++
Viral hemorrhagic fever is
a severe, sometimes fatal, multisystem syndrome characterized by
diffuse vascular damage and dysregulation; hemorrhage does not necessarily
occur; when it does, it is rarely a sufficient cause for demise.
The etiologic agents of this syndrome are zoonotic, lipid-enveloped
ribonucleic acid (RNA) viruses and include dozens of members from
4 families of viruses: arenaviruses, bunyaviruses, filoviruses,
and flaviviruses (Table 307-1). These agents
are localized geographically and are associated with specific vector
hosts or reservoirs,1-5 although imported cases
and infections caused by laboratory accidents and nosocomial transmission
can occur outside their respective ranges.6 The
diseases they cause are either endemic or episodic with both annual
cycles and longer secular trends. Some are associated with high
lethality and potential for person-to-person transmission. The challenges
for clinicians evaluating suspect cases are to exclude more likely
conditions that are potentially life-threatening and treatable (especially
malaria and typhoid fever); narrow the differential diagnosis based
on the travel history; institute appropriate precautions for the
diseases in the narrowed differential that are associated with person-to-person
transmission; and seek expert guidance for diagnostic confirmation
and treatment guidelines.
++
Most arboviruses (arthropod-borne viruses) are maintained in
natural cycles of infection between mosquitoes or ticks and vertebrate hosts.
The viruses may be carried through the winter or dry months by persistence
in dormant vectors, by vertical transovarial transmission in mosquitoes,
by transstadial transmission in ticks, or in persistently infected
vertebrates. In tropical locations, enzootic transmission can occur
throughout the year. Human infections occur through accidental
exposure to the enzootic cycle or during epizootics. Large urban
epidemics occur as a result of vector-borne interhuman transmission
of arboviruses like yellow fever and dengue, which produce sufficient
viremia in humans to infect mosquitoes. Some arboviruses are primarily
transmitted to humans as zoonoses. Omsk hemorrhagic fever can be
transmitted from infected muskrats to trappers during skinning.7 Rift
Valley fever and Crimean-Congo hemorrhagic fever can be transmitted
from infected livestock to herders and butchers during slaughter.4
++
Zoonotic transmission to humans also occurs with arenaviruses,
which cause Lassa and other hemorrhagic fevers and lymphocytic choriomeningitis,
and with the hantaviruses, which cause hantavirus pulmonary syndrome.3 These
viruses are spread from the excretions of various persistently or
transiently infected rodents to humans through inhalation, ingestion,
or direct contact. Filoviruses may be transmitted to humans in rare instances
by bats or other infected mammals.5 Person-to-person
spread of Crimean-Congo hemorrhagic fever, Ebola, and Marburg viruses
has led to sizable outbreaks, often with substantial nosocomial
transmission.8 Occasional person-to-person transmission
has also been documented for the New World arenaviruses (Junin and
Machupo) and Andes virus–related hantavirus pulmonary syndrome.3
++
Infection in children is determined by a combination of their
susceptibility to infection and contact with the reservoir/vector.9 During periods
of hyperendemic or epidemic yellow fever or dengue transmission,
adults may have preexisting immunity, so the highest proportion
of cases occurs in children and adolescents.10-13 Pediatric
cases of Lassa fever and town-based Bolivian hemorrhagic fever occur because
of peridomestic contact with the vector/reservoir.14 In
contrast, children are rarely affected by sylvatic yellow fever
or infection with the New World arenaviruses that are predominantly
acquired in forests or fields by hunters and farmers.3 Few
pediatric cases have been noted during outbreaks of Ebola hemorrhagic
fever in otherwise susceptible populations, because this disease
is primarily spread through direct contact with patients or inadvertent
exposures in the health care setting.5 The notable
exception was during the largest Marburg outbreak in northern Angola in
2004–2005 during which around 75% of cases occurred
in children under the age of 5 years, possibly due to nosocomial
transmission in a pediatric ward and from contaminated medical supplies.8
++
Since each of these diseases occurs in a specific geographic
and ecologic pattern, diagnosis requires consideration of the possibility
of exposure and an estimation of the incubation period. The suspicion
of viral hemorrhagic fever should immediately trigger consultation
for a specific etiology.
