|Year : 2017 | Volume
| Issue : 4 | Page : 593-596
Melioidosis: Reinfection going incognito as relapse
Isra Halim, Tushar Shaw, Chaitanya Tellapragada, KE Vandana, Chiranjay Mukhopadhyay
Department of Microbiology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India
|Date of Web Publication||1-Feb-2018|
Dr. Chiranjay Mukhopadhyay
Department of Microbiology, Kasturba Medical College, Manipal - 576 104, Karnataka
Source of Support: None, Conflict of Interest: None
Melioidosis has recently gained importance as an emerging disease in India. Recurrent melioidosis has been reported from different parts of the world and can be due to relapse or reinfection. Distinction between relapse and reinfection is important for epidemiology, investigation and management. Here, we present the data regarding rate of recurrence and utility of multilocus sequence typing (MLST) in differentiating relapse form reinfection amongst melioidosis patients from a tertiary care hospital in South India. Amongst the 31 patients who survived and underwent follow-up, 4 (13%) presented with recurrence. Three cases (75%) were identified as reinfection and one (25%) as relapse based on MLST. Re-exposure to environmental Burkholderia pseudomallei amongst patients with melioidosis in endemic areas is likely. In such a scenario, more often than not, recurrence of melioidosis can be attributed to reinfection.
Keywords: Burkholderia pseudomallei, melioidosis, multilocus sequence typing, recurrence
|How to cite this article:|
Halim I, Shaw T, Tellapragada C, Vandana K E, Mukhopadhyay C. Melioidosis: Reinfection going incognito as relapse. Indian J Med Microbiol 2017;35:593-6
|How to cite this URL:|
Halim I, Shaw T, Tellapragada C, Vandana K E, Mukhopadhyay C. Melioidosis: Reinfection going incognito as relapse. Indian J Med Microbiol [serial online] 2017 [cited 2019 Aug 22];35:593-6. Available from: http://www.ijmm.org/text.asp?2017/35/4/593/224420
| ~ Introduction|| |
Melioidosis caused by the aerobic Gram-negative bacilli Burkholderia pseudomallei has been the implicated pathogen in myriad clinical presentations from local deep organ abscesses and pulmonary manifestations to more fulminant neurological or septicaemic disease. Treatment of the disease is striving, and despite the prolonged antibiotic therapy, recurrence of the disease has been often reported in endemic regions., The past decade has increasingly recognised most of the Indian subcontinent to be endemic for melioidosis. Patients diagnosed with melioidosis belong to a cohort susceptible to repeated infection. Recurrence can occur due to relapse from the same isolate or due to reinfection by a new strain. Distinction between relapse and reinfection is important for broadening our understanding regarding the epidemiology and management of the disease. Relapses have frequently been reported in literature, often conscripted as the most common complication amongst patients with melioidosis. Reinfections with different strains, however, are more often the exception than the norm, more so within a very brief time interval. It is a high hope to diagnose a case of reinfection from the Indian subcontinent, where the disease is still unheard of, amongst most of the treating physicians and microbiologists. Re-exposure to environmental B. pseudomallei in endemic areas is likely. More often than not, these repeated melioidosis events could be reinfections and should be meticulously investigated before dismissing them as recurrences. The aim of the present study was to identify the cases of recurrent melioidosis and to distinguish reinfection from relapse based on multilocus sequence typing (MLST).
| ~ Materials and Methods|| |
The study population comprised patients diagnosed with melioidosis at a tertiary care teaching hospital in South India during a period of 2 years (January 2013–December 2014). Microbiological culture of the relevant clinical specimens based on the presenting illness was used as the diagnostic modality for melioidosis in the present study. The study protocol was approved by the Institutional Ethical Committee, and an informed written consent was obtained from all the study participants during recruitment. Data regarding the predisposing factors such as diabetes mellitus, chronic renal failure, thalassemia, connective tissue disease requiring steroid therapy or other immunosuppressive treatment, alcoholism, chronic liver disease, malignancy and traumatic injury of the study participants were recorded using a structured questionnaire. Once recruited, the study participants were followed up initially until the completion of their course of oral antibiotic therapy. Further, each patient was reviewed by the end of every 3 months for 1 year. Commonly employed antibiotics included meropenem or ceftazidime as intensive treatment for 2 weeks followed by cotrimoxazole or doxycycline for 12 weeks as eradication therapy (http://www.cdc.gov/melioidosis/treatment).
