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66 Cards in this Set

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Describe leptospira
fine spiral bacteria of 0.2um in diameter by 6-20um length

Caused by spirochetes of the genus, Leptospira

Spirochete, free-living
Features of both gram + and gram – bacteria
Total genome size: 4.8 Mb
No plasmids

Spiral, motile, obligate aerobes
6-20 um x 0.1-0.2 um
Who gets leptospirosis?
Acute zooanthroponosis caused by pathogenic spirochetes of the genus Leptospira
Primarily a disease of mammals, but humans are infected occasionally through direct or indirect contact with animals

A zoonotic disease with highly varied manifestations
Most mammals are susceptible to infection
clinical manifestations of leptospirosis
Clinical manifestations go from none to a severe, even lethal disease characterized by vasculitis, with pulmonary, hepatic, renal, and hemorrhagic manifestations
How is leptospira transfered
Infected mammals shed leptospires into urine for prolonged periods of time
A disease of the environment
How is it lepto grown in the lab?
Grown in specialized culture medium- EMJH, Fletcher’s, Korthoff
How do you see leptospira?
Visualized by darkfield or phase contrast microscopy
Name the etiological agents of lepto
2 species
L. interrogans and L. biflexa
Spiral, motile, obligate aerobes
6-20 m x 0.1-0.2 m
> 210 serovars 23 serogroups
Complex taxonomy
Serovars not related to virulence
Leptospira interrogans - describe it's microbiology
Flexible
Finelly coiled
Gram -
6-12 m long
0.1 m wide

Motile
Aerobic

LPS
describe leptospira
Thin, coiled, gram (-), aerobic, 6-20m long

Motile with hooked ends and paired axial flagella
Taxonomy of Leptosiraceae
Order: Spirochaetales
Genus: Leptospira
Classic taxonomy
Basic taxon is serovar
Single non-pathogenic species: L. biflexa
Single pathogenic species: L. interrogans
More than 25- pathogenic serovars within one species
Typical reservoir hosts of common leptospiral serovars
Pigs -Pomona and Tarassovi
Cattle -Hardjo and Pomona
Horses -Bratislava
Dogs -Canicola
Sheep- Hardjo
Racoon- Grippotyphosa
Rats - Icterohaemorrhagiae and Copenhageni - Largest Reservoir!!
Mice - Ballum, Arborea and Bim
Marsupials - Grippotyphosa
Bats - Cynopteri and Wolffi
Risk Factors for Leptospirosis
Occupational:
Farmers
Abattoir workers
Trappers
Veterinarians
Sewer Workers
Rice field workers
Military personnel

Recreational:
Freshwater swimming
Canoeing, kayaking

Household:
Pets (dogs, rodents, hedgehogs …)
Domesticated livestock
Rainwater catchment
Urban environment
Domiciliary rodent infestation
1) Entry - possible injestion

2) Spread - Rapid after entering
lymphatics and blood
stream

3) Disease - Tissue tropism
not demonstraded

Invasion facilitated by
flagella and release of
hyaluronidase
Clinical presentations
Asymptomatic 5-15 %
Anicteric 90-95 %
Weil syndrome - 5-10%
Incubation period
Incubation 2-30 days
What is Weil Syndrome?
The disease was first described by Adolf Weil in 1886 when he reported an "acute infectious disease with enlargement of spleen, jaundice and nephritis".
Anicteric leptospirosis (Fort Bragg fever)
Fort Bragg fever
Anicteric leptospirosis, which is more common in children, and characterized by an abrupt 'toxic' state, with fever, shaking chills, headache, N&V and severe myalgias–especially of the legs, lethargy, dehydration, photophobia, orbital pain, generalized lymphadenopathy, and hepatosplenomegaly
Icteric leptospirosis (Weil's syndrome)
Weil’s syndrome was characterized by intense jaundice, acute renal failure, skin ecchymoses and conjunctival suffusion, in addition to meningitis
Aseptic meningitis
fever, HA, sore throat, malaise, nausea, vomiting, stiff neck, nucal rigidity, acute confusion, paresis, transient paralysis
Epidemiology
Worldwide Tropics
Occupational disease
-Garbage collectors -Butchers
-Farm workers -Children
-Domestic employees -Animal handlers
Recreational risk in young male adults
Rainy season, flooding, sewage
What is this?
stages of lepto
Pathogenesis
Penetration through skin and mucosas; possibly by ingestion

