Colin Farquharson - leptospirosis presentation

AN ACUTEAN ACUTE
ANGLEANGLE
Dr Colin A J Farquharson
MB FRCP FESC FRACP FACC FRSA
FCSANZ FSCCT
Consultant Cardiologist
Diana, Princess of Wales Hospital
Grimsby, UK

Patient - 69 year old male
• Usually fit and well
• Presented to A&E – referred to SHO Med 18.15hrs
• 5 day history of feeling generally unwell
• Attended A&E after complaining of fever / dyspnoea / rapid
onset jaundice / dizziness
• Unable to pass urine for one day
• PMH of BPH – only medication was Flomax
• Penicillin allergic
Colin Farquharson, Cardiologist, Grimsby UK

Other Relevant History
• No foreign travel
• No unusual foods / new POM or OTC drugs
• No recreational drugs
• Was an avid fisherman – angled at least weekly
• Last went fishing at pond near Binbrook 7 days
previously – felt unwell 2 days after then
• On that occasion, had forgotten waders – had
therefore fished in bare feet / rolled-up trousers

On Initial Examination
• Very jaundiced and clinically dehydrated, Temp 40.1ºC
• Alert and orientated – GCS 15/15
• HR 140bpm, BP 70/40mmHg (Shock Index 2.0)
• Normal Heart Sounds
• Bibasal pulmonary crackles, sp02 91% on 15litres / min
• Abdominal examination unremarkable
• No rash / purpura / meningism
• Full neuro exam – power 3/5 & absent reflexes lower limbs
• Had athlete’s foot left foot with some cracked interdigital
skin Colin Farquharson, Cardiologist, Grimsby UK

Initial Investigations
• Na 130, K 3.7, urea 44.2, creatinine 609
• ALT 250, Bilirubin 250, Amylase 345, Alb 23
• CK 327,320
• pH 7.4, PO2 9.2, HCO3 13.6
• Hb 14, WCC 11.4, Plts 24, PT/APTT normal
• ECG: Sinus tachycardia rate approx 140bpm
• CXR

ECG on admission

CXR

WHAT IS THE LIKELY
DIAGNOSIS ??
• LEPTOSPIROSIS causing WEIL’S DISEASE?
• PNEUMOCOCCAL SEPTIC SHOCK?
• ACUTE LEGIONELLA INFECTION?
• OTHER CAUSE OF SEPTIC SHOCK / MULTI-
SYSTEM FAILURE?

Initial Management
• IV Plasma-expanders – 1,500ml given in A&E
• IV Antibiotics – high dose Cefotaxime / Clarithromycin
• Blood / urine cultures
• IV platelets requested
• Urine for Legionella / Pneumococcal antigens
• Urinary catheter / CVP line insertion
• Repeat clotting / FBC / U&Es / Acid-base balance
• Transfer to HDU as prelude to ITU care (no ITU beds at
time but was likely to require haemofiltration urgently)
• Malaria screen

On arrival to HDU…
• Given more IV plasma expanders / platelets
• Repeat clotting showed PT / APTT deranged
- given IV FFP prior to IV CVP line insertion
• Given NIV as unable to oxygenate properly despite
high-flow oxygen via rebreather mask
• Approx 1 hour after giving IV antibiotics
- Rapidly mentally obtunded / headache / tachypnoeic
- BP became unrecordable and HR rapidly elevated
- Very warm to touch – inappropriately vasodilated
- Profuse haemoptysis – became torrential +++
- CVP line inserted rapidly …Colin Farquharson, Cardiologist,
Grimsby UK

..HDU continued…
• Whilst being urgently tranfused, developed respiratory
followed by cardio-respiratory arrest (Primary rhythm PEA)
- CPR commenced
- IV Adrenaline / Volplex / O neg blood given
- ET tube inserted – profuse bleeding up tube with real
difficulty in squeezing Ambu-bag to ventilate patient
- Spontaneous circulation restored but no respiratory effort
- Transferred to ITU
- Given heroic doses of IV inotropes / vasopressors but
unable to get BP above 40/20mmHg …

.. Ending in ITU
• Bedside echocardiogram showed globally virtually
akinetic heart despite high-dose inotropic and
vasopressor support
• Developed agonal bradycardic rhythm followed by
asystole which was not resuscitated
• Pronounced dead 4 hours after original admission
Rest In Peace

So what did the patient die of?
• My primary diagnosis still remained Leptospirosis
causing Weil’s disease with multi-organ failure
• Cause of acute decline may have been related to a
Jarish-Herxheimer reaction induced by antibiotic
therapy
• Public Health was notified of the possible diagnosis
• Referred to Coroner’s Office for mandatory PM

Post-mortem Findings
• Patchy petechial haemorrhaging throughout
myocardium
• Pulmonary oedema with haemorrhage
• Congested “wet” spleen
• Enlarged pallid liver with patchy inflammation
and haemorrhage
• Patchy acute interstitial nephritis
• Congested meninges

