Progressive Dyspnoea: Pulmonary fibrosis.

Revising a little physiology of the lungs.

The lungs are very soft spongy organs whose purpose is to allow air from the atmosphere (by volume, dry air contains 78.09% nitrogen, 20.95% oxygen, 0.93% argon, 0.04% carbon dioxide, and small amounts of other gases. Air also contains a variable amount of water vapor, on average around 1% at sea level, and 0.4% over the entire atmosphere). The pressure in the pulmonary capillaries is always kept below the plasma protein oncotic pressure to prevent the transudation of interstitial fluid so the inside of the pulmonary capillary wall is kept dry. The input pressure into the capillary bed represents the mean pulmonary arterial pressure (15 mmHg). The output pressure represents the pulmonary venous pressure, which is also equivalent to the pulmonary capillary wedge pressure or left atrial pressure (5 to 6 mmHg). Total blood flow represents the cardiac output (5 to 6 L/min).

Pulmonary blood pressure is normally a lot lower than systemic blood pressure. Normal pulmonary artery pressure is 8-20 mm Hg at rest. If the pressure in the pulmonary artery is greater than 25 mm Hg at rest or 30 mmHg during physical activity, it is abnormally high and is called pulmonary hypertension.

The pressure drop from the pulmonary arteries to the left atrium is approximately 10 mmHg compared against a 100 mmHg pressure gradient in the systemic circulation. Therefore, PVR (pulmonary vascular resistance) is one-tenth of the resistance of systemic circulation. Low PVR maximizes the distribution of blood to the peripheral alveoli and ultimately allows for proper gas exchange. Multiple mechanisms regulate and contribute to pulmonary vascular resistance. Broad categories include pulmonary vascular pressure, lung volume, gravity, smooth muscle tonicity, and alveolar hypoxia. All these can be can play a role in interstitial lung diseases.

Complete pulmonary function testing (PFT; spirometry, lung volumes, diffusing capacity for carbon monoxide [DLCO]) and resting and ambulatory pulse oximetry are obtained in virtually all patients with suspected ILD. These tests are helpful in establishing the pattern of lung involvement (eg, restrictive, obstructive, or mixed) and assessing the severity of impairment. In patients with IPF, PFTs typically demonstrate a restrictive pattern (eg, reduced forced vital capacity [FVC], but normal ratio of forced expiratory volume in one second [FEV1]/FVC), a reduced DLCO, and, as the disease progresses, a decrease in the six-minute walk distance.

What does the pulmonary capillary wedge pressure represent?

It measures the left atrial pressure and is normally 5-6 mmHg,

A 65 year old man sees his doctor because he is feeling very tired and gets breathless within 50 feet of walking on flat ground. Two months ago he could walk for 2 kilometre daily at a brisk pace as part of his physical fitness regime. He has an irritating cough but does not bring up any sputum. He is afebrile, has no chest pain or muscle aches and pains in his limbs or trunk. His appetite is as usual. What other information would you ask him for?

Is he a smoker? Ask for details.

Has he been exposed to silica or dust? He could have visited a mine or inspected a stone crusher or gone on a desert safari?

Has he been treated with radiation or any drugs for cancer therapy?

Has he been started on new drugs for joint diseases like rheumatoid arthritis?

Does he feel that his eyes are dry? Does he have a dry mouth? (Sjogren’s syndrome, scleroderma).

Do his fingers and toes become cold and blue in cold water? Look for other manifestations of SLE, rheumatoid arthritis.

Does he think his muscles are getting weak i.e. he cannot climb stairs, get out of a low or soft chair or carry heavy grocery bags etc? Is he Cushingoid? May have been on corticosteroids causing proximal myopathy.

Is there a family history of lung disease or any of these diseases: ILD, premature graying, cryptogenic cirrhosis, aplastic anemia, other bone marrow diseases

You suspect fibrosis in the lungs. When you take a history and examine this patient what will you look for?

First exclude heart failure as it is much more common than ILD. Does he have hypertension or heart failure or an arrhythmia? Any ECG changes of IHD?

