Acute Febrile Illnesses

HAMZE WABARI
MD
 Outline of Presentation
Typhoid fever

Relapsing fever

Typhus fever

Malaria
 Enteric Fever (Typhoid Fever)
Enteric fever (more commonly termed typhoid fever )
remains endemic in many developing countries.

Given the ease of modern travel, cases are regularly

reported from most developed countries, usually from
returning travelers.
 Etiology
S. enterica serovar Typhi (S. Typhi), a gram-negative
bacterium.

A very similar but often less severe disease is caused by

Salmonella Paratyphi A and rarely by S. Paratyphi B
(Schotmulleri) and S. Paratyphi C (Hirschfeldii).

 The ratio of disease caused by S. Typhi to that caused by S.

Paratyphi is approximately 10 : 1.
 Epidemiology
More than 26.9 million typhoid fever cases occur annually,
of which 1% result in death.

The majority of this disease burden is witnessed in Asia.

The incidence of typhoid fever may vary considerably in the

developing world, with estimated rates ranging from 100-
1,000 cases per 100,000 population.

The age-specific incidence is highest in children <5 yr old, in

association with comparatively higher rates of complications
and hospitalization.
 Cont’d…
There is an increase in nalidixic acid–resistant and even
ceftriaxone-resistant isolates of S . Typhi, as well as the
emergence of fluoroquinolone-resistant isolates.

Direct or indirect contact with an infected person (sick or

chronic carrier) is a prerequisite for infection.

Ingestion of foods or water contaminated with S. Typhi from

human feces is the most common mode of transmission.
 Pathogenesis
Enteric fever occurs through the ingestion of the organism.

After ingestion, S. Typhi organisms are thought to invade the

body through the gut mucosa in the terminal ileum.

S. Typhi crosses the intestinal mucosal barrier after

attachment to the microvilli by an intricate mechanism:
Membrane ruffling,
Actin rearrangement, and
Internalization in an intracellular vacuole.
 Cont’d…
After passing through the intestinal mucosa, S. Typhi
organisms enter the mesenteric lymphoid system and then
pass into the bloodstream via the lymphatics.

This primary bacteremia is usually asymptomatic, and blood

culture results are frequently negative at this stage of the
disease.

The bloodborne bacteria are disseminated throughout the

body and are thought to colonize the organs of the RES,
where they may replicate within macrophages.
 Clinical Manifestations
The incubation period is usually 7-14 days but depends on
the infecting dose and ranges (3 and 30 days).

Low-grade fever, malaise, and slight, dry cough.

Abdominal discomfort and multiple complications.

Diarrhea, toxicity, and complications (DIC) are also more

common in infancy, resulting in higher case fatality rates.
 Cont’d…
Neurologic manifestations and GI bleeding, are rare in
children.
Common Clinical Features of Typhoid Fever in Children
 Complications
Hepatitis.
Jaundice.
Cholecystitis.
Intestinal hemorrhage (<1%) and perforation (0.5–1%).
Peritonitis.
Toxic myocarditis.
Neurologic complications: delirium, psychosis, increased ICP,
acute cerebellar ataxia, chorea, deafness, and GBS.
Other: DIC, HUS, pyelonephritis, nephrotic syndrome,
meningitis, endocarditis, parotitis, orchitis, and suppurative
lymphadenitis.
 Diagnosis
Results of blood cultures are positive in 40–60% and serial
blood cultures may be required to identify Salmonella
bacteremia.

Stool and urine culture results may become positive after

the 1st wk.

The stool culture result is also occasionally positive during

the incubation period.
 Cont’d…
Leukocytosis is common and may reach 20,000-25,000
cells/µL.

Thrombocytopenia may be a marker of severe illness and

may accompany DIC.

