I corticosteroidi sono farmaci ampiamente utilizzati, ad oggi, nel terapia del COVID-19. La letteratura scientifica relativa all’uso di questa classe di farmaci è eterogenea sia nei metodi di ricerca, sia negli esiti.
La produzione scientifica ormai procede ad un ritmo per cui è facile non riuscire a stare al passo, e nel caso della pandemia è certamente sovrabbondante, dato l’interesse mondiale. A mio avviso, oggi più che mai, è importante leggere in modo critico la letteratura, altrimenti si rischia di ritrovarsi in fallacie logiche tali per cui si valuta esclusivamente o in modo sbilanciato:
– la quantità di evidenze (trascurando la qualità): fallacia di appello alla maggioranza
– l’autorevolezza della fonte: appello all’autorità
– le evidenze più recenti (trascurando fatti già noti), o viceversa gli studi più datati: appello alla novità, o alla tradizione
– i risultati degli studi (ignorando il contesto): eliminazione delle prove
Ecc. ecc. l’elenco sarebbe lungo. Meno tempo abbiamo per leggere e ragionare, maggiore la quantità di informazioni che circolano: la combinazione di questi due fattori ci rende particolarmente proni (me compreso) a saltare alle conclusioni.
Riassumo qui le mie personali conclusioni relative alla revisione critica della letteratura sui corticosteroidi, includendo l’uso pratico che viene fatto degli stessi farmaci nel contesto della terapia domiciliare, sul territorio (non ospedaliera) del covid. A seguire, riporto tutta la bibliografia consultata, con degli estratti per significativi di ogni articolo.
CORTICOSTEROIDI PER OS
- La letteratura riguarda soprattutto pazienti che richiedono ossigeno o ventilazione meccanica. Le linee guida suggeriscono di usare steroidi solo in pazienti ospedalizzati. In questo contesto molte ricerche indicano esiti migliori in pazienti che vengono sottoposti a steroidi.
- I corticosteroidi utilizzati in influenza e altri coronavirus (per la SARS, MERS…) spesso non hanno mostrato utilità, anzi peggiori outcome. Questo potrebbe dipendere in parte dalla specificità del covid, in parte dall’eterogeneità degli studi, in termini di timing della somministrazione, dosi utilizzate, selezione del campione, ecc.
- Alcuni studi riportano un effetto positivo dello steroide (spesso metilprednisone) se somministrato ad almeno 8 giorni circa da inizio sintomi, in corrispondenza della supposta “fase polmonare” del covid. Spesso i criteri per includere i pazienti nel gruppo a cui dare il corticosteroide sono vari e sono volti a individuare al meglio la fase in cui la viremia è minima o nulla, mentre la sintomatologia è “guidata” dalla risposta infiammatoria sbilanciata del soggetto. Tra questi criteri figurano: SpO2 (<90% o <93%), PaO2/FiO2, infiltrati bilaterali in imaging, PCR, ferritina, ecc.
- In uno studio si suggerisce che nei pz >60 anni convenga cominciare a dare i cortisonici con maggior anticipo (sempre in setting ospedaliero: “precoce” significa entro i primi 2 gg dall’ammissione)
- In diverse review “avverse” all’uso di cortisonici è stata effettuata una revisione forse non sufficientemente attenta della letteratura, utilizzando sicuramente potenti strumenti analitici e statistici, ma senza una accurata selezione a monte. Ad esempio sono stati presi “tutti gli studi con corticosteroidi” senza distinguere il tipo di steroide (è una classe eterogenea in termini di efficacia ed effetti collaterali), il timing di somministrazione, la dose.. in almeno un caso sono stati anche inclusi studi relativi a differenti agenti patogeni (influenza, coronavirus vari). In bibliografia sono riportati maggiori dettagli in proposito. L’apice mi pare sia uno studio su pazienti oncologici, non malati di covid, in cui tutta la discussione del paper verte sull’uso dei cortisonici nel covid.
- In uno studio italiano si è trovato beneficio SOLO in pazienti con ventilazione meccanica, con o senza ossigeno.
- Gli effetti collaterali anche dell’uso acuto di corticosteroidi sono presenti e noti, vanno contestualizzati come sempre nel rapporto rischio/beneficio per il paziente.
- Tranne il trial RECOVERY (in cui è stato usato il desametasone) e pochi altri, la maggior parte dei gruppi di ricerca ha scelto il metilprednisone perché ha maggior tropismo per il tessuto polmonare. Inoltre uno studio recente ha riscontrato che il metilprednisone riesce a inattivare diversi geni in relazione all’infezione da sars-cov2. In comparazione, il desametasone è più potente, ha una emivita più lunga e dà una maggior soppressione surrenalica, MA ha quasi nulla attività mineralcorticoide e quindi è versatile in relazione alle frequenti comorbidità riscontrate nei pazienti.
- Le dosi usate di metilprednisone spesso sono elevate, intorno almeno a 1mg/kg/die ma anche di più. Al contrario, per il desametasone in diversi casi è stata testata la dose di 6mg/die, adatta ad un peso di circa 70kg. Spesso non è chiaro il criterio di scelta della dose, a volte effettuato in base al peso, a volte indipendentemente dal peso, a volte con dosaggio moderato e in altre occasioni si è arrivati fino a 200-500mg di metilprednisone /die
- In uno studio sembra che sia metilprednisone sia desametasone diano stessi benefici in pz che NON richiedono ventilazione meccanica
- Nel trattamento domiciliare del covid, si tende a utilizzare il corticosteroide laddove si sia ragionevolmente nella fase “infiammatoria” o “polmonare” della malattia, in particolare non prima della VII-VIII giornata da inizio sintomi, quando ci sia un abbassamento repentino della saturazione verso valori che tendono al critico (es. <93%), una positività al walking test e/o una febbre persistente che non trova risoluzione con antinfiammatori. L’esame obiettivo e l’ecografia polmonare rafforzano i riscontri clinici e strumentali.
