Current recommendations for the self-management of SARS-Cov-2 disease (COVID-19) include self-isolation, rest, hydration, and the use of NSAID in case of high fever only. It is expected that many patients will add other symptomatic/adjuvant treatments, such as herbal medicines.To provide a benefits/risks assessment of selected herbal medicines traditionally indicated for “respiratory diseases” within the current frame of the COVID-19 pandemic as an adjuvant treatment.positive, promising, negative, and unknown.The plant selection was primarily based on species listed by the WHO and EMA, but some other herbal remedies were considered due to their widespread use in respiratory conditions. Preclinical and clinical data on their efficacy and safety were collected from authoritative sources. The target population were adults with early and mild flu symptoms without underlying conditions. These were evaluated according to a modified PrOACT-URL method with paracetamol, ibuprofen, and codeine as reference drugs. The benefits/risks balance of the treatments was classified as Althaea officinalis, Commiphora molmol, Glycyrrhiza glabra, Hedera helix, and Sambucus nigra), promising in 12 cases , and unknown for the rest. On the same grounds, only ibuprofen resulted promising, but we could not find compelling evidence to endorse the use of paracetamol and/or codeine.A total of 39 herbal medicines were identified as very likely to appeal to the COVID-19 patient. According to our method, the benefits/risks assessment of the herbal medicines was found to be positive in 5 cases (Our work suggests that several herbal medicines have safety margins superior to those of reference drugs and enough levels of evidence to start a clinical discussion about their potential use as adjuvants in the treatment of early/mild common flu in otherwise healthy adults within the context of COVID-19. While these herbal medicines will not cure or prevent the flu, they may both improve general patient well-being and offer them an opportunity to personalize the therapeutic approaches. The outbreak of Coronavirus SARS-Cov-2 disease (COVID-19) in Wuhan (China) in late 2019 and its Worldwide spread has caused hundreds of thousands of deaths so far. As of July 2020, the disease seems to be mostly affecting Europe and the Americas. Most people infected with the COVID-19 virus will experience mild to moderate respiratory illness and recover without requiring special treatment. Older people and those with underlying medical problems such as cardiovascular disease, diabetes, chronic respiratory disease, and cancer are more likely to develop serious illness . Teens aThere is not yet any evidence-based specific therapy for COVID-19, and the real efficacy and safety of current therapeutic approaches will need further scrutiny when enough multi-site clinical data become available. The examples of ibuprofen and hydroxychloroquine illustrate how clinical protocols may include and/or exclude drugs in their therapeutic approaches based on limited evidence . PredictEarly COVID-19 symptoms include fever, dry cough, and dyspnea, among other similar ones to other viral respiratory diseases such as common flu . TherefoThe clinical spectrum of the infection goes from mild upper respiratory tract illness to the so-called ‘severe acute respiratory syndrome’: respiratory failure, shock, and multiple organ failure ; and mayThe precise pathology of the disease is not yet clear, but seems to include a systemic pro-inflammatory response, inducing hemodynamic changes and, consequently, a predisposition to ischemia and thrombosis . A hallmDue to the emergence of the propagation of the disease, Health Systems have become overloaded, even having sufficient diagnostic capacity and hospital facilities to handle such an outbreak. In the most vulnerable regions, the COVID-19 epidemic effectively paralyzes health systems at the expense of primary health care . Some meImportantly, at this stage, we are starting to build up an evidence-base for the best strategy to treat, mitigate, and prevent the diseases. Currently, none of the approaches used is evidence-based.In the worldwide search for a response to the COVID-19 pandemic, news about “alternative remedies against COVID” have been disseminated . As of JEchinacea species (Asteraceae) have an important role with the immune system due to their alkylamide interacting with the cannabinoid receptors (Curcuma longa L. (Zingiberaceae), is suggested as a potential clinical option for the treatment of SARS-CoV-2 infection, due to its action in several steps of a viral infection such as protease inhibition, cellular signalling pathways modulation, among others  mentioned in this study that had their in vitro potential and immune capacity assessed, were also included in our study. Moreover, in an elegant evidence-based analysis, eighteen phytotherapeutic preparations were mentioned as having some role in the clinical management of viral respiratory diseases, showing different levels of immunological response (Echinacea purpurea(L.) Moench, Glycyrrhiza glabra L., Sambucus nigra L., and Scutellaria baicalensis Georgi] were also included in our study.In another paper , 11 mediresponse . Four plThe rationale used in our study was to include, mostly, species known in the Americas and Europe and those already more widely available for the management of respiratory conditions , mainly Apart from a handful of antiviral drugs with limited efficacy, there is only symptomatic therapy for influenza.There is no specific therapy for COVID-19.There are several herbal medicines recognized by various Health Authorities for the treatment of flu, its symptoms, and other respiratory disorders.Health authorities in Europe and the Americas have warned the population against taking any natural/herbal medicines/supplements. They sustain this advice on theoretical potential effects on the immune system due to unspecific anti-inflammatory effects in early stages, facilitating the infection as well as potential immunostimulation, contributing to the aggravation of the “cytokines storm”. As of today, there is no clinical backup for such strong recommendations other than trying to prevent unspecific herb-drug interactions should the patient need emergency care.There is a significant OTC use for these herbal medicines, and a realistic prospect is that patients will self-administer them to increase their well-being.To apply a decision-making framework to provide a benefits/risks assessment for selected herbal medicines traditionally indicated for “respiratory diseases” within the current frame of the COVID-19 pandemic.For a treatment to be recommended as adjuvant therapy for respiratory diseases in the context of COVID-19, we here determine that the treatment is effective and that its expected benefits outweigh its potential risks to patients. Briefly, this assessment is informed by the body of evidence about each treatment’s safety and efficacy retrieved in a literature search. This assessment is also informed by a number of other factors, including the severity of the underlying condition and how well patients’ medical needs are addressed by currently available therapies (“reference drugs”). The decision also reflects current applicable laws, regulations, and healthcare recommendations, taking into consideration the uncertainty associated with COVID-19.A search was conducted, considering herbal medicines traditionally used to relieve cold and flu symptoms. The criterion used to limit the investigation, and to grant minimal evidence of efficacy was that the species, linked to the chosen indications, must be listed at least in one of the following organizations: World Health Organization Monographs (WHO); European Medicines Agency (EMA); European Scientific Cooperative on Phytotherapy; ANVISA , Ministry of Health of Chile, Ministry of Health of Cuba, Ministry of Health of Colombia, and Government of Canada. Several South American Countries use the Brazilian Pharmacopeia documents as a reference, so they are also covered within this search. Based on these documents, a list of target species was prepared to establish a search of clinical evidence for the given indication. We refer to these as “herbal medicines” as they are endorsed by Scientific and/or Regulatory committees.We also included some species which are not listed in monographs based on their significant widespread use in the self-management of respiratory diseases. Some of them are also linked to food uses. We refer to these as “herbal remedies”.Ephedra sp.) and species which are only indicated for relieving mucous phlegm. Furthermore, we do not assess multi-herbal preparations.We did not consider species that have given rise to major safety concerns  in adults otherwise healthy (= Target Population). The patient did not have a test or was negative for COVID-19, but continues at risk of infection (= Uncertainty). The patient uses herbal medicines alone or with drugs . The patient experiences relief of upper respiratory symptoms within 1-2 weeks (= Favorable effect). The treatment interferes with hospital/emergency treatment in case of severe acute respiratory syndrome (Unfavorable effects).Frame the problem. The appearance of early/mild respiratory symptoms during the pandemic including fever, cough, catarrh, aches, and pains, nasal congestion, runny nose, sore throat, cough, sneezing  medications endorsed by health authorities are non-steroidal anti-inflammatory drugs (NSAIDs) , antipyretics (acetaminophen/paracetamol), and cough medicines . They may be taken as monotherapy or alternating therapies. Therefore, one of each category  was chosen to be evaluated based on the same criterion.Assess the balance between favorable and unfavorable effects and the associated uncertainty. All possible combinations of clinical and safety grades lead to four possible results: “positive”, “promising”, “negative”, and “unknown”. The last two categories allowed for the inclusion of two different degrees of uncertainty  were used.All possible combinations of clinical and safety grades lead to four possible results: “positive”, “promising”, “negative”, and “unknown”. The last two categories allowed for the inclusion of two different degrees of uncertainty. We are aware that for many herbal drug preparations, preclinical evidence exists, and this is not considered in this assessment since it cannot be translated directly into clinical practice. However, such estimation might be of relevance to unveil potential mechanisms of action only so in that case this information was included.Based on the defined parameters, three recommended drugs for early symptoms of COVID-19 - codeine, ibuprofen, and paracetamol - were evaluated.Indications in the context of respiratory conditions. Fever, pain, inflammation.Posology. Up to 2,400 mg a day in doses not bigger than 400 mg every 6 h.In vitro and in vivo studies showed evidence of antipyretic and mild analgesic activities  for treating pain or respiratory symptoms , the conclusion was NSAIDs are somewhat effective in relieving the discomfort caused by cold. However, there is no clear evidence of their effect in easing respiratory symptoms. Therefore, the balance of benefits and risks needs to be considered when using NSAIDs for colds . There iSafety. Side effects of ibuprofen include anemia, decreased hemoglobin, eosinophilia, hemorrhage, vomiting, and hypertension. Other side effects include upper gastrointestinal hemorrhage, upper gastrointestinal tract ulcers, dizziness, and dyspepsia. A comprehensive list of very common (10% or more) to common (1% to 10%) adverse effects include nausea (up to 57%), vomiting (up to 22%), flatulence (up to 16%), diarrhea (up to 10%); epigastric pain, heartburn, abdominal distress, indigestion, dyspepsia, abdominal discomfort, constipation, abdominal cramps/pain, fullness of GI tract, bloating, GI hemorrhage, melena (1% to 10%) . HoweverSpecific warnings and precautions of use. Ibuprofen may cause severe cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may be increased in patients with cardiovascular disease or risk factors for cardiovascular disease. Ibuprofen is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery. NSAIDs can also cause an increased risk of serious gastrointestinal adverse events, especially in the elderly, including bleeding, ulceration, and perforation of the stomach or intestines, which can also be fatal .Overall assessment. According to well-established use, ibuprofen may be useful in the symptomatic relief of respiratory conditions by reducing fever and aches. However, there is only a relatively low number of clinical studies, and meta-analyses do not provide consistent evidence that ibuprofen is effective in reducing symptoms and duration and prevention of the common cold. Overall, the clinical evidence is High. Ibuprofen may have antiplatelet activities; its safety may be considered Medium.Indications in the context of respiratory conditions. Cough.Posology. Up to 360 mg a day in doses not bigger than 60 mg every 4 h.in vitro, ex vivo, and in vivo studies show evidence of anti-cough activity  in controlling cough . OverallSafety. Commonly reported side effects of codeine include drowsiness, lightheadedness, dizziness, sedation, shortness of breath, nausea, vomiting, sweating, and constipation. Other possible effects include bronchospasm, laryngospasm, respiratory depression; heartbeat irregularities, blood pressure changes, syncope, itching, facial swelling, pruritus, urticaria, histamine release; dry mouth, loss of appetite, nausea, vomiting, paralytic ileus, toxic megacolon, anorexia, stomach cramps; miosis, blurred or double vision; euphoria, dysphoria, unusual dreams, hallucinations, insomnia, anxiety (0.1% to 1%); respiratory arrest, dyspnea; flushing, hypotension, palpitations, circulatory depression, shock, cardiac arrest, circulatory depression, bradycardia, tachycardia, edema . OverallSpecific warnings and precautions of use. Death due to respiratory depression has been reported in children . MoreoveOverall assessment. According to established use, codeine may be useful in the symptomatic relief of cough. However, clinical studies and meta-analyses do not provide consistent evidence that codeine is effective in treating cough. Overall, the clinical evidence is Low. Due to the severe side effects, codeine safety may be considered Low.Indications in the context of respiratory conditions. Fever, pain.Posology. Up to 4 g a day in dose not bigger than 1 g every 6 h.in vitro and in vivo studies show evidence of antipyretic and mild analgesic activities  did not show any efficacy in flu, according to a clinical trial involving 80 patients . In a sySafety. Paracetamol (acetaminophen) is hepatotoxic , and sevSpecific warnings and precautions of use. Not indicated in cases of liver disease and alcoholism .Overall assessment. According to a well-established use, paracetamol may be useful in the symptomatic relief of respiratory conditions by reducing fever and aches , and prevention of the common cold. The clinical evidence may be considered Low or at best Medium. It is known to be hepatotoxic, and a frequent incidence of respiratory adverse effects may justify serious concerns and a safety rating of Low.Risk is inherent to any therapeutic intervention . The level of risk of herbal interventions in adults experiencing common flu symptoms without underlying conditions is very low. According to WHO, COVID-19 is self-limiting and mild in this segment of the population . HoweverGeneral warning: allergic reactions and gastrointestinal (GI) disturbances are common adverse effects in all medicines and apply to herbal ones. Their use in pregnancy and lactation, babies, children, and the elderly, as well as patients with known severe conditions, is to be individually assessed by a registered healthcare professional.The recommendations made here are for medicinal products regulated by national authorities to ensure their quality and safety. Other products may be unsafe due to contamination, adulteration, and the presence of naturally occurring toxins in levels above those permitted.Allium sativum is indicated for respiratory disease, namely cold and cough , glucosides , amino acids , monoterpenoids , peptides, minerals, flavonoids, and vitamins . In the Posology . Fresh garlic: 2.0–4.0 g average daily dosage . HoweverCytomegalovirus (HCMV), Influenza B virus, Herpes simplex virus type 1, Herpes simplex virus type 2, vesicular stomatitis virus, Parainfluenza virus type 3, Vaccinia virus, and human Rhinovirus type 2 , arabinans, glucans, arabinoglucans, mainly of acidic polysaccharides; flavonoids ; phenolic acids; coumarin (scopoletin); tannins .Posology . 0.5–5.0 g in 150 ml of water as a macerate, three times daily . MarshmaPreclinical evidence. This herbal medicine has been experimentally proven for respiratory disease symptom, namely, cough. The aqueous extract of marshmallow roots inhibited the tracheobronchial smooth muscle contractions in rats in a dose-dependent manner . The antAlthaea officinalis preparations have been trialed clinically for respiratory disease, and the following symptom was evaluated: cough. In a randomized clinical study, 63 adults suffering from dry cough associated with angiotensin-converting enzyme inhibitors ingested 20 drops, three times per day, of either a marshmallow root preparations or a placebo, for four weeks. The severity of the cough in the marshmallow group was significantly reduced  Maxim.].Indications in the context of respiratory conditions: nd fever . It is oChemical composition. Relevant secondary metabolites are diterpenes like andrographic acid, their glucosides (deoxyandrographolide-19β-D-glucoside) and dimers  and labdane diterpenoids like andrographolide, neoandrographolide; flavonoids ; steroids . 1–3 g as a decoction, three times daily . HoweverA. paniculata and andrographolide have been linked to the increasing proliferation of lymphocytes and the production of IL-2 and inhibition of the tumor cell proliferation immune system . Treatment with andrographolide decreased the virus loads and the expression of the inflammatory cytokines. Also, diminished lung pathology and overall survival rate . Anti-ine system . Also, de system . Neoandr effects . Androgr markers . A rangetituents .Clinical evidence. This herbal medicine has been trialed clinically for cold symptoms. Three systematic reviews pointed to the beneficial effects and safety of Andrographis for relieving symptoms of acute respiratory tract infections and shortening time to the symptom . The mosSafety. An assessment report of EMA concludes that while ‘there is a clear effect on some CYP isoenzymes, the available acute, and reproductive toxicity and genotoxicity data support the safety of Andrographis’ . On the Specific warnings and precautions of use. Allergic reactions may be of concern .Overall assessment. Andrographis may be useful in the symptomatic relief of respiratory symptoms, especially in terms of alleviating the symptoms of uncomplicated upper respiratory tract infections. Its traditional use as cold therapy in the context of upper respiratory conditions is not backed up by robust clinical data, but the evidences allow to infer a potential use in the relief of early symptoms of COVID-19. The clinical evidence may be considered High, and as although no severe concerns are reported, this herbal medicine may exert immunomodulatory activities so can be cautiously rated as Medium safety.Commiphora molmol is indicated symptoms of respiratory disease, namely mild inflammation of pharyngeal mucosa  .Posology . It is preferable to use a commercial preparation with a defined composition, such as a tincture (0.5–5 ml in 150 ml of water for rinsing or gargling three times daily) .C. molmol has been used as a remedy since ancient times  was evaluated about the anti-nociceptive effect. The volunteers (89 men and 95 women), presenting headache, fever-dependent pain, joint pain, muscle aches, lower back pain, or menstrual cramps, received extract (200 mg or 400 mg), or placebo, for 20 days. According to this RCT, the extract presented a similar effect to some frequently used drugs, such as diclofenac, ibuprofen, and paracetamol, although requiring a longer time of use (20 days). In the male group, the extract, at the dose of 400 mg, the effect was significant against all the symptoms. For the female group, the extract was effective against low back pain and fever-dependent pain at the doses of 200 mg/day. Furthermore, no side effect was reported by any of the volunteers  ; triterpPosology . 1–2 g of dried leaves (or 4–5 g of fresh leaves) in 150 ml, up to three times daily .Cymbopogon citratus has been experimentally evaluated for fever. However, the evaluation of the antipyretic activity of C. citratus herbal tea in rats (p.o. or i.p.) did not result in body temperature reduction , and other lipopolysaccharides (LPS)-induced pathways, suppression of COX-2 and peroxisome proliferator-activated receptor alpha (PPAR-α)  . Another-antigen . Citral, in mice .Clinical evidence. This herbal medicine has been not trialed clinically for respiratory disease. Overall, the clinical evidence is Low.C. citratus safe with no health issues from its usage due to the acceptable concentration limit of the essential oil compounds  granted registrations for Echinacea purpurea (L.) Moench (purple coneflower) for a preventive continuous use for maximal ten days, specifically excluding pediatric populations and with autoimmune illnesses as a contraindication  but are not considered to be of therapeutic relevance  may well be preferable over solid formulations.In vitro studies were reported against a range of respiratory viruses but for some preparations only at higher concentrations  in rat’s spleen macrophage  and prevention of the common cold. The clinical evidence may be considered High except for E. pallida. Although in the COVID-19 context, caution needs to be taken in order to avoid immunostimulation in complications in later phases of the disease, this herbal medicine safety can be rated as Medium.Overall assessment: Eucalyptus globulus is indicated for symptoms of respiratory disease, namely cough ; phenolic acids , tannins , flavonoids (quercetin derivatives) .Posology . 1.5–3 g of dried leaves in 150 ml, up to four times daily .In vitro and in vivo studies with leaves extracts, essential oil, and 1,8-cineol are supportive for some ethnomedicinal use , and the following symptoms were evaluated: cough and throat irritation. In an aromatherapy experiment with 48 students diagnosed with allergic rhinitis, eucalyptus reduced coughing, itching sensation in the throat and oral cavity, as well as other symptoms. After four weeks of treatment, the volunteers related a reduction of the discomfort provoked by rhinitis  ; stilbenPosology. 1.5 to 2.5 g in 200 ml of boiling water (brew for 15 min) three times daily .F. vulgare presented analgesic and anti-inflammatory activity in rats , which is known as a potential carcinogen. No clinical reports of fennel’s toxicity are known. The dose and the relevance of some studies with pure estragole at high doses have been disputed. Overall, the evidence is very limited, and there is no known reason for concern . AdminisOverall assessment. Even though its profile fits as safety relief therapy for cough in the context of upper respiratory affections, therapeutic benefits are likely to be limited. The clinical evidence is Low. This herbal medicine safety can be rated as High, although the recommended dosage must be observed.Glycyrrhiza glabra is indicated for symptoms of respiratory disease, namely, cough, sore throat ; triterpenes (glycyrrhetinic acid); flavonoids ; coumarins ; essential oil .Posology . 