Acute, Chronic, and Latent Infection with (Re)Activation Melioidosis



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Submitted Sep 18, 2023
Published Oct 25, 2023
10.24018/clinicmed.2023.4.5.316

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Melioidosis can present as an acute as well as chronic disease and can be fatal. Type 2 diabetes mellitus is one of the most common risk factors for acquiring this infectious disease.We present a case of a 36-year-old diabetic male patient who presented in March 2022 with acute severe melioidosis and later developed chronic melioidosis. He did not take complete treatment and presented again in January 2023 with features of Latent infection with reactivation. The blood and pus culture showed positive results for Burkholderia pseudomallei (B. pseudomallei). The use of granulocyte colony-stimulating Factor (G-CSF) in addition to antimicrobial treatment with meropenem and later ceftazidime therapy played an effective role in the recovery of the patient. In this case report we present the acute and chronic manifestations with which he reported along with management of the case, review the literature on the impaired immunity in type 2 diabetic patient in melioidosis, latent infection with (re)activation, the suggested role of G-CSF and antimicrobial therapy.

Keywords: Eradication Phase Intensive Phase Latent Infection Osteomyelitis

Introduction

Melioidosis is an infection caused by the intracellular, gram-negative saprophyte Burkholderia pseudomallei. It is endemic in South Asia including India, Southeast Asia, China, Northeast Thailand, and North Australia [1], [2]. It is transmitted mainly through percutaneous exposure to contaminated water or wet-season soils. Inhalation and ingestion are other potential routes. Person-to-person transmission is highly atypical. It can present as an acute infection, chronic infection, or latent infection with reactivation [3]. Most infections are asymptomatic or subclinical [4]. Symptomatic infections usually present as acute infections with significant morbidity. Patients with certain co-morbidities (Diabetes Mellitus, hazardous Alcohol use, and chronic pulmonary-renal disease) present with severe clinical disease in adults. Pneumonia is the most common presentation and is seen in acute as well as chronic infections [3], [5]. Other common presentation includes skin infections (ulcers, abscesses, macular lesions), Genito-urinary infections (prostatic abscesses), bacteraemia (almost 50% cases) and septic shock (up to 25% cases) [3], [6], [7]. Less commonly bone and joint infection, abscesses in viscera, and neurologic infection can occur secondary to bacteraemia [8]–[13]. Persistent infection after appropriate and adequate treatment is unlikely but has been described [14], [15]. We present a case of melioidosis who presented with acute melioidosis, later developed chronic melioidosis, and then was lost to follow-up. He again presented after 10 months with reactivation of latent infection. The presentation, diagnosis, and management of the case are discussed with a review of the literature.

Case Presentation

A 36 years male patient with, a known case of uncontrolled type 2 diabetes mellitus did a long walk of almost 30 km barefoot on 14.03.2022 (Govardhan parikrama) followed by swelling and pain in the left knee which increased over the next few days to involve the whole left lower limb. A week later he developed a high-grade fever with chills, dry cough, and breathlessness (functional class 3). He took local consults and his left lower limb was placed in Thomas splint. He attended Fortis Escorts Hospital, Jaipur (India) on 25.03.2022 with marked dyspnoea and oxygen saturation (Spo2) of 68% on ambient air. He was evaluated in triage. His arterial blood gas (ABG) showed acute respiratory alkalosis, concomitant metabolic alkalosis, and severe hypoxemia and it was consistent with type 1 respiratory failure. His blood pressure was 150/82 mm Hg, pulse rate 118/minute, Respiratory rate 30/minute, temperature 99°F, and GCS E4V5M6. On clinical examination, he had swelling from thigh to feet in the left leg, tenderness over calves, swelling over left knee joint, mild hepatosplenomegaly, bilateral decreased air entry over lung bases, bilateral crept over infra scapular, scapular, and infra-axillary lung regions. His random blood glucose was 214 mg/dl and his blood ketones were positive (0.9 mmol/L). He was admitted to the medical intensive care unit (MICU) for management. His relevant haematology and biochemistry are mentioned in Table I. Non-contrast computed tomography (NCCT) chest shows bilateral pleural effusion (Left > Right), extensive interstitial and alveolar edema, multifocal consolidation, and mildly prominent main pulmonary artery (MPA) (Fig. 1). Computed tomography pulmonary angiogram (CTPA) done on 25.03.2022 shows pulmonary thromboembolism (PTE) involving segmental and subsegmental branches of the right descending interlobar artery and right upper lobar artery. it also shows prominent MPA with MPA/Aorta ratio >1 suggestive of pulmonary hypertension (PHT) (Fig. 2). He was managed with Intravenous (IV) human insulin, IV heparin as per protocol, antimicrobials, non-invasive ventilation, and supportive management. Venous peripheral color doppler of lower limbs did not show any evidence of venous thrombosis. Ultrasound examination of the left knee shows significant left knee joint/suprapatellar bursa effusion with fine internal echoes. Left knee joint aspiration was done on 26.03.2022. It was purulent and sent for cultures and routine tests.

