Other Systemic Infections

LEARNING OBJECTIVES

At the end of this chapter, the student should be able to:

1. Recognize the common systemic infections based on clinical

manifestations,
2. Compare and contrast dengue fever and chikungunya based on
etiology, mode of transmission, signs and symptoms, and prevention;
3. Describe the characteristics of the causative organisms of each
systemic infection;
4. Discuss the appropriate laboratory diagnosis and treatment of each
infection; and
5. Discuss the prevention and control of common systemic infections.

Dengue Fever

Dengue fever is an arthropod-borne infection and is common in the Far

East. The incidence is highest during the rainy season because the
vector, Aedes aegypti which is a household mosquito, lays its eggs in
clean stagnant water. Humans are reservoir hosts for Dengue virus.

Etiologic Agent

Dengue fever is caused by Dengue virus under the family Flaviviridae

(historically classified as Arboviruses). It is a single stranded,
enveloped RNA virus, and there are four strains of the virus.

Mode of Transmission

Dengue fever is transmitted through the bite of a female mosquito

known as Aedes aegypti which is the more effective vector in urban
areas or cities. In rural areas the vector is Aedes albopictus that breeds
in vegetations as well as banana and abaca plantations. The mosquito
is also known as Asian tiger mosquite because of the dots on its body
and stripes on its legs. It is a low-flying day-biting mosquito with short
range flights. Hence the most common sites of bites are the lower
extremities. The peak of biting is 2 to 3 hours after daylight and a few
hours before nighttime. Humans are the only known hosts.
Clinical Findings

Classical Dengue Fever

 This is manifested by abrupt onset of high-grade fever for 3 to 6 days

which then subsides and reappears after 2 to 3 days. This pattern is
described as “camel-back” or “saddle-back” pattern of fever. The fever
is accompanied by generalized and excruciating muscle and bone
pains, hence the term “break-bone fever.” Patients may also manifest
severe headache and retro-orbital pain. This is also associated with
transient punctuate rash over the knees and elbows referred to as
Herman’s sign (Figure 24.2). On the 3rd to 5th day, the rash becomes
morbilliform or scarlatiniform over the trunk, face, and extremities.
There is also generalized lymphadenopathy and leucopenia.

Dengue Hemorrhagic Fever (DHF) or Shock Syndrome (DSS)

 This occurs when a patient who had previous infection with one
serotype of the virus becomes infected by a different serotype. There is
a tendency for bleeding and shock due to increased amounts of
cytokines that causes increased vascular permeability and plasma
leakage. It has been observed that the risk for DSS or DHF is more
likely in cases of secondary infection with serotype 2 after a previous
infection with serotype 1 of the virus. The third and fourth infections
are usually associated with a milder clinical course.
 During the early phase of the infection, the patient presents with
classical dengue fever. Two to five days later, the infection worsens
with manifestations of prostration, restlessness, facial flushing,
abdominal pain, and dehydration. Signs and symptoms of bleeding are
also present like appearance of petechiae, epistaxis, hematemesis or
melena, purpura, or ecchymosis. Hepatomegaly may also be present
indicating posible development of hepatitis. Development of DHF
usually occurs if the patient is bitten again by a mosquito that carries a
different strain of the virus than that which caused the first infection.
The bleeding manifestations can be attributed to the decrease in
platelet count (thrombocytopenia) due to type III hypersensitivity
reaction elicited by the virus. As bleeding or third space loss continues,
the patient may manifest signs and symptoms of circulatory collapse
(DSS) such as cold extremities and tachycardia.
  The World Health Organization case definition of DHF includes: (1)
fever, (2) hemorrhagic manifestations, (3) thrombocytopenia (platelet
count ≤ 100,000/ ca mm, and (4) hemoconcentration (increase in
hematocrit).

Laboratory Diagnosis

The diagnosis is mainly based on the clinical manifestations and blood

picture of the patient. Culture and identification using living cells like
suckling mice and mosquito cell lines are done but not usually
requested. Serology (MAC-ELISA, complement fixation, hemagglutinin
inhibition) can also be done for the isolation and identification of the
virus. Detection of viral nucleic acid and antigens can be achieved with
the use of PCR.

