Azithromycin doesn’t prevent future wheezing in babies hospitalized with RSV

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The antibiotic azithromycin has anti-inflammatory properties that can be beneficial in some chronic lung diseases, such as cystic fibrosis. With that in mind, researchers investigated its potential to prevent future recurrent wheezing among infants hospitalized with respiratory syncytial virus (RSV).

With such babies at increased risk of developing asthma later in childhood, the scientists hoped to find a therapy to reduce this risk.

However, among infants hospitalized with RSV, there was no difference in the amount of wheezing in babies treated with azithromycin versus those who received a placebo, according to a new study led by researchers at Washington University School of Medicine in St. Louis and Vanderbilt University.

Further, while the difference in the amount of wheezing did not reach statistical significance, the study hints that treatment with antibiotics of any kind may increase wheezing in infants hospitalized with the virus.

Results of the study were presented Feb. 27 at the annual meeting of the American Academy of Allergy, Asthma & Immunology in Phoenix and published simultaneously in The New England Journal of Medicine – Evidence.

In infants and young children, RSV can cause bronchiolitis, an infection of the small airways in the lungs. Nearly all children contract RSV at some point in early childhood, and a small percentage develop bronchiolitis severe enough to be hospitalized. Infants hospitalized with RSV bronchiolitis are at an increased risk of developing asthma.

“About half of infants admitted to a hospital with RSV will be diagnosed with asthma by age 7,” said first author Avraham Beigelman, MD, an associate professor of pediatrics and a pediatric allergist and immunologist in the Division of Allergy & Pulmonary Medicine in the Department of Pediatrics at Washington University School of Medicine. “We are interested in finding approaches to prevent the development of asthma after RSV infection. Azithromycin has anti-inflammatory effects in other airway diseases, such as cystic fibrosis. We also had data in mice and data from a smaller clinical trial of hospitalized infants that suggested azithromycin reduced wheezing following RSV infection. So, we were surprised by the negative results of this larger trial.”

The current trial confirmed, as anticipated, that azithromycin lowers a marker of airway inflammation called IL-8. Infants treated with azithromycin had lower levels of IL-8 in their noses than infants who received a placebo, confirming anti-inflammatory effects of azithromycin.

Even so, azithromycin-treated patients did not have reduced risk of developing recurrent wheezing compared with the placebo group. While the difference did not reach statistical significance, the data actually leaned toward azithromycin increasing risk of wheezing, with 47% of patients who had received azithromycin experiencing recurrent wheezing versus 36% of the placebo group. Recurrent wheezing was defined as three episodes of wheezing during the two to four years of follow up.

With parental permission, the researchers randomly assigned 200 infants hospitalized at St. Louis Children’s Hospital for RSV bronchiolitis to receive either oral azithromycin or a placebo for two weeks. The babies were otherwise healthy and ranged in age from 1 month to 18 months.

The researchers received approval from the Food and Drug Administration (FDA) to give infants azithromycin as part of this clinical trial. Azithromycin is a commonly prescribed antibiotic used in children age 2 and older.

Patients were enrolled during three consecutive RSV seasons, from 2016 to 2019, and were followed for two to four years after hospitalization. The researchers also kept track of whether the infants received any other antibiotics before or during their hospital stays.

A child’s pediatrician could choose to prescribe other antibiotics if, for example, the child also developed an ear infection or was suspected of developing bacterial pneumonia or other bacterial infection. Amoxicillin was the most common additional antibiotic prescribed.

While the study was not designed to parse the effects of different combinations of antibiotics, Beigelman said they found evidence suggesting that azithromycin alone—among patients who did not receive any other antibiotics – could increase the risk of recurrent wheezing. The researchers also found a suggestion of increased recurrent wheezing risk among patients who had received any antibiotic (such as amoxicillin from the pediatrician).

“There may be an increase in risk of recurrent wheezing with any antibiotic use,” Beigelman said. “We want to be cautious in our interpretation of this potentially negative effect of antibiotics, as the study was not designed to test the effects of different antibiotics. However, this is an important message to be communicated to pediatricians, since antibiotics are frequently given to patients with RSV bronchiolitis despite the fact that this practice is not supported by clinical guidelines. At the very least, azithromycin and antibiotics in general have no benefit in preventing recurrent wheeze, and there is a possibility they are harmful.”

Beigelman said the researchers also collected airway microbiome samples from these patients and plan to investigate whether bacteria colonizing the airway may interact with the antibiotics and have an impact on wheezing. They also plan to analyze stool samples collected from the same infants to see whether the gut microbiome may have a role in wheezing and the subsequent risk of developing asthma in childhood.


