Agranulocytosis occurrence following recent acute infectious mononucleosis

a b s t r a c t

Infectious mononucleosis secondary to Epstein-Barr virus typically follows a relatively benign and self-limited course. A small subset of individuals may develop further progression of disease including hematologic, neuro- logic, and Cardiac abnormalities. A mild transient neutropenia occurring during the first weeks of Acute infection is a common finding however in rare cases a more profound neutropenia and agranulocytosis may occur up to 6 weeks following the onset of initial symptoms. We describe the case of an 18-year-old woman who presented 26 days following an acute infectious mononucleosis diagnosis with agranulocytosis and fever. No source of in- fection was identified and the patient had rapid improvement in her symptoms and resolution of her neutrope- nia. The presence of fever recurrence and other non-specific symptoms in individuals 2-6 weeks following acute infectious mononucleosis symptom onset may warrant further assessment for this uncommon event.

Introduction

Epstein-Barr virus (EBV) leading to acute infectious mononucleosis (IM) typically follows a relatively benign and self-limited course charac- terized by fever, sore throat, cervical lymphadenopathy, myalgias, and fatigue [1]. For unclear reasons, a small subset of individuals may devel- op further progression of disease including hematologic (hemolytic anemia, thrombocytopenia), neurologic (cranial nerve palsies, trans- verse myelitis, meningoencephalitis) and cardiac (myocarditis, pericar- ditis) abnormalities. A mild neutropenia is a common event in the initial stages of acute IM and is reported to occur in up to 80% of infected indi- viduals [2]. In rare cases however, a more profound neutropenia and agranulocytosis may occur up to 6 weeks following initial acute EBV- IM symptom onset [3].

Case report

An 18-year-old woman presented to the Emergency Department with a three-day history of subjective fever, weakness, myalgias, and lower abdominal pain. Twenty-six days previously she was evaluated with a clinical presentation verified with laboratory studies consistent

* Corresponding author at: Sparrow Hospital, Department of Emergency Medicine, 1215 E. Michigan Ave, Lansing, MI 48912, United States.

E-mail address: [email protected] (D.P. Betten).

with EBV associated acute IM (EBV IgM positive, anti-EBNA negative, EBV IgG negative). She recovered fully back to her normal physical state for a duration of 2 weeks until becoming ill over the last three days. In the Emergency Department, her temperature was 101.3 F, pulse of 115 beats per minute, respirations of 18 per minute, and blood pressure of 107/79 mm Hg. Physical examination was unremark- able with the exception of tachycardia and moderate lower abdominal pain. Laboratory studies included a hemoglobin of 13.4 g/dL, platelets of 180 x 10³/uL, WBC count of 0.7 x 10³/uL with a peripheral smear identifying 89% lymphocytes, 11% monocytes, and 0% granulocytes. A urinalysis and CT scan of the abdomen were unremarkable. The patient was admitted to the hospital under isolation precautions and started on Empiric antibiotics (piperacillin/tazobactam) for fever of unknown source in the setting of severe neutropenia.

The patient remained hemodynamically stable with no clear source of infection identified on blood and urine cultures. Fever resolution oc- curred within 24 h. additional laboratory testing performed included a negative anti-granulocyte antibody immunofluorescent assay, negative plasma parvovirus B19 PCR, and negative cANCA and pANCA titers. A bone marrow biopsy demonstrated normal erythropoiesis, normal mat- uration of lymphocytes and monocytes with an absence of mature neu- trophils suggesting maturation arrest of granulopoiesis. Four days following admission the patient had returned back to her baseline state of physical health with a gradual resolution of her neutropenia over the following month (Fig. 1).

http://dx.doi.org/10.1016/j.ajem.2016.11.042

Fig. 1. Absolute Neutrophil count (10³/uL) following time from hospital admission.

Discussion

The occurrence of severe neutropenia following acute IM is an ex- ceedingly uncommon event [4]. A mild transient decline in neutrophils is common in the first weeks following acute infection however the more dramatic and the uncommon profound decline in granulocytes (neutrophils, eosinophils, basophils) is typically not appreciated until 2-6 weeks following acute IM symptom onset [4-6]. Following a period of improvement from the primary IM symptoms, fever, malaise, and often a recurrence of lymphadenopathy develop similar to the Acute stages of infection occur. Fever resolution and clinical improvement with laboratory studies returning to normal over a 1-2 week periodic is typical. Exceptions from this benign self-limited course do exist. A 24-year-old man presented 15 days after an acute IM diagnosis with fever, cervical adenopathy, and neutrophil absence. Within 24 h of ad- mission to the hospital the patient died from acute respiratory failure secondary to staphylococcal pneumonia [6]. An 18-year-old woman ap- proximately 6 weeks following laboratory confirmed EBV-IM presented with significantly altered mental status, elevated temperature, gingivostomatitis and massive splenomegaly with an absolute neutro- phil count of 0.156 x 10³/uL [7].

The true incidence of post infectious mononucleosis agranulocytosis

is unknown [8]. It is unclear whether the presence of this profound neu- tropenia represents a continued and worsening progression of the mild neutropenia identified in the early stages of acute EBV-IM infection or if this occurs following a temporary neutrophil recovery to baseline levels. The absence of routinely obtained follow-up laboratory studies follow- ing acute EBV-IM and the presumed rarity of this event leads to a lack of clarity in our understanding of the time frame of this progression of neutropenia.

Varying mechanisms behind neutropenia following acute EBV-IM have been proposed. Medication induced agranulocytosis has been de- scribed with a number of medications including several common antibi- otics [9]. Cephalexin had been taken three weeks previously by our patient however resolution of neutropenia is typically rapidly corrected following antibiotic discontinuation making this an unlikely etiology

[10]. A direct cytotoxic effect from the EBV itself may be responsible and results from a direct or indirect destruction of neutrophil progenitor cells in the bone marrow leading to myelocyte maturation arrest [5]. There is an increasing amount of evidence supporting an autoimmune mechanism involving an EBV induced polyclonal activation of B cells resulting in anti-neutrophil antibody production [11]. Negative results of our patient’s Antibody testing may suggest an alternative to the auto- immune mechanism, however given the multiple potential untested antibodies responsible that may lead to immature granulocyte destruc- tion this mechanism should still be strongly considered [12]. The pres- ence of anti-HNA-a1 specific antibodies that was not specifically evaluated in our patient has been noted to be present in previous cases of agranulocytosis following acute EBV-IM diagnosis [4,13].

Although severe neutropenia following EBV virus is typically self- limited, an evaluation for source of fever should be performed. Isolation precautions and the potential benefit of empiric antibiotics as neutro- phil counts return towards normal may be appropriate to minimize the likelihood of bacterial superinfection while in this transient immu- nocompromised state.

Conclusion

Agranulocytosis should be considered as a possible complication fol- lowing acute EBV-IM. The presence of fever recurrence and other signs and symptoms of infection in an individual 2-6 weeks following initial acute IM symptoms may warrant further assessment for this uncom- mon event.

References

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