In ILD other than disease-specific symptoms, cough, progressive exertional dyspnea, and exercise limitation are the main presenting symptoms. The diagnosis is often delayed by several months or even years. A thorough history, including environmental exposures, medication use, and extrapulmonary signs, should be taken as given above. On chest auscultation, fine crackles (also called Velcro rales or crepitations) are indicative of fibrosis, although squeaks may be heard in patients with hypersensitivity pneumonitis. Premature graying of hair and hematologic abnormalities may be a sign of telomeropathy-related fibrosis. In CTDs, pulmonary fibrosis may develop either after the underlying condition is diagnosed or before the extrapulmonary manifestations are observed. Hands, joints, and skin should be thoroughly examined.  

What tests will you do to confirm your diagnosis?

 There is no laboratory test specific for a diagnosis of IPF, so the role of laboratory testing in patients with newly identified ILD is to identify or exclude processes in the differential diagnosis.

Chest imaging.

  1. Chest Xray.
  2. HRCT. A diagnosis of IPF cannot be made based on HRCT appearance alone. The characteristic HRCT features of IPF include peripheral, basilar predominant opacities associated with honeycombing and traction bronchiectasis-bronchiolectasis. Honeycombing refers to clusters of cystic airspaces approximately 3 to 10 mm in diameter, usually in a subpleural location. While honeycombing is essential to making a definite HRCT diagnosis of usual interstitial pneumonia (UIP), it is absent in probable and indeterminate UIP

Serological tests.

  1. Rule out connective tissue disorders: SLE, rheumatoid arthritis: antinuclear antibodies, anti-cyclic citrullinated peptide antibodies, and rheumatoid factor.
  2. Determine degree of inflammation currently: C-reactive protein (CRP) and erythrocyte sedimentation rate are nonspecific measures.
  3. If suggestive symptoms or signs are present: antisynthetase and other myositis panel antibodies (eg, anti-Jo-1, anti-PL7, anti-melanoma differentiation associated gene [MDA]-5), creatine kinase, aldolase, Sjögren’s antibodies (anti-SS-A, anti-SS-B), and scleroderma antibodies (anti-topoisomerase [scl-70], anti-PM-1).

Complete lung function

The CLP are done to establish the pattern of lung involvement (eg, restrictive, obstructive, or mixed). The major types of pulmonary function tests (PFTs) are spirometry, spirometry before and after a bronchodilator, lung volumes, and quantitation of diffusing capacity for carbon monoxide. Additional PFTs, such as measurement of maximal respiratory pressures, flow-volume loops, submaximal exercise testing, and bronchoprovocation challenge, are useful in specific clinical circumstances. Before doing lung function tests withhold bronchodilators i.e. short-acting inhaled bronchodilators (eg, albuterol, salbutamol, ipratropium) should not be used for four hours prior to testing. Long-acting beta-agonist bronchodilators (eg, salmeterolformoterol) are typically held for 12 hours prior to testing. The ultra long-acting beta agonists (eg, indacaterololodaterol, vilanterol) and the long-acting anticholinergic agents glycopyrrolate (glycopyrronium), tiotropium, and umeclidinium are held for 24 hours. Aclidinium would be held for 12 hours, based on twice daily dosing. 

Spirometry, the most readily available and useful pulmonary function test, measures the volume of air exhaled at specific time points during a forceful and complete exhalation after a maximal inhalation. The total exhaled volume, known as the forced vital capacity (FVC), the volume exhaled in the first second, known as the forced expiratory volume in one second (FEV1), and their ratio (FEV1/FVC) are the most important variables reported.

When to use spirometry? Spirometry is a key diagnostic test for asthma and chronic obstructive pulmonary disease (COPD) (when performed before and after bronchodilator) and is useful to assess for asthma or other causes of airflow obstruction in the evaluation of chronic cough. It is also used to monitor a broad spectrum of respiratory diseases, including asthma, COPD, interstitial lung disease, and neuromuscular diseases affecting respiratory muscles.

