Identification and Care of Patients with Hantavirus Disease

Coordinator: Welcome and thank you for standing by. At this time all lines have been placed in listen-only mode until the question and answer session. At that time if you'd like to ask a question please press Star 1. Today's call is being recorded. If anyone has any objections you may disconnect at this time. I would now like to turn the call over to Marcy Friedman. Thank you. You may begin.

Marcy Friedman: Thank you Kim. Good afternoon, I am Marcy Friedman and I'm representing the Clinician Outreach and Communication Activity, COCA, with the Emergency Risk Communication branch at the Centers for Disease Control and Prevention. I'm delighted to welcome you to today's COCA call, "Identification and Care of Patients with Hantavirus Disease". 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 page at emergency.C-D-C.G-O-V/C-O-C-A. Click on the June 30 COCA Call. And the slide set is located under "Call Materials".

Free continuing education is offered for this COCA Call. Instructions on how to earn continuing education will be provided at the end of the call. 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 content to insure there is no bias. This presentation will not include any discussions of the unlabeled use of a product or products under investigational use.

At the end of the presentation you will have the opportunity to ask the presenters questions. On the phone dialing Star 1 will put you in the queue to ask your question. You may also submit questions through the webinar system at any time during the presentation by selecting the Q&A tab at the top of the webinar screen and simply typing in your question. Questions are limited to clinicians who would like information on preventing, recognizing and managing hantavirus disease. For those who have media questions please contact CDC Media Relations at 404-639-3286 or email media@cdc.gov. If you are a patient please refer your questions to your healthcare provider.

At the conclusion of today's session the participant will be able to describe the risk factors, endemic areas, and incubation period of hantavirus infection, identify the clinical presentation and methods to identify a patient with hantavirus in the clinical setting, and understand the parameters of clinical management and critical care for patients with hantavirus. Today's first presenter is Dr. Barbara Knust. Dr. Knust has served as epidemiologist in the Viral Special Pathogens Branch at the Centers for Disease Control and Prevention for seven years. In that capacity she managed the National Surveillance System for hantavirus, responded to clinical and public inquiries, developed educational materials, and assisted state and local health departments in investigations of hantavirus cases.

Our second presenter is Dr. Gregory Mertz. Dr. Mertz is a board-certified Sub-specialist in Infectious Diseases and former Chief of the Division of Infectious Diseases at the University of New Mexico Health Sciences Center where he is now working as a retiree. He has cared for patients with hantavirus cardiopulmonary syndrome since 1993. He was the site principal investigator for a CDC sponsored open trial of IV Ribavirin and subsequently the overall principle investigator through a National Institutes of Health collaborative antiviral study group sponsored controlled trial of IV Ribavirin for the treatment of hantavirus cardiopulmonary syndrome in North America. From 1999 through April 2016, Dr. Mertz was the principal investigator at the National Institutes of Health International Collaborations in infectious diseases research grant U19/U01 focused on epidemiology, natural history and management of hantavirus cardiopulmonary syndrome in Chile and Panama.

Today's third presenter is Dr. Michelle Harkins. Dr. Harkins has served as Division Chief Pulmonary Critical Care in Sleep Medicine for the last 3 years in the Department of Internal Medicine at the University of New Mexico and has been on faculty since 1999 and she has taken care of numerous hantavirus patients in the University of New Mexico ICU. She has served as a medical director of the medical intensive care unit for the last several years and has given regional and national presentations on this topic.

In the first part of the presentation Dr. Knust will talk about hantavirus overview and epidemiology, specifically hantavirus global overview, US epidemiological summary, diagnostics of hantavirus, and hantavirus surveillance in the United States. In the second part of the presentation Dr. Mertz will talk about the incubation period, clinical presentation, and course of illness associated with hantavirus pulmonary syndrome. Many clinicians and investigators including Dr. Mertz prefer to describe the illness as hantavirus cardiopulmonary syndrome to stress the importance of cardiogenic shock. In the third and last part of the presentation led by Dr. Harkins she will discuss triage, emergency planning, and treatment options for hantavirus cardiopulmonary syndrome patients. At this time please welcome Dr. Knust.

Dr. Barbara Knust: Thank you very much and thanks to all of you who are joining today for this discussion. We hope that it will be helpful for you. So to give an overview of hantavirus and the epidemiology, first of all hantaviruses belong to the Bunyavirus family and are primarily found in rodent reservoirs. Human infections occur through inhalation of excreta and also through the bites of infected animals. There are two primary manifestations in humans when they become infected with hantavirus. There's a hemorrhagic fever with renal syndrome and which primarily results in renal failure type of symptoms but can also have hemorrhagic symptoms as well. And this is caused by Old World hantaviruses and rodent reservoirs that are present mainly in Europe and Asia, although the Seoul virus is likely to be present throughout the world because the rodent reservoir for Seoul virus is the Norwegian rat which is present throughout the world, including within the US.

