Colin Farquharson - leptospirosis presentation

AN ACUTE AN ACUTE ANGLE ANGLE

Dr Colin A J Farquharson MB FRCP FESC FRACP FACC FRSAFCSANZ FSCCTConsultant CardiologistDiana, Princess of Wales HospitalGrimsby, 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


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 …


..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 realdifficulty 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 admissionRest 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 urineColin Farquharson, Cardiologist, Grimsby UK

Genetic relationships of the pathogenic leptospires defined mainly by DNA-DNA hybridization

(adapted from Ramadass et. al.1992)

L. interrogansL. interrogansaustralisaustralis

bataviaebataviae

bratislavabratislava

pomonapomona canicolacanicola

copenhagenicopenhageni hardjohardjo

L. kirschneriL. kirschneri cynoptericynopteri

gripotyphosagripotyphosa

L. noguchiiL. noguchiifort bragfort brag

L. borgpeterseniiL. borgpeterseniihardjobovis balcanicahardjobovis balcanica

ballumballum javanica javanica

L.santarosaiL.santarosaishermanishermani

L weiliiL weiliicelledonicelledoni


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 Walesi.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)Colin Farquharson, Cardiologist, Grimsby UK

http://www.hpa.nhs.uk/cfi/other_ref_labs/lru.htm

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 graveyardsColin Farquharson, Cardiologist, Grimsby UK

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


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 stageColin Farquharson, Cardiologist, Grimsby UK

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



http://microbewiki.kenyon.edu/index.php/Image:Humanlepto.jpg

http://microbewiki.kenyon.edu/index.php/Image:Leptospirosisanimalkidney.jpg

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


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 fevershepatitis of various aetiologiesviral meningitismalaria 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.


Jarisch-Herxheimer Reaction• 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 thereaction.


Jarisch-Herxheimer 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.


Jarisch-Herxheimer Reaction• The reaction is also seen in other diseases, such as:

Borreliosis (Lyme disease & tick-borne relapsing fever)LeptospirosisBrucellosisTyphoid feverTrichinellosis Q fever

• At least 3 patients documented in literature as dying as a consequence of Jarisch-Herxheimer reaction in leptospirosis


Health & Medicine

Colin Farquharson - leptospirosis presentation