CHAPTER CHAPTER

30 CEREBROSPINAL, SYNOVIAL, SEROUS

BODY FLUIDS, AND ALTERNATIVE
SPECIMENS
Donald S. Karcher, Richard A. McPherson

­ EREBROSPINAL FLUID, 510

C PLEURAL FLUID, 527 PERITONEAL FLUID, 533
Specimen Collection and Opening Specimen Collection, 527 Transudates and Exudates, 533
Pressure, 510 Transudates and Exudates, 527 Specimen Collection, 533
Indications and Recommended Recommended Tests, 527 Recommended Tests, 534
Tests, 511 Gross Examination, 528 Gross Examination, 534
Gross Examination, 511 Microscopic Examination, 528 Microscopic Examination, 534
Microscopic Examination, 512 Chemical Analysis, 529 Chemical Analysis, 535
Chemical Analysis, 515 Immunologic Studies, 531 Microbiological Examination, 536
Microbiological Examination, 521 Microbiological Examination, 531 ALTERNATIVE SPECIMENS, 536
SYNOVIAL FLUID, 522 PERICARDIAL FLUID, 531 Saliva, 536
Specimen Collection, 523 Specimen Collection, 531 Meconium, 536
Recommended Tests, 523 Gross Examination, 532 Hair and Nails, 536
Gross Examination, 523 Exudates And Transudates, 532 Breath Testing, 537
Microscopic Examination, 524 Microscopic Examination, 532 Tissue Aspirates, 537
Chemical Analysis, 526 Chemical Analysis, 532 CHEMICAL MEASUREMENTS IN
Lipids, 526 Immunologic Studies, 533 BODY FLUIDS, 537
Immunologic Studies, 527 Microbiological Examination, 533
Microbiological Examination, 527 SELECTED REFERENCES, 538

KEY POINTS
•  erebrospinal fluid is an essential part of a neurologic examination,
C predominantly along the superior sagittal sinus.
comprising special attention to cell counts, basic chemical analyses,
and microbiological cultures with specific antibody titers.
•  etermining the etiologic cause of fluid accumulation in various body
D (2) it confers a protective effect against sudden changes in acute venous
cavities (synovial fluid in joints, pleural fluid in the chest, pericardial
fluid around the heart, and peritoneal fluid in the abdomen) is critical
for proper treatment of these disorders.
•  erous fluids can be distinguished as either transudates that arise due
S
to an imbalance of hydrostatic pressures or exudates caused by an
inflammatory process.
•  ppropriate laboratory examination of these fluids is critical for the
A tight junctions; and the choroid plexus, where a single layer of special-
diagnosis of numerous diseases (bacterial, viral, and fungal infections;
distinction between various arthritides; primary [e.g., mesothelioma]
and metastatic malignancies; among others).
•  ccurate test interpretation depends on appropriate specimen
A glucose, urea, and creatinine diffuse freely but require 2 hours or longer to
­collection, physician/laboratory communication, analytically sound
laboratory methods, and reliable reference values.
•  lternative or nonstandard specimens can have an important role in
A
diagnostic or forensic testing; however, performing these tests may
require additional method validation to ensure their appropriateness
and accuracy.
­CEREBROSPINAL FLUID
In adults, approximately 500 mL of cerebrospinal fluid (CSF) is produced
each day (0.3–0.4 mL/min). The total adult volume varies from 90 to 150 mL,
about 25 mL of which is in the ventricles and the remainder in the subarach-
noid space. In neonates, the volume varies from 10 to 60 mL. Thus, the total
CSF volume is replaced every 5 to 7 hours (Wood, 1980). An estimated 70%
of CSF is derived by ultrafiltration and secretion through the choroid plex-
uses. The ventricular ependymal lining and the cerebral subarachnoid space
account for the remainder. CSF leaves the ventricular system through the
medial and lateral foramina, flowing over the brain and spinal cord surfaces
within the subarachnoid space. CSF resorption occurs at the arachnoid villi,
The CSF has several major functions: (1) It provides physical sup-
port because a 1500-­g brain weighs about 50 g when suspended in CSF;
(respiratory and postural) and arterial blood pressure or impact pressure;
(3) it provides an excretory waste function because the brain has no lym-
phatic system; (4) it is the pathway whereby hypothalamus releasing factors
are transported to the cells of the median eminence; and (5) it maintains
central nervous system (CNS) ionic homeostasis.
The blood-­brain barrier (BBB) consists of two morphologically distinct
components: a unique capillary endothelium held together by intercellular
ized choroidal ependymal cells connected by tight junctions overlies fenes-
trated capillaries. The CSF ionic components (e.g., H+, K+, Ca++, Mg++,
bicarbonate) are tightly regulated by specific transport systems, whereas
equilibrate. Proteins cross by passive diffusion at a rate dependent on the
plasma-­to-­CSF concentration gradient and inversely proportional to their
molecular weight and hydrodynamic volume (Fishman, 1992). Thus, the
BBB maintains the relative homeostasis of the CNS environment during
acute perturbations of plasma components.
SPECIMEN COLLECTION AND OPENING
PRESSURE
CSF may be obtained by lumbar, cisternal, or lateral cervical puncture
or through ventricular cannulas or shunts. Details of the performance of
lumbar puncture are described elsewhere (Herndon & Brumback, 1989;
Ward & Gushurst, 1992).
A manometer should be attached before fluid removal to record the
opening pressure. CSF pressure varies with postural changes, blood pres-
sure, venous return, Valsalva maneuvers, and factors that alter cerebral
blood flow. The normal opening adult pressure is 90 to 180 mm of water in
the lateral decubitus position with the legs and neck in a neutral position.

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It may be slightly higher if the patient is sitting up and varies up to 10   BOX 30.1 
mm with respiration. However, the pressure may be as high as 250 mm of Diseases Detected by Laboratory Examination of CSF
water in obese patients. In infants and young children, the normal range is
10 to 100 mm of water, with the adult range attained by 6 to 8 years of age High Sensitivity, High Specificity*
(Fishman, 1992). Opening pressures above 250 mm H2O are diagnostic Bacterial, tuberculous, viral, and fungal meningitis
of intracranial hypertension, which may be due to meningitis, intracranial Viral encephalitis 

PART 3
hemorrhage, and tumors (Seehusen et al., 2003). If the opening pressure
High Sensitivity, Moderate Specificity
is greater than 200 mm H2O in a relaxed patient, no more than 2.0 mL
should be withdrawn. Subarachnoid hemorrhage
Multiple sclerosis
Idiopathic intracranial hypertension is most commonly seen in obese
Central nervous system syphilis
women during their childbearing years. When an elevated opening pres-
Infectious polyneuritis
sure is noted, CSF must be removed slowly and the pressure carefully Paraspinal abscess 
monitored. Additional CSF should not be removed if the pressure reaches
50% of the opening pressure (Conly & Ronald, 1983). Moderate Sensitivity, High Specificity
Elevated pressures may be present in patients who are tense or straining Meningeal malignancy 
and in those with congestive heart failure, meningitis, superior vena cava Moderate Sensitivity, Moderate Specificity
syndrome, thrombosis of the venous sinuses, cerebral edema, mass lesions, Intracranial hemorrhage
hypoosmolality, or conditions inhibiting CSF absorption. Opening pres- Subdural hematoma
sure elevation may be the only abnormality in cryptococcal meningitis and
pseudotumor cerebri (Hayward et al., 1987). Decreased CSF pressure may CSF, Cerebrospinal fluid.
be present in spinal-­subarachnoid block, dehydration, circulatory collapse, * Sensitivity is the ability of a test to detect disease when it is present; specificity is
and CSF leakage. A significant pressure drop after removal of 1 to 2 mL the ability of a test to exclude disease when it is not present (see Chapter 8).
Modified from American College of Physicians, Health and Public Policy Commit-
suggests herniation or spinal block above the puncture site, in which case tee: The diagnostic spinal tap, Ann Intern Med 104:880, 1986, with permission.
no further fluid should be withdrawn.
Up to 20 mL of CSF may normally be removed. Prior to collecting
the sample, the clinician should be aware of the quantity of CSF required   BOX 30.2 
for the requested tests to ensure that a sufficient sample is submitted. In Recommended CSF Laboratory Tests
addition, the clinician should always provide an appropriate clinical his-
tory to the laboratory. The sample site (e.g., lumbar, cisternal) should be Routine
noted because cytologic and chemical parameters vary at different sites. Opening CSF pressure
The necessity for a simultaneous serum glucose should also be considered. Total cell count (WBC and RBC)
This is best obtained 2 to 4 hours before lumbar puncture because of the Differential cell count (stained smear)
delay in serum-­CSF equilibrium. Glucose (CSF/plasma ratio)
The CSF specimen is usually divided into three serially collected sterile Total protein 
tubes: tube 1 for chemistry and immunology studies; tube 2 for microbio- Useful Under Certain Conditions
logical examination; and tube 3 for cell count and differential. An additional
Cultures (bacteria, fungi, viruses, Mycobacterium tuberculosis)
tube may be inserted in the No. 3 position for cytology if a malignancy is Gram stain, acid-­fast stain
suspected. Under certain conditions, some variations are critical. For exam- Fungal and bacterial antigens
ple, if tube 1 is hemorrhagic because of a traumatic puncture, it should not Enzymes (LD, ADA, CK-­BB)
be used when protein studies are the most important aspect of the analysis Lactate
(i.e., suspected multiple sclerosis). Indeed, tube 3 should be examined for Multiplex polymerase chain reaction (PCR) assay (bacteria, fungi, TB,
the major purpose of CSF collection. Perhaps the only definite statement viruses)
one can make is that tube 1 should never be used for microbiology because Cytology
it may be contaminated with skin bacteria. If questions arise, communica- Isoelectric focusing and IgG immunoblotting
tion between the laboratory and clinician before CSF analysis is critical. Proteins (C-­reactive, 14-­3-­3, τ, β-­amyloid, transferrin)
Glass tubes should be avoided because cell adhesion to glass affects the VDRL test for syphilis
cell count and differential. Specimens should be delivered to the labora- Fibrin-­derivative d-­dimer
tory and processed quickly to minimize cellular degradation, which begins Tuberculostearic acid
within 1 hour of collection. Refrigeration is contraindicated for culture
specimens because fastidious organisms (e.g., Haemophilus influenza, Neis- ADA, Adenosine deaminase; CK-­BB, creatine kinase-­BB; CSF, cerebrospinal fluid;
LD, lactate dehydrogenase; RBC, red blood cell; TB, tuberculosis; VDRL, venereal
seria meningitidis) will not survive. It is also contraindicated for samples in disease research laboratory; WBC, white blood cell.
which flow cytometry is likely to be needed for detection of leukemia or Modified from Kjeldsberg CR, Knight JA: Body fluids: laboratory examination of
lymphoma cells, as refrigeration may affect expression and/or detection of ­amniotic, cerebrospinal, seminal, serous, and synovial fluids, ed 3, Chicago, 1993,
certain surface antigens on these cells.  © American Society for Clinical Pathology, with permission.

Microorganisms (bacteria, fungi, amebas), radiographic contrast material,

INDICATIONS AND RECOMMENDED TESTS
Indications for lumbar puncture can be divided into four major disease cat-
egories: meningeal infection, subarachnoid hemorrhage, primary or metastatic
malignancy, and demyelinating diseases (American College of Physicians,
1986). Identification of infectious meningitis, particularly bacterial, is the most
important indication for CSF examination (Box 30.1). Recommended labo-
ratory tests are directed toward identification of these disorders (Box 30.2).
CSF examination for other diseases is generally less helpful but often provides
supportive evidence of a clinical diagnosis or helps to rule out other diseases
(Irani, 2009). Limited routine studies followed by reflexive ordering of more
focused tests (as needed) on the stored specimen have been advocated as a way
of improving test efficiency (Albright et al., 1988).  cells and/or by interfering with automated instrument counting.
GROSS EXAMINATION
Normal CSF is crystal clear and colorless and has a viscosity similar to that of
water. Abnormal CSF may appear cloudy, frankly purulent, or pigment tinged.
Turbidity or cloudiness begins to appear with leukocyte (white blood cell
[WBC]) counts over 200 cells/μL or red blood cell (RBC) counts of 400/μL.
However, grossly bloody fluids have RBC counts greater than 6000/μL.
aspirated epidural fat, and a protein level greater than 150 mg/dL (1.5 g/L)
may also produce varying degrees of cloudiness. Experienced observers may
be able to detect cell counts of less than 50 cells/μL with the unaided eye by
observing for the Tyndall effect (Simon & Abele, 1978). Here, direct sun-
light directed on the tube at a 90-­degree angle from the observer will impart
a “sparkling” or “snowy” appearance as suspended particles scatter the light.
Clot formation may be present in patients with traumatic taps, com-
plete spinal block (Froin syndrome), or suppurative or tuberculous menin-
gitis. It is not usually seen in patients with subarachnoid hemorrhage. Fine
surface pellicles may be observed after refrigeration for 12 to 24 hours.
Clots may interfere with cell count accuracy by entrapping inflammatory
Viscous CSF may be encountered in patients with metastatic mucin-­
producing adenocarcinomas, cryptococcal meningitis due to capsular poly-
saccharide, or liquid nucleus pulposus resulting from needle injury to the
annulus fibrosus.
Pink-­red CSF usually indicates the presence of blood and is grossly
bloody when the RBC count exceeds 6000/μL. It may originate from a
subarachnoid hemorrhage, intracerebral hemorrhage, or cerebral infarct,
or from a traumatic spinal tap.

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CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
  TABLE 30.1
Xanthochromia and Associated Diseases/Disorders
CSF Supernatant Color Associated Diseases/Disorders
Pink RBC lysis/hemoglobin breakdown products
Yellow RBC lysis/hemoglobin breakdown products
Hyperbilirubinemia
CSF protein >150 mg/dL (1.5 g/L)
Orange RBC lysis/hemoglobin breakdown products
Hypervitaminosis A (carotenoids)
Yellow-­green Hyperbilirubinemia (biliverdin)
Brown Meningeal metastatic melanoma
CSF, Cerebrospinal fluid; RBC, red blood cell.
Xanthochromia
Xanthochromia commonly refers to a pale pink to yellow color in the
supernatant of centrifuged CSF, although other colors may be present
(Table 30.1). To detect xanthochromia, the CSF should be centrifuged and
the supernatant fluid compared with a tube of distilled water. Xanthochro-
mic CSF is pink, orange, or yellow owing to RBC lysis and hemoglobin
breakdown. Pale pink to orange xanthochromia from released oxyhemo-
globin is usually detected by lumbar puncture performed 2 to 4 hours after
the onset of subarachnoid hemorrhage, although it may take as long as
12 hours. Peak intensity occurs in about 24 to 36 hours and then gradually
disappears over the next 4 to 8 days. Yellow xanthochromia is derived from
bilirubin. It develops about 12 hours after a subarachnoid bleed and peaks
at 2 to 4 days but may persist for 2 to 4 weeks.
Visible CSF xanthochromia may also be due to the following: (1) oxy-
hemoglobin resulting from artifactual RBC lysis caused by detergent con-
tamination of the needle or collecting tube, or a delay of longer than 1 hour
without refrigeration before examination; (2) bilirubin (bilirachia) in jaun-
diced patients; (3) CSF protein levels over 150 mg/dL, which are also pres-
ent in bloody traumatic taps (>100,000 RBCs/μL) or in pathologic states
such as complete spinal block, polyneuritis, and meningitis; (4) disinfectant
contamination; (5) carotenoids (orange) in people with dietary hypercaro-
tenemia (i.e., hypervitaminosis A); (6) melanin (brownish) from meningeal
metastatic melanoma; and (7) rifampin therapy (red-­orange).
Although careful gross CSF inspection has good sensitivity (Britton
et al., 1983), spectrophotometry can also help to differentiate hemoglobin-­
derived substances from other xanthochromic pigments with different
maximal absorption peaks (Smith et al., 2013). 
Differential Diagnosis of Bloody CSF
A traumatic tap occurs in about 20% of lumbar punctures. Therefore, dis-
tinction of a traumatic puncture from a pathologic hemorrhage is of vital
importance. Although the presence of crenated RBCs is not useful, the
following observations may be helpful in distinguishing the two forms of
bleeding.
1. In a traumatic tap, the hemorrhagic fluid usually clears between the first
and third collected tubes but remains relatively uniform in subarach-
noid hemorrhage.
2. Xanthochromia, microscopic evidence of erythrophagocytosis, or
hemosiderin-­laden macrophages indicate a subarachnoid bleed in the
absence of a prior traumatic tap. RBC lysis begins as early as 1 to 2
hours after a traumatic tap. Thus, rapid evaluation is necessary to avoid
false-­positive results.
3. A commercially available latex agglutination immunoassay test for
cross-­linked fibrin derivative d-­dimer is specific for fibrin degrada-
tion and should theoretically be negative in traumatic taps (Lang et al.,
1990). However, it has been shown to not effectively distinguish suba-
rachnoid hemorrhage from traumatic lumber puncture (Eclache et al.,
1994).  Differential Cell Count
MICROSCOPIC EXAMINATION
Total Cell Count
Although the traditional manual method for cell counting in CSF sam-
ples, using undiluted CSF in a manual counting chamber, continues to be
a useful approach, because of the low cell counts frequently encountered
in CSF, the precision of manual counting in these samples is inherently
limited (Barnes et al., 2004, Zimmerman et al., 2011). Improvements in
the hardware and software in flow cytometers now allow reliable use of
these instruments in performing automated total WBC counts and WBC
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differential counts (Hoffman & Janssen, 2002; Aune et al., 2004), and even
in detecting bacteria (Nanos & Delanghe, 2008) in CSF samples. Although
these instruments are increasingly used clinically to perform these counts
on CSF samples, the low clinical decision levels for total WBC count in
CSF and persistent technical limitations of flow cytometers at low WBC
levels and with certain WBC types continue to be cause for concern (Hoff-
man & Janssen, 2002; Andrews et al., 2005; Glasser et al., 2009; Kleine
et al., 2009). When issues of turnaround time and cost are considered, how-
ever, automated total WBC and WBC differential counts in CSF samples
is a reasonable alternative to manual counting (Zimmerman et al., 2011;
Li et al., 2014), with added manual examination of the sample to avoid
missing pathologic cell types as a useful cross-­check (Strik et al., 2005).
When considering use of automated cell counters with CSF samples, labo-
ratories should carefully follow manufacturer and Clinical and Laboratory
Standards Institute guidelines (CLSI Approved Guideline H56-­A, 2006)
when implementing these automated methods.
The normal leukocyte cell count in adults is 0 to 5 cells/μL. It is higher
in neonates, ranging from 0 to 30 cells/μL, with the upper limit of normal
decreasing to adult values by adolescence. No RBCs should be present in
normal CSF. If numerous (except with a traumatic tap), a pathologic pro-
cess is probable (e.g., trauma, malignancy, infarct, hemorrhage). Although
RBC counts have limited diagnostic value, they may give a useful approxi-
mation of the true CSF WBC count or total protein in the presence of a
traumatic puncture by correcting for leukocytes or protein introduced by
the traumatic puncture. To be valid, all measurements (WBC, RBC, pro-
tein) must be performed on the same tube. This procedure also assumes
that the blood is derived exclusively from the traumatic tap. The corrected
WBC count is as follows:
WBCcorr = WBCobs − WBCadded
where
WBCadded = WBCBLD × RBCCSF / RBCBLD
and
WBCobs = CSF leukocyte count
WBCadded = leukocytes added  to CSF  by traumatic tap
WBCBLD = peripheral blood leukocyte count
RBCCSF = CSF  erythrocyte count
RBCBLD = peripheral blood erythrocyte  count
An analogous formula may be used to correct for added total protein
(TP):
TPadded = [TPserum × (1 − HCT)] × RBCCSF /RBCBLD
In the presence of a normal peripheral blood RBC count and serum
protein, these corrections amount to about 1 WBC for every 700 RBCs
and 8 mg/dL protein for every 10,000 RBCs/μL. This latter RBC correc-
tion factor is reasonably accurate as long as the peripheral WBC count is
not extremely high or low.
An observed/expected (added) WBC count ratio greater than 10 has a
sensitivity of 88% and a specificity of 90% for bacterial meningitis. When
the predicted WBC count is below the observed count, the probability of
bacterial meningitis appears to be low (Mayefsky & Roughmann, 1987;
Bonadio et al., 1990). 
Suggested differential count reference ranges are presented in Table 30.2.
A differential performed in a counting chamber is unsatisfactory because
the low cell numbers give rise to poor precision and identifying the cell
type beyond granulocytes and “mononuclears” is difficult in a wet prepara-
tion. Direct smears of the centrifuged CSF sediment are also subject to
significant error from cellular distortion and fragmentation.
The cytocentrifuge method is rapid, requires minimal training,
and allows Wright staining of air-­dried cytospins. It is the recommended
method for differential cell counts in all body fluids (Rabinovitch & Corn-
bleet, 1994). Cell yield and preservation are better than with simple centrif-
ugation. From 30 to 50 cells can be concentrated from 0.5 mL of “normal”
  TABLE 30.2
CSF Reference Values for Differential Cytocentrifuge Counts
Cell type Adults, % Neonates, %

Lymphocytes 62 ± 34 20 ± 18

PART 3
Monocytes 36 ± 20 72 ± 22
Neutrophils 2±5 3±5
Histiocytes Rare 5±4
Ependymal cells Rare Rare
Eosinophils Rare Rare

CSF, Cerebrospinal fluid.

Figure 30.2  Choroid plexus cells in cerebrospinal fluid.

Figure 30.1  Cerebrospinal fluid cytology (lymphocyte to monocyte distribution

ratio 70 : 30).

CSF. Variable artifactual distortions may be seen, but they are minimized
when the specimen is fresh, albumin is added to the specimen (2 drops
of 22% bovine serum albumin), and the cell concentration is adjusted to
about 300 WBCs/L prior to centrifugation (Kjeldsberg & Knight, 1993). Figure 30.3  Cluster of blastlike cells in cerebrospinal fluid from a premature new-
Manual differential cell counting on a cytocentrifuge preparation of CSF born. (From Kjeldsberg CR, Knight JA: Body fluids: laboratory examination of amniotic,
continues to be the most reliable method, even with low cell numbers. cerebrospinal, seminal, serous and synovial fluids, ed 3, Chicago, 1993, © American
Although automated differential counts may be safely performed on CSF Society for Clinical Pathology, with permission.)
samples using flow cytometers (Hoffman & Janssen, 2002; Aulesa et al.,
2003; Li et al., 2014), confirmation of the automated differential count   BOX 30.3 
by manual examination of a cytocentrifuged smear is recommended with
some instruments (Aune et al., 2004; Strik et al., 2005) and is a requirement Causes of Increased CSF Neutrophils
with specimens at risk for containing neoplastic cells. Effective detection of Meningitis
neoplastic cells, such as leukemic cells, using the cytocentrifuge method on
Bacterial meningitis
CSF appears to be highly instrument dependent (Huppmann et al., 2012).
Early viral meningoencephalitis
Filtration and sedimentation methods are too cumbersome for routine Early tuberculous meningitis
use. However, filtration does allow concentration of large volumes of CSF Early mycotic meningitis
for cytologic examination or culture while retaining the fluid filtrate for Amebic encephalomyelitis 
additional studies.
Other infections
In adults, normal CSF contains small numbers of lymphocytes and
monocytes in an approximate 70 : 30 ratio (Fig. 30.1). A higher proportion Cerebral abscess
of monocytes is present in young children, in whom up to 80% may be nor- Subdural empyema
mal (Pappu et al., 1982). Erythrocytes due to minor traumatic bleeding are AIDS-­related CMV radiculopathy 
commonly seen, especially in infants. Small numbers of neutrophils (poly- Following seizures
morphonuclear leukocytes [PMNs]) may also be seen in “normal” CSF Following CNS hemorrhage
specimens, most likely as a result of minor hemorrhage (Hayward & Oye, Subarachnoid
1988) and improved cell concentration methods. No general consensus Intracerebral 
regarding an upper limit of normal for PMNs has been established. Many Following CNS infarct
laboratories accept up to 7% neutrophils with a normal WBC count. Over Reaction to repeated lumbar punctures
60% neutrophils has been reported in high-­risk neonates without meningi- Injection of foreign material in subarachnoid space (e.g., methotrexate,
tis (Rodriguez et al., 1990). The number of PMNs may be decreased by as contrast media)
much as 68% within the first 2 hours after lumbar puncture owing to cell Metastatic tumor in contact with CSF
lysis (Steele et al., 1986).
Traumatic puncture may result in the presence of bone marrow cells, AIDS, Acquired immunodeficiency syndrome; CMV, cytomegalovirus; CNS, central
cartilage cells, squamous cells, ganglion cells, and soft-­tissue elements. nervous system; CSF, cerebrospinal fluid.
In addition, ependymal and choroid plexus cells may rarely be seen (Fig.
30.2). Moreover, blastlike primitive cell clusters, most likely of germinal 60%. However, in about one-­quarter of cases of early viral meningitis, the
matrix origin, are sometimes found in premature infants with intraven- proportion of PMNs also exceeds 60%. Viral-­induced neutrophilia usu-
tricular hemorrhage (Fig. 30.3). ally changes to a lymphocytic pleocytosis within 2 to 3 days. A total PMN
Increased CSF neutrophils occur in numerous conditions (Box 30.3). count of over 1180 cells/μL (or more than 2000 WBCs/μL) has a 99%
In early bacterial meningitis, the proportion of PMNs usually exceeds predictive value for bacterial meningitis (Spanos et al., 1989). Persistent

513
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CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
  BOX 30.4    BOX 30.6 
Causes of CSF Lymphocytosis Causes of CSF Eosinophilic Pleocytosis
Meningitis Commonly associated with:
Viral meningitis Acute polyneuritis
Tuberculous meningitis CNS reaction to foreign material (drugs, shunts)
Fungal meningitis Fungal infections
Syphilitic meningoencephalitis Idiopathic eosinophilic meningitis
Leptospiral meningitis Idiopathic hypereosinophilic syndrome
Bacterial due to uncommon organisms Parasitic infections 
Early bacterial meningitis where leukocyte counts are relatively low Infrequently associated with:
Parasitic infestations (e.g., cysticercosis, trichinosis, toxoplasmosis)
Bacterial meningitis
Aseptic meningitis due to septic focus adjacent to meninges 
Leukemia/lymphoma
Degenerative Disorders Myeloproliferative disorders
Subacute sclerosing panencephalitis Neurosarcoidosis
Multiple sclerosis Primary brain tumors
Drug abuse encephalopathy Tuberculous meningoencephalitis
Guillain-­Barré syndrome Viral meningitis
Acute disseminated encephalomyelitis 
CNS, Central nervous system; CSF, cerebrospinal fluid.
Other Inflammatory Disorders
Modified from Kjeldsberg CR, Knight JA: Body fluids: laboratory examination of
Handl syndrome (headache with neurologic deficits and CSF lymphocytosis) ­amniotic, cerebrospinal, seminal, serous and synovial fluids, ed 3, Chicago, 1993,
Sarcoidosis © American Society for Clinical Pathology, with permission.
Polyneuritis
CNS periarteritis

CNS, Central nervous system; CSF, cerebrospinal fluid.

