ACUTE FEBRILE ILNESS
Natanan
(MD, Internist)
Outline
 Introduction
 Definition
Pathogenesis
Causes with clinical features &
Management
Introduction
• Body temperature is controlled by the
hypothalamus
• The core body temperature in the range of
36.5– 37.5°C
• A normal body temperature is ordinarily
maintained despite environmental variations.
Definition
• According to studies of healthy individuals 18–
40 years of age, the mean oral temperature is
36.8° ± 0.4°C (98.2° ± 0.7°F), with low levels at
6 a.m. and higher levels at 4–6 p.m.
• The maximal normal oral temperature is
37.2°C (98.9°F) at 6 a.m. and 37.7°C (99.9°F) at
4 p.m.; these values define the 99th percentile
for healthy individuals
Fever versus Hyperthermia
• Fever is an elevation of body temperature that
exceeds the normal daily variation and occurs
in conjunction with an increase in the
hypothalamic set point.
• A fever of >41.5°C (>106.7°F) is called
hyperpyrexia.
• Hyperthermia (heat stroke): uncontrolled
increase in body temperature that exceeds the
body’s ability to lose heat.
What is AFI?
• The CDC generally defines acute febrile illness (AFI) for
surveillance and research purposes as an illness with
a sudden onset of fever (typically defined as a temperature
of 38.0°C (100.4°F) or higher) lasting for a limited duration
(e.g., 2 to 14 days), often without an immediately obvious or
localized source of infection.
Acute Febrile Infection
• Fever is their prominent symptom which is usually
high grade and sudden onset.
• Associated symptoms like
chills,rigors,arthalgia,headache,malaise and rash
are usually present.
• No Prominent organ specific symptoms and signs.
• Common Differentials in our setting:
 Malaria, Typhoid fever, Ricketssial
diseases(Typhus), Relapsing Fever ,CNS
infections(meningitis)
Malaria
• Malaria is a protozoan disease transmitted by
the bite of infected Anopheles mosquitoes
• Four species of the genus plasmodium cause
nearly all malarial infections in humans.
Almost all deaths are by P. falciparum
• P. falciparum (most severe), P. vivax (most
widespread), P. ovale, P. malariae, and P.
knowlesi (primarily affects macaques but can
infect humans).
LIFE CYCLE
• MALARIA IN ETHIOPIA
– 75% of the country is malarious.
– Distribution varies from place to place depending
on climate and altitude
• Incubation period
Pathogenesis
• Complex process.
• Plasmodium parasites hijack red blood cells (RBCs), causing
them to stick to blood vessel walls (cytoadherence),
• Blocking microcirculation and triggering host immune
responses, leading to anemia, fever, and severe
complications like cerebral malaria.
• Key events include parasite sequestration in tissues,
release of inflammatory molecules, RBC destruction
(hemolysis), and immune system overactivation, all driven
by parasite proteins like PfEMP1 and host responses to
damage-associated molecular patterns (DAMPs).
• The peculiar pathogenesis of Plasmodium
falciparum, which makes it the most deadly
– Cytoadherence and Sequestration
– Antigenic Variation
– High Parasite Biomass: P. falciparum has the
ability to invade red blood cells of all ages (young
and old),
– Systemic Inflammation
Clinical features Uncomplicated
Malaria
• Malaria progresses through liver
(asymptomatic multiplication), blood
(symptomatic), and gametocyte (transmission)
stages,
• The classic blood stage featuring a
– fever paroxysm:
– a cold stage (shivering/chills),
– a hot stage (high fever/headache), and
– a sweating stage (fever drops, sweating)
Complicated P.falciparum
• Severe malaria may lead to death unless it is
diagnosed early and appropriately managed
• It mostly occurs in children under 5 years of
age, pregnant women and non-immune
individuals.
