Early antibiotic exposure and development of asthma and allergic rhinitis in childhood

Overuse of antibiotics is a growing public health concern. While in the last two decades outpatient antibiotic prescriptions have decreased significantly, inpatient broad spectrum antibiotic use has continued to rise [1‐3]. In fact, despite efforts to promote conservative antibiotic stewardship in the United States, antibiotics are still the most frequently dispensed outpatient prescription medication, accounting for approximately 25% of all pediatric medication prescriptions [3]. Notably, five out of the top six prescribed medications for the children in the United States are antibiotics, with Amoxicillin and Azithromycin being the most common [3]. A large study investigating bacterial prevalence and antibiotic prescribing trends for pediatric acute respiratory tract infections (ARTIs), estimated that about 30% of antibiotic prescriptions are unnecessary [4, 5]. Consequently, there are about 11.5 million antibiotics prescribed annually for illnesses in which a bacterial pathogen is not the expected etiology of the illness, and thus antibiotics are not warranted [4]. Though antibiotics are an important part of modern healthcare, there are some potential adverse effects of which to be aware, including unwanted side effects, antibiotic resistance, and alteration of the gut microbiota. In particular, the gut microbiome hypothesis has recently emerged as a link between antibiotic exposure and disease development. It has been suggested that the relationship between early antibiotic exposure and dysbiosis of the gut microbiota may have significant implications for the health of children now and as they grow into adults.

The gut microbiota is comprised of trillions of microbes in the human intestinal tract, and contains over a thousand of different species of bacteria [6]. Previous studies have suggested that the first year of life represents a critical period of development and that by about three years of age, the microbiota is fully mature [7, 8]. The gut microbiota has also been demonstrated to play an important role in the human immune sys and maintenance of homeostasis. Alterations in the gut microbiota are a purported mechanism underlying the “hygiene hypothesis” [9], in which children who are exposed to a wide range of environmental and nutritional factors that promote a diverse and robust microbiota are less prone to atopy and asthma. In fact, gut dysbiosis has been linked to early disruptions in the regulation of the immune system [10], and thus to the development of chronic atopic and inflammatory respiratory diseases such as asthma and allergic rhinitis [11‐13]. Additionally, according to the Center for Disease Control (CDC), the prevalence of these diseases in the United States has continued to rise in the past two decades despite significant medical advancements [14]. New evidence suggests that there may be a connection between early antibiotic exposure altering the development of the gut microbiota, and subsequently the immune system, increasing the risk for developing the aforementioned diseases [15, 16]. However, relatively few studies have investigated the effects of timing of antibiotic exposure on future health outcomes, and whether there is a period during early development when the gut microbiota are most susceptible to gut dysbiosis. In addition, few studies have examined the relationship between increasing antibiotic doses and subsequent effects on propensity for disease development in a dose response relationship. Our study aims to investigate this temporal relationship, as well as the effects of early antibiotic exposure on the future propensity for disease development later in childhood. Consistent with the gut microbiome hypothesis, we hypothesize that children exposed to antibiotics during the first year of life will be more likely to be diagnosed with asthma or allergic rhinitis later in childhood, compared to children not receiving antibiotics during their first year of life. We also hypothesize that this relationship will present in a dose-dependent manner, with higher doses of antibiotics leading to increasing propensity to develop disease outcomes.

Our disease prevalence rates were comparable to national data for asthma and allergic rhinitis [19, 20]. Consistent with our hypothesis, children exposed to antibiotics throughout the first year of life were more likely to have a diagnosis of asthma when compared to children who had did not receive antibiotics in the first year of life. These results suggest that the first year of life may be an especially sensitive time for the development of asthma when an antibiotic insult is inflicted upon the developing gut microbiota. We also found a significant positive relationship between lifetime antibiotic exposure and future likelihood to have a diagnosis for asthma and allergic rhinitis compared to children who had never been exposed to antibiotics. These adjusted odds ratios were greater than the one observed in children receiving antibiotics in the first year, indicating that although the gut microbiota may stabilize and mature by the first year of life, it may still be sensitive to insult as the child grows, or that the insults may be cumulative and irreversible. In addition, we observed a significant dose response relationship in both the associations between antibiotics in the first year of life and the development of asthma, and between lifetime antibiotics and the development of asthma and allergic rhinitis. This relationship suggests that antibiotic insult to the gut microbiota may be additive, such that the more a child is exposed to antibiotics, the greater their likelihood to develop disease in childhood. This is consistent with our hypothesis that repeated antibiotics can exacerbate microbiota dysbiosis [15, 16].

