macrolides are a group of antibiotics whose activity stems from the presence of the macrolide ring to which one or more deoxy sugars , usually cladinose and desosamine , may be attached . lactone rings are usually 14 , 15 or 16 membered . macrolides which tend to accumulate within leukocytes and are transported into the site of infection are used to treat respiratory and soft - tissue infections caused by gram - positive bacteria such as streptococcus pneumoniae and haemophilus influenzae . in addition to the typical antibiotic effect , two properties including the anti - inflammatory and the immunomodulatory actions are inherent in this group of drugs . these anti - inflammatory and immunomodulatory actions of macrolides encouraged a number of researchers to explore a potential application of macrolides even for respiratory viral infection [ 15 ] . the purpose of this paper is to summarize the properties of macrolides and their efficacy in a range of respiratory viral infection . we performed an electronic article search through pubmed using combinations of the following keywords : macrolides ( azithromycin , clarithromycin , dirithromycin , erythromycin , roxithromycin , and telithromycin ) and respiratory viral infection ( respiratory syncytial virus , rhinovirus , adenovirus , metapneumovirus , influenza virus , and parainfluenza virus ) . all types of articles such as randomized controlled trials , clinical observational cohort studies , review articles , and case reports were included . at present , macrolides are known to possess anti - inflammatory and immunomodulatory actions extending beyond their antibacterial activity in pulmonary inflammatory disorders such as diffuse panbronchiolitis ( dpb ) , asthma , and cystic fibrosis . both in vitro and in vivo data show macrolides to downregulate prolonged inflammatory response , reduce airway mucus secretion , inhibit the bacterial adhesion biofilm , reduce the production of reactive oxygen species , inhibit neutrophil activation and mobilization with an acceleration of the apoptotic process , and also block the activation of nuclear transcription factors [ 611 ] . after macrolides accumulating within cells , they may interact with receptors or second messengers responsible for the regulation of cell cycle and cellular immunity . however , the anti - inflammatory effects observed with macrolides are modest if compared to the anti - inflammatory effects of corticosteroids and require much higher doses , questioning their real use as an anti - inflammatory agent . as macrolides have anti - inflammatory and immunomodulatory effect , the scenario thus depicted is sufficiently suggestive to consider the possible use of these drugs in respiratory viral infection presenting an inflammatory basis . the common causes of respiratory viral infection include rhinovirus ( rv ) , respiratory syncytial virus ( rsv ) , adenovirus , metapneumovirus , influenza virus , and parainfluenza virus . recent studies have shown that the high mortality rate of respiratory virus infections is a result of an overactive inflammatory response . respiratory viral infections are characterized by the appearance of cytokine storms which is extreme production and secretion of numerous proinflammatory cytokines . severity of infection is closely related with virus - induced cytokine dysregulation which is responsible for the development of fatal clinical symptoms , such as massive pulmonary edema , acute bronchopneumonia , alveolar hemorrhage , reactive hemophagocytosis , and acute respiratory distress syndrome . numerous in vitro , in vivo , and clinical studies have established that viruses are potent inducers of various cytokines and chemokines including tnf- , interferon ( ifn)- , ifn-/ , il-6 , il-1 , mip ( macrophage inflammatory protein)-1 , mig ( monokine induced by ifn- ) , ip ( interferon - gamma - inducible protein)-10 , mcp ( monocyte chemoattractant protein)-1 , rantes , and il-8 [ 1217 ] . it is known that macrolides downregulate the inflammatory cascade , they attenuate excessive cytokine production in viral infections , and they may reduce virus - related exacerbation . furthermore , macrolides may influence phagocyte activity by modifying their miscellaneous functions including chemotaxis , phagocytosis , oxidative burst , bacterial killing , and cytokine production . it has also been reported that macrolides could interfere with the influenza virus replication cycle , resulting in the inhibition of virus production from infected cells , mainly by inhibiting intracellular hemagglutinin ha0 proteolysis [ 19 , 20 ] . the following review will introduce recent research findings regarding the effectiveness of macrolides antibiotic on different forms of respiratory viral infections ( table 1 ) . among in vitro , in vivo , and clinical studies , in vitro studies , especially cell culture studies , were most frequently performed to evaluate the effect of macrolides on respiratory viral infection . numerous in vitro studies with various respiratory virus revealed that macrolides are effective on respiratory viral infections . rv is the most common cause of viral upper respiratory tract infections ( uris ) and is responsible for about one half of all cases of the common cold . although rv does not cause necrosis of epithelial cells or substantial histological changes in nasal mucosa , rv infection induces the hypersecretion of mucus , as well as the increased expression and secretion of various cytokines , including interleukin ( il)-6 , il-8 , il-9 , il-1b , il-11 , and tnf- , and the influx of neutrophils , which correlate with the severity of cold symptoms [ 35 , 36 ] . it is well known that approximately 90% of more than 100 different rv serotypes bind to icam-1 , and rv infection upregulates icam-1 expression on airway epithelial cells , thus facilitating further viral attachment and entry [ 36 , 37 ] . as icam-1 is the receptor for the major rv and since il-1b , il-6 , and il-8 play significant roles in the pathophysiology of rv infection , macrolides which are known to have inhibitory effect on those cytokines may be able to modulate inflammatory processes during rv infection . studies have been done to determine anti - inflammatory properties of macrolide antibiotics against rv infection . among these macrolides , erythromycin is the first drug which was studied about their efficacy on rv . erythromycin is a macrolide antibiotic with potent anti - inflammatory effects that is used for treating chronic lower respiratory tract infections . examined the effects of erythromycin on rv ( rv2 and rv14 ) infection in airway epithelium . in their study , erythromycin reduced the supernatant rv14 titers , rv14 rna , the susceptibility to rv14 infection , and the production of icam-1 and cytokines which was upregulated by rv14 . erythromycin also reduced the supernatant rv2 titers , rv2 rna , the susceptibility to rv2 infection , and cytokine production , although the inhibitory effects of erythromycin on the expression of the low - density lipoprotein receptor , the minor rv receptor , were small . in addition , erythromycin may also modulate airway inflammation by reducing the production of proinflammatory cytokines and icam-1 induced by rv infection . erythromycin reduced the nf-b activation by rv14 and decreased the number of acidic endosomes in the epithelial cells . another type of macrolide antibiotics , bafilomycin a1 also inhibits infection of rv , in human airway epithelial cells by the reduction of icam-1 and by affecting the acidification of endosomes , where rv rna enters into the cytoplasm of infected cells . bafilomycin a1 and erythromycin could reduce proinflammatory cytokines including il-6 after rv infection in airway epithelial cells [ 22 , 38 ] . jang et al . investigated the effect of clarithromycin on rv infection in a549 cells . in their study , clarithromycin treatment inhibited the rv - induced increase in icam-1 mrna and protein , as well as the rv induced secretion of il-1 , il-6 , and il-8 . these effects were greater in cells treated with 10  m than in those treated with 100  m cm , and the maximum effect was observed 3 days after viral infection . in contrast , secretion of il-8 was not inhibited significantly when clarithromycin was added at the time of viral infection . in their study , rv titer , as measured by culture on mrc-5 cells , was reduced by clarithromycin , with the degree of reduction being greater when clarithromycin was added 3 days before infection than it was added at the time of infection . through these findings , they suggested that , in a549 cells , clarithromycin inhibits the induction of icam-1 expression , cytokine elaboration , and viral infection . wang et al . investigated the inhibitory effects of clarithromycin on secondary bacterial infection after rv infection . rv - induced uris may enhance secondary bacterial infections via upregulation of cell adhesion molecules in the nasal mucosa , leading to acute bacterial rhinosinusitis . staphylococcus aureus binds to human fibronectin ( fn ) and haemophilus influenza adheres to the carcinoembryonic antigen - related cell adhesion molecules ( ceacams ) of epithelial cells . in their study , clarithromycin treatment alone had no effect on the baseline levels of mrna and protein expression of fn and ceacam , but significantly reduced the rv - induced increases in the mrna and protein levels of fn and ceacam to the levels found in noninfected controls . they also demonstrated clarithromycin treatment - induced reduction of bacterial adhesion to rv - infected human nasal epithelial cells . thus , they suggested that clarithromycin may be effective at preventing secondary acute bacterial rs following rv infection . mucus with a high concentration of muc5ac or muc5b has a high viscosity and is likely to cause airway narrowing . muc5ac mrna expression was also attenuated by erythromycin treatment , suggesting that erythromycin affects pretranscriptional mechanisms . gielen et al . investigated the anti - rv ( rv 1b and rv16 ) potential of macrolides including azithromycin , erythromycin , and telithromycin , through the induction of antiviral gene mrna and protein . azithromycin , but not erythromycin or telithromycin , significantly increased rv 1b- and rv 16-induced ifns and ifn - stimulated gene mrna expression and protein production . furthermore , azithromycin significantly reduced rv replication and release . rv - induced il-6 and il-8 protein and mrna expressions were not significantly reduced by azithromycin before treatment . these results demonstrated that azithromycin has antirhinoviral activity in bronchial epithelial cells by increasing the production of ifn - stimulated genes . ex - vivo studies seem to indicate that short - term administration of macrolides may enhance the immune