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Glanders and Melioidosis
Introduction
Glanders is an infectious disease caused by Burkholderia mallei, a gram-negative aerobic nonmotile bacterium. Melioidosis is an infectious disease caused by Burkholderia pseudomallei, a gram-negative aerobic, motile bacterium. The two bacteria are closely related, and both can cause disease in animals and humans. Historically, glanders was a common disease of horses, donkeys, and mules. Melioidosis was first described as a case series of 38 patients in Rangoon, Burma, by pathologist Alfred Whitmore in 1912.[1][2]
Etiology
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Etiology
Glanders is rare in humans, but those in close contact with infected solipeds such as horses, mules, and donkeys may become infected. The bacteria enter through the eyes, nose, mouth, or wounds in the skin. Burkholderia mallei is an obligate mammalian pathogen and must cause the disease to be transmitted between hosts. Melioidosis may present in an acute form with an incubation period of one day to three weeks. However, latent melioidosis may not present for decades. Melioidosis often infects those with underlying risk factors such as diabetes, kidney disease, alcohol abuse, and thalassemia, although healthy patients may also contract the disease. Burkholderia pseudomallei live in soil and water, and patients almost always report exposure to mud or pools of water.
Epidemiology
Glanders has been eliminated from the United States but is still present in Africa, Asia, the Middle East, Central America, and South America. Melioidosis is endemic to southeast Asia and northern Australia but has also occurred in South America, Central America, Africa, and the Middle East. In 2016, a statistical model estimated that there would be 165,000 new cases of melioidosis worldwide and suggested that the disease is significantly underreported. Because it resides in soil and water, weather events such as flooding and typhoons have been implicated in outbreaks of melioidosis. No vaccine is available for either disease. Humans may contract glanders from contact with infected animals; animals without clinical symptoms can still be infectious to humans. Glanders can be transmitted by contact with mucous membranes, inhalation, and contact with breaks in the skin. Person-to-person transmission is rare for both glanders and melioidosis but can occur.[3][4][5][6][7][8][9][10]
Pathophysiology
Burkholderia mallei and Burkholderia pseudomallei can enter cells and spread from cell to cell by polymerizing actin; this can lead to the fusion of cells and the formation of multinucleated giant cells. Both are resistant to a large number of antibiotics because of their ability to pump them out of the cell, and both possess type VI secretion systems. Burkholderia mallei cause damage to and death of endothelial cells lining blood vessels, which increases the likelihood of thrombi formation. Numerous virulence factors of Burkholderia pseudomallei have been described.[11][12][13][14]
Toxicokinetics
Burkholderia pseudomallei can produce both endotoxins and exotoxins. In addition, Burkholderia lethal toxin 1 has been shown to act on eukaryotic initiation factor 4A (eIF4A), halting its helicase activity on double-stranded RNA and thus inhibiting translation.
History and Physical
The incubation period of glanders is usually 1 to 21 days but can be months or years. In humans, the first symptom of glanders is usually fever, followed by pneumonia, pustules, and abscesses. The acute form of the disease usually is fatal within 7 to 10 days of onset. Chronic glanders does occur, which can cause death within months; survivors remain carriers of disease. The incubation period of melioidosis also can be highly variable; it may range from as little as 2 days to as long as several years. Symptoms of acute melioidosis include fever, cough, pleurisy, arthralgia, myalgia, headache, anorexia, and night sweats. Melioidosis may present in many ways, ranging from acute or chronic localized infections to sepsis. Abscesses of the liver, spleen, prostate, and parotid glands have been documented. Intra-abdominal infections may be present without focal abdominal pain. These abscesses often appear loculated on CT scans and have been described as having a “honeycomb” appearance. Chronic melioidosis is defined as a duration of symptoms longer than 2 months and occurs in 10% of patients.[15][16][17][18][19][20][21]
Evaluation
Both glanders and melioidosis can be cultured in a lab. Burkholderia pseudomallei can be diagnosed by blood culture, sputum culture, urine culture, and a throat swab; however, blood cultures are rarely positive in cases of Burkholderia mallei. Cultures of these diseases must be performed under BSL-3 precautions. Indirect hemagglutination, latex agglutination, and direct immunofluorescence tests are available in some countries. Diagnosis of melioidosis cannot be made by imaging; however, CT or ultrasound of the abdomen is recommended to assess for abscesses of the liver, spleen, or prostate that may not be clinically apparent. Chest X-ray is also routinely performed and may show consolidations, cavitary lesions, effusions, empyemas, and multiple lung abscesses.[22][23][24]
Treatment / Management
Patients with significant pulmonary involvement may progress to respiratory failure, requiring mechanical ventilation. Sepsis and coagulopathy also may occur. Treatment of glanders with imipenem and doxycycline for 2 weeks, followed by azithromycin and doxycycline for six months, was successful in a laboratory worker that became infected with the disease. A CT scan after this therapy showed improvement of splenic and hepatic abscesses.
