Malaria

Manifestations

The incubation period for malaria is around 7-30 day. There is a brief prodromal period with symptoms of
fever, headache, and myalgia. Symptoms begin with a cold stage (a shaking chill), following by a fever stage
(40–41°C) that lasts about 24 hours, and finally a wet stage. The wet stage occurs several hours after the
fever, when the body temperature drops quickly to normal and profuse sweating begins. The patient is
exhausted but well until the next cycle of fever begins. Other symptoms include splenomegaly and anemia.

Three basic types of malaria

1. Benign tertian (P vivax and P ovale) with a fever every 2nd day (e.g., Monday; fever, Tuesday; no fever,
Wednesday; fever).

2. Benign quartan (P malariae) with a fever every 3rd day (e.g., Monday; fever, Tuesday; no fever,
Wednesday; no fever, Thursday; fever).

3. Malignant tertian (P falciparum), in which the cold stage is less pronounced and the fever stage is more
prolonged and intensified (if the fever is recurring it occurs every 2nd day). However, the fever is usually
continuous or only briefly remittent. There is no wet stage. This type of malaria is more dangerous because
of the complications caused by capillary blockage (i.e., convulsion, coma, acute pulmonary insufficiency,
and cardiac failure). Large numbers of erythrocytes are parasitized and destroyed, which may result in
dark-colored urine (blackwater fever; intravascular hemolysis, hemoglobinuria, and kidney failure.).

Two species of Plasmodium, P vivax and P ovale, can remain in the liver, if not treated properly. The
organisms leave the liver and re-infect erythrocytes, causing the symptoms described above. Relapsing
malaria occurs when there are relapses many years after the initial episode of malarial disease.
Types of fever

Difference of viral vs bacterial meningitis

Malaria
Malaria
Summary

Malaria is a potentially life-threatening tropical disease caused by Plasmodium parasites, which are

transmitted through the bite of an infected female Anopheles mosquito. The clinical presentation and
prognosis of the disease depend on the Plasmodium species. Malaria has an incubation period of 7–42
days and may present with relatively unspecific symptoms like fever, nausea, and vomiting. Therefore, it is
often misdiagnosed. Clinically suspected cases are confirmed by direct parasite detection in a blood smear.
Patients are treated with antimalarial drugs (e.g., chloroquine, quinine), some of which may also be used as
a prophylaxis during trips to endemic regions. However, the most important preventive measure is
adequate protection against the Anopheles mosquito (e.g., mosquito nets, repellents, protective clothing,
etc.). Malaria is a notifiable disease and should be suspected in all patients with fever and a history of
travel to an endemic region.

Epidemiology

 Distribution
o Most cases of malaria occur in tropical Africa (West and Central Africa).
o Transmission also occurs in other tropical and subtropical regions such as Asia (e.g., India,
Thailand, Indonesia), and Latin America (e.g., Brazil, Colombia)

Etiology

 Pathogen: Plasmodia
o Eukaryotic parasites (belonging to the Sporozoa group)
o For different species, see the table below.
 Vector: the female Anopheles mosquito 

 Host: humans
 Partial resistance against malaria
o Carriers of sickle-cell mutation 

o Other hemoglobinopathies (e.g., thalassemia, Hb C)

o Infection with malaria subsequently leads to the development of

specific Plasmodium antibodies that result in partial immunity for a limited amount of time
(less than a year) 

Different species Disease Fever spikes

of plasmodium
Plasmodium vivax Tertian malaria (usually less severe) Every 48
hours
Plasmodium ovale
Plasmodium malariae Quartan malaria (usually less severe) Every 72
hours
Plasmodium falciparum Falciparum malaria (most severe form; also known Irregular 
as malignant tertian malaria)
Different species Disease Fever spikes
of plasmodium
Plasmodium knowlesi  Quotidian malaria Irregular

Pathophysiology

Life cycle of Plasmodium (simplified) 

Asexual development in humans

1. Transmission of Plasmodium sporozoites  via Anopheles mosquito bite → sporozoites travel through

the bloodstream to the liver of the host

2. Liver: sporozoites enter hepatocytes → sporozoites multiply asexually → schizonts  are formed

containing thousands of merozoites  → release of merozoites into the bloodstream

3. Circulatory system → two possible outcomes:

 Merozoites enter erythrocytes → maturation to trophozoites  → red cell schizonts are formed

containing thousands of merozoites → release of merozoites into the bloodstream (which
causes fever and other manifestations of malaria) → penetration of erythrocytes recurs
 Merozoites enter erythrocytes → differentiation into gametocytes (male or female)

Sexual development in female Anopheles mosquito

 A mosquito bites an infected human and ingests gametocytes → gametocytes mature within the
mosquito intestines → sporozoites are formed and these migrate to the salivary glands →
transmission of sporozoites to humans via mosquito bite
Developmental stages of Plasmodium in RBCs

 Immature trophozoite: thick, dark purple ring-shaped inclusions (similar to signet ring cell

carcinoma)
 With Plasmodium falciparum: fine rings

 Mature trophozoite: ameboid rings 

 With Plasmodium falciparum: finer rings in comparison to immature trophozoites

 Immature schizont: irregular round, ameboid, almost filling the entire erythrocyte

 With Plasmodium falciparum: hardly detectable in the blood

 Mature schizont: conglomerate of 6–24 merozoites (round with central darkening), which develops
from an immature schizont
 With Plasmodium falciparum: hardly detectable in the blood

 Gametocytes 
  Macrogamete: mature female (sexual) form, visible as a round structure filling almost the
entire erythrocyte 

 Microgamete: mature male (sexual) form, visible as a round structure within

the erythrocyte. In comparison to macrogametes, it is smaller and has a brighter nucleus. 

