Infection induced asthma

Infection induced asthma DEFAULT

Infection Related Asthma

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The Relationship Between Colds and Asthma

Colds and asthma are both characterized by inflammation of the airways and have a complicated, two-way-street effect on the lungs. Even if asthma is well-controlled with daily medications, a cold can trigger an attack in some people. On the flip side, asthma can increase vulnerability to colds and other respiratory tract infections.

When a cold triggers an asthma attack, it is typically referred to as viral-induced asthma. Having a cold and asthma together can make asthma symptoms harder to control or turn an otherwise mild respiratory infection into a serious medical event.

It is important that people living with asthma do their best to avoid colds and to be compliant in taking medications that reduce airway hyperresponsiveness and control asthma symptoms.

Viral-induced asthma is common, affecting roughly 85% of children and 50% of adults with asthma. It is not the same as cold-induced asthma, in which an attack is triggered by inhaling cold air.

7 Things Everyone With Asthma Needs to Know

Susceptibility to Colds

Poorly controlled asthma can permanently damage the lining of the airways (a process known as progressive remodelling) by exposing them to persistently high levels of inflammation. Over time, this can cause the airways to thicken and lose their flexibility while increasing their susceptibility to respiratory infections.

Scientists are not entirely sure why this is, but some contend remodeling of airways blunts the local immune response. Research suggests damaged epithelial cells lining the airways are less able to produce interferon-beta (IF-β), a type of inflammatory compound called a cytokine that exerts strong antiviral activity.

Others believe that asthma, a disease characterized by an abnormal immune response, simply affects how the immune system responds to certain viral infections. Genetics may also play a part.

But while managing asthma with medication can help temper inflammation that can increase susceptibility to colds, certain medications that can help control asthma—like inhaled steroids—can suppress the immune system. And if you get sick, this can increase the risk of a secondary pneumonia infection.

Risk Factors for an Asthma Attack

Inflammation and Your Lungs

A garden-variety cold is caused by any one of over 200 viral strains, the most common of which are rhinoviruses, followed by coronaviruses, influenza viruses, adenoviruses, and respiratory syncytial virus (RSV).

When a respiratory infection occurs, the immune system responds by releasing cytokines that draw defensive white blood cells to the site of the infection. (This includes a type of white blood cell known as an eosinophil commonly seen in allergic asthma.)

Many of these cytokines—most especially interleukin types 4, 5, 9, 10, 11, and 13—are responsible for triggering airway hyper-responsiveness and bronchoconstriction in people with asthma. In essence, the inflammation caused by a cold can "spill over" to the lower respiratory tract and instigate an attack.

Research also suggests that antigens on certain respiratory viruses can trigger an allergic response in people with asthma. Antigens are the proteins of the surface of cells that the immune system reacts to. In some cases, the antigen will spur allergic inflammation that only adds to the burden of viral inflammation.

Although viral-induced asthma has long been considered separate from allergic asthma, evidence suggests that viral-induced asthma can affect people with allergic and non-allergic forms of the disease, including exercise-induced asthma and eosinophilic asthma.

This dual source of inflammation may explain why certain people are more prone to viral-induced asthma than others.

Colds, even recurrent colds, do not "cause" asthma. With that said, children under 2 who experience a severe respiratory infection are more likely to develop asthma than those who do not.

Symptoms of Viral-Induced Asthma

Given that colds affect every part of the upper respiratory tract—from the nasal passages to the larynx (voice box)—and asthma affects every part of the lower respiratory tract from the larynx to the lungs, the symptoms of each are relatively distinctive and easy to differentiate when one of the conditions occurs on its own.

While there is some overlap—such as with cough and breathing difficulties—cold symptoms are generally centered around the nose and throat, while asthma symptoms come more from the chest.

Common Cold Asthma Attacks
Breathing problemsCommon, usually mild with nasal and sinus congestionCommon, usually severe with shortness of breath, wheezing, and difficulty breathing
CoughCommon, sometimes with phlegmCommon, often dry (hacking) but occasionally wet (with phlegm)
Nasal problemsCommon, including runny nose, sneezing, post-nasal drip, and congestionNo
Throat painCommon, usually with mild sore throatCommon, including throat tightness, hoarseness, or irritation 
FeverCommon, usually mildUncommon
Body achesCommon, usually mild muscle and joint achesNo
Chest painOccasional, mostly due to prolonged coughingCommon, including chest pain and tightness

The same may not be said if a cold and asthma co-occur. With viral-induced asthma, the symptoms of a cold typically precede an asthma attack and eventually involve both the upper and lower respiratory tract.

What this means is that the sneezing, coughing, headache, and nasal congestion characteristic of a cold will be followed by the wheezing, shortness of breath, and chest pain characteristic of asthma. And if a cold develops rapidly, the cascade of symptoms may occur all at once.

With viral-induced asthma, there may also be symptoms less commonly seen with either disease, including high fever and chills. This typically happens if there is a secondary infection of the lungs, including bacterial pneumonia.


The overlap of symptoms in people with viral-induced asthma can make diagnosis difficult. While classic cold symptoms are easily recognized by healthcare providers, the co-occurrence of wheezing, shortness of breath, and chest pains can often suggest other diseases, including severe bronchitis or pneumonia.

The diagnosis of viral-induced asthma requires a thorough review of your symptoms and medical history along with a physical exam and other diagnostic tests.

Diagnostic Work-Up

Diagnosing viral-induced asthma typically requires some detective work. As part of the diagnostic work-up, the healthcare provider will want to know:

  • Preceding and current symptoms
  • The progression of symptoms (i.e., which came first)
  • Your history of respiratory infections
  • Your family history of chronic respiratory illnesses
  • Any chronic illnesses you have (such as COPD or congestive heart failure)
  • Your smoking history

Your healthcare provider may also take the time of year into consideration. For example, respiratory infections occurring in early fall are more likely due to a rhinovirus, while those occurring in winter are more likely due to influenza or RSV. These factors, along with age, can make a difference in how your condition is treated.

A physical exam would include an evaluation of breathing sounds (including crackles, rales, vibrations, or wheezing), abnormalities of which can point the healthcare provider in the direction of the likely cause. With asthma, wheezing is considered one of the defining features of the disease. Any accompanying sounds may suggest which type of virus is involved.

Lab and Imaging Tests

If the symptoms are severe and abnormal breathing sounds are detected, your healthcare provider may order blood tests to investigate whether viral pneumonia, RSV, or influenza is involved. (Blood tests for rhinovirus or adenovirus are also available, but are less commonly used because there are no direct treatments for either.)

If a bacterial infection is suspected, a throat swab or sputum culture may be performed.

The healthcare provider may also order a chest X-ray or a computed tomography (CT) scan to check if there is evidence of pneumonia or other lung abnormalities.

In emergency situations, pulse oximetry or an arterial blood gas (ABG) test will be used to see if blood oxygen levels are low. Other pulmonary function tests (PFTs) may be performed to evaluate how well your lungs are functioning during and after an acute attack.

Allergen testing may be useful in diagnosing allergic asthma, but it does not necessarily exclude viral-induced asthma as a cause.

Even if a respiratory virus cannot be identified, the co-occurrence of a respiratory infection with a reduced forced expiratory volume (FEV1) of 20% or more is strongly suggestive of viral-induced asthma, particularly in people with well-controlled disease.

Given that viral-induced asthma is as common as it is, findings like these will often warrant treatment even if the viral culprit is not identified.

How Allergies and Asthma Are Connected


Because cytokines induced by a virus are produced independently of those induced by asthma, asthma medications will never fully prevent or relieve asthma symptoms induced by a cold.

Until the trigger (in this case, the cold) is fully resolved, breathing difficulties may persist as inflammation from the upper respiratory tract "fuels" inflammation in the lower respiratory tract, and vice versa.

This is especially true when eosinophils are produced in excess. This can lead to a condition known as eosinophilia in which the accumulation of eosinophils causes inflammatory damage to the airways. It is this sort of damage that can increase the risk of severe illness, including pneumonia, in people with viral-induced asthma.


If a cold is a trigger for an attack, the resolution of the infection (which usually happens within two weeks) will usually improve breathing problems as well.

Still, the standard treatment of a cold or flu should be accompanied by the appropriate use of asthma medications. This may include the increased use of a short-acting beta-agonist (also known as a rescue inhaler).

Cold Treatment
  • Symptoms may be managed with decongestants, cough formula, antihistamine, and nonsteroidal anti-inflammatory drugs.

