| disease | Leptospirosis |
| alias | Leptospirosis, Leptospinosis |
Leptospirosis (commonly known as hook body disease) is an acute infectious disease caused by various types of pathogenic Leptospira. It is a zoonotic disease transmitted through contact with infected wild animals or livestock, where the bacteria enter the human body via exposed skin. Rodents and pigs are the primary sources of infection. Clinical manifestations vary in severity depending on individual immune levels and the infecting strain. Typical cases present with sudden onset, early symptoms including high fever, fatigue, generalized muscle pain, conjunctival congestion, calf muscle tenderness, and superficial lymph node enlargement. The intermediate stage (second stage) may be accompanied by diffuse pulmonary hemorrhage, significant liver and kidney damage, and central nervous system impairment. In the advanced stage, most patients recover, while a few may experience post-fever complications such as uveitis and cerebral arteritis. Diffuse pulmonary hemorrhage, liver failure, and kidney failure are often the main causes of death.
bubble_chart Epidemiology
This disease is widespread throughout the world, with more severe prevalence in tropical and subtropical regions. It has been detected in all 31 provinces (including Taiwan), municipalities, and autonomous regions of China, particularly in the southwestern and southern provinces.
(1) Source of pestilence
Rats and pigs are the two main sources of pestilence. Their carrier rates, distribution of bacterial populations, and roles in pestilence vary by region. Among domestic rodents, species such as the striped field mouse, yellow-haired rat, and yellow-breasted rat have higher carrier rates and host more bacterial populations. Among livestock, pigs play a significant role as host animals because the bacterial populations they carry are identical to those prevalent in humans, and they meet all the conditions of a major pestilence source: ① wide distribution and large numbers; ② close contact with humans, as pig urine can contaminate various water sources in residential areas; ③ high carrier rates and prolonged bacterial shedding (over 370 days); ④ large urine volume with high quantities of leptospires; ⑤ pigsties are generally damp and watery, harboring large numbers of leptospires in the soil and stagnant water. Additionally, dogs, cattle, and others are also important sources of pestilence. Recent serological studies suggest that animals such as snakes, chickens, ducks, geese, frogs, and rabbits may serve as reservoir hosts for leptospires.
The urine of leptospirosis patients can shed bacteria for up to six months, but because the urine is acidic, it is often unsuitable for leptospiral growth. Moreover, asymptomatic infections can result in healthy carriers, but due to low and irregular bacterial shedding, the role of humans as a pestilence source is often overlooked. However, in Vietnam, an outbreak of leptospirosis was traced back to humans as the possible source. Among 66 convalescent patients, 12.1% shed bacteria (urine pH 6.2–7.2), and carriers urinated indiscriminately, contaminating surface water, leading to potential human infection.(2) Transmission routes
1. Contact transmission: Leptospires can persist long-term in wild animals, transmitting to livestock and then to humans, or from livestock back to wild animals and then to humans, creating a continuous cycle. The contaminated urine of rats and pigs pollutes the external environment (water and soil, etc.), and frequent contact with contaminated water or soil allows leptospires to enter the body through broken skin. Prolonged and repeated exposure to contaminated water or soil, especially in alkaline environments with temperatures above 22°C, facilitates leptospiral growth, increasing the likelihood of infection.
2. Transmission via nasal mucosa or digestive tract mucosa: Mucous membranes, including those of the digestive, respiratory, and reproductive systems, are easy entry points for leptospires. Drinking large amounts of water dilutes gastric acid, and consuming food contaminated with rodent or pig urine or untreated food increases the risk of leptospiral invasion through the digestive tract mucosa.
3. Others: Leptospires have been isolated from amniotic fluid, placenta, umbilical bleeding, breast milk, and the liver and kidney tissues of late-aborted fetuses, indicating possible transmission through breastfeeding or congenital infection. However, infection through patient urine is rare. Blood-sucking arthropods like ticks and mites may also transmit the bacteria through bites.
The general population is universally susceptible to this disease. Those frequently exposed to contaminated water, such as farmers, fishermen, sewer workers, slaughterhouse workers, and animal handlers, have higher incidence rates. Individuals entering endemic areas from outside, lacking immunity, are often more susceptible than locals. Recovery confers strong homologous immunity. Sporadic cases occur year-round in warmer regions, slaughterhouses, and mining areas.
(4) Epidemiological characteristics
1. The majority of cases occur among young adult farmers (those engaged in herding and fishing also have high incidence rates). Rural children are not uncommon, with the highest age distribution between 10–39 years, and males accounting for over 80%.
2. The peak season is July to September, with the highest incidence in August and September, earning it names like "threshing yellow" or "rice epidemic disease."
3. Epidemic Forms Based on the epidemiological characteristics of leptospirosis in China, it can be roughly divided into four main types: ① Rain Water (2nd solar term) type: During continuous rainfall, water accumulates inside and outside villages, and the excrement of infected animals overflows, contaminating the environment; ② Paddy field type: Rodents are the primary source of pestilence in paddy fields. They steal rice grains and urinate in the fields, leading to farmers' infection through contact with contaminated water; ③ Flood type: When floods occur, livestock pens, toilets, and other places containing leptospira are inundated, polluting the water. This often results in outbreaks, with pigs being the main source of pestilence; ④ Sporadic type: Due to the wide variety and distribution of leptospira-carrying animals, many places can be contaminated. People may contract the disease through contact with contaminated materials during labor or daily life. There is usually no clear exposure history, and the clinical manifestations are complex, often leading to misdiagnosis.
The pathogen of this disease is Leptospira. Leptospira appears as slender, filamentous, cylindrical, and finely coiled with 12–18 regular and tight spirals, resembling an unextended watch spring. One or both ends of the leptospira are curved into a hook shape, giving the bacterium a C or S form. The length of the bacterium varies, generally ranging from 4 to 20 μm, with an average of 6–10 μm, and a diameter averaging 0.1–0.2 μm. Leptospira exhibits vigorous motility, rotating along its long axis. The central part of the bacterium is relatively rigid, while the ends are flexible, conferring strong penetrating ability.
