Opportunistic etiological agents causing lung infections: emerging need to transform lung-targeted delivery
Engineered Universal Blood Made Possible By Bacterial Enzymes
Credit: Mathias Jensen
Bacterial enzymes can cleave sugars that are part of a type A or B blood cell antigen, converting them to type O.
Bacterial enzymes may help increase the supply of universal blood.
There is an outsize demand for type O blood, specifically because it includes red blood cells that can be transfused into anyone without the risk of the recipient's immune system attacking those cells. This is because types A and B blood cells have characteristic sugar molecules attached to the H antigen, while type O blood cells simply present the H antigen. This feature makes type O blood the most valuable in an emergency when a patient needs a transfusion but there's no time to determine their blood type. This demand means that type O blood is the first to run out during a blood shortage, but a solution may be on the way.
Labs from Lund University and the Technical University of Denmark led by Martin Olsson and Maher Abou Hachem, respectively, took enzymes from a bacterium called Akkermansia muciniphila, which degrades mucin in the human gut. The mucin that A. Muciniphila targets has sugar molecules on its surface, similar to those on type A and B red blood cells, which make the enzymes this bacterium produces an attractive prospect for blood conversion. The enzymes were able to degrade the sugars on the surface of blood cells and convert type A and B blood to universal O blood. (Nat. Microbiol. 2024, DOI 10.1038/s41564-024-01663-4)
As early as 1982, researchers used an enzyme called α-galactosidase from green coffee beans to remove the characteristic sugar from the surface of type B blood cells and convert them to type O (JAMA, J. Am. Med. Assoc. 1982, DOI 10.1001/jama.1982.03320260004002). While this suggested that enzymatic blood conversion is possible, not all the blood cells created by that process were compatible with recipient plasma. The cause for that wasn't clear.
The new research suggests that enzymes used in the past were likely not accounting for extended forms of the surface antigens found on type A and B red blood cells.
"We knew they were there," Olsson says. "But everyone thought they were harmless." The researchers now believe that these extensions probably do matter and that the enzymes from the gut bacteria identified by this group can target these extensions. Up to 98% of the engineered O cells that were made from type B passed the compatibility test, and almost 50% of the cells made from type A passed. This is likely because type A cells are a more complicated target, with three extended forms, while type B cells have only one known extended form.
These enzymes have another critical advantage over the coffee bean enzyme used previously: they're much more efficient, and as a result, you need fewer of them to convert the blood cells. This saves enzymes and reduces the risk of possible off-target effects.
That risk may not be completely gone, however. "We don't know what else those enzymes they are adding might be doing. Because there may be other important sugars on the surface of the red blood cell that are being removed that, in another context, could cause issues," says Stephen Withers, a researcher who is on the board of directors for Avivo, a company that's developing more universally accepted blood and organs. He was not involved with the study and published a separate method for converting type A blood in 2019.
Hachem mentioned that avoiding unintended effects is important and an issue the team will continue to study. The researchers may also need to identify additional enzymes to convert blood antigen extensions that have not yet been discovered.
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Pneumonia: What To Know
Pneumonia is a lung infection that can range from mild to so serious that you have to go to the hospital. It happens when an infection causes air sacs in your lungs (the alveoli) and tubes in your airways that connect to them (bronchioles) to fill with fluid or pus. That can make it hard for you to breathe in enough oxygen.
Anyone can get this lung infection. But children younger than 2 and people over 65 are at higher risk. That's because their immune systems might not be strong enough to fight it. Lifestyle habits, like smoking cigarettes and drinking too much alcohol, can also raise your chances of getting pneumonia.
You can get pneumonia in one or both lungs. Pneumonia in both lungs is sometimes called bilateral pneumonia or double pneumonia. You can also have pneumonia and not know it. This is sometimes called walking pneumonia.
Causes include bacteria, viruses, and fungi. If your pneumonia results from bacteria or a virus, you can spread it to someone else.
Pneumonia can be grouped into types based on what caused it. Many things can lead to pneumonia, but some of the most common are:
Bacterial pneumonia
More people get this type of pneumonia than any other. While several types of bacteria can cause it, the most common in the U.S. Is streptococcus. People sometimes get bacterial pneumonia after a viral infection like a cold or the flu.