Since its discovery in 1956, respiratory syncytial virus (RSV) has become recognized as a leading global cause of morbidity and mortality, especially amongst infants in the first six months life. RSV is the commonest cause of childhood acute respiratory infection (ARI) and the major single cause of hospitalization during infancy. In recent decades, it has been realized that it also afflicts various at-risk adults, including frail elderly and

immunocompromised persons. In resource-poor settings, it is an important cause of death due to due to lower respiratory tract infection, second only to pneumococcal pneumonia and H. influenzae type B. Resource-limited countries have more than twice the incidence severe disease seen in developed countries and, remarkably, 99% of the global deaths caused by RSV infection (1).
Given this appalling disease toll and the fact that current treatment is simply supportive, it is clear that prevention, early diagnosis and the discovery of specific therapies has enormous potential to improve global health amongst the most vulnerable in society. RSV remains one of the last major viruses for which we currently (in early 2016) have no safe and effective vaccine.

Not only does RSV cause acute disease, but those with severe infections can apparently be left with long term sequelae. These include persistent wheeze and in some cases established inflammatory airway disease (2,3), highlighting the importance of understanding which immune responses correlate with protection and what makes some individuals at risk of severe or delayed disease. Molecular techniques such as real time PCR (qPCR) have now become more affordable and offer rapid and accurate diagnostics, with the ability to identify the disease earlier in at-risk patients, at levels of viral burden too low for conventional detection and affording the potential for community-based epidemiology (4,5). Intensive research in recent decades has accelerated progress on many fronts, with several promising new vaccines in advanced stages of development (6,7). In countries with limited access to healthcare, an effective and affordable vaccine would be transformative.

EPIDEMIOLOGY
RSV causes significant morbidity and mortality across the globe and is the leading cause of pneumonia and bronchiolitis in infants. In addition to a currently poorly quantified burden in the elderly, it is estimated to cause 30 million acute respiratory infections and more than 60,000 childhood deaths worldwide each year (1,8). The main burden of disease is in the under 5 age group but RSV has considerable impact on various at risk adult populations (9,10). In the USA, RSV is estimated to cause 17,358 deaths per year, 22 % of which are in persons less than 65 years of age (11).
Seasonality
Seasonality of RSV infection varies across the globe. Temperate zones tend to experience RSV epidemics during late autumn, winter and/or spring (12) whereas tropical and arctic climates see less well defined annual variation with year-round disease described in some settings (13). In northern tropical areas the seasonality is associated with a decrease in temperature and increase in rainfall, whereas in more tropical climates yearly outbreaks can occur during the warm and rainy seasons (see figure 1) (14,15).
In Europe, RSV is predominantly a disease of winter with peaks of illness in December and January in the United Kingdom, Belgium, Germany and the Netherlands with a later peak of March in Mediterranean countries such as Greece (16,17); biennial cycles of RSV activity have been described in northern Europe (15).

The association of an increase in RSV cases with declining temperatures has been attributed to increased indoor crowding leading to enhanced viral transmission, to lower temperatures increasing viral stability and to chilling increasing host susceptibility or activation of dormant virus (18).

Figure 1. Annual cycle of global peak RSV incidence and associated climactic factors. Temperate countries typically have peak incidence of RSV during their winter months, which are associated with lower temperatures, higher rainfall and higher humidity. There is greater variability in tropical regions, which are prone to biennial and perennial RSV. Limited information is available for some regions, e.g. Africa. Data from [12–15].

