DIGGING UP THE DIRT? Lai-yang Lee Infectious Diseases Registrar Monash Medical Centre

Mrs PS Profile

57yo female Born Malaysia Regular return visits Last visit April 2014 for 5/52 Lives at home with husband

Non smoker No alcohol

PMHx - Lupus

Late 2013- early 2014 Photosensitive rash, alopecia, inflammatory arthritis, arthralgia, dyspnoea ANA/ENA/dsDNA/RF/antiCCP Negative ESR 64 CRP <1 Skin biopsy forehead: Limited changes consistent with discoid lupus erythematosus

Treatment Plaquenil, prednisolone, methotrexate, azathioprine

Oct 2014 Prednisolone 10mg od Methotrexate 20mg od Azathioprine 125mg od L arm pain – MRI Myositis Biopsy – inflammatory changes

Dec 2014 Monash Lupus Clinic

Vasculitic, photosensitive rash & synovitis ANA 1:160 (1/3 positive) Cardiolipin Ab 13.1 CCP Ab <0.5 C3 0.86 C4 0.31 Hb 113 WCC 3 Plt 127 ALT 60 GGT 93 AST 63 ALP 69 Bili 7

Lupus with overlap features HCQ 400mg BD Pred 25mg od AZA 125mg od MTX ceased

Follow up Reduce prednisolone Improved rash, arthralgia, myalgia Persistent lethargy, dyspnoea, anorexia

CT

Jan 2015

Respiratory review

FEV1 1.4L FVC 1.64L FER 90% DLCO 63% Planned for bronchoscopy & biopsy

Admission D0 3-4/52 N & V 2/52 cough White sputum No fevers 5kg LOW

Examination Temp 38.8 BP 104/73 HR 120 sinus

CVS: Nil significant findings

Resp: L basal fine crackles

Abdo: Nil significant findings

No lymphadenopathy

Initial investigations Na 129 Cr 60 eGFR >90

ALP 111 GGT 91 ALT 34, Bil 52 Alb 17

INR 1.2 LDH 622

CK 41

CRP 78

BC pending

What are our differentials?

DDX Febrile neutropenia with thrombocytopenia

? 2nd to SLE ?AZA toxicity ?Infection ? Primary haematological disease

Management Prednisolone 15mg-> 50mg Plaquenil 400mg bd -> 200mg bd Aza withheld

Tazocin Vancomycin

Haematology consulted GCSF Tranexamic acid FFP

D1 – D2

Hb 99 WCC 0.3 Plt 11

INR1.5 APTT 38 Fib 1.3 ALP 208 GGT 186 ALT 37 Total Bili 67

Met calls Hypotension Labile temperature Tachycardia

Not responding to IVT Concern re fluid overload T/f to ICU

What are your thoughts now?

D3 ICU

↑O2 requirement ↑ WOB & RR

Commence Bi-pap Diuresis FFP Cryoprecipitate Methyl pred pulse x3

HIV negative

Crypto ag (serum) negative

Quantiferon TbAg 1.28 Mitogen control 0.48 EBV Ig G detected Ig M Not detected CMV Ig G detected Ig M Not detected

C3 0.12 C4 0.05

D4 60% FIO2

During ID/ICU round: “ do you think this patient may have TB or is it just fluid overload?”

D4 Suggest

Bronchoscopy Empiric Bactrim Azithromycin

Ongoing haematology review

D5 Empiric Voriconazole commenced Echo

Mildly dilated LV EF 65% Normal rv size,

BMAT

BMAT

x4

Fat space

Bony trabeculae

X 10

X 40

Fat

X 60

x20

X 20

What do we think this is? Would you change your management? Tony- if noone says histo shall we say we are concerned about it etc…

D6

Change to Ambisome Steady deterioration, drowsy, non communicative

Intermittent temp spikes Persistent tachycardia Falling MAP Oliguric

Evolving multi-organ failure

D6 Metabolic acidosis Lactate 5.5 Coagulopathic Obstructive LFT ALP >1000 CMV PCR positive BM aspirate NG

D6 Intubated

Noradrenalin

Chest & abdo imaging Bronchoscopy

Ganciclovir added

D6 U/S: ?? Necrotic gall bladder/ gb empyema Not for surgery

Taz/azithro/vanc ceased Moxiflox commenced

D7 Acidotic Fluid overloaded despite CVVHDF Increasing noradrenalin requirement

BAL PJP PCR negative Bactrim ceased Fungal elements

CMV VL 5666 copies/mL

D8 Noradrenalin 5-> 50

Unable to support with progressive multi-organ failure

Passed away at 0820

Investigations

BAL AFB smear neg TB PCR neg

Blood cultures x8 negative

BMA D6 HBA/MAC Choc Yeast SAB No growth CMM No growth

Confirmation of Diagnosis

BMA culture: Histoplasma capsulatum

Fungal rRNA PCR & sequencing

Fungal DNA detected

Fungal Identification Histoplasma capsulatum

Summary 57yo Malaysian lady with lupus, moderately immunospressed Rash, arthralgia, dyspnoea Admit with febrile neutropenia, thrombocytopenia, dyspnoea Quickly pancytopenic, further immunosuppressed