Clinical features

 Incubation: 7–42 days
o Relapse in P. ovale or P. vivax infection

o Following the successful treatment of tertian malaria, some Plasmodium forms

(hypnozoites) may persist within the liver and cause reinfection after lying dormant for
months or even years.

The incubation period of malaria is a minimum of seven days; if a fever occurs before the seventh day
following exposure in an endemic region, it is most likely not due to malaria!

 Course: tertian and quartan malaria are associated with less severe symptoms, the involvement of
fewer organs (rarely CNS or gastrointestinal symptoms), and a markedly lower risk of severe
malaria.
 Flu-like symptoms
 High fever
o Tertian malaria: periodic fever spikes every 48 hrs
o Quartan malaria: periodic fever spikes every 72 hrs
o Falciparum malaria (malignant tertian malaria): irregular fever spikes without a noticeable
rhythm

o Diaphoresis (sweating)
 Weakness, paleness, dizziness 

 Increased bleeding risk  → in severe cases, disseminated intravascular coagulation may occur.

 Gastrointestinal: diarrhea, abdominal pain, nausea, and vomiting
 Liver: hepatosplenomegaly, discrete jaundice

 Severe malaria: can lead to severe organ dysfunction 

o Most commonly a result of falciparum malaria

o Kidneys: flank pain, oliguria, hemoglobinuria
o Cerebral: hallucinations, confusion, impaired consciousness, or even coma
o Cardiopulmonary: heart failure, pulmonary edema, shock

Malaria can present in many different ways, and is therefore often misdiagnosed. In patients
with fever who have recently traveled to endemic regions, malaria must always be considered!
Diagnostics

 History: recent or distant travel to regions where malaria is endemic

 CBC
 o Hemolytic anemia: ↓ Hb, ↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes 

o Thrombocytopenia 

o Possibly leukocytopenia
 Blood smear: confirms suspected cases by visualizing parasites within RBCs 
o Best initial test: thick blood smear (high sensitivity); detects the presence of parasites. 
o Confirmatory testing: thin blood smear
 Lower sensitivity than thick blood smear, but higher specificity

 Parasites are visible within red blood cells since the morphology of erythrocytes is

preserved.

 Allows determination of Plasmodium species

 Evaluation of parasite and erythrocyte morphology

 Schüffner granules with P. vivax and P. ovale 

 Rapid diagnostic tests (RDTs)

o Determination of specific malaria antigens, e.g., HRP2, pLDH, and aldolase

o Benefits: quick determination of malaria infection in areas lacking high-quality malaria

microscopy

o All RDT results should always be confirmed via microscopy (if available).

 Serological tests

o Not appropriate for acute diagnosis of malaria because antibodies are undetectable for 1–2

weeks

o Positive serological results indicate past contact with Plasmodium

If symptoms persist despite negative microscopy and rapid testing, diagnostics should be repeated every
eight hours for several days!
Treatment

When choosing antimalarial drugs, age, side effects, cost, geographic region, and dosing schedule should
all be taken into consideration.

Tertian malaria

Plasmodium species Treatment
P. vivax, P. Chloroquine OR hydroxychloroquine
ovale (chloroquine-sensitive) + Primaquine: to eradicate hypnozoites of P. vivax and P.
ovale and prevent relapse

P. vivax (chloroquine-resistant) Artemether-lumefantrine
Plasmodium species Treatment

Quartan malaria

 Treatment of choice: chloroquine or hydroxychloroquine 

Falciparum malaria

Severity of disease Region  Treatment

Uncomplicated falciparum Chloroquine-sensitive  Chloroquine OR hydroxychloroquine
malaria

Chloroquine-resistant
Artemether-lumefantrine
OR Atovaquone-proguanil
OR Quinine PLUS doxycycline
OR Quinine PLUS tetracycline
OR Quinine PLUS clindamycin
OR Mefloquine 

Severe falciparum malaria All regions Artesunate  followed by

artemether/lumefantrine 
OR Quinidine PLUS doxycycline
OR Quinidine PLUS tetracycline
OR Quinidine PLUS clindamycin
Intensive care and supportive therapy
(lowering fever, avoiding hypoglycemia) are
essential.

Plasmodium falciparum and, more recently, Plasmodium vivax are increasingly resistant to chloroquine.

Side effects of antimalarial medication

Drug Most important side effects

Chloroquine or hydroxychloroquin Irreversible retinopathy!
e CNS: agitation, anxiety, confusion
Gastrointestinal discomfort

Primaquine Hemolytic crisis in G6PD deficiency 

Mefloquine CNS: dizziness, confusion,

nightmares, hallucinations, seizures
Rash
Gastrointestinal discomfort
Drug Most important side effects
Atovaquone-proguanil Gastrointestinal discomfort

Quinine CNS: headache, mental status altered

Gastrointestinal discomfort
Fever, flushing

Doxycycline or tetracycline Photosensitivity
Nephro- and hepatotoxicity
Damage to mucous membranes (these antibiotics should be
taken with a lot of water)

