Red Cell Parasites (RBCs)

Learning Objectives:

  1. Overview of vector-borne infections
  2. Clinical features of babesiosis
  3. Epidemiology of malaria
  4. Clinical features of malaria
  5. Recognition & diagnosis of severe malaria
  6. Treatment & prevention of malaria, especially severe malaria

There are two main groups of vector-borne infections that are discussed below;

  1. Those transmitted by Ticks &

  2. Transmitted by Mosquitoes

 

Tick-borne Infections

Infection Organism Tick Vectors
Lyme Disease Borrelia burgdorferi Ixodes spp.
Babesiosis Babesia microti Ixodes
Anaplasmosis Anaplasma species Ixodes
Tick-Borne Encephalitis (TBE) TBE virus Ixodes
Rocky Mountain Spotted Fever Rickettsia rickettsii Dog/wood tick
Crimean-Congo haemorrhagic fever CCHF virus Hyalomma tick

 

 

Human Babesiosis

Usually affects 4 legged mammals (cattle) → *Causes Hemolysis of RBCs → problems

  • Coastal regions of northeastern US (eg. Massachussetts) & pockets in Europe
  • Risk of severe infection: immunosuppression esp. asplenia, HIV infection, elderly.
  • Healthy patients: mild or asymptomatic

Asplenia: because the removal of RBC waste is done by spleen. If Spleen is not functioning well; it has serious consequences

 Symptoms usually appear 1-4 wks after tick bite; gradual onset

  • Malaise, anorexia, rigors, chills, myalgia
  • Intermittent or sustained fever

Haemolysis

  • Decreased Hb; increased reticulocytes
  • Urinalysis: haemoglobinuria
  • Others: raised ESR; thrombocytopenia; abnormal LFTs

Diagnosis of Babesiosis

Giemsa-stained thin blood films:

  1. Ring forms (like those of P. falciparum),
  2. Maltese crosses, etc.

PCR, antibody tests may be available in specialist labs (eg. CDC)

  • Always correlate with patient’s travel history

Treatment

  • Quinine plus clindamycin for 7-10 days
  • Alt: atovaquone plus azithromycin

Prevention

  • Avoidance of areas endemic for Ixodes ticks
  • If in endemic areas: protective clothings, insect repellant, etc.

 

Mosquito-borne infections

  • Due to global warming; certain spread-areas (tropical) mosquitoes are expanding
Infection Organism Vector(mosquito)
Malaria Plasmodium spp. Anopheles spp.
Dengue Dengue virus Aedes spp.
Chikungunya Chikungunya virus Aedes spp.
Yellow Fever Yellow fever virus Aedes spp.
Zika Disease Zika virus Aedes, Culex spp.
West Nile Fever West Nile virus Culex spp.
Lymphatic Filariasis Wuchereria & Brugia spp. Anopheles, Aedes, & Culex

 

Malaria

Disease caused by protozoan parasites of the Plasmodium genus

  • >200 Plasmodium species

Different species infect different hosts: humans, primates, non-primate mammals, birds, reptiles

 About half the world’s population at risk of malaria

  • > 200 million cases of malaria

90% cases in Africa; 7% in Southeast Asia; 2% in eastern Mediterranean

Est. 429,000 deaths in 2015:

  • 303,000 under 5 yrs old
  • 90% deaths in Africa

Infections can “return” to previously cleared areas; as the rise in global movement comes with spread of diseases

 

Adverse consequences

People living in the poorest countries are the most vulnerable;

  • Limited access to disease management (swamps: Breeding grounds)
  • Incomplete/ Inadequate treatments
  • Widespread drug resistance in parasites
  • Childhood mortality

Pregnant women: increased mortality risk; spontaneous abortion/stillbirth; maternal anemia; low birth weight

Economic consequences

  1. Adverse effects on productivity
  2. Average loss of 1.3% of annual economic growth in countries with intense transmission
  3. Single episode of malaria: loss of 5-20 working days
  4. An infected agricultural family up to 60% less productive than an unaffected family
    1. Because they are labour intensive → cycle of proverty

Progress

  1. Between 2010 & 2015, incidence rates fell by 21%; mortality rates fell by 30%
  2. 57 countries/territories have reduced incidence by >75%
  3. African children aged 2-10:
    1. 33% infected with malaria in 2000
    2. 16% infected with malaria in 2015
  4. Malaria no longer the leading cause of death among children in sub-Saharan Africa

Malaria – pathogen:

Human: caused by 5 Plasmodium spp:

  1. P. falciparum: most deadly
  2. P. vivax; P. ovale; P. malariae
  3. P. knowlesi (zoonosis; malaria in long-tailed macaques in parts of SE Asia) → humans are “bystanders”
 Transmission of malaria