- Questo uso pragmatico consente nella maggior parte dei casi di ottenere la defervescenza e il recupero di valori di saturazione più elevati, nonchè un complessivo miglioramento delle condizioni del paziente, che spesso si va a situare nella “curva di uscita” dalla malattia, per quanto diversi sintomi tendano a persistere per settimane o, in casi sfortunati, anche mesi.
- In relazione ad un uso dei corticosteroidi troppo precoce (spesso prima della VI giornata da inizio sintomi), si osserva spesso un decorso più difficile della patologia, con aggravamenti che non di rado conducono all’ospedalizzazione
- Sarebbe utile avere letteratura che confermi l’uso pragmatico di questi farmaci nel contesto domiciliare, ma purtroppo la pressochè totalità dei lavori scientifici prodotti fa riferimento esclusivamente al setting ospedaliero
- Diverse ricerche segnalano un miglioramento dei tempi di recupero e – recentemente – anche delle ospedalizzazioni quando viene somministrato precocemente un corticosteroide inalatorio
- I migliori sembrano il budesonide, come grandezza della particella, e il ciclesonide che ha anche attività antivirale (in vitro). Oltre a ciclesonide, è stato proposto il mometasone, che dovrebbe avere anch’esso attività antivirale
- Budesonide ha meno effetti collaterali di beclometasone
- Sembrano rari e di piccola entità gli effetti sistemici dei cortisonici inalatori, in particolare se si sceglie accuratamente quale molecola dare e con le giuste modalità di somministrazione
In ultimo e prima della bibliografia, merita una menzione il protocollo proposto dal gruppo FLCCC (il sito è questo: https://covid19criticalcare.com/ ) : la sperimentazione portata avanti in 2 ospedali americani ha condotto ad una mortalità del 5% (solitamente si aggira su valori >20%), su 300 pazienti. Non mi trovo d’accordo su alcuni aspetti delle loro proposte terapeutiche (in termini di quantità di farmaci proposti, conclusioni derivate dalla letteratura scientifica, dosi di integratori…) ma è un riferimento interessante.
QUANDO E COME USARE CORTISONICI:
Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report (RECOVERY. Luglio 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383595/ )
- In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis (WHO, REACT working group, Ottobre 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489434/ )
- Administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality in critically ill patients with COVID-19
Early course corticosteroids in hospitalized patients with COVID-19. Clin Infect Dis 2020 (Ottobre 2020) (231)
- An early short course of methylprednisolone in patients with moderate to severe COVID-19 reduced escalation of care and improved clinical outcomes. Viene preso come riferimento l’ospedalizzazione.
- Studies of corticosteroid therapy for phylogenetically similar coronavirus infections showed no benefit and potential harm (https://pubmed.ncbi.nlm.nih.gov/32043983/ = Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury, Feb 2020)
- Data are conflicting; corticosteroid use in previous viral respiratory illnesses has demonstrated delayed viral clearance and increased mortality [11, 25]. On the contrary, short-course corticosteroids in some reports are beneficial and safe in critically ill patients with SARS-CoV-2 and were not found to be an independent risk factor of prolonged viral RNA shedding [17, 26, 27]. These discordant findings may be explained by the observational nature of the studies, heterogeneity in patient acuity, inconsistent dosing regimens and duration, and timing of initiation of therapy [10, 17].
- The pulmonary phase is associated with progressive dyspnea and radiographic findings of pneumonia . Symptom onset to dyspnea and ARDS development occurs between a median of 5–7 days and 8–12 days, respectively [6, 12, 28]. The present study findings support that timing is key.
- In this study, 3 days of early corticosteroids were administered at a median 2 days into hospitalization and 8 days from symptom onset. However, the administration of a 3-day course of corticosteroids later in the disease course (median 5 days after hospitalization), as occurred in our SOC group, did not appear to confer the same benefit.
Risposta a questo articolo: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337659/
- Patients with >8 days of symptoms will presumably be in the inflammatory phase of the disease and benefit from anti-inflammatory therapies such as steroids.
- Questa considerazione origina da questo articolo dello stesso autore: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449182/ (Agosto 2020): Steroid treatment reduced mortality by 41.8% relative to the mortality with no steroid treatment .
- Dice anche: In general, guidelines recommend not using corticosteroids in patients with COVID-19 or using them only in intubated patients
- Shorter duration of fever and a faster improvement of SpO2 in cases of severe SARS-CoV-2 pneumonia treated with 1 to 2 mg/kg/day of methylprednisolone during a period of 5 to 7 days. -> trovato anche in questo studio preliminare: (A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia.)
Prolonged Low-Dose Methylprednisolone in Patients With Severe COVID-19 Pneumonia (settembre 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543560/ )
- Inclusion criteria were the following: (1) SARS-CoV-2 positive (on swab or bronchial wash); (2) age >18 years and <80 years; (3) PaO2:FiO2 <250 mmHg; (4) bilateral infiltrates; (5) CRP >100 mg/L; and/or 6) diagnosis of acute respiratory distress syndrome (ARDS) according to the Berlin definition  as an alternative to criteria (4) and (5)
- In patients with severe COVID-19 pneumonia, early administration of prolonged, low dose MP treatment was associated with a significantly lower hazard of death (71%) and decreased ventilator dependence. Treatment was safe and did not impact viral clearance
- No differences were noted between groups in intrapatient median lymphocyte variation at days 3, 7, and 14 compared with baseline
- Our study protocol involved an initial iv bolus to achieve rapid, almost complete glucocorticoid receptor saturation, followed by an infusion to reach a total 160-mg dose over the first 24 hours and to maintain high levels of response throughout the treatment period. After day 7, treatment duration was guided by monitoring the anti-inflammatory response and oxygenation parameters. Our study investigated a dose that was greater than double the one investigated in the RECOVERY RCT and included tapering to minimize the risk of rebound inflammation.
