93: Rash Decisions

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.

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?

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?

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?

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?

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?

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?

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.

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?

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?

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?

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?

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.

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

Thanks for listening, stay safe, and I'll see you next time.