Trans R Soc Trop Med Hyg

doi:10.1093/trstmh/tru148

High dose corticosteroids in severe leptospirosis: a systematic review

Chaturaka Rodrigoa,b, Nipun Lakshitha de Silvaa,b, Ravindi Goonaratnea, Keshinie Samarasekaraa,

REVIEW
Indika Wijesinghea, B. Parththipana and Senaka Rajapaksea,b,*

a
Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka; bTropical Medicine Research Unit,
Faculty of Medicine, University of Colombo, Sri Lanka

*Corresponding author: Tel: +94112695300; Fax: +94112689188; E-mail: senaka.ucfm@gmail.com

Downloaded from http://trstmh.oxfordjournals.org/ at University of Prince Edward Island on November 1, 2014

Received 3 February 2014; revised 23 July 2014; accepted 23 July 2014

The role of corticosteroids in the treatment of severe leptospirosis is unclear. The rationale for their use is that, in
severe leptospirosis, there is a severe immunological response that is harmful to the host resulting in multi-organ
dysfunction, which is potentially offset by the nonspecific immunosuppression of high dose steroids. We con-
ducted a systematic review of studies that have assessed the use of high dose corticosteroids in patients with
severe leptospirosis by searching MEDLINE and Scopus SciVerse without any language or time restrictions. We
identified five studies, including one open randomized clinical trial, which had assessed the use of high dose ster-
oids in severe leptospirosis. Four studies demonstrated a benefit of corticosteroids in treating severe disease with
pulmonary involvement when administered early in the course of the disease, but these studies had several
methodological constraints as highlighted in the text. Only the randomized controlled trial study showed that
corticosteroids are ineffective and may increase the risk of nosocomial infections. There is no robust evidence
to suggest that high dose corticosteroids are effective in severe leptospirosis, and a well-designed randomized
clinical trial is needed to resolve this.

Keywords: Adult respiratory distress syndrome, ARDS, Corticosteroids, Leptospirosis, Steroids

Introduction multi-organ dysfunction in severe leptospirosis is still an enigma.

Leptospirosis is a zoonotic disease caused by spirochetes of the
genus Leptospira. It has a worldwide distribution but is endemic
in tropical regions. It causes considerable morbidity and mortality,
especially at times of epidemics in endemic areas.1 Contact with
water, soil or food contaminated by urine of infected animals is
the usual mode of transmission to humans. The bacteria enter
the human body through skin or mucous membranes, especially
through abraded skin. An accurate assessment of disease burden
is difficult due to problems in diagnosis and under-reporting. The
incidence of leptospirosis is on the rise in developing nations, but
on the decline in developed countries.2 However, it is estimated
that around 10 000 cases of severe leptospirosis worldwide are
hospitalized annually.3 The disease is endemic in areas with
high rainfall, close human contact with livestock, poor sanitation
and workplace exposure to the organism.4,5
Many studies have assessed the mortality predictors of lepto-
spirosis and a significant number of them have repeatedly pointed
towards organ dysfunction as a salient predictive factor.6 Acute
leptospirosis can be complicated by dysfunction of various organs
leading to acute kidney injury, hepatitis, pulmonary hemorrhages,
myocarditis and meningitis.7 For reasons not yet fully explained,
only a minority of infected people will go on to develop severe
disease with multi-organ failure.8 The pathogenesis of this
Current thinking is that both pathogen related factors (infecting
serovar/species, inoculum size) and host factors (immunological
response) contribute to this heterogeneity.6
Several studies have detailed the immunological basis of the
pathophysiological mechanisms which lead to organ dysfunction
in leptospirosis. Studies of immunochemical markers have shown
that both cell mediated and humoral immunity are activated in
severe leptospirosis. In an analysis of 44 Thai patients with defin-
ite or suspected leptospirosis, De Fost et al.9 showed that markers
of cell mediated immune activity (IFN-g-inducible protein-10,
granzyme B and monokine induced by IFN-g) were raised com-
pared to healthy controls. Whether certain hosts of a particular
genetic makeup have increased vulnerability to leptospirosis is
unclear. A study by Fialho et al.10 compared leptospirosis patients
with healthy controls for HLA alleles and genetic polymorphisms
in the cytokine genes. Significant associations were found for cer-
tain alleles of the HLA-A and -B loci plus several HLA haplotypes.
Polymorphisms in IL-4 and IL-4Ra genes were also significantly
associated with a past history of leptospirosis. However, these
findings have not been confirmed in larger population samples.
Studies have assessed different mediators of sepsis and cytokines
in relation to severe leptospirosis and found significant associa-
tions with mortality for some individuals. These mediators include
human serum mannose-binding lectin (which identifies

