BRUCELLOSIS / MedUrgent

BRUCELLOSIS

(Malta fever, Undulant Fever, Common Remittent Fever, Mediterranean fever)

Brucellosis is a zoonotic disease caused by the non-motile gram negative coccobacilli. Recognized forms include Brucella abortus cattle and camels), B.melitensis (goats and sheep), B. suis (pigs and rodents) and B. canis (wild rodents and dogs). The bacteria are excreted in milk, urine and genital discharge. Humans contract the disease through direct contact with infected animals and their carcasses or secretions. Other modes of transmission include unboiled or pasteurized milk and handling of fresh infected meat. Infection may be transmitted by ingestion, inhalation or through abrasions of the skin and mucosa and the incubation period varies from one to 4 weeks.

Brucella abortus: This is the least virulent of the forms of infection and is a primary disease in cattle. No serious disease is usually seen but the organisms are secreted in the milk from the mammary glands for a long period of time. Infection of the genital tracts, placenta, and amniotic fluid can lead to abortion of pregnant cattle. B. Abortus fever is endemic in North America, Europe and Africa to a lesser extent.

Brucella melitensis: This is a primary infection of sheep and goats in which the disease is often mild and in apparent.It causes no abortion in infected animals, but the urine, milk, stools, uterine and vaginal discharges become heavily infected. This species is considered to be the most virulent and in humans it can cause a severe illness and suppuration. It is considered to be endemic in the Mediterranean region and Africa including Sudan.

Brucella Suis: this is a primary infection of pigs. It may be found both in the secretions (milk) and the meat. Therefore, pork eaters are at a risk of contracting the diseases. It is endemic in North America and Europe but not described in Africa. Other animals such as dogs, horses, and wild rodents may also be infected.

Route of transmission 1- GIT: This is the major route of transmission and is due to the ingestion of contaminated raw milk or milk products eg cheese and ice-cream.

2- Skin: Via the products of the infected animal eg placenta, amniotic fluid through contact with an abraded or ulcerated skin.

3- Inhalation: of animal disuse or the dust of their products. 

4-Conjunctiva: If these come in contact with infected material, then uveitis may develop as well as neuritis. Generally, brucellosis is an occupational disease seen more commonly among herdsmen, farmers, slaughter house workers and meat packers.

From the entry site, bacteria are transmitted through lymphatics to the reticulo-endothelial system leading to granuloma or abscess formation. The parasite is essentially intracellular and within the host, the organisms are engulfed by polymorphs, or settle in the lymph glands from where they are taken by the lymphatics to the reticuloendothelial system (liver, spleen, lymph nodes, bone marrow or the kidney) . The granuloma consists of macrophages with central caseation and abscess formation particularly with B. Suis. Liberation of bacteria is followed by invasion of the blood, leading to bacteraemia, endotoxin liberation and formation of antibodies (B.abortus: IgA, B.melitensis: IgM, B.suis: IgA and IgM).

Immunologically, two types of reactions are seen:

(a) The first is a cellular hypersensitivity reaction showing the classical microgranuloma. It may occur in various organs and consists of lymphocytes, giant cells, epithelioid cells, necrosis and center of caseation. The hypersensitivity can be manifested by skin reactions. (b) The second type is a humoral reaction. Brucella species produce the main antigens which stimulate IgA and IgM antibody production. These antibodies form the basis for the Widal test and the Coombs test for brucellosis. The organisms multiply in the mononuclear cells leading to their distention and rupture. This is followed by the release of pyrogenes that cause the febrile episode, and it is this mode which is responsible for the periodic nature of the fever.

CLINICAL MANIFESTATIONS

The disease may be asymptomatic with only accidental finding of positive serological test, positive brucellin test or by detection of the organisms in the urine. It may present as acute brucellosis and may present with complications with periods of high grade fever, profuse sweating, arthralgia, anemia, psychic symptoms, hepatosplenomegaly and weight loss.

Acute Brucellosis: has an incubation period of 1-3 weeks, with either a very rapid or gradual onset. Symptoms include fever with chills but characteristic undulations occur after 7-10 days. The fever may he associated with profuse nocturnal sweating, persistent headache, backache accompanied by tenderness of the spine, arthralgia or arthritis of big joints and mental symptoms such as depression, acute psychoses,

insomnia or nervousness on the 5th or 7th day. Some patients may present with excessive weight loss despite good appetite and dragging pain in the left quadrant of the abdomen due to the grossly enlarged spleen.

Hepatomegaly is seen less commonly in about 8-10% of the patients: however, lymphadenopathy is seen in approximately 40-50% of patients. The nodes are firm or soft, discrete and tender. Lymphnodenopathy commonly affected are the cervical, supraclavicular and axillary nodes.

Chronic brucellosis usually presents with general ill health, anorexia, weight loss, low grade fever, sweating, general fatigue and headache, but the patient remains ambulant. However, mental symptoms such as depression may be present.

