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1. Patient Profile A.N is a 2Y 5M Malay Boy 2nd MCDA Twin Weight 11kg (5th centile) Height 88cm (25th centile) DOA : 19-12-2023 DOD : 18-1-2023

2. Issues Previously well child who presented with non-resolving CAP, referred from GP for recurrent cough (other symptoms such as poor oral intake with lethargy or increasing abdominal distension) not responding to outpatient treatment Psychosocial impact to the family

3. Illness PROGRESSION 17/12/23 (D16 of illness) Abdominal distension A/W Rapid Breathing Sought treatment in GP Given Nebulization and Discharged 2/12/23 Prolonged Cough for 3 weeks Admitted: 19/12/23 (D18 of illness) Fever with Bilateral facial swelling A/W lethargic and poor oral intake 16/12/23 (D15 of illness) Sought treatment in GP o Given antibiotics Sy Augmentin 225 mg BD (20mg/kg/dose) x 3/7 His twin brother also prolonged chesty cough for 3 weeks and developed fever on the day of admission However he did not complained any abdominal distension and facial swelling. 12/12/23 (D11 of illness) Sought treatment in GP Given antipyretics and mucolytics 4/12/23 (D3 of illness) Sought treatment in GP Given antipyretics and mucolytics

4. Diet History Mixed feeding till 6 months Weaning at 6 months old tolerating solid meals around 3 times/day with snacking in between Breakfast – Bread with toast – 350 Kcal Lunch and Dinner – Rice small bowl with chicken/meat and vegetables (carrots/ broccoli) – 300 Kcal Bottle feeding Fernleaf 150mls of milk x 5times/day - 625 Kcal Total estimated calorie intake per day 1275 kcal/day body mass index (BMI) is 14.2

5. Birth history Birth History Born at 37 weeks, 2nd MCDA twin SVD BW 1.6 kg ANC : MCDA twin with IUGR NICU admission for weight establishment (10days), no oxygen requirement Subsequently discharged well

6. Development History : appropriate to age of 2 years old Speech : Can speak about 20 meaningful words, build 2-3word sentences understand 1-2 step command Social : He plays well with his twin brother Able to undress self but need assistance when put on cloth Able to brush teeth with help Able to use spoon and drink with a cup Gross Motor can run jump on two feet attempting to go on stairs able to kick ball forward throw ball overhead Fine Motor : Can scribble spontaneously draws a straight line can build a tower of 9 blocks

7. Immunization History: Complete till 18months old Social History: Father 31years, Architect at Sepang Mother 31years, Pegawai Pentadbir at UKM Twins (Patients only children) Lives at Bandar Baru Selak Tinggi

8. History of staycation on 24/11/23 at D’Laman Rose in Banting

9. Examination Alert pink not jaundice, Warm peripheries, Good pulse volume, CRT< 2secs Not tachyonic, mild subcostal recession, No Harrison sulci Bilateral nasal turbinate congested Vital Signs BP 103/77 HR 130 RR 30 T 37 Bilateral facial swelling extending from preauricular to post auricular right side 5x7cm and left 4x5cm , overlying skin normal, not tender Skin overlying swelling normal Not tender, not warm, diffuse, edges not well demarcated No deep parotid swelling No gum swelling Lungs: Good and equal A/E with Bilateral crepitations Abdomen: Soft and distended, Hepatomegaly 4cm palpable splenomegaly 2cm palpable CVS S1S2 no murmur Tonsils grade 3 bilaterally , slightly inflamed No axillary LN palpable Shorty inguinal LN palpable Testis not swollen Neurological - unremarkable

10. Differential diagnosis Autoimmune Disorders Systemic Lupus Erythematosus (SLE) prolonged cough respiratory symptoms, hepatosplenomegaly, and fever Boy No Malar rash, Photosensitivity, Oral ulcers No Arthritis No Seizures OR psychosis Not pallor and no bleeding tendency Hematological Disorder Acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) respiratory symptoms, hepatosplenomegalyand fever No Pallor No Bleeding tendencies Only small LNs palpable Infection POINTS FOR POINTS AGAINST Partially treated pneumonia prolonged cough with fever with Lungs findings Hepatosplenomegaly Parotid swelling Tuberculosis prolonged cough hepatosplenomegaly, and fever, parotid swelling No hx of contact with PTB No LOW and LOA Thriving child Melioidosis prolonged cough hepatosplenomegaly, and fever, parotid swelling Hx of travelling to Banting Exposure stagnant Water activity EBV respiratory symptoms, hepatosplenomegaly, and fever parotid swelling CMV respiratory symptoms, hepatosplenomegaly, and fever Parotid swelling Mycoplasma Infection respiratory symptom and fever Parotid swelling Hepatosplenomegaly Leptospirosis prolonged cough Hepatosplenomegaly Hx Exposure Stagnant Water Short duration of fever No diarrhea and vomiting Not jaundice Exposure Water activity

