Brucellosis: A Comprehensive Literature Review of Global Epidemiology, Pathogenesis, Diagnostic Advances and Management with A Focus on Central Asia
1. Nishankulova Elnura Dilmurtzhanovna (enika9995@gmail.com)
2. Anushree Yadav (yadavanushree504@gmail.com)
Pinjari Alfiya Sadaf Riyaz Ahmed (alfiyapinjari02@gmail.com)
Sweta Swapan Bacher (swetabacher55@gmail.com)
Shaikh Mohammed Ismail Afroz (ismailshaikh8102@gmail.com)
Mohammad Jabbar Kazi (jk7008488@gmail.com)
Dhiraj Ravindra Kakuste (dhirajkakuste26@gmail.com)
Khan Mohd Irfan (moirfan2502@gmail.com)
Mohd Ahmed (ahmed07chaudary@gmail.com)
(1. Teacher, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic
2. Students, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.)
ABSTRACT
Background: Brucellosis is an important bacterial zoonosis affecting human health, livestock and socioeconomic development across the globe. The infection is due to range of bacteria in the Brucella genus. Transmission occurs through contact with infected animals or eating of infected animal products. Unfortunately, this infection remains endemic in many developing countries including Central Asia despite improvements in diagnostic techniques and veterinary control.
Objectives: This article aims to provide an overview of epidemiology, transmission, pathogenesis, symptoms, diagnosis, treatment and prevention of human brucellosis. The importance of this infection to public health will be discussed in relation to Kyrgyzstan and surrounding countries.
Methods: A narrative literature review was conducted using relevant scientific articles and health sources. Articles were found using databases such as PubMed, PubMed Central, Google Scholar and institutionally published papers. Keywords such as ‘brucellosis’, ‘Brucella infection’, ‘human brucellosis’, ‘brucellosis epidemiology’, ‘diagnosis’, ‘antibiotic treatment’, ‘Central Asia’ and ‘Kyrgyzstan’ were used to identify relevant articles. Articles discussing human and animal infection, laboratory diagnosis, treatment and prevention were included. The findings were qualitatively analysed.
Results: The literature review has shown that brucellosis is an important zoonotic infection. It affects those involved in livestock farming. Brucella melitensis is a common cause of human infection however B. abortus, B. suis and B. canis can also cause infection. Symptoms may vary greatly; however commonly present with prolonged fever, sweating, fatigue, joint pain, splenomegaly and enlargement of the liver. Diagnosis of brucellosis includes clinical evaluatin alongside serological investigations, culture and molecular techniques. Treatment includes antibiotics. Livestock, consuming unpasteurised dairy products and occupation remain major concerns in Kyrgyzstan.
Conclusion: An integrated approach is required between human healthcare, veterinary, food safety and public health. Improving early diagnosis, vaccinating livestock, protecting workers and working together within the region will help reduce Brucellosis transmission and complications.
INTRODUCTION
Brucellosis is a zoonotic bacterial infection that is one of the major public health issues globally. The infection is caused by the genus Brucella which are small Gram-negative coccobacilli bacteria. These bacteria are able to survive within the host cell, particularly macrophages, and therefore cause chronic infections with various presentations [1,2].
The disease is an important issue in both human and domesticated animals. In livestock it often causes reproductive issues such as abortion, infertility, placental inflammation and milk yield. In humans it can cause an acute febrile illness or chronic complicated multi-system disease [1,3].
Transmission occurs through contact with infected animals, animal tissue/secretions or consuming unpasteurized milk and dairy. The infection can be airborne causing inhalation of infectious aerosols, this is common in laboratory workers and vets. Transmission between humans is rare [4]. Whilst brucellosis is well controlled in some countries with vaccinations, monitoring and food safety programmes there are still many regions where the disease is endemic. The Mediterranean basin, Middle East, Africa, South Asia and Central Asia all have a large burden of disease. This can be due to differing animal management and veterinary treatment, as well as food preparation and healthcare practices [1,4].
Kyrgyzstan is an important area to study as livestock farming plays an important role in rural communities and the economy. Many sheep, goats and cattle are kept and animals are moved seasonally. A review found that brucellosis is still present in humans and animals in Kyrgyzstan despite improvements in vaccinations and disease control in livestock [5]. The disease presents with non-specific symptoms meaning patients are often treated for other febrile illnesses. This delay in diagnosis can cause prolonged illness, relapse and complications in certain organs [2,6].
