Page 477 - Clinical Immunology_ Principles and Practice ( PDFDrive )

458 ParT FOur Immunological Deficiencies

to tertiary care and research centers for investigation of rare the clinical presentation of these disorders. The medical history,
diseases is recommended. particularly the frequency, severity, and etiology of infections,
is most helpful to orient the diagnostic workup. Commonly
MOLECULAR TESTING FOR PRIMARY ordered tests in primary care, such as a CBC and serum Ig levels,
IMMUNE DEFECTS are helpful to support possible diagnosis and referral to the clinical
immunologist. Immunological testing according to clues obtained
Molecular testing for specific PIDs is available through commercial from the medical history helps narrow the differential diagnoses
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and research laboratories. Biochemical and genetic testing should to specific immunodeficiencies, which are confirmed by molecular
be considered. If autosomal recessive SCID is suspected, the methods. Description of new T-cell subsets (e.g., Th17 and
adenosine deaminase (ADA) and purine nucleoside phosphorylase regulatory T cells [Tregs]) has helped explain the immunopatho-
(PNP) enzyme activities in the RBCs should be determined. genesis of certain clinical manifestations, such as the occurrence
White blood cells must be used to measure the activity of these of autoimmunity in patients with combined immunodeficiency,
enzymes in recently transfused individuals, since donor RBCs and “cold abscesses” in the autosomal dominant HIES. Testing
will elevate the enzyme activity in deficient patients. AT has the for these lymphocyte phenotypes is being integrated in the clinical
consistent laboratory finding of elevated alpha-fetoprotein (AFP) evaluation. Identification of genetic defects can now be accom-
levels along with variable abnormalities in B- and T-cell function. plished by increased availability of whole exome sequencing, as
Nearly 300 defective genes and gene products have been identified an alternative to genetic analysis of candidate genes. Technological
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to result in congenital immunodeficiency syndromes. In these advances are making molecular diagnosis available for most
cases, the diagnosis can be confirmed with molecular genetic patients with immunodeficiency conditions.
analysis (Chapter 33). For example, gene mutations in BTK leading
to the absence of Bruton tyrosine kinase (BTK) results in arrest
of B-cell development at the pre–B cell stage in congenital X-linked ON THE HOrIZON
agammaglobulinemia. Similarly, abnormal T-cell development • Early diagnosis of severe combined immunodeficiency (SCID) and
leading to SCID results from mutations in at least 15 genes, non-SCID is the key to successful hematopoietic stem cell transplanta-
including IL2RG and JAK3. Patients with gene mutations that tion (HSCT).
may result in disease but have not been investigated need to be • Development of DNA sequence analysis for >300 types of primary
immunodeficiency (PID).
carefully evaluated to demonstrate the pathogenic nature of the • Wide availability of whole-genome sequencing methods to determine
genetic change. Some genetic changes do not have clinical sig- molecular defects for difficult to diagnose immunodeficiency
nificance and are known as single nucleotide polymorphisms syndromes
(SNPs). Standard protocols using Southern, Northern, and
Western blot analyses, PCR analysis, and DNA sequence analysis
are helpful to identify affected patients, affected fetuses prenatally, ILLUSTRATIVE CASES
and carriers of genetic mutations (Chapter 96). Most recently,
the use of whole exome sequencing for immunodeficiency Case 1
syndromes has facilitated the identification of new genes causing A 6-month-old Caucasian female infant was brought with a
immunodeficiencies by examining all known gene exons without history of rash and otitis media that had been recurrent since
bias, and simultaneously. This methodology for diagnosis is 2 weeks of age. The infant had poor weight gain, frequent spitting
particularly helpful when the clinical presentation does not match up, coughing spells, and persistent diarrhea. Maternal HIV testing
any of the already described immunodeficiency syndromes. 25 showed negative results. Physical examination revealed an emaci-
ated infant without palpable lymphoid tissue and severe oral
CONCLUSIONS thrush. Cystic fibrosis was ruled out by using genetic studies.
Stool viral cultures were persistently positive for rotavirus.
Immunodeficiency was suspected because of the infant’s failure
CLINICaL PEarLS to thrive, persistent chronic diarrhea, and recurrent infection.
Management of Immunodeficiency Patients An evaluation of the immune system was performed (Table
32.3). Humoral immunity testing showed Ig levels below or
• Lymphopenia is a hallmark of T-cell immunodeficiency in infancy. just above the lower limit of normal. Isohemagglutinins were
Unexplained lymphopenia should be recognized and evaluated.
• Normal range for immunoglobulin levels and lymphocyte counts varies not tested as the patient was less than 1 year old. As she had not
with age; age-matched controls should be used for interpretation. been immunized, specific antibody titers to vaccines were not
• Survival and morbidity outcomes of hematopoietic stem cell transplanta- tested. Stool α 1 -antitrypsin levels were normal, suggesting that
tion (HSCT) for severe combined immunodeficiency (SCID) are best protein was not being lost in stool, and urinalysis did not show
when performed in the first 4 months of age. protein loss. CBC revealed profound lymphopenia and absolute
• Delays in treatment of immunodeficiency leads to infections causing neutropenia. The neutropenia had resolved upon subsequent
permanent damage to organ systems, such as the lungs, where evaluations, but the lymphopenia persisted. A thymic shadow was
bronchiectasis or bronchiolitis obliterans may develop secondary to
recurrent pneumonias. not present on the chest radiograph. Evaluation of lymphocyte
• Implementation of universal screening of newborn infants by DNA subsets by flow cytometry revealed that the CD4 and CD8
analysis of dried blood spots on Guthrie cards (T-cell receptor excision T-cell and B-cell numbers were all markedly low. The patient’s
circle [TREC]) detect all T-cell deficiencies. lymphocytes had no proliferative response when stimulated with
phytohemagglutinin. The history and the physical examination,
The approach to the patient with suspected immune deficiency along with laboratory values, including low Ig levels and markedly
requires knowledge of developmental pathways and function of low lymphocyte numbers with poor proliferative response to
the different compartments of the immune system, as well as mitogen stimulation, strongly suggested the diagnosis of SCID.