Pediatric Leptospirosis 

Leptospirosis is a worldwide zoonosis caused by pathogenic species of the genus Leptospira. In 90% of cases, leptospirosis manifests as an acute febrile illness with a biphasic course and an excellent prognosis. Nonspecific signs and symptoms of leptospirosis (eg, fever, headache, nausea, vomiting) are often confused with viral illness.

In 10% of cases, the presentation is more dramatic, and the infection has a mortality rate of 10%. Known as Weil disease or icteric leptospirosis, the classic definition of this form of leptospirosis includes fever, jaundice, renal failure, and hemorrhage. Other organ systems (ie, pulmonary system, cardiac system, CNS) are also frequently involved.

Weil is credited with first describing leptospirosis as a unique disease process in 1886, 30 years before Inada and colleagues identified the causal organism.^[1]

The genus Leptospira belongs to the Leptospiraceae family of the order Spirochaetales. The nomenclature system used to organize leptospires has been revised, making review of the literature often confusing. The traditional system divided the genus into 2 species: the pathogenic Leptospira interrogans and the nonpathogenic Leptospira biflexa. These species were divided further into serogroups, serovars, and strains based on shared antigens. L interrogans included more than 250 serovars.

The current classification system is based on DNA homology and recognizes the heterogeneity of the classic leptospires, dividing L interrogans and L biflexa into 12 named species, 4 unnamed species, and 2 additional genera.^[2]

• Leptospira interrogans
• Leptospira weilii
• Leptospira santarosai
• Leptospira noguchi
• Leptospira borgpetersenii
• Leptospira kirschner
• Leptospira alexanderi
• Leptospira inadai (pathogenicity unclear)
• Leptospira fainei (pathogenicity unclear)
• Leptospira meyeri (pathogenicity unclear)
• L biflexa (saprophytes)
• Leptospira wolbachi (saprophytes)
• Unnamed Genomospecies 1 (pathogenicity unclear), 3 (saprophytes), 4, and 5 (saprophytes)
• Turneria parva (formerly Leptospira parva, saprophytes)
• Leptonema illini (saprophytes)

Within these species, leptospires are further grouped by serogroups, serovars, and strains on the basis of microscopic agglutination testing (MAT). Serologic grouping may, however, cross DNA based species boundaries. Although certain species (eg, L interrogans) have a classic association with Weil disease, knowledge of the species type does not necessarily help predict disease severity.

Leptospires infect many types of mammals including rats, dogs, cats, cattle, pigs, squirrels, raccoons, mongooses, and bandicoots.^{[3, 4]} Leptospiral species' and serogroups' host animals vary from region to region. Individual animals may carry several serovars.

Leptospirosis in animals is often subclinical. An infected animal may appear healthy even as it sheds leptospires in its urine. Leptospirosis has also been reported in immunized dogs, a finding possibly explained by either partial immunity or vaccines that did not cover the serovars responsible for the infection. Humans are dead-end hosts for the leptospire. Although both nosocomial and congenital leptospirosis have been described, both are rare.^{[5, 6]}

Leptospires are transmitted via infected urine. Leptospires infect humans by invasion across mucosal surfaces or nonintact skin. Infection may occur via direct contact with urine or through contact with contaminated water and soil. In favorable conditions, leptospires can survive in freshwater for as many as 16 days and in soil for as many as 24 days.^[7]

Many published case series focus on seasonal outbreaks and leptospirosis acquired occupationally or recreationally. Seasonal outbreaks associated with changes in local water levels have been described: flood conditions increase risk of exposure to the population at large, and drought causes leptospire concentrations to peak in isolated pools.^{[8, 9]} Animal handlers, farmers, and people active in freshwater sports are well-known high-risk groups for leptospirosis.^{[10, 11]}

Leptospire invasion across the epithelium is followed by proliferation and widespread dissemination. Every major organ system may be affected, and leptospire antigens can be detected in affected tissues. Leptospire-mediated injury characterizes the initial phase of the disease. A host-immune response marks onset of the second phase of symptoms.

Although direct invasion of tissue may cause some pathologic effects, researchers note that the marked degree of multiorgan tissue injury appears inconsistent with the number of leptospires found on microscopic examination of tissue. Other mediators induced by the leptospire are the suspected causes of the disease's various manifestations. Research has suggested endotoxin, hemolysin, and lipase as possible sources of pathogenicity. However, the true mechanism of host tissue injury remains unclear and likely involves a complex set of interactions.

The most consistent pathologic finding in leptospirosis is vasculitis of capillaries manifested by endothelial edema, necrosis, and lymphocytic infiltration. Capillary vasculitis is found in every affected organ system. The resulting loss of RBCs and fluid through enlarged junctions and fenestrae, which cause secondary tissue injury, probably accounts for many of the clinical findings.

