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Unusual Clinical Manifestations of Leptospirosis

Unusual Clinical Manifestations of Leptospirosis

� Symposium www.jpgmonline.com Unusual Clinical Manifestations of

Bal AM

Department of Medical ABSTRACTABSTRACT Microbiology, Aberdeen Leptospirosis has protean clinical manifestations. The classical presentation of the is an acute biphasic Royal Infirmary, Aberdeen, Scotland, UK febrile illness with or without . Unusual clinical manifestations may result from involvement of pulmonary, cardiovascular, neural, gastrointestinal, ocular and other systems. Immunological phenomena secondary to Correspondence: antigenic mimicry may also be an important component of many clinical features and may be responsible for Bal Abhijit M reactive . Leptospirosis in early pregnancy may lead to fetal loss. There are a few reports of leptospirosis E-mail: [email protected] 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 or in simultaneous infections with more than two pathogens.

PubMed ID : 16333189 KEY WORDS: Cardiac , , Congenital , Guillain-Barre syndrome, , J Postgrad Med 2005;51:179-83 Pancytopenia, Pregnancy, Leptospirosis

eptospirosis is a that is caused by the tival congestion and a of non-specific features that may spirochete interrogans. The species has sev­ include mild cough, , rash, , , Leral serological variants - the serovars. Antigenically related and vomiting. This phase is followed by a brief afebrile period serovars are grouped together into serogroups. Serovar distri­ of variable duration that, in turn, is followed by the immune bution varies with the geographical region. Recently, DNA phase of illness. The common organs involved during this phase relatedness studies have classified the genus Leptospira into are the liver and kidneys. Both organ derangements are revers­ 13 species. However, serovar based taxonomy continues to have ible. The severe form of leptospirosis, also known as Weil’s epidemiological value.[1] disease, is characterised by a fulminant course with rapid on­ set of hepatic and renal failure and high mortality. In a retro­ Leptospirosis classically manifests as a biphasic illness. The spective report of 34 patients with leptospirosis, the common first phase is characterised by high and coincides with clinical features included fever (100%), (75%), my­ leptospiremia. This is followed by a brief period when the pa­ algia (55%), arthralgia (45%) and vomiting (39%).[2] In one of tient is afebrile. Fever returns heralding the second phase of the largest reported series that included 353 cases, fever, head­ illness that may be accompanied by jaundice and renal failure. ache, , chills, and anorexia were present in more than During this period, leptospires are not found in the blood but 80% of patients.[3] Interestingly, an association between sever­ are excreted in the urine. Unfortunately, classical presentation ity of illness and infection with serovar Icterohaemorrhagiae is not synonymous with the most common presentation, a fact was also observed. During the in Mumbai in the year not always appreciated in clinical medicine. Leptospirosis has 2000, the common clinical included fe­ protean manifestations and rare and unusual presentations ver, headache, myalgia, conjunctival suffusion and cough with should be kept in mind in relevant epidemiological scenario. .[4]

This communication intends to summarise the unusual clini­ In an area, suspecting leptospirosis on clinical grounds cal features of leptospirosis. A thorough knowledge of clinical should not be very difficult. However, the disease is not com­ manifestations is especially valuable in communities that lack monly thought of and hence the diagnosis is often missed due diagnostic facilities and hence the need for clinical judgement to lack of awareness amongst the medical and medical sup­ and suspicion is paramount. port team. As an aid to clinical diagnosis, Faine proposed a clinical scoring system.[5] In my own experience, the scoring Classical features of leptospirosis system had a moderately good sensitivity (81.8%) and specificity (72.9%). The positive predictive value was 40.9% Leptospirosis classically presents as a biphasic illness. The first and the negative predictive value was 94.5% when compared phase of the disease is commonly referred to as the septicemic with serology.[6] In one published work, the sensitivity, phase. It is characterised by fever, headache, myalgia, conjunc­ specificity, positive predictive value and negative predictive

