International Journal of Infectious Diseases 60 (2017) 4–10

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Changing patterns in leptospirosis: a three-decade study in Brazil

Elizabeth De Francesco Dahera,* , Gabriela Studart Galdino de Carvalhoa ,
Douglas de Sousa Soaresa , Matheus Henrique Mendesa , Sérgio Luiz Arruda Parente Filhoa ,
Hermano Alexandre Lima Rochab , Geraldo Bezerra da Silva Juniorc
a
Department of Internal Medicine, School of Medicine, Walter Cantídio University Hospital, Federal University of Ceará, Fortaleza, Ceará, Brazil
b
Department of Community Health, School of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil
c
School of Medicine, Public Health Graduate Program, Health Sciences Center, University of Fortaleza, Fortaleza, Ceará, Brazil

A R T I C L E I N F O S U M M A R Y

Article history: Background: This study was conducted to investigate changes in the clinical pattern of leptospirosis over
Received 7 March 2017 time, analyzing its clinical and laboratory presentations in a metropolitan city of Brazil.
Received in revised form 25 April 2017 Method: This was a retrospective study including all patients with leptospirosis admitted to tertiary care
Accepted 28 April 2017
hospitals in Fortaleza in the northeast of Brazil, between 1985 and 2015. Patients were divided into three
Corresponding Editor: Eskild Petersen, Aar-
hus, Denmark
groups according to the year of hospital admission: group I for the years 1985–1995, group II for 1996–
2005, and group III for 2006–2015. Demographic, clinical, and laboratory data were compared between
the groups.
Keywords:
Leptospirosis
Results: A total of 507 patients were included. Their mean age was 37.3  15.9 years and 82.4% were male.
Changing patterns The mean time between symptom onset and admission was 7  4 days. There was a linear decrease in the
Laboratory findings levels of serum urea (190.1  92.7, 135  79.5, and 95.6  73.3 mg/dl, respectively, p < 0.0001) and
Acute kidney injury creatinine (5.8  2.9, 3.8  2.6, and 3.0  2.5 mg/dl, respectively, p < 0.0001) in each decade, while levels
Mortality of hemoglobin (10.31 1.9, 10.8  2.0, and 11.5  2.1 g/dl, respectively, p < 0.0001) and platelets
(57.900  52.650, 80.130  68.836, and 107.101  99.699  109/l, respectively, p < 0.0001) increased.
There was a tendency towards a linear decrease in mortality (22%, 14%, and 11.6%, respectively, p = 0.060).
Conclusions: Leptospirosis showed significant changes over time in this region. The main changes point to
a decrease in disease severity and complications, such as acute kidney injury. Mortality has decreased,
being close to 11%.
© 2017 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).

Introduction conditions (slums), a lack of basic sanitation, the presence of

Leptospirosis remains the most important zoonosis worldwide,
with a higher frequency in low-income tropical countries
(Victoriano et al., 2009; Adler and de la Peña Moctezuma, 2010;
Haake and Levett, 2015). It has traditionally been associated with
rural areas and people undertaking certain risk occupations,
including abattoir and sewage workers, military personnel, and
individuals involved in water sports or recreation. However, its
epidemiological pattern has changed over the last decades, with a
marked move to urban areas, especially during natural disasters
(Sarkar et al., 2002). This disease is endemic in Brazil, with
outbreaks during the rainy season, mostly due to precarious living
* Corresponding author at: Rua Vicente Linhares, 1198 Fortaleza, CEP 60270-135,
CE, Brazil. Tel/Fax: (+55 85) 3224-9725/(+55 85) 3261-3777.
E-mail addresses: ef.daher@uol.com.br, geraldobezerrajr@yahoo.com.br
(E. De Francesco Daher).
vectors, and frequent exposure to a contaminated environment
during seasonal heavy rainfall and flooding (Sarkar et al., 2002; Ko
et al., 1999; Costa et al., 2015).
Leptospirosis has been recognized as an important cause of
undifferentiated fever and is usually misdiagnosed as malaria or
dengue, as well as other causes of acute febrile illness, including
recently emerging viral diseases such as Zika and chikungunya
(Costa et al., 2015; Patterson et al., 2016). Its clinical presentation
may vary from a mild non-specific influenza-like infection to a
severe disease with life-threatening complications, such as acute
kidney injury (AKI), jaundice, pulmonary hemorrhage (Weil’s
disease), myocarditis, and liver failure (Daher et al., 2010; Daher
et al., 2011).
Unfortunately, mortality from severe leptospirosis remains
unacceptably high, ranging from 5% to 20%, even when optimal
treatment is provided (Goswami et al., 2014). Due to the lack of an
adequate diagnostic test, the underreporting of cases and deaths is

