A case report of hemophagocytic syndrome induced by Brucella melitensis biovar 3

Hemophagocytic syndrome (HPS) is also called hemophagocytic lymphohistiocytosis (HLH). Hemophagocytic syndrome caused by Brucella infection is a rare and life-threatening complication. We report a case of a 55-year-old female farmer from China, whose symptoms included fever, pancytopenia, and liver damage. Early on, we identified the phenomenon of hemophagocytosis through blood culture and bone marrow examination, thereby confirming the case. The pathogen was precisely identified as Brucella melitensis Biovar 3 using AMOS-PCR technology and a systematic evolutionary analysis of the IS711 sequence, which was highly homologous to a strain of badger isolated from the same area previously. This provided molecular evidence for the potential animal-to-human transmission chain from wild animals. The patient received combined treatment with anti-infective drugs (doxycycline and rifampicin), corticosteroids, and intravenous immunoglobulin, and then followed a stepwise dose reduction treatment plan. After discharge, we conducted personalized follow-up management for the patient. This case highlights the potentially fatal complications that brucellosis can cause — hemophagocytic syndrome — and it is particularly common among individuals in high-risk occupations. For patients with brucellosis accompanied by unexplained blood cell reduction and abnormal liver function, a bone marrow puncture examination should be conducted as soon as possible. In the subsequent treatment, a combined treatment plan of “antibiotic therapy plus immunomodulation” can be adopted. Furthermore, it highlights the emerging zoonotic threat posed by B. melitensis biovar 3 in endemic areas.

1 Introduction

Brucellosis, a zoonotic infectious disease, is caused by the bacterium Brucella. Human infection with brucellosis primarily arises from exposure to cattle, sheep, dairy products, and excreta contaminated with Brucella (1). In livestock farms, cats and dogs can play a pivotal role in the dissemination and prevalence of brucellosis, serving as potential vectors and asymptomatic carriers (2). Brucellosis is prevalent in China, especially in many regions where animal husbandry is well-developed, namely, Xinjiang, Inner Mongolia, and Qinghai. The clinical manifestations of brucellosis encompass fever, hyperhidrosis, fatigue, and muscle pain, among others. Infection with Brucella can lead to complications affecting various bodily systems, with osteoarthritis being the most frequently encountered complication in clinical settings. However, the hemophagocytic syndrome (HPS) caused by the B. melitensis biovar 3 is rare (3–5). This study describes a patient who lives in Xinjiang and experienced brucellosis-associated hemophagocytic syndrome and presents a pertinent literature review.

2 Case presentation

A 55-year-old female without preexisting diseases began to experience upper abdominal pain in early January 2024, mainly in the middle and upper abdomen, accompanied by nausea, intermittent fever, and the highest body temperature of 39.9°C. On February 25, 2024, the patient was sent to the First Affiliated Hospital of Shihezi University due to the deterioration of the aforementioned symptoms. Initial laboratory examinations disclosed notable inflammatory and hematologic irregularities in line with a severe systemic infection (Table 1). Systemic inflammation was manifested by elevated C-reactive protein (39.83 mg/L), interleukin-6 (58.57 pg/mL), and procalcitonin (0.25 ng/mL). Liver function assessments indicated hepatic involvement, with substantial elevations in aspartate aminotransferase (342.5 U/L), alanine aminotransferase (120.2 U/L), alkaline phosphatase (188.1 U/L), and glutamyl transpeptidase (110.0 U/L), accompanied by hypoalbuminemia (27.2 g/L). Markedly elevated levels of lactate dehydrogenase (1072.0 U/L) and hydroxybutyrate dehydrogenase (733.0 U/L) implied extensive cellular damage. Coagulopathy was suggested by an elevated D-dimer level (5.05 mg/L). Moreover, a complete blood count revealed pancytopenia (Table 2), a crucial characteristic that spurred further exploration for hemophagocytic syndrome. Abdominal ultrasound showed gallbladder wall thickening. Pleural effusion color ultrasound indicated bilateral pleural effusion, with a depth of 3.2 cm on the right and 1.6 cm on the left. Abdominal CT scans revealed a cyst in the upper left outer lobe of the liver, cholecystitis, gallbladder socket effusion, splenomegaly, and fluid accumulation in the abdominal cavity and pelvis. The electrocardiogram and cardiac color ultrasound showed no abnormalities. According to the results from the clinical check, the treatment regimen encompassed the administration of Ceftriaxone (2 g q12h i.v.) for infection control, Monoammonium Cysteine Sodium Chloride Injection, and Polyene Phosphatidylcholine Injection, both aimed at enhancing liver function therapy.

