Hantavirus disease in the Four Corners

>> My name is Dr. Aaron Kofman from the Centers for Disease Control and Prevention. This presentation will cover important information for medical providers about hantavirus disease in the Four Corners region. At the end, you 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; and understand the parameters of clinical management and critical care for patients. I'll start with an overview of hantaviruses; then move on to the epidemiology of hantavirus disease in the United States and, more specifically, in the Four Corners region; and then review the clinical presentation, laboratory testing, and treatment. I will end with a few points on reporting suspected or confirmed hantavirus disease cases. I will start with a general overview of hantavirus. Hantaviruses are a group of viruses that belong to the Bunyavirales order. Rodents are the natural reservoir for these viruses. Hantaviruses are envelope viruses, meaning that the virus is coated with a lipid membrane. This membrane makes hantaviruses very susceptible to disinfection and easily killed by household bleach, detergents, soap, and other disinfectants. Hantaviruses are divided into two groups, Old World and New World. Old World hantaviruses are primarily found in Europe and Asia. Infection can cause hemorrhagic fever with renal syndrome, or HFRS. Several pathogenic Old World hantaviruses have been identified, including Puumala virus, Hantaan virus, Dobrava virus, and Seoul virus. New World hantaviruses are primarily found in North, Central, and South America. Infection with New World hantaviruses can cause hantavirus pulmonary syndrome, or HPS. Because of the profound cardiac features, HPS is also sometimes referred to as hantavirus cardiopulmonary syndrome. Like Old World hantaviruses, several pathogenic strains of New World hantaviruses have been identified. In the Four Corners region, cases of hantavirus disease are due to infection with the New World hantavirus called Sin Nombre virus. In general, each hantavirus has a single primary rodent host species in which the virus is maintained. Hantavirus infection does not cause any apparent illness in the rodent. Infected rodents can shed the virus in saliva, urine, and feces for the length of their lives; but viral shedding is greatest three to eight weeks after acute infection. This map shows the geographic distribution of New World hantaviruses. The virus names in red indicate viruses that are pathogenic to humans. The italicized text below the virus name indicates the name of the rodent reservoir for each New World hantavirus. The deer mouse pictured here is the primary rodent reservoir for Sin Nombre virus. It's distinguishable by having a tawny brown upper body and white underneath on its belly and on the underside of its tail. On the right is a map depicting the deer mouse habitat in North America. A nationwide study found that approximately 10% of deer mice tested throughout the range of the species showed evidence of infection with Sin Nombre virus. Hantavirus is maintained within the rodent reservoir and is transmitted from rodent to rodent primarily through fighting and through bites and scratches from one infected animal to another. No other small mammals such as voles, cats, and dogs have ever been found to transmit hantavirus to people, nor have they been found to develop any clinical symptoms of hantavirus. Hantaviruses are not transmitted by mosquitoes, ticks, or any other arthropods. I will now talk about the epidemiology of hantavirus. This is a map of all the hantavirus pulmonary syndrome cases by state since 1993. As of the end of 2021, approximately 850 cases in 41 states have been reported. The highest incidence of hantavirus is in the Western United States, particularly in New Mexico, Colorado, Arizona, and California. These four states account for almost half of the total cases reported in the US. This map focuses on hantavirus cases reported in Navajo Nation from 1993 to June 2016 by county where they were likely exposed to the virus. There was a total of 110 cases reported, or approximately 18% of the US national total, during that time period. McKinley County had the most reported hantavirus cases with 33, followed by Apache County with 31. The bars in this graph depict the annual number of hantavirus cases from 1993 through 2021 in the US. An average of 20 to 40 cases of hantavirus are reported each year. The number of cases has been known to vary based on seasonal weather patterns. It has been hypothesized that the increased precipitation associated with the El Nino phenomenon may lead to increased human hantavirus cases. Increased precipitation leads to increased vegetation, which leads to increased deer mouse population densities, which increases the possibility of rodent/human interactions and increased disease transmission to humans. The 1993 through 1994 outbreak and the 1997 through 1998 outbreak followed El Nino years. The blue line depicts the annual case fatality rate. Although the case fatality rate varies each year, it has been fairly consistent, averaging around 33%, except in 1993 when hantavirus was first described. This graph depicts the number of reported hantavirus cases by month of symptom onset for the Four Corners region from 1993 to 2021. There is an increase in hantavirus cases during the spring and summer months, which correlates with large increases in deer mice populations in these seasons. This may also have something to do with rodents or human behavior. There is also a slight increase in cases during the fall months. People can get infected with hantavirus by breathing in air contaminated with the virus. How does this happen? As we know, infected rodents shed hantavirus in their urine, saliva, and feces. When fresh rodent urine, droppings, or nesting material are stirred up, tiny particles