Transactions of the Royal Society of Tropical Medicine and Hygiene Advance Access published March 25, 2015

Trans R Soc Trop Med Hyg doi:10.1093/trstmh/trv026

Atypical manifestations of leptospirosis REVIEW

Senaka Rajapaksea,*, Chaturaka Rodrigoa, Krishan Balajia and Sumadhya Deepika Fernandob a

Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Sri Lanka; bDepartment of Parasitology, Faculty of Medicine, University of Colombo, Sri Lanka *Corresponding author: Tel: +94 112 689188; E-mail: [email protected]

Received 14 January 2015; revised 9 February 2015; accepted 11 February 2015

Keywords: Atypical manifestations, Leptospirosis, Weil’s disease

Introduction Leptospirosis is a zoonotic illness caused by a spirochaete belonging to the genus Leptospira. Its annual incidence rate is estimated to be more than 10 cases per 100 000 of population in tropical climates, and significantly less (0.1–1 per 100 000) in temperate climates).1,2 The disease is endemic in areas with high rainfall, close contact with livestock, poor sanitation and workplace exposure to the organism.3 Any mammal has the potential to be the animal reservoir for the organism, and transmission to humans often occurs from rodents. Pathogenic leptospira are excreted in the host’s urine to the environment. Transmission to humans can be direct (inoculation from tissues, body fluids and urine of infected animals) or indirect (entry via mucosal surfaces or breached skin from sources contaminated with leptospira).1 Leptospirosis infection results in a wide spectrum of clinical manifestations, involving many organs. Many infections are asymptomatic, or pass off as a mild febrile episode. A proportion of those infected develop severe disease with multi organ dysfunction. The case-fatality ratio in severe disease can exceed 40%.4 The typical severe form of leptospirosis, is characterized by jaundice, haemorrhage and renal failure. However, severe leptospirosis can still occur without jaundice. In addition, central nervous system manifestations such as meningitis, cardiovascular instability due to myocarditis, and pulmonary haemorrhage are well recognised, potentially life-threatening complications.4 Diagnosing and treating leptospirosis is a challenge to even an experienced clinician, due to the diversity of clinical presentations, overlapping symptoms and signs with other diseases (dengue, rickettsioses, hanta virus infection), and rapid onset and

progression of illness. The lack of intensive care units and haemodialysis facilities in peripheral hospitals to which these patients present further adds to the challenges in providing optimal care. Antibiotics and supportive care form the mainstay of treatment. Although immune mediated mechanisms are thought to be responsible for severe disease, immunomodulation with corticosteroids has shown no evidence of benefit.5 In endemic areas, leptospirosis is often diagnosed and treated on clinical grounds. In most cases, acute febrile illness with a history of exposure is treated as for leptospirosis. The epidemiological reference standard for laboratory diagnosis is the microscopic agglutination test (MAT).6 The MAT has limited sensitivity during the acute phase of illness, requires special facilities, is expensive and is only available in a few reference laboratories. Other available immunological tests include IgM ELISA, microcapsule agglutination test, Lepto-dipstick, Lepto Dri Dot and Leptocheck-WB test.6 All these tests can be negative in early leptospirosis, as it takes time for antibodies to form. Overall, the laboratory confirmation of leptospirosis is not routinely available to the treating clinician. Though the typical clinical picture of severe leptospirosis is well established and easily recognizable for experienced clinicians in endemic areas, rare and unusual clinical presentations can cause diagnostic confusion. This article aims to summarize the unusual or atypical clinical manifestations of leptospirosis.

Methods We performed a Pubmed and Scopus search for all case reports/ case series with the key word ‘leptospirosis’ or ‘leptospira’ or

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Leptospirosis is an illness with a wide spectrum of clinical manifestations, and severe illness affects nearly all organ systems. Serious and potentially life threatening clinical manifestations of acute leptospirosis are caused by both direct tissue invasion by spirochaetes and by the host immune responses. In its severe form, leptospirosis can cause multi-organ dysfunction and death in a matter of days. Therefore it is critical to suspect and recognize the disease early, in order to initiate timely treatment. While the classical presentation of the disease is easily recognized by experienced clinicians practising in endemic regions, rarer manifestations can be easily missed. In this systematic review, we summarize the atypical manifestations reported in literature in patients with confirmed leptospirosis. Awareness of these unusual manifestations would hopefully guide clinicians towards early diagnosis.

