Melioidosis

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Melioidosis
thalassaemia, alcoholism, chronic kidney disease[1]
Diagnostic methodGrowing the bacteria in culture mediums[1]
Differential diagnosisTuberculosis[2]
PreventionPrevention from exposure to contaminated water, antibiotic prophylaxis[1]
TreatmentCeftazidime, meropenem, trimethoprim/sulfamethoxazole[1]
Frequency165,000 people per year[1]
Deaths89,000 people per year[1]

Melioidosis is an

bacterium called Burkholderia pseudomallei.[1] Most people exposed to B. pseudomallei experience no symptoms; however, those who do experience symptoms have signs and symptoms that range from mild, such as fever and skin changes, to severe with pneumonia, abscesses, and septic shock that could cause death.[1] Approximately 10% of people with melioidosis develop symptoms that last longer than two months, termed "chronic melioidosis".[1]

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.

co-trimoxazole.[1] In countries with the advanced healthcare system, approximately 10% of people with melioidosis die from the disease. In less developed countries, the death rate could reach 40%.[1]

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.

co-trimoxazole is used as a preventative only for individuals at high risk for getting the disease after being exposed to the bacteria in laboratory settings.[1] One study conducted in 2018 determined that the drug could be useful in preventing melioidosis in high-risk renal failure patients undergoing haemodialysis.[4] There is no approved vaccine for melioidosis.[1]

Approximately 165,000 people are infected by melioidosis per year, resulting in about 89,000 deaths, based on a mathematical model published in 2016.[5] Diabetes is a major risk factor for melioidosis; over half of melioidosis cases are in people with diabetes.[1] Increased rainfall and severe weather events such as thunderstorms are associated with an increased number of melioidosis cases in endemic areas.[2]

Signs and symptoms

Acute

Schematic depiction of the signs of melioidosis
Chest X-ray showing opacity of the left middle and lower areas of the lung.[6]
CT and MRI scans showing lesion of the right frontal lobe of the brain.[6]
Septic arthritis of the left hip with joint destruction.[6]

Most people exposed to B. pseudomallei experience no symptoms.[2] The mean incubation period of acute melioidosis is 9 days (range 1–21 days).[1] Nevertheless, symptoms of melioidosis can appear in 24 hours for those who experienced near drowning in water.[7] 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".[1]

bacteremia (in 40 to 60% of cases), pneumonia (50%), and septic shock (20%).[1][9]
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.[2] 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 lower lobes of the lungs.[2] In 10% of cases, people develop secondary pneumonia caused by other bacteria after the primary infection.[3] In northern Australia, 60% of the infected children presented with only skin lesions, while 20% presented with pneumonia.[3]

Depending on the course of infection, other severe manifestations develop. Approximately 1 to 5% of those infected develop

mononuclear cells with elevated CSF protein.[10]

Chronic

Chronic melioidosis is usually defined by symptoms lasting greater than two months and occurs in about 10% of patients.[1] 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.[2] 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.[10]

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".[2] 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.[11] 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.[12] This reinstates another report that put the longest latency period for melioidosis as 29 years.[13] Patients with latent melioidosis may be symptom-free for decades.[11] Less than 5% of all melioidosis cases have activation after a period of latency.[1] Various comorbidities such as diabetes, renal failure, and alcoholism can predispose to reactivation of melioidosis.[2]

Cause

Bacteria

Burkholderia pseudomallei with bipolar Gram staining, referred to as a "safety-pin" appearance.[6]

Melioidosis is caused by

intracellular pathogens.[14] It is also aerobic and oxidase test positive.[2] A granule at the centre of the bacterium makes it resemble a "safety pin" when Gram stained.[2] 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's resistance to various kinds of antibiotics is because of its production of a glycocalyx polysaccharide capsule.[15] 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.[2] In humans and animals, another similar organism named Burkholderia mallei is the causative agent of the disease glanders.[1] B. pseudomallei can be differentiated from another closely related, but less pathogenic species B. thailandensis by its ability to assimilate arabinose.[10] B. pseudomallei is highly adaptable to various host environments ranging from inside mycorrhizal fungi spores to amoeba.[2] Its adaptability may give it a survival advantage in the human body.[1]

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 was introduced to Central and South America in the 17th to 19th centuries seem to have a common ancestor from Africa.[16] B. mallei is a clone of B. pseudomallei that has lost substantial portions of its genome as it adapted to live exclusively in mammals.[3] This makes the B. mallei genome much smaller than B. pseudomallei.[17]

