Gastroenterology

Fitz-Hugh-Curtis syndrome in adolescent and young adult females: Utility of a decision rule

a b s t r a c t

Background: The diagnosis of Fitz-Hugh-Curtis syndrome (FHC) is often missed or delayed in patients with right upper quadrant pain (RUQ).

Objective: To develop a decision rule that predicts FHC in females with RUQ pain based on a constellation of his- torical features, physical examination findings and laboratory results.

Methods: We conducted a prospective study to test the utility of our FHC decision rule in sexually active females,

aged 13-20 years, with RUQ pain who were seen in an urban ED over 57 months. The decision rule was based on 4 features: 1. Presence of pleuritic chest pain, 2. Tenderness over the anterior border of liver, 3. History of wors- ening pain on R lateral position and 4. An Erythrocyte sedimentation rate > 30 mm/h. The rule was considered positive if all 4 features were present. FHC was diagnosed in patients with RUQ pain and a positive GEN- PROBE Aptima Combo Assay for either gonorrhea or chlamydia on urine or endocervical specimens.

Results: 130 patients were enrolled. 24 were excluded, leaving 106 (81.5%) for analysis. 34/106 (32%) had STI/ FHC. There were no differences in mean age or sexual characteristics between those with and without STI/FHC. A positive FHC decision rule had a positive predictive value of 75% (95%CI: 46.8%-91.1%) based on 96 cases for whom all features were available for analysis.

Conclusion: Our decision rule shows promise in allowing for the early identification of FHC in adolescent and young adult females. Additional study is needed to corroborate these findings and test its generalizability.

(C) 2021

  1. Introduction

Fitz-Hugh-Curtis Syndrome (FHC) is an important but unusual com- plication of sexually transmitted infection (STI) in women. FHC has been reported to occur in 4-14% of all sexually active women with pel- vic inflammatory disease (PID) and as many as 27% of adolescents with PID [1-3]. The clinical features associated with FHC syndrome are due to perihepatic inflammation as well as adhesions between the liver cap- sule and abdominal wall. The primary symptom of FHC is right upper quadrant (RUQ) pain and many patients lack the typical genitourinary and lower abdominal symptoms of an STI. Even in the presence of some lower tract symptoms such as vaginal discharge, the severity of RUQ pain can often lead both the patient and the clinician to focus on the RUQ region and conditions that are commonly associated with

* Corresponding author at: Division of Pediatric Emergency Medicine, Children’s Hospital at Montefiore, 3415 Bainbridge Avenue, Bronx, NY 10467, United States of America.

E-mail address: [email protected] (H. Khine).

that region such as cholelithiasis, pyelonephritis, and pulmonary embo- lism. As a result, the diagnosis of FHC is often missed or delayed.

Given the non-specific nature of FHC and the potential for underdi- agnosis, we sought to develop a clinical decision rule that would allow for its early identification. This rule would help prevent an extensive work up for other etiologies of RUQ pain and allow for a timely diagno- sis. This in turn would help reduce the associated morbidity of FHC and prevent ongoing spread of an STI within the community.

In a recent review of cases, we identified several historical and clin- ical features that were common among patients with an FHC diagnosis [4]. These included: (1) RUQ pain with pleuritic chest pain, (2) general- ized RUQ pain including the epigastric and the posterior regions; (3) in- ability to lie on the affected side, and (4) tenderness along liver edge from epigastric region to the posterior of RUQ region. In the current study, we assessed the utility of these diagnostic features in conjunction with an elevated erythrocyte sedimentation rate [5-9] in identify- ing FHC in adolescent and young adult females who present with RUQ pain.

https://doi.org/10.1016/j.ajem.2021.07.053

0735-6757/(C) 2021

  1. Methods
    1. Sample and procedures

We conducted a prospective cohort study at a large urban pediatric emergency department (PED) from June 2013-March 2018. Adolescent females aged 13-20 years who presented to the PED with a chief com- plaint of abdominal pain were eligible for the study. Patients were re- cruited into the study when the study investigators (HK, SW, JT) were available for patient enrollment. The inclusion criteria for the study were: history of Sexual activity, report of either isolated RUQ abdominal pain or RUQ pain in conjunction with pain in other quadrants. A written informed consent was obtained from the patient. Parental consent was waived since the study involved sexual health information. The study was approved by the institutional review board.

    1. Measures

Demographic data and detailed sexual history were obtained from the patient at the time of enrollment. Information collected included pa- tient’s age, ethnicity, number of life-time partners, history of pregnancy, history of sexually transmitted infection (STI) and its treatment. We also recorded the following historical features: duration of pain, quality of pain, associated symptoms, presence or absence of pleuritic pain and ac- centuation of pain when lying on the R side.

