodilator spirometry. There are however patients with COPD that also have an asthmatic component and do show some reversibility. Emphysema can also be present without obstruction in the spirometry and can be recognized by diffusion capacity of the lungs for carbon monoxide (DLCO). 

COPD severity is staged according to the GOLD ABE strategy. The GOLD stages are based on FEV1: over 80% is GOLD class 1, 50-79% is GOLD 2, 30-49% is GOLD 3, and <30% is GOLD class 4. To not underestimate the severity of symptoms and risk of exacerbations in predicting outcomes also the ABE assessment is used, which assesses symptoms by using modified medical research council (mMRC) dyspnea scale or COPD assessment test (CAT) and number of exacerbations. All patients should be tested for alpha-1 antitrypsin deficiency. In the analysis of patients with COPD usually a chest radiography is performed to evaluate for comorbidities or exclude complications of COPD. 

Figure 17. Spirometry in different lung diseases. (a) shows spirometry as produced by a person with healthy lungs. Image (b) shows spirometry in obstructive lung diseases such as asthma where the expiration becomes concave (orange arrow). The curve will not respond (much) to bronchodilators in COPD. Image (c) shows restrictive lung disease. PEF/MEF= peak or maximal expiratory flow, FEF= forced expiratory flow, FVC= forced vital capacity. Adapted from NTVG ‘COPD: denken in behandelbare kenmerken’ 2021.

Arterial blood gas may show hypoxemia and/or hypercapnia depending on the disease severity, but is often normal. Respiratory acidosis or hypoxemia can be seen, especially in patients with acute COPD exacerbation.

Furthermore, imaging modalities may be helpful in the diagnosis of COPD. A high-resolution CT scan of the chest may show the distribution of emphysema throughout the lungs and can also be useful to exclude other lung diseases. On plain chest radiography, the classic signs of COPD are overexpanded lung, a flattened diaphragm, increased retrosternal airspace, and bullae. It can also aid the exclusion of other lung diseases, such as pneumonia, pulmonary edema, lung cancer or a pneumothorax.

Treatment

Smoking cessation is the mainstay in the treatment of COPD. Pharmacologic therapies to aid in smoking cessation are heavily encouraged; nicotine replacement therapies in any form (patch, gum, lozenges, etc) or nicotinic acid receptor agonist/antagonist have shown to be very successful in reducing tobacco cigarette cravings. Enrollment in rehabilitation programs that facilitate the education of COPD, exercise, and healthy eating habits have proven to be beneficial in improving quality of life and breathing capacity.

Bronchodilators and anticholinergic inhalers are standard as pharmacologic therapies in COPD patients; although bronchodilators do not permanently restore lung function, it has been shown to improve symptoms, airflow limitation (namely by reducing hyperinflation) and exercise capacity. Combination therapy with long-acting beta-agonists (LABAs) and inhaled corticosteroids may also benefit certain patients, namely patients with history of or concomitant asthma, high blood eosinophils and multiple exacerbations/history of hospitalization. Occasionally, for patients with frequent exacerbations despite optimal therapy, treatment with macrolides (e.g. azithromycin) with anti-inflammatory effects in addition to antibiotic effect can be considered. Hypoxic patients may require long-term oxygen therapy. Patients with chronic hypercapnia/respiratory acidosis can be treated with chronic non-invasive ventilation.

If alpha-1 antitrypsin deficiency is identified in genetic testing, intravenous alpha-1 antitrypsin augmentation therapy can be undergone. Lung volume reduction by endobronchial valves or surgery can be helpful in patients with severe emphysema. In patients with severe refractory COPD/emphysema without significant comorbidities as last resort lung transplantation can be considered. 

Prognosis

The cessation of smoking, engagement in exercise regimens, and changing nutritional habits has shown to slow the decline of lung function.

Cystic Fibrosis

Key points

• Cystic fibrosis (CF) is caused by impaired chloride and sodium transport due to a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. It mostly affects Caucasians of Northern European descent.
• Screening programs make diagnosis possible prior to the onset of symptoms. Otherwise, early symptoms include meconium ileus, respiratory symptoms, and failure to thrive.
• There are five types of CFTR dysfunction and the severity of disease depends on which type of CFTR dysfunction is present.
• Diagnosis is made through sweat chloride testing and CFTR gene sequencing. 
• Treatment consists of CFTR modulators which specifically target the defective protein. Additionally, sputum thinners, bronchodilators, and chest physiotherapy are used to keep the airways clear. 
• Prognosis has improved with these interventions with survival in developed countries now up to the fourth decade of life.

General 

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel found in all exocrine tissues. The genetic mutation is implicated in the altered transport of chloride and sodium; this  changes the viscosity of mucoid secretions in the lungs, pancreas, liver and reproductive tract, leading to chronic airway infections, pancreatic insufficiency, intestinal dysfunction, dysfunction in sweat glands and urogenital dysfunction. 

In recent years the quality of life and survival of patients with CF has improved dramatically. 

Epidemiology

Most patients are diagnosed within the first 2 years of life. Due to increased newborn screening, prevalence is likely to increase in coming years. Although cystic fibrosis has been reported in all racial and ethnic groups, it mostly affects Caucasians (1 in 3,000 live births) of Northern European descent. It affects male and female patients equally.

Symptoms 

Nowadays because of newborn screening many CF patients are diagnosed prior to getting symptoms. Prior to screening the first symptoms in infants were meconium ileus where the first feces (meconium) fails to pass through the gastrointestinal system which results in obstruction, respiratory symptoms, and failure to thrive. Clinical manifestations of CF are predominantly seen in the respiratory tract and pancreas. Chronic sinusitis and nasal polyps are common. Persistent coughing with heavy sputum production and bloody cough (hemoptysis) embody most pulmonary manifestations. Chronic airway infection ultimately leads to bronchiectasis. Bacterial infection should be anticipated as respiratory injury persists; Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, Burkholderia cepacia are frequent colonists. Wheezes, crackles, and hyperresonant lungs are normally evident on examination. 

Figure 18. Due to impaired CFTR transport and function mucus changes composition and water accumulates in the cell. This dehydrates the mucus and thickens it. This affects different parts of the body where mucus plays a vital role as is shown in this figure. Created with Biorender.com

In the pancreas, the obstruction of pancreatic ducts leads to progressive tissue death; fibrotic scars and fatty tissue replacement of the dead tissue, accompanied with cyst formation and acinar tissue invasion. Exocrine pancreatic insufficiency causes fat and protein malabsorption which causes loose and fatty stools (steatorrhea) characterized by foul-smelling and frequent stools. Patients also suffer from poor weight gain and poor growth (failure to thrive) due to malabsorption and low absorption of fat-soluble vitamins (A, D, E, and K). In about 10% of CF patients defective pancreatic secretion can lead to pancreatitis. Circulating serum immunoreactive trypsinogen, the diagnostic indicator in newborn screening exams, is present because of reduced pancreatic function. Around a third of patients develop CF-induced diabetes mellitus as damage to the endocrine pancreatic infrastructure becomes more extensive.  

Abdominal distension or pain is expected as atypical mucus production interferes with the normal passage of stools through the gastrointestinal tract; meconium ileus in infants or distal intestinal obstructive syndrome adults can be detected. 

Infertility affects both men and women. At least 97% of men with cystic fibrosis are azoospermic due to obliteration of vas deferens and around 20% of women are infertile due to effects of chronic lung disease on menstrual cycle and thick mucus that blocks sperm motility.

Risk factors

–

Cause 

Cystic fibrosis is caused by an autosomal recessive mutation of CFTR; a chloride channel and regulatory protein found in all exocrine tissues. Abnormal transport of chloride, sodium and bicarbonate causes thick mucus in the lungs, pancreas, liver, reproductive tract and intestine and saltier sweat gland secretion. The class of CFTR mutation that the individual inherits predicts the degree of disease, in general classes I to III cause more severe disease:

• Class 1 dysfunction is the result of nonsense, frameshift, or splice-site mutation which leads to premature termination of the mRNA sequence. This fails to translate the genetic information into a protein product with a subsequent total absence of CFTR protein, and approximately 2% to 5% of cystic fibrosis cases result.
• Class 2 dysfunction results in abnormal post-translational processing of the CFTR protein. This step in protein processing is essential for the proper intracellular transit of the protein. As a result, CFTR is unable to be moved to the correct cellular location.
• Class 3 dysfunction is characterized by diminished protein activity in response to intracellular signaling. The result is a fully formed protein channel in the cellular membrane that is non-functional.
• Class 4 dysfunction is when the protein is produced and correctly localized to the cell surface. However, the rate of chloride ion flow and the duration of channel activation after stimulation is reduced. .
• Class 5 dysfunction is the reduced amount of functional CFTR channels in the cellular membrane as a result of rapid degradation by cellular processes. It includes mutations that alter the stability of mRNA and others that alter the stability of the mature CFTR protein.

In healthy individuals, CFTR acts as a channel spanning the cell membranes of acinar and epithelial cells and controls the movement of ions and secretions. Most of the damage in CF arises from thickened mucosal secretions which block the narrow passages of affected organs. These blockages lead to remodeling and infection in the lung, damage by accumulated digestive enzymes in the pancreas, and blockage of the intestines by thick feces.

In the respiratory epithelial cells, CFTR enables the extension of cilia, which allows for the clearance of mucus. Similarly, in airway submucosal glands, CFTR is crucial for the creation and regulation of mucus secretion. CFTR functions similarly in pancreatic acini and ducts, within the intestinal lumen, and in bile canaliculi. 

Impaired clearance of mucus alters the pH of the respiratory tract, rendering CF airways incapable at clearing bacteria; CF airways are thus often plagued by chronic respiratory infection. 

Video: 00:51 t/m 03:57

The result of all mutations is decreased secretion of chloride and consequently increased resorption of sodium into the cellular space. The increased sodium reabsorption leads to increased water resorption and manifests as thicker mucus secretions on epithelial linings and more viscous secretions from exocrine tissues. Thickened mucus secretions in nearly every organ system involved result in mucous plugging with obstruction pathologies. The most commonly affected organs include the sinuses, lungs, pancreas, biliary and hepatic systems, intestines, and sweat glands.

Diagnosis

In most developed countries newborns are screened for CF as part of a standard newborn screening panel. This offers the opportunity for early diagnosis and improved outcomes; CF newborns are found to have raised immunoreactive trypsinogen (IRT). Some cases of CF may also be discovered on prenatal ultrasound exhibiting meconium peritonitis, bowel dilation, or absent gallbladder. 

Clinical symptoms suggestive of CF (in one or many organs, as described above) OR a positive newborn screening test OR a sibling with CF, warrant further diagnosis with sweat chloride testing. When sweat chloride test ≥ 60 mmol/L (abnormal) or 30-59 mmol/L (intermediate) CFTR gene sequencing is performed. When 2 CF causing variants are found diagnosis is confirmed. When 1 or no CF variant is found, CF is still possible and the sweat test is repeated and extended DNA analysis performed. Chloride sweat test under 30 is considered normal, but if there are strongly suggestive symptoms further tests should be performed. 

In cystic fibrosis, the plain chest radiography features may overlap with many other inflammatory or destructive disorders of the airway. Classic chest radiographic findings are bronchiectasis,hyperinflation, peribronchial cuffing, mucoid impaction, cystic radiolucencies, and an increase in interstitial markings. Lung function gradually worsens in patients with progressive lung disease like CF, leading to reversible and irreversible changes in vital capacity (VCmax) and forced expiratory volume (FEV1).

Treatment

There is no cure for CF. The goals of medical therapies are aimed at reducing symptoms and improving lung function and quality of life. Various medications are used in those with CF to attain these treatment goals:

• • CFTR modulators: drugs that improve the function, production, and processing of the defective CFTR gene. This reduces exacerbations, improves lung function (FEV1), and quality of life.

• Dornase alpha (inhaled): thins the sputum in the airways which makes it easier to clear the airways. Inhaling hypertonic saline and mannitol as this helps with mucus clearance.

