Measles + Malaria + Travellers

Question 1

Pathogen that causes measles

Answer 1

Measles virus - RNA Virus

Question 2

Clinical features of measles

Answer 2

PRODROME Period: 2-4 days

• Fever: usually striking, conjunctivitis, coryza, cough
• Koplik spots: characterized as clustered, white lesions on the buccal mucosa (opposite the lower 1st & 2nd molars) and are pathognomonic for measles.

EXANTHEM Phase

• Erythematous blanching macular rash that begins on the face and descends
• Persistent prodrome symptoms and lymphadenopathy
• Modified, attenuated illness possible in those with incomplete immunity

The most important findings of measles are the 3 Cs and 1 K: Coryza, Cough, Conjunctivitis, and Koplik spots.

Question 3

How is measles diagnosed?

Answer 3

Gold standard: detection of measles specific IgM antibodies

Biopsy: affected LN show paracortical hyperplasia and Warthin Finkeldey cells (multinucleated giant cells formed by lymphocytic fusion)

Question 4

Treatment for measles

Answer 4

• No effective treatment
• Vit A deficiency contributes to prolonged recovery and measles complications - vitamin A replacement!
• Measles is susceptible to ribavirin in vitro

Question 5

Complications of measles

Answer 5

• Diarrhoea, gastroenteritis
• Croup/bronchopneumonia/sinusitis
• Coinfection with bacterial pathogens, eg: otitis media, pneumonia
• Long term sequelae including bronchiectasis
• Meningitis
• Encephalitis (1 per 1000)
• Subacute sclerosing pan-encephalitis (1 per 10,000)

Question 6

What is subacute sclerosing panencephalitis?

Answer 6

• Lethal, generalised demyelinating inflammation of the brain caused by persistent measles virus infection
• Usually develops >7 years after measles infection
• Characterised by:
  (1) Dementia
  (2) Epilepsy
  (3) Decerebration
  (4) Vegetative state

Diagnosis

• EEG: delta waves
• CSF: anti-measlses IgG

Leads to death within 1-3 years of diagnosis

Question 7

What are the types of malaria parasites?

Answer 7

• Parasitic amoeba that infects erythrocytes
• Types - falciparum and vivax are most common
  ○ Plasmodium falciparum (severe disease)
  ○ P. vivax (relapsing/recurrent attacks)
  ○ P. ovale(relapsing/recurrent attacks)
  ○ P. malariae
  ○ P. knowlesi
• Vector: the female Anopheles mosquito

Question 8

What leads to partial resistance against malaria?

Answer 8

• Carriers of sickle‑cell mutation: Individuals with either certain Duffy antigens or no Duffy antigens are resistant to P. vivax and P. knowlesi, eg: in sickle cell anaemia (no duff antigens)
• Other hemoglobinopathies (e.g., thalassemia, G6PD deficiency) - make parasite infected erythrocytes more susceptible to dying from oxidative stress
• 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)

Question 9

Characteristics of the different malaria

Answer 9

P. vivax + P. ovale: tertian malaria (usually less severe) - fever spikes ever 48 hours

P. malariae: quartan malaria (usually less severe) - fever spikes every 72 hours

P. falciparum: most severe, malignant tertian, irregular spikes

P. knowlesi: quotidian malaria (everyday), irregular

Question 10

Lifecycle of plasmodium falciparum

Answer 10

Asexual Development in Humans - sporozoites - merozoites - trophozoites - merozoites

