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Журнал «Медицина неотложных состояний» Том 19, №4, 2023

Морфологічні зміни легеневої тканини в пацієнтів із COVID-індукованим гострим респіраторним дистрес-синдромом залежно від варіанта респіраторної терапії

Авторы: V. Korsunov (1), T. Bocharova (2), V. Skoryk (3), M. Georgiyants (1), М. Lyzohub (4), І. Оdinets (1), K. Lyzohub (1), Y. Lisiienko (1)
(1) — Kharkiv National Medical University, Kharkiv, Ukraine
(2) — Kharkiv International Medical University, Kharkiv, Ukraine
(3) — Kharkiv Regional Clinical Hospital, Kharkiv, Ukraine
(4) — State Institution “Sytenko Institute of Spine and Joint Pathology of the National Academy of Medical Sciences of Ukraine”, Kharkiv, Ukraine

Рубрики: Медицина неотложных состояний

Разделы: Клинические исследования

Актуальність. Морфологічні дослідження легеневої тканини в пацієнтів із COVID-індукованим гострим респіраторним дистрес-синдромом наведені в літературі переважно для опису перебігу хвороби, а не відповідно до типу респіраторної підтримки. Мета: проаналізувати вплив різних варіантів респіраторної терапії на морфологічні зміни легеневої тканини пацієнтів, які померли від COVID-19. Матеріали та методи. Досліджені пацієнти з COVID-індукованим респіраторним дистрес-синдромом (n = 30) були розподілені на 3 групи. Група 1 включала хворих, які отримували неінвазивну вентиляцію в режимі постійного позитивного тиску в дихальних шляхах (CPAP) через лицеву маску (n = 10), група 2 — осіб на низькопотоковій кисневій терапії 15 л/хв через лицьову маску (n = 10), група 3 — пацієнтів, яким проводилась інвазивна вентиляція легень через інтубаційну трубку (n = 10). Результати. Морфологічна будова легень пацієнтів групи 1 відповідала ексудативній фазі дифузного альвеолярного ушкодження (ДАУ) з вираженим набряково-геморагічним синдромом, а також характеризувалася невідповідністю його класичних стадій тривалості захворювання. Так, у частині спостережень зміни в легенях, характерні для ранньої ексудативної стадії, були виявлені після 14 діб від початку захворювання за відсутності змін, специфічних для пізньої проліферативної стадії. Ознаки інтерстиціальної пневмонії з формуванням фіброзуючого альвеоліту спостерігалися лише в 12,5 % хворих. Морфологічною особливістю структури легень у пацієнтів групи 2 була наявність великих вогнищ ателектазів, що супроводжувалося витонченням альвеолярних перетинок, а також їх розривом. Крім того, спостерігалися сформовані гіалінові мембрани, які блокували поверхню альвеол, що призводило до різкого зменшення площі газообміну й розвитку альвеолярно-капілярного блоку. Це, можливо, стало причиною порушення вентиляційної функції легень. У пацієнтів групи 3 в легеневій тканині спостерігалася картина проліферативної фази ДАУ з ознаками інтерстиціальної пневмонії, потовщенням альвеолярних перетинок за рахунок мононуклеарної інфільтрації та інтерстиціального фіброзу й розвитком вогнищевого фіброзуючого альвеоліту. Крім того, в окремих випадках були виявлені ознаки вогнищевої бактеріальної та зливної бронхопневмонії за рахунок приєднання вторинної бактеріальної інфекції, особливо на тлі тривалої механічної вентиляції. Висновки. Низькопотокова киснева терапія може призводити до прогресування дихальної недостатності внаслідок самоушкодження інтактної легеневої тканини. Ми також виявили негативний вплив інвазивної вентиляції на кількість бактеріальних ускладнень та стимуляцію фіброзу. Найcприятливіша морфологічна картина спостерігалась у пацієнтів, які отримували неінвазивну вентиляцію в режимі CPAP.

