Abstracts
This case illustrates a rare presentation (as lymphadenopathy and fever) of one of the most common zoonotic diseases worldwide-brucellosis-in a 22-year-old Brazilian male (a chef) who had recently returned to Brazil after having lived in and traveled around Europe for one year. The histopathology, clinical history, and response to treatment were all consistent with a diagnosis of brucellosis, which was confirmed by PCR in a urine sample. We also review some aspects of brucellosis, such as the clinical features, diagnosis, and management.
Brucellosis; Fever; Lymph nodes; Brucella; Mononuclear phagocyte system; Granuloma
Ilustramos aqui um caso de uma apresentação atípica (na forma de linfadenomegalia e febre) de uma das doenças zoonóticas mais comuns no mundo - brucelose - em um paciente brasileiro de 22 anos (chefe de cozinha) que retornara ao Brasil recentemente após ter morado e viajado na Europa por um ano. A histopatologia, a história clínica e a resposta ao tratamento foram consistentes com o diagnóstico de brucelose, que foi confirmada por PCR em uma amostra de urina. Também revisamos alguns aspectos da brucelose, como manifestações clínicas, diagnóstico e tratamento.
Brucelose; Febre; Linfonodos; Brucella; Sistema fagocitário mononuclear; Granuloma
Introduction
The case reported here illustrates the differential diagnosis of febrile lymphadenopathy secondary to necrotizing granulomas. Lymphadenopathy and fever secondary to necrotizing granulomas can be a challenging clinical scenario. The differential diagnosis of necrotizing granuloma typically includes, but is not limited to, fungal or mycobacterial infections. Although bacteria such as Brucella spp. can cause necrotizing granulomas, they are often overlooked as causes of granulomatous lesions. When such bacteria represent a potential etiologic factor, a negative bacterial culture should be interpreted with caution, given that Brucella spp. are fastidious organisms. We also review various aspects of brucellosis, the most common zoonotic disease worldwide.
Case report
A previously healthy 22-year-old man was referred to our hospital with an 8-week history of cervical and mediastinal lymphadenopathy, fatigue, and intermittent fever. The patient reported no excessive sweating or weight loss. He had been living in Europe (in London) for one year, where he had been working as a chef, when his illness prompted him to return to Brazil.
On physical examination, we observed painless, rubbery bilateral anterior cervical lymph nodes, 2 cm in diameter, and a nonhealing sinus tract at the site of a previous fine needle aspiration that had been performed at another facility and had yielded an inconclusive result. There were no skin or oral lesions, the teeth were in good condition, and the patient had no respiratory complaints. A chest X-ray showed widening of the right paratracheal stripe, and a subsequent CT scan of the chest revealed enlarged mediastinal lymph nodes (Figure 1). The patient had a normal white cell count (6.5 × 109/L), with normal lymphocytes. His liver function was normal; an autoantibody panel was negative; he produced an induration of 20 mm (positive result) in response to a PPD skin test; and a cryptococcal antigen test was negative. In addition, serologic testing for HIV was negative, as were tests for histoplasmosis (immunodiffusion), toxoplasmosis (ELISA), tularemia (agglutination), and cat scratch disease (indirect fluorescence assay). An excisional cervical lymph node biopsy showed a suppurative (neutrophilic), necrotizing granulomatous lesion (Figure 2). However, on direct examination of the specimen, we identified no bacteria (Gram staining), fungi (Grocott methenamine silver staining), or acid-fast bacteria (Ziehl-Neelsen staining). Cultures for bacteria, mycobacteria, and fungi were also negative.
(A) Chest X-ray, posteroanterior view, showing a widened paratracheal stripe (arrow). (B) Highresolution CT of the chest revealing enlarged mediastinal lymph nodes (arrow).
Photomicrographs of a cervical lymph node biopsy sample. Lymphoid tissue is replaced by necrotizing granulomatous inflammation (panel A). Note palisading epithelioid cells (panel B, arrows), extensive neutrophil-rich suppurative necrosis (panel C, letter N), and scattered giant cells (panel D, arrows). Hematoxylin-eosin staining (magnification varies; see the scale bars displayed in the panels).
