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Mental Health Services: The Missing Piece or Missing Peace for Patients With Atopic Dermatitis
There is a well-established connection between the mind and the skin, and it is clear that this relationship is bidirectional—not only does skin disease increase the risk for depression, anxiety, sleep disturbance, and suicidality, but psychologic stress actually can worsen skin disease through multiple mechanisms, including direct damage to the skin barrier.1,2 Psychologic stress also impacts the microbiome, another critical driver of skin disease.3,4 The concept of the itch-scratch cycle vividly illustrates the vicious interplay between the mind and body in atopic dermatitis (AD).
However, patients with AD are not the only ones impacted—caregivers also experience psychologic stress. Remarkably, one study of patients with AD and their caregivers found that the caregivers actually reported significantly worse mental health and anxiety (P=.01 and P=.03, respectively) than patients themselves, even when controlling for the severity of disease.5
Thus, it would seem obvious for mental health to be a central component of AD care—to improve patient and caregiver quality of life while also improving symptoms. Research has actually borne this out, with one systematic review and meta-analysis concluding that psychological intervention has a beneficial effect on AD,6 and another that the addition of psychological and educational interventions to conventional treatment provided better therapeutic results in alleviating eczema severity and psychological symptoms.7 One study demonstrated that patients with AD who received cognitive behavioral therapy via the internet displayed a statistically significant improvement in their disease (P<.001) as measured by the Patient-Oriented Eczema Measure compared with those in the control group who received standard care alone. They also reported improvements in perceived stress, sleep problems, and depression in the intervention group that were sustained at 1-year follow-up.8 These findings are particularly impactful because clinical results were achieved while leveraging an internet-based approach to therapy.
Regrettably, despite the preponderance of evidence supporting the connection between mental health and AD, there remain considerable unmet needs. A recent cross-sectional survey of 954 adults with AD and caregivers of children with AD (N=954) conducted by the National Eczema Association found that half of patients were never asked about mental health during any of their visits, and of those referred for mental health resources, only 57% utilized the recommended services.9 Importantly, patients aged 18 to 34 years reported wanting to be asked about mental health. Of those who did receive referrals, most were for counseling services (23%), followed by alternative mental health therapy such as music or art therapy (15%), cognitive behavioral therapy (13%), or peer/social support groups (12%). Approximately 10% reported receiving a pamphlet or a brochure only.9
Physicians who treat patients with AD can and must do better, but first we must explore why these referral rates are so low. As with many complex problems, there is unlikely to be one simple unifying reason. As expected, the answer is nuanced and multifaceted, and—most importantly—staggeringly incomplete.
For starters, mental health interventions rarely are as easy as applying a cream or taking a pill. Hedman-Lagerlöf et al8 specifically pointed out that although their approach—using internet-based cognitive behavioral therapy—was explicitly designed to be more accessible with fewer resources, it required approximately 35 hours of treatment over 12 weeks, requiring both substantial time and commitment from patients who often are already burned out and exhausted due to AD. They even underscored that the most commonly reported adverse effect of therapy was increased stress or worry, making it a difficult sell.8
Even before most patients have a chance to consider the time required and the potential adverse effects of mental health interventions for AD, greater hurdles exist. Finances, medical insurance, and wait times were highlighted as barriers to care in a systematic review.10 These are deep-seated problems in the United States; while they may be surmountable in certain geographic areas, the frequency with which these concerns arise means that it does not take too many failed attempts at referring patients for mental health services before clinicians just give up—similar to any form of operant conditioning.
A more elusive concept is stigmatization. Although it may not be quantifiable, the idea is that patients may encounter additional challenges when seeking mental health care, either because the interactions themselves may worsen their symptoms (eg, increased anxiety) or they may be more likely to have a negative perception of the experience.11 A 2020 systematic review of barriers to addressing common mental health problems found that stigma was the most prominent barrier in adolescents, with the second most prominent being negative attitudes and beliefs about mental health services and professionals.12 As a clinician, I can attest that I have sometimes detected skepticism when I have suggested mental health services to patients and have even been asked outright if I thought the problem was all in their head. My patients with AD generally have been much more open to the idea of mental health support, especially after I explain the powerful mind-body connection, than patients with other conditions—most notably delusions of parasitosis—who have been much more dismissive of such overtures. An oft-cited paper from 1976 frames the problem perfectly, describing what can happen after a referral for mental health services.13 The authors stated that the suggestion of mental health makes patients feel that the dermatologist does not believe them in the first place. Beyond this, the authors pointed out that referring the patient elsewhere reduces their hopes for dermatologic treatment.13
Knowing now—perhaps more than ever before—that the mind and skin are intimately connected compels us to solve these problems and find ways around these obstacles. Selecting the optimal forms of mental health services for each patient, having the structural support of the health care system, and winning the trust of patients and caregivers while combating stigma are undoubtedly tall orders; however, understanding the stakes for patients with AD, their caregivers, and society as a whole should inspire us to keep pushing forward.
