Back
to Microbiology Home Page Clinical Leptospirosis in Humans. Copyright S. Faine This text is taken from the book Leptospira and Leptospirosis, published by CRC Press, Boca Raton, Florida USA in 1994. The book is now out of print and the CRC Press have returned the copyright to the author. You may use the material in the text with acknowledgements but you may not reproduce it without permission. The text was revised and updated in September - October 1993. A new edition of the book is planned for some time in 1997. The author thanks Mr. A.C.Stott for his assistance in preparing this chapter for electronic media, and Dr. Ben Adler for encouraging its preparation.
CHAPTER 12
D. Renal symptoms and insufficiency
E. Liver symptoms and jaundice
F. Involvement of the nervous system
G. Respiratory tract involvement
I. Bleeding and hematological changes
J. Ocular manifestations and changes
K. Leptospirosis in pregnancy; fetal and congenital leptospirosis
II. Clinical laboratory observations
Leptospirosis is an acute febrile generalized disease whose manifestations arise from the effects of a general vasculitis. There are many possible clinical presentations and courses. Numerous excellent accounts of leptospirosis have been published over the years.(1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17) The earlier classical accounts emphasized the dramatic severe icteric forms, although leptospirosis without jaundice was recognized early.(2) Most patients were diagnosed late in the illness, after admission to hospital, although some information comes from experimental human infection carried out for fever therapy in an era when that was acceptable, and the only treatment available to offer.(18) None of the presenting features of leptospirosis are specific for that disease, whether of the mild, almost insignificant or the florid, fulminating fatal septicemic type, or any of the infinite grades between them. At the time of onset it is not possible to tell clinically immediately whether it is an attack of the mild or the severe type, nor how severe the final illness will be. Where leptospirosis is common, predictions may be made on clinical suspicion and epidemiological grounds. The large excess of serologically positive people who are not known to have had leptospirosis, in populations where there is a significant incidence of clinical cases, shows that subclinical and inapparent infections are common. Although rarely reported, simultaneous infections with more than one serovar may occur in humans as well as in animals.(19, 20).
The main clinical features will be dealt with individually.
A. Presentation, onset and course
The incubation period may be as short as 2 days, or as long as 30 days. Prolonged incubation periods have been reported. The usual range is 5-14 days. All types of leptospirosis start the same way. The main presenting symptoms, usually present in most cases, are sudden onset of headache, muscle pains and tenderness, and fever, sometimes with rigors, accompanied by nausea with or without vomiting, conjunctival suffusion, a transient skin and mucosal rash and by photophobia and other signs of meningism. The subsequent course depends on the infecting serovar, the numbers of infecting leptospires, the nutrition of the patient and the immediate medical attention sought or available. About 5-15% of those infected with serovars known to cause severe disease (e.g. copenhageni, icterohaemorrhagiae, bataviae) have been reported to develop the severe, icteric typical Weil's disease syndrome, but that figure depends on the proportion of mild cases diagnosed. The mortality rate in severe types of leptospirosis is reported to range from approximately 5-40%. Infections with other serovars which cause milder illness are almost never icteric nor fatal, although the patient's state of health is a factor deciding the outcome. It is clear that the symptoms at onset resemble those of many common other acute febrile illnesses, including influenza, hepatitis and several other acute illnesses of viral origin. In the mild forms, the initial symptoms coincide with the "septicemic" or "leptospiremic" phase of the disease, lasting from one to several days. Muscle pains and concomitant tenderness may be excruciating, and dehydration may exacerbate the vomiting. Fever may reach 38-39°C, but subsides within a week. Leptospires circulate in the blood and can be recovered in cultures of blood, urine and cerebrospinal fluid. Some patients have hypotension and bradycardia. At this stage derangement of function of the kidneys and liver are almost invariable, detectable as transient albuminuria and nitrogen retention. The septicemic phase usually lasts about 4-7 days. The patient then feels better, the temperature subsides and recovery of all organs and functions is usually complete in 3-6 weeks after onset. In more severe forms, the initial illness is prolonged and diphasic. The fever subsides after 4-7 days, followed by 1-3 days of apparent recovery, without fever or fresh symptoms. The fever then recurs, in the so-called "tissue" or "immune phase", rising to 40°C in a "saddle-shaped" fever chart, now accompanied by more severe headaches, rigors and chills, and worsening prostration. The distinction between these phases is often unclear; they merge into a single continuous illness. In addition to generalized pains in the neck, abdomen, and limbs, there are particularly severe muscle pains, especially in the calf muscles, thigh and back, and pain over the tibia, affecting the gait and ability to move. Nose bleeds (epistaxis) and other bleeding tendencies develop. Symptoms and signs of renal and hepatic failure appear, leading to varying degrees of uremia, jaundice and bleeding in the skin and internally. Hemorrhages can occur almost anywhere. Hepatomegaly and splenomegaly are seen uncommonly, (despite their inclusion in Weil's classic account) in about 10% of patients. Protracted vomiting, and either diarrhea or constipation may occur. Symptoms of acute abdominal emergencies, such as cholecystitis and appendicitis may require surgical intervention. Sore throat and dry cough are common, sometimes with bloodstained sputum. In infections with certain serovars, gross hemoptysis (which is otherwise rare) and adult respiratory distress syndrome are seen (see below). Aseptic meningitis may occur at this stage. In some patients mental confusion, hallucination and psychosis complicate the physical illness. Leptospires are no longer found in the blood, but may be excreted transitorily in the urine.
Patients who survive the renal and myocardial failure of severe leptospirosis usually recover completely in 6-12 weeks. In fatal cases death results mainly from severe renal failure, or in those who overcome that, from irreversible myocardial failure. Fatal hemoptysis and respiratory failure have occurred in some recent epidemics, notably with serovar lai.