In Europe there's also a similar syndrome to hemorrhagic fever with renal syndrome except it's a milder case of disease and so that's called nephropathia epidemica.

In the US we primarily see hantavirus pulmonary syndrome or hantavirus cardiopulmonary syndrome. HPS symptoms are caused by rodents that are distributed throughout the New World and there are numerous species across North and South America. The next slide just shows a series of the different species of hantaviruses and the rodents that are associated with those species of hantavirus. The yellow highlighted names of the viruses are the ones that have been shown to cause human disease. However it's very possible that some of these other hantavirus species might also cause disease.

The important takeaway from this other than just the fact that there is a wide diversity of hantaviruses, and also rodent species that can carry hantaviruses throughout the Americas, is that the symptoms, the clinical pictures can vary in terms of severity but there frequently is pulmonary and cardiopulmonary manifestations across these. And also the diagnostic testing can be, frequently it's cross-reactive. And so with the diagnostic testing and especially serology we can identify hantavirus infection even if it is with a species that might be different than what we might expect.

In the United States in particular there's really four rodent reservoirs and four different species of hantavirus that we see that has been described here. The photo of the rodent there is the deer mouse. And it's a very distinguishable by having a kind of a tawny brown upper body and then white for underneath on its belly and also on the underside of its tail. And the photo in the upper left-hand corner Photo A is the distribution of the deer mouse throughout much of North America.

The deer mouse is the carrier of Sin Nombre Virus. And that is the most frequent species that causes HPS in the U.S. In Photo B that is the distribution of the white-footed mouse which looks very similar to the deer mouse and is the reservoir for New York virus. Photo C if the is the distribution of the hispid cotton rat which carries Black Creek Canal virus. And photo D is the distribution of the Rice Rat which carries Bayou virus.

In the next slide we have a description of the ecology of hantavirus. And so hantavirus is maintained within the rodent reservoir and it is transmitted from rodent to rodent primarily through fighting and through bites and scratches from one infected animal to another. And so this is frequently just maintained at a low level. And people become exposed to hantavirus through activities that bring them into contact with infected rodents. There is the possibility that other animals might get exposed to hantavirus such as coyotes or cats however they've never been found to develop any clinical symptoms or be of any risk for other people to become infected. Except for Andes virus hantavirus is not transmitted from human to human.

And so in terms of the epidemiology of hantavirus people who are at risk of coming into contact with rodent excreta or with rodents themselves or from rodent excreta that could be aerosolized into an environment, are the people that are at greatest risk for becoming exposed to hantavirus. And so that includes people living in areas where deer mice are found and white-footed mice. But deer mice in particular are-these rodent species are found in rural areas. And a lot of places they actually live in, what we call the peridomestic environment which is the area around houses sometimes even going into houses in rural areas. So that includes people involved in agriculture such as farmers, people that our outdoor enthusiasts and participate in camping and hiking, and people who are involved either occupationally or just through their regular activities in doing things like opening and cleaning buildings that are not usually frequented by humans such as summer homes, sheds, or attics.

In the US there's approximately 20 to 40 cases that are reported annually of hantavirus. And more than 95% of those cases are exposed west of the Mississippi River. However it's very important to note that people frequently will travel to the western US. And so getting a travel history on a person who has a relevant clinical picture of hantavirus is important and also assessing types of rodent exposure that they might have either at the home or also in while on vacation.

In terms of a descriptive demographics we have more males who the - who have cases of hantavirus. And we think that might have to do with just the type of exposures that some males are more likely to have. And also by race, there's a, you know, greater representation among white or Caucasians and among American Indians. And this may also be due to the types of occupations and also the types of settings where people are living that are also high incidence areas for hantavirus. Approximately 36% percent of hantavirus pulmonary syndrome cases are fatal.

And the next slide shows a map of the total hantavirus pulmonary syndrome cases cumulative by state since 1993. And it's actually been updated with the most recent numbers as of June 23 this year. So we see that in the western US - particularly in New Mexico, Colorado, Arizona and California - that's where we would consider to be our higher incidence area of hantavirus. These are also areas again where people frequently go in on vacation. So just because you have a patient who doesn't live in one of those states doesn't mean that you shouldn't be considering hantavirus in your differential if it looks possible. And it's approximately 672 cases in 31 states that have been reported.