  BOX 30.5 
Inflammatory and Infectious Causes of CSF Plasmacytosis
Acute viral infections
Guillain-­Barré syndrome
Multiple sclerosis
Parasitic CNS infestations
Sarcoidosis
Subacute sclerosing panencephalitis
Syphilitic meningoencephalitis
Tuberculous meningitis

CNS, Central nervous system; CSF, cerebrospinal fluid.

neutrophilic meningitis (over 1 week) may be noninfectious or due to less

common pathogens such as Nocardia, Actinomyces, Aspergillus, and the zygo-
Figure 30.4  Eosinophils in cerebrospinal fluid from a child with a malfunctioning
mycetes (Peacock et al., 1984). ventricular shunt.
Increased CSF lymphocytes have been reported in various diseases/
disorders (Box 30.4). Lymphocytosis (>50%) may occur in early acute bac-
terial meningitis when the CSF leukocyte count is under 1000/μL (Pow-
ers, 1985). Reactive lymphoplasmacytoid and immunoblastic variants may
be present, particularly with viral meningoencephalitis. Blastlike lympho-
cytes may be seen admixed with small and large lymphocytes in the CSF
of neonates.
Plasma cells, not normally present in CSF, may appear in a variety
of inflammatory and infectious conditions (Box 30.5), along with large
and small lymphocytes, and in association with malignant brain tumors
(Fishman, 1992). Multiple myeloma may also rarely involve the meninges
(Varga et al., 2018).
Although eosinophils are rarely present in normal CSF, they may be
increased in a variety of CNS conditions (Box 30.6). For example, eosino-
philia is frequently mild (1%–4%) in a general inflammatory response, but
in children with malfunctioning ventricular shunts, it may be marked (Fig.
30.4). A suggested criterion for eosinophilic meningitis is 10% eosinophils
(Kuberski, 1981); parasitic invasion of the CNS is the most common cause
worldwide. Coccidioides immitis is a significant cause of CSF eosinophilia in
endemic regions of the United States (Ragland et al., 1993).
Increased CSF monocytes lack diagnostic specificity and are usu- Figure 30.5 Hemosiderin-­laden macrophages (siderophages) from the cerebro-
ally part of a “mixed-­cell reaction” that includes neutrophils, lympho- spinal fluid of a patient with a subarachnoid hemorrhage. Hemosiderin crystals
cytes, and plasma cells. This pattern is seen in tuberculous and fungal (golden-­yellow) are also present. (From Kjeldsberg CR, Knight JA: Body fluids: labo-
meningitis, chronic bacterial meningitis (i.e., Listeria monocytogenes and ratory examination of amniotic, cerebrospinal, seminal, serous and synovial fluids, ed 3,
others), leptospiral meningitis, ruptured brain abscess, Toxoplasma men- Chicago, 1993, © American Society for Clinical Pathology, with permission.)
ingitis, and amebic encephalomeningitis. A mixed-­cell pattern without
neutrophils is characteristic of viral and syphilitic meningoencephalitis. Morphologic CSF examination for tumor cells has moderate sensitiv-
Macrophages with phagocytosed erythrocytes (erythrophages) appear ity and high specificity (97%–98%) (Marton & Gean, 1986). Sensitivity
from 12 to 48 hours following a subarachnoid hemorrhage or traumatic depends on the type of neoplasm. CSF examination of leukemic patients
tap. Hemosiderin-­laden macrophages (siderophages) appear after about has the highest sensitivity (about 70%), followed by metastatic carcinoma
48 hours and may persist for weeks (Fig. 30.5). Brownish yellow or red (20%–60%) and primary CNS malignancies (30%). Sensitivity may be
hematoidin crystals may form after a few days. optimized by using filtration methods with larger fluid volumes or by

514
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Figure 30.6  Acute lymphoblastic leukemia in cerebrospinal fluid. Note the uni-
formity of the blast cells.
Figure 30.7  Acute myeloid leukemia in cerebrospinal fluid.
performing serial punctures in patients in whom a neoplasm is strongly
suspected. Processing of CSF samples using liquid-­ based thin-­ layer
methods also increases sensitivity in the detection of neoplastic cells and
enhances preservation of these cells for potential immunocytochemical
analysis (Sioutopoulou et al., 2008). These liquid-­based methods are now
commonly used for cytopathologic examination of CSF and other body
cavity fluid specimens.
Leukemic involvement of the meninges is more frequent in patients
with acute lymphoblastic leukemia (Fig. 30.6) than in those with acute
myeloid leukemia (Fig. 30.7). Both are significantly more common than
CNS involvement in the chronic leukemias. A leukocyte count over
5 cells/μL with unequivocal lymphoblasts in cytocentrifuged preparations
is commonly accepted as evidence of CSF involvement. The incidence
of CNS relapse in children with lymphoblasts but cell counts lower than
6 cells/μL appears to be low and is not significantly different from cases
in which no blasts are identified (Odom et al., 1990; Gilchrist et al., 1994;
Tubergen et al., 1994). As noted previously, the ability to detect leuke-
mic cells in CSF using the cytocentrifuge method is highly instrument
dependent; low levels of these cells may be missed with certain instruments
(Huppmann et al., 2012).
Non-­ Hodgkin lymphomas involving the leptomeninges are usually
high-­grade tumors (lymphoblastic, large-­cell immunoblastic, and Burkitt
lymphomas; Fig. 30.8); low-­grade lymphomas and Hodgkin lymphoma are
significantly less common (Bigner, 1992; Walts, 1992). T cells predomi-
nate in normal and inflammatory conditions, whereas most lymphomas,
especially those occurring in immunocompromised hosts, are of B-­cell lin-
eage. Lymphoblastic lymphoma, the most common T-­cell lymphoma to
involve the CSF, can be detected by terminal deoxynucleotidyl transferase
stain.
Multiparameter flow cytometric immunophenotypic studies, deoxyri-
bonucleic acid (DNA) analysis by polymerase chain reaction (PCR), and,
more recently, DNA sequence analysis have been shown to significantly
improve diagnostic sensitivity and specificity in CSF samples involved by
leukemic or lymphoma cells (Rhodes et al., 1996; Finn et al., 1998; Scrideli &
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PART 3
Figure 30.8  Burkitt lymphoma in cerebrospinal fluid. The cells are characterized
by blue cytoplasm with vacuoles and a slightly clumped chromatin pattern. (From
Kjeldsberg CR, Knight JA: Body fluids: laboratory examination of amniotic, cerebrospi-
nal, seminal, serous and synovial fluids, ed 3, Chicago, 1993, © American Society for
Clinical Pathology, with permission.)
Queiroz, 2004; Bromberg et al., 2007; Quijano et al., 2009; Martinez-­
Laperche et al., 2013; Lacayo et al., 2013, Bento et al., 2018). Considering
their greater sensitivity in detecting leukemia or lymphoma cells in CSF
samples, whenever available, these advanced technologies should be part of
the complete evaluation in patients being worked up for these conditions.
Amebas, fungi (especially Cryptococcus neoformans), and Toxoplasma gon-
dii organisms may be present on cytocentrifuge specimens but may be dif-
ficult to recognize without confirmatory stains. 
CHEMICAL ANALYSIS
Reference values for lumbar CSF in adults are listed in Table 30.3.
Proteins
Total Protein
More than 80% of the CSF protein content is derived from blood plasma
in concentrations of less than 1% of the plasma level (Table 30.4).
Prealbumin (transthyretin), transferrin, and small quantities of nerve
tissue–specific proteins are the major qualitative differences that normally
exist between CSF and plasma proteins. Although some authors have
argued against routine measurement of total protein (American College of
Physicians, 1986), it is the most common abnormality found in CSF. Thus,
an increased CSF protein serves as a useful, albeit nonspecific, indicator of
meningeal or CNS disease.
Reference Values.  CSF total protein reference values vary considerably
among laboratories owing to differences in methods, instrumentation, and
type of reference standard used. CSF protein levels of 15 to 45 mg/dL have
long been accepted as the “normal” reference range (Silverman & Christen-
son, 1994). Other studies using different methods have shown generally higher
reference ranges, approximately 15 to 60 mg/dL (Lott & Warren, 1989).
Although discrepancies in gender and in those older than 60 years of
age have been reported, the differences are probably not significant. How-
ever, infants have significantly higher CSF protein levels than older chil-
dren and adults. Thus, mean levels of 90 mg/dL for term infants and 115
mg/dL for preterm infants were reported; the upper levels were 150 mg/
dL and 170 mg/dL, respectively (Sarff et al., 1976). Others have noted that
the CSF protein concentration falls rapidly from birth to 6 months of age
(mean levels, 108 mg/dL to 40 mg/dL), plateaus between 3 and 10 years
of age (mean, 32 mg/dL), and then rises slightly from 10 to 16 years of age
(mean, 41 mg/dL) (Biou et al., 2000).
Elevated CSF protein levels may be caused by increased permeability of
the BBB, decreased resorption at the arachnoid villi, mechanical obstruc-
tion of CSF flow due to spinal block above the puncture site, or an increase
in intrathecal immunoglobulin (Ig) synthesis. Common conditions associ-
ated with elevated lumbar CSF protein values (>65 mg/dL) are summa-
rized in Box 30.7.
Low lumbar CSF total protein levels (<20 mg/dL) normally occur in some
young children between 6 months and 2 years of age and in patients with con-
ditions associated with increased CSF turnover. These include (1) removal of
large CSF volumes; (2) CSF leaks induced by trauma or lumbar puncture;
(3) increased intracranial pressure, probably due to an increased rate of protein
resorption by the arachnoid villi; and (4) hyperthyroidism (Fishman, 1992).
515
CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
  TABLE 30.3   BOX 30.7 
Adult Lumbar CSF Reference Values Conditions Associated with Increased CSF Total Protein
Analyte Conventional Units SI Units Traumatic Spinal Puncture
Increased Blood-­CSF Permeability
Protein 15–60 mg/dL 0.15–0.60 g/L Arachnoiditis (e.g., following methotrexate therapy)
Prealbumin 2%–7% Meningitis (bacterial, viral, fungal, tuberculous)
Albumin 56%–76% Hemorrhage (subarachnoid, intracerebral)
α1-­Globulin 2%–7% Endocrine/metabolic disorders
Milk-­alkali syndrome with hypercalcemia
α2-­Globulin 4%–12%
Diabetic neuropathy
β-­Globulin 8%–18% Hereditary neuropathies and myelopathies
γ-­Globulin 3%–12% Decreased endocrine function (thyroid, parathyroid)
Electrolytes Other disorders (uremia, dehydration) 
Osmolality 280–300 mOsm/L 280–300 mmol/L Drug Toxicity
Sodium 135–150 mEq/L 135–150 mmol/L Ethanol, phenothiazines, phenytoin 
Potassium 2.6–3.0 mEq/L 2.6–3.0 mmol/L CSF Circulation Defects
Mechanical obstruction (tumor, abscess, herniated disk)
Chloride 115–130 mEq/L 115–130 mmol/L
Loculated CSF effusion 
Carbon dioxide 20–25 mEq/L 20–25 mmol/L
Increased Immunoglobulin (Ig) G Synthesis
Calcium 2.0–2.8 mEq/L 1.0–1.4 mmol/L Multiple sclerosis 
Magnesium 2.4–3.0 mEq/L 1.2–1.5 mmol/L
Neurosyphilis
Lactate 10–22 mg/dL 1.1–2.4 mmol/L Subacute sclerosing panencephalitis 
pH Increased IgG Synthesis and Blood-­CSF Permeability
Lumbar fluid 7.28–7.32 Guillain-­Barré syndrome
Cisternal fluid 7.32–7.34 Collagen vascular diseases (e.g., lupus, periarteritis)
Chronic inflammatory demyelinating polyradiculopathy
pCO2
Lumbar fluid 44–50 mm Hg CSF, Cerebrospinal fluid.
Cisternal fluid 40–46 mm Hg
pO2 40–44 mm Hg Methods.  Turbidimetric methods, commonly based on trichloroace-
tic acid (TCA) or sulfosalicylic acid and sodium sulfate for protein precipi-
Other Constituents
tation, are popular because they are simple, rapid, and require no special
Ammonia 10–35 μg/dL 6–20 μmol/L instrumentation. However, they are temperature sensitive and require
Glutamine 5–20 mg/dL 0.3–1.4 mmol/L much larger specimen volumes (about 0.5 mL). A false protein elevation
Creatinine 0.6–1.2 mg/dL 45–92 μmol/L may be observed using TCA methods in the presence of methotrexate
Glucose 50–80 mg/dL 2.8–4.4 mmol/L (Kasper et al., 1988). Benzethonium chloride and benzalkonium chloride
Iron 1–2 μg/dL 0.2–0.4 μmol/L have been used as precipitating agents in automated methods and micro-
methods (Luxton et al., 1989; Shephard & Whiting, 1992).
Phosphorus 1.2–2.0 mg/dL 0.4–0.7 mmol/L
Colorimetric methods include the Lowry method, dye-­ binding,
Total lipid 1–2 mg/dL 0.01–0.02 g/L methods using Coomassie brilliant blue (CBB) or Ponceau S, and the
Urea 6–16 mg/dL 2.0–5.7 mmol/L modified Biuret method. The CBB method is rapid and highly sensi-
Urate 0.5–3.0 mg/dL 30–180 μmol/L tive and can be used with small sample sizes. Immunochemical methods
Zinc 2–6 μg/dL 0.3–0.9 μmol/L measure specific proteins, require only 25 to 50 μL of CSF, and are
relatively simple to perform once conditions and reagents have been
CSF, Cerebrospinal fluid; pCO2, partial pressure of carbon dioxide; standardized. Automated methods are now almost always used and show
pO2, partial pressure of oxygen. good correlation with traditional standard methods (Lott & Warren,
1989). 
  TABLE 30.4 Albumin and IgG Measurements
Mean Concentrations of Plasma and CSF Proteins The permeability of the BBB may be assessed by immunochemical quan-
tification of the CSF albumin/serum albumin ratio in grams per decili-
Protein CSF, mg/L Plasma/CSF Ratio
ter (g/dL). The normal ratio of 1 : 230 (Tourtellotte et al., 1985) yields an
Prealbumin 17.3 14 unwieldy decimal of 0.004, which prompted the use of the CSF/serum
Albumin 155.0 236 albumin index, which is arbitrarily calculated as follows:
Transferrin 14.4 142 CSF albumin  (mg / dL)
CSF/Serum  albumin index = (Eq. 30.1)
Ceruloplasmin 1.0 366 Serum albumin  (g / dL)
Immunoglobulin (Ig) G 12.3 802 An index value less than 9 is consistent with an intact barrier. Slight
IgA 1.3 1346 impairment is considered with index values of 9 to 14, moderate impair-
α2-­Microglobulin 2.0 1111 ment with values of 14 to 30, and severe impairment with values greater
Fibrinogen 0.6 4940 than 30 (Silverman & Christenson, 1994). The index is slightly elevated in
IgM 0.6 1167 infants up to 6 months of age, reflecting the immaturity of the BBB, and
increases gradually after 40 years of age. A traumatic tap invalidates the
β-­Lipoprotein 0.6 6213
index calculation.
CSF, Cerebrospinal fluid. Increased intrathecal IgG synthesis is reflected by an increase in the
Modified from Felgenhauer K: Protein size and cerebrospinal fluid composition, CSF/serum IgG ratio:
Klin Wochenschr 52:1158, 1974, with permission.
CSF IgG  (mg / dL)
CSF/Serum IgG ratio = (Eq. 30.2)
Protein electrophoresis of concentrated normal CSF reveals two dis- Serum IgG  (g / dL)
tinct differences from serum: a prominent transthyretin (prealbumin) The normal ratio is 1/390 or 0.003 (Tourtellotte et al., 1985). Similar
band and two transferrin bands. Transthyretin is relatively high because to the albumin index, the CSF/serum IgG index may be obtained by using
of its dual synthesis by the liver and choroid plexus. The second trans- milligrams per deciliter for the CSF IgG value. The CSF/serum IgG index
ferrin band, referred to as β2-­transferrin, migrates more slowly than its normal range is 3.0 to 8.7.
serum equivalent owing to cerebral neuraminidase digestion of sialic acid The CSF/serum IgG index can be elevated by intrathecal IgG syn-
residues.  thesis or increased plasma IgG crossover from breakdown of the BBB. Ig