response , whereas long - term administration results in immunosuppression . rsv bronchiolitis is the most common lower respiratory tract infection in infancy , occurring in 90% of children of 2  yrs or under . development of an effective therapy against the short - term morbidity by rsv bronchiolitis could be important in reducing subsequent morbidity . rsv causes widespread damage to bronchial epithelium and stimulates epithelial cells to secrete a wide range of pro - inflammatory cytokines and chemokines . il-8 is a key chemokine produced by rsv - infected airway cells and is involved in the activation and recruitment of neutrophils . several reports showed that macrolide antibiotics may also modulate airway inflammation induced by rsv infection [ 2830 ] . suppressive effects of macrolides on the plasma il-4 , il-8 , and eotaxin levels may have a role in suppression of airway hyperresponsiveness or may inhibit cholinergic neuroeffector transmission in human airway smooth muscle , thereby influencing bronchial tone [ 31 , 3943 ] . macrolides attenuate the release of eotaxin , granulocyte - macrophage colony - stimulating factor ( gmcsf ) , and rantes . it may also protect epithelial cells at inflamed sites by inhibiting the release of reactive oxygen species from eosinophils [ 32 , 44 ] . in the rsv infection , rhoa , isoform a of the ras - homologus ( rho ) family , has various functions including stimulus - evoked cell adhesion and motility , enhancement of contractile response , and cytokine production . the activated form of rhoa moves to the cell membrane and is implicated in the rsv infection [ 30 , 45 , 46 ] . reported that bafilomycin a1 and clarithromycin inhibit infection by rsv and decrease the susceptibility of cultured human tracheal epithelial cells to rsv infection , partly through the reduced expression of activated rhoa which is an rsv f protein receptor . because activated rhoa interacts with the rsv f protein , these findings suggest that clarithromycin may inhibit rsv infection , partly through the reduction of activated rhoa in the cells . clarithromycin also reduced baseline and rsv infection - induced release of proinflammatory cytokines in supernatant fluids including il-1 , il-6 , and il-8 . it has been shown that viral titers in supernatant fluids and rna of rsv in the human tracheal epithelial cells increased with time , and clarithromycin reduced viral titers of rsv in supernatant fluids concentration - dependently , rna of rsv replication , and the susceptibility to rsv infection . human influenza virus infection causes rapid onset constitutional symptoms , including fever and lower respiratory tract symptoms , and also induces exacerbations of bronchial asthma and chronic obstructive pulmonary disease ( copd ) in the winter . human influenza viruses attach to sialic acid with an 2,6linkage ( sa2,6gal ) on the airway epithelial cells . the viruses are then delivered into the cytoplasm , and ribonucleoproteins ( rnps ) of viruses , which include viral rna , are released from acidic endosomes into the cytoplasm of the cells . there are several reports which showed the efficacy of macrolide antibiotics on influenza virus infection . miyamoto et al . showed the ability of clarithromycin in inhibition of human influenza a virus production in vitro at a middle - to - late stage of viral replication cycle . they found that treatment with clarithromycin at a final concentration of 25  g / ml had a strong inhibitory effect on plaque reduction of the tested human influenza a viruses . in addition to decrease of progeny virus production , clarithromycin decreased apoptotic cell numbers of infected host cells . these findings suggested that clarithromycin acts directly on virus - infected cells and contributes to the prevention of virus production by inhibiting viral replication in infected host cells . the influenza virus replication cycle can be divided into 5 steps : ( 1 ) binding of viral hemagglutinin to sialic acid receptor on host cell surface ( adsorption step ) , ( 2 ) internalization of virus by receptor - mediated endocytosis and fusion of viral ha2 with endosomal membranes triggered by influx of protons through m2 channel ( endocytosis and fusion step ) , ( 3 ) release of viral genes into the cytoplasm ( uncoating step ) , ( 4 ) packaging of viral proteins with viral genes after viral rna replication , transcription and translation , and budding of new viruses ( packaging and budding step ) , and ( 5 ) release of new viruses by sialidase cleaving sialic acid receptors ( release step ) . clarithromycin had no or little inhibitory effect on hemagglutination , hemolysis activity ( membrane fusion ) , and sialidase activity . these results suggest that decrease of progeny virus production is not due to inhibition of viral hemagglutinin and sialidase activities , which play an important role at the beginning and the end of viral replication , respectively . after clarithromycin was incubated with virus - infected cells at different times , it has been found that clarithromycin predominantly inhibited viral replication after viral adsorption to host cells at about the 47th hour . clarithromycin therefore might act on middle - to - late stage of viral replication cycle , presumably via blockage of producing viral protein . these findings strongly encourage the potential use of clarithromycin as an anti - influenza virus chemotherapeutic