The research investigator performed a focus exam and noted the fol- lowing findings: vital signs, presence or absence of pleuritic pain,(ask- ing the patient to take a deep breath and to point where the pain is experienced, chest or abdomen) tenderness along either the anterior liver edge alone or both the anterior and posterior liver edge, (palpating from below the xiphoid bone, moving laterally along the inferior border of the rib to the back on the right side) and accentuation of pain when lying on the R side (eliciting pain by asking the patient to move from a supine position to a right lateral decubitus position). The laboratory data collected for the study included a white blood cell count and ESR. The extent of workup including other laboratory tests and im- aging studies the patient received was left to the discretion of the treating physician. Testing for gonorrhea or chlamydia was done using the GEN-PROBE Aptima Combo Assay(R) with the site of sample collec- tion being determined by the treating physician, either via urine collec- tion or endocervical specimen. The discharge diagnosis was recorded. For the purpose of this study, patients were given a diagnosis of FHC if they had both RUQ pain and a positive result for either gonorrhea or chlamydia on either urine or endocervical specimens.

    1. Statistical analyses

To create a FHC decision rule, the following clinical features were ex- amined for their associations with a positive STI test: (1) pleuritic chest pain (history of or present on exam), (2) tenderness along liver border (anteriorly, or both anteriorly and posteriorly), (3) accentuation of pain when lying on the R side (history of or evidence on exam) and (4) ele- vated ESR. For factors 1 and 3, the historical component was compared to the physical examination component to identify the better predictor of FHC.

Bivariate statistical analyses comparing demographic characteristics, sexual history and clinical features in patients with and without STI in- fections were performed using chi square tests for categorical data and t-tests for continuous data. In addition, we calculated odds ratios (ORs) when comparing categorical variables in patients with vs. without pos- itive STI findings. We also used ROC analyses to identify appropriate cut- offs for lab values significantly associated with positive STI findings. Fi- nally, we created the FHC decision rule based on having all of the iden- tified predictor variables present and calculated its sensitivity, specificity, positive predictive value, and negative predictive value for diagnosing likely FHC.

  1. Results

During the study period, 130 patients who met the inclusion criteria were approached and enrolled. Of these, 24 patients were excluded for the following reasons: 12 patients did not have RUQ pain on examina- tion, 4 had charts with missing identifier information, 8 did not have any STI testing, leaving 106 (81.5%) for overall analysis. An additional 10 cases were excluded due to missing clinical data on one or more of the criteria included in the decision rule, leaving 96 cases for that analysis.

Of the 106 included patients, 67% were Hispanic, 31% were Black, 1% white and 1% was classified as other, which is reflective of the distribu- tion of patients served at our institution. Among those included in the study, 32% (34/106) had a documented STI infection with either chla- mydia (n = 29) or gonorrhea (n = 1) or both (n = 4). There were no differences in mean age, in the number of lifetime sexual partners, his- tory of STI or history of pregnancy between those with and without an STI (Table 1). Table 2 shows the working diagnosis given by the treating physician at the time of disposition from the ED. The most common di- agnosis among the STI positive group was FHC (28/34, 82%). The diag- noses in order of frequency among the STI negative group were: FHC or GI related complaints (17/72, 24% each), GU related (12/72, 17%) and abdominal pain NOS or biliary related (8/72, 11% each).

Table 3 shows the associations between historical factors, physical exam and laboratory data and the diagnosis of STI. Findings of pleuritic chest pain on exam and by patient report both were associated with positive STI testing, but the exam result had a stronger association. Ten- derness along the anterior border on exam was also significantly associ- ated with positive STI testing as was having both anterior and posterior pain on exam, but the former had a stronger association with having an STI. History of increased pain when lying on the R side had a stronger as- sociation with FHC than physical exam finding. Fever was not a good predictor of a positive STI test but presence of vaginal discharge among those who had pelvic exam was associated with having an STI.

Among the laboratory values, mean WBCs did not differ between those with and without STIs, 10.5 x 103 vs. 10.2 x 103, respectively. However, patients with STIs had higher mean ESRs than those without (47.6 vs 20.4, p < .0001). Using ROC analysis, it was determined that an ESR level above 30 was the best cut-off to predict a positive STI result (Table 3).

Using the best associated factors described above, the FHC decision rule was derived to include: (1) pleuritic chest pain on exam, (2) tender- ness along the anterior border of liver edge on exam, (3) patient report of worsening pain when lying on R side and (4) ESR >30. The sensitivity of the FHC decision rule was 34.6% (95% CI: 17.21% to 55.67%), and the specificity was 95.7% (95%CI: 88.0% to 99,1%). The positive predictive value for patients satisfying all 4 criteria was 75%, (CI: 46.8%-91.1%) with an odd ratio of 11.8 (95%CI: 2.9-48.5). Among the STI positive pa- tients, 100% of patients in both FHC rule positive and FHC rule negative groups were Chlamydia positive with 1 patient having gonococcal co- infection in each group.

