Diagnosis and Discussion - Case 1124

Final Diagnosis

Spleen with infectious mononucleosis and laceration.

Discussion

Given the patient’s presentation, initial laboratory findings, and imaging studies, infectious mononucleosis was a strong diagnostic consideration. Furthermore, gross and microscopic evaluation of the spleen, in conjunction with ancillary studies, confirmed this diagnosis.

Infectious mononucleosis is a result of infection with Epstein-Barr virus (EBV), and less commonly cytomegalovirus (CMV) and other viruses.1 EBV or human herpesvirus 4 (HHV4) is a double-stranded DNA virus and it is part of the herpesviruses family.2,3 Route of transmission usually involves respiratory secretions and saliva.2,4 EBV establishes primary infection by replicating in oropharyngeal epithelial cells and resting B-cells.1,2 During the incubation period, cytotoxic T-cells along with natural killer cells (NK) are activated.1 This process results in cell-mediated immune response and the presenting symptoms of infectious mononucleosis.1,3 Secondary to the virus’ ability to escape the immune system recognition, it can progress to a latent stage within the circulating memory B-cells. 1,2 Then it can undergo multiple cycles of reactivation via differentiation of memory B-cells into plasma cells, which in turn induces virion amplification by lytic replication in epithelial cells, which shed the virus into mucosal secretions. 2,3 Primary B lymphocytes are infected when the EBV glycoprotein gp350/220 interacts with the CD21 surface receptor of B-cells. 2,3 Incubation period lasts approximately 4-6 weeks, after which initial symptoms develop, including fever, fatigue, pharyngitis/tonsillar exudate, anterior or posterior cervical lymphadenopathy, and hepatosplenomegaly. 4

In developing countries, by age 5-9, the majority (>90%) of children have already been exposed to EBV, almost twice as frequent of what is observed in developed countries (~50%).4 Around 83% of teenagers aged 18-19 years in the United States are considered to be positive for EBV, with only about one quarter developing symptoms.4 In these cases, most patients develop self-limiting disease, however there are rare cases where complications develop, such as hepatitis, splenic rupture, and severe tonsillar hypertrophy that can result in airway obstruction.1

Laboratory findings associated with infectious mononucleosis are lymphocytic leukocytosis and presence of atypical cytotoxic lymphocytes in peripheral blood smears. 1,5,6 These cells can be referred to as Downey-type cells, and have a characteristic abundant pale cytoplasm and deeply basophilic cytoplasmic rim that shows scalloping around surrounding erythrocytes. 5,7 They can also display cytoplasmic granules, indicative of a cytotoxic/suppressor T-cell or NK-cells.5 In cases of splenic rupture, a predominance of neutrophils instead of lymphocytes can be identified as a response of peritoneal irritation from the splenic hemorrhage, with reaction from the bone marrow in the form of neutrophilia prominent enough to obscure the pre-existing lymphocytosis.6 An elevation in liver enzymes and bilirubin can also be observed in cases with liver damage.1,7,8 Imaging usually reveals hepatosplenomegaly.1 Flow cytometric immunophenotypic studies are not routinely performed, however it can reveal a predominance of CD8-positive cytotoxic cells, with a decreased CD4 to CD8 ratio.7

Serologic diagnosis of EBV can be achieved by performing a series of tests. The first screening study is the Monospot test or heterophile antibody.1,8 This test identifies the presence of circulating antibodies by documenting agglutination of horse or sheep erythrocytes.9 It is important to note that the sensitivity and specificity of this test is 63-84% and 84-100%, respectively.1,8 Around 85% of patients with infectious mononucleosis will have a positive result, however in some cases the amount of antibodies might not be enough to reach the limit of detection.1 This happens often within the first 7 days of symptoms and accounts for approximately 25% of false-negatives during this period 1,7,8 There is a small proportion of patients that never develop positivity for a Monospot test.1 Another test that is useful during the acute phase of the disease is the EBV viral capsid antigen (VCA) IgM antibody test.1,8 Meanwhile, the EBV VCA IgG antibodies are usually identified indefinitely after infection.8 In cases of past or chronic infection, an EBV nuclear antigen (EBNA) IgG antibody can be performed.1 Another test that can be performed is EBV DNA copy number quantification by real-time polymerase chain reaction (qPCR), however a consensus on interpretation of detection in different compartments or quantitative thresholds is lacking.10