Tests 25.03.22 27.03.22 31/03/22 02.04.22 07.02.22
ESR (<20 mm 1st hour) 30 85 110
CRP (0–5 mg/L) 317.7 242.3 74.8
D-Dimer (<500 mcg/ml) 2160 2320
Ferritin (13–150 ng/ml) 969
Creatinine (0.5–0.9 mg/dl) 0.61 0.66 0.57 0.65 0.76
Hb (14–18 gm/dl) 11.0 10.6 10.1 11.7 10.4
TLC (4–11 × 103/uL) 7.4 6.3 6.6 10.7 8.3
DLC (%) N84L12 N76L19 N66L28 N77L18 N71L24
Platelets (103/uL) 241 233 442 631 576
AST/ALT (<32 U/L) 40/41 59/112
Protein/Albumin (6.4–8.3 gm/dl) 6.0/3.6
Procalcitonin (Normal <0.046 ng/ml) 0.17
NT-proBNP (<125 pg/ml) 2893 288
HbA1c (Non-diabetic<6%) 11.9
Table I. Haematology and Biochemistry (First Admission 25.03.2022 to 08.04.2022)

Fig. 1. NCCT chest 25.03.2022 showing multilobar bilateral pneumonia with mild bilateral pleural effusion.

Fig. 2. CTPA 25.03.2022 showing right side pulmonary vein embolism.

On 27.03.2022 his paired blood cultures were reported growing gram-negative bacilli (GNB) and on 28.03.2022 pus culture also grew GNB. Antibiotics were escalated including meropenem, vancomycin, and polymyxin-b. Left knee joint lavage was done on 28.03.2022. On 29.03.2022 GNB was reported as Burkholderia pseudomallei and antibiotics were accordingly changed to meropenem and trimethoprim-sulfamethoxazole (TMP-SMX) in adequate dosages (Fig. 3). The duration of intensive antibiotic therapy was planned for 8 weeks in view of extensive pulmonary disease and septic arthritis. However, he was discharged after 15 days. A repeat NCCT chest done on 06.04.22 showed consolidation involving lateral basal and posterior basal segments of the right lower lobe, consistent with infective aetiology. As compared to the previous scan dated 25.03.2022, significant resolution in the number and sizes of consolidations was noted with near resolution of bilateral pleural effusions. He returned after 1½ months with a persistent cough, swelling in his left knee with difficulty in walking. He did not complete the intensive antibiotic phase and was only taking TMP-SMX. He had now developed chronic melioidosis symptoms. However, he did not follow the advice and was lost to follow-up.

Fig. 3. Colony morphology of B. pseudomallei on MacConkey agar isolated from the patient—dry, wrinkled, round, whitish, shiny with metallic sheen colonies.

He again attended triage on 27.12.2022 with complaints of pain, swelling, and stiffness in the right knee of 10 days duration. He was referred to orthopedic surgeon this time by the triage and admitted for management. He was admitted in the Department of Orthopaedics and was managed conservatively. Contrast enhanced magnetic resonance imaging (CEMRI) of the right knee was done and it showed mild marrow edema, partial anterior cruciate ligament tear, and mild subcutaneous edema along the medial aspect of the right knee joint. He was discharged on 30.12.2022 on supportive treatment.

He again attended triage on 19.01.2023 with Complaints of inability to walk, polyarthralgia, nausea, vomiting, marked weakness, fever for about a week with chills, and not being able to eat anything for the last 7–8 days. On examination his vitals were as follows: Pulse rate 118/minute, regular; blood pressure 144/82 mm Hg, respiratory rate 22/minute, afebrile and SpO2 100% on air. His random blood glucose was 282 mg/dl and blood ketones were 0.3 mmol/L. He was unable to walk and bear weight on his right leg. He had right upper calf swelling below the popliteal fossa ?abscess and multiple tender swollen joints (bilateral shoulder, elbow, wrist, metacarpal-phalangeal, knee, ankle, and talar and subtalar joints), bilateral mild pedal edema up to lower 1/3rd of legs and scattered bilateral crept over subscapular and scapular areas. He was admitted for further management and all relevant investigations were done. Venous doppler of both lower limbs did not show any evidence of deep venous thrombosis. Ultrasonography of right calves showed a collection of app. 86 × 59 × 51 mm with internal echoes in superficial muscle plain in the right posterolateral aspect of the upper leg, extending towards the popliteal fossa with moderate subcutaneous edema in the overlying calf region. Around 25 ml fluid (pus) was aspirated and it was sent for fluid analysis and cultures. MRI knee could not be done due to marked pain and inability to extend knee. Hematology and biochemistry are mentioned in Table II.