agent . there were several reports which evaluated the effects of macrolide on influenza - virus - induced respiratory infection . sato et al . evaluated the effects of erythromycin on influenza - virus - induced pneumonia in mice infected with a lethal dose of influenza virus a / kumamoto / y5/67 ( h2n2 ) . in their report , erythromycin may have substantial therapeutic value for various acute inflammatory disorders such as influenza - virus - induced pneumonia . the effects were by inhibiting inflammatory cell responses and suppressing nitric oxide ( no ) which plays critical role in the pathologic events of various inflammatory diseases , overproduced in the lung . regarding the no , erythromycin treatment resulted in a dose - dependent decrease in the level of nitrite / nitrate ( metabolites of no ) in the serum and the no - synthase-(nos- ) inducting potential in the lungs of the virus - infected mice . as a result , administration of erythromycin significantly improved the survival rate of mice infected with influenza virus , and the survival rate of the virus - infected mice increased in a dose - dependent fashion . it has also been found in their study that the induction of ifn- in the mouse lung was inhibited and the number of inflammatory cells after virus infection was significantly reduced by erythromycin treatment on day 6 after infection . in addition to being an antibiotic able to prevent complications and aggravation of symptoms , clarithromycin has been reported to alleviate pneumonia secondary to influenza virus infection in mice . in their study , clarithromycin has been shown to suppress the inflammatory cytokines such as tnf- , but augment il-12 production , resulting in alleviation of influenza infection itself in infected mice . these studies indicated that clarithromycin may play a role in vivo as an immunomodulator for influenza virus infection . the protective role of il-12 against influenza infection was assessed by analyzing the efficacies of orally administered clarithromycin as an immunomodulator and intranasal administration of recombinant il-12 in influenza - virus - infected mice . reported that , in infected mice , clarithromycin at 20  mg / mouse / day significantly elevated the levels of il-12 and ifn- in the bronchoalveolar lavage on days 2 and 3 , respectively , but the levels in the sera were not affected . in accordance with the locally elevated level of f il-12 , clarithromycin reduced virus yield and the number of infiltrated cells , the severity of pneumonia , and mortality of the treated mice . thus , the augmentation of il-12 production in the respiratory tract was essential in reducing virus yield in the early phase of influenza and may be crucial for recovery from influenza infection . there is another report which revealed the effect of macrolides on reducing the receptor for virus on the airway epithelial cells and reducing entry of virus into the cytoplasm . human seasonal influenza viruses and classical h1n1 swine influenza viruses bind to sa2,6gal , and most avian and equine viruses bind to sa2,3gal . clarithromycin reduced the expression of sa2,6gal , a receptor for human influenza , on the mucosal surface of human tracheae , and reduced the number of acidic endosomes from which viral rnps enter into the cytoplasm . these findings suggest that a clinically used clarithromycin may inhibit type a seasonal human influenza virus infection via reducing its receptor on the airway epithelial cells and reducing entry of viral rnps , into the cytoplasm . although the mechanisms for the reduction of sa2,6gal expression by clarithromycin are uncertain , these effects are similar to those of clarithromycin on the reduced expression of activated rhoa , one of receptors for rsv , and on inhibition of rsv infection . these effects are also similar to those of erythromycin on the reduced expression of icam-1 , a receptor for rv , and on inhibition of the rv infection . recently , yamaya et al . demonstrated that clarithromycin reduces flua viral titers and cytokines secretion in supernatant fluids and susceptibility of the cells to infection by the virus . although numerous in vivo studies have established that macrolides have inhibitory effects on respiratory viral infections , the outcomes of clinical studies are controversial and the clinical benefits of macrolides in respiratory virus infection are still uncertain . in in vitro study , jang et al . reported that clarithromycin inhibits the rv - induced induction of icam-1 expression , cytokine elaboration , and viral infection in a549 cells . however , there is a controversial report performed in a double - blinded clinical trial showing that clarithromycin treatment had little or no effect on the severity of cold symptoms or the intensity of neutrophilic nasal inflammation . those of the in vivo clinical trial may be due to differences in dosage or mode of treatment . for example , in the clinical trial , 1,000  mgday of clarithromycin , a higher dose than the 250  mgday usually used for low - dose , long - term treatment , was started 24  h before inoculation of rv . however , it was found that clarithromycin started 3 days before rv infection was more effective than clarithromycin started at the time of infection and that 10  m clarithromycin , the usual blood level in clinical use , was more effective than 100  m in reducing viral titer and cytokine secretion . ex vivo studies seem to indicate that short - term administration of macrolides may enhance the immune response , whereas long - term administration results in immunosuppression . however , other study described that short - term administration of a macrolide is not beneficial for acute uncomplicated colds caused by rv infection . severe rsv infections during early infancy are associated with the excessive production of th2 cytokines , which has been suggested as a risk factor for the later development of asthma and allergic sensitization . they regulate immunologic activities by enhancing production of ifn- and by reducing production of il-4 and il-5 . treatment that restores the th1/th2 cytokine balance to the relative type 1 predominance may ameliorate short- and long - term effects of rsv disease . studied the use of 3 weeks of macrolide therapy in the treatment of rsv bronchiolitis in a double - blind , randomized , placebo - controlled trial . in their study , treatment with clarithromycin daily for 3 weeks was associated with a statistically significant reduction in the length of hospital stay , the duration of need for supplemental oxygen , the need for 2-agonist treatment , and readmission to the hospital within 6 months after discharge . furthermore , there were significant decreases in plasma il-4 , il-8 , and eotaxin levels after 3 weeks of treatment with clarithromycin . as previously described , rsv is the leading cause of viral lower respiratory tract disease ( lrtd ) in infants and young children . in contrast to favorable effects of macrolides on rsv infection reported in number of papers , kneyber et al . , however , reported that the use of macrolide antibiotics would not lead to a reduced duration of hospitalization in mild - to - moderate rsv lrtd . in their study , azithromycin was not associated with a stronger resolution of clinical symptoms represented by the rsv symptom score . various inflammatory mediators are suggested to be associated with the pathogenesis and severity of influenza virus infection . increases in proinflammatory cytokines and monokines , including interleukin il-1 , il-6 , and il-8 , are observed in the serum in the patients and in the lung of mice infected with influenza virus [ 41 , 42 ] . although the clinical benefits of macrolides in influenza virus infection are still uncertain , reduction of proinflammatory cytokines by clarithromycin may modulate influenza - virus - induced inflammation and severity of the disease and may prevent copd exacerbations . clarithromycin inhibits the activation of nf-b , migration of neutrophils , and the production of proinflammatory cytokines by interfering with extracellular signal - regulated kinases . it also promotes the induction of siga and igg in the airway fluids of mice infected with influenza a virus . sawabuchi et al . investigated the immunomodulatory effects of clarithromycin on mucosal immune responses in the nasopharyngeal aspiration of pediatric patients with influenza . in their study , low induction of antiviral siga which represents the first immunological barrier to pathogens however , the addition of clarithromycin to oseltamivir augmented siga production and restored local mucosal siga levels , indicating that clarithromycin boosted the nasopharyngeal mucosal immune response in children presenting with influenza a , even in those treated with oseltamivir who had low production of mucosal anti - viral siga . they downregulate the inflammatory cascade , attenuate excessive cytokine production in viral infections , and they may reduce virus - related exacerbations . based on existing evidence , macrolides may be considered as promising treatment option in treatment of respiratory viral infections . however , confirmation in larger series , as well as identification of their precise mechanism affecting virus - induced inflammation or viral replicationn , is still awaited .
background . 
 macrolides have received considerable attention for their anti - inflammatory and immunomodulatory actions beyond the antibacterial effect . 
 these two properties may ensure some efficacy in a wide spectrum of respiratory viral infections . 
 we aimed to summarize the properties of macrolides and their efficacy in a range of respiratory viral infection . 
 methods . 
 a search of electronic journal articles through pubmed was performed using combinations of the following keywords including macrolides and respiratory viral infection . 
 results . both in vitro and in vivo studies 
 have provided evidence of their efficacy in respiratory viral infections including rhinovirus ( rv ) , respiratory syncytial virus ( rsv ) , and influenza virus . 
 much data showed that macrolides reduced viral titers of rv icam-1 , which is the receptor for rv , and rv infection - induced cytokines including il-1 , il-6 , il-8 , and tnf-. macrolides also reduced the release of proinflammatory cytokines which were induced by rsv infection , viral titers , rna of rsv replication , and the susceptibility to rsv infection partly through the reduced expression of activated rhoa which is an rsv receptor . 
 similar effects of macrolides on the influenza virus infection and augmentation of the il-12 by macrolides which is essential in reducing virus yield were revealed . 
 conclusion . 
 this paper provides an overview on the properties of macrolides and their efficacy in various respiratory diseases .