Haemoflagellates

Question 1

Describe Life cycle of African Trypanosome

Answer 1

1. tsets fly takes a blood meal & injects metacyclic trypomastigotes
2. injected metacyclic trypomastigotes turn into blood strem trypomastigotes which are carried to other sites
3. trypomastigotes multiply by binary fission in various body fluids e.g. blood, lymph, spinal fluid releasing more
4. trypomastigotes in blood
5. tsetse fly takes a blood meal and ingests trypomastigotes
6. bloodstream trypomastigotes transform into procyclic trypomastigotes in fly’s midgut. They multiply by binary fission
7. procyclic trypomastigotes leave midgut and transform into epimastigotes
8. epimastigotes multiply in salivary gland. they transform into metacylclic mastigotes and so on …

Question 2

What are the main hemoflagellates?

Their vectors?

The diseases they cause?

Answer 2

1. Trypanosoma cruzi
   
   • ​Reduviid Bug
     
     • Chagas Disease
2. Trypanosoma brucei
   
   • Tsetse fly
     
     • Sleeping Sickness
     • Animal trypanosomiasis
     • Also cause animal trypanosomiasis (Nagana)
3. Leishmania spp
   
   • ​Sandfly
     
     • Leishmaniasis

Question 3

What are the 4 distinct stages of development of the hemoflagellate parasites?

Which pertain to which species?

Which are found in the mammalian phase of the life cycle and which in the vector phase?

Which pertain to which species of hemoflagellate?

Answer 3

• Mammalian Forms
  
  • 1. Trypomastigote
  • 2. Amastigote
• Insect (vector forms)
  
  • 3. Promastigote
  • 4. Epimastigote
• T. brucei
  
  • ​trypomastigote ⇒ epimastigote
• T. cruzi
  
  • ​​trypomastigote ⇒ amastigote ⇒ epimastigote
• Leishmania spp.
  
  • ​amastigote ⇒ promastigote

Question 4

What is th kDNA of Hemoflagellate parasites?

Answer 4

• kDNA is the mitochondrial DNA of kinetoplasmid organisms
• located in kinetoplast
• used for diagnostics and for identifying parasite species

Question 5

What trypanosomes cause human sleeping sickness?

Animal trypanosomiasis (Nagana Disease)?

Answer 5

• Human sleeping sickness
  
  • T. brucei rhodesiense
  • T. burecei gambiense
• Animal trypanosomiasis (Nagana disease)
  
  • T. brucei brucei
  • T. vivax, T. congolense, T. evansi

Question 6

What are the Stages of Sleeping Sickness (HAT)?

Answer 6

• Stage 1 (hemolymphatic phase)
  
  • Trypanosomes multiply in subcutaneous tissues, blood, lymph
• Stage 2 (neurological phase)​​
  
  • ​parasites cross BBB to infect CNS
  • changes of behaviour, confusion, sensory disturbances, poor coordination
  • disturbance of sleep cycle
  • fatal if untreated

Question 7

Contrast the Sleeping Sickness associated with T. b. rhodensiense with that of T. b. gambiense.

Answer 7

• T. b. rhodesiense Sleeping Sickness (HAT)
  
  • rapid onset
  • zoonotic disease, typically savanah habitats
  • flies feed on game animals
  • at risk: hunters, honey gatherers, fishermen, firewood gatherers
• T. b. gambiense Sleeping Sickness (HAT)
  
  • transmitted only from human to human
  • responsible for >90% of sleeping sickness cases
  • riverine sites, affecting women and children who may go down to wash
  • pigs are possible reservoir (but may not be part of the cycle)
  • Game animals may be infected with trypanosomes similar to Tbg

Question 8

Outline the Life Cycle of Trypanosoma brucei.

What species cause what disease?

Answer 8

• T. brucei rhodesiense
• T. brucei gambiense

1. tsetse fly injects metacyclic trypanosome (usually over 40,000 each time they feed) which
2. immediately transforms into bloodstream form trypomastigotes (long slenders), and divide by binary fission in interstitial spaces at site of bite
3. metabolic wastes and cell debris build up, leading to extensive necrosis and formation of soft painless chancre
4. trypomastigote replication by binary fission in blood, producing both long slenders and short stumpies. Short stumpies are pre-adapted to vector
5. are taken up by a following tsetse fly bite and trypanosomes transform in fly midgut to procyclic then to salivary glands where they form metacyclic trypanosome

• NOTES
• insect cycle
  
  • vector remains infected for life (2-3 mo for females)
  • minimum infective dose is 300-500 orgs
  • insect cycle takes 25-50 days
  • if tsetse ingests more than one strain of trypanosome, possibility of genetic exchange between two strains
• human cycle
  
  • trypomastigote from site of injection enters blood stream through lymphatics and divides futher, producing patent parasitemia, which is high with T.b. rhodensiense but low in T.b. gambiense so that blood smears usually remain negative.
  • at some point tryps enter CNS

Question 9

Discuss Antigenic Variation and its role as defense mechanism for African trypanosomes.

What other recent discoveries regarding trypanosome/host relationships contribute to the difficulties in controlling African trypanosomiasis epidemics?

Answer 9

1. VSGs
   
   • african tryps coated by 10-20 millions of identical Variant Surface Glycoproteins (VSG’s)
   • trypanosomes contain hundreds of VSG genes coding for antigenically different VSG’s
   • only one VSG protein is expressed at a time
   • VSG switching eludes Ab response and complicates vaccine production
2. the extent of assymptomatic carriage of the parasite
3. the fact that trypanosomes hide in the skin of human hosts

Question 10

• Describe this picture. What organism? What does it demonstrate?

Answer 10

• African trypanosomiasis
• The picture is of long slender trypanosomes dividing by binary fission in the bloodstream.
• Note the two flagellae, two nuclei and 2 kinetoplasts

Question 11

• What species?
• What characteristics of this species are demonstrated.
• What is the difference in behaviour and antigenicity of the two forms?

Answer 11

• African trypanosomiasis. T. brucei
• It demonstrateds the pleomorphism of trypomastigote forms in African trypanosomiasis.
• Note Stumpy and slender forms.
  
  • Only the stumpy form infects tsetse flies
  • But only the slender from divides in blood
  • “slenders” that replicate and undergo antigenic variation; and smaller “stumpies” that do not undergo antigenic variation but are pre-adapted to survive in the tsetse fly (MacGregor et al., 2011, Dyer et al., 2013)
  • slender forms in the skin can develop into stumpies

Question 12

Chagas disease:

Causative agent?

Vector?

How transmitted?

How many infected?

How many at risk.

Answer 12

• Trypanosoma cruzi
• Transmitted by triatomine (kissing ) bugs aka reduviid bugs
• The bug bites and then defecates, the bug feces containing the metacyclic trypomastogite, the infective form of the trypanosome.
• skin penetration occurs when host scratches at site of bite and carries the bug poop to the site of the bite; or via adjacent mucus membranes

Question 13

Describe the life cycle of Trypanosoma cruzi

Answer 13

Question 14

What is this?

Note identifying features.

Answer 14

• T. cruzi in bloodstream as trypomastigote
• note “C shape when fixed”
• note dense kinetoplast at one end

Question 15

Describe the distribution of pathogenic agents responsible for African trypanosomiasis.

What is the difference between the two organisms?

Which causes most disease and how much?

Answer 15

• West of a line extended south through Rift Valley:
  
  • T. bruceii gambiensis
• East of that line
  
  • T. bruceii rhodesiensis
• Uganda may have either
• TbG currently causes over 98% of reported cases
• Gambiense= Gradual onset
• Rhodesiense= Rapid onset

Question 16

What is this?

