Call Transcript: Healthy Swimming: Prevent and Treat Infections Caused by Brain-Eating Amebas and Chlorine-Tolerant Parasites
Moderators:Leticia R. Davila
Presenters:Jennifer Cope, MD, MPH and Michele Hlavsa, RN, MPH
Date/Time:June 19, 2014 2:00 pm ET
Welcome everyone and thank you for standing by. At this time all participants have been placed in a listen only mode until the question and answer session of today’s conference. At that time, if you would like to ask a question, please press star 1 on your touchtone phone.
Today’s conference is being recorded. If you have any objections to the recording you may disconnect at this time. I would now like to turn today’s conference over to Ms. Leticia Davila. Thank you. ma’am. You may begin.
Leticia Davila: Thank you (David). Good afternoon. I am Leticia Davila, and I am representing the Clinician Outreach and Communication Activity (COCA) with the Healthcare Preparedness Activity at the Centers for Disease Control and Prevention. I am delighted to welcome you to today’s COCA webinar — Healthy Swimming: Prevent and Treat Infections Caused by Brain–Eating Amebas and Chlorine–Tolerant Parasites.
We are pleased to have with us today Dr. Jennifer Cope and Ms. Michele Hlavsa from CDC. They will discuss the primary amebic meningoencephalitis (PAM) and diarrhea resulting from Cryptosporidium, how to prevent these diseases, and what to do if you suspect your patient has one of them.
You may participate in today’s presentation by audio only, via webinar, or you may download the slides if you are unable to access the webinar. The PowerPoint slide set and the webinar link can be found on our COCA web site at emergency.cdc.gov/coca. Click on COCA calls. The webinar link and slide set are located under the call in number and call passcode.
At the conclusion of today’s session, the participant will be able to describe the epidemiology, clinical features, diagnostic testing and treatments available; discuss the steps that can be taken to prevent PAM and cryptosporidiosis; and state the protocol for contacting CDC to obtain clinical consultation, diagnostic testing, and the investigative drug miltefosine for treatment of PAM.
In compliance with continuing education requirements, CDC, our planners, presenters and their spouses/partners wish to disclose they have no financial interest or other relationships with the manufacturers of commercial products, suppliers of commercial services or commercial supporters. Planners have reviewed the content to insure there is no bias.
The presentation will not include any discussion of the unlabeled use of a product or a product under investigational use with the exception of Dr. Cope’s discussion on the new drug. She will be discussing the drug that was recently approved in the US for the treatment. But it is still be using and under investigational — excuse me — but is still being used under an investigational new drug protocol. CDC does not accept commercial support.
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Today’s presenter, Ms. Michele is Chief of CDC’s Healthy Swimming Program in the Domestic Water, Sanitation and Hygiene Team in the National Center for Emerging Zoonotic and Infectious Diseases. She was an Epidemic Intelligence Service Officer prior to joining the Healthy Swimming Program, and has worked on outbreak investigations of waterborne and foodborne diseases at CDC.
Her areas of expertise include the transmission of pathogens that cause recreational water illness, and the development of appropriate prevention and control measures.
Our second presenter, Dr. Jennifer Cope, is a medical epidemiologist with the Waterborne Disease Prevention Branch. She completed an internal medicine residency at Emory University, and an Infectious Disease Fellowship at the University of Maryland Medical Center. She has an MPH from Emory and is board certified in both internal medicine and infectious diseases.
Dr. Cope is CDC’s subject matter expert on free living ameba infections. Her work includes clinical consultation with physicians who suspect a free living ameba infection in their patients, overseeing an investigational new drug protocol, collecting free living ameba infection case reports, and publishing findings.
Again the PowerPoint slide set and the webinar link are available from our COCA web page at emergency.cdc.gov/coca.
At this time I would like to poll the audience for a few questions. You did see one question that appeared before the call began. And I would like to now continue on with the second poll question.
To select your response please click the corresponding colored box or the radio button. Please make your selection now. We will go on to the next question. Please make your selection now. Perfect. I would like to now turn it over to Ms. Michele. You may begin.
Thank you, Leticia. So the objectives of this presentation on cryptosporidiosis covers describing the epidemiology, clinical features, diagnostic testing and treatment for cryptosporidiosis as well as discussing steps that can be taken to prevent cryptosporidiosis.
Before I get too far into the talk, I want to make sure we’re all on the same page and we know some basic facts. So there’s an estimated three quarter of a million cases of cryptosporidiosis in the US each year. However we only hear about 1%–2% of these cases. So we roughly have seven to eight thousand reported to CDC each year.
The reason why there are so many cases is in one bowel movement a person can release tens of millions to hundreds of millions of oocysts. It only takes ten or fewer oocysts to cause infection. More than 95% of cryptosporidiosis cases in humans are caused by Cryptosporidium parvum or Cryptosporidium hominis.
Cryptosporidium parvum can be transmitted zoonotically from animal to humans, namely pre-weaned calves, or it can be spread anthroponotically. Cryptosporidium hominis, as the name suggests, is predominantly spread or transmitted anthroponotically.
