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Brucellosis Treatment & Management

  • Author: Wafa Al-Nassir, MBBS; Chief Editor: Michael Stuart Bronze, MD  more...
 
Updated: Mar 15, 2016
 

Approach Considerations

The goal of medical therapy in brucellosis is to control symptoms as quickly as possible in order to prevent complications and relapses.

Initial care for brucellosis is supportive. Given the nonspecificity of patient complaints, a diagnosis of brucellosis in the emergency department (ED) is unlikely. With an appropriate history, an astute clinician may suspect it. Appropriate precautions (eg, mask, gloves, and eye protection) should be taken for respiratory procedures or handling body fluids. Specimens from the patient should be handled in the laboratory under biosafety level III conditions.

Multidrug antimicrobial regimens are the mainstay of therapy because of high relapse rates reported with monotherapeutic approaches. The risk of relapse is not well understood; resistance is not a significant issue in treating brucellosis.[52]

Depending on what other systems are involved, more specialized care may be needed. Transfer to another facility depends on the needs of the patient. Because most patients do not require highly specialized interventions, the need to transfer should not be frequent. Personnel involved in the transfer should maintain respiratory and contact precautions, and the vehicle should be decontaminated after transport as needed.

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Initial Supportive Care

Given that the symptoms generally are vague and the presentation is rarely life-threatening, emergency medical service (EMS) care should focus on stabilization, as needed, and transport. As in the care of any patient with a potentially transmissible disease, appropriate precautions (eg, gloves, mask, and gown) should be used.

If a proximate bioterrorist attack is known or strongly suggested at the time of patient contact, appropriate decontamination is warranted. In the event of a covert undiscovered attack, patients may become symptomatic well after the time that decontamination is necessary. If the patient presents as part of a known, immediately proximate bioterrorism incident, EMS providers should notify the hospital to undertake appropriate decontamination and isolation measures.

Respiratory isolation usually is not necessary, provided that close contact with the respiratory tract is not made. Masks should be worn for intubation, suctioning, or other maneuvers that may expose the caregiver to a large concentration of aerosolized particles. Supportive care should be provided for any specific symptoms, and appropriate tests should be targeted to affected organ systems as determined by the history and physical findings.

The development of an effective Brucella vaccine for use in humans would be an important step to controlling and probably eradicating brucellosis. However, the vaccine strategy is currently applicable only in control of livestock disease.

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Pharmacologic Therapy

Antibiotics

Although multiple antibiotics display in vitro activity against Brucella species, clinical response has been demonstrated with only a limited number of agents. Drugs that display clinical activity with low relapse rates include the following:

  • Doxycycline
  • Gentamicin
  • Streptomycin
  • Rifampin
  • Trimethoprim-sulfamethoxazole (TMP-SMZ)

Other agents with potential roles include the following:

  • Chloramphenicol
  • Imipenem-cilastatin
  • Tigecycline
  • Fluoroquinolones

In those cases where relapse has occurred, the development of antibiotic resistance does not appear to be the underlying cause.

Optimal antibiotic therapy for brucellosis has been studied to some degree; however, recommendations may differ.

For simple infection, doxycycline (100 mg PO twice daily for 6 weeks) may be the most appropriate monotherapy; however, relapse rates with such monotherapy approach 40% and as a result, rifampin (600-900 mg/day) is usually added. Fluoroquinolones (eg, ciprofloxacin) have been used as monotherapy as well but also carry a high relapse rate; adding these agents to doxycycline offers no specific advantages over other combination regimens but may be preferred in areas where resistance to rifampin is high.

For acute brucellosis in adults and children older than 8 years, the World Health Organization (WHO) guidelines recommend the following:

  • Doxycycline 100 mg PO twice daily plus rifampin 600-900 mg/day PO – Both drugs are to be given for 6 weeks; this regimen is more convenient but probably increases the risk of relapse
  • Doxycycline 100 mg PO twice daily for 6 weeks and streptomycin 1 g/day IM for 2-3 weeks – This regimen is believed to be more effective, mainly in preventing relapse; gentamicin can be used as a substitute for streptomycin and has shown equal efficacy
  • Ciprofloxacin-based regimens have shown efficacy equal to that of doxycycline-based regimens

A 2012 Cochrane review found that a regimen consisting of doxycycline for 6 weeks plus streptomycin for 2-3 weeks was more effective than one consisting of doxycycline plus rifampicin for 6 weeks.[53] The investigators also found that a regimen consisting of a fluoroquinolone plus rifampicin for 6 weeks was as effective overall as doxycycline plus rifampin (though the evidence for this conclusion was of low quality) and was slightly better tolerated.