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
   a. Plasmodium Vivax and Ovale are associated with the development of dormant stages (hypnozoites) which persist for several years in hepatocytes and later develop into schizonts.
3. Circulatory System (two possible outcomes)
   a. 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
   b. 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
• Malaria is caused by plasmodia transmitted via the saliva of female Anopheles mosquitoes. During development, there is a generational (asexual/sexual reproduction) and host change (between mosquito and human).
• Human Host
○ Liver (exoerythrocytic) stage: Following a bite from an infected mosquito, sporozoites (spindle-shaped, infective pathogen) reach the liver via the blood or lymphatic system and mature into schizonts within the hepatocyte.
○ Asexual propagation produces thousands of daughter cells (merozoites), which are transmitted to the bloodstream via merosomes.
○ Plasmodium Vivax and Ovale are associated with the development of dormant stages (hypnozoites) which persist for several years in hepatocytes and later develop into schizonts.
• Blood (erythrocytic) Stage:
○ Merozoites infect erythrocytes and develop into trophozoites, which then mature into schizonts.
○ Asexual propagation produces merozoites, which are then released into the bloodstream via merosomes. This cycle repeats itself over a course of 48-72 hours causing periodic decay of erythrocytes and the resulting pathognomic spiking fevers of malaria.
• Mosquito Host
Ingested gametocytes mature into flagellated microgametes (♂) or macrogametes (♀) within the gastrointestinal tract of the mosquito. The mature sexual forms merge into a mobile zygote, which in turn develops into a sporozoite-containing oocyst. The sporozoites are released, enter the salivary glands, and may eventually be transferred to a new host.

Question 11

What does P vivax and ovale develop to survive?

Answer 11

Plasmodium Vivax and Ovale are associated with the development of dormant stages (hypnozoites) which persist for several years in hepatocytes and later develop into schizonts

• Primaquine for 7-14 days
• MUST have normal glucose-6-phosphate dehydrogenase (G6PD) function or these drugs cause haemolysis

Question 12

Clinical features of malaria

Answer 12

• Any patient with a fever (>37.5C) who has recently visited a malaria endemic area should be suspected of malaria
• Clinical features are of limited value in distinguishing malaria from non-malarial causes of fever
• Patients who have had repeated malaria exposure through living in an endemic area will have partial immunity and can have asymptomatic parasitaemia. There is no test that can differentiate symptomatic from asymptomatic parasitaemia
• Incubation Period: 7-30 days
The incubation period of malaria is a minimum of seven days; if fever occurs before the seventh day following exposure in an endemic region, it is most likely not due to malaria

Question 13

Clinical features of malaria

Answer 13

General Symptoms
• Flu like symptoms, headache
• Diaphoresis
• High fever
○ Tertian malaria: periodic fever spikes every 48 hrs (P vivax + Ovale)
○ Quartan malaria: periodic fever spikes every 72 hrs (P malariae)
○ Falciparum malaria (malignant tertian malaria): irregular fever spikes without a noticeable rhythm

Organ-Specific Symptoms
• Blood
○ Thrombocytopenia: increased bleeding risk
○ Haemolytic anaemia: weakness, paleness, dizziness
• Gastrointestinal
○ Nausea, vomiting
○ Diarrhoea, abdominal pain
• Liver: hepatosplenomegaly, discrete jaundice

Severe Malaria
• Description: potentially fatal manifestation or complication of malaria
• Etiology: most commonly a result of falciparum malaria
• Pathophysiology: infected erythrocytes occlude capillaries, which can lead to severe organ dysfunction
• Manifestations
○ Kidneys: flank pain, oliguria, hemoglobinuria, acute kidney injury
○ Cerebral: hallucinations, confusion, impaired consciousness, seizures, or even coma
○ Cardiopulmonary: heart failure, pulmonary edema, ARDS, shock
○ Hematologic: severe anemia, coagulation disorders
○ Metabolic: hypoglycemia, metabolic acidosis
○ Hyperparasitemia: > 5% of RBC are infected with plasmodia

Question 14

Investigations for malaria

Answer 14

BLOOD:
• Clues on the full blood count such as thrombocytopoenia are non-specific
• Haemolytic anaemia

MICROSCOPY
• Thick films (screening)
- High sensitivity
- Detects the presence of parasites

• Thin films (density and speciation) - confirmatory testing, identifies the species
- Lower sensitivity than thick blood smear, but higher specificity
- Allows determination of Plasmodium species
- Schuffner granules (fine, brick red dots) within the cytoplasm of P. vivax and P. ovale.
• Evaluation of negative test results
- If parasite densities are very low, malaria may be initially undetectable.
- If an initial test result is negative, blood smears should be repeated three times every 12–24 hours
- If all three sets are negative, malaria can be ruled out.