- Nicholas MN, Gooderham MJ. Atopic dermatitis, depression, and suicidality. J Cutan Med Surg. 2017;21:237-242. doi:10.1177/1203475416685078
- aarouf M, Maarouf CL, Yosipovitch G, et al. The impact of stress on epidermal barrier function: an evidence‐based review. Br J Dermatol. 2019;181:1129-1137.
- Prescott SL, Larcombe DL, Logan AC, et al. The skin microbiome: impact of modern environments on skin ecology, barrier integrity, and systemic immune programming. World Allergy Organ J. 2017;10:29.
- Zhang XE, Zheng P, Ye SZ, et al. Microbiome: role in inflammatory skin diseases. J Inflamm Res. 2024;17:1057-1082.
- Chong AC, Schwartz A, Lang J, et al. Patients’ and caregivers’ preferences for mental health care and support in atopic dermatitis. Dermatitis. 2024;35(suppl 1):S70-S76.
- Chida Y, Steptoe A, Hirakawa N, et al. The effects of psychological intervention on atopic dermatitis. a systematic review and meta-analysis. Int Arch Allergy Immunol. 2007;144:1-9.
- Hashimoto K, Ogawa Y, Takeshima N, et al. Psychological and educational interventions for atopic dermatitis in adults: a systematic review and meta-analysis. Behav Change. 2017;34:48-65.
- Hedman-Lagerlöf E, Fust J, Axelsson E, et al. Internet-delivered cognitive behavior therapy for atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2021;157:796-804. doi:10.1001/jamadermatol.2021.1450
- Chatrath S, Loiselle AR, Johnson JK, et al. Evaluating mental health support by healthcare providers for patients with atopic dermatitis: a cross‐sectional survey. Skin Health Dis. Published online June 15, 2024. doi:10.1002/ski2.408
- Toy J, Gregory A, Rehmus W. Barriers to healthcare access in pediatric dermatology: a systematic review. Pediatr Dermatol. 2021;38(suppl 2):13-19.
- Borba CPC, DePadilla L, McCarty FA, et al. A qualitative study examining the perceived barriers and facilitators to medical healthcare services among women with a serious mental illness. Womens Health Issues. 2012;22:E217-E224.
- Aguirre Velasco A, Cruz ISS, Billings J, et al. What are the barriers, facilitators and interventions targeting help-seeking behaviours for common mental health problems in adolescents? a systematic review. BMC Psychiatry. 2020;20:293.
- Gould WM, Gragg TM. Delusions of parasitosis. an approach to the problem. Arch Dermatol. 1976;112:1745-1748.
There is a well-established connection between the mind and the skin, and it is clear that this relationship is bidirectional—not only does skin disease increase the risk for depression, anxiety, sleep disturbance, and suicidality, but psychologic stress actually can worsen skin disease through multiple mechanisms, including direct damage to the skin barrier.1,2 Psychologic stress also impacts the microbiome, another critical driver of skin disease.3,4 The concept of the itch-scratch cycle vividly illustrates the vicious interplay between the mind and body in atopic dermatitis (AD).