J Postgrad Med September 2005 Vol 51 Issue 3 179 � � Bal: Clinical features of leptospirosis value of the scoring system was reported to be 81.8%, 72.9%, caused such outbreaks. Independent predictors of mortality 40.9% and 94.5% respectively when compared with serology.[6] in pulmonary leptospirosis include hemodynamic disturbance, Use of the scoring system would help exclude the diagnosis of level more than 265.2 µmol/L and serum leptospirosis. Modifications in the scoring system have been potassium level more than 4.0 µmol/L.[21] Karande and col­ proposed recently and merit further evaluation.[7] leagues[22] recently reported a case of pneumonia in a nine­ year-old boy who presented with fever, cough, hemoptysis, and In an endemic area, leptospirosis is often confused with den­ conjunctival suffusion. The patient was diagnosed to be suf­ gue fever due to the similarities of clinical features. LaRocque fering from leptospirosis following a rise in titer of and colleagues summarised the data regarding clinical presen­ reactive with serovar Australis. An study has reported tations of the two illnesses comparing 938 patients of dengue the presence of diffuse bilateral in fa­ fever with 63 patients of leptospirosis.[8] Presence of rash, pru­ tal cases of leptospirosis.[23] A rare case of lung due to ritus and a positive tourniquet test was significantly associ­ leptospirosis has been reported in literature.[24] ated with . Karande and colleagues in their report of a concurrent epidemic of leptospirosis and dengue fever in Neurological manifestations Mumbai, noted that clinical features such as conjunctival suf­ Although asymptomatic aseptic is a common fea­ fusion, hemorrhage, abdominal pain, hepatosplenomegaly and ture of leptospirosis, severe symptomatic involvement is rare. were significantly associated with leptospirosis, while Rare clinical presentations include myeloradiculopathy, my­ [9] arthralgia was significantly associated with dengue fever. elopathy and cerebellar dysfunction.[25] Kavitha and Shastry[26] reported a case of following leptospirosis. Although no single clinical feature is pathognomonic of lept­ Their patient presented with fever and jaundice and subse­ ospirosis, a cluster of findings should lead to clinical suspi­ quently developed weakness of lower limbs and urinary reten­ cion. Therapy should be initiated on the basis of clinical judge­ tion. Sensory perceptions were decreased below T4 level and ment, as laboratory confirmation can be delayed by days and the illness was consistent with transverse myelitis. The patient weeks or is unavailable in several regions and early institution had a positive anti-leptospira IgM serology. Costa et al[27] re­ of appropriate therapy is known to reduce mortality.[10] ported a rare case of facial palsy following leptospiral infec­ Severe leptospirosis may carry a high mortality if treatment is tion. The patient had a clinical illness consistent with lept­ not instituted early. Poor prognostic markers in leptospirosis ospirosis. The authors did not perform microagglutination test include hypotension (relative risk [RR]= 10.3), oliguria (RR = (MAT) that is generally believed to be the confirmatory test. 8.8), hyperkalemia (RR= 5.9), and presence of pulmonary rales However, seroconversion was observed the macroagglutination (RR= 5.2).[11] Other studies have reported dyspnea (odds ra­ test. Although comparative clinical trials are lacking due to tio [OR]= 11.7), white blood cell count greater than 12,900/ rarity of presentation, has been used in such [28] [29] mm3 (OR= 2.5), repolarization abnormalities on electrocar­ cases Mumford et al have reported a case of fatal lept­ diograms (OR= 5.9), alveolar infiltrates (OR= 7.3),[12] ospirosis with flaccid paraplegia in a patient with biochemical hemoptysis, metabolic acidosis, and as evidence of renal and hepatic involvement. Guillain Barre syn­ markers of increased mortality. In hospitals that have adequate drome has been reported following an illness consistent with [30] facilities,[13] patients with these risk factors should preferably leptospirosis. This patient had a history of fever, myalgia, be treated in an intensive care unit. and headache three weeks prior to the onset of paraplegia. The serum sample at the onset of the neurological illness had a Unusual manifestations of leptospirosis titre of 6400 and a later sample had a titre of 800 with strong­ est reactivity to serovar Copenhageni. It is interesting to note Pulmonary involvement that it was the falling titre and not the rising titre that was a Although pulmonary involvement is not uncommon in lept­ clue to diagnosis as the patient presented comparatively late ospirosis, it is usually not suspected. In one study, 10 out of in illness. Because of the time lag between icteric illness and 176 hospital admissions with community-acquired pneumo­ neurological manifestations, it may not be possible to obtain a nia had positive leptospiral serology although only one patient culture confirmation or a rising titre. An absence of had documented seroconversion.[14] Severe hemorrhagic pneu­ such a confirmation therefore should not rule out an associa­ monitis may be a prominent manifestation of infection.[15] tion. Whether leptospires are causally related to such neuro­ Three radiographic patterns have been described in patients logic illness is a matter of conjecture. Treatment of neurologi­ with pulmonary involvement during leptospiral infection- small cal sequelae is supportive. It is unlikely that treatment of un­ nodular densities, diffuse ground glass densities and rarely, con­ derlying cause will alter the natural course of the neurological fluent areas of consolidation.[16] Pulmonary involvement may illness. be the presenting feature of the illness or may complicate a frankly icteric disease.[17] Epidemic leptospirosis with pulmo­ Ocular manifestations nary haemorrhage without jaundice or renal failure has been Ocular manifestations of leptospirosis can lead to significant reported.[18] Severe pulmonary involvement in leptospirosis has morbidity. During the acute phase of illness, conjunctival con­ been reported from Andaman and Nicobar islands. Serovar gestion is a common clinical finding.[31] is a rare sequel Grippotyphosa and more recently,[19] serovar Valbuzzi,[20] have of the disease. It usually presents as a panuveitis with or with­