  • Nasal washing may help clear mucus build-up.

  • Flu may be shortened with the early use of antiviral drugs like Tamiflu (oseltamivir) and plenty of bed rest.

According to the National Heart, Lung, and Blood Institute, a short-acting beta-agonist like albuterol can be used every four to six hours during a cold to reduce the risk of an asthma attack.

Using rescue inhalers for more than six hours should be avoided unless your healthcare provider tells you otherwise. If asthma symptoms require you to use rescue inhalers more frequently than every six hours, you probably need to step up your asthma treatment. Speak to your doctor.

One of the areas in which treatments can vary is in the use of antihistamines. Though antihistamines can provide relief of nasal congestion caused by a cold, they tend to be less useful in treating viral-induced asthma as they have no real effect on the virus itself.

If you have a history of severe viral-induced asthma, speak with your healthcare provider about taking oral corticosteroids at the start of a cold. There is some evidence that they can help, especially people who required emergency care or hospitalization after a severe attack.

How Asthma Treatment Differs in Children


Clearly, one of the best ways to avoid viral-induced asthma attacks is to avoid colds. This is often easier said than done, particularly during cold and flu season or in families with young children. Cold viruses are easily passed by sneezing and cough or by touching surfaces contaminated with germs.

The Centers for Disease Control and Prevention (CDC) recommends the following measures for preventing a cold:

  • Stay away from people who are sick.
  • Wash your hands frequently with soap and water for at least 20 seconds.
  • Avoid touching your face, nose, or mouth with unwashed hands.
  • Disinfect frequently touched surfaces and items, including counters and toys.

To further reduce the risk of viral-induced asthma, adhere to your daily asthma medications, taking them as prescribed and on schedule. If you have a history of severe viral-induced attacks, ask your healthcare provider if a short course of oral corticosteroids is reasonable.

You should also steer clear of secondhand smoke and other asthma triggers until the cold is fully resolved. If you are a smoker and cannot quit, ask your healthcare provider about smoking cessation aids (including nicotine patches and oral medications) to help you stop.

There are currently no vaccines to prevent a cold, but annual flu shots can help reduce your risk of influenza and, with it, the risk of an asthma attack.

Do I Need the Flu Shot If I Have Asthma?

A Word From Verywell

If you find that a cold or flu triggers an asthma attack, let your healthcare provider know. This occurs more frequently than many people think and may indicate the need for more aggressive asthma treatment, especially if you are prone to respiratory infections.

You should also speak with your healthcare provider if you use your rescue inhaler more than twice weekly. Using an inhaler this often is a sign of poorly controlled disease, which places you at an increased risk of a viral-induced attack. By finding the right combination of controller medications, you may significantly reduce your risk.

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  1. Skappak C, Ilarraza R, Wu YQ, Drake MG, Adamko DJ. Virus-induced asthma attack: The importance of allergic inflammation in response to viral antigen in an animal model of asthma. PLoS One. 2017;12(7):e0181425. doi:10.1371/journal.pone.0181425

  2. Saraya T, Kurai D, Ishii H, et al. Epidemiology of virus-induced asthma exacerbations: with special reference to the role of human rhinovirus. Front Microbiol. 2014;5:226. doi:10.3389/fmicb.2014.00226

  3. Patella V, Bocchino M, Steinhilber G. Asthma is associated with increased susceptibility to infection. Minerva Med. 2015;106(4 Suppl 3):1-7.

  4. Kau AL, Korenblat PE. Anti-interleukin 4 and 13 for asthma treatment in the era of endotypes. Curr Opin Allergy Clin Immunol. 2014;14(6):570-5. doi:10.1097/ACI.0000000000000108

  5. Skappak C, Ilarraza R, Wu YQ, Drake MG, Adamko DJ. Virus-induced asthma attack: The importance of allergic inflammation in response to viral antigen in an animal model of asthma. PLoS ONE. 2017;12(7):e0181425. doi:10.1371/journal.pone.0181425

  6. Kurai D, Saraya T, Ishii H, Takizawa H. Virus-induced exacerbations in asthma and COPD. Front Microbiol. 2013;4:293. doi:10.3389/fmicb.2013.00293

  7. Noor A, Fiorito T, Krilov LR. Cold weather viruses. Pediatr Rev. 2019;40(10):497-507. doi:10.1542/pir.2018-0237

  8. Oo S, Le Souef P. The wheezing child: an algorithm. Austral Fam Phys. 2015;44(6):360-4.

  9. McCracken JL, Veeranki SP, Ameredes BT, Calhoun WJ. Diagnosis and management of asthma in adults: A review. JAMA. 2017;318(3):279-90. doi:10.1001/jama.2017.8372

  10. Adeli M, El-shareif T, Hendaus MA. Asthma exacerbation related to viral infections: An up to date summary. J Family Med Prim Care. 2019;8(9):2753-9. doi:10.4103/jfmpc.jfmpc_86_19

  11. Doran E, Cai F, Holweg CTJ, Wong K, Brumm J, Arron JR. Interleukin-13 in asthma and other eosinophilic disorders. Front Med (Lausanne). 2017;4:139. doi10.3389/fmed.2017.00139

  12. National Heart, Lung, and Blood Institute. Guidelines for the diagnosis and management of asthma: Expert panel report 3 (EPR3). Updated September 2013.

  13. Oliver BG, Robinson P, Peters M, Black J. Viral infections and asthma: an inflammatory interface?. Eur Respir J. 2014;44(6):1666-81. doi:10.1183/09031936.00047714

  14. Centers for Disease Control and Prevention. Common colds: Protect yourself and others. Updated February 11, 2019.

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In recent years, a wide range of preclinical and clinical studies has led to important insights regarding the role of viruses in asthma pathogenesis and exacerbations, as well as mediating factors involved in these processes. In a paper published in May 2020 in the Journal of Allergy and Clinical Immunology, the Microbes in Allergy Committee of the American Academy of Allergy, Asthma & Immunology reviewed notable findings in this area.1

Polymorphisms and Innate Immune Genes

Across multiple cohorts, researchers have identified polymorphisms in antiviral and innate immune genes including STAT4, JAK2, MX1, VDR, DDX58, and EIF2AK2, and these polymorphisms are associated with respiratory virus susceptibility and severity, virus-induced asthma exacerbations, and asthma or virus-induced wheezing phenotypes.2 In addition, various genes including ADAM33, IL4R, CD14, TNF, IL13, and IL1RL1 have been linked with both illness severity and asthma risk.1

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Rhinovirus virulence has been found to vary by species, with 1 study showing greater odds of moderate to severe illnesses with rhinovirus A (odds ratio [OR], 8.2; 95% CI, 2.7-25.0] and rhinovirus C (OR, 7.6; 95% CI, 2.6-23.0) compared with rhinovirus B in nasal lavage samples collected from 209 infants.3 The findings further showed that a greater number of wheezing illnesses were caused by rhinovirus A (n=27) and C (n=14) compared with rhinovirus B (n=0).

Rodent studies have found that rhinovirus infection “leads to the expression of epithelial-derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin, as well as to an increase in ILC2 cells as an important source of airway IL-13,” as explained in the new review.1 These pathways are also known to be involved in the response to rhinovirus and associated asthma exacerbations in humans. Mice treated with anti-IL-25 demonstrated attenuation of ILC2 expansion, mucous metaplasia, and airway responsiveness.4

Respiratory Syncytial Virus

In research published in 2017, the use of palivizumab to prevent severe respiratory syncytial virus (RSV) in high-risk infants led to a reduction in physician-diagnosed recurrent wheezing during the first 6 years of life (15.3% vs 31.6% in the treated vs untreated groups, respectively [P =.003]).5 However, this strategy did not affect the risk of asthma development. “Ultimately, RSV appears to have the greatest impact on asthma risk during a critical window of lung development for infants born during the fall (in the Northern Hemisphere), who are at approximately 4 months of age during the peak of the winter RSV season,” according to the AAAAI paper.1

The Role of Specific Bacteria

A range of findings suggest a connection between the presence of specific bacteria and illness severity, including results of multiple infant studies indicating that the presence of Streptococcus, Moraxella, or Haemophilus within the upper airway during upper respiratory infections was associated with a greater likelihood of lower airway symptoms. RSV bronchiolitis has been linked to an increased abundance of Streptococcus and Haemophilus, while rhinovirus-bronchiolitis has been linked to an increased abundance of Moraxella and Haemophilus.