Artemether-lumefantrine Gastrointestinal discomfort

Prolonged QT interval

Quinidine Palpitations, angina pectoris

CNS: dizziness, fatigue, headache
Rash
Gastrointestinal discomfort

Artesunate Hemolytic crisis in G6PD deficiency 

Prevention

Mosquito bite prevention

 Avoid exposure
 Exercise particular caution during peak biting periods 
 Mosquito nets
 Protective clothing (covering most of the skin, light colors)
 Mosquito repellent, such as DEET (N,N-diethyl-meta-toluamide)
 Mosquito control
 Reduce breeding sites (e.g., eliminate pools of water, optimize plant watering)
 Insecticide spraying

Malaria prophylaxis

 Should be initiated before traveling to regions with a high risk of malaria: e.g., tropical Africa, Asia,
and Latin America
 Drug of choice is based on the area
 Areas with P. falciparum
 If chloroquine-resistant P. falciparum (most malaria endemic regions): atovaquone-
proguanil, doxycycline, mefloquine
 If chloroquine-sensitive P. falciparum: chloroquine
  Areas without P. falciparum (some areas of Central/South America, Mexico, China, South
Korea): primaquine
 Agents that are safe during pregnancy: chloroquine, mefloquine

Prophylactic medication cannot prevent infection but suppresses the clinical course and symptoms by
killing the parasite before it can cause a severe infection. There is no prophylactic medication that provides
protection against all potential parasites.

Standby emergency treatment

 Indication
 Traveling to endemic regions with a medium to high risk of malaria
 Depending on the risk, either prophylactic or standby emergency treatment may be
recommended (when in doubt: prophylactic medication).
 Drugs
 Atovaquone-proguanil
 Artemether-lumefantrine
 (Chloroquine) 

Dengue
Summary

Dengue is a viral disease transmitted by mosquitoes (especially Aedes aegypti) and is widely distributed
throughout the tropics and subtropics. Dengue classically presents with high fever, headache, body
aches, exanthem, and generalized lymphadenopathy. Symptoms usually subside within one week. Some
cases progress to the more severe dengue hemorrhagic fever (DHF) with thrombocytopenia, spontaneous
bleeding, and potentially shock (dengue shock syndrome). Treatment is supportive. A vaccination is
available for use in children, living in endemic areas, with confirmed prior dengue virus infection.

Epidemiology

 Distribution: tropical regions worldwide, particularly Asia (e.g., Thailand)

 Incidence
 Most common viral disease affecting tourists in tropical regions
 ∼ 400 million infections per year worldwide

Etiology

 Pathogen
 Dengue virus (Serotype: DENV 1–4) 
  RNA virus of the genus Flavivirus
 Transmission route [3]
 Vector-borne: mosquitoes most commonly from the species Aedes aegypti 

Clinical features

Classic dengue fever

 Incubation period: 2–14 days

 Children are usually asymptomatic
 Starts with fever and malaise that lasts ∼ 1 week
 Severe arthralgia and myalgia (often referred to as “break-bone fever”)
 Severe headache and retro-orbital pain
 Maculopapular, measles-like exanthem (typically appears 2–5 days following fever)
 Generalized lymphadenopathy

If symptoms appear more than 2 weeks after returning from a dengue-endemic region, it is very unlikely
that dengue is the cause!

Dengue hemorrhagic fever (DHF)

 Occurs in 1–2% of cases

 Generally develops as the initial fever subsides (∼ 1 week after onset)

 Clinical manifestations
 Temperature change: ranges from hypothermia to a second spike in fever
 Abdominal pain, vomiting
 Changes in mental status (e.g., confusion)
 Hemorrhagic manifestations (e.g., petechiae, epistaxis, gingival bleeding) 
 Positive capillary fragility test [7]
 Increased vascular permeability → signs of pleural effusion and/or ascites

 Dengue shock syndrome (DSS): DHF + shock

Dengue hemorrhagic fever is more frequent in individuals who experience a repeat infection with a second
serotype, especially serotype 2!
Diagnostics

 Laboratory tests
 Leukopenia
 Thrombocytopenia

 ↑ AST
 Hct elevated ≥ 20% of normal values if vascular permeability (in DHF)

 Best test for confirming infection: serology (IgM, IgG)

 Alternatives
 PCR
 Molecular methods (ELISA): detection of viral antigen

Differential diagnoses
  Malaria
 Other viral hemorrhagic fevers
 Especially Chikungunya (exhibits similar symptoms with an emphasis
on bilateral polyarthralgia)
 Zika virus infection

Treatment

 Symptomatic treatment
 Fluid administration to avoid dehydration
 Acetaminophen 
 Dengue hemorrhagic fever
 Blood transfusions in case of significant internal bleeding (e.g., epistaxis, gastrointestinal
bleeding, or menorrhagia)
 IV fluids

Prevention

 Avoid exposure, use of mosquito repellent (see also → mosquito bite prevention)

 A tetravalent attenuated live vaccine (CYD-TDV) has been approved for use in children between 9–
16 years of age who live in endemic areas and have a laboratory confirmed prior dengue
virus infection.

Dengue
Severe dengue
Severe dengue should be considered if the patient is from an area of dengue risk presenting with fever of
2–7 days plus any of the following features:
• There is evidence of plasma leakage, such as:
– high or progressively rising haematocrit;
– pleural effusions or ascites;
– circulatory compromise or shock (tachycardia, cold and clammy extremities, capillary refill time greater
than three seconds, weak or undetectable pulse, narrow pulse pressure or, in late shock, unrecordable
blood pressure).
• There is significant bleeding.
• There is an altered level of consciousness (lethargy or restlessness, coma, convulsions).
• There is severe gastrointestinal involvement (persistent vomiting, increasing or intense abdominal pain,
jaundice).
• There is severe organ impairment (acute liver failure, acute renal failure, encephalopathy or encephalitis,
or other unusual manifestations, cardiomyopathy) or other unusual manifestations.