Transmission

B. pseudomallei is normally found in soil and surface water, and is most abundant at soil depths of 10 to 90 cm.[1] It has been found in soils, ponds, streams, pools, stagnant water, and rice paddy fields.[2] B. pseudomallei can survive in nutrient-poor conditions such as distilled water, desert soil, and nutrient-depleted soil for more than 16 years.[1] 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.[1]

Bacteria can enter the body through wounds, inhalation, and ingestion of contaminated soil or water.[1] Person-to-person transmission is extremely rare.[2] 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.[10][15] Transmission from animals to humans is rare.[1][2]

Inadequate chlorination of water supply has been associated with B. pseudomallei outbreak in Northern and Western Australia.[18][19] There were also several cases of bacteria being found in unchlorinated water supply in rural Thailand.[20] 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.[21]

Pathogenesis

Diagram showing the pathogenesis of melioidosis
Ways of B. pseudomallei bacteria infecting human cells and blood stream.[6]

B. pseudomallei has the ability to infect various types of cells and to evade human immune responses. Bacteria first enter at a break in the skin or

endothelial cells, platelets, and monocytes. Once bound, the bacteria enter host cells through endocytosis, ending up inside an endocytic vesicle. As the vesicle acidifies, B. pseudomallei uses its type 3 secretion system (T3SS) to inject effector proteins into the host cell, disrupting the vesicle and allowing the bacteria to escape into the host cytoplasm. Within the host cytoplasm, the bacteria evade being killed by host autophagy using various T3SS effector proteins. The bacteria replicate in the host cytoplasm.[1][10]

Inside the host cell, the bacteria move by inducing the polymerization of the host

latent infection. This same process in infected neurons can allow bacteria to travel through nerve roots in the spinal cord and brain, leading to inflammation of the brain and spinal cord. In addition to spreading from cell to cell, the bacteria can also spread through the bloodstream, causing sepsis. The bacteria can survive in antigen-presenting cells and dendritic cells. Thus, these cells act as vehicles that transport the bacteria into the lymphatic system, causing widespread dissemination of the bacteria in the human body.[1][10]

While B. pseudomallei can survive in phagocytic cells, these cells can kill B. pseudomallei by several mechanisms. Macrophages activated by

coagulation cascade, however the thick bacterial capsule prevent the action of the complement membrane attack complex.[1][10]

Additional elements of the immune system are activated by the host toll-like receptors such as TLR2, TLR4, and TLR5 that recognize the conserved pieces of the bacteria such as LPS and flagella. This activation results in the production of cytokines such as Interleukin 1 beta (IL-1β) and Interleukin 18 (IL-18). IL-18 increases IFN production through natural killer cells while IL-1beta reduces the IFN production. These immune molecules drive the recruitment of other immune cells such as neutrophils, dendritic cells, B cells, and T cells to the site of infection. T cells seem to be particularly important for controlling B. pseudomallei; T cell numbers are increased in survivors, and low T cell numbers are associated with a high risk of death from melioidosis. Despite this, HIV infection is not a risk factor for melioidosis. Although macrophages show deregulated cytokine responses in individuals with HIV infection, bacterial internalization and intracellular killing are still effective. People infected with B. pseudomallei may develop antibodies against the bacteria, and people that live in endemic areas tend to have antibodies in their blood that recognize B. pseudomallei. However, the effectiveness of these antibodies at preventing melioidosis is unclear.[1][10]

B. pseudomallei can remain latent in the human body for up to 29 years until it is reactivated during human immunosuppression or stress response. However, the site of bacteria during latent infection and the mechanism by which they avoid immune recognition for years are both unclear. Amongst mechanisms suggested are: residing in the nucleus of the cell to prevent being digested, entering a stage of slower growth, antibiotic resistance, and genetic adaption to the host environment. Granulomas (containing neutrophils, macrophages, lymphocytes, and multinucleated giant cells) formed at the infection site in melioidosis have been associated with latent infection in humans.[1]

Diagnosis

Appearance of B. pseudomallei colonies on Ashdown's medium after four days of incubation.[6]
Immunofluorescent microscopy showing the presence of B. pseudomallei.[6]
Right-most slide showing positive latex agglutination for melioidosis.[6]