For brucellosis in children younger than 8 years, administration of rifampin and TMP-SMZ for 6 weeks is the therapy of choice.[54, 55] The relapse rate appears to be approximately 5% or lower.

Treatment of brucellosis in pregnant women is a challenging problem, and the available data are limited. TMP-SMZ has been effective in this population, either as monotherapy or as part of combination therapy with rifampin or gentamicin. The most common recommendation is for rifampin, either alone or in combination with TMP-SMZ. It should be kept in mind that the use of TMP-SMZ by the end of pregnancy is associated with kernicterus.

In patients with spondylitis or sacroiliitis, doxycycline and rifampin combined with an aminoglycoside (gentamicin) for the initial 2-3 weeks, followed by 6 weeks of rifampin and doxycycline, is usually recommended.

Patients with nervous system infections typically require combination therapy. Doxycycline is generally preferred to tetracyclines or aminoglycosides because the latter are less likely to cross the blood-brain barrier in adequate quantities. Many authorities prefer a 3-drug (doxycycline-streptomycin-rifampin or doxycycline−TMP-SMZ−rifampin) regimen to a 2-drug regimen. A brief course of adjunctive corticosteroid therapy has been used to control the inflammatory process, but studies are limited.

Third-generation cephalosporins have been used in Brucella meningitis, but susceptibility is variable and must be ensured by in vitro sensitivity studies. Duration of therapy has ranged in various cases from 1-19 months, with treatment continued until the cerebrospinal fluid (CSF) is found to be without evidence of organisms or inflammation. In the year following cessation of treatment, agglutinins for Brucella should be followed in serum to ensure that relapse does not occur.

Some patients presenting with acute brucellar meningoencephalitis cannot be distinguished reliably from patients with herpes encephalitis, and the presentations of other patients may not be distinguishable from that of bacterial meningitis. In such cases, the initial therapeutic interventions should include agents appropriate for the management of those conditions.

Patients with endocarditis require aggressive therapy. Aminoglycoside therapy in conjunction with doxycycline, rifampin, and TMP-SMZ for at least 4 weeks, followed by at least 2-3 active agents (without aminoglycosides) for another 8-12 weeks, is preferred.

Chronic brucellosis is treated with triple-antibiotic therapy. The combination of rifampin, doxycycline, and streptomycin often is used.

Corticosteroids and other agents

The use of corticosteroids is reserved for symptomatic Brucella meningitis. Although these agents are generally recommended, scientific evidence supporting their use is lacking. No consensus exists on optimal dosing, frequency, or duration of therapy.

Any additional drugs needed for symptomatic treatment (eg, antipyretics, analgesics) must be administered as well. Additional medication is based on the patient’s presenting symptoms.

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Surgical Intervention

The main roles of surgery in patients with brucellosis lie in the treatment of endocarditis and in the drainage of pyogenic joint effusions or paraspinal abscesses.[56, 57]

Previously healthy native valves, diseased native valves, and prosthetic valvular structures have been involved in brucellosis.[58] Valvular lesions are typically large and destructive, regardless of the organism involved. Accordingly, valve replacement surgery is often recommended in addition to a prolonged course of antibiotics.

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Diet and Activity

No special diet is required for the treatment of brucellosis. Discuss with patients the importance of consuming pasteurized milk and milk products and avoiding other possible sources of infection. Obviously, the impact of such education will have the greatest effect on family and friends who may be at risk for infection.

Restriction of activity with bed rest appears to confer benefit in the acute phase of brucellosis, increasing the rate of recovery.

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Prevention

Prevention of brucellosis in humans depends on eradication or control of the disease in animals and on avoiding potential sources of infection. Better handling of infected animals or animal products is paramount. Public awareness and education play major roles in prevention.

Consumption of unpasteurized milk and milk products, as well as of raw or undercooked meats, should be avoided. Education may be provided to the patient and family concerning risks and should emphasize avoiding anything identified as a specific cause in the case at hand. Should the identified source be a live animal, the herd or flock from which it came should be investigated. In endemic areas, investigation is warranted for all animals.

Scrupulous hygiene may prevent infection, especially when practiced by individuals likely to have close contact with goats, sheep, cows, camels, pigs, reindeer, rabbits, or hares. Obviously, this contact is of greatest importance in areas of endemic disease.