This review will outline the key aspects of brucellosis. Clinicians, lab staff, vets and public health officials all need a good understanding of this disease.
MATERIALS AND METHODS
This article was written as a narrative literature review. Literature Search: PubMed, PubMed Central, Google Scholar and health publications were searched for relevant scientific articles. Information was also obtained from WHO, CDC, and peer reviewed articles. Search terms used include:
● Brucellosis in humans
● Brucella species and pathogenesis
● Epidemiology of brucellosis globally
● Clinical presentation and complications
● Human brucellosis diagnosis in the lab
● Antibiotic treatment
● Brucellosis in Kyrgyzstan
● Livestock vaccinations and One Health
Literature Selection: Publications relevant to brucellosis were those relating to the epidemiology, microbiology, transmission, pathogenesis, clinical presentation, diagnosis in the lab, and treatment/prevention. Peer reviewed articles were prioritised looking at reviews, diagnosis, epidemiology and clinical guidelines. Articles which provided information regarding brucellosis in humans and animals in Central Asia were also considered.
Data Extraction: The information from the chosen articles was split into categories. These included the bacteria, epidemiology, transmission, intracellular survival, clinical presentation, diagnosis, antibiotic treatment and prevention.
Findings were qualitatively compared to highlight common presentations, problems with diagnosis, and differences in prevention strategies in different regions. Data was not collected from patients, labs or statistical analysis as this was intended to be a literature review.
RESULTS
Etiology
Brucellosis is caused by the Brucella genus which are facultative intracellular bacteria. They are aerobic Gram-negative coccobacilli and are usually non-spore forming and non-flagellated. The bacteria are small in size and are able to survive inside host cells [2,7].
There are various species however the most clinically important are:
● Brucella melitensis – most commonly seen in sheep and goats and an important cause of disease in humans.
● Brucella abortus – most commonly seen in cattle.
● Brucella suis – commonly seen in pigs and certain wild animals.
● Brucella canis – mainly seen in dogs.
Other Brucella species have been found in marine animals and wildlife [2,7].
The differences in species of Brucella is important as they can cause disease in different animals, will have different epidemiology and can cause different issues in the lab. B. Melitensis is an important classical zoonotic species as it can cause disease in humans, and is seen in small ruminants [1,5].
Epidemiology
Brucellosis can occur in many parts of the world. However, the prevalence varies greatly from country to country. Countries with a large burden of disease often have poor disease control in livestock, poor veterinary treatment and consumption of unpasteurized dairy.
The disease can be seen in all ages and genders however those working in certain jobs may be more likely to become infected. Farmers, shepherds, vets, abattoir workers, butchers and lab workers are all at increased risk as they are regularly in contact with potentially infected material [1,4].
Epidemiology can also be closely linked to the disease in animals. Areas with high sheep and goat farming may have increased Brucella melitensis transmission. Brucella abortus is commonly seen in cattle. Cases can occur throughout the year but can be increased during certain times of the year due to animal reproduction, animal handling and dairy production.
Brucellosis in Kyrgyzstan and Central Asia
Central Asia is an important endemic area as animal husbandry is a large part of the economy. In Kyrgyzstan livestock farming, home dairy production and seasonal animal movements will impact the epidemiology.
A review was carried out looking at human and animal brucellosis in Kyrgyzstan. This looked at the epidemiology between 2010 and 2020. This found that brucellosis in humans is an important public health issue however improved vaccinations and disease control in animals has reduced the number of cases [5].
During the period 2010-2020, 18,279 cases were recorded. There were higher rates of infection in areas with lots of livestock production including Jalal-Abad, Talas, Naryn and Issyk-Kul. Exposure to aborted animals, unpasteurized home-made dairy products and direct contact with livestock were important risk factors [5]. This shows that knowing the epidemiology of brucellosis needs to consider animals, food production and occupation.
