1752 Part XVI ◆ Infectious Diseases
with older adolescents who receive a three-dose series. Vaccination is
also recommended for adults through age 45 yr if they have not been
previously vaccinated.
It is important that vaccination take place in children before they
become sexually active, because the rate of HPV acquisition is high
shortly after the onset of sexual activity. Vaccine can be given to ado-
lescents as young as 9 yr of age, and a catch-up vaccination is recom-
mended in girls 13-26 yr and in boys 13-21 yr. For males who are gay,
bisexual, or have sex with males, who are immunocompromised
(including HIV infection), or who are transgender, catch-up vaccination
can continue through age 45. For any adolescent who receives his or
her first HPV vaccine dose at age 15 or older, a three-dose series at 0,
1-2, and 6 mo is recommended. The three-dose series is also recom-
mended for adolescents and young adults 9-26 yr old who have an
immunocompromising condition. Individuals who are already infected
with one or more vaccine-related HPV types prior to vaccination are
protected from clinical disease caused by the remaining vaccine HPV
types. Therefore, a history of prior HPV infection is not a contraindication
to vaccine receipt. However, HPV vaccines are not therapeutic.
Postlicensure vaccine safety surveillance has not identified any serious
adverse events attributable to HPV vaccine receipt. Three large obser-
vational studies and safety monitoring through active and passive
surveillance networks among more than 1 million individuals have not
identified any association between HPV vaccination and outcomes such
as autoimmune disorders, stroke, or venous thrombotic emboli. Vac-
cination can cause fever in approximately 1 in 60 and discomfort at the
injection site for 1 in 30 vaccine recipients. Syncope has also been found
to be correlated with vaccine administration in 0.1% of vaccine recipients.
Therefore, it is advised that adolescents remain seated for 15 min fol-
lowing vaccination.
Despite an excellent safety and efficacy profile, HPV vaccine uptake
has been slow. Immunization rates consistently lag behind rates for the
other vaccines included in the adolescent immunization platform. In
2015, only 56.1% of 13- to 17-yr-olds received at least one HPV vaccine
dose compared with 81.6% who received at least one dose of the
quadrivalent meningococcal vaccine and 86.4% who received Tdap.
Reasons for the slow uptake include inconsistent provider recommenda-
tion, lack of knowledge about HPV, parental belief that vaccination is
not necessary for younger adolescents, and misconceptions about vaccine
safety, among others. There is a growing body of literature evaluating
interventions to improve HPV vaccine uptake. One important strategy
is a strong, consistent recommendation in which HPV vaccines are
presented in the same way as Tdap and meningococcal vaccines.
Bibliography is available at Expert Consult.
Chapter 294
Arboviral Infections
Scott B. Halstead
The arthropod-borne viral infections are a group of mosquito- or tick-
transmitted pathogens of several taxa manifested clinically mostly as
neurologic infections, influenza-like illnesses, or acute viral exanthems.
In temperate countries, arboviruses are transmitted during warmer
weather; however, in tropical and subtropical countries, arboviruses
may be transmitted year around either in an urban cycle (human to
mosquito to human) or by arthropods that feed on other vertebrate
species and then feed on humans.
ETIOLOGY
The principal arthropod-borne viral infections in North America are
West Nile encephalitis (WNE), St. Louis encephalitis (StLE), Powassan
(POW) encephalitis, a complex of California encephalitis group viruses,
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and, less frequently, western equine encephalitis (WEE), eastern equine
encephalitis (EEE), and Colorado tick fever (Fig. 294.1). In 2013,
chikungunya virus (CHIK) emerged from its original African zoonosis
via Asia into the Western Hemisphere, exposing many residents of the
United States who were traveling in the region. A few cases occurred
domestically in southern states. In 2015, Zika virus (ZIKV), a flavivirus
also maintained in Africa zoonoses, was introduced into the Americas,
again from endemic areas in Asia. Limited transmission occurred within
the continental United States. The major source of infection among
Americans for each of these viruses has been travel to tropical and
subtropical countries.
Throughout the world outside North America, there are many
arboviruses that pose major health problems (Fig. 294.2). In descending
order, these are the dengue viruses (DENV; Chapter 295), transmitted
in all subtropical and tropical countries; Japanese encephalitis (JE),
transmitted in northern, southern, and Southeast Asia; tick-borne
encephalitis (TBE), transmitted across Europe and into northern and
eastern Asia; yellow fever (YF; Chapter 296), transmitted from zoonotic
cycles in Africa and South America; and Venezuelan equine encephalitis
(VEE), transmitted in parts of South and Central America.
The etiologic agents belong to different viral taxa: alphaviruses of the
family Togaviridae (CHIK, EEE, VEE, WEE), flaviviruses of the family
Flaviviridae (DENV, JE, POW, STLE, TBE, WNE, YF, ZIKV), the Cali-
fornia complex of the family Bunyaviridae (California encephalitis),
and Reoviridae (Colorado tick fever virus). Alphaviruses are 69 nm,
enveloped, positive-sense RNA viruses. Studies suggest that this group
of viruses had a marine origin (specifically the southern ocean) and
that they have subsequently spread to both the Old and New Worlds.
VEE circulates in nature in six subtypes. Virus types I and III have
multiple antigenic variants. Types IAB and IC have caused epizootics
and human epidemics. Flaviviruses are 40- to 50-nm, enveloped, positive-
sense RNA viruses that evolved from a common ancestor. They are
mosquito-borne (WNE, STLE, JE, YF, DENV, ZIKV) and tick-borne
(POW, TBE) agents, globally distributed, and responsible for many
important human viral diseases. The California serogroup, 1 of 16
Bunyavirus groups, are 75- to 115-nm enveloped viruses possessing a
three-segment, negative-sense RNA genome. Reoviruses are 60- to 80-nm
double-stranded RNA viruses.
DIAGNOSIS
For arboviral infections not described separately, the etiologic diagnosis
is established by testing either an acute-phase serum to detect the virus,
viral antigen, or viral RNA (influenza-like illnesses or viral exanthems)
or by recovery of virus from CNS tissue or CSF. More commonly, the
diagnosis is established serologically. Serum obtained ≥ 5 days after the
onset of illness is tested for the presence of virus-specific immunoglobulin
(Ig) M antibodies using an enzyme-linked immunosorbent assay IgM
capture test, an indirect immunofluorescence test, or a precipitin test.
Alternatively, acute and convalescent sera can be tested for a four-fold
or greater increase in enzyme-linked immunosorbent assay, hemag-
glutination inhibition, or neutralizing antibody titers. Commercial
serologic diagnostic kits are marketed for DENV, CHIK, JE, TBE, WN,
YF, or ZIKV viral infections. The serum and CSF should be tested for
JE or WN virus–specific IgM. However, IgM may reflect past infection,
because it may be present up to 12 mo after infection. For suspected
flavivirus infections, including Zika virus, it may be possible to establish
infection using a serologic test, calling upon the specificity of neutralizing
antibodies. The most common of these is the plaque or focus-reduction
neutralizing antibody test. Reference laboratories offer tests for all of
the pathogenic flaviviruses. The diagnosis may also be established by
the isolation of virus in cell cultures, by identification of viral RNA, or
by detection of viral proteins (e.g., dengue NS1) from blood, brain
tissue obtained by brain biopsy, or tissues obtained at autopsy.
PREVENTION
Several vaccines for Japanese encephalitis and tick-borne encephalitis
are licensed in endemic and nonendemic countries. An experimental
vaccine for VEE is available to protect laboratory workers. Travelers
who plan to be in rural areas of Asia during the expected period of
 Chapter 294 ◆ Arboviral Infections 1753

Human Eastern Equine Encephalitis Cases by State, 1964-2010 Human Western Equine Encephalitis Cases by State, 1964-2007
EEE Human cases WEE Human cases
VT 13 VT
NH 10 NH

27 78
MA 37 1 43 MA
4
1 RI 6 40 2 RI
16 16 1
2 5
CT 26 CT
3 6 1
4 NJ 20 53 173 NJ
36 7
17
DE 3 3 DE
13 2 13
6 7 28 MD 16 MD
17 94
AK 2 AK
DC DC
70
WV WV
HI Puerto Rico HI Puerto Rico
A B
Human Saint Louis Encephalitis Cases by State, 1964-2010 Human California Serogroup* Viral Encephalitis Cases by State, 1964-2010
SLE Human cases CAL Human cases
4 VT VT
NH 1 NH
2 1
19 MA MA
2
8 367
3 10 58
5 5 RI 586 RI 1
1 33 31
25 37 134 8
14 441 CT 1 918 CT 2
4
1 697 369 241 143
88 8 1 28
123 127 77 NJ 131 1 14 NJ 3
68 23
6 237
141 DE 1 163 DE
41 12 79 2 5
7 3
348 150 5 14 7 27
MD 9 MD 4
168 25
1021 5
AK DC 9 AK DC
380 4
WV 12 WV 602
HI Puerto Rico HI Puerto Rico

C D *The majority of reported California serogroup cases are La Crosse virus (LAC).

Powassan Virus Neuroinvasive Disease Cases Reported by State, 2001-2012

POWV Human cases
VT
NH
2
MA
19
10 13
RI
1
1
CT

1 NJ

DE

MD

AK DC

WV
HI
E Puerto Rico

Fig. 294.1 The distribution and incidence of reported cases of eastern equine encephalitis (A), western equine encephalitis (B), St. Louis
encephalitis (C), California serogroup encephalitis (D), and Powassan encephalitis; (E), reported by state to the Centers for Disease Control and
Prevention, 1964 to 2010. (From Division of Vector-Borne Diseases, Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/
ncidod/dvbid/arbor/arbocase/htm.)

seasonal transmission should receive JE vaccine. Similarly, travelers
who plan to travel, camp, or picnic in rural areas of Europe and East
Asia should consult local health authorities concerning the need to be
vaccinated against TBE. An inactivated vaccine manufactured in Japan
by intracerebral injection of young mice and available throughout the
world has been taken off the market owing to a high incidence of
adverse events. In 2008-2009, tissue culture–based JE vaccine (Ixiaro)
was licensed in Europe, Australia, and the United States. In the United
States, this vaccine is licensed for use in children and adults and is
distributed by Novartis (Basel). This vaccine is administered intramus-
cularly as two doses of 0.5 mL each, 28 days apart. The final dose should
be completed at least 1 wk prior to the patient’s expected arrival in a
JE endemic area. This vaccine contains alum and protamine sulfate and
has exhibited only mild adverse events. A highly efficacious live-attenuated
single-dose JE vaccine developed in China for children is licensed and
marketed in Asian countries. This vaccine can be coadministered with
live-attenuated measles vaccine without altering the immune responses
to either vaccine. In humans, prior dengue virus infection provides
partial protection from clinical JE.
No TBE vaccines are licensed or available in the United States. Two
inactivated cell culture–derived TBE vaccines are available in Europe,
in adult and pediatric formulations: FSME-IMMUN (Baxter, Austria)
and Encepur (Novartis, Germany). The adult formulation of FSME-
IMMUN is also licensed in Canada. Two other inactivated TBE vaccines
are available in Russia: TBE-Moscow (Chumakov Institute, Russia) and
EnceVir (Microgen, Russia). Immunogenicity studies suggest that the

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1754 Part XVI ◆ Infectious Diseases
Flaviviridae
Zika Virus
Japanese encephalitis virus
Yellow fever virus
West Nile virus
Saint Louis encephalitis virus
Tick-borne encephalitis virus
Dengue virus
A B
Bunyaviridae
Crimean–Congo hemorrhagic
fever virus
Toscana virus
La Crosse virus
Rift Valley fever virus
C
Fig. 294.2 World distribution of major arbovirus infections. (From Charlier C, Beaudoin MC, Couderc T, et al: Arboviruses and pregnancy:
maternal, fetal, and neonatal effects, Lancet Child Adolesc 1:134-146, 2017, Fig. 1.)
European and Russian vaccines should provide cross-protection against
all three TBE virus subtypes. For both FSME-IMMUN and Encepur,
the primary vaccination series consists of three doses. The specific
recommended intervals between doses vary by country and vaccine.
Because the routine primary vaccination series requires ≥ 6 mo for
completion, most travelers to TBE-endemic areas will find avoiding
tick bites to be more practical than vaccination.
For all viral diseases discussed in this chapter, personal measures
should be taken to reduce exposure to mosquito or tick bites, especially for
short-term residents in endemic areas. These measures include avoiding
evening outdoor exposure, using insect repellents, covering the body with
clothing, and using bed nets or house screening. Commercial pesticides,
widely used by rice farmers, may be useful in reducing populations of
vector mosquitoes or ticks. Fenthion, fenitrothion, and phenthoate are
effectively adulticidal and larvicidal. Insecticides may be applied from
portable sprayers or from helicopters or light aircraft.
Bibliography is available at Expert Consult.
294.1 Eastern Equine Encephalitis
Scott B. Halstead
In the United States, EEE is a disease with a very low incidence, with
a median of eight cases occurring annually in the Atlantic and Gulf
states from 1964 to 2007 (Fig. 294.1). Transmission occurs often in
focal endemic areas of the coast of Massachusetts, the six southern
counties of New Jersey, and northeastern Florida. In North America,
the virus is maintained in freshwater swamps in a zoonotic cycle involving
Culiseta melanura and birds. Various other mosquito species obtain
viremic meals from birds and transmit the virus to horses and humans.
Virus activity varies markedly from year to year in response to still
unknown ecologic factors. Most infections in birds are silent, but
infections in pheasants are often fatal, and epizootics in these species
are used as sentinels for periods of increased viral activity. Cases have
been recognized on Caribbean islands. The case:infection ratio is lowest
in children (1 : 8) and somewhat higher in adults (1 : 29).
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Togaviridae (alphaviruses)
Venezuelan equine
encephalitis virus
Sindbis virus
O’Nyong-nyong virus
Ross River virus
Chikungunya virus
EEE virus infections result in fulminant encephalitis with a rapid
progression to coma and death in one third of cases. In infants and
children, abrupt onset of fever, irritability, and headache are followed
by lethargy, confusion, seizures, and coma. High temperature, bulging
fontanel, stiff neck, and generalized flaccid or spastic paralysis are
observed. There may be a brief prodrome of fever, headache, and diz-
ziness. Unlike most other viral encephalitides, the peripheral white
blood cell count usually demonstrates a marked leukocytosis, and the
cerebrospinal fluid (CSF) may show marked pleocytosis. Pathologic
changes are found in the cortical and gray matter, with viral antigens
localized to neurons. There is necrosis of neurons, neutrophilic infiltra-
tion, and perivascular cuffing by lymphocytes.
The prognosis in EEE is better for patients with a prolonged prodrome;
the occurrence of convulsions conveys a poor prognosis. Patient fatality
rates are 33–75% and are highest in the elderly. Residual neurologic
defects are common, especially in children.
The diagnosis of encephalitis may be aided by CT or MRI and by
electroencephalography. Focal seizures or focal findings on CT or MRI or
electroencephalography should suggest the possibility of herpes simplex
encephalitis, which should be treated with acyclovir (see Chapter 279).
294.2 Western Equine Encephalitis
Scott B. Halstead
WEE infections occur principally in the United States and Canada west
of the Mississippi River (see Fig. 294.1), mainly in rural areas where
water impoundments, irrigated farmland, and naturally flooded land
provide breeding sites for Culex tarsalis. The virus is transmitted in a
cycle involving mosquitoes, birds, and other vertebrate hosts. Humans
and horses are susceptible to encephalitis. The case:infection ratio varies
by age, having been estimated at 1 : 58 in children younger than 4 yr of
age and 1 : 1,150 in adults. Infections are most severe at the extremes
of life; one third of cases occur in children younger than 1 yr of age.
Recurrent human epidemics have been reported from the Yakima Valley
in Washington State and the Central Valley of California; the largest
outbreak on record resulted in 3,400 cases and occurred in Minnesota,
1760 Part XVI ◆ Infectious Diseases

Table 294.2 CDC Recommendations for Preconception Counseling and Prevention of Sexual Transmission of Zika Virus
Among Persons With Possible Zika Virus Exposure: United States, August 2018
EXPOSURE SCENARIO RECOMMENDATIONS (UPDATE STATUS)
Only the male partner travels to an area with The couple should use condoms or abstain from sex for at least 3 mo after the male partner’s
risk for Zika virus transmission and couple is symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic).
planning to conceive (Updated recommendation)
Only the female partner travels to an area The couple should use condoms or abstain from sex for at least 2 mo after the female partner’s
with risk for Zika virus transmission and symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic).
couple is planning to conceive (No change in recommendation)*
Both partners travel to an area with risk for The couple should use condoms or abstain from sex for at least 3 mo from the male partner’s
Zika virus transmission and couple is symptom onset (if symptomatic) or last possible Zika virus exposure (if asymptomatic).
planning to conceive (Updated recommendation)
One or both partners have ongoing The couple should talk with their health care provider about their plans for pregnancy, their risk
exposure (i.e., live in or frequently travel to for Zika virus infection, the possible health effects of Zika virus infection on a baby, and ways
an area with risk for Zika virus transmission) to protect themselves from Zika. If either partner develops symptoms of Zika virus infection or
and couple is planning to conceive tests positive for Zika virus infection, the couple should follow the suggested timeframes
listed above before trying to conceive. (No change in recommendation)*
Men with possible Zika virus exposure whose The couple should use condoms or abstain from sex for the duration of the pregnancy.
partner is pregnant (No change in recommendation)*
*Petersen EE, Meaney-Delman D, Neblett-Fanfair R, et al: Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus
for persons with possible Zika virus exposure—United States, September 2016, MMWR Morb Mortal Wkly Rep 65:1077–1081, 2016.
From Polen KD, Gilboa SM, Hills S, et al: Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for men with
possible Zika virus exposure: United States, August 2018, MMWR 67(31):868–870, 2018.

