LEPTOSPIROSIS

Diagnosis, Diagnostics, Immunodiagnosis & Immunodiagnostics:

ABSTRACTS

January 2003

6115. Chung KJ, Hsiao CT, Liu JW, Lee CH. Case reports of leptospirosis in southern Taiwan. J Formos Med Assoc. 2002 Jul;101(7):514-8.

Leptospirosis, a zoonotic disease with worldwide distribution, is often overlooked in Taiwan. Clinicians at our medical center in southern Taiwan became alert to the potential for leptospirosis after the first documented case of severe leptospirosis--Weil's syndrome was diagnosed at our emergency department in early September 2000. Four additional cases of leptospirosis were subsequently diagnosed within a 2-month period. All of the patients were hospitalized, and presented with high fever, severe myalgia, jaundice, and acute renal failure. Two of these patients who rapidly received doxycycline therapy survived, while the remaining three patients who received delayed penicillin therapy died. These cases suggest that the incidence of leptospirosis may have been underestimated in Taiwan, and underscore the urgent need for increased clinician awareness of this infectious disease.

6116. Mackintosh C, Haigh JC, Griffin F. Bacterial diseases of farmed deer and bison. Rev Sci Tech. 2002 Aug;21(2):249-63. Review.

The most important aerobic bacterial diseases of farmed deer and bison include bovine tuberculosis, Johne's disease (paratuberculosis), yersiniosis, leptospirosis, brucellosis, pasteurellosis, anthrax, salmonellosis and colibacillosis. Anaerobic bacterial infections affecting the same animals include necrobacillosis and a number of clostridial diseases such as tetanus, blackleg, malignant oedema and pulpy kidney. The relative importance of these diseases will vary throughout the world according to timing and circumstance, but bovine tuberculosis and Johne's disease are likely to present the most significant problems with respect to diagnosis, control, trade in live animals and the establishment of wildlife reservoirs of infection. The authors summarise the aetiology, the principal species of animal affected, geographical distribution, transmission, clinical signs, pathology, diagnosis, treatment and control of these diseases.

6117. Sharma A, Joshi SA, Srivastava SK, Bharadwaj R, Khare PM. Leptospirosis in the causation of hepato-renal syndrome in and around Pune. Indian J Path Microbiol. 2000; 43(3): 337-41. No abstract.

6118. Shibuya N, Shibuya K, Kato H, Yanagisawa M. Kawasaki disease before kawasaki at Tokyo university hospital. Pediatrics. 2002 Aug;110(2 Pt 1):e17.

OBJECTIVE: Kawasaki disease (KD) was first reported by Tomisaku Kawasaki in 1967 in Japan. Large-scale nationwide epidemiologic surveys have been conducted continuously by the Japan Kawasaki Disease Research Committee; however, there were very few reports of KD before 1967. This study was performed to clarify when KD appeared in Japan. DESIGN: We investigated the medical charts of patients who had been hospitalized at Tokyo University Hospital between 1940 and 1965. RESULTS: We identified 10 patients whose clinical signs fulfilled the criteria for KD. The ages of the patients ranged from 8 months to 5 years, and their final diagnoses were Stevens-Johnson syndrome, allergic toxic erythema, Izumi fever, scarlet fever, and cervical lymphadenitis. These 10 patients presented between 1950 and 1964, and no confirmed cases were seen between 1940 and 1949. CONCLUSIONS: Our findings suggested that KD patients were rare before 1950 in Japan.

Pathogenesis:

6119. Arzouni JP, Parola P, La Scola B, Postic D, Brouqui P, Raoult D. Human infection caused by Leptospira fainei. Emerg Infect Dis. 2002 Aug;8(8):865-8.

We report a human case of leptospirosis in which the spirochete was detected by dark-field microscopy examination of cerebrospinal fluid (CSF) and isolated from both CSF and blood. Leptospira fainei was identified by sequencing the 16S rDNA gene, which had been amplified by polymerase chain reaction. This case confirms the role of L. fainei as a human pathogen and extends its distribution to southern Europe.

6120. Smythe LD, Smith IL, Smith GA, Dohnt MF, Symonds ML, Barnett LJ, McKay DB. A quantitative PCR (TaqMan) assay for pathogenic Leptospira spp. BMC Infect Dis. 2002 Jul 8;2(1):13.