Table 1

Table 1. Summary of the laboratory tests in the patient.

Table 2

Table 2. Follow-up records of blood tests in patients.

Because the patient had a history of exposure to cattle and sheep, and lived in an area where brucellosis is endemic. To make a clear diagnosis, before administering antibiotics on February 28th, when the patient was admitted to the hospital, we strictly followed the aseptic operation procedures to collect blood samples and inoculate them into BACTEC blood culture bottles (see Supplementary Methods). On March 4th, the blood culture results were positive. The pathogen detected through AMOS-PCR (as shown in Tables 3, 4) was the Brucella melitensis (Figure 1) According to the results of the pathogen, the treatment regimen was adjusted to ceftriaxone (2 g/12h IV infusion), rifampicin (0.6 g/d, oral), and doxycycline (100 mg, twice/d, oral) for targeted anti-infective therapy.

Table 3

Table 3. Primers and sequences for Abortus, Melitensis, Ovis, and Suis-PCR (AMOS-PCR).

Table 4

Table 4. Reaction conditions for AMOS-PCR.

Figure 1

Figure 1. Patient’s blood culture positive result chart.

Furthermore, given the patient’s progressive decrease in complete blood count, the clinical team decided to perform a bone marrow aspiration (see Supplementary Methods) on February 28th to identify the cause. Results of a bone marrow smear on March 5th revealed hyperplastic bone marrow, with 3% histiocytes and hemophagocytes, along with thrombocytopenia (Figure 2). In combination with the findings of hemophagocytosis in the bone marrow and based on HLH-2004 criteria, the patient was finally diagnosed with brucellosis-associated hemophagocytic syndrome (Table 5). Therefore, based on the original anti-infective regimen, intravenous dexamethasone (15 mg, once daily) was immediately added for immunosuppressive therapy. Two days after the initiation of the protocol, her temperature normalized. Following the aforementioned treatment, on March 10th the patient was discharged. The discharge plan was: 1) Doxycycline (100 mg, twice daily, orally), Rifampin (0.6 g, once daily, orally), and Levofloxacin (0.5 g, once daily, orally) (for brucellosis treatment). 2) Bicyclic alcohol tablets (25 mg, three times daily, orally) and Glucolactone tablets (0.2 g, three times daily, orally) (for liver protection treatment). 3) Prednisone acetate tablets (45 mg, once daily, orally) (for Hemophagocytic syndrome treatment).

Figure 2

Figure 2. Depicts a bone marrow smear, exhibiting characteristics of hyperplastic bone marrow. Histiocytes and hemophagocytes comprise approximately 3% of the cellular composition, with a concurrent presence of thrombocytopenia. Original magnification×1,000.

Table 5

Table 5. The patient was diagnosed according to the HLH-04 standard.

Post-discharge, the patient was followed up in March, April, May, and June. The patient did not experience abdominal pain, fever, or other discomfort. The resolution of the pleural effusion was confirmed by ultrasound, and red blood cells, hemoglobin, and platelets returned to normal levels. However, the white blood cell count (2.9×10⁹/L) was lower than normal. Levofloxacin was discontinued after six weeks of treatment, while Rifampin and Doxycycline were used for a total of 16 weeks. Concurrently, the oral hormone underwent a gradual reduction in dosage and was ultimately discontinued within an overall treatment duration of 11 weeks, until the number of white blood cells returned to the normal level (Table 2). The development, diagnosis, and treatment of this disease are shown in Figure 3. During the treatment of this disease, the trends of changes in blood cells, liver function, and kidney function can be observed in Figures 4–6.

Figure 3

Figure 3. The onset, progression, diagnosis, and treatment of this patient.