516
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derived from plasma crossover may be corrected by dividing the CSF/
serum IgG index by the CSF/albumin index to yield the CSF IgG index.
CSF IgG  (mg / dL) / Serum  IgG  (g / dL)
CSF  IgG  index =
CSF albumin (mg / dL) / Serum albumin (g / dL)
(Eq. 30.3)
or
CSF IgG  (mg / dL) × Serum  albumin (g / dL)
CSF  IgG  index =
Serum IgG (g / dL) × CSF albumin (mg / dL)
(Eq. 30.4)
The reference range for the IgG index varies, reflecting variations in
determination of the four index components. A reasonable normal upper
limit is 0.8 (Souverijn et al., 1989). However, each laboratory should deter-
mine its own critical ratio.
The IgG synthesis rate is calculated by an empirical formula (Tour-
tellotte et al., 1985):
(Eq. 30.5)
All protein concentrations are expressed in milligrams per deciliter. The
first bracketed term represents the difference between measured CSF IgG
and the IgG expected from diffusion across a normal BBB; 369 is the nor-
mal serum/CSF ratio. The second bracketed term represents the difference
between measured CSF albumin and expected albumin if the blood-­brain
barrier is intact; 230 is the normal serum/CSF albumin ratio. The CSF
albumin excess is multiplied by the IgG/albumin ratio and the molecular
weight ratio of IgG to albumin (0.43) to correct for changes in CSF IgG due
to increased barrier permeability. The number 5 converts the result from a
concentration to a daily amount, assuming an average daily CSF production
of 500 mL (i.e., 5 dL). The formula does not consider variations in CSF pro-
duction or Ig consumption. It assumes that the IgG/albumin ratio remains
constant over various degrees of BBB impairment—a concept that may lead
to variable error (Lefvert & Link, 1985). The reference interval for the syn-
thesis rate is –9.9 to +3.3 mg/day. Values greater than 8.0 mg/day indicate an
increased rate (Silverman & Christenson, 1994).
CSF IgG is normally 3% to 5% of total CSF protein. However, in
multiple sclerosis (MS), the concentration approaches that of plasma
(15%–18%) (Hersey & Trotter, 1980). The CSF IgG index and the IgG
synthesis rate have a sensitivity of 90% in patients with definite MS, but the
sensitivity is lower in patients with possible MS, in whom accuracy is most
needed (Marton & Gean, 1986). In addition, the specificity for MS is only
moderate because increased intrathecal IgG synthesis occurs in many other
inflammatory neurologic diseases.
The Ig index and synthesis rate calculations may also be applied to IgM,
IgA, Ig light chains, and specific antibodies to infectious microorganisms.
For example, increased synthesis of IgM and free κ light chains have been
suggested as markers for MS (Rudick et al., 1989; Lolli et al., 1991).
Electrophoretic Techniques.  Although the diagnosis of MS is ulti-
mately a clinical one, significant advances have been made in laboratory test-
ing for this disorder. CSF total protein is increased in less than 50% of patients
with MS. Indeed, if the CSF protein exceeds 100 mg/dL, the patient prob-
ably does not have MS. However, the γ-­globulin fraction, as determined by
CSF electrophoresis, is often increased in MS. Thus, the CSF total protein/γ-­
globulin ratio exceeds 0.12 in about 65% of cases (Johnson & Nelson, 1977).
Using electroimmunodiffusion, a CSF IgG/albumin ratio greater than 0.25
is present in about 75% of cases (Tourtellotte et al., 1971). Levels greater
than the mean CSF IgG index + 3SD are present in 80% to 85% of MS cases,
although the upper reference level varies significantly among laboratories.
High-­ resolution agarose gel electrophoresis of concentrated CSF
from patients with MS often shows discrete populations of IgG, the oligo-
clonal bands. Although these discrete IgG populations are normally absent,
two or more bands are necessary to support the diagnosis of MS; a single
band is not considered a positive result. Using this technique, oligoclonal
bands have been reported in 83% to 94% of patients with definite MS,
40% to 60% of those with probable MS, and 20% to 30% of possible MS
cases. However, they are also frequently present in patients with subacute
sclerosing panencephalitis, various viral CNS infections, neurosyphilis,
neuroborreliosis, cryptococcal meningitis, Guillain-­Barré syndrome, trans-
verse myelitis, meningeal carcinomatosis, glioblastoma multiforme, Burkitt
lymphoma, chronic relapsing polyneuropathy, Behçet disease, cysticercosis,
and trypanosomiasis, among others (Trotter & Rust, 1989; Chalmers et al.,
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1990; Fishman, 1992; Hall & Snyder, 1992). Subsequent studies have shown
that agarose gel electrophoresis sensitivity for MS is less than previously
reported (see later discussion).
Oligoclonal light chains (both κ and λ) are present in about 90% of
MS patients (Gallo et al., 1989; Sindie & Laterte, 1991). They have also
occasionally been identified in the CSF of those who are negative for IgG
PART 3
oligoclonal bands. Detection of free light chains in CSF and comparison
to serum has been shown to be a sensitive marker for intrathecal immuno-
globulin synthesis (Fischer et al., 2004).
Coomassie brilliant blue or paragon violet stains can resolve oligo-
clonal bands in only 5 μg of IgG (Silverman & Christenson, 1994). How-
ever, silver staining is 20 to 50 times more sensitive than CBB and can
be used on unconcentrated CSF. It is important to note that these electro-
phoretic techniques must be simultaneously carried out on the patient’s
serum to be certain that a polyclonal gammopathy is not present (e.g., liver
disease, systemic lupus, rheumatoid arthritis [RA], chronic granulomatous
disease) because these disorders may be accompanied by Ig diffusion into
the CSF, yielding false-­positive results.
Immunofixation electrophoresis (IFE) is more sensitive than agarose
gel electrophoresis and does not require CSF concentration (Cawley et al.,
1976). Another study reported a sensitivity of 74% using this technique
compared with 57% for agarose gel electrophoresis (Cavuoti et al., 1998).
More recently, using a semiautomated immunofixation-­peroxidase tech-
nique, the sensitivity was 83% and the specificity was 79% in patients with
clinically definite MS (Richard et al., 2002).
Isoelectric focusing and IgG immunoblotting (IgG-­IEF) per-
formed on paired CSF and serum samples is the most sensitive and now
the recommended method for the detection of oligoclonal bands (Anders-
son et al., 1994; Fortini et al., 2003; Keren, 2003). One study showed that
IgG-­IEF detected 100% of definite MS, but only about 50% were positive
by agarose electrophoresis (Lunding et al., 2000). Others detected 91% of
MS cases but only 68% with agarose (Seres et al., 1998). Similarly, a semi-
automated IgG-­IEF technique identified 90% of MS cases compared with
60% for agarose electrophoresis (Fortini et al., 2003). In 2005, an inter-
national consensus standard for the diagnosis of MS established IgG-­IEF
as the method of choice for qualitative detection of oligoclonal IgG bands
as evidence of intrathecal synthesis of IgG (Freedman et al., 2005). More
recent studies have reinforced the utility of IgG-­IEF in diagnosing MS
and distinguishing this disease from other disorders (Dobson et al., 2013).
Figure 30.9 shows the different patterns seen on IgG-­IEF in paired CSF
and serum samples from patients with MS and other conditions.
Oligoclonal bands (OCBs) in CSF have a high sensitivity but low speci-
ficity for MS; thus, they are useful for screening but not for diagnosis. The
overlap of positive OCB findings in infectious and other inflammatory con-
ditions has stimulated the search for new biomarkers in CSF that are more
specific for MS (Gastaldi et al., 2017) and that have potential prognostic
relevance. Candidate markers showing promise include the following:
• Immunoglobulin free light chains (FLCs) as an indicator of B-­cell activity
are found in serum as well as other body fluids and could potentially be
useful for diagnosing true MS patients who happen to be OCB nega-
tive. Early studies indicate utility for FLC measurements in CSF (espe-
cially because such measurements are automated); however, larger patient
groups should be evaluated for wide acceptance (Presslauer et al., 2016).
• Oligoclonal IgM bands in CSF appear to be a very powerful marker
for more severe and more aggressive MS (Villar et al., 2005). Unfor-
tunately, hydrophobicity of IgM requires its chemical reduction prior
to electrophoresis, which may still be affected by artifacts from reas-
sociation of monomeric IgM. Nevertheless, oligoclonal IgM in CSF
(which is directed against myelin lipid, usually phosphatidylcholine) is
considered a very promising prognostic test for MS but will require
more developmental work for standardization (Thangarijh et al., 2008).
• 
The measles-­ rubella-­zoster (MRZ) reaction consists of measuring
antibody titers to those viruses in CSF and serum. The MRZ reac-
tion is positive if at least two of those indexes (CSF titer/serum titer)
are positive. MRZ is considered highly specific for MS and could be
recommended for patients with suspected MS who are OCB negative
(Brettschneider et al., 2009).
• Neurofilaments are released into CSF following neuron and axon inju-
ry. They are also found in serum and, as such, could be used to monitor
progression of MS as a highly prognostic marker once measurements
become well established and are widely practiced (Petzold, 2015).
Further advances in CSF proteomic testing whereby literally hundreds
of individual protein species can be identified is likely to provide more
diagnostic power for neurologic diseases in coming years (Núñez Galindo
et al., 2019; Jankovska et al., 2019).
In summary, the diagnosis of MS, as with many other neurologic dis-
orders, is ultimately a clinical one based on neurologic history and physical
517
 6.5 pH 9.0
CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
CSF
S Type 1
CSF
S Type 2
CSF
S Type 3
CSF
S Type 4
CSF
S Type 5
Figure 30.9  Immunoglobulin G isoelectric focusing (IgG-­IEF) analysis of cerebro-
spinal fluid (CSF) illustrating the different patterns seen in paired CSF and serum
(S) samples from patients with multiple sclerosis (MS) and other conditions. The 5
classic patterns are: Type 1, no bands in CSF or S samples; Type 2, oligoclonal IgG
bands in CSF and none in the S sample, indicative of intrathecal IgG synthesis; Type
3, oligoclonal bands in CSF (like Type 2) and additional identical oligoclonal bands
in CSF and S samples, still indicative of intrathecal IgG synthesis; Type 4, identical
oligoclonal bands in CSF and S samples, indicative of a systemic and not intrathecal
immune reaction with a normal or abnormal blood–CSF barrier and passive transfer
of oligoclonal bands from S to CSF; and Type 5, identical monoclonal bands in
CSF and S samples, indicative of the presence of a paraprotein (monoclonal IgG
component). (Modified from Freedman MS, Thompson EJ, Deisenhammer F, et al.:
Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple
sclerosis: a consensus statement, Arch Neurol 62:865, 2005; used with permission.)
examination. Nevertheless, advanced laboratory results in CSF—such as
elevated IgG indices, particularly the detection of oligoclonal IgG bands and
neuroimaging techniques—have proved invaluable in the diagnosis of MS.  including human immunodeficiency virus (HIV)-­1, other inflammatory
Other CSF Proteins
Approximately 300 different proteins have been identified in CSF using
two-­dimensional electrophoresis, the first dimension being isoelectric
focusing and the second polyacrylamide gel in the presence of sodium
dodecyl sulfate (Harrington et al., 1986). Using this technique, four
abnormal proteins were identified in patients with Creutzfeldt-­Jakob
disease (CJD). Two of these proteins (molecular mass about 40 kilodal-
tons [kDa] each) were present in some, but not all, patients with herpes
simplex encephalitis, Parkinson disease, Guillain-­Barré syndrome, and
schizophrenia. They were not present in various other neurologic disor-
ders or in 100 normal CSF control specimens. However, these and two
other proteins (molecular masses about 26 and 29 kDa) were present in
all cases of CJD and in 5 of 10 cases of herpes simplex encephalitis. Nei-
ther of these latter proteins was present in any other neurologic disease
or in controls.
Increased concentrations of various specific CSF proteins have been
associated with several CNS diseases (Table 30.5).
Myelin Basic Protein.  Myelin basic protein (MBP), a component
of the myelin nerve sheath, is released during demyelination as a result of
various neurologic disorders, especially MS. Thus, MBP has been shown
to positively correlate with CSF leukocyte count, intrathecal IgG synthe-
sis, and the CSF/serum albumin concentration quotient (Sellebjerg et al.,
1998). These results supported the use of MBP in CSF as a surrogate dis-
ease marker during acute MS exacerbations. Others have found that analy-
sis of antibody against MBP in patients with a clinically isolated syndrome
is a rapid and precise method for predicting early conversion to clinically
definite MS (Berger et al., 2003). However, increased CSF levels have also
been reported in Guillain-­Barré syndrome, lupus erythematosus (LE), sub-
acute sclerosing panencephalitis, and various brain tumors, and following
CNS irradiation and chemotherapy (Mahoney et al., 1984; Brooks, 1989).
Measurement of CSF MBP levels has also been proposed as a prognos-
tic marker in patients with serious head injury (Noseworthy et al., 1985).
More recently, the clinical utility of MBP measurement in patients with
MS has been questioned based on similarity of abnormal results to other
established laboratory methods, such as presence of OCBs on protein elec-
trophoresis, for diagnosing MS (Greene et al., 2012).  gestive of AD, together with the exclusion of other causes of dementia.
518
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  TABLE 30.5
CSF Proteins and Central Nervous System Diseases
Protein Major Diseases/Disorders
α2-­Macroglobulin Subdural hemorrhage, bacterial
meningitis
β-­Amyloid and τ proteins Alzheimer disease
β2-­Microglobulin Leukemia/lymphoma, Behçet
syndrome
C-­reactive protein Bacterial and viral meningitis
Fibronectin Lymphoblastic leukemia, AIDS,
meningitis
Methemoglobin Mild subarachnoid/subdural
hemorrhage
Myelin basic protein Multiple sclerosis, tumors, others
Protein 14-­3-­3 Creutzfeldt-­Jakob disease
Transferrin CSF leakage (otorrhea, rhinorrhea)
AIDS, Acquired immunodeficiency syndrome; CSF, cerebrospinal fluid.
α2-­Macroglobulin.  Except for a small amount transported across the
BBB in pinocytic vesicles, α2-­macroglobulin (A2M) is normally excluded
from the CSF because of its large size. The number of these vesicles is
increased in certain polyneuropathies, resulting in an increased CSF A2M
level. Significant elevation reflects subdural hemorrhage or breakdown of
the BBB, as occurs in bacterial meningitis. A2M measurement alone, or
in relationship to albumin and IgG, may assist in the evaluation of neuro-
logic disorders and increased CSF protein, and in the rapid differentiation
between bacterial and aseptic meningitis (Meucci et al., 1993; Kanoh &
Ohtani, 1997). 
β2-­Microglobulin.  This protein is part of the human leukocyte anti-
gen class I molecule on the surfaces of all nucleated cells. CSF levels above
1.8 mg/L are associated with leptomeningeal leukemia and lymphoma but
are not highly specific (Weller et al., 1992) in that they have a maximal
positive predictive value of 78% in cases with a positive cytology (Jeffrey
et al., 1990). β2-­Microglobulin (B2M) has also been shown to be a marker
for neuro-­Behçet syndrome (Kawai & Hirohata, 2000). Viral infections,
conditions, and various malignancies have also been associated with ele-
vated levels. The measurement of B2M remains primarily investigational. 
C-­Reactive Protein.  Early studies indicated that CSF C-­reactive
protein (CRP) is useful in differentiating viral (aseptic) meningitis from
bacterial meningitis (Corral et al., 1981; Abramson et al., 1985; Stea-
rman & Southgate, 1994). Others reported that CSF CRP is a more
useful screening test for viral versus bacterial meningitis, especially in
children (Sormunen et al., 1999). A meta-­analysis of CRP studies since
1980 suggested that a normal CSF or serum CRP has a high prob-
ability of ruling out bacterial meningitis (i.e., negative predictive value
about 97%) (Gerdes et al., 1998). Another study found not only that
CSF CRP levels were increased in bacterial meningitis, but that these
levels were significantly higher in patients with gram-­negative bacterial
meningitis than in those with gram-­positive bacterial meningitis (Rajs
et al., 2002). This assay has been found to be more specific than blood
CRP levels in the laboratory diagnosis of meningitis in children (Malla
et al., 2013). 
Fibronectin.  This large glycoprotein (molecular mass ≈420 kDa) is
normally present in essentially all tissues and body fluids. Its primary func-
tion is its role in cell adhesion and phagocytosis (Ruoslahti et al., 1981).
Thus, cell adhesion allows leukocytes to adhere to and pass through the
vascular endothelia and migrate to the inflammatory site.
In children with acute lymphoblastic leukemia, elevated CSF fibro-
nectin levels are associated with a poor prognosis, presumably due to leu-
kemic involvement of the CNS (Rautonen et al., 1989). Significant CSF
elevations have also been reported in Burkitt lymphoma (Rajantie et al.,
1989), some metastatic solid tumors, astrocytomas, and bacterial menin-
gitis (Weller et al., 1990; Torre et al., 1991). Decreased levels have been
reported in viral meningitis and in the acquired immunodeficiency syn-
drome (AIDS)–dementia complex (Torre et al., 1991, 1993). Detection
of fibronectin with alternatively spliced extra domain A is found in lower
amounts in CSF from children with bacterial meningitis as opposed to viral
meningitis or without meningitis (Pupek et al., 2013). 
β-­Amyloid Protein 42 and Tau (τ) Protein.  The diagnosis of
Alzheimer disease (AD) is based on the presence of dementia and a spe-
cific clinical profile (i.e., from medical history, clinical examination) sug-
Pathologically, the disease is characterized by the presence of neurofibril-
lary tangles and amyloid plaques.
Studies indicate that measurement of biochemical markers increases
diagnostic accuracy, especially early in the course of the disease, when clini-
cal symptoms are mild and vague and overlap with cognitive changes that
accompany aging and ischemic dementia. Thus, increased CSF levels of
microtubule-­associated tau (τ) protein and decreased levels of β-­amyloid
protein ending at amino acid 42 (β-­amyloid protein 42) have been shown to
significantly increase the accuracy of AD diagnosis (Andreasen et al., 2001;
Riemenschneider et al., 2002; Sunderland et al., 2003). The positive predic-
tive value for early AD is greater than 90% (Andreasen et al., 2001). Others
have found that the calculated ratio of phosphorylated τ protein (P-­tau) to β-­
amyloid peptide is superior to either measure alone (Maddalena et al., 2003).
The results were as follows: distinguishing patients with AD from healthy
controls—sensitivity 96%, specificity 97%; patients with AD from those
with non-­AD dementia—sensitivity 80%, specificity 73%; and patients with
AD from those with other neurologic disorders—sensitivity 80%, specificity
89%. These assays all appear to have a place in the biochemical diagnosis of
early AD (Blennow & Zetterrberg, 2009), although development of a highly
effective CSF assay to diagnose AD remains elusive.  CSF values below 40 mg/dL (2.2 mmol/L) or ratios below 0.3 are con-
Protein 14-­3-­3.  The transmissible spongiform encephalopathies
constitute a group of uniformly fatal neurodegenerative diseases. Of these,
CJD is the major spongiform disease in humans. Two proteins, designated
130 and 131, have been detected in low concentrations in CSF from CJD
patients. These proteins have the same amino acid sequence as protein
14-­3-­3 (Hsich et al., 1996). In patients with dementia, a positive immuno-
assay for the 14-­3-­3 protein in CSF strongly supports a diagnosis of CJD.
In a subsequent study of patients with suspected CJD, the sensitivity of the
14-­3-­3 protein determined by immunoassay was 97%, and the specificity
was 87% (Lemstra et al., 2000). False-­positive results were seen primarily
in patients with stroke and meningoencephalitis.
Others, using a modified Western blot technique, reported a 94.7%
positive predictive value and a 92.4% negative predictive value for CJD
(Zerr et al., 1998). False-­positive results were seen in patients with her-
pes simplex encephalitis, atypical encephalitis, metastatic lung cancer, and
hypoxic brain damage.
Detecting elevation of protein 14-­3-­3 in combination with elevation of
other brain-­derived proteins, such as τ protein, in CSF appears to be useful
in the diagnosis of CJD (Sanchez-­Juan et al., 2006, Muayqil et al., 2012).  matic tap may also cause a spurious increase in CSF glucose.
Transferrin and CSF Leakage.  CSF leakage usually presents as otor-
rhea or rhinorrhea following head trauma, in some cases beginning months to
years after the injury. Recurrent meningitis is a serious complication, making
accurate identification of the leaking fluid very important. In this regard, pro-
tein and glucose measurements are too nonspecific to be of value. Transferrin,
an iron-­binding glycoprotein with a molecular mass of about 77 kDa, is syn-
thesized primarily in the liver. However, two transferrin isoforms are present
in the CSF; the major isoform (β1-­transferrin) is present in all body fluids. The
second isoform (β2-­transferrin), present only in the CNS, is produced in the
CNS by the catalytic conversion of β-­1-­transferrin by neuraminidase. Immu-
nofixation electrophoresis readily identifies both isoforms (see Chapter 20).
Detection of β2-­transferrin in CSF by protein electrophoresis with
transferrin immunofixation is a noninvasive, rapid, and inexpensive test
of high sensitivity and specificity that requires as little as 0.1 mL of fluid
(Ryall et al., 1992; Normansell et al., 1994). Several reports have dem-
onstrated the value of this technique in the diagnosis of CSF otorrhea
and rhinorrhea—conditions in which both isoforms are readily identi-
fied (Irjala et al., 1979; Rouah et al., 1987; Zaret et al., 1992). Others
have stressed the importance of β2-­transferrin identification in both CSF
and inner ear perilymphatic leakage, as well as possible sources of error
due to the presence of a transferrin allelic variant (Skedros et al., 1993a,
1993b; Sloman & Kelly, 1993). β2-­transferrin is sufficiently stable in CSF
stored at room temperature and/or when mixed with nasal mucus that a
negative result in a patient-­collected nasal fluid specimen up to 1 week
old is a reliable negative finding for CSF leakage (Bleier et al., 2011).  Isoprostanes are prostaglandin-like compounds resulting from non-
Methemoglobin and Bilirubin.  Although most cases of subarachnoid
and intracerebral hemorrhage are readily identified by computed tomogra-
phy (CT), patients with mild subarachnoid hemorrhage, small subdural or
cerebral hematomas, and blood seepage from an aneurysm or neoplasm
and from small cerebral infarcts often are not identified by this technique.
In these cases, CSF spectrophotometric analysis has been shown to detect
methemoglobin in colorless CSF (<0.3 μmol/L) (Trbojevic-­ Cepe et al.,
1992). An increase in CSF bilirubin is also recognized as a key finding sup-
porting the diagnosis of subarachnoid hemorrhage (UK National External
Quality Assessment Scheme for Immunochemistry Working Group, 2003).
A single net bilirubin absorbance cutoff point of >0.007 absorbance units is
recommended in the decision tree for interpretation and reporting of results.
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Guidelines for the use of CSF spectrophotometric analysis in the detection
of hemoglobin breakdown products have been developed (Beetham, 2009). 
Glucose
Derived from blood glucose, fasting CSF glucose levels are normally 50 to 80
mg/dL (2.8–4.4 mmol/L)—about 60% of plasma values. Rigorous evaluation
PART 3
of CSF and serum glucose levels in a large number of children confirmed that
the CSF glucose level is normally approximately 60% of the serum glucose
level during childhood (Nigrovic et al., 2012). Results should be compared
with plasma levels, ideally following a 4-­hour fast, for adequate clinical inter-
pretation. The normal CSF/plasma glucose ratio varies from 0.3 to 0.9, with
fluctuations in blood levels caused by the lag in CSF glucose equilibration
time. A good rule of thumb is that CSF glucose is about two-thirds of the level
of serum glucose. This enables the detection of low CSF glucose in patients
with abnormal glucose levels. Thus in a diabetic patient with a serum glucose
level of 250 mg/dL, the expected CSF glucose would be around 167 mg/dL
in CSF. If the patient were found to have a CSF glucose of, say, 100 mg/dL,
there would be evidence for a possible microorganism-induced lowering of
CSF glucose even though the absolute value of CSF glucose is elevated.
sidered to be abnormal. Hypoglycorrhachia is a characteristic finding of
bacterial, tuberculous, and fungal meningitis. However, sensitivity can be
as low as 55% for bacterial meningitis (Hayward et al., 1987); thus, a nor-
mal level does not exclude these conditions. Some cases of viral meningo-
encephalitis also have low glucose levels but generally not to the degree
seen in bacterial meningitis. Meningeal involvement by a malignant tumor,
sarcoidosis, cysticercosis, trichinosis, ameba (Naegleria), acute syphilitic
meningitis, intrathecal administration of radioiodinated serum albumin,
subarachnoid hemorrhage, symptomatic hypoglycemia, and rheumatoid
meningitis may also produce low CSF glucose levels (Fishman, 1992).
Decreased CSF glucose results from increased anaerobic glycolysis in
brain tissue and leukocytes and from impaired transport into the CSF. Bac-
teria are usually present in insufficient quantities to be a major contributor
to the use of glucose in CSF. CSF glucose levels normalize before protein
levels and cell counts during recovery from meningitis, making it a useful
parameter in assessing response to treatment.
Increased CSF glucose is of no clinical significance, reflecting
increased blood glucose levels within 2 hours of lumbar puncture. A trau-
 
Lactate
CSF and blood lactate levels are largely independent of each other. The
reference interval for older children and adults is 9.0 to 26 mg/dL (1.0–2.9
mmol/L) (Knight et al., 1981). Newborns have higher levels, ranging from
about 10 to 60 mg/dL (1.1–6.7 mmol/L) for the first 2 days and from 10 to 40
mg/dL (1.1–4.4 mmol/L) for days 3 to 10 (McGuinness et al., 1983). Elevated
CSF lactate levels reflect CNS anaerobic metabolism due to t­ issue hypoxia.
Lactate measurement has been used as an adjunctive test in differentiat-
ing viral meningitis from bacterial, partially treated bacterial, mycoplasma,
fungal, and tuberculous meningitis, in which routine parameters yield
equivocal results (Cunha, 2012). In patients with viral meningitis, lactate
levels are usually below 25 mg/dL (2.8 mmol/L) and are almost always less
than 35 mg/dL (3.9 mmol/L), whereas bacterial meningitis typically has
levels above 35 mg/dL (Bailey et al., 1990; Cameron et al., 1993). Using
30 to 36 mg/dL as the cutoff value for bacterial meningitis, the sensitiv-
ity and specificity are about 80% and 90%, respectively. Viral meningitis,
­partially treated bacterial meningitis, and tuberculous meningitis often
have intermediate lactate levels that overlap each other, limiting the use of
lactate measurements in this differential diagnosis.
Persistently elevated ventricular CSF lactate levels are associated with
a poor prognosis in patients with severe head injury (DeSalles et al., 1986). 
F2-­Isoprostanes
enzymatic free radical-initiated peroxidation of arachidonic acid. A
subclass of these compounds have a characteristic so-called F2 ring
structure and are therefore called F2-isoprostanes. F2-­ isoprostanes
are increased in diseased regions of the brain in patients with AD
(Pratico et al., 1998) and are markers of free radical brain injury associ-
ated with advanced age and latent AD (Montine et al., 2011). Com-
pared with age-­matched controls, CSF F2-­isoprostanes are elevated in
patients with probable AD (Montine et al., 1999). Therefore, in con-
junction with CSF τ and β-­amyloid protein, the measurement of CSF
F2-­isoprostanes appears to enhance the accuracy of the laboratory diagno-
sis of AD (Montine et al., 2001) and by itself appears to correlate with the
degree of cognitive decline in some AD patients (Duits et al., 2013). 
519
 Enzymes
CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
A wide variety of enzymes derived from brain tissue, blood, or cellular ele-
ments have been described in the CSF. Although CSF enzyme assays are
not commonly used in the diagnosis of CNS diseases, there are diseases/
disorders in which they may prove useful.
Adenosine Deaminase
Adenosine deaminase (ADA) catalyzes the irreversible hydrolytic deamina-
tion of adenosine to produce inosine. Because ADA is particularly abundant
in T lymphocytes, which are increased in tuberculosis, its measurement has
been recommended in the diagnosis of pleural, peritoneal, and meningeal
tuberculosis. Higher ADA levels are present in tuberculous infections than
in viral, bacterial, and malignant diseases (Blake & Berman, 1982; Mann
et al., 1982, Choi et al., 2002), and measuring ADA in CSF appears to
be a sensitive and specific assay in diagnosing tuberculous meningitis (Xu
et al., 2010, Saini et al., 2017). ADA appears to have limited utility in HIV-­
associated neurologic disorders (Corral et al., 2004).  are generally proportional to the degree of existing hepatic encephalopathy
Creatine Kinase
Brain tissue is rich in creatine kinase (CK) because it participates in main-
taining an adequate supply of adenosine triphosphate. Increased CSF CK
activity has been reported in numerous CNS disorders, including hydro-
cephalus, cerebral infarction, various primary brain tumors, and subarach-
noid hemorrhage, among others (Savory & Brody, 1979). In patients with
head trauma, CSF CK levels correlate directly with the severity of the con-
cussion (Florez et al., 1976).
CSF CK-­MM and CK-­MB are not normally present; when identi-
fied, they are due to blood contamination (CK-­MM) and an equilibrium
between CK-­BB and CK-­MM to produce CK-­MB. Because the CK-­BB
isoenzyme accounts for about 90% of brain CK activity and mitochondrial
CK (CKmt) the other 10%, CK isoenzyme measurements are more spe-
cific than total CK for CNS disorders (Chandler et al., 1984).
CSF CK-­BB is increased about 6 hours following an ischemic or anoxic
insult. Global brain ischemia following respiratory or cardiac arrest results
in diffuse cerebral injury with peak CK-­BB levels in about 48 hours (Chan-
dler et al., 1986). Here, CSF CK-­BB activity less than 5 U/L (upper normal
level) indicates minimal neurologic damage; 5 to 20 U/L indicates mild to
moderate CNS injury; and levels between 21 and 50 U/L are commonly
correlated with death. Death occurs in essentially all patients with levels
above 50 U/L.
Increased CSF CK-­BB levels also correlate with the outcome following a
subarachnoid hemorrhage (Coplin et al., 1999). A CK-­BB level greater than
40 U/L increases the chance of an unfavorable early or late outcome to 100%.  convulsions and bacterial meningitis. γ-­Aminobutyric acid (GABA), a major
Lactate Dehydrogenase
Lactate dehydrogenase (LD) activity is high in brain tissue, with a predomi-
nance of the electrophoretically fast-­moving isoenzyme fractions LD1 and
LD2. Total LD activity of 40 U/L is a reasonable upper limit of normal
for adults and 70 U/L for neonates (Donald & Malan, 1986; Engelke et al.,
1986). LD is useful in differentiating a traumatic tap from intracranial hem-
orrhage because a current traumatic tap with intact RBCs does not signifi-
cantly elevate the LD level (Engelke et al., 1986). Sensitivity and specificity
are about 70% to 85% depending on the cutoff value. As with lactate, LD
activity is significantly higher in bacterial meningitis than in aseptic meningi-
tis (Donald & Malan, 1986; Engelke et al., 1986). Using a cutoff of 40 U/L,
the sensitivity is about 86% and the specificity about 93%.
Total CSF LD levels are also increased in patients with CNS leukemia,
lymphoma, metastatic carcinoma, bacterial meningitis, and subarachnoid
hemorrhage (Kjeldsberg, 1993). CSF LD isoenzymes have been shown to
add considerable specificity in the evaluation of various metastatic brain
tumors (Fleisher et al., 1981). The LD5/total LD ratio is increased (i.e.,
above 10%–15%) in patients with leptomeningeal metastases from car-
cinoma of the breast and lung and malignant melanoma. LD isoenzyme
analysis is also useful in detecting CNS involvement by leukemias and lym-
phomas (Lossos et al., 2000). Isoenzyme analysis shows a distinct pattern
in young children with infantile spasms (Nussinovitch et al., 2003a) and
febrile convulsions (Nussinovitch et al., 2003b). Compared with controls,
both disorders are characterized by decreased LD1, increased LD2 and
LD3, and no changes in LD4 and LD5.
CT is of limited value in estimating recovery potential and neurologic
outcome during the early stages of ischemic brain injury. However, com-
pared with controls (mean LD, 11.2 U/L), patients with an early stroke
had a mean level of 40.9 U/L, and those with a transient ischemic attack
(TIA) had a mean value of 11.8 U/L (Lampl et al., 1990). In patients with
hypoxic brain injury, an increased LD level 72 hours following resuscita-
tion i­ndicates a poor prognosis (Karkela et al., 1992).  blastic component, and α-­fetoprotein, a glycoprotein produced by yolk sac
520
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Lysozyme
Lysozyme (muramidase) catalyzes the depolymerization of mucopolysaccha-
rides. Because the enzyme is particularly rich in neutrophil and macrophage
lysosomes, its activity is very low in normal CSF. However, CSF lysozyme
activity is significantly increased in patients with both bacterial and tubercu-
lous meningitis. Thus, discriminant analysis demonstrated that 97% of patients
with bacterial meningitis had increased lysozyme levels (Ribeiro et al., 1992).
Others found that patients with tuberculous meningitis had significantly higher
CSF lysozyme levels than those with bacterial meningitis, partially treated bac-
terial meningitis, and controls (Mishra et al., 2003). The diagnostic sensitivity
and specificity for tuberculous meningitis were 93.7% and 84.1%, respectively.
Increased levels are also present in cerebral atrophy, various CNS tumors, mul-
tiple sclerosis, intracranial hemorrhage, and epilepsy (Kjeldsberg, 1993). 
Ammonia, Amines, and Amino Acids
CSF ammonia levels vary from 30% to 50% of blood values. Elevated levels
but are difficult to quantify. Moreover, because hepatic encephalopathy gen-
erally correlates with blood ammonia levels, the measurement of CSF ammo-
nia has little, if any, clinical value. However, cerebral glutamine, synthesized
from ammonia and glutamic acid, serves as the means for CNS ammonia
removal. Thus, CSF glutamine levels reflect the concentration of brain
ammonia. Glutamine reference intervals are method dependent; the upper
reference level is about 20 mg/dL. Values over 35 mg/dL are usually associ-
ated with hepatic encephalopathy (Fishman, 1992). Elevated CSF glutamine
levels have also been reported in patients with depression (Levine et al., 2000)
and encephalopathy secondary to hypercapnia and sepsis (Mizock et al.,
1989). Measurement of a variety of biogenic amines in CSF has been shown
to assist in the diagnosis of bacterial and viral meningitis (Taj et al., 2018).
A major etiologic theory of schizophrenia involves dopamine. The cor-
nerstone for this theory is the fact that neuroleptic drugs that block dopa-
mine receptors are effective in the treatment of this disorder. Thus, it has
been reported that CSF levels of homovanillic acid (HVA), a metabolite of
the biogenic amines, are related to the severity of schizophrenic psychosis
(Maas et al., 1997). However, HVA concentration varied as a function of
psychosis rather than being related to the diagnosis of schizophrenia per se.
Others have reported decreased CSF levels of 5-­hydroxyindoleacetic acid,
a metabolite of serotonin, in schizophrenic patients with suicidal behavior
(Cooper et al., 1992). This report adds support for a possible relationship
between suicide and CNS serotonin metabolism.
Although free CSF amino acids are relatively high in infants younger than
30 days of age, their concentration is further increased in those with febrile
inhibitory brain transmitter, is significantly decreased in basal ganglia neurons
and is very low or undetectable in the CSF of patients with AD and Huntington
disease (Achar et al., 1976; Dubowitz et al., 1992). CSF GABA was detected
in all patients with migraine attacks, but not in those with tension headaches
or in the control group without headaches (Welch et al., 1975). Infants with
startle disease, a rare inherited autosomal-­dominant disorder characterized by
seizures or the so-­called stiff baby syndrome, have significantly decreased
CSF GABA levels (Dubowitz et al., 1992; Berthier et al., 1994). 
Electrolytes and Acid-­Base Balance
There are no clinically useful indications for the measurement of CSF
sodium, potassium, chloride, calcium, or magnesium. Measurements of
CSF pH, partial pressure of carbon dioxide (pCO2), and bicarbonate are
also not practical for patient care (Fishman, 1992). 
Tumor Markers
Numerous studies have shown that various tumor markers are increased in
the CSF of patients with both primary and metastatic tumors.
Carcinoembryonic Antigen
Carcinoembryonic antigen (CEA) is an oncofetal protein produced by a
variety of carcinomas. An early study found increased CEA levels in 44%
of patients with metastatic brain tumors (Suzuki & Tanaka, 1980). Others
reported that CSF levels of CEA have a sensitivity of only about 31%,
although the specificity is about 90% for detecting metastatic carcinoma
of the leptomeninges (Klee et al., 1986; Twijnstra et al., 1986). CSF lev-
els of CEA in patients with benign, primary malignant, and metastatic
brain tumors are approximately 0.31 ng/mL, 0.92 ng/mL, and 6.3 ng/mL,
respectively (Batabyal et al., 2003). CSF CEA levels are particularly sensi-
tive in detecting leptomeningeal carcinoma metastasis (Kang et al., 2010).
Other oncofetal proteins include human chorionic gonadotropin (hCG),
produced by choriocarcinoma and malignant germ cell tumors with a tropho-
  TABLE 30.6
Typical Lumbar CSF Findings in Meningitis
Test Bacterial Viral Fungal Tuberculous