Capillary vasculitis and leakage cause petechiae, intraparenchymal bleeding, and bleeding along serosa and mucosa. Thrombocytopenia sometimes is observed but is not a consistent finding in patients with bleeding. No disseminated intravascular coagulation (DIC) occurs. Prothrombin time (PT) sometimes increases in patients with leptospirosis, but vitamin K administration and concomitant correction of the PT do not alter the course of bleeding.

Direct hepatic injury appears to cause jaundice, although jaundice resulting from hemolysis and biliary obstruction has been suggested. Vascular congestion and disorganization of the liver cell plates are hallmarks of liver tissue injury in patients with leptospirosis. Hemolytic anemia is not associated consistently with jaundice.

Pulmonary findings are caused by alveolar capillary injury, either focal or diffuse. Interstitial and intra-alveolar edema and bleeding occur in areas affected by vasculitis and, in severe cases, may progress to frank hemorrhage. Regions without infiltrate also are free of vasculitis.

Renal findings include tubular necrosis and, later in the disease course, interstitial nephritis. Capillary vasculitis is readily identified. Although the glomeruli are spared, the progression from normal renal function to decreased glomerular filtration rate (GFR) to renal failure requiring dialysis can be rapid.

Cardiac lesions have been identified in postmortem examinations. In a series of 20 fatal cases, epicardial and endocardial petechiae were present in 70% of the patients, myocardial interstitial edema was present in 90%, lymphocyte/plasma cell infiltrate (consistent with myocarditis) was present in 50%, and coronary arteritis was present in 70%.

Hemorrhage, focal necrosis, and inflammatory infiltration have been documented within the adrenal gland. Although these complications do not appear clinically, some researchers speculate that adrenal insufficiency may mediate, in part, the final vascular collapse associated with fatal leptospirosis.

Frequency

United States

Leptospirosis, as a clinical entity, is underdiagnosed and underreported. The reported annual incidence ranged from 0.02-0.04 cases per 100,000 persons in 1985-1994. In 1994, 38 leptospirosis cases were reported nationwide,^[12] and the Council of State and Territorial Epidemiologists recommended removing leptospirosis from the list of notifiable diseases. Hawaii, which reports the highest annual occurrence rate, had 22 of those 38 confirmed cases. Between June 1998 and February 1999, Hawaii reported 405 suspected cases of leptospirosis; 61 of those cases were confirmed.^[13] Case numbers widely varied from island to island within the state. Incidence rates ranged from 2.3-40.2 cases per 100,000 persons, with the highest numbers of cases on Kauai and Hawaii. Serologic MAT of healthy blood donors among the military population in Hawaii showed a seroprevalence of 1.4%.^[14]

These reported cases starkly contrast with the prevalence rates found under active surveillance.^[15] Using active surveillance measures, Hawaiian researchers projected the state's true local incidence at approximately 128 cases per 100,000 persons. Major risk factors identified in Hawaii include the use of water catchment systems, wild pig hunting, and the presence of skin wounds.

Although less dramatic and often unrecognized, people with no obvious risk factor have significantly higher background infection rates than reports often indicate. Approximately 30% of children in urban Detroit^[16] and 16% of adults in Baltimore^[17] demonstrated serologic evidence of past infection. This pattern has been reproduced elsewhere; rural and suburban seropositivity rates reportedly lag behind urban rates. The Detroit study also showed correlation between degree of rat infestation and seropositivity rates. This finding suggests rats are major, if not the most important, vectors for human leptospirosis in the mainland United States. In Hawaii, the state with the highest reported incidence of leptospirosis, feral pigs are also important vectors.^[15]

International

Leptospirosis has been documented worldwide, but formal reporting systems widely vary. Reported incidence rates often are comparable to those in the United States and suffer from the same pitfalls. High-risk areas include the Caribbean islands, Central and South America, Southeast Asia, and the Pacific islands. Frequently, the disease gains public attention when outbreaks occur in association with natural disasters, such as flooding in Nicaragua in 1995 or among foreign travelers, as with extreme athletes competing in tropical rainforests.

Mortality/Morbidity

In 10% of cases, leptospirosis has severe manifestations including renal failure, hepatitis, pulmonary hemorrhage, reaching mortality rates of 10%.

Sex

Leptospirosis is most common among adult males, probably resulting from occupational and recreational exposures. In the converse, the difference in rates may be caused by practitioners who are more likely to look for and, hence, diagnose the disease in patients who have obvious risk factors. When population groups other than adult males are actively surveyed, prevalence rates are higher than those previously reported.

Age

Although most case series and reviews of leptospirosis indicate men as the key risk group, outbreaks have been reported in which more than 40% of patients were younger than 15 years, a reversal of traditional prevalence rates. Potential explanations in such cases include childhood predilections to play with suspected vectors (eg, dogs) or indiscriminate contact with water. Active surveillance measures have detected leptospire antibodies in as many as 30% of children in some urban American populations.