Smoking is associated with constant cough which is resistant to oseltamivir therapy for suspected COVID-19

Smoking depresses pulmonary immune function and is a risk factor contracting more serious outcomes among people who become infected. The association between smoking and persistent respiratory symptoms which are resistant to oseltamivir for suspected coronavirus disease 2019 (COVID-19) was evaluated. A total of 22 COVID-19 suspected medical personnel and their cohabitation families without hypoxia and lung diseases, who came to the adult fever clinic were studied. All patients received oseltamivir and antibacterial therapy together. The median age was 40 years. The study patients were divided into 2 groups; individuals who currently smoke in 11 patients (current smokers) and never smoked in 11 (never smokers). Four (36%) of 11 current smokers experienced constant cough even after oseltamivir administration, compared with 0% of never smokers (χ2=4.90; p<0.05). The cough score decreased from 1.5±0.5 at baseline to 0.3±0.5 during the one week after ciclesonide administration (p<0.001) and constant cough disappeared in three cases out of four current smokers. Because current smokers are at a higher risk to develop constant cough which is resistant to oseltamivir therapy for suspected COVID-19 as compared to never smokers, smoking cessation should be recommended at an early stage. Ciclesonide may improve the constant cough in suspected COVID-19.


Main Text
In late December 2019, an outbreak of an emerging coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in Wuhan, China and rapidly spread in China and outside 1 .The World Health Organization (WHO) declared the epidemic of COVID-19 as a pandemic on 12 March 2020 2 .In the early stage of an infection with SARS-CoV-2, the most prevalent symptoms are fever and acute cough 3 .I reported that oseltamivir helped improve not only fever but also acute cough in the early stage of suspected COVID-19 4 .But part of patients had constant cough and sputum production after oseltamivir treatment.For such "oseltamivir resistant cases", an effective new therapy is urgently required.
An elderly COVID-19 patient with underlying disease is the typical patient that may experience a severe disease course 5 .Elderly patients also have an immune system that does not respond well enough to ght an infectious agent.In addition, most of the elderly patients have other comorbidities such as diabetes mellitus, chronic obstructive pulmonary disease, cardiovascular disease, etc.Under these circumstances, the already deteriorated immune system tries to defend itself against these diseases by further reducing its overall activity and capability of ghting an infection.Smoking depresses pulmonary immune function and causes chronic in ammation in the lungs, so the immune system is constantly defending itself against chronic in ammation.COVID-19 is more likely to deteriorate due to an increase in comorbidities in elderly, which may lead to immune dysfunction in elderly COVID-19 patients, and the defense mechanisms are impaired, so they may develop life-threatening complications 6 .The WHO con rmed that smokers may experience severe complications from COVID-19, compared with never smokers 7 .However, the in uence of smoking behavior on the respiratory symptoms of COVID-19 has not been investigated su ciently.
The aim of this study was to investigate the association between smoking and persistent respiratory symptoms which are resistant to oseltamivir for suspected COVID-19.

Patients characteristics
The study population included 22 patients meeting the inclusion criteria in this study who had at least 7 days of follow-up at the time of the present analysis.The baseline characteristics of the whole population are shown in   The study was divided into two groups; individuals who currently smoke in 11 patients (current smokers) and never smoked in 11 (never smokers).Never smokers were younger on average than current smokers (p<0.01).There were no differences in sex, BMI, and SpO2 between the two groups.The peak temperature was signi cantly lower in current smokers than in never smokers (37.7±0.2 °C versus 38.4±0.8 °C; p< 0.01).Cough signi cantly decreased only in never smokers after oseltamivir administration (p<0.05).Four of 11 current smokers (36%) experienced constant cough, compared with 0% of never smokers (χ 2 =4.90; p<0.05,Table 3).

Effect of ciclesonide
Only four patients in current smokers had a constant cough despite oseltamivir administration.Three patients out of four were female (75%).Median age of four patients was 55 years (IQR 46-63 years).No patient was elderly.Most patients had underlying diseases [3 (75%)], including dyslipidemia [3 (75%)], hypertension [1 (25%)], and diabetes [1 (25%)].One patient was obese.Three patients out of four presented with sputum production as well as cough several days after symptom onset, despite oseltamivir administration.Because our hospital was unable to provide a respirator, it was felt to be great dangerous in having patients with worsening respiratory symptoms.Ciclesonide was administered 6-10 days after onset of respiratory symptoms or fever because of constant cough.
At the start of ciclesonide, there was no fever above 37.2℃ and SpO2 could be maintained at 96% or more with room air in four patients.We let 3 medical personnel come back 4-7 days after ciclesonide initiation, because their symptoms completely disappeared.And the sputum also disappeared in these 2 patients.Another patient in her 40s without underlying diseases and obesity had attained slight reductions 7 days after ciclesonide initiation, but her cough grew worse after ciclesonide was discontinued and two inhales of uticasone propionate / formoterol fumarate dehydrate (375/15μg) at one time, twice daily were administered.And her sputum production also persisted.Her chest computed tomography did not show any pneumonia.Overall, ciclesonide were well tolerated.None of the participating subjects developed an acute exacerbation during the trial period.After ciclesonide administration, the cough score decreased from 1.5±0.5 at baseline to 0.3±0.5 during the one week of treatment (p<0.001).

