A report by a team of researchers led by CDC epidemiologist Tyler Sharp examines the case of a 63-year-old Texas woman who became ill in August 2012 while on a one-month vacation to New Mexico — one month later to become only the third locally acquired dengue-related death documented in the 50 United States. All the fatalities occurred in the past 10 years and were geographically associated with Texas.
The report, entitled Fatal Hemophagocytic Lymphohistiocytosis Associated with Locally Acquired Dengue Virus Infection — New Mexico and Texas, 2012″, published in the Jan. 24 issue of the CDC journal Morbidity and Mortality Weekly Report, says that on September 2, 2012, the Texas woman visited an outpatient clinic in central Texas reporting a 7-day history of fatigue, anorexia, headache, hematuria, and leg pain. She was diagnosed with dehydration, given 1 L of intravenous normal saline, and sent home with instruction to see her primary care physician if her symptoms did not resolve.
Two days later, the patient went to her primary care physician complaining of fatigue, anorexia, headache, leg cramps, fever, and chills. Physical examination also revealed hypotension and fever. A weakly positive anti-West Nile Virus immunoglobulin M (IgM) diagnostic test result was received on September 10, whereupon the patient was diagnosed with West Nile virus (WNV) infection and prescribed bed rest for 2 weeks.
On September 22, the woman went to a regional emergency department presenting with persistent fatigue, fever, and chills. and at triage, the patient was found to be hypotensive, tachycardic, afebrile, and had low oxygen saturation. Laboratory results revealed a low platelet count, anemia , and acute liver injury. She was transferred to a tertiary care hospital for inpatient management, at admission reporting extreme fatigue, difficulty walking, shortness of breath without cough, anorexia, fever, chills, and dark urine. Abdominal ultrasound revealed diffuse fatty infiltration of the liver. Over the next 7 days, the patient developed bilateral pleural effusions, splenomegaly, anasarca, hemoptysis, and watery diarrhea with blood. Interferon therapy was initiated because of the possibility of WNV-induced hepatitis. On September 26 (hospital day 5), the patient had fever, tachypenia, neutropenia , and elevated liver enzymes. Titers taken to detect antinuclear antibodies and rheumatoid factor were positive, a presumptive diagnosis of virus-induced Hemophagocytic lymphohistiocytosis (HLH) was made, and a bone marrow biopsy and aspiration was performed. Hemodialysis was initiated on hospital day 10 because of kidney failure, and the following day the patient developed respiratory distress and was intubated. HLH is a rare but potentially fatal disease of normal but overactive histiocytes and lymphocytes. often caused by an inherited problem of the immune system.
The patient received a diagnosis of severe metabolic acidosis and volume overload on hospital day 11, and soon after became encephalopathic and unresponsive. Palliative care was initiated, and the previously collected liver and bone marrow biopsies were sent to CDC for confirmation of WNV infection On October 3, the patient died, almost exactly a month after first falling ill. RNA extracted extracted from the patient’s bone marrow aspirate and tested by RT-PCR assays specific for WNV and flaviviruses also revealed 98% nucleotide identity with DENV-3 (a dengue fever variant, which was confirmed with DENV-type specific RT-PCR.
According to the patient’s husband, the vacationing couple had traveled from Texas on August 1 to Santa Fe, New Mexico, where they took regular walks and frequently spent evenings on their patio. The patient and her husband visited an international fair featuring American Indian arts and crafts during August 18-19, but in part because of the patient’s illness, the couple returned to Texas on August 28, earlier than had been planned. The woman had not been outside the continental United States since May 2012, when she visited France.
Four other persons traveled to Santa Fe with the couple, none of whom reported fever in the two weeks before or after the patient’s illness onset. All five of her travel companions provided a serum specimen for detection of anti-DENV IgM and IgG antibodies, and none had evidence of recent or past DENV infection, respectively. Eighteen persons from Texas donated blood that was used in the 27 units given to the patient before the bone marrow biopsy was performed on September 27. Of 17 donors who were contacted, none reported fever in the 2 weeks before or 1 week after donating blood. Fourteen donors provided a serum specimen for diagnostic testing, and none had evidence of recent or past DENV infection.