transcription polymerase chain reaction (rRT-PCR) and serum Zika

virus immunoglobulin M (IgM) enzyme-linked immunosorbent assay
(ELISA). If the IgM is positive, the plaque reduction neutralization test
(PRNT) is used to confirm the specificity of the IgM antibodies against
Zika virus and to exclude a false-positive IgM result. If CSF is available,
it should be tested for Zika virus RNA (via rRT-PCR), as well as Zika
virus IgM. CSF specimens need not be collected for the sole purpose
of Zika virus testing but may be reasonable for the evaluation of infants
with microcephaly or intracranial calcifications. A definitive diagnosis
of congenital Zika virus infection is confirmed by the presence of Zika
virus RNA in samples of serum, urine, or CSF collected within the first
2 days of life; IgM antibodies may be positive or negative. A negative
rRT-PCR result with a positive Zika virus IgM test result indicates
probable congenital Zika virus infection.
Fetuses or infants born to mothers who test positive for ZIKV infection
should be studied sonographically or for clinical evidence of congenital
Zika syndrome, a comprehensive evaluation (including ophthalmologic
examination, laboratory tests, and specialist consultation) should be
performed prior to hospital discharge.
PROGNOSIS
The prognosis of newborns with congenital Zika syndrome is unclear.
Reported acute mortality rates among live-born infants range from 4%
to 6%. The combination of Zika virus–related microcephaly and severe
cerebral abnormalities generally has a poor prognosis, but little is known
about the prognosis for congenitally infected infants with less severe
or no apparent abnormalities at birth.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis for congenital Zika virus infection includes
other congenital infections and other causes of microcephaly.
PREVENTION
The prevention of the congenital Zika syndrome includes avoidance, if
possible, of travel to endemic regions; if travel to endemic regions cannot
be avoided, careful contraception (male and female) is essential, especially
with the knowledge that Zika virus can persist in semen for months
after a primary infection (Table 294.2).
Bibliography is available at Expert Consult.
Chapter 295
Dengue Fever, Dengue
Hemorrhagic Fever, and
Severe Dengue
Scott B. Halstead
Dengue fever is a benign syndrome caused by several arthropod-borne
viruses and is characterized by biphasic fever, myalgia or arthralgia,
rash, leukopenia, and lymphadenopathy. Dengue hemorrhagic fever
(Philippine, Thai, or Singapore hemorrhagic fever; hemorrhagic dengue;
acute infectious thrombocytopenic purpura) is a severe, often fatal,
febrile disease caused by one of four dengue viruses. It is characterized
by capillary permeability, abnormalities of hemostasis, and, in severe
cases, a protein-losing shock syndrome (dengue shock syndrome),
which is thought to have an immunopathologic basis.
A revised case definition adopted by the World Health Organization
(WHO) in 2009 includes as severe dengue those cases accompanied
by fluid loss leading to shock, fluid loss with respiratory distress, liver
damage evidenced by elevations of ALT or AST to > 1000 U/L, severe
bleeding, and altered consciousness or significant heart abnormalities.
ETIOLOGY
There are at least four distinct antigenic types of dengue virus (dengue
1, 2, 3, and 4), members of the family Flaviviridae. In addition, three
other arthropod-borne viruses (arboviruses) cause similar dengue fever
syndromes with rash (Table 295.1; see also Chapter 294).
EPIDEMIOLOGY
Dengue viruses are transmitted by mosquitoes of the Stegomyia family.
Aedes aegypti, a daytime biting mosquito, is the principal vector, and all
four virus types have been recovered from it. Transmission occurs from
viremic humans by bite of the vector mosquito where virus multiplies

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 Chapter 295 ◆ Dengue Fever, Dengue Hemorrhagic Fever, and Severe Dengue 1761

during an extrinsic incubation period and then by bite is passed on to children and susceptible foreigners may be the only persons to acquire
a susceptible human in what is called the urban transmission cycle. In overt disease, because adults have become immune.
most tropical areas, A. aegypti is highly urbanized, breeding in water
stored for drinking or bathing and in rainwater collected in any container. Dengue-Like Diseases
Dengue viruses have also been recovered from Aedes albopictus, as in Dengue-like diseases may occur in epidemics. Epidemiologic features
the 2001 and 2015 Hawaiian epidemics, whereas outbreaks in the Pacific depend on the vectors and their geographic distribution (see Chapter
area have been attributed to several other Aedes species. These species 294). Chikungunya virus is enzootic in subhuman primates throughout
breed in water trapped in vegetation. In Southeast Asia and West Africa, much of West, Central, and South Africa. Periodic introductions of
dengue virus may be maintained in a cycle involving canopy-feeding virus into the urban transmission cycle have led to pandemics, resulting
jungle monkeys and Aedes species, which feed on monkeys. in widespread endemicity in the most populous areas of Asia. In Asia,
In the 19th and 20th centuries, epidemics were common in temperate A. aegypti is the principal vector; in Africa, other Stegomyia species
areas of the Americas, Europe, Australia, and Asia. Dengue fever and may be important vectors. In Southeast Asia, dengue and chikungunya
dengue-like disease are now endemic in tropical Asia, the South Pacific outbreaks occur concurrently in the urban cycle. Outbreaks of o’nyong-
Islands, northern Australia, tropical Africa, the Arabian Peninsula, the nyong fever usually involve villages or small towns, in contrast to the
Caribbean, and Central and South America (Fig. 295.1). Dengue fever urban outbreaks of dengue and chikungunya. West Nile virus is enzootic
occurs frequently among travelers to these areas. Locally acquired disease in Africa. Chikungunya is now endemic in urban cycles in tropical
has been reported in Florida, Arizona, and Texas, and imported cases countries throughout the world. Intense transmission in Caribbean and
in the United States occur in travelers to endemic areas. More than 390 Central and South American countries beginning in 2013 results in the
million dengue infections occur annually; approximately 96 million emergence of limited chikungunya transmission in the United States.
have clinical disease.
Dengue outbreaks in urban areas infested with A. aegypti may be Dengue Hemorrhagic Fever
explosive; in virgin soil epidemics, up to 70–80% of the population may Dengue hemorrhagic fever occurs where multiple types of dengue
be involved. Most overt disease occurs in older children and adults. virus are simultaneously or sequentially transmitted. It is endemic in
Because A. aegypti has a limited flight range, spread of an epidemic tropical America, Asia, the Pacific Islands, and parts of Africa, where
occurs mainly through viremic human beings and follows the main warm temperatures and the practices of water storage in homes plus
lines of transportation. Sentinel cases may infect household mosquitoes; outdoor breeding sites result in large, permanent populations of A.
a large number of nearly simultaneous secondary infections give the aegypti. Under these conditions, infections with dengue viruses of all
appearance of a contagious disease. Where dengue is highly endemic, types are common. A first infection, referred to as a primary infection,
may be followed by infection with a different dengue virus, referred
to as a secondary infection. In areas of high endemicity, secondary
infections are frequent.
Table 295.1 Vectors and Geographic Distribution of Secondary dengue infections are relatively mild in the majority of
Dengue-Like Diseases instances, ranging from an inapparent infection through an undifferenti-
ated upper respiratory tract or dengue-like disease, but may also progress
GEOGRAPHIC to dengue hemorrhagic fever. Nonimmune foreigners, both adults and
GENUS AND children, who are exposed to dengue virus during outbreaks of hemor-
VIRUS DISEASE VECTOR DISTRIBUTION rhagic fever have classic dengue fever or even milder disease. The
Togavirus Chikungunya Aedes aegypti Africa, India, differences in clinical manifestations of dengue infections between natives
Aedes africanus Southeast Asia, and foreigners in Southeast Asia are related to immunologic status.
Aedes Latin America, Dengue hemorrhagic fever can occur during primary dengue infections,
albopictus United States most frequently in infants whose mothers are immune to dengue. Dengue
Togavirus O’nyong- Anopheles East Africa hemorrhagic fever or severe dengue occurs rarely in individuals of
nyong funestus African ancestry because of an as yet incompletely described resistance
gene that is consistent with the low incidence of severe dengue throughout
Flavivirus West Nile Culex molestus Europe, Africa, much of Africa and among African populations in the American tropics
fever Culex univittatus Middle East, India
despite high rates of dengue infection.

Jan isoth 10C

Presence of dengue 10-degree

High isotherms
Medium
Low

July isoth 10C

Fig. 295.1 Global dengue burden, 2014. (From Guzman MG, Harris E: Dengue, Lancet 385:453-462, 2015, Fig. 1.)

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1762 Part XVI ◆ Infectious Diseases
PATHOGENESIS
The pathogenesis of dengue hemorrhagic fever is incompletely under-
stood, but epidemiologic studies usually associate this syndrome with
second heterotypic infections with dengue types 1-4 or in infants born
to mothers who have had two or more lifetime dengue infections.
Retrospective studies of sera from human mothers whose infants acquired
dengue hemorrhagic fever and prospective studies in children acquiring
sequential dengue infections have shown that the circulation of infection-
enhancing antibodies at the time of infection is the strongest risk factor
for development of severe disease. The absence of cross-reactive neutral-
izing antibodies and presence of enhancing antibodies from passive
transfer or active production are the best correlates of risk for dengue
hemorrhagic fever. Monkeys that are infected sequentially or are receiving
small quantities of enhancing antibodies have enhanced viremias. In
humans studied early during the course of secondary dengue infections,
viremia levels directly predicted disease severity. When dengue virus
immune complexes attach to monocyte/macrophage Fc receptors, a
signal is sent that suppresses innate immunity, resulting in enhanced
viral production. In the Americas, dengue hemorrhagic fever and dengue
shock syndrome have been associated with dengue types 1-4 strains of
recent Southeast Asian origin. Outbreaks of dengue hemorrhagic fever
in all areas of the world are correlated with secondary dengue infections
while recent outbreaks in India, Pakistan, and Bangladesh are related
to imported dengue strains.
Early in the acute stage of secondary dengue infections, there is rapid
activation of the complement system. Shortly before or during shock,
blood levels of soluble tumor necrosis factor receptor, interferon-γ, and
interleukin-2 are elevated. C1q, C3, C4, C5-C8, and C3 proactivators
are depressed, and C3 catabolic rates are elevated. Circulating viral
nonstructural protein 1 (NS1) is a viral toxin that activates myeloid
cells to release cytokines by attaching to toll receptor 4. It also contributes
to increased vascular permeability by activating complement, interacting
with and damaging endothelial cells, and interacting with blood clotting
factors and platelets. The mechanism of bleeding in dengue hemorrhagic
fever is not known, but a mild degree of disseminated intravascular
coagulopathy, liver damage, and thrombocytopenia may operate syn-
ergistically. Capillary damage allows fluid, electrolytes, small proteins,
and, in some instances, red blood cells to leak into extravascular spaces.
This internal redistribution of fluid, together with deficits caused by
fasting, thirsting, and vomiting, results in hemoconcentration, hypo-
volemia, increased cardiac work, tissue hypoxia, metabolic acidosis,
and hyponatremia.
Usually no pathologic lesions are found to account for death. In rare
instances, death may be a result of gastrointestinal or intracranial
hemorrhages. Minimal to moderate hemorrhages are seen in the upper
gastrointestinal tract, and petechial hemorrhages are common in the
interventricular septum of the heart, on the pericardium, and on the
subserosal surfaces of major viscera. Focal hemorrhages are occasionally
seen in the lungs, liver, adrenals, and subarachnoid space. The liver is
usually enlarged, often with fatty changes. Yellow, watery, and at times
blood-tinged effusions are present in serous cavities in approximately
75% of patients at autopsy.
Dengue virus is frequently absent in tissues at the time of death; viral
antigens or RNA have been localized to hepatocytes and macrophages
in the liver, spleen, lung, and lymphatic tissues.
CLINICAL MANIFESTATIONS
Dengue Fever
The incubation period is 1-7 days. The clinical manifestations are variable
and are influenced by the age of the patient. In infants and young children,
the disease may be undifferentiated or characterized by fever for 1-5
days, pharyngeal inflammation, rhinitis, and mild cough. A majority
of infected older children and adults experience sudden onset of fever,
with temperature rapidly increasing to 39.4-41.1°C (103-106°F), usually
accompanied by frontal or retroorbital pain, particularly when pressure
is applied to the eyes. Occasionally, severe back pain precedes the fever
(back-break fever). A transient, macular, generalized rash that blanches
under pressure may be seen during the first 24-48 hr of fever. The pulse
rate may be slow relative to the degree of fever. Myalgia and arthralgia
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occur soon after the onset of fevers and increase in severity over time.
From the second to sixth day of fever, nausea and vomiting are apt to
occur, and generalized lymphadenopathy, cutaneous hyperesthesia or
hyperalgesia, taste aberrations, and pronounced anorexia may develop.
Approximately 1-2 days after defervescence, a generalized, morbil-
liform, maculopapular rash appears that spares the palms and soles. It
disappears in 1-5 days; desquamation may occur. Rarely there is edema
of the palms and soles. About the time this second rash appears, the
body temperature, which has previously decreased to normal, may
become slightly elevated and demonstrate the characteristic biphasic
temperature pattern.
Dengue Hemorrhagic Fever and
Dengue Shock Syndrome (DHF/DSS)
The differentiation between dengue fever and dengue hemorrhagic fever
is difficult early in the course of illness. A relatively mild first phase
with abrupt onset of fever, malaise, vomiting, headache, anorexia, and
cough may be followed after 2-5 days by rapid clinical deterioration
and collapse. In this second phase, the patient usually has cold, clammy
extremities, a warm trunk, flushed face, diaphoresis, restlessness, irritabil-
ity, midepigastric pain, and decreased urinary output. Frequently, there
are scattered petechiae on the forehead and extremities; spontaneous
ecchymoses may appear, and easy bruising and bleeding at sites of
venipuncture are common. A macular or maculopapular rash may
appear, and there may be circumoral and peripheral cyanosis. Respirations
are rapid and often labored. The pulse is weak, rapid, and thready, and
the heart sounds are faint. The liver may enlarge to 4-6 cm below the
costal margin and is usually firm and somewhat tender. Approximately
20–30% of cases of dengue hemorrhagic fever are complicated by shock
(dengue shock syndrome). Dengue shock can be subtle, arising in patients
who are fully alert, and is accompanied by increased peripheral vascular
resistance and raised diastolic blood pressure. Shock is not from conges-
tive heart failure but from venous pooling. With increasing cardiovascular
compromise, the diastolic pressure rises toward the systolic level and
the pulse pressure narrows. Fewer than 10% of patients have gross
ecchymosis or gastrointestinal bleeding, usually after a period of uncor-
rected shock. After a 24- to 36-hr period of crisis, convalescence is
fairly rapid in the children who recover. The temperature may return
to normal before or during the stage of shock. Bradycardia and ventricular
extrasystoles are common during convalescence.
Dengue With Warning Signs and Severe Dengue
In hyperendemic areas, among Asian children, the DHF/DSS continues
to be the dominant life-threatening event, always challenging to an
identifying physician using classical WHO diagnostic criteria. When
the four dengue viruses spread to the American hemisphere and to
South Asia, there were millions of primary and secondary dengue
infections, many of them adults of all ages. Dengue disease in these
areas presented a wider clinical spectrum resulting in a new diagnostic
algorithm and case definitions (see below).
DIAGNOSIS
A clinical diagnosis of dengue fever derives from a high index of suspicion
and knowledge of the geographic distribution and environmental cycles
of causal viruses (for nondengue causes see Chapter 294). Because
clinical findings vary and there are many possible causative agents,
the term dengue-like disease should be used until a specific diagnosis is
established. A case is confirmed by isolation of the virus, viral antigen,
or genome by polymerase chain reaction analysis, the detection of IgM
dengue antibodies as well as demonstration of a four-fold or greater
increase in antibody titers. A probable case is a typical acute febrile
illness with supportive serology and occurrence at a location where
there are confirmed cases.
The WHO criteria for dengue hemorrhagic fever are fever (2-7 days
in duration or biphasic), minor or major hemorrhagic manifestations
including a positive tourniquet test, thrombocytopenia (≤100,000/μL),
and objective evidence of increased capillary permeability (hematocrit
increased by ≥ 20%), pleural effusion or ascites (by chest radiography
or ultrasonography), or hypoalbuminemia. Dengue shock syndrome
 Chapter 295 ◆ Dengue Fever, Dengue Hemorrhagic Fever, and Severe Dengue 1763
DENGUE ± WARNING SIGNS
with warning
without
Probable dengue Warning signs*
live in/travel to dengue endemic area.
Fever and 2 of the following criteria:
a
Laboratory-confirmed dengue
a inter
Fig. 295.2 Suggested dengue case classification and levels of severity. (From World Health Organization (WHO) and Special Programme for
Research and Training in Tropical Diseases (TDR): 2009 Dengue: guidelines for diagnosis, treatment, prevention and control, Fig. 1.4, http://apps.
who.int/iris/bitstream/handle/10665/44188/9789241547871_eng.pdf?sequence=1.)
criteria include those for dengue hemorrhagic fever as well as hypoten-
sion, tachycardia, narrow pulse pressure (≤20 mm Hg), and signs of
poor perfusion (cold extremities).
In 2009, the WHO promulgated guidelines for the diagnosis of probable
dengue, dengue with warning signs, and a category called severe dengue
(Fig. 295.2). The presence of warning signs in an individual with probable
dengue alerts the physician to the possible need for hospitalization.
Severe dengue is a mixture of syndromes associated with dengue infection,
including classical DHF/DSS, but also rare instances of encephalitis or
encephalopathy, liver damage, or myocardial damage. Severe dengue
also includes respiratory distress, a harbinger of pulmonary edema
caused by overhydration, an all too common outcome of inexpert
treatment (see Treatment and Complications sections).
Virologic diagnosis can be established by serologic tests, by detection
of viral proteins or viral RNA, or by the isolation of the virus from
blood leukocytes or acute-phase serum. Following primary and secondary
dengue infections, there is an appearance of antidengue (immunoglobulin
[Ig] M) antibodies. These disappear after 6-12 wk, a feature that can
be used to date a dengue infection. In secondary dengue infections,
most dengue antibody is of the IgG class. Serologic diagnosis depends
on a four-fold or greater increase in IgG antibody titer in paired sera
by hemagglutination inhibition, complement fixation, enzyme immunoas-
say, or neutralization test. Carefully standardized IgM and IgG capture
enzyme commercial immunoassays are now widely used to identify
acute-phase antibodies from patients with primary or secondary dengue
infections in single-serum samples. Usually such samples should be
collected not earlier than 5 days and not later than 6 wk after onset. It
may not be possible to distinguish the infecting virus by serologic
methods alone, particularly when there has been prior infection with
another member of the same arbovirus group. Virus can be recovered
from acute-phase serum after inoculating tissue culture or living
mosquitoes. Viral RNA can be detected in blood or tissues by specific
complementary RNA probes or amplified first by polymerase chain
reaction or by real-time polymerase chain reaction. A viral nonstructural
protein, NS1, is released by infected cells into the circulation and can
be detected in acute-stage blood samples using monoclonal or polyclonal
antibodies. The detection of NS1 is the basis of commercial tests, including
rapid lateral flow tests. These tests offer a reliable point-of-care diagnosis
of acute dengue infection.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis of dengue fever includes dengue-like diseases,
viral respiratory and influenza-like diseases, the early stages of malaria,
mild yellow fever, scrub typhus, viral hepatitis, and leptospirosis.
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SEVERE DENGUE
Severe plasma leakage
leading to:
Severe bleeding
Severe organ involvement
vation and medical
Four arboviral diseases have dengue-like courses but without rash:
Colorado tick fever, sandfly fever, Rift Valley fever, and Ross River
fever (see Chapter 294). Colorado tick fever occurs sporadically
among campers and hunters in the western United States; sandfly
fever in the Mediterranean region, the Middle East, southern Russia,
and parts of the Indian subcontinent; and Rift Valley fever in North,
East, Central, and South Africa. Ross River fever is endemic in much
of eastern Australia, with epidemic extension to Fiji. In adults, Ross
River fever often produces protracted and crippling arthralgia involving
weight-bearing joints.
Because meningococcemia, yellow fever (see Chapter 296), other
viral hemorrhagic fevers (see Chapter 297), many rickettsial diseases,
and other severe illnesses caused by a variety of agents may produce a
clinical picture similar to dengue hemorrhagic fever, the etiologic
diagnosis should be made only when epidemiologic or serologic evidence
suggests the possibility of a dengue infection.
LABORATORY FINDINGS
In dengue fever, pancytopenia may develop after the 3-4 days of
illness. Neutropenia may persist or reappear during the latter stage
of the disease and may continue into convalescence, with white blood
cell counts < 2,000/μL. Platelet counts rarely fall below 100,000/μL.
Venous clotting, bleeding and prothrombin times, and plasma fibrinogen
values are within normal ranges. The tourniquet test result may be
positive. Mild acidosis, hemoconcentration, increased transaminase
values, and hypoproteinemia may occur during some primary dengue
virus infections. The electrocardiogram may show sinus bradycardia,
ectopic ventricular foci, flattened T waves, and prolongation of the
P-R interval.
The most common hematologic abnormalities during dengue
hemorrhagic fever and dengue shock syndrome are hemoconcentra-
tion with an increase of > 20% in the hematocrit, thrombocytopenia,
a prolonged bleeding time, and a moderately decreased prothrombin
level that is seldom < 40% of control. Fibrinogen levels may be subnor-
mal, and fibrin split-product values are elevated. Other abnormalities
include moderate elevations of serum transaminase levels, consump-
tion of complement, mild metabolic acidosis with hyponatremia,
occasionally hypochloremia, slight elevation of serum urea nitrogen,
and hypoalbuminemia. Roentgenograms of the chest reveal pleural
effusions (right > left) in nearly all patients with dengue shock syn-
drome. Ultrasonography can be used to detect serosal effusions of
the thorax or abdomen. Thickening of the gallbladder wall and the
presence of perivesicular fluid are characteristic signs of increased
vascular permeability.
1764 Part XVI ◆ Infectious Diseases
TREATMENT
Treatment of uncomplicated dengue fever is supportive. Bed rest is
advised during the febrile period. Antipyretics should be used to keep
the body temperature < 40°C (104°F). Analgesics or mild sedation may
be required to control pain. Aspirin is contraindicated and should not
be used because of its effects on hemostasis. Fluid and electrolyte
replacement is required for deficits caused by sweating, fasting, thirsting,
vomiting, and diarrhea.
Dengue Hemorrhagic Fever and
Dengue Shock Syndrome
Dengue shock syndrome is a medical emergency that may occur
in any child who lives in or has a recent travel history to a tropical
destination. Management begins with diagnostic suspicion and the
understanding that shock often accompanies defervescence. Detailed
instructions for case management are available at the Geneva or New
Delhi WHO websites: http://www.who.int/csr/don/archive/disease/
dengue_fever/dengue.pdf. Management of dengue hemorrhagic fever
and dengue shock syndrome includes immediate evaluation of vital
signs and degrees of hemoconcentration, dehydration, and electrolyte
imbalance. Close monitoring is essential for at least 48 hr because
shock may occur or recur precipitously, usually several days after the
onset of fever. Patients who are cyanotic or have labored breathing
should be given oxygen. Rapid intravenous replacement of fluids and
electrolytes can frequently sustain patients until spontaneous recovery
occurs. Normal saline is more effective than the more expensive
Ringer lactated saline in treating shock. When the pulse pressure is
≤10 mm Hg or when elevation of the hematocrit persists after the
replacement of fluids, plasma or colloid preparations are indicated. Oral
rehydration of children who are being monitored is useful. Prophylactic
platelet transfusions have not been shown to reduce the risk of hemor-
rhaging or improve low platelet counts and may be associated with
adverse effects.
Care must be taken to avoid overhydration, which may contribute
to cardiac failure. Transfusions of fresh blood may be required to control
bleeding but should not be given during hemoconcentration but only
after evaluation of hemoglobin or hematocrit values. Salicylates are
contraindicated because of their effect on blood clotting.
Sedation may be required for children who are markedly agitated.
Use of vasopressors has not resulted in a significant reduction of
mortality rates over that observed with simple supportive therapy.
Disseminated intravascular coagulation may require treatment (see
Chapter 510). Corticosteroids do not shorten the duration of disease
or improve the prognosis in children receiving careful supportive
therapy.
COMPLICATIONS
Hypervolemia during the fluid reabsorptive phase may be life-threatening
and is heralded by a decrease in hematocrit with wide pulse pressure.
Diuretics and digitalization may be necessary.
Primary infections with dengue fever and dengue-like diseases are
usually self-limited and benign. Fluid and electrolyte losses, hyperpyrexia,
and febrile convulsions are the most frequent complications in infants
and young children. Epistaxis, petechiae, and purpuric lesions are
uncommon but may occur at any stage. Blood from epistaxis that is
swallowed, vomited, or passed by rectum may be erroneously interpreted
as gastrointestinal bleeding. In adults and possibly in children, underlying
conditions may lead to clinically significant bleeding. Convulsions may
occur during a high temperature. Infrequently, after the febrile stage,
prolonged asthenia, mental depression, bradycardia, and ventricular
extrasystoles may occur in children.
In endemic areas, dengue hemorrhagic fever should be suspected in
children with a febrile illness suggestive of dengue fever who experience
hemoconcentration and thrombocytopenia.
PROGNOSIS
Dengue Fever
The prognosis for dengue fever is good. Care should be taken to avoid
the use of drugs that suppress platelet activity.
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Dengue Hemorrhagic Fever
The prognosis of dengue hemorrhagic fever is adversely affected by a
late diagnosis and delayed or improper treatment. Death has occurred
in 40–50% of patients with shock, but with adequate intensive care,
deaths should occur in < 1% of cases. Infrequently, there is residual
brain damage as a consequence of prolonged shock or occasionally of
intracranial hemorrhage. Many fatalities are caused by overhydration.
PREVENTION
Dengue vaccines have been under development continuously since the
1970s. One such vaccine, Dengvaxia, developed by Sanofi Pasteur, is a
mixture of four chimeras, DENV structural genes coupled with non-
structural genes of yellow fever 17D. In 2015, Dengvaxia completed
phase III per protocol analyses on 32,568 children, vaccinated and
controls, ages 2-16 yr. These studies revealed poor protection of seronega-
tives and good protection of seropositives with a reduction of hospitaliza-
tion and severe disease in vaccinated children 9 yr old versus controls.
Based on these data, this vaccine was endorsed by the WHO for targeted
use in individuals 9 yr of age and older, living in countries that are
highly endemic for dengue; it now is licensed for use in 14 countries.
Other dengue type 1-4 vaccines are under development by the U.S.
National Institutes of Health and Instituto Butantan in Sao Paulo, Brazil,
and Takeda, Inc. Dengvaxia seronegative recipients who were incom-
pletely protected were apparently sensitized to experience the enhanced
disease of hospitalized dengue.
Prophylaxis in the absence of vaccine consists of avoiding daytime
household-based mosquito bites through the use of insecticides, repel-
lents, body covering with clothing, screening of houses, and destruction
of A. aegypti breeding sites. If water storage is mandatory, a tight-fitting
lid or a thin layer of oil may prevent egg laying or hatching. A larvicide,
such as Abate (O,O′-[thiodi-p-phenylene] O,O,O,O′-tetramethyl phos-
phorothioate), available as a 1% sand-granule formation and effective
at a concentration of 1 ppm, may be added safely to drinking water.
Ultra-low-volume spray equipment effectively dispenses the adulticide
malathion from trucks or airplanes for rapid intervention during an
epidemic. Mosquito repellants and other personal antimosquito measures
are effective in preventing mosquito bites in the field, forest, or jungle.
Bibliography is available at Expert Consult.
Chapter 296
Yellow Fever
Scott B. Halstead
Yellow fever is an acute infection characterized in its most severe form
by fever, jaundice, proteinuria, and hemorrhage. The virus is mosquito-
borne and occurs in epidemic or endemic form in South America and
Africa. Seasonal epidemics occurred in cities located in temperate areas
of Europe and the Americas until 1900, and epidemics continue in
West, Central, and East Africa.
ETIOLOGY
Yellow fever is the prototype of the Flavivirus genus of the family
Flaviviridae, which are enveloped single-stranded RNA viruses 35-50 nm
in diameter.
Yellow fever circulates zoonotically as five genotypes: type IA in West
Central Africa, type IB in South America, type II in West Africa, type
III in East Central Africa, and type IV in East Africa. Types IA and IB
virus are capable of urban transmission between human beings by Aedes
aegypti. Sometime in the 1600s, yellow fever virus was brought to the
American tropics through the African slave trade. Subsequently, yellow
fever caused enormous coastal and riverine epidemics in the Atlantic and
Caribbean basins until the 20th century, when the virus and its urban
1756 Part XVI ◆ Infectious Diseases

