Pneumonitis is defined as a focal or diffuse inflammation of the lung parenchyma, and is a known, potentially fatal toxicity of anti–programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors. Herein we discuss two patients who developed pneumonitis secondary to anti–PD-1/PD-L1 immune checkpoint inhibitor therapy and illustrate a stepwise approach to the diagnostic evaluation and management of anti–PD-1/PD-L1–related pneumonitis. In the majority of patients who develop this toxicity, pneumonitis appears to clinically resolve with corticosteroid therapy alone; however, a subset of patients require additional immunosuppressive medications. Patients who clinically improve with steroid treatment must be monitored closely in the outpatient setting. If pneumonitis management results in complete clinical and radiologic resolution, patients may be able to restart their immune checkpoint inhibitor therapy. It is currently unclear which population of patients is more susceptible to developing higher-grade or steroid-refractory pneumonitis.
These two cases describe the clinical presentation, diagnostic evaluation, management, and outcomes of two patients who developed anti–PD-1–related pneumonitis: one patient with NSCLC who received single-agent anti–PD-1 therapy, and a second patient with small-cell lung cancer treated with an anti–CTLA-4/PD-1 combination immune checkpoint inhibitor regimen.
These cases illustrate that there are both diagnostic and therapeutic challenges in identifying and managing patients who develop suspected anti–PD-1/PD-L1–related pneumonitis. The differential diagnosis for pneumonitis is wide, and drug-induced pneumonitis is a diagnosis of exclusion. Thus, in a patient in whom pneumonitis is suspected, providers must also consider competing causes for the clinical presentation, such as lung infection and/or progressive metastatic disease in the lung. Therapeutically, because pneumonitis may result in rapid patient decompensation, providers may elect to begin management with both antibiotics and corticosteroids before diagnostic tests are complete. The work-up often includes an extensive infection workup, high-resolution CT scan of the chest, and, for CTCAE grade 2 or higher presentations of pneumonitis, a bronchoscopic examination to rule out infection or disease progression. In the largest reported series of patients with anti–PD-1/PD-L1–related pneumonitis from two large academic centers, radiologic features on CT scan were categorized as cryptogenic organizing pneumonia–like (19%), resembling hypersensitivity pneumonitis (22%), discrete focal ground glass opacities (37%), or interstitial changes (7%). Fifteen percent of patients had a constellation of these findings, and were categorized radiologically as having pneumonitis not otherwise specified. Of note, although rare, anti–PD-1 therapy–related myocarditis can present with fulminant heart failure that may radiographically mimic pneumonitis; the presence of arrhythmias, chest pain, or evidence of volume overload on examination should prompt a cardiology evaluation.
- Following a stepwise approach will help physicians arrive at a reliable diagnosis and treatment plan for suspected anti–PD-1/PD-L1–related pneumonitis. In symptomatic patients, an extensive infection workup, radiologic imaging with a chest CT scan, and bronchoscopy should be strongly considered.
- Restarting immune checkpoint inhibitors can be considered if the pneumonitis initially presents as ≤ grade 2, and within a few days of initiation of pneumonitis management is downgraded to ≤ grade 1, without recrudescence of symptoms after corticosteroid taper.
- In the future, it will be critical to understand the mechanistic underpinnings of anti–PD-1/PD-L1–related pneumonitis, in order to tailor management approaches.
After the diagnosis of pneumonitis has been made, this toxicity must be graded and treated based on the CTCAE-defined grade. Broadly, grade 1 pneumonitis can be treated by withholding immune checkpoint inhibitors and by careful clinical observation. It has been advised that the immune checkpoint inhibitor regimen not be restarted until CT scans show improvement or there is complete resolution of pneumonitis. Patients with grade 2 pneumonitis (symptomatic pneumonitis) should receive prednisone, 0.5–1 mg/kg/d, or the equivalent, and patients with grade 3 pneumonitis should receive a higher dose: 1–2 mg/kg or the equivalent. If there is clinical improvement within a few days of implementation of this course of management, a 4- to 6-week corticosteroid taper may be completed. If the patient does not clinically improve within approximately 2 to 7 days of the start of corticosteroid administration, additional immunosuppressive medications may be considered (infliximab, cyclophosphamide, or mycophenolate mofetil); however, outcomes of these therapies have been variable in reported series. In addition, administration of an interferon gamma release assay for tuberculosis and additional considerations may be prudent before initiation of treatment with these agents. In patients who develop a recrudescence of symptoms during or after steroid tapering, an underlying infectious etiology, such as Pneumocystis jirovecii or bacterial pneumonia, should be considered, or a repeat clinical/radiologic evaluation for recurrent pneumonitis should be performed. In selected cases, when corticosteroids are restarted or given over an extended taper, antimicrobial prophylaxis should be considered in accordance with local practices. Finally, after the acute treatment phase, along with CT imaging, pulmonary function tests (including carbon monoxide diffusion [DLCO] and spirometry) may be useful in tracking the response of the pneumonitis to immunosuppressive management. A diagnostic evaluation and management algorithm based on clinical practice and published literature[16,19-21] for anti–PD-1/PD-L1–related pneumonitis has been included in this article (Figure 3).