Blood Culture Findings
• Leptospirosis species grown in
blood culture at reference lab at
Hereford , UK
(Leptospira icterohaemorrhagiae
species)

Cause Of Death
• LEPTOSPIROSIS (WEIL’S DISEASE)
CAUSING MULTI-ORGAN FAILURE
• POSSIBLY COMPLICATED BY
JARISCH-HERXHEIMER REACTION
TO ANTIBIOTICS

Leptospirosis
• Spirochetal disease, finely coiled, motile,
0.1 microns x 6 – 20 microns
• Systemic infection manifested as
widespread vasculitis
• Zoonosis – more common in tropics
• Over 200 pathogenic serovars known
• Animals often mildly affected but spread
disease via urine

Genetic relationships of the pathogenic leptospires
defined mainly by DNA-DNA hybridization
(adapted from Ramadass et. al.1992)
L. interrogansL. interrogans
australisaustralis
bataviaebataviae
bratislavabratislava
pomonapomona canicolacanicola
copenhagenicopenhageni hardjohardjo
L. kirschneriL. kirschneri
cynoptericynopteri
gripotyphosagripotyphosa
L. noguchiiL. noguchii
fort bragfort brag
L. borgpeterseniiL. borgpetersenii
hardjobovis balcanicahardjobovis balcanica
ballumballum javanicajavanica
L.santarosaiL.santarosai
shermanishermani
L weiliiL weilii
celledonicelledoni

Occurrence
• Worldwide occurrence, including in the UK
• Primarily a disease of tropical and subtropical regions
• Uncommon in temperate climates
• Leptospires are naturally aquatic organisms - found in
fresh water, damp soil, vegetation, and mud. Flooding after
heavy rainfall may spread the organism because, as water
saturates the soil, leptospires pass directly into surface
waters.
• Leptospirosis is uncommon in the UK - usually less than 40
cases per year in England and Wales
i.e. less than one case per million population per year

Laboratory confirmed reports of
leptospirosis in the UK 1998 - 2006
1998 1999 2000 2001 2002 2003 2004 2005 2006
Scotland 1 1 0 0 3 0 2 4 3
England &
Wales
29 41 54 48 54 28 29 41 44
N. Ireland 4 1 0 0 1 0 1 1 3
(Source: Leptospirosis Reference Laboratory, Hereford)

Reservoirs of Infection
• Almost all mammals can carry disease
• Rats / River voles common vectors
• Dogs (can spread to humans by face
licking)
• Livestock
• Other Rodents including rabbits
• Wild animals
• Cats (rare)

Animal Vectors
• Commonest sources of infection in the UK are rats and cattle
• Humans are considered to be a dead-end (accidental) host of
leptospires
• Infected animals carry bacteria in their kidneys. They excrete
leptospires in their urine for some time, and spread infection to
other animals or humans coming into direct or indirect
contact with the urine
• Often the infected animal does not become ill
• In general, herbivores or omnivores seem more likely to
becomeand remain infected
• Urine of pure carnivores tends to be acidic (low pH) – the acidity
may damage the leptospires in the kidney, clearing infection

Sources of Human Infections
• Contaminated water or soil from infected
urine
• Direct animal contacts
• Occupational exposure : farmers, vets and
abattoir workers
• Recreational exposure: campers,
fishermenswimmers, visiting graveyards

Routes of Infection
• Infection acquired by direct or indirect contact with
infected animal urine, tissues or secretions, or water
contaminated with infected animal urine
• Leptospires enter the body through cut or damaged
skin, but may also pass across damaged or intact
mucous membranes and eyes
• Person-to-person spread is very rare, if it occurs at all
• Leptospirosis can also be acquired abroad e.g. in
travellers on adventure holidays with water contact,
such as rafting or fishing.

Microbiology and distribution
• Except for tropical areas, leptospirosis cases have a
relatively distinct seasonality with most of them occurring
August through October (in the Northern Hemisphere).
• At least 5 different serovars of importance cause disease
(icterohaemorrhagiae, canicola, pomona, grippotyphosa,
and bratislava)
• There are other (less common) infectious strains. It
should however be noted that genetically different
leptospira organisms may be identical serologically &
vice versa Colin Farquharson, Cardiologist, Grimsby UK

Pathogenesis
• Entry sites : skin wounds or abrasions in hand
and feet and mucous membranes, conjunctivae,
nasal, oral
• Bacteraemia involving the entire body including
eye & CSF
• Systemic effects and vasculitis due to endotoxin
(a hyaluronidase) and burrowing motility
• Hemorrhagic necrosis esp. in liver, lung, and
kidneys  jaundice, ARF, haemorrhage

Phase I (Septicaemic)
• Following incubation period of 2-10 days
• High spiking fever, headache, myalgia, & joint
phenomena e.g. arthralgia
• Usually lasting 4 – 7 days
• Proteinuria and increased creatinine
• Organism detectable but serological diagnosis
not possible

Phase II (Immune)
• Much more variable
• Induction of IgM antibodies
• Sometimes 1-3 day freedom from symptoms,
then recurrence again
• Usually lower fever, but with CNS signs
• May be cultured from urine but not from the
blood or CSF at this stage

