Febrile neutropenia in an immunocompetent patient with brucellosis: a case report and literature review

Abstract

Introduction and importance:

Brucellosis is a zoonotic disease that can affect various organs, with symptoms like fever, lymphadenopathy, and arthritis. Hematologic complications, including febrile neutropenia, are rare. This report highlights the diagnostic and therapeutic challenges of brucellosis with febrile neutropenia.

Case presentation:

A 36-year-old man presented with a 3-week history of fever, polyarthralgia, and night sweats. Examination showed febrile symptoms, joint swelling, and cervical lymphadenopathy. Laboratory tests revealed neutropenia and elevated inflammatory markers. Imaging was unremarkable, and blood cultures were negative, but brucellosis was confirmed by serology. Treatment with doxycycline and rifampicin led to clinical improvement.

Clinical discussion:

Brucellosis diagnosis can be challenging due to nonspecific symptoms and requires high suspicion, especially in non-endemic areas. In this case, early identification and targeted therapy led to symptom resolution. This case underlines the importance of considering zoonotic diseases in febrile neutropenia with inconclusive initial findings.

Conclusion:

Brucellosis with febrile neutropenia is rare but manageable with timely diagnosis and treatment, leading to favorable outcomes.

Introduction

Brucellosis is a zoonotic disease that is transmitted to humans through consumption of unpasteurized dairy products, direct contact with infected animal parts, or inhalation of infected aerosol particles^[1,2]. Less than 10% of human brucellosis cases are clinically identified and reported^[3]. In endemic regions, brucellosis is always included in the differential diagnoses for fever of unknown origin^[4].

The most common symptoms of brucellosis are fever, fatigue, sweating, arthritis, hepatosplenomegaly, lymphadenopathy, and cytopenia. Neutropenia as a hematological manifestation of brucellosis is extremely uncommon^[5]. Brucellosis diagnosis is confirmed based on clinical symptoms consistent with the disease, positive blood culture results, and/or a standard tube agglutination test showing a titer >1/160 upon admission for all patients^[6,7]. Since brucellosis does not respond to the standard antibiotic treatment for febrile neutropenia, it can lead to treatment failure^[8]. Brucellosis with febrile neutropenia is a rare combination to find in case reports. With a review of the clinical signs, test findings, and therapeutic strategy in this specific case, the goal of this case report is to document the infrequent occurrence of brucellosis with febrile neutropenia. This case report has been meticulously prepared in accordance with the SCARE 2023 guidelines^[9].

Case presentation

A 36-year-old male with no prior medical history presented at a tertiary care hospital in New Jersey with a three-week history of fever and malaise. The patient described his fever as being cyclical, with peak temperatures in the late evening. He also reported associated profuse diaphoresis, decreased appetite, nonproductive cough, and pharyngitis. He denied recent travel history, sick contacts, exposure to animals, or consumption of uncooked meat. He was in a monogamous relationship. He denied both smoking history and illicit drug use and reported occasional alcohol consumption. He worked in a restaurant and handled raw meat.

On the initial examination, he was found to be febrile with a temperature of 39.6°C (103.3°F). He exhibited swelling and tenderness in both wrists and the proximal interphalangeal and distal interphalangeal joints of both hands, along with left-sided anterior cervical lymphadenopathy. Laboratory studies revealed the following: hemoglobin (Hb) 13.7 g/dL, mean corpuscular volume 85.2 fL, leukocyte count 1.40 × 10³/µL, and platelet count 204 × 10³/µL. A manual differential showed a suppressed absolute neutrophil count (ANC) of 0.7 × 10³/µL. A peripheral smear showed normocytic normochromic red blood cells, decreased white blood cells (WBCs), normal platelets, and occasional atypical lymphocytes but no malignant cells. Inflammatory markers were slightly elevated: erythrocyte sedimentation rate at 62 mm/h and C-reactive protein at 3.5 mg/dL. He also had elevated transaminases with aspartate aminotransferase at 131 U/L and alanine aminotransferase at 132 U/L. An extensive infectious workup, including blood cultures, urine cultures, sputum cultures, respiratory panel, acute hepatitis panel, HIV 1/2 antibody (Ab), HIV 1 RNA, HIV-p24 antigen (Ag), COVID-19 polymerase chain reaction, and Rapid Influenza A/B tests, were all unremarkable.

Due to his constellation of symptoms, he underwent a chest X-ray, as well as contrast-enhanced computed tomography scans of the chest, abdomen, and pelvis. All imaging studies were unremarkable for acute pathology. The echocardiogram revealed no abnormalities.