Infants and Children
Pneumonia is the leading cause of mortality of children worldwide with RSV being the commonest single cause of acute respiratory infection (ARI) in young children (8,19). By 18 months of age, 87% of children have antibodies to RSV and by the age of 3 years, virtually all children have been infected (20).
A large meta-analysis estimated there to be 33.8 million cases of RSV associated ARI worldwide in 2005 in children less than 5 years of age but this is likely to be an underestimate; previous studies using active methods for data collection, such as home visits, have shown much higher incidence rates (1). In the USA, RSV has been estimated to account for 20% of acute respiratory infection hospitalisations in children under 5 (17 per 1000 children under 6 months and 3 per 1000 under 5) but 99% of RSV deaths occur in low-income countries with a lack of access to basic, supportive care being a key factor (1,8). Children are at highest risk of death in the first 6 months of life (11).
The majority of children suffering from RSV ARI have no underlying comorbidities. Low birth weight and prematurity are major risk factors for hospitalisation, as is congenital or acquired immunodeficiency and various cardiopulmonary, chronic lung disease and neurodevelopmental disorders (21,22). Environmental factors contributing to increased susceptibility are side-stream tobacco smoke exposure, lack of breastfeeding and low socioeconomic status (23).
Adults and Elder Persons
There remains no globally accepted definition or reliable classification of acute respiratory infection, making it difficult to compare studies and to make accurate estimates of disease burden. Adding to these problems, variations in sampling methodology and diagnostic testing across studies provides further hurdles. With major differences in healthcare provision and access to resources in different geographical and socioeconomic settings, it is difficult to estimate the true impact of RSV disease in diverse settings. Despite these caveats, we can state with reasonable certainty that it is rare for healthy immunocompetent adults to require hospitalisation due to RSV infection.
However, infection with RSV is so prevalent that it is estimated to cause a disease burden at least comparable to influenza in elderly persons (24). Given the aging population structure in Western countries, adult RSV-associated mortality is becoming an ever greater problem that poses a huge health and economic burden (9,11). A recent north- American study examined the impact of RSV during four consecutive winters amongst healthy elderly patients (n=608), high-risk adults (those with chronic heart or lung disease, n= 540) and patients hospitalised with acute respiratory illness (n=1388). The average age across all groups was more than 70 years; RSV infection developed annually in 3–7% of healthy elderly patients, 4–10% of high-risk adults and was present in 8–13% of patients hospitalised with acute respiratory infection. During the study period, RSV infection accounted for 11 % of hospitalizations for pneumonia, 11 % for chronic obstructive pulmonary disease (COPD), 5 % for congestive heart failure, and 7 % for asthma (10). In the UK, it is estimated that amongst the adult population, those over the age of 65 account for 36 % of GP episodes, 79% of hospitalisations and 93% of deaths due to RSV each season and RSV was responsible for more morbidity than influenza (24).
Globally, RSV accounts for 7.4% of elderly (>65 years) individuals presenting with influenza-like-illness (25).

The Immunocompromised

In both children and adults, various immunodeficiency states predispose to RSV infection and disease. In addition to HIV-infected children being liable to develop RSV-ARI, they are 3.5 times more likely to be hospitalized than non HIV infected children (21), are more likely to present with pneumonia, have greater evidence of bacterial co-infection and higher mortality rates than HIV-uninfected children (26).

RSV is a common cause of ARI in haematopoietic stem cell transplant (HSCT) patients, with rates of infection being as high as 2–17% in some settings. As well as increased susceptibility to infection, these patients are also liable to progress to more severe disease. RSV pneumonia in this patient group has a mortality of up to 83% (27).

Factors linked to severity and poor outcome include male sex, the type of graft (allogeneic), myeloablative regimen, cytomegalovirus seropositivity, increasing age, unrelated donor transplant, graft-versus-host disease (GVHD) and becoming infected within the first 3 months of transplant (28).

Figure 2. Diagrammatic cross-section through an infectious RSV filament. ss: single-stranded.

IMMUNE RESPONSE

As described previously, virtually all children have been infected by the age of 2; most immunocompetent children clear the infection within 3 weeks (59). Some infants are predisposed to more severe infection and those infected in the first 6 months are subsequently prone to wheeze until at least 6 years of age (3), and possibly through to adulthood (2).
Early Immune Responses
The recognition of pathogen-associated molecular patterns (PAMPs) present on viruses by pattern recognition receptors (PRRS) such as Toll-like receptors (TLRs) and RNA- sensing RIG-I– like receptors (RLRs) leads to the release of antimicrobial mediators by the host mucosal immune system and serves to form an effective first line of resistance against infection. Type 1 responses are characterized by release of type I IFNs (IFN-α and IFN-β) and Type III IFNs (IFN-λ1, IFN-λ2, IFN-λ3(60)). These are potent antiviral mediators induced early in infection from epithelial cells and resident immune cells with alveolar macrophages recently being discovered in a murine model to be major contributors to IFN production leading to the subsequent recruitment of inflammatory monocytes to the lungs (61).

