Recurrent tuberculosis

A CASE OF A CASE OF RECURRENT RECURRENT

TUBERCULOSISTUBERCULOSIS

A CASE OF A CASE OF RECURRENT RECURRENT

TUBERCULOSISTUBERCULOSIS-LAVANYALAVANYA

DR. S. BALASUBRAMANIAN’S UNITDR. S. BALASUBRAMANIAN’S UNITSR. CONSULTANTSR. CONSULTANT

KKCTHKKCTH

PRESENTING COMPLAINTS

• 8 year old boy • 3o consanguineous marriage• low grade fever and swelling left

parotid area - 15 days• poor weight gain --- 2- 3 years.

PAST HISTORY• @ 2/12, (at Trichy)• Head injury with seizures• CT - bilateral subdural hematoma.• oral phenytoin.• BCG adenitis + and ATT

(HR) initiated.

• @7/12, (at KKCTH)• wheeze assoc LRI, anemia and

hepatosplenomegaly with ↓BCG adenitis .• +ve CMV IgM . • Symptomatic treatment given and

ATT continued (for 9 months)

• @ 6 yrs of age, (at KKCTH)• fever x 1 month

pain - right knee and thigh

Investigations• TC- (18,500 p-78%)

CRP (143.6) ESR (100/132)

ASO (380)

• Mantoux negative• Aspirate from the right hip: LDH(3640), Proteins (5.9)• –ve gram stain and AFB.

• Persistent fever• Further work up :• RA factor - negative• ANA - negative• CT PNS – lytic lesion in mandible• Chest X-ray - osteitic changes in

the 3rd, 4th and 5th ribs.

• HIV ELISA –ve• NBT test –ve• BONE SCAN - multifocal bone

involvement• BONE BIOPSY - mycobacterial

osteomyelitis

• Treated with 4 drug regime of ATT ( HRZE ), given for 3 months • HR initiated for continuation.• Culture- Mycobacterium .TB

resistant to INH. • RE continued for 8 months.

• This was when he presented to us…

EXAMINATION• He was under nourished, pale.• right parotid swelling

hepatosplenomegaly non healing ulcer over the biopsy

site (symphysis pubis).

INVESTIGATIONS• TC- (22,300 P65,L30) • ESR (110/133) • CRP(182), • Haemoglobin(9). • Chest X-ray, RFT & urine analysis

normal.

• Immunoglobulin-N (IgG-2460, IgM-209, IgA-577, IgE-8)• Repeat NBT test –ve. • ANA , ANCA -ve.• Flowcytometry – N.• TB Quantiferon Gold –ve.

• GJ AFB x 3 – negative• Bone marrow - reactive. • Whole body MRI – s/o foci of TB (right

cerebellum, right upper ribs, right lung, right tensor fasciaelata & both iliac bones)

• CSF analysis (TC-60, L95 P5 ; Sug63 Pro52 Cl 114)CSF Culture –ve AFB

THE STORY SO FAR…• BCG adenitis• Multifocal osteomyelitis • Cold abscess over parotid with

multiple bony foci and CNS involvement

• (responding to treatment)• … WHY IS HE RELAPSING ???

POSSIBILITIES• Drug resistance only H resistance, responds to treatment• Paradoxical response no worsening during treatment, relapses• Immunodeficiency probably abnormal host response

• Any ideas from the post graduates????

MY DEAR WATSON• IS IT

• INTRINSIC IMPAIRMENT OF IFNγ PATHWAY RESPONSE

1.Interferon gamma receptor ligand- binding chain (IFN gamma R1), 2.Interferon gamma receptor signalling chain (IFN gamma R2), 3.Interleukin 12 p40 subunit (IL-12 p40), 4.Interleukin 12 receptor beta 1 chain (IL-12R beta 1) genes

CALL FOR HELP…• Mail to Dr. Casanova in France

(nearly 100 papers on IFN gamma pathway abnormalities)

• Blood specimens sent as suggested for further analysis.