• Bronchodilators

• Long term antibiotics: to aggressively control respiratory infections. Azitromycin is suggested in patients with chronic P. aeruginosa infection.

Additionally, chest physiotherapy using postural drainage, chest percussion, positive expiratory pressure, flutter valve devices, vibration, and/or breathing techniques can aid in clearing the lower airways. Lung transplantation may be considered as a last-resort.

To combat the nutritional defects that arise as a result of pancreatic dysfunction, pancreatic enzyme supplements and multivitamins are used.

Prognosis

The prognosis of CF patients has crept steadily upwards and patients are now estimated to live until the fourth decade of life in developed countries such as the United States. Countries without indiscriminate newborn screenings exhibit poor prognostic outcomes due to later diagnosis and intervention; mean survival age in these countries is approximately 20 years.

Lung transplantation confers a median survival of 10 years.

Restrictive Lung Disease

Interstitial Lung Disease (ILD)

Interstitial lung disease (ILD) describes a heterogeneous collection of more than 200 lung disorders that involve the parenchyma of the lung, the alveoli, the alveolar epithelium, the capillary endothelium, and the spaces between those structures and the lymphatic tissue and the perivascular tissue.

Etiological classification is often difficult due to the heterogeneous and extensive nature of ILD. However, a useful approach can be dividing ILD into two groups based on the predominant underlying pathology:

1. Inflammation and fibrosis. Injury (due to many different triggers) to the epithelial surface causes inflammation and can eventually cause irreversible scarring/fibrosis (figure 19).
2. Granulomatous reaction. Characterized by accumulation of macrophages, T-cell lymphocytes, and epithelioid cells into structures called granuloma. Granulomatous disease can eventually also turn into fibrosis as well (figure 19).

Figure 19. Alveoli in normal healthy lungs compared to alveoli and bronchioles in pulmonary fibrosis. Created with Biorender.com

The most common ILDs are sarcoidosis (20%), idiopathic pulmonary fibrosis (IPF, 20%), pulmonary fibrosis associated with connective tissue disease (CTD-ILD, 20%) and chronic hypersensitivity pneumonitis, which is also called extrinsic allergic alveolitis (20%).

The most frequently reported symptom in ILDs is dyspnea (usually progressive exertional). Patients may also complain of non-productive cough. Chest pain is uncommon in patients with ILD. Patients with CTD-ILD can have clinical findings suggestive of a connective tissue disease. These include joint pain or swelling, musculoskeletal pain, Raynaud’s phenomenon, dry mouth or dry eyes, etc. Inspiratory crackles are typically heard on physical examination.

Relevant findings in the patient’s history are prior exposure to inhaled dust, metals, asbestos, mold, or birds, in order to detect conditions such as asbestosis, pneumoconiosis, and hypersensitivity pneumonitis. Medication and drug history to exclude drug toxicities should also be taken, accompanied by a thorough family history to detect autoimmune conditions like rheumatoid arthritis, scleroderma, Sjögren disease, or poly/ dermatomyositis, as these conditions may trigger ILD.

Extensive laboratory tests with serologic studies, chest imaging (high-resolution CT or HRCT), pulmonary function testing (spirometry) and in some cases immunological bronchoalveolar lavage (BAL) or lung biopsies are performed in order to make a specific diagnosis. 

Idiopathic Interstitial Pneumonia

Interstitial Pulmonary Fibrosis (IPF)

Key points

• Interstitial pulmonary fibrosis (IPF) causes dyspnea on exertion and a persistent cough. 
• IPF incidence increases with age, but its cause is unknown. It often occurs sporadically but there are familial cases.
• Diagnosis is made on imaging, which shows a typical picture of basal fibrosis that gradually lessens toward the apical lung fields.
• Treatment consists of antifibrotic therapy, supportive measures, and supplemental oxygen in patients with saturation < 88%.

Most common presenting symptoms of the fibrotic transformation in interstitial pulmonary fibrosis (IPF) are dyspnea on exertion and a persistent cough. On physical examination there are inspiratory crackles. Most patients are diagnosed more than a year after symptom onset due to the non-specific nature of its presentation. Of all the interstitial lung diseases, IPF has a distinctly poor prognosis.

Incidence increases with age, most commonly affecting patients in the sixth and seventh decade and occurs more often in men than women. The specific cause of IPF is unknown. Likely caused by epithelial cell injury and dysregulated repair. IPF is usually sporadic, but can also be familial like in familial pulmonary fibrosis (FPF).

The HRCT lung scan typically shows fibrosis: reticular opacities, traction bronchiectasis, honeycombing, figure 20. The fibrosis is mostly seen subpleural and with an apicobasal gradient, meaning fibrosis is predominantly seen in the basal fields, radiologically this pattern is called usual interstitial pneumonitis (UIP). Findings that are atypical for IPF are upper or mid zone predominance, extensive mat glass consolidation, nodules and mediastinal or hilar lymphadenopathy. Lung function tests reveal restrictive lung function with reduced DLCO.

Figure 20. HRCT of a patient with IPF. Adapted from NTVG ‘Idiopathische pulmonale fibrose: nieuwe inzichten’ 2015.

Treatment with antifibrotic therapy (pirfenidone or nintedanib) is recommended, since it has been shown that they reduce the rate of lung function decline and a longer time to first exacerbation. General supportive measures will include smoking cessation, pulmonary rehabilitation which can help improve functionality, and good pulmonary hygiene.  Supplemental oxygen is necessary for those who demonstrate hypoxemia (SaO2 below 88%). For relatively fit patients with minimal comorbidities as last resort lung transplantation can be considered.

Non-Idiopathic Interstitial Pulmonary Fibrosis (Non-IPF)

Key points

• Non-idiopathic interstitialpulmonary fibrosis (non-IPF) include several diseases that cause fibrosis and inflammation due to an unknown cause. 
• Non-IPF diseases are varied with different causes and different imaging results. Most are characterized by ground-glass abnormalities.
• Treatment consists of removing triggers or treating underlying disease, supportive measures, and sometimes glucocorticoid and immunosuppressive therapies.

Non-IPF diseases, their appearance on chest imaging and treatment strategies are listed in table 1 below.

Non-IPF disease	Cause	Chest imaging
Non-specific interstitial pneumonitis (NSIP)	Idiopathic or associated with connective tissue disease, drugs, human immunodeficiency virus (HIV), or hypersensitivity pneumonitis.	High-resolution CT shows bilateral, subpleural ground-glass opacities. Reticulation may be present in later stages of disease. Honeycombing is unusual.
Cryptogenic organizing pneumonia (COP)	Idiopathic or associated with connective tissue disease, drugs, malignancy, and others.	Bilateral, consolidative, or ground-glass opacities in either a patchy or diffuse distribution, many times migratory and recurrent.
Acute interstitial pneumonia (AIP)	Unknown	Similar to acute respiratory distress syndrome (ARDS)
Respiratory bronchiolitis (RB-ILD)	Related to smoking	Patchy ground-glass opacities in upper lung, or ill-defined centrilobular nodules, and bronchial wall thickening.
Desquamative interstitial pneumonitis (DIP)	Mostly related to smoking, sometimes to rheumatoid arthritis.	Ground-glass opacities.
Lymphocytic interstitial pneumonitis (LIP)	Unknown, sometimes associated with autoimmune diseases (eg, Sjögren’s syndrome, systemic lupus erythematosus) and HIV.	Ground-glass attenuation, centrilobular nodules, ground glass-consolidatiations, septal thickening. Lung cysts are also common, especially in HIV-associated LIP

Table 1. Overview of different types of non-IPF disease, their cause, and findings on chest imaging.

Treatment consists of removing any triggers (like smoking) or treating underlying disease when applicable. Glucocorticoids and immunosuppressive agents are used frequently if the lungfunction is severly impaired and/or when removing the eliciting trigger does not lead to improvement. AIP patients often need invasive ventilation and treatment with corticosteroids and empiric antibiotics is recommended. These patients have a high in-hospital mortality. In some patients progressive fibrosis similar to IPF can be observed during the course of disease. In these patients antifibrotic therapy can be considered. 

Granulomatous Interstitial Lung Disease

Sarcoidosis

Key points

• Sarcoidosis is a chronic disease that can affect multiple organ systems throughout the body. The lungs are most commonly affected.
• Non-caseating granulomas form in this disease due to an aggregation of CD4+ Th1 lymphocytes and macrophages in multiple systems
• Patients present with constitutional symptoms and symptoms of the affected organ system. Respiratory symptoms can include persistent dry cough, fatigue, and dyspnea.
• Histologic identification of noncaseating granulomas are required for the diagnosis of sarcoidosis.
• Treatment is often not necessary. However, if there is a risk of death or (permanent) disability patients may be treated with anti-inflammatory drugs such as glucocorticoids. 

General 

Sarcoidosis is a chronic, multisystem disorder of unknown etiology suggested by the presence of noncaseating granulomas most commonly in the lung, but any organ can be affected.

Epidemiology

Incidence in Europe and the United State ranges from 10 to 40 per 100.000. However, sarcoidosis occurs more commonly in African American communities, with slightly higher incidence in female patients. Clinical manifestations begin to appear between 20-40 years of age, but can also occur in children and the elderly.

Symptoms

Clinical manifestation may be only focused on the organ involved. Since the lung is almost always involved, respiratory symptoms are common. Occasionally, disease is accidentally detected on a chest radiography in asymptomatic patients. Symptoms are variable; in the acute or subacute form typically patients present with constitutional symptoms (fever, malaise, weight loss) and usually respiratory symptoms (like persistent dry cough, fatigue, vague retrosternal chest discomfort, polyarthritis and shortness of breath) that have arisen abruptly over the course of a few weeks. Iritis, peripheral neuropathy, arthritis, and cardiomyopathy are observed less commonly. 

Lymphadenopathy is very common, and though it most often involves hilar or mediastinal lymph nodes it may more rarely lead to visible lymph nodes. Erythema nodosum (EN) is identified by painful nodules on shins and is a common skin manifestation. Combination of erythema nodosum, bilateral hilar adenopathy and joint symptoms (arthritis of the ankles, knees, wrists or elbows) is called Lofgren’s syndrome. 

Insidious form develops over months, usually involving respiratory symptoms without any constitutional symptoms. This is the group of patients who most commonly develop chronic sarcoidosis with irreversible damage to the affected organ (50% develop permanent abnormalities, 5-15% progress to pulmonary fibrosis).

Other organs commonly involved are the skin (25%, most commonly is erythema nodosum, plaques, maculopapular eruption, subcutaneous nodules, or lupus pernio), eye (25% most commonly uveitis which can cause blindness), upper respiratory tract, nervous system (5%, unilateral facial paralysis, peripheral neuropathy, optic nerve dysfunction, etc.) and the heart (5% with significant heart involvement with arrhythmias and serious conduction disturbance).

Cause 

Sarcoidosis is an inflammatory disease of unknown etiology that manifests as noncaseating granulomas (due to an aggregation of CD4+Th1 lymphocytes and macrophages) in multiple systems. Various associations have been described, including occupational and environmental exposures to beryllium, dust, and other agents causing asthma. Various microorganisms like mycobacteria and propionibacteria have been associated.

Genetic components and disease in more than one family member are usually related with antigens of the major histocompatibility complex (MHC), especially DR alleles. Few studies have described other less common genomes and angiotensin converting enzyme genotypes in few patients.

Cytokines, including Th1, interleukin (IL) 2, IL6, IL 8, IL12, IL 18, IL 27, and interferon (IFN) gamma, and tumor necrosis factor (TNF) alpha are closely associated with formation of granulomas in sarcoidosis.

Diagnosis

Diagnosis is made by combination of clinical, radiography and histology findings. Pulmonary function test, electrocardiogram (and transthoracic echocardiography may be indicated in patients with chronic exercise intolerance or suspected pulmonary hypertension. The first often reveals reduced forced vital capacity (FVC) and reduced diffusing capacity of the lungs for carbon monoxide (DLCO). 