Despite the 20-mm PPD induration, mycobacterial infection does not typically present an
exuberant inflammatory response manifesting as suppurative, necrotizing granulomatous
lesions. Although the most common cause of such lesions is fungal infection, there have
been reports in which suppurative, necrotizing granulomatous lesions have been
attributed to infection with certain bacteria(
11. El-Zammar OA, Katzenstein AL. Pathological diagnosis of granulomatous
lung disease: a review. Histopathology. 2007;50(3):289-310.
http://dx.doi.org/10.1111/j.1365-2559.2006.02546.x
http://dx.doi.org/10.1111/j.1365-2559.20...
): Francisella tularensis (tularemia); Bartonella
henselae (cat scratch disease); Actinomyces
spp.; Burkholderia pseudomallei
(melioidosis); Chlamydia trachomatis (Lymphogranuloma venereum); and
Brucella spp. (brucellosis).
A detailed history regarding exposures was taken. As a chef, the patient had a variety of gastronomic experiences during his stay in London and his travels around Europe (to Eastern Europe, Portugal, and Spain). He reported exposure to unpasteurized sheep cheese and to exotic raw meats. Therefore, we considered brucellosis a possible differential diagnosis. Because the bacterial culture results were negative, we employed PCR as an alternative method to reach the diagnosis. We performed PCR using primers targeting the bcsp31 gene sequence for Brucella spp. (the B4/B5 primer pair) in urine. The PCR was positive for Brucella spp., which allowed us to confirm the suspected diagnosis of brucellosis, given that the histopathology, clinical history, and response to treatment (mentioned further on) were all consistent with that diagnosis.
Discussion
Brucellosis is a chronic granulomatous zoonosis caused by intracellular bacteria of the
genus Brucella. It is transmitted to humans through contact with fluids
from infected animals (especially through the consumption of mutton and beef, as well as
of the milk of sheep and cows) or through direct contact with infected animal parts
(such as the placenta, by inoculation through ruptures of skin and mucous membranes) or
even by inhalation of aerosolized infectious particles. (
22. Bosilkovski M, Krteva L, Dimzova M, Vidinic I, Sopova Z, Spasovska K.
Human brucellosis in Macedonia - 10 years of clinical experience in endemic region.
Croat Med J. 2010;51(4):327-36.
http://dx.doi.org/10.3325/cmj.2010.51.327
http://dx.doi.org/10.3325/cmj.2010.51.32...
) Consumption of unpasteurized dairy products is the most common means of
transmission.(
22. Bosilkovski M, Krteva L, Dimzova M, Vidinic I, Sopova Z, Spasovska K.
Human brucellosis in Macedonia - 10 years of clinical experience in endemic region.
Croat Med J. 2010;51(4):327-36.
http://dx.doi.org/10.3325/cmj.2010.51.327
http://dx.doi.org/10.3325/cmj.2010.51.32...
,
33. Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The
new global map of human brucellosis. Lancet Infect Dis. 2006;6(2):91-9.
http://dx.doi.org/10.1016/S1473-3099(06)70382-6
http://dx.doi.org/10.1016/S1473-3099(06)...
)
Human brucellosis is one of the most common zoonotic diseases worldwide. Although its
epidemiology has drastically changed over the past decades and control of the disease
has been achieved in a number of areas where it was traditionally endemic, the
Mediterranean basin (around which our patient had been traveling) continues to be
recognized as a region in which brucellosis is endemic.(
33. Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The
new global map of human brucellosis. Lancet Infect Dis. 2006;6(2):91-9.
http://dx.doi.org/10.1016/S1473-3099(06)70382-6
http://dx.doi.org/10.1016/S1473-3099(06)...
)
The wide spectrum of clinical manifestations of human brucellosis has earned it a place
alongside syphilis and tuberculosis as one of the "great imitators". In patients with
brucellosis, practically every organ and system of the human body can be affected. The
physical examination findings are generally nonspecific, although lymphadenopathy,
hepatomegaly, or splenomegaly is often present due to the tropism of Brucella
spp. for the reticuloendothelial system. In addition, isolated lymphadenopathy
is rare in human brucellosis. Because of the protean clinical manifestations, the
cornerstone of making the clinical diagnosis of brucellosis is taking a detailed history
and paying careful attention to epidemiological information. Special attention must also
be paid to determining whether the patient has ingested contaminated dairy products or
has been in contact with infected animals. Detailed patient interviews are crucial to
making the diagnosis of human brucellosis, especially in urban and non-endemic areas, as
well as when travelers acquire the disease abroad and become ill in non-endemic
settings.(
33. Pappas G, Papadimitriou P, Akritidis N, Christou L, Tsianos EV. The
new global map of human brucellosis. Lancet Infect Dis. 2006;6(2):91-9.
http://dx.doi.org/10.1016/S1473-3099(06)70382-6
http://dx.doi.org/10.1016/S1473-3099(06)...