A transient petechial or punctate red palatal enanthem occurs in the first day or two. The skin is suffused, described as a warm pink in color, early in the illness; the patient may complain of an overall warm sensation. Exanthematous rashes, are recorded in 10-30% of patients in the first week, lasting 1-2 days, sometimes localized to the trunk, shins or elsewhere. The appearance of the rashes is usually either morbilliform but not confluent, or macular or urticarial; they are sometimes itchy. Occasionally the rash may be purpuric and confluent. The pre-tibial rash associated with "pre-tibial" or "Fort Bragg" fever was characteristic of an epidemic of leptospirosis caused by serovar autumnalis.( 21, 22 ) The rashes presumably originate from epithelial vascular damage. Later, in the severe type of leptospirosis, purpuric blotches occur as part of the general hemorrhagic tendency, often associated with jaundice, herpes labialis and epistaxis, at the same time as manifestations of internal bleeding. Capillary fragility is increased, while bleeding, clotting and prothrombin times are often normal.( 6, 12, 13 )
The severe muscle pains of leptospirosis (see above) result from the specific muscle fibre inflammation (Chapter 11). The calf and back muscles particularly are excruciatingly tender to touch.( 6, 13, 23, 24) Arthritis, either in a single joint or as a migrating polyarthritis, has been reported rarely.(25, 26 )
D. Renal symptoms and insufficiency
Although much attention and literature is concerned with the serious, sometimes dramatic kidney lesions and failure in severe leptospirosis, these are symptoms are not prominent in mild leptospirosis, and are frequently not apparent in some patients with severe forms.( 27, 28 ) In the septicemic phase, any or all of red cells, leukocytes or granular casts are found in the urine of most patients. Hemoglobin and pigment casts also occur. There is frequently proteinuria and myoglobinuria. Abnormalities can be detected on urinalysis in 80-90% of patients. When renal failure occurs, as it is seen in patients with the severe type of disease admitted to hospitals, it may occur within 3-4 days of onset. Blood urea and creatinine rise rapidly, with accompanying increases in blood potassium, uric acid and phosphate levels. The functional abnormality is much greater than suggested by histological changes; normal para-amino hippurate clearance and glomerular filtration point to proximal tubular lesions. Blood urea levels may rise to 4000 mg/L (70 mmol/L) or higher. Dehydration may contribute to the high levels. The urine/plasma (U/P) urea and osmolar ratios were sensitive and specific markers of pre-renal azotemia, distinct from renal failure, in a series of jaundiced patients; U/P urea ratios of >7 and U/P osmolar ratios of >1.2 indicated pre-renal azotemia, while lower values were consistent with renal failure.(15 )
Thrombocytopenia is common in some infections.( 29) Intravascular coagulation and hemolysis occur, and serum complement (C'3) is often decreased, while the erythrocyte sedimentation rate and plasma fibrinogen may be increased. In anicteric patients, renal failure may or may not be oliguric and prerenal. Hemorrhage, shock, hypotension, and confusion accompany severe, typical Weil's disease syndrome in icteric patients. Very high levels of blood uric acid and phosphate, and urinary uric acid and creatinine ratios are also found. Oliguria is a striking but uncommon feature. Renal failure, sometimes with oliguria, can be severe in patients with a bilirubin level above 250 mg/L.( 27, 28)
Hemolytic uremia syndrome occurs in rare cases of severe leptospirosis, probably as a result of the action of leptospiral toxins. It is characterized by disseminated intravascular coagulation, thrombocytopenia, bizarre shaped erythrocytes, hemolysis, reticulocytosis and renal failure.
E. Liver symptoms and jaundice
In many patients the liver is enlarged and tender. In icteric patients, jaundice usually appears on days 4-6, up to 9 days after onset. The primary cause of jaundice is hepatocellular damage and disorganisation of liver structure and function (Chapter 11). An additional hemolytic component of jaundice results from an increase in circulating hemoglobin and bilirubin originating in hemolysis and breakdown of erythrocytes in areas of hemorrhage. Serum bilirubin levels may be very high. Serum aminotransferase (AST, aspartate aminotransferase, or GOT, glutamate oxaloacetate transaminase; GGT, gamma glutamyl transpeptidase; and ALT, alaninine aminotransferase or GPT, glutamate pyruvate transaminase) levels are frequently normal, but sometimes raised to 2-3 times normal levels. A raised serum bilirubin level with normal amninotransferases is highly suggestive of leptospirosis rather than hepatitis.
F. Involvement of the nervous system
Sudden severe headache is an almost invariable feature of leptospirosis.
1. Meningism, leptospiral encephalitis, meningitis and neuritis
Neck stiffness may be hard to differentiate from muscle spasm in the early stages. The cerebrospinal fluid (CSF) at this time is usually normal, except for raised pressure. Serous meningitis is the most common form of neurological complication, in the second phase. It may be the presenting symptom and form of leptospirosis for patients seeking hospitalization following an ill defined fever. It is recognized by rigidity and neck stiffness, (Kernig's sign), photophobia, severe headache and vomiting. At first lumbar puncture yields normal CSF, but later the pressure is raised, protein levels rise to 1.0-2.0 g/L and following a transient granulocytosis, the dominant cells are lymphocytes, rising to 0.01-0.2 x 109/L, even as high as 1.5 x 109/L. Glucose and chloride are usually normal. Agglutinating antibodies appear simultaneously with leucocytosis. It may take up to 3 weeks for the symptoms and CSF changes to return to normal.