1.5 g of roots in 150 ml, as herbal decoction two times daily .Influenza virus. Also, inhibited the SARS-related coronavirus proliferation in vitro. Glycyrrhizic acid inhibited the growth of the Influenza virus, inflammatory cytokines, as well as the cytopathic effect of the Respiratory Syncytial Virus (RSV)  exerted a similar effect to prednisolone  in mast cells degranulation . Glycyrrus (RSV) .Glycyrrhiza glabra preparations have been trialed clinically for respiratory disease (asthma). An RTC, involving 36 patients presenting chronic asthma, showed licorice in a dose of 3.5 mg/kg in 200 ml water, three times daily, was able to improve the pulmonary function’s parameter similarly to prednisolone (0.15 mg/kg) as a single daily dose  for productive (chesty) coughs (Indication in the context of respiratory conditions. ) coughs . Other r) coughs .Chemical composition. Flavonoids and other phenolics ; polyacePosology. Pharmaceutical preparation with a defined chemical profile and an adequate dose need to be used .H. helix extract and isolated compounds exerted a spasmolytic effect in isolated guinea-pig ileum  and 7 non-randomized observational studies  is indicated for symptoms of respiratory disease, as expectorant ; flavonoids  ; lignansPosology . 5 g in 150 ml of water as an infusion .J. pectoralis presented inhibitory effects on the tracheal smooth muscle of rats subjected to challenge with ovalbumin (OVA) in an allergen model that reproduces many features of clinical asthma such as bronchial hyper-reactivity. Administered by gavage to sensitized rats after challenge with saline or OVA, the extract of J. pectoralis decreased the exacerbated responsiveness of rat trachea caused by the challenge with the sensitizing antigen. The oral administration of the standardized extract reduced the hyperresponsiveness in OVA-challenged trachea in preparations stimulated with KCl (potassium chloride) or ACh (acetylcholine). These effects on rat airways are possibly related to its anti-inflammatory activity, as observed by its ability to significantly inhibit the increase of the levels of TNF-α and IL-1β, pro-inflammatory cytokines, in bronchoalveolar lavage of OVA-challenged rats. These work findings reinforce the notion that the extract of J. pectoralis possesses potential anti-asthmatic properties -magnoflorine, magnofficine, (R)-asimilobine, corytuberine, anonaine, liriodenine) and benzylisoquinoline derivatives -tembetarine, lotusine, (R)-oblongine, reticuline); essential oil   and honokiol ; isoquinoline-type alkaloids, the majority of which are aporphine (udesmol) .Posology . 3-9 g of crude drug (decoction) daily in divided doses .in vitro models have demonstrated multiple biological properties of honokiol, including anti-asthma (through IL4 and IFN-NF-kB)  . Other rN-NF-kB)  and antiN-NF-kB) .Clinical evidence. Magnolia preparations have been trialed clinically for asthma. Preliminary clinical studies showed the benefits of magnolia for oral health . In non-M. oficinalis is Medium.Safety. Magnolol and honokiol are the main ingredients of magnolia bark and, therefore, were considered directly relevant to evaluate the safety of the product. Full clinical monitoring, including biochemical and hematological analysis, showed no evidence of toxicity reported in subjects consuming magnolia bark containing supplements at a dose of 750 mg/person/day (approximately 15 and 60 mg/person per day of honokiol and magnolol respectively) for 42 days . AccordiSpecific warnings and precautions of use. None known.M. officinalis preparations are not clinically proven to provide symptomatic relief of flu symptoms and its active principle (magnolol) may enhance the entry SARS-CoV-2 virus into the cell, the clinical evidence may be considered Medium and the safety, in the COVID-19 context, Medium.Overall assessment. Magnolia bark has been used in Chinese and Japanese traditional medicines for the treatment of asthma, allergic disease, as well as for the alleviation of headaches, muscular pain, and fever . As M. oMalva sylvestris is indicated for respiratory disease, namely oral or pharyngeal irritations and dry cough ; flavonoids ; tannins ; hydroxyPosology . 1.8 g in 150 ml as infusion or decoction three times daily .Malva sylvestris preparations have been experimentally studied for cough. The anti-tussive activity of its mucilage and isolated rhamnogalacturonan was evaluated in cats. Both substances suppressed the cough reflex and decreased the frequency of cough, especially in the laryngopharynx area, although the polysaccharide was more active than mucilage ,; phenolic acids   ; coumaric acids) ; terpenoc acids) .Posology . 3 g of dried leaves in 150 ml, as an infusion, 2 times daily. However, the use of dosage forms, with defined composition, is recommended.M. glomerata ethanolic extract was evaluated through an allergic pleurisy model in rats and resulted in the inhibition of leukocyte infiltration  had an unequivocal bronchodilator action and evident dose-dependent antitussive effect  extract presented LD50 ~ 3000 mg/kg and did not produce any biochemical, hematological, and morphological changes in mice  ; phenoliPosology . 1-3 g in 150 ml of boiling water, as an infusion, 3-4 times daily .O. gratissimum was evaluated in OVA-sensitized guinea-pig about anti-tussive and anti-asthma activities. The aqueous extract did not exert effect in pre-convulsive dyspnea; however, reduced in a significant manner, the volume of tracheal liquid, although it did not interfere in the fluid viscosity, and reduced in more than 80% the number of cough episodes . Also, inhibited LPS-induced NO, IL-1β, and TNF-a production in RAW 264.7 cells .Specific Warnings and precautions of use. Due to the presence of estragole, a naturally occurring genotoxic carcinogen, posology    .O-galloyl-C-glucosyl flavones., scopoletin, 6,8-dihydroxy-5,7-dimethoxycoumarin, 5,6,7-trimethoxycoumarin. Other coumarins, as well as, quercetin 3-O-β-D-glucoside, myricetin, and other flavonoids have been isolated from both species. Pelargonium sidoides yielded some benzopyranones. Umckalin is only known from P. sidoides -catechin, gallic acid, and methyl gallate, including some unusual sidoides ; pelargoeniforme .Posology. Oral drops, tablets, and syrups are most commonly used . Commerc® interfered in vitro with the replication of different respiratory viruses, including human coronavirus (Influenza virus (in vitro and in vivo)  , and Rhie asthma . EPs 763nd TNF-α .Pelargonium sidoides preparations have been trialed clinically for cough. In a randomized, controlled trial, involving 124 adults presenting acute bronchitis, were treated with 30 drops of EPs 7630®, for seven days. The treated group showed a significant improvement regarding the Bronchitis Severity Score (BSS) compared with the placebo group  might occur with no major concerns about interaction risks . HoweverSpecific warnings and precautions of use. As with all other products discussed here, there is no evidence for specific therapeutic benefits, and it is important to communicate this to potential users. The safety concerns listed above need to be kept in mind.Overall assessment. Umkaloabo may be useful in the symptomatic relief of respiratory symptoms through exerting a soothing effect on the respiratory tract. A relatively large number of clinical studies and a series of meta-analyses provide evidence that Umkaloabo preparations seem to be efficacious both in the treatment (reducing symptoms and duration) and prevention of the common cold. However, it must be discontinued to avoid immunostimulation in complications in later phases of the disease. The clinical evidence is High, and this herbal medicine is considered presenting Medium safety.Pimpinella anisum is indicated for cough and fever (Indications in the context of respiratory conditions. nd fever  and as and fever .trans-anethole as the main compound)  ; chlorogompound) .Posology . 1,5 g of the dried fruits in 150 ml, as an infusion, three times daily .P. anisum presented myorelaxant effect in isolated tracheal chains of guinea-pig. The relaxant effect was similar to promoted by theophylline. Interesting to note that the essential oil did not present a significant effect , twice a day for 40 days. All patients presented a reduction of cough episodes after 21 days of treatment (from more than 6 episodes/day to none), as well as dyspnea and wheezing. Also, an improvement in the breath-holding time and respiratory rate was observed . 2 g of leaves in 150 ml boiling water, two to three times daily; 160-190 mg of powdered plant coated tablet or lozenges, maximum dose of 1.28 g daily . It is pP. lanceolata reduces the number of coughs provoked by citric acid, in guinea-pig, in a similar way to codeine   ; steroid; essentiPosology . 2–9 g in 150 ml as a decoction, daily .Platycodon chinensis has been experimentally proven for cough and fever in mice  (Specific warnings and precautions of use. Radix em (CNS) . TherefoOverall assessment. Based on traditional use, preparations could be useful in respiratory symptoms relief, through exerting an antitussive effect, although it is not backed up by robust clinical data. The clinical evidence is Low, but this herbal medicine is considered presenting High safety.Polygala senega is indicated for cough  ; monosacPosology . Herbal tea (dried root): 0.5–1.0 g three times a day . It is pPreclinical evidence. This herbal medicine has not been experimentally proven for symptoms of respiratory disease. However, the expectorant activity of the crude drug is due to the constituent saponins, which produce local irritation of the mucous membranes of the throat and respiratory tract. This irritation stimulates an increase in bronchial secretions, thereby diluting the mucus, reducing its viscosity and facilitating expectoration . IsolatePolygala senega preparations have not been trialed clinically for respiratory diseases. French patent mentioned that a triterpene acid isolated from P. senega possesses anti-inflammatory action . 4–5 g, as a decoction, 3–4 times a day. Not to be taken for more than a week .Preclinical evidence. This herbal medicine has been experimentally proven for respiratory disease. A hydroalcoholic extract presented a myorelaxant dose-dependent effect in rabbit isolated tracheal preparation. The effect was cholinergic-like . HoweverPolypodium vulgare has not been trialed clinically for respiratory diseases. Overall, the clinical evidence is Low.Clinical evidence. Safety. Overall, the safety is High as there are no reports to infer that the preparation from this plant may interfere with the disease or NSAIDs.Specific warnings and precautions of use. A mild laxative effect may happen when this plant is used as expectorant . MoreovePolypodium vulgare preparations could be useful in the relief of the respiratory symptoms, through exerting an antitussive effect. Although the clinical evidence is Low, this herbal medicine is considered presenting High safety.Overall assessment. Potentilla erecta is indicated for cough and symptomatic treatment of minor inflammations of the oral mucosa ; condensed tannins/proanthocyanidins -catechin = procyanidin B6, -2,3-trans-3,4-cis-bi-(+)-catechin, -all-trans-bi-(+)-catechin = procyanidin B3), -all-trans-bi-(+)-catechin, procyanidin B1, procyanidin B2, procyanidin B5, (+)-catechin--(+)-catechin--(+)-catechin, (+)-catechin--(+)-catechin--(+)-catechin; triterpenoids: 2α,3β-dihydroxyurs-12 -en-28-oic acid β-D-glucopyranosyl ester, 3-epi-pomolic acid 28-entoside .Posology . 