Background. Morphologic examination of lung tissue in COVID-related acute respiratory distress syndrome is shown in publications predominantly regarding the course of disease but not the type of respiratory support. The aim of the single center study was to determine the influence of different types of respiratory therapy on morphologic findings in lung tissue of patients, who had died from COVID-19. Material and methods. The examined patients with COVID-related related acute respiratory distress syndrome (n = 30) were divided into three groups. Group 1 included those who received non-invasive lung ventilation in continuous positive airway pressure (CPAP) mode through a face mask (n = 10), group 2 consisted of patients who received oxygen therapy with a flow of
15 l/min through a rebreather mask (n = 10), and group 3 included people who underwent invasive lung ventilation through an endotracheal tube (n = 10). Results. In lung tissue of patients of group 1, we revealed prevalence of edema and hemorrhagic changes as well as discrepancy of diffuse alveolar damage (DAD) manifestations and duration of the disease. So, morphological manifestations of exudative phase of DAD were found even after 14 days of disease, and interstitial pneumonia with fibrosing alveolitis was observed only in 12.5 % of patients. The presence of dystelectasis, compensatory emphysema and thinning of the alveolar wall were typical morphological findings in the patients of group 2. Numerous hyaline membranes covered alveolar walls and led to a decrease in gas exchange area, alveolar-capillary block and were the cause of impaired lung ventilation function. Morphological signs of proliferative phase of DAD in patients of group 3 were accompanied by the development of alveolar fibrosis and secondary bacterial bronchopneumonia, especially in prolonged invasive lung ventilation. Conclusions. Low-flow oxygen therapy may lead to the progression of respiratory failure due to self-damaging of intact lung tissue. We have also revealed negative impact of invasive pulmonary ventilation on the number of bacterial complications and fibrosis stimulation. The most favorable morphologic changes were found in patients with non-invasive CPAP ventilation.

Ключевые слова

COVID-асоційований гострий респіраторний дистрес-синдром; морфологія легеневої тканини; респіраторна терапія

COVID-related acute respiratory distress syndrome; lung tissue morphology; respiratory therapy

doi: http://dx.doi.org/10.22141/2224-0586.19.4.2023.1589

Introduction

Pathophysiology of respiratory distress in COVID-19 is generally described as pulmonary vasculitis induced by inflammation leading to pulmonary collapse, secondary edema, and microthrombosis [3]. Bilateral lung injury by ground glass opacity type leads to ventilation/perfusion mismatch and blood shunting. To differentiate acute respiratory distress syndrome (ARDS) induced by COVID-19 (CARDS) from classic ARDS, a hypothesis of two time-related phenotypes of CARDS was proposed: early type L, characterized by low elastance (i.e., high compliance 50 ± ± 14 ml/cm H2O), low ventilation-to-perfusion ratio, low lung weight and low recruitability, and late type H, cha-racterized by high elastance, high right-to-left shunt, high lung weight and high recruitability [4]. Intensive care physicians faced with dilemma regarding the start of respiratory support for patients with CARDS whose low-flow oxygen therapy failed. It is traditionally thought that early intubation and mechanical ventilation (MV) in case of ARDS may increase survival [5]. However, mortality in intubated COVID-19 patients on MV turned out to be very high [6]. At the same time, the results of starting treatment of ARDS with non-invasive ventilation (NIV) are controversial [7, 8]. That is why in Surviving Sepsis Campaign: guidelines on the management of critically ill adults with coronavirus disease 2019 (2020), there was the statement: “The balance between benefit and harm when using NIPPV in adults with COVID-19 is unclear” [9].

Respiratory therapy itself may cause damage of lungs. There are described ventilator-induced lung injury (VILI) and patient self-inflicted lung injury (P-SILI) phenomena that may influence the course of ARDS. We cannot exclude the fact that VILI is one of the causes for adverse outcome of invasive ventilation and P-SILI occurs during spontaneous and assisted breathing. Continuous positive airway pressure (CPAP) technology may reduce negative effects of P-SILI, and decrease the requirements of invasive ventilation, thus preventing VILI [12]. High positive end-expiratory pressure (PEEP) has lung-protective effect and may reduce fluctuations of transpulmonary pressure [13].

