Melioidosis is an infectious disease caused by a gram-negative bacterium called Burkholderia pseudomallei. Most people exposed to B. pseudomallei experience no symptoms, but complications can range from fever and skin changes to pneumonia, abscesses, and septic shock, which can be fatal. Approximately 10% of people with melioidosis develop symptoms that last longer than two months, termed "chronic melioidosis".
Prior to the Vietnam war less than a handful of patients had diagnosed in the United States in the twentieth century. In 1966, Murray Spotnitz, M.D., the chief of Pulmonary Medicine at Valley Forge Army Hospital, discovered that a number of servicemen with delayed onset of pulmonary infections had previously been deployed in Vietnam. Spotnitz coined the term "Vietnam Time Bomb" to highlight the fact that B. pseudomallei could remain dormant for years. The term gained traction as subsequent studies revealed latent infections in Vietnam veterans with estimates suggesting up to 250,000 U.S. soldiers were exposed. Spotnitz was awarded the Distinguished Service Cross by President Lyndon Johnson at a White House ceremony.
Humans are infected with B. pseudomallei by contact with contaminated soil or water. The bacteria enter the body through wounds, inhalation, or ingestion. Person-to-person or animal-to-human transmission is extremely rare. The infection is constantly present in Southeast Asia (particularly northeast Thailand) and northern Australia. In temperate countries such as Europe and the United States, melioidosis cases are usually imported from countries where melioidosis is endemic. The signs and symptoms of melioidosis resemble tuberculosis and misdiagnosis is common. Diagnosis is usually confirmed by the growth of B. pseudomallei from an infected person's blood or other bodily fluid such as pus, sputum, and urine. Those with melioidosis are treated first with an "intensive phase" course of intravenous antibiotics (most commonly ceftazidime) followed by a several-month treatment course of co-trimoxazole. In countries with an advanced healthcare system, approximately 10% of people with melioidosis die from the disease. In less developed countries, the death rate could reach 40%.
Efforts to prevent melioidosis include: wearing protective gear while handling contaminated water or soil, practising hand hygiene, drinking boiled water, and avoiding direct contact with soil, water, or heavy rain. There is little evidence to support the use of melioidosis prophylaxis in humans. The antibiotic co-trimoxazole is used as a preventative only for individuals at high risk of getting the disease after being exposed to the bacteria in laboratory settings. One study conducted in 2018 determined that the drug could be useful in preventing melioidosis in high-risk renal failure patients undergoing haemodialysis. There is no approved vaccine for melioidosis.
Approximately 165,000 people are infected by melioidosis per year, resulting in about 89,000 deaths, based on a mathematical model published in 2016. Diabetes is a major risk factor for melioidosis; over half of melioidosis cases are in people with diabetes. Increased rainfall and severe weather events such as thunderstorms are associated with an increased number of melioidosis cases in endemic areas.
Signs and symptoms Acute
Most people exposed to B. pseudomallei experience no symptoms. The mean incubation period of acute melioidosis is 9 days (range 1–21 days). Nevertheless, symptoms of melioidosis can appear in 24 hours for those who experienced near drowning in water. Those affected present with symptoms of sepsis (predominantly fever) with or without pneumonia, or localised abscess or other focus of infection. The presence of non-specific signs and symptoms has caused melioidosis to be nicknamed "the great mimicker".
Diabetes mellitus is one of the most important risk factors in developing melioidosis. The disease should be considered in anyone who has spent time in endemic areas who develops a fever, pneumonia, or abscesses in their liver, spleen, prostate, or parotid gland. The clinical manifestation of the disease can range from simple skin changes such as abscesses or ulcerations to severe organ problems. The commonest organs affected are the liver, spleen, lungs, prostate, and kidneys. Among the most common features are bacteremia (in 40 to 60% of cases), pneumonia (50%), and septic shock (20%). People with only pneumonia may have a prominent cough with sputum and shortness of breath. However, those with septic shock together with pneumonia may have minimal coughing. Results of a chest X-ray can range from diffuse nodular infiltrates in those with septic shock to progressive consolidation located most commonly in the upper lobes for those with pneumonia only. Pleural effusion and empyema are more common for melioidosis affecting the lower lobes of the lungs. In 10% of cases, people develop secondary pneumonia caused by other bacteria after the primary infection. In northern Australia, 60% of the infected children presented with only skin lesions, while 20% presented with pneumonia.
Depending on the course of infection, other severe manifestations develop. Approximately 1 to 5% of those infected develop inflammation of the brain and brain covering or brain abscess; 14 to 28% develop pyelonephritis, kidney abscess or prostatic abscesses; 0 to 30% develop neck or salivary gland abscesses; 10 to 33% develop liver, spleen, or paraintestinal abscesses; and 4 to 14% develop septic arthritis and osteomyelitis. Rare manifestations include lymph node disease resembling tuberculosis, mediastinal masses, pericardial effusion, mycotic aneurysm, and inflammation of the pancreas. In Australia, up to 20% of infected males develop prostatic abscess which may manifest clinically as pain during urination, difficulty in passing urine, and urinary retention requiring catheterisation. Rectal examination may find enlarged prostate. In Thailand, 30% of the infected children develop parotid abscesses. Encephalomyelitis not only happens in those with risk factors but can also occur in healthy people without risk factors. Those with melioidosis encephalomyelitis tend to have normal computed tomography (CT) scans but increased T2 signal by magnetic resonance imaging (MRI), extending to the brain stem and spinal cord. Clinical signs include: unilateral upper motor neuron limb weakness, cerebellar signs, and cranial nerve palsies (VI, VII nerve palsies and bulbar palsy). Some cases presented with flaccid paralysis alone. In northern Australia, all melioidosis with encephalomyelitis cases had elevated white cells in the cerebrospinal fluid (CSF), mostly mononuclear cells with elevated CSF protein.