Tests 19.01.23 21.01.23 25.01.23 28.01.23 03.02.23 10.02.23 15.02.23
ESR (<20 mm 1st hour) 110 120 105 130
CRP (0–5 mg/L) 294.8 188.6 170.7
D-Dimer (<500 mcg/ml) 2230 7750 7490 7860 6940
Ferritin (13–150 ng/ml) 3129 2870
Creatinine (0.5–0.9 mg/dl) 0.66 0.64 0.64 0.53
Hb (gm/dl) 10.5 8.8 7.7 9.3 9.6 9.2 9.3
TLC (4–11 × 103/UL) 10.7 9.9 8.9 13 22 4.90 8.7
DLC P79L15 P79L16 P80L16 P77L10S10 P82L11S5 P55L39 P60L32
Platelets (103/UL) 306 246 243 304 464 323 303
AST/ALT (<32 U/L) 113/102 40/29 28/20
Serum Proteins/Albumin (6.4–8.3 gm/dl) 7.4/2.1
Procalcitonin (<0.046 ng/ml) 0.82
Table II. Hematology and Biochemistry (Third Admission 19.01.23 to 17.02.23)

Pus culture and paired blood cultures were reported growing gram-negative bacilli (GNB) on 20.01.2023 and identified as Burkholderia pseudomallei. A Fluorodeoxyglucose Positron emission tomography (FDG-PET) scan for deep-seated abscess and/or multiple-site osteomyelitis was done on 23.01.2023. It shows symmetric abnormal FDG uptake within the soft tissue of bilateral knee, ankle, and small joints of both feet, fluid pockets within the related intra-articular spaces, centrally necrotic hypodense collections within the proximal calf muscles on the right side (likely abscess of 70 × 100 mm size), numerous subcentimeter diameter soft tissue density nodular opacities within the peripheral lung fields on either side along with other features suggestive of chronic healed inflammatory etiology, hepatosplenomegaly, and bone marrow increased FDG uptake in the skeleton (Figs. 4, 5). The right calf abscess required incision and drainage and it was done under general anesthesia (GA) on 25.01.2023. 200 ml pus was drained. Underlying necrotizing myositis and fasciitis were noted and pus culture was sent. It grew Burkholderia pseudomallei. He was managed with IV fentanyl infusion for pain, meropenem (1 gram intravenously 8 hourly), TMP-SMX (320 mg of the trimethoprim component) IV twice daily, Granulocyte colony-stimulating factor (GCSF) 300 microgram subcutaneously daily and supportive treatment. His NCCT chest done on 29.01.2023 showed features suggestive of infective etiology. USG for local swelling over both ankles was done on 29.01.2023. It shows heteroechoic areas measuring 20 × 6 mm and 16 × 7 mm in the intramuscular plane on the medial aspect of the right foot evolving abscess. MRI was planned but could not be done due to severe pain and the patient not being able to keep his foot still for an MRI.

Fig. 4. FDG-PET scan dated 23.01.23 showing symmetric abnormal FDG uptake within the soft tissue of bilateral knee, ankle, and small joints of both feet, fluid pockets within the related intra-articular spaces and bone marrow increased FDG uptake in the skeleton (likely reactive).

Fig. 5. FDG-PET scan image dated 23.01.23 showing centrally necrotic hypodense collections within the proximal calf muscles on the right side (likely abscess of 70 × 100 mm size), subcentimeter diameter soft tissue density nodular opacities within the peripheral lung fields on either side and hepatosplenomegaly.

