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322 Laboratory Medicine in Psychiatry and Behavioral Science
White blood cell (WBC) count differential: neutrophils
Type of test Blood
Background and explanation
of test
Neutrophils—the most abundant WBC type in the circula-
tion—are the body’s primary defense against microbial inva-
sion and important modulators of inflammation. These cells
identify and destroy invading pathogens through phagocyto
-
sis, degranulation, cytokine expression, and the formation of
neutrophil extracellular traps (NETs), which are fiber net
-
works containing DNA, enzymes, and other toxic substances.
Two populations of neutrophils of approximately equal size
exist in the blood, one in rapid circulation and the other mov
-
ing slowly along the inner walls of the vasculature (the “mar-
ginated pool”). These latter cells can be called up quickly in a
process of demargination to assist at sites of infection or tissue
injury.
Mature neutrophils have an elongated, pinched nucleus
said to be “segmented.” Immature neutrophils have a band-
shaped nucleus and are known as bands or stabs. When these
latter forms are detected in a blood sample, a “left shift” to
-
ward more immature cells recruited from the bone
marrow
is noted. Recruitment of cells from the marginated
pool, on
the other hand, does not result in a left shift.
The association of high neutrophil counts in peripheral
blood—neutrophilia—with cancer and infection has been
known for some time. Research has greatly increased under
-
standing of the adverse effects of neutrophils in amplification
of the inflammatory response and release of toxic molecules
that can destroy surrounding tissue, contribute to microvas
-
cular thrombosis and cancer cell metastasis, and result in per-
manent injury to the lungs, heart, and kidneys. In severe cases
of COVID-19, the formation of unregulated NETs is thought
to give rise to the acute respiratory distress syndrome, throm
-
bus formation, and other organ failures.
Each of the five types of WBC is counted, and the value is
expressed as a percentage of the total WBC count. Increases
or decreases in the total WBC count and in each cell type have
diagnostic importance. Although the percentage shows only
the relative number of each cell type, the absolute number can
be calculated by multiplying the percentage of that cell type
by the total WBC count. The absolute value is used to deter-
mine whether the count of a particular cell type is increased.
Relevance to psychiatry and
behavioral science
A decline in the number of neutrophils can occur with many
psychotropic drugs, including the following:
• Antipsychotics: amoxapine, chlorpromazine, clozapine,
fluphenazine, haloperidol, perphenazine, prochlorpera-
zine, risperidone, thiothixene, trifluoperazine
• Antidepressants: desipramine, imipramine, mirtazapine
• Anticonvulsants: carbamazepine, ethosuximide, pheny-
toin, valproate
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323 Laboratory Tests
White blood cell (WBC) count differential: neutrophils (continued)
Relevance to psychiatry and Severe neutropenia is defined by an ANC of <500 cells/
behavioral science (continued) mm
3
. This condition is well established as an adverse effect
of clozapine and occurs much more rarely with other psy
-
chotropic drugs. The risk of severe neutropenia is highest in
the first 18 weeks of clozapine treatment, but the condition
can occur at any time and is not dosage-dependent. Manage
-
ment of neutropenia is discussed in the Clozapine entry in
the Psychotropic Medications chapter.
Preparation of patient Fasting is not required. Any physiological stress should be
avoided just before testing.
Indications • WBC differential often included as routine component
of CBC.
• WBC differential may be added when WBC count is ab-
normal, to help determine source of abnormality.
• Routine monitoring for patients treated with clozapine
• Patient with fever, lymphadenopathy, or oral ulcerations
Reference range 3,000–7,000 cells/mm
3
(50% of total WBC count)
1,200–6,600 cells/mm
3
in adults with benign ethnic neutro-
penia. Individuals of African, Middle Eastern, and West In-
dian descent commonly have a lower baseline neutrophil
count in the absence of disease. This is known as “benign
ethnic neutropenia.”