  1. Parasite
  2. Vector
  3. Host (human etc.) / reservoir
  4. Environment

 

P. falciparum infection

Attributable factors for mortality:

  1. Cerebral malaria
  2. Severe anaemia
  3. Respiratory failure
  4. Renal failure
  5. Severe malaria of pregnancy

1) Hemolysis → Cytokine release

→ Inflammatory response

2) RBCs made to stick to each other

→ Thrombosis (occlusion)

 Pathophysiology

Sequestration of erythrocytes in the deep venous vasculature:

  1. Cytoadherence/rosetting: binding of infected red cells to endothelial cells & uninfected red cells, respectively
  2. Sequestration can occur throughout the body: brain, lungs, kidneys, placenta, etc.
  3. Avoidance of filtration by spleen

Malaria – vector

  • Transmitted exclusively by Anopheles

mosquitoes (>20 important species)

  • Most species bite at night (dusk to dawn)

(mosquitoes have their specific lifespans and biting habits)

African vector species tend to have longer lifespans and stronger human-biting tendency

 

Breed in stagnant shallow freshwater collections

  • eg. puddles, ricefields, etc.

Urban settings: construction sites, waste dumps, etc.

High risk groups:

  • young children, pregnant women, etc.

Acquired partial immunity can develop over years of exposure (can reduce risk of severe disease)

Genetic traits:

  • Sickle-cell trait (heterozygous HbS)
  • Thalassaemias (heterozygous)
  • Glucose-6-phosphate dehydrogenase (G6PD) deficiency (heterozygous)
  • Duffy antigen negativity (P. vivax)
 Malaria (environment)

Climactic factors that can affect population dynamics of the mosquitoes

  • Amount of rainfall
  • Temperature
  • Humidity

Eg. in tropics, peak transmission during & just after the rainy season

 

Hypnozoites

  • Latent parasites in the liver for mths/yrs
  • P. vivax & P. ovale
  • Relapses in malaria if not specifically treated
    • Hence, treatment has to include steps to eradicate the dormant component

Cycles of invasion & growth in erythrocytes produce exponential rise in parasites
Clinical Features

(malaria)

 Additional Information
1. Incubation period:

Very variable

 Primary attacks: average 8-25 days, but may be longer

(immune status, infecting strain/dose, prior chemoprophylaxis)

  • Relapses from hypnozoites (mths/yrs)
  • Late-onset; re-infection: variable

Fever within 7d of entering endemic area: malaria unlikely

Hx travel to endemic area up to 1 yr of onset of fever: suspect malaria; seek medical help
2. Travel history Know the countries that are prone to malaria

  • Esp. Africa
3. Presentation
  • Fever, headache, fatigue
  • Night sweats, chills, rigors, arthralgia, myalgia, insomnia, abd cramps, diarrhoea
  • Pallor, jaundice, hepatosplenomegaly
4. Malaria paroxysms Sometimes present in infection

  • Chills/rigors→ fever → profuse sweating, fatigue, sleep

Coincides with rupture of schizonts; associated with release of high levels TNF-α. *P. falciparum infection may produce continuous rather than cyclical fevers

 

Severe Malaria

Clinical Features:

  • Decreased consciousness – GCS<11
  • Multiple seizures (>2 in 24 hrs)
  • Prostration – generalised weakness – person unable to sit, stand or walk without assistance
  • Pulmonary oedema, often with tachypnoea >30/min; and O2 sats <92%
  • Significant /spontaneous bleeding
  • Jaundice (bilirubin >3mg/dl)
  • Shock (adult systolic bp < 80 mm Hg etc.
 Laboratory findings:

  1. Severe anaemia (Hb <5g/dl [children]; <7g/dl [adults])
  2. Hypoglycaemia (blood glucose <2.2 mmol/l)
  3. Renal impairment (serum creatinine >256 µmol/l or urea >20mmol/l)
  4. Metabolic acidosis eg. lactic acidosis
  5. Hyperparasitaemia (P. falciparum parasitaemia > 10%)

 

Management of Malaria

  1. Early accurate diagnosis
  2. Prompt effective Rx (within 24-48 hrs onset)
  3. Rational use of antimalarial Rx; compliance with Rx
  4. Combination therapy
  5. Optimal dosing

 

Because Malaria has vague symptoms; there are many Differential Diagnosis:

  1. Influenza → shorter incubation period
  2. Enteric (typhoid) fever → shorter incubation period
  3. Bacteraemia/sepsis/meningitis
  4. Dengue fever
  5. Acute schistosomiasis
  6. Leptospirosis
  7. Trypanosomiasis
  8. Yellow fever, etc.

