MEDINA, Miguel Andrei C.

2016-00448
FINAL EXAM – OS 216 Immunology
We have as our patient M.C., a 9-month old Filipino male referred for the chief complaint of
recurrent infection. On history, it was noted that since M.C. was 2 months old, the patient had
already been hospitalized twice for pneumonia, requiring at least a week of unrecalled IV
antibiotics. Last week, the patient was again discharged from the hospital after his second bout
of diarrhea. On review of systems, it was noted that the patient was feverish and had cough
and colds, but without vomiting and urinary changes. There were rashes noted along the diaper
area, and the patient had good suck and good activity, and exhibited no seizures.
There was no noted food or drug allergies or previous surgeries. There was hypertension on the
paternal side of the patient, and there was no history of early deaths in the family. The patient
has been exclusively breastfed but is presently eating mashed carrots and sayote as
complementary food.
The patient was born full term to a 25 y/o G2P1 (1001) via SVD at a local hospital, with no
prenatal or postnatal complications. Newborn screening revealed normal results.
The patient was given BCG at birth, but no other vaccines have since been given. The patient
exhibits the ability to smile socially and to sit with support.
The patient lives in a concrete house along a busy street, with adjacent vacant lots. There were
no nearby canals or garbage dumps. The patient is not living with any pets, but it was reported
that the patient has stuffed toys to play with, and that their home contained curtains.
The patient is the second of 2 siblings from a non-consanguineous marriage; the mother is a
coffee shop barista while the father is a bank employee. M.C. has an older sister who is healthy.
On physical examination, the patient was awake, playful, and not in cardiorespiratory distress.
BP was 90/60 mmHg, HR 96 beats per minute, and the RR was 18 breaths/minute. Assuming
the heart rate was obtained while the patient was awake, the patient’s heart rate was slightly
lowered for his age (lower cut-off was 100 bpm). The patient’s respiratory rate was markedly
lowered (lower cut-off was 30 breaths/minute). Z-score was below -2 for weight for height,
indicating that the patient is wasted. The patient had pink palpebral conjunctivae and anicteric
sclerae. The tonsils were not appreciated. The oral mucosa was moist, but there was note of
whitish plaques on the tongue. There was note of right ear discharge. The patient had equal
chest expansion and clear breath sounds without any rales or wheezes. There were no heaves
or thrills. The apex beat was found at the 5 th ICS L anterior axillary line, with good S1 and S2,
NRRR, with no murmurs. The abdomen was globular and exhibited normoactive bowel sounds.
There were no masses or tenderness on palpation. The nailbeds were pink, and the peripheral
pulses were full and equal. There was no note of edema or cyanosis. The extremities exhibited
the full range of motion. There was noted maculopapular rashes along the diaper area. The
neurological exam was unremarkable.
The patient’s recurrent infections are highly suspicious for primary immunodeficiency. The
Jeffrey Modell Foundation developed the so-called “10 warning signs of primary
immunodeficiency,” and our patient exhibits some of these warning signs. The 10 warning signs
of primary immunodeficiency in children are as follows:
1. Four or more new ear infections within one year
2. Two or more serious sinus infections within one year
3. Two or more months on antibiotics with little effect
4. Two or more pneumonias within one year
5. Failure of an infant to gain weight or grow normally
6. Recurrent, deep skin or organ abscesses
7. Persistent thrush in mouth or fungal infection on skin
8. Need for intravenous antibiotics to clear infections
9. Two or more deep-seated infections including septicemia
10. A family history of primary immunodeficiency
Specifically, the presence of two hospitalizations due to pneumonia within a year, the chronic
diarrhea of the patient and the subsequent failure to gain weight, the presence of oral thrush
(the whitish plaques) on the tongue, and the need for IV antibiotics to clear infections all point
towards M.C. having a primary immunodeficiency. The absence of the tonsils is also highly
suspicious for a primary immunodeficiency. The (+) right ear discharge, suspicious for otitis
media, may also point towards having an immunodeficiency if it is recurrent. Further probing
on the history of this right ear discharge is warranted.
Other clues which may be elicited in the history which support a diagnosis of primary
immunodeficiency may include the presence of developmental delays, recurrent fevers, the
presence of poor wound healing, atypical and severe eczema, and hypersensitivity to sunlight.
