Brucellosis is a major public health concern worldwide with a prevalence of 10/1 lakh population. Although brucellosis is endemic in several countries it goes under-diagnosed and under-reported. The diverse presentations of brucellosis have led clinicians a challenge in its diagnosis and management. Musculoskeletal manifestation and lesions of spine are the common focal manifestation of brucellosis. Differentiating Brucella spondylitis from tubercular spondylitis is a clinical challenge. We herewith highlight the prevalence of brucellosis, the need, and method for early diagnosis and management to prevent disability and mortality.
Keywords: Brucella spondylitis, brucellosis, doxycycline, neurobrucellosis, serum tube agglutination test, tubercular spondylitis
| Introduction|| |
Brucellosis a bacterial zoonosis is known since ancient times. It is transmitted directly or indirectly to humans from infected animals predominantly domesticated ruminants and swine. It is also known as “undulant fever,” “Mediterranean fever” or “Malta fever.” David Bruce (1887) a pathologist working in the British army first isolated the organism during Malta fever outbreak among British soldiers. He also established the linking of fever in brucellosis patients due to the consumption of unpasteurized goat milk. Alice Evans, an American microbiologist suggested the name “Brucellosis” in 1918 in honor of Bruce.,
| Brucella, the Organism|| |
Brucella is a group of nonsporing noncapsulated Gram-negative facultative intracellular coccobacilli which are partially acid fast. Being obligate aerobes, they grow well in media enriched with blood, serum, or liver extract and addition of erythritol improves the growth. All major Brucella species are catalase and oxidase positive except Brucella neotomae and Brucella ovis. All Brucella species are urease positive and reduce nitrates to nitrites.
Brucella phylogenetically belongs to alpha 2 class of proteobacteria and has the ability to interact intracellularly with eukaryotic cells. The genus Brucella based on pathogenicity and host preference is divided into several species as mentioned in [Table 1].,,
|Table 1: Classification of different species of Brucella with their host preference and zoonotic potential|
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| Epidemiology|| |
Brucellosis is a major debilitating disease present throughout the world. Globally, more than 500,000 cases of human Brucellosis are reported every year. The highest prevalence is seen in Middle East, Asia, Africa, South and Central America, the Mediterranean basin, and the Caribbean Islands. In developed countries due to proper screening of livestock and their vaccination, the incidence of brucellosis is rare. It is estimated that the incidence is 25 times higher than reported one and hence, brucellosis is included in the category of neglected endemic zoonoses by the World Health Organization.,,
| Brucellosis in India|| |
About 69% of the Indian population live in approximately 649,481 villages where people are in close approximation with cattles (Census 2011). The development of agriculture and incorporation of animal husbandry is responsible for the close proximity of man and animals even today in many developing countries, including India. This proximity has led to the transmission of various zoonoses including brucellosis from animals to man. The prevalent species involved in human disease are Brucella melitensis and Brucella abortus; the former species is responsible for severe and prolonged disease with resultant disability., The prevalence of human brucellosis in India shows wide variation from low to high prevalence as shown in [Table 2].,,,,,,,,,
| Karnataka|| |
The overall prevalence of Brucellosis in Karnataka was 7.0% and in North Karnataka, the seropositivity was 5.1%. With the majority of patients from Gadag, Koppal, and Haveri districts of North Karnataka.
Though brucellosis is in an increasing trend the epidemiological data are lacking in several countries including India. The various causes being nonspecific clinical features, a broad etiological spectrum of acute febrile illness, slow growth rate in culture, and complexity in serodiagnosis. The scarce data published until now represents only the tip of the iceberg and the true prevalence remains to be estimated.
| Mode of Transmission and Survival|| |
The modes of transmission of brucellosis are ingestion, inhalation, mucosal or percutaneous exposure. Most often it occurs by direct or indirect contact with infected animals and their products. Foodborne transmission is also of great concern; in people consuming raw unpasteurized milk and its products like cheese. Other modes of transmission are travel from or to endemic zones, person-to-person transmission through blood transfusion, organ transplant, and bone marrow transplant., Transmission through inhalation in abattoir employees and accidental exposure in laboratory workers while handling cultures is also seen.
