Shigellosis Research Paper Example

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Introduction

Shigellosis, an infectious disease of immense public heath significance, is characterized by the frequent passage of loose stools mixed with visible blood and mucus and accompanied by fever, abdominal cramps, and tenesmus. This disease is an important cause of morbidity and mortality, particularly in children younger than 5 years of age in developing countries. Globally, at least 165 million cases of shigellosis occur and 1 million people die of it each year (von Seidlein et al., 2006). The causative agent is Shigella spp., consisting of four serogroups, S. sonnei, S. boydii, S. flexneri, and S. dysenteriae. This research paper provides concise information about the epidemiology, clinical features including complications, bacteriology, and antimicrobial susceptibility pattern of Shigella spp., case management, and prevention and control of the disease, including current status of vaccine development.

Epidemiology

Shigellosis can occur in sporadic, epidemic, and pandemic forms. The transmission of the disease takes place person to person and through food and water. Human volunteer studies have shown that the minimum infective dose for shigellosis may be as low as 10–100 organisms. Since the infectious dose is small, the disease is highly contagious. The disease is more rampant in situations where there is overcrowding with poor sanitation and personal hygiene, as, for example, in developing countries and refugee camps and after floods, earthquakes, and tsunamis in which large populations are displaced. Shigella is one of the three most commonly identified pathogens in outbreaks due to recreational water exposure (the others being Giardia lamblia and Cryptosporidium), presumably due to fecal contamination by children. The disease has a short incubation period of 1–4 days, which is usually followed by acute symptoms. Communicability lasts for as long as the organism is excreted in the stool, sometimes up to 4 weeks. Secondary attack rates are high among household contacts (maybe up to 40%). S. sonnei occurs mostly in developed countries whereas S. flexneri is seen in endemic form in many developing countries. S. dysenteriae type 1 is often multidrug-resistant.

dysenteriae type 1 causes large epidemics and has the capacity for pandemic spread. For example, in 1969–70 an epidemic of shigellosis caused by S. dysenteriae type 1 occurred in Central American countries (Mata et al., 1970) and rapidly spread to different areas of Africa and parts of Asia. The pandemic then involved Bangladesh during 1972–78, southern India (Vellore) during 1972–73, Sri Lanka in 1976, Maldives in 1982, eastern India (Pal, 1984) in 1984, and Andaman and Nicobar Islands (Bhattacharya et al., 1988) in 1985. Each region experienced a severe shigellosis epidemic caused by multidrugresistant S. dysenteriae type 1.

Clinical Features

Although S. dysenteriae type 1 causes the most severe dysentery, shigellosis can occur as asymptomatic infection to mild diarrhea wherein the patient passes a few loose stools daily and generally recovers within a week. At times, this pathogen can cause life-threatening dysentery, in which the patient frequently (50–100 times daily) passes loose stools mixed with frank blood and mucus and accompanied by high fever, severe abdominal cramps, and tenesmus (incomplete sense of defecation with severe rectal pain). Children suffering from shigellosis often vomit and may have convulsions. Anorexia is particularly conspicuous. The differential diagnosis of shigellosis includes inflammatory colitis caused by other bacterial or protozoal colitis, namely, Campylobacter jejuni, Salmonella enteritidis, Clostridium difficile, Yersinia enterocolitica, enterohemorrhagic Escherichia coli, enteroinvasive E. coli, and the protozoan parasite Entamoeba histolitica. In the absence of a cure or anti-infective therapy, it is necessary to consider noninfectious conditions like ulcerative colitis and Crohn’s disease. AIDS patients may develop chronic carriage of Shigella.

Complications

Most cases of shigellosis recover rapidly with appropriate antibiotic therapy. However, shigellosis caused by S. dysenteriae type 1 sometimes develops one or more complications. The complications (Bhattacharya et al., 1988) may be classified as intestinal or extraintestinal. The intestinal complications include rectal prolapse, paralytic ileus, and toxic megacolon (sometimes due to injudicious use of anticholinergic drugs or morphine or codeine), intestinal perforation, intestinal hemorrhage, and protein-losing enteropathy. Extraintestinal complications are pneumonia; meningitis; vaginitis; keratoconjunctivitis; arthralgia; arthritis; skin rashes (‘rose spots’); peripheral neuritis; leukemoid reaction (white blood cell count >50 000 mm -3); and hemolytic uremic syndrome (HUS), which is characterized by a triad of hemolytic anemia, thrombocytopenia, and acute renal failure. Hypoglycemia, sometimes with seizures and electrolyte abnormalities, may occur. High levels of Shiga-family toxins expressed primarily by this organism cause HUS. It usually develops at the end of the first week of illness, when dysentery is already resolving.