The slow vital capacity (SVC) can also be measured with spirometers which collect data for at least 30 seconds. The SVC may be a useful measurement when the FVC is reduced and airway obstruction is present. Slow exhalation results in a lesser degree of airway narrowing, and the patient may produce a larger, even normal vital capacity. In contrast, the vital capacity with restrictive disease is reduced during both slow and fast maneuvers. 

Performance of spirometry before and after bronchodilator is used to determine the degree of reversibility of airflow limitation. Administration of albuterol by metered-dose inhaler (MDI) is indicated if baseline spirometry demonstrates airway obstruction or if one suspects asthma or COPD. Albuterol (4 inhalations of 90 to 100 mcg) or an equivalent short-acting beta agonist is administered by metered dose inhaler with a spacer or chamber device.

In a patient with airway obstruction, an increase in the FEV1 of more than 12 percent and greater than 0.2 L suggests acute bronchodilator responsiveness . In patients with asthma, bronchodilator administration often results in improvement, and in some patients with asthma, post-bronchodilator testing may improve to normal spirometry values. Among patients with COPD, administration of bronchodilator sometimes leads to a significant change in FEV1, but reversal to normal spirometry rules out a diagnosis of COPD.

 Airway obstruction located in the pharynx, larynx, or trachea (upper airways) is usually impossible to detect from standard FVC maneuvers. Whenever stridor is heard over the neck and for evaluation of unexplained dyspnea flow-volume loops, which include forced inspiratory and expiratory maneuvers, are performed. Reproducible forced inspiratory vital capacity (FIVC) maneuvers may detect variable extrathoracic upper airway obstruction, as can be seen with vocal fold paralysis or dysfunction, which causes a characteristic limitation of flow (plateau) during forced inhalation but little if any obstruction during exhalation.

Bronchoprovocation challenge.  Spirometry is used to assess the airway hyperresponsiveness to a variety of bronchoprovocation challenges, such as methacholine, histamine, mannitol, and isocapnic hyperpnea. 

When is supine and sitting spirometry used? How can you assess diaphragmatic weakness? To evaluate respiratory muscle weakness, spirometry can be obtained with the patient supine and sitting. Diaphragmatic weakness is suggested by a decrease in the supine VC >10 percent. Unilateral diaphragmatic paralysis is usually associated with a decrease in VC of 15 to 25 percent; bilateral diaphragmatic paralysis can be associated with a decrease in supine VC approaching 50 percent.

Imaging with the patient in the prone position should be performed only if there are subtle dependent opacities of unclear clinical significance.

When should lung volumes be determined and how? Measurement of lung volumes is important when spirometry shows a decreased forced vital capacity. Body plethysmography is the gold standard for measurement of lung volumes, particularly in the setting of significant airflow obstruction. Alternative methods include helium dilution, nitrogen washout, and measurements based on chest imaging.

Maximal inspiratory pressure (MIP), measured at RV, is the maximal pressure that can be produced by the patient trying to inhale through a blocked mouthpiece after a full exhalation. Maximal expiratory pressure (MEP) is the maximal pressure measured during forced expiration (with cheeks bulging) through a blocked mouthpiece after a full inhalation (TLC). Measurement of maximal inspiratory and expiratory pressures is indicated whenever there is an unexplained decrease in vital capacity or respiratory muscle weakness is suspected clinically.

Measurement of the single-breath diffusing capacity for carbon monoxide (DLCO, also known as transfer factor or TLCO) is quick, safe, and useful in the evaluation of restrictive and obstructive lung disease, as well as pulmonary vascular disease.

In the setting of restrictive disease, the diffusing capacity helps distinguish between intrinsic lung disease, in which DLCO is usually reduced, and other causes of restriction, in which DLCO is usually normal. In the setting of obstructive disease, the DLCO helps distinguish between emphysema and other causes of chronic airway obstruction.

Six-minute walk test — The six-minute walk test (6MWT) is a good index of physical function and therapeutic response in patients with chronic lung disease, such as COPD, pulmonary fibrosis, or pulmonary arterial hypertension. During a 6MWT, healthy subjects can typically walk 400 to 700 m. In addition to total distance walked, the magnitude of desaturation and timing of heart rate recovery have been associated with clinical outcomes.

