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    Multiple Infections in a HIVnegative patient

    Bonnie WongDivision of Infectious Diseases

    Department of Medicine and TherapeuticsPrince of Wales Hospital

    History

    Mr Au, 49 year old security guard Good past health Presented with one week history of right

    sided pleuritic chest pain with SOBOE Weight loss of 10lbs in the past two months

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    Physical Examination Febrile, 39C CVS: NAD Chest: RLZ crepitations Abdomen: NAD CNS: NAD No palpable lymphadenopathy

    Investigations

    CXR: increased cardiothoracic ratio and minimal right pleural effusion

    WCC 13, neutrophil predominant CRP 160, ESR 120 ALT 104, ALP 360, Alb 26 INR 1.3 RFT normal

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    Managed as chest infection with para pneumonic effusion and was treated with amoxicillin clavulanate empirically

    Fever did not respond Noticed to have diarrhoea ~3 times/day after

    admission

    Investigations

    USG abdomen: right pleural effusion, gallstones, prominent hepato duodenal node

    Failed bedside tapping USG guided tapping yielded 50ml of straw coloured pleural fluid, exudative, WCC 3900,

    neutrophil 72%, Gram stain and ZN stain ve (pleural biopsy not done)

    Pleural fluid cytology: mainly polymorphs, histiocytes and reactive mesothelial cells

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    Investigations Bedside echocardiogram: no valvular defect,

    satisfactory ejection fraction, loculated pericardial effusion, no constriction nor tamponade

    Investigations

    HIV negative HbsAg, anti HCV negative Fasting glucose 4.8 ANA 1:40 homogenous, ENA: anti Ro +ve,

    ANCA ve Normal C3/C4 Stool for C. diff toxin negative

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    Investigations Stool culture: Gp D Salmonella Blood culture: Salmonella Enteritidis

    Sensitive to cefotaxime, chloramphenicol Resistant to ampicillin, ciprofloxacin,

    cotrimoxazole

    Antibiotic was changed to i.v. ceftriaxone 2g Q24H

    Progress

    Fever persisted

    How would you proceed?

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    No more diarrhoea No joint pain/bone pain

    Further investigations Repeat CXR: blunted right CP angle Bronchoscopy was arranged

    No endobronchial lesion BAL : C/ST: oral commensals

    Gram stain and ZN stain negativeAmplified TB direct test negativefungal/legionella culture negativecytology: negative for malignant cells

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    Further imaging CT thorax with contrast

    1.4 cm thick pericardial effusion Multiple enlarged mediastinal lymph nodes Right lower basal segment patchy consolidation

    Surgeons called in VATS pericardial window and biopsy Open and close procedure: failed to obtain

    biopsy due to dense adhesion between the

    heart and pericardium

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    Empirical anti TB treatment HRMZ + prednisolone were started in view of

    the clinical suspicion of TB pleuritis and pericarditis

    Progress

    Fever settled nicely and the overall well being improved

    Ceftriaxone was given for 14 days and repeat

    blood culture had documented clearance of bacteraemia Patient was discharged and referred to Chest

    Clinic for DOT and was scheduled for re admission to the CTS ward for mediastinoscopy in a weeks time

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    Another story begins Cervical mediastinoscopy was performed a

    week later Biopsy was taken but the procedure was

    complicated with profuse venous bleeding requiring manual compression for 45 minutes

    Haemodynamics were stabilized eventually

    However

    The patient developed high fever up to 40C and shock with BP 70/40mmHg soon after being transferred back to ward

    Admitted to ICU requiring inotropic support

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    Blood culture showed Salmonella Enteritidis x 2 sets

    Same sensitivity profile as the previous culture Antibiotics were changed to iv ceftriaxone

    Mediastinal LN biopsy benign fibroadipose tissue with haemorrhage and

    fibrin exudate No significant inflammatory infiltrates or

    granuloma formation No lymphoid tissue No evidence of malignancy Staining for organisms all negative

