Cytomegalovirus Mononucleosis

Cytomegalovirus mononucleosis presentation is indistinguishable from mononucleosis caused by Epstein-Barr virus (EBV) apart from several details discussed later. Mononucleosis manifests chiefly in young children and adolescents who had no prior immunocompromising diseases [2].

Presentation in this disease roughly consists of a triad of fatigue, fever, and lymphadenopathy. Fatigue, although a subjective symptom, is very well documented in the literature [1] [2]. Fever up to 40.9°C can last for more than a week. Lymphadenopathy in CMV mononucleosis does not only affect cervical lymph nodes, but also involves mesenteric nodes. Patients present with abdominal pain due to these enlarged nodes along with hepatomegaly and splenomegaly. Swelling of the eyelids follows cervical lymphadenopathy with a disturbance of blood flow in the facial area [2].

To differentiate the mononucleosis caused by CMV from that caused by EBV, physicians must primarily seek immunologic evidence. Although, some features of presentation can help to distinguish the two conditions. CMV is thought to provoke larger mesenteric lymphadenopathy and swelling of the eyelids. Likewise, a skin rash commonly develops due to a reaction of complement fixing antibodies (for which CMV is responsible) to antibiotics [3]. The rash can be macular, papular, maculopapular or similar to the rubella rash [4]. To confirm a rash caused by CMV, a use of antibiotics has to be documented and possible prior causative agents excluded from history [2].

Additionally, sore throat, inflamed and hypertrophied tonsils with possible purulent plaques, and hyperemic pharynx is often documented on examination [2] [5].

Cytomegalovirus mononucleosis can be diagnosed by detecting IgM or IgG antibodies to CMV. Reagents for immunoglobulin precipitation tend to be expensive and an algorithm of immunological testing was proposed by Tsaparas et al [6]. It is based on exclusion and suggests that:

1. Firstly, an assessment of heterophile antibodies (monospot test) must be made. Heterophile antibodies are present in EBV infection and mostly negative in CMV and other causative agents. Hence positive results exclude CMV.
2. Lymphocytosis or more than 10% of atypical lymphocytes are pathognomic for either EBV or CMV, and exclude HIV as the causative agent.
3. Negative serology for EBV-specific IgM antibodies excludes EBV.
4. If EBV IgM is negative, then specific IgM for CMV will either confirm CMV or exclude it.
5. If CMV IgM serology is negative, there should be a suspicion of toxoplasmosis, hepatitis A, B, C or herpesvirus 6 mononucleosis.

Other tests for providing evidence is pp65 phosphoprotein antigen detection and polymerase chain reaction (PCR) in qualitative or quantitative modality. Pp65 method is proposed to be very accurate, efficient, and overall a cost-effective test [7].

Blood analyses comprises of a complete blood count with findings of leukopenia (that is more common in CMV infection) or lymphocytosis. Also, atypical lymphocytes or virocytes are sought as they are pathognomic for mononucleosis [2] [8]. Thrombocytopenia is not a common finding in a mononucleosis patient but is seen more frequently in CMV rather than EBV infection [2] [9].

Ultrasonography is useful in monitoring abdominal organ enlargement, specifically spleen, liver, and mesenteric lymph nodes [2].

In CMV mononucleosis aspartate and alanine transaminases are elevated and should be monitored for a possible liver damage [10].

1. Cengiz AB, Cultu-Kantaroğlu O, Seçmeer G, Ceyhan M, Kara A, Gürgey A. Infectious mononucleosis in Turkish children. Turk J Pediatr. 2010; 52(3):245-54.
2. Medović R, Igrutinović Z, Radojević-Marjanović R. Clinical and laboratory differences between Epstein–Barr and cytomegalovirus infectious mononucleosis in children. Srp Arh Celok Lek. 2016 Jan-Feb; 144(1-2):56-62.
3. Klemola E, Von Essen R, Henle G, Henle W. Infectious-mononucleosis-like disease with negative heterophil agglutination test. Clinical features in relation to Epstein-Barr virus and cytomegalovirus antibodies. J Infect Dis. 1970 Jun; 121(6):608-14.
4. Cohen JI, Corey GR. Cytomegalovirus infection in the normal host. Medicine (Baltimore). 1985 Mar; 64(2):100-14.
5. Balasubramanian S, Ganesh R, Kumar JR. Profile of EBV associated infectious mononucleosis. Indian Pediatr. 2012; 49(10):837-8.
6. Tsaparas YF, Brigden ML, Mathias R, Thomas E, Raboud J, Doyle P. Proportion positive for Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, Toxoplasma, and human immunodeficiency virus types 1 and 2 in heterophile-negative patients with an absolute lymphocytosis or an instrument-generated atypical lymphocyte flag. Arch Pathol Lab Med. 2000;124:1324–30.
7. Franco RF, Montenegro RM, Machado AB, Paris F, Menezes DS, Manfro RC. Evaluation of diagnostic tests for cytomegalovirus active infection in renal transplant recipients. J Bras Nefrol. 2017 Mar; 39(1):46-54.
8. Balasubramanian S, Ganesh R, Kumar JR. Profile of EBV associated infectious mononucleosis. Indian Pediatr. 2012; 49(10):837-8.
9. Son KH, Shin MY. Clinical features of Epstein–Barr virus-associated infectious mononucleosis in hospitalized Korean children. Korean J Pediatr. 2011; 54(10):409-13.
10. Van den Bruel A, Thompson MJ, Haj-Hassan T, et al. Diagnostic value of laboratory tests in identifying serious infections in febrile children: systematic review. BMJ. 2011; 342:d3082.