BACKGROUND: Leptospirosis is an emerging infectious disease. The differential diagnosis of leptospirosis is difficult due to the varied and often "flu like" symptoms which may result in a missed or delayed diagnosis. There are over 230 known serovars in the genus Leptospira. Confirmatory serological diagnosis of leptospirosis is usually made using the microscopic agglutination test (MAT) which relies on the use of live cultures as the source of antigen, often performed using a panel of antigens representative of local serovars. Other techniques, such as the enzyme linked immunosorbent assay (ELISA) and slide agglutination test (SAT), can detect different classes of antibody but may be subject to false positive reactions and require confirmation of these results by the MAT. METHODS: The polymerase chain reaction (PCR) has been used to detect a large number of microorganisms, including those of clinical significance. The sensitivity of PCR often precludes the need for isolation and culture, thus making it ideal for the rapid detection of organisms involved in acute infections. We employed real-time (quantitative) PCR using TaqMan chemistry to detect leptospires in clinical and environmental samples. RESULTS AND CONCLUSIONS: The PCR assay can be applied to either blood or urine samples and does not rely on the isolation and culture of the organism. Capability exists for automation and high throughput testing in a clinical laboratory. It is specific for Leptospira and may discriminate pathogenic and non-pathogenic species. The limit of detection is as low as two cells.

Therapy:

6121. Arzouni JP, Parola P, La Scola B, Postic D, Brouqui P, Raoult D. Human infection caused by Leptospira fainei. Emerg Infect Dis 2002 Aug;8(8):865-8

-We report a human case of leptospirosis in which the spirochete was detected by dark-field microscopy examination of cerebrospinal fluid (CSF) and isolated from both CSF and blood. Leptospira fainei was identified by sequencing the 16S rDNA gene, which had been amplified by polymerase chain reaction. This case confirms the role of L. fainei as a human pathogen and extends its distribution to southern Europe.

6122. Chung KJ, Hsiao CT, Liu JW, Lee CH. Case reports of leptospirosis in southern Taiwan. J Formos Med Assoc 2002 Jul;101(7):514-8.

6123. Mackintosh C, Haigh JC, Griffin F. Bacterial diseases of farmed deer and bison. Rev Sci Tech 2002 Aug;21(2):249-63.

April 2003

6776. Kishor KK, Rao PV, Bhat KR, Shastry BA. Pancreatitis in Weil's disease. Trop Doct 2002 Oct;32(4):230-1. No abstract.

Pathogenesis:

6777. Rajajee S, Shankar J, Dhattatri L. Pediatric presentations of leptospirosis. Indian J Pediatr 2002 Oct;69(10):851-3

OBJECTIVE: Leptospirosis in children is an often under diagnosed condition due to the non specificity of the presentations except for the classical Weil's disease. METHODS: Children presenting with symptoms and signs suggestive of Leptospirosis were included in the study. Diagnostic criteria were fever, myalgia, conjunctival suffusion, Jaundice, headache, altered sensorium, seizures, bleeding manifestation and oliguria. Their clinical profile, lab parameters (general and specific), response to treatment and outcome were analysed. RESULT: One hundred and thirty nine cases were diagnosed during a 4-year period. The commonest symptoms were fever 133 (96%), headache and myalgia 34 (24%). Jaundice was present in only 25 (18%) of cases with renal failure in 2 cases. The frequently encountered clinical signs were hepatomegaly in 100 (72%), myalgia in 34 (24%) with icterus in 25 (18%), 12 (9%) of children presented with shock and 10 (7%) had meningitis. CPK estimated was a useful index of myositis. The diagnosis was confirmed by Dark field microscopy and paired or single high serological tests (MAT, ELISA IgM). Overlapping infections such as culture positive Salmonella typhi with leptospirosis (Serology positive) or Dengue Hemorrhagic fever with Leptospirosis presented with complications such as a myocarditis, shock and ARDS. CONCLUSION: Presentation of non-icteric forms of Leptospirosis are often non-specific and may be missed unless there is a high index of suspicion. This study emphasizes the myositis and meningitis forms of leptospirosis. Delayed diagnosis leads to increased mortality and morbidity.