In this slide we show the annual number of hantavirus cases since 1993 up through 2015 in the blue bar. And the black line is just the annual case fatality rate which averages out to 36%. And although the case fatality rate does move a little bit by year it has been fairly consistently 36% except for the very first year were hantavirus was first described. We see approximately between 20 to 40 cases per year although there certainly are some years with higher numbers of cases and some years with lower number numbers of cases.

1993 is notable and that's the - and the reason that our surveillance goes back to 1993 is that that was the year where there was an outbreak in the Four Corners region were hantavirus was first really discovered in the US. In particular Sin Nombre virus was first described in that year and the hantavirus cardiopulmonary syndrome was first described. And that was a - it was considered to be an outbreak year and that there were high populations of rodents that year. Testing of cases with similar clinical symptoms have found hantavirus cases that did occur previous to 1993, however they were never, they were not recognized at the time. And it's likely that hantavirus has been endemic in that area for quite a long time. However it really took an outbreak to really recognize it as a syndrome and as a new disease.

And the next slide just shows the number of HPS cases by month of onset to show you that really the spring and summer are what we would consider to be the high incidence times of the year for hantavirus. We don't know exactly what the reasons for this is, if it has something to do with rodent behavior or if it has something to do with human behavior. It may well be a combination of the two. But right now in the end of June we really would consider ourselves to be sort of in the height of hantavirus season. However we do see cases throughout the year.

For hantavirus diagnostics, serology is the most common means of diagnosis in the US and testing is available through commercial and public health labs. PCR testing is also possible to perform however it's less common which detects the virus RNA during the acute phase. And the viremia of a patient does decrease fairly quickly and so that's why serology is used because frequently patients may have already passed the point of having detectable viremia by the time hantavirus is suspected. Immunohistochemistry is also available for postmortem detection.

So for hantavirus antibody testing IgM and IgG develop rapidly after onset of symptoms that are detectable at the first test. There is cross-reactivity between different hantavirus species in the US. There is a commercial assay currently available and an assay that's available from CDC and also at state health departments. The commercial assay does have some possibility of having false positive results and so it is important to interpret results carefully when a commercial assay is ordered.

Frequently what we see with false positive results is an IgM only positive result that is just barely above the cutoff value whereas a person who is confirmed to have hantavirus virus by a commercial assay will have both IgM and IgG detectable in a much higher levels than the cutoff value. For hantavirus surveillance it is actually notifiable throughout the US and both hantavirus infection with pulmonary symptoms and hantavirus infection without pulmonary infections that's lab confirmed are notifiable conditions. And it's very important that providers should contact the local or state health department when they are suspecting a hantavirus case so that in order for them to assist them with diagnostic testing. And there's also things that the state and local health department may do in addition as that may include environmental investigations to ensure that other people may not also be at risk of developing hantavirus from rodent exposures. And that is the end of my component. I would like to turn it over now to Dr. Gregory Mertz. Thank you.

Dr. Gregory Mertz: Thank you. I'm going to proceed to my first slide here if I can. This is a photograph that shows a typical area where cases are acquired in the northwestern part of New Mexico or Northeastern Arizona. And it turns out that in addition to there being a large number of cases in the Four Corners states the University of New Mexico because of its geographic location has a kind of natural referral pattern from Northeastern Arizona and from Southwestern Colorado. So our clinical experience has actually been greater than you would expect from just looking at the numbers of cases in New Mexico.

Now the incubation period of this disease is really impossible to determine in the majority of cases. And that's because the individual has - acquires disease in or around the home or in a shed near the home that they may have been in and out of over a number of times over the past several months. And so for most patients you're really not going to be able to determine when they acquired it. But I would - I want to show two slides where incubation periods were determined pretty precisely in order to give you an idea of what part of the history you might want to focus on.

First is a study that my collaborators and I published from Chile. In the small green area you can see the duration of exposure of the individuals and in the white lines indicate the incubation period before the onset of fever. And we picked these individuals because they traveled from large urban areas such as Santiago where there's no transmission of hantavirus to an endemic area. They were there for just one or two days and then returned and became ill in the city they lived in.

You can see in this series of 11 patients that the mean was 18 days and the range is ten to 34 days. And this is really I think one of two studies that really allows a good determination of the incubation period. The other is - was published as a result of the 2012 outbreak, of Sin Nombre virus infection in Yosemite. In that case nine of ten individuals that acquired hantavirus acquired the disease in some cabins at Yosemite. And typically the individuals stay for just one or two nights in those cabins. So it's a similar situation to the patients that we described in Chile where you have a short period of exposure and then very good data on when they became ill.