Occasionally encephalitis may occur, in which the patients may lose memory and hallucinate, be delirious, confused, disorientated, or semi-comatose, or develop extrapyramidal symptoms. Convalescence from meningitis or encephalitis may be prolonged and involve periods of physical, muscular weakness and mental exhaustion for months. Occlusal cerebral vascular disease (cerebral panarteritis) in late serovar pomona infections has been described, affecting mainly the carotid artery. It was suggested that these lesions were responsible for cerebral ischemia and infarcts, especially in children.(30) In Moyamoya syndrome, a net of abnormal cerebral vessels representing collateral vessels bypassing a carotid constriction or blockage, mainly at the base of the brain or in the basal gangliar area can be demonstrated by carotid angiography. Leptospirosis was considered to be the cause of the ischemic variety of this disease.(31) Cerebral edema may arise primarily or as the result of treatment used for the management of renal failure.(32)
Various episodes of localized neuritis or polyneuritis have been reported, but must be relatively rare. In some publications, where the neurological complications occurred months after the initial illness, the diagnosis of leptospirosis was assumed rather than proved.(13, 16, 33, 34 )
2. Confusion, and psychiatric changes
A number of patients suffer prolonged mental symptoms after leptospirosis, ranging from mood changes, irritability and irrational thoughts to dementia, serious psychosis and depression. Inability to concentrate or to carry out skilled tasks may affect employability. The condition may persist for several months to two or more years; it may be permanent. The relationship of such changes to physical effects of leptospirosis, including the cerebral arteritis mentioned above, is not well documented. In order to incriminate leptospirosis as a cause of the mental condition, the initial diagnosis must be proved, and the symptoms date clearly from after the time of recovery from the illness.(35, 38 )
G. Respiratory tract involvement
Recently, respiratory manifestations of leptospirosis have attracted attention relatively frequently. In the mild forms cough and hemoptysis may occur, as a result of alveolar and interstitial hemorrhage. In more severe illness, pulmonary edema and adult respiratory distress syndrome occur; the latter is an important potentially fatal syndrome.(39, 43) Epidemics of leptospirosis in Korea (44, 45) Brazil, and occasionally elsewhere (46) were characterized by massive pulmonary hemorrhages, including fatal sudden hemoptysis, leading to diagnostic confusion with epidemic hemorrhagic fever (Hantaan virus infection). An extreme variety of changes may be seen in chest radiographs.
Cardiomyopathy probably occurs more frequently than recognized, (ca. 40% in one study), but cardiomyositis was independent of skeletal myositis. Most commonly conduction defects and arrhythmias are seen, especially delayed PR conduction (first degree atrioventricular heart block) with low voltages and ST and T wave abnormalities. Among a variety of arrhythmias, atrial fibrillation is common. Transient pericardial friction rubs in the absence of pericardial effusion or uremia also occur. Myocarditis is a cause of death in those whose renal failure can be managed successfully.(13, 24, 25, 47, 49 )
I. Bleeding and hematological changes
Hemorrhages of varying severity frequently occur in any organ or tissue. They may bleed into the lumina of the respiratory, gastro-intestinal, renal and genital tracts, subarachnoid space and adrenals, causing appropriate symptoms and occasional fatal results. Toxic vasculitis is considered to cause the bleeding, but thrombocytopenia occurs in severe cases with renal failure.(29, 50, 51) Hemolysis, leading to hemolytic anemia, may result from phospholipase toxin activity.(52 )Anemia may also result from blood loss by extravasation due to hemorrhage, and uremia.
J. Ocular manifestations and changes
The initial "pink eye" conjunctival suffusion, resembling a conjunctivitis but not of inflammatory origin, is an almost invariable accompaniment of leptospirosis. It is most marked in the palpebral conjunctiva. If jaundice occurs early, it is superimposed on a background of yellowing sclera. Recovery occurs spontaneously in the first week.
Inflammation of the uveal tract, presenting as iritis, iridocyclitis or occasionally chorioretinitis are important but less frequent complications.(13, 53, 54 )Symptoms may develop as early as the second week or as late as a year after infection, when their relationship to a possibly mild or subclinical and undiagnosed leptospiral infection will be hard to determine. The clinical course is variably uveitis, recurrences, or chronic inflammation leading to cataracts and hypopyon in the anterior chamber. Leptospires may be isolated from the aqueous humor.(12 )
K. Leptospirosis in pregnancy; fetal and congenital leptospirosis.
Leptospirosis in pregnancy usually affects the fetus either by its febrile and pathological effects on the mother, or by primary infection of the fetus by invasion of leptospires from the maternal circulation and tissues, via the placenta.(55 ) In the first case, the effects will be nonspecific and may lead to fetal retardation, and placental or fetal ischemia or death. In the second case, the fetus may be infected at any stage of its development. The pathological effects are the same as those in the adult, i.e. vasculitis, hemorrhage, nephritis and liver failure and jaundice. In the first two trimesters, there is no fetal immunity and fetal death from ischemia following hemorrhage, nephritis and placentitis is likely. If the fetus and mother recover, there are not usually any ill effects; otherwise abortion or stillbirth result. In a well documented case of serovar pomona infection in late pregnancy the fetus was born apparently healthy but affected with congenital leptospirosis.(56) In an infection with serovar hardjo hardjobovis in the 37th week of gestation, the fetus died of intrauterine infection, with typical placentitis; leptospires were detected in the tissues, despite antileptospiral IgM antibodies in the cord blood.(57, 58) There are several reports of leptospirosis in pregnancy in humans, but it is essential to ensure that the infection of the fetus itself is proved before accepting that fetal changes or death were due to leptospirosis.(56, 57, 58, 59, 60, 61, 62, 63) In another report, a lactating mother infected her child through breast milk which contained leptospires.(64) (See Chapter 15).
L. Chronic, persistent and late onset leptospirosis.
The subject of persistent leptospirosis has been inadequately documented. Prolonged mental illness and neuropathies may be regarded as persistent sequelae rather than persistent infections. Eye symptoms and headaches may continue for a long time.(65) However, persistent symptomatology begs the question of its relationship to the continuing presence of leptospires in an organ or in tissues. Blood cultures were reportedly positive on the 30th day (66) and 90th day (33) in two patients. Continuing infection and reactivation in an immunologically privileged site in uveitis is discussed above. Prolonged leptospiruria is not a feature of leptospirosis in humans, although renal carriage of leptospires has led to rare examples of human to human transmissions by urine or sexual contact.(67, 68 )Nevertheless, people with low immunity, and perhaps others, may continue to harbour leptospires for long periods, as much as 90 days.(33, 53, 69 )
Leptospirosis is diagnosed less frequently in children than might be expected from their exposure to hazards, possibly due to failure to consider the diagnosis, or to different manifestations in children. In one of the few reports of pediatric leptospirosis, special features of myocarditis and a serious desquamating rash, resembling Kawasaki disease, were recorded.(70) Epidemics of water-borne leptospirosis in children who swam in contaminated streams or pools were characterized by initial gastrointestinal presenting symptoms and a good prognosis.(70a, 70b, 70c )
Serological and specific tests for leptospirosis are dealt with in Chapter 14 and reference 17.
