CIS School on Primary Immune Deficiencies Mystery Case Case Presentation

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CIS School on Primary Immune DeficienciesMyster
y CaseCase Presentation

• Shuba Iyengar, MD
• Allergy/Immunology
• Childrens Hospital, Boston

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35 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.
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? 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
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VS 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
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Work-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.
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Work-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.
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Work-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
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• 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

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(No Transcript)
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? 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
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• 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.
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• 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.

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• 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.

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• 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?

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References

• 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.