- strict criteria that allowed us to include in the analyses only patients affected by severe pneumonia/ARDS with high levels of systemic inflammation and need for respiratory support.
- early low-dose prolonged MP treatment can decrease ICU burden and mortality
Rationale for Prolonged Corticosteroid Treatment in the Acute Respiratory Distress Syndrome Caused by Coronavirus Disease 2019 (Aprile 2020, commento) (230) : argomenti a favore dell’uso di cortisonici, include riferimenti utili in letteratura
Beneficial effect of corticosteroids in severe COVID-19 pneumonia: a propensity score matching analysis. (Maggio 2020, preprint) (232) -> fatto su pz che richiedono ossigeno
Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China (Luglio 2020) (233) -> in questo caso si riscontra che l’uso di cortisonici migliora outcome in pz con ARDS. studio retrospettivo di coorte
Successful use of methylprednisolone for treating severe COVID-19 (Agosto 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256545/) (235):
- Despite controversies, we think that timely and appropriate application of glucocorticoid plays a crucial role in the treatment of these patients
- application in 15 severe and critical patients (with pulse single dosage of 40-500 mg methylprednisolone according to severity, oxygenation index, speed of progression, production of inflammatory factors, body weight, age, and underlying diseases condition, rather than continuous low-dose glucocorticoid for days)
- Interim guidance for the management of COVID-19 by the World Health Organization recommends against routinely giving systemic glucocorticoids.3
- Commento inerente: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7159292/ On the use of corticosteroids for 2019-nCoV pneumonia: According to the expert consensus statement, the following basic principles should be followed when using corticosteroids: (1) the benefits and harms should be carefully weighed before using corticosteroids; (2) corticosteroids should be used prudently in critically ill patients with 2019-nCoV pneumonia; (3) for patients with hypoxaemia due to underlying diseases or who regularly use corticosteroids for chronic diseases, further use of corticosteroids should be cautious; and (4) the dosage should be low-to-moderate (≤0·5–1 mg/kg per day methylprednisolone or equivalent) and the duration should be short (≤7 days).
Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19 (meta analisi, settembre 2020, https://jamanetwork.com/journals/jama/fullarticle/2770279) (237)
- lo studio recovery non aveva riscontrato grandi effetti, eccetto in casi particolari: (RECOVERY) trial reported its findings from 6425 patients randomized to 6 mg/d of dexamethasone or usual care. Overall, dexamethasone resulted in an absolute reduction in mortality of 2.8% (22.9% vs 25.7% for usual care; age-adjusted rate ratio, 0.83 [95% CI, 0.75-0.93]). The benefit was greatest for patients who were receiving invasive mechanical ventilation at the time of randomization with mortality of 29.3% for dexamethasone vs 41.4% for usual care (rate ratio, 0.64 [95% CI, 0.51-0.81]).7 The signal seen in this trial led most ongoing trials of corticosteroids to suspend recruitment.
- prende in considerazione pz critici: In this prospective meta-analysis of 7 randomized clinical trials that included 1703 critically ill patients with COVID-19 recruited from countries on 5 continents, administration of corticosteroids was associated with lower all-cause mortality at 28 days after randomization.
- The findings contrast with outcomes reported for the administration of corticosteroids among patients with influenza, for whom mortality and hospital-acquired infections may be increased by the administration of corticosteroids.26
Second week methyl-prednisolone pulses improve prognosis in patients with severe coronavirus disease 2019 pneumonia: An observational comparative study using routine care data (Settembre 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508405/) (238)
- recommendation of MP for patients with COVID-19 pneumonia with altered/worsening inflammatory parameters (lymphopenia, thrombocytopenia, rising ferritin, D-dimers and or C-reactive protein) and clinical deterioration, particularly those showing impending respiratory failure with decreasing SpO2/FiO2 values. MP were encouraged to be given during the second week after the onset of symptoms, always according to the attending physician best judgment.
- This study supports the utility of glucocorticoids to improve the outcome of patients with COVID-19 pneumonia. Glucocorticoid use, however, should not be indiscriminate, but rather restricted to patients with laboratory evidence of inflammation and progressing respiratory compromise, and best used as short-course pulse therapy (125–250 mg/d of methyl-prednisolone during 3 days) administered during the second week after the onset of symptoms, where the hyperinflammatory reaction takes usually place.
- Our study confirms that patients with COVID-19 disease with a high inflammatory profile and respiratory compromise are most likely to benefit from glucocorticoid therapy. In addition, our study found that only in patients treated in the second week after the onset of symptoms seemed MP to be effective
COVID-19 illness in native and immunosuppressed states: A clinical–therapeutic staging proposal (marzo 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118652/): descrive gli stadi del covid e l’uso di farmaci per ogni stadio
Effect of dexamethasone on days alive and ventilaor-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489411/ , Ottobre 2020) (239)
- Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days.
Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial (Dicembre 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7758541/ ) (240)
- questo studio prende in considerazione la fase PRECOCE polmonare
- The diagnosis of COVID-19 in subjects was performed based on the following criteria: 1) identification of SARS-CoV-2 via reverse transcription-PCR in nasopharyngeal swab or sputum samples and 2) abnormal computed tomography (CT) scan findings (bilateral, subpleural, peripheral ground-glass opacities) with blood arterial oxygen saturation measured by pulse oximetry (SpO2) <90% at rest. The early pulmonary phase was defined as the start of pulmonary involvement, including hypoxia (SpO2 <93%), tachypnoea (respiratory rate >18 breaths·min−1) and little dyspnoea, and based on CT scan findings
- Patients were included in the study if they met the following criteria: 1) aged ≥18 years, 2) confirmed COVID-19 with SpO2 <90%, elevated C-reactive protein (CRP) (>10 mg·L−1) and interleukin (IL)-6 (>6 pg·mL−1) at the early pulmonary phase
- Patients in the methylprednisolone group had a significantly reduced median±range time to event (discharge or death) compared with patients in the standard care group
- SpO2 and Borg score were significantly improved after 3 days of treatment and at discharge time in the methylprednisolone group, whereas SpO2 was significantly decreased in the standard care group
- The results showed that after treatment pulmonary involvement was improved 20–30% in eight out of the 11 patients and 50–60% in three out of the 11 patients (supplementary figure S2). CT scan findings and improvement in pulmonary involvement after treatment in a patient in the methylprednisolone group are shown in supplementary figure S3.
