ORIGINAL ARTICLE

Diagnosing joint infections: synovial fluid differential is moresensitive than white blood cell count

Sean Baran • Connie Price • David J. Hak

Received: 10 July 2013 / Accepted: 29 September 2013

� Springer-Verlag France 2013

Abstract In order to identify the predictive value of

synovial fluid white blood cell (WBC) count and differ-

ential white blood cell count in identifying nonprosthetic

joint infection in immunocompetent and immunosup-

pressed populations, we retrospectively reviewed 96 adult

patients who underwent hip or knee aspiration because of

symptoms suggesting a possible nonprosthetic joint infec-

tion. Medical history, including immunosuppressive dis-

ease or drugs, was recorded, and synovial fluid cell count,

differential, and culture results were compared. There were

44 patients with positive synovial cultures. Of 36 patients

who had a synovial WBC C50,000/mm3, 89 % had posi-

tive cultures. The sensitivity to synovial WBC C50,000/

mm3 was 0.727 (95 % CI 0.570–0.845), and specificity was

0.923 (95 % CI 0.806–0.975). There were 12 patients with

a synovial WBC \50,000/mm3 that had positive cultures.

The sensitivity of percentage polymorphonuclear cells

(%PMNs) to predict positive cultures when the %PMNs

were at least 80, 85, and 90 % was 0.932, 0.886, and 0.818,

respectively. The specificity when the %PMNs was at least

80, 85, and 90 % was 0.598, 0.577, and 0.673, respectively.

Among the 29 % of immunocompromised patients, the

sensitivity to synovial WBC C50,000/mm3 was 0.714

(95 % CI 0.420–0.904), and specificity was 1.000 (95 % CI

0.732–1.000). Twenty-nine percent of patients with a

synovial WBC \50,000/mm3 had positive cultures. The

sensitivity of %PMNs to predict positive cultures when the

%PMNs was at least 80, 85, and 90 % was 1.000, 0.929,

and 0.786, respectively. The specificity when the %PMNs

were at least 80, 85, and 90 % was 0.500, 0.643, and 0.714,

respectively. We found that the synovial WBC differential

(percentage synovial fluid PMNs) is a more sensitive pre-

dictor for nonprosthetic adult joint infection than the

synovial absolute WBC count. This was true in both the

general population and the immunosuppressed population.

Keywords Septic arthritis � Joint infection �Diagnosis

Introduction

Septic arthritis is a potentially devastating condition,

associated with significant morbidity and even mortality,

which requires emergent diagnosis and treatment [1].

Prompt diagnosis is imperative for initiating appropriate

treatment. Synovial fluid aspiration and analysis has long

been recognized and recommended for its usefulness in the

evaluation of the acutely tender, red, warm, and swollen

joint. The sophistication of individual assays in synovial

fluid analysis has grown immensely since Bauer and

Our local IRB reviewed and approved this study.

This study was performed at Denver Health Medical Center, Denver,

Colorado.

S. Baran

Department of Orthopaedic Surgery, Mayo Clinic,

200 First Street SW, Rochester, MN 55905, USA

e-mail: Sean.Baran@mayo.edu

C. Price

Department of Internal Medicine, Denver Health Medical

Center, University of Colorado Denver, School of Medicine,

777 Bannock St, MC0188, Denver, CO 80204, USA

e-mail: Connie.Price@dhha.org

D. J. Hak (&)

Department of Orthopaedic Surgery, Denver Health Medical

Center, University of Colorado Denver, School of Medicine,

777 Bannock St, MC0188, Denver, CO 80204, USA

e-mail: David.Hak@dhha.org

123

Eur J Orthop Surg Traumatol

DOI 10.1007/s00590-013-1331-x

Ropes’ early reports that variation in cell content and gross

appearance may be indicative of different arthritic diseases

[2]. Despite this growing sophistication, no single synovial

fluid test has been proven adequately discriminatory in the

diagnosis of the septic joint [3]. Even the synovial fluid

white blood cell (WBC) count, which has traditionally been

held as a useful marker of joint infection, displays a tre-

mendous amount of overlap with the other inflammatory

arthritides [4, 5]. Multiple studies have concluded that

synovial fluid WBC count is insufficient to rule in or out

septic arthritis [3–7]. Some research suggests that the

synovial fluid white blood cell differential (dWBC) count

may be a better marker of joint infection, but the amount of

evidence is scant, and the conclusions are mixed [5, 8–12].

