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Unusual Clinical Manifestations of Leptospirosis

Bal AM

Department of Medical
Microbiology, Aberdeen
Royal Infirmary,
Aberdeen, Scotland, UK
Correspondence:
Bal Abhijit M
E-mail: a.bal@abdn.ac.uk

PubMed ID

: 16333189

J Postgrad Med 2005;51:179-83

ABSTRACT
ABSTRACT

Leptospirosis has protean clinical manifestations. The classical presentation of the disease is an acute biphasic
febrile illness with or without jaundice. Unusual clinical manifestations may result from involvement of pulmonary,
cardiovascular, neural, gastrointestinal, ocular and other systems. Immunological phenomena secondary to
antigenic mimicry may also be an important component of many clinical features and may be responsible for
reactive arthritis. Leptospirosis in early pregnancy may lead to fetal loss. There are a few reports of leptospirosis
in HIV- infected individuals but no generalisation can be made due to paucity of data. It is important to bear in
mind that leptospiral illness may be a significant component in cases of dual infections or in simultaneous
infections with more than two pathogens.
KEY WORDS: Cardiac arrhythmia, Cholecystitis, Congenital infection, Guillain-Barre syndrome, Pancreatitis,
Pancytopenia, Pregnancy, Leptospirosis

eptospirosis is a zoonosis that is caused by the

spirochete Leptospira interrogans. The species has sev
eral serological variants - the serovars. Antigenically related
serovars are grouped together into serogroups. Serovar distri
bution varies with the geographical region. Recently, DNA
relatedness studies have classified the genus Leptospira into
13 species. However, serovar based taxonomy continues to have
epidemiological value.[1]

Leptospirosis classically manifests as a biphasic illness. The

first phase is characterised by high fever and coincides with
leptospiremia. This is followed by a brief period when the pa
tient is afebrile. Fever returns heralding the second phase of
illness that may be accompanied by jaundice and renal failure.
During this period, leptospires are not found in the blood but
are excreted in the urine. Unfortunately, classical presentation
is not synonymous with the most common presentation, a fact
not always appreciated in clinical medicine. Leptospirosis has
protean manifestations and rare and unusual presentations
should be kept in mind in relevant epidemiological scenario.
This communication intends to summarise the unusual clini
cal features of leptospirosis. A thorough knowledge of clinical
manifestations is especially valuable in communities that lack
diagnostic facilities and hence the need for clinical judgement
and suspicion is paramount.
Classical features of leptospirosis
Leptospirosis classically presents as a biphasic illness. The first
phase of the disease is commonly referred to as the septicemic
phase. It is characterised by fever, headache, myalgia, conjunc

J Postgrad Med September 2005 Vol 51 Issue 3

tival congestion and a host of non-specific features that may

include mild cough, lymphadenopathy, rash, anorexia, nausea,
and vomiting. This phase is followed by a brief afebrile period
of variable duration that, in turn, is followed by the immune
phase of illness. The common organs involved during this phase
are the liver and kidneys. Both organ derangements are revers
ible. The severe form of leptospirosis, also known as Weils
disease, is characterised by a fulminant course with rapid on
set of hepatic and renal failure and high mortality. In a retro
spective report of 34 patients with leptospirosis, the common
clinical features included fever (100%), headache (75%), my
algia (55%), arthralgia (45%) and vomiting (39%).[2] In one of
the largest reported series that included 353 cases, fever, head
ache, myalgia, chills, and anorexia were present in more than
80% of patients.[3] Interestingly, an association between sever
ity of illness and infection with serovar Icterohaemorrhagiae
was also observed. During the epidemic in Mumbai in the year
2000, the common clinical signs and symptoms included fe
ver, headache, myalgia, conjunctival suffusion and cough with
hemoptysis.[4]
In an endemic area, suspecting leptospirosis on clinical grounds
should not be very difficult. However, the disease is not com
monly thought of and hence the diagnosis is often missed due
to lack of awareness amongst the medical and medical sup
port team. As an aid to clinical diagnosis, Faine proposed a
clinical scoring system.[5] In my own experience, the scoring
system had a moderately good sensitivity (81.8%) and
specificity (72.9%). The positive predictive value was 40.9%
and the negative predictive value was 94.5% when compared
with serology. [6] In one published work, the sensitivity,
specificity, positive predictive value and negative predictive

