Drs. Michael Moran and Swapnil Lanjewar from the University of Wisconsin-Madison walk through a case and their approach to the common ID consult for fever and rash.

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Febrile is produced with support from the Infectious Diseases Society of America (IDSA). Audio editing/mixing by Bentley Brown.

Hi, everyone.

Welcome to Febrile, a cultured podcast about all things infectious disease.

We use consult questions to dive into ID clinical reasoning, diagnostics,

and antimicrobial management.

I'm Sara Dong, your host and a MedPeds ID doc.

Today, we have a team visiting from the University of Wisconsin, Madison.

First, let's meet Dr.

Michael Moran.

Michael is an adult Infectious Diseases Fellow at the University of Wisconsin.

Hi, my name is Michael Moran.

I'm excited to be on the podcast.

Also joining is Dr.

Swapnil Lanjewar.

Swapnil is a Clinical Assistant Professor in ID at the University of Wisconsin.

He completed his medical schooling in India and pursued his IM residency

at the Cleveland Clinic in Ohio.

He did his fellowship in ID at the University of Wisconsin Madison.

Hi, this is Swapnil Lanjewar, and I'm

super excited to be here.

Both me and Michael, we are big fans of the Febrile podcast, so we are absolutely

thrilled to join you here today, Sara.

Well, I'm very excited to have you.

Of course, before we jump into the case, we always ask one question.

We are everyone's favorite cultured podcast, so I'd love to hear about a

little piece of culture, something non medical that you've enjoyed recently

or like to do in your free time.

Michael, what do you got?

Yeah, I mean, so in fellowship, I think I've been

trying to find a lot of things to like kind of dump my brain.

And I was just recently introduced to 90 Day Fiancé, which I had

until now never watched before.

And it was like this week and it is absolutely wild.

And so I've been kind of going down a rabbit hole in that of just that's

the opposite of anything medicine.

So I understand all the hype now.

Yeah.

What about you Swapnil?

One of my biggest hobbies is playing table tennis.

I grew up in India and I used to train formally in table tennis.

And I used to play competitively at the state and national level tournaments.

But these days it's mostly limited to playing with some

friends over the weekend.

Do you get really aggressive?

You're very competitive.

I am actually.

Awesome.

Well, I will hand it over to Michael.

Tell us about the case.

So today we are getting a call from the medicine team to get

some help looking at a patient for the management of someone they admitted

overnight with a fever and a rash, and this occurred this past March.

When they called us, they gave us a little story about our patient.

She's a 47 year old female, has a past medical history of gout and hypertension,

and notably about eight weeks ago, she was seen by rheumatology due to a

one year history of polyarthralgia and was diagnosed with seronegative RA.

At that appointment, she was started on sulfazalazine and low dose oral prednisone

of about five milligrams a day, resulting in significant symptomatic improvement.

In regards to her current presentation, the medicine team tells us that

about three weeks ago, she started experiencing high grade fevers to 103 to

104 degrees Fahrenheit with associated night sweats and some loss of appetite

and bilateral upper abdominal pain.

About 10 days prior to this presentation, these symptoms were persisting, so she

presented to her local ER for evaluation.

Her exam at that time, along with routine labs like a CBC and CMP,

were within normal limits, although she did have an elevated CRP.

They tell us a CT chest abdomen pelvis was performed and was negative, and as

this was late winter, early spring, a respiratory pathogen panel multiplex PCR,

was done and negative, but with no other explanation, she was discharged home

with a tentative diagnosis of a viral syndrome, as she was otherwise well.

At home, her fever still continued on a daily basis without improvement,

which brings us to our current hospital admission, where she is now

presenting with the new development of a rash, which started about

three days prior to presentation.

The primary team tells us the rash is pink, macular, and

patchy, located all over her body.

The rash is not itchy and non painful.

They tell us there have been no new medications in the last one

to two weeks to explain this.

The team tells us the patient is currently hemodynamically stable, but

has a temp of 102 degrees Fahrenheit.