Glanders is fatal in 95% of cases without treatment, and death occurs within 7 to 10 days of onset. Mortality is 50% with appropriate antibiotic treatment. Mortality of the septicemic form of melioidosis exceeds 90%, but mortality may decrease to as low as 10% in uncomplicated cases managed with appropriate antibiotic therapy.
Surgical management of prostatic abscesses and septic arthritis caused by melioidosis is indicated; however, surgical intervention often is not indicated for hepatic and splenic abscesses. The treatment of choice for acute melioidosis is intravenous ceftazidime. Meropenem and imipenem also have been shown to be effective. In the acute phase of the disease, patients are treated with intravenous antibiotics for at least 2 weeks. Following the conclusion of intravenous antibiotic administration, patients are treated with doxycycline and trimethoprim/sulfamethoxazole for up to 20 weeks to eradicate the disease. Abscesses in most organ systems of patients with melioidosis often resolve after antibiotic therapy; however, prostatic abscesses usually require surgical debridement.[25][26][27][28][29] Treatment with meropenem and granulocyte colony-stimulating factor has been shown to significantly decrease mortality in critically ill patients with melioidosis in Australia. Recurrence of melioidosis may occur in up to 20% of patients; however, this can be reduced to as little as 4% with trimethoprim/sulfamethoxazole eradication therapy. Because of the risk of relapse, lifelong follow-up is recommended.[30][31][32][33] No vaccines are currently available for glanders or melioidosis. There are no approved antibiotic prophylaxis regimens for glanders or melioidosis, but one study demonstrated that mice receiving trimethoprim/sulfamethoxazole as pre-exposure prophylaxis or as post-exposure prophylaxis within 24 hours following exposure to Burkholderia pseudomallei had a 100% survival rate.[34][35][36][37][38](A1)
Differential Diagnosis
- Anthrax
- Bacterial pneumonia
- CBRNE-plague
- CBRNE-smallpox
- Malaria
- Mycoplasmal pneumonia
- Typhoid fever
- Viral pneumonia
Prognosis
The mortality rate in the cutaneous form of systemic and untreated glanders is 90% to 95% but 50% if properly treated.
Complications
- Septic shock
- Abscesses of the liver, spleen, and prostate
- Death
Pearls and Other Issues
Burkholderia mallei was used by the Germans in World War I to infect livestock being shipped to Allied countries. It has been alleged that the Soviet Union employed it as a biological weapon in Afghanistan between 1982 and 1984. Burkholderia pseudomallei was investigated as a possible biological warfare agent by both the United States and the Soviet Union, however, it has never been successfully weaponized.[39][40]
Enhancing Healthcare Team Outcomes
Glanders is an uncommon zoonotic disease that is transmitted to humans from solipeds such as horses, mules, and donkeys. It has been eradicated in many parts of the world. Transmission is uncommon even in the setting of frequent close contact with infected animals. However, occupational exposure is a key risk factor. Melioidosis is endemic in Southeast Asia, China, and northern Australia. There have also been cases in India as well as the Middle East, Africa, and Central and South America. It is found in soil and water, and it is known to cause disease in animals such as cats, goats, sheep, and horses. A history of contact with soil and surface water is almost always present in humans with melioidosis. Contaminated groundwater, flooding, and typhoons have been implicated in outbreaks of melioidosis. Epidemiological surveillance is vital to detect any outbreak or local emergence in humans or animals. Expert evidence indicates that glanders and melioidosis are best managed by an interprofessional team of health care workers that includes an epidemiologist, an infectious disease consultant, internists, a pharmacist, and a nurse. (Level V)
Since glanders and melioidosis can present with the involvement of almost any organ system, high suspicion should be maintained in those with identified risk factors. The medical laboratory is essential to help make the diagnosis of the disease. In the setting of a large outbreak in people without risk factors, a biological attack should be considered, and public health and law enforcement officials should be notified. Once the infection is treated, the pharmacist should ensure that the patient remains compliant with drug therapy. In addition, if there is any evidence of recurrence, the patient should be referred to an internist for evaluation; rates of recurrence of melioidosis may be as high as 20% but can be reduced with appropriate therapy. (Level V)
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