Early presentation of pembrolizumab-associated pneumonitis

Abstract

Pembrolizumab is a selective anti-PD-L1 humanised monoclonal antibody approved by the Food and Drug Administration for treating multiple cancers, including cervical cancer, non-small cell lung cancer (NSCLC), renal cell carcinoma, bladder cancer, and squamous head and neck cancer. Pneumonitis is a rare but known complication of pembrolizumab treatment for NSCLC. The median time frame of its appearance is 2.8 months. However, we present a case of pneumonitis appearing within 48 hours. The patient presented with rapidly progressive respiratory failure, and imaging demonstrated diffuse bilateral patchy involvement of the upper lung lobe and pre-hilar regions, which likely indicate pneumonitis. Because of likely grade 3 pneumonitis, he was treated with steroids and showed immediate improvement of symptoms. Repeated CT imaging showed resolution of bilateral patchy infiltrates. He was discharged to the rehabilitation unit. Rapid recognition of pneumonitis as a side effect of pembrolizumab is important because early treatment can help prevent respiratory failure and possible death.

Background

Pembrolizumab is a selective anti-programmed death-1 ligand (PD-L1) humanised monoclonal antibody that has been approved by the Food and Drug Administration for use in the treatment of multiple cancers including cervical cancer, non-small cell lung cancer (NSCLC), bladder cancer, head and neck squamous cell cancer, and advanced renal cell cancer.¹ Common adverse effects associated with pembrolizumab include oedema, arrhythmias, electrolyte abnormalities, cytopenia, renal dysfunction, dyspnoea and cough.² Although pneumonitis is a rare but known cause of pembrolizumab use that can occur within an average time frame of 2.8 months, we report a case of pembrolizumab-associated pneumonitis occurring within 48 hours of starting immunotherapy.²

Case presentation

We present the case of a 59-year-old man who presented to the emergency department with acute respiratory failure and altered mental status. The patient denied fever, chills, sick contacts, worsening cough or sputum production. His medical history was significant for advanced stage IV NSCLC with brain metastasis, which was initially treated with conventional chemoradiation, and was also a former smoker. He was recently started on pembrolizumab less than 48 hours before presenting to the hospital with respiratory failure.

Chest radiography performed on initial presentation indicated interstitial prominence of the lungs along with air bronchograms predominantly in the left lung (figure 1). PCR testing for COVID-19 was negative. He was initially started on intravenous antibiotics in view of possible underlying pneumonia. However, further evaluation by CT imaging of the chest showed bilateral perihilar upper lobe airspace disease with diffuse bilateral patchy involvement in the bilateral upper lung lobes and perihilar regions suggestive of pneumonitis (figure 2).

Figure 1.

Chest X-ray shows interstitial prominence of the lungs along with air bronchograms predominantly in the left lung.

Figure 2.

Initial CT scan shows diffuse bilateral patchy involvement in bilateral upper lobes and perihilar regions.

Based on the recent pembrolizumab use and imaging findings, he was diagnosed with pembrolizumab-associated pneumonitis. The last dose of pembrolizumab was given 48 hours prior to presentation, and was not continued afterwards.

Differential diagnosis

In pembrolizumab-associated pneumonitis, the patient can present from being asymptomatic to having progressive shortness of breath (SOB) with or without fever. Imaging findings can show a variety of changes including non-specific interstitial pneumonia, organising pneumonia or diffuse alveolar damage.³ Other aetiologies can be ruled out based on clinical presentation and imaging findings.

In the current pandemic of the novel coronavirus infectious disease, pembrolizumab-associated pneumonitis must be distinguished from COVID-19. Patients present similarly with SOB and imaging findings of bilateral interstitial infiltrates. COVID-19 PCR should be performed for every patient presenting with those symptoms. Our patient has a negative COVID-19 PCR.

Pembrolizumab-associated pneumonitis should be distinguished from an infectious pneumonia, which can include bacteria, virus and fungi as sources.⁴ Patients with infectious causes present with fevers, produce productive sputum and have elevated white blood cells. If patients have pneumonitis, they will initially present more with respiratory failure.⁵ In infectious pneumonia, we will see ground-glass shadows in early stages that can appear as a lobar pneumonia on imaging.⁴ Patients who have neurological deficits, especially after brain metastasis, are at high risk of aspiration and hence aspiration must be considered while treating patients presenting with pneumonitis. Appropriate antibiotics should be commenced in such circumstances.

Hypersensitivity pneumonitis can be ruled out based on history of allergies and environmental exposure. If the patient has a lung tumour, it can be suspicious of disease progression if presenting with cough, weight loss and haemoptysis. Imaging can also demonstrate an increase in ground-glass appearance in lungs. Radiation pneumonia can occur around 2–6 months after radiation therapy. The lesions seen on imaging are in the area of the field of radiation and patients can also present with cough, SOB and fever.

Our patient did not present with the appropriate clinical history, symptoms and associated imaging findings to fulfil the criteria of other diagnoses.

Outcome and follow-up

The patient was started on intravenous methylprednisolone 40 mg every 6 hours for 5 days followed by oral prednisone 40 mg once daily for 4 days, then 20 mg once daily for 10 days, then 10 mg once daily for 4 days, then 5 mg once daily thereafter for six additional days. The tapering course of steroids led to significant improvement in his respiratory status. On presentation, the patient was requiring supplemental oxygen up to 6 L nasal cannula. Oxygen was eventually titrated down, and he was breathing on room air 10 days after starting steroids. Repeat chest X-rays demonstrated improvement of interstitial prominence and air bronchograms (figure 3). Subsequent CT scans of the chest showed resolution of bilateral patchy infiltrates seen during the initial imaging (figure 4). He was discharged to the inpatient rehabilitation unit for continuation of care. Pembrolizumab was not restarted, and the patient began to receive treatment with selpercatinib.

