Case 18- Malaria Flashcards
Malaria transmission
Has a two stage/host lifecycle. Malaria is transmitted by female mosquitos of the Anopheles complex. There are more then 70 species. Anopheles gambiae is closely associated with the transmission of malaria.
Alternative transmission routes for malaria
- Transfusion transmitted (TT) malaria- blood infusion, inadequate screening of blood
- Mother to foetus (Congenital malaria)- actual number hard to estimate, difference between endemic and non-endemic area
- Needle stick injury- health care professionals, IV drug use and needle share
Plasmodium lifecycle- whats infected first
- Mosquito takes blood meal from human and injects parasite into blood
- Liver infected initially, replication and amplification of parasite
- RBC’s subsequently infected
- Infected blood taken up upon second mosquito bite
Symptoms of Malaria
Blackwater fever= results from massive intravascular haemolysis (blood in urine), malaria is primary an intra-erythrocytic parasite. Within a few days of onset you get chills, with rigor, high fever, jaundice and vomiting. Cycles of chills and fevers. Rapidly progressive anaemia, dark red or black urine. Kidney damage likely.
Malaria species
5 main species of malaria which infect humans:
- Plasmodium falciparum (accounts for 75% of infections)
- Plasmodium vivax (accounts for 20% of infections)
- Plasmodium knowlesi
- Plasmodium malariae
- Plasmodium ovale
Plasmodium parasite
Eukaryotic, unicellular organism with the phylum Apicomplexa. Characterised by having an organelle called the ‘apicoplast,’ which is essential for infecting target cells. The Apicoplast has its own genome (plastid) which encodes enzymes for FA synthesis.
Uncomplicated Malaria
- Classical early symptoms (rare to observe) lasts 6-10 hours. A cold stage (sensation of cold, shivering). A hot stage (fever, headaches, vomiting, seizures in young children) and finally a sweating stage (sweats, return to normal, temperature, tiredness)
- Attacks occur every 2 days (tertian malaria) or every 3 days (quartan malaria).
- Symptoms- headache, fever, fatigue, muscular/back pain, chills, sweating, dry cough, spleen enlargement, nausea and vomiting
Malaria- what causes Paroxyms of fever
The parasite infects liver cells which rupture. The parasite can then infect RBCs, The RBCs lyse and cause the release TNFalpha and other inflammatory factors leading to fever. There is periodic waves of infection, replication and reinfection.
Malaria- how often is the fever
- Tertian fever (every 48 hours)- Plasmodium vivax or Plasmodium ovale
- Quartan fever (every 72 hours)- Plasmodium malariae
- Plasmodium falciparum- can be 24 or 48 hours
Recurrent malaria
- Caused by P.vivax and P.ovale infections. P.falciparum due to re-infection
- Patients having recovered from the first episode of illness may suffer several additional attacks (relapses) after months or even years without symptoms
- Reactivation is due to dormant liver stage parasite (hypnozoites) that may reactivate
P.falciparum
Time of onset- 6 days
Severity- severe
Relapse- no
P.vivax
Time to onset- 8 days
Severity- mild/severe
Relapse-yes
P.ovale
Time to onset- 9 days
Severity- mild
Relapse- yes
P.malariae
Time to onset- 14 days
Severity- mild
Relapse- no
Malaria symptoms
Fever, pain, convulsions -> coma -> death
Complicated (severe) Malaria
Defined by WHO as a patient presenting with any of the following complications:
- Decreased consciousness
- Significant weakness
- Inability to feed
- Two or more convulsions
- Low blood pressure
- Breathing problems
- Circulatory shock
- Kidney failure
- Haemoglobin in the urine
- Bleeding problems, or haemoglobin ≤ 50 g/L (5 g/dL)
- Pulmonary oedema
- Blood glucose ≤ 2.2 mmol/L (40 mg/dL)
- Acidosis or lactate levels ≥ 5 mmol/L
- Parasitemia ≥ 105/µL (ca. 5%) in low-intensity transmission areas, or 2.5 x 105/µL in high-intensity transmission areas
Problems with severe malaria
It is a medical emergency and should be treated urgently and aggressively
Why does P.falciparum cause moe severe disease
Infected RBCs develop knobs which contain histidine rich proteins. These can adhere to endothelial cells to the receptors ICAM-1, thrombopodin, CD36 which can cause exacerbation of microvascular pathology. Sequestration of RBSs in the blood vessels lead to tissue damage and Cerebral malaria (high mortality). The knobs cause the RBCs to become more sticky and adhere to blood vessels
Malaria epidemiology
Partial immunity can be gained in areas when malaria is endemic but this is incomplete protection. Genetic traits affecting RBCs are more prevailent in malaria endemic areas which can cause protection. Sickle cell trait (heterozygous) gives some protection against P.falciparum.