++
All of these diseases typically present with nonspecific signs
and symptoms like fever, myalgia, headache, and sometimes gastrointestinal
symptoms. Thus, differentiating viral hemorrhagic fever from other
febrile illnesses can be particularly difficult during the initial
stages.1-2 The subsequent development of hypotension,
a flushed appearance suggesting early vascular injury, petechiae,
and hemorrhage should trigger further diagnostic studies. Rash is
seen only in Ebola, Marburg, dengue, and Lassa fevers. The major
pitfall in diagnosis among travelers is entertaining the possibility
of hemorrhagic fever at the expense of performing a thorough evaluation
of more common and treatable conditions, such as malaria or typhoid
fever.
++
Disease manifestations of viral hemorrhagic fever in children
resemble those in adults, with notable exceptions.9 Dengue
hemorrhagic fever and dengue shock syndrome in infants is thought
to be precipitated by decreasing levels of maternal antibody, which
are cross-reactive but nonprotective at lower levels. The swollen
baby syndrome of Lassa fever is another uniquely pediatric disease.
++
Thrombocytopenia is the only universal clinical laboratory feature
of viral hemorrhagic fever, although it may be rare in Lassa fever.
Except for hantaviruses, these viruses can be readily isolated from
acute-phase samples in specialized laboratories using appropriate
biocontainment conditions.2 Enzyme-linked immunosorbent
assays for antigen, IgM, and IgG antibodies are rapid, sensitive,
and specific. The older indirect immunofluorescent antibody, complement
fixation, and hemagglutination inhibition assays are less sensitive
and specific than enzyme-linked immunosorbent assays. Plaque-reduction
neutralization test can be used to detect neutralizing antibodies
to some viruses. Nucleic acid tests like polymerase chain reaction
and nucleic acid sequence–based assays provide direct and
rapid detection of viral RNA in blood and tissue. Immunohistochemical
techniques using virus-specific antibodies have improved postmortem
tissue diagnosis. The Centers for Disease Control and Prevention’s
Special Pathogens Branch (Tel. 404-639-1115) can provide immediate
assistance with appropriate diagnosis and response.
+++
Filoviral Hemorrhagic
Fevers
++
The hemorrhagic fevers caused by Marburg and Ebola viruses are
among the most lethal: case-fatality rates range from approximately
25% to 90% among those with Marburg hemorrhagic
fever and 30% to 90% in outbreaks of Ebola hemorrhagic
fever.5 The 5 known subtypes of Ebola virus (Reston, Sudan,
Zaire, Cote d’Ivoire, and Bundibugyo, a newly identified
subtype from Uganda) differ in virulence.5,16 Growing
evidence points to cave-dwelling bats as the natural reservoir for
Marburg virus.17 Similarly, forest-dwelling bats
may be the natural reservoir for Ebola virus.18 Of
the 3 subtypes that have caused large epidemics in humans, the Zaire
subtype causes the highest case-fatality rate, followed by Sudan
and Bundibugyo. Only 1 human infection with the Cote d’Ivoire
subtype has been documented. Human-to-human spread occurs through
direct contact with symptomatic individuals, resulting in chains
of transmission that are often amplified in the nosocomial setting.8 Illness
begins with an abrupt onset of fever, prostration, headache, and
myalgia. Patients frequently appear restless and anxious, and they
later become apathetic and exhibit other encephalopathic signs.1,2,5 After
3 to 8 days, a morbilliform, usually confluent, nonpruritic rash
starts on the upper trunk and spreads centrifugally to involve the
entire body except the face and neck, and conjunctival injection
and edema can be seen. Profuse vomiting and watery diarrhea commence,
accompanied by intense abdominal pain. Chest pain is a variable
feature that was often noted in the Ebola-Sudan outbreak in 1976
but not in other Marburg and Ebola-Zaire outbreaks. Bleeding occurs
in about 50% of patients, primarily from the gastrointestinal
tract in the form of melena and hematemesis, but also from the vagina,
gums, and nares. Multisystem organ failure from pneumonitis, hepatitis,
pancreatitis, and tubulointerstitial nephritis combined with intractable
hypotension usually leads to death. Recovery can occur within 7
to 10 days, but convalescence can take weeks to months.
