Rapamycin reduces splenomegaly and lymphadenopathy in Common Variable Immunodeficiency (CVID): A Case Report Dr Sarah Sasson Immunopathology Registrar SydPath, St Vincent's Hospital, Sydney
Rapamycin reduces
splenomegaly and lymphadenopathy in
Common Variable Immunodeficiency (CVID):
A Case Report
Dr Sarah Sasson
Immunopathology Registrar
SydPath, St Vincent's Hospital, Sydney
HPI
• 57F hospitalised with H. influenzae pneumonia (sensitive)
First major infection
• PMHx: COPD and 160 pack years smoking
Meds: Budesonide-Efomoterol, Terbinafine, Bupropion
• SHx: Nil Allergies, Nil recent travel, Nil IVDU, Nil pets
• 1.2g IV benzylpenicillin QID and prednisone 50mg PO daily (weaning).
Failure to clinically improve by Day 10
DDx underlying malignancy, sarcoidosis, CTD
Investigations
• FBC/EUC/LFT
• Random Glucose 12.2 (3.0-7.8)
• HBA1c 6.3 (<6%)
• HIV Ab/Ag Neg
• HBV sAg Neg
• HCV Ab Neg
• EBV IgG and IgM Neg
• CMV DNA Neg
• Aspergillous serology Neg
• Mycobacteria serology Neg
• Pertussis Serology Neg
• Sputum (no AFB)
• ANA Neg
• ENA Neg
• ANCA Neg
• ds DNA Neg
• RF Neg
• CCP Neg
• CRP 64
• ESR 28
• INR 1.0
• Axillae lymph node biopsy:
reactive lymphoid hyperplasia
Immunoglobulin g/L
IgG 0.3 (6.7-14.4)
IgA <0.3 (0.7-3.4)
IgM 0.2 (0.5-2.4)
IgG
Subclass
g/L
IgG1 0.3 (4.2-10.1)
IgG2 <0.1 (1.9-6.2)
IgG3 0.3 (0.11-0.79)
IgG4 <0.1 (0.04-1.64)
Progress
• Provisional diagnosis of CVID made
• Treated with IVIG; Discharged Day 13
• Outpatient monthly IVIG
• Outpatient BMAT: sparse plasma cells; no other
abnormality
• Over the following year lymphadenopathy and
splenomegaly worsened
• Developed thrombocytopenia
• PET Scan Feb 2014 showed widespread avid lesions
consistent with lymphoma or granulomatous disease
Repeat LN biopsy histology: Atypical lymphoid follicular structures
• 13% of lymphocytes are B-cells
• 9% switched memory B-cells and 48% CD21low B-cells
EUROclass criteria for CVID prognostication
Higher association with splenomegaly and granulomatous disease
Note: Additionally CD4 and CD8+ T-cells displayed a CD45RA-CCR7-
activated/terminally differentiated phenotype
Wehr et al Blood 2008
E.Deenick and S. Tangye
Investigating the role of the mTOR pathway
Control tonsil Patient A
pS6-HRP
(CD20-chromagen)
Minimal EBER+ (<10% of follicles)
Patient commenced on Rapamycin
6mg STAT then 2mg PO daily (aim for trough 5-10microg/L)
2 months
• Reduction of tracer uptake into lymph nodes; Marked reduction in hepatosplenomegaly
• Decreased SUVmax of spleen (2.9 compared with previous 4.4)
Baseline
Summary
With Non-infectious
complications
Without Non-infectious
complications
Resnick et al Blood 2012
• Late diagnosis of CVID at 57 years
Clinical course not characterised by recurrent infections
• Patients with CVID have decreased survival over 40yrs
• Non-infectious complications are associated with higher mortality
• Unfortunately good evidence for the treatment of such complications is lacking
• Rapamycin has been used successfully in
autoimmune lymphoproliferative syndrome
(ALPS).
• A syndrome characterised by defective
lymphocyte apoptosis and
hyperproliferation mediated by the mTOR
pathway.
• Characterised by expansion of CD4- CD8-
DN T-cells.
• ALPS commonly effects cervical lymph
nodes and is EBV driven.
Rapamycin in ALPS
Week 0
Week 6 of
Rapamycin
Dragana et al Pediatr Blood Cancer 2009
• Preliminary work suggests the mTOR pathway may be upregulated in some
cases of CVID-associated splenomegaly and lymphadenopathy
• In such cases mTOR inhibitors may be useful therapy
• The optimal duration of this therapy is unclear
• Whole exome sequencing with candidate mutated genes: AID, UNG, PI3K,
ICOS, CTLA-4
Conclusions
Acknowledgements
SydPath
Dr Adrienne Morey
A/Prof William Sewell
Sandy Smith
St Vincent’s Hospital
Dr Mark Danta
Dr Louise Emmett
Dr Keith Fay
Prof Tony Kelleher
Dr Tri Phan
The Garvan Institute
Dr Elissa Deenick
Prof Stuart Tangye
Thank You
Questions?