Contrary to our hypothesis, we did not find a significant positive association between antibiotic exposure in the first year of life and development of allergic rhinitis. Relatively few studies have examined the relationship between antibiotics within the first year of life and allergic rhinitis; however, previous studies in different countries have indicated a weak, positive relationship between antibiotic exposure in the early stages of life and allergic rhinitis [21, 22]. Our study results may have been limited by smaller sample size from a single institution, and inability to distinguish between different antibiotic classes.

In terms of allergic rhinitis, the gut microbiota is emerging as a novel target for early intervention in the setting of rising pediatric atopic diseases. Dysbiosis in the gut microbiota has previously been correlated with allergic diseases, and past research has suggested that the gut microbiota is most sensitive to change during the first year of development. However, varying conclusions have been made regarding the association between antibiotic exposure and development of allergic diseases [23‐26]. Recent studies have suggested that a higher bacterial ratio between Klebsiella, an opportunistic pathogen, and Bifidobacterium, a commensal inhabitant of the gut microbiota, may predispose to allergic diseases [27]. In support of this, further studies have indicated that the administration of infant probiotics may alter this ratio favorably and be protective against the future development of allergic disease [28]. The effects also seem to be long-term, as previous research has demonstrated incomplete recovery of the gut microbiome and decreased microbiota diversity after antibiotic administration [29]. While our study did not find a significant correlation between first year antibiotics and allergic rhinitis, we did find a correlation between first year antibiotics and asthma which is frequently associated with allergic rhinitis [30]. Thus, it is plausible that a correlation does exist between early antibiotics and allergic rhinitis which our study did not identify. Furthermore, it is also a possibility that the first year of life is not as sensitive for antibiotics increasing the risk for developing allergic rhinitis, and that a more chronic temporal relationship exists, as we found both a significant overall and dose response relationship between lifetime antibiotics and allergic rhinitis. Further studies are required to explore this timeline.

There are several limitations to our study. First, we cannot exclude reverse causality as a reason for the positive association that we found between lifetime antibiotic exposure and asthma and allergic rhinitis, as evidence has shown that these conditions may predispose individuals to develop respiratory infections, and thus subsequently increase use of antibiotics [31]. Furthermore, the timeline between antibiotic exposure and diagnosis was not able to established in our study, increasing the risk of reverse causality. Also, diagnoses of asthma and allergic rhinitis were based on ICD 9 and 10 codes, thus these diseases could have been incorrectly coded in our sample or been missed in mild cases not formally diagnosed with ICD coding. Additionally, the average age of our sample at the time of this study was 5.7 years, and our study may require a relatively older sample in order to accurately capture development of the target childhood diseases. Antibiotic exposure was counted as number of outpatient orders placed in addition to number of times antibiotics were administered in the hospital. Routes of administration, such as oral vs. intravenous, were not distinguished, and thus could have affected exposure levels in our study. Children who received an outpatient antibiotic order may not necessarily have taken the antibiotic as prescribed and/or children may have been prescribed antibiotics from providers outside of the institution that our study was unable to capture, thus potentially skewing the dose-response relationship. Lastly, one of the major challenges in studying the relationship between the gut microbiome and disease development is acknowledging the complex and multifactorial nature of this relationship and controlling for confounding factors. Subsequently, our study controlled for age, race, gender, living in an area of poverty, NICU stay, prematurity, birthweight and delivery method [32, 33]. However, certain exposures, such as environmental factors, maternal age and antibiotic administration, and infant diet were unable to be controlled for due to the nature of data extraction, and thus may have influenced our results. Future steps to expand upon this study would include categorizing antibiotics by class (narrow spectrum and broad spectrum) and waiting for our sample size to grow to capture more disease diagnoses.

In conclusion, while not indicative of causation, our results suggest that there is a significant positive relationship between early antibiotic administration and the propensity to develop asthma and allergic rhinitis. While the first year of life does not appear to be a sensitive time period for the gut microbiota in regards to allergic rhinitis, it does appear to be important for the development of asthma, and our data further suggests that antibiotic exposure past the first year of life may still have a significant impact on the microbiota and increase the risk of developing future allergic diagnoses. Given these findings, it is plausible that antibiotics may lead to dysbiosis of the pediatric gut microbiota, lending evidence that careful antibiotic stewardship and minimal dosing should be practiced, especially in the pediatric population.