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C. Rodrigo et al.

pathogens activating the immune system),11 soluble ST2

receptors, long pentraxin PTX3, copeptin and platelet activating
factor acetylhydrolase (based on limited studies on animal
models).12–14
The role of corticosteroids in treatment of severe leptospirosis,
in particular for pulmonary complications including adult respira-
tory distress syndrome (ARDS), has been assessed in a handful of
studies. The argument here is that multi-organ failure with lepto-
spirosis may be due to over activity of the immune system rather
than due to the effects of the pathogen; thus, treatment with
therapeutic doses of steroids may help to counter the immune
activation which takes place. Therefore, non-specific suppression

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of the immune system by steroids is thought to help reduce mor-
tality and morbidity in patients with severe leptospirosis. However,
the few studies in this area have come to conflicting conclusions
and sample sizes have been a significant limitation. In ARDS as a
whole the benefit of corticosteroids is unclear in spite of there
being a systematic review15 and meta-analysis16 on the subject,
and no firm recommendation can currently be made for its use in
ARDS. This systematic review aims to critically evaluate the place
of high dose corticosteroids in severe leptospirosis, based on
current best evidence.

Methods
Our aim was to include interventional studies of any design where
treatment doses of corticosteroids have been administered to
patients with leptospirosis. We searched MEDLINE/PUBMED for
publications with the search terms ‘leptospirosis’, ‘leptospira’, ‘lep-
tosp*’, ‘Weil’s’ or ‘Weil’ in any field and ‘steroid’, ‘corticosteroid’,
‘prednisolone’, ‘methylprednisolone’ or ‘dexamethasone’ in the
title and abstract, with no time limits (the search contained arti-
cles published up to 31 January 2014). Searching with alternative
terms ‘canicola fever’, ‘mudwater fever’, ‘canefield fever’ and
‘swamp fever’ instead of leptospirosis was also performed to
increase the yield of the search. A similar search was done in
SciVerse Scopus with the same search terms and conditions.
The reference lists were imported into ENDNOTE X6 (Thomson
Reuters, Carlsbad, CA, USA) and duplicates were removed. Three Figure 1. PRISMA flowchart of literature search.
reviewers independently evaluated the abstracts of all retrieved
publications and selected studies likely to provide relevant data.
Full texts of these publications were retrieved and read independ-
Several case reports have described postulated benefits of cor-
ently by the reviewers. All studies describing a clinical trial in lepto-
ticosteroids in severe leptospirosis (Table 2). However, we did not
spirosis where one or more trial arms had received corticosteroids
include these case reports in the main review as they would not
as a mode of treatment were included in the review. The char-
constitute high quality evidence. They are also affected by publi-
acteristics of studies, methodological quality, results and limi-
cation bias where positive results are more likely to be reported (or
tations were extracted to a data sheet. The PRISMA checklist
published) than negative results.
was followed for reporting of the systematic review.17
One of the first observational studies that assessed the role of
steroid pulse therapy for severe leptospirosis was carried out in
India by Trivedi et al.19 Out of 77 patients with retrospectively
Results
confirmed leptospirosis, 117% (13/77) developed pulmonary
There were 152 hits after deleting the duplicates from both data- complications. Of these patients with pulmonary complications,
bases and after the screening process only six abstracts were eight had been treated with high dose steroids. Six patients out
retained as relevant to the review. Out of the selected abstracts of this group of eight survived, while only one patient survived
one was a protocol published for a randomized control trial and in the group that was not treated with steroids. The authors
its results had not been published at the time of this analysis.18 concluded that high dose steroids are effective for patients
There was also one abstract for which the full text could not be diagnosed with pulmonary complications of leptospirosis when
obtained.19 The PRISMA diagram for the search is given in administered early during the course of illness. However, this
Figure 1 and details of included studies are provided in Table 1. was a retrospective observational study with a high risk of bias.