Leptospira is Gram-negative. Under dark-field microscopy, bright, motile spirochetes are easily observed. Electron microscopy reveals that the structure of Leptospira primarily consists of an outer membrane, flagella (also called axial filaments), and a cylindrical protoplasmic body (cylindrical bacterial body). Leptospira is an aerobic bacterium with modest nutritional requirements and grows well in commonly used Korthof medium. The optimal incubation temperature is 25–30°C. Leptospira is highly sensitive to desiccation, dying within minutes in dry conditions, and is easily inactivated by dilute hydrochloric acid, 70% alcohol, bleaching powder, Lysol, phenol, soapy water, and 0.5% mercuric chloride. Leptospira has weak resistance to physicochemical factors, such as ultraviolet light and heat (50–55°C for 30 minutes), which can kill it.
According to statistics from the International Society for Microbiology in 1986, there are 23 serogroups and 200 serovars of Leptospira identified worldwide. In China, 19 serogroups and 161 serovars have been documented, making it the country with the highest number of identified serovars globally. The most common serovars in China include 13 serogroups and 15 serotypes (Table 11-48). Different types of Leptospira vary in their virulence and pathogenicity to humans. Certain pathogenic serovars can produce metabolic products such as endotoxin-like substances, cytotoxic factors, cytopathic substances, and hemolysins both in vitro and especially in vivo.
Table 11-48 Standard Strains of 13 Serogroups and 15 Serotypes of Leptospira in China
| Serogroup | serogroup | Serotype | serotype |
| Jaundice Hemorrhage | (L. icterohemorrhagie) | Lai | (L. lai) |
| Java | (L. javania) | Java | (L. java-5) |
| Canicola | (L. canicola) | Canicola | (L. canicola) |
| Ballum | (L. ballom) | Ballum | (L. ballom) |
| Pyrogenes | (L. pyrogenes) | Pyrogenes | (L. pyrogenes) |
| Manhao | (L. manhao) | Manhao | (L.manhaoⅡ) |
| Autumn | (L.autumnalis) | Autumn | (L.autumnalis) |
| Australia | (L.australis) | Australia | (L.australis) |
| Pomona | (L.pomona) | Pomona | (L.pomona) |
| Influenza cold-damage disease | (L.grippotyphosa) | Influenza cold-damage disease | (L.grippotyphosa) |
| Seven-day fever | (L.hebdomadis) | Seven-day fever | (L.hebdomadis) |
| Alf | (L.hebdomadis w olffi) | ||
| Hemolysis | (L.hemolytica) | ||
| Batavia | (L.batavia) | Bashzan | (L.batavia) |
| Tarassov | (L.tarassovi) | Tarassov | (L.tarassovi) |
1. Routes of invasion, in vivo replication, and systemic infection-toxicity symptoms Leptospira invades the human body through skin breaks or various mucous membranes such as the oral cavity, nasal passages, intestines, and conjunctiva. It then travels via lymphatic vessels or small blood vessels to the bloodstream and various organs (including cerebrospinal fluid and the eyes), rapidly multiplying and causing bacteremia. Due to its unique spiral motility and secretion of hyaluronidase, Leptospira exhibits strong penetrating ability, leading to severe infection-toxicity symptoms within the first week of onset, as well as lesions in the liver, kidneys, lungs, muscles, and central nervous system. The pathological basis is systemic capillary injury. In mild cases, there is often no obvious visceral organ injury, with minor pathological changes, while infection-toxicity-induced microvascular dysfunction is more pronounced. Electron microscopy reveals widespread mitochondrial swelling, reduced cristae, decreased glycogen, and increased lysosomes.
2. Visceral organ damage The severity of organ damage varies depending on the Leptospira strain, virulence, and the host's immune response. Leptospirosis presents with complex and diverse manifestations, with varying degrees of pathology. Clinically, different clinical types may emerge due to the predominance of lesions in specific organs, such as pulmonary diffuse hemorrhage type, jaundice-hemorrhage type, renal failure type, and meningoencephalitis type.
3. Mid-late stage [third stage] nonspecific and specific immune responses The human body's initial response to Leptospira invasion is characterized by an increase in blood neutrophils, but without significant leukocyte infiltration or suppuration, only mild inflammatory reactions. Reticuloendothelial cell hyperplasia is prominent, with strong phagocytic activity. Swelling of inguinal and other superficial lymph nodes may occur. These are all nonspecific responses.
Around 1 week after onset, specific antibodies begin to appear, with IgM emerging first, followed by IgG, peaking at about 1 month into the course of the disease. As antibodies appear, leptospiremia gradually subsides. Leptospira in the kidneys is unaffected by specific antibodies in the blood and can survive, multiply, and often be excreted in urine. When the immune response occurs and the pathogen decreases or disappears from the body, some patients may experience post-fever, ocular, or neurological sequelae, which may be related to hypersensitivity reactions or to Leptospira itself (some consider it residual infection).
bubble_chart Pathological Changes
Pathological Anatomy Under general circumstances, infections by more virulent leptospira serotypes such as the jaundice hemorrhagic type, autumn type, Australian type, and canine type often lead to jaundice, hemorrhage, and renal failure. In contrast, infections by less virulent types like the cold-damage disease influenza type, 7-day fever type, and particularly the Pomona type typically result in milder forms of leptospirosis. However, the severity of the condition may be related to the individual's immune status.
