Nebulized alteplase in coronavirus disease 2019 pneumonia: a case series

Abstract

Background

Many patients with severe coronavirus disease 2019 pneumonia exhibit signs of microthrombosis. Previous studies discussed intravenous fibrinolytic agents as potential add-on therapy in these patients. Therefore, we propose the inhalative administration of fibrinolytics as a possible safer alternative.

Case presentation

This case series describes five white male patients, aged 51–78 years, treated with off-label inhalation of alteplase between November and December 2020. All patients suffered from severe severe acute respiratory syndrome coronavirus 2 infection with respiratory failure. Pulmonary embolism was ruled out by pulmonary angiogram in computed tomography scans, and all patients showed signs of coronavirus disease 2019 pneumonia. Four patients improved clinically, while one patient with advanced chronic diseases died due to multiple organ failure. No directly associated adverse effects were observed following inhalation of alteplase.

Conclusion

This case series warrants further attention to investigate inhalative alteplase as an additional treatment in patients with severe coronavirus disease 2019 infection.

Background

At the time when the coronavirus disease 2019 (COVID-19) pandemic first emerged, there was no established causal pharmacological treatment for the virus [1]. Most infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) manifested with mild to moderate symptoms. However, in up to 5% of patients, the disease severity ranged from severe pneumonia and acute respiratory distress syndrome (ARDS) to shock, multiple organ failure, and death [2].

Severe COVID-19 cases are primarily driven by a cytokine storm, along with excessive endothelial activation and coagulopathies, which elevate the risk of thrombosis, including pulmonary embolism and microthrombosis[3,4,5,6,7].

The tissue plasminogen activator (tPA) alteplase is a systemically applied fibrinolytic agent frequently applied in patients with acute pulmonary embolism or stroke. The intravenous application has also been reviewed in small number of patients suffering from ARDS with or without severe COVID-19 [8,9,10,11,12,13,14,15]. Fibrinolytic agents are sometimes applied “off-label” through inhalation to reduce the systemic drug effects, including in patients with acute respiratory distress syndrome (ARDS) [16,17,18]. Therefore, inhalation with tPA poses a theoretically sound countermeasure to prevent or treat thromboembolic events in patients with COVID-19.

Through analyzing this retrospective case series at hand descriptively, we aim to draw attention to this subject matter and discuss the possible application of nebulized inhaled fibrinolytics in patients with severe COVID-19 infection.

Case presentation

All patients were white males which tested positive for SARS-CoV-2 in polymerase chain reaction (PCR) tests and exhibited radiological signs of ground-glass opacities (GGOs) with or without consolidations in computed tomography scans (CT scans) of the chest. Pulmonary embolism was excluded in all patients by pulmonary contrast-enhanced angiograms. All cases received optimal supportive therapy as recommended by the World Health Organization (WHO) and international guidelines in 2020 [1]. Accordingly, we administered dexamethasone 6 mg intravenously, as well as antipyretics, analgetics, and low-molecular heparin in prophylactic doses. All patients presented with elevated fibrinogen, d-dimers, and inflammatory markers c-reactive protein (CRP) and interleukin (IL)-6 and received treatment for respiratory failure, including high-flow oxygen and prolonged non-invasive ventilation (Fig. 1). The laboratory results for coagulation and inflammatory parameters over time are detailed in Supplementary Table 1.

Fig. 1

Levels of CRP, platelet count, d-dimer, and fibrinogen prior to and following inhalation of alteplase. All patients received inhaled alteplase at day 0. Patient 5 received an additional inhalation on days 6–10

Case 1

A 68-year-old male with a history of coronary and peripheral artery disease, chronic kidney failure [estimated glomerular filtration rate(eGFR) of 39.21 mL/min/1.73 m²], hypertension, multiple myeloma (active treatment with velcade/bendamustine/dexamethasone), hypothyroidism, hyperlipidemia, and obstructive sleep apnea, smoking [60 packs per year (PY)] presented to the hospital with three days of shortness of breath and chest pain. Oxygen therapy was started with 4 L/min. Due to progressive respiratory failure, a high-flow nasal cannula (HFNC) was administered, as the patient did not tolerate non-invasive ventilation (NIV). Antiplatelet therapy included acetyl salicylic acid (ASA) and ticagrelor. Alteplase was inhaled at 5 mg three times a day (TID) on days 8–12. Inflammatory markers, including CRP and IL-6, improved, similarly to fibrinogen and d-dimer values. HFNC was discontinued on day 13 and replaced with oxygen therapy at 3–4 L/min until day 21. The patient was then discharged to a rehabilitation clinic.

Case 2

A 51-year-old male with a history of non-Hodgkin's lymphoma (in remission) presented with a week of shortness of breath and loss of smell and taste. Extensive NIV therapy was established with 8 mbar positive end-expiratory pressure (PEEP), 2 mbar pressure support (PS), and 60% oxygen flow. During short therapy breaks, oxygen therapy was administered with 8 L/min. Due to an increase in d-dimer to 12.2 μg/mL on day 6, a follow-up CT scan was performed, revealing no signs of pulmonary embolism but showing bilateral ground-glass opacities and consolidations. Because of the significant increase in d-dimer, the dose of low-molecular weight heparin (Enoxaparin) was increased to 8000 IU twice a day (BID) until discharge. Additionally, alteplase 10 mg was inhaled TID on days 5 and 6, and 5 mg TID on days 7–9. NIV therapy was discontinued on day 10 and switched to oxygen insufflation via nasal cannula at 4 L/min. This was terminated on day 13, and the patient was subsequently discharged home.