- 94.1% of patients in the methylprednisolone group had recovered by a median duration of 11.8 days. However, only 57.1% of patients in the standard care group had recovered by a median duration of 16.4 days.
- It seems that the administration time and pulmonary phase of patients are key factors in corticosteroid treatment efficacy
Use of Corticosteroids in Coronavirus Disease 2019 Pneumonia: A Systematic Review of the Literature (Aprile 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193030/) :
- la revisione della letteratura mostra esiti contrastanti sull’uso dei cortisonici, ma alcune evidenze mostrano effetto utile di metilprednisone in casi di covid severo.
A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia (Aprile 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186116/)
- Severe case was defined when any of the following criteria was met: (1) respiratory distress, respiratory rate per min ≥ 30; (2) in the resting state, means oxygen saturation ≤ 93%; (3) arterial blood oxygen partial pressure/oxygen concentration ≤ 300 mmHg.
- patients with methylprednisolone treatment had a faster improvement of SpO2. Moreover, patients without methylprednisolone treatment had significantly longer interval of using supplemental oxygen therapy
Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial (Ottobre 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489418/) (241)
The interplay between inflammatory pathways and COVID-19: A critical review on pathogenesis and therapeutic options (Dicembre 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709793/): revisione delle terapie
The pathogenesis and treatment of the `Cytokine Storm’ in COVID-19 (giugno 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194613/ )
- For patients with progressive deterioration of oxygenation indicators, rapid imaging progress, and excessive inflammatory response, the use of glucocorticoid in the short term (3–5 days) is appropriate, and the recommended dose is no more than equivalent to methylprednisolone 1–2 mg/kg/day.69 It should be noted that large doses of glucocorticoid may delay the clearance of coronavirus due to immunosuppression.
Clinical Efficacy of Corticosteroids in the Early Stages of Deterioration in COVID-19 Pneumonia (luglio 2021 – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285565/ )
- we recommend considering the following parameters for the optimal timing of glucocorticoid usage in treating COVID-19 pneumonia: (1) continuous fever, (2) respiratory rate >30 breaths/min, (3) severe respiratory distress, (4) arterial oxygen saturation measured by pulse oximeter (SpO2) ≤93% on room air, (5) progressive decline in lymphocyte count, and (6) rapid expansion of lung lesions on CT. Any changes in the factors described above should be considered the initial sign of a cytokine storm and prompt early intervention with glucocorticoids.
A review on function and side effects of systemic corticosteroids used in high-grade COVID-19 to prevent cytokine storms (Febbraio 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975631/ )
- The best time to prescribe corticosteroids in the treatment of COVID-19 patients is when the patient’s condition is deteriorating, i.e., progressing to ARDS. Some patients usually have a sudden worsening 1-2 weeks after the onset. Increased resting respiratory rate, drop in oxygen saturation level when the person is breathing the room air, and multi-lobular progression on imaging within 48 h are some good indicators of the right time to take glucocorticoids (Zhou et al., 2020).
- MA ANCHE: In the second stage (pulmonary phase), virus multiplication and localization of the disease and inflammation in a number of areas of the body, such as the lungs, may occur, which can lead to hypoxia. Bilateral infiltrates, ground-glass opacities in radiography, increasing lymphopenia, and transaminitis may help to diagnose this stage. At this point, corticosteroids should be avoided, and antiretroviral therapy and supportive measures should be considered unless the hypoxia ensues. If hypoxia occurs, mechanical ventilation and the use of anti-inflammatory drugs such as a low to moderate dose of corticosteroids may be effective for the patient (Shang et al., 2020; Siddiqi and Mehra, 2020)
- Timely use of glucocorticoids can improve fever and provide better oxygen delivery, but some studies have suggested that the use of these agents is incorrect due to weakened immune response and reduced virus clearance (Zhang et al., 2020).
- In patients with COVID-19 with symptoms of non-severe pneumonia who took ciclesonide experimentally, the number of lymphocytes increased significantly and it was demonstrated that ciclesonide could inhibit the exacerbation of COVID-19 (Yamasaki et al., 2020).
DA LEGGERE: A new interventional home care model for COVID management: Virtual Covid IP (luglio 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299213/ )
- If the oxygen saturation was downtrending or inflammatory markers were rising, steroids (Dexamethasone 4mg/6 mg (once daily), 0.15 mg/kg/dose PO every 24 h for 10 days; max: 6 mg daily was initiated and dosages of which were modified if required. Home therapy with corticosteroids was limited to 7–10 days duration.
Can we predict the severe course of COVID-19 – a systematic review and meta-analysis of indicators of clinical outcome? (luglio 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321230/ )
- This comprehensive meta-analysis found age, cerebrovascular disease, CRP, LDH and cTnI to be the most important risk-factors that predict severe COVID-19 outcomes and will inform clinical scores to support early decision-making.