179

Bal: Clinical features of leptospirosis

value of the scoring system was reported to be 81.8%, 72.9%,

40.9% and 94.5% respectively when compared with serology.[6]
Use of the scoring system would help exclude the diagnosis of
leptospirosis. Modifications in the scoring system have been
proposed recently and merit further evaluation.[7]
In an endemic area, leptospirosis is often confused with den
gue fever due to the similarities of clinical features. LaRocque
and colleagues summarised the data regarding clinical presen
tations of the two illnesses comparing 938 patients of dengue
fever with 63 patients of leptospirosis.[8] Presence of rash, pru
ritus and a positive tourniquet test was significantly associ
ated with dengue fever. Karande and colleagues in their report
of a concurrent epidemic of leptospirosis and dengue fever in
Mumbai, noted that clinical features such as conjunctival suf
fusion, hemorrhage, abdominal pain, hepatosplenomegaly and
edema were significantly associated with leptospirosis, while
arthralgia was significantly associated with dengue fever.[9]
Although no single clinical feature is pathognomonic of lept
ospirosis, a cluster of findings should lead to clinical suspi
cion. Therapy should be initiated on the basis of clinical judge
ment, as laboratory confirmation can be delayed by days and
weeks or is unavailable in several regions and early institution
of appropriate therapy is known to reduce mortality.[10]
Severe leptospirosis may carry a high mortality if treatment is
not instituted early. Poor prognostic markers in leptospirosis
include hypotension (relative risk [RR]= 10.3), oliguria (RR =
8.8), hyperkalemia (RR= 5.9), and presence of pulmonary rales
(RR= 5.2).[11] Other studies have reported dyspnea (odds ra
tio [OR]= 11.7), white blood cell count greater than 12,900/
mm3 (OR= 2.5), repolarization abnormalities on electrocar
diograms (OR= 5.9), alveolar infiltrates (OR= 7.3), [12]
hemoptysis, metabolic acidosis, and thrombocytopenia as
markers of increased mortality. In hospitals that have adequate
facilities,[13] patients with these risk factors should preferably
be treated in an intensive care unit.
Unusual manifestations of leptospirosis
Pulmonary involvement
Although pulmonary involvement is not uncommon in lept
ospirosis, it is usually not suspected. In one study, 10 out of
176 hospital admissions with community-acquired pneumo
nia had positive leptospiral serology although only one patient
had documented seroconversion.[14] Severe hemorrhagic pneu
monitis may be a prominent manifestation of infection. [15]
Three radiographic patterns have been described in patients
with pulmonary involvement during leptospiral infection- small
nodular densities, diffuse ground glass densities and rarely, con
fluent areas of consolidation.[16] Pulmonary involvement may
be the presenting feature of the illness or may complicate a
frankly icteric disease.[17] Epidemic leptospirosis with pulmo
nary haemorrhage without jaundice or renal failure has been
reported.[18] Severe pulmonary involvement in leptospirosis has
been reported from Andaman and Nicobar islands. Serovar
Grippotyphosa and more recently,[19] serovar Valbuzzi,[20] have