2.2.3 Referral centres

Referral centres receiving severely ill dengue patients must be able to give prompt attention to referred
cases. Beds should be made available to those patients who meet the admission criteria, even if elective
cases have to be deferred. If possible, there should be a designated area to cohort dengue patients, and a
high-dependency unit for closer monitoring of those with shock. These units should be staffed by doctors
and nurses who are trained to recognize high-risk patients and to institute appropriate treatment and
monitoring.
A number of criteria may be used to decide when to transfer a patient to a high- dependency unit. These
include:
– early presentation with shock (on days 2 or 3 of illness);
– severe plasma leakage and/or shock;
– undetectable pulse and blood pressure;
– severe bleeding;
– fluid overload;
– organ impairment (such as hepatic damage, cardiomyopathy, encephalopathy, encephalitis and other
unusual complications).
1
Yellow Fever
A 32-year-old woman presents to a local clinic in Nigeria. She had been working in the rainforest as part of
a conservation movement and had been bitten multiple times over the past few days by mosquitos and
other flying insects. Three days ago, she developed a flu-like viral illness and recently began having minor
nosebleeds. She also noted that her skin looked more yellow than normal. On exam, she is jaundiced with
scleral icterus. She is also noted to have hepatomegaly and gingival bleeding. Laboratory testing reveals a
transaminitis and hyperbilirubinemia. She is told that she needs to be admitted for close monitoring.

Classification
 yellow fever virus
o a positive-stranded, linear RNA virus
o a flavivirus and arbovirus with icosahedral capsid
o transmitted by Aedes mosquito
o reservoir is human or monkey
Epidemiology
 incidence
o endemic in South America and Africa
 risk factors
o exposure to endemic areas
o mosquito bites
Pathogenesis
 the virus spreads via blood
 it infects the liver
o liver cells die via apoptosis
o coagulopathy occurs due to loss of hepatic synthesis of clotting factors
Associated conditions
 hemorrhagic fever
Prevention
 live-attenuated virus vaccine
o given at age 9-12 months in endemic areas
o given 10 days prior to travel to endemic areas
Prognosis
 most patients recover without complications
 however, in severe cases, mortality rate is up to 60%

Presentation
Symptoms
 most patients are asymptomatic
 if symptomatic
o flu-like prodrome
o headache
o myalgias
o nausea
o black vomitus
Physical exam
 high fever
 jaundice
 scleral icterus
 hepatomegaly
 minor hemorrhage
 o epistaxis
o mucosal bleeding
o melena

Labs
 diagnostic
o reverse transcriptase-polymerase chain reaction
o serology with enzyme-linked immunosorbent assay
 transaminitis (AST > ALT)
 elevated prothrombin and partial thromboplastin times
 hyperbilirubinemia
Guaiac stool testing
 occult blood
Liver biopsy
 Councilman bodies
o eosinophilic apoptotic globules
 typically found on autopsy
Making the diagnosis
 most cases are clinically diagnosed, especially in those who have recently traveled to an endemic
area

Differential diagnosis
 Dengue fever
o distinguishing factor
 may also be hemorrhagic but does not affect the liver
 will not present with jaundice, scleral icterus, and hepatomegaly
 Chikungunya
o distinguishing factor
 typically does not present with hemorrhage

Treatment
 Conservative
o supportive care
 indication
 all patients
 modalities
 rehydration
 close monitoring
 pain control

Filariasis
 Lymphatic filariasis
 Pathogens
o Wuchereria bancrofti: a nematode; responsible for most cases of lymphatic filariasis
worldwide
o Brugia malayi and Brugia timori: found in Asia
 Mode of transmission: female mosquito bite (Aedes, Mansonia, Anopheles, and Culex)
 Incubation period: 9–12 months
 Life cycle: Mosquito introduces filarial larvae into host via bite wound → Larvae mature into adult
worms that reside in the lymphatic system → Adult worms produce microfilariae → Microfilariae
move throughout vascular and lymphatic system → Microfilariae are consumed by a female fly
during a blood meal → Microfilariae mature into larvae, thus completing the cycle.
 Clinical features
o Fever
o Painful lymphadenopathy (due to worms invading lymph nodes, causing inflammation) and
retrograde lymphangitis → lymphedema with disfiguration of the lower extremities
(elephantiasis)
o Hydrocele
 Diagnosis
o Blood smear obtained at night (and staining with Giemsa or hematoxylin and eosin):
detection of microfilariae
o Serology: elevated levels of antifilarial IgG4
 Treatment
o Diethylcarbamazine (DEC): drug of choice
o Ivermectin: used in areas where onchocerciasis is prevalent, as DEC can worsen onchocercal
eye disease
o Elevation of the affected extremity, exercise, and wearing therapeutic shoes: recommended
for those with lymphedema
o Surgery for hydrocele
Different species of the following genera of mosquitoes are vectors of W. bancrofti filariasis depending on
geographical distribution. Among them are: Culex (C. annulirostris, C. bitaeniorhynchus, C.
quinquefasciatus, and C. pipiens); Anopheles (A. arabinensis, A. bancroftii, A. farauti, A. funestus, A.
gambiae, A. koliensis, A. melas, A. merus, A. punctulatus and A. wellcomei); Aedes (A. aegypti, A. aquasalis,
A. bellator, A. cooki, A. darlingi, A. kochi, A. polynesiensis, A. pseudoscutellaris, A. rotumae, A. scapularis,
and A. vigilax); Mansonia (M. pseudotitillans, M. uniformis); Coquillettidia (C. juxtamansonia). During a
blood meal, an infected mosquito introduces third-stage filarial larvae onto the skin of the human host,
where they penetrate into the bite wound . They develop in adults that commonly reside in the lymphatics
. The female worms measure 80 to 100 mm in length and 0.24 to 0.30 mm in diameter, while the males
measure about 40 mm by .1 mm. Adults produce microfilariae measuring 244 to 296 μm by 7.5 to 10 μm,
which are sheathed and have nocturnal periodicity, except the South Pacific microfilariae which have the
absence of marked periodicity. The microfilariae migrate into lymph and blood channels moving actively
through lymph and blood . A mosquito ingests the microfilariae during a blood meal . After ingestion, the
microfilariae lose their sheaths and some of them work their way through the wall of the proventriculus
and cardiac portion of the mosquito’s midgut and reach the thoracic muscles . There the microfilariae
develop into first-stage larvae and subsequently into third-stage infective larvae . The third-stage infective
larvae migrate through the hemocoel to the mosquito’s prosbocis and can infect another human when the
mosquito takes a blood meal .