Discuss:

Which bug?

Time Course?

African vs European patients?

Answer 16

• Chancre: localised erythema at site of bite indurated, may ulcerate
  
  • maybe tender
  • Appears day 5 – 15 after bite, lasts ~ 3 wk
  • Commoner with Rhodesiense; Rare with Gambiense.
    
    • Rare in Africans at time of presentation of TbG.
    • Present in 25-40% Europeans at time of presentation of TbG.

Question 17

What is this?

Describe the usual presentation of the acute form.

Answer 17

• Parasitaemia related:
  
  • Initial non-specific
  • Human African Trypanosomiasis
    • myalgia
      headache
      intermittent fever: approximate cycle of 7-10 days
      weight loss
      transient oedema (facial) pruritis
      rashes lymphadenopathy anaemia
      hepatitis

Question 18

What is this?

Discuss clinical significance.

Answer 18

• Winterbottom’s sign
  
  • enlargement of post cervical lymph nodes in African Trypanosomiasis
  • occurs independently of site of intial innoculum
  • do needle aspirate and stain to identify tryps to make dx
  • (Slavers used to check for this to exclude from transportation)

Question 19

What are the complications of Human African Trypanosomiasis (HAT)?

Answer 19

• CVS
  
  • Myocarditis, pericardial/pleural effusions, ascites
• Endocrone
  
  • hypogonadism, hypothyroidism, hypoadrenalism
• CNS
  
  • psychosis, convulsions (esp children)
  • insomnia/somnolence
  • hyperesthesia, paraesthesia
  • tremors, ataxia, focal signs, Parkinsonian like features
  • coma
• General
  
  • wasting, malnutrition, secondary infections

Question 20

• Compare Tb Rhodesiense vs Gambiense in terms of:
  
  • Incumbation
  • Onset
  • Primar Complex
  • Fever
  • Early features
  • Rash
  • Late features
  • Duration
  • Trypanosomes

Answer 20

Question 21

• Staging of HAT
• Why important?

Answer 21

• Stage 1 - (Early) No invasion of CNS
• Stage 2 - (Late) Invasion of CNS
• Important wrt clinical management

Question 22

HAT: How do you make the diagnosis?

Answer 22

• Find the parasite!
  
  • aspiration from chancre/node
  • thick/thin films/wet prep
    
    • may use blood concentration techniques
      
      • e.g Microhaematocrit centrifugation (MCHT)
      • Quantitiative Buffy Coat (QBC) most sensitive
  • marrow, (tissue fluids)
  • CSF

Question 23

What is this?

Answer 23

• Trypanosome brucei in aspirated lymph node

Question 24

• What is this?

Answer 24

• Trypanosome brucei in per blood thin smear, Giemsa Stain

Question 25

What is this?

What is the differential Diagnosis?

Answer 25

• Cutaneous Leishmaniasis
• CL - Differential diagnosis
  • tropical and traumatic ulcerative lesions
  • foreign-body reactions
  • superinfected insect bites
  • myiasis
  • impetigo
  • fungal and mycobacterial infections,
  • sarcoidosis
  • neoplasms.

Question 26

What is this? and what kind of infection?

What sort of sample would you find this?

What other findings would be compatible with this condition?

How should the sample be examined after direct microscopy?

Answer 26

• A is a T. bruceii trypanosome in the CSF, adjacent to a number of blood cells
• B is a morular cell of Mott - a plasma cells with globular cytoplasmic inclusions containing immunoblobulin proteins
• CSF
  
  • should be examined within 20 min
  • direct micro for trypanosomes
  • WCC > 5 WBCs/mm³ indicates CSF involvement requiring treatment
  • elevated protein, IGM
  • centrifugation
  • presence of IgM and neopterin are indicators of CNS involvement
  • morula cells of Mott are rarely seen

Question 27

What is this and what is it’s clinical utility?

How should it be used?

Answer 27

• it is a Card Agglutination Test for Tryponosomes (CATT test)
  
  • useful for population screening for HAT in Tb gambiense but not rhodesiense.
  • in Gambiense screening should be done on basis of cervical lymphadenopathy aspirate if this is apparent
  • otherwise CATT. positives should be repeated on diluted blood sample and investigated if this is possible
  • in Rodesiense, CATT is of no use. Population screening is done on the basis of risk and the presence of symptoms.

Question 28

• Which drugs are available for treatment of HAT?
• How much do they cost?

Answer 28

• provided free of charge to endemic countries through WHO partnership
• Sanofi-aventis: pentamidine, melarsoprol, eflornithine
• Bayer: suramin

Question 29

Outline treatment choices and common side effects for treatment of HAT by stage of disease.

Answer 29

• Gambiense
  
  • Stage 1
    
    • pentamidine: may cause pancreatitis, diabetes
    • or Suramin: nephrotoxicity and hypersensitivity reactions
  • Stage 2
    
    • Eflornithine (DMFO or difluromethornithine)
    • or Malarsoprol (MelB) + prednisolone
    • or (recently introduced) NECT - nifurtimox + ethornithine Combination Therapy: effective, better side effect profile.
• Rhodesiense
  
  • Stage 1
    
    • Suramin (does not cross BBB)
  • Stage 2
    
    • Melarsoprol (?+ prednisolol): arsenical may cause hypersensitivity encephalopathy in 15%, of which 50% mortality
    • exfoliative dermatitis (Stevens Johnson)
  • _{table below from Lancet 2010; 375:148-159}

Question 30

How common are relapses of HAT after treatent with:

Pentamidine?

Melarsoprol?

How should they be treated in case of Gambiense? Rodesiense?

Answer 30

• Pentamidine: 1-10%
• Melarsoprol: 20-30%
• Gambiense: use either melarsoprol (MelB) or eflornithine, whichever not used previously; or nifurtimox; or combination nifurtimox and MelB.
• Rhodesiense: melarsoprol. If further relapse consider eflornithine plus melarsoprol (rct shows more effective, easier to use

Question 31

How often and for how long should patients have f/u LP’s after treatment for HAT?

For Gambiense?

For Rhodesiense?

Answer 31

• All should have f/u LP’s for 2 years
• Gambiense: LP q 6 months
• Rhodesiense: LP q 3 mo x 1 yr the q 6 mo
• If initially Stage 1, but f/u:
  
  1. csf 6-19 WBC’s/mm³ ⇒ rpt LP 1-2 mo
  2. .csf > 20 wbc/mm³ ⇒ then tx as stage 2
• If initiallly Stage 2, CSF WCC at f/u is more important than actual value

Question 32

Outline tools for case detection and treatment for HAT in areas of low and high prevalence.

Answer 32

• Case detection & treatment:
  
  • low prevalence - passive surveillance
  • suspect high risk areas or epidemics: spot or regular surveillance using mobile teams
• Vector control:
  
  • any situation: traps, insecticides, education
  • epidemic/priority development area: traps, insecticides, education, spraying

Question 33

Describe the lifecycle of T. cruzi.

Answer 33

1. Triatomine bug takes a blood meal and passes metacyclic trypanomastigote in feces, enters human via bite wound or conjunctiva
2. trypanomastigote penetrates various cells at bite wound; inside cells transform into amastigotes
3. amastigotes multiply by binary fission in cells of infected tissues
4. intracellular amistigotes transform into trypanomastigotes, then burst out of cell into bloodstream; some infect other cells and transform into intracellular amastigotes and so on in intrahuman infective cycle with ongoing tissue damage.
5. triatomine bug takes a blood meal and ingests trypanomastigotes
6. epimastigotes in midgut
7. multiply by binary fission
8. metacyclic trypomastigotes in hindgut and so on …

Question 34

How does orally transmitted Chagas occur?