Investigation
Rapid diagnostic tests (RDT)
Microscopy-thick and thin blood films for
malaria parasites,
CBC , LFT, RFT
Lumbar puncture to exclude meningitis / in
case of severe malaria
MANAGEMNT PRINCIPLE
• The management of severe malaria is a
medical emergency based on three core
principles:
– Prompt, aggressive antimalarial treatment,
– Comprehensive supportive care for organ
complications, and
– Rigorous monitoring.
• Uncomplicated Malaria: Patients can usually be treated with oral
medications, often as an outpatient.
• Severe Malaria: This is a medical emergency requiring immediate
hospitalization and aggressive treatment with intravenous (IV)
antimalarial therapy.
– Artemisinin-based combination therapies (ACTs): The World Health
Organization (WHO) recommends ACTs as the first-line treatment for
uncomplicated P. falciparum malaria
– Intravenous Artesunate: This is the recommended initial treatment for
all severe malaria cases
– Chloroquine phosphate or Hydroxychloroquine: These may be used
for specific malaria species (P. vivax, P. ovale, P. malariae, and P.
knowlesi)
– Primaquine or Tafenoquine: These drugs are necessary to eradicate
dormant liver stages (hypnozoites) of P. vivax and P. ovale to prevent
relapse.
Enteric Typhoid Fever
• Enteric fevers, primarily Typhoid Fever,
are caused by the bacterium Salmonella
enterica serotype Typhi,
• Spread through the fecal-oral route by
ingesting contaminated food/water often
from asymptomatic carriers or those with
poor hygiene, leading to systemic infection.
• The etiologic agents of enteric fever—S. typhi
and S. paratyphi serotypes A, B, and C—have
Incubation period
• The incubation period for typhoid fever
typically ranges from 6 to 30 days, with an
average of 7 to 14 days,
• It can sometimes be as short as 3 days or
longer, depending on the number of bacteria
ingested.
• Symptoms like gradual fever, headache, and
fatigue start slowly and worsen over several
days
The Four Stages of Typhoid Fever
Stage 1: Early Illness (Approx. Week 1)
• Symptoms: Gradual fever increase, headache, malaise (feeling unwell), dry cough,
abdominal pain, and fatigue, resembling the flu.
• Pathology: Bacteria move into the bloodstream.
Stage 2: High Fever & Gastrointestinal Issues (Approx. Week 2)
• Symptoms: High fever (up to 104°F/40°C), abdominal pain, constipation or diarrhea,
delirium, and a rash of small, pink spots (rose spots) on the chest/abdomen.
• Pathology: Bacteria multiply in the gut and immune response begins.
Stage 3: Severe Complications (Approx. Week 3)
• Symptoms: If untreated, this stage brings severe symptoms like intestinal bleeding
(hemorrhage) or perforation, inflammation, and confusion.
• Pathology: Serious internal damage occurs.
Stage 4: Recovery (Approx. Week 4 & Beyond)
• Symptoms: Fever and symptoms subside with proper antibiotic treatment, but
weakness can persist.
• Without Treatment: This stage can bring relapse, persistent severe complications, or
even death. Some individuals become asymptomatic carriers
Clinical Signs/Symptoms
• Headache (80%), epistaxis, Abdominal pain,
myalgia, arthralgia and cough
• Relative bradycardia at the peak of high fever
• hepatosplenomegaly (3–6%),
• Early physical findings of enteric fever include
rash (“rose spots”30%),
• Abdominal tenderness (4–5%) splenomegaly (5–
6%), and  coated tongue (51–56%), vomiting
(18%), and diarrhea (22–28%) more commonly
than constipation (13–16%)
Complications
• Primarily involving life-threatening gastrointestinal
issues like bleeding and intestinal perforation (hole),
often appearing weeks into the illness.
• Other serious issues include neurological problems
(encephalopathy, meningitis),
• Heart inflammation (myocarditis),
• Gallbladder problems,
• Kidney failure, and pneumonia, with potential for
sepsis and shock.
• Pregnant women risk miscarriage, and even after
recovery, people can become asymptomatic carriers.
