Đề ôn thi thử môn hóa (860)

CHAPTER 103  Congenital Immunodeficiency

In addition to evaluating antibody quantity and quality, it is
essential to determine whether patients have normal B-cell numbers by evaluating lymphocyte subsets. The use of more detailed
B-cell immunophenotyping to evaluate B-cell development, the
presence of CD271 memory B cells, and the ability of memory B
cells to undergo immunoglobulin class switching has become
standard of care in many clinics, as it provides valuable diagnostic
and prognostic information.105
Flow cytometry testing to assess the expression of specific
proteins that are defective in B-cell and antibody deficiency
disorders—including BTK, CD40 ligand, CD40, ICOS, CD27,
BAFF receptor, and so on—can be performed in specialty laboratories and offer the ability to rapidly obtain a molecular diagnosis. This is typically supplemented by sequencing of specific
genes.

Diagnostic Testing: T Cells
T-cell testing begins with determination of whether the absolute
lymphocyte count is normal and assessment of lymphocyte subsets (CD41, CD81, CD561, CD162, CD191, Treg). Gross Tcell function can be ascertained beginning with T-cell proliferation assays. Vaccine responses with tetanus or diphtheria can also
be quantified. Diagnosis of specific T-cell defects are usually made
with flow cytometry to demonstrate alteration or absence of some
lymphocyte protein or focused genetic testing. Interrogation of
specific T-cell subsets and activation can also be used to identify
poorly functioning T-cell pathways.

Treatment of Immune System Disorders
Treatment: Complement
Patients with complement deficiency are susceptible to fulminant
sepsis and other deep-seated infections caused by encapsulated
organisms. For this reason, patients should be given a letter,
laminated card, medical alert bracelet/necklace, or Health Data
“Me” app that they can keep with them at all times with contact

information for their primary care physician and clinical immunologist and a message indicating that they have a complement
deficiency. The message should emphasize that there should be no
delay in giving parenteral antibiotics should they be ill. For patients who live at a distance from skilled medical care, consideration should be given to providing a dose of parenteral antibiotic,
such as ceftriaxone, that can be administered by the patient or a
family member when they become ill, before a lengthy trip to the
hospital. The efficacy of chronic prophylactic antibiotics to prevent infection in patients with complement deficiency is not well
studied and remains a significant question in this group of disorders. In addition to preparing for and treating infections, patients
should also be regularly screened for autoimmunity by history,
physical examination (i.e., blood pressure monitoring), and laboratory testing—including blood urea nitrogen, creatinine, and
urinalysis—to monitor for signs of glomerulonephritis because
this is a common autoimmune manifestation.

Treatment: Phagocytes
As noted earlier, management of phagocytic disorders revolves
around having a heightened suspicion for infections, aggressively
treating acute infections using antibiotics and G-CSF as needed
and developing a prophylaxis regimen that is both effective and

1227

reasonable from a patient standpoint. At times, patients continue
to have recurrent or severe infections despite these efforts and require more definitive therapy. As indicated earlier, HSCT has
been shown to be effective in many, but not all, phagocytic disorders. Gene therapy has been attempted for both X-linked CGD106
and for LAD-I,107 but neither has been particularly successful thus
far and at this point is considered to be experimental. Ongoing
research to address the challenges of gene therapy that are unique
to these two disorders is underway.

Treatment: B Cells and Antibodies
Immunoglobulin Replacement

In patients with antibody deficiency, replacement of IgG is critical
to maintaining health and preventing long-term complications
associated with recurrent infections. Immunoglobulin replacement therapy has been found to be effective when administered
intravenously (IVIg), subcutaneously (SCIg), and intramuscularly
(IMIg). US Food and Drug Administration–approved products
support administration via any of these routes. With that said,
because of significant discomfort associated with IMIg administration, this route is rarely used in North America. Most patients
are maintained on either IVIg or SCIg depending on patient
preference and provider recommendations related to each patient’s clinical need. Because the half-life of IgG in the circulation
is approximately 21 days under normal circumstances, IVIg is
typically administered every 3 to 4 weeks, providing high peak
levels followed by a decline over the ensuing weeks to a trough
before the next infusion. In contrast, SCIg is typically administered 1 to 2 times per week in smaller doses, providing a more
steady-state level of IgG in the circulation. IgG products are prepared from the pooled plasma collected from thousands of healthy
donors and therefore contain a broad range of antibodies. A reasonable starting dose of either IVIg or SCIg is 400 to 600 mg/kg
per month. This can be divided into the number of doses required
to administer the necessary monthly volume (IgG preparations
range in concentration from 5 g/100 mL [5%] to 20 g/100 mL
[20%]). In most patients, a trough IgG level of 600 mg/dL in the
blood is a reasonable initial minimum target. However, the dose
should then be adjusted to achieve a trough IgG level that prevents both acute infections and development of progressive lung
disease. There is evidence that, at least for bacterial pneumonia,
higher IgG trough levels are directly correlated with a decreased
risk of infection.108 Supplemental IgG is generally effective at
preventing lower respiratory tract infections (bronchitis and
pneumonia), but the response of upper tract disease (particularly
sinusitis) is more variable. Some patients have persistent sinus
symptoms that can be a significant clinical problem despite IgG
therapy. In these patients, the addition of prophylactic macrolide
therapy or increasing the frequency or dose of IgG infusions may

be beneficial.
Side effects with IVIg therapy are relatively common, occurring in up to 25% of treated patients.109 These include headaches, nausea, vomiting, chills, fatigue, fever, rash, and aseptic
meningitis. These can often be managed by changing the IgG
product being used; pretreating with diphenhydramine, acetaminophen, and corticosteroids before infusion; by augmenting hydration; or slowing the rate of infusion. Patients who
have persistent symptoms despite these measures will often
tolerate subcutaneous IgG supplementation. Side effects with
SCIg are rarer and consist mainly of transient local inflammatory reactions.