Dendritic cells are also key to bridging innate and adaptive responses by transporting viral antigens to cervical and pulmonary lymph nodes and presenting them to CD4+ T-cells, which in turn activates CD8+ T-cells and B-lymphocytes. They return to the site of infection to further promote local induction of pro-inflammatory mediators and cellular efflux (62).
There is debate about whether defective or exuberant immune responses are responsible for the infection spreading from a limited mucosal infection (in most people) to more extensive lung immunopathology or even extrapulmonary manifestations (in susceptible individuals) (63–65). An insufficient type 1 response as well as exaggerated type 2 responses (characterised by IL-4, IL-5 and IL-13) have been implicated in causing susceptibility to RSV bronchiolitis (66,67) and an inability to produce sufficient IFN-γ early in life may increase risk of developing severe disease (68). Gene polymorphisms of TLR4, IL-4 receptor α and IL-8 have also been associated with severe RSV bronchiolitis, highlighting the important role of innate immunity, although their biological role in active disease is yet to be fully understood (69–71).
The naieve immune system of infants is characeterized by hyporesponsiveness to infections and viral mimetic stimuli in vitro when compared to adults (64,72) with premature infants of less than 35 weeks gestational age being at the highest risk due to compromised pulmonary development and deficient serum immunoglobulins (73). In term infants, maternal specific RSV-neutralizing antibodies are present from the third trimester and are stable until birth, with higher cord blood levels being protective against RSV infection although only protective for the first 6 months of life (74).
Established Infection, Reinfection and Resolution
Once infection is established, cellular immunity and immunoregulation plays a critical role in promoting viral clearance and limiting pathology, which is clearly demonstrated in paediatric patients with primary or acquired immunodeficiency who have a much longer duration of infection and can shed virus for several months (75,76). Classically, helper T cells that make interferon gamma (Th1 Cells) are important in antiviral defense, but it is possible that other helper T cell subsets contribute towards eliminating the virus (77). In
particular, IL-10 producing cells inhibit disease and inflammation in mice infected with RSV, especially during recovery (78). Cytotoxic CD8+ lymphocytes (CTLs) may cause neutrophil efflux (79,80) whilst more abundant airway resident memory T cells (Trm) at
baseline correlate with reduced viral load and symptoms during experimental human adult infection (81). Interestingly, virus and T cell inflammation may remain present in asymptomatic convalescent volunteers in this model (81). Certain macrophage subtypes (M2) and pDCs likely play an important role in modulating local immune responses and restricting T cell-mediated inflammation (82,83). The ability of RSV to re-infect may also be explained by defective RSV-specific IgA memory B cell responses (84,85). Some individuals suffer dual infection with RSV and other viruses, which can lead to greater severity of disease and is associated with decreased IFN-γ responses (86).

It is thought that the increased susceptibility and severity of RSV in the elderly is secondary to immunosenescence, but how this occurs has not been fully defined. It has been shown that elderly and younger individuals have comparable RSV neutralization antibody titres, but there may be an impairment of T cell mediated immunity (87,88). Studies of RSV disease in mice indicate the importance of regulatory T cells (Treg) in maintaining an effective and non-pathogenic response to RSV infection, and have highlighted the dysregulation of immune responses that are characteristic of bronchiolitis (89).

CLINICAL MANIFESTATIONS
Acute Presentation in Children
RSV infection in children can result in a range of disease phenotypes from mild upper respiratory tract symptoms to life-threatening lower airway involvement necessitating hospital admission and mechanical ventilation. Infants are at greater risk from RSV infection than older children with an increased likelihood of lower airway involvement in the form of both bronchiolitis and pneumonia (1).
Clinical presentation of RSV often begins with typical upper respiratory tract signs and symptoms including coryza, cough and a febrile illness (90). On examination, a rhinitis and pharyngitis may be seen in association with conjunctival signs and erythema to the tympanic membrane (64). Less frequently bulging of the tympanic membrane may be seen if otitis media is also present. Nasal congestion and generalised malaise can lead to poor feeding and subsequently dehydration (64).

In approximately one third of infants with viral respiratory infections, progression to lower respiratory tract involvement is observed (64), most commonly in the form of bronchiolitis although pneumonia and laryngotracheitis (croup) can also develop (91). Bronchiolitis presents as worsening respiratory function with tachypnoea, wheeze and noisy breathing, as well as systemic viral features such as fever and lethargy (90,91). Some infants develop vomiting and poor feeding with dehydration (64).

