A case of PUO-Human Brucellosis

Brucellosis is also known as undulant fever, Mediterranean fever or Malta fever,is a zoonosis and the infection is almost invariably transmitted by direct or indirect contact with infected animals or their products. It is essentially a disease of animals, especially domesticated livestock,caused by bacteria of the Brucella group with humans as an accidental host. The human disease usually manifests itself as an acute febrile illness which may persist and progress to a chronically incapacitating disease with severe complications. The clinical picture is not specific and requires support with the laboratory tests.In absence of specific treatment,the disease may persist for weeks or months leading to cardiovascular and neurological complications . The duration of the human illness and its long convalescence means that brucellosis is an important economic as well as a medical problem for the patient because of time lost from normal activities. Our case is a 35 year old male farmer presenting with fever and behavioural disturbances, an atypical presentation, which would have been misdiagnosed without high index of suspicion.Thus it emphasizes that physicians should consider the diagnosis of Brucellosis in certain groups like farmers ,farm workers,shephards, veterans, laboratory workers,etc.


Introduction
Brucellosis is a zoonotic infection caused by the bacterial genus Brucella. The bacteria are transmitted from animals to humans by ingestion through infected milk and milk products, direct contact with an infected animal, or inhalation of aerosols 1 . Humans are accidental hosts, but brucellosis continues to be a major public health concern worldwide and is the most common zoonotic infection 1 . Brucella is disseminated via hematogenous route with a focal localization in various organ systems. With a wide spectrum of clinical manifestations, it can affect any organ or tissue in the human body. The most commonly affected systems are the musculoskeletal, gastrointestinal, genitourinary, hematological, respiratory and cardiovascular systems 2 . Neuropsychiatric symptoms like headache, depression, altered behaviour and fatigue are not uncommon despite the rare involvement of the nervous system 3 .
In spite of its worldwide distribution, the fact of being considered endemic in some locations, and because of its broad spectrum of clinical manifestations-therefore having many differential diagnoses, both infectious and non-infectious 4 , brucellosis remains under diagnosed and underreported 5 .
The purpose of this paper is to report such a case of brucellosis that presented with neuropsychiatric symptoms during its course but not associated with neurological involvement.

Case Report
A 35 year male, with an occupation of farming and cattle rearing practices presented with fever and altered behaviour. Fever was typically intermittent, high grade and associated with chills for last one month. He had history of psychotic behaviour of sudden onset for 2 days and hence was referred to our centre. He also had history of backache and headache for last 1month.
No history of evening rise of temperature, night sweats, significant weight loss. No history of convulsions, vomiting, pain in abdomen, burning micturition, cough, breathlessness, chest pain or palpitation. No history of past medical and psychiatric illness. Chronic alcoholic since 10 years, abstinence since 1 month. History of regular consumption of raw and unpasteurized milk and milk products. Appetite is decreased. Bowel/Bladder-normal and sleep-normal.

Systemic Examination
CNS-Terminal neck stiffness present, DTR-present, Power-V/V in all limbs, Plantar response-Flexor, Pupils-Both normal in size reacting to light. Other systems were within normal limit. A psychiatric opinion was sought. An organic cause for acute psychosis was most likely. Based on the presentation, the following D/D were considered, 1  Normal -Patient was started on IV Broad-spectrum antibiotics, anti-pyretics and analgesics for backache. He was given mild sedation and was restrained physically for aggressive behaviour. Despite of the treatment, fever recurred daily and disorientation increased. His B. Melitensis Slide agglutination test came to be positive with the high titre of 1:320.
Empirical antimicrobial therapy was initiated for brucellosis with Cap. Doxycycline ( 200mg/day). Awaited Blood culture also came to be positive for B. Melitensis thus confirming the diagnosis. Inj.Streptomycin (750mg)IM was hence added to the above regimen. He responded well to treatment and thus further investigations like ANA, DsDNA were not carried out.
An X-ray Thoraco-Lumbar spine was done to rule out any vertebral involvement, but was normal. Thus based on -1) H/O Relapsing fever; 2) Occupational history with exposure to domesticated livestock and consumption of raw, unpasteurised milk; 3) Musculoskeletal symptoms like backache; 4) Laboratory evidence of High Brucella titre and Positive blood culture. a diagnosis of Human Brucellosis was confirmed. He was discharged and maintained at the following regimen-1. Inj. Streptomycin 0.75gm IM for 21 days 2. Cap. Doxycycline 100mg p.o Bd for 6 weeks.
On follow-up, the patient was asymptomatic, afebrile and had resumed his routine activities. Our patient had presented with Fever with Acute psychosis which is an unusual presentation of Brucellosis and hence would have been misdiagnosed. These unusual features of brucellosis may be underestimated components of the disease.

Human Brucellosis
Brucellosis is a bacterial zoonosis transmitted directly or indirectly to humans from infected animals, predominantly domesticated ruminants a nd swine 6 . The disease has various names including Mediterranean fever, Malta fever and gastric remittent fever. It is also called as undulant fever because of its remittent character 6 . Brucella organisms, which are small aerobic intracellular coccobacilli, localize in the reproductive organs of host animals, causing abortions and sterility. They are shed in large numbers in the animal's urine, milk, placental fluid, and other fluids. To date, 8 species have been identified, named primarily for the source animal or features of infection. Of these, the following 4 have moderate-to-significant human pathogenicity 6

Epide miology
Brucellosis causes more than 500,000 infections per year worldwide. Its geographic distribution is limited by effective publi c and animal health programs, and the prevalence of the disease varies widely from country to country 1.