In summary, the erythrocyte sedimentation rate is invariably raised. Erythrocyte count and hemoglobin are usually unchanged in mild cases, unless bleeding develops. In severe cases there is always anemia if the patient is jaundiced, probably due to both the bleeding and hemolysis. There is usually a slight polymorphonuclear (granulocytic) leucocytosis (11-20 x 109/L), sometimes up to 40 x 109, with severe jaundice. Neutrophilia, over 70%, is usual even in mild forms, in contrast to viral hepatitis. Thrombocytopenia at levels of 80-150 x 109/L is common, dropping to much lower (5 x 109/mL) in severe cases.
Nitrogen retention occurs invariably, if transiently, in mild forms. Blood urea levels of 70 mmol/L (4g/L) may be encountered, but dehydration may contribute to these levels. Serum creatinine is also raised. High ratios of U/P urea and osmolarity were consistent with pre-renal azotemia in jaundiced patients (see above).
Serum amylase was raised in 65% of, mostly jaundiced hospitalized patients in one series; it was up to three times normal levels in 23% of them, although pancreatitis was uncommon and renal failure did not account for the raised amylase levels.(15 )
On urinalysis, albuminuria is always present, but sometimes slight and transient in mild cases. Hyaline, granular and cellular casts are commonly seen; red cell casts are not indicative of leptospirosis. Bile pigments in urine reflect jaundice. Oliguria indicates renal failure due to interstitial nephritis.
Leptospirosis presents in so many nonspecific ways that an initial accurate clinical diagnosis is likely only where there is a suitable combination of endemicity, specific diagnosis of similar patients and experience of clinicians. The most frequent mistaken diagnoses are influenza, "viral illness", aseptic meningitis, hepatitis or pyrexia of unknown origin. There are many anecdotes of repeated seasonal epidemics of "influenza" which, in retrospect, were mild forms of leptospirosis. Leptospirosis is highly occupational in some regions (see Chapter 15, 17) particularly in those patients who work in contact with animals or contaminated environments. In selected occupational groups, the diagnosis should be considered early in any patient whose initial clinical diagnosis is suspected but not proved to be influenza, a viral illness, a rickettsiosis (Q fever, typhus), borreliosis, brucellosis, toxoplasmosis, malaria, pyelonephritis or a variety of locally prevalent similar diseases. In patients presenting with meningitis, the alternative diagnoses may be bacterial or viral meningitides, encephalitis or non-paralytic poliomyelitis. Bacterial meningitis is characterized by a more rapid severe clinical meningitic course, granulocytosis and specific agents or antigens in the CSF. Viral meningitides have different courses from leptospirosis, which can be distinguished by its nitrogen retention and proteinuria, bleeding tendencies, history of contact with animals or suspect occupation. Bacteriological, viral and serological laboratory tests confirm the diagnoses. In severe forms, especially if icteric, the patient's illness may resemble viral hepatitis, dengue, epidemic hemorrhagic fever, yellow fever, malaria, or septicemia with jaundice. In viral hepatitis, serum transaminases are much higher than in leptospirosis. Clinically, leptospirosis begins more suddenly and severely, invariably accompanied by conjunctival suffusions, headaches, muscle pains, and proteinuria, and patients develop bleeding manifestations more frequently. Fever continues much longer during jaundice than in hepatitis, when it subsides soon after the onset of icterus.(6,12,13 )
The diagnosis of leptospirosis can be simplified in many instances by referring to a checklist of main clinical and laboratory observations.(12) (Table 8).
Table 8. CHECKLIST FOR THE LIKELIHOOD OF DIAGNOSIS OF LEPTOSPIROSIS IN HUMANS.a
This checklist is designed for the use of those who deal directly with the patient.
To use the list, note the main clinical features listed, mark the box "Yes" or "No", and write the appropriate score in the right-hand column.
A presumptive diagnosis of leptospirosis may be made if:
Part A, or Parts A and B together score 26 or more
or Parts A, B and C total 25 or more
A score between 20 and 25 suggests leptospirosis as a possible but unconfirmed diagnosis.
| Part A. | Score | |
| Has the patient Headache of sudden onset? | Yes=2 | |
| No = 0 | ||
| Fever? | Yes = 2 | |
| No = 0 | ||
| If "Yes" is the temperature 39°C or more? | Yes = 2 | |
| No = 0 | ||
| Conjunctival suffusion (bilateral)? | Yes = 4 | |
| No = 0 | ||
| Meningism? | Yes = 4 | |
| No = 0 | ||
| Muscle pains (especially calf muscles)? | Yes = 4 | |
| No = 0 | ||
| Are all 3 features (conjunctival suffusion, muscle pains and meningism) present together? | Yes = 10 | |
| No = 0 | ||
| Jaundice? | Yes = 1 | |
| No = 0 | ||
| Albuminuria or nitrogen retention? | Yes = 2 | |
| No = 0 | ||
| Total score for Part A: | ||
| Part B. | ||
| Epidemiological factors:Has there been contact with animals at home, work, leisure or in travel,or contact with known (or possibly) contaminated water? | Yes = 10 | |
| No = 0 | ||
| Total score for Part A and B: | ||
| Part C. | ||
| Bacteriological laboratory findings:Isolation of leptospires in culture | Diagnosis certain | |
| Positive serology- leptospirosis endemic: | ||
|
Single positive, low titer |
Yes = 2 | |
| No = 0 | ||
|
Single positive, high titer |
Yes = 10 | |
| No = 0 | ||
|
Paired sera, rising titer |
Yes = 25 | |
| No = 0 | ||
| Positive serology, leptospirosis not endemic: | ||
|
Single positive, low titer |
Yes = 5 | |
| No = 0 | ||
|
Single positive, high titer |
Yes = 15 | |
| No = 0 | ||
| Paired sera, rising titer | Yes = 25 | |
| No = 0 | ||
| Total score (A + B + C) |
aReproduced with permission from Faine, S., ed., Guidelines for the Control of Leptospirosis. WHO Offset Publication No. 67, Geneva, World Health Organisation, 1982.