294.5 Powassan Encephalitis 294.7 Colorado Tick Fever

Scott B. Halstead Scott B. Halstead

POW virus is transmitted by Ixodes cookei among small mammals in
eastern Canada and the United States; it has been responsible for 39
deaths in the United States since 2008 (see Fig. 294.1). Other ticks may
transmit the virus in a wider geographic area, and there is some concern
that Ixodes scapularis (also called Ixodes dammini), a competent vector
in the laboratory, may become involved as it becomes more prominent
in the United States.
In a limited experience, POW encephalitis has occurred mainly in
adults with vocational or recreational exposure and has a high fatality rate.
POW encephalitis has occurred mostly in adults living in enzootic
areas with vocational or recreational exposure; it is associated with
significant long-term morbidity and has a case-fatality rate of 10–15%.
Bibliography is available at Expert Consult.
294.6 La Crosse and California Encephalitis
Scott B. Halstead
Colorado tick fever virus is transmitted by the wood tick Dermacentor
andersoni, which inhabits high-elevation areas of states extending from
the central plains to the Pacific coast. The tick is infected with the virus
at the larval stage and remains infected for life. Squirrels and chipmunks
serve as primary reservoirs. Human infections typically occur in hikers
and campers in indigenous areas during the spring and early summer.
Colorado tick fever begins with the abrupt onset of a flulike illness,
including high temperature, malaise, arthralgia and myalgia, vomiting,
headache, and decreased sensorium. Rash is uncommon. The symptoms
rapidly disappear after 3 days of illness. However, in approximately half
of patients, a second identical episode reoccurs 24-72 hr after the first
one, producing the typical saddleback temperature curve of Colorado
tick fever. Complications, including encephalitis, meningoencephalitis,
and a bleeding diathesis, develop in 3–7% of infected persons and may
be more common in children younger than 12 yr of age.
Recovery from Colorado tick fever is usually complete. Three deaths
have been reported, all in persons with hemorrhagic signs.

La Crosse viral infections are endemic in the United States, occurring
annually from July to September, principally in the north-central and
central states (see Fig. 294.1). Infections occur in peridomestic environ-
ments as the result of bites from Aedes triseriatus mosquitoes, which
often breed in tree holes. The virus is maintained vertically in nature
by transovarial transmission and can be spread between mosquitoes
by copulation and amplified in mosquito populations by viremic infec-
tions in various vertebrate hosts. Amplifying hosts include chipmunks,
squirrels, foxes, and woodchucks. A case:infection ratio of 1 : 22-300
has been surmised. La Crosse encephalitis is principally a disease of
children, who may account for up to 75% of cases. A mean of 100 cases
has been reported annually for the past 10 yr.
The clinical spectrum includes a mild febrile illness, aseptic meningitis,
and fatal encephalitis. Children typically present with a prodrome of
2-3 days of fever, headache, malaise, and vomiting. The disease evolves
with clouding of the sensorium, lethargy, and, in severe cases, focal or
generalized seizures. On physical examination, children are lethargic
but not disoriented. Focal neurologic signs, including weakness, aphasia,
and focal or generalized seizures, have been reported in 16–25% of
cases. CSF shows low to moderate leukocyte counts. On autopsy, the
brain shows focal areas of neuronal degeneration, inflammation, and
perivascular cuffing.
Recovery from California encephalitis is usually complete. The case
fatality rate is approximately 1%.
294.8 Chikungunya Fever
Scott B. Halstead
Chikungunya virus is enzootic in several species of African subhuman
primates but also is endemic in urban Aedes aegypti or Aedes albopictus
transmission cycles in Africa and Asia. Chikungunya exited Africa
historically producing Asian pandemics in 1790, 1824, 1872, 1924,
1963, and 2005. In 1827, chikungunya reached the Western Hemisphere,
predominantly the Caribbean region, probably brought by the slave trade.
In 2005, another Asian pandemic proceeded east from an initial outbreak
on Reunion and then traveling to Asia across the Indian Ocean. In 2013,
chikungunya virus from this epidemic was introduced into Latin America.
Clinical manifestations begin 3-7 days after a mosquito bite; the onset
is abrupt, with high fever and often severe joint symptoms (hands, feet,
ankles, wrists) that include symmetric bilateral polyarthralgia or arthritis.
Most pediatric patients are relatively asymptomatic, but all ages are
vulnerable to classic disease. There may be headache, myalgias, con-
junctivitis, weakness, lymphopenia, and a maculopapular rash. Mortality
is rare; some individuals develop prolonged joint symptoms (tenosy-
novitis, arthritis) lasting over a year. The acute episode lasts 7-10 days.
The differential diagnosis includes dengue, West Nile, enterovirus diseases,
leptospirosis, rickettsial disease, measles, parvovirus disease, rheuma-
tologic diseases, and other alphavirus diseases (e.g., Ross River virus)
in endemic areas. Fig. 294.4 lists the diagnostic criteria.

Criteria Definition

1 Clinical criteria: Possible case when not explained by other medical

Acute onset of fever !38.5°C and severe condition: dengue or alphaviral infection, arthritic disease,
arthralgia or arthritis endemic malaria

2 Epidemiologic criteria: Probable case if clinical and epidemiologic criteria are

a met: other pathogens with similar clinical manifestations
within 15 days before onset of symptoms can cocirculate within the same geographic region

3 Laboratory criteria:
After acute phase
Confirmed case if a patient tests positive for 1 of the
A Fig. 294.4 Diagnostic criteria for
laboratory criteria, irrespective of clinical manifestations
chikungunya virus fever. (From Burt
FJ, Rolph MS, Rulli NE, et al: Chikun-
samples gunya: a re-emerging virus, Lancet
379:662-668, 2012, Fig. 6.)

