Nontyphoidal Salmonellosis

1. Introduction

Nontyphoidal Salmonellosis (NTS) refers to infections caused by Salmonella serotypes other than S. Typhi and S. Paratyphi. While typhoidal Salmonella strains are host-restricted to humans and cause systemic enteric fever, nontyphoidal strains have a broad host range involving both animals and humans. NTS is a major global public health burden, primarily causing self-limiting acute gastroenteritis in healthy individuals but capable of causing life-threatening invasive disease (bacteremia, meningitis) in young infants, the elderly, and immunocompromised hosts.

2. Etiology and Microbiology

• Organism: Salmonella are motile, non-spore-forming, gram-negative bacilli belonging to the family Enterobacteriaceae. They are facultative anaerobes that generally do not ferment lactose.
• Classification: All medically relevant Salmonella belong to the species Salmonella enterica. NTS comprises over 2,500 serotypes. The most common serotypes associated with human disease globally are S. Typhimurium and S. Enteritidis.
• Host Range: Unlike S. Typhi, NTS strains infect a wide variety of animals, including poultry, cattle, pigs, reptiles, and amphibians, which serve as reservoirs for human infection.

3. Epidemiology and Transmission

• Modes of Transmission:
  • Foodborne: This is the most common route. Contaminated poultry, eggs, milk, and dairy products are frequent sources.
  • Zoonotic: Direct contact with infected pets, particularly reptiles (turtles, iguanas) and amphibians, is a significant risk factor for children.
  • Fecal-Oral: Person-to-person spread can occur but is less common than with Shigella due to the higher inoculum required.
• Vulnerable Populations: The incidence is highest in infants and young children. Severe invasive disease is more common in neonates, infants <3 months, and children with underlying immunodeficiencies (e.g., HIV, sickle cell disease) or malnutrition.
• Invasive NTS in Africa: In sub-Saharan Africa, NTS has emerged as a leading cause of community-acquired bacteremia in children, often associated with HIV, malaria, and malnutrition, with high case fatality rates.

4. Pathogenesis

The severity of NTS infection depends on the inoculum size, serotype virulence, and host defense mechanisms.

1. Inoculum: A relatively large inoculum (${10}^6–{10}^8$ organisms) is typically required to cause disease in healthy adults, but a much lower dose can infect infants and patients with reduced gastric acidity (e.g., those on antacids).
2. Invasion: Upon reaching the small intestine, bacteria adhere to and invade the intestinal epithelium, particularly M cells overlying Peyer’s patches. This process is mediated by the Salmonella Pathogenicity Island 1 (SPI-1), which encodes a type III secretion system (TTSS) that injects effector proteins into host cells, causing cytoskeletal rearrangement ("membrane ruffling") and bacterial uptake.
3. Inflammation: Bacterial invasion triggers the release of proinflammatory cytokines (IL-8), attracting neutrophils (PMNs). This inflammatory response, unlike in typhoid fever, remains largely localized to the intestine in immunocompetent hosts, resulting in enterocolitis and diarrhea.
4. Systemic Spread: In susceptible hosts, bacteria may survive within macrophages (mediated by SPI-2) and disseminate to the bloodstream and distant organs.

5. Clinical Manifestations

NTS infection can present as asymptomatic carriage, gastroenteritis, bacteremia, or focal extraintestinal infection.

5.1. Acute Gastroenteritis

This is the most common presentation.

• Incubation Period: 6 to 72 hours (median 24 hours).
• Symptoms: Abrupt onset of nausea, vomiting, and crampy abdominal pain (often periumbilical or lower quadrant), followed by diarrhea.
• Stool Characteristics: Diarrhea ranges from loose watery stools to dysentery with blood and mucus. In infants, stools may be green and slimy.
• Systemic Signs: Fever (${38}^{\circ }\text{C}-{39}^{\circ }\text{C}$) is common, occurring in about 70–80% of patients.
• Course: The illness is usually self-limiting, resolving within 2–7 days.

5.2. Bacteremia

Transient bacteremia occurs in 1–5% of immunocompetent children with NTS gastroenteritis but is much more frequent in high-risk groups.

• Risk Factors for Bacteremia:
  • Age: Neonates and infants <3 months (risk up to 30%).
  • Immunocompromise: HIV/AIDS, malignancy, corticosteroid use.
  • Sickle Cell Disease: Functional asplenia predisposes to severe NTS sepsis and osteomyelitis.
  • Malnutrition.
  • Specific Serotypes: S. Choleraesuis and S. Dublin are more invasive.

5.3. Focal Extraintestinal Infections

Bacteremia can lead to seeding of almost any organ.

• Meningitis: Seen primarily in infants <4 months. It is severe, with high mortality and high rates of neurologic sequelae (seizures, hydrocephalus).
• Osteomyelitis: Salmonella is a common cause of osteomyelitis in children with sickle cell disease.
• Others: Septic arthritis, endocarditis, pneumonia, urinary tract infection, and abscesses (hepatic, splenic).

5.4. Carrier State

Chronic carriage (excretion >1 year) is rare in children (<1%) compared to S. Typhi and is usually associated with biliary tract abnormalities.

6. Diagnosis

• Stool Culture: The gold standard for gastroenteritis. Selective media like Salmonella-Shigella (SS) agar, Xylose-Lysine-Deoxycholate (XLD), or Hektoen enteric agar are used to inhibit normal flora.
• Blood Culture: Essential for all febrile infants, toxic children, and those with suspected systemic disease.
• Fecal Leukocytes: Often present, indicating colitis, but nonspecific.

7. Treatment

7.1. Fluid and Electrolyte Management

The cornerstone of therapy for NTS gastroenteritis is rehydration (oral or intravenous) and correction of electrolyte imbalances.

7.2. Antibiotic Therapy

Antibiotics are NOT recommended for uncomplicated gastroenteritis in healthy children over 3 months of age. Antibiotics do not shorten the duration of symptoms and may prolong the carrier state and promote resistance.

Indications for Antibiotics: Antibiotic therapy is mandatory for patients at risk of invasive disease:

1. Age: Infants <3 months (some experts suggest <6 months).
2. Immunocompromised: HIV, malignancy, primary immunodeficiency, congenital asplenia.
3. Chronic Conditions: Sickle cell disease, inflammatory bowel disease.
4. Severe Illness: Signs of sepsis, severe toxicity, or documented bacteremia/extra-intestinal foci.

Choice of Antimicrobial:

• Empiric Therapy: A third-generation cephalosporin (e.g., Ceftriaxone or Cefotaxime) is the drug of choice for invasive disease or high-risk infants due to increasing resistance to ampicillin and chloramphenicol.
• Alternatives: Fluoroquinolones (e.g., Ciprofloxacin) or Azithromycin are alternatives, though resistance to quinolones is rising.
• Duration:
  • Gastroenteritis (high-risk): 3–5 days.
  • Bacteremia: 10–14 days.
  • Meningitis: $\ge$ 4 weeks.
  • Osteomyelitis: 4–6 weeks.

8. Prevention

• Hygiene: Thorough handwashing, especially after handling raw meat or pets.
• Food Safety: Proper cooking of poultry and eggs; avoiding unpasteurized milk.
• Pet Safety: Excluding reptiles and amphibians from households with infants or immunocompromised children.
• Infection Control: Contact precautions for hospitalized diapered children with NTS gastroenteritis.