Leptospirosis and Anthrax

J.N. Medical College, Belgaum 1
06/08/14

Mr A is a 38 year old sheep farmer who
presented with a 3 day history of generalised
muscle aches, anorexia, mild diarrhoea and
vomiting. Mr A had a fever of 38 degrees and a
normal physical examination.

The initial diagnosis was a viral illness with
gastroenteritis and he was advised to take
paracetamol, rest and return if the symptoms
changed or worsened

The patient returned within 2 days with a
backache and worsening of his generalised
muscle pain. He also had hyperaemic
conjunctiva and headaches that were the worst
he had ever experienced. Further examination
did not demonstrate any further clinical signs
and he did not have any neck stiffness.

 Due to rapid ecological changes, many
zoonosis have emerged as epidemics
 Leptospirosis is a zoonosis spread throughout
the world
 Surveillance data suggests - most common
zoonosis in the world

 The disease is often overlooked and under
reported
 It is an emerging zoonotic disease of major
public health problem
 It often peaks seasonally sometimes in
outbreaks

Leptospira -from the Greek leptos, meaning
fine or thin, and the Latin spira, meaning coil
1886- Adolf Weil described the disease
1907- Stimson named the organism Spirochaeta
interrogans
1915- etiologic agent by Inada and Ido
1930- it was identified as a separate disease
entity

 It is most widespread disease in the world
 Incidence of the disease is significantly higher
in tropical countries as compared to temperate
regions
 Outbreaks mostly occur – heavy rainfalls and
consequent flooding

 The number of human cases worldwide is not
known precisely know
 The WHO estimates- incidence ranges from
approx 0.1 - 1 per 1,00,000 per year in
temperate climates
 10 - 100 per 1,00,000 in the humid tropics.

Epidemics of Leptospirosis - Andaman and
Nicobar islands, southern and western parts of
India
For the past 10 years Mumbai - seasonal
increase
 A post – cyclone outbreak was reported in
Orissa, India in 1999.

 Outbreaks of leptospirosis have increasingly
been reported from Kerala, Gujarat, Tamil Nadu
and Karnataka
 Sporadic cases have been reported from Goa,
Andhra Pradesh and Assam

SS.. NNoo.. YYeeaarr SSttaattee
11 11998844 TTaammiill NNaadduu
22 11998888 AAnnddaammaann && NNiiccoobbaarr
33 11999944 GGuujjaarraatt
44 11999955 GGuujjaarraatt
55 11999977 GGuujjaarraatt,, AA && NN
66 11999999 GGuujjaarraatt,, TTaammiill NNaadduu
77 22000000 MMaahhaarraasshhttrraa,, GGuujjaarraatt,, TTaammiill NNaadduu,, KKeerraallaa
88 22000011 MMaahhaarraasshhttrraa,, GGuujjaarraatt,, TTaammiill NNaadduu,, KKeerraallaa && GGooaa
99 22000022 KKeerraallaa,, MMaahhaarraasshhttrraa,, GGuujjaarraatt,, TTaammiill NNaadduu
1100 22000033 KKeerraallaa,, GGuujjaarraatt,, TTaammiill NNaadduu,, AA && NN
1111 22000044 Kerala, Gujarat, Andaman & NNiiccoobbaarr,, KKaarrnnaattaakkaa

 7th Day disease
 Weil’s disease
 Ictero-hemorrhagic fever
 Swineherd's disease
 Rice-field fever
 Pea picker’s disease
 Cane-cutter fever

 Swamp fever
 Mud fever
 Hemorrhagic jaundice
 Stuttgart disease
 Infectious jaundice
 Canicola fever

1) Agent
 Order: Spirochetales
 Family: Leptospirideae
 Genus: Leptospira
 Species: L. interrogans (pathogenic) and L.
biflexa (saprophytic)
 Serovars: > 250
 Serogroups: 23; L. icterohemorrhagica,
gryppotyphosa, caniciola, pomona, andmanii, etc

 MORPHOLOGY:
Delicate, flexible
Helical rods
Actively motile. aerobic
Hooked ends- umbrella
handles
Seen best with dark field
Microscopy
6-20micrmeter long
0.1micrometer thick

o Electron Microscopy
show thin axial filament
a delicate membrane
o In dark field it
chain of miniature cocci.