1. **Lungs** The primary pathological changes in the lungs are hemorrhages, with diffuse hemorrhage being the most prominent. This represents a systemic intense reaction to highly virulent and numerous leptospira, sometimes resembling a hypersensitivity reaction. The initial site of diffuse pulmonary hemorrhage is the capillaries, starting as small punctate hemorrhages that gradually expand, merge into patches, or form masses. Histological examination reveals intact pulmonary capillaries with extreme congestion, stasis, and extravasation (without obvious vascular rupture). The bronchial lumens and alveoli are filled with red blood cells, and some alveoli contain air, occasionally with minor serous exudation. Pulmonary edema is rare. Hemorrhages are diffusely distributed, often beneath the pleura. Ultrastructural studies show that most alveolar capillary microstructures remain clear, with occasional dendritic protrusions of endothelial cytoplasm; some mitochondria are swollen, vacuolated, and lose cristae. Degenerated leptospira may occasionally be seen within degenerated endothelial cells, and red blood cells may extrude between capillary endothelial cells. The lungs weigh 1–2 times more than normal and appear purplish-black. The cut surface is dark red, oozing dark red or foamy bloody fluid, with the trachea and bronchi almost entirely filled with blood.
When large amounts of blood accumulate in the lungs, prolonged hypoxia of the vascular wall occurs. If combined with cardiopulmonary dysfunction, this further promotes the progression of diffuse pulmonary hemorrhage.
2. **Kidneys** The renal lesions in leptospirosis primarily involve degeneration and necrosis of renal tubular epithelial cells. Some renal tubular basement membranes rupture, and the tubular lumens expand, filling with blood cells or hyaline casts, which may obstruct the lumen. Renal biopsies in many leptospirosis patients reveal interstitial nephritis, suggesting that interstitial glomerulonephritis is a fundamental pathological change. Electron microscopy shows no alterations in glomerular endothelial cells but reveals immune complexes and complement deposits on the glomerular basement membrane. The renal interstitium exhibits edema, with infiltration by monocytes, lymphocytes, and a few eosinophils and neutrophils. Small hemorrhagic foci may be seen in some cases. Leptospira can often be found in renal tissues. Glomerular lesions are generally mild, though intracapsular hemorrhage and cloudy swelling of epithelial cells may occasionally occur.
3. **Liver** The extent of liver injury varies, with longer disease duration correlating with more severe damage. In mild cases, the liver appears grossly normal, but microscopy reveals grade I interstitial edema, vascular congestion, and scattered focal necrosis. Severe cases present with jaundice, hemorrhage, or even hepatic failure. Microscopically, hepatocytes show degeneration, fatty changes, necrosis, and severe disarray. Electron microscopy reveals swelling of hepatic sinusoids or microvilli of bile canaliculi, leading to luminal occlusion. Hepatocyte mitochondria are swollen with loss of cristae. Hepatocytes exhibit separation, and leptospira may be found in the separated spaces.
Jaundice in this disease may result from hepatic inflammation, necrosis, bile canalicular obstruction, and hemolysis, among other factors. Due to these causes and the resulting coagulation dysfunction, severe jaundice, hemorrhage, and even acute hepatic failure may occur clinically.
4. **Heart** Myocardial damage is often a significant pathological feature of leptospirosis. The pericardium may show scattered hemorrhagic spots and focal necrosis, with interstitial inflammation and edema. Myocardial fibers generally exhibit cloudy swelling, and some cases display focal myocardial necrosis and myofibril lysis. Electron microscopy reveals swollen, vacuolated mitochondria with loss of cristae, blurred and fragmented myofilaments, and disappearance of intercalated discs. Vascular injury primarily manifests as systemic capillary damage.
5. **Other Organs**
The brain membrane and brain parenchyma may exhibit vascular damage and inflammatory infiltration. Subdural or subarachnoid hemorrhages are often observed, along with encephalitis, cerebral infarction, and brain atrophy. Microscopically, lymphocyte infiltration can be seen in the white matter of the brain and spinal cord.
In addition to hemorrhage, most cases of adrenal lesions show a reduction or disappearance of cortical lipids. There are focal or diffuse inflammatory infiltrates in the cortex and medulla.
Skeletal muscles, especially the gastrocnemius, exhibit swelling, loss of striations, and hemorrhage. There are vacuoles and fusion in the sarcoplasm, leading to residual fine granules or complete disappearance of sarcoplasm and myofibrils, resulting in lytic necrosis with only the muscle membrane outline remaining. Hemorrhage and leptospira can be observed in the muscle interstitium. Under electron microscopy, the myofilament structure is clear, and mitochondria appear swollen.
bubble_chart Clinical Manifestations
The incubation period ranges from 2 to 20 days, generally 7 to 12 days. The clinical manifestations can be directly influenced by differences in the immune levels of the infected individuals and the variations in the infecting strains. Edward and Domm classified leptospirosis into the initial stage [first stage] (i.e., the septicemic phase) and the intermediate stage [second stage] (i.e., the immune reaction phase). Domestically, Dr. Cao divided the progression of the disease into the early stage, intermediate stage [second stage], and advanced stage. This staging is of significant importance in guiding clinical practice, particularly in early diagnosis and treatment:
(1) Early Stage (Leptospiremic Phase) This phase typically occurs within the first 3 days of onset, with the following prominent manifestations:
1. Fever Most patients experience an abrupt onset, accompanied by fear of cold and shivering. Body temperature can rapidly rise to around 39°C. Remittent fever is common, though sustained or intermittent fever may also occur in some cases.
2. Headache Headache is particularly notable, along with generalized myalgia, especially in the gastrocnemius, neck, back, thigh, and chest/abdominal muscles.
3. Generalized lack of strength Weakness in the legs is especially pronounced, making it difficult to walk during seasonal epidemics, and patients may be unable to leave their beds.
4. Conjunctival membrane congestion Two distinctive features are observed: no discharge, pain, or photophobia; and persistent congestion that remains even after fever subsides.
5. Tenderness in the gastrocnemius muscle This may be bilateral or unilateral, varying in severity. Mild cases present only with calf distension and grade I pain upon pressure, while severe cases involve intense pain, inability to walk, and refusal to be touched.
6. Generalized superficial lymphadenopathy This can appear early in the disease, commonly affecting the inguinal and axillary lymph nodes. The nodes are typically the size of soybeans or broad beans, tender but without signs of inflammation or suppuration.
This phase may also present with digestive symptoms such as nausea, vomiting, anorexia, and diarrhea; respiratory symptoms like sore throat, cough, pharyngeal congestion, and tonsillar swelling. Some patients may exhibit hepatosplenomegaly or a bleeding tendency. A very small number may display toxic psychiatric symptoms.