A. General management and treatment
In the mild forms of leptospirosis management is symptomatic, as indicated by the nature and severity of the manifestations. Bed rest in a darkened room, analgesics, cool sponging and adequate attention to rehydration following vomiting assist with manangement of the fever and the painful early symptoms. Relatives should be warned of the possibilities and consequences of delirium. Bed rest for one to two weeks is required; early ambulation and return to work is said to lead to recrudescence and exacerbation of symptoms. Return to work should be gradual. Recovery is generally complete, although sedatives, antidepressants and hypnotics for disorders of sleep may be required. The severe form of leptospirosis requires intensive-care renal management, including the availability of peritoneal dialysis. Initially, progress is monitored with blood count, serum creatinine and or urea and electrolytes, urinary output volume and fluid balance, with routine hourly, then 4-hourly, measurements of temperature, blood pressure and pulse rate. Liver function tests, serum transaminases, bleeding, clotting and prothrombin times, electrocardiogram, chest X-ray and blood grouping are basic parameters. Intravenous infusions of saline, electrolytes, plasma or blood may be indicated for fluid deficit or hypotension. Restricted dietary fluids and a high carbohydrate, protein free diet are required in mild renal failure. Oliguria due to dehydration or hypotension alone may be corrected and diuresis established by fluid replacement and restoration of blood pressure; diuresis in such cases may be assisted with furosemide in doses up to 500 mg. If oliguria is due to acute renal failure (tubular necrosis, interstitial nephritis) it, and other indications of renal failure, should be treated by peritoneal dialysis without delay, certainly as soon as the blood urea level reaches 35 mmol/L (2000 mg/L). Dialysis support should continue until natural renal function recovers, which it usually will unless the patient succumbs to other lesions.(12, 15, 16 ) Liver failure is treated conventionally by elimination of gut nitrogen, protein free diet and correction of fluid and electrolyte balance, and neomycin, 1 g 4-hourly by mouth. Management of bleeding may require blood transfusion, or platelet transfusion. Steroid therapy has been successful for treating thrombocytopenia.(71) Myocarditis requires appropriate cardiological support.
B. Specific and antibiotic treatment
Leptospires are sensitive to most antibiotics except chloramphenicol. Although there is still some dispute about the value of penicillin therapy, the broad concensus is that it is valuable given as early as possible in infection. Effective antibiotic treatment should be instituted generally within the first 7-10 days after infection, (not 7-10 days after diagnosis, onset of symptoms, or hospitalization), since leptospires are removed from the tissues by natural immune mechanisms after that time. In most studies of hospitalized, jaundiced patients the illness on admission was near or past its tenth day after infection. High doses (6-8 megaunits of benzyl (crystalline) penicillin daily, in divided doses intramuscularly or intravenously, are recommended. Alternatively 4-5 megaunits of equal parts of procaine penicillin and crystalline penicillin are given daily intramuscularly, reducing the dose to half after the fever subsides, for a total of 5-7 days, continuing 1.5 megaunits of procaine penicillin daily until 2 days after albuminuria ceases.(12) In one publication, 10-20 megaunits per day were used routinely. (72) A well controlled study in severe leptospirosis patients using 6 megaunits per day (1.5 megaunits 6 hourly) intravenously showed that the treatment, even if commenced late, was effective in improving all measurable parameters in the patients.(73) A contrary result was obtained in another careful analysis (15) and a short prophylactic course of an unspecified dose of an undefined penicillin preparation failed to protect against a laboratory infection with an Icterohaemorrhagiae serogroup leptospira.(74 ) Despite these negative findings, penicillin as described remains the recommended treatment. Defervescence can be expected within 24hr.(12, 14, 16, 27) Alternative antibiotics for those allergic to penicillin include erythromycin, (250 mg 6-hourly for 5 days). A controlled trial of doxycycline given in 100 mg oral doses twice daily showed that it reduced the severity and duration of illness.(75) Although tetracyclines have been recommended (in doses of 500 mg tetracycline immediately, followed by 250 mg 8-hourly orally, or intramuscularly or intravenously if the patient is vomiting or unable to absorb orally, for 24 hr, then 250-500 mg 6-hourly for 6 days), they cannot be recommended nowadays where alternatives are available. The use of tetracyclines is contraindicated in the presence of renal failure because it is nephrotoxic; likewise they should not be used in pregant women or in children because of their effects on developing teeth and bone.(12, 14, 16) There is little apparent advantage currently in using newer, more expensive and more toxic antibiotics. Jarisch-Herxheimer (JH) reactions may occur following the institution of penicillin therapy. In typical examples, fever rose to 37.8-38.4°C with severe rigors and hypotension, 4-5 h after the institution of intravenous penicillin therapy.(76) The mechanism of the Jarisch-Herxheimer reaction in leptospirosis is not established. Toxins released by lysis of the leptospires by antibiotic may induce cytokines. Treatment with penicillin released limulus lysate active material in some patients, independent of and in the absence of a JH reaction. Management of the JH reaction is supportive and symptomatic; its effects are temporary and should not contraindicate antibiotic therapy.(76, 77 ) There is no place currently for immunotherapy in the treatment of leptospirosis.
