key: cord-0926361-s2hlxeqj
authors: Dirican, Adem; Ildir, Selin; Uzar, Tugce; Karaman, Irem; Ozkaya, Sevket
title: The role of endotheliitis in COVID‐19: Real‐world experience of 11 190 patients and literature review for a pathophysiological map to clinical categorisation
date: 2021-09-18
journal: Int J Clin Pract
DOI: 10.1111/ijcp.14843
sha: 06b3755b8ad826b690d449a0d19ea9c497b4194c
doc_id: 926361
cord_uid: s2hlxeqj

OBJECTIVE: COVID‐19 may yield a variety of clinical pictures, differing from pneumonitis to Acute Respiratory Distress Syndrome along with vascular damage in the lung tissue, named endotheliitis. To date, no specific treatment strategy was approved for the prevention or treatment of COVID‐19 in terms of endotheliitis‐related comorbidities. Here, we presented our treatment strategies for 11 190 COVID‐19 patients depending on categorisation by the severity of both the respiratory and vascular distress and presented the manifestations of endotheliitis in skin, lung and brain tissues according to the different phases of COVID‐19. METHODS: After a retrospective examination, patients were divided into three groups according to their repercussions of vascular distress, which were represented by radiological, histopathological and clinical findings. We presented the characteristics and courses of seven representative and complicated cases which demonstrate different phases of the disease and discussed the treatment strategies in each group. RESULTS: Among 11 190 patients, 9294 patients met the criteria for Group A, and 1376 patients were presented to our clinics with Group B characteristics. Among these patients, 1896 individuals (Group B and Group C) were hospitalised. While 1220 inpatients were hospitalised within the first 10 days after the diagnosis, 676 of them were worsened and hospitalised 10 days after their diagnosis. Among hospitalised patients, 520 of them did not respond to group A and B treatments and developed hypoxemic respiratory failure (Group C) and 146 individuals needed ventilator support and were followed in the intensive care unit, and 43 (2.2%) patients died. CONCLUSION: Distinctive manifestations in each COVID‐19 patient, including non‐respiratory conditions in the acute phase and the emerging risk of long‐lasting complications, suggest that COVID‐19 has endotheliitis‐centred thrombo‐inflammatory pathophysiology. Daily evaluation of clinical, laboratory and radiological findings of patients and deciding appropriate pathophysiological treatment would help to reduce the mortality rate of COVID‐19.

Novel coronavirus disease 2019 has resulted in a dramatic pandemic crisis by causing mainly a respiratory disease that can rapidly progress to pneumonia and, in severe cases, to acute respiratory distress syndrome (ARDS). 1 Accordingly, we adopted our treatment strategies depending on the categorisation of patient groups by severity of both the respiratory and vascular distress. In this paper, we aimed to present the clinical, radiological and histopathological manifestations of COVID-19-related endotheliitis as well as present our treatment categories which focused on preventing endotheliitis-related consequences in different phases of the disease.

All COVID-19 patients who were diagnosed and treated in Samsun VM Medicalpark Hospital, Turkey, between March 2020 and April 2021, were retrospectively evaluated. Patients who were suspected to be infected by SARS-CoV-2 were confirmed with clinical, laboratory (positive reverse-transcriptase-polymerase chain reaction assay of nasopharyngeal swabs or serological IgM/IgG rapid antibody test against SARS-CoV-2) and radiological (consistent HRCT findings) results included in the study. Demographic characteristics, presenting symptoms of the patients at the time of admission, radiological images, hospitalisation status and the presence of the need for respiratory support were retrieved from patient records at the time of admission (Table 1 ). Confidentiality of the study participants' information was maintained throughout the study. The study was performed in accordance with the Helsinki Declaration and approval for this study procedure was obtained from the Istinye University Institutional Review Boards/ethical committees with respect to its scientific content.

This heterogeneous population of patients were divided into three groups (A, B and C) according to their repercussions of vascular and respiratory distress, which were represented by radiological, histopathological and clinical findings. Divisions into three groups were made according to combined criteria that were adopted from WHO severity classification and the extent of endotheliitis, which were represented by the clinical symptoms, baseline oxygenations status, radiological findings (chest X-ray/CT findings) and haemodynamic differences. 4 Accordingly, three escalating phases of COVID-19 disease progression with associated signs, symptoms and potential phase-specific treatments were described as early infection phase

• Novel coronavirus disease 2019 (COVID-19) has resulted in a dramatic pandemic crisis by causing mainly a respiratory disease that can rapidly progress to pneumonia and, in severe cases, to acute respiratory distress syndrome (ARDS).

• SARS-CoV-2 infection is a multisystemic disease which courses rapidly with respiratory failure and complications secondary to vascular alterations (ie, microvascular thrombosis, endotheliitis and cytokine-induced plasma toxicity).

