Melioidosis: The Great Mimicker

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Chapter 5 Melioidosis: The Great Mimicker R Chandni INTRODUCTION Melioidosis is a clinically diverse disease caused by the facultative intracellular Gram-negative bacterium, B.

1 Chapter 5 Melioidosis: The Great Mimicker R Chandni INTRODUCTION Melioidosis is a clinically diverse disease caused by the facultative intracellular Gram-negative bacterium, B. pseudomallei, an environmental saprophyte which is widely distributed in soil and fresh surface water in endemic regions. Melioidosis is a disease known as the great mimicker because of its similarity to other infections and the difficulty with its diagnosis. 1 BACKGROUND AND HISTORY Alfred Whitmore and CS Krishnaswami first described melioidosis as a Glanders-like disease among morphine addicts in Rangoon in Stanton and Fletcher in proposed the name Melioidosis, derived from the Greek melis meaning a distemper of asses and suffixes -oid (similar to) and -osis (a condition). Melioidosis is thus a condition similar to Glanders. This Gram-negative environmental bacterium has been previously known as Bacillus pseudomallei and since 1992 as Burkholderia pseudomallei. EPIDEMIOLOGY ABSTRACT Melioidosis is an infectious disease of humans and animals, caused by Burkholderia pseudomallei, a Gram-negative soil bacterium. It is predominantly a disease of tropical climates with reports from various parts of India; lately, it has been listed as an important potential bioterrorism weapon. The bacterium causing melioidosis is found in contaminated water and soil and spreads to humans through inhalation or inoculation. Melioidosis is probably under reported in India. Early diagnosis and treatment is essential for better outcome. With its protean clinical manifestations ranging from asymptomatic infection to overwhelming sepsis, the diagnosis of melioidosis needs a high index of suspicion along with the isolation and identification of B. pseudomallei from clinical specimens. The diagnosis can be made easily, even in nonendemic areas, if duly considered by the clinicians and microbiologists. Melioidosis is an infectious disease endemic in southeast Asia, northern Australia, much of the Indian subcontinent, southern China, Hong Kong, and Taiwan (Figure 1). 4 In northern Australia and northeast Thailand, it accounts for 20% of all community-acquired septicemias. It is the most common cause of severe communityacquired pneumonia in northern Australia. The highest risk for melioidosis exists for military personnel, adventure travelers, ecotourists and construction workers whose contact with contaminated soil or water may expose them to the bacteria. B. pseudomallei has been isolated from ill troops of all nationalities who served in areas with endemic disease, with a latency of as long as 62 years and hence it is called the Vietnamese time bomb. 5 Melioidosis is prevalent in many parts of India, but is underdiagnosed and under-reported. 6 This was reported in a 9-yearold boy in from Vellore. Case series of melioidosis has been reported from Vellore 8 and from coastal regions of Kerala and Karnataka. There are also other reports from India B. pseudomallei are oxidase-positive, motile Gram-negative bacillus, showing bipolar staining. Currie BJ et al. 16 have documented the incubation period for melioidosis from defined inoculating events to be 1 21 (mean 9) days. While most cases are considered to be from percutaneous inoculation, 17 inhalation is also a well-recognized mode of infection. Melioidosis is highly seasonal, with 75 85% of cases occur during the rainy season and are often more severely ill after heavy monsoonal rainfall. 18 It is a category B bioterrorism agent. CLINICAL MANIFESTATIONS Melioidosis can be categorized as an acute or localized infection, acute pulmonary infection, acute bloodstream infection or disseminated infection. Subclinical infections are also possible. Melioidosis may present as localized infection (such as cutaneous), pneumonia, meningoencephalitis, visceral abscesses (liver, spleen, kidneys, prostate), septic arthritis (Figure 2), osteomyelitis, fever of unknown origin (FUO) or chronic suppurative infection. The latter may mimic tuberculosis, with fever, weight loss, productive cough and upper lobe infiltrate, with or without cavitation. Melioidosis may also present as suppurative parotitis (in children). The incubation period is generally 1 21 days, but may extend to months or years; generally symptoms appear 2 4 weeks after exposure. With a high inoculum, symptoms can develop in a few hours. More than 50% of cases present with pneumonia. Overall, about half of the patients are bacteremic and up to a quarter can present with septic shock. Without appropriate treatment, case-fatality ratio may reach 90% within 48 hours of developing symptoms. Although healthy people may get melioidosis, 19 the major risk factors are diabetes, excessive alcohol use, liver disease, chronic renal disease, chronic lu ng disease, urolithiasis, thalassemia, cancer or another immunosuppressing condition not related to human immunodeficiency virus (HIV) and occupational exposure. The use of steroids increases the risk of melioidosis and it includes steroid-containing herbal remedies (yaa chud) in Thailand. 20 Morbidity and mortality of melioidosis are also higher in people with major risk factors.