ANTIGEN BASED RAPID DIAGNOSTIC TESTS (RDTS)

• Some genus specific, and some able to distinguish P. falciaparum from P. vivax
• Unable to determine parasite density
• RDTs can stay positive for several weeks after successful treatment
• Increasing reports of mutations in antigen encoding genes (eg: pfhrp2 and pfhrp3)
• Determination of specific malaria antigens, eg: HRP2, pLDH, aldolase

• Serological tests

• Not appropriate for acute diagnosis of malaria because antibodies are undetectable for 1–2 weeks after primary infection
• Positive serological results indicate prior exposure to Plasmodium

Question 15

Management of malaria

Answer 15

• Management varies by Plasmodium species and by severity
• Severe malaria is when there are signs of end-organ dysfunction or high parasitaemia (>10%)
○ Anaemia, jaundice, seizures, kidney injury, shock, impaired consciousness
• Most severe disease is P. falciparum but P. vivax also causes severe disease
• Severe malaria is an emergency that requires prompt treatment in a high acuity environment

Antimalarials:
• Artemisinins clear parasitaemia faster than quinine and reduce mortality
• IV artesunate is the standard treatment for severe falciparum malaria
• IV artesunate + ceftriaxone + paracetamol. Safe in pregnancy
Ceftriaxone to prevent bacterial superinfection
Paracetamol to prevent haemolytic AKI

Question 16

Treatment for P falciparum

Answer 16

IV artesunate is the standard treatment for severe falciparum malaria

IV artesunate + ceftriaxone + paracetamol. Safe in pregnancy
Ceftriaxone to prevent bacterial superinfection
Paracetamol to prevent haemolytic AKI

Artesunate: need to rule out G6PD deficiency or will cause haemolytic anaemia

Question 17

Treatment for P vivax or P ovale (uncomplicated malaria)

Answer 17

1st Line: PO Artemether + Lumefantrine

Alternatives

• Atovaquone + proguanil (need fatty meal)
• Quinine + doxycycline
• Quinine + clindamycin - use in pregnancy, children
• Chloroquine or hydroxychloroquine if chloroquine sensitive
• Artemether-lumefantrine or atovaquone-proguanil or quinine + doxycycline if chlorquine resistant

PLUS

Primaquine for 7-14 days to eradicate hypnozoites
When using primaquine - need to check for G6PD DEFICIENCY before use

Question 18

Malaria prophylaxis

Answer 18

Atovaquone + proguanil OR doxycycline OR mefloquine

Doxycycline and mefloquine are not sufficiently effective against eh primary liver stages

Question 19

When do you treat as severe malaria

Answer 19

Severe Malaria - P. falciparum

• Central nervous system involvement (cerebral malaria)
• Acute renal failure
• Severe anaemia
• Adult respiratory distress syndrome
• Shock
• Haemorrhage
• Macroscopic haemoglobinuria

Treat as severe malaria if signs of above or
PARASITEMIA >2% in low transmission setting

Question 20

Side effects of the following malaria drugs

• Quinine
• Mefloquine

Answer 20

Quinine

• Hypoglycaemia
• QT prolongation
• Haemolysis
• Thrombocytopenia
• TTP

Mefloquine - avoid in epileptics, psychiatric history

• Depression
• Psychosis
• Seizures

Question 21

Which anti malaria drugs can be used in pregnancy?

Answer 21

Artesunate
Quinine
Chloroquine
Clindamycin

Question 22

Dengue Pathogenesis

Answer 22

Flavivirus (RNA), 4 serotypes DEN 1-4

• Transmission by Aedes (A. egypti mosquito)
• Lifelong immunity after infection, ONLY to the one serotype acquired
• Antibody dependent enhancement on re-infection - 2nd infection with ANOTHER serotype is often MORE SEVERE than the first

Question 23

Clinical features of Dengue Fever

Answer 23

Dengue fever is caused by an arthropod-borne Flavivirus with an incubation period of seven days. The new WHO classification (2009) is Dengue without warning signs (fever, headache, nausea, rash, leukopaenia), Dengue with warning signs (pain abdomen, persistent vomiting, mucosal bleed, hepatomegaly, raised haematocrit and low platelets) and severe Dengue (shock from capillary leakage).