However, patients with AD are not the only ones impacted—caregivers also experience psychologic stress. Remarkably, one study of patients with AD and their caregivers found that the caregivers actually reported significantly worse mental health and anxiety (P=.01 and P=.03, respectively) than patients themselves, even when controlling for the severity of disease.5
Thus, it would seem obvious for mental health to be a central component of AD care—to improve patient and caregiver quality of life while also improving symptoms. Research has actually borne this out, with one systematic review and meta-analysis concluding that psychological intervention has a beneficial effect on AD,6 and another that the addition of psychological and educational interventions to conventional treatment provided better therapeutic results in alleviating eczema severity and psychological symptoms.7 One study demonstrated that patients with AD who received cognitive behavioral therapy via the internet displayed a statistically significant improvement in their disease (P<.001) as measured by the Patient-Oriented Eczema Measure compared with those in the control group who received standard care alone. They also reported improvements in perceived stress, sleep problems, and depression in the intervention group that were sustained at 1-year follow-up.8 These findings are particularly impactful because clinical results were achieved while leveraging an internet-based approach to therapy.
Regrettably, despite the preponderance of evidence supporting the connection between mental health and AD, there remain considerable unmet needs. A recent cross-sectional survey of 954 adults with AD and caregivers of children with AD (N=954) conducted by the National Eczema Association found that half of patients were never asked about mental health during any of their visits, and of those referred for mental health resources, only 57% utilized the recommended services.9 Importantly, patients aged 18 to 34 years reported wanting to be asked about mental health. Of those who did receive referrals, most were for counseling services (23%), followed by alternative mental health therapy such as music or art therapy (15%), cognitive behavioral therapy (13%), or peer/social support groups (12%). Approximately 10% reported receiving a pamphlet or a brochure only.9
Physicians who treat patients with AD can and must do better, but first we must explore why these referral rates are so low. As with many complex problems, there is unlikely to be one simple unifying reason. As expected, the answer is nuanced and multifaceted, and—most importantly—staggeringly incomplete.
For starters, mental health interventions rarely are as easy as applying a cream or taking a pill. Hedman-Lagerlöf et al8 specifically pointed out that although their approach—using internet-based cognitive behavioral therapy—was explicitly designed to be more accessible with fewer resources, it required approximately 35 hours of treatment over 12 weeks, requiring both substantial time and commitment from patients who often are already burned out and exhausted due to AD. They even underscored that the most commonly reported adverse effect of therapy was increased stress or worry, making it a difficult sell.8
Even before most patients have a chance to consider the time required and the potential adverse effects of mental health interventions for AD, greater hurdles exist. Finances, medical insurance, and wait times were highlighted as barriers to care in a systematic review.10 These are deep-seated problems in the United States; while they may be surmountable in certain geographic areas, the frequency with which these concerns arise means that it does not take too many failed attempts at referring patients for mental health services before clinicians just give up—similar to any form of operant conditioning.
A more elusive concept is stigmatization. Although it may not be quantifiable, the idea is that patients may encounter additional challenges when seeking mental health care, either because the interactions themselves may worsen their symptoms (eg, increased anxiety) or they may be more likely to have a negative perception of the experience.11 A 2020 systematic review of barriers to addressing common mental health problems found that stigma was the most prominent barrier in adolescents, with the second most prominent being negative attitudes and beliefs about mental health services and professionals.12 As a clinician, I can attest that I have sometimes detected skepticism when I have suggested mental health services to patients and have even been asked outright if I thought the problem was all in their head. My patients with AD generally have been much more open to the idea of mental health support, especially after I explain the powerful mind-body connection, than patients with other conditions—most notably delusions of parasitosis—who have been much more dismissive of such overtures. An oft-cited paper from 1976 frames the problem perfectly, describing what can happen after a referral for mental health services.13 The authors stated that the suggestion of mental health makes patients feel that the dermatologist does not believe them in the first place. Beyond this, the authors pointed out that referring the patient elsewhere reduces their hopes for dermatologic treatment.13
Knowing now—perhaps more than ever before—that the mind and skin are intimately connected compels us to solve these problems and find ways around these obstacles. Selecting the optimal forms of mental health services for each patient, having the structural support of the health care system, and winning the trust of patients and caregivers while combating stigma are undoubtedly tall orders; however, understanding the stakes for patients with AD, their caregivers, and society as a whole should inspire us to keep pushing forward.
There is a well-established connection between the mind and the skin, and it is clear that this relationship is bidirectional—not only does skin disease increase the risk for depression, anxiety, sleep disturbance, and suicidality, but psychologic stress actually can worsen skin disease through multiple mechanisms, including direct damage to the skin barrier.1,2 Psychologic stress also impacts the microbiome, another critical driver of skin disease.3,4 The concept of the itch-scratch cycle vividly illustrates the vicious interplay between the mind and body in atopic dermatitis (AD).