Modes of Transmission
1) Ingestion; 2) Inhalation; 3) Mucosal or percutaneous exposure; 4) Person-to-person (rare) 6 Human Brucellosis is usually associated with accidental occupational or domestic exposure to infected animals or their produc ts 6 . 3.1.3 High-risk groups-Farmers, shepherds, goatherds, veterinarians, laboratory workers and employees in slaughter houses and meat-processing plants 6 .

Pathogenesis
i. Brucella can gain entry into the human body through breaks in the skin, mucous membranes, conjunctivae, and respiratory and gastrointestinal (GI) tracts. ii. Once within the bloodstream, the organisms quickly become intracellular pathogens contained within circulating polymorphonucl ear cells (PMNs) and macrophages, making use of numerous mechanisms to avoid or suppress bactericidal responses. iii. The organism is a -stealth‖ pathogen whose survival strategy is centered on processes that avoid triggering innate immune res ponses and permit survival within the monocytes 6 .The smooth Brucella LPS, plays a key role in pyrogenecity and in resistance to phagocytosis 6 . iv. Brucellae that survive are transported into the lymphatic system and may replicate there locally; they also may replicate in the kidney, liver, spleen, breast tissue, or joints, causing both localized and systemic infection.

Clinical Features 3.3.1 Incubation period-
1week to several months 6 . The fever of brucellosis shows an undulating pattern that persists for weeks before commencement of an afebrile period that may be followed by relapse. It is usually associated with profuse sweats, especially at nights 6 .
Fever of unknown origin (FUO) is a common initial diagnosis in patients in areas of low endemicity 7 . Constitutional symptoms of brucellosis include anorexia, asthenia, fatigue, weakness, and malaise, and weight loss and are ve ry common (> 90% of cases).

Musculoskeletal involve ment
The most common are musculoskeletal pain and physical findings in the peripheral and axial skeleton ( 40% of cases). Osteomye litis more commonly involves the lumbar and low thoracic vertebrae than the cervical and high thoracic spine. Individual joints that are most commonly affected by septic arthritis are the knee, hip, sacroiliac, shoulder, and sternoclavicular joints; the pattern may be one of monoarthriti s or polyarthritis. Osteomyelitis may also accompany septic arthritis. Hence, Tuberculosis of spine should be always ruled out.

Cardiovascular involve ment
Endocarditis from brucellae(~1%) affecting aortic valve commonly(native and prosthetic) is reported, with septic embolization a common complication of this form of brucellosis. Other cardiac complications, such as pulmonary edema or dysrhythmia s, are rare. Brucella endocarditis is the form most commonly associated with fatalities.

Neurobrucellosis
It refers to a variety of neurological complications associated with brucellosis. Direct invasion of the central nervous system occurs in about 5% of cases of B. melitensis infection, and meningitis or meningo-encephalitis are the most common manifestations. Brucella meningitis can be acute or chronic. Analysis of cerebrospinal fluid (CSF) usually reveals elevated protein content, normal or low glucose concentration, and a lymphocytic pleocytosis.
Our patient had presented with acute psychosis, but his CSF picture was non-conclusive. This suggests that though rarely but brucellosis can present with neuropsychiatric symptoms without even actual involvement of CNS. Similarly it can spread throughout the body to infect almost every organ including respiratory, genito-urinary, skin and eye 8.

Diagnostic Work-up
1) All routine investigations like hemogram, LFT, RFT,etc 2) Culture-Diagnosis of brucellosis is definitive when Brucella organisms are recovered from blood, bone marrow, or other tissue. Because the reticuloendothelial system holds a high concentration of brucellae, bone marrow culture is thought to be the criterion standa rd. Sensitivity is usually 80-90% 9 . 3) Serology-Serologic testing is the most commonly used method of diagnosing brucellosis. Repeated serologic testing is recommended if the initial titer is low. The tube agglutination test is the most popular test tool for the diagnosis of brucellosis. Titers higher than 1:160 in conjunction with a compatible clinical presentation are considered highly suggestive of infection. Enzyme-linked immunosorbent assay (ELISA) typically uses the cytoplasmic proteins as antigens and measures IgM, IgG, and IgA is also used 10  Triple drug regimen including an initial course of an aminoglycoside (streptomycin) combined with rifampin and doxycycline for 6months. Inj.Ceftriaxone 1-2gm IV 12hourly can be added effectively as a supplementation to the above standard regimen.

Prognosis
Relapse occurs in up to 30% of poorly compliant patients. Mortality is less than 1%.Death is usually a consequence of cardiac involvement. 6 Vaccine based on live attenuated Brucella strains, such as B. abortus 19BA or 104M and B. Melitensis strain 16M have been tried but use is limited due to short-term efficacy and high reactogenicity.

Prevention and patient education
Promoting animal vaccination, control of animal movement, protective devices for the lab workers, general awareness, hygienic farming and rearing practices and pasteurization of all milk products can help in preventing animal-to-human transmission.

Conclusion
Our case is unique and interesting due to unusual presentation of Brucellosis as fever with acute psychosis, which without hi gh index of suspicion would have lead to erroneous diagnosis. Our report emphasizes the need to remind clinicians to consider brucellosis in the differential diagnosis of unexplained febrile illness. We also hope to inspire clinicians to obtain information about patient activities including trav el, food-consumption, occupation and outdoor recreation such as wild-swine hunting. Early identification and diagnosis of Brucellosis can help to prevent significant mortality and morbidity.