Beneficial Treatment Outcomes of Severe COVID-19 Patients Treated Entirely in Primary Care Settings With Dexamethasone Including Regimen—Case Series Report (Agosto 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387596/ )
Therapeutic Application of Corticosteroids in COVID-19: A Focus on Optimum Dose and Duration of Therapy (giugno 2021, https://accp1.onlinelibrary.wiley.com/doi/full/10.1002/jcph.1929 )
- gli studi condotti finora spesso non sono chiari o coerenti riguardo alle dosi dei diversi corticosteroidi usati, al timing e alla durata della terapia. Gli studi sul metilprednisone spesso usano dosi elevate (1-2mg/Kg, o 200-500mg/die) confrontandole con dosi di desametasone equivalente molto più basse, ad esempio.
STUDI CONTRARI A CORTICOSTEROIDI
Therapeutic role of corticosteroids in COVID-19: a systematic review of registered clinical trials (Marzo 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968560/ ):
- Few preliminary trial findings show promising results and recommend the use of methylprednisolone and dexamethasone in the severe form of the disease; however, there is insufficient data to prove its benefits over its risks. Routine use of corticosteroids should be favored only after a better insight is obtained, with the completion of these trials.
- N.B. lo studio considera i corticosteroidi tout court, senza fare distinzioni, tanto che include studi con cortic. inalatori e sistemici nello stesso calderone. Non sembra analizzare i cortic in base al timing
Corticosteroids in COVID-19: We Should Be Mindful of Their Acute Toxicities (COMMENTO, Luglio 2021, https://accp1.onlinelibrary.wiley.com/doi/full/10.1002/jcph.1936 )
- Although corticosteroids have shown benefit in COVID-19, the risk they bear should not be belittled. Judicious, evidence-based use of steroids by assessing the risk-benefit ratio and taking into account the patient’s preexisting conditions is recommended. People are generally concerned about the long-term harm associated with steroid use. But corticosteroid use may have acute, life-threatening consequences. Knowledge of its acute toxicities seems highly relevant in the present context.
- N.B. come effetti collaterali acuti prende in considerazione: l’anafilassi (riconoscibile e dose indipendente); riattivazioni o superinfezioni, ipertensione e aritmie, sudden death in caso di infusione pulsatile, glaucoma e corioretinopatia, problemi GI (anche perforazioni), alterazioni psichiche, miopatia, ipercoagulabilità
The proportion and effect of corticosteroid therapy in patients with COVID-19 infection: A systematic review and meta-analysis (Aprile 2021, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249481 )
- The proportion of COVID-19 patients who received corticosteroids was significantly lower than that of patients who did not receive corticosteroids. Corticosteroid use in subjects with severe acute respiratory syndrome coronavirus 2 infections delayed viral clearance and did not convincingly improve survival; therefore, corticosteroids should be used with extreme caution in the treatment of COVID-19.
- N.B. anche in questa review si fa di tutta l’erba un fascio raccogliendo studi diversi, con corticosteroidi diversi
Early changes in immune cell subsets with corticosteroids in patients with solid tumors: implications for COVID-19 management (Novembre 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681794/ )
- Timing is crucial, and steroids may be better reserved for situations where toxic inflammation has clearly overwhelmed any developing antiviral responses. If a decision is made to proceed with glucocorticoids, it should be weighed carefully against the need to clear virally infected cells, the patient’s current clinical condition, and other approaches that may not be as cytotoxic to lymphocytes.
- MA ANCHE: Brun-Buisson et al26 found that corticosteroids increased the risk of death in ARDS associated with influenza A/H1N1 pneumonia by twofold to threefold when given within the first 3 days of the disease course, but not when given later.
- N.B. lo studio è fatto su pz oncologici, ricavando interpretazioni su popolazione generale: non è chiaro lo scopo del paper, dato che i pz oncologici studiati neanche avevano il covid. N.B. non sempre l’uso di steroidi contribuisce a linfopenia, cfr ciclesonide
Severity and Mortality Associated with Steroid Use among Patients with COVID-19: A Systematic Review and Meta-Analysis (Maggio 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101483/ )
- No significant differences in mortality between the steroid and nonsteroid treatment groups (RR = 0.95; 95% CI: 0.80–1.13; p = 0.57). There was no significant reduction in mortality in critically ill COVID-19 patients treated with corticosteroid (RR = 0.89; 95% CI: 0.62–1.27; p = 0.52). Significant differences were observed in severe disease conditions between the steroid and nonsteroid treatment groups (RR = 1.10; 95% CI, 1.03–1.19, p = 0.007).
- Nonhuman studies and studies that did not report mortality and severity data were excluded from the review.
- In the 26 included studies [17–19, 21–23, 25–30, 32–35, 37–42, 44, 45, 47, 48] with 13,565 patients, there were no significant differences in mortality between the steroid and nonsteroid treatment groups (RR = 0.95; 95% CI: 0.80–1.13; p = 0.57, I2 = 78%, p < 0.0001) (Figure 2). The sensitivity analysis showed that the exclusion of three studies [18, 21, 33] changed the above conclusion. Quindi: 3 studi cambiano le conclusioni. Inoltre gli studi con i campioni più ampi sono quasi tutti a favore, nella stessa tabella fornita in questa review
- In the 5 included studies [22, 31, 36, 44, 46] with 1,564 critically ill COVID-19 patients, there were no significant differences in mortality between the steroid and nonsteroid treatment groups (RR = 0.89; 95% CI: 0.62–1.27; p = 0.52, I2 = 78%, p = 0.001) QUESTO riguarda i pz in condizioni critiche
- Anche questo studio non fa distinzione tra tipo di corticosteroide e timing di somministrazione
Impact of early corticosteroids on 60-day mortality in critically ill patients with COVID-19: A multicenter cohort study of the OUTCOMEREA network (Agosto 2021 , https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255644 )
- Importantly, early CS treatment was associated with a lower mortality rate in patients aged 60 years or more (IPTWHR, 0.53;95% CI, 0.3–0.93; p = 0.03). In contrast, CS was associated with an increased risk of death in patients younger than 60 years without inflammation on admission (IPTWHR = 5.01;95% CI, 1.05, 23.88; p = 0.04).
