Thread by @JonathanRyderMD

1/ "Does DVT/PE cause fever?" 🌡️🤒🌡️🤒🌡️

This #Tweetorial was inspired by a recent @DxRxEdu thread. So I did a deep dive into the evidence behind this dogma and also asked, "if so, how?"

https://twitter.com/DxRxEdu/status/1254054132031336448

2/ We will start with a poll:

"Does DVT/PE cause fever?"

3/ Dating back to 1959, Israel & Goldstein found fever to be the most common sign in patients with PE (78.9%), 10% with temp >39.5C. They admit infection to be an underlying cause. Additionally, PE made based on CXR & EKG findings & autopsy.

annals.org/aim/article-ab…

4/ In 1979, Murray et al found fever (rectal T>38C) in 24/35 patients with PE, 20 without any cause other than PE.

In PE with fever, mean admission temp of 38.3C. 25% >39C.

50% of fever cases had fever >5 days. By day 7, 18/19 were afebrile.

amjmed.com/article/0002-9…

5/ Murray was one of the first to speculate on the pathophysiology of fever & many current papers still cite this reasoning

6/ In 1987, Watanakunakorn & Hayek report 7 cases of unexplained high grade fevers (>39C), in which the final etiology was found to be PE.

They note that in the 3 surviving patients, their fevers resolved within 72h with heparin treatment.

pmj.bmj.com/content/63/745…

7/ In 1997, AbuRahma et al evaluated patients with fever of unknown origin (FUO) sent for doppler imaging.

5 of 89 patients found to have DVT as probable cause of FUO. All fevers improved with heparin. Suggests heparin is anti-inflammatory

surgjournal.com/article/S0039-…

8/ In 2000, Stein et al used PIOPED database and found fever (>37.8C) in 43 of 311 (14%) patients with PE that did not have other cause of fever.

Pulm hemorrhage/infarct frequency similar in fever & non-fever groups. DVT s/s in 56% of PE w/ fever group

journal.chestnet.org/article/S0012-…

9/ Kazmus et al looked at 1847 patients referred to vasc lab for DVT & checked temps.

Temp of those with DVT significantly higher (p<0.035):
- +DVT: 98.7 +/- 1.10
- No DVT: 98.5 +/- 1.10

However, not clinically significant difference (0.2F)

ncbi.nlm.nih.gov/pubmed/10888140

10/ In 2011, Barba et al looked at 14,814 patients with DVT

4.9% with fever (>38C).

Fever group more likely to have surgery, immobility, infection & upper ext DVT.

Fever group with ⬆️mortality & ⬆️recurrence. ⬆️PEs & ⬆️infections as cause of death.

link.springer.com/article/10.100…

11/ In 2018, Saad et al found fever (>38C) in 24.5% of 241 patients with PE without alternate cause.

Fever group with ⬆️mortality, ⬆️massive/submassive PEs, ⬆️DVTs

bmjopenrespres.bmj.com/content/5/1/e0…

12/ At this point, I've made a decent case that DVT/PE are associated with fevers.

There are confounders here no doubt (unidentified or unaccounted infections, differing diagnostic methods for DVT/PE, etc).

Some DVT/PE have fevers without other causes though.

But why & how?

13/ First, we must remember how fever is generated.

Pyrogenic cytokines (e.g. IL-1, IL-6 & TNF-alpha) are the major players in activating the hypothalamus.

H/t to @tony_breu for diagram.
cell.com/current-biolog…

14/ Inflammation is at the core of fever generation.

For DVT/PE this is a tricky situation, a bit of a chicken & the egg.

Inflammation is a known risk factor for DVT/PE.

But is there a mechanism by which DVT/PE can produce the inflammation independently?

Photo: @CPSolvers

15/ Roumen-Klappe et al compared 40 patients with DVT to 33 controls.

Pts with DVT had ⬆️levels of IL-6, IL-8 & CRP on admission.

Upon treatment w/ heparin, IL-6 & CRP declined, but IL-8 did not.

They suggest thrombosis as cause of inflammation.

linkinghub.elsevier.com/retrieve/pii/S…

15/ Kokturk et al found that patients w/ PE & fever had ⬆️WBC, ⬆️CRP, ⬆️ESR, ⬆️IL-6, and ⬆️TNF-alpha, similar levels to patients with CAP.

These values improved in the PE w/ fever group while on heparin, despite not receiving antibiotics.

journals.sagepub.com/doi/full/10.11…

16/ Poterucha et al provides a mechanism by which thrombosis results in inflammation.

IL-1, IL-6, IL-8 & CRP all increase as a result of thrombus formation.

Clot➡️inflammation➡️more clots.

thieme-connect.com/products/ejour…

17/ So if DVT/PE cause inflammation independently, then how can we counter this inflammation?

Well, we usually treat with anticoagulation.

Many of the above studies hint that heparin improves inflammation & fevers, but how?

Does heparin have anti-inflammatory properties?

18/
It does!

Heparin has these anti-inflammatory properties:
1) 🛑neutrophil activation/function
2) ⬇️production of NF-kB, TNF-alpha, IL-6, IL-8 & IL-1 beta
3) 🛑vascular smooth muscle proliferation
4) ⬇️inflammation via anticoagulation ⬇️further clots

thieme-connect.com/products/ejour…

19/ I want to include a pearl of wisdom here as suggested by @DxRxEdu

When fever accompanies DVT/PE, it's important not to anchor.

While some DVT/PE may cause fever, many also have underlying infections, malignancies & autoimmune diseases. Be thorough!

https://twitter.com/DxRxEdu/status/1254841853175828481?s=20

20/ Let's repeat this poll:

Does DVT/PE cause fever?

20/
In summary:
💥Some DVT/PE have fevers with no underlying cause
💥Thrombosis leads to increased inflammatory cytokines (IL-6, IL-8, TNF-alpha)➡️fever
💥Heparin has anti-inflammatory properties
💥Avoid premature closure with DVT/PE + fever

Appreciate feedback & commentary!