Acute Febrile Illnesses

Solomon Bekele
Sirak Melkeneh
Sonia Worku
Fri. May 15, 2014
OBJECTIVES
• Understanding what fever is and its basic pathophysiology
• Discuss the major acute febrile illnesses and their management
OUTLINE
• Fever
• Fever of unknown origin
• AFI
• Meningitis
• Malaria
• Relapsing fever
• Typhus fever
• Typhoid fever
FEVER
“ትኩሳት”

Solomon Bekele
Fever
• Elevation of body temperature that exceeds the normal daily variation and occurs
in conjunction with an increase in the hypothalamic set point
Harrison’s definition
• Normal values
• Oral temperature: 36.80 ± 0.40c

• Max. a.m. temp = 37.20c Any temp. above these

values defines a fever
• Max. p.m. temp = 37.70c
• Hyperpyrexia = >41.50c

• Normal daily variation being 0.50c

Variations
1. From thermometer placement
• Oral = 36.8 ± 0.40c
• Rectal = + 0.60c
• Axillary = - 0.60c
2. Due to circadian rhythms
• Lowest: 6 a.m.
• Highest: 4 – 6 p.m.
3. Due to women’s menstrual cycle
• Lower morning temp. during follicular phase
• Raise by ~ 0.60c following ovulation
4. Postprandial elevation, fall after alcohol consumption
Hyperthermia
• Not synonymous with fever Causes:
• Heat stroke
• An uncontrolled increase in body
temperature that exceeds the • Drug induced hyperthermia
body's ability to lose heat • Neuroleptic malignant syndrome
• Hypothalamic set point is not
changed • Serotonin syndrome
• Pyrogenic molecules are not involved • Malignant hyperthermia
• Diagnosis: history of preceding • Endocrinopathies
events or drugs the person is taking
• CNS damage
Pathophysiology of Fever
• Hypothalamus controls body temperature
• Hypothalamus receive two kinds of signals:
1. From warmth/cold receptors in the skin
2. From the temp. of blood bathing the body
• Thermoregulatory center integrates these two signals to maintain normal body
temperature, “normothermia” at a certain set point.
• During fever the "set-point" in the hypothalamus shifts upwards, e.g. from 370c to
390c
Cont’d
• Pyrogen: any substance that causes fever
• Can be either:
1. Exogenous pyrogens
• LPS (endotoxin)
• Group A and B streptococcal toxin
• TSST of staph.
2. Endogenous pyrogens (pyrogenic cytokines)
• IL-1, IL-6
• TNF-α
• IFN-α, etc..
Causes of Fever
• Infectious disease: AFI, HIV, gastroenteritis…
• Immune-mediated disorders: SLE, sarcoidosis, IBD…
• Tissue destruction: trauma, surgery, infarction…
• Malignancies
• Endocrine disorders
• Drugs
• Fever of unknown origin
• “LOVE”!?
 Pathway of fever production
Heat conservation
Microbial products Cytokines, trauma, Heat production
necrotic tissue, hypoxia