Treatment

There is no specific treatment for dengue. Management of the infection

is supportive care.

Prevention and Control

A vaccine against dengue (Dengvaxia) has been developed and

became commercially available in the Philippines, Mexico, Brazil, Peru,
Indonesia, Singapore, Thailand, Guatemala, El Salvador, Costa Rica,
and Paraguay which are all endemic for dengue. The vaccine
(Dengvaxia or also known as CYD-TDV) was developed by Sanofi
Pasteur. It is a live recombinant tetravalent dengue vaccine from
yellow fever 17D vaccine strain. The vaccine should be given in a
series of 3 doses every 6 months. It is recommended to be given to
seropositive individuals (those who had previous dengue infection).

Prevention is mainly focused on education of the public, active

surveillance of cases, and mosquito control. Mosquito control by larval
source reduction (destroying the breeding places of the mosquito) is
the best way of preventing the disease. Secondary preventive
measures include prevention of mosquito bites by applying mosquito
repellants, wearing thick clothing, and screening windows and doors.
Fogging is no longer recommended as it does not really destroy the
mosquitoes but merely drives them away.
Chikungunya

Chikungunya is a re-emergent infection caused by alphavirus (Simliki

Forest virus) that belongs to the family Flaviviridae. It is transmitted
through bite of the mosquito Aedes aegypti. It is similar to dengue
fever based on benign clinical syndrome of break-bone fever, but
without retro-orbital pain and only mild headache. Unlike dengue, it
presents with more severe muscle and joint pains that the patient
literally folds up. Sequelae of chikungunya are crippling joint pain and
hemorrhagic fever.

Features Dengue Fever Chikungunya

Etiology Dengue Virus Flavivirus Alphavirus Flavivirus
Vector Aedes aegypti (rural) Aedes aegypti (rural)
Aedes albopictus Aedes albopictus
(urban) (urban)
Incubation Period 2-7 days 2-4 days
Age Group All ages All ages
% Symptomatic 20%-60% 70%
Symptoms
Fever Present Present
Headache Severe Mild
Rash Present Present
Retroorbital pain Present Absent
Joint pain Present More severe
Sequelae DHF or DSS Crippling arthritis
Vaccine Yes None

Zika

Zika virus infections are already in existence in Southeast Asia, Africa,

and the Pacific Idands. For a long time there had never been any
reported case of Zika infection until 2015 an outbreak was confirmed in
newborns
  Etiology

Zika is caused by the Zika virus under the family Flaviviridae. It is

single stranded RNA virus with an envelope.

Modes of Transmission

1. Bite of mosquito – Aedes aegypti and Aedes albopictus are two species
of mosquito that can carry the virus.
2. Mother to fetus – Zika virus can be passed to the fetus from the
pregnant mother during pregnancy. The Zika virus has been proven to
cause microcephaly and other severe fetal brain defects.
3. Sexual contact – Zika virus can be spread by an infected man to his
sexual partner even before the appearance of symptoms. Studies have
shown that the virus is present in semen longer than in blood.
4. Blood transfusion – the virus can also be transmitted by blood
transfusion, requiring blood from donors to be tested for the virus. A
significant number of blood donors tested positive for Zika in Brazil and
Polynesian countries.

Clinical Findings

Zika does not cause any symptoms or may cause only mild symptoms
that may last for several days to a week. If symptomatic, the common
manifestations are fever, headache, joint pain, muscle pain,
conjunctivitis, or a rash. Severe disease is uncommon. An infected
person is protected from future infections after recovery.

Treatment and Prevention

There is no treatment for Zika. The treatment is supportive like rest

and plenty of fluids. Prevention includes vector control, practicing safe
sex, and screening of blood donors.

