Interstitial Lung Disease

Interstitial lung disease (ILD) is not a single disease but a broad category of more than 200 distinct disorders that share a common final pathway: inflammation and/or fibrosis of the lung interstitium — the tissue and space around the alveoli — that stiffens the lung, impairs gas exchange, and, in the fibrotic subtypes, is only ever partially reversible at best.

Idiopathic pulmonary fibrosis — the focus of this chapter

Idiopathic pulmonary fibrosis (IPF) is a specific, chronic, progressively fibrosing ILD of unknown cause, limited to the lungs, and the most common and best-studied of the idiopathic interstitial pneumonias.^[1] It is also the ILD subtype with the most mature pharmacotherapy evidence base — the two antifibrotic agents detailed in Choose Initial Treatment were developed and approved specifically for IPF — which is why it anchors this chapter even though the diagnostic and monitoring principles in Assessment & Diagnosis and Monitoring & Follow-Up apply more broadly across fibrotic ILD. Without disease-modifying treatment, IPF has historically carried a median survival of roughly 3 to 5 years from diagnosis, worse than many cancers, which is the context for why the treatment goal in this chapter is to slow progression rather than promise a cure (see Treatment Targets).^[2]

Epidemiology in Canada

National Canadian administrative data (2007-2011) found an all-ages IPF prevalence of 41.8 per 100,000 population (14,259 cases) and an incidence of 18.7 per 100,000 (6,390 cases) using a broad case definition, with both rates higher in men; a narrower case definition requiring additional diagnostic confirmation gave a prevalence of 20.0 per 100,000 (6,822 cases) and an incidence of 9.0 per 100,000 (3,057 cases).^[3] Prevalence rises steeply with age, from 25.9 per 100,000 at ages 50-59 to 507.0 per 100,000 at age 90 and older, and varies geographically across Canada, with the lowest rates in British Columbia, Alberta, Saskatchewan, and Manitoba and the highest in Quebec.^[3]

Other ILD subtypes a pharmacist should recognize

The classic IPF presentation

IPF typically develops insidiously in a patient in their 60s or 70s, with progressive exertional dyspnea and a dry, nonproductive cough that build gradually over months to years rather than announcing themselves acutely.^[1] By the time most patients present for evaluation, symptoms have often been quietly progressing for a year or more, which is part of why a high index of suspicion in an older patient with unexplained breathlessness matters.

Classic examination findings

• Bibasilar, fine inspiratory crackles — classically described as "Velcro" crackles for their dry, fine, late-inspiratory quality — heard best at the lung bases posteriorly and often the first physical clue before imaging is obtained.
• Digital clubbing — a common associated finding in more established disease, though its absence does not exclude the diagnosis.
• Exertional desaturation on pulse oximetry, sometimes present even when resting saturation is still normal — a reason exercise oximetry has a specific role in the diagnostic and monitoring pathway (see Assessment & Diagnosis and Monitoring & Follow-Up).
• Signs of right heart strain (elevated jugular venous pressure, peripheral edema, a loud P2) in more advanced disease with secondary pulmonary hypertension.

Clues that point away from "plain" IPF

Certain features on history and exam should prompt a broader work-up rather than an assumption of IPF, since they change both diagnosis and treatment (see Assessment & Diagnosis and Special Populations):

• Connective tissue disease clues — joint pain or swelling, Raynaud phenomenon, skin thickening or sclerodactyly, proximal muscle weakness, or dry eyes/mouth alongside the respiratory symptoms.
• Exposure clues — symptoms that relate temporally to an occupational or environmental exposure (birds, mould, hot tubs, farming), sometimes with partial improvement away from the exposure — suggestive of hypersensitivity pneumonitis rather than IPF.^[4]
• Medication timeline clues — new or worsening respiratory symptoms after starting amiodarone, methotrexate, nitrofurantoin, bleomycin, or a newer targeted cancer therapy.^[5]
• Age under 50, a family history of pulmonary fibrosis, or a rapidly progressive course over weeks rather than months to years — all atypical for IPF and worth a broader differential.