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    Repeat CT No aneurysm identified in aorta and major

    branches Enlarged mediastinal LNs, slightly decreased in

    size as compared to last scan Mild collapse/consolidation in right lower lobe,

    resolved pleural effusions and pericardial effusion

    Gallstones

    Fever settled promptly Discharged and continued with daily

    outpatient intravenous ceftriaxone for

    another 6 weeks Referred to surgeon for elective

    cholecystectomy

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    And things go on Readmitted at around week 5 of the second

    course of iv ceftriaxone with spike of fever and dizziness

    In shock on presentation Marked leukocytosis on admission, WCC 36

    (neutrophil 85%)

    Antibiotics were switched to meropenem and azithromycin

    ESR 119 WCC 36.5 Repeat echo: NAD, pericardial effusion

    resolved

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    Sudden onset of right facial asymmetry Vesicles over right auricle No other focal neurological deficit

    CT brain (plain): NAD

    LP performed OP 22cmH2O WCC 129, lymphocyte predominant, RBC 2 Glucose 3, TP 0.33 VZV PCR positive Cytology: large no. of lymphocyte

    MRI brain Small infarct at left MCA and ACA territory

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    Put on i.v. acyclovir for two weeks then switched to valacyclovir for another week

    Fever persisted WCC 17 CRP 133

    Bone marrow examination Normocellular marrow with trilineage

    haematopoiesis Lympho histiocytic infiltration and focal necrosis

    No granuloma seen No clonal TCR or IgH gene rearrangement Grocott and ZN stain negative MTB DNA sequence negative

    Ddx: severe infections and lymphoma

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    PETCT Multiple patchy air space consolidation in

    posterior segment of right upper lobe (SUVmax 7.5), rest of lungs clear

    SUVmax 2.6 9.5 over multiple jugular, supraclavicular, paratracheal, subcarinal, para aortic, cardiophrenic, axillary,

    peripancreatic and

    portal

    LNs

    Spleen showed mild diffuse increased in FDG uptake of SUVmax ~4.1

    Supraclavicular LN USG guided FNAC: QI Incisional biopsy:

    reactive lymphoid hyperplasia No necrosis or granulomatous inflammation No vasculitis Immunohistochemical stains confirm the reactive

    pattern No light chain restriction No evidence of lymphoma Gram, Grocott, ZiehlNeelsen, Wade Fite, PAS and

    Warthin Starry stains are all negative

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    Developed high fever the day after incisional biopsy of supraclavicular LN

    Blood culture grew Salmonella Enteritidis AGAIN!

    Given two months of meropenem Switched to daily outpatient iv ertapenem AntiTB meds with HRMZ continued

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    ESR > 130 despite receiving 5 months of HRMZ and un interrupted treatment with ceftriaxone/meropenem

    forehead

    forearm

    elbow

    Face and neck

    forearm

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    Gram stain on aspirates of skin lesions

    Budding yeast

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    Umbilicated skin rash: biopsy: features of fungal infection

    Penicilliosis serology was positive, blood

    culture negative itraconazole was added

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    Positive melioidosis serology and positive PCR from the LN sample

    put on septrin and doxycycline

    maintenance therapy

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    Cholecystectomy performed Bile and gallbladder specimen: culture

    negative, histology: features compatible with chronic cholecystitis

    Repeat HIV and HTLV1 serology negative CD4/CD8 ratio: 0.9 Natural Killer cells (CD56) :1.5% (635%), 0.04

    x 10^9/L (0.11 0.89) Total B cells (CD19): 2.4% (521%), 0.07 x

    10^9/L (0.08 0.45)

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    Latest progress Just completed 6 months eradication therapy

    with doxycycline and Septrin ESR, CRP and WCC normalized ALP normalized Hb level on normalizing trend Pending FU CT for monitoring of

    lymphadenopathy

    Recurrent Salemonella enteritidis bacteraemia

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    Route of acquisition Mainly foodborn Intensive epidemiological and laboratory

    investigations identified shell eggs as the major vehicle for SE infection in humans

    Salmonella enterica serotype Enteritidis and eggs: a national epidemic in the United States.Clin Infect Dis. 2006 Aug 15;43(4):5127.