http://dx.doi.org/10.1016/j.ijid.2017.04.023
1201-9712/© 2017 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 E. De Francesco Daher et al. / International Journal of Infectious Diseases 60 (2017) 4–10
still common, leading to underestimations of morbidity and
mortality (Costa et al., 2015). On the other hand, some studies have
shown that the clinical pattern of leptospirosis has been changing.
An increase in the severe forms of the disease has been reported, as
well as its epidemiological spread, but mortality has decreased in
recent decades, mainly due to improvements in treatment and
medical education programs (Daher et al., 2011; Everard et al.,
1995; Daher et al., 1999). Nevertheless, AKI remains one of the
most severe complications associated with increased mortality
(Silva Junior et al., 2011).
Therefore, the aim of this study was to investigate changes in
the clinical patterns of leptospirosis over time, analyzing its clinical
and laboratory presentations in a metropolitan city of Brazil.
Methods
Study population
The study included all patients with a confirmed diagnosis of
leptospirosis admitted consecutively to the São José Infectious
Diseases Hospital, Walter Cantídio University Hospital, and
Fortaleza General Hospital, in Fortaleza in the northeast of Brazil,
from January 1985 to December 2015.
Study design
This was a retrospective cross-sectional study covering three
decades. Data were collected from the medical records of patients
with leptospirosis admitted to the tertiary care hospitals men-
tioned above, which are the three reference hospitals in this region.
Patients were divided into three groups according to the period of
hospital admission: group I for the years 1985–1995, group II for
1996–2005, and group III for 2006–2015. Demographic, clinical,
and laboratory data were compared between these groups to
investigate differences over this three-decade period.
Case definition
Leptospirosis was defined as the presence of a positive serology
result with a microscopic agglutination test (MAT) titer higher than
1:800, associated with an epidemiological and clinical history
compatible with leptospirosis.
Parameters assessed
Demographic characteristics such as age, sex, time between
symptom onset and hospital admission, and length of hospital stay
were recorded. The clinical investigation included a record of all
clinical signs and symptoms presented by each patient at hospital
admission and during their hospital stay, vital signs (systolic and
diastolic blood pressure, heart rate, and respiratory rate),
development of AKI, and need for dialysis. Laboratory data on
hospital admission included an assessment of serum urea,
creatinine, sodium, potassium, direct bilirubin, indirect bilirubin,
aspartate aminotransferase (AST), alanine aminotransferase (ALT),
lactate dehydrogenase (LDH), creatine phosphokinase (CPK),
hemoglobin, hematocrit, white blood cell (WBC) count, platelet
count, and arterial blood gas analysis.
Definitions
AKI was defined according to the Kidney Disease Improving
Global Outcomes (KDIGO) criteria; this is currently the most
accepted definition and classification for AKI (Kidney Disease
Outcomes Quality Initiative, 2012). Thrombocytopenia was defined
as a platelet count lower than 150  109/l, anemia as hemoglobin
5
<12 g/dl, and leukocytosis as a WBC count >12  109/l. Hypoalbu-
minemia was considered as serum albumin <3.5 g/dl. The
occurrence of metabolic acidosis was considered in the presence
of a pH <7.35 and serum bicarbonate <20 mEq/l, and severe
metabolic acidosis at a pH <7.10. Tachypnea was defined as a
respiratory rate higher than 25 breaths per minute. Oliguria was
defined as urine output <400 ml/day after 24 h of effective
hydration. Hypotension was defined as a mean arterial blood
pressure (MAP) of <60 mmHg, and therapy with vasoactive drugs
was initiated when MAP remained lower than 60 mmHg despite
the use of parenteral fluids. Hypertension was defined as a systolic
pressure 140 mmHg and/or diastolic pressure 90 mmHg.
Regarding dialysis therapy, hemodialysis was the method of
choice rather than peritoneal dialysis, and the intention was for
this to be initiated early after intensive care unit admission (ICU)
( < 24 h after AKI diagnosis) and performed daily (until a significant
improvement in renal function).
Statistical analysis
The results are shown in the tables; values were recorded as the
mean  standard deviation (SD). All data were analyzed using IBM
SPSS Statistics version 20.0 software (IBM Corp., Armonk, NY, USA).
The Kolmogorov–Smirnov test was used for numerical variables, to
assess variable distribution. Analysis of variance (ANOVA) was
used for comparisons of the data between the three groups
studied. The significance level was set at 5% (p < 0.05).
Ethics
The study protocol was approved by the Ethics Committee of
São José Infectious Diseases Hospital, Walter Cantídio University
Hospital, and Fortaleza General Hospital, Fortaleza, Ceará, Brazil.
Patient identity was protected, since all data were anonymized.
Results
A total of 507 patients were included. Their mean age was
37.3  15.9 years and 82.4% were male. There were 86 patients in
group I, 187 in group II, and 234 in group III. There was a male
predominance in all groups (76.7%, 80.7%, and 85.9%, respectively),
and patients in group I were older (43.2  17.8 vs. 34.4  13.7 vs.
37.3  16.2 years, respectively, p < 0.0001). The mean time
between symptom onset and hospitalization was nearly 7 days
in all groups, as shown in Table 1.
The analysis of clinical manifestations showed a progressive
decrease in the frequency of arrhythmias (20% vs. 11.1% vs. 0.06%,
respectively, p < 0.0001), chills (67.1% vs. 56.3% vs. 25.3%,
respectively, p < 0.0001), dehydration (60% vs. 57.4% vs. 18.2%,
respectively, p < 0.0001), mental confusion (21.2% vs. 9.5% vs. 0%,
respectively, p < 0.0001), jaundice (98.8% vs. 84.9% vs. 56%,
respectively, p < 0.0001), and secondary infections (11.8% vs.
7.7% vs. 4.0%, respectively, p = 0.04). Diastolic blood pressure levels
increased linearly (66.5  16.1 vs. 67.4  14.2 vs. 72.3  15.4 mmHg,
respectively, p < 0.002). Of note, initial lung manifestations, which
had decreased significantly in the last decade, were more
prevalent in the second decade, as shown in Table 2.
Laboratory data on hospital admission showed a linear
reduction in the levels of serum urea (190  92.7 vs.
135  79.5 vs. 95.6  73.3 mg/dl, respectively, p < 0.0001) and
creatinine (5.8  2.9 vs. 3.8  2.6 vs. 3.0  2.5 mg/dl, respectively, p
< 0.0001), suggesting the occurrence of milder AKI in the last
decade. The levels of direct bilirubin showed a consecutive
reduction (15.1 10.1 vs. 11.7  8.4 vs. 5.5  6.3 mg/dl, respectively,
p < 0.0001), while hemoglobin (10.3  1.9 vs. 10.8  2.0 vs.
11.5  2.1 g/dl, respectively, p < 0.0001) and platelet levels
6 E. De Francesco Daher et al. / International Journal of Infectious Diseases 60 (2017) 4–10

