- Email: [email protected]
Leptospirosis
Pediatric Infectious Disease 2012 January–March Volume 4, Number 1; pp. 4–8
Review Article
Leptospirosis Ira Shah
ABSTRACT Leptospirosis is a zoonotic infection caused by the spirochete leptospira, and humans are incidental hosts. Infection occurs when humans come in contact with urine (directly or indirectly) of infected carrier hosts. The most important reservoirs are rodents and rats worldwide. Leptospira enter the human body via cuts or abrasions in skin, through mucus membranes, lungs in form aerosol droplets, and conjunctival membranes. There are seven distinct species of pathogenic leptospires. Despite the possibility of severe complications, the disease is usually non-fatal and selflimiting. Leptospire-mediated injury characterizes the initial phase of the disease which is also called septicemic phase, and host immune response marks the onset of second phase of symptoms called immune phase of the disease. Clinical symptoms include fever, headache, myalgia, and vomiting, and thus this disease is difficult to differentiate from other viral illnesses. Symptoms last for 4–7 days. Subsequently, the patient may be asymptomatic for 1–3 days followed by reappearance of fever. Aseptic meningitis and renal dysfunction are seen during this phase which is the immune phase. The microscopic agglutination test (MAT) is considered to be the gold standard for diagnosis and can identify specific serotypes. The enzyme-linked immunosorbent assays (ELISA) are popular and several assays are available. Several commercial kits are available to detect IgM and sometimes also IgG antibodies. However, it is less specific, and weak cross-reactions due to the presence of other diseases may be observed. Treatment with injectable penicillin is needed for severe disease. For mild disease, ampicillin, amoxicillin, or doxycycline (in children >8 years of age) can be given. Keywords: Children, India, leptospirosis
INTRODUCTION
GLOBAL UPDATE
Leptospirosis is a zoonotic infection caused by the spirochete leptospira, and humans are incidental hosts. Infection occurs when humans come in contact with urine (directly or indirectly) of infected carrier hosts. Leptospirosis results in an acute febrile illness that cannot be distinguished from other viral illnesses, as symptoms commonly seen are fever, headache, vomiting, and nausea. In 10% of individuals, the disease leads to renal and hepatic dysfunction with hemorrhage also known as Weil’s disease or icteric leptospirosis which may be associated with multisystem organ dysfunction in form of pulmonary, cardiac, and central nervous system (CNS) affection.1–4
Leptospirosis is an underdiagnosed and underreported condition.5 Although, first described by Adolf Weil in 1886, it has been around for 100 of years with icteric form of the disease being reported in ancient China, India, and Europe.6 However, the first credited account of a leptospire being isolated was in 1916 by Inada et al.7 Rats as a reservoir host were identified in Japan in early 1900s, and basic pathology as well as epidemiology was derived by 1940. Recent research has been on deoxyribonucleic acid (DNA) sequencing, factors that confer virulence, immunity, and aid in development of vaccine.6 Although leptospirosis continues to be predominantly an occupational disease or
Incharge, Pediatric HIV Clinic, TB Clinic and Co-incharge, Pediatric Liver Clinic, Department of Pediatrics, B.J. Wadia Hospital for Children, Mumbai – 400012 and Consultant in Pediatric Infectious Diseases and Pediatric Hepatology, Nanavati Hospital, Mumbai – 400056, Maharashtra, India. Correspondence: Dr. Ira Shah, email: [email protected] doi: 10.1016/S2212-8328(12)60002-2
ISSN: 2212-8328 Copyright © 2012. The Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved.