Brucella acts as a potential agent of bioterrorism and remains on the category B biodefense research list of both the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases. Its propensity for airborne transmission and induction of chronic debilitating disease requiring combined antibiotic regimens for treatment, its abundance around the world and its vague clinical characteristics defying rapid clinical diagnosis are some of the characteristics that apply to the pathogen's weapons potential. B. melitensis and Brucella suis are developed as biological weapons in several countries. Few drawbacks in the context of bioterrorism are minimal mortality, availability of treatment options, protracted inoculation period and the emergence of new, more virulent potential weapons are the drawbacks in the context if bioterrorism.
Under normal storage conditions Brucella can survive in unheated and untreated milk for 87 days, in water for 60 days, and less than a week in yogurt. In commonly used dairy products like refrigerated milk, it survives for up to 8–10 days, 1 month in ice cream, and around 4 months in butter. It survives for several weeks in frozen meat. The survival rate is improved at pH of <4, at temperature of 4°C and in moist condition. They survive in damp soil of <10°C for more than 8 weeks and in winter in manure soil for several weeks, in broth at pH more than 5.5 they survive for 4 weeks., The process of pasteurization of milk and thorough cooking of meat products can kill the bacteria.
| Pathogenicity|| |
Brucella species are facultative intracellular bacteria that survive and replicate invading the host cell. There are three distinct phases in pathogenesis:
- The incubation phase before clinical symptoms are evident
- The acute phase during which time the pathogens invade and disseminate in host tissue
- The chronic phase that can eventually result in severe organ damage and death of the host.
The pathogen can invade and replicate within phagocytic and nonphagocytic cells, macrophages being the target cells. Even though 90% of organisms are killed by macrophages, the small population left behind is sufficient to replicate within macrophages, allowing penetrance into host cells. The “O” chain of nonclassical Brucella lipopolysaccharide (LPS) is the major virulence factor. It helps in the entry of organism through lipoid rafts and survival by preventing phagosome lysosome fusion and phagocytosis creating modified phagosome a Brucella containing Vacuole (BCV). This BCV fuses with Endoplasmic reticulum where replication takes place. Initial replication takes place in lymph nodes and then spreads hematogenously resulting in chronic localizing infection in reticuloendothelial, musculoskeletal, and genitourinary system.
Intracellular survival of Brucella also requires a number of other virulence factors such as Vir B (Type 4 secretion system), Type 3 secretion system, and the BvrR/BvrS gene sensing system. Heat shock protein 60 (a member of the GroEl family ochaperones) and cell envelope components like osmoregulatory periplasmic glucan also acts as virulence factors.
| Clinical Features|| |
Brucellosis has a varied incubation period of 1 week to several months and presents with undulating fever (rising and falling) type, associated with chills, malaise, anorexia, weakness, and nonspecific myalgia.
Varied focal features are present in majority of the patients with brucellosis. Osteoarticular involvement is the most common focal manifestation accounting for 10%–85% and presents as spondylitis, sacroiliitis, peripheral arthritis, osteomyelitis, bursitis, and tenosynovitis. Brucella spondylitis presents with fever and back pain radiating to the legs and mimics tubercular spondylitis misguiding the clinician to start empirical anti-tubercular treatment. The points of difference between the two are given in [Table 3].
|Table 3: Difference between Brucella spondylitis and tubercular spondylitis|
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Neurobrucellosis (6%–7%) refers to a variety of neurological complications associated with brucellosis. It presents commonly as meningitis (acute or chronic), meningoencephalitis, cerebral vasculitis, mycotic aneurysms, brain abscesses, infarct, or hemorrhage. Brain scans are normal in meningitis. Cerebrospinal fluid (CSF) analysis reveals elevated proteins, normal or low glucose, and lymphocytic pleocytosis. Isolation of organism from CSF is rare but specific antibodies can be demonstrated in CSF and serum. Peripheral nerve complications include neuropathy or radiculopathy, Guillain–Barré syndrome, and a poliomyelitis-like syndrome (uncommon form of myelitis that presents similar to polio, due to nonpoliovirus pathologies like motor neuron disease).