Critical value(s) Neutropenia:
• Mild: 1,000–1,500 cells/mm
3
• Moderate: 500–1,000 cells/mm
3
• Severe:<500 cells/mm
3
Neutrophilia:
• >7,700 cells/mm
3
Increased levels • Infections: acute bacterial infections, fungal and spiro-
chetal infections, some parasitic and rickettsial infec-
tions
• Inflammation: vasculitis, rheumatoid arthritis, pancreati-
tis, gout, acute asthma, hypersensitivity reactions, rheu-
matic fever
• Tissue necrosis: MI, burns, tumors, lead or mercury poi-
soning, digitalis toxicity, venoms
• Acute hemorrhage, hemolytic anemia, hemolytic trans-
fusion reaction
• Diabetic ketoacidosis, preeclampsia, uremia
• Myeloproliferative diseases (e.g., leukemia)
• Cancers such as carcinoma
• Early viral infections, some parasitic infections
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324 Laboratory Medicine in Psychiatry and Behavioral Science
White blood cell (WBC) count differential: neutrophils (continued)
Increased levels (continued) • Postoperative state
• Smoking
Decreased levels • Decreased production: genetic and stem cell disorders,
acute overwhelming bacterial infections, viral infec
-
tions, certain rickettsial and protozoal infections, drugs,
chemicals, ionizing radiation, venoms, hematopoietic
diseases (e.g., aplastic anemia, iron deficiency anemia)
• Decreased cell survival: infections in patients with little
marrow reserve (e.g., elderly), collagen vascular dis-
eases (e.g., SLE), autoimmune disease, drug hypersensi-
tivity, and splenic sequestration
• Pregnancy: progressive decrease in segmented neutro-
phils until time of labor and delivery
• Numerous drugs, including antimicrobial, analgesic,
anti-inflammatory, cardiovascular, psychotropic, anti-
histamine, and antithyroid agents
Change in ratio • Degenerative shift to the left: increase in the number of
band forms without leukocytosis. This is found in cer-
tain overwhelming infections and has a poor prognosis.
• Regenerative shift to the left: increase in the number of
bands with leukocytosis. This is found in bacterial infec-
tions and has a good prognosis.
• Shift to the right: decreased bands are seen, with in-
creased segmented neutrophils. This is found in liver
disease, megaloblastic anemia, hemolysis, use of drugs,
cancer, and allergies.
• Hypersegmentation of neutrophils with no band forms: This
is found in pernicious anemia and other megaloblastic
anemias and in chronic morphine addiction.
Interfering factors Neutrophilia can be caused by physiological stress (excite-
ment, intense emotion, heat/cold exposure, exercise, vomit-
ing, menstruation, labor/delivery, or electric shock) or by
administration of steroids, in which case the neutrophilia
peaks in 4–6 hours and normalizes by 24 hours.
Reduced neutrophilic response to infection or stress can be
seen with old age or debility.
Cross-references Clozapine
Complete Blood Count
White Blood Cell Count
Atallah-Yunes SA, Ready A, Newburger PE: Benign ethnic neutropenia.Blood Rev 37:100586, 2019
Borges L, Pithon-Curi TC, Curi R, Hatanaka E: COVID-19 and neutrophils: the relationship between hy-
perinflammation and neutrophil extracellular traps.Mediators Inflamm 2020:8829674, 2020
Castanheira FVS, Kubes P: Neutrophils and NETs in modulating acute and chronic inflammation.Blood
133(20):2178–2185, 2019
Fischbach FT, Fischbach MA: A Manual of Laboratory and Diagnostic Tests, 10th Edition. Philadelphia,
PA, Wolters Kluwer Health/Lippincott Williams and Wilkins, 2018
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325 Laboratory Tests
White blood cell (WBC) count differential: neutrophils (continued)
Nader DN: Neutrophilia. Medscape, October 3, 2019. Available at: https://emedicine.medscape.com/
article/208576-overview. Accessed October 2021.
Shaul ME, Fridlender ZG: Tumour-associated neutrophils in patients with cancer.Nat Rev Clin Oncol
16(10):601–620, 2019
Silvestre-Roig C, Braster Q, Ortega-Gomez A, Soehnlein O: Neutrophils as regulators of cardiovascular
inflammation.Nat Rev Cardiol 17(6):327–340, 2020
Zuo Y, Yalavarthi S, Shi H, et al: Neutrophil extracellular traps in COVID-19.JCI Insight 5(11):e138999,
2020
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CHAPTER 2
Diseases and
Conditions
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328 Laboratory Medicine in Psychiatry and Behavioral Science
22q11.2 deletion syndrome
Clinical findings The 22q11.2 deletion syndrome (which now subsumes DiGeorge and ve-
locardiofacial syndrome) arises from a hemizygous microdeletion from
the long arm of chromosome 22, in most cases affecting >100 genes. As
could be expected, the effects of this deletion are numerous and varied,
involving cardiac and palatal malformations; immune dysfunction; en
-
docrine, genitourinary, and GI problems; and significant brain abnor-
malities associated with developmental delays, cognitive deficits, and
neuropsychiatric illness. This is the most common microdeletion syn
-
drome in humans, occurring in up to 1 in 2,000 live births. Prenatal and
newborn screening for this condition began in the 1990s, and individu
-
als born before that time may remain undiagnosed as adults.