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Gastrointestinal manifestations The common gastrointestinal manifestations of leptospirosis include nonspecific symptoms such as nausea, vomiting and anorexia, hepatitis, icterus and elevation of liver transaminases and alkaline phosphatase. Acalculous cholecystitis has been reported in association with acute leptospirosis in several occasions. Some authors have also reported leptospirosis as a mimic of acute cholecystitis. Monno and Mizushima7 reported a case of a 66 year old man with confirmed leptospirosis (by MAT) who developed acalculous cholecystitis and pancreatitis during the acute illness. Liver transaminases, g-Glutamyl-transferase and alkaline phosphatase levels were elevated 2–5 times above baseline. Pancreatic isozymes lipase and trypsin were elevated 17–25 times above the upper limit of normal. Ultrasound revealed an enlarged gall bladder with sludge and probe tenderness. The liver and pancreas appeared normal ultrasonically. In addition to these complications the patient also had meningitis and acute kidney injury secondary to rhabdomyolysis. He was treated supportively with haemodialysis and intravenous antibiotics, and improved within 7 days of starting treatment. Ultrasonographic appearance of the gall bladder was normal one month post infection. Three patients with leptospirosis and cholecystitis during acute phase were reported from Thailand.8 One of them underwent surgical exploration, although leptospira was not isolated from surgical specimen. In all patients, leptospirosis was confirmed by rising titre of anti-leptospira antibodies, and in one instance by blood culture. All three patients recovered fully. Guarner et al.9 reported an interesting case series of athletes participating in a triathlon in Illinois, USA. Out of 876 athletes, 122 requested

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medical attention for an acute febrile illness. Twenty-two were hospitalized and two of them went on to have cholecystectomy for suspected cholecystitis. Later, Leptospira antigens were demonstrated by immunohistochemistry (the complete bacterium was found in one specimen) in the specimens removed. There is no consensus on whether these episodes of cholecystitis were due to leptospirosis, but it is possible that, during the leptospiraemic phase of the illness, both immune mediated mechanisms and direct pathogen invasion may have led to gall bladder inflammation. Acalculous cholecystitis has also been describe in dengue,10 and both these infections are an important differential diagnosis to consider in order to avoid unnecessary surgical exploration.11 Acute pancreatitis is another rarely reported complication of leptospirosis. In addition to the cases already described above, there are a handful of patients described with pancreatitis in acute leptospirosis.7,12–17 Unlike cholecystitis, pancreatitis has been associated with fatality.18,19 Kaya et al.18 reported two cases of acute pancreatitis with serologically confirmed leptospirosis. The clinical features resembled a typical attack of acute pancreatitis, presenting with acute abdomen and marked elevation of serum amylase and lipase. One patient, a 68 year old woman, underwent surgical exploration, and was found to have an oedematous gall bladder and an oedematous necrotic pancreas with sero-haemorrhagic peritoneal fluid. The patient succumbed to her illness despite surgical intervention, appropriate antibiotic therapy and supportive treatment. The other patient had a similar presentation but clinical severity was less. Pancreatitis was confirmed by computed tomography which showed pancreatic oedema and heterogeneity of peri pancreatic tissue, plus an intra-abdominal fluid collection. The patient survived with supportive treatment, intravenous antibiotics and haemodialysis (for concurrent acute kidney injury). It is interesting to note that despite the high incidence of leptospirosis all over the world, only a handful of case reports describe an association with acute pancreatitis. However, hyper-amylasaemia is observed in a significant number of patients with leptospirosis, although it is difficult to prove that this originates from the pancreas, as renal failure may also contribute to it.20 Still, a histopathological evaluation of 13 cases of fatal human leptospirosis (all patients had renal impairment and hyper-amylasaemia) showed that all patients had one or more histological features of pancreatic inflammation (fat necrosis in four, oedema in nine, haemorrhage in five, congestion in four and inflammatory lymphocytic infiltration in eight patients), despite never being diagnosed as having acute pancreatitis before death.21 Therefore pancreatitis may be underdiagnosed. The pathophysiology of pancreatitis is also not clear. The release of pro-inflammatory cytokines in acute pancreatitis is probably mediated via the toll-like receptor 4 (TLR-4) gene. Up-regulation of the TLR-4 gene is linked to multi-organ involvement in acute pancreatitis.22 It has also been demonstrated that Leptospira lipoprotein 32 (LipL32) activates TLR-2 in the lung and kidney at the onset of immunological damage to the respective organs.23,24