Figure 3.

Chest X-ray shows improvement with interstitial prominence and air bronchograms after treatment.

Figure 4.

CT image shows resolution of bilateral patchy infiltrates after treatment.

Discussion

The PD-L1 is a co-inhibitor expressed by T cells which downregulates T cell activity and T cell function.² The PD-L1 is normally expressed in tissues such as the lungs.² Tumour cells contain PD-L1, which will also help cancer cells avoid the natural immune system when they bind to the PD receptors on T cells, thus inactivating them.¹ PD-L1 immune checkpoint inhibitor antibodies restore the function of T cell function when they improve the antitumour response.²

Pembrolizumab is a monoclonal IgG₄ antibody that intercepts this pathway.² Although it is effective in this regard, it does have a range of side effects including maculopapular erythematous rash, pruritus, mucosal toxicity, hepatotoxicity and pneumonitis.²

Pneumonitis is rare but can be a life-threatening complication with drugs such as pembrolizumab. A systematic review of 19 trials reported a significantly increased incidence of pneumonitis associated with PD-L1 inhibitors.⁶ There is a 3% chance of occurrence of these instances when patients are on this therapy. The severity of cases can range from mild to severe, with the cases being severe seen in ~1% of patients.² Severe cases are generally seen more often in patients with NSCLC. The median time of onset is 2.8 months.² Leroy et al reported three cases of pembrolizumab-induced pneumonitis with the earliest onset after four infusions.⁷ Pneumonitis occurs due to an alteration in immune tolerance, leading to increased activation of immune cells against normal lung parenchyma.² This drug reaction is unlike other hypersensitivity, non-immunological, and/or toxic reactions that typically occur with other drugs.⁸ Pneumonitis occurs more frequently in patients with a history of asthma/chronic obstructive pulmonary disease or radiation with 2% and 4% increase, respectively.⁷ Patient presentation can range anywhere from asymptomatic to mild cough, SOB and chest pain, and in severe cases, the disease can lead to life-threatening respiratory failure.

In grade 1 pneumonitis, patients are generally asymptomatic. Classification is based on confinement to one lobe of the lung or <25% involvement of the lung parenchyma.⁹ Grade 2 pneumonitis involves the demonstration of more symptoms such as SOB and cough. The oxygen requirement of these individuals also increases. Grade 3 pneumonitis involves severe symptoms; patients exhibit these symptoms during normal activities of daily life. Imaging can help highlight the inclusion of all lung lobes, or there can be involvement of >50% lung parenchyma.¹⁰ In these individuals, supplementary oxygen is likely required. CT imaging of pneumonitis can exhibit various patterns reflecting acute respiratory distress syndrome, cryptogenic organising pneumonia, non-specific interstitial pneumonia and hypersensitivity pneumonia.¹¹ Our patient presented with similar reports of SOB and hypoxia. CT scan findings of bilateral patchy airspace disease and infiltrates in our patient also correlate with the findings in a study of three cases by Leroy et al.⁷

Management of grade 1 pneumonitis is based on monitoring for clinical or radiological changes. Grade 2 pneumonitis is treated with corticosteroids, which are usually intravenous methylprednisolone 0.5–1.0 mg/g/day and tapering of steroids over 1 month.¹¹ Repeat imaging should be considered in a few days to weeks. In grades 3 and 4, high-dose steroids should be administered at 2–4 mg/kg/day. In these individuals, immunosuppressors, such as infliximab or mycophenolate, may be required if the patients do not respond to steroids.^11–13 The steroids in this case require a longer tapering period, usually around 6 weeks. In this case, pembrolizumab should be discontinued. Patients with grade 3 or moderate grade 2 toxicity who do not respond to treatment within 3 months require discontinuation of pembrolizumab therapy.¹⁴

To the best of our knowledge, this case report is the first to describe the earliest presentation of pembrolizumab-associated pneumonitis in a patient with NSCLC. Our patient presented pneumonitis within 48 hours of initiation of pembrolizumab immunotherapy. Although such an early onset of pneumonitis is rare, patients on immunotherapy must be evaluated with early radiographic imaging because early diagnosis and treatment with corticosteroids will resolve pneumonitis in over half of the patients.

Learning points.

• Pembrolizumab is a selective anti-PD-L1 humanised monoclonal antibody that has been approved by the Food and Drug Administration for use in multiple cancers including cervical cancer, non-small cell lung cancer (NSCLC), bladder cancer, head and neck squamous cell cancer, and advanced renal cell cancer.

• Programmed death-1 ligand (PD-L1) is a co-inhibitor expressed by T cells which downregulates T cell activity and function. It is normally expressed in the lungs; cancer cells express PD-L1, which binds to T cells, thus allowing cancer cells to evade the immune system.

• Pneumonitis is a rare but known complication of pembrolizumab, and grading is based on location and symptoms in the patient.

• Treatment involves administration of steroids, and immunosuppressants are administered if the patient does not respond.

Ethics statements

Patient consent for publication

Consent obtained from next of kin.