Culture

Bacterial culture has 60% sensitivity in diagnosing melioidosis.[23] B. pseudomallei is never part of human flora. Therefore, any growth of the bacteria is diagnostic of melioidosis. Other samples such as throat, rectal swabs, pus from abscesses, and sputum can also be used for culture.[1] However, culture from CSF is difficult because in one case series, only 29% of the neuromelioidosis cases are culture positive.[10] When bacteria do not grow from people strongly suspected of having melioidosis, repeated cultures should be taken as subsequent cultures can become positive.[1] B. pseudomallei can be grown on any blood agar, MacConkey agar, and agar containing antibiotics such as Ashdown's medium (containing gentamicin),[10] and Ashdown's broth (containing colistin)[3] for better isolation of B. pseudomallei from other types of bacteria.[10] Agar plates for melioidosis should be incubated at 37 °C (98.6 °F) in air [2] and inspected daily for four days. On the agar plates, B. pseudomallei forms creamy, non-haemolytic, colonies after 2 days of incubation. After 4 days of incubation, colonies appear dry and wrinkled.[1] Colonies of B. pseudomallei that are grown on Francis medium (a modification of Ashdown medium with gentamicin concentration increased to 8 mg/L and neutral red indicator replaced with 0.2% bromocresol purple) are yellow.[24] For laboratories located outside endemic areas, Burkholderia cepacia selective agar can be used if Ashdown's medium is not available.[2] It is important not misinterpret the bacterial growth as Pseudomonas or Bacillus spp. Other biochemical screening tools can also be used for detecting B. pseudomallei, including the API 20NE or 20E biochemical kit combined with Gram stain, oxidase test, typical growth characteristics, and resistance to certain antibiotics of the bacteria.[3] API 20NE biochemical kit is 99% sensitive in identifying B. pseudomallei.[10]

Molecular methods such as 16S rDNA sequencing, multiplex polymerase chain reaction (PCR), and real-time PCR can also be used to identify B. pseudomallei in culture.[1][25][26][27] Other bacterial genes such as fliC genes encoding flagellin, rpsU gene encoding for ribosomal protein, and TTS genes encoding Type III secretion systems has also been employed for detection. Another method of gene detection namely multiple cross displacement amplification for the bacterial TTS1 gene detection produces results within an hour.[27]

Hematological and biochemical tests

General blood tests in people with melioidosis show low white blood cell counts (indicates infection), raised liver enzymes, increased bilirubin levels (indicates liver dysfunction), and raised urea and creatinine levels (indicates kidney dysfunction). Low blood glucose and acidosis predicts a poorer prognosis in those with melioidosis. However, other tests such as C-reactive protein and procalcitonin levels are not reliable in predicting the severity of melioidosis infection.[15]

Serological tests

haemagglutination assay (IHA) have been used to detect the presence of antibodies against B. pseudomallei. However, different groups of people have widely different levels of antibodies, so interpretation of these tests depends on location. In Australia, less than 5% of people have B. pseudomallei antibodies, so the presence of even relatively low amounts of antibody is unusual and could suggest melioidosis. In Thailand, many people have antibodies against B. pseudomallei so the diagnosis of melioidosis should not be reliant entirely on the serological tests done in endemic areas.[1][3] Indirect immunofluorescent test (IFAT) uses either B. pseudomallei or B. thailandensis antigens to look for the total number of antibodies in human serum. Using IFAT is labour intensive and is not used in large scale investigations.[28]

Antigen detect tests allow rapid detection of melioidosis. Examples of antigen detection tests are: latex agglutination test and

Latex agglutination uses antibodies coated on latex beads to detect B. pseudomallei antigens in solid or liquid media, although not all the assays can detect different species of Burkholderia.[29] Latex agglutination is useful in screening for suspected B. pseudomallei colonies.[1] IgG and IgM ELISAs has been used to detect lipopolysaccharide (LPS) antigens of B. pseudomallei, but plagued with low sensitivity.[30] Commercial ELISA kits for melioidosis no longer available in the market due to low sensitivity to human antibodies detection.[10] Nevertheless, antigen detection tests may be useful in severely ill patients because the bacterial load is high enough for detection. Other methods of antigen detection such as direct immunofluorescence, antibody-sandwich ELISAs, and lateral flow immunoassays using monoclonal antibody.[30]