Laboratory tests are not specific, hypercalcemia or hypercalciuria are present in 5% and 20% of cases, respectively. Furthermore, erythrocyte sedimentation rates (ESR), angiotensin-converting enzyme (ACE) levels and soluble interleukin 2 receptor (sIL-2R) are typically markedly increased. Mantoux testing or iGRA/Quantiferon should always be tested.

Thoracic sarcoidosis can be staged on a chest radiography by using the Scadding criteria:

• Stage 1: no abnormalities on chest radiography. Represents 5-15% of patients at presentation.
• Stage 2: hilar or mediastinal lymphadenopathy, 25-60% of patients at presentation.
• Stage 3: lung parenchymal involvement without lymph node involvement (adenopathy), 10-15% at presentation.
• Stage 4: end stage disease/ lung fibrosis, 5% at presentation.

Of note, high-resolution (HR) CT of the chest and positron emission tomography (PET) CT provide more information to guide severity and/or treatment. In lung involvement HRCT can help visualize abnormalities ranging from bilateral hilar or mediastinal adenopathy, hilar adenopathy with parenchymal infiltration to end stage sarcoidosis with pulmonary fibrosis. A galaxy sign can sometimes be seen when granulomas coalesce (figure 21). 

Figure 21. (a) Chest x-ray images demonstrating a bilateral reticulonodular interstitial pattern, both lung hila are enlarged. (b) Chest CT of the same patient, again the bilateral reticulonodular pattern is visible as well as bilateral hilar and mediastinal lymphadenopathy. (c) Chest CT of a different patient which shows the ‘galaxy sign’ that can sometimes be seen in sarcoidosis. Adapted from NTVG ‘Een paradox: sarcoïdose bij een HIV positieve patiënt’ 2015 and NTVG ‘Een man met het ‘galaxy sign’’ 2013.

The identification of noncaseating granulomas, with aggregates of epithelioid histiocytes, giant cells, and mature macrophages are required for the diagnosis of sarcoidosis. Since lung is most commonly involved the most common approach is a transbronchial biopsy (figure 22) combined with immunologic bronchoalveolar lavage (BAL). This typically reveals high lymphocytes and elevated CD4/CD8 ratio). 

Figure 22. Histopathology of upper lobe biopsy of the lung. The image demonstrates the presence of a non-caseating granuloma in the tissue. Adapted from NTVG ‘Een paradox: sarcoïdose bij een HIV positieve patiënt’ 2015.

Treatment

Since sarcoidosis can resolve spontaneously only patients whose quality of life is significantly impaired, have a permanent disability and/or risk for death should be treated with systemic immunosuppression. Indications include pulmonary compromise with persistent infiltrates and reduced lung function, cardiac disease, neurosarcoidosis, ocular disease refractory to topical treatment, and symptomatic hypercalcemia. The therapy of choice are glucocorticoids (0.5-1mg/kg for 4-6 weeks, followed by a  gradual taper over 2-3 months). 

General treatment goals are to achieve either disease regression or short-term disease stabilisation (when irreversible) with higher dose glucocorticoid treatment. Some cases may require long-term maintenance steroids if symptoms do not wane and stabilize and/or get many side effects from long term glucocorticoids use. Agents such as methotrexate, azathioprine, infliximab, leflunomide may be considered as steroid-sparing agents in patients who are unable to tolerate steroids. 

Prognosis

Overall prognosis in sarcoidosis is good. In stage 1 and 2 disease spontaneous recovery is common (60-90% and 40-70%, respectively) and no treatment is needed. Less than 10% die from the disease, usually due to end stage lung disease.

Hypersensitivity Pneumonitis (HP) / Extrinsic Allergic Alveolitis

Key points

• Hypersensitivity pneumonitis (HP) or extrinsic allergic alveolitis (EAA) is a complex syndrome characterized by inflammation of the alveolar walls and terminal airways.
• Commonly, organic agents in the workplace or from a hazardous environment are the causative trigger in susceptible individuals.
• There are three forms of HP: the acute form in which symptoms like fever, chills, malaise cough, dyspnea, and chest tightness develop in 4 to 8 hours after (heavy) exposure), a subacute form in which these symptoms take weeks to gradually develop and a chronic form where symptoms creep in insidiously.

General

Hypersensitivity pneumonitis (HP), also called extrinsic allergic alveolitis (EAA), is a complex syndrome of varying intensity, clinical presentation, and natural history. The syndrome is characterized by the inflammation of alveolar walls and terminal airways brought on by inhalation of organic agents by a susceptible host. Sufferers are typically found to be exposed to the allergen by their occupation or hazardous environment.

Symptoms

Hypersensitivity pneumonitis (HP) can be categorized as acute, subacute, and chronic based on the duration of the illness.

Acute

In the acute form of HP, symptoms may develop 4–8 hours following heavy exposure to the provoking antigen. Common manifestations include fever, chills, malaise, cough, chest tightness, dyspnea, rash, swelling and headache. Symptom resolution occurs within 12 hours to several days following once exposure is ceased.

Subacute

Patients with subacute HP will gradually develop dyspnea, fatigue and weight loss over the course of a couple of weeks. Symptoms are similar to the acute form of the disease, but are less severe and more prolonged. If the causative agent is no longer inhaled most patients report their symptoms to disappear in days to months. 

Chronic

In chronic HP, patients often lack a history of acute episodes. They have an insidious onset of cough, progressive dyspnea, fatigue, and weight loss. A gradual onset usually occurs with long term low dose exposure to the antigen. Avoiding any further exposure is recommended. Nail clubbing is observed in 50% of patients. Tachypnea, respiratory distress, and inspiratory crackles over lower lung fields often are present. 

Cause 

Hypersensitivity pneumonitis may also be called many different names, based on the provoking antigen. Agents implicated in the diagnosis of HP are numerous. A few are included in table 2 below:

Type	Antigen	Exposure
Bird breeders’/ bird fanciers’ lung	Avian proteins	Feathers and bird droppings (also feather pillows and feather jackets)
Bagassosis or humidifier lung	Thermophilic sacchari	Moldy bagasse (pressed sugarcane)
Cheese workers’ lung	Penicillum casei	Moldy cheese
Farmers’ lung	Thermophilic actinomycetes	Moldy hay, grain, silage
Hot tub lung	Cladosporium sp.	Mold on ceilings
Mushroom workers’ lung	Thermophilic actinomycetes	Mushroom compost

Table 2. Overview of some agents implied in HP.

Of these types, farmers’ lung and bird breeders’ lung are the most common. Prevalence varies across regions, climates, and farming practices. HP affects 0.4–7% of the farming population.

Diagnosis

All forms may be associated with elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Serum precipitins against suspected antigen (see in table X above) is an important part of the workup. During the acute and subacute phase on high-resolution (HR) CT, ground glass changes predominate in the lower lobes with subpleural sparing and centrilobular nodule. In the chronic form of HP, pulmonary fibrosis can be seen.

High lymphocyte levels in bronchoalveolar lavage (BAL) is universal for all HPs, however it is not pathognomonic. Lung biopsy is rarely performed, since the diagnosis can be established by history, exposure to certain antigens/finding of antibody to that antigen and BAL in most cases.

Pulmonary function tests can show restrictive or obstructive patterns with a reduced diffusion capacity of lungs for carbon monoxide (DLCO). Some patients in the acute phase of HP have bronchial hyperreactivity. 

Treatment

Identification and avoidance of the provoking agent is curative in most cases. In severe symptoms and physiologic impairment corticosteroids are the treatment of choice. 

Granulomatous Infections

The different entities of granulomatous infections are discussed in separate chapters:

• Fungal infection;
• Tuberculosis;
• Non-tuberculous mycobacteria.

Other Types of Interstitial Lung Disease

Key points

• Lymphangioleiomyomatosis (LAM) is common in females and often leads to cystic lung destruction. LAM cannot be cured so treatment focuses on reducing symptoms and disease progression.
• Pulmonary Langerhans cell histiocytosis (PLCH) is primarily seen in young smokers, Langerhans-like cells are often found in transbronchial biopsy or bronchoalveolar lavage (BAL). Disease often improves with smoking cessation.
• Pulmonary alveolar proteinosis (PAP) refers to an impaired production of surfactant. This may be congenital, acquired (due to a disruption in GM-CSF signaling), or secondary to certain agents or hematological disease.
• Eosinophilic pneumonia refers to a group of syndromes and diseases all characterized by eosinophilia in the peripheral blood and eosinophilic infiltrates in the lung.

Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare, progressive and systemic disease that is characterized by proliferation of atypical pulmonary interstitial smooth muscle and cyst formation, typically resulting in cystic lung destruction. It predominantly affects Caucasian females, especially during childbearing years. Its progression is insidious; patients exhibit progressive dyspnea, recurrent pneumothorax, or chylous pleural effusion. Approximately 30% of patients have renal angiomyolipomas. In females with typical cysts suggestive of LAM and vascular endothelial growth factor-D (VEGF-D) > 800 pg-ml is diagnostic for LAM. Lung biopsy is not required. Management in LAM is aimed at controlling the symptoms, improving the quality of life, and slowing the progression of the disease. Bronchodilators are used for symptomatic control and relief of symptoms in patients who show reversibility on pulmonary function tests (spirometry). Avoidance of estrogen containing medication is advised. A mechanistic target of rapamycin (mTOR) inhibitor, sirolimus, has shown to reduce the abnormal proliferation and growth of smooth muscle cells in the lung parenchyma, thus improving lung function. Sirolimus is advised in patients with moderate to severe lung impairment.  

Pulmonary Langerhans Cell Histiocytosis

Pulmonary Langerhans cell histiocytosis (PLCH) is a rare cystic interstitial lung disease caused by proliferation of abnormal Langerhans cells. It primarily affects young adult smokers. High resolution (HR) CT findings can range from nodules to cysts. Patients can present with cough, dyspnea, or (recurrent) pneumothorax. CD1a and CD207 positive and Langerhans-like cells are typically found in transbronchial biopsy or bronchoalveolar lavage (BAL). When radiological findings and transbronchial biopsy or BAL are not sufficient, a surgical lung biopsy is often performed. Up to 60% of patients improve with smoking cessation alone. If this alone does not lead to improvement corticosteroids can be given. For patients who do not respond to glucocorticoids cladribine or cytarabine can be used.

Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis (PAP) is caused by accumulation of surfactant-derived lipoprotein compounds within the alveoli due to impaired ability to process surfactant. There are three main categories: 

• Disruption of granulocyte macrophage colony stimulating factor (GM-CSF)) signaling, which is due to autobodies against GM-CSF and most common in adults;
• Disorders of surfactant production, like in congenital PAP, which affects neonates.
• Or secondary to exposure to certain agents or hematologic disorders.

Typical age of presentation is 30-50 years and males predominate. Patients present with insidious exertional dyspnea, cough, constitutional symptoms. Radiographically bilateral ground glass opacities and thickened interlobular structures and interlobular septa. are seen. A bronchopulmonary lavage (BAL) yielding a “milky” and PAS-positive lipo-proteinaceous substance is diagnostic of PAP when coupled with positive radiographic features. A full lung lavage through an endotracheal tube can be curative for some patients with PAP, while others resolve spontaneously without medical intervention. Inhaled GM-CSF (sargramostim) or subcutaneous GM-CSF can be used in patients who have not responded to whole-lung lavage.

Eosinophilic Pneumonia

The eosinophilic pneumonias consist of distinct individual syndromes characterized by (commonly) peripheral blood eosinophilia and eosinophilic pulmonary infiltrates. 

Loffler syndrome, a transpulmonary passage of helminth larvae (hookworm, Strongyloides or Ascaris), causing pulmonary migratory opacities on the chest radiography.  Larvae enter the lungs via the bloodstream and mature in the alveoli, ascend the airways and then descend into the small bowel. Opacities usually clear spontaneously and completely in several weeks. 