And this is a little different. The median incubation period range was 30 days and the range was from 20 to 49 days. And I call your attention to the 49-day incubation period because we've - many of us in writing about this have said that it could occur up to six weeks after an exposure whereas this is more than six weeks. While the medians differ a little, whether it's three weeks or four weeks I think this is pretty much right on. It also fits with a few cases in the United States there were two little boys that caught mice and put them in their pockets and were bitten by the mice and the incubation period was known there. And also in Chile with the Andes Virus there's person to person transmission. And there the average falls very closely to a three-week incubation period.

So the one aspect of the disease in Chile is this risk of person to person transmission from an index case who acquires the virus from some kind of rural exposure followed by transmission usually within the family although we described a few cases of nosocomial transmission. Realizing that this was occurring in family clusters we designed a prospective study where we enrolled household contacts of index patients and followed them weekly for a month. And one of the important findings which I think is also relevant here is that we were able to find - we were able to detect virus by PCR in blood for up to two weeks before the onset of fever. So there's a period of viremia that that occurs when a person remains asymptomatic. And there's - there are one or two case reports for example one from Sweden with pulmonary virus where a patient became ill and they happen to have some blood from an unrelated clinical encounter several weeks prior to onset of symptoms. And they also were able to find Puumala virus by PCR in that individual. So I don't believe this is a unique - that this is unique to Andes virus.

And so the schematic shows the course of infection with hantavirus. In green is a - is viremia with a free virus. There's of course an incubation period. You can see here that the viremia precedes the onset of illness which I think is shown in orange. But it's not until the onset of fever that you see the development of the IgG and IgM antibodies. IgM of course starts a little sooner but in - but for most patients but we really don't see until they present during the cardiopulmonary phase you're going to see both IgG and IgM antibody. The other thing I'd like to call your attention to though is that if you look at cell-associated virus we've been able to in Chile to detect virus for three months after the onset of illness. So I would certainly discourage anyone who's had hantavirus from donating blood probably for at least six months after the onset of the illness.

This is a slide showing the - another aspect of the antibody response. And that is that on the day of hospital admission which is typically at the onset of the cardiopulmonary phase which follows the febrile prodrome patients in this upper line here who are destined to have a mild disease at a low risk of death already have high neutralizing antibody titers to Sin Nombre in this case, whereas patients that are likely to die and have a very severe course have very low neutralizing antibody titers on the day of admission. And this has suggested some that possibly passive administration of neutralizing antibody might be beneficial to patients.

So this is the overall course of hantavirus cardiopulmonary syndrome. So there is a two to six day prodrome where there's fever. Patients typically have abdominal pain, nausea, vomiting, back pain, headache. And although many of these patients seek medical evaluation they're generally sent home during this phase. If they would have - be antibody positive but with the current status of antibody testing most if you sent off and antibody test you probably have a five-day turnaround in most centers and patient probably would have gone home and then re-presented to the hospital by the time you got your result. The only clue really other than epidemiologic clues is that they may be thrombocytopenic at this phase. And I think if that's the case they might certainly warrant more careful follow-up.

The onset of the cardiopulmonary phase though is very abrupt. There's a rapid onset of cough and shortness of breath and hypoxia. The chest x-rays you can see at the top develops quickly progresses to bilateral infiltrates and shortly after the onset of this phase the patient may go into shock. If they're hospitalized it's actually the shock, not for the respiratory failure that kills almost all the patients.

The one fortunate thing about these findings of increased hematocrit, low platelets, increased, increased immunoblasts, leukocytosis, and leukocytosis is that they're almost universally present at the onset of this the cardiopulmonary phase. And it turns out that they're very helpful in establishing a presumptive diagnosis that you can use to guide medical intervention. After, if the patient survives the cardiopulmonary phase, there's a rapid diuresis, chest x-ray clears very quickly and the patients can generally be extubated within 12 hours or so of the onset of the cardiopulmonary phase. And then this is followed by a convalescent phase which it says here months but it's probably more like several years of convalescent symptoms.

Just to make the point of how rapidly these patients deteriorate patients almost invariably are admitted only after the onset of the cardiopulmonary phase. As I said before if they go to a doctor during the febrile prodrome they're almost certainly going to be sent home just because the presentation isn't characteristic enough. Once you enter that cardiopulmonary phase though you have a very high risk of death within the first 24 hours. So the decisions about transporting the patient, about supportive care so forth has to be made very, very quickly. You do not have a day or two to think about those decisions.

