key: cord-0280791-pczmh0o1
authors: Filimonova, Elena V.; Davydova, Lyubov A.; Lysenko, Mariana A.; Tsarenko, Sergey V.
title: Interstitial inflammation and pulmonary fibrosis in COVID-19: The potential role of cytostatic therapy for severe lung injury
date: 2022-05-27
journal: nan
DOI: 10.1016/j.rmcr.2022.101676
sha: 1b81815b7dbe5ad683f330c316c477bc4e7c001d
doc_id: 280791
cord_uid: pczmh0o1

The progression of secondary pulmonary damage in SARS-COV-2 infection, associated with interstitial damage, inflammation and alveolar consolidation and eventually resulted in the development of pulmonary fibrosis (PF), remains one of the key clinical dilemmas for the treatment of patients in intensive care units (ICU). Currently, there is no standardized algorithm for PF prevention and timely management, although few studies have discussed the use of antifibrotic agents in COVID-19 patients. One of the treatment options for patients with interstitial PF, when irresponsive to the given corticosteroid therapy, is the administration of cytostatic agents, in particular, cyclophosphamide. Cyclophosphamide is one of the well-studied drugs in the cytostatic group, which effectiveness in inhibiting systemic inflammation suggests its ability to reduce the progression of the secondary lung damage, interstitial abnormalities and PF caused by the so-called “cytokine storm". The presented case reports provide data on the use of cyclophosphamide (Сy) in the management of severe respiratory failure in COVID-19 patients stationed in ICU. We describe three clinical cases characterized by different types of respiratory support, including extracorporeal membrane oxygenation.

Declared by the World Health Organization (WHO) on March 11, 2020, the COVID-19 pandemic continues to pose a significant challenge for public health at present: the questions of pathogenesis, diagnosis, and treatment of the novel coronavirus infection are widely discussed in Russian and international medical literature.

Disease severity and hospitalization rate of COVID-19 are higher in elderly people and patients with chronic comorbidities, notably, arterial hypertension, diabetes mellitus, coronary heart disease, and chronic obstructive pulmonary disease (COPD). So far, the globally accumulated facts are as follows: male patients demonstrate a higher predisposition to severe COVID-19 [1] ; the mortality rate is less than 5% in patients aged <80 without comorbidities [2] ; 50% of those infected have asymptomatic course of the disease; if presenting clinical symptoms, 80% of patients have only mild form of acute respiratory infection.

The most frequent COVID-19 manifestation is a bilateral pneumonia, which accounts for 3-4% of the cases, with subsequent progression to severe acute respiratory distress syndrome (ARDS) [3] . According to Grasseli et al., 40-96% of ARDS patients died in intensive care units (ICU) in Lombardy, Italy, which makes ARDS one of the major risk factors associated with mortality among COVID-19 patients in ICUs [1] . In the first 2 months of the pandemic, ICU and in-hospital mortality rates were 48.8% and 53.4%, respectively, due to the demand for prolonged mechanical ventilation in those patients. In a series of studies conducted in China, 28-day mortality rate of ICU patients was 39%, with up to 97% in the ICU patients on mechanical ventilation [1] .

The main cause of death in ICU patients was sepsis. Among the most frequent autopsy findings, there were also suppurative lung disease, diffuse alveolar damage, pulmonary embolism, cardiopulmonary, and multiple organ system failure [2] .

The international clinical guidelines and approved treatment strategies for ICU patients comprise symptomatic therapy with concomitant conditions in consideration, administration of antiviral and immunomodulatory drugs as well as pathogen-specific therapy [3] . However, secondary pulmonary damage, associated with interstitial inflammation and alveolar consolidation, commonly develops in case of severe course of the disease and eventually results J o u r n a l P r e -p r o o f in, that is usually referred to, as pulmonary fibrosis (PF). Currently, there is no standardized algorithm for PF prevention and its timely management, which makes it one of the key clinical dilemmas for the treatment of ICU patients.

Despite the novelty of the problem, few studies have discussed the use of antifibrotic agents in COVID-19 patients. ERS guidelines recommended nintedanib and pirfenidone for the treatment of idiopathic pulmonary fibrosis (IPF) in 2015 [12] . Earlier these drugs showed their effectiveness in preventing the decline in forced vital capacity (FVC), decreasing IPF exacerbations and hospital admissions in those patients [4] .

A similar clinical and radiological picture can be observed in patients with organizing pneumonia (OP).

Firstly, OP demonstrates the same CT pattern as in COVID-19-associated severe lung damage, so-called ground-glass opacities, consolidation, reticulation, and parenchymal distortion of 70-90% of lung volume. OP comprises granulation tissue and proliferation of fibroblasts within the lung parenchyma. Viral infections are amongst the most common etiologies of secondary OP.

