Flow chart of study selection for inclusion in this systematic review study summarized as Fig. 1.
Thirty-two cases with a mean age of 40.9 ± 22.5 years were retrieved from 28 articles. Fifteen patients were males, 14 females, and 3 patients undefined. Table 1 presents the origin of the patients.
Table 1
Country
|
Number of patients
|
Turkey
|
18
|
Saudi Arabia
|
4
|
France
|
2
|
Spain
|
1
|
China
|
1
|
Jordan
|
1
|
Portugal
|
1
|
Greece
|
1
|
Japan
|
1
|
The Caucasus
|
1
|
Kuwait
|
1
|
• Geographic distribution of the patients |
Blood culture was performed as the main diagnostic modality in the patients. Nine patients died of conditions such as septic shock and progressive neoplasms, 22 survived and one excluded from follow-ups. The most prevalent neoplasms with coexistent Brucellosis were hematological malignancies (50%). Table 2 summarizes the details of cancer types in patients. Brucella melitensis was recovered as the most prevalent species in 23 cases as it causes the most invasive and severe brucellosis infection in the world [9].
Table 2
Organ
|
Number of patients
|
Hematologic
|
16
|
Gastrointestinal
|
4
|
Lymphoproliferative
|
3
|
Urogenital
|
2
|
Musculoskeletal
|
1
|
Salivary gland
|
1
|
Lung
|
1
|
Thyroid
|
1
|
Brain
|
1
|
Breast
|
1
|
Ovary
|
1
|
• Organs affected by neoplasms in the patients |
An obvious history of consuming unpasteurized dairy products was reported in only 25% of the patients. Moreover, 18% of the patients were farmers or those who lived in rural areas, two were working as a technician in laboratories that two outbreak of brucellosis were recently reported in one of these laboratories [6, 9]. One patient had a 15-year history of chronic and recurrent brucellosis [10]. The transmission routes of brucellosis were therefore identified and reported in only a few patients. Although assessing the history of the transmission routes of brucellosis is necessary, it may be unreliable [11]. Thus, diagnostic tests should be performed to rule out brucellosis in patients with clinically-suspected brucellosis even without a history of the condition, particularly in the endemic areas.
According to Fig. 2, the patients presented with different complaints. Broad-range symptoms and multi-organ involvement mimicking many diseases make the diagnosis of brucellosis difficult [12–14]. The most prevalent complaints of the patients included constitutional symptoms such as fever and neutropenia, which were associated with the highest mortality. Interestingly, a completely-asymptomatic patient was diagnosed through the follow-up computed tomography (CT) scan after cancer treatment [15].
Febrile Neutropenia
Although febrile neutropenia has rarely been reported in brucellosis patients so far, presentation of brucellosis in 31.25% of patients was febrile neutropenia in this study. Three patients had acute lymphoblastic leukemia, two had acute myeloblastic leukemia, and two had gastric cancer and the others had breast cancer, non-Hodgkin Lymphoma and B cell lymphoma. Brucellosis developed after a cancer diagnosis in 90% of the patients and caused a challenging treatment of their neoplasms. Brucellosis and malignancy were concurrently diagnosed in one patient [16]. All the patients presenting with febrile neutropenia came from Turkey as an endemic area with proper diagnostic infrastructure. Brucellosis was diagnosed within 14 days after the emergence of its symptoms in patients with febrile neutropenia. Diagnosis was performed based on positive blood cultures in about 90% of patients and based on bone marrow cultures and the tube agglutination test in one patient. About 40% of patients were treated with doxycycline and rifampin, 30% with streptomycin, doxycycline and TMP-SMZ, 10% with TMP-SMZ and rifampin and 10% with ciprofloxacin, doxycycline, and rifampin. A delayed diagnosis possibly coupled with pulmonary embolism caused the death of one patient before initiating Brucellosis treatment [12]. one patient died due to septic shock despite receiving anti-Brucella medications [17] and two died probably of progressive neoplasms [1, 12].
Blood culture as the commonly-used standard diagnostic test was reported positive in about 65.6% of the patients. Highly-available serological tests, including the serum tube agglutination test, were preferred in clinical practice since the recovery of the pathogen in the cultures takes time. Researchers claimed that given the low sensitivity of agglutination tests in endemic areas, these tests might be insufficient in screening brucellosis patients with febrile neutropenia. They suggested applying the PCR as an alternative for diagnosis [18]. However, data are lacking regarding the standardization of PCR.
Brucellosis was detected after cancer diagnosis in the majority of the patients and of those who died when cancer and brucellosis were concurrently diagnosed in 37.5%. In patients with neoplasms, infections were major causes of morbidity and mortality and the risk of infection is related to the intensity and duration of immunosuppressive or cytotoxic treatments [10]. Brucellosis detected after the diagnosis of malignancies reveals high mortality in these patients, either due to brucellosis or underlying diseases, which confirms the need for more meticulous care in managing infections in these patients. The manifestation time of brucellosis compared to the time of receiving chemotherapeutics in the patients is a prominent finding (Table 3).