Findings point to a connection between the presence of bacteria and airway inflammation. For example, researchers have noted an association between Haemophilus influenzae colonization of the infant airway before viral infection and increased expression of local inflammatory cytokines. In mouse models, intranasal administration of Lactobacillus rhamnosus was associated with improved immune response, which may indicate that certain bacteria could have protective and prophylactic effects against viral infection.6

The Gut Microbiome

Accumulating evidence suggests that the gut microbiome influences antiviral immune defense and the development of asthma, including an earlier study demonstrating that intact commensal microbiota were required for the proper activation of inflammasomes in response to respiratory influenza virus infection.7

Studies have elucidated that “unique components of the viral genome contribute to respiratory illness, and knowledge of these factors may also assist in development of vaccine and therapeutic strategies aimed at the proteins responsible for specific disease characteristics.”1

Potential of Pre-Seasonal Treatment

In the PROSE study ( Identifier: NCT01430403) of children with atopic asthma, pre-seasonal treatment with omalizumab decreased fall exacerbations compared with placebo and inhaled corticosteroid boost.8 Omalizumab also improved interferon-α responses to rhinovirus, and greater increases in interferon-α were associated with fewer exacerbations (OR, 0.14; 95% CI, 0.01-0.88).

Vitamin D Supplementation

In a meta-analysis of 2 clinical trials, vitamin D supplementation (2400 or 4000 IU per day) during pregnancy led to a 25% reduction in asthma and/or the risk of recurrent wheeze in infants during the first 3 years of life, especially in women with adequate serum vitamin D levels at baseline.9 “It was suggested that the beneficial effects of vitamin D may be related to enhancement of in utero lung growth and development and promotion of antimicrobial effects, thereby reducing early-life respiratory infections and/or providing immune modulation effects,” wrote the authors of the AAAI report.1

The authors anticipate that research in the next 5 years will further clarify the role of respiratory and gut microbiota in the development of virally induced asthma. They also emphasize the importance of primary prevention a major goal to minimize the effect of viral infections on wheezing and asthma.

For additional discussion regarding the effect of viruses on asthma, we checked in with James E. Gern MD, professor of pediatrics and medicine; Chief of the Allergy, Immunology, and Rheumatology Division; and Vice Chair of Research in the Department of Pediatrics at the University of Wisconsin School of Medicine and Public Health in Madison. Dr Gern coauthored a 2017 review on the role of viral infections in asthma development and exacerbation in children.10

What is known thus far about the effects of respiratory viruses on asthma, and what has been noted thus far with COVID-19 in particular?

Dr Gern: Viruses are linked to asthma in all age groups. Infants who wheeze with respiratory viruses are very likely to go on to develop asthma. RSV may be linked to nonallergic asthma, while children with allergies who wheeze with rhinoviruses are at very high risk of developing asthma.

In children and adults with established asthma, respiratory viruses are common causes of acute exacerbations of asthma. COVID-19 illnesses can also cause wheezing illnesses but are more likely to cause cold or flu-like symptoms.

What are some of the treatment challenges in treating respiratory viruses in asthma patients, and how should these be addressed in clinical practice?

Dr Gern: Patients with asthma who contract a respiratory virus infection are at risk for acute wheezing, and this can sometimes progress to an acute exacerbation. At present, there are no antiviral treatments to prevent or treat an ongoing virus-induced exacerbation of asthma. Instead, prevention is focused on minimizing baseline airway inflammation using treatments such as inhaled corticosteroids and — for more severe asthma — treatments with biologics.

What are your thoughts about the new AAAAI workgroup report on this topic?

Dr Gern: This paper is a nice summary of which individuals are at risk for virus-induced wheezing and exacerbations, current strategies for treatment and prevention, and ongoing research into mechanisms and new approaches to treatment.  

What should be the focus of future research regarding the effect of viruses on asthma?  

Dr Gern:  Antivirals with efficacy against rhinoviruses would be a welcome treatment option and could also help to prevent asthma in infants prone to recurrent wheezing. The airway microbiome is an important cofactor for virus-induced wheeze, and more information in this area could lead to treatments. Since allergic inflammation increases the risk for virus-induced wheezing illnesses, treating baseline inflammation in asthma makes a lot of sense. Finally, better understanding of natural resistance mechanisms against respiratory viruses is likely to yield new targets for therapy.


1. Altman MC, Beigelman A, Ciaccio C, et al. Evolving concepts in how viruses impact asthma: a Work Group Report of the Microbes in Allergy Committee of the American Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol. 2020;145(5):1332-1344.

2. Loisel DA, Du G, Ahluwalia TS, et al. Genetic associations with viral respiratory illnesses and asthma control in children. Clin Exp Allergy. 2016;46(1):112-124.

3. Lee WM, Lemanske RF Jr, Evans MD, et al. Human rhinovirus species and season of infection determine illness severity. Am J Respir Crit Care Med. 2012;186(9):886-891.

4. Hong JY, Bentley JK, Chung Y, et al. Neonatal rhinovirus induces mucous metaplasia and airways hyperresponsiveness through IL-25 and type 2 innate lymphoid cells. J Allergy Clin Immunol. 2014;134(2):429-439.

5. Mochizuki H, Kusuda S, Okada K, et al. Palivizumab prophylaxis in preterm infants and subsequent recurrent wheezing. Six-year follow-up study.Am J Respir Crit Care Med. 2017;196(1):29-38.

6. Tomosada Y, Chiba E, Zelaya H, et al. Nasally administered Lactobacillus rhamnosus strains differentially modulate respiratory antiviral immune responses and induce protection against respiratory syncytial virus infection.BMC Immunol. 2013;14:40.

7. Ichinohe T, Pang IK, Kumamoto Y, et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection.Proc Natl Acad Sci U S A. 2011;108(13):5354-5359.

8. Teach SJ, Gill MA, Togias A, et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol. 2015;136(6):1476-1485.

9. Wolsk HM, Chawes BL, Litonjua AA, et al. Prenatal vitamin D supplementation reduces risk of asthma/recurrent wheeze in early childhood: A combined analysis of two randomized controlled trials.PLoS One. 2017;12(10):e0186657.

10. Jartti T, Gern JE. Role of viral infections in the development and exacerbation of asthma in children.J Allergy Clin Immunol. 2017;140(4):895-906. 


AsthmaCOVID19Lung InfectionsSours:
Asthma Exacerbation Case Study 1 - Treatment (Asthma Flare / Attack)

Infection-mediated asthma: etiology, mechanisms and treatment options, with focus on Chlamydia pneumoniae and macrolides

Respiratory Researchvolume 18, Article number: 98 (2017) Cite this article

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Asthma is a chronic respiratory disease characterized by reversible airway obstruction and airway hyperresponsiveness to non-specific bronchoconstriction agonists as the primary underlying pathophysiology. The worldwide incidence of asthma has increased dramatically in the last 40 years. According to World Health Organization (WHO) estimates, over 300 million children and adults worldwide currently suffer from this incurable disease and 255,000 die from the disease each year. It is now well accepted that asthma is a heterogeneous syndrome and many clinical subtypes have been described. Viral infections such as respiratory syncytial virus (RSV) and human rhinovirus (hRV) have been implicated in asthma exacerbation in children because of their ability to cause severe airway inflammation and wheezing. Infections with atypical bacteria also appear to play a role in the induction and exacerbation of asthma in both children and adults. Recent studies confirm the existence of an infectious asthma etiology mediated by Chlamydia pneumoniae (CP) and possibly by other viral, bacterial and fungal microbes. It is also likely that early-life infections with microbes such as CP could lead to alterations in the lung microbiome that significantly affect asthma risk and treatment outcomes. These infectious microbes may exacerbate the symptoms of established chronic asthma and may even contribute to the initial development of the clinical onset of the disease. It is now becoming more widely accepted that patterns of airway inflammation differ based on the trigger responsible for asthma initiation and exacerbation. Therefore, a better understanding of asthma subtypes is now being explored more aggressively, not only to decipher pathophysiologic mechanisms but also to select treatment and guide prognoses. This review will explore infection-mediated asthma with special emphasis on the protean manifestations of CP lung infection, clinical characteristics of infection-mediated asthma, mechanisms involved and antibiotic treatment outcomes.