Section 1 Chapter 5 Melioidosis: The Great Mimicker Figure 1: Endemicity of melioidosis infection Figure 2: Swollen right elbow joint DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS Melioidosis must be

Among infections causing FUO, it must be thought of after excluding tuberculosis and other common infections presenting as abscesses.

2 Section 1 Chapter 5 Melioidosis: The Great Mimicker Figure 1: Endemicity of melioidosis infection Figure 2: Swollen right elbow joint DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS Melioidosis must be considered as a diagnostic possibility in patients presenting with fever, weight loss, cough, lymphadenopathy, hepatosplenomegaly, abscesses, anemia or sepsis. Among infections causing FUO, it must be thought of after excluding tuberculosis and other common infections presenting as abscesses. Laboratory Diagnosis of Melioidosis An early diagnosis is important, particularly in resource poor settings where cases of suspected bacterial sepsis are likely to be treated with empiric antibiotic regimens that do not provide adequate cover for melioidosis. Melioidosis should be considered as a potential diagnosis for any patient who comes from or has traveled to endemic areas and laboratories should be aware of the differential features of the disease and the causative organism. The culture of B. pseudomallei from any specimen in a patient with appropriate clinical features remains the diagnostic gold standard. Samples of blood, urine and respiratory secretions should be obtained for culture from all patients, together with synovial, peritoneal and pericardial fluid, sputum, pus and wound swabs when relevant. The laboratory should be notified when melioidosis is suspected, since selective techniques may increase the isolation rate and the organism may be overlooked or discarded as a contaminant by the unwary (Figure 3). Furthermore, it is classified as a category 3 pathogen because of the risk of infection to the laboratory staff. Colonial morphology and simple biochemical tests would suggest the identity of the organism, which can then be confirmed by additional tests (Figures 4 to 6). 21 The most widely used serologic test for melioidosis is the indirect hemagglutination assay, but its utility is limited. Falsenegative serology has been reported in acute sepsis, and significant background rates of positive antibody to B. pseudomallei occur in healthy individuals in endemic areas. Sensitive polymerase chain reaction (PCR) amplification techniques for detecting the deoxyribonucleic acid (DNA) of B. pseudomallei in clinical specimens have been found useful for diagnosis. Diagnosis can be made by microscopic demonstration of small bipolar Gram-negative rods with the characteristic safety pin appearance (Figures 7A and B) which is confirmed by culture of the bacteria with a fourfold or greater rise in the titer of serum antibody to the organism. Chest radiography findings in acute pneumonia due to melioidosis may include small infiltrates, discrete, diffuse or patchy lobar or multilobar consolidation, necrotizing lesions, cavitation 15

Infectious Diseases Section 1 Figure 3: Blood culture brain heart infusion both showing pellicle formation on surface (likely to be mistaken for contaminants) Figure 6: B.

Figure 4: Blood culture of B. pseudomallei. Blood agar hemolytic colony and abscesses with fluid levels and pleural effusions (Figures 8 and 9).

There is an emerging consensus on the initial (Phase 1) treatment, subsequent eradication (Phase 2) therapy and most recently postexposure (Phase 0) prophylaxis (Table 1).

22,23 The response to therapy is often poor, with a mean duration of fever of 9 days.

3 Infectious Diseases Section 1 Figure 3: Blood culture brain heart infusion both showing pellicle formation on surface (likely to be mistaken for contaminants) Figure 6: B. pseudomallei colony morphology as demons trated on Ashdown s selective medium (violet colored rugose colonies) A B Figures 7A and B: Gram s stain bipolar staining with safety pin appearance Figure 4: Blood culture of B. pseudomallei. Blood agar hemolytic colony and abscesses with fluid levels and pleural effusions (Figures 8 and 9). To evaluate for asymptomatic abscesses in the prostate, spleen (frequently multifocal), liver (Figures 10A and B) and kidneys, a computed tomography (CT) scan of the abdomen and pelvis should be performed. TREATMENT Treatment of melioidosis is a challenge even where there are adequate resources to support patients with multiple organ failure and extensive clinical experience. There is an emerging consensus on the initial (Phase 1) treatment, subsequent eradication (Phase 2) therapy and most recently postexposure (Phase 0) prophylaxis (Table 1). The combination of agents used, duration of therapy and need for adjunct modalities depends on the type, severity and antimicrobial susceptibility of infection. 22,23 The response to therapy is often poor, with a mean duration of fever of 9 days. Treatment failure has been defined in studies as fever for longer than 14 days or bacteremia for longer than 7 days. Figure 5: Blood culture of B. pseudomallei. MacConkey s agar nonlactose fermenting colonies converted to lactose fermenting dry colonies (48 hours after incubation) PROGNOSTIC FACTORS AND OUTCOME Mortality in melioidosis is high (19 35%). Markers of organ dysfunction, including leukopenia (particularly lymphopenia), hepatic dysfunction, renal dysfunction, respiratory failure, metabolic derangements (hypoglycemia and acidosis) and bacteremia predict mortality