Figure 4

Figure 4. Graphical representation of the associated trends in white blood cell count, platelet count, and red blood cell count in this patient.

Figure 5

Figure 5. The trend of the patient’s liver function-related indicators.

Figure 6

Figure 6. The trend of the patient’s renal function-related indicators.

3 Results

3.1 Pathogen identification

The PCR products (Figure 7) were then sequenced, and a phylogenetic tree was constructed based on the 731 bp sequence of the IS711 duplicate. The analysis of the research results indicated that the Brucella isolated in this study exhibited a high degree of similarity to Brucella melitensis isolated from a badger in Xinjiang, China (Figure 8).

Figure 7

Figure 7. Results of the identification of this Brucella by AMOS-PCR.

Figure 8

Figure 8. Phylogenetic tree of the IS711 tandem sequence of Brucella melitensis (•) isolated from the patient’s blood. According to the adjacency method (NJ; 500 bootstrap replicates with MEGA7) and maximum likelihood (ML, 1000 bootstrap replicates) analyses. Scale bars represent the inferred substitutions for each nucleotide site.

3.2 Literature review

Based on brucellosis and hemophagocytic lymphohistiocytosis, the related cases published by PubMed in the last 20 years were reviewed. The diagnosis of brucellosis complicated with hemophagocytic syndrome is mainly based on blood culture and bone marrow puncture, symptoms, and laboratory examination. Most studies only control the disease by actively treating the primary infection, and a few studies adopt the method of treating the primary infection and gamma globulin or hormone shock (Table 6).

Table 6

Table 6. Literature review.

4 Discussion

This case reports a patient with brucellosis causing hemophagocytic syndrome, whose clinical presentation included fever, splenomegaly, hemopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated serum ferritin, and hemophagocytosis was seen by bone marrow aspiration. The diagnosis of brucellosis causing hemophagocytic syndrome was confirmed by a detailed history taking, physical examination, and key ancillary investigations, and was finalized based on blood cultures and HLH-2004 guidelines. In terms of treatment, we used anti-Brucella treatment and treatment for hemophagocytic syndrome, and adjusted the treatment plan according to the patient’s condition. The treatment results showed that the patient’s symptoms were significantly relieved, and the disease was effectively controlled. Brucellosis-induced phagocytic syndrome mainly occurs in the acute phase of brucellosis, and the occurrence of combined phagocytic syndrome should be alerted when clinical findings of fever, splenomegaly, or liver function abnormalities, hematocrit, elevated serum ferritin (15), and elevated sCD25 are found in brucellosis infection.

In addition, during the follow-up of this case, we noted a clinical problem of persistent leukopenia. As shown in Table 2, although the patient’s anemia and thrombocytopenia resolved rapidly after the initiation of antimicrobial and immunosuppressive therapy, the white-cell counts, particularly neutrophils, remained at the lower limit of normal throughout the months-long follow-up period. This phenomenon is more likely to reflect a delayed recovery of bone marrow hematopoiesis after hemophagocytic lymphohistiocytosis than a simple drug side effect. Hemophagocytic syndrome strongly inhibits bone marrow hematopoietic precursor cells through multiple mechanisms, such as cytokine storm, direct hemophagocytosis, and infectious destruction. This inhibition not only leads to a rapid decline in blood cell lines but also destroys the structure and function of the bone marrow microenvironment, making the reconstruction of the microenvironment and the recovery of hematopoietic function take longer (16, 17). Immunosuppressive agents such as glucocorticoids themselves have significant myelosuppressive effects, and long-term use may also contribute to this phenomenon. This observation suggests that for survivors of brucellosis-associated HPS, the full recovery of bone marrow function may be a slower process that requires long-term hematologic monitoring. Fortunately, in this case, leukopenia caused no new infectious events and eventually normalized.

