key: cord-0824712-d6f8u1k3
authors: Dirican, A.; Uzar, T.; Karaman, I.; Uluisik, A.; Ozkaya, S.
title: Trying to Find the Answer for Two Questions in Patients with COVID-19:1. Are pulmonary infiltrates of COVID-19 infective or inflammatory in nature (Pneumonia of Pneumonitis)?2. Is Hydroxychloroquine plus Azithromycin or Favipiravir plus Dexamethasone more effective in the COVID-19 treatment?
date: 2020-08-31
journal: nan
DOI: 10.1101/2020.08.25.20181388
sha: 3ac90de8f59085636ee318e61fb58b4e61e6d2c2
doc_id: 824712
cord_uid: d6f8u1k3

Background: During the current pandemic, a great effort is made to understand the COVID-19 and find an effective treatment. As of 17 August 2020, there is no specific drug or biologic agent which have been approved by the FDA for the prevention or treatment of COVID-19. Methods: We retrospectively analyzed the clinical and radiological findings of 211 COVID-19 in-patients that were treated between March - August 2020. Confirmation of a COVID-19 diagnosis was made according to a positive RT-PCR result with a consistent high-resolution-CT (HRCT) finding. Radiological images and the rate of clinical response of patients were investigated. Result: While 128 patients (58.7) did not develop pneumonia, the mild, moderate and severe pneumonia ratios were 28(13.2%), 31(18.7%) and 27(22.9%). 72 patients (34.1%) whose PCR tests were positive did not show any symptom and they were followed in isolation without treatment. 52 patients (24.6%) received hydroxychloroquine plus azithyromycine, 57 patients (27%) received favipiravir and 30 patients (14.2%) received favipiravir plus dexamethosone as the first line of treatment. 63.1% of pneumonia patients who received hydroxychloroquine plus azithyromycine, 28.3% of patients who received favipravir and 10% of patients who received favipravir plus dexamethasone showed a failure of treatment. Conclusion: The pulmonary infiltrates of COVID-19 are not infective; therefore, the characteristic of the disease should be described as COVID-19 pneumonitis instead of pneumonia. The favipiravir plus dexamethasone seems to be the only drug combination to achieve the improvement of radiological presentation and clinical symptoms in COVID-19 pneumonia patients.

After the coronavirus disease 2019 (COVID-19) emerged in the Wuhan, China in late 2019 from a zoonotic source; the outbreak spread rapidly throughout the world. On March 11 2020, World Health Organization (WHO) declared the COVID-19 outbreak a pandemic (1) .

Although the majority of COVID-19 cases are either asymptomatic or mild, COVID-19 may cause a respiratory compromise requiring hospitalization and supportive care in the significant proportion of patients (2) . As of August 17 2020, this pandemic caused the death of more than 772.000 people with a significant economical and sociological burden globally (3) . Besides its high infectivity rate, COVID-19 also has high morbidity and mortality due to autoimmune destruction of the lungs stemming from the release of the pro-inflammatory cytokines (2) .

It is known that; the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mainly affects the respiratory tract and reaches the lungs, eventually causes the potentially fatal pneumonia in severe cases (2) . Since the studies investigating the pathophysiological characteristic of this novel disease are still ongoing, the search for the effective therapies requires a comprehensive approach. As of 17 August 2020, there is no specific drug or biologic agent which is approved by the FDA for the prevention or treatment of COVID-19 (4) . Numerous other antiviral agents, immunotherapies, and vaccines continue to be investigated and used as potential therapies in the clinical trials. Several guidelines and reviews of pharmacotherapy for COVID-19 investigating the potential drugs have also been published (4, 5) . Existing drugs with well-documented effects including hydroxychloroquine, azithromycine, favipiravir and dexamethasone are being used as combination or alone to diminish the symptoms of respiratorily compromised severe COVID-19 patients. (4, 5) .

To find an effective treatment, the most important point to be illuminated in patients with ; is the question of whether lesions in the lung are infective or inflammatory in nature. Therefore, in this retrospective study, we aimed to find the answer of the two questions: "Are pulmonary infiltrates of COVID-19 infective or inflammatory in nature?" and "Is Hydroxychloroquine plus Azithromycin or Favipiravir plus Dexamethasone more effective in the COVID-19 treatment?".

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We retrospectively analyzed the radiological and clinical findings of COVID-19 in-patients and out-patients that were treated in Samsun VM Medicalpark Hospital between March-August 2020. This study was approved by the Institutional Review Board of SB (IRB No. 2020-07-21T10-25-53) and performed in accordance with the principles of the Declaration of Helsinki.