(2) Intermediate Stage [Second Stage] (Organ Injury Phase) Occurring approximately 3 to 14 days after onset, this phase follows the early septicemic infection and manifests as organ injury, such as hemoptysis, diffuse pulmonary hemorrhage, jaundice, widespread bleeding in the skin and mucous membranes, proteinuria, hematuria, cast formation, renal insufficiency, and meningoencephalitis.
The clinical manifestations during this phase are the primary basis for classifying the disease into pulmonary hemorrhage type, jaundice-hemorrhage type, renal type, and meningoencephalitis type.
1. Influenza cold-damage disease type Most patients exhibit systemic symptoms, including abrupt onset, chills, fever (38–39°C), headache, conjunctival membrane congestion, and prominent myalgia, especially in the gastrocnemius. Additional symptoms include stuffy nose, sore throat, and cough. The clinical presentation resembles epidemic common cold, upper respiratory infection, or cold-damage disease. There is no jaundice or central nervous system involvement, cerebrospinal fluid is normal, and the lungs show no significant lesions. This represents a continuation of early leptospiremic symptoms. The natural course lasts 5–10 days. In rare severe cases, bleeding may occur in the digestive tract, skin, or vagina. Some severe cases are dominated by gastrointestinal symptoms such as nausea, vomiting, and diarrhea, possibly accompanied by hypotension or shock.
2. Pulmonary hemorrhage type Building upon leptospiremia, this type presents with cough, bloody sputum, or hemoptysis. Based on the extent and severity of lesions on chest X-rays and cardiopulmonary function, it can be clinically classified into ordinary pulmonary hemorrhage type and diffuse pulmonary hemorrhage type.
(1) Ordinary pulmonary hemorrhage type: Clinically similar to leptospiremia, accompanied by varying degrees of hemoptysis or bloody sputum. Chest signs are minimal, and X-rays show grade I pulmonary lesions (increased lung markings). If treatment is deficient, it may progress to diffuse pulmonary hemorrhage type.
(2) Diffuse pulmonary hemorrhage type (massive pulmonary hemorrhage type): After the invasion of Leptospira into the human body, following the incubation period and a brief early infection phase, within 2-3 days, sudden onset of facial pallor occurs, followed by increased heart rate and respiration, flusteredness, dysphoria, and ultimately progressing to circulatory and respiratory failure. Both lungs are filled with moist rales, hemoptysis progressively worsens, but may also be absent. The primary manifestation is extensive internal pulmonary hemorrhage, which has become a common cause of death in recent years among non-jaundice type leptospirosis cases. X-ray imaging reveals widespread diffuse patchy softening shadows in both lungs. At the terminal stage, a large amount of fresh blood gushes from the mouth and nose until death. If penicillin and hydrocortisone treatment is administered promptly, most patients can experience a turnaround, with subjective symptoms improving within 3-5 days and signs rapidly alleviating. Pulmonary lesions often completely resolve within 2-4 days. According to research by West China University of Medical Sciences on this type, it is believed to result from the body's hypersensitivity reaction to the pathogen and its toxic substances. The reasons are: ① Clinically, the onset is sudden, recovery is rapid, and pulmonary lesions disappear quickly without vascular rupture, suggesting that massive hemorrhage is a severe consequence of congestion, static blood, and hemorrhage; ② Hormone therapy is highly effective; ③ The coagulation mechanism remains normal, with no DIC phenomenon, and anticoagulation therapy is unnecessary.
This type can also be divided into the following late stage [third stage], but the late stage [third stage] is not distinctly separated. ①Prodromal stage: The patient's complexion is pale (occasionally flushed), with flusteredness and dysphoria. Respiration and heart rate progressively increase, rales gradually appear in the lungs, and there may be bloody sputum or hemoptysis. Chest X-rays show increased markings, scattered patchy shadows, or small areas of fusion. ②Hemorrhagic stage: If not treated promptly, the complexion may rapidly turn extremely pale or grayish-blue, with cyanosis of the lips, worsening flusteredness and dysphoria. Respiration and heart rate significantly accelerate, the first heart sound weakens or becomes galloping, bilateral lung rales gradually increase, and hemoptysis persists. Chest X-rays show expanding patchy shadows and large areas of fusion. ③Critical stage: If the above symptoms are not effectively controlled, the patient's condition may rapidly deteriorate within a short period (approximately 1–3 hours), progressing from dysphoria to unconsciousness. There may be gurgling sounds in the throat, irregular breathing, extreme cyanosis, and continuous gushing of bright red blood (foamy) from the mouth and nose. Heart rate slows, and eventually, breathing stops.
3. Jaundice-hemorrhagic type: Originally referred to as external ear diseases, it is mostly caused by Leptospira serotype jaundice-hemorrhagic. Clinically characterized by jaundice and hemorrhage, it has a high fatality rate. This type can be divided into three stages: septicemia stage, jaundice stage, and stage of convalescence. Jaundice appears 3–7 days after the onset of illness, with 80% of cases exhibiting varying degrees of hemorrhagic symptoms, such as epistaxis, petechiae and ecchymoses on the skin and mucous membranes, hemoptysis, hematuria, vaginal bleeding, and hematemesis. In severe cases, gastrointestinal bleeding may lead to shock and death. A few patients may experience massive pulmonary hemorrhage during the peak of jaundice, though it is less acute and severe compared to the non-jaundice type. Liver and kidney damage are predominant in this type, with hyperbilirubinemia (total bilirubin typically exceeding five times the normal level), while AST rarely exceeds five times the normal level. The kidneys are affected in 70–80% of cases, with varying severity—mild cases show proteinuria, hematuria, a few white blood cells, and casts, which usually normalize within about 10 days. Severe cases may develop renal insufficiency, oliguria or anuria, acidosis, uremic unconsciousness, or even death. Renal failure is a common cause of death in the jaundice-hemorrhagic type, accounting for about 60–70% of fatalities. Additionally, 20–30% of cases may exhibit meningeal irritation symptoms.