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Table 1. Summary of clinical trials assessing the role of steroids in severe leptospirosis
Authors and year
Ittyachen et al. 200520
Kularatne et al. 201123
Shenoy et al. 200624
Niwattayakul et al. 201026
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Transactions of the Royal Society of Tropical Medicine and Hygiene
Methods Sample size Results Limitations
Setting Kerala, India (2004) Sample size: 8 Survival rate was 88% (7/8 No control group
Design Prospective interventional pilot study patients) without long term Small sample size
(no control group) complications
Diagnosis Specific laboratory criteria not Mean duration of MP treatment
mentioned was 4 days
Treatment All patients with ARDS and
leptospirosis were treated with
non-invasive ventilation and i.v. MP,
40 mg 6 hourly in addition to
standard treatment
Outcome Survival
Setting Kandy, Sri Lanka (2008) Sample size: 62 Mortality was 10.7% (16/149) in No control group
Design A descriptive prospective study with the group that received MP. Not all patients with severe
no control group. Comparison of Comparable mortality in the leptospirosis had received
results with a retrospective pre-MP retrospective cohort was 22% MP during the period of
cohort. (17/78). The difference marked in study, increasing the risk
Diagnosis MAT moderately severe leptospirosis. of bias.
Treatment i.v. MP 500 mg daily for 3 days Observed benefit was restricted to
followed by oral MP 8 mg/d for 5 days those with pulmonary
Outcome Survival involvement
Setting: Mumbai, India (2005) Sample size: MP group; 17, Mortality in MP group and non-MP Not a randomized
non-MP group was 18% (3/17) and 62% controlled trial. High risk
group; 13 (8/13) respectively (p,0.025). of bias.
Design Prospective study: Those who received Benefit was restricted to those Small sample size
MP compared with patients who did with moderate to severe
not receive it during the same pulmonary involvement.
epidemic.
Diagnosis Rapid dipstick test for IgM confirmed
by IgM ELISA
Treatment i.v. MP 1 g/d for 3 days followed by
oral prednisolone 1 mg/kg/d for
7 days for test group and standard
treatment only for control group
Outcome Survival
Setting Northeastern and southern Thailand Sample size: Group 1¼23 No mortality benefit or other Small sample size with
(2003–2006) Group 2¼22 outcomes in either arm (per inadequate
Group 3¼23 protocol or intention to treat statistical power
analysis)
Statistically significant increase in
nosocomial infections in
dexamethasone group
Continued
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C. Rodrigo et al.

An interventional pilot study by Ittyachen et al.20 studied

methylprednisolone (MP) as an adjuvant in treatment of ARDS
Inclusion of leptospirosis

due to leptospirosis. There were eight patients who were admitted

to a medical intensive care unit with ARDS (diagnosed based on
mimics in the study

North American European consensus conference criteria)21 due

to leptospirosis (diagnosed based on World Health Organization
criteria).22 The intervention was a combination of non-invasive
Limitations

ventilation and intravenous MP, while the outcome measure

was survival. The initial dose of MP was 40 mg 6 hourly and
later on, with clinical improvement, it was given at 8 h and 12 h
intervals followed by a tapering dose of oral prednisolone. Seven
patients (87%, 7/8) survived and resumed normal life within

