TYPHOID FEVER

Mar 27, 2017,

OUTLINE

Definition

Pathophysiology

Risk factor

Epidemiology

Symptoms and signs

Various presentation of typhoid fever

Treatment

Reference    

                                                                        TYPHOID FEVER

           Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness caused primarily by Salmonella enterica, subspecies enterica serovar typhi and, to a lesser extent, related serovars paratyphi A, B, and C. The protean manifestations of typhoid fever make this disease a true diagnostic challenge. The classic presentation includes fever, malaise, diffuse abdominal pain, and constipation. Untreated, typhoid fever is a grueling illness that may progress todelirium, obtundation, intestinal hemorrhage, bowel perforation, and death within 1 month of onset. Survivors may be left with long-term or permanent neuropsychiatric complications. S typhi has been a major human pathogen for thousands of years, thriving in conditions of poor sanitation, crowding, and social chaos. It may have responsible for the Great Plague of Athens at the end of the Pelopennesian War. The name S typhi is derived from the ancient Greek typhos, an ethereal smoke or cloud that was believed to cause disease and madness. In the advanced stages of typhoid fever, the patient's level of consciousness is truly clouded. Although antibiotics have markedly reduced the frequency of typhoid fever in the developed world, it remains endemic in developing countries.  S paratyphi causes the same syndrome but appears to be a relative newcomer. It may be taking over the typhi niche, in part, because of immunological naivete among the population and incomplete coverage by vaccines that target typhi. Note that some writers refer to the typhoid and paratyphoid fever as distinct syndromes caused by the typhi versus paratyphi serovars, while others use the term typhoid fever for a disease caused by either one. We use the latter terminology. We refer to these serovars collectively as typhoidal salmonella.

                                                                       PATHOPHYSIOLOGY

               All pathogenic Salmonella species, when present in the gut are engulfed by phagocytic cells, which then pass them through the mucosa and present them to the macrophages in the lamina propria. Nontyphoidal salmonellae are phagocytized throughout the distal ileum and colon. With toll-like receptor (TLR)–5 and TLR-4/MD2/CD-14 complex, macrophages recognize pathogen-associated molecular patterns (PAMPs) such as flagella and lipopolysaccharides. Macrophages and intestinal epithelial cells then attract T cells and neutrophils with interleukin 8 (IL-8), causing inflammation and suppressing the infection. In contrast to the nontyphoidal salmonellae, S typhi and paratyphi enter the host's system primarily through the distal ileum. They have specialized fimbriae that adhere to the epithelium over clusters of lymphoid tissue in the ileum (Peyer patches), the main relay point for macrophages traveling from the gut into the lymphatic system. The bacteria then induce their host macrophages to attract more macrophages. ] S typhi has a Vi capsular antigen that masks PAMPs, avoiding neutrophil-based inflammation, while the most common paratyphi serovar, paratyphi A, does not. This may explain the greater infectivity of typhi compared with most of its cousins. Typhoidal salmonella co-opt the macrophages' cellular machinery for their own reproduction as they are carried through the mesenteric lymph nodes to the thoracic duct and the lymphatics and then through to the reticuloendothelial tissues of the liver, spleen, bone marrow, and lymph nodes. Once there, they pause and continue to multiply until some critical density is reached. Afterward, the bacteria induce macrophage apoptosis, breaking out into the bloodstream to invade the rest of the body. The bacteria then infect the gallbladder via either bacteremia or direct extension of infected bile. The result is that the organism re-enters the gastrointestinal tract in the bile and reinfects Peyer patches. Bacteria that do not reinfect the host are typically shed in the stool and are then available to infect other hosts.

.                                               LIFE CYCLE OF SALMONELLA TYPHI.

             Chronic carriers are responsible for much of the transmission of the organism. While asymptomatic, they may continue to shed bacteria in their stool for decades. The organisms sequester themselves either as a biofilm on gallstones or gallbladder epithelium or, perhaps, intracellularly, within the epithelium itself. The bacteria excreted by a single carrier may have multiple genotypes, making it difficult to trace an outbreak to its origin. Contamination of ingested feeds completes the cycle.

                                                     RISK FACTORS

              Typhoidal salmonella have no nonhuman vectors. An inoculum as small as 100,000 organisms of typhi causes infection in more than 50% of healthy volunteers. Paratyphi requires a much higher inoculum to infect, and it is less endemic in rural areas. Hence, the patterns of transmission are slightly different. The following are modes of transmission of typhoidal salmonella:

• Oral transmission via food or beverages handled by an often asymptomatic individual—a carrier—who chronically sheds the bacteria through stool or, less commonly, urine

• Hand-to-mouth transmission after using a contaminated toilet and neglecting hand hygiene

• Oral transmission via sewage-contaminated water or shellfish (especially in the developing world).

