A presentation of Professor Katie Flanagan on disseminated mycobacterial infection in a Malaysian lady with IFN-γ autoAbs successfully treated with Rituximab, and a review of the literature on this rare condition.

1. Assoc/Prof Katie Flanagan
Infectious Diseases Physician, LGH
Clinical Associate Professor, University ofTasmania

2.  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

3.  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

4.  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

5.  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

6.  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

7.  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

8.  Admitted for Rifampicin,Tigecycline, Amikacin (3x a wk)
then switched to Ethambutol andTigecycline 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

9.  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

10.  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

11.  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

12.  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?

13.  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
ImpairedTNF-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

15.  Large case series of HIV-negative adults with disseminated
mycobacterial infection fromThailand /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

16. Gp 1
Infected with NTM
Gp 2
Infected with another
opportunist +/- NTM
Gp 3
DisseminatedTB
Gp 4
PulmonaryTB
Gp 5
Healthy Controls

17. All of Group 1 and most of
Group 2 had an NTM infection

18. 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)
fromTB cases and controls

19.  PBMC isolated (thus free of autologous plasma) and tested for IFN-g
augmentation of LPS stimulatedTNF-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
stimulatedTNF-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

21.  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

22.  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 bornAsians hints at genetic
and environmental factors
 This is a newly defined
Adult Onset Immunodeficiency Syndrome

24.  Rituximab is a monoclonalAb 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

25.  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

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

28.  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………….