Allergic bronchopulmonary aspergillosis (ABPA), typically in patients with asthma or cystic fibrosis. It is a hypersensitivity reaction to Aspergillus fumigatus in the airways. Patients have recurrent episodes of obstruction, productive cough or hemoptysis. Chest imaging can show transient or recurrent infiltrates or bronchiectasis. Besides (or instead) of systemic glucocorticoids patients can be treated with antifungal therapy (itraconazole or voriconazole).

Eosinophilic granulomatosis with polyangiitis (EGPA, in the past called Churg-Strauss), vasculitis disease characterized by asthma, sinusitis/nose polyps, pulmonary infiltrates, peripheral eosinophilia. Other organs such as the skin, heart, kidney or central/peripheral nervous system can also be involved. Antineutrophil cytoplasmic antibodies (ANCAs) are found in less than 50% of patients. Glucocorticoids are the key component of treatment, for patients with severe EGPA remissing induction by combination of glucocorticoids and other immunosuppressive (e.g cyclophosphamide, rituximab) can be used 

Acute eosinophilic pneumonia is characterized by rapid onset of acute febrile illness often less than a week with cough, and progressive worsening of dyspnea. Diagnosis is made according to diffuse radiographic opacities, bronchoalveolar lavage (BAL) with more than 25% of eosinophils (in acute stage eosinophilia in the peripheral blood may be absent) and no evidence of infection or other known cause. The cause is unknown, but acute eosinophilic pneumonia may be associated with recent initiation of resumption of cigarette smoking, exposure to smoke, fine sand or dust. After excluding infection patients are treated with systemic glucocorticoids. 

Chronic eosinophilic pneumonia and idiopathic disorders predominantly affect female patients and nonsmokers. Subacute onset of cough, fever, dyspnoea, weight loss and wheezing. Astma accompanies or precedes chronic eosinophilic pneumonia in 50% of cases. Glucocorticoids are the mainstay of treatment. 

Drug-induced eosinophilic pneumonia can be caused by many medications or toxins, such ad NSAIDs, mesalamine, sulfasalazine and certain antibiotics

Hypereosinophilic syndrome (HES) is an idiopathic disease (lack of evidence of allergic, parasitic or other known cause of eosinophilia) with marked peripheral eosinophilia and multisystemic organ dysfunction. The lungs are involved in 65% of patients, other organs involved are the heart, brain, kidneys, bone marrow, GI tract. Management depends on the underlying cause. Noninfectious conditions are treated with systemic glucocorticoids.

Disturbances in Gas Exchange

The main function of the respiratory system is to remove carbon dioxide (CO2) from the blood entering the pulmonary circulation and provide adequate oxygen (O2) to blood leaving the pulmonary circulation. In order to do that there must be adequate delivery of O2 and removal of CO2 within the alveoli and airways (ventilation), adequate circulation of blood through the pulmonary circulation (perfusion), adequate movement of gas between alveoli and the pulmonary circulation (diffusion) and appropriate contact between pulmonary capillary blood and alveolar gas (ventilation-perfusion matching).

If normal gas exchange is impaired this can have lethal consequences. The system of respiration plays a key role in maintaining the delicate balance of normal blood acidity (pH). This is due to the fact that CO2 is an acid. Lowering the partial pressure of CO2 (pCO2) in the blood can aid in making the blood and body less acidic when needed. Conversely, a build-up of pCO2 makes the blood and body more acidic. The pH homeostasis of the body is maintained by an interplay between the lungs and kidneys (which are able to regulate the presence of the alkali bicarbonate (HCO3–)).

Respiratory Acidosis

Key points

• Respiratory acidosis refers to an acidosis (pH < 7,35) due to a build-up of the acidic CO2 which is also known as hypercapnia.
• Respiratory acidosis may be compensated by raising bicarbonate level, this is a slow mechanism as it takes time for the kidneys to fully adapt.
• Hypercapnia itself may make patients sleepy or even comatose in severe cases. Other presenting symptoms depend on the length of disease and may well reflect the underlying lung disease rather than the actual hypercapnia.
• Causes include reduced neural signaling for respiration (due to stroke, drug use, or diseases like myasthenia gravis) as well as (chronic) lung disease like COPD.
• Diagnosis can be made using an arterial blood gas and treatment should focus on supporting the patient (i.e. ventilation if needed) and treating the underlying cause.

General 

Respiratory acidosis is a medical emergency in which decreased ventilation increases the concentration of carbon dioxide (hypercapnia) in the blood and decreases the blood’s pH (respiratory acidosis). In acute respiratory acidosis as an immediate compensation the bicarbonate (HCO3–) increases slightly due to cellular buffering mechanism (around 1 mmol/L for every 10 mmHg increase in pCO2). In chronic respiratory acidosis the kidneys, which are slower to respond to pH changes compared to the lungs, compensate by increasing the bicarbonate by approximately 4 mmol/L for every 10mmHg increase in pCO2. 

Symptoms 

Signs and symptoms vary based on the length, severity, and progression of the respiratory acidosis. Patients can present with dyspnea, anxiety, wheezing, sleep disturbances, somnolence and even coma. In some cases, patients demonstrate signs of cyanosis arising from hypoxemia or neurological disturbances such as altered mental status, myoclonus, and seizures. Development of CO2 narcosis depends on baseline paCO2. Normally there are no alterations in consciousness until pCO2 exceeds 75 mmHg and in individuals with chronic hypercapnia consciousness alterations may not be experienced until pCO2 exceeds 90 mmHg. In patients with CO2 narcosis the relaxation of smooth muscle can cause dilation of cerebral blood vessels, causing increased intracranial pressure.

Cause 

Respiratory acidosis is classified into acute and chronic disturbances. In acute respiratory acidosis is associated with cerebrovascular accidents (e.g stroke, encephalitis), use of central nervous system depressants (opioids, sedatives such as benzodiazepines and anesthetic agents), inhibition of respiratory muscles in conditions like myasthenia gravis, muscular dystrophy or Guillain-Barre syndrome.

Chronic respiratory acidosis or acute on chronic respiratory acidosis is often caused by chronic obstructive pulmonary disease (COPD) during an exacerbation of in response to (too much) oxygen. Chronic respiratory acidosis can also be seen in obesity hypoventilation syndrome, also known as Pickwickian syndrome, amyotrophic lateral sclerosis, in patients with severe thoracic skeletal defects or muscular inhibition disorders. 

Diagnosis

An arterial blood gas (ABG) is necessary to evaluate patients with suspected respiratory acidosis. In respiratory acidosis, the ABG will show an elevated pCO2 (>45 mmHg)  and decreased pH (<7.35) with sometimes elevated HCO3– (>30 mmHg). 

If the problem is REspiratory, the pH and pCO2 go in REverse directions.

If the problem is MEtabolic, the pH and pCO2 go in the saME direction.

Treatment

Once the diagnosis has been made, the underlying cause of respiratory acidosis has to be treated. Bronchodilators and glucocorticoids can be used in treating patients with exacerbation of obstructive airway diseases. Naloxone can be used in patients who overdosed on opioids. 

Since acute respiratory acidosis can be life-threatening, measures to restore adequate alveolar ventilation (with invasive or non-invasive ventilation) should be taken simultaneously with treating the underlying cause.

Respiratory Alkalosis

Key points

• Respiratory alkalosis refers to an alkalosis (pH < 7.45) due to low acidic CO2, which results from rapid ventilation (hyperventilation).
• Patients experience shortness of breath and commonly also report light-headeness, numbness around the mouth, paresthesias and chest tightness.
• Causes include hyperventilation syndrome, liver cirrhosis, sepsis, and pregnancy.
• Diagnosis is made using arterial blood gas. Treatment focuses on the underlying etiology. In hyperventilation syndrome this may consist of reassurance, sedatives, or physiotherapy in chronic cases.

General 

Respiratory alkalosis refers to the state in which carbon dioxide is reduced through hyperventilation (CO2 output in the lungs exceeds its metabolic production), causing alkalosis (pH > 7.45).

Symptoms

Given that respiratory alkalosis is derived from hyperventilation, the primary complaint is shortness of breath. Rapid decline in cerebral flow due to low pCO2 commonly causes a sensation of light-headedness, numbness around the mouth, paresthesias, and chest tightness. Emergence of tetany is a poor sign, as it suggests low ionized calcium, an effect of severe alkalosis.

Cause 

Respiratory alkalosis is most commonly associated with hyperventilation syndrome, but is also observed in liver cirrhosis, bacterial sepsis, and pregnancy.

Diagnosis

Laboratory findings are characterized by elevated blood pH (>7,45) and reduced pCO2 (< 35 mmHg). In chronic disease the kidneys may compensate by decreasing serum bicarbonate. 

If the problem is REspiratory, the pH and pCO2 go in REverse directions.

If the problem is MEtabolic, the pH and pCO2 go in the saME direction.

Treatment

Treatment is aimed at the management of the underlying cause. A physician may utilize reassurance techniques to calm an anxious patient with acute hyperventilation syndrome; however, if unsuccessful, a sedative can be administered. In chronic hyperventilation syndrome patients can benefit from psychosomatic physiotherapy.

Oncology

Small-Cell Lung Carcinoma

Key points

• Small-cell lung carcinoma (SCLC) is a highly malignant and rapidly metastasizing tumor that often presents in the central airways. 
• Metastasis is mainly seen in the brain, liver, and /or bones.
• Patients may present with (bloody) cough, dyspnea, and weight loss but the tumor may also compress adjacent structures causing vena cava superior syndrome or present with a paraneoplastic syndrome (like SIADH).
• Imaging modalities are the first step in diagnosis, biopsy may aid in characterizing the tumor. Laboratory testing is mainly used to detect complications of the tumor.
• Prognosis is poor, SCLC is very aggressive and has often already metastasized at the time of diagnosis. The disease may be treated with curative intent (with chemoradiotherapy) if the SCLC is limited to the thorax. If not, treatment is palliative chemotherapy or best-supportive care. 

General 

Small-cell lung carcinoma (SCLC), is an anaplastic, highly malignant, bronchogenic carcinoma. Incidence is closely associated with tobacco smoking. SCLC often metastasizes rapidly to other parts of the body, including the brain, liver, and bone. A mutation in the p53 gene is reported in 75%-100% of the cases. Other molecular abnormalities that contribute to the development of SCLC have also been described. In many patients disease has already metastasized at the time of diagnosis.

Epidemiology

SCLC makes up 15% of lung cancers and almost exclusively affects patients who smoke.

Symptoms 

Small-cell carcinoma of the lung usually presents in the central airways (90-95%). Cough with or without blood (hemoptysis), dyspnea, weight loss, and fatigue/ generalized weakness are common manifestations. 

Due to its usual central position, SCLC can sometimes present with a vena cava superior syndrome due to obstruction or invasion of the tumor into the vena cava superior. This impairs drainage and typically leads to edema of the face (especially after bending or lying down), neck (collar of Stokes), and upper limbs. Additionally, there often is venous distension in the neck and on the upper chest and arms.

Some patients may also present with a paraneoplastic syndrome (damage at locations remote from the site of lung cancer that are not the result of mass effect). The most common paraneoplastic syndrome in SCLC is hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Over half of all patients present with local and distant metastases with common sites being the liver, adrenal glands, bone, and brain.

Diagnosis

Initial imaging workup includes plain chest radiography and contrast-enhanced computed tomography (CT) scans of the chest and upper abdomen (figure 23), positron emission tomography (PET)/CT and brain MRI.

Laboratory studies are ordered to evaluate for the presence of neoplastic syndromes and metastases include complete blood count, electrolytes (which screens for SIADH), calcium (elevated in bone metastases), alkaline phosphatase (elevated in bone metastases), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (elevated ALT, AST and bilirubin may indicate liver metastasis), and creatinine.

The method of attaining tissue depends on tumor location. A biopsy is typically obtained via CT-guided biopsy or transbronchial/EBUS. 

Figure 23. CT scan of a patient with metastasized small-cell lung carcinoma. The primary tumor is visible in the right hilus and there is extensive liver metastasis. Adapted from NTVG ‘Tumorlysissyndroom bij kleincellig longcarcinoom’ 2016.