1.5–2.0 g per 100 ml of water, as an infusion, or 0.8–3.0 g per 100 ml of water, as a decoction. The preparation should be used to rinse the mouth several times daily . It is pHerpes viridae has been demonstrated for extracts of P. erecta and hydrolyzable and condensed tannins isolated from this plant. In particular, the antiviral activity against Herpes virus types I and II was reported, as well as the cytotoxic activity against Influenza virus type A2 and Cowpox  ; flavonoPosology. 0.2–0.5 g in 150 ml of boiling water, as an infusion, 3 times daily . It is pP. veris dry extract presented potential anti-inflammatory activity in vitro, reducing IFN-γ, and inhibited prostaglandin and leukotriene synthesis. Also, inhibited the replication of human rhinovirus (HRV) and respiratory syncytial virus (RSV)  . A hydroema test .Primula veris has not been trialed clinically for respiratory diseases. Overall, the clinical evidence is Low.Clinical evidence. Safety. Cases of nausea, vomiting, gastric disturbances, and allergies may occur in doses higher than recommended . OverallP. veris and warfarin . 3 g dry stem barks in 150 ml as a decoction, 2–3 times a day . 1–3 g oSalix alba extract showed significant analgesic as well as anti-inflammatory properties in mice and showed more potency than the standard drug aspirin in all the doses tested  had no effect on kidney function, hematological parameters, cholesterol levels, or liver function. The results of the histological evaluation showed no pathological changes in the heart, brain, lungs, kidneys, bone, liver, mammary tissue, reproductive organs, intestines, or stomach ; and essential oil ; sterols ; phenolic acids and their corresponding glycosides . 3–5 g of dried flowers in 25 ml as an infusion three times daily. Store in a well-closed container, protected from light . 2–5 g din vitro . 1-2 g of dried roots in 150 ml of boiling water, as an infusion, three times daily . 3-9 g oScutellaria baicalensis has been not experimentally proven for symptoms of respiratory disease. Other related experimental effects include anti-inflammatory. The anti-inflammatory activity was evaluated by in vitro and in vivo experiments. Extracts inhibited the production of NO, interleukin (IL)-3, IL-6, IL-10, IL-12p40, IL-17, interferon-inducible protein (IP)-10, keratinocyte-derived chemokine, and vascular endothelial growth factor (VEGF) in LPS-induced RAW 264.7 cells  are the main components reported for marianum ; flavonomarianum .Posology . It is preferable to use a commercial preparation with a defined composition and an adequate dose.Silybum marianum has not been experimentally proven for symptoms of respiratory disease. Silybin, the main flavonolignan from the seed of S. marianum, has demonstrated an anti-inflammatory activity by inhibiting the spontaneous and LPS-stimulated NF-kB activation as well as the production of inflammatory cytokines ; phenolic acids , tannins , flavonoids  .Posology . 1–2 g of dried leaves in 150 ml, as an infusion, 3–4 times daily .Thymus vulgaris has not been experimentally proven for symptoms of respiratory disease. However, the myorelaxant effect of ethanolic extract and flavonoids from T. vulgaris was evaluated in isolated guinea-pig trachea contracted by acetylcholine. The extract promoted relaxation, similar to DL-isoprenaline , type 2 (HSV-2), and HSV-1 acyclovir-resistant  are considered unsafe due to thymol  ; flavonoPosology. 1.5 g in 150 ml of boiling water, as an infusion, 2–4 times daily Preclinical evidence. This herbal medicine has not been experimentally proven for the symptoms of respiratory disease. However, procyanidins present in small flowers were evaluated about an inflammatory response in human neutrophils in the concentration ranging from 5 to 20 μM. All compounds were able to decrease ROS production from f-MLP-stimulated neutrophils. Most compounds were able to inhibit LPS-induced IL-8 release. Some trimeric and tetrameric derivatives were also able to decrease the production of MIP-1β. A hydromethanolic extract presented anti-inflammatory and antinociceptive activities in rats, in a similar way than indomethacin and acetylsalicylic acid, respectively .Clinical evidence. This herbal medicine has been not trialed clinically for respiratory diseases. Overall, the level of evidence is Low.Safety. Overall safety is High, as there are not reports to infer that the preparations from the plant may interfere with the disease.T. cordata exert an anxiolytic effect and can, potentially, interact with serotonergic drugs . 1 g of dried rhizoma in 150 ml, 3–4 times daily .in vivo as in vitro models  received an enteral diet enriched with ginger or placebo, through a nasogastric tube, during 21 days. On day 5, the patients that received ginger presented lower serum levels of IL-1, IL6, and TNFa, while the level of RBC glutathione presented higher in comparison with the placebo group. Moreover, a significant improvement in oxygenation was observed in the ginger group. The same results were observed on day 10. The authors described that there was a significant difference in the duration of mechanical ventilation and in the time expended in the intensive care unit. However, barotrauma, organ failure, and mortality between ginger and placebo groups were similar . OverallSafety. Although regulatory authorities recommend avoiding the use in pregnancy and lactation , ginger Specific warnings and precautions of use. Stomach upset, eructation, dyspepsia, and nausea have been reported . High doZingiber officinale profile and chemistry fit as an anti-inflammatory therapy in the context of upper respiratory affections. Therefore, this herbal medicine may be useful in the relief of respiratory symptoms through exerting an anti-inflammatory effect. The clinical evidence is Medium. This herbal medicine is considered presenting Medium safety.Overall assessment. Some species, although without the support of official documents, have been widely used to relieve common cold symptoms, usually as homemade preparations. Some of them are analyzed here, in the COVID-19 context.Citrus limon has been used to relieve cough, and as expectorant in bronchitis   ; flavonovatives) , coumarivatives) .Posology. Slices of whole fruit or fresh pericarp, as a decoction, 2–3 times daily; expressed juice .Preclinical evidence. This herbal medicine has not been experimentally proven for respiratory disease.Clinical evidence. This species has not been trialed clinically for respiratory disease. Overall the clinical evidence is Low.Citrus limon is an edible fruit, therefore, considered safe, although there may be a risk of minor burns on the skin if in contact with sun exposure, due to the presence of furanocoumarins  ; phenoliPosology . 1–2 g of leaves in 150 ml, as an infusion, up to three times daily .Culcitium canescens has not been experimentally proven for respiratory disease.Preclinical evidence. Clinical evidence. This species has not been trialed clinically for respiratory disease. Overall the clinical evidence is Low.Safety. Little or anything is known about the toxicity of this plant .Specific warnings and precautions of use. None.Culcitium canescens profile and chemistry fit as an anti-inflammatory therapy in the context of upper respiratory affections, and preparations are traditionally used, the lack of knowledge about this species does not allow a clear recommendation for the relief of early symptoms of COVID-19. The clinical evidence is Low.Overall assessment. Although Laurus nobilis is used to treat respiratory infections (Indications in the context of respiratory conditions. fections .a-terpinyl acetate as the major compounds) ; sterols ; flavonoids  . Leaves:mpounds) . Furthermpounds) .L. nobilis is given by the American Pharmaceutical Association: 1–2 tablespoons leaf/cup water and 3 times/day or 1–2 drops of essential oil added to honey, or tea . The only dosage information on , or tea .in vitro study examining SARS-CoV and the effect of several essential oils. The authors reported that a distilled oil extracted from Laurus nobilis berries was an effective virucidal against SARS-CoV. This essential oil also contained eremanthin and dehydrocostus lactone as minor constituents at 3.65% and 7.57%, respectively. These compounds are somewhat unusual in essential oils, but at least one in vitro study found that dehydrocostus lactone had activity against the hepatitis B virus, an enveloped DNA virus . 1–2 g of dried leaves or stem in 150 ml of water .Lippia genus have demonstrated a significant inhibitory effect on ROS and NO production and mitochondrial activity in LPS-induced inflammation in RAW 264.7 macrophage cells. Additionally, these fractions exhibited non-selective inhibitions against the activity of the cyclooxygenases COX-1 and COX-2 . Therefore, safety is High.Specific warnings and precautions of use. None.Lippia graveolens profile and chemistry fit as an anti-inflammatory therapy in the context of upper respiratory affections. Therefore, this herbal medicine could be useful in the relief of respiratory symptoms through exerting an anti-inflammatory effect. The clinical evidence is Low. This herbal medicine is considered presenting High safety.Overall assessment. Indications in the context of respiratory conditions. Black seeds are globally known as a spice and as such as a food item. In Arabic medicine, they have very high status as an herbal medicine used for a wide range of diseases. In the context of COVID-19, the relevant uses are for asthma and in the more general management of inflammatory conditions. In many Arabic countries, black seed is used for asthma and cough, among many other uses, especially for gastrointestinal diseases , rheumatism, skin diseases .Chemical composition. Relevant secondary metabolites in the seed include large quantities of fixed oil , various triterpenoids, including saponins; essential oil, with a relatively high concentration of thymoquinone , which is also a key therapeutically relevant of the fixed oil, where it can be found in concentrations varying from 3.5 to 8.7 mg/g of fixed oil . ThymoquPosology. Capsules containing fatty oil with a defined amount of thymoquinone are likely to be the best option. Herbal teas and other hydrophilic preparations seem less likely to have benefits, and potentially the essential oil may offer some relief.N. sativa seeds (extraction at room temperature for 72 h) showed ameliorating effects on lung inflammation and oxidative stress induced by lipopolysaccharide. In general, many study focus on the effects of N. sativa preparations  of chopped arations , but mosN. sativa oil (0.7% thymoquinone) improved asthma control with a trend in pulmonary function improvement. Two of the five subscores  showed a significant improvement. The other three were not significantly improved. At the same time, a remarkable normalization of blood eosinophilia count was observed   ; phenoliuteolin) , terpenouteolin) .Posology . 