6778. Zuerner RL, Huang WM. Analysis of a Leptospira interrogans locus containing DNA replication genes and a new IS, IS1502. FEMS Microbiol Lett 2002 Oct 8;215(2):175-82.

A region of the Leptospira interrogans serovar pomona genome encoding DNA replication genes was characterized. This region, designated the ppa-ntrC locus, includes 19 open reading frames and a new insertion sequence, IS1502. Although this locus resembles replication origins from many eubacteria, it lacks several genes common to homologous loci. Some replication-related genes were previously located near rrf, and may have been moved to that location by homologous recombination between short sequence elements common to both loci. Further analysis showed that the ppa-ntrC region has undergone substantial change during spirochete evolution. Transcription analysis using RT-PCR revealed uniquely organized polycistronic mRNAs in the ppa-ntrC locus. The dnaN and recF intergenic region of serovar pomona was different from the homologous sites of 41 L. interrogans serovars by the presence of IS1502. The distribution of IS1502 throughout pathogenic Leptospira species varies. This result suggests that IS1502 may have been recently introduced into Leptospira.

July 2003

7307. Oliveira MA, Caballero OL, Vago AR, Harskeerl RA, Romanha AJ, Pena SD, Simpson Low-stringency single specific primer PCR for identification of Leptospira. J Med Microbiol 2003 Feb;52(Pt 2):127-35.

Thirty-five Leptospira serovars from the species Leptospira interrogans, Leptospira borgpetersenii, Leptospira santarosai, Leptospira kirschneri, Leptospira weilii, Leptospira biflexa and Leptospira meyeri were characterized by the low-stringency single specific primer PCR (LSSP-PCR) technique. LSSP-PCR analysis was performed to detect DNA polymorphisms in a 285 bp DNA fragment amplified from genomic DNA with G1 and G2 selected primers. Similar LSSP-PCR profiles were obtained for serovars from the same genomic species, while serovars from non-related species produced distinct multiband patterns. Based on the data from sequence analysis, all genomic fragments amplified with G1 and G2 primers from distinct serovars of Leptospira were 285 bp in length, with nucleotide variation observed most frequently among different genomic species. The simplicity and accuracy of the LSSP-PCR technique were found to be suitable for identification of Leptospira species.

Pathogenesis:

7308. Levett PN. Usefulness of serologic analysis as a predictor of the infecting serovar in patients with severe leptospirosis. Clin Infect Dis 2003 Feb 15;36(4):447-52.

The diagnosis of leptospirosis is often made using the microscopic agglutination test (MAT), in which live antigens representing >20 serogroups undergo reaction with patient serum samples to detect agglutinating antibodies. Data derived from this assay are often used to infer the identity of the infecting leptospiral serovar or serogroup; however, paradoxical reactions and cross-reactions between serogroups are common. To evaluate the usefulness of this approach, data on culture-proven cases of leptospirosis that occurred in Barbados from January 1980 through December 1998 were reviewed. A total of 151 isolates of 4 serovars were identified. The sensitivity of MAT for the prediction of the infecting serovar was determined. Overall, the predominant serogroup at a titer of >or=100 correctly predicted 46.4% of all serovars isolated. If a titer of >or=800 was used as the cutoff, sensitivity decreased slightly to 44.4%. The overall specificity for all serogroups was 64.8%. Serologic analysis appeared to be of little value for the identification of the infecting serovar in individual cases of leptospirosis in humans. Presumptive serogroup reactivity data should be used only to gain a broad idea of the serogroups present at the population level.

7309. Luks AM, Lakshminarayanan S, Hirschmann JV. Leptospirosis presenting as diffuse alveolar

hemorrhage: case report and literature review. Chest 2003 Feb;123(2):639-43.

The literature on diffuse alveolar hemorrhage heavily emphasizes the causal role of vasculitides. We present a patient with diffuse alveolar hemorrhage caused by leptospirosis. Although the pathology in leptospirosis occurs secondary to a vasculitic process, this disease is not listed as a cause of diffuse alveolar hemorrhage in the review literature. In the right clinical scenario, the disease should be considered in a patient presenting with diffuse alveolar hemorrhage.