So far, her repeat labs and new CT chest abdomen pelvis are still unremarkable.

The team is planning to hold off on any antibiotics because

she otherwise looks good.

All right.

Thank you so much for the case, Michael.

So I will summarize what I gathered here.

So it looks like we have a 47 year old female with past medical history of

gout and recently diagnosed seronegative rheumatoid arthritis for which she was

started on treatment about two months ago and she's now presenting due to fever of

unknown etiology over the last four weeks and a new rash since last three days.

And this is in the setting of nearly normal labs and imaging about 10 days ago?

Exactly.

So Swapnil, if you were called about a case like this, how would you approach

developing an evaluation and treatment plan for a patient with fever and rash?

Fever with rash is an important topic and it's quite

a challenging one, actually, for the infectious disease clinician.

This is because the list of differentials is quite big.

So I remember that as a trainee, this topic used to be pretty intimidating

for me, And even sometimes I struggle with a patient with fever and rash.

But over the years, I developed a structured and organized approach

for myself that I can share today.

And this is my personalized approach.

If you already have an approach nailed down which works well for you, then I

think you should keep doing that one.

For the purposes of this podcast, I will break down my approach in three parts.

First is what I do before I see the patient, second is what I do while I'm

seeing a patient, and third is what I do after I'm done seeing the patient.

Let's come to what I do before I see the patient.

I try to get a few questions answered absolutely before I hang

up the phone with the primary team.

When they're telling me about the case, I try not to interrupt them, and this is

because I want to make sure that they're not losing their train of thought, and

they don't forget giving me an important piece of information, and then I pay

attention to how sick is the patient.

Like, am I getting a call from the ICU, or is the patient's primary

care physician calling me about this?

If the patient is in ICU, super sick, hemodynamically unstable,

then I want to make sure that I'm not missing a never miss diagnosis.

For example, you know, is it a surgical disease?

Is it necrotizing fasciitis?

Or is this a hemorrhagic rash because of septicemia from either a

perforated viscus or a really terrible bad piomyositis or a huge abscess

which requires emergent surgery?

Or is it related to a toxic shock syndrome from a retained foreign body like a

tampon or a line or device infection which is causing the septic shock?

These are some never miss diagnoses and then if the season and location

are right, I will also think about tick borne infections like Babesia

and Rocky Mountain Spotted Fever that I want to make sure I'm not missing.

And if the patient is immune compromised, I absolutely don't want

to miss any terrible fungal infection.

So, apart from that, I also want to make sure whether or not I need to put

this patient into prompt isolation.

If there's anything like a meningococcal disease or a viral hemorrhagic fever

like Ebola based on epidemiologic risk factors for the patient, then you

want to make sure you put the patient in isolation as soon as possible.

Sometimes, somebody who's really sick with HIV and miliary TB can

actually have a skin rash too.

So, these are some considerations regarding whether they

need prompt isolation.

And lastly, if this is an exotic disease, you know, like malaria or so, based on

their epidemiologic risk factors again.

Technically, the textbook approach is also to think of bioterrorism,

but I really hope that none of us in real life have to think about that.

So, these are things I do before I see the patient while I'm still on

the phone with the primary team.

If they don't have a never miss diagnosis and you receive such a

call in middle of night, then it will make me feel comfortable.

Okay, fine.

I think I covered everything.

I can go back to sleep safely.

Next comes what I do while I'm seeing the patient.

So obviously this, I'll divide this between two parts,

history taking and examination.

History taking is one of the most important skills for any

infectious disease clinician.

When you have so many questions that you need to ask to the patient.

It's very easy to forget some crucial pieces of information,

so over the years, I've developed a personal template for myself.

I try to follow this template just so that I don't miss anything

important to ask the patient.

After I'm done asking them relevant questions about the

HPI, I'll ask five main group of questions to elicit differentials.