Rapid deterioration with multi- organ failure Diagnosed with disseminated histoplasmosis

HISTOPLASMOSIS

Histoplasmosis World wide distribution Mississippi & Ohio River catchments USA Other regions- Africa, Australia, eastern Asia in particular India & Malaysia

Best growth in soil with high nitrogen content

Bat or bird guano Soil can remain contaminated for 10yrs

Epidemiology

Risk factors Environmental exposure Activity performed Duration & degree of dust or soil exposure Longer more intense exposure→ more severe pulmonary disease Underlying illness eg CMID

Transmission Inhalation of microconidia

Incubation 1-3 weeks Reinfection incubation 4-7 days No human to human transmission

H.capsulatum var duboisii

Indolent at onset Skin & bones If widespread infection → liver, spleen → fatal febrile wasting illness if untreated

H.capsulatum var capsulatum 1) Asymptomatic pneumonitis 2) Acute pulmonary disease 3) Chronic pulmonary disease 4) Widespread disseminated disease

Disseminated disease Often asymptomatic haematogenous spread Even with CMI, pts may have remaining foci of viable organsms in various organs Reactivation years later Severe syndrome: hypotension, DIC, renal failure, ARDS Unique mainfestations: Addison’s, MM lesions

Specimen Sputum, BAL Blood Urine Lymph node Bone marrow Other tissue CSF

Direct stains Giemsa/ Wright’s / GMS/ PAS/ Gram Not HE

Small 2-4um oval budding yeast (presumptive dx) Free or within macrophage

Isolation Laboratory associated infection post exposure to airborne conidia Percutanous innoculation

All procedures involving manipulation of sporulating cultures should be handled in Class II biological safety cabinet under biosafety level 3 containment

Biosafety level 2 practices are recommended for handling clinical specimens Isolation may take 2-4 weeks

Thermally dimorphic fungus Filamentous mould in environment & below 35⁰C Macroconidia

Thick walled, 8-15um Tubercules/projections on surface

Microconidia Smooth walled, 2-4um Infectious particle

Thermally dimorphic Yeast in tissue and over 35⁰C H.capsulatum

Small oval budding cells 2-4um Often within macrophages

H. duboisii Thick walled, 8-15um Narrow based budding

Identification

Characteristic morphologic feature

Conversion to yeast phase

Gen-Probe AccuProbe test

PCR

Exo-antigen test

Antigen detection Not performed in Australia

Urine or blood

EIA for antigenemia in disseminated histoplasmosis

Assess Rx success/failure

Serology Westmead (immunodiffusion) Latex agglutination Complement fixation More useful in acute pulmonary disease Sensitivity 80% disseminated disease Immunocompromised pts 20-50% test negative

Treatment - Disseminated Moderately severe to severe

Liposomal amphotericin B 3mg/kg daily 1-2/52 Or Amphotericin B 0.7/1.0mg/kg daily Followed with oral itraconazole 200mg tds 3/7 Then 200mg bd for total minimum 12/12

Mild to moderate Itraconazole 200mg TDS for 3/7 then BD for 12/12 Lifelong suppressive therapy with itraconazole 200mg daily may be required in immunosuppressed pts if immunosuppression cannot be reversed or in pts who relapse despite appropriate therapy

Check itraconazole levels

IDSA recommend antigen level measurement during therapy & 12/12 post therapy

Treatment outcome Occasionally able to clear without treatment Without treatment mortality 80-100% With treatment mortality 7-25%

HISTOPLASMOSIS IN AUSTRALIA

Uncommon in SLE Incidence 0.64- 1.04% (1 case per year) 15 cases reported Varied presentations including skin lesions, fever, malaise, fatigue, dyspnoea

Sx onset to diagnosis delayed (median 6.5months) Presentation may overlap with lupus flare Course variable vary from rapidly progressing to subacute or chronic Inherent defects in humoral and cellular immunity & chronic immunosuppression-> increased risk

Summary High degree of clinical suspicion is required Dormant infectious organisms can reactive in setting of immunosuppression Laboratory safety Prolonged incubation

Acknowledgements • Rheumatology unit

• Dr Anna Antony & Dr Emily Ong

• Haematology Unit

• Dr Nora Lee & Dr Alison Slocombe

• Respiratory Unit

• Infectious Diseases &Microbiology laboratory