Patients with enteric fever frequently have
anemia and either leukopenia or leukocytosis;
Blood, bone marrow, and intestinal
secretions (stool)are all cultured, the yield is
Bone marrow culture is 55–90% sensitive
Serology, Widal test: detecting antibodies
against Salmonella Typhi bacteria (O and H
antigens), poor and variable sensitivity and
specificity
Treatment
• Initial treatment is based on the likely resistance patterns in the
geographic area
– Where fluoroquinolone resistance is low, ciprofloxacin is a common first choice.
– In areas with high fluoroquinolone resistance (common in South Asia and
Africa), azithromycin or ceftriaxone (a third-generation cephalosporin) are typically
recommended options.
– For extensively drug-resistant (XDR) strains, options are limited, with oral
azithromycin or parenteral meropenem being primary choices.
• Treatment Duration: Treatment courses typically range from 7 to 14 days,
or until the patient has been without a fever for several days.
• Route of Administration: Uncomplicated cases with oral antibiotics, while
severe cases require hospitalization and intravenous medication.
• Chronic Carriers: Individuals who continue to shed bacteria in their stool
for over a year require prolonged antibiotic treatment (e.g., a 28-day
course of a fluoroquinolone).
• Surgical removal of the gallbladder (cholecystectomy) may be necessary
in cases associated with gallstones.
Typhus
• Typhus is a group of bacterial illnesses (like epidemic,
murine, and scrub typhus) causing fever, headache,
and body aches, transmitted by infected fleas, lice, or
chiggers.
Types & Transmission
• Epidemic Typhus: Spread by body lice, often in
crowded, unsanitary conditions (historical "jail fever").
• Murine Typhus: Carried by fleas from rodents (rats,
cats) and other animals.
• Scrub Typhus: Transmitted by mites (chiggers) in bushy,
overgrown areas
Epidemic(Louse born) Typhus
• The infected louse leaves a febrile person and deposits
infected feces on its subsequent host during its blood
meal; the patient autoinoculates the organisms by
scratching.
• The rickettsiae multiply in the louse’s midgut epithelial
cells and are shed in its feces.
• Lice acquire R.prowazekii when they ingest blood from
a rickettsemic patient.
• The human body louse (Pediculus humanus corporis)
lives in clothing under poor hygienic conditions and
usually in impoverished cold areas.
• Brill-Zinsser disease: a recrudescent illness
occurring years after acute epidemic typhus,
probably as a result of waning immunity.
• Brill-Zinsser disease is generally a mild illness.
Severe symptoms and death are rare,
primarily occurring in elderly and debilitated
patients
Clinical features
• Epidemic typhus symptoms include a sudden
onset of high fever, headache, and chills,
appearing 7-14 days after exposure.
• Other common symptoms are a rash on the
trunk that spreads to the body (sparing the
face, palms, and soles),
• Muscle and joint pain, confusion, nausea,
vomiting, and a cough.
Diagnosis
• Serologic tests are the mainstay of diagnosis since isolation
of R. prowazekii is generally impractical.
• Serology (Antibody Tests)
– IFA (Indirect Immunofluorescence Assay): Gold standard, detects
specific antibodies (IgG, IgM) in blood.
– Paired Sera: Essential for acute diagnosis; a four-fold rise in
antibody titer between early and later samples confirms recent
infection.
• Molecular Tests:
– PCR (Polymerase Chain Reaction): Detects Rickettsia
prowazekii DNA in blood or skin biopsies, helping distinguish from
other typhus types.
• Tissue Stains:
– IHC (Immunohistochemistry): Detects bacteria in skin biopsies.
Prevention
• Delousing — Eradication of human infestation
with lice will prevent transmission of epidemic
typhus
• Antibiotic prophylaxis — The use of
chloramphenicol or tetracycline for
prophylaxis may be highly effective in
interrupting typhus outbreaks.
• Vaccination
• Environmental control
TREATMENT
• Early Treatment is Crucial: Antibiotics started
soon after symptoms begin to prevent severe
complications like kidney or nervous system
problems.