11. Blood investigations FBC: HB: 11.9 HCT: 34.3 WBC: 24.2 (Neu:7.7/ Lym : 15.2) PLT: 259 RP: Na: 136 K: 4.4 Urea: 3.8 Creat:43 LFT: Alb: 39 / Total Protein: 81/ T. bil : 4.7/ ALP: 237/ AST: - ESR: 56 CRP: 29 LDH: 386 FBP (20/12/2023) : Leukocytosis, lymphocytosis, monocytosis and white cell changes are in keeping with underlying infection and inflammation. No features suggestive of leukemia in this blood film.

12. Cxr 19/12/2023

13. U/S Abdomen/HBS and Parotid (20/12/2023) PUT USG PIC OF SPLEENIC NODULES 1. Bilateral parotid and submandibular glands findings suggestive parotitis and sialadenitis. 2. Bilateral cervical lymphadenopathies. DDx infective/inflammatory changes ( ie TB lymphadenitis) or lymphoma. 3. Hepatosplenomegaly with numerous micronodules within the spleen.

14. OTHER INVESTIGATION(S) TO CONSIDER?

15. UFEME: Negative NPA Respi viruses panel: negative Culture results: Blood c&s (19/12/2023): NG Blood c&s (21/12/2023): NG Urine c&s : No Growth Stool c&s : No Growth EBV IgM: positive Meliodosis IgM (20/12/23): positive with titre 1:320 Leptopsira IgM: negative Monospot test: negative Mycoplasma IgM: negative PTB work up : AFB x 1: No AFB AFB x 2: No AFB AFB x 3: No AFB Mantoux : 22/12/23 - Negative MTB C&S: pending Other investigations

16. PROGRESS IN WARD

17. Illness PROGRESSION DISCHARGED on 18/1/2024 Admitted for 31 days On admission: Started IV Ceftazidime after review USG US HBS on 16.1.2024. (D26 of Treatment) Liver is normal in size, echogenicity with regular echotexture and smooth margin. No focal liver lesion. Liver span measures 10cm. Hepatic and portal veins are patent. Spleen is normal measuring 7.7cm in span. Multiple hypoechoic micronodules are still seen, however appear slightly lesser in the current study. Impression : Resolving splenic micronodules. US HBS - 4.1.2024 (D15 of Treatment) Liver is normal in size, echogenicity with regular echotexture and smooth margin. No focal liver lesion. Liver span measures 9.1cm. Hepatic and portal veins are patent. Spleen is normal measuring 7.2cm in span. Numerous hypoechoic micronodules within appears similar to the previous study. Impression : Persistent splenic micronodules. Fever Settled after Cough settle

18. FBC (26/12/2023): Hb: 11.3 HCT: 33.7 WBC 4.3 (ANC: 1.86/ALC: 10.8) PLT 279 ESR: 56 >> 41 >> 79 >>30 CRP: 29 >> 16 >>3 LDH: 386 >> 262 They were discharged after completion of intensive therapy IV Ceftazidime 50mg/kg/dose QID total 28 days Discharged with Oral Augmentin 20mg/kg/dose for another 20 weeks. Throughout admission he gained weigh 11 kg  11.4 kg Repeated Meliodosis IgM (15/1/24 @ D25 of antibx ) : positive with titre 1:320 Repeated Meliodosis IgM of his twin brother (15/1/24 @ D25 of antibx ): positive with titre 1:640 On Examination alert, conscious active, cheerful not septic looking pink, warm peripheries good pv , crt < 2sec + no LN palpable Lungs: equal air entry CVS: no murmur Abd: soft, liver 2cm palpable, spleen not palpable

19. TCA Family medicine clinic on 14/2/24 intermittent cough no fever No abdominal distension tolerating orally well PU and BO normal compliance to antibiotic o/e alert, pink, active, smiling, no subcostal or intercostal recession t: 36.5 spo2: 98 rr : 24 hr: 122bpm wt : 11.2kg lung: clear cvs : drnm pa: soft throat: not injected plan 1) syr prospen 2.5 ml TDS (mother will buy from pharmacy) 2) Reassurance