Treatment

Without treatment, SCLC has the most aggressive clinical course of any type of pulmonary tumor. Compared with other cell types of lung cancer, SCLC has a greater tendency to be widely disseminated by the time of diagnosis but is much more responsive to chemotherapy and radiation therapy; cisplatin/carboplatin and etoposide have high response rates.  Treatment is highly dependent on stage. 

Patients with limited-stage SCLC (limited to the thorax) are candidates for curative-intent chemoradiotherapy. 

Patients with extensive-stage disease are treated with palliative chemotherapy. In some countries, the first choice of treatment is a combination of chemotherapy and immunotherapy (carboplatin-etoposide-atezolizumab), but considering its small survival benefit and high costs other countries have chemotherapy alone as the standard of care. Selected patients with low bulk metastatic ED who have complete or near complete response after chemotherapy can benefit from thoracic radiotherapy after chemotherapy.

Since brain metastases are common, cranial irradiation can be performed prophylactically or patients are followed up with MRI. 

Prognosis

Prognosis is poor. In limited-stage SCLC those who receive treatment have a 20-25% 5-year survival rate. In extended disease median survival with treatment is 6-11 months and without treatment 2-4 months. 

Non-Small Cell Lung Carcinoma

Key points

• Non-small cell lung carcinoma (NSCLC) makes up 80-90% of all lung cancers, and almost half of the NSCLC are adenocarcinomas.
• Patients may present with cough, dyspnea and weight loss if the tumor is located in the central airways. However, other presentations include pain due to bone metastasis, Pancoast syndrome, Horner syndrome, and vena cava superior syndrome.
• Diagnosis is made through imaging as well as biopsy. Herein, the location of the tumor decides how the biopsy is obtained.
• Localized disease may be treated curatively with radiotherapy and/or surgery. Locally metastasized disease can be treated with chemoradiation sometimes followed by immunotherapy. Otherwise, metastasized disease is treated palliatively.
• Prognosis depends on the stage of the disease, type and molecular profile of the tumor. 

General 

Non-small cell lung carcinoma (NSCLC) accounts for approximately 80% to 90% of all lung cancers. Three major histologic types of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma is the most common type of NSCLC, accounting for approximately half of all cases.

Epidemiology

Lung cancer is the most common form of cancer globally, claiming an estimated 1.8 million lives in 2018.1 Approximately 70% of patients present with advanced stage NSCLC.

Symptoms 

Some NSCLC patients are asymptomatic at diagnosis, and present due to an incidental discovery. Those with symptoms are often associated with the area in which the lesion infiltrates. Centrally located lesions manifest with generalized symptoms of dyspnea, cough, hemoptysis, chest pain, and weight loss. Some patients may present with symptom complexes, which include:

• Pancoast syndrome, characterized by symptoms of shoulder pain and brachial plexopathy;
• Horner syndrome: ptosis, meiosis, and ipsilateral anhidrosis which are caused by involvement of the vertebral sympathetic nerves, hoarseness due to recurrent laryngeal nerve involvement; or
• Vena cava superior syndrome, which is noted by arm and face engorgement. 

Metastases to intrathoracic nodes, pleura, contralateral lung, liver, adrenal glands, bone, and brain are common and manifest accordingly. 

Risk factors 

Tobacco use is the primary risk factor for lung cancer; the causal relationship between lung cancer and smoking was established in the 1950s. Chronic obstructive pulmonary disease (COPD), environmental exposure to asbestosis or certain occupational exposures also increase one’s risk. 

Diagnosis

A complete blood count and chemistry panel, T/PET CT (figure 24), lungfunction tests and sometimes (in stage 3 lung cancer) MRI brain should be included in the standard diagnostic workup. Tissue diagnosis and staging are crucial to helping guide treatment recommendations 

Localized lesion biopsy is usually done by CT-guided transthoracic biopsy or bronchoscopy. In patients with central and/or large lesions in the lung or signs of mediastinal or hilar metastasis mediastinal staging has to be done by endobronchial ultrasound (EBUS), esophageal ultrasound (EUS), or mediastinoscopy. In patients with metastasized disease the aim is to obtain a biopsy of one of the metastatic lesions.

Figure 24. Imaging studies of non-small cell lung carcinoma. Image (a) and its explanatory duplicate show the remaining mass after two years of chemotherapy as well as a fluid collection directly below it. Image (b) shows an FDG-PET scan with high signal intensity in the same location as the mass. This is highly suspicious for a recurrent tumor. Adapted from NTVG ‘Salvage-chirurgie voor lokaal recidief longcarcinoom’ 2018.

In determining the best systemic treatment, programmed death-ligand 1 (PDL-1) is important as high PDL-1 expression equals a bigger chance of the tumor responding to immunotherapy. Additionally, molecular diagnostic studies are used to determine the presence of certain targetable gene alterations in the tumor (epidermal growth factor receptor (EGFR), KRAS, mesenchymal epithelial transition factor (MET), etc) which respond well to targeted therapy.

Treatment

Treatment depends on the stage of the disease. In localized disease surgery or radiotherapy (stereotactic body radiotherapy or SBRT) is curative. Depending on surgical findings, patients may require adjuvant chemotherapy or radiation therapy. Patients with mediastinal or hilar metastasis are mostly treated with chemoradiotherapy and after completing treatment adjuvant immunotherapy (durvalumab). 

Patients with metastasized disease can be treated with palliative systemic therapy. The form of therapy depends on histological or cytological findings: patients with high PDL-1 without any targetable mutations are treated with immunotherapy, patients with low PDL-1 without targetable mutations with combination of chemotherapy and immunotherapy and patients with targetable mutations can be treated with targeted therapy.

Prognosis

Localized NSCLC usually has a good prognosis. Furthermore, prognosis of advanced and metastasized lung cancer has improved dramatically since immunotherapy and targeted therapies have been developed. Stage 3 lung cancer treated with chemoradiotherapy and adjuvant durvalumab has an average 5-year survival of 43%. Stage 4 lung cancer without targetable mutations treated with (chemo)immunotherapy has an average 5 year survival of 25-32%. Patients with squamous cell carcinoma usually have worse response rates compared to  adenocarcinoma. 

In patients with targetable mutations prognosis varies, for patients with the most common epidermal growth factor receptor (EGFR) mutation treated with tyrosine kinase inhibitors (TKI) an average 5 year survival is around 50%.

Malignant Mesothelioma

Key points

• Malignant mesothelioma is a highly aggressive cancer that is linked to asbestos exposure in over 70% of cases. It can affect different tissues with mesothelial cells but is most commonly found in the lung (malignant pleural mesothelioma). 
• Symptoms include dyspnea, cough, pain in the chest. On examination there is dullness on percussion and decreased breath sounds due to pleural effusion.
• DIagnosis is made through pathology findings on biopsy, which usually necessitates surgery.
• Curative treatment is often not possible. There are palliative systemic options (chemotherapy and immunotherapy) in patients with unresectable tumors.
• Prognosis is very poor, patients generally survive for 9-17 months after diagnosis.

General

Mesothelioma is a rare, highly aggressive cancer that arises from the mesothelial cells that form the lining of the pleural, peritoneal, pericardial, and tunica vaginalis cavities. Although it can arise in any of these tissues, malignant pleural mesothelioma is the most common type. The onset of the cancer is closely linked to exposure to asbestos. Up to 70% of cases are associated with documented exposure to asbestos fibers, with a latency period of approximately 30-40 years from the time of exposure to development of mesothelioma. 

On gross pathology, pleural mesothelioma is characterized by discrete plaques and nodules that make up a sheet-like tumor. Mesothelioma is divided into three subtypes based on histology: epithelial, sarcomatoid, and biphasic. 

Epidemiology

High rates of disease occur in people who mine asbestos, produce/work with products from asbestos, live with asbestos workers, or work in buildings containing asbestos. In Europe the incidence varies from 1-8 per 100.000.

Symptoms 

Clinical manifestations match that of many other afflictions of the lungs and presentation differs according to pathogenesis in the pleural, peritoneal, or pericardial space. Shortness of breath (dyspnea), cough, and pain in the chest due to an accumulation of fluid in the pleural space (pleural effusion) are often symptoms of pleural mesothelioma. 

Peritoneal mesothelioma presents with abdominal swelling and pain due to ascites (a buildup of fluid in the abdominal cavity). Common symptoms include weight loss, fever, night sweats, poor appetite, vomiting, constipation, and umbilical hernia. 

Finally, the dominant complaint in pericardial mesothelioma cases is substernal chest pain; constrictive pericarditis, heart failure, and cardiac tamponade have been observed when the tumor infiltrates or encases the heart. Distant metastasis is uncommon, but can involve the liver, bone or central nervous system. 

When evaluating a patient for mesothelioma, care should be taken to establish a thorough history of the symptoms (onset, duration, and progression), and any exposure to asbestos and/or radiation. Note that there is a 30-40 year delay between exposure to asbestos and symptom onset.

Physical examination findings commonly reveal dullness on percussion, decreased breath sounds on auscultation, ascites, and murmurs. 

Cause 

Most mesothelioma cases are caused by exposure to asbestos. The greater the exposure, the greater the risk of development. Other risk factors include radiation therapy and certain genetic factors (for example germline mutations in BAP1). 

Diagnosis

Nearly all patients with pleural mesothelioma present with pleural effusion, however thoracentesis of pleural effusion rarely provide sufficient material to make diagnosis of pleural mesothelioma definitive. In such instances surgical biopsy is performed (usually) via video-assisted thoracoscopic surgery (VATS) or thoracoscopy..

On gross pathology, pleural mesothelioma is characterized by discrete plaques and nodules that make up a sheet-like tumor. 

Treatment

In most cases of unresectable pleural mesothelioma palliative systemic treatment is given according to the histology of the tumor:

• sarcomatoid type: immunotherapy (combination of nivolumab/ipilimumab);
• epithelioid type: chemotherapy (carboplatin/pemetrexed) is the treatment of choice as no significant survival benefit was found when treated with immunotherapy compared to chemotherapy, however immunotherapy is a reasonable alternative.

Surgery is not considered the standard of care, but there are a few patients who can have a greater survival benefit with surgery. Surgery with either radical extrapleural pneumonectomy or pleurectomy/decortication is usually given in combination with chemotherapy and radiotherapy.

Prognosis of malignant pleural mesothelioma is poor, overall survival 9-17 months after diagnosis. Mesothelioma derived from the epithelium is associated with a better prognosis than mesothelioma derived from sarcoid tissue. 

Pulmonary Embolism

Key points

• Pulmonary embolism (PE)  is an acute obstruction of the pulmonary artery or one of its branches. It is often caused by deep vein thrombosis (DVT).
• People who are immobilized, obese, have underlying malignancy or a clotting disorder, smoke, are pregnant, or use estrogen-based drugs are most at risk.
• Symptoms may be sudden (acute dyspnea, ventilation-related chest pain, hemoptysis) or more insidious (slowly progressive impaired exercise tolerance).
• As symptoms overlap with other disorders and diagnosis requires CT angiography – which is costly and not always readily available – risk stratification scores have been developed to estimate the risk of PE (like the YEARS criteria or Wells score).
• Treatment consists of hemodynamic support when needed and anticoagulation therapy to prevent clots from progressing. Clots are then broken down by the body naturally.

General 

Pulmonary embolism (PE) is an acute obstruction of the pulmonary artery or one of its branches and can be caused by a thrombus, air, tumor, or fat. PE usually arises from thrombi in the deep veins of the lower extremities and/or pelvis, known as a deep vein thrombosis (DVT). Dislodgement of the DVT or parts of the DVT can result in the blood clot traveling up the venous system through the right heart and lodging in the pulmonary vasculature. The pulmonary trunk, main pulmonary artery, segmental or subsegmental branches are all common locations for a pulmonary embolus to lodge. Once lodged in the pulmonary vasculature depending on the size and location of the PE, this can cause heart strain and decreased oxygenation. The most serious consequence of pulmonary embolism is when the clot blocks the right and left pulmonary artery, blocking the heart’s right ventricular outflow tract. 