Table 1
Comparison of demographic data between groups I, II, and III.a

Group I, 1985–1995 Group II, 1996–2005 Group III, 2006–2015 p-Value

(n = 86) (n = 187) (n = 234)
Age (years) 43.2  17.8 34.4  13.7 37.3  16.2 <0.0001
Sex
Male (%) 66 (76.7) 151 (80.7) 201 (85.9) 0.121
Female (%) 20 (23.3) 336 (19.3) 33 (14.1)
Hospital stay (days) 13.2  8.7 8.1  5.0 11.1  8.2 <0.0001
Time between symptom onset and 72 73 75 0.822
hospitalization (days)
Mortality (%) 22 14 11.6 0.060
a
Analysis of variance (ANOVA). Values are expressed as the mean  standard deviation, or as the number (percentage). p-Values of <0.05 were considered statistically
significant.

(57.9  52.6 vs. 80.1  68.8 vs. 107.1  99.7  109/l, respectively,
p < 0.0001) were higher in each decade, as shown in Table 3.
The percentage of patients with severe AKI (KDIGO stage 3)
decreased consecutively (96.3% vs. 70.1% vs. 57.4%, respectively,
p < 0.0001), as shown in Figure 1. Consequently, the need for
dialysis also decreased (75.6%, 29.5%, and 31.6%, respectively,
p < 0.0001). The use of antibiotics increased progressively (43.8%,
93.8%, and 94.5%, respectively, p < 0.0001), while the use of
vasoconstrictors, that could only be analyzed in the last two
decades, was significantly lower in the third decade (31.0% vs.
16.1%, p = 0.05), as shown in Table 4. Mortality also showed a trend
towards a linear reduction (22% vs. 14% vs. 11.6%, respectively,
p = 0.060), as illustrated in Figure 2.
Discussion
This is the first study in the literature to assess data from
leptospirosis patients over a three-decade period. Differences in
clinical and laboratory patterns were evaluated across this three-
decade period, as well as changes in treatment. The study period
encompasses the time from the recording of the first cases in the
study region up to recent years, and important changes were
observed throughout these decades, including a decrease in AKI
severity and mortality rates.
Leptospirosis is a serious public health problem and a neglected
disease, with a higher prevalence in tropical areas, including Brazil
(Daher et al., 2010; Slack, 2010). McBride et al. (2005) recognized
that advances have been made in understanding the pathogenesis
of leptospirosis, and found that the effects of educational programs
in endemic areas had an important impact in decreasing mortality
(Daher et al., 2011). There has been a clear improvement in the
disease diagnosis, mainly due to physician awareness of the
differential diagnosis of febrile illnesses in tropical countries, as
well as more experience with febrile diseases affecting returning
travelers in developed countries (McBride et al., 2005; Ricaldi and
Vinetz, 2006; Waggoner et al., 2015).
Consistent with previous studies, most patients in the present
study were male. The male sex has been extensively associated
with the risk of leptospirosis infection, due to the connection of
leptospirosis infection with occupations traditionally attributed to
men, such as abattoir and sewage workers, as well military
personnel. Consequently, males are usually more exposed to
Leptospira spirochetes (Sarkar et al., 2002; Mikulski et al., 2015).
Furthermore, patients diagnosed in the last two decades of this
study were significantly younger than those in the first decade.
This fact may have strongly influenced the reduction in mortality
and presence of less severe forms of the disease in recent years,
since older patients usually have more comorbidities and a higher