3–5 g of fresh leaves in 150 ml, as an infusion, up to three times daily .P. amboinicus present in vitro anti-inflammatory activity .Specific warnings and precautions of use. The use is contraindicated for hypersensitivity to the active substance. Children, under 30 months of age, should not use this plant due to thymol containing preparations, can induce laryngospasm  into western therapy since the SARS outbreak in 2003. Based on clinical results, the General Office of the National Health, and the Office of the State Administration of Traditional Chinese Medicine encouraged the integration of herbal TCM and Western medicine in the treatment of respiratory complications in Coronavirus infections with different prescriptions recommended in different stages of disease . After STherefore, it is not surprising that thousands of TCM practitioners across China have been working along with regular medical doctors to control the COVID-19 disease. The clinical data generated from tens of thousands of confirmed cases are being subjected to meta-analyses to ascertain their actual effectiveness . In the Tinospora cordifolia (Willd.) Myers (Menispermaceae), Zingiber officinale Roscoe (Zingiberaceae), Curcuma longa L. (Zingiberaceae), Ocimum sanctum L. (Lamiaceae), Glycyrrhiza glabra L. (Fabaceae), Adhatoda vasica Ness (Acanthaceae), (Acanthaceae), Andrographis paniculata (Burm.f.) (Acanthaceae), Swertia chirata Buch.-Ham. ex Wall. (Gentianaceae), Moringa oleifera Lam (Moringaceae), Triphala  and Trikatu   is systematizing the available evidence about Traditional, Complementary and Integrative Medicine  potentially useful in the COVID-19 pandemic .Traditional herbal medicines are poorly or not regulated as licensed/registered medicines in quite a few countries, including the USA, and therefore are considered “food,” precluding any high-level discussion on their potential contributions to human health. Consequently, the U.S. Food and Drug Administration (FDA) considers fraudulent to sell any herbal products with attached claims and has sent warning letters to companies offering herbal products such as teas, essential oils, and tinctures claiming to prevent, treat or cure the symptoms of COVID-19. It is also encouraging the public to report the unlawful sales of medicinal products on the Internet . The Norsuspected side effects your patients experience while infected, regardless of the medicines intended to treat the disease or pre-existing conditions. Suspected side effects should be reported even if the medicine is not authorized for use in COVID-19. When reporting a suspected side effect in a patient, you should tell us of any other medicines being taken around the same time, including non-prescription medicines, herbal remedies, or contraceptives”  are regulated by the EMA as OTC medicinal products for the relief of mild, self-limiting conditions, including flu symptoms and cough. Surprisingly, there is not any overarching official guidance with respect to the use of THMP in the context of the pandemic. In principle, THMP would not qualify as therapy for COVID-19 symptoms as it is considered a severe life-threatening condition. However, this disease is self-limiting in most of the patients and - in the absence of a positive result in a test – COVID-19 patients are just ‘flu’ patients and, as such, could self-medicate with THMP. Several herbal drugs here reviewed have been registered as THMP. EMA stresses in its guidelines to healthcare professionals to report all “eptives” .We have witnessed how, in different countries, the authorities have developed an array of tools both to inform and enforce guidelines: Italian police are acting at retail commerce level by seizing on the spot any products sold under fraudulent claims; the Brazilian Ministry of Health is fighting back any misleading claims with a dedicated channel in WhatsApp . The casThe WHO regional office for Africa has issued a statement supporting scientifically-driven traditional medicine as “a valid approach towards the treatment of the virus, as long as their efficacy and safety are proven through rigorous clinical trials” , in reacThe potential risks and public impact associated with any advice on this disease are huge, and understandably; so, Herbalists associations are more cautious than usual in promoting herbal medicines in this context. In the UK, the NMHI just encourages its members to “integrate the herbal advice they provide with any conventional treatment or management strategies that are appropriate for their patients, and to observe the current infection control and management guidelines formulated by the Department of Health” ; and theDespite the massive use of codeine, paracetamol, and ibuprofen for the relief of respiratory diseases, the clinical body of evidence supporting their use in flu is very low. These drugs are mostly used based on medical experience and clinicians are familiar with their benefits/risks profiles. These drugs have very common toxicities and their adverse effects are potentially dangerous in the context of COVID-19 .It is surprising the lack of clinical trials to substantiate the use of both paracetamol and ibuprofen in the treatment of cold/flu symptoms. As noted in previous sections, clinical evidence is somewhat higher for ibuprofen than for paracetamol.There is quite a consensus in that the patient may safely choose to use herbal medicines and food supplements in the prevention of COVID-19. In line with EMA, we advise the patients to keep a diary of the medication  to inform medical doctors and other health care professionals in case of hospitalization worsening of the disease.Two types of interactions are important in COVID-19: disease-herbal medicine and herbal medicine-drug interactions. There is a complicated relationship between the immune system and viral infections: infection is favored by a weak immune response, whilst complications arise from an ‘overreaction’ of the immune system known as “cytokines storm”. As a result, health authorities discourage any therapies modulating the function of immune cells in any of both directions -including anti-inflammatory drugs- and reserve those to clinical management of advanced stages of COVID-19.To complicate matters further, a significant fraction of COVID-19 patients in advance stages may require emergency treatment consisting of mechanical ventilation under general anesthesia. It is standard protocol for anesthetists to advise against taking herbal supplements at least 2 to 3 weeks before surgery or other procedures requiring anesthesia, due to potential pharmacodynamic and pharmacokinetic interactions with these procedures .As a result of all the above, the use of any herbal-based products has been strongly discouraged by medical authorities, even for typical symptoms of the early stages of COVID-19. Patients are asked to rest, take paracetamol - if fever is dangerous only - and plenty of water. Such “Keep calm and carry on” clinical advice is not realistic and causes dissatisfaction in patients that are not ready to just ‘sit and suffer’ with the added distress of the potentially lethal complications. It is all human that they will try whatever is offered from alternative medicinal systems to minimize both symptoms and viral load.Interestingly, there is seldom any mention to anti-tussive medication, one of the most characteristic symptoms of the COVID-19 disease, which chiefly contributes to its spread. Available cough medicines range from OTC products such as simple linctus  and THMP (in Europe) to pharmacy/prescription-only opioids such as dextromethorphan or codeine.Early clinical data on the evolution of COVID-19 patients pointed out to a deleterious influence of ibuprofen and ketoprofen even taken as short as 2–4 days during the onset of the infection , and proThe basis for lower use of NSAIDs has been substantiated on two lines of thinking: (a) they non-specifically impair the immune response thus potentially facilitating the viral infection; (b) some NSAIDs such as ibuprofen, potentially increase the expression of proteins necessary for the entry of the virus into the cell. The later includes proteins vimentin (streptococcus) and ACE-2 (coronavirus).Surprisingly, paracetamol counts among its many potential adverse effects “very common incidence” (1% to 10%) of dyspnea, abnormal breath sounds, pulmonary edema, hypoxia, pleural effusion, stridor, wheezing, and coughing.The French authorities have issued a detailed document warning against all herbal medicines with anti-inflammatory and immunomodulatory activities and discouraging their liberal use if flu symptoms appear, whilst the COVID-19 pandemic is going on - unless the patient is tested negative .Rheum officinale Baill. and Polygonum multiflorum Thunb (Coronaviruses have spike or surface (S) glycoproteins giving them their characteristic shape and name. These help the virus to enter the host cell by a receptor-mediated process . Althougum Thunb .Scutellaria sp., Magnolia sp., Salvia sp., Curcuma sp., and Rosmarinus officinalis L., by COVID-19 patients, needs further evaluation , Larch (Larix sp.) arabinogalactans-rich extracts, and plant extracts or food supplements rich in Vitamin D  in hospitalized patients with COVID-19 has been a controversial matter during the pandemic. Initial studies seemed to point towards patients the benefits of VTE prophylaxis in emergency care. Currently, there is insufficient data to recommend for or against the use of thrombolytics or increasing anti-coagulant doses in hospitalized COVID-19 patients. More epidemiologic studies with better control for underlying comorbidities, prophylactic anticoagulation, and COVID-19-related therapies are needed .A. sativum L.) and guaco (M. glomerata Spreng.). Although caution needs to prevail in assessing whether they are providing a benefit that outweighs the potential risks in case the disease gets complicated. This assessment needs to take into consideration quantitative scientific criteria that, in many times, are lacking. A case in point is the ‘zero tolerance’ to garlic, despite experimental evidence showing that an equivalent of 0.6% allicin does not impair platelet function and does no potentiate platelet-inhibiting drugs , because they may  increase the risk of liver damage in patients under anesthesia.Echinacea , St. John’s wort , and valerian  because they may increase the effects of anesthesia and make it harder to wake up. They may also cause irregular heart rhythms.Ginkgo , licorice (Glycyrrhiza glabra L.), and milk thistle [Silybum marianum (L.) Gaertn.], because they may cause high blood pressure and a rapid heart rate.Ginseng , ginkgo, green tea , feverfew , ginger  and Saw palmetto , because they may cause prolonged bleeding.Garlic , ibuprofen and codeine. These drugs resulted not to be backed up by robust clinical evidence, and their safety profile was concerning in some cases. According to this ‘baseline’, five herbal medicines were found as potentially valid candidates in managing early or mild symptoms of cold, flu and bronchitis in the context of COVID-19 as they provide with ample safety margins and good evidence for efficacy: Allium sativum, Andrographis paniculata, Echinacea angustifolia, Echinacea purpurea, Eucalyptus globulus essential oil, Justicia pectoralis, Magnolia officinalis, Mikania glomerata Pelargonium sidoides, Pimpinella anisum, Salix sp, and Zingiber officinale. The authors recommend the scientific community to prioritize working on these herbals towards their full integration into clinical use. These two groups are, in the opinion of the authors, comparable in terms of safety -and sometimes efficacy- with the three reference drugs currently in clinical use for the target symptoms, so these herbal medicines may help to mitigate the discomfort in the early stages of the disease, based on their anti-inflammatory, immunomodulatory, and antitussive properties.A second group of twelve herbal medicines is to be considered as promising candidates, due to their reasonable safety margins and emerging evidence for efficacy: Glycyrrhiza glabra, Magnolia officinalis, Mikania glomerata, and Pimpinella anisum. These plants cannot be candidates to treat respiratory infections but may be safe to use if the