Incidence and etiology of childhood and adult onset asthma

Asthma incidence is highest in childhood and thereafter decreases and remains stable at ~1–3 new cases per 1000 per year throughout late adolescence and adulthood [1]. In adult populations, the prevalence of active cases of childhood-onset asthma (COA) and adult-onset asthma (AOA) are approximately equal, or favor AOA [2]. Reasons for this counterintuitive prevalence ratio include (1) the propensity for COA to remit more frequently than AOA and (2) the greater number of years of adulthood in which to accrue new cases [2]. Of relevance to clinical management and population disease burden is the wide range of asthma severities, from mild intermittent to severe persistent; the most severe 20% of cases account for 80% of health care utilization and morbidity [3]. Robust population-based data indicate that around half of adults with asthma remain sub-optimally controlled, even when treated with currently available anti-inflammatory medications, and ~15% of adults with active asthma are severely uncontrolled [4–6]. These data indicate the need for novel therapies that are effective in the most severe and treatment-resistant cases of asthma that account for the majority of morbidity, mortality and health care utilization. The emerging evidence that a wide variety of microbes are present in the lower airway and may play a role in asthma pathogenesis suggests that manipulating the airway microbiome may be a novel approach towards this goal. Studies confirm the existence of an infectious etiology mediated by Chlamydia pneumoniae (CP) [7] and possibly other viral [8], bacterial [9] and fungal [10] microbes. Among the various infections associated with asthma, the obligate intracellular respiratory pathogen CP is of particular interest, as it is associated with both asthma severity and treatment resistance [11–13]. Although this review focuses on CP we will discuss Mycoplasma pneumoniae (MP) briefly under Treatment (Section V). It is possible that microbes such as CP and MP that have been implicated in recurrent wheeze and asthma etiology may serve as cofactors for viral infections, but certainly appear to act independently in asthmatic disease. The etiology of asthma remains unknown and is almost certainly multifactorial. Many “triggers” for asthma attacks are well known (e.g., allergens, viral respiratory infections, fumes, cold air, exercise) but underlying mechanisms for why some exposed individuals develop asthma while most do not remain elusive [14]. Genetic studies have failed to locate a unique “asthma gene” and instead point towards complex multifactorial genetic and environmental factors [15]. A currently popular paradigm, the “Hygiene Hypothesis,” posits that the increased incidence of allergies (hayfever and eczema) and asthma noted in recent decades, is associated with less exposure to childhood infections and bacterial products (e.g., endotoxin). Emerging evidence supports the Hygiene Hypothesis for hayfever and eczema but not for asthma which appears instead to be related to infections throughout the life cycle [16–18]. The host lung and gut microbiome as they relate to asthma are active areas of research [19]. Yet it must be pointed out that studies of bacterial rRNA may fail to detect CP due to low copy numbers or sampling problems due to deep tissue intracellular locations for this species [20, 21].

The human microbiome and asthma risk

An increasing number of studies have now confirmed that the host microbiome has a significant impact on the risk of asthma development. A study published in 2010 by Hilty and colleagues using 16S RNA clone-library sequencing showed that when compared with healthy controls, patients with asthma had significantly more pathogenic Proteobacteria and fewer Bacteroidetes [22]. Careful assessment of both healthy controls and asthmatic patients has confirmed the presence of bacterial communities. However, the bacterial burden was significantly greater in patients with asthma than in the healthy controls [23]. The microbial burden was even greater in asthmatics with greater bronchial reactivity upon methacholine challenge. These patients showed marked improvement in bronchial reactivity to methacholine after 6 weeks on clarithromycin. Importantly, greater bronchial reactivity also correlated with greater relative abundance of members of certain bacterial communities known to exhibit characteristics that contribute to asthma pathophysiology, including species capable of inducing nitric oxide reductase, produce sphingolipids or have the ability to metabolize steroid compounds [24, 25]. A recent study showed that 1-month old infants who had positive oropharynx cultures of Streptococcus pneumoniae, Moraxella catarrhalis, or Haemophilus influenzae showed increased susceptibility for development of childhood asthma [19, 26]. Another recent study concluded that the nasopharyngeal microbiome within the first year of life was a determinant for infection spread to the lower airways and predicted the severity of accompanying inflammatory symptoms, as well as risk for future asthma development. The authors showed that early asymptomatic colonization of the nasopharynx with Streptococcus was a strong asthma predictor [27]. These authors also demonstrated that antibiotic usage disrupted this asymptomatic colonization and prevented asthmatic onset [27]. These findings support the hypothesis that colonization of the developing airway by certain microbes (both viral and bacterial) can significantly alter the airway architecture and overall immune function, influencing how the airway responds to a variety of insults [28]. These findings also suggest that antimicrobial agents may represent an effective therapeutic tool with the potential to curtail both the duration and severity of asthma exacerbations initiated by a variety of microbes and exposes the limitation of the hygiene hypothesis in this regard [26]. The microbiome studies cited here have not specifically targeted CP and MP in upper airways. Studies that have specifically tested for these atypical organisms have reported positive detection [29, 30]. Intracellular detection of CP in adenoid tissue of symptomatic children was extremely common [30] and raises questions regarding a potential for CP-microbiome interactions.

Role of viral infection on wheezing and asthma exacerbation

Infections in early life can act either as inducers of wheezing or as protectors against the development of allergic disease and asthma. Many young children have wheezing episodes associated with early-life respiratory infections. The infections most likely to be associated with these wheezing episodes include respiratory syncytial virus (RSV), human rhinovirus (hRV), human metapneumovirus, parainfluenza viruses and coronavirus [31]. The hygiene hypothesis has proposed that, for some infants, frequent early life infections may protect against asthma [17] and this certainly appears to be the case for most infants, as wheezing episodes with respiratory infections diminish as the child ages. However, for others, early-life wheezing episodes may mark the beginning of asthma. Regarding established asthma, many types of viral respiratory infections have been shown to have a significant influence. In fact, viral respiratory infections are diagnosed in 80% of episodes of asthma in both children and adults [32, 33]. The question then remains; what factors determine if a viral respiratory infection provokes the onset of chronic asthma? Factors appear to include the type of virus and the viral infectious dose as well as host susceptibility factors leading to inflammation, airway cellular infiltration with neutrophils and eosinophils or the presence of allergens in the airway and their interactions with the host immune system. If this combination of host and pathogen factors results in airway inflammation and hyperresponsiveness, the outcome could be asthma. Could CP play a key role in this complex scenario? A clue to the answer to this question was found in a secondary analysis [34] of data from a community-based pediatric viral respiratory infection study that identified viral infections in 80–85% of exacerbations [33]. One hundred and eight children with asthma symptoms completed a 13-month longitudinal study in which exacerbations were recorded, and CP PCR and CP-specific secretory IgA (CP-sIgA) antibodies were measured both during exacerbations and during asymptomatic periods. CP PCR detections were similar between the symptomatic and asymptomatic episodes (23% v 28%, respectively). Children reporting multiple exacerbations remained CP PCR positive (P < 0.02) suggesting chronic infection. CP-sIgA antibodies were more than seven times greater in subjects reporting four or more exacerbations compared to those who reported just one (P < 0.02). The authors suggested that immune responses to chronic CP infection may interact with allergic inflammation to increase asthma symptoms [34]. Notably, MP was not found to be important in this study.

Chlamydia pneumoniae (CP) infections and asthma initiation and severity

Emerging evidence links CP infection with both de novo asthma (asthma onset during/after an acute lower respiratory tract infection in a previously non-asthmatic individual – also referred to as the “infectious asthma” syndrome) and with asthma severity [11, 12, 35, 36]. This section will review what is known about CP in asthma initiation and severity, and the multiple experimentally established mechanisms that might mediate these associations. Therapeutic implications are reviewed in Section V.

De novo wheezing during an acute lower respiratory tract infection is remarkably common [37]. Most of these wheezing episodes appear to resolve without chronic sequelae but sometimes chronic asthma develops. Surprisingly, clinical studies report that asthma onset after an acute respiratory illness is exceedingly common (up to 45% of adult-onset asthma cases [38]. This strong temporal association of respiratory infections and asthma onset has been confirmed in a population-based study [39]. The most reliable way to establish whether a specific respiratory pathogen can initiate asthma would be to perform large, long-term prospective microbiological and clinical cohort studies of the general (non-asthmatic) population. Such a study would be very expensive and has not yet been undertaken. A second approach would be to perform prospective studies in selected non-asthmatic patients exhibiting “risk factors” for asthma in clinical settings [40]. If the selected “risk factors” do indeed identify people at higher likelihood of developing the “infectious asthma” syndrome, this type of study might be feasible. Characteristics associated with CP/MP biomarker-positive “infectious asthma” include patients with severe, treatment-resistant asthma, exhibiting a neutrophilic airway inflammation or test PCR positive for Cp or MP. It should however, be noted that there is currently no test or set of tests that will definitively diagnose who will benefit maximally from azithromycin treatment. Factors that predict risk in non-asthmatics for developing the “infectious asthma” syndrome include a previous history of self-limited lower respiratory tract illnesses such as acute bronchitis (often with wheezing) and/or pneumonia [35, 38, 39]. Other risk factors may be operative but are poorly understood at this time.