During the follow-up visits, patients were examined thoroughly for clinical and microbiological cure of the disease. Recurrent disease was defined as clinical features of melioidosis in association with one or more cultures positive for B. pseudomallei in a patient with a history of one or more previous episodes. Amongst patients with recurrence of clinical signs and/or symptoms of the melioidosis, relevant clinical specimens were subjected to microbiological culture and polymerase chain reaction (PCR) targeting the TTS1 gene specific for B. pseudomallei as described previously. This included patients who had recurrent symptoms after completing treatment, together with patients who were undergoing oral therapy. Paired isolates (from initial and recurrence) obtained from patients with recurrent melioidosis were subjected to MLST as described previously. Alleles at each of the seven loci were assigned, and the allelic profile was used to define the sequence type (ST) using the B. pseudomallei MLST website (http://pubmlst.org/bpseudomallei/). Further, minimum inhibitory concentrations for ceftazidime, meropenem, doxycycline and cotrimoxazole amongst the paired isolates were tested as per the CLSI guidelines (M45-A2). Isolates from the same patient with different ST were defined as reinfection while those with similar ST were categorised as relapse.
| ~ Results|| |
Thirty-eight patients with microbiological culture-confirmed melioidosis were recruited during the study duration. The mean age of study population was 52.73 ± 14.31 years. Majority of them were males (n = 30, 78.9%). Eight (21%) of the study population were agriculturists by profession. Twenty-seven (71%) patients were diabetic and 7 (18.4%) of them had chronic kidney disease. Of the 38 patients, 20 (52.6%) presented with systemic form (bacteraemia) of the disease followed by localised and pulmonary forms in 13 (35.1%) and 4 (10.8%) patients, respectively. Detailed description of baseline demographics, clinical signs and symptoms, comorbidities, course of treatment and the clinical outcomes amongst the study population is enlisted in [Table 1].
|Table 1: Detailed description of cases diagnosed with melioidosis from January 2013 to December 2014|
Click here to view
Amongst 37 cases, 30 (81%) received the complete course of pathogen-specific antibiotic therapy, 4 (10.8%) were discharged against medical advice before the initiation of specific antibiotic therapy and 3 (8.1%) patients expired before the diagnosis was made. Amongst the 30 patients who received complete antimicrobial therapy, ceftazidime (n = 15, 50%) followed by meropenem (n = 13, 43.3%) was commonly used for the initial intensive phase therapy and cotrimoxazole (n = 14, 46.6%) followed by amoxicillin-clavulanic acid (n = 10, 33.3%) for eradication-phase therapy. Amongst the 30 patients with follow-up data available, 5 (16.6%) patients presented with clinical signs and symptoms suggestive of recurrent melioidosis. However, microbiological culture positivity of B. pseudomallei which is confirmatory for the diagnosis of recurrent melioidosis was observed amongst 3 (10%) patients and the other 2 patients were negative for B. pseudomallei both by culture and PCR. At all instances, throat swab and urine samples were collected and confirmed by B. pseudomallei specific culture and PCR. Based on the MLST, two of the three patients were found to be infected with new ST during the recurrence of the disease, suggesting a reinfection. Details regarding the clinical features, treatment and STs amongst patients with recurrent melioidosis are mentioned in [Table 2].
| ~ Discussion|| |
Recurrence of symptoms after effective treatment of melioidosis is a vexing clinical problem. Relapse with the same strain and reinfection with a new strain have both been documented with recurrent form of the disease. Understanding the cause of recurrence is vital for clinical management. In such cases, molecular typing technique such as MLST can act as an important tool to differentiate between relapse and reinfection. Based on the comparison of the seven housekeeping genes, consecutive isolates can be designated as similar or different strains. However, because of high rates of homologous recombination in B. pseudomallei, MLST might be a less reliable option to establish a genotypic relationship amongst its STs. The possibility of a mutation in one or few housekeeping genes, although remote, would be sequenced to generate a novel ST. Thus, what might have actually been a case of relapse with B. pseudomallei may be misinterpreted as a reinfection. Conversely, it could also be possible that a patient has been reinfected with a B. pseudomallei strain with ST identical to that of the primary isolate; in such instances, this might erroneously be labelled as relapse. In such a scenario, more advanced technology such as whole genome sequencing might be required.