asthmatic patient suffers flu symptoms.The following plants have good evidence for the treatment of asthma: The rest of herbal medicines  appear to have a good safety profile, but simply there is not enough evidence – clinical or pre-clinical – about their action on the target symptoms  or conditions . Therefore, they must be categorized as of ‘unknown’ potential and would need much more research to build up the necessary evidence to justify their use in the management of flu, let alone in the context of COVID-19.Several food/herbal-based remedies are associated with the treatment of common cold and flu because they include vitamins (such as lemon juice), aromatic principles with perceived benefits for the upper respiratory system , or because they are culturally considered as a “cure-all” (such as Nigella). Some of them are presented to the public in a “pharmaceutical forms” , thus looking like a “safe and effective medicinal approach”. The regulatory status of these products varies from country to country, and we advise here that only products that are regulated as  medicines should be used since this is an essential requirement for a product’s safety.Citrus limon, Culcitium canescens, Laurus nobilis, Lippia graveolens, and Plectranthus amboinicus. We subjected the evidence for the efficacy and safety of these plants to the same Benefit/Risks assessment applied to the “officially recognized” herbal medicines, and the collected preclinical, clinical, and safety data are provided.The following herbals and foods were identified by the authors as falling into this category: Nigella may be considered as a borderline “promising” treatment example as there is some preliminary clinical evidence for its relief of cough but it seems to be restricted to asthma patients, so from a physiopathological point of view is not clear how useful it would be in cold/flu. As for the others, although considered safe, there is simply not enough evidence – clinical or pre-clinical – in relation to their benefits on the target symptoms  or conditions .Despite their lack of evidence in the treatment of flu, lemon, bay leaves, mint, and Nigella are deeply ingrained ‘polyvalent’ remedies in many cultures all over the World. Therefore, a succinct discussion on their efficacy and safety in the treatment of respiratory conditions is essential:Citrus limon (L.) Burm.f fruits, alone or associated with salt, honey or ginger has been used to relieve cough and fever related to flu and cold in several traditional systems  is widely used to treat bronchitis, fever and other respiratory disorders  is globally known as a spice and as a food item. In Arabic medicine, this species has very high status as a herbal medicine used for a wide range of diseases. In the context of COVID-19, the relevant uses are for asthma and in the more general management of inflammatory conditions. With regards to respiratory diseases its use can be traced back at least to Avicenna , who indicated it for shortness of breath and for stopping phlegm and Imam Ibn Qayyim Al-Jawziyya (1292–1350 C.E.), who recommended it for gasping and hard breathing  preparations , which also is included in this Research Topic of Frontiers in Pharmacology, Sect. Ethnopharmacology, and thus these studies mutually complement each other.positive in 5 cases, promising in 10 cases, and unknown for the rest. On the same basis, only ibuprofen resulted promising, but we could not find compelling clinical evidence for a positive assessment to endorse the adjuvant use of paracetamol and/or codeine due to their common adverse effects in the respiratory function.A total of 39 herbal medicines were identified as very likely to appeal to COVID-19 patients. According to our method, the benefits/risks assessment of the herbal medicines was found Althaea officinalis, Commiphora molmol, Glycyrrhiza glabra, Hedera helix, and Sambucus nigra have safety margins superior to those of reference drugs and enough levels of evidence to merit their potential clinical use as adjuvants in the treatment of early/mild cases of COVID-19.Our work suggests that Herbal medicines are not a “magic bullet” to solve the problems related to flu - let alone COVID-19 or any other coronavirus - neither can avoid the virus infection but may alleviate symptoms and potentially improve the general wellbeing of patients. It requires a careful assessment of whether such adjuvant therapies are justified or not. Then again, it can only be a suitable therapy at a stage when the severity of the disease is minor. Overall, we highlighted the potential of some medicinal plants for the adjuvant management of early symptoms of flu within the context of COVID-19 in otherwise healthy adults. For an herbal medicine to be a medicine high quality, chemically well-characterized, and pharmacologically well-studied preparations are acceptable only. Equally, it will be essential that such well-characterized preparations are used in all future pharmacological and clinical studies .In a broader context, this study also offers a novel approach for assessing the risks and benefits of using herbal medicines. Since the PrOACT-URL strategy is used here for the first time with a set of herbal medicines, we want to highlight the opportunities for a rigorous and evidence-based approach will have in a balanced assessment of such medicines.DS Conceptualization of overarching research goals and aims, data/evidence collection, data curation, coordination of the overall work, formal analysis of study data, preparation, creation and/or presentation of the published work, critical review and revision. JP-G: Conceptualization of overarching research goals and aims, development and design of the methodology, visualization/data, formal analysis of study data, preparation, creation and/or presentation of the published work, critical review and revision. FB: Data/evidence collection, formal analysis of study data, critical review and revision. OE, YF-B, CJ, PM, EP, and MT: Data/evidence collection, formal analysis of study data. MH: Conceptualization of overarching research goals and aims, data/evidence collection, formal analysis of study data, critical review and revision.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Capes-PrInt (88887468871/2019-00).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The increasing use of preprints to disseminate evidence on the effect of interventions for the coronavirus disease 2019 (COVID-19) can lead to multiple evidence sources for a single study, which may differ in the reported evidence. We aim to describe the proportion of evidence on the effect of interventions for COVID-19 from preprints and journal articles and map changes in evidence between and within different sources reporting on the same study.p value > or < 0.05 in any outcome) and abstract conclusions . Changes in study results were further classified as important changes if they (1) represented a change in any effect estimate by ≥ 10% and/or (2) led to a change in the p value crossing the threshold of 0.05.Meta-research study. We screened the Cochrane living systematic review and network meta-analysis (COVID-NMA) database to identify all preprints and journal articles on all studies assessing interventions for COVID-19 published up to 15 August 2020. We compared all evidence sources  and the first and latest versions of preprints for each study to identify changes in two evidence components: study results  had been reported in a preprint: 66 (20%) of these had an associated journal article (median time to publication 76 days [interquartile range (IQR) 55–106]) and 91 (27%) had > 1 preprint version. A total of 139 studies  were reported in multiple evidence sources or versions of the same source: for 63 (45%), there was a change in at least one evidence component between or within sources . For studies with both a preprint and an article, a median of 29% (IQR 14–50) of total citations were attributed to the preprint instead of the article.Results on the effect of interventions for COVID-19 are often reported in multiple evidence sources or source versions for a single study. Evidence is not stable between and within evidence sources. Real-time linkage of all sources per study could help to keep systematic reviews up-to-date. The coronavirus disease 2019 (COVID-19) pandemic has created a need for rapid performance and dissemination of systematic reviews on the effectiveness of preventive, therapeutic, and post-acute care interventions to guide clinical practice, policy-making, and guideline development .One author (G.C.) designed an algorithm that relies on preprint metadata obtained via the Crossref API .https://retractionwatch.com/retracted-coronavirus-covid-19-papers/). We used an algorithm to automatically extract the number of versions on the preprint server for each preprint and the date of online publication for each preprint and journal article.We classified each source as a preprint or journal article. For journal articles, we manually extracted whether the journal had issued corrections or a retraction notice by searching the journal website and Retraction Watch  or more than one version of the same evidence source .between the following evidence sources:First preprint version versus journal articleLatest preprint version versus journal article (if > 1 preprint versions were available)First, we sought to compare important evidence components within evidence sources .Second, we sought to compare evidence components p value changed from > to < 0.05, or vice versa), for any outcome. To characterize the magnitude of change in results, we considered the change to be important if (1) it represented an increase or decrease by ≥ 10% of the initial value in any effect estimate and/or (2) it led to a change in the p value crossing the threshold of 0.05. For evidence source pairs that had a change in results, we additionally extracted whether the sample size had changed among or between evidence sources. The sample size was defined as the number of individuals enrolled in the study or the number of countries/regions analyzed (for population-level studies of policy interventions).Change in any study result. We searched for numeric changes in at least one of the following effect-size metrics: hazard ratio, odds ratio, relative risk, event rate, correlation or regression coefficient (for country-level studies), or in the statistical significance .If the abstract conclusion reported uncertainty in the findings .Change in the study conclusion reported in the abstract. First, we assessed the conclusion to determine two aspects:To perform these comparisons, we downloaded all abovementioned sources for each study in portable document format (PDF). We entered each pair of files in PDF Converter (Enterprise 8). This software allows users to compare documents by automatically detecting and highlighting changes in text (words added or deleted between versions). We reviewed the highlighted text to identify changes in the following evidence components, which may affect systematic reviewers’ appraisal of the effect of the intervention assessed in the study:We considered any change in conclusion among positive, neutral, or negative or change between reporting versus not reporting uncertainty to constitute change in the conclusion.To describe the dissemination of the different evidence sources, we used an algorithm designed by one of the authors (G.C.) to automatically extract the following usage data for each preprint–journal article pair: citation count, Altmetric Attention Score (extracted from the Dimensions database) , and theWe sought to identify changes in evidence in a subgroup of studies currently being used for quantitative evidence