Section 1 Chapter 5 Melioidosis: The Great Mimicker Figure 8: Chest X-ray posteroanterior (PA) view. Nonhomogeneous opacities in both lung fields Figure 9: Chest X-ray posteroanterior (PA) view.

Application Agent Amount* Route Frequency Duration Variations Phase 0: Postexposure prophylaxis Within 24 hours of high TMP-SMX 320:1600 mg PO 12 hourly 3 weeks AMOX/CLAV if allergic to

4 Section 1 Chapter 5 Melioidosis: The Great Mimicker Figure 8: Chest X-ray posteroanterior (PA) view. Nonhomogeneous opacities in both lung fields Figure 9: Chest X-ray posteroanterior (PA) view. Right upper lobe cavity with air fluid level with no evidence of fibrosis TABLE 1 Treatment of melioidosis: postexposure (Phase 0), initial (Phase 1) and subsequent eradication (Phase 2) therapy Application Agent Amount* Route Frequency Duration Variations Phase 0: Postexposure prophylaxis Within 24 hours of high TMP-SMX 320:1600 mg PO 12 hourly 3 weeks AMOX/CLAV if allergic to TMPprobability exposure SMX Phase 1: Acute and severe infection, induction stage Alternative agents for primary therapy Adjunct therapy for deep-seated focal infection Ceftazidime 2 g IV 8 hourly 14 days 4 8 weeks for deep infection or Meropenem or Imipenem and TMP-SMX 1 g (2 g for CNS infection) IV 8 hourly 14 days 1 g IV 8 hourly 14 days 320:1600 mg PO 12 hourly 14 days for neurological, prostatic, bone, joint infections and folic acid 5 mg PO Daily and consider G-CSF Phase 2: Eradication stage (after Phase 1 or for primary use in superficial infections) 2 of, in order of preference 263 μg SC Daily 3 days Within 72 hours of admission TMP-SMX 320:1600 mg PO 12 hourly 3 months Subject to antibiotic Doxycycline 100 mg PO 12 hourly 3 months Susceptibility AMOX/CLAV 500/125 mg PO 8 hourly 3 months Folic acid 5 mg PO Daily 3 months With TMP-SMX Abbreviations: TMP-SMX, Trimethoprim-sulfamethoxazole; PO, Oral; AMOX/CLAV, Amoxicillin/clavulanic acid; IV, Intravenous; CNS, Central nervous system; G-CSF, Granulocyte-colony stimulating factor; SC, Subcutaneous * Doses may require adjustment in renal failure Suggested by expert consensus, but lacks trial-based clinical evidence Doses provided as guide only based on 70 kg male Some recommend 5 months eradication therapy After apparently successful treatment, relapse is well described and associated with mortality similar to that for the initial episode. It occurs in 13 23% of cases and a median of 6 8 months (but up to many years) later. 25 PREVENTION Currently, no vaccines are available for human use to protect against melioidosis. The efficacy of postexposure prophylaxis in preventing human disease after exposure is unknown. In areas of endemic disease, skin lacerations, abrasions or burns that have been contaminated with soil or surface water should be immediately and thoroughly cleaned. CONCLUSION Melioidosis is an infection caused by B. pseudomallei, a widely distributed environmental saprophyte in soil and fresh surface water in endemic regions. The predominant modes of transmission are percutaneous inoculation and inhalation. The most important risk factors for melioidosis are diabetes, hazardous alcohol use and chronic renal disease. The common clinical manifestations are 17

Infectious Diseases Section 1 and PM Anitha, Department of Microbiology, Government Medical College, Kozhikode for the support given to me. A B Figures 10A and B: Computed tomography (CT) abdomen.

Culture is the mainstay of diagnosis and serologic testing alone is not reliable for diagnosis.