• Distinctive manifestations in each COVID-19 patient, including non-respiratory conditions in the acute phase and the emerging risk of long-lasting complications, suggest that COVID-19 has an endotheliitis-centred thrombo-inflammatory pathophysiology.

• Potential pathophysiological mechanisms contributing to endotheliitis includes cytokine storm and toxic plasma, thromboinflammation and systemic microangiopathy that could be used as a target to provide appropriate treatment agents.

• Endotheliitis can explain the mechanism behind the respiratory failure in COVID-19, and the difference of The treatment modalities for each group were adopted from current local guidelines, as well as interventions that were later standardised according to clinical observation of momentary changes by two different pulmonologists. 5-7

Group A included patients who had any of the various signs and symptoms of COVID-19 (eg, fever, cough, sore throat, headache, muscle pain, diarrhoea, loss of taste and smell) but did not have shortness of breath. Group A patients either presented no imaging findings of pneumonia or they presented with the typical radiological representation of minimal patchy, subpleural, peripheral, perivascular ground-glass opacities (GGO) ( Figure 1I ,II). The placement of GGOs in the early presentation of the disease is compatible with the distribution of microvascular capillaries of the lung.

If the pulmonary involvement was absent or mild-to-moderate and the patient was suitable for ambulatory treatment, Favipiravir tablet (1600 mg BID for the first day, followed by 600 mg BID for 4 days, making 5 days in total), Dexamethasone (0.1-0.2 mg/kg/day), Azithromycin tablet, low-molecular weight heparin (LMWH) and acetylsalicylic acid (ASA) therapies were applied for 1 week.

Patients who showed evidence of lower respiratory disease during clinical assessment (respiratory symptoms) or imaging (findings of pneumonia) but an oxygen saturation (SpO 2 ) ≥94% on room air at sea level, were hospitalised for close follow-up. Patients with comorbidities or special conditions (ie, age >65, diabetes, cancer, obesity, cardiovascular disease, chronic lung disease, sickle cell disease, chronic kidney disease, being pregnant, cigarette smoking, transplant or immunosuppression recipient) were also hospitalised because of their high risk of severity. 4 Patients who had moderate pulmonary involvement or unresponsive to the Group A treatment in terms of the clinical symptoms, with no evident respiratory failure, but had been indicated for hospitalisation were classified as Group B. Group B corresponds to the progressive phase of the disease, which is characterised by multifocal, bilaterally diffused GGOs with poorly circumscribed consolidations scattered in peripheral zones of lungs, along with vascular and intra-lobular septal thickenings called "crazy paving pattern" (Figure 1 -IIIb). 7 For this group, Favipiravir tablet (1600 mg BID for the first day, followed by 600 mg BID for 4 days, making 5 days in total), Dexamethasone (0.1-0.2 mg/kg/day) or methylprednisolone (1-2 mg/kg/day), Azithromycin tablet or fluoroquinolone, LMWH, ASA and Famotidine tablet therapies were prescribed. Although the treatment takes 1 week, we observed that this phase has the peak stage in 10-13 days and may include potential secondary complications. Thus, patients require a close follow-up by serial chest X-rays to establish a baseline to assess the improvement of aeration.

Patients with moderate to severe pulmonary involvement (lung infiltrates >50%), accompanied by respiratory failure (SpO 2 <94% on room air at sea level and, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO 2 /FiO 2 ) <300 mm Hg, respiratory frequency >30 bpm) or to the patients who were recalcitrant to standard therapy and had deteriorating clinical status with laboratory (particularly increasing ferritin levels) and radiological findings were classified as Group C. In addition, patients who showed rapid progression (>50%) on CT imaging and who presented with respiratory failure or shock within 24-48 hours were also included in this group. This group represents the progressive, peak, dissipative and severe phases of the disease. The radiological findings of Group C were microscopic lacerations and infiltrations in perialveolar vessels which were radiologically appeared as developing pulmonary GGOs, consolidation and diffuse alveolar damage (DAD), which may be accompanied by pneumothorax, pneumomediastinum or intracranial haemorrhage at this stage ( Figure 1IV -VII).

For this severe group of patients, Favipiravir tablet (1600 mg BID for the first day, followed by 600 mg BID for 4 days, continued for 5 or 10 days in total), methylprednisolone (250-1000 mg/d for at least 3 days), convalescent plasma (once in a were presented and cases were presented in Figure 1 .

Case 1 ( Figure 1I ) was a 51-year-old female patient who was admitted to the hospital with complaints of cough and fever. She was diagnosed with COVID-19 due to PCR positivity. HRCT images showed patchy, subpleural and peripheral perivascular ground-glass opacities, corresponding to the early phase of pneumonitis. She received Group A treatment.