Infectious Mononucleosis

 Etiology

The causative agent is Epstein-Barr virus (EBV), a double-stranded,

enveloped DNA virus under the family of Herpesviridae. The B
lymphocytes are the major targets of EBV. The virus can cause latent
infection of the B cells. This agent is oncogenic and capable of
 immortalizing and transforming infected cells. It is strongly associated
with transformation to nasopharyngeal carcinoma, Burkitt’s lymphoma,
and other B-cell lymphomas. The virus causes an opportunistic
infection in the tongue and mouth (hairy cell oral leukoplakia) in AIDS
patients. EBV stimulates cell growth as B cell mitogen and prevents
apoptosis causing immortalization of B cells.

 Mode of Transmission

EBV is primarily transmitted through the exchange of saliva, hence, the

infection is also known as “kissing disease.”

 Clinical Findings

The incidence is highest among adolescents and young adults. The

infection is manifested by clinical triad of sore throat,
lymphadenopathy, and splenomegaly with associated fever, anorexia,
and lethargy, Hepatitis is also common (hepatosplenomegaly).

 Diagnosis

Diagnosis can be obtained by hematologic examination which shows

lymphocytosis with atypical lymphocytes known as Downey cells.
Detection of antibodies against the viral capsid antigen is an important
diagnostic tool. Serologic tests like a positive heterophil antibody test
is also useful for early detection.

 Treatment and Prevention

There is no specific antiviral drug or vaccine for EBV.

Cytomegalovirus Infection

Cytomegalovirus (CMV) is a double-stranded DNA virus under the

Herpesviridae family and the largest among the Herpesviruses. It
causes enlargement of the infected cells (cytomegaly). Infections with
this virus are common, primarily affecting newborns, normal healthy
adults, and immunocompromised individuals. CMV establishes latency
in monocytes, myeloid stem cells, lymphocytes, macrophages, and
 other cells. It can be isolated in the blood, saliva, stool, tears, throat,
semen, vaginal and cervical secretions, and amniotic fluids and tissues.

 Modes of Transmission

Since CMV can be isolated or is present in body fluids and tissues, the
virus can be transmitted through the oral route, sexual contact, tissue
transplantation, and blood transfusion. The virus may also spread
through congenital transmission.

Clinical Syndromes

 Congenital and Neonatal Infections

Cytomegalovirus is the most common viral cause of congenital

infections and mental retardation. Approximately 90% of cases are
asymptomatic. The remaining 10% present with congenital
abnormalities such as microcephaly, mental retardation, visual
defects like cataract and glaucoma, deafness, hepatosplenomegaly,
rash, and congenital heart defect. Neonatal CMV infections are
acquired during delivery as the infant passes through the birth
canal, from the mother’s milk, or through blood transfusion. Infected
newborns continue to excrete the virus through the feces for
months after infection.

 Mononucleosis-like Syndrome

Mononucleosis-like syndrome may be asymptomatic or may present

as mild mononucleosis syndrome similar to Epstein-Barr virus
(fever, mild pharyngitis, and lymphadenopathy) but unlike EBV, CMV
is negative for heterophil antibodies. A comparison between EBV
and CMV mononucleosis syndrome is summarized in Table 24.2.

Features Mononucleosis-like Infectious

Syndrome (CMV) Mononucleosis (EBV)
Etiology Cytomegalovirus Epstein-Barr Virus
Mode of transmission Oral secretions Oral secretions
Fever Present but milder Present
lymphadenopathy
Sore throat Present but milder Present
Hepatosplenomegaly Present Present
Lymphocytosis Present Present
Atypical lymphocytes Present Present
 Heterophil antibody Negative Positive
test

Infection in Immunocompromised Patients

CMV commonly causes chorioretinitis (common in AIDS patients),

encephalitis, pneumonia, and esophagitis. CMV is a common pathogen in
bone marrow transplant patients.

Laboratory Diagnosis

Diagnosis of the disease can be done by means of the following:

1. Histological examination of tissues and urine. Specific intracellular

inclusion bodies called “owl’s eye” inclusions are histologic hallmarks
of CMV infection.
2. Culture in fibroblast cells.
3. Serological detection of IgM and IgG antibodies to CMV antigens.

