Page 1006 - Hall et al (2015) Principles of Critical Care-McGraw-Hill

CHAPTER 80: Viral Hemorrhagic Fevers 737

liver. YFV infects first the Kupffer cells then the hepatocytes, resulting
TABLE 80-3 Warning Signs and Severe Dengue
in steatosis and virus-induced apoptosis with formation of Councilman
Warning Signs Severe Dengue bodies (apoptotic hepatocytes). 45
Abdominal pain and tenderness Severe plasma leakage: shock and fluid Epidemiology YF originated in Africa and was introduced to America with
accumulation with respiratory distress the slave trade. It was a major scourge in the 18th and 19th centuries in
Persistent vomiting Severe bleeding Africa and America, but vector control and the development of an effec-
tive vaccine have decreased the prevalence.
Clinical fluid accumulation Severe organ impairment: liver, CNS, heart
There are three transmission cycles: The jungle and the urban cycles
Mucosal bleeding are present in both America and Africa, but the intermediate cycle is
Lethargy, restlessness only present in the African savannas. The jungle cycle is maintained in
the forest canopy between monkeys and mosquitoes. Human infection
https://kat.cr/user/tahir99/
Liver enlargement >2 cm
occurs occasionally. In the savanna, treehole-breeding Aedes mosquitoes
Increased hematocrit with decrease in platelets transmit YFV from monkeys to people and from person to person. The
urban cycle is due to A aegypti transmission of YFV from person to per-
son with large epidemics. There are an estimated 200,000 clinical cases
43
in vascular permeability leads to plasma leakage (hemoconcentration), annually, 90% in Africa, with 30,000 deaths. 8,46
clinical effusions (pleural, pericardial, and peritoneal effusions; hydrops Three million persons from nonendemic countries travel to endemic
of the gallbladder), and hypotension. Hemorrhagic complications are usu- areas. During epidemics, the risk of infection of unvaccinated travelers
ally mild (petechiae) but may be more severe (purpura, large ecchymoses, may be as high as 1 in 267. In countries with high rates of immuniza-
46
bleeding at sites of venipuncture, and gastrointestinal bleed). Shock (DSS) tion, outbreaks are rare; however, the risk of jungle YF is unaffected
is due to intravascular hypovolemia from plasma leakage rather than (zoonotic transmission). At-risk travelers without contraindications
from bleeding. In epidemics associated with virulent DENV serotypes, should be immunized and provided with an international certificate of
there are many severe primary dengue cases with hepatomegaly, high vaccination. CDC publishes YF distribution maps and lists country-
43
transaminases, and liver failure. 26,32 The liver pathology shows midzonal specific immunization requirements in the “yellow book.” 47,48
necrosis and Councilman bodies like in YF. Myocarditis and neurologic
26
presentations are rare manifestations of severe dengue. 38 The Clinical Spectrum YFV infection may lead to asymptomatic infection, non-
The World Health Organization (WHO) published two clinical classi- specific fever, or a severe HF. Case fatality of clinical cases is 20% to 50%.
fications to categorize severity of dengue. A first classification defined DF, Three to six days after infection through a mosquito bite, the “period
DHF, and DSS. 33,39 A recent classification defines dengue without danger of infection” starts with a sudden onset of fever and systemic symp-
40
signs, dengue with danger signs, and severe dengue (Table 80-3). toms (headache, low back pain, and myalgia). Relative bradycardia and
Diagnosis In primary dengue infection, IgM then IgG antibodies appear injection of the conjunctivae, face, and tip of the tongue are character-
istic. Labs show leukopenia, neutropenia, and elevated transaminases.
at the end of the febrile phase and the titers rise slowly. In secondary
dengue infection, IgG antibodies appear early in the acute phase and the After 3 to 6 days, the fever resolves and viremia is cleared (period of
remission). In 75% to 85% of cases, the illness resolves (abortive YF). In
