What is the relationship between ketosis and high-grade fevers?

Relationship Between Ketosis and High-Grade Fevers

Ketosis can play a dual role in high-grade fevers, potentially beneficial in bacterial infections but potentially harmful in viral infections, based on the metabolic adaptations that occur during infection-induced anorexia. 1

Metabolic Shifts During Infection and Fever

• During infection and fever, the body undergoes significant metabolic changes, shifting from glucose to lipid utilization as the primary energy source through increased lipolysis of fat stores 1, 2
• This metabolic shift is mediated by inflammatory cytokines, adrenalin, glucocorticoids, and glucagon, which upregulate hormone-sensitive lipase 1
• Plasma triglycerides and free fatty acids (FFAs) can increase up to four-fold in septic patients, indicating their mobilization as a primary fuel source 1, 3

Ketosis in Bacterial vs. Viral Infections

• In bacterial infections and sepsis, ketosis appears to be protective, as ketone bodies:

  • Activate muscle regeneration pathways that are downregulated during infection 1
  • Block inflammation by inhibiting NLRP3 inflammasomes 1
  • Activate neuroprotective subsets of macrophages 1

• In contrast, during viral infections, ketosis may be detrimental:

  • Force-feeding increased survival rates in mouse models of viral infection 1
  • Glycolytic inhibition promoted endoplasmic reticulum (ER) stress-induced apoptotic pathways associated with lethal outcomes 1
  • Glucose appears crucial for adaptation to stress induced by anti-viral inflammation 1

Role of PPAR-α in Fever and Ketosis

• Peroxisome proliferator-activated receptor-alpha (PPAR-α) is a key transcription factor facilitating the metabolic shift from glucose to lipid utilization during infection 1

• PPAR-α signaling:

  • Induces autophagy in the liver 1
  • Promotes utilization and catabolism of fatty acids 1
  • Inhibits uptake of circulating triglycerides for storage 1
  • Induces expression of downstream factors including fibroblast growth factor 21 (FGF21) and ketone bodies 1

• PPAR-α deficiency is associated with:

  • Increased steatosis (toxic hepatic build-up of FFAs) 1
  • Hyperglycemia 1
  • Decreased ketone body production 1
  • Reduced survival in sepsis models 1

Clinical Implications

• High-grade fevers can lead to increased metabolic demands and accelerate ketosis, especially when accompanied by reduced food intake (sickness-associated anorexia) 1

• In COVID-19 patients, ketosis has been observed in 6.4% of hospitalized patients, with or without diabetes, and was associated with:

  • Longer hospital stays (19.0 vs. 16.0 days) 4
  • Higher mortality rates (21.4% vs. 8.9%) 4

• Symptoms of "keto flu" may overlap with fever symptoms, including headache, fatigue, nausea, dizziness, and gastrointestinal discomfort 5

Management Considerations

• During acute illnesses with high-grade fever:

  • Individuals with type 1 diabetes should continue insulin 1
  • Testing blood glucose and blood or urine ketones is important 1
  • Adequate fluid intake is essential to prevent dehydration 1
  • Ingestion of 150-200g carbohydrate daily (45-50g every 3-4 hours) can reduce or prevent starvation ketosis 1

• In bacterial infections, particularly sepsis:

  • Excessive administration of glucose may worsen outcomes by promoting excessive immune activation through enhanced glycolysis 2, 3
  • Force-feeding may interfere with beneficial metabolic adaptations, including PPAR-α upregulation 1, 2

• In viral infections:

  • Maintaining adequate glucose intake may be more beneficial 1
  • Glucose appears crucial for adaptation to stress induced by anti-viral inflammation 1

Pitfalls and Caveats

• The relationship between ketosis and fever is bidirectional and context-dependent - beneficial in some infections but potentially harmful in others 1
• Distinguishing between beneficial adaptive ketosis and pathological ketoacidosis is crucial, especially in diabetic patients with infections 4
• Symptoms of ketosis may be mistaken for worsening infection or vice versa 5
• The metabolic response to infection varies based on pre-existing conditions like obesity and diabetes, which may alter the typical ketotic response 1