Appropriate antibiotic therapy is an established factor in determining disease outcome of melioidosis. Besides administration of inappropriate initial intensive treatment, relapses have also been attributed to poor compliance during the eradication phase of therapy. The use of amoxicillin-clavulanic acid monotherapy for eradication has been attributed to higher incidence of relapse. In the present study, 33% (n = 10) cases received amoxicillin-clavulanic acid as oral regimens, but relapse was witnessed amongst none of the cases.
On the contrary, reinfection necessitates aggressive prevention strategies amongst cases. Reinfection could indicate an exposure to a new strain from the environment which could be attributed to higher burden of the pathogen in the environs of the individuals affected. Unrecognised host factors could also be contributory to reinfection with B. pseudomallei.
A few instances were individual infection seem to have occurred due to concurrent infection from different B. pseudomallei strains at different sites. The occurrence of a new strain from the same individual might attribute to the presence of different strains in the ecosystem. Hence, an individual might get infected with more than one strain in the initial episode and what might look like reinfection could be relapse.
One of the limitations of this study was access to small population of cases diagnosed with melioidosis for follow-up. Despite this, our results show considerable concordance to rates of recurrence reported earlier from other parts of the world., In our study population, we did not witness a major change in the antibiogram between the isolates obtained at two different instances. This suggests that antibiogram may not be conclusive in distinguishing isolates from relapse or reinfection. This study defines the role of molecular typing which can be an important tool in differentiating cases of relapse from reinfection. From a clinical standpoint, this study emphasises not only the importance of maintaining a high index of suspicion of recurrence amongst melioidosis patients presenting repeatedly with similar symptoms but also the significance of regular comprehensive follow-up of these patients, even months after completing the eradication therapy.
Financial support and sponsorship
This study was supported by project grant no. 5/3/3/16/2012-ECD-I from the Indian Council of Medical Research, New Delhi, India.
Conflicts of interest
There are no conflicts of interest.
| ~ References|| |
Chaowagul W, Suputtamongkol Y, Dance DA, Rajchanuvong A, Pattara-arechachai J, White NJ, et al.
Relapse in melioidosis: Incidence and risk factors. J Infect Dis 1993;168:1181-5.
Currie BJ, Fisher DA, Anstey NM, Jacups SP. Melioidosis: Acute and chronic disease, relapse and re-activation. Trans R Soc Trop Med Hyg 2000;94:301-4.
Limmathurotsakul D, Chaowagul W, Chantratita N, Wuthiekanun V, Biaklang M, Tumapa S, et al.
A simple scoring system to differentiate between relapse and re-infection in patients with recurrent melioidosis. PLoS Negl Trop Dis 2008;2:e327.
Pitt TL, Trakulsomboon S, Dance DA. Recurrent melioidosis: Possible role of infection with multiple strains of Burkholderia pseudomallei
. J Clin Microbiol 2007;45:680-1.
Winstanley C, Hart CA. Presence of type III secretion genes in Burkholderia pseudomallei
correlates with Ara(-) phenotypes. J Clin Microbiol 2000;38:883-5.
Maharjan B, Chantratita N, Vesaratchavest M, Cheng A, Wuthiekanun V, Chierakul W, et al.
Recurrent melioidosis in patients in northeast Thailand is frequently due to reinfection rather than relapse. J Clin Microbiol 2005;43:6032-4.
Godoy D, Randle G, Simpson AJ, Aanensen DM, Pitt TL, Kinoshita R, et al.
Multilocus sequence typing and evolutionary relationships among the causative agents of melioidosis and glanders, Burkholderia pseudomallei
and Burkholderia mallei
. J Clin Microbiol 2003;41:2068-79.
Limmathurotsakul D, Chaowagul W, Chierakul W, Stepniewska K, Maharjan B, Wuthiekanun V, et al.
Risk factors for recurrent melioidosis in Northeast Thailand. Clin Infect Dis 2006;43:979-86.
Chia-Lin C, Yu-Mei L, Jung-Jung M. Recurrent melioidosis in Taiwan, 2004-2012. Epidemiol Bull 2014;30:156.
[Table 1], [Table 2]