PulmCrit Wee - Patient with nonfocal exam and thrombocytopenia

The case:

A ~65 year-old human presents to the ICU with a working diagnosis of vasopressor-dependent septic shock. The patient was previously healthy with no significant medical problems or medications. History is notable for mild nonspecific symptoms (chills, nausea, and a headache), with nothing in particular standing out. Physical examination is unrevealing, with the patient looking OK. Imaging studies including chest radiograph and CT of the abdomen and pelvis, are also unrevealing. Labs are shown below. What do you think the patient has?

What do you think?

The answer is below

👇

The answer:

Anaplasmosis with features of hemophagocytic lymphohistiocytosis (HLH). The key clues to this diagnosis:

Septic shock with no defined focus of infection (despite a good history/physical and CT scan).
Thrombocytopenia and leukopenia.
Some features of HLH (ferritin >6,000 and markedly elevated D-dimer – along with the cytopenias as above).
Patient presenting in Vermont during the summer of 2021 (i.e., the zombie apocalypse).

Annual anaplasmosis cases in the United States.

We've seen a few of these cases so far this season, which is more than usual (I tweeted about a different one a few months ago, see below). The Vermont Department of Health just issued a Health Advisory Notice about increased tick-borne illnesses, so I figured a little spaced repetition might be useful on this topic. Due to global warming and the migration of tick vectors, anaplasmosis is increasingly common in the northeast. Clinicians in border areas like Vermont, New Hampshire, upper New York, and Pennsylvania, who previously haven't seen much of this, will need to be aware of it.

happy anaplasmosis season!
animal vectors are migrating north due to global warming, so we’re seeing this more in vermont
doxy first, ask questions later
can cause secondary HLH, so adjuvant tx with steroid may be considered in critical illnesshttps://t.co/CNHzQG26LN pic.twitter.com/BNJJBp9QJN

— (@PulmCrit) April 24, 2021

The patient had no known tick bite, although further history eventually elicited some walks in the woods with a pet dog. Only about half of patients have a history of known tick bite, so the absence of known tick exposure cannot exclude this.

The patient was treated with empiric doxycycline and stress-dose steroid (50 mg hydrocortisone IV q6hr). Improvement was very rapid, with peripheral norepinephrine infusion weaned off within <12 hours. I was tempted to increase the steroid dose when the ferritin results returned at >6000, but the patient was already improving at that point, so there was no need to do so. If the patient hadn't been improving, then escalation to ~20 mg dexamethasone daily might have been reasonable. Anaplasmosis is well known to cause features of hemophagocytic lymphohistiocytosis (HLH) and some have reported treatment involving steroid plus anti-inflammatory agents like anakinra. After the patient had recovered, the soluble IL-2 receptor came back highly elevated – also consistent with an HLH-type of inflammation.

Doxycycline was initiated immediately after admission based on a suspicion of tick-borne illness. The anaplasmosis PCR returned positive several days later (long after the patient had improved and graduated from the ICU).

In addition to empiric therapy for anaplasmosis, we did also consider other possible causes of HLH. While waiting for the anaplasmosis PCR to return we also sent off a panel of tests to investigate for other causes of HLH (e.g., HIV, HSV, EBV, CMV). These all eventually came back negative.

The blood smear revealed some Pseudo-Pelger-Huet cells. These are weird, bilobed neutrophils that may be associated with hematologic malignancies or some acute infections (including anaplasmosis). A few days into the hospitalization, the blood smear also revealed atypical lymphocytes, which suggests something unusual going on beyond typical septic shock (e.g., viral infection, drug reaction, unusual infections such as babesiosis, leptospirosis, tularemia). So, there were some clues in the blood smear suggesting the presence of an unusual process here.

It's notable that the patient's procalcitonin was quite elevated at 6.3. This could be misleading, potentially pointing towards the diagnosis of a more typical bacterial pathogen. However, available reports indicate that anaplasmosis can cause elevated procalcitonin levels (probably as a reflection of the ongoing cytokine derangement). Anaplasmosis should thus be included in our cognitive heuristics of “sepsis mimics” that fail to respond to usual antibiotic treatment.

Tick-borne illnesses including anaplasmosis and babesiosis are increasingly common in the Northeast.
Suspect anaplasmosis in patients presenting with thrombocytopenia and sepsis of unknown etiology along with other clues, such as exposure to ticks, ferritin elevation, or leukopenia.
If anaplasmosis is suspected in a sick patient, doxycycline should be initiated immediately. The definitive test is anaplasmosis PCR, which will take some days to return. The goal is for the patient to be recovered and out of the ICU before the anaplasmosis PCR returns.
Anaplasmosis can cause HLH, although ideally rapid treatment will prevent the development of a full-blown HLH picture. For patients who are on vasopressor or in multiorgan failure, adjunctive steroid may be considered to treat this inflammation. More advanced immunomodulators have been reported in some case reports, but in most situations they don't seem to be needed.

References:

Epidemiology figures from the CDC site on anaplasmosis.
More about the critical care diagnosis & management of anaplasmosis in the IBCC.
More about HLH in the IBCC.

Opening image: Photo by Jr Korpa on Unsplash