Transcript (B), Chediak-Higashi syndrome.

CASE STUDIES IN
IMMUNOLOGY
NIRAJ PATEL, MD, MS
INFECTIOUS DISEASES AND IMMUNOLOGY
Case 1
 7-year-old girl is brought in by her father
for evaluation of full body rash and
swelling
 Symptoms present for 2 weeks
 After obtaining a careful history and
performing a physical examination, you
determine that the child has urticaria
Case 1 (cont)
 Of the following, the MOST likely cause is
A. artificial food coloring
B. milk
C. new laundry detergent
D. shrimp
E. upper respiratory tract viral infection
Urticaria vs. Angioedema
Urticaria – superficial dermis
Characterized by intense pruritis due to
histamine effect
Angioedema – deeper dermal and
subcutaneous layers
May be pruritic but often is a deeper and dull
discomfort – burning quality
URTICARIA
MAST Cell
Degranulation
Acute vs. Chronic Urticaria
•Acute Urticaria – lasts 6-8 weeks or less
•Viral syndromes (especially in young children)
•Insect bites or stings (fire ants, scabies)
•Food induced reactions (eat this - get that)
•Medication related (antibiotics, NSAIDs, narcotics,
angioedema due to ACE inhibitors)
•Chronic Urticaria – lasting longer than 8 weeks
•Physical urticarias (dermographism, cholinergic, cold)
•Urticarial vasculitis
•Urticaria/angioedema associated with autoimmunity
•Autoimmune urticaria
•Idiopathic urticaria
Case 2
 12 yr old Asian boy presents to clinic with a 3
month history of painful recurring hives
 Parents tried keeping a food diary, eliminating
Yellow Dye Number 5, changing laundry
detergents, bath soaps and shampoos and
nothing has helped
 Taking cetirizine 10 mg daily which keeps him
hive-free. He is otherwise healthy but parents
are requesting a referral to identify the cause
of the hives.
Case 2 (cont)
What is the most likely cause?
A. Viral illness
B. Allergy to dust mites
C. Allergy to soy
D. Autoimmune vasculitis
Case 2 answer
 Answer is D. The most common cause of
chronic (>6 weeks in duration) hives in children
is either autoimmune or idiopathic. Signs of a
worrisome vasculitis rather than benign
urticaria include lesions that are painful instead
of itchy; lesions that scar; and lesions that last
longer than 72 hours.
 Answer choices (A) viral illness, (B) allergy to
dust mites, and (C) allergy to soy are most likely
to cause acute hives
Acute vs. Chronic Urticaria
•Acute Urticaria – lasts 6-8 weeks or less
•Viral syndromes (especially in young children)
•Insect bites or stings (fire ants, scabies)
•Food induced reactions (eat this - get that)
•Medication related (antibiotics, NSAIDs, narcotics,
angioedema due to ACE inhibitors)
•Chronic Urticaria – lasting longer than 8 weeks
•Physical urticarias (dermographism, cholinergic, cold)
•Urticarial vasculitis
•Urticaria/angioedema associated with autoimmunity
•Autoimmune urticaria
•Idiopathic urticaria
Therapeutic Options
 Antihistamines for most with acute short-lasting
urticaria
 Start with non-sedating, long-acting second
generation H1 antagonists (Allegra, Zyrtec, Claritin)
and supplement with short-acting, sedating H1
antagonists prn.
 Combination therapy with H2 if H1 antagonists
do not suffice (30% of cases)
 Steroids and other immunosuppressants
reserved for severe urticaria associated with
angioedema of oropharnyx or other systemic
signs, moderate to severe drug reactions,
urticarial vasculitis, and refractory cases of CIU
Case 3
A 17 year old is about to leave for
college and she has marked in her
chart that she is allergic to penicillin
When you try to question her about
this history, she states her mom told
her that she had a rash when she
was 2 years old and received a
course of amoxicillin
Case 3 (cont)
Which of the following is the BEST statement regarding
penicillin allergy?