• As in other rickettsial diseases, tetracyclines and
chloramphenicol are the most effective agents for
epidemic typhus.
• The drug of choice is doxycycline.
• Alternate antibiotics: Azithromycin and rifampin.
Relapsing fever
• Is a bacterial infection caused by Borrelia
spirochetes,
• Characterized by recurring episodes of fever,
headache, and muscle pain, separated by days
or weeks of feeling well, due to the bacteria
changing their surface proteins.
• It's spread by lice (louse-borne, LBRF) or
ticks (tick-borne, TBRF) and can be serious,
requiring prompt antibiotic treatment.
• Relapsing fever risk factors center on exposure
to infected liceor ticks
• Often in specific environments like war zones,
refugee camps, or rural areas with poor
hygiene, poverty, or overcrowding, leading to
close contact with vectors.
CLINICAL MANIFESTATIONS
• The incubation period between the exposure and
the first fever is between 3 and 12 days.
• Relapsing fever presents with the sudden onset
of fever, punctuated by an intervening afebrile
period, and then recurrent fevers.
• TBRF, multiple febrile periods each last from one
to three days.
• LBRF, the first episode of fever is unremitting for
three to six days; it is typically followed by a
single milder episode
Other symptoms
• Generalized – Patients with relapsing fever generally present with
nonspecific symptoms (eg, headache, myalgia, arthralgia, shaking chills,
and abdominal complaints).
• Neurologic : Neurologic manifestations, such as delirium, apathy, stupor,
dizziness, or, rarely, coma, can be seen in both TBRF and LBRF.
• Localized neurologic signs (eg, hemiplegia, facial palsy, myelitis,
meningitis, and radiculopathy) are more common with TBRF and are due
to direct invasion of spirochetes [.
• Cardiopulmonary –Myocarditis , pulmonary symptoms range from acute
respiratory distress syndrome, which is typically seen in patients with
TBRF, to a nonproductive cough in patients with LBRF.
• Hematologic –mainly seen in patients with LBRF. Such patients can
present with a bleeding disorder, which is probably the consequence of
thrombocytopenia, impaired hepatic production of clotting factors, and/or
blockage of small vessels by aggregates of spirochetes, erythrocytes, and
platelets.
Physical examination
• Exam findings seen in patients with both TBRF
and LBRF include splenomegaly that may be
accompanied by abdominal or left shoulder pain,
and hepatomegaly, which is seen in the majority
of patients with LBRF and in about 10 percent of
patients with TBRF.
• Other exam findings, such as localized neurologic
findings, are more common in TBRF than LBRF.
Investigation
•
Microscopy (Gold Standard):
– Specimen: Thick or thin blood films (Giemsa or Wright stain).
– Timing: Crucial to collect blood during a feverish (febrile) period when spirochetes are in
the bloodstream.
– Procedure: Examine under oil immersion; look for spirochetes free in plasma or
adhering to red blood cells.
– Challenges: Spirochete numbers decrease with each relapse, making them hard to spot.
• Polymerase Chain Reaction (PCR):
– Advantages: More sensitive than microscopy, can detect DNA during afebrile periods or
after treatment.
– Use: Available through specialized labs (like CDC, ARUP), helps
differentiate Borrelia species.
General Lab Findings
• Hematology: Mild anemia, normal to increased white blood cell count.
• Biochemistry: Elevated liver enzymes (bilirubin, aminotransferases), increased urea nitrogen,
creatinine, and sometimes proteinuria/hematuria.
Important Considerations
• Differential Diagnosis: Always rule out malaria with a rapid test in endemic areas.
• Specimen: Whole blood in EDTA tube (lavender/pink top); serum/plasma is often
unacceptable.
Treatment
• Prompt Treatment: Antimicrobial therapy should be administered to all
patients diagnosed with relapsing fever.
• Supportive Care: managing pain and fever and preventing or correcting
dehydration and electrolyte imbalances with fluids.