180

caused such outbreaks. Independent predictors of mortality

in pulmonary leptospirosis include hemodynamic disturbance,
serum creatinine level more than 265.2 mol/L and serum
potassium level more than 4.0 mol/L.[21] Karande and col
leagues[22] recently reported a case of pneumonia in a nine
year-old boy who presented with fever, cough, hemoptysis, and
conjunctival suffusion. The patient was diagnosed to be suf
fering from leptospirosis following a rise in titer of antibodies
reactive with serovar Australis. An autopsy study has reported
the presence of diffuse bilateral pulmonary hemorrhage in fa
tal cases of leptospirosis.[23] A rare case of lung abscess due to
leptospirosis has been reported in literature.[24]
Neurological manifestations
Although asymptomatic aseptic meningitis is a common fea
ture of leptospirosis, severe symptomatic involvement is rare.
Rare clinical presentations include myeloradiculopathy, my
elopathy and cerebellar dysfunction.[25] Kavitha and Shastry[26]
reported a case of transverse myelitis following leptospirosis.
Their patient presented with fever and jaundice and subse
quently developed weakness of lower limbs and urinary reten
tion. Sensory perceptions were decreased below T4 level and
the illness was consistent with transverse myelitis. The patient
had a positive anti-leptospira IgM serology. Costa et al[27] re
ported a rare case of facial palsy following leptospiral infec
tion. The patient had a clinical illness consistent with lept
ospirosis. The authors did not perform microagglutination test
(MAT) that is generally believed to be the confirmatory test.
However, seroconversion was observed the macroagglutination
test. Although comparative clinical trials are lacking due to
rarity of presentation, doxycycline has been used in such
cases[28] Mumford et al[29] have reported a case of fatal lept
ospirosis with flaccid paraplegia in a patient with biochemical
evidence of renal and hepatic involvement. Guillain Barre syn
drome has been reported following an illness consistent with
leptospirosis.[30] This patient had a history of fever, myalgia,
and headache three weeks prior to the onset of paraplegia. The
serum sample at the onset of the neurological illness had a
titre of 6400 and a later sample had a titre of 800 with strong
est reactivity to serovar Copenhageni. It is interesting to note
that it was the falling titre and not the rising titre that was a
clue to diagnosis as the patient presented comparatively late
in illness. Because of the time lag between icteric illness and
neurological manifestations, it may not be possible to obtain a
culture confirmation or a rising antibody titre. An absence of
such a confirmation therefore should not rule out an associa
tion. Whether leptospires are causally related to such neuro
logic illness is a matter of conjecture. Treatment of neurologi
cal sequelae is supportive. It is unlikely that treatment of un
derlying cause will alter the natural course of the neurological
illness.
Ocular manifestations
Ocular manifestations of leptospirosis can lead to significant
morbidity. During the acute phase of illness, conjunctival con
gestion is a common clinical finding.[31] Uveitis is a rare sequel
of the disease. It usually presents as a panuveitis with or with

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Bal: Clinical features of leptospirosis