Elevated thermoregulatory
set point
FEVER

Macrophages,
endothelium, RES PGE2

Pyrogenic cytokines (IL-1, Systemic Hypothalamic endothelium

IL-6, TNF, IFN) circulation (cytokine receptors and TLR)
Effects of fever
• It enhance immune function;
• Increases motility and activity of the white blood cells;
• Stimulates the interferon production and activation of T cells;
• Inhibits growth of some microbial agents:
• Many of the microbial agents that cause infection grow best at normal body temperatures, and
their growth is inhibited by temperatures in the fever range.
• Metabolic effects:
• Increased need for oxygen; 13%
• Increase in HR & RR
• Increased use of body proteins as an energy source;
• With prolonged fever, there is increased breakdown of endogenous fat stores;
• If fat breakdown is rapid, metabolic acidosis may result.
Types of fever
1. Continuous fever: temp. remains above normal throughout the day and do not fluctuate
more than 10c in 24hr. e.g. : lobar pneumonia, UTI…
2. Remittent fever: temp. remains above normal throughout the day and fluctuates more than
10c in 24hr. e.g. : infective endocarditis
3. Intermittent fever: temp. returns to normal for more than 24hrs. and then elevates again
• Tertian fever (48hrs. periodicity)
• Quartan fever (72hrs. periodicity)
4. Relapsing fever: there is one or more episodes of fever, each as long as several days, with
one or more days of normal temperature between episodes; e.g. Relapsing fever
5. Pel-Ebstein fever: recurs at variable intervals of several days or weeks and lasts for one to
two weeks before waning. E.g. Hodgkin lymphoma
6. Wunderlich curve of typhoid fever: fever with a slow stepwise increase and a high
plateau.
Treatment of fever and hyperthermia
• Treatment of fever is often a debated issue.
• Lowering elevated core temp. decreases the effects of fever
• Treatment of fever and its symptoms with antipyretics does not slow the resolution
of common viral and bacterial infections.
Mechanism of antipyretic agents
• Lowering hypothalamic set point by reducing the level of PGE 2
• The synthesis of PGE2 depends upon the constitutively expressed enzyme
cyclooxygenase
• The substrate for cyclooxygenase is arachidonic acid released from the cell membrane
• Thus, inhibitors of cyclooxygenases (either COX-1 or COX-2) are antipyretics
Cont’d
• Acetaminophen is poor peripheral COX inhibitor and lacks anti-inflammatory activity.
• The inhibition of another enzyme, COX-3, by acetaminophen may account for the
antipyretic effect of this agent. (COX-3 is not found outside the CNS)
• Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and specific
inhibitors of COX-2 are also excellent antipyretics
Treating hyperthermia
• Antipyretics have no place
• Physical cooling with sponging, fans, cooling blankets, and even ice baths should be
initiated immediately
• Administration of IV fluids and
• Appropriate pharmacologic agents
Fever of Unknown Origin (FUO)
• Definition
1. In 1961 Petersdorf and Beeson suggested the following criteria
• Temperatures of >38.3°C (>101°F) on several occasions
• A duration of fever of >3 weeks; and
• Failure to reach a diagnosis despite 1 week of inpatient investigation
• Durack and Street classified FUO into four
1. Classic FUO
2. Nosocomial FUO
3. Neutropenic FUO
4. FUO associated with HIV infection
Cont’d
1. Classic FUO: definition which includes outpatient setting; broader
• 3 outpatient visits
• 3 days in a hospital without elucidation of a cause
• 1 week of “intelligent and invasive” investigation
Causes of FUO
 Three general categories of illness account for the majority of "classic" FUO cases
1. Infections
• Tuberculosis: most common infection in most FUO
• Abscess: occult abscesses in the abdomen and pelvis
• Osteomyelitis
• Infective endocarditis
2. Connective tissue diseases
• Juvenile idiopathic arthritis (Still’s disease)
• Giant cell arteritis
3. Malignancies: the most common malignancies to present with FUO are:
• Lymphoma, especially non-Hodgkin's
• Leukemia
• Renal cell carcinoma
• Hepatocellular carcinoma or other tumors metastatic to the liver
Cont’d
2. Nosocomial FUO:
• A temperature of 38.3°C (101°F) develops on several occasions in a
hospitalized patient who is receiving acute care and in whom infection was not
manifest or incubating on admission.
• Surgery or procedure sites: abscess, hematoma, or FB
• Intravascular lines, septic phlebitis, and prostheses
Cont’d
3. Neutropenic FUO:
• Temperature of 38.3°C (101°F) on several occasions in a patient whose neutrophil
count is <500/L or is expected to fall to that level in 1–2 days
• Candida and Aspergillus infections are common
• Herpes simplex virus or CMV infections
4. HIV-associated FUO:
• Temperature of 38.3°C (101°F) on several occasions over a period of >4 weeks for
outpatients or >3 days for hospitalized patients with HIV infection.
• HIV
• Infection due to Mycobacterium avium, tuberculosis, toxoplasmosis,
pneumocystis, cryptococcosis, and non-Hodgkin's lymphoma and drugs.
• FUO has an infectious etiology in >80% of HIV-infected patients
Diagnosis
• Detailed history and repeated physical • Erythrocyte sedimentation rate or C-reactive
examination protein
• Complete blood count, including differential • Serum lactate dehydrogenase
and platelet count • Tuberculin skin test
• Blood cultures (three sets drawn from • HIV antibody assay and HIV viral load for
different sites over a period of at least several patients at high risk
hours without administering antibiotics)
• Rheumatoid factor
• Routine blood chemistries, including liver
enzymes and bilirubin • Creatine phosphokinase
• Hepatitis serology (if liver tests abnormal) • Antinuclear antibodies
• Urinalysis, including microscopic • Serum protein electrophoresis
examination, and urine culture • CT scan of abdomen
• Chest radiograph • CT scan of chest
Treatment of FUO
• No therapy should be started before the cause is known
• Observation and examination, with the avoidance of empirical antimicrobial
therapy
• However, vital sign instability or neutropenia are indications for antibiotic therapy
• Fluoroquinolone plus piperacillin
• Rheumatic fever and Still's disease respond to aspirin and non-steroidal anti-
inflammatory drugs (NSAIDs)
• Glucocorticoids for temporal arteritis, polymyalgia rheumatica, and
granulomatous hepatitis
“Patience, compassion, equanimity, vigilance, and intellectual flexibility are
indispensable attributes for the clinician in dealing successfully with FUO”
Acute Febrile Illnesses (AFI)
• FEVER as the most prominent symptom
• Sudden onset, i.e. 14days
• High grade
• Associated symptoms
• Chills, rigors
• Arthralgia
• Headache
• Malaise
• Rash
• NO prominent organ specific symptoms or signs
• E.g. cough, coryza, chest pain, dysuria, frequency, vomiting, diarrhea, abdominal pain,
local tenderness etc…
AFI list
• Meningitis
• Malaria
• Relapsing fever
• Typhoid fever
• Typhus fever
• Chagas disease
• Dengue fever…
Meningitis
Introduction
• Meningitis is inflammatory disease of the meninges, leptomeninges
• Typically caused by an infection with microorganisms.
• Most infections are due to viruses, but bacteria, fungi, and protozoa can also be
the causes
• Different etiologies in different age groups and predisposing conditions
• Acute or chronic
• Acute meningitis
• Acute bacterial meningitis
• “Aseptic” viral meningitis
• Chronic meningitis
• Neurological symptoms/ CSF abnormalities persist for > 4weeks
Causes of acute meningitis
1. Bacterial causes 2. Viral causes
• Enteroviruses: Echovirus and Coxsackie viruses
• Streptococcus pneumoniae Account for >75% • Arboviruses: West Nile Virus
• Neisseria meningitidis of all bacterial • Herpes viruses: HSV 1+2, VZV, CMV, EBV
meningitis • Mumps
• Haemophilus influenza • HIV
• Listeria monocytogenes 3. Fungal
• Cryptococcus
• Streptococcus agalactiae (GBS)
4. Protozoa and helminthes
• Gram negative bacilli: • Naegleria fowleri
• Salmonella sp • Acanthamoeba
• Angiostrongylus cantonensis
• post trauma or neurosurgery
5. Non-infectious causes
• associated with disseminated strongyloidiasis • Neoplastic meningitis
• Syphilis • Drugs
• Sarcoidosis
• Borrelia burgdorferi • SLE
Predisposing factor Vs. etiology

Predisposing Factor Bacterial Pathogen

Age <1 Streptococcus agalacticae, Escherichia coli, Listeria
monocytogenes, Klebsiella pneumoniae
month
1-23 month S.agalacticae, E.coli, Haemophilus influenzae, Streptococcus
pneumoniae, Neisseria meningitidis