Opening pressure Elevated Usually normal Variable Variable

≥1000/μL

PART 3
Leukocyte count <100/μL Variable Variable
Cell differential Mainly neutrophils* Mainly lymphocytes† Mainly lymphocytes Mainly lymphocytes
Protein Mild to marked increase Normal to mild increase Increased Increased
Glucose Usually ≤40 mg/dL Normal Decreased Decreased: may be
<45 mg/dL
CSF/serum glucose ratio Normal to marked decrease Usually normal Low Low
Lactic acid Mild to marked increase Normal to mild increase Mild to moderate increase Mild to moderate increase

Data from Body BA, Oneson RH, Herold DA: Use of cerebrospinal fluid lactic acid concentration in the diagnosis of fungal meningitis, Ann Clin Lab Sci 17:429, 1987; Tang
LM: Serial lactate determinations in tuberculous meningitis, Scand J Infect Dis 20:81, 1988; Arevalo CE, Barnes PF, Duda M, Leedom JM: Cerebrospinal fluid cell counts and
chemistries in bacterial meningitis, South Med J 82:1122, 1989; Fishman RA: Cerebrospinal fluid in diseases of the nervous system, ed 2, Philadelphia, 1992, Saunders; ­Wubbel
L, McCracken GH Jr: Management of bacterial meningitis, Pediatr Rev 19:78, 1998; Zunt JR, Marra CM: Cerebrospinal fluid testing for the diagnosis of central nervous
system infection, Neurol Clin 17:675, 1999.
CSF, Cerebrospinal fluid.
*Lymphocytosis present in about 10% of cases.
†Neutrophils may predominate early in disease.

elements of germ cell tumors. Both β-­hCG and α-­fetoprotein may be useful in
the diagnosis and monitoring of the response to therapy in patients with CNS
germ cell tumors (Seregni et al., 2002; Ferguson et al., 2008, Tian et al., 2011).
Elevation of CSF ferritin is a sensitive indicator of CNS malignancy
but has very low specificity because it is also increased in patients with
inflammatory neurologic diseases (Zandman-­Goddard et al., 1986). This
assay has greater diagnostic utility in detecting subarachnoid hemorrhage
in patients presenting late (Petzold et al., 2011). 
As discussed in Chapter 21, assay for placental alkaline phosphatase
(PLAP) in CSF is useful in determining whether a tumor in the pineal body
is a germ cell tumor or a pinealoma. Elevated levels of PLAP in CSF are
indicative of germ cell tumors, which are radio-sensitive, thereby obviating
the need for invasive surgery for tumor removal.

MICROBIOLOGICAL EXAMINATION
A thorough and prompt examination of CSF is essential for the diagno-
sis of CNS infection because an inaccurate or delayed report may result
in significant mortality or morbidity. Although changes in opening pres-
sure, total cell and differential counts, total protein, and glucose suggest
an infectious origin (Table 30.6), Gram stain, culture, and other relevant
studies are critical for a definitive diagnosis.
Bacterial Meningitis
The most common agents of bacterial meningitis are group B streptococcus
(neonates), Neisseria meningitidis (3 months and older; Fig. 30.10), Streptococ-
cus pneumoniae (3 months and older), Escherichia coli and other gram-­negative
bacilli (newborn to 1 month), Haemophilus influenzae (3 months to 18 years),
and Listeria monocytogenes (neonates, older adults, alcoholics, and immuno-
suppressed) (Graves, 1989; Wenger et al., 1990). H. influenzae, once the most
common bacterial cause of meningitis in young children, has decreased dra-
matically from widespread use of H. influenzae type b vaccine. CSF shunts,
head trauma, and neurosurgery place patients at risk for CNS infections from
Staphylococcus species, gram-­negative bacilli, and P
­ ropionibacterium species.
The Gram stain remains an accurate, rapid method by which to diagnose
CNS infection. All specimens should be concentrated by centrifugation before
Gram stain and culture. Depending on the type of infecting microorganism
and its concentration in the CSF, Gram stain sensitivity ranges from 60% to
90%, with the greatest sensitivity corresponding to higher concentrations of
bacteria (about 105 colony-­forming units/mL). For example, the sensitivity of
the Gram stain for detecting Listeria monocytogenes and gram-­negative bacilli
is 50% or less (Greenlee, 1990). For patients with many polymorphonuclear
leukocytes but no organisms seen on Gram stain, the more sensitive acridine
orange stain may be helpful. Cultures have a sensitivity of 80% to 90% but are
about 30% less sensitive in partially treated cases (Greenlee, 1990).
Although standard culture-­ based methods remain the mainstay for
diagnosis, the BinaxNOW Streptococcus pneumoniae antigen test, an immu-
nochromatographic membrane assay that detects the presence of the C poly-
saccharide cell wall antigen common to all pneumococcal serotypes, has been
proven to be a valuable tool for the rapid diagnosis of pneumococcal meningi-
tis from CSF. Latex agglutination bacterial antigen tests performed on CSF to
detect H. influenzae, N. meningitidis, S. pneumoniae, and β-­hemolytic group B
streptococci have historically been used as adjuncts to Gram stain and culture.
Figure 30.10  Cerebrospinal fluid Gram stain showing gram-­negative diplococci
characteristic of N. meningitidis.
However, the sensitivity is approximately the same as the Gram stain. Per-
haps the best application of latex agglutination antigen tests is seen in partially
treated, community-­acquired meningitis that is negative for microorganisms
by Gram stain (Perkins et al., 1995; Wilson, 1997, Mohammadi et al., 2013).
The PCR and sequencing of 16S ribosomal ribonucleic acid (RNA) in
CSF have been shown to be very useful in the diagnosis of bacterial men-
ingitis (Schuurman et al., 2004). Compared with bacterial culture, the assay
shows a sensitivity of 86%, a specificity of 97%, a positive predictive value of
80%, and a negative predictive value of 98%. Nucleic acid amplification tests
may also be helpful in patients already receiving antimicrobial therapy and
in detecting more fastidious pathogens such as N. meningitidis (Porritt et al.,
2000; Seward & Towner, 2000; Baethgen et al., 2003). Significant advances
have been made over the past few years in the rapid diagnosis of bacterial,
fungal, and viral meningitis and viral encephalitis using multiplex PCR-­based
assays, such as the Cepheid Xpert (Sunnyvale, CA) and Biofire FilmArray
(Salt Lake City, UT) systems (Slika et al., 2013; Leber et al., 2016; Liesman
et al., 2018). This approach to rapid diagnosis has revolutionized how bacte-
rial, fungal, and viral infection is detected in the CNS and other sites. 
Spirochetal Meningitis
The incidence of neurosyphilis increased in the 1980s and 1990s, par-
ticularly in patients with HIV infection. In one report, 44% of patients
with neurosyphilis had AIDS (Flood et al., 1998). The diagnosis of CNS
infection in patients with syphilis relies primarily on CSF parameters and
serologic testing, although molecular DNA testing may now represent
another approach. Abnormalities in CSF protein and cell counts are com-
mon in syphilitic meningitis but are nonspecific. CSF serologic testing
to diagnose neurosyphilis is difficult. The standard nontreponemal test
performed on CSF is the venereal disease research laboratory (VDRL)
test. If few erythrocytes are contaminating the CSF, the VDRL speci-
ficity is high, but its sensitivity is only 50% to 60% (Davis & Schmitt,

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 1989). Treponemal tests, such as the treponemal antibody absorption
CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
(FTA-­ABS) test, are both sensitive and specific for syphilis; however,
their use in CSF for neurosyphilis is controversial. The CSF FTA-­ABS
is highly sensitive, but false-­positive results may occur. In the absence
of CSF abnormalities or clinical suspicion, it should not be used as a
screening test. Thus, the following generalizations have been proposed
(Davis & Schmitt, 1989): (1) a nonreactive serum FTA-­ABS test rules
out neurosyphilis; (2) a reactive serum FTA-­ABS test with a nonreac-
tive CSF FTA-­ABS test essentially rules out neurosyphilis; (3) a reactive
CSF VDRL test makes a diagnosis of neurosyphilis likely; and (4) a reac-
tive CSF FTA-­ABS test may indicate active neurosyphilis, asymptomatic
neurosyphilis, treated neurosyphilis, or a false-­positive reaction. Other
studies have demonstrated the utility of PCR-­based assays as a potentially
sensitive and specific means of diagnosing neurosyphilis (Leslie et al.,
2007); although these tests may not represent a clear advance over CSF
serologic assays (Marks et al., 2018).
Diagnosis of Lyme meningitis represents another challenge for the lab-
oratory. The mainstay of diagnosis remains serologic analysis performed
on a serum specimen, using an enzyme-­ linked immunosorbent assay
(ELISA)–based screening assay followed by confirmation with Western
blot. PCR-­based analysis may be performed on CSF specimens; however,
the sensitivity of this approach may be low, particularly in patients with
chronic neuroborreliosis (Steere, 2010).
Rapid diagnosis of leptospiral and other bacterial infections is now
possible using genomic methods, including next-­ generation DNA
sequencing analysis. Studies have shown that patients with neurolepto-
spirosis in whom a diagnosis could not be established by conventional
methods may be successfully diagnosed using next-­generation sequenc-
ing analysis of CSF (Wilson et al., 2014; Wilson et al., 2019). This
methodology offers another approach to rapid diagnosis of a range of
infections, as well as a way to rapidly track infection outbreaks (Sherry
et al., 2013).  DNA-­specific sequences have shown great promise in the rapid and accu-
Viral Meningitis
Enteroviruses (echoviruses, coxsackieviruses, polioviruses) and arboviruses
are responsible for the majority of meningitis cases. A seasonal peak in
spring to autumn has been noted for these agents. As an example, echo-
viruses 9 (E9) and 30 (E30) were found to be mainly responsible for an
increase in cases of aseptic meningitis (Morbidity and Mortality Weekly
Report, 2003). Most patients present with a CSF pleocytosis; although
neutrophils may be observed early in the infection, patients soon develop a
predominance of lymphocytes.
Before molecular diagnostic testing, viral meningitis was a diagnosis
of exclusion because the sensitivity of viral cultures can be low. Thus, in
an early study, a specific etiologic diagnosis by viral cultures varied from
72% for enteroviruses to 5% for herpes simplex virus (HSV) (Marton &
Gean, 1986).
Reverse transcriptase polymerase chain reaction (RT-­PCR) is sig-
nificantly more sensitive than cell culture (Dumler & Valsamakis, 1999;
Hausfater et al., 2004). In recent years, PCR-­based assays have evolved
as the gold standard for the increasingly rapid diagnosis of viral menin-
gitis secondary to enterovirus, HSV, cytomegalovirus, varicella zoster,
and JC virus. The use of RT-­PCR may result in significant cost sav-
ings by shortening hospital stays and eliminating unnecessary diagnostic
and therapeutic interventions (Ramers et al., 2000). For patients with
arbovirus-­associated meningitis, acute and convalescent serologic testing
in serum remains the cornerstone for diagnosis, with CSF testing a pos-
sible adjunct. Presumptive diagnosis of West Nile viral meningitis may
be made on a CSF specimen using an IgM antibody-­capture ELISA. PCR
testing for West Nile virus and other arboviruses may also be done on
CSF specimens. Although these assays have low sensitivity because of the
short-­lived nature of the viremia in these diseases, they may still be use-
ful in diagnosing arbovirus infections (Vaughn et al., 2010; Vanichanan
et al., 2016).
PCR amplification of HSV DNA has revolutionized the testing for
HSV infection in CSF and has replaced brain biopsy as the primary
method used in the early diagnosis of HSV meningoencephalitis (Tun-
kel, 2008). False negatives might occur in very early infections and with
bloody taps, necessitating analysis of a second CSF specimen (Tyler,
2004). 
Human Immunodeficiency Virus
A wide variety of CSF abnormalities may be found in HIV-­positive patients
with or without neurologic disease, including lymphocytic pleocytosis,
elevated IgG indexes, and OCBs (Chalmers et al., 1990; Hall & Snyder,
1992). Identifying opportunistic infection is the most important indication
522
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for examining the CSF. Serious fungal infections may exist in the presence
of few or no CSF parameter abnormalities. 
Fungal Meningitis
Cryptococcus neoformans is the most frequently isolated fungal pathogen
from CSF. India ink or nigrosin stains for cryptococcus capsular halos have
a sensitivity of about 25%, increasing to 53% with multiple lumbar punc-
tures, and to greater than 90% in untreated HIV-­infected patients (Mar-
ton & Gean, 1986). Detection of cryptococcal antigen from sera or CSF
using latex agglutination has higher sensitivity, ranging from 60% to 95%.
False-­negatives due to a prozone effect or low concentration of polysaccha-
ride antigen may occur. Early disease, intraparenchymal infection, infec-
tion with nonencapsulated C. neoformans variants, and immune complexes
(corrected with pronase treatment) may also produce false negatives. Con-
versely, sera or CSF from patients with rheumatoid factor or Trichosporon
asahii infection may be falsely positive. If clinical suspicion for dimorphic
or filamentous fungi is high, large volumes of CSF (approximately 15–20
mL) are optimal for culture to improve the recovery of fungal organisms.
PCR-­based assays have so far not been shown to reliably detect C. neofor-
mans infection in CSF (O’Halloran et al., 2017). 
Tuberculous Meningitis
Abnormal CSF with elevated protein and lymphocytic predominance are
the hallmark features of tuberculous meningitis. The sensitivity of CSF
acid-­fast stains for the diagnosis of tuberculous meningitis is highly vari-
able, ranging from 10% to 12% (Greenlee, 1990) to greater than 50%
(Thwaites et al., 2004). Large volumes of CSF, often obtained from mul-
tiple lumbar punctures with the use of concentration techniques, are rec-
ommended to improve the sensitivity of both acid-­fast stain and culture
(Marton & Gean, 1986).
PCR nucleic acid amplification for detecting Mycobacterium tuberculosis
rate diagnosis of tuberculous meningitis (Lin et al., 1995; Desai & Pal,
2002), but PCR methods using a single primer are associated with rela-
tively low sensitivity (Pai et al., 2003). Multiplex PCR analysis, using prim-
ers to multiple relevant tubercular genes, appears to be a significantly more
sensitive method in the rapid diagnosis of tuberculous meningitis (Kusum
et al., 2011; DiDiodato et al., 2019).
Dot-­ELISA has been standardized to detect tuberculosis antigens and
antibodies against M. tuberculosis in CSF. Using this technique, a positive
reaction was present in 86% of cases with suspected tuberculous meningitis
(Kashyap et al., 2003). Only 5% of patients with other disorders, mainly
pyogenic meningitis, were positive.
Other tests have been shown to be useful in some cases of tuberculous
meningitis. ADA levels are significantly higher in tuberculous meningitis
than in other types of meningitis and CNS disorders (Pettersson et al.,
1991; Choi et al., 2002; Solari et al., 2013), although the degree of increase
indicative of tuberculous infection varies depending on the specific assay
used. 
Primary Amebic Meningoencephalitis
This rare disease is caused by the free-­living ameba Naegleria fowleri, Acan-
thamoeba species, and Balamuthia mandrillaris. Naegleria and Balamuthia are
more likely to cause an acute inflammatory response with a neutrophilic
pleocytosis, decreased glucose level, elevated protein concentration, and
the presence of erythrocytes. Gram stain is always negative. Acanthamoeba
more often produces a granulomatous meningitis. Motile Naegleria tro-
phozoites may be visualized by light or phase-­contrast microscopy in direct
wet mounts, allowing rapid diagnosis. Intact and degenerating organisms
may be identified on Wright-­or Giemsa-­stained cytospins but must be
distinguished from macrophages (dos Santos, 1970; Benson et al., 1985).
Acridine orange stain is useful in differentiating amebas (brick red) from
leukocytes (bright green). Immunocytochemical staining of CSF speci-
mens using an antibody to Naegleria fowleri has been shown to improve
microscopic detection of this organism (Visvesvara, 2010). Multiplex PCR-­
based methods are an even more sensitive modality for detecting multiple
amebic organisms in CSF (Qvarnstrom et al., 2006). 
SYNOVIAL FLUID
Synovium refers to the tissue lining synovial tendon sheaths, bursae, and
diarthrodial joints, except for the articular surface. It is composed of one to
three cell layers that form a discontinuous surface overlying fatty, fibrous,
or periosteal joint tissue.
Synovial fluid (SF) is an ultrafiltrate of plasma combined with hyal-
uronic acid produced by the synovial cells or synoviocytes. Small ions and
  TABLE 30.7
Synovial Fluid Findings by Disease Category
CATEGORY
Group I Group II Group III Group IV
Finding Normal ­Noninflammatory ­Inflammatory Infectious ­Hemorrhagic

PART 3
Clarity Transparent Transparent Transparent/opaque Opaque Opaque
Color Clear to pale yellow Xanthochromic Xanthochromic to White Red-­brown or
white/bloody ­xanthochromic
WBCs/mL 0–150 <3000 3000–75,000 50,000–200,000 50–10,000
PMNs, % <25 <30 >50 >90 <50
RBCs No No No Yes Yes
Glucose (blood/SF 0–10 (0–0.56 mmol/L) 0–10 (0–0.56 mmol/L) 0–40 (0–2.2 mmol/L) 20–100 0–20 (0–1.11 mmol/L)
­difference, mg/dL) (1.11–5.5 mmol/L)

Modified from Kjeldsberg CR, Knight JA: Body fluids: laboratory examination of amniotic, cerebrospinal, seminal, serous and synovial fluids, ed 3, Chicago, 1993, © American
Society for Clinical Pathology, with permission.
PMNs, Polymorphonuclear cells, neutrophils; RBCs, red blood cells; SF, synovial fluid; WBCs, white blood cells.

molecules (e.g., Na+, K+, glucose, urea) readily pass into the joint space
and therefore are similar in concentration to plasma. Large molecules are
absent or present only in trace amounts. Resorption of synovial molecules
is by lymphatics and is not size dependent. SF acts as a lubricant and pro-
vides nutrients for the avascular articular cartilage.
Examination of the SF is essential to distinguish infectious from non-
infectious arthritis. Results from gross and microscopic examination of
SF have traditionally been divided into “reaction types,” as depicted in
Table 30.7. These groupings are largely descriptive, and considerable
overlap among them is evident. Except for Gram stain, culture, and crystal
examination, SF parameters can be nonspecific and must be integrated into
the clinical context.
Noninflammatory effusions (Group I) typically have leukocyte
counts less than 3000/μL, with a minority of neutrophils. Osteoarthritis,
traumatic arthritis, neuropathic osteoarthropathy, pigmented villonodular
synovitis, and early rheumatic fever usually present with little inflamma-
tory response. Early rheumatoid arthritis, early bacterial infection, and
viral arthritis may also present as noninflammatory effusions.
Inflammatory effusions (Group II) have leukocyte counts between
3000 and 75,000/μL, with neutrophils accounting for more than 50% of
the population. RA, systemic lupus erythematosus (SLE), Reiter syndrome,
rheumatic fever, acute crystal-­induced arthritis, arthritis associated with
inflammatory bowel disease, psoriatic arthritis, and fat droplet synovitis are
examples of this reaction group.
Purulent (infectious) effusions (Group III) typically have leukocyte
counts greater than 50,000/μL, of which 90% or more are neutrophils.
Bacterial, fungal, and tuberculous joint infections constitute this group.
Hemorrhagic effusions (Group IV) may be seen in association with
traumatic arthritis, pigmented villonodular synovitis, synovial heman-
gioma, neuropathic osteoarthropathy, joint prostheses, and hematologic
disorders (hemophilia, anticoagulant therapy, sickle cell disease or trait).
SPECIMEN COLLECTION
Joint fluid aspiration (arthrocentesis) should be confined to patients with
an undiagnosed effusion or a significant clinical change related to a known
effusion. It should be performed by an experienced operator using good
sterile technique. Caution is necessary to avoid aspirating a sterile joint
in someone with bacteremia or through a cutaneous or periarticular soft-­
tissue infection into a sterile joint. Large joints such as the knee normally
contain no more than 4.0 mL of SF; thus, small sample size is common
unless an effusion is present.
Synovial fluid must be collected with sterile, disposable needles and
plastic syringes to avoid contamination by birefringent particulates. The
syringe may be heparinized with 25 U of sodium heparin/mL of SF in
routine arthrocentesis. Oxalate, lithium heparin, and powdered ethylene-
diaminetetraacetic acid (EDTA) anticoagulants should be avoided because
they form crystal artifacts that may be misleading during the microscopic
examination. Before aspiration, the joint should be turned or otherwise
manipulated to ensure mixing of its contents.
Ideally, the specimen should be separated into three parts: 3 to 10 mL
into a sterile heparinized tube or syringe for microbiological studies; 2 to 5
mL in an anticoagulant tube (sodium heparin or liquid EDTA) for micro-
scopic examination; and about 5 mL into a plain (no anticoagulant) tube for
chemical analysis (normal SF does not clot because fibrinogen is absent).
  BOX 30.8 
Recommended Synovial Fluid Tests
Routine tests
Gross examination (color, clarity)
Total and differential leukocyte counts
Gram stain and bacterial culture (aerobic and anaerobic)
Crystal examination with polarizing microscope and compensator
Useful tests in certain circumstances
Fungal and acid-­fast stains and cultures
Multiplex PCR assay for bacterial, fungal, and mycobacterial DNA
Serum–synovial fluid glucose differential
Lactate and other organic acids
Complement
Enzymes
Uric acid
DNA, Deoxyribonucleic acid; PCR, polymerase chain reaction.
Modified from Kjeldsberg CR, Knight JA: Body fluids: laboratory examination of
­amniotic, cerebrospinal, seminal, serous and synovial fluids, ed 3, Chicago, 1993,
© American Society for Clinical Pathology, with permission.
Heparin concentrations greater than 125 U/mL have an inhibitory effect
on some pathogenic bacteria (Rosett & Hodges, 1980). Specimens for cul-
ture, therefore, should be at least 1 to 2 mL in volume if they are submitted
in green-­top sodium heparin tubes (Becton Dickinson, Rutherford, NJ)
containing 143 U/tube of heparin, or submitted in recapped syringes after
removal of the needle and excess air.
Dry taps may still have fluid within the needle, which may be suf-
ficient for the most critical tests. Such specimens should be submitted
with the needle still on the syringe and carefully recapped or with its tip
stuck into a sterile cork. Good communication with the laboratory is cru-
cial to the appropriate processing of such specimens. Saline injection and
reaspiration is also effective in collecting SF following a dry tap (Partridge
et al., 2018). 
RECOMMENDED TESTS
Laboratory examination of SF is of major importance in the differential
diagnosis of joint disease, especially in crystal-­ induced and infectious
arthritis. When either is suspected, arthrocentesis and a systematic exami-
nation of the SF are imperative and, when examination is carried out prop-
erly, are usually diagnostic. In other joint diseases, a specific diagnosis may
not be possible. Nevertheless, fluid examination is still important if only to
rule out infectious arthritis, which is a critical diagnosis to make in that a
joint may be irreversibly damaged within 2 to 3 days if not properly treated.
This is especially true when Staphylococcus aureus is the infectious organism.
Therefore, routine tests should be directed toward the diagnosis of these
two disorders (Box 30.8). Although other tests are not of practical value
for routine use, they may provide important diagnostic information under
certain circumstances. 
GROSS EXAMINATION
Total volume should be recorded at the bedside, especially if the sample
is to be divided for submission to different laboratory sections.