Viral pneumonia
Viruses, such as cold and flu viruses, cause about a third of all cases of pneumonia. They're the most common cause of the condition in children under 5. This type of infection isn't usually as serious as bacterial pneumonia, but it can be. Viral pneumonia raises your risk of also getting bacterial pneumonia.
Fungal pneumonia
Fungi found in dirt or bird poop can also cause a pneumonia infection. This type is more likely to affect people with weaker immune systems, such as those who have long-lasting health problems.
Walking pneumonia
This is a nickname for a less serious type that's officially called mycoplasma pneumonia. It's named for the bacteria that causes it. Young adults and older children most often get this type, which often doesn't require bed rest.
Your symptoms can vary, depending on the cause of your pneumonia, your age, and your overall health. They usually develop over several days.
Common signs of pneumonia include:
Along with these symptoms, older adults and people with weak immune systems might be confused or have problems with thinking. They might also have a lower-than-usual body temperature.
The symptoms of viral pneumonia tend to come on slowly, and they are often mild at first. They may include:
If you have trouble breathing, coughing that doesn't stop, chest pain, or a fever of 102 F or higher, see your doctor.
Symptoms of pneumonia in babies
Babies with pneumonia may not show any symptoms. But they could seem tired or restless. They might also have a cough, fever, vomiting, or trouble breathing. It also may be hard for them to eat.
You get pneumonia when a potentially harmful substance that your body could usually fight off overwhelms your immune system and infects your lungs.
Viruses that can lead to viral pneumonia include:
Causes of bacterial pneumonia include:
Fungal pneumonia causes include:
Aspiration pneumonia
You can get aspiration pneumonia when you breathe in a foreign substance, like vomit, saliva, or food. You're more likely to get it if something has interfered with your gag reflex, such as a brain injury or overuse of drugs or alcohol.
Is pneumonia contagious?
Bacterial and viral types of pneumonia are contagious. The germs that cause them may spread through the air when someone who is infected talks, coughs, or sneezes. You might also get pneumonia after touching a surface that has the germs on it, then touching your mouth or nose.
Can the flu turn into pneumonia?
Influenza viruses can cause pneumonia, particularly in people who have other health conditions or are at higher risk of it for another reason
Can COVID turn into pneumonia?
The virus that causes COVID-19 can lead to pneumonia. It can also make you more prone to get an infection from other types of viruses or bacteria by weakening your immune system or causing you to need a ventilator.
Hospital-acquired pneumonia
If you get pneumonia while you're in a hospital, that's called hospital-acquired pneumonia. It tends to be more serious, since it can be caused by antibiotic-resistant bacteria and those who get it have other health issues. You might also hear the term health care-associated pneumonia. This refers more broadly to pneumonia you catch while in any health care facility, such as a long-term care facility or dialysis center.
Ventilator-associated pneumonia
You have ventilator-associated pneumonia if you get the infection while using a ventilator, a machine that helps you breathe.
Community-acquired pneumonia
Most cases are what's called community-acquired pneumonia, which means you didn't get it in a hospital.
Anybody can get pneumonia , though it most commonly affects babies and people over 65.
You're also at higher risk if you:
Your doctor will start with questions about your symptoms and your medical history, like whether you smoke and whether you've been around sick people at home, school, or work. Then, they'll listen to your lungs. If you have pneumonia, they might hear cracking, bubbling, or rumbling sounds when you breathe in.
If your doctor thinks you might have pneumonia, they'll probably give you tests, including:
If your symptoms started in the hospital or you have other health problems, your doctor might give you more tests, such as:
Pneumonia vs. Bronchitis
Like pneumonia, bronchitis can give you a long-lasting cough, fever, fatigue, and chest pain. You can also get pneumonia after having bronchitis. But bronchitis, which results from inflammation in the tubes that carry air to your lungs, tends to be much less serious. See your doctor if you have these symptoms so they can figure out which condition you have and how best to treat it.
Pneumonia can have several complications, including:
Your treatment will depend on what caused your pneumonia, how serious it is, and your overall health. Most people are able to recover at home with rest and medication.
Pneumonia medication
If you have bacterial pneumonia, you'll get antibiotics. Make sure you take all of the medicine your doctor gives you, even if you start to feel better before you're through with it.