1228

S E C T I O N X I   Pediatric Critical Care: Immunity and Infection

Prophylactic Antibiotics
It has been increasingly recognized that in many patients with
antibody deficiency, replacement of IgG (even to normal levels)
may not prevent all clinically significant infections. The addition
of prophylactic antibiotics has been used as an adjunct to IgG
therapy to try to improve control of infections and decrease
morbidity. Unfortunately, to date there have been no wellperformed studies that argue strongly either for or against the use
of prophylactic antibiotics to improve outcomes. Further studies
are needed to clarify the role of prophylactic antibiotics and to
define the optimal regimen.

stem cell sources have been tried, including matched bone marrow,
matched peripheral blood, cord blood, and haploidentical. Lastly, a
variety of prophylactic immunosuppressive regimens have been
used in the early posttransplant period to limit GVHD and prevent
graft rejection. Each option has advantages and disadvantages,
which has led to the spectrum of transplant regimens that have

been attempted for SCID. Current efforts are underway to assess
which regimens offer the best outcomes and lowest risk.110–113

Treatment: T Cells

Amaya-Uribe L, Rojas M, Azizi G, Anaya JM, Gershwin ME. Primary
immunodeficiency and autoimmunity: A comprehensive review.
J Autoimmun. 2019;99:52-72.
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J Allergy Clin Immunol Pract. 2016;4:38-59.
Dotta L, Tassone L, Badolato R. Clinical and genetic features of Warts,
Hypogammaglobulinemia, Infections and Myelokathexis (WHIM)
syndrome. Curr Mol Med. 2011;11:317-325.
Frank MM. Complement deficiencies. Pediatr Clin North Am. 2000;47:
1339-1354.
Hanna S, Etzioni A. Leukocyte adhesion deficiencies. Ann N Y Acad Sci.
2012;1250:50-55.
Hussain A, Yu L, Faryal R, et al. TEC family kinases in health and
disease–loss-of-function of BTK and ITK and the gain-of-function
fusions ITK-SYK and BTK-SYK. FEBS J. 2011;278:2001-2010.
Lee WI, Torgerson TR, Schumacher MJ, et al. Molecular analysis of a
large cohort of patients with the hyper immunoglobulin M (IgM)
syndrome. Blood. 2005;105:1881-1890.
Mamcarz E, Zhou S, Lockey T, et al. Lentiviral gene therapy combined
with low-dose busulfan in infants with SCID-X1. N Engl J Med.
2019;380:1525-1534.
Notarangelo L, Casanova JL, Conley ME, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification
Committee Meeting in Budapest, 2005. J Allergy Clin Immunol.
2006;117:883-896.
Resnick ES, Moshier EL, Godbold JH, et al. Morbidity and mortality in

common variable immune deficiency over 4 decades. Blood. 2012;
119:1650-1657.
Rezaei N, Moazzami K, Aghamohammadi A, Klein C. Neutropenia and
primary immunodeficiency diseases. Int Rev Immunol. 2009;28:
335-366.
Segal BH, Leto TL, Gallin JI, et al. Genetic, biochemical, and clinical
features of chronic granulomatous disease. Medicine (Baltimore).
2000;79:170-200.
Kuhns DB, Alvord WG, Heller T, et al. Residual NADPH oxidase and
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363:2600-2610.

SCID was uniformly lethal in the first years of life until Good and
colleagues successfully reconstituted an affected infant with a
transplant of sibling bone marrow. Experience in subsequent years
has shown that patients with B-cell2positive SCID (IL2RG,
JAK3, IL7RA, etc.) readily reconstitute their T-cell deficiency but
may not develop significant B-cell chimerism. The reasons for this
are not entirely understood, but various hypotheses have been put
forward. From a practical standpoint, a lack of donor B-cell
engraftment may lead to a chronic need for IgG replacement
therapy even after transplant because patients may not be able
to mount sufficient antibody responses. Patients with B-cell2
negative SCID are more likely to have successful donor engraftment of both T- and B-cell lineages and more likely to recover full
humoral immune function.
One of the most significant challenges in the treatment of
SCID is that in the absence of family history, most patients come
to attention because of infections. These are most commonly
PJ pneumonia and severe viral infections (see earlier discussion).
PJ pneumonia can be treated but may lead to lung damage,

whereas viral infections may or may not be controllable. In addition, many SCID infants have significant diarrhea and weight loss
by the time they reach a transplantation center. Together, these
complications increase the risk of adverse outcomes during transplantation for SCID and have been the major impetus for adding
SCID to state newborn screening panels. Initial management
before transplantation involves aggressive supportive care, antimicrobials to treat any intercurrent infections (bacterial, viral, and
fungal), antimicrobial prophylaxis to prevent future infections,
and IgG replacement therapy.
There is significant debate about the best pretransplant conditioning regimen for patients with SCID to balance safety and efficacy. In general, those patients that have a matched sibling donor
receive no conditioning before receiving unmanipulated bone marrow. For other patients, a variety of conditioning regimens have
been tried, ranging from no conditioning to fully myeloablative
regimens. Similarly, a range of manipulated and unmanipulated

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