Table 2.
Major human studies (pediatric and adult population) assessing the impact of pathogenic bacteria and microbiota during the development, the attack and the natural history of pediatric asthma.
| Compartment | Study | Design and age-group | Main results | |
|---|---|---|---|---|
| Asthma development | Hypopharynx | Bisgaard H, et al. 2007[32] | Hypopharyngeal samples were cultured from 321 neonates at 1 month of age | 21% of children were colonized with S. pneumoniae, M. catarrhalis, H. influenzae, or a combination of these organisms. Colonization with one or more of these organisms, but not colonization with S. aureus, was significantly associated with persistent wheeze. Neonates colonized in the hypopharyngeal region with one or a combination of these organisms, were at increased risk for recurrent wheeze and asthma early in life. |
| Gut microbiota |
Arrieta MC, et al. 2015 [100] |
319 children enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study | Children at risk of asthma exhibited transient gut microbial dysbiosis during the first 100 days of life Relative abundance of the bacterial genera Lachnospira, Veillonella, Faecalibacterium, and Rothia was significantly decreased in children at risk of asthma. This reduction in bacterial taxa was accompanied by reduced levels of fecal acetate. Inoculation of germ-free mice with these four bacterial taxa ameliorated airway inflammation in their adult progeny. |
|
| Lung | Loewen K, et al. 2015[102] | 213, 661 mother–child dyads with a median follow-up time of 9.3 years from birth Maternal antibiotic use was determined from records of oral antibiotic prescriptions |
36.8% of children were exposed prenatally to antibiotics and 10.1% developed asthma. Prenatal antibiotic exposure was associated with an increased risk of asthma. Maternal antibiotic use during 9 months before pregnancy and 9 months postpartum were similarly associated with asthma. |
|
| Hoskin-Parr L, et al. 2013[103] | 4,952 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Child antibiotic use and asthma, eczema and hay fever symptoms were reported | Children reported to have taken antibiotics during infancy (0–2 yr) were more likely to have asthma. The risk increased with greater numbers of antibiotic courses. The number of courses was also associated with a higher risk of eczema and hay fever but not atopy. |
||
| Gut microbiota | Patrick DM, et al. 2020[104] | 2,644 children from the Canadian Healthy Infant Longitudinal Development (CHILD) prospective birth cohort and among them, 917 were analyzed for fecal microbiota | Reduction in asthma incidence over the study period was associated with decreasing antibiotic use in the first year of life.Asthma diagnosis in childhood was associated with infant antibiotic use (adjusted odds ratio [aOR] 2.15) , with a significant dose–response; α-diversity of the gut microbiota was associated with a 32% reduced risk of asthma at age 5 years. |
|
| Acute asthma | Nasopharynx | Mansbach JM, et al. 2016[106] | The MARC-35 prospective cohort study of 1,016 infants (age less than 1 year) hospitalized with bronchiolitis and followed for the development of recurrent wheezing | RSV infection was associated with high abundance of Firmicutes and Streptococcus and a low abundance of Proteobacteria and the genera Haemophilus and Moraxella. RV infection was associated with low Streptococcus and high Haemophilus and Moraxella. RSV/RV coinfections had intermediate abundances. |
| Nasopharynx | De Steenhuijsen Piters WA, et al. 2016[105] | 106 children less than 2 years of age with RSV infection/26 asymptomatic healthy control | 5 nasopharyngeal microbiota clusters were identified, characterized by high levels of either Haemophilus influenzae, Streptococcus, Corynebacterium, Moraxella, or Staphylococcus aureus. RSV hospitalization were positively associated with H. influenzae and Streptococcus RSV-induced expression of IFN-related genes is independent of the microbiota cluster |
|
| Nasopharynx | Kloepfer KM, et al. 2017[107] | 17 adult subjects collected nasal mucus samples on a weekly basis for 5 consecutive weeks | Asymptomatic RV infections were associated with a significant increase in the abundance of Dolosigranulum and Corynebacterium.RV infection preceded the increased odds of detection of Streptococcus and Moraxella by 1 week. | |