The classic Widal test measures antibodies against O and H

antigens of S. Typhi but lacks sensitivity and specificity in
endemic areas.
 Differential Diagnosis
Acute gastroenteritis.
Bronchitis.
Bronchopneumonia.
Malaria.
Sepsis with other bacterial pathogens;
Infections caused by tuberculosis, brucellosis, tularemia,
leptospirosis, and rickettsial diseases.
Viral infections such as Dengue fever, acute hepatitis, and
infectious mononucleosis.
 Treatment
Adequate rest, hydration, and attention are important to
correct fluid and electrolyte imbalance.

Antipyretic therapy as required and soft, easily digestible

diet should be continued.

Therapy with either chloramphenicol or amoxicillin is

associated with relapse rates of 5–15% and 4–8%,
respectively.

Azithromycin, quinolones and third-generation

cephalosporins is associated with higher cure rates.
 Prognosis
The prognosis depends on the rapidity of diagnosis and
institution of appropriate antibiotic therapy.

Other factors are:

The patient/s, age, general state of health, and nutrition;
The causative salmonella serotype; and
The appearance of complications.

Infants and children with underlying malnutrition and

patients infected with MDR isolates are at higher risk for
adverse outcomes.
 Cont’d…
Despite appropriate therapy, 2–4% of infected children may
experience relapse after initial clinical response to
treatment.

Individuals who excrete S. Typhi for ≥3 mo after infection

are regarded as chronic carriers.

A chronic urinary carrier state can develop in children with

schistosomiasis.
 Prevention
Central chlorination and domestic water purification.

Effective handwashing.

Effective immunization an important element of effective

control.
 Relapsing Fever (Borrelia)
Relapsing fever is characterized by recurring fevers and flu-
like symptoms such as headaches, myalgia, arthralgia, and
rigors.

Relapsing fever is an arthropod (lice or ticks)-transmitted

infection.
 Etiology
Caused by spirochetes of the genus Borrelia.
Louse-borne (epidemic) relapsing fever:
Caused by B. recurrentis and is transmitted from person
to person by the human body louse.

Human infection occurs as a result of crushing lice during

scratching, facilitating entry of infected hemolymph
through abraded or normal skin or mucous membranes.
 Cont’d…
Tick-borne (endemic) relapsing fever:
Caused by several species of Borrelia and is transmitted
to humans by Ornithodoros ticks.

Human infection occurs when saliva, coxal fluid, or

excrement is released by the tick during feeding.
 Epidemiology
Louse-borne relapsing fever tends to occur in epidemics
associated with war, poverty, famine, and poor personal
hygiene, often in association with typhus.

Rodents (e.g., squirrels and chipmunks) are the principal

reservoirs of Ornithodoros ticks.
 Pathogenesis
Relapsing fever is cyclical because the Borrelia organisms
undergo antigenic (phase) variation.

Multiple variants evolve simultaneously during the first

relapse, with one type becoming predominant.

During febrile episodes, spirochetes enter the bloodstream,

induce the development of specific immunoglobulin M and
G antibodies.

During remission, Borrelia spirochetes may remain in the

bloodstream, but spirochetemia is insufficient to produce
symptoms.
 Clinical Manifestations
Characterized by febrile episodes lasting 2-9 days, separated
by afebrile intervals of 2-7 days.

Louse-borne disease has an incubation period of 2-14 days,

longer periods of pyrexia, fewer relapses, and longer
remission periods than tickborne disease.

The incubation period of tickborne is 7 days (2-9 days).

Each form is characterized by sudden onset of high fever,

lethargy, headache, photophobia, nausea, vomiting, myalgia,
and arthralgia.
 Cont’d…
During the end of the primary febrile episode, a diffuse,
erythematous, macular, or petechial rash lasting up to 2 days
may develop over the trunk and shoulders.

Lymphadenopathy, pneumonia, and splenomegaly.

Hepatic tenderness with hepatomegaly.

