INTRODUCTION
The Epstein-Barr virus is a human herpesvirus, to which most people are exposed in childhood and acquire active immunity. However, a subset of patients, typically Caucasian adolescents,Reference Nye1 are infected later in life through intimate contact with a host and develop infectious mononucleosis. Infectious mononucleosis is characterized by a triad of symptoms: fever, pharyngitis, and lymphadenopathy.
Infectious mononucleosis is almost invariably self limited, and the treatment is conservative. Patients are asymptomatic within 1–2 weeks, except fatigue that can persist for months.Reference Rea, Russo, Katon, Ashley and Buchwald2 In the emergency department (ED) setting, these patients may have the diagnosis confirmed with a single rapid blood test and are discharged home without advanced blood work or imaging.
An exceeding rare sequela of infectious mononucleosis is acute acalculous cholecystitis, a condition more typically seen in patients with prolonged admissions in the intensive care unit (ICU). Acute acalculous cholecystitis is an acute inflammatory and necrotic process of the gallbladder in the absence of a gallstone, with high morbidity and mortality.Reference DuPriest, Khaneja and Cowley3 It occurs as a consequence of major trauma, malignancy, burns, and sepsis, among other severe causes. Once diagnosed, the treatment of acute acalculous cholecystitis ranges from symptomatic management to antibiotics and surgery.
CASE REPORT
An 18-year-old female presented to the ED with a one-week history of profound fatigue. She also complained of fever, painful swelling in her neck, and reported right upper quadrant abdominal pain. She was otherwise healthy, with no significant past medical history.
Her triage vitals were: heart rate 95 beats/minute, blood pressure 106/71 mm Hg, respiratory rate 20 breaths/minute, oxygen saturation 98% on room air, and a temperature of 37.8°C (100.4°F). On physical exam, she had marked lymphadenopathy of the head and neck with an erythematous pharynx. Her examination revealed a soft abdomen with significant tenderness in the right upper quadrant and a positive Murphy’s sign. She was not jaundiced and had no stigmata of liver disease. Her cardiac and respiratory exams were within normal limits.
Because of her pronounced right upper quadrant abdominal pain, bloodwork was obtained. It revealed leukocytosis, moderate transaminitis, hyperbilirubinemia, elevated alkaline phosphatase, and elevated lipase (see Box 1). A monospot test was positive.
Box 1. Relevant bloodwork
ALT=alanine aminotransferase; AST=aspartate aminotransferase.
* Abnormal values
Based on a physical exam and the cholestatic picture in the bloodwork, an abdominal ultrasound was ordered that revealed a distended gallbladder with diffuse wall thickening measuring up to 10 mm. There was a small amount of pericholecystic fluid. The patient had a positive sonographic Murphy’s sign. No gallstones or biliary tract dilatations were seen.
A diagnosis of acute acalculous cholecystitis was made. She was admitted under general surgery, observed, and treated symptomatically. With conservative therapy, the patient made a complete recovery and was discharged home two days later with no complications.
DISCUSSION
An adolescent or a young adult patient who presents with the clinical triad of infectious mononucleosis (pharyngitis, fever, and lymphadenopathy) rarely presents a diagnostic dilemma. The diagnosis is confirmed with a rapid test in the heterophile antibody (monospot) assay, which has high sensitivity and specificity (85% and 100%, respectively).Reference Linderholm, Boman, Juto and Linde4 These patients do well with symptomatic treatment and are not referred or admitted.