Hemophagocytic syndrome is a syndrome of excessive inflammatory response caused by abnormal activation, proliferation, and secretion of large amounts of inflammatory cytokines by lymphocytes, monocytes, and macrophages due to abnormalities in hereditary or acquired immunoregulatory functions. Secondary phagocytic syndromes, on the other hand, are often caused by a variety of triggers such as tumors, rheumatic immune diseases, and infections. The main triggers of hemophagocytic syndrome due to infections are viruses, bacteria, and fungi. Among them, Brucella invasion can activate the immune system, and the cytokines secreted by the immune system play a key role in the immune response. Studies have shown that the frequency of γ-interferon (IFN-γ) and tumor necrosis factor-α (TNF-α) in patients with acute-phase Brucella is significantly higher than that in healthy people (18). On the one hand, IFN-γ activates other cytokine pathways through the activation of macrophages, leading to a cascade response of inflammatory factors; it also activates the JAK-STAT signal pathway and activates the transcription of inflammatory factor-related genes. On the other hand, TNF-α activates the NF-κB pathway, causing increased secretion of cytokines (e.g., IL-12, IL-2, IL-1, IL-6, IL-10, granulocyte-macrophage colony-stimulating factor (GM-CSF), etc.) (19, 20). These inflammatory factors can lead to clinical signs of phagocytic syndrome, such as bone marrow suppression, lymph node enlargement, fever, and abnormal organ function (19).

Since hemophagocytic syndrome is caused by the excessive release of inflammatory mediators, the main treatment is cytokine reduction and supportive therapy. Currently, the treatment of phagocytic syndrome is based on the HLH-2004 protocol, which covers immunosuppressive regimens such as dexamethasone, cyclosporine, and etoposide. In secondary phagocytic syndromes caused by infections, the primary therapeutic goal is to remove the infectious agent, and antimicrobial or antiviral drugs are the key to treatment and should be administered at the start of therapy. In cases of high cytokine levels, a combination of high-dose intravenous immunoglobulins and steroids should also be considered. In addition, in secondary phagocytic syndromes caused by (non-viral) infections, adjuvant corticosteroids or anti-cytokine therapy targeting IL-1 or IL-6 may be used to accelerate recovery and/or improve survival (20–23).

The systems most commonly involved in brucellosis complications are the osteoarticular system, followed by the digestive, respiratory, genitourinary, cardiovascular, and neurological systems, as well as the blood and skin. Among the other hematologic diseases caused by brucellosis are those detailed in Table 7.

Table 7

Table 7. Disease of the blood system caused by brucellosis.

In recent years, the hemophagocytic syndrome caused by brucellosis has become an increasingly important clinical problem. Due to the lack of specificity of the clinical manifestations of brucellosis and the fact that hemophagocytic syndrome is a life-threatening inflammatory syndrome, clinicians are prone to miss and misdiagnose these diseases. Early diagnosis and timely treatment play a decisive role in saving patients’ lives and improving their prognosis.

For brucellosis-induced hemophagocytic syndrome, treatment should be devoted to controlling Brucella infection and suppressing excessive immune response. In the course of treatment, patients’ clinical symptoms and laboratory indicators should be closely monitored, and the treatment program should be adjusted in time.

Phylogenetic analysis based on the IS711 locus revealed that the patient’s B. melitensis Biovar 3 strain clustered closely with a sequence previously isolated from a badger in the same region of Xinjiang. This high homology provides compelling molecular evidence for a potential zoonotic transmission chain from wild animals to humans in this endemic area. It underscores the importance of wildlife reservoirs in the epidemiology of human brucellosis. However, it is important to acknowledge the limitations of our phylogenetic inference. Based on a single genetic marker (IS711), which, while useful for species and biovar identification, lacks the resolution of whole-genome sequencing (WGS) for precise strain tracking and robust phylogenetic conclusions. A more definitive analysis, such as core-genome SNP (Single Nucleotide Polymorphism) comparison with other human-derived B. melitensis genomes from across Asia, would be required to accurately determine the genotype of our isolate and its exact placement within the global B. melitensis population structure.

5 Conclusion

HPS secondary to Brucella melitensis infection, though rare, represents a severe and potentially fatal complication of brucellosis, particularly in individuals with occupational exposure to livestock. This case clearly demonstrates the significance of conducting early diagnosis through comprehensive microbiological, molecular, and histopathological evaluations. For cases of unexplained blood cell reduction and abnormal liver function, Brucellosis should be suspected; failure to diagnose promptly can lead to rapid deterioration of the condition. The successful treatment of this patient relied on early bone marrow puncture, as well as targeted anti-infection therapy (effective against Brucella) and immunomodulation (corticosteroids and intravenous immunoglobulin). This highlights the need for a comprehensive treatment strategy in the treatment of HPS.