CNS: lethargy, stupor, meningismus, convulsions, peripheral

neuritis, focal neurologic deficits, and cranial nerve paralysis.
Severe manifestations: myocarditis, hepatic failure, and DIC.
 Diagnosis
Demonstration of spirochetes by darkfield microscopy or in
thin or thick blood smears stained with Giemsa or Wright
stain and by blood culture.
Stained thin smear of a
newborn's peripheral
blood, showing the
presence of numerous
spirochetes.
 Treatment
Oral or parenteral tetracycline or doxycycline is the drug of
choice.

Erythromycin (<8yrs).

Penicillin and chloramphenicol are also effective.

 Prognosis
With adequate therapy, the mortality rate for relapsing
fever is <5%.

Pregnant women and their neonates are at increased risk

for tickborne recurrent fever.

Neonates have up to a 33% case-fatality rate.

 Prevention
No vaccine is available.

Avoidance or elimination of the arthropod vectors.

Good personal hygiene and delousing of persons, dwellings,

and clothing with insecticides.

Giving prophylactic doxycycline for 4 days after a tick bite

may prevent relapsing fever caused by B. persica.
 Epidemic (Louse-Borne) Typhus
(Rickettsia prowazekii)
Etiology
Humans are considered the principal reservoir of R.
prowazekii, the causative agent of epidemic or louse-
borne typhus.

Another reservoir exists in flying squirrels, their

ectoparasites, and potentially ticks.

R. prowazekii is the most pathogenic member of the

genus Rickettsia and multiplies to very large intracellular
quantities.
 Epidemiology
Seen in winter or spring and especially during times of poor
hygienic practices associated with crowding, war, famine,
extreme poverty, and civil strife.

Most cases of louse-borne typhus in the developed world

are sporadic, but outbreaks have been identified in Africa
(Ethiopia, Nigeria, Rwanda, and Burundi).
 Transmission
Human body lice become infected by feeding on persons
who have rickettsiae circulating in their blood.

The ingested rickettsiae infect the midgut epithelial cells of

the lice and are passed into the feces.

Then are introduced into a susceptible human host through

abrasions or perforations in the skin, through the
conjunctivae, or rarely through inhalation.
 Clinical Manifestations
Louse-borne typhus can be mild or severe in children.

The incubation period is usually <14 days.

The typical clinical manifestations: fever, severe headache,

abdominal tenderness, and rash in most patients, as well as
chills, myalgias, arthralgias, anorexia, nonproductive cough,
dizziness, photophobia, nausea, abdominal pain, tinnitus,
constipation, meningismus, visual disturbances, vomiting,
and diarrhea.
 Treatment
The treatment of choice is doxycycline.

Alternative treatments: tetracycline or chloramphenicol.

Prevention
Immediate destruction of vectors.

Antibiotic therapy and delousing measures interrupt

transmission, reduce the prevalence of infection in the
human reservoir, and diminish the impact of an outbreak.
 Malaria (Plasmodium)
Malaria is an acute illness characterized by paroxysms of
fever, chills, sweats, fatigue, anemia, and splenomegaly.

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.

It has played a major role in human history, causing harm to

more people than perhaps any other infectious disease.
 Etiology
It is caused by intracellular plasmodium transmitted to
humans by female Anopheles mosquitoes.

Species: P. falciparum, P. malariae, P. ovale, P. vivax and P.

knowlesi (a primate malaria species).

Malaria can be transmitted through blood transfusion and

use of contaminated needles and transplacentally.
 Epidemiology
Malaria is a major worldwide problem, occurring in 95
countries that comprise half the world's population.

The principal areas of transmission are Africa, Asia, and

South America.

P. falciparum and P. malariae are found in most malarious

areas.

P. falciparum is the predominant species in Africa, Haiti, and

New Guinea.
 Cont’d…
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, Europe, the Caribbean, as well as Australia,
Chile, Palestine, Japan, Lebanon, and Taiwan.
Cont’d…
 Cont’d…
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%).
 Pathogenesis
Plasmodium species exist in a variety of forms and have a
complex life cycle that enables them to survive in different
cellular environments:
Human host (asexual phase) and
Mosquito (sexual 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.
 Cont’d…
After 1-2 wk, the hepatocytes rupture and release
thousands of merozoites into the circulation.