,
44. Franco MP, Mulder M, Gilman RH, Smits HL. Human brucellosis. Lancet
Infect Dis. 2007;7(12):775-86.
http://dx.doi.org/10.1016/S1473-3099(07)70286-4
http://dx.doi.org/10.1016/S1473-3099(07)...
)
The gold standard for the diagnosis of brucellosis is isolation of the bacteria from
blood or tissue samples. Making a diagnosis of brucellosis can be quite challenging,
because blood cultures or cultures of the tissue fragment are positive in only 15-70% of
cases, as well as because the detection of Brucella spp. requires a
prolonged incubation time.(
55. Memish Z, Mah MW, Al Mahmoud S, Al Shaalan M, Khan MY. Brucella
bacteraemia: clinical and laboratory observations in 160 patients. J Infect.
2000;40(1):59-63. http://dx.doi.org/10.1053/jinf.1999.0586
http://dx.doi.org/10.1053/jinf.1999.0586...
) Bone marrow cultures can increase the sensitivity by 15-20% over that of
blood cultures.(
44. Franco MP, Mulder M, Gilman RH, Smits HL. Human brucellosis. Lancet
Infect Dis. 2007;7(12):775-86.
http://dx.doi.org/10.1016/S1473-3099(07)70286-4
http://dx.doi.org/10.1016/S1473-3099(07)...
) However, in many cases, clinicians must use a wide range of nonspecific
routine hematological and biochemical tests, together with
Brucella-specific assays (serological and molecular techniques), in
order to reach a definitive diagnosis.(
66. Araj GF. Update on laboratory diagnosis of human brucellosis. Int J
Antimicrob Agents. 2010;36 Suppl 1:S12-7.
http://dx.doi.org/10.1016/j.ijantimicag.2010.06.014
http://dx.doi.org/10.1016/j.ijantimicag....
,
77. Yu WL, Nielsen K. Review of detection of Brucella spp. by polymerase
chain reaction. Croat Med J. 2010;51(4):306-13.
http://dx.doi.org/10.3325/cmj.2010.51.306
http://dx.doi.org/10.3325/cmj.2010.51.30...
) Each of those tests has advantages and limitations, therefore requiring
careful interpretation of the results. Serological assays, which are mainly based on the
identification of lipopolysaccharide antigens of Brucella, have high
sensitivity but low specificity (as low as 64% in some reports), due to cross-reactivity
with other bacterial species.(
44. Franco MP, Mulder M, Gilman RH, Smits HL. Human brucellosis. Lancet
Infect Dis. 2007;7(12):775-86.
http://dx.doi.org/10.1016/S1473-3099(07)70286-4
http://dx.doi.org/10.1016/S1473-3099(07)...
,
88. Sohrabi M, Mohabati Mobarez A, Khoramabadi N, Hosseini Doust R,
Behmanesh M. Efficient Diagnosis and Treatment Follow-up of Human Brucellosis by a
Novel Quantitative TaqMan Real-Time PCR assay: a Human Clinical Survey. J Clin
Microbiol. 2014;52(12):4239-43.
http://dx.doi.org/10.1128/JCM.01819-14
http://dx.doi.org/10.1128/JCM.01819-14...
) The fact that antibodies can be detectable for months after therapy further
complicates the use of serological assays for the identification of relapse and
reinfection. Nevertheless, a number of serological methods can be useful. One such
method is serum agglutination testing, the modality for which there is the greatest
amount of data in the literature. In an appropriate clinical scenario, a fourfold or
greater increase in the Brucella agglutination titer between acute- and
convalescent-phase serum samples, obtained ≥ 2 weeks apart, confirms a diagnosis of
brucellosis. Absolute thresholds for serum agglutination testing should be
individualized: positivity is defined as a titer of 1:160-1:320 in endemic regions and
as a titer of 1:80 in non-endemic regions.(
99. Christopher S, Umapathy BL, Ravikumar KL. Brucellosis: review on the
recent trends in pathogenicity and laboratory diagnosis. J Lab Physicians.
2010;2(2):55-60. http://dx.doi.org/10.4103/0974-2727.72149
http://dx.doi.org/10.4103/0974-2727.7214...