Transmission and Risk Factors
Brucella organisms can be transmitted to humans via: Consumption of infected animal products – Unpasteurized milk, fresh cheese, cream and other dairy products can be a major source of infection if they have come from infected animals. If they are not heated sufficiently then viable bacteria can be present. Direct contact with animals – Infection can occur if bacteria enters through broken skin or mucous membranes from infected blood, reproductive tissue, placenta, aborted foetuses and uterine secretions. Inhalation – Aerosolisation can occur during animal birthing, abattoir work, lab work and handling contaminated materials. Occupational risk – Those working in farming, veterinary, animal breeding, abattoirs and microbiology labs are at increased risk of infection due to regular contact with infected animals. Other – Blood transfusions, organ transplants, and breastfeeding have been reported but are rare. Spread between humans is generally rare [4,8].
Important risk factors include poor animal health monitoring, poor PPE, poor disposal of animal reproductive materials, consuming raw dairy products and low public awareness.
Pathogenesis
Brucella is highly pathogenic due to the ability to survive in host cells. Once entered into the body they can enter via mucous membranes or broken skin. They will then travel to regional lymph nodes. Macrophages and other phagocytes will engulf the bacteria however unlike many extracellular bacteria Brucella can interrupt the destruction of the bacteria in the cell and create a safe environment.
Once inside the cell they will be taken up by vacuoles surrounded by a membrane. These vacuoles will develop into a suitable environment for survival and replication using the intracellular trafficking pathways. The type IV secretion system (particularly the VirB system) is an important part of this process as it will deliver effector proteins into the host cell [7,9].
This ability to interrupt the host cell means Brucella can be partially prevented from being completely destroyed by the immune system. Infected macrophages can transfer the bacteria to the lymphatic tissues and reticuloendothelial system including the liver, spleen and bone marrow.The immune system will respond both innately and adaptively. Macrophage, natural killer cells and T lymphocytes will help fight the infection. Cell mediated immunity and T-helper 1 cells and Interferon gamma are important in activating macrophages to help limit the growth of bacteria inside the cell.
Failure to completely destroy the bacteria can cause chronic infections, recurring fevers and inflammatory symptoms. The interaction between the bacteria survival and immune response causes varied clinical presentations [7,9].
Clinical Presentation
The incubation period can vary however is commonly several weeks to two months. Presentation will depend on the species causing infection, quantity of bacteria, route of infection, immune response and when it is diagnosed [4]. The disease can present in acute, subacute or chronic forms. Some patients will have localised disease in an organ whilst others will have more systemic symptoms.
Common Symptoms
● Intermittent/chronic fever
● Sweating
● Fatigue
● Headache
● Loss of appetite
● Muscle and joint pain
● Weight loss
● Malaise
Some patients will have undulant fever. This means they will get bouts of high temperature but then feel better. Not all patients will have this.
Musculoskeletal disease is one of the most common presentations. Patients can develop joint pain, joint inflammation, sacroiliitis, spondylitis and osteomyelitis. Sacroiliac and vertebral disease can cause significant pain and impact function. Spondylitis is very important as it can cause long term disability if not recognised quickly.
Brucella can affect the liver, spleen and lymphatic tissues. Hepatosplenomegaly can occur, alongside abnormal liver enzymes. Granulomatous inflammation can also occur.
Neurobrucellosis is a rare but important complication. Patients can develop meningitis, meningoencephalitis, radiculopathy, cranial nerve and other neurological issues. Patients can suffer from constant headaches, neck stiffness, changes in mental state and neurological symptoms. Cerebro spinal fluid should be tested if suspected.
Brucella endocarditis is a rare but one of the most serious complications. This can occur in native or prosthetic valves and can cause valve damage, heart failure and systemic emboli. Whilst rare it can significantly contribute to severe disease.
The male genital tract can be affected causing epididymo-orchitis in the epididymis and testes. Female complications have also been reported. Infection can occur during pregnancy and this should be considered. Overall brucellosis can cause varied presentations meaning a thorough history and appropriate investigations are important for accurate diagnosis [2,6].
Diagnosis
Early and accurate diagnosis is important to stop prolonged infection and serious complications. As the symptoms are non-specific, investigations are usually needed. Assess symptoms, duration, occupation, animal contact and diet. Ask about unpasteurized dairy products and animal reproductive materials.