GGOs in transaxial images were located in the subpleural area, where the microvascular endoteheliitis and endothelial destructions mostly likely occur, due to the interaction with toxic plasma in the capillaries of pulmonary interstitial space. She was completely recovered on the 14th days at control appointment, after 5 days of treatment with favipiravir.

Case 2 ( Figure 1II ) was a 51-year-old male patient who was admitted to the hospital with complaints of fever and chest pain. His COVID-19 PCR test was positive. In addition to the characteristics of an early phase COVID-19 pneumonitis (end-capillary microangiopathy, explained in Figure 1I ) his HRCT images showed perivascular consolidation. It appeared as the continuation of the crazy-paving pattern, which was demonstrated by the thickening in inter-lobular and intra-lobular septa. Lung involvement was limited and monofocal. Hence, the patient received Group A treatment. He was completely recovered on the 14th days at the control appointment, after 5 days of treatment with favipiravir.

Consists of seven cases with variable stages of COVID-19 and examples of early and severe endotheliitis in the brain, pulmonary and skin tissues. Histopathological and radiological findings of pneumonitis changed depending on the phase of the disease (early, progressive, severe and dissipative, respectively), which leads to a divergence in treatment groups. Examples of patients who were convenient for Group A treatment are depicted in Sections I and II. I. Case 1. HRCT images showed patchy, subpleural and peripheral perivascular ground-glass opacities, corresponding to the early phase of pneumonitis. She received Group A treatment. GGOs in transaxial images were located in the subpleural area, where the microvascular endoteheliitis and endothelial destructions mostly likely occur because of the interaction with toxic plasma in the capillaries of pulmonary interstitial space. II. Case 2. HRCT images showed characteristics of an early phase COVID-19 pneumonitis (end-capillary microangiopathy, explained in 1I) and perivascular consolidation. It appeared as the continuation of the crazy-paving pattern, which was demonstrated by the thickening in inter-lobular and intra-lobular septa. Lung involvement was limited and monofocal. Hence, the patient received Group A treatment. An example of a patient who was convenient for Group B treatment is depicted in Section III. III. Case 3. Transaxial HRCT image in the first day of positivity shows bilateral and patchy nodulary GGOs as expected in early phase (IIIa). On the 5th day of positivity, affected pulmonary areas were advanced into scattered consolidations (IIIb). This appearance was noted as the progressive phase of pneumonitis and was considered as the representation of clinical deterioration clinically (ie, dyspnoea, respiratory failure). On the 15th day of positivity, fibroreticular consolidations were conspicuous (IIIc). The dissipative phase was the healing process, characterised by the resolution in lung parenchyma and residual GGO, observed after 35 days of positivity (IIId). Parenchymal bands, originated from previous fibroreticular proliferation, were also visible (IIId). If the patients have a tendency of severe phase and/or unresponsiveness to Group The demonstration of endotheliitis in the biopsy section of lung parenchyma ( Figure 1VIII ), radiological images of the brain ( Figure 1IX ) and lung ( Figure 1X ,XI) and skin manifestation ( Figure 1XII ) of endotheliitis are also presented in Figure 1 .

Our classification of patient population and treatment groups was understood, yet detrimental, inflammatory profile. 11 Therefore, we advise the categorisation and treatment strategies to be selected by monitoring radiological findings 12 and the severity of clinical features (such as dyspnoea and oxygen saturation).

Pathophysiology of COVID-19 is closely related to cytokine storm, which arises from the consecutive and intricate activation of numerous inflammatory cells that cause excessive and/or unregulated, proinflammatory cytokine release. 13 Cytokines force blood plasma to undergo a chemical alteration, revealing toxic and irritant char- They also indicated that clinically not all patients with ARDS present DAD. However, the presence of DAD with ARDS contributes to worsening of clinical outcomes compared with those without DAD.

Early and late endotheliitis lesions on pulmonary HRCT are seen in rhage) in the brain, kidneys and heart ( Figure 1IX ).

Endothelial dysfunction plays a key role in understanding the mul- In the clinical presentation, aggravation of dyspnoea and hypoxaemia symptoms were attributed to dysfunctional crosstalk between leucocytes and endothelial cells that manifest as vascular immunopathology predominantly confined to the lungs. Eventually, since microvascular walls are prone to damage, the destruction most conveniently occurs as endotheliitis at the site of pulmonary interstitial capillaries, with the help of lung elasticity and thin vascular walls, conveys into the perivascular space. 29 Remarkably, because of SARS-CoV-2's endotheliophilic nature, endothelial and epithelial infections appear to be the predominating factors during the course of the disease. 3 On the other hand, alveolar-centred infection and the disruption of alveolar epithelial-endothelial barriers contribute to the development of DAD and pneumonitis, which manifest as GGOs in alveolar spaces 30, 31 (Figure 1III ,VIII). The aforementioned endothelial damage may spread to different systems and become lethal ( Figure 1VII ).