4. Renal failure type: Clinically characterized by prominent kidney damage, presenting as proteinuria, hematuria, casts, oliguria, or anuria, along with varying degrees of azotemia and acidosis. Azotemia typically begins on the third day of illness, peaks at 7–9 days, and normalizes after three weeks. This type lacks jaundice, making it distinguishable from renal failure in the jaundice-hemorrhagic type. Severe cases may die from renal failure.
5. Meningoencephalitis type: Among sporadic cases of aseptic meningitis, leptospiral meningoencephalitis accounts for about 5–13%. Clinically, it is characterized by encephalitis or meningeal symptoms, including severe headache, generalized pain, vomiting, calf muscle pain, diarrhea, dysphoria, confusion, neck stiffness, and positive Kernig’s sign. Before the immune phase, cerebrospinal fluid cell counts may not be elevated, generally ranging from 10 to a few hundred/mm3, occasionally reaching 1,000/mm3. Protein reactions are weakly positive, while glucose and chloride levels are usually normal. Clinically, it resembles aseptic meningitis.
(3) Stage of convalescence or post-symptomatic phase: After fever subsides, symptoms gradually resolve. However, a few patients may experience fever recurrence days to three months later, accompanied by symptoms, known as post-symptoms.
1. Post-fever: Fever reappears 1–5 days after the first fever subsides, typically at 38–38.5°C. Half of the patients exhibit elevated peripheral blood eosinophils. Regardless of treatment, the fever resolves within 1–3 days. In rare cases, a third fever may occur (around day 18 of illness), subsiding naturally within 3–5 days.
2.Post-Leptospirosis Ocular Complications More common in the north, possibly related to the Pomona serotype. Often occurs 1 week to 1 month after illness, with uveitis, iridocyclitis, and choroiditis being the most frequent manifestations. Episcleritis, retrobulbar optic neuritis, and vitreous opacity may also occur.
3. Neurological sequelae
(1) Reactive meningoencephalitis A small number of patients develop meningeal inflammation symptoms during the post-fever period, but cerebrospinal fluid tests show normal results, and the condition may resolve spontaneously without treatment.
(2) Occlusive cerebral vasculitis Also known as moyamoya disease, it is observed in cases of the Pomona serovar of leptospirosis and is one of the most common and severe neurological complications of leptospirosis. First reported by Takeuchi in 1961, it has been identified since 1958 in China as a sporadic condition of unknown cause affecting rural children and young adults in endemic areas such as Hubei, Guangdong, and Zhejiang. In 1973, it was confirmed to be caused by leptospiral infection. The incidence rate accounts for approximately 0.57%–6.45% of leptospirosis cases, with 90% of patients being under 15 years old and the remainder being young adults. There is no gender difference in incidence. The peak onset occurs about one season later than the local leptospirosis epidemic, typically between October and December, with symptoms appearing up to 9 months after the initial infection. Clinical manifestations include hemiplegia, aphasia, and recurrent transient limb paralysis. Cerebral angiography confirms stenosis in the supraclinoid segment of the internal carotid artery and the proximal segments of the anterior and middle cerebral arteries, with most cases showing a characteristic vascular network in the basal ganglia. Leptospirae are occasionally found in brain tissue during autopsy, and the prognosis is generally poor.
In addition to the above neurological sequelae, there have been reports of peripheral nerve damage and spinal cord impairment.
4. Pretibial fever In very rare cases, patients develop nodular erythema on the skin of both shins during the convalescent stage, accompanied by fever, which subsides within about 2 weeks. This condition is related to an immune response.
bubble_chart Auxiliary Examination
(1) Routine examination and hematological examination: In non-jaundice cases, the total white blood cell count and neutrophil count are normal or show grade I elevation; in jaundice cases, the white blood cell count is mostly increased, with half ranging from 10×109 to 20×109/L, and the highest reaching 70×109/L. A few cases may exhibit a leukemoid reaction. Neutrophils are elevated, mostly between 81–95%. Bleeding patients may present with anemia and thrombocytopenia, with the lowest platelet count reaching 15×109/L. In routine urine tests, 70% of patients show grade I proteinuria, along with the presence of white blood cells, red blood cells, or casts. Jaundice cases exhibit elevated bilirubin, with two-thirds of cases below 342 μmol/L and the highest reaching 1,111 μmol/L. Bilirubin levels typically rise continuously during the first to second week of illness, gradually decline in the third week, and may persist for over a month. Serum transaminase levels may increase, but the degree of elevation does not correlate with disease severity and cannot serve as a direct indicator of liver damage. In 50% of cases, creatine phosphokinase (CPK) is elevated (averaging five times the normal value).
(2) Specific tests
1. Pathogen isolation: Leptospira are difficult to stain and are rarely observable under a regular microscope. Dark-field microscopy must be used to directly detect the spirochetes. Leptospira can be isolated from blood and cerebrospinal fluid within the first 10 days of illness. By the second week, they can be detected in urine. Isolating Leptospira from body fluids or tissues requires specialized laboratory techniques and culture media.
Recently, methods such as ultracentrifugation followed by direct microscopy, fluorescent antibody staining, silver staining of blood smears, and toluidine blue staining have been employed to directly detect the pathogen, achieving rapid diagnosis with a positivity rate of around 50%, aiding early diagnosis.
Animal inoculation is a reliable method for isolating the pathogen. Patient blood or other body fluids are injected intraperitoneally into animals (young guinea pigs or golden hamsters). In advanced cases, urine may be injected subcutaneously into the animal’s abdomen. After 3–5 days, peritoneal fluid is examined under dark-field microscopy, or heart blood may be collected for examination after 3–6 days. Animal inoculation has a high positivity rate but requires more time and is costly.