If you have viral pneumonia, antibiotics won't help. You'll need to rest, drink a lot of fluids, and take medicine for your fever. Antiviral medications can work well against some, but not all, of the viruses that cause pneumonia.
Your doctor will prescribe antifungal medication to treat fungal pneumonia.
Atypical pneumonia treatment
Atypical pneumonia is caused by bacteria that are hard for doctors to detect with standard methods, such as mycoplasma and legionella. With a mild case, you may be able to recover with rest and self-care at home. If it's more serious, your doctor will treat it with antibiotics.
Pneumonia nebulizer
Your doctor may prescribe a nebulizer or inhaler to you or your child to help with breathing. But this won't treat the pneumonia itself.
Hospitalization for pneumonia
If your symptoms are serious or if you have other conditions that make you more likely to have complications, your doctor may send you to the hospital. While you're there, your doctor will probably give you fluids or antibiotics through an IV. You may need oxygen therapy or breathing treatments. And the doctors might need to drain fluid from your lungs.
How long does pneumonia last?
Depending on what type of pneumonia you have and how sick you are, it could take anywhere from a week to a month or more to recover. You'll probably feel fatigued for a month or so. Most people continue to feel tired for about a month. You need lots of rest while you're recovering, so don't try to rush it. Ask your doctor when you can return to your usual activities. Limit contact with other people while you're sick so you don't spread the germs that cause pneumonia.
Signs that pneumonia is improving
You can tell you're recovering when your symptoms improve. While you'll probably be tired for a while, you should notice:
There are some things you can do at home to ease your symptoms and help you recover:
To avoid pneumonia and the germs that can cause it, take these steps:
Pneumonia vaccine
There are two types of vaccines that can prevent infection with the pneumococcus bacteria, the most common cause of bacterial pneumonia. They're recommended for:
Children under 2, kids ages 2-5 who are at high risk for pneumonia, and those who go to group child care should also get a pneumonia vaccine.
A flu shot can also help prevent pneumonia in both kids and adults. So can vaccines that protect against:
Pneumonia is a lung infection most often caused by bacteria or a virus. It may be mild enough that you can recover at home, or serious enough to put you in a hospital. Vaccines can protect you against pneumonia. See a doctor if you have trouble breathing, chest pain, a high fever, or a cough that doesn't go away.
What are the 4 stages of pneumonia symptoms?
Bacterial pneumonia has four stages:
Pneumonia vaccine: How often?
Three pneumonia (pneumococcal) vaccines are widely used in the U.S.: PCV15, PCV20, and PCV23. PCV13 is an older vaccine, but it is still used occasionally. Doctors may use them for different people, depending on their age and health condition:
Your doctor can tell you how many shots you need and when.
How The Widal Test Is Clouding India's Sense Of Its Typhoid ProblemExplained
More often than not, the experience for patients with a fever is to get tested and treated for a typhoid infection. The test is a rapid blood test called the Widal test. The subsequent treatment usually consists of tablets, typically in urban areas, or injections in rural ones.
Typhoid spreads through contaminated food and water and is caused by Salmonella typhiand other related bacteria. Also known as enteric fever, it presents with a high fever, stomach pain, weakness, and other symptoms like nausea, vomiting, diarrhoea or constipation, and a rash. Some people, called carriers, may remain symptom-free and shed the bacteria in their stool for several months to years.
These symptoms mimic those of malaria, dengue, influenza, and typhus, to name a few, each with different treatment modalities. If left untreated, typhoid can be life-threatening. Per the World Health Organisation, 90 lakh people are diagnosed worldwide with typhoid every year and 1.1 lakh die of it. A small 2023 study reported the burden to be 576-1173 cases per 100,000 child-years (one child year is one child being followed up for one year) in urban areas and 35 per 100,000 child years in rural Pune.
How is typhoid fever diagnosed?The gold standard for diagnosing typhoid — in addition to a detailed medical history and a thorough examination — is to isolate the bacteria from a patient's blood or bone marrow and grow them in the lab. Stool and urine samples can also yield the same but with lower sensitivity.