What are the clinical implications?

Answer 34

• has been associated with outbreaks of disease in new areas
• a high proportion of sylvatic animals and domestic dogs are infected
• sylvatic bugs enter houses and bugs or bug feces finds its way into food and fruit juices, also among cane that is pulped with infected bugs on it
• orally transmitted disease has a higher infectious dose and is associated with greater morbidity and mortality

Question 35

What is the global burden of Chagas disease?

Where does it occur?

Answer 35

• approximately 10 million in endemic areas, primarily South and Central America, Mexico, southern US
• cases elsewhere associated with immigration
  
  • 325,000 cases in Europe
  • 100,000 cases in Europe, most in Spain

Question 36

• Describe the Stages of Chagas Disease
  *

Answer 36

• Acute
  
  • Incubation 6-10 d post bug exposure
  • 10-20 d post transfusion
  • mostly mild sx, only 1-2% diagnosed
  • mostly <15 yr age
  • in cases of extremely high inoculum with eg. drinking contaminated sugar cane or juice, may get acute infection suff severe to kill
• Indeterminate
  
  • life-long, from 8-10 wk following acute phase
  • assymptomatic for 10-30 yr
• Chronic
  
  • 10-40% of total population infected
  • Cardiac/GI tract/other

Question 37

• Outline the epidemiologic profile of chagasic patients
  
  • Age?
  • social factors?
  • What leads them to seek care?

Answer 37

• mean age: 38 yrs
• rural areas, or at periphery of towns
• low educational level
• manual labour
• seek care due to +ve serology, abnormal ecg or symptoms (cardiac or GI)

Question 38

• What factors may be associated with the progression of cardiopathy in Chagas disease?

Answer 38

• disease duration
• male sex
• intense physical activity
• parasite strain
• exposure to reinfection
• genetic background, black?
• age
• severity of acute infection
• nutritional status
• alcoholism
• comorbidities

Question 39

• Describe Chagas pathogenesis and pathology

Answer 39

• local multiplication in macrophages at site of innoculation
• tissue dissemination - prediliction for muscle ⇒ amistigotes in ‘pseudocysts’ ⇒ destruction of Purkinje fibres + ganglia in conducting system of heart; destruction of autonomic ganglia of gut tissue
• organ localisation: amastigotes become scarce
  
  • ?autoimmune mechanisms involved in continued muscle deterioration?

Question 40

• Describe the acute presentation of Chagas disease.
• What does the picture represent?

Answer 40

• often mild/assymptomatic
• local redness + swlling + nodes
• Chagoma at bite site
• Romana’s sign - periorbital swelling
• fever, nodes, hepatosplenomegaly
• tachycardia, peripheral edema
• +/- anemia; +/- morbilliform rash
• +/- meningoencephalitis; +/- myocarditis

Question 41

What are the chronic clinical manifestations of Chagas Disease?

Answer 41

• Cardiovascular: cardiomyopathy leading to
  
  • arrhythmias, thrombosis, emboli, cardiac failure (esp Rt sided)
  • megaesophagus often assoicated with parotid hypertrophy (‘cat face’)
  • megacolon
  • other, eg neurological, endocrine

Question 42

What does this picture show?

Describe the course of disease related to this organ.

Answer 42

• an aneurysm associated with circumscribed thinning of the apical region of left ventricle
• myocarditis is frequently associated with the acute stage, usually returns to normal without treatment
• after assymptomatic period of 10-13 yrs, chronic Chagas heart disease, characterized by myocardial fibrosis is seen in high percentage of carriers of T. cruzi

Question 43

What is shown in these x-rays?

What organism is the cause of this disease?

Answer 43

• Chagas esophagopathy
  
  • a) anectasic
  • b)-d) mild to severe megaesophagus
• Trypanosoma cruzi

Question 44

What is shown here?

What complication is it commonly associated with?

Answer 44

• parotid hypertrophy conferring “feline facies” to patient with Chagas Disease
• megaesophagus

Question 45

What is shown here?

In what country are these most likely to be found and why?

Answer 45

• A) megaesophagus and megastomach
• B) megaseophagus and megaduodenum
• C) megabulp and megajejunum
• D) megacolon
• All GI complications of chronic Chagas disease
• mainly Brasil, ascribed to different pathogenic properties of regional strains of T. cruzi

Question 46

• What is this?

Answer 46

• Megacolon caused by degeneration of Auerbach and Meissner plexuses in Chagas Disease

Question 47

Outline the pattern of T. cruzi infection in immunocompromised patients.

What course does it take.

Post-transplant patients?

HIV +ve patients?

Answer 47

• immunosuppression produces a “recrudescence” of a previously stable chronic infection that may be clinically similar to acute Chagas
• post-transplant patients may develop skin lesions resembling cellulitis that may necrose
• HIV +ve: meningoencephalitis is common
  
  • subcortical brain abscesses similar radiologically to cerebral toxo
  • (but toxo commoner in thalamus and basal ganglia)
  • cardiac failure and arrhythmias also common

Question 48

What is this?

List 6 ways in which the diagnosis can be made?

(roughly in order of clinical significance)

Answer 48

• peripheral blood identification by microscopy
  
  • ​for diagnosis in Acute Chagas
• serology
  
  • ​very important in Chagas because trypanosomes only readily identifiable in blood in Acute phase.
  • rapid Ab tests available, important for blood donor screening but cross-reactions with Leishmania, T. rangeli (non-pathogenic trypanasome)
• Xenodiagnosis
• PCR
• culture
• animal inoculation

Question 49

What is this?

What are idenitifying characteristics?

Answer 49

• T. cruzi in Geimsa stained blood film
• C-shaped trepanomastigote, note darkly staining nucleus and kinetoplast, flagellum

Question 50

Discuss the role of serological testing in Chagas Disease.

Answer 50

• Serological methods important as T. cruzi trypomastigotes only found in blood during early acute phase of infection.
• Antibodies can be demonstrated 1 month after infection.
• Immune Fluorescent AB/Enzyme-linked Immunosorbent Assay & many rapid tests now available, important for blood donor screening.
• Rapid Ab test - ‘Stat Pack’
• Cross reaction occurs with Leishmania and T. rangeli (non-pathogenic trypanosome transmitted by Rhodnius bugs in Latin America.

Question 51

What is T. rangeli?

Answer 51

• T. rangeli is a non-pathogenic typanosome transmitted by Rhodnius bugs in Latin America, which is also a vector of Chagas.
• Serology for T. cruzi cross reacts with T. rangeli (also with Leishmaniasis)

Question 52

• What is this?
• What is wrong with this picture?

Answer 52

• a little boy with Romana’s sign undergoing xenodiagnosis
• as Romana’s sign occurs with Acute Chagas, the blood should bear trypanomastigotes and infection shoud stil be detectable at this stage by direct microscopy

Question 53

What pharmacologic treatments are available for the condition associated with finding this organism in blood?

What side ffects are possible?

Are they effective?

Answer 53

• Acute Chagas
• nitroderivatives:
  
  • Nifurtimox or Benznidazole
  • Adverse effects highly dose dependent:
    
    • hypersensitivity (rash, fever, generalized edema, lymphadenopathy, joint and muscle pain.)
    • Bone marrow depression
    • peripheral polyneuropathy
  • treats symptoms of Acute Chagas, but does not decrease parasitemia and has little effect on course of Chronic Chagas
• poroconazole
  
  • not validated by RCT

Question 54

Discuss the drug treatment of chronic T. cruzi infections with nitroderivatives.

Answer 54

• Pires L., et al, Am J Trop Med Hyg. 2000 Sep-Oct;63(3-4):111-8.
  