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2 weeks. The majority of the patients were given MP for 4 days
and the duration of administration of MP was found to be related
to duration of ICU stay. Although the investigators concluded that
MP is life saving in combination with non-invasive ventilation in
patients with ARDS due to leptospirosis, there were major defi-
ciencies in study design that prevents a robust conclusion. This
was a single arm prospective study without a control group for
comparison. The authors claim that mortality rates for patients
Results

with leptospirosis induced ARDS with similar treatment (except

for MP) neared 100% (numbers not mentioned) in their previous
practice. However, this observation was retrospective and not a
part of the study protocol. Six out of the eight patients included
were below 45 years of age; younger age is a known predictor of
ARDS: Adult respiratory distress syndrome; MAT: Microscopic agglutination test; MP: methylprednisolone.

better outcome.6 Furthermore, none of the patients had oliguric

acute kidney injury that required dialysis, indicating that the
degree of renal impairment was not severe. Renal impairment is
Sample size

a major factor determining survival in leptospirosis with multi-

organ dysfunction. The sample size was also small, although
the authors mention that it was a pilot study that showed the
need for further investigation of this treatment modality.
Kularatne et al.23 studied the efficacy of bolus MP in severe
Group 2: i.v. dexamethasone 200 mg/d
Treatment All groups consisted of patients with

leptospirosis in a descriptive study over a period of one year in a

for 3 days followed by 1 mg/kg/d of
infusion daily till bleeding subsided

tertiary care hospital in Sri lanka. The study compared two groups
Survival, duration of mechanical
four fold rise in antibody titre as
Positive PCR for lipL21 gene or a

Group 1: desmopressin 0.3 mg/kg

of patients with leptospirosis at two time periods; the group trea-

Prospective open randomized

ventilation and duration of

oral prednisolone for 4 days
Group 3: standard treatment

ted after implementation of universal MP bolus dosing for severe

leptospirosis and a retrospective cohort treated before the imple-
mentation of this policy. The group that was managed before the
severe leptospirosis:

introduction of MP was taken as ‘pre-MP period’ group which con-

assessed by MAT
controlled trial

stituted 78 patients, the other group termed the ‘MP period’ group
constituted 149 patients. Severity of the illness was assessed
bleeding
Methods

using a score ranging from 0–6 based on organ impairment; a

score ≥2 was required to qualify for MP treatment. MP was
given at a dose of 500 mg daily intravenously for 3 days followed
by oral administration of 8 mg/d for 5 days. Based on the scoring
Diagnosis

Outcome

system there were 60 patients classified as severe (score .2) in

Design

the pre-MP group and 72 patients in the MP group. However,

only 62 of them received MP as the other 10 were terminally ill.
Overall the death rates between the pre-MP and MP groups were
statistically significant (22% [17/78] vs. 11% [16/149], p¼0.025).
Analyzing the data closely the death rates showed a significant
difference, favoring survival in the MP group when the severity
Table 1. Continued

Authors and year

score was 4. The survival rate at score of 4 in the pre-MP group

was 38% (5/13) whereas it was 100% (16/16) for the MP group
(p,0.001). There was no significant difference in numbers surviv-
ing at a score of 5 or 6 indicating that in those with severe estab-
lished disease with multi-organ involvement, MP may be less
useful. When efficacy of MP in relation to involved organ system
was considered, it was shown that only patients with pulmonary

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Transactions of the Royal Society of Tropical Medicine and Hygiene

Table 2. Case reports of severe leptospirosis treated with steroids (in addition to standard treatment including antibiotics unless otherwise
specified)

Authors Brief description

Jayakrishnan et al.30
Minor et al.31
Montero-Tinnirello et al.32
Thunga et al.33
Single patient with severe pulmonary leptospirosis treated with i.v. MP. The patient recovered.
Single patient with severe leptospirosis with acute kidney injury, treated with i.v. MP (without antibiotics). The patient
recovered.
Single patient with severe pulmonary leptospirosis unsuccessfully treated with i.v. MP. The patient succumbed to his
illness.
Single patient with severe pulmonary leptospirosis treated with i.v. MP. The patient recovered.