Haematological manifestations The commonly observed haematological changes in leptospirosis include a decline in absolute neutrophil and lymphocyte counts in

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‘lepto*’ or ‘weil*’ in any field, without language or time restrictions. There were 1206 abstracts in the original search with duplicates removed. The software, Endnote X7 (Thomson Reuters, Carlsbad, CA 92011, USA) was used to filter articles. Bibliographies of cited literature were also searched. All abstracts were read through independently by the authors, and relevant papers were identified for review of the full papers. Related papers were also included. Typical disease was defined as a febrile illness with any of the following clinical manifestations: arthralgia, myalgia, icterus, hepatitis, spontaneous bleeding (intestinal, pulmonary, haematemesis and haematuria) and acute oliguric kidney injury. Less typical but commonly reported, well established end organ consequences of the infection were also included, i.e., pneumonitis, pulmonary haemorrhage, myocarditis and meningitis. Non-specific symptoms such as nausea, vomiting and loss of appetite were considered common to many patients with leptospirosis and other illnesses mimicking leptospirosis. All other manifestations were considered to be ‘atypical’. We categorized the atypical manifestations based on the systems affected (Table 1) as gastrointestinal, neurological, ocular, cardiovascular, haematological, renal and other miscellaneous manifestations. A separate section discusses pregnancy related complications of the infection. Common clinical manifestations for each organ system are discussed briefly before moving on to the atypical manifestations. In all papers included in this review, a laboratory diagnosis for leptospirosis was essential, by any of the established diagnostic tests such as MAT, IgM ELISA or genomic diagnosis.

Organ system

Clinical manifestation

References

Gastrointestinal

Acute pancreatitis

Harshey et al.12, Bell et al.11, Ribiczey et al.14, Edwards et al.20, Jaspersen et al.15, Monno et al.7, O’Brien et al.96, Pai et al.17, Daher et al.21, Kaya et al.18, Spichler et al.19, Chong et al.16, Ranawaka et al.13 Bell et al.11, Monno et al.7, Chong et al.16, Vilaichone et al.8, Anton Aranda et al.97, Guarner et al.9 Bee et al.26, Stefos et al.27, Somers et al.28 Somazgul et al.30, Bowsher et al.31 Laing et al.37, Hanvanich et al.36, Sukran et al.38, Quinn et al.39

Occular manifestations

Acute cholecystitis Pancytopaenia or erythroid hypoplasia Autoimmune haemolytic anaemia Thrombotic thrombocytopaenic purpura and haemolytic uraemic syndrome Acute disseminated encephalomyelitis Hydrocephalus and raised intracranial pressure Encephalitis induced coma Intracranial vascular events; bleeding and thrombosis Cerebellar syndrome Transverse myelitis Guillain Barre syndrome Mononeuritis and mononeuritis multiplex including cranial nerve palsies Uveitis and its associated anterior and posterior chamber abnormalities

Renal manifestations Cardiac manifestations Leptospirosis in pregnancy

Optic neuritis/papillitis (possible association) and severe visual impairment Retinal phlebitis Proximal tubule and thick ascending loop dysfunction leading to electrolyte and metabolic abnormalities Arrhythmias; Atrial fibrillation, flutter and sinus bradycardia Miscarriage, stillbirth, congenital leptospirosis, post-partum haemorrhage and sepsis

Haematological

Neurological

Panicker et al.40, Alonso-Valle et al.43, Chandra et al.41, Mathew et al.44 Sakellaridis et al.45, Castano et al.46 Dimopoulou et al.47 Panicker et al.40, Turhan et al.49 Panicker et al.40, Thukral et al.51 Kavitha et al.48 Panicker et al.40, Bal et al.52 Costa et al.55, Sharma et al.56, de Souza et al.57, Hancox et al.53, Yaqoob et al54. Alexander et al.58, Rowen et al.66, Sturman et al.68, Murdoch D.64, Barkay et al.59, Watt G.69, Merien et al.62, Levin et al.60, Rathinam et al.65, Chu et al.70, Mancel et al.61, Michot et al.63, Jurczyk et al.98 Mancel et al.61, Levin et al.60 Rathinam et al.65 Lin et al.75, Krishnan et al.73, Liberopoulos et al.74, Spichler et al.76, Liberopoulos et al.74 Fernando et al.82, De Souza et al.99, Assimakopoulous et al.100 Carles et al.92, Faine et al.86, Gainder et al.89, Gaspari et al.101, Hicham et al.102, Koe et al.90, Shaked et al.88, Sharma et al.87, Tramoni et al.93