Microscopy

By microscopy, B. pseudomallei is seen as

Immunofluorescence microscopy is highly specific for detecting bacteria directly from clinical specimens, but has less than 50% sensitivity.[1][3]

Imaging

Various imaging modalities can also help with the diagnosis of melioidosis. In acute melioidosis with the spreading of the bacteria through the bloodstream, the chest X-ray shows multifocal nodular lesions. It may also show merging nodules or

CT scan has higher sensitivity when compared with an ultrasound scan. In liver and splenic abscesses, an ultrasound scan shows "target-like" lesions while CT scan shows "honeycomb sign" (abscess with loculations separated by thin septa) in liver abscesses.[10] For melioidosis involving the brain, MRI have higher sensitivity than a CT scan in diagnosing the lesion. MRI shows ring-enhancing lesions for brain melioidosis.[10]

Prevention

Melioidosis is a notifiable disease in Australia

BSL-3 precautions.[33] On the other hand, in other endemic areas where the B. pseudomallei samples were handled less stringently, there has been no confirmed laboratory-acquired infection reported. This phenomenon may show that the risk of infection with B. pseudomallei is less than a typical biohazard type 3 agent.[34] There are also several cases of hospital-acquired infection of melioidosis.[1] Therefore, healthcare providers are recommended to practice hand hygiene and universal precautions.[1]

Large-scale water chlorination has been successful at reducing B. pseudomallei in the water in Australia.[35][1] In middle to low-income countries, water should be boiled before consumption.[1] In high income countries, water could be treated with ultraviolet light for those at risk of contracting melioidosis.[36][1] Those who are at high risk of contact with the bacteria should wear protective gear (such as boots and gloves) during work.[1] Those staying in endemic areas should avoid direct contact with soil, and outdoor exposure to heavy rain or dust clouds. Bottled water or boiled water are preferred as drinking water.[37][1] A study conducted from 2014 to 2018, however showed no significant differences on whether behavioural changes can reduce the risk of contracting melioidosis. Modification of behavioural changes or more frequent interventions may be needed to ensure a definite reduction in risk of getting melioidosis.[38]

Antibiotic prophylaxis

Administering cotrimoxazole three times a week throughout a wet season for dialysis patients has no obvious benefit of preventing melioidosis. Besides, high cost and side effects of this drug limits its use to only those with high risk of getting melioidosis.

co-amoxiclav and doxycycline can be used for those who are intolerant to co-trimoxazole. Low-risk individuals would receive frequent monitoring instead.[40]

Vaccination

Further information: Burkholderia pseudomallei § Vaccine candidates

Several vaccine candidates have been tested in animal models. Nevertheless, no vaccine candidates have been tried in humans. Major hurdles of the vaccines are limited efficacy in animal models, establishing the best method of vaccine administration in humans and logistical and financial issues in establishing human trials in endemic areas.[10]

Treatment

The treatment of melioidosis is divided into two stages: an intravenous intensive phase and an eradication phase to prevent recurrence. The choice of antibiotics depends upon the susceptibility of the bacteria to various antibiotics. B. pesudomallei are generally susceptible to ceftazidime, meropenem, imipenem, and co-amoxiclav. These drugs generally kill bacteria. B. pseudomallei is also susceptible to doyxcycline, chloramphenicol, and co-trimoxazole. These drugs generally inhibit the growth of the bacteria. However, the bacteria are resistant to penicillin, ampicillin, 1st and 2nd generation cephalosporin, gentamicin, streptomycin, tobramycin, macrolides, and polymyxins.[1] On the other hand, 86% of the B. pseudomallei isolates from the region of Sarawak, Malaysia are susceptible to gentamicin and this has not been found elsewhere in other parts of the world.[41]

Prior to 1989, the standard treatment for acute melioidosis was a three-drug combination of

co-trimoxazole and doxycycline; this regimen is associated with a mortality rate of 80% and is no longer used unless no other alternatives are available.[42] All three drugs are bacteriostatic (they stop the bacterium from growing, but do not kill it) and the action of co-trimoxazole antagonizes both chloramphenicol and doxycycline.[43]