Identifying Brucella from blood, bone marrow or other samples is a strong indicator of infection. This can help identify the species. However, it can take a long time for the bacteria to grow and will depend on the sample, duration and antibiotic use. Culturing Brucella can be a risk to the lab as an aerosol can be produced. This means it is important to inform the lab if the patient is suspected so the correct precautions can be put in place [6,8]. Serology is widely used to identify Antibodies.
● Rose Bengal Plate Test – A rapid test to identify antibodies.
● Standard Agglutination Test (SAT) – Measures antibody agglutination.
● Coombs Antiglobulin test – Can be useful in some cases.
● ELISA – Identifies IgM and IgG antibodies specific to Brucella.
The results should be interpreted alongside clinical findings, history, duration of disease and seroprevalence in the region. Not all patients with positive antibodies will have active infection, particularly in endemic areas.
PCR can be used to identify genetic material from Brucella. This can give rapid results and can help identify the species if validated correctly. However it will depend on the sample, lab and timing.A systematic review was carried out in 2024 looking at 38 studies. This found Rose Bengal, IgG/IgM ELISA and PCR offered promising results. However, it also showed there was poor quality data [10]. Therefore, diagnosis should be based on combining clinical, epidemiological and lab findings.
Treatment
The aim of treatment is to remove the infection, prevent relapse, reduce complications and return to normal function. As Brucella can survive inside cells, long term combination antibiotic treatment is usually favoured. A common treatment for uncomplicated adult infection is the combination of doxycycline and rifampicin. This should be taken for 6 weeks or more. Another common combination is doxycycline and an aminoglycoside (streptomycin/gentamicin). [2,11].
The choice of antibiotics will depend on the age, pregnancy, organs affected, tolerance, contraindications and local guidelines.Those with focal complications may need longer treatment and specialist assessment. Neurobrucellosis, endocarditis and osteoarticular infections will often require individual combination treatment. Endocarditis may also require surgery.
Children and pregnant women require special consideration. Certain antibiotics may not be suitable to use. Qualified clinicians should choose the treatment based on recommendations for each age group. Improvements in symptoms does not necessarily mean the bacteria has been fully removed. Monitoring should be carried out to identify any ongoing symptoms, relapse and complications.
Prevention
Preventing brucellosis in humans relies heavily on preventing infection in animals.
Animal Vaccinations: Vaccinating susceptible animals is an important part of preventing disease in endemic areas. Vaccinating cattle, sheep and goats can reduce the number of infected animals and therefore reduce human infection. Vaccines should be chosen and administered under veterinary supervision as some live vaccines can be a risk to humans.
Food Safety: Pasteurizing milk and ensuring proper food preparation is an important prevention strategy. Avoid consuming raw milk and unpasteurized cheese in endemic areas.
Occupational Protection: Farmers, vets and abattoir workers should wear the appropriate gloves, PPE, masks or respiratory protection depending on the risk of exposure. Extra care should be taken when handling placenta, aborted foetuses, blood and other potentially infectious material.
Public Health: Community awareness should be raised to educate people about the transmission, importance of animal vaccinations and risks of consuming unpasteurized dairy products.
Monitoring: Monitoring of human and animal cases can help identify outbreaks and high-risk areas. Collaboration between health professionals and vets will help investigate possible sources of infection.
Lab Safety: Microbiology labs should follow correct containment and safety procedures when handling suspected Brucella samples as accidental exposure can cause occupational infection [4,5,8].
One Health and Public Health Importance
Brucellosis shows how human, animal and environmental factors are closely linked. This means collaboration between sectors is needed to prevent disease. The One Health approach recognises how human infection links to animal reservoirs, farming, food production and environmental exposure. This means animal monitoring, vaccinations, safe food preparation and reporting of human disease should be combined.
In Kyrgyzstan and other Central Asian countries, cross border animal movement and similar farming practices mean it is an important area to collaborate. Improved communication between veterinary departments, hospitals, diagnostic labs and public health will help identify sources of transmission quicker.
Improved technology and molecular epidemiology can help increase our understanding of Brucella species circulating and transmission. This will help create more effective and sustainable prevention strategies [5,12].