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Table 1. Summary of reported atypical manifestations in leptospirosis

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(microangiopathic haemolysis, thrombocytopaenia and visual hallucinations) with strong MAT positivity that responded to plasmapharesis.38

Neurological manifestations The commonest neurological manifestation of leptospirosis is aseptic meningitis which characteristically presents with headache and mild neck stiffness. The exact prevalence of meningitis is unclear as the symptoms are often mild. Thrombocytopaenia during the acute phase of illness is another factor discouraging clinicians from performing lumbar puncture to establish diagnosis. Small scale studies have placed the prevalence of aseptic meningitis to be around 50%, by clinical features.40 However, it has also been observed that up to 90% of patients may have evidence of lymphocytic pleocytosis in cerebrospinal fluid (CSF) during the acute phase of illness.40 There are few cases of post infectious acute disseminated encephalomyelitis (ADEM) associated with acute leptospirosis.41,42 Alonso-Valle43 reported a case of an 18 year-old male with confirmed leptospirosis and meningitis, developing confusion on day 10 of illness while convalescing. Magnetic resonance imaging (MRI) showed extensive multifocal T2 hyper-intensity supporting a diagnosis of ADEM. The lumbar puncture at this time was supportive of resolving meningitis. The neurological manifestations subsided 24 hours later and the patient made a complete recovery. Chandra et al.41 reported of a similar presentation which recovered after intravenous immunoglobulin therapy. In a case series in South India where 31 patients with confirmed neuroleptospirosis were studied, 7 (26%) had diffuse oedema on computed tomography of brain during acute stage. Eight patients succumbed to their illness and post mortem studies revealed evidence of ADEM in two of them.44 Hydrocephalus following acute leptospirosis has been reported in only one instance, but interestingly without obvious clinical features of meningitis, which made it unlikely to be a sequel to meningitis.45 MRI showed bilateral lateral ventricular enlargement with increased T1 hyper-intensity. The patient made a brief recovery following ventriculostomy before succumbing to myocardial infarction. The CSF protein content was very high, almost similar to that of serum protein (2.4 and 2.6 g/dl respectively) which could have potentially altered CSF viscosity and circulation. Castano and colleagues46 reported another patient who had symptoms of raised intracranial pressure including abducent nerve palsy and optic nerve damage with severe papilloedema within 15 days of developing fever and icterus. The CSF pressure was 600 mm of water and did not respond to several therapeutic lumbar punctures, necessitating the placement of a temporary ventriculo-peritoneal shunt. Again there were no clinical features of meningitis, and the cytology was normal in CSF. The patient recovered with the placement of the shunt together with standard management of leptospirosis. Other reported rare central nervous system manifestations of acute neuroleptospirosis include encephalitis-induced coma, myelitis, cerebral venous sinus thrombosis and intracranial bleeds.40,47–49 Bleeding in leptospirosis can be due to a combination of factors including, thrombocytopaenia, presumptive vasculitis and hypoprothrombinaemia.40 Post infective cerebellar dysfunction is rare in leptospirosis, and most case series place