out hypopyon. Visual damage can occur in as many as 35% of

patients.[32] Topical quinolones have been used to treat such
infections.[33] A majority (95.5%) of 73 cases of leptospiral uvei
tis reported by Rathinam et al[32] had panuveitis, retinal
periphlebitis (51.4%) and hypopyon (12.6%). A few patients
had anterior uveitis without hypopyon (2.7%) and isolated vit
reous inflammatory reaction (1.8%).
Gastrointestinal manifestations
Pai and Adhikari reported a rare case of pancreatitis following
leptospirosis.[34] Hyperamylasemia was persistent but returned
to normal in three months following the institution of lept
ospira-specific therapy. There are other reports too of pancrea
titis complicating leptospirosis.[35] Monno and Mizushima re
ported a rare case of acute acalculous cholecystitis in a patient
with infection due to serovar Autumnalis.[36] In an outbreak of
leptospirosis reported from the United States, two out of 22
hospitalised patients had symptoms suggestive of acute chole
cystitis. Gross examination of the gall bladders removed at sur
gery revealed thickened walls with smooth serosal surface and
bile-stained mucosa. Calculi were not found. The submucosal
tissue had mononuclear cell infiltration and also showed
edematous changes. Leptospires were detected by immuno
histochemistry techniques. Staining for the granular and
filamentous antigens was found positive in the vessel walls and
also in the submucosa.[37] Paz and colleagues [38] reported a case
of enteritis in an Israeli patient who had a history of travel to
Thailand, a region where leptospirosis is an emerging disease.[39]
The patient presented with fever, diarrhea, and vomiting and
leptospiral serology was performed because creatinine levels
were high. The patient had a rising antibody titers detected by
MAT. He was treated with penicillin and azithromycin along
with intravenous fluids. Peritonitis is another rare manifesta
tion of leptospirosis.[40]
Cardiac involvement
An analysis of data of 50 patients with serologically proven
leptospirosis demonstrated that 70% of the patients had
electrocardiographic abnormalities, with atrial fibrillation be
ing the commonest major arrhythmia noted.[41] Thirty-six per
cent of the patients had conduction system abnormalities and
30% had T wave changes. Another series has reported AV block
in 44% of patients with leptospirosis.[42] A glycoprotein frac
tion of leptospiral cell wall has been incriminated in the
pathogenesis of these rhythm disturbances. This protein is
thought to inhibit the Na-K ATPase and may be responsible
for the arrhythmia.[43] Univariate analysis has shown that car
diac arrhythmia is more common in patients dying of lept
ospirosis than in the survivors.[44] Other reported cardiac ab
normalities include myocarditis [45] and pericarditis.[46] In seven
cases of fatal leptospirosis, petechial haemorrhages were found
in the heart and the pericardium in all the autopsy specimens
and interstitial myocarditis was found in five specimens.[47] In
another study, acute coronary arteritis was found in 70% of
patients who died of leptospirosis and evidence of aortitis was
present in more than half.[48] One case of leptospira endocar
ditis, possibly caused by serovar Icterohaemorrhagiae has been

J Postgrad Med September 2005 Vol 51 Issue 3

reported in literature.[49]
Musculoskeletal symptoms
Various musculoskeletal abnormalities have been reported in
patients with leptospiral infection. In a case reported by
Coursin and colleagues,[50] a 63-year-old man presented with
multiorgan dysfunction and rhabdomyolysis. Although myal
gia and mild elevation of muscle enzymes are common in lept
ospirosis, severe involvement of muscle tissue is rare. A fatal
case of rhabdomyolysis was reported by OLeary et al.[51] In
this report, acute infection with leptospira belonging to
serogroup Grippotyphosa was diagnosed on the basis of serol
ogy. Skeletal muscle involvement independently correlates with
the severity of disease.[52]
Hematological manifestations
Somers et al[53] reported a rare case of erythroid hypoplasia in a
case of leptospirosis. The patient presented with fever, jaun
dice, shortness of breath, and meningism. His haematologic
parameters showed normocytic normochromic anaemia,
reticulocytopenia, and thrombocytopenia. Severe erythroid
hypoplasia was observed on bone marrow examination. It is
possible that this complication results from a direct action of
toxic leptospiral products on the progenitor cells of the mar
row. Stefos and colleagues reported two cases of pancytopenia
following infection with leptospira.[54] Interestingly, neither
patient had a history of jaundice. According to Bishara and co
workers,[55] pancytopenia could occur in as many as 28% of pa
tients with leptospirosis. Most of the infections in their series
of cases were caused by leptospira belonging to serogroup
Icterohaemorrhagiae and it is possible that infection with this
serogroup is associated with hematologic abnormalities. Iso
lated thrombotic thrombocytopenia purpura has been reported
following infection with leptospires.[56]
Immunological manifestations
Rare immune-mediated manifestations of leptospirosis include
antiphospholipid syndrome[57] and reactive arthritis.[58] Such
manifestations are likely to be a result of an immunologic cross
reactivity. Antibodies generated in response to leptospiral in
fection may cross react with host antigens and could lead to
an inflammatory response. Finsterer et al[59] have reported an
interesting case of carpal tunnel syndrome in a pet-shop worker
who was later found to have a positive leptospiral IgG and IgM
serology. Symptoms improved on doxycycline therapy, although
the antibody levels remained elevated over the next three years.
Explaining the disappearance of symptoms is difficult espe
cially because the patient continued to have high antibody
titres and hence immunological cross reactivity could still have
taken place. The authors hypothesized that persistence of an
tibodies could be the result of re-exposure at workplace or a
long- term immunological response. However, this does not
necessarily explain the resolution of symptoms. A plausible
explanation is that immune-mediated illness is caused by an
tigen-antibody complexes rather than by cross-reactive anti
bodies. Doxycycline therapy, by eradicating the leptospires and
thereby removing the source of antigens, could prevent the

