Tackling Respiratory Infections in the 21st Century

Introduction
Respiratory infection trends
Antimicrobial resistance and respiratory infections
Using data for surveillance
Influenza prevention and treatment
Diagnosis of respiratory infections
Current instances of diagnostic platforms
How COVID-19 changed the picture
References
Further reading

Introduction

While earlier ages of the world were marked by devastating plagues of infectious disease, with millions of deaths, the new century boasted incredible advances in medical science that led to its eventually being termed ‘modern medicine.’ Along with better healthcare availability and the provision of sanitary facilities, water, and other hygiene essentials, infections became less common and their impact noticeably less.

However, infections are still a major contributor to the disease burden in developing areas of the world, even today. Older infectious conditions refuse to die out, even as new ones emerge.

The main architects of this shift include the anthropogenic changes in demographic, climatic, and technological profiles over the last few years. The encroachment of human activity and dwellings into the habitat of wild creatures has increased the risk of spillover of viruses, bacteria, fungi, and protozoal infections into humans.

*Image Credit: Buravleva stock/Shutterstock.com*

The subsequent spread of these pathogens is then driven by factors such as loss of immunity to specific disease agents, increasing aging of the population, the emergence of novel strains or new virological characteristics, and the change in the habitat of the animal hosts and vectors driven both by human activity and climate change.

Air pollution, linked closely to the use of fossil fuels in industry, transport, and electricity generation, among other uses, is another major contributor to the risk of respiratory viral infections. This is especially so in slums and among the marginalized and poor.

Globalization promotes the faster and farther spread of pathogens and their vectors into new populations via animal and animal product trade, human movement, and changing transportation patterns.

Respiratory infection trends

Lower respiratory tract infections are now the third leading killer in the world today, exacerbated by the rise of antimicrobial resistance. Post-transplant viral infections with organisms other than the commonly seen cytomegalovirus and Epstein-Barr virus (EBV) are also being detected with higher frequency as medicine advances.

Fungal respiratory infections are becoming more frequent, while uncommon fungal pathogens are being identified in people with severe immunodeficiency from any cause. Tuberculosis has been spreading more rampantly than ever before since the onset of drug resistance, with multi-drug resistance posing an intractable problem worldwide.

What makes tuberculosis (TB) the world's most infectious killer? – Melvin Sanicas

Coinfection with HIV/TB is another diagnostic conundrum that is very difficult to treat, especially as pediatric and elderly tuberculosis is on the rise. Biologics such as anti-tumor necrosis factor (TNF)-α drugs, used to treat autoimmune disease, can also cause the reactivation of dormant TB. This disease causes 5,000 deaths a year, or almost a couple of million deaths a year.

Another possibility is the increase in occupational lung disease due to the airborne circulation of microbes such as influenza, varicella, respiratory syncytial virus, and hantavirus. Tuberculosis remains the most significant occupational infection globally, with infection rates being 5-10-fold increased in healthcare workers and symptomatic TB being up to 5-fold higher.

Protozoa and helminths continue to cause lung disease in many regions. The risk can only increase as HIV, solid organ transplants and immunosuppression predispose to reactivating dormant infestations.

Influenza, severe acute respiratory syndrome viruses, and RSV cause the highest proportion of hospitalizations and deaths due to respiratory infection. Influenza A has multiple subtypes characterized by different combinations of hemagglutinin and neuraminidase antigens. The flu viruses are likely to continue to threaten human health well into the future.

The ongoing outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has taken over 6 million lives in its sudden and vicious progression over the world in just over two years.

Antimicrobial resistance and respiratory infections

Antimicrobial resistance (AMR), coupled with genetic modifications through recombination, gene reassortment, or cascade mutations, have led to viruses crossing the species barrier, with a higher risk for the emergence of pandemic viruses.

A recent study in The Lancet reported that respiratory infections were among the top three infectious syndromes most closely associated with severe outcomes due to antimicrobial resistance (AMR). Chest infections attributable to AMR caused over 400,000 directly-associated and 1.5 million indirectly-associated deaths.

Using data for surveillance

A fresh and extensive evaluation of the risk posed by infectious respiratory disease is urgently required. The utility of global surveillance was demonstrated during the ongoing coronavirus disease 2019 (COVID-19) pandemic.

Such surveillance and data collection from integrated sources, including digital surveillance, can yield interesting and fruitful results using novel bioinformatics tools. This data is crucial in predicting and preparing for overwhelming waves.

Influenza prevention and treatment

Antigenic drift and occasional antigenic shifts threaten human health by producing new variants that evade pre-existing immunity. This means new vaccines have to be formulated each year, targeting high-risk groups such as the elderly, pregnant women, children below the age of five, healthcare workers, and people with certain predisposing illnesses.