TSETSE FLY – SLEEPING DISEASE

African trypanosomiasis (African sleeping sickness)
Summary

African trypanosomiasis (sleeping sickness) is an infectious disease caused by

the protozoan parasite Trypanosoma brucei, which is transmitted by the bite of the tsetse fly. The disease
is endemic to sub-Saharan Africa; all cases that occur in the US are the result of travel to endemic regions.
There are two forms of the disease with distinct geographical distributions and rates of clinical
progression. West African sleeping sickness is caused by T. b. gambiense and progresses slowly, while East
African sleeping sickness is caused by T. b. rhodesiense and progresses rapidly. Patients with either subtype
of the disease initially present with a painful nodule or chancre at the site of the bite, followed by a
hemolymphatic phase with fever and lymphadenopathy (stage I). Eventually, patients
develop CNS symptoms (stage II), which are characterized by behavioral changes and a reversal of
the sleep-wake cycle. If the disease is left untreated, patients will succumb to coma and die. The disease is
diagnosed if the trypomastigote is found in chancre fluid, lymph node aspirates, or blood smears. The drug
of choice for stage I T. b. gambiense infection is pentamidine, while suramin is the drug of choice for stage
I T. b. rhodesiense. An eflornithine-nifurtimox combination is the drug of choice for stage II T. b.
gambiense infection, while melarsoprol is the drug of choice for stage II T. b. rhodesiense. No vaccine or
chemoprophylaxis for African trypanosomiasis is available.

Epidemiology

 Distribution: Sub-Saharan Africa 
 Incidence: < 15,000 estimated cases in 2014 

Etiology

 Pathogen: Trypanosoma brucei
 T. brucei is a hemoflagellate protozoan. 
  Two subspecies: Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense 
 Route of infection: vector transmission by the bite of the tsetse fly 

Classification
West African sleeping sickness (Gambian East African sleeping sickness (Rhodesian
trypanosomiasis) trypanosomiasis)
Pathogen Trypanosoma brucei gambiense Trypanosoma brucei rhodesiense
Vector Tsetse fly

Glossina palpalis  Glossina morsitans 

Regional Central and West Africa   Eastern and southeastern Africa  

distribution
Incidence in the Extremely rare  1–2 cases per year 
US
Primary Humans  Cattle, antelope 
reservoir
Clinical course Chronic, slowly progressive disease  Acute disease with poor demarcation
between stages 
Pathophysiology

 Life cycle in the tsetse fly 

1. Ingestion of the trypomastigote form of T. brucei by the tsetse fly during a blood meal

1. Transformation of the trypanosomal form of T. brucei into procyclic trypomastigotes within

the gut of the tsetse fly

1. Procyclic trypomastigotes leave the gut and transform into epimastigotes.

1. Migration of epimastigotes to the salivary glands, where they transform into

metacyclic trypomastigotes

1. Injection of metacyclic trypomastigotes from the salivary gland to the bite site during the

next blood meal
 Life cycle in the human body 

1. Multiplication of the metacyclic trypomastigotes at the inoculation site causes a primary

indurated lesion

1. Entry into the bloodstream and transformation of

metacyclic trypomastigotes into trypomastigotes

1. Stage I (hemolymphatic phase): multiplication of trypomastigotes in blood (parasitemia)

and lymphoid tissue

1. Stage II (neurologic phase): Trypomastigotes cross the blood-brain barrier and enter

the CNS → Immune-mediated damage causes
progressive meningoencephalitis and diffuse demyelination.
Clinical features

Stage I (hemolymphatic phase) 

 Trypanosomal chancre (local primary lesion)

 A red, painful, indurated, nodular swelling 2–5 cm in size that develops at the bite
site within 2 weeks of the bite
 Resolves spontaneously within 1–2 weeks 
 Intermittent fever: caused by antigenic variation , malaise, headache, weight loss, arthralgia
 Painless lymph node enlargement 
 Winterbottom sign: painless cervical lymphadenopathy in the posterior triangle of the neck 
 Erythematous, annular (targetoid), or maculopapular rash that may or may not be pruritic 
 Symptoms of anemia