181

Bal: Clinical features of leptospirosis

formation of the immune complexes leading to a decrease in

the inflammatory response.
Endocrine abnormalities
Panidis et al[60] described a rare case of male hypogonadism,
presumably related to hormone deficiency at the
hypothalamus-pituitary level, following leptospirosis. Abnor
malities in hormonal secretion have been found in experimen
tal infection in animals,[61] but there is paucity of data regard
ing the incidence and effects of such abnormalities following
infection in humans.
Leptospirosis in pregnancy and congenital leptospirosis
In a review of 15 patients with documented leptospirosis late
in pregnancy, Shaked et al[62] found that eight women had abor
tions, two delivered healthy babies, four delivered babies who
had signs of active leptospirosis and in one case, the clinical
outcome was not stated. Carles et al[63] reported 11 cases of
leptospirosis in pregnant women in French Guiana and foetal
death occurred in more than 50% of the cases. Chedraui and
San Miguel[64] reported a case of leptospirosis in a 28-week preg
nant patient. The patient presented with fever, myalgia and
jaundice and serology was positive for serovar
Icterohaemorrhagiae. The patient was treated with penicillin
and delivered a healthy baby at 37 weeks. Leptospirosis, early
in pregnancy often leads to abortion. Congenital infections
are rare and long-term serious effects have not been docu
mented. Hence, leptospirosis acquired in pregnancy is not an
indication for its termination. In one report, transmission of
infection to infant was thought to have taken place through
the breastmilk.[65]
Leptospirosis in HIV seropositive individuals
Jones and Kim[66] reported a case of leptospirosis in a patient
with acquired immunodeficiency syndrome. The patient ini
tially presented with non-specific illness but later developed
jaundice, renal failure and acute respiratory distress syndrome.
The recovery was probably slower than is usual for leptospiro
sis and there was residual renal impairment. Others have re
ported a similar clinical course of illness as in non
immunocompromised patients.[67]

superinfection could possibly have resulted from a transient

immunosuppression associated with the disease or its treat
ment. Wongsrichanalai et al[75] reported two cases of dual in
fection with malaria parasites and leptospira. One patient was
infected with Plasmodium falciparum and the other with P.
vivax. Co-infection with three different pathogens has also been
reported in what probably is an extremely rare event. Lu and
Tseng [76] described a Taiwanese patient with fever and pneu
monia in whom blood cultures grew Burkholderia pseudomallei
and serological tests were consistent with scrub typhus and
leptospirosis. Melioidosis is an emerging disease in Taiwan and
B. pseudomallei shares similar ecological niche with leptospira
and Orientia tsutsugamushi, the causative organism of scrub
typhus. It is important to look for leptospirosis in an appropri
ate setting particularly if the patient does not show clinical
signs of improvement despite pathogen-directed therapy for
an established alternative infectious etiology.
Conclusions
It is imperative that a high index of suspicion for the disease
be maintained particularly in endemic areas. There is a need
for increasing the awareness of the disease so that timely
therapy can be instituted to patients. An effective network of
clinicians, medical microbiologists, public health doctors and
program managers needs to be in place during epidemics. It is
equally important to collect and report data to a centralised
surveillance cell so that future planning and monitoring can
be done easily. Clinicians need to be aware of the possibility of
leptospirosis, even if the illness presents with unusual features.
A problem-solving approach to the clinical suspicion and di
agnosis of leptospirosis has recently been elucidated and could
be a useful guide for doctors.[77]
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