containing the virus can get into the air. People can also get infected through the bites of infected rodents or by eating contaminated food. There is no human-to-human transmission of Sin Nombre virus. People who are exposed to rodents or rodent excreta are the ones at greatest risk for exposure to hantavirus. This includes people working in the agriculture industry, like farmers and ranchers; construction workers; and those working in forestry and Park Service. People who clean rodent-infested areas or live near rodent infestations are also at risk for exposure. Another risk factor is opening and cleaning previously unused buildings such as cabins, sheds, barns, or other storage facilities where rodents can live and nest. People can also get exposed to hantavirus through recreational activities such as camping and hiking, though the risk of exposure is much lower. I will now discuss the clinical presentation of hantavirus. The typical incubation period for Sin Nombre hantavirus infection is two to four weeks with a range of nine to 49 days. The acute course of hantavirus disease can be broken into two stages. The first stage is the febrile prodrome. This lasts approximately three to six days; and patients may report fever, chills, malaise, back pain, myalgia, and headache. Although many of these patients seek medical evaluation, they are often diagnosed with a nonspecific viral syndrome; and hantavirus is not suspected. The second stage is the cardiopulmonary stage. The onset of this stage is very abrupt and characterized by a rapid onset of non-cardiogenic pulmonary edema, shortness of breath, cough, and hypoxia. Shortly after the onset of this phase, the patient may develop circulatory shock. Without adequate treatment, most deaths occur within 24 to 48 hours of the onset of this phase. Cases of hantavirus disease with mild or no pulmonary symptoms have been reported. One study described four laboratory confirmed hantavirus infections in patients with mild or no pulmonary symptoms. All four patients reported high fever, headache, and myalgia. All four patients also demonstrated hemoconcentration, elevated white blood cell count with a left shift, and thrombocytopenia. Only one patient reported shortness of breath without evidence of pulmonary edema on chest X-ray. Data on non-pulmonary hantavirus infection began to be collected systematically in 2015; and, since then, 29 cases have been reported. In 2016, non-pulmonary hantavirus became a nationally notifiable disease. Clinicians at the University of New Mexico developed criteria observed from a peripheral blood smear that could be used to make a presumptive diagnosis of hantavirus during the cardiopulmonary phase. The peripheral blood smear screen is based on these five criteria: thrombocytopenia with a platelet count less than 150,000; elevated white blood cell count with a left shift; presence of immunoblasts where immunoblasts account for greater than 10% of the lymphocyte population; a lack of toxic changes in neutrophils; and hemoconcentration. The clinical performance of this screening method was evaluated by looking at 11 years of hantavirus cases at the University of New Mexico. They found that the presence of four out of five criteria was 96% sensitive and 99% specific for hantavirus infection. They also found that, out of the five criteria, thrombocytopenia was the most sensitive individual criterion, being present in more than 95% of patients and starting during the prodromal phase. The presence of increased immunoblasts had the greatest positive predictive value at 71%. Here is a graph describing the serial hematologic findings in a patient with severe Sin Nombre virus infection. The open circles depict hematocrit percentage, the closed circles depict the platelet count, the squares depict the immunoblast count, and the triangles depict the total white blood cell count. There is a precipitous drop in the platelet count, going down from approximately 120,000 to 50,000 over a 24-hour period. As the patient progresses through the cardiopulmonary phase, we can also see a rapidly rising white blood cell count, which eventually includes immunoblasts and a rapidly rising hematocrit. Hemoconcentration is most frequently seen in severe and fatal cases. As you can see, serial hematologic testing is important in order to identify potential indicators of worsening clinical disease. Here is a graphical depiction of the hantavirus illness course. First, there is a prodromal period where the patient will complain of fever and myalgia. At this stage, the platelet counts will start to decline. If you were to perform serologic testing, IgM and IgG antibodies would be positive at this stage. Virus titer is not included on this graph, but virus RNA is detectable by PCR during both the prodrome and the cardiopulmonary phases. It often declines as antibody levels increase. The febrile prodrome is followed by the cardiopulmonary phase, which is marked by cough, shortness of breath, and the development of bilateral pulmonary infiltrates. With the passage to the cardiopulmonary phase, you will see a rapid increase in white blood cell count with a left shift, increased presence of immunoblasts, and hemoconcentration. Patients with mild hantavirus pulmonary disease may only require supplemental oxygen, but those with severe disease will quickly progress to respiratory failure, with or without circulatory shock. Patients who survive the cardiopulmonary phase will enter the diuretic phase. Clinical improvement is usually rapid, and many ventilator-dependent patients can be extubated within a day or two. Finally, the convalescent phase is characterized by weakness, fatigue, and poor exercise tolerance and may persist for months or years. I will now talk about laboratory testing. Currently, there is no rapid point-of-care diagnostic test for New World hantaviruses