#161 A Rash Approach to Rashes

July 15, 2019 | By Beth Garbitelli

Rash Decisions with Dr. Helena Pasieka MD and The DermSiders

Tackle rashes with wisdom from Kashlak’s resident Skinternist (or Internist-Externist) Dr. Helena Pasieka (MedStar, Georgetown), board certified in both Internal Medicine and Dermatology.  She offers “a rash approach to rashes” including: initial triage, ‘inside job’ vs ‘outside job’, differential diagnosis, a review of common culprits, basic management techniques, and how to determine if the reaction is life-threatening. Plus, Dr Pasieka teaches us how to handle family and friends asking, “Can you take a look at this rash?”. 

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Credits

Written and Produced: Beth Garbitelli MS2

Infographic and Cover Art: Beth Garbitelli MS2

Hosts: Stuart Bringham MD, Matthew Watto MD, Paul Williams MD  

Editor: Matthew Watto MD

Guest: Helena Pasieka MD 

Time Stamps

• 00:00 Intro, disclaimer, guest bio
• 04:10 Guest one-liner, book recommendations 
• 09:56 Case of a rash; initial thought process (sick versus not sick); review of systems
• 18:05 Grouping rashes: inside job versus outside job
• 22:07 Terminology: Many people dont speak derm
• 26:03 Skin itching versus Skin pain; Morbilliform drug eruption
• 30:08 Urticaria (hives) vs morbilliform rash; Cotton tipped applicators and dermatographism
• 35:42 Itching is not all about histamine; Treatment of hives
• 38:26 Treatment of morbilliform rash
• 40:00 Case summary and review of concepts learned thus far
• 41:00 AGEP
• 45:14 SJS/TEN; Nikolsky’s sign
• 53:20 Complications of TEN – Ocular surface disease; Vulvar disease
• 58:02 DRESS (now DIHS)
• 66:30 Tips for asking about time course of meds and symptoms; Recap of DRESS (DISH)
• 70:00 How to handle family and friends ask for rash evaluation
• 76:20 Outro
• 78:00 Post-credits scene

Rash Pearls from Dr. Pasieka

Dermatology is medicine. Remember what you learned in intern year: how to differentiate sick versus not sick. This is the first threshold for addressing rash. 

“Inside job”: Does the rash have an internal cause (e.g. histamine degranulation, or systemic illness)? These rashes from an ‘inside job’ like hives are diffuse, symmetric, and bilateral. 

“Outside job”: Rashes with an external cause tend to be unilateral and asymmetric e.g. contact dermatitis, cellulitis, or other types of infection. 

Familiarize yourself with what  different types of eruptions look like on ALL pigments of skin.

Suspected severe drug reaction with rash: Perform a thorough physical exam with a focus on mucosal regions (oral, nasal, ocular, vulvar/vaginal in women, urethral, perianal).  

Describe what you see in regular, old words. Don’t try to “speak derm” if you don’t speak derm. You’ll cause more confusion. 

Urticarial (hives) or morbilliform? 1) Use a skin marker to draw around the rash. Then, examine the next day. Hives may change location, but morbilliform lesions do not move. 2) Use the wooden end of a cotton tipped applicator to check for dermatographism (suggestive of urticaria) –Dr Pasieka’s expert recommendation

Morbilliform Rashes: An itchy, symmetric, bilateral, diffuse, truncal rash is likely to be a benign morbilliform drug eruption. These are common and you can “treat through” if organs are spared and the reaction is limited to skin. 

Timing differentiates types of severe drug reaction: It can be tedious to figure out when people started and stopped medications. But, the timeline is critical in determining between AGEP (<3 days), SJS/TEN (4-10 days), and DRESS/DIHS (often 6 weeks). 

Patients with SJS or TEN will feel very sick, have mucosal site involvement,  skin pain, and a positive Nikolsky sign. When patients fit these criteria, admit them to the ICU, call dermatology immediately, stop every drug that is unnecessary, and carefully initiate a fluids. 

Complications of SJS/TEN: Over 50% of patients surviving TEN suffer from long-term sequelae of the disease, including ocular and gynecological issues. Consult with ophthalmology and gynecology early if managing patients who have experienced SJS/TEN. 

How to handle family and friends asking about rashes: Tell them you need to see ALL the skin. Lighting is not great at parties. Maybe there’s too many cocktails on board. And, anything less than a full skin exam is doing them a disservice (Dr. Pasieka’s expert recommendation).

Rash Decisions

Rashes, Remember the fundamentals 

Dermatology is medicine. Remember what you learned in intern year: how to differentiate sick versus not sick. When a patient presents with a rash, perform an assessment of the patient’s current state and how sick they appear.  This is the initial threshold for serious cutaneous reactions to drugs and other life-threatening emergencies in dermatology. Go back to fundamentals. Namely, a thorough review of systems and physical exam are essential for proper assessment of potential drug rash. 

