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?