2-50 years S.pneumoniae, N.meningitidis

>50 years S.pneumoniae, N.meningitidis, L.monocytogenes, Gram

negative bacilli

Immunocompromised including S.pneumoniae, N.meningitidis, L.monocytogenes, Gram

negative bacilli, Pseudomonas aeruginosa, Mycobacterium
HIV tuberculosis, Cryptococcosis

Basilar skull fracture S.pneumoniae, H.influenzae, Group A streptococci

Post neurosurgery Staphylococcus aureus, coagulase negative staphylococci,

Gram negative bacilli, P.aeruginosa
Acute bacterial meningitis
• Acute bacterial meningitis is a medical emergency
• From its original recognition in 1805 until the early 1900s, bacterial meningitis
was virtually 100 percent fatal
• Early diagnosis & appropriate antimicrobial therapy is important in outcome of
patients with bacterial meningitis
Epidemiology
• Bacterial meningitis is distributed worldwide
• Incidence is 3/100,000 population in temperate climate, incidence higher in the
tropics
• Risk factors for acute bacterial meningitis
• Bacterial virulence factors, pili/capsule
• Host factors: immunocompromised, alcoholic, DM
• Environmental factors; climate, overcrowding
• Prior viral/mycoplasma upper respiratory infections
• Genetic factors; complement deficiencies, hyposplenic states
Epidemic meningococcal disease in
African Meningitis Belt

• Epidemics occur every 5- 10 years in 21 countries

(Senegal – Ethiopia)
• Epidemics occur in dry season and decrease in the
rainy season
• Epidemics caused by serogroup A, less frequently
serogroup C
• 800 000 cases were reported in the last 15 years
(1996–2010).
• Of these cases, 10% resulted in deaths, with
another 10–20% developing neurological sequelae
Pathophysiology
Nasopharyngeal
colonization
Meningeal invasion
- Fimbriae/pili mediate
adherence to epithelial Blood stream invasion Traverse Blood Brain
cells Barrier, BBB,
(Bacterial capsule)
Separating apical tight Site of CNS invasion, ?
junctions of columnar Choroid plexus
epithelial cells

Inflammation in the sub-arachnoid

space
Bacterial survival in the sub-
Interleukins, IL-1β, IL-6,IL-8, Interferon
-ý arachnoid space
TNF-α, MIP-1 and 2, PAF Low complement and
PGE2, prostacyclin immunoglobulin
Nitric oxide concentration
Cont’d Inflammatory
cytokines

Leukocyte adherence
Altered BBB Alteration in cerebral Direct neuronal
to cerebral capillary
permeability blood flow injury
endothelial cells

• Microvascular vasculitis, thrombosis

• Cerebral ischemia/infarction
• Increased intracranial pressure
• Cerebral edema: vasogenic, cytotoxic, interstitial
• Obstructive and communicating hydrocephalus
• Coma/death
Clinical features
• Acute fulminant illness vs. subacute infection
• Classic triad; only 44%of patients
• Fever
• Headache
• Nuchal rigidity
• Decreased level of consciousness
• Nausea, vomiting and photophobia
• Papilledema, dilated and poorly reactive pupil, CN VI palsy, and the Cushing reflex
• Seizure: focal or generalized
• Cerebral herniation: 1-8% of cases
• Skin lesions: petechiae and palpable purpura
Classic signs of meningeal irritation
• Neck stiffness: Passive or active flexion of the neck will
usually result in an inability to touch the chin to the chest

• Kernig’s sign: The test is positive when there is resistance

to extension at the knee to >135 degrees or pain in the
lower back or posterior thigh