So fortunately this - you can make once the cardiopulmonary phase begins so if you have bilateral infiltrates and hypoxia your - you can do a peripheral blood count and peripheral blood smear and presence of four or five of the following of these findings have a very high sensitivity and specificity. So if you have thrombocytopenia myelocytosis, lack of significant toxic granulation in neutrophils, hemoconcentration, and more than 10% of lymphocytes with immunoblastic morphologic features you have a very high degree of confidence of making a presumptive diagnosis. Of these five, the least sensitive is hemoconcentration because it's only the sickest patients who develop profound hemoconcentration. And these are the immunoblasts of that are evident on peripheral smear.

So how helpful is this? Well in a number of - we've done a number of studies, treatment oriented studies where we've used this algorithm to decide whether or not to enter patients on treatment. We didn't want to wait until they - the antibody test came back. So in a study in the United States 24 patients with suspected hantavirus cardiopulmonary syndrome in the cardiopulmonary phase infection was subsequently confirmed in 23 of 24 who - in whom we made a presumptive diagnosis based on smear evaluation.

In 12 patients where we tried to enroll them just based on fever and thrombocytopenia, none of these patients exposed to Ribavirin had infection which really argues against intervening prior to the onset of the cardiopulmonary phase. And I'm going to stop there and turn the presentation over to Michelle.

Dr. Michelle Harkins: Thanks Greg. So this is really a diagnostic dilemma at times. As Greg mentioned patients may come in in the prodrome phase and be sent home because the symptoms are really nonspecific for hantavirus. So they had fever, they may have myalgia, and headache, and very frequently GI complaints, which could be anything. And so the patients may be sent home.

But if they do present in an endemic area and you're thinking of hantavirus and they may or may not have thrombocytopenia, we tell our providers out in our rural areas to consider having them have closer follow-up, come back the next day for another CBC for example in 8 to 12 hours and start looking at that platelet count and looking for the other markers that he mentioned on a peripheral smear. And if the platelet count is falling or the suspicion is higher for hantavirus then we take calls from all over the state, in fact even all over the country at 1-800-272-2000. And then if you ask for the medical critical care intensive doctor or the ID physician to call and discuss a potential case. Is this consistent with hantavirus? We may ask some other questions.

But yes if we are patients in the rural areas we get called frequently to have discussions. And we may bring those patients to the ICU even if they're not ICU level at that time because they do progress rapidly into the cardiopulmonary phase. So we work well with our rural providers here in New Mexico, Arizona, and Southern Colorado and try to advise and accept these patients to be seen. But this is the number to call us at the medical center here.

So the key point that I want to reiterate as Greg mentioned these patients die very rapidly. We take patients coming in on 2 or 3 liters of oxygen and then in 40 minutes to an hour we're putting them on ECMO because they do have a very abrupt onset of cardiopulmonary arrest essentially as they progress through the cardiopulmonary stage if they are going to do so.

So what we tell our providers out in the rural areas is to transfer the patient prior to them getting into a cardiopulmonary phase to a tertiary center, preferably one with ECMO which we do at our center. You don't really want to wait and stabilize these patients and try to make their numbers look better because they're really not going to get better if they're starting to enter their cardiopulmonary phase. We avoid fluid resuscitation. So this flies in the exact opposite of the Surviving Sepsis Campaign. So these patients present, you may think they're septic or they - you may think they're dehydrated because they've got a GI illness and so they get a lot of fluid. And that I think is part of the fact that tips patients over into a tenuous status for the cardiopulmonary phase because basically any fluid that you give them does end up in their lungs because they have a profound capillary leak so they become more hypoxic, they have progression of cardiac failure and then end up sometimes just dying from their disease at that time.

So we suggest using inotropes early whether norepinephrine, epinephrine, even dopamine to support their hemodynamics if they're hypotensive rather than using fluids. So again the exact opposite of sepsis where you're going to give a lot of fluids and you may be able to avoid pressors.

We also provide oxygen and try to avoid intubation unless it's absolutely necessary at the time especially for transfer because these patients when you intubate them with sedation and they're already hemoconcentrated and they're in risk of cardiopulmonary collapse you take away that venous return and plus getting the sedating medication. So we've had several patients arrest at intubation.

So you want to arrange air transport with the ability for pressure initiation and some clinical awareness of hantavirus to a center preferably with ECMO but obviously not every center does ECMO in the U.S., but you want to have an advance care type air transport system to get them to a facility that can take care of the patient if your facility is not really able to.