Studies in mice suggest that capillary leak and hemorrhage result from LPS mediated disruption of vessel wall via intercallation of glycoprotein toxin
Pathogenesis - first week
First week
Leptospira in blood and CSF
Blood vessels, liver, kidney, muscles and lungs are affected early
Pathogenesis
Penetration through skin and mucosas; possibly by ingestion

Studies in mice suggest that capillary leak and hemorrhage result from LPS mediated disruption of vessel wall via intercallation of glycoprotein toxin
Pathogenesis - from second week on
From second week
Antibody raise, immunological damage
LPS and TNF-
Pathogenesis - first week
First week
Leptospira in blood and CSF
Blood vessels, liver, kidney, muscles and lungs are affected early
What is the Septicemic phase?
Septicemic phase

One to several days
Fever, conjunctival
suffusion, myalgias,
bradycardia, (+ cultures)
hypotension, dehydration
Recovery 5d - 6w
Pathogenesis - from second week on
From second week
Antibody raise, immunological damage
LPS and TNF-
Immune phase
Fever recurrence, rigors,
headaches, prostration,
myositis (high CK), rash,
mono or polyarthritis,
organ manifestations
Convalescence 6-12 w

Jaundice and bilirubinemia out of proportion with hepatocellular damage is the usual finding in leptospirosis
Significant jaundice + aminotransferases no more than 3-4 X normal + alkaline phosphatase as high as 10 X normal; the mechanism of the cholestasis in leptospirosis is not clear

Second fever
Severe paraspinal and calf tenderness
Acalculous cholecystitis
Guaiac positive stools
Irritability and depression well into convelescent phase

In severe or prolonged disease, renal damage will occur and the sediment is usually active.  
Non-oliguric hypokalemic renal failure as found in this case is characteristic. 
Progression to oliguric renal failure is predictive of higher mortality
What is the Septicemic phase?
Septicemic phase

One to several days
Fever, conjunctival
suffusion, myalgias,
bradycardia, (+ cultures)
hypotension, dehydration
Recovery 5d - 6w
Weil Syndrome - from slides
Temp 40°C

Warm and flushed skin
Jaundice
Muscle tenderness

Acute tubular necrosis and hypovolemia resulted in renal failure

High CPK from skeletal muscle involvement
Immune phase
Fever recurrence, rigors,
headaches, prostration,
myositis (high CK), rash,
mono or polyarthritis,
organ manifestations
Convalescence 6-12 w

Jaundice and bilirubinemia out of proportion with hepatocellular damage is the usual finding in leptospirosis
Significant jaundice + aminotransferases no more than 3-4 X normal + alkaline phosphatase as high as 10 X normal; the mechanism of the cholestasis in leptospirosis is not clear

Second fever
Severe paraspinal and calf tenderness
Acalculous cholecystitis
Guaiac positive stools
Irritability and depression well into convelescent phase

In severe or prolonged disease, renal damage will occur and the sediment is usually active.  
Non-oliguric hypokalemic renal failure as found in this case is characteristic. 
Progression to oliguric renal failure is predictive of higher mortality
Neurologic manifestations
Headache, meningismus, meningitis
Mononuclear pleocytosis, protein elevation, normal glucose in CSF
Occasional encephalitis
Rarely
Transverse myelitis, Guillain-Barré, cranial nerve
paralysis
Weil Syndrome - from slides
Temp 40°C

Warm and flushed skin
Jaundice
Muscle tenderness

Acute tubular necrosis and hypovolemia resulted in renal failure

High CPK from skeletal muscle involvement
Icteric leptospirosis
Fever, jaundice and purpura
Neurologic manifestations
Headache, meningismus, meningitis
Mononuclear pleocytosis, protein elevation, normal glucose in CSF
Occasional encephalitis
Rarely
Transverse myelitis, Guillain-Barré, cranial nerve
paralysis
Icteric leptospirosis
Fever, jaundice and purpura
what is this?
Conjunctival suffusion and hemorrhages, no conjunctivitis
Lumbar puncture aseptic meningitis
Lymphocytic pleocytosis, counts </= 500, mild protein elevation, normal glucose
Coagulation alterations
Thrombocytopenia
Abnormal bleeding and coagulation times
Low factor V
Increased fibrin split products