Patients who were suspected to be infected with COVID-19 were confirmed with laboratory results and included in the study. Only laboratory-confirmed cases were included in the study.

Total of 211 patients have been included in the study. All the recovered patients were discharged with 2 consecutive negative RNA detection (interval above 24 h) and clinical improvement and followed for another 14 days after discharge.

Patients with pneumonia were divided into three groups by means of severity as mild, moderate and severe depending on the total volume of radiologic infiltrations. Small and by one by ground-glass opacities or consolidations considered as mild pneumonia ( Figure 1 ).

Those with total volume of diffuse ground-glass opacities or consolidations, smaller than the volume of right upper lobe considered as moderate pneumonia ( Figure 2 ). Severe pneumonia defined as the total volume of diffuse ground-glass opacities bigger than the volume of right upper lobe ( Figure 3 ).

Respiratory samples were obtained by nasopharyngeal and nasal swabs and analyzed by reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay. Confirmation of a COVID-19 diagnosis was made according to a positive RT-PCR result with a consistent highresolution-CT (HRCT) finding. Also, the patients whose multiple nasopharyngeal swap samples were negative for SARS-CoV-2 but serological IgM/IgG antibody was positive in rapid antibody test included in the study.

At the beginning, all patients were prescribed with oral hydroxychloroquine sulfate 400 mg two times in the first day as the loading dose and, 200 mg two times per day for the following four days. Azithromycin 500 mg were prescribed as the loading dose in the first day and 250 mg one time per day for the following four days. Favipravir was loaded as 1600 mg two times in the first day as the loading dose and 600 mg two times for the following four days as the maintenance dose. The dose of the systemic steroid (dexamethasone or methylprednisolone) All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 31, 2020. . https://doi.org/10.1101/2020.08.25.20181388 doi: medRxiv preprint was adjusted according to daily status of the patient. All the patients who seem to recover by fibrosis were prescribed as long-term low dose oral steroid. The treatment was considered as effective if clinical and radiological recovery was observed at the end of the treatment.

The quantitative data were described as the mean ± standard deviation, or as the median (min − max). The qualitative data were described by number of cases (proportion, %). All of the analysis was performed using SPSS Version 22.0.

Total number of 211 patients were included in the study. The characteristics of patients were shown in Table 1 The given drugs and treatment failure rates were shown in Table III 

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The copyright holder for this preprint this version posted August 31, 2020. . https://doi.org/10.1101/2020.08.25.20181388 doi: medRxiv preprint As of August 16 2020, there is no FDA-approved specific drug for COVID-19. However, an array of already-existing drug is approved for their other indications, and multiple investigational agents are currently being studied for the treatment of COVID-19 in different clinical trials around the globe (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) . A large volume of data from randomized controlled trials, observational cohorts, and case series are emerging at a very rapid pace; some in peerreviewed journals, others as pre-peer-review manuscripts, and, in some cases, as press releases.

On Favipiravir is a viral RNA polymerase inhibitor, which acts by its metabolite ribofuranosyl-5′-triphosphate (RTP) that inhibits influenza virus RNA polymerase activity (11) . Favipiravir was urgently used and presented good inhibitory effects on Ebola virus in 2014. Favipiravir is also proven to protect mice from lethal infection with various types of Influenza viruses (12) .

It is the first approved drug with the potential curative effect on COVID-19 in China, which then played an important role in the prevention and control of SARS-CoV-2 infection (13) .

Although there have been many registered clinical trials focusing on antiviral drugs for COVID-19, how antivirals may contribute to control the disease progression remains unclear.

Q. Cai et al. reported that favipravir causes an improvement of chest imaging by inhibiting the replication of SARS-CoV-2 (13) . They also stated that the relationship between viral clearance and improvement in CT image together helps improvement of clinical picture of the All rights reserved. No reuse allowed without permission.

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The copyright holder for this preprint this version posted August 31, 2020. . https://doi.org/10.1101/2020.08.25.20181388 doi: medRxiv preprint patient. We observed that, for our patients, favipiravir was the only drug to achieve clinical (especially in fever) and radiological improvement in patients with COVID-19.