� 180 J Postgrad Med September 2005 Vol 51 Issue 3 Bal: Clinical features of leptospirosis � out hypopyon. Visual damage can occur in as many as 35% of reported in literature.[49] patients.[32] Topical quinolones have been used to treat such infections.[33] A majority (95.5%) of 73 cases of leptospiral uvei­ Musculoskeletal symptoms tis reported by Rathinam et al[32] had panuveitis, retinal Various musculoskeletal abnormalities have been reported in periphlebitis (51.4%) and hypopyon (12.6%). A few patients patients with leptospiral infection. In a case reported by had anterior uveitis without hypopyon (2.7%) and isolated vit­ Coursin and colleagues,[50] a 63-year-old man presented with reous inflammatory reaction (1.8%). multiorgan dysfunction and rhabdomyolysis. Although myal­ gia and mild elevation of muscle enzymes are common in lept­ Gastrointestinal manifestations ospirosis, severe involvement of muscle tissue is rare. A fatal Pai and Adhikari reported a rare case of pancreatitis following case of rhabdomyolysis was reported by O’Leary et al.[51] In leptospirosis.[34] Hyperamylasemia was persistent but returned this report, acute infection with leptospira belonging to to normal in three months following the institution of lept­ serogroup Grippotyphosa was diagnosed on the basis of serol­ ospira-specific therapy. There are other reports too of pancrea­ ogy. Skeletal muscle involvement independently correlates with titis complicating leptospirosis.[35] Monno and Mizushima re­ the severity of disease.[52] ported a rare case of acute acalculous cholecystitis in a patient with infection due to serovar Autumnalis.[36] In an outbreak of Hematological manifestations leptospirosis reported from the United States, two out of 22 Somers et al[53] reported a rare case of erythroid hypoplasia in a hospitalised patients had symptoms suggestive of acute chole­ case of leptospirosis. The patient presented with fever, jaun­ cystitis. Gross examination of the gall bladders removed at sur­ dice, , and meningism. His haematologic gery revealed thickened walls with smooth serosal surface and parameters showed normocytic normochromic anaemia, bile-stained mucosa. Calculi were not found. The submucosal reticulocytopenia, and thrombocytopenia. Severe erythroid tissue had mononuclear cell infiltration and also showed hypoplasia was observed on bone marrow examination. It is edematous changes. Leptospires were detected by immuno­ possible that this results from a direct action of histochemistry techniques. Staining for the granular and toxic leptospiral products on the progenitor cells of the mar­ filamentous antigens was found positive in the vessel walls and row. Stefos and colleagues reported two cases of pancytopenia also in the submucosa.[37] Paz and colleagues [38] reported a case following infection with leptospira.[54] Interestingly, neither of enteritis in an Israeli patient who had a history of travel to patient had a history of jaundice. According to Bishara and co­ Thailand, a region where leptospirosis is an emerging disease.[39] workers,[55] pancytopenia could occur in as many as 28% of pa­ The patient presented with fever, diarrhea, and vomiting and tients with leptospirosis. Most of the infections in their series leptospiral serology was performed because creatinine levels of cases were caused by leptospira belonging to serogroup were high. The patient had a rising antibody titers detected by Icterohaemorrhagiae and it is possible that infection with this MAT. He was treated with and along serogroup is associated with hematologic abnormalities. Iso­ with intravenous fluids. Peritonitis is another rare manifesta­ lated thrombotic thrombocytopenia purpura has been reported tion of leptospirosis.[40] following infection with leptospires.[56]

Cardiac involvement Immunological manifestations An analysis of data of 50 patients with serologically proven Rare immune-mediated manifestations of leptospirosis include leptospirosis demonstrated that 70% of the patients had antiphospholipid syndrome[57] and reactive arthritis.[58] Such electrocardiographic abnormalities, with atrial fibrillation be­ manifestations are likely to be a result of an immunologic cross ing the commonest major arrhythmia noted.[41] Thirty-six per­ reactivity. Antibodies generated in response to leptospiral in­ cent of the patients had conduction system abnormalities and fection may cross react with host antigens and could lead to 30% had T wave changes. Another series has reported AV block an inflammatory response. Finsterer et al[59] have reported an in 44% of patients with leptospirosis.[42] A glycoprotein frac­ interesting case of carpal tunnel syndrome in a pet-shop worker tion of leptospiral cell wall has been incriminated in the who was later found to have a positive leptospiral IgG and IgM pathogenesis of these rhythm disturbances. This protein is serology. Symptoms improved on doxycycline therapy, although thought to inhibit the Na-K ATPase and may be responsible the antibody levels remained elevated over the next three years. for the arrhythmia.[43] Univariate analysis has shown that car­ Explaining the disappearance of symptoms is difficult espe­ diac arrhythmia is more common in patients dying of lept­ cially because the patient continued to have high antibody ospirosis than in the survivors.[44] Other reported cardiac ab­ titres and hence immunological cross reactivity could still have normalities include [45] and .[46] In seven taken place. The authors hypothesized that persistence of an­ cases of fatal leptospirosis, petechial haemorrhages were found tibodies could be the result of re-exposure at workplace or a in the heart and the in all the autopsy specimens long- term immunological response. However, this does not and interstitial myocarditis was found in five specimens.[47] In necessarily explain the resolution of symptoms. A plausible another study, acute coronary arteritis was found in 70% of explanation is that immune-mediated illness is caused by an­ patients who died of leptospirosis and evidence of aortitis was tigen-antibody complexes rather than by cross-reactive anti­ present in more than half.[48] One case of leptospira endocar­ bodies. Doxycycline therapy, by eradicating the leptospires and ditis, possibly caused by serovar Icterohaemorrhagiae has been thereby removing the source of antigens, could prevent the