 Culture:
o Leptospira grows best under aerobic conditions
at 280 to 300c best demonstrated in Semisolid
agar media
o Optimal Media
Stuart’s and Fletcher’s Media
EMJH (semisynthetic media)
Optimal growth after 1 – 2 weeks

 Resistance :
o Susceptible to heat
o Sensitive to acid
o Destroyed by chlorine, antiseptics
o Hence their survival depends on-
Temperature, acidity, salinity
Die rapidly in non aerated sewage, acid urine,
saltish and brackish water

o Source of infection:
Urine of infected animals
Rodents excrete in urine for lifelong.
o Animal reservoirs:
Wild and domestic animals
Rodents – Rats, mice and voles
Domestic animals – cows, buffalo, sheep,
goats, pigs, horses.
Pet animals – dogs

Host :
 Animals- Rodents, insectivores, dogs, cattle,
pigs, horses, etc
 Humans – accidental infection
contact with infected urine
 Even some birds
• Micro-abrasions, intact skin and mucosa
• Infected animal tissues and blood

 Age: children > adults
 Sex: males > females
 Immunity : serovar specific immunity
 Occupation:

1 Farmers
2 Sewage workers
3 Veterinarians
4 Fishermen and water bailiffs
5 Abattoir workers
Recreational hazard- water sports, tourists

 Leptospira – survive for weeks in soil and water
 Poor housing, limited water supply, inadequate
waste disposal are risk factor both rural and
urban population.

Mode of transmission:
1) Direct contact
2) Indirect contact
3) Droplet infection

 Incubation period : usually 10days
2-20days
 Entry: through cuts and abrasions in skin &
mucous membranes of the eyes, nose and
mouth
Inhalation- rare
Ingestion- rare
Human-to-human transmission –rare

 Leptospiremic/ Septicaemic phase
› Systemic vasculitis
› Migration of organisms into tissues-inflammation
and multi-organ dysfunction
from direct cyto-toxicity
 Immune phase/ Leptospiruric Phase
› Second fever and organ involvement
through immunological mechanisms-
 Persistence of organisms
› Renal tubules, aqueous humor

Wide range of severity and clinical features
A. Subclinical infection
B. Self limited systemic illness 90 %
C. Severe potentially fatal illness consisting of
 Renal failure 15 %
 Liver failure 15%
 Pneumonitis >30 to 40% mortality
 Hemorrhagic diathesis

 Leptospiremic/ Septicaemic phase
 Immune phase/ Leptospiruric Phase

 High fever and chills
 Severe headache, eyeball pain, photophobia
 Mental confusion
 Muscle pain & tenderness (calves and back)
 Redness in the eyes & conjunctival injection
 Sore throat
 Rash- maculopapular

 Abdominal pain
 Vomiting and diarrhea
 Jaundice, hepatosplenomegaly
 Lymphadenopathy -rare
 Hemorrhages in skin and mucous
membranes
 Cough, chest pain & hemoptysis

 Early myalgia.
 Hepatitis with fever.
 Renal impairment.
 Lymphocytic meningitis.
 Conjunctivitis.
 Rash, sometimes haemorrhagic.
 Thrombocytopenia.
 Blood, protein and/or bilirubin in the urine.
 Rare, nodular pneumonitis.

 Severe Leptospirosis (Weil's
Syndrome)
Weil's syndrome-,characterized by jaundice,
renal dysfunction, and hemorrhagic diathesis
By pulmonary involvement in many cases
mortality rates of 5–15
This syndrome is frequently but not exclusively
associated with infection due to serovar L.
icterohaemorrhagiae/copenhageni.

