Co-infection of Brucellosis and Epstein–Barr virus infection in a child

INTRODUCTION

Brucellosis was first described in the year 1859 by British Royal Army Medical Corps physician J.A. Marston among troops in Malta during the Crimean war. This bacterium was named in remembrance of Sir. David Bruce a Scottish Microbiologist. The history of brucellosis dates to several centuries in the past when this disease was noted to be more common among people in contact with domestic animals. Of late, it is less commonly seen in the general population. We would like to report an interesting case of brucellosis presenting as co-infection with Epstein–Barr virus (EBV) infection in a child in this case report and emphasise the importance of clinical history in diagnosing this case.

CASE REPORT

A 15-year-old boy was referred to our centre with a 2-month history of fever, cough, weakness and weight loss. On examination, he had significant cervical lymphadenopathy, moderate splenomegaly, non-tender hepatomegaly and occasional rhonchi on chest auscultation. The child was evaluated under the suspicion of pyrexia of unknown origin (PUO) to rule out chronic granulomatous infections and non-infectious conditions, such as tuberculosis, typhoid, leptospirosis, infectious mononucleosis, malaria, sarcoidosis, systemic lupus erythematosus and systemic-onset juvenile idiopathic arthritis, among others.

Initial history did not suggest any clear exposure to zoonotic diseases, nor did it mention consumption of unpasteurised milk or meat. However, a detail history when revisited revealed that the child had been treated with alternative medicine, which was mixed with raw goat milk and given to the child. This raised a strong suspicion of brucellosis. Based on this, a culture for Brucella was ordered.

Although the complete blood count and C-reactive protein were normal, the peripheral blood smear revealed atypical lymphocytes and liver function tests were deranged, as seen in Table 1. The serological tests were positive for both EBV and Brucella species (melitensis and abortus), as seen in Table 2. To rule out haemophagocytic lymphohistiocytosis and lymphoreticular malignancy, a bone marrow examination was performed. Chest X-ray done on the child showed non-significant bilateral infiltrates. Tests for tuberculosis were negative. Ultrasound examination confirmed significant hepatosplenomegaly.

Given that EBV resolves spontaneously, the focus shifted to treating brucellosis. The child was started on gentamicin and doxycycline initially. After 5 days of therapy, the child became afebrile, and blood cultures later confirmed the growth of Brucella melitensis which clinched the diagnosis. Following 7 days of gentamicin, the child was discharged on doxycycline and rifampicin for 6 weeks. On follow-up, the child showed significant improvement in the organomegaly, laboratory parameters and completely recovered without any long-term sequelae.

DISCUSSION

Annual global incidence^[1] of brucellosis is noted to be 2.1 million which is significantly higher than previous estimates. Historically,^[2] only B. melitensis, Brucella abortus and Brucella suis were considered human pathogens. However, more recent reports have identified other, newly recognised species within this genus that can also cause human disease. Humans typically contract the disease through consumption of unpasteurised dairy products (e.g. cheese, milk, cream and butter), as well as organ meats (e.g. spleen and liver) from infected animals that are improperly cooked. The disease was named brucellosis in honour of Sir David Bruce, a Scottish physician who first identified the causative organism as a Gram-negative coccobacillus. The name B. melitensis was derived from Melita,^[2] the Latin word for Malta, in reference to the geographic origin of the disease. Conventionally, in the past, the Maltese people distributed raw goat milk directly to households, increasing the likelihood of transmission of this infection.

Brucellosis^[3] often presents with non-specific symptoms, mimicking several infectious (tuberculosis) and non-infectious conditions (connective tissue disorders). The cornerstone of an accurate diagnosis relies heavily on a meticulous patient history and interpreting the clinical findings in the context of epidemiological factors. In our index case, the key exposure of consumption of contaminated dairy products was revealed only after repeated questioning, highlighting the importance of thorough history-taking. The most common clinical feature of brucellosis is fever, present in 85-90% of cases, along with sweating, myalgia and fatigue. Brucellosis is classified based on the duration of symptoms as acute (<2 months), subacute (2–12 months) and chronic relapsing (>1 year). In the index patient as symptoms, lasted for nearly 3 months, this was consistent with the subacute form of the disease. Childhood brucellosis rarely progresses to chronicity.

