Background

Since December 2019, SARS-Coronavirus-2 (SARS-CoV-2) global pandemic has deeply disrupted health, social and economic aspects of daily life worldwide. Facing this unprecedented outbreak, the cancer community is dealing with many arising and tough challenges. Patients with cancer have historically been considered more susceptible to viral infections because of their own immunosuppression and according to several studies are at major risk of developing severe complications of the Coronavirus Disease 2019 (COVID-19), including interstitial pneumonia.1 2

In the last decade, immunotherapy has dramatically changed the therapeutic landscapes of clinical oncology. With the aim to retrain immune system against cancer cells, several monoclonal antibodies (mAbs) targeting the immune checkpoints, such as programmed death 1 (PD-1), its ligand (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), have now joined the therapeutic armamentarium of several malignancies, including non-small cell lung cancer (NSCLC), melanoma and squamous head and neck cancer (SHNC).3

This novel class of immunomodulating agents called immune checkpoint inhibitors (ICIs) presents a peculiar safety profile, with a large spectrum of immune-related adverse events (ir-AEs) potentially affecting any tissue or organ. Immune-mediated pneumonitis is one of the most frequent, severe and potentially life-threatening ir-AEs. When considering clinical trial population, the frequency of anti-PD-1-related pneumonia across all cancer types is around 2.7%.4 In a real-life setting of patients with NSCLC, the overall incidence appears to be significantly higher (19%) and the development of immune-related pneumonia is more frequently associated with anti-PD-1 agents compared with those targeting PD-L1.5 6 ,7 Its management differs according to clinical and radiological presentation, from a watchful-waiting approach for asymptomatic cases to high-dose immunosuppressive steroid therapy (1–2 mg/kg of prednisone or equivalent) if respiratory symptoms are present or airway support is needed.7

Given the rapid spread of SARS-CoV-2 across the general population and the continuously growing number of patients with cancer receiving immunotherapy, to clinically distinguish between COVID-19 and ICIs-related pneumonia can be very difficult. Both entities are interstitial lung diseases often sharing several clinical and radiological features. Fever, dyspnea and productive cough represent the most common presenting symptoms, while ground-glass opacities (GGOs) with peripheral distribution are typical radiological findings on chest CT scan .8–12 These two conditions exhibit frequently also the same histopathologic picture, including alveolar damage, interstitial proliferation and fibrosis.8–12 In alveoli SARS-CoV-2 seems to have the capacity to engage and even directly infect immune cells such as neutrophils, macrophages and T lymphocytes, leading to a massive production of inflammatory cytokines such as interleukin 6 (IL-6).8–12 A similar pathogenic mechanism is thought to be responsible also for the development of immune-mediated pneumonitis, with pathological reports showing interstitial inflammation and lymphocytic infiltrate.8–12 Taking together these observations, an aberrant inflammation and reprogrammed immune cells functions seem to sustain both COVID-19 and ICIs-related pneumonia, with the potential risk of a mutual and amplifying interplay.8–12

No specific correlation has been demonstrated so far between ICIs treatment and disease severity or mortality for COVID-19.12–14 However, the potential effects of immunotherapy in patients recovered from SARS-CoV-2 infection are largely unknown and still have to be investigated.

Case presentation

Here, we describe the clinical case of a 65-year-old woman affected by relapsing oral cavity SHNC. In July 2018, the patient underwent left hemiglossectomy and homolateral cervical lymphadenectomy, with a pathological Tumor, Node, Metastasis (pTNM) stage T2N0 and no evidence of residual disease. No adjuvant treatments were indicated and the patient started a clinical and radiological follow-up. In February 2020, due to a left parapharyngeal relapse involving homolateral neurovascular bundle, the patient received cervical radiotherapy (70 Gy in 35 fractions) with concurrent cisplatin chemotherapy (100 mg/m² every 21 days) for three cycles. In June 2020, the patient experienced a further local disease progression and was referred to our phase I unit for enrollment in an early phase trial exploring safety and activity of a combination regimen including an anti-PD-L1 agent with an oral multi tyrosine kinase inhibitor (TKI) targeting several receptors, such as hepatocyte growth factor receptor (HGFR), rearranged during transfection (RET) and vascular endothelial growth factor receptor types 1–3 (VEGFR 1-3).

