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Leptospirosis is an important zoonotic disease, causing about 60,000 deaths annually. In this review, we have described in detail the immunopathogenesis of leptospirosis, the influence of cytokines, genetic susceptibility on the course of the disease, and the evasion of the immune response. These data are combined with information about immunological and pathomorphological changes in the kidneys, liver, and lungs, which are most affected by Weil's disease. The review also suggests a possible role of the gut microbiota in the clinical course of leptospirosis, the main mechanisms of the influence of gut dysbiosis on damage in the liver, kidneys, and lungs through several axes, i.e., gut-liver, gut-kidney, and gut-lungs. Modulation of gut microbiota by probiotics and/or fecal microbiota transplantation in leptospirosis may become an important area of scientific research.

We report an autopsy case of a 60-year-old man with Weil's disease who died of fulminant hepatic failure. Ante-mortem blood culture yielded the growth of Leptospira interrogans (serovar icterohaemorrhagiae). At autopsy, the liver weighed 1210 g and showed a typical appearance of "acute yellow liver atrophy". Zone 3 (centrilobular region) showed submassive necrosis of hepatocytes accompanied by marked hemorrhage. Hepatocytes in zones 1 and 2 were well preserved, and the leptospira antigen was immunohistochemically demonstrated in several hepatocytes. Dissociation of liver cell plates was not observed. An immunohistochemical study demonstrated that CD31-positive, sinusoidal endothelial cells had almost completely disappeared in zone 3. This finding suggested that severe and selective damage to endothelial cells in zone 3 was the main cause of the submassive hepatocellular necrosis, which led to fulminant hepatic failure in the present case., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Unlabelled: HISTORY AND DIAGNOSIS: A 30-year-old patient was hospitalised with fever and jaundice. No long-term medication was taken. The patient worked as a plumber in refurbishment projects. He presented with headaches, myalgia and arthralgia of varying location and a fever of 38.9 °C. Skin and sclerae were visibly jaundiced. His cardiovascular system was normal. Further routine examination did not reveal any additional signs., Investigations: Having ruled out an acute gallbladder infection or mechanical obstruction of the bile ducts by abdominal ultrasound, an infectious etiology appeared likely, alongside possible toxicological and immunological reasons. Clinical history and diagnosis led to an urgent suspicion of leptospirosis which was confirmed by IgM titer rise within five days in ELISA., Treatment and Course: The patient was treated immediately with ceftriaxone. During his stay in the hospital, his fever, jaundice and subjective symptoms subsided. Initial pathological markers also showed a significant trend towards reversion to normal levels. The patient was discharged from the hospital without any symptoms after 16 days., Conclusion: Leptospirosis is a significant differential diagnosis in patients with fever, jaundice, headaches and myalgia. Clinical history can provide vital clues for diagnosing this illness. Individuals that are prone to be exposed to water contaminated with rodent urine are at heightened risk of developing the disease. Climatic conditions such as heavy rainfalls or flooding also appear to increase the risk of infection., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Leptospirosis is a re-emerging zoonosis with protean clinical manifestations. Recently, the importance of pulmonary hemorrhage as a lethal complication of this disease has been recognized. In the present study, five human necropsies of leptospirosis (Weil's syndrome) with extensive pulmonary manifestations were analysed, and the antibodies expressed in blood vessels and cells involved in ion and water transport were used, seeking to better understand the pathophysiology of the lung injury associated with this disease., Principal Findings: Prominent vascular damage was present in the lung microcirculation, with decreased CD34 and preserved aquaporin 1 expression. At the periphery and even inside the extensive areas of edema and intraalveolar hemorrhage, enlarged, apparently hypertrophic type I pneumocytes (PI) were detected and interpreted as a non-specific attempt of clearence of the intraalveolar fluid, in which ionic transport, particularly of sodium, plays a predominant role, as suggested by the apparently increased ENaC and aquaporin 5 expression. Connexin 43 was present in most pneumocytes, and in the cytoplasm of the more preserved endothelial cells. The number of type II pneumocytes (PII) was slightly decreased when compared to normal lungs and those of patients with septicemia from other causes, a fact that may contribute to the progressively low PI count, resulting in deficient restoration after damage to the alveolar epithelial integrity and, consequently, a poor outcome of the pulmonary edema and hemorrhage., Conclusions: Pathogenesis of lung injury in human leptospirosis was discussed, and the possibility of primary non-inflammatory vascular damage was considered, so far of undefinite etiopathogenesis, as the initial pathological manifestation of the disease.