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Maroun et al.34
Meaudre et al.35
Turhan et al.36
Lawrence et al.37
Courtin et al.38
Kingscote et al.39
Single patient with severe pulmonary leptospirosis treated with i.v. MP. The patient recovered.
Single patient with severe leptospirosis (acute kidney injury, rhabdomyolysis) treated with i.v. MP and i.v.
immunoglobulins. The patient recovered.
Single patient with severe pulmonary leptospirosis treated with i.v. MP. The patient succumbed to her illness.
Single patient with severe leptospirosis treated with high dose i.v. steroids (name of steroid cannot be traced).
The patient recovered.
Single patient with severe leptospirosis treated with high dose i.v. steroids (name of steroid cannot be traced).
The patient recovered.
Single patient with severe leptospirosis (acute kidney injury and hepatitis) treated with i.v. hydrocortisone.
The patient recovered.

MP: methylprednisolone.

involvement (as opposed to those with cardiac, hepatic, hemato-
logical and renal involvement) benefited (p,0.012). The authors
recommended early use of MP in severe leptospirosis, especially
for those with pulmonary involvement. While this is a very import-
ant study, significant methodological limitations need to be
pointed out. Although the clinical criteria that were considered
in diagnosis were mentioned, the exact diagnostic tests used, as
well as the cut-off value for the microscopic agglutination test,
were not specified. The study compared two groups within two
different time frames and as a result there could be other con-
founding factors that might add to the bias. For example, in the
setting of an epidemic, clinicians become more alert with early
diagnosis resulting in a better outcome for those who present
later in the course of the epidemic. Also with the commencement
of a new treatment modality, the medical staff could be more
alert and educated regarding the disease and treatment which
will improve the quality of care. The severity score also had
vague terminology such as ‘poor general condition’ with subject-
ive clinical observations given equal importance as more serious
complications like renal and hepatic failure. The clinical score uti-
lized is not a previously validated one. Although there are several
criteria listed to gain a single point, it is not specified to which
extent these clinical symptoms or laboratory values needed to
be fulfilled to award that point (i.e. some or all). These issues
could potentially affect the validity of the results.
A study by Shenoy et al.24 investigated the use of bolus MP in
leptospirosis with pulmonary involvement in 30 Indian patients in
2005. Diagnosis of leptospirosis was confirmed by IgM ELISA.
Pulmonary leptospirosis was identified by symptoms or diffuse
lung infiltrates on chest X-ray. Patients were divided into two
groups; those who received 1) i.v. MP 1 g/day bolus for 3 days
followed by oral prednisolone 1 mg/kg/day for 7 days (MP group,
n¼17) and 2) standard treatment without MP (non-MP group,
n¼13). The two groups were analyzed according to severity of
lung injury based on acute lung injury (ALI) and acute physiology
and chronic health evaluation III (APACHE)25 scores, and survival.
In the MP group, only three patients (18%, 3/17) succumbed while
eight patients (62%, 8/13) died in the non-MP group (p,0.025).
The MP group responded significantly better when severe lung
injury was present (ALI score .2.5 and APACHE III score .60)
(p,0.05). However there was no difference in outcome when
MP was administered to patients with mild pulmonary involve-
ment (ALI ,2.5). Despite administration of MP, all patients
who had four organ systems (pulmonary, hepatic, renal and
hematological) involved had died. In the non-MP group, two out
of the eight patients who died had involvement of all four of the
above mentioned systems. Requirement of ventilator support was
also reduced in the MP group compared to the non-MP group. The
three patients who died in the MP group presented later than 12
hours after the onset of dyspnea, suggesting that early adminis-
tration of bolus MP may have a beneficial effect in countering
fatality. Authors had not specified the time of presentation from
the onset of dyspnoea of the eight patients who succumbed in the
non-MP group.
A prospective randomized controlled trial to study desmopres-
sin and high dose dexamethasone as adjunctive treatment for
pulmonary involvement in severe leptospirosis was carried
out by Niwattayakul et al.26 Desmopressin increases circulating
factor VIII levels and is useful in treating mild haemophilia and
von Willibrand disease. Some case reports have indicated that it
may play a role in treating severe leptospirosis as well.27 Three
treatment groups were defined as desmopressin group (n1¼23),
dexamethasone group (n2¼22) and control group (n3¼23). The
desmopressin group received 0.3 mg/kg of desmopressin in

