Le Infezioni in Medicina, n. 3, 369-372, 2024
doi: 10.53854/liim-3203-11
ORIGINAL ARTICLES
Comparative Clinical Characteristics of Cytomegalovirus and Epstein-Barr Virus Mononucleosis in Immunocompetent Hosts: Experience from a Tropical Setting
Dheeraj Mohan1, Vettakkara Kandy Muhammed Niyas1, Rajalakshmi Arjun1, Alan Francis James2
1Department of Infectious Diseases, KIMSHEALTH, Thiruvananthapuram, Kerala, India;
2Department of Internal Medicine, KIMSHEALTH, Thiruvananthapuram, Kerala, India
Article received 19 June 2024, accepted 12 August 2024
Corresponding author
Vettakkara Kandy Muhammed Niyas
E-mail: niyas987@gmail.com
SummaRY
Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV) are herpesviruses that cause different clinical syndromes depending on the host’s immune status. EBV is known for causing infectious mononucleosis (IMN), which presents with fever, pharyngitis, cervical lymphadenopathy, and atypical lymphocytes. CMV can also cause a mononucleosis syndrome with similar symptoms but is less frequently reported. Comparative studies on IMN and CMV mononucleosis from India are rare. This study aimed to elucidate the clinical characteristics of IMN and CMV mononucleosis in a South Indian tertiary care center, emphasizing the differences in their presentations. A retrospective analysis using Electronic Medical Records (EMR) from a tertiary care hospital at Thiruvananthapuram, Kerala, was conducted, including patients diagnosed with IMN or CMV mononucleosis based on clinical and serological tests during 2017 to 2023. Immunocompromised patients were excluded. The study compared demographic, clinical, and laboratory characteristics between the two groups. Out of 136 IMN cases and 17 CMV mononucleosis cases, the CMV group had a significantly higher median age (34.0 years) compared to the IMN group (20.0 years). The CMV group experienced a longer duration of fever (median 14.0 days) compared to the IMN group (5.0 days). Sore throat, cervical lymphadenopathy, and tonsil enlargement were significantly less common in CMV cases. The study concludes that CMV mononucleosis is more likely in older adults with prolonged fever and an absence of sore throat, tonsillitis, or cervical lymphadenopathy.
Keywords: Epstein-Barr Virus, Cytomegalovirus, Infectious Mononucleosis, Mononucleosis syndrome, Herpesviruses.
INTRODUCTION
The herpesviruses Epstein-Barr Virus (EBV) and Cytomegalovirus (CMV) cause distinct clinical syndromes based on the immune status of the host. EBV is well-known for causing infectious mononucleosis (IMN), which is characterized by fever, pharyngitis, cervical lymphadenopathy, and atypical lymphocytes in the peripheral smear [1, 2]. CMV, although less commonly reported, can also lead to a mononucleosis syndrome with similar clinical presentations [3]. While the clinical features of IMN and CMV mononucleosis are well documented in the literature, there is a noticeable lack of studies from India. IMN and CMV mononucleosis are overlooked as causes of acute febrile illnesses in patients in tropical countries. To the best of our knowledge, no study has directly compared the clinical features of IMN and CMV mononucleosis in this region. The aim of our study is to elucidate the clinical characteristics of IMN and CMV mononucleosis presenting to a tertiary care center in south India, with a particular emphasis on the differences between their clinical presentations.
PATIENTS AND METHODS
An Electronic Medical Record (EMR)-based retrospective analysis of Cytomegalovirus (CMV) mononucleosis and Infectious Mononucleosis (IMN) diagnosed at KIMSHEALTH, a tertiary care hospital in Thiruvananthapuram, Kerala (India) during 2017 to 2023 was conducted. The diagnosis of IMN was established if all the following criteria were met:
1) febrile illness,
2) peripheral total lymphocyte count ≥5000 cells/µL and/or atypical lymphocyte number ≥10% total lymphocytes,
3) presence of IgM antibodies against viral capsid antigen (VCA).
A diagnosis of CMV mononucleosis was made if all the following criteria were met:
1) febrile illness,
2) peripheral total lymphocyte count ≥5000 cells/µL and/or atypical lymphocyte number ≥10% total lymphocytes,
3) presence of IgM antibodies against CMV.
Patients who tested positive for both IgM viral capsid antigen and IgM CMV, and those with an alternate diagnosis were excluded from the study. We excluded patients who were immunocompromised and those who were on immunosuppressive drugs. Clinical and laboratory characteristics were compared between the two groups. Both clinical and ultrasound findings were used to assess hepatomegaly and splenomegaly. All categorical variables were expressed as counts and percentages (n, %), and all continuous variables were expressed as medians with interquartile ranges (IQR). The Chi-square test was used for the analysis of categorical variables, and the Mann-Whitney U test was employed for continuous variables.