Children and adolescents with this syndrome exhibit various physical
conditions and anomalies as well as developmental delays, learning dis
-
abilities, and variable degrees of intellectual disability. They are more
likely than unaffected individuals to develop ADHD, autism spectrum
disorder, anxiety disorders, mood disorders, and psychotic disorders/
schizophrenia. Attention, executive function, working memory, visuo
-
spatial abilities, motor skills, and social skills are impaired. There is in-
creased risk of behavioral disorders.
Later in life, affected individuals are more likely to come to clinical at-
tention because of neuropsychiatric problems. Mood episodes (both ma-
nia and depression), anxiety disorders, and psychosis are commonly
seen. Because this deletion syndrome represents the strongest known
molecular genetic risk factor for the development of psychosis, it is of
particular interest to psychiatric researchers as a model for the study of
schizophrenia.
Some combination of the following abnormalities is seen, starting early
in life:
• Congenital heart disease
• Malformation of the palate
•Hypocalcemia
• Immune deficiency
• Learning difficulties
• Facial dysmorphism in affected Whites (long face, malar flatness)
•Dysphagia
• Growth hormone deficiency
• Autoimmune disease
• Hearing loss and other sensory deficits
• Numerous other structural abnormalities involving virtually all
organ systems (e.g., thyroid, parathyroid, thymus)
Personality and temperament are often characterized as follows:
• Disinhibited and/or impulsive
• Shy and/or socially withdrawn
•Anxious
• Socially awkward
Cognitive and developmental problems include the following:
• Intellectual disability (mild) in up to half of children
• Substantially higher verbal than performance IQ scores
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329 Diseases and Conditions
22q11.2 deletion syndrome (continued)
Clinical findings
(continued)
• Developmental motor and language delays
• Autism and autism spectrum disorders
Laboratory testing At the initial visit for undiagnosed adults suspected of having 22q11.2
deletion syndrome:
• Clinical genetic testing of the patient, offspring, and parents (sib-
lings if the parents are unavailable). Consultation with a specialist
in 22q11.2 deletion syndrome is advised for this purpose. Pene
-
trance of deletion is complete, although the variability of clinical
syndrome is marked. Anticipation is not known to occur.
• Cognitive testing/capacity assessment
• Recommended laboratory tests: CBC with differential, electrolytes,
TSH, pH-corrected ionized calcium, magnesium, PTH, creatinine,
LFTs, lipid profile, glucose, HbA1c
Laboratory tests should be repeated at annual or biennial follow-up
visits.
Antshel KM, Fremont W, Roizen NJ, et al: ADHD, major depressive disorder, and simple phobias are
prevalent psychiatric conditions in youth with velocardiofacial syndrome. J Am Acad Child Adolesc
Psychiatry 45:596–603, 2006
Davies RW, Fiksinski AM, Breetvelt EJ, et al: Using common genetic variation to examine phenotypic ex-
pression and risk prediction in 22q11.2 deletion syndrome.Nat Med 26(12):1912–1918, 2020
Fung WL, Butcher NJ, Costain G, et al: Practical guidelines for managing adults with 22q11.2 deletion
syndrome. Genet Med 17(8):599–609, 2015
Gothelf D: Velocardiofacial syndrome. Child Adolesc Psychiatr Clin N Am 16(3):677–693, 2007
Green T, Gothelf D, Glaser B, et al: Psychiatric disorders and intellectual functioning throughout devel-
opment in velocardiofacial (22q11.2 deletion) syndrome. J Am Acad Child Adolesc Psychiatry
48:1060–1068, 2009
Lajiness-O’Neill R, Beaulieu I, Asamoah A, et al: The neuropsychological phenotype of velocardiofacial
syndrome (VCFS): relationship to psychopathology. Arch Clin Neuropsychol 21:175–184, 2006
McDonald-McGinn DM, Sullivan KE, Marino B, et al: 22q11.2 deletion syndrome.Nat Rev Dis Primers
1:15071, 2015
O’Rourke L, Murphy KC: Recent developments in understanding the relationship between 22q11.2 dele-
tion syndrome and psychosis.Curr Opin Psychiatry 32(2):67–72, 2019
Tang KL, Antshel KM, Fremont WP, Kates WR: Behavioral and psychiatric phenotypes in 22q11.2 dele-
tion syndrome. J Dev Behav Pediatr 36(8):639–650, 2015
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330 Laboratory Medicine in Psychiatry and Behavioral Science
Adrenal insufficiency (AI)
Clinical findings
Laboratory testing
AI is characterized by inadequate circulating cortisol levels, either from
disease of the adrenal cortex itself (primary AI) or lack of stimulation
by ACTH (central AI). Primary AI also involves inadequate aldosterone
production. AI can present acutely or as a chronic illness. AI is most
commonly caused by the use of exogenous glucocorticoid drugs that
suppress the HPA axis. Other causes of AI include pituitary adenomas,
autoimmune disease, TBI, and high-dose opioid treatment, among oth
-
ers. In the era of COVID-19, AI patients may be at particular risk be-
cause glucocorticoid levels can be insufficient for the severity of illness,
so the systemic inflammatory response can be heightened. In these
cases, a specific recommendation is made for the immediate doubling
of cortisol replacement therapy.