At the same time, the delay of intubation when indicated is one of the main risks of NIV in acute respiratory failure [14]. Ineffective NIV may be an independent risk factor of increased mortality in COVID-19 patients [8]. That is why recommendations of using NIV in COVID-19 patients are still controversial [15]. Forrest I. et al. comparing invasive and noninvasive ventilation in 688 ARDS patients revealed mortality of 85 % (128/154) in invasive ventilation vs 32 % (171/534) in NIV [16]. Daniel P. et al. examined 222 COVID-19 patients, 30-day mortality in those who were primarily intubated was 82 % (75/91) vs 84 % (37/44) in people, who were intubated after ineffective NIV. In patients on NIV, mortality rate was significantly lower, 69 % (60/87) [17]. Bonnesen B. et al. showed that there is enough evidence that in case of ineffective 6–15 l/min oxygen therapy through nasal cannula, CPAP with PEEP 10–12 cm Н2О is indicated for a long time [18]. A brief review by Radovanivic D. et al. included 23 manuscripts (4,776 patients). 46 % of patients received non-invasive respiratory support, of which 48.4 % with CPAP, 46 % with NIV, and 4 % with either CPAP or NIV. Non-invasive respiratory support failed in 47.7 % of patients, of which 26.5 % were intubated and 40.9 % died. In-hospital mortality was higher in patients treated with NIV compared to CPAP (35.1 vs. 22.2 %) [19]. As a result, CPAP is considered to be the most effective method of non-invasive respiratory support for COVID-19 patients. The same opinion have Pelosi P. et al. who state that CPAP should be the primary method of respiratory therapy in patients with L-phenotype ARDS, and it can decrease transpulmonary pressure and P-SILI [13].

Analyzing the above-mentioned publications, we revealed that evidence is based on clinical results, laboratory and instrumental investigations. Morphologic examination of lung tissue is rarely described in publications regarding the course of disease but not the type of respiratory support [20, 21]. Having a significant own experience of treatment of COVID-19 patients, we decided to compare morphologic findings in those who had died from ARDS depending on respiratory therapy: low-flow oxygen therapy, CPAP, or invasive ventilation.

The purpose of the single center study was to determine the influence of different types of respiratory therapy on morphologic findings in lung tissue of patients, who had died from COVID-19.

Material and methods

The study was conducted from June 2020 to February 2021 in the intensive care unit of the Regional Clinical Infectious Diseases Hospital (Kharkiv). The investigation was performed in accordance with World Medical Association Declaration of Helsinki. The study was approved by the Biomedical Commission No. 1 of the Kharkiv Medical Academy of Postgraduate Education on 11.02.2021. All patients provided written informed consent during hospitalization. The diagnosis of coronavirus disease was confirmed by polymerase chain reaction nasal swab test of SARS-CoV-2 RNA. Verification of pneumonia was performed by computed tomography or chest radiography. The diagnosis of ARDS was made according to the Berlin Definition (2012). All patients underwent complete blood count (CBC), biochemical tests to assess the severity of COVID-19 and to evaluate the function of vital organs and systems. Body mass index (BMI) was calculated by the formula: BMI = body mass / height2 (kg/m2). Patients’ monitoring (Comen C50) during intensive care included electrocardiography to determine heart rate, measurement of mean blood pressure by oscillometric method and pulse oximetry (SpO2). The lactate dehydrogenase (LDH) level was evaluated by kinetic method. C-reactive protein (CRP) level was measured by the turbidimetric method (Biosystems kits, Spain). D-dimer was determined by ELISA (Vector-Best kits, Ukraine). Interleukin 6 (IL-6) and procalcitonin levels were evaluated by ELISA (eBioscience kits, USA). All biochemical studies were performed on a Chemray 120 Mindray analyzer. All patients (n = 30) were divided into three groups. Group 1 included those who received non-invasive lung ventilation in CPAP mode through a face mask (n = 10), group 2 consisted of patients who received oxygen therapy with a flow of 15 l/min through a rebreather mask (n = 10), and group 3 included people who underwent invasive lung ventilation through an endotracheal tube (n = 10).

NIV and mechanical ventilation were carried with same ventilators: Newport E 360t, Resvent RS 300, Monnal T75 and Tecme TS with assessment of ventilation parameters: Vt (ml), MV (l/min), f (for 1 min), Pin (cm H2O), Pmean (cm H2O), PEEP (cm H2O), FiO2 (%) using graphics monitors. Oxygen saturation index (OSI) was calculated by formula: OSI = (FiO2 × Pmean × 100) / SpO2, where FiO2 is the oxygen fraction in the gas mixture, Pmean is the average airway pressure. The respiratory rate oxygenation (ROX) index was calculated by the formula: ROX = (SpO2 / FiO2) / RR, where RR is the respiratory rate [12]. Intensive care of patients was carried out according to the relevant guidelines of the Ministry of Health of Ukraine and included anticoagulants, corticosteroids, restrictive fluid therapy, antibacterial drugs depending on indications, the use of sympathomimetics and sedatives as needed, treatment of comorbidities (coronary heart disease, hypertension, and diabetes mellitus) [24–28].