) Other methods, such as ELISA, the direct antiglobulin (Coombs) test, and
the immunocapture test, are available but do not seem to overcome the aforementioned
problems.(
99. Christopher S, Umapathy BL, Ravikumar KL. Brucellosis: review on the
recent trends in pathogenicity and laboratory diagnosis. J Lab Physicians.
2010;2(2):55-60. http://dx.doi.org/10.4103/0974-2727.72149
http://dx.doi.org/10.4103/0974-2727.7214...
)
Another technique that has been increasingly used in the diagnosis of brucellosis is
PCR. PCR is not a routine diagnostic method but can be performed on any clinical
specimen and has been shown to have excellent sensitivity and specificity.(
77. Yu WL, Nielsen K. Review of detection of Brucella spp. by polymerase
chain reaction. Croat Med J. 2010;51(4):306-13.
http://dx.doi.org/10.3325/cmj.2010.51.306
http://dx.doi.org/10.3325/cmj.2010.51.30...
,
88. Sohrabi M, Mohabati Mobarez A, Khoramabadi N, Hosseini Doust R,
Behmanesh M. Efficient Diagnosis and Treatment Follow-up of Human Brucellosis by a
Novel Quantitative TaqMan Real-Time PCR assay: a Human Clinical Survey. J Clin
Microbiol. 2014;52(12):4239-43.
http://dx.doi.org/10.1128/JCM.01819-14
http://dx.doi.org/10.1128/JCM.01819-14...
,
1010. Queipo-Ortu-o MI, Colmenero JD, Mu-oz N, Baeza G, Clavijo E, Morata
P. Rapid diagnosis of Brucella epididymo-orchitis by real-time polymerase chain
reaction assay in urine samples. J Urol. 2006;176(5):2290-3.
http://dx.doi.org/10.1016/j.juro.2006.07.052
http://dx.doi.org/10.1016/j.juro.2006.07...
11. Baddour MM, Alkhalifa DH. Evaluation of three polymerase chain
reaction techniques for detection of Brucella DNA in peripheral human blood. Can J
Microbiol. 2008;54(5):352-7. http://dx.doi.org/10.1139/W08-017
http://dx.doi.org/10.1139/W08-017...
-
1212. Sanjuan-Jimenez R, Morata P, Bermúdez P, Bravo MJ, Colmenero JD.
Comparative clinical study of different multiplex real time PCR strategies for the
simultaneous differential diagnosis between extrapulmonary tuberculosis and focal
complications of brucellosis. PLoS Negl Trop Dis. 2013;7(12):e2593.
http://dx.doi.org/10.1371/journal.pntd.0002593
http://dx.doi.org/10.1371/journal.pntd.0...
) Genus-specific PCR targeting bcsp31 seems to have greater
sensitivity than do those targeting any other Brucella gene sequence
available.(
77. Yu WL, Nielsen K. Review of detection of Brucella spp. by polymerase
chain reaction. Croat Med J. 2010;51(4):306-13.
http://dx.doi.org/10.3325/cmj.2010.51.306
http://dx.doi.org/10.3325/cmj.2010.51.30...
) The sensitivity and specificity of PCR assays are both between 90% and
100%.(
88. Sohrabi M, Mohabati Mobarez A, Khoramabadi N, Hosseini Doust R,
Behmanesh M. Efficient Diagnosis and Treatment Follow-up of Human Brucellosis by a
Novel Quantitative TaqMan Real-Time PCR assay: a Human Clinical Survey. J Clin
Microbiol. 2014;52(12):4239-43.
http://dx.doi.org/10.1128/JCM.01819-14
http://dx.doi.org/10.1128/JCM.01819-14...
,
1212. Sanjuan-Jimenez R, Morata P, Bermúdez P, Bravo MJ, Colmenero JD.
Comparative clinical study of different multiplex real time PCR strategies for the
simultaneous differential diagnosis between extrapulmonary tuberculosis and focal
complications of brucellosis. PLoS Negl Trop Dis. 2013;7(12):e2593.
http://dx.doi.org/10.1371/journal.pntd.0002593
http://dx.doi.org/10.1371/journal.pntd.0...
) As in other infectious diseases, PCR testing is becoming an excellent
alternative method for diagnosing brucellosis when standard methods have failed or are
not available, especially when the clinical and histopathological aspects are consistent
with the diagnosis.(
99. Christopher S, Umapathy BL, Ravikumar KL. Brucellosis: review on the
recent trends in pathogenicity and laboratory diagnosis. J Lab Physicians.