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The incidence of febrile convulsions is high in infants. The prognosis
is generally good, although in large outbreaks in Africa and India, severe
disease and deaths have been attributed to chikungunya infections,
predominantly in adults.
Bibliography is available at Expert Consult.
294.9 Venezuelan Equine Encephalitis
Scott B. Halstead
VEE virus was isolated from an epizootic in Venezuelan horses in 1938.
Human cases were first identified in 1943. Hundreds of thousands of
equine and human cases have occurred over the past 70 yr. During
1971, epizootics moved through Central America and Mexico to southern
Texas. After two decades of quiescence, epizootic disease emerged again
in Venezuela and Colombia in 1995. Between December 1992 and
January 1993, the Venezuelan state of Trujillo experienced an outbreak
of this virus. Overall, 28 cases of the disease were reported, along with
12 deaths. June 1993 saw a bigger outbreak, in which 55 humans died,
as well as 66 horses. A much larger outbreak in Venezuela and Colombia
occurred in 1995. On May 23, 1995, equine encephalitis-like cases were
reported in the northwest portion of the country. Eventually, the outbreak
spread toward the north, as well as to the south. The outbreak caused
about 11,390 febrile cases in humans, as well as 16 deaths. About 500
equine cases were reported with 475 deaths.
The incubation period is 2-5 days, followed by the abrupt onset of
fever, chills, headache, sore throat, myalgia, malaise, prostration,
photophobia, nausea, vomiting, and diarrhea. In 5–10% of cases, there
is a biphasic illness; the second phase is heralded by seizures, projectile
vomiting, ataxia, confusion, agitation, and mild disturbances in conscious-
ness. There is cervical lymphadenopathy and conjunctival suffusion.
Cases of meningoencephalitis may demonstrate cranial nerve palsy,
motor weakness, paralysis, seizures, and coma. Microscopic examination
of tissues reveals inflammatory infiltrates in lymph nodes, spleen, lung,
liver, and brain. Lymph nodes show cellular depletion, necrosis of
germinal centers, and lymphophagocytosis. The liver shows patchy
hepatocellular degeneration, the lungs demonstrate a diffuse interstitial
pneumonia with intraalveolar hemorrhages, and the brain shows patchy
cellular infiltrates.
There is no specific treatment for VEE. The treatment is intensive
supportive care (see Chapter 85), including control of seizures (see
Chapter 611).
In patients with VEE meningoencephalitis, the fatality rate ranges
from 10% to 25%. Sequelae include nervousness, forgetfulness, recurrent
headache, and easy fatigability.
Several veterinary vaccines are available to protect equines. VEE
virus is highly infectious in laboratory settings, and biosafety level three
containment should be used. An experimental vaccine is available for
use in laboratory workers. Several vaccine constructs are in the pipeline
for potential use in humans.
294.10 Japanese Encephalitis
Scott B. Halstead
JE is a mosquito-borne viral disease of humans, as well as horses, swine,
and other domestic animals. The virus causes human infections and
acute disease in a vast area of Asia, northern Japan, Korea, China,
Taiwan, the Philippines, and the Indonesian archipelago and from
Indochina through the Indian subcontinent. Culex tritaeniorhynchus
summarosus, a night-biting mosquito that feeds preferentially on large
domestic animals and birds but only infrequently on humans, is the
principal vector of zoonotic and human JE in northern Asia. A more
complex ecology prevails in southern Asia. From Taiwan to India, C.
tritaeniorhynchus and members of the closely related Culex vishnui
group are vectors. Before the introduction of JE vaccine, summer
outbreaks of JE occurred regularly in Japan, Korea, China, Okinawa,
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Chapter 294 ◆ Arboviral Infections 1757
and Taiwan. Over the past decade, there has been a pattern of steadily
enlarging recurrent seasonal outbreaks in Vietnam, Thailand, Nepal,
and India, with small outbreaks in the Philippines, Indonesia, and the
northern tip of Queensland, Australia. Seasonal rains are accompanied by
increases in mosquito populations and JE transmission. Pigs serve as an
amplifying host.
The annual incidence in endemic areas ranges from 1-10 per 10,000
population. Children younger than 15 yr of age are principally affected,
with nearly universal exposure by adulthood. The case:infection ratio
for JE virus has been variously estimated at 1 : 25 to 1 : 1,000. Higher
ratios have been estimated for populations indigenous to enzootic areas.
JE occurs in travelers visiting Asia; therefore, a travel history in the
diagnosis of encephalitis is critical.
After a 4- to 14-day incubation period, cases typically progress through
the following four stages: prodromal illness (2-3 days), acute stage (3-4
days), subacute stage (7-10 days), and convalescence (4-7 wk). The onset
may be characterized by an abrupt onset of fever, headache, respiratory
symptoms, anorexia, nausea, abdominal pain, vomiting, and sensory
changes, including psychotic episodes. Grand mal seizures are seen in
10–24% of children with JE; parkinsonian-like nonintention tremor
and cogwheel rigidity are seen less frequently. Particularly characteristic
are rapidly changing central nervous system signs (e.g., hyperreflexia
followed by hyporeflexia or plantar responses that change). The sensory
status of the patient may vary from confusion through disorientation
and delirium to somnolence, progressing to coma. There is usually a
mild pleocytosis (100-1,000 leukocytes/μL) in the cerebrospinal fluid,
initially polymorphonuclear but in a few days predominantly lymphocytic.
Albuminuria is common. Fatal cases usually progress rapidly to coma,
and the patient dies within 10 days.
JE should be suspected in patients reporting exposure to night-biting
mosquitoes in endemic areas during the transmission season. The etio-
logic diagnosis of JE is established by testing acute-phase serum collected
early in the illness for the presence of virus-specific IgM antibodies or,
alternatively, demonstrating a fourfold or greater increase in IgG antibody
titers by testing paired acute and convalescent sera. The virus can also
be identified by the polymerase chain reaction.
There is no specific treatment for JE. The treatment is intensive
supportive care (see Chapter 85), including control of seizures (see
Chapter 611).
Patient fatality rates for JE are 24–42% and are highest in children
5-9 yr of age and in adults older than 65 yr of age. The frequency of
sequelae is 5–70% and is directly related to the age of the patient and
severity of disease. Sequelae are most common in patients younger than
10 yr at the onset of disease. The more common sequelae are mental
deterioration, severe emotional instability, personality changes, motor
abnormalities, and speech disturbances.
Bibliography is available at Expert Consult.
294.11 Tick-Borne Encephalitis
Scott B. Halstead
TBE refers to neurotropic tick-transmitted flaviviral infections occurring
across the Eurasian land mass. In the Far East, the disease is called
Russian spring-summer encephalitis; the milder, often biphasic form in
Europe is simply called TBE. TBE is found in all countries of Europe
except Portugal and the Benelux countries. The incidence is particularly
high in Austria, Poland, Hungary, Czech Republic, Slovakia, former
Yugoslavia, and Russia. The incidence tends to be very focal. Serop-
revalence is as high as 50% in farm and forestry workers. The majority
of cases occur in adults, but even young children may be infected while
playing in the woods or on picnics or camping trips. The seasonal distribu-
tion of cases is midsummer in southern Europe, with a longer season
in Scandinavia and the Russian Far East. TBE can be excreted from the
milk of goats, sheep, or cows. Before World War II, when unpasteurized
milk was consumed, milk-borne cases of TBE were common.
Viruses are transmitted principally by hard ticks of Ixodes ricinus in
Europe and Ixodes persulcatus in the Far East. Viral circulation is

do not possess catalase or glutathione reductase/glutathione peroxidase,
which are key enzymes in scavenging free radicals. All trypanosomes
also have an unusual reduced nicotinamide adenine dinucleotide phos-
phate (NADPH)–dependent disulfide reductase. Drugs that stimulate
hydrogen peroxide (H2O2) generation or prevent its utilization are
potential trypanosomicidal agents. Other biochemical pathways that
have been targeted include ergosterol synthesis using azole compounds
and the hypoxanthine-guanine phosphoribosyltransferase pathway
using allopurinol.
Drug treatment for T. cruzi infection is currently limited to nifurtimox
and benznidazole. Both are effective against trypomastigotes and
amastigotes and have been used to eradicate parasites in the acute stages
of infection. Treatment responses vary according to the phase of Chagas
disease, duration of treatment, dose, age of the patient, and geographic
origin of the patient. For acute disease, the average cure rate is about
60–80%. Cure of chronic disease is difficult to assess due to the different
definitions of cure, whether with a negative serology or quantitative
polymerase chain reaction. In recent trials, benznidazole has shown a
cure rate of about 30% using ELISA, and 46–90% using PCR. A trial
for chronic disease efficacy with nifurtimox is ongoing. Neither drug
is safe in pregnancy. Recent trials with posaconazole, fexinidazole,
and E1224 (a prodrug of ravuconazole) for chronic disease have been
disappointing.
Benznidazole is a nitroimidazole derivative that may be slightly more
effective than nifurtimox. Recent work in metabolomics has shown that
benznidazole’s primary mechanism of action involves covalent binding
with trypanosomal protein thiols and low-molecular-weight thiols,
resulting in depletion of these molecules and disruption of the parasite
metabolism. The recommended treatment regimen for children <12 yr
old is 10 mg/kg/day orally (PO) divided twice daily (bid) for 60 days,
and for those >12 yr old, 5-7 mg/kg/day PO bid for 60 days. This drug
is associated with significant toxicity, including rash, photosensitivity,
peripheral neuritis, granulocytopenia, and thrombocytopenia.
Nifurtimox generates highly toxic oxygen metabolites through the
action of nitroreductases, which produce unstable nitroanion radicals,
which in turn react with oxygen to produce peroxide and superoxide
free radicals. The treatment regimen for children 1-10 yr old is 15-20 mg/
kg/day PO divided 4 times daily (qid) for 90 days; for children 11-16 yr,
12.5-15 mg/kg/day PO qid for 90 days; and for children >16 yr, 8-10 mg/
kg/day PO divided 3-4 times daily for 90-120 days. Nifurtimox has
been associated with weakness, anorexia, gastrointestinal disturbances,
toxic hepatitis, tremors, seizures, and hemolysis in patients with glucose-
6-phosphate dehydrogenase deficiency.
With the adoption by WHO of control and elimination strategies for
Chagas disease, both acute and chronic disease should be treated.
Serologic conversion is seen as an appropriate treatment response for
chronic disease, although some patients who achieve this still eventually
develop symptoms. One study reported cure rates as high as 97% for
chronic disease in patients <16 yr old and supports early and aggressive
case finding and treatment. Continuing efforts for elimination will
necessitate development of more accurate diagnostics and more effective
drugs, particularly for chronic disease. Treatment of congestive heart
failure is generally in line with recommendations for management of
dilated cardiomyopathy from other causes. β-Adrenergic blockers have
been validated in the management of these patients. Digitalis toxicity
occurs frequently in patients with Chagas cardiomyopathy. Pacemakers
may be necessary in cases of severe heart block. Although cardiac
transplantation has been used successfully in chagasic patients, it is
reserved for those with the most severe disease manifestations. Plas-
mapheresis to remove antibodies with adrenergic activity has been
proposed for refractory patients; this approach has worked in patients
with dilated cardiomyopathy from other causes, but its application to
Chagas disease is unproved.
A light, balanced diet is recommended for megaesophagus. Surgery
or dilation of the lower esophageal sphincter treats megaesophagus;
pneumatic dilation is the superior mode of therapy. Nitrates and nife-
dipine have been used to reduce lower esophageal sphincter pressure
in patients with megaesophagus. Treatment of megacolon is surgical
and symptomatic. Treatment of meningoencephalitis is also supportive.
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Chapter 314 ◆ Malaria (Plasmodium) 1851
In accidental infection when parasitic penetration is certain, treatment
should be immediately initiated and continued for 10-15 days. Blood
is usually collected and serologic samples tested for seroconversion at
15, 30, and 60 days.
PREVENTION
Massive coordinated vector control programs under the auspices of
WHO and the Pan-American Health Organization and the institution of
widespread blood donor screening and targeted surveillance of chroni-
cally infected mothers and infants at risk have effectively eliminated
or at least drastically reduced transmission in most endemic countries.
Chagas disease remains linked to poverty, and thus improvement of
living conditions is likewise essential to successful control and eradica-
tion. Education of residents in endemic areas, use of bed nets, use
of insecticides, and destruction of adobe houses that harbor reduviid
bugs are effective methods to control the bug population. Synthetic
pyrethroid insecticides help keep houses free of vectors for up to 2 yr
and have low toxicity for humans. Paints incorporating insecticides
have also been used. A therapeutic vaccine composed of bivalent
recombinant T. cruzi antigens has been shown to be effective in pre-
clinical proof-of-concept animal models and is currently undergoing
further development.
Blood transfusions in endemic areas are a significant risk. Gentian
violet, an amphophilic cationic agent that acts photodynamically, has
been used to kill the parasite in blood. Photoirradiation of blood contain-
ing gentian violet and ascorbate generates free radicals and superoxide
anions that are trypanosomicidal. Mepacrine and maprotiline have
also been used to eradicate the parasite in blood transfusions.
Because immigrants can carry this disease to nonendemic areas,
serologic testing should be performed in blood and organ donors
from endemic areas. Potential seropositive donors can be identified by
determining whether they have been or have spent extensive time in an
endemic area. Questionnaire-based screening of potentially infected blood
and organ donors from areas endemic for infection can reduce the risk
for transmission. Seropositivity should be considered a contraindication
to organ donation, particularly for heart transplantation.
Bibliography is available at Expert Consult.
Chapter 314
Malaria (Plasmodium)
Chandy C. John
Malaria is an acute illness characterized by paroxysms of fever, chills,
sweats, fatigue, anemia, and splenomegaly. It has played a major role
in human history, causing harm to more people than perhaps any other
infectious disease. Although substantial progress has been made in
combating malaria in endemic areas, with a 37% reduction in malaria
incidence and 60% reduction in malaria mortality, malaria remains one
of the leading causes of morbidity and mortality worldwide, with an
estimated 214 million cases and 438,000 deaths in 2015. Malarial deaths
in areas of high malaria transmission occur primarily in children <5 yr
of age, but in areas of low transmission, a large percentage of deaths
may occur in older children and adults. Although malaria is not endemic
in the United States, 1,500-2,000 imported cases are seen in the United
States each year. Physicians practicing in nonendemic areas should
consider the diagnosis of malaria in any febrile child who has returned
from a malaria-endemic area within the previous year, because delay
in diagnosis and treatment can result in severe illness or death.
ETIOLOGY
Malaria is caused by intracellular Plasmodium protozoa transmitted to
humans by female Anopheles mosquitoes. Before 2004, only 4 species
1852 Part XVI ◆ Infectious Diseases
Countries endemic for malaria, 2016
Countries not endemic for malaria, 2000
Fig. 314.1 Global spatial distribution of malaria, 2000 compared to 2016. (From World Malaria Report 2016. Geneva: World Health Organization;
2016. License: CC BY-NC-SA 3.0 IGO.)
of Plasmodium were known to cause malaria in humans: P. falciparum,
P. malariae, P. ovale, and P. vivax. In 2004, P. knowlesi (a primate malaria
species) was also shown to cause human malaria, and cases of P. knowlesi
infection have been documented in Malaysia, Indonesia, Singapore,
and the Philippines. Malaria also can be transmitted through blood
transfusion and use of contaminated needles and transplacentally from
a pregnant woman to her fetus. The risk for blood transmission is low
in the United States, but may occur through transfusion of whole blood,
packed red blood cells (RBCs), platelets, and leukocytes and through
organ transplantation.
EPIDEMIOLOGY
Malaria is a major worldwide problem, occurring in 95 countries that
comprise approximately half the world’s population (Fig. 314.1). The
principal areas of transmission are Africa, Asia, and South America. P.
falciparum and P. malariae are found in most malarious areas. P. falci-
parum is the predominant species in Africa, Haiti, and New Guinea.
P. vivax predominates in Bangladesh, Central America, India, Pakistan,
and Sri Lanka. P. vivax and P. falciparum predominate in Southeast
Asia, South America, and Oceania. P. ovale is the least-common species
and is transmitted primarily in Africa. Transmission of malaria has
been eliminated in most of North America (including the United States),
Europe, and most of the Caribbean, as well as Australia, Chile, Israel,
Japan, Lebanon, and Taiwan.
Most cases of malaria in the United States occur among previously
infected visitors to the United States from endemic areas and among
U.S. citizens who travel to endemic areas without appropriate chemopro-
phylaxis. The most common regions of acquisition of the approximately
1,700 cases of malaria reported to the Centers for Disease Control and
Prevention (CDC) among U.S. citizens in 2013 were Africa (82%), Asia
(11%), and the Caribbean and Central or South America (7%). Although
only 17% of malaria cases occurred in children (<18 yr old), children
<5 yr old were more likely to develop severe malaria (37%) than were
persons ≥5 yr old (15%). All the 10 deaths from malaria were caused by
P. falciparum. Rare cases of apparent locally transmitted malaria have
been reported since the 1950s. These cases may result from transmis-
sion from untreated and often asymptomatic infected individuals from
malaria-endemic countries who travel to the United States and infect
local mosquitoes or from infected mosquitoes from malaria-endemic
areas that are transported to the United States on airplanes.
PATHOGENESIS
Plasmodium species exist in a variety of forms and have a complex life
cycle that enables them to survive in different cellular environments in
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Countries endemic in 20001 no longer endemic in 2016
Not applicable
the human host (asexual phase) and the mosquito (sexual phase) (Fig.
314.2). A marked amplification of Plasmodium, from approximately
102 to as many as 1014 organisms, occurs during a 2-step process in
humans, with the 1st phase in hepatic cells (exoerythrocytic phase) and
the 2nd phase in the RBCs (erythrocytic phase). The exoerythrocytic
phase begins with inoculation of sporozoites into the bloodstream by
a female Anopheles mosquito. Within minutes, the sporozoites enter
the hepatocytes of the liver, where they develop and multiply asexually
as a schizont. After 1-2 wk, the hepatocytes rupture and release thousands
of merozoites into the circulation. The tissue schizonts of P. falciparum,
P. malariae, and apparently P. knowlesi rupture once and do not persist
in the liver. There are 2 types of tissue schizonts for P. ovale and P. vivax.
The primary type ruptures in 6-9 days, and the secondary type remains
dormant in the liver cell for weeks, months, or as long as 5 yr before
releasing merozoites and causing relapse of infection. The erythrocytic
phase of Plasmodium asexual development begins when the merozoites
from the liver penetrate erythrocytes. Once inside the erythrocyte, the
parasite transforms into the ring form, which then enlarges to become
a trophozoite. These latter 2 forms can be identified with Giemsa stain
on blood smear, the primary means of confirming the diagnosis of
malaria (Fig. 314.3). The trophozoite multiplies asexually to produce a
number of small erythrocytic merozoites that are released into the
bloodstream when the erythrocyte membrane ruptures, which is associ-
ated with fever. Over time, some of the merozoites develop into male
and female gametocytes that complete the Plasmodium life cycle when
they are ingested during a blood meal by the female anopheline mosquito.
The male and female gametocytes fuse to form a zygote in the stomach
cavity of the mosquito. After a series of further transformations, spo-
rozoites enter the salivary gland of the mosquito and are inoculated
into a new host with the next blood meal.
Physiology and pathogenesis in malaria differ according to species.
Infection with all species leads to fever, caused by the host immune
response when erythrocytes rupture and release merozoites into the
circulation, and anemia, caused by hemolysis and bone marrow sup-
pression. Severe malaria is more common in P. falciparum because of
several process, including higher-density parasitemia, which may lead
to excessive production of proinflammatory cytokines; cytoadherence
of P. falciparum-infected erythrocytes to the vascular endothelium; and
polyclonal activation, resulting in both hypergammaglobulinemia and
the formation of immune complexes. Cytoadherence of infected
erythrocytes to vascular endothelium can lead to obstruction of blood
flow and capillary damage, with resultant vascular leakage of blood,
protein, and fluid and tissue anoxia. Parasite anaerobic metabolism
may also lead to hypoglycemia and metabolic acidosis. The cumulative
 Chapter 314 ◆ Malaria (Plasmodium) 1853

i ! Infective Stage Human Liver Stages

d ! Diagnostic Stage Liver cell Infected

liver cell
Mosquito Stages 2
Ruptured 1 i
12
oocyst Mosquito takes A
a blood meal Exo-erythrocytic Cycle
Release of (injects sporozoites)
11 Oocyst sporozoites
i Ruptured schizont
4 3
Schizont

Sporogonic Cycle Human Blood Stages

5 Immature
trophozoite
10 Ookinete 8 (ring stage)
Mosquito takes d
a blood meal
(ingests gametocytes)
Macrogametocyte
B

Erythrocytic Cycle Mature d

trophozoite
Microgamete entering
macrogamete 9
P. falciparum
6
Exflagellated Ruptured
microgametocyte schizont
7 Schizont d
Gametocytes d 7

P. vivax Gametocytes
P. ovale
P. malariae

Fig. 314.2 Life cycle of Plasmodium spp. (From Centers for Disease Control and Prevention: Laboratory diagnosis of malaria: Plasmodium spp.
https://www.cdc.gov/dpdx/malaria/index.html.)