Leptospirosis is a zoonotic infection with higher incidence in tropics. Leptospirosis, is known for its variable manifestations, and is a clinical challenge for physicians in the tropics. Experienced clinicians, at times can mistake leptospirosis for non-medical conditions. A few reports of leptospirosis presenting as acalculous cholecystitis was found in review of literature. We intent to highlight acalculous cholecystitis as a rare but clinically significant presentation of leptospirosis., (Copyright © 2011 Hainan Medical College. Published by Elsevier B.V. All rights reserved.)

Tubular dysfunction is a hallmark of severe leptospirosis. Antimicrobial therapy is thought to interfere on renal involvement. We evaluated the expression of a proximal tubule type-3 Na+/H+ exchanger (NHE3) and a thick ascending limb Na+-K+-2Cl(-) cotransporter (NKCC2) in controls and treated hamsters. Animals infected by a serovar Copenhageni isolate, were treated or not with ampicillin (AMP) and/or N-acetylcysteine (NAC). Leptospiral antigen(s) and expression of renal transporters were evaluated by immunohistochemistry, and serum thiobarbituric acid (TBARS) was quantified. Infected hamsters had high amounts of detectable leptospiral antigen(s) in target tissues while renal expression of NHE3 and NKCC2 decreased. Ampicillin treatment was associated with minimal or no detection of leptospiral antigens, normal expression of NHE3 and NKCC2 transporters, and reduced levels of TBARS. NAC effect was restricted to lowering TBARS. Early and late AMP treatment rescued tubular defects in severe leptospirosis disease, and there was no evidence of benefit from antioxidant therapy.

Thirty three cases of death from icterohemorrhagic leptospirosis were clinically and morphologically analyzed. The disease is characterized by the affliction of two major target organs: the kidney and liver. Infectious-toxic shock underlies the pathogenesis of specific fetal complications of icterohemorrhagic leptospirosis. In the latter, acute renal-hepatic failure is always followed by the structural damage and dysfunction of other organs, which are less pronounced and, at the same time, presents multiple organ dysfunction.

A total of 2400 patients with pyrexia of unknown origin and or suspected leptospirosis were included in this study. Dark field microscopy detected Leptospira in 690 cases, Leptospira serological Investigations proved positive in 570 out of these 690 patients. Among them 212 had the classical icteric and the other 358 had anicteric type of presentation. Notably eptospira interrogans serovar ictero haemorrhagiae infection was encountered in 212 patients. In 30 patients, who had multi organ dysfunction which included renal failure, hepatic dysfunction or meningitis was due to Leptospira interrogans Serovar cannicola. Coexsistense of leptospirosis and hepatitis B virus infection were noted in 15 patients. Antibody to Leptospira interrogans was demonstrated by Micro agglutination test (MAT) in addition to dark field microscopy positivity in these cases. Similarly HIV antibody was demonstrated in 30 of the 330 anicteric patients. 554 out of 570 cases responded to intra venous penicillin (216), and oral Doxycycline (182) and Augmentin (156), and the remaining 16 patients succumbed to death.

In relation to the explosive increase of new and reemerging infectious diseases that threaten the humanity, and as a result of this clinical case, a literature review is done on Leptospirosis stressing out the necessity of having in mind the leptospirosis in the differential diagnostic for fever and jaundice syndrome.

Two patients who lived in Buenos Aires suburbs died from leptospirosis in July 2000 and March 2001. They developed a nonspecific febrile illness followed by hemorrhagic pneumonia and respiratory distress in absence of typical manifestations such as jaundice, nephropathy, thrombocitopenia or hemorrhages in other organs. In the house and surroundings of one patient rodents were captured and three strains of leptospira, serogroup Icterohaemorrhagiae were isolated. Laboratory guinea pigs were inoculated and they were sacrificed as soon as respiratory symptoms appeared. Necropsy showed primary lung injury, which was similar to the histopathological lesions found in one of the patients. Neither jaundice, nor renal damage was found. Pericardiac hemorrhages were considered as a possible cause of cardiopulmonary collapse. This clinical form has not been reported previously in this region, where conditions are indeed suitable for the human illness to appear.

A study made in three autopsies suggested development during the second to third week of leptospirosis icterohaemorrhagica against the background of secondary immunodeficiency (due to severity of the underlying condition or induced by glucocortocoid and antibiotic therapy) Aspergillus affection of the heart that had significantly aggravated the clinical course of leptospirosis and appeared to be the immediate provoking cause of acute cardiovascular insufficiency with a fatal result to follow. Two cases demonstrated an isolated fungal infection of the myocardium. In one of these running a longer (20 days in duration) course there took place a hematogenic dissemination of the aspergilli present in the liver during the development of the metastatic focus in the myocardium. The observations done suggest that each case requires individual consideration as to part the fungus infection plays in the outcome of the pathological process depending upon its type and extension in the organ.