5 Infectious Diseases Section 1 and PM Anitha, Department of Microbiology, Government Medical College, Kozhikode for the support given to me. A B Figures 10A and B: Computed tomography (CT) abdomen. Multiple welldefined hypodense areas of varying sizes in liver and spleen are suggestive of multiple abscesses pneumonia and localized skin infection. Culture is the mainstay of diagnosis and serologic testing alone is not reliable for diagnosis. All cases of melioidosis, even mild disease, should be treated with initial intensive therapy of 2 weeks followed by eradication therapy of 3 months. An increased awareness, high index of suspicion, early diagnosis and initiation of appropriate therapy is necessary for a favorable outcome. ACKNOWLEDGMENTS I am grateful to Drs R Krishnan, PK Sasidharan, NK Thulasidharan and V Udayabhaskaran, Department of Medicine and Drs S Remadevi REFERENCES 1. Yee KC, Lee MK, Chua CT, et al. Melioidosis, the great mimicker: a report of 10 cases from Malaysia. J Trop Med Hyg. 1988;91(5): Whitmore A, Krishnaswami CS. An account of the discovery of a hitherto undescribed infective disease occurring among the population of Rangoon. Indian Med Gaz. 1912;47: Stanton AT, Fletcher W. Melioidosis, a new disease of the tropics. Trans 4th Congress Far East Assoc Trop Med. 1921;2: Cheng AC, Currie BJ. Melioidosis: epidemiology, pathophysiology, and management. Clin Microbiol Rev. 2005;18(2): Clayton AJ, Lisella RS, Martin DG. Melioidosis: a serological survey in military personnel. Mil Med. 1973;138(1): John TJ. Emerging and re-emerging bacterial pathogens in India. Indian J Med Res. 1996;103: Cherian T, Raghupathy P, John TJ. Plague in India. Lancet. 1995;345(8944): Jesudason MV, Anbarasu A, John TJ. Septicemic melioidosis in a tertiary care hospital in south India. Indian J Med Res. 2003;117: Saravu K, Vishwanath S, Kumar RS, et al. Melioidosis a case series from south India. Trans R Soc Trop Med Hyg. 2008;102(Suppl 1):S Kanungo R, Padhan P, Bhattacharya S, et al. Melioidosis a report from Pondicherry, South India. J Assoc Physicians India. 2002;50: Vidyalakshmi K, Chakrapani M, Shrikala B, et al. Tuberculosis mimicked by melioidosis. Int J Tuberc Lung Dis. 2008;12(10): Remadevi, Philomina B, Girija KR, et al. Burkholderia pseudomallei recurrent localized infections. J Acad Clin Microbiol. 2005;7(2): John TJ, Jesudason MV, Lalitha MK, et al. Melioidosis in India: the tip of the iceberg? Indian J Med Res. 1996;103: Kang G, Rajan DP, Ramakrishna BS, et al. Melioidosis in India. Lancet. 1996;347(9014): Mathew S, Perakath B, Mathew G, et al. Surgical presentation of melioidosis in India. Natl Med J India. 1999;12(2): Currie BJ, Fisher DA, Howard DM, et al. The epidemiology of melioidosis in Australia and Papua New Guinea. Acta Trop. 2000;74(2-3): Leelarasamee A, Bovornkitti S. Melioidosis: review and update. Rev Infect Dis. 1989;11(3): Currie BJ, Jacups SP. Intensity of rainfall and severity of melioidosis, Australia. Emerg Infect Dis. 2003;9(12): Lim MK, Tan EH, Soh CS, et al. Burkholderia pseudomallei infection in the Singapore Armed Forces from 1987 to 1994-an epidemiological review. Ann Acad Med Singapore. 1997;26(1): Suputtamongkol Y, Chaowagul W, Chetchotisakd P, et al. Risk factors for melioidosis and bacteremic melioidosis. Clin Infect Dis. 1999;29(2): Walsh AL, Wuthiekanun V. The laboratory diagnosis of melioidosis. Br J Biomed Sci. 1996;53(4): Timothy JJI. The treatment of melioidosis. Pharmaceuticals. 2010;3(5): doi: /ph Simpson AJ, Suputtamongkol Y, Smith MD, et al. Comparison of imipenem and ceftazidime as therapy for severe melioidosis. Clin Infect Dis. 1999;29(2): Cheng AC, Jacups SP, Anstey NM, et al. A proposed scoring system for predicting mortality in melioidosis. Trans R Soc Trop Med Hyg. 2003;97(5): Currie BJ, Fisher DA, Anstey NM, et al. Melioidosis: acute and chronic disease, relapse and re-activation. Trans R Soc Trop Med Hyg. 2000;94(3):

Emergence of Pediatric Melioidosis in Siem Reap, Cambodia. Premjit Amornchai

Emergence of Pediatric Melioidosis in Siem Reap, Cambodia Premjit Amornchai Melioidosis Gram s stain: safety-pin appearance Organism: Burkholderia pseudomallei Aerobic, motile, GNB Soil and water saprophyte