In terms of risk factors of cryptosporidiosis, contact with infected persons — particularly caregivers of young children. We see a lot of transmission of Cryptosporidium in childcare centers and in households as well as contact with infected animals which is another risk factor, particularly pre-weaned calves. After calves are weaned, the Cryptosporidium in their intestines changes to other species, which do not tend to cause infection in humans.
Additionally ingestion of contaminated recreational water — or the water we swim in such as in pools — can lead to cryptosporidiosis or Cryptosporidium infection, drinking contaminated water, or eating contaminated food. We have found primarily that consuming unpasteurized apple cider or consuming foods that have been handled by infected food handlers is causing outbreaks or food borne outbreaks of cryptosporidiosis. International travel is another risk factor for cryptosporidiosis.
In terms of the epidemiology — what are we seeing? So here this graph covers 1995–2012. Nineteen ninety five is the first year national reporting of cryptosporidiosis began in the US. And 2012 is the last year in which we have data.
We see that the rate of laboratory-confirmed cryptosporidiosis, which is shown in blue, has been increasing over time, peaking in 2007. That is likely caused by the huge statewide, possibly regional outbreak of cryptosporidiosis in Utah that year.
The other line — the orange line — covers non-confirmed cases, so cases that are probable, suspect, or the case status is unknown. They’re somehow related to a laboratory case — a laboratory-confirmed case. That has also increased over time in terms of rate, namely in 2011 and 2012. And I’ll get more into that as the talk goes on.
This map here shows cryptosporidiosis rates by state or jurisdiction because we’re including New York City and the District of Columbia — the darker the shading on the map, the higher the rate. So we tend to see higher rates in northern tier states.
But this map needs to be interpreted with a grain of salt in terms of the fact that risk factors might be different state to state. So therefore maybe we see higher rates in the northern Midwest because that’s where we see cattle. It might be because of a number of cases associated with outbreaks.
So for example that huge outbreak I told you about earlier in 2007 in Utah, it would affect the shading of that state for that year. Some differences might also reflect capacity to detect, investigate, and report cases. Some states invest more in their public health capacity than others.
This graph here looks at cryptosporidiosis case counts and rates by age group and by year. So the blue bars and the yellow bars provide case counts for 2011, which is in blue, and 2012, which is in yellow. And then the right y-axis is covering the case count.
So we see increased case counts in those 1–4 year olds. We see another peak in child-bearing age people 25–29, 30–34. And we see a bit of a bump in the 80+. In terms of rate which is demarked by the yellow — excuse me orange line — that we see also an increase in those who are 1–4 years, those of child-bearing age, and those 65+.
This graph here looks at cryptosporidiosis in terms of age group and sex. So what we see here is in the 1–4 years of age, in the 5–9, 10–14 — we see that males have a higher rate of cryptosporidiosis than females. That then changes as the population reaches child-bearing age. And women tend to have a higher rate than men throughout the rest of the lifespan.
We suspect that this for two reasons. It’s likely that women are most likely the caregivers caring for young children who have crypto. And it could also be that women are more likely to seek healthcare, therefore more likely to be tested, and their case is more likely to be reported.
In this next graph here, we look at the seasonality of cryptosporidiosis. This is by bi-weekly onset of symptoms. So we see a peak which is roughly week 30 or July/August in cases that are reported to CDC. This is likely because of swimming. Cryptosporidium is an important etiologic agent in terms of recreational water. It is the leading cause of waterborne disease outbreaks in the US for the last years we have available data — the last 10 years — so that would be 2001–2010.
So this graph here looks at outbreaks associated with swimming, and divides them into outbreaks associated with crypto or caused by Cryptosporidium and associated with treated recreational water. By treated recreational water I mean pools and water parks — so water that is chlorinated or brominated. And those bars are in blue.
In terms of what we see in yellow, these are all the other outbreaks — so outbreaks of other etiology or cryptosporidiosis outbreaks associated with untreated recreational water. So this would be our lakes and our oceans.
As we see in this graph, the blue bars do definitely increase over time. The yellow bars, while increasing, seem to be more stable. So definitely Cryptosporidium is a big player in waterborne disease outbreaks that we see in terms of recreational water across the United States.
Next I want to present on clinical features. In terms of what we see in immunocompetent patients, profuse watery diarrhea that’s prolonged 3 or more days is a hallmark symptom of cryptosporidiosis. In the literature, we see reports of frequent abdominal pain, nausea, and vomiting.
There are some reports of possibly respiratory or pulmonary symptoms caused by Cryptosporidium. There have been studies where they looked at patients with Cryptosporidium that have no other explanation — no other etiology. But they have been able to isolate Cryptosporidium from the sputum.
On the opposite gamut of clinical presentation, there are patients who are asymptomatic. And it’s also important to keep in mind that on reinfection, Cryptosporidium results in an anamnestic response in the immune system. Therefore patients have less symptoms or no symptoms on reinfection.
