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Acta Medica Mediterranea, 2015, 31: 1319
EPIDEMIOLOGICAL, CLINICAL AND LABORATORY FINDINGS IN ADULT PATIENTS WITH ACUTE
BRUCELLOSIS: A CASE-CONTROL STUDY
MOHAMMAD NASSAJI1, ALI GOVHARY2, RAHEB GHORBANI3
1
Associate professor of Infectious diseases, Research Center for Social Determinants of Health, Faculty of Medicine, Semnan
University of Medical Sciences, Semnan, Iran - 2Assistant professor of Infectious diseases, Department of Internal Medicine,
Kowsar Hospital, Semnan University of Medical Sciences, Semnan, Iran - 3Professor of Biostatistics, Research Center for Social
Determinants of Health, Department of Community Medicine, Faculty of Medicine, Semnan University of Medical Sciences,
Semnan, Iran
ABSTRACT
Introduction: Brucellosis is one of the most common infectious diseases in Middle East region. The aim of this study was to
evaluate epidemiological, clinical and laboratory findings of patients with acute brucellosis and comparing with controls.
Materials and methods: In this cross-sectional study, adult patients with acute brucellosis and the same number of controls
were included. The diagnosis of brucellosis was made by clinical findings, positive agglutination titer and response to treatment.
Epidemiological characteristics, clinical symptoms, signs and laboratory findings were evaluated.
Results: One hundred and seventeen patients and matched controls were enrolled. The most common potential source of
infection was the consumption of unpasteurized fresh cheese (60.7%). Occupational exposure was recorded in 52.1% of patients.
The most frequent symptoms were skeletal pain (91.5%), fever (82.1%) and sweating (76.1%). The most frequent findings
were sacroiliitis (24.8%), arthritis (13.7%), and splenomegaly (12.8%). Spondylitis was significantly more common in patients >45
years old (p=0.003). Sacroiliitis was significantly more common in men than women (p=0.029). The most frequent laboratory
abnormalities were positive C-reactive protein (69.2%), anemia (52.1%), and elevated erythrocyte sedimentation rate (45.3%). The
statistically significant laboratory parameters difference between two groups were hemoglobin, erythrocyte sedimentation rate,
aminotransferases, white blood cells, Platelet count and cell distribution width. Most patients responded to treatment in second
weeks of therapy. No therapeutic failure was observed. Relapse of diases was detected in three patients.
Conclusion: Acute brucellosis should be considered in patients with the clinical triad of skeletal pain, fever and sweating in
conjunction with anemia, positive CRP and elevated ESR in endemic areas. Consumption of unsafe dairy products especially fresh
cheese could be the main route of infection. Treatment with World Health Organization regimen appears to be an effective therapy
for acute brucellosis.
Key words: Acute brucellosis, Epidemiology, Clinical manifestations, Laboratory findings.
Received January 30, 2015; Accepted March 30, 2015
Introduction
Brucellosis is a widespread bacterial zoonosis
and a disease of global importance with more than
500 000 new cases annually and prevalence rates in
some countries exceeding ten cases per 100 000
population. It causes substantial morbidity in human
population(1). The disease is endemic in the countries
of the Mediterranean basin, Middle East, the Indian
subcontinent and parts of Mexico and Central and
South America. The proportion of male patients is
greater than female patients amongst both children
and adults. Human brucellosis can occur in any age
group, but the majority of cases are found in young
men between the ages of 20 and 40 years(2).
Brucellosis is a systemic disease with wide
spectrum of clinical presentation that can involve
any organ of the body. Disease findings, however,
may vary between different areas and populations(3).
Acute brucellosis usually consists of the insidious
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Mohammad Nassaji, Ali Govhary et Al
onset of fever, night sweats, skeletal pain, anorexia,
weight loss, fatigue and weakness. Physical findings
are variable and nonspecific. Hepatomegaly,
splenomegaly, and lymphadenopathy may be
observed in less than one-third of patients. Focal
features are present in the majority of patients. The
most common are musculoskeletal involvement(4).