Table 3
Number
|
Timing of Brucellosis diagnosis (in patients brucellosis detected after cancer diagnosis)
|
1
|
Before initiating remission-induction chemotherapy
|
2
|
Five months after the treatment completion
|
3
|
On the 56th day of chemotherapy
|
4
|
During the second course of remission-induction chemotherapy
|
5
|
Not mentioned
|
6
|
Not mentioned
|
7
|
Four months after receiving two chemotherapy regimens
|
8
|
Five days after receiving two chemotherapy regimens
|
9
|
Eight days after receiving two chemotherapy regimens
|
10
|
Before initiating chemotherapy
|
11
|
After achieving the third complete remission (5 years after diagnosing acute lymphoblastic leukemia)
|
12
|
After chemotherapy
|
13
|
After the first course of chemotherapy
|
14
|
After the first course of chemotherapy
|
15
|
After the first course of chemotherapy
|
• Time of diagnosing brucellosis (in all the patients with brucellosis emerging after cancer diagnosis) |
Doxycycline, rifampin, and Trimethoprim-Sulfamethoxazole were the most commonly used antibiotics (used for the treatment of 65.6%, 59.3%, and 21.8% of the patients, respectively). Streptomycin, ciprofloxacin, and tetracycline were also used in 25%, 15.6%, and 15.6% of patients, respectively. Doxycycline and rifampin were, however, the most commonly used medication regimens in both treated patients and those who died.
Despite extensive studies, the best antibiotic treatment for brucellosis needs to be clarified [3]. But the current evolving data stresses the importance of aminoglycoside based regimens. The course of antimicrobial treatment of Brucellosis can be problematic, owing to its high recurrence rates [19]. Although there are controversies in the treatment of Brucellosis, early diagnosis and treatment significantly affect the prognosis. Neoplastic diseases were treated using various chemotherapy regimens and surgical methods. Comparing treatments between different patients is difficult due to variations in the type and stage of their underlying diseases.
Any interfering factors such as complications related to cancer medications and infections impose serious risks on these patients for improving prognosis. Paying special attention to opportunistic infections and endemic diseases in patients receiving chemotherapy regimens may reduce mortality [8].
Mortality
Death was reported in 9 patients. The crude mortality rate does not necessarily reveal the virulence of the disease and it could be due to underestimation of confirmed cases in other countries. Figure 3 shows the clinical presentation of the patients who died. Hematologic malignancies were the most prevalent neoplastic disease in these patients (66.6%). Lymphoproliferative malignancies were observed in two of these patients and Ewing’s sarcoma in one. Given Brucella melitensis as the most prevalent Brucella species in most of the patients died (55.5%) and the type of Brucella appears useless in the prognosis of cancer in all studied patients [6]. The patients’ manifestations were also different.
The detection of brucellosis after cancer diagnosis in five (55.5%) patients suggests that brucellosis in the presence of neoplastic diseases or during the course of chemotherapy can play a key role in patients’ outcomes. Delayed Brucellosis diagnosis and treatment in patients with neoplasms may result in poor outcomes. Contracting brucellosis before the initiation of any neoplastic treatment deemed not significantly affect cancer prognosis.
Exploring the main cause of death in these patients showed that not only the type of neoplasm but also diagnostic methods, the timings of diagnosis, treatment, and complication management significantly affected the outcome; for instance, an 11-year-old female patient presenting with fever, sweating, and low back pain was diagnosed with and treated for brucellosis. She underwent more investigations given her lack of improvement and development of neurological symptoms. On the 22nd day of the treatment, she was ultimately diagnosed with Ewing’s sarcoma. Despite undergoing pharmacological treatments and surgery, her paraplegia persisted and the patient died owing to peri-sacral decubitus ulcers. MRI of the thoracolumbar spine on the 22nd day of treatment showed Ewing’s sarcoma. Although the patient ultimately underwent surgery, paraplegia persisted, peri-sacral decubitus ulcers developed and she died of the infection [20]. Further studies are recommended to be conducted on diagnosing comorbid diseases.
Septic shock was the cause of death in (6.25%) two patients that differential diagnostic tests for microorganisms other than Brucella were negative. But in this articles did not mentioned obviously weather the septic shock caused by brucellosis. One of them was a 46-year-old male with hepatosplenomegaly and pancytopenia from a village in Algeria. Hairy cell leukemia was diagnosed and Brucella grew on bone marrow culture. Doxycycline and rifampin were prescribed and mechanical ventilation was initiated for progressive pneumonia. Splenectomy was performed and the patient died of septic shock 10 days later [17, 21].
In conclusion, accurate managing of complications for underlying diseases and treatments is essential in improving patient prognosis. Researches were done on anti-tumor effects of the Brucella species and Brucella vaccines, but have not resulted in compelling evidence for their effects [20]. Clarifying the potential interactions between cytotoxic and antimicrobial drugs used in brucellosis is crucial for determining the need for delaying the initiation of chemotherapy in patients with brucellosis [22].