During the screening procedures, chest CT scan showed, as an occasional finding, GGOs in the middle right lobe suggestive for COVID-19, with a score of 4/6 according to COVID-19 Reporting and Data System (CO-RADS) criteria (figure 1A).15 No recent chest CT scans were available for a direct comparison, although the CT scout of a positron emission tomography scan performed at the beginning of May did not display any radiological alteration on the lungs.

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Figure 1

Screening CT scan showing ground-glass opacities (GGOs) in middle lobe (A) and first evaluation CT scan showing a worsening of GGOs even including right lower lobes (B).

The patient was asymptomatic and blood exams, including absolute lymphocyte count, C reactive protein (CRP) and IL-6, were within the normal range. The patient was suddenly admitted to a specific path in emergency room to rule out SARS-CoV-2 infection. Two consecutive nasopharyngeal swabs (NFSs) resulted negative, whereas IgG against SARS-CoV-2 were positive (48.1 AU/mL, with a threshold positivity of 15 AU/mL), clearly indicating a previous exposure to the virus. After a careful multidisciplinary discussion with radiologists, pneumologists and infectivologists, the scenario was interpreted as a recovered COVID-19 with lung radiological alterations still under resolution.

The patient started the experimental treatment with the anti PD-L1 mAb administered intravenously every 3 weeks and a daily oral TKI assumption. As per protocol, the first tumor assessment was performed 6 weeks later, after the first three cycles of immunotherapy. Alongside a stable disease according to response evaluation criteria in solid tumor (RECIST) version 1.1, chest CT scan showed an enlargement of GGOs, even affecting bilateral lower lobes and matching again a score of 4/6 according to CO-RADS criteria (figure 1B).15 An active infection was unlikely considering the good and stable clinical conditions, the absence of respiratory symptoms and results of blood exams (including IL-6) still within the normal range. The patient was hospitalized in an isolated ward to perform further investigations. A new NFS was negative and a bronco-alveolar lavage (BAL) did not detect malignant cells or any pathogens into a broad microbiological panel including SARS-CoV-2, Aspergillus fumigatus, Pneumocystis jirovecii, Mycobacterium tuberculosis and common respiratory viruses (influenza virus, parainfluenza virus, cytomegalovirus, respiratory syncytial virus, rhinovirus, metapneumovirus, adenoviruses, enteroviruses and common coronaviruses). As finding potentially suggestive for immune-related pneumonitis, a particularly high lymphocyte count of 26% was observed in the BAL.

A CT-guided lung biopsy was performed to complete the diagnostic work-up. The microbiological analysis was negative, while pathological examination coupled with immunohistochemical analysis for cluster differentiation 8 (CD8) and 68 (CD68) and the more common cytokeratines showed a mixed picture of interstitial proliferation, CD8+ lymphocytic infiltration and alveolar damage, with no evidence of malignancy (figure 2A–D).

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Figure 2

Pathological issues showing interstitial fibrosis and inflammatory infiltrate (A,B), CD8+ lymphocytic infiltrate (C) and CD68+ alveolar histiocytes (D).

Given the absence of infections and malignant lymphangitis, clinical, radiological and pathological data taken together were consistent with immune-mediated pneumonitis. Our hypothesis is that immunotherapy with PD-L1 blockade led to a worsening in GGOs detecting during screening procedure, with the COVID-19 lung injury acting as an inflammatory primer for the subsequent ICI-related pneumonia development. Due to the complete absence of symptoms, this lung toxicity was classified as grade 1 according to common toxicity criteria for adverse events (CTCAE) version 4, and no further interventions were needed. An involvement of TKI assumption in the worsening of radiological findings was very unlikely. Its well-established safety profile along with its mechanism of action do not suggest any role in the development of this lung damage.

Considering the clinical and radiological benefit on the underlying tumor, the patient restarted experimental immunotherapy after 6 weeks from the last infusion and is currently on-treatment. The last tumor assessment performed after two other infusions of anti-PD-L1 agent showed a further shrinkage of local disease in the neck configuring a partial response (PR), while GGOs appeared unmodified.