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the first 5 days since the onset of symptoms followed by a progressive rise over the next 14 days.25 Thrombocytopaenia is observed in a majority of patients within the first 5 days of the onset of fever. There is also a decline in haemoglobin level and haematocrit over the course of the illness.25 Persistent pancytopaenia has been reported rarely as a complication of severe leptospirosis. Bee et al.26 report a patient with serologically confirmed severe leptospirosis (with renal failure secondary to rhabdomyolysis) developing pancytopaenia one month after the initial presentation in association with another febrile episode, where white blood cell and platelet counts were disproportionately low compared to the haemoglobin level, which was moderately reduced. A gap of one month between acute leptospirosis and discovery of pancytopaenia raises a doubt whether pancytopaenia was a direct consequence of leptospirosis or just coincident. Later on, another two cases of pancytopaenia during acute leptospirosis were reported by Stefos and colleagues.27 Bone marrow examination showed hypoplastic marrow with an extremely low number of megakaryocytes. Both patients recovered with standard treatment of intravenous penicillin. Repeat bone marrow examination one month later showed recovery. During the peak of pancytopaenia, the haemoglobin, leucocyte count and platelet count hovered around 10g/dl, 3500/ml and 14–25 000/ml respectively in all patients. Erythroid hypoplasia alone has been reported in acute severe leptospirosis (confirmed with ELISA and MAT) in one instance.28 Bishara et al.29 observed pancytopaenia in 28% of a cohort of 46 leptospirosis patients with acute disease and concluded that it is more common than anticipated. However examination of haematological parameters in a larger prospective cohort of 201 patients followed-up in Sri Lanka showed that 16% had leucopenia and 74% had thrombocytopaenia within the first 5 days of acute illness.25 There was a general tendency for a decline in haemoglobin level and haematocrit between days 3 and 10 of the illness. There are few cases of autoimmune haemolytic anaemia (AIHA) reported following acute leptospirosis.30,31 Solmazgul and colleagues30 report of a patient with severe AIHA complicating leptospirosis. There was no alternative explanation for the haemolysis, and the anaemia was not responsive to steroids. Haemolysis was controlled within 48 hours by administering intravenous immunoglobulin. There is also a single case report of leptospira pneumonitis and associated cold agglutinin disease.31 The anaemia in this patient was caused by anti-I antibodies on a background of pneumonia. Repeated testing for Mycoplasma was negative, but MAT indicated a positive seroconversion for leptospirosis. Interestingly the anaemia responded to intravenous methylprednisolone. It is also known that antiphospholipid antibody levels are raised in some patients with leptospirosis, especially in severe disease.32 This resolves as the infection settles and its clinical significance is unknown.33 However, it is notable that elevated pulmonary arterial pressure has been observed in association with elevated anticardiolipin IgM antibodies in acute leptospirosis, which may be a consequence of pulmonary thromboemboli.34 Thrombotic thrombocytopaenic purpure (TTP) and haemolytic uraemic syndrome (HUS) which is characterized by thrombocytopaenia and microangiopathic haemolysis have been reported in association with leptospirosis in few instances.35–39 In the most recent case report, Sukran et al.38 describe a patient with classical features of TTP

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Ocular manifestations Conjunctival suffusion, subconjunctival haemorrhages, icterus and muddy sclera are well known ocular manifestations of acute leptospirosis. Uveitis following leptospirosis is rare but has been reported as far back as 1952.58 Since then many sporadic reports of leptospiral uveitis have been reported, and leptospirosis is now a recognised cause of uveitis.59–69 Significant damage to the eye can occur with severe ocular involvement (on most occasions as chronic sequelae of acute illness). Uveitis is commonly observed from 2 weeks up to 6 months following the acute febrile illness. A retrospective analysis of 13 patients with ocular leptospirosis over 4 years showed a myriad of manifestations involving 17 eyes (bilateral involvement in four patients and unilateral involvement in nine patients).61 These included: pan-uveitis (5/ 17, 29%), anterior uveitis (5/17, 29), posterior uveitis (2/17, 12%), optic neuritis (11/17, 65%) and interstitial keratitis (3/17, 18%). Other observations included: posterior synchiae, vitritis, hypopyon and pars planitis. The final visual impairment was categorized as severe in six eyes (defined by absolute central scotoma or visual acuity ,6/60 despite standard treatment). The exact onset of symptoms in this cohort is not clear as there had been a delay from onset of complaints to initial recorded ophthalmological examination for many patients. Rathinam and colleagues65 reported 73 patients with ocular leptospirosis during an epidemic in South India. In 61 patients, there was a symptom free period between 1 and 10 months from the onset of febrile illness to onset of ocular symptoms. There was unilateral eye involvement in 35 patients and bilateral eye involvement of 38 patients. Observations included: panuveitis (106/111, 95.6%), hypopyon (14/111, 12.6%) and retinal phlebitis (57/111, 51.4%). Ninety-one eyes were followed-up for at least 8 months and the majority recovered with only one eye showing severe visual deterioration. This is in contrast to the previous study which reported a higher percentage of permanent visual damage. In both series the diagnosis of leptospirosis was confirmed by MAT (performed in a reference laboratory) or by genomic tests. Overall, it can be concluded that leptospirosis is a recognized cause of uveitis which can lead to many pathological changes

