In response to the need for clear and concise recommendations for the management of IR-pneumonitis in the setting of the global COVID-19 pandemic, these recommendations were drafted with multidisciplinary cross-institutional input from medical oncology, infectious diseases including hospital epidemiology and infection control, pulmonary medicine and radiology subspecialists with expertise in IR-pneumonitis and COVID-19. The most pressing clinically-relevant questions and recommendations were discussed using an iterative, modified Delphi methodology.

The primary objectives of this position paper are to outline diagnostic evaluation and management principles for IR-pneumonitis in the setting of COVID-19. This includes emerging issues related to appropriate: (1) isolation procedures, (2) imaging and interpretation, (3) adaptations to invasive testing for IR-pneumonitis, (4) adaptations to current medical management of IR-pneumonitis, (5) immunosuppressive therapy for steroid-refractory IR-pneumonitis, and (6) management of suspected concurrent IR-pneumonitis and COVID-19 infection.

The recommendations in this clinical guidance document represent expert opinion that is based on limited and primarily retrospective data. Recommendations are subject to change as new data become available.

Previous to the COVID-19 pandemic, published consensus guidelines for the diagnosis and management of IR-pneumonitis had been developed by multiple oncologic societies.3 4 17 18 We propose that selected recommendations within these guidelines be adapted in the context of COVID-19, and outline these changes in table 1. These recommendations provide overall guidance in common clinical scenarios, however specific management decisions should be made on a case-by-case basis, weighing individual risks/benefits in the context of patient goals, comorbidities, disease status, and provider safety. In addition, wherever possible, multi-specialty input should be sought.19

The WHO and other groups have established guidelines for the appropriate screening and triage of patients with suspected COVID-19.20–22 When possible, routine patient visits and monitoring of otherwise clinically asymptomatic individuals receiving cancer treatments should be conducted via telemedicine.21 22 If in-person clinical evaluation is required, we recommend screening for the new onset of symptoms concerning for COVID-19 by phone prior to the scheduled visit, and again at in-person registration, to ensure patients are seen in a setting where appropriate infection prevention practices can be instituted such as a dedicated COVID-19 assessment area.

For patients who screen positive for symptoms concerning for IR-pneumonitis and/or COVID-19 when in the oncology clinic, such patients should be isolated in a separate dedicated COVID-19 screening/testing area to limit exposure to other patients and healthcare workers. Specifically, this includes ensuring that the patient immediately dons a face mask, and is placed in a private room (ideally with negative-pressure capabilities) with the door closed. Staff assessing these patients should be trained on optimal infection prevention practices including appropriate donning and safe doffing of personal protective equipment (PPE) which may include a fit-tested N95 or other respirator, protective eyewear, gown and gloves. Due to nationwide PPE shortages we recognize many facilities may not have sufficient respirators for all healthcare workers evaluating patients with COVID-19, and may preserve respirators for those undergoing aerosol generating procedures. On vacating the clinic room, it is vital to clean, disinfect, and await adequate air exchange, as directed by institutional guidance from infection control specialists. These measures are important in order to prevent potential onward transmission from a patient with suspected IR-pneumonitis and/or COVID-19 to ensure patients are seen in a setting where appropriate infection prevention practices can be instituted, such as a dedicated COVID-19 assessment area including mobile drive-through testing .

The most common appearances of IR-pneumonitis and COVID-19 infection on chest X-ray and chest CT imaging are depicted in figure 1. Since interstitial lung changes are poorly appreciated on chest X-ray, diagnostic chest CT is the recommended imaging modality for the evaluation of IR-pneumonitis.4 The spectrum of imaging findings of IR-pneumonitis on chest CT are described using radiographic patterns according to American Thoracic Society and European Respiratory Society classifications of interstitial pneumonias and related conditions including (1) acute interstitial pneumonia/acute respiratory distress syndrome (ARDS) pattern; (2) cryptogenic organizing pneumonia (COP) pattern; (3) non-specific interstitial pneumonia pattern; and (4) hypersensitivity pneumonitis pattern.1 23–27 Among these, the most common pattern is the COP pattern, characterized by multifocal bilateral parenchymal consolidations and ground glass opacities (GGOs) in a peripheral and lower lung distribution on chest CT.23 In addition, many patients frequently have diffuse bilateral lung involvement and the distribution is often independent from that of tumor involvement of the lung.2

