Leptospirosis and Anthrax

1J.N. Medical College, Belgaum

06/08/14

J.N. Medical College, Belgaum 2

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 disease1907- Stimson named the organism Spirochaeta

interrogans1915- etiologic agent by Inada and Ido1930- 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


Kerala, Gujarat, Andaman & Nicobar, KarnatakaKerala, Gujarat, Andaman & Nicobar, Karnataka200420041111

Tamil NaduTamil Nadu1984198411

Andaman & NicobarAndaman & Nicobar1988198822

Kerala, Gujarat, Tamil Nadu, A & NKerala, Gujarat, Tamil Nadu, A & N200320031010

Kerala, Maharashtra, Gujarat, Tamil NaduKerala, Maharashtra, Gujarat, Tamil Nadu2002200299

Maharashtra, Gujarat, Tamil Nadu, Kerala & GoaMaharashtra, Gujarat, Tamil Nadu, Kerala & Goa2001200188

Maharashtra, Gujarat, Tamil Nadu, KeralaMaharashtra, Gujarat, Tamil Nadu, Kerala2000200077

Gujarat, Tamil NaduGujarat, Tamil Nadu1999199966

Gujarat, A & NGujarat, A & N1997199755

GujaratGujarat1995199544

GujaratGujarat1994199433

StateStateYearYearS. No.S. No.



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, flexibleHelical rodsActively motile. aerobicHooked ends- umbrella handlesSeen best with dark field Microscopy6-20micrmeter long0.1micrometer thick


o Electron Microscopy

show thin axial filament

a delicate membraneo 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 heato Sensitive to acido Destroyed by chlorine, antisepticso 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 –rare33J.N. Medical College, Belgaum

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 featuresA. Subclinical infectionB. 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


http://www.cfsph.iastate.edu/DiseaseInfo/ImageDB/LEP/LEP_002.jpg

Liver: › Centrilobular necrosis and Kupffer cell

hyperplasia

› No hepatocellular necrosis


http://www.cfsph.iastate.edu/DiseaseInfo/ImageDB/LEP/LEP_001.jpg

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 changesMeningitis 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 organism1. Before tenth day of illness:Blood -i. Dark field examination of the patient’s bloodii. 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)


SerologyAggutination 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.


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


http://tos.beastlet.com/girl2.jpg

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 birds81J.N. Medical College, Belgaum

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”.82J.N. Medical College, Belgaum



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 minutesSurvive for years in soil

Favorable soil factors for spore viabilityHigh moistureOrganic content Alkaline pHHigh 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. Ingestion


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 lesionsPapule/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’Fadyeanstain).

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 shakePlace in plastic bag or leakproof containerIf visibly contaminated or container

unavailableGently cover – paper, clothing, box, trash canLeave room/area, isolate room from othersThoroughly wash hands with soap and waterReport 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 edition2. Goldman Cecil Medicine- 23rd ed.3. Park’s textbook of Preventive &Social Medicine 22nd

edition4. Text Book of Public Health and Community Medicine-

AFMC Pune5. Leptospirosis – An Overview TK Dutta, M Christopher.6. Ananthanarayan and Paniker’s Textbook Of

Microbiology- 18th edn7. 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


http://www.who.org.in/


Health & Medicine

Leptospirosis and Anthrax