Intensive phase

co-amoxiclav) may be used if none of the above four drugs is available;[1] co-amoxiclav prevents death from melioidosis as well as ceftazidime.[7] Co-amoxiclav is also used if patient has allergy towards sulfonamide, unable to tolerate co-trimaxazole, in pregnant patients or in children. High dose of co-amoxiclav (20 mg/kg for amoxicillin and 5 mg/kg for clavulanate) is recommended to prevent treatment failures.[44][45] Intravenous antibiotics are given for a minimum of 10 to 14 days. The median fever clearance time in melioidosis is 9 days.[1] The treatment duration is in accordance with Darwin melioidosis treatment guidelines where there is low rate of recrudescence and relapse.[46]

Meropenem is the preferred antibiotic therapy for neurological melioidosis and those with septic shock admitted into intensive care units. Co-trimoxazole is recommended in addition to ceftazidime for neurological melioidosis, osteomyelitis, septic arthritis, skin and gastrointestinal infection, and deeply seated abscess. For deep-seated infections such as abscesses of internal organs, osteomyelitis, septic arthritis, and neurological melioidosis, the duration of antibiotics given should be longer (up to 4 to 8 weeks). The time taken for the fever to be resolved can be more than 10 days in those with deep-seated infection. According to the 2020 Revised Royal Darwin Hospital Guideline, the dosage for intravenous ceftazidime is 2g 6-hourly in adults (50 mg/kg up to 2g in children less than 15 years old). The dosage for meropenem is 1g 8-hourly in adults (25 mg/kg up to 1g in children).[46] Acquired resistance to ceftazidime, carbapenems, and co-amoxiclav is rare in the intensive phase but resistance to cotrimoxazole during eradication therapy is technically difficult to assess.[47] There are no differences between using cefoperazone/sulbactam or ceftazidime to treat melioidosis as both shows similar death rates and disease progression following treatment. However, data are lacking to recommend cefoperazone/sulbactam usage.[47][48] For those with kidney impairment, the dosage of ceftazidime, meropenem, and co-trimoxazole should be lowered.[3] Once the clinical condition improved, meropenem can be switched back to ceftazidime.[1]

Eradication phase

Following the treatment of the acute disease, eradication treatment with

fluoroquinolone (e.g., ciprofloxacin) or doxycycline for the oral eradication phase is ineffective.[1]

In Australia, co-trimoxazole is used with children and pregnant mothers after the first 12 weeks of pregnancy. Meanwhile, in Thailand, co-amoxiclav is the drug of choice for children and pregnant women.

folic acid (0.1 mg/kg up to 5 mg in children).[1][46] There are also cases where melioidosis is successfully treated with co-trimoxazole for 3 months without going through intensive therapy provided that there is only skin manifestations without the involvement of internal organs or sepsis.[1] Resistance to cotrimoxazole is rare in Asia.[50] Besides that, it is difficult to determine the resistance reliably because resistance to cotrimoxazole is defined when minimum inhibitory concentration (MIC) of more than 4 mg/L is required to completely inhibit the growth of 80% of the bacteria (80% inhibition point). Interpretation of 80% inhibition point is subjective and prone to human error.[51] In 2021, European Committee on Antimicrobial Susceptibility Testing (EUCAST) released a new guideline on interpreting the susceptibility of B pseudomallei towards various antibiotics on disc susceptibility testing. The new guideline includes "S" for susceptible organism, "I" for susceptible organism only after increased exposure (when dosage or concentration of the drug increases) and "R" for resistant organism.[52]

Surgery

Surgical drainage is indicated for single, large abscesses in the liver, muscle, and prostate. However, for multiple abscesses in the liver, spleen, and kidney, surgical drainage may not be possible or necessary. For septic arthritis, arthrotomy washout and drainage are required. Surgical debridement may be necessary.[1] For those with mycotic aneurysm, urgent surgery is required for prosthetic vascular grafts. Lifelong therapy with co-trimoxazole may be needed for those with prosthetic vascular grafts according to a review of case reports in 2005.[53] Other abscesses rarely need to be drained because most resolve with antibiotic treatment.[1] Prostate abscess may require routine imaging. Antibiotics treatment for prostatic abscess may be enough except for abscesses more than 10 to 15 mm where surgical drainage is required.[54][55][56]

Others

Several immunomodulating therapies are suggested to boost the human body immune function against the bacteria because the pathogenesis of melioidosis is thought to be contributed by defects in

neutrophils.[1] The Royal Darwin Hospital 2014 guidelines recommended granulocyte colony-stimulating factor (G-CSF) as immunomodulating therapy for those with septic shock at 300 ug daily as soon as the bacteriological laboratory flag the culture as possibly Burkholderia pseudomallei. The main contraindication of starting (G-CSF) is a heart event. The G-CSF is continued for ten days depends on clinical response or a contraindication develops such as white cell count greater than >50,000 X106/litre.[46]