Weil’s Disease
• Much less common but more severe form
• Non-specific prodromal illness initially
• Usually followed by severe Jaundice,
Azotaemiaand Haemorrhage from Lungs / GI
tract / other organs (3-6 days)
• Rapid-onset oliguric renal failure and hepatic
dysfunction then dominate the clinical picture
• Mortality 10-40% even with treatment

Clinical Signs of Leptospirosis
• Pulmonary infiltrates, pneumonitis, haemorrhage
• Conjunctival injection
• Jaundice
• Muscle tenderness
• Abdominal tenderness
• Neurological irritation
• Abnormal chest auscultation
• Erythema nodosum, petechiae, neck stiffness, and
generalised lymphadenopathy

Colin Farquharson, Cardiologist, Grimsby
UK

Laboratory Diagnosis
• Microbiological identification :
• Blood or CSF  first 10 days
• Urine  second week thereafter
• Can also culture from fresh kidney biopsy
• Diagnosis of leptospirosis is confirmed with tests such as
detection of IgM via ELISA & PCR
• MAT (microscopic agglutination test) is considered gold
standard in diagnosis (gives serogroup differentiation)
• Other tests :
• Elevations of Urea and creatinine
• Elevations of AST / ALT / GGT levels

Chest X-ray appearances
• 33 – 64 % of patients show CXR abnormalities
• Bilateral nodules, rosette densities
• Diffuse ill-defined infiltrates
• Can cause massive confluent consolidation
• Bilateral, non-lobar, peripheral predominance
• Rarely causes intense pleural reaction
• Complete resolution can occur within 5-10 days
Colin Farquharson, Cardiologist, Grimsby
UK

Treatment
• Early anti-microbial therapy is important, since they can shorten
the course and prevent carrier state
• Choice: Benzylpenicillin, Ampicillin (high-dose)
• Mild cases or contacts can be given oral Doxycycline or
Amoxicillin
• If penicillin allergic, 3G cephalosporins recommended
• May rarely cause the Jarish-Herxheimer reaction, but at present
the current advice is to continue with antibiotics even if this
occurs (this is however controversial!)
• Severe cases will require supportive therapy e.g. vaso-pressor
support / dialysis / ventilation
• Corticosteroids recommended by some if severe haemorrhagic
effects e.g. Prednisolone 60mg / day for 7-10 days

Differential Diagnosis
• Very large due to diverse symptomatology
• For forms with middle to high severity, the list includes
dengue fever and other haemorrhagic fevers
hepatitis of various aetiologies
viral meningitis
malaria and typhoid fever.
• Light forms should be distinguished from influenza & other related
viral diseases
• Factors like certain dwelling areas, contact with stagnant water
(swimming, working on flooded meadows, etc) and/or rodents in the
medical history support the leptospirosis hypothesis and serve as
indications for specific tests and therapy

Prevention of Leptospirosis
• Vaccination of domestic animals
• No human vaccine available (in the UK) that is effective against
leptospirosis
• For people who may be at high risk for short periods (e.g. through
their occupation) taking e.g. doxycycline (200mg weekly) may be
effective
• Rodent control
• Protective gloves and boots
• Avoid swimming / wading in potentially contaminated waters
• Wash or shower promptly after water sports, especially if fallen in
inadvertently

Jarisch-Herxheimer Reaction
• Reaction occurs when large quantities of endotoxin are released
from the intracellular matrix into the body as bacteria (typically
Spirochetes) die, usually due to antibiotic treatment.
• Typically, the death of these bacteria and the associated release
of endotoxins occurs faster than the body can remove the
toxins via the natural detoxification process performed by the
kidneys and liver.
• The reaction is manifested by:
worsening fever, chills, headache & meningism, myalgia
profound hypotension (related to inappropriate vasodilatation)
exacerbation of cutaneous lesions.
• Duration in syphilis is normally only a few hours but can be
much longer in other diseases. The intensity of the reaction
reflects the intensity of inflammation / bacterial load present.

• Shows an sharp increase in inflammatory
cytokines during the period of exacerbation,
including:
TNF-alpha, Interleukin-6 and Interleukin-8
• Both Adolf Jarisch (an Austrian dermatologist)
and Karl Herxheimer (a German dermatologist)
are jointly credited with the discovery of the
reaction.

• Both Jarish & Herxheimer independently observed
reactions in patients with syphilis treated with
mercury
• The reaction was first seen following treatment in
early and later stages of syphilis treated with
Salvarsan, mercury, or antibiotics.
• Seen in 50% of patients with primary syphilis and
about 90% of patients with secondary syphilis.

• The reaction is also seen in other diseases, such as:
Borreliosis (Lyme disease & tick-borne relapsing
fever)Leptospirosis
Brucellosis
Typhoid fever
Trichinellosis
Q fever
• At least 3 patients documented in literature as dying as
a consequence of Jarisch-Herxheimer reaction in
leptospirosis

Colin Farquharson - leptospirosis presentation

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