                  Paratyphi is more commonly transmitted in food from street vendors. It is believed that some such foods provide a friendly environment for the microbe. Paratyphi is more common among newcomers to urban areas, probably because they tend to be immunologically naïve to it. Also, travellers get little or no protection against paratyphi from the current typhoid vaccines, all of which target typhi.

                  Typhoidal salmonella are able to survive a stomach pH as low as 1.5. Antacids, histamine-2 receptor antagonists (H2 blockers), proton pump inhibitors, gastrectomy, and achlorhydria decrease stomach acidity and facilitate S typhi infection.

                  HIV/AIDS is clearly associated with an increased risk of nontyphoidal Salmonella infection; however, the data and opinions in the literature as to whether this is true for S typhi or paratyphi infection are conflicting. If an association exists, it is probably minor.

                   Other risk factors for typhoid fever include various genetic polymorphisms. These risk factors often also predispose to other intracellular pathogens. For instance,PARK2 and PACGR code for a protein aggregate that is essential for breaking down the bacterial signaling molecules that dampen the macrophage response. Polymorphisms in their shared regulatory region are found disproportionately in persons infected with Mycobacterium leprae and S typhi. On the other hand, protective host mutations also exist. The fimbriae of S typhi bind in vitro to cystic fibrosis transmembrane conductance receptor (CFTR), which is expressed on the gut membrane. Two to 5% of white persons are heterozygous for the CFTR mutation F508del, which is associated with a decreased susceptibility to typhoid fever, as well as to cholera and tuberculosis.

                                                                                    EPIDEMIOLOGY

                Typhoid fever occurs worldwide, primarily in developing nations whose sanitary conditions are poor. Typhoid fever is endemic in Asia, Africa, Latin America, the Caribbean, and Oceania, but 80% of cases come from Bangladesh, China, India, Indonesia, Laos, Nepal, Pakistan, or Vietnam.Within those countries, typhoid fever is most common in underdeveloped areas.

             Typhoid fever infects roughly 21.6 million people (incidence of 3.6 per 1,000 population) and kills an estimated 200,000 people every year. In the United States, most cases of typhoid fever arise in international travelers.

The average yearly incidence of typhoid fever per million travelers from 1999-2006 by county or region of departure was as follows:

• Canada - 0

• Western Hemisphere outside Canada/United States - 1.3

• Africa - 7.6

• Asia - 10.5

• India - 89 (122 in 2006)

• Total (for all countries except Canada/United States) - 2.2

mortality/morbidity

            With prompt and appropriate antibiotic therapy, typhoid fever is typically a short-term febrile illness requiring a median of 6 days of hospitalization. Treated, it has few long-term sequelae and a 0.2% risk of mortality. Untreated typhoid fever is a life-threatening illness of several weeks' duration with long-term morbidity often involving the central nervous system. The case fatality rate in the United States in the pre-antibiotic era was 9%-13%.

Race

             Typhoid fever has no racial predilection.

Sex

             Fifty-four percent of typhoid fever cases in the United States reported between 1999 and 2006 involved males.

Age

             Most documented typhoid fever cases involve school-aged children and young adults. However, the true incidence among very young children and infants is thought to be higher. The presentations in these age groups may be atypical, ranging from a mild febrile illness to severe convulsions, and the S typhi infection may go unrecognized. This may account for conflicting reports in the literature that this group has either a very high or a very low rate of morbidity and mortality.

                                                       SYMPTOM AND SINGS OF TYPHOID FEVER

               Classic typhoid fever syndrome The clinical syndromes associated with S typhi and paratyphi are indistinguishable. Typhoid fever begins 7-14 days after ingestion of the organism . The fever pattern is stepwise, characterized by a rising temperature over the course of each day that drops by the subsequent morning. The peaks and troughs rise progressively over time.

              Over the course of the first week of illness, the notorious gastrointestinal manifestations of the disease develop. These include diffuse abdominal pain and tenderness and, in some cases, fierce colicky right upper quadrant pain. Monocytic infiltration inflames Peyer patches and narrows the bowel lumen, causing constipation that lasts the duration of the illness.      