Table 2
Comparison of signs, symptoms, and vital signs between groups I, II, and III.a

Group I, 1985–1995 Group II, 1996–2005 Group III, 2006–2015 p-Value

(n = 86) (n = 187) (n = 234)
Signs and symptoms
Arrhythmias (%) 17 (20) 6 (11) 1 (0.6) <0.0001
Chills (%) 57 (67) 90 (56.3) 57 (25.3) <0.0001
Headache (%) 56 (65.9) 129 (79.6) 132 (58.7) <0.0001
Crackles (%) 12 (14) 36 (22.8) 20 (8.9) 0.001
Dehydration (%) 51 (60) 93 (57.4) 41 (18.2) <0.0001
Mental confusion (%) 18 (21.2) 4 (9.5) 0 (0) <0.0001
Jaundice (%) 84 (98.8) 141 (84.9) 126 (56) <0.0001
Secondary infections (%) 10 (11.8) 12 (7.7) 9 (4) 0.041
Myalgia (%) 78 (91.8) 157 (94.6) 166 (73.8) <0.0001
Petechiae (%) 11 (12.9) 32 (20.8) 8 (3.6) <0.0001
Tachypnea (%) 17 (20) 53 (33.5) 20 (8.9) <0.0001
Dyspnea (%) 1 (1.2) 69 (42.3) 71 (31.6) <0.0001
Oligo/anuria (%) 20 (23.5) 53 (33.3) 57 (25.3) 0.143
Fever (%) 84 (98.8) 159 (95.8) 205 (91) 0.019
Calf pain (%) 70 (82.4) 57 (80.3) 109 (52.4) <0.0001
Edema (%) 12 (14.1) 24 (45.3) 21 (15.4) <0.0001
Vital signs
SBP (mmHg) 110.0  20.3 108.1  19.7 116.4  21.3 0.001
DBP (mmHg) 66.5  16.1 67.4  14.2 72.3  15.4 0.002
HR (/min) – 97.3  17.3 96.6  18.4 0.786
RR (/min) – 26  8 26  10 0.716

SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; RR, respiratory rate.
a
Analysis of variance (ANOVA). Values are expressed as the mean  standard deviation, or as the number (percentage). p-Values of <0.05 were considered statistically
significant.
 E. De Francesco Daher et al. / International Journal of Infectious Diseases 60 (2017) 4–10 7

Table 3
Comparison of laboratory data between patients from groups I, II, and III.a

Parameters Group I, 1985–1995 Group II, 1996–2005 Group III, 2006–2015 p-Value
(n = 86) (n = 187) (n = 234)
Creatinine (mg/dl) 5.8  2.9 3.8  2.6 3.0  2.5 <0.0001
Urea (mg/dl) 190.1  92.7 135.3  79.5 95.6  73.3 <0.0001
Potassium (mEq/l) 4.0  1.0 3.6  1.1 3.9  1.9 0.019
Sodium (mEq/l) – 132.3  6.3 133.2  14.5 0.583
AST (UI/l) 75.5  54.5 141.1  145.3 169.9  259.2 0.006
ALT (UI/l) 51.9  33.5 102.4  122.9 116.0  196.0 0.019
LDH (UI/l) 595.7  249.0 719.7  482.4 890.7  634.8 0.048
CPK (UI/l) 289.5  395.6 1358.5  3550 1799  4163.7 0.164
Direct bilirubin (mg/dl) 15.1  10.1 11.7  8.4 5.5  6.3 <0.0001
Indirect bilirubin (mg/dl) 5.6  4.4 5.3  5.2 2.56  4.0 <0.0001
Hematocrit (%) 32.3  5.9 32.0  6.2 34.2  21.8 0.376
Hemoglobin (g/dl) 10.3  1.9 10.8  2.0 11.5  2.1 <0.0001
WBC (109/l) 16.34  10.84 12.96  6.4 13.6  14.2 0.110
Platelets (109/l) – 94.75  82.73 123.048  115.493 0.021
Serum pH 7.37  0.11 7.36  0.08 7.37  0.08 0.747
Bicarbonate (mEq/l) 18.8  6.6 18.8  4.4 18.3  4.7 0.668
SaO2 (%) – 93.0  8.9 93.1  8.9 0.944

AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; CPK, creatine phosphokinase; WBC, white blood cell count; SaO2, oxygen
saturation.
a
Analysis of variance (ANOVA). Values are expressed as the mean  standard deviation. p-Values of <0.05 were considered statistically significant.