Anti-PDI (programmed cell death) agents could be useful in melioidosis treatment especially for those with septic shock. This is because Burkholderia pseudomallei bacteria increases the expression of PDI-1 that regulates and inhibits the formation of T-cells that are essential for fighting against melioidosis.[57]

Prognosis

In well-resourced settings, where the disease can be detected and treated early, the risk of death is 10%. In resource-poor settings, the risk of death from the disease is more than 40%.[1]

Recurrent melioidosis can occur either due to re-infection or relapse after the completion of eradication therapy. Re-infection is due to a new strain of B. pseudomallei bacteria. Meanwhile, relapse is due to failure to clear infections after the eradication therapy. Recurrent melioidosis is rare since 2014 due to improved antibiotic therapy and prolongation of the intensive phase of therapy as evident in Darwin Prospective Melioidosis Study.[58] On the other hand, recrudescence are those who present with symptoms during the eradication therapy. Recrudescence rates may be improved by ensuring adherence to a full course of eradication therapy e.g. by reducing self-discharge against medical advice.[59]

Underlying medical conditions such as diabetes mellitus, chronic kidney disease, and cancer can worsen the long-term survival and disability of those who recover from infection. One of the complications of melioidosis is encephalomyelitis. It can cause quadriparesis (muscle weakness in all the limbs), partial flaccid paraparesis (muscle weakness of both legs), or foot drop. For those with previous melioidosis-associated bone and joint infections, complications such as sinus tract infection, bone and joint deformities with limited range of motion can occur.[1]

Epidemiology

Number of deaths by each country due to melioidosis in 2018.[6]

Melioidosis is an understudied disease that remains endemic in developing countries. In 2015, the International Melioidosis Society was formed to raise awareness of the disease.[1] In 2016, a statistical model was developed which predicted that the number is 165,000 cases per year with 138,000 of those occurring in East and South Asia and the Pacific.[60] In approximately half of those cases (54% or 89,000), people will die.[1] Under-reporting is a common problem as only 1,300 cases were reported worldwide since 2010, which is less than 1% of the projected incidence based on the modelling.[1] Lack of laboratory diagnostic capabilities and lack of disease awareness amongst health care providers also causes under diagnosis. Even if bacterial cultures show positive result for B. pesudomallei, they can be discarded as contaminants especially in laboratories in non-endemic areas.[1] In 2015, it was estimated that the yearly disability-adjusted life year (DALY) was 84.3 per 100,000 people. As of 2022, melioidosis is not included in the WHO list of neglected tropical diseases.[61][62]

Geography

Melioidosis is endemic in parts of southeast Asia (including Thailand,[63] Laos,[64] Singapore,[65] Brunei,[66] Malaysia,[67] Myanmar[68] and Vietnam[69]), southern China,[70] Taiwan[71] northern Australia.[72] India,[73] and South America.[74] Since 1991, a total of 583 cases were reported in India. Most Indian cases are located in Karnataka and Tamil Nadu.[73] Fifty-one cases of melioidosis were reported in Bangladesh from 1961–2017. Nonetheless, lack of awareness and resources gives rise to under diagnosis of the disease in the country.[75] The true burden of melioidosis in Africa and Middle East remain unknown due to low amount of data. Several melioidosis cases were reported over the years. Although 24 African countries and three Middle Eastern countries predicted to be endemic with melioidosis, however not a single case was reported from these specific countries.[76] In the United States, two historical cases (1950 and 1971) and four recent cases (2010, 2011, 2013, 2020) have been reported amongst people that did not travel overseas.[3][77] Despite extensive investigations, the source of melioidosis was never confirmed. One possible explanation is that importation of medicinal plant products or exotic reptiles could have resulted in the introduction of melioidosis in the United States.[3] In 2021, there was a melioidosis outbreak in several states in the United States due to usage of contaminated aromatherapy spray imported from India.[78] There are also cases of infection through imported tropical fishes in home aquariums.[79] In Europe, more than half of the melioidosis cases are imported from Thailand.[80]

Age, risk factors

Melioidosis is found in all age groups.