               The individual then develops a dry cough, dull frontal headache, delirium, and an increasingly stuporous malaise. At approximately the end of the first week of illness, the fever plateaus at 103-104°F (39-40°C). The patient develops rose spots, which are salmon-colored, blanching, truncal, maculopapules usually 1-4 cm wide and fewer than 5 in number; these generally resolve within 2-5 days.These are bacterial emboli to the dermis and occasionally develop in persons with shigellosis or nontyphoidal salmonellosis.

              During the second week of illness, the signs and symptoms listed above progress. The abdomen becomes distended, and soft splenomegaly is common. Relative bradycardia and dicrotic pulse (double beat, the second beat weaker than the first) may develop.

                In the third week, the still febrile individual grows more toxic and anorexic with significant weight loss. The conjunctivae are infected, and the patient is tachypneic with a thready pulse and crackles over the lung bases. Abdominal distension is severe. Some patients experience foul, green-yellow, liquid diarrhea (pea soup diarrhea). The individual may descend into the typhoid state, which is characterized by apathy, confusion, and even psychosis. Necrotic Peyer patches may cause bowel perforation and peritonitis. This complication is often unheralded and may be masked by corticosteroids. At this point, overwhelming toxemia, myocarditis, or intestinal hemorrhage may cause death.

                 If the individual survives to the fourth week, the fever, mental state, and abdominal distension slowly improve over a few days. Intestinal and neurologic complications may still occur in surviving untreated individuals. Weight loss and debilitating weakness last months.

                Some survivors become asymptomatic S typhi carriers and have the potential to transmit the bacteria indefinitely.

  Various presentations of typhoid fever

                The clinical course of a given individual with typhoid fever may deviate from the above description of classic disease. The timing of the symptoms and host response may vary based on geographic region, race factors, and the infecting bacterial strain. The stepladder fever pattern that was once the hallmark of typhoid fever now occurs in as few as 12% of cases. In most contemporary presentations of typhoid fever, the fever has a steady insidious onset. Young children, individuals with AIDS, and one third of immunocompetent adults who develop typhoid fever develop diarrhea rather than constipation.

                  In addition, in some localities, typhoid fever is generally more apt to cause diarrhea than constipation. Atypical manifestations of typhoid fever include isolated severe headaches that may mimic meningitis, acute lobar pneumonia, isolated arthralgias, urinary symptoms, severe jaundice, or fever alone. Some patients, especially in India and Africa, present primarily with neurologic manifestations such as delirium or, in extremely rare cases, parkinsonian symptoms or Guillain-Barré syndrome. Other unusual complications include pancreatitis, meningitis, osteomyelitis, and abscesses anywhere on the body.

                                                                        LIST OF SYMPTOMS AND SIGNS

Stepladder fever pattern or insidious onset fever

Acute high fever

Chill/ Rigors

Anorexia

Diaphoresis

Neurologic

Malaise

Insomnia

Confusion/delirium

Psychosis

Catatonia

Frontal headache

Meningeal signs

Parkinsonism

Ear, nose, and throat

Coated tongue

Sore throat

Pulmonary

Mild cough

Bronchitic cough

Rales

Pneumonia

Cardiovascular

Dicrotic pulse

Myocarditis

Pericarditis

Thrombophlebitis

Gastrointestinal

Constipation

Diarrhea

Bloating with tympany

Diffuse mild abdominal pain

Sharp right lower quadrant pain

Gastrointestinal hemorrhage

intestinal perforation

Hepatosplenomegaly

Jaundice

Gallbladder pain

Urogenital

 Urinary retention

Hematuria

Renal pain

Musculoskeletal

Myalgias

Arthralgias

Rheumatologic Arthritis (large joint)

Dermatologic

Rose spots

Miscellaneous

Abscess (anywhere)

                                                                                  TREATMENT

                   If appropriate treatment is initiated within the first few days of full-blown illness, the disease begins to remit after about 2 days, and the patient's condition markedly improves within 4-5 days. Any delay in treatment increases the likelihood of complications and recovery time.                                         

                                                                              REFERENCE

1)Christie AB. Infectious Diseases: Epidemiology and Clinical Practice. 4th ed. Edinburgh, Scotland: Churchill Livingstone; 1987.

2)Raffatellu M, Chessa D, Wilson RP, Tükel C, Akçelik M, Bäumler AJ. Capsule-mediated immune evasion: a new hypothesis explaining aspects of typhoid fever pathogenesis. Infect Immun. 2006 Jan. 74(1):19-27.

3)Parry CM, Hien TT, Dougan G, et al. Typhoid fever. N Engl J Med. 2002 Nov 28. 347(22):1770-82. [Medline].

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