in the anterior and posterior chambers. Eye involvement can be unilateral or bilateral and the majority develop the ocular manifestations after the acute febrile episode resolves. The long term prognosis is unclear, with contradictory claims by different investigators. It is also difficult to assess the overall percentage of patients with ocular manifestations within all patients with leptospirosis, as both series have been published by clinicians receiving referrals for ophthalmological involvement. Yet, given the small numbers reported with ocular complications even during an epidemic, it is probably safe to assume that uveitis and its associations are not a common manifestation in acute leptospirosis. However, its incidence as a chronic sequelae of infection is probably underestimated as most patients are not followed up longterm after resolution of the acute illness. Pathogenesis of uveitis can be related to host immune mechanisms (slow migration of antibodies to anterior chamber) as well as direct invasion by the organism, as leptospira DNA has been demonstrated in the aqueous humour of patients.70 In equine studies, it has been demonstrated that leptospiral lipoproteins LruA and LruB to induce a cross reacting immune response against lens proteins alpha-crystallin B and vimentin.71 The investigators also demonstrated that anti LruA and LruB containing sera (as opposed to pre-immune sera) recognized purified recombinant human alpha-crystallin B and anti Lru A containing sera also recognized vimentin. These antibodies were found in higher concentrations following leptospirosis uveitis than in normal eyes. These findings demonstrate that immune cross reaction by antileptospirosis antibodies may gradually damage ocular structures and does not necessarily have to coincide with the acute infection.

Renal manifestations Leptospirosis is a well-recognized cause of acute kidney injury by interstitial nephritis and acute tubular necrosis.72 The majority of patients with acute severe leptospirosis have evidence of renal failure, and it is a major cause of mortality (i.e., from uraemia, fluid overload, acidosis, pericarditis or hyperkalaemia). The patients need to be temporarily supported by standard management of acute kidney injury including dialysis (if required) until the infection is resolved. There are several case reports of unusual metabolic manifestations secondary to tubular dysfunction, which differs from the typical acute kidney injury observed in leptospirosis. Krishna et al.73 report a patient who had severe hypokalaemia to the extent of it causing paralysis during acute illness. The patient was admitted with clinical features of severe hypokalaemia, including muscle weakness and difficulty in swallowing, respiratory paralysis, paralytic ileus and hyporeflexia. He also had myalgia and conjunctival suffusion. The progression of clinical symptoms was rapid, with the patient needing respiratory support (elective intubation and ventilation) within 24 hours of the onset of myalgia. There was no significant renal impairment at this point in time and investigations revealed a normal anion gap metabolic acidosis with renal trans-tubular potassium gradient .5 suggesting renal tubular dysfunction. Interestingly, within the next 48 hours typical features of severe leptospirosis became apparent (icterus, oliguria, fever, rising serum creatinine, thrombocytopaenia and severe myalgia). The patient was treated for presumed leptospirosis, and the serological diagnosis was made later. The overall picture pointed towards proximal renal tubular dysfunction (hypokalaemia

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the percentage of cerebellar involvement to be around 3–5% of all patients with neuroleptospirosis.40,50,51 There are multiple manifestations of neuroleptospirosis related to the peripheral nervous system such as Guillain Barre syndrome, radiculopathy, mono and polyneuropathies including cranial nerve palsies and autonomic instability.40,52–54 However some of these manifestations are so rarely reported that it is difficult to differentiate a definite from a probable association. For example, facial nerve palsy in association with leptospirosis has been reported only twice in literature and that also during convalescence.55,56 In another example, de Souza et al.57 report right common peroneal nerve palsy in a patient with severe leptospirosis complicated with renal failure. However the nerve palsy developed 3 weeks in to the illness and following an intensive care unit stay. It persisted for several months before resolving. This makes it difficult to confidently attribute the neuropathy to leptospirosis as even a pressure palsy during ICU stay could have caused this clinical picture. There are occasional case reports of mononeuritis multiplex following clinically confirmed leptospirosis.54

