Title: CIS School on Primary Immune Deficiencies Mystery Case Case Presentation
1CIS School on Primary Immune DeficienciesMyster
y CaseCase Presentation
- Shuba Iyengar, MD
- Allergy/Immunology
- Childrens Hospital, Boston
235 year old Female with a significant history of
autoimmune disease ? Insulin Dependent diabetes
mellitus, type I diagnosed at age 8 and
associated with -end stage renal disease
(hemodialysis dependent)
-coronary artery disease s/p CABG x 3
-diabetic retinopathy ? Hypothyroidism ?
Psoriatic arthritis Fam Hx Arthritis in the
maternal grandmother and paternal grandfather.
Coronary artery disease in the paternal
grandfather. No other autoimmune disease. No
frequent infections. Brother healthy.
3? No significant infections until 6 months ago
? Past 6 months (all admissions at outside
hospitals) - 2 episodes of FUO -groin
abscess requiring ID (culture negative)
-abdominal wall and leg cellulitis (p.aeruginosa)
-splenic abscess (culture
negative)
? Current Admission -presented to
outside facility with fever, body aches, and
diffuse LAD -fever work-up
included Pan CT showing bilateral
axillary lymphadenopathy Open lymph node
biopsy suspicious for T-cell lymphoma, but
T-cell rearrangement studies normal
(polyclonal population) BAL and serum
for adenovirus (3 million copies/ml by PCR)
-worsening respiratory status prompted transfer
to Stanford
4VS HR 100, BP 94/53, RR 24, O2 sat 97 on
FiO2 of 40, Temp 38.4 C GEN ill-appearing
woman, sedated on ventilator HEENT unable to
visualize tonsils secondary to intubation no
obvious thrush LYMPH NODES shoddy submandibular
and cervical lymph nodes 1-cm left
supraclavicular node right axilla with 2-cm x
1-cm lymph node (mobile,soft) CV RRR, no
murmurs RESP diffuse rales and wheezes
bilaterally ABD mild hepatomegaly SKIN
granulation tissue within R proximal thigh
(healed groin abcess) no current areas of
infection no rash EXT no nail pitting no digit
swelling (dactylitis) JXT no swelling, warmth,
or erythema
5Work-up included ? Repeat Imaging CXR
(Figure1), Chest CT (Figure 2)
Fig.2 Dense consolidation with air
bronchograms involving much of the left lung.
Patchy opacities through the right lung
consistent with infectious etiology.
Figure 1 Extensive parenchymal consolidation of
the left lung suggestive of severe pneumonia.
6Work-up included ? Lung biopsy (Figure 3) ?
Bone Marrow (Figures 4,5)
Figures 4,5
Figure 3
Normal Marrow Aspirate
Patients marrow with reactive lymphoid aggregate
Lung, left upper lobe biopsy--adenovirus
pneumonia with diffuse alveolar damage pattern.
7Work-up included ? Flow Cytometry ? T cells
functional studies abnormal (in setting on
chronic steroid use)mildly depressed response to
mitogen, tetanus, diptheria
granulocyte
CD5
ssc
macrophage
FSC
CD45
lymphocytes
Gating strategy-gated on all CD45 cells
(normal range)
CD38
CD31024 (700-2100 /uL) CD19 B-cells0 (100-500
/uL) CD4 T-cells439(300-1400/uL) CD8
T-cells551(200-900 /uL) CD3-/1656
NKcells90(90-600 /uL)
Immunoglobulin Levels IgG lt7 (gt613) IgA lt6
(69-309) IgM lt5 (53-334)
CD19
Flow shows no CD19 cells
8- 35 year old female
- History of significant autoimmune disease (IDDM,
hypothyroidism, psoriatic arthritis) - Negative infection history until 6 months prior
- Disseminated adenoviral infection (BAL, serum
PCR) with severe pneumonia - Mild hepatomegaly and diffuse LAD
- Normal labs
- HIV, CMV, EBV negative (by PCR)
- Hemoglobin, ANC, LFTs, bilirubin
- No B cells or immunoglobulin
9(No Transcript)
10? CVID-recent h/o infections h/o auto-immune
disease ? Goods Syndrome-no thymoma (per
CT) ? Tcell Lymphoma-Lymph node and bone marrow
biopsy results negative ? Autosomal Recessive
Agammaglobulinemia- not likely negative
infectious history until 6 months prior ?
