Diseases

Naegleria fowleri should be quickly suspected in people with exposure to freshwater who have the symptoms of meningitis or meningoencephalitis listed above. The characteristics of the presentation may be nonspecific at first, leading clinicians to suspect more common diseases such as bacterial or viral meningitis. Routine tests may show a high blood white cell count, but brain scan may be normal. It is important not to delay a spinal tap if at all possible while waiting for a brain scan. If performed early, the spinal fluid may not suggest serious infection, and some victims were sent home from the emergency room, only to return with worsening disease. If suspicion is high, the spinal tap should be repeated in eight to 12 hours. Spinal fluid reflects inflammation with elevated levels of white blood cells and red blood cells. Routine Gram's staining does not detect the amoeba, however it may be seen on the routine Wright-Giemsa stain that is performed for the cell count. A wet mount of spinal fluid must be performed immediately to look for the moving amoeba under the microscope. The amoeba do not move unless the fluid is warmed. They will also move if a drop of distilled water is added to spinal fluid on the slide. This examination may be unsuccessful if there are many white blood cells due to intense inflammation; amoeba and white blood cells appear very similar to most technicians who are not experienced in looking for Naegleria.The CDC Emergency Operations Center offers 24/7 assistance with diagnosis and should be consulted immediately at 770-488-7100.Definitive tests for N. fowleri infection are done in only a few labs in the country, including the CDC. They use one of the following three methods:

1. N. fowleri nucleic acid tests in CSF or biopsy tissue using PCR
2. N. fowleri antigen tests in CSF or biopsy tissue using immunohistochemistry (IHC)
3. It is also possible to culture N. fowleri on a petri dish that is covered with a layer of bacteria. The culture is then observed for winding trails caused by the amoebae consuming the bacteria. This is not routinely done.

The CDC PCR test is highly sensitive and specific for Naegleria fowleri, meaning it picks up even small numbers of amoebae and is rarely negative if the amoeba is truly present.

PAM is entirely preventable. The risk can be eliminated by avoiding untreated freshwater recreation during hot periods of the year. Consistent use of nose clips is probably next best, by keeping freshwater out of the nose. Avoidance of jumping, diving, and submerging the head are basic precautions. While it is recommended to avoid stirring up the bottom of lakes, amoeba are present at all levels where water temperatures are between 76 F-115 F. This makes warm surface water in the middle of a lake a risk, as well as the shore.While common sense suggests that signs will be posted if there is a risk, this is rarely the case, and safety is in the hands of the swimmer. Most untreated freshwater is not tested for microbes. Recreational lakes and rivers with beaches may be tested for bacteria that cause diarrheal illness but rarely for amoebae. Even testing of such waters is not reassuring, because it may be found one week and not the next. The CDC recommends that all swimmers assume there is a low risk of amoebic meningitis at all times in untreated freshwater during hot months and take precautions to keep water out of the nose.It is not possible to eliminate the amoeba from untreated freshwater since, like fish, it is simply a part of the life cycle. Chlorination to a level of 1 part per million (ppm) of free chlorine is needed to eliminate amoebae and other waterborne pathogens from pools; 3 ppm is recommended for hot tubs.In addition to untreated freshwater, chlorine levels may be low in plumbing systems the further they are from a treatment plant. Chlorine also may dissipate in unused water pipes in a home, and hot water heaters are excellent incubators at temperatures under 120 F. Hot water heaters should be kept at minimum 120 F (higher may pose a scalding risk to children and the elderly). All the faucets should be run regularly with very hot water. Children should be taught not to suck water up the nose in the tub or shower. Outdoor hoses should not be used for drinking as they are contaminated and may force water up the nose by accident. If a filter is attached to the end of a hose used to fill kiddie pools or water toys, it should be labeled as NSF-certified to filter "cysts", or filter particles down to 1 micron. Care should be taken to clean and dry water play items in between uses and keep them away from dirt.Those who flush their sinuses or nose should never use water straight from the faucet to prepare irrigation solution. The water should be boiled for at least one minute (longer at higher altitudes above sea level) and then allowed to cool. It can be used for a day or so. Purified or distilled water may also be purchased for this use.Public swimming pools may not always be well maintained, especially during heavy use or traveling, but anyone can use standard pool test strips to check the chlorine and pH of a public facility before going in. People can empower themselves and get free pool test strips at HealthyPools.org (http://www.healthypools.org/freeteststrips/).

PAM is not contagious from person to person. The only way to become infected with Naegleria fowleri is for the amoeba to reach the tissues far up at the roof of the nasal cavity.