We examined dams' paired serum samples and foetal kidneys (histopathologically and attempting leptospiral cultures) from 120 Brazilian Holstein abortions from 10 herds near Sao Paulo, Brazil, in 1996. Leptospiras was isolated from 15 foetuses. The Leptospira interrogans serovar hardjo was obtained from four, pomona from three and wolffi from eight foetuses. Ten of these 15 foetuses showed a four-fold rise in titres between the day of abortion and the second samples taken 15 days later. Fifty-seven other foetuses had histologic evidence of leptospires; 27 of their dams (47%) had four-fold rises in titres. In total, 72 of 120 aborted foetuses had evidence of leptospiral infection.

Morphologic findings on the liver during different time periods of Leptospira infection suggest the leading role in the pathogenesis of the damaged organ early in the course of the disease of a toxic vascular affection of the microcirculatory bed presenting with hyperpermeability of the vascular wall, interstitial edema, dyscomplexation of the liver crosspieces together with inflow of bile to the sinusoidal capillaries. To a lesser extent jaundice is related to the hepatocyte dystrophic and necrotic changes as evidenced by the absence of marked disturbances in the protein-synthetizing function of the liver and low enzymatic activity. At week 2 to 3 of the illness against the background of diminution of the edema and partial or complete restoration of the liver constitution (especially so in less afflicted peripheral portions of the lobes) jaundice with high bilirubinemia is caused by a toxic affliction of hepatocytes and advancing centrolobular cholestasis. High values for bilirubin might be related not only to grave alternative changes in hepatocytes but to microcirculatory abnormalities as well, which fact accounts for the absence in leptospirosis of a direct relationship of the blood level of bilirubin to the degree of affliction of the hepatic cells.

To investigate the contribution of the previously demonstrated in vitro apoptosis to the pathogenesis of leptospirosis, guinea pigs were infected with Leptospira interrogans serovar icterohaemorrhagiae strain Verdun and sequentially killed to collect target organs involved in the natural history of the disease (liver, kidneys, lungs, spleen and heart). The combination of histopathological procedures and a specific TUNEL assay showed a significant Leptospira-induced programmed cell death of hepatocytes with a peak at 48 h post inoculation. Hepatocyte nuclei showed morphological changes including fragmented and condensed nuclei. This phenomenon occurred early in the course of the disease at a time where infecting leptospires were present at a low density between the liver parenchyma cells.

Background: Equine uveitis is a spontaneous disorder of horses that can serve as a model for the study of human uveitis. Although the initial presentation is that of an anterior uveitis, retinal involvement has been noted in some cases. We report here the immunohistopathology of retinas from horses with uveitis., Methods: Sections of eyes recovered from horses with naturally occurring uveitis and from Shetland ponies with experimental leptospira-induced uveitis were stained by hematoxylin and eosin for histopathological evaluation. Immunohistochemistry was used to evaluate retinas for MHC Class II antigen expression and infiltration of T and B lymphocytes., Results: Histopathological abnormalities in retinas from horses with uveitis ranged from minimal to total loss of retinal tissue. MHC Class II antigen-positive round and dendritiform cells were seen in these retinas, but were not seen in retinas from horses without uveitis. There was no significant reactivity noted in the retinal pigment epithelial cells or Muller cells. Numbers of MHC Class II antigen-expressing cells and T lymphocytes correlated with the extent of retinal histopathology. B lymphocytes were seen primarily in retinas from horses that were seroreactive for Leptospira interrogans serovar pomona. Retinas from ponies with experimental uveitis had changes similar to those from horses with spontaneous uveitis., Conclusions: These results suggest that retinal pathology may be a primary immunological event in equine uveitis, provide evidence that leptospira-associated uveitis may be a distinct subset of equine uveitides, underscore the relevance of the study of equine uveitis to human uveitis, and support the plausibility of a post-infectious immunopathogenesis of some naturally occurring uveitides in both humans and horses.

Objectives: To study the ocular manifestations during the acute phase of leptospirosis and their incidence in hospitalized patients due to systemic complications, and to verify the importance of routine ophthalmologic care in these cases., Methods: Twenty-one patients, 20 males and 1 female, with clinical and laboratory (ELISA IgM) diagnoses of leptospirosis were subjected to ophthalmologic examination., Results: We observed conjunctival hyperemia in 18 patients (85.7%), increased retinal venous caliber in 12 patients (57.1%), optic disc redness in 12 patients (57.1%), subconjunctival hemorrhage in four patients (19.0%), optic disc edema in one patient (4.8%), retinal vasculitis in one patient (4.8%), retinal hemorrhage in one patient (4.8%), hard exudates in one patient (4.8%), and papillitis in one patient (4.8%). No anterior chamber reaction was found., Conclusions: We observed a high incidence of several ocular manifestations in the acute phase of leptospirosis. Despite the systemic severity and high incidence of ocular disorders in the acute phase of leptospirosis, the short-term visual outcome of these patients was good.