- The aim of this study was to assess in critically ill COVID-19 patients the effect of early CS administration on 60-day mortality, ICU-bloodstream infections (ICU-BSI) and hospital-acquired pneumonia and ventilator-associated pneumonia (HAP-VAP)
- Patients over 18 years were eligible for inclusion in the analysis if they were admitted to one of the ICUs belonging to the OutcomeReaTM network and if they developed a severe COVID-19 disease confirmed by a positive SARS-CoV-2 test
- The Early-CS group comprised all patients who received corticosteroids for the first time during the first two days after ICU admission. The Non-early CS group included patients who did not receive steroids during the first two days after ICU admission. High doses of corticosteroids concerned patients receiving more than 10 mg of dexamethasone, and more than 200 mg of hydrocortisone
- QUINDI: lo studio confronta pz in terapia intensiva in cui i corticosteroidi sono stati dati nei primi 2 gg VS altri in cui sono stati introdotti in seguito. Non vi è differenza se non in pz >60 anni in cui probabilmente è meglio cominciare prima
Effect of Corticosteroids on Mortality in Hospitalized COVID-19 Patients Not Receiving Invasive Mechanical Ventilation (Giugno 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251340/)
- corticosteroids were overall not associated with a difference in hospital mortality for patients with COVID‐19 with OSCI 3–5. In the subgroup of patients with NIMV (OSCI 5), corticosteroids reduced ICU admission, whereas the effect on mortality requires further studies
- Our data suggest that corticosteroids are not beneficial in patients without invasive mechanical ventilation (with a score of 3,4, or 5 on the WHO COVID‐19 OSCI 10 ). In particular, this appears to be evident in all patients with a score of 3 or 4, i.e., patients with or without oxygen therapy who are not on positive pressure noninvasive ventilation.
- Studio di tipo osservazionale che appare ben strutturato
- GLI STESSI AUTORI pubblicano un altro studio con circa gli stessi pazienti:
- Corticosteroid treatment has no effect on hospital mortality in COVID-19 patients (Gennaio 2021, studio precedente con un campione leggermente più ampio, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806743/ )
- The crude mortality in our study was higher in patients treated with corticosteroids than in patients who did not receive them. The risk of in-hospital death did not differ between patients who were treated and those who were not treated with corticosteroids when adjusted for patients’ characteristics
- A positive finding associated with the use of steroids was a reduced ICU admission rate compared to patients not receiving them. Corticosteroids can improve compliance and hypoxemia in ARDS patients23, reducing the indication for ICU admission in our hospital during the COVID-19 pandemic, which was triggered by hypoxemia severity and dyspnea. In this sense, therapy with corticosteroids could be useful in reducing pressure on the Intensive Care Units
The association between corticosteroid uses and mortality among severe COVID-19 patients (Febbraio 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486875/ )
- è un COMMENTO riferito alla metanalisi di Yang et al. (questo: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195158/ che però prende in considerazione TUTTI i coronavirus e non solo sars-cov2, riscontrando un effetto negativo dei corticosteroidi) e al gruppo REACT del WHO per quanto riguarda l’uso di corticosteroidi
QUALI CORTICOSTEROIDI USARE
Prednisone and methylprednisolone disposition in the lung (1983 !! https://pubmed.ncbi.nlm.nih.gov/6138595/ ): il metilprednisone ha un tropismo migliore verso i polmoni rispetto al prednisone
Clinical and Scientific Rationale for the “MATH+” Hospital Treatment Protocol for COVID-19 (Dicembre 2020, https://journals.sagepub.com/doi/10.1177/0885066620973585?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed )
- The MATH+ protocol (Table 1) reviewed above has been implemented in the treatment of COVID-19 patients at 2 hospitals in the United States; United Memorial Hospital in Houston, Texas (J.V) and Norfolk General Hospital in Norfolk, Virginia (P.E.M). The average hospital mortality at these 2 centers in over 300 patients treated is 5.1%, which represents more than a 75% absolute risk reduction in mortality compared to the average published hospital mortality of 22.9% among COVID-19 patients.
- the RECOVERY RCT utilized a small dose of dexamethasone and did not incorporate tapering to prevent rebound inflammation
- N.B: dexamethasone is the corticosteroid associated with greater suppression of the adrenal gland
COVID-19: disease pathways and gene expression changes predict methylprednisolone can improve outcome in severe cases (Marzo 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989618/ ) (141)
- If a patient has developed severe respiratory symptoms and is hypoxic, the host response that lead to ARDS, sepsis, and organ failure has already been initiated (Mehta et al., 2020). At this point, the focus should shift to supporting the patient’s systems and preventing collapse triggered by hyper-inflammation (Ayres, 2020)
- Methylprednisolone (MP) is the drug that was identified as the most likely to work by inhibiting the inflammatory pathway. This drug targets 27 genes that are found to be DE in COVID19vsControl. Out of these 27 genes, the drug would revert the changes in 25 of them
- When comparing the two groups, those patients treated with a 3-day methylprednisolone protocol spent less time in the hospital (5 vs 8 days) and were less likely to be admitted to the ICU (27% vs 44%), being placed on a ventilator (22% vs 37%) or dying (14% vs 26%).