rice paddy farmers),[10] recreational exposure to soil, water, being male, age greater than 45 years, and prolonged steroid use/immunosuppression.[1] However, 8% of children and 20% of adults with melioidosis have no risk factors.[1] HIV infection does not appear to predispose to melioidosis, although several other co-infections have been reported.[10] Infant cases have been reported possibly due to mother-to-child transmission, community-acquired infection, or healthcare-associated infection.[1] Those who are well may also be infected with B. pseudomallei. For example, 25% of children started producing antibodies against B. pseudomallei between 6 months to 4 years of staying in endemic areas although they did not experience any melioidosis symptoms; suggesting they were exposed to it over this time. This means that many people without symptoms will test positive in serology tests in endemic areas.[2] In Thailand, the seropositivity rate exceeds 50%, while in Australia the seropositivity rate is only 5%.[3] The disease is clearly associated with increased rainfall, with the number of cases rising following increased precipitation. Severe rainfall increases the concentration of the bacteria in the topsoil, thus increasing thus of transmitting the bacteria through the air.[10] A recent CDC Advisory indicated that the recent detection of the organism in the environment in Mississippi following the occurrence of two indigenous cases of melioidosis, confirms that parts of the southern USA should now be regarded as melioidosis-endemic.[82]

History

Pathologist

Myanmar, in a report published in 1912.[83] Whitmore was able to grow the organism in culture and its showed similarity with B. mallei, another bacteria that was known causing glanders in animals. Therefore, he named the new organism Bacillus pseudomallei. He did no further work on the organism.[84] Arthur Conan Doyle may have read Whitmore's report before writing a short story that involved the fictitious tropical disease "Tapanuli fever" in a Sherlock Holmes story[85] titled "The Adventure of the Dying Detective" published in 1913.[15] In the same year, melioidosis outbreak occurred inside the Institute for Medical Research (IMR), Kuala Lumpur, Malaya after its laboratory animals such as guinea pigs and rabbits were infected.[67] William Fletcher and Ambrose Thomas Stanton, doctors who worked at the IMR, were the next ones to study the organism. They were unable identify the organism that caused the outbreak. It was only in 1917, when Fletcher isolated an organism similar to Whitmore's bacillus from a Tamil rubber estate worker, the presence of the new species of bacteria was confirmed.[84] The term "melioidosis" was first coined in 1921. The name melioidosis is derived from the Greek melis (μηλις) meaning "a distemper of asses" with the suffixes -oid meaning "similar to" and -osis meaning "a condition", that is, a condition similar to glanders.[86] B pseudomallei is similar in clinical presentation and genome make-up with B. mallei[87] but is distinguished from it due to epidemiological and zoonotic characteristics.[88]

The first human case of melioidosis in South Asia was reported in Sri Lanka in 1927.

panda or horses from Iran.[15][95] It is unclear how imported melioidosis is able to persist in a completely new environment. Eventually, the outbreak terminated by itself after a period of time.[90] It was only during the 1980s, Infectious Disease Association of Thailand started took notice of this disease. First conference on melioidosis was held in 1985 in Thailand. It was during this meeting that collaboration between Sappasitprasong Hospital, Thailand, and Wellcome-Mahido-Oxford Tropical Medicine Research Programme was established. Such collaboration made Thailand a world leader in clinical and epidemiology research on melioidosis.[90]

In 1989, several studies conducted in Thailand demonstrated ceftazidime as an effective antibiotic against melioidosis.

co-trimoxazole was established as the only oral eradication therapy rather than combination therapy of co-trimoxazole with doxycycline.[99] In 2016, a statistical model was developed to predict the occurrence of global melioidosis per year.[5]

Synonyms

Biological warfare

Interest in melioidosis has been expressed because it has the potential to be developed as a

Pingfang District by the Japanese during World War II.[15] The Soviet Union reportedly used B. mallei during the Soviet–Afghan War in 1982 and 1984.[104] B. pseudomallei, like B. mallei, was studied by both the US[105] and Soviet Union as a potential biological warfare agent, but never weaponized.[104] Other countries such as Iran, Iraq, North Korea, and Syria may have investigated the properties of B. pseudomallei for biological weapons.[2] The bacterium is readily available in the environment. It can also be aerosolized and transmitted via inhalation.[2] However, the B. pseudomallei has never been used in biological warfare.[2] The actual risk of the deliberate release of B. pseudomallei or B. mallei is unknown.[106]

References

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External links

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