Macroscopic examination usually reveals an enlarged spleen without distinct nodules within the spleen parenchyma, however laceration and hemorrhage can be documented.11 Histologically, the spleen displays immunoblastic hyperplasia, lymphocytic vasculitis, red pulp expansion with activated T- and B-cells, and in cases of rupture, hemorrhage and laceration.11,12 Immunoblasts can be highlighted with an immunohistochemical stain for CD30 and CD45, with a polytipic pattern of kappa and lambda expression.11,13 The white pulp shows many reactive CD8-positive T-cells.11 Expression of EBV can be identified with in-situ hybridization studies.11

Management of uncomplicated infectious mononucleosis is generally focused on symptomatic relief (antipyretics, analgesics, and rest).1

One of the most severe—although rare—acute complications is splenic rupture.1,4 The incidence of this event ranges from 0.1-0.2% to 0.5%, and is usually observed within the first 21 days of symptom development.1,4,6,14 The mechanism of this complication is usually due to contact sports or trauma, which is why after diagnosis of infectious mononucleosis it is routinely recommended to avoid physical activity for 3-4 weeks after the onset of symptoms.1,4 The mechanism behind spontaneous splenic rupture is much less understood and should be considered when there is no history of trauma within the last 6 weeks.4,6,14 This event usually develops within 31 days of infection and only 7% of patients present within 7 days of infection.6 Various reports have identified triggers to this complication in association with increased abdominal pressure, including vomiting, coughing, defecation, and sneezing.4,14 Spontaneous splenic rupture has been observed more commonly in males and in patients younger than 35 years-old.6 Reported signs and symptoms include abdominal pain, left shoulder pain, and hypotension that could progress to hypovolemic shock.6 Management can be tailored depending on the degree of splenic injury, ranging from conservative therapies (splenic artery embolization) to more aggressive surgical management in severe cases. 4,6 Mortality rate associated with this complication is reported up to 22.7%, with an average of 8.3-9%.4,6 Some factors associated with increased mortality include age greater than 40 years, the presence of a neoplastic disorder, and identification of hepatosplenomegaly.6 After splenomegaly, there is increased susceptibility to encapsulated bacteria, as they cannot be properly opsonized and eliminated in the spleen.6 The most common culprits are Gram-positive diplococci (e.g. Streptococcus pneumoniae), Gram-negative diplococci bacteria (e.g. Neisseria meningitidis) and bacilli or coccobacilli (e.g. Haemophilus influenzae type b).6 Prophylactic vaccination and antibiotics can help reduce severe infections in these patients.6

Another complication that can develop is liver damage presenting as hepatitis with transient elevation of liver enzymes.1 Rare cases can present as liver failure.1 An additional complication is airway swelling with can result in obstruction in around 1-3.5% of cases.1 It is usually observed in young children and presents as stridor, cyanosis, and increased breathing rate.1 Management involves systematic steroids with significant results in the following 12-36 hours after administration.1,8

Additionally, EBV has been associated with autoimmune disorders, such as systemic lupus erythematous, rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome, and others. 1,6 Furthermore, EBV DNA has been identified in reportedly 2% of all malignancies in humans, including post-transplant lymphoproliferative disorders (PTLDs), Hodgkin lymphoma, diffuse large B-cell lymphomas (DLBCL), T-cell lymphoma, NK cell leukemia, nasopharyngeal carcinoma, gastric adenocarcinoma, and breast carcinoma, among others.1,2

Current studies regarding the development of a vaccine have been generally successful in preventing infectious mononucleosis, but failing to prevent EBV infection.1,3