The acute presentation of AI—adrenal crisis—is characterized by an
abrupt deterioration in health status, with hypotension, fever, rapidly
progressive delirium, and stupor. With the administration of parenteral
glucocorticoids, symptoms resolve over 1–2 hours. If the condition is
not recognized and treated emergently, it can be fatal.
Chronic adrenal insufficiency is more likely to be encountered in the
psychiatric setting. Onset is insidious, and symptoms are nonspecific.
Clinical wisdom dictates that if you think of AI, you need to rule it out. Prom
-
inent signs of chronic AI include the following: hypotension, orthostasis,
weakness, weight loss, pain (myalgias, arthralgias), skin pigmentation
(resembling tanning, especially in skin creases and around nipples), pig
-
mentation of mucous membranes, vitiligo, loss of libido, amenorrhea,
anorexia, nausea, vomiting, salt craving, and hair thinning.
Most patients with AI have psychiatric symptoms, which include the
following: depression, anxiety, mania, apathy, profound fatigue, con
-
fusion, poor concentration, executive dysfunction, delusions, halluci-
nations, agitation, aggression, disinhibition, social withdrawal, and
sleep disturbances. EEG changes often seen to accompany mental sta
-
tus changes include diffuse slowing and bursts of sharp- and slow-
wave discharges, which may persist after clinical symptoms have re-
solved.
The gold standard of testing for AI is the so-called short corticotropin
test in which a dose of ACTH is administered parenterally, and serum
cortisol is checked 30 and/or 60 minutes later. If the response to stim-
ulation is subnormal, adrenal insufficiency is diagnosed, and a basal
ACTH level is checked. If the ACTH level is high, primary adrenal
insufficiency is diagnosed. If the ACTH level is low or low-normal,
central adrenal insufficiency is diagnosed, and MRI of the brain is per
-
formed to evaluate the pituitary gland. Note that in acute secondary
adrenal insufficiency due to pituitary stroke, results of the ACTH stim-
ulation test may be normal. In the workup of the underlying cause of
AI, autoantibodies against 21-hyroxylase are checked.
Numerous other laboratory abnormalities are seen in AI, including
low sodium, high potassium, high calcium, high bicarbonate, low bi-
carbonate with low pH (metabolic acidosis), elevated BUN, elevated
creatinine, anemia, lymphocytosis, and eosinophilia.
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331 Diseases and Conditions
Adrenal insufficiency (AI) (continued)
Almeida MQ, Mendonca BB: Adrenal insufficiency and glucocorticoid use during the COVID-19 pan-
demic. Clinics (Sao Paulo) 75:e2022, 2020
Anglin RE, Rosebush PI, Mazurek MF: The neuropsychiatric profile of Addison’s disease: revisiting a for-
gotten phenomenon.J Neuropsychiatry Clin Neurosci 18(4):450–459, 2006
Bancos I, Hahner S, Tomlinson J, Arlt W: Diagnosis and management of adrenal insufficiency.Lancet Di-
abetes Endocrinol 3(3):216–226, 2015
Charmandari E, Nicolaides NC, Chrousos GP: Adrenal insufficiency. Lancet 383(9935):2152–2167, 2014
Donegan D: Opioid induced adrenal insufficiency: what is new?Curr Opin Endocrinol Diabetes Obes
26(3):133–138, 2019
Pazderska A, Pearce SH: Adrenal insufficiency: recognition and management.Clin Med (Lond) 17(3):258–
262, 2017
Rushworth RL, Torpy DJ, Falhammar H: Adrenal crisis. N Engl J Med 381(9):852–861, 2019
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