Speaker's Highlight

• Don Sin University of British Columbia, St. Paul Hospital (Canada)
  Kenneth R. Chapman Toronto General Hospital Research Institute (Canada)
• Parameswaran Nair McMaster University (Canada)
  Carolyn Calfee UCSF (U.S.A.)
• Gregory P. Downey University of Colorado School of Medicine (U.S.A.)
  David A. Schwartz University of Colorado School of Medicine (U.S.A.)
• Neil Schluger Tuberculosis Control Branch, California Department of Public Health (U.S.A.)
  Nick Kim Critical Care & Sleep Medicine, University of California San Diego (U.S.A.)
• Nicola Hananiah Baylor College of Medicine (U.S.A.)
  Jae-Joon Yim Seoul National University College of Medicine (Republic of Korea)
• Koichiro Asano Tokai University School of Medicine (Japan)
  Diahn-Warng Perng Taipei Veterans General Hospital (Taiwan)
• Konstantinos Kostikas University of Ioannina (Greece)
  Karin Klooster University Medical Center Groningen (Kingdom of the Netherlands)

• Pulmonary toxicity from immune checkpoint inhibitors: a clinical overview

  Immune checkpoint inhibitors have reshaped cancer treatment in Australia and overseas, with agents such as nivolumab, pembrolizumab, atezolizumab and ipilimumab now subsidised through the Pharmaceutical Benefits Scheme for melanoma, lung cancer, renal cell carcinoma and a growing list of other tumours. Their effectiveness rests on releasing the natural brakes on the immune system, but that same mechanism can sometimes turn on the lungs. Pulmonary toxicity, most often presenting as checkpoint inhibitor pneumonitis, has emerged as one of the more serious immune-related adverse events seen in everyday respiratory and oncology practice.

  For respiratory physicians, medical oncologists and general practitioners who share the care of these patients, recognising the early warning signs is critical. Lung involvement can progress from a mild dry cough and exertional breathlessness to respiratory failure within days. The challenge is amplified in Australia, where patients often travel long distances from regional areas to metropolitan cancer centres for treatment and follow-up.

  This overview explores the mechanisms behind checkpoint inhibitor pneumonitis, the typical clinical presentation, the diagnostic pathway recommended by Australian bodies such as the Thoracic Society of Australia and New Zealand, and the practical steps for grading severity and starting treatment. It also considers how care is delivered within the Australian health system, from PBS eligibility criteria to the growing role of telehealth for country patients.

  How checkpoint inhibitor pneumonitis develops

  The pathophysiology of checkpoint inhibitor pneumonitis is not fully understood, but it is thought to involve unchecked T-lymphocyte activity, a breakdown of peripheral immune tolerance and the unmasking of subclinical autoimmune reactivity in the lung parenchyma. Antibodies targeting PD-1, PD-L1 and CTLA-4 can all trigger this response, although combination regimens carry a substantially higher incidence than monotherapy.

  A history of thoracic radiotherapy, pre-existing interstitial lung disease, chronic obstructive pulmonary disease and an EGFR-mutant non-small cell lung cancer diagnosis all increase risk. Australians receiving immunotherapy for mesothelioma, an area of active local research, also appear to be at meaningful risk of pulmonary complications.

  Timing varies widely. Most cases develop between six weeks and six months after the first dose, but pneumonitis can appear within days of the first infusion or many months after the last cycle. This unpredictability means clinicians need to keep pneumonitis in mind at every visit, not only during the early induction phase.

  Recognising the clinical picture

  The symptoms of checkpoint inhibitor pneumonitis are non-specific and overlap with many other conditions seen in a respiratory clinic. A new or worsening dry cough, progressive dyspnoea on exertion, low-grade fever and fatigue are the most common complaints. Some patients describe feeling "a bit off", a presentation that can easily be dismissed without a high index of suspicion.

  General practitioners in the community, and emergency clinicians at centres such as Royal Melbourne Hospital, the Peter MacCallum Cancer Centre and Chris O'Brien Lifehouse in Sydney, all play a frontline role in early identification. Any patient on checkpoint inhibitor treatment who develops new respiratory symptoms deserves a same-day review and a low threshold for chest imaging rather than reassurance alone.

  The differential diagnosis is wide. Infection, including opportunistic pathogens in those already on corticosteroids, disease progression, pulmonary embolism, cardiac failure, radiation pneumonitis and coexisting endocrine immune-related adverse events must all be considered before settling on a diagnosis.

  Diagnostic workup and severity grading

  High-resolution computed tomography of the chest is the cornerstone of diagnosis. The four most frequently described patterns are organising pneumonia, non-specific interstitial pneumonia, hypersensitivity pneumonitis and diffuse alveolar damage. Bilateral ground-glass opacities with a peripheral or basal distribution are the commonest findings, but a normal scan does not exclude the diagnosis when clinical suspicion is high.