First group is occupational history, second group is outdoor exposures,

then indoor exposures, then regarding something they ingested or injected,

and the fifth one would be non exposure related differentials.

Going to occupational exposures, this is important to elicit because if

they are a butcher, let's say, there have been periodic outbreaks of Staph

and Strep infection amongst butchers.

If somebody's a chef who's handling raw meat, then I'll think about Salmonella.

And if they are routinely tasting raw oysters, then you

also have to consider Vibrio.

If they are a taxidermist, I know that there have been some

outbreaks of Q fever before.

So if they're a fisherman, I would think about something like Vibrio

if they are on the coast and are having a lot of exposures there.

So that's about occupational exposures.

Coming to outdoor exposures, I tend to categorize them

in three main subcategories.

Travel related and then hiking or camping related, or water body related exposures.

Hiking and camping related outdoor activities.

You know, what, what were they doing outside?

Were they doing something that involved turning of soil?

Were they out exploring caves?

Were they in contact with wild animals like, you know, flying

squirrels and snakes and bears?

Or were they in contact with any farm animals?

And then, have they been annoyed by some insects or arthropods like

ticks or lice or mosquitoes or flies?

Because all of these can contribute to your list of differentials as well.

Now, with regards to travel related exposures, then I ask

them where exactly they travel.

Was it a domestic travel or international travel?

Of course, we all know domestic travel related exposures differentials you have

to consider like in the southwest U.

S.

you think about Cocci[dioides].

Here in the Midwest we always think about Histo[plasma] and Blasto[myces].

In New England you would consider things like Lyme disease

based on the season as well.

And then when it comes to international travel, my first

question is always did you check the CDC website before you traveled?

Regardless of the answer, I will always pull up my phone and I'll go

on cdc.gov/travel and and pick their destination of travel and see what

all exposures that can occur in those particular areas of the world because

I can never remember, you know, specifics regarding to each country.

Like for example, if somebody traveled to India, you have to think about

typhoid, you have to think about malaria, even kala azar or leishmaniasis.

The list is pretty extensive.

That's in with regards to travel.

Next is outdoor exposure is water bodies, right?

So it could be oceans or You know, ponds, lakes, uh, streams and rivers,

or it could be flood water as well, and then recreational outdoor water

body exposures like swimming pools, or even water parks, and have they had any

injuries in the water, because there will be very specific bacterial and parasitic

infections that I would be considering with exposure to such water bodies.

In terms of indoor exposures, I asked them about have they had sick

contacts, like sick contacts with other adults or children or indoor animals.

So adults as in you can get of course you know all types of respiratory

infections and URIs from adults as well.

STDs would be a big thing from adults like syphilis and then gonococcal infection.

All of these can cause fever and rash and then risk factors for TB

as well would be elicited here.

Then in terms of contact with kids or little humans, you know, they are sources

of all kinds of viral and bacterial infections like vaccine preventable

diseases, measles, rubella, or parvovirus B19, HHV6, CMV, EBV, the list goes on.

Indoor animals, you could either think about pets as well as insects

as well, annoying indoor insects.

Some people have, you know, all kinds of exotic pets, like including.

Uh, you know, salamanders, and turtles, and snakes, and so obviously that's

going to make you think about salmonella.

And then indoor annoying bugs, like you know, have they had bed

bugs, or spiders, or rodents?

All of these can be associated with some, some other, uh, pathology

that will give you fever and rash.

And then, uh, coming next to something they ingested or injected, so injection

was injection drug use or if they have any recent vaccines that were injected that

can cause fever and rash too, or recent tattoos, and then something they ingested

would be, you know, drugs or food, and so in terms of drugs, there can be Steven

Johnson and toxic epidermal necrolysis, DRESS syndrome, small vessel vasculitis,

In terms of some food they ate, like raw oysters, again, you

have to think about Vibrio.

Raw meat would make you think about salmonella again, or unpasteurized

cheese and dairy products make you think about either brucella or Q fever too.