The source of nearly all of the Naegleria fowleri infections reported since 1962 in the U.S. has been exposure to untreated freshwater during the summer. Activities that pose a risk include submerging the head, jumping feet first, diving, wakeboarding, and water skiing. Water sources include freshwater lakes, rivers, drainage ditches, and ponds. Other freshwater sources have included hot springs, poorly chlorinated swimming pools, untreated well water, water heaters, neti pots, hose water, and warm water discharge from power plants.Cases have historically occurred in the South, in Florida, and Texas. In recent years, cases have been reported as far north as Minnesota, from Lake Havasu City in Arizona, from Los Angeles in California, and other sites. Climate change is thought to be playing a role in its spread.Of the 37 cases reported from 2005 to 2015, 33 people acquired PAM from recreational exposure to freshwater, three from using a neti pot with contaminated tap water, and one from playing on a hose-fed Slip 'N Slide toy. Most patients are young, healthy, and active, between 10 and 14 years of age. The full range of ages is 5-19.Neti pots are sinus irrigation systems that are designed to flush water deep into the nasal cavity. They are often successfully used by allergy and sinus sufferers. Many people are not aware that public drinking water is not tested for amoeba and is only chlorinated enough to kill some diarrhea-causing bacteria; drinking water is not sterile and contains a living ecosystem of bacteria, fungi, and amoebae. These are usually harmless but occasionally are not. Higher levels of chlorine are needed to kill most infection-causing parasites like amoeba and other protozoa. In addition, private water cisterns and water storage tanks may pose a risk.In parts of the world where chlorination is poor, nasal rinsing may be used to purify the body before prayer -- an act called ritual ablution. In Pakistan, recent years have seen reports from 10 to 15 cases per year of PAM, and chlorination of drinking water or pools has been lax.It is not possible to give an accurate estimate of invasive Naegleria fowleri infection compared to the many more probable exposures. It is easy to consider, however, that cases are missed because health professionals lack awareness, there is misdiagnosis or trouble making a diagnosis before death, or there is a lack of diagnosis because autopsy is not routinely performed. Few medical situations require a legally mandatory autopsy by the medical examiner, and many facilities don't do them anymore. Autopsies are not covered by insurance and cost up to $5,000. Most death certificates are signed by a doctor based on a best guess. Underreporting may occur because there is no mandatory federal reporting, and states differ in the requirement to report diseases related to amoebae.Other amoeba have been transmitted by transplanted tissue, but Naegleria fowleri has not caused disease. Between 1995 and 2012, 21 organs have been transplanted from individuals who died from PAM; however, no cases of transplant-related PAM have been recorded, which is reassuring. The risk is not zero, though, because Naegleria can spread in the blood to other organs, probably when the blood-brain barrier has been destroyed.Swallowing the amoeba has not been associated with infection. Properly chlorinated and maintained recreational water systems or seawater have not been associated with infection.Humidifiers or vaporizers do not pose a risk; droplets produced by these devices are very small and cannot carry an amoeba or cyst without the organism drying out.

After exposure to a contaminated water source, symptoms of PAM develop within two to 12 days of exposure, usually within one week (incubation period). Initial symptoms may include disturbance of taste or smell, but this may not be noticed. Most cases begin with

• frontal headache,
• fever,
• nausea and vomiting, and
• stiffness of the neck (unable to touch the chin to the chest).

As the illness progresses over several hours to a few days, most cases describe

• seizures,
• confusion or loss of attention to surroundings,
• hallucinations,
• coma, and
• death

The infection progresses so quickly that the disease may not be diagnosed until after death if an autopsy is performed. Most victims die within two to four days of first symptoms from severe inflammation and swelling of the brain.

N. fowleri exposure occurs when people come into contact with warm freshwater through swimming, diving, water skiing, water toys, or other recreational activity. Public drinking water and well water also pose a risk. Although contact with infected water is common in the United States, symptomatic disease caused by N. fowleri is not often reported.PAM occurs when N. fowleri is aspirated or forced high into the nasal cavity. The amoeba produces enzymes that digest mucus and protein, which it swallows up with its "feeding cups" or amoebastomes. N. fowleri is attracted to chemicals released by nerve cells. The olfactory nerves (nerves of smell) travel from the roof of the nasal cavity through perforations in the skull (cribriform plate) into the base of the brain. The amoeba consumes the nerve cells, migrating along these tracts until it reaches the brain. The brain is an especially rich food source, with high oxygen levels, glucose, and living cells. Damage to the brain is caused by severe inflammation, direct injury, and bleeding. Death is caused by the resulting severe brain swelling.