The patient received intravenous fluids and was started on empiric therapy with piperacillin-tazobactam. However, he continued to have fevers despite multiple days of empiric antibiotic therapy. On further investigation, the patient reported eating unpasteurized dairy products that were brought from the Dominican Republic. Brucellosis antibody screen was collected. His antibiotic regimen was changed to doxycycline. The following day, laboratory testing resulted positive IgG brucella antibodies. He was started on rifampicin 600 mg daily and doxycycline 100 mg twice daily for 8 weeks. Two days after targeted brucellosis therapy, the patient had an improved ANC of 1.1 × 10³/µL and an improved WBC of 2.0 × 10³/µL. He was discharged home with close follow-up. The patient had resolution of all symptoms, normalization of his WBC count, and resolution of transaminitis at his 8-week follow-up appointment.

Discussion

Brucellosis is a systemic zoonotic infection transmitted by contact with the fluids of infected animals or ingestion of their unpasteurized dairy products or undercooked meat^[10]. The prevalence of brucellosis is estimated to be 15.53%^[11]. The estimated annual incidence of brucellosis in the Americas is 3335. Central America has the highest risk of acquiring brucellosis, followed by South America (northern and southern parts of the continent), and finally North America^[12]. Brucella melitensis is likely the most common cause of febrile neutropenia^[13]. A study by Ozcay et al and Sari et al has reported four cases of febrile neutropenia, and brucella was the causative organism^[14].

The diagnosis of brucellosis is challenging because clinical features resemble both infectious and non-infectious diseases^[15]. It has a wide range of clinical presentations, from being asymptomatic to involving multiple organs^[16]. The disease is classified based on the duration and severity of the symptoms into acute (less than 8 weeks), subacute (from 8 to 52 weeks), or chronic (more than 1 year). Localized disease is referred to when there is involvement of a single organ^[17]. In a study conducted in Turkey involving 233 cases of brucellosis, findings indicated that 55% of patients experienced anemia, 21% had leukopenia, 26% showed thrombocytopenia, and 8% exhibited pancytopenia^[18]. While the exact mechanisms are not fully understood, hypersplenism, hemophagocytosis, hemolysis, and granulomatous bone marrow lesions appear to be key factors contributing to these abnormalities in peripheral blood^[19].

Systemic symptoms include insidious fever, sometimes with an irregular pattern (which is why this disease is also known as undulant fever), night sweats, myalgia, arthralgia, anorexia, depression, headaches, and lethargy^[20]. The diagnosis of brucellosis requires the isolation of Brucella from blood or body tissues, or the combination of suggestive clinical presentation and positive serology. Tube and slide agglutination tests are used for diagnosis. Slide agglutination test is sensitive (>99%). However, the specificity of this test is low. It may be used as a screening test in the endemic regions^[21]. Isolation of Brucella spp. from the clinical specimen is the gold standard because serological testing does not provide direct evidence for the presence of the pathogen^[22,23].

The diagnosis is challenging due to the nature of bacteremia. During the treatment, two or three agents are combined. Due to the high recurrence rates, single-agent therapy that was previously employed is no longer used. Standard treatment entails administering 100 mg of doxycycline twice daily for 6 weeks and 1 g of streptomycin intramuscularly b.i.d. for 2 weeks. An alternate treatment plan can include 600–900 mg/day of rifampicin plus 100 mg of doxycycline twice a day. While the combination with rifampicin led to a higher recurrence rate, the combination with streptomycin has been demonstrated to be more successful^[24]. However, the World Health Organization (WHO) recommends the use of doxycycline and rifampin likely due to the association with streptomycin, which is administered intramuscularly because of its poor oral absorption and associated risks^[25]. Adding trimethoprim and sulfamethoxazole to current treatment plans improves success rates. Moreover, extending treatment to 6 weeks or more reduces recurrence risk compared to shorter regimens^[26]. There are currently no universally accepted guidelines for treating immuno-compromised patients. Studies conducted in vitro have indicated a notable susceptibility to amikacin and third-generation cephalosporins^[27,28].

In our literature review, we identified cases similar to ours, although they differed in presentations, immune status, other medical conditions, and initial treatments administered. Notably, only one case involved an immunocompetent individual. For instance, a case documented by Cuczzu et al^[5] described a 2-year-old immunocompetent female with an ANC of less than 500 cells/mm³. This highlights the rarity of febrile neutropenia in immunocompetent individuals compared to immunocompromised patients, who often present with common secondary diseases such as non-Hodgkin lymphoma, acute lymphoblastic leukemia, and acute myeloblastic leukemia, typically accompanied by significantly lower ANC values. This distinction underscores the importance of considering brucellosis in cases of febrile neutropenia, even among immunocompetent individuals, as demonstrated in the current case report (Table 1).

Table 1.