A. She should continue to avoid all PCN and cephs as
there is 80% chance she will have an adverse reaction
upon repeat exposure
B. She should be referred to an allergist for skin testing to
penicillin and possible oral challenge
C. Order RAST to PCN to assess likelihood of being
persistently allergic to PCN
D. Tell her that oral medications are more likely to cause
adverse reactions, so only IV, IM forms of PCN she be
administered in the future
E. She should try to find out more history from her mother
Case 3 answer
 Answer is B. Incidence of drug IgE-mediated reaction is
≤10%. Most clinicians would continue avoiding this drug
class based on history. Concomitant viral infections or illdefined immune mechanisms are most common cause of
such rashes. Cephs with a side chain unrelated to drug
associated with a rash (e.g. amoxicillin) is generally
acceptable. 2nd and 3rd generation cephs are less likely to
cross react than 1st generation cephs. Overall, cross
reactivity rate remains less than 10% for all cephs.
 Penicilloyl (major determinant of PCN) is commercially
available as skin testing reagent. This, along with Penicillin
G is 95% sensitive in detecting persistent PCN allergy. On
the other hand, if test is positive, there is a 60% chance of
reacting.
 Serum sickness, EM, and TEN are non-IgE mediated
reactions and cannot therefore be evaluated by immediate
hypersensitivity skin testing. If a patient has suffered such
a reaction, the general method of management is
avoidance.
Cross reacting Antibiotics
Modified from Pichichero, Pediatrics 2005; 115:1048-57
Case 4
 12 yo female presents to ER with 1 week history
of an enlarging buttock boil. She has a history of
numerous abscesses, including 3 which required
incision and drainage.
 Hospitalized at 8 yo for Staphylococcus aureus
bacteremia and 10 yo for MRSA pneumonia and
pneumatocele. Her father also has boils.
 Temp is 102, other VSS. PE significant for
coarse facial features, a double row of teeth,
scoliosis of 20 degree curvature, and numerous
scars from prior abscesses.
 Laboratories show a normal white blood cell
count and normal IgG, IgA, and IgM.
Case 4
The most likely diagnosis is:
A. leukocyte adhesion defect
B. chronic granulomatous disease
C. hyperIgE syndrome
D. hyperIgM syndrome
E. severe combined immunodeficiency
Case 4 answer
 The correct answer choice is (C), hyperIgE syndrome.
HyperIgE syndrome, or Job’s syndrome, characterized by
recurrent infections usually with Staphylococcus aureus and
Candida spp.. Defect is in STAT 3 protein, an intracellular
signaling protein important for inflammation. HyperIgE syndrome
is autosommal dominant inheritance pattern. Abscesses
typically require incision and drainage. HyperIgE is a multisystem
disorder. Nonimmunologic characteristics are retained primary
teeth, scoliosis, neonatal eczema, broad nasal bridge, coarse
facies. The IgE level is typically elevated but can be normal.
Treatment is bactrim prophylaxis.
 Choice (A), leukocyte adhesion defect (LAD) does result in
recurrent staphylococcal infections. However, usually associated
with elevated white blood cell count and delayed umbilical cord
separation. Associated features of scoliosis and retained primary
teeth are not associated with LAD or (B) chronic granulomatous
disease (CGD). HyperIgM (D) and severe combined
immunodeficiency (E) usually present with
hypogammaglobulinemia, particularly IgG and IgA. Severe
combined immunodeficiency also usually presents in the first year
of life.
http://img.medscape.com/pi/emed/ckb/pediatrics_general/884940-886988-680.jpg
What do these 3 animals have in common?
Case 5
 15 month old male presents to office with
recurrent viral, bacterial infections since birth
 Hospitalized twice for severe sepsis and
bleeding associated with infections.
Worsening peripheral neuropathy for past 3
months
 PE normal except for skin which is pale white
 Labs: neutropenia and bone marrow smear
showing giant inclusion bodies inside WBCs.