2010;2(2):55-60. http://dx.doi.org/10.4103/0974-2727.72149
http://dx.doi.org/10.4103/0974-2727.7214...
,
1313. Mitka S, Anetakis C, Souliou E, Diza E, Kansouzidou A. Evaluation of
different PCR assays for early detection of acute and relapsing brucellosis in humans
in comparison with conventional methods. J Clin Microbiol. 2007;45(4):1211-8.
http://dx.doi.org/10.1128/JCM.00010-06
http://dx.doi.org/10.1128/JCM.00010-06...
14. Nimri LF. Diagnosis of recent and relapsed cases of human
brucellosis by PCR assay. BMC Infect Dis. 2003;3:5.
http://dx.doi.org/10.1186/1471-2334-3-5
http://dx.doi.org/10.1186/1471-2334-3-5...
-
1515. Morata P, Queipo-Ortu-o MI, Reguera JM, García-Ordo-ez MA, Cárdenas
A, Colmenero JD. Development and evaluation of a PCR-enzyme-linked immunosorbent
assay for diagnosis of human brucellosis. J Clin Microbiol. 2003;41(1):144-8.
http://dx.doi.org/10.1128/JCM.41.1.144-148.2003
http://dx.doi.org/10.1128/JCM.41.1.144-1...
) A growing body of evidence indicates that PCR assays are accurate methods
for the diagnosis of brucellosis, although there is a need for standardization before
their widespread use as such can be recommended.
The goal of brucellosis treatment is the resolution of infection and the prevention of
complications, relapses, and sequelae. The optimal treatment of uncomplicated
brucellosis (without spondylitis, neurobrucellosis, or endocarditis) is based on a
6-week regimen of doxycycline, combined with streptomycin for 2-3 weeks or with rifampin
for 6 weeks.(
1616. Ariza J, Bosilkovski M, Cascio A, Colmenero JD, Corbel MJ, Falagas
ME, et al. Perspectives for the treatment of brucellosis in the 21st century: the
Ioannina recommendations. PLoS Med. 2007;4(12):e317.
http://dx.doi.org/10.1371/journal.pmed.0040317
http://dx.doi.org/10.1371/journal.pmed.0...
) Although the streptomycin-containing regimen is slightly more efficacious
in preventing relapse, parenteral administration of streptomycin complicates its use,
and the doxycycline-rifampin regimen is therefore used more frequently, because of its
convenience.(
1717. Pappas G, Siozopoulou V, Akritidis N, Falagas ME.
Doxycycline-rifampicin: physicians' inferior choice in brucellosis or how convenience
reigns over science. J Infect. 2007;54(5):459-62.
http://dx.doi.org/10.1016/j.jinf.2006.09.015
http://dx.doi.org/10.1016/j.jinf.2006.09...
,
1818. Solís García del Pozo J, Solera J. Systematic review and
meta-analysis of randomized clinical trials in the treatment of human brucellosis.
PLoS One. 2012;7(2):e32090.
http://dx.doi.org/10.1371/journal.pone.0032090
http://dx.doi.org/10.1371/journal.pone.0...
) A 6-week regimen of quinolone plus rifampin is slightly more well tolerated
than is that of doxycycline plus rifampin, and low quality evidence did not show any
difference in overall effectiveness.(
1919. Yousefi-Nooraie R, Mortaz-Hejri S, Mehrani M, Sadeghipour P.
Antibiotics for treating human brucellosis. Cochrane Database Syst Rev.
2012;10:CD007179.
doi:http://dx.doi.org/10.1002/14651858.CD007179.pub2
http://dx.doi.org/10.1002/14651858.CD007...
) There is also some evidence that a three-drug regimen (involving the
addition of trimethoprim-sulfamethoxazole to either of the abovementioned two-drug
regimens, or a combination of streptomycin, rifampin and doxycycline) is an effective
therapy in complex cases. Extended treatment (for at least 12 weeks) and the use of
three-drug regimens should be considered in patients with complicated
disease.(
2020. Mantur BG, Amarnath SK, Shinde RS. Review of clinical and laboratory
features of human brucellosis. Indian J Med Microbiol. 2007;25(3):188-202.
doi:http://dx.doi.org/10.4103/0255-0857.34758
http://dx.doi.org/10.4103/0255-0857.3475...
)
In the case presented here, the patient was treated with doxycycline and rifampin. After 6 weeks, he presented complete resolution of fatigue and lymphadenopathy. At this writing, the patient has been followed for two years after the completion of treatment and there has been no evidence of relapse.