synthesis in the COVID-NMA. These are RCTs and non-randomized studies that are interrupted time series or non-randomized studies using causal inference analysis or multivariable regression adjustment, with ≥ 150 incident users.In addition to the study results and conclusion, we searched for changes in the following methodologic components that could affect the appraisal of risk of bias , 9: blinOne reviewer (T.O.) extracted data for all included studies by using a structured, piloted form  as median and interquartile range (IQR). Because our sample included evidence sources published over an 8-month period, we accounted for the difference in exposure time by dividing each usage metric by the number of days since the date of first online publication.n = 90, 17%) and antimalarial agents   or the USA .We identified 556 studies assessing interventions for COVID-19  of all studies had been reported in a preprint (Table n = 218) were directly published as journal articles. Among the 338 studies reported as preprints, 66 (20%) had then been published as journal articles. The median delay from publication of the first preprint version to publication of the associated journal article was 76 days (IQR 55–106)  did not intend to submit the preprint to a journal  had been submitted for publication, and 9 (3%) will be submitted. A small proportion of authors (n = 91) of preprints, > 1 version was uploaded to the preprint server , and 2% of journal articles had been updated .Regarding the update of evidence over time, for 27% (n = 63) of studies, we identified changes in at least one evidence component between or within evidence sources for the same study (Table n = 42) of studies had changes in study results and 24% (n = 33) had changes in the abstract conclusion. Regarding important changes in results , 21% (n = 29) of studies had important changes in study results  studies: 66 had a preprint and a journal article and 91 had > 1 preprint version . For 45% , the most common change was from positive without reporting uncertainty, to positive with reporting of uncertainty (n = 12). In terms of changes among positive, neutral, and negative, the most common changes were from neutral to positive (n = 6)  Fig. .Fig. 3Dn = 56) had been reported in a preprint, 25% (n = 14) had then been published as journal articles, and 36% (n = 31) were directly published as journal articles. The median delay from the publication of the first preprint version to publication of the associated journal article was 74 days (IQR 36–97). For 30% of preprints, > 1 version was uploaded to the preprint server . One journal article had been retracted and one had a published correction.There were 87 studies in the COVID-NMA subgroup, which consists of RCTs and observational studies included in the Cochrane living systematic review and is available online to support decision-makers. Overall, 64% . Five studies (20%) had changes in methodologic components that may affect risk of bias assessment and 8 (32%) had changes in the abstract conclusion.In total, 25 studies of the COVID-NMA subgroup had multiple evidence sources or multiple versions of the same source (Table n = 2); (2) reporting of additional information about the conduct of the study that indicates prevalent user bias (n = 1); and (3) addition or removal of information about allocation concealment in RCTs (n = 2).Finally, we identified the following changes that may affect risk of bias assessment: (1) addition of information about the propensity score model of non-randomized studies, such as additional confounders entered in the model, and specification of the propensity score being time-dependent . Of the total citations for each study, a median of 29% (IQR 14–50) was attributed to preprints.Usage data for preprint–journal article pairs are presented in Additional file n = 4, 6% for both preprints and articles). Furthermore, we examined the breakdown of the Altmetric Score for the 66 preprint–journal article pairs. Specifically, we examined their score in the Policy documents domain, which reflects the citations a report has received in policy documents. Of the 66 preprint–journal article pairs, 9 preprints (14%) and 10 articles (15%) had a score > 0 in the Policy documents domain .A similar proportion of preprints and articles had an Altmetric Attention score of 0 .This meta-research study showed that results for most studies assessing the effect of interventions for COVID-19 were initially disseminated in preprints, and the delay in publication of these results in journal articles takes 2 months. One-third of studies disseminated as preprints had at least one update since they first appeared online, with the addition of either more preprint versions or associated journal articles. Nearly half of these studies had changes in at least one important evidence component between or within evidence sources.Preprints make a vital contribution to the body of evidence on the effect of interventions for COVID-19. The delay between preprint publication and journal article publication is 76 days IQR 55–106); hence, for several months, preprints constitute the main source of evidence for a study. However, preprints constitute “living evidence” that is not stable. This flexibility allows researchers to keep up with evolving datasets  and disseminate findings from interim analyses. Therefore, it is possible to observe changes in the reported evidence among sources for the same study, even though both sources were accurate at the time of redaction. For example, the first version of a preprint may accurately report the findings of an interim analysis of an RCT, before participant enrollment has been completed. The final version of the preprint, reporting the analysis of the complete dataset could have a different sample size and different results. The flexibility of preprints also allows authors to correct potential errors in the report following crowd-sourced peer review . One consequence of this flexibility is that evidence changes can lead to misleading results of systematic reviews. Systematic reviewers need to be aware of updates in the evidence reported in preprints in order to update the review accordingly. One such example is the ELACOI RCT [6; hence,To our knowledge, only one other study assessed changes in preprint–article pairs of studies of COVID-19 of any design . The autOur findings point to a pressing need for systematic reviewers to monitor the literature for updates so as to use the latest evidence source for each study. This task is near impossible to perform manually  . DespiteThe large-scale use of preprints is a novel development for the biomedical sciences , and newThis is the first study to assess changes between evidence sources for studies evaluating interventions for COVID-19. First, we used a large database to capture all relevant evidence sources published during the first semester of the pandemic. Second, we assessed changes in important evidence components that may affect the results of systematic reviews and thereby affect decision-making. Third, we elicited information about the publication status of preprints by contacting authors. Finally, we designed an algorithm that links preprints to their associated journal articles and flags the appearance of new preprint versions.Our study has limitations. First, we extracted usage data soon after publication, and a different amount of time had elapsed from the publication of each study to retrieval of usage data. However, preprints tend to receive the majority of views near the time of upload on the server . AdditioThe results of studies assessing the effect of interventions for COVID-19 are often initially disseminated in preprints. The delay in publication of these results in journal articles was > 2 months, so preprints are a key evidence source for systematic reviews. Studies disseminated as preprints are often reported in multiple preprint versions and in associated journal article, and the evidence reported across these information sources is not stable over time. This situation could affect the results of systematic reviews and thus clinical and policy decision-making. Real-time linkage of all evidence sources for the same study is needed to avoid decision-making based on outdated evidence.Additional file 1: Methods S1-S3, Tables S1-S2, Figure S1. Methods S1. Search strategy used in the COVID-NMA database. Methods S2 – Email template used to contact preprint authors. Methods S3. Data extraction form. Table S1. Sensitivity analysis of change in evidence components using important change in study results. Table S2. Usage data for preprint–journal article pairs. Figure S1. Distribution of usage data in preprint-journal article pairs.


No difference in BAs concentration was observed between hypertensive and normotensive subjects. Total BAs and glycine conjugated BAs were significantly higher in participants with steatosis compared to those without (p = 0.004 for both). The values of total glycine-conjugate acids were positively correlated with cDC and this association remained significant in linear regression after adjusting for sex, age, pubertal stage, body mass index and aspartate aminotransferase. Conclusion. The results suggest a possible role of BAs in the pathogenesis of liver and/or vascular damage in children and adolescent. Further studies are hence needed to validate these preliminary findings.Background. Childhood obesity is becoming a major health issue and contributes to increasing the risk of cardiovascular disease in adulthood. Since dysregulated metabolism of bile acids (BAs) plays a role in progression of obesity-related disorders, including steatosis and hypertension, this study aimed to investigate BAs profiles in obese children with and without steatosis and hypertension, as well as exploring the interplay between BAs profile and vascular function. Methods. BAs concentrations were quantified with liquid chromatography-tandem mass spectrometry in 69 overweight/obese children and adolescents . Liver steatosis was defined with abdomen ultrasonography, whilst hypertension was defined according to the current European guidelines. Vascular function was assessed with ultrasound technique, by measuring carotid intima media thickness (cIMT) and common carotid artery distensibility (cDC). Results. Total and individual glycine-conjugated BAs concentrations were found to be significantly higher in males compared to females, as well as in pre-pubertal compared to pubertal stage ( The prevalence of overweight and obesity continues to increase worldwide, since these conditions represent one of the leading health issues in both childhood and adulthood ,2. OverwNon-alcoholic fatty liver disease (NAFLD), a definition which encompasses a broad spectrum of pathologies ranging from fatty liver alone to steatohepatitis with fibrosis and even cirrhosis, is increasingly found in obese children and adolescents, thus representing the most frequent form of chronic liver disease in this population . Nearly In light of all these considerations, the identification of biomarkers which could help accurately predicting the progression of these obesity-related disorders in childhood shall be seen as a primary healthcare goal.Primary bile acids (BAs), cholic acid (CA) and chenodeoxycholic acid (CDCA), are endogenous steroid molecules synthesized in the liver from cholesterol, and stored in gallbladder in conjugated form (with either taurine or glycine) for facilitating their water solubility . After nBAs are bioactive molecules which function by activating a family of receptors, known as bile acid-activated receptors (BARs), expressed throughout the body in many different cells. Although participation