In young infants apnoea has also been described (92) and indeed may be the presenting symptom early in the disease. Signs of respiratory distress including nasal flaring, costal and intercostal recession and cyanosis, should be assessed for by clinicians in determining the need for admission to hospital in addition to other markers of disease severity including hydration status and level of alertness. Polyphonic expiratory wheeze and fine crepitations made be heard on auscultation of the chest (91). According to current guidelines, chest radiographs are not routinely performed in children with simple bronchiolitis but may show features of hyper-expansion including increased anterior-posterior diameter and diaphragmatic flattening as well as patchy bilateral infiltrates and atelectasis (figure 3) (90,93). Pneumonia with consolidation seen on chest x-ray can be due to the virus itself or a secondary bacterial infection. Extra-pulmonary manifestations of RSV are uncommon but have been described and include seizures, hyponatraemia, cardiac arrhythmia and failure and hepatitis (65).

Figure 3. Chest radiograph of a 3-month-old infant with severe RSV bronchiolitis. demonstrating a collapsed right upper lobe, hyperinflated left lung and bilateral perihilar, peribronchial thickening. The patient is intubated and has a nasogastric tube in situ.

The differential diagnosis for children presenting with signs and symptoms of lower and upper respiratory infection includes other viral infections such as rhinovirus, metapneumovirus and influenza, primary bacterial pneumonia, congenital conditions such as cystic fibrosis, asthma and inhaled foreign bodies.

Longer Term Complications in Children
In addition to the significant health burden of acute RSV infection, there is evidence of longer term consequences to respiratory function with the development of persistent airway disease. Although a causal relationship remains unclear, an association between RSV infection as an infant and subsequent wheezing, allergy and asthma, sometimes persisting into adulthood, has been demonstrated (2,90,94).
Several longitudinal cohort studies have tracked the incidence of respiratory illness in children with RSV infection in infancy. The Tuscon Children’s Respiratory Study examined outcomes in children with clinician confirmed RSV lower respiratory tract

infection (as defined by the presence of cough, wheeze, breathlessness, hoarseness or stridor, in the presence of an RSV positive diagnostic test) contracted up to the age of three years. They reported an increased prevalence of wheeze in these children up to the age of 11 and persistently impaired lung function until age 13 (95). Sigurs and colleagues investigated a more severely affected group of children who had been hospitalized with RSV lower respiratory tract infection in the first year of life. Their findings correlated with those seen in the less severely affected children; with an increased prevalence of asthma/ recurrent wheeze as well as atopy and clinical allergy which persisted throughout childhood (2). Indeed the data collected from these participants at age 18 continued to show differences between healthy controls and affected individuals both in the relative rates of allergy, asthma and recurrent wheeze as well as abnormalities in lung function.
They postulated that persistent clinical and lung function abnormalities represent the consequences of airway remodelling stimulated by early RSV infection. The potential pathogenic mechanisms for this remain unclear although impaired T-regulatory function, persistent activation of innate immunity and an early Th2 helper switch have been implicated (96).
Debate remains as to the extent which early RSV infection is causal of later airway disease, by altering immune responses and subsequent airway maturation, or whether children with a predisposition to wheeze and asthma are more likely to develop severe RSV infection. To address this question, a double-blind placebo controlled trial was designed to investigate if prevention of RSV, using the monoclonal antibody palivizumab during RSV season, would impact on subsequent rates of wheeze. The results demonstrated a substantial reduction in episodes wheeze for up to one year in healthy preterm babies in the treatment group compared to those in the placebo group (97). Of note, the effect of palivizumab on wheeze reduction persisted even after treatment had been stopped and RSV season was complete, suggesting that wheeze reduction was not simply attributable to fewer acute RSV episodes. The authors thus argue their findings support the concept of RSV as a pathogenic stimulus in the development of recurrent wheeze. They postulate that epithelial damage from RSV infection alters local pulmonary immune responses resulting in airway hyper-responsiveness. However, the testing of a high-potency derivative of palivizumab (motavizumab) showed no such effect in term babies, despite a substantial reduction in hospital admissions and non-inferiority compared to palivizumab (98,99).
The reasons for the disparity between these two monoclonal drugs are unclear and may simply be evidence against a direct causal relationship between RSV and subsequent wheeze. Another possible explanation lies in the differences between the study populations; with the palivizumab study investigating outcomes in preterm babies and based on parent-reported episodes of wheeze whereas the motavizumab study examined healthy term infants and relied on medically attended wheezing episodes (99).

reference link : https://library.oapen.org/bitstream/handle/20.500.12657/47857/Bookshelf_NBK442240.pdf;jsessionid=A0548D5E4AB27604490DB3CBC028DC08?sequence=1


More information: Beigelman A et al. Azithromycin to prevent recurrent wheeze following severe RSV bronchiolitis. The New England Journal of Medicine – Evidence. Feb. 27, 2022.

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