Most patients with leptospirosis will recover in 2-6 weeks if not jaundiced, but may not be fit to return to a normal life for a further 4 weeks. The death rate in jaundiced patients may be very low, if penicillin treatment is begun early and if renal and liver failure can be treated successfully. The death rates in recent well-treated and well documented studies were 0.0, 2.5, or 5.7%.(15, 72, 73 )Patients who recover from the severe forms, including renal failure and jaundice, can expect complete recovery. A certain proportion of patients may need support for psychological and mental problems, lasting 1-2 years or more after their illness. Ten per cent or more of patients complain of recurring, persistent headaches and uveitis for some years.(65 )
Patients cannot be reinfected and do not develop a second infection with the same serovar so long as they maintain even a low level of agglutinating antibodies in their serum. There is a dearth of information about reinfection once antibody has fallen below detectable levels. Second infections are usually with a different serovar. There is no evidence for general immunity against all serovars or serogroups of leptospires. Simultaneous infection with more than one serovar has been reported.(12, 14, 16, 19, 78) In concomitant leptospirosis and HIV infection each disease proceeded independently.(79 )
1. Inada, R., Ido, Y., Hoki, R., Kaneko, R., and Ito, H., The etiology, mode of infection, and specific therapy of Weil's disease. (Spirochaetosis icterohaemorrhagica), J. Exp. Med., 23, 377402, (1916).
2. Uhlenhuth, P. and Fromme, W., Untersuchungen über die Aetiologie, Immunität und spezifische Behandlung der Weilschen Krankheit (Icterus infectiosus), Zeitschr. Immunforsch. I. Orig., 25, 317483, (1916).
3. Buchanan, G., Spirochaetal Jaundice. Special Report Series, Medical Research Council, (London), No. 113, (1927).
4. Pettit, A., Contribution a l'Étude des Spirochétidés. 1, III. Spirochaeta icterohaemorrhagiae, Chez l'auteur, Vanves (Seine), (1928).
5. Uhlenhuth, P. and Fromme, W., Weilsche Krankheit, in Handbuch der pathogenen Mikroorganismen, Vol. 7 (i), 3e Auflage ed., Kolle, W., Kraus, R., and Uhlenhuth, P., Eds., G. Fischer, Jena, (1930), 487-660.
6. Austoni, M., Le Leptospirosi, Tipografia del Seminario, Padova, (1953).
7. Broom, J. C., Leptospirosis in tropical countries, Trans. Roy. Soc. Trop. Med. Hyg., 47, 273-291, (1953).
8. Alston, J. M. and Broom, J. C., Leptospirosis in man and animals, E. & S. Livingstone, Edinburgh and London, (1958).
9. Edwards, G. A. and Domm, B. M., Human leptospirosis, Medicine, 39, 117-156, (1960).
10. Turner, L. H., Leptospirosis I, Trans. Roy. Soc. Trop. Med. Hyg., 61, 842-855, (1967).
11. Feigin, R. D. and Anderson, D. C., Human leptospirosis, CRC Crit. Rev. Clin. Lab. Sci., 5, 413-465, (1975.)
12. Faine, S., Guidelines for the the control of leptospirosis, Offset Publication No. 67, World Health Organization, Geneva, (1982).
13. Gsell, O., Leptospirosen, in Klinik der Gegenwart. Handbuch der Praktischen Medizin, Vol. 2, Bock, H. E., Gerok, W., and Hartmann, F., Eds., Urban & Schwarzenberg, München Wien Baltimore, (1983), E122-E146/4.
14. Alexander, A. D., Leptospirosis, in Infectious Diseases, 4th ed., Hoeprich, P., Ed., Lippincot, Boston, (1989), 812-819.
15. Edwards, C. N., Nicholson, G. D., Hassell, T. A., Everard, C. O. R., and Callender, J., Leptospirosis in Barbados. A clinical study, West Ind. Med. J., 39, 27-34, (1990).
16. Brouqui, P., Baranton, G., and Raoult, D., Les Leptospiroses, Encycl. Med. Chirurg., 9, 110, (1990).
17. Faine, S., Leptospirosis. Chapter 65, in Infectious Diseases, 5th ed., Hoeprich, P. D., Jordan, M. C., and Roland, A. R., Eds., Lippincott, Philadelphia, (1994), 619-625.
18. Korthof, G., Experimentelles Schlammfieber beim Menschen, Zentralbl. Bakteriol. Parasitenkd, Abt. I., 125, 429-434, (1932).
19. Wiesmann, E. and Suter, L., Doppelinfektion (Simultaninfektion) mit Leptospira pomona und hyos, Schweiz. Med. Wochenschr., 86, 814-815, (1956).
20. Smith, D. J. W. and Doherty, R. L., Double infection with two serotypes of leptospirae: a case report, Med. J. Aust., 2, 643-648, (1956).
21. Daniels, W. W. and Grennan, H. A., Pretibial fever an obscure disease, J. Amer. Med. Assoc., 122, 361-365, (1943).
22. Gochenour, W. S., Smadel, J. E., Jackson, E. B., Evans, L. B., and Yager, R. H., Leptospiral etiology of Fort Bragg fever, Publ. Hlth. Rep., 67, 811-813, (1952).
23. Solbrig, M. V., Sher, J. H., and Kula, R. W., Rhabdomyolysis in leptospirosis (Weil's disease), J. Infect. Dis., 156, 692-693, (1987).
24. Watt, G., Padre, L. P., Tuazon, M., and Calubaquib, C., Skeletal and cardiac muscle involvement in severe, late leptospirosis, J. Infect. Dis., 162, 266-269, (1990).
25. Sutliff, W. D., Shepard, R., and Dunham, W. B., Acute Leptospira pomona arthritis and myocarditis, Ann. Internal Med., 39, 134-140, (1953).
26. Winter, R. J. D., Richardson, A., Lehner, M. J., and Hoffbrand, B. I., Lung abscess and reactive arthritis: rare complications of leptospirosis, Brit. Med. J., 288, 448-449, (1984).
27. Sitprija, V., Renal involvement in leptospirosis, in Nephrology, Robinson, R. R., Ed., SpringerVerlag, New York, (1984), 1041-1052.
28. Sitprija, V., The kidney in acute tropical disease, in Tropical Nephrology, Kibukamusoke, J. W., Ed., Citforge, Canberra, Australia, (1984), 148-169, chap. 5.