titers rise rapidly. IgM are positive in 80% by day 5 of illness. Various
techniques to detect dengue antibodies are commercially available: 15% to 25% of cases, a 3- to 8-day long period of intoxication manifests
as a severe VHF with fever, jaundice, vomiting, epigastric pain, renal
Capture ELISA is highly sensitive and specific. Dengue IgM is not sero-
type specific and may cross-react with other flaviviruses. 25,41 Detection failure, prostration, and hemorrhagic complications. The liver is tender.
Hemorrhagic manifestations are severe: petechiae, ecchymoses, bleeding
of NS1 antigen by ELISA confirms the diagnosis early in the acute phase
with a good sensitivity (82%) before IgM appears. 25,41 PCR and viral from puncture sites, epistaxis, gum bleeding, metrorrhagia, melena, and
coffee ground emesis (black vomit). Laboratory abnormalities include
isolation are only useful in epidemiological research.
neutrophilic leukocytosis, elevated transaminases, hyperbilirubinemia,
Management of Severe Dengue Patients with DF should not receive aspirin or proteinuria, elevated creatinine, thrombocytopenia, and coagulopathy.
ibuprofen but should be kept well hydrated. Patients with danger signs Patients with hepatorenal syndrome have a high mortality. Refractory
may deteriorate rapidly. Patients with severe dengue are admitted to shock, encephalopathy, metabolic acidosis, hypoglycemia, and hypo-
the ICU to help manage fluid balance. Intravenous isotonic crystalloid thermia predict a poor outcome. Convalescence results in resolution of
fluids (0.9% normal saline or lactated Ringer solution) are helpful to liver and kidney abnormalities. 43
reverse hemoconcentration but excessive infusion may result in pulmo-
nary edema. To manage refractory shock, colloidal solutions (plasma Diagnosis Confirming the diagnosis of YF relies on serology using IgM-
capture ELISA, MIA (microsphere-based immunoassay), and IgG ELISA.
47
or dextran) and vasopressors have been tried. WHO guidelines for the
management of severe dengue in small hospitals emphasize fluid man- Management of Yellow Fever There is no specific therapy and management is
agement based on hemoconcentration and body weight. 42 supportive. 43,49
Dengue only requires BSL-2 precautions, and there is no person-to- 17D Yellow Fever Vaccine Since 1937, at least 500 million doses of the live,
person transmission. attenuated 17D YF vaccine have been administered. Protective immu-
nity develops in >95% of recipients and lasts for at least 30 years, but
Yellow Fever the WHO recommends a booster every 10 years. Vaccination of travelers
The Pathogen and the Life Cycle Yellow fever virus (YFV) is a flavivirus transmit- prevents both infection and spread of YF by viremic travelers. 46
ted from person to person through the bite of female Aedes aegypti and The vaccine is very safe overall. Anaphylaxis is reported in 0.8 per
50
other mosquitoes. The genome encodes three structural proteins and 100,000 doses, often with a history of allergy to eggs or gelatin. YF
seven nonstructural proteins. 43,44 There is only one serotype, but there vaccine–associated neurologic disease (YEL-AND) rarely complicates
are at least seven genotypes. YF is present in tropical and subtropical primary YF immunization as manifested by viral encephalitis, acute
44
regions of Africa and America. YF was endemic in North America and disseminated encephalomyelitis (ADEM), and Guillain-Barré syndrome
Europe but has been eradicated. YF has never been endemic in Asia, but (GBS). YF vaccine is contraindicated in infants younger than 9 months
the vector is present. old due to a higher risk of YEL-AND. The risk of YEL-AND is 0.4 to
Pathogenesis The pathogenesis of YF has been studied in macaques. After 0.8 cases per 100,000 doses overall, but higher above age 65. 46,51,52
inoculation by an infected mosquito, YFV replicates locally in dendritic YF vaccine–associated viscerotropic disease (YEL-AVD) has been
cells and draining lymph nodes. Viremia seeds lymphoid tissues and the recognized in primary vaccines since 1998. 53-55 Two to five days after

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