In the immunocompetent patient, cryptosporidiosis is self-limiting. The median duration recorded in the paper I cite here is 11 days. That tends to be a bit longer than what we see in outbreaks. However, this paper did not do a good job documenting in terms of the immune status of patients. In outbreaks, we typically see 5, 6, 7 days — maybe a little bit beyond that.
Regardless of the duration, oftentimes cryptosporidiosis patients experience waxing and waning of symptoms. So one day they could be completely fine. The next day they have diarrhea and the next day they could be fine. And this goes back and forth until their symptoms completely resolve.
In terms of what we see in immunocompromised patients, the severity of disease depends on the degree of immunosuppression. So with very limited immunosuppression we basically see similar clinical presentation as we would in immunocompetent patients — basically the disease is self-limiting.
As immune suppression increases we see chronic and severe diarrhea. And it can go all the way to life-threatening malabsorption and wasting, which was what we saw in the 1980s. Cryptosporidiosis was a hallmark opportunistic infection in the HIV-infected population.
However that’s the incidence of cryptosporidiosis in this population has dramatically decreased since the introduction of highly active antiretroviral therapy. In immunocompromised patients we do see reports of extra-intestinal cryptosporidiosis, namely biliary or respiratory, as well as rarely pancreatic.
In terms of diagnostic testing, the one thing we have found with healthcare providers is they aren’t aware that the labs do not test for Cryptosporidium typically when they’re doing routine and ova parasite testing. That basically stems back to the history of microscopy for ova and parasites.
So typically when microscopy was done for ova and parasites, extra work had to be done to test for Cryptosporidium as well as Cyclospora. So therefore the labs were not doing these tests. So if you want your patient tested for Cryptosporidium, we recommend specifically requesting Cryptosporidium testing. Otherwise a negative O&P might not be telling you exactly what’s going on with the patient if you’re concerned about cryptosporidiosis.
In terms of testing and making sure that your test result is a negative, we recommend testing three stool specimens collected on separate days. This is important because excretion of the oocysts can be intermittent.
The gold standard testing for Cryptosporidium is direct fluorescent antibody testing. However, the labs are moving away from microscopic techniques and going to more rapid techniques — immunodiagnostic techniques. One of the issues that has come up is a question about false positives in immunochromatographic rapid card tests.
There is a report out that suggests that there are false positives resulting from these tests. However, in looking further at who was tested, the patients who were tested did not have symptoms consistent with cryptosporidiosis. So therefore, they should have not been tested in the first place.
The other thing that has come up is we have here at CDC since tried to test this immunochromatographic rapid card test and put it up head to head against DFA or direct fluorescent antibody testing. We have found no difference in the results between the two here. These are preliminary data. We are working to finalize them.
But given that this report came out and that there was a question of false positives, the definition or the national definition used for reporting cryptosporidiosis cases to CDC has been changed if the testing that confirms infection involved in immunochromatographic rapid card test.
If the test is positive the case is only considered probable, and it’s not considered confirmed. However given the results of our head to head comparison of the two tests, it seems like our next step here at CDC will be educate users on how to use it because maybe it is a user issue that’s creating these false positives.
Okay. Now I will go into treatment or Slide 24. So in terms of what options there are for treatment, there is Alinia or nitazoxanide. It is available for immunocompetent patients only according to FDA. That was approved for those 1–11 years old in 2004, and those 1 year of age and older in 2005.
There were three studies done in immunocompetent populations. And basically they found a significant increase in clinical cure or patients reporting no symptoms or less than three bowel movements in 24 hours, etc., or in parasitic cure we also saw significant increase in treatment versus placebo. And that was basically, you know, not finding any parasites in stool specimens.
I would caution that when reading these studies, one thing to keep in mind is that these stool specimens were collected 7–10 days out. And also it’s not clear in these studies how the lab testing or diagnostic testing was done in these studies. So that’s just something to keep in mind when reading through them.
In terms of what the label says for cryptosporidiosis treatment of immunocompetent patients, basically from 1–3 year olds it’s 100 milligrams of nitazoxanide every 12 hours with food. For 4–11 year olds it’s 200 milligrams every 12 hours with food. And both of those groups — basically 1–11 year olds — should be treated with oral suspension.
For those 12 years and older, it’s 500 milligrams every 12 hours with food. And this could be in tablet form or oral suspension. Regardless of age, the duration of treatment is three days.
Now what are the options for treating immunocompromised patients? FDA has not approved any treatment for cryptosporidiosis in this population. Currently the mainstay of treatment is immune restoration. In each of the infected patients specifically, it is recommended that to treat – symptomatically treat diarrhea with anti-motility agent and to also aggressively rehydrate the patient and replace any electrolytes lost, if needed.
There are those who believe that protease inhibitors should be included in treating patients with cryptosporidiosis who have HIV. And that’s because it is thought to possibly have a direct — or protease inhibitors are thought to possibly have a direct anti-Cryptosporidium effect. What happens is they increase interferon gamma, and that’s actually what inhibits Cryptosporidium.