Renal Failure:
› Migrate to interstitium, renal tubules and tubular
lumen – interstitial nephritis and tubular necrosis
› Hypovolemia

Liver:
› Centrilobular necrosis and Kupffer cell
hyperplasia
› No hepatocellular necrosis

Pulmonary: Hemorrhage
and not much inflammation
- hemoptysis, patchy lung
- infiltrates and ARDS
Muscles: Direct cytotoxicity
CNS: Organisms in the CSF X 2 weeks with
mild CSF changes
Meningitis in immune phase

 Rhabdomyolysis
 Hemolysis
 Myocarditis
 Pericarditis
 CHF
 Necrotising Pancreatitis
 MOF

 Faine had evolved a criteria (WHO Guidelines)
for diagnosis of Leptospirosis
 On basis of clinical (A),
epidemiological (B)
laboratory data (C) (A+B+C)

 Diagnosis of Leptospirosis
(Part A) or (Part A& Part B Score) : 26 or more
Part A, B & C (Total) : 25 or more

 Isolation of organism
1. Before tenth day of illness:
Blood -
i. Dark field examination of the patient’s blood
ii. Culture on a semisolid medium (eg. Fletcher’s
EMJH)

2. After tenth day of illness:
Urine -
i. Dark field examination of the patient’s urine
ii. Culture of urine (for several months in untreated
patient)

 Serology
Aggutination tests : Paired sera (fourfold or
greater rise in titer)
i. Microscopic, using live organisms (MAT)
ii. Macroscopic, using killed antigen

o ELISA IgM and Slide agglutination tests (SAT) :
- Measure IgM antibodies
- Single sample adequate
- The ELISA IgM test helpful for early diagnosis
(positive 2 days into illness)
o Dot-ELISA and dip-stick methods:
- Newer screening methods (for detecting IgM
antibodies)

 Detection of specific DNA
PCR test
Leptospiral DNA: - Detected in blood, urine, CSF,
and aqueous humor

In September 2002, my mother was admitted in
a Hyderabad nursing home with what was
thought to be viral hepatitis. The doctor said she
was doing fine. But she died after 12 days. She
was only 47 years old. I was 17.
Ten days later, I developed the same symptoms
that my mother had.

The doctor in Tirupati we consulted insisted that
it was viral hepatitis. When I didn’t get better, a
trainee nurse suggested a blood test for
Leptospirosis, which was confirmed at Tirupati
and Chennai labs
Alekhya Mandadi,
Tirupati, Andhra Pradesh

 Influenza
 Meningitis (encephalitis)
 Viral hepatitis
 Rickettsiosis
 Malaria
 Typhoid fever
 Septicemia
 Toxoplasmosis
 Legionnaire’s disease

 General and Supportive Care
› Antipyretics
› Antimicrobial
› Rest
› Hydration
› Ventilator support
› Liver support
› Renal support
› Transfusion support

 Antimicrobials
 Penicillin- 6 million units daily intravenously is
the drug of choice in severe leptospirosis
Effective if started within first four days of illness.
Jarisch-Herxheimer reactions may occur
Total duration of therapy should be 10-14 days

 Amoxycillin and erythromycin
 Doxycycline in a dosage of 100 mg twice daily
for 7 days
Effective in treatment of mild and moderate
leptospirosis

 Anicteric leptospirosis usually has a good
prognosis.
 Without jaundice the disease is almost never
fatal
 Fatal pulmonary haemorrhage and myocarditis
have been reported occasionally in anicteric
cases
 case fatality rate for Weil’s disease is 15-40%
 higher for patients over 60 years of age

 Prevention and control should be targeted at:
a) Source of infection
b) Route of transmission
c) Infection/ Disease in humans

a) Source of infection
 Prevent contamination of living, working and
recreational areas by urine of infected animals.
 Control rodent populations in areas of human
habitation.
 Contact with wildlife ( e.g., do not feed pets
outside or allow animals to roam unsupervised)

 Do not allow animals to urinate in or near ponds
or pools.
 Keep animals away from gardens, playgrounds,
sandboxes, and other places children may play.
 Among domesticated animals, vaccination of
swine, cattle, and dogs.

b) Interruption of transmission
 Avoid swimming- contaminated water
 Protective clothing, footwear
 Adopt a reasonable standard of hygiene
 Public health engineering
 Waste management

c) Human protection
 Chemoprophylaxis
Effective prophylaxis consists of doxycycline,200
mg orally once weekly, during the risk of
exposure
 Vaccination
 IEC activities

 Government of India – pilot project
 For control of Leptospirosis
(Gujarat, TN- 2008 trial ; Karnataka , Maharashtra
2011)
 NCDC is the nodal agency
 Main Objective-
Reduce morbidity and mortality related to
leptospirosis

