Brucellosis – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

  • Systemic bacterial infection caused by Brucella sp. in infected animal products or vaccine
  • Incubation period usually 5–60 days, but highly variable and may be several months
  • Characterized by intermittent or irregular fevers, with symptoms ranging from subclinical disease to infection of almost any organ system
  • Bone and joint involvement common
  • May be chronic or recurrent
  • System(s) affected: Cardiovascular; Endocrine/Metabolic; GI; Musculoskeletal; Nervous; Pulmonary; Renal/Urologic; Skin/Exocrine
  • Synonym(s): Undulant fever; Malta fever

Pediatric Considerations

May be mild, subclinical

Pregnancy Considerations

High rates of miscarriage or abortion (can occur in subclinical cases). Early antibiotic treatment is preventive.

Epidemiology

  • Predominant age: All ages, but especially 20–60 years (occupational exposure), sometimes children (milk-related outbreaks)
  • Predominant gender:
    • Male > Female (occupational exposure)
    • Female ≥ Male (milk exposure)

Incidence

∼100 per year (0.34/100,000), but probably underreported (1,2)

Prevalence

  • Common in developing countries; consider in immigrants
  • Highest rates in Hispanic population along US–Mexico border
  • Considered a potential biologic terror agent in aerosolized form
  • Reportable in all states except Nevada

Risk Factors

  • In US, from occupational exposure to infected animals (especially cattle, sheep): Veterinarians, meat processors, farm workers who may experience accidental exposure to vaccine
  • Consumer exposure to unpasteurized milk products, cheese, especially Hispanics along US–Mexico border
  • Exposure while traveling in countries where endemic (Mediterranean, Middle East, North and East Africa, central Asia, India, Mexico, Central and South America)
  • Worse in chronically ill, immunosuppressed, and malnourished
  • Iron deficiency increases susceptibility.

Genetics

  • Some evidence for intrauterine transmission
  • Some complications may have genetic predisposition (2).

General Prevention

  • Avoid infected dairy products.
  • For occupational exposure, use caution, animal vaccination, protective goggles, protective gloves. Possibility exists for future human vaccine.
  • Postexposure prophylaxis same as treatment in large-scale exposure such as bioterrorism
  • Susceptible to heat, disinfectant, but can survive in dust, soil, or water for weeks

Etiology

  • Brucella ingestion from tissue or milk
  • Worst disease: B. melitensis, B. suis; also B. canis, B. abortus; enters through mucous membrane or broken skin; occasionally inhaled
  • Facultative intracellular parasite
  • Person-to-person transmission rare; sexual, vertical, and possibly breast milk; case report of neonatal brucellosis from a blood transfusion
  • Potential airborne biologic weapon

Immunoglobulin G, Immunoglobulin M, Brucella, Chickenpox, malta fever, accidental exposure, iron deficiency, bacterial infection, musculoskeletal, immunosuppressed, antibiotic treatment, Diagnosis

Physical Exam

  • Fever (may be undulant, increased in afternoon and evening, maximum 101–104°F daily), weakness, headache, sweating, chills, generalized aching, arthralgia (90%) (2)[A]
  • Also common: Weight loss, depression, irritability, hepatosplenomegaly (20–30%)
  • Hepatic dysfunction (abnormal liver function test): 30–60%
  • GI symptoms (unusual)
  • Lymphadenopathy, especially cervical, inguinal (12–21%)
  • Orchitis, epididymitis (normal urinalysis) (2–40%)
  • Nephritis, prostatitis (rare)
  • Cystitis
  • Pulmonary: Cough or other pulmonary symptoms; radiograph may be normal (15–25%)
  • Cutaneous: Many transient, nonspecific rashes have been described; also, purpura from thrombopenia (5%)
  • Visual disturbances, eye pain
  • Chronic fatigue syndrome and various neuropsychiatric symptoms described. Relationship is unclear.
  • Also localized suppurative infections (see Complications)
  • Malodorous perspiration (2)
  • Noncaseating granulomas (1); possibly some