Renal disease was observed in two rehabilitated Pacific harbor seals (Phoca vitulina richardsii) from a facility in California (USA). The seals had leukocytosis and high serum phosphorus, blood urea nitrogen and creatinine concentrations. A retrospective study of leptospiral antibody serum titers indicated both seals had elevated titers to Leptospira interrogans serovar grippotyphosa. A third seal, which died about the time when the index cases occurred, also had elevated titers to L. interrogans serovar grippotyphosa. Post mortem histopathologic examination of all three seals showed tubular necrosis consistent with interstitial nephritis; spirochetes were seen within the kidney parenchyma of the third seal. Sea lions (Zalophus californianus) or elephant seals (Mirounga angustirostris) housed near the harbor seals were possible sources of exposure, but local wildlife also could have been responsible.

Glycolipoprotein (GLP) cytotoxin was extracted from Leptospira interrogans serovar canicola. The silver staining profile of GLP subjected to SDS-PAGE under denaturing conditions showed a number of bands in the mol. weight range of 14-66 kDa. Mouse Monoclonal Antibodies (MAbs) IgG3 recognizing a band near to 24 kDa of leptospiral GLP were produced (clone number MGLP-01). The agglutinating property of MAbs was established by microscopic agglutination test (MAT) using 25 different serovars as antigens. Only the homologous serovar was agglutinated by MAbs suggesting that the recognized epitope is a specific surface-exposed antigen. The MAbs were applied to demonstration of leptospiral antigens in tissue damage by avidin-biotin immunoperoxidase staining. Golden hamsters were experimentally infected with a virulent strain of L. interrogans serovar canicola. Histologically kidneys stained by routine hematoxylin and eosin showed changes characterized by injury of tubular epithelial cells leading to acute tubular necrosis (ATN). Typical, well-defined morphologic leptospires or finely granular deposits were found by immunoperoxidase staining near to blood vessels, within inflammatory infiltrates and intraluminal in proximal and distal parts of the nephron. Binding of leptospiral antigens to capillary endothelial cells, tubular epithelial cells and macrophages were also demonstrated. This entails a basis for further studies either in research or in diagnostic histopathology.

Raccoons may represent a source of leptospires for humans and domestic animals. We describe a case of severe interstitial nephritis associated with the serovar bratislava of Leptospira interrogans (1st report in wildlife), and the seroprevalence to 4 leptospire serovars in a recreational area in Quebec.

Morphologic studies were made on the brain tissue and internal organs of those deceased (n = 75) who had died of leptospirosis icterohemorrhagica during different periods of the condition, with the results obtained being compared to clinical and laboratory findings. It has been shown that realization of the pathogenic potential of the disease-producing germ is exercised both through direct generalized injury to the endothelium of microvessels, parenchymal cells (predominantly those of the liver and kidneys) by toxic substances of Leptospira and (to a larger degree) through disorders of hemostasis presented as thrombosis of vessels of the microcirculatory bed with subsequent development of hemorrhagic manifestations and alterative changes of hypoxic genesis in vital organs. Early haemocoagulatory disorders are characterized by marked and stable hypocoagulation, with direction of the processes of fibrin formation and fibrinolysis being different, which fact is consistent with diversity of structural formations originating from fibrin in the microcirculatory bed of the deceased. Prophylaxis of grave pathologic changes in the organism leading to lethal outcome consists in correction of hemostatic disorders during early phases of the disease course, which is to be pathogenetically substantiated and situational one because of the problem posed by verification of stages of that syndrome of disseminated intravascular coagulation in patients with grave course of leptospirosis icterohemorrhagica.

A total of 120 patients were examined presenting with a grave course of icterohemorrhagic leptospirosis; a pathomorphologic investigation of the brain from 75 deceased was done. Practically in all cases, the affection was accompanied by neurotoxicosis, with microcirculatory disturbances being its morphological substrate. The leading clinical syndromes of the affection of the central nervous system appeared to be general cerebral, meningeal, and encephalitic syndromes. Meningitis was diagnosed in 29.2%, meningoencephalitis in 5% of patients. Morphologic studies showed that predominantly focal serous meningitides and meningoencephalitides are significantly more common that they are diagnosed in clinical settings. They tend to develop during the second and third weeks of the course of the illness. Lumbal puncture is to be carried out on a differentiated basis only, since it may cause dysbalance in metabolic processes of the organism together with progression of those events being related to brain swelling.