The incremental shuttle walk test (ISWT) is a 12 level test in which the subject walks at a progressively increasing speed for 12 minutes over a 10 meter course, where each 10 m trip between cones is a “shuttle”. Heart rate can be monitored by pulse oximetry or telemetry. The walking speed increases every minute from an initial 0.5 m/sec to 2.37 m/sec at level 12. The test is stopped when the subject is limited by dyspnea or heart rate (>85 percent predicted maximum), is unable to maintain the required speed, or completes the 12 levels. The primary outcome is the distance covered, which is calculated from the number of completed shuttles.

Pulse oxygen saturation 

A clear consensus has not been reached about what value for resting oximetry differentiates normal and abnormal. At sea level, values for pulse oxygen saturation (SpO2) ≤95 percent are considered abnormal, although a decrease to 96 percent in a patient who has previous values of 99 percent could be abnormal. Exertional decreases in SpO2 ≥5 percentage points are also considered abnormal. A value of SpO2 ≤88 percent is generally an indication for supplemental oxygen, although the benefits of supplemental oxygen in patients with normal resting saturations and exertional decreases to ≤88 percent are unclear. Confirm by checking ABGs.

Arterial blood gases  are a helpful adjunct to pulmonary function testing in selected patients. The primary role of measuring ABGs in stable outpatients is to confirm hypercapnia when it is suspected on the basis of clinical history (eg, respiratory muscle weakness, advanced COPD), an elevated serum bicarbonate level, and/or chronic hypoxemia. ABGs also provide a more accurate assessment of the severity of gas exchange impairment in patients who have low normal pulse oxygen saturation (eg, <92 percent).

When do you need to do pulmonary function tests?

  1. Evaluation of symptoms such as chronic persistent cough, wheezing, dyspnea, and exertional cough or chest pain
  2. Objective assessment of bronchodilator therapy
  3. Evaluation of effects of exposure to dusts or chemicals at work
  4. Risk evaluation of patients prior to thoracic or upper abdominal surgery
  5. Objective assessment of respiratory impairment
  6. Monitoring disease course and response to therapy

Why does pulmonary fibrosis develop?

The brief answer is we don’t know. Keep exposure to birds and molds in mind as well as pulmonary sarcoidosis, an underlying autoimmune disease, or if no cause is identified, an idiopathic interstitial pneumonia

The formation of fibrosis is an essential response against pathogens and in normal wound healing. Much is still unknown about the pathophysiology of specific disease entities and the factors that differentiate normal wound repair from progression to fibrosis. What factors are needed to cause persistent pulmonary fibrosis? Triggers, susceptibility, and initial inflammatory responses are required to initiate and maintain fibrosis and and the degree of each varies among diseases. The current assumption is that in later phases, common mechanisms play a role. At this stage clinical intervention is unlikely to help the patient.

At present the most favored hypothesis for the formation of pulmonary fibrosis is the early aging of alveolar epithelial cells and subclinical pathogenic stimulus. Senescence of alveolar epithelial cells and fibroblasts appears to be a central phenotype that promotes lung fibrosis.

What role do bacteria play in the development of fibrosis?

Innate immune cells, such as monocyte-derived alveolar macrophages, appear to be critical for the development of lung fibrosis. In one study, bacterial DNA could not be detected in lung tissue from patients with IPF, but other work has identified an abundance of prevotella, veillonella, and escherichia in bronchoalveolar-lavage fluid from such patients. In addition, both an increased overall bacterial burden and an abundance of streptococcal and staphylococcal organisms have been associated with an increased risk of disease progression in patients with IPF.

Diffuse parenchymal lung diseases encompass a large number of conditions, which are fortunately rare. They have an intrinsic heterogeneity. In most of them, the pulmonary alveolar walls are infiltrated by various combinations of inflammatory cells, fibrosis, and proliferation of certain cells that make up the normal alveolar wall. Since these pathologic abnormalities predominate in the lung interstitium, the disorders are termed interstitial lung diseases (ILDs). The commonest of these lung diseases is idiopathic pulmonary fibrosis (IPF). Among all patients with fibrotic ILDs other than IPF, 13 to 40% have a progressive fibrosing phenotype i.e. are genetic in susceptibility.