Table 4
Comparison of treatment instituted for patients with severe leptospirosis between groups I, II, and III.a

Group I, 1985–1995 Group II, 1996–2005 Group III, 2006–2015 p-Value

(n = 86) (n = 187) (n = 234)
Vasoconstrictors (%) – 9 (31.0) 31 (16.1) 0.05
Ceftriaxone (%) 9 (64.3) 0 (0) 125 (67.9) 0.046
Penicillin (%) 7 (22.6) 114 (82.6) 64 (28.4) <0.0001
Diuretics (%) 3 (11.5) 10 (34.5) 42 (21.8) 0.118
Need for dialysis (%) 65 (75.6 54 (29.5) 74 (31.6) <0.0001
Hemodialysis (%) 3 (4.6) 53 (98.1) 67 (90.5) <0.0001
Peritoneal dialysis (%) 62 (95.4) 1 (1.9) 7 (9.5) <0.0001
a
Analysis of variance (ANOVA). Values are expressed as the number (percentage). p-Values of <0.05 were considered statistically significant.

risk of death. Older age and the presence of comorbidities have
been extensively associated with death in leptospirosis patients
(Ko et al., 1999; Daher et al., 1999; Dupont et al., 1997).
In contrast to previous reports, the clinical presentation on
admission of the leptospirosis patients in the present study seems
to have become milder over the last decade. A progressive decrease
in some of the life-threatening manifestations, such as arrhyth-
mias, chills, dehydration, mental confusion, jaundice, and second-
ary infections, was noted, suggesting a decrease in severe
leptospirosis, mostly in the last decade. It was also observed that
the time between symptom onset and hospital admission
remained nearly the same, while the length of hospital stay
decreased. This probably reflects a milder form of disease, which
may be attributed to better sanitary conditions in Brazil and early
diagnosis. Poor sanitation has been strongly associated with the
development of leptospirosis in many countries (Mwachui et al.,
2015). In addition, only people with severe forms of the disease
would have been diagnosed and hospitalized in the first decade of
this study. The diagnosis and hospitalization of milder cases have
become more frequent in recent years, probably due to effective