IPF-specific risk factors

• Older age — IPF is rare before age 50 and its incidence and prevalence rise steeply thereafter; most patients are diagnosed in their 60s or 70s.^[3]
• Male sex — both prevalence and incidence are consistently higher in men than women in Canadian national data.^[3]
• Cigarette smoking history — a well-established epidemiologic risk factor, with risk generally tracking cumulative pack-years.
• Genetic predisposition — the MUC5B promoter polymorphism is the strongest common genetic risk factor identified for IPF, and rare variants in telomere-related genes (e.g., TERT, TERC) underlie a meaningful subset of familial pulmonary fibrosis, where two or more first-degree relatives are affected.

Risk factors for the other subtypes named in Clinical Snapshot

• Hypersensitivity pneumonitis — an identifiable, repeated inhalational antigen exposure is central: avian protein (pet birds, feather bedding), mould in a damp home or workplace, hot tub or humidifier aerosols, and farming (mouldy hay, grain dust) are classic triggers.^[4]
• Drug-induced ILD — amiodarone, methotrexate, nitrofurantoin, and bleomycin are long-recognized causative agents, joined by a growing list of newer targeted cancer therapies.^[5] Cumulative dose and duration of exposure matter for some of these agents (e.g., amiodarone, nitrofurantoin) more than for others.
• Connective-tissue-disease-associated ILD — a diagnosis of systemic sclerosis, rheumatoid arthritis, an inflammatory myopathy, or Sjögren syndrome is itself the risk factor; ILD can occasionally precede the systemic diagnosis.

High-resolution CT chest — the central diagnostic study

HRCT of the chest is the pivotal diagnostic test. The current international classification recognizes four HRCT pattern categories: UIP pattern, probable UIP pattern, indeterminate for UIP, and alternative diagnosis.^[1] In a patient with a classic clinical presentation and a typical UIP pattern on HRCT (basal- and subpleural-predominant reticulation with honeycombing, without features suggesting an alternative diagnosis), HRCT findings alone are often sufficient to confirm IPF without proceeding to surgical lung biopsy.^[1][6]

Pulmonary function testing

Spirometry and diffusing capacity for carbon monoxide (DLCO) are performed in every patient being evaluated for fibrotic ILD. The expected pattern is restrictive — a reduced forced vital capacity (FVC) with a preserved or increased FEV1/FVC ratio — together with a reduced DLCO, which is the primary objective measure used to screen for both resting and exertional hypoxemia and is the strongest predictor of gas-exchange impairment in fibrotic ILD.^[7]

Multidisciplinary discussion — the diagnostic gold standard

Integrated review by pulmonology, radiology, and pathology together is considered the gold-standard approach to diagnosing fibrotic ILD, since no single test reliably distinguishes IPF from its mimics in every patient.^[6][1] This multidisciplinary discussion (MDD) format is why IPF diagnosis is genuinely a team exercise rather than a single clinician reading a single scan.

Serologic testing and surgical lung biopsy

Screening serology for connective tissue disease (e.g., ANA, RF, myositis-specific antibodies as clinically indicated) is a routine part of the initial evaluation, given how commonly CTD-ILD is mistaken for IPF at first presentation.^[6] Surgical lung biopsy is reserved for patients whose HRCT and clinical features do not together establish a confident diagnosis — it becomes unnecessary once imaging is unequivocally typical for UIP in the right clinical context.^[6]

Differential diagnosis

Hypersensitivity pneumonitis, connective-tissue-disease-associated ILD, drug-induced ILD, and sarcoidosis are the principal alternatives to rule in or out (see Clinical Snapshot and Risk Factors) through a careful exposure history, medication timeline, and CTD-directed history/examination/serology, alongside the imaging and multidisciplinary review above.