• Monitoring for Jarisch-Herxheimer Reaction: A common complication
after the first dose of antibiotics is the JHR, which involves a sudden
worsening of symptoms (chills, high fever, rapid heart rate, low blood
pressure).
• Patients must be monitored closely for several hours after the first dose
to manage this reaction, which can be severe or fatal in LBRF cases
• Vector Control: For louse-borne fever, eliminating body lice through
hygiene measures (showering, washing clothes in hot water, using
pediculicides) is essential to control the infection's spread.
• For tick-borne fever, avoiding rodent-infested areas and using insect
repellent helps prevent further infections.
• LBRF: Doxycycline (200 mg single dose),
tetracycline (500 mg single dose), or
erythromycin (500 mg single dose).
• TBRF: Doxycycline (100 mg twice daily),
tetracycline (500 mg every 6 hours), or
erythromycin (500 mg every 6 hours).
• Patients with CNS and pregnant : IV
ceftriaxone or pencillin G for 10-14 days
Jarisch-Herxheimer
• Two phases
• Chill phase: Is a condition of worsening of the patients
condition soon after the intiation of antibiotic
treatment, caused by mediatiors like TNF Reaction
(JHR) > Increase PVR 41, rigors, hyper metabolism &
Decrease in PVR Lasts 10-30 min.
• Flush phase: decrease in Pul. arterial pressure & Lasts
Decrease in temperature, diaphoresis, decreased
effective circulatory volume increase in Pul. Arterial
pressure < Mortality reaches 20% in malnourished
Sleep, exhaustion, recovery with disappearance of
spirochetes 8 hrs & stressed population.
Acute pyogenic meningitis
• A severe, rapidly progressing infection of the
brain's protective linings (meninges) and the
fluid around the brain and spinal cord (CSF),
caused by bacteria.
• Is medical emergency with symptoms like
high fever, severe headache, and stiff neck,
Acute Bacterial Meningitis
Etiology:
•
•
•
•
•
•
Streptococcus
pneumoniae (Pneumococcus): ~30-50%
(most frequent in elderly/general adults).
Neisseria
meningitidis (Meningococcus): ~10-37%
(more common in younger adults).
Haemophilus influenzae: Less common
now, but historically significant, ~2-26%
(higher in younger adults).
Staphylococcus aureus(Staph): ~1-14%
(often associated with head trauma or
hospital-acquired).
Listeria monocytogenes (Listeria): ~3-10%
(more common in older
adults/immunocompromised
Group B. streptoccocus
Predisposing
factors/s.pneumonia
• Head trauma
• Hypogammaglobulinemia
• Diabetes,
• Splencetomy
• Alcoholism
• Otitis media and Sinusitis
• Pneumococcal
Pneumonia
• Streptococcus pneumoniae (Pneumococcus): Common
in elderly, immunocompromised, and after pneumonia.
• Neisseria meningitidis (Meningococcus): Associated
with crowding and younger adults, though also older
adults.
• Listeria monocytogenes: Higher risk in elderly,
immunocompromised, or alcoholic patients.
• Haemophilus influenzae: Less common now due to
vaccines, but linked to skull fractures.
• Staphylococcus aureus: Linked to neurosurgery or
trauma
Pathogenesis
Clinical features
• The "classic triad" of symptoms is fever, neck
stiffness (nuchal rigidity), and altered mental
status presents in only 40-50%.
• More Reliable Indicator: Nearly all (95%) adult
patients present with at least two of the following
four symptoms: fever, headache, neck stiffness,
and altered mental status.
• Other symptoms Photophobia,Phonophobia,
Seizures or focal neurological deficits (e.g., cranial
nerve palsies, limb weakness)
• A rapidly spreading petechial or purpuric
rash (purpura fulminans) is highly suggestive of
meningococcal infection.
• Atypical Presentations:
– Infants and Young Children: Symptoms are often nonspecific, including irritability, poor feeding, lethargy,.
– Elderly and Immunocompromised Patients: Signs might
be masked or subtle and less frequent.
