Melioidosis and Glanders

Melioidosis (also referred to as Whitmore's disease) and glanders are related zoonotic diseases, caused by Gram negative rods, Burkholderia pseudomallei and Burkholderia mallei respectively.

Melioidosis is a tropical and sub-tropical disease, endemic in areas lying between latitudes 20° north and south. Sporadic cases are seen outside these areas, usually among immigrants and travellers. Both humans and susceptible animals can be infected.

Glanders is primarily a disease of equine species that can, on occasion, be transmitted to humans. Glanders is rare in most of the world, but sporadic cases occur in parts of Africa, the Middle East, South and South East Asia, and Turkey.

Renewed interest in these diseases has been sparked by concerns about bioterrorism. It seems likely that, in the past, both organisms have been developed for biological warfare. Glanders may have been used by the Japanese in China in the 1940s.
Features that make these organisms suitable for deliberate release include:¹

• Organisms are easily available and reasonably easy to cultivate.
• Ability to cause severe, rapidly fatal invasive infections.
• Ability to initiate infections via aerosols, inoculation and, possibly, ingestion.
• Intrinsic resistance to many antibiotics.
• Ability to infect a wide range of animals as well as humans.
• Long term persistence in the environment under suitable conditions (B. pseudomallei).
• No currently available vaccination.

At the present time, the Health Protection Agency (HPA) thinks it unlikely that either organism is available in a weaponised form.² Nevertheless, they have produced guidelines for such a release.¹

Glanders

• Glanders is typically transmitted to humans from infected horses, donkeys or mules via direct contact with broken skin or mucous membranes. Transmission through intact skin has been reported but is not well documented. Transmission can also occur by inhalation of droplets from an infected animal or patient.
• Unsurprisingly, those most at risk are those in close and frequent contact with infected animals e.g. vets, abattoir workers and laboratory staff.
• The high incidence of infection amongst those working with B.mallei in the past implies that it may be more infectious than B. pseudomallei although the infectious dose is unclear.

Melioidosis

• The bacteria of melioidosis are environmental organisms, found in water, soil, or plants. They may also be transmitted from infected animals.
• Spread is via direct contact with a contaminated source, especially during the rainy season. Ingestion of contaminated material or dust/aerosol inhalation may also occur. Transmission between humans is rare but has been documented.
• Middle-aged and older individuals or those with comorbidities such as diabetes and renal failure are most at risk.
• The infectious dose of B. pseudomallei for humans is not known, but probably varies with host resistance. Most infections in previously healthy individuals have followed gross contamination (e.g. near-drowning, contaminated war wounds, inoculation with contaminated medications, lab accidents) but other cases are thought to have occurred following relatively minor exposure (e.g. inhalation of aerosols by helicopter crew).
• The incubation period in naturally acquired infections is hugely variable, between days to years. Following the use of aerosol-based biological weapons, it would be anticipated to be 10-14 days.
  

  Think of melioidosis in unwell travellers returning from Southeast Asia, especially Thailand, and Northern Australia.4

• It has also been observed in the South Pacific, Africa, India, the Middle East, and Central and South America.⁵
• Environmental disasters such as the 2004 Asian tsunami have unmasked locations of sporadic cases and improved access to diagnostic laboratory facilities has helped to define endemic regions.⁶
• Cases identified in temperate climates are almost invariably imported from the tropics: in the UK, 22 travel-associated cases were diagnosed in the decade 1997-2006, with exposures in Thailand, Viet Nam, India, and Bangladesh.²

The clinical syndromes produced by glanders and melioidosis are similar. Signs and symptoms are predominantly non-specific.⁷ Experience of glanders in humans is more limited than that of melioidosis.

Clinical forms

• In the localised form, bacteria enter the skin through a laceration or abrasion and an ulcer develops. There may be regional lymphadenopathy. Bacteria that enter the host through mucous membranes can cause increased mucus production in the affected areas.
• A pulmonary form occurs when bacteria in aerosol form enter the respiratory tract by inhalation or by haematogenous spread. Pneumonia, pulmonary abscesses and effusions can occur. Abscesses can disseminate to skin but they may take months to appear.
• Bacteraemia and septicaemia can occur if immunity is reduced by diseases such as diabetes or HIV infection. The patient develops respiratory distress, headaches, fever, diarrhoea, pus-filled lesions on the skin and abscesses throughout the body. Septicaemia may be overwhelming, with a 90% fatality rate and death occurring within 24-48 hours.
• The chronic form involves multiple abscesses which may affect the liver, spleen, skin, or muscles. Mycotic aneurysm, pericarditis, osteomyelitis epididymo-orchitis and prostatitis may all develop as a consequence of infection. Melioidosis can also become resurgent many years after the primary infection.

