Abstract
Melioidosis is an underdiagnosed and underreported disease in India with protean clinical manifestations. Mortality in this study population was 17%. The predominant risk factor for melioidosis was diabetes mellitus. Multifocal disease was present in 66% and pulmonary involvement in 61% of patients. In a country like India where the conditions are conducive for endemic melioidosis and due to the clinical similarity of melioidosis to diseases like tuberculosis, it is essential for clinicians to have a high degree of suspicion and pursue suitable diagnostic strategies for melioidosis in the appropriate clinical setting.
Introduction
The soil saprophyte Burkholderia Pseudomallei, a fastidious, facultative, intracellular, Gram-negative bacterium, is the aetiological agent of melioidosis. Melioidosis occurs through direct human contact with contaminated soil or water, either by inhalation, cutaneous inoculation or by ingestion. 1–3 The protean clinical manifestations of melioidosis include a rapidly progressive septicaemia, soft tissue collections with a sub-acute to chronic presentation, or an indolent, sub-clinical infection with delayed conversion to clinically evident disease. 3 The majority of cases (75–85%) occur during the monsoons, possibly due to movement of the bacilli from deeper clay layers to the surface during rainfall, and subsequent human exposure. 1,4
Melioidosis is endemic in Southeast Asia and Northern Australia (between latitudes 20°N and 20°S) and has been identified by the Centre for Disease Control as a potential bioterrorism agent. 2,3 However, melioidosis continues to be underdiagnosed and underreported in India. The reason for this may be multi-factorial, including lack of awareness, a low index of clinical suspicion and inadequate laboratory diagnostic facilities. 5 Melioidosis, first described in India in 1991, is an emerging infectious disease in this country. 6 The aim of the study was to delineate the clinical spectrum of melioidosis and analyze predictors of mortality in a South Indian tertiary care hospital.
Methods
A retrospective study of 41 consecutive patients with culture-proven (blood or body fluid/pus) melioidosis admitted to a tertiary care hospital in South India over a period of five years (January 2004–December 2008) was conducted. A chart review including recording of demographic characteristics, clinical presentation, risk factors, laboratory findings and culture characteristics of patients was conducted. Analysis was done with SPSS (12) using chi-square test for categorical variables, paired t-test for continuous data and odds ratio for assessment of risk. Multivariate logistic regression analysis was done using death as the dependent variable and clinical parameters with P < 0.01 as the independent variables.
Results
A total of 41 patients with culture-proven melioidosis were included in the study. The mean patient age was 48.5 (12.7) years. Of the patients, 93% were males, 34% were farmers and 52% were from Northeast India. Mortality was 17% (7/41). Fever, chills and rigors, anorexia, weight loss and cough with mucoid expectoration were the primary symptoms. Of the patients, 79% had pre-existing diabetes, usually with poor glycaemic control (mean HbA1c 9.86 [2.7]). Patients who died had a longer history of detected diabetes (7.35 [7.64] years) compared with those that survived (3.01 [3.2] years) (P = 0.232). On univariate analysis the presence of chills and rigors (P = 0.007), altered sensorium (P = 0.001), chronic alcohol consumption (P = 0.027) and chronic liver disease (P = 0.018) were associated with increased mortality (Table 1).