Progressive pulmonary fibrosis — a newer, broader concept

The 2022 international guideline update formally recognized progressive pulmonary fibrosis (PPF): a non-IPF fibrotic ILD that nonetheless behaves progressively (worsening symptoms, physiology, and/or imaging over time) despite management directed at its underlying cause.^[8] This matters clinically because it is the basis for extending antifibrotic therapy beyond IPF into selected non-IPF fibrotic ILD (see Choose Initial Treatment).

IPF is not curable with current pharmacotherapy — antifibrotic treatment aims to slow the rate of fibrotic progression, not to reverse fibrosis that has already occurred. Setting this expectation explicitly and early avoids a common and understandable misunderstanding once a patient starts a disease-modifying drug (see Common Errors to Avoid).

• Slow disease progression — reduce the rate of decline in lung function (FVC) and, where the evidence supports it, reduce exacerbation frequency and disease-related hospitalization, using antifibrotic therapy where the patient's diagnosis and preferences support it.^[7]
• Manage symptoms — dyspnea and chronic cough are the two symptoms with the greatest day-to-day impact on quality of life and deserve dedicated attention independent of whether antifibrotic therapy is being used (see Non-Pharmacologic Treatment and Pharmacologic Treatment Options).
• Preserve quality of life — through pulmonary rehabilitation, appropriately timed oxygen therapy, and proactive psychosocial support.
• Individualize goals of care early — given the unpredictable, often progressive course of fibrotic ILD, begin advance care planning conversations well before a crisis, not only once decline is already advanced (see Non-Pharmacologic Treatment).^[7]

Pulmonary rehabilitation

Pulmonary rehabilitation carries only a weak recommendation in IPF given the limited number of well-controlled ILD-specific studies, but randomized trials still show real improvements in 6-minute walk distance, dyspnea, and quality of life.^[7] In resource-limited settings, prioritize referral for patients with advanced disease, reduced functional capacity, or those being considered for lung transplant, since they may derive the most benefit; adapt the educational and exercise components specifically for ILD rather than assuming an unmodified COPD-oriented program transfers directly.^[7]

Cough and dyspnea — non-pharmacologic strategies first

Chronic cough is reported in up to 85% of patients with fibrotic ILD, meaningfully reduces quality of life, and is itself an independent predictor of mortality — it is not a trivial nuisance symptom.^[7] Dyspnea is present in virtually every patient with advanced disease and is a similarly important predictor of prognosis.^[7] Non-pharmacologic strategies recommended for both include pacing and energy conservation, breathing retraining, body positioning, relaxation techniques, external airflow (a simple fan directed at the face), and cognitive behavioural therapy.^[7] These are first-line and should be tried and reinforced before or alongside any pharmacologic symptom management (see Pharmacologic Treatment Options).

Vaccination

Keep routine immunization current, and specifically ensure annual influenza vaccination and age-appropriate pneumococcal vaccination, given the added risk a respiratory infection poses on top of already-compromised lung function — and the recognized role infection can play as a trigger for acute exacerbation (see Special Populations).

Smoking cessation

Counsel every current smoker to quit — smoking is an established IPF risk factor (see Risk Factors) and continued smoking compounds an already-progressive disease process.

Advance care planning and palliative support — start early, not late

Given the unpredictable and often progressive course of fibrotic ILD, initiate advance care planning discussions with every patient during the course of their disease, not only once a crisis is imminent.^[7] A useful prompt for clinicians deciding when to raise goals-of-care is the "surprise question": would I be surprised if this patient were to die within the next 12 months? If the answer is no, it is a reasonable moment to revisit prognosis and priorities.^[7] Real Canadian data underscore how late this conversation tends to happen in practice: in one retrospective study of 404 patients with IPF, only 13.7% had ever been referred to palliative care, and 71% of those referrals occurred within 30 days of death.^[7] Palliative care should be integrated with disease-centred management early in the course of any severe, life-limiting fibrotic ILD, not reserved for the final days.^[7]