Leptospirosis
disease of freshwater flooding, since 1970, it has also been increasingly recognized as disease of recreation with outbreak being reported with canoeing, kayaking, windsurfing, swimming, waterskiing, wading through puddles, white-water rafting, and other outdoor sports played in contaminated water.8–10 Adult males are at more risk of leptospirosis due to higher occupational and recreational exposure, however children <15 years of age have been implicated in outbreaks due to indiscriminate contact with water. Urban dwellers are also at higher risk due to increased exposure to rat urine. Leptospirosis is noted to have seasonal distribution with increased incidence seen with rainfall or higher temperature and epidemics have been associated with changes in human behavior, animal or sewage contamination of water and following natural disasters such as cyclones or floods. Areas with high endemicity include the Caribbean Islands, Central and South America, Southeast Asia, and the Pacific Islands.2 Incidence of leptospirosis reported worldwide ranges from 0.02–0.04 cases per 100,000 persons in low-endemic areas to over 2.3–40.2 cases per 100,000 persons in high-endemic areas.11,12
LEPTOSPIROSIS AND INDIA In India, leptospirosis was first reported in Andaman Islands in 1930s. Subsequently, it has been reported from Orissa, Maharashtra, Karnataka, Tamil Nadu, and Kerala. Since 1980s there has been a rise in the incidence of leptospirosis, and now leptospirosis is reported to occur every rainy season in areas with flooding and poor sewage drainage.1 Although initially leptospirosis was reported in the form of Weil’s disease,5 it is now increasingly seen as fever with thrombocytopenia and even as non-oliguric renal failure.13
Transmission Leptospira infects many types of mammals including rats, dogs, cats, cattle, pigs, squirrels, raccoons, mongoose, and bandicoots. Infection in animals is usually subclinical, and urinary shedding of leptospires from infected animals is the most important source of transmission. Leptospires can persist for long periods (months) in the renal tubules of animals, and thus these animals serve as reservoirs.14 The most important reservoirs are rodents and rats worldwide. Leptospira enter the human body via cuts or abrasions in skin, through mucus membranes, lungs in form aerosol droplets, and conjunctival membranes. Most cases occur in the rainy season and during flooding, as leptospires survive in fresh water and
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5
damp soil, and increased infection is seen with floods and water collection. Not all leptospira are pathogenic to humans, and there are several saprophytic leptospires that do not cause disease that are present in surface waters, moist soil, and in tap water. Of the common pathogenic leptospires, Leptospira interrogans is the commonest. There are seven distinct species of pathogenic leptospires, which have >250 serologic variants.1 Although, isolation of particular serovar is important from epidemiologic purpose, it is generally believed that serovar-specific antibodies are protective life long. However, infection by other serovars is still a possibility.
Pathogenesis Leptospires on entering the body migrate to the lymphatic and circulatory system within minutes. However, the growth rate of leptospires is slow, and therefore after an incubation period of 2–20 days, symptoms arise. The organisms have a particular predilection for kidneys and liver. In the kidneys, it migrates to the interstitium, renal tubules, and lumen causing interstitial nephritis and acute tubular necrosis (ATN). Direct leptospire injury may cause ATN, whereas interstitial nephritis occurs due to antigen–antibody complexes of the immune phase. In the liver, centrilobular necrosis with proliferation of Kupffer cells in seen resulting in hepatic dysfunction. Leptospiras also disrupt the endothelial lining of blood vessels leading to capillary leaks and hemorrhages. Capillary vasculitis is found in every affected organ system. There may be associated thrombocytopenia. Despite the possibility of severe complications, the disease is usually non-fatal and self-limiting. Leptospire-mediated injury characterizes the initial phase of the disease which is also called septicemic phase, and host immune response marks the onset of second phase of symptoms called immune phase of the disease. However, the true mechanism of host tissue injury remains unclear and likely involves a complex set of interactions.15
Clinical Features Clinical symptoms include fever, headache, myalgia, and vomiting, and thus this disease is difficult to differentiate from other viral illnesses. Symptoms last for 4–7 days. Subsequently, the patient may be asymptomatic for 1–3 days followed by reappearance of fever. Aseptic meningitis and renal dysfunction are seen during this phase which is the immune phase. Uveitis is also a feature of this phase. Symptoms during the second phase may last for 6 days to 4 weeks. Ten percent of patients may go on to develop severe
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Pediatric Infectious Disease 2012 January–March; Vol. 4, No. 1
disease characterized by jaundice, renal failure, shock, and circulatory collapse. Multi-organ dysfunction, development of adult respiratory distress syndrome (ARDS), and mortality rate of 5–10% have been noted despite intensive care unit (ICU) care. Other biochemical abnormalities that occur are mild elevated liver transaminases, hypokalemia (due to renal tubular wasting), hyponatremia, thrombocytopenia, and elevated prothrombin time. White cell count may be normal, but there may be shift to left with neutrophilic predominance. Erythrocyte sedimentation rate may be elevated.16 Renal involvement is seen in all phases of the disease, and renal failure has been found to range from 50% to 79%. However, symptomatic renal failure in the form of azotemic, anuria, and oliguria is seen with severe disease1,17 and occurs after 4–10 days after the onset of symptoms. Other features which may be seen in leptospirosis include conjunctival hyperemia, myositis, lymphadenopathy, hemoptysis, cough, maculopapular rash, and bleeding manifestations such as hemoptysis, epistaxis, gingival oozing, petechiae, and pulmonary hemorrhage. Vasculitis can lead to third spacing of fluids and hypovolemic shock with vascular collapse. Myocarditis and atrioventricular blocks have also been noted.18