Dengue fever is the most common viral disease transmitted to humans through the bite of infected mosquitos — particularly species Aedes aegpyti and Aedes albopictus — carrying any one of four distinct, but closely related, serotypes of the virus that cause dengue (DEN-1, DEN-2, DEN-3 and DEN-4). After virus incubation of 4-10 days, an infected mosquito is capable of transmitting the Dengue virus for the rest of its life. Unlike other mosquitoes, Ae. aegypti is a daytime feeder; its peak biting periods being early morning and in the evening before dusk. A female Ae. aegypti bites multiple people during each feeding period.
Dengue disease is is characterized by fever, headache, myalgia, and leukopenia. Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome that can be familial or acquired, characterized by persistent fever, pancytopenia, splenomegaly, and increased serum ferritin. Acquired HLH is most frequently associated with Epstein Barr virus infection, but also has been associated with dengue. Crohn’s disease (which this patient suffered from) and immunosuppression are associated with an increased risk for developing HLH. HLH was recently estimated to have a prevalence of 1 per 100,000 children in Texas and a survival rate of 67% . Familial HLH typically manifests early in life and is invariably fatal without treatment, including chemotherapy and immunotherapy followed by hematopoietic stem cell transplantation . HLH in adolescents and adults is more often acquired following infection or malignancy and can be successfully treated with therapy against the trigger and corticosteroids This report describes a fatal case of acquired HLH that was apparently triggered by infection with DENV-3, and as noted was the first dengue-associated HLH case documented in the country. HLH is a rare complication of dengue, with only 27 cases documented since 1966, including eight (30%) fatal cases. Clinicians in areas with endemic dengue should be aware of dengue-associated HLH because the clinical similarity of severe dengue and HLH might contribute to underrecognition of HLH. Approximately 95% of persons with dengue will experience an acute febrile illness without clinically significant hemorrhage or plasma leakage
An editorial note on the CDC report says that although the location where the patient became infected with DENV-3 could not be conclusively identified, there are several possible scenarios. The DENV incubation period ranges from 3 to 10 days, and the patient was in Santa Fe for 26 days (August 126) before illness onset. Although competent mosquito vectors of DENV are not known to establish stable populations at elevations above approximately 5,577 feet (1,700 meters) , and Santa Fe sits at an elevation of 7,260 feet (2,213 meters), an imported mosquito might have survived in the warm August weather, fed on a DENV-infected person, and subsequently infected the patient. Alternatively, infection via contaminated blood products is a rare route of DENV transmission, which could not be ruled out because four blood donors did not provide a serum specimen for testing. Finally, it is possible that the patient’s initial illness was caused by an unidentified agent, and she was infected with DENV-3 while en route to or in Texas, after which she developed HLH caused by infection with the unidentified agent and/or DENV-3.
The editor says physicians and public health professionals in the United States should be aware of dengue and request diagnostic testing that includes both molecular and serologic diagnostics for patients with dengue-like symptoms. Competent DENV vectors are present in most states, and importation of DENV via travelers has resulted in recent dengue outbreaks in Florida, Hawaii, and Texas. All suspected dengue cases should be reported to state and local health departments, but approximately 80% of all laboratory-positive dengue cases tested at private laboratories during 20082011 were not reported to public health authorities, and the actual incidence of dengue in the United States is unknown.
When reporting cases of Dengue, Dengue Hemorrhagic Fever, or Dengue Shock Syndrome, local and/or regional health agencies must complete a Mosquito-borne Disease Case Investigation Form which you can download here:
The CDC report’s editorial note advises that persons living in or traveling to areas where risk for dengue exists should avoid mosquito bites by using insect repellent, staying in residences with air conditioning or intact mosquito screens on windows and doors, and emptying or covering all water containers such as flower pots, tires, cisterns or other artificial containers that can serve as mosquito breeding sites. Dengue-carrying mosquitos, breed in standing water and are often found in urban and semi-urban areas, typically bite during the daytime, indoors and outdoors, particularly two to three hours after dawn and during the early evening. Aedes aegpyti tends to take most of its meals from humans, and Infected humans are the main carriers and multipliers of the virus, serving as a source of the virus for uninfected mosquitoes. The incubation period of DEV in humans is 3 to 14 days (typically 5 to 7 days), and infected humans may remain viremic for up to 12 days (typically 4 to 5 days) after their first symptoms appear, during which time they can infect susceptible female Aedes mosquitoes that feed on them.