Consanguinity may also predispose someone to having a primary immunodeficiency, but luckily
in this case the parents assert that their marriage was non-consanguineous. PID in the family
may also increase the risk for developing PID, but in this case, there were no unexplained early
deaths in the family, which may help us rule out this possibility. A history of autoimmunity or
hematologic disease may also predispose to having a primary immunodeficiency. Specific to this
case, more details on the reaction of the patient to the BCG vaccine should be elicited as this
would help narrow down our differentials.
As mentioned earlier, the oral thrush, absence of the tonsils, and the wasting of our patient are
all highly suspicious for a primary immunodeficiency. Other findings in the physical examination
which are associated with having an immunodeficiency include the presence of cold abscesses,
petechiae, pale skin, vitiligo, eczema, absence of sweating, nail dystrophy, and having abnormal
hair or teeth. The patient may also present with oral ulcers, gingivostomatitis, and periodontitis.
The patient may also present with retinal lesions. The lymph nodes may also be absent, or
lymphadenopathy may instead be present. The absence of the spleen is also another possible
finding. Instead, organomegaly of the liver or spleen may also occur. Neurological problems
such as ataxia and microcephaly/macrocephaly may also be associated with having a primary
immunodeficiency. Digital clubbing and angioedema may also be seen on PE.
A primary and a secondary immunodeficiency can be differentiated because secondary
immunodeficiency is caused by an underlying disease process or other unrelated cause, while
primary immunodeficiency is immunodeficiency due to gene mutations which are not caused
by another entity. Examples of secondary immunodeficiency include infections such as HIV,
measles, malaria, or influenza; protein losing conditions such as nephrotic syndrome;
immunodeficiency caused by medications (such as steroids/immunosuppressants), metabolic
issues such as diabetes and nutrient deficiencies; stress, and other conditions such as
prematurity, having malignancies (e.g., multiple myeloma), or being elderly.
The aforementioned warning signs and the history/PE all point towards a primary
immunodeficiency rather than a secondary immunodeficiency. Because the father is a bank
employee and the mother is working as a barista, and they have raised a healthy older sister, it
seems that the patient’s economic conditions are adequate, so deficiencies in nutrition which
would cause a secondary immunodeficiency may be unlikely. In addition, it was mentioned in
the history that the patient was presently eating various vegetables as complementary food to
breast milk, so nutritional deficiencies may be ruled out. An infection being passed down (e.g.
HIV) which may cause immunodeficiency would also be unlikely because of the healthy older
sister. Nevertheless, probing about sexual activities of the parents outside of the marriage,
specifically after the birth of the older sister, may be warranted. There was no note of
persistent intake of medicines which may cause a secondary immunodeficiency, but this should
be probed further.
Determining which arm of immunity is affected by this deficiency requires us to once again look
back at the patient’s history and PE. The two bouts of pneumonia were said to be resolved
using IV antibiotics. This points towards a bacterial etiology for the pneumonia. The arm which
is responsible for immunity against bacteria are the phagocytes, B-cells, and the complement
system. According to Ostapchuk et al. (2004), S. pneumoniae is the most common bacterial
cause of community-acquired pneumonia after the neonatal period. The B-cells are especially
important for protection against Streptococcus infections, so from this detail in the history, an
insult to the B-cell lineage is to be considered.
The recurrent diarrhea may point towards a recurrent rotavirus infection. Crawford et al. (2017)
mentions that rotaviruses are ubiquitous and would have infected almost every child by the age
of 3-5 years. Normally, high antibody levels are maintained in adults, which explains why
rotaviruses usually infect infants and younger children. Immunoglobulins (esp. IgA) and
interferons are important for protection against rotavirus infections. A deficiency in B-cells
would be compatible with the lack of Ig, thus explaining these recurrent rotavirus infections on
top of the recurrent pneumonia.
However, the recurrent rotavirus infections may also be compatible with a T-cell defect because
this infection is viral. Furthermore, the presence of oral thrush, an opportunistic fungal
infection by Candida albicans, may point towards an insult of the T-cell lineage. It’s important
to note that an isolated T-cell lineage insult is rare, and most common conditions affect both
the B- and T-cell arms of immunity, but with predominance to the T-cell line. Hence, besides an
isolated B-cell line insult, we should now also consider the possibility of having a combined B-
and T-cell defect to explain the patient’s findings.