Leptospirosis in Pregnancy Leptospirosis in pregnancy is a complicated problem, and infection in first two trimesters can lead to spontaneous abortions. Third-trimester infections can also lead to abortion or perinatal death in one-third of the pregnancies. Although congenital leptospirosis has been reported with successful treatment intervention, such cases have been few.19
DIAGNOSIS OF LEPTOSPIROSIS Leptospires may be isolated from blood, cerebrospinal fluid, and most tissues during the septicemic phase which lasts for about 5–7 days. However, since this phase usually presents with non-specific symptoms, it is usually missed. The immune stage is characterized by circulating antibodies and disappearance of leptospires from the circulation. However, leptospires may still be isolated from urine for several weeks up to 2 months post-infection. The leptospires can be identified using dark-field microscopy or direct fluorescent-antibody assay. Serologic assays for detection of antibodies are microscopic agglutination test (MAT), enzyme-linked immunosorbent assay (ELISA), and indirect hemagglutination assay. Seroconversion usually occurs after 5–7 days after the onset of disease but may sometimes occur only after 10 days or
Shah
longer. IgM class antibodies usually appear somewhat earlier and may be present for up to 2 months after the infection and at lower titers for years. IgG antibody is usually erratic and often may not be detected or may be detectable for only relatively short periods of time. Thus, the presence of antibodies is by itself no proof of current infection, as some antibodies may persist for long periods after an infection. Generally, seroconversion or four-fold rise in titer in consecutive serum samples is considered to be diagnostic proof of recent infection. A high IgM time, that is, a titer severalfold above the cut-off point in a single serum sample is consistent with current or recent leptospirosis. The MAT is considered to be the gold standard for diagnosis and can identify specific serotypes. The MAT uses a battery of antigens from common endemic leptospire serovars. A single titer exceeding 1:200 or serial titers exceeding 1:100 suggests leptospirosis. Test accuracy is affected by selection of antigens for the test and laboratory needs facility to culture and maintain panels of live leptospires to keep up the antigen battery. This test is important from the epidemiologic point of view to identify the serovar. The ELISAs are popular and several assays are available. Several commercial kits are available to detect IgM and sometimes also IgG antibodies. The advantage is that only one genus-specific antigen which is shared by all leptospires is used, and culture of leptospires in the local laboratory is not required to provide the antigen. However, it is less specific, and weak cross-reactions due to the presence of other diseases may be observed. Also serotype differentiation cannot be done. However serotype differentiation may not be required for clinical management of patient and is only important from epidemiological point of view. Other serological tests are indirect hemagglutination assay and dipstick IgM dot assays that have lesser sensitivity and specificity as compared to ELISA test.3 Polymerase chain reaction (PCR) based techniques have been developed but have limited epidemiologic, economic, and public health value.1
TREATMENT Treatment of leptospirosis consists of antibiotics with supportive care and close monitoring of renal, hepatic, and circulatory function. Early antibiotic treatment aids in faster recovery and prevents progression of the disease. Although antibiotic efficacy may decrease after day 10 of illness due to disappearance of leptospires and appearance of antibodies, antibiotic therapy should not be denied. Severe infections should be managed by Intravenous Penicillin in doses of
Leptospirosis
50,000–100,000 U/kg/day in four to six divided doses for 7–10 days. In patients with penicillin allergy, erythromycin (30–50 mg/kg/day in three to four doses for 7–10 days) may be given. For mild cases, oral amoxicillin (30–40 mg/kg/day 4 times a day for 7–10 days), ampicillin (50–100 mg/kg/day 4 times a day for 7–10 days) and doxycycline (2 mg/kg/dose 2 times a day for 7 days in children >8 years of age) can be used. Third-generation cephalosporins, such as ceftriaxone and cefotaxime, and quinolones may also be useful.20 For patients with renal failure not responding to medical line of management, dialysis may be required. There have been some reports of use of high-dose pulse steroids (methyl prednisolone—30 mg/kg/day) for treatment of immune-complex-mediated renal failure, but its role is not fully established.21 Additional supportive care may include inotropic agents and diuretics.
PREVENTION Eradication of leptospires from animals is difficult, and this leads to constant source of infection. Also, the presence of large number of serovars makes control complicated. Practicing good personal hygiene, avoiding wading, or exposure to rodent-urine-contaminated water is advisable. For those exposed adults, doxycycline in dose of 200 mg weekly may help prevent disease. Role of antibiotics prophylaxis in children is not established although amoxicillin has been tried. In some countries, vaccines that are serovar-specific are available but must be repeated yearly and are associated with painful swelling on revaccination. Thus, they are recommended only in high-risk groups.