Non exposure related would be the next big category.

So autoimmune diseases, SLE, rheumatoid arthritis, or cutaneous

vasculitis, or erythema nodosum, cancer, especially liquid malignancies,

or cutaneous T cell lymphomas, and then other diseases like sarcoid.

Kawasaki, GVHD, HLH, so these are some of the differentials that come to my mind.

Michael, could you perhaps provide us with some HPI obtained by ID here?

Thanks for all that explanation Swapnil.

When we went and saw the patient, she tells us the fever started

about three weeks ago, occurring on almost a daily basis, but no

particular timing during the day.

She does get occasional drenching night sweats though.

She also describes having no energy and poor appetite over the last four to five

weeks, as well as a frontal headache which occurs on and off during these fevers.

She rates these headaches as a 4 out of 5 out of 10 in intensity, but has no

associated photophobia or neck stiffness.

In addition to this, she notes some abdominal pain on and off in

her bilateral upper quadrants, as well as a sharp 5 out of 6 out of

10 intensity without radiation.

She has no associated nausea, vomiting, or diarrhea.

With regards to her rash, she has trouble telling us exactly when it was started.

She is of African American ethnicity and notes that it's possible the

rash could have been there in early stages without her being able to tell.

She does recollect having some local skin sensitivity over her anterior

thighs, but no pain or pruritis.

She believes that this started about three days ago on her thighs and chest, and

her husband's in the room with us, and he tells us that the rash is also on her

upper back, abdomen, and posterior thighs.

She denies any mucosal pain or skin breakdown.

Otherwise, review of systems is unremarkable.

With regards to exposure history, she lives in the Midwest with her husband in a

single family home for the last 15 years.

They have no kids.

She has always been in a monogamous relationship and has no history of

prior sexually transmitted infections.

She works as a software engineer, with the majority of her work being remote.

She is a never smoker and only drinks socially with no illicit drug use.

She reports no new medications in the last two months aside from the

sulfasalazine and prednisone for her RA.

She does not take any other supplements or over the counter

meds, although she has been taking Tylenol and Ibuprofen for her fevers.

She has no pets or any exotic animal exposures.

She has never noticed any rodents or insects in the home.

And in terms of travel, she has never been to the Southwest U.

S., but she did say that she went to Cancun with her family about six weeks ago

and swam in the ocean while she was there.

She reports that she has not spent any time outdoors here in the

Midwest in the last five months because she hates being in the cold.

And before that, she used to go hiking on nearby trails and lakes with her husband.

She does not garden and has no soil exposures.

Her neighbor recently had COVID two weeks ago, and there was no family

history of recurrent infections.

Her sister in law's family did recently visit them for about three days, and

they have two kids of the ages of three and nine, and both kids had

the sniffles while they were here.

So Swapnil, based off this history alone, any differentials going through your mind?

Yeah, so Michael, fever with rash is actually a unique

entity in ID where I often do not start thinking of the differentials

until I lay my eyes on the patient.

This is because the examination of rash is actually going to

significantly influence my thought process regarding differentials.

While examining the rash, I'm looking at is it macular, papular, or maculopapular?

Do they have plaques or nodules?

I also look for secondary features into the rash, like do they have crusting

or scaling there or excoriation or any other important secondary

features like ulcers or eschars?

And this is because appearance of the rash is going to help you narrow

down your differential significantly.

There are multiple viral infections that will cause a maculopapular rash,

like herpes virus infections, EBV, CMV, HHV 6, then vaccine preventable viruses

and childhood infections like measles, rubella, parvirus B19, and adeno.

You can see maculopapular rash in some bacterial infections as well,

like some STDs like syphilis and gonorrhea, and then you can see

that in other bacterial infections like mycoplasma, relapsing fevers.

Even some rickettsial infections like Rocky Mountain spotted fever

and some tick borne infections will give you a maculopapular rash.