Bacteriology And Pathogenesis

Each of the serogroups of the Shigella spp. has several serotypes, that is, S. dysenteriae type 1–12, S. sonnei phase II and I, S. boydii type 1–18, and S. flexneri type 1–6. However, most of the shigellosis cases are caused by S. sonnei, S. flexneri type 2a, and S. dysenteriae type 1. Gram-negative, facultative nonmotile bacilli, shigellae are ingested orally and can easily pass the gastric acid barrier since they can survive in low pH because of a genetically regulated property. Then they attach to the epithelial cells of the colon and express their pathogenicity through their ability to invade intestinal cells. A smooth lipoprotein cell wall antigen and Shiga toxin cause invasiveness and have cytotoxic, neurotoxic, and enterotoxic activities, the last of which results in watery diarrhea, which may be the early manifestation of the disease. Although the organisms invade and multiply in the colonic epithelial cells and cause ulcerations and produce bloody diarrhea (‘biphasic manifestation’), they rarely enter into the bloodstream. Edema is caused by inflammation of the muscularis mucosae and submucosa. Histological studies of rectal mucosa have found that changes are more severe in S. dysenteriae type 1 infection than in other Shigella spp. (Anand et al., 1986).

Presence of 140 mDa plasmid, ipaH, sen and ial genes and the ability to bind Congo Red and production of keratoconjunctivitis in eyes of guinea pig serves as virulence markers of Shigella strains.

Antimicrobial Susceptibility Pattern

dysenteriae type 1 strains are notorious for developing drug resistance to a large number of antibiotics. Antibiotics that were once highly effective became useless after being used for some time. For example, in the 1940s, when sulfonamides were introduced, they were highly effective against shigellosis but soon became ineffective. Similarly, drug resistance occurred to tetracycline, chloramphenicol, ampicillin, and cotrimoxazole (trimethoprim-sulfamethoxazole). In the 1984 epidemic in eastern India, the S. dysenteriae type 1 strains were multidrug-resistant and sensitive to only nalidixic acid (Bose et al., 1984). Clinicians in Calcutta found excellent results with the use of nalidixic acid for the treatment of multidrug-resistant shigellosis cases. Similar reports were also available from Andaman and Nicobar Islands (India). However, nalidixic acid-resistant S. dysenteriae type 1 was reported from Tripura, an eastern Indian state, in 1988. Although in the late 1980s, fluoroquinolones (Bennish et al., 1990; Bhattacharya et al., 1991; norfloxacin, ciprofloxacin, and ofloxacin) were very effective against shigellosis, they were soon found to be less effective, and the causative agent of these outbreaks in Bangladesh and India (Siliguri, Diamond Harbour, Kolkata, Aizwal) was S. dysenteriae type 1 strains resistant to these drugs (Bhattacharya et al., 2003; Sur et al., 2003). In fact, the clinicians had only azithromycin and ceftriaxone as available effective drugs for the treatment of such cases. The disadvantages of ceftriaxone are that it is relatively costly and must be administered by parenteral route. In Bangladesh, pivmicillinum was found to be effective against shigellosis. In general, S. dysenteriae type 1 is frequently resistant to common and inexpensive antibiotics and sensitive only to more-expensive or parenteral agents throughout its range.

Mechanism Of Antibiotic Resistance

Transmission of resistance takes place by clonal spread, especially of S. dysenteriae type 1, and also by horizontal transfer through plasmids, transposon-mediated conjugation, and mutations in the chromosome. Multidrugresistant genes in the integrons of the organism and its epidemic nature make shigellosis a very difficult public health problem to tackle. In Australia and Ireland, where trimethoprim-sulfamethoxazole, streptomycin, and spectinomycin were extensively used for treatment of shigellosis, S. sonnei strains soon showed class 2 integrons with a gene cassette array analogous to that found in transposon Tn7, namely, dfrA1, sat1, and aadA1, which conferred resistance to these drugs. Tetracycline resistance of Shigella has been found to be due to both clonal spread and horizontal gene transfer. Quinolone resistance is due to chromosomal mutation.