Symptoms

• Symptoms include:
  • Fever
  • Rigors
  • Night sweats
  • Myalgia
  • Anorexia
  • Headache
• Depending upon the route of infection there may also be:
  • Chest pain
  • Cough
  • Photophobia
  • Lacrimation
  • Diarrhoea

Signs

• Examination may show:
  • Fever
  • Cervical lymphadenopathy
  • Papular or pustular skin lesions
  • Hepatomegaly or splenomegaly
• Septicaemia is associated with flushing, cyanosis, and a disseminated pustular eruption. Pustules are often associated with regional lymphadenitis, cellulitis, or lymphangitis.
• Rarely lesions such as ecthyma gangrenosum and skin abscesses that sometimes ulcerate may appear.

The differential diagnosis will depend on the clinical presentation and context.

• Anthrax
• Plague
• Other causes of pneumonia

Recognition of cutaneous manifestations may be very important, especially in identifying biological attack.⁸

The diagnosis is inevitably a challenge:

• FBC shows a mild leukocytosis.
• Isolation of bacterium by culture from a clinical specimen (blood, urine, sputum, skin biopsy and throat swabs) is the gold standard of diagnosis. However, blood cultures may be negative even in septicaemic patients.
• Agglutination tests may be positive after 7 to 10 days but interpretation is difficult in endemic areas.
• Complement fixation tests that show a 4-fold increase in the titre for melioidosis are considered positive.
• PCR and other techniques such as gene sequencing are being developed to enable rapid differentiation and typing: given the potential use of these organisms in bioterrorism, rapid and unequivocal detection and identification is critical.⁹
• CXR may demonstrate bilateral bronchopneumonia, miliary nodules, segmental or lobar infiltrates, and cavitating lesions.
• Ultrasound and CT scanning may show multiple, small abscesses in the liver and the spleen.

Non-drug

• For healthcare workers involved in the management of hospitalised patients, standard Universal Precautions (i.e. gloves, gowns, masks and hand washing) is thought to provide sufficient protection against transmission.¹
• Supportive intensive care may be required in the severely ill.
• Note that long follow-up (5 years+) is required following recovery and patients should be warned that there may be a lifelong risk of relapse and to seek help, alerting health care staff to their history, if they develop a severe febrile illness.

Drugs

• Long courses of antibiotics are required, possibly with more than one agent. There is a very limited evidence-base about the best form of treatment and duration, particularly for glanders. The suggested regimen depends upon the type of condition:¹
  • For severely ill patients with melioidosis, intravenous ceftazidime, meropenem or imipenem with cilastatin are suggested as initial treatment .
  • Parenteral therapy should continue for at least 2 weeks, followed by oral therapy for a total of 6 months. Oral 'eradication' therapy consists of doxycycline with co-trimoxazole, or co-amoxiclav.
  • For localised disease or milder infections, the oral regimens alone may be used for 12-20 weeks.
  • Suppurative disease outside the lungs requires prolonged treatment for 6 to 12 months.
  • Cases of glanders can be treated with the same regimens used for melioidosis or a combination of gentamicin and co-trimoxazole.
• For those exposed to heavy contamination, prophylaxis over 7 days with co-trimoxazole or doxycycline may be attempted but its efficacy is unproven.

Surgical

Surgical drainage of pus is beneficial.

Possible complications include septicaemia, osteomyelitis, meningitis and abscesses in brain, liver or spleen.

• Untreated, the death rate for melioidosis with septicaemia approaches 100%. With optimal treatment, it can be reduced to 20-40% and 5% for localised disease.¹⁰
• Human glanders has been too rare to make an accurate estimate of mortality rate, but it is likely to be similar to that of melioidosis.
• Awareness is essential to allow early diagnosis and to reduce morbidity and mortality.¹¹

• No vaccine is available for human glanders or melioidosis currently, although research is being directed towards this goal for both health and biosecurity purpose.¹²
• Where melioidosis is endemic, preventative measures include:¹³
  • Prompt cleaning of scrapes, burns, or other open wounds.
  • Individuals with diabetes and skin lesions should avoid contact with soil and standing-water.
  • Protective clothing such as rubber boots and gloves should be used for agricultural work.
  • Maintenance of a safe water supply for both humans and farmed animals.
  • Pasteurisation of dairy products.
• Pathology specimens and corpses should be treated with due care. Undertakers and pathologists must be informed and post mortem examinations kept to a minimum.