effects of these pathologic processes may lead to cerebral, cardiac,
pulmonary, renal, and hepatic failure.
Immunity after Plasmodium sp. infection is incomplete, preventing
severe disease but still allowing future infection. In some cases, parasites
circulate in small numbers for a long time but are prevented from
rapidly multiplying and causing severe illness. Repeated episodes of
infection occur because the parasite has developed a number of immune-
evasive strategies, such as intracellular replication, vascular cytoadherence
that prevents infected erythrocytes from circulating through the spleen,
rapid antigenic variation, and alteration of the host immune system
resulting in partial immune suppression. The human host response to
Plasmodium infection includes natural immune mechanisms that prevent
infection by other Plasmodium spp., such as those of birds or rodents,
as well as several alterations in erythrocyte physiology that prevent or
modify malarial infection. Erythrocytes containing hemoglobin S (sickle
erythrocytes) resist malaria parasite growth, erythrocytes lacking Duffy
blood group antigen are relatively resistant to P. vivax, and erythrocytes
containing hemoglobin F (fetal hemoglobin) and ovalocytes are resistant
to P. falciparum. In hyperendemic areas, newborns rarely become ill
with malaria, in part because of passive maternal antibody and high
levels of fetal hemoglobin. Children 3 mo to 2-5 yr of age have little
specific immunity to malaria species and therefore suffer yearly attacks
of debilitating and potentially fatal disease. Immunity is subsequently
acquired, and severe cases of malaria become less common. Severe
disease may occur during pregnancy, particularly first pregnancies or
after extended residence outside the endemic region. Both T-cell and
antibody responses are important in development of biologic and clinical
immunity to Plasmodium spp.
CLINICAL MANIFESTATIONS
Children and adults are asymptomatic during the initial phase of infec-
tion, the incubation period of malaria infection. The usual incubation
periods are 9-14 days for P. falciparum, 12-17 days for P. vivax, 16-18
days for P. ovale, and 18-40 days for P. malariae. The incubation period
can be as long as 6-12 mo for P. vivax and can also be prolonged for
patients with partial immunity or incomplete chemoprophylaxis. A
prodrome lasting 2-3 days is noted in some patients before parasites are
detected in the blood. Prodromal symptoms include headache, fatigue,
anorexia, myalgia, slight fever, and pain in the chest, abdomen, and joints.
Children with malaria often lack the typical paroxysms in adults (high
fever, followed by shaking chills and then diaphoresis) and may have
nonspecific symptoms, including fever (may be low-grade but is often
>40°C [104°F]), headache, drowsiness, anorexia, nausea, vomiting, and
diarrhea. While the rupture of schizonts that occurs every 48 hr with P.
vivax and P. ovale and every 72 hr with P. malariae can result in a classic
pattern of fevers every other day (P. vivax and P. ovale) or every 3rd day
(P. malariae), periodicity is less apparent with P. falciparum, and mixed
infections and may not be apparent early on in infection, when parasite

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1854 Part XVI ◆ Infectious Diseases

A B C D

E F G H
Fig. 314.3 Giemsa-stained thick (A) and thin (B-H) smears used for the diagnosis of malaria and the speciation of Plasmodium parasites.
A, Multiple signet-ring Plasmodium falciparum trophozoites, which are visualized outside erythrocytes. B, A multiply infected erythrocyte containing
signet-ring P. falciparum trophozoites, including an accolade form positioned up against the inner surface of the erythrocyte membrane.
C, Banana-shaped gametocyte unique to P. falciparum. D, Ameboid trophozoite characteristic of Plasmodium vivax. Both P. vivax– and Plasmodium
ovale–infected erythrocytes exhibit Schüffner dots and tend to be enlarged compared with uninfected erythrocytes. E, P. vivax schizont. Mature
P. falciparum parasites, by contrast, are rarely seen on blood smears because they sequester in the systemic microvasculature. F, P. vivax spherical
gametocyte. G, P. ovale trophozoite. Note Schüffner dots and ovoid shapes of the infected erythrocyte. H, Characteristic band-form trophozoite
of Plasmodium malariae, containing intracellular pigment hemozoin. (A, B, and F, From Centers for Disease Control and Prevention: DPDx: laboratory
identification of parasites of public health concern. https://www.cdc.gov/dpdx/malaria/index.html; C, D, E, G, and H, courtesy of David Wyler,
Newton Centre, MA.)

Table 314.1 World Health Organization Criteria for
Severe Malaria, 2000
broods have not yet synchronized. Patients with primary infection, such as
travelers from nonendemic regions, also may have irregular symptomatic
episodes for 2-3 days before regular paroxysms begin, so most travelers
presenting with malaria lack a classic malaria fever pattern. Distinctive
physical signs may include splenomegaly (common), hepatomegaly, and
pallor as a consequence of anemia. Typical laboratory findings include
anemia, thrombocytopenia, and a normal or low leukocyte count. The
erythrocyte sedimentation rate is often elevated.
P. falciparum is the most severe form of malaria and is associated
with higher-density parasitemia and a number of complications (Fig.
314.4). The most common serious complication is severe anemia, which
also is associated with other malaria species. Serious complications that
appear unique to P. falciparum include cerebral malaria, respiratory
distress from metabolic acidosis, acute renal failure, hypotension, and
bleeding diatheses (Table 314.1) (see later, Complications of Plasmodium
falciparum Malaria). The diagnosis of P. falciparum malaria in a nonim-
mune individual constitutes a medical emergency. Severe complications
and death can occur if appropriate therapy is not instituted promptly.
In contrast to malaria caused by P. ovale, P. vivax, and P. malariae,
which usually result in parasitemias of <2%, malaria caused by P. fal-
ciparum can be associated with parasitemia levels as high as 60%. The
differences in parasitemia reflect that P. falciparum infects both immature
and mature erythrocytes, whereas P. ovale and P. vivax primarily infect
immature erythrocytes and P. malariae infects only mature erythrocytes.
Like P. falciparum, P. knowlesi has a 24 hr replication cycle and can also
lead to very-high-density parasitemia.
P. vivax malaria has long been considered less severe than P. falciparum
malaria, but recent reports suggest that in some areas it is as frequent
a cause of severe disease and death as P. falciparum. Severe disease and
death from P. vivax are usually caused by severe anemia and sometimes
splenic rupture. P. ovale malaria is the least common type of malaria. It
is similar to P. vivax malaria and usually is found in conjunction with
P. falciparum malaria. P. malariae is the mildest and most chronic of
all malaria infections. Nephrotic syndrome is a rare complication of P.
malariae infection that is not observed with any other human malaria
species. Nephrotic syndrome associated with P. malariae infection is
poorly responsive to corticosteroids. Low-level, undetected P. malariae
infection may be present for years and is sometimes unmasked by immu-
nosuppression or physiologic stress such as splenectomy or corticosteroid
treatment. P. knowlesi malaria is most often uncomplicated but can lead
to severe malaria and death if high-density parasitemia is present.
Recrudescence after a primary attack may occur from the survival
of erythrocyte forms in the bloodstream. Long-term relapse is caused
by release of merozoites from an exoerythrocytic source in the liver,
which occurs with P. vivax and P. ovale, or from persistence within the
erythrocyte, which occurs with P. malariae and rarely with P. falciparum.
A history of typical symptoms in a person >4 wk after return from an
endemic area is therefore more likely to be P. vivax, P. ovale, or P.
malariae infection than P. falciparum infection. In the most recent survey
of malaria in the United States (2013) by the CDC, among individuals
in whom a malaria species was identified, 61% of cases were caused by
P. falciparum,14% by P. vivax,2% by P. malariae,4% by P. ovale, and 2%
by mixed-species infection; 94% of P. falciparum infections were
diagnosed within 30 days of arrival in the United States, and 99% within
90 days of arrival. In contrast, 54% of P. vivax cases occurred >30 days
after arrival in the United States.
Congenital malaria is acquired from the mother prenatally or peri-
natally but is rarely reported in the United States. Congenital malaria
usually occurs in the offspring of a nonimmune mother with P. vivax or
P. malariae infection, although it can be observed with any of the human
malaria species. The first sign or symptom typically occurs between
10 and 30 days of age (range: 14 hr to several months of age). Signs
and symptoms include fever, restlessness, drowsiness, pallor, jaundice,

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100
Jaundice Anemia
Proportion of patients (%)
Acidosis Convulsions
80
Coma Shock
Renal failure
60
40
20
0
0 5 10 20 30
A Age (years)
Coma or
convulsions
6%
23%
19%
43%
7% 13%
6%
Uremia
Acidosis
B and may be the preferred method of detection in these children, who,
Fig. 314.4 Manifestations of severe falciparum malaria by age (A) and
mortality in children associated with central nervous system involvement,
acidosis, and uremia (B). Data from 3,228 prospectively studied African
children with severe falciparum malaria. Uremia here is defined as a
blood urea nitrogen >7.14 mmol/L. Surface areas denote the relative
prevalence of the different severity signs, which frequently coexist. The
percentages denote the observed mortality associated with the presenting
signs. (From White NJ, Pukrittayakamee S, Hien TT, et al: Malaria, Lancet
383:723–735, 2014; based on data from von Seidlein L, Olaosebikan
R, Hendriksen ICE, et al: Predicting the clinical outcome of severe fal-
ciparum malaria in African children: findings from a large randomized
trial. Clin Infect Dis 54:1080–1090, 2012.)
poor feeding, vomiting, diarrhea, cyanosis, and hepatosplenomegaly.
Malaria in pregnancy is a major health problem in malaria endemic
countries, can be severe, and is associated with adverse outcomes in
the fetus or neonate, including intrauterine growth restriction and low
birthweight, even in the absence of transmission from mother to child.
DIAGNOSIS
Any child who presents with fever or unexplained systemic illness and
has traveled or resided in a malaria-endemic area within the previous
year should be evaluated for malaria. Malaria should be considered
regardless of the use of chemoprophylaxis. Important criteria that suggest
P. falciparum malaria include symptoms occurring <1 mo after return
from an endemic area, >2% parasitemia, ring forms with double-
chromatin dots, and erythrocytes infected with>1 parasite.
The diagnosis of malaria is established by identification of organisms
on Giemsa-stained smears of peripheral blood (see Fig. 314.3) or by
rapid immunochromatographic assay (rapid diagnostic test). Giemsa
stain is superior to Wright stain or Leishman stain. Both thick and thin
blood smears should be examined. The concentration of erythrocytes
on a thick smear is 20-40 times that on a thin smear and is used to
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Chapter 314 ◆ Malaria (Plasmodium) 1855
quickly scan large numbers of erythrocytes. The thin smear allows for
positive identification of the malaria species and determination of the
percentage of infected erythrocytes and is useful in following the response
to therapy. Identification of the species is best made by an experienced
microscopist and checked against color plates of the various Plasmodium
spp. (see Fig. 314.3). Morphologically, it is impossible to distinguish P.
knowlesi from P. malariae, so polymerase chain reaction (PCR) detection
by a reference laboratory or the CDC is required. Although P. falciparum
is most likely to be identified from blood just after a febrile paroxysm,
most children with malaria will have a positive blood smear regardless
of the time the smear is obtained. Most guidelines recommend at least
40 50 60 3 negative blood smears to rule out malaria in children in whom malaria
is strongly suspected, because low-level parasitemia could potentially
go undetected early in the illness. However, few data are available on
the utility of repeated blood smears for malaria detection, and most
case reports and series document a positive initial smear.
The BinaxNOW Malaria test is approved by the U.S. Food and Drug
Administration (FDA) for rapid diagnosis of malaria. This immunochro-
matographic test for P. falciparum histidine-rich protein (HRP2) and
aldolase is approved for testing for P. falciparum and P. vivax. Aldolase
is present in all 5 of the malaria species that infect humans. Thus, a
positive result for P. vivax could be because of P. ovale or P. malariae
infection. Sensitivity and specificity for P. falciparum (94–99% and
94–99%, respectively) and P. vivax (87–93% and 99%, respectively) are
good, but sensitivity for P. ovale and P. malariae is lower. Sensitivity for P.
falciparum decreases at lower levels of parasitemia, so microscopy is still
advised in areas where expert microscopy is available. The test is simple
to perform and can be done in the field or laboratory in 10 min. PCR
is more sensitive than microscopy but is technically more complex. It is
available in some reference laboratories and can be useful for confirmation
and for diagnosis of multiple species of malaria, but the time delay in
availability of results generally precludes its use for acute diagnosis of
malaria. PCR detection may detect asymptomatic parasitemia in children
with very-low-level parasitemia (e.g., internationally adopted children
from malaria-endemic areas), with greater sensitivity than microscopy,
since asymptomatic, do not require immediate treatment.
Differential Diagnosis
The differential diagnosis of malaria is broad and includes viral infections
such as influenza and hepatitis, sepsis, pneumonia, meningitis, encepha-
litis, endocarditis, gastroenteritis, pyelonephritis, babesiosis, brucellosis,
leptospirosis, tuberculosis, relapsing fever, typhoid fever, yellow fever,
viral hemorrhagic fevers, amebic liver abscess, neoplasm, and collagen
vascular disease.
TREATMENT
Physicians caring for patients with malaria or traveling to endemic
areas need to be aware of current information regarding malaria because
resistance to antimalarial drugs has complicated therapy and prophylaxis.
The best source for such information is the CDC Malaria webpage
(https://www.cdc.gov/malaria/resources/pdf/treatmenttable.pdf),which
provides up-to-date guidelines for malaria treatment, and an algorithm
for an approach to malaria treatment (Fig. 314.5). In cases where treat-
ment is unclear or complex, the CDC Malaria Hotline is an excellent
resource and is available to physicians 24 hr a day (844-856-4713, from
9 AM to 5 PM Eastern Time Monday-Friday, and 770-488-7100 at all
other times and on holidays; request to speak to the CDC Malaria
Branch Expert).
Fever without an obvious cause in any patient who has left a P.
falciparum–endemic area within 30 days and is nonimmune should be
considered a medical emergency. Thick and thin blood smears should be
obtained immediately, and all children with symptoms of severe disease
should be hospitalized. If negative, blood films should be repeated every
12 hr until 3 smears are documented as negative. If the patient is severely
ill, antimalarial therapy should be initiated immediately. Outpatient
therapy generally is not given to nonimmune children but may be
considered in immune or semi-immune children who have low-level
parasitemia (<1%), no evidence of complications defined by the World
1856 Part XVI ◆ Infectious Diseases

History of travel to malaria-endemic

area or clinical suspicion of malaria

Perform thick and thin blood films

and read within a few hours

No Blood film Yes

positive?

Repeat blood films every

12 to 24 h for a total of 3 sets

No Blood film Yes

Calculate parasitemia
positive?

Consider alternate diagnoses Evaluate clinical status

and disease severity

Uncomplicated malaria Severe malaria and/or

Patient unable to take
oral medication
Determine species

Non-falciparum species Plasmodium falciparum or

species not yet identified

P. malariae P. ovale or P. vivax acquired in P. knowlesi Acquired in Acquired in Acquired in

P. vivax Papua New Guinea chloroquine- chloroquine- mefloquine-
acquired outside or Indonesia sensitive area resistant area resistant area
Papua New Guinea
or Indonesia
Chloroquine or Atovaquone-proguanil
Atovaquone-proguanil Hydroxychloroquine or
or Artemether-lumefantrine
Chloroquine or Quinine plus or
Hydroxychloroquine tetracycline or doxycycline Quinine plus
or tetracycline or doxycycline
Mefloquine or clindamycin

Chloroquine or Atovaquone-proguanil Intravenous quinidine

Hydroxychloroquine or plus tetracycline, or
Artemether-lumefantrine doxycycline, or
or clindamycin
Quinine plus
tetracycline or doxycycline If quinidine is unavailable
Plus
or clindamycin contact CDC malaria
or hotline for artesunate
Mefloquine
Admit to intensive care
unit for continuous
cardiac monitoring.
Primaquine if not
Admit to hospital to monitor for Prevent and treat
G6PD deficient
progression of disease severity complications.