For a composite end point of preventing ICU admission, need for mechanical ventilator or mortality, the number needed to treat (NNT) to benefit a single patient was only 5 when methylprednisolone was used early in hospitalization. To prevent mortality, the NNT to benefit a single patient was only 8 for all hospitalized patients. This is in contrast to the
- RECOVERY trial (NCT04323592) for dexamethasone, where NNT was 8 for patients on mechanical ventilation and 25 for patients needed oxygen to prevent mortality
- The results of these study, based on all annotations available to date, suggest that MP would revert the largest number of the gene perturbed by COVID-19, followed by dexamethasone
- A recent article in Lancet reports that clinical evidence does not support corticosteroid treatment for COVID-19 (Russell et al., 2020). However, this report looks at corticosteroids as an entire class of drugs. A recent retrospective study of 201 patients with COVID-19 in China found that treatment with MP for those who developed ARDS was associated effective in decreasing the risk of death
- Patients with PCR confirmed COVID-19 who required 4 liters or more of oxygen per minute on admission, or who had escalating oxygen requirements from baseline, were recommended to receive IV methylprednisolone 0.5 to 1 mg/kg/day in 2 divided doses for 3 days
Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial (Aprile 2021 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035859/)(282)
- In hospitalized hypoxic COVID-19 patients, methylprednisolone demonstrated better results compared to dexamethasone.
- Mechanistically, methylprednisolone achieves higher lung tissue-to-plasma ratios in animal models than dexamethasone, which may thus be more effective for lung injury
- The differences found may instead be explained by the relatively higher dose of corticosteroid given that the estimated 6 mg of dexamethasone a day is equivalent to approximately 32 mg of methylprednisolone . This suggests the control group was receiving about 0.5 mg/kg day based on a standard 70 kg male and thus the methylprednisolone group received a more potent dose. Whether due to differences in dosage or medication, 2 mg/kg of methylprednisolone led to better outcomes in hypoxic hospitalized COVID-19 patients compared to 6 mg/day of dexamethasone.
- Although managing patients suffering from COVID-19 with glucocorticoids may have some complications such as superimposed infection, immunosuppression, and hyperglycemia, recent studies reported no significant complications in their study course. However, hyperglycemia was more frequent in those who received methylprednisolone, managed without substantial complications
A Comparison of Methylprednisolone and Dexamethasone in Intensive Care Patients With COVID-19 (Giugno 2021 – https://journals.sagepub.com/doi/10.1177/0885066621994057 ) (283)
- 50-day mortality was 41.3% in usual care, 26.5% in dexamethasone, and 16.4% in methylprednisolone.
- in patients with COVID-19 requiring mechanical ventilation, methylprednisolone was superior to dexamethasone. However, in patients who did not require mechanical ventilation, both steroids decreased mortality to low rates and no difference between the 2 steroids could be detected
QUINDI: Metilprednisolone meglio di Desametasone, anche se in un setting terapeutico domiciliare precoce “potrebbero” avere stessa efficacia (in pz che non arrivano a richiedere ventilazione meccanica)
ANCHE IN QUESTO STUDIO:
Comparison of efficacy of dexamethasone and methylprednisolone in moderate to severe covid 19 disease (Dicembre 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654232/ )
- Dexamethasone and methylprednisolone both are equally effective in treating moderate to severe covid 19 disease.
A review on function and side effects of systemic corticosteroids used in high-grade COVID-19 to prevent cytokine storms (Febbraio 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975631/ )
- Among all, hydrocortisone and prednisone have the highest protein binding (Lester et al., 1998; Czock et al., 2005). Cortisol with 8 to 12 hours has the shortest, and dexamethasone and betamethasone with 36 to 54 hours have the longest biological half-life (Melby, 1977).
- the efficacy of methylprednisolone and dexamethasone has been reported to be the same in moderate to severe cases (Fatima et al., 2020), however, methylprednisolone is sometimes better than dexamethasone in preventing mortality due to its better pharmacodynamics and pharmacokinetics (Liu et al., 2020). On the other hand, there have been reports that dexamethasone is more effective in reducing C-reactive protein (CRP) and improving P/F ratio (pO2 divided by the fraction of inspired oxygen (FIO2)) (Rana et al., 2020).
- MATH+ medication regimen has been suggested as one of the effective protocols in the pulmonary phase of the disease, which includes methylprednisolone, (“M”), high-dose vitamin C infusion (“A”), thiamine (“T”), heparin (“H”), ivermectin, and supplemental components (“+”) such as melatonin, vitamin D, zinc, and magnesium (Turkia, 2020).
- according to a hypothesis based on computational studies, dexamethasone prevents virus entrance by occupying the SARS-CoV-2 spike pseudotyped virus binding site in the ACE2 (Zhang et al., 2021).
- Measurement of blood ferritin activity in patients can play an important role in determining the time window of dexamethasone administration, because the level of ferritin in patients who die is much higher than those who recover, and in fact can be a good criterion for assessing cytokine storm (Burugu et al., 2020).
- Despite its high potency, dexamethasone is often tolerable but should be used with caution in gastrointestinal cases. Recent research has shown that dexamethasone is a very effective drug to prevent fatalities in critically-ill patients (Jamaati et al., 2020).
Prehospital pulse oximetry: a red flag for early detection of silent hypoxemia in COVID-19 patients (giugno 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278215/ )(185)
- In summary, this retrospective study based on prehospital first responder data highlighted a relatively higher discrepancy between SpO2i and RRi in COVID-19 ARF patients, in comparison with previous non-COVID-19 ARF patients.
- prehospital pulse oximetry might be used as a red flag for early detection of “silent hypoxemia” in COVID-19 patients
- occhio alla discrepanza tra SpO2 e Freq respiratoria, se il rapporto è >4 (in pz che desatura), potrebbe progredire verso insufficienza respiratoria
CORTISONICI INALATORI: UTILI?
A review on function and side effects of systemic corticosteroids used in high-grade COVID-19 to prevent cytokine storms (Febbraio 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975631/ )
- This article supports the inhibitory effects of inhaled corticosteroids for several reasons. First of all, these compounds significantly reduce the risk of disease recurrence and progression to ARDS due to their regulatory role in inflammatory and immune responses (Halpin et al., 2020; Nicolau and Bafadhel, 2020). More importantly, inhaled corticosteroids have been shown to be associated with decreased gene expression of proteins ACE2 and TMPRSS2 in the epithelial cells of the oral mucosa and type 2 alveolar cells, thereby reducing the replication of coronaviruses, including SARS-CoV-2. ACE2 and TMPRSS2 are associated with the entry of the virus into the cell and are involved in the binding of the spike protein and the beginning of the viral infection cycle (Choi et al., 2020; Nicolau and Bafadhel, 2020).
