Role of Nintedanib in COVID-19-Related Lung Fibrosis

In December 2020, Indonesia was introduced to the long Coronavirus disease 2019 (COVID-19) phenomenon. The Centers for Disease Control and Prevention (CDC) introduced the term "post-COVID condition" as a health problem that persists after four weeks from the first exposure to COVID-19. The National Institute for Healthcare and Care Excellence (NICE) classifies COVID-19 infections into three categories based on disease duration: (1) acute infection for up to 4 weeks; (2) ongoing infection within 4-12 weeks; and (3) post-COVID-19 syndrome for more than 12 weeks and not associated with an alternative diagnosis. One of these phenomena is lung fibrosis. About 80% of COVID-19 survivors had mild to severe chest X-rays in 6 months of follow-up with decreasing lung function. COVID-19-related lung fibrosis is still not widely researched. COVID-19 survivors who develop lung fibrosis usually recover independently, but some develop persistent lung fibrosis. The use of antifibrotic agents, such as nintedanib, has long been approved for idiopathic pulmonary fibrosis (IPF). However, its use in the cases of lung fibrosis due to COVID-19 has not been widely studied. Nintedanib is a tyrosine kinase inhibitor. It inhibits receptor activity of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF). Those actions will eventually inhibit the proliferation, migration, and transformation of fibroblasts into myofibroblasts in lung fibrogenesis. Therefore, an anti-fibrotic agent is potentially needed to inhibit COVID-19-related lung fibrosis to improve quality of life and prevent further lung damage.


Coronavirus disease 2019 (COVID-19) is an infectious disease caused by Severe Acute Respiratory
Syndrome Corona Virus 2 (SARS-CoV-2). This disease causes clinical manifestations in respiratory, pulmonary, and systemic complications. COVID-19 is a respiratory virus, which is virus that takes the respiratory tract as a place of entry. The virus can proliferate in the airway epithelial cells, then spreads through the pulmonary bloodstream and causes pathological changes in the lungs and tissues or organs outside the lungs. 1 In April 2020, the Centers for Disease Control and Prevention (CDC) introduced the term "post-COVID condition", which describes a health problem that persists after four weeks from the first exposure to a COVID-19 survivor. The National Institute for Healthcare and Care Excellence (NICE) classifies COVID-19 infections into three categories based on disease duration: (1) acute infection for up to four weeks; (2)

LITERATURE REVIEW
several studies suggest that 10% of all COVID-19 survivors experienced a post-COVID condition phenomenon, which they call "long haulers." In most cases, COVID-19 patients experience improvement in their condition after 2-6 weeks after being infected, but some symptoms can persist or reappear weeks to months after the patient has recovered. [2][3][4] One of the long-term COVID-19 symptoms is damage to the lung organs with findings of fibrosis. Lung fibrosis is the formation of scar tissue in the lung tissue around the alveoli or interstitial tissue, leading to decreased elasticity of the lungs, respiratory function, and oxygen levels in the blood. Therefore, the therapy in lung fibrosis inhibits the process of wider lung damage. 3 Nintedanib works by inhibiting intracellular tyrosine kinases and the development of lung fibrosis. It inhibits the kinase activity of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF), leading to inhibition of proliferation, migration, and transformation of fibroblasts into myofibroblasts in the lung fibrogenesis. 7 There is still a lack of data on the role of nintedanib in cases of COVID-19-related lung fibrosis. Therefore, this literature review aimed to deepen our knowledge of the role of nintedanib, which has the potential to inhibit fibrosis due to COVID-19.

COVID-19-Related Lung Fibrosis and the Risk Factors
Fibrosis is the depositing of fibrotic connective tissue or scar tissue. Lung fibrosis is damage to the lung structure due to the formation of scar tissue in the lungs, characterized by the accumulation of extracellular matrix (ECM). 8  The risk factors for lung fibrosis due to COVID-19 are elderly and the severity of the disease, including comorbidities such as hypertension, diabetes, and coronary heart disease. Other factors are the length of stay in the Intensive Care Unit (ICU), the duration under mechanical ventilator, smokers, and alcohol drinkers. 6 In the elderly, it is hypothesized that the resistance of fibroblasts and myofibroblasts to apoptosis is correlated with an increase in plasminogen activator-1 (PAI-1) as an effector of Transforming Growth Factor-Beta (TGFβ), leading to persistent lung fibrosis. 11 Based on the World Health Organization (WHO) data, the degree of COVID-19 disease is 80% mild symptoms, 14% moderate-severe symptoms, and 6% critical symptoms. Factors associated with the degree of disease, such as hypertension, diabetes, and coronary heart disease, were also found in cases of lung fibrosis by   15,16 Other mediators, including histamine, bradykinin, and leukotrienes, are released due to the alveolar endothelial injury, which increases endothelial permeability. This will cause fluid to flow into the alveolar and interstitial spaces. Respiratory distress syndrome will appear when the alveolar space is filled with fluid, fibrin, and debris. Ground glass opacity (GGO), consolidation, and septal thickness on lung imaging are characteristics of the presence of airspace exudates, alveolar collapse, and interstitial edema. When traction bronchiectasis is present, pulmonary CT scans may exhibit irregular interlobular septal thickening and reticular patterns. This fibrotic process exhibits symptoms including diffuse alveolar destruction, acute fibrinous, and pneumonia, which are typical of pulmonary fibrosis brought on by SARS-CoV1/2. 11