Accurate diagnosis of brucellosis continues to
be a challenge among clinicians because of its nonspecific clinical and laboratory features and slow
growth of Brucella in culture media. The limitations
of culture make serology the most useful tool for the
laboratory diagnosis of brucellosis (5). Standard
agglutination test (SAT) remains the most popular
and yet used worldwide diagnostic tool, because it is
easy to perform and does not need expensive equipment and training. SAT titers above 1:160 are considered diagnostic in conjunction with a compatible
clinical presentation(6).
Brucellosis produces a variety of non-specific
hematologic and biochemical abnormalities. White
blood cell (WBC) count is usually normal or low,
with relative lymphocytosis. Mild anemia may be
documented. The erythrocyte sedimentation rate
(ESR) and C-reactive protein (CRP) levels are often
normal but may be raised. Minor abnormalities in
hepatic enzymes are relatively common(7).
Laboratory findings have been varied between
different populations and studies. For example,
hematologic abnormalities such as anemia and
leukopenia are common in Mediterranean populations, whereas, thrombocytopenia is fairly uncommon(8).
Most previous studies especially about laboratory findings were case series without a control
group. On the others hand most of these studies
comprised all forms (acute, subacute and chronic) of
this diseases. So that, this study was designed to
determine clinical manifestations and laboratory
findings of patients with acute brucellosis in an
endemic region and comparing laboratory findings
of patients with healthy control group.
healthy adult normal population who underwent
medical check-ups from the same region and was
matched with respect to age and gender. Individuals
with history of systemic diseases, blood disorders,
hepatic diseases and recent infection (<3month)
were excluded.
The diagnosis of acute brucellosis (<2 month)
was made based on a clinical picture compatible
with brucellosis together with positive SAT (1:160
or higher titers) or four-fold rise in Brucella antibody titer and adequate response to anti-brucellosis
therapy. Focal involvement or complications was
defined as the presence of symptoms, physical
signs, laboratory and or imaging finding at a particular anatomic site in patients.
Data about gender, age, body mass index
(BMI), smoking status, the potential source of infection, duration of the symptoms before diagnosis and
history of previous brucellosis were registered for
individuals who met inclusion criteria. Clinical
symptom and findings were recorded. Laboratory
assessments included complete blood count (CBC),
blood group, CRP (quantitative method), ESR, alanine (ALT) and aspartate aminotransferases (AST),
alkaline phosphatase and urine analysis.
All patients were treated by World Health
Organization (WHO) oral regimen consists of 200
mg doxycycline plus 600-900 mg rifampicin daily
for a minimum of 6 weeks(9). All patients were followed up to completing therapy and one year after
treatment.
Patients were divided to three groups according to age to compare the clinical findings.
Informed consent was obtained from all subjects before enrollment. Research Council and
Ethical Committee of the Semnan University of
Medical Science approved the study protocol.
Data were analyzed by one sample
Kolmogorov-Smirnov, Chi Square, Fisher Exact,
Mann Whitney, student’s t tests using Statistical
Package for the Social Sciences software version
16.0 SPSS ( Inc., Chicago, Illinois, USA).
Materials and methods
Results
This cross-sectional study was conducted from
June 2012 to March 2014 in university affiliated
Clinics for Infectious Diseases of Semnan
University of Medical Science, Iran. Adult patients
(≥ 18 years old) who were admitted with diagnosis
of acute brucellosis were considered for participation in the study. Control group was selected from
Of all patients admitted with diagnosis of acute
brucellosis that were screened, 117 met inclusion
criteria and were enrolled. Same number of controls
was selected. The mean (± SD) age of patients was
36.0 ±15.8 years and the controls was 37.2 ±12.3
that showed no statistically significant difference
(P=0.717). Among both groups 70.1% were male.
Epidemiological, clinical and laboratory findings in adult patients with acute brucellosis: A case-control study
Two groups were matched based on age and gender.
Mean BMI (±SD) of patients was 24.2±3.4 and
for control was 25.9±4.4 Kg/m2. BMI of patients
was significantly lower than controls (p=0.001).