The Bad Actors

Certain drugs are more commonly associated with the life-threatening drug reactions and rashes, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). They include antibiotics (trimethoprim-sulfamethoxazole and other sulfonamide antibiotics, as well as aminopenicillins, quinolones, and cephalosporins), allopurinol, aromatic anticonvulsants, certain antiretroviral medications, NSAIDs and more (Dodiuk-Gad, 2015 ; Lin 2004). 

The Full Monty

ROS for Rashes

A complete review of systems is very important (Santistevan 2017).  Symptoms to ask about specifically include fever, feelings of malaise, flu-like feelings, pharyngitis, and upset stomach.  While diarrhea and vomiting are uncommon with drug eruptions, unsettled stomach, and pharyngitis can indicate involvement of the alimentary canal (Schwartz 2013).  Additionally,  determine a timeline for symptom progression.  Assess how the skin feels to patient. Is it painful or not painful?  Skin that feels itchy to the point of burning/tingling, or painful like a sunburn is concerning. Per Dr. Pasieka, rashes that itch are usually benign. 

Rashes and Skin Type

Familiarize yourself with what  different types of eruptions look like on ALL pigments of skin. Drug reactions may have more severe complications in those with more deeply pigmented skin (Thorel 2019).

Physical Exam for Rashes

Perform a thorough physical exam with a focus on mucosal regions (oral, nasal, ocular, vulvar/vaginal in women, urethral, perianal) (Schwartz 2013).  Signs of conjunctivitis or irritated eyes may also indicate severe drug reaction (Harr 2010) .  The GU systems may also be implicated so symptoms of urethritis, painful defecation, or blood in stool must be ascertained in somebody with this history (Schwartz 2013).

The genitourinary components of this exam are often missed but are a critical aspect. A full body skin exam is extremely important in a potential drug rash since in over 90% of  SJS/TEN cases have mucosal site involvement (Harr 2010) .  This can be a litmus test for your threshold of suspicion. 

Inside Job versus Outside Job

Kashlak Pearl: Dr. Pasieka finds it helpful to think about rashes based on cause, an internal cause such as histamine degranulation (‘inside job’) versus external causes such as contact dermatitis (‘outside job’).  Rashes from an ‘inside job’ like hives or urticaria are diffuse, symmetric, and bilateral. In an ‘outside job’ like contact dermatitis, cellulitis, other types of infection, rashes are unilateral and asymmetric. 

Location can indicate certain types of causes as well.  Drug reactions tend to evolve centrally, moving from trunk to extremities. Eczema, contact dermatitis, allergic manifestations, and tinea tend to manifest distally per Dr. Pasieka. 

‘Not Everyone Speaks Derm’

Describe what you see in regular, old words.  You’re there to be an advocate for your patients. Trying to use a speciality-specific vernacular that you don’t speak well can cause more confusion. Don’t say erythematous, just describe the color (ie: red, lilac, purple, brown), per Dr. Pasieka. 

Example: “Gentleman is here and looks unwell, his mucosal sites are inflamed. He’s complaining of a sore throat. He has dry eye, and when I look at his skin, it is inflamed, pink and purple, moist, and in some areas, it is eroded. Patient has skin pain, not skin itching.”

‘Not-Sick’ with a Drug Rash

Kashlak Pearl: Dr.  Pasieka points out, a patient with an itchy, truncal rash with pristine mucosa (ie: without dry eye, ocular pain, conjunctivitis, urethritis, perirectal pain) in the absence of blisters and erosions on skin, is unlikely to be experiencing a life-threatening reaction.

An itchy, symmetric, bilateral, diffuse, truncal rash in the absence of other signs mentioned above,  is likely a benign morbilliform drug eruption. These are common, pesky, and uncomfortable. Exanthematous drug eruptions, also called morbilliform or maculopapular drug rashes, occur in 1 to 5% of first-time users of many types of drugs (Stern 2012).

In absence of concerning drug reaction symptoms (pain, mucosal involvement, pancytopenia, LFT abnormalities,  renal dysfunction), you may treat through it with palliative treatment only if the causative drug is a clinical need (ie: in hypersensitivity in HIV-positive patients, patients with cystic fibrosis, etc.) (Scherer 2013). 

Urticaria or Morbilliform? 

Urticaria and morbilliform rashes have a different treatment algorithm. Urticaria changes or disappears rapidly while morbilliform rashes will persist for 48-72 hours regardless of therapy. 

Kashlak Pearl: Dr. Pasieka  advises using a skin marker (‘give the patient a temporary tattoo’) to draw around the rash. Then, examine the next day. An urticarial rash may change locations, but morbilliform lesions will not move around.  