His blood culture sent on 27.01.2023 was again reported growing Burkholderia pseudomallei. Meropenem and TMP-SMX were continued and GCSF was given for a total of 10 days. NCCT chest done on 29.01.2023 shows bilateral mild pneumonitis and fibrotic bands in the right lower lobe-sequelae of old infection (Fig. 6). The blood culture sent on 02/02/2023 was sterile and meropenem was de-escalated to ceftazidime 2 gm intravenously every six hours in continuous infusion to complete the course of initial intensive therapy. He took LAMA (Left against medical advice) discharge on 17.02.2023 and was advised to continue Ceftazidime intravenously till 03.03.2023 to complete the intensive treatment. His payor Ex-Servicemen Contributory Health Scheme (ECHS) authorities were informed for close monitoring. TMP-SMX was converted to oral form. Blood cultures done on 07.02.2023 and 15.02.2023 were sterile. He was reviewed in the outpatient clinic on 20.04.2023. He was able to walk, had no pains over his joints, and was feeling better. He was advised to continue TMP-SMX (eradication phase of treatment) for a total duration of at least 6 months.

Fig. 6. Axial view of NCCT chest done on 29.02.23 showing bilateral pneumonitis and fibrotic band in the right lower lobe.

Discussion

Melioidosis is a clinically diverse disease and is endemic in certain parts of the world as mentioned earlier. However, it has been suggested that the disease is severely under-reported in up to 79 countries in which it is known to be endemic and probably endemic who have never reported the disease [16]. The disease mortality is reported to be 10%–50% [17]. With early recognition of the disease, diagnosis, treatment with ceftazidime and meropenem, improvement in intensive care, and follow-up to complete the intensive antibiotic therapy phase, the disease mortality has decreased considerably and can now be under 10%. Nevertheless, the mortality risk depends on the disease’s clinical syndrome. Bacteraemia, respiratory failure, and renal failure were identified as independent risk factors for mortality and treatment failure [18]. The most common comorbidities for severe or fatal Melioidosis are Diabetes mellitus, chronic respiratory or renal failure, and hazardous alcohol use. It is estimated that 46% of patients with melioidosis have diabetes and this highlights the interaction between the global diabetes epidemic and melioidosis in under-resourced tropical countries [19]. The relapse rate is estimated to be around 10% and is due to the Intracellular survival of the bacteria within macrophages which may progress to chronic infections [20]. The case discussed had exposure risk, and diabetes mellitus as comorbidity and had all presentations of the clinical spectrum (acute, chronic, and latent infection with reactivation) over a 10-month timeline.

In the index case discussed, he first presented on 25.03.2022 with high blood glucose, and ketoacidosis and was diagnosed with sub-massive right-side PTE. He had no evidence of underlying DVT or other risk factors for thrombosis. Diabetes mellitus with DKA is associated with a hypercoagulable hyperosmolar state and can present as PTE even without DVT or other risk factors [21]. He also had Gram negative bacteraemia which could also be a risk factor for septic thrombosis [22]. His paired blood cultures and fluid from the knee joint grew Burkholderia pseudomallei. He had disseminated infection with involvement of the respiratory system and septic arthritis. He was managed with intensive antibiotic therapy and a total of 8-week therapy was advised. However, he was discharged after 2 weeks and did not complete intensive antibiotic therapy. He returned after 1½ months with chronic symptoms but was again lost to follow-up. He did not take the eradication phase treatment.

Like tuberculosis, infection with B. pseudomallei can uncommonly be latent and activate subsequently. It can have prolonged latency and is difficult to diagnose. The longest reported latent period between exposure in an endemic region and the development of melioidosis in a nonendemic region is 29 years [23], [24]. The index case attended triage on 27.12.2022 with pain, swelling, and stiffness in the right knee. CEMR of the right knee shows some subcutaneous edema along the medial aspect of the knee joint. Since it also shows a partial thickness tear of the posterolateral bundle of the anterior cruciate ligament, he was discharged on supportive treatment. Infection wasn’t suspected by the treating unit at this time. He returned 20 days later with similar complaints, multiple joint pains, fever, chills, and swelling below the right knee joint medially. Investigations show bacteraemia with Burkholderia pseudomallei, right upper calves muscle abscess, bone and joint involvement at multiple sites and active infection with chronic healed inflammatory lesions in bilateral lungs.

Pneumonia, skin infection, genitourinary, and bacteraemia are the commonest clinical presentations. Less common sites of infection include bone and joint involvement, neurologic involvement, parenchymal abscesses, and parotitis. Rare sites of infection reported in the literature include mycotic aneurysms, mediastinal masses, pericardial collections, and adrenal abscesses [8], [9], [25]. Our patient besides having bronchopneumonia, bacteraemia, and skin manifestations (intra-muscular collection) also had fewer common manifestations including multiple sites of septic arthritis and osteomyelitis. This can occur as a secondary manifestation in cases that initially presented with a different site of involvement (e.g., pneumonia) as in this case [8], [25]. The lower limbs are the most commonly affected site as in this case. Nonetheless, cases have been described with the involvement of upper limbs, vertebrae, and pelvis as well [26]. Growth of B. pseudomallei from culture of any site is diagnostic of melioidosis. In our case the paired blood cultures and pus culture were positive.