Furthermore, phylogenetic analysis linking the isolate to a zoonotic strain from Xinjiang emphasizes the role of wildlife reservoirs in human brucellosis and calls for heightened surveillance of Brucella transmission dynamics in endemic regions. Public health measures should prioritize education for high-risk occupations (e.g., farmers and herders) and optimize diagnostic protocols in resource-limited settings to mitigate delays in treatment. Future research should not only explore the immunopathogenic mechanism of HPS caused by Brucella to optimize treatment plans and enhance therapeutic outcomes, but also incorporate high-resolution genomic monitoring of Brucella isolates to elucidate the transmission dynamics and the potential virulence of specific genotypes.

Data availability statement

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

Ethics statement

The studies involving humans were approved by The Ethics Committee of the First Affiliated Hospital of Shihezi University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. The animal study was approved by The Ethics Committee of the First Affiliated Hospital of Shihezi University. The study was conducted in accordance with the local legislation and institutional requirements. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

CW: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Resources, Visualization, Writing – original draft, Writing – review & editing. HZ: Writing – original draft, Writing – review & editing. JC: Writing – original draft, Writing – review & editing, Supervision. XG: Conceptualization, Data curation, Writing – review & editing. MT: Data curation, Resources, Writing – review & editing. YZ: Conceptualization, Writing – review & editing. MY: Software, Writing – review & editing. KZ: Methodology, Writing – review & editing. SX: Conceptualization, Data curation, Formal Analysis, Project administration, Validation, Writing – original draft, Writing – review & editing, Funding acquisition, Investigation, Methodology, Resources, Software, Supervision, Visualization. TC: Conceptualization, Data curation, Formal Analysis, Project administration, Validation, Writing – original draft, Writing – review & editing.

Funding

The author(s) declare financial support was received for the research and/or publication of this article. Supported by the State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases (2024KF10006); The “Tianshan Talent” High-level Talents Project in the Field of Medicine and Health under the Third Batch of the “2 + 5” Key Talent Program (TSYC202401B078); Development and Clinical Implementation of an Integrated Traditional Chinese-Western Medicine Protocol for Human Brucellosis in the Xinjiang Production and Construction Corps Region (2023AB018-14); Tianshan Young Talent Scientific and Technological Innovation Team: Innovative Team for Research on Prevention and Treatment of High-incidence Diseases in Central Asia (2023TSYCTD0020); Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2020-PT330-003).

Acknowledgments

We thank this woman for participating in this study. We thank all the medical staff who participated in the diagnosis and treatment of the patient at the First Affiliated Hospital of Shihezi University.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2025.1695579/full#supplementary-material

References

1. Ran X, Chen X, Wang M, Cheng J, Ni H, Zhang XX, et al. Brucellosis seroprevalence in ovine and caprine flocks in China during 2000-2018: a systematic review and meta-analysis. BMC Vet Res. (2018) 14:393. doi: 10.1186/s12917-018-1715-6

PubMed Abstract | Crossref Full Text | Google Scholar

2. Dadar M, Tiwari R, Sharun K, and Dhama K. Importance of brucellosis control programs of livestock on the improvement of one health. Vet Q. (2021) 41:137–51. doi: 10.1080/01652176.2021.1894501

PubMed Abstract | Crossref Full Text | Google Scholar

3. Kaya S, Elaldi N, Deveci O, Eskazan AE, Bekcibasi M, and Hosoglu S. Cytopenia in adult brucellosis patients. Indian J Med Res. (2018) 147:73–80. doi: 10.4103/ijmr.IJMR_542_15

PubMed Abstract | Crossref Full Text | Google Scholar

4. Jin M, Fan Z, Gao R, Li X, Gao Z, and Wang Z. Research progress on complications of Brucellosis. Front Cell Infect Microbiol. (2023) 13:1136674. doi: 10.3389/fcimb.2023.1136674

