It has been over a century and a half when John Snow undertook the study of the Cholera epidemic of 1854 in London. His work, which was published in the 1855 book On the Mode of Communication of Cholera, is considered a milestone in epidemiology. The observations by Snow of the water-born transmission of cholera and the handle of the Broad Street pump was a work of genius that continues to inspire epidemiologists. Appearing before the local body of government on September 7, 1854, John Snow argued that the source of the outbreak of a cholera epidemic was water from a communal water pump. His investigation identified the pump at Broad Street near its intersection with Cambridge Street as the source of contaminated water. Cholera which is an acute, diarrheal illness caused by infection of the intestine with the bacterium Vibrio cholerae, causes significant morbidity and mortality in many developing countries. This paper examines the cholera epidemics (and pandemics) in recent history including the outbreak of 1854 in London and the role played by John Snow which had laid the foundations for the modern principles of epidemiology.

Introduction

It has been over a century and a half when John Snow undertook the study of the Cholera epidemic of 1854 in London. His work, which was published in the 1855 book, On the Mode of Communication of Cholera is considered a milestone in epidemiology. The observation by Snow of the water-born transmission of cholera, and the handle of the Broad Street pump was a work of genius that continues to inspire epidemiologists. Appearing before the local body of government on September 7, 1854, John Snow, an anesthetist in London, argued that the source of the outbreak of a cholera epidemic was water from a communal water pump. Working with the data reproduced in table 1 (Bingham et al., 2004), Snow identified the pump at Broad Street near its intersection with Cambridge Street as the source of contaminated water. What followed is best told in his own words: “I had an interview with the Board of Guardians of St. James’s parish on the evening of Thursday, 7th September, and represented the above circumstances to them. In consequence of what I said, the handle of the pump was removed on the following day” (Snow, 1855).

Each year, outbreaks of cholera to cause death estimated at 120,000 worldwide, with the vast majority occurring in children (WHO, 1995). Epidemiology of cholera is characterized by several key principles including (i) Cases tend to be concentrated in specific location and occur during a specific season (ii) the highest infection rates in children of 1-5 years in areas where infection is endemic (iii) antibiotic resistance patterns often change from year to year, (iv) pathogen strain often exhibit clonal diversity, and (v) prevention measures against the disease include sanitation, hygiene and immunity improvement.

Cholera has been ranked as one of the “emerging and reemerging infections” (Satcher, 1995) facing many developing countries. Several recent events highlight the importance of epidemiological disease include the 1991recurrence of cholera in Latin America (Levine, 1991) ( Ries et al., 1992); the 1994 outbreak of cholera which took place in a Rwandan refugee camp in Goma, Zaire, which resulted in approximately 70,000 cases and 12,000 deaths in (Siddique, 1995), and the outbreak of V. cholerae O139 in the India subcontinent from 1992 to 1993, possibly marked the start of the eighth cholera pandemic (Ramamurthy et al., 1993)(Swerdlow et al., 1993).

Pathogenesis and transmission of Cholera

Vibrio Cholerae are comma-shaped, gram-negative bacteria that have been the cause of several great long-lasting epidemics and pandemics of diarrheal disease. Many of these pandemics began in the Ganges Valley of India and Bangladesh, which is never free from cholera. Although there are 140 serotypes of V. cholera, until recently only 1 stereotype was associated with several diarrhea. Beginning in 1992, a new V.cholerae stereotype (0139, also known as Bengal) has been associated with sever, watery diarrhea (Faruque et al., 1998)

The vibrios never invade the epithelium but instead remain within the lumen and secrete an enterotoxin, which is encoded by a virulence phage. Flagellar proteins involved in motility and attachment are necessary for efficient bacterial colonization, as has been described for Campylobacter. The vibrio hemagglutinin, which is a metalloprotease, is important for detachment of Vibrio from epithelial cells. The secretory diarrhea characteristic of the disease is caused by release of cholera toxin. Cholera toxin is composed of five binding peptides B and a catalytic peptide A (McKenzie et al., 1984). The B peptide, serving as a “landing pad”, bind to carbohydrates on GM1 ganglioside on the surface of epithelial cells of the small intestine, enabling calveolar-mediated endosomal entry of toxin subunit A into the cell (Laloi et al. 1996). Reverse transport of the subunit A from endosome into the cell cytoplasm is followed by cleavage of the disulfide bond linking the two fragments of peptide A (A1 and A2). Catalytic peptide A1 is generated, leading to the following sequence (Dertzbaugh et al., 1993):

A1 interacts with 20-kD cytosolic proteins called ADP-ribosylation factors (ARF).

The ARF-A1 complex catalyzes ADP-ribosylation of a 49-kD G-protein (called Gsα) (Randazzo et al., 2000).

Binding of NAD and GTP generates an activated Gsα, which in turn binds to and stimulates adenylate cyclase. ADP-ribosylated Gsα is permanently in an active GTP-bound state, resulting in persistent activation of adenylate cyclase.

The activated adenylate cyclase generates high levels of intracellular cAMP from ATP.