+++
New World Arenaviral
Fevers
++
Junin, Machupo, Guanarito, and Sabiá viruses, the etiologic
agents of Argentine, Bolivian, Venezuelan, and Sabiá hemorrhagic fevers
respectively, are maintained by specific sigmodontine rodents indigenous
to the Americas.2 Argentine hemorrhagic fever is almost
exclusively an occupational disease of agricultural workers, although
the proportion of pediatric cases is increasing, to approximately
10% of all cases, as increasing numbers of adults in high-risk
areas have been vaccinated.9 Prepartum maternal infection
can result in spontaneous abortion, congenital malformations, and
neonatal death, as well as maternal death; the virus has also been
isolated from breast milk. Bolivian hemorrhagic fever and Venezuelan hemorrhagic
fever are acquired in a peridomestic setting, and cases occur in
all age groups. All 4 diseases present with a similar nonspecific
history of fever, headache, myalgia, weakness, and gastrointestinal
symptoms. Retroorbital pain, photophobia, and epigastric abdominal
pain may occur, but pharyngitis and other respiratory signs and symptoms
are uncommon. Patients become increasingly toxic and develop a flushed
appearance, conjunctival injection, and fine petechial eruptions
on the oral pharynx, upper trunk, and axillae. Most enter a convalescent
phase after the first week of illness, but more than one third develop
neurologic complications (altered mental status, ataxia, or tremors)
or a hypotensive-hemorrhagic phase associated with a capillary leak
syndrome. New World arenaviruses cause an overall case-fatality
rate of 10% to 30%.3
++
Lassa fever is a common febrile illness in West Africa, with
as many as 300,000 cases and 5000 deaths annually.19 Lassa
fever may account for as much as 10% of febrile children
admitted to hospitals in disease-endemic areas. The disease is characterized
by insidious onset of fever, weakness, myalgia, and generalized
malaise followed by lower backache, substernal or epigastric pain,
dizziness, cough, and gastrointestinal symptoms. Purulent pharyngitis,
conjunctivitis, edema (particularly of the head and neck), and mucosal
bleeding are highly specific signs of Lassa fever. Fulminant disease
is marked by hypovolemic shock; facial and neck edema; encephalopathy;
and respiratory distress due to laryngeal edema, pneumonitis, pulmonary edema,
and pleural effusion. Permanent sensorineural hearing loss can occur
as a late sequela. Maternal infection can result in maternal and
fetal death, especially near term, as well as congenital Lassa fever
in neonates. Children younger than 2 years of age with Lassa fever
can develop swollen baby syndrome, characterized by widespread edema,
abdominal distention, and bleeding.9,19
+++
Hemorrhagic
Fever with Renal Syndrome
++
Hemorrhagic fever with renal syndrome is caused by 4 murine and
arvicoline rodent-borne Old World hantaviruses: Hantaan, Dobrova-Belgrade,
Seoul, and Puumala, which occur primarily in Asia and Europe.20-21 Men,
particularly agricultural and forestry workers, are at greatest
risk for infection in sylvatic locations. There is an unexplained paucity
of cases among children, and it is possible that symptomatic disease
may be milder in children. The most severe form of hemorrhagic fever
with renal syndrome is caused by Hantaan virus and is classically
associated with 5 consecutive phases with characteristic physiological
derangement: febrile, hypotensive, oliguric, diuretic, and convalescence.
Hemorrhage is generally noted during the oliguric phase. However,
there is considerable variation in the incidence of various manifestations,
and the severity of individual phases that may overlap.
+++
Hantavirus Pulmonary
Syndrome
++
Hantavirus pulmonary syndrome is caused by a number of New World
sigmodontine rodent-borne hantaviruses indigenous to rural areas
of the Americas and is a consequence of sylvatic or peridomestic
transmission.3 As with their Old World cousins,
there is a relative paucity of pediatric cases. A brief, nondescript
febrile prodrome with chills, myalgia, malaise, diarrhea, and headache
is generally followed by the precipitous onset of the cardiopulmonary
phase with hypotension and increased vascular permeability, resulting
in pulmonary edema and hypoxia. Death can occur within 2 days of
admission from respiratory failure and cardiogenic shock. In South
America, Andes virus infection may be associated with facial flushing, petechiae,
and occasionally frank hemorrhage, and it can be transmitted person
to person. Overt hemorrhage occurs rarely in severe cases in North
America. Bilateral interstitial pulmonary infiltrates in conjunction
with shock are a hallmark of severe disease, as is the triad of thrombocytopenia,
immature neutrophils, and circulating immunoblasts. Atypical presentations
with prominent renal insufficiency and myositis have been reported,
as have asymptomatic and mild infections without pulmonary involvement.