ILDs can be divided into five broad clinical categories, however clinicians most often see patients with CTD–ILD, IPF, CHP, sarcoidosis, or unclassifiable fibrotic ILD.

  1. ILDs related to distinct primary diseases (e.g., sarcoidosis, Langerhans-cell granulomatosis, eosinophilic pneumonia, lymphangioleiomyomatosis, and pulmonary alveolar proteinosis);
  2. ILDs related to environmental exposures, including pneumoconiosis due to inhalation of inorganic substances (asbestos, silica, other fumes, vapors, dusts) and hypersensitivity pneumonitis mostly related to inhalation of organic particles (e.g., domestic or occupational exposure to mold or birds or other exposures);
  3. ILDs induced by drugs, illicit drugs, or irradiation; amiodaronebleomycin, long-term nitrofurantoin, biologic therapies)
  4. ILDs associated with connective tissue disorders (CTDs), including RA–ILD and SSc–ILD, idiopathic inflammatory myopathy, and primary Sjögren’s disease.
  5. Idiopathic interstitial pneumonias, which include IPF, idiopathic nonspecific interstitial pneumonia.

Currently, there is a specific interest in the potential development of fibrosis after coronavirus disease 2019 (Covid-19). Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of pulmonary symptoms, male sex, older age, obesity, and coexisting conditions appear to be risk factors for the development of SARS. Pulmonary fibrosis is a known complication of acute respiratory distress syndrome (ARDS), and there are similarities in the fibroproliferative response and risk factors between lung fibrosis in the context of ARDS and lung fibrosis in the context of other diseases. Nevertheless, analysis of long-term follow-up data after ARDS or infection with another strain of SARS-CoV in 2003 showed fibrotic changes that remained mostly stable over time and had little clinical relevance.

Having made a diagnosis of IPF it is necessary to distinguish it from other forms of ILD.

Shown below are some patterns of imaging in ILD.

Some atypical features of IPf include including upper-lung or midlung predominance, peribronchovascular predominance, subpleural sparing, predominant consolidation, extensive ground-glass opacities, extensive mosaic attenuation , and diffuse nodules or cysts, should raise suspicion of an interstitial lung disease other than IPF.

Lung biopsy.

When the combination of clinical and imaging data is not diagnostic, a thoracoscopic lung biopsy can be considered if the results are expected to influence therapy. Biopsy samples should be taken from multiple lobes, and surgeons should avoid sampling the most severely affected areas, since samples from these areas typically show advanced, nondiagnostic fibrosis. The procedure should not be performed in high-risk patients, including those with high oxygen requirements (e.g., >2 liters per minute), pulmonary hypertension, rapid disease progression, severely reduced FVC or DLco, multiple coexisting conditions, or frailty. Transbronchial lung cryobiopsy has been increasingly advocated as a replacement for thoracoscopic biopsy.

Nonpharmacologic management strategies help patients with IPF live healthier, more normal lives, and the importance of these approaches cannot be overemphasized. Smoking cessation should be a priority for patients who are actively using tobacco products. Influenza, pneumococcal, and other age-appropriate vaccines should be administered. Oxygen administration reduces exertional dyspnea and improves exercise tolerance.57 An oxyhemoglobin saturation of 88% or less at rest, during exertion, or during sleep should prompt initiation of home oxygen therapy. The oxygen prescription should be informed by 6-minute walk tests or treadmill testing of oxygen saturation, as well as by nocturnal oximetry or polysomnography when indicated 

Pulmonary rehabilitation, a structured exercise program designed for adults with advanced lung disease, has been shown to improve exercise capacity and health-related quality of life for patients with IPF.

Only a minority of patients with IPF receive a transplant. Lung transplantation can prolong survival and improve quality of life for highly selected candidates however, only 66% of transplant recipients with IPF survive for more than 3 years after transplantation and only 53% survive for more than 5 years. Common complications include primary graft dysfunction, acute and chronic forms of allograft rejection, cytomegaloviral and other infections, and cancer. IPF has not been shown to recur in the allograft. 