However, patients with AD are not the only ones impacted—caregivers also experience psychologic stress. Remarkably, one study of patients with AD and their caregivers found that the caregivers actually reported significantly worse mental health and anxiety (P=.01 and P=.03, respectively) than patients themselves, even when controlling for the severity of disease.5
Thus, it would seem obvious for mental health to be a central component of AD care—to improve patient and caregiver quality of life while also improving symptoms. Research has actually borne this out, with one systematic review and meta-analysis concluding that psychological intervention has a beneficial effect on AD,6 and another that the addition of psychological and educational interventions to conventional treatment provided better therapeutic results in alleviating eczema severity and psychological symptoms.7 One study demonstrated that patients with AD who received cognitive behavioral therapy via the internet displayed a statistically significant improvement in their disease (P<.001) as measured by the Patient-Oriented Eczema Measure compared with those in the control group who received standard care alone. They also reported improvements in perceived stress, sleep problems, and depression in the intervention group that were sustained at 1-year follow-up.8 These findings are particularly impactful because clinical results were achieved while leveraging an internet-based approach to therapy.
Regrettably, despite the preponderance of evidence supporting the connection between mental health and AD, there remain considerable unmet needs. A recent cross-sectional survey of 954 adults with AD and caregivers of children with AD (N=954) conducted by the National Eczema Association found that half of patients were never asked about mental health during any of their visits, and of those referred for mental health resources, only 57% utilized the recommended services.9 Importantly, patients aged 18 to 34 years reported wanting to be asked about mental health. Of those who did receive referrals, most were for counseling services (23%), followed by alternative mental health therapy such as music or art therapy (15%), cognitive behavioral therapy (13%), or peer/social support groups (12%). Approximately 10% reported receiving a pamphlet or a brochure only.9
Physicians who treat patients with AD can and must do better, but first we must explore why these referral rates are so low. As with many complex problems, there is unlikely to be one simple unifying reason. As expected, the answer is nuanced and multifaceted, and—most importantly—staggeringly incomplete.
For starters, mental health interventions rarely are as easy as applying a cream or taking a pill. Hedman-Lagerlöf et al8 specifically pointed out that although their approach—using internet-based cognitive behavioral therapy—was explicitly designed to be more accessible with fewer resources, it required approximately 35 hours of treatment over 12 weeks, requiring both substantial time and commitment from patients who often are already burned out and exhausted due to AD. They even underscored that the most commonly reported adverse effect of therapy was increased stress or worry, making it a difficult sell.8
Even before most patients have a chance to consider the time required and the potential adverse effects of mental health interventions for AD, greater hurdles exist. Finances, medical insurance, and wait times were highlighted as barriers to care in a systematic review.10 These are deep-seated problems in the United States; while they may be surmountable in certain geographic areas, the frequency with which these concerns arise means that it does not take too many failed attempts at referring patients for mental health services before clinicians just give up—similar to any form of operant conditioning.
A more elusive concept is stigmatization. Although it may not be quantifiable, the idea is that patients may encounter additional challenges when seeking mental health care, either because the interactions themselves may worsen their symptoms (eg, increased anxiety) or they may be more likely to have a negative perception of the experience.11 A 2020 systematic review of barriers to addressing common mental health problems found that stigma was the most prominent barrier in adolescents, with the second most prominent being negative attitudes and beliefs about mental health services and professionals.12 As a clinician, I can attest that I have sometimes detected skepticism when I have suggested mental health services to patients and have even been asked outright if I thought the problem was all in their head. My patients with AD generally have been much more open to the idea of mental health support, especially after I explain the powerful mind-body connection, than patients with other conditions—most notably delusions of parasitosis—who have been much more dismissive of such overtures. An oft-cited paper from 1976 frames the problem perfectly, describing what can happen after a referral for mental health services.13 The authors stated that the suggestion of mental health makes patients feel that the dermatologist does not believe them in the first place. Beyond this, the authors pointed out that referring the patient elsewhere reduces their hopes for dermatologic treatment.13
Knowing now—perhaps more than ever before—that the mind and skin are intimately connected compels us to solve these problems and find ways around these obstacles. Selecting the optimal forms of mental health services for each patient, having the structural support of the health care system, and winning the trust of patients and caregivers while combating stigma are undoubtedly tall orders; however, understanding the stakes for patients with AD, their caregivers, and society as a whole should inspire us to keep pushing forward.