At present, immunization is not an option for patients; the vaccine is attenuated for animals but not for humans and may cause disease in humans.[59] However, immunization of at-risk animals reduces the number of infected animals and therefore the reservoir of infection. Results from a study of the planned brucellosis control program in Egypt showed that removal of infected animals under the actual implementation of the program would likely permit brucellosis to remain endemic in the goat and sheep population.[60]

All persons with an occupational risk for brucellosis should be informed about the use of protective devices (eg, goggles, masks, and gloves) to avoid exposure to aerosols, body fluids, or the brucellosis vaccine. In particular, laboratory personnel should be advised of the potential diagnosis so they will use biosafety level-3 precautions when in contact with suspicious specimens.

Bioterrorism

Serious concerns have been expressed concerning the utilization of Brucella species in biologic weapons. Airborne transmission of these bacteria is readily achieved via the mucous membranes of the conjunctivae, nasal passages, oropharynx, and respiratory tract. Infection may occur as the result of lodging of organisms in cuts or abrasions. As few as 10-100 organisms may produce infection via aerosol exposure. The resulting disease may exhibit any of the various manifestations of which Brucella species are capable.

Bichat guidelines have been established for the management of individuals at risk for or manifesting evidence of brucellosis after bioterroristic exposure. Treatment regimens combining doxycycline with either streptomycin or rifampin are thought adequate in such situations; the combination of ofloxacin with rifampin is also cited. To date, however, no studies have conclusively established the efficacy of postexposure prophylaxis as a method of preventing brucellosis.[61]

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Consultations

The primary specialist to consult is an infectious disease specialist. Proper serologic tests, cultures, further diagnostic evaluations, and the correct antibiotic therapy should be determined in collaboration with this specialist.

Depending on the clinical manifestations of the disease and the degree of damage to individual organ systems, additional specialists may be consulted, such as the following:

  • Orthopedic or neurologic surgeon (for management of inflammatory disturbances of vertebrae and spinal disks)
  • Cardiothoracic surgeon (if endocarditis is suspected or documented)
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Long-Term Monitoring

Outpatient care consists of completing the prescribed course of antibiotic therapy, treating any exposed patients, and avoiding contact with the initial source of infection. Care is continued until the infection is cured and laboratory findings return to reference ranges. Serologic studies and enzyme-linked immunosorbent assay (ELISA) can be used to document patient response to therapy. After an adequate course of therapy, persistent or recurrent symptoms of brucellosis should prompt a search for localized suppurative lesions.

Careful follow-up is essential for ensuring that the patient complies with the full 6-week antibiotic regimen and for determining whether a relapse has occurred. In some instances, the disease takes a relapsing and remitting course. In such cases, triple-drug therapy may be undertaken for periods as long as 6 months or more.

Relapsing brucellosis must be distinguished from instances of reinfection. The degree of immunity induced by an initial attack of brucellosis may be inadequate to prevent reinfection. Second, third, or even more instances of reinfection may occur, especially in veterinarians and other individuals who are continually exposed to animals.

Some individuals acquire infection-induced hypersensitivity to Brucella antigens. This may result in a severe local reaction caused by accidental self-inoculation with Brucella vaccines. Reactions of this sort are especially likely to be experienced by veterinarians and others who are responsible for inoculating animal herds.

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Contributor Information and Disclosures
Author

Wafa Al-Nassir, MBBS Infectious Diseases Consultant, National Guard Health Affairs, Saudi Arabia

Wafa Al-Nassir, MBBS is a member of the following medical societies: American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Coauthor(s)

Robert A Salata, MD Chief and Clinical Program Director of Division of Infectious Diseases, Vice Chair for International Affairs, Professor, Department of Medicine, Case Western Reserve University School of Medicine

Robert A Salata, MD is a member of the following medical societies: American Association of Immunologists, American Federation for Medical Research, American Medical Association, Central Society for Clinical and Translational Research, Infectious Diseases Society of America, Ohio State Medical Association, Society for Healthcare Epidemiology of America

Disclosure: Nothing to disclose.

Michelle V Lisgaris, MD Assistant Professor of Medicine, Case Western Reserve University School of Medicine

Michelle V Lisgaris, MD is a member of the following medical societies: American College of Physicians, American Medical Association, Infectious Diseases Society of America, Society for Healthcare Epidemiology of America

Disclosure: Nothing to disclose.

Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP Assistant Professor of Pediatrics, Co-Director of Antimicrobial Stewardship, Medical Director, Division of Pediatric Infectious Diseases and Immunology, Connecticut Children's Medical Center

Nicholas John Bennett, MBBCh, PhD, MA(Cantab), FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics

Disclosure: Received research grant from: Cubist Pharmaceuticals, Durata Therapeutics, and Biota Pharmaceutical<br/>Received income in an amount equal to or greater than $250 from: HealthyCT insurance<br/>Medico legal consulting for: Various.

Chief Editor

Michael Stuart Bronze, MD David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America

Michael Stuart Bronze, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, Oklahoma State Medical Association, Southern Society for Clinical Investigation, Association of Professors of Medicine, American College of Physicians, Infectious Diseases Society of America

Disclosure: Nothing to disclose.

Acknowledgements

Walid Abuhammour, MD, FAAP Professor of Pediatrics, Michigan State University College of Medicine; Director of Pediatric Infectious Disease, Department of Pediatrics, Hurley Medical Center

Walid Abuhammour, MD, FAAP is a member of the following medical societies: American Medical Association, Infectious Diseases Society of America, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Jeffrey D Band, MD Professor of Medicine, Oakland University William Beaumont School of Medicine; Director, Division of Infectious Diseases and International Medicine, Corporate Epidemiologist, William Beaumont Hospital; Clinical Professor of Medicine, Wayne State University School of Medicine

Disclosure: Nothing to disclose.

Nicholas John Bennett, MB, BCh, PhD Fellow in Pediatric Infectious Disease, Department of Pediatrics, State University of New York Upstate Medical University

Nicholas John Bennett, MB, BCh, PhD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Pediatrics

Disclosure: Nothing to disclose.

Itzhak Brook, MD, MSc Professor, Department of Pediatrics, Georgetown University School of Medicine

Itzhak Brook, MD, MSc is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians-American Society of Internal Medicine, American Federation for Clinical Research, American Medical Association, American Society for Microbiology, Armed Forces Infectious Diseases Society, Association of Military Surgeons of the US, Infectious Diseases Society of America, International Immunocompromised Host Society, International Society for Infectious Diseases,Medical Society of the District of Columbia, New York Academy of Sciences, Pediatric Infectious Diseases Society, Society for Ear, Nose and Throat Advances in Children, Society for Experimental Biology and Medicine, Society for Pediatric Research, Southern Medical Association, and Surgical Infection Society

Disclosure: Nothing to disclose.

Robert G Darling, MD, FACEP Adjunct Clinical Assistant Professor of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Director, Center for Disaster and Humanitarian Assistance Medicine

Robert G Darling, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, American Telemedicine Association, and Association of Military Surgeons of the US

Disclosure: Nothing to disclose.

Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University

Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Ronald A Greenfield, MD Professor, Department of Internal Medicine, University of Oklahoma College of Medicine

Ronald A Greenfield, MD is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Central Society for Clinical Research, Infectious Diseases Society of America, Medical Mycology Society of the Americas, Phi Beta Kappa, Southern Society for Clinical Investigation, and Southwestern Association of Clinical Microbiology

Disclosure: Pfizer Honoraria Speaking and teaching; Gilead Honoraria Speaking and teaching; Ortho McNeil Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Astellas Honoraria Speaking and teaching; Cubist Honoraria Speaking and teaching; Forest Pharmaceuticals Speaking and teaching

Gerald E Maloney Jr, DO, FAAEM Senior Instructor, Department of Emergency Medicine, Case Western Reserve University School of Medicine; Director of Medical Toxicology, Department of Emergency Medicine; Associate Medical Director, MetroLifeFlight, MetroHealth Medical Center, Cleveland, OH

Gerald E Maloney Jr, DO, FAAEM is a member of the following medical societies: American Academy of Clinical Toxicology, American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Medical Toxicology, American College of Osteopathic Emergency Physicians, American Osteopathic Association, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Jerry L Mothershead, MD Medical Readiness Consultant, Medical Readiness and Response Group, Battelle Memorial Institute; Advisor, Technical Advisory Committee, Emergency Management Strategic Healthcare Group, Veteran's Health Administration; Adjunct Associate Professor, Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences

Jerry L Mothershead, MD is a member of the following medical societies: American College of Emergency Physicians and National Association of EMS Physicians

Disclosure: Nothing to disclose.