  • randomized 10 yr f/u of 91 chronic Chagas pts and 41 controls
  • “These results show that nitroderivative therapy for T. cruzi infections is unsatisfactory and cannot be recommended since it fails to eradicate the parasite or change the progression of heart disease in chronic Chagas patients.”
  • other concerns:
    
    • severe side effects lead to non-compliance in pts older than 20 yrs
    • rx may release parasitemia due to drug-induced immunosuppression and ecological pressure for parasite resistance, probably through selection of highly virulent clone
    • lack of clinical findings showing benefit of treatment
    • treatment may be oncogenic: high incidence of malignant lymphoproliferative tumours in transplanted Chagas pts vs non-Chagas transplant controls & such tumours can be produced experimentally in animals with benznidazole
    • treatment with nitroderivatives does not eradicate infection or abrogate humoral or cell-mediated immune responses associated with autoimmunity and pathogenesis of typical Chagas heart complications

Question 55

To whom should should treatment be offered for Chagas Disease?

Acute vs chronic disease?

Age of patient?

Immunosuppression?

Particular complications?

Absolute contraindications.

Answer 55

Question 56

What treatment should be offered for pts with megabowel or cardiac complications of Chagas Disease?

Answer 56

• Symptomatic rx or surgery for megabowel, depending on severity and responsiveness
• Symptomatic treatment for cardiac complications
  
  • nb Dr. Wilson, Recife, 40 pacemakers per week

Question 57

What are the 2011 treatment recommendations for immunocompetent patients with Chagas Disease.

Acute vs chronic

What adjunctive treatments?

Answer 57

Question 58

What are the 2011 treatment recommendations wrt HIV and immunotransplanted with Chagas Disease.

Acute vs chronic?

Adjunctive treatments?

Answer 58

Question 59

What disease control measures can be taken wrt epidemiologic control of Chagas Disease?

Answer 59

• House interior insecticide spraying
• screening blood donors for t. cruzi
• improving housing
• Food hygeine

Question 60

Leishmaniasis: Geography and Disease Burden

Geography: where are the cases from?

How many at risk?

How many cases?

Answer 60

• 90% cases from Bangladesh, India, Nepal, Sudan, Ethiopia & Brazil
  
  • but note also southern Europe
• 350 million at risk of infection
• 1.5 -2 million cases/year
• 75% cases are Cutaneous Leishmaniasis
• Visceral Leishmaniasis causes

Question 61

What are the clinical features of visceral leishmaniasis?

Age

Duration of symptoms.

Answer 61

• Incubation:1-2mths->10yrs
• Asymptomatic–subclin–acute–subacute-chronic
• Onset usually insidious, low grade fever, progressive splenomegaly, hepatomegaly, anaemia, wasting, pigmentation, nodes, intercurrent infections.
• Postkala-azar dermal leishmaniasis (PKDL )after drug treatment

Question 62

Describe the Clinical Course of Visceral Leishmaniasis.

Incubation.

Spectrum of disease.

Symptoms.

Answer 62

• Incubation: 1-2 mnths ⇒ 10 yrs
• Clinical Spectrum: Assymptomatic-subclinical-acute-chronic
• Onset usually insidious, low grade fever, progressive splenomegaly, hepatomegaly, anemia, wasting, pigmentation, nodes, intercurrent infections
• sometimes abrupt onset with high swinging fever
• Post kala-azar dermal leishmaniasis (PKDL)

Question 63

What clinical finding is represented here?

What is the differential diagnosis.

Answer 63

• Massive splenomegaly DDx:
  
  • Hyper-reactive malaria splenomegaly (HMS)
  • Portal hypertension
  • Splenic hydatid cyst
  • lymphoma, leukemia, myelodysplasia
  • hemoglobinopathies, hemolytic anemias
  • glycogen storage and other metabolic diseases
  • Stills disease
  • amyloidosis

Question 64

What is the differential diagnosis of moderate splenomegaly.

What additional demographic information about VL is conveyed in the picture attached?

Answer 64

• any diseases included in the differential diagnosis of massive splenomegaly (attached image) plus:
  
  • Bacterial endocarditis, brucellosis
  • HIV, Infectious Monocleosis (IMN), CMV, Toxo
  • Leptospirosis, Relapsing fever
  • Trypanosomiasis
  • Schistosomiasis
  • Typhoid, Typhus
  • Tuberculosis
  • Syphilis
  • SLE, RA, other autoimmune diseases

Question 65

What intercurrent infections or complications may adversely effect patients with Visceral Leishmaniasis?

What is the mortality rate of VL in general?

Treated vs untreated.

Answer 65

• Measles, pneumonia, bacillary dysentery, TB, Brucellosis, HIV
• Malnutrition
• Malabsorption
• Bleeding
• Nephritis
• Uveitis
• PKDL
• Death: 0-50% treated; 85-90% untreated

Question 66

• How is the DIAGNOSIS of Visceral Leishmaniasis made?

Answer 66

• presence of anemia, leukopenia, thrombocytopenia
• Serological: IFA (Immune Fluorescent Ab), ELISA, DAT, K39 Dipstick
• these are all good tests with good sensitivity and specificity
• because of regional variations, an RDT for one area eg rK39 may be excellent in one area (rK39) but not good elsewhere
• Parasitological: (see image)
  
  • Aspirate from spleen, lymph node, marrow, liver or
    
    • buffy coat
• Leismanin skin test NEGATIVE (only turns positive after curative treatment)

Question 67

Lab findings in Visceral Leishmaniasis

Answer 67

Question 68

What is this?

How sensitive and specific is this procedure for VL?

What other sampling sites may be useful?

Answer 68

• L. donovani bodies (amastigotes) in a splenic aspirate
• >90% S & S
• bone marrow, liver, lymph node

Question 69

What serologic tests for VL are available?

What is the role of serology in VL?

Answer 69

• because VL a chronic disease, Ab detection tests likely positive in most cases
• Types
  
  • IFAT (+ve early; -ve 6-9 mo post cure)
  • ELISA: rk 39 Ag best
  • DAT
  • Dipstick (rk39)

Question 70

What is this?

What is it’s clinical utility?

How Sensitive and Specific?

What are it’s limitations?

Answer 70

• rK39 Dipstick for Antibody detection for Visceral Leishmaniasis
• useful, but geographically very specific
  
  • i.e. in India sensitivity ~100%, specificity ~98% but poor in Sudan

Question 71

What is this?

Discuss its clinical utility in the diagnosis of Visceral Leishmaniasis.

S&S

Geographic applicability

Limitations/problems

Answer 71

• DAT-FD (Direct Agglutination Test using freeze dried Ag) best
• Sens/Spec ~95%
• Main advantage is it is applicable in all regions and for all VL species
• Cost 1-2 Euro/test
• Limitations:
  
  • need to do multiple dilutions
  • so takes a long time ~18 hrs
• Remains positive long after ‘cure’

Question 72

• Discuss the Fast agglutination-screening test in the diagnosis of Visceral Leishmaniasis.
• What are it’s advantages?

Answer 72

• It is fast <3 hr to process
• Detects Ab (serum/blood on filter paper)
• Single serum dilution at cut off 1:800 or 1:1600
• qualitative results similar to DAT
• Uses freeze-dried Ag thus higher Ag stability, reproducability, specificity and sensitivity.

Question 73

What are the problems common to all serologic tests used in the diagnosis of VL?

Answer 73

• serology detects assymptomatics
• serology detects past infections
• test remains positive after treatment
• MAY BE NEGATIVE IN HIV-COINFECTED PTS.
  