Diagnosis of malaria
Use a blood smear. Thick smear for quick determination of parasitaemia (% infected RBCs). The Giesma stain is used the most and has to be done in a few hours.
Treatment for Malaria
For P.falciparum the first line is Artemisinin. There is resistance to Chloroquine and mefloquine. Resistance to artemisin is on the rise and should not be used by itself. Artemisin Combined Therapy (ACT)- Artemisin + i.e. chloroquine.
Prevention of Malaria
- Vaccination- RTS, S/AS01- trade name Mosquirix, prevents infection of the liver. Has a poor efficacy and protective effect goes after 4 years
- Insecticide can be put on mosquito nets
- Removal of standing water
- Release of sterile male mosquito’s
- Release of fungally infected mosquito’s
Leishmaniasis
Caused by transmission of an obligate intracellular parasite from Leishmania. The vector is the phlebotomine (blood feeding) sand flies
The main disease forms of Leishmaniasis
- Cutaneous Leishmaniasis- most common form
- Visceral Leishmaniasis- most serious, life threatening
Cutaneous Leishmaniasis
- May develop weeks to months after insect bite
- Lumps appear- may ulcerate, pain in some cases
- Diffuse cutaneous Leishmaniasis- anergic response to the parasite by the host
- Mucosal Leichmaniasis- less common, mainly in S.America
Visceral Leishmaniasis
- Disease develops months to years after infection/bite i.e. black fever
- Presentation may include- fever, weight loss, enlargement (swelling) of the spleen and the liver, anaemia, leukopenia and thrombocytopenia
- Leishmania spp infection is the most common cause of splenomegaly
- Fatal if not treated properly
Adaptions of Leishmania
Leishmania infects phagocytic cells such as neutrophils and macrophages- residues in endosomes. The bacteria avoids immune surveillance and inhibits the innate immune response. Primary replication is in the neutrophil but then the Leishmania hides in macrophages. The Leishmania chemotactic factor (LCF) is released to attract more neutrophils.
Lifecycle of Leishmania
- Sandfly takes a blood meal and regurgitates promastigotes into the skin
- The Promastigotes are phagocytosed by Macrophages
- The Promastigotes transform into amastigotes inside Macrophages
- The Amastigotes multiply in cell, including Macrophages of various tissues
- Another Sandfly takes a blood meal from the same person
- There is ingestion of the parasitic cell by the sandfly
- Amastigotes transform into the promastigote stage in the gut
- They divide in the sandfly gut and migrate to the probiscis
- The sandfly then takes a blood meal and passes the Leishmania on to the human
Cutaneous Leishmanias characteristics
Type- localised and diffuse infections appear as skin reactions
Pathogen- Oriental sore
Location-Afghanistan, Brazil, Iran
Mucocutaneous leishmaniasis characteristics
Type- reaction to a bite, can go by metastasis into the mucous membrane and be fatal
Pathogen- L.braziliensis
Location- Bolivia, Brazil and Peru
Visceral leishmaniasis characteristics
Types- fever, swelling of the liver and spleen, anaemia
Pathogen- L.donovani complex
Location- Bangladesh, Brazil, India
Treatment for Leishmania
- Treatment only given for visceral leishmaniasis
- For visceral Leishmaniais- Liposomal amphotericin B
- Miltefosine- for all Leishmaniasis forms but is species dependent
- Pentavalent antimonial (SbV) compounds
- Sodium stibogluconate
Prevention of Leishmania
- Avoid contact with sandflies, wear longsleeves, apply insecticide to exposed skin- DEET (N,N-diethylmetatoluamide) is the most effective
- Use nets covered in insecticide
African Trypanosomiasis
Caused by the unicellular flagellated eukaryote Trypanosoma, extracellular unlike malaria. Causes Trypanosoma brucei (African sleeping sickness). Transmitted by the tsetse fly (genus Glossina)- many species
Types of African Trypanosomiasis
- Trypanosoma brucei gambiense (West African sleeping sickness)- humans are the primary reservoir
- Trypanosoma brucei rhodesiese (East African sleeping sickness)- wild animals/livestock are the primary reservoir
Trypanosoma brucei lifecycle
- Tsetse fly takes a blood meal (injects metacyclic trypomastigotes)
- The injected metacyclic trypomastigots transforms into the bloodstream trypomastigotes which are carried to other sites
- Trypomastigotes multiply by binary fission in various body fluid i.e. blood, lymph and spinal fluid
- The Trypomastigotes move back into the blood
- The Tsete fly takes a blood meal (bloodstream trypomastigotes are ingested)
- Within the fly bloodstream trypomastigotes transform into procyclic trypomastigotes in the tsetes fly’s midgut, procyclic trypomastigotes multiply by binary fission
- Procyclic trypomastigotes leave the midgut and transform into epimastigotes