Summary of literature review

Case report	Age (years)	Sex	Secondary medical condition	Immune status	Absolute neutrophil count (ANC) (cells/mm3)	Empiric treatment	Definitive treatment
Arda et al[31]	56	Male	Non-Hodgkin lymphoma	Immuno-compromised	90/mm3	Meropenem + Neutromycin + Teicoplanin + Amphotericin B	Doxycycline + Rifampin + Ciprofloxacin
	59	Male	Acute lymphocytic leukemia	Immuno-compromised	167/mm3	Imipenem/Cilastatin + Teicoplanin	Not given
Cuczzu et al[5]	2	Female	No	Immuno-competent	<500/mm3	Cefuroxime and Meropenem + Clarithromycin	Trimethoprim-sulfamethoxazole (TMP-SMZ) + Rifampicin
Ozcay et al[14]	12	Female	Acute lymphoblastic leukemia	Immuno-compromised	Nil	Ceftazidime + Amikacin	Rifampin + Tetracycline
Ozbalci et al[20]	42	Female	Acute myeloblastic leukemia	Immuno-compromised	0/mm3	Imipenem/Cilastatin + Ciprofloxacin + Teicoplanin	Doxycycline + Rifampicin
Metan et al[32]	17	Female	Acute lymphocytic leukemia	Immuno-compromised	300/mm3	Cefepime + Amikacin and Piperacillin-Tazobactam	Doxycycline + Rifampin
Kasap et al[33]	8	Male	Acute lymphoblastic leukemia and Epididymoorchitis	Immuno-compromised	Nil	Meropenem + Vancomycin + Amikacin + Ornidazole + amphotericin-B	Doxycycline + Rifampicin +
Solmaz et al[34]	56	Male	Acute myeloblastic leukemia	Immuno-compromised	200/mm3	Piperacillin/Tazobactam + vancomycin and Meropenem + Linezolid	Doxycycline + Rifampicin
Caglar Citak et al[13]	6	Male	Acute lymphoblastic leukemia	Immuno-compromised	100/mm3	Meropenem + Amikacin + Teicoplanin + Amphotericin B and ciprofloxacin and linezolid	TMP-SMZ + Rifampicin
Sari R et al[8]	NA	NA	Malignancy	Immuno-compromised	NA	Cefepime + Amikacin	Streptomycin + doxycycline + TMP-SMZ

Empiric treatment: therapy when culture/serology results are pending; Definitive treatment: therapy when culture/serology results are definite; NA: not available.

Our patient lived in a region where brucellosis was not endemic, but he was in close contact with the risk factors leading to infection. Increased awareness of brucellosis, specifically regarding its transmission sources and preventive measures, can help reduce its spread^[29]. As there is currently no vaccine to protect humans against infection, brucellosis is a major health concern in underdeveloped nations. Developing an effective vaccination against Brucella is necessary due to the economic impact of infectious diseases on both humans and animals, as well as their clinical manifestations^[30].

Although systemic symptoms are a prevalent manifestation of brucellosis, febrile neutropenia is an uncommon manifestation. Brucellosis should be considered in the differential when determining the cause of febrile neutropenia. Early diagnosis of brucellosis and administration of the appropriate treatment typically result in a favorable outcome without complications.

Conclusion

A rare presentation of brucellosis is febrile neutropenia. It is critical to include zoonotic diseases in the differential of febrile neutropenia, even when initial cultures are unremarkable. A comprehensive patient history is instrumental in guiding appropriate laboratory testing, facilitating early diagnosis, and prompting the initiation of treatment. These findings emphasize the importance of maintaining a high index of suspicion for brucellosis and other zoonotic diseases in febrile neutropenic patients, leading to improved clinical outcomes and the prevention of potential complications.

Ethical approval

This case report, lefted on an individual patient, received approval from the Institutional Review Board.

Consent

We obtained written informed consent from the patient after explaining the study's purpose, potential risks and benefits, and the intended use of the data for publication. The patient was assured of privacy and willingly consented to the publication of this research.

Sources of funding

All the authors declare to have received no financial support or sponsorship for this study.

Author’s contribution

F.M.K., conceptualization, methodology, project administration, and writing – original draft preparation; A.K., conceptualization, investigation, and writing – review and editing; S.R., A.R., methodology and writing – review and editing; A.Q., A.C., writing – original draft.

Conflicts of interest disclosure

All the authors declare to have no conflicts of interest relevant to this study.

Research registration unique identifying number (UIN)

Our case report is exempt from the registration requirements of the Declaration of Helsinki 2013, as it does not qualify as structured research involving human subjects. Case reports inherently left on individual patient experiences and do not necessitate a Unique Identifying Number (UIN) or registration in public databases. Nonetheless, our study adheres to ethical standards and maintains transparency in line with relevant guidelines.

Guarantor

Fasih Mand Khan.

Data availability statement

The dataset supporting the conclusions of this article is included within the manuscript and is not publicly available due to privacy concerns; however, the corresponding author can be contacted for reasonable data access requests. We support ethical use and transparency in research.

Provenance and peer review

The paper was submitted unsolicited.

Acknowledgements

None.