• Brudzinski's sign: positive when there is spontaneous

flexion of the hips during attempted passive flexion of
the neck
The sensitivity of these signs is low and so their absence does
not exclude meningitis .
Diagnosis
1. Diagnosis of bacterial meningitis is made by CSF examination
CSF parameter Typical finding in bacterial
meningitis
Opening pressure 200-500mmH2O
White blood cell count 10-10,000/µl; %Neutrophils >80%
RBC Absent in non-traumatic tap
Protein >45 mg/dl; 100-500mg/dl
Glucose <40mg/dl; CSF:serum glucose<0.4
Gram Stain Positive in 60-90%
Culture Positive in 70-85%
Cont’d
2. Laboratory studies
• Usually unrevealing
• Increased WBC, thrombocytopenia
• Hyponatremia
3. Blood culture
• Positive in 50-90% of cases, lowest in meningococcal infections
• Useful in the event that CSF cannot be obtained
• Two sets of blood cultures should be obtained from all patients prior to the initiation of
antimicrobial therapy.
4. Imaging
• CT or MRI does not aid in the diagnosis of bacterial meningitis
• Useful in patients with focal neurologic findings, ↑ICP, seizures, prolonged fever
Delaying LP
• Purpose
• To exclude a mass lesion or increased intracranial pressure and prevent
cerebral herniation
• IDSA recommends a CT scan of the head before doing LP in patients with
• Immunocompromised state (eg, HIV infection, immunosuppressive therapy,
solid organ or hematopoietic stem cell transplantation)
• History of CNS disease (mass lesion, stroke, or focal infection)
• New onset seizure
• Papilledema Contraindications to LP
• Abnormal level of consciousness 1. Possible raised ICP
2. Thrombocytopenia or other bleeding diathesis
• Focal neurologic deficit 3. Spinal or epidural abscess, LP site skin infection
Management of bacterial meningitis
1. Empirical antimicrobial therapy
• The goal is to begin antibiotic therapy within 60 min of arrival in the ER.
Indication Regimen
Preterm infants – infants<1mo Ampicillin + cefotaxime
Infants 1 – 3mo Ampicillin + cefotaxime or ceftriaxone
Immunocompetent; 3mo – 55yrs Cefotaxime, ceftriaxone or cefepime +
vancomycin
Adult > 55yrs Ampicillin + cefotaxime, ceftriaxone or
cefepime + vancomycin
Hospital-acquired meningitis, Ampicillin + ceftazidime or meropenem +
posttraumatic or post neurosurgery vancomycin
meningitis.
Specific antimicrobial therapy for acute
bacterial meningitis
Microorganism Antimicrobial therapy
Haemophilus influennzae, type B Cefotaxime of Ceftriaxone
Neisseria Penicillin sensitive Penicillin G or Ampicillin
meningitidis Penicillin resistant Cefotaxime or Ceftriaxone
Streptococcus Penicillin sensitive Penicillin G
pneumoniae Penicillin resistant Vancomycin + Cefotaxime or
Ceftriaxone
Listeria monocytogenes Ampicillin + gentamicin
Pseudomonas auerginosa Ceftazideme or Cefepime
Enterobacteriacae Cefotaxime of Ceftriaxone
Adjunct treatment of acute bacterial
meningitis
1. Dexamethasone; just before 1st dose of antimicrobial therapy improves outcomes
• Inhibits synthesis of inflammatory cytokines
• Decreases CSF outflow resistance
• Stabilizing BBB
• Decreases incidence of sensorineural hearing loss
• 0.15mg/kg (10mg), IV, q6hrs. for 4 days, the first dose administered 15 –
20min before the first dose of antimicrobial agent
2. ICP management
• Elevate patient’s bed to 300
• Mannitol; 1g/kg
• Hyperventilation; PaCO2 25-30mmhg
Follow up
1. Vital signs: q30’ – 1hr
• PR, BP, RR, T0
2. Neurologic assessment
• Level of consciousness,
• Pupils, motor, Cranial nerves
3. Repeat LP!
• No evidence of improvement by 48 hours after the initiation of appropriate
therapy
• Persistent fever for more than eight days without another explanation
Complications of acute bacterial meningitis
• Cranial nerve palsies: III, IV
• Blistering skin lesions; Cutaneous vasculitis
• SIADH - 30-50% of cases,
• Hyponatremia, decreased serum osm.
• Exacerbate cerebral edema, hyponatremic Sz.
• Pericarditis, arthritis- due to bacterial dissemination, or immune
complex deposition.
• Visual & hearing impairment
Malaria
Outline
• Definition and Etiology
• Epidemiology
• Life cycle and pathogenesis
• Clinical features
• Diagnosis
• Treatment
• Prevention
Definition
• Malaria is a protozoan disease transmitted to man by the bite of the female
anopheles mosquitoes. (Anopheles arabiensis is the main malaria vector)
• Five species of the genus Plasmodium cause nearly all malarial infections in
humans. These are: -
• P. falciparum, P. vivax, P. ovale, P. malariae,
• P. knowlesi —in Southeast Asia (monkey malaria parasite)
• Almost all deaths are caused by falciparum malaria.
Epidemiology

• Malaria have a global distribution with prevalence of 500 million people affected
every year and about 2 million people die of malaria/year.
• Approximately 52 million people (68%) live in malaria risk areas in Ethiopia,
primarily at altitudes below 2,000 meters.
• On average, 60% of malaria cases have been due to P. falciparum, with the
remainder 40% caused by P. vivax. P. ovale and P. malariae cause <1%.
• The principal determinants of the epidemiology of malaria are the number
(density), the human-biting habits, and the longevity of the anopheline
mosquito vectors.
Contd.
• Malaria is common in both low and high land areas.
• Epidemics are commonly observed in areas with elevations between 1600 to 2150
meters during the months between September and December (Major) & April
to May (Minor) .
• Endemicity of malaria based on spleenic rates (palpable spleen) in children
between 2 & 9 years is classified in to 4 endemicity areas:-
• Hypo endemic - < 10% Unstable
• Meso-endemic - 10-50% transmission
• Hyper-endemic - 51-75%
Stable
• Holo-endemic - > 75% transmission
Life cycle and pathogenesis
Clinical features
• Incubation period between 10-14 days in P. vivax, P. ovale, & P.falciparum, and 18
days to 6 weeks in P. malariae.
• Early non-specific symptoms - malaise, fatigue, headache, muscle pain and
abdominal discomfort followed by fever, nausea and vomiting.
• Classical regular paroxysms of high grade fever, chills and rigor, occurring
every
- Due to rupture of Schizonts
• 2 days in P. vivax and P.ovale, Occurs in 3 stages:
• 3rd day in P.malariae, 1.Cold stage
• Irregularly in P.falciparum 2.Hot stage
3.Sweating stage
Uncomplicated vs
Complicated

• Uncomplicated malaria: - fever, malaise, and mild anemia, a palpable spleen and
liver and mild jaundice.

• Complicated Malaria: - Is defined as life threatening malaria caused by P.

falciparum, and the asexual form of the parasite demonstrated in a blood film. The
WHO uses cutoffs of 5 percent (in low transmission areas) and 10 percent (in high
transmission areas) to define hyperparasitemia for diagnosis of severe disease.
Clinical Criteria for Complicated malaria
Cerebral Malaria
• Failure to localize or respond appropriately to noxious stimuli; coma persisting for
>30 min after generalized convulsion.
• The onset may be gradual or sudden
• Manifest as diffuse symmetric encephalopathy (No meningeal sign).
• Convulsions, usually generalized(50%);
• On routine funduscopy, patients have retinal hemorrhages; with pupillary
dilatation, discrete spots of retinal opacification, papilledema, cotton wool spots
and decolorization of a retinal vessel.
Cont.
• Causes of neurological manifestations in malaria:
• High-grade fever
• Antimalarial drugs
• Hypoglycemia
• Hyponatremia
• Severe anemia
• May have residual neurologic deficit such as: hemiplegia, cerebral palsy, cortical
blindness, deafness, and impaired cognition and learning (all of varying duration).
• The majority of these deficits improve markedly or resolve completely within 6
months.
Hypoglycemia

• Plasma glucose level of <2.2 mmol/L (<40 mg/dL).