Over a 10-year time period, Hahn et al. [35] collected prospective CP microbiologic testing and clinical data on 10 patients with de novo wheezing. Nine of these subjects exhibited an acute bronchitic illness and one had community-acquired pneumonia. All 10 met serological criteria for an acute primary (n = 8) or secondary (n = 2) CP infection. Of the nine patients with acute bronchitis and wheezing, four improved without treatment and five progressed to chronic asthma. The patient with pneumonia was treated with a traditional short course of a macrolide with resolution of pneumonic infiltrate, yet developed chronic bronchitis and CP was isolated by culture from his sputum 6 months later. This type of study has not been replicated but raises several questions. CP is well known to cause protean manifestations of acute respiratory illness; these observations suggest that CP may also be capable of causing protean manifestations of chronic respiratory conditions (e.g., asthma, chronic bronchitis and COPD, reviewed in [41]). Whereas some of the CP infected patients with de novo wheezing resolved their acute illness without treatment, others developed chronic sequelae; identification of underlying protective and promoting factors might help address the current asthma pandemic.

Once established, CP-associated asthma has been linked with increased severity in several studies. Cook et al. [42] first identified CP biomarkers in what they referred to as “brittle asthma” (asthma that was hard to control and more severe than average). An accumulating body of evidence supports the association of CP infection with asthma severity [11, 12, 43] and with steroid resistant asthma [44]. Multiple mechanisms support the biologic plausibility of these associations (reviewed in [45]). Exposure to cigarette smoke is an established factor tied to steroid resistance in asthma [46]. Similar to cigarette smoke, CP induces pulmonary bronchial epithelial ciliostasis [47]. Additionally CP infects alveolar macrophages and lung monocytes leading to enhanced production of TNF-α, IL-1β, IL-6 and IL-8; infects human bronchial smooth muscle cells to produce IL-6 and basic fibroblast growth factor (with potential effects on bronchial hyper reactivity and lung remodeling that have yet to be thoroughly investigated); and chronic infection exposes tissues to chlamydial heat shock protein 60 (cHSP60) and bacterial lipopolysaccharide (LPS) that have been associated with increased inflammation and asthma (reviewed in [48]). Lastly, CP-specific IgE has been demonstrated to be strongly associated with severe persistent asthma (80% of cases) [43] and other chronic respiratory illnesses in children severe enough to justify undergoing bronchoscopy [49]. Whereas exposure to recognized allergens can be mitigated, exposure to unrecognized bacterial “allergens” may result in chronic unrelenting exposures that could contribute to severity [43, 50]. It may prove difficult or even impossible to unravel exactly which mechanism(s) contribute to producing an “infectious asthma” phenotype.

In regard to the involvement of CP in asthma pathogenesis, the controversy of whether the association is causal or coincidental can be settled in two ways: (1) patients diagnosed with asthma can be treated with the aim of evaluating the effects of antibiotics in ameliorating asthma symptoms compared to untreated of placebo controls and (2) animal models can be performed to evaluate the role of CP in asthma initiation and/or exacerbation. Experimental animal inoculation studies may help to elucidate mechanisms underlying CP asthma pathogenesis. Over the past three decades, animal models of asthma have been extensively utilized to elucidate mechanisms of the disease, determine the activities of genes of interest, investigate cellular pathways and predict the safety and efficacy of various drugs being considered for asthma treatment.

Initial murine models of chlamydial lung infections were carried out in adult mice and seemed to closely represent acute human asthma. These studies utilized the mouse pneumonitis biovar of C. trachomatis (MoPn) since it is well known as a natural mouse pathogen [51] and would therefore represent the best choice for investigating host-pathogen interactions in this context. These early studies recorded extensive lung consolidation after 7 days of airway infection and found significant airway inflammation characterized by neutrophil infiltration in airway exudates [52]. These early studies also confirmed that multiple reinfections were required to induce symptoms of chronic asthma and that a Th1 immune response contributing IFN-γ and subsequently activated macrophages was necessary to clear the infection [53, 54].

More recently, many studies have utilized neonatal mouse models for infectious asthma since early studies demonstrate that neonatal T cell immune responses in both mice and human are skewed toward a Th2 cellular phenotype as a result of placental immune pressure. These Th2 cells are much less effective in the immune response compared to their adult counterparts [55, 56]. Horvat, et al. later demonstrated that neonatal chlamydial lung infection induced mixed T-cell responses that drive allergic airway disease (AAD) using a BALB/c mouse model with ovalbumin to induce AAD [57]. Further work from this group confirmed that chlamydial infection in neonatal and infant, but not adult mice, exacerbated the development of hallmark features of asthma in ovalbumin-induced allergic airways disease models. Some of these notable features include increased mucus-secreting cell numbers, IL-13 expression, and airway hyperresponsiveness [58]. Studies from our own lab confirm that early-life chlamydial airway infection induces a Th2 immune response, both airway eosinophilia and neutrophilia, and permanent alteration of lung structure and function with concomitant enhancement of the severity of allergic airways disease in later life [59]. We confirmed that neonatally infected mice never cleared the infection, showed dissemination to the liver and spleen through the peripheral circulation, and the development of Chlamydia-specific IgE antibodies in the infected neonates but not adult controls [59]. Recently, Hansbro et al. completed work using a bone marrow chimera reconstitution that clearly demonstrated that infant lung infection results in lasting alterations in hematopoietic cells, leading to increased severity of AAD later in adult life [60]. A significant study by Kaiko et al. [61], demonstrated that infection of bone marrow-derived dentritic cells (BMDC) promoted Th2 immunity and airways hyperreactivity in a mouse model. Intratracheal passive transfer of infected BMDC but not uninfected control BMDC into naïve Balb/c mice resulted in increased IL-10 and IL-13 in the BAL fluid [61]. These animals also showed significant increases in airways resistance and a reduction in airways compliance compared to their uninfected counterparts. These are hallmarks of asthma and further confirm the role of chlamydial infection in asthma initiation and pathology, at least in mice. A further set of experiments by Schröder et al. [62] demonstrated that adoptive transfer of lung dendritic cells from CP infected mice, but not from uninfected mice, produced eosinophilic airway inflammation after challenge with an exogenous allergen (human serum albumin) that was dose-, timing-, and MyD88-dependent. Taken together, these findings suggest it is plausible that CP infection solely of lung dendritic cells may be sufficient to induce an asthma “phenotype” that may demonstrate characteristics that are both “infectious” and “allergic”.

These animal model studies have added significantly to our understanding of the mechanisms involved in the inflammatory process of chlamydial infection leading to asthma initiation and exacerbation. It also appears that the damage caused by chlamydial airway infections over time leads to an exaggerated airway repair or airway wall remodeling. The major features of this type of response include epithelial cell shedding, goblet cell hyperplasia, hypertrophy and hyperplasia of the airway smooth muscle bundles, basement membrane thickening and increased vascular density through angiogenesis [63]. The functional and mechanical consequences of this type of aberrant repair leads to bronchial wall thickening which can uncouple the bronchial wall from the surrounding parenchyma, significantly enhancing airway narrowing and severe obstruction [63]. This type of airway damage might prove irreversible even with long-term inhaled steroid treatment. Moreover, it is well documented that corticosteroid use drives CP out of a persistent state into active replication, since corticosteroids negatively impact several aspects of cell-mediated immunity while favoring the shift from a Th1 towards a Th2 immune response [64]. This shift in response significantly impedes the ability of the host to eradicate intracellular pathogens like CP and may lead to the release of cHSP60 which exacerbates the inflammatory process [11]. There is also evidence that CP infection may promote airway remodeling by decreasing the ratio of MMP9 to TIMP1 secreted by inflammatory cells, and by altering cellular responsiveness to corticosteroids [65]. See Fig. 1 for a summary of established and suspected mechanisms whereby CP infection may contribute to asthma pathogenesis.