CLINICAL DILEMMAS WITH LEPTOSPIROSIS The author first reported Weil’s disease in 1999 and subsequently has seen various different manifestations of leptospirosis in children. Although leptospirosis by convention is classified into septicemic phase and immune phase; clinically it is very difficult to differentiate between the two. Also leptospirosis is confirmed by isolation of leptospira antibodies by ELISA, most of the diagnosed cases of leptospira have been identified only once the antibodies have already formed. Isolation of leptospira in culture from blood and tissues is not always found. Thus, it is quite possible that septicemic phase of leptospirosis may be going unrecognized and what may be seen clinically may be due to immune reactions of the body. However, from a management point
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of view, it really makes no difference to identify septicemic versus immune phase. What is important is to identify the severe variety of leptospirosis from the milder ones. Thus, from a practical aspect, it would be better to classify leptospirosis into icteric versus non-icteric variety. Icteric variety is also called Weil’s disease and is characterized by fever, jaundice, and renal failure. Non-icteric variety may present as aseptic meningitis, fever with thrombocytopenia, and fever with non-oliguria failure. Icteric leptospirosis should be differentiated from other viral hepatitis with fulminant hepatitis, such as hepatitis A and E. The most important differentiating feature is the presence of renal failure very early in the course of the disease, thrombocytopenia, and mildly elevated liver enzymes as compared to viral hepatitis where liver enzymes may be markedly elevated, and there is associated encephalopathy with fever disappearing on appearance of jaundice.5 Interestingly, all our patients with leptospirosis were boys and on retrospective questioning did mention wading or playing in flooded streets a few days ago suggesting recreational hazard as a common factor of transmission. Non-icteric leptospirosis may present with aseptic meningitis. However, the commonest presentation is non-oliguric renal failure, and fever or fever with thrombocytopenia. In August 2005, among 32 patients with fever, vomiting, diarrhea, and bleeding manifestations who presented in the monsoon season, we found that patients with leptospirosis had elevated blood urea nitrogen (BUN), elevated serum creatinine, and near normal platelet count. Also, mildly elevated liver transaminases were seen in only 16.7% of patients. Thus, we could differentiate dengue (as patients with dengue had hemoconcentration, thrombocytopenia, elevated SGPT, and hepatomegaly), malaria (patients with malaria had anemia, splenomegaly, and lowest platelet count), and leptospirosis.22 In June 2005, we also found that children with fever presented with hyponatremia, elevated BUN, creatinine, and hyperkalemia without oliguria suggestive of nonoliguric renal failure and tested positive for leptospira IgM by a commercial ELISA. These patients responded to penicillin and did not require dialysis.13 Thus, spectrum of leptospirosis is varied. However, if caught early, one can prevent progression of the disease to a severe variety. A high index of suspicion would be necessary especially in the monsoons.
CONCLUSION Leptospirosis is a common zoonotic disease in humans leading to acute febrile illness especially in monsoons. It is
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characterized by fever, myalgia, headache, and non-oliguric renal failure. High suspicion and early treatment with antibiotics is essential to prevent complications. Ten percent of patients may develop Weil’s disease characterized by fever, jaundice, and renal failure associated with multi-organ dysfunction and 5–10% mortality rate. Treatment with injectable penicillin is needed for severe disease. For mild disease, ampicillin, amoxicillin, or doxycycline (in children >8 years of age) can be given. Avoiding exposure to rodent-urineinfested waters is advisable to prevent leptospirosis.
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9. 10.
11.
12.
13.
REFERENCES 1. 2.
3.
4. 5.
6.
7. 8.
Shah I. Leptospirosis. In: Dengue Leptospirosis, Malaria Shah I, ed. Pediatric Oncall: Mumbai 2007:17–24. Hickey PW. Leptospirosis. E-medicine Available from URL http://emedicine.medscape.com/article/965698-print. Accessed on January 15, 2009. World Health Organization. Human leptospirosis: guidance for diagnosis, surveillance and control. Available at URL http://whqlibdoc.who.int/hq/2003/WHO_CDS_CSR_EPH_ 2002.23.pdf. Accessed on September 17, 2008. Leptospirosis worldwide. Wkly Epidemiol Rec 1999;74: 237–42. Shah I, Warke S, Deshmukh CT, Kamat JR. Leptospirosis— an underdiagnosed clinical condition. J Postgrad Med 1999; 45:93–4. The history of leptospirosis and Weil’s disease. Available on URL http://www.leptospirosis.org. Accessed on February 10, 2009. Inada R, Ido Y, Hoki R, et al. Etiology, made of infection and specific therapy of Weil’s disease. J Exp Med 1916;23:377–402. CDC. From the Centers for Disease Control and Prevention. Update: outbreak of acute febrile illness among athletes participating in Eco-challenge-sabah 2000—Borneo, Malaysia, 2000. JAMA 2001;285:728–30.
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16. 17. 18.