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Cardiac manifestations Myocarditis is a well-recognized fatal complication of acute leptospirosis.72,78,79 The clinical manifestations include hypotension, arrhythmias and electrocardiographic (ECG) and echocardiographic feature; however it is often difficult to differentiate whether these features are due to primary myocardial involvement or a result of generalised haemodynamic and metabolic derangement which occurs in leptospirosis.80 Heart failure with fluid overload and pericarditis can also happen as sequelae to acute kidney injury.79,81 In a case series of 22 patients, 13 (59%) had ECG abnormalities during acute febrile stage including: sinus tachycardia, transient atrial fibrillation and dynamic T wave inversions.82 Nine (41%) patients had echocardiographic abnormalities such as mild mitral or aortic regurgitation, apical hypokinesia and wall motion abnormalities. When taken together with clinical features, myocarditis was diagnosed in only two patients, suggesting that asymptomatic ECG and echocardiographic evidence of cardiac involvement is more frequent than anticipated. Numerous ECG changes have been reported with leptospirosis, however it is unclear whether these are a result of metabolic derangement or actual myocardial involvement.80 However, definite histological evidence of myocardial involvement has been described in autopsy studies.83,84 Management depends on anticipation and early diagnosis based on clinical suspicion followed by supportive therapy ideally in a cardiac intensive care unit.

Respiratory manifestations Severe leptospirosis is associated with pulmonary complications with fatal consequences that are just as important as acute

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kidney injury with respect to observed mortality.72 These include diffuse alveolar haemorrhage, pneumonitis and secondary involvement of lungs as part of multi organ dysfunction syndrome due to generalized sepsis.72 Clinical manifestations can vary from simple dyspnoea or haemoptysis to respiratory failure. There have been many case series and even clinical trials on patients with severe haemorrhagic pulmonary leptospirosis, and thus this is no longer considered a rare manifestation and hence will not be discussed in detail in this paper. We have previously reviewed the evidence for using steroids in severe leptospirosis, and pulmonary involvement is probably the only situation in which it has shown a positive impact on outcome.85 However the evidence base is still not strong and needs further well designed clinical trials for a firm recommendation.

Leptospirosis in pregnancy The impact of leptospirosis in pregnancy is largely underestimated due to unavailability of data. However, it is an established cause of miscarriage, in-utero deaths, stillbirths, oligohydramnios and post-partum sepsis86–89 Also, there are case reports of healthy deliveries even when the mother had severe leptospirosis, although intervention was necessary in cases of foetal distress.88,90 Trans-placental transmission of the pathogen and congenital infection is possible as well as transmission through breastfeeding.88,91 In a study in French Guiana, foetal death occurred in more than 50% of a cohort of 11 women diagnosed with acute leptospirosis (confirmed by serology or antigen detection in urine).92 An important consideration in pregnancy is to make the correct distinction between haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome and acute severe leptospirosis in patients with jaundice, as both are life threatening conditions. Considering a differential diagnosis of leptospirosis in every HELLP syndrome suspected patient with a careful history on risk factors for leptospirosis can avoid diagnostic delays. Severe maternal leptospirosis causes placentitis and placental ischaemia which results in foetal compromise. It can also cause post-partum complications such as post-partum haemorrhage.93 Severe leptospirosis with coagulopathy also presents a potential hazard for epidural anaesthesia if the need arises for emergency caesarean section. Following delivery, the newborn needs to be tested for congenital leptospirosis, and breast feeding should be avoided until the illness resolves in the mother.

Other rarely reported associations Kantarci and colleagues94 report a patient who was found to have a spontaneous intrahepatic porto-systemic venous shunt 4 months after an episode of leptospirosis. The authors suggest the possibility of vasculitis induced by the initial infection causing endothelial damage and vascular malformations. However, no similar associations have been reported by others. There are case reports of leptospirosis in patients with long term comorbidities that increase their vulnerability to unusual complications (e.g., blindness in a patient with sickle cell trait).95 We have not covered such reports as these are special situations.