In terms of resources for treating cryptosporidiosis in immunocompromised patients, CDC, NIH and others have put out opportunistic infection treatment guidelines for HIV infected pediatric patients as well as adult patients. Pantenburg, Cabada and White in Texas have put out a great review on how to treat cryptosporidiosis in immunocompromised patients and go through all the studies that have come out and the treatment options for immunocompromised patients.
In terms of prevention — and I know you’re all very busy with your patients. And it’s sometimes hard to get prevention messages in. But I do definitely want to emphasize our recommendations for preventing waterborne cryptosporidiosis because that is such a big issue in the United States.
Our number one recommendation for cryptosporidiosis patients is not to swim while ill with diarrhea and not to swim the 2 weeks after symptoms have completely resolved. And the reasoning behind this is there is no way in our pools and in our water parks, etc. that we can remove or efficiently and quickly inactivate Cryptosporidium.
So basically CDC recommends that pools be maintained at 1–3 mg/L or parts per million — PPM — free chlorine. And that basically inactivates most of pathogens within minutes if not seconds. However, for Cryptosporidium at 1 mg/L free chlorine, Cryptosporidium can survive for 10.6 days.
So it’s really important to keep that Cryptosporidium out of the water to begin with. And to protect everyone from Cryptosporidium, it’s really important to avoid ingestion of recreational water. And this is key because again the Cryptosporidium is going to stay in that water for a long time.
The reason why we talk about not swimming while ill with diarrhea for 2 weeks is that patients tend to continue shedding Cryptosporidium for about 2 weeks after their symptoms have resolved. For all other enteric diseases we generally recommend returning to swimming or getting back into the water after the diarrhea has resolved.
Another big issue is not to drink water or use ice that has been inadequately treated. And that applies to here while we’re doing our back country hiking and taking water from lakes and streams and rivers, or whether we’re traveling internationally.
We have found that the treatment processes in the US that we’ve put in place and the regulations we have put in place have basically prevented outbreaks of cryptosporidiosis that have been associated with treated drinking water. And for more detailed prevention measures on how to prevent cryptosporidiosis when traveling, I have a link here to the CDC’s Yellow Book, which is a great travelers’ health resource.
In terms of other prevention measures, it’s very important to remember to wash hands with soap and water for at least 20 seconds before handling food or after toileting or changing diapers, etc. I think, you know, the general public I think has gotten a little used to the alcohol-based hand sanitizers. They are basically ineffective against Cryptosporidium, so that hard outer shell that protects Cryptosporidium from chlorine protects Cryptosporidium from alcohol as well.
The other big issue — and I think this is the hardest prevention recommendation to make, enforce and implement — is keeping children with diarrhea out of childcare settings. And this is really important because we have found in doing studies in the US that there is increased risk for cryptosporidiosis in immunocompetent persons when they are exposed to 3–11 year olds with diarrhea.
So this here is basically a reminder for me to tell you that CDC has a cryptosporidiosis website, cdc.gov/parasites/crypto/. It’s there with resources for everyone regarding treatment, diagnosis and other things, as well as a Solve the Outbreak app which actually includes solving an outbreak of cryptosporidiosis.
We have currently received a grant for revising the Cryptosporidium website or cryptosporidiosis website which we hope to have ready for next year’s summer swim season. So we do ask if you all visit the website and have any recommendations on resources that you can’t find there that you would like to see up there, if you’d please let us know.
And here is our standard disclaimer. So if you have not appreciated or don’t like anything I’ve said in the last few minutes, you are free to ignore me basically. And I’ll turn it over to Jenn now.
Thanks Michele. Good afternoon. Similar to what Michele covered with crypto, the objectives during this portion of the talk will be to describe the epidemiology, clinical features, diagnostic testing, and treatments available for primary amebic meningoencephalitis caused by Naegleria fowleri.
We will also discuss steps that can be taken to prevent primary amebic meningoencephalitis — PAM for short. And then finally we’ll state the protocol for contacting CDC to obtain clinical consultation, diagnostic testing, and the investigative drug miltefosine for treatment of PAM.
To give you some context before jumping into the epidemiologic data we have on PAM cases in the US, I want to give you a little bit of background on Naegleria and the disease it causes.
Primary amebic meningoencephalitis or PAM is a rare and serious brain infection. Since 1962 there have been 132 cases identified in the US. Nearly all of those have been diagnosed at CDC. And CDC continues to be one of the only places with the ability to confirm these infections.
PAM has a high mortality. There have been only three known survivors in the US. It is an acute and fulminant disease, with death usually occurring approximately 10 days after exposure.
PAM is caused by the free-living ameba Naegleria fowleri. Most PAM infections are associated with swimming in warm lakes and rivers where water containing — when water containing Naegleria goes up the nose into the brain. In the US all infections were from southern tier states until 2010.
Naegleria fowleri is a thermophilic or heat loving free-living ameba which means it can live in the environment without the need for a host. It grows best at 113°F. It was originally identified by Fowler as the cause of primary amebic meningoencephalitis in Australia in 1962.