RESULTS
One-hundred-thirty-six cases of IMN and seventeen cases of CMV mononucleosis that satisfied the diagnostic criteria was included in this study. Among the 136 cases of IMN, 102 were inpatients and 34 were outpatients, while among the 17 CMV cases, 9 were inpatients and 8 were outpatients. In the comparative analysis of clinical and laboratory characteristics between patients with Cytomegalovirus (CMV) mononucleosis and Infectious Mononucleosis (IMN), significant differences were observed (Table 1). The median age was significantly higher in the CMV group (34.0 years) compared to the IMN group (20.0 years) (P<0.001). 76.5% of patients with CMV mononucleosis was more than 30 years in age, while only 11.7% of EBV cases were in this age group. The proportion of male patients was also higher in the CMV group (76.5%) than in the IMN group (47.1%) (P=0.042). The duration of fever was notably longer in the CMV group, with a median of 14.0 days, compared to 5.0 days in the IMN group (P=0.001). Sore throat was significantly less common in the CMV group (11.8%) versus the IMN group (58.8%) (P=0.001). Cervical lymphadenopathy and tonsil enlargement were markedly less frequent in the CMV group (5.9% each) compared to the IMN group (64.7% and 55.1%, respectively) (P<0.001 for both). Splenomegaly and hepatomegaly did not show significant differences between the groups. Laboratory findings revealed lower median Total Leukocyte Count (TLC) and Absolute Lymphocyte Count (ALC) in the CMV group (10300 and 7319 cells/µL, respectively) compared to the IMN group (13450 and 8300 cells/µL, respectively) (P=0.017 and P=0.032). Aspartate Aminotransferase (AST) levels were significantly lower in the CMV group (59.00 IU/L) compared to the IMN group (101.00 IU/L) (P=0.023), while Alanine Aminotransferase (ALT) levels did not differ significantly. The month-wise distribution of both infections is illustrated in Figure 1. Neither infection showed any significant seasonal predilection. No anti-viral agents were used in any of the patients and there was no mortality in both groups.
Table 1 - Comparative Clinical and Laboratory Characteristics Between Patients with Cytomegalovirus (CMV) Mononucleosis and Infectious Mononucleosis (IMN). All categorical variables expressed as n%. All continuous variables expressed as median IQR.
Figure 1 - Month wise distribution of IMN and CMV mononucleosis during 2017 to 2023.
DISCUSSION
CMV mononucleosis is usually suspected when testing of antibodies against EBV (heterophile antibody tests or IgM VCA) is negative. Our study shows that there are differences in clinical presentation that should raise the possibility of CMV as the cause of mononucleosis at the outset. In our study CMV mononucleosis occurred at a higher age compared to IMN (median age of presentation 34 vs 20 years). Previous studies have shown a similar finding, with maximum occurrence at 24 years in a review of published cases by Evans in 1978 [4]. 45% of CMV cases were aged more than 30 years in this review, compared to 76.5% in our study. We also observed that 76.5% of CMV mononucleosis cases were men. Such a sex difference was not noted in previous studies [4, 5].
Prolonged duration of fever in CMV mononucleosis compared to IMN observed in our study is well described in literature [6, 7]. As per our findings, absence of sore throat, tonsillitis and cervical lymphadenopathy favor CMV mononucleosis over IMN in a patient with mononucleosis syndrome. In a report of 82 cases by Horwitz et al, only 17.1% of cases of CMV mononucleosis had cervical lymphadenopathy while sore throat/pharyngitis was present in 30.1% of the cases [5]. Tonsillitis was uncommon (6%) in the study by Cohen et al., whereas cervical lymphadenopathy was noted in 28% of cases [8]. Lymphadenopathy occurs more commonly in pediatric cases of CMV mononucleosis compared to adults, as per previous studies [9, 10].
Absolute lymphocytosis and presence of atypical lymphocytes in peripheral smear occurs in both IMN and CMV mononucleosis. Though we observed that the total leucocyte count and absolute lymphocyte count is significantly higher in IMN compared to CMV mononucleosis, it’s unlikely that these parameters will help in clinical differentiation of the two syndromes. Hepatic transaminase elevation is also common in both diseases. In our study statistically significant differences in AST values was noted, with IMN patients having higher values.
Most patients with CMV mononucleosis and IMN improve without any specific anti-viral treatment. No antivirals were used in any of our patients. There has been reports of successful treatment of severe CMV infections in immunocompetent patients with ganciclovir and foscarnet [11]. Studies have failed to show any clear benefit of antiviral agents like acyclovir in IMN, including patients with severe disease [12].
Our study provides valuable insights into the distinct clinical characteristics of CMV mononucleosis and IMN in an Indian population. However, it is limited by the retrospective design and limited number of CMV mononucleosis cases.
CONCLUSIONS
Though both IMN and CMV have overlapping clinical features, CMV mononucleosis is more likely in patients with mononucleosis syndrome presenting at a higher age, with prolonged fever, and without sore throat, tonsillitis, or cervical lymphadenopathy when compared to IMN.
Acknowledgements
We thank StatSolutions India for their help in statistical analysis and data visualization.
Conflicts of interest
None to declare.
Funding
None to declare.
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