100%
p <0.001
90%
80%
70%
60%
50%
40% KDIGO 1
30% KDIGO 2
20% KDIGO 3
10%
0%
1985 - 1995 1996 - 2005 2006 - 2015

Figure 1. Acute kidney injury stages according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria, in patients with leptospirosis in the three different
decades.
8 E. De Francesco Daher et al. / International Journal of Infectious Diseases 60 (2017) 4–10
Figure 2. Decrease in mortality of leptospirosis cases over the three-decade period p = 0.06.
medical education programs (Daher et al., 2011). The early
diagnosis of leptospirosis has been associated with fewer
complications and a faster recovery from the infection (Daher
et al., 2010; Dupont et al., 1997; Spichler et al., 2008).
Moreover, changes in the hemodynamic status and laboratory
parameters were observed, including a decrease in bilirubin
levels and an increase in hemoglobin and platelet levels. The
better hemodynamic status of the patients on admission,
demonstrated by higher blood pressure levels, confirms the
presence of the milder forms of the disease in the last decade.
Hyperbilirubinemia is extremely common in leptospirosis
patients, more frequently in association with skin rash, which
usually leads to the presence of a ‘rubinic jaundice’ pattern (Puca
et al., 2016). Elevated bilirubin levels and jaundice have been
associated with death and poor outcomes in leptospirosis (Daher
et al., 2016; Herrmann-Storck et al., 2010; Abgueguen et al., 2008),
and their lower levels in the last decades among the study
patients also reflect a reduction in disease severity in these
patients through the decades.
Improvements in hematological parameters, including hemo-
globin and platelet levels, may be evidence of a less severe
infection and may have contributed to the decrease in mortality. A
decrease in hemoglobin levels is a common finding in leptospirosis
patients and has been associated with severe disease and poor
outcomes (De Silva et al., 2014; Prabhu and Ramesh, 2016). In
addition, thrombocytopenia is also extremely frequent in lepto-
spirosis patients and it is usually associated with hemorrhagic
phenomena and complications. It has been strongly associated
with mortality and severity in leptospirosis and it has been
included in a recent diagnostic scoring system for leptospirosis in a
resource-limited setting (Spichler et al., 2008; Rajapakse et al.,
2016). In a study carried out in Puerto Rico, elevated WBC levels
were associated with fatal outcomes (Sharp et al., 2016). In the
present study, this elevation may have resulted from a more severe
disease presentation on admission and a possible secondary
infection.
The presence of arrhythmias is also a predictor of death in
leptospirosis. Arrhythmias are the most common cardiac manifes-
tation of leptospirosis and often derive from electrolyte disorders,
such as hypokalemia and hypocalcemia, which are usually
secondary to AKI (Sacramento et al., 2002; Navinan and Rajapakse,
2012; Soares et al., 2017). Electrocardiographic abnormalities have
been described as risk factors for death in leptospirosis patients
(Daher et al., 1999; Dupont et al., 1997).
Interestingly, there was a significant linear reduction in serum
urea and creatinine in the patients included in the present study. A
progressive reduction of severe AKI cases (KDIGO stage 3) in each
decade was also shown, suggesting early diagnosis and treatment.
Consequently, less renal replacement therapy was needed over the
last decades, a relevant factor that has contributed to the decrease
in mortality, since AKI is strongly associated with a higher risk of
death in leptospirosis (Silva Junior et al., 2011; Daher et al., 2008;
Teles et al., 2016). Leptospirosis is a significant cause of AKI in low-
and middle-income tropical countries (Bouchard and Mehta,
2016). AKI is also an important component of the severe form of
leptospirosis (Weil’s syndrome), leading to several complications.
Referral to specialized care, including a nephrologist consultation,
as well as early implementation of dialysis, seems to be essential
for slowing the progression of AKI to more severe forms and for
decreasing mortality (Andrade et al., 2007). Regarding the
treatment of AKI, intermittent peritoneal dialysis (IPD) was the
predominant method in the period from 1985 to 1996, used in
95.4% of patients who needed dialysis; daily hemodialysis (DHD)
was the method most often used in the period from 1997 to 2015.
The institution of early hemodialysis (<24 h after AKI diagnosis)
instead of IPD was essential for the better prognosis of patients in
the second and third decades of the study, with proven benefits in
leptospirosis patients (Andrade et al., 2007). Furthermore, it is
hypothesized that the reduction in AKI development and AKI
severity, as well as the establishment of early and effective renal
replacement therapy were key points in the reduction of mortality
in these patients in recent years.
A clear decreasing trend in mortality was seen over these three
decades (decreasing from 22% to 14%, and then to 11.6% in the last
decade), which probably reflects the early diagnosis of complica-
tions and the provision of adequate treatment. Although previous
studies have shown evidence that mortality does not seem to be
significantly influenced by antibiotic use (Daher et al., 2012; Costa
et al., 2003), a recent study by the present investigator group found
that ceftriaxone was a protective factor for ICU admission in
leptospirosis patients (Daher et al., 2016). There is also evidence
that the use of penicillin is associated with a reduction in hospital
length of stay and fewer complications, including AKI (Daher et al.,
2012). It was also demonstrated in the present study that the use of
 E. De Francesco Daher et al. / International Journal of Infectious Diseases 60 (2017) 4–10
antibiotics increased progressively throughout the decades in this
cohort (43.8%, 93.8%, and 94.5%, respectively, p < 0.0001), although
it was not directly associated with a decline in mortality according
to the multivariate analysis. The use of antibiotics in leptospirosis is
now a consensus in the literature and it is believed that the
increase in use has probably contributed to a reduction in
mortality, since the use of antibiotics has been associated with a
shorter length of hospital stay, milder AKI, and less need for dialysis
(Daher et al., 2012), as well as a lower frequency of ICU admission
(Daher et al., 2016).
In summary, leptospirosis is a life-threatening neglected
tropical disease and its presentation has changed significantly in
the study region over time. The main changes point to a reduction
in severity and complications, such as AKI. Mortality has shown a
clear decreasing trend in recent decades.
Study limitations
The main limitations of this study derive from its retrospective
design. Admission data were not available in some patient records.
The study was performed in only one region of Brazil, so disease
patterns may differ in other regions of Brazil and worldwide.
Non-technical summary
Leptospirosis is a bacterial disease transmitted by rat urine,