- Nicholas MN, Gooderham MJ. Atopic dermatitis, depression, and suicidality. J Cutan Med Surg. 2017;21:237-242. doi:10.1177/1203475416685078
- aarouf M, Maarouf CL, Yosipovitch G, et al. The impact of stress on epidermal barrier function: an evidence‐based review. Br J Dermatol. 2019;181:1129-1137.
- Prescott SL, Larcombe DL, Logan AC, et al. The skin microbiome: impact of modern environments on skin ecology, barrier integrity, and systemic immune programming. World Allergy Organ J. 2017;10:29.
- Zhang XE, Zheng P, Ye SZ, et al. Microbiome: role in inflammatory skin diseases. J Inflamm Res. 2024;17:1057-1082.
- Chong AC, Schwartz A, Lang J, et al. Patients’ and caregivers’ preferences for mental health care and support in atopic dermatitis. Dermatitis. 2024;35(suppl 1):S70-S76.
- Chida Y, Steptoe A, Hirakawa N, et al. The effects of psychological intervention on atopic dermatitis. a systematic review and meta-analysis. Int Arch Allergy Immunol. 2007;144:1-9.
- Hashimoto K, Ogawa Y, Takeshima N, et al. Psychological and educational interventions for atopic dermatitis in adults: a systematic review and meta-analysis. Behav Change. 2017;34:48-65.
- Hedman-Lagerlöf E, Fust J, Axelsson E, et al. Internet-delivered cognitive behavior therapy for atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2021;157:796-804. doi:10.1001/jamadermatol.2021.1450
- Chatrath S, Loiselle AR, Johnson JK, et al. Evaluating mental health support by healthcare providers for patients with atopic dermatitis: a cross‐sectional survey. Skin Health Dis. Published online June 15, 2024. doi:10.1002/ski2.408
- Toy J, Gregory A, Rehmus W. Barriers to healthcare access in pediatric dermatology: a systematic review. Pediatr Dermatol. 2021;38(suppl 2):13-19.
- Borba CPC, DePadilla L, McCarty FA, et al. A qualitative study examining the perceived barriers and facilitators to medical healthcare services among women with a serious mental illness. Womens Health Issues. 2012;22:E217-E224.
- Aguirre Velasco A, Cruz ISS, Billings J, et al. What are the barriers, facilitators and interventions targeting help-seeking behaviours for common mental health problems in adolescents? a systematic review. BMC Psychiatry. 2020;20:293.
- Gould WM, Gragg TM. Delusions of parasitosis. an approach to the problem. Arch Dermatol. 1976;112:1745-1748.
- Nicholas MN, Gooderham MJ. Atopic dermatitis, depression, and suicidality. J Cutan Med Surg. 2017;21:237-242. doi:10.1177/1203475416685078
- aarouf M, Maarouf CL, Yosipovitch G, et al. The impact of stress on epidermal barrier function: an evidence‐based review. Br J Dermatol. 2019;181:1129-1137.
- Prescott SL, Larcombe DL, Logan AC, et al. The skin microbiome: impact of modern environments on skin ecology, barrier integrity, and systemic immune programming. World Allergy Organ J. 2017;10:29.
- Zhang XE, Zheng P, Ye SZ, et al. Microbiome: role in inflammatory skin diseases. J Inflamm Res. 2024;17:1057-1082.
- Chong AC, Schwartz A, Lang J, et al. Patients’ and caregivers’ preferences for mental health care and support in atopic dermatitis. Dermatitis. 2024;35(suppl 1):S70-S76.
- Chida Y, Steptoe A, Hirakawa N, et al. The effects of psychological intervention on atopic dermatitis. a systematic review and meta-analysis. Int Arch Allergy Immunol. 2007;144:1-9.
- Hashimoto K, Ogawa Y, Takeshima N, et al. Psychological and educational interventions for atopic dermatitis in adults: a systematic review and meta-analysis. Behav Change. 2017;34:48-65.