Among the cases, 23 (19.7%) were current regular
cigarette smokers whereas in control group 18
(15.4%) were smoker (P=0.390). The mean (± SD)
number of pack-year smoking was 9.8±11.3 in cases
and 13.9±8.4 in control group that was not significantly different (P=0.056). The most common
potential source of infection was determined to be
the consumption of unpasteurized fresh cheese
(60.7%). Occupational exposure was recorded in
52.1% of patients with brucellosis. Eight patients
(6.8%) had previous history of brucellosis. In most
patients (53%) the diagnosis was established during
second to four weeks after the onset of symptoms.
Baseline characteristics and clinical finding of
patients are showed in table 1. Skeletal pain
(91.5%), fever (82.1%) and night sweating (76.1%)
were the most common presenting symptoms. The
most frequent findings were sacroiliitis (24.8%),
peripheral arthritis (13.7%), and splenomegaly
(12.8%). When comparing clinical findings between
two genders, sacroiliitis was significantly more
common in men than women (30.5% versus 11.4%,
p=0.029).
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with spondylitis. No significant side effect was
found to lead stopping of the treatment.
We analyzed finding in three age subgroups
(<30, 30-45 and >45 years old). Spondylitis was significantly more common in patients >45 years old
(p=0.003) whereas, hepatomegaly was more common in <30 years old (p=0.011) (Table 2).
Table 2: Age distribution of clinical finding in 117 adult
patients with acute brucellosis.
The most common blood group among the
patients was A (45.3%), while among controls was
O (36.7%). However, distribution of ABO blood
groups in the patients with brucellosis was not significantly different from of control group (P=0.187).
Table 1: Demographic and clinical characteristics of 117
adult patients with acute brucellosis.
Most patients (53.8%) responded to treatment
in second weeks of therapy. No therapeutic failure
was observed during treatment with the given regimen. Relapse was detected in three (2.56%) patients
during follow up and occurred in two of these cases
Table 3: Distribution of laboratory findings among
patients with acute brucellosis and control group.
* >2 RBC, ** >5 WBC, WBC, white blood cell; ALT, alanine
aminotransferases; AST, aspartate aminotransferases; ALP.
alkaline phosphatase; PMN, polymorphonuclear neutrophil;
ESR, erythrocyte sedimentation rate
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The most frequent laboratory abnormalities in
the examined patients were positive CRP (in
69.2%), anemia (in 52.1%), and elevated ESR (in
45.3%). Leukocyte and platelet count was normal in
most patients (76.9% and 84.6% respectively).
Elevated ALT and AST levels were detected in
43.6% and 29.9% of patients respectively.
According to laboratory parameters, the statistically
significant difference between two groups were
hemoglobin, ESR, ALT, AST, WBC and platelet
count (Table 3). The mean (± SD) of mean platelet
volume (MPV) was 9.1 ±2.7 and 9.1±1.3 in patients
and controls respectively (p=0.903). The mean
(±SD) of red cell distribution width (RDW) was significantly higher in patients than controls (3.2±1.8
versus 12.6±0.8, p=0.004). When laboratory parameters were compared between patients with and
without osteoarticular involvement, no significant
difference was detected between two groups.
Discussion
Brucellosis is the most common zoonotic
infectious disease in the world. Although has been
controlled in many developed countries, it remains
an important health problem in developing countries(10).
Human brucellosis affects all age groups but it
is more common in young adults(11). The mean (±
SD) age of our patients was 36.0 ±15.8 years that is
consistent with most previous studies(12-14). Some
studies, however, reported higher(15, 16) or lower mean
ages(17, 18).
As expected, this study showed a higher numbers of male genders (70.1%) among patients with
brucellosis. Sex distribution in our patients is similar
to most others studies(13, 19-21). The predominance of
males over females may be due to the increased
involvement of adult men in livestock breeding and
contact with animals. This reflects the importance of
economic impacts of this disease that affects the
productive group of population. In contrast, in three
other studies, more females were affected than
males(17, 22, 23).
BMI of patients with acute brucellosis was significantly lower than controls. To our knowledge, no
study evaluated the BMI of patients. Anorexia and
weight loss due to diseases can be a reason.
Individuals that are at the risk of brucellosis occupationally are more active. This may be another explanation for lower BMI in these patients.