However, because they are rare, many of the complications of infectious mononucleosis do not receive much attention despite their severity. Patients are told to avoid contact sports to prevent splenic injury, but, often, the discussion ends there. However, clinicians need to be aware of other non-splenic sequelae. Epstein-Barr virus has been associated with multi-system disease including, but not limited to, multiple sclerosis, myocarditis, myositis, and glomerulonephritis.Reference Jenson5 Of note, not all cases of infectious mononucleosis are caused by the Epstein-Barr virus, with approximately 10% of cases arising from other viruses such as HIV, cytomegalovirus, and hepatitis B.Reference Evans6
The pathophysiology of infectious mononucleosis causing acute acalculous cholecystitis is not fully understood. There are two proposed mechanisms. The first is that cholestasis caused by hepatic or gallbladder pathology leads directly to acute acalculous cholecystitis by the release of proinflammatory cytokines, disrupting bile flow.Reference Shaukat, Tsai, Rutherford and Anania7 However, the second theory is that systemic illness in the absence of cholestasis causes inflammation of the gallbladder (common infections include: cholera, tuberculosis, salmonellosis, brucellosis, and hepatitis A).Reference Barie and Eachempati8-Reference Gora-Gebka, Liberek and Bako10 While Epstein-Barr virus is not a common pathogen causing acute acalculous cholecystitis, it is described.
The infectious theory is more consistent with the literature than the cholestatic theory. According to a systematic review by Kottanattu in 2016, only one of the 37 patients (3%) with Epstein-Barr virus–associated acute acalculous cholecystitis had cholestatic biochemistry. This makes the proposed cholestasis mechanism at least epidemiologically less likely. Further, parallels can be drawn to other disease states: the systemic illness mechanism is in keeping with the proposed pathophysiology of Epstein-Barr virus causing acute pancreatitis, which is also rare but well documented.Reference Kottanattu, Lava and Helblinga11
Acute acalculous cholecystitis secondary to infectious mononucleosis is increasingly being described and is important for the emergency physician to consider.Reference Beltrame, Andres, Tona and Sperti12-Reference Iaria, Arena and Di Maio14 Given the right clinical context (i.e., the infectious mononucleosis triad but with abdominal pain and/or cholestasis), more liberal use of ultrasound should be considered. Furthermore, for patients with right upper quadrant abdominal tenderness in the absence of a cholestatic picture, clinicians should not be falsely reassured that acute acalculous cholecystitis is ruled out. In those cases, an ultrasound should still be considered because cholestasis is not a prerequisite for this condition.
In 2016, Agergaard and Larsen conducted a literature review identifying 26 cases involving infectious mononucleosis–associated acute acalculous cholecystitis.Reference Agergaard and Larsen15 Interestingly, there was a strong sex preponderance, with 25 of the 26 cases being females presenting with abdominal pain. The case presented herein is consistent with that pattern. Similar to the findings of this review, our patient’s management and outcome were typical; she did not require antibiotics, corticosteroids, or surgery, and she made a full recovery. It seems the acute acalculous cholecystitis that patients develop from Epstein-Barr virus is far more benign than if it arises from other sources and requires less intervention if any.Reference Kottanattu, Lava and Helblinga11
CONCLUSION
Patients diagnosed with infectious mononucleosis should be screened for sequelae of the infection, beginning with a detailed history and physical. For those presenting atypically or with a protracted course, bloodwork and possibly abdominal imaging should be considered. In these patients, the possibility of acute acalculous cholecystitis should be entertained because of its ease of diagnosis and potentially aggressive management requirements. Currently, it is likely underdiagnosed in the ED.
LEARNING POINTS
1) Adolescents and young adults with fever, lymphadenopathy, and pharyngitis can be clinically diagnosed with infectious mononucleosis, which is easily confirmed using a monospot test.
2) Patients with atypical presentations of infectious mononucleosis should be thoroughly evaluated for several rare complications including acute acalculous cholecystitis especially young females with abdominal pain.
3) Infectious mononucleosis–associated acute acalculous cholecystitis often requires supportive management, though in select cases, antibiotics and surgery may be indicated.
4) Emergency physicians should be aware of this entity. It is likely underdiagnosed. Despite often not requiring active management, these cases should be identified promptly to monitor for severe complications such as gallbladder perforation and sepsis.