Pulmonary embolism (PE) is the third most common cause of acute cardiovascular syndrome: annual incidence rates range from 39-116 per 100.000 people. Early diagnosis and treatment is paramount to survival.

Symptoms 

The patient can present with a range of signs and symptoms, ranging from no symptoms to shock or sudden death. The most common symptoms are dyspnea, chest pain, cough, and symptoms of DVT (diffuse and progressively increasing leg pain and swelling). Hemoptysis can also be a presenting symptom. With severe PE, patients can present with shock, arrhythmia or syncope.

Risk Factors

Prolonged immobilization that causes stasis in the deep veins is the main risk factor. This may occur after surgery, prolonged bed-rest, or prolonged sitting during travel. The risk of blood clots is also increased with cancer, heavy smoking, inherited thrombophilias, estrogen-based medication, pregnancy, obesity, etc. 

Classification

PE can be classified based on the time course of symptom presentation (acute or chronic) and the overall severity of disease. Disease severity is stratified based upon three levels of risk according to presence of absence of hemodynamic stability: massive, submassive, and low-risk:

• Massive PE, or hemodynamically unstable PE, is characterized by the presence of pulselessness, bradycardia, or sustained hypotension (systolic blood pressure < 90 mmHg or a drop of 40mmHg or more from baseline for > 15 minutes or hypotension that requires vasopressor /inotropic support).
• Submassive PE is defined by the presence of either right ventricular dysfunction or myocardial necrosis in the absence of hypotension. 
• Low risk PE, clinical presentation is mild and nonemergent; hypotension, shock, right ventricular dysfunction and myocardial necrosis are all absent. 

Diagnosis

The diagnosis of PE is based primarily on clinical criteria combined with selective testing because the typical clinical presentation (shortness of breath, chest pain) cannot be definitively differentiated from other causes of chest pain and shortness of breath. PE must be distinguished from other life-threatening causes of chest pain including acute myocardial infarction, aortic dissection, and pericardial tamponade. 

Diagnostic approach combines clinical and pretest probability assessment by using a blood test known as a D-dimer to confirm or exclude the disease. The YEARS criteria may be used in hemodynamically stable patients. These criteria use clinical information (like presence of DVT, coughing up blood (hemoptysis), and whether PE is the most likely diagnosis) combined with the d-dimer level to determine the risk of PE in specific patients. Other hospitals still use the (age adjusted) Wells criteria in combination with D-dimer. Patients with high suspicion for PE according to Wells criteria undergo CT-angiography (CT-A) without testing D-dimer and patients with low susceptibility according to Wells criteria first undergo D-dimer and only get a CT-A if the D-dimer is positive (above 500 or when using age-adjusted D-dimer age per 10 cutoff in patients above 50 years).

Use of clinical prediction rules integrating PE severity and comorbidity, preferably the pulmonary embolism severity index (PESI) should be considered for risk assessment in the acute phase of PE. CT (pulmonary) angiography (CTPA or CT-A) This is the recommended first line diagnostic imaging test in most people (figure 25). A negative CT pulmonary angiogram excludes a clinically important pulmonary embolism.

Other tools that may be routinely employed in patients presenting with potential PE (i.e. dyspnoeic, hypoxic patients with breathing-associated chest pain) includes electrocardiogram (ECG) due to a differential of acute coronary syndrome. ECG cannot be used to diagnose pulmonary embolism definitively. However, in PE where the embolisms block blood flow to such an extent that the pressure causes right atrial dilatation a P pulmonale may be seen as well as a right bundle branch block and a right heart axis, which signify right ventricle stress. 

Figure 25. Image (a) shows two pulmonary embolisms: an acute embolism in the left pulmonary artery while the embolism in the right pulmonary artery is considered older as it has transformed to follow the arterial wall and does not occlude the artery (which the embolism on the left does). Image (b) shows a different patient with a saddle embolism which straddles the bifurcation of the pulmonary trunk, stretching into both the left and right pulmonary arteries – these large embolisms are more likely to bring about significant hemodynamic changes. Adapted from NTVG ‘Acute longembolie<,’ 2012.

Treatment

Anticoagulant therapy is the mainstay therapy for PE. Patients are usually started on direct oral anticoagulants (DOAC) or low molecular weight heparin (LMWH). LMWH sometimes need to be bridged with a vitamin K antagonist (VKA) until the recommended international normalized ratio (INR – which measures clotting ability) of 2.5 is reached.

In massive PE causing hemodynamic instability systemic thrombolytic therapy is recommended. Norepinephrine and/or dobutamine should be considered in patients with high risk PE. In patients where thrombolysis is contraindicated, surgical pulmonary embolectomy of percutaneous catheter-directed treatment  should be considered. Acutely, supportive treatments, such as oxygen or analgesia, may be indicated. 

Pulmonary Hypertension

Key points

• Pulmonary hypertension (PH) refers to high pressure in the pulmonary artery. Most cases result from (left) heart failure or lung disease like chronic obstructive pulmonary disease.
• Common symptoms include dyspnea, chest pain, or fainting which may all be exacerbated by exertion. Causative underlying disease may cause symptoms as well.
• Diagnosis is made  by measuring pulmonary artery pressure using heart catheterization. If it exceeds 20mmHg, PH can be diagnosed.
• Other modalities, like imaging, pulmonary function testing, electrocardiogram, and echocardiogram are used to determine severity and cause of disease.
• PH due to underlying disease is treated by addressing its cause. If this does not yield the desired results or if there is no underlying cause, drugs are used to lower pulmonary pressures. Transplantation is curative.

General

Pulmonary hypertension (PH) is diagnosed when the mean pulmonary artery pressure exceeds 20mmHg in rest. It encompasses a heterogeneous group of disorders associated with a variety of cardiovascular and respiratory diseases. Treatment is focused on the management of symptoms and resolution of underlying diseases.

Epidemiology

Prevalence of PH is approximately 1%. The leading cause of PH are diseases causing backward left sided heart failure, followed by lung disease (especially chronic obstructive pulmonary disease; COPD). Since cardiac and pulmonary causes are more common in individuals aged above 65, prevalence of PH is higher in those patients.

Symptoms 

Symptoms include dyspnea (shortness of breath), syncope (fainting), and chest pain which all commonly occur during exertion (or shortly after in the case of syncope). Additionally, patients may complain of fatigue, bendopnea (dyspnea when bending forward), palpitations, hemoptysis (bloody cough), and weight gain due to fluid retention.

PH is often initially associated with changes in heart sound: a loud P2, which represents the pulmonary valve closing. The P2 follows A2 (which is the aortic valve closing) and together this makes up the second heart sound (S2 or the “dub” in lub-dub). There may be narrowed splitting of S2. A third heart sound (S3) may also be heard on auscultation, this sound closely follows the regular heart sounds and creates what is known as a gallop rhythm. An S3 sound is associated with heart disease. Furthermore, on palpation there may be a parasternal heave, and sometimes the tap of the pulmonary valve closing can be felt. 

As PH worsens, right ventricular failure can develop, which is associated with increased jugular venous pressure (JVP), ascites, peripheral edema, and hepatojugular reflux. Certain signs pointing towards underlying cause of PH are digital clubbing (in fibrotic lung disease, PVOD, etc), crackles suggesting lung or heart disease, telangiectasia, sclerodactyly (systemic sclerosis). A pansystolic murmur of tricuspid insufficiency can also be present on physical examination and is suggestive long-standing PH.

Risk Factors

Risk factors include a family history for PH and diseases like prior pulmonary embolism, human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS), sickle cell disease, COPD, sleep apnea, and mitral valve disease. Those who use cocaine or live at high altitudes are also more at-risk. The underlying mechanism typically involves inflammation of the arteries in the lungs.

Cause

PH is defined as an elevated mean pulmonary arterial pressure >20mmHg at rest as measured by right heart catheterization. The underlying pathology provoking PH is an increase in the mean pulmonary arterial pressure, increase in right sided cardiac output, and an increase in mean pulmonary venous pressure. This can be evoked idiopathically or by a myriad of lung and heart disease; these etiologies are classified into 5 groups:

• Group 1: pulmonary arterial hypertension (PAH). This group encompasses all diseases that may cause PAH, including idiopathic and hereditary PAH, pulmonary veno-occlusive disease (PVOD), connective tissue disease, HIV, portal hypertension, drug and/or toxin use, and parasitic infections like schistosomiasis.
• Group 2: left-sided heart disease. This is often characterized by chronically elevated filling pressure in the left ventricle, leading to left atrial dilation and potentially mitral valve disease.
• Group 3: lung disease and hypoxemia. This group includes COPD, obstructive sleep apnea syndrome (OSAS), and interstitial lung disease (ILD).
• Group 4: chronic thromboembolic disease or other pulmonary artery obstruction.
• Group 5: PH due to unclear or multifactorial mechanisms, such as chronic hemolytic anemia, sarcoidosis, chronic kidney disease, and myeloproliferative disorders.

Diagnosis

Although blood work is frequently unremarkable, workups should still include routine biochemistry, hematology, immunology, HIV testing and thyroid function tests.

Echocardiographic assessment is usually performed in order to determine the probability of pulmonary hypertension. On echocardiogram, the pulmonary arterial systolic pressure can be estimated by measuring the peak tricuspid regurgitation velocity.  

The gold standard for diagnosis of PH is measuring mean pulmonary arterial pressure (PAP) however, which requires heart catheterization. PH is characterized as a mean PAP ≥ 20 mmHg. Catheterization may also be used to assess the severity, and determine the prognosis and response to therapy in pulmonary hypertension.

Pulmonary function tests and analysis of arterial blood gas are necessary to distinguish between the different PH groups and assess the need for oxygen therapy. Chest radiography and CT imaging are valuable in ruling out certain etiologies of pulmonary hypertension and delineating the anatomy of the pulmonary vasculature. Ventilation/perfusion lung scan and CT pulmonary angiography is recommended in the work up of patients with suspected chronic thromboembolic PH (group 4).

Additionally, no matter the underlying pathology, PH always leads to right ventricular overload and hypertrophy (RVH) and right atrial enlargement. This may be seen on electrocardiogram (ECG) which may be normal in early stages of PH but as disease advances, RVH may be seen on ECG as an R wave larger than the S wave in V1, and RVH may cause a right axis deviation. Right atrial enlargement may be represented by a large amplitude of the first phase of the biphasic P wave in V1. Furthermore, ECG may reveal a right bundle branch block (RBBB), P pulmonale (increased amplitude of the P wave in II and V1), signs of right ventricular hypertrophy and a right ventricular strain pattern (ST depression/T wave inversion in V1-V4 and II, III, aVF).   Structural changes to the heart may also be diagnosed on echocardiography. This may show flattening of the interventricular septum and increased right ventricle/left ventricle diameter ratio. It can also detect the cause of suspected PH particularly if it is associated with left heart disease.

Treatment 

The choice of treatment for PH requires the assessment of the clinical severity of the disease and the identification of any underlying cause. Patients who have PH secondary to a medical condition such as left heart failure, lung disease, or thromboembolic disease (PH group 2, 3, and 4 respectively) should receive treatment to resolve the underlying cause. To date, there is no specific treatment to target pulmonary arterial hypertension (group 1), however there are medications to manage the disease. All PAH patients must undergo vasoreactivity testing in order to assist in the selection of the optimal therapy; if pulmonary vasculature is reactive, calcium channel blockers are appropriate (nifedipine or diltiazem); if pulmonary vasculature is not reactive (usually connective tissue disease PH or HIV PH) or patients who have failed vasoreactive therapy, endothelin receptor antagonist, phosphodiesterase 5 inhibitors or prostanoids are used. 

In refractory patients lung transplantation is curative. Other invasive measures include creating a left shunt, though this is a temporary measure only. Likewise, pulmonary thromboendarterectomy (PTE) or balloon pulmonary angioplasty (BPA) can be used when PH secondary to chronic pulmonary thrombosis is unresponsive to more conservative therapies.