• 7 drug regimen of ATT initiated.• Ofloxacin (15 mg/kg), clarithromycin

(10 mg/kg), HRZES for 2 months • HRE continuation initiated….• Recurrence of parotid abscess.• I&D done and sample sent for culture.• HRZE+ Oflox given for 2 months

• He was reviewed after 2 months:• Culture : Mycobacterium avium

intracellulare.• TREATMENT: • Clarithromycin(25mg/kg)• Ciprofloxacin(20mg/kg)• HRE

• On Sat, Nov 14, 2009 at 8:56 PM, Jacinta BUSTAMANTE

Dear Dr Balasubramanian,

Some time ago, you sent in our lab the blood samples from your patient Mohammed Thaseem Anwar. He suffered disseminated mycobacterial infections. (BCG disease versus tuberculosis disease). The test in the lab show low response of activation BCG+IFNg in term of IL12 production and he had also the IFNg detected in plasma. We found  a new variation in IFNGR1 gene located in exon 2. We need study your patient and we need characterize the defect. At the moment we don't know if he suffer a complete or partial defect and the treatment depend of the disease. Could you have to contact your patient and send us an other blood samples? Thanks you very much for help,

Sincerely,

Jacinta

Jacinta Cecilia Bustamante MD, PhDLaboratoire de Génétique Humaine des Maladies Infectieuses INSERM - U550 Faculté de Médecine Necker 156 rue de Vaugirard 75015 Paris, FRANCE, UE

Téléphone 33 1 40 61 53 38 FAX 33 1 40 61 56 88 E-mail jacinta.bustamante@inserm.fr web site http://www.hgid.net

DIAGNOSIS• new variation in IFNGR1 gene

located in exon 2.

• Gamma interferon RECEPTOR defect

Gamma interferon Gamma interferon receptor defectreceptor defect

Gamma interferon Gamma interferon receptor defectreceptor defect

• IFN-gamma receptor ligand-binding chain (IFNgammaR1) deficiency

• life-threatening AR immune disorder.

• deleterious mutations • Present with disseminated TB or

BCG and NTM infection.

• Intrinsic impairment in IFN-gamma pathway, particular to mycobacteria.

• (not susceptible to any other agents)• inhibit activation of macrophages –

up regulation of TNFα is impaired intracellular pathogens +++.

• Affected children die of mycobacterial infection.

• Mutations - premature stop codon -precluding cell surface expression of the receptors. 

• Treatment is long term ATT.

• complete IFNgammaR1 deficiency-fatal lepromatoid BCG infection and disseminated NTM infection

• partial IFNgammaR1 deficiency -curable tuberculoid BCG infection and clinical tuberculosis.

• Only 2 case reports are published.• Further work up in him is pending.• Waiting for him to come for

review.

TAKE HOME MESSAGE• TRY, TRY, TRY UNTIL YOU

SUCCEED!!!• It is imperative to keep searching

for a cause in children with recurrent complaints.

References1.Disseminated Mycobacterium tuberculosis infection due

to interferon γ deficiency. Response to replacement therapy

Author AffiliationsCorrespondence to:

Dr Suranjith Luke SeneviratneDepartment of Clinical Immunology, Manchester Royal Infirmary Manchester M13 9WL, UK;suran200@yahoo.co.uk

2. Extensively drug resistant tuberculosis in a 7-year-old child with interferon-{gamma} and interleukin-12 deficiency

K. Kulkarni,M. Singh, P. Soneja, J. Mathew, R. K. MarwahaBMJ Case Reports 2009;2009:bcr0620080293

3.Variable outcome of experimental interferon-gamma therapy of disseminated Bacillus Calmette-Guerin infection in two unrelated interleukin-12Rbeta1-deficient Slovakian children.

• Ulrichs T, Fieschi C, Nevicka E, Hahn H, Brezina M, Kaufmann SH, Casanova JL, Frecerova K.

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