Unfortunately, the recognized ‘‘gold standard’’ for the

diagnosis of septic arthritis remains the level of clinical

suspicion of a physician experienced in the diagnosis of

joint pathology [3, 4].

This situation presents a serious problem for the physi-

cian lacking sufficient experience in the diagnosis of joint

pathology and, most importantly, for the patient with a

potentially septic joint. The diagnosis is even further con-

founded in the immunosuppressed population, as their

synovial fluid WBC values have been shown to have an

even greater degree of overlap with the other inflammatory

arthritides [8, 12, 13].

The purpose of this study was to examine the predictive

value of the synovial fluid WBC and dWBC in the diag-

nosis of an adult septic joint in patients who underwent

synovial fluid aspiration at a major tertiary care center. Our

hypothesis was that dWBC would be a more sensitive, and

possibly more specific, marker of a septic joint than the

absolute synovial WBC count.

Patients and methods

This retrospective case–control study was conducted to

determine the sensitivity and specificity of synovial WBC

count and dWBC count to diagnose septic arthritis. The

institutional review board at our institution approved this

study.

The study population includes all patients who under-

went synovial fluid aspiration and analysis with cell count

of the hip or knee between May 2003 and May 2009 at an

academic, urban, tertiary care center which has greater than

900,000 patient contacts annually.

The hospital database for infectious diseases was que-

ried for all synovial fluid aspiration results between May

2003 and May 2009 and initially sorted based on the

synovial fluid culture results. The electronic medical

records associated with each culture-positive aspiration

were then reviewed and abstracted for demographics,

medical history, including immunosuppressive medication

or disease, joint sampled, synovial fluid culture results, and

synovial fluid analysis results. Only those cases in which

the patient had undergone aspiration of the hip or knee

were included. Cases were excluded if the patient was less

than 18 years of age, had been an inmate in the county jail

at the time of aspiration, or if the synovial fluid analysis

had been done at an outside facility. For those patients who

had undergone multiple aspirations during a single hospital

course or within 1 month of an initial aspiration, only the

initial synovial fluid analysis was included. Culture results

were reviewed to evaluate for possible contaminants, and

those that were listed as contaminants (i.e., broth-only

growth) were excluded. Finally, aspirations from prosthetic

joints were excluded because the number of infected total

joint arthroplasties was too low to analyze independently.

A cohort of 44 consecutive cases in which the patient

had culture-confirmed septic arthritis (i.e., growth of a

pathologic organism) were identified, and subsequently, a

cohort of 52 consecutive patients with negative culture

results during the same time period were established. The

same information that was abstracted for the culture-posi-

tive aspirations was abstracted from associated medical

records of the culture-negative cases. The same inclusion/

exclusion criteria were applied to these cases. In addition,

the case was excluded if the joint was treated as septic

based on clinical criteria, or if the negative culture was

obtained after repeat aspiration during the course of the

treatment of a previously diagnosed septic joint.

Statistical analysis

Sensitivity and specificity were reported with 95 % confi-

dence intervals (CI).

Results

The search of the database identified 44 consecutive

patients with culture-positive synovial fluid aspirates in the

6-year study. From the same time period, 52 consecutive

patients with culture-negative synovial fluid aspirates were

identified for comparison, yielding a total of 96 cases for

study. Patient demographics are summarized in Table 1.

The median age was 47 years with a range of 21–85 years.

Women comprised 39 % of the study population.

The knee (96 %) was more commonly involved than the

hip (Table 1). The most common organism (Table 2)

identified was Staphylococcus aureus (59 %) followed by

beta-hemolytic streptococcus (25 %).

In 36 of the 96 patients, the synovial WBC was

C50,000/mm3. Of these 36 patients, 32 (89 %) had positive

culture results. Of 60 patients with a synovial WBC

Eur J Orthop Surg Traumatol

123

\50,000/mm3, 12 (20 %) had positive culture results. The

sensitivity to synovial WBC C50,000/mm3 was 0.727

(95 % CI 0.570–0.845), and specificity was 0.923 (95 % CI

0.806–0.975) (Fig. 1).