Illustration of role of chronic CP intracellular infection in asthma pathogenesis. The figure illustrates multiple pathways whereby chronic intracellular CP infection (1) is directly responsible for Immunopathologic damage and/or (2) indirectly influences allergic response as demonstrated in multiple animal models. Effects on the clinical manifestations of viral infections and the microbiome as they relate to asthma are speculative at this time. CP infection has also been shown to enhance histidine decarboxylase (HDC) to produce histamine as shown in cell culture, and the production of Cp-specific IgE antibodies is demonstrated in human asthma patients. Finally, CP infection of the airways (i) may induce hyperresponsiveness through infection of bronchial smooth muscle cells, (ii) produces inflammatory cytokines and (iii) induces ciliostasis of bronchial epithelial cells similar to the effects of cigarette smoking

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Asthma subtypes and infection

The concept that asthma is a syndrome with different underlying etiologies is well accepted. The use of the word “phenotype” to describe asthma subtypes based primarily on the inflammatory composition of respiratory secretions and/or peripheral blood is more problematic. The original definition of “phenotype” referred to relatively stable somatic manifestations of underlying genetics (such as eye color) whereas current asthma inflammatory “phenotyping” is based on cross sectional sampling of a dynamic physiologic process (host inflammatory response) and does not account for the fact that inflammatory composition is not necessary a fixed characteristic [66]. In the context of a review that focuses on chlamydial infection we are reluctant to place too much emphasis on asthma phenotypes based on inflammatory cell compositions because well described host responses to acute, sub-acute and chronic chlamydial infections involve a wide array of inflammatory cells (including eosinophils, neutrophils and monocytes) the composition of which varies significantly at different temporal stages of the infection [67]. We have commented on some fairly well defined asthma categories but even these can change over time (e.g., mild asthma can become severe, stable asthma can become uncontrolled). The dynamic and often unpredictable nature of asthma symptomatology is one of the factors that make asthma research so challenging.

Atopic/non-atopic asthma

Historically asthma was categorized as either allergic or non-allergic but this distinction was put into question as early as the 1980s [68]. An early report of the association between CP and asthma did find independent associations of CP biomarkers, clinical allergy and asthma [40] yet in the clinical setting there is overlap between atopy and CP infection [69]. The animal models described earlier indicate that CP can promote both asthma and atopy, thus an absolute distinction between these two categories as indicators of differing underlying etiologies may not be warranted. Macrolide treatment trials that examine subgroup responses are one approach to examining the predictive value of this and other subgroups.

Eosinophilic/neutrophilic asthma

Asthma has also been characterized as either “eosinophilic” or “neutrophilic” based on the cellular composition of respiratory secretions or bronchoalveolar lavage fluid (BALF) [70]. Simpson et al. [71] performed an RCT of a macrolide (clarithromycin) in severe refractory asthma in adults and reported no overall benefit in the group as a whole. However, there was a positive effect in the pre-specified subgroup of patients with “neutrophilic” asthma as defined by sputum IL-8 and neutrophil numbers. The predictive power of these findings is limited since it is unclear whether sputum composition is stable over time in severe refractory asthma (or any asthma, for that matter).


The majority of people with asthma can be well controlled with conventional guideline-based anti-inflammatory treatments (mainly inhaled steroids, sometimes in combination with an inhaled long-acting bronchodilator) [72]. Nevertheless, a significant minority of people with asthma is not well controlled by guideline treatments [73, 74]. The proportion of all people with “refractory” asthma (asthma that is not responsive to guideline therapies) has been estimated at between 5 and 15% but the contribution of refractory asthma to asthma morbidity and mortality is considerably greater, as the most severe 20% of asthma cases account for 80% of asthma morbidity and health care costs [3]. If patients with the “overlap syndrome” (asthma and COPD) are included, the numbers of people with refractory disease increases significantly [75]. Of the various novel therapies under consideration for refractory asthma [76], macrolides appear to be one of the most promising. A 2013 meta-analysis of 12 randomized, controlled trials (RCTs) of macrolides for the long term management of asthma in both adults and children found positive effects on peak expiratory flow rate (PEFR – a measure of pulmonary function), asthma symptoms, asthma quality of life (AQL), and airway hyper responsiveness (AHR), but not on forced expiratory flow rate in 1 s (FEV1) [77]. The updated 2015 Cochrane review of 18 RCTs [78] reported positive benefits on asthma symptoms and FEV1 but not on AQL (AHR and PEFR were not analyzed). A joint European Respiratory Society/American Thoracic Society (ERS/ATS) guideline on severe asthma recommends against the use of macrolides (“conditional recommendation, very low quality evidence”) [79]. The ERS/ATS guideline states “this recommendation places a relatively higher value on prevention of development of resistance to macrolide antibiotics, and relatively lower value on uncertain clinical benefits.” The inconsistent findings of the meta-analyses, along with the uncertainties surrounding the clinical benefits of macrolides, underscore the need for higher quality evidence. This section adds some evidence not included in the meta-analyses, reviews what is known about macrolide side effects (including the clinical consequences of resistance) and suggests research approaches to obtain better evidence. We conclude with some provisional recommendations for clinicians who may be approached by patients with new-onset, uncontrolled and/or refractory asthma who are asking for macrolide treatment.

Current evidence for all asthma treatments is limited due to selection bias initiated by researchers, clinicians, and even asthma patients themselves. Researcher bias. The academic literature is replete with asthma efficacy studies lacking in generalizability [80]. The efficacy trials on which current asthma treatment guidelines are based systematically exclude >90% of people with asthma encountered in the general clinical population [81, 82]. Only pragmatic effectiveness trials, with minimal exclusions, are able to provide evidence applicable to the general population [44]. Clinician bias. A recent trial of azithromycin for acute exacerbations of asthma (AZALEA) is notable because over 95% of patients with an exacerbation were not eligible for enrollment primarily because they had received an antibiotic from a treating clinician [83]. An accompanying editorial speculated that one possible reason for the negative results of AZALEA was that clinicians were somehow able to identify and treat likely candidates, making them ineligible for the research [84]. Be that as it may, AZALEA is an example of asthma research made less informative due to non-researcher clinician behavior. Patient bias. Hahn et al. [44] performed a pragmatic trial of azithromycin for asthma (AZMATICS) in which the likely candidates excluded themselves from randomization. This unanticipated event occurred because AZMATICS was an Internet-based trial; people with severe, refractory asthma identified themselves as likely candidates and contacted the PI for enrollment; but upon learning that they had a 50% chance of receiving placebo, they opted out of randomization in favor of receiving a comparable azithromycin prescription from their personal clinician [85]. Rather than lose data on this “open-label” (OL) group, the study protocol was altered to include a third (OL) arm. Randomized results were similar to AZALEA (negative – see Fig. 2); however, OL subjects exhibited large and unprecedented improvements in symptoms and quality-of-life (QOL) that persisted long after treatment was completed (Figs. 2 & 3). Because the OL group was not randomized, these results do not appear in any meta-analysis of RCTs; nevertheless they strongly suggest that future macrolide RCTs should focus on the severe end of the asthma spectrum, as also recommended by others [42, 71, 86], and preferably engage patient populations that are unlikely to want to opt out of randomization.

Azithromycin improves asthma symptoms and patient quality of life. Subjects with severe refractory asthma treated with azithromycin (Open Label) had fewer persisting asthma symptoms a and greater asthma quality of life b than groups with lesser asthma severity randomized to azithromycin or to placebo [44]

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Asthma quality of life (AQL) improvement scores at 12 months (9 months after completing azithromycin). The minimum clinically important score is ≥0.5; a score of 1.5 is considered a large important change [44]

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Macrolide mechanisms of action in asthma are thought to be directly anti-inflammatory, indirectly anti-inflammatory (i.e., antimicrobial), or both. It is difficult to invoke direct anti-inflammatory macrolide effects as responsible for large clinical benefits persisting to 9 months after treatment completion. Antimicrobial effects, against specific respiratory pathogens or against the general lung microbiome, remain likely possibilities. Circumstantial evidence suggests that macrolide treatment effects may, at least in part, be attributable to antimicrobial actions against chronic atypical infections [9, 87]. This issue is by no means settled and requires further research that may be challenging given the selection biases noted above coupled with likely low sensitivity of lung sampling leading to false negative diagnosis of, for example, chronic CP lung infection [20].