Microscopic examination of the lungs was performed using routine histological techniques. Samples of lung tissue taken during autopsy were fixed in 10% formalin, passed through alcohols in increasing concentration and imbibed into paraffin. The obtained sections with 5-μm thickness were stained with hematoxylin and eosin and examined with a microscope Zeiss Axioskop 40 FL, HBO 50. Photomicrographs were taken using the program Zeiss ZEN Microscopy Software.

Statistical analysis of the results was performed using the program Statistica 10. Data are presented as M [25–75] and P ± Sp. Significance of differences in parameters was assessed using the nonparametric Wilcoxon test and the parametric Student’s test. The results were considered reliable at values of p < 0.05.

Results

Clinical characteristics of patients are reported in Table 1. There was no statistical difference in age and BMI between groups.

Initial CBC was performed upon admission to all patients. The results are shown in Table 2. In patients of group 1, CBC was normal, in group 2, a significantly lower level of platelets was found, and patients of group 3 had a significantly increased level of leucocytes.

Dynamics of CBC on the fourth day is shown in Table 3. According to the obtained data, leukocytosis was observed in patients of all groups.

Biochemical test upon admission (Table 4) demonstrated increased levels of LDH, CRP, IL-6, procalcitonin and D-dimer.

Obtained data are consistent with most publications and demonstrate severity of coronavirus disease with hyperinflammation that require intensive care.

At the beginning of respiratory therapy, we calculated OSI and ROX index. OSI was calculated for patients of group 1 and 3 as it requires the measurement of Pmean. In groups 1 and 3, OSI exceeded 12.3 (severe ARDS). In patients of group 3, OSI was highest because of high Pmean during invasive mechanical ventilation.

ROX index was calculated to understand indications for invasive ventilation to maintain target oxygenation (Table 5).

Initial level of FiO2 and PEEP in patients of groups 1 and 3 did not differ (p > 0.05). Individuals of groups 1 and 2 had tachypnea, patients of group 3 had tachypnea more than 40 min–1 before intubation. Pmean and Ppeak were highest in patients of group 3, who were on invasive ventilation in the pressure controlled ventilation mode (Table 6).

Patients of group 1 were admitted to the hospital on day 11.5 [8–13] of disease, group 2 — on 12.5 [9–14], and group 3 — on day 11 [8–16]. Average time of respiratory support in the intensive care unit was 7 [4–14] days in group 1, 3 [3–8] days in group 2, and 7.5 [5–10] days in group 3. Length of hospital stay in patients of group 1 was 22 [18–25] days, in group 2 — 14 [13–18] days, in group 3 — 21 [14–23] days.

The most frequent morphological findings among patients with different type of respiratory support are presented in Table 7.

Morphologic structure of lungs in patients of group 1 re-presented exudative phase of diffuse alveolar damage (DAD) with significant edema and hemorrhagic syndrome, desquamative interstitial pneumonia and hyaline membrane formation. Despite prolonged treatment, morphologic changes were characteristic of the early phase of DAD; the signs of fibrosing alveolitis were found only in one patient. Lung tissue was dense, dark cherry, with focal dystelectasis, massive hemorrhages and hemorrhagic infarcts. Numerous parietal and occluding thrombi and thromboemboli were found in pulmonary artery brunches and veins. Polymorphic cellular exudate with lymphocytes, plasmacytes, monocytes, single neutrophils and huge amounts of erythrocytes were found microscopically in lung tissue (Fig. 1).

Dense eosinophilic masses covered alveolar epithelium with formation of typical hyaline membranes and were separately present in the alveolar lumen but sometimes, in 75 % of cases, were phagocyted by alveolar macrophages. Desquamated alveolar epithelium with metaplastic chan-ges and proliferation of type II alveolocytes were found in some observations. Mononuclear inflammatory infiltration by lymphocytes, plasmacytes and macrophages as well as erythrocytes were identified in 87.5 % cases in alveolar walls thickened due to edema (Fig. 2).