Relapses may occur in 10-15% of treated patients. Common manifestations and complications include:

• Arthritis: Distressing pain with limitation of movement involving the large joints that become swollen and painful with fluid accumulation. In the sacro-iliac joint it causes sacroilitis. The intervertebral joints may be affected leading to destruction of the spine, vertebrae, and intervertebral discs with symptoms and signs of root pain or paraplegia. Pain and swelling may extend to the extra-articular connective tissue. The organisms and may antibodies be found in the exudates. Radiologically: osteosclerosis of the affected bones may be demonstrated, however, osteomyelitis seldom occurs.

• Splenomegaly: Huge spleen is a common finding and it may lead to dragging left hypochondrial pain, infarction, peri-splenitis and hypersplenism that leads to pancytopoenia. Splenomegaly may be associated with suppuration and abscess formation.

• Lymphadenopathy: Commonly affect the cervical, supraclavicular and axillary lymph nodes.

• Hepatomegaly: Enlarged tender liver with or without jaundice which is secondary to involvement of the reticular endothelial system. Liver granuloma and abscess formation may occur

• Anemia: Moderate to severe anemia due to hypersplenism

• Dermatosis: Various types of skin lesions are seen and may be associated with peripheral neuritis. Skin sensitivity reactions may occur in those who handle animal products. Respiratory System: Pneumonia, pleural effusion and empyema are common

• CNS: cranial nerve palsy, meningitis, encephalomyelitis that may be associated with cranial nerve palsies, depression and suicidal attempts

• CVS bacterial endocarditis in patients who already have valvular heart disease which is almost always fatal. Thrombophlebitis may also occur.

• Eyes: Uveitis, keratitis and choroiditis

• Genito-urinary System: Pyelonephritis and epididymo-orchitis

 

Investigations

• Complete blood count shows anemia of chronic disease, leucopenia with relative lymphocytosis and high ESR

• Blood culture, however, results of culture take weeks to appear

• Occasionally the organisms may be recovered from the urine, bone marrow aspirate, LN aspirate, joint fluid or splenic aspirate

• Liver biopsy may establish the diagnosis by demonstration of the characteristic microgranuloma

• Widal test for brucellosis (a significant titer of 1/160 or above)

• Anti-human globulin test such as Coombs test for Brucellosis does not differentiate between an active recent or past infection - Complement Fixation test

• ELISA                           

• PCR

• Brucellin test which is similar to the tuberculin test. 0.1ml of a polyvalent antigen is injected intradermally and a reaction develops after 2436 hours. Although a negative skin test does not exclude brucellosis, similarly a positive reaction does not differentiate between past or recent infections. This is mainly used for epidemiological studies or research.

Treatment in adults

• The disease may be self-limiting with recovery in 50% of patients within one year in untreated cases. The death rate is 2% and is mainly due to endocarditis. o Bed rest, good diet, multivitamins and iv fluids to replace deficit due to excessive sweating

• Antipyretics (paracetamol 13 - 15 mg/kg/day in divided 4 doses - PRN)

• Chemotherapy Tetracycline 500mg given 4 hourly or 6 hourly given orally on daily basis for approximately 3 weeks for the acute febrile non-complicated cases. Streptomycin 1g daily by 1/M may be given as a combined treatment of as alternative, Co-trimoxazole 2 tables twice daily for 4 weeks to reduce the relapse rate.

 Combination therapy of two of the following drugs:

1. Rifampicin 15mg/kg/day orally for 6 weeks

2.Trimethoprim sulfamesaxasole (4mg+20mg/kg/day in 2 divided doses) for 6 weeks or Gentamycin 4 - 7 mg/kg/day im for 2 weeks

• Relapses (10 - 15%) should be treated similarly.

• Brucella endocarditis: Hydrocortisone may be added.

• Chronic infection, the combination of tetracycline and streptomycin may be used but for 6-12 weeks). Rifampicin 300 mg - 600 mg daily may be used instead of the streptomycin, and Co-trimoxazole as an alternative to tetracycline.

For Brucella endocarditis, Tetracycline at the same dose as above as well as Gentamycin given intramuscularly at a dose of 5mg/kg/day is used for approximately 12 weeks. (Rifampicin may be used instead of the gentamycin). In the very ill patients a short course of hydrocortisone 100mg IV every 8 hrs is given for 4 days.

The best form of treatment now considered is Rifampicin 600mg/day and Doxycycline 100mg/day for 6 weeks. Another combination is tetracycline for 6 weeks with streptomycin for the first three weeks.

 

Treatment in children

A combination therapy of two of the following drugs may be used:

• Rifampicin 15mg/kg/day orally for 6 weeks

• Trimethoprim sulfamethazole is given orally (4mg+20mg/kg) for 6 weeks. Gentamycin IM in a dose of 4-7mg/kg/day for 2 weeks.