+++
Crimean-Congo
Hemorrhagic Fever
++
Congo-Crimean hemorrhagic fever virus (CCHFV) is also a member
of the Bunyaviridae family. It has a wide geographic distribution
throughout parts of Africa, the Middle East, Asia, and Eastern Europe,
which mirrors the distribution of its vector, the Hyalomma genus
of ticks (eFig. 307.3). Many types of mammals
and perhaps birds serve as reservoirs for the virus as transmitted
by ticks, but humans seem to be the only species that develop disease
with the infection. In addition to tick bites, contact with human
or animal blood (particularly inoculation) also serves as an important
route of infection, with numerous nosocomial outbreaks of CCHFV
reported. Risk factors for acquisition in endemic areas include
outdoor recreational activity, farming, and blood contact through
abattoir, veterinary, or health care work. Clinical disease with
CCHFV usually follows a 3- to 9-day incubation period. Symptom
onset is usually abrupt with severe headache, high fever, myalgia,
weakness, anorexia, back and abdominal pain, and nausea often accompanied
by vomiting. Hyperemia commonly occurs, most notably on the face, mucous
membranes, and upper part of the body. Early nonspecific symptoms
are followed by more severe manifestations after the sixth day of
illness, including hemorrhage from the nose, mouth, and gastrointestinal
tract and large ecchymotic areas on the limbs caused by disseminated
intravascular coagulation.1-2 During this stage,
most patients become obtunded with halting speech; dizziness and
mild meningeal signs are common. Elevated bilirubin and liver enzyme levels
are usually present. Patients may become delirious or comatose;
death occurs in approximately 30% of cases.
++
++
Rift Valley fevor virus (RVFV) is a member of the Buyaviridae
family. Rift Valley fever is a primarily mosquito-borne veterinary disease
occurring in sub-Saharan Africa and Madagascar (eFig.
307.4), where intermittent epizootics associated with heavy
rainfall cause serious losses of domestic livestock from abortions
and death.4 An isolated epidemic also occurred
in Saudi Arabia and Yemen from 2000 to 2001. Humans can be infected
by direct or aerosol exposure to blood from infected animals, from
ingestion of raw milk, as well as by mosquito bite. Usually it manifests
as a self-limited but severe illness characterized by fever, headache,
chills, anorexia, myalgia, and prostration, with impaired hepatic
and renal function. The illness typically resolves after 2 to 5
days, but approximately 1% of infected patients develop
hemorrhagic fever; less than 1%, encephalitis; and 15% retinitis. The
hemorrhagic fever usually involves severe necrotizing hepatitis.
Encephalitis, associated with confusion, meningismus, paresis, hallucinations,
convulsions, and recrudescence of fever, can occur 1 to 4 weeks
after the initial febrile illness, as can retinitis, which can cause
permanent vision loss.2,4 Overall mortality with
RVFV infection is 1% or less, but mortality with severe
disease in recent series has been 29% to 33%.
++
++
Dengue fever is the most common arboviral infection worldwide.
Dengue hemorrhagic fever causes hundreds of thousands of life-threatening
infections annually in the tropics, mostly in children.9 The
geographic range of dengue has been expanding dramatically over the
past 40 years; it is now hyperendemic in the tropics (eFig.
307.1). Dengue virus
is a Flavivirus with 4 serotypes, transmitted by Aedes specie mosquitoes,
predominantly Ae aegypti, which are present in most
tropical urban areas of the world.11-13Ae albopictus have
also been implicated in fairly substantial outbreaks, especially
as they have been introduced into new areas, sometimes outcompeting Ae
aegypti. In the United States, these mosquitoes can be
found in Hawaii year-round and in the southeastern states in the summer
months, contributing to an epidemic in Hawaii in 2001–2002
and regular autochthonous transmission in southern Texas. Epidemics
arise in susceptible populations after the virus is introduced by
viremic persons into areas with competent vectors. In areas where transmission
is endemic, dengue is principally a disease of childhood. Infections
occur in almost 100% of children before 8 years of age. Infections
can occur in all age groups when the people exposed are immunologically naïve,
such as when a new strain is introduced in a population or when
travelers from nonendemic areas travel to dengue-endemic regions.
++
++
Asymptomatic DENV infection is common. The incubation period
for disease in symptomatic individuals is typically 4 to 7 days.