29. Edwards, C. N., Nicholson, G. D., and Everard, C. O. R., Thrombocytopenia in leptospirosis, Am. J. Trop. Med. Hyg., 31, 827-829, (1982).
30. Chen, Y., A clinicopathological analysis of 12 cases of cerebrovascular leptospirosis, Ching Hua Shen Ching Ching Shen Ko Tsa Chih (Chinese J. Neurol. Psychiat., 23, 226-228, (1990).
31. Cheng, M. K., A review of cerebrovascular surgery in the People's Republic of China, Stroke, 13, 249-255, (1982).
32. Davenport, A., Bramley, P. N., and Wyatt, J. I., Morbidity and mortality due to cerebral edema complicating the treatment of severe leptospiral infection, Am. J. Kidney Dis., 16, 160-165, (1990).
33. Raoult, D., Jeandel, P., Rougier, Y., Mailloux, M., and Auger, C., Leptospirose à L. icterohaemorrhagiae avec encéphalite grave et hémoculture positive au 90e jour de la maladie, Méd. Mal. Infect., 12, 292-294, (1982).
34. Estavoyer, J. M., Stimmesse, B., Jacquet, G., and Barale, T., Manifestations encéphalitiques des leptospiroses. A propos d'un cas, Méd. Mal. Infect., 13, 338-340, (1983).
35. Bouman, L., Psychische stoornissen bij de ziekte van Weil, Ned. Tijdschr. Geneeskd., 79, 10-78 (1935).
36. Ram, P. and Karim, I., Severe psychiatric disturbance in leptospirosis, Fiji Med. J., 6, 70-72, (1978).
37. Marshall, R. B. and Scrimgeour, G., Schizophreniform psychosis associated with leptospirosis, New Zealand Med. J., 88, 212-213, (1978).
38. Avery, T. L., Leptospirosis and mental illness, New Zealand Med. J., 96, 589, (1983).
39. Silverstein, C. M., Pulmonary manifestations of leptospirosis, Radiology, 61, 327-334, (1953).
40. Zaltzman, M., Kallembach, J. M., Goss, G. D., Lewis, M., Swi, S., and Gear, J. H. S., Adult respiratory distress syndrome in Leptospira canicola infection, Brit. Med. J., 283, 519-520, (1981).
41. Berendsen, H. H., Rommes, J. H., Hylkema, B. S., Meinesz, A. F., and Sluiter, H., Adult respiratory failure with leptospirosis, Ann. Internal Med., 101, 402, (1984).
42. O'Neil, K. M., Rickman, L. S., and Lazarus, A. A., Pulmonary manifestations of leptospirosis, Rev. Infect. Dis., 13, 705-709, (1991).
43. RiosGonçalves, A. J., Capone, G., Paz, N. A., Paulo, R. V. V., Dias, T. B. C. M., Lago, V. C. C., and Carvalho, L. M. A., Leptospirose. Observaço~es sobre as mudanças dos padro~es clínicos no Rio de Janeiro após a grande epidemia de 1988, Arq. Bras. Med., 64, 389-397, (1990).
44. Shim, Y. H., Shim, B. S., Choe, K. H., Kim, D. S., Shin, K. C., Lee, K. L., Lee, Y. W., Kim, Y. J., Chin, C. J., Lee, J. T., and Chai, I. S., Epidemic pulmonary hemorrhagic fever. I. Epidemiological and clinical observations, J. Korean Med. Ass., 23, 131-144, (1980).
45. Choi, I. J., Kim, T. S., Jin, S. Y., Shin, K. C., Choi, M. R., Coe, K. H., and Shim, Y. H., Acute febrile alveolar hemorrhage. 1. An autopsy proven leptospirosis case, J. Korean Med. Ass., 28, 362-370. Illustrations, (1985).
46. Burke, B. J., Searle, J. F., and Mattingly, D., Leptospirosis presenting with profuse hemoptysis, Brit. Med. J., 2, 982 (1976).
47. Sodeman, W. A. and Killough, J. H., The cardiac manifestations of Weil's disease, Am. J. Trop. Med. Hyg., 31, 479-488, (1951).
48. Ram, P., Mortality in human leptospirosis, Fiji Med. J., 10, 84-86, (1982).
49. De Brito, T., Morais, C. F., Yasuda, P. H., Lancellotti, C. P., HoshinoShimizu, S., Yamashiro, E., and Ferreira Alves, V. A., Cardiovascular involvement in human and experimental leptospirosis: pathologic findings and immunohistochemical detection of leptospiral antigen, Ann. Trop. Med. Parasitol., 81, 207-214, (1987).
50. Edwards, C. N., Nicholson, G. D., Hassell, T. A., Everard, C. O. R., and Callender, J., Thrombocytopenia in leptospirosis: the absence of evidence for disseminated intravascular coagulation, Am. J. Trop. Med. Hyg., 35, 352-354, (1986).
51. Raoult, D., Jeandel, P., Mailloux, M., and Rougier, Y., Thrombocytopenia and renal failure in leptospirosis, Am. J. Trop. Med. Hyg., 32, 1464, (1983).
52. Trowbridge, A. A., Green, J. B., Bonnett, J. D., Shohet, S. B., Ponnappa, B. D., and McCombs, W. B., Hemolytic anemia associated with leptospirosis. Morphologic and lipid studies, Am. J. Clin. Pathol., 76, 493-498, (1981).
53. Gsell, O., Leptospirosen (Mit Anhang Bakteriologischserologische Methodik von E. Wiesmann), Huber, Bern, (1952).
54. Barkay, S. and Garzozi, H., Leptospirosis and uveitis, Ann. Ophthalmol., 16, 164-168, (1984).
55. Topciu, V., Manu, E., Strubert, L., Duma, G., and Levin, S., Voie transplacentaire dans un cas de leptospirose humaine, Gyn. Obst. (Paris), 65, 617-620, (1966).
56. Gsell, H. O., Olafsson, A., Sonnabend, W., Breer, C., and Bachmann, C., Intrauterine Leptospirosis pomona, Dtsch. Med. Wschr., 96, 1263-1268, (1971).