2. Serological tests
(1) Agglutination-lysis test (microscopic agglutination test, MAT): This test has high specificity and sensitivity but requires live strains of different serotypes. Agglutinins generally appear 7–8 days after illness onset, gradually increasing. A titer exceeding 1:400 is considered positive and may persist for months to years. A fourfold or greater increase in titer between paired sera collected two weeks apart is considered positive.
(2) Enzyme-linked immunosorbent assay (ELISA): ELISA yields earlier and more sensitive positive results than MAT. The overall concordance rate between MAT and ELISA has been found to be 86.2%. In recent years, Leptospira IgM antibody detection has been widely adopted internationally, offering high specificity.
(3) Indirect hemagglutination test (IHA): An antigenic component extracted from Leptospira is adsorbed onto the surface of human type O red blood cells for sensitization. When exposed to homologous antibodies, red blood cell agglutination occurs. This test exhibits genus-specificity for Leptospira infection but lacks serogroup or serotype specificity. It yields positive results earlier than MAT, is simple to perform, and does not require specialized equipment, making it suitable for widespread use in primary healthcare settings.
(4) Indirect hemolysis test: Fresh sheep red blood cells are sensitized with Leptospira antigen. In the presence of complement, hemolysis occurs when mixed with serum containing antibodies. This test is more sensitive than the indirect hemagglutination test.
(5) Indirect Fluorescent Antibody Method: This method involves preparing a smear of standard leptospira strains, then applying the patient's serum to a slide with known strains. After washing, if the patient's serum contains antibodies, the antigen-antibody complex forms. Subsequently, anti-human globulin fluorescent antibodies bind to this complex, producing fluorescence, which indicates a positive result. This method lacks type specificity. The detection time for antibodies and the time for seroconversion to negative are earlier compared to the microscopic agglutination test, making it somewhat significant for early diagnosis.
All the above tests detect the corresponding antibodies in the blood using known leptospiral antigens, which cannot achieve early diagnosis. In recent years, latex agglutination inhibition tests, reverse indirect hemagglutination tests, and indirect fluorescent antibody staining tests have been developed to detect leptospires present in the blood at an early stage, achieving preliminary results in early diagnosis.
3. Early Diagnosis
(1) Leptospira DNA Probe Technology: This has long been applied in clinical practice. Schoone et al. (1984) demonstrated that a probe prepared from the DNA of the Copenhagen strain Wijnberg of the Jaundice hemorrhagic group could detect 2pg of homologous DNA on a nitrocellulose filter membrane. Additionally, cross-hybridization was observed with the Patoc I strain of different serogroups causing the nature of disease. The authors concluded that DNA probe hybridization is a highly sensitive method for early diagnosis.
(2) DNA Gene Amplification Technology: The polymerase chain reaction (PCR) DNA amplification technique has now been introduced into the field of leptospirosis diagnosis. Since PCR only requires primers to conduct the test, it is simple and suitable for epidemiological studies involving large numbers of specimens. Van Eys et al. (1989) used PCR amplification to study cattle urine infected with the Hardjo strain of Leptospira and proposed that PCR DNA amplification could serve as a novel method for diagnosing leptospirosis.
Leptospirosis is an acute {|###|}pestilence{|###|} caused by the pathogenic {|###|}nature of disease{|###|} Leptospira (referred to as leptospira for short). Rodents, pigs, and other livestock are the main sources of {|###|}pestilence{|###|}. Leptospira is excreted in the urine of infected animals, contaminating water sources. Humans become infected through contact with contaminated water via the skin or mucous {|###|}membrane{|###|}. The disease often occurs during the rice harvesting season in summer and autumn or after heavy rains and floods.
1. Epidemiology During the summer and autumn seasons in endemic areas, a history of contact with contaminated water within 3 weeks prior to illness onset is common.
2. Clinical Manifestations The incubation period is mostly 1–3 weeks.
(1) Septicemic Phase: From onset to about 1 week, leptospira is present in the blood. This phase may present with the following clinical types: ① Common Type: Sudden {|###|}fear of cold{|###|}, chills, and fever, with sustained or remittent fever. Generalized muscle pain, especially severe pain in the gastrocnemius. The patient is weak, with conjunctival {|###|}membrane{|###|} congestion but no itching or discharge. Superficial lymphadenopathy is common, particularly in the inguinal lymph nodes. In severe cases, significant toxemia may occur, with {|###|}complexion{|###|} pallor, cold extremities, weak pulse, hypotension, oliguria, or anuria appearing 2–5 days after onset, leading to shock. Vomiting and diarrhea are often present, while fever and congestion symptoms are less noticeable. ② Pulmonary Hemorrhage Type: 3–5 days after the septicemic phase, coughing with blood-streaked sputum begins. The patient appears pale, with {|###|}flusteredness dysphoria{|###|}, increased respiratory and heart rates, and progressively worsening moist rales in the lungs—a precursor to massive pulmonary hemorrhage. Within hours, extreme pallor, cyanosis of the lips, and widespread moist rales may develop. Frequent {|###|}hemoptysis{|###|} occurs, and if uncontrolled, massive bleeding from the mouth and nose, respiratory distress, or asphyxia due to airway obstruction by blood clots may follow. ③ {|###|}Jaundice{|###|} Hemorrhagic Type: 3–6 days after onset, {|###|}jaundice{|###|} appears, accompanied by hepatomegaly and tenderness. {|###|}Jaundice{|###|} peaks around day 10, and severe cases may develop liver necrosis. Severe cases often present with {|###|}epistaxis{|###|}, skin and mucous {|###|}membrane{|###|} bleeding, {|###|}hematemesis{|###|}, {|###|}hematochezia{|###|}, {|###|}hematuria{|###|}, and vaginal bleeding. Cells, protein, and casts are commonly found in the urine. Severe cases may progress to oliguria, anuria, uremia, and acidosis. ④ Meningoencephalitis Type: 4–7 days after onset, severe {|###|}headache{|###|}, {|###|}vomiting{|###|}, neck stiffness, and positive Kernig’s sign appear. Cerebrospinal fluid shows slightly increased cell counts and grade I protein elevation, with leptospira isolatable. A few severe cases may present with encephalitis symptoms, including {|###|}unconsciousness{|###|}, convulsions, and even circulatory or respiratory failure.