Dengue is an acute febrile illness that presents with fever and 2 or more of the following

• Nausea, vomiting (50%)
• Blanching rash (50%)
• Aches and pains
• Tourniquet test positive: A test is considered positive when 20 or more petechiae per 2.5cm (1 inch) square are observed.
• Leukopenia
• Diarrhoea
• URTI symptoms

Warning Signs of Dengue

• Abdominal pain /tenderness
• Persistent vomiting
• Clinical fluid accumulation
• Mucosal bleed
• Lethargy, restlessness
• Liver enlargement
• Increase in HCT concurrent with rapid decrease in platelet count

Question 24

Investigations for Dengue

Answer 24

• ELISA - arbovirus IgM serology
• Leukopenia
• Thrombocytopenia (up to 55%)
• Haematocrit (fluctuations > 20%)
• LFTs
• Low protein
• CXR: pleural effusons• Some degree of thrombocytopenia and leukopenia common
  • Severe neutropenia may occur
  • Coagulation derangements - Increased APTT, decreased fibrinogen
  • Mild to moderate transaminase, increased AST>ALT
  • Choice of diagnostic test depends on time since fever onset
  ○ Before d5 PCR or NS1 antigen, after d4-5 antigen disappears and antibodies appear so serology
  ○ IgM in 50% by d3-5 and 99% by d10, IgG low levels by end of first week then lifelong
  ○ Cross reactivity with other flaviviruses for all serology (which can make it conrusion)

Question 25

Criteria for severe dengue

Answer 25

(1) Severe plasma leakage leading to
- Shock
- Fluid accumulation with respiratory distress

(2) Severe bleeding
>20% rise haematocrit
>20% drop in haematocrit after fluids

(3) Severe organ involvement
- LFT: AST or ALT >1000
- CNS: impaired consciousness

Question 26

Complications and treatment of dengue

Answer 26

Complications

• Dengue haemorrhagic fever
• Dengue haemorrhagic fever - dengus shock syndrome

Mx

• Supportive, fluid resus, avoid aspirin/nsaids
• Prevention, vector avoidance

Question 27

Features of typhoid
Clinical presentation
Complications

Answer 27

• Salmonella typhi, paratyphi
• Faecal-oral spread, usually water borne

Presentation

• Fever, abdominal pain, constipation (not diarrhoea, salmonella in blood causes constipation)
• Hepatosplenomegaly
• Neuropsychiatric manifestations
• Relative bradycardia
• Rose spots - faint salmon coloured, maculopapular, truncal distribution

Complications (3rd-4th week)

• Intestinal haemorrhage
• Intestinal perforation
• Neuropsychiatric
• Myocarditis
• Bone + joint
• Endocarditis, pericarditis
• Splenic/liver abscess
• Endovascular (grafts, atherosclerotic plaques, aneurysms,) especially > 50 years

Question 28

Diagnosis and treatment of typhoid

Answer 28

Diagnosis

• Blood culture
• Stool culture
• Leukopenia/anaemia, thrombocytopenia
• Abnormal LFTs - elevated 2-3x ULN
• Mild increased CK

Treatment

• Azithromycin, ciprofloxacin, ceftriazone
• Dex if severe

Question 29

Chronic carriers of typhoid

Answer 29

• Definition: persistence of salmonellae in stool or urine for > 1 year
• Higher frequency if biliary abnormalities or concurrent bladder infection with Schistosoma
• Association with carcinoma of gallbladder

Give cipro

Question 30

Amoebiasis

Answer 30

Entamoeba histolytica

• Cysts remain viable for weeks-months in moist environments outside the body
• Ingestion –> excystation (small intestine) –> trophozoite infection (colon)