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 Color should be evaluated in a clear glass tube against a white back-
CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
ground. Normal SF is colorless but is often pale yellow because of diapede-
sis of a few RBCs associated with even mild trauma. Noninflammatory and
inflammatory disorders impart a straw to yellow color (xanthochromia).
Septic fluid may be yellow, brown, or green depending on the chromogens
produced by the offending organism and the host response, including the
presence of WBCs and RBCs.
A traumatic tap produces an uneven distribution of blood during
arthrocentesis or streaking in the syringe. Although pale yellow xantho-
chromia is difficult to distinguish from normal, a red-­brown color follow-
ing centrifugation is good evidence of pathologic hemarthrosis.
Clarity relates to the number and type of particles within the SF.
Because normal SF is transparent, newsprint is easily read through the
tube. Although translucent fluid obscures details, black and white areas can
be distinguished, but opaque fluid completely obscures the background.
Leukocytes are most commonly responsible for changes in clarity.
However, very large numbers of crystals may produce an opaque, milky,
opalescent fluid without leukocytes. A shimmering, oily-­appearing speci-
men suggests an abundance of cholesterol crystals, which may grossly Figure 30.11  Lupus erythematosus cell in the synovial fluid from a patient with
resemble pus. systemic lupus erythematosus.
Increased turbidity is less often due to concentrations of fibrin, free-­
floating rice bodies (fragments of degenerating proliferative synovial cells
or microinfarcted synovium), metal and plastic particles from patients with
joint prostheses, or cartilage fragments in osteoarthritis. A ground pep-
per appearance from pigmented cartilage fragments may be the result of a
metabolic disorder (i.e., ochronosis). 

MICROSCOPIC EXAMINATION
Total Cell Count
Total leukocyte counts should be performed promptly to avoid degenera-
tive cell loss, which begins as soon as 1 hour following arthrocentesis. Cell
counts may still be performed using a standard hemocytometer in smaller
laboratories. However, automated cell counting now offers more reliable
results (Ottink et al., 2019). Leukocyte counts over 50,000/μL require dilu-
tion, which should be done with saline, not acetic acid, to avoid mucin
clot formation and cell clumping. Flow cell–based automated cell counters
may be used, but their use risks clogging the machine aperture or obtain-
ing spuriously high cell counts from non-­WBC particles (e.g., crystals, fat
globules). Pretreatment of highly viscous SF samples with hyaluronidase
improves automated cell counting using these instruments (Aulesa et al.,
2003). Automated cell counting in SF samples using digital image–based
technology avoids the clogging and spurious count problems and offers a
reliable method for these counts (Walker et al., 2009; Scott, 2014).
Leukocyte counts greater than 10,000/μL, and often greater than
50,000/μL, are characteristic of crystal-­induced arthritis (e.g., gout, pseud-
ogout), chronic inflammatory arthritis (e.g., RA, SLE, ankylosing spondyli-
tis), and septic arthritis (Kjeldsberg, 1993). Osteoarthritis, osteochondritis
dissecans, trauma, and synovioma usually have total WBC counts less than
10,000/μL.
Erythrocytes should be routinely counted unless it is an obvious trau-
matic tap. If a large number of RBCs interferes with the leukocyte count,
they may be lysed by dilution with 0.3 normal saline or 1% saponin in saline.
The upper reference level for SF leukocytes is 150 to 200/μL (Kjelds-
berg, 1993). Elevated cell counts are used to help divide findings into
different disease categories but are nonspecific for any particular disease
because of extensive overlap.  chronic in SLE or undifferentiated connective tissue disorders. Reiter
Differential Leukocyte Count
Cytospin preparations are preferred over smears from centrifuged SF
because the cell morphology is significantly better preserved. Treatment
with hyaluronidase may be necessary to produce thin smears in viscous
specimens. Liquid-­based thin-­layer processing instruments may also be
used effectively to produce good-­quality preparations of SF for microscopic
examination (Policarpio-­Nicolas & Valente, 2013). Automated leukocyte
differential counts utilizing flow cytometers may be reliably performed on
SF samples (Aulesa et al., 2003), with even better performance, including
detection of crystals, using digital image–based instruments (Walker et al.,
2009; Scott, 2014).
Neutrophils normally account for about 20% of SF leukocytes. Neu-
trophils generally exceed 50% in urate gout, pseudogout, and RA; they
most often exceed 75% in acute bacterial arthritis. When 75% is used as
a cutoff, the sensitivity for an inflammatory process is about 75% and the
specificity is 92% (Shmerling et al., 1990). These cells frequently exhibit
degenerative changes and may contain bacteria, crystals, lipid droplets,
vacuoles, or dark blue to black granular inclusions thought to consist of
Figure 30.12  Reiter cells in the synovial fluid from a patient with Reiter syndrome.
immune complexes (ragocytes, RA cells). The presence of ragocytes in
patients with RA may indicate a poorer outcome (Davis et al., 1988).
Lupus erythematosus (LE) cells, sometimes present in patients
with lupus arthritis, are most often neutrophils that have phagocytosed
the nuclei of degenerating cells (Fig. 30.11). However, LE cells are not
pathognomonic for SLE because they have also been identified in the SF
of RA patients (Hunder & Pierre, 1970).
Lymphocytes, normally constituting about 15% of SF cells, are promi-
nent in early RA and other autoimmune disorders, as well as in chronic infec-
tions. Reactive forms, including immunoblasts, are occasionally present.
Monocytes and macrophages are the most common cells present in
normal SF, accounting for approximately 65% of the cell count. Mono-
cytosis may be self-­limited in viral arthritis or serum sickness, or more
cells, originally believed to be specific for Reiter syndrome, are macro-
phages containing degenerating neutrophils (Fig. 30.12).
Eosinophilia, defined as more than 2% of the leukocyte count, has been
reported in Lyme disease, RA, rheumatic fever, metastatic carcinoma, para-
sitic infection, chronic urticaria, and angioedema, and following arthrography
(allergic reaction to dye) and irradiation (Podell et al., 1980; Kay et al., 1988).
Synovial cells, termed synoviocytes, have no pathologic significance.
They appear similar to mesothelial cells and may be difficult to distinguish
from monocytes and macrophages.
Lipid bodies are associated with trauma, aseptic necrosis, and RA.
These droplets often form Maltese crosses under polarized light, can be
associated with a leukocyte response, and may cause spurious elevations of
the automated WBC count (Wise et al., 1987). 
Crystal Examination
Crystals in SF lead to acute inflammation with increased WBC counts
and a neutrophil-­predominant infiltrate. Crystal identification, especially
if intracellularly in neutrophils or macrophages, is pathognomonic for a
crystal-­induced arthritis (Judkins & Cornbleet, 1997).

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 Gout refers to the process of crystal deposition in articular tissue.
Common usage typically implies urate gout; an inflammatory response to
crystal deposition is referred to as gouty arthritis. The most common types
of endogenous crystals responsible for gouty arthritis are monosodium
urate monohydrate (urate gout), calcium pyrophosphate dihydrate
(pyrophosphate gout, chondrocalcinosis, or “pseudogout”), apatite and

PART 3
other basic calcium phosphates (BCPs; apatite gout), calcium oxalate
(oxalate gout), and lipids (lipid gout).
Except for BCP, all of the above crystals can be detected by polar-
ized light microscopy. A high-­quality polarizing microscope with a first-­
order red plate compensator should be used. The polarizer filter is placed
directly above the light source. The analyzer (another polarizing filter) is
placed between the specimen slide and the microscope oculars, oriented
90 degrees from the polarizer to produce a dark background. The com-
pensator is placed between the polarizer and analyzer, usually oriented 45
degrees (halfway) between the planes of the two polarizing filters.
Initial examination should be performed on a wet preparation using
polarized light. Phase-­contrast microscopy enhances crystal detection. The
slide and coverslip must be cleaned and carefully dried immediately before Figure 30.13 Monosodium urate crystals under polarized light from a patient
use to avoid birefringent dust particulate artifacts. The coverslip edges are with urate gout.
sealed with nail polish or other sealant, which retards but does not prevent
evaporation. The coverslip edge is used to find the proper plane of focus;
however, crystals in this location should be ignored because they are most
likely artifacts. Most crystals are scanned with a 10× objective and are evalu-
ated with at least a 40× objective, concentrating especially on cellular areas.
Complete examination requires 100× oil immersion, however, because
apparently negative fluids on scanning may contain a large population of
small crystals (Gatter & Schumacher, 1991). Aligning the crystals’ orienta-
tion to the compensator by rotating the microscope stage or the compensator
facilitates recognition and identification. Crystal morphology, the extinction
angle, strength, and signs of any birefringence (i.e., the ability to refract
light and split the incident light into two rays: a fast ray and a slow ray) are
noted. The sensitivity and specificity of polarized microscopy for crystals are
78% and 79%, respectively, for monosodium urate (Hasselbacher, 1987),
and 12% and 67% for calcium pyrophosphate dihydrate (McGill & York,
1991). Repeat examination following 24 hours of refrigeration at 4°C may
result in a significant increase in the number of crystal-­positive fluids (Yuan
et al., 2003). Cytospin preparations are also used effectively in the detection
of crystals in SF samples (Theiler et al., 2014).
The Diff-­Quik staining method may be a reliable alternative to polar-
ized microscopy. Overall specificity, sensitivity, and accuracy are 87.5%,
94.4%, and 91.9%, respectively. The overall positive predictive value is Figure 30.14 Monosodium urate crystals in synovial fluid. Compensated po-
larized light. (From Kjeldsberg CR, Knight JA: Body fluids: laboratory examination
92.7%; the negative predictive value is 90.3% (Selvi et al., 2001). Other of amniotic, cerebrospinal, seminal, serous and synovial fluids, ed 3, Chicago, 1993,
more sophisticated and reliable methods, such as X-­ray crystallography © American Society for Clinical Pathology, with permission.)
and Fourier transform infrared spectroscopy, have been described for iden-
tifying and characterizing crystals in biological specimens but are seldom
used clinically (Rosenthal & Mandel, 2001).
Monosodium urate (MSU) crystals appear as needle-­shaped rods 5 to
20 μm long, but they may be only 1 to 2 μm in length or, rarely, may appear
as rounded spherolites. They are strongly birefringent (Fig. 30.13): yellow
when oriented parallel to the compensator and blue with perpendicular
orientation (negative birefringence or elongation; Fig. 30.14). A control
slide of MSU crystals should always be used for comparison. Alternatively,
betamethasone, a steroid that appears as a strongly negative birefringent
rod, can be used to prepare a reference slide for the polarizing microscope
(Judkins & Cornbleet, 1997).
MSU crystals are found in 90% of acute urate gout and in about 75%
of patients between attacks. Intracellular MSU crystals are characteristic
of acute urate gout. They may also occasionally be observed as a result of
inflammation in septic arthritis (McCarty, 1988).
Calcium pyrophosphate dihydrate (CPPD) crystals are found in a
group of conditions collectively known as CPPD crystal deposition disease or
pseudogout. These crystals appear as rhomboids, rods, or rectangles 1 to 20
μm in length. CPPD crystals are weakly birefringent with positive elonga-
tion (blue when aligned with the compensator axis; Fig. 30.15). Many are
Figure 30.15 Calcium pyrophosphate dihydrate crystals in synovial fluid from
too small to polarize the light, making them difficult to detect without
a patient with pseudogout. Compensated polarized light. (From Kjeldsberg CR,
phase-­contrast microscopy. Knight JA: Body fluids: laboratory examination of amniotic, cerebrospinal, seminal, se-
CPPD crystals are associated with degenerative arthritis and are seen rous and synovial fluids, ed 3, Chicago: © American Society for Clinical Pathology;
in arthritides associated with hypomagnesemia, hemochromatosis, hyper- 1993, with permission.)
parathyroidism, and hypothyroidism (Jones et al., 1992).
Calcium hydroxyapatite and the other BCP crystals are typically too
small and nonbirefringent (isotropic) to see with light microscopy unless Calcium oxalate dihydrate crystals are 5-­to 30-­μm bipyramidal
they are clumped into 1-­to 50-­μm spherical microaggregates. Alizarin octahedral “envelopes” with variable birefringence and positive elonga-
red S dye may be used to stain these and other calcium-­containing crys- tion. They are seen in arthropathy associated with chronic renal dialysis
tals (Lazcano et al., 1993). At present, identification of BCP crystals is not and primary oxalosis, a rare inborn error of metabolism. The monohydrate
important for diagnosis or prognosis, or as a guide in treatment. form is birefringent but nondescript in shape.

525
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CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
Figure 30.16  Cholesterol crystals in synovial fluid. Polarized light.
Lipid crystals or particles are 1-­to 20-­μm spheres with a Maltese
cross appearance and positive birefringence under compensated polarized
light. They have been implicated as a cause of acute arthritis (McCarty,
1988).
Crystalline corticosteroids from intraarticular injection may have an
appearance similar to MSU or CPPD crystals and persist up to 1 month
following injection. Most often, they have blunt, jagged edges without
clear crystal structure because they are prepared by grinding up larger
crystalline forms. Triamcinolone hexacetonide is negatively birefringent,
but most others show positive birefringence.
Cholesterol crystals typically appear as irregular birefringent plates,
often with notched corners (Fig. 30.16). In chronic effusions (e.g., tuber-
culous arthritis, RA, SLE), needle-­or rhomboid-­shaped crystals similar to
MSU or CPPD may be present (Ettlinger & Hunder, 1979). Very small
(1–5 microns) irregular, rod-­and needle-­shaped cholesterol crystals have
been identified by X-­ray diffraction analysis and by ultrastructural stud-
ies in osteoarthritis effusions (Fam et al., 1981). Cholesterol crystals are
ethanol and ether soluble and are not phagocytosed by leukocytes. If cho-
lesterol crystals are detected, quantitative analysis should show that the SF
cholesterol level exceeds the plasma level.
Glove powder (modified cornstarch) introduced during joint sur-
gery appears as round, strongly birefringent particles 5 to 30 μm in diam-
eter, with a central notch and a Maltese cross appearance when polarized.
A variety of other crystals or particulates may be present in SF. These
include monoclonal Ig crystals or cryoglobulins, Charcot-­Leyden crystals,
amyloid fragments, cartilage fragments, collagen fibrils and fibrin strands,
hematoidin crystals from prior hemorrhage, crystals from certain antico-
agulants, nail polish, prosthetic fragments, and dust particles (Gatter &
Schumacher, 1991).  monly associated with septic arthritis due to gram-­positive cocci and gram-­
CHEMICAL ANALYSIS
Chemical analyses of SF generally offer only supportive information to
the routine tests. High viscosity may be remedied by dilution with normal
saline, sonication, or hyaluronidase treatment. Reference intervals for the
more important chemical analytes are shown in Table 30.8.
Mucin Clot Test
Addition of acetic acid to SF precipitates hyaluronate into a mucin clot,
which may be graded as good, fair, or poor. A fair to poor mucin clot test
reflects dilution and depolymerization of hyaluronic acid—a nonspecific
finding of several inflammatory arthritides. Although of historic interest,
the mucin clot test has minimal clinical utility today and is rarely used
(Baker, 1991).  pected but crystals are not identified or when microscopic crystal analysis
Glucose
Proper interpretation of SF glucose values requires comparison with serum
levels, ideally preceded by a fast of 8 hours to allow glucose to equilibrate
across the synovial membrane. The serum-­synovial differential is less than
10 mg/dL in normal and many noninflammatory conditions. In septic
arthritis, this difference ranges from 20 to 60 mg/dL but overlaps sig-
nificantly with other inflammatory conditions, thereby limiting its clinical
usefulness. When a cutoff value of 75 mg/dL is used, the sensitivity of low
glucose for detecting an inflammatory joint disease is only 20%; the speci-
ficity is 84% (Shmerling et al., 1990).
526
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  TABLE 30.8
Reference Intervals for Synovial Fluid Constituents
Constituent Synovial Fluid Plasma
Total protein 1–3 g/dL 6–8 g/dL
Albumin 55%–70% 50%–65%
α1-­Globulin 6%–8% 3%–5%
α2-­Globulin 5%–7% 7%–13%
β-­Globulin 8%–10% 8%–14%
γ-­Globulin 10%–14% 12%–22%
Hyaluronic acid 0.3–0.4 g/dL
Glucose 70–110 mg/dL 70–110 mg/dL
Uric acid 2–8 mg/dL 2–8 mg/dL
Lactate 9–29 mg/dL 9–29 mg/dL
Modified from Kjeldsberg CR, Knight JA: Body fluids: laboratory examination of
­amniotic, cerebrospinal, seminal, serous and synovial fluids, ed 3, Chicago, 1993,
© American Society for Clinical Pathology, with permission.
In vitro glycolysis by large numbers of leukocytes may falsely reduce
SF glucose values unless testing is performed within 1 hour of collection.
Tubes containing sodium fluoride, an inhibitor of glycolysis, prevent the
loss of glucose. 
Protein
The mean normal protein concentration is 1.38 g/dL in living volunteers
(Weinburger & Simkin, 1989) and a reliable reference interval is 1.0 to
3.0 g/dL. With increasing inflammation, larger proteins (e.g., fibrinogen)
enter the synovial space. Spontaneous clot formation may be detected in
nonanticoagulated specimen tubes. Although elevation of the SF protein
level may be associated with inflammatory and infectious conditions, mea-
surement of SF protein is highly nonspecific; the sensitivity is about 52%
and the specificity 56% for inflammatory disorders (Shmerling et al., 1990). 
Enzymes
Numerous enzymes have been studied in SF, including lactate dehydroge-
nase, aspartate aminotransferase, adenosine deaminase, acid and alkaline
phosphatase, and lysozyme, among others (Kjeldsberg, 1993). Lactate
dehydrogenase is elevated in RA, gout, failed arthroplasties, and infec-
tious arthritis. This increase most likely reflects the neutrophil infiltrate.
Elevated acid phosphatase may have negative prognostic value in RA but
is not specific (Luukkainen et al., 1989). 
Organic Acids
When compared with nonseptic monoarticular arthritis, SF lactic acid
levels are usually increased in patients with septic arthritis (Kjeldsberg,
1993). Levels significantly greater than 30 mg/dL (3.7 mmol/L) are com-
negative bacilli. Measurement of D-­lactate levels in SF appears to be a
useful method for rapid diagnosis of bacterial synovitis (Gratacos et al.,
1995). In other studies, however, normal or intermediate lactate levels nei-
ther rule in nor rule out infection. Moreover, gonococcal arthritis is noto-
rious for having normal SF lactate levels (Curtis et al., 1983).
When gas-­liquid chromatography is used, the presence of other organic
acids not normally present in SF (e.g., n-­valeric, n-­hexanoic, and suc-
cinic acids) may be very helpful in differentiating septic from nonseptic
arthritis (Borenstein et al., 1982). 
Uric Acid
Synovial fluid uric acid levels generally, although not always, parallel serum
levels in gout and noninflammatory arthropathies. This assay provides lit-
tle clinical value in SF analysis except in some cases in which gout is sus-
is not available (Reeves, 1965; Vaidya et al., 2018). Increased SF uric acid
levels in these cases support a diagnosis of gout. 
LIPIDS
In contrast to plasma, normal SF contains extremely low concentrations of
lipids. Synovial fluid lipid abnormalities include (1) rare cholesterol-­rich
pseudochylous effusions typically associated with chronic RA; (2) lipid drop-
lets, usually the result of trauma; and (3) extremely rare chylous effusions
seen in association with RA, SLE, filariasis, pancreatitis, and trauma (Wise
et al., 1987). These diseases can usually be differentiated clinically and by
gross and microscopic examination; quantification of lipids currently has no
clinical value in joint fluid analysis, except in cases in which cholesterol crys-
tals may resemble MSU or CPPD. In these cases, a cholesterol level that
exceeds the plasma level supports the presence of cholesterol crystals.  Transudates: Increased Hydrostatic Pressure or Decreased Plasma
IMMUNOLOGIC STUDIES
Rheumatoid factor (RF) is found in the SF of about 60% of RA patients,
usually at a titer equal to or slightly lower than the serum titer. Antinu-
clear antibodies (ANAs) are found in the SF of about 70% of patients
with SLE and 20% of patients with RA. Neither is specific enough for
practical use. SF complement levels, normally about 10% of serum levels,
increase to 40% to 70% of serum activity with inflammation, proportional
to the increase in protein exudation. Complement consumption in SLE,
and RA in particular, results in levels less than 30% of serum complement.  Viral or mycoplasma pneumonia
MICROBIOLOGICAL EXAMINATION
Immediate transportation of joint fluid and good communication of clini-
cal suspicions to the laboratory are extremely important in the rapid iden-
tification of an infectious agent.
Septic arthritis may be acute or chronic; Gram stain and culture should
be performed as part of the routine SF evaluation. Gram stain sensitivity
varies from about 75% for staphylococcal infections and 50% for most
gram-­ negative organisms to less than 25% for gonococcal infections
(Goldenberg & Reed, 1985). Concentration methods, including cytocen-
trifugation, may increase the sensitivity of the Gram stain.
Culture sensitivity ranges from 75% to 95% for nongonococcal joint
infections in patients who have not received antibiotics. For patients with
gonorrhea, the sensitivity is only 10% to 50% (Shmerling, 1994). In partially
treated patients, the use of resin-­containing blood culture bottles for cultur-
ing SF may improve isolation and identification of the responsible organism.
The use of PCR with primers to detect bacterial DNA is helpful, par-
ticularly for the more fastidious, uncultivable pathogens (e.g., Borrelia
burgdorferi, Chlamydia spp., Mycoplasma spp.) (Nocton et al., 1994; Li et al.,
1996; Jalava et al., 2001; Pons et al., 2018). Viruses are often associated
with acute infectious arthritis; depending on the putative virus, serology,
viral culture, and detection of viral DNA by nucleic acid amplification
should be performed.
Depending on the clinical history, infectious arthritis may be associ-
ated with particular exposures and their associated pathogens. Arthritis
develops in approximately 60% of patients with Lyme disease resulting
from exposure to ticks infected with Borrelia burgdorferi (Golightly, 1993).
The PCR test for detecting B. burgdorferi DNA in SF is positive in 96% of
untreated cases (Nocton et al., 1994; Exner & Lewinski, 2003).
In patients with a travel history or outdoor occupations, SF/tissue
should be examined for fungal pathogens by KOH/calcofluor white stain
and cultured on selective fungal media. For example, a patient with a recent
travel history to Arizona may present with a monoarticular arthritis sec-
ondary to Coccidioides immitis.
Patients with chronic arthritis and risk factors for Mycobacterium tuber-
culosis or nontuberculous infections should undergo a synovial biopsy (Ver-
ettas et al., 2003; Titov et al., 2004). Ziehl-­Neelsen or Kinyoun stains for
acid-­fast organisms have a sensitivity of about 20%. Cultures for M. tuber-
culosis are positive in about 80% of proven cases. Because conventional cul-
ture methods for M. tuberculosis are often very time-­consuming, applying
PCR in SF for the detection of M. tuberculosis is a useful technique for more
rapid diagnosis (Fujimoto et al., 2010).  is needed.
PLEURAL FLUID
The pleural cavity is a potential space lined by mesothelium of the visceral
and parietal pleurae. The pleural cavity normally contains a small amount
of fluid that facilitates movement of the two membranes against each other.
This fluid is a plasma filtrate derived from capillaries of the parietal pleura.
It is produced continuously at a rate dependent on capillary hydrostatic
pressure, plasma oncotic pressure, and capillary permeability. Pleural fluid
is reabsorbed through the lymphatics and venules of the visceral pleura.
An accumulation of fluid, called an effusion, results from an imbal-
ance of fluid production and reabsorption. This fluid accumulation in the
pleural, pericardial, and peritoneal cavities is known as a serous effusion.
SPECIMEN COLLECTION
Thoracentesis is indicated for any undiagnosed pleural effusion or for
therapeutic purposes in patients with massive symptomatic effusions.
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  BOX 30.9 
Classification of Pleural Effusions
Oncotic Pressure
Congestive heart failure
PART 3
Hepatic cirrhosis
Hypoproteinemia (e.g., nephrotic syndrome) 
Exudates: Increased Capillary Permeability or Decreased Lymphatic
Resorption
Infections
Bacterial pneumonia
Tuberculosis, other granulomatous diseases (e.g., sarcoidosis,
histoplasmosis)
Neoplasms
Bronchogenic carcinoma
Metastatic carcinoma
Lymphoma
Mesothelioma (increased hyaluronate content of effusion fluid)
Noninfectious inflammatory disease involving pleura
Rheumatoid disease (low pleural fluid glucose in most cases)
Systemic lupus erythematosus (LE cells are occasionally present)
Pulmonary infarct (may be associated with hemorrhagic effusion) 
Fluid from Extrapleural Sources
Pancreatitis (elevated amylase activity in effusion fluid)
Ruptured esophagus (elevated amylase activity and low pH)
Urinothorax (elevated creatinine and low pH)
LE, Lupus erythematosus.
Pleural fluid samples are frequently collected, handled, and/or analyzed in
a less than satisfactory manner. Indeed, improper collection/handling and
undertesting or inappropriate testing are more common than with other
body fluids. The laboratory often receives a large syringe or vacuum bottle,
which must be circulated through the various laboratory sections. More-
over, a large blood or fibrin clot may be present as the result of inadequate
anticoagulation or mixing.
Except for an EDTA tube for total and differential cell counts, the
specimen should be collected in heparinized tubes to avoid clotting. Ali-
quots for aerobic and anaerobic bacterial cultures are best inoculated into
blood culture media at the bedside. If malignancy, fungal infection, or
mycobacterial infection is suspected, all remaining fluid (≥100 mL) should
be submitted to maximize the yield of stains and culture. Because serous
effusions are more forgiving than CSF in maintaining cellular integrity,
fresh specimens for cytology may be stored for up to 48 hours in the refrig-
erator with satisfactory results. For pH measurements, the fluid should be
collected anaerobically in a heparinized syringe and submitted to the labo-
ratory on ice. Grossly purulent specimens do not require pH measurement
and may clog the analyzer. 
TRANSUDATES AND EXUDATES
It has long been recognized that the initial classification of a pleural fluid
as a transudate or an exudate greatly simplifies the process of arriving at
a correct final diagnosis. Moreover, it determines whether further testing
Transudates are usually bilateral owing to systemic conditions leading
to increased capillary hydrostatic pressure or decreased plasma oncotic
pressure (Box 30.9). Malignant effusions may infrequently be transudative
as the result of a simultaneous confounding clinical condition, such as con-
gestive heart failure (Ashchi et al., 1998). Exudates are more often unilat-
eral, associated with localized disorders that increase vascular permeability
or interfere with lymphatic resorption (see Box 30.9). 
RECOMMENDED TESTS
The evaluation of serous body fluids (pleural, pericardial, peritoneal)
is directed first toward differentiating transudative from exudative effu-
sions. Transudates generally require no further workup. However, the
fluid should be retained for 7 to 10 days in case further testing is needed.
To separate the two, several chemical parameters have been proposed,
although none is 100% accurate (Table 30.9).
Classical teaching stressed that exudates and transudates can be distin-
guished on the basis of total protein concentrations above (exudates) or
527
CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
  TABLE 30.9
Laboratory Criteria for Pleural Fluid Exudate
Pleural fluid/serum protein ratio ≥0.50
Pleural fluid/serum LD ratio ≥0.60
Pleural fluid LD
≥2/3 upper limit of normal
serum LD
Pleural fluid cholesterol >45 mg/dL
Pleural fluid/serum cholesterol ratio ≥0.30
Serum–pleural fluid albumin gradient ≤1.2 g/dL
Pleural fluid/serum bilirubin ratio ≥0.60
LD, Lactate dehydrogenase.
below (transudates) 3.0 g/dL. However, using total protein alone misclassi-
fies both exudates and transudates by about 30% (Melsom, 1979). It is now
well accepted that test combinations increase sensitivity, improve accuracy,
and serve as the basis for well-­established diagnostic criteria (Light et al.,
1972; Light, 2002). According to Light’s criteria, an exudate meets one or
more of the following criteria: (1) pleural fluid/serum protein ratio greater
than 0.5; (2) pleural fluid/serum LD ratio greater than 0.6; and (3) pleural
fluid LD level greater than two-­thirds of the serum upper limit of normal.
Using these criteria, the sensitivity and specificity are about 98% and 80%,
respectively.
Several alternative measurements have been proposed to differenti-
ate exudates from transudates. Testing for total cholesterol, the albumin
gradient, or a combination of LD and total cholesterol may discriminate
effusions with equivocal Light’s criteria results. For example, the albumin
gradient is recommended to confirm a clinical transudate misclassified as
an exudate by Light’s criteria (Light, 1997, 2002), that is, a serum albumin
level greater than 1.2 g/dL higher than the pleural fluid level indicates
that the fluid is a transudate (Burgess et al., 1995). In many such cases,
the patient is being diuresed. Other test combinations have equaled but
not surpassed the performance of Light’s criteria. In most cases, the same
categorization of pleural fluids as exudates or transudates may be achieved
using measurements of protein and LD alone without comparison with
a blood sample, as was accomplished with application of Light’s criteria
(Light, 2002; Murphy & Jenkinson, 2008). The traditional use of Light’s
criteria for distinguishing between transudates and exudates has recently
been recommended for simplification based on measurements of LD and
cholesterol only in the fluid and not in comparison with simultaneous val-
ues in serum (Lépine et al., 2019). In that study of 400 consecutive tho-
racenteses, values in pleural fluid of LD greater than 0.6 times the upper
limit of normal for serum and of cholesterol greater than 40 mg/dL (1.04
mmol/L) showed the best sensitivity and negative likelihood ratio for clas-
sifying an effusion as exudative. This approach spares additional blood
draws and testing without adversely impacting diagnostic sensitivity.
Some tests, such as the combination of pleural fluid LD and cholesterol
or cholesterol alone, may be more convenient and cost-­effective by avoid-
ing the need for simultaneous blood tests (Costa et al., 1995; Hamal et al.,
2013). Bilirubin measurement is not a strong discriminator of effusions
(Heffner et al., 1997).
Further analysis of exudates is directed toward ruling out malignancy
and infection. Cytology and appropriate bacterial stains and cultures or
PCR-­based microbial assays are the most useful tests in this regard. More-
over, given that pleural fluid DNA levels are significantly increased in
exudates, quantitative analysis may be an effective method to evaluate the
causes of serous effusion (Chan et al., 2003). Recommended tests for the
evaluation of pleural effusions are summarized in Box 30.10. The types of
tests ordered and the interpretation of test results should always be cor-
related with clinical findings and differential diagnosis. Total leukocyte,
differential, and RBC counts are of limited use in the evaluation of serous
effusions.  highly effective in the rapid detection of malignant cells, especially hema-
GROSS EXAMINATION
Transudates are typically clear, pale yellow to straw colored, and odorless,
and do not clot. Approximately 15% of transudates are blood tinged. A
bloody pleural effusion (hematocrit >1%) suggests trauma, malignancy, or
pulmonary infarction (Jay, 1986). A traumatic tap is suggested by uneven
blood distribution, fluid clearing with continued aspiration, or formation
of small blood clots. A pleural fluid hematocrit greater than 50% of the
blood hematocrit is good evidence for a hemothorax (Light, 1995).
Exudates may grossly resemble transudates, but most show variable
degrees of cloudiness or turbidity, and they often clot if not heparinized. A
528
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  BOX 30.10 
Pleural Effusion: Recommended Tests
Routine Tests
Gross examination
Pleural fluid/serum protein ratio (used for Light’s criteria)
Pleural fluid/serum LDH ratio (used for Light’s criteria)
Examination of Romanowski-­stained smear (malignant cells, LE cells) 
Useful Tests in Most Patients
Stains and cultures for microorganisms
Cytology 
Useful Tests in Selected Cases
Pleural fluid cholesterol
Pleural fluid/serum cholesterol ratio
Albumin gradient
pH
Lactate
Enzymes (ADA, amylase)
Interferon-­γ
C-­reactive protein
Lipid analysis
Multiplex PCR assay for bacterial, fungal, viral, and mycobacterial DNA
Tumor markers
Immunologic studies
Tuberculostearic acid
Pleural biopsy
ADA, Adenosine deaminase; LD, lactate dehydrogenase; LE, lupus erythematosus.
Modified from Kjeldsberg CR, Knight JA: Body fluids: laboratory examination of
­amniotic, cerebrospinal, seminal, serous and synovial fluids, ed 3, Chicago, 1993,
© American Society for Clinical Pathology, with permission.
feculent odor may be detected in anaerobic infections. Turbid, milky, and/
or bloody specimens should be centrifuged and the supernatant examined.
If the supernatant is clear, the turbidity is most likely due to cellular ele-
ments or debris. If the turbidity persists after centrifugation, a chylous or
pseudochylous effusion is likely.
True chylous effusions are produced by leakage from the thoracic duct
resulting from obstruction by lymphoma, carcinoma, or traumatic disrup-
tion. A creamy top layer of chylomicrons may form in the specimen on
standing. Idiopathic congenital chylothorax is the most common form of
pleural effusion in the newborn.
Pseudochylous or chyliform effusions may have a milky, greenish, or
“gold paint” appearance. They accumulate gradually through the break-
down of cellular lipids in long-­standing effusions such as rheumatoid pleu-
ritis, tuberculosis, or myxedema. Features that distinguish true chylous
from pseudochylous effusions are summarized in Table 30.10. 
MICROSCOPIC EXAMINATION
Cell Counts
Total cell counts may be performed using manual hemocytometer meth-
ods. However, automated cell counts are increasingly used with pleural and
other serous fluid specimens (Aulesa et al., 2003; Conner et al., 2003; Yang
et al., 2013). Leukocyte counts have limited utility in separating transu-
dates (<1000/μL) from exudates (>1000/μL). Although RBC counts above
100,000/μL are highly suggestive of malignancy, trauma, or pulmonary
infarction, they are not specific for these conditions. 
Differential Leukocyte Count and Cytology
Examination is commonly performed on a stained smear, preferably pre-
pared by cytocentrifugation and with the air-­dried smear stained with a
Romanowski stain. Examination by the hematology laboratory can be
tologic malignancies (Kendall et al., 1997). Filtration or automated con-
centration methods with Papanicolaou stain may also be used, especially if
cell loss is a matter of concern. Automated WBC differential counts may be
done on pleural fluid samples, with increasingly reliable results using more
recent technology (Conner et al., 2003; Fuster et al., 2018). Liquid-­based
thin-­layer methods are often used to prepare pleural and other serous fluid
specimens for cytopathologic examination and show good performance in
the detection of malignant cells (Moriarity et al., 2008).
Cytologic analysis will establish the diagnosis of metastatic carcinoma
in 70% or more of cases when both smears and cell blocks are examined
(Light, 2002). The sensitivity is significantly lower if the patient has meso-
thelioma (10%), squamous cell carcinoma (20%), lymphoma (25%–50%),
  TABLE 30.10
Characteristic Features of Chylous and Pseudochylous Effusions
Feature Chylous Pseudochylous