Kashlak Pearl: Another ‘tip’ is to assess for dermatographism using a cotton tip applicator’s wooden end. Draw something with the applicator (tic-tac-toe, ‘Go Yankees’, etc.) Check it after five minutes. All skin types will become irritated, but look and feel for raised/welted skin, indicating urticaria (Schaefer 2017). 

Kashlak Pearl: Dr Pasieka notes, antihistamines will stop new hives from forming in the next 6-12 hrs, but do not treat the hives already present. 

Itch

The phenomenon of itch is very complex and involves more than just histamines (Yosipovitch 2013). In a morbilliform rash, antihistamines may assist with itch relief but will not completely relieve symptoms (Stern 2012). Dr. Pasieka recommends, if a rash is not dermatographic, doesn’t look juicy or dermal, then treat with topical steroid ointments (like triamcinolone) twice a day and withdraw the potential causative agent (Stern 2012). “Make them greasy”. It will take up to 72 hours before a morbilliform drug rash will regress, even with treatment.  

‘Sick’ with a Drug Rash

Use timing to assist in differentiating between the main types of severe drug reaction. It can be tedious to figure out when people started and stopped medications, but the timeline is critical in determining if a patient has Acute generalized exanthematous pustulosis (AGEP), Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), or Drug reaction with eosinophilia and systemic symptoms (DRESS), also termed drug-induced hypersensitivity syndrome (DIHS).

AGEP: Rash in Less than 3 Days

AGEP begins 1-3 days after drug therapy.  It is rarely life-threatening, but can be severe in up to 20% of cases leading to systemic involvement (Feldmeyer 2016). Mortality from AGEP comes from  insensible losses, loss of heat, and electrolyte imbalances; especially in patients with predisposing issues such as renal dysfunction or cardiac disease (Hotz 2013). Dr Pasieka notes, a classic presentation is a patient treated with an IV 3rd generation cephalosporins for hospital-acquired pneumonia. Other typical causative agents include several types of antimicrobials, antimalarials, and calcium channel blockers (Chu UpToDate 2019).

The rash of AGEP is studded with innumerable, pinpoint pustules (Feldmeyer 2016). Additionally, it will be brightly erythematous, often in areas where skin touches skin (ie: flexural areas, intertriginous regions) (Szatkowski 2015). Dr. Pasieka points out, when those little pustules are clustered together, there may be superficial desquamation and a denuded-ness to the upper layer of skin.  AGEP involves a paper thin, very wet, stratum corneum, whereas SJS/TEN rashes implicate the thick dermis below it. 

SJS/TEN: Rash in 4 days to 2 Weeks

SJS & TEN are the same disease on a continuum of severity. They occur from drugs started between 4 and 14 days before rash onset. SJS involves less than 10% of body surface area (BSA),  SJS/TEN overlap is 10-30%, and TEN involves greater than 30% BSA. SJS and TEN also feature total epidermal detachment, indicated by a positive Nikolsky sign (Schwartz 2013). Dr Pasieka describes how to check for the Nikolsky sign: take a finger against normal appearing skin and push down (apply lateral pressure), or pull the edge of an existing blister. A positive Nikolsky sign is the top layers sloughing off of the lower layers from this motion.  

Patients with SJS or TEN will feel very sick, have mucosal site involvement, skin pain, and a positive Nikolsky (Schwartz 2013).  When seeing a patient that fits these criteria, admit them to the ICU, call dermatology immediately, stop every drug that is unnecessary, and carefully initiate a fluid regimen (Dr. Pasieka’s Expert Recommendation).  

Ocular Complications – SJS/TEN 

Over 50% of patients surviving TEN suffer from long-term sequelae of the disease (Harr 2010). 

Survivors of SJS/TEN can have severe ocular surface disease (Kohanim 2016). Patients may experience chronic dry eye, corneal opacification, corneal ulceration, and symblepharon (partial or complete adhesion of the palpebral conjunctiva of the eyelid to the bulbar conjunctiva of the eyeball). Bring ophthalmology on board sooner rather than later!

Genito-urinary Complications – SJS/TEN 

Up to 70% of women with SJS/TEN will have acute manifestations of vulvar or vulvarvaginal lesions (Meneux 1997). Women surviving SJS/TEN have increased risk for urethral stenosis, vaginal stenosis, and vaginal adhesions/agglutination/adenosis (Niemeijer 2009).  Patients may also experience dyspareunia, pain and irritation (Olteanu 2018). Consult with gynecology early to ensure these issues are addressed with SJS/TEN survivors. 