There are several species of Naegleria, but Naegleria fowleri is the only one that causes PAM. It can also affect animals such as cattle. Worldwide there have been approximately 300–400 cases identified. After the organism was identified in 1962, there was a retrospective pathology study done in Virginia which found cases going all the way back to 1937.
With that background, let’s look at the epidemiology of PAM in the US. This graph shows year along the bottom and number of cases of PAM on the vertical axis since 1962. We have had as little as zero infections reported in a year to as many as eight. While overall the numbers haven’t gone up, since 2005 there have not been any years with zero cases.
This graph shows age group and gender information for US PAM cases. Age group in years is along the bottom on the x-axis, and number of cases is again on the vertical axis. Female cases are in red and male in green. As you can see, PAM cases tend to be younger with a peak in the 10–14 year age group, and are mostly male. The median age is 11 and a half years.
This graph shows data on month of illness onset and probable water exposure for PAM cases. The month of the year is along the bottom, and the number of cases again on the vertical axis. This graph clearly demonstrates how cases cluster in the summer months of July and August.
You can also see most of the cases are the bright red color, indicating that their probable water exposure was a lake, pond or reservoir. Other reported water exposures include canal, ditch or puddle, river or stream, geothermally heated water, tap water, swimming pools and unknown or multiple exposures.
Here is a map of the United States showing the states that have reported PAM cases. Eighteen states have reported at least one PAM case. The yellow color indicates states that have reported ten or more cases which you can see is two states, Florida and Texas. Half of all US PAM cases have reported water exposure in Florida or Texas.
Moving on to Slide 45, I wanted to go a little bit into more detail about the geographic distribution of Naegleria fowleri infection. This map shows the location of all US PAM cases from 1962–2009. During this time period the northern most cases were from Missouri and Virginia.
We notice that the distribution of cases seemed to be clustered with three groups of cases — one in the west, one extending from Texas northward into Oklahoma, and the third along the East coast. Cases sometimes recurred at certain lakes, including the foci in Richmond, Virginia.
The Richmond cases all occurred in one of two lakes in the area. At that time they dealt with the problem by filling in one lake with dirt and had not had another case since doing that.
Here we put rough circles around the cases through 2009 to mark the pre-2010 geographic range. Now here are the cases just from 2010 through 2012. While some still fall in the three clusters, there are some that are clearly outside.
Beginning in 2010 the first case in Virginian since 1969 was reported. We also saw the first case in Kansas and the first case in Indiana. Minnesota reported its first case ever in 2010 as well, six hundred miles further north than previously recorded, which had occurred in Missouri.
The 2010 Minnesota case occurred during a prolonged unusual heat spell. And then in August 2012 a second case was reported to have been exposed at the same lake in Minnesota.
In 2011, sorry — in addition to a change in the geographic distribution of PAM cases, we have also seen some new modes of transmission in the US since 2010. In 2011, the first cases of PAM in the US associated with the use of tap water in neti pots were reported. Both cases occurred in Louisiana, although they were separated by 350 miles. Both cases were associated with the use of neti pots, which are devices used to rinse the sinuses.
PAM cases in Australia and Pakistan had been associated with sinus rinsing. But these were the first US cases and the first associated specifically with neti pots. Both of the case patients’ residential plumbing systems were positive for Naegleria fowleri. Testing of the municipal water systems that supplied the case patients’ homes were negative at that time.
Previous research has shown that other free living amebas are commonly found in residential premise plumbing. Just a little more about PAM and its association with nasal irrigation as well as the use of neti pots. There was at least one PAM death in the 1970s in Australia due to rinsing nasal passages in the shower. There have been 13 deaths in healthy young adults in Pakistan, likely from performing Muslim ritual ablution, which involves putting water up the nose to cleanse the nasal passages in preparation for prayer.
I’m sure many of you have patients who use neti pots, or you may even use them yourself. Neti pots come from an ancient yogic cleansing method and may be used for nasal irrigation during illness or on a regular basis. Their use was recommended by Dr. Oz and Oprah in 2007, and sales apparently increased three to four fold. Millions are now sold each year.
As I mentioned Pakistan had reported PAM cases that are likely associated with ritual ablution. In 2012, we had the first PAM case associated with ritual ablution reported to us at CDC. This case occurred in a 47 year old Muslim male from St. Thomas, US Virgin Islands.
PAM was suspected when the patient’s CSF showed motile ameba, a hallmark of N. fowleri infection. CDC was notified of a possible PAM case. And the case was then confirmed at CDC. Further investigation showed that the patient had no recreational fresh water exposure and practiced ritual ablution that included nasal rinsing.
CDC then sent a team down to do an environmental investigation of the case-patient’s home. The CDC team took 17 water samples from the case-patient’s home, and three of those were positive for Naegleria fowleri. Positive samples included water from the shower head, the shower head itself, and a water sample from the hot water heater.
The team also visited the patient’s mosque. Three samples were collected from the mosque — two samples from the men’s ablution area and the water filter used by the mosque. None of those samples from the mosque were positive for N. fowleri.