Switch to oral medicines

to complete the treatment
regimen after appropriate
clinical response

Repeat blood films if symptoms recur

Fig. 314.5 Algorithm for approach to patient with malaria in the United States. (From Centers for Disease Control and Prevention. http://www
.cdc.gov/malaria/resources/pdf/algorithm.pdf.)
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Health Organization (WHO), no vomiting, and a lack of toxic appearance;
who are able to contact the physician or emergency department at any
time; and in whom follow-up within 24 hr is ensured.
Plasmodium Falciparum Malaria
Malarious regions considered chloroquine-sensitive include Central
America west of the Panama Canal, Haiti, the Dominican Republic,
and most of the Middle East except Iran, Oman, Saudi Arabia, and
Yemen. The CDC website (http://www.cdc.gov/MALARIA/) should be
consulted for updated information on chloroquine susceptibility in an
area, and current treatment options. Individuals traveling from areas
with chloroquine-susceptible P. falciparum can be treated with chloro-
quine if they do not have severe malaria. Malaria acquired in P. falciparum
areas with chloroquine resistance or where there is any doubt about
chloroquine sensitivity after conferring with the CDC should be treated
with drugs other than chloroquine. Trials in Asia and Africa have
definitively proved that artesunate treatment of severe malaria is associ-
ated with decreased mortality compared to quinine treatment. However,
artesunate is still not FDA-approved in the United States for treatment
of malaria, or available outside of special-request indications from the
CDC, so intravenous (IV) quinidine gluconate remains first-line therapy
for severe malaria in the United States (Table 314.2). Monotherapy with
artesunate agents should never be used because of the development of
resistance and treatment failures. Nonetheless, in endemic countries,
artesunate derivatives in combination with other antimalarial agents
have become the treatment of choice (Tables 314.3 and 314.4). Children
with severe malaria should be admitted to the intensive care unit for
monitoring of complications, plasma quinidine levels, and adverse effects
during quinidine administration. During administration of quinidine,
blood pressure monitoring for hypotension and cardiac monitoring for
widening of the QRS complex or lengthening of the QTc interval should
be performed continuously, and blood glucose monitoring for hypo-
glycemia should be performed periodically. Cardiac adverse events may
require temporary discontinuation of the drug or slowing of the IV
infusion. Parenteral therapy should be continued until the parasitemia
is <1%, which usually occurs within 48 hr, and the patient can tolerate
oral medication. Quinidine gluconate (United States) or quinine sulfate
(other countries) is administered for a total of 3 days for malaria acquired
in Africa or South America and for 7 days for malaria acquired in
Southeast Asia. Doxycycline, tetracycline, or clindamycin is then given
orally to complete the therapeutic course (see Tables 314.2 and 314.4).
Although there are no data to support the use of quinidine followed
by atovaquone-proguanil or artemether-lumefantrine, the difficulty
of maintaining compliance with oral quinine has led many clinicians
to complete oral therapy after IV quinine with a complete course of
atovaquone-proguanil or artemether-lumefantrine.
Parenteral artesunate or artemether can be substituted for quinine
for treatment of severe malaria in children and adults (see Table 314.2).
Artesunate is now available on special request from the CDC (770-488-
7788) for treatment of severe malaria but requires a specific indication
such as adverse reaction to quinidine, contraindication to quinidine,
or lack of availability of quinidine. Empirical therapy should not be
delayed while awaiting delivery of artesunate. Children who receive
artesunate can follow up with artemether-lumefantrine oral therapy.
Oral and rectal administration of these artemisinin-based antimalarial
drugs is effective in treatment of malaria, but such formulations are
not indicated or approved in the United States.
Patients from areas with chloroquine-resistant P. falciparum who
have mild infection, parasitemia <1%, no evidence of complications,
and no vomiting and who can take oral medication can be considered
for oral therapy with either oral atovaquone-proguanil (Malarone),
oral artemether-lumefantrine (Coartem), or oral quinine plus doxycy-
cline, tetracycline, or clindamycin (see Table 314.2). However, as noted
in Fig. 314.5, all children with clinical (symptomatic) malaria, even
those started on oral therapy, should be admitted to evaluate for progres-
sion of disease. Semi-immune children have been treated as outpatients,
but there is limited data on the safety of this approach. Coartem is
FDA-approved for the treatment of uncomplicated malaria and is an
appealing choice because it is highly effective and well-tolerated. Pediatric
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Chapter 314 ◆ Malaria (Plasmodium) 1857
dosing is well established, but pediatric dispersible tablets, available in
some other countries, are not yet available in the United States. Coartem
should not be used in children with known QT interval prolongation.
Patients who acquire P. falciparum in Thailand, Myanmar, or Cambodia
should receive Coartem or Malarone in preference to quinine. Mefloquine
is contraindicated for use in patients with a known hypersensitivity to
mefloquine or with a history of epilepsy or severe psychiatric disorders.
Mefloquine is not recommended for persons with cardiac conduction
abnormalities but may be administered to persons who are concurrently
receiving β-blockers if they have no underlying arrhythmia. Quinidine
or quinine may exacerbate the adverse effects of mefloquine and should
generally not be given to patients who have received mefloquine unless
there are no other alternatives.
Patients with uncomplicated P. falciparum malaria acquired in areas
without chloroquine resistance should be treated with oral chloroquine
phosphate. If the parasite count does not drop rapidly (within 24-48 hr)
and become negative after 4 days, chloroquine resistance should be
assumed, and the patient should be started on a different antimalarial
regimen.
Supportive therapy is important and may include RBC transfusion(s)
to maintain the hematocrit at >20%, supplemental oxygen and ventilatory
support for pulmonary edema or cerebral malaria, careful IV rehydration
for severe malaria, IV glucose for hypoglycemia, anticonvulsants for
cerebral malaria with seizures, and dialysis for renal failure. Exchange
transfusion has been advocated for children and adults with parasitemia
>10% and evidence of severe complications (e.g., severe malarial anemia,
cerebral malaria), but no randomized clinical trial has been conducted
to assess its utility, and some groups, including the CDC, no longer
advocate its use for severe malaria. Corticosteroids are not recommended
for cerebral malaria because they do not improve outcomes.
Plasmodium Vivax, P. Ovale, P. Malariae,
or P. Knowlesi Malaria
Uncomplicated infection caused by P. vivax, P. ovale, or P. malariae can
usually be treated with chloroquine, except in areas with chloroquine
resistance (Papua New Guinea and Indonesia, see Table 314.2). Chlo-
roquine remains the initial drug of choice for P. vivax malaria in the
absence of good data on drug alternatives. Indications for using alternative
therapy are worsening or new symptoms, persistent P. vivax parasitemia
after 72 hr, and possibly acquisition of infection in Oceania or India.
Patients with P. vivax or P. ovale malaria should also be given primaquine
once daily for 14 days to prevent relapse from the hypnozoite forms
that remain dormant in the liver. Some strains may require 2 courses
of primaquine. Testing for glucose-6-phosphate dehydrogenase deficiency
must be performed before initiation of primaquine, because it can cause
hemolytic anemia in such patients. Unfortunately, no alternatives to
primaquine currently exist for eradication of the hypnozoite forms of
P. vivax or P. ovale. Patients with any type of malaria should be monitored
for possible recrudescence because it may occur >90 days after therapy
with low-grade resistant organisms. If vomiting precludes oral administra-
tion, chloroquine can be given by nasogastric tube. Based on limited
evidence, chloroquine plus sulfadoxine-pyrimethamine should be used
to treat P. knowlesi infections. For cases of severe malaria caused by
any Plasmodium spp., IV quinidine or quinine with a 2nd drug
(clindamycin, doxycycline, or tetracycline) should be used, as for P.
falciparum. Patients with any type of malaria must be monitored for
possible recrudescence with repeat blood smears at the end of therapy,
because recrudescence may occur >90 days after therapy with low-grade
resistant organisms. For children living in endemic areas, mothers should
be encouraged to seek evaluation for malaria any time the child has a
fever, because many clinics in endemic areas now have accurate rapid
diagnostic tests available. If such children are severely ill, they should
be given the same therapy as nonimmune children.
COMPLICATIONS OF PLASMODIUM
FALCIPARUM MALARIA
WHO has identified 10 complications of P. falciparum malaria that
define severe malaria (see Table 314.1 and Fig. 314.4). The most common
complications in children are severe anemia, impaired consciousness
1858 Part XVI ◆ Infectious Diseases

Table 314.2 CDC Guidelines for Treatment of Malaria in the United States (Based on Drugs Currently Available for Use in
the United States–Updated July 1, 2013)

RECOMMENDED DRUG AND

CLINICAL DIAGNOSIS/ REGION INFECTION RECOMMENDED DRUG AND PEDIATRIC DOSE ; PEDIATRIC DOSE
PLASMODIUM spp. ACQUIRED ADULT DOSE SHOULD NEVER EXCEED ADULT DOSE
Uncomplicated Chloroquine-resistant or Atovaquone-proguanil (Malarone) Atovaquone-proguanil (Malarone)
malaria/P. falciparum unknown resistance2 Adult tab = 250 mg atovaquone/100 mg Adult tab = 250 mg atovaquone/100 mg
or proguanil proguanil
× Pediatric (ped) tab = 62.5 mg
atovaquone/25 mg proguanil
×
P. vivax ×
P. ovale: P. vivax ×
P. ovale ×
×
> ×

<
<
<
≥

= =
× ×
× ×
×

× ×

= =
=
(=
= =

P. falciparum
or =

(=
= or
or

(=
=

2
P. falciparum

< < P. falciparum

<
P. vivax,

Continued

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 Chapter 314 ◆ Malaria (Plasmodium) 1859

Table 314.2 CDC Guidelines for Treatment of Malaria in the United States (Based on Drugs Currently Available for Use in
the United States–Updated July 1, 2013)—cont’d
RECOMMENDED DRUG AND
CLINICAL DIAGNOSIS/ REGION INFECTION RECOMMENDED DRUG AND PEDIATRIC DOSE ; PEDIATRIC DOSE
PLASMODIUM spp. ACQUIRED ADULT DOSE SHOULD NEVER EXCEED ADULT DOSE

P. malariae
P. knowlesi or or

P. vivax P. ovale

P. vivax,
×
×
or or

× ×

P. vivax

Atovaquone-proguanil plus primaquine Atovaquone-proguanil plus primaquine

phosphate phosphate
Atovaquone-proguanil: Atovaquone-proguanil:

Primaquine phosphate: Primaquine phosphate:

Mefloquine plus primaquine phosphate Mefloquine plus primaquine phosphate

Mefloquine: Mefloquine:
Primaquine phosphate: Primaquine phosphate:

Uncomplicated malaria: Chloroquine-sensitive Chloroquine phosphate:

alternatives for
pregnant women or
Hydroxychloroquine:

Chloroquine-resistant Quinine sulfate plus clindamycin

Quinine sulfate:
Clindamycin:
or
P. falciparum Mefloquine:
P. vivax)
P. vivax P. ovale

P. vivax.
P. vivax P. vivax
P. vivax
P. vivax
P. vivax ,
P. falciparum P. vivax

P. falciparum

P. vivax P. ovale P.
vivax P. ovale
=

Continued

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1860 Part XVI ◆ Infectious Diseases

Table 314.2 CDC Guidelines for Treatment of Malaria in the United States (Based on Drugs Currently Available for Use in
the United States–Updated July 1, 2013)—cont’d
RECOMMENDED DRUG AND
CLINICAL DIAGNOSIS/ REGION INFECTION RECOMMENDED DRUG AND PEDIATRIC DOSE ; PEDIATRIC DOSE
PLASMODIUM spp. ACQUIRED ADULT DOSE SHOULD NEVER EXCEED ADULT DOSE
Severe malaria All regions Quinidine gluconate plus 1 of the Quinidine gluconate plus 1 of the
following: doxycycline, tetracycline, or following: doxycycline, tetracycline, or
clindamycin clindamycin
Quinidine gluconate: Quinidine gluconate:
(=
Doxycycline:
(=
<
=

=
>

< =
Tetracycline:
Clindamycin:
=
=
Doxycycline:

=
Investigational new drug (contact CDC for
= information): Artesunate followed by 1
Tetracycline: of the following: atovaquone-proguanil
Clindamycin: (Malarone), clindamycin, or mefloquine.
Artemether-lumefantrine is not included
in CDC treatment table but may also be
given as follow-up drug after artesunate
if available.

=
Investigational new drug (contact CDC
for information):
Artesunate followed by 1 of the
following: atovaquone-proguanil
(Malarone), doxycycline (clindamycin in
pregnant women), or mefloquine.
Artemether-lumefantrine is not included
in CDC treatment table but may also be
given as follow-up drug after artesunate
if available.
or

>
P. falciparum.

>

(including cerebral malaria), respiratory distress (a result of metabolic
acidosis), multiple seizures, prostration, and jaundice.
Severe malarial anemia (hemoglobin level <5 g/dL) is the most
common severe complication of malaria in children and is the leading
cause of anemia leading to hospital admission in African children.
Anemia is associated with hemolysis, but removal of infected erythrocytes
by the spleen and impairment of erythropoiesis likely play a greater
role than hemolysis in the pathogenesis of severe malarial anemia. The
primary treatment for severe malarial anemia is blood transfusion. With
appropriate and timely treatment, severe malarial anemia usually has
a relatively low mortality (approximately 1%).
Cerebral malaria is defined as the presence of coma in a child with
P. falciparum parasitemia and an absence of other reasons for coma.
Children with altered mental status who are not in coma fall into the
larger category of impaired consciousness. Cerebral malaria is most
common in children in areas of midlevel transmission and in adolescents
or adults in areas of very low transmission. It is less frequently seen in
areas of very high transmission. Cerebral malaria often develops after

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 Chapter 314 ◆ Malaria (Plasmodium) 1861

that funduscopic findings of malaria retinopathy (retinal hemorrhages,

Table 314.3 Treatment of Uncomplicated Malaria in peripheral whitening, macular whitening, vessel changes) are relatively
Malaria Endemic Areas specific for cerebral malaria, so children with cerebral malaria who do not
REGIMENS have malaria retinopathy should be carefully assessed for other causes of
coma. However, they should still be treated for cerebral malaria because
Plasmodium
a growing body of evidence suggests that even in these children, P.
falciparum
falciparum is a contributor to their comatose state. Treatment of cerebral
malaria other than antimalarial medications is largely supportive and
includes evaluation of and treatment of seizures and hypoglycemia. A
† study using MRI to assess children with cerebral malaria documented that
cerebral edema with increased intracranial pressure is the leading cause
of death in children with cerebral malaria, but treatment with mannitol
P. falciparum and corticosteroids has not improved outcomes in these children.
Respiratory distress is a poor prognostic indicator in severe malaria
and appears to be caused by metabolic acidosis rather than intrinsic
pulmonary disease. To date, no successful interventions for treatment
of metabolic acidosis in children with severe malaria have been described,
and primary therapy of malaria appears to be the most effective way
Plasmodium vivax,‡ to address acidosis.
Plasmodium malariae,‡ Seizures are a common complication of severe malaria, particularly
Plasmodium ovale,‡ cerebral malaria. Benzodiazepines are first-line therapy for seizures,
Plasmodium knowlesi‡ and intrarectal diazepam has been used successfully in children with
malaria and seizures. Many seizures resolve with a single dose of
diazepam. For persistent seizures, phenobarbital or phenytoin are the
standard medications used. Phenytoin may be preferred for seizure
treatment, particularly in hospitals or clinics where ventilatory support
†

‡ is not available. However, no comparative trials of the 2 drugs have

P. vivax
P. vivax P. ovale
Lancet
Table 314.4 Treatment of Severe Malaria in Adults and
Children in Malaria-Endemic Areas
†
† cerebral malaria and also in children with repeated episodes of uncom-
Lancet
the patient has been ill for several days but may develop precipitously.
Cerebral malaria has a fatality rate of 15–40% and is associated with
long-term cognitive impairment in children. Repeated seizures are
frequent in children with cerebral malaria. Hypoglycemia is common,
but children with true cerebral malaria fail to arouse from coma even
after receiving a dextrose infusion that normalizes their glucose level.
Physical findings may include high fever, seizures, muscular twitching,
rhythmic movement of the head or extremities, contracted or unequal
pupils, retinal hemorrhages, hemiplegia, absent or exaggerated deep
tendon reflexes, and a positive Babinski sign. Lumbar puncture reveals
increased pressure and mildly increased cerebrospinal fluid protein, typi-
cally with no CSF pleocytosis and a normal CSF glucose. Studies suggest
been performed. There are currently no drugs recommended for seizure
prophylaxis in children with severe malaria. Phenobarbital prophylaxis
decreased seizure activity but increased mortality in one major study
of children with severe malaria, probably because the respiratory
depression associated with phenobarbital may have been exacerbated
by benzodiazepine therapy.
Hypoglycemia is a complication of malaria that is more common
in children, pregnant women, and patients receiving quinine therapy.
Patients may have a decreased level of consciousness that can be con-
fused with cerebral malaria. Any child with impaired consciousness
and malaria should have a glucose level checked, and if glucometers
are not immediately available, an empirical bolus of dextrose should
be given. Hypoglycemia is associated with increased mortality and
neurologic sequelae.
Circulatory collapse (algid malaria) is a rare complication that
manifests as hypotension, hypothermia, rapid weak pulse, shallow
breathing, pallor, and vascular collapse. It is most likely caused by
bacterial superinfection, since up to 15% of children in endemic areas
with severe malaria may have concurrent bacteremia. Death may occur
within hours. Any child with severe malaria and hypotension or
hypoperfusion should have a blood culture obtained and should be
treated empirically for bacterial sepsis.
Long-term cognitive impairment occurs in 25% of children with
plicated disease. Prevention of attacks in these children may improve
educational attainment.
Hyperreactive malarial splenomegaly (HMS) is a chronic complica-
tion of P. falciparum malaria in which massive splenomegaly persists
after treatment of acute infection. Major criteria include splenomegaly
(>10 cm), IgM > 2 SD above local mean, high levels of antibodies to a
blood-stage P. falciparum antigen, and a clinical response to an anti-
malarial drug. HMS occurs exclusively in children in endemic areas
with repeated exposure to malaria and is thought to be caused by an
impaired immune response to P. falciparum antigens. Prolonged anti-
malarial prophylaxis (for at least 1 yr, typically with chloroquine, quinine,
or mefloquine) is required to treat this syndrome if the child remains
in a malaria-endemic area. Spleen size gradually regresses on antimalarial
prophylaxis but often increases again if prophylaxis is stopped.
Other complications in children include acute kidney injury and
jaundice, both of which are associated with a worse outcome and
prostration. A growing literature demonstrates that although renal failure
requiring dialysis is rare in children with severe malaria, acute kidney

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1862 Part XVI ◆ Infectious Diseases

injury is common and is associated with increased mortality. Prostration
is defined as the inability to sit, stand, or eat without support, in the
absence of impaired consciousness. Prostration has also been associated
with increased mortality in some studies, but the pathophysiology of
this process is not well understood. Uncommon complications include
hemoglobinuria, abnormal bleeding, and pulmonary edema. Of note,
pulmonary edema is more frequent in adolescents and adults.
PREVENTION
Malaria prevention consists of reducing exposure to infected mosquitoes
and chemoprophylaxis. The most accurate and current information on
areas in the world where malaria risk and drug resistance exist can be
obtained by contacting local and state health departments or the CDC
or consulting Health Information for International Travel, which is
published by the U.S. Public Health Service.
Travelers to endemic areas should remain in well-screened areas from
dusk to dawn, when the risk for transmission is highest. They should
sleep under permethrin-treated mosquito netting and spray insecticides
indoors at sundown. During the day, travelers should wear clothing that
covers the arms and legs, with trousers tucked into shoes or boots.
Mosquito repellent should be applied to thin clothing and exposed areas
of the skin, with applications repeated as noted on the repellent instruc-
tions, and at least every 4 hr. A child should not be taken outside from
dusk to dawn, but if at risk for exposure, a solution with 25–35% N,
diethyltoluamide (DEET) (not >40%) should be applied to exposed
areas, except for the eyes, mouth, or hands. Hands are excluded because
they are often placed in the mouth. DEET should then be washed off
as soon as the child comes back inside. The American Academy of
Pediatrics recommends that DEET solutions be avoided in children
<2 mo old. Adverse reactions to DEET include rashes, toxic encepha-
lopathy, and seizures, but these reactions occur almost exclusively with
inappropriate application of high concentrations of DEET. Picaridin is
an alternative and sometimes better-tolerated repellent. Even with these
precautions, a child should be taken to a physician immediately if the
child develops illness when traveling to a malarious area.
Chemoprophylaxis is necessary for all visitors to and residents of the
tropics who have not lived there since infancy, including children of all ages
(Table 314.5). Healthcare providers should consult the latest information