Dengue has emerged as a worldwide problem only since the 1950s. In recent years, transmission has increased, and Dengue has become a major international public health concern Although dengue rarely occurs in the continental United States, it is endemic to most tropical and subtropical areas of the world, predominantly in urban and semi-urban areas, and widespread in regions of Central and South America; the Caribbean; South and Southeast Asia; Western, Eastern and Middle Africa; and Oceania, in Puerto Rico and in many popular tourist destinations in Latin America, Southeast Asia and the Pacific islands A dengue epidemic in Hawaii in 2001 underscored that many locations in the United States are susceptible to dengue epidemics because they harbor the particular types of mosquitoes that transmit dengue virus.
The World Health Organization (WHO) says Aedes albopictus, popularly referred to a the “Asian tiger mosquito.” a secondary dengue vector in Asia, has also spread to North America and Europe largely due to the international trade in used tires (a breeding habitat) and other goods (e.g. lucky bamboo). They note that Ae. albopictus is highly adaptive and therefore can survive in cooler temperate regions of Europe. Its spread is due to its tolerance to temperatures below freezing, hibernation, and ability to shelter in microhabitats.
WebMD News HealthDay’s Alan Mozes reports that experts now warn that Ae. albopictus has the potential to cause havoc across the United States, although as yet it hasn’t led to widespread disease in the country. Mozes cites Dr. Gabriel Hamer, a Clinical Assistant Professor r in the Department Of Entomology at Texas A&M University observing that “What we have here is an invasive daytime-feeding, disease-carrying mosquito that, since it first arrived on the East Coast in the 1980s, has been pretty aggressive in mowing down its natural competitors. And now it’s really starting to move through the country in full force. That makes it, at the very least, a nuisance and an annoyance, and at worst, a serious vector for major pathogens.”
Aa retrospective study, by researchers at the Baylor College of Medicine National School of Tropical Medicine at Baylor College of Medicine at Houston, published on October 9, 2013 in the journal Vector-Borne and Zoonotic Diseases and covering three years of blood and cerebrospinal fluid samples submitted for West Nile virus testing in the Houston area, found that 47 of the samples tested positive for dengue fever virus.
Dr. Kristy Murray, associate professor and associate vice chair of research in the department of pediatrics at BCM and director of the Laboratory of Viral and Zoonotic Diseases at Texas Childrens Hospital in Houston and a member of the National School of Tropical Medicine commented in a BCM release that We started with dengue virus since it was highest on the list of possible transmission here in Houston because we have the right kind of mosquitoes and a very large, densely populated city full of frequent travel to endemic areas, including Mexico and Central and South America.
Outbreaks of dengue fever, the most common viral disease transmitted to humans through the bite of infected mosquitos — particularly species Aedes aegpyti and Aedes albopictus — were reported in both Texas and Florida in 2013. Dengue-carrying mosquitoes, which breed in standing water and are often found in urban and semi-urban areas, and Dengue has become a major international public health concern. McClatchy Foreign Staffer Tim Johnson in a report published Oct.14 notes that 2013 was a particularly bad year for dengue in the Western Hemisphere, with the Pan American Health Organization reporting 1.4 million cases, and that the Florida Department of Health issued an alert in late August amid an outbreak there, with the state reporting 19 cases by mid-September, happily none lethal.
The Texas Department of State Health Services has a Dengue Fever Web page containing descriptive, avoidance, and reporting information. Several Texas laws require specific information regarding notifiable conditions be provided to the Texas Department of State Health Services (DSHS). Health care providers, hospitals, laboratories, schools, and others are required to report patients who are suspected of having a notifiable condition within one week.
With more than one-third of the worlds population living in areas at risk for infection, dengue virus is a leading cause of illness and death in the tropics and subtropics.. Dengue is caused by any one of four related viruses transmitted by mosquitoes. There are not yet any vaccines to prevent infection with dengue virus and the most effective protective measures are those that avoid mosquito bites. When infected, early recognition and prompt supportive treatment can substantially lower the risk of medical complications and death.
Worldwide, about 50 million official cases of dengue infection occur each year (although other estimates run as high as 400 million) , with 22,000 deaths, mostly in children. This includes 100 to 200 cases in the United States, mostly in people who have recently traveled abroad. Many more cases likely go unreported because some healthcare providers do not recognize the disease. In the Western hemisphere, the estimated economic burden of dengue is about $2.1 billion per year.