When there are secondary features to the rash like skin necrosis, then there are

some very specific bacterial infections that will come to my mind like pseudomonas

which can cause ecthyma gangrenosum and then the Rickettsia typhi group like the

murine and scrub typhus group, then the rat bite fevers like from Spirillum minus

and from Streptobacillus monoliformis.

And then some endemic fungal infections as well will cause some

necrotic appearance to the rash.

Other secondary features like vesicles will make me think about viral etiology

like a Coxsackievirus or HSV or VZV, um, even smallpox and monkeypox.

And then bacterial causes like rickettsial pox can also cause vesicles.

And then Vibrio, uh, can cause bullae.

And then lastly, if the rash is petechial or perpiric rash, then the biggest viral

differentials would be viral hemorrhagic fevers, especially if they have this low

epidemiologic risk factors of travel.

I would think about dengue and then viral hemorrhagic fevers, like Ebola,

Marburg, chikungunya as well, yellow fever can cause petechial or perpiral rash.

And then certain important bacterial causes of petechial rash would be

meningococcal infections, even sometimes severe Capnocytophaga infections, and

then rat bite fever can also cause a petechial or perpireal rash, and then

Staph aureus, and then relapsing fever, and rickettsial infections, again, like

Rocky Mountain spotted fever, or epidemic typhus, or from Rickettsia prowazekii.

These can all cause the petechial rash as well.

So, Michael, can you share the exam findings with us for the rash?

Yeah, certainly.

On exam, we repeated her vitals, and she had a low grade temp of 100.

6 degrees Fahrenheit.

Her heart rate was 108, but she had a normal respiratory rate, blood

pressure, and oxygen saturation.

And her BMI is 33.

And on exam, she's alert and oriented times three and in no acute distress.

Some pertinent positives and negatives on her exam, she has

a mild periorbital edema and has evidence of cervical lymphadenopathy,

which was non tender on palpation.

Her heart sounds are normal and her respiratory exam is benign.

Her abdomen was soft, obese, with normal bowel sounds and

no organomegaly appreciated.

She had a normal neuro exam.

In regards to her skin exam, there was a symmetric, macular, and patchy

widespread erythematous rash over her cheeks, anterior and posterior

thighs, legs, chest, and back.

She had no mucosal involvement and notes the rash was mildly blanching.

So, with that exam, are there any other differentials that come to mind?

Yeah, that definitely helps narrow down

the list of differentials.

I will divide my list of differentials according to viral versus bacterial

versus fungal, parasitic, or non infectious etiologies.

Viral wise, herpes viruses come to mind, especially with the history of contact

with little kids who have been sick.

So, EBV and HHV6 would be coming to mind.

Because there are no vesicular features, I'm not thinking of chickenpox or VZV or

HSV or any of the other herpes viruses.

Um, Coxsackie and adenovirus would still be on my list of differentials.

And then, Parvovirus B19 again, because of the risk associated

with contact with little kids.

I assume the kids are vaccinated, otherwise I would think of

measles and rubella too.

Uh, in terms of bacterial causes, if this was the appropriate

season, I would have considered tick borne infections definitely.

But it's March, and typically incubation period for most tick borne infections

tends to be around two weeks or so.

So I don't think this is tick borne infection.

Unless the patient has any recent history of blood transfusion or

so, but I don't think there was any such history, so I wouldn't

consider tick borne infections here.

STDs would still remain on my list of differential, even though she states that

she is in a monogamous relationship, I would still consider syphilis, and then

Neisseria gonorrhoeae, and then some non STD infections like Mycoplasma can

still be on the differential for me.

I don't think that the rash sounds fungal or any kind of parasitic infection, so

I think we can safely rule those out.

In terms of non infectious etiologies, I would consider possibility of DRESS

syndrome or autoimmune disease, of course, given her recent history of

rheumatoid arthritis, cancer, possibly hematologic malignancies could still

be in the list of differentials.

That would be my list so far.

Do we have any labs and imaging results back so far, Michael?

We do.