Onset Sudden Gradual

PART 3
Appearance Milky-­white, or Milky or greenish, metallic
yellow to bloody sheen
Microscopic Lymphocytosis Mixed cellular reaction,
­examination cholesterol crystals
Triglycerides*† ≥110 mg/dL <50 mg/dL (<0.56 mol/L)
(≥1.24 mmol/L)
Lipoprotein Chylomicrons Chylomicrons absent
­electrophoresis present

Modified from Kjeldsberg CR, Knight JA: Body fluids: laboratory examination of
­amniotic, cerebrospinal, seminal, serous and synovial fluids, ed 3, Chicago, 1993,
© American Society for Clinical Pathology, with permission.
*Values in parentheses are SI units.
†Triglyceride levels between 50 mg/dL and 110 mg/dL are equivocal and require
Figure 30.17  Mesothelial cells in pleural fluid.
electrophoresis to confirm chylothorax.

or sarcoma (25%). Preparation of cell blocks is unnecessary, except for

effusions in which malignancy is an important consideration (Sumedha,
2017; Jonasson et al., 1990). Well-­differentiated carcinoma cells may be
easily recognized (Figs. 30.17 and 30.18) or may be highly undifferenti-
ated (Fig. 30.19). A panel of immunocytochemical or immunohistochemi-
cal stains may be necessary for confirmation. These studies are enhanced
by the use of liquid-­based preparation methods or cell block technology
(Sioutopoulou et al., 2008; Dey et al., 2017).
Mesothelial cells are common in pleural fluids from inflammatory
processes (see Fig. 30.17). However, they are conspicuously scarce in
patients with tuberculous pleurisy and rheumatoid pleuritis and in patients
who have had pleurodesis. Fibrin deposition and fibrosis occurring in these
conditions prevent mesothelial cell exfoliation.
Neutrophils predominate in pleural fluid from patients with pleural
inflammation (Box 30.11). More than 10% of transudates will also have
a predominance of neutrophils, but this has limited clinical significance.
Lymphocytes predominate in the disorders summarized in Box 30.11.
Most are small, but medium, large, and reactive (transformed) variants may
be seen. Nucleoli and nuclear cleaving are more prominent in effusions
than in the peripheral blood; these features may be particularly prominent Figure 30.18  Well-­differentiated breast carcinoma cells in pleural fluid.
in cytocentrifuge preparations. Plasma cells may also be observed. Lym-
phocytosis associated with transudates is of limited clinical significance.
Low-­grade non-­Hodgkin lymphoma and chronic lymphocytic leuke-
mia (CLL) may be difficult to distinguish from benign lymphocyte-­rich
serous effusion (Fig. 30.20). Immunophenotyping by flow cytometry or
immunocytochemistry in conjunction with cellular morphology is usually
helpful in making a correct diagnosis. The relative proportions of T and
B cells are not definitive by themselves for separating benign from malig-
nant exudates (Ibrahim et al., 1989). However, the pattern of expression
of Ig light chains and/or other distinctive cell marker combinations may
allow specific diagnosis of lymphoproliferative disorders. Molecular DNA
analysis may be another useful adjunct to morphologic analysis. An unusual
form of high-­grade B-­cell non-­Hodgkin lymphoma, called primary effusion
lymphoma, may be seen in pleural, peritoneal, and/or pericardial fluid speci-
mens, typically from immunocompromised patients, with a characteristic
highly anaplastic and immunoblastic morphologic appearance and without
expression of most B cell–associated antigens (Karcher & Alkan, 1997).
The diagnosis is usually confirmed by demonstrating in the neoplastic cells
the presence of human herpesvirus-­8 (HHV-­8)–associated antigens and/or
DNA by immunophenotypic and/or molecular analysis.
An eosinophilic effusion is one that has 10% or more eosinophils. Figure 30.19  Small-­cell carcinoma of the lung showing typical molding of nuclei.
The most common causes are related to the presence of air or blood in
the pleural cavity (see Box 30.11). Most of these are exudates; however,
in about 35% of patients, the cause is unknown (Adelman et al., 1984). A Glucose
small number of mast cells or basophils often accompany eosinophils. The glucose level of normal pleural fluid, transudates, and most exudates
Eosinophil-­derived Charcot-­Leyden crystals may also be seen.  is similar to serum levels. Decreased pleural fluid glucose, accepted as a
level below 60 mg/dL (3.33 mmol/L) or a pleural fluid/serum glucose ratio
CHEMICAL ANALYSIS less than 0.5, is most consistent and dramatic in rheumatoid pleuritis and
grossly purulent parapneumonic exudates (Sahn, 1982). Low pleural fluid
Protein glucose may also be present in malignancy, tuberculosis, nonpurulent bac-
The measurement of pleural fluid total protein or albumin has little clinical terial infection, lupus pleuritis, and esophageal rupture. 
value except when combined with other parameters to differentiate exu-
dates from transudates. Protein electrophoresis shows a pattern similar to Lactate
serum, except for a higher proportion of albumin; it has little value for Pleural fluid lactate levels can be a useful adjunct in the rapid diagno-
differential diagnosis (Light, 1995).  sis of infectious pleuritis. Levels are significantly higher in bacterial and

529
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CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
  BOX 30.11 
Cellular Differential of Pleural Effusions
Neutrophilia (>50%)
Bacterial pneumonia (parapneumonic effusion)
Pulmonary infarction
Pancreatitis
Subphrenic abscess
Early tuberculosis
Transudates (>10%) 
Lymphocytosis (>50%)
Tuberculosis
Viral infection
Malignancy (lymphoma, other neoplasms)
True chylothorax
Rheumatoid pleuritis
Systemic lupus erythematosus
Uremic effusions
Transudates (≈30%)  Figure 30.20  Pleural effusion in patient with non-­Hodgkin lymphoma, small lym-
Eosinophilia (>10%)
Pneumothorax (air in pleural space)
Trauma
Pulmonary infarction
Congestive heart failure
Infection (especially parasitic, fungal)
Hypersensitivity syndromes
Drug reaction
Rheumatologic diseases
Hodgkin disease
Idiopathic
tuberculous pleural infections and other complicated parapneumonic pleu-
ral effusions than in other pleural conditions (Santotoribio et al., 2016).
Values greater than 90 mg/dL (10 mmol/L) have a positive predictive value
for infectious pleuritis of 94% and a negative predictive value of 100%
(Gastrin & Lovestad, 1988).  Urinothorax, a collection of urine presumably produced by lymphatic
Enzymes
Amylase elevations above the serum level (usually 1.5–2.0 or more times
greater) indicate the presence of pancreatitis, esophageal rupture, or malig-
nant effusion (Light & Ball, 1973). Elevated amylase derived from esopha-
geal rupture or malignancy is the salivary isoform, which differentiates it
from pancreatic amylase (Kramer et al., 1989).
Pleural fluid LD levels rise in proportion to the degree of inflammation.
In addition to their use in separating exudates from transudates, declining
LD levels during the course of an effusion indicate that the inflammatory
process is resolving. Conversely, increasing levels indicate a worsening
condition requiring aggressive workup or treatment.
ADA, which is particularly rich in T lymphocytes, is significantly
increased in tuberculous pleuritis. At a level of 50 U/L, the sensitivity,
specificity, positive predictive value, negative predictive value, and effi-
ciency for tuberculosis are 91%, 81%, 84%, 89%, and 86%, respectively
(Burgess et al., 1996). When the lymphocyte/neutrophil ratio is 0.75 or
greater, the percentages are 88%, 95%, 95%, 88%, and 92%, respectively.
ADA levels of 40 U/L or greater are present in about 99.6% of patients
with verified tuberculous pleuritis (Lee et al., 2001). However, in patients
with lymphocyte-­rich pleural fluids from nontuberculous causes, ADA lev-
els less than 40 U/L are present in 97.1% of cases. Factors such as patient
age may impact ADA levels in pleural fluid, with lower levels and the need
for a lower cutoff value for tuberculous effusions in older patients (Tay
et al., 2013).  and a pleural fluid/serum cholesterol ratio of 0.32 or higher have sensitivity
Interferon-­γ
Pleural fluid interferon (IFN)-­γ levels are significantly increased in the
pleural fluid of patients with tuberculous pleuritis. The sensitivity of levels
of 3.7 IU/L or greater is 99%, and the specificity is 98% (Villena et al.,
1996a). Test sensitivity does not differ in HIV-­positive and HIV-­negative
patients. Only about 20% of patients with effusions due to hematologic
malignancies have IFN-­γ levels slightly above 3.7 IU/L (Villena et al.,
2003a).  sitivity of 93.7%, a specificity of 76.5%, and a positive predictive value of
pH
Pleural fluid pH measurement has the highest diagnostic accuracy in
assessing the prognosis of parapneumonic effusions (Heffner et al., 1995).
530
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phocytic type. The cells are small round forms, difficult to distinguish from benign
lymphocytes. (From Kjeldsberg CR, Knight JA: Body fluids: Laboratory examination
of amniotic, cerebrospinal, seminal, serous and synovial fluids, ed 3, Chicago, 1993, ©
American Society for Clinical Pathology, with permission.)
A parapneumonic exudate with a pH greater than 7.30 generally resolves
with medical therapy alone. A pH less than 7.20 indicates a complicated
parapneumonic effusion (loculated or associated with empyema), requiring
surgical drainage.
Patients with borderline complicated exudates (pH 7.20–7.30) may be
closely watched with repeat measurements. A concomitant pleural glucose
level below 60 mg/dL (3.33 mmol/L), however, strongly suggests impend-
ing empyema. Rheumatoid pleuritis and malignant effusions with a poor
response to pleurodesis also have pH values below 7.20 and a low glucose
level (Rodriquez-­Panadero & Mejias, 1989). A pH below 6.0 is character-
istic of esophageal rupture, although the pH in severe empyema may be
6.0 or less (Good et al., 1980).
drainage of perirenal accumulations into the pleural cavity, is also associ-
ated with a pleural fluid pH less than 7.30. These effusions are transuda-
tive, because of their low protein content, and smell of urine. They have a
creatinine level greater than in simultaneously drawn serum (Miller et al.,
1988). 
Lipids
Some serous effusions appear to be chylous (i.e., a milky appearance) but
are not (pseudochylous), whereas others may not look chylous but are
(Maldonado et al., 2009). Although pseudochylous fluids may be partially
due to increased leukocytes and necrotic debris, they are primarily due to
the presence of increased lecithin-­globulin complexes. A true chylous effu-
sion has chylomicrons on lipoprotein electrophoresis. Lipid measurements
are also helpful in identifying chylous effusions (Staats et al., 1980). Thus,
pleural fluid triglyceride levels above 110 mg/dL indicate a chylous effu-
sion; values from 60 to 110 mg/dL (0.68–1.24 mmol/L) are less certain and
require lipoprotein electrophoresis to confirm a chylothorax, particularly
in fasting and postoperative patients (Maldonado et al., 2009). Nonchylous
and pseudochylous effusions generally have triglyceride levels below 50
mg/dL (0.56 mmol/L) and no chylomicrons on electrophoresis (see Table
30.10).
Cholesterol measurements may be useful in separating transudates
from exudates, especially when there is a question regarding Light’s cri-
teria (Hamal et al., 2013). A total cholesterol value of 54 mg/dL or more
and specificity values similar to Light’s criteria (Suay et al., 1995). Elevated
levels and the presence of cholesterol crystals may be seen with pleural
effusions that have been present for several years. 
C-­Reactive Protein
Pleural fluid CRP is a clinically useful screening test for organ disease,
index of disease activity, and measure of response to therapy (Castano &
Amores, 1992). Pleural fluid CRP levels >30 mg/L reportedly have a sen-
98.4% in parapneumonic infections (Turay et al., 2000). In a more recent
study, mean CRP values were ≥138 mg/L in parapneumonic infections
compared with <64 mg/L in other types of exudative effusions (Izhakian
et al., 2016). Measurement of pleural fluid CRP contributes to both the
diagnosis and assessment of severity of parapneumonic effusions (Porcel
et al., 2012).  routine diagnosis, although it may be helpful in the diagnosis of otherwise
Tuberculostearic Acid (10-­Methyloctadecanoic Acid)
Tuberculostearic acid (TSA) was first isolated from the bacillus Mycobacte-
rium tuberculosis. This fatty acid is a structural component of mycobacteria
and is not normally present in human tissue. Using gas chromatography–
mass spectroscopy, TSA was measured in sputum, bronchial washings,
and pleural fluid from patients with pulmonary tuberculosis (Muranishi
et al., 1990). Here, pleural fluid TSA was identified in 24 of 32 (75%)
patients with active tuberculosis; bronchial washings were positive for
TSA in 15 of 22 cases. In patients with other pulmonary disorders, only
4 of 46 pleural fluids and 3 of 69 bronchial washings had detectable lev-
els. A later smaller study reported the following for pleural fluid TSA:
Sensitivity 54%, specificity 80%, positive predictive value 75%, nega-
tive predictive value 61%, and efficacy 66% (Yorgancioglu et al., 1996).
Combining TSA and ADA analysis in pleural fluid samples appears to
increase the diagnostic sensitivity for tuberculous pleuritis (Muranishi
et al., 1992).  Pleural biopsy yields the highest culture sensitivity (50%–75%) and may
Tumor Markers
Although not recommended as a routine test, various tumor markers are
often a useful adjunct in enigmatic noninflammatory exudates with nega-
tive cytology. Several tumor markers—especially CEA, CA 15-­3, CA 549,
CA 72-­4, CA 125, and CYFRA 21-­1, among others—have been studied in
pleural fluids. CEA is probably the most useful single marker for adeno-
carcinomas, but reported cutoff values vary considerably. The sensitivity
of CEA for malignant effusions varies depending on tumor origin and is
about 50% overall. Although complicated parapneumonic effusions may
result in elevated CEA levels (Garcia-­Pachon et al., 1997), they are usually
not a problem to distinguish clinically.
A combination of tumor markers increases the accuracy of diagnosis
of malignant effusions. Thus, a combination of CEA, CA 15-­3, and CA
72-­4 had an accuracy of 90% with 78% sensitivity, 95% specificity, 88%
positive predictive value, and 91% negative predictive value (Villena et al.,
1996b). Similarly, CA 15-­3 and CEA combined had an accuracy of 87%
(Romero et al., 1996); a combination of CA 549, CEA, and CA 15-­3 had
a sensitivity of 65%, specificity 99%, and accuracy 85% (Villena et al.,
2003b). The use of the cytokeratin 19 fragment (CYFRA 21-­1) may also be
useful in combination with other tumor markers. Complicating the use of
these tests, different tumor markers may be positive in both malignant and
inflammatory pleural effusions (Topolcan et al., 2007). Pleural fluid tumor
marker levels may be particularly useful in specimens with inconclusive
cytologic results (Antonangelo et al., 2015).
Other tumor markers may also be useful in the diagnosis of unexplained
effusions. For example, a marked increase in pleural fluid prostate-­specific
antigen (PSA) can lead to the correct diagnosis of metastatic prostate can-
cer in pleural and pericardial effusions, even when negative by cytologic
examination (Chin et al., 1999).  tuberculous, or fungal infection, or in association with autoimmune disor-
MicroRNA (miRNA)
A new adjunctive approach to diagnosis of serous cavity fluids is the analysis
of microRNA (miRNA), which has great stability in such a fluid environ-
ment and can be detected and examined even in fluids in which malignant
cells can be rare or degenerated and, thus, not fit for standard cytologic
evaluation (Nicolè et al., 2019). Using miRNA has the potential for greatly
enhancing examination of serous fluids and diagnosing malignancy.  The postpericardiotomy syndrome is a fairly common but non-
IMMUNOLOGIC STUDIES
Approximately 5% of patients with RA and 50% with SLE develop pleural
effusions sometime during the course of their disease.
RF is commonly present in pleural effusions associated with seroposi-
tive RA. Although a pleural fluid titer of 1 : 320 or greater in a patient with
known RA is reasonable evidence of rheumatic pleuritis (Halla et al., 1980),
elevated RF titers up to 1 : 1280 have been identified in 41% of patients
with bacterial pneumonia, 20% of patients with malignant effusions, and
14% of patients with tuberculosis, making this test of little value (Levine
et al., 1968).
ANA titers once appeared to be useful in the diagnosis of effusion due
to lupus pleuritis; (Good et al., 1983). Later studies have indicated no ben-
efit of this testing in pleural fluid specimens over and above serum testing
(Porcel et al., 2007).
Decreased complement levels (CH50 <10 U/mL or C4 level below
10 × 10–5 U/g protein) are present in most patients with rheumatoid or
lupus pleuritis (Hunder et al., 1972; Halla et al., 1980). However, decreased
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complement is not highly specific for these diseases and is of little value for
enigmatic effusions. 
MICROBIOLOGICAL EXAMINATION
PART 3
Bacteria most commonly associated with parapneumonic effusions are
Staphylococcus aureus, Streptococcus pneumoniae, β-­hemolytic group A strep-
tococci, enterococci, and some gram-­negative bacilli. Anaerobic bacteria
are isolated in a significant proportion of cases; thus, both anaerobic and
aerobic cultures should be performed. The sensitivity of the Gram stain is
approximately 50% (Ferrer et al., 1999); concentration methods, such as
cytocentrifugation, may increase the sensitivity. Use of resin-­containing
blood culture bottles may improve the isolation of certain bacteria in par-
tially treated patients.
For patients with suspected M. tuberculosis, direct staining of tubercu-
lous effusions for acid-­fast bacteria has a sensitivity of 20% to 30%, and
positive cultures are found in 50% to 70% of cases (Baer & Smith, 2001).
provide a rapid presumptive diagnosis of tuberculosis by histopathologic
demonstration of granulomas or acid-­fast bacteria. Combining culture and
acid-­fast stains with pleural biopsy increases the sensitivity to about 95%
(Jay, 1986). Real-­time PCR analysis of pleural fluid specimens shows good
sensitivity and specificity for the diagnosis of M. tuberculosis and may pro-
vide an effective less invasive alternative method for rapid diagnosis (Rosso
et al., 2011; Saeed et al., 2017).
ADA can provide rapid chemical evidence for tuberculous effusions
independent of HIV status (Burgess et al., 1996; Riantawan et al., 1999;
Lee et al., 2001). Although the ADA-­2 isoenzyme form is elaborated
by activated lymphocytes in tuberculosis, only mild elevations occur in
lymphocyte-­rich pleural effusions from nontuberculous causes. However,
the relatively low prevalence of tuberculous pleurisy in North America
anticipates a lower positive predictive value rate compared with the excel-
lent results reported in the Asian and European literature, where tubercu-
losis is more common. Combining ADA measurement and real-­time PCR
analysis provides good diagnostic efficiency in tuberculous pleural effu-
sions (Kaur et al., 2012).
Pleural fluid interferon-­γ is significantly increased in tuberculous pleu-
ritis and may be helpful in some cases because it is independent of HIV
status and is only modestly increased in about 20% of hematologic malig-
nancies (Villena et al., 2003a). 
PERICARDIAL FLUID
From 10 to 50 mL of fluid is normally present in the pericardial space,
produced by a transudative process similar to pleural fluid. Pericardial
effusions are most often caused by viral infection; enterovirus is the most
common etiologic agent. They may also develop as a result of bacterial,
ders, renal failure, myocardial infarction, mediastinal injury, or the effects
of various drugs, or they may be idiopathic (Box 30.12). HIV-­infected
patients commonly have asymptomatic pericardial effusions, which may
become large in more advanced disease (Silva-­Cardosa et al., 1999), or
they may be associated with primary effusion lymphoma (Karcher & Alkan,
1997). Many of the recommended laboratory tests described for pleural
fluid also pertain to pericardial effusions (see Box 30.10).
specific complication of cardiac surgery (or other cardiac damage) that
develops days to weeks following the initial injury. It is characterized by
the development of fever, pleuritic chest pain, and other signs of pleural,
pericardial, and, less often, lung inflammation (Tamarappoo et al., 2016).
Exudative pleural effusions develop in more than 80% of cases. These are
often serosanguineous to hemorrhagic and typically have a pH greater
than 7.4 and a normal glucose level (Stelzner et al., 1983). No specific tests
are available for diagnosing this syndrome. Diagnosis, therefore, remains
one of clinical exclusion. Although the cause is uncertain, the time course,
presence of antimyocardial antibodies, and response to antiinflammatory
therapy suggest an immune-­mediated process. Increased levels of antimy-
ocardial antibodies relative to serum, decreased complement levels, and
immune complexes have been documented in pleural fluid from a single
patient with the syndrome (Kim & Sahn, 1996).
SPECIMEN COLLECTION
Pericardial effusions of unknown origin or large effusions with signs of car-
diac tamponade are generally submitted for laboratory examination. Fluid
531

CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
  BOX 30.12 
Causes of Pericardial Effusions
Idiopathic (most often viral)
Infection
Bacteria
Tuberculosis
Fungi
Viruses
AIDS-­related (usually viral)
Neoplasm
Metastatic carcinoma
Lymphoma
Drugs
Hydralazine
Procainamide
Phenytoin
Renal failure
Hemorrhage
Trauma
Anticoagulant therapy
Leakage of aortic aneurysm
Autoimmune disorders
Hypothyroidism
Rheumatoid arthritis
Systemic lupus erythematosus
Inflammatory bowel disease
Wegener’s granulomatosis
Acute myocardial infarction
Radiation therapy
AIDS, Acquired immunodeficiency syndrome.
may be obtained by pericardiotomy following limited thoracotomy, or by
pericardiocentesis (sterile needle aspiration). 
GROSS EXAMINATION
Normal pericardial fluid is pale yellow and clear. Large effusions (>350 mL)
are most often caused by malignancy or uremia, or they may be idiopathic.
In HIV-­associated cardiac tamponade, 45% of cases are idiopathic, and
tuberculous and bacterial effusions each account for about 20% of cases
(Chen et al., 1999). Infection or malignancy typically produces turbid effu-
sions, whereas effusions due to uremia are usually clear and straw colored.
These and several other disorders may produce hemorrhagic effusions.
Blood-­like fluid obtained by pericardiocentesis might represent a hem-
orrhagic effusion or inadvertent aspiration of blood from the heart. Blood
obtained from the heart chamber will have a hematocrit comparable with
that of peripheral blood, and blood gas analysis yields results similar to
venous or arterial blood. In contrast, the hematocrit of a hemorrhagic effu-
sion is usually lower than that of peripheral blood. Blood from a cardiac
puncture clots, but a hemorrhagic effusion usually does not.
A milky appearance suggests the presence of a chylous or pseudochy-
lous effusion. Identification and differentiation of these effusions are dis-
cussed in the Pleural Fluid section earlier in the chapter.  tuberculous pericarditis is significantly higher than in other pathologic
EXUDATES AND TRANSUDATES
According to Light’s criteria, a pleural exudate has one or more of the fol-
lowing: pleural fluid/serum protein ratio >0.5; pleural fluid/serum LD ratio
>0.6; and pleural fluid LD level >200 U/L. Light’s criteria have also been
shown to be the most reliable diagnostic tool for identifying pericardial
exudates and transudates (Burgess et al., 2002a).
Routine testing of pericardial effusions should probably be limited to
cell count, glucose, total protein, LD, bacterial culture, and cytology (Mey-
ers et al., 1997). Other more specific tests are appropriate only when there
is a high clinical suspicion of unusual causes of pericardial effusion.  results in a sensitivity and specificity of 100% for the diagnosis of tuber-
MICROSCOPIC EXAMINATION
The hematocrit and RBC count document the presence of a hemorrhagic
effusion but are of limited value for differential diagnosis. Total leuko-
cyte counts over 10,000/μL suggest bacterial, tuberculous, or malignant
pericarditis; however, low counts may be encountered in these conditions,
limiting the value of this measurement (Agner & Gallis, 1979). Leukocyte
differential counts may be helpful in determining the cause of certain peri-
cardial effusions, particularly when combined with other pericardial fluid
findings (Reuter et al., 2006). Even when the differential count is not help-
ful, examination of a stained smear should always be performed to evaluate
for atypical or malignant cells.
Cytologic identification of malignant cells is usually not difficult. Meta-
static carcinomas of the lung and breast are most frequently observed in
malignant pericardial effusion. Cytology has a sensitivity of 95% and a
specificity of 100% (Meyers et al., 1997). 
CHEMICAL ANALYSIS
Chemical parameters for the diagnosis of pericardial effusions have not
been studied to the same extent as in other body fluids. Although peri-
cardial effusions are very similar to pleural fluids, routine application of
these tests requires additional studies to fully appreciate their diagnostic
importance.
Protein
A value greater than 3.0 g/dL has a sensitivity of 97% for exudative effu-
sions but a specificity of only 22%, which significantly limits its usefulness.
Thus, total protein has no discriminating power in pericardial diagnosis
(Meyers et al., 1997). 
Glucose
Pericardial glucose levels less than 60 mg/dL have a diagnostic accuracy of
only 36% in identifying pericardial exudates (Meyers et al., 1997). Values
less than 40 mg/dL (<2.22 mmol/L) are common in bacterial, tuberculous,
rheumatic, or malignant effusions. 
pH
Pericardial fluid pH may be markedly decreased (<7.10) in rheumatic or
purulent pericarditis. Malignancy, uremia, tuberculosis, and idiopathic dis-
orders may have moderate decreases in the range of 7.20 to 7.30 (Kindig &
Goodman, 1983). 
Lipids
Separation of true chylous from pseudochylous effusions may be facilitated
by triglyceride and cholesterol measurements, as well as by lipoprotein
electrophoresis for chylomicrons (see Table 30.10). See the section on
Lipids in the Pleural Fluid section earlier in the chapter for further details
on the diagnosis of chylous effusions. 
Enzymes
A pericardial fluid LD level greater than 200 U/L has been suggested as a
cutoff for pericardial exudates (Burgess et al., 2002a). Moreover, the mea-
surement of LD and creatine kinase in postmortem pericardial fluid within
48 hours of death may be useful in establishing acute myocardial injury
when such injury is suspected but cannot be established by the usual his-
tologic methods (Luna et al., 1982; Stewart et al., 1984). Pericardial fluid
levels of CK-­MB, myoglobin, and troponin I in postmortem pericardial
fluid are significantly increased in patients with myocardial injury (Perez-­
Carceles et al., 2004).
ADA activity is a useful adjunctive test for tuberculous pericarditis in
suspicious cases with negative acid-­fast stains. The median ADA level in
effusions (Burgess et al., 2002b). Using a cutoff of 30 U/L, the sensitivity is
94%, specificity 68%, and positive predictive value 80%. Using a cutoff of
40 U/L, the sensitivity and specificity are 93% and 97%, respectively (Koh
et al., 1994). Combining pericardial ADA levels with other findings adds to
the diagnostic utility of measuring this analyte (Reuter et al., 2006). 
Interferon-­γ
Increased IFN-­γ levels have been reported in tuberculous serous effusions,
including tuberculous pericarditis (Burgess et al., 2002b). Here, the IFN-­
γ level was greater than 1000 pg/L, which was significantly higher than
in effusions from other pathologic conditions. A cutoff value of 200 pg/L
culous pericarditis. As with ADA, combining IFN-­γ levels with other peri-
cardial fluid findings improves the diagnostic utility of this assay (Reuter
et al., 2006). 
Polymerase Chain Reaction
PCR is a sensitive technique and may be more specific than adenosine
deaminase in the diagnosis of tuberculous pericarditis (Lee et al., 2002).
However, a negative test does not rule out tuberculous pericarditis because
some pericardial fluids from patients with large tuberculous effusions may
not contain M. tuberculosis. PCR-­based analysis is superior to ADA levels in

532
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diagnosing tuberculous pericarditis (Pandie et al., 2014) and provides high
sensitivity and specificity in the rapid diagnosis of this condition (Saeed
et al., 2017). 
IMMUNOLOGIC STUDIES
A negative ANA test makes the diagnosis of lupus serositis highly unlikely.
Conversely, high ANA titers in pericardial effusions lack specificity, even
when they are as high as 1 : 5120 (Leventhal et al., 1990; Wang et al., 2000).
If a high ANA titer is unexplained, malignancy should be considered.  Resorption
MICROBIOLOGICAL EXAMINATION
The sensitivity of the Gram stain and culture for bacterial pericarditis is
similar to other serous body fluids (i.e., about 50% and 80%, respectively).
Important aerobic bacteria include S. aureus, S. pneumoniae, S. pyogenes,
and gram-­negative bacilli. Although infectious pericarditis due to anaero-
bic bacteria may be encountered rarely, the bacteria are sometimes not
recognized because of inconsistent methods used for their isolation and
identification (Brook, 2002). For this reason, proper laboratory technique
is of particular importance when infection with an anaerobic organism
is suspected. The major anaerobic organisms are the Bacteroides fragilis
group, anaerobic streptococci, Clostridium species, Fusobacterium species,
and B­ ifidobacterium species.
Identification of a specific etiologic agent in viral pericarditis is dif-
ficult because the viruses (e.g., coxsackieviruses, influenza virus, mumps)
are rarely isolated from pericardial fluid. Obtaining acute and convalescent
sera for antibody response to suspected viral pathogens may help support
the diagnosis (Bellinger & Vacek, 1987). Viral infection probably accounts
for most idiopathic HIV-­associated pericardial effusions.
The sensitivity of acid-­fast stains and culture for tuberculous pericar-
ditis is about 50% (Agner & Gallis, 1979). PCR-­based assays now provide
high sensitivity (84.3%) and specificity (100%) in the rapid diagnosis of
tuberculous pericarditis and pleuritis (Saeed et al., 2017) and are superior
to ADA levels in making this diagnosis (Pandie et al., 2014).
PCR-­based assays may aid in the rapid diagnosis of a variety of other
bacterial and other infections in the pericardial space (Tenenbaum et al.,
2005; Levy et al., 2006).  if there is a change in the clinical picture of a patient with ascites, such as
PERITONEAL FLUID
Ascites is the pathologic accumulation of excess fluid in the peritoneal
cavity. Up to 50 mL of fluid is normally present in this mesothelial-­lined
space. As with pleural and pericardial fluids, it is produced as an ultrafil-
trate of plasma dependent on vascular permeability and on hydrostatic and
oncotic pressure.
TRANSUDATES AND EXUDATES
Common causes of peritoneal effusions are listed in Box 30.13. The labora-
tory criteria for classifying ascitic fluid as a transudate or an exudate are not
as well defined as they are for pleural and pericardial fluids. For example,
infected or malignancy-­ related samples are not uncommonly reported
with protein concentrations in the transudative range (i.e., <3.0 g/dL), and
many patients with cirrhotic or heart failure ascites have protein values in
the exudative range (>3.0 g/dL) (Runyon et al., 1992).
The serum-­ascites albumin gradient (SAAG), defined as the serum
albumin concentration minus the ascitic fluid albumin concentration, is
widely considered to be the most reliable method to differentiate peritoneal
transudates from exudates (Runyon et al., 1992; Tarn et al., 2010). Ascites
caused by portal hypertension has a gradient of at least 1.1 g/dL (>11 g/L;
transudate), whereas ascites produced by other causes has a gradient less
than 1.1 g/dL (exudate) (Runyon et al., 1992). The diagnostic accuracy is
98% for the SAAG compared with only 52% to 80% for four other mark-
ers: ascitic fluid total protein, ascites/serum total protein ratio, ascitic fluid
LD concentration, and ascites/serum LD ratio (Akriviadis et al., 1996).
An ascitic fluid/serum bilirubin ratio of 0.6 or greater is also signifi-
cantly associated with exudates (Elis et al., 1998). Indeed, the accuracies
of the SAAG, bilirubin ratio, and Light’s criteria were 84%, 81.5%, and
80.2%, respectively. Others have suggested that if the ascitic fluid LD is
>130 U/L and the ascitic fluid/serum total protein ratio is >0.4, the fluid
should be regarded as an exudate (Paramothayan & Barron, 2002).
Although the serum-­ascites albumin gradient is probably the best single
method to differentiate an ascitic exudate from a transudate, other methods
compare favorably and no ideal biochemical markers allow complete dis-
crimination between ascitic fluid exudates and transudates.  pected acute peritonitis or pancreatitis. A WBC count in the lavage fluid
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  BOX 30.13 
Causes of Peritoneal Effusions
Transudates: Increased Hydrostatic Pressure or Decreased Plasma
Oncotic Pressure
Congestive heart failure
PART 3
Hepatic cirrhosis
Hypoproteinemia (e.g., nephrotic syndrome) 
Exudates: Increased Capillary Permeability or Decreased Lymphatic
Infections
Primary bacterial peritonitis
Secondary bacterial peritonitis (e.g., appendicitis, bowel rupture)
Tuberculosis
Neoplasms
Hepatoma
Lymphoma
Mesothelioma
Metastatic carcinoma
Ovarian carcinoma
Prostate cancer
Colonic adenocarcinoma
Pancreatic carcinoma
Trauma
Pancreatitis
Bile peritonitis (e.g., ruptured gallbladder) 
Chylous Effusion
Damage to or obstruction of thoracic duct (e.g., trauma, lymphoma, car-
cinoma, tuberculosis and other granulomas [e.g., sarcoidosis, histoplasmo-
sis], parasitic infestation)
SPECIMEN COLLECTION
Paracentesis
Diagnostic paracentesis is performed in most patients with new ascites or
rapid fluid accumulation or fever development. A minimum of 30 mL is
needed for complete evaluation. If possible, at least 100 mL should be pro-
vided for cytologic examination. Samples for cell counts should be placed
in an EDTA-­anticoagulated venipuncture tube. Culture specimens should
include blood culture bottles that have been inoculated at the bedside with
ascitic fluid (10 mL per culture bottle). 
Diagnostic Peritoneal Lavage
This procedure is no longer recommended as a routine technique for the evalu-
ation of abdominal trauma. Concerns of oversensitivity and nonspecificity, and
improvements in noninvasive diagnostic procedures such as computed tomog-
raphy and ultrasound, have limited its common use to (1) rapid screening for
significant abdominal hemorrhage in hemodynamically unstable patients and (2)
evaluation of hollow viscous injuries (Pryor et al., 2004; Whitehouse et al., 2009).
A catheter is placed through a small incision into the abdominal cavity.
If less than 15 mL of gross blood can be aspirated, diagnostic peritoneal
lavage (DPL) is performed by infusing 1.0 L of saline or Ringer’s solution
(20 mg/kg in children) and retrieving the fluid by gravity drainage. At least
600 mL should be recovered to avoid falsely low counts (Sullivan et al.,
1997). The catheter is sometimes left in place so that DPL may be repeated
in 2 to 3 hours if initial results are negative or indeterminate.
Commonly accepted criteria for DPL interpretation after trauma are
shown in Box 30.14. The positive predictive value is only 23% for an iso-
lated (no other abnormal criteria) leukocyte count of 500/μL or greater
(Soyka et al., 1990).
The conventional DPL criteria may be unreliable in detecting hollow
viscous injury when blood is present from a simultaneous solid-­organ injury
not requiring surgical repair, resulting in unnecessary exploratory laparoto-
mies. Suggested modifications of DPL criteria to adjust for this source of
bleeding include either of the following: (1) WBC count greater than or
equal to RBC count divided by 150, where RBC is 10 × 104/mm3 or greater
(Otomo et al., 1998); or (2) cell count ratio greater than 1.0 (Fang et al.,
1998). The cell count ratio is defined as the ratio between WBC and RBC
counts in the lavage fluid divided by the WBC/RBC ratio in the peripheral
blood. These criteria have a reported specificity of 97% for hollow-­organ
injury, especially if DPL is performed at least 3 hours following injury.
Other applications of DPL include the evaluation of patients with sus-
533
CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
  BOX 30.14    BOX 30.15
Criteria for Evaluation of Peritoneal Lavage
Positive Result
Aspiration of >15 mL gross blood on catheter placement
Grossly bloody lavage fluid
RBC >100,000/μL after blunt trauma
RBC >50,000/μL after penetrating trauma
WBC >500/μL
Amylase >110 U/dL 
Indeterminate Result
Small amount of gross blood on catheter placement
RBC 50,000–100,000/μL after blunt trauma
RBC 1000–50,000/μL after penetrating trauma
WBC 100–500/μL  Lactate
Negative Result
RBC <50,000/μL after blunt trauma
RBC <1000/μL after penetrating trauma
WBC <100/μL
RBC, Red blood cells; WBC, white blood cells.
Modified from Feied CF: Diagnostic peritoneal lavage, Postgrad Med 85:40, 1989,
with permission.
of 200 cells/mm3 is associated with a 99% probability of acute peritonitis
(Larson et al., 1992).  © American Society for Clinical Pathology, with permission.
Peritoneal Dialysis
Dialysate fluid from renal patients undergoing chronic ambulatory perito-
neal dialysis should be submitted to the laboratory to check for infection. 
Peritoneal Washings
This procedure is performed intraoperatively to document early intraab-
dominal spread of gynecologic and gastric carcinomas. Samples are gener-
ally sent for cytologic examination only. 
RECOMMENDED TESTS
The most important tests for the evaluation of ascitic fluid are listed in
Box 30.15. Relative importance varies depending on the type of sample and
the clinical findings. For example, RBC and WBC counts are more impor-
tant than cytology or the SAAG in the evaluation of abdominal effects of
trauma. Gross examination may provide immediate information in the
clinical and laboratory triage. 
GROSS EXAMINATION
Whereas transudates are generally pale yellow and clear, exudates are
cloudy or turbid because of the presence of leukocytes, tumor cells, or
increased protein levels. The presence of food particles, foreign material,
or green-­yellow bile staining in a DPL specimen suggests perforation of
the gastrointestinal or biliary tract. Acute pancreatitis and cholecystitis
may also cause greenish discoloration.
Blood-­tinged or grossly bloody fluid must be distinguished from a trau-
matic tap in which the blood usually clears with continued paracentesis.
As little as 15 mL of blood per liter of fluid produces a bright red opaque
color such that newsprint cannot be read through the lavage tubing. In
most cases, the ability to read newsprint through the tubing results in a
negative DPL. Opaque specimens require cell counts because newsprint
readability is lost well below the 100,000 RBCs/μL criterion for a positive
DPL (Bellows et al., 1998). Bloody ascites is also seen in malignancy and
tuberculosis.
Milky fluid that does not clear with centrifugation suggests a chylous or
pseudochylous effusion. True chylous peritoneal effusions are significantly
less common than chylous pleural effusions. They are caused by disruption
or blockage of lymphatic flow by trauma, lymphoma, carcinoma, tuber-
culosis, other granulomatous diseases (e.g., sarcoidosis), hepatic cirrho-
sis, adhesions, or parasitic infestation. Differentiation of true chylous and
pseudochylous effusions is discussed in the Gross Examination section in
the Pleural Fluid section later in the chapter.  Cytology has an overall sensitivity of 40% to 65% for malignant asci-
MICROSCOPIC EXAMINATION
The total leukocyte count is useful in distinguishing ascites due to uncom-
plicated cirrhosis from spontaneous bacterial peritonitis (SBP), which is
534
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Recommended Tests in Peritoneal Effusions
Useful in Most Patients
Gross examination
Cytology
Stains and culture for microorganisms
Serum-­ascites albumin gradient (SAAG) 
Useful in Selected Disorders
Total leukocyte and differential cell counts
RBC count (lavage)
Bilirubin
Creatinine/urea nitrogen
Enzymes (ADA, ALP, amylase, LD, telomerase)
Cholesterol (malignant ascites)
Fibronectin
Multiplex PCR assay for bacterial, fungal, and mycobacterial DNA
Tumor markers (CEA, PSA, CA 19-­9, CA 15-­3, CA-­125)
Immunocytology/flow cytometry
Tuberculostearic acid
ADA, Adenosine deaminase; ALP, alkaline phosphatase; CEA, carcinoembryonic
antigen; LD, lactate dehydrogenase; PSA, prostate-­specific antigen; RBC, red blood
cell.
Modified from Kjeldsberg CR, Knight JA: Body fluids: Laboratory examination of
amniotic, cerebrospinal, seminal, serous and synovial fluids, ed 3, Chicago, 1993,
Figure 30.21  Neutrophils in a patient with bacterial peritonitis.
caused by migration of bacteria from the intestine into the ascitic fluid.
Approximately 90% of patients with SBP will have leukocyte counts
greater than 500/μL, more than 50% of which are neutrophils (Fig. 30.21)
(Runyon & Hoefs, 1984; Stewart et al., 1986).
The ascitic fluid total neutrophil count is the preferred method for
the diagnosis of SBP. Cutoff values of 250 and 500 neutrophils/μL have
been recommended, with a diagnostic accuracy of about 94% for 500
neutrophils/μL and about 90% for 250 neutrophils/μL (Stassen et al.,
1986; Albillos et al., 1990).
Cell counts, total protein, and albumin gradient values vary with fluid
shifts associated with ascites formation and resolution. For example, diure-
sis may cause the WBC count to increase from 300/μL to 1000/μL or more.
When obtained by DPL, a leukocyte count of 200/μL or more is reported
to be associated with a 99% probability of acute peritonitis (Alverdy et al.,
1988; Larson et al., 1992).
Eosinophilia (>10%) is most commonly associated with the chronic
inflammatory process associated with chronic peritoneal dialysis. It has also
been reported in congestive heart failure, vasculitis, lymphoma, and rup-
tured hydatid cyst.
tes. Peritoneal carcinomatosis accounts for about two-­thirds of malignant
effusions; cytology has a sensitivity of over 95% when confined to these
cases (Runyon et al., 1988). Liquid-­based thin-­layer preparations of peri-
toneal effusions and pelvic washings have been shown to be superior to
standard cytologic preparations in the detection of carcinoma (Moriarity
et al., 2008). Immunocytochemical stains are useful in characterizing atypi-
cal cells in equivocal cases.  Using a cutoff value of 85 μg/mL (85 mg/L), fibronectin was more reliable
CHEMICAL ANALYSIS
Protein
The SAAG is superior to total protein content in differentiating cirrho-
sis from other causes of peritoneal effusions (Runyon et al., 1992). SBP
is commonly associated with low total protein (<3.0 g/dL) and a high
SAAG (>1.1 g/dL), making total protein measurements of little value in
this disorder. Extracellular fluid shifts associated with ascites formation and
­resorption also cause variations in protein content.  purpose (Tarn et al., 2010).
Glucose
Early reports indicated that peritoneal fluid glucose levels of 50 mg/dL or
less are present in 30% to 60% of cases of tuberculous peritonitis and in
about 50% of patients with abdominal carcinomatosis (Polak & Torres da
Costa, 1973; Brown & An, 1976). Another study found decreased glucose
levels in most cases of tuberculous ascites (Bansal et al., 1998). Still, glucose
measurements are of little value because the sensitivity and specificity are
generally too low to be of practical value (Tarn et al., 2010).  equivocal cases. Malignant and tuberculous ascites are also associated with
Enzymes
Amylase activity in normal peritoneal fluid is similar to plasma lev-
els. A level greater than three times the plasma value is good evidence
of pancreas-­ related ascites, including acute pancreatitis and pancreatic
pseudocyst (Runyon, 1987a). Amylase is not recommended in the rou-
tine evaluation of ascites, however, because the prevalence of pancreatic
ascites is low. Retrospective amylase measurement on a stored specimen is
indicated if initial studies are not diagnostic. Amylase levels in peritoneal
lavage fluid may be valuable in patients following blunt and penetrating
abdominal trauma (McAnena et al., 1991). Here, amylase levels greater
than or equal to 20 U/L have a sensitivity of 87%, a specificity of 75%, and
a positive predictive value of 46% for significant intraabdominal injury.
In these cases, laparotomy should be considered. Gastroduodenal perfora-
tion, acute mesenteric vein thrombosis, intestinal strangulation, or necrosis
may also produce elevated amylase levels. Although various nonpancreatic
malignancies may rarely produce amylase elevations, isoenzyme evaluation
usually identifies the salivary isoform in these latter cases (Kosches et al.,
1989).
Elevated alkaline phosphatase (ALP) levels greater than 10 U/L in
DPL fluid are useful in predicting hollow visceral injury in patients who
would otherwise not undergo laparotomy (specificity 99.8%, sensitivity
94.7%) (Jaffin et al., 1993). Ascitic fluid ALP measurements may also be
helpful in the differentiation of primary bacterial peritonitis from second-
ary bacterial peritonitis due to bowel perforation. Secondary peritonitis has
significantly higher mean ALP levels than SBP. ALP levels >240 U/L were
present in 92% of patients with secondary peritonitis versus 12% with SBP
(Wu et al., 2001). The sensitivity and specificity for differentiating second-
ary peritonitis from SBP were 92% and 88%, respectively.
LD activity is often increased in malignant effusions (Gerbes et al., 1991;
Tarn et al., 2010). An ascitic fluid/serum LD ratio greater than 0.6 has a
reported sensitivity of 80% (Boyer et al., 1978). Combined measurement
of ascitic fluid LD and cholesterol totally discriminated peritoneal carci-
nomatosis from cirrhosis and hepatocarcinoma-­related ascites (Castaldo
et al., 1994; Halperin et al., 1999). Although both serum and peritoneal
fluid LD levels are significantly higher in patients with ovarian cancer than
in those with benign ovarian tumors or other gynecologic malignancies,
peritoneal fluid LD has higher diagnostic sensitivity (87%) and diagnostic
accuracy (90%) than serum LD (60% and 77%, respectively) (Schneider
et al., 1997). LD has also been used for the early diagnosis of SBP, in which
it has a diagnostic accuracy of about 74% using an ascitic fluid/serum ratio
cutoff of 0.4 (Lee et al., 1987).
The presence of telomerase is a specific discriminatory marker in
malignant ascites (Tangkijvanich et al., 1999; Hess et al., 2002). Telomer-
ase activity was detected in 81% of malignant peritoneal effusions with a
sensitivity of 76% and a specificity of 95.7%.
ADA is commonly used in high-­prevalence areas to identify patients
with tuberculous peritonitis (Burgess et al., 2001). Using receiver operat-
ing characteristic curves and a cutoff value of 30 U/L, the sensitivity and
specificity were 94% and 92%, respectively. Using a cutoff value of 33
U/L, the sensitivity, specificity, positive and negative predictive values,
and overall diagnostic accuracy for diagnosing tuberculous peritonitis
were 100%, 96.6%, 95%, 100%, and 98%, respectively (Dwivedi et al.,
1990). ADA is not thought to be helpful in low-­prevalence areas (Tarn
et al., 2010).  of 100 ng/L, the sensitivity and specificity were both 100% in cirrhotic
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Fibronectin
in differentiating malignant from sterile ascites (diagnostic accuracy, 79%)
than were total protein, LD, γ-­glutamyltransferase, pH, amylase, trigly­
cerides, leukocyte count, and cytologic examination (Colli et al., 1986). In
a subsequent study using a cutoff of 94.6 μg/mL, the sensitivity, specificity,
PART 3
positive accuracy, negative accuracy, and overall diagnostic accuracy in the
diagnosis of malignant ascites were 100%, 95%, 93.8%, 100%, and 97.1%,
respectively (Sood et al., 1997). Further studies have supported the util-
ity of fibronectin measurement in the diagnosis of malignant ascites (Lee
et al., 2006). However, this measurement is still not used routinely for this
 