Research into the production of a universal influenza vaccine or broadly neutralizing antibodies is urgently needed, considering the suboptimal levels of immunity, its rapid waning with current vaccines, and the delay in producing a new vaccine following an antigenic shift.

Oral medications

Oral influenza medications such as the neuraminidase inhibitor (NAI) oseltamivir, zanamivir, laninamivir, and peramivir are used both for treatment and post-exposure prophylaxis. Oral COVID-19 medications to prevent the progression of mild disease to severe have proved highly acceptable and useful.

While oseltamivir resistance is on the rise, the others remain effective. Also available are baloxavir and favipiravir, the first being an endonuclease inhibitor and the latter a broad-spectrum antiviral. Anti-hemagglutinin antibodies and non-NAIs like pimodivir are also being developed.

The anti-RSV monoclonal antibody palivizumab, created by Astra-Zeneca, is now marketed by Swedish Orphan Biovitrum AB (publ) (Sobi) for protecting at-risk infants during high-incidence periods. Moderna, which created the second messenger ribonucleic acid (mRNA) COVID-19 vaccine, developed an RSV mRNA vaccine.

Diagnosis of respiratory infections

Simple, rapid, and relatively inexpensive diagnostic testing is a must to identify respiratory infections early enough to prevent severe disease. Recent advances include lab-on-a-chip (LOC) technologies that use microfluidic components with biosensors to carry out a complex test with rapidity and specificity, using tiny amounts of reagent and sample, with very low costs. These platforms can be used as multiplexed assays for point-of-care testing (POCT).

Along with the use of oral medications at an early stage, the POCTs may reduce the toll of respiratory infections and the risk of outbreaks and AMR. Newer POCT platforms use smart materials and approaches based on nucleic acid amplification techniques (NAAT); virus epitope recognition by antibodies, aptamers, or cavities combined with optical, electrical, electrochemical, magnetic, or other techniques to produce a detectable signal; and immunological tests for viral detection.

The CRISPR-based systems can detect nucleic acid very efficiently, especially with Cas-systems like SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) from Sherlock Biosciences, aimed at SARS-CoV-2.

Serological Testing for COVID-19

Other POCT devices use non-molecular methods, such as nanoparticles, to detect biomolecules in real-time with very high sensitivity and a short turnaround time. Immunofluorescence tests are also in use, as are enzyme-linked immunosorbent assays (ELISA), protein arrays, and photon excitation assays.

Biosensors provide rapid, portable, and sensitive miniaturized platforms for the detection of antigens or antibodies. Surface plasmon resonance (SPR) uses reflectance based on biomolecule-metal surface binding to detect specific targets. Hybrid nanobiomolecules or transistor-coupled DNA probes are other approaches

Whole-genome sequencing (WGS) using high-throughput portable platforms, and next-generation sequencing (NGS) technologies, also provide rapid, efficient viral detection. Multiplex LOC systems will allow several pathogens to be tested with one sample, saving time and samples.

Current instances of diagnostic platforms

Examples of such systems include the Alere BinaxNOW® (formerly Alere i) Influenza A&B platform (Abbott, United States), the QuickVue® Influenza A + B (Quidel Corporation, United States) and the FILMARRAY Respiratory Panel (bioMérieux, France).

Others include Nanosphere Verigene® RV+ test, and Hologic Gen-Probe Prodesse assays. These are based on PCR technology. Others like mariPOC® Respi test (ArcDia International Oy Ltd,Finland), BD veritor™ Influenza A + B, BD veritor™ RSV (Becton Dickinson, United States), and SD Bioline Influenza Ag (Standard Diagnostics Inc., Korea) are non-NAAT assays.

Meanwhile, integrated sample preparation and testing systems like the cobas® Liat® system (Roche Diagnostics, Switzerland) and GeneXpert (Cepheid, United States) are now available for influenza A, influenza B, SARS-CoV-2 and RSV simultaneous testing.

How COVID-19 changed the picture

In less than a year, the COVID-19 pandemic led to an unprecedentedly rapid rollout of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The non-pharmaceutical interventions implemented in this period brought other respiratory infections down to a record low in most countries. Now, with relaxations rife, a rebound surge in these diseases is on the horizon.

Pre-pandemic, influenza and respiratory syncytial virus (RSV) infections themselves caused over 30,000 hospitalizations and 3,000 deaths weekly at their peak. During the pandemic, mask-wearing in public became commonplace. So did vaccination and the use of rapid antigen tests for diagnosis following exposure to SARS-CoV-2.

Importantly, all these steps could be used with great success to counteract the flu, RSV, and other contagious respiratory diseases as well. Moreover, a number of biosensors have been designed for remote SARS-CoV-2 diagnosis and data collection. These gave rise to the popular lateral flow assays (LFA) and microfluidic analytic devices.

*Image Credit: steved_np3/Shutterstock.com*

LFA are cheap, sensitive, and easy to use and have already been used to diagnose the flu and other viruses. All these can be adopted for the mass diagnosis and early treatment of respiratory infections.