IgG, IgA, and IgM are normal, and T and B
cells are normal in number
Case 5
The most likely diagnosis is:
A. Wiskott-Aldrich syndrome
B. Chediak-Higashi syndrome
C. severe-combined immunodeficiency
D. transient hypogammaglobulinemia of
infancy
E. X-linked agammaglobulinemia
Case 5 answer
 The correct choice is (B), Chediak-Higashi syndrome.
Chediak-Higashi syndrome is rare and presents in infancy with
recurrent viral and bacterial infections. Symptoms include severe
infections with Staphylococcus aureus, peripheral neuropathy,
bleeding, and oculocuataneous albinism. The defect is in the
LYST gene, which assists in lysosomal fusion with the
phagosome in WBCs. Defective formation of phagolysosomes
results in the inability of white blood cells to lyse bacteria once
ingested. This appears as accumulation of “giant inclusion
bodies” seen on bone marrow smear, which is the diagnostic
method.
 Wiskott-Aldrich syndrome (A) features a triad of recurrent
sinopulmomary infections, eczema, and thrombocytopenia.
Severe combined immunodeficiency (C) usually presents less
than 12 months of age with absent IgG, IgA, and IgM and
generally a lack of T cells (if B cells are present, they are
generally non-functional). Transient hypogammaglobulinemia of
infancy (D) is usually associated with a low IgG, and X-linked
agammaglobulinemia is associated with
panhypogammaglobulinemia (IgG, IgA, IgM).
CHEDIAK-HIGASHI SYNDROME
 Autosommal recessive
 Impaired phagolysosomal formation
 Finding: Giant lysosome granules in
phagocytes (neutrophils)
 Staphylococcus aureus and viral
infections
CHEDIAK-HIGASHI SYNDROME
oculocutaneous albinism
Peripheral neuropathy
Diagnosis: Bone marrow smear
Treatment: bone marrow
transplantation, frequent antibiotics
http://img.medscape.com/pi/emed/ckb/dermatology/1048885-1068184-344.jpg
Case 6
 8 mo male presents to office with history of
recurrent pneumonia and otitis media.
 Hospitalized at 5 mo of age for pneumonia and
bacteremia with Streptococcus pneumoniae.
Hospitalized again at 6 mo for Haemophilus
influenzae meningitis. He has chronic otorrhea
for 2 mo.
 PE: well appearing small infant. Weight and
length are <5%. Tonsils are absent and there
are no palpable lymph nodes.
Case 6
Which of the following is the most likely
diagnosis?
A. DiGeorge syndrome
B. Wiskott-Aldrich syndrome
C. X-linked agammaglobulinemia
D. hyperIgE syndrome
E. chronic granulomatous disease
Case 6 answer
 The correct answer is (C) X-linked agammaglobulinemia. Xlinked agammaglobulinemia (XLA) occurs in males and
characterized by recurrent sinopulmonary infections. Onset of
infections occur after 4-6 months of age when maternal
immunoglobulin begins to wane. XLA is caused by a mutation in the
Bruton’s tyrosine kinase (BTK) gene and results in lack of B cells,
cells responsible for producing antibody. Hence, all
immunoglobulins IgG, IgA, and IgM are low. Since B cells make
up a high proportion of lymphoid tissue including tonsils and lymph
nodes, these structures are typically small or absent in patients with
XLA. Poor weight gain, along with recurrent infections, should raise
suspicion of immunodeficiency.
 (A) DiGeorge syndrome associated with features like dysmorphic
facies, congenital heart defect, absent thymus, hypocalcemia, and
seizures. (B) Wiskott-Aldrich syndrome associated with eczema,
thrombocytopenia. (D) HyperIgE (Job’s syndrome) associated with
recurrent staphylococcal and candidal infections, and (E) CGD
associated with granulomas and recurrent infections with
Staphylococcus aureus, Aspergillus fumigatus, and Serratia
marscescens most commonly.