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C. Rodrigo et al.
50 ml of saline as an infusion over 30 minutes daily as long as
bleeding persisted, and the dexamethasone group received
200 mg i.v. infusion of dexamethasone daily for 3 days followed
by 1 mg/kg/day oral prednisolone for 4 days. All patients with a
suspicion of leptospirosis were included in the study followed
by later confirmation of infection with PCR and microscopic agglu-
tination test. Outcome was measured on survival, duration of
mechanical ventilation and duration of bleeding. Analysis was
done on both an intention to treat and a per protocol (including
only those with confirmed leptospirosis) basis. Of the 68 patients
enrolled, 76% (52/68) were confirmed as having leptospirosis.
Fifteen patients of the total sample succumbed, of these eight
had confirmed leptospirosis (five in the desmopressin group,
one in the dexamethasone group and two in the control group).
There was no significant mortality benefit in either arm as per
intention to treat or per protocol analysis. In addition to the lack
of a mortality benefit, the three arms also did not differ in other
outcome measures (duration of bleeding and duration of mech-
anical ventilation). The main adverse effect in the dexamethasone
group was the development of nosocomial infections, which was
noted in six patients; this was statistically significant. This study
shows no evidence to support the use of either desmopressin or
dexamethasone in severe leptospirosis with pulmonary involve-
ment. However, the authors admit that the study lacks statistical
power to infer conclusions, since it did not reach the target sample
size of 69 confirmed leptospirosis patients. Absence of validated
criteria to classify the severity of lung involvement of the patients
and inclusion of leptospirosis mimics in the study make the results
more difficult to interpret. However, it must be noted that the
three groups did not differ significantly on parameters of severity
of organ involvement, enabling a valid comparison of outcomes in
between them.
Discussion
Based on current evidence, a clear recommendation on the use of
corticosteroids for treatment of severe leptospirosis cannot be
made. Studies are few in number and are of poor methodological
quality. Of the five studies identified four have suggested that
steroids do have a beneficial role in leptospirosis especially in
patients with lung involvement.19,20,23,24 However, it must be
noted that these four studies are prospective case series; one
had a single arm only and the other three compared the cortico-
steroid group with a historical cohort. Only the randomized con-
trolled trial failed to show a benefit of steroids in severe
leptospirosis but it was statistically underpowered to make a
robust conclusion.26 Notably, the risk of nosocomial infections
appeared to be greater with corticosteroid treatment.
All studies reviewed had significant bias. The interpretation of
study results is also complicated by the fact that different treat-
ment regimens of corticosteroids have been used in different
studies. In three studies MP was given at the initiation of treat-
ment but at different doses. The study in which dexamethasone
was used at initiation was unable to show a benefit of treatment
but showed an increase in nosocomial infections. The dose of
dexamethasone used in this study was high compared to the
equivalent doses of MP used by Ittyachen et al.20 and Kularatne
et al.23 but comparable to the dose of MP used by Shenoy
et al.24 The latter has not reported the incidence of nosocomial
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infections in their cohort. In the studies where MP was used,
the frequency of therapy, duration and changeover to oral therapy
were variable. Nonetheless, these variations alone are not
sufficient to explain the difference in outcome seen in the studies.
Antibiotic therapy also varied from study to study. However,
as current evidence does not support any benefit in outcome
depending on antibiotic therapy this is unlikely to have had a
significant impact.
Another problem with the studies quoted above is that even for
pulmonary involvement there is no uniform way to assess the
severity of involvement across the studies, which is a crucial factor
in determining whether the steroids are be effective or not.
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Shenoy et al.24 have shown that steroids were beneficial when
pulmonary involvement was severe but not when it was mild.
Even though we have mentioned that steroids have failed to dem-
onstrate any potential benefit in ARDS, the meta-analysis was car-
ried out in 200816 and since then the definition of ARDS has
changed and is now categorized as mild, moderate and severe.