Contact with domestic animals and consump-
Mohammad Nassaji, Ali Govhary et Al
tion of raw and unpasteurized products of animal
origin are the main risk factors for brucellosis in
most endemic countries(24). Approximately, 52% of
our patients had a history of occupational exposure
to livestock, such as agriculture and ranching. This
result is in concordance with the studies published
by some other authors(12, 18). This suggests that brucellosis occurs because of incomplete eradication of
disease in animals and the continued consumption
of unpasteurized dairy products in endemic regions.
A study from Greece showed that infected patients
had a relevant occupational history in fewer than
20% of cases(25).
Consumption of unpasteurized fresh cheese was
reported in 60.7% among our patients. Similarly, history of consuming of unpasteurized dairy products
was positive between 60-75% in some previous studies(13, 16, 22). Lower rate of the consumption of raw
dairy products in other studies has been reported as
occurring in 34.7% of cases in the Balkan by
Bosilkovski et al, 22.4% by Hasanjani Roushan et al
and 22.1% by Savas et al studies(12, 19, 23).
Typically acute cases of brucellosis present
with fever, fatigue, anorexia, skeletal pain, night
sweating and weight loss. In this study, the main
symptoms at presentation were skeletal pain
(91.5%), fever (82.1%), night sweating (76.1%) and
anorexia (65%). Result of this study was very similar to that reported by researchers elsewhere(16, 17, 20, 25).
In Guler et al study, the most frequent symptoms
were found to be weakness (64.3%) followed by
fever (63.2%), sweating (62.7%), and arthralgia
(59.1%)(13). In another study the reported most clinical findings were as: sweating (76.1%), fever (67%)
and arthralgia (53.8%)(19).
Reported physical findings are variable in different studies. Splenomegaly is reported to occur in
15-60% of cases with brucellosis(26, 27). In our study,
the frequency of splenomegaly was 12.8% that is
lower than most other studies. Splenomegaly was
reported 51% in Bosilkovski et al, 16% in Dilek et
al, 26.9% in Andriopoulos and 19.2% in Mantur et
al studies (12, 17, 25, 28) . Also, the frequency of
hepatomegaly (4.3%) and adenopathy (0.9%) in our
study was lower than most previous study(1, 15, 18, 21).
The possible explanation for lower rate of
organomegaly in our patient can be as follow. We
only selected patients with acute brucellosis whereas, most other studies comprised all kind of patients
including subacute and chronic. The longer duration
of disease, the more chance for development of
organomegaly.
Epidemiological, clinical and laboratory findings in adult patients with acute brucellosis: A case-control study
Also, the higher rates observed in some other
studies might have resulted from the fact that the
diagnoses of organomegaly were made based on not
only physical examinations, but also ultrasonography. On the other hand, previous experience in our
region showed lower rate of organomegaly in
patients with brucellosis(19, 29). It proposes that physical findings can vary in different population and
regions.
Brucellosis often results in involvement of the
musculoskeletal system such as sacroiliitis, arthritis,
spondylitis, tenosynovitis and osteomyelitis. The
prevalence and pattern of musculoskeletal system
involvement depends on the infecting strain of the
Brucella and duration of the disease and occurs in
20-85% of cases(11, 30). In our study, osteoarticular
involvement was observed in 47.9% of acute cases
that was near the results of some other studies(12, 13, 25).
Lower rates of involvement were observed in different studies (15, 22, 29, 31) . In Mediterranean region,
Brucella sacroiliitis is a common presentation(24).
Sacroiliitis was the most frequent osteoarticular
involvement in our study that is similar to that found
by some other researchers(15, 29, 32). In contrast, other
authors reported that spondylitis(13, 25, 33) or peripheral
arthritis(19, 20, 22) was the most frequent osteoarticular
complication. Different percentage of clinical findings between reports in the literature may be due to
characteristics of the study populations, the prominent strain of Brucella, diagnostic methods used,
and the different diagnostic criteria employed.