So, on a CBC with differential, she has a white count of 7.

9 with a mildly elevated lymphocyte count of 3, 670, but

a normal eosinophil count at 110.

Her hemoglobin is 9.

3 and her platelet count is 116, so mildly low.

The pathology department did a formal read on her blood smear, which

shows numerous reactive appearing immunoblasts, and they note a reactive

process is favored, but correlation with flow studies is necessary.

Serum chemistry studies are all within normal limits.

In liver function testings, note an elevated ALT at 430,

AST at 345, and Alk phos 180.

A total bilirubin elevated at 3.8 with a direct bilirubin 2.8.

In terms of other labs, she has a normal uric acid and an elevated LDH at 1, 317.

On her repeat CT chest abdomen and pelvis, they do note a mild

thickening in her urinary bladder as evidence of possible cystitis.

As well as some mild splenomegaly and mild enlargement of the axillary

lymph nodes, presumably reactive without lymphadenopathy in the chest.

So Swapnil, given these findings so far, what would be your

recommendations to the team for any further workup of this patient?

My next set of recommendations would be that we

should check for, you know, the routine things, like multiple blood cultures,

and then I'll recommend serology for EBV and CMV, and of course viral

loads for EBV and CMV as well here.

I'll recommend PCR for HHV6, Parvovirus B19, given the history

that was provided, and then Adenovirus PCR from the blood tube.

Given that this patient had transaminitis, I will screen

her for hepatitis A, B, and C.

I'll still recommend STD workup here by screening for syphilis, so

treponemal antibody, and then the urine gonorrhea and chlamydia screen.

I'll also screen for HIV here.

I'll add some workup for culture negative endocarditis by checking for Bartonella

PCR and Q fever serologies as well.

Since there was this concern for HLH that I was thinking about because of

the splenomegaly and cytopenias and these weird fevers, I'll also recommend

screening for HLH by sending ferritin and triglycerides, soluble IL 2, and

also check for flow cytometry because of the presence of those atypical or

cells or immunoblasts that were mentioned earlier on the peripheral smear.

And last but not the least, I'll recommend dermatology consultation

as well for a skin biopsy here.

Yeah, so the lab was working quick this week, so we

have lots of results to talk about.

We have multiple sets of blood cultures that were drawn and are negative.

The Q fever phase 1 and phase 2 serologies were negative, as

well as serologies for Bartonella quintana and Mycoplasma serology.

Her urine gonorrhea and chlamydia screen was negative, as well as a

treponemal antibody, and an HIV fourth generation combo assay was negative.

We repeated the nasopharyngeal swab for respiratory viral panel, which was

negative, which included parvovirus B19, an adenovirus, a CMV serum viral

load was negative, and EBV serologies note a positive IgG, but a negative

IgM and a negative EBV viral load.

The hepatitis A, B, and C screens are negative.

In regards to the HLH workup, her ferritin is elevated at 6,

883, and elevated triglycerides at 226, a soluble IL 2 of 7, 252.

With a reference range of the upper limit of normal being 858.

So with those findings so far, how would you further narrow your differential?

This definitely helps me further narrow down

on my list of differentials.

And quite frankly now, I don't think this is any kind of

infectious process going on.

My concern is strongly for non infectious processes.

You know, DRESS would still be on my list of differentials, like drug related

eosinophilia and systemic, uh, symptoms.

I would think about autoimmune pathology still, so at this point,

I might consider engaging our rheumatology colleagues as well.

And hematologic malignancies are still on my list of differential,

so I hope that the team now formally consults, uh, hematology based on

the elevated soluble IL 2 and super elevated ferritin of more than 6, 000.

Now HLH has jumped high on my list of differentials here.

So, Michael, do you have any results so far regarding the skin biopsy?

We do.

The pathology department tells us that her right thigh skin biopsy pathology

shows an unusual constellation of findings with spongiosis, lichenoid

interface features, and a mixed dermal infiltrate with focal hemorrhage.