Diagnostic Tests & Interpretation

Lab

Initial lab tests

  • Isolation of organism from blood, discharge, bone, or other tissue: Bone marrow is gold standard (3)[A]:
    • Fastidious and slow growing
    • Watch for 3–4 weeks, with periodic subcultures
    • Automated systems shorten time, but not all recognize brucellosis.
    • Polymerase chain reaction (PCR) accurate, including nonblood samples, but not available in most clinical labs (3)[A]
    • Skin tests not standardized; not recommended for diagnosis
  • Acute illness: Blood culture positive 70%, bone marrow 90%
  • May have thrombocytopenia, disseminated intravascular coagulation, granulopenia, lymphopenia, lymphocytosis
  • 30–60% with abnormal liver function test
  • Up to 70% may have normal labs.
  • Serology: Use at least 2 tests to confirm (4)[A]:
    • Brucella standard tube agglutination paired sera, >1:160 or 4× rise (cheapest)
    • Easy, accurate, and rapid dipstick for IgM now exists for developing countries.
  • More effective enzyme linked immunosorbent assay (ELISA), indirect fluorescent antibody test, Coombs tests, immunocapture-agglutination (Brucella apt). With ELISA, IgM, IgG, or IgA may be present at low levels >1 year even if treated.
  • IgM increases initially for several weeks, declines by 3 months
  • IgG begins to rise in 2 weeks, may stay up (low levels) for >1 year if treated or not treated (although IgM increase may be lower or gone by 6 months if treated; can also persist >1 year at low levels). IgG titer rises again with reinfection or reactivation. IgG and IgA titer >1:160 at 1 year implies ongoing disease (4)[A].
  • New research: Gene cloning and amplification for discriminatory markers detection and strain differences; PCR-ELISA
  • Drugs that may alter lab results: None
  • Disorders that may alter lab results:
    • Serologic cross-reaction with F. tularensis, Yersinia enterocolitica, V. cholerae, or vaccinated patients
    • Has been misdiagnosed in culture as Moraxella phenylpyruvica

Imaging

  • Bone scan, computed tomography, depending on location
  • Chest x-ray: Pleural effusion, lung cavitation
  • Joint radiographs frequently normal, requiring scan or magnetic resonance imaging

Diagnostic Procedures/Surgery

Bone marrow biopsy, biopsy of affected area

Pathological Findings

  • Facultative intracellular gram-negative coccobacillus; can survive inside phagocytic cells, circulation lymph nodes, and into circulation
  • Immune reaction in arthritis, including elevated C3, C4; antinuclear antibody, and rheumatoid factor
  • Variable tissue reaction depending on site, organisms; causes local microabscesses

P.199

Differential Diagnosis

  • Many nonspecific systemic febrile illnesses; a great mimic
  • Tularemia
  • Psittacosis
  • Rickettsial disease
  • Tuberculosis
  • Visceral leishmaniasis
  • Other disease of infected organs
  • HIV infection

Treatment

Medication

First Line

  • Optimal therapy includes 2 drugs, at least 1 with good intracellular penetration. In some cases, 3 drugs may give a better long-term cure.
  • Longer courses (months) may improve relapse rate in complicated disease.
  • Rifampin 600–1,200 mg and doxycycline 200 mg given together every day for at least 6 weeks (possibly for several months with severe complications):
    • 5–10% relapse rate, not related to drug resistance; use same drugs for relapse
    • Usual cause is localized sequestration of organisms or noncompliance with medication (5)[A]
  • Steroids in Herxheimer reaction, severe illness, and pancytopenia
  • Contraindications:
    • Avoid doxycycline in children and pregnant women (affects bone).
  • Precautions:
    • May get Herxheimer reaction when therapy initiated
  • Significant possible interactions:
    • Rifampin is a potent inducer for the hepatic P450 enzyme system, and may increase metabolism of many drugs metabolized by the liver.
    • Doxycycline: Antacids, anticoagulants, barbiturates, carbamazepine, hydantoins, cimetidine, digoxin, insulin, iron salts, lithium, methoxyflurane, oral contraceptives, penicillins, sodium bicarbonate

Second Line

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  • Doxycycline orally b.i.d. and streptomycin by injection is very effective (streptomycin currently not available in the US except by special request from Centers for Disease Control); slightly more effective than doxycycline/rifampin, especially with spondylitis, but more toxic and less convenient (5).
  • In children and pregnant women, rifampin 15 mg/kg for 4–5 weeks plus cotrimoxazole for 6 weeks or gentamicin for 7 days or netilmicin 5–6 mg/kg IM. Significant cotrimoxazole resistance in some countries (1)[A].
  • Ofloxacin or ciprofloxacin plus rifampin effective in a recent study, but not as effective as 1st-line treatment (6)[A],(7)[B].
  • Sensitivities don’t reflect in vivo action (2)[A].

