What is the differential diagnosis for a patient presenting with fever, chills, shortness of breath, fatigue, nausea, epigastric pain, and diarrhea?

Differential Diagnosis for Fever, Chills, Shortness of Breath, Fatigue, Nausea, Epigastric Pain, and Diarrhea

This constellation of symptoms demands immediate consideration of infectious gastroenteritis with systemic involvement, COVID-19, severe bacterial infection with sepsis, and community-acquired pneumonia with gastrointestinal manifestations.

Primary Infectious Considerations

Bacterial Gastroenteritis with Systemic Features

• Shigella, Salmonella, Campylobacter, and STEC are the most likely bacterial pathogens when fever, abdominal pain, and diarrhea occur together 1, 2.
• Bacterial diarrhea typically presents acutely with rapid onset, high fever (often >38°C), pronounced systemic symptoms including chills and fatigue, and visible blood in stool 2, 3.
• Epigastric pain combined with fever and diarrhea suggests Salmonella, Shigella, Campylobacter, Yersinia, or noncholera Vibrio species 1.
• The presence of nausea lasting more than 24 hours alongside diarrhea makes preformed toxin ingestion (Staphylococcus aureus, Bacillus cereus) less likely 1.

COVID-19 and Viral Infections

• COVID-19 must be considered as it presents with fever, cough, shortness of breath, chills, fatigue, nausea, abdominal pain, and diarrhea in <10% of patients 1.
• GI symptoms may precede respiratory symptoms by several days in COVID-19, making early recognition critical 1.
• Norovirus typically causes vomiting and nonbloody diarrhea lasting 2-3 days with low-grade fever, but the presence of shortness of breath and epigastric pain makes this less likely 1.

Severe Sepsis and Systemic Bacterial Infections

• Altered mental status, dyspnea, gastrointestinal symptoms, and muscle weakness predict severe sepsis with odds ratios of 4.29,2.92,2.31, and 2.24 respectively 4.
• Community-acquired pneumonia, particularly legionellosis, presents with fever, shortness of breath, and diarrhea 5.
• Blood cultures are indicated when signs of septicemia are present (fever with chills, shortness of breath, systemic symptoms) 1, 2, 3.

Secondary Considerations

Parasitic Infections

• Entamoeba histolytica causes persistent diarrhea with visible blood, epigastric/abdominal pain, but typically lacks the acute fever and respiratory symptoms seen here 2, 3.
• Consider parasitic causes if symptoms persist beyond 14 days or if there is recent travel to endemic areas 1, 6.

Non-Gastrointestinal Infections Causing Diarrhea

• Malaria, dengue fever, tick-borne infections (ehrlichiosis, Rocky Mountain spotted fever), and Lyme disease can present with fever, chills, fatigue, and diarrhea 5.
• These systemic infections cause diarrhea through cytokine action, intestinal inflammation, and increased gut permeability 5.

Immediate Diagnostic Workup

Essential Initial Testing

• Single diarrheal stool specimen for culture (Salmonella, Shigella, Campylobacter, Yersinia), C. difficile testing, and STEC detection 1, 2, 3.
• Blood cultures are mandatory given fever with chills, shortness of breath, and systemic symptoms suggesting possible bacteremia or sepsis 1, 2, 3.
• COVID-19 testing (nasopharyngeal RT-PCR) should be performed in high-prevalence settings or with respiratory symptoms 1.
• Complete blood count to assess for leukocytosis (bacterial infection) or lymphopenia (viral infection) 6.
• Chest imaging if shortness of breath is prominent to evaluate for pneumonia 5.

Additional Testing Based on Clinical Context

• Fecal calprotectin to distinguish inflammatory from non-inflammatory diarrhea 6.
• Liver function tests if hepatotoxic drug therapy is being considered or if COVID-19 is suspected 1.
• Stool pathogen panels (multiplex molecular testing) can detect multiple bacterial, viral, and parasitic pathogens simultaneously 1, 2.

Critical Clinical Distinctions

Red Flags for Severe Disease

• Bloody stools with severe abdominal pain and minimal fever suggest STEC, and antibiotics must be avoided due to hemolytic uremic syndrome risk 1, 2, 3.
• Persistent abdominal pain with fever may indicate Yersinia enterocolitica mimicking appendicitis 1.
• Shortness of breath with systemic symptoms (fever, chills, fatigue) in the context of diarrhea raises concern for severe sepsis or pneumonia with gastrointestinal involvement 4, 5.

Timing and Progression

• Symptoms lasting <24 hours suggest preformed toxin ingestion 1.
• Symptoms lasting 2-3 days suggest viral gastroenteritis 1.
• Acute onset with rapid progression over hours to 1-2 days suggests bacterial infection 2, 3.
• Persistent symptoms beyond 14 days require parasitic workup 1, 6.

Common Pitfalls to Avoid

• Do not assume viral gastroenteritis when shortness of breath is present—this demands evaluation for pneumonia, COVID-19, or severe sepsis 1, 4, 5.
• Do not delay infectious workup before initiating immunosuppression if inflammatory bowel disease is being considered 1.
• Do not use empirical antibiotics in immunocompetent patients with bloody diarrhea while awaiting STEC results, as this increases hemolytic uremic syndrome risk 2, 3.
• Do not miss COVID-19 by focusing solely on GI symptoms—respiratory and systemic features may develop after GI symptoms 1.
• Fever may be absent in elderly or immunocompromised patients despite severe infection 7.