→ if 1st suspicion is not treated by issued drugs (think of malaria)

  • If it patient has travel history
  • If fever starts more than a week after first day in country (exposure)
  • Employ the right tests to confirm suspicions

 

Diagnostic Tests

(with Clinical suspicions)

  • Thick and thin Giemsa-stained blood films
  • Rapid diagnostic tests ; RDTs
    • Detection of Plasmodium antigens: sensitive; detection at parasitaemia of 0.002-0.004% (100-200 parasites/µl)
  • PCR-based or other NAATs
  • Others: FBC, U&E, glucose, lactate, blood gases, urinalysis, etc.

Anti-malarial drugs

  1. Chloroquine; mefloquine; primaquine
  2. Quinine
  3. Artemisinins
  4. Doxycycline
  5. Clindamycin
  6. Sulphadoxine-pyrimethamine
  7. Atovaquone-proguanil (Malarone)
Chloroquine

Cheap, widely available

Resistance widespread in many regions

 Mefloquine

Useful against most chloroquine-R strains except eg. SE Asia (Thailand, Vietnam, Cambodia, Laos, Myanmar) where mefloquine-R strains are commonly found.

  • Side-effects: GI upset, nightmares, mood changes, arrhythmias
Artemisinin Drugs

  • Artesunate
  • Artemether
  • Dihydroartemisinin etc.

Usually in combination with other antimalarial drugs (artemisinin-based combination therapy, ACT)

  • + lumetantrine, amodiaquine, mefloquine, etc.
 Quinine

Alternative Rx for severe malaria

  • Safe in pregnancy
  • Bitter taste; GI upset
  • Cinchonism: nausea, dysphoria, tinnitus, high-tone deafness
  • Increased risk of arrhythmias (prolonged QT interval)
  • Increase in insulin secretion (increased risk of hypoglycaemia)
Artemisinin derivatives

Derived from herbal plant Artemisia annua

Used in China for centuries as Rx for fevers

  • Effective against multidrug-resistant Plasmodium spp.
  • Clinical improvement usually within 24-36 hrs
  • Well tolerated and safe in adults, children & pregnant women

→ Artemisinin Drugs are now the First line drugs to be used for malaria and severe malaria

  • Has a better side effect profile (to quinine etc.)
  • And taken together with other oral drugs; helps reduce % of resistance against drug

 

WHO 2015 “Guidelines”

P. falciparum malaria can be fatal if not diagnosed & treated promptly

  1. Numerous trials showing significant reduction in mortality with IV artesunate when compared to IV quinine
    1. Eg. AQUAMAT trial (Lancet 2010; 376:1647-57.)

Severe falciparum malaria for adults & children:

  1. Artesunate IV/IM for at least 24 hrs
  2. If above is not available: IM Artemether preferred to IV quinine
  3. Follow-on oral therapy:
    1. 3 days of oral ACT +/- primaquine
    2. Alt: Quinine + doxycycline/clindamycin

Uncomplicated falciparum malaria:

  • 1st line: 3 days of oral ACT: (artesunate + amodiaquine; artemether + lumefantrine, etc.)
  • plus single dose of primaquine in low-transmission areas (gametocytes)
    • (exception: pregnant women in 1st trimester: 1 wk of quinine + clindamycin)
  • Other regimens:
    • Artesunate + doxycycline/clindamycin
    • Quinine + doxycycline/clindamycin

Uncomplicated P. vivax/P. ovale/P. malariae/P. knowlesi malaria

  • Chloroquine (if from chlor-S regions)
  • ACT (if chloroquine-R: Indonesia, Peru)

Prevention of relapsing malaria (ie. Rx against P. ovale/vivax hypnozoites) — “dormant”

  • Primaquine (special precaution: G6PD deficiency)

 

Vector control

  1. Insecticide-treated mosquito nets (ITNs)
  2. Indoor residual spraying (IRS) with insecticides
  3. Environmental management eg. swamps/marshes, urban development,
  4. Education of public

 

Personal protection

Chemoprophylaxis:

  • Choice depends on geographical resistance pattern, duration of travel, costs, factors affecting compliance, side-effects, etc.
  • No regimen is 100% effective
  • Areas with chloroquine-S P. falciparum: Chloroquine
  • Areas with chloroquine-R P. falciparum: Mefloquine
  • Areas with chloroquine- & mefloquine-R: Doxycycline or Atovaquone + proguanil

Other measures

  • Mosquito repellents; cover as much skin with clothings as possible, mosquito nets, etc.

Challenges (malaria)

  1. Progress slowest in worst-affected countries
  2. Artemisinin resistance
    1. Reported in Greater Mekong region: Thailand, Myanmar, Kampuchea, Viet Nam, Laos
  3. Insecticide resistance
  4. P. vivax malaria in some countries
  5. Vaccine development – modest success so far.