Secondly, OP often has dramatic reversibility when managed with corticosteroids, therefore presents a beneficial treatment option in severe forms of COVID-19 pneumonia and late phase post-pneumonic complications [6, 7] . Generally, corticosteroids remain the mainstay for interstitial lung disease therapy, both in mono-and combination (with cytostatic agents) therapies [8] .

The administration of cytostatic agents, in particular, cyclophosphamide (Cy), mycophenolate [8, 9, 10] , and antitumor drugs [12, 13] may present an additional therapy option for patients with PF and OP, when irresponsive to the given therapy. Cyclophosphamide is one of the most studied drugs in the cytostatic group, which effectiveness in inhibiting systemic inflammation suggests its ability to reduce the progression of the secondary lung damage, interstitial abnormalities and PF caused by the so-called "cytokine storm" [10, 11, 14] .

However, the major concern regarding the indication of cytostatic agents is the wide range of its adverse effects. Clinicians need to consider key aspects of Cy pharmacodynamics and toxicity to adequately assess the risk-benefit ratio. Prospective studies in this field may admit Cy with respect to its side effects as an inexpensive option to treat severe COVID-19-associated pulmonary fibrosis.

Here we present several clinical cases of the use of Cy in the management of severe respiratory failure in COVID-19 patients stationed in ICU. The off-label use of low-dose Cy was approved by the local ethics committee of the clinical hospital. We did not observe organ toxicity during the Cy treatment. Minimal leucocyte level was 3.1*10 9 /L, platelets -76*10 9 /L, daily controlled. showed bilateral ground-glass opacities combined with consolidation and 'crazy-paving' pattern.

Owing to the ongoing respiratory deterioration and poor radiological findings, Cy therapy of 100 mg/daily was started on admission to ECMO ICU.

J o u r n a l P r e -p r o o f VV-ECMO together with shifting to lung-protective ventilation was initiated on day 10. Three days later tracheostomy was applied and myoplegia was prevented. The patient was emerged and demonstrated an adequate lung contribution (increased Vt and compliance). In 12 hours, ECMO parameters were reduced to the minimum, which resulted in his discharge from ECMO. On day 18 from the disease onset, the patient was decannulated. He was provided with 5 L/min oxygenation for the subsequent 5 days. On day 28 from the start of the disease, the patient was discharged with no oxygen dependence.

Starting from day 9 of the disease onset for the duration of 13 days, the patient was administered cumulatively 1300 mg of Cy, with no signs of systemic toxicity observed. Minimal number of WBC during the hospitalization was 3.4* 10 9 /L and number of platelets was 148*10 9 /L.

According to the accumulated data, we suggest using Cy as a treatment option for patients not responding to corticosteroids or IL-6 inhibitors. Cy should be used only in case of severe forms of respiratory distress considering all contraindications, such as cytopenia, sepsis, and pregnancy.

We successfully used Cy in patients receiving different respiratory support, though strongly advocating for acknowledging the risk of secondary bacterial ventilator-associated pneumonia in ventilated patients. In the presented above cases, all mechanically ventilated patients had received antibiotics prior to the Cy administration and improved rapidly without ventilator-associated pneumonia progression. We do not recommend the administration of prophylactic antibiotics in patients on high flow oxygenation or non-invasive ventilation and administering ABT only in presence of the infection criteria (e.g., fever, positive blood culture, increased sputum production, leukocytosis, new radiological findings). Thrombocytopenia and leucopenia require a thorough monitoring throughout the whole period of Cy administration. Additionally, we suggest lower doses of Cy in elderly patients in comparison to younger ones on account of existing age-related myelosuppression.

Therefore, a low-dose Cy therapy may be considered relatively safe and reasonably effective in COVID-19 patients with severe lung injury and deteriorating respiratory conditions. It may help to reduce interstitial inflammation and alveolar consolidation, which eventually cause pulmonary fibrosis. Further investigation and research on animals and humans are necessary.

Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy

Causes of death and comorbidities in hospitalized patients with COVID-19

Provisional guidelines on prevention, diagnosis and treatment of new coronavirus infection

Antifibrotic therapy for fibrotic lung disease beyond idiopathic pulmonary fibrosis

The fibroproliferative response in acute respiratory distress syndrome: mechanisms and clinical significance

Influenza A (H1N1) organizing pneumonia

Organizing pneumonia: A late phase complication of COVID-19 responding dramatically to corticosteroids

Acute and subacute idiopathic interstitial pneumonias (In invited review series: Idiopathic interstitial pneumonia-Part 2: Specific disease entities)

Alkylating drugs applied in noncytotoxic doses as a novel compounds targeting inflammatory signal pathway

Effect of cytostatic agents on the number of alveolar phagocytes and the efficacy of ceftriaxone in an experimental murine lung infection

Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels

Current and future perspectives on management of systemic sclerosis-associated interstitial lung disease

The 2015 guidelines for idiopathic pulmonary fibrosis: an important chapter in the evolution of the management of patients with IPF

Low dose cyclophosphamide: Mechanisms of T cell modulation