Forty-one (93 %) of 44 patients with culture-positive

aspirates had a dWBC count with a %PMNs of at least

80 %. The sensitivity of %PMNs to predict positive cul-

tures when the %PMNs were at least 80, 85, and 90 % was

0.932 (95 % CI 0.803–0.982), 0.886 (95 % CI

0.746–0.957), and 0.818 (95 % CI 0.668–0.913), respec-

tively. Of 56 patients with culture-negative aspirates, 28

(85 %) had a dWBC count with %PMNs less than 80 %.

The specificity when the percentage PMNs was at least 80,

85, and 90 % was 0.538 (95 % CI 0.396–0.675), 0.577

(95 % CI 0.433–0.710), and 0.673 (95 % CI 0.528–0.793),

respectively.

Patients with immunosuppression

Immunosuppression (disease and/or medication) was pres-

ent in 28 patients (Tables 3, 4). Seventeen (61 %) of 28

patients had a known immunocompromising disease, and

nine additional patients were taking an immunosuppressive

medication. The remaining two patients had a known diag-

nosis of an immunocompromising disease and were also

taking an immunosuppressive medication. Seven patients

0

0.2

0.4

0.6

0.8

1

WBC > 50k 80% PMNs 85% PMNs 90% PMNs

Sensitivity Specificity

Fig. 1 Solid bars represent sensitivity values, and white bars

represent specificity values for WBC C50,000/mm3 (WBC), PMNs

C80 % (80), PMNs C85 % (85), and PMNs C90 % (90) for native

joints. Positive and negative error bars indicate 95 % CI

Table 3 Immunosuppressive diseases observed

Disease Number of patients affected

Type 1 diabetes mellitus 3

Type 2 diabetes mellitus 13

Human immunodeficiency virus 2

End-stage renal disease 4 (3 had comorbid DM)

Table 4 Immunosuppressive medications observed

Medication Number of patients taking

Prednisone 7

Hydroxychloroquine 7

Methotrexate 3

Sulfasalazine 3

Loxapine 1

Table 5 Isolated pathogens in immunosuppressed population

Organism Number of

patients

Percentage of patients

(%)

Staphylococcus aureus 9 64

MRSA 2 14

MSSA 7 50

Beta-hemolytic

streptococcus

3 21

Escherichia coli 1 7

Haemophilus influenzae 1 7

Table 1 Patient demographics

Median age (years) (range) 47 (21–85)

Sex (female) 39 %

Joint involved

Knee 96 %

Hip 4 %

Immunosuppressiona 30 %

a Includes patients with an immunosuppressive disease and/or on an

immunosuppressive medication

Table 2 Isolated pathogens

Organism Number of

patients

Percentage of

patients (%)

Staphylococcus aureus 26 59

MRSA 9 20

MSSA 17 39

Beta-hemolytic streptococcus 11 25

Streptococcus pneumoniae 1 2

Streptococcus milleri 1 2

Haemophilus influenzae 1 2

Bacteroides fragilis 1 2

Escherichia coli 1 2

Candida spp. 2 5

Eur J Orthop Surg Traumatol

123

were on greater than one immunosuppressive medication,

and the most common immunosuppressive medication was

prednisone. The most common immunocompromising dis-

ease was type 2 diabetes mellitus. Culture-positive aspirates

were present in 14 (50 %) of the 28 immunosuppressed

patients. The most common organism was S. aureus (64 %),

followed by beta-hemolytic strep (21 %) (Table 5).

There were nine immunosuppressed patients with a

synovial WBC C50,000/mm3, and 100 % of these patients

had culture-positive aspirates. Of 19 patients with a synovial

WBC\50,000/mm3, five (26 %) had positive culture results.

The sensitivity in immunosuppressed patients to synovial

WBC C50,000/mm3 was 0.714 (95 % CI 0.420–0.904), and

specificity was 1.000 (95 % CI 0.732–1.000) (Fig. 2).