- Hedman-Lagerlöf E, Fust J, Axelsson E, et al. Internet-delivered cognitive behavior therapy for atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2021;157:796-804. doi:10.1001/jamadermatol.2021.1450
- Chatrath S, Loiselle AR, Johnson JK, et al. Evaluating mental health support by healthcare providers for patients with atopic dermatitis: a cross‐sectional survey. Skin Health Dis. Published online June 15, 2024. doi:10.1002/ski2.408
- Toy J, Gregory A, Rehmus W. Barriers to healthcare access in pediatric dermatology: a systematic review. Pediatr Dermatol. 2021;38(suppl 2):13-19.
- Borba CPC, DePadilla L, McCarty FA, et al. A qualitative study examining the perceived barriers and facilitators to medical healthcare services among women with a serious mental illness. Womens Health Issues. 2012;22:E217-E224.
- Aguirre Velasco A, Cruz ISS, Billings J, et al. What are the barriers, facilitators and interventions targeting help-seeking behaviours for common mental health problems in adolescents? a systematic review. BMC Psychiatry. 2020;20:293.
- Gould WM, Gragg TM. Delusions of parasitosis. an approach to the problem. Arch Dermatol. 1976;112:1745-1748.
Practice Points
- The mind-body connection plays a role in many conditions, including atopic dermatitis.
- Atopic dermatitis can make patients feel anxious, stressed, and depressed; at the same time, those feelings can lead to worsening of the condition.
- There are many barriers to getting mental health care in the United States, from financial constraints to stigmatization.
- Mental health is part of overall health and should be more highly prioritized by all physicians.
Dietary Triggers for Atopic Dermatitis in Children
It is unsurprising that food frequently is thought to be the culprit behind an eczema flare, especially in infants. Indeed, it often is said that infants do only 3 things: eat, sleep, and poop.1 For those unfortunate enough to develop the signs and symptoms of atopic dermatitis (AD), food quickly emerges as a potential culprit from the tiny pool of suspects, which is against a cultural backdrop of unprecedented focus on foods and food reactions.2 The prevalence of food allergies in children, though admittedly fraught with methodological difficulties, is estimated to have more than doubled from 3.4% in 1999 to 7.6% in 2018.3 As expected, prevalence rates were higher among children with other atopic comorbidities including AD, with up to 50% of children with AD demonstrating convincing food allergy.4 It is easy to imagine a patient conflating these 2 entities and mistaking their correlation for causation. Thus, it follows that more than 90% of parents/guardians have reported that their children have had food-induced AD, and understandably—at least according to one study—75% of parents/guardians were found to have manipulated the diet in an attempt to manage the disease.5,6
Patients and parents/guardians are not the only ones who have suspected food as a driving force in AD. An article in the British Medical Journal from the 1800s beautifully encapsulated the depth and duration of this quandary: “There is probably no subject in which more deeply rooted convictions have been held, not only in the profession but by the laity, than the connection between diet and disease, both as regards the causation and treatment of the latter.”7 Herein, a wide range of food reactions is examined to highlight evidence for the role of diet in AD, which may contradict what patients—and even some clinicians—believe.
No Easy Answers
A definitive statement that food allergy is not the root cause of AD would put this issue to rest, but such simplicity does not reflect the complex reality. First, we must agree on definitions for certain terms. What do we mean by food allergy? A broader category—adverse food reactions—covers a wide range of entities, some immune mediated and some not, including lactose intolerance, irritant contact dermatitis around the mouth, and even dermatitis herpetiformis (the cutaneous manifestation of celiac disease).8 Although the term food allergy often is used synonymously with adverse food reactions, the exact definition of a food allergy is specific: “adverse immune responses to food proteins that result in typical clinical symptoms.”8 The fact that many patients and even health care practitioners seem to frequently misapply this term makes it even more confusing.
The current focus is on foods that could trigger a flare of AD, which clearly is a broader question than food allergy sensu stricto. It seems self-evident, for example, that if an infant with AD were to (messily) eat an acidic food such as an orange, a flare-up of AD around the mouth and on the cheeks and hands would be a forgone conclusion. Similar nonimmunologic scenarios unambiguously can occur with many foods, including citrus; corn; radish; mustard; garlic; onion; pineapple; and many spices, food additives, and preservatives.9 Clearly there are some scenarios whereby food could trigger an AD flare, and yet this more limited vignette generally is not what patients are referring to when suggesting that food is the root cause of their AD.
