|Naegleria fowleri in human cerebrospinal fluid (image from CDC)|
Let's talk a little about this rare but terribly dangerous infection after the jump....
Biology of Amoebae
The amoeba (sometimes called ameba; plural amoebae or amebae) is a type of protozoa. Protozoa are a diverse and colorful group of organisms that aren't necessarily all that closely related to each other, but they don't really fit into the other major classifications of animals, plants, fungi, or bacteria. Some protists have characteristics that are thought to be very similar to ancient types of cells, but unlike bacteria, they are eukaryotic, which means that they have a nucleus and other functional compartments (organelles) that are enclosed by membranes.
|Amoeba phagocytosis (adapted from Wikimedia Commons)|
Many people may remember seeing amoeba crawling around under the microscope during high school biology lab classes. Amoebae were discovered in1757 by August Johann Rosel von Rosenhof (1705-1751). The ability of the amoebae to change shape as they swim around fascinated early scientists, who called them Proteaus animalcule after the Greek god Proteus, who could change shape. Eventually, though, the term amoeba came into use from the word amibe derived from the Greek word for change.
|The life and infective cycles of N. fowleri (from the CDC)|
One genus, or related group, of ameoba is Naegleria, which are named after the French zoologist Matthieu Naegler. These ameoba live in warm fresh water as well as in soil. The most common members of the Naegleria genus include Naegleria fowleri, Naegleria gruberi, and Naegleria lovaniensis. Over 40 different species of Naegleria amoebae have been identified. However, only Naegleria fowleri (N. fowleri) is dangerous to humans. An infection with N. fowleri can lead to primary amoebic meningoencephalitis, or PAM. This is very rare, though; there were only about 111 total cases of PAM in the US from 1962 to 2008. However, once an infection occurs, N. fowleri is one of the most deadly pathogens known with a nearly 100% fatality rate.
N. fowleri is a widespread microorganism found in all types of fresh water. N. fowleri is named after one of the first two Australian doctors to discover the potential for amoebae to cause disease in humans in 1965, Drs. Fowler and Carter, who wrote an important paper on the subject. Before 1958, when another scientist named C.G. Culbertson isolated amoebae that could infect and kill mice and monkeys, it was generally considered that free-living amoebae were non-pathogenic (not disease causing). The term free-living means that these amoebae can grow and reproduce outside of any external host, unlike some other kinds of pathogenic organisms. However, despite the fact that these free living amoeba can and do live freely, we now know that some of these species of free-living amoebae, like N. fowleri, can also live inside of a host and cause disease.
N. fowleri are thermophilic, which means that they like heat (thermo = heat, philic = love). Most N. fowleri infections in the US have occurred in the southern states where the climate is warmest. They can live in water up to 45°C (113°F) and have been found in hot springs and areas with thermal pollution, such as runoff of hot water that was used to cool power plants or manufacturing machinery. However, N. fowleri can also be found in naturally warm freshwater lakes and ponds, warm groundwater, and improperly chlorinated or treated swimming pools. Infection with this organism usually results from swimming in contaminated water and getting that water inside the nasal cavity.
|Life cycles stages of N. fowleri (from the CDC)|
Sometimes, for reasons that may be due to changes in extracellular salt concentration, the trophozoite cell can turn into a flagellate. The flagellate cell (shown on the right) has two "tails" (flagella) that allow it to swim more rapidly. However, the flagellate cell doesn't eat or divide, and also doesn't usually last very long. It typically reverts back to the trophozoite stage within an hour or so. This ability to undergo a rapid change in cell shape (morphology) has resulted in some scientists using a related non-disease-causing amoeba species, N. gruberi, to study flagella formation and other changes in cell morphology in the lab.
|Another image of N. fowleri life stages (from the CDC)|
It is assumed that infection occurs by getting the N. fowleri trophozoite into the nose, but its also possible that cysts could also lodge in the nose and then morph (excyst) into trophozoites. It is important to note that, as far as we know, you can't get N. fowleri from drinking or bathing in contaminated water, though you can certainly get a lot of intestinal diseases like Giardia from drinking untreated lake, river, or stream waters. A case of PAM caused by drinking water containing amoebae has never been reported. It seems that you can only get N. fowleri through your nose, and there has been no known person-to-person transmission of this organism.
Once the amoebas are in the nose, that's when it gets very Star Trek-esque. The N. fowleri trophozoites start to feed on cells in the nasal cavity of their host and eventually migrate to the brain by following the olfactory nerves (responsible for transmitting your sense of smell) through the cribiform plate, the bone that forms the roof of the nasal cavity. The trophozoites ingest cells such as erythrocytes (blood cells), epithelial cells, nerve cells, and other cells in the nasal cavity and brain. When cerebrospinal fluid and tissue from PAM patients are examined, only the trophozoite stage is seen, which is why it is believed that this is the active infecting form of the amoeba.