It is also important to note that the first bout with pneumonia occurred around 2 months after
birth. This detail would be incompatible with an isolated B-cell line insult because of the
presence of maternal antibodies circulating in the body of the baby. Hence, even though
antibodies are important for defense against bacterial infections, this detail points us more
towards a predominant T-cell lineage insult, which characteristically presents earlier on (2-6
months of age).
Therefore, taking all these points into consideration, we could make an educated guess that the
affected arms are the B- and T-cell lineage but with predominance towards the T-cell arm.
However, history and PE can only go so far. Assumptions based on epidemiology were made as
to the etiology of the recurrent bouts with pneumonia and diarrhea. What can be ascertained
for now is the presence of a primary immunodeficiency. Detailed lab work-up will be able to say
for sure which arms of immunity are affected and may change our impression. Labs will allow
us to clinch the diagnosis of the specific immunodeficiency.
With that said, Severe Combined Immunodeficiency (SCID) is an excellent differential for this
case. This condition affects both the B- and T-cell arms of immunity but is predominantly a T-
cell problem. It is characterized by low to absent T-cells with varying B and NK cell levels. This
condition is caused by mutations in any one of 13 genes that code for crucial components of
lymphoid cell development. The clinical picture of our patient, who has persistent thrush,
pneumonia, diarrhea, and with failure to thrive is characteristic of a severe combined
immunodeficiency. The absent tonsils and the otitis media may also be explained by this
condition. Screening for SCID is done in the United States but not in the Philippines, so despite
the report of the parents that newborn screening was normal, SCID could still be a possibility.
The most common gene mutation involved in SCID is a mutation of the IL2RG gene which is
found in the X-chromosome, making X-linked SCID the most common presentation of this
disease. Other genes which may be involved are autosomal recessive and are not as common.
These genes may include the Jak3, IL7R alpha, CD45, CD3 delta or epsilon, ADA, RAG1/RAG2,
and the ARTEMIS genes. Because our patient is male, he is especially vulnerable to X-linked
genetic mutations. Because of this, we take X-linked Severe Combined Immunodeficiency as our
primary working impression for this case.
As mentioned earlier, the pathophysiology of X-linked SCID involves a mutation in the IL2RG
gene which codes for a common gamma chain found in cytokine receptors. This gamma chain is
a critical common component to various cytokine receptors which include the IL-2, IL-4, IL-7, IL-
9, IL-15, and IL-21 receptors. This common gamma chain functions in increasing the affinity of
the receptors for their respective cytokine and is also important in mediating intracellular
signaling. With deficient cytokine receptors, cytokine pathways important for lymphocyte
development and function will be impaired, explaining the immunodeficiency in X-linked SCID
patients. In X-linked SCID, T- and NK- cells are absent/uniformly low but with (+) B-cells. Despite
this, because of the defect in the common gamma chain, the B- cells are nonfunctional, and this
fact combined with the low/absent T- and NK-cell levels explains the various recurrent
infections and the failure of our patient to thrive.
Of course, other types of SCID should remain as differentials as they essentially present the
same way. For example, Jak3-deficient SCID is another form of severe combined
immunodeficiency which, like X-linked SCID, characteristically presents with low or absent T-
and NK-cells, but with an elevated percentage of B-cells. This condition is much rarer as it is
autosomal recessive, accounting for only 6% of SCID patients. This disorder is otherwise
identical to X-linked SCID, only being differentiated via genetic testing.
As mentioned earlier, history and PE can only go so far. Instead, there are other
immunodeficiencies which may be considered as differentials.
For example, X-linked agammaglobulinemia is another possible differential in this case. As
mentioned earlier, the patient is male, and susceptible to X-linked insults. This condition is
characterized by markedly low gammaglobulin levels due to a mutation in the Btk gene. The
low immunoglobulins would be able to explain the recurrent pneumonias of the patient, and
because immunity to rotaviruses are also partly mediated by Ig, it could also explain our
patient’s recurrent bouts with diarrhea. Furthermore, while it was noted on history that the
patient received the BCG vaccine at birth, there was no note of complications. According to
Norouzi et al. (2012), the critical arm in preventing BCG infections are the pathways involving
IFN-gamma, a cytokine produced by T-cells and NK-cells. Assuming that there were no
complications with the vaccine, then this would imply that the T-cell lineage was intact and that
we were dealing with an isolated B-cell lineage insult, casting doubt on our primary working
impression of X-linked SCID, wherein patients usually develop BCGosis or BCGitis upon receiving
the BCG vaccine. Despite this, the (+) oral thrush in the patient is uncharacteristic of a condition
which involves an isolated B-cell lineage insult, and complications from XLA first present later in
age (5-7+ months) due to protection from maternal antibodies, so XLA may be unlikely. Later
on, a chest x-ray may be able to detect a BCG reaction (a miliary pattern) which may have gone
unnoticed.