Stage II (neurologic phase) 

 Headache
 Behavioral changes: confusion, apathy, psychosis
 Daytime somnolence, which may be associated with night-time insomnia 
 Ataxia
 Kerandel sign: delayed hyperesthesia 
 Cachexia
 Coma
 Death 

Diagnostics

 General findings
 CBC: anemia, granulocytopenia
 ↑ ESR
 ↑ IgM levels 
 Confirmatory tests
 Local primary lesion: direct visualization of trypomastigotes in chancre fluid
 Stage I: direct visualization of trypomastigotes in thin and thick peripheral blood
smears or lymph node aspirates 
 Stage II: lumbar puncture and CSF examination
 Trypomastigotes may be directly visualized. 
 Lymphocytic pleocytosis 
 ↑ Protein and IgM levels

A history of travel to an endemic region is an important diagnostic clue!

CSF examination must be performed for all patients with suspected or confirmed African trypanosomiasis
to rule out stage II disease because the drug of choice depends on the stage of the disease.
Treatment

General

 Early in-patient treatment is very important. 

  The drug of choice for trypanosomiasis is dependent on the stage of the disease and the subspecies
of T. brucei (see the table below).
 Follow-up: CSF examination should be repeated every six months for two years. 

Trypanosomal therapy

West African sleeping sickness East African sleeping sickness

Stage I First-line: pentamidine Suramin
Second-line: suramin

Stage First-line: eflornithine AND nifur Melarsoprol

II  timox 
Second-line: melarsoprol

African trypanosomiasis is considered lethal without therapy!

Prevention

 Instructions for people traveling to or working in endemic regions

 Use preventive measures in the daytime 
 Wear long-sleeved protective clothing with neutral colors 
 Use insect repellants
 Public health measures in endemic regions
 Vector control methods such as insecticide spraying and fly traps
 Population screening programs and early treatment of infections to decrease the number of
human hosts

No chemoprophylaxis and no vaccine for T. brucei is available.

Tick paralysis
Lyme disease
Summary

Lyme disease (or borreliosis) is a tick-borne infection caused by certain species of the Borrelia genus (B.
burgdorferi in the US), a genus of facultative intracellular bacteria. There are three stages of Lyme
disease. Stage I (early localized disease) is characterized by erythema migrans (EM), an expanding circular
red rash at the site of the tick bite, and may be associated with flu-like symptoms. In stage II (early
disseminated disease), patients may present with neurological symptoms (e.g., facial palsy),
migratory arthralgia, and cardiac manifestations (e.g., myocarditis). Stage III (late disease) is characterized
by chronic arthritis and CNS involvement (late neuroborreliosis) with possible progressive
encephalomyelitis. Lyme disease is a clinical diagnosis in patients presenting with EM. Serological tests
(e.g., Western blot; enzyme-linked immunosorbent assay) can help support the clinical diagnosis, especially
if the presence of EM is not known or questionable. Lyme disease is treated with antibiotics; the drugs of
choice are doxycycline for localized disease and ceftriaxone for disseminated disease.

Epidemiology

 Incidence: most commonly reported vector-borne disease in the US

  Geographical distribution: primarily the Northeast and upper Midwest .

Etiology

 Pathogen
 In the US: Borrelia burgdorferi, an anaerobic, facultative intracellular spirochete bacteria
 Vector
 Various tick species: mainly Ixodes scapularis (deer or black-legged tick) in the northeastern
and upper midwestern US
 Ixodes pacificus (western black-legged tick) in the northeastern US
 Ixodes ricinus (castor bean tick) in Europe

 Typically found in forests or fields on tall brush or grass

 The incidence of Lyme disease is highest between April and October (especially from June to
August). 

 Peromyscus leucopus, the white-footed mouse, is the primary reservoir of B. burgdorferi in

the US.
 Increased risk of disease for:
 Outdoor workers (landscapers, farmers, etc.)
 Outdoor enthusiasts (i.e., hikers, hunters, etc.)

Clinical features

Stage I (early localized Lyme disease)

 Symptoms develop within 7–14 days after a tick bite.

 Erythema chronicum migrans (EM)

 Occurs in 80% of infected individuals

 Usually a circular, slowly expanding red ring around the bite site with central clearing 

 Typically warm, painless

 EM is often the only symptom.

 Self-limiting (typically subsides within 3–4 weeks)

 Flu-like symptoms

Stage II (early disseminated Lyme disease)

 Symptoms develop 3–10 weeks after a tick bite 

 Migratory arthralgia that can progress to Lyme arthritis

 Spreads from one joint to another 

 Generally in large joints (especially knee or elbow)
 Early neuroborreliosis
 Cranial nerve disorders
 Most commonly peripheral facial nerve palsy 
  Nocturnal radicular pain, paresthesia, and paresis
 Meningitis
 Polyneuropathy (mononeuritis multiplex, asymmetrical)
 Lyme carditis
 Risk of cardiac arrhythmias (e.g., AV Block) and rarely myopericarditis

 Adams-Stokes syndrome
 Cutaneous manifestations
 Multiple erythema migrans lesions

 Ocular manifestations: including conjunctivitis, retinal vasculitis, optic neuropathy, and uveitis

Stage III (late Lyme disease)

 Symptoms develop months to years after the initial infection 

 Chronic Lyme arthritis (10% of cases)
 Lasts over a year and may be intermittent or persistent
 Typically in large joints (especially knee or elbow)
 Late neuroborreliosis manifestations include:
 Aseptic (lymphocytic) meningitis
 Progressive encephalomyelitis

 Cognitive impairment

 Gait abnormality

 Bladder dysfunction

 Psychiatric abnormalities (e.g., depression, anxiety, bipolar disorder etc.)

