Fever pattern may foretell prognosis of COVID-19

Hospitalized COVID-19 patients with prolonged fever showed more pronounced inflammatory response and were more likely to require ICU admission than cases with saddleback fever or with fever lasting ≤7 days, a Singapore study reveals.

“Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19,” said the researchers led by Dr Deborah Ng from National Centre for Infectious Diseases (NCID), Singapore, on behalf of the NCID COVID-19 Outbreak Research Team.

“Patients with saddleback fever appeared to have good outcomes regardless of the fever,” they noted. “Based on this study, patients with saddleback fever who remain well can be monitored in the community, while patients who have fever for >7 days should be admitted for closer monitoring.”

The hospital-based case-control study included 142 patients who were admitted to the NCID with COVID-19. Patients were categorized as having prolonged fever (lasting >7 days), saddleback fever (defined as recurrent fever which lasts for <24 hours, after defervescence beyond day 7 of illness), or controls if their fever was ≤7 days. [Open Forum Infect Dis 2020;7:ofaa375]

Among these patients, 12.7 percent had prolonged fever (median interquartile range [IQR], 10 days) while 9.9 percent had saddleback fever, with fever recurring at a median IQR of 10 days.

When compared with controls, both prolonged and saddleback fever were associated with hypoxia, with the highest rate seen in cases with prolonged fever (27.8 percent and 14.3 percent vs 0.9 percent for prolonged and saddleback fever vs control, respectively; p<0.01 and p=0.03 for each respective comparison).

While prolonged fever was associated with a higher rate of ICU admission vs controls (11.1 percent vs 0.9 percent; p=0.05), saddleback fever was not, despite both being associated with hypoxia.

Moreover, cases with prolonged fever also showed significantly higher plasma levels of inflammatory biomarkers such as interleukin (IL)-6 (p<0.01), IL-1RA (p<0.05), and induced protein-10 (IP-10; p<0.001) compared with controls during the early acute disease phase.

Meanwhile, the levels of IP-10 in patients with saddleback fever was lower than those with prolonged fever (p<0.001) — at a level almost matching that in controls.

“The differences in cytokine and chemokine profiles among [the three groups] ... suggest that different immunological responses could result in the differences in the clinical phenotype observed,” said Ng and co-authors.

“[The] lower IP-10 level [with saddleback fever] is consistent with the finding that saddleback fever cases tend to have better clinical outcomes than prolonged fever cases,” they noted.

The findings of the study are useful for informing the optimal placement of patients with COVID-19, the researchers pointed out. Home or community isolation facilities are commonly used globally for less sick patients such that hospital beds are free up to cater for sicker patients. 

“This suggests that in patients with prolonged fever, close monitoring for deterioration should be instituted, while patients with saddleback fever who remain well and do not require supplemental oxygenation are unlikely to require close monitoring in the hospital,” explained Ng and co-authors.

“In addition, as these patients with saddleback fever tend to do well, there is also no need for repeat laboratory testing or chest X-ray, as the results are unlikely to change management or clinical outcomes,” they said.