Case Report: Periorbital Edema as an Overlooked Presentation of Epstein-Barr Virus

Authors: Simran Ohri, Iden Amiri, Gitanjali M. Fleischman, David Fleischman

Abstract

Introduction

Infectious mononucleosis (IM), most commonly caused by Epstein-Barr virus (EBV), classically presents with fever, pharyngitis, and cervical lymphadenopathy. However, less common manifestations such as bilateral periorbital edema, known as Hoagland sign, may precede or obscure more typical features, complicating diagnosis. Although described in the literature for decades, Hoagland sign remains underrecognized in clinical practice, especially in pediatric and young adult patients. This oversight can lead to misdiagnosis, delayed testing, unnecessary antibiotic use, and patient distress.

Case Presentation

We present 2 cases of female patients, one pediatric and one young adult, who initially presented with bilateral periorbital edema and nonspecific systemic symptoms. In both cases, infectious mononucleosis was not initially suspected. One patient was treated for streptococcal pharyngitis and later developed a rash typical of antibiotic-associated IM. The second patient was denied EBV testing at an urgent care clinic despite a direct request, due to provider unfamiliarity with the association between periorbital edema and IM. Both were eventually diagnosed with EBV via serologic testing and recovered with supportive care.

Conclusion

These cases highlight a critical gap in provider awareness that, if addressed, could reduce diagnostic delays and improve patient care. Recognizing Hoagland sign as a valid early clue for IM, particularly in female patients,can help differentiate benign viral illness from more concerning differentials such as orbital cellulitis, nephrotic syndrome, or allergic reactions. This report serves as a clinical reminder to include EBV in the differential diagnosis of atraumatic, bilateral eyelid swelling and to educate frontline providers on this underappreciated presentation.

Introduction

Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, infects over 90% of the global population by adulthood and is the most common cause of infectious mononucleosis (IM) ​ [1]. EBV is typically transmitted via oral secretions, and infection in adolescents and young adults often presents as a constellation of fever, sore throat, lymphadenopathy, fatigue, and atypical lymphocytosis​​ [1, 2]. While most cases follow a predictable clinical course, the spectrum of EBV-related manifestations is broad, including both systemic and localized complications. Less common presentations, such as ocular involvement, are increasingly being recognized in the literature​​ [2, 3].

Among these atypical findings, periorbital edema, known as Hoagland sign, has been described as a rare but notable early manifestation of EBV-induced IM. First reported in 1952, Hoagland sign is typically bilateral, painless eyelid swelling that occurs in the absence of conjunctival injection or visual disturbance [3, 4]. Although initially reported in up to one-third of cases, its current clinical prevalence appears much lower, and its diagnostic utility is often underappreciated​ [5]. Importantly, this sign may precede more classical features such as fever, sore throat, or cervical adenopathy, making early recognition particularly valuable [4, 6]. In a study of 26 serologically confirmed IM patients, Hoagland sign was observed in 14 (54%) and was more frequent than hepatosplenomegaly [7]. Pediatric cohorts also report variable rates, from 9% in a Western India series to higher proportions reported in Taiwan and Eastern India, underscoring differences in ascertainment and timing of examination [8–10].

Recent studies suggest a potential sex-based predilection for this finding, with women being disproportionately affected, raising the possibility of overlooked presentations in certain populations [5]. Prospective data showed a non-significant trend toward higher frequency among females, supporting sex-based differences while highlighting the need for larger samples [7]. Moreover, the pathophysiology behind this edema remains unclear, with proposed mechanisms ranging from lymphatic congestion to viral dacryoadenitis [2, 6]. Despite these observations, literature on this presentation remains limited, with fewer than 30 well-documented cases prior to 2023​ [3].

While the presence of bilateral periorbital edema, known as Hoagland sign, in EBV-induced IM is well documented in the medical literature, awareness among frontline providers remains limited. This lack of recognition can lead to misattribution of symptoms to allergies, nephrotic syndrome, or cellulitis, resulting in diagnostic delays, unnecessary treatments, and increased patient anxiety. This report highlights how improved provider familiarity with this clinical sign, particularly when it is the presenting or sole symptom, can facilitate more timely diagnosis, appropriate counseling, and avoidance of unnecessary interventions.