In considering these two cases, the patient in Case 1 was diagnosed quickly and managed effectively with corticosteroids at his initial presentation; however, symptoms re-emerged, and subsequent treatment with corticosteroids was less effective. In addition, the patient developed progressive disease, which ultimately was the cause of death. This case highlights the diagnostic complexity of identifying anti–PD-1/PD-L1–related pneumonitis in patients with NSCLC, as well as the fact that pneumonitis may occur concurrently with disease progression. Further, it was not possible to perform bronchoscopy in this patient to truly rule out infection in the lung, which may have further complicated this clinical presentation and management.
In Case 2, the patient’s pneumonitis was highly steroid-responsive, but as in Case 1, a re-emergence of symptoms was seen after a 4-week steroid taper, warranting a slower taper. In both cases, the patients were followed closely and re-emergence of symptoms was treated expeditiously, with repeat evaluation for infection or other causes. After discharge, the patients were also followed closely in the outpatient setting. The patient in Case 1 was treated with antimicrobial prophylaxis after receiving an extended course of corticosteroids. Neither patient was treated with additional immunosuppression beyond corticosteroids, since both demonstrated improvement shortly after initiation of steroid therapy; however, given the recurrent nature of the first patient’s pneumonitis, it is unclear whether he might have benefited from additional immunosuppression at some stage during his steroid therapy, and if so, when this might have ideally been instituted. In addition to these clinical observations, our cases highlight the variability in radiologic findings in patients with anti–PD-1/PD-L1–related pneumonitis, as depicted in Figures 1 and 2.
Outpatient monitoring is also essential to improving the chances of recognizing pneumonitis early. Before starting immune checkpoint inhibitors, baseline radiologic imaging with high-resolution chest CT (with and without contrast) should be performed. It is critical that patients be made aware of the possible signs and symptoms of pneumonitis to report to their providers, including new or worsening dyspnea on exertion, shortness of breath, cough, chest pain, and fever. Patients with confirmed pneumonitis should be followed with regular CT imaging of the chest, at least every 1 to 2 weeks in severe cases, until they improve or resolve to ≤ grade 1, and thereafter as clinically indicated. Pulmonary function tests may be useful in this population of patients, and pulse oximetry, both at rest and on exertion, as well as spirometry and DLCO may be considered. Patients who may be eager to restart immune checkpoint inhibitor therapy after recovering from pneumonitis. However, restarting immune checkpoint inhibitors should be considered cautiously, particularly if they presented with pneumonitis of CTCAE severity ≥ grade 2. In a series of patients published by Naidoo and colleagues, among patients who presented with grade 2 or milder pneumonitis and who were re-challenged with immune checkpoint inhibitors, 25% developed recurrent pneumonitis. Careful deliberation is necessary when restarting immune checkpoint inhibitors in patients who present with pneumonitis of severity ≥ grade 3, as there are few published data to guide clinicians.
These two cases do not highlight certain clinical features that are important in diagnosing anti–PD-1/PD-L1–related pneumonitis. Notably, the timing of anti–PD-1/PD-L1–related pneumonitis onset may vary widely. The patients in both Case 1 and Case 2 developed pneumonitis shortly after the start of therapy; however, pneumonitis has been reported to have occurred more than a year after the first dose of immune checkpoint inhibitor therapy. The incidence rate of pneumonitis across cancer types appears to vary; however, new data suggest that the incidence of pneumonitis in lung cancer patients may be higher than in other cancers. Highlighted in Figure 3 are possible immunosuppressive treatments for steroid-refractory pneumonitis. Steroid-refractory pneumonitis is extremely rare: in the previously reported series of patients who received anti-PD-1/PD-L1 immune checkpoint inhibitors at two large academic centers, the incidence rate of pneumonitis was 5% (N = 43), and of the affected patients, only 11.6% required additional immunosuppression. In this study, patients who received further immunosuppressive treatment did not recover from their pneumonitis, and this group included those treated with infliximab, cyclophosphamide, and mycophenolate mofetil. The foregoing immunosuppressive therapies, as well as intravenous immunoglobulin (IVIG), have been used successfully to manage other irAEs, such as colitis and neurologic toxicities. It is postulated that IVIG may be a useful treatment for pneumonitis, since it may not be associated with the same rate of infective complications as other immunosuppressive medications. Mycophenolate mofetil has previously been used for the treatment of interstitial lung diseases. Currently, there are few published data to guide clinicians regarding the selection and dosing of immunosuppressive agents for steroid-refractory pneumonitis; however, prospective studies are planned.
As more patients receive immune checkpoint inhibitors, oncologists will need to become adept at identifying and managing the side effects of these agents, through experience and education. To facilitate this, the National Comprehensive Cancer Network (NCCN) has created an “Immunotherapy Teaching/Monitoring Tool” to help physicians learn more about immune checkpoint inhibitors and track their patients’ symptoms; also, an upcoming joint NCCN/American Society of Clinical Oncology panel is developing guidelines on immune-related toxicities. Future research aimed at identifying potential biomarkers for clinically important immune-related toxicities, such as pneumonitis, is needed.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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