• is associated with a poor prognosis and is particularly problematic in children and
pregnant women.
• Results from: -
• Failure of hepatic gluconeogenesis
• Increase in the consumption of glucose by both host and the malaria parasites.
• Quinine - Hyperinsulinemic hypoglycemia
Acidosis
• Arterial pH of <7.25 or plasma bicarbonate level of <15 mmol/L; venous lactate
level of >5 mmol/L.
• Acidosis is an important cause of death from severe malaria;
• Results from:
• Anaerobic glycolysis in host tissues where sequestered parasites interfere with
microcirculatory flow
• Parasite lactate production
• Hypovolemia
• Insufficient hepatic and renal lactate clearance
• Manifest as laboured deep breathing often termed “respiratory distress”
• The prognosis of severe acidosis is poor.
 Noncardiogenic pulmonary edema

• The pathogenesis is uncertain but may be related to

• Sequestration of parasitized red cells in the lungs and/or
• Cytokine induced leakage from the pulmonary vasculature.
• This complication may develop even after several days of antimalarial therapy,
and can be aggravated by overly vigorous administration of intravenous fluid
• The mortality rate is >80%.
Renal Failure
• Urine output (24 h) of <400 mL in adults; no improvement with rehydration;
serum creatinine level of >265 mol/L (>3 mg/dL).
• is common among adults with severe falciparum malaria
• Results from:
• Erythrocyte sequestration and agglutination interfering with renal microcirculatory flow and
metabolism (acute tubular necrosis).
• In survivors, urine flow resumes in a median of 4 days, and serum creatinine
levels return to normal in a mean of 17 days.
Anemia
• Severe normochromic, normocytic anemia with Hematocrit of <15%.
• In endemic areas(stable transmission) most develop severe chronic anemia.
• In nonimmune individuals and areas with unstable transmission, develop acute
anemia.
• Results from:
• Hemolysis of parasitized red cells
• Increased splenic sequestration and clearance of erythrocytes with diminished
deformability
• Cytokine suppression of hematopoiesis
• Shortened erythrocyte survival
• Repeated infections and ineffective treatments
Liver dysfunction

• Serum bilirubin level of >50 mmol/L (>3 mg/dL) if combined with other evidence
of vital-organ dysfunction.
• Mild hemolytic jaundice is common in malaria.
• Severe jaundice is associated with P. falciparum infections; is more common
among adults than among children.
• Results from hemolysis, hepatocyte injury, and cholestasis.
Chronic complications of malaria

1. Hyperreactive Malarial Splenomegaly

• Is mainly due to P. vivax and P. malariae.
• The pathogenesis is believed to be related to overproduction of IgM in response to
repeated infection, with subsequent formation of immune complexes that cause
prolonged stimulation of splenic reticuloendothelial cells.
• Present with an abdominal mass or a dragging sensation in the abdomen and
occasional sharp abdominal pains suggesting perisplenitis.
• Anemia and some degree of pancytopenia are usually evident.
 2. Quartan Malarial Nephropathy
Cont. • Is due to repeated infections with P. malariae causing soluble
immune-complex injury to the renal glomeruli, resulting in
nephrotic syndrome.
• The histologic appearance is that of focal or segmental
glomerulonephritis with splitting of the capillary basement
membrane.
3. Burkitt's Lymphoma
• Is due to immune dysregulation by malaria resulting in
increased risk for EBV infection.
Diagnosis
• There are two approaches of malaria diagnosis: -
1. Clinical Diagnosis: is made when a patient: -
• has fever or history of fever in the last 48 hours and
• Lives in malaria-endemic areas or
• Has a history of travel within the last 30 days to malaria-endemic areas.
• Basing the diagnosis on clinical features alone is not recommended. Unless there
is an ongoing malaria epidemic or laboratory diagnosis is not available.
Cont.
2. Parasitological diagnosis:
• Microscopic diagnosis and Multispecies RDTs are the methods used.
• Light microscopy:
• Thick blood films used for detecting as few as 20 parasites/μl.
• Thin blood film stained with Giemsa is useful for identifying the malaria
parasite species.
• The recommended method to determine parasite load is by quantifying the
percentage of parasitized red blood cells.
• Multispecies RDTs: can detect both P. falciparum and P. vivax.
Treatment
General Management

• Bring down fever (cold sponges, Paracetamol)

• Ensure adequate fluid intake, check input and output and control water and
electrolyte balance.
• Check renal function tests and blood sugar .
For comatose or unconscious patients proper nursing care:
• Position the patient on his/her sides; turn every 2 hours to avoid bed sores.
• Catheterize the bladder, monitor input-output.
• Avoid fluid overload
• Monitor blood glucose regularly
• Ensure adequate nutrition
Uncomplicated malaria