Pneumothorax

Key points

• Pneumothorax occurs when gas escapes into the pleural space, limiting the lung on the affected side in its expansion and respiration.
• There are several types of pneumothorax, and it may occur spontaneously in both healthy or diseased lungs or as a result of trauma.
• Patients may have mild to severe symptoms of dyspnea and chest pain that develop acutely. On examination there may be reduced breath sounds on the affected side, as well as decreased chest excursions.
• Chest radiography can be used to diagnose pneumothorax and will show the air filled space as hyper lucent, with a visible pleural line.
• Treatment depends on the severity of disease. In large pneumothorax gas may be removed by placing a drain. If there is a high risk of recurrence, surgical interventions, such as pleurectomy and bullectomy, can be performed to reduce the risk.  

A pneumothorax refers to the abnormal collection of gas in the pleural space. A primary spontaneous pneumothorax is one that occurs without an apparent cause and in the absence of significant lung disease. A secondary spontaneous pneumothorax occurs in the presence of existing lung disease; the main underlying causes for secondary pneumothorax are lung disease such as chronic obstructive pulmonary disease, emphysema or interstitial lung disease (ILD). A pneumothorax can also be caused by physical trauma to the chest or as a complication of a healthcare intervention. A tension pneumothorax is generally considered to be present when any form of pneumothorax leads to significant impairment of respiration and/or blood circulation.

Symptoms can be mild or nonexistent, but pneumothorax is usually characterized by acute dyspnea and chest pain. In larger pneumothorax a typical physical finding is decreased chest excursion on the affected side and reduced breath sounds, absent tactile or vocal fremitus (vibration). Evidence of tachycardia, hypotension, and displacement of chest organs, in addition to the aforementioned symptoms, suggest a tension pneumothorax.

A plain chest radiograph is the most appropriate first investigation. Gas outside of the lung will show up more lucent compared to normal gas holding lung tissue. Radiographs should demonstrate a visceral pleural line during maximal inspiration or deep sulcus sign in supine patients as shown in figure 26.

Figure 26. Plain chest radiography in a patient with bilateral pneumothorax. Visceral pleural lines are seen where the lung tissue ends and the lucent gas collection begins. Adapted from NTVG ‘Dubbelzijdige pneumothorax na acupunctuur bij een jonge vrouw,’ 2002.

Initial management of stable patients depends upon the size of the pneumothorax and associated symptoms. A pneumothorax is considered large if there is more than 2 cm between the pleural line and the chest wall at the level of the hilum. The common practice in treatment of medium/large pneumothorax is chest tube thoracostomy or needle aspiration. Of note, a recent study has shown that the size of the pneumothorax does not influence the success rate and that watchful waiting in selected individuals (healthy patients with mild symptoms and no hemodynamic compromise or oxygen requirement) even if they have a large pneumothorax might also be appropriate. In small pneumothorax watchful waiting (with or without oxygen) is the appropriate approach. 

In patients with prolonged air leak after tube thoracostomy, prior history of pneumothorax, or a high risk profession (like professional deep water divers or pilots), definitive treatment with surgical (or less frequently medical chemical) pleurodesis can be performed. In pleurodesis the visceral pleura is fused with the parietal pleura to prevent future pneumothorax. Surgical treatment (eg. mechanical abrasion, pleurodesis,  pleurectomy) is mostly performed through video-assisted thoracic surgery (VATS).

Primary Spontaneous Pneumothorax

A primary spontaneous pneumothorax (PSP) tends to occur in young, tall adults without underlying lung problems. Although PSP is not associated with a clinical lung disease, most affected patients have unrecognized lung abnormalities. PSP is thought to be caused by the rupture of blebs (small air-filled lesions just under the pleural surface) and is commonly associated with male smokers. Smoking is a risk for PSP probably due to airway inflammation and bronchiolitis.

Secondary Spontaneous Pneumothorax

Secondary spontaneous pneumothorax (SSP), by definition, occurs in individuals with significant underlying lung disease. Most SSPs occur as a complication of chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and tuberculosis in endemic areas. Symptoms in SSPs are more severe than in PSPs, as the unaffected lungs are generally not as able to replace the loss of function in the affected pulmonary tissue. This results in more pronounced respiratory distress.

Traumatic Pneumothorax

A traumatic pneumothorax can be the result of blunt or penetrating trauma. An iatrogenic pneumothorax refers to one caused by medical error, such as when performing transthoracic needle aspiration, thoracentesis, and/or administering a central intravenous catheter.

Tension Pneumothorax

Tension pneumothoraces occur in clinical situations involving ventilation, resuscitation, trauma, or in people with lung disease. Tension pneumothorax arises when the opening that allows air to enter the pleural space functions as a one-way valve, allowing more air to enter with every breath but no option for air to escape. When air in the pleural space builds up enough it may interfere with other processes in the thoracic cavity. The unaffected lung may be compromised in its expansion and thus ventilation and the venous return to the heart may be impaired as the vena cava is squeezed off. This may result in hypotension and hemodynamic instability. This may result in death, unless treated timely.

Diagnosis requires the demonstration of hyperresonance to percussion and absence of breath sounds accompanied by an enlarged hemithorax. Additionally, on palpation of the neck the trachea may be in a deviated position. Positive radiographs should portray the shift of the mediastinum and air in the hemithorax. 

Respiratory Insufficiency

Key points

• Respiratory insufficiency, or failure, is a consequence of respiratory disease that has impaired gas exchange. This may lead to hypoxemia and/or hypercapnia.
• Hypoxemia and hypercapnia both result in dyspnea, hypercapnia however may also elicit headaches and altered mental status.
• There are two types of respiratory insufficiency which are distinguished based on their main consequence: type I is characterized by hypoxemia and type II by hypercapnia. Note that both of these may be present at the same time.
• Diagnosis is generally made on arterial blood gas and calculation of the alveolar-arterial gradient can aid in finding the underlying cause.
• Treatment consists of addressing the underlying cause and supportive measures including (non-)invasive ventilation.

General 

Respiratory insufficiency, also known as respiratory failure, emerges as a result of inadequate gas exchange. Reduced oxygen level is known as hypoxemia; a rise in arterial carbon dioxide tension is called hypercapnia. Clinically, respiratory failure appears with an increased respiratory rate, abnormal blood gasses demonstrating hypoxemia and/or hypercapnia. 

Symptoms 

Acute respiratory failure predominantly demonstrates the signs and symptoms of the underlying condition. Depending on the stage of insufficiency, manifestations of hypoxemia or hypercapnia will be evident. Dyspnea is the cardinal sign shared by both hypoxemia and hypercapnia manifestations; however, respiratory insufficiency due to hypercapnia is often also accompanied by headaches, altered mental status. Patients in distress can be seen using accessory muscles, patients with chronic obstructive pulmonary disease (COPD) may pursed-lip breathing.

Cause 

Type I

Type I occurs when the respiratory system cannot adequately provide oxygen to the body causing hypoxemia (PaO2 below 60 mmHg). The difference between the oxygen pressure in the blood (the PaO2) and the oxygen pressure in the alveoli (the PAO2) is called the alveolar-arterial gradient (or A-a gradient). The partial pressure of oxygen in the alveoli depends on the partial pressure of oxygen in the inhaled air. Normally, there is no gradient as oxygen is able to diffuse freely past the alveolar membrane.

When alveolar-arterial gradient is normal it suggests there is a problem with inhaling air or the inhaled air itself rather than with the alveoli. Etiologies include:

• Alveolar hypoventilation (also causes increase in PaCO2), for example in central nervous system depression (obesity hypoventilation syndrome, hypothyroidism, toxic metabolic encephalopathy), neuromuscular disease, or chest wall abnormalities.
• Low atmospheric fraction of inspired oxygen (as is present at high altitudes).

An increased alveolar-arterial gradient signifies that oxygen is not able to reach the blood easily. This happens in:

• Diffusion defect like in emphysema or interstitial lung disease (ILD).
• Ventilation/perfusion mismatch as in pneumonia, pulmonary embolism, atelectasis, congestive heart failure, chronic obstructive pulmonary disease (COPD).

Type II

Type II respiratory insufficiency results from alveolar hypoventilation and the inability to rid carbon dioxide causing hypercapnia (PaCO2 above 45mmHg). It occurs when there is a failure of the respiratory pump in conditions such neuromuscular disorder (for example ALS (amyotrophic lateral sclerosis) or myasthenia gravis), use of sedatives, dead space ventilation (acute respiratory distress syndrome (ARDS), pulmonary embolism, emphysema), muscle abnormalities (muscular dystrophy or diaphragmatic paralysis). Increased CO2 production in conditions such as fever, thyrotoxicosis, or sepsis can also lead to type II respiratory failure.

Diagnosis

Respiratory failure is recognized predominantly by clinical presentation. Since it can be caused by multiple etiology a single algorithm for evaluating respiratory failure does not exist. Arterial blood gas exams are the mainstay tool in identifying hypoxemia or hypercapnia and are also useful in differentiating acute from chronic respiratory failure. The latter often shows components of metabolic compensation that make up for the accumulation of carbon dioxide, which is explained in more detail here. 

Laboratory assays and if needed infectious workup is necessary to diagnose the underlying etiology . Most imaging modalities, including plain chest radiography, CT, MRI, electrocardiogram (ECG), and ultrasound, are helpful in determining the etiological origin of lung failure.

Treatment

Treatment of the underlying cause should be the first step in managing respiratory insufficiency while providing supportive care with oxygenation and ventilation. This may be done with non-invasive ventilation but also includes invasive ventilation in cases of severe respiratory failure.

Acute Respiratory Distress Syndrome

Key points

• Acute respiratory distress syndrome (ARDS) is a dangerous, rapidly developing inflammatory lung condition that can arise due to various reasons.
• The inflammation in ARDS causes capillary leak in the lungs which limits diffusion and creates non-cardiogenic pulmonary edema.
• Patients initially complain of mild dyspnea, but within 72 hours this often intensifies to the point where mechanical ventilation is necessary.
• On examination patients often have tachypnea and increased breathing work, with hypotension, and cold, sometimes even blue, extremities.
• Diagnosis is made based on the PaO2/FiO2 ratio which is below 300 mmHg in ARDS. Treatment is aimed at the underlying disease, but even with timely treatment mortality of ARDS is high.

General 

Acute respiratory distress syndrome (ARDS) is a serious and potentially life-threatening inflammatory lung condition that develops rapidly (usually within 24 to 48 hours) in the setting of a variety of etiologies, including sepsis, toxic exposures, adverse drug reactions, trauma, or other critical illnesses. In ARDS alveolar injury leads to non-cardiogenic pulmonary edema, impaired gas exchange, and decreased lung compliance. 

ARDS is defined by progressive dyspnea with the exhibition of bilateral lung infiltrates and severe progressive hypoxemia in the absence of any evidence of cardiogenic pulmonary edema. Diagnosis requires the demonstration of a PaO2/FiO2 ratio of less than 300 mmHg.

The vast majority of patients with ARDS are managed in an intensive care unit (ICU), where many will require mechanical ventilation at some point during the course of their illness and recovery. ARDS may be categorized as mild, moderate, or severe based on the degree to which oxygenation is impaired; however, all levels of severity carry a high mortality rate if appropriate measures to improve oxygenation and minimize the risk of further lung injury are not taken.

Symptoms 

Patients initially complain of mild dyspnea; within 6-72 hours, the respiratory distress intensifies and dyspnea, requiring mechanical ventilation. Physical examination typically reveals tachypnea and increased work of breathing. Patients have low oxygen saturation, despite administration of 100% oxygen, with associated peripheral vasoconstriction, hypotension, and cold – sometimes cyanotic – extremities. The physical exam should also be directed to identify associated organ failures such as shock or coma.

Risk factors

The most potent risk factor in the development of ARDS is chronic alcoholism. It seems there is also likely to be a genetic determinant that increases the risk of ARDS. Other risk factors include advanced age, cigarette smoke exposure, thoracic surgery, and acute pancreatitis.