Lung fragments from 12 patients were collected immediately after death and studied by light and electron microscopy and by immunohistochemistry to describe the main morphologic and ultrastructural aspects of the lung and platelets in leptospirosis (Weil's syndrome), to search for the possibility of disseminated intravascular coagulation (DIC), and to assess the relationship between endothelial lesions and local platelet aggregation and the leptospiral antigen distribution, as well as its relationship with the intensity of the lesions. The immunohistochemical results for fibrin aggregates were positive in the lumen and/or on the vascular endothelium in nine cases and on the alveolar surface in seven cases, leading to the diagnosis of the adult respiratory distress syndrome in these seven cases. Test results for leptospiral antigen by immunohistochemistry were positive in eight cases with no direct relationship between antigen deposits in the pulmonary vascular endothelium and intensity of the lesions. The ultrastructural findings were uniform and constant. Capillary lesions were characterized by swelling of endothelial cells, an increase in pinocytotic vesicles, and giant dense bodies in the cytoplasm of these cells. No necrosis, rupture, nor exposed subendothelial collagen was observed outside the hemorrhagic areas, and the intercellular junctions were preserved. The lung involvement in severe human leptospirosis presents as hemorrhagic pneumopathy with septal capillary lesions that are the usual cause of death. The thrombocytopenia that was verified in 11 of 12 patients in our study seems to bear no relationship to DIC and seems to be determined by activation, adhesion, and aggregation of platelets to the stimulated vascular endothelium, with an amorphous electron-dense substance between the endothelial cells and the adherent platelets in places where the subendothelial collagen was not exposed.

Superoxide dismutase (SOD) activity and the degree of lipid peroxidation were studied over a two week period in guinea pigs infected with Leptospira interrogans derived from wild mice. The total SOD activity in infected host liver increased by four-fold two days after infection; this was followed by a 20% decrease resulting in levels comparable to normal, uninfected liver. During the period of decreasing SOD activity after day two, the levels of TBA-reactive material (TBARS) are increased by three-fold in infected guinea pig, liver, compared to uninfected liver. The results indicate that SOD attenuates intracellular superoxide-mediated toxic effects in guinea pigs infected with L. interrogans. In addition, electron microscopy structure demonstrates correlated pathogenic shrinkage of mitochondrial and Kupffer cell structures.

Acute leptospirosis in Europe (Weil's disease) is a rare and in more than 90% of the cases undiagnosed febrile, self-limited disease. We report the case of a 39-year-old sewerage worker, who was admitted to our hospital with fever, jaundice, pain in his calves and acute renal failure. Serology revealed elevated antibody titers against Leptospira canicola, L. icterhaemorrhagica and L. sejroe. The patient developed disseminated intravascular coagulation (DIC) with diffuse gastrointestinal bleeding due to thrombocytopenia. The ECG showed atrial fibrillation with irregularly irregular rhythm. Cardiac arrest developed, most likely due to hypoxia, with a drop in the blood pressure. Despite immediate resuscitation efforts the patient developed severe hypoxic brain damage and died a few days later. Autopsy disclosed histologic signs of a generalized leptospiral infection, signs of shock and within the lungs a necrotizing herpes simplex virus pneumonia causing the death of the patient. The virus pneumonia most probably was caused by retrograde canalicular dissemination of oral secretions since herpetic tracheitis and esophagitis were found and herpetic lesions were readily identified on the lips and tongue. A medical opinion asked for by the professional association having liability for occupational safety and insurance was given, the disease being recognized as an occupational disease.

Objective: To evaluate antimicrobial agents for treatment of models of acute and persistent leptospirosis caused by Leptospira interrogans serovar pomona., Design: Randomized trials comparing dosages and regimens of various antimicrobial agents for treatment of acute and persistent leptospirosis., Animals: 245 Golden hamsters to model acute leptospirosis and 121 mixed-breed swine to model persistent leptospirosis., Procedure: Hamsters and swine were inoculated with L interrogans serovar pomona. Antimicrobial agents were given to hamsters for 3 or 5 days after inoculation, with necropsy at 14 days after inoculation. Swine were treated for 1, 3, or 5 days beginning at 3 weeks after inoculation, and were necropsied 7 to 10 days after completion of antimicrobial agent treatment. Hamster tissue and swine tissue and urine specimens were examined by culture, fluorescent antibody testing, and histologic examination for presence of leptospires., Results: All untreated control hamsters became infected and manifested clinical signs and lesions of acute leptospirosis. Leptospires were not detected in hamsters treated with dihydrostreptomycin/penicillin G (25 mg/kg of body weight). Administration of ampicillin at all dosages reduced the number of hamsters infected, as confirmed at necropsy; the other agents tested required dosages greater than label recommendations to reduce the number infected. All untreated control swine became infected and shed leptospires in urine through the time of necropsy. Leptospires were not detected in kidneys or urine of swine treated with dihydrostreptomycin/penicillin G (25 mg/kg) for 1, 3, or 5 days, or in swine treated with oxytetracycline (40 mg/kg for 3 or 5 days), tylosin (44 mg/kg for 5 days), or erythromycin (25 mg/kg for 5 days). Treatment with ceftiofur and ampicillin was not effective in elimination of L interrogans serovar pomona in swine., Conclusions: Dihydrostreptomycin/penicillin G is effective for treatment of acute and persistent leptospirosis. Differences between the effectiveness of antimicrobial agents in the acute and persistent model of leptospirosis emphasize the importance of using the appropriate model for treatment evaluation. Antimicrobial agents evaluated for treatment of persistent leptospirosis in swine required the use of dosages above those recommended by the manufacturer., Clinical Relevance: Use of antimicrobial agents at extra-label dosages for treatment of persistent leptospirosis may cause residue problems in food animals; however, these regimens may be useful for treatment of breeding stock or animals destined for import/export.