  • (in which case Ag detection is useful)

Question 74

Discuss the clinical ulitily of Urine Ag tests and VL

What about the latex agglutination test (KAtex; Kalon Biological, UK)

Answer 74

• useful for diagnosis and monitoring response to treatment
• K39 and K26 Ag detection in urine 96% sensitive and 100% specific in VL
• Not detectable 3 wks after treatment
• Latex agglutination test (KAtex; Kalon Biological, UK)
  
  • geographic variation in sensitivity (48-95% and specificity 82-00%.
  • high sensitivity in two studies of HIV co-infected pts during clinical episodes when parasite load was high
  • negative following satisfactory clinical response
  • may be helpful in monitoring effect of treatment and efficacy of treatment and relapses

Question 75

What are the 3 typological variants of PKDL?

Pathogenesis?

Treatment?

Answer 75

• variants as per picture
• process is likely auto-immune reaction to residual skin trypanosomes, possibly related to upregulation of interferon gamma and other cytokines in skin after treatment of VL
• in Sudan most cases resolve spontaneously, only severe cases need treatment
• in India all need treatment
• (Lancet Infect Dis. 2003 Feb;3(2):87-98. Post-kala-azar dermal leishmaniasis. Zijlstra EE1, Musa AM, Khalil EA, el-Hassan IM, el-Hassan AM.)
• also some suggestion pattern of UV exposure may influence pattern of PKDL

Question 76

Discuss the clinical utility of PCR in dx of VL

Answer 76

• capable of detecting infection with a single parasite
• increasingly used for dx of VL and monitoring for relapse in HIV co-infected pts
• high sensitivity (82-100% for bone marrow and 72-100% for per blood.
• may be useful as test of cure
• PCR based RDT’s currently under development for field use.

Question 77

Treatment of Visceral Leishmaniasis:

What are the main drugs available?

Answer 77

• Pentavalent antimonials (SbV)
  
  • Sodium stilboglucamate (‘SSG’ or Pentostam)
  • Meglumine antimonoate (Glucantime)
  • nb widespread antimony resistance in Nepal, Bangladesh, India (but not Brazil or Sudan)
• AmBisome - liposomal amphotericin B
• Aminosidine (paromomycin) - alone or prefferably in combination with SSG (synergistic)
• Pentamidine - ? 2nd line treatment
• Oral miltefosine
• Treat intercurrent infections, provide supportive care.

Question 78

What does this map represent?

Answer 78

• Antimony resistance in Asia: India, Bangladesh, Nepal

Question 79

Discuss use of Miltefosine.

What disease is it used to treat?

How effective is it?

dosing?

Answer 79

• originally developed as oral neoplastic agent
• first hightly effective oral rx for VL
• 100 mg/day (or 2.5 mg/kg/d in children) x 4 wk ⇒>95% cure
• side effects: GI upset, rarely severe BUT
  
  • abortifacient, teratogenic ?decreased male fertility
• Long half lif (2-3 wks) + narrow therapeutic index, therefore possible risk of developing resistance
• therefore consider combination treatment

Question 80

Discuss use of Paromomycin (PM) (‘Aminosidosine’)

What disease and how?

Answer 80

• Visceral Leishmaniasis
• 15-20 mg/kg/day IM
• may be used alone for 21 days or
• combination treatment with SSG or pentamidine, allowing a shorter duration of treatment
• MSF regimen: SSG + PM x 17 days

Question 81

What is this?

How common is it and when does it occur?

How is it diagnosed?

How treated?

Answer 81

• Post Kala Azar Dermal Leishmaniasis (PKDL)
• Bangladesh 18% within 2 yrs of Rx for VL
• Sudan 50% within 6 months of Rx for VL
• Increased risk with interrupted/short course SSG
• Dx: Skin Biopsy; Buffy PCR (+ve in 40-75% of cases)
• Rx: Miltefosine 95% cure rate; other anti-leish Rx

Question 82

What is this?

What may it imply?

Answer 82

• Köbner phenomenon in PKDL
• likely reflects autoimmune component related to upregulation of interferon gamma, interleukin 10 and other cytokines post tx of VL

Question 83

What is this?

Answer 83

• PKDL resembling lepromatous leprosy

Question 84

What is this?

Answer 84

• PKDL response to 2 month therapy with miltefosine

Question 85

• What is the relationship between HIV and VL?

Answer 85

• recognized since 1986
• HIV & VL are mutually reinforcing: HIV increases susceptibility to VL and VL accelerates progression of HIV infection
• increased risk of treatment failure for VL in HIV
• reactivation of latent VL infection
• VL spread more widely through Asia, Southern Europe, South America with expansion of HIV epidemic, some evidence of HIV and VL being spread particularly through IVDU (see attached map)

Question 86

HIV & VL Co-infection:

Clinical Features

Answer 86

• 96 European pts (29-33 yrs)
  
  • Male 86%
  • Fever, hepatomegaly, splenomegaly, lymphadenopathy, pancytopenia, hypergammaglobulinemia common (70-90%)
  • Positive serology for VL in only 50%
  • Atypical clinical features:
    
    • dysphagia
    • cutaneous or mucocutaneous skin lesions
    • nodular or ulcerative lesions on tongue, esophagus, stomach, rectum, larynx, lungs
    • course variable from assymptomatic to rapidly progressive
    • 30% die during or within one month of treatment
    • mean survival 12 months
    • only 16% survive > 3 yrs
    • relapses inevitable q 3-6 months
  • HAART may delay onset/control relapses

Question 87

• How is the diagnosis of VL made in HIV-VL coinfection?

Answer 87

• Serology: ONLY 50% POSITIVE
• Parasitological dx:
  
  • 50% in blood
  • 94% in bone marrow

Question 88

• How is HIV-VL co-infection treated?
  
  • comment on effect of coinfection on toxicity
    
    • relapse rate

Answer 88

• Toxicity of pentavalent antimony increased
• outcome with meglumin antimonate v conventional amph B similar
• relapse rates similar (30-40%)
• possibilities for prevention of relapse:
  
  • monthly/fortnightly pentamidine/AmBisome
  • daily miltefosine

Question 89

Comment on Leishmaniasis and IRIS

Answer 89

• leishmaniasis may be unmasked by HAART
  
  • VL, PKDL, cutaneous manifestations
  • may be associated with unusual sites of disease (eg. eye)
  • response to standard tx variable

Question 90

What does this diagram represent?

Answer 90

• The pathogenesis of leishmaniasis in transplant patients via
  
  • reactivation
  • or de novo infection via
    
    • transfusion of leishmania-infected blood or
    • infected sandfly

Question 91

What are the 4 forms of Cutaneous Leishmaniasis?

Describe the geographic distribution?

Answer 91

1. Cutaneous Leishmaniasis (CL)
2. Diffuse Cutaneous Leishmaniasis (DCL)
3. Leishmaniasis Recidivans (LR)
4. Mucosal Leishmaniasis (ML)

• 90% cases occur in Afghanistan, Algeria, Brazil, Pakistan, Peru, Saudi Arabia, Syria

Question 92

Describe the lifecycle of Leishmania organisms in Leishmaniasis.

Answer 92

Question 93

What is this?

Answer 93

• Giemsa staining of touch preparation of a cutaneous lesion showing presence of intracellular parasites inside macrophages

Question 94

What is this?

How is it treated?

Answer 94

• Leishmaniaisis Recidivans (LR).
• This is characterized by a relapse of cutaneous disease within the sites of previous healed CL lesions.
• can occur decades after resolution of the primary lesions and often form within the edge of the previous scar.
• The lesions in leishmaniasis recidivans (LR) are reminiscent of those in discoid lupus or lupoid leishmaniasis and require treatment often with dual therapy.