  1. Discussion

young females aged 15-24 years are responsible for half of all new STIs and 61.8% of all chlamydia infections are found among this age group [10]. Due to the lack of adequate diagnostics, the incidence of FHC among Young females with STI is not well defined, but appears to be disproportionately higher than in adults. [3] In our study, the inci- dence of FHC was 34% among adolescents and young adults presenting with right upper quadrant pain. The relatively high proportion of FHC in our cohort may reflect the relatively lower incidence of other diseases that can cause RUQ pain, like biliary disease and nephrolithiasis when compared to adults.

The lack of classic lower tract symptoms of pelvic pain and vaginal discharge in conjunction with isolated RUQ pain may obscure a

Table 1

Patient’s characteristics by sexually transmitted infection (STI).

STI positive

STI negative

P value?

OR1 (95% CI)

n = 34

n = 72

Age (yrs) Mean +- standard deviation

18.3 +- 1.3

18.3 +- 1.6

0.975

Not applicable

Life-time partners Median (range)

4.6 (1-20)

3.0 (1-72)

0.077

Not applicable

Hx of STI (%)

12/32 (37.5)

23/70 (32.9)

0.647

1.23 (0.51-2.93)

Hx of pregnancy (%)

12/33 (36.4)

27/67 (40.3)

0.704

0.84 (0.36-2.00)

* P-value for comparison between STI positive and STI negative.

1 Reference group is STI negative.

Table 2

Working diagnosis at disposition by sexually transmitted infection (STI).

Table 3

Clinical characteristics of patients with sexually transmitted infection (STI).

STI positive STI negative

Features STI

positive

n = 34

n = 72

PID/FHC

28 (82%)

17(24%)

GU related Dx

0 (0%)

12 (17%)

Musculoskeletal

1 (3%)

3 (<1%)

Biliary related Dx

0 (0%)

8 (11%)

GI related

1 (2%)

17(24%)

Appendicitis

0 (0%)

3 (4%)

Abdominal pain NOS

2(6%)

8 (11%)

Chest pain

1(3%)

1(<1%)

P value? OR (95% CI)

Blank (No diagnosis) 1 (3%) 3 (4%)

diagnosis of FHC. As a result, patients with FHC may have Persistent symptoms without a definitive diagnosis, despite extensive medical evaluation [4]. Many FHC cases are reported as incidental findings in pa- tients undergoing surgical procedures for other diagnoses [4,11-13]. The resulting Delay in diagnosis can lead to a variety of long-term con- sequences such as chronic abdominal pain, PID, infertility and increased incidence of ectopic pregnancies in affected patients [14,15].

The clinical characteristics of our decision rule correlate with the pathology of FHC. Patients with FHC have a perihepatitis with inflamma- tion surrounding the liver capsule and adhesions extending to the dia- phragm. The adhesions between liver capsule and the diaphragm, often described as violin strings, explain the pleuritic nature of pain that is present in patients with FHC. Referred shoulder pain from diaphragmatic irritation can be associated with pleuritic pain. Isolated pleuritic chest pain can be mistaken for pathology involving the lung such as pulmonary embolism or pleurisy associated with viral infection. However, the find- ing of tenderness along the entire liver edge from xiphoid to lateral aspect of the right abdominal wall with pleuritic chest pain is consistent with an abdominal source of the pain. The extent of involvement in the RUQ region from xiphoid to lateral wall of the right side of abdomen is in contrast to pain associated with cholelithiasis, which has more discrete involvement in the RUQ region, referred to as Murphy’s sign.

Intensification of pain when lying on the right side likely results from increased pressure over the inflamed liver capsule. This contrasts with other conditions in which holding the fetal position alleviates the pain, such as in patients with biliary colic or renal colic. Some, but not all, prior studies have noted the utility of an elevated ESR in the making the diagnosis of FHC [5-9]. Given the indolent nature of this infection and as- sociated chronic inflammation, an elevated ESR can occur, despite normal acute inflammatory markers such as white blood cell count and C-reactive protein (CRP). Though an elevated ESR can be seen in a wide range of dis- orders, an elevated ESR in the context of the other features of the FHC rule supports a diagnosis of FHC. While the finding of vaginal discharge on physical examination was highly associated with STI, patients who pres- ent with predominantly RUQ pain may or may not receive a pelvic exam- ination, therefore it was not considered a reliable physical finding on all patients with RUQ pain and not included in the FHC rule.

