Flu remains a significant global health threat, causing severe illness and complications, especially for vulnerable groups such as the elderly, children, and individuals with underlying health conditions. Research shows that flu symptoms can be mistaken for a common cold, leading to delays in treatment. Studies highlight age-related differences in symptoms, complications, and death rates, with young children and elderly adults being more affected. New findings also uncover the role of a specific sensory pathway that signals illness to the brain, which may lead to more effective treatments in the future.
Despite the gradual fading of the COVID-19 pandemic, our concern for infectious diseases seems to have waned. However, influenza and other respiratory infections remain significant causes of global death and hospitalization, and their threat should not be underestimated.
Influenza is not just a simple cold; it often brings about more severe symptoms throughout the body, such as prolonged high fever, extreme fatigue, severe cough, and difficulty breathing. One of the key features of the flu is its rapid progression—the symptoms can worsen quickly within a short time, especially for individuals with underlying conditions or weakened immune systems. Influenza can lead to serious complications and even prove fatal.
Because flu symptoms are so similar to those of a common cold, many people mistakenly treat the flu as a regular cold, opting for self-care or over-the-counter medications. This approach can have serious consequences. In fact, the dangers of influenza far exceed what we might assume.
Global Research Reveals the Multifaceted Impact of Influenza
A global study, published in the Open Forum Infectious Diseases journal under the title "Age Differences in Comorbidities, Presenting Symptoms, and Outcomes of Influenza Illness Requiring Hospitalization: A Worldwide Perspective From the Global Influenza Hospital Surveillance Network", unveiled the different effects of influenza across various age groups. This research, conducted by the Global Influenza Hospital Surveillance Network (GIHSN), covered 18 countries and analyzed data from over 16,000 hospitalized patients during the 2018-2019 flu season. The results highlighted significant age-related differences in flu complications, symptoms, and mortality.
The GIHSN used standardized monitoring across 19 global locations, including the northern and southern hemispheres and tropical regions. Patients meeting the influenza-like illness (ILI) criteria—fever, headache, body aches, discomfort, and at least one respiratory symptom—were recruited. After confirming the flu infection through RT-PCR, detailed data on demographics, pre-existing conditions (e.g., cardiovascular disease, diabetes, chronic obstructive pulmonary disease), and clinical outcomes (ICU admissions and mortality rates) were collected.
The study confirmed that the A/H1N1pdm09 strain was the most widespread (accounting for 49.2% of confirmed cases), although all four flu strains (A/H1N1pdm09, A/H3N2, B/Yamagata-like, and B/Victoria-like) were observed worldwide. However, the study found significant age-related differences in viral strain and patient characteristics:
- Symptoms: Fever and cough were the most common symptoms, but their prevalence decreased with age. On the other hand, shortness of breath, which is rare in younger adults, significantly increased with age, suggesting different clinical presentations of the flu in older adults.
- Complications: The rate of complications varied by age and geographic location. Children under 5 typically had no pre-existing conditions, while older adults had higher rates of cardiovascular diseases, diabetes, and chronic obstructive pulmonary disease. Low-income regions saw higher rates of infections with co-morbidities like HIV and tuberculosis.
- Viral Strain Distribution: A/H1N1pdm09 was more prevalent in younger populations, while A/H3N2 was more common in older adults. B-type flu virus was predominantly detected in both the youngest and oldest age groups. This finding underscores the importance of considering the circulating strains when assessing the risk of severe flu.
- Mortality and ICU Admissions: Older adults and those with diabetes or chronic obstructive pulmonary disease had significantly higher risks of death or ICU admission. Interestingly, the risk was lower for males. Flu vaccination was associated with a reduced risk of complications. Notably, people of all ages had cases requiring ICU admission or resulting in death, illustrating the broad impact of the flu.
Figure caption: Odds ratios (circles) and corresponding 95% confidence intervals (horizontal lines) in the logistic regression model for the composite severe outcome of death or intensive care unit admission among laboratory-confirmed influenza cases during the 2018/2019 influenza season
Overall, this research emphasizes the critical role both the virus itself and individual patient factors play in the development of severe flu. The age-related differences in complications and symptoms significantly affect the severity and outcomes of the disease, making timely medical intervention crucial.
Sensory Pathways Play a Key Role During Infection
A major symptom of the flu is the feeling of "weakness." This is not just an exaggeration; it’s the body's way of signaling that you need to stop and rest.
A groundbreaking study by Harvard Medical School researchers in 2023 revealed the scientific mechanism behind this sensation of weakness—an unknown sensory pathway that detects prostaglandin E2 (PGE2) through specific neurons and sends signals to the brain, triggering the sickness response. These neurons are located in the glossopharyngeal nerve, playing a pivotal role during infections.