Table 314.5 Chemoprophylaxis of Malaria for Children

AREA DRUG DOSAGE (ORAL) ADVANTAGES DISADVANTAGES BEST USE
†
<
≥
area 1
4
1
2
1
4
>
‡

< <

<

>

area Plasmodium falciparum

Plasmodium vivax

< <
<

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on resistance patterns before prescribing prophylaxis for their patients.
Chloroquine is given in the few remaining areas of the world free of
chloroquine-resistant malaria strains. In areas where chloroquine-resistant
P. falciparum exists, atovaquone-proguanil, mefloquine, or doxycycline
may be given as chemoprophylaxis. Atovaquone-proguanil is generally
recommended for shorter trips (up to 2 wk) because it must be taken
daily. Pediatric tablets are available and are generally well tolerated,
although the taste is sometimes unpleasant to very young children.
For longer trips, mefloquine is preferred, since it is given only once
a week. Mefloquine does not have a pediatric formulation and has an
unpleasant taste that usually requires that the cut tablet be disguised
in another food, such as chocolate syrup. Mefloquine should not be
given to children if they have a known hypersensitivity to mefloquine,
are receiving cardiotropic drugs, have a history of convulsive or certain
psychiatric disorders, or travel to an area where mefloquine resistance
exists (the borders of Thailand with Myanmar and Cambodia, western
provinces of Cambodia, and eastern states of Myanmar). Atovaquone-
proguanil is started 1-2 days before travel, and mefloquine is started
2 wk before travel. It is important that these doses are given, both to
allow therapeutic levels of the drugs to be achieved and to be sure that
the drugs are tolerated. Doxycycline is an alternative for children >8 yr
old. It must be given daily and should be given with food. Side effects
of doxycycline include photosensitivity and vaginal yeast infections.
Primaquine is a daily prophylaxis option for children who cannot tolerate
any of the other options, but it should be provided in consultation with
a travel medicine specialist if needed, and all children should be checked
for glucose-6-phosphate dehydrogenase deficiency before prescribing
this medication, because it is contraindicated in children with G6PD
deficiency. Provision of medication can be considered in individuals
who refuse to take prophylaxis or will be in very remote areas without
accessible medical care. Provision of medication for self-treatment
of malaria should be done in consultation with a travel medicine
specialist, and the medication provided should be different than that
used for prophylaxis.
A number of other efforts are currently underway to prevent malaria
in malaria-endemic countries. Some have been highly successful, leading
to a significant decrease in malaria incidence in many countries in
Africa, Asia, and South America in the last decade. These interventions
include the use of insecticide-treated bed nets (which have decreased
all-cause mortality in children <5 yr old in several highly malaria
endemic areas by approximately 20%), indoor residual spraying with
long-lasting insecticides, and the use of artemisinin-combination
therapy for first-line malaria treatment. The first malaria vaccine to
have any degree of efficacy is the RTS,S vaccine, which is based on
the circumsporozoite protein of P. falciparum. In various clinical trials,
this vaccine has shown an efficacy of 17–56% against uncomplicated
malaria and 38–50% against severe malaria in young children in
malaria-endemic areas for as long as48 mo after vaccination. Given
the relatively low efficacy of this vaccine, it is still unclear if it will
be implemented as part of a combination strategy that includes the
already successful interventions mentioned. Numerous other vaccines
are also in current clinical trials, and it is hoped that future vaccines
will improve on the efficacy of the RTS,S vaccine. There is currently no
vaccine with sufficient efficacy to be considered for prevention of malaria
in travelers.
Intermittent prevention treatment during infancy has been particu-
larly successful in reducing the incidence of malaria in sub Saharan
Africa. Sulfadoxine-pyrimethamine given to infants at the 2nd and
3rd doses of the diphtheria, tetanus toxoid, and pertussis vaccine is safe
and relatively effective. Intermittent prevention treatment has also been
given to pregnant women; 3 doses of sulfadoxine-pyrimethamine have
resulted in a reduction of low-birthweight infants.
Bibliography is available at Expert Consult.
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Chapter 315 ◆ Babesiosis (Babesia) 1863
Chapter 315
Babesiosis (Babesia)
Peter J. Krause
Babesiosis is a malaria-like disease caused by intraerythrocytic protozoa
that are transmitted by hard body (ixodid) ticks. The clinical manifesta-
tions of babesiosis range from subclinical illness to fulminant disease
resulting in death.
ETIOLOGY
More than 100 species of Babesia infect a wide variety of wild and
domestic animals throughout the world. Only a few of these species
have been reported to infect humans, including Babesia crassa-like
pathogen, Babesia divergens, Babesia duncani, Babesia microti, Babesia
venatorum, and Babesia sp. XXB/HangZhou, and KO1.
EPIDEMIOLOGY
Babesia organisms are transmitted to humans from vertebrate reservoir
hosts by the Ixodes ricinus family of ticks. B. microti is the most common
cause of babesiosis in humans. The primary reservoir for B. microti in
the United States is the white-footed mouse, Peromyscus leucopus, and
the primary vector is Ixodes scapularis, the black-legged tick. I. scapularis
ticks also transmit the causative agents of Lyme disease, human granu-
locytic anaplasmosis, Borrelia miyamotoi infection, Ehrlichia muris–like
agent ehrlichiosis, and Powassan virus encephalitis and may simultane-
ously transmit 2 or more microorganisms. White-tailed deer (Odocoileus
virginianus) serve as the host on which adult ticks most abundantly
feed but are incompetent reservoirs. Babesiosis may be transmitted
through blood transfusion, and B. microti is the most frequently reported
transfusion-transmitted microbial agent in the United States. Rarely,
babesiosis is acquired by transplacental transmission.
In the United States, human B. microti infection is endemic in the
Northeast and Upper Midwest (Fig. 315.1). Most cases occur in June,
July, and August. B. duncani infects humans along the Pacific coast. B.
divergens–like infections have been described in Kentucky, Missouri,
and Washington State. In Europe, human babesiosis caused by B.
divergens, B. microti, and B. venatorum occurs sporadically. In Asia, B.
venatorum is endemic in northeastern China. Cases of B. microti infection
have been described in Taiwan, mainland China, and Japan. Cases of
Babesia crassa and Babesia sp. XXB/HangZhou have been reported in
China and KO1 in Korea. Human babesiosis also has been documented
in Africa, Australia, Canada, India, and South America.
In certain sites and in certain years of high transmission, babesiosis
constitutes a significant public health burden. On Nantucket Island,
case rates as high as 280 per 100,000 population have been recorded,
placing the community burden of disease in a category with gonorrhea
as “moderately common.” Comparable incidence rates have been
described elsewhere on the southern New England coast.
PATHOGENESIS
The pathogenesis of human babesiosis is not well understood. Lysis of
infected erythrocytes with resultant anemia and the excessive production
of proinflammatory cytokines such as tumor necrosis factor and
interleukin-1 may account for most of the clinical manifestations and
complications of the disease. The spleen has an important role in clearing
parasitemia, as do T and B cells, macrophages, polymorphonuclear
leukocytes, cytokines, antibody, and complement.
CLINICAL MANIFESTATIONS
The clinical severity of babesiosis ranges from subclinical infection to
fulminant disease and death. In clinically apparent cases, symptoms of
babesiosis begin after an incubation period of 1-9 wk from the beginning
of tick feeding or 1 wk to 6 mo after transfusion. Typical symptoms in
moderate to severe infection include intermittent fever to as high as
1622 Part XVI ◆ Infectious Diseases

the cause of mite-transmitted rickettsialpox; R. felis, the cause of cat
flea–transmitted typhus; and R. australis, the cause of tick-transmitted
Queensland tick typhus. One proposal creates subspecies of R. conorii,
including subsp. conorii (classical MSF), subsp. indica (Indian tick
typhus), subsp. caspia (Astrakhan fever), and subsp. israelensis (Israeli
spotted fever). The recognition that R. parkeri and “R. philippi” (Rickettsia
364D) both cause mild spotted fever in North America and the association
of high seroprevalence for spotted fever group Rickettsia infections in
humans where Amblyomma ticks frequently contain R. amblyommatis
suggest that the full range of agents that can cause spotted fever is still
to be discerned.
Infections with other members of the spotted fever and transitional
groups are clinically similar to MSF, with fever, maculopapular rash,
and eschar at the site of the tick bite. Israeli spotted fever is generally
associated with a more severe course, including death, in children.
African tick bite fever is relatively mild, can include a vesicular rash,
and often manifests with multiple eschars. New potentially pathogenic
rickettsial species have been identified, including R. slovaca, the cause
of tickborne lymphadenopathy or Dermacentor-borne necrosis and
lymphadenopathy. R. aeschlimannii, R. heilongjiangensis, R. helvetica,
R. massiliae, and R. raoultii are all reported to cause mild to moderate
illnesses in humans, although few cases have been described. Fortunately,
the vast majority of infections respond well to doxycycline treatment
if instituted early in illness; however, this is a significant challenge.
Bibliography is available at Expert Consult.
255.1 Rocky Mountain Spotted Fever
(Rickettsia rickettsii)
Megan E. Reller and J. Stephen Dumler
RMSF is the most frequently identified and most severe rickettsial disease
in the United States. It is also the most common vector-borne disease
in the United States after Lyme disease. Although considered uncommon,
RMSF is believed to be greatly underdiagnosed and underreported.
RMSF should be considered in the differential diagnosis of fever,
headache, and rash in the summer months, especially after tick exposure.
Because fulminant disease and death are associated with delays in
treatment, patients in whom the illness is clinically suspected should
be treated promptly.
ETIOLOGY
RMSF results from systemic infection of endothelial cells by the obligate
intracellular bacterium Rickettsia rickettsii.
EPIDEMIOLOGY
The term Rocky Mountain spotted fever is historical, because the agent
was discovered in the Bitterroot Range of the Rocky Mountains of
Montana. Few cases are reported from this region. Cases have been
reported throughout the continental United States (except Vermont
and Maine), southwestern Canada, Mexico, Central America, and South
America, but not from outside of the Western Hemisphere. In 2010,
the Centers for Disease Control and Prevention (CDC) reporting criteria
for Rocky Mountain spotted fever changed to spotted fever group
rickettsiosis, because serology often does not distinguish R. rickettsii
from infection by other spotted fever group Rickettsia. Additionally,
cases detected by enzyme immunoassay were classified as probable.
Thus, in 2012, 2,802 confirmed and probable cases of spotted fever
rickettsiosis were reported in Morbidity and Mortality Weekly Reports
Summary of Notifiable Diseases. Unlike in prior years, most cases were
reported from the west south-central states, especially from Arkansas,
Oklahoma, and Missouri; high numbers of cases were also reported
from North Carolina, Tennessee, Virginia, New Jersey, Georgia, Alabama,
and Arizona (Fig. 255.1). The incidence of RMSF cycles over 25-35 yr
intervals but has generally increased over the past decades. The mean
number of cases reported each year to the CDC has steadily increased
(515 during 1993–1998, 946 during 1999–2004, 2,068 during 2005–2010,
and 3,692 during 2011–2016), of which approximately 14% occur in
those younger than 19 yr. Habitats favored by ticks, including wooded
areas or coastal grassland and salt marshes, and, in the southwestern
United States and Mexico, shaded areas where dogs congregate and
acquire infected ticks are those that place children at increased risk for
infection. Foci of intense risk for infection are found both in rural and
urban areas, most recently in Mexico. Clustering of cases within families
likely reflects shared environmental exposures. In the United States,
90% of cases occur between April and September, months in which

>60
>20 to ≤60
>5 to ≤20
>0 to ≤5
0

Fig. 255.1 Reported incidence rate* of spotted fever rickettsiosis,† by county—United States, 2000–2013. *As reported through national surveil-
lance, per 1,000,000 persons per year. Cases are reported by county of residence, which is not always where the infection was acquired. † Includes
Rocky Mountain spotted fever (RMSF) and other spotted fever group rickettsioses. In 2010, the name of the reporting category changed from
RMSF to spotted fever rickettsiosis. (From Biggs HM, Behravesh CB, Bradley KK, et al: Diagnosis and management of tickborne rickettsial diseases:
Rocky Mountain spotted fever and other spotted fever group rickettsioses, ehrlichioses, and anaplasmosis—United States, MMWR Recomm Rep
65:1–44, 2016, Fig. 1.)