Treatment and Prevention

The drug recommended for CMV is ganciclovir. An alternative drug is

foscarnet. CMV infections can be prevented by using mechanical barriers like
condoms. Avoidance of unusual sexual practices such as unprotected anal
sex is also important since sexual contact is a common route of transmission.
Blood and organ donors should also be screened for CMV. There is an
available vaccine for CMV which is a live, attenuated vaccine.

Rickettsial Infections

Rickettsial infections are transmitted by the bite of arthropods like

ticks, mites, lice, and fleas except for Q fever, which is transmitted by
inhalation of aerosols. Rickettsial infections are zoonotic (with animal
reservoirs) except for Epidemic typhus which occurs only in humans.
Rickettsial infections are divided into six groups, namely: (1) Typhus
Group - Epidemic typhus, Murine typhus (Endemic typhus), and Scrub
typhus; (2) Spotted Fever Group-Rocky Mountain Spotted Fever, (3)
Traditional group- Rickettsialpox; (4) Q Fever, (5) Trench fever, and (6)
Ehrlichiosis.
 The Spotted Fever group is characterized by rashes that appear first on
the extremities, with involvement of the palms and soles. The Typhus
group is also characterized by maculopapular rashes that are
prominent in the trunk and extremities with sparing of the palms and
soles.

General Characteristics

1. Very small size (0.3 x 1-2 um)

2. Have gram-negative cell wall composed of peptidoglycan, muramic acid,

and diaminopimelic acid

3. Stain poorly with Gram stain but stain well using Giemsa or Gimenez stain

4. Pleomorphic cocci or short bacilli

5. Obligate intracellular parasites

6. Transmitted by arthropod vector except Q fever

7. Easily destroyed by heating, dyeing, and bactericidal agents like

tetracycline

8. Growth enhanced by sulfonamides

Disease Etiology Vector

Rocky Mountain Rickettsia rickettsil Tick
Spotted
Rickettsialpox Rickettsia akari Mite
Epidemic typhus Rickettsia prowazekil Louse
Murine typhus Rickettsia typhi Flea
Scrub typhus Orientia tsutsugamushi Mite
Ehrlichiosis
Human monocyte Ehrlichia chaffeensis Tick
ehrlichiosis
Human Anaplasma Tick
granulocyte phagocytophilum
ehrlichiosis Ehrlichia ewingil Tick
Ewingii
ehrlichiosis
Q fever Coxiella burnetii None
Spotted Fever Group

 Rocky Mountain Spotted Fever

The causative agent is Rickettsia rickettsii and is transmitted through

the bite of ticks. This is common in the mountainous areas of the
United States. The early manifestations are similar to Rickettsialpox.
Maculopapular rashes appear on the hands and feet, then later in the
trunk in the following 2-6 days.

Typhus Group

 Epidemic Typhus (Louse-borne Typhus)

The etiologic agent is Rickettsia prowazekii and is transmitted through

the bite of lice. The manifestations are similar to the other rickettsial
infections, with the same non-specific symptoms and maculopapular
rashes, although there is sparing of the palms and soles. It also
presents with more severe systemic infection and prostration, and is
 more fatal. This is associated with a recrudescent infection known as
Brill-Zinsser Disease.

 Endemic Typhus (Murine Typhus)

The etiologic agent is Rickettsia typbi which is transmitted by the bite

of a flea. This presents with similar features as Epidemic typhus
however it is milder and rarely fatal except in the elderly.

 Scrub Typhus

The causative organism is Orientia tsutsugamushi (formerly known as

Rickettsia tsutsugamushi). This is transmitted through the bite of
mites. This infection resembles Epidemic typhus clinically except for
the eschar (punched out ulcer covered with blackened scab that
indicates the site of the mite bite) with associated generalized
lymphadenopathy and lymphocytosis. The disease may also involve
severe cardiac and cerebral complications.