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CDC. Outbreak of leptospirosis among while-water rafters— Costa Rica occupational infections. MMWR 1996;46:577–9. Gaynor K, Katz AR, Park SY, et al. Leptospirosis on Oahu: an outbreak associated with flooding of a university campus. Am J Trop Med Hyg 2007;76:882–5. US Department of Health and Human Services. Summary of Notifiable diseases, United States 1995. MMWR Morb Mortal Wkly Rep 1996;44:1–87. Lettieri C, Moon J, Hickey P, et al. Prevalence of leptospira antibodies in US Army blood bank donors in Hawaii. Mil Med 2004;169:687–90. Shah I. Non oliguric renal failure—a presentation of leptospirosis. Ann Trop Med Parasito 2009;103:53–6. Palaniappan RV, Ramanujam S, Chang YF. Leptospirosis: pathogenesis, immunity and diagnosis. Curr Opin Infect Dis 2007;20:284–92. Kaufman AF, Wenger JD, Last JM, Wallace RB, eds. Leptospirosis. In: Maxcy-Rosenau-Last Public Health and Preventive Medicine 13th ed, Norwalk, CT. 1992:264–5. Speelman P, Fauci AS, Brainwald E, eds. Leptospirosis. In: Harrison’s Principles of Internal Medicine 14th ed. 1998:756. Masgrave JE, Person DA. Acute renal failure in children due to leptospirosis. Pac Health Dialog 1996;3:200–1. Watt G, Padre LP, Tuazon M, Caleebaquib C. Skeletal and cardiac muscle involvement in severe, late leptospirosis. J Infect Dis 1990;162:266–9. Shaked Y, Shpilberg O, Samra D, Samra Y. Leptospirosis in pregnancy and its effect on the fetus: case report and review. Clin Infect Dis 1993;17:241–3. Costa E, Lopes AA, Sacramento E, et al. Penicillin at the late stage of leptospirosis: a randomized controlled trial. Rev Inst Med Trop Sao Paulo 2003;45:141–5. Maloni J, Pryor J, Lusangulira K. Leptospirosis in Pohnpei (1986–1995): a case series on the use of dopamine/steroid for Weil’s syndrome. Pacific Health Dialog 1996;3:153–61. Shah I, Katira B. Clinical and laboratory profile of dengue, leptospirosis and malaria in children: a study from Mumbai. Arch Dis Child 2007;92:561.
Review Article
Leptospirosis Ira Shah
ABSTRACT Leptospirosis is a zoonotic infection caused by the spirochete leptospira, and humans are incidental hosts. Infection occurs when humans come in contact with urine (directly or indirectly) of infected carrier hosts. The most important reservoirs are rodents and rats worldwide. Leptospira enter the human body via cuts or abrasions in skin, through mucus membranes, lungs in form aerosol droplets, and conjunctival membranes. There are seven distinct species of pathogenic leptospires. Despite the possibility of severe complications, the disease is usually non-fatal and selflimiting. Leptospire-mediated injury characterizes the initial phase of the disease which is also called septicemic phase, and host immune response marks the onset of second phase of symptoms called immune phase of the disease. Clinical symptoms include fever, headache, myalgia, and vomiting, and thus this disease is difficult to differentiate from other viral illnesses. Symptoms last for 4–7 days. Subsequently, the patient may be asymptomatic for 1–3 days followed by reappearance of fever. Aseptic meningitis and renal dysfunction are seen during this phase which is the immune phase. The microscopic agglutination test (MAT) is considered to be the gold standard for diagnosis and can identify specific serotypes. The enzyme-linked immunosorbent assays (ELISA) are popular and several assays are available. Several commercial kits are available to detect IgM and sometimes also IgG antibodies. However, it is less specific, and weak cross-reactions due to the presence of other diseases may be observed. Treatment with injectable penicillin is needed for severe disease. For mild disease, ampicillin, amoxicillin, or doxycycline (in children >8 years of age) can be given. Keywords: Children, India, leptospirosis
INTRODUCTION
GLOBAL UPDATE
Leptospirosis is a zoonotic infection caused by the spirochete leptospira, and humans are incidental hosts. Infection occurs when humans come in contact with urine (directly or indirectly) of infected carrier hosts. Leptospirosis results in an acute febrile illness that cannot be distinguished from other viral illnesses, as symptoms commonly seen are fever, headache, vomiting, and nausea. In 10% of individuals, the disease leads to renal and hepatic dysfunction with hemorrhage also known as Weil’s disease or icteric leptospirosis which may be associated with multisystem organ dysfunction in form of pulmonary, cardiac, and central nervous system (CNS) affection.1–4
Leptospirosis is an underdiagnosed and underreported condition.5 Although, first described by Adolf Weil in 1886, it has been around for 100 of years with icteric form of the disease being reported in ancient China, India, and Europe.6 However, the first credited account of a leptospire being isolated was in 1916 by Inada et al.7 Rats as a reservoir host were identified in Japan in early 1900s, and basic pathology as well as epidemiology was derived by 1940. Recent research has been on deoxyribonucleic acid (DNA) sequencing, factors that confer virulence, immunity, and aid in development of vaccine.6 Although leptospirosis continues to be predominantly an occupational disease or
Incharge, Pediatric HIV Clinic, TB Clinic and Co-incharge, Pediatric Liver Clinic, Department of Pediatrics, B.J. Wadia Hospital for Children, Mumbai – 400012 and Consultant in Pediatric Infectious Diseases and Pediatric Hepatology, Nanavati Hospital, Mumbai – 400056, Maharashtra, India. Correspondence: Dr. Ira Shah, email: [email protected] doi: 10.1016/S2212-8328(12)60002-2
ISSN: 2212-8328 Copyright © 2012. The Indian Academy of Pediatrics, Infectious Disease Chapter. All rights reserved.