Azithromycin is generally well tolerated and is widely used for a variety of acute respiratory illnesses. Concerns about adverse effects of azithromycin include development of antibiotic resistance, sudden cardiac death, hearing loss and effects on the host mcrobiome. Development of resistance is a possibility whenever antibiotics are used; azithromycin is no exception. However, there are no reports of patient harm from resistant organisms in any cardiorespiratory trial performed to date [89]. Rather, the only detectable clinical effects of azithromycin in these trials were decreased incidences of sinusitis, acute bronchitis and pneumonia, and less use of other antibiotics [88, 89]. Sudden cardiac death attributable to azithromycin (1 in 4000 prescriptions in high cardiac risk patients) was plausibly documented in an epidemiologic study of a Medicaid population in Tennessee [91]. The same risk was also present for a quinolone (levofloxacin). Subsequent population-based studies in average risk populations showed no increased risk of sudden death [92, 93]. Mild hearing loss was reported in an excess of <1% of heart disease subjects randomized to 600 mg azithromycin once weekly for 12 months [88, 90]. Hearing test changes leading to discontinuation of azithromycin occurred in 2.8% of 1142 severe COPD subjects randomized to 250 mg azithromycin daily for 1 year [90]. The clinical significance of these hearing test changes is unclear. Notably, it is likely that daily azithromycin dosing is unnecessary [94] and may lead to increased adverse events [91]. The prolonged half-life of azithromycin within cells, including within immune system cells, allows weekly dosing and may be preferable to daily dosing when targeting either immune cells or intracellular pathogens such as CP.

Although largely speculative at this time, it appears that macrolide effects against the lung microbiome may be potentially harmful or helpful in asthma. Segal et. al. reported that an 8 week treatment with azithromycin did not alter bacterial burden but reduced α-diversity [95]. They also observed significant reduction in certain pro-inflammatory cytokines, which might explain the non-specific anti-inflammatory effects proven beneficial in COPD and asthma [95]. Published findings from Slater et al. that specifically evaluated azithromycin effects on the lung microbiome revealed a significant reduction in bacterial richness in the airway microbiota [96]. Importantly, reductions were most significant in three pathogenic genera: Pseudomonas, Haemophilus and Staphylococcus [96]. Overall, available data suggest that azithromycin treatment of severe asthma, while controversial, may benefit those with confirmed atypical bacterial infection [97]. Resistance, adverse events including sudden death, hearing loss and changes in host microbiome should be monitored in future pragmatic trials.

Protean manifestations of chronic CP infection, that may include asthma, chronic bronchitis, COPD, and the “overlap syndrome” (asthma and COPD) argue in favor of pragmatic trials with broad inclusion criteria that include patients with lung multi-morbidity. At least nine domains distinguish pragmatic (or effectiveness) trials from explanatory (efficacy) trials (Table 1) [98]. In the context of future RCTs of macrolides for asthma, we propose that the most important pragmatic domains are (1) broad eligibility to account for the protean clinical manifestations of both chronic reactive/obstructive lung disease and CP infections as discussed previously and (2) a comprehensive patient-centered primary outcome. Asthma exacerbations are a current popular choice as a primary outcome because they are clinically relevant [99]. However, exacerbations are only one of many outcomes that are important to asthma patients [100]. Compared to exacerbations, asthma quality-of-life (QOL) more comprehensively measures patient-important outcomes. QOL includes, but is not limited to, the adverse effects of exacerbations on patient well-being [100] and QOL has proven robust in the sole pragmatic macrolide-asthma trial performed to date [44] (Figs. 2 and 3). Many patients in this pragmatic trial [44] had significantly decreased asthma QOL at study entry and large important improvements in QOL after azithromycin, but did not experience exacerbations. This significant subgroup would have been either possibly ineligible for inclusion or not counted as successes in a trial using exacerbations as the primary outcome.

Full size table

Pragmatic trials primarily ask Does this treatment work? Explanatory trials primarily ask What is the mechanism? Addressing target groups/mechanisms in pragmatic trials of macrolides is desirable and possible as secondary aims by specifying a priori hypotheses coupled with subgroup analyses. We recommend studying a wide array of biomarkers using this approach. It is notable that RCTs of macrolides have been performed and/or macrolides are being recommended in the treatment of many chronic lung conditions (diffuse pan-bronchiolitis, cystic fibrosis, bronchiectasis, COPD, post-transplant bronchiolitis obliterans) [101, 102]. A planned trial will test the effectiveness of azithromycin in patients with the “overlap syndrome” (asthma-COPD) [103]. It is time to add asthma to the growing list of chronic respiratory conditions that are being evaluated by robust macrolide RCTs that are pragmatic in nature.

In the meantime, patients with severely uncontrolled and/or refractory asthma, or new-onset asthma are increasingly searching the Internet for new information and are sometimes better informed than their doctor about current evidence regarding macrolides for asthma (Hahn: personal observations). Pending more robust data from asthma RCTs that have yet to be performed, how should practicing clinicians respond when such patients request macrolide treatment? As stated above, the ERS/ATS guidelines on severe asthma recommend against the use of macrolides, albeit with caveats that the evidence for this recommendation is weak and provisional [79]. Informal guidelines from a pulmonology research group state that they recommend macrolide treatment only for confirmed diagnoses of atypical lung infection [104]. From a practical standpoint, their recommendation limits treatment only to those who have undergone bronchoscopy; even then the diagnostic sensitivity is likely to be less than perfect due to sampling issues discussed earlier. Both these recommendations have met resistance from patients who have read and understood the evidence (Hahn: personal communication). We offer a third alternative recommendation, repeated word for word from the conclusion of the sole practice-based pragmatic trial of azithromycin for asthma conducted to date [44]:

“Pending further randomized trials, given the relative safety of azithromycin and the significant disease burden from severe refractory asthma, prescribing prolonged azithromycin therapy to patients with uncontrolled asthma may be considered by managing clinicians, particularly for patients who have failed to respond to conventional treatment and as an alternative to instituting immunomodulatory agents”.

Interested clinicians and others wishing more information on patient experiences, scientific evidence and treatment alternatives are referred to a book on the subject [69].


Evidence supports a complex interaction between host genetics/immune response and environmental factors (e.g., viral infections, microbiome) in the development, exacerbation and severity of asthma. Emerging evidence from animal models and human studies points to Chlamydia pneumoniae (CP) as a key player in this complex scenario. Future research is required to unravel the quantitative contribution of CP to asthma pathogenesis, and pragmatic treatment trials are recommended to investigate therapeutic implications.


Allergic airway disease

Airway hyper responsiveness

Adult-onset asthma

Asthma quality of life

Azithromycin for acute exacerbations of asthma

AZithroMycin/Asthma: trial in community settings

Bone marrow-derived dendritic cells

Chlamydia heat shock protein 60

Childhood-onset asthma

Chronic obstructive pulmonary disease

Chlamydia pneumoniae

European Respiratory Society/American Thoracic Society

Forced expiratory flow rate in 1 second

Human rhinovirus

Interferon gamma



Mycoplasma pneumoniae

Open label

Polymerase chain reaction

Peak expiratory flow

Peak expiratory flow rate


Randomized control trials

Respiratory syncytial virus

Tumor necrosis factor alpha


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Induced asthma infection


Respiratory Infections

Respiratory infections (also called respiratory illnesses) are common. These infections affect your lungs, nose, sinuses, and throat, especially when you have asthma. They can cause a runny nose, cough, fever, or sore throat. Respiratory infections are a main asthma trigger and can cause severe symptoms (an asthma episode or attack).
Common respiratory infections include:

You can have more than one respiratory infection at the same time.

Respiratory illness is a common asthma trigger
Respiratory illnesses are a common asthma trigger, especially in children.

What Do I Do If I Have a Respiratory Illness?  

  • Talk with your doctor about your symptoms. Ask if you can take over-the-counter medicines to reduce some of your symptoms.
  • Follow your Asthma Action Plan. Be sure your Asthma Action Plan tells you what to do if you get sick. If it doesn’t, call your doctor to ask if you should change how you take your prescribed asthma medicine while you are sick. If you get symptoms of flu or COVID-19, or any symptoms that concern you, contact your doctor right away.
  • Keep your quick-relief asthma medicine with you at all times to treat asthma symptoms.
  • Call 911 immediately if you have any of these danger signs:
    • Trouble walking or talking due to shortness of breath
    • Cyanosis which is tissue color changes on mucus membranes (like lips and around the eyes) and fingertips or nail beds – the color appears grayish or whitish on darker skin tones and bluish on lighter skin tones
    • Fast breathing with chest retractions (when skin sucks in between or around the chest plate and/or rib bones when inhaling)
    • Other signs of a severe asthma attack

How Can I Prevent Respiratory Infections? 