Glucocorticoids have been widely used in the syndromes closely related to COVID-19, including Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), severe Influenza infections and community-acquired pneumonia. Commonly, in all of those severe viral pneumonias, the host immune response plays a key role in determining the pathophysiological effects of organ failure (2) . The RECOVERY trail has recently demonstrated that the dexamethasone reduced the risk for death among seriously ill COVID-19 patients by up to one third (2) . However, the drug did not appear to help patients with less serious presentations of COVID-19. The benefit was thought to occur in patients who were being treated more than 7 days after symptoms onset, when inflammatory lung damage likely to constitute the clinical picture (2) . Guidelines issued by the U.K. chief medical officers and by the National Institutes of Health (NIH) in the United States have already been updated to recommend the use of glucocorticoids in severe patients hospitalized with COVID-19 (2, 4, 5, 14) . In the presented case series, we showed that severe patients who failed to respond to the hydroxychloroquine plus azithromycin combination were successfully treated with favipiravir plus dexamethasone, consistent with the idea of the existence of inflammatory lung environment.

After early May when the clinicians at our hospital have realized that hydroxychloroquine was not as effective as favipravir for the recovery of pneumonia patients, all the patients with pneumonia were prescribed with favipravir instead of hydroxychloroquine. However, creating a randomized controlled group would not be ethical at the time of the pandemic, therefore we were not able to compare the effects of drug by the matched randomized group. Instead, we reported histopathology data of COVID-19 pneumonia deriving from the accidental cases of two patients who underwent lobectomies for lung cancer (16) . Pathologic findings were All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 31, 2020. Supportively, we concluded that; SARS-CoV-2 first starts as an infection of the nasopharynx and progresses as the inflammation of the lung parenchyma, depending on the degree of the response that is shown by the host immunity. We also think that pulmonary radiological findings that appear as opacities are also caused by the inflammatory reaction against the virus. The response to the anti-inflammatory therapy that is proven by radiological and clinical improvement, as well as published pathological data all support this finding.

However, one limitation of this study includes lack of pathological investigation of patients due to inability to take a biopsy during clinical practice due to the circumstances during pandemic.

Segmental small pulmonary vessel enlargement on chest CT has been stated as a unique feature associated with COVID-19, different from other viral or bacterial pneumonia findings on chest CT (21). Lang et. al also stated that medium to small vessel dilatations are not confined to areas of diseased lung, and often involves subpleural distal vessels, suggesting a diffuse vascular process (22) . One theory behind those findings is the possibility of COVID-19-induced secondary pulmonary vasculitis that is responsible for vascular changes and abundance of pulmonary parenchymal ground-glass opacification (21, 22) . The vascular dilatations seen in ground glass-opacities of COVID-19 can be a good indication to differentiate COVID-19 from other etiologies of ground-glass opacities, as seen in our cases (Figure 7 and 8) . Those vascular dilatations might indicate that COVID-19 starts as a vasculitis and progresses to the perivascular inflammation. It is not clear if it is an immune-All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 31, 2020. . https://doi.org/10.1101/2020.08.25.20181388 doi: medRxiv preprint complex vasculitis or not, and further pathological examinations must be done to have a clear result.

This study has some limitations. Since this study was not designed to compare the two groups at the same time but rather to compare the outcomes of two different groups of patients treated at different times retrospectively, the study lack of the features of a randomized control trial. Future studies with matched control groups and patients with other appropriate pathologies, including bacterial or other viral pneumonias would be helpful to explain the findings and clarify the extent of the vascular findings. Well-designed large randomized clinical trials are also necessary to identify effective treatments based on a high level of evidence. Further imaging and pathologic studies are also required to investigate the diffuse pulmonary vascular dysregulations that are caused by unclear mechanisms.

In conclusion, we suggest that the SARS-CoV-2 causes an infectious disease which progresses to an inflammatory lung disease. The pulmonary infiltrates seem to be not infective; therefore, the characteristic of the disease should be described as COVID-19 pneumonitis instead of pneumonia. We concluded that, although the hydroxychloroquine plus azithromycin can be used effectively in the infected people without pneumonia, there is no clinical benefit from the use of such combination in infected patients who developed pneumonia. The favipiravir plus dexamethasone seems to be the only drug combination to achieve the improvement of radiological presentation and clinical symptoms in severe COVID-19 patients.

The authors have no conflicts of interest to declare. All of authors read and approved the final form of the manuscript.

The research article data that used to support the findings of this study is available from the corresponding author upon request. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 31, 2020. . https://doi.org/10.1101/2020.08.25.20181388 doi: medRxiv preprint glass infiltrates that were seen at thorax HRCT, treatment with hydroxychloroquine plus azithromycin was started. Figure 6B . Despite five days of treatment with hydroxychloroquine plus azithromycin, the fever and cough complaints of patient in Figure 6A did not resolve. Since the control CT on the 7th day revealed an increase in the ground-glass infiltrates, treatment with favipravir plus dexamethasone was started. All rights reserved. No reuse allowed without permission.

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