Bosilkovski et al.,^[4] reported 317 cases of childhood brucellosis out of total 1691 patients in their retrospective study. These children were aged 7–14 years (median age 9 years). Common findings included fever (78%), joint pains (72%) and hepatomegaly (68%). Splenomegaly was also noted in a significant proportion of patients. Hepatomegaly often accompanied with mild-to-moderate elevation of transaminases. In our case, the patient had splenomegaly, hepatomegaly, with elevated liver enzymes, which improved after treatment.

Patra et al.,^[5] noted neurobrucellosis in 2.8% in their case series. Fever with headache and altered sensorium were the major presenting complaints. In a systematic review by Dhar et al.,^[6] it was noted that meningitis with or without encephalitis was the most common presentation. These cases mimicked tuberculosis in several aspects. Sixth cranial nerve (abducens) palsy was noted as the most common presentation. We did not notice any of the symptoms related to neurobrucellosis in our patient.

In a retrospective study by Akkoc et al.,^[7] osteoarticular involvement was noted in 50% (94) out of 185 children with brucellosis. The hip joint was most commonly affected. Raised ESR (>20) and increasing age were independent predictors of osteoarticular involvement in this cohort. We did not notice any joint symptoms till date.

Kaman et al.,^[8] noted haematological manifestations in a cohort of 212 patients. Anemia (66, 31%), leukopenia (22, 10%), thrombocytopenia (10, 5%) and pancytopenia (4, 2%) were the important findings noted in this study. The presence of haematological manifestations was significantly common in children with fever, hepatosplenomegaly with positive blood culture and raised aspartate aminotransferase and alanine aminotransferase. These patients needed intravenous immunoglobulin in addition to antibiotics. Although we noticed atypical lymphocytes on peripheral smear, the bone marrow was normal.

Cardiac complications were noted to be the most common reason for mortality in brucellosis, by Tasdemir et al.^[9] These patients needed surgical treatment in addition to medications. Ocular manifestations are also rarely reported in the literature.^[10]

Co-infections of brucellosis with EBV are rarely reported in published literature till date. Our case was initially suspected to be infectious mononucleosis due to positive EBV serology where both the immunoglobulin G and immunoglobulin M titres were elevated which confirmed active infection with EBV, but Brucella culture confirmed the diagnosis [Table 2]. The patient’s prompt response to treatment in 6 weeks further solidified the diagnosis.

Blood culture remains the gold standard^[2] for diagnosing brucellosis. In chronic cases, blood culture yield may be lower. Serological tests provide early diagnostic support. Higher cutoff values (>1:160) are used in endemic areas. Polymerase chain reaction is notably useful for diagnosing neurobrucellosis, though its high cost limits its use in general populations.

The treatment of brucellosis typically involves combination therapy for at least 6 weeks. The World Health Organization’s recommended regimen^[2] consists of doxycycline plus rifampin. For children under 8 years, doxycycline is substituted with cotrimoxazole. Recent studies suggest that adding gentamicin for 7–10 days to the standard regimen improves outcomes. In severe cases, the duration of treatment can be extended to beyond 6 weeks.

CONCLUSION

Brucellosis clinically manifests in varied forms, making it difficult to diagnose without a detailed patient history, especially regarding exposure to contaminated dairy products or meat. It should be kept as a differential diagnosis in the management of any child with PUO. Co-infections with EBV can make the diagnosis more challenging. It could have been better if the serology was repeated to demonstrate a change in the titres to confirm the EBV infection which was a limitation in our index case. This was not done as it did not alter the treatment and due to additional cost constraints. Treatment usually involves doxycycline and rifampicin for a minimum of 6 weeks, with gentamicin added for severe cases. Early diagnosis and treatment are imperative to prevent chronic complications.