Finally last summer a 4-year-old child was diagnosed with PAM on autopsy. An investigation into the case found that the child had no contact with water from a lake, pond or river in the days preceding his illness, but that he had played all day on a slip and slide.
An environmental investigation was conducted and water samples were sent to CDC in addition to the actual hoses that had supplied the slip and slide and the slip and slide itself. Naegleria fowleri was found in water from the residential plumbing system, hot water heater and the hoses that had supplied the slip and slide.
When it was noted that this case was from the same Louisiana parish as one of the neti pot cases from 2011, the municipal water system was tested again, and this time was found to have Naegleria fowleri in it.
To summarize, we have noted several changes in the epidemiology of PAM in the US since 2010 including the first cases in Minnesota, Kansas and Indiana, the first cases associated with tap water and neti pot use, the first case in the US associated with ritual nasal cleansing or ritual ablution, and then finally the first death associated with water from a treated municipal drinking water system.
So I hope that spending some time on the epidemiology of PAM in the US and noting some of changes we’ve seen over the last 4 years helps you understand why even though historically this has been an infection seen mostly in southern-tier states, that we now think it’s something every clinician should be aware of.
As I mentioned at the very beginning, PAM is an acute disease that rapidly leads to death. On average people die within 10 days of exposure to the ameba, with approximately 5 days from the time of exposure to when symptoms begin, and 5 days from symptom onset to death.
The disease presents very much like bacterial meningitis, which can lead to delays in diagnosis and proper treatment. Early symptoms include fever, headache, nausea and vomiting. Later patients develop neck stiffness, altered mental status and seizures.
In a review of cases reported to CDC, in about 25% of cases, the trophozoites were seen in the CSF while the patient was still alive. But more often the diagnosis is not made until after they died and an autopsy was done. In those cases the ameba is usually seen in tissue sections of the brain. Prior to 2013 only one of 128 US cases had survived, and that one had occurred back in 1978.
Moving on to Slide 65, more often than not a lumbar puncture is the first procedure performed in these cases. So CSF can give the first clue as to what is going on with the patient.
In order to potentially observe motile trophozoites in the CSF, we recommend preparing a wet mount. Otherwise the CSF will look very similar to the CSF of someone with bacterial meningitis, including greatly elevated white blood cells with polymorphonuclear cell predominance, elevated protein, and low glucose. Pressure is usually elevated. The red cell count may be elevated in PAM patients due to brain tissue hemorrhage.
This picture is a wet mount of Naegleria fowleri trophozoites that have been cultured from the CSF of a patient with PAM. This is a view using phase contrast microscopy at 600X magnification.
This is what an actual wet mount prepared directly from the CSF of a patient with PAM might look like. I know it might be hard to see, but the arrow is pointing to a form with irregular borders that represents a Naegleria fowleri trophozoite.
The best way to visualize the morphology of Naegleria fowleri is to stain fixed CSF with Giemsa-Wright stains. This image shows a cytospin of fixed CSF showing a Naegleria fowleri trophozoite indicated by the arrow, stained with Giemsa-Wright amidst PMNs and a few lymphocytes. Within the trophozoite, the nucleus and nucleolus can be seen.
Brain imaging in PAM patients is often not helpful early in the course of the illness as it is often normal. CT findings may include cerebral edema with contrast enhancement and obliteration of basalilar cisterns. MRI may show one or more small enhancing round lesions.
Moving on to diagnosis and treatment — there are a couple ways by which we can diagnose Naegleria infection. First as I’ve mentioned, you can directly visualize the trophozoites moving in the CSF under the microscope. However, they are not always seen in the CSF. And even if they are, we still confirm the infection with other methods.
First we can do immunohistochemistry which is a method that uses antibodies specific to Naegleria fowleri to stain tissue if the Naegleria antigens or proteins are present. Secondly we can do polymerase chain reaction or PCR which detects Naegleria DNA if it is present.
PCR has become the gold standard and is usually the first test done when we receive a CSF specimen at CDC from a patient in which PAM is expected. We can usually have results within a few hours of receiving the specimen.
PAM is an infection with a high fatality rate. Until last summer there had only been one US survivor. This original survivor was treated with a combination of antibiotics. And since 1978 when that case occurred, we continue to recommend using that same combination of antibiotics.
Unfortunately no one else survived. So we’re not sure exactly why the girl in 1978 survived. But theories include that she had a better immune response than other cases or that the ameba she was infected with was not as virulent.
Our lab has tested many drugs to see if they have activity against Naegleria fowleri in the lab environment. There are several drugs that do, but unfortunately this doesn’t always translate into working in the human body.
One drug called miltefosine has shown improved survival rates in other free-living ameba infections. However because it was not initially licensed in the US and had to be approved by FDA and shipped over from Germany in order to use it¸ we had not been able to try it in a Naegleria patient yet because they had usually died by the time we were able to get the drug.
Therefore CDC worked to develop an investigational new drug protocol and received FDA approval last summer to purchase and hold the drug here in Atlanta so that we can get it out to a patient within 12–24 hours. And we were able to do that just last summer.