    Turtle associated human salmonellosis In 1970s, 14% of all nontyphoidal salmonellosis

    was attributed to transmission by turtles in US 7% in the past decade

    Increasing popularity of turtles and other pet reptiles Infected by faecal oral route, by claw scratches

    and bites, indirect contact Highest risk in young children, elderly persons, in

    immunocompromised hosts, those with impaired gastric acid secretion (RR 2 for those on antacids)

    Turtle Associated Human SalmonellosisCID 2003;37:e167 9

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    Risk factors HIV Malignancy Sarcoidosis Autoimmune disease Concomittant infection

    TB or NTM infection Disseminated histoplasmosis Schistosoma mansoni infection

    Factors predisposing Salmonellosis Deficiencies in components of the innate

    immune system Gastric secretion Defect in neutrophil and macrophage functions

    Antibody deficiencies Defects in cellmediated immunity Deficiencies in Th1 cytokines (IL12, IFN

    gamma) or cytokine receptors (IL12Rbeta 1 subunit, IFNgamma R chains 1 and 2

    Resistance and susceptibility to Salmonella infections: lessons from mice and patients with immunodeficiencies. Reviews in Medical Microbiology. 14(2):53 62, April 2003.

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    The interacting cytokine and receptor pathways that regulate the resistance to and killing of mycobacteria and Salmonella.

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    MSMD Mendelian susceptibility to mycobacterial

    disease (MSMD; Mendelian susceptibility in Man 209950)

    Extraintestinal nontyphoid salmonellosis diagnosed in less than one half of patients with MSMD

    Altered IL12/IFN gamma axis

    Clinical Tuberculosis in 2 of 3 Siblings with Interleukin 12 Receptor beta1 Deficiency. CID 2003;37:302 6

    Clinical spectrum Pericarditis

    Peritonitis Empyema Endocarditis Meningitis Osteomyelitis, septic arthritis Abscess: lung, liver, brain, skin and soft tissue

    Salmonella enteritidis pericarditis: case report and review of the literature.Ann Ital Med Int. 2002 JulSep;17(3):189 92

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    Postulation Widespread contamination of poultry good by

    salmonella species Antibiotic usage in food animals contribute to

    human salmonellosis

    Illegal use of nitrofurans in food animals: Contribution to human salmonellosis. Clin Microbiol Infect. 2006 Nov;12(11):1047 9.

    Antibiotic resistance in SE From the National Antimicrobial Resistance

    Monitoring System, during 1996 2003, SE had a relatively low proportion of resistance to any of the individual antimicrobial agents

    One exception: resistant to quinolones, represented by nalidixic acid, increased from 0.9% to 5.1%

    Also observed in Campylobacter species in humans and poultry

    FDA withdrew its approval of the use of fluoroquinolones in poultry in 2005

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    Melioidosis

    Burkholderia pseudomallei Aerobic gram negative bacillus Endemic in southeast Asia and north Australia Soildwelling, esp. rice paddy fields, also found

    in surface water

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    Pathogenesis Percutaneous inoculation

    Local ulcer Inhalation Ingestion Case of venereal transmission reported Acquisition at work (laboratory technicians)

    Melioidosis in Hong Kong First reported in Hong Kong in 1975 when 24

    dolphins in Ocean Park died of melioidosis Soil sampling and a small serological survey done in

    1980s suggested that melioidosis in endemic in Hong Kong

    5 out of 22 (23%) elderly patients admitted to general medical wards had haemagglutinating antibodies against Burkholderia pseudomallei

    Melioidosis An Overlooked Problem In Hong KongThe Hong Kong Practitioner. March 1985

    Successful treatment of melioidosis caused by a multiresistantStrain in an immunocompromised host with third generation Cephalosporins. Am Rev Respir Dis 1983;127:650 654.