The erythrocytic phase 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.

The trophozoite multiplies asexually to produce a number of

small erythrocytic merozoites.
 Cont’d…
Merozoites develop into male and female gametocytes that
complete the Plasmodium life cycle when they are ingested
during a blood meal.

The male and female gametocytes fuse to form a zygote in

the stomach cavity of the mosquito.

After a series of further transformations, sporozoites enter

the salivary gland of the mosquito and are inoculated into a
new host with the next blood meal.
 Clinical Manifestations
Children and adults are asymptomatic during the initial
phase of infection.

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.

Prodromal symptoms include headache, fatigue, anorexia,

myalgia, slight fever, and pain in the chest, abdomen, and
joints.
 Cont’d…
Children have nonspecific symptoms, including fever,
headache, drowsiness, anorexia, nausea, vomiting, and
diarrhea.

P. falciparum is the most severe form of malaria and is

associated with higher-density parasitemia and a number of
complications.

WHO Criteria for Severe Malaria, 2000: Impaired

consciousness, Prostration, Respiratory distress, Multiple
seizures, Jaundice, Hemoglobinuria, Abnormal bleeding,
Severe anemia, Circulatory collapse, Pulmonary edema.
 Diagnosis
Important criteria that suggest P. falciparum malaria:
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.
 Cont’d…
The concentration of erythrocytes on a thick smear is 20-40
times that on a thin smear and is used to 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.

Morphologically, it is impossible to distinguish P. knowlesi

from P. malariae, so PCR detection is required.
 Differential Diagnosis
Viral infections: influenza and Gastroenteritis.
hepatitis, yellow fever, viral Pyelonephritis.
hemorrhagic fevers.
Babesiosis.
Sepsis.
Brucellosis.
Pneumonia.
Leptospirosis.
Meningitis.
Tuberculosis.
Encephalitis,
Relapsing fever.
Endocarditis.
Typhoid fever.
Amebic liver abscess.
 Treatment
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.

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.
 Plasmodium Falciparum Malaria
Individuals traveling from areas with chloroquine-
susceptible P. falciparum can be treated with chloroquine if
they do not have severe malaria.

Intravenous (IV) quinine sulfate as first-line therapy for

severe malaria.

Artemether-lumefantrine.

Doxycycline, tetracycline, or clindamycin is then given orally

to complete the therapeutic course.
 P. Vivax, P. Ovale, P. Malariae, or
P. Knowlesi Malaria
Uncomplicated infection caused by P. vivax , P. ovale , or P.
malariae can be treated with chloroquine.

Patients with P. vivax or P. ovale malaria should be given

primaquine once daily for 14 days to prevent relapse from
the hypnozoite forms that remain dormant in the liver.
 Complications of P. falciparum
Severe malarial anemia (hemoglobin level <5 g/dL).
Cerebral malaria.
Respiratory distress.
Seizures.
Hypoglycemia.
Circulatory collapse (algid malaria).
Long-term cognitive impairment.
Hyperreactive malarial splenomegaly (HMS).
Other: AKI, jaundice, prostration,
 Prevention
Malaria prevention consists of reducing exposure to
infected mosquitoes and chemoprophylaxis.
Travelers to endemic areas should remain in well-screened
areas from dusk to dawn, when the risk for transmission is
highest.
Mosquito repellent should be applied to thin clothing and
exposed areas of the skin.
 Chloroquine is given in the few remaining areas of the
world free of chloroquine-resistant malaria strains.
Atovaquone-proguanil, mefloquine, or doxycycline may be
given as chemoprophylaxis.
 Reading Assignment
Diarrheal Diseases.
End…