Assoc/Prof Katie Flanagan

Infectious Diseases Physician, LGH

Clinical Associate Professor, University of Tasmania

60 year old Malaysian woman living in Australia for >20 years

Previously fit and well, no significant medical history, no allergies

Problems began 2005 at age 53 years

Developed a cervical mass

Saw haematologist Diagnosis reactive LNA

No FNA/Bx performed

No treatment

Discharged

Dec 2006 Swelling recurred FNA: Reactive changes Developed sinus and tissue debrided Tissue grew Mycobaterium Avium Complex:

Sensitivities not on file Rx Oral Clarithromycin x 10 wks

Mass persisted

June 2007 Seen by ID at RHH Right cervical LNA persists and referred for excision because thought unlikely to tolerate Rx August 2008 Pain, swelling left knee, chronic discharging ulcer left knee, patella and pre-patellar tissue debrided (RHH Plastic surgeons) Multiple nodules to thigh, multiple LNs in abdomen LN Bx grew MAC: R to clarithromycin Treated with Azithromycin, Rifampicin, Moxifloxacin

Admission LGH with severe drug reaction DRESS (drug reaction / pustulosis / eosinophilia) Thought to be due to rifampicin but recurrent rash with azithromycin so

this was possibly the cause

Oct 2008 Seen by ID at RHH Now on Clarithromycin monotherapy Changed to Clarithro + Ciprofloxacin

Clear documented drug reaction with rash to Ciprofloxacin

Nov 2008 CT brain/neck/chest/abdo Rt cervical necrotic LNs (lgest 8x6x9mm), borderline pretracheal node, smaller mediastinal nodes, numerous nodules in rt lung, left inguinal nodes + fat stranding, lymph nodes extend along ext iliac chain, lt paraortic nodes, no nodes necrotic, L4 sclerotic lesion ?treated OM, lt iliac bone sclerosis

Bone marrow grew MAC (25/11/2008) S to clofazamine and rifabutin I to amikacin and ethambutol R to clarithromycin and ciprofloxacin

MRI brain – nil significant

T cell subsets normal

HIV-1/-2 negative

HTLV-1/-2 negative

Bone marrow histology – granulocytic hyperplasia and

reactive changes

Cytogenetics normal

TCR gamma rearrangement and Ig heavy chain

rearrangement polyclonal

Admitted for Rifampicin, Tigecycline, Amikacin (3x a wk) then switched to Ethambutol and Tigecycline stopped

Plan for 4-6 months Amikacin and 18-24m Rx in total Amikacin stopped after 2 months and left on Ethambutol

and Rifampicin in Jan 2009 July 27th 2009 Seen at Royal Melbourne Clinical Immunology Dept

Normal lymphocyte proliferation

Normal neutrophil oxidative burst

Possible IFN-g deficit on IFN-g/IL-12 axis testing but assays relatively experimental and nil found to warrant IFN-g therapy

2009 – 2012

Episode of meningitis of unknown cause Residual weakness and decreased coordination in legs

Progressive painful neuropathy

Persistent multi-resistant E coli in urine

May 2012 First seen by me at LGH Still on Ethambutol and Clarithromycin Painful neuritis causing considerable morbidity Generally unwell, weak, deteriorating clinically

Treated UTI successfully with meropenem CT Brain/Neck/Chest/Abdo/Pelvis (4/5/12) Enlarged Rt supraclavicular LN, enlarged node/mass in mediastinum, pretracheal/subcarinal nodes, compressing trachea and left brachiocephalic vein, pericardial thickening and effusion, RUL lung nodules/infiltrates. No nodes in abdo/pelvis

Lymph Node Bx (18/5/12) Histolology: Granulomatous inflammation with a focus of necrosis, AFB negative

Mycobacterium fortuitum grown S Amikacin, Cipro, Moxi, Linezolid I Cefoxitin R Clarithro, Bactrim, Doxy, Imipenem, Tobramycin Quantiferon test (22/5/12) PHA Mitogen Positive Control: Zero response suggesting IFN-g deficiency

6 years on treatment for atypical mycobacterial infections

(MAC, now a fairly resistant M. fortuitum). Has been on Clarithromycin for years despite long standing

resistance to this ABx. Unable to tolerate Ciprofloxacin, Moxifloxacin, Azithromycin,

Ethambutol, possibly Rifampicin Zero IFN-g response to PHA suggests deficiency

Question

Would immunotherapy combined with ABx allow us to treat her successfully, although she may need lifelong treatment?