One may question the need for a decision rule for FHC, but rather screen every patient with RUQ pain to exclude FHC. Routine practice

Patient history

Pain with deep breathing

No (n = 41) 17.1%

Yes (n = 65) 41.5% 0.009 3.45 (1.33-8.94)

Increased pain when lying on R side

No (n = 48)

18.8%

Yes (n = 58)

43.1%

0.01

3.28 (1.34-8.01)

Physical exam

Pleuritic chest pain

No (n = 49)

12.2%

Yes (n = 56)

50.0%

<0.001

7.16 (2.63-19.52)

Tenderness along anterior liver border

No (n = 26)

15.4%

Yes (n = 79)

38.0%

0.033

3.36 (1.05-10.72)

Tenderness along anterior and posterior

border

No (n = 61)

23.0%

Yes (n = 43)

46.5%

0.012

2.91 (1.25-6.80)

Pain worse when lying on R side

No (n = 25)

36.0%

Yes (n = 32)

56.3%

0.129

2.28 (0.78-6.69)

Fever

No (n = 101)

31.7%

Yes (n = 4)

50.0%

0.443

2.16 (0.29-16.00)

Vaginal discharge

No (n = 28)

28.6%

Yes (n = 23)

65.2%

0.009

4.68 (1.43-15.36)

Lab tests

ESR >30

No (n = 53)

13.2%

Yes (n = 25)

66.7%

<0.0001

8.36 (2.72-25.65)

Decision rule

FHS Rule negative (n = 84)

20.2%

FHC Rule positive1 (n = 12)

75.0%

<0.0001

11.82 (2.88-48.47)

* P-value for comparison between STI+ and STI- patients.

1 Presence of all of the following: (1) pleuritic chest pain, (2) tenderness along anterior liver border, (3) Increased pain when lying on R side and (4) ESR > 30; FHC = Fitz-Hugh- Curtis Syndrome.

of screening for STI in all female patients with RUQ pain would increase the identification of patients with FHC. However, the decision rule al- lows for early Empiric treatment of affected patients and prevents the difficulties of follow up among adolescent and young adult patients, which has been well documented in the literature [16,17]. Because of the difficulties and resources required for follow-up in this cohort, Pattishall et al. have argued that providers should consider empiric STI treatment in high-risk Pediatric populations with unreliable follow up and lower tract symptoms suggestive of STI to reduce the number of pa- tients who are lost to follow up [18]. Given that the FHC decision rule has a positive predictive value of 75%, we strongly believe that empiric STI treatment in patients with a positive FHC decision rule result is jus- tified. We note that left untreated, there is high morbidity among FHC patients including chronic abdominal pain, Ectopic pregnancy and infer- tility as seen in patients with untreated PID.

There are several limitations to our study. It took place at a single center and the assessments were done by a limited number of clinicians. However, the questions and maneuvers needed for this decision rule do not require any additional skills except for doing a focused history and examination to get the detailed information. We were unable to report on Interobserver variability due to infrequent presentations and un- availability of a second investigator during the exams. However, this is a simple rule that can be adopted by any clinician. Another limitation of the study is the lack of long term follow up of the patients. However, in our prior case series, we reported on the long term follow up of 4 pa- tients with similar clinical features. One of these patients had her diag- nosis confirmed laparoscopically. None of the patients had Alternative diagnoses made that would explain their symptoms [4]. Additional lim- itations to our study are its small sample size and missing clinical infor- mation in a subgroup. However, the findings are encouraging enough to consider applying them in clinical situations.

In summary, FHC is a known complication of STI and often eludes cli- nicians due to its unconventional presentation. An FHC decision rule with the following 4 clinical features was found to be highly predictive for FHC in our study population: (1) pleuritic chest pain on exam,

(2) tenderness along the anterior liver border on exam, (3) patient re- port of worsening pain when lying on R side and (4) ESR >30. We be- lieve the FHC decision rule has potential to aid clinicians in both making a diagnosis of FHC and determining those patients, for whom empiric treatment would be beneficial, thereby minimizing loss to fol- low up. Additional studies are needed to confirm our findings and test their applicability in a general population.

Contributors’ statement

Dr. Khine conceptualized and designed the study; participated in the enrollment process, organized the data, assisted with data analysis. De- signed figures and tables, drafted the initial manuscript and reviewed and revised the manuscript.

Ms. Wren conceptualized and designed the study, assisted with en- rollment, reviewed and revised the manuscript.

Dr. Silver carried out the data analysis, designed figures and tables, reviewed and revised the manuscript.

Dr. Tun assisted in enrollment of patients, reviewed and revised the manuscript.

Dr. Goldman assisted in the design of the study, in the data analysis and drafted the initial manuscript and critically reviewed and revised the manuscript.

All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Funding/support

This research did not receive any specific grant from funding agen- cies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

The authors have no conflicts of interest relevant to this article to disclose.

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