Ekanem et al 32 stated that higher inflammatory markers (ferritin, CRP and fibrinogen), increased fibrosis in HRCT images, and absence of receiving an interleukin-6 inhibitor or convalescent plasma are associated with a higher probability of severity and mortality via the spontaneous pneumothorax (SPT). They also suggested that there must be factors uniquely associated with COVID-19 that contribute to the incidence of SPT since half of the patients were not on a ventilator when the pneumothorax was diagnosed. In Group C ( Figure 1IV -VII), we also observed that endothelial damage, along with thromboinflammation, brought increased incidence of pneumothorax secondary to DAD in patients with ARDS. Here, among 11 190 patients, 30 patients developed either SPT, pneumomediastinum or subcutaneous emphysema with a 13.3% mortality rate.

The most important reason behind these complications was most likely DAD, which stems from the high transpulmonary pressure and alveolar wall vulnerability, with decreased compliance and increased frailty, resulting in an air leakage into the chest compartments. 33 SPT that is observed in severe COVID-19 patients is thought to be derived from reduced alveolar vessel calibre because of the virusinduced cytolysis, mononuclear immunological response to injury and the small vessel thrombosis at the site of the perialveolar area, which should be differentiated from iatrogenic pneumothorax related to mechanical ventilation. 34

Planning effective therapy for COVID-19 infection is a complex process. According to Mastellos et al 35 Antiviral drugs are being used to decrease the viral load.

Correspondingly, favipiravir was the drug of choice that is recommended by the Turkish Republic of Health Ministry Guidelines. 5, 6 However, it should be noted that antiviral therapy fails to prevent pulmonary involvement, which is the result of the inflammatory process rather than the effect of SARS-CoV-2 infection itself. 40 Systemic corticosteroid drugs (dexamethasone and methylprednisolone) are the only effective therapeutic agents to repair nonimmune capillary microvascular endotheliitis, hence, advised to be used even in the presence of minimal ground-glass opacities. 41 In our clinical experience, to benefit the best of steroids, steroids should be utilised in the early phase rather than the progressive phase (approximately the second week of infection). Minimally distributed GGOs may easily progress to severe ARDS in the absence of steroid treatment (Figure 1VIIa- [44] [45] [46] Immunomodulatory therapies help to diminish the cytokine response of the body. Tocilizumab therapy, a monoclonal IL-6 antagonist, reduced the likelihood of progression to the composite outcome of mechanical ventilation or death. 47 and steroid treatment to be started in the early period in patients who worsen after theoretical viral clearance is completed in the first 5-10 days. 5

We acknowledge that there are confounding factors related to the management of COVID-19 patients because of the lack of a standardised guideline for the treatment of each and every patient.

However, while the in-hospital mortality was reported to be up to 25% in different prospective trials, we believe that our standardised treatment approach, which has a result of 2.2% in-hospital mortality, represent the success of the personalised management of each COVID-19 patient in a single centre. 50, 51 As the COVID-19 pandemic continues, our current strategy represents a snapshot that would most probably change drastically over time. Our categorisation strategy has enabled us to implement systematic practices that we saw as beneficial instead of following a "random" approach for each new patient. We would like to declare that our study did not interfere with any patient's right to receive treatment by addressing a control group in a pandemic situation. Here, we also did not aim to demonstrate the effectiveness of the therapy in the means of laboratory data, however, we aimed to present the representations of the required interventions in each group of patients by preventing the progression of endotheliitis. Therefore, we used the current literature to support our clinical observation and own perspective. In the end of the study, our aim was to declare our own point of view by using our clinical experience, clinical representation of endotheliitis and the current literature. We would like to approach the vascular distress phenomenon as a clinical parameter that can be used practically in the clinics, both by recognising radiological images and clinical findings of the patients. to develop novel prognostic biomarkers and establish precise predictive thresholds for known biomarkers to foresee the severity for COVID-19 pneumonitis that is characterised by vasculopathy and a wide range of immune derangements.

The patients signed written informed consents to be able to provide data in this study. The study was approved by the Republic of Turkey

in accordance with the principles of the Declaration of Helsinki.

The authors have declared no disclosures.

AD and SO diagnosed, treated the patients and designed the analysis, SI, TU and IK collected the data, analysis tools and wrote the paper.

The research article data used to support the findings of this study are available from the corresponding author upon request.

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The role of endotheliitis in COVID-19: Real-world experience of 11 190 patients and literature review for a pathophysiological map to clinical categorisation