New, more convenient sample types are being explored, including saliva and exhaled air, for both diagnosis and monitoring. The Internet of Things (IoT) can integrate data from medical devices, imaging, laboratory tests, healthcare providers, treatment plans, and telehealth data to detect changes early. When coupled with global positioning systems (GPS), outbreaks can be picked up in advance.

The IoT has been co-opted to COVID-19 management through many robots and applications, like ‘RapidPlex,’ a graphene-sensor-based multiplexed telemedicine platform for COVID-19 biomarkers developed by the California Institute of Technology (Caltech).

Optimizing nano-enabled viral biosensing, IoT, and artificial intelligence (AI) could open avenues for various integrated low cost highly performant detection technology for error-free, smart controlling at a personalised level. IoT technology coupled with POCT platforms would be instrumental in offering diagnostic platforms and therapeutic approaches for future global health challenges.”

Potential COVID-19 treatments include interferon-based therapies that may prevent and reduce morbidity and mortality. These agents could possibly help dampen the impact of future pandemic viruses while specific antivirals and vaccines are being developed.

The outcome may be a future that is not obsessively focused on COVID-19 prevention alone but on improving the quality of inspired air to prevent multiple airborne respiratory infections together by learning from the innovations of this period.

References

Baker, R. E. et al. (2021). Infectious Disease in An Era of Global Change. Nature Reviews Microbiology. https://doi.org/10.1038/s41579-021-00639-z. https://www.nature.com/articles/s41579-021-00639-z
Cold, Flu … and COVID Season (2022). https://publichealth.jhu.edu/2022/cold-flu-and-covid-season.
Antimicrobial Resistance Collaborators (2022). Global Burden of Bacterial Antimicrobial Resistance In 2019: A Systematic Analysis. The Lancet. https://doi.org/10.1016/S0140-6736(21)02724-0. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02724-0/fulltext
Park, S. et al. (2019). Emerging Respiratory Infections Threatening Public Health in The Asia-Pacific Region: A Position Paper of the Asian Pacific Society of Respirology. https://doi.org/10.1111/resp.13558. https://onlinelibrary.wiley.com/doi/full/10.1111/resp.13558
Peltola, V. et al. (2021). Editorial: Respiratory Virus Infection: Recent Advances. Frontiers in Medicine. https://doi.org/10.3389/fmed.2020.00257. https://www.frontiersin.org/articles/10.3389/fmed.2020.00257/full
Principi, N. et al. (2019). Drugs for Influenza Treatment: Is There Significant News? Frontiers in Medicine. https://doi.org/10.3389/fmed.2019.00109. https://www.frontiersin.org/articles/10.3389/fmed.2019.00109/full
Pircalabioru, G. G. et al. (2022). Advances in the Rapid Diagnostic of Viral Respiratory Tract Infections. Frontiers in Cellular and Infectious Microbiology. https://dx.doi.org/10.3389%2Ffcimb.2022.807253. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8895598/
Afroj, S. et al. (2021). Graphene‐Based Technologies for Tackling COVID‐19 and Future Pandemics. Advanced Functional Materials. Graphene‐Based Technologies for Tackling COVID‐19 and Future Pandemics. https://doi.org/10.1002/adfm.202107407. https://onlinelibrary.wiley.com/doi/10.1002/adfm.202107407
Schmidt, A. C. et al. (2001). Current research on respiratory viral infections: Third International Symposium. Antiviral Research. https://dx.doi.org/10.1016%2FS0166-3542(01)00136-X. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133842/
Mesic, A. et al. (2022). Interferon-Based Agents for Current and Future Viral Respiratory Infections: A Scoping Literature Review of Human Studies. PLOS Global Health. https://doi.org/10.1371/journal.pgph.0000231. https://journals.plos.org/globalpublichealth/article?id=10.1371/journal.pgph.0000231
Basile, K. et al. (2018). Point-Of-Care Diagnostics for Respiratory Viral Infections. Expert Reviews in Molecular Diagnosis. https://dx.doi.org/10.1080%2F14737159.2018.1419065. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103700/#S0002title
Nelson, P. A. et al. (2020). Current and Future Point-of-Care Tests for Emerging and New Respiratory Viruses and Future Perspectives. Frontiers in Cellular Infection and Microbiology. https://doi.org/10.3389/fcimb.2020.00181. https://www.frontiersin.org/articles/10.3389/fcimb.2020.00181/full

Tackling Respiratory Infections in the 21st Century

Introduction

Respiratory infection trends

Antimicrobial resistance and respiratory infections

Using data for surveillance

Influenza prevention and treatment

Oral medications

Diagnosis of respiratory infections

Current instances of diagnostic platforms

How COVID-19 changed the picture

References

Further Reading

Dr. Liji Thomas