(2) Immune Reaction Phase: Around 1 week after onset, an immune reaction occurs, leading to a brief recurrence of fever. Some cases may develop uveitis or optic neuritis, while a few may experience cerebral {|###|}stirred pulse{|###|} inflammation months later, causing neurological symptoms such as {|###|}headache{|###|}, {|###|}paralysis{|###|}, and aphasia.
3. Laboratory Tests
(1) Blood Tests: Elevated total white blood cell count and neutrophil count.
(2) Pathogen Isolation: Culture early-stage patient blood in Korthof medium to isolate leptospira.
(3) Serological Tests: ① Agglutination-lysis test: A titer of 1:400 or higher is positive; a fourfold or greater increase in paired serum titers confirms diagnosis. ② Latex agglutination test and reverse latex agglutination test can provide rapid diagnosis.
4. Differential Diagnosis This disease must be distinguished from bacterial sepsis, epidemic encephalitis B, viral hepatitis, and epidemic hemorrhagic fever.
bubble_chart Treatment Measures
(1) Symptomatic and supportive therapy In the early stage, patients should rest in bed and be provided with a high-calorie, vitamin B and C-rich, and easily digestible diet; maintain water, electrolyte, and acid-base balance; those with severe bleeding should receive immediate blood transfusions and timely application of hemostatic agents. For patients with massive pulmonary hemorrhage, keep them calm and administer sedatives as appropriate; for those with liver function impairment, liver-protective therapy should be implemented, avoiding hepatotoxic drugs; treatment for heart, liver, kidney, or brain failure can refer to relevant chapters.
For all types of leptospirosis, early detection, early diagnosis, early bed rest, and on-site treatment should be emphasized to reduce unexpected complications during transportation.
(2) Antibacterial therapy To eliminate and inhibit pathogens in the body, early administration of effective antibiotics is crucial. If treatment is delayed and organ function is compromised, the therapeutic effect will diminish. Penicillin should be used early, as it can hasten fever reduction, shorten the course of illness, and prevent or alleviate jaundice and bleeding. The initial dose is 400,000 units, followed by a daily dose of 1.2–1.6 million units, divided into 3–4 intramuscular injections, to avoid the Jarisch-Herxheimer reaction. The dose for children may be reduced or similar to that for adults. The treatment course lasts 7 days or until 2–4 days after body temperature normalizes. For severe cases, the dose may be increased to 1.6–2.4 million units daily, divided into 4 intramuscular injections, combined with adrenal corticosteroids. Other antibiotics such as tetracycline, gentamicin, streptomycin, erythromycin, chloramphenicol, doxycycline, and ampicillin also show certain efficacy.
In recent years, domestically synthesized imidazole esters and methazolamide have achieved satisfactory results in treating this disease. Both drugs can be taken orally with minimal side effects. The dose of imidazole ester is 1 g initially for adults, followed by 0.5 g four times daily, discontinued 2–4 days after body temperature normalizes. For severe cases, the dose may be increased to 3 g daily, divided into three oral doses, and reduced to 2 g daily after improvement. The average treatment course is 5–7 days. About 8.1% of cases may experience the Jarisch-Herxheimer reaction, which is milder than that caused by penicillin and does not require special treatment. This drug is rapidly absorbed by the digestive tract, distributed throughout the body, and crosses the blood-brain barrier, making it suitable for preventive use. The main side effects include digestive symptoms and rashes.
The dose of methazolamide is 1 g initially for adults, followed by 0.5 g 3–4 times daily, with a treatment course of 5–7 days or discontinued 3 days after fever subsides. The cure rate of this drug reaches 94.31%, with no Jarisch-Herxheimer reaction. Some patients may experience dizziness, abdominal pain, borborygmus, or occasional rashes and dry mouth.
The Jarisch-Herxheimer reaction mostly occurs 30 minutes to 4 hours after the first dose of penicillin G injection, caused by the release of toxins from a large number of killed leptospira. Symptoms include sudden chills, high fever, headache, generalized pain, increased heart and respiratory rates, worsening of existing symptoms, and may be accompanied by hypotension, cold limbs, shock, or a sudden drop in body temperature. The reaction typically lasts 30 minutes to 1 hour and may occasionally lead to diffuse pulmonary hemorrhage. Immediate treatment includes intravenous infusion of 200–300 mg hydrocortisone or intravenous injection of 5–10 mg dexamethasone, along with sedative, antipyretic, and anti-shock measures.
(3) Treatment of sequelae Generally, symptomatic treatment can provide relief. For severe cases, adrenal corticosteroids may accelerate recovery.
1. Uveitis: Mydriasis, use 1% atropine solution for eye drops several times a day. If the iris adhesion prevents sufficient pupil dilation, 10% neosynephrine solution eye drops, 1% neosynephrine subconjunctival injection, or strong mydriatics (1% atropine, 4% cocaine, 0.1% adrenaline, each 0.1ml) subconjunctival injection can be used to maximize pupil dilation and try to separate the formed posterior iris adhesions. After mydriasis, apply 1% atropine eye drops 1-3 times daily until 2 weeks after recovery. Apply hot compresses to the eyes 2-4 times a day, 20 minutes each time. Use cortisone eye drops or subconjunctival injection locally. Severe cases may take oral adrenal corticosteroids. Other treatments include 1-2% dionine eye drops, oral sodium salicylate; for posterior uveitis, intravenous nicotinic acid, tolazoline, 654-2, sodium bicarbonate, and vitamin B1, B2, etc. If all treatments fail, immunosuppressants can be used.
2. For cerebral obstructive vasculitis, high-dose penicillin G and adrenal cortex hormones are often administered. Vasodilators such as nicotinic acid, anisodamine hydrobromide (AT-3), aminophylline, as well as physical therapy and acupuncture may also be used. Early treatment is crucial to prevent varying degrees of sequelae.