Traditional Group

 Rickettsialpox

The etiologic agent is Rickettsia akari and is transmitted through the

bite of mites. It is a mild disease resembling Varicella. The infection is
manifested by fever, headache, chills, myalgia, and the appearance of
a firm red macule at the bite site which later develops into a deep-
seated vesicle that ruptures and presents with a blackened scab known
as eschar.

 Q Fever (Query Fever)

The etiologic agent Coxiella burnetti, transmitted by inhalation of dust

containing the organism or aerosols. The infection resembles influenza
and non-bacterial pneumonia, hepatitis, or encephalopathy. The
infection does not present any rash or local lesion.

 Ehrlichiosis

The disease is caused by Ebrlichia sennetsu for Sennetsu Fever and

Ehrlichia chaffeensis for Human Ehrlichiosis. These organisms
parasitize lymphocytes, neutrophils, and monocytes, and manifest non-
specific symptoms with thrombocytopenia.
 Leptospirosis

Etiologic Agent

Leptospirosis is caused by a spirochete Leptospira interrogans.

This spirochete is tightly-coiled with a hook on one or both ends
and is highly motile. The reservoir hosts are rats and other
rodents (most common reservoir), household pets, and livestock
(accidental hosts). Leptospira is excreted in the urine of reservoir
hosts and contaminate soil and water. The infection is worldwide
in distribution.

Mode of Transmission

Since leptospira excreted with urine can contaminate water and

soil, it is commonly acquired when the organism enters through
breaks in the skin or mucous membrane by wading or swimming
in contaminated water. It can also be transmitted through
ingesting contaminated water and food. Individuals at risk of the
infection are sewage workers, farmers, and miners.

Clinical Syndrome

Leptospirosis is a biphasic infection. It initially presents flu-like

symptoms of fever, severe headache, myalgia, and chills. These
symptoms will recede for a short period. This will then be
followed by the immune period and manifest with signs and
symptoms of meningitis, In severe cases, the meningitis is
associated with impaired renal function and liver damage (Weil’t
disease or infective jaundice). Patients who survive the infection
may recover from the renal failure and hepatic damage.

Laboratory Diagnosis

Leptospira cannot be stained with dyes but can be visualized

using darkfield microscopy. Aside from the clinical findings,
diagnosis is confirmed by an increase in agglutinating antibodies.

Treatment. Prevention, and Control

The recommended drug is penicillin. There has been no reported

development of resistance to the drug to date. The effective
prophylaxis for exposed individuals is doxycycline. The disease
 can be prevented by avoiding wading in contaminated water and
avoiding contact with contaminated soil. Rodent control is also
important in the control and prevention of the spread of
infection.

 Lyme Disease (Lyme Borreliosis)

Etiologic Agent

Lyme disease is caused by Borrelia burgdorferi, a flexible

spirochete with coarse, irregular coils. It is equipped with
endoflagella and is highly motile.

Mode of Transmission

Lyme disease is an arthropod-borne infection transmitted

through the bite of a tick (Ixodes). Reservoir of Borrelia
burgdorferi is the wood rat and the obligatory hosts are
mammals, particularly deer where the tick completes its life
cycle.

Clinical Findings

Lyme disease is a progressing disease divided into three stages.

During the first stage, a painless, circular red rash known as
erythema chronicum migrans that is spread with a clear center
at the site of the bite. This is the characteristic finding
accompanied by arthralgia. This may or may not be
accompanied by non-specific symptoms of fever, headache,
chills and fatigue. After a few weeks or months, the second stage
sets in and manifests as myocarditis or pericarditis, aseptic
meningitis, Bell’s palsy, and neuropathies. This is then followed
by a latent period lasting several weeks and months. The third
stage is manifested by arthritis involving the large joints like the
knees and a progressive chronic involvement of the central
nervous system.

Laboratory Diagnosis

Borrelia burgdorferi can be stained with Giemsa or silver stains

and can be visualized by darkfield microscopy. Culture is rarely
positive. Serological tests like ELISA or indirect
immunofluorescence are valuable in the diagnosis. Confirmatory
 test is Western Blot Assay. Polymerase chain reaction (PCR) is
also valuable in detecting Borrelia burgdorferi DNA.