DIC
Pulmonary disease
Dry cough
Shortness of breath
Hemoptisis
Chest pain

Radiological infiltrates

Severe vascular injury can cause pulmonary hemorrhage
Renal manifestations
Acute renal failure
Creatinine 2-8 mg/dl
Not always related to disease severity
Abnormal urinalysis 80-90%
Leucocytes, hyaline, granular or hematic casts,
hemoglobinuria
Anuria is rare and poor prognostic sign
Renal leptospirosis
Interstitial nephritis

Acute tubular necrosis*

Impaired capillary permeability
Hypovolemia

Renal failure

Urine is a reliable body fluid to
study because leptospires are present from start to finish of Sxs.
What is the cause of most leptospirosis associated deaths?
Renal failure has been the cause of most leptospirosis associated deaths
but hemodialysis and peritoneal dialysis have reduced mortality
GI manifestations
Nonspecific
Nausea,vomiting, abdominal pain*, diarrhea,
anorexia. Pancreatitis is rare
Direct hyperbilirrubinemia
Increased aminotransferases
Elevated alkaline phosphatase
Hypoalbuminemia
Ocular manifestations
Ocular
-Subconjunctival hemorrhage*
-Conjunctivitis, anterior uveitis
General Manifiestations
General
-Pharyngitis
-Parotitis
-Adenomegaly
-Splenomegaly
-Arthritis
-Myocarditis
-Exanthema
-Urticaria
Diagnosis
Dark field direct examination

Cultures*, isolation is gold standard.
Fletcher, Stuart, PLM-5 media (serum + 5FU)

Animal inoculation

Serology*

PCR

Blood, serum, urine, CSF, aqueous humor
What is unique about patients with severe disease?
Patients with severe disease usually have >10,000 organisms per ml of blood or tissue
Isolation of Leptospira in culture is __and __
Isolation of Leptospira in culture is difficult and insensitive
Culture in special media in tubes held at __ for prolonged periods is necessary
Culture in special media in tubes held at 28-30°C for prolonged periods is necessary
__is only positive in the __of illness after which __becomes progressively more positive
Blood is only positive in the first week of illness after which urine becomes progressively more positive
__ are only visible and confirmed using__
Cultured leptospires are only visible and confirmed using dark-field microscopy
Diagnosis is most often __and __, __, or a commercially available __
Diagnosis is most often serological and retrospective [MAT], IgM ELISA, or a commercially available rapid dipstick test
__ diagnosis is effective, quantitative, and rapid compared to other techniques but remains a research tool
PCR-based diagnosis is effective, quantitative, and rapid compared to other techniques but remains a research tool
Differential diagnosis
Malaria*
Hepatitis*
Dengue* and yellow fever
Salmonella and brucella infections
Hemorrhagic fevers
Infectious mononucleosis
Cholecystitis, cholangitis

* top 3
Laboratory Diagnosis
Culture
Microagglutination test
Enzyme-linked immunosorbent assay (ELISA)
Molecular
Culture - what is needed
Culture
Specimen transport, inoculation
Specialized medium, 28-30 ºC incubation
Microscopic examination of cultures
What is the Microagglutination test looking for?
Microagglutination test
Lipopolysaccharide (LPS)
What is the Enzyme-linked immunosorbent assay (ELISA) test looking for?
Enzyme-linked immunosorbent assay (ELISA)
IgM, IgG
What does molecular testing do?
Molecular
PCR
Real time PCR, quantification of leptospiremia
Molecular typing methods for specific identification
Treatment
Specific
Penicillin* or Ampicillin* or Ceftriaxone
Doxicycline*

Non-specific

Mild to moderate forms
Hydration and symptom relief

Severe forms
Life support in intensive care units
Prognosis
Good in anicteric forms
In icteric forms, mortality, usually from acute renal failure or irreversible myocardial failure is 15-40 %
Full recovery is expected within 6-12 weeks
Traveller's Prophylaxis recs
Some travelers should be advised to take doxycycline 200mg. twice per week, we tend to treat individuals
Summary
Outbreak due to leptospirosis
High attack rate
10% had febrile jaundice
Inconclusive zoonotic source
IgM ELISA (Antigen=L. biflexa serovar Patoc) insensitive in this setting
Prevention
Personal protection measures
Individuals exposed to single events with high risk of infection or visitors of endemic areas can be given prophylactic doses of doxycicline
Environmental sanitation
Control of reservoirs
Animal vaccination