- Cough is one of the most common complications of inhaled forms of corticosteroids, which is mostly due to the presence of excipients such as propellants and surfactants in the drug dosage form (Barnes and Pedersen, 1993; Hanania et al., 1995; Roland et al., 2004). These additives are found in MDIs, and because DPI products do not contain these excipients, throat irritation and cough with DPI is less common
- The shorter the drug is in the bloodstream and the sooner it is cleared from the blood, the less systemic side effects it will have. Budesonide, for example, has fewer side effects than beclomethasone due to its high clearance rate and rapid hepatic metabolism (Hanania et al., 1995). Lipophilic corticosteroids such as fluticasone and mometasone have a low clearance rate due to high tissue uptake
- Among corticosteroids, ciclesonide, in addition to its anti-inflammatory and immunosuppressive effects, also has anti-viral properties. Ciclesonide and mometasone can disrupt viral replication as much as lopinavir.
- Oropharyngeal candidiasis, hoarseness, PSC, respiratory infections, cough, thirst, osteoporosis, skin bruising, wheezing, dysphonia, local irritation, and sore throat are common side effects of beclomethasone dipropionate
- At regular doses, budesonide is generally well-tolerated, but side effects such as oral candidiasis, dysphonia, skin bruising, osteoporosis, slowing lower-leg growth, subcapsular and nuclear cataract, adrenal suppression, and sore throat have been reported. Inhalation of budesonide up to a dose of 800 micrograms does not alter cortisol levels, but at higher doses, despite high therapeutic efficacy, adrenal suppression can be expected.
The peripheral lymphocyte count as a predictor of severe COVID-19 and the effect of treatment with ciclesonide (Dicembre 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332917/ )
- The treatment group received 2 inhalations of 400 μg ciclesonide once a day, for a daily total of 800 μg
Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial (Agosto 2021, https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)01744-X/fulltext ) (186)
- A previous efficacy trial (STOIC phase 2, open-label trial) found benefit from inhaled budesonide for COVID-19 in patients not admitted to hospital, but effectiveness in high-risk individuals is unknown.
- Inhaled budesonide improves time to recovery, with a chance of also reducing hospital admissions or deaths (although our results did not meet the superiority threshold), in people with COVID-19 in the community who are at higher risk of complications.We found that inhaled budesonide reduced time to recovery by 3 days, with a high probability of also reducing COVID-19-related hospital admissions or deaths by an absolute difference of 2%
- There was no evidence in the STOIC trial of a negative effect of budesonide on SARS-CoV-2 viral loads, and in PRINCIPLE there were no concerning safety signals for inhaled budesonide.
- People in the community were eligible if they were aged at least 65 years, or at least 50 years with comorbidities, and had ongoing symptoms from PCR-confirmed or suspected COVID-19 (in accordance with the UK National Health Service definition of high temperature, new, continuous cough, or change in sense of smell or taste),17, 18 which had started within the previous 14 days.
- Participants received usual care plus inhaled budesonide 800 μg twice daily for 14 days (Pulmicort Turbohaler, AstraZeneca, Luton, UK), or usual care alone.
STOIC trial: Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial (Luglio 2021, https://www.thelancet.com/article/S2213-2600(21)00160-0/fulltext ) (187)
- In early reports from China,1, 2 Italy,6 and the USA7 describing patients with COVID-19 admitted to hospital, patients with asthma and chronic obstructive pulmonary disease (COPD) were significantly under-represented
- Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery after early COVID-19.
- Adults aged older than 18 years with symptoms of COVID-19 (new onset cough and fever or anosmia, or both) within 7 days were eligible for inclusion
- Participants who met the inclusion criteria were randomly assigned to usual care or intervention with budesonide dry powder inhaler (Pulmicort Turbuhaler, AstraZeneca, Gothenburg, Sweden) at a dose of 400 μg per actuation (two puffs to be taken twice per day; total dose 1600 μg).
- This effect, with a relative reduction of 91% of clinical deterioration is equivalent to the efficacy seen after the use of COVID-19 vaccines
Association between pre-existing respiratory disease and its treatment, and severe COVID-19: a population cohort study (Agosto 2021, https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(21)00095-3/fulltext ) (189)
- In another post-hoc analysis, people with two or more prescriptions for ICS in the 150 days before study start were at a slightly higher risk of severe COVID-19 compared with all other individuals (ie, no or one ICS prescription)
beclomethasone covid: in pubmed ZERO risultati
Clinical trials of inhaled beclomethasone and mometasone for COVID‐19 should be conducted (Agosto 2020, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436531/ )
- The antiviral effects of inhaled corticosteroids as well as their smaller particle sizes, which is related to their ability to efficiently reach the alveoli, should be noted. Previous studies have not reported the anti‐SARS‐COV‐2 effects of beclomethasone in vitro. We propose that clinical trials that test the clinical effects of beclomethasone, which has a similar particle size to ciclesonide, as well as studies that confirm its antiviral effects, should be conducted. This is because, if either or both drugs are found to be effective, it may be possible to speculate whether these effects are due to their antiviral or their anti‐inflammatory effects. If beclomethasone is found to be clinically effective but not antiviral, the effect of particle size can be estimated by comparing it to budesonide, which also has no antiviral effect. For the same reason and in anticipation of the unique antiviral effect that is different from ciclesonide, we propose that clinical trials of mometasone, which have a smaller but similar particle size to budesonide, should also be conducted.