The susceptibility to Leptospira interrogans serovar copenhageni in Mongolian gerbils treated with 10 micrograms of serum thymic factor (FTS) 1 day before infection was examined. Susceptibility of gerbils treated 5 times with 10 micrograms of FTS was also investigated. Mortality of FTS-treated gerbils was significantly lower than that of controls when small challenge doses were used. To analyse the FTS-induced resistance to leptospiral infection, natural killer (NK) cell activity and macrophage activity were studied. Macrophage activity was unaltered but NK cell activity was enhanced in FTS-treated gerbils, with or without leptospiral infection. Since no side-effects of FTS were observed, this compound should be considered for the treatment of leptospirosis.

A case of renal icterohemorrhagic leptospirosis involving a patient with acquired immunodeficiency syndrome (AIDS) is reported. Despite the low levels of CD4+ T lymphocytes, the clinical course of leptospirosis was similar to that observed in non-immunodepressed patients, and no worsening of AIDS occurred due to the infection by the spirochete. Serologic conversion was observed in the microscopic agglutination test, with maximum titer of 1:3,200. The patient had positive urine cultures for Leptospira interrogans for two months, whereas blood cultures were negative.

Human leptospirosis, one of the main urban endemics/epidemics in Brazil, has dramatically grown in the last three decades, especially after floods caused by summer rains. This presentation describes recent changes in the clinical patterns of this pathology in our region, expressed by the emergence of massive haemoptysis and acute respiratory distress syndrome, or both conditions associated. The evident changes in the respiratory structures emerged as a serious life threat and death mechanisms, becoming the main cause of death in leptospirosis among us because of their high incidence. This new face of the disease demands a revision of current concepts about its seriousness and raises speculations about the pathogenesis of such alterations.

Establishing an early and certain diagnosis of leptospirosis has been a difficult task. So, we analysed the histopathological alterations of the gastrocnemius muscle, and studied, for the first time, the usefulness of the immune histochemical method of peroxidase-antiperoxidase for the demonstration of the spirochete and of its products in this tissue. Histopathological observations have shown a picture of myositis, characterized by interstitial inflammatory infiltrate and necrotic-degenerative abnormalities of muscle fibers. The lesions were considered minimal in 69.45% of the patients, moderate in 19.45%, severe in 5.55% and absent in the remaining. On the other hand, the immune histochemical method identified the etiology in 94.45% what was considered very expressive.

To study the pulmonary complications in leptospirosis case records of 23 such patients admitted at the Hospital Universitário Antônio Pedro, Universidade Federal Fluminense, Niterói, Brasil, were reviewed. Hemoptysis were seen in 21.7% and sputal blood in 30.4% of patients. Arterial gasometry detected hypoxemia and hypocapnia in most cases. Thoracic radiology showed an alveolar pattern in 60% of the patients, alveolo-interstitial in 20%, interstitial in 6%, and in 14% the lungs were considered to be normal. Necropsy of 13 cases showed edema, congestion and hemorrhage in the lungs in all cases. Hyaline membrane was found in 30% and fibrin thrombi in 46% of these cases, resulting in a diagnosis of adult respiratory distress syndrome and acute disseminated intravascular coagulation (consumption coagulopathy) in leptospirosis.