Eosinophils are not present in number, but these findings are

consistent with a reaction to a medication or other ingestant.

So dermatology is now suspecting DRESS syndrome, likely related to the

sulfosalazine that she was prescribed.

But, with our concern for HLH, hematology has a few other

additional workup to obtain.

They did do a flow cytometry on the peripheral blood, which showed polytypic

T cells with increased CD8 T cells and polyclonal B cells without evidence of

a B cell lymphoproliferative disorder.

These findings are consistent with the reactive process,

such as a viral infection.

They recommended the bone marrow biopsy, which was done, and showed cellular

marrow with trilineage hematopoiesis, with increased megakaryocytes, 1 percent

BLAST, and small aggregates of T cells consistent with reactive process.

No evidence of a lymphoproliferative disorder.

They also did a PET CT, which showed hypermetabolic lymph nodes throughout

the neck, chest, abdomen, and pelvis, with an enlarged and abnormally avid

spleen, which would be concordant with lymphoma if clinically suspected.

So right now, our final diagnosis is DRESS, and dermatology was considering a

DRESS and HLH overlap, but hematology did not feel that it was consistent with HLH.

So Swapnil, can you discuss DRESS and why we were thinking HLH and why we

could possibly have an overlap here?

Yeah.

So DRESS syndrome, the DRESS word stands for drug reaction with

eosinophilia and systemic symptoms.

I don't really like that name DRESS that much because you can actually

have DRESS without eosinophilia.

That's why a better term for it is drug induced hypersensitivity syndrome.

It's a rare and potentially life threatening disorder that can occur

about two to eight weeks from the initial exposure to the offending drug.

And the typical pathogenesis for DRESS is that it's a T cell

mediated hypersensitivity reaction.

And then another thing we often see in DRESS is that there

is simultaneous evidence of reactivation of HHV 6 or EBV or CMV.

These group of herpes viruses, there is this controversy whether this is

reactivation in the setting of DRESS or are they actually playing any role

in the pathogenesis of DRESS itself?

In terms of manifestations, the classic one is a morbilliform rash

and the word morbilliform means that it essentially looks like measles.

It's a faint pink maculopapular rash which can be circular or elliptical

and it's typically symmetric rash.

This can be associated with fevers.

Lymphadenopathy as well, and some patients might have facial,

hand, or feet swelling too.

Another significant hallmark is visceral organ involvement like, you

know, hepatitis, like our patient had, or renal, or pulmonary, or

cardiac involvement, and when there's pulmonary or cardiac involvement, it's

pretty severe stress at that point.

Common culprits for DRESS tend to be anti epileptic drugs like phenytoin,

or carbamazepine, or lamotrigine.

In terms of antibiotics, sulfa group antibiotics are also a known culprit here.

Tetracycline group antibiotics, especially like minocycline or

minocycline, however you want to say it, penicillins and vancomycin.

And then other important drug that is described for DRESS is allopurinol.

But again, this list continues to grow along with our experience.

Now for the diagnosis of DRESS, There's a really good scoring

system called as RegiSCAR Scoring System, which stands for Registry of

Severe Cutaneous Adverse Reactions.

So that's why RegiSCAR it, it is readily available on Med Calc.

You have to go through this questionnaire regarding whether your patient has fever,

lymphadenopathy, atypical lymphocytes, or eosinophilia, and what's the extent

of their skin involvement and what's their pathology on biopsy of the skin.

Do they have involvement of internal organs, and what's the

resolution time for their rash?

So a score of 6 or more is supposed to be definitive diagnosis for DRESS.

When it comes to treatment, the first line is supportive care, and if the

disease is severe, like if there's end organ involvement as well, then you can

consider glucocorticoids at a dose of 0.

5 to 1 milligram per kg per day of prednisone equivalent.

And then you taper it over the next 8 to 12 weeks or so.

When you're giving them steroids, you absolutely make sure that

you're also giving PJP prophylaxis because you're giving high dose

steroids for more than a month or so.