Question 95

What is this?

How caused?

Natural History?

Answer 95

• Chiclero’s ulcer caused by L. mexicana
  
  • Forest worker typically
  • Infection results in a single ulcerative lesion, most commonly involving the ear pinna, without a tendency for cutaneous metastasis, lymphatic or mucosal involvement.
  • The majority of cases of “Chiclero’s ulcer” spontaneously re-epithelialize without treatment within 3–9 months.

Question 96

What is this?

Answer 96

• sporotrichoid lymphatic spread of cutaneous leishmaniasis
  
  • (due to L. major from Afghanistan)

Question 97

What is this?

What is the differential diagnosis?

Answer 97

• severe ulcerating cutaneous leishmaniasis lesion
• (in pt co-infected with HIV)
• Differential dx
  
  • tropical and traumatic ulcerative lesions
  • foreign body reactions
  • superinfected insect bites
  • myiasis
  • impetigo
  • fungal
  • mycobacterial infections
    
    • lupus vulgaris (cut tb)
    • buruli ulcer
  • sarcoidosis
  • neoplasms

Question 98

• What is this?
• How is the diagnosis confirmed?

Answer 98

• cutaneous leishmaniasis ulcer
• dx by core biopsy edge of ulcer +/- scrape centre
  
  • impression smear ⇒ giemsa stain
  • histology
  • pcr
  • culture

Question 99

What does this slide show?

Answer 99

• (Leishmania tropica) amastigotes from impression smear of a biopsy specimen from skin lesion
  
  • left: intact macrophage filled with amistigotes
  • right: amistigotes being freed from rupturing macrophage

Question 100

What is this?

What is used as the Antigen?

Clinical utility?

Pitfalls?

Answer 100

• Leishmanin test or Montenegro test
• Uses promastigote suspension as Ag (area and species specific)
• Positive in most cases of CL and MCL (except some L. aethiopica and DCL)
• Negative in VL but may become +ve after successful treatment
• may be positive due to previous exposure

Question 101

What do these pictures represent?

What is it known as colloquially? (etymology?)

Where is if found?

What species cause the majority of cases?

Pathophysiology?

Answer 101

• Mucocutaneous leishmaniasis, “a dreaded complication of New World Cutaneous Leishmaniasis”
• aka espundia, from latin for sponge
• Most cases caused by Vianna subgenus, esp L. braziliensis, L. panamensis, L. guyanensis
• Onset usually few years after resolution of original cutaneous lesion, may occur while primary lesion still present or even decades later
• hematogenous or lymphatic spread from skin to nasopharyngeal mucosa (rarely urogenital)
• nodule initially, then widespread destruction with chronic granulomatous destructive lesions, secondary bacterial infection
• risk in endemic areas 1-10% within 1-5 yrs, possibly higher

Question 102

What is this?

What is the differential diagnosis?

Answer 102

• mucocutaneous leishmaniasis
• ddx:
  
  • histoplasmosis
  • mucormycosis
  • leprosy
  • midline granuloma/lymphoma
  • neoplasms
  • rhinoscleroma - chronic granulomatous condition caused by Klebsielly rhinoscleromatis
  • sarcoidosis
  • syphilis
  • tertiary yaws
  • Wegener’s granulomatosis

Question 103

• What is the reason for systemic treatment of Cutaneous Leishmaniasis?
• Comment on the difficulty of treating Mucocutaneous Leishmaniasis.
• What are the best treatment options?

Answer 103

• adequate systemic treatment of CL is assumed (but not proven) to decrease already low risk (<5%) of developing mucosal disease
• ML harder to treat than CL and becomes increasingly difficult as it progresses
• Currently best treatment options are:
  
  • pentavalent antimony drugs (cure rates about 75% for mild disease & 10-63% for more advanced disease) OR
  • conventional amphotericin B
    
    • with concomitant steroids if respiratory compromise develops

Question 104

Is Miltefosine an option for the treatment of mucosal leishamanisis?

Answer 104

• Based on one unrandomized trial in Bolivia (Clin Infect Dis. 2007 Feb 1; 44(3):350-6)
  
  • oral miltefosine at least as effective as parenteral amphotericin B
  • cure rates approx. those of parenteral pentavalent antimony for mild and extensive disease in neighbouring Peru
  • less toxic than antimony and much less toxic than amph B
  • oral vs parenteral
  • trial suggests miltefosine should be TOC for mucosal disease in North and South America

Question 105

What questions influence the decision to treat cutaneous leishmaniasis and how to treat it?

Answer 105

• is patient at risk of mucosal leishmaniasis?
• locationoflesion(s)(eg,ontheface)
• number,size,evolution,persistence
• other features (eg, nodular lymphangitis).

Question 106

What is this?

What are more preferable treatment options for patients with non-metastasising, self-limiting CL?

Answer 106

1. paromomycin ong (available in Israel)
2. intralesional antimony therapy
3. heat treatment, cryotherapy
4. Topical amphotericin B (L. majorI)

Question 107

What oral agents are available for CL?

In what context should they be used?

Answer 107

• generally for treatment (or no treatment) for rel benign, cosmetically unimportant lesions, esp if caused by L. Major (old world) or L. mexicana (new world)
• Ketoconazole - modest activity against L. mexicana and L (V) panamensis; usefulness against L. major infection unclear.
• Itraconazole - better tolerated than ketoconazole but may be less effective, at leasta against the Viannia subgenus.
• Fluconazole (L. major) - po x 6 wk (NEJM 2002)
• Miltefosine

Question 108

What treatments should be used for CL if optimal effectiveness is important?

Answer 108

• Parenteral treatment:
  
  • IV/IM antimony therapy prob still best option if optimal effectiveness important
  • short-course pentamidine (effective in Colombia, predominantly Viannia subgenus)

Question 109

What disease is represented in this photo?

What are the organisms responsible?

What part of the immune response is deficient in the pathogenesis?

What is the appearance?

How treated? (Old World vs New World)

Answer 109

• Diffuse Cutaneous Leishmaniasis
• Old World: L. aethiopica - Ethiopia, Kenya
• New World: L. mexicana, amazonensis, venezualiensis
• A single lesion gives rise to multiple soft, fleshy nodules or plaques
• may be extensively depigmented
• ulceration is rare because Cell Mediated Immunity is lacking to Leishmania Ags
• Treatment of DCR:
  
  • Old World: SSG + aminosidine or Pentamidine (causes diabetes in 10%, pancreatitis)
  • New World: SSG

Question 110

What is this?

Where does it occur?

What is the course?

Typical appearance? Diff Dx?

How diagnosed?

How treated?

Answer 110

• leishmaniasis recidivans (caused by L.tropica in Kabul, Afghanistan)
• found in Iran and Iraq
• Chronic with waxing and waning for 20-40 years, characterized by central healing and scarring with active lesions around edge “lupoid leishmaniasis” - mimics lupus vulgaris
• Organisms are scanty in lesion, so culture may be helpful
• Tx: SSG (parenteral, intralesional), heat treatment.

Question 111

What are the first line treatments for Cutaneous Leishmaniasis?

Simple vs complex?

Old world vs New?

According to species?

Answer 111

Question 112

What options are available for the prevention and control of Leishmaniasis?

Answer 112

• destroy sandfly habitats
• eliminate/treat reservoirs for leishmania
• avoid bites
• residual insecticides
• habitation improvement
• also vaccines under development:
  
  • Leishmania antigens + sandfly salivary antigens
  • live attenuated L. major promastigote vaccine developed but risk of aggressive lesion or LR. has not progressed, remains experimental

Question 113

What is the main vector for T. brucei rhodesiensis?