The search for leptospiral antigens (L. interrogans serogroup icterohaemorrhagiae) was carried out in 24 guinea pigs experimentally inoculated with 1 ml of culture containing 10(7)-10(8) leprospires and sequentially sacrificed from the first until the 6th day of infection. Semiquantitative analysis of histopathological variables comprising kidney interstitium, tubules and glomeruli was done in 1 micron sections of tissue embedded in glycolmetacrylate. Leptospiral antigen (LAg) and its glycolipoprotein (GLP) expression were detected through PAP in paraffin embedded tissue. The mild interstitial involvement of the kidney, manifested chiefly by oedema and focal interstitial nephritis seen at the 4th day, progressed to tubular damage at the 6th day, characterized by either swelling or cytoplasmic acidophilia of epithelial cells with loss of cell cohesion and sloughing of cells into the tubular lumina. Brush border alterations and mitochondrial changes were observed. Endothelial cell injury was noted in the interstitial vessels. LAg expression was parallel to the kidney changes: small deposits of elongated forms of LAg were detected at the 4th day either within the vascular lumen or free in the interstitium. A rise in the antigen expression was observed at the 5th day when it was seen either around tubules or in their walls. LAg was detected inside the tubular lumina at the 6th day of infection when granular LAg and GLP were abundant. This sequence reproduces the pathway of leptospires in the kidney and the crescent amounts of antigens detected toward the end of the experiment, with antigen concentration in cases of major tissue damage suggesting a direct action of the microorganisms and/or their products in the pathogesis of the lesions.

We report a case of the respiratory distress syndrome occurring in a patient with leptospirosis ictero-haemorrhagica (LIH). The respiratory failure was associated with pulmonary haemorrhage. There was a rapid favourable outcome after treatment with antibiotics and artificial ventilation. The diagnosis of LIH has been confirmed by serological examination. The mechanisms of the pulmonary disorder during the course of LIH were discussed.

Information is lacking on the prevalence and severity of cardiac and striated muscle injury in late leptospirosis, and it is unclear whether patients with one type of myositis are at increased risk of developing another. Therefore, 38 patients with severe, late Weil's disease were evaluated for heart and skeletal muscle involvement: 37% had myositis and 39% had abnormal electrocardiograms (ECGs). First-degree atrioventricular heart block and changes suggestive of acute pericarditis were the most common ECG findings. Two patients had transient pericardial friction rubs, but neither pericardial effusion, shock, nor congestive heart failure occurred. Cardiac involvement was not associated with skeletal muscle injury (P = .35), although both manifestations were correlated with severity of disease. Thus, ECG changes and myositis were prominent features of late Weil's disease but cardiac morbidity was not.

Morphological lesions in parenchimal and mesenchimal structures of liver and kidney were studied in guinea-pigs experimentally infected with Leptospira interrogans serogroup icterohaemorrhagiae in comparison with a group of non-infected guinea-pigs. All specimens were submitted to conventional light microscopy as well as to high resolution light microscopy, in one micrometer sections of tissue embedded in glycolmethacrylate. High resolution light microscopy, applied for the first time in leptospirosis, was proved very useful, since it enabled us to visualize cellular structures in the same slide used for panoramic view. Cell cohesion, brush borders, pynocytotic vesicles and organellae distributions were parameters especially suitable for analysis at this low-cost, highly precise procedure in microscopy.

Infectious toxic shock, acute renal and acute hepatorenal insufficiency are the principal morphoclinical syndromes in malignant forms of icterohemorrhagic leptospirosis. The major complications of acute renal and hepatorenal failure are pyoseptic involvements of the lungs, heart, and pancreas. Direct or indirect signs of the DIC syndrome and intravascular platelet aggregation are characteristic of all the principal clinical syndromes of malignant forms of leptospirosis.

Eight cases of pulmonary involvement were observed in 17 severe cases of ictero-haemorrhagic leptospirosis. Haemoptysis (7 cases) occurred on the 4th day of the infectious syndrome and was associated with other haemorrhagic manifestations in 4 cases. Cough, pain and polypnoea were not constant. Chest X-ray showed diffuse, non-specific changes, such as nodular opacities or infiltrates. Septicaemia was confirmed in all cases with acute renal failure in 7 cases and meningitis in 6 cases. Severe thrombocytopenia was demonstrated in 2 cases. Six patients recovered quickly with regression of the lung changes within 12 days. Two patients died, one of a fulminant haemoptysis related to a disseminated intravascular coagulation syndrome, and the other of acute respiratory failure. All cases were confirmed serologically. Although lung changes in leptospirosis are usually benign and mild, haemoptysis and polypnoea with diffuse radiological changes are poor prognostic factors. The pathological changes were similar to those of haemorrhagic alveolitis. These changes may be either due to the liberation of toxins or to an immunological phenomenon.

In experiments on guinea pigs the pathogenicity of leptospires is manifested by their adhesion to liver cells, colonization of the surface of these cells, accumulation of leptospires in the renal interstice and their colonization of the nephrothelial surface of proximal convoluted tubules in the kidneys, by toxic microcirculatory disturbances, dystrophy and necrosis of nephrothelial cells. Then the primary toxic action of circulating leptospires, microcirculatory disturbances and hemorrhagic syndrome augment during the colonization of the surface of liver cells, accompanied by their dystrophy and dissociation, as well as by jaundice. The accumulation of leptospires in the renal interstice and their subsequent multiplication on the nephrothelium of the proximal convoluted tubules are responsible for the development of interstitial nephritis and necrotic nephrosis. The persistence of lesions in the liver and kidneys, occurring in some cases in spite of elimination of the infective agent from these organs due to increasing antibody production suggests the toxic action of immune complexes.