Case 7
 A 15 month old male presents to the office with a
history of bilateral otorrhea 3 weeks ago. He was
hospitalized at 6 and 9 months of age for
pneumonia, and bacterial meningitis at 11
months of age.
 PE shows a well appearing infant and is
otherwise unremarkable.
 Laboratory analysis shows IgG <120 and normal
IgA and IgM. Antibody to diphtheria, tetanus,
and S. pneumoniae are normal. Lymphocyte
enumeration reveals normal absolute numbers
of T, B, and NK cells.
Case 7
The most appropriate management for this
child is:
A. intravenous immunoglobulin
B. prophylactic antibiotics
C. initiate immunization to encapsulated
bacteria
D. bone marrow transplant
E. avoid live viral vaccines
Case 7 answer
 Correct answer choice is (B), prophylactic antibiotics. Infant
has transient hypogammaglobulinemia of infancy (THI). THI
occurs between 1-2 years of age and characterized by recurrent
bacterial infections. Most likely etiology is prolonged period for
physiologic B-cell function. THI is transient due to presence of B
cells. Distinguished from XLA where no B cells are present. In
XLA, IgG, IgA, and IgM are all low. In THI, IgG is low but IgA,
IgM are normal. Treatment for THI is prophylactic antibiotics (B).
Patients with THI usually reach normal antibody levels by 2-4
years of age.
 IVIG (A) is treatment of choice for XLA but can inhibit antibody
production in THI and is not usually indicated as treatment.
Patient has normal antibody responses to childhood vaccines,
and additional immunizations to encapsulated bacteria (C) would
not be warranted. Bone marrow transplantation (D) is treatment
of choice for severe combined immunodeficiency and other T cell
disorders, not THI. Patients who have THI are recommended to
receive their full childhood immunization series (E), although
antibody response to vaccine may be diminished.
Antibody Deficiency Syndromes
*Adapted from New Orleans Pediatric Board Review, Ricardo Sorensen
X-linked
Agammaglobulinemia
Common
Variable
Hypogammaglobulinemia
Transient
Hypogammaglobulinemia
Age of onset
Congenital (> 6
mo)
Any
1-2 years
IgM
low
Normal/low
Normal
IgG
Absent/low
low
low
IgA
Absent/low
Absent/low
Normal
Molecular
Defect
B cell tyrosine
kinase
TACI; ICOS
More to come!
?
B cells
Absent/low
Present
Present
IVIG
Yes
Yes
No
Case 8
 A 3 year old female presents to the office for a well child
check up.
 She began to lose motor milestones at age 2 years, and
has a history of repeated sinusitis and pneumonias often
requiring hospitalization and intravenous antibiotics.
Recently, the child has had difficulty maintaining gait
while walking and the parents report the child as
stumbling frequently.
 A paternal grandmother died at age 24 from severe
pneumonia.
 Physical examination is remarkable for several
prominent vessels under the skin and eye.
Case 8
The most likely diagnosis is:
A. leukocyte adhesion deficiency
B. DiGeorge syndrome
C. common variable immunodeficiency
D. chronic granulomatous disease
E. ataxia-telangiectasia
Case 8 answer
 The correct answer choice is (E), ataxiatelangiectasia. Ataxia-telangiectasia (AT) is an
autosommal recessive disorder. Although ataxia and
telangiectasias are unique features associated with this
disorder, the initial manifestation of AT is lost of motor
milestones. AT is associated with defective DNA
damage repair. Therefore, patients with AT should avoid
radiation (such as certain imaging modalities like CT)
due to DNA breakage which cannot be repaired. An
elevated alpha fetal protein suggests the diagnosis of
AT. Treatment is by bone marrow transplant.