• If the RDT or microscopy test indicates P. falciparum infection,

• First line treatment is AL (Co- artem).
• AL is available in a fixed dose combination tablets containing artemether 20 mg
and lumefantrine 120 mg.
• The dosage depends on the patient‘s body weight and is taken every 12 hours for
3 days.
• Adults - 4 tablets BID for 3 days.
Cont.
• If the RDT or microscopy test indicates P. vivax infection only (and no P.
falciparum),
• First line treatment is Chloroquine.
• Total dose of 25 mg base per kg over 3 days (10 mg base per kg on Day 1, 10 mg
base per kg on day 2, and 5 mg base per kg on day 3). one 250 mg chloroquine
phosphate salt tablet contains 150 mg chloroquine base.
• Adults – 4 tablets per day for 3 days
• For P. vivax, radical cure with primaquine is recommended for patients with
limited risk re-infection, i.e. who are not living in malaria-endemic areas, in
addition to chloroquine.
Cont.
• Mixed infection of P. falciparum and P.vivax first line treatment is AL (Co-
artem).
• Pregnant women in the first trimester and children weighing less than five kg
should be treated with oral quinine when P. falciparum infection is present
otherwise Chloroquine is safe in pregnancy and for infants.
• Oral quinine dosage is 8.3 mg base/kg (=10 mg quinine sulphate salt/kg) three
times daily for seven days.
• Adults – 600mg PO TID per day (Three quinine sulphate salt tablets).
Treatment Failure
• The majority of treatment failures occur after two weeks of initial treatment.
• Result from either treatment failure or a new infection.
• If occur between 4- 14 days and parasites are detected, the treatment should be
changed to the second-line drug, i.e. Quinine.
• All presumed treatment failures after two weeks of initial treatment should be
considered as new infections, and be treated with the first-line antimalarial drug.
Complicated malaria

• First line treatment due to P. falciparum is either:

• IV or IM artesunate (preferred); OR
• IM artemether (alternate)
• If artesunate is not available: IV or IM quinine infusion
• Artesunate is given 2.4 mg/kg IV or IM given on admission, at 12hrs, at 24hrs
then once a day for 5-7 days.
• Once the patient with severe malaria regains consciousness and tolerates oral
therapy, oral AL therapy should be started.
Treatment of Complications

1. Cerebral Malaria: -
• Diagnosing and managing hypoglycemia.
• Look for and treat convulsions with Diazepam 0.15 mg/kg IV;
• Check the rate of quinine infusion as sub-optimal dosing is a recognized cause of
behavior change or for deterioration of patients after improvement
Cont.
2. Severe Anemia: -
• If haemoatcrit is below 15% (hemoglobin less than 5g/dl) and/or associated with
acidosis, shock or high parasitemia blood transfusion is indicated:
• 10 ml/kg of packed cells OR 20 ml/kg of whole blood.
Cont.
3. Hypoglycemia:
• An initial slow injection of 50% dextrose (0.5 g/kg) should be followed by an
infusion of 10% dextrose (0.10 g/kg per hour).
• The blood glucose level should be checked regularly thereafter as recurrent
hypoglycemia is common, particularly among patients receiving quinine or
quinidine.
Cont.
4. Acute Pulmonary edema:
• Position patient upright (sitting position),
• Give oxygen therapy;
• Give diuretics (furosemide 40 mg IV).
• Assess the need for intubation and mechanical ventilation.
Side effects and Contradictions of antimalarial drugs

1. Artemether-lumefantrine
Side effects: dizziness and fatigue, anorexia, nausea, vomiting, abdominal pain,
palpitations, myalgia, sleep disorders, arthralgia, headache and rash.
Contraindications:
• Artemether-lumefantrine should not be used as malaria prophylaxis either alone or
in combination;
• Persons with a previous history of reaction after using the drug;
• Pregnant women in the first trimester and infants less than 5 kg;
Cont.
2. Chloroquine
Side effects: Dizziness, skeletal muscle weakness, mild gastrointestinal
disturbances (nausea, vomiting, abdominal discomfort and diarrhea) and pruritus.
Contraindications:
• Persons with known hypersensitivity
• Persons with a history of epilepsy
• Persons suffering from psoriasis
Cont.
3. Quinine
• Quinine is a natural alkaloid derived from cinchona.
• It is powerful schizonticide and has also anti-inflammatory action.
Side effects:
• Dizziness, tinnitus, blurred vision, nausea, vomiting and tremors, known
collectively as ‘Cinchonism’. These symptoms are not severe enough to stop
treatment and subside spontaneously when administration of the drugs ends.
• Hypoglycemia, Hypotension.
• Contraindications: No contraindication to the oral administration
 Diagnosis Algorithm
Suspected Clinical malaria

Clinical Diagnosis (if RDT is

Negative Multispecies RDT/Microscopy
not available)

Signs and symptoms of P. falciparum or mixed (P.

P. vivax
severe malaria falciparum and P.vivax)

Severe Non complicated Treat with

Yes No chloroquine
Malaria malaria

Give first dose of rectal

Look for other causes of
artesunate or IM Treat with Co-artem(AL)
acute fever
artemether
Prevention
1. General measures
• Draining water collections and swampy areas
• Use of chemical impregnated mosquito nets around beds
• Wire mesh across windows
• Staying indoors at night
• Use of long sleeved shirts and long trousers
• Use insecticide spray
• Application of insect repellents to exposed skin (e.g.diethyltoluamide)
• DDT sprayed in the interior of houses.
Cont.
2. Chemoprophylaxis:
It is indicated for:
• Pregnant women in endemic areas
• Children between 3 months and 4 years in endemic area (born to non-immune
mother)
• Travelers to malarious areas
Cont.
Drugs used are:
• Mefloquine 250mg/week orally;
• Doxycycline 100mg daily orally;
• Maloprim (Pyrimethamine+ dapson) 1 tab orally/wk;
• Chloroquine+ proguanil combination;
• Chloroquine 2 tabs of 150 mg tablet orally every week (for Chlroquine sensitive P.
falciparum).
Relapsing Fever
Outline
• Definition and Etiology
• Epidemiology
• Life cycle and pathogenesis
• Clinical features
• Complications
• Diagnosis
• Treatment
Definition
• is an acute febrile illness caused by Borrelia species, presenting with recurrence
of characteristic febrile periods lasting for days alternating with afebrile periods.
• Based on its Vector can be classified as: -
• Louse borne (Endemic) relapsing fever:- transmitted by body louse Pediculus humanis var
corporis
• Tick borne (Epidemic) relapsing fever: - transmitted by tick (Ornithodoros)
Etiology
• Caused by Borrelia species, which are slender actively motile spirochetal gram
negative helical bacteria.
• B. recurrentis
• B. duttoni
• demonstrates remarkable antigenic variation and strain heterogeneity which help
the parasite to escape the immune response of the host and result in recurrence of
febrile episodes.
Epidemiology