Last summer we saw the first two US PAM survivors since 1978. A 12-year-old Arkansas girl was treated with a combination of drugs that included miltefosine. Additionally her elevated intracranial pressure was managed aggressively with neurosurgical interventions as well as therapeutic hypothermia. She has since made a full recovery.
A second patient — an 8-year-old boy from Texas — survived but has sustained what is likely permanent brain injury. He was treated with the same drug combination as the Arkansas girl, but therapeutic hypothermia was not used in his case. He also presented several days into his illness, while the Arkansas girl presented within about 24 hours of symptom onset. Ultimately we think it was a combination of factors that led to the successful outcome.
Based on the survivors from last summer, we recommend the following treatment regimen. It is recommended that the deoxycholate amphotericin B formulation be used, and not liposomal or lipid complex formulations, since the deoxycholate form has lower MICs in vitro against Naegleria fowleri. And this is the formulation that has been used in the three survivors.
Intrathecal administration may be considered in addition to IV. Patients may be transitioned to PO administration if their condition improves. However, miltefosine is only available in a PO formulation, so may need to be administered via an NG tube if the patient is comatose. Dexamethasone was also used in the treatment of the survivors.
If you suspect you have a patient with PAM, please contact the CDC 24/7 to speak with a subject matter expert about your patient. The person who takes the initial call will have you give a brief history of your patient and why you think they might have PAM.
If amebas have been seen in the CSF, we will have you send a high quality photograph of the CSF to our telediagnosis team if possible, and have our parasitologist look at the picture to confirm if it looks like Naegleria.
We will also provide instructions for sending specimens to CDC for confirmatory testing. We will also provide treatment recommendations and send miltefosine as quickly as possible, if indicated. All of this can be obtained as I said 24/7 by calling the CDC Emergency Operations Center at 770-488-7100.
Ultimately, we’d like to prevent these deadly infections from ever happening. The only certain way to prevent a Naegleria fowleri infection due to swimming is to refrain from water-related activities in warm, fresh water. Personal actions to reduce the risk of Naegleria fowleri infection should focus on limiting the amount of water going up the nose.
Some of these actions are listed here on this slide, such as holding the nose shut, avoid putting your head under the water, avoid water-related activities during periods of high water temperature, and avoid digging in or stirring up the sediment where Naegleria fowleri tends to hide. These recommendations make common sense, but are not based on any scientific testing since the low numbers of infections make it difficult to ever show that they would be effective.
When it comes to using tap water for sinus rinsing and neti pots, the point to emphasize with water used for this purpose is that tap water is not sterile. So tap water should not be used in sensitive areas of the body such as the sinuses.
Water for nasal or sinus rinsing should be treated in some way, and these are also listed on this slide. These include boiling, filtering, buying distilled or sterile water, and disinfecting with chlorine bleach.
Speaking of — these instructions are also listed on our website. And speaking of our website, please check it out at cdc.gov/parasites/naegleria/. We’ve worked hard to keep this website up to date with information that is useful to both clinicians and the general public.
In conclusion, the changing epidemiology means all clinicians should be aware of PAM because of the data indicating a geographic shift north and new transmission patterns via neti pots and tap water.
Clinicians should consider a PAM diagnosis in a patient with nasal fresh water exposure such as swimming, neti pot use or practicing ritual ablution, and a CSF profile consistent with bacterial meningitis. We recommend doing a CSF wet mount in a patient like this to look for motile Naegleria trophozoites.
Finally, we are available here at CDC 24/7 for consultation by calling the Emergency Operations Center. And if you don’t remember any of this, please just Google CDC and Naegleria, and you’ll find our website, which has all of this information and more. Thank you.
Thank you, Ms. Hlavsa and Dr. Cope, for providing our COCA audience with such a wealth of information. We will now open up the lines for the question and answer session. And also remember you can submit questions through the webinar system. Operator?
Thank you and we will now begin the question and answer session.
If you would like to ask a question, please press star 1 on your touchtone phone. Please be sure your phone is unmuted in order to ask your question. If you wish to withdraw your question at any time you may press star 2.
Once again, if you would like to ask a question, please press star 1 on your touchtone phone.
One moment please, for our first question.
And operator, while we gear up for the questions, I do have a question that has come through the webinar system, and the question is about Cryptosporidium. Concerning the recommendation for avoiding recreational water for two weeks after symptoms have resolved, for adults who are not incontinent, are there oocysts on perianal skin or even hands? Or is this a concern that incontinence could occur?
So in terms of what we all carry on our rear ends, actually there has been a study done on this. The typical person in the US carries about — I think it’s 0.14 grams of feces on their rear end. They actually took underwear from people and measured this and did all of this work.
They found that on children, they carry up to ten grams. So if we put that into perspective, a thousand kids going to a water park translates to about 10,000 grams or translates to 10 kilograms or 22 pounds of poop. So, you know, we’re not doing a really good job about showering before we get into the pool. And we need to be staying out of the pool without diarrhea.
The problem is a lot of people think that pool water is sterile — the chlorine kills everything instantly. And that’s definitely not the case. So basically anyone with diarrhea whether they’re continent or incontinent needs to stay out.