 Leptospirosis Burden Epidemiology
Reference Group (LERG)
Goals:
 To provide estimates on the global burden of
Leptospirosis according to age, sex and region.
 To increase awareness of and commitment to
the disease in developing countries.
 To encourage developing countries to
undertake active disease surveillance and
strengthen control measures. J.N. Medical College, Belgaum 71

 In the ICD10 disease classification
system, leptospirosis is code A27
 The International Leptospirosis
Society (ILS) was formed in 1994 to promote
knowledge on leptospirosis through the
organisation of regional and global leptospirosis
meetings

 Leptospirosis should be a notifiable disease
 Need to increase awareness
 Better diagnosis and surveillance programmes

A 40 y/o police officer presents with fever and
muscle aches. He is pale, has a temperature of
102°F. His physical exam and labs are
unremarkable so he is discharged and given flu
instructions. He says his partner is also ill.

Later, a 35 y/o female clerk also presents
complaining of myalgias, shaking chills, and
vomiting. She is pale, and has a temperature of
102.4°F. Her physical exam is non-focal, she
improves with antipyretics and the patient is
sent home with viral syndrome instructions.

The next day several more patients present with
fever, chills and myalgias

The 40 yr policeman returns 3 days later
because he is feeling much worse and is short
of breath.
This is the chest x-ray that was obtained

A mother brings in her adolescent son for a
strange black scab/rash that started out as
a small papule but formed a black painless
eschar over the past 5 days

 The word “Anthrax” originates from Greek for
black or coal
 The black eschar which is characteristic of the
cutaneous form of Anthrax infection.
 It is principally a disease of herbivores
But has the potential to infect all mammals
and even some birds

 Bacillus anthracis , zoonotic disease
 Anthrax may be the prototypic disease of
bioterrorism
 Humans almost invariably contract anthrax
directly or indirectly from animals
 “Malignant pustule” and “Wool sorter’s disease”.

Bacillus anthracis
› Aerobic, Gram positive rod
› Long (1-10μm), thin (0.5-2.5μm)
› Forms inert spores when exposed to O2
 Infectious form, hardy
 Approx 1μm in size
› Vegetative bacillus
Non-infectious, fragile

 Environmental Survival
Spores
Resistant to drying, boiling <10 minutes
Survive for years in soil
Favorable soil factors for spore viability
High moisture
Organic content
Alkaline pH
High calcium concentration

 Anthrax is a seasonal disease
 The occurrence of anthrax among animals in
any one place is related to temperature and
rains.
 However, the conditions which predispose to
outbreaks differ widely

› Primarily disease of herbivorous animals
 Sheep, goats, cattle
 Many large documented epizootics
 Carnivores are not immune
› Human disease
 Epidemics have occurred but uncommon
 Rare in developed world

 Many countries have weaponized anthrax
› Former bioweapon programs
 U.S.S.R.,U.S.,U.K., and Japan
› Recent bioweapon programs
 Iraq
› Attempted uses as bioterrorism agent
 WW I: Germans inoculated Allied livestock
 WW II: Alleged Japanese use on prisoners

 In September 2001, the American public was
exposed to anthrax spores as a bio-weapon
delivered through the U.S. Postal System
 CDC identified 22 confirmed cases

 Features of anthrax suitable as BT agent
› Fairly easy to obtain, produce and store
› Spores easily dispersed as aerosol
› Moderately infectious
› High mortality for inhalational (86-100%)

Three forms of natural disease
› Inhalational
 Rare (<5%)
 Most likely encountered in bioterrorism
event
› Cutaneous
 Most common (95%)
 Direct contact of spores on skin
› Gastrointestinal
 Rare (<5%), never reported in U.S.
 IngestionJ.N. Medical College, Belgaum 94

Mortality
› Inhalational 86-100% (despite treatment)
 Era of crude intensive supportive care
› Cutaneous <5% (treated) – 20% (untreated)
› GI approaches 100%

Incubation Period
› Time from exposure to symptoms
› Very variable for inhalational
 2-43 days reported
 Theoretically may be up to 100 days
 Delayed germination of spores