Some investigators have reported different
forms of the clinical findings and complication in
women and men. In the present study when comparing based on gender, there were significantly more
males (30.5%) than females (11.4%) with sacroiliitis. In accordance with present study, Sacroiliitis
and spondylitis were observed more frequently in
men than in women in another study(19). In contrast,
Geyik et al. reported that sacroiliitis and polyarthritis were more common in females(32).
The most common laboratory abnormalities
reported in patients with brucellosis are anemia,
leukopenia, thrombocytopenia and elevated aminotransferases (1). Hemoglobin, WBC and platelet
count was significantly lower in patients than controls and ESR, ALT, AST and RDW was significantly higher in patients. We found anemia in
52.1%, leukocytosis in 13.7%, leukopenia in 9.4%,
and thrombocytopenia in 8.5% of patients with
acute brucellosis. These finding is nearly similar to
some previous studies(14, 21).
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Some study reported higher rate of hematological alterations in their patients. In Guler et al study,
anemia (70%) leukopenia (21.3%), leukocytosis
(9.1%), and thrombocytopenia (22.9%) was reported
in patients(13). Lower rate of hematological alterations have been reported in some other studies(8, 1618)
. Hematological alterations in brucellosis rarely
constitute a true complication and resolve promptly
with treatment. Anemia, the most common finding
in patients with brucellosis, may be results from
alteration in iron metabolism secondary to infection,
hypersplenism, bone marrow suppression or autoimmune hemolysis(34).
Different elevated levels of ESR and CRP are
predictable during any infections. Elevated ESR and
CRP were detected in 45.3% and 69.2% of our
patients respectively. Similar results reported by
other studies(13, 15, 17, 22). In consistence with our finding, elevated CRP was more common than ESR in
these studies and can be a better inflammatory
marker in acute brucellosis. Lower rate of ESR elevation was reported in Rahil et al study(21).
Elevated ALT and AST levels were detected in
43.6% and 29.9% of patients respectively. Diagnosis
of clinical hepatitis was made in none of them.
Previous studies showed different rising in level of
liver aminotransferases(21, 33, 35).
WHO has recommended the use of a six-week
course of doxycycline plus rifampicin therapy as the
treatment of choice(9). We used this treatment regimen for all patients. Most patients responded to
treatment in second weeks of therapy and no treatment failure was detected. Only few studies reported
duration for response to treatment. Malik published
a study that included 73 patients diagnosed in a hospital in Saudi Arabia. The mean defervescence time
was 4.32±1.47 days and the duration of the hospital
stay was 7.75±2.12 days(36). In the study of Aygen et
al the average time to defervencence for patients
was less than 7 days (range: 2 to 15 days)(15). In these
studies, only defervescence was criteria for
response. Whereas, we also used relief of other
prominent symptoms for criteria of response. It can
be probable explanation for the longer duration of
response to treatment in our patients.
The study has some limitations. First, the eligible participant number is relatively small in this
study. Second, we did not use culture for diagnosis
of brucellosis because of diagnostic constraints.
More studies especially with larger sample are recommended.
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Mohammad Nassaji, Ali Govhary et Al
Conclusion
The most epidemiological and clinical findings
in this study were very similar to that reported by
most authors. The main route of transmission of brucellosis in our region is likely to be the consumption
of unsafe dairy products especially fresh cheese and
contact with domestic animals. Skeletal pain
(91.5%), fever (82.1%) and sweating (76.1%) were
the most common presenting symptoms. The most
frequent laboratory abnormalities in the examined
patients were positive CRP, anemia and elevated
ESR. Most laboratory findings were statistically significant difference between patients and controls.
The clinical triad of skeletal pain (especially
sacroiliitis), fever and sweating in conjunction with
anemia, positive CRP and elevated ESR strongly
suggest acute brucellosis. Most risk factors for brucellosis acquisition are modifiable and education
regarding this issue would be useful in preventing
human brucellosis. Brucellosis can be treated easily
with WHO recommended antimicrobial drugs when
used at an appropriate dose for an appropriate time.
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12)
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Acknowledgment
The research was supported by Research Committee of Semnan
University of Medical science.
_______
Corresponding author
MOHAMMAD NASSAJI
Kowsar Hospital, Basij Blvd
Semnan
(Iran)