A CASE OF RECURRENT TUBERCULOSIS -LAVANYA DR. S. BALASUBRAMANIAN S UNIT SR. CONSULTANT KKCTH
PRESENTING COMPLAINTS 8 year old boy 3 o 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 ligandbinding 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, PhD Laboratoire 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 receptor 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 deficiencyfatal 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.
References 1.Disseminated Mycobacterium tuberculosis infection due to interferon γ deficiency. Response to replacement therapy Author Affiliations Correspondence to: Dr Suranjith Luke Seneviratne Department 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. Marwaha BMJ 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.
THANK YOU