So it's a multi-disciplinarian team that takes care of these patients. So typically we'll get a call from an outside provider via our (PALs) which is the 272-2000 number with a suspected hantavirus patient. So that call either goes to ID or critical care faculty. And if we suspect or have high enough index of suspicion that this patient may ultimately have hantavirus we'll bring them to our facility so we'll call our ICU charge nurse. But it really takes a whole group of providers. Our pediatric intensive care faculty are the ones that actually run our ECMO. So they'll contact the ECMO team and the CT surgery faculty or other surgeons that are going to place our cannulas. And we also have the (Heme) pathologist come in to read the peripheral smear because we may not have the luxury of waiting till we get antibody test positive. And depending on the likelihood of disease all of us could be awaiting the arrival of the patient especially depending on how severe or how ill they sound from the outside institution. So we may all be awaiting their arrival and then make our decisions about what to do with the patient whether it's watchful waiting or being more aggressive in our approach.

So Ribavirin as Dr. Mertz mentioned given early in hemorrhagic fever and renal syndrome in China you will get a seven-fold reduction in mortality risk. But unfortunately the risk of hantavirus cardiopulmonary syndrome in the New World are inconclusive. It does inhibit the virus in vitro and you can pretreat deer mice to reduce their seroconversion rate. However we haven't really found that it's been helpful in treating patients with hantavirus in the New World here. There's also in vitro and in vivo inhibition of Andes virus and it can provide some protection in lethal hamster models. So maybe there's a little proposed exposure prophylaxis but that hasn't been fully worked out.

So this is just a glance of a study with Dr. Mertz performed looking at survival of patients that did not need ECMO giving them Ribavirin versus placebo. And there really was no significant benefit and there was slow accrual. So this is not a very common disease. And so it would take many years to really be able to accrue enough patients. But there really wasn't any even signal or trend or benefit forgiving Ribavirin to patients with hantavirus. So that is really not much of an option for us.

There's also a study in Chile looking at methyl prednisolone versus placebo. In this it's just a Kaplan survival analysis by treatment arm based on severity of disease for the patients admitted in Chile, a SOFA score which is just a prediction model for severity of illness and mortality, a sequential organ failure assessment tool to predict whether patients are likely to die in their course of sepsis or in the ICU. And so a higher score indicates a sicker patient.

And whether given methylprednisolone or placebo this was 16 milligrams per kilo per day for three days for methylprednisolone did not really have any affect in survival compared to placebo, even looking at the severity of the illness compared to less severe patients. Immune serum, so serum from survivors with neutralizing antibodies, may combat the viremia that is present. We know that patients that survive this disease do have detectable antibodies for quite some time afterwards. There have been many animal models looking at passive production protection from hantavirus challenge when given neutralizing antibodies. But there are no controlled human trials and this obviously is not available in the US currently.

So really the management of hantavirus cardiopulmonary syndrome is expectant and its critical care management. So with monitoring their PaO2 to FiO2 to ratios, monitoring their cardiac index, their lactate which could be a marker of hypoperfusion. And so we watch them in the critical care setting again because these patients can progress very rapidly through the cardiopulmonary phase. We give pressers, again norepinephrine, dopamine, epinephrine for example, over IV fluids.

And if ECMO is available we'll actually place the vascular sheaths early and the patient may or may not need to initiate ECMO. But if they do we try to intubate them while initiating ECMO at the same time if our medical management fails. And again there's unfortunately no role for antivirals or methylprednisolone as they've been ineffective in placebo-controlled trials.

So why do we use ECMO for hantavirus? Well our early experience in the 90s here showed that this was a short duration of a critical illness. And autopsy findings from the patients that died did not have any significant tissue damage. And so we felt that most likely this is circulating inflammatory mediators that are causing cardiopulmonary dysfunction. And it had occurred typically in previously healthy patients.

So our criteria currently for the patients that will use ECMO is if they are at less than equal to 65 years of age only because older patients just don't seem to do as well with this. If there are no other major organ system failure such as cirrhosis, end-stage renal disease, neurologic dysfunction, and of course if they have hantavirus by history clinical judgment and meeting significant number of criteria, we'll put patients on ECMO if they have four out of five criteria and if they have a cardiac index that's falling despite resuscitation or rapid decline in their clinical status of refractory hypotension or refractory hypoxemia. So as long as they have a history that's compatible and our clinical judgment suggests these patients are not going to do well and a smear that suggests that the patient does indeed have hantavirus we'll place them on ECMO without confirmatory antibody testing results.

So this is veno-arterial ECMO. So we have to support the cardiac status. So this is just like cardiac bypass. We'll put large bore cannulas in the femoral vein and femoral arteries. We also put in distal profusion cannula via the posterior tibial artery because we've had problems with leg ischemia given the large bore cannulas in the femoral artery. And whether this is an open procedure versus percutaneous we do this at the bedside in the ICU. And then sometimes we'll have to put another cannula to promote venous drainage in the IJ.