Discussion
Early oseltamivir administration improved acute cough as well as fever in COVID-19 suspected outpatients without hypoxia when it is used in combination with antibacterial therapy 4 .However, there are occasionally patients, especially smokers, whose cough and sputum production do not su ciently decrease after oseltamivir therapy.This study suggests that active smoking is linked with the persistent respiratory symptoms in suspected COVID-19.The nding that smoking is associated with COVID-19 progression is not surprising because of the adverse effects of smoking on pulmonary immune function 11, 12 .Because COVID-19 can predominantly damage the lungs, smoking cessation should be encouraged.In addition, the viral entry has been shown to cause cytokine storm involving excessive production of proin ammatory cytokines including interleukin (IL)-6, which is augmented by smoking.

Shin et al. made a simple hypothetical model of COVID-19 for the in ammatory processes and cytokine
storm, an immune in ammatory overreaction.First, cytokine storm may start from the early course of disease to later stage according to the degree of activation of host in ammatory response and it may be rapidly progressive at any time.Second, there may be no correlation between clinical and pathologic views 13 .The patient may be non-symptomatic or have mild symptoms despite severely progressed conditions, which will delay the appropriate treatment at an early stage.If the COVID-19 symptoms are severe, the patients are hospitalized and the treatment is done, though they have not been established yet.However, no treatment is provided for the patients with mild symptoms who are isolated at home or shelter.Among them, there will be also some cases in whom cytokine storm has progressed 14 , leading to sudden death.I guess that the constant cough in current smokers after oseltamivir administration means a respiratory symptom at an early stage of cytokine storm.Active smoking could trigger off cytokine storm secondary to COVID-19.
The increase in various proin ammatory cytokines induced by COVID-19 might be suppressed by short course of low dose steroids in an early stage of disease.But steroids may not be effective in a later stage of disease such as cytokine storm even though high dose of steroids are used.It is to be desired that the treatment should be initiated before COVID-19 pneumonia with hypoxia appears, and then it is expected to have the effect of improving the respiratory symptoms and preventing progression to severe pneumonia.In addition, there are limited evidences from case reports suggesting that ciclesonide prevents progression to severe pneumonia when administered in the middle stage of CIVID-19 15 .In the present study, COVID-19-suspected patients in oseltamivir resistant cases took inhaled ciclesonide and their respiratory symptoms improved, although the possibility that this would have been the natural course of the disease in these patients cannot be excluded.Therefore, the inhalation of ciclesonide is a potentially useful new therapeutic strategy in COVID-19 cases.Systemic steroid treatment is controversial in COVID-19 due to the possibility of prolonging viremia and complications such as secondary infection 16 , although systemic administration of dexamethasone is being considered in later stage 17 .Ciclesonide is a safe drug that is widely used as a steroid for inhalation from premature babies and newborns to the elderly and is said to be effective in controlling chronic in ammation of the respiratory tract.Ciclesonide is an inhaled prodrug that stays on the lung surface with only minor increases in blood levels.In a report published on 12 March 2020, they showed that while uticasone demonstrated no antiviral effects, ciclesonide almost completely suppressed the growth of SARS-CoV-2 at low concentration 18 .Ciclesonide seemed to be more effective on constant cough than uticasone that had an accompanying long-acting beta-agonist in a ciclesonide resistant case of this study.In addition, ciclesonide has anti-in ammatory effects that suppress the in ammatory mediators, such as IL-6 released from lung epithelial cells, thereby reducing cytokine storm.
Until now, no speci c treatment has been recommended for COVID-19.But the consensus on the management of COVID-19 infected patients is moving toward the need of a biphasic approach.During the rst phase of the disease (from onset of the symptoms up to 7 days) antiviral therapy could be considered.In the second in ammatory phase of the disease, the use of anti-in ammatory therapy such as with steroids or cytokine inhibitors may be useful 19 .Once, cytokine storm occur, antiviral treatment alone is not enough and should be combined with appropriate anti-in ammatory treatment.Early recognition and appropriate treatment of cytokine storm will decrease the mortality in COVID-19.I provide a simpli ed approach through two steps.Early oseltamivir administration helps improve fever in the rst phase.In addition to antivirals, current smokers should quit smoking immediately.In the second phase, a ciclesonide inhalation may be considered, if cough persists even after oseltamivir administration.The presence of constant cough in oseltamivir resistant cases may select for a population with a greater likelihood to bene t from ciclesonide.