Hemophagocytic Lymphohistiocytosis-Bone
marrow and inflammatory markers negative
isolated thrombocytopenia and high ferritin
(2129), normal triglycerides, no
hypofibrinogenemia
11- Characterized by reduced serum immunoglobulins
(in at least 2 isotypes) 2 standard deviations
below the mean - Heterogeneous clinical features
- 22 develop at least one autoimmune condition
(usually autoimmune hemolytic anemia/
thrombocytopenia) - Median IgG levels and B cell counts are 220 and
8 respectively (listed below). - Accompanying agammaglobulinemia and no B cells
rare (lt5 of patients).
Cunningham-Rundles et al. Clin Immunol. 1999
Jul92(1)34-48.
12- Patient had T cell dysfunction (in setting of
chronic steroid use), but preserved T cell
numbers. - Lymphoma work-up was negative.
- Mutation studies for BAFFR, TACI, CD19, ICOS and
not performed. - Unfortunately, she died from her disseminated
adenoviral infection (serum PCR40 million
copies/ml) despite treatment with IVIG and
cidofivir.
13- Non-enveloped double-stranded DNA viruses
- 51 immunologically distinct serotypes (A through
F) - Spectrum of infections ranging from respiratory
disease (mainly species HAdV-B and C), and
conjunctivitis (HAdV-B and D), to gastroenteritis
(HAdV-F serotypes 40 and 41). - Estimated incidence of adenovirus in the adult
BMT population is 9.1 (n4768), and 26 in
children post-BMT (Baldwin et al). - Less characterized in PID population. However,
in a published registry of 201 XLA patients, 1 pt
had a fatal adenoviral encephalitis (reference
Hans and Charlotte). - Disseminated infection is defined as a positive
serum PCR and positive cx in 2 other
organ-systems - Disseminated adenovirus infection in the setting
of profound immunosuppression in children has
case fatality rates as high as 60, with the
highest risk of death in those who develop
pneumonia or hepatitis. - Increasing use of routine surveillance for
adenovirus. This is because detection of
adenoviral DNA in serum samples has been shown to
be a marker for progression to severe
disseminated disease.
14- Study of 57 HSCT patients (mean age8 years),
Adenoviral serum PCR and tissue cx was screened
weekly for 100 days post-BMT (Yusuf et al.) - For a positive PCR/cx, cidofovir was given (5
mg/kg weekly) for 2 weeks, then every 2 weeks
until 3 consecutive negative samples obtained. - 8 patients (14) presented with disseminated
disease. - Cidofivir treatment resulted in complete
resolution of clinical symptoms in 56 (98)
patients in whom the virus became undetectable by
all methods. - Is there a role for adenoviral surveillance
PCR/cx in the PID population? - Why do some adenoviral infections progress to
invasive disease in the immunosuppressed
population, while others remain asymptomatic?
15References
- Cunningham-Rundles C, Bodian C. Common variable
immunodeficiency clinical and immunological
features of 248 patients. Clin Immunol. 1999
Jul92(1)34-48. - Castigli E, Geha RS. Molecular basis of common
variable immunodeficiency. J Allergy Clin
Immunol. 2006 Apr117(4)740-6 - Cunningham-Rundles C, Ponda PP. Molecular defects
in T- and B-cell primary immunodeficiency
diseases. Nat Rev Immunol. 2005 Nov5(11)880-92.
- Baldwin A, Kingham H, Darville M, et al. Outcome
and clinical course of 100 patients with
adenovirus infection following bone marrow
transplantation. Bone Marrow Transplant 2000 26
133338.