Dengue fever can be mild in young children but in older children
and adults is associated with significant fever, chills, headache, retroorbital
pain, myalgia, arthralgia, and low back pain accompanied by anorexia,
nausea, and vomiting.22 Facial flushing is common, and
in fair-skinned persons, a centrifugally spreading morbilliform
rash may be detected late in the illness in more than half of patients. Illness
is self-limited and sometimes is complicated by minor hemorrhagic
phenomena, such as epistaxis and minor gum, gastrointestinal, and
vaginal mucosal bleeding. The tourniquet test (20 or more petechiae
appearing below a blood pressure cuff inflated for 5 minutes to
halfway between systolic and diastolic pressures) may be positive
in one third of patients. Lowered platelet, total leukocyte, and absolute
monocyte and neutrophil counts reflect bone marrow suppression and
peripheral destruction of platelets.
++
The self-limited hemorrhagic phenomena should be differentiated
from dengue hemorrhagic fever, characterized by thrombocytopenia,
generalized bleeding, and evidence of increased vascular permeability
(eg, hemoconcentration, pleural effusions, ascites, or hypoalbuminemia).
Advanced cases are called dengue shock syndrome, which is dengue hemorrhagic
fever with hypotension and a narrow pulse pressure and causes a
case-fatality rate as high as 44%.11-13,22 Cross-protective immunity
among dengue serotypes is limited, and sequential infection, particularly
when dengue 2 virus causes the second infection, increases the risk
for dengue hemorrhagic fever and dengue shock syndrome. The onset
of hypotension may be precipitous and typically occurs with defervescence.
This interval of vascular instability may be as brief as 24 to 48 hours
and reverses spontaneously. Hemodynamic monitoring and supportive
fluid, cardiovascular support, and avoidance of aspirin reduce dengue
hemorrhagic fever mortality from 25% to less than 5%.
++
Yellow fever is transmitted between nonhuman primates in the
tropical rainforest by Aedes species mosquitoes in Africa and Haemagogus
species mosquitoes in South America.10 A sylvatic
cycle occurs in the moist savanna regions of Africa in which forest
Aedes species mosquitoes transmit yellow fever between primates
and humans. Large epidemics of urban yellow fever can occur in cities
in endemic areas of Africa and South America infested by peridomestic Ae
aegypti that transmit the disease in a human-mosquito-human
cycle, as with dengue (eFig. 307.2).10,13 Yellow
fever epidemics mostly affect children and young adults who have
not acquired immunity to yellow fever or to heterologous flaviviruses
that may offer some cross-protective immunity and who tend to develop more
severe disease with high case-fatality ratios.
++
++
The disease classically has been divided into three stages: infection,
remission, and intoxication.10 The period of infection
is characterized by sudden onset of fever, headache, malaise, and
musculoskeletal pain, low back pain, and nausea. Physical signs
include conjunctival suffusion, flushing of the skin, and relative bradycardia
despite fever, known as Faget sign. In about 15% to 25% of
cases, the remission phase is temporary, lasting only 2 to 24 hours,
and the illness resumes in a more severe form. Patients in the period
of intoxication develop fever, vomiting, abdominal pain, jaundice,
hematemesis, and other forms of hemorrhage. Patients are typically
dehydrated with hypotension, reduced urinary output, and, frequently,
proteinuria. Myocarditis, azotemia, encephalopathy, progressive
liver damage, bleeding, and shock can occur; 20% to 50% of cases
that enter the period of intoxication die.
+++
Tick-Borne Hemorrhagic
Fevers
++
Kyasanur Forest disease and Omsk hemorrhagic fever are tick-borne
flavivirus infections that are seasonally transmitted in the areas
of southern and central India and southwestern Siberia, respectively.3,7 Kyasanur Forest
disease is maintained in a forest cycle involving Haemaphysalis ticks,
birds, and small mammals. It is transmitted by tick bite to nonhuman
primates and humans, mainly villagers and lumbermen. Omsk hemorrhagic fever
is primarily transmitted directly from infected muskrats to humans
during hunting through direct contact with blood, urine, or feces;
by tick bite; or through ingestion of unpasteurized milk from infected
sheep and goats. Kyasanur Forest disease and Omsk hemorrhagic fever
are self-limited illnesses characterized by acute fever, chills,
myalgia, headache, vomiting, and diarrhea lasting 4 to 10 days in
half of all cases, and hypotension, which can persist for several
days. Hemorrhagic manifestations tend to be minor in Omsk hemorrhagic
fever. Hepatitis and acute renal failure can occur in both illnesses,
and bronchitis, pneumonia, alveolar hemorrhage, and pulmonary edema
develop in 40% of cases. Signs of encephalitis appear late
in the course of illness in 50% of Kyasanur Forest disease
cases but are less prominent in Omsk hemorrhagic fever. The case-fatality
rate for both illnesses is less than 5%.