20. Psychosocial impact to the family He is a product of non consanguineous marriage Father 31years, Architect at Sepang Mother 31years, Pegawai Pentadbir at UKM Bangi Twins (Patients only children) Lives at Bandar Baru Bangi with Gross monthly income of 9000 – 10000k Mother was just recently reported for duty as administrator in UKM Bangi 3 weeks prior to admission and was on probation period. Due to the circumstances she was required to take unpaid leaves as the guardian in the ward. Both parent also developed URTI sx during the first 2 weeks of admission

21. In summary AN is a 2 years 5 Month old 2 nd MCDA twin admitted for melioidosis infection with pulmonary and spleen involvement. Due to his illness he and his twin brother required prolonged hospitalization for long duration antibiotic and had psychosocial impact to the family

22. Paediatric MELIODOSIS

23. INTRODUCTION Melioidosis is caused by the gram-negative bacillus, Burkholderia pseudomallei . [1] first documented in an outbreak in 1913 involving laboratory guinea pigs and rabbits at the Institute for Medical Research, Kuala Lumpur. Since then, melioidosis has been recognized as an endemic disease in Malaysia. Pediatric melioidosis is reported to be less common than adult disease, constituting between 5–15% of all melioidosis cases. [2]

24. Why it is endemic in Malaysia ? Melioidosis is considered endemic in Malaysia due to several environmental and geographical factors that favor the growth and persistence of Burkholderia pseudomallei . Tropical Climate with heavy rainfall - provides an ideal environment for the survival and proliferation of Burkholderia pseudomallei in soil and water. Agricultural Activities - significant industry in Malaysia, with extensive rice cultivation and other agricultural practices that involve soil disturbance. These activities can aerosolize contaminated soil particles, leading to the inhalation/ingestion of Burkholderia pseudomallei by humans and animals High Prevalence in Animals - domestic and wild animals serve as reservoirs for Burkholderia pseudomallei , contributing to the maintenance and transmission of the bacterium in the environment

25. MODES OF TRANSMISSION Infection is acquired from: i . Inhalation of contaminated dust particles ii. Direct contact with contaminated soil and water through penetrating wounds, existing skin abrasions, burns iii. Aspiration or ingestion of contaminated water

26. HIGH RISK GROUPS B.pseudomallei behaves as an opportunistic pathogen. In children - Predisposing illnesses were reported in 10 % to 20% of the infected children. Diabetes mellitus, hematologic malignancies, thalasaemia , chronic renal failure, nephrotic syndrome, rheumatic heart disease and hepatitis A were the reported underlying diseases found in children with melioidosis [1] In the study from Kuala Lumpur, 69% of children had an underlying medical condition, mainly haematological malignancy. In Sabah, where high rates of β-globin gene deletions are found in the local ethnic population, 41% of children had thalassemia major. [2]

27. CLINICAL PRESENTATIONS The incubation period is usually 1-21 days (mean of 9 days) but can be as long as months and even years. Latent intervals as long as 62 years have been reported in natural melioidosis. Asymptomatic infection is also common as evidenced by positive serology in up to 50% of healthy adults in endemic countries. [1]

28. Melioidosis was classified as either localized or disseminated. A localized disease was defined as a single, discrete, culture-positive focus of infection, in the absence of a positive blood culture and clinical/radiological evidence of dissemination to other sites. Disseminated disease was defined as the presence of infection in ≥2 discrete body sites and/or a positive blood culture.[5]

29. Pneumonia: The commonest presentation with or without multiple abscesses namely in the liver, spleen and prostate. Pneumonia, multiple organ involvement and septicaemia of unknown origin have been associated with higher mortality. Septicemia: Overwhelming sepsis is a serious presentation. There will probably be evidence of a primary local inflammation corresponding to the route of infection Metastatic foci of infection are established rapidly during bacteremia, particularly in lungs (multifocal pneumonia, which may cavitate) liver, spleen and kidneys (multiple abscesses) skin and soft tissues (cellulitis, pustules) bones and joints lymph nodes and prostate Localised infection is common in children especially involving the head and neck region. In Thailand, 40% of the localised melioidosis were due to unilateral suppurative parotitis [1] Pyrexia of unknown origin: The fever is usually high-grade and swinging. [1]

30. [1]

31. WHEN TO SUSPECT ACUTE MELIOIDOSIS A patient residing and/or working in an endemic area and other sporadic areas. A patient with diabetes mellitus. A patient with a high-grade fever - either acute or prolonged. History of exposure to contaminated environment (dust, soil or water). Progressive pneumonia (CXR deteriorating within a few hours or 2-3 days) not responding to commonly-used antibiotics. The presence of hepatomegaly and/or splenomegaly – suggestive of multiple abscesses. [1]