When observed in lab experiments, the trophozoites grow "sucker-like" appendages called amoebastomes that help the amoebae feed on human cells by pinching off and ingesting little bits of the host cells. The amoeba basically eat their way through tissue to the brain, and then begin eating the brain, causing a type of tissue damage called hemorrhagic necrosis.
Primary Amoebic Meningoencephalitis (PAM)
Neurological and other symptoms can occur after a 3-7 day incubation period, and death usually results after 5-8 days. Because of this, diagnosis must occur very early and very quickly to have a fighting chance of successful treatment. Historically, PAM has been most often diagnosed post mortem (after death). Public awareness of the disease is important, particularly so that doctors can be alerted to any recent freshwater exposures when patients come in with symptoms that could be due to PAM. There are histological stains and other molecular techniques that can be used to examine the cerebrospinal fluid (CSF) and allow pathologists to detect the presence of N. fowleri. Another issue that hampers the diagnosis of PAM is that the symptoms are often very similar to the much more common bacterial meningitis. Symptoms can start out as mimicking a simple viral infection (headache, fever, nausea, etc.) but progress to confusion, seizures, lack of awareness, or hallucinations.
|A stain showing N. fowleri in the CSF (image from the CDC)|
In addition to swimming, there is another way to contract N. fowleri and PAM that I haven't yet heard discussed in much detail in the news stories surrounding the two most recent PAM cases. In some cultures, rinsing the nasal passages out is an important religious or cultural ritual. This practice goes back at least as far as 1000 BC to the Hindu practice of Ayurvda. Saline irrigations became more popular in the US in 1970s when people began to embrace yoga and its surrounding culture. Neti pots are containers used in the yogic practice of jala neti (or Vyutkrama) to flush water into one nostril with the head tilted to the side to allow it to run out of the other nostril. Ritual washing and cleansing by irrigation of the mouth and nostrils is also a part of some Muslim customs. In developing countries with a lack of clean water, these kind of nasal washes or rituals may be a source of exposure to N. fowleri.
Additionally, today many patients with nasal diseases such as sinusitis use nasal washing (or irrigation) as a therapy prescribed by their doctors. Flushing bacteria, viruses, allergens, and mucus out of the nose and sinuses with salt water can be very beneficial to many patients. Additionally, nasal irrigation has minimal or no side effects. Over 70% of rhinologists (doctors who study the nose; a sub-specialty of ear-nose-and-throat doctors or ENTs) recommend nasal irrigation to at least some of their patients. An entire industry has emerged to produce saline rinse bottles, salt solutions, and additives for intranasal use (one of the most popular companies is NeilMed). In my own field of research, I work with a lot of ENTs, and they all recommend that their patients use high-volume nasal rinses like the NeilMed system.
However, because of the risk of N. fowleri infection, the instructions to these commercially available rinse bottles and neti pots always say to only use sterilized (previously boiled) luke-warm water. As little as 1-2 parts per million (ppm) of chlorine can kill N. fowleri, so in most areas of the developed world, the tap water is completely safe and free from N. fowleri. However, if tap water is improperly chlorinated, or of the chlorine levels drop as it gets to your home, it can be a deadly source of N. fowleri.
In 2011, two separate, unrelated patients died from PAM caused by N. fowleri infection. The only known nasal water exposure they had was through sinus rinsing using neti pots. Researchers identified N. fowleri in water samples from both of their homes. These were the first cases of N. fowleri infection as a result of exposure to water from a treated municipal supply. It is important to note that the N. fowleri were not detected in the municipal supply in these cases, but these and other amoebae were somehow introduced in the plumbing of these two houses, where the amoeba had colonized the hot water systems.
Even though N. fowleri don't live in the salt water found in the ocean and instead prefers fresh water, N. fowleri can still survive just fine in the saline solutions used in neti pots or sinus rinse bottles, which usually includes sodium chloride (salt) and some sodium bicarbonate (baking soda). These nasal rinse solutions are generally designed to have the same amount of salt as is found in the extracellular fluids in your body. While this is more salt than is found in fresh water, it is still over 3 times less salt than is found in the ocean.
Naegleria thrive in warm water over 30°C (86°F). The range of N. fowleri in the US appears to be expanding northward, which may in part be due to increasing temperatures in some areas due to climate change (ie. global warming). This may lead to more cases of PAM in future, particularly if the use of saline irrigation for sinusitis continues to increase and people don't properly sterilize the water they use. Chronic sinusitis affects millions of Americans and accounts for 1 in 5 antibiotic prescriptions in adults. It affects a lot of people, which equals a lot of neti pots and sinus rinse bottles. By all means, if your ENT or family physician tells you to use some kind of sinus rinse, do it; it's great natural symptom relief. Just sterilize the water before you do it (and let it cool; don't flush your nose with boiling water). As I previously mentioned, you can't get N. fowleri from drinking water. It needs to go up your nose. Don't freak out about drinking your tap water because of N. fowleri; there's no danger there.
