John Snow: Cholera

Leptospira interrogans are flexible, gram-negative spirochetes (spiral or cork-screw bacteria) with internal flagella that they use to propel themselves by twisting back and forth 1. “They are motile, with hooked ends and paired axial flagella (one on each end), enabling them to burrow into tissue. Motion is marked by continual spinning on the long axis” 2. Leptospira cells are encased in a three to five layer membrane and have relatively simple nutritional needs. The only known organic compounds necessary for its growth are vitamins B1 and B12.

L. interrogans is one of two species of Leptospira, and contains over 200 pathogenic strains, the most prevalent being canicola, grippotyphosa, hardjo, icterohaemorrhagiae, and pomona. These pathogenic bacteria, which are referred to as Leptospires, are the infectious agents that cause the zoonotic disease Leptospirosis. This disease is known to affect both humans and animals, and is considered the most common zoonosis in the world 2. It has the potential to become even more prevalent with global warming.

The primary hosts for this disease are wild and domestic animals, and the disease is a major cause of economic loss in the meat and dairy industry. Humans acquire the infection by contact with the urine of infected animals, but human-to-human transmission is extremely rare 1. Mucous membranes and broken skin are most likely the sites of entry for this bacterium, but they are also believed to enter the host through sodden and waterlogged skin, through the lungs (after inhalation of aerosolized body fluid), or through the placenta during pregnancy.

“Virulent organisms in a susceptible host gain rapid access to the bloodstream through the lymphatics, resulting in leptospiremia and spread to all organs. The incubation period is usually 5-14 days but has been described from 72 hours to a month or more” 2. A generalized infection may develop, but no lesion develops at the site of entry. The host responds by producing antibodies that rapidly eliminate the leptospires from all tissues except the brain, eyes, and kidneys. Leptospires surviving in the brain and eyes multiply slowly if at all; however, in the kidneys they multiply in complex tubules and are shed in the urine 1.

The leptospires can stay in the host for weeks to months, and in rodents they may be shed in the urine for its entire lifetime. Exotic-pet trade further increases the likelihood of transmission. In 2005, leptospirosis was transmitted from southern flying squirrels imported from Miami, Florida, to two Japanese animal handlers employed by an importer of exotic pets. Endemic canine leptospirosis is becoming more common in the United States, and California has seen a re-emergence of disease since 2000 2. The first recorded case was in 1886 and was referred to as Weil’s disease, which could be deadly.

It was initially believed to be related to the plague, but not as contagious. These days, however, most human cases of leptospirosis are not life threatening. Case fatality is low but increases with advancing age and may reach 20% or more in those with jaundice or kidney damage 3. The mortality rate in severe leptospirosis has been described as ranging from 5-40%, but the mild form of the illness is rarely fatal. The elderly and people with impaired immune systems are at the highest risk of mortality. “No evidence suggests that leptospirosis affects persons of various races, ages, or sexes differently.

However, because occupational exposure constitutes a major risk for development of disease, a disproportionate number of working-aged males seem to be affected” 2. Clinical manifestations of the disease are associated with a general fever, headache, muscle pain, and nausea, and therefore are often misdiagnosed as meningitis or hepatitis. Jaundice has been seen in more severe infections 1. In the early course of infection, leptospires have to survive and spread in the bloodstream before causing damage to target organ systems, the three most frequently involved being the central nervous system, kidneys, and liver.

In the kidneys, interstitial nephritis, tubular necrosis, and impaired capillary permeability, as well as associated hypovolemia, result in renal failure. “The damage to the vascular system as a whole can result in capillary leakage, hypovolemia, and shock. Many patients with leptospirosis may develop disseminated intravascular coagulation (DIC), hemolytic uremic syndrome (HUS), thrombotic thrombocytopenic purpura (TTP), and vasculitis. Thrombocytopenia indicates severe disease and should raise suspicion for a risk of bleeding” 2.

Leptospirosis is a disease found throughout the world, but it is more widespread in tropical areas, where the infectious agent may be one of many strains carried by a large variety of hosts 4. It can contaminate natural bodies of water, which also serve as a source of the infection and occasionally it is transmitted through ingestion of contaminated food or by inhalation of droplet aerosols of contaminated fluids. It is no longer a reportable disease in the United States; however, numerous states, including Hawaii, continue to report.