Similar to IR-pneumonitis, chest X-ray appears to be less sensitive in detecting lung pathology for COVID-19 compared with CT imaging. In the largest single retrospective compilation of patient data from 1099 patients from 552 hospitals in 30 municipalities in mainland China, 59% of patients with COVID-19 had abnormal chest radiograph findings, whereas 86% had abnormal chest CT findings.28 The imaging manifestations of COVID-19 pneumonia are also variable, and have a wide spectrum ranging from normal chest CT in PCR-positive patients to fulminant and extensive bilateral interstitial opacities29–37 (figure 1). Evolving knowledge indicates that the typical CT imaging features of COVID-19 pneumonia include peripheral, bilateral GGOs or multifocal rounded GGOs that are noted with or without consolidation, or other findings suggestive of organizing pneumonia.38 Therefore, the radiographic pattern of typical COVID-19 pneumonia certainly overlaps with a COP pattern of IR-pneumonitis, which is the most frequently observed pattern. Similarly, the most fulminant cases from both entities result in the manifestations of ARDS characterized by diffuse or multifocal extensive GGOs and consolidations on imaging. In both entities, imaging manifestations reflect the lung’s response to injury, and the lung’s response patterns are often limited to several types as previously described.26 Thus, overlap is inevitable, making it difficult to distinguish between entities based on imaging alone.

Further complicating the diagnosis, abnormalities on chest CT may precede positive COVID-19 testing in some patients.32 35 Several studies have shown that completely asymptomatic infection may have imaging abnormalities (which tend to be less severe than in symptomatic patients).35 Conversely, a substantial percentage of patients with confirmed COVID-19 may initially present with normal CT imaging.30 The optimal approach to the longitudinal management of these patients has not been elucidated. Relevant to these cases, the WHO recommends symptomatic treatment and self-isolation only for patients with mild symptoms not requiring hospitalization.20 39 Therefore, in patients in whom grade 1 IR-pneumonitis is suspected, asymptomatic COVID-19 should now be considered in the differential diagnosis. Specific management recommendations for grade 1 IR-pneumonitis are outlined in the management section below.

The standard evaluation for IR-pneumonitis involves completion of a broad assessment of common respiratory pathogens via laboratory and non-invasive testing including but not limited to a respiratory viral panel, testing for atypical lung infections (eg, Mycoplasma, Aspergillus, Pneumocystis jiroveci), sputum culture and blood culture. In addition, a contrast-enhanced chest CT scan is recommended to assess lung tumor progression, and may require CT angiography technique if pulmonary embolism is suspected. Other common pulmonary comorbidities, particularly in patients with lung cancers, such as exacerbations of chronic obstructive pulmonary disease or congestive heart failure, should also be considered. Evaluation in symptomatic and critically ill cases may also include bronchoscopy with bronchoalveolar lavage (BAL) ±lung biopsy in order to assess for respiratory pathogens that may have been missed on non-invasive testing, as well as for malignant lung infiltration.