Profile of patients with melioidosis – clinical and laboratory parameters
*Alcohol consumer – daily consumption of alcohol >10 years, >80 ml hard liquor
†CLD – Chronic liver disease
‡AST - Serum aspartate transaminase (normal range 8–40 U/L)
§ALT - Serum alanine transaminase (normal range 5–35 U/L)
**ALP – Serum alkaline phosphatase (normal range 40–125 U/L)
Tachypnea, fever and tachycardia were the predominant clinical signs. Tachycardia (P = 0.004), hepatomegaly (P < 0.001), hypoxia (P < 0.001), altered sensorium (P < 0.001) and neck stiffness (P = 0.018) were associated with increased mortality. Leucocytosis, hypoalbuminaemia, mild hepatitis (elevated serum aspartate [AST] and alanine transaminase [ALT]) and an elevated alkaline phosphatase were laboratory characteristics of this cohort of patients. The presence of hypoalbuminemia (P = 0.008) and elevated serum AST (P = 0.001) at admission were associated with increased mortality on univariate analysis. A clinical diagnosis of tuberculosis was made in 37% (15/41) of the patients on admission and 29% (12/41) had received prior anti-tuberculous therapy (ATT). The mean duration of symptoms at presentation in this study was 94.6 (140.6) days, suggesting an essentially sub-acute to chronic presentation.
Of the patients, 66% had multifocal disease (defined as patients with two or more organs involved or one organ plus a positive blood culture) (Table 2). Pulmonary melioidosis was the most frequent organ system involved (61%). Blood cultures were positive in 54%. Patients with single-organ disease defervesced faster (1.7 [1.9] days vs. 7.6 [8.2] days) compared to multifocal disease after initiating appropriate therapy. On antimicrobial susceptibility testing (39 patient cultures), bacteria were universally susceptible to ceftazidime and carbapenams, but resistant to aminoglycosides (100%), ciprofloxacin (83%) and piperacillin-tazobactam (5.2% [1/19]).
Organ involvement in melioidosis (mutually inclusive – a single patient may have multiple organ involvement)
*Multifocal defined as being blood + one other organ involvement OR two or more sites involved
†Include one parotid abscess, one necrotizing lymph node, one surgical postoperative wound pus swab
Patients who died were all diabetics with multifocal and septicaemic forms of melioidosis. They had a more rapid course in terms of duration of symptoms (57.1 [54.3] days vs. 102.3 [151.8] days) and hospital stay (6 [9.8] days vs. 17.9 [9.9] days) compared to survivors. The presence of hypoxia (adjusted OR = 25.43 [95% CI = 1.41–458.75]) and altered sensorium (adjusted OR = 19.94 [95% CI = 1.29–307.79]) at admission were independently associated with increased risk of death on multivariate analysis.
Discussion
This study highlights a male preponderance with the disease being common in professions in which there is exposure to wet soil and ground water like farming. In endemic regions, risk factors for melioidosis in published studies include immune-suppressed states like diabetes mellitus, drugs, steroid use and haematological malignancies, excess alcohol use and chronic liver disease, renal failure and chronic respiratory disease. 7 Diabetes was the principal risk factor for melioidosis in this study.
Pulmonary melioidosis is the commonest form of the disease across countries. 2,8,9 This trend was reflected in this study where along with fever, the common associated symptom was that of productive cough, with these patients being diagnosed with pulmonary melioidosis on investigation. However, 84% (21/25) of patients with pulmonary melioidosis had involvement of other organs – usually focal suppurative lesions. The sub-acute and chronic forms of the disease would allow the clinician to pursue adequately the diagnosis of melioidosis in the appropriate clinical setting through investigations carried out at equipped laboratories.
On univariate analysis the presence of chills, chronic alcohol consumption, underlying chronic liver disease, tachycardia, hepatomegaly, hypoxia, altered sensorium, hypoalbuminaemia and elevated serum AST were associated with increased mortality. On multivariate analysis, hypoxia and altered sensorium were independently associated with mortality. Similar trends have been observed along with high APACHE II scores and elevated concentrations of IL-6 and IL-10 to be predictors of mortality. 10
With over 30 million diabetics, and its geographic location, tropical climate and large agricultural population, India would be the ideal milieu for endemic melioidosis. The primary concern about melioidosis in developing countries is the similarity of its clinical presentation to tuberculosis – pulmonary or disseminated. Of the patients, 29% had received empirical ATT in this study. This highlights the possibility of misplaced diagnosis and treatment if clinicians are not alert to melioidosis as a clinical entity.