Leptospirosis
disease of freshwater flooding, since 1970, it has also been increasingly recognized as disease of recreation with outbreak being reported with canoeing, kayaking, windsurfing, swimming, waterskiing, wading through puddles, white-water rafting, and other outdoor sports played in contaminated water.8–10 Adult males are at more risk of leptospirosis due to higher occupational and recreational exposure, however children <15 years of age have been implicated in outbreaks due to indiscriminate contact with water. Urban dwellers are also at higher risk due to increased exposure to rat urine. Leptospirosis is noted to have seasonal distribution with increased incidence seen with rainfall or higher temperature and epidemics have been associated with changes in human behavior, animal or sewage contamination of water and following natural disasters such as cyclones or floods. Areas with high endemicity include the Caribbean Islands, Central and South America, Southeast Asia, and the Pacific Islands.2 Incidence of leptospirosis reported worldwide ranges from 0.02–0.04 cases per 100,000 persons in low-endemic areas to over 2.3–40.2 cases per 100,000 persons in high-endemic areas.11,12
LEPTOSPIROSIS AND INDIA In India, leptospirosis was first reported in Andaman Islands in 1930s. Subsequently, it has been reported from Orissa, Maharashtra, Karnataka, Tamil Nadu, and Kerala. Since 1980s there has been a rise in the incidence of leptospirosis, and now leptospirosis is reported to occur every rainy season in areas with flooding and poor sewage drainage.1 Although initially leptospirosis was reported in the form of Weil’s disease,5 it is now increasingly seen as fever with thrombocytopenia and even as non-oliguric renal failure.13
Transmission Leptospira infects many types of mammals including rats, dogs, cats, cattle, pigs, squirrels, raccoons, mongoose, and bandicoots. Infection in animals is usually subclinical, and urinary shedding of leptospires from infected animals is the most important source of transmission. Leptospires can persist for long periods (months) in the renal tubules of animals, and thus these animals serve as reservoirs.14 The most important reservoirs are rodents and rats worldwide. Leptospira enter the human body via cuts or abrasions in skin, through mucus membranes, lungs in form aerosol droplets, and conjunctival membranes. Most cases occur in the rainy season and during flooding, as leptospires survive in fresh water and
Review Article
5
damp soil, and increased infection is seen with floods and water collection. Not all leptospira are pathogenic to humans, and there are several saprophytic leptospires that do not cause disease that are present in surface waters, moist soil, and in tap water. Of the common pathogenic leptospires, Leptospira interrogans is the commonest. There are seven distinct species of pathogenic leptospires, which have >250 serologic variants.1 Although, isolation of particular serovar is important from epidemiologic purpose, it is generally believed that serovar-specific antibodies are protective life long. However, infection by other serovars is still a possibility.