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 Chapter 255
humans spend the most time outdoors. The highest age-specific incidence
of RMSF among children is seen in those older than 10 yr of age, with
males outnumbering females; however, the highest case fatality rate for
RMSF is observed in those less than 10 yr of age.
TRANSMISSION
Ticks are the natural hosts, reservoirs, and vectors of R. rickettsii and
maintain the infection in nature by transovarial transmission (passage
of the organism from infected ticks to their progeny). Ticks harboring
rickettsiae are substantially less fecund than uninfected ticks; thus,
horizontal transmission (acquisition of rickettsiae by taking a blood
meal from transiently rickettsemic hosts such as small mammals or
dogs) contributes to maintenance of rickettsial infections in ticks.
Uninfected ticks that simultaneously feed (cofeed) with infected transmit-
ting ticks easily become infected, even if feeding on an immune host
and are also likely to be major contributors to natural transmission and
maintenance. Ticks transmit the infectious agent to mammalian hosts
(including humans) via infected saliva during feeding. The pathogen
R. rickettsii in ticks becomes virulent after exposure to blood or increased
temperature; thus, the longer the tick is attached, the greater the risk
of transmission. The principal tick hosts of R. rickettsii are Dermacentor
variabilis (the American dog tick) in the eastern United States and
Canada, Dermacentor andersoni (the wood tick) in the western United
States and Canada, Rhipicephalus sanguineus (the common brown dog
tick) in the southwestern United States and in Mexico, and Amblyomma
cajennense and Amblyomma aureolatum in Central and South America
(Fig. 255.2).
Dogs can serve as reservoir hosts for R. rickettsii, can develop RMSF
themselves, and can bring infected ticks into contact with humans.
Serologic studies suggest that many patients with RMSF likely acquired
the illness from ticks carried by the family dog.
Humans can also become infected when trying to remove an attached
tick, because R. rickettsii–containing tick fluids or feces can be rubbed
into the open wound at the bite site or into the conjunctivae by con-
taminated fingers. Inhalation of aerosolized rickettsiae has caused severe
infections and deaths in laboratory workers, highlighting another
mechanism of infection.
a b c
d e 1 mm
Fig. 255.2 Tick vectors of agents of human rickettsial diseases. An
unengaged nymph (A), engorged nymph (B), and adult female (C) of
Ixodes scapularis (deer tick), the vector of Anaplasma phagocytophilum
and Ehrlichia muris–like agent (EMLA), the causes of human granulocytic
anaplasmosis and EMLA ehrlichiosis, respectively. An adult female (D)
of Amblyomma americanum (lone star tick), the vector of Ehrlichia
chaffeensis and Ehrlichia ewingii, the causes of human monocytic
ehrlichiosis and ewingii ehrlichiosis, respectively. An adult female (E) of
Dermacentor variabilis (American dog tick), the vector of Rickettsia
rickettsii, the cause of Rocky Mountain spotted fever.
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◆ Spotted Fever Group Rickettsioses 1623
PATHOLOGY AND PATHOGENESIS
Systemic infection is most obvious on the skin (rash), but nearly all
organs and tissues are affected. Following inoculation of tick saliva into
the dermis, rickettsial outer surface proteins bind to the vascular
endothelial cell surface proteins, which signals focal cytoskeletal changes
and endocytosis. Thereafter, rickettsia phospholipase-mediated dissolution
of the endosomal membranes allows escape into the cytosol. Members
of the spotted fever group actively nucleate actin polymerization on 1
pole to achieve directional movement, allowing some rickettsiae to
propel into neighboring cells despite minimal initial damage to its host
cell. The rickettsiae proliferate and damage the host cells by oxidative
membrane alterations, protease activation, or continued phospholipase
activity. It is likely that some aspects of intracellular infection are mediated
by rickettsial protein effectors delivered into the host cell by bacterial
secretion systems.
The histologic correlate of the initial macular or maculopapular rash
is perivascular infiltration of lymphoid and histiocytic cells with edema
but without significant endothelial damage. Proliferation of rickettsiae
within the cytoplasm of infected endothelial cells leads to endothelial
injury and lymphohistiocytic or leukocytoclastic vasculitis of small
venules and capillaries, which allows extravasation of intravascular
erythrocytes into the dermis and manifests as a petechial rash (Fig.
255.3). This process is systemic and ultimately results in widespread
microvascular leakage, tissue hypoperfusion, and possibly end-organ
ischemic injury. Infrequently, inflammation leads to nonocclusive
thrombi. Very rarely, small and large vessels become completely obliter-
ated by thrombi, leading to tissue infarction or hemorrhagic necrosis.
Interstitial pneumonitis and vascular leakage in the lungs can lead to
non-cardiogenic pulmonary edema, and meningoencephalitis can cause
significant cerebral edema and herniation.
The presence of the infectious agent initiates an inflammatory cascade,
including release of cytokines and chemokines such as tumor necrosis
factor-α, interleukin-1β, interferon-γ, and regulated upon activation,
normal T-cell expressed and secreted (RANTES). Infection of endothelial
cells by R. rickettsii induces surface E-selectin expression and proco-
agulant activity followed by chemokine recruitment of lymphocytes,
macrophages, and, occasionally, neutrophils. Local inflammatory and
immune responses are suspected to contribute to the vascular injury;
however, the benefits of effective inflammation and immunity are greater.
Blockade of tumor necrosis factor-α and interferon-γ action in animal
models diminishes survival and increases morbidity; reactive oxygen
intermediates, nitric oxide expression, and sequestration of tryptophan
from rickettsiae are mechanisms by which rickettsiae are killed within
cells. Direct contact of infected endothelial cells with perforin-producing
Fig. 255.3 Immunohistochemical stain demonstrating Rickettsia (red)
in infection of blood vessel endothelial cells. (From Biggs HM, Behravesh
CB, Bradley KK, et al: Diagnosis and management of tickborne rickettsial
diseases: Rocky Mountain spotted fever and other spotted fever group
rickettsioses, ehrlichioses, and anaplasmosis—United States, MMWR
Recomm Rep 65:1–44, 2016, Fig. 20.)
1624 Part XVI ◆ Infectious Diseases
CD8 T lymphocytes and interferon-γ–producing natural killer cells,
accompanied by rickettsia antibody, helps control the infection. The
timing and balance between rickettsia-mediated increases in vascular
permeability and the benefits of induction of innate and adaptive
immunity are likely the major determinants of severity and outcome.
CLINICAL MANIFESTATIONS
The incubation period of RMSF in children varies from 2 to 14 days
(median: 7 days). In 49% of cases, patients or their parents report a
history of removing an attached tick, although the site of the tick bite
is usually inapparent. Epidemiologic clues include living in or visiting
an endemic area, playing or hiking in the woods, typical season, similar
illness in family members, and close contact with a dog. In patients
presenting for care, the illness is initially nonspecific, and most patients
are not diagnosed during their first visit with a healthcare practitioner.
Manifestations often (>50%) include fever, rash (frequently involving
the palms or soles), nausea and vomiting, and headache, and less often
(<50%) myalgias, abdominal pain, diarrhea, conjunctival injection,
altered mental status, lymphadenopathy, and peripheral edema. Pain
and tenderness of calf muscles are particularly common in children.
The typical clinical triad of fever, headache, and rash is observed
in 58% of pediatric patients overall, and rash involving soles and palms
first appearing after day 3 is associated with significantly higher risk of
death among Mexican children. Fever and headache persist if the illness
is untreated. Fever can exceed 40°C (104°F) and can remain persistently
elevated or can fluctuate dramatically. Headache is severe, unremitting,
and unresponsive to analgesics.
Rash usually appears after only 1-2 days of illness, and an estimated
3–5% of children never develop a rash that is recognized. Initially,
discrete, pale, rose-red blanching macules or maculopapules appear;
characteristically this initial rash is observed on the extremities, including
the wrists, ankles, or lower legs (Fig. 255.4). In 65% of patients, the
initial rash spreads rapidly to involve the entire body, including the
soles and palms. The rash can become petechial or even hemorrhagic,
sometimes with palpable purpura.
In severe disease, the petechiae can enlarge into ecchymoses, which
can become necrotic (Fig. 255.5). Severe vascular obstruction secondary
to the rickettsial vasculitis and thrombosis is uncommon but can result
in gangrene of the digits, earlobes, scrotum, nose, or an entire limb.
Central nervous system infection usually manifests as changes in
mental status (33%) or as photophobia (18%), seizure (17%), or men-
ingismus (16%). Patients can also manifest ataxia, coma, or auditory
Fig. 255.4 Maculopapular rash with central petechiae associated with
Rocky Mountain spotted fever. (From Biggs HM, Behravesh CB, Bradley
KK, et al: Diagnosis and management of tickborne rickettsial diseases:
Rocky Mountain spotted fever and other spotted fever group rickettsioses,
ehrlichioses, and anaplasmosis—United States, MMWR Recomm Rep
65:1–44, 2016, Fig. 21.)
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deficits. Cerebrospinal fluid parameters are usually normal, but one-third
have pleocytosis (<10-300 cells/μL), either mononuclear or less often
neutrophil-dominated. Some (20%) have elevated protein (<200 mg/
dL) in the cerebrospinal fluid; hypoglycorrhachia is rare. Neuroimaging
studies often reveal only subtle abnormalities. However, with advanced
disease and neurologic signs, a unique but nonspecific “starry sky”
appearance may be observed on brain MRI that reflects the same systemic
vasculitis observed with skin lesions.
Other
Pulmonary disease occurs more often in adults than in children. However,
33% of children examined have a chest radiograph interpreted as an
infiltrate or pneumonia. The clinical presentation in these cases can
manifest as rales, infiltrates, and noncardiogenic pulmonary edema.
Other findings can include conjunctival suffusion, periorbital edema,
dorsal hand and foot edema, and hepatosplenomegaly. Severe disease
can include myocarditis, acute renal failure, and vascular collapse.
Persons with glucose-6-phosphate dehydrogenase deficiency are at
increased risk for fulminant RMSF, defined as death from R. rickettsii
infection within 5 days. The clinical course of fulminant RMSF is
characterized by profound coagulopathy and extensive thrombosis
leading to kidney, liver, and respiratory failure. Features associated with
increased risk of death include altered mental status, admission to an
intensive care unit, need for inotropic support, coma, and need for
rapidly administered intravenous fluid.
Occasionally, clinical signs and symptoms suggest a localized process
such as appendicitis or cholecystitis. Thorough evaluation usually reveals
evidence of a systemic process, and unnecessary surgical interventions
are avoided.
LABORATORY FINDINGS
Laboratory abnormalities are common but nonspecific. Thrombocyto-
penia occurs in 60%, and the total white blood cell count is most often
normal, with leukocytosis in 24% and leukopenia in 9%. Other char-
acteristic abnormalities include a left-shifted leukocyte differential,
anemia (33%), hyponatremia (<135 mEq/mL in 52%), and elevated
serum aminotransferase levels (50%).
DIAGNOSIS
Delays in diagnosis and treatment are associated with severe disease
and death. Because no reliable diagnostic test is readily available to
confirm RMSF during acute illness, the decision to treat must be based
on compatible epidemiologic, clinical, and laboratory features. RMSF
should be considered in patients presenting spring through fall with
an acute febrile illness accompanied by headache and myalgia
Fig. 255.5 Late-stage petechial purpuric rash involving the sole of
the foot in a patient with Rocky Mountain spotted fever. (From Biggs
HM, Behravesh CB, Bradley KK, et al: Diagnosis and management of
tickborne rickettsial diseases: Rocky Mountain spotted fever and other
spotted fever group rickettsioses, ehrlichioses, and anaplasmosis—United
States, MMWR Recomm Rep 65:1–44, 2016, Fig. 22.)
 Chapter 255
(particularly if they report exposure to ticks or contact with a dog or
have been in forested or tick-infested rural areas). A history of tick
exposure, a rash (especially if on the palms or soles), a normal or low
leukocyte count with a marked left shift, a relatively low or decreasing
platelet count, and a low serum sodium concentration are all clues that
can support a diagnosis of RMSF. In patients without a rash or in
dark-skinned patients in whom a rash can be difficult to appreciate,
the diagnosis can be exceptionally elusive and delayed. One half of
pediatric deaths occur within 9 days of onset of symptoms. Thus,
treatment should not be withheld pending definitive laboratory results
for a patient with clinically suspected illness. Further, prompt response
to early treatment is diagnostically helpful.
If a rash is present, a vasculotropic rickettsial infection can be
diagnosed as early as day 1 or 2 of illness with biopsy of a petechial
lesion and immunohistochemical or immunofluorescent demonstration
of specific rickettsial antigen in the endothelium. Although very specific,
the sensitivity of this method is probably 70% at most. Furthermore,
it can be adversely influenced by prior antimicrobial therapy, suboptimal
selection of skin lesions for biopsy, and examination of insufficient
tissue because of the focal nature of the infection. Tissue or blood can
also be evaluated for R. rickettsii nucleic acids by polymerase chain
reaction (PCR) at the CDC and selected public health or reference
laboratories; PCR on blood is less sensitive than PCR on tissue and of
similar sensitivity to tissue immunohistology, probably because the level
of rickettsemia is generally very low (<6 rickettsiae/mL). Since eschars
are rare with RMSF, scab scrapings or skin swabs are not useful specimens
for the detection of rickettsemia by PCR.
Definitive diagnosis is most often accomplished by serology, which
is retrospective, because a rise in titer is not seen until after the 1st wk
of illness. The gold standard for the diagnosis of RMSF is a 4-fold
increase in immunoglobulin G antibody titer by indirect fluorescent
antibody assay between paired acute and convalescent (at 2-4 wk) sera
or demonstration of seroconversion with a minimum convalescent titer
higher than the positive cutoff (e.g., 128). A single titer is neither sensitive
(patients can die before seroconversion) nor specific (an elevated titer
can represent prior infection). Despite the historic role of IgM testing,
its role in early diagnosis has recently become controversial and cannot
be advocated. With current serologic methods, RMSF cannot be reliably
distinguished from other spotted fever group rickettsiae infections. Cross
reactions with typhus group rickettsiae also occur, but titers may be
lower for the typhus group. Cross reactions are not seen with Ehrlichia
or Anaplasma infections. Currently, ELISA serologic methods can only
provide “probable” rather than confirmed evidence of infection. Weil-Felix
antibody testing should not be performed, because it lacks both sensitivity
and specificity. RMSF and other spotted fever group rickettsioses are
reportable diseases in the United States.
DIFFERENTIAL DIAGNOSIS
Other rickettsial infections are easily confused with RMSF, especially all
forms of human ehrlichiosis and murine typhus and novel spotted fever
group rickettsioses that result from R. parkeri or “R. philipii str. 364D”
infections. RMSF can also mimic a variety of other diseases, such as
meningococcemia and enteroviral infections. Negative blood cultures
can exclude meningococcemia. PCR can differentiate enterovirus from
R. rickettsii in patients with aseptic meningitis and cerebrospinal fluid
pleocytosis. Other diseases in the differential diagnosis are typhoid
fever, secondary syphilis, Lyme disease, leptospirosis, rat-bite fever,
scarlet fever, toxic shock syndrome, rheumatic fever, rubella, parvovirus
infection, Kawasaki disease, idiopathic thrombocytopenic purpura,
thrombotic thrombocytopenic purpura, Henoch-Schönlein purpura,
hemolytic uremic syndrome, aseptic meningitis, acute gastrointestinal
illness, acute abdomen, hepatitis, infectious mononucleosis, hemo-
phagocytic and macrophage activation syndromes, dengue fever, and
drug reactions.
TREATMENT
The time-proven effective therapies for RMSF are tetracyclines and
chloramphenicol. The treatment of choice for suspected RMSF
in patients of all ages, including children under 8 years of age, is
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◆ Spotted Fever Group Rickettsioses 1625
doxycycline (4 mg/kg/day divided every 12 hr PO or IV; maximum:
200 mg/day). Tetracycline (25-50 mg/kg/day divided every 6 hr PO;
maximum: 2 g/day) is an alternative. Chloramphenicol (50-100 mg/
kg/day divided every 6 hr IV; maximum: 4 g/day) should be reserved
for patients with doxycycline allergy and for pregnant women, because
chloramphenicol is an independent risk factor for increased mortality
vs tetracyclines. If used, chloramphenicol should be monitored to
maintain serum concentrations of 10-30 μg/mL. Chloramphenicol is
preferred for pregnant women because of potential adverse effects of
doxycycline on fetal teeth and bone and maternal liver function. RMSF
is a life-threatening illness for which prompt therapy is imperative, and
multiple recent studies demonstrate a negligible risk for tooth discolor-
ation in children younger than 8 yr of age with the use of doxycycline.
Chloramphenicol is rarely associated with aplastic anemia and is no
longer available as an oral preparation in the United States. An additional
benefit of doxycycline over chloramphenicol is its effectiveness against
potential concomitant Ehrlichia or Anaplasma infection. Sulfonamides
should not be used, because they are associated with greater morbidity
and mortality with all rickettsial infections. Other antibiotics, includ-
ing penicillins, cephalosporins, and aminoglycosides, are not effective.
The use of alternative antimicrobial agents, such as fluoroquinolones
and the macrolides (azithromycin and clarithromycin), has not been
evaluated.
Therapy should be continued for a minimum of 5-7 days and until
the patient has been afebrile for at least 3 days. Treated patients usually
defervesce within 48 hr, so the duration of therapy is usually <10 days.
SUPPORTIVE CARE
Most infections resolve rapidly with appropriate antimicrobial therapy
and do not require hospitalization or other supportive care. Among
those hospitalized, 36% require intensive care. Particular attention to
hemodynamic status is mandatory in severely ill children, because
iatrogenic pulmonary or cerebral edema could be easily precipitated
owing to diffuse microvascular injury of the lungs, meninges, and brain.
Judicious use of corticosteroids for meningoencephalitis has been
advocated by some, but no controlled trials have been conducted.
COMPLICATIONS
Complications of RMSF include noncardiogenic pulmonary edema from
pulmonary microvascular leakage, cerebral edema from meningoen-
cephalitis, and multiorgan damage (hepatitis, pancreatitis, cholecystitis,
epidermal necrosis, and gangrene) mediated by rickettsial vasculitis
and/or the accumulated effects of hypoperfusion and ischemia (acute
renal failure). Long-term neurologic sequelae can occur in any child
with RMSF but are more likely to occur in those hospitalized for ≥2 wk.
Examples of neurologic sequelae include speech or swallowing disorders;
global encephalopathy; cerebellar, vestibular, and motor dysfunction;
hearing loss; and cortical blindness. Learning disabilities and behavioral
problems are the most common neurologic sequelae among children
who have survived severe disease.
PROGNOSIS
Delays in diagnosis and therapy are significant factors associated with
severe illness or death. Before the advent of effective antimicrobial
therapy for RMSF, the case fatality rate was 10% for children and 30%
for adults. The overall case fatality rate decreased to an historic low
(0.3–0.4%) from 2003 to 2012; however, many experts attribute this
decrease to detection and reporting of other less virulent emerging
forms of spotted fever group rickettsioses that cannot be readily dif-
ferentiated from RMSF using current serologic tests. The overall case
fatality rate of children 5-9 yr of age was 2.4%, and rates as high as
8.5% and 11.8% were documented in Texas (1986–1996) and in Arizona
(1999–2007), respectively, and rates as high as 30–40% are now reported
from outbreaks in Mexico. Diagnosis based on serology alone under-
estimates the true mortality of RMSF, because death often occurs within
14 days (before developing a serologic response). Deaths occur despite
the availability of effective therapeutic agents, indicating the need for
clinical vigilance and a low threshold for early empiric therapy. Even
with administration of appropriate antimicrobials, delayed therapy can
1626 Part XVI ◆ Infectious Diseases
lead to irreversible vascular or end-organ damage and long-term sequelae
or death. Early therapy in uncomplicated cases usually leads to rapid
defervescence within 1-3 days and recovery within 7-10 days. A slower
response may be seen if therapy is delayed. In those who survive despite
no treatment, fever subsides in 2-3 wks.
PREVENTION
No vaccines are available. Prevention of RMSF is best accomplished by
preventing or treating tick infestation in dogs, avoiding areas where ticks
reside, using insect repellents containing N, N-diethyl-3-methylbenzamide
(DEET) or new alternatives (https://www.epa.gov/insect-repellents/find-
repellent-right-you), wearing protective clothing, and carefully inspecting
children after play in areas where they are potentially exposed to ticks.
Recovery from infection yields lifelong immunity.
Prompt and complete removal of attached ticks helps reduce the risk
for transmission because rickettsiae in the ticks need to be reactivated
to become virulent, and this requires at least several hours to days of
exposure to body heat or blood. Contrary to popular belief, the application
of petroleum jelly, 70% isopropyl alcohol, fingernail polish, or a hot
match are not effective in removing ticks. A tick can be safely removed
by grasping the mouth parts with a pair of forceps at the site of attachment
to the skin and applying gentle and steady pressure to achieve retraction
without twisting, thereby removing the entire tick and its mouth parts.
The site of attachment should then be disinfected. Ticks should not be
squeezed or crushed, because their fluids may be infectious. The removed
tick should be soaked in alcohol or flushed down the toilet, and hands
should be washed to avoid accidental inoculation into conjunctivae,
mucous membranes, or breaks in skin. Typically, prophylactic antimi-
crobial therapy is not recommended because tetracyclines and chlor-
amphenicol are only rickettsiastatic; however, the evidence to support
this position is meager.
Bibliography is available at Expert Consult.
255.2 Mediterranean Spotted Fever
or Boutonneuse Fever
(Rickettsia conorii)
Megan E. Reller and J. Stephen Dumler
MSF or boutonneuse fever is caused by R. conorii and its related subspe-
cies; it is also called by other names, such as Kenya tick typhus, Indian
tick typhus, Israeli spotted fever, and Astrakhan fever. It is a moderately
severe vasculotropic rickettsiosis in adults but comparatively milder in
children, with more frequent lymphadenopathy; often, MSF is initially
associated with an eschar at the site of the tick bite. Minor differences
in clinical presentation could be associated with genetic diversity of the
rickettsial subspecies.
ETIOLOGY
MSF is caused by systemic endothelial cell infection by the obligate
intracellular bacterium R. conorii. Similar species are distributed globally,
such as R. sibirica, R. heilongjiangensis, and R. mongolotimonae in Russia,
China, Mongolia, and Pakistan; R. australis and R. honei in Australia;
R. japonica in Japan; R. africae in South Africa; and R. parkeri and “R.
philippi str. 364D” in the Americas (see Table 255.1). Analysis of antigens
and related DNA sequences show that all are closely related within a
broad genetic clade that includes spotted fever group Rickettsia species
such as R. rickettsii, the cause of RMSF.
EPIDEMIOLOGY
R. conorii is distributed over a large geographic region, including India,
Pakistan, Russia, Ukraine, Georgia, Israel, Morocco, southern Europe,
Ethiopia, Kenya, and South Africa. Reported cases of MSF in southern
Europe have steadily increased since 1980, and the seroprevalence is
11–26% in some areas. The peak in reported cases occurs during July
and August in the Mediterranean basin; in other regions it occurs during
warm months when ticks are active.
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TRANSMISSION
Transmission occurs after the bite of the brown dog tick, R. sanguineus,
or for other Rickettsia spp. tick genera such as Dermacentor, Haema-
physalis, Amblyomma, Hyalomma, and Ixodes. Clustering of human
cases of boutonneuse fever, infected ticks, and infected dogs implicate
the household dog as a potential vehicle for transmission.
PATHOLOGY AND PATHOGENESIS
The underlying pathology seen with MSF is nearly identical to that of
RMSF, except that eschars are often present at the site of tick bite where
inoculation of rickettsiae occurs. The histopathology of the resultant
lesion includes necrosis of dermal and epidermal tissues with a superficial
crust; a dermis densely infiltrated by lymphocytes, histiocytes, and
scattered neutrophils; and damaged capillaries and venules in the dermis.
Immunohistochemical stains and nucleic acid amplification tests confirm
that the lesions contain rickettsia-infected endothelial cells, and poten-
tially other cells such as macrophages. The necrosis results from both
direct rickettsia-mediated vasculitis and resultant extensive local
inflammation. Thus, rickettsiae have ready access to lymphatics and
venous blood and disseminate to cause systemic disease.
CLINICAL MANIFESTATIONS AND
LABORATORY FINDINGS
Typical findings in children include fever (37–100%), a maculopapular
rash that appears 3-5 days after onset of fever (94–100%), hepatospleno-
megaly (20–83%), myalgias and arthralgias (10–42%), headache (8–63%),
nausea, vomiting, or diarrhea (5–28%), and lymphadenopathy (52–54%).
In 60–90% of patients, a painless eschar or tache noire appears at the
site of the tick bite, often on the scalp, with accompanying regional
lymphadenopathy (50–60%) (Fig. 255.6). The infection can be severe,
mimicking RMSF, although morbidity and fatalities in children are less
frequent than in adults. Findings can include seizures, purpuric skin
lesions, meningitis and neurologic deficits, respiratory and/or acute
renal failure, and severe thrombocytopenia. Even though the case fatality
rate can be as high as 10% in adults and severe infections occur in
approximately 9% of children, pediatric deaths are rare. As with RMSF,
a particularly severe form occurs in patients with glucose-6-phosphate
dehydrogenase deficiency and in patients with underlying conditions
such as alcoholic liver disease or diabetes mellitus.
DIAGNOSIS
Laboratory diagnosis of MSF and related spotted fever group rickettsioses
is the same as that for RMSF. Cases can be confirmed by immunohis-
tologic or immunofluorescent or demonstration of or amplification of
nucleic acids from rickettsiae in skin biopsies, in vitro cultivation via
centrifugation-assisted shell vial tissue culture, or demonstration of
seroconversion or accompanied by a 4-fold rise in serum antibody titer
to spotted fever group rickettsiae between acute and convalescent sera.
Antibodies to spotted fever group antigens cross react, so RMSF or
other spotted fever group rickettsiosis in the United States or MSF in
Europe, Africa, and Asia cannot be distinguished by these methods.
Fig. 255.6 Various appearances of eschars associated with Rickettsia
parkeri rickettsiosis. (From Biggs HM, Behravesh CB, Bradley KK, et al:
Diagnosis and management of tickborne rickettsial diseases: Rocky
Mountain spotted fever and other spotted fever group rickettsioses,
ehrlichioses, and anaplasmosis—United States, MMWR Recomm Rep
65:1–44, 2016, Fig. 24.)