32. INVESTIGATIONS [1]

33. COLLECTION AND TRANSPORTATION OF SAMPLE FOR DIAGNOSIS OF MELIOIDOSIS [1]

34. SEROLOGY- immunofluorescence antibody test IFAT Titre (IgM antibody) [1]

35. [1]

36. Challenges in growing Burkholderia pseudomallei in culture Need for Specialized Culture Media : Specialized selective and differential media, such as Ashdown's agar or Burkholderia cepacia selective agar, are often required for optimal isolation and identification of the bacterium from clinical specimens Contamination by Other Organisms : The growth of Burkholderia pseudomallei in culture may be inhibited by the presence of other microorganisms commonly found in environmental samples. Slow Growth Rate : exhibits a slow growth rate compared to other bacteria, requiring extended incubation periods for visible growth to occur which can lead to delays in the detection and identification of the bacterium in culture, particularly if suboptimal incubation times are used [4]

37. TREATMENT Patients with CNS involvement — For patients with neurological melioidosis, we use meropenem and administer it at a higher dose (40 mg/kg up to 2 g IV every eight hours) [1] [5] to prevent mortality from severe illness associated with melioidosis

38. Duration of intensive antibiotic therapy — Initial intensive IV antibiotic therapy is given for at least 14 days [6]

39. to prevent relapse of melioidosis.

40. Rationale For Long Duration Of Antibiotics Intracellular Persistence : has the ability to invade and survive within host cells, particularly macrophages make it difficult for antibiotics to effectively reach and eliminate all bacteria Biofilm Formation : capable of forming biofilms can protect bacteria from antibiotics and the host immune system, leading to persistent infection and requiring prolonged antibiotic therapy to eradicate the infection Abscess Formation : can harbor bacteria and create a protected environment where antibiotics may have limited penetration. Risk of Relapse : Melioidosis has a high rate of relapse, even after apparently successful initial treatment. Deep-seated Infections : require prolonged antibiotic therapy to penetrate infected tissues and achieve bactericidal concentrations. [4]

41. POST EXPOSURE PROPHYLAXIS There is no human study however there were recommendations for accidental laboratory exposures and preparedness for bioterrorism. Co-trimoxazole 2-4 tab bd for 3 weeks within 24 hours of high probability of exposure may be considered. Amoxicillin/Clavulanic acid can be use for prophylaxis for those can’t tolerate Co-trimoxazole. [1]

42. [1]

43. PROTOCOL DURING FOLLOW UP The total duration of follow-up for children who remain asymptomatic, without co-morbidity or long- term complications is 5 years. During maintenance therapy patients need to be reviewed monthly or every 2 months . After completing the maintenance phase follow-ups may be done every 4 to 6 months . [1] Clinical assessment is done during follow-up to monitor for antibiotic adherence , disease relapse and late complications of the affected system / organ as follow : Recurrent symptoms and signs of melioidosis Late complications of the affected organ e.g. seizures, neurodevelopment delay or regression, joint deformity, chronic lung disease.

44. Mortality And Recurrence It is estimated that more than 2000 patients die of melioidosis per year, which is much higher than death resulting from dengue or tuberculosis infection. Despite advances in treatment, the case fatality ranged from one-third to about half of patients (33–54%) in four of the five Malaysian case series. the mortality was about threefold higher among bacteraemic cases compared with nonbacteraemic cases (48–65% vs. 19%). The normal pathological consequence of bacteraemia is septic shock. In Malaysia, the reported rate of culture-confirmed clinical recurrence varied from 2.6% to 19%

45. In Malaysia, the reported rate of culture-confirmed clinical recurrence varied from 2.6% to 19% Risk factors for recurrence amongst Malaysian severity of disease (positive blood culture, multifocal disease) incomplete or inadequate treatment during the intensive phase of treatment, and improper eradication therapy and nonadherence or duration less than 12 weeks presence of underlying conditions [2]

46. References Guidelines for clinical and public health management of Melioidosis in Pahang Melioidosis in Malaysia: Incidence, Clinical Challenges, and Advances in Understanding Pathogenesis Trop Med Infect Dis. 2018 Mar; 3(1): 25. Pediatric melioidosis in Sarawak, Malaysia: Epidemiological , clinical and microbiological characteristics . PLoS Negl Trop Dis. 2017 Jun 9;11(6):e0005650. doi : 10.1371/journal.pntd.0005650. eCollection 2017 Jun. Melioidosis: Epidemiology, Pathophysiology, and Management Allen C. Cheng1,2 and Bart J. Currie. CLINICAL MICROBIOLOGY REVIEWS, Apr. 2005, p. 383–416 Melioidosis: Treatment and prevention - https://www.uptodate.com/contents/melioidosis-treatment-and-prevention