Patient education and advocacy

ILD has a significant impact on quality of life, family life, and emotional and physical wellbeing; a large multidisciplinary team (physicians, nurses, and allied health professionals) is the norm at most ILD centres.^[7] Direct patients toward reliable, Canadian, ILD-specific resources rather than unfiltered internet searches — the Canadian Pulmonary Fibrosis Foundation (cpff.ca) and the Canadian Lung Association (lung.ca) are two recommended starting points.^[7]

Acute exacerbation of IPF — a distinct, high-mortality deterioration

Acute exacerbation of IPF (AE-IPF) is defined as an acute, clinically significant respiratory deterioration characterized by new, widespread alveolar abnormality (typically bilateral ground-glass opacity and/or consolidation superimposed on the patient's baseline UIP pattern) occurring within about a month, and not fully explained by fluid overload or heart failure.^[11] It can be idiopathic or triggered by an identifiable cause such as infection, aspiration, surgery, or a procedure, and it carries a substantially higher mortality than the patient's usual gradual disease trajectory.^[11] An AE-IPF diagnosis genuinely requires excluding infection, pulmonary embolism, and other acute processes first (see Red Flags & Refer) — it is a diagnosis made partly by exclusion, and it needs urgent, hospital-level, specialist management, not a routine outpatient visit.

Connective-tissue-disease-associated ILD (CTD-ILD)

Treatment differs meaningfully from IPF: immunosuppressive agents such as mycophenolate mofetil, azathioprine, and cyclophosphamide are commonly used based on longstanding practice patterns, observational studies, and randomized trial evidence in some CTD-ILD subtypes, generally slowing disease without reversing existing fibrosis.^[7] Nintedanib is specifically Health Canada-authorized to slow FVC decline in systemic sclerosis-associated ILD (see Choose Initial Treatment) and can be used alongside disease-directed immunosuppression rather than as a substitute for it — do not extrapolate the IPF-specific "avoid immunosuppression" rule to this population.

Hypersensitivity pneumonitis

Identifying and removing the causative antigen is the central intervention; immunosuppression is individualized to disease severity and trajectory.^[4] A chronic, fibrotic form of HP that behaves progressively despite antigen avoidance and appropriate immunosuppression may meet criteria for progressive pulmonary fibrosis and become a candidate for antifibrotic therapy (see Assessment & Diagnosis and Choose Initial Treatment).^[8]

Pregnancy and breastfeeding

Nintedanib is contraindicated in pregnancy given its teratogenic potential in animal studies; confirm a negative pregnancy test before starting in anyone of reproductive potential.^[10] Pirfenidone has not been studied in pregnancy and should be avoided.^[9] Data on either agent in breastfeeding are inadequate to exclude risk to the infant — this is an individualized decision weighing the mother's clinical need against the limited safety data, made with the ILD care team rather than a default either way.^[9][10] Fibrotic ILD in pregnancy overall is uncommon and warrants specialist-directed, individualized management.

Hepatic impairment

Pirfenidone: use with caution in mild-to-moderate hepatic impairment (Child-Pugh A/B — exposure increases roughly 60% in Child-Pugh B) with closer monitoring for toxicity; avoid in severe hepatic impairment or end-stage liver disease.^[9] Nintedanib: reduce to 100 mg twice daily in mild hepatic impairment (Child-Pugh A, given roughly 2.2-fold increased exposure); treatment is not recommended in moderate or severe hepatic impairment (Child-Pugh B/C), which have not been adequately studied.^[10]

Renal impairment

Pirfenidone: use with caution in mild-to-moderate renal impairment; contraindicated in severe renal impairment (CrCl under 30 mL/min) or end-stage renal disease requiring dialysis.^[9] Nintedanib: no dose adjustment is required in mild-to-moderate renal impairment; safety and efficacy in severe renal impairment (CrCl under 30 mL/min) have not been studied.^[10]