The Labyrinth of Testing for Food Allergies
Although there is no reliable method for testing for irritant dermatitis, understanding the other types of tests may help guide our thinking. Testing for IgE-mediated food allergies generally is done via an immunoenzymatic serum assay that can document sensitization to a food protein; however, this testing by itself is not sufficient to diagnose a clinical food allergy.10 Similarly, skin prick testing allows for intradermal administration of a food extract to evaluate for an urticarial reaction within 10 to 15 minutes. Although the sensitivity and specificity vary by age, population, and the specific allergen being tested, these are limited to immediate-type reactions and do not reflect the potential to drive an eczematous flare.
The gold standard, if there is one, is likely the double-blind, placebo-controlled food challenge (DBPCFC), ideally with a long enough observation period to capture later-occurring reactions such as an AD flare. However, given the nature of the test—having patients eat the foods of concern and then carefully following them for reactions—it remains time consuming, expensive, and labor intensive.11
To further complicate matters, several unvalidated tests exist such as IgG testing, atopy patch testing, kinesiology, and hair and gastric juice analysis, which remain investigational but continue to be used and may further confuse patients and clinicians.12
Classification of Food Allergies
It is useful to first separate out the classic IgE-mediated food allergy reactions that are common. In these immediate-type reactions, a person sensitized to a food protein will develop characteristic cutaneous and/or extracutaneous reactions such as urticaria, angioedema, and even anaphylaxis, usually within minutes of exposure. Although it is possible that an IgE-mediated reaction could trigger an AD flare—perhaps simply by causing pruritus, which could initiate the itch-scratch cycle—because of the near simultaneity with ingestion of the offending food and the often dramatic clinical presentations, such foods clearly do not represent “hidden” triggers for AD flares.3 The concept of food-triggered AD (FTAD) is crucial for thinking about foods that could result in true eczematous flares, which historically have been classified as early-type (<2 hours after food challenge) and late-type (≥2 hours after food challenge) reactions.13,14
A study of more than 1000 DBPCFCs performed in patients with AD was illustrative.15 Immediate reactions other than AD were fairly common and were observed in 40% of the food challenges compared to only 9% in the placebo group. These reactions included urticaria, angioedema, and gastrointestinal and respiratory tract symptoms. Immediate reactions of AD alone were exceedingly rare at only 0.7% and not significantly elevated compared to placebo. Just over 4% experienced both an immediate AD exacerbation along with other non-AD findings, which was significantly greater than placebo (P<.01). Although intermediate and late reactions manifesting as AD exacerbations did occur after food ingestion, they were rare (2.2% or less) and not significantly different from placebo. The authors concluded that an exacerbation of AD in the absence of other allergic symptoms in children was unlikely to be due to food,15 which is an important finding.
A recent retrospective review of 372 children with AD reported similar results.4 The authors defined FTAD in a different way; instead of showing a flare after a DBPCFC, they looked for “physician-noted sustained improvement in AD upon removal of a food (typically after 2–6-wk follow-up), to which the child was sensitized without any other changes in skin care.” Despite this fundamentally different approach, they similarly concluded that while food allergies were common, FTAD was relatively uncommon—found in 2% of those with mild AD, 6% of those with moderate AD, and 4% of those with severe AD.4
There are other ways that foods could contribute to disease flares, however, and one of the most compelling is that there may be broader concepts at play; perhaps some diets are not specifically driving the AD but rather are affecting inflammation in the body at large. Although somewhat speculative, there is evidence that some foods may simply be proinflammatory, working to exacerbate the disease outside of a specific mechanism, which has been seen in a variety of other conditions such as acne or rheumatoid arthritis.16,17 To speculate further, it is possible that there may be a threshold effect such that when the AD is poorly controlled, certain factors such as inflammatory foods could lead to a flare, while when under better control, these same factors may not cause an effect.