What is the main vector for T. brucei gambiense?

Who bit Aunt Betsey?

Answer 113

• T. brucei rhodesiense: Glossina morsitans
• T. brucei gambiense: Glossina palpalis

A Glossina morsitans bit Aunt Betsey.

Tsk, Tsk, tsetse.

Question 114

Which trypanosome would one be most likely to contract here?

What would the likely vector be.

What are the main hosts for this trypanosome?

Answer 114

• T. b. rhodesiense
• animals SOMETIMES humans are the host
• predominantly Glossina morsitans
• Habitats primarily savanah

Question 115

What kind of trypanosome would one likely contract here?

Which vector?

What host?

Answer 115

• Flies infected with T. b. gambiense are common in riverine sites
• Likely fly would be Glossina palpalis group
• Main host for T. b. gambiense is human and transmission is Human to Human
• (However G. palpalis group feeds on riverine wildlife such as lizards and there is controversial speculation about animal reservoir for T. b. gambiense)

Question 116

What kind of tsetse would likely hone in this animal?

How would it locate the animal?

What kind of disease would it likely carry?

Answer 116

• Glossina morsitans
• Initially using chemical cues such as CO2 and odours to locate their hosts. When they get closer they use visual cues, predominantly using blue colours.
• riverine tsetse (G. palpalis group) less responsive to host odours because of restricted topography of riverine habitats.

Question 117

What is this?

Outline its life cycle.

How long for female to produce one larvum?

How long from the emergence of female to production of one egg?

Answer 117

• female produces single egg which develops into larva within her uterus
• every nine days mother produces larvum which burrows into ground, where it pupates
• adult fly emerges from the pupa after about 30 days
• 50 days elapse between the emergence of one female fly and its progeny

Question 118

What are 3 key features of the tsetse life cycle with respect to vector control?

Answer 118

1. They have a slow reproductive strategy so only have to kill a few (~4%/day) to eliminate a population.
2. Only adults are vulnerable (hard to find the larvae and pupae underground) so need to kill them as they emerge from the ground.
3. Males and females rely on blood for growth and reproduction; they range widely seeking hosts (riverine tsetse ~300 m, savannah tsetse ~500 to 1000 m) … so might kill them when they visit hosts but areas cleared of tsetse rapidly reinvaded.

Question 119

What effective methods of control are available for the tsetse fly?

Answer 119

• ground spraying long lasting insecticide such as DDT & deldrin killing tsetse as they rest on treated surfaces
  
  • insecticide lasts long enough for pupae to emerge
• sequential aerosol spraying (endosulfan, deltamethrin) at night
  
  • rpt x 5 cycles by which time all flies will have emerged
• insecticidal baits for animal hosts eg warthog, treat cattle
• tsetse odour-baited traps

Question 120

What does this diagram represent?

What are the implications for the treatment and control of HAT?

Answer 120

• important research by Casas-Sanchez and Acosta-Serrano 2016 demonstrating via mouse model that mice infected with T.b.gambiense and T.b.rhodesiense via G. morsitans developed significant skin populations of stumpy forms of tryps that resided in the skin and could give rise to Tsetse reinfection
• this, together with other research demonstrating tryps in historical skin biopsies from assymtomatic people, has raised sig new questions that throw into doubt the WHO plan to eliminate HAT by 2020.
  
  • do skin tryps hide in skin and evade immune system
  • are tryps in human skin involved in transmission of ghat
  • are there assymptomatic carriers bearing skin tryps
  • is GHAT anthroponotic?
  • is there a previously unrecognized animal reservoir?

Question 121

• Which is the parasitic stage of Leishmania donovani that the sandfly takes up with a blood meal from an infected human?

Answer 121

• Amastigotes are the tissue stage of Leishmania lifecycle and are seen in tissue taken for diagnostic testing (eg skin biopsy, bone marrow, splenic biopsy). Amastigotes of the various species of Leishmania are morphologically indistinguishable and are identified by molecular tests. The lifecycle stage of Leishmania that infects the human host is the promastigote – these transform into intracellular amastigotes, which are taken up by the sandfly vector.

Question 122

What are these organisms?

How do you differentiate microscopically?

Vector?

Answer 122

• T. brucei on left, T. cruzi on right
• motile blood stage forms primarily distinguished by size of kinetocyte, much more prominent in T. cruzi
• T. cruzi forms C-shape
• T. brucei has dividing forms present in blood
  
  • also both short stumpies and long slender forms
• geographically distinct & different vectors
  
  • T. Cruzi South and Central America & transmitted by triatomine bugs
  • T. brucei Sub Saharan Africa and transmitted by Tsetse Fly

Question 123

These organisms can be found in peripheral blood in acute phases of what diseases?

List drugs used for treatment.

Answer 123

• T. cruzi treated with Nifurtimox or Benznidazole (poroconazole in trials)
• T. brucei gambiense treated with (Stage 1) Pentamidine or Suramin; (Stage 2) eflornithine or melarsoprol or recently NECT (nifurtimox + eflornithine combination)
• T. Brucei rhodesiense treated with (St. 1 ) Suramin; (St.2) Melarsoprolol

Question 124

What drugs for disseminated cutaneous Leishmaniasis?

Answer 124

• Rx for disseminated
• Sodium stibogluconate IV
• Liposomal amphotericin
• Pentamidine parenteral • Oral miltefosine
• ? Length of secondary suppression

Question 125

• Briefly Compare and contrast Rhodesian HAT and Gambian HAT wrt
  
  • organism, vector
  • geography and lifecycle
  • course
  • treatment

Answer 125

• There are two forms of Human African Trypanosomiasis (HAT). Rhodesian HAT caused by Trypanosoma brucei rhodesiense transmitted largely by savannah tsetse (Glossina). Gambian HAT caused by T. b. gambiense transmitted by riverine tsetse.

Rhodesian HAT is a zoonosis found in East and Southern Africa, with wild hosts (buffalo, warthog, bushbuck) and livestock (cattle) acting as reservoir hosts. The progression of disease is acute with patients presenting symptoms in weeks and death occurring in months. Treatment of first and second stages of the disease is with suramin and malarsoprol respectively.

Gambian HAT is an anthroponosis found in Central and West Africa. This is the chronic form of the disease with the neurological symptoms presenting ~18 months after initial infection and death typically occurring ~3 y post-infection. First and second stage treatment of the disease is with pentamidine and NECT (Nifurtimox- Eflornithine Combination Therapy) respectively.

There are no vaccines or preventive drugs for these diseases, the disease is ultimately fatal if untreated.

Question 126

What organisms cause Visceral Leishmaniasis in different parts of the world?

Answer 126

• L. chagasi and L. amazonis are the chief causes of Leishmaniasis in the New World.
• L. tropica is the chief cause of Old World disease.
• L. infantum is the chief cause in the Mediterranean as far as China.
• L. donovani predominates in India and East Africa.

Question 127

Does Visceral Leishmaniasis have a zoonotic reservoir?

Which Species, where?

How about Europe & NA?

Answer 127

• L. infantum (Med, Middle East, Central Asia, China) is a disease of dogs and humans.
• L. donovani in India is a disease only of humans. In East Africa there may be a rodent reservoir.
• In Europe and North America it is a zoonosis, found in dogs

Question 128

Describe the natural History of Chagas Disease.

Answer 128

Question 129

How is Chagas disease Transmitted?

Answer 129

• 1. acquired via bite of Triatomine bug
     
     2. acquired via ingestion of food contaminated with triatomine insects or feces (eg fruit juice) or ingesting contaminated uncooked meat. (widespread mammalian zoonosis)
     3. infected blood (but now widespread screening)
     4. transplant recipients (ditto)
     5. Congenital transmission. Unlike toxoplasma, Chagas can be transmitted placental through successive pregnancies.
     6. IVDU

Question 130

• What is the best way to diagnose Visceral Leishmaniasis in remote areas?

