Melioidosis, A Deadly Forgotten Cause of Pyrexia of Unknown Origin in India

AUTHORS: 1. Dr. Arundhati Dileep, 2. Dr. Aneet Patel, 3. Dr. Pratibha Dileep, 4. Dr. Kushal Shah, 5. Dr. Chintan Dhebar, 6. Dr. Kapildev Thakkar

Introduction.

Melioidosis is an Infectious disease transmitted by Burkholderia pseudomallei, a Gram- negative obligatory aerobic, non-spore forming bacillus [1].

It is transmitted through abrasions in the skin and/or by direct inhalation [5]. Patients with diabetes mellitus, Cirrhosis, Chronic Kidney Disease, Alcoholism and having an immunocompromised state are more susceptible to the disease.

Most of India’s rural population are farmers working on agricultural land, and remains at high risk to be infected. Recent evidence has, reported an increase in the cases of melioidosis diagnosed from India, due to improved diagnostic techniques and PCR-based diagnostics [8] despite this it is still remains under reported in India because of: (i) Lack of awareness of disease, (ii) low index of suspicion, and (iii) under-recognition of disease [9, 10].

CASE REPORT:

A 33-year-old gentleman with a history of Diabetic Mellitus, a native of the state of Rajasthan, presented with the complaints of fever, headache and generalized weakness for past fourteen days. He was occasional drinker and had no history of tobacco use. He worked as a receptionist in a hotel and denied any recent travel. Review of systems was unremarkable, he denied nausea, vomiting, diarrhea, history of convulsions or loss of consciousness.

The patient initially received treatment at a primary care center, investigations revealed thrombocytopenia (Platelet Count : 28,000 Cells/cumm), transaminitis [AST: 322(IU/L), ALT: 183(IU/L)], elevated creatinine (1.73mg/dl), hyponatremia  upto 118 mEq/L and  elevated Serum Ammonia levels of (42 units ). He also had elevated blood sugars and acetone levels . Ultrasound Abdomen showed splenomegaly upto 14cm and hepatomegaly. CT chest showed tiny non-specific nodules scattered in bilateral lung parenchyma. Despite receiving adequate treatment his condition deteriorated.  He developed altered mental status and was transferred to quaternary care center for further management

Upon in the ED, he was found to be hemodynamically stable except he was febrile temperature was 101 F. Vitals: BP:118/90mmHg, Pulse:100B/min, Respiratory Rate, Spo2:98% on nasal O2 by 2 liters per min

On physical examination he was found to be a well-nourished, drowsy who was only responding to painful stimulus. Pertinent findings included nuchal rigidity and positive Babinski’s. Pupils were equally reacting to light and accommodation, the rest of the systemic examination was within normal limits.

The initial laboratory findings,

 Serology for HIV, HBsAg and HCV were negative. Serum  ammonia <9L. ABG was consistent with High anion gap metabolic acidosis with  respiratory alkalosis and hypoxia. COVID 19 RT PCR was negative

Ultrasound abdomen was suggestive of hepatomegaly and associated splenomegaly measuring upto 13.7cm with a few small hypo echoic infiltrations that measured 8x 8mm. Echocardiography was unremarkable.

CT Scan Brain  (Figure 1) and high-resolution CT of the Thorax (Figure 2) were  done.

Figure 1: The CT brain was suggestive of minimal prominence of subarachnoid space overlying the right cerebral hemisphere.

Patient  was admitted to the ICU for suspected DKA associated with meningitis. Septic workup including blood cultures, Fungal cultures and including COVID 19  swab was sent.  Lumbar puncture was done. Total count: 5 cells with a 100% lymphocytic predominance, CSF RBS: 208/ Matching RBS: , CSF Protein: 47, ADA:0.01 GeneXpert: Negative. Patient was started on broad spectrum antibiotics including Meropenem and doxycycline, Artesunate along with Insulin drip for DKA. EEG was recommended by the neurology team which was didn’t show any significant abnormalities.

Due to the refractory persistent high grade fever and not much clinical improvement tropical fear panel was sent antibodies to scrub Typhus (IGM) by Elisa and Widal tests by slide agglutination, Chikungunya and Dengue PCR, THPA -Treponema Pallidium Hemagluttination assay which all turned out to be negative.

Thirty hours post incubation blood cultures grew  GNB bacilli. On the third day inoculation it was identified as Bulkhoderia Psuedomallei which was sensitive to Meropenem (MIC: 2), Trimethoprim Sulfamethaoxazole (MIC<=20), Ceftazidime (MIC: 8), Minocycline (MIC: 2)

Patient was continued on Meropenem and started on Trimethoprim Sulfamethoxazole  and doxycycline was stopped. Later patient showed marked clinical improvement .

which later lead to clinical improvement with resolution of the altered mentation. A detailed history  was obtained from the patient to identify the source of his infection, he revealed that he had been swimming in a nearby well and had been walking barefoot to the location for the last 3 months. It was now assumed that the bacterial source would have been from the well and that there could have been a possibility of an abrasion on the foot which was could have been the port of entry for the bacteria.

Unfortunately the following day patient again became agitated and altered and developed  high grade fever.