Case Report

Case One: Pediatric Presentation

A 13-year-old female presented to an ophthalmology clinic with 3 weeks of bilateral periorbital edema, fever, and headache. The patient had no changes in vision, eye pain or redness, and had intact extraocular movements with an otherwise normal ophthalmic exam (Fig. 1a). Prior to presentation, she was seen at an outside clinic where she was monospot negative and group A streptococcus (GAS) positive. Laboratory testing showed a white blood cell count of 13.9 K/μL (reference 4.0–10.5 K/μL) with 72% lymphocytes (25–46%), elevated transaminases with an Alanine aminotransferase (ALT) of 270 IU/L (3–37 IU/L) and an Aspartate aminotransferase (AST) 164 IU/L (20–50), and high triglycerides of 106 mg/dL (0–89 mg/dL). Creatinine, albumin, and urinalysis were within normal limits. Maxillofacial computed tomography scan (CT) demonstrated mild sinus disease throughout with bilateral preseptal edema, and nasal endoscopy uncovered strikingly enlarged adenoids. After beginning prescribed Augmentin, the patient reported improvement in eyelid swelling but continued fatigue and fever as well as a new facial rash (Fig. 1b). On exam, the patient had marked cervical lymphadenopathy without post-auricular lymphadenopathy, and a mild erythematous rash on the cheeks and lower face. There was no palpable splenomegaly, and abdominal imaging was not performed. Dilated fundus examination was normal, with no evidence of uveitis or retinitis. Differential diagnosis included periorbital cellulitis, angioedema, nephrotic syndrome, and infectious mononucleosis. The lack of erythema, eye pain, or visual changes made periorbital cellulitis less likely. The patient also lacks atopic features, and allergic angioedema would not explain the patient’s liver enzymes or lymphocytosis. While nephrotic syndromes should be suspected in patients with periorbital edema, the patient’s albumin and kidney function tests were within normal limits and urinalysis detected no proteinuria or hematuria. IM was suspected, necessitating comprehensive antibody testing for EBV, cytomegalovirus (CMV), adenovirus, and human herpesvirus 6 (HHV-6). EBV serology demonstrated elevated viral capsid antigen (VCA) IgM titers, consistent with acute primary infection, along with detectable VCA IgG, which may reflect recent or past exposure. Early antigen (EA) testing was not performed. These results, in combination with the clinical picture, confirmed the diagnosis of infectious mononucleosis. The patient’s symptoms improved with supportive care.

Case Two: Young Adult Presentation

A 22-year-old previously healthy female presented to her primary care physician with 1 week of constitutional symptoms including fatigue and mild bilateral periorbital edema (Fig. 2a). On examination, visual acuity was 20/20 in both eyes with normal confrontation visual fields. Extraocular movements were full, and there was no conjunctival injection, chemosis, or proptosis. The patient denied any subjective visual changes or eye pain. Dilated fundus examination revealed no signs of uveitis or retinitis. There was no reported abdominal pain or tenderness, and no palpable splenomegaly on clinical examination. Abdominal imaging was not performed, and there were no findings suggestive of splenic enlargement. There was no palpable cervical or post-auricular lymphadenopathy. She was initially advised that the edema was due to seasonal allergies and was managed conservatively with observation. However, as the periorbital swelling persisted and fatigue worsened, she was referred for telehealth evaluation with ophthalmology.

On recommendation of the consulting ophthalmologist, the patient presented to a local urgent care clinic requesting EBV serologies for suspected IM. However, the urgent care provider declined to order the test, citing unfamiliarity with the association between periorbital edema and IM. As symptoms continued, the patient re-presented several weeks later and was able to obtain laboratory testing at another facility.

Initial labs revealed a white blood cell count of 6.8 K/μL (reference 4.0–10.5 K/μL) with lymphocytes at 34% (25–46%) and mild eosinophilia at 7% (1–4%). Liver function tests were within normal limits, including ALT of 23 IU/L (3–37 IU/L) and AST of 18 IU/L (20–50 IU/L). Lipid panel revealed elevated cholesterol of 217 mg/dL (100–199 mg/dL) and triglycerides of 104 mg/dL (<150 mg/dL). Kidney function and urinalysis were unremarkable.

EBV serologies returned positive for VCA IgM and IgG, confirming a diagnosis of acute infectious mononucleosis. The patient was managed conservatively with supportive care including rest, fluids, and analgesics. Her periorbital edema and systemic symptoms resolved gradually over 2 weeks without complication (Fig. 2b).

Discussion

Both patients presented with periorbital edema as a key early feature of IM, yet in each case, this clinical clue was either overlooked or misattributed, leading to delayed testing or treatment paths inconsistent with their underlying viral illness. IM, colloquially referred to as the “kissing disease” as its transmission mainly occurs through oral secretions, classically presents with fever, pharyngitis, cervical lymphadenopathy, and fatigue [3, 6]. In larger cohorts of adolescents and young adults, fever and lymphadenopathy predominate while the prevalence of specific signs varies across settings [10, 11]. This variability likely contributes to underrecognition of Hoagland sign. In addition, the pediatric patient’s laboratory findings show mild elevation in white blood cell count with marked lymphocytosis, characteristic of viral infections such as EBV. EBV is the most common cause of IM [1]. During primary infection, EBV enters epithelial cells in the oropharynx and infects B cells leading to lymphocytosis [2]. This initial phase of infection has an incubation period of 4 to 6 weeks which commonly leads to false negative early heterophile antibody testing and should not automatically rule out IM in cases with classic signs [6]. A recent rapid evidence review and a diagnostic accuracy meta-analysis also emphasize timing effects on serology performance and the limited standalone value of individual signs and symptoms [12, 13]. Monospot may also be negative in cases of IM caused by atypical organisms such as CMV, adenovirus, and HHV-6.