Burkholderia pseudomallei is intrinsically resistant to penicillin, ampicillin, first- and second-generation cephalosporins, gentamicin, tobramycin and streptomycin. Quinolones generally show resistance or intermediate results [27], [28]. The main therapeutic options for melioidosis include beta-lactams (e.g., ceftazidime, certain beta-lactam-beta-lactamase inhibitor combinations), carbapenems, trimethoprim-sulfamethoxazole (TMP-SMX), and doxycycline, depending on the phase of treatment i.e., initial intensive phase followed by eradication phase. For patients with non-pulmonary focal sites of infection, such as neurologic, prostatic, bone, joint, cutaneous, and soft tissue melioidosis, the addition of TMP-SMX to ceftazidime or a carbapenem during initial intensive therapy is suggested. Initial intensive IV antibiotic therapy is given for at least 14 days. However, longer durations of at least four to eight weeks are justified in certain cases, such as patients who have prolonged critical illness, extensive pulmonary disease, deep-seated collections or organ abscesses, osteomyelitis, septic arthritis, or neurologic melioidosis. Additional management components include abscess drainage, recombinant G-CSF for patients with severe sepsis/shock, and supportive care as was done in this case. Subsequent eradication phase begins immediately on completion of the intensive antimicrobial phase to prevent relapse of melioidosis. The case discussed did not took eradication phase treatment in the initial presentation and presented later with a relapse of Melioidosis. Per oral (PO) TMP-SMX alone is suggested for eradication therapy. Doxycycline is an alternative agent when TMP-SMX cannot be used because of intolerance or toxicity. However, it is less effective than TMP-SMX. The optimal duration of eradication therapy is unknown. A minimum of three months is warranted. For patients with osteomyelitis or neurologic melioidosis, the duration is extended to six months. Even longer durations, and potentially lifelong therapy, may be necessary following vascular surgery with grafts for mycotic aneurysms. The patient had been instructed to take eradication phase treatment for 6 months and remain in close follow-up.

Diabetes mellitus has been the most common comorbidity in melioidosis patients. Immunity, neutrophilic functions, and inflammatory responses are said to be altered or defective in Diabetes mellitus [29]–[31]. Defective neutrophilic function (s) may trigger a disoriented compensatory inflammatory response in diabetic patients infected by B. pseudomallei regardless of the bacterial load [31]. Good glycaemic control is shown to regulate this inflammatory response [31]. In the present case, the patient had poorly controlled diabetes due to his poor compliance with medication. This increased his susceptibility to acquiring the melioidosis infection and the subsequent complications. The above findings in concern of host immunity have helped in conceptualizing the effective role of G-CSF in increasing survival and reducing the mortality of severe septic melioidosis [32], [33]. G-CSF exerts its immunity-boosting effect by stimulating the proliferation, differentiation, and defence function of PMNs [24], [31]. In other words, G-CSF ameliorates functional neutrophil defects seen in Melioidosis. A study in Australia indicated a 10% to 95% reduction in mortality rate in melioidosis patients treated with intravenous G-CSF (300 µg once daily for at least 10 days) compared to the non-treated group [32]. The case discussed was also given 300 ug G-CSF IV for 10 days along with good glycaemic control. Thus, it can be inferred that the extensive glycaemic control, G-CSF use, appropriate antimicrobial treatment, ICU, and supportive care in this patient have helped in his recovery. It also shows that reactivation/relapse of latent melioidosis is not uncommon and is particularly seen in those having underlying risk factors with a history of severe, multifocal, bacteraemic melioidosis and poor compliance for the eradication phase of treatment.

Take Home Message

  1. Melioidosis can present as acute, chronic, and latent infection with relapse/reactivation. Severe melioidosis with bacteraemia and multiorgan involvement can be fatal.
  2. Treatment of melioidosis consists of an intensive phase with parenteral antibiotics to prevent mortality from severe illness followed by an eradication phase with oral antibiotics to prevent relapse.
  3. The granulocyte stimulating factor (G-CSF) may play a substantial role in the management of sepsis and/or septic shock, secondary to severe melioidosis particularly for those with co-morbidity of diabetes mellitus.
  4. With antibiotic therapy and intensive care, the estimated overall mortality can be less than 10 percent.
  5. The main preventive strategy is avoiding exposure in endemic areas.

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