multiple infection shiv negative

8/9/2019 Multiple Infection Shiv Negative

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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

multiple infection shiv negative

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