Treatment and Prevention

For mild infections, effective treatment involves amoxicillin or

doxycycline. For late-stage infections, the more effective drug is
penicillin G or ceftriaxone. No resistance to the aforementioned
drugs has been reported so far.

Prevention is focused on preventing tick bites by wearing thick

clothing and application of insect repellants.

 Relapsing Fever

Etiologic Agent

Borrelia recurrentis is the major etiologic agent for Relapsing

Fever. Other Borreliae like B. bermsii can also cause the infection.
The organism is very flexible and highly motile (motility is
rotatory and twitching). The organism can survive low
temperature (4°C) in blood or culture for months.

Mode of Transmission

Relapsing fever is transmitted from one person to another

through the bite of the human body louse (Pediculus bumanus).
The main reservoirs are rodents and other small animals. The
infection is transmitted from these reservoirs through bite of
ticks (Ornithodorus).

Clinical Findings

During the bite, the vector introduces the organism into the skin
and multiplies in the tissues. The infection initially manifests as
fever, headache, and chills. The fever lasts for a few days and
resolves but recurs after a week with associated multi-organ
dysfunction. There are around 3-10 recurrences, with each
recurrence the manifestations become less severe.

Laboratory Diagnosis

Examination of the peripheral blood smear using Giemsa or

Wright stain will demonstrate the spirochetes. The best time for
 collecting specimen is during the height of the fever where the
spirochete is always present. Culture using special media is also
useful in the diagnosis. Serological tests however are not useful
in the diagnosis.

Treatment and Prevention

An effective drug in the treatment of early infection and

prevention of relapses is tetracycline. Avoidance of areas
infested by arthropod vectors and protection from bites are
important in preventing infection.

CHAPTER SUMMARY

Dengue fever, chikungunya, and Zika fever are all caused by Flaviviruses and
all are arthropod-borne infections acquired through bite of mosquitoes-Aedes
aegypti and Aedes albopictus.

Dengue fever and chikungunya are both manifested by joint pains (break-
bone fever) but the joint pain is more severe in chikungunya.
Secondary infection with another strain or serotype of dengue virus can lead
to dengue hemorrhagic fever or dengue shock syndrome which can be fatal.

Zika is a re-emerging infection. Most cases are asymptomatic. Aside from

mosquito bite, it can also be transmitted from the infected mother to the
fetus causing microcephaly and other brain defects.

A vaccine for dengue fever was made available but it has encountered much
controversy in the Philippines.

EBV infectious mononucleosis and CMV mononucleosis-like syndrome are

very much alike. Both are associated with lymphocytosis and formation of
atypical lymphocytes. Diagnosis can be established by heterophil antibody
test where EBV would yield a positive result.

Cytomegalovirus is the most common viral cause of congenital infection. It is

detrimental when acquired during the first trimester of pregnancy where the
various body organs are undergoing development. The congenital infection is
manifested by microcephaly, mental retardation, cataract, deafness, and
congenital heart defect.

Rickettsial infections are also arthropod-borne infections acquired through

bites of ticks, mites, lice, or fleas except Q fever which is transmitted through
the respiratory route. All infections present with maculopapular rashes
except rickettsialpox which is vesicular with eschar formation.

Among the rickettsial infections, only epidemic typhus caused by Rickettsia

prowazekii is associated with recrudescent infection, Brill Zinsser disease.

Both rickettsiapox and scrub typhus are manifested by eschar.

Leptospirosis is caused by Leptospira interrogans, a spirochete with fine

regular coils and hook on one or both ends. The infection is associated with
urine of rodents and other animals and acquired through breaks in the skin
and mucous membrane.

Lyme disease and relapsing fever are both arthropod-borne infections caused
by Borrelia burgdorferi and Borrelia recurrentis respectively.

Both Leptospira and Borrelia are highly flexible and highly motile organisms.

The best control measures for arthropod-borne infections is prevention and

protection from arthropod bites and vector control.