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INFECTIOUS DISEASES &

IMMUNOPATHOGENESIS

RESEARCH GROUP

Dr Robert Norton

Director of Microbiology and Pathology

Townsville, Queensland

Australia

MELIOIDOSIS IN

NORTHERN AUSTRALIA

– AN ENVIRONMENTAL

DISEASE

No (financial or other) conflicts to disclose

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So why do you need to know about

Melioidosis ?

Increased travel to and from endemic regions

Was once this……

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Is now this……

Climate change

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From this

Because of this

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To this

And then there’s this

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We may use it as a biological weapon

History of Melioidosis

“There is prevalent in Rangoon a

particular septicaemic or pyaemic

disease caused by an infestation with a

bacillus whose characteristics are so

distinct from other known pathogenic

bacteria that it can be readily isolated

and certainly identified”

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Worldwide distribution of Melioidosis

• Taxonomical changes:

Bacillus mallei, Bacillus whitmori,

Pfeifferella pseudomallei;

Malleomyces pseudomallei;

Pseudomonas pseudomallei;

Burkholderia pseudomallei

Burkholderia pseudomallei • Gram negative, oxidase positive, aerobic non-fermenter

• A widely distributed environmental organism

• Isolated more commonly from soil in NE Thailand & Australia

• A Category B bioterrorism agent (CDC)

• Clear relationship between the water content of soil and organism

numbers.

• Possible interaction between B. pseudomallei and specific plant roots

,amoebae and soil type.

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Route of Acquisition & Risk Factors

Definitive evidence Inoculation

Aspiration of fresh water

Circumstantial evidence Inhalation

Ingestion of contaminated water

Person to person

Zoonotic spread

15-25 cases per year in our region

Age (30 - 65 years)

Sex - M>F

Indigenous ethnicity

Outdoor occupation

Diabetes mellitus, renal disease

Immune suppression

Alcohol intake

Malczewski A et al. Trans R Soc Med 2005;99:856-860

Year 2000 Annual rainfall 2400mm

23 cases; 7 fatalities

0

1200

Month

Rain

fall

(m

m)

0

15

Nu

mb

er

of

Cases

Rainfall No. of Cases

Incidence Correlates With Rainfall

Malczewski A et al. Trans R Soc Med 2005;99:856-860

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DIAGNOSIS

Clinical suspicion

Culture of blood, pus, sputum

Serology is of limited value as it is

often negative early in the

disease

Sub-acute or Chronic Presentation Visceral abscesses

Pancreas, Liver, Spleen, Prostate

Osteomyelitis or pyogenic arthritis

Soft tissue abscesses

Muscle

Sub-cutaneous

Skin-ulcers

Pneumonia

Septicaemia

Meningo-encephalitis

Acute Presentation

Antibody positive

Reactivation if immunocompromised

Latent Infection

Spectrum of Diverse Clinical Presentations

Townsville data (1996 – 2013)

Organ No.patients (n %) Mortality (n %)

Lung 103 (45%) 25 (24%)

Genitourinary 23 (10%) 1 (4%)

Skin and soft tissue 19 (8%) 0

Bone and joint 14 (6%) 0

Neurological 13 (5.6%) 5 (38%)

No source 19 (8%) 3 (16%)

Other/Mixed source

38 (16.6%) 9 (24%)

Total 229 43 (18.7%)

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Outcomes

• If untreated or inadequately treated: >70% mortality

• With optimal treatment including availability of ICU – 15-20%

• Mortality related to co-morbidities and organ involvement. (CNS infection –

40%)

Case 1 – Melioidosis and Pneumonia

AK

35 year old solicitor.

No risk factors

House was affected by flooding in recent rains.

Three week history of cough, breathlessness, fever and weight loss.

Sputum grew B.pseudomallei.

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Case 1 - Progress

• Commenced on Ceftazidime and cotrimoxazole.

Serology

Date from admission IHA EIA IgG / IgM

Day 0 1:40 Neg/Neg

Day 22 1:640 Neg/Pos

Day 52 1:2560 Pos/Pos

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Case 1 - Progress

• Completed 4 weeks Ceftazidime

• Kept on maintenance cotrimoxazole for a further 3 months.

• Full recovery.