Gastrointestinal manifestations most often follow foodborne infection and resemble enteric fever ranging from nausea, vomiting, abdominal discomfort to acute abdomen mimicking acute appendicitis, cholecystitis, acute pancreatitis, ileitis, and intestinal obstruction. They may have hepatomegaly (10%), hepatosplenomegaly with a spectrum of hepatic lesions such as hepatocellular necrosis and Hepatic abscess.,
The Respiratory manifestations such as (a) interstitial pneumonitis, (b) bronchopneumonia, (c) lung nodules, (d) lymphadenopathy (hilar and paratracheal), (e) pleural effusions, and (d) empyema are commonly present among abattoir employees. Orchitis and epididymitis are the most frequent Genitourinary manifestations (10%) of brucellosis in men, mimicking testicular cancer or tuberculosis. In females cases, pelvic abscesses, and salpingitis have been reported. Renal involvement is rare and may mimic renal tuberculosis.
Cardiovascular manifestations include endocarditis, myocarditis, and pericarditis. Infective endocarditis involves both native and prosthetic valves and is the most common cause of death in brucellosis. Aortic valve is involved more commonly than mitral valve. Dermatological manifestations like rashes, nodules and ophthalmic manifestations like uveitis, iridocyclitis are present.
Though several organs are involved the Case fatality rate is <2%.
| Diagnosis|| |
Since the clinical picture of brucellosis is very vague, diagnosis is made based on the history of exposure, clinical features, and specific laboratory tests. Blood culture and serology are the two important diagnostic methods used. The biphasic Ruiz-Castaneda system which uses both solid and liquid medium is the traditional method. This reduces the need for subcultures. Blood, bone marrow (superior to blood), pus, tissue, CSF, and pleural/joint/ascitic fluid are used for culture. Though blood culture is the gold standard, it is only 40%–70% successful. The majority of the blood cultures are positive between day 2 and day 21 and 2% become positive after 27 days. Thus, before labeling a culture as negative, it should be incubated for a minimum of 45 days. The traditional methods are replaced by lysis centrifugation technique and automated culture system which helps in speedier diagnosis.
In the absence of traditional methods, serodiagnosis (agglutination tests) based on smooth LPS of outer membrane is carried out. It includes Rose Bengal test, serum agglutination test, the antiglobulin or Coombs test, complement fixation test, and the recently introduced immunocapture test. The sensitivity of Rose Bengal plate test is 99% and is used for mass screening but the positive reports need to be confirmed by serum tube agglutination test (STAT).
STAT, the most popular serological test which measures the total agglutinating antibodies immunoglobulin M (IgM) and Immunoglobulin G (IgG) is easy to perform. To determine the quantity of IgG antibodies specifically, 0.005 M 2 mercaptoethanol which inactivates the agglutinability of IgM is used. STAT titers of 1:160 and above are considered diagnostic except in endemic areas where higher titers of 1:320 are the cut off.
Coombs tests are more sensitive in confirmation of relapse. It can also detect incomplete antibodies. Recently, new immunocapture-agglutination assay for detecting anti-Brucella antibodies (Brucella Capt) is introduced which detects both agglutinating and nonagglutinating antibodies. It is a possible substitute for Coombs test and a better marker for disease activity.
|Table 4: Sensitivity and Specificity of different serological tests used in brucellosis|
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Enzyme-Linked Immunosorbent Assay (ELISA) is a standardized assay for brucellosis. It measures IgG, IgM, and IgA. Molecular methods like Polymerase chain reaction (PCR) though needs standardization are rapid, very sensitive, and specific. It also helps in diagnosing Brucella at genus, species, and biovar level for epidemiological purpose using tandem repeat sequences. PCR and ELISA are very useful in diagnosing neurobrucellosis, local infection, and relapse., Sensitivity and specificity of these various tests are under research.
| Treatment|| |
The aim is to treat and relieve the symptoms of the current infection and prevent relapse. Focal infections need specific interventions along with antibiotic therapy. Brucella strains show in vitro sensitivity to many antimicrobials which are ineffective therapeutically. It should be kept in mind that tuberculosis should always be excluded and drugs used in the treatment of active tuberculosis should be used cautiously to prevent resistance. Initially, monotherapy with streptomycin was in use, but relapses were common, thus dual therapy with Streptomycin and Tetracyclines (Doxycycline) has become the norm. The use of alternatives like Rifampicin depends on local and national policies.