During the last part of the 20th century, many tropical regions of the world saw an increase in dengue cases. Epidemics also occurred more frequently and with more severity. In addition to typical dengue, dengue hemorrhagic fever (DHF) and dengue shock syndrome also have increased in many parts of the world. Before 1970, only nine countries had experienced Severe Dengue epidemics, but the disease is now endemic in more than 100 countries in Africa, the Americas, the Eastern Mediterranean, South-east Asia and the Western Pacific. The American, South-east Asia and the Western Pacific regions are the most seriously affected. Over 2.5 billion people — over 40% of the world’s population- are now at risk from dengue, and the World Health Organization (WHO) currently estimates there may be 50-100 million dengue infections worldwide every year.
Developing a vaccine against dengue/severe dengue has been challenging, and the WHO says licensure of a vaccine is not imminent. There is currently no vaccine or medication that protects against the disease, although there has been recent progress in vaccine development, and no specific treatment for the disease but medically treating the symptoms can help with recovery. The WHO has set out guidelines for management of the severe disease, i.e. DHF and DSS. and critical in this regard is early and effective plasma replacement, though debate exists as to the specific approach to be used for severe disease , e.g. use of colloid or crystalloid solutions in patients with worsening shock. Most commonly after being bitten by an infected mosquito symptoms will take four to seven days to appear, and usually include flu-like symptoms such as high fever (40C/ 104F), severe headache, joint and muscle pain, bone pain, pain behind the eyes, nausea, vomiting, swollen glands, and often a rash, but some people infected with the virus will show no symptoms.
The disease is usually self-limiting. Most people recover from Dengue Fever in two to seven days, after an incubation period of 410 days after the bite from an infected mosquito. However in about one percent of cases, dengue fever victims will develop potentially lethal complication called Severe Dengue, or Dengue Haemorrhagic Fever (DHF) — also variously known as ‘O’nyong-nyong Fever; Dengue-Like Disease; Breakbone Fever, Hemorrhagic Dengue, Dengue Shock Syndrome, Philippine Hemorrhagic Fever, Thai Hemorrhagic Fever, and Singapore Hemorrhagic Fever — an incredibly severe form of the disease first recognized in the 1950s during dengue epidemics in the Philippines and Thailand. Symptoms of DHF include high fever, plasma leakage, fluid accumulation, respiratory distress, severe bleeding under the skin, severe abdominal pain, vomiting, rapid breathing, bleeding gums, fatigue, restlessness, blood in vomit or organ impairment such as encephalopathy and fulminant liver failure. DHF can lead to shock, but for severe dengue, medical care by physicians and nurses experienced with the effects and progression of the disease can save lives decreasing mortality rates from more than 20 percent to less than 1 percent. Infants between 5 and 8 months of age are at a high risk for severe disease, and Severe Dengue is a leading cause of serious illness and death among children affecting most Asian and Latin American countries, and has become a leading cause of hospitalization and death among children in these regions, with 2.5 percent of such cases proving fatal.
Recovery from infection by one provides lifelong immunity against that particular causative serotype. However, cross-immunity to the other serotypes after recovery is only partial and temporary. Subsequent infections by other serotypes increase the risk of developing severe Dengue and Dengue Haemorrhagic Fever.
The CDC report “Fatal Hemophagocytic Lymphohistiocytosis Associated with Locally Acquired Dengue Virus Infection — New Mexico and Texas, 2012” is co-authored by Tyler M. Sharp (Corresponding author), PhD, Gilberto A. Santiago, PhD, Jorge L. Muoz-Jordan, PhD, and Kay M. Tomashek, MD of the Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, CDC; Linda Gaul, PhD, and Rebecca Lueptow, MPH, of the Texas Department of State Health Services; Atis Muehlenbachs, MD, PhD, Julu Bhatnagar, PhD, Dianna M. Blau, DVM, PhD, and Sherif R. Zaki, MD, PhD of the Division of High Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, CDC; Paul Ettestad, DVM of the New Mexico Department of Health; and Jack D. Bissett, MD, nv Suzanne C. Ledet, MD of the Seton Medical Center Austin, Texas.
U.S. Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report
Baylor College of Medicine
Texas A&M University
The Texas Department of State Health Services