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Why is it still so difficult to treat respiratory diseases despite no new pathogens?

View: 1006 / Time: 2024-10-08
01 Background
As 2024 begins, the world is facing a peak flu season. Our attention is once again drawn  to well-known upper respiratory diseases: influenza, COVID-19, and respiratory syncytial virus (RSV). These pathogens are transmitted through normal social interactions and either lack corresponding vaccines or have low vaccination rates[1]. After the relaxation of control measures, many countries have experienced similar outbreaks of respiratory diseases in children[2,3]. One of the reasons is that the levels of antibody against respiratory pathogens decreased significantly during the period of preventive measures. As a result, the World Health Organization's chief epidemiologist also pointed out in an interview that the main reason for the current surge in pediatric respiratory diseases is the "Immunity Gap."
Additionally, other possible reasons include: 1) The current season is the peak period for respiratory pathogens. 2) The epidemic cycle of Mycoplasma pneumoniae is approximately four years, and this year happens to be a peak year. 3) Over-testing for pathogens in children has made pediatric medical treatment even more demanding.
1 
Figure 1. Comparison of current influenza surveillance data with historical data in America[4].
Currently, the most effective protective measures remain wearing masks and regular handwashing. If an infection occurs, it should be faced calmly, as recovery usually provides some level of immune protection. After this year's outbreak, the overall immunity level is expected to rise, reducing the likelihood of similar large-scale outbreaks in the future.
For children significantly affected by the immunity gap, rapid and accurate diagnosis of the cause and appropriate treatment will be more effective in quickly and effectively curing respiratory diseases, thereby alleviating parental concerns and anxiety.

02 Rapid and accurate etiological diagnosis
Rapid and accurate etiological diagnosis is crucial for respiratory infections. Traditional clinical diagnostic methods include microbial culture, antigen/antibody immunoassays, and real-time quantitative PCR. However, microbial culture is time-consuming and has low sensitivity. Antigen/antibody immunoassays and real-time quantitative PCR can only detect a limited number of suspected microorganisms at a time. Therefore, in recent years, methods based on high-throughput sequencing, such as metagenomic next-generation sequencing (mNGS) and targeted next-generation sequencing (tNGS), have gained popularity. These methods allow for the analysis of the genetic sequences of numerous pathogens in a single test, including the whole genomic composition of bacterial, viral, fungal, and other microbial communities, greatly promoting the rapid identification of pathogenic microorganisms. (Click to read "New Product Launch | NEX-t Panel: A More Precise and Cost-effective tNGS Pathogen Detection Solution" and "Application of tNGS in Pathogen Detection Analysis for Clinical Samples".)

03 Appropriate Treatment
Take Mycoplasma pneumoniae pneumonia (MPP) as an example, which has dominated pediatric outpatient clinics recently. The symptoms include persistent high fever, severe coughing, and even wheezing and difficulty breathing. Meanwhile, its Chest X-rays and CT scans usually show widespread infection. However, parents are often troubled by questions such as, "Why is azithromycin being administered daily, yet there’s no improvement?" "The fever has subsided, but the cough hasn't gotten any better," and "After 5-6 days of treatment, why is the chest X-ray still showing progression?" The underlying cause of the poor treatment response in many children is the increasing resistance of Mycoplasma pneumoniae to antibiotics. Macrolide antibiotics (such as azithromycin, roxithromycin, and erythromycin, etc.) are the recommended first-line treatment in the pediatric guidelines for MPP[5]. However, the resistance rates have exceeds 80% in pediatric patients and over 60% in adult patients.
2 
Figure 2. There are multiple strategies that microbes use to develop resistance to antimicrobial drugs.
The resistance mechanism of Mycoplasma pneumoniae to macrolide antibiotics primarily due to mutations in the 23S rRNA gene at positions 2063, 2064, or 2617. When dealing with macrolide-resistant Mycoplasma pneumoniae infections, it is advisable to use newer tetracycline antibiotics (such as doxycycline and minocycline) and quinolone antibiotics, which have proven efficacy. The gold standard method for confirming macrolide-resistant Mycoplasma pneumoniae is to perform the minimum inhibitory concentration (MIC) testing using positive colonies from solid culture. However, since the culture process requires at least 7 days, it is challenging to implement this method in clinical practice.

