Our third article in the series on sepsis, centers on obscure causes that sometimes make sepsis difficult to diagnose. Throughout the discussion, we suggest relevant analytics  from our clinical knowledge base, which can be helpful tools for clinical decision support.

The diagnosis of sepsis can be fairly straightforward when the typical signs and symptoms are present and if there are known sources of sepsis infection.  However, some cases of sepsis may be easily missed or mistaken for something else. A delay in diagnosis results in a delay in therapy and this can increase the possibility of permanent injury for the patient.

Obscure Causes Sepsis Infection

Some situations where the diagnosis of sepsis can be challenging:

  1. There are no or only vague symptoms
  2. The patient only has low-grade fever
  3. The bacteremia is intermittent
  4. The chief complaint is misleading
  5. There is a false-positive or false-negative blood culture
  6. The clinician suspects another cause for fever that may overlap clinically


Some septic patients are asymptomatic or have only minor symptoms. The patient and family may be aware that something is not “right” but there is nothing definite to point to. There may be little to indicate to the clinician what is really going on.

Afebrile Bacteremia in a Geriatric Patient

Fever Only

Some patients present with only a fever. The patient may be worked up for fever of unknown origin (FUO), which can be an expensive and time-consuming process.

Index for Predicting Bacteremia or Occult Bacterial Infection in Adults with Acute Unexplained Fever

Laboratory Risk Index Score (Lab Score) for Identifying a Severe Bacterial Infection in a Child With Fever But Without Source

Intermittent or Episodic

Rarely a patient may have brief episodes of bacteremia. The patient may confuse the clinician since the patient has signs of sepsis but blood cultures taken after the period of bacteremia may be negative. It takes an astute clinician to identify the underlying cause.

Situational Sepsis (Shampoo Sepsis, Manipulation-Related Bacteremia)

Misleading Presentation

Sometimes sepsis can present with a sign or symptom that may mislead the clinician. For example, a patient may present with delirium or jaundice rather than fever. Or the patient may have a known problem such as cancer that obscures the early signs of sepsis.

Clinical Features for Sepsis-Associated Delirium

Cholestasis Associated with Sepsis and Systemic Inflammation (Sepsis-Associated Cholestasis)

Risk Factors for Breakthrough Bacteremia in a Patient with Cancer

False-Positive or False-Negative Blood Culture

In practice the interpretation of blood cultures can be challenging. While one hopes that the results of a blood culture are true, the clinician often must try to determine the significance of an isolate or the lack thereof. How many culture bottles are positive? What has been isolated? Were antibiotics started before the cultures were taken? Was the skin adequately cleaned prior to collection? Was enough blood collected? The patient may or may not be started on antibiotics based on what heuristic that the clinician is using.

Criteria for Distinguishing True Bacteremia from Contaminated Blood Cultures

Febrile “Look-Alike”

There are many causes of fever, and sometimes the clinician may focus on a diagnosis other than sepsis. These may include:

  1. Drug fever (such as  “pseudosepsis” in an older adult with salicylate intoxication)
  2. Postoperative fever
  3. A febrile transfusion reaction

It is important for the clinician to evaluate these febrile “look-alikes” for findings that lead to the correct diagnosis.

Managing Postoperative Fever in a Gynecologic Patient


The diagnosis of sepsis is not always straightforward. Sometimes making the diagnosis can be difficult and requires sifting through subtle or misleading clinical findings. Failure to diagnose or a delay in diagnosis can have negative consequences for the patient.

When confronted with an unusual clinical situation medical algorithms may provide additional clinical decision support that can help the clinician make the right diagnosis.