This is the first line treatment.

Second line treatment is you could consider immunosuppressive drugs like

cyclosporine and you could add IVIG and consider other immunosuppressants like

JAK inhibitors, but typically I also let dermatology drive the ship on that.

That's about DRESS syndrome.

And then other thing which dermatology and myself, we were thinking about HLH.

HLH is a life threatening hyper inflammatory syndrome where there is

intense immune activation characterized by fever, cytopenias, and hepatosplenomegaly,

and highly elevated inflammatory markers.

This is definitely a life threatening condition, and if you are thinking

about HLH, you should work fast on whether or not you can rule in or

rule out this diagnosis because time is of the essence in such patients.

So there are basically 9 criteria for HLH out of which you need at least 5 of them.

Criteria include fever, splenomegaly, and then peripheral blood cytopenias with

at least 2 of the following, you know.

There should be hemoglobin less than 9 or platelets less

than 100 or ANC less than 1000.

Then hypertriglyceridemia is one criteria, so fasting triglycerides

more than 265, or low or absent NK cell activity, or ferritin required is at

least more than 500, but in reality most patients with HLH are going to have

their ferritin in multiple thousands.

And then elevated soluble IL 2 as well, and then elevated CXCL 9,

and evidence of hemophagocytosis on biopsy from bone marrow.

But you can also see that from biopsy from spleen, lymph nodes, or liver.

Our patient, after discussion with hematology, did not

meet all of these criteria.

Our patient had only evidence of fever, and then the splenomegaly was there.

Technically, it was pretty mild.

She did have ferritin elevation of more than 500 and elevated soluble IL 2.

But, the bone marrow biopsy did not show any concern for hemophagocytosis.

Based on all of this, only four criteria were met, and that's why hematology

did not think that this was HLH.

So, Michael, what happened finally with the patient?

Yeah, so, coming back to our patient, she was initially treated

with IV dexamethasone at dose equivalent of about 1 mg per kg of prednisone, and

later switched to PO prednisone, which was tapered over the next eight weeks.

The team used atovaquone for PJP prophylaxis to avoid any sulfa

drugs, and her symptoms improved very quickly, and she made a full recovery.

This is such a great ID related topic.

The other thing I just wanted to add that I think you've said and implied, but

just to deliberately say aloud, is the mainstay of treatment is also stopping

the offending drug or agent, or whatever it is you think that is inducing DRESS.

And I think we all know that, but maybe just also saying that again out

loud, because oftentimes it's a bit of a conversation, you know, if these

patients are sick for other reasons, to also avoid giving them new meds,

like new empiric antibiotics, if you are in a place to be able to do so.

I think sometimes that's a hard conversation if these, because often

these patients are in the ICU, they have these very impressive rash, they can

look quite ill, but yeah, I just wanted to re emphasize that because sometimes

it's actually not that easy because the drug that's causing it isn't that clear.

If they look unwell, people want to add new things, so balancing all of that.

Do you guys want to do take home points?

Like, each of you have one thing that you emphasize.

I will say that one of the biggest take home points from my

standpoint here would be that this case shows the importance of not anchoring to

infectious etiologies as the diagnosis every time you hear the word fever.

Oftentimes, it is infectious disease clinicians who are also diagnosing

non infectious causes of fever like DRESS syndrome or autoimmune pathology,

rheumatological diagnosis as well.

So it is important to keep non infectious etiologies in mind as

well for patients having fever.

Yeah, I think the takeaway that I've had from this case is that,

you know, anytime you're called from the primary team for a rash, which

happens fairly often in ID, is really doing a comprehensive med list look and

getting that good exposure history, and then always just looking at UpToDate or

another resource for those medication lists or offending agents like Swapnil

talked about to kind of jog your memory so you aren't missing something.

Since the differential is so broad, it can really be so many different things.

Thanks again to Michael and Swapnil for joining Febrile today.

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