Dilemma of decoding a difficult fever

Pushkala Mittur Sundararajan*

Department of Paediatrics, Kauvery Hospital, Chennai, Tamilnadu, India

*Correspondence: Email: lakshmisundararajan@gmail.com

Abstract

Background: Infectious mononucleosis (IM) is a self-limiting illness usually caused by Epstein–Barr virus (EBV).

Case presentation: A 13-year-old previously healthy adolescent presented with a prolonged highgrade fever, lethargy, pharyngotonsillitis and hepatosplenomegaly. Investigations done were inconclusive. His presentation mimicked a bacterial infection. However, his illness persisted and worsened despite appropriate antibiotic therapy. Finally, a serological test was done which was strongly positive for EBV infection. The antibiotics were stopped and he recovered with symptomatic management without any complications.

Conclusion: Infectious mononucleosis is characterized by fever with a triad of pharyngitis, hepatosplenomegaly and lymphadenopathy. Presence of unusual findings may be misleading resulting in a delayed or wrong diagnosis. Early recognition and awareness are important to avoid inappropriate usage of antibiotics and to prevent complications.

Keywords: Epstein–Barr virus, Infectious mononucleosis (IM), Viral capsid antigen (VCA), Pharyngitis, Hepatosplenomegaly

Background

Infectious mononucleosis is characterized by pharyngitis, fever and lymphadenopathy [1]. Prolonged illness [2], complications like myocarditis, nephritis, pneumonia, thrombocytopenia, meningitis [3] and long-term sequelae, such as acute lymphocytic leukaemia and malignant lymphoma have been reported [4,5]. Awareness is essential to avoid complications. Here, we present one such challenging case.

Case Presentation

A 13-year-old male presented with high-grade, intermittent fever of ten days along with headache, throat-ache and lethargy. He had a normal birth, immunisation and developmental history. He had a past history of vesicouretric reflex (bilateral) which resolved with antibiotic prophylaxis. He lives in a joint family. The grandfather was hospitalized twice in the last two months, initially for COVID-19 infection. He recovered but subsequently developed an unknown fever. His liver enzyme levels were deranged but cause of the fever remained a mystery. On examination he was febrile, bilateral acute otitis media (+), congested throat (+), hepatosplenomegaly (+). No other palpable nodes, rhinitis, cough, conjunctivitis, rashes, weight loss, pallor or appetite loss (Table 1).

Table 1. Correlation of the anthropometric variables of the child.

Observed Expected Percentile Percentage (%)
Weight 33.5 kg 43 kg 5 – 10th 77
Height 152.5 cm 155 cm 25 – 50th 98
Body mass index 14.4 kg/m2 18.5 – 24.9 - -

Course

He was started on amoxicillin along with supportive measures. Three days later, he remained febrile. On examination he had bilateral acute otitis media, exudative tonsillitis and bilateral painful jugulodigastric lymph nodes. Hepatosplenomegaly regressed. His counts were repeated (which were normal) and liver function tests were elevated. His dengue serology IgM was positive. A throat swab was done and antibiotics stepped up to cephalexin. After 72 hours, his fever and lethargy increased while activity and oral intake reduced. His urine output was borderline. He was febrile, ill looking, otitis media, exudative and follicular tonsillitis along with lymphadenopathy worsened. His counts and smear were normal and liver function tests still elevated. The throat swab showed Acinetobacter. As his clinical condition had worsened, he was advised admission.

Diagnostic dilemma?

  1. Exudative tonsillitis with painful lymphadenopathy unresponsive to antibiotics.
  2. History of VUR in the past – recurrence of urinary tract infection.
  3. Dengue IgM positive.
  4. Acinetobacter in throat.
  5. Hepatosplenomegaly regressed but fever persisted.

Based on the clinical suspicion, an IgM to viral capsid antigen of Epstein–Barr virus was done which was strongly positive. Rapid streptococcal antigen test was negative. The cultures were negative. A USG abdomen showed few mesenteric nodes. The antibiotics were stopped. Acinetobacter in the throat swab was considered a contaminant.

The fever subsided on Day 20 with symptomatic treatment. He was discharged. His liver function test was repeated after 15 days which normalised (Table 2).

Table 2. Investigative profile of the patient.

S.No. Investigation 21.10.2020 24.10.2020 27.10.2020 27.10.2020
1 3Complete blood count
Hemoglobin 13.4 13.3 13.0
PCV 38.8 38.1 37.7
WBC 10100 10100
Differential counts
Polymorphs 78.1 28
Lymphocytes 10.6 67
Monocytes 10.2 10
Eosinophils 0.6 0.3
Basophils 0.7 0.2
RBC count 4.63 4.6
MCV 83.7 82
MCH 28.9 28.3
MCHC 34.5 34.5
Platelets 203000 250000 240000
2 Liver function test
SGOT 126.1 135 22.87
SGPT 157.8 131 30.56
3 Renal function test
Urea 18.9
Creatinine 0.53
Uric acid 5.20
Calcium 9.42
Phosphate 4.08
4 Electrolytes
Sodium 139.3
Potassium 4.03
Chloride 101.8
Bicarbonate 23.5
5 C-reactive protein 13.65 15
WIDAL (Day 10 of fever) -
6 Dengue
NS1 antigen -
IgM +**
IgG -
7 Urine routine
Colour Yellow
Appearance Turbid
pH 5.5
Specific gravity 1.030
Urine glucose -
Urine phosphorous -
Urine ketones -
Bilirubin -
Urobilinogen 0.2
Urine nitrate -
Pus cells 1 – 3
Epithelial cells Occasional
RBC Nil
Casts Nil
Crystals
Uric acid crystals 8 – 10
8 Peripheral smear
RBC Normocytic Normocytic
normochromic normochromic
anaemia anaemia
WBC Normal in
number Reactive
morphology and distribution lymphocytes (+)
Platelets Adequate Adequate
Malarial
parasites No atypical cells or blast cells
negative
9 USG abdomen Few mesenteric lymph nodes in the right iliac fossa Splenomegaly 11.9 cm
10 RT–PCR for COVID19 (–)
11 COVID antibody Both IgG and IgM (–)
12 Throat swab for culture and sensitivity Acinetobacter sensitive to piperacillin and tazobactum, vancomycin, and cefaperazone sulbactum
13 Rapid streptococcal antigen detection test -
14 IgM to VCA of EBV Strongly positive, result > 5.5 Negative (< 0.8)
15 Urine culture and sensitivity No growth
16 Blood cultures No growth