An estimated 100-200 cases are identified annually in the United States, with about 50% of cases occurring in Hawaii. The state of Hawaii is affected more than any other state. Although little can be done about controlling the disease in wild animals, leptospirosis in domestic animals can be controlled through vaccination. However, there is no human vaccination. Leptospirosis is treated primarily with antimicrobial therapy. In uncomplicated infections that do not require hospitalization, oral doxycycline has been shown to decrease duration of fever and most symptoms.

Hospitalized patients should be treated with intravenous penicillin G 1. As with L. interrogans, Leishmania donovani is a zoonotic microbe found primarily in the tropics and subtropics. This microbe causes visceral leishmaniasis in humans and carnivores, and can be lethal if untreated. Leishmaniasis infections are considered zoonotic diseases because the infection is maintained in dogs, wild rodents, and other animals in endemic areas.

Leishmaniasis is a vector-borne disease that is transmitted by sandflies, and the settings in which it is found range from rain forests in Central and South America to deserts in West Asia. However, more than 90 percent of the world’s cases of leishmaniasis are in India, Bangladesh, Nepal, Sudan, and Brazil 5. “This infection disproportionately affects poorer people in developing areas of the world. Because of the debilitating and disfiguring results of infection, these diseases are a great barrier to socioeconomic progress in endemic areas” 6.

As of 2001, it was estimated that 12 million people worldwide have been infected with leishmania, and 2 million new cases are believed to occur each year. Recent environmental changes such as urbanization, deforestation, and new irrigation schemes have expanded endemic regions and have led to sharp increases in the number of reported cases. “The incidence of leishmaniasis is increasing, mainly because of man-made environmental changes that increase human exposure to the sandfly vector. Poverty and malnutrition play a major role in the increased susceptibility to the disease.

Extracting timber, mining, building dams, widening areas under cultivation, creating new irrigation schemes, expanding road construction in primary forests such as the Amazon, continuing widespread migration from rural to urban areas, and continuing fast urbanization worldwide are among the primary causes for increased exposure to the sandfly” 7. Leishmaniasis is a disease that involves the reticuloendothelial system. Parasitized macrophages spread the infection to all parts of the body but more so to the spleen, liver, and bone marrow.

The spleen is enlarged, and is soft and fragile; “its vascular spaces are dilated and engorged with blood” 7. Leishmaniasis has 2 major forms: cutaneous, characterized by skin sores, and visceral, which affects internal organs and is characterized by high fever, substantial weight loss, swelling of the spleen and liver, and anemia. If untreated, the disease can be fatal within two years and is often caused by bacterial pneumonia, septicemia, dysentery, tuberculosis, cancrum oris, and uncontrolled hemorrhage 7.

Visceral leishmaniasis is the most severe form. “Visceral leishmaniasis is establishing itself in previously unaffected areas by piggy-backing on the spread of the HIV epidemic. Leishmania co-infection with HIV has become a serious global health threat. The two infections are involved in a deadly synergy, because leishmania infection exacerbates the immunocompromised state of infected individuals, thereby promoting HIV replication and resulting in earlier onset of AIDS.

The combination of HIV co-infection, expansion of endemic regions, and evolving drug resistance has created great need for more effective anti-leishmanial drugs and other control measures” 6. Visceral leishmaniasis is also called kala-azar, a Hindi term meaning “black fever. ” The causal agent, Leishmania donovani, was also named for physician Charles Donovan, who discovered the agent in India in 1903 8. Leishmaniasis is transmitted by the bite of infected female phlebotomine sandflies.

The sandflies become infected by ingesting infected cells during blood meals, and they inject the microbe from their proboscis during these meals. The parasite has 2 forms: the amastigote form and the promastigote form. The amastigote form occurs in humans, whereas the promastigote form occurs in the sandfly. Physical symptoms include anemia, which is almost always present and usually severe. The skin is dry, thin, and scaly, and hair is lost. As the disease progresses, the skin on the hands, feet, abdomen and face may become darkened, which is why the disease is also termed black fever 7.