Cyclic AMP stimulates secretion of chlorides and bicarbonate, with associated sodium and water secretion. Chloride and sodium reabsorption is also inhibited. The reabsorptive function of the colon is overwhelmed, and liters of dilute “rice water” diarrhea containing flecks of mucus-up to 14 L/day, equivalent to the circulating blood volume, causing dehydration and electrolyte imbalances. Because overall absorption in the gut remains intact, oral formula can replace the massive sodium, chloride, bicarbonate, and fluid losses and reduce the mortality rare from 50% to less than 1% (Sharma et al., 1997)

Epidemiology of Cholera

Early Pandemics

Since the beginning of the first pandemic in 1817, seven cholera pandemics have occurred (Pollitzer,1959), excluding the seventh pandemic, which took place on the Indonesian island of Sulawesi in (65), pandemics occurred in the Indian subcontinent in the Ganges delta and spread to other countries over many years (Snow, 1855). In 1830, the epidemiological and public health approaches to cholera developed in the context of some understanding of the nature of certain infectious diseases, including smallpox and syphilis, with little agreed differentiation of the fevers. In his late 18th century doctrine, Benjamin Rush describes “there was but one fever in the world’ ” (Shryock, 1936) had received broad support. “Exciting factor” in the cholera epidemic was sometimes considered as shaping existing fevers into its own image, and the arrival of cholera coincided with an increase in mortality and/or transferred deaths between categories was questioned.

The second cholera pandemic of the early 1830s invaded the British Isles, and was marked by epidemiological observations made by John Snow on the waterborne cholera transmission in London between 1847 and 1854(Snow, 1855). Ships carrying Irish immigrants caused the second pandemic in Canada (Marian, 1957). During the third pandemic (1852-1859), cholera was raging in the United States, and during the 1870s at the end of the fourth pandemic, towns and villages along the Ohio, Missouri, and Mississippi, rivers experienced cholera (Billings et al., 1975). The fifth pandemic mainly affected South America; causing large epidemics in several countries with Argentina, Chile, and Peru suffering high casualties. (Gil et al. 2004).

Robert Koch isolated the cholera bacterium, known as “comma bacilli” during the fifth pandemic in feces of patients in Egypt in 1883 and India in 1884(Koch, 1884). Between 1899 and 1923, the sixth pandemic involved populations expanded in the Balkan Peninsula and the Middle East (Pollitzer, 1959). Apart from a large epidemic in Egypt in 1947 (Shousha, 1947), cholera was confined to southern and Southeast Asia since the mid-1920s until the 1961 outbreak of the seventh pandemic in. Both the sixth pandemic and possibly the fifth pandemic were caused by V. cholerae of classical biotype.

The Seventh Pandemic

The seventh pandemic is considered the largest of the pandemic in the geographical distribution, and was caused by V. cholerae O1- biotype El Tor (Table 2). The 1961 pandemic first invaded the island of Sulawesi in Indonesia and spread to other islands, including Borneo, Sarawak Java, Taiwan, the Philippines, and Sabah. It affected the entire archipelago of South Asia at the end of 1962 (Kamal, 1974). , In Asian mainland, from 1963-1969, the pandemic affected Cambodia, Thailand, Vietnam, Malaysia, Burma, India, Pakistan, and Bangladesh. Cholera reached Pakistan shortly after El Tor, and outbreaks were reported in Iraq, Iran, Afghanistan, and in the neighboring republics of the Soviet Union (Kamal 1974).

By 1970, El Tor cholera had reached the Arabian Peninsula, Syria and Jordan, and to a lesser degree, in Israel (Cohen et al., 1971). The seventh pandemic was in sub-Saharan West Africa in early 1970, causing explosive epidemics as a result of more than 400 000 cases of high mortality, attributed mainly a lack of background immunity of the population, and lack of healthcare infrastructures (Goodgame et al., 1975). During this epidemic, cholera invaded the coast and the interior through waterways and continued to spread to the interior of the Sahel countries by land to travel to nomadic tribes. During the 1970 cholera epidemic, 28 were newly affected were reported and 16 are in Africa (Kaper et al., 1995).

In South America, the seventh pandemic which began in Peru in January 1991 caused a return of cholera to the continent after more than a century in an explosive epidemic (Levine, 1991) (Ries et al., 1992). Subsequently, neighboring Ecuador and Colombia also reported cholera epidemic. In each of these countries were people of low socio-economic status, lack of clean water and sanitation, the most affected (Pan American Health Organization, 1991). In April 1991 a small outbreak was reported in Santiago, the capital of Chile (Levine, 1991). Cholera then invaded more countries in South and Central America along the Pacific coast. The Pan American Health Organization estimated that during 1991 and 1992 there were 750,000 cases of cholera and 6,500 deaths in the Americas (Pan American Health Organization, 1991).

Recently, the July 1994 outbreak in Goma, Zaire, (Siddique, 1995), is considered one of the worst outbreaks in recent history. Nearly a million people were displaced to Zaire and sheltered in refugee camps as a result of Conflicts between tribes in neighboring Rwanda. Outbreak of cholera in refugee camps affected by poverty caused an estimated 12,000 deaths among Rwandan refugees during a period of three weeks (Siddique, 1995). The seventh pandemic was active causing seasonal outbreaks in several developing countries. However, in 1992, V. cholerae belonging to serogroup non-O1 (now known as O139) caused massive epidemics of cholera in Bangladesh and India and spread to other countries, which could represent the beginning of the eighth pandemic

Conclusion

John Snow achievement was based on the logical organization of his remarks. He recognized a natural experiment, and its quantitative approach to the analysis of the occurrence of disease in human populations, which is actually a summary of the views of modern epidemiology. It has been over a century and a half since Dr. Snow had published his findings. And in spite the medical and epidemiological advancement in combating the disease, yet, the threat of cholera remains very real and cholera continues to be a global threat to public health and an important indicator of the lack of social development, especially in developing countries which suffer from lack of access to drinking water and lack of sanitation. The disease continues to challenge the increasing proportion of vulnerable populations living in unsanitary conditions, such as slums and refugee camps. The treatment centers and water purification units in poor nations are only interim measures, and steady decline in the spread of the illness should not be seen as a complete victory.