- Epimastigotes multiples in the salivary glans and transform into metacylic trypomastigotes
West African sleeping sickness
- Caused by Trypanosoma brucei gambiense, causes slow onset chronic trypanosomiasis
- Common in central Africa and limited areas of West Africa- Congo, Sudan
- 90% of cases are in Africa and Humans are the primary reservoir
East African sleeping sickness
- Caused by Trypanosoma brucei rhodesiense, causes fast onset acute trypanosomiasis
- Found in Eastern and South Eastern Africa- Tanzania, Uganda
- Most severe of the two types, causes fast onset acute trypanosomiasis in humans. There are also animal reservoirs making it difficult to eradicate
The first stages of the African Trypanosomiasis disease
Haemolymphatic phase- characterised by fever, headaches, joint pains and itching. Intermittent fever, the intervals can be days to weeks. Invasion of the lymphatic system- leads to Winterbottom’s sign which is swollen lymph nodes at the back of the neck. Untreated leads to anaemia, endocrine, cardiac and kidney dysfunction
The second stage of the African Trypanosomiasis disease
Neurological stage- parasitic invasion of CNS (crosses BB barrier), disruption of sleep. Symptoms include confusion, tremor and general muscle weakness is often confused with Parkinsons. Psychotic symptoms- aggressive, apathy. If untreated mortality is 100%
Treatment of African Trypanosomiasis
T.b. rhodesiense, haemolytic stage- Suramin
T.b. rhodesiense, CNS involvement- Melarsoprol
T.b. gambiense, Hemolymphatic stage- Pentamidine
T.b. gambiense, CNS involvement- Eflornithine
American Trypanosomiasis (Chagas disease)
- Caused by the parasite Trypanosoma cruzi
- Endemic in Mexico, Central/South America
- Transmitted by Triatominae insects- kissing bug, assassin bug or vampire bug
- Takes blood meal then defecates releasing parasites to infect human host via bite of mucosal tissues
Trypanosoma cruzi lifecycle
- Triatomine bug takes a blood meal- passes metacyclic trypomastigotes in the faeces, trypomastigotes enter bite wound or mucosal membranes such as conjunctiva
- Metacyclic trypomastigotes penetrate various cells at bite wound site. Inside cells they transform into amastigotes
- Amastigotes multiply by binary fission in cells of infected tissues
- Intracellular amastigotes transform into trypomastigotes then burst out of the cell and enter the bloodstream
- Triatomine bug takes a blood meal
- Forms an Epimastigotes in the gut
- Multiplies in the midgut
- Metacyclic trypomastigotes in the hingut
Chagas disease- acute phase sonn after infection
Infection may be mild or asymptomatic. May be fever or swelling around the site of infection, rarely inflammation around the heart or brain. You get Romana’s sign which is unilateral painless oedema of the palpebral and periocular tissue.
Chagas disease- prolonged (chronic) asymptomatic form of the disease
May be for life, few are aware of being infected. 30% develop serious, life threatening symptoms such as heart rhythm abnormalities that can cause sudden death, a dilated heart that doesn’t pump blood well and a dilated oesophagus or colon, leading to difficulties with eating or passing stool
Treatment for Chagas disease
- Treatment for acute and congenital infections- or if the patient is immunocompromised
- Two drugs- nifurtimox and benznidazole (preferred)
- Mechanism- due to formation of radical species which damage parasitic DNA and/or protein
Other routes of infection for Trypanosomiasis
- Mother to baby (congenital)
- Contaminated blood products (transfusion)
- An organ transplanted from an infected donor
- Laboratory accident
- Contaminated food or drink (rare)
Antiprotozoal drugs- Artesunate (Artemisinin analogue)
- First line treatment for severe malaria
- Not used as monotherapy to prevent resistance
Antiprotozoal drugs- Doxycycline
Repurposed antibiotic, only used for prophylaxis
Antiprotozoal drugs- Chloroquine
Interferes with parasites ability to use haemoglobin as a nutrient. Causes build up of toxic by products which eventually kills the parasite and the infected cell. Resistance is common
Antiprotozoal drugs- Quinine
Used when Artesunate is not available and where there is Chloroquine resistance. Mechanism of action not fully understood.
Antiprotozoal drugs- Mefloquine
Possibly inhibits acetylcholinesterase activity
Antiprotozoal drugs- Primaquine
Inhibitor of respiratory chain, only treatment for dormant P.vivax/ovale
Antiprotozoal drugs- Proguanil
Targets parasites DHF reductase, inhibts folate recycling
Treatment for uncomplicated malaria
ACT for 3 days, unless you’re a pregnant women in the first trimester or a HIV patient on certain ART combinations.
Treatment for complicated/severe malaria
Intravenous ACT for 24 hours or until you can tolerate oral medication. Oral ACT for 3 days