Case 2 – Neurological disease

• A 12 year old non-indigenous female

– Admitted to a regional hospital. Fever, headache, cough, vomiting,

photophobia, Ophthalmoplegia (bilateral).

– LP, CSF (protein 520, WCC 190, Gram stain - No organisms seen).

– Dropped GCS (<8/15) with respiratory arrest.

– Intubated uneventfully and transferred to ICU.

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Case 2

• Social History

• Used to live in PNG (malaria 4 yrs ago).

• Was helping her father with irrigation pipes in the rain before

onset of symptoms.

• Progress

• CT head Normal

• Started on meropenem, ceftriaxone, ciprofloxacin ,

cotrimoxazole and acyclovir.

Chest X ray on admission to ICU

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T2 weighted MRI

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Diagnosis: CNS and pulmonary melioidosis.

Protracted clinical course including severe neurological deficit and

prolonged ICU stay.

Discharged home following rehabilitation and on maintenance

cotrimoxazole.

Case 2

• Clinical suspicion

• Early microbiological diagnosis

• Imaging to determine the extent of disease

• Drainage of abscesses as necessary

• Combination therapy with Ceftazidime or Meropenem with

Cotrimoxazole or Doxycycline

• Prolonged suppressive therapy with Cotrimoxazole or

Doxycycline

Management

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Oxidase pos, Gram negative bacillus

Gentamicin and colistin resistant

Amoxycillin/clavulanate sensitive

PCR on blood is insensitive

Laboratory Diagnosis (Presumptive)

The place of serology

• Indirect haemaglutination assay

– Of limited value in diagnosis

– 50% of culture positive specimens are IHA negative at the time of presentation.

– A reasonable marker of active disease if strongly positive.

• Enzymeimmunoassay (EIA) IgG

– More sensitive than the IHA

– Of limited use in an endemic area where background seropositivity can be 7%

– Does not distinguish between previous disease or exposure and current disease

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Host factors

Genotype

Genetic predisposition – ?TLR, TNF receptors

Antibody to B. pseudomallei

Appears post infection and does not seem to prevent relapse

Cell Mediated Immunity to B. pseudomallei

Highly significant

Bacterial factors

Virulence Determinants

Lipopolysaccharide (endotoxin)

Exotoxins - cytolethal toxin, haemolysin

Iron - fur (ferric uptake regulator)

Type III secretion system proteins

Factors Influencing Disease Outcome

Melioidosis and Cystic fibrosis

• Uncommon

• Related to residence in or travel to an endemic area

• Human to human transmission is speculative at this point

• Tends to colonise rather than cause severe sepsis.

• Nevertheless does need to be treated.

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B.pseudomallei and the environment

• A clear relationship between disease and intensity of rainfall . Particularly with

cyclonic conditions.

• Contact in certain areas within the endemic region are more likely to result in

infection than others,

• Contact with surface water seems more important than contact with soil.

• The presence of risk factors is an important part of risk assessment.

– Diabetes

– Alcohol consumption

– Indigenous ethnicity

B.pseudomallei and the environment

Isolates are genetically diverse and only occasionally is there

a clear proven link between an environmental isolate and a clinical one.

M.Corkeron et al, Epidemiol Infect 2010, 22:1-7.

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Current Research

• Diagnostics

– Antigen detection using a lateral flow immunoassay

– Improving serological diagnosis with improved antigens

• Environmental

– Determining the ecological niche and interaction with soil types

• The role of diabetes in the pathogenesis of this disease

– Cellular and cytokine responses in diabetics vs non-diabetics

B.pseudomallei as an agent of bioterrorism

• Is currently a recognised agent of bioterrorism

– Can survive in the environment for lengthy periods

– Can be difficult to identify in laboratories unfamiliar with it

– Difficult to treat with simple antibiotics

– Will use up resources

– Has a high mortality if not treated adequately particularly among diabetics

– Can be weaponised

– No vaccine

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Conclusions

• Burkholderia pseudomallei is an important cause of community acquired

pneumonia in endemic regions of Australia.

• With increased travel, patients may and have presented to hospitals in

southern areas where the diagnosis may not be apparent,

• Laboratory diagnosis is primarily by culture.

• There is a clear relationship between the intensity of rainfall in an endemic

area and disease.

• Treatment is with meropenem or ceftazidime followed by maintenance

cotrimoxazole or doxycycline.