Immunosuppressed patients with culture-positive aspi-

rates had a dWBC count with %PMNs of at least 80 % in

every case. The sensitivity of %PMNs to predict positive

cultures when the %PMNs were at least 80, 85, and 90 % was

1.000 (95 % CI 0.732–1.000), 0.929 (95 % CI 0.642–0.996),

and 0.786 (95 % CI 0.488–0.943), respectively. Seven of 14

immunosuppressed patients with culture-negative aspirates

had a dWBC count with %PMNs less than 80 %. The

specificity when the %PMNs were at least 80, 85, and 90 %

was 0.500 (95 % CI 0.240–0.760), 0.642 (95 % CI

0.356–0.860), and 0.714 (95 % CI 0.420–0.904), respec-

tively. These data are summarized in Table 2.

Discussion

Prompt diagnosis and treatment of intra-articular infections

is imperative to limit adverse outcomes [1]. Following

septic arthritis, permanently reduced joint function is

observed in around 40 % [1]. Synovial fluid white blood

cell (WBC) count has traditionally been used to diagnose

joint infection. The American Rheumatism Association has

classified WBC into three categories: \2,000 WBC/mm3

(noninflammatory), 2,000–50,000 WBC/mm3 (inflamma-

tory), and [50,000 WBC/mm3 (infectious) [8]. Impor-

tantly, these cutoffs are merely guidelines, since there is a

significant amount of overlap in the observed synovial

WBC values between infectious arthritis and various

inflammatory arthritides [4, 5]. Multiple studies have

examined the synovial WBC value as a predictive criterion

for diagnosing septic arthritis. While various sensitivities

and specificities for synovial absolute WBC values have

been reported, each of these studies has concluded that

synovial WBC alone is insufficient to diagnose or rule out

joint infection [3–7].

We found sensitivity and specificity values for the WBC

C50,000/mm3 of 0.727 and 0.923, respectively. These

values are consistent with previously reported values in the

literature. Importantly, using a 50,000/mm3 cutoff for

infectious arthritis may have resulted in delayed diagnosis

of 20 % of the septic joints observed in this study. These

results further support the need for a better marker of joint

infection.

We found that the dWBC, specifically the %PMNs, is a

more sensitive marker of joint infection than the synovial

fluid WBC. In our series, a %PMNs value of at least 80 %

had a sensitivity to predicting joint infection of 0.932,

which was a 20 % increase in sensitivity compared with

the synovial WBC value. In contrast to using the standard

cutoff of WBC C50,000/mm3, which may have resulted in

delayed diagnosis in up to 20 % of the observed cases of

joint infection, using a cutoff of %PMNs greater than 80 %

would have resulted in only 7 % of cases experiencing

delayed diagnosis. We found that the %PMNs represent a

more sensitive marker for joint infection than synovial

absolute WBC count and is therefore a more useful clinical

value in ruling out joint infection. When the %PMNs are

less than 80 %, it is unlikely that the etiology of the joint

inflammation is due to infection. However, in our series,

we found that the specificity of %PMNs remained low, and

therefore, it is not useful as a marker to rule in the diag-

nosis of a septic joint.

Evidence regarding the use of the dWBC in identifying

an infectious etiology of arthritis is limited, and the con-

clusions in the literature are mixed. McCutchan and Fisher

reported that the dWBC is of minimal value as it is not

consistently different in aspirates from infectious arthritis

versus inflammatory arthritis [8]. Coutlakis et al. [5]

commented in a 2002 study that the percentage of neu-

trophils tends to be higher in fluids with higher total white

blood cell counts. However, the article contains no further

0

0.2

0.4

0.6

0.8

1

WBC > 50k 80% PMNs 85% PMNs 90% PMNs

Sensitivity Specificity

Fig. 2 Solid bars represent sensitivity values, and white bars

represent specificity values for WBC C50,000/mm3 (WBC), PMNs

C80 % (80), PMNs C85 % (85), and PMNs C90 % (90) for native

joints in immunosuppressed patients. Positive and negative error bars

indicate 95 % CI

Eur J Orthop Surg Traumatol

123

analysis or discussion regarding this topic. Three older

studies propose that increased PMNs above 90 % sug-

gested septic arthritis, and in a 2007 review of the litera-

ture, Margaretten et al. [7, 9–11] reported that when the

percentage of PMNs is at least 90 %, there is an increased

likelihood ratio of the diagnosis.