Khaled Nashar, MD Instructor of Clinical Internal Medicine, Section of Hospitalist Medicine, Division of General Internal Medicine, Department of Medicine, University of Pittsburgh Medical Center

Khaled Nashar, MD is a member of the following medical societies: American College of Physicians, American Medical Association, and American Society of Hypertension

Disclosure: Nothing to disclose.

Robert Stanley Rust Jr, MD, MA Thomas E Worrell Jr Professor of Epileptology and Neurology, Co-Director of FE Dreifuss Child Neurology and Epilepsy Clinics, Director, Child Neurology, University of Virginia School of Medicine; Chair-Elect, Child Neurology Section, American Academy of Neurology

Robert Stanley Rust Jr, MD, MA is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Headache Society, American Neurological Association, Child Neurology Society, International Child Neurology Association, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mark R Schleiss, MD American Legion Chair of Pediatrics, Professor of Pediatrics, Division Director, Division of Infectious Diseases and Immunology, Department of Pediatrics, University of Minnesota Medical School

Mark R Schleiss, MD is a member of the following medical societies: American Pediatric Society, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Aashit K Shah, MD Professor of Neurology, Director, Comprehensive Epilepsy Program, Program Director, Clinical Neurophysiology Fellowship, Detroit Medical Center, Wayne State University School of Medicine

Aashit K Shah, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, and American Neurological Association

Disclosure: UCB pharma Consulting fee Speaking and teaching

Russell W Steele, MD Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine

Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Florian P Thomas, MD, MA, PhD, Drmed Director, Regional MS Center of Excellence, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, and Sigma Xi

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

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Well-formed hepatic granuloma from patient with brucellosis.
Brucella species are poorly staining, small gram-negative coccobacilli (0.5-0.7 × 0.6-1.5 µm) and are seen mostly as single cells with an appearance resembling "fine sand."
Table 1. Currently Recognized Brucella Species
Organism Animal Reservoir Geographic Distribution
Brucella melitensis Goats, sheep, camels Mediterranean, Asia, Latin America, parts of Africa and some southern European countries
Brucella abortus Cows, buffalo, camels, yaks Worldwide
Brucella suis Pigs (biotype 1-3) South America, Southeast Asia, United States
Brucella canis Canines Cosmopolitan
Brucella ovis Sheep No known human cases
Brucella neotomae Rodents Not known to cause human disease
Brucella pinnipediae and Brucella cetaceae Marine animals, minke whales, dolphins, seals Case reports describing some human cases (mainly neurobrucellosis)
Table 2. Symptoms and Signs of Brucellosis
Study No. of Patients Fever or Chills Arthralgia or Arthritis Sweating Constitutional symptoms* Hepatomegaly Splenomegaly
Memish et al (2000)[13] 160 146 (91.3%) 105 (65.6%) 30 (18.8%) 70 (43.8%) 9 (5.6%) 11 (6.9%)
Kokoglu et al (2006)[14] 138 108 (78.3%) 107 (77.5%) 100 (72.5%) 98 (71%) 37 (26.8%) 50 (36.2%)
Mantur et al (2006)[15] 495 417 (84.2%) 117 (23.6%) 19 (3.8%) 6 (1.2%) 56 (11.3%) 95 (19.2%)
Ruiz-Mesa et al (2005)[16] 711 702 (98.7%) 353 (49.6%) 597 (84%) 533 (75%) 250 (35.2%) 148 (20.8%)
Barroso Garcia et al (2002)[17] 565 441 (78.1%) 248 (43.9%) 483 (85.5%) 472 (83.5%) 422 (74.7%) 152 (26.9%)
Hasanjani Roushan et al (2004)[18] 469 314 (67%) 252 (53.7%) 357 (76.1%) ... ... 27 (5.8%)
Pappas et al (2005)[19] 100 91 (91%) 44 (44%) .. 26 (26%) 7 (7%) 16 (16%)
Troy et al (2005)[20] 28 25 (89%) 15 (54%) .. 13 (46%) 8 (29%) 5 (18%)
Andriopoulos et al (2007)[21] 144 144 (100%) 125 (86.8%) 138 (95.8%) 140 (97.2%) ... 74 (51.4%)
Giannakopoulos et al (2006)[22] 52 42 (81%) 43 (83%) 8 (15%) 7 (13%) ... ...
Mantur et al (2004)[23] 93 49 (53%) 19 (20%) ... ... ... ...
Tsolia et al (2002)[24] 39 27 (69%) 27 (69%) 8 (21%) 13 (33%) 11 (28%) 15 (38%)
* Anorexia, asthenia, fatigue, weakness, malaise.
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