 Peripheral polyneuropathy

Diagnostics

Approach
  After a tick bite, observe for erythema chronicum migrans. Suspicious rashes may be monitored
over several days.
 If the patient history and clinical presentation indicate Stage I Lyme disease, empiric antibiotics may
be started without further testing.

 If symptoms of Lyme disease arise in a patient with possible exposure (especially if a history of
recent travel to an area with high vector density) → conduct two-step serological testing

 If signs of neuroborreliosis are present and other tests are inconclusive, consider additional
procedures, such as a lumbar puncture for cerebrospinal fluid testing.

Two-step serological testing 

 Initial test: enzyme-linked immunosorbent assay (ELISA)

 Confirmatory test: Western blot

 Detect IgG and IgM antibodies against Borrelia
 Results are only significant with corresponding clinical symptoms because:

o Positive results only demonstrate exposure to Borrelia (not necessarily current infection).

o False negative results are possible if seroconversion has not yet occurred (may take up to 8
weeks).
o Various diseases can lead to a false positive serology as a result of cross-reactions, including:
 Syphilis
 Rocky Mountain spotted fever
 Systemic lupus erythematosus
 Rheumatoid arthritis

Other tests

 Cerebrospinal fluid testing
 o Signs of lymphocytic meningitis, including elevated protein (due to a disrupted blood-
brain barrier) and pleocytosis
o Measure intrathecal IgG or IgM antibodies 
 Arthrocentesis
o Commonly conducted if signs of arthritis are present, but results do not allow differentiation
from septic arthritis without PCR
o Synovial fluid findings
 Appearance: yellow and cloudy
 Leukocyte count: 3000–100,000/mm3 with > 50% neutrophils
 PCR test: positive
 Negative findings: Gram stain, culture, crystals

Differential diagnoses

 For erythema migrans
o Cellulitis
o Contact dermatitis (discoid eczema)
o Erythema marginatum (rheumatic fever)
o Erythema multiforme

o Granuloma annulare

o Annular erythema
 For Lyme carditis
o See myocarditis.
o See arrhythmias.
 For Lyme arthritis
o See differential diagnoses of infection-associated arthritis.
o See differential diagnoses of inflammatory arthritis.
 For neuroborreliosis
o See “Etiology” of major neurocognitive disorder.
o See “Differential diagnoses” of vitamin B12 deficiency.

Differential diagnoses of tick bite

Tick-borne Pathophysiology / Epid Clinical features Diagnostics Treatment
diseases (e emiology
ndemic to
US) [8]
Lyme Pathogen: Borrel Incubation Confirmat No
disease ia burgdorferi period: 3–30 days ory test neurological
Vector Early localized Tw manifestations 
Ixodes Lyme disease o-step serological Doxyc
scapularis Flu-like  testing ycline
Ixodes symptoms OR
pacificus Erythe1. Amoxi
Distribution: upp ma migrans at the site cillin
er midwestern, of tick bite 1. OR
northeastern US, and Early confirm the Cefuro
West Coast  disseminated Lyme diagnosis  xime axetil
disease 
Tick-borne Pathophysiology / Epid Clinical features Diagnostics Treatment
diseases (e emiology
ndemic to
US) [8]
Migrato Neurological
ry arthralgia manifestations:
Facial intravenous ceftriaxo
nerve ne
palsy, meningitis, poly
neuropathy
Myocar
ditis, pericarditis, cond
uction blocks (e.g., AV
block)
Multipl
e erythema
migrans lesions
Late Lyme
disease 
Chronic
arthritis
Late
neuroborreliosis (e.g., 
progressive
encephalomyelitis,
aseptic meningitis)

Tick Tick neurotoxin  Incubation No confir Locate

paralysis period: 2–7 days matory test  and remove the tick! 
Weakness in Supportive
lower therapy (e.g.,
extremities  → ascendi ventilatory support
ng flaccid in a patient with
paralysis that respiratory failure)
progresses rapidly
over 24–48
hours → can lead to
respiratory failure due
to respiratory muscle
weakness
No fever or
rash

Rocky Pathogen: Ricke Incubation Confirmat Doxycycline

Mountain ttsia rickettsii period: 2–14 days ory test
spotted Vector Flu-like sympto Det
fever (RMS Dermace ms ection of R.
F) ntor variabilis Blanching mac rickettsii DNA by P
Dermace ulopapular rash (90% CR in a skin
ntor andersoni of cases): begins on biopsy specimen
Tick-borne Pathophysiology / Epid Clinical features Diagnostics Treatment
diseases (e emiology
ndemic to
US) [8]
Rhipiceph wrists and ankles 2–5 or acute phase
alus sanguineus days after onset whole blood
Distribution: nort of fever → spreads to specimen
heast and south US  trunk, palms, and soles OR
→ Ser
becomes petechial an ologic test: Four-
d/or hemorrhagic in fold increase
50% of cases in IgG-specific IFA 
Ankle and/or antibody assay
wrist swelling
Gastrointestina
l symptoms (e.g.,
nausea, vomiting,
abdominal pain)
Meningitis,
focal neurological
deficits
Rapid clinical
deterioration
with shock and multi-
organ dysfunction