Additional Treatment

General Measures

  • Supportive care
  • In milk-related or occupational outbreak, look for other cases.
  • Bed rest during febrile periods and restricted activity in acute cases

Issues for Referral

Need for procedures

Surgery/Other Procedures

Specific complications may require surgical drainage or valve replacement (endocarditis).

In-Patient Considerations

Admission Criteria

  • Outpatient in mild cases, hospitalization in severe illness
  • Cardiac care unit for patients with complicating cardiac disease

Ongoing Care

Follow-Up Recommendations

Patient Monitoring

  • Check serology at 6 months and 1 year for chronic disease (difficult to evaluate if continuing exposure).
  • Investigate any suspicion of recurrence.
  • PCR recently shown to be sensitive and specific for monitoring treatment relapse

Diet

  • No special diet
  • May need to provide supplemental foods, such as milkshakes, to counter weight loss

Patient Education

  • Food Safety and Inspection Service, Office of Public Awareness, Department of Agriculture, Room 1165-S, Washington, DC 20205; (202)720-9904; http://www.fsis.usda.gov/
  • Education about exposure

Prognosis

  • Untreated case fatality <2%
  • Most cases resolve with treatment in 2–3 weeks in acute uncomplicated cases, but at least 6 weeks treatment recommended

Complications

  • Relapse rate overall: 5–10%
  • Complications present: 10–15% (4)[A]
  • Localized suppurative infections: Osteoarticular (20–85%). Includes arthritis (possibly also immune effect), bursitis, tenosynovitis, osteomyelitis, sacroiliitis, vertebral or paraspinous abscess
  • Endocarditis: Rare, but main cause of death in brucellosis
  • Thrombophlebitis
  • Neurobrucellosis: Most are meningeal. Also peripheral neuritis (usually single; bilateral is possible), encephalitis, myelitis, radiculopathy. Possibly neuropsychiatric symptoms.
  • Intrinsic ocular lesions: Uveitis, retinal thrombophlebitis, nummular keratitis
  • Pneumonitis with pleural effusion
  • Hepatitis
  • Cholecystitis
  • Chronic infection: Persistent (>1 year) signs of infection, elevated titers, occasional bacteria in blood or tissue. Chronic fatigue syndrome with everything negative is controversial.

References

1. Sauret JM, Vilissova N. Human brucellosis. J Am Board Fam Pract. 2002;15:401–6.

2. Pappas G, et al. Brucellosis. N Eng J Med. 2005;352(22):2325–36.

3. Al Dahouk S, Tomaso H, Nöckler K, et al. Laboratory-based diagnosis of brucellosis–a review of the literature. Part I: Techniques for direct detection and identification of Brucella spp. Clin Lab.2003;49:487–505.

4. Al Dahouk S, Tomaso H, Nöckler K, et al. Laboratory-based diagnosis of brucellosis–a review of the literature. Part II: serological tests for brucellosis. Clin Lab. 2003;49:577–89.

5. Pappas G, et al. New approaches to the antibiotic treatment of brucellosis. Intl J Antimicrob Ag. 2005;26(2):101–5.

6. Skalsky K, Yahav D, Bishara J, et al. Treatment of human brucellosis: systematic review and meta-analysis of randomised controlled trials. BMJ. 2008;336:701–4.

7. Keramat F, Ranjbar M, Mamani M, Hashemi SH, Zeraati F, et al. A comparative trial of three therapeutic regimens: ciprofloxacin-rifampin, ciprofloxacin-doxycycline and doxycycline-rifampin in the treatment of brucellosis. Trop Doct. 2009;39:207–10.

Codes

ICD9

023.9 Brucellosis, unspecified

Snomed

75702008 Brucellosis (disorder)

Clinical Pearls

  • Infection is caused by infected animal products or animal vaccine. More common outside US. In US, most cases result from occupational exposure to infected animals (especially cattle, sheep): Veterinarians, meat processors, and farm workers who may experience accidental exposure to vaccine and ingestion of raw milk.
  • Characterized by intermittent or irregular fevers, with symptoms ranging from subclinical disease to infection of almost any organ system
  • Concern that this may become a weaponized bioterrorism agent

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