How to detect and guide appropriate antibiotic use in the face of various types of resistance genes in clinical settings?
Both mNGS and tNGS can detect resistance genes while identifying pathogens, with a turnaround time of less than 24 hours. However, mNGS faces challenges in excluding human genetic background, which limits the sensitivity of detecting resistance genes and results in higher costs. In contrast, tNGS analyzes only specific sequences of the pathogen, enabling the identification of pathogens and associated resistance genes with higher sensitivity.
Nanodigmbio launched the tNGS solution, NEX-t Panel v1.0, which can be used not only for the identification of thousands of pathogens (viruses, bacteria, fungi, parasites) but also for resistance analysis. The panel covers over 1,000 genes for resistance analysis, categorized as shown in the following table:
Table 1. Categories of resistance genes covered by the NEX-t Panel.
表1 
Understanding the molecular mechanisms behind the resistance phenotypes of major clinical pathogens aids in better performing drug susceptibility testing, providing a reference for rapid and accurate prescription decisions. The resistance interpretation and pathogen association databases provided by Nanodigmbio can be used for data analysis and automated reporting to improve analysis efficiency.
Antibiotic resistance often involves the cooperative action of multiple genes, leading to significant variations in corresponding treatment options. Take methicillin/beta-lactam resistance as an example, methicillin-resistant Staphylococcus aureus (MRSA) exhibits resistance due to the presence of mecA gene. The mecA gene encodes penicillin binding protein 2a (PBP2a), which has low affinity for β-lactam antibiotics. Therefore, strains carrying the mecA gene are resistant to β-lactam antibiotics, such as penicillins and cephalosporins. However, these strains may still be sensitivity to newer cephalosporin antibiotics like ceftaroline.
Some MRSA strains may be negative for the mecA gene but carry another mec gene, the mecC gene. The mecC gene encodes the PBP2c protein, which similarly exhibits low affinity for β-lactam antibiotics, leading to resistance. mecC-positive MRSA strains typically exhibit resistance to cefoxitin but sensitivity to Oxacillin in terms of their antimicrobial susceptibility profiles.
To fully interpret resistance gene detection, it is essential to consider the entire information flows from disease, pathogen, to resistance or virulence genes. This comprehensive approach ensures a more accurate correlation of results with clinical pathological phenotypes, thereby enhancing the rationale for analysis and effectively guiding clinical treatment decisions.

04 Conclusion
Recently, large-scale outbreaks of Mycoplasma pneumoniae pneumonia and influenza caused by virus around the world are likely residual effects of the immunity gap following the relaxation of control measures. With the prevalence of respiratory pathogen infections, the issue of pathogen resistance cannot be ignored. Viruses, due to their simple structure, are more prone to genetic mutations, leading to the emergence of new strains that can evade existing immunity, making viruses highly susceptible to resistance. To address the challenges of resistance in influenza viruses, mycoplasma pneumoniae, and other respiratory pathogens, there is an urgent need for a rapid and sensitive detection system. Nanodigmbio has launched the tNGS solution, specifically the NEX-t Panel v1.0, which is designed for pathogen identification and resistance testing, providing a more economical and convenient approach to addressing these critical healthcare needs.

Reference
[1] https://www.chinacdc.cn/
[2] Riepl A, Straßmayr L, Voitl P, et al. The surge of RSV and other respiratory viruses among children during the second COVID-19 pandemic winter season[J]. Frontiers in Pediatrics, 2023, 11: 1112150.
[3] Eden J S, Sikazwe C, Xie R, et al. Off-season RSV epidemics in Australia after easing of COVID-19 restrictions[J]. Nature Communications, 2022, 13(1): 2884.
[4] https://www.who.int/
[5] National Health Commission of the People’s Republic of China. Guidelines for the diagnosis and treatment of Mycoplasma pneumoniae pneumonia in children (2023 edition)[J]. International Journal of Epidemiology and Infectious Disease, 2023, 50(2): 79-85.

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