PubMed Abstract | Crossref Full Text | Google Scholar

5. González-Espinoza G, Arce-Gorvel V, Mémet S, and Gorvel JP. Brucella: reservoirs and niches in animals and humans. Pathogens. (2021) 10. doi: 10.3390/pathogens10020186

PubMed Abstract | Crossref Full Text | Google Scholar

6. Heydari AA, Ahmadi F, Sarvghad MR, Safari H, Bajouri A, and Saeidpour M. Hemophagocytosis and pulmonary involvement in brucellosis. Int J Infect Dis. (2007) 11:89–90. doi: 10.1016/j.ijid.2006.01.003

PubMed Abstract | Crossref Full Text | Google Scholar

7. Erduran E, Makuloglu M, and Mutlu M. A rare hematological manifestation of brucellosis: reactive hemophagocytic syndrome. J Microbiol Immunol Infect. (2010) 43:159–62. doi: 10.1016/s1684-1182(10)60025-4

PubMed Abstract | Crossref Full Text | Google Scholar

8. Erdem E, Yıldırmak Y, and Günaydın N. Brucellosis presenting with pancytopenia due to hemophagocytic syndrome. Turk J Haematol. (2011) 28:68–71. doi: 10.5152/tjh.2011.09. (Hemofagositik sendroma bağlı pansitopeni ile başvuran bruselloz olgusu.).

PubMed Abstract | Crossref Full Text | Google Scholar

9. Yaman Y, Gözmen S, Özkaya AK, Oymak Y, Apa H, Vergin C, et al. Secondary hemophagocytic lymphohistiocytosis in children with brucellosis: report of three cases. J Infect Dev Ctries. (2015) 9:1172–6. doi: 10.3855/jidc.6090

PubMed Abstract | Crossref Full Text | Google Scholar

10. Aydın S, Günal Ö, Taşkın MH, Atilla A, and Kılıç SS. Brucellosis as a cause of hemophagocytic syndrome. Mikrobiyol Bul. (2015) 49:292–4. doi: 10.5578/mb.9332 (Hemofagositik sendrom sebebi olarak bruselloz.)

PubMed Abstract | Crossref Full Text | Google Scholar

11. Jin JG. Fludarabine is effective in treating refractory hemophagocytic lymphohistiocytosis with brucellosis. Int J Rheum Dis. (2017) 20:2256–7. doi: 10.1111/1756-185x.12995

PubMed Abstract | Crossref Full Text | Google Scholar

12. Al Noumani J, Al Busaidi I, and Al Hajri M. Brucellosis-induced hemophagocytic lymphohistiocytosis. Cureus. (2021) 13:e15677. doi: 10.7759/cureus.15677

PubMed Abstract | Crossref Full Text | Google Scholar

13. Zhang Y, Li K, Yang L, and Li T. Bone marrow histiocytic hyperplasia and hemophagocytosis revealing brucellosis. Int J Lab Hematol. (2022) 44:49–50. doi: 10.1111/ijlh.13589

PubMed Abstract | Crossref Full Text | Google Scholar

14. Park D, Yoon K, Lo A, and Bolos D. Hemophagocytic lymphohistiocytosis induced by brucellosis: A case report. Cureus. (2024) 16:e64287. doi: 10.7759/cureus.64287

PubMed Abstract | Crossref Full Text | Google Scholar

15. Carter SJ, Tattersall RS, and Ramanan AV. Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. Rheumatol (Oxford). (2019) 58:5–17. doi: 10.1093/rheumatology/key006

PubMed Abstract | Crossref Full Text | Google Scholar

16. Paolino J, Berliner N, and Degar B. Hemophagocytic lymphohistiocytosis as an etiology of bone marrow failure. Front Oncol. (2022) 12:1016318. doi: 10.3389/fonc.2022.1016318

PubMed Abstract | Crossref Full Text | Google Scholar

17. Brisse E, Wouters CH, Andrei G, and Matthys P. How viruses contribute to the pathogenesis of hemophagocytic lymphohistiocytosis. Front Immunol. (2017) 8:1102. doi: 10.3389/fimmu.2017.01102

