Typhoid Fever: Pathophysiology & Clinical Features

Typhoid Fever: Pathophysiology & Clinical Features

We continue with our Back to College series to bring to you Typhoid Fever: Pathophysiology & Clinical Features.

Background

Typhoid fever, also known as enteric fever, is a potentially fatal multisystemic illness caused primarily by Salmonella enterica. These are subspecies enterica serovar typhi. Additionally, 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 can may progress to delirium, 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 been responsible for the Great Plague of Athens. 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.

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. 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.

Typhoidal salmonella co-opt the macrophages’ cellular machinery for their own reproductionas they are carried through the mesenteric lymph nodes to the thoracic duct and the lymphatics and then through to the reticuloendothelial tissues. 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. Salmonella can survive weeks outside the body.

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.

Transmission

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)

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.

Second Week: Signs & Symptoms

  • 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

Third Week: Signs & Symptoms

  • 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, orchitis, osteomyelitis, and abscesses anywhere on the body. 

Reference:

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