Human leptospirosis is a subject of increasing interest. Although this disease was frequently associated with individuals whose occupation or geographic location placed them in close proximity to wild animals or farm animals, recent cases have been particularly prevalent in young children and adolescents in urban and suburban America. Many of the recent cases have been acquired from household pets, particularly from dogs or hamsters. In particular, healthy dogs who have been immunized with leptospiral organisms, thereby creating a significant risk for their owners. This article will review the pathophysiology, clincal manifestations, laboratory diagnosis, treatment, and prevention of leptospirosis in the modern era, with particular emphasis on a more complete understanding of the epidemiology of this disorder.

Irradiated hamsters were infected with Leptospira interrogans serovar ballum in order to study the effects of impairment of the reticulo-macrophage system on the progression of the disease and the development of haemoglobinaemia. Infected and irradiated hamsters were compared with infected controls, irradiated controls and untreated controls. Red blood cells (RBCs) from untreated controls were biconcave disks while those from irradiated controls were echinocytes. Red blood cells from animals of both infected groups which were severely affected and moribund were in the form of pitted spherocytes and were associated with increased icteric indices and haemoglobinaemia. Red blood cells from less severely affected animals were echinocytic. Pitted spherocytes, however, were seen in some irradiated-infected hamsters before increased icteric indices and haemoglobinaemia were present. Both irradiated-infected and irradiated hamsters showed severe depletion of haemopoietic cells and lymphoid cells, with regeneration occurring in those animals which survived for longer. Red cell sequestration and erythrophagocytosis were present in infected-only hamsters. In irradiated-infected animals, severe anaemia was caused by both persistence of fixed macrophages, RBC sequestration and erythrophagocytosis, and haemorrhage due to vascular damage and renal papillary necrosis. A severe leucopaenia affected the irradiated hamsters' ability to suppress leptospiral multiplication resulting in the presence of larger numbers of organisms.

Thirty-seven guinea-pigs experimentally infected with a virulent strain of L. icterohaemorrhagiae, were submitted to a renal function study as evaluated through the maximal urinary concentration (MUC) test, blood urea nitrogen (BUN) and afterwards had their kidneys examined by light and electron microscopy. Vascular changes were also studied after the administration of colloidal carbon as a marker. Through the MUC test and BUN determination, two groups of tubulo-interstitial lesions can be visualised, one in animals without renal sufficiency, manifested chiefly by cell edema with RE dilation and another, in animals with renal insufficiency, characterised not only by marked cell edema and mitochondrial changes, but also by proximal tubule regenerative aspects without overt tubular necrosis. Interstitial edema and focal nephritis was prominent in both groups, a finding which minimises their role in the pathogenesis of renal failure in experimental leptospirosis. Vascular injury, affecting the vessels of the renal microcirculation chiefly at the cortico-medular junction, was observed in both groups. Its severity and extension ran parallel to the intensity of the tubular injury. This suggests a simultaneous action of a noxious agent liberated by the leptospires over both structures, tubular damage being accentuated by the local circulatory changes.

Epidemiological and clinical aspects of 50 consecutive patients, 47 adults and three children, hospitalized between 1977 and 1987 for human leptospirosis, were reviewed. 45 (90%) of the patients were from rural regions. 32 (64%) cases occurred in individuals at occupational risk for the infection. 35 (70%) cases were registered in the warm season. The source of infection was known in 34 (68%) cases. Weil's disease was diagnosed in 31 (62%) patients, aseptic meningitis in 12 (24%) and acute unexplained fever in seven (14%). Haemodialysis was required for 11 (35%) patients with Weil's disease. Three (6%) patients died. Cause of death was massive gastrointestinal haemorrhage in two and renal failure in one. Leptospira icterohaemorrhagiae was responsible for 39 (78%) cases, Leptospira canicola for six (12%), Leptospira grippotyphosa for two (4%), and Leptospira australis, Leptospira ballum and Leptospira sejroe, for one case each. A muscle biopsy was performed in six patients and a renal biopsy in three. Focal necrotic muscular changes, with mild mononuclear infiltrate, were found. Pigmented casts in distal convoluted tubules, mild interstitial inflammatory infiltrate and mesangial enlargement of some glomeruli were observed in kidney biopsies. A good knowledge of the protean clinical manifestations of leptospirosis and an accurate laboratory study are required for a correct diagnosis.