PubMed Abstract | Crossref Full Text | Google Scholar

18. Xu G, Zhang P, Dang R, Jiang Y, Wang F, Wang B, et al. Dynamic changes of th1 cytokines and the clinical significance of the IFN-γ/TNF-α Ratio in acute brucellosis. Mediators Inflamm. (2019) 2019:5869257. doi: 10.1155/2019/5869257

PubMed Abstract | Crossref Full Text | Google Scholar

19. Kim YR and Kim DY. Current status of the diagnosis and treatment of hemophagocytic lymphohistiocytosis in adults. Blood Res. (2021) 56:S17–s25. doi: 10.5045/br.2021.2020323

PubMed Abstract | Crossref Full Text | Google Scholar

20. Nguyen TTT, Kim YT, Jeong G, and Jin M. Immunopathology of and potential therapeutics for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome: a translational perspective. Exp Mol Med. (2024) 56:559–69. doi: 10.1038/s12276-024-01182-6

PubMed Abstract | Crossref Full Text | Google Scholar

21. Koumadoraki E, Madouros N, Sharif S, Saleem A, Jarvis S, and Khan S. Hemophagocytic lymphohistiocytosis and infection: A literature review. Cureus. (2022) 14:e22411. doi: 10.7759/cureus.22411

PubMed Abstract | Crossref Full Text | Google Scholar

22. Madkaikar M, Shabrish S, and Desai M. Current updates on classification, diagnosis and treatment of hemophagocytic lymphohistiocytosis (HLH). Indian J Pediatr. (2016) 83:434–43. doi: 10.1007/s12098-016-2037-y

PubMed Abstract | Crossref Full Text | Google Scholar

23. Cron RQ, Goyal G, and Chatham WW. Cytokine storm syndrome. Annu Rev Med. (2023) 74:321–37. doi: 10.1146/annurev-med-042921-112837

PubMed Abstract | Crossref Full Text | Google Scholar

24. Sevinc A, Buyukberber N, Camci C, Buyukberber S, and Karsligil T. Thrombocytopenia in brucellosis: case report and literature review. J Natl Med Assoc. (2005) 97:290–3.

PubMed Abstract | Google Scholar

25. Citak EC, Citak FE, Tanyeri B, and Arman D. Hematologic manifestations of brucellosis in children: 5 years experience of an anatolian center. J Pediatr Hematol Oncol. (2010) 32:137–40. doi: 10.1097/MPH.0b013e3181ced382

PubMed Abstract | Crossref Full Text | Google Scholar

26. Akbayram S, Dogan M, Akgun C, Peker E, Parlak M, Caksen H, et al. An analysis of children with brucellosis associated with pancytopenia. Pediatr Hematol Oncol. (2011) 28:203–8. doi: 10.3109/08880018.2010.536298

PubMed Abstract | Crossref Full Text | Google Scholar

27. El-Koumi MA, Afify M, and Al-Zahrani SH. A prospective study of brucellosis in children: relative frequency of pancytopenia. Mediterr J Hematol Infect Dis. (2013) 5:e2013011. doi: 10.4084/mjhid.2013.011

PubMed Abstract | Crossref Full Text | Google Scholar

28. Starakis I, Polyzogopoulou E, Siagris D, Mazokopakis E, and Gogos CA. Unusual manifestation of brucellosis: liver abscess and pancytopenia caused by Brucella melitensis. Eur J Gastroenterol Hepatol. (2008) 20:349–52. doi: 10.1097/MEG.0b013e3282ef9493

PubMed Abstract | Crossref Full Text | Google Scholar

29. Akbayram S, Dogan M, Akgun C, Peker E, Parlak M, and Oner AF. Disseminated intravascular coagulation in a case of brucellosis. Clin Appl Thromb Hemost. (2011) 17:E10–2. doi: 10.1177/1076029610378501

PubMed Abstract | Crossref Full Text | Google Scholar

30. Rahdar HA, Kodori M, Salehi MR, Doomanlou M, Karami-Zarandi M, Jasemi S, et al. Multiple myeloma or brucellosis: A case report. Infect Disord Drug Targets. (2020) 20:102–5. doi: 10.2174/1871526519666190307123047

PubMed Abstract | Crossref Full Text | Google Scholar