Lactate
Ascitic fluid lactate has been used with pH measurements to differenti-
ate SBP from uncomplicated ascites. Sensitivity and specificity for lactate
levels are approximately 90% using a cutoff of 40 mg/dL (4.44 mmol/L),
with a positive predictive value of 62% (Stassen et al., 1986). Although not
as accurate as leukocyte counts, the high specificity of lactate in hepatic
ascites suggests that it has some value in the diagnosis of SBP in otherwise
elevated lactate levels.
Patients with hollow viscous perforation, gangrenous intestine, peri-
tonitis, or intraabdominal abscess have a peritoneal fluid minus plasma
lactate level of at least 13.5 mg/dL (1.5 mmol/L), which reportedly sepa-
rates these patients completely from those with other conditions producing
acute abdominal problems (DeLaurier et al., 1994). The peritoneal-­serum
lactate ratio is also useful in identifying postoperative patients in need of
reintervention (Bini et al., 2014). 
Creatinine and Urea
Measurement of creatinine and urea nitrogen is useful to differentiate
between peritoneal fluid and urine (Tarn et al., 2010). Elevated perito-
neal fluid urea nitrogen and creatinine, in association with elevated serum
urea but normal serum creatinine (due to back-­diffusion of urea), suggests
­urinary bladder rupture. 
Bilirubin
The mean (±SD) ascitic fluid bilirubin concentration in various types of
ascites has been reported as 0.7 ± 0.8 mg/dL, and the mean ascitic fluid/
serum bilirubin ratio as 0.38 ± 0.44 (Runyon, 1987b). An ascitic fluid bili-
rubin greater than 6.0 mg/dL and an ascitic fluid/serum bilirubin ratio over
1.0 suggest choleperitoneum from a ruptured gallbladder. A ratio of 0.6
or greater has been advocated as an additional marker for an exudative
process, although its accuracy is not as high as that of the SAAG (Elis et al.,
1998). 
pH
Ascitic fluid pH has been thought to be helpful in the diagnosis of SBP in
patients with cirrhotic ascites, especially if it is used in conjunction with
the leukocyte count (Attali et al., 1986; Stassen et al., 1986). A pH less than
7.32 or a blood–ascitic fluid pH difference of more than 0.1 has a reported
sensitivity and specificity of about 90% for SBP, with the pH differential
being slightly more accurate. However, peritoneal fluid pH appears useless
in detecting SBP in the absence of neutrophils (Runyon & Antillon, 1991).
Patients with an ascitic fluid pH of less than 7.15 have a poor prognosis
(Attali et al., 1986). Low pH is also found in patients with malignant and
pancreatic ascites and tuberculous peritonitis. Overall, however, peritoneal
fluid pH is not thought to contribute significantly to clinical decision-­
making (Tarn et al., 2010). 
Cholesterol
The ascitic fluid cholesterol level is a moderately useful index in separat-
ing malignant ascites (>45–48 mg/dL) from cirrhotic ascites (Mortensen
et al., 1988; Castaldo et al., 1994). The sensitivity and specificity average
just over 90% using a cutoff value of 45 to 48 mg/dL (1.2 mmol/L). Thus,
using a cutoff value of 48 mg/dL, the sensitivity, specificity, positive and
negative predictive value, and overall diagnostic accuracy for differentiat-
ing malignant from nonmalignant ascites were reported as 96.5%, 96.6%,
93.3%, 98.3%, and 96.6%, respectively (Garg et al., 1993). 
Interleukin-­8
Interleukin-­8, a cytokine produced by a variety of cells in response to stim-
uli such as bacterial lipopolysaccharide, is significantly higher in SBP com-
pared with sterile ascites (Martinez-­Bru et al., 1999). Using a cutoff value
535
 patients. Interleukin-­8 levels also correlate with the stage of disease in
CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
patients with endometriosis (Malhotra et al., 2007).  toneal fluid has been used to detect bacteria in SBP (Enomoto et al., 2014).
Tuberculostearic Acid (10-­Methyloctadecanoic Acid)
As noted in the Pleural Fluid section, TSA was detected in pleural fluid in
75% of patients with pulmonary tuberculosis using gas chromatography–
mass spectroscopy (Muranishi et al., 1990). Using quantitative chemical
ionization gas chromatography–mass spectrometry, the measurement of
TSA is a valuable technique to identify tuberculous peritonitis as well as
tuberculous meningitis (spinal fluid) and pneumonia (pleural fluid) (Brooks
et al., 1998). 
Tumor Markers
Because of their reportedly low sensitivity and specificity, the measurement
of tumor markers in peritoneal fluid is generally considered to be of little
value. However, they are often useful in selected cases, such as in following
a patient’s response to therapy and in the early detection of tumor recur-
rence. They may also be very useful in cases in which cytology is negative
but suspicion of malignant ascites is high. In one study, cytologic exami-
nation was positive in only 40% (35 of 89 patients) of malignant cases,
while tumor markers were positive in 80% (Cascinu et al., 1997). More-
over, excluding small-­cell lung and renal cancers, for which specific tumor
markers are lacking, tumor markers (i.e., CEA, CA 19-­9, CA 15-­3, PSA)
in ascitic fluid for other carcinomas were positive in 97% of cases. These
tumor markers, as well as α-­fetoprotein, were also found to be highly spe-
cific (over 90%) for serous fluid malignancies, although their sensitivities
were low (19%–38%) (Sari et al., 2001). The measurement of PSA may
also be a valuable marker for the diagnosis of malignant effusions due to
prostate cancer (Appalaneni et al., 2004).
CEA has a sensitivity of 40% to 50% and a specificity of about 90%
for malignant effusions, using a cutoff value of 3.0 ng/mL (Mezger et al.,
1988). In a similar study using a 5-­mg/mL cutoff, the specificity was about
97% (Gulyas et al., 2001). Elevated CEA levels in peritoneal washings sug-
gest a poor prognosis in gastric carcinoma (Irinoda et al., 1998).
Ascitic fluid CA-­125 is elevated to some degree in a variety of nonma-
lignant conditions. Indeed, cardiovascular and chronic liver disease may
be the most frequent diagnoses in patients with increased CA-­125 levels
(Miralles et al., 2003), thereby supporting the general opinion that CA-­
125 in ascitic fluid lacks adequate specificity as a marker for malignancy.
Extremely high levels are likely to be caused by epithelial carcinomas of
the ovary, fallopian tubes, or endometrium. The sensitivity for ovarian
carcinoma depends on the tumor’s stage (range, 40% to 95%) and his-
tologic subtype (mucinous adenocarcinomas have lower values) (Molina
et al., 1998).
DNA ploidy analysis by flow cytometry or image analysis may pro-
vide useful complementary diagnostic information in cases with equivocal
cytology results when the malignant cells carry an aneuploid karyotype,
although the added value of DNA ploidy analysis over cytology is small
(Bisht et al., 2014). Image analysis appears to be more practical than flow
cytometry when the tumor cells are scarce (Rijken et al., 1991). 
MICROBIOLOGICAL EXAMINATION
Primary peritonitis occurs at any age and is seen in children with nephrotic
syndrome and in adults with cirrhotic liver disease. SBP occurs in patients
with ascites in the absence of recognized secondary causes such as bowel
perforation or intraabdominal abscess. The bacteria in SBP are most often
normal intestinal flora, and more than 92% are monomicrobial. Aerobic
gram-­negative bacilli (e.g., E. coli, Klebsiella pneumoniae) are responsible for
two-­thirds or more of all cases (Gilbert & Kamath, 1995), followed by
S. pneumoniae, Enterococcus spp., and, rarely, anaerobes. The Gram stain
has a sensitivity of 25% in SBP (Lee et al., 1987), and routine cultures
are positive in only about 50% of cases (Castellote et al., 1990). Inocu-
lation of blood culture bottles at the bedside and concentration of large
volumes of fluid can improve sensitivity, but up to 35% of infected patients
may still have negative ascitic fluid cultures (Marshall, 1988). Use of resin-­
containing blood culture bottles may improve the isolation of certain bac-
teria in partially treated patients.
Ascitic fluid total neutrophil count is the preferred method for the
diagnosis of SBP (see the Microscopic Examination section earlier in the
chapter). As noted earlier, in difficult cases, several analytes may be useful
in differentiating SBP from secondary bacterial or tuberculous peritonitis.
Because of the low number of bacteria in many cases of SBP, sensitive
methods for detection of bacteria in these specimens are often needed.
PCR has been successfully used in the detection of bacterial DNA in
culture-­negative ascitic fluid (Such et al., 2002; Soriano et al., 2011). More
536
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recently, in situ hybridization performed on leukocytes suspended in peri-
Multiplex PCR-­based detection systems have been shown to be effective in
the rapid diagnosis of SBP (Almuhayawi et al., 2014).
The sensitivity of acid-­fast stains for M. tuberculosis is no more than
20% to 30%, and cultures have a sensitivity of only 50% to 70% (Reimer,
1985). Application of PCR to detect M. tuberculosis DNA may be used, but
a negative result does not exclude the diagnosis (Schwake et al., 2003). In
a patient with a high clinical suspicion for tuberculous peritonitis, laparo-
scopic examination with biopsy may be indicated. 
ALTERNATIVE SPECIMENS
SALIVA
Saliva is generally easily collected by noninvasive means; thus, its acquisi-
tion is well accepted by patients. Because it is a filtrate of plasma, saliva has
concentrations of some small molecules that are in equilibrium with the
free (unbound) active fractions of those substances in plasma. This prop-
erty has been especially useful for measuring free cortisol, which is the
physiologically important fraction that reflects the secretion rate of cor-
tisol and, thus, is important for diagnosis. Salivary cortisol measurements
have been used to assess adrenal function in critically ill subjects (Arafah
et al., 2007) and in those with Cushing syndrome and adrenal insufficiency
(Raff, 2009), with late-­night (or midnight) salivary cortisol being an effec-
tive screening test for Cushing syndrome (Raff et al., 1998). Unfortunately,
salivary concentrations of several other steroid hormones are not reliable
measures of plasma free levels because of rapid fluctuations in their salivary
concentrations (e.g., estradiol, progesterone, testosterone, dehydroepian-
drosterone, aldosterone) (Wood, 2009).
Saliva also contains some antibody molecules that apparently derive
from plasma. Thus, measurements are sometimes performed on saliva to
detect antibodies against infectious agents in circumstances when collec-
tion of saliva is much more convenient or acceptable to patients. Testing
of saliva for antibodies against HIV has been practiced widely in sexually
transmitted disease clinics, although episodes of false-­positive results have
diminished confidence in these point-­ of-­care tests (Cummiskey et al.,
2008).
Genetic testing requires DNA from the patient that can be obtained
conveniently from leukocytes in blood specimens or even more con-
veniently from buccal cells in saliva or from swabs of the interior of the
mouth.
Drug testing has also been performed in saliva to provide evidence
of ingestion of illicit substances. Although drugs such as amphetamines,
cocaine, and opioids are present in oral fluid at concentrations similar to
those in plasma, local absorption of these drugs in the mouth can increase
their concentration in saliva after use (Drummer, 2006). 
MECONIUM
The analysis of body fluids can provide unique information based on ana-
tomic location (often remote or not readily accessible) or sequences of
metabolic processes and normal clearance of chemical constituents from
the body. An example of this clinical utility is the examination of meco-
nium from newborns for the detection of illicit drugs such as cocaine and
amphetamines that the mother might have abused while pregnant. The
drugs cross the placenta from maternal circulation into that of the fetus,
which excretes the drug or its metabolites in bile that remains in the meco-
nium until birth (Concheiro et al., 2013). This window of drug detection
in meconium is much broader than that for testing of urine or blood by
several weeks and covers second and third trimesters of pregnancy. Such
testing is considered more reliable than self-­reporting by mothers due to
fear of reprisal and possible loss of custody. These results can be used both
for medical management of the mother and baby as well as for medical-­
legal purposes. Recently, measurement of ethyl glucuronide in meconium
was found to be an objective measure of maternal alcohol use (Himes et al.,
2015). 
HAIR AND NAILS
Drug testing has time limitations of detection in blood for periods of min-
utes to hours after ingestion. The need to detect illicit drug use over longer
periods of time has prompted analysis of other body sources. Concentra-
tions of drugs in saliva follow the same time course as blood of minutes
to hours after ingestion. Detection in urine can be as soon as minutes up
to many days after drug use. Sweat concentrations also rise in minutes
but may persist for weeks. True long-­term detection is possible in hair
and nails, where drugs of abuse can be detected days to even years after
ingestion. Although numerous companies offer drug testing of hair or nail
specimens, there has not been official adoption of this strategy by gov-
ernment agencies, largely because of issues of uncertainty as to whether
the substances detected from hair or nail specimens were actually “in” the
hair following ingestion and incorporation into that tissue, or whether the
detected drug was simply “on” the surface of the specimen because of inci-
dental contact that did not involve ingestion (Curtis & Greenberg, 2008).
Cerumen
Forensic analysis of drugs can include nonstandard specimens that are con-
venient to collect or might have an accumulation of drugs for an extended
period of time. For example, a recent study has shown potential utility
of earwax (cerumen) as an alternative forensic specimen to detect psycho-
tropic drugs such as antiepileptics, anxiolytics, antipsychotics, and drugs
of abuse as well as metabolic disorders with long-­term representation of
metabolites (Shokry & Filho, 2017; Shokry et al., 2017). Collection of ear-
wax is relatively noninvasive and presumably also free of contamination,
which can be advantageous for acceptance of its use in forensic testing.
Analysis of this type of specimen was done by liquid chromatography–mass
spectrometry (LC-­MS).  also be collected by direct aspiration with a needle guided through ultra-
Fingerprints
Fingerprints have also been explored as alternative specimens for detection
of drugs such as acetaminophen, dihydrocodeine, and methylephedrine
using LC-­MS (Kuwayama et al., 2016). Fingerprint fluid could potentially
be used for drug testing when sample collection of standard fluids such as
blood, urine, or even saliva might be delayed or not feasible.  surgical procedure. CEA has also been used for this purpose (Rockacy &
BREATH TESTING
Exhaled Nitric Oxide and Exhaled Breath Condensate
Inflammatory disorders of the lungs—including asthma, chronic obstruc-
tive pulmonary disease, and chronic cough—have largely been evaluated in
the past by bronchoscopy, lavage, biopsy, and analysis of induced sputum.
Noninvasive techniques for monitoring these disorders are now available
as detection of chemical constituents in exhaled breath. Exhaled nitric
oxide (NO) is an inflammatory mediator that is unstable in tissues but is
much more stable in the gas phase, in which it can be measured in single
breath exhalations by specialized devices expressing NO content in parts
per billion. This use is currently considered investigational but theoreti-
cally has great potential for monitoring pulmonary inflammation by non-
invasive means with much greater frequency than by invasive procedures
(Dweik et al., 2011).
A second approach to monitoring pulmonary disease is to measure
nonvolatile inflammatory markers in exhaled breath condensate (EBC)
collected from exhaled breath that is condensed by passage through a cool-
ing device. Such specimens of respiratory fluid are scant, but they contain
a rich assortment of substances such as cytokines, leukotrienes, oxidants,
antioxidants, and so on that can reveal inflammatory activity by noninva-
sive means (Horvath et al., 2005). Even pH of EBC has been found useful
in assessing lung disease; EBC tends to be slightly alkaline (mean pH 7.7 ±
0.49) in health, but it becomes more acidic with disease changes in the
lower airways (Vaughan et al., 2003). EBC analysis is currently considered
investigational.  drainage or lavage fluids. These types of fluids are not normally present
Carbon-­13-­Urea Breath Test
Diagnosis of infection with Helicobacter pylori may be aided by the carbon-­
13-­urea breath test in which the patient drinks a solution of 13C-­urea.
H. pylori has the enzyme urease, which breaks down urea, releasing 13CO2
into the patient’s breath. Samples of breath taken in a balloon or other
specialized collection devices are analyzed by mass spectrometry (Patel
et al., 2014) (see Chapters 4, 5, and 24). Detection of 13CO2 indicates
infection with H. pylori. An alternative procedure utilizes 14C in place of
13C, although 14C detection is based on low-­ level radioactivity. 13C has
the advantage of not being radioactive but the disadvantage of not being
measured in most local laboratory facilities. The 13C-­urea breath test has
special utility for pediatric patients (Frenck et al., 2006).
Opportunities for analysis of additional body fluid types will increase
as collection methodologies expand, particularly in collaboration with
invasive radiologic approaches. Some problems expected with these new
unique specimens include scant specimen volumes, unknown protein and
other chemical composition that might adversely affect measurements, and
lack of reference ranges to distinguish normal healthy results from those
in disease.  ranges for analysis of body fluids fly in the face of Clinical Laboratory
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TISSUE ASPIRATES
Breast nipple aspirate fluid can be obtained by noninvasive means such as
massage or with automated collection devices to yield material suitable for
cytologic examination for early detection of breast cancer. This new collec-
tion approach may lead to other effective applications of cancer detection
PART 3
using modalities such as proteomics or still to be discovered biomarkers
(Alexander et al., 2004).
Fine-­needle aspiration for cytologic examination is frequently used to
evaluate head and neck masses. Rapid identification of a mass of parathyroid
tissue has been done by measuring parathyroid hormone (PTH) in saline,
into which the needle aspirate is flushed (Conrad et al., 2006). This method
was shown to be 99% accurate for diagnosis of parathyroid tissue because
the measured values of PTH are orders of magnitude higher in parathy-
roid aspirates than in those from other tissues such as thyroid, adipose, or
lymphatic. This type of specimen is truly unusual and would not likely be
included in any manufacturer’s claims for assay performance. However, the
use of this specimen is well recognized by endocrine s­urgeons who now
consider it a standard of practice.
Another diagnostic application of tumor markers is for aspirates col-
lected from pancreatic cysts during surgery, although such fluids might
sound. High levels of CA19-­9 in pancreatic cyst fluid suggest malignancy,
whereas low levels are more consistent with benign processes (Khalid &
Brugge, 2007). CA19-­9 measurement in pancreatic cyst fluid is an aid to
diagnosing malignancy in conjunction with cytology and other studies.
The advantage of CA19-­9 in this context is its relatively fast turnaround
time by immunoassay that might be completed during the time period of
Khalid, 2013). 
BILLING FOR TESTS IN NONSTANDARD
SPECIMENS
Although considerations of medical necessity provide strong motivation
for performing tests in unusual specimen types to provide unique informa-
tion that could not be obtained by other means, reporting of the results and
subsequent billing may lead to confusion. Most laboratory computer sys-
tems have strictly defined specimen types, such as blood, serum, urine, and
CSF. When dealing with an unusual specimen type that is not individually
coded or recognized in a computer system, laboratories should take care
not to enter these results as though they were serum or other commonly
tested fluid. For both medical needs and reimbursement, some disclaimer
should be included to indicate the specimen type so that it is not confused
with serum or other conventional fluid. 
CHEMICAL MEASUREMENTS IN
BODY FLUIDS
Plasma, serum, CSF, and urine are standard fluids that are often submit-
ted for chemical analysis. Manufacturers generally provide product claims
for their assays in one or more of these body fluids, but they have not
established assay behavior in other specimen types, such as pleural fluid,
peritoneal fluid, SF, and other accumulations of abnormal fluids, such as
in health but rather can form as the result of various pathologic processes,
such as hemodynamic imbalance, infection, inflammation, malignancy, or
other organ dysfunction. Consequently, the composition of these fluids
can range widely, thereby leading to unpredictable effects on laboratory
measurements. Matrix effects from variations in protein concentration can
alter fluid surface tension, viscosity, and miscibility in a reaction mixture.
All of these variations might cause differences in measurements because of
errors in pipetting fixed volumes or in speed and completeness of mixing
with reagents in an assay. Other constituents present in these pathologic
fluids (e.g., hyaluronic acid in SF) but not in serum also have the potential
to alter measurements in assays intended for use in serum. This potential
for erroneous measurements in body fluids due to matrix effects should be
recognized when such requests for analysis are received.
A second issue concerning chemical measurements in pathologic fluids
is what reference range to use for comparison in an interpretive report.
Because abnormal fluid accumulations do not exist in a state of health, they
cannot, of course, be collected from a normal healthy population to estab-
lish reference ranges.
These two issues of potential interferences and lack of reference
537
 Improvement Act requirements for assay validation. In fact, the lack of
CHAPTER 30  CEREBROSPINAL, SYNOVIAL, SEROUS BODY FLUIDS, AND ALTERNATIVE SPECIMENS
manufacturers’ claims for body fluid testing might actually place a greater
burden on a laboratory to validate these assays than for use in serum for
which manufacturer claims are typically cleared by the U.S. Food and Drug
Administration. Without such validation, measuring chemical constituents
in body fluids could be considered an off-­label use of commercial assays.
In recognition of these difficulties faced by laboratories, the Clinical
and Laboratory Standards Institute (CLSI) has developed the document
C49-­A, Analysis of Body Fluids in Clinical Chemistry, to provide guid-
ance in this situation (CLSI, 2007). The specific recommendations from
the CLSI are as follows:
1. Review performance claims of the manufacturer for the possibility of
extending a commercial assay to body fluids with special attention to
accuracy, precision, analytic measurement range, reference interval
(usually in comparison with simultaneous measurement in serum, in
addition to the patient’s body fluid), and interferences from substances
in the body fluid.
2. Existing methods may be suitably modified for body fluid analysis when
necessary to obtain medically relevant information. Matrix effects that
could alter the accuracy of measurement must be recognized. Further-
more, lack of a reference range for the analyte in body fluids should
be compensated for by interpretation of results in comparison with a
simultaneously collected serum specimen.
3. The preconditions for using a routine assay for an alternate body fluid
are that the measurement system in another specimen type (serum plas-
ma, urine)
a. Has acceptable test characteristics.
b. Has a reference method by which to ascertain bias.
c. Has calibrators and controls.
d. Undergoes external proficiency testing whenever available.
4. Specimen collection of body fluid and its handling, processing, and
storage should follow guidelines for specimens of plasma or serum col-
lected for that measurement. Special attention should be directed to the
possibility of interference from anticoagulants into which a body fluid
might be collected (e.g., heparin, EDTA, citrate).
5. Unusual properties of a body fluid such as high viscosity should be given
consideration if they have the potential to alter the analyte concentra-
tion in the final solution of the reaction mixture (e.g., inaccurate pipet-
ting, inadequate mixing).
6. The presence of an interferent in a body fluid can be assessed by test-
ing the fluid neat and at 1 : 2 and 1 : 4 dilutions. Recovery of similar
concentrations suggests lack of interference. Low concentrations can be
checked for interference by mixing with a routine (serum) sample with a
high measurable value to measure recoverability.
7. Result reporting should include the measured value and the type of fluid
analyzed plus a statement that accuracy might be affected by sample type
and that results should be interpreted in the clinical context. The labora-
tory is urged to contact ordering physicians to explain these limitations.
A key point is that to be useful clinically, measurements in body flu-
ids need not necessarily be highly accurate but instead must be within a
clinically acceptable range of the true value. This CLSI document provides
an extensive list of applications of many different chemical analytes that
may provide medically unique information about the source of a body fluid
(e.g., creatinine in peritoneal fluid to evaluate urinary tract injury, amylase
in peritoneal fluid to evaluate for pancreatitis, triglycerides in pleural fluid
as an indicator of chylous effusion from lymphatic damage).

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