7310. Oliveira MA, Caballero OL, Vago AR, Harskeerl RA, Romanha AJ, Pena SD, Simpson AJ, Koury

MC. Low-stringency single specific primer PCR for identification of Leptospira. J Med Microbiol

2003 Feb;52(Pt 2):127-35.

7311. Ruof HR, Rudin C, Heininger U. Influenza-like symptoms and thrombocytopenia in a teenager. Pediatr

Infect Dis J 2003 Jan;22(1):89, 101-2. No abstract available.

7312. Tattevin P, Dupeux S, Hoff J. Leptospirosis and the antiphospholipid syndrome. Am J Med 2003 Feb

1;114(2):164. No abstract available.

Therapy:

7313. Pea L, Roda L, Boussaud V, Lonjon B. Desmopressin therapy for massive hemoptysis associated with severe leptospirosis. Am J Respir Crit Care Med 2003 Mar 1;167(5):726-8.

Massive hemoptysis in patients with severe leptospirosis is often resistant to conventional therapies and can rapidly become fatal. Desmopressin is a fast-acting blood-saving agent used in various hereditary and acquired clotting disorders. We used desmopressin infusions to treat massive pulmonary hemorrhage in six leptospirosis patients with respiratory failure, shock, and multiple organ dysfunction. Hemoptysis ceased rapidly in every case, and five patients finally recovered. Two additional patients with less severe hemoptysis were also successfully treated.

7314. Watt G, Jongsakul K, Suttinont C. Possible scrub typhus coinfections in Thai agricultural workers hospitalized with leptospirosis. Am J Trop Med Hyg 2003 Jan;68(1):89-91.

Possible coinfections with Orientia tsutsugamushi the causative agent of scrub typhus, were prospectively evaluated in rice farmers hospitalized with leptospirosis in Northeast Thailand. Of 22 adults with leptospirosis diagnosed by the microscopic agglutination test, 9 also had serologic evidence of scrub typhus. Of 9 individuals with possible coinfections, 5 had signs or symptoms typical of scrub typhus and atypical of leptospirosis. Patients who appeared to have mixed infections had significantly higher median platelet counts and significantly lower median serum bilirubin and creatinine concentrations (P < 0.05, Mann-Whitney U test) than did individuals with leptospirosis alone. One patient with serologic evidence of scrub typhus and leptospirosis was treated only with penicillin, to which scrub typhus is not sensitive. Respiratory distress worsened during therapy, and the patient died of respiratory failure. Physicians should consider the possibility of scrub typhus infection in leptospirosis patients who respond poorly to treatment or who have atypical disease manifestations.

October 2003

8038. Divate SA, Chaturvedi R, Jadhav NN. Leptospirosis associated with diffuse alveolar haemorrhage. J Postgrad Med 2002, 48(2), 131-2. ISA 000682, Vol 39, No 1, 1 Jan 2003.

8039. Panaphut T, Domrongkitchaiporn S, Vibhagool A, Thinkamrop B, Susaengrat W. Ceftriaxone compared with sodium penicillin g for treatment of severe leptospirosis. Clin Infect Dis. 2003 Jun 15;36(12):1507-13. Epub 2003 Jun 06.

A prospective, open-label, randomized trial at Khon Kaen Hospital (Thailand) was conducted from July 2000 through December 2001 to compare the clinical efficacies of ceftriaxone and sodium penicillin G for the treatment of severe leptospirosis. A total of 173 patients with severe leptospirosis were randomly assigned to be treated with either intravenous ceftriaxone (1 g daily for 7 days; n=87) or intravenous sodium penicillin G (1.5 million U every 6 h for 7 days; n=86). The primary outcome was time to fever resolution. Survival analysis demonstrated that the median duration of fever was 3 days for both groups. Ten patients (5 in each group) died of leptospirosis infection. There were no statistically significant differences in the duration of organ dysfunction. Ceftriaxone and sodium penicillin G were equally effective for the treatment of severe leptospirosis. Once-daily administration and the extended spectrum of ceftriaxone against bacteria provide additional benefits over intravenous penicillin.