Further confounding the diagnosis of septic arthritis is the

presence of immunosuppression. Patients with septic

arthritis who are taking immunosuppressive medications

tend to have WBC values in the inflammatory range (i.e.,

2,000–50,000 WBC/mm3) instead of the infectious range

[8]. McGillicuddy et al. [7] reported that there was no sta-

tistically significant relationship between WBC levels and

immunosuppression in culture-positive synovial fluid aspi-

rates. The literature regarding septic arthritis among patients

with an immunosuppressive disease is largely based upon

those with HIV infection, as HIV has been recognized to

significantly increase the probability of septic arthritis [12].

However, most of the evidence supporting this claim has

come from small studies and case reports. Zalavras et al. [13]

did find that patients with HIV infection in whom the serum

CD4 count was less than 200/mm3 tended to have WBC

values in the inflammatory range.

Using WBC C50,000/mm3 as a clinical marker for joint

infection, we found a sensitivity of 0.714 in the immuno-

suppressed population compared with a sensitivity of 0.727

in the overall population. The proportion of joint infections

in which the diagnosis would have been delayed using the

WBC cutoff rises to an unacceptable 36 % in the immu-

nosuppressed population, underscoring the necessity of a

more sensitive clinical marker. Our study demonstrates a

dramatically improved sensitivity for predicting joint

infection when using the %PMNs as a clinical marker. In

this study, a cutoff of 80 % PMNs resulted in early

detection of joint infection in 100 % of the observed

immunosuppressed patients. Interestingly, the specificity of

WBC C50,000/mm3 is 100 % in this study among immu-

nosuppressed patients. While this finding is potentially

useful to rule in the diagnosis, the more clinically useful

finding for early diagnosis is the increased sensitivity of the

dWBC.

Based on the results of this study, we believe clinicians

should use the dWBC value to increase early suspicion for

the potentially septic joint, especially in the immunosup-

pressed patient. Importantly, we do not advocate singular

reliance upon the dWBC. Rather, the clinician should

continue to rely upon the entire clinical picture to arrive at

the proper diagnosis. However, with the observed increase

in sensitivity of the dWBC over the WBC, it is likely that

joint infection will represent a greater possibility in the

early differential diagnosis of red, warm, tender, swollen

joint. Further, by maintaining this increased suspicion in

the face of a ‘‘noninfectious’’ WBC value, the physician

will potentially miss fewer cases of joint infection early in

their course.

Staphylococcus aureus is the most common etiologic

organism in septic arthritis. McGillicuddy et al. found that

the organism accounted for 55 % of the cases in their

49-patient study [8]. Li et al. [14] found an even higher

incidence, with 76 % of cases caused by S. aureus, in a

study of 55 patients. Similarly, Kaandorp et al. [15] found

that in a population of 157 patients with septic arthritis, S.

aureus was causative in 44 % of cases. Our results showing

64 % of positive cultures growing S. aureus are consistent

with these authors’ previous findings. This proportion

remained relatively constant regardless of the presence of

immunosuppression.

Study limitations

This study has several limitations. First, it is a hospital-

based retrospective, case–control study, and therefore,

the data utilized were originally recorded for the pur-

poses other than research, and the accuracy of these

recordings cannot be guaranteed. The study population is

limited to patients seen at a single major, urban, tertiary

care center. However, the records collected were not

limited only to hospital admissions, but rather included

all patients (both inpatient and outpatient) who under-

went synovial fluid analysis, which eliminates Berkson’s

bias from our study. Second, the population size is rel-

atively small. Third, the data collected only included

hips and knees, which may possibly limit the general-

izability of our findings to other joints. However, we did

choose to include only hips and knees because these are

the only two joints from which an adequate amount of

synovial fluid can routinely be obtained for differential

cell count analysis. Finally, our study does not address

infection in prosthetic joints, a subset of the population

known to experience higher rates of joint infection than

the general population.

Conflict of interest The authors report no conflicts of interest

regarding this manuscript. None of the authors, nor their institutions,

received any payment or services from a third party for any aspect of

the submitted work.

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