like Sin Nombre virus. Thrombocytopenia is seen early during the prodromal phase. A presumptive diagnosis may be made in the cardiopulmonary phase by evaluating the CBC with differential and blood smear using the five criteria described previously. Confirmatory diagnosis of hantavirus infection is made by testing with an enzyme-linked immunosorbent assay, or ELISA, capable of detecting IgM and IgG antibodies. These appear during the febrile prodrome and are 95 to 100% sensitive and specific for early hantavirus infection. Serological testing should not be used to screen for hantavirus infection in asymptomatic individuals because antibodies are not present during the incubation period. Laboratory testing is available through several sources, including through state, tribal, local, and territorial health departments and commercial laboratories. However, false positive results have been reported with the commercial assay; so it's important to interpret the results carefully when a commercial assay is ordered. It's also important for providers to contact their state, tribal, local, and territorial health departments when they suspect hantavirus and want to arrange for diagnostic testing. Confirmatory testing is available through CDC's Viral Special Pathogens Branch. So what are the keys in making the diagnosis of hantavirus disease? First, consider the disease in patients presenting with a febrile illness. Second, remember that infections can occur at any time of year. However, we do see peaks in the spring and summer. In Navajo Nation, we also see a peak in cases during the fall months. It is interesting that the peak in spring and summer is outside the typical influenza season. So, if you are seeing a patient in the spring and summer with an influenza-like illness, consider hantavirus in your differential diagnosis. Another key to making the diagnosis is asking about exposure to rodents and rodent droppings and nests. You have to ask about rodents and rodent droppings because half of confirmed hantavirus cases do not report seeing rodents. If you're concerned about hantavirus, order a CBC with differential and a blood smear; and look for the five peripheral blood smear criteria, and repeat if necessary. Now, what should you do if you're unsure of the diagnosis? One thing you can do is consider repeating the CBC with differential and blood smear in 12 to 24 hours. In patients with hantavirus disease, platelet counts can decrease by more than 20,000 in a 12-hour period. Patients during the cardiopulmonary phase of hantavirus disease will also demonstrate a rising white blood cell count with a left shift and hemoconcentration. Another resource is to speak with the on-call infectious disease physician and the medical critical care physician at the University of New Mexico. UNM has a long history of treating hantavirus disease patients and is available for consultation. I will now talk about treatment for hantavirus. Treatment of hantavirus disease is supportive. No antiviral drugs or immunotherapeutic agents have been found to be effective. There is no vaccine currently available. Inotropes should be administered early for hypotension. Avoid fluid resuscitation, as it may exacerbate pulmonary edema. Provide supplemental oxygen as needed. Take caution with intubation as the effective hemoconcentration in the setting of sedation and intubation can decrease venous return and has led to instances of cardiac arrest. Most importantly, transfer the patient immediately to a center capable of extracorporeal membrane oxygenation, or ECMO. So why do we use ECMO for hantavirus? First, hantavirus disease usually occurs in young previously healthy adults. Second, hantavirus disease, while it can be quite severe, has a short duration of critical disease. Finally, the cardiopulmonary dysfunction seen in hantavirus disease is most likely due to circulating inflammatory mediators; and autopsies performed on fatal cases did not show significant tissue damage. A retrospective review of the medical records of 51 consecutive patients with severe hantavirus disease treated with ECMO at the University of New Mexico found that all these patients had a 100% predicted mortality prior to initiation of ECMO. The patients were divided into two groups. Group A consisted of 26 patients who were intubated when they became hypoxic and were not cannulated for ECMO until they became hemodynamically unstable. Group B consisted of 25 patients who had elective insertion of percutaneous vascular sheaths shortly after arrival in the hospital and were concurrently intubated and cannulated for ECMO when they became unstable. The overall survival rate was 66%. Survival in Group A was 53.9%, and survival in Group B was 80%. Early transfer to an ECMO center improved survival. I will now discuss reporting hantavirus disease. HPS became a nationally notifiable disease in 1995 and is now reported through the Nationally Notifiable Disease Surveillance System, or NNDSS, when there is a clinically compatible case of HPS with laboratory evidence of hantavirus infection. This was expanded to include non-pulmonary hantavirus infection in 2014. This begins by reporting patients with high suspicion of hantavirus infection to the appropriate people within the healthcare facility and the state, tribal, local, and territorial health department. Reporting hantavirus cases to the local jurisdiction is very important to ensure public health follow-up. Patient information to share includes basic demographic information, symptoms and clinical illness, dates of symptom onset, and relevant exposure to rodents. For hantavirus related questions, visit the Centers for Disease Control and Prevention website; or contact the CDC's Viral Special Pathogens Branch at spather@cdc.gov. Here is a list of references cited in this presentation. Thank you for your attention.