J Postgrad Med September 2005 Vol 51 Issue 3 181 � � Bal: Clinical features of leptospirosis formation of the immune complexes leading to a decrease in superinfection could possibly have resulted from a transient the inflammatory response. immunosuppression associated with the disease or its treat­ ment. Wongsrichanalai et al[75] reported two cases of dual in­ Endocrine abnormalities fection with parasites and leptospira. One patient was Panidis et al[60] described a rare case of male hypogonadism, infected with Plasmodium falciparum and the other with P. presumably related to hormone deficiency at the vivax. Co-infection with three different pathogens has also been hypothalamus-pituitary level, following leptospirosis. Abnor­ reported in what probably is an extremely rare event. Lu and malities in hormonal secretion have been found in experimen­ Tseng [76] described a Taiwanese patient with fever and pneu­ tal infection in animals,[61] but there is paucity of data regard­ monia in whom blood cultures grew Burkholderia pseudomallei ing the incidence and effects of such abnormalities following and serological tests were consistent with and infection in humans. leptospirosis. is an emerging disease in Taiwan and B. pseudomallei shares similar ecological niche with leptospira Leptospirosis in pregnancy and congenital leptospirosis and , the causative organism of scrub In a review of 15 patients with documented leptospirosis late typhus. It is important to look for leptospirosis in an appropri­ in pregnancy, Shaked et al[62] found that eight women had abor­ ate setting particularly if the patient does not show clinical tions, two delivered healthy babies, four delivered babies who signs of improvement despite pathogen-directed therapy for had signs of active leptospirosis and in one case, the clinical an established alternative infectious etiology. outcome was not stated. Carles et al[63] reported 11 cases of leptospirosis in pregnant women in French Guiana and foetal Conclusions death occurred in more than 50% of the cases. Chedraui and San Miguel[64] reported a case of leptospirosis in a 28-week preg­ It is imperative that a high index of suspicion for the disease nant patient. The patient presented with fever, myalgia and be maintained particularly in endemic areas. There is a need jaundice and serology was positive for serovar for increasing the awareness of the disease so that timely Icterohaemorrhagiae. The patient was treated with penicillin therapy can be instituted to patients. An effective network of and delivered a healthy baby at 37 weeks. Leptospirosis, early clinicians, medical microbiologists, public health doctors and in pregnancy often leads to abortion. Congenital infections program managers needs to be in place during . It is are rare and long-term serious effects have not been docu­ equally important to collect and report data to a centralised mented. Hence, leptospirosis acquired in pregnancy is not an surveillance cell so that future planning and monitoring can indication for its termination. In one report, transmission of be done easily. Clinicians need to be aware of the possibility of infection to was thought to have taken place through leptospirosis, even if the illness presents with unusual features. [65] the breastmilk. A problem-solving approach to the clinical suspicion and di­ agnosis of leptospirosis has recently been elucidated and could Leptospirosis in HIV seropositive individuals be a useful guide for doctors.[77] Jones and Kim[66] reported a case of leptospirosis in a patient with acquired syndrome. The patient ini­ References tially presented with non-specific illness but later developed jaundice, renal failure and acute respiratory distress syndrome. 1. Levett PN. Leptospirosis. In: Mandell GL, Bennett JE, Dolin R, editors. Prin­ The recovery was probably slower than is usual for leptospiro­ ciples and Practice of Infectious . 6th edn. Philadelphia: Elsevier Churchill Livingstone; 2005. p. 2789-95. sis and there was residual renal impairment. Others have re­ 2. Jaureguiberry S, Roussel M, Brinchault-Rabin G, Gacouin A, Le Meur A, ported a similar clinical course of illness as in non­ Arvieux C, et al. 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