Wiskott-Aldrich syndrome (WAS) is another disease which may be considered. It is an X-linked
condition caused by mutations to the WAS gene. Classically, this condition is characterized by
susceptibility of infections in the setting of microthrombocytopenia and eczema. There was no
note of eczema in our patient. However, different mutations on the WAS gene may present
with different phenotypes without eczema. Patients with WAS are usually grouped into three:
X-linked thrombocytopenia, X-linked neutropenia, and classical WAS. The first two groups
present with mild or no eczema. However, patients in these first two groups only present with
milder immunodeficiencies compared to SCID.
DiGeorge syndrome (DGS) is another possibility, which also presents with a deficiency in the T-
cells. This syndrome results from 22q11.2 deletions, and presents with characteristic cardiac
abnormalities, abnormal facies, thymic dysplasia, cleft palate, and hypocalcemia. There was no
note of any cardiac abnormalities, abnormal facies, or cleft palate on the physical exam.
However, these syndromic features may actually be absent, subtle, or not recognized. Absence
of these syndromic features does not rule out DiGeorge syndrome, although it does make it
unlikely. Partial DGS is possible, being the most common non-SCID cause of T-cell lymphopenia,
and may also present with recurrent pneumonias or otitis media. However, these patients do
not usually suffer from opportunistic infections such as those from Candida albicans.
We have already identified from the history and PE that this patient most likely has a primary
immunodeficiency, however, it may still be possible that we were mistaken, and that a
secondary immunodeficiency is at play.
HIV/AIDS can also present with classical symptoms of SCID, causing recurrent infections and the
failure to thrive. As mentioned earlier, this may be unlikely because of the healthy older sister,
but sexual activities of both parents, especially after the birth of the older sister, should still be
investigated. HIV/AIDS can be differentiated from SCID through labs. HIV presents with a thymic
shadow on x-ray and will also present with normal lymphocyte count with elevated CD8+ cells.
Nutrient deficiency/extreme malnutrition may also cause the patient’s failure to thrive, but as
mentioned earlier, this was unlikely given the stable socioeconomic situation of the parents, the
healthy older sister, and the insistence that the patient was being fed vegetables as
complementary food to breastfeeding.
In any case, lab work-up will be able to screen for these conditions in addition to other
immunodeficiencies and help narrow them down.
The simplest test to order is a CBC with a manual differential count. A normal result for the
absolute lymphocyte count rules against a T-cell defect such as SCID. For our patient, we expect
this to be markedly low because T-cells normally make up around 70% of circulating
lymphocytes. A condition such as SCID would thus present with striking lymphopenia.
Occasionally however, the absolute lymphocyte count is falsely normal because of maternal
lymphocytes in the circulation. If clinical suspicion for SCID is high, then this should be
investigated further. At 9 months of age, the lower limit of normal lymphocyte counts is 4,500
lymphocytes/mm3.
The CBC would also help us exclude Wiskott-Aldrich syndrome, if the platelet size and count
were within normal limits. If Howell-Jolly bodies were not present, then this would rule against
congenital asplenia, another possible differential. A chest x-ray may be ordered to look for the
presence/absence of the thymic shadow and may also reveal concurrent BCGosis. In our
patient, we would expect an absent thymic shadow and miliary patterns on x-ray. The absence
of a thymic shadow would already cast doubt on the patient having HIV. Nevertheless, PCR
tests to screen for HIV may be useful to definitively rule out HIV. A Candida albicans
intradermal skin test may be ordered. Because the patient is <6 years old, this can be done with
0.1 mL of a 1:100 dilution of a potent extract. A skin reaction would indicate a functioning
immune system and would rule against a T-cell lineage insult, however this test is not as
reliable in patients younger than a year. In our patient, we can expect this to be abnormal,
especially since the patient is already presenting with (+) oral thrush. The erythrocyte
sedimentation rate may also be obtained, and a normal result indicates that chronic bacterial or
fungal infection was unlikely.