Answer 130

• DAT on plasma or urine is reliable, sensitive and easy to carry out in a remote area. A new reliable freeze-dried version (DAT-FD) with a sensitivity and specificity >95% is now available for use in the field.
• The demonstration of amastigotes in splenic aspirate or bone marrow is probably the ideal way to prove the diagnosis. Promastigotes are very temporary occupants of blood.
• The fast agglutination test (FAST) that detects antibodies on filter paper gives accurate results in <3 h and is used widely nowadays.
• In India the K39 RDT is accurate, cheap and available.
• These tests have replaced the largely insensitive fluorescent antibody test (FAT).
• The Formol Gel Test (FGT) depends on a reversal of the albumin/globulin ratio in the blood, which occurs because of a raised plasma IgG, and simultaneous albuminuria. Not specific.
• ELISA testing gives highly accurate results, but this test is not available in the majority of remote hospitals.

Question 131

What is a midline granuloma?

(in the differential for MC Leishmaniasis)

Answer 131

• an destructive form of lymphoma affecting nasal sinuses and/or septum
• dx by histology

Question 132

What is a rhinoscleroma?

Answer 132

• Rhinoscleroma is a chronic granulomatous condition of the nose and other structures of the upper respiratory tract. Rhinoscleroma is a result of infection by the bacterium Klebsiella rhinoscleromatis. It is a disease of low resource economies, poor nutrition and overcrowding.

Question 133

• Differential diagnosis of Mucocutaneous Leishmaniasis.

Answer 133

• histoplasmosis
• leprosy
• midline granuloma
• neoplasms
• blastomycosis
• rhinoscleroma (Klebsiella spp)
• sarcoidosis
• syphilis
• tertiary yaws

Question 134

Describe Treatment for Visceral Leishmaniasis

Answer 134

• choice of first and second line drugs varies by region, may depend on local practices

Question 135

Describe the early symptoms of Human African Trypanosomiasis

Answer 135

• Early-stage symptoms
• -non-specific, onset 1–3 weeks after tsetse fly bite
• headache, malaise, arthralgia, weight loss, fatigue, and intermittent fever with rigors—the latter suggesting an alternative or additional diagnosis of malaria.
• lymphadenopathy or enlargement of spleen, liver, or both
• myocarditis, pericarditis, and congestive cardiac failure
• iritis, keratitis, and conjunctivitis
• endocrine dysfunction including menstrual abnormalities, impotence, alopecia, and gynaecomastia
• fertility problems including sterility, prematurity, abortion, and stillbirths
• Winterbottom’s sign a typical feature of T b gambiense HAT.
• travellers and expatriates from non-endemic countries presentation atypical, with acute febrile illness irrespective of the variant of HAT
• diarrhoea, hepatomegaly, or jaundice were frequent early- stage symptoms that could result in an erroneous gastroenterological diagnosis
• Another finding that has begun to challenge the classical symptom complex is the occurrence of neurological features during early-stage disease, eg two different areas in Uganda had altered gait and tremors, somnolence, urinary incontinence, and cranial neuropathies—findings that can hardly be explained by non- specific effects of systemic infection on the CNS. ?early CNS invasion

Question 136

Describe the late symptoms of HAT

Answer 136

• wide constellation of symptoms and signs can occur, with almost all regions of the nervous system potentially involved.
• mental disturbances, motor system disturbances, sensory system involvement, and abnormal reflexes.
• typical sleep disturbances that give the disease its name occur in 74% of patients: reversal of the normal sleep/ wake cycle, with nocturnal insomnia and daytime somnolence, uncontrollable episodes of sleep, and an alteration of the structure of sleep itself, with the early onset of rapid eye movement sleep rather than at the end of stage 4 sleep.
• Motor disturbances can occur, with motor weakness reported in 35% of cases, gait dis- turbance in 22%, tremor in 21%, abnormal movements in 11%, and speech disturbances in 14% of cases.
• Myelitis, myelopathy, muscle fasciculation, and peripheral motor neuropathy
• Psychiatric involvement: 25% of patients displaying behavioural disturbances.
• lassitude, hallucinations, delirium, anxiety, irritability, and excessive sexual impulses. Headache also common, occurring in 79% of patients in one study.
• sensory disturbances such as deep hyperaesthesia, pruritus, anaesthesia and paraesthesia, seizures, and visual problems such as optic neuritis, double vision, optic atrophy, and papilloedema.
• In travellers and expatriates with HAT from non-endemic countries both lymphadenopathy and sleep disturbances are only occasionally found and progression to late-stage disease is rapid. By contrast, in African immigrants, HAT is characterised by low-grade fever and neurological and psychiatric symptoms and signs.

Question 137

What is Mazzoti reaction?

Answer 137

• The Mazzotti reaction, first described in 1948, is a symptom complex seen in patients after undergoing treatment of onchocerciasis with the medication diethylcarbamazine (DEC). Mazzotti reactions can be life-threatening, and are characterized by fever, urticaria, swollen and tender lymph nodes, tachycardia, hypotension, arthralgias, oedema, and abdominal pain that occur within seven days of treatment of microfilariasis. The Mazzotti reaction correlates with intensity of infection; however, there are probably multiple infection intensity-dependent mechanisms responsible for mediating this complex reaction.[1]
• Patch test
• The phenomenon is so common when DEC is used for the treatment of onchocerciasis that this drug is the basis of a skin patch test used to confirm that diagnosis. The drug patch is placed on the skin, and if the patient is infected with the microfilaria of O. volvulus, localized pruritus and urticaria are seen at the application site.

Question 138

How is leishmania transmitted?

Is visceral leishmaniasis a zoonosis?

Answer 138

• through the bite of an infected phlebotamine sandfly.
• It depends
• L. infantum is primarily zoonotic
• L. donovanis is primarily anthropotic but both can participate in anthropo-zoonotic cycles
• Becaus L. donovani is primarily anthropotic, control of the disease might be more responsive to treatment programmes directed at humans
• Because L. infantum has a large sylvatic zoonotic reservoir, it would be hard to eradicate.

Question 139

How is diagnosis of African trypanosomiasis made?

Answer 139

• The diagnosis of African Trypanosomiasis is made through laboratory methods, because the clinical features of infection are not sufficiently specific. The diagnosis rests on finding the parasite in body fluid or tissue by microscopy. The parasite load in T. b. rhodesienseinfection is substantially higher than the level in T. b. gambiense infection.

T. b. rhodesiense parasites can easily be found in blood. They can also be found in lymph node fluid or in fluid or biopsy of a chancre. Serologic testing is not widely available and is not used in the diagnosis, since microscopic detection of the parasite is straightforward.

The classic method for diagnosing T. b. gambiense infection is by microscopic examination of lymph node aspirate, usually from a posterior cervical node. It is often difficult to detect T. b. gambiense in blood. Concentration techniques and serial examinations are frequently needed. Serologic testing is available outside the U.S. for T. b. gambiense; however, it normally is used for screening purposes only and the definitive diagnosis rests on microscopic observation of the parasite.

All patients diagnosed with African trypanosomiasis must have their cerebrospinal fluid examined to determine whether there is involvement of the central nervous system, since the choice of treatment drug(s) will depend on the disease stage. The World Health Organization criteria for central nervous system involvement include increased protein in cerebrospinal fluid and a white cell count of more than 5. Trypanosomes can often be observed in cerebrospinal fluid in persons with second stage infection.