This is shown to correlate better with ICU stay and survival than
the old definition which did not allow for such flexibility.28 It will be
interesting to see if any benefit of steroid treatment will be
observed when individual categories are considered.
One protocol which was published in 201118 shows a strong
methodology, recruiting 266 patients in a double blind rando-
mized controlled trial. Results of this study have not yet been
published.
With available evidence the recommended mainstay of treat-
ing patients with severe leptospirosis is organ support. The key
clinical question is whether, based on the limited evidence avail-
able, it is justifiable to attempt a short course of MP in severe
leptospirosis patients with pulmonary involvement early in the
course of management (within 12 hours of diagnosis, if pos-
sible). Given the fact that one study which used a higher dose
of steroids (Niwattayakul et al.26) reported a higher incidence
of nosocomial events, it may be safer to use a moderate dose
as such used by Kularatne et al.23 This currently remains the
clinicians’ prerogative, given the high rate of mortality with
ARDS in leptospirosis. Though antibiotics have not shown benefit
in severe leptospirosis, starting patients on empirical antibiotics
may be advisable if giving steroids as the risk of nosocomial
infections remains high.
Considering the lack of evidence from well designed studies
on use of steroids in leptospirosis, as well as the morbidity and
mortality associated with severe disease, it would be timely to
conduct adequately powered randomized controlled trials of
corticosteroids in severe leptospirosis. Such studies should pay
careful attention to methodological rigidity, in particular with
regard to the following: 1) clear clinical and immunological diag-
nosis with exclusion of alternate infections which give rise to a
similar picture, 2) clear categorization of disease severity and in
particular pulmonary involvement, 3) uniformity in timing the
dosing of corticosteroids and 4) clear outcome measures
(i.e. improvement of lung injury, pulmonary mortality and
overall mortality). Currently studies have mainly focused
on the impact of corticosteroids in lung injury. The impact of
corticosteroids on other organ dysfunction also requires further
study. The other key issue is whether the effect of corticoster-
oids in severe leptospirosis is a non-specific effect on lung injury
per se, rather than an effect specific to patients with
leptospirosis.
Transactions of the Royal Society of Tropical Medicine and Hygiene
Limitations
This review falls short of making a definite recommendation on
the use of steroids in pulmonary leptospirosis and also in severe
disease involving other organ systems. This is due to the lack of
evidence from controlled clinical trials in published literature.
Four out of five trials included in this review concentrate more
on pulmonary involvement in severe leptospirosis and there are
no clinical trials on other organ damage in the severe form of
this disease. We also could not find the full text article of one clin-
ical study out of the five studies that were eligible to be included in
this review. The variety of diagnostic tests used in different trials
makes it difficult to do a valid head-to-head comparison. The true
sensitivities and specificities of the microscopic agglutination test
and other tests for leptospirosis are difficult to establish as there is
no feasible gold standard diagnostic test with which to compare
them.29
Conclusions
Available data on the use of high dose corticosteroids in the treat-
ment of leptospirosis are from five studies with methodological
constraints and limited sample size. Four studies have shown
benefit with corticosteroid treatment (i.e. MP and prednisolone)
in severe leptospirosis with pulmonary involvement, while the
only randomized controlled trial (which used dexamethasone
and prednisolone) did not show significant benefit. No recommen-
dation can currently be made based on clinical evidence regarding
the place of corticosteroids in severe leptospirosis. Further rando-
mized controlled trials are needed to clarify the role of steroids in
the treatment of severe leptospirosis.
Authors’ contributions: SR, NLdeS and CR conceived the review and
designed the search methodology; NLdeS, KS, RG, IW and BP performed
the literature search; SR, CR, RG, KS, BP and NLdeS extracted and
reviewed the data. CR, NLdeS and SR drafted the manuscript. CR and SR
critically revised the manuscript. All authors read and approved the final
manuscript. SR is the guarantor of the paper.
Funding: None.
Competing interests: None declared.
Ethical approval: Not required.
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