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Dental Pain and a Rash

Case

A 6 year-old otherwise healthy male presented to the emergency department accompanied by his parents. They note that 5 days prior to presentation, the patient developed a rash on his legs which was described as multiple “small red dots” with no other associated symptoms. On further history, they state that they just returned from a hiking vacation to Pennsylvania. While on vacation, one of the patient’s teeth, which had previously been loose, fell out. The family noticed prolonged bleeding and oozing at the site of the lost tooth and swelling of the gums over the next day and a half.  They also noted that the patient was progressively fatigued, developed a low-grade fever, and had more bruising than expected on his legs after hiking. He was seen at an urgent care in Pennsylvania one day prior to presenting to the emergency department and was started on amoxicillin for presumed dental infection. The concerned family presented to the emergency department as the patient was still fatigued, continued to have persistent bruising, and the rash had spread onto his torso and back.

The patient lived at home, in a wooded area, with his parents and 3 other siblings, and was up to date on all his vaccinations. There were no reported sick contacts and family cannot recall any tick bites.  

 Review of Systems:

Constitutional: decreased appetite, fatigue, irritability, no weight change

HENT: dental pain, swollen gums, recent dental bleeding following tooth loss, halitosis

Skin: pallor, petechial rash, bruising

Heme: fatigue, easy bruising/bleeding, lymphadenopathy

All others negative.

Physical Exam:

Vitals: BP 95/59, HR 134, Temp 99.9 F (37.7 C), RR 22, Weight 23.5 kg, SpO2 97%

Constitutional: awake and cooperative, pale, fatigued, but nontoxic

HEENT: conjunctival pallor, tonsillar and posterior oropharyngeal exudates, halitosis, minimal gum line swelling, stable clot at site of recently lost tooth, cervical, axillary, and possible supraclavicular lymphadenopathy, full range of motion of neck, normal voice

CV: tachycardic regular rhythm, no murmurs, strong pulses

Resp: lungs clear, no respiratory distress, normal work of breathing

Abd: soft, nontender, nondistended, borderline large spleen

MSK: normal ROM all extremities, no difficulty with ambulation, no joint swelling

Neuro: awake, normal gait and coordination, preserved strength all extremities

Skin: cap refill < 3sec, scattered petechiae across legs, posterior thighs, torso, face, back; multiple bruises noted on lower extremities, small bug bite on posterior right shoulder with minimal surrounding erythema

Labs:

Lab work-up, including CBC, BMP, LFTs, UA were significant for a leukocytosis to 14.0, anemia to 10.2, and thrombocytopenia, with a platelet count of 17. The CBC differential also identified 24.0% atypical lymphocytes in the sample. Rapid strep and heterophile antibody tests were negative. LDH levels were elevated to 613.

Imaging:

And then a single test was ordered that revealed the diagnosis…

Definitive Test

EBV viral titers. IgM resulted as >4.0, which indicates a strongly positive test.

Diagnosis

EBV mononucleosis. However, the differential for this case is quite broad, including CMV, acute HIV, viral illness, leukemia, lymphoma, tick borne illness, and immune thrombocytopenia (ITP).

Discussion

This disease process was first described in 1885 as “glandular fever,” given is predilection for causing swelling of the lymph nodes. It was subsequently renamed infectious mononucleosis in the 1920’s, and a decade later the heterophile antibody was discovered. Further research in the 1960’s determined that Epstein Barr Virus (EBV) is the main culprit behind infectious mononucleosis. The virus itself is highly prevalent – 50% of persons are carriers by age 5 and 90% by age 25. While EBV is the most common cause of infectious mononucleosis, other viral entities such as CMV, HIV, adenovirus, human herpes virus 6, hepatitis A/B/C, and herpes simplex virus 1/2 can be causative agents.

Patients with infectious mononucleosis can most easily be identified by the classic triad of fever (up to 10 days), exudative pharyngitis, and lymphadenopathy. Other symptoms include fatigue (lasting weeks), loss of appetite, headache, nausea, abdominal discomfort in the left upper quadrant near the spleen, and rash. These symptoms and exam findings are highly variable between patients and tend to vary greatly by age group, making diagnosis more challenging.  Pediatric patients are more likely to present with splenic enlargement, rash, and even some atypical symptoms such as failure to thrive (infants), otitis media, and URI-like symptoms. In contrast, adult patients are more likely to complain of headache, fatigue, and tend to have more significant laboratory abnormalities.