The researchers confirmed the role of PGE2 and its interaction with the EP3 receptor in the sickness behavior during flu infections. They infected mice with the H1N1 flu virus and observed typical disease behaviors, including reduced food and water intake, decreased activity, weight loss, and eventually, lower survival rates as the virus dose increased. Significantly, they found that administering ibuprofen or aspirin (which inhibit PGE2 synthesis) significantly alleviated these symptoms and improved survival rates. This was further confirmed by blocking the EP3 receptor, which replicated the effects of the drugs.
To locate the precise location of the EP3 receptor, the researchers used genetically modified mice to conditionally knock out the Ptger3 gene (which codes for the EP3 receptor). Their experiments confirmed that blocking the EP3 receptor in peripheral neurons rather than central neurons led to a significant reduction in flu symptoms, confirming the key role of peripheral EP3 receptors.
Figure caption: Rare transcriptome-defined sensory neurons mediate influenza responses
The team identified a specific subgroup of neurons in the glossopharyngeal nerve expressing the Gabra1 gene as the crucial players in this pathway. Knocking out the EP3 receptor in these neurons resulted in significantly reduced disease symptoms, similar to the effects of ibuprofen.
To conclusively confirm the role of Gabra1 neurons, the researchers used two approaches: diphtheria toxin-mediated ablation of Gabra1 neurons and bilateral glossopharyngeal nerve transection. Both approaches significantly reduced influenza-induced disease symptoms, further demonstrating that these neurons are a key component of the airway-to-brain sensory pathway.
Note: PGE2 (prostaglandin E2) acts through glossopharyngeal sensory neurons
These findings have important implications for developing new treatments for the flu and other respiratory diseases. Targeting this specific sensory pathway could offer a more effective and targeted approach to alleviating symptoms and potentially easing the burden of these diseases. In the future, interventions targeting this pathway could help patients recover faster, minimizing the discomfort and inconvenience caused by the flu.
The Ease of Influenza Transmission, Especially Among Children
Influenza viruses spread quickly within households, with children being particularly important sources of transmission. While treating infected individuals promptly is important, it’s equally essential to isolate them from others to prevent further spread of the virus.
A new study published in PNAS Nexus explored the dynamics of viral shedding and symptom expression, offering new perspectives for improving isolation strategies to curb transmission.
Viral shedding refers to the process of virus release from an infected individual into the environment, which is a key step in virus transmission. Researchers from the CDC and other institutions conducted a multi-season family transmission study from 2017 to 2020, tracking flu infections within households. Participants provided nasal swabs and daily symptom diaries. The nasal swabs were analyzed using RT-qPCR to measure viral load, while symptom diaries recorded the presence of eight flu-like illness (ILI) symptoms: fever, cough, sore throat, runny nose, nasal congestion, fatigue, shortness of breath, and wheezing.
The study established three symptom scores:
- SILI: A weighted score for fever, cough, and sore throat.
- SANY: A weighted score focusing on fever, shortness of breath, and wheezing, emphasizing lower respiratory symptoms.
- SUNW: A non-weighted count of all reported symptoms.
Using this data, the researchers developed models to analyze the relationship between viral shedding (Ct values) and symptom scores, considering factors like age and vaccination status. The best-fitting models were used to estimate key metrics such as the duration and peak of viral shedding and symptoms, and to simulate the impact of different isolation strategies.
The study involved 116 households with sufficient data. Key findings include:
- Age Differences: Children under 5 had significantly higher viral shedding peaks, longer shedding durations, and higher ILI symptom scores compared to older age groups, indicating that young children may be more important spreaders of the virus.
- Pre-symptomatic Shedding: Most participants (63 out of 105) shed less than 10% of the total viral load before symptoms appeared, suggesting that while pre-symptomatic shedding occurs, it represents a smaller proportion of total viral shedding.
- Post-isolation Shedding: Viral shedding after the recommended isolation period (24 hours after fever subsides or 5 days after symptom onset) varied depending on individual factors and assumptions about viral infectivity, highlighting the difficulty in establishing universally effective isolation periods.
- Vaccination Impact: Vaccination status influenced symptom dynamics, particularly with the SILI score, suggesting that vaccination may modify symptom severity or duration.
- Infectiousness: The study emphasized that Ct values represent total viral RNA, not necessarily infectious virus. They explored different assumptions about viral infectivity at various time points, showing that the residual transmission potential after isolation depends heavily on these assumptions.
These findings indicate that while current isolation strategies are helpful, they may not fully capture the transmission dynamics of the flu, particularly among young children. Further research is needed to better understand the relationship between viral load, infectivity, and symptoms, allowing for optimized isolation strategies and reduced flu transmission.
Conclusion
The research highlighted above underscores that influenza is much more than a common cold. It’s a serious acute respiratory infection with severe symptoms and complications, especially for the elderly, children, and those with underlying health conditions. Additionally, the differences in symptoms, complications, and viral strains across age groups further stress the importance of timely medical diagnosis.
Researchers have also discovered a key sensory pathway that alerts the brain during flu infection, paving the way for the development of more effective treatments.
Furthermore, the research confirms that flu viruses spread easily within households, with children being more likely to transmit the virus. While isolation measures are effective, further studies are needed