Lung transplantation — the only potentially curative option

Refer patients with IPF or fibrotic nonspecific interstitial pneumonia for lung transplant evaluation at, or shortly after, the time of diagnosis, given the poor and genuinely unpredictable prognosis — do not wait for a specific lung-function threshold to be crossed the way non-IPF referral timing works.^[7] For non-IPF fibrotic ILD, refer when FVC falls under 80% predicted, DLCO falls under 40% predicted, any supplemental oxygen requirement develops, or the disease fails to respond to pharmacotherapy.^[7] Antifibrotic therapy is not a contraindication to transplant listing — although there is a theoretical concern about perioperative bleeding risk, available data have not shown a clinically significant signal, and antifibrotics are not contraindicated on transplant waitlists.^[7]

• Respirology clinic assessment approximately every 3 to 6 months, with more frequent review around the time of diagnosis or for a patient with higher-risk features for progression (older age, male sex, lower baseline FVC/DLCO, a UIP pattern on CT) or who is actively progressing.^[12]
• FVC and DLCO measured regularly, typically every 3 to 6 months, with less frequent testing reasonable in a patient with mild or long-stable disease.^[12]
• 6-minute walk test or walking oximetry every 6 to 12 months, depending on local availability, disease severity, and rate of progression.^[12]
• Follow-up chest CT periodically to assess for progression and guide treatment decisions, typically every 2 to 3 years in an otherwise stable patient with no evidence of symptom or pulmonary function worsening.^[12]
• Routine screening echocardiography is not recommended for most fibrotic ILD subtypes, outside a specific suspicion of pulmonary hypertension or cardiac dysfunction, or lung transplant evaluation.^[12]
• Do not repeat autoimmune/CTD serology once negative, unless new features suggestive of connective tissue disease develop.^[12]
• Antifibrotic-specific liver monitoring on the product-specific schedule in Choose Initial Treatment — pirfenidone: baseline, monthly for 6 months, then every 3 months; nintedanib: baseline, monthly for 3 months, then periodically (e.g., every visit) thereafter.^[9][10]
• For a patient on immunosuppression for non-IPF fibrotic ILD, routine laboratory monitoring typically includes CBC, renal function (creatinine), and liver function tests (ALT, alkaline phosphatase, GGT, bilirubin), on a schedule specific to the agent used.^[12]
• Confirm annual influenza vaccination and age-appropriate pneumococcal vaccination status at a routine visit.
• Screen for common comorbidities at each visit — coronary artery disease, gastroesophageal reflux, pulmonary vascular disease, obstructive sleep apnea, depression, and anxiety are all more prevalent in fibrotic ILD than in the general population.^[12]
• Monitor weight and nutritional status given the antifibrotic-associated weight loss reported with both pirfenidone and nintedanib.^[9][10]

1. Continued functional decline despite antifibrotic therapy: first confirm adherence and true tolerability rather than assuming drug failure. The guideline gives no recommendation for switching from one antifibrotic to the other, and does not support combining both — reassess overall trajectory, evaluate for an unrecognized acute exacerbation trigger or an alternate/overlapping diagnosis, and revisit lung transplant candidacy (see Special Populations) rather than escalating the same regimen indefinitely.
2. Pirfenidone-associated photosensitivity or GI intolerance: reinforce sun-protection counseling and food administration first; use dose reduction or temporary interruption per the monograph, with re-escalation back through the titration schedule once resolved — do not abandon a genuinely disease-modifying therapy at the first mild, manageable adverse effect.^[9]
3. Nintedanib-associated diarrhea: start hydration and an anti-diarrheal (e.g., loperamide) at first sign; escalate to dose reduction (100 mg twice daily) or temporary interruption for a persistent or more severe episode; reserve permanent discontinuation for severe diarrhea that persists despite symptomatic management.^[10]
4. Liver enzyme elevation on either antifibrotic: apply the specific agent's threshold precisely (see Choose Initial Treatment) rather than defaulting to permanent discontinuation for a mild, asymptomatic elevation — but do not rechallenge after a marked elevation or any elevation accompanied by symptoms of liver injury or hyperbilirubinemia.^[9][10]
5. Refractory cough or dyspnea despite non-pharmacologic measures: add a low-dose opioid (morphine or hydromorphone) as the guideline-preferred pharmacologic option, titrated carefully to effect (see Pharmacologic Treatment Options).^[7]
6. Suspected acute exacerbation of IPF: arrange urgent, hospital-level specialist assessment; rule out infection, pulmonary embolism, and other acute processes before attributing the deterioration to the underlying fibrotic disease itself.^[11]
7. Non-IPF progressive fibrotic ILD not stabilizing on disease-directed immunosuppression alone: reassess whether the patient now meets criteria for progressive pulmonary fibrosis and could benefit from adding nintedanib to the existing regimen (see Assessment & Diagnosis and Choose Initial Treatment).^[8]