Babesiosis Pathogen: Babes Incubation Confirmat Mild

ia species (typically Bab period: 1–6 weeks ory test disease: atovaquone 
esia microti) Flu-like Per and azithromycin
Vector: Ixodes symptoms ipheral blood Severe
scapularis Hemolytic smear showing int disease : quinine and 
Distribution: mid anemia → raerythrocyte clindamycin
west and northeast US dark urine and/or rings and/or malt
icterus ese cross
Mild splenome OR
galy and/or hepatome Ba
galy besia DNA detecti
Gastrointestina on by PCR of
l symptoms (e.g., blood
nausea, vomiting,
abdominal pain)
Typically no
rash

Ehrlichiosis Pathogen: Ehrlic Incubation Peripheral Doxycycline

hia chaffeensis, Ehrlichi period: 1–2 weeks blood
a ewingii Flu-like smear shows mor
Vector: Amblyo symptoms ulae
mma americanum Gastrointestina within leukocytes
l symptoms (e.g., . 
Tick-borne Pathophysiology / Epid Clinical features Diagnostics Treatment
diseases (e emiology
ndemic to
US) [8]
Distribution: sou nausea, vomiting, Confirmat
theastern and south- abdominal pain) ory test
central US Typically no Ehr
rash  lichia DNA detecti
on by PCR of
blood
OR
Fo
ur-fold increase
in IgG-specific IFA 
antibody assay
between the
acute and
convalescent
serum samples

Anaplasmo Pathogen: Anapl Incubation Peripheral Doxycycline

sis asma phagocytophilum period: 1–2 weeks blood
Vector Flu-like smear shows mor
Ixodes symptoms ulae
scapularis Gastrointestina within granulocyt
Ixodes l symptoms (e.g., es.
pacificus nausea, vomiting, Confirmat
Distribution: upp abdominal pain) ory test
er midwest and Cough Det
northeastern US Typically no ection
rash of Anaplasma DN
A by PCR of blood
OR
Ser
ologic test: Four-
fold increase
in IgG-specific IFA 
antibody assay
between the
acute and
convalescent
serum samples

Tularemia [ Pathogen:Franci Incubation Confirmat Streptomycin

9][10]
sella tularensis period: 3–5 days ory test OR
Vector High fever Pos Gentamicin
Dermace itive culture from OR
ntor variabilis skin lesions Doxycycline
Dermace S and/or lymph
ntor andersoni kin ulcer at the site node aspirate/bio
Tick-borne Pathophysiology / Epid Clinical features Diagnostics Treatment
diseases (e emiology
ndemic to
US) [8]
Amblyom where F. psy 
ma americanum tularensis enters the OR
Distribution: all body Ser
states except Hawaii  T ologic test: four-
ender fold increase in F.
regional lymphadenop tularensis specific 
athy antibody titers
between the
acute and
convalescent
serum samples

Tick-borne Pathogen: Borrel Incubation Confirmat No CNS involv

relapsing ia hermsii period: 4–18 days ory test ement
fever [11] Vector: Ornithod Recurring Dir First-
oros species episodes of ect observation line: tetracycline
Distribution: high fever lasting 3 of spirochetes in p Secon
western US  days followed by an eripheral blood d-line:  erythromycin
afebrile period of 7 smears CNS involvem
days ent: ceftriaxone
Arthralgia
Gastrointestina
l symptoms (e.g.,
nausea, vomiting,
abdominal pain)
Less
commonly, symptoms
of meningitis
Macular rash
or
scattered petechiae in 
15–20% of cases 

Treatment
Stages Presentation General therapy Therapy in
pregnant/nursing
patients
Localized Lyme Erythema migrans First-line oral a First-line
disease Flu-like symptoms ntibiotics: oral antibiotics:
Doxycy Amoxicillin
cline  Cefuroxim
Disseminated Isolated CN palsy Amoxic e axetil
Lyme disease Mild carditis illin
Borrelial lymphocytoma Cefuro
Stages Presentation General therapy Therapy in
pregnant/nursing
patients

Initial arthralgia/arthritis
xime axetil
Neurological signs Hospitalize patient
(except isolated CN palsy) Intravenous antibiotics
Meningitis Drug of choice: ceftriaxone
Polyneuropathy Cefotaxime
Ocular Penicillin G
manifestations
Chronic
neuroborreliosis
Encephalopathy
Severe carditis
Recurrent arthritis after
oral therapy

Doxycycline is relatively contraindicated in pregnant/nursing women due to its adverse effects on growing

bones and teeth! Administer amoxicillin (or cefuroxime axetil) instead!

If infection is likely (e.g., EM is present) → start antibiotic treatment!

References:[12]
Prevention

 There is no approved vaccine on the market.

 Avoid areas known for Lyme disease. 
 Prevent and properly manage tick bites to avoid exposure. 
 Wear protective clothing: e.g., long-sleeved shirts, long pants, and light colors.
 Use tick repellent and pesticides.
 Check body for tick bites.
 Remove ticks immediately! 

1. Grasp the tick with tweezers directly above the skin's surface.

1. Carefully pull upward with even pressure. 

1. Do not use nail polish remover, adhesives, oils, or similar substances to remove

the tick. The tick should be removed quickly rather than waiting for it to detach slowly.

1. Disinfect the site of the bite and dispose of the tick

 Observe the bite site for early detection of EM.