MRI Brain with contrast was done which was suggestive of right sided fronto-parietal subdural predominantly CSF signal Intensity collection associated with reactive pachy meningeal thickening and enhancement. A mild local mass effect and a minimal midline shift of approx. 3.5mm to the left side. (Figure 3)

Neurosurgery was consulted they recommended conservative management with no acute surgical intervention at this point unless there is further deterioration. Infectious Diseases was consulted who recommended repeat fungal and blood cultures and patient was initiated on Amphotericin B .Repeat blood cultures grew Burkholderia Cepacia, which was sensitive to both Meropenem (MIC: 2), Trimethoprim Sulfamethoxazole ( MIC<=20).

Despite being on antibiotic and antifungal regimen patient continued remaining febrile. However 12 days after admission and there was improvement in the mental status and he was transferred to the medical floor and later discharged on day 17. He was treated for a total of 3 weeks of meropenem and was continued on doxycycline and Trimethoprim Sulfamethoxazole for another three months.

Figure 2: The HRCT thorax was done and was suggestive of bilateral minimal pleural effusion R>L, and marked diffuse smooth interlobar and interlobular septal thickening with diffuse ground glass haziness present and cavitatory consolidation on left side.

Discussion:

Melioidosis is caused by soil and water bacterium pseudoalkaloid that lives in tropical regions. It remains an elusive bacterium that is thriving within the Asian subcontinent for decades. High risk patients include, Diabetics and alcoholic, other risk factor include patients who have undergone splenectomy, who have aplastic anaemia, cystic fibrosis, Glucose six phosphate deficiency and systemic lupus erythromatosus [11]. Numerous Literature have reported high rate of relapses in B. Pseudomallei Infection. [12]. It has been found that relapses should be treated as a first episode [13]

Pseudomallei can enter the skin through skin abrasions, but can also be transmitted by ingestion or inhalation. It usually acts as an opportunistic pathogen causing disease in people with either DM or on immunosuppressant’s, Tuberculosis, cirrhosis, alcoholism or renal failure.

B. Mallei and Pseudomallei both can cause diseases in humans and animals and are inherently resistant to many antibiotics. However, it has been seen that B. Mallei is unable to survive outside mammalian body whereas B. Pseudomallei has been found to survive in the environment.

Interestingly, HIV infection doesn’t increase the risk for melioidosis, hence it can be assumed that innate immunity is responsible for clearing B. Pseudomallei infection [14]

The clinical spectrum of the disease can range from asymptomatic to fulminant multiorgan involvement it has a potential to remain latent for years, and then reactivate at a later stage in life.

Like many other saprophytic, these organisms are very hard to kill, and can survive in many adverse situations they are resistant to complement and lysosomal defensins. B Pseudomallei produced a glycocalyx capsule. An important virulence determinant it forms a slime and prevents antibiotic,

It is commonly seen in rice farmers. It is a dangerous organism and, in the lab, it is

References:

1. Punyagupta S. Melioidosis: A great imitator. Ramathibodi Med J 1983;6:147-53.

2. 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;47:262-7

3. Stanton AT, Fletcher W. Melioidosis, a new disease of the tropics. Trans Fourth Congr Far East Assoc Trop Med 1921; 2: 196–198.

4. Burkholder W. Sour skin, a bacterial rot of onion bulbs. Phytopathology 1950; 40: 115–118.

5. Leelarasamee A, Bovornkitti S. Melioidosis: Review and update. Rev Infect Dis 1989;11:413-25.

6. Chaowagul W, White NJ, Dance DA, Wattanagoon Y, Naigowit P, Davis TM, et al. Melioidosis: A major cause of community-acquired septicemia in Northeastern Thailand. J Infect Dis 1989;159:890-9.

7.  Currie BJ, Fisher DA, Howard DM, Burrow JN, Lo D, Selva- Nayagam S, et al. Endemic melioidosis in tropical northern Australia: A 10-year prospective study and review of the literature. Clin Infect Dis 2000;31:981-6.

8. Cousins S. India is at high risk from surge in cases of melioidosis, warn researchers. BMJ 2016;352:i275.

9. John TJ. Melioidosis, the mimicker of maladies. Indian J Med Res 2004;119:6-8.

10. Jesudason MV, Shanthakumari R, John TJ. Burkholderia pseudomallei-an emerging pathogen in India. Indian J Med Microbiol 1997;15:1-2.

11. Cheng AC, Currie BJ. Melioidosis: Epidemiology, pathophysiology, and management. Clin Microbiol Rev 2005;18:383-416.

12. 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.

13. 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.

14. Mitali Sarkar-Tyson, Richard W. Titball, Chapter 43 - Burkholderia mallei and Burkholderia pseudomallei, Editor(s): Alan D.T. Barrett, Lawrence R. Stanberry, Vaccines for Biodefense and Emerging and Neglected Diseases,Academic Press, 2009, Pages 831-843, ISBN 9780123694089.

15. Nicholas J White, 71 - Melioidosis and Glanders, Editor(s): Alan J. Magill, David R Hill, Tom Solomon, Edward T Ryan, Hunter's Tropical Medicine and Emerging Infectious Disease (Ninth Edition), W.B. Saunders, 2013, Pages 580-583, ISBN 9781416043904,