Radiation Recall-Pneumonitis T78.8

Radiation recall pneumonitis is a rare, acute inflammatory reaction that occurs in the pre-irradiated lung area as an expression of a hypersensitivity reaction when antineoplastic substances such as paclitaxel, etoposide, pemetrexed, but also PD-L1 ("programmed cell death-ligand 1") inhibitors or other immune checkpoint inhibitors (ICI) are administered after completion of irradiation (Antonia SJ et al. 2017). Subsequent COVID vaccination also led to radiation recall pneumonitis in one individual case (Shinada K et al. 2022).

The radiation-induced inflammation and fibrosis of the lungs is similar to that of other tissues. By breaking chemical bonds, ionizing radiation generates highly reactive free radicals that influence and change cellular structures such as lipids, peptides or DNA. The effect on the tissue is controlled by cytokine expression, including TGF-beta, interleukin-6, TNF-alpha, which probably begins immediately after irradiation and lasts for months. The cytotoxic effect on the lung tissue is primarily a consequence of DNA damage. This causes cell death of the endothelial cells in the capillaries of the alveolar septa as well as the lung epithelial cells that line the alveolar spaces of the lungs - the so-called type I and type II pneumocytes. Damage to the pneumocytes caused by irradiation leads to a loss of barrier function, surfactant production, an associated reduction in surface tension and a transudation of serum proteins into the alveolar spaces. This damage results in increased capillary permeability with the development of interstitial pulmonary edema.

Effector cells (neutrophils, monocytes, macrophages and lymphocytes) attracted to the interstitium and alveoli by the proinflammatory cytokines and chemokines released define the subacute phase and induce radiation pneumonitis.

Activated fibroblasts play a decisive role in irreversible remodeling in the late phase - several months after irradiation. Extensive production of collagen, infiltration with inflammatory cells and finally occlusion of the alveoli are the consequences (Ziegeltrum J et al.2021). The remodeling of the lung parenchyma, which radiologically appears as radiation fibrosis, leads to stiffening and hardening of the lung parenchyma. As a result, gas exchange is reduced and total lung capacity decreases. The fibrosis is described as modified conventional (extending incompletely from anterior to posterior), "mass-like" (seam-like around the irradiated, usually irregular tumor area) or "scar-like" (streaky-scarred residue with volume reduction)

However, lung changes outside the direct irradiation area are also possible, in the sense of a hypersensitivity reaction caused by lymphocytic alveolitis.

Lung function tests can help to assess the severity of the lung impairment and also facilitate differential diagnosis with other lung diseases, such as COPD. Patients with radiation pneumonitis/radiation fibrosis show a reduction in total lung capacity, forced vital capacity, residual volume and/or diffusion capacity depending on the volume and degree of inflammation/fibrosis.

It is not possible to identify radiation pneumonitis in the laboratory. The peripheral blood often shows only a slight leukocytosis, LDH (lactate dehydrogenase) and/or CRP (C-reactive protein) may be moderately elevated with normal procalcitonin. Overall, these parameters are non-specific.

A radiogenically induced form of eosinophilic pneumonia has also been described in atopic or asthmatic patients, which can also manifest itself outside the radiation field (Nakayasu H et al. 2017). The morphology is very similar to radiogenic organizing pneumonia.

1. Antonia SJ et al. (2017) Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med 377: 1919-1929;
2. Choi YW et al. (2004) Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis. Radiographics 24:985-98
3. Ikezoe J et al. (1988) CT appearance of acute radiation-induced injury in the lung. AJR AmJ Roentgenol 150:765-770
4. Kalisz KR et al. (2019) Immune Checkpoint Inhibitor Therapy-related Pneumonitis: Patterns and Management. Radiographics 39:1923-1937.
5. Nakayasu H et al. (2017) Chronic eosiophilic pneumonia after radiation therapy for squamous cell lung cancer. Respiratory Medicine Case Reports 22:147-149
6. Shinada K et al. (2022) Radiation recall pneumonitis after COVID-19 vaccination. Thorac Cancer 13:144-145.
7. Teng F et al. (2020) Radiation recall pneumonitis induced by PD-1/PD-L1 blockades: mechanisms and therapeutic implications. BMC Med 18:275.
8. Togashi Y et al. (2010) A case of radiation recall pneumonitis induced by erlotinib, which can be related to high plasma concentration. J Thorac Oncol 5:924-925.
9. Ziegeltrum J et al.(2021) Radiotherapy-associated pneumonitis. In the focus of oncology. 24:28-32.