Sodium stibogluconate is usually the drug of choice in the treatment of visceral leishmaniasis, however sometimes the microbe can build a resistance to it if there is a delayed diagnosis or if it is interrupted and at a low dose. A high-protein and high-calorie diet is required during the course of treatment 7. Legionnaires’ pneumonia is caused by Legionella pneumophila, another gram-negative bacilli. This pneumonia, and the bacterium, were not discovered until 1976, when there was an outbreak of disease at a Legionnaire’s meeting in Philadelphia 9. The clinical manifestations of Legionella infections are primarily respiratory.

Two very different kinds of respiratory illness may result from infection: the most common presentation is acute pneumonia, which varies in severity from mild illness that does not require hospitalization (walking pneumonia) to fatal pneumonia. Typically, patients have high, unremitting fever and cough but do not produce much mucus. Other symptoms such as headache, confusion, muscle aches, and gastrointestinal disturbances, are common. “The pathogenesis of Legionella infections begins with a supply of water containing virulent bacteria and with a means for dissemination to humans.

Person-to-person transmission has never been demonstrated, and Legionella is not a member of the bacterial flora of humans” 10. Infection begins in the lower respiratory tract. Alveolar macrophages, which are the primary defense against bacterial infection of the lungs, engulf the bacteria; however, Legionella is a facultative intracellular parasite and multiplies freely in macrophages 10. The only documented source of Legionella species is water, especially the surface waters of rivers and lakes and drinking water.

L. pneumophila does not multiply in sterile tap water, but the addition of free-living amoebae results in growth of the bacilli in vitro. Evaporative condensers and cooling towers are proven sources of outdoor infection. Indoors, nebulizers and humidifiers filled with contaminated drinking water have spread L. pneumophila to susceptible patients. The automatic misting devices that keep supermarket produce fresh have even been involved in outbreaks of pneumonia. Aerosols are produced in numerous ways in our environment, from taking a shower to flushing the toilet.

Clusters of L. pneumophila have occurred after exposure to whirlpool spas in hotels or cruise ships, but in most cases we do not know the source of the infection. There are no distinguishing features of Legionella pneumonia, so the diagnosis must come from the laboratory. The diagnosis is confirmed in the lab by culture, demonstration of bacterial antigen in body fluids, or detection or a serologic response 10. “This genus is so common in water systems that molecular analysis of environmental and clinical stains is often helpful in pinpointing the source.

Unfortunately, decontamination can be expensive. The two most common means of eradicating Legionella are periodic superheating of water with attendant dangers of scalding, and continuous chlorination, which accelerates deterioration of plumbing systems unless carefully monitored. Even “chlorinated” drinking water must be treated because the levels of chlorine decrease with increasing distance from the distribution center, particularly in hot water” 10. Immunization has been proposed as a means of preventing Legionella infection in susceptible populations.

This approach works in experimental animals but has not been attempted in humans. Men are affected more frequently than women, and the mean age of patients with this disease is 52. 7 years, with increasing incidence until age 79. The incidence in people younger than 35 is less than 0. 1 cases per 100,000 people. Older patients also have higher mortality rates. L. pneumophila is more common in the summer, especially in August, and is slightly more prevalent in the northern US. Risk factors for this disease are smoking, diabetes, cancer, AIDS, renal disease, alcohol abuse, surgery, old age, and chronic cardiopulmonary disease 11.

Legionella infections may be sporadic or epidemic, but both cases are more common during summer than winter months. There are several complications that can arise as a result of Legionnaire’s disease. These include dehydration, septic shock, hyponatremia, respiratory insufficiency, hypoxic respiratory failure, endocarditis, gastrointestinal symptoms (diarrhea, vomiting, anorexia), multiple organ failure, coma, or death in 10% of treated patients and in as many as 80% of untreated patients 11.

The preferred drug for symptomatic Legionella infections is erythromycin. If the patient is seriously ill, it is important to deliver the antibiotic intravenously at first, and then oral therapy may be used. Rifampin is sometimes added as a second antibiotic in seriously ill patients. Mortality is low in patients who do not have impaired immune systems. Similarly, even susceptible experimental animals survive infection unless fairly large doses of bacteria are given. Resistance to commonly prescribed medications is generally not an issue 12.

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Leptospira interrogans are flexible, gram-negative spirochetes (spiral or cork-screw bacteria) with internal flagella that they use to propel themselves by twisting back and forth 1. “They are motile, with hooked ends and paired axial flagella (one on each end), enabling …

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