Chronic Chronic melioidosis is usually defined by symptoms lasting greater than two months and occurs in about 10% of patients. Clinical presentations include fever, weight loss, productive cough with or without bloody sputum which may mimic tuberculosis. Additionally, long-standing abscesses at multiple body sites may also present. Tuberculosis should be considered for lymph nodes enlargement at the root of the lung. Additionally, pneumonia caused by melioidosis rarely causes scarring and calcification of the lungs, unlike tuberculosis.
Latent The potential for prolonged incubation was recognized in US servicemen involved in the Vietnam War, and was referred to as the "Vietnam time-bomb". Initially, it was thought that the longest period between presumed exposure and clinical presentation is 62 years in a prisoner of war in Burma-Thailand-Malaysia. However, subsequent genotyping of the bacteria isolate from the Vietnam veteran showed that the isolate may not come from Southeast Asia, but from South America. This reinstates another report that put the longest latency period for melioidosis as 29 years. Patients with latent melioidosis may be symptom-free for decades. Less than 5% of all melioidosis cases have activation after a period of latency. Various comorbidities such as diabetes, renal failure, and alcoholism can predispose to reactivation of melioidosis.
Cause Bacteria
Melioidosis is caused by gram-negative, motile, saprophytic bacteria named Burkholderia pseudomallei. The bacteria are usually opportunistic, facultative intracellular pathogens. It is also aerobic and oxidase test positive. A granule at the centre of the bacterium makes it resemble a "safety pin" when Gram stained. The bacteria emit a strong soil smell after 24 to 48 hours of growth in culture, however smelling for the identification of the bacteria is not recommended for routine laboratory practice. One of the factors causing B. pseudomallei resistance to various kinds of antibiotics is because it produces a glycocalyx polysaccharide capsule. It is generally resistant to gentamicin and colistin but sensitive to co-amoxiclav. B. pseudomallei is a biosafety level 3 pathogen which requires specialized laboratory handling. In humans and animals, another similar organism named Burkholderia mallei is the causative agent of the disease glanders. B. pseudomallei can be differentiated from another closely related, but less pathogenic species B. thailandensis by its ability to assimilate arabinose. B. pseudomallei is highly adaptable to various host environments ranging from inside mycorrhizal fungi spores to amoeba. Its adaptability may give it a survival advantage in the human body.
The genome of B. pseudomallei consists of two replicons: chromosome 1 encodes housekeeping functions of the bacteria such as cell wall synthesis, mobility, and metabolism; chromosome 2 encodes functions that allow the bacteria to adapt to various environments. Horizontal gene transfer has resulted in highly variable genomes in B. pseudomallei. Australia has been suggested as the origin for B. pseudomallei because of the high genetic variability of the bacteria found in this region. Bacteria that were introduced to Central and South America in the 17th to 19th centuries seem to have a common ancestor from Africa. B. mallei is a clone of B. pseudomallei that has lost substantial portions of its genome as it adapted to live exclusively in mammals. This makes the B. mallei genome much smaller than B. pseudomallei.
Transmission B. pseudomallei is normally found in soil and surface water, and is most abundant at soil depths of 10 to 90 cm. It has been found in soils, ponds, streams, pools, stagnant water, and rice paddy fields. B. pseudomallei can survive in nutrient-poor conditions such as distilled water, desert soil, and nutrient-depleted soil for more than 16 years. It can also survive in antiseptic and detergent solutions, acidic environments (pH 4.5 for 70 days), and in environments at temperatures ranging from 24 °C (75.2 °F) to 32 °C (89.6 °F). However, the bacteria may be killed by the presence of ultraviolet light.
Bacteria can enter the body through wounds, inhalation, and ingestion of contaminated soil or water. Person-to-person transmission is extremely rare. Melioidosis is a recognised disease in animals including pigs, cats, dogs, goats, sheep, horses, and others. Cattle, water buffalo, and crocodiles are considered to be relatively resistant to melioidosis despite their constant exposure to mud. Birds are also considered resistant to melioidosis although several cases had been reported in Australia and aquatic birds. Transmission from animals to humans is rare.
Inadequate chlorination of the water supply has been associated with B. pseudomallei outbreak in Northern and Western Australia. There were also several cases of bacteria being found in unchlorinated water supply in rural Thailand. Based on the whole genome sequencing of the bacteria, the variety of the bacteria B. pseudomallei in Papua New Guinea is narrow due to limited movements of the indigenous people. This findings supports the hypothesis that humans play an important role in bacterial dispersal.
Pathogenesis