which is very common in tropical countries. The characteristics of
patients with leptospirosis in a large city in Brazil were assessed,
over a period of three decades. There is evidence that the disease
has become milder, including milder forms of renal failure, one of
the most severe disease complications. A decrease in mortality was
also found. These findings could be due to more frequent and
earlier identification of the disease by clinicians, and consequently
to better health care provision.
Financial support
E. F. Daher and G. B. Silva Junior are recipients of a grant from the
Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq). The funders had no role in the study design, data collection
and analysis, decision to publish, or preparation of the manuscript.
Conflict of interest
The authors declare no conflicts of interest regarding this
manuscript.
Acknowledgements
We are very grateful to the team of clinicians, medical residents,
medical students, and nurses from São José Infectious Diseases
Hospital, Walter Cantídio University Hospital, and Fortaleza General
Hospital for the assistance provided to the patients and for the
technical support provided for the development of this research.
References
Abgueguen P, Delbos V, Blanvillain J, Chennebault JM, Cottin J, Fanello S, et al.
Clinical aspects and prognostic factors of leptospirosis in adults. J Infect
2008;57:171–8.
Adler B, de la Peña Moctezuma A. Leptospira and leptospirosis. Vet Microbiol
2010;140:287–96.
Andrade L, Cleto S, Seguro AC. Door-to-Dialysis Time and Daily Hemodialysis in
Patients with Leptospirosis: Impact on Mortality. Clin J Am Soc Nephrol
2007;2:739–44.
Bouchard J, Mehta RL. Acute Kidney Injury in Western Countries. Kidney Dis (Basel)
2016;2:103–10.
9
Costa E, Lopes AA, Sacramento E, Costa YA, Matos ED, Lopes MB, et al. Penicillin at
the late stage of leptospirosis: a randomized controlled trial. Rev Inst Med Trop
Sao Paulo 2003;45:141–5.
Costa F, Hagan JE, Calcagno J, Kane M, Torgerson P, Martinez-Silveira MS, et al. Global
Morbidity and Mortality of Leptospirosis: A Systematic Review. PLoS Negl Trop
Dis 2015;9:e0003898.
Daher E, Zanetta DM, Cavalcante MB, Abdulkader RC. Risk factors for death and
changing patterns in leptospirosis acute renal failure. Am J Trop Med Hyg
1999;61:630–4.
Daher EF, Marques CN, Lima RSA, Silva Júnior GB, Barbosa AS, Barbosa ES, et al. Acute
kidney injury in an infectious disease intensive care unit - an assessment of
prognostic factors. Swiss Med Wkly 2008;138:128–33.
Daher EDF, de Abreu KLS, da Silva Junior GB. Leptospirosis-associated acute kidney
injury. J Bras Nefrol 2010;32:400–7.
Daher EF, Silva GB, Lima RSA, Mota RMS, Rocha HAL, de Abreu KLS, et al. Different
Patterns in a Cohort of Patients with Severe Leptospirosis (Weil Syndrome):
Effects of an Educational Program in an Endemic Area. Am J Trop Med Hyg
2011;85:479–84.
Daher EF, Silva GB, de Abreu KLS, Mota RMS, Batista DV, Rocha NA, et al.
Leptospirosis-associated acute kidney injury: penicillin at the late stage is
still controversial: Penicillin in leptospirosis. J Clin Pharm Ther 2012;37:
420–5.
Daher EF, Soares DS, de Menezes Fernandes ATB, Girão MMV, Sidrim PR, Pereira
EDB, et al. Risk factors for intensive care unit admission in patients with severe
leptospirosis: a comparative study according to patients’ severity. BMC Infect
Dis 2016;16:40.
De Silva NL, Niloofa MJR, Fernando N, Karunanayake L, Rodrigo C, De Silva HJ, et al.
Changes in full blood count parameters in leptospirosis: a prospective study. Int
Arch Med 2014;7:31.
Dupont H, Dupont-Perdrizet D, Perie JL, Zehner-Hansen S, Jarrige B, Daijardin JB.
Leptospirosis: prognostic factors associated with mortality. Clin Infect Dis
1997;25:720–4.
Everard CO, Edwards CN, Everard JD, Carrington DG. A twelve-year study of
leptospirosis on Barbados. Eur J Epidemiol 1995;11:311–20.
Goswami RP, Goswami RP, Basu A, Tripathi SK, Chakrabarti S, Chattopadhyay I.
Predictors of mortality in leptospirosis: an observational study from two
hospitals in Kolkata, eastern India. Trans R Soc Trop Med Hyg 2014;108:
791–6.
Haake DA, Levett PN. Leptospirosis in humans. Curr Top Microbiol Immunol
2015;387:65–97.
Herrmann-Storck C, Saint-Louis M, Foucand T, Lamaury I, Deloumeaux J, Baranton G,
et al. Severe leptospirosis in hospitalized patients, Guadeloupe. E merg Infect
Dis 2010;16:331–4.
Kidney Disease Outcomes Quality Initiative. KDIGO clinical practice guidelines for
acute kidney injury – Summary of recommendation statements. Kidney Int
Suppl 2012;2:1–138.
Ko AI, Galvão Reis M, Ribeiro Dourado CM, Johnson WD, Riley LW. Urban epidemic of
severe leptospirosis in Brazil. Salvador Leptospirosis Study Group. Lancet
1999;354:820–5.
McBride AJ, Athanazio DA, Reis MG, Ko AI. Leptospirosis. Curr Opin Infect Dis
2005;18:376–86.
Mikulski M, Boisier P, Lacassin F, Soupé-Gilbert MRE, Mauron C, Bruyere-Ostells L,
et al. Severity Markers in severe leptospirosis. Eur J Clin Microbiol Infect Dis
2015;34:687–95.
Mwachui MA, Crump L, Hartskeerl R, Zinsstag J, Hattendorf J. Environmental and
behavioural determinants of leptospirosis transmission: a systematic review.
PLoS Negl Trop Dis 2015;9:e0003843.
Navinan MR, Rajapakse S. Cardiac involvement in leptospirosis. Trans R Soc Trop
Med Hyg 2012;106:515–20.
Patterson J, Sammon M, Garg M. Dengue, Zika and Chikungunya: emerging
arboviruses in the new world. West J Emerg Med 2016;17:671–9.
Prabhu MV, Ramesh V. Fever, thrombocytopenia, and AKI-A profile of malaria,
dengue, and leptospirosis with renal failure in a South Indian tertiary-care
hospital. Clin Nephrol 2016;86:128–30.
Puca E, Pilaca A, Kalo T, Pipero P, Bino S, Hysenaj Z, et al. Ocular and cutaneous
manifestation of leptospirosis acquired in Albania: a retrospective analysis with
implications for travel medicine. Travel Med Infect Dis 2016;14:143–7.
Rajapakse S, Weeratunga P, Niloofa R, Fernando N, de Silva NL, Rodrigo C, et al. A
Diagnostic Scoring Model for Leptospirosis in Resource Limited Settings. PLoS
Negl Trop Dis 2016;10:e000451.
Ricaldi JN, Vinetz JM. Leptospirosis in the tropics and in travelers. Curr Infect Dis Rep
2006;8:51–8.
Sacramento E, Lopes AA, Costa E, Passos OL, Costa YA, Matos ED. Electrocar-
diographic alterations in patients hospitalized with leptospirosis in the
Brazilian city of Salvador. Arq Bras Cardiol 2002;78:267–70.
Sarkar U, Nascimento SF, Barbosa R, Martins R, Nuevo H, Kalofonos I, et al.
Population-based case-control investigation of risk factors for leptospirosis
during an urban epidemic. Am J Trop Med Hyg 2002;66:605–10.
Sharp TM, García BR, Pérez-Padilla J, Galloway RL, GuerrA M, Ryff KR, et al. Early
Indicators of Fatal Leptospirosis during the 2010 Epidemic in Puerto Rico. PLoS
Negl Trop Dis 2016;10:e0004482.
Silva Junior GB, Abreu KL, Mota RM, Barreto AG, Araújo SM, Rocha HA, et al. RIFLE
and Acute Kidney Injury Network classifications predict mortality in
leptospirosis-associated acute kidney injury. Nephrology (Carlton) 2011;16:
269–76.
10 E. De Francesco Daher et al. / International Journal of Infectious Diseases 60 (2017) 4–10