Thank you. Operator?
We currently have no questions via the phone lines. But as a reminder if you would like to ask a question please press star 1 on your touchtone phone.
Thank you. I’ll continue with ones that have come through the webinar system. The next question is is iodine an effective water treatment for crypto or Naegleria?
As far as crypto is concerned, iodine is in the same chemical family as chlorine, so not it is not an effective treatment.
With regards to Naegleria, Naegleria is moderately sensitive to chlorine. And so I don’t know how it translates across to iodine. So it could potentially have some — be effective against Naegleria.
Thank you. The next question says there is a lot of open water swimming going on in lakes. They don’t wear a nose clip. But if they — if someone did, is it possible that water can enter through your mouth while swimming?
So it is possible. I think we tend to be — and this is Michele. I think we tend to be better about keeping water out of our mouths when we are in lakes. If that question is specifically to Naegleria and whether or not it’s a risk factor to swallow water for Naegleria, maybe Jen could speak to that.
Yes. Naegleria is not transmitted by drinking or swallowing water. So yes, if the nose clips are in place, that should be a good way to prevent getting water up the nose, which is how Naegleria is transmitted.
Thank you. The next question, can clinical labs attempt Naegleria cultivation by placing CSF on an E. coli lawn — a prepared plate of E. coli lab strains?
Yes, they can.
Thank you. Operator, are there any questions in the queue?
We currently have no questions at this time.
Thank you. I do have another question. The next question is, are there any resources for treating cryptosporidiosis in transplant patients?
So in terms of resources, not really. When you look at the literature basically it talks about case reports. There is one case series. It seems to be very dependent on where the immune system of the patient is or how immune suppressed they are.
What we basically find when you go through all the case reports and the case series, is that some patients without treatment completely recover or, you know, the cryptosporidiosis completely resolves. And as far as I know, there are no reports in the literature about someone dying specifically because of cryptosporidiosis.
So there are transplant patients with cryptosporidiosis that have been reported to die. But the cryptosporidiosis was not reported to be the cause of it — the death.
Thank you. The next question are there any current studies in progress in reference to the geographic distribution of PAM and associated environmental factors, in particular states with a high incidence of cases, such as Florida and Texas?
To my knowledge there’s not — there’s certainly not any large scale studies in progress. That’s why we continue to encourage that cases be reported to us because our informal surveillance is one of the best ways for us to continue to track geographic changes in PAM.
There have been — in the past there have been small scale projects done, kind of sampling water, you know, in Florida and Texas in particular have been interested in this because of having the bulk of cases. But no, there are not any formal studies ongoing.
Thank you. Operator?
Yes. Your next question comes from Lori. Your line is open.
Oh yes. I was wondering for Naegleria, is there a recommendation on the chlorine parts per million?
Are you specifically referring to pools and Naegleria?
So basically CDC recommends that pools be maintained at 1–3 mg/L or ppm — parts per million. And as far as I know there are no reports of Cryptosporidium, sorry — Naegleria associated with a well maintained pool.
Okay. Thank you.
Your next question comes from Debbie. Your line is open.
Regarding the Cryptosporidium and pulmonary problems, what is — how is that detected and what is the treatment?
I’ll have to follow upon the treatment with you. So if you follow up with Leticia that would be great. But in terms of how it was detected, basically the patients had sputum samples taken.
But I can follow up on the treatment. I don’t remember off the top of my head if and how they were treated.
Okay. Thank you.
And ma’am, if you would like to send us your question via email at C-O-C-A — COCA — at cdc.gov and we’ll be able to forward that question to the presenters.
Thank you very much.
Thank you. Operator?
We have no further questions in queue.
I do have one question. It says I have read Campylobacter has been found to cause severe infection in Tough Mudder like — oh, in Tough Mudder and like Dirty Go runs events. Are participants in these huge events at risk for these two infections as well?
Funny that’s coming up — that was a big issue in the past year. Actually, I believe it was in Michigan last year. There was an outbreak of norovirus associated with Tough Mudder. And what had basically happened is when they looked at what point patients’ symptoms started and what point they started the race, they found that there were symptomatic patients that went into the race. And then they found that the number of cases among participants greatly increased in the next 12, 24, 36 hours.
I think that that’s kind of a new exposure public health is learning to deal with because you can’t exactly chlorinate these venues. But it is something that CDC’s looking into further to see how we can provide guidance to our state partners and to the people — I guess the hosts of these events to see how we can prevent. But as I said before, given that it’s mud there’s no way to disinfect it.
And with regards to Naegleria, it certainly seems like the potential is there to, you know, to getting water or muddy water up the nose. And those could certainly be venues where Naegleria is present. But to date, we have not had a case reported to us that was associated with one of those events.
Thank you. Operator, are there any questions in the queue — and if so, how many?
We currently have no questions at this time.
Perfect. Thank you so much.
On behalf of COCA, I would like to thank everyone for joining us today, with a special thank you to Dr. Cope and Ms. Hlavsa.
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