The duration of treatment for acute (<6 months) nonfocal brucellosis in adults is 6-week course of therapy with two antimicrobials agents. Complex or focal disease requires more than or equal to 3 months therapy. Compared to short-term regimens long-term regimens are more effective in preventing relapses.
The gold standard regimen for treatment of brucellosis in adults is Streptomycin IM (0.75–1 g daily for 14–21 days) with Doxycycline (100 mg bd for 6 weeks). The WHO regimen is Rifampin (600–900 mg/day) with doxycycline (100 mg bd) for 6 weeks. The former regimen is preferred because of increased clearance rate of doxycycline when given with Rifampicin. In conditions like pregnancy where doxycycline is contraindicated, patients can be treated with Trimethoprim–sulfamethoxazole (80 mg TMP/400 mg SMZ) with streptomycin or Rifampicin. Gentamicin IV (5–6 mg/kg/day for at least 2 weeks instead of streptomycin can be used as an alternative. Combined therapy with fluoroquinolones has higher failure rates. Triple drug regimen with doxycycline, rifampicin and with initial course of aminoglycoside is superior to double drug regimen and should be considered in patients with complicated disease.,
In patients with neurological complications along with standard regimen ceftriaxone supplementation for 3–6 months is also added. Brucella endocarditis is treated with antibiotics (triple-drug regimen) with ceftriaxone or fluoroquinolones for 4–6 months, the need for valve replacement or mitral balloon valvulotomy varies with patient condition. Among osteoarticular complications, sacroiliitis needs no specific treatment whereas spondylitis or osteomyelitis with paravertebral or epidural abscess needs long-term treatment with a standard regimen for more than or equal to 8 weeks with rare necessity of surgical drainage. Patients should be followed up clinically for 2 years to detect relapse.,,
As such, there is no proper guide for prophylaxis T. Doxycycline and Rifampicin for 3 weeks in low-risk exposure and 6 weeks after a major exposure have been recommended by many authorities but it is poorly tolerated. Doxycycline monotherapy of the same duration is the substitute. Rifampicin is contraindicated in patients exposed to vaccine strain RB 51, a rough rifampicin-resistant strain.
| Chronic Brucellosis|| |
If the symptoms persists for 12 months and more it is termed as chronic brucellosis, these patient falls under three categories
- Relapse is defined as the recurrence of characteristic signs and symptoms (with or without a positive culture) after the completion of a course of treatment mostly within 6 months. The patient presents with fever and elevated IgG antibodies in the serum. Treatment is with antimicrobials
- Chronic localized infection is defined as the recurrence of characteristic signs and symptoms (with or without a positive blood culture) caused by the failure to eliminate a deep focus of infection, such as osteomyelitis, or deep tissue abscess and they require surgical intervention in addition to antimicrobials
- Delayed convalescence is defined as the persistence of symptoms, without objective signs of infection, such as fever, in patients who have completed a course of therapy, and in whom titers of antibodies have declined or even disappeared.
| Prevention|| |
Vaccines with live attenuated Brucella strains like B. abortus strain 19BA or 104M are given to high-risk exposures in some countries but it has short-term efficacy. Testing and slaughtering of infected animals, control of animal movement, and active immunization of animals are the mainstay of veterinary prevention which is the first step for control of human disease.
| Conclusion|| |
Due to its subtle clinical symptoms, long latent period and lack of awareness, brucellosis is being misdiagnosed and poorly managed. Only rapid and effective management may prevent irreversible complications. Brucellosis mimicking tuberculosis in many aspects should also be taken into consideration. Proper liaison between the medical and veterinary professionals and raising awareness about occupational risk hazards could aid in decreasing the incidence of brucellosis.
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Source of Support: None, Conflict of Interest: None
[Table 1], [Table 2], [Table 3], [Table 4]