 Transmission
› No human-to-human (very rare)
› Naturally occurring cases
 Skin exposure
 Ingestion
 Airborne
› Bioterrorism
 Aerosol (likely)
 Small volume powder (possible)
 Foodborne (unlikely)

 Anthrax has at least three proteins which play a
role in virulence
A-B model of toxicity
Edema factor (EF), Lethal factor (LF) and
Protective antigen (PA)
EF and LF need PA to get into the cell to cause
damage

 Progression of painless lesions
Papule/macule – pruritic
Vesicle/bulla – clear or serosanguinous
Ulcer – non-pitting, gelatinous edema
Eschar – black, depressed, scars

 Initially starts with a non-specific flu-like illness
and then progresses to:
› Respiratory Distress
› Shock
› May see a widened mediastinum on x-ray

 Nausea, anorexia, vomiting, fever
 Progresses to severe abdominal pain and
bloody emesis and diarrhea
 Ascites may develop on day 2 - 4
 Death 2 to 5 days after onset of symptoms
 Very difficult to diagnose

 Microscopy
 Blood culture
 Serology- Specific Enzyme - Linked
Immunosorbent Assays (ELISAs)

Stained with polychrome
methylene blue (M’Fadyean
stain).
On blood agar, the colony is
non-haemolytic

PLET agar. These are typically ‘”bee’s-eye”

Anthrax Meningitis :
 Haematogenous spread of the pathogen
Meningitis - to 100% mortality.

Inhalational, GI, Sepsis
 Ciprofloxacin, 400 mg IV q12h or
 Doxycycline, 100 mg IV q12 plus
 Clindamycin, 900 mg IV q8h and/or rifampin,
300 mg IV q12h; switch to PO when stable x60
d total

Cutaneous Anthrax
 without systemic signs, extensive edema or
lesions located on head and neck.
 Initial recommended treatment:
Doxycycline 100mg BD or Ciprofloxacin
500mg BD PO for 60 days
(Amox 500 mg PO q8h, likely to be effective if
strain penicillin sensitive)

Cutaneous Anthrax
 with systemic signs,
extensive edema or lesions
on the head and neck.
 Initial recommended treatment:
› Doxycycline or Ciprofloxacin IV
› May switch to PO when clinically appropriate

 Control of the disease in animals
 Correct disposal of carcasses of anthrax cases
 Proper disinfection, decontamination and
disposal of contaminated materials

 Vaccine
› Anthrax Vaccine Adsorpbed (AVA)
› Supply- controlled by CDC
 Newer vaccines including a plasmid DNA
vaccine and vaccines for intranasal use are
under development

Chemoprophylaxis:
 Ciprofloxacin or Doxycycline for four weeks for
unimmunized individuals.
 longer duration - for complete clearance of
spores from the lungs

 Suspicious letters/packages – “Do not X-ray”,
“Fragile”, “Confidential”
Do not open or shake
Place in plastic bag or leakproof container
If visibly contaminated or container
unavailable
Gently cover – paper, clothing, box, trash can
Leave room/area, isolate room from others
Thoroughly wash hands with soap and water
Report to local security / law enforcement

 NCDC under the Ministry Of Health –
Proposed to set up Surveillance system for
micro-organisms with bio-terrorism potential

Single inhalational case is an emergency
› Contact Local Health Departments

1. Harrison’s Principles of Internal Medicine- 18th edition
2. Goldman Cecil Medicine- 23rd ed.
3. Park’s textbook of Preventive &Social Medicine 22nd
edition
4. Text Book of Public Health and Community Medicine-
AFMC Pune
5. Leptospirosis – An Overview TK Dutta, M Christopher.
6. Ananthanarayan and Paniker’s Textbook Of
Microbiology- 18th edn
7. National Health Programs Of India -J. Kishore’s 11th
edn

8) Infection Microbiology and Management Barbara
Bannister
9) Guidelines for the Surveillance and Control of Anthrax in
Human and Animals. 3rd edition
10) Leptospirosis in India and the Rest of the World
Rao R. Sambasiva, Gupta Naveen.
11) www.who.org.in
12) www.google.in

Leptospirosis and Anthrax

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