In the event that the absolute lymphocyte count was abnormal, then T-cell subset enumeration
by flow cytometry should be done as a follow-up. We expect CD3+ levels to be markedly
lowered (less than 300/mm3) in a patient with SCID. CD3+ T-cells usually constitute 70% of
peripheral lymphocytes. There may be cases of severe immunodeficiency in which T-cells are
phenotypically normal. In this case, testing for T-cell function may also be warranted. T-cell
proliferative responses to mitogens such as phytohemagglutinin, concanavalin A, or pokeweed
mitogen are absent or low in SCID because of the defect caused by the lack of a common
gamma chain.
Because we are considering XLA, we can also measure serum IgA levels. A normal value would
rule out selective IgA deficiency, the most common B-cell defect and another differential, and
would also rule against XLA. In SCID, we would also expect serum IgA levels to be markedly
lowered. In that case, measurement of other classes of immunoglobulins may also be taken.
SCID patients would most commonly present with depressed immunoglobulins of all classes.
The diagnosis of SCID can be made in a patient less than two years of age who exhibits the
clinical signs of having a predominant T-cell immunodeficiency and who has an absolute
lymphocyte count of less than 3000/mm 3, less than 20% CD3+ T-cells on flow cytometry, and
proliferative responses to mitogens less than 10% of control. Alternatively, diagnosis can be
made in the setting of these clinical symptoms and the presence of maternal lymphocytes in
circulation. Definitive diagnosis of SCID can be done through genetic testing, which would also
identify the specific genetic mutation. Our PWI, X-linked SCID, would present with a defect in
the IL2RG gene.
Genetic testing can also help rule out other combined immunodeficiencies such as WAS and
DGS. As mentioned earlier, these conditions usually present with characteristic features but
rarely, they may have phenotypes which may mimic SCID. Partial DGS, in particular, is the most
common non-SCID genetic cause of T-cell lymphopenia and should be ruled out via genetic
testing. Obtaining B and NK cell counts through flow cytometry is unnecessary for the diagnosis
of SCID but may help point us towards the specific SCID defect. For X-linked SCID, we would
expect (-) NK cells but (+) B cell levels. The absence of the common gamma chain (CD132) on
lymphocyte surfaces by flow cytometry may also indicate X-linked SCID. Both these tests are
not as definitive as genetic testing, however, and some X-linked SCID patients may present with
some NK cells, or present with lymphocytes expressing nonfunctional common gamma chains
on their surface.
Patients found to have abnormalities on any of these tests should be characterized as
completely as possible before definitive treatment is to start.
Infants with suspected SCID should be placed in protective isolation. Live vaccines should be
withheld. Any blood products given to the patient must be irradiated, leukodepleted, and CMV
negative. The mother’s serum should be tested for CMV and breastfeeding should be stopped if
ever this test comes back positive to avoid risk of transmission to the patient. Testing for CMV,
EBV, and other respiratory viruses in the patient may be indicated. Individuals infected with
CMV are often asymptomatic because of their healthy immune systems but in SCID patients,
CMV may cause problems. Prophylaxis against infections in SCID patients is also warranted.
Immune reconstitution via IV Ig 400-600 mg/kg, TMP-SMX to protect against P. jirovecii,
fluconazole for fungal prophylaxis, and acyclovir for herpesvirus prophylaxis are just some of
the ways this can be done. Definitive treatment for all forms of SCID is hematopoietic stem cell
transplantation (HSCT) from a tissue-matched donor. Patients have the highest chance of
 restoration of immune function if they receive an HLA-matched sibling donor, which will
facilitate the engraftment of NK, T-, and B-cells. Reduced-intensity or myeloablative
conditioning may need to be done in the event that haplocompatible (half-matched) relatives
or closely matched unrelated donors are used. Gene therapy is an alternative treatment but is
still being studied.
SCID is a true pediatric emergency and prognosis is poor if immune function is not restored
using HSCT. Most patients die at age 1 from infections caused by the lack of immunity.
Nevertheless, SCID is not a death sentence, and proper management of the case will allow the
patient to live a complete and healthy life.
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