CLINICAL MATTERS
A flurry of respiratory illnesses in the last few weeks triggered school closures anew. Thankfully, it wasn’t from a resurgence of Covid-19 cases. Neither was it from Nipah virus, which triggered some panic in Cagayan de Oro but was found to be fake news. While there were several viruses implicated in the recent spate of respiratory infections, including RSV (respiratory syncytial virus) and a smattering of SARS-CoV-2, the most common respiratory virus identified was influenza.
We got a bit of a break from the flu during the Covid-19 pandemic partly because of the measures we used such as masking and physical distancing. Now that these public health standards are no longer mandatory, influenza is picking up the slack.
Influenza, much like SARS-CoV2, uses RNA (ribonucleic acid) as its genetic material. Compared to DNA, RNA is much more prone to mistakes and mutations. In addition, the genome of influenza is divided into eight segments. When two different virus subtypes infect the same cells, it can mix up the different segments and give rise to a new recombinant virus.
There are four antigenic types of influenza viruses: influenza A, B, C, and D. Influenza A and B are the ones that are of public health importance and covered by the vaccines. Between these two, influenza A is the one that causes pandemic influenza. It is the most clinically important type. This is why the influenza vaccines have classically included two subtypes of influenza A and only one lineage of influenza B. In recent years, influenza B has been causing more disease and so the current vaccines now contain two subtypes of A and two lineages of B—a quadrivalent vaccine as opposed to the old school trivalent vaccines. Recently the WHO noted that influenza B/Yamagata has not circulated since 2019, and next year’s vaccines might be trivalent again.
Influenza A viruses are named based on two important surface proteins: hemagglutinin (H) and neuraminidase (N). These proteins have many subtypes—H has 18 subtypes and N has 11 subtypes—and mixtures of the protein subtypes are used in the standard nomenclature describing influenza A subtypes. For instance, the pandemic virus from 2009 is officially named influenza A(H1N1)pdm09. This means it is influenza type A, with a subtype 1 H gene and a subtype 1 N gene, and it caused the pandemic of 2009. Another notorious A(H1N1) is the Spanish flu from 1918. Influenza B viruses are not referred to as subtypes but are grouped into lineages based on the place where they were initially isolated from: B/Yamagata and B/Victoria are the current circulating lineages, which have further “clades” and “subclades” under them.
While most people who develop influenza will get better on their own, some people develop severe disease and can have life-threatening complications. These complications include severe viral pneumonia, post-viral bacterial pneumonia, and acute respiratory distress syndrome (ARDS). Elderly and immunocompromised patients are at highest risk for severe disease and should be prioritized for vaccination. For the rest of the population, even if they do not develop severe disease, influenza infection can have a significant impact in terms of missed workdays and productivity. This is why influenza vaccines are recommended for everyone.
Influenza vaccine efficacy depends on whether the actual circulating virus subtype or lineage matches the ones selected for the vaccine. Because it takes several months to produce influenza vaccines, the selection of which subtypes and lineages to include is an imperfect process. Vaccine efficacy against symptomatic influenza generally ranges from 40 percent to 60 percent. The true value of influenza vaccination, however, is in its ability to prevent severe disease and ICU admission in the elderly. Some studies have shown that flu vaccines can prevent up to 80 percent of ICU admissions. Even if the flu vaccine subtype isn’t an exact match with the one causing an infection, it is thought that the vaccine subtypes still provide partial protection against infections and severe disease. Each year, flu vaccination prevents millions of influenza infections, tens of thousands of hospitalizations, and thousands of deaths.
Influenza can be treated with antiviral medications. The current drug of choice is oseltamivir. It is an oral drug that is taken twice a day for five days. As early as 2009, we reported some instances of drug resistance mutations in A(H1N1)pdm09 against oseltamivir in the Philippines but this was not very common. Another drug, zanamivir, is an inhaled antiviral but is not available locally. Favipiravir, which was briefly used during the Covid-19 pandemic, was developed. It is still used as an anti-viral against influenza. The very first commercially available antiviral against influenza was amantadine. Unfortunately, it was mixed in with feed to prevent influenza among chickens, and circulating flu viruses became resistant to it. Nowadays, amantadine resistance is up to 98 percent in seasonal influenza viruses and the drug is no longer viable as an antiviral.
Influenza infects not only humans, but also birds, pigs, and other animals. Avian influenza, including A(H5N1) and other subtypes, is particularly deadly to humans when it makes the jump between species. Fortunately, avian influenza is not efficiently transmitted between humans. This is because it has the tendency to target human cells that are deep in the lungs—hence causing severe pneumonia—and not cells in the throat.
Human influenza viruses that target the throat are more contagious because they are closer to the surface and are present in large numbers that can be sneezed or coughed out.
Since these viruses don’t affect the deeper lung cells, however, they don’t cause as much severe pneumonia compared to bird flu. Influenza from pigs is perhaps more concerning because pigs can be easily infected by human and avian influenza viruses where these can mix and give rise to new viruses that can infect both throat and lung cells. A(H1N1)pdm2009 was one such virus that originated from pigs and caused a pandemic.
Prior to Covid-19, most infectious diseases doctors thought that the next deadly pandemic was going to be influenza. This is due to historical precedent, such as the Spanish flu, and the propensity of influenza A to reassort and mix in different animal hosts. The threat of a deadly influenza pandemic is a clear and present danger and should not be overlooked.
While we do have vaccines and effective treatment, the hundreds of millions of people who get sick every year not to mention the circulating viruses in animal reservoirs can give rise to a truly awful virus.
Getting your flu vaccine, wearing masks when cases are high, and applying the lessons of the Covid-19 pandemic will go a long way toward protecting us from this deadly virus that is very much around.