Hematologic abnormalities expected in infectious mononucleosis include moderate leukocytosis (10 - 25,000) with a lymphocytic predominance (about 50%) and atypical lymphocytes (>10%). Some patients (25-50%) will develop a mild thrombocytopenia and almost all adult patients will have slight elevations in their liver function tests (LDH, AST, alkaline phosphatase, bilirubin).

Many providers will use the Monospot or heterophile antibody test as a way to rapidly evaluate for infectious mononucleosis; this test is a latex agglutination assay that detects IgM antibodies against the EBV viral coat which happen to cross react with antigens present on sheep and horse red blood cells. These assays have been found to have sensitivities between 81-90% and specificities between 98-100%. Unfortunately, the clinical utility of this test is highly dependent upon the patient population in which it is being used. Multiple studies (albeit with conflicting results and of admittedly poor quality) have demonstrated that pediatric populations tend to manifest a weak heterophile response which results in many false negative tests. One study cites a response rate of 5% for children under 2 years of age, 50% for ages 2-3, and 80% for those 4 and older.  Another study estimated a 38% response rate for children under 13, as compared to  86% in those older than 13. While the exact numbers are unknown, it is important for the clinician to be aware that child may have false negative heterophile tests. If there is enough clinical suspicion for the disease in the setting of a negative heterophile test, EBV viral titers (IgG, IgM, early antigen, nuclear antigen) should be ordered.

The management of infectious mononucleosis is largely supportive care and symptomatic treatment. Oral steroids may help with the discomfort from the pharyngitis, though there is no demonstrated effect on the duration of illness. Multiple studies have looked at the role of antiviral medications, acyclovir and valacyclovir, but none have demonstrated a clinically meaningful difference. Traditionally, it has been recommended that patient’s with infectious mononucleosis refrain from contact sports and settings where they may sustain blunt abdominal trauma for 21 days from time of diagnosis due to the risk of splenic rupture.

The profound thrombocytopenia (platelets <50k) seen in this case is a rare complication of infectious mononucleosis. It can occur in up to 0.5% of adults and 1-2% of children, but the true incidence has been difficult to identify as the literature on the topic largely consists of case reports. The mechanism is thought to be a peripheral process due to splenic sequestration or an immune mediated process. While there are no clear guidelines for management, some suggest treating similarly to ITP and considering the use of steroids. Fortunately, most patients will recover spontaneously.

Case resolution

 The patient was admitted to the hematology/oncology service at the pediatric hospital for further management. His peripheral smear was confirmed by pathology to contain only atypical lymphocytes without evidence of blast cells. Over the next two days his platelet counts began to spontaneously recover and he was discharged home.  

Take Aways

  • The presentation of infectious mononucleosis differs in the adult and pediatric populations.

  • The heterophile antibody (Monospot) test can be falsely negative in the pediatric population (particularly for patients under the age of 13), and if a clinical suspicion remains, viral titers should be sent.

  • The management of infectious mononucleosis is largely supportive and care should be taken to avoid contact sports and high risk activity to minimize the risk of splenic rupture for 3 weeks from initial presentation.

 Faculty Reviewer: Dr. Shideh Shafie


References

  1. Jenson HB. Epstein-Barr virus. In: Detrick B, Hamilton RG, Folds JD, eds. Manual of Molecular and Clinical Laboratory Immunology. 7th ed. Washington, DC: American Society for Microbiology; 2006:637–647

  2. Walter, R., Hong, T. and Bachli, E. (2002) ‘Life-threatening thrombocytopenia associated with acute Epstein-Barr virus infection in an older adult’, Annals of Hematology, 81(11), p. 672. doi: 10.1007/s00277-002-0557-1.

  3. Michele L. Pipp, Norman D. Means, John W. Sixbey, Kimberly L. Morris, Crystal L. Gue, Larry M. Baddour, Acute Epstein-Barr Virus Infection Complicated by Severe Thrombocytopenia. Clinical Infectious Diseases. Volume 25, Issue 5, November 1997, Pages 1237–1239,

  4.  James G. Marks, Jeffrey J. Miller, in Lookingbill and Marks' Principles of Dermatology (Sixth Edition), 2019

  5. Grimm J. Is infectious mononucleosis a pediatric disease?. Med J DY Patil Univ.
    2017;10:445-6.

  6. Richard J. Schaller, Francis L Counselman. Infectious mononucleosis in young children. Volume 13, Issue 4, July 1995, Pages 438-440

  7.  DynaMed [Internet]. Ipswich (MA): EBSCO Information Services. 1995 - . Record No. T114945, Epstein-Barr Virus-associated Infectious Mononucleosis; [updated 2019 Jul 30, cited September 27, 2019]