++
Acute infection can be asymptomatic or clinically apparent, with
resolution. Supportive therapy for shock, hemorrhage, and secondary infection
are critical for the management of cases of more severe viral hemorrhagic
fevers.1-2,15 Anecdotal experience suggests the
use of ribavirin in Rift Valley fever may exacerbate or cause encephalitis,
and further evidence is necessary to recommend its use.1-2,23 However,
in controlled trials of adults, ribavirin reduced mortality and
morbidity in Lassa fever and hemorrhagic fever with renal syndrome.22,24 Retrospective
studies have indicated that ribavirin may decrease mortality among
patients with Crimean-Congo hemorrhagic fever,24 and anecdotal
experience suggests its efficacy in treating New World arenaviral
hemorrhagic fevers.3 Early transfusion of immune
plasma is an effective therapy for Argentine hemorrhagic fever,
and immunoglobulin has been used with some success in a few cases
of Crimean-Congo hemorrhagic fever.7
+++
Prevention and Control
++
Vector-borne infections can be prevented by avoiding at-risk
locations during the seasons and/or times of day when risk
is greatest. Simple measures include covering exposed areas of the
body with clothing, avoiding outdoor activities at dusk and dawn
when certain vectors are most active, and using insecticide-treated
bed nets. Protective clothing and repellents can reduce arthropod exposure
and bites. Repellents containing N,N-diethyl-meta-toluamide (DEET)
or picaridin are the most effective formulations; however, no definitive
studies have determined what concentrations of DEET are safe to
use in children.25 The American Academy of Pediatrics
has stated that DEET is not harmful to children in concentrations
of up to 30% when used appropriately but does not recommended
its use in infants under 2 months old. Oil of lemon eucalyptus has
also been approved by the FDA for use as an insect repellent but
needs to be applied more frequently and should not be used on children
under 3 years of age according to the product label. Permethrin
effectively repels and kills mosquitoes and ticks when sprayed on
clothing and bed nets and remains effective after several washings.
++
Minimizing human-rodent interactions is the cornerstone of preventing
infections with hantaviruses and arenaviruses.3 Eliminating
rodent shelter, excluding rodents, and controlling rodent populations
are readily accomplished in urban settings but are more difficult
in the rural occupational or recreational setting. Although the
reservoir hosts of filoviruses remain uncertain, people should avoid
contact with ill or dead primates as well as unprotected exposure
to bats and their excreta that may harbor Marburg virus, particularly
in enclosed spaces such as caves and mines. The risk of infection
from imported nonhuman primates has been minimized by the implementation
of new quarantine regulations and reliance on captive-bred animals.
Prevention of nosocomial transmission, through contact and droplet
precautions and decontamination of clinical specimens, is the most
critical aspect of the strategy to minimize the risk for the arenaviral
and filoviral infections.8
++
Live attenuated vaccines are available for both yellow fever13 and
Argentine hemorrhagic fever,3 and a formalin-inactivated
vaccine for Kyasanur Forest disease virus has been used in India.7 Inactivated
tick-borne encephalitis vaccines may provide some cross-protection
against Omsk hemorrhagic fever virus.7 Yellow fever
vaccine is contraindicated in children under 6 months old and not
recommended until 9 months of age because of the risk of vaccine-associated
encephalitis. Yellow fever immunization is also contraindicated during
pregnancy because of a theoretical risk to the fetus. Yellow fever
vaccine has been associated with rare neurotropic and viscerotropic
severe adverse events that are more common among the elderly. It
is safe and effective overall and is required by some countries
for entry.10 Consultation at a travel clinic is
advised to provide travelers with appropriate pretravel counseling
and immunization.
++
The findings and conclusions in this report are those of the
authors and do not necessarily represent the views of the Centers
for Disease Control and Prevention (Figs. 307-1, 307-2, 307-3, and 307-4).