However, performing culture tests in smaller clinical settings presents practical problems. Cultures are time-consuming and skill- and resource-intensive. Prior antibiotic treatment can also affect the results of cultures — a common issue due to the indiscriminate use of antibiotics in India. Some PCR-based molecular methods are known to be better but are limited by cost; the need for specialised infrastructure and skilled personnel; and the inability to retrieve live bacteria for further tests.
Against this backdrop, in India, clinicians use the Widal test extensively to diagnose typhoid in both public and private sectors.
As with other infections, our immune system produces antibodies in the blood against the bacteria, causing enteric fever. The Widal test rapidly detects and quantifies these antibodies. It's a point-of-care test and doesn't need special skills or infrastructure. Developed in the late 1800s by a French physician, it is no longer used in many countries because of its flaws — flaws that are rendered by the scale of the test's use in India to be abusive.
Why is the Widal test inappropriate?A single positive Widal test report doesn't necessarily mean a typhoid infection is present, and a negative report doesn't confirm the disease's absence. To diagnose an active infection, clinicians must test at least two serum samples taken at least 7-14 days apart, so that they may detect a change in concentrations of the antibodies. But getting two samples is rarely feasible and time-consuming.
Second, in areas with high and continuous typhoid burden, certain levels of antibodies against the bacteria may already be present in the blood. Without knowing the baseline cut-off, it isn't possible to correctly interpret the test. A related issue is that different manufacturers of the test specify different cut-off values in their kits' user manuals.
Third, the reagents used in the Widal test to reveal the presence of various antibodies can cross-react with antibodies produced against infections by other bacteria, viruses or parasites, or even in typhoid-vaccinated individuals, leading to false positives. Prior antibiotic therapy can also affect antibody levels and yield a false negative.
Correct diagnosis and appropriate treatment of enteric fever are important because serious complications, like severe intestinal bleeding or perforation, can develop within a few weeks if the disease is mismanaged. False negatives can thus delay diagnosis and lead to fatal outcomes.
What are the consequences of the test's use?Because of the Widal test's propensity for erroneous results, the actual burden of typhoid in India remains obfuscated. A lack of awareness of the proper time at which to collect a blood sample, along with a lack of standardisation of kits and poor quality-control compound the problem.
Further, a single test costs a couple hundred rupees. Patients in many States have also reported being charged Rs 500 to Rs 4,000 per dose of antibiotic injections by local healthcare providers following a typhoid diagnosis based on a single Widal test. Patients in both urban and rural areas have reported selling assets to receive these antibiotics.
The irrational use of antibiotics is a major cause of antimicrobial resistance (AMR). Bacteria have also been known to be able to transmit AMR between strains and species, and they are not limited by geographical borders. This is why the threat of AMR in one country represents the threat of AMR everywhere. Some strains of Salmonella are also resistant to multiple drugs. Continued irrational use of the Widal test, which facilitates unnecessary use of antibiotics, will therefore only make it more and more difficult to control this preventable disease while adding to the financial woes of the patients already suffering.
What do we need instead of the Widal test?We need to discover better point-of-care tests that can replace the Widal test. And until they're available, clinicians can consider using best-practice heuristics that provide a rational diagnosis and subsequent treatment options based on the regional data of effective antibiotics available against the bacteria.
These options should be coupled with ensuring adequate and safe food and water and functional sanitation to address the disease's root cause.
Improving access to better diagnostic tests could also address this problem. Doing a blood or bone marrow culture is often not feasible as it requires laboratory infrastructure that most parts of the country lack. Healthcare workers can instead benefit from a 'hub and spoke' model, with sample collection sites at the periphery and district hospitals and medical colleges as the hubs that process samples. The latter facilities could also serve as research centres that generate regional prevalence and susceptibility data.
Next, we need better surveillance to stay on top of the AMR caused by the overuse of the Widal test. The Indian Council for Medical Research publishes an annual report highlighting the typhoid bacteria's resistance patterns. As per the last report, in 2021, the number of samples tested to report susceptibility ranged from one from the 'East' region to 126 samples from the 'North'.
Finally, as typhoid also has symptom-free carriers, constant environmental vigilance and data-sharing are imperative.
Dr. Vasundhara Rangaswamy is a microbiologist and a rural physician. Dr. Parth Sharma is a public health physician, writer, and researcher.
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