Clonal Spread Of Multidrug-Resistant S. Dysenteriae Type 1 May Result In Epidemics

Several outbreaks of multidrug-resistant S. dysenteriae type 1 in eastern India (2002), Mizoram (2003; Niyogi et al., 2004), and Bangladesh and sporadic cases admitted to the Infectious Diseases Hospital and B. C. Roy Children’s Hospital in Kolkata have shown genetic similarity in antimicrobial resistance pattern, pulsed field gel electrophoresis, and plasmid DNA. From the 2002 epidemic, the new clone of the strain caused sporadic cases in Kolkata, followed by an epidemic in Mizoram. Further, it has been observed that these strains are not similar to those of the preceding outbreak (1988; Pazhani et al., 2004).

Case Management

Many studies have convincingly demonstrated that appropriate antibiotic therapy shortens the duration of diarrhea, improves clinical signs and symptoms, and hastens recovery. Oral antibiotics are preferred. The choice of antibiotic depends on the drug resistance pattern of circulating shigellae strains in the locality. Antibiotic resistance may change quickly, and therefore periodic evaluation of drug sensitivity pattern is of paramount importance for successful therapy of patients. Any antibiotic used successfully for some time becomes ineffective for the treatment of shigellosis, and this is particularly true for S. dysenteriae type 1. This pandemic strain is notorious for developing multidrug resistance and often poses great therapeutic challenges. Currently, these strains in some parts of the world have even developed resistance to newer fluoroquinolones such as norfloxacin and ciprofloxacin. However, the strains are still sensitive to ceftriaxone and other third-generation cephalosporins. Oral rehydration therapy may be particularly useful if the disease is accompanied by dehydration and also improves patients’ general sense of well-being. The use of antimotility agents such as atropine with diphenoxylate (Lomotil) and loperamide is strongly discouraged because they may delay excretion of organisms and thus facilitate further invasion of the colonic epithelium. Nutritional support during the illness and after recovery deserves special attention. Although anorexia in the early stages of the disease prevents adequate intake of food, appetite improves within a few days with appropriate antibiotic therapy. Mortality rates of up to 10% have been reported for hospitalized patients, and should renal failure develop as a consequence of HUS development, renal dialysis may be required. Children under 5 years of age with bloody diarrhea are presumed to be suffering from shigellosis and for all such children treatment with an appropriate antibiotic is recommended.

Prevention And Control

Prevention and control strategies should mainly be focused on supply of safe drinking water, provision of proper and adequate sanitation facilities, and maintenance of good personal hygiene. Emphasis should be given to hand washing (Sircar et al., 1987), especially before eating, before feeding children, before cooking, and after ablution. As mentioned above, the infectious dose of this organism is among the lowest known (10–100 organisms), and so scrupulous attention to hygiene and disinfection is warranted. Because the disease spreads through food, water, and person-to-person contact, special protective hygienic measures should be adopted, especially in places where there is a chance of widespread dissemination of the organism, as in epidemic situations.

Vaccine Development

Vaccination for infectious diseases is an attractive disease prevention strategy. However, vaccine development for shigellosis poses a veritable challenge in that shigellosis is caused by at least three different strains (having multiple serotypes), and thus at least a trivalent vaccine would be most suitable. Immunity to Shigella is serotype-specific. Presently several vaccines are under trial, including a parenteral conjugate vaccine consisting of S. sonnei detoxified lipopolysaccharide linked to a Pseudomonas aeruginosa carrier protein (O-rEPA) which is in Phase III trial. In the United States and Bangladesh, Phase I and II trials have been conducted of a live attenuated S. flexneri 2a strain, SC 602. Another live attenuated vaccine with S. flexneri 2a strain CVD 1207 and S. dysenteriae type I strain CVD 1253 has proved to be safe and immunogenic. A Shigellaproteosome vaccine consisting of Shigella lipopolysaccharide noncovalently linked to micelles from the outer membrane protein of Group B Neisseria meningitides has been demonstrated for nasal administration.

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