• Louse borne relapsing fever is now an important disease only in the northeastern
Africa, specially the highlands of Ethiopia where an estimated 10,000 case occur
annually.
• In Ethiopia it mainly affects homeless people.
• Some of the risk factors for LBRF are over crowding like in military camps,
civilian population disrupted by war and other disasters.
• Tick borne relapsing fever highly endemic in sub-Saharan Africa.
Life cycle and Pathogenesis

• Body lice become infected by B. recurrentis while feeding on spirochetemic

human blood, the only reservoir of infection.
• Portal of entry, infected lice crushed into abraded skin.
• In Tick borne relapsing fever rodents are the primary hosts and vector ticks
become infected when they feed on spirochetemic rodents.
• There is high level of spirochetemia for which neutralizing antibodies and
cytokines are produced, clearing of the circulating Borrelia in 3-5 days, then new
antigenic variants appear.
Clinical Features
• Incubation period is 7 days (ranging from 2-18 days).
• The onset is sudden with high grade irregular fever (≥39◦C), headache, chills,
myalgias, arthralgias, and insomnia.
• The febrile episodes are characterized by crisies marked by labile blood pressures
and pulse. The greatest risk of death is during and immediately following the
period of hypotension.
• Patient will be withdrawn, disinterested to food and other stimuli and thirsty.
• On average those with LBRF experience only one relapse whereas TBRF 3
relapses
Cont.
• Delirium associated with high grade fever, tachycardia and dry tongue, injected
conjunctiva and photophobia.
• Upper abdominal tenderness with hepatosplenomegally,
• Scattered petechiae over the trunk, extremities and mucous membrane in 1/3
LBRF and fewer TBRF
• Symptoms and signs of meningial irritation may be seen in some patients.
• Icteric sclera may be found in late stage of the disease.
Complications
• Epistaxis, blood streaked sputum other bleeding tendencies
• Neurologic manifestations like iridocyclitis, meningitis,
coma, isolated cranial nerve palsies,
• Pneumonitis,
• Myocarditis
• Splenic rupture
Diagnosis
• Diagnosis of relapsing fever is made based on demonstration of the organisms in
blood, bone marrow, CSF etc
• Blood Film: with Giemsa or Wright stained peripheral blood smear.
• Should be taken during the febrile periods.
• Positive in > 70% of Louse borne relapsing fever.
Treatment
• Antibiotics and observingChoice
for Jarisch-Herxheimer reaction.
Louse Borne (single Tick Borne (for 7
dose) days)
Erythromycin 500mg 500mg every 6 hrs

Tetracycline 500mg 500mg every 6 hrs

Doxycycline 100mg 100mg every 12 hrs
Chloramphenicol 500mg 500mg every 6 hrs
Penicillin G (procaine) 600,000 I.M stat 600,000 IM daily

• Delousing the patient - to prevent transmission and recurrence

Jarisch-Herxheimer reaction
• is an acute exacerbation (1- 4 hrs of 1st dose) of symptoms that may occur on
initial treatment of relapsing fever with an effective antibiotic.
• The reaction is common in LBRF treated with tetracycline. Because it rapidly
alters the morphology of the dividing spirochetes, making them susceptible to
phagocytosis.
• Symptoms often include hypotension, tachycardia, chills, rigors, diaphoresis, and
marked elevation of body temperature.
Cont.
Treatment
• Close monitoring of vital signs
• Careful fluid management
• Control high body Temperature
• Short term digoxin I.V administration in patients with evidence of myocardial
dysfunction
• Patients with LBRF who develop the Jarisch-Herxheimer reaction should be
transferred to an intensive care unit for close monitoring of fluid balance, arterial
and central venous pressure, and myocardial function.
References
• Harrison’s principle of Internal Medicine,18th edition
• FDRE National malaria guidelines,3rd edition, 2012
• Uptodate 21.2
• Medscape
Typhoid Fever
Typhoid fever

• Systemic infection characterized by fever and abdominal pain

• S. typhi and S. paratyphi A and B .
• non capsulated, gram negative motile aerobic and none spore forming bacteria
• It contains:
• LPS, lipolysaccharide
• Oligosaccharide somatic antigen “O” antigen
• Flagella “H” antigen
• Virulence “Vi’ antigen
Epidemiology

• Typhoid/enteric fever is endemic in most developing countries in

Africa, Asia and Latin America

• It is primarily a disease of children and young adults

• In developed countries it occurs in travelers to endemic regions

• Man is the ONLY reservoir of Salmonella typhi

• It is transmitted by ingestion of food/water contaminated by feces of

patients/carriers
Epidemiology contd.
• Up to 10% of patients continue to excrete the
organism in feces for three months

• 2-3% become chronic carriers; excrete the organism

for > 1yr

• S. typhi had become increasingly resistant to a

number of 1st line antibiotics
Pathogenesis
• The portal of entry is the gastrointestinal tract
• Infecting dose, ID50, is 10,000,000 organism
• Organism destroyed by acid in stomach

• Conditions that decrease either stomach acidity (age <1yr,antiacid use) or

intestinal integerity

(IBD,GI surgery ,antibiotic ) increase sustablity to salmonella infecion

• Incubation period is 7-10 days
• Organism multiplies within mononuclear phagocytic cells of the
intestinal lymphoid follicles
Pathogenesis contd.