Crash alveolar hemorrhagic syndrome with perivascular and interalveolar hemorrhages were identified in the lung of all patients in this group.

Lung tissue of the patients of group 2 was dense, dark red with huge areas of atelectasis in the lower parts and emphysema in the anterior parts. Interalveolar edema mixed with erythrocytes, lymphocytes, alveolar macrophages as well as desquamated alveolar and bronchial epithelium were found microscopically. Formation of typical hyaline membranes was noted the in 50 % of cases (Fig. 3). Mononuclear infiltration and edema determined thickening of the alveolar wall that is a typical manifestation of interstitial proliferative pneumonia. Hyperemia in all branches of pulmonary arteries with thrombi formation as well as focal hemorrhagic infarctions were also observed. Focal atelectasis in the terminal parts of respiratory parenchyma, emphysematous dilated bronchioles and alveoli lead to thinning and sometimes rupture of the alveolar walls in 86 % cases (Fig. 4).

Airless, dense, rusty color lung tissue with huge hemorrhagic areas, fibrin plaques on pleura and fibrinopurulent exudate in pleural cavities were detected in the patients of group 3. Arterial and venous hyperemia, focal hemorrhagic infarctions and huge amounts of occluding fibrin thrombi were found microscopically most often. The alveoli were filled in with polymorphic cellular inflammatory exudate mixed with erythrocytes and fibrin, signs of focal bacterial bronchopneumonia complicated with fibrinopurulent pleurites were detected in 50 % of cases (Fig. 5). We also found areas of obliterative productive bronchiolitis with soft granulation tissue growth as well as areas of fibrosing alveolitis and lung carnification (Fig. 6).

Discussion

The course of ARDS in COVID-19 patients has three stages according to the clinical and morphological dynamics of lung tissue damage.

1. Exudative stage with formation of fulminant COVID-19 interstitial pneumonia.

2. Proliferative stage with persistent COVID-19 interstitial pneumonia.

3. Fibrotic stage with formation of fibrotic COVID-19 interstitial pneumonia [19, 20].

Each of these stages develops in different periods of di-sease and is characterized by typical macro- and microscopic changes. Exudative stage represents acute phase of DAD with the development of pulmonary edema and hyaline membrane formation. This stage lasts typically 10 days after the disease beginning.

Proliferative stage (up to 20 days after the disease onset) is characterized by a wide range of morphologic changes, а combination of persistent signs of exudative stage with hyperplastic, reactive and disregeneration changes, initial signs of fibrosis.

Morphologic signs of fibrotic stage (21–45 days of disease) represent disregulatory metaplastic and dysplastic changes, multiple fibrosis and fibrotic remodeling of lung tissue [19, 20].

Our data revealed some representative features of the DAD manifestations depending on the type of respiratory support.

Morphological features of lungs in the group 1 patients were prevalence of edema and hemorrhagic changes, di-screpancy of DAD manifestations and duration of the di-sease. So, morphological manifestations of exudative phase of DAD was found even after 14 days of disease, and interstitial pneumonia with fibrosing alveolitis were observed only in 12.5 % of patients.

The presence of dystelectasis, compensatory emphysema and thinning of the alveolar wall were typical morphological findings in patients of group 2. Numerous hyaline membranes, which covered alveolar walls, lead to a decrease in gas exchange area, alveolar-capillary block and were the cause of impaired lung ventilation function.

Morphological signs of proliferative phase of DAD in patients of group 3 were accompanied by the development of alveolar fibrosis and secondary bacterial bronchopneumonia, especially in the those with prolonged invasive lung ventilation.

Conclusions

The obtained data have some controversy with previous publications. As the length of hospital stay and time in the intensive care unit did not differ between groups, our data allow making a conclusion about the influence of respiratory therapy on morphologic changes in lung tissue. We believe that low-flow oxygen therapy may lead to P-SILI pheno-mena, thus, to the progression of respiratory failure due to self-damaging of intact lung tissue.

We have also revealed negative impact of invasive pulmonary ventilation on a number of bacterial complications and fibrosis stimulation.

The most “favorable” morphologic changes were found in patients of group 1 (non-invasive CPAP ventilation). We can make a precursory conclusion as to the advantages of this type of respiratory therapy for COVID-19 patients regarding its minimal influence on lung tissue.

Received 02.04.2023

Revised 13.04.2023

Accepted 21.04.2023

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