57. Faine, S., Adler, B., Christopher, W., and Valentine, R., Fatal congenital human leptospirosis, Zentralbl. Bakteriol. Mikrobiol. Hyg. Abt. I. Orig. Reihe A., 257, 548, (1984).
58. Faine, S. and Valentine, R., Leptospirosis hardjo in pregnancy, Med. J. Aust., 140, 311-312, (1984).
59. Lindsay, S. and Luke, I. W., Fatal leptospirosis (Weil's disease) in a newborn infant. Case of intrauterine fetal infection with report of an autopsy, J. Pediatr., 34, 90-94, (1949).
60. Chung, H. L., Ts'ao, W. C., Mo, P. S., and Yen, C., Transplacental or congenital infection of leptospirosis. Clinical and experimental observations, Chinese Med. J., 82, 777-782, (1963).
61. Coghlan, J. D. and Bain, A. D., Leptospirosis in human pregnancy followed by death of the foetus, Brit. Med. J., 1, 228-230, (1969).
62. de Silva, K. and Jayaweera, B. A., Leptospiral problems in pregnancy, Ceylon Med. J., 15, 96-103, (1970).
63. Ram, P. and Schramm, M., Leptospirosis and pregnancy, Fiji Med. J., 9, 160-162, (1981).
64. Bolin, C. A. and Koellner, P., Humantohuman transmission of Leptospira interrogans by milk, J. Infect. Dis., 158, 246-247, (1988).
65. Shpilberg, O., Shaked, Y., Maier, M. K., Maier, M. K., Samra, D., and Samra, Y., Longterm followup after leptospirosis, Southern Med. J., 83, 405-407, (1990).
66. Raoult, D., Jeandel, P., Rougier, Y., Auger, C., and Mailloux, M., Hémocultures tardivement positives dans les leptospiroses, Presse Méd., 12, 1727-1728, (1983).
67. Spinu, I., Topciu, V., Trinh, T. H. Q., and Vo, V. H., L'homme comme réservoir de virus dans une épidémie de leptospirose survenue dans la jungle, Arch. Roum. Path. Exp. Microbiol., 22, 1081-1100, (1963).
68. Szalka, A. and Binder, L., Leptospirosis emberrol emberre terjedo ritka esete (Sexual transmission of leptospirosis), Orv. Het., 115, 1531-1532, (1974).
69. Murgatroyd, F., Chronic meningitis in Weil's disease, Brit. Med. J., 1, 711, 1937.70. Wong, M. L., Kaplan, S., Dunkle, L. M., Stechenberg, B. W., and Feigin, R. D., Leptospirosis: a childhood disease, J. Pediatr., 90, 532-537, (1977).
70. Wong, M. L., Kaplan, S., Dunkle, L. M., Stechenberg, B. W., and Feigin, R. D., Leptospirosis: a childhood disease, J. Pediatr., 90, 532-537, (1977).
70a. Sasaki, D. M., Pang, L., Minette, H. P., Wakida, C. K., Fujimoto, W. J., Manea, S. J., Kunioka, R., and Middleton, C. R., Active surveillance and risk factors for leptospirosis in Hawaii, Am. J. Trop. Med. Hyg., 48, 35-43, (1993).
70b. Katz, A. R., Manea, S. J., and Sasaki, D. M., Leptospirosis on Kauai: investigation of a common source waterborne outbreak, Am. J. Public Health, 81, 1310-1312, (1991).
70c. Jackson, L. A., Kaufmann, A. F., Adams, W. G., Phelps, M. B., Andreasen, C., Langkop, C. W., Francis, B. J., and Wenger JD, Outbreak of leptospirosis associated with swimming, Pediatr. Infect. Dis. J., 12, 48-54, (1993).
71. Kahn, J. B., A case of Weil's disease requiring steroid therapy for thrombocytopenia and bleeding, Am. J. Trop. Med. Hyg., 31, 12131215, (1982).
72. Gendron, Y., Prieur, J., Gaufroy, X., and Gras, C., Leptospirosis in French Polynesia: 120 case reports (Translated from French), Med. Trop., 52, 2127, (1992).
73. Watt, G., Padre, L. P., Tuazon, M. L., Calubaquib, C., Santiago, E., Ranoa, C. P., and Laughlin, L. W., Placebocontrolled trial of intravenous penicillin for severe and late leptospirosis, Lancet, 1, 433435, (1988).
74. Gilks, C. F., Lambert, H. F., Broughton, E. S., and Baker, C. C., Failure of penicillin prophylaxis in laboratory acquired leptospirosis, Postgrad. Med. J., 64, 236238, (1988).
75. McClain, J. B. L., Ballou, W. R., Harrison, S. M., and Steinweg, D. L., Doxycycline therapy for leptospirosis, Ann. Internal Med., 100, 696698, (1984).
76. Friedland, J. S. and Warrell, D. A., The JarischHerxheimer reaction in leptospirosis: possible pathogenesis and review, Rev. Infect. Dis., 13, 207210, (1991).
77. Watt, G., Padre.LP, Tuazon, M., and Calubaquib, C., Limulus lysate positivity and Herxheimerlike reactions in leptospirosis: a placebocontrolled study, J. Infect. Dis., 162, 564567, (1990).
78. Doherty, R. L., A second infection with leptospirosis, Med. J. Aust., 1, 5960, (1956).
79. da Silva, M. V., Batista, L., Camargo, E. D., Leitao, P. A., Szalkay, V. G., Rosenthal, C., Vaz, A. J., and de Souza, A. M., Leptospirose em doentes com anticorpos anti-HIV: relato de dois casos, (Leptospirosis in patients with anti-HIV antibodies: report of 2 cases), Rev. Soc. Bras. Med. Trop., 23, 229-231, (1990).
Back
to Microbiology Home Page
Copyright © Monash University 1995,1996 - All Rights
Reserved - Caution
Maintained by A.C.Stott (Mr.)
tony.stott@med.monash.edu.au
Last updated : October 30, 1997