Diagnosis of Lung Fibrosis due to COVID-19
Lung fibrosis due to COVID-19 is characterized as a change in the structure of the lung parenchyma by reported. 17 The examination of lung function in a patient with lung fibrosis showed a restrictive form of the disorder with hypoxemia and hypocapnia at rest. Several studies suggest that desaturation <88% on the 6-minute walk test (6MWT) predicts mortality in lung fibrosis. 18

Management of Respiratory Disease Patients' Treatment of Lung Fibrosis due to COVID-19
The treatment approach in lung fibrosis due to COVID-19 is currently studied in phases 3 and 4.
However, managing lung fibrosis is generally divided into non-pharmacological and pharmacological therapies. For non-pharmacological therapy, patients with lung fibrosis who experience desaturation during activity or rest can be given long-term oxygen therapy.
Respiratory rehabilitation, such as simple breath control exercises, is also recommended in patients with pulmonary fibrosis. A report by the Cochrane Council in  Pregnancy is included in category D because, in experimental animals, it influences the embryogenic process. 19 The most common side effects of nintedanib are gastrointestinal disorders such as diarrhea, followed by nausea and constipation. In 670 subjects who received nintedanib 2x150 mg for 52 weeks, there was an increase in liver enzymes in 351 subjects, but none of these subjects experienced an increase of >2 upper limits normal for Aspartate Transaminase (AST) and Alanine Transaminase (ALT), or an increase in total bilirubin less than 1x upper limit normal. 20 to 61.7%, and 6MWT of 1300 steps and 98% SpO2. 22 Ogata, et al. reported a case study on a 78-yearold woman with a history of COVID-19 critical symptoms, comorbid hypertension, post-ICU treatment with a ventilator for four weeks, and a CT scan of the thorax in the form of fibrosis of both lungs. During the 28 days post-ICU, the patient experienced a drastic decrease in lung function, both from the CT scan of the thorax and spirometry. The patient then underwent respiratory rehabilitation and was given nintedanib 150mg BID. The patient experienced side effects of nintedanib, namely an increase in liver function. The dose was reduced to 2x100mg, and the liver function improved. The patient experienced significant improvement after three months of nintedanib administration. The patient could walk independently with nasal cannula oxygen supplementation at 4 lpm. CT scan of the thorax revealed progressively diminishing lung fibrosis in two months. 23 Umemura, et al. conducted a clinical trial of administering nintedanib to ARDS patients due to COVID-19 who were on a ventilator. It was found that the group who was given nintedanib had a 23% lower risk of mortality during 28 days of monitoring and a higher P/F ratio in nintedanib group than the control group. 24 Crestani, et al. are recruiting a clinical trial of nintedanib for the treatment of SARS-CoV2-induced pulmonary fibrosis (NINTECOR), which is estimated to finish in 2024 and requires 250 COVID-19-related lung fibrosis survivors to interfere with nintedanib 150mg BID for 12 months. 25 Marwah, et al. published a case series of four patients with moderate to severe COVID-19 symptoms and lung fibrosis as revealed by a CT scan. The decision to take nintedanib 150mg BID for four weeks was made.

Pharmacokinetics of Nintedanib
All patients were well-tolerated and showed a significant reduction in lung fibrosis. 26 George, et al. reported a case study on a 67-yearold woman who had a critical case of COVID-19 and developed lung fibrosis. The patient was given nintedanib 150mg BID for three months, resulting in improved lung function using a serial 6MWT, spirometry, and chest CT scan. 27 Bussolari, et al. reported a case series of three patients aged between 42 and 52 years old with severe COVID-19 and obesity who started nintedanib 150mg BID due to the difficulty of obtaining lung function and restoration. Soon after the beginning of the treatment, systemic inflammation and respiratory function rapidly improved. Serial chest CT scans confirmed the progressive lung amelioration, also reflected by functional tests during follow-up. 28

SUMMARY
Nintedanib is a tyrosine kinase inhibitor and is currently one of the drugs used in treating pulmonary fibrosis. It inhibits the receptor kinase activity of VEGF, PDGF, and FGF, inhibiting the fibroblasts' proliferation, migration, and transformation into myofibroblasts in lung fibrogenesis. It has been reported in some cases of COVID-19-related lung fibrosis and has shown a significant effect on reducing the appearance of lung fibrosis and improving lung function and quality of life in patients. There are no reports of harmful interactions with nintedanib with other drugs. Nintedanib has tolerable side effects such as diarrhea and mild elevation of liver enzymes. According to several clinical studies, nintedanib treatment in both acute and long-term phases of COVID-19 patients has shown beneficial effects on lung fibrosis reduction and potentially improved quality of life.