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    Burden of disease 20% of community acquired septicaemic

    cases in northeast provinces in Thailand Accounts for 39% of fatal septicaemia and

    36% of fatal community acquired pneumonia Commonest cause of fatal community

    acquired bacteraemic pneumonia in Northen Territory of Australia

    Clinical presentation Subclinical infection

    May be reactivated years later when the host is immunocompromised either by disease or drugs

    Acute infection Indistinguishable from ordinary gram negative septicaemia

    Subacute and chronic infections Follow or precede, or appear in the absence of acute

    infection Mimick pulmonary tuberculosis, histology can also

    show caseating granuloma

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    Site of infection Primary bloodstream infection HEENT: acute suppurative parotitis (especially in

    children), lymphadenitis Lung: acute necrotizing pneumonia, subacute

    cavitating apical pneumonia, accompanied by weight loss (often mimicking tuberculosis) Intraabdominal: liver/splenic abscess, pyelonephritis SSTI: disseminated pustules, subcutaneous

    abscess Bone: osteomyelitis CNS: delirium, confusion, stupor, brain abscess

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    Risk factors DM Thalassaemia Aboriginality Male gender Soil/water exposure Renal disease Excessive alcohol consumption

    Diagnosis Isolation of organism from blood, sputum, pus and other body fluids

    Gold standard Selective culture media for better isolation (Ashdown medium)

    Antigen detection Done on specimen or on culture supernatant Not widely available

    Serological test 4 fold rise in antibody titre with paired sera A high single titre Indirect haemagglutination (IHA), enzyme linked immunosorbent assay

    (ELISA) Limited by high rates of background antibody positivity

    Molecular methods 16S mRNA sequencing Not widely available

    High index of suspicion in endemic areas

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    Treatment principle Treatment should consist of combination of

    drugs for prolonged period, except in mild cases, in order to prevent relapses

    Drain all the drainable collections Surgical intervention necessitated if failed

    medical treatment, e.g. lobectomy in unresolving pneumonia

    Monitoring of antibiotic sensitivity serially

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    TreatmentInduction therapy(Intensive phase) Preferred

    TMPSMX + Ceftazidime Meropenem Imipenem

    Alternatives Ceftazidime (a/w 50% of

    relapse) Amoxicillin clavulanate

    Maintenance therapy(Eradication phase) Preferred

    TMPSMX +/ doxycycline Alternatives

    Chloramphenicol + doxycycline + TMPSMX(conventional therapy before 1989, bacteriostatic rather than bactericidal)

    Amoxicillin clavulanate + amoxicillin (associated with higher Rx failure rate)

    Melioidosis: Epidemiology, Pathophysiology, and ManagementClinical Microbiology Reviews, Apr. 2005, p.383 416

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    Follow up monitoring Antibody level is not a good guide of response

    to treatment Close monitoring for relapse

    Relapse

    Occurs in 13 to 23% of cases and a medial of 6 to 8 months (can be up to years) after apparently successful treatment

    Mortality similar to that of the initial infection Relapse vs reinfection

    4 to 7% are reinfection cases in Thailand and Australia One out of 5 recurrent cases is reinfection in the

    cohort in Malaysia No difference in acute outcome

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    Risk factors associated with relapse

    Poor adherence to therapy Use of doxycycline monotherapy or

    amoxicillin clavulanate in the eradication phase

    Severe disease (RR 4.7 c.f. localized disease)

    Eradication therapy < 8 weeks (RR 2.5)Relapse in melioidosis: incidence and risk factors. J. Infect. Dis. 168:1181 85.Melioidosis: acute and chronic disease, relapse and re activation.Trans. R. Soc. Trop. Med. Hyg. 94:301 304.Risk factors for recurrent melioidosis in Northeast ThailandCID 2006;43: 979 86.

    Prevention

    No effective vaccine available Education in endemic areas

    Minimize exposure to soil, surface water, esp. for patients with DM

    Footwear and gloves for gardening Avoid travel to high risk areas for at risk

    population

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    Weapon of bioterrorism Category B bioterrorism agent as classified by

    CDC

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    Porphyria cutanea tarda and melioidosis

    Porphyria cutanea tarda Metabolic disorder in the haem biosynthetic pathway Inherited, more commonly acquired Cutaneous lesions, often associated with systemic

    disease Case report of recurrent photosensitive vesicles,

    blisters and skin fragility over forearms and hands, 6 months after being put on doxycycline and amoxycillin

    Porphyria cutanea tarda and melioidosis.Hong Kong Med J. 2001 Jun;7(2):197 200.

    Thank You