Not All That Fevers is Sepsis

Written by Dr. Aria Fariborzi (PGY3)

A middle-aged female with a history of chronic autoimmune hepatitis presented to the emergency department with a new, bifrontal headache that began 3 days prior. Her headache was preceded by sudden-onset episodes of left-sided facial droop beginning 3 days ago, lasting approximately 1 hour before spontaneously resolving. Collateral was obtained from the family at the bedside who noted that she has been intermittently confused.  She denies any recent head trauma, travel, new medication use, rash, visual changes, pulse synchronous tinnitus, oral contraceptive use.

In the emergency department, the patient was found to be febrile to 100.3F and borderline tachycardic to the low 110’s. 

Her neurologic exam showed that she was alert and oriented to person, place, and time. There was decreased sensation to light touch over the left arm and left face. Scleral icterus was noted. Otherwise, though, she had full strength to her upper and lower extremities; extraocular movements were intact; pupils were equal, round, and reactive to light; and tongue was midline.

Labs revealed a new macrocytic anemia with a hemoglobin of 8.1, thrombocytopenia to a platelet count of 24, and liver tests revealing total bilirubin of 4.3 with an indirect bilirubin predominance (direct bilirubin 0.4). LDH and haptoglobin were added on given concern for a hemolytic process. LDH returned elevated at 1,341 and haptoglobin <10. ADAMTS13 levels were sent off, however it is a send-out test that takes numerous days to return.

At this point, there was significant concern that the patient may have thrombotic thrombocytopenic purpura given her neurologic deficit, microangiopathic hemolytic anemia, and fever. A PLASMIC score of 5 was calculated, risk stratifying the patient as intermediate risk, with a 6% risk of severe ADAMTS13 deficiency. 

Hematology was then consulted who reviewed the patient’s blood smear (Figure 1) as below and noted the numerous schistocytes with few platelets, significantly increasing the concern for TTP.

Figure 1: Our patient's blood smear

A Shiley dialysis catheter was placed in the right internal jugular vein by the ED in order to emergently initiate plasma exchange. While awaiting a bed to be assigned, an MRI of the brain was obtained, which showed a focal acute infarct within the right lentiform nucleus/subinsular zone and a few isolated foci of nonspecific scattered subcortical white matter signal hyperintensity. This infarct is likely due to the microthrombi formed from unopposed Von Willebrand Factor polymerization.

The patient was assigned a bed and was transported out of the ED to the medicine floors where she underwent multiple days of plasma exchange therapy as well as treatment with caplacizumab with full resolution of her symptoms. The ADAMTS13 levels returned profoundly low (<0.03) which further confirmed the initial diagnosis suspected by the emergency department. 

Case Discussion:

TTP is a serious hematologic emergency characterized by a deficiency in ADAMTS13 enzyme or by inhibition of ADAMTS13 by autoantibodies that inhibit its activity.

Visually illustrated in Figure 2 below, ADAMTS13 usually cleaves von Willebrand Factor (vWF) multimers; however, a deficiency of it will allow for platelets to bind to highly adhesive, ultra-large vWF multimers. Red blood cells passing through these multimers will get cleaved, leading to laboratory evidence of intravascular hemolysis (high LDH, low haptoglobin, elevated total bilirubin with indirect bilirubin prominence).

Figure 2: Pathophysiology of TTP (Source - https://emcrit.org/ibcc/tma/)

In addition, large vWF multimers are highly thrombogenic which can lead to serious manifestations of end organ damage (stroke, decreased renal function, etc). 

It is incredibly important to be hypervigilant in the emergency department for this diagnosis as the most severe cases of TTP, such as the one we encountered, require immediate emergent intervention with plasma exchange +/- caplacizumab. 

In addition, keep in mind that the “classic” pentad is not always present. Our patient in particular, had completely normal renal function.

Aria's Pearls:

1. Not all that is febrile and altered is sepsis. Don’t forget alternative causes for fevers such as TTP.

2. Remember the headache “maimers”: psuedotumor, TTP, GCA.

3. TTP and malaria, especially falciparum, mimic each other (febrile, altered, MAHA). Obtaining a travel history can be very useful in helping differentiate the two.