SAN DIEGO – With dengue disease now knocking on the door of the United States, it’s a good time for American physicians to get up to speed regarding the most rapidly spreading mosquito-borne viral disease in the world.
That’s a particularly sound idea if they – or their patients – plan to visit anywhere in the Caribbean, Central America, Brazil, East Asia, or large swathes of Africa, where the disease is a major and rapidly growing public health problem. The World Health Organization estimates 3.6 billion people worldwide are at risk for dengue disease, with up to 100 million symptomatic infections occurring annually, 250,000-500,000 cases of severe dengue, and 21,000 deaths due to the disease. There have been recent outbreaks in South Florida, Texas, and Hawaii, Dr. Federico Narvaez noted at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.
The most important thing for clinicians to know about dengue disease is how to identify the subset of up to 10% of symptomatic dengue patients who – absent appropriate intervention – will progress to severe disease marked by pronounced plasma leakage leading to shock, respiratory failure, severe hemorrhage, and/or organ failure, he stressed. This is a disease that can cause death within the space of 24-48 hours in a person who was healthy just a few days before. And there are a handful of warning signs that predictably occur on day 3 or 4 of the illness, when the initial high fever comes down, before things take a dramatic turn for the worse.
“Timely diagnosis improves prognosis. If properly managed, the case fatality rate of severe dengue is less than 1%,” said Dr. Narvaez of the National Pediatric Reference Hospital and the Nicaragua Ministry of Health in Managua.
The traditional WHO classification for dengue into self-limited dengue fever, dengue hemorrhagic fever, and dengue shock syndrome was replaced in 2009 by a system that Dr. Narvaez and other experts consider a big step forward in guiding clinical management. Under the revised WHO classification, dengue disease is divided into dengue without warning signs, dengue with warning signs, and severe dengue.
In a study of 544 laboratory-confirmed cases of pediatric dengue in Managua, Dr. Narvaez and coinvestigators compared the former and revised WHO classifications and demonstrated that the 2009 revised system boosted the positive predictive value for need for inpatient care from 43% to 67% (PLoS Negl Trop Dis. 2011 Nov;5:e1397. doi: 10.1371/journal.pntd.0001397. Epub 2011 Nov 8).
Some key points about dengue disease: It has two distinct mosquito vectors, Aedis aegypti and A. albonictus. There are four cocirculating serotypes; infection with one doesn’t protect against infection with the others. Three-quarters of infections are asymptomatic. Symptomatic infections follow a three-stage course: the febrile, critical, and recovery phases. And the primary pathophysiology of dengue disease is plasma leakage.
The febrile phase is marked by abrupt onset of high fever plus various combinations of severe headache, facial flushing, a transient macular or maculopapular rash, retro-orbital pain, and/or the intense arthralgias/myalgias which have led to dengue being known as ‘breakbone fever.’
The critical phase begins around the time of defervescence. This is when clinically significant plasma leakage can occur, with resultant compensated or decompensated shock and other severe complications. The critical phase is the time for vigilance regarding the appearance of the 2009 WHO warning signs of increased risk for shock: abdominal pain, an abrupt rise in hematocrit concurrent with a rapid drop in platelets, mucosal bleeding, development of ascites or other clinically apparent fluid accumulation, liver enlargement of more than 2 cm, persistent vomiting, and restlessness/lethargy.
In a soon-to-be-published study of 812 Nicaraguan dengue patients, 220 of whom developed shock, Dr. Narvaez and coworkers found that the presence of any of the warning signs except persistent vomiting was associated with significantly increased likelihood of subsequent shock, with the magnitude of increased risk ranging from 1.31 to 2.3. Moreover, other studies have demonstrated that by acting upon these warning signs by means of cautious administration of intravenous fluids and other supportive measures, the risk of developing shock is reduced.
The WHO warning signs are particularly valuable in the often resource-poor countries where dengue is most common. In such settings most front-line primary care physicians lack ready access to ultrasound imaging of the gallbladder looking for evidence of wall thickening. A thickened gallbladder wall is an expression of subclinical plasma leakage, which has been shown in multiple studies to be even better at identifying patients at risk for severe dengue than the WHO warning signs.