The disease causes different clinical types and varying severity of illness, leading to significant differences in prognosis. Mild or subclinical cases have a good prognosis and low fatality rate, while severe cases such as massive pulmonary hemorrhage, shock, liver and kidney dysfunction, microcirculatory disorders, or severe central nervous system damage have a high fatality rate. The average mortality rate of this disease is around 10%. If antibiotics and symptomatic treatment are administered within two days of onset, the fatality rate can be reduced to below 6%. The fatality rate of anicteric leptospirosis is the lowest, at about 1–2% domestically and internationally. Patients with ocular or neurological complications may sometimes experience long-term sequelae.
(1) Managing the source of pestilence Rodents should be exterminated in epidemic areas, and domestic animals such as pigs, dogs, sheep, and cattle should be properly managed. Strengthen quarantine measures for animal hosts. Patients should be isolated promptly, and their excretions such as urine and sputum should be disinfected.
(2) Cutting off the transmission route of pestilence Conduct surveys of paddy fields, ponds, ditches, stagnant water pits, and areas planned for reclamation in epidemic regions. Modify the epidemic foci by combining local conditions with water conservancy projects. Strengthen the management of epidemic water and feces, build toilets, and improve pigsties to prevent livestock feces and urine from entering nearby ponds, paddy fields, or stagnant water. Contaminated water sources and stagnant water can be disinfected by spraying with bleaching powder or other effective drugs. Manage food properly to prevent contamination by the excretions of infected rodents.
(3) Protecting susceptible populations
1. Personal protection In epidemic areas and during epidemic seasons, prohibit young adults and children from swimming, wading, or fishing in contaminated water. Workers and farmers who come into contact with epidemic water should wear long boots and rubber gloves as much as possible, avoid skin damage, and reduce the chance of infection.
2. Use of polyvalent vaccines In areas with perennial outbreaks, polyvalent vaccines containing local prevalent strains should be used. These include two main categories: 3-valent vaccines (containing jaundice hemorrhagic type, autumn type, and Canicola type) and 5-valent vaccines (jaundice hemorrhagic type, canine type, influenza cold-damage disease type, Pomona type, autumn type, or Australian type). Both can be prepared as regular vaccines (approximately 200 million bacteria per milliliter) and concentrated vaccines (approximately 600 million bacteria per milliliter). Vaccinees develop immunity to the same type of Leptospira, lasting about one year. The target groups for vaccination are susceptible populations and those exposed to epidemic water. Vaccination should be completed one month before the epidemic season. For adults, the first subcutaneous injection is 1 ml, and the second is 2.0 ml; for children aged 2–6, the first and second doses are 0.25 ml and 0.5 ml, respectively; for those aged 7–14, half the adult dose is used. The interval between the two injections for all age groups is 7–10 days. Immunity develops about one month after vaccination, so vaccination should be completed before the busy farming season (conducted in April–May each year). For personnel entering epidemic areas, work can only begin 1–5 days after completing the full vaccination course. Immunity lasts about one year, so full vaccination is required. A single injection has little effect, while two injections can reduce the incidence or alleviate symptoms. In new epidemic areas, universal vaccination must be conducted continuously for 3–4 years to stabilize the situation.
For laboratory and epidemiological staff, as well as new workers entering epidemic areas who are suspected of infection but show no obvious symptoms, intramuscular injection of penicillin G 800,000–1.2 million units daily for 2–3 days can be used as preventive medication.
Generally speaking, complications occurring in the early and intermediate stages (second stage) are called complications, while those occurring in the advanced stage are called sequelae. The complications of this disease are still predominantly ocular and neurological.
The clinical manifestations of this disease are very complex, making early diagnosis difficult and prone to misdiagnosis or missed diagnosis. Clinical confirmation requires positive etiological or serological test results, which often take time to obtain. Therefore, to ensure accurate diagnosis, a comprehensive analysis must be conducted by combining epidemiological characteristics, early clinical features, and laboratory tests, while also differentiating it from other diseases.
(1) Fever Diseases that should be differentiated from other acute febrile illnesses include: cold-damage disease, influenza, upper respiratory infection, malaria, acute schistosomiasis, scrub typhus, pneumonia, epidemic hemorrhagic fever, and septicemia. In addition to clinical features, epidemiological history, proteinuria, and the presence of azotemia often provide important clues for differential diagnosis.
(2) Jaundice Differentiation should be made from jaundice-type hepatitis. Hepatitis is characterized by prominent gastrointestinal symptoms such as loss of appetite, without conjunctival congestion or calf muscle tenderness. The white blood cell count is normal or decreased, with significant abnormalities in liver function tests (ALT, AST), while CPK is not elevated. Epidemiological history and serological tests can aid in differentiation.
(3) Nephritis Leptospirosis patients with kidney damage but without jaundice need to be differentiated from nephritis. Leptospirosis presents with an acute infectious febrile onset, conjunctival congestion, significant myalgia, mostly normal blood pressure, and no edema.
(4) Myalgia Differentiation should be made from acute wind-dampness fever. The pain in acute wind-dampness fever is often migratory joint pain, whereas the myalgia in leptospirosis is primarily localized to the calf muscles.
(5) Hemorrhage or Hemoptysis Hemorrhage should be differentiated from upper consumptive thirst gastrointestinal bleeding, hematuria, leukemia, thrombocytopenia, and aplastic anemia. Peripheral blood tests, bone marrow examination, and GI tests can help distinguish it from hemorrhagic diseases. Hemoptysis should be differentiated from pulmonary subcutaneous nodules, bronchiectasis, and tumors, with differentiation achieved through chest X-rays or CT scans.
(6) Meningoencephalitis Meningoencephalitis-type leptospirosis and epidemic encephalitis B both occur in summer and autumn, with no history of exposure to contaminated water. Neither presents with generalized soreness, calf muscle tenderness, conjunctival congestion, or lymphadenopathy. Epidemic encephalitis B is more severe, with more pronounced cerebral symptoms such as spasm and unconsciousness compared to leptospirosis. Routine urine tests and liver function are usually normal.