Why do some people but not others get PAM?
While PAM is a rare disease, it has been reported on every continent except for Antarctica and it is clear that N. fowleri have a world-wide distribution. What we really don't know is why millions of people swim in fresh water each year, yet very very few actually get infected with N. fowleri and get PAM. In fact, N. fowleri have even been reported to be isolated from the nasal cavities of otherwise healthy individuals. Any reasons why some people are more susceptible to this disease than others remain a mystery. The victims tend to have an average age of about 12 years old and are more frequently male, but this could simply be because teen and pre-teen boys are more likely to jump into bodies of fresh water for a swim. We just don't know.
Reducing the risk of PAM
There are some suggestions that have been published to reduce the risk of infection with N. fowleri and PAM (adapted from Yoder et al., Grate et al., and the CDC PAM fact sheet):
For swimming in warm freshwater lakes, streams, ponds, etc.
- Avoid getting water up the nose by holding the nose shut while diving or use nose clips
- Don't dig or stir up sediment in the water; avoid shallow or stagnant water.
- Forcefully blow water out of the nose after swimming to remove any N. fowleri that may have been inhaled.
- Avoid swimming and swimming-related activities when the water temperature is high
- Avoid swimming in lakes known to be associated with N. fowleri infections
- For swimming pools, make sure filters are functional and there is adequate chlorination to at least 1-2 parts per million (ppm; approximately 1-2 mg/L)
- Don't use untreated tap water to make the rinse solution. Use sterilized water that has been previously boiled (at least 3 minutes) or properly filtered (1 µm or smaller pore-size filter)
- Rinse the bottle or neti pot after each use with the same sterile water and not tap water.
Text ©2013, TheMadScienceBlog. Images are public domain.
Sources and Further Reading
- N. Achilles and R. Mosges. "Nasal Saline Irrigations for the Symptoms of Acute and Chronic Rhinosinusitis." Current Allergy and Asthma Reports. 2013. 13:229-235.
- M. Fowler and R.F. Carter. "Accute pyogenic meningitis probably due to Acanthamoeba sp.: a preliminary report. British Medical Journal. 2965. 5464:740-742.
- I. Grate. "Primary Amebic Meningoencephalitis: A Silent Killer." Canandian Journal of Emergency Medicine. 2006. 8:365-369.
- US Centers for Disease Control (CDC) page on free living amoebae
- US CDC webpage on Naegleria and fact sheet on Primary Amebic Meningoencephalitis (fact sheet link opens a PDF)
- T.W. Heggie. "Swimming with Death: Naegleria fowleri Infection in Recreational Waters." Travel Medicine and Infectious Disease. 2010. 8:201-206.
- J.F. Jonkheer. "Origin and Evolution of the Worldwide Distributed Pathogenic Amoeboflagellate Naegleria fowleri." Infection, Genetics, and Evolution. 2011. 1520-1528.
- R. Khianey and J. Oppenheimer. "Is Nasal Saline Irrigation All It Is Cracked Up to Be?" Annals in Allergy, Asthma, and Immunology. 2012. 109:20-28.
- F. Marciano-Cabral and G.A. Cabral. "The Immune Response to Naegleria Fowleri Amoebae and Pathogenesis of Infection." FEMS Immunology & Medical Microbiology. 2007. 51:243-259.
- R. Siddiqui and N.A. Kahn. "Is Ritual Cleansing a Missing Link Between Fatal Infection and Brain-Eating Amoebae?" Correspondence to Clinical Infectious Disease. 2012. 54:1817-1818.
- F.L. Schuster and G.S. Visvesvara. "Free-Living Amoebae as Opportunistic and Non-Opportunistic Pathogens of Humans and Animals." International Journal for Parisitology. 2004. 34:1001-1027.
- G.S. Visvesvara. "Infections with Free-Living Amebae." Chapter 10 in Handbook of Clinical Neurology. 114:153-168.
- G.S. Visvesvara, et al. "Pathogenic and Opportunistic Free-Living Amoebae: Acantamoeba spp., Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea." FEMS Immunology & Medical Microbiology. 2007. 50:1-26.
- J. Yoder, et al. "The Epidemiology of Primary Amoebic Meningoencephalitis in the USA, 1962-2008." Epidemiology and Infections. 2010. 138:968-975.
- J. Yoder, et al. "Primary Amebic Meningoencephalitis Deaths Associated with Sinus Irrigation Using Contaminated Tap Water." Clinical Infectious Diseases. 2012. 55:e79-85.