Limitations of the study
This study has some limitations; however, in the current context, it is believed that the results should be shared with the scienti c community.First, the number of patients was too small to draw de nite conclusions.Further studies are clearly needed.Second, there was no control group for patients without use of ciclesonide, therefore, it is di cult to directly compare constant cough in patients with and without use of ciclesonide.Third, this study was performed in Japan, a country that the test for SARS-CoV-2 could only be performed if pneumonia was present or a con rmed close contact with a SARS-CoV-2 patient in the beginning.Therefore, there was a lack of coronavirus tests in this study and patients with other in uenza-like respiratory diseases may have been included, though COVID-19 has been spreading during the study in Sapporo.Fourth, a de nitive diagnosis of in uenza may also require a PCR test in general.
However, in uenza diagnosis information was obtained through use of rapid diagnosis kits by medical institution and the sensitivity of the in uenza antigen test is equal to that of the PCR test for SARS-CoV-2.Therefore, it is believed that this diagnosis information was reliable.

Conclusions
This study demonstrated that active smoking is associated with persistent respiratory symptoms after oseltamivir administration in suspected COVID-19, and smoking cessation may help in improving outcomes.In addition, the inhalation of ciclesonide has an excellent therapeutic potential in patients with constant cough at an early course of suspected COVID-19.Large scale controlled studies should therefore be performed to establish the e cacy of ciclesonide on the long-term prognosis in COVID-19 patients without hypoxia which does not su ciently respond to oseltamivir therapy.

Study Design and Participants
A total of 34 medical personnel and their cohabitation families with medication in the fever clinic, from 1 March 2020, to 14 September 2020 were prospectively enrolled in the study if they ful lled ve primary criteria: i) age≧20 years, ii) peak temperature (≧37.5℃),iii) one or more respiratory symptoms; iv) a nose swab for in uenza A and B was negative, v) peripheral capillary oxygen saturation (SpO2)≧96% (Fig. 1).Exclusion criteria were as follows: 1) history of asthma; 2) incidences of self-reported wheeze, pharmacy data indicating asthma-like symptoms or variability in lung function in the previous year 8 ; 3) current treatment that might in uence the cough; 4) any concurrent airway disease (e.g.pneumonia, cancer, tuberculosis); and 5) uncontrolled systemic disease or pregnancy.Nine with low grade fever were excluded.Three patients with hypoxia and lung diseases were excluded.Thus, the study population consisted of 22 patients without low grade fever, hypoxia, and lung diseases.Eligible participants to receive oseltamivir 75 mg were given orally twice a day for 5 days.
A small series of four consecutive suspected COVID-19 patients whose cough did not decrease even after the administration of oseltamivir therapy received inhalation of ciclesonide.Daily inhalation of ciclesonide [Alvesco Inhalation 200 μg inhaler (56 puffs/kit); Teijin, Tokyo, Japan], 800 μg/day, was administered to the patients.Either two puffs of 200 μg metered-dose inhaler (MDI) of open-label ciclesonide in the morning and the evening for a total of 7 days.

Case De nition and Variable Measurement
A suspected case of COVID-19 was de ned an individual who had an in uenza-like illness, as shown by peak temperature≧37.5℃,one or more respiratory symptoms (cough, sputum, or sore throat), and a nose swab for in uenza was negative.In uenza antigen tests were performed immediately after sample collection.This antigen test ImunoAce Flu is licensed for the diagnosis of human in uenza A and B (Tauns Laboratories, Shizuoka, Japan) and has a sensitivity of 67% 9 .
Patients completed a daily diary card for cough (score 0=absent, 1=mild, 2=moderate, 3=severe) 10 and other respiratory tract symptoms regarding the previous day and night.The primary outcome measure was the decrease in daily cough score during the 1 week treatment period.Patients were shown how to complete the daily record card for the symptoms: cough, sputum production, wheezing, shortness of breath, and chest tightness; the scores were 0=no symptoms ranging to 3=severe symptoms.This was to be completed every morning and every evening during the 1 week of treatment.Patients with smoking history were identi ed.For patients with smoking history, the amount of smoking, the years of smoking history, and the years of smoking cessation were individually collected.

Statistical Analysis
Data expressed as mean ± standard deviation or percentages of patients.Differences were compared by Wilcoxon non-parametric test for Gaussian variable.The ratio between baseline and after medication was compared by χ 2 test.Differences between the two groups were evaluated using the χ 2 test for 2×2 contingency tables.p<0.05 was considered signi cant for all tests.

Figure 1 Flow
Figure 1