| Blood | Giuffrida LM, et al. 2017[108] | 14 asthmatic and 29 non-asthmatic adult patients with acute respiratory infection 10 healthy individuals |
Higher blood concentrations of CCL2 and CCL5 in infected asthmatic patients than in non-asthmatic patients. Both asthmatic and non-asthmatics with pneumonia or bronchitis had higher concentrations of blood cytokines. | |
| Pharynx | Kama Y, et al. 2020[109] | Pharyngeal samples of outpatients and/or in patients children with acute exacerbations of asthma (n = 111) (median age: 2.8/2.6, respectively) | The 3 major bacterial pathogens were Streptococcus pneumoniae (29.7%), Moraxella catarrhalis (11.7%), and Haemophilus influenzae (10.8%). Patients with S. pneumoniae colonization had significantly shorter wheezing episodes and reduced lung inflammation (including lower level of TNF-α) |
|
| Asthma natural history | Nasopharynx | Teo SM, et al. 2018[110] | 244 infants with acute respiratory tract illnesses (ARIs) followed through their first five years of life | Dominance with Moraxella, Haemophilus and Streptococcus cluster were positively associated with acute respiratory tract illness. This change frequently preceded the detection of viral pathogens and acute symptoms. These changes were associated with ensuing development of persistent wheeze in children developing early allergic sensitization |
| Nasal microbiota | Zhou Y, et al. 2019[113] | A 1 year longitudinal study in school-age children with mild-moderate persistent asthma treated with daily ICS (mean age 8.0 ± 1.8 years) | Children with nasal microbiota dominated by the commensal Corynebacterium / Dolosigranulum cluster at steady state experienced the lowest rates of exacerbation and disease progression. A switch towards the Moraxella- cluster was associated with highest risk of severe asthma exacerbation. |
|
| Lung | Mansbach JM, et al. 2020[111] | 842 infants hospitalized for bronchiolitis with a follow-up at 3 years | Increased abundance of Moraxella or Streptococcus species 3 weeks after day 1 of hospitalization was associated with an increased risk of recurrent wheezing. Increased Streptococcus species abundance the summer after hospitalization was also associated with a greater risk of recurrent wheezing |
|
| Oropharynx | Cuthbertson L, et al. 2019[112] | Oropharyngeal swabs were collected from 109 children hospitalized for acute wheezing/75 non-wheezing controls. | No significant difference in bacterial diversity between wheezers and healthy controls In wheezers, attendance at kindergarten or preschool was, associated with increased bacterial diversity.in contrast with rhinovirus (RV) infection |
|
| Nasopharynx | McCauley K. et al. 2019[35] | 312 school-age asthmatic patients enrolled in a trial of omalizumab, nasal secretion samples collected after randomization | Nasal microbiotas dominated by Moraxella species were associated with increased exacerbation risk and eosinophil activation. Staphylococcus or Corynebacterium species–dominated microbiotas were associated with reduced respiratory illness and exacerbation events. Streptococcus species–dominated microbiota increased the risk of RV. |
|
| Sputum | Abdel-Aziz MI. et al. 2020[114] | Sputum samples were collected in 100 severe asthmatics of the U-BIOPRED adult patients cohort at baseline and after 12–18 months of follow-up | Two microbiome-driven clusters were identified, characterized by asthma onset, smoking status, treatment, lung spirometry results, percentage of neutrophils and macrophages in sputum. Patients of the most severe cluster displayed a commensal-deficient bacterial profile which was associated with worse asthma outcomes. Longitudinal clusters revealed high relative stability after 12–18 months in the severe asthmatics. |
|
| Lung (BAL) | Robinson PFM, et al. 2019[34] |
Children: 35 wheezers categorized as MTW or EVW BAL obtained at steady state |
There was no relationship between lower airway inflammation or infection and clinical preschool wheeze phenotypes. 2 groups identified: 1) a Moraxella species dysbiotic microbiota cluster that associated with airway neutrophilia and a mixed microbiota; 2) a mixed microbiota cluster with a macrophage- and lymphocyte-predominant inflammatory profile |
|
BAL: Broncho-alveolar lavage; EVW: Episodic Viral Wheeze, MTW: Multiple trigger Wheeze, RSV: Respiratory syncytial virus; RV: Rhinovirus.