Our case illustrates a rare presentation of brucellosis, one of the most common zoonotic diseases worldwide. It also highlights the importance of taking a detailed epidemiological history as an important tool to guide clinicians to a correct diagnosis of infectious granulomatous diseases such as brucellosis.
References
-
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» http://dx.doi.org/10.1111/j.1365-2559.2006.02546.x -
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» http://dx.doi.org/10.3325/cmj.2010.51.327 -
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» http://dx.doi.org/10.1016/S1473-3099(06)70382-6 -
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» http://dx.doi.org/10.1016/S1473-3099(07)70286-4 -
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» http://dx.doi.org/10.1053/jinf.1999.0586 -
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» http://dx.doi.org/10.1016/j.ijantimicag.2010.06.014 -
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» http://dx.doi.org/10.3325/cmj.2010.51.306 -
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» http://dx.doi.org/10.1128/JCM.01819-14 -
9Christopher S, Umapathy BL, Ravikumar KL. Brucellosis: review on the recent trends in pathogenicity and laboratory diagnosis. J Lab Physicians. 2010;2(2):55-60. http://dx.doi.org/10.4103/0974-2727.72149
» http://dx.doi.org/10.4103/0974-2727.72149 -
10Queipo-Ortu-o MI, Colmenero JD, Mu-oz N, Baeza G, Clavijo E, Morata P. Rapid diagnosis of Brucella epididymo-orchitis by real-time polymerase chain reaction assay in urine samples. J Urol. 2006;176(5):2290-3. http://dx.doi.org/10.1016/j.juro.2006.07.052
» http://dx.doi.org/10.1016/j.juro.2006.07.052 -
11Baddour MM, Alkhalifa DH. Evaluation of three polymerase chain reaction techniques for detection of Brucella DNA in peripheral human blood. Can J Microbiol. 2008;54(5):352-7. http://dx.doi.org/10.1139/W08-017
» http://dx.doi.org/10.1139/W08-017 -
12Sanjuan-Jimenez R, Morata P, Bermúdez P, Bravo MJ, Colmenero JD. Comparative clinical study of different multiplex real time PCR strategies for the simultaneous differential diagnosis between extrapulmonary tuberculosis and focal complications of brucellosis. PLoS Negl Trop Dis. 2013;7(12):e2593. http://dx.doi.org/10.1371/journal.pntd.0002593
» http://dx.doi.org/10.1371/journal.pntd.0002593 -
13Mitka S, Anetakis C, Souliou E, Diza E, Kansouzidou A. Evaluation of different PCR assays for early detection of acute and relapsing brucellosis in humans in comparison with conventional methods. J Clin Microbiol. 2007;45(4):1211-8. http://dx.doi.org/10.1128/JCM.00010-06
» http://dx.doi.org/10.1128/JCM.00010-06 -
14Nimri LF. Diagnosis of recent and relapsed cases of human brucellosis by PCR assay. BMC Infect Dis. 2003;3:5. http://dx.doi.org/10.1186/1471-2334-3-5
» http://dx.doi.org/10.1186/1471-2334-3-5 -
15Morata P, Queipo-Ortu-o MI, Reguera JM, García-Ordo-ez MA, Cárdenas A, Colmenero JD. Development and evaluation of a PCR-enzyme-linked immunosorbent assay for diagnosis of human brucellosis. J Clin Microbiol. 2003;41(1):144-8. http://dx.doi.org/10.1128/JCM.41.1.144-148.2003
» http://dx.doi.org/10.1128/JCM.41.1.144-148.2003 -
16Ariza J, Bosilkovski M, Cascio A, Colmenero JD, Corbel MJ, Falagas ME, et al. Perspectives for the treatment of brucellosis in the 21st century: the Ioannina recommendations. PLoS Med. 2007;4(12):e317. http://dx.doi.org/10.1371/journal.pmed.0040317
» http://dx.doi.org/10.1371/journal.pmed.0040317 -
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*
Study carried out in the Department of Pulmonology, Instituto do Coração - InCor, Heart Institute - University of São Paulo School of Medicine Hospital das Clínicas, São Paulo, Brazil.
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Financial support: None.
Publication Dates
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Publication in this collection
18 Apr 2015 -
Date of issue
Mar-Apr 2015
History
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Received
17 Sept 2014 -
Accepted
29 Oct 2014