Finally, it is important to also consider the emotional and/or psychological aspects related to food and diet. The power of the placebo in dietary change has been documented in several diseases, though this certainly is not to be dismissive of the patient’s symptoms; it seems reasonable that the very act of changing such a fundamental aspect of daily life could result in a placebo effect.18,19 In the context of relapsing and remitting conditions such as AD, this effect may be magnified. A landmark study by Thompson and Hanifin20 illustrates this possibility. The authors found that in 80% of cases in which patients were convinced that food was a major contributing factor to their AD, such concerns diminished markedly once better control of the eczema was achieved.20
Navigating the Complexity of Dietary Restrictions
This brings us to what to do with an individual patient in the examination room. Because there is such widespread concern and discussion around this topic, it is important to at least briefly address it. If there are known food allergens that are being avoided, it is important to underscore the importance of continuing to avoid those foods, especially when there is actual evidence of true food allergy rather than sensitization alone. Historically, elimination diets often were recommended empirically, though more recent studies, meta-analyses, and guidance documents increasingly have recommended against them.3 In particular, there are major concerns for iatrogenic harm.
First, heavily restricted diets may result in nutritional and/or caloric deficiencies that can be dangerous and lead to poor growth.21 Practices such as drinking unpasteurized milk can expose children to dangerous infections, while feeding them exclusively rice milk can lead to severe malnutrition.22
Second, there is a dawning realization that children with AD placed on elimination diets may actually develop true IgE-mediated allergies, including fatal anaphylaxis, to the excluded foods. In fact, one retrospective review of 298 patients with a history of AD and no prior immediate reactions found that 19% of patients developed new immediate-type hypersensitivity reactions after starting an elimination diet, presumably due to the loss of tolerance to these foods. A striking one-third of these reactions were classified as anaphylaxis, with cow’s milk and egg being the most common offenders.23
It also is crucial to acknowledge that recommending sweeping lifestyle changes is not easy for patients, especially pediatric patients. Onerous dietary restrictions may add considerable stress, ironically a known trigger for AD itself.
Finally, dietary modifications can be a distraction from conventional therapy and may result in treatment delays while the patient continues to experience uncontrolled symptoms of AD.
Final Thoughts
Diet is intimately related to AD. Although the narrative continues to unfold in fascinating domains, such as the skin barrier and the microbiome, it is increasingly clear that these are intertwined and always have been. Despite the rarity of true food-triggered AD, the perception of dietary triggers is so widespread and addressing the topic is important and may help avoid unnecessary harm from unfounded extreme dietary changes. A recent multispecialty workgroup report on AD and food allergy succinctly summarized this as: “AD has many triggers and comorbidities, and food allergy is only one of the potential triggers and comorbid conditions. With regard to AD management, education and skin care are most important.”3 With proper testing, guidance, and both topical and systemic therapies, most AD can be brought under control, and for at least some patients, this may allay concerns about foods triggering their AD.
- Eat, sleep, poop—the top 3 things new parents need to know. John’s Hopkins All Children’s Hospital website. Published May 18, 2019. Accessed September 13, 2022. https://www.hopkinsallchildrens.org/ACH-News/General-News/Eat-Sleep-Poop-%E2%80%93-The-Top-3-Things-New-Parents-Ne
- Onyimba F, Crowe SE, Johnson S, et al. Food allergies and intolerances: a clinical approach to the diagnosis and management of adverse reactions to food. Clin Gastroenterol Hepatol. 2021;19:2230-2240.e1.
- Singh AM, Anvari S, Hauk P, et al. Atopic dermatitis and food allergy: best practices and knowledge gaps—a work group report from the AAAAI Allergic Skin Diseases Committee and Leadership Institute Project. J Allergy Clin Immunol Pract. 2022;10:697-706.
- Li JC, Arkin LM, Makhija MM, et al. Prevalence of food allergy diagnosis in pediatric patients with atopic dermatitis referred to allergy and/or dermatology subspecialty clinics. J Allergy Clin Immunol Pract. 2022;10:2469-2471.
- Thompson MM, Tofte SJ, Simpson EL, et al. Patterns of care and referral in children with atopic dermatitis and concern for food allergy. Dermatol Ther. 2006;19:91-96.
- Johnston GA, Bilbao RM, Graham-Brown RAC. The use of dietary manipulation by parents of children with atopic dermatitis. Br J Dermatol. 2004;150:1186-1189.
- Mackenzie S. The inaugural address on the advantages to be derived from the study of dermatology: delivered to the Reading Pathological Society. Br Med J. 1896;1:193-197.
- Anvari S, Miller J, Yeh CY, et al. IgE-mediated food allergy. Clin Rev Allergy Immunol. 2019;57:244-260.
- Brancaccio RR, Alvarez MS. Contact allergy to food. Dermatol Ther. 