Pharmacological therapy is available but is prohibitively expensive.

Two medications, nintedanib and pirfenidone, have been shown to be safe and effective in the treatment of IPF; both are recommended for use in patients with IPF In placebo-controlled, randomized trials, each drug has been shown to slow the rate of FVC decline by approximately 50% over the course of 1 year. Both have shown some efficacy in reducing severe respiratory events, such as acute exacerbations, and hospitalization for respiratory events. Pooled data and meta-analyses suggest that these agents may reduce mortality. The cost of each medication is estimated to exceed $100,000 annually. Patients should initially be prescribed 150 mg of nintedanib, to be taken by mouth twice daily. The medication should be taken with food and can be continued indefinitely. Patients taking nintedanib commonly have diarrhea, which can often be managed with antidiarrheal agents. The dose can be decreased to 100 mg twice daily if unmanageable side effects occur. Monitor liver function tests ans avoid if patient is on anticoagulants. Caution should be used when treating patients with cardiovascular risk factors, including those who have coronary artery disease.

Treatment guidelines for IPF include a strong recommendation against the use of prednisone in combination with azathioprine and oral N-acetylcysteine, a regimen associated with an increase in mortality by a factor of 9, as compared with placebo. A clinical trial showed no effect of N-acetylcysteine monotherapy on lung function. Interferon-γ, endothelin antagonists, and warfarin are ineffective or harmful in patients with IPF.

There are no data from clinical trials to support the use of antacids to slow the progression of IPF or ILD.

A phase 2 trial of pamrevlumab, an intravenously administered antibody targeting connective-tissue growth factor, slowed the decline in FVC, as compared with placebo, over a period of 48 weeks. PBI-4050, which targets multiple profibrotic cytokines and alters fibroblast function, may improve FVC when administered in combination with nintedanib. 

TD139, an inhaled galectin-3 inhibitor, has been shown to lower galectin-3 expression on alveolar macrophages in IPF.

Trials of BMS-986020 ( number, NCT01766817. opens in new tab), an oral LPA antagonist, and BG00011 (NCT01371305. opens in new tab), a monoclonal antibody targeting the αVβ6 integrin, have been completed, and the results are pending. A phase 1 study has shown that PRM-151 (recombinant pentraxin-2) is safe in patients with IPF; a phase 2 study (NCT02550873. opens in new tab) has been completed.

Two clinical trials of antimicrobial therapy potentially targeting the lung microbiome in IPF are ongoing (NCT02759120. opens in new tab; and EudraCT number, 2014-004058-32. opens in new tab).

Controlling cough.

There are several possible approaches for the management of cough in IPF, though none are universally effective.

  1. A trial of thalidomide confirmed that it could be used to ameliorate cough in patients with IPF.
  2. pirfenidone may attenuate cough.
  3. The P2X3 antagonist AF-219/MK-7264 (gefapixant) suppresses idiopathic cough; a trial of this agent in patients with IPF has been completed.
  4. Inhaled cromolyn preparation was shown to ameliorate cough in patients with IPF.

Watch out for complications.

Patients with IPF are at increased risk for venous thromboembolism, lung cancer, and pulmonary hypertension.

Incidental pulmonary nodules should be managed according to established guidelines for high-risk patients.

Pulmonary hypertension occurs in some patients with IPF, management in the outpatient setting should consist solely of supplemental oxygen, without pulmonary vasodilator therapy.

Once believed to be a single disease caused by smoking and characterized by a progressive loss of lung function with age, COPD should currently be considered a clinical syndrome with many causes in addition to smoking. This does not mean that health care professionals should refrain from encouraging all their patients who smoke to quit, but it does mean that the pathogenic mechanisms in mild-to-moderate COPD may differ from those in severe-to-very-severe cases of airflow limitation.

Idiopathic Pulmonary Fibrosis

List of authors.

  • David J. Lederer, M.D., 
  • and Fernando J. Martinez, M.D.

May 10, 2018
N Engl J Med 2018; 378:1811-1823
DOI: 10.1056/NEJMra1705751.

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I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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