Intestinal disease

• Asymptomatic infection
• Symptomatic non-invasive infection
• Acute dysentry
• Fulminant colitis and perforation
• Toxic megacolon

Extraintestinal disease

• Liver abscess (complicated by peritonitis, empyema, pericarditis)
• Lung abscess, brain abscess, genitourinary disease

Question 31

Diagnosis of amoebiasis

Answer 31

Diagnosis
- At least 3 fresh stool specimens: cysts and trophozoites
Haemophagocytosis diagnostic for invasive colonic disease
Cannot distinguish between histolytica (invasive) and dispar (non-invasive)
- Serology: antibodies detectable in 99% of patients with liver abscess
- CTAP: usually solitary abscess, R lobe > L lobe

Question 32

Management of amoebiasis/entamoeba histolytica

Answer 32

Metronidazole

Paromomycin or diloxanide furoate prevents continued luminal infection

Question 33

What is campylobacter jejuni resistant to?

Answer 33

Quinolones

Question 34

A 38 year-old-man is going to Kenya to do some aid work. He comes to your clinic to ask about malaria prophylaxis advice. He has a long history of depression and is not currently on any treatment. He likes bushwalks and hikes and plans to spend a lot of time outdoors. He is otherwise well without any medical problems. What is the best choice for malaria prophylaxis?
A. Doxycycline
B. Chloroquine
C. Mefloquine
D. Atovaquone plus proguanil

Answer 34

Atovaquone plus proguanil is good prophylaxis against Plasmodium falciparum. This is a good choice for this man. Doxycycline is a reasonable option but can cause photosensitive dermatitis and may not be a good option for someone who will be spending a lot of time outdoors. Chloroquine is no longer suitable in most malaria-endemic areas due to resistance profile. Mefloquine can cause neuro-cognitive side effects and exacerbate pre-existing psychiatric conditions.

Question 35

Any traveller who has been bitten or scratched by an animal requires evaluation for what prophylaxis?

Answer 35

Rabies (virus)
Rabies vaccine and immunoglobulin

• Animal Hosts: wolves, foxes, coyotes, racoons, domestic cats.
• Infection by contact with respiratory secretions.
  • Infection: break in skin (eg.bite), viral replication in muscle, retrograde neural spread to CNS, widespread
  infection via peripheral nerves.
  • Clinical: fever, headache, malaise in prodrome (4-10 days); encephalitic- hydrophobia, delirium, agitation,
  arrhythmias, autonomic dysfunction; paralytic- ascending flaccid paralysis
  • Management: wound care*, post-exposure rabies immune globulin (1/2 into wound) & vaccination (days 0,
  3, 7, 28)

Question 36

How does influenza change?

Answer 36

Due to antigenic drift and shift

• ANTIGENIC DRIFT: involves the accumulation of a series of minor genetic mutations.
  Mutations in haemagglutinin (HA) and neuraminidase (NA) proteins
• Haemagglutinin binds to sialic acid residues on respiratory epithelial cells
  Immunity to influenza A and B is mediated by IgG and IgA ab against haemagglutinin.
• Overtime, haemagglutinin proteins can change enough that our ab can no longer recognise the virus
• ANTIGENIC SHIFT: involves “mixing” of genes from influenza viruses from different species (eg: jumping from pigs to humans)

Question 37

Rickettsia

Answer 37

• Small gram negative bacteria
• Intracellular growth
• Arthropod associated
• Diagnosis based on serology or PCR

Clinical Features

• Rash, centripetal and eschar
• Headache + myalgia prominent
• Fever, lymphadenopathy + conjunctival injection
• Rare complications: myocarditis, meningoencephalitis, renal failure

Deranged LFT

Good response to doxycycline

Question 38

In influenza, what antivirals can be used?