August 2012 Saw immunologists again at RMH Normal Igs, normal lymphocyte subsets

IFN-g / IL-12 pathway testing Reduced IFN-g in whole blood to PHA, IL-12, LPS+IL-12 Impaired TNF-a production to LPS+IFN-g

Separated PBMC – completely normal IFN-g production to PHA+IL-12 Indicates a neutralising factor in serum

Thought most likely due to anti-IFN-g autoantibodies as

recently described in Asian population

Large case series of HIV-negative adults with disseminated mycobacterial infection from Thailand / Taiwan suggested a common syndrome of adult onset immunodeficiency

Since 2004, 25 adult cases of disseminated NTM & other opportunistic infections in the absence of HIV infection but presence of neutralizing anti-IFN-g autoantibodies have been described. Most from East Asia

Set out to analyse humoral and cellular function in patients and healthy controls from regions where the syndrome appears to have high prevalence

Gp 1 Infected with NTM Gp 2 Infected with another opportunist +/- NTM Gp 3 Disseminated TB Gp 4 Pulmonary TB Gp 5 Healthy Controls

All of Group 1 and most of

Group 2 had an NTM infection

Plasma tested for 41 anti-cytokine autoantibodies (particle based assay) Anti-IFN-g autoantibodies present in 81% of group 1 and 96% group 2 compared to only 1 patient in groups 3, 4 and 5 Mainly IgG4 No association with disease activity Only anti-IFN-g autoantibodies distinguished patients with opportunisitic infections (Gps 1 & 2) from TB cases and controls

PBMC isolated (thus free of autologous plasma) and tested for IFN-g

augmentation of LPS stimulated TNF-a production

Present in those with blocking anti-IFN-g autoantibodies therefore ruling out major genetic defects associated with disseminated mycobacterial infection

PBMCs incubated in 10% plasma and the for IFN-g augmentation of LPS stimulated TNF-a production was absent in antibody positive plasma specimens

IFN-g induced STAT1 phosphorylation abrogated in antibody positive

specimens from Gp 1 and Gp 2 patients whilst IFN-a STAT1 phosphorylation was intact confirming specificity of the IFN-g defect

12 group 1 & 2 patients did not have anti-IFN-g

autoantibodies 10 in group 1 (all had NTM alone)

6 had disease limited to LNs

3 had disseminated disease limited to bone

5 of the 10 had been cured prior to enrolment

2 in group 2 (neither had NTM) 1 had neutralising anti-GMCSF autoantibodies with disseminated

crypotococcus

1 had cryptococcal meningitis alone

The anti-IFN-g autoantibodies uniquely distinguished cases from control groups

The trigger for production of the autoantibodies is not known

Fact that mostly occurs in Asian born Asians hints at genetic and environmental factors

This is a newly defined Adult Onset Immunodeficiency Syndrome

Rituximab is a monoclonal Ab against human CD20 expressed by mature B cells and plasmablasts

Causes rapid and sustained depletion of circulating and tissue B cells

FDA approved from Rx of B cell lymphoma and rheumatoid arthritis

Treated 4 patients with high titre anti-IFN-g monoclonal autoantibodies with rituximab

All had aggressive disseminated NTM that was refractory to Rx

All were females

Used a B cell lymphoma protocol: 375mg/m2 weekly for ≥4 doses, then at wider intervals All received 8 – 12 doses in the first year Additional doses determined by recurrence

All achieved remission or cure Well tolerated All had persistent declines in Ab titres during and after treatment

Rituximab weekly x 4 weeks then monthly

Linezolid 600mg od

Amikacin 5x a week for 1 month then 3x week for 5 months

Cefoxitin 2g qds x 1 month

I met her 2weeks ago to discus treatment options………….