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and normal anion gap metabolic acidosis in the presence of a urinary pH ,5.5). Similarly, another group reported reversible proximal renal tubular dysfunction in a 72 year-old man with confirmed leptospirosis.74 Again, hypokalaemia was observed without deranged serum creatinine or blood urea nitrogen levels. In addition this patient had overt features of clinical leptospirosis as well as features of proximal tubule dysfunction, including hypophosphataemia with phosphaturia, hypouricaemia with inappropriate uricosuria, renal glycosuria and inappropriate excretion of b2-microglobulin. The patient was treated as for leptospirosis, and recovery of tubular function was complete within 40 days of admission. There are few other case reports where patients had presented with severe hypokalaemia and hypomagnesamia during acute leptospirosis.74–76 The pathogenesis of these unusual manifestations is probably due to proximal tubular dysfunction caused by the inflammatory reaction against leptospira residing in proximal tubules.77 In addition there is also evidence of thick ascending loop dysfunction due to inflammation disrupting the sodium-potassium-chloride co-transporter, which increases the amount of sodium exiting to distal convoluted tubule.75 The relatively unaffected distal tubule retains more sodium at the expense of potassium, aggravating the hypokalaemia caused by proximal tubule dysfunction. These findings characteristically occur in the absence of significant renal impairment, where hyperkalaemia and other metabolic abnormalities caused by oliguric renal failure will not mask the features of tubular dysfunction.

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Conclusions

11 Bell MJ, Ternberg JL, Feigin RD. Surgical complications of leptospirosis in children. J Pediatr Surg 1978;13:325–30. 12 Harshey JS. Acute pancreatitis in Weil’s disease. Case report and review of the literature. Ohio Med 1961;57:1261–2. 13 Ranawaka N, Jeevagan V, Karunanayake P et al. Pancreatitis and myocarditis followed by pulmonary hemorrhage, a rare presentation of leptospirosis – a case report and literature survey. BMC Infect Dis 2013;13:38. 14 Ribiczey P, Szekeres I, Turoczi I. Acute pancreatitis as a complication of leptospirosis[ in Hungarian]. Orv Hetil 1988;129:1367–9. 15 Jaspersen D, Hammar CH, Fassbinder W. Jaundice and pancreatitis in a 50-year-old patient (Leptospirosis icterohaemorrhagica) [in German]. Med Klin (Munich) 1991;86:518–20. 16 Chong VH, Goh SK. Leptospirosis presenting as acute acalculous cholecystitis and pancreatitis. Ann Acad Med Singapore 2007; 36:215–6. 17 Pai ND, Adhikari P. Painless pancreatitis: a rare manifestation of leptospirosis. J Assoc Physicians India 2002;50:1318–9.

Authors’ contributions: SR and CR conceptualised the manuscript. SR, CR, KB and SDF reviewed the literature and extracted data. All authors contributed towards writing the manuscript, and read and approved the final version. SR is the guarantor of the paper. Funding: None. Competing interests: None declared.

18 Kaya E, Dervisoglu A, Eroglu C et al. Acute pancreatitis caused by leptospirosis: report of two cases. World J Gastroenterol 2005; 11:4447–9. 19 Spichler A, Spichler E, Moock M et al. Acute pancreatitis in fatal anicteric leptospirosis. Am J Trop Med Hyg 2007;76:886–7. 20 Edwards CN, Evarard CO. Hyperamylasemia and pancreatitis in leptospirosis. Am J Gastroenterol 1991;86:1665–8.

Ethical approval: Not required.

21 Daher Ede F, Brunetta DM, de Silva Junior GB et al. Pancreatic involvement in fatal human leptospirosis: clinical and histopathological features. Rev Inst Med Trop Sao Paulo 2003;45: 307–13.

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Leptospirosis is an illness with a bewildering array of clinical manifestations. While the common manifestations are easily recognized by practising clinicians in endemic areas, rare manifestations can potentially outfox the smartest of clinicians. This is complicated by the unavailability of rapid diagnostic tests that can be applied at bedside. Eventually, the diagnosis will be made (as observed in many of the cited case reports) after exhausting resources on many irrelevant investigations and usually aided by a leptospirosis specific complication which the patient develops later in the course of illness. Unfortunately for the patient, leptospirosis is an acute illness that can take a turn for the worse within a few hours. Being aware of rare manifestations of the disease will enable early recognition and timely institution of treatment which is of utmost importance to improve survival.

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Atypical manifestations of leptospirosis.

Leptospirosis is an illness with a wide spectrum of clinical manifestations and severe illness affects nearly all organ systems. Serious and potential...
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