• Prescribing the combination of prednisone, azathioprine, and N-acetylcysteine, or starting anticoagulation, specifically to treat IPF — the guideline gives a strong recommendation against both, based on evidence of harm.^[2]
• Prescribing ambrisentan, or reflexively adding sildenafil or N-acetylcysteine monotherapy, for IPF specifically — none is recommended, and ambrisentan carries a strong recommendation against use.^[2]
• Extrapolating the "avoid immunosuppression" rule for IPF onto every fibrotic ILD — immunosuppression remains appropriate and guideline-supported for connective-tissue-disease-associated ILD and hypersensitivity pneumonitis; the harm signal is specific to IPF (see Special Populations).
• Withholding anticoagulation or immunosuppression from a patient with fibrotic ILD who has an independent, unrelated indication for it (e.g., atrial fibrillation, a separate autoimmune condition) — the recommendation against these agents applies to using them as IPF treatment, not to every possible indication a patient with IPF might otherwise have.
• Telling a patient that antifibrotic therapy will improve or reverse their lung function — it slows the rate of decline; setting this expectation clearly avoids a painful misunderstanding later (see Treatment Targets).
• Skipping or shortening the antifibrotic-specific liver-monitoring schedule, or applying one agent's schedule to the other — pirfenidone and nintedanib have different monitoring intervals (see Choose Initial Treatment and Monitoring & Follow-Up).
• Omitting photosensitivity/sun-protection counseling when starting pirfenidone, or diarrhea/GI-perforation-risk counseling when starting nintedanib.
• Permanently discontinuing an antifibrotic after a single mild, asymptomatic liver enzyme elevation instead of following the product-specific dose-interruption-and-rechallenge pathway.^[9][10]
• Treating a sudden worsening of dyspnea or hypoxemia as routine, gradual disease progression rather than urgently evaluating for an acute exacerbation of IPF, infection, or pulmonary embolism (see Red Flags & Refer and Special Populations).
• Deferring advance care planning and palliative care conversations until very late in the disease course — real Canadian data show most palliative referrals for IPF happen only in the final month of life.^[7]

Antifibrotic Agents

The two guideline-endorsed, disease-modifying agents for IPF, and (for nintedanib) selected non-IPF progressive fibrotic ILD. No guideline preference exists between them — choose based on adverse-effect profile and patient preference. See Choose Initial Treatment for the full titration schedules and dose-modification thresholds.

Symptom-Directed Pharmacotherapy

For dyspnea and/or chronic cough that remain burdensome despite the non-pharmacologic strategies in Non-Pharmacologic Treatment. Guideline-preferred pharmacologic option for both symptoms once non-pharmacologic measures are insufficient.

Non-IPF Fibrotic ILD — Disease-Specific Immunosuppression

For connective-tissue-disease-associated ILD or hypersensitivity pneumonitis only. These agents have been shown to cause harm when used to treat IPF and are not an IPF-directed option (see Choose Initial Treatment and Common Errors to Avoid).