The pediatric patient was prescribed Augmentin after testing positive for GAS and developed a facial rash, which is characteristic in IM patients after penicillin treatment. GAS positivity in patients with IM can be seen due to swelling of the adenoids trapping pre-colonized GAS and should not preclude a diagnosis of IM [14]. This distribution of rash raises concern for a parvovirus-B19-induced slapped cheek syndrome, but the full clinical picture points to IM as a more likely diagnosis for several reasons. IM causes liver dysfunction in over 80% of cases, as evidenced by this patient’s elevated liver function tests, which would not be explained by parvovirus or GAS [15]. In addition, her elevated triglycerides can be explained by EBV’s propensity for inducing fatty acid synthesis in newly-infected B cells [16].

The young adult patient’s case underscores the clinical blind spots that can arise when Hoagland sign is not widely recognized. Despite presenting with classic constitutional symptoms and bilateral periorbital edema, her symptoms were initially attributed to allergies, and a request for EBV testing was declined by an urgent care provider unfamiliar with this association. The absence of more dramatic laboratory abnormalities and normal liver function tests, potentially due to the timing of testing during the convalescent phase, further complicated her presentation. Nevertheless, serologic testing ultimately confirmed infectious mononucleosis. This delay highlights how under-recognition of Hoagland sign, especially in adult patients, may lead to diagnostic inertia, unnecessary frustration for patients, and missed opportunities for early reassurance and counseling.

A key finding in both cases is the patients’ early presentation with bilateral periorbital edema. The differential diagnoses of bilateral eyelid swelling are vast, including angioedema, contact dermatitis, orbital cellulitis, trichinosis, dermatomyositis, nephrotic syndrome, and IM, therefore a careful history is essential [4]. As outlined in the introduction, reported prevalence varies widely across cohorts, reflecting differences in timing of examination and care setting. These data support the assertion that eyelid edema is an early but underrecognized clue rather than a rare anomaly. Patients lack cardinal signs of inflammation which differentiates it from more emergent, vision threatening causes of periorbital edema that must be ruled out first, such as periorbital cellulitis. As in both patients, eyelid edema in IM is not associated with conjunctivitis, skin hyperemia, or vision changes and is temporary, lasting from days to weeks. The mechanism of edema is not well understood, but it has been hypothesized that nasopharyngeal replication of the virus may obstruct lymphatic drainage [3].

As seen in the second patient, even a direct request for EBV testing was initially declined due to unfamiliarity with the association between periorbital edema and IM. In the absence of classic symptoms, this finding is often misattributed to allergic reactions, nephrotic syndrome, or sinus-related issues, leading to unnecessary testing, inappropriate treatment, and patient anxiety. Integrating Hoagland sign into the differential diagnosis for atraumatic bilateral eyelid swelling, particularly in young women, can reduce diagnostic delays, avoid unnecessary antibiotics or imaging, and provide more accurate anticipatory guidance. Emphasizing this connection in medical education and primary care settings may bridge this knowledge gap and improve patient outcomes.

This report is limited by the inclusion of only 2 cases, which may not be representative of the broader spectrum of Hoagland sign presentations in infectious mononucleosis. The rarity of documented cases and the potential for selection bias, particularly as patients with subtle or transient eyelid edema may not seek ophthalmic evaluation, limit the generalizability of these observations. Larger case series or prospective studies would be valuable to further clarify the prevalence, demographic patterns, and clinical implications of this finding. Some recommendations, such as routine EBV testing based solely on periorbital edema, should be tempered given the small sample size and limited generalizability.

Hoagland sign presents early in the disease process and may be the only presenting complaint in both pediatric and adult patients. It is therefore imperative for clinicians to maintain a high index of suspicion for IM in patients with periorbital edema even with a negative monospot test.

These 2 cases illustrate the diagnostic complexity posed by atypical presentations of EBV IM. In both a pediatric and adult patient, bilateral periorbital edema emerged as an early, and in 1 case, the initial manifestation of disease, preceding or obscuring more classic symptoms. Although well-documented in the literature, Hoagland sign remains underrecognized in clinical practice. Improved awareness of this early manifestation of IM may reduce diagnostic delays and unnecessary interventions.

This report reinforces the need for heightened clinical awareness of this sign, particularly in patients with nonspecific systemic symptoms and negative initial serologic testing. Early recognition of periorbital edema in the context of IM may reduce diagnostic delays, prevent unnecessary imaging or antibiotic therapy, and support appropriate patient counseling, especially regarding activity restrictions and supportive care.

Statement of Ethics

This retrospective review of patient data did not require ethical approval in accordance with local guidelines. The protocol was reviewed, and the need for approval was not required by the Institutional Review Board at the University of North Carolina at Chapel Hill. Written informed consent was obtained for publication from all individuals featured in the report, including consent for the publication of clinical details and images. For the pediatric patient, consent was obtained from her legal guardian. Written informed consent was obtained from all participants for both their medical records and photographic documentation of their disease presentation for publication. Informed consent from patient one was obtained from her legal guardian, and in patient 2, directly from the patient. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000549142).

Conflict of Interest Statement

The authors have no relevant conflicts of interest to declare.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

Iden Amiri and Simran Ohri were responsible for manuscript writing and literature review. David Fleischman and Gitanjali Fleischman were responsible for reviewing and editing the manuscript.