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Case history

image A 69-year-old man with a history of stage IV melanoma presented with a 3 week history of dyspnoea. He had been diagnosed with a stage III melanoma, BRAF wild-type, 4 years previously and had undergone a radical resection with lymph node dissection, followed by surveillance. After 3 years he presented with a gastrointestinal bleed, leading to the diagnosis of small bowel recurrence. He underwent palliative bowel surgery; however, radiological assessment confirmed residual nodal and likely bowel disease. He was commenced on dual immunotherapy with ipilimumab and nivolumab. He completed four cycles of combination immunotherapy followed by maintenance anti-programmed cell death protein 1 (PD-1) monotherapy. Restaging contrast CT showed a good response with near complete resolution of disease. Immunotherapy was discontinued because of immune-related toxicity with colitis and hypophysitis.

Five months after completion of immunotherapy, the patient was hospitalized with breathlessness. Chest X-ray showed bilateral patchy consolidation in the mid- and lower zones. CT chest demonstrated confluent ground glass change and diffuse panlobar patchy consolidation with a peribronchial distribution. The differential diagnosis included atypical infection, immunotherapy-induced pneumonitis and tumour-related infiltrative lymphangiosis. The patient received intravenous antibiotics and oxygen therapy but deteriorated, developing life-threatening type 1 respiratory failure requiring invasive ventilation on the intensive care ward. He was started on intravenous high-dose co-trimoxazole for Pneumocystis jirovecii pneumonia based on the CT changes and history of steroid use for previous immune-mediated toxicity. A diagnosis of immunotherapy-induced pneumonitis was considered and he was commenced on intravenous steroids, albeit at a reduced dose because of reluctance from the intensive care physicians (0.7 mg/kg per day methylprednisolone equivalent).

The patient's respiratory function improved and he was extubated, unfortunately prior to invasive sputum sampling: although routine sputum returned negative for atypical organisms and respiratory viruses, expectorated sputum alone was insufficient to exclude a diagnosis of P. jirovecii pneumonia.

Despite his improving breathlessness, diagnostic bronchoscopy was performed to ascertain the underlying aetiology. Histology showed only minor reactive changes with no evidence of pneumonitis and no malignant cells. Microbiology was negative for all organisms tested, including Legionella, Mycoplasma and P. jirovecii pneumonia. He was switched to alternative oral antibiotics and a reducing course of oral steroids. His breathing improved and he no longer required oxygen. At last review in early 2018, he remained fully recovered and in remission from his melanoma.

What is the evidence base for the use of dual immunotherapy in this patient?

What is the survival benefit of using maintenance therapy after dual immunotherapy?

What is the likelihood of developing life-threatening respiratory complications after dual immunotherapy?

Why was there such diagnostic uncertainty in treating this patient's respiratory illness?

What is the evidence base for the use of dual immunotherapy in this patient?

Dual immunotherapy with ipilimumab (anti-cytotoxic T lymphocyte-associated protein 4 [CTLA-4] monoclonal antibody) plus nivolumab (anti-PD-1 monoclonal antibody) has become the gold standard of treatment for patients with stage IV melanoma. Several landmark phase III clinical trials have ...

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