However, performing a bronchoscopy to diagnose suspected IR-pneumonitis may increase viral transmission risk of COVID-19 through aerosolization and may precipitate respiratory failure in patients with a tenuous clinical status. Precautions to minimize coughing and aerosolization, such as elective intubation, and the use of disposable bronchoscopes (if available) should be considered. Overall, we recommend that bronchoscopy for suspected IR-pneumonitis should be avoided or only completed in selected cases in which appropriate airborne precautions have been taken, and in consultation with both pulmonary medicine and infectious disease specialists. In selected cases in which this is needed, this procedure should ideally be performed in a negative pressure room with full COVID-19 precautions including appropriate donning of PPE. These recommendations align with those laid out by the Surviving Sepsis Campaign guidelines on the management of critically ill adults with COVID-19.40

While the majority of cases of IR-pneumonitis will improve with high-dose corticosteroids, steroid-refractory pneumonitis is not uncommon.2 In the event of IR-pneumonitis that does not clinically improve after ≥48 hours of high-dose steroids, multiple guidelines recommend consideration of alternative immunomodulating agents including infliximab, cyclophosphamide, mycophenolate mofetil, or intravenous immunoglobulin.3 4 17 18 However, prospective data in support of these strategies are lacking, and are based largely on case series and case reports.53 54

One attractive potential treatment for steroid-refractory IR-pneumonitis is anti-IL-6 therapy. IL-6 is a prominent cytokine implicated in acute inflammation, particularly in phenomena such as cytokine release syndrome (CRS) secondary to chimeric antigen receptor (CAR)-T cell therapy.55 Anti-IL-6 agents such as tocilizumab and sarilumab are standard-of-care treatments for CRS from CAR-T.18 This treatment may also be an effective strategy for irAEs. In a single-center retrospective study of 34 patients with steroid-refractory irAEs, including 12 with IR-pneumonitis, 79.4% of patients demonstrated clinical improvement following tocilizumab treatment.56 A prospective study of tocilizumab for the treatment of gastrointestinal (GI) and rheumatologic irAEs is ongoing (NCT03601611), but additional prospective studies are warranted to further evaluate the efficacy of anti-IL-6 therapy in the treatment of IR-pneumonitis.

Cytokine release and severe systemic inflammation also appear to play a prominent role in severe ARDS secondary to COVID-19 infection. Multiple retrospective studies suggest COVID-19 infected patients requiring ICU-level care have higher levels of markers of systemic inflammation including D-dimer, multiple interleukins and tumor necrosis factor alpha (TNFα).12 13 Furthermore, higher levels of inflammatory markers including CRP, ferritin, IL-6 and D-dimer have been observed in non-survivors compared with survivors of COVID-19.42 44 45 57 Thus anti-inflammatory treatments, such as anti-IL-6 therapy, are mechanistically appealing for the treatment of COVID-19. Early data have been encouraging, with multiple case reports supporting the efficacy of tocilizumab in the treatment of severe COVID-19 infection.58–60 In addition, a prospective Chinese trial showed improved oxygenation in patients treated with tocilizumab,61 resulting in the approval of this therapy for the treatment of severe COVID-19 in China. These encouraging data have led to the development of multiple ongoing prospective clinical trials for anti-IL-6 therapy in patients with severe COVID-19, of which there are >40 trials enrolling patients worldwide at the time of this publication. Furthermore, the Society for Immunotherapy of Cancer recently published a consensus statement on IL-6 targeted therapies for COVID-19, advocating for maximal expeditious effort to make available anti-IL-6 agents for compassionate use, as well as suggesting monitoring of FiO₂, PaO₂/FiO₂, CRP, and IL-6 in patients with COVID-19 receiving anti-IL-6 agents.62

Since there are published data in support of the potential benefit of anti-IL-6 therapy for both steroid-refractory IR-pneumonitis and severe COVID-19 infection, anti-IL-6 may be a reasonable treatment option for immunotherapy-treated patients with steroid-refractory IR-pneumonitis in the era of COVID-19 infection, as well as in the setting of possible concurrent IR-pneumonitis and COVID-19 infection. Anti-IL-6 therapy should not, however, replace initial management with corticosteroids in these patients. Rather, early implementation (≤48 hours of high-dose steroids if no clinical improvement or sooner if further deterioration) of anti-IL-6 therapy should be considered in an effort to limit prolonged exposure to high-dose corticosteroids.