• After initial intracellular replication the organism is

released into the circulation:
• Sustained bacteremia
• Widely disseminated and seeds the liver, spleen, bone
marrow, gall bladder
• It induces local and systemic humoral and cellular
responses
• Endotoxin may activate clotting/fibrinolytic cascade
• Local inflammation at Peyer’s patches may cause tissue
necrosis
Clinical manifestations

• The onset is usually sub acute

• During the 1st week,
• temperature rises in stepladder fashion, and remains
constant
• Patients develop headache, dry cough, abdominal pain
• Liver and spleen palpable in about 50% of cases
• Relative bradycardia & Epistaxis
• Rose spots, pink macules, may be present
Second wk

• Fever becomes continuous

• The patient becomes very ill and withdrawn confused, delirious and
even comatose

3rd wk
• The patient goes to a pattern of “typhoidal state" characterized by
extreme toxemia,
disorientation, and “pea-soup” diarrhea and

• may be complicated by intestinal

perforation and hemorrhage.
Fourth wk

• Fever starts to decrease and resolution of symptoms.

• At this point patient may lose weight.
• Relapse may occur in 10% of cases
Complications
• With appropriate therapy mortality <1%
• In some endemic regions it may be as high as 30%

• GI Perforation (1_3%) & Hemorrhage (10%)

• May develop despite clinical improvement
• Relapse occurs in 5-10% of patients
• Neurologic manifastion 2-40%
GBS,Neuritis,Neuropsychitric sm
• Chronic carriers in about 3%--- high in women & among
patient with biliary abnormality & GI maligancy
Less common complications
• Splenic and liver abscess
• Meningitis .
• Arthritis, osteomyelitis
• Parotitis and orchitis
• Nephritis
• Myocarditis
• Bronchitis and pneumonia

• N.B these complications can be prevented by prompt diagnosis and

treatment
Laboratory diagnosis
• In the 1st week
Blood culture (40__ 80% senstivity)
Bone marrow culture (55_90%) Its yield is not reduced by
up to 5 day of prior antibiotic therapy
Serological test, the Widal test becomes positive in 7-10 days
• A four-fold rise in titer
• A single titer of >1/160 WITH compatible clinical illness
• False positive/negative results are common
• Stool and Urine culture in the 3rd week
TREATMENT

First line
• Ciprofloxacin 500mg PO BID for 10day
• Ceftriaxone 1-2gm IM or IV for 10 _14day

Alternative
• Azithromycine 1gmPO daily for 5 day
• Chloramphenicol 500 mg Po QID for 14 day
1gm IV QID FOR 2-3day & then PO
• Norfloxacin 400mg twice daily for 10 days
Adjunct therapy
• Dexamethasone, 3mg/kg, IV for 48 hours

• Perforation is usually managed by surgery

• Sever GI bleeding may require blood transfusion

Prevention and control
• Improve environmental sanitation
• Identification and treatment of Chronic carriers
• Avoid food handling by chronic carriers
• Vaccination for travelers to endemic areas
Live oral vaccine (TY21a) 3 doses can be given to those
over 6 years. Protective for several years
Purified Vi polysaccharide vaccine given in a single dose to
those over 2 years and HIV positives, is as effective as live
vaccine.
TYPHUS
• Rickettisial ds
1. Louse-borne [epidemic typhus] R.prowazeki by body lice
2. Brill-zinsser ds-reactivation
3. Flea-borne/ murine /endemic typhus-by R.typhi & transmit flea from
rodent
Pathophysiology

• Rickettsia multiply in the endothelial cells of capillaries causing

lesions in the skin, brain,lung, heart, kidneys and skeletal muscles.
• Endothelial proliferation coupled with peri-vascular reaction causes
thromboses and small hemorrhages.
• Tissue and organ injury is commonly due to increased vascular
permeability with resulting edema, hypovolemia and organ ischemia.
• This leads to multi-system involvement with complications such as
non-cardiogenic pulmonary edema, cardiac dysrhythemia, encephalitis,
renal and hepatic failure and bleeding.
• Usually we may find thrombocytopenia,abnormal liver function tests
& hyponatremia and mild leukocytosis or leukopenia could be there
Louse borne Typhus
•Is endemic in the highlands of Ethiopia, and it also
occurs in sporadic epidemics

•Epidemic typhus is a classic disease of poverty,

overcrowding, and infestation with lice.

•Persons at risk prisoners, soldiers, homeless,

medical personnel.
CLINICAL FEATURES
•Incubation period, seven days.
•Severe –mortality rate 20%

•Prodromal symptoms, malaise, myalgia, headache.

•Abrupt onset of fever and chills.

•Rash appears after 4-5 days.

• is macular/papular/petechial. trunk , axillary fold &
extrimitis –spares face,palms ,soles
• Conjutivae injectIon ,photophobia & eye pain
• Tongue-dry,brown & furred
• Deafness,tinntus & vertigo
• 70%-cough
• Back & leg pain-vasculitis in severe case

• Neurologic manifestation common

 Flea-borne
C/m
• Ip-1-2wks
• Similar-less sever –mortality rate [1-2%]
• Headache & muscular pain-predominant
• Serious neurological & renal comp.-unusual
Complications of Endemic and Epidemic Typhus

• Skin necrosis, gangrene of digits,

• Venous thrombosis
• Interstitial pneumonia in severe cases
• Myocarditis
• Oliguric renal failure
• Parotitis
• Cerebral hemorrhage
• Hemolysis
• Respiratory failure
 Diagnosis
• History,clinical presentation and the epidemiologic of
disease
• Serologic test
• Indirect fluoresent antibody test
• Weil-felix agglutination test-not specific or
sensitive

Treatment
• Doxycycline 100mg PO bid / 7—15days
Chloramphenicol -500mg QID/ 7--15day
Tetracycline-25mg/kg
Prevention
• Malathine, peremethrine applied on clothings or bedding
• Rodent control using chemical ( Warfarin)
• antibiotic prophylaxixs like doxycycline 200mg once weekly
• for
Travelers or health care workers residing in areas in which epidemic
typhus is present .
continued for one week after leaving such areas.