Slack A. Leptospirosis. Aust Fam Physician 2010;39:495–8.
Soares DS, Galdino GS, Rodrigues BC, Silva Junior GB, Daher EF. Arrhythmias in
leptospirosis-associated acute kidney injury: a case series. Braz J Infect Dis in
press 2017; in press.
Spichler AS, Vilaça PJ, Athanazio DA, Albuquerque JO, Buzzar M, Castro B, et al.
Predictors of lethality in severe leptospirosis in urban Brazil. Am J Trop Med Hyg
2008;79:911–4.
Teles F, de Mendonça Uchôa JV, Mendonça DMB, Costa AFP. Acute kidney injury in
leptospirosis: the Kidney Disease Improving Global Outcomes (KDIGO) criteria
and mortality. Clin Nephrol 2016;86:303–9.
Victoriano AFB, Smythe LD, Gloriani-Barzaga N, Cavinta LL, Kasai T, Limpakarnja-
narat K, et al. Leptospirosis in the Asia Pacific region. BMC Infect Dis 2009;9:1.
Waggoner JJ, Soda EA, Seibert R, Grant P, Pinsky BA. Molecular detection of
Leptospira in two returned travelers: higher bacterial load in cerebrospinal fluid
versus serum or plasma. Am J Trop Med Hyg 2015;93:238–40.