Pathogenesis:

8040. Cullen PA, Haake DA, Bulach DM, Zuerner RL, Adler B. LipL21 is a novel surface-exposed lipoprotein of pathogenic Leptospira species. Infect Immun. 2003 May;71(5):2414-21.

Leptospira is the etiologic agent of leptospirosis, a bacterial zoonosis distributed worldwide. Leptospiral lipopolysaccharide is a protective immunogen, but the extensive serological diversity of leptospires has inspired a search for conserved outer membrane proteins (OMPs) that may stimulate heterologous immunity. Previously, a global analysis of leptospiral OMPs (P. A. Cullen, S. J. Cordwell, D. M. Bulach, D. A. Haake, and B. Adler, Infect. Immun. 70:2311-2318, 2002) identified pL21, a novel 21-kDa protein that is the second most abundant constituent of the Leptospira interrogans serovar Lai outer membrane proteome. In this study, we identified the gene encoding pL21 and found it to encode a putative lipoprotein; accordingly, the protein was renamed LipL21. Southern hybridization analysis revealed the presence of lipL21 in all of the pathogenic species but in none of the saprophytic species examined. Alignment of the LipL21 sequence from six strains of Leptospira revealed 96 to 100% identity. When specific polyclonal antisera to recombinant LipL21 were used, LipL21 was isolated together with other known leptospiral OMPs by both Triton X-114 extraction and sucrose density gradient membrane fractionation. All nine strains of pathogenic leptospires investigated by Western blotting, whether culture attenuated or virulent, were found to express LipL21. In contrast, the expression of LipL21 or an antigenically related protein could not be detected in nonpathogenic L. biflexa. Infected hamster sera and two of eight human leptospirosis sera tested were found to react with recombinant LipL21. Native LipL21 was found to incorporate tritiated palmitic acid, consistent with the prediction of a lipoprotein signal peptidase cleavage site. Biotinylation of the leptospiral surface resulted in selective labeling of LipL21 and the previously known OMPs LipL32 and LipL41. These findings show that LipL21 is a surface-exposed, abundant outer membrane lipoprotein that is expressed during infection and conserved among pathogenic Leptospira species.

8041. Ren SX, Fu G, Jiang XG, Zeng R, Miao YG, Xu H, Zhang YX, Xiong H, Lu G, Lu LF, Jiang HQ, Jia J, Tu YF, Jiang JX, Gu WY, Zhang YQ, Cai Z, Sheng HH, Yin HF, Zhang Y, Zhu GF, Wan M, Huang HL, Qian Z, Wang SY, Ma W, Yao ZJ, Shen Y, Qiang BQ, Xia QC, Guo XK, Danchin A, Saint Girons I, Somerville RL, Wen YM, Shi MH, Chen Z, Xu JG, Zhao GP. Unique physiological and pathogenic features of Leptospira interrogans revealed by whole-genome sequencing. Nature. 2003 Apr 24;422(6934):888-93.

Leptospirosis is a widely spread disease of global concern. Infection causes flu-like episodes with frequent severe renal and hepatic damage, such as haemorrhage and jaundice. In more severe cases, massive pulmonary haemorrhages, including fatal sudden haemoptysis, can occur. Here we report the complete genomic sequence of a representative virulent serovar type strain (Lai) of Leptospira interrogans serogroup Icterohaemorrhagiae consisting of a 4.33-megabase large chromosome and a 359-kilobase small chromosome, with a total of 4,768 predicted genes. In terms of the genetic determinants of physiological characteristics, the facultatively parasitic L. interrogans differs extensively from two other strictly parasitic pathogenic spirochaetes, Treponema pallidum and Borrelia burgdorferi, although similarities exist in the genes that govern their unique morphological features. A comprehensive analysis of the L. interrogans genes for chemotaxis/motility and lipopolysaccharide synthesis provides a basis for in-depth studies of virulence and pathogenesis. The discovery of a series of genes possibly related to adhesion, invasion and the haematological changes that characterize leptospirosis has provided clues about how an environmental organism might evolve into an important human pathogen.

Therapy:

8042. Vinetz JM. A mountain out of a molehill: do we treat acute leptospirosis, and if so, with what? Clin Infect Dis. 2003 Jun 15;36(12):1514-5. Epub 2003 Jun 06. No abstract.

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