DISCUSSION
This literature review found brucellosis is an important zoonotic disease which still affects people today due to the complex nature of the disease in relation to animal infection, occupationally acquired infections, dietary habits and public health services. A key point to note is the strong association between brucellosis in animals and humans. Unlike many infectious diseases, brucellosis is mainly maintained by infection in animals meaning it cannot be controlled effectively by treating clinically. Preventing infection within animals is crucial to decreasing the burden of disease within humans [1,4].
The Kyrgyzstan example supports this as their review found there was a large amount of disease within humans and animals between 2010-2020. Whilst livestock vaccination programs had been introduced and improved they found that there were regional differences and ongoing disease within humans showing brucellosis was not completely stopped [5].
This would have a large impact on rural communities as they are likely to keep animals within the home and prepare their own dairy products. This can cause infection as people are consuming homemade cream, fresh cheese and other unpasteurised products. People that assist with birthing animals and handling reproductive material would also be exposed multiple times.
A further challenge in managing brucellosis is that it presents with non-specific symptoms. This can make it difficult to diagnose as people will often present with fever, tiredness, headaches and muscular pains which could be caused by many infectious diseases or inflammatory conditions. In endemic areas this can cause delays in diagnosis and incorrect initial treatment. It is important clinicians consider brucellosis in those presenting with prolonged fever and history of animal contact or unpasteurised dairy products [2,6].
Due to the bacteria's ability to survive within the intracellular environment this can cause prolonged disease, relapsing symptoms and possible complication of focal disease. Recent research has discovered more about Brucella's intracellular lifecycle and how bacterial effectors alter the cells signalling pathways [9].
Another issue to consider is that diagnosing brucellosis can be difficult. Culture can be useful to confirm infection but sensitivity can vary depending on how long the person has had disease, quality of samples and if they have taken any antibiotics previously. There is also a risk of infection in the lab so strict biosafety measures must be followed. Serology can be more readily available in many healthcare settings however interpreting the results can be tricky.
A systematic review published in 2024 found tests such as Rose Bengal, ELISA and PCR can be used to help diagnose brucellosis. However, they noted there was large variation between diagnostic studies and there was low certainty around the evidence [10]. This shows there needs to be standardised protocols in place to help diagnose the disease.
Brucellosis in humans will often require long-term combination antibiotic treatment. Whilst many guidelines recommend doxycycline-based combinations, this can vary depending on severity of disease and whether there are complications involving specific organs. If the treatment isn't given for long enough, poor adherence or incorrect antibiotics are used this can increase the chance of relapse. Individual treatment is important [2,11].
To prevent brucellosis there needs to be an increased focus on animal management and food safety. Livestock vaccinations have been shown to have many benefits within endemic areas however they require consistent vaccination, correct application and reliable monitoring. Raising public awareness is also important as people may continue to consume unpasteurised dairy products without knowing the risks.
The One Health approach can be used to help manage this. By working together with doctors, vets, lab staff and agricultural departments this can help investigations during outbreaks, identify the source and prevent further disease. In Central Asian countries it is also important to work with other regions to share information as livestock can move between countries and they may have similar production methods. There are still many areas to research within this topic. There isn't much good quality surveillance data, diagnostic standards vary, not enough characterisation of the strains using molecular techniques and little information on long term treatment outcomes. Further epidemiological studies and human-animal surveillance programmes are required.
Overall there is evidence to suggest brucellosis should be looked at as a public health and veterinary problem. It is important to identify this early and provide the right antibiotic treatment. To decrease long term disease, it is important to control the infection source.
CONCLUSION
Brucellosis remains an important zoonotic disease and public health issue. It is commonly seen in regions where there is lots of livestock and inconsistent food safety practices. It presents with variable symptoms and the bacteria can survive within the intracellular environment causing serious focal complications. Accurate diagnosis of this disease requires considering the clinical symptoms, epidemiological history and correct investigations. Combination antibiotic treatment is the main treatment for human disease. Early identification and appropriate follow up is needed to reduce the risk of relapse.
The epidemiology in Kyrgyzstan and other Central Asian countries has shown the importance of livestock vaccination, safe dairy practices, occupational protection and improved disease surveillance. Future prevention should aim to improve collaboration between medical and veterinary professionals using the One Health approach. Long term reduction of brucellosis will rely on good prevention strategies, easy access to diagnostics, public awareness and ongoing research. It is important to tackle both human disease and animal sources.
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