Infections like the flu are a major cause of asthma episodes or attacks. And according to the Centers for Disease Control and Prevention (CDC), people with asthma are at higher risk for developing serious complications (like pneumonia) from the flu. Follow these steps to protect yourself and your loved ones from respiratory infections:

  • Wash your hands often with soap and warm water for 20 seconds, especially after touching frequently used surfaces like doorknobs.
  • Avoid touching your eyes, nose, or mouth.
  • Get a yearly flu shot.
  • Talk with your doctor about getting the pneumococcal [noo-muh-KOK-uhl] shot. You should only need the shot once and a booster as needed.
  • Stay away from people who are sick. If you have symptoms, stay home.
  • Keep your breathing equipment clean. This includes your asthma inhaler, nebulizer and nebulizer tubing, and mouthpiece.
  • Do not share your breathing equipment or medicines with others.

While COVID-19 is spreading, also follow these steps:

  • Stay at least 6 feet (2 meters) from other people.
  • Avoid large crowds.
  • Wear a face mask or covering.
  • Travel only if necessary.

It’s important to always keep your asthma under control. It is very important when you’re sick. If your asthma is well-controlled when you get sick, you reduce your chances of having an asthma attack, having complications, or being hospitalized.

Steps to stop the spread of respiratory infections

What Is a Complication?

A complication is another illness or health problem that is caused by certain illnesses or is more likely to happen when you get a certain illness. For example, you are more likely to get pneumonia – a respiratory infection – when you have the flu.

Respiratory Illness Resource Center

Protect Yourself From Respiratory Infections: People with asthma and their caregivers need to know about respiratory infections. They are a major cause of asthma symptoms and attacks. And some illnesses can lead to other serious conditions, like pneumonia. This blog post talks about four common infections, such as the flu, COVID-19, pneumococcal disease, and the common cold.

Coronavirus (COVID-19): What People With Asthma Need to Know: This blog post gives general information on COVID-19. It helps people with asthma understand risk, prevention, and what to do if you catch it.

What People With Asthma Need to Know About Face Masks During the COVID-19 Pandemic: Face masks are an important part of protecting ourselves and others against COVID-19. But can people with asthma wear face masks? What are the best options for people with asthma, especially if your job requires them? This blog post addresses many of the questions you may have about asthma and face masks.

Cleaning Your Hands With Soap and Hand Sanitizer: What Is Best to Protect Yourself From COVID-19 and Other Illnesses?: Keeping your hands clean is one of the easiest ways to reduce the spread of the coronavirus that causes COVID-19. It can also help help protect you from colds, flu, and other respiratory infections. Learn the right way to clean your hands with soap and water or hand sanitizer to help reduce the spread of the coronavirus.

4 Things You Must Know About the Flu If You Have Asthma: People with asthma are at high risk of having serious complications from the flu. Learn how to protect yourself and what to do if you do catch it.

Flu Facts: Flu Vaccine and Asthma: This blog post answers many of the most common questions people with asthma have about the flu vaccine. Get the facts on why the flu vaccine is the best way to protect yourself from the influenza virus.

Medical Review May 2021 by Neeru Khurana Hershey, MD, PhD

Allergen-induced asthma

What to do when illness makes your asthma worse

Most of the time, your asthma symptoms don’t bother you…until you get sick. Then, next thing you know, you’re waking up in the middle of the night coughing and wheezing nonstop. It’s called a viral-induced asthma flare, and it occurs when your condition is exacerbated by a respiratory illness. Luckily, there are effective treatments, besides using your inhaler in the wee hours, that will have you breathing easily—and sleeping through the night—again.

Can a virus make asthma worse? 

Studies show that viral infections cause asthma symptoms to worsen. One of the most common triggers of an asthma attack is viral or bacterial infections, like a cold, flu, pneumonia, or sinus infection. When you are sick, your airways become inflamed and narrowed—making it more challenging to take in air. Respiratory viruses often cause an increase in mucus, which can also make breathing difficult.

Shortness of breath is a symptom of COVID-19, and for people with asthma it can be even worse. People with asthma are at higher risk for severe illness if they catch the novel coronavirus, according to the Centers for Disease Control and Prevention (CDC), for many of the same reasons other respiratory illnesses exacerbate symptoms.

What are the symptoms of a viral-induced asthma flare?

“An asthma flare-up is bronchospasm and inflammation of the lungs,” says Pierrette Mimi Poinsett, MD, a medical consultant atMom Loves Best. “Respiratory infections including viruses can trigger asthma flares.” The symptoms of a viral-induced asthma flare-up are similar to regular asthma symptoms, and can include:

  • Wheezing
  • Coughing
  • Chest tightness
  • Shortness of breath
  • Fatigue
  • Nasal congestion
  • Headache
  • Sinus pain

It’s a good sign that it’s viral-related if your asthma is typically well-controlled, and these signs appear alongside a viral illness. 

Asthma symptoms occur on a spectrum from mild to severe. A serious asthma attack can be life-threatening, so it’s important to recognize the symptoms. If you develop signs such as difficulty breathing, flaring of the nostrils, difficulty talking or walking, and/or bluish tint to lips, skin, or nails, call 911 and seek medical help immediately.

What makes asthma worse? In addition to viral illness, some other commontriggers of an asthma flare-up are:

  • Exercise
  • Stress
  • Irritants in the air like smoke
  • Weather—cold temperatures or allergy season
  • Medications like beta-blockers
  • Gastroesophageal reflux

When an asthma flare-up occurs, it could take several days or weeks before your bronchial tubes are no longer constricted, depending on how severe the condition is.

What helps asthma when you are sick?

There are no treatments specifically for viral-induced asthma symptoms, but there are a number of treatments that can alleviate cough, chest tightness, and wheezing. The best way to manage asthma is prevention and long-term control that stops attacks before they happen. 

First, develop an asthma action plan with your healthcare provider before you get sick. This is a very specific document that is based on your numbers when you breath into a peak flow meter and symptoms. There are three zones: green, yellow, and red.

  1. Green zone is the level where you do not have symptoms and your peak flow is at its highest (peak flows are monitored over two to three weeks to determine personal best peak flow). Peak flows are measured daily to monitor your current zone.
  2. Yellow zone is notable for decreased peak flow and the onset of symptoms.
  3. Red zone is notable for severely decreased peak flow and severe symptoms. It is an emergency zone that indicates the need to contact your healthcare provider or go for emergency care. 

Each zone should have corresponding medications that are recommended to help control your asthma. “Frequently being in the yellow or red zone is a sign of severe asthma,” Dr. Poinsett says.

What are the types of asthma medications that help when you’re sick?

“Asthma medications are divided into two major classes: long-term control medications and quick-relief medications,” says Dr. Poinsett.

Long-term control medications are also known as anti-inflammatory, controller, or maintenance medications. These medications reduce the swelling in the lung and mucus production. Long-term control medications are taken regularly—even without symptoms—for optimal effect. These can include inhaled corticosteroids, oral medications, and combination inhalers.

Quick-relief medications are also known as rescue medications and are used to treat acute symptoms of asthma when you are in the yellow or red zone.

Your action plan when sick may be a combination of the two. For example, your healthcare provider may recommend you start using a steroid inhaler at the first signs of a viral illness to prevent a flare. “Medications likealbuterol relax the muscle spasm and lead to better air entry to the deep parts of the lungs,” saysSumana Reddy, MD at Acacia Family Medical Group in Prunedale, California. Short-acting rescue inhalers like these can help when your asthma acts up when you are sick—and you may need to use them more frequently than usual.

Your healthcare provider may recommend anebulizer, which is medicine given through a mask to help get medication to your lungs while you are sick. You might also need an oral steroid likeprednisone, depending on the severity of your symptoms. 

RELATED: Albuterol side effects

How can I stop or prevent my asthma from getting worse?

“Following an Asthma Action Plan is the best way to monitor asthma,” Dr. Poinsett advises.

In addition, you can take steps to avoid your triggers. If illness makes your asthma flare, that can include:

  • Washing hands often
  • Wearing a mask when you are near people who may be sick
  • Maintaining a distance of at least 6 feet from sick people
  • Getting a flu shot annually to prevent illness
  • Starting additional treatment measures at the first sign of illness

You should discuss with your healthcare provider if your asthma is getting worse beyond when you’re sick since you may require an adjustment in your medication. It is important to take your medication on a regular basis as prescribed to prevent flare-ups from happening. 


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