in digestion and absorption of dietary fats and liposoluble vitamins seems to be the main physiological role of BAs , severalDysregulated BAs metabolism is hence suggested to play a crucial role in the pathogenesis of dyslipidemia, fatty liver disease, diabetes, obesity, and atherosclerosis . Serum BWe then hypothesized that serum BAs could be differently represented in obese children according to the presence of steatosis or hypertension and could be associated with either blood pressure (BP) or vascular elasticity and morphology. Therefore, this exploratory study aimed to investigate BAs profile in obese children with and without obesity-related complications, as well as to explore the relation between BAs profile and markers of early atherosclerosisSixty-nine consecutive overweight/obese children and adolescents  were recruited from October 2012 to September 2014 from the “Paediatric Obesity Outpatients Unit” of the University Hospital of Verona and the “Local Health Unit n. 20” of Verona. Inclusion criteria were: age between 5–18 years; overweight or obesity  . The WHOExclusion criteria were hepatic or renal chronic diseases, malignancies, diabetes mellitus, lipid-lowering or antihypertensive therapy, and secondary causes of obesity. The study was approved by the Ethical Committee of the University Hospital of Verona , and written informed consent was obtained from all participants’ parents, in accordance with local laws and regulations.During the visit, BP was measured with a semiautomatic oscillometric device  3 times, 3 min apart with the patient lying supine for at least 10 min before the first measurement in a room with controlled temperature (22–24 °C). The mean value of 3 clinostatic measurements was calculated and considered for z-score and percentile calculation. BP levels were then confirmed with measurement in sitting position using an oscillometric device and auscultatory method. All values derived from BP measurements were transformed in z-score and percentile, according to normative values ,20. The The presence of significant liver steatosis was defined according to ultrasonographic characteristics by an experience sonographer using abdomen US . Diffuse liver hyperechogenicity relative to the kidneys, ultrasonography beam attenuation, or poor visualization of intrahepatic vessel borders and diaphragm were suggestive of hepatic steatosis ,22. AccocDC was calculated as: DC = ΔA/(A × ΔP), where A is the diastolic lumen area, ΔA is the stroke change in lumen area and ΔP is pulse pressure (PP). Changes in diameters were detected using ultrasound B-mode image sequences of right and left common carotid arteries acquired at different steps and analyzed with the aforementioned automatic system . The relFasting blood samples were collected in the morning, between 8:00 and 9:00 A.M. Subjects were asked to abstain from strenuous exercise and avoid consuming caffeine-containing beverages within the 12 h before visit and venous sampling. Laboratory measurements, including fasting plasma glucose (FPG), insulin, total cholesterol, high density lipoprotein (HDL)-cholesterol, triglycerides, AST, ALT and gamma-glutamyl transferase (GGT) were measured with standardized laboratory methods on routine clinical chemistry instrumentation .BAs concentrations were assayed in serum according to a previously published technique . BrieflySerum BA concentrations are reported as median and interquartile range (IQR). The concentrations of the parameters tested were compared with Wilcoxon–Mann Whitney U test. The Spearman coefficient (rs) was calculated for quantifying the correlation between variables. Multivariate linear regression models were performed for testing if the association between BAs and markers of vascular damage remained significant after adjusting for age, sex, pubertal stage, BMI and AST.p-values of <0.05 were considered statistically significant. The SPSS Statistics package 21.0.0  was used for all analyses.All statistical tests were two-tailed and The general characteristics of the 69 obese subjects included in this study are shown in Since the values of some BAs were below the limit of quantitation (LOQ) of the assay, BAs detected in less than 75% of the samples  were excluded from our statistical analysis. Of the 15 serum BAs, a final number of 12 , glycochenodeoxycholic acid—GCDCA, glycodeoxycholic acid—GDCA, glycoursodeoxycholic acid—GUDCA, taurocholic acid—TCA, taurodeoxycholic acid—TDCA, taurochenodeoxycholic acid—TCDCA, hyodeoxycholic acid—HDCA, and UDCA) could be accurately quantified and were hence included in our analysis.p = 0.005). All individual glycine-conjugated BAs  were also found to be higher in male than in female obese children/adolescents .As shown in p = 0.02 and p = 0.03, respectively).Total glycine-conjugated BAs concentrations and GCA levels were higher in pre-pubertal than in the pubertal subjects (No significant difference in BAs concentration could be found between hypertensive and normotensive obese children/adolescents .p = 0.004 for both)  detectable steatosis than in those without (or both) .p < 0.05 for all).Primary glycine-conjugated BAs concentrations (GCA and GCDCA) and primary taurine-conjugated cholic acid  were found to be higher in obese children/adolescents with steatosis than in those without  and between single or total BAs levels and age in the whole children population .p < 0.05), as well as between glycine-conjugated BAs and age , whilst no significant correlations were observed in girls.After stratifying the population by sex, a significant negative correlation was found in boys between total BAs and age , as well as between glycine-conjugated BAs and alanine aminotransferase (ALT) . All single glycine-conjugate BAs  were positively correlated with both AST and ALT .A significant positive correlation was found between glycine-conjugated BAs and aspartate aminotransferase (AST)  . This association remained statistically significant and in multivariate linear regression analysis after adjusting for sex, age, pubertal stage, BMI, and AST . Among single BAs, only GUDCA was positively correlated with cDC (both 10−3-Kpa and percentile)   (measured as 10 < 0.05) .p < 0.05, for GDCA; r = 0.27 and r = 0.25, p < 0.05, for TDCA). All these correlations were no longer significant, however, after adjusting for sex, age, pubertal stage, BMI, and AST (we excluded from the adjustment ALT and GGT because these variables were in multi-collinearity with AST).GDCA and TDCA values were positively correlated with carotid intima-media thickness (cIMT)   and taurine-conjugated BAs , seem to be significantly higher in children and adolescents with steatosis compared to those without. In particular, primary glycine conjugated BAs and primary taurine-conjugated cholic acid were found to be higher in young subjects with steatosis than in those without. Moreover, glycine-conjugated BAs were also found to be significantly correlated with AST and ALT, which are well-known markers of liver damage.2). Conjugated primary BAs (GCA and GCDCA) were found to be significantly higher in NASH and NAFLD patients than in healthy controls, especially in NASH.Similar changes in circulating BAs have been earlier described by Puri and colleagues  in 86 adThe increase of circulating levels of primary BAs and in particular conjugated primary BAs in children with steatosis may entail three different mechanisms, i.e., increased synthesis of primary BAs, decreased conversion to secondary BAs in the intestine or, finally, decreased bile excretion.Interestingly, Puri et al. analyzed the expression of cytochrome 7α1 hydroxylase (Cyp7A) , the enzIn favour of the third mechanism , comes the observation that increased glycine conjugated BAs concentrations , has been previously described in obstructive cholangiopathy and biliary atresia ,44. In tAnother important aspect to consider is that, compared with CDCA, CA and its conjugates exhibit an overall lower potency as farnesoid-x-receptor (FXR) agonist , which pThe increases concentration of CA and its conjugates in children with steatosis may hence ultimately foster insulin resistance, thus supporting the hypothesis that abnormal BAs profile may have a role in the pathogenesis and severity of liver disease starting from the childhood.Unexpectedly, we failed to observe a significant association between severity of obesity (assessed as BMI and waist/height ratio) and total BAs values or their profile. However, our results are in keeping with those reported by Higgins et al., in 30 obese and 15 normal weight children . In this−3-Kpa and percentile), a correlation that remained significant even after adjusting for sex, age, pubertal stage, BMI, and AST. Among the single BAs, GUDCA was positive correlated with cDC; GDCA and TDCA were also found to be positively correlated with cIMT, but these associations were no longer significant after adjusting for sex, age, pubertal stage, BMI, and AST.We have finally explored the effect of BAs on vascular elasticity and morphology, showing that total glycine-conjugate acids were positively correlated with cDC  and enhanced cIMT are considered suitable indicators of early subclinical atherosclerosis and future CVD ,53,54. S2+-activated K+ (BKCa) channels that regulate arterial tone and induces vessel relaxation [2+-antagonistic property. In another study, Khurana sand colleagues reported that deoxycholylglycine (DCG), a conjugated secondary bile acid, displayed vasodilatory effect in mice by impairing Ca2+ sensitivity of small resistance arteries and reducing Rho kinase activator (ROCK)-induced vasoconstriction, finally inhibiting ROCK activation as a consequence of attenuated RhoA membrane translocation [BAs, after intestinal metabolism by the microbiota, partly enter systemic circulation and reach a series of target organs other than the liver, where they act as natural ligands for several receptors. The two most important of such receptors are the G protein-coupled bile acid receptor 1 (GPBAR1) and the previously mentioned FXR, which are largely expressed in different cells . GPBAR1 is also expressed in vascular endothelial and smooth muscle cells, and this would suggest a role for this receptor in regulating systemic circulation . BAs alslaxation . In the laxation , the autlocation . Althouglocation , in somelocation .FXR ligands also play a role in inhibiting vascular smooth muscle cell inflammation and migration, thus reducing the atherosclerotic process . AlthougThe observation that BAs act as hormones by activating different receptors but also by activating receptor-independent cellular signalling cascades and regulating epigenetic machinery led to consider them as novel promising therapeutic agents in different diseases . Even ifThe present study has several limitations. First, only fasting BAs concentrations were measured in our study, and some components of BAs were under the LOQ. Second, due to the large number of investigations performed and to the difficulty of obtaining parental consent to carry out additional tests in children, the sample size was quite limited. Third, we did not have a population of healthy controls matched by sex and age and could not conduct a case-control study. Finally, the cross-sectional design of this study would not allow to infer any causal relationship between the measured variables.In conclusion, we observed significant differences in the circulating BAs profile in a group of obese children and adolescents, depending on sex, pubertal stage and presence of steatosis. An association between some BAs and vascular damage indices was also noted, thus paving the way to future studies aimed at reproducing and validating our preliminary findings.