Answer 38

Neuraminidase Inhibitors: oseltamivir, zanamivir

M2 inhibitors: amantadine, rimantadine

Question 39

Treatment of H1N1 (swine flu)

Answer 39

Oseltamivir

Zanamivir is the treatment of choice for patients who become ill
while receiving oseltamivir prophylaxis for H1N1 influenza

Question 40

Causes of aseptic meningitis (negative CSF)

Answer 40

• Enteroviral: echovirus, coxsackie
• Mumps
• EBV
• CMV
• HIV
• HSV
• TB
• Cryptococcus
• Leptospirosis
• Syphilis

Non infectious: sarcoid, vasculitis CNS lymphoma

Question 41

Causes of diffuse erythematous rash

Answer 41

Infectious Causes

• Scarlet fever (streptococcal)
• Toxic shock syndrome (streptococcal/staphylococcal)
• Staphylococcal scalded skin syndrome
• Dengue
• Enteroviral infection

Question 42

Impetigo

Answer 42

• Group B/C/G streptococci
• Erythematous papule –> vesicle –> pustule –> yellow crust and purulent discharge
• Spread to close contacts, schools
• Associated scabies

TX
- Non-endemic:
Localised skin sore - mupirocin ointment
Multiple sores - oral fluclox

• Endemic:
  benzathine benzylpenicillin intramuscularly or bactrim

Question 43

Influenza pathophysiology

Answer 43

Haemagglutinin: binds to sialic acid on respiratory epithelial cells for viral entry

Neuraminidase: allows daughter virions to be released from on cell to infect other cells

Diagnosis with PCR

Question 44

Oseltamivir for influenza

Answer 44

• Neuraminidase inhibitor (like zanamivir or peramivir)
• Sialic acid analogue
• Reduces duration of symptoms by 1 – 2 days
• May also reduce secondary cases
• Better effect if started earlier => empiric!
• More effective for Flu A than Flu B
• Resistance increasing
• S/E – Nausea & vomiting
• Dose adjust
• Role in prophylaxis (at half dose)
• Illness reduced by 17 hours
• Better for prevention - symptomatic influenza reduced
• Can cause neuropsychiatric side effects: perceptual disturbance, delirium, mood disorders

Question 45

Pertussis

• Diagnosis
• Treatment

Answer 45

Diagnosis
- Pertussis (whooping cough) is caused by Bordetella pertussis. It classically presents with a persistent cough (lasting longer than 2 weeks) with one or more of the following features:
(a) paroxysms of coughing
(b) inspiratory whoop
(c) post-tussive vomiting.
Older children and adults may not have the classical symptoms of pertussis and may present with only a persistent cough.

Pertussis infection is diagnosed by nucleic acid amplification testing (NAAT) (eg polymerase chain reaction [PCR]). For both children and adults, the optimal diagnostic sample for NAAT is a nasopharyngeal swab, a throat swab is less sensitive. NAAT is most sensitive in the first 3 weeks of illness

Tx:
Azithromycin or clarithromycin or bactrim
Advise patients to avoid contact with others, especially young children and infants, until antibiotic therapy has been taken for at least 5 days. After 3 weeks of cough or other symptom onset, patients are rarely infectious and antibiotic therapy is not indicated.

Question 46

Who needs pertussis prophylaxis?

Answer 46

Contacts are individuals who have been within 1 metre of an infectious pertussis case for more than 1 hour.
Evidence to support antibiotic prophylaxis for contacts is limited. Its use is focused on preventing pertussis in infants younger than 6 months.

In community settings, prescribe pertussis prophylaxis to the following patient groups if they are contacts of a pertussis case:

infants younger than 6 months
women in the last month of pregnancy
individuals who may transmit pertussis to infants younger than 6 months. This includes children and adults who:
have contact with the pertussis case in a childcare setting (need for prophylaxis varies depending on the whether an outbreak has occurred, the age of children at the childcare setting and vaccination status—seek advice from the local public health authority)
reside in a household with an infant less than 6 months of age; if the pertussis case is a member of the household, all household members should receive prophylaxis
reside in a household with a woman in the last month of pregnancy; if the pertussis case is a member of the household, all household members should receive abx prophylaxis