Pathogenesis Leptospires on entering the body migrate to the lymphatic and circulatory system within minutes. However, the growth rate of leptospires is slow, and therefore after an incubation period of 2–20 days, symptoms arise. The organisms have a particular predilection for kidneys and liver. In the kidneys, it migrates to the interstitium, renal tubules, and lumen causing interstitial nephritis and acute tubular necrosis (ATN). Direct leptospire injury may cause ATN, whereas interstitial nephritis occurs due to antigen–antibody complexes of the immune phase. In the liver, centrilobular necrosis with proliferation of Kupffer cells in seen resulting in hepatic dysfunction. Leptospiras also disrupt the endothelial lining of blood vessels leading to capillary leaks and hemorrhages. Capillary vasculitis is found in every affected organ system. There may be associated thrombocytopenia. Despite the possibility of severe complications, the disease is usually non-fatal and self-limiting. Leptospire-mediated injury characterizes the initial phase of the disease which is also called septicemic phase, and host immune response marks the onset of second phase of symptoms called immune phase of the disease. However, the true mechanism of host tissue injury remains unclear and likely involves a complex set of interactions.15
Clinical Features Clinical symptoms include fever, headache, myalgia, and vomiting, and thus this disease is difficult to differentiate from other viral illnesses. Symptoms last for 4–7 days. Subsequently, the patient may be asymptomatic for 1–3 days followed by reappearance of fever. Aseptic meningitis and renal dysfunction are seen during this phase which is the immune phase. Uveitis is also a feature of this phase. Symptoms during the second phase may last for 6 days to 4 weeks. Ten percent of patients may go on to develop severe
6
Pediatric Infectious Disease 2012 January–March; Vol. 4, No. 1
disease characterized by jaundice, renal failure, shock, and circulatory collapse. Multi-organ dysfunction, development of adult respiratory distress syndrome (ARDS), and mortality rate of 5–10% have been noted despite intensive care unit (ICU) care. Other biochemical abnormalities that occur are mild elevated liver transaminases, hypokalemia (due to renal tubular wasting), hyponatremia, thrombocytopenia, and elevated prothrombin time. White cell count may be normal, but there may be shift to left with neutrophilic predominance. Erythrocyte sedimentation rate may be elevated.16 Renal involvement is seen in all phases of the disease, and renal failure has been found to range from 50% to 79%. However, symptomatic renal failure in the form of azotemic, anuria, and oliguria is seen with severe disease1,17 and occurs after 4–10 days after the onset of symptoms. Other features which may be seen in leptospirosis include conjunctival hyperemia, myositis, lymphadenopathy, hemoptysis, cough, maculopapular rash, and bleeding manifestations such as hemoptysis, epistaxis, gingival oozing, petechiae, and pulmonary hemorrhage. Vasculitis can lead to third spacing of fluids and hypovolemic shock with vascular collapse. Myocarditis and atrioventricular blocks have also been noted.18
Leptospirosis in Pregnancy Leptospirosis in pregnancy is a complicated problem, and infection in first two trimesters can lead to spontaneous abortions. Third-trimester infections can also lead to abortion or perinatal death in one-third of the pregnancies. Although congenital leptospirosis has been reported with successful treatment intervention, such cases have been few.19
DIAGNOSIS OF LEPTOSPIROSIS Leptospires may be isolated from blood, cerebrospinal fluid, and most tissues during the septicemic phase which lasts for about 5–7 days. However, since this phase usually presents with non-specific symptoms, it is usually missed. The immune stage is characterized by circulating antibodies and disappearance of leptospires from the circulation. However, leptospires may still be isolated from urine for several weeks up to 2 months post-infection. The leptospires can be identified using dark-field microscopy or direct fluorescent-antibody assay. Serologic assays for detection of antibodies are microscopic agglutination test (MAT), enzyme-linked immunosorbent assay (ELISA), and indirect hemagglutination assay. Seroconversion usually occurs after 5–7 days after the onset of disease but may sometimes occur only after 10 days or
Shah
longer. IgM class antibodies usually appear somewhat earlier and may be present for up to 2 months after the infection and at lower titers for years. IgG antibody is usually erratic and often may not be detected or may be detectable for only relatively short periods of time. Thus, the presence of antibodies is by itself no proof of current infection, as some antibodies may persist for long periods after an infection. Generally, seroconversion or four-fold rise in titer in consecutive serum samples is considered to be diagnostic proof of recent infection. A high IgM time, that is, a titer severalfold above the cut-off point in a single serum sample is consistent with current or recent leptospirosis. The MAT is considered to be the gold standard for diagnosis and can identify specific serotypes. The MAT uses a battery of antigens from common endemic leptospire serovars. A single titer exceeding 1:200 or serial titers exceeding 1:100 suggests leptospirosis. Test accuracy is affected by selection of antigens for the test and laboratory needs facility to culture and maintain panels of live leptospires to keep up the antigen battery. This test is important from the epidemiologic point of view to identify the serovar. The ELISAs are popular and several assays are available. Several commercial kits are available to detect IgM and sometimes also IgG antibodies. The advantage is that only one genus-specific antigen which is shared by all leptospires is used, and culture of leptospires in the local laboratory is not required to provide the antigen. However, it is less specific, and weak cross-reactions due to the presence of other diseases may be observed. Also serotype differentiation cannot be done. However serotype differentiation may not be required for clinical management of patient and is only important from epidemiological point of view. Other serological tests are indirect hemagglutination assay and dipstick IgM dot assays that have lesser sensitivity and specificity as compared to ELISA test.3 Polymerase chain reaction (PCR) based techniques have been developed but have limited epidemiologic, economic, and public health value.1
TREATMENT Treatment of leptospirosis consists of antibiotics with supportive care and close monitoring of renal, hepatic, and circulatory function. Early antibiotic treatment aids in faster recovery and prevents progression of the disease. Although antibiotic efficacy may decrease after day 10 of illness due to disappearance of leptospires and appearance of antibodies, antibiotic therapy should not be denied. Severe infections should be managed by Intravenous Penicillin in doses of
Leptospirosis
50,000–100,000 U/kg/day in four to six divided doses for 7–10 days. In patients with penicillin allergy, erythromycin (30–50 mg/kg/day in three to four doses for 7–10 days) may be given. For mild cases, oral amoxicillin (30–40 mg/kg/day 4 times a day for 7–10 days), ampicillin (50–100 mg/kg/day 4 times a day for 7–10 days) and doxycycline (2 mg/kg/dose 2 times a day for 7 days in children >8 years of age) can be used. Third-generation cephalosporins, such as ceftriaxone and cefotaxime, and quinolones may also be useful.20 For patients with renal failure not responding to medical line of management, dialysis may be required. There have been some reports of use of high-dose pulse steroids (methyl prednisolone—30 mg/kg/day) for treatment of immune-complex-mediated renal failure, but its role is not fully established.21 Additional supportive care may include inotropic agents and diuretics.
