Turning Up the Heat: The effects of bacterial and viral co-infection in children

Background:

In young children the gastrointestinal tract (GIT) is a common infection site, with severe infections causing gastroenteritis (irritation and inflammation of the stomach and gut). These infections are most commonly caused by viruses and bacteria, although there are also cases of parasitic causes, such as giardia. Rotavirus and norovirus are most commonly found to be viral sources of infection while varieties of E. coli (EPEC and EAEC in the case of  this study) are frequent bacterial infecting agents. Globally, acute gastroenteritis (AGE), more commonly known as the stomach flu (not to be mistaken for influenza), is responsible for over 1.3 million deaths every year, about 15% of all childhood deaths in children under five (Mathew, S. et al. 2019). This early life (6 months or younger) AGE has also been linked with a significant increase in the development of asthma, allergic rhinitis (hay fever), and atopic dermatitis (eczema) later in childhood. This is exacerbated if the gastroenteritis results in a long term imbalance to the microbiome in the child’s developing GIT, with the effects potentially worsened by the application of antibiotics (Pan, H.H. et al. 2019). 

 

This image shows the common signs and symptoms of gastroenteritus: headache, fever, vomiting, muscle pain, abdominal cramps, diarrhea, and bloody stool
Figure 1. Common signs and symptoms associated with gastroenteritus. From Khan Academy

Central Goal:

The authors of this paper (Mathew, S. et al. 2019), studied the effects that viral and mixed viral-bacterial infections had on the gut microbiome and health of young children.

Evidence:

Researchers collected clinical conditions and fecal samples from 79 children (70 infected and 9 healthy), aged 3 months to 9 years (median 14 months) who visited the pediatric emergency center in Doha, Qatar. Clinical conditions included diarrhea and vomiting frequency, temperature of maximum fever, duration of hospital stay, and degree of dehydration. The fecal samples were collected before any medication was administered and used to determine the presence and composition of the viral and bacterial operational taxonomic units. An operational taxonomic unit is a cluster or group of organisms which have been lumped by similarities within a region of their genetic code; this grouping effectively separates microbes into various species.

This paper found that, “GIT microbiome in children is largely colonized by bacteria belonging to Bacteroides, Firmicutes and Proteobacteria phyla” (Mathew, S. et al. 2019). A similar abundance of these bacterial groups was also observed in Palmer, C. et al. (2007), with these three microbial phyla making up over 98% of the total microbial load in both papers. Palmer, C. et al. (2019) also found that the bacterial composition of all the infants in the experiment increased their diversity with age. As subjects neared their first birthday they started to resemble adult samples, retaining their abundant bacteroides and firmicutes communities while also seeing an increase in the abundance of verrucomicrobia and a drop in proteobacteria. In general, the more dominant adult microbiomes seem to commandeer their infantile precursors.

The taxonomic diversity and abundance of these gut bacterial communities was disrupted by the presence of a viral infection with a greater overall loss of microbial species diversity and abundance observed in patients with bacterial co-infections. This reduction in diversity was also linked to increased frequency of diarrhea and vomiting, a higher maximum fever, and an increase in hospitalization time. There was also an increased severity of infection as the age of the children decreased, which is likely due to the younger children having a less developed immune system to help fight the infection.

My Questions and Concerns

There were no norovirus cases with both EPEC (Enteropathogenic E. coli) and EAEC (Enteroaggregative) infections, these are very similar strains of E. coli although EPEC is more commonly found in young children while EAEC is commonly associated with adult AGE. It seems like the reason for not capturing any NoV + EPEC + EAEC might be due to a lack of total enrollment in the study and the relative rarity of an infection by both bacteria and NoV. There is no support in the literature for why NoV + EPEC + EAEC wouldn’t be able to simultaneously infect the same individual at the same time much like RV + EPEC + EAEC. A review by Lima, A. A. et al. (2019) primarily looks at the individual associations between each AGE causing disease and the individual. They do mention that the most abundant instance of infection by three different diseases at the same time were by EAEC + EPEC + salmonella subspecies. At the same time norovirus infections were observed to have a relatively low prevalence in children with three different pathogens.

There were no subjects in the study with only bacterial infections. While the presence of a bacterial infection alone may not have a high enough associated virulence to necessitate a hospital visit, these cases were all taken from children entering a pediatric emergency center which likely sees the most severe cases. A larger sample size may help to capture these rare cases of bacterial-only AGE if they do exist.I would have also liked to see another set of collected samples for the children in this study that looks at GIT microbiome a month or two after the initial sample was collected (a sample taken a similar amount of time before infection would be useful as well, but impossible to preemptively collect).

“When comparing the total number of bacteria genera as a whole, RV vaccinated children either with one or two doses of vaccine, showed less abundance of bacterial genera compared to non-vaccinated children” (Mathew, S. et al. 2019). What is the reason for this correlation? There is a direct relationship between rotavirus and bacterial infections in the increase of virulence.

Further Readings:

A paper by Pan, H.H. et al. (2019) does an amazing job of capturing the temporal effects (4.5 years apart) of these infections even though the primary objective of that paper is not specifically looking at this aspect of the relationship between the hosts and their diseases. There is also a great set of articles covering more about gastroenteritis at Khan Academy.

References:

  1. Kaur, P., Chakraborti, A., & Asea, A. (2010). Enteroaggregative Escherichia coli: An Emerging Enteric Food Borne Pathogen. Interdisciplinary Perspectives on Infectious Diseases, 254159. DOI: 10.1155/2010/254159
  2. Lima, A. A., Oliveira, D. B., Quetz, J. S., Havt, A., Prata, M. M. G., Lima, I. F. N., …, Guerrant, R. L. (2019). Etiology and severity of diarrheal diseases in infants at the semiarid region of Brazil: A case-control study. PLoS Neglected Tropical Diseases, 13:(2), 1–14. DOI: 10.1371/journal.pntd.0007154
  3. Mathew, S., Smatti, M. K., Ansari, K. A., Nasrallah, G. K., Al Thani, A. A., & Yassine, H. M. (2019). Mixed viral-bacterial infections and their effects on gut microbiota and clinical illnesses in children. Scientific Reports, 9:1-12. DOI: 10.1038/s41598-018-37162-w
  4. Ochoa, T. J., & Contreras, C. A. (2011). Enteropathogenic escherichia coli infection in children. Current opinion in infectious diseases, 24:5,478–483. DOI:10.1097/QCO.0b013e32834a8b8b
  5. Palmer, C., Bik, E. M., DiGiulio, D. B., Relman, D. A., Brown, P. O. (2007). Development of the human infant intestinal microbiota. PLOS, 5:7, 1556-1573. DOI: 10.1371/journal.pbio.0050177
  6. Pan, H. H., Lue, K. H., Sun, H. L., & Ku, M. S. (2019). Gastroenteritis during infancy is a novel risk factor for allergic disease. Medicine, 98:35 DOI: 10.1097/MD.0000000000016540
  7. Schnadower, D., Tarr, P. I., Gorelick, M. H., O’Connell, K., Roskind, C. G., Powell, E. C., …, Freedman, S. B. (2013). Validation of the modified Vesikari score in children with gastroenteritis in 5 US emergency departments. Journal of Pediatric Gastroenterology and Nutrition, 57(4), 514–519. DOI:10.1097/MPG.0b013e31829ae5a3
  8. What is gastroenteritis? (n.d.). Khan Academy, Retrieved from https://www.khanacademy.org