–*: Negative, +**: Positive

Discussion

Infectious mononucleosis is caused by Epstein–Barr virus in 90% and cytomegalovirus in 5 –10% of cases. In infants and young children, it is either asymptomatic or mild. Approximately 50% of adolescents present with moderate symptoms [6]. Tonsillar enlargement occurs due to inflammation of the lymphoid tissue in Waldeyer’s ring, rarely causing airway compromise [7]. Mild hepatocellular hepatitis is estimated to be 10% in adolescents can resolve spontaneously, as in our case [8]. He did not have atypical lymphocytes in his smear and despite adding amoxicillin, no rashes were noticed. Hence, antibody testing was done to confirm the diagnosis. The EBV-specific serology is a confirmative diagnostic tool. Within one to two weeks, antibodies to EBV-specific antigens appear at the expected titres [9]. The serology of anti-VCA IgM generally persists for about 1 – 2 months. The Paul–Bunnell test for detecting heterophil antibodies by agglutination of sheep or horse red blood cells, is available as a convenient latex agglutination or solid phase immunoassay form. The test is however insensitive initially and the false negative rate is as high as 25% in the first week, 5 – 10% in the second week and 5% in the third week [10]. As per the antibody results (mentioned in the Table 3) [11], our patient fits into the acute primary infection. He also had acute otitis media which did not respond to antibiotics. Literature search revealed a 14-month baby with EBV induced acute severe otitis media which resolved with symptomatic management [12].

Table 3. Staging EBV infection by enzyme immunoassay antibody results.

Stage of infection Time after onset of illness VCA IgM VCA IgG EBNA-I IgG
EBV Naive Nil –*
Acute primary infection 0 – 3 weeks +** ±***
Subacute infection 4 weeks 3 months + +
Convalescent infection 4 – 6 months ± + ±
Past infection > 6 months - + +

–*: Negative, +**: Positive, ±***: Positive or negative

Conclusion

  1. Every exudative tonsillitis with painful lymphadenopathy may not be bacterial.
  2. In some patients with infectious mononucleosis, the peripheral smear may be normal (absence of atypical lymphocytes). If there is still a clinical suspicion, antibodies to viral capsid antigen are more specific to diagnosing EBV infection.
  3. Although investigations may be indicative of certain diseases, clinical correlation is extremely important.

Though the child initially was started on antibiotics, timely stopping is crucial to avoid over treating and inappropriate usage in children. as soon as the results of IgM to EBV was available the child was discontinued and managed without antibiotics.

Acknowledgements

Thankful to Dr. Venkita Suresh (GMD) for his constant motivation and the Department of Administration, Kauvery Hospital, Chennai.

Competing interests

The authors have no competing interest to declare.

References

  1. Johannsen EC, Kaye KM. Epstein-bar virus (infectious mononucleosis, Epstein Barr virus - associated malignant diseases, and other diseases). In: Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, USA: Churchill Livingstone; 2015:1754–1771.
  2. Cameron B, Bharadwaj M, Burrows J, et al. Prolonged illness after infectious mononucleosis is associated with altered immunity but not with increased viral load. J Infect Dis. 2006;193:664–671.
  3. Jenson HB. Acute complications of Epstein-Barr virus infectious mononucleosis. Curr Opin Pediatr. 2000;12:263-268.
  4. Sehgal S, Mujtaba S, Gupta D, Aggarwal R, Marwaha RK. High incidence of Epstein Barr virus infection in childhood acute lymphocytic leukemia: A preliminary study. Indian J Pathol Microbiol. 2010;53:63-67.
  5. Lu G, Xie ZD, Zhao SY, et al. Clinical analysis and follow-up study of chronic active EpsteinBarr virus infection in 53 pediatric cases. Chin Med J. 2009;122:262-266.
  6. Allen C, Rooney CM, Gottschalk S. Infectious mononucleosis and other Epstein-Barr virus - associated diseases. In: Hoffman R, Benz EJ, Silberstein LE, Heslop HE, Weitz JI, Anastasi J, eds. Hematology: Basic Principles and Practice. 6th ed. Philadelphia: Elsevier Inc; 2013:708- 720.
  7. Carrington P, Hall JI. Fatal airway obstruction in infectious mononucleosis. BMJ. 1982;292:195.
  8. Lawee D. Mild infectious mononucleosis presenting with transient mixed liver disease. Can Fam Physician. 2007;53:1314–1316.
  9. Fleisher GR, Collins M, Fager S. Limitations of available tests for diagnosis of infectious mononucleosis. J Clin Microbiol. 1983;17:619–624.
  10. Ebell MH. Epstein-Barr virus infectious mononucleosis. Am Fam Physician. 2004;70:1279– 1290.
  11. Mumba MB, Anastasia S, Khozhbaudievna BK. Infectious mononucleosis in a 3-year-old male child: a case report and review of the literature. Med J Zambia. 2019;46(4):362–366.
  12. Tomiyama M. A case of severe acute otitis media complicated by infectious mononucleosis. 2015

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