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Successful Treatment with High-dose Steroids for Acute Exacerbation of Idiopathic Pulmonary Fibrosis Triggered by COVID-19

We herein report a case of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) triggered by COVID-19. An 87-year-old woman tested positive for COVID-19 on a polymerase chain reaction test, and computed tomography revealed ground-glass opacity (GGO) superimposed on a background pattern consistent with usual interstitial pneumonia. Considering these data, we diagnosed her with AE-IPF. She experienced worsening of dyspnea and expansion of the GGO. Therefore, we introduced high-dose steroids (methylprednisolone 250 mg/day for 3 days). After the treatment, the pulmonary infiltrates improved. She was discharged from our hospital without severe disability. High-dose steroids can be a viable treatment option for AE-IPF triggered by COVID-19.


Introduction
Coronavirus disease 2019 (COVID-19) pneumonia is an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 infection. Several drugs, including steroids and remdesivir, have been shown to be effective in recent randomized controlled trials for patients with severe COVID-19 (1,2). However, despite the development of therapeutic strategies, patients with COVID-19 still exhibit a high mortality rate, especially among the elderly and those with comorbidities, including diabetes, renal failure, and respiratory diseases (3,4). In particular, respiratory diseases, such as chronic obstructive pulmonary disease and interstitial lung disease (ILD), are also strongly associated with a high mortality (3,5).
Idiopathic pulmonary fibrosis (IPF) is an irreversible and progressive ILD with an unknown etiology. Some patients with IPF experience acute exacerbation (AE) of the disease, with episodes of the sudden acceleration of the disease process (6,7). AE-IPF is a severe and life-threatening complication of IPF that occurs without any identifiable causes or triggers, such as surgical intervention or infection (8).
We herein report a patient with AE-IPF triggered by COVID-19 who was successfully treated with a high-dose steroid.
Intern Med 61: 233-236, 2022 DOI: 10.2169/internalmedicine.8163-21 quarantine her from her family. She had a cough and slightly worsening dyspnea without hypoxia (oxygen saturation of 98% on ambient air). There were no extra-thoracic manifestations suggesting the presence of an underlying connective tissue disease (CTD). Routine blood tests showed a white blood cell count of 2,880/mm 3 , C-reactive protein of 0.09 mg/dL, lactate dehydrogenase 204 U/mL, D-dimer 1.8 μg/mL, KL-6 370 U/mL, ferritin 106.7 ng/mL, and positivity for anti-SSA(Ro) antibody. Chest X-ray and computed tomography (CT) showed bilateral ground-glass opacity (GGO) superimposed on a background reticular shadow and honeycomb in the bilateral lower lobes, suggesting the usual interstitial pneumonia pattern (Fig. 1A, 2A-B, 3A). Given these findings, we diagnosed her with AE-IPF triggered by COVID-19 and placed her on favipiravir from the first day of admission.
Five days later, she experienced hemoptysis, worsening of dyspnea (without hypoxia), elevated D-dimer 4.3 μg/mL, and expansion of GGO on CT (Fig. 1B, 2C-D, 3B). Therefore, we decided to initiate intravenous high-dose steroids (methylprednisolone 250 mg/day for 3 days followed by methylprednisolone 1.0 mg/kg/day, total 40 mg/day). In addition, we switched her anti-viral therapy from favipiravir to remdesivir. With this treatment, the dyspnea and pulmonary infiltrate of the left lower lobe gradually improved (Fig. 1C, 2E-F, 3C). The systemic steroid was tapered from day 8 of steroid therapy initiation and discontinued entirely on day 32. Finally, she was discharged from our hospital on day 34 without severe disability.

Discussion
We successfully treated a patient with AE-IPF triggered by COVID-19 with high-dose steroids. The recent guidelines  concerning the management of patients with COVID-19 recommend the short-term use of low dose steroids (e.g. dexamethasone 6.0 mg for 10 days) based on the recovery study (1,9,10). However, the optimum dose and duration of steroid therapy, especially in high-risk groups, including those with IPF, remain unclear.
A recent study reported that high-dose steroids (methylprednisone 250 mg/day for 3 days) was a viable treatment option for severe COVID-19 (11). Kitayama et al. also reported a case of COVID-19 pneumonia resembling an AE-ILD rescued by steroid pulse therapy (12). Both patients with COVID-19 and IPF are exposed to hyperinflammatory states with elevated levels of cytokines, including interleukin 6 (IL-6) (13-15). Furthermore, high-dose steroids, including pulse therapy, are often used to manage AE-IPF (16,17). These data imply that AE-IPF triggered by COVID-19 may need higher doses of steroids to suppress the disease activity than those with idiopathic and other triggers. Although the optimal duration of maintenance steroid therapy in AE-IPF is unclear, we terminated steroid therapy on day 32. This is because our patient was elderly, so we were concerned about adverse events with long-term maintenance steroid therapy. In addition, most studies have applied a short-term protocol of steroid therapy (3-10 days) for severe COVID-19 patients (1,2,11). In contrast, the Japanese guideline for the treatment of IPF suggests long-term maintenance of steroid therapy after an AE event (17). Further evidence is needed to answer clinical questions concerning maintenance steroid therapy in AE-IPF triggered by COVID-19.
The present patient met the diagnostic criteria for AE-IPF, and an AE event was triggered by COVID-19 (8). Previous studies have suggested that some cases of AE-IPF are induced by viral infections (18,19). Song et al. noted no marked differences in the prognosis between patients with "idiopathic" AE and those whose condition was triggered by infection (20). In contrast, Kondoh et al. reported that AE-ILD triggered by COVID-19 had a worse prognosis than that triggered by other causes (21). Furthermore, Drake et al. reported that patients with COVID-19 with preexisting ILD had a significantly higher mortality than those without ILD (5). These data indicate that AE-IPF triggered by COVID-19 results in greater disease severity than idiopathic and other infection-triggered AE-IPF. Although the 90-day mortality rate of AE-ILD triggered by COVID-19 is especially high (75%), our patient recovered without severe disability with steroid pulse therapy from the early stage of the disease onset (21). These findings suggest that the early initiation of intensive treatment, including pulse steroid therapy, may be beneficial for patients with AE-IPF triggered by COVID-19.
In summary, we reported a patient with AE-IPF triggered by COVID-19 successfully treated with high-dose steroids. Both patients with COVID-19 and IPF are exposed to hyperinflammatory states. Therefore, high-dose steroids can be a useful treatment option for AE-IPF triggered by COVID-19 to control disease activity.
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images The authors state that they have no Conflict of Interest (COI).