  Bronchoscopy with bronchoalveolar lavage is recommended in most patients with moderate or severe symptoms. The procedure helps exclude infection, supports the diagnosis of pneumonitis when lymphocytosis is found, and provides samples for cytology and viral studies. Transbronchial biopsy may add value when the diagnosis remains uncertain, although the yield is variable and the procedure carries additional risk in hypoxic individuals.

  Severity grading follows the Common Terminology Criteria for Adverse Events, version 5. Grade 1 is asymptomatic imaging disease, grade 2 involves mild symptoms limiting instrumental activities of daily living, grade 3 denotes severe symptoms and grade 4 indicates life-threatening respiratory compromise.

  Treatment and monitoring

  Management is driven by grade. Asymptomatic grade 1 disease can usually be managed with close surveillance and continuation of the checkpoint inhibitor, provided imaging and symptoms do not worsen. Grade 2 disease typically requires withholding the drug and starting oral prednisolone at 1 to 2 mg per kilogram per day, with a slow taper over four to six weeks once symptoms have stabilised.

  Higher grades demand urgent admission, intravenous methylprednisolone and, where there is no response within 48 to 72 hours, escalation to second-line immunosuppression. Infliximab is the most commonly used biologic, with mycophenolate mofetil reserved for those in whom TNF blockade is contraindicated. Prophylactic antimicrobials and Pneumocystis cover should be considered whenever high-dose steroids continue for more than a few weeks.

  Re-challenge with the same or a different checkpoint inhibitor may be considered after full resolution, particularly when the original cancer response has been strong. Decisions are made by a multidisciplinary team that includes respiratory, oncology, pharmacy and radiology input, an arrangement increasingly formalised in Australian tertiary cancer services.

  Drug class	Example agents	Approximate incidence of pneumonitis	Common CT pattern	Typical time to onset
  Anti-PD-1	Nivolumab, pembrolizumab	3 to 5% as monotherapy	Organising pneumonia, NSIP	2 to 4 months
  Anti-PD-L1	Atezolizumab, durvalumab	2 to 4% as monotherapy	Organising pneumonia, ground-glass opacity	2 to 4 months
  Anti-CTLA-4	Ipilimumab	1 to 2% as monotherapy	NSIP, hypersensitivity pattern	1 to 3 months
  Combination PD-1 plus CTLA-4	Nivolumab plus ipilimumab	8 to 15%	Organising pneumonia, diffuse alveolar damage	6 to 12 weeks

  Australian clinical practice considerations

  Within Australia, the Pharmaceutical Benefits Scheme subsidises several checkpoint inhibitor agents for specific indications, and adherence to PBS criteria shapes prescribing in public hospitals and private clinics. Resources such as eviQ and the Thoracic Society of Australia and New Zealand provide protocols tailored to Australian workflows, while the Therapeutic Goods Administration's Blue Card adverse event reporting system captures real-world toxicity data.

  Many tertiary centres now run dedicated immune-related toxicity clinics, often staffed by respiratory and oncology specialists together. For patients in the bush and in remote communities, telehealth has become a vital tool, allowing regional patients on immunotherapy to be reviewed by metropolitan specialists without long drives or flights.

  When reviewing any patient on a checkpoint inhibitor with new respiratory symptoms, a structured framework can be useful.

  Initial assessment priorities for suspected checkpoint inhibitor pneumonitis

  • Document the last infusion date, cumulative dose, exact agent and line of treatment
  • Examine for coexisting immune-related adverse events, particularly thyroid dysfunction and skin toxicity
  • Arrange high-resolution chest CT on the same day, along with oxygen saturation and inflammatory markers
  • Engage the treating oncology team, respiratory specialist and pharmacist together rather than working in silos

  Australian system considerations

  • Confirm PBS eligibility and update any prior approvals as needed
  • Use telehealth to involve a respiratory specialist early, particularly for rural and remote patients
  • Report serious or unexpected pulmonary events to the Therapeutic Goods Administration via the Blue Card
  • Provide the GP and patient with a clear written plan covering red flag symptoms and the fastest route back into specialist care

  The single most practical step for clinicians is to treat any new respiratory symptom in a patient on a checkpoint inhibitor as pneumonitis until proven otherwise. Early high-resolution imaging, prompt multidisciplinary discussion and timely corticosteroid therapy where indicated can change the trajectory of this potentially life-threatening complication, regardless of whether the patient is being managed in Sydney, Perth or a small town hundreds of kilometres from the nearest tertiary cancer centre.

  Richard Russell Nuffield Department of Clinical Medicine, University of Oxford (United Kingdom)
• Mona Bafadhel King’s College London (United Kingdom)
  David Jackson Guy’s and St Thomas’ Hospital, King’s College London (United Kingdom)
• James Chalmers University of Dundee (United Kingdom)
  David Price University of Aberdeen (United Kingdom)