• Meningeal signs: Positive Kernig's and Brudzinski's signs (physical
exam maneuvers indicating meningeal irritation), though their
absence does not reliably rule out the disease.
Complications
•
•
Neurological Complications:
– Sensorineural hearing loss (most frequent permanent sequela) and vision loss.
– Seizures or epilepsy.
– Increased intracranial pressure leading to brain edema, hydrocephalus (excess fluid), or
potentially fatal brain herniation.
– Cerebrovascular complications including vasculitis, blood clots, and stroke (ischemic
infarction).
– Cognitive impairments (memory/concentration problems, learning disabilities) and
behavioral problems.
– Focal neurologic deficits such as cranial nerve palsies (weakness of facial muscles,
vision/hearing issues) or paralysis.
Systemic Complications:
– Septic shock (dangerously low blood pressure) and systemic inflammatory response
syndrome (SIRS).
– Disseminated intravascular coagulation (DIC), an excessive clotting that leads to
bleeding.
– Organ failure (e.g., kidney, respiratory).
– Hyponatremia (low sodium levels) due to syndrome of inappropriate antidiuretic
hormone secretion (SIADH).
– Arthritis.
Investigations
• Blood Tests: Blood cultures and a complete
blood count (CBC) with CRP are drawn early.
• Lumbar Puncture (Spinal Tap): The definitive
test, obtaining CSF for analysis.
• Head CT (If Indicated): Performed before the
lumbar puncture if signs of increased
intracranial pressure (like neurological deficits,
seizures, or altered mental status) are present
to rule out brain abscess or herniation risk.
Treatment
• Bacterial meningitis is a medical emergency.
• Empirical antimicrobial therapy is initiated before the results
of CSF Gram’s stain and culture are known.
• The goal is to begin antibiotic therapy within 60 min of a
patient’s arrival in the emergency room.
• Adjunct dexamethasone therapy 20 min before antibiotic
therapy.
• Adults (18-50 yrs)
: Ceftriaxone or Cefotaxime plus Vancomycin.
• Adults (>50 years old or immunocompromised): The above
combination plus Ampicillin (to cover Listeria
monocytogenes).
• Supportive Care: Pain/fever control, fluids, and sometimes
anti-seizure meds.
Acute viral meningoencephalitis
• Is a serious inflammation affecting both the brain
(encephalitis) and its surrounding protective
membranes (meningitis).
– Enteroviruses (Most Common), Coxsackievirus, Echovirus
– Herpesviruses: HSV-1 & 2 (HSV-2 linked to recurrent
meningitis), VZV (shingles), CMV, EBV, HHV-6,
– Arboviruses (Seasonally): West Nile Virus (WNV), Zika,
Chikungunya, La Crosse, St. Louis, Eastern Equine
Encephalitis.
– Respiratory Viruses: Adenovirus, Influenza, Parainfluenza.
– Other Viruses: Mumps virus (less common now due to
vaccination), Lymphocytic Choriomeningitis Virus (LCMV),
HIV, SARS-CoV-2 (rarely
Clinical features
• Constitutional signs can include malaise,
myalgia, anorexia, nausea and vomiting,
abdominal pain, and/or diarrhea.
• Headache is almost invariably present and
often characterized as frontal or retroorbital
and frequently associated with photophobia
and pain on moving the eyes
• Nuchal rigidity is present in most cases but
may be mild.
Diagnosis
• CSF analysis
• PCR tests on CSF identify the specific virus
(like Enterovirus or HSV),
• EEG monitors brain activity, and other lab
tests (blood, swabs) support diagnosis.
• Neuroimaging (MRI/CT)
Treatment
• Prognosis is excellent
• Rest & Hydration:Pain/Fever Relief
• Specific Treatments (For Certain Viruses)
– Herpes Simplex / Varicella (Chickenpox): Treated with
antiviral drugs like acyclovir.
– HIV-related Meningitis: Managed with antiretroviral
therapy.
– Arboviruses: Vaccines (like Japanese Encephalitis)
exist, and some experimental treatments for specific
viruses are available