PREVENTION Eradication of leptospires from animals is difficult, and this leads to constant source of infection. Also, the presence of large number of serovars makes control complicated. Practicing good personal hygiene, avoiding wading, or exposure to rodent-urine-contaminated water is advisable. For those exposed adults, doxycycline in dose of 200 mg weekly may help prevent disease. Role of antibiotics prophylaxis in children is not established although amoxicillin has been tried. In some countries, vaccines that are serovar-specific are available but must be repeated yearly and are associated with painful swelling on revaccination. Thus, they are recommended only in high-risk groups.
CLINICAL DILEMMAS WITH LEPTOSPIROSIS The author first reported Weil’s disease in 1999 and subsequently has seen various different manifestations of leptospirosis in children. Although leptospirosis by convention is classified into septicemic phase and immune phase; clinically it is very difficult to differentiate between the two. Also leptospirosis is confirmed by isolation of leptospira antibodies by ELISA, most of the diagnosed cases of leptospira have been identified only once the antibodies have already formed. Isolation of leptospira in culture from blood and tissues is not always found. Thus, it is quite possible that septicemic phase of leptospirosis may be going unrecognized and what may be seen clinically may be due to immune reactions of the body. However, from a management point
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of view, it really makes no difference to identify septicemic versus immune phase. What is important is to identify the severe variety of leptospirosis from the milder ones. Thus, from a practical aspect, it would be better to classify leptospirosis into icteric versus non-icteric variety. Icteric variety is also called Weil’s disease and is characterized by fever, jaundice, and renal failure. Non-icteric variety may present as aseptic meningitis, fever with thrombocytopenia, and fever with non-oliguria failure. Icteric leptospirosis should be differentiated from other viral hepatitis with fulminant hepatitis, such as hepatitis A and E. The most important differentiating feature is the presence of renal failure very early in the course of the disease, thrombocytopenia, and mildly elevated liver enzymes as compared to viral hepatitis where liver enzymes may be markedly elevated, and there is associated encephalopathy with fever disappearing on appearance of jaundice.5 Interestingly, all our patients with leptospirosis were boys and on retrospective questioning did mention wading or playing in flooded streets a few days ago suggesting recreational hazard as a common factor of transmission. Non-icteric leptospirosis may present with aseptic meningitis. However, the commonest presentation is non-oliguric renal failure, and fever or fever with thrombocytopenia. In August 2005, among 32 patients with fever, vomiting, diarrhea, and bleeding manifestations who presented in the monsoon season, we found that patients with leptospirosis had elevated blood urea nitrogen (BUN), elevated serum creatinine, and near normal platelet count. Also, mildly elevated liver transaminases were seen in only 16.7% of patients. Thus, we could differentiate dengue (as patients with dengue had hemoconcentration, thrombocytopenia, elevated SGPT, and hepatomegaly), malaria (patients with malaria had anemia, splenomegaly, and lowest platelet count), and leptospirosis.22 In June 2005, we also found that children with fever presented with hyponatremia, elevated BUN, creatinine, and hyperkalemia without oliguria suggestive of nonoliguric renal failure and tested positive for leptospira IgM by a commercial ELISA. These patients responded to penicillin and did not require dialysis.13 Thus, spectrum of leptospirosis is varied. However, if caught early, one can prevent progression of the disease to a severe variety. A high index of suspicion would be necessary especially in the monsoons.
CONCLUSION Leptospirosis is a common zoonotic disease in humans leading to acute febrile illness especially in monsoons. It is
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characterized by fever, myalgia, headache, and non-oliguric renal failure. High suspicion and early treatment with antibiotics is essential to prevent complications. Ten percent of patients may develop Weil’s disease characterized by fever, jaundice, and renal failure associated with multi-organ dysfunction and 5–10% mortality rate. Treatment with injectable penicillin is needed for severe disease. For mild disease, ampicillin, amoxicillin, or doxycycline (in children >8 years of age) can be given. Avoiding exposure to rodent-urineinfested waters is advisable to prevent leptospirosis.
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