Case 3

A 66-year-old male with a history of hypertension, prostate cancer, and active urinary cancer was admitted after 5 days of fever, shortness of breath, and slight confusion. Following initial oxygen insufflation, NIV therapy was started on day 3, along with alteplase 5 mg TID for a total of 5 days. On day 8, NIV was switched to HFNC and, after 8 days, substituted by oxygen insufflation per nasal cannula. The patient was discharged home on day 21.

Case 4

A 63-year-old male was admitted with 5 days of shortness of breath. He had a history of atrial fibrillation, hypertension, type 2 diabetes, severe chronic obstructive pulmonary disease with long-term oxygen therapy (LTOT: 2 L/min), and pulmonary hypertension. CT scan of the chest showed GGOs, paraseptal emphysema, a pulmonary mass in the left upper lung, and enlargement of the pulmonary trunk and arteries. The patient did not tolerate NIV; therefore, HFNC was established. Inhalative therapy with alteplase 5 mg was given TID for a total of 5 days. Laboratory findings showed an improvement of the inflammatory markers in the following days after admission, but later the laboratory findings and the general condition of the patient worsened gradually. On day 8 of hospitalization, the patient passed away due to respiratory failure.

Case 5

A 59-year-old male was admitted with a history of hypertension and obesity. He reported shortness of breath and reduced general condition. CT scan of the chest showed extensive GGOs and slight pleural effusion on the left side. HFNC was initiated, followed by NIV. On day 3, the patient inhaled alteplase 5 mg TID for the following 3 days. The therapy was repeated 4 days later due to a marked increase in d-dimer for 5 more days. NIV was discontinued on day 11 and switched to oxygen insufflation until day 31. Finally, the patient was discharged 34 days after admission.

Discussion

We report a case series of five patients with severe COVID-19 infection suffering from respiratory failure treated with off-label inhalation of tPA (alteplase). Four patients improved clinically, while one died due to multiple organ failure. No acute adverse effects were observed. Respiratory failure parameters, d-dimer and fibrinogen improved in all surviving patients following off-label treatment (Fig. 1).

Fibrinolytics are commonly used in patients suffering from extensive pulmonary embolism. Intravenous application is associated with significant complications: in the largest randomized study, involving 506 patients undergoing tenecteplase treatment for intermediate-risk pulmonary embolism, 32 (6.3%) suffered major extracranial bleeding and 10 (2%) hemorrhagic stroke [19]. Severe COVID-19 infection is often associated with a state of hyper-coagulopathy; resulting in microthrombosis of pulmonary arterioles not detected by contrast CT scans [4,5,6,7]. Some reports suggest that intravenous fibrinolytics may be beneficial for patients with COVID-19, both with and without ARDS [8,9,10,11,12,13,14,15]. However, the risk of significant bleeding appears elevated, particularly in the presence of enhanced fibrinolytic-type disseminated intravascular coagulation (DIC) [20]. As bleeding complications pose a life-threatening condition, inhalative application of fibrinolytics may be a safer alternative for patients with severe COVID-19 pneumonia [16, 20, 21]. Indeed, Wu et al. demonstrated in a small case series of 13 patients with moderate to severe COVID-19 infection that inhalation of 5 mg plasminogen twice-daily often improved oxygen saturation and heart rate without reporting major bleeding complications [11].

Off-label use of recombinant tPA is frequently used in children with plastic bronchitis in different regimens with single dosages ranging from 5 to 12 mg per inhalation without major bleeding complications [18, 22]. In this case series, dosages of 5–10 mg three times daily were used without any bleeding complications. The application route may not only have a safer complications profile but also result in a higher concentration of tPA in the lung. The effect may be through direct fibrinolytic effects on microthrombi in arterioles and on exceeding fibrin detritus in the alveoli resulting in increased pulmonary circulation and ventilation. Furthermore, previous studies demonstrated anti-inflammatory effects of tPA, which may be beneficial in patients with COVID-19 [23, 24].

On the other hand, the inhalative application may have several drawbacks. First, the application of inhaled therapeutics may cause an increase in virus aerosol in the patients' room, posing an additional risk for healthcare workers. Therefore, an exhalation filter was used during application. Second, the amount of deposition remains unknown, as particles may impact in the upper and small airways.

Limitations

We acknowledge several limitations in our study. Firstly, this is a case report series, which inherently limits the generalizability of the findings due to the small sample size and lack of control groups. The concurrent use of low-molecular weight heparin (LMWH) and glucocorticoids, such as dexamethasone, alongside inhaled alteplase, presents a potential bias in our results. This combination therapy complicates the isolation of the specific effects of inhaled alteplase. Therefore, the observed improvements in clinical outcomes cannot be solely attributed to alteplase.

Conclusion

Our findings primarily underscore the possible safety of inhaled alteplase in patients with severe COVID-19 pneumonia. While clinical improvements were observed, these cannot be definitively attributed to alteplase due to the concurrent use of other therapies. Given the encouraging safety profile of inhaled alteplase observed in this study, future research should focus on randomized controlled trials to evaluate its efficacy. These studies should aim to isolate the effects of inhaled alteplase by minimizing the use of concurrent therapies. Additionally, larger-scale studies could help establish standardized dosing regimens and identify specific patient populations that may benefit the most from this treatment. The insights gained from our study can guide the design and implementation of these future investigations.