Cause 

ARDS develops in the setting of a variety of etiologies, including sepsis, toxic exposures, adverse drug reactions, trauma, or other critical illnesses. ARDS is caused by an alveolar injury which causes diffuse inflammation leading to diffuse alveolar damage which in turn increases permeability of the alveolar-capillary membrane. This leads to non-cardiogenic pulmonary edema, impaired gas exchange, and decreased lung compliance. 

Diagnosis

The diagnosis of ARDS is made based on the demonstration of the following criteria: acute onset, bilateral chest radiography infiltrates, and a PaO2/FiO2 ratio below 300 mmHg. This ratio takes the measured partial pressure of oxygen in the blood (PaO2) and divides it by fractional inspired oxygen (FiO2) – which is the fraction of air that actually is made up of oxygen. In normal air this is 21%, in which case the FiO2 is 0.21. This ratio can also be used to classify ARDS:

• Mild ARDS: PaO2/FiO2 of 200-300 mmHg,
• Moderate ARDS: PaO2/FiO2 of 100-200 mmHg, or
• Severe ARDS: PaO2/FiO2 below 100 mmHg.

Clinically, the syndrome is characterized by the development of dyspnea and hypoxemia that progressively worsens until mechanical ventilation and intensive care unit (ICU)-level care is required. Patient history is directed at identifying the underlying disease that precipitated the ARDS.

Treatment

The majority of medical therapies for ARDS are aimed at treating its underlying cause. Most patients with ARDS will require endotracheal intubation and mechanical ventilation at some point during the course of their illness and recovery.

Prognosis

Outcomes for all forms of ARDS remain poor; mortality is estimated at 35% for mild, 40% for moderate, and 46% for severe ARDS. Patients with preexisting disease, alcoholism or advanced age are at higher risk of complications and death. 

Lung Transplantation

Key points

• Lung transplantation is a surgical procedure in which diseased lungs are partially or completely replaced by healthy lungs from a donor.
• It is a last resort therapeutic measure, which should only be applied in patients with end-stage lung disease.
• Lung transplantation should only be considered in patients who do not have any chronic heart, kidney, or liver disease; chronic infections; or who still smoke or drink alcohol.
• Following a transplant there is a strict management plan to try and prevent rejection of the new lung (tissue). Patients are bound to a lifelong regiment of immunosuppressive drugs and monitoring of the lung function.
• Mortality is highest the first month after transplantation as people are most susceptible to infection, cardiovascular failure, and graft rejection at that time. Median post transplantation survival is 7-8 years. 

Lung transplantation is a surgical procedure in which a patient’s diseased lungs are partially or totally replaced by healthy lungs from a donor. Donor lungs can be retrieved from a living donor or a deceased individual. With some lung diseases, a recipient may only need to receive a single lung; in other lung diseases, such as cystic fibrosis and bronchiectasis, it is imperative that a recipient receive two lungs. While lung transplants carry certain associated risks, they can also extend life expectancy and enhance the quality of life for end-stage pulmonary patients.

Qualifying Conditions

Lung transplantation is a last resort therapeutic measure reserved for patients with end-stage lung disease; all other treatments must be exhausted before a transplant is considered. Allocation of donor lung(s) to patients on the waiting list is based on a Lung Allocation Score (LAS) and includes a measure of urgency of need for transplant and a post-transplant likelihood of survival.

Lung transplantation may be necessary in a variety of conditions:

• 27% of lung transplants go to patients with chronic obstructive pulmonary disease (COPD), including emphysema;
• 30% of lung transplants go to patients with idiopathic pulmonary fibrosis;
• 14% of lung transplants go to patients with cystic fibrosis;
• 12% of lung transplants go to patients with idiopathic pulmonary hypertension;
• 5% of lung transplants go to patients with alpha 1-antitrypsin deficiency;
• 2% of lung transplants go to patients to replace previously transplanted lungs that have since failed.

Contraindications

Despite the severity of a patient’s respiratory condition, certain pre-existing conditions may make a person a poor candidate for lung transplantation. Concurrent chronic illness (e.g., congestive heart failure, kidney disease, liver disease), infections (such as HIV or hepatitis), older age, or the concurrent use of alcohol, tobacco or illicit drugs disqualify a patient for a lung transplant. Certain psychiatric conditions may make patients poorly compliant to post-surgical management, thus should be evaluated carefully. 

Post-Transplant Management 

Administration of antibiotics is necessary to combat the high risk of sepsis or infection following transplantation surgery. Rejection of the new organ is also a primary concern, both immediately after the surgery and throughout the patient’s life. In order to prevent rejection and consequential damage to the transplanted lung, patients must take a regimen of lifelong immunosuppressive drugs; which must be strictly adhered to. First year mortality is lowest for chronic obstructive pulmonary (COPD) and highest for idiopathic pulmonary arterial hypertension (IPAH), mortality at 10 years is highest for COPD and idiopathic pulmonary fibrosis and lowest for cystic fibrosis and alpha-1 antitrypsin deficiency patients.

Periodic bronchoscopy, spirometry, and transbronchial biopsies are advised to monitor for any problems.

Prognosis

Survival is influenced greatly by age and the underlying disease that warranted the transplant; patients above age 65 had grim outcomes compared to individuals between 18-50 years of age. Median posttransplantation survival is 7-8 years (bilaterale lung recipients have a better median survival than single lung recipients). 

Within the first 30 days after surgery, infection, graft failure, or cardiovascular failure are of great concern and comprise major causes of death. In contrast, individuals with successful transplant report significant improvements in quality of life. Those who have received bilateral transplants typically demonstrate normal pulmonary function, while recipients of unilateral transplants exhibit slightly reduced function, as evidence of the diseased lung. 

Obstructive Sleep Apnea

Key points

• Obstructive sleep apnea (OSA) refers to the (partial) collapse of the airways when muscle tone decreases in sleep. This leads to hypoxemia and disrupted sleep.
• Patients report exhaustion in the morning, excessive daytime sleepiness, choking or gasping for breath at night and their partner may report loud snoring.
• OSA is associated with obesity, male sex, and older age. It is diagnosed with poly(somno)graphy (PG/PSG). 
• Treatment consists of lifestyle measures and methods to keep the airway open at night. The most effective way is continuous positive airway pressure (CPAP) overnight, though other options are also available.

General 

Obstructive sleep apnea (OSA) is characterized by episodes of complete collapse of the airway or partial collapse during sleep. These are associated with a decrease in oxygen saturation during the night or arousal from sleep in order to restore the airways and oxygenation. This disturbance results in fragmented, nonrestorative sleep and leaves patients exhausted in the morning. Other symptoms include loud, disruptive snoring, witnessed apneas during sleep, and excessive daytime sleepiness. OSA has significant implications for cardiovascular health, mental illness, quality of life and driving safety.

Epidemiology

The prevalence varies from 15-30% in males and 5-15% in females. Prevalence is higher in Hispanic, African American, and Asian populations. Prevalence also increases with age, and when individuals reach 50 years of age or more. Males are often affected from middle-age and female patients are often postmenopausal when OSA arises.

Symptoms 

The typical adult OSA patient is an overweight or obese individual with excessive daytime sleepiness and loud nightly snoring. They may also complain of waking to gasp for breath or choking, sleep maintenance insomnia, night sweats, nighttime reflux, and nocturia in the absence of excessive nighttime liquid intake. A physical exam is typically notable for a larger than average neck circumference (17 inches in males) with crowded oropharynx (Mallampati score 3 to 4) and large tongue. Retrognathism (a posteriorly placed maxilla or mandible resulting in a chin that seems too far ‘back’ in the face) may be present. Patients with refractory atrial fibrillation, resistant hypertension, and history of a stroke should be screened for sleep apnea regardless of symptoms.

The typical child with OSA will have loud nightly snoring, may be hyperactive rather than sleepy, and may have academic difficulties. These children can be incorrectly diagnosed with attention deficit hyperactivity disorder (ADHD). Night sweats, nighttime reflux, sleep maintenance insomnia, restless sleep with frequent limb movements, and secondary nocturnal enuresis may also be present. A physical exam is often notable for adenoidal facies, tonsillar hypertrophy, hyponasal speech, and high arched palate. Patients with Down syndrome and any other condition associated with hypotonia should be screened for obstructive sleep apnea regardless of symptoms.

Risk factors 

Obese individuals are at a significantly higher risk for development. Male sex, older age, craniofacial and upper airway abnormalities are also a well defined risk factor.

Cause 

OSA occurs when there is not enough space to accommodate sufficient airflow in a portion of the upper airway during sleep. When muscle tone is decreased (which is common during sleep), the result is a repetitive total or partial collapse of the airway. In children, the most common cause of obstructive sleep apnea is enlarged tonsils and/or adenoids. In adults, it is most commonly associated with obesity, male sex, and advancing age.

Diagnosis

Nighttime in-laboratory level 1 polysomnography (PSG) is the standard gold test for diagnosis of OSA. During the test, patients are monitored to detect the following parameters:

• Nasal and oral airflow are monitored by electroencephalogram (EEG) leads, pulse oximetry, temperature and pressure sensors, 
• Motion is detected by respiratory impedance plethysmography or similar resistance belts around the chest and abdomen
• Muscle contraction in the chin, chest, and legs with electrocardiogram (ECG) leads, and electromyography (EMG) sensors

Sleep-related obstructive events per hour of sleep are measured in the apnea-hypopnea index (AHI) and the respiratory disturbance index (RDI) which is the sum of apneas, hypopneas, respiratory effort related arousals (RERAs) divided by total sleep time in hours. A hypopnea can be based on one of two criteria. It can either be a reduction in airflow of at least 30% for more than 10 seconds associated with at least 4% oxygen desaturation or a reduction in airflow of at least 30% for more than 10 seconds associated with at least 3% oxygen desaturation or an arousal from sleep on EEG.

Home sleep tests (HST) have gained popularity due to their relative accessibility and lower cost. If there is a high likelihood of moderate or severe uncomplicated OSA and no suspected non respiratory sleep disorders this test is usually performed.  

The AHI is the average number of obstructive events per hour. In adults, if the AHI is greater than or equal to 15 events per hour the diagnosis of obstructive sleep apnea is made. An AHI of 15 to 29.9 events per hour is classified as moderate OSA, while 30 or more events per hour is classified as severe OSA. An AHI index 5 to 14.9/hour is considered mild OSA. 

Children are diagnosed with mild OSA with an AHI 1 to 4.9 per hour and clinical sequelae. An AHI of 5 to 9.9 events per hour is moderate and 10 or greater per hour is severe. Either adult or child criteria can be used for patients 13 to 17 years old at the discretion of the clinician depending on the clinical picture.

Treatment

Management begins with patient education. Behavior modification (losing weight, exercising, changing sleeping position if OSA is positional) is indicated for most patients. Patients should be counseled to avoid alcohol, benzodiazepines, opiates, and some antidepressants which may worsen their condition. For adults, the use of continuous positive airway pressure (CPAP) is the most effective treatment, and diligent adherence to nightly CPAP use can result in near complete resolution of symptoms. For patients unable or unwilling to use CPAP or those who will be unable to access electricity reliably, custom fitted and titrated oral appliances (mandibular reposition device, as shown in figure 27) can be used to bring the lower jaw forward and relieve airway obstruction. For OSA with a strong positional component, a positioning device to keep a patient on their side can be an option. Although weight loss is recommended and can often decrease the severity of obstructive sleep apnea, it is not usually curative by itself. 

The primary treatment for obstructive sleep apnea in a child is tonsillectomy and adenoidectomy. The consideration for surgery should be balanced with the severity of symptoms, physical exam, and age. 

Figure 27. Mechanism of action of a mandibular reposition device. (a) demonstrates how the lower jaw sinks in sleep and the resulting posterior movement of the tongue (arrows) which subsequently blocks the pharynx. (b) shows how the mandibular reposition device in blue lifts the jaw and the tongue (arrows), freeing up the pharynx. Adapted from NTVG ‘Obstructieve slaapapneu’ 2019.