Infectious mononucleosis like illness with costochondritis and profound relative lymphocytosis due to Coxsackie A

1 Introduction

Infectious mononucleosis (IM) like illness is characterized by fever, fatigue, often bilateral posterior cervical lymphadenopathy, exudative or non-exudative pharyngitis, splenomegaly and a rash. IM like syndrome laboratory features include mildly elevated serum transaminases (<5xn), lymphocytosis (>51%) with or without atypical lymphocytes. The IM syndrome is classically caused by Epstein – Barr virus (EBV) (˜85%) and less commonly may be due to cytomegalovirus (CMV) (˜10%) or Toxoplasma gondii. [[1], [2], [3]] Other etiologies of (IM) like syndrome, <1.5%, include viral hepatitis, adenovirus, rubella, Herpes simplex, Human herpes virus -6 (HHV-6), parvovirus B19 and HIV [[4], [5], [6]]. Only rarely has (IM) like illness been ascribed to Coxsackie B virus (two cases due to B) and only one case has been reported due to Coxsackie A [[7], [8], [9], [10]]. We present a 35 year old female with (IM) like syndrome with fever, fatigue, chest pain due to costochondritis (usually due to Coxsackie B), macular rash, and relative lymphocytosis (>51%) The clue to the diagnosis was her costochondritis which prompted ordering Coxsackie A and B titers. Her markedly elevated Coxsackie IgG A₂₄ titers 1:1600 (n < 1:100) which were diagnostic.

2 Case

A 35 year old female was admitted for evaluation of fever, fatigue and rash. Three days prior to admission she developed profound malaise and fever of 103 °F with chills. She also complained of prominent headache and a noted central rash. She denied known sick contacts or recent travel. She had no allergies and was not taking any medications.

On admission her vital signs included a temperature of 103 °F, heart rate of 130/minute. Physical examination was unremarkable except for a truncal non-blanching and non-pruritic macular rash sparing her face, palms, soles and exquisite point tenderness over a right anterior chest costochondral cartilage. There was no conjunctival suffusion or cervical adenopathy. Laboratory tests included a white blood cell (WBC) count of 2.5 K/uL (n = 3.9–11 K/ul) with 60% lymphocytes (n = 21–51%), 5% atypical lymphocytes (n = 0–5%) and 10% neutrophils (n = 42–75%). Her platelet count was 184 K/uL (n = 160–392 K/uL). The erythrocyte sedimentation rate (ESR) was 58 mm/hr and C-reactive protein (CRP) was 3.7 mg/L (n < 3 mg/L). Serum aspartate aminotransferase (AST) was 73 IU/L (n = 13–39 IU/L) alanine aminotransferase (ALT) was 69 IU/L (n – 4–36 IU/L) and alkaline phosphatase was 82 IU/L (n = 25–100 IU/L). Her serum lactate dehydrogenase level was not elevated.

On hospital day #2 (HD #2) she spiked a fever to 102.9 °F. Her WBC count decreased to 2.1 K/uL and her relative lymphocytosis increased to 79% (n = 21–51%). Fevers decreased by HD #3 and her macropapular rash was less intense. Her serum transaminases peaked on HD #3, with an ALT of 109 IU/L (n = 4–36) and AST 88 IU/L (n = 13–39 IU/L). Monospot and HIV screen were negative. Her IgM and IgG titers for EBV, CMV, HHV-6, parvovirus B19, and Toxoplasma gondii were negative. Fevers resolved by HD #4. Coxsackie A₂₄ titer of 1:1600 (n < 1:100). All Coxsackie B and A IgG titers were negative, i.e., only Coxsackie A₂₄ was highly elevated.

3 Discussion

The diagnosis of EBV or CMV infectious mononucleosis (IM) in immunocompetent hosts is relatively straightforward. Fevers and sore throat with debilitating fatigue are the usual symptoms of EBV or CMV IM. On physical examination, non-exudative pharyngitis with bilateral posterior cervical adenopathy are common findings. In addition, a truncal maculopapular rash and splenomegaly may be present. In terms of non-specific laboratory tests with EBV or CMV, after 2 weeks lymphocytosis with atypical lymphocytes is the rule. (Table 1) Mildly elevated serum transaminases and an elevated ESR are other common laboratory abnormalities with IM like illnesses due to EBV, CMV, HHV-6. A specific serologic diagnosis is made by demonstrating an elevated IgM EBV or IgM CMV titer [[1], [2], [3]]. Unlike other viral routinely testing, IgM titers are not done with Coxsackie viruses because of cross reactions and diagnosis is based on highly elevated IgG titers.

Table 1.

Differential Diagnosis of Relative Lymphocytosis.

Infectious causes	Non-infectious causes
Acute infection (convalescence)	Acute lymphocytic leukemiaa
Whipple’s disease	Chronic lymphocytic leukemiaa
Tuberculosis	Carcinomas
Brucellosis	Multiple myeloma
Pertussisa	Rheumatoid arthritis
Tularemia	Hashimoto’s thyroiditis
Secondary syphilis	Myxedema
EBVa	Adrenal insufficiency
CMVa	Thyrotoxicosis
Human herpes virus – 6 (HHV – 6)a	Vasculitis
Viral hepatitis	Dilantin (DPH)
Mumps	p-amino salicylic acid (PAS)
Rubella	Serum sickness
Varicella zoster virus (VZV)a
Kala-azar
Toxoplasmosisa
Histoplasmosis
Rocky Mountain spotted fever
Chikungunya fever
Typhoid/enteric fever
MERS
Coxsackie virusa

Adapted from: Cunha CB, Cunha BA (Eds). Antibiotic Essentials (15^th ed) Jay Pee Medical Publishers, New Delhi, 2017.

^aMay develop extreme lymphocytosis.

The Coxsackie A and B infection is clinical with supporting laboratory data. In this case, the patient presented with a IM-like illness rarely due to Coxsackie viruses. Accordingly, Coxsackie titers are not ordinarily ordered in the workup of Monospot negative IM. However, in this case, the clinical association of costochondritis and Coxsackie B prompted ordering Coxsackie A and B IgG titers. The usual diagnostic problem with interpreting Coxsackie A/B IgG titers is to differentiate past exposure from re-activation infection. Typically, post-exposure titers are low (usually 1:8 – 1:128 and involve multiple serotypes. While PCR culture and other Dx methods may be preferable, this single A₂₄ titer is diagnostic due to the degree of elevation and that it alone was singularly increased.

IM like illnesses should be suspected when tests for EBV and CMV are negative or if other clinical features suggest an alternate diagnosis. In the case presented, several elements of an IM like illness were present [[4], [5], [6]]. However, costochondritis was the clue to the diagnosis that prompted serological testing for Coxsackie A and B. The cause of her IM like illness was Coxsackie A₂₄ [[7], [8], [9], [10]].

4 Conclusion

For clinicians, her case is most interesting from three aspects., Firstly, her profound relative lymphocytosis of 79% is reportedly rare and is usually occurs only with EBV or CMV IM. Secondly, her costochondritis, which is usually due to Coxsackie B, is rarely due to Coxsackie A. Lastly, an IM like illness due to Coxsackie A is extremely rare, and we believe this to be only the second such reported case. Furthermore, it is the only Coxsackie A case with such a profound relative lymphocytosis of 79% (n = 21–51%).