This young female patient presented with a case of spontaneous splenic rupture secondary to infectious mononucleosis within 4 days of symptom development, a rare but serious complication of EBV infection. She additionally developed hepatitis with elevation of liver enzymes. Serology tests and peripheral blood smear were consistent with an acute infection, and notably the Monospot test was falsely negative, a finding that can be observed within the first few days of infection. Given the significant concern for hemodynamic compromise, she was managed with splenectomy, after which she recovered without incidents and was discharged home. EBV infection is an exceedingly common infection worldwide, and although infrequent, spontaneous splenic rupture is an important complication that can ensue after acute infection and should be identified and managed promptly to avoid catastrophic results.

References

  1. Fugl, A., Andersen, C.L. Epstein-Barr virus and its association with disease - a review of relevance to general practice. BMC Fam Pract 20, 62 (2019). https://doi.org/10.1186/s12875-019-0954-3
  2. Yu, H.; Robertson, E.S. Epstein–Barr Virus History and Pathogenesis. Viruses 2023, 15, 714. https://doi.org/10.3390/v15030714
  3. Rühl, J., Leung, C.S. & Münz, C. Vaccination against the Epstein–Barr virus. Cell. Mol. Life Sci. 77, 4315–4324 (2020). https://doi.org/10.1007/s00018-020-03538-3
  4. Frank, EA., LaFleur, JR., Okosun, S. Nontraumatic Splenic Rupture due to Infectious Mononucleosis. J Acute Care Surg. 2019;9(2):69-71.   Published online October 30, 2019 DOI: https://doi.org/10.17479/jacs.2019.9.2.69
  5. Foucar K, Reichard K, Czuchlewski D. Bone Marrow Pathology. 3rd ed. Chicago: ASCP Press; 2010.
  6. Tchouankeu S, et al. Spontaneous Spleen Rupture: An Unexpected Consequence of Infectious Mononucleosis - A Case Report. Front Med Case Rep 2020; 1(5): 1-10.
  7. Karcheva, M. et al. Infectious Mononucleosis – Diagnostic Potentials. Journal of IMAB. 1,9-13 (2008)
  8. Kinderknecht, James J. MD. Infectious Mononucleosis and the Spleen. Current Sports Medicine Reports 1(2):p 116-120, April 2002.
  9. Virella, G. (Ed.). (2019). Medical Immunology, 7th Edition (7th ed.). CRC Press. https://doi.org/10.1201/9780429278990
  10. Kanakry JA, et al. The clinical significance of EBV DNA in the plasma and peripheral blood mononuclear cells of patients with or without EBV diseases. Blood. 2016 Apr 21;127(16):2007-17. doi: 10.1182/blood-2015-09-672030. Epub 2016 Jan 7. PMID: 26744460; PMCID: PMC4841041.
  11. Siliézar MM, et al. Spontaneously Ruptured Spleen Samples in Patients with Infectious Mononucleosis Analysis of Histology and Lymphoid Subpopulations. Am J Clin Pathol 2018;150(4):310-7.
  12. Kojima M, et al. Epstein-Barr virus-associated B-cell lymphoma of the spleen resembling infectious mononucleosis morphologically. Leuk Lymphoma. 2012 Dec;53(12):2504-6. doi: 10.3109/10428194.2012.685167. Epub 2012 May 21. PMID: 22506563.
  13. Louissaint, A., Ferry, J., Soupir, C. et al. Infectious mononucleosis mimicking lymphoma: distinguishing morphological and immunophenotypic features.Mod Pathol 25, 1149–1159 (2012). https://doi.org/10.1038/modpathol.2012.70
  14. Won AC, Ethell A. Spontaneous splenic rupture resulted from infectious mononucleosis. Int J Surg Case Rep. 2012;3(3):97-9. doi: 10.1016/j.ijscr.2011.08.012. Epub 2011 Oct 1. PMID: 22288057; PMCID: PMC3267253.