DRESS/DIHS: Rashes 6 Weeks Out

DIHS Rash

DRESS/DIHS has no “classic” rash. But, it often presents with facial edema denoted by effacement of the nasolabial folds (Eshki 2009). DRESS/DIHS rash is heterogeneous and varies greatly from patient to patient (may resemble erythema multiforme, eczema , lichenoid, morbilliform, etc). 

Kashlak Pearl: Dr. Pasieka assesses for facial edema by comparing the patient’s face to their driver’s license or student ID.  

DIHS Diagnosis

There are two recently developed diagnostic criteria, European Registry of Severe Cutaneous Adverse Reaction and Japanese Research Committee on Severe Cutaneous Adverse Reaction scoring system. These are mainly for research purposes, but may inform the probability of DRESS/DIHS (Husain 2013). 

Kashlak Pearl: Dr. Pasieka asks patients to recall drug initiation based on seasons or holidays since this reaction occurs many weeks later. 

DIHS Symptoms

DRESS/DIHS patients feel sick with systemic symptoms like fever, malaise, and GI upset. In addition to rash, at least 70% of DRESS/DIHS patients display liver abnormalities (Husain 2013). Cardio-pulmonary systems are not often involved. But, when present can be a cause for mortality due to severe refractory pneumonitis, cardiac myositis, acute heart failure, or arrhythmias (Husain 2013). Dr. Pasieka notes, there’s often lag in the onset of hypothyroidism (after acute thyroiditis) by about 6-8 weeks. Stay vigilant!

DIHS Treatment

To treat, stop the offending medication and initiate a steroid course. Due to rebound potential, the systemic steroids must be administered with a slow prolonged taper (Husain 2013). Dr. Pasieka explains that in some cases topical steroids may be used and the patient closely monitored, if organs are spared and the reaction is limited to skin. 

Goal

 Listeners will learn how to screen, assess, and categorize potential drug rashes seen in clinic as well as differentiate between severe adverse drug rashes.

Learning objectives

After listening to this episode listeners will…  

1. Differentiate between benign and severe drug reaction rashes and identify when referral is needed.
2. Complete a thorough review of systems and physical exam for potential drug rash exposures, including assessments of mucosal involvement.  
3. Determine if a benign rash is urticaria or morbilliform and initiate appropriate therapy
4. Compare and contrast 3 major severe drug reactions: AGEP, SJS/TEN, DRESS/DIHS
5. Coordinate specialty ophthalmology and gynecology care for SJS/TEN survivors.

Links* 

1. My Grandfather’s Blessings by Rachel Naomi Remen, MD
2. Kitchen Table Wisdom by Rachel Naomi Remen, MD
3. Mountains Beyond Mountains: The Quest of Dr. Paul Farmer, a Man Who Would Cure the World by Tracy Kidder
4. Cutting for Stone by Abraham Vergese
5. Anything (Me Talk Pretty One Day, Dress Your Family in Corduroy and Denim, etc)  by David Sedaris
6. Conan O’Brien Need a Friend, Episode #12 – David Sedaris 

*The Curbsiders participates in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising commissions by linking to Amazon. Simply put, if you click on my Amazon.com links and buy something we earn a (very) small commission, yet you don’t pay any extra.

References

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3. Lin MS, Dai YS, Pwu RF, Chen YH, Chang NC. Risk estimates for drugs suspected of being associated with Stevens–Johnson syndrome and toxic epidermal necrolysis: a case-control study. Intern Med J 2004. [https://www.ncbi.nlm.nih.gov/pubmed/15737140]
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14. Hotz C, Valeyrie-Allanore L, Haddad C, Bouvresse S, Ortonne N, Duong TA, Ingen-Housz-Oro S, Roujeau JC, Wolkenstein P, Chosidow O. Systemic involvement of acute generalized exanthematous pustulosis: a retrospective study on 58 patients. Br J Dermatol  2013 [https://www.ncbi.nlm.nih.gov/pubmed/23855377]
15. Kohanim S, Palioura S, Saeed HN, et al. Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis–A comprehensive review and guide to therapy. I. Systemic disease. Ocul Surf. 2016 [https://www.ncbi.nlm.nih.gov/pubmed/26549248]
16. Meneux E, Paniel BJ , Pouget F,  Revuz J, Roujeau JC, Wolkenstein P. Vulvovaginal sequelae in toxic epidermal necrolysis. J Reprod Med 1997 [https://www.ncbi.nlm.nih.gov/pubmed/9109082]
17. Niemeijer, I, Praag C, Gemund M. Relevance and Consequences of Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in Gynecology.. Archives of Gynecology and Obstetrics [https://www.ncbi.nlm.nih.gov/pubmed/19277691]
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Disclosures

Dr. Pasieka  reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 

Citation

Pasieka, Helena. Guest expert. “#161 A Rash Approach to Rashes”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/ July 15, 2019.