Naegleria fowleri is an amoeba in the phylum of protozoa called Percolozoa. It normally lives in freshwater and soil, consuming organic matter and bacteria. The organism goes through three stages in its life cycle: cyst, flagellate, and trophozoite. Cysts are highly stable in the environment and can withstand near-freezing temperatures. The flagellate form is an intermediate stage that moves about but does not consume nutrients or reproduce. The trophozoite form is the active, eating, reproducing phase. Animals and humans are "accidental hosts." PAM occurs only when an animal or human enters the environment at a time when amoebae are actively reproducing and seeking food. Naegleria are "thermophilic," meaning that they become active in warmer water. They live in both tropical and temperate climates throughout the world. The organism is commonly found in any freshwater, including rivers, lakes, drainage ditches, ponds, or any other water exposed to soil. It is also common in hot springs or in localized areas where warmer water is discharged into lakes. It has been found in poorly chlorinated swimming pools. Where the water temperature is cool, Naegleria may be found in the sediment at the bottom of lakes in its protective cyst form, where it survives winters. The most infectious form is the trophozoite stage, but cysts may also become infectious within a few hours of detecting favorable conditions. The flagellated stage can become trophozoite within minutes.In recent years, Naegleria fowleri was discovered in public drinking water and plumbing in New Orleans. Naegleria is resistant to low levels of chlorine, and chlorine dissipates the further treated water travels from a treatment plant. This was discovered after three fatal cases in which the only risk factors were irrigation of sinuses with tap water and playing on a hose-fed Slip 'N Slide. Naegleria was found in the hose, in drinking water, and hot water heaters in these cases. Australia has known of Naegleria in drinking water for 30 years, when the first cases of PAM were described related to public drinking water. Since then, Australia has maintained a water treatment system that eliminates it. Louisiana implemented the Australian model in 2013, which includes regular monitoring for Naegleria and chlorine, and increasing chlorine for 60 days if the amoeba is found. (This is called a "chlorine burn.")Naegleria fowleri cannot live in saltwater and is not found in the ocean.Although there are many species of Naegleria, only Naegleria fowleri causes human and animal infection. There are other free-living amoebas that cause human disease, including Balamuthia mandrillaris, various Acanthamoeba species, and Sappinia species.

The prognosis for infected patients is very poor, as 99% of infections are fatal despite intensive treatment. The rare survivor may have residual neurological problems, such as seizure disorders.There is reason for hope, however, if treatment is started immediately with a regimen that includes miltefosine. This is the best reason for providers and the public to be aware of the risk factors and make the diagnosis quickly.

Because Naegleria meningoencephalitis is so uncommonly diagnosed and rapidly progresses to death, there are no studies comparing one treatment regimen to another, and performing comparative human studies would be unethical. This makes all uses of medications against N. fowleri "off label." Treatment is currently very intensive, and based on prior successful regimens, combinations of drugs, and advances in managing traumatic brain injuries.Amphotericin B is an intravenous (IV) drug usually used for fungal infections. It is the drug of choice but often fails if given alone. In addition to intravenous treatment, amphotericin B can be instilled directly into the spinal fluid (intrathecally). Other antifungal drugs that have shown success include fluconazole or miconazole; these may be given via IV and intrathecally. Antibiotics that kill Naegleria include azithromycin (Zithromax, Zmax, AzaSite) and rifampin (Rifadin) and are given via IV, as well.In addition to antimicrobials, anti-inflammatory and other drugs are used to reduce brain swelling. Brain swelling may be relieved by insertion of a shunt tube (ventriculostomy) to drain excess spinal fluid. The body may be cooled to 93 F (hypothermia). The use of artificial respiration techniques such as "hyperventilation" and induced coma also help reduce swelling and protect brain function while the amoebae are killed.The most important advance in treatment is the availability of miltefosine in the U.S. This drug, which is highly active against amoebae, was not available outside of Europe until the FDA approved its use by the CDC under an experimental treatment protocol. This made it possible to stock the drug at the CDC, from where it could be shipped within hours to a hospital. In 2013, miltefosine was used in two cases, and both patients survived. One recovered with minimal brain damage and was discharged home after two months hospitalization. The other (who was treated late into illness) suffered permanent disability. Miltefosine has been provided in other cases since without success, however, it is usually days into the infection.In 2016, miltefosine was approved by the FDA for the treatment of a parasitic infection, leishmaniasis, and it is now commercially available. Recognizing the critical need, the pharmaceutical company, Profunda, Inc., has made a treatment supply of miltefosine available to hospitals on a consignment basis. The hospitals can stock the drug on-site in the event it is needed to treat PAM; they are charged for the drug only if it is used, and the company will restock it when it expires.It is strongly recommended that an infectious-disease doctor and the CDC Emergency Operations Center be consulted immediately to guide therapy. Again, the CDC Emergency Operations Center is available 24/7 at 770-488-7100.

The first health professional a person with PAM sees may be a primary-care provider such as a pediatrician, family medicine doctor, adult-medicine doctor, or nurse practitioner, but most go to an emergency room when symptoms like headache and fever are severe or are not going away. People with suspected PAM are usually hospitalized under the care of a personal physician, a hospitalist, or a critical-care doctor and an infectious-disease doctor often assists with evaluation and treatment decisions. In addition, a physician skilled in intrathecal pump placement is usually consulted.

The CDC is the most thorough and evidence-based source of information on Naegleria fowleri and other free-living amoeba: http://www.cdc.gov/parasites/naegleria/general.html.