 The features in this child are not associated with the
remaining answer choices (A-D).
http://www.google.com/imgres?imgurl=http://geneticpeople.com/wp-content/uploads/2010/02/Ataxiatelangiectasia1.gif&imgrefurl=http://geneticpeople.com/%3Ftag%3Dmutation%26paged%3D4&usg=__p8KxhlmyOhBtsJFtpiisbsQexps=&h=526&
w=652&sz=276&hl=en&start=1&zoom=1&um=1&itbs=1&tbnid=wIgIKiXGxTMpVM:&tbnh=111&tbnw=138&prev=/images%3Fq%3Dataxia%2Btelang
iectasia%26um%3D1%26hl%3Den%26safe%3Dactive%26tbs%3Disch:1
http://images.google.com/imgres?imgurl=http://www.nature.com/embor/journal/v5/n8/images/7400210f1.jpg&imgrefurl=http://www.nature.com/embor/journal/v5/n8/fig_tab/7400210_f1.html&usg=__8gzOaxOJqqZgNeph_5F8VYD
Case 9
 A 9 year old female presents to the office with
recurrent sinusitis since age 4.
 She has had 3 pneumonias in the same time
period which were successfully treated with
antibiotics.
 PE is unremarkable. Laboratory analysis shows
IgG 800, IgM 150, and IgA <6. Antibody to
diphtheria, tetanus, and S. Pneumoniae are
within the normal range. Lymphocyte
enumeration shows normal T, B, and NK cells.
Case 9
Which of the following should most likely
be avoided?
A. live viral vaccines
B. obtaining sinus culture results
C. allergy testing to environmental (indoor
and outdoor) allergens
D. intravenous immunoglobulin
E. prophylactic antibiotics
Case 9 answer
 Correct choice is (D), intravenous immunoglobulin.
Patient has selective IgA deficiency, most common primary
immunodeficiency (frequency ~ 1:400-1:500 persons).
Selective IgA deficiency presents with recurrent
sinopulmonary infections. IgG, IgM are normal, and IgA
absent. IVIG (D) contains small amounts of IgA. Some
patients with selective IgA deficiency have preformed
antibodies to IgA resulting in anaphylactic reaction when
given IVIG.
 Patients with selective IgA deficiency tolerate live viral
vaccines (A). Sinus culture results (B) would direct
antibiotic therapy in the future, and allergy testing (C) may
reveal other factors for increased risk for sinusitis.
Prophylactic antibiotics (E) may be helpful in patients with
recurrent sinusitis or bronchitis.
Case 10
 6 month old Caucasian male infant presents to the
Emergency Room with a 6 day history of pallor,
fussiness, hypoxia, and pulmonary infiltrates.
 Past medical and family history are non-contributory.
 On physical exam, the infant is ill-appearing,
tachypneic and is less than the 10% for weight.
Laboratory analysis shows an IgG of 16, IgA <6, and
IgM of 350. Antibody to diphtheria, tetanus, and S.
Pneumoniae are absent. Lymphocyte enumeration
shows normal number of T, B, and NK cells and
normal function. HIV PCR is negative.
Case 10
The most likely diagnosis is:
A. severe combined immunodeficiency
B. X-linked agammaglobulinemia
C. HIV infection
D. DiGeorge syndrome
E. hyperIgM syndrome
Case 10 answer
 Correct choice is (E), hyperIgM syndrome. HyperIgM
syndrome (HIM)usually is X-linked disease (males), but can
be AR. IgG, IgA are low, and IgM is elevated. Patients
characterized by opportunistic infections, particularly PCP
and cryptosporidia. HIM occurs because failure to express
CD40L (CD-154) on T cells, which is critical for B cells to
class switch. First antibody produced is IgM, but affected
patients cannot class switch and produce other Igs.
Patients with HIM display increased IgM, reduced levels of
IgG, IgA, IgE. Treatment: antibody replacement and bone
marrow transplantation.
 Severe combined immunodeficiency (A) is characterized by
absent T cells. XLA associated with agammaglobulinemia
(low IgG, IgA, and IgM), not elevated IgM. HIV (C) less
likely with negative PCR. DiGeorge syndrome (D)
characterized by low or absent T cells.
THANKS!