So this picture is just a schematic of our ECMO circuit. So you have a one cannula, large cannula that sits at the IVC and RA junction to drain the venous blood. It goes through roller pumps that acts as the cardiac output. And you can dial up and down liters per minute flow. And then it goes through an oxygenating lung and then back up into the femoral artery. And the side here just shows that there's a posterior tibial artery cannula displaced down so that you have perfusion in your lower extremity.

This is just a picture of our ECMO circuit. Obviously the darker blood venous and then it gets oxygenated in the white cylinder and then returns back. So this is retrograde flow so it is not obviously normal perfusion for a person but we do retrograde flow up through the aorta.

So a typical ECMO course, so if a patient does progress through the cardiopulmonary phase, meets our indications we will place them on ECMO, they're paralyzed and sedated. We put them on typical ventilator settings AC or SIMV just average settings. But we do, do lung protective settings with our title volumes of 6 to 7 cc's per kilo.

Typically hemodynamic improvement is within 12 hours. Pulmonary improvement is within 48 to 72 hours and most ECMO runs are around four to five days once the capillary leak resolves and cardiac function improves. And then we'll wean them off of the ECMO and then they'll be on the ventilator afterwards and just have routine ICU care at that point until can ween them from the ventilator.

Our statistics really from the late 90s up through this May we've treated approximately 75 patients that have been hantavirus positive in our ICU. Not all have needed ECMO. Unfortunately even recently - and I have to add one more to this - three patients within the last few months have died prior to transport to UNM. They've been mostly from the Four Corners area. One presented with GI complaints the first day and was sent home and then presented back with shock the next day. And then another patient just presented late in the cardiopulmonary phase and had a rapid demise.

Overall looking at our number of patients we've treated 59 since '94 up through March of this year with ECMO and 73% of those patient survived the run of ECMO and then 63% of those patients survived a hospital discharge. And well we don't have 100% survival through ECMO and hospital discharge these are patients that would've died without any intervention of ECMO. So we do think we made some progress. Our age range is nine to 69 and more men. And this just gives you the duration of number of hours of ECMO. And with that I'll conclude with a picture of our Sandia Mountains. Thank you.

Marcy Friedman: Thank you presenters for providing our COCA audience with such a wealth of information about hantavirus. We will now open all the lines for the question and answer session. As a reminder questions are limited to clinicians who would like information on identifying and caring for patients with hantavirus disease. For those who have media questions please contact CDC Media Relations at 404-639-3286 or send an email to media@cdc.gov. If you're a patient please refer your questions to your healthcare provider. When asking a question please state your organization and also remember you can submit questions to the Webinar system as well by selecting the Q&A tab at the top of the Webinar screen and typing your question. Operator do we have any questions on the phone at this time?

Coordinator: And again as a reminder if you'd like to ask a question please press Star 1 and please record your name once prompted. Again to ask a question please press Star 1. One moment please.

Marcy Friedman: Okay while we're waiting for the operator to come back on the line we do have a question that came in through the webinar system. The first question we have for the presenters is, "What do I do if the patient is hypotensive and I suspect hantavirus?"

Dr. Michelle Harkins: Good question. So if you're patient if you really suspect hantavirus and again that can be from clinical history, exposure history-unfortunately many patients don't remember an exposure to mouse droppings, et cetera - but if you really suspect hantavirus and they have thrombocytopenia, hemoconcentration, et cetera - all the things that we've mentioned - don't give them fluids for their hypotension. You really want to give them pressers. So whether it's norepinephrine, dopamine, epinephrine but we really try to run these patients as dry as possible. And even when they're sitting in our ICU and they haven't progressed to the full cardiopulmonary phase we give no fluids. We very - we limit their PO oral intake drastically so that they hopefully can run their viral course without having capillary leak and then worsening hypoxemia.

Marcy Friedman: Okay, thank you. Operator, do we have any questions coming in from the phone?

Coordinator: I show no questions on the phone.

Marcy Friedman: Okay. I'll move on to the second question I received from the Webinar system. And that question is, "Does the patient need to meet all criteria on peripheral smear to consider hanta as the leading diagnosis?"

Dr. Michelle Harkins: I would say you don't have to meet all five criteria. I think a high index of suspicion especially in the western United States and in endemic areas and whether the patient has been cleaning out a shed or doing some type of, you know, outdoors type activity where they might've had exposure and they come with classic prodrome symptoms and they have thrombocytopenia I think you're going to have to look a little closer. And whether you repeat the CBC or have them come back if they - to just follow-up that might be important. But you don't have to meet all five criteria. We will take patients that have two or three criteria with a good story and bring them to our ICU and follow them. I don't know if you have anything else to add Greg?

Dr. Gregory Mertz: Yes Greg Mertz. But certainly with four or five it's just - it's highly sensitive with four or five. Again the hemoconcentration is - tends to be limited to the sickest patients. A question that was - I gave a talk in our region a week or two ago and a physician asked about whether their hospitals should set up a system where they've been called - where maybe before calling UNM they would call in a hematopathologist to look at slides there.

And there's no right or wrong answer to that but I - my thought about that was that - my concern about that is that might delay the call to us and the transfer. And I think that we would rather get patients that turn out not to have hantavirus then have patients with hantavirus delayed by too much investigation at the referring hospital.

Marcy Friedman: Okay thank you so much. Operator do you have any questions through the phone?

Coordinator: I show no questions. And again as a reminder if you'd like to ask a question please press Star 1 and please record your name when prompted.

Marcy Friedman: Thank you. It looks like we have one more question that came through the Webinar system. And this should probably be our final question due to time constraints. And that question is, "Once patients are taken off ECMO how long on average do they stay on a ventilator?"

Dr. Michelle Harkins: That really varies by patient but I would say once they get off of ECMO we may have, you know, patients that are on the ventilator for another three to five to seven days even. And so it may be quite some time while they're on the ventilator. And a lot of that too they are - have critical illness, maybe myopathy from their paralytics and sedation. And it just takes another, you know, three to seven days or so to wean them off the ventilator. And then, you know, get them strong enough to be able to convalesce on the floor and then go home. But it varies by patient to patient but it does take a few days to get them off the ventilator.

Marcy Friedman: Okay and I think we have time for one extra question that just came in through the webinar system. And that question is, "If a patient contracts hantavirus is there any evidence that exposure confers future immunity?"

Dr. Gregory Mertz: This is Greg Mertz. There - yes there is - there's good evidence that there's long-lasting immunoresponses in patients. So I - and I don't know of any case with any hantavirus whether we're talking about the old world hantaviruses that cause HFRS or the new New World hantaviruses that cause hantavirus cardiopulmonary syndrome of recurrent infection with the same virus. On the other hand there's relatively little cross neutral-although there's a lot of cross-reacting antibody between antibodies to the nucleocapsid area. So actually - and it's something that the diagnostic testing takes advantage of. For example the commercially available assay in the United States I think uses antigen from Puumala virus nucleocapsid. And patients infected with a wide variety of hantaviruses will have antibody that reacts to that nucleocapsid antigen.

On the other hand neutralizing antibody tends to be much more virus specific. So I certainly wouldn't if you had someone who had had hantavirus infection in the southwest and wanted to go trap mice in southern Chile I would not tell them that they did not need to take precautions.

Marcy Friedman: Okay that appears to be the end of the questions for today's call. On behalf of COCA I would like to thank everyone for joining us today with a special thank you to our presenters Doctors Knust, Mertz and Harkins. We invite you to communicate with our presenters after the Webinar. If you have any additional questions for today's presenters please email us at coca@cdc.gov. Put June 30 COCA Call in the subject line of your email and we will ensure that your question is forwarded to the presenters for a response. Again that address is C-O-C-A@cdc.gov.

The recording of this call and the transcript will be posted to the COCA Web site at emergency.C-D-C.G-O-V/C-O-C-A within the next few days. Free continuing education is available for this call. Those who participated in today's COCA conference call and would like to receive continuing education should complete the online evaluation by July 29, 2016 using Course Code WC2286. All continuing education credits and contact hours for COCA conference calls are issued online through TCE Online, the CDC training and continuing education online system at www.cdc.gov/tceonline. To receive information upcoming COCA calls subscribe to COCA by visiting the COCA Web site at emergency.cdc.gov/coca/subscribe. Please join us on Wednesday, July 27 at 2:00 pm Eastern for the second COCA call in a series of four to discuss CDC's Guideline for Prescribing Opioids for Chronic Pain. Get detailed information about this call by visiting the COCA Web page at emergency.cdc.gov.

You can connect with COCA on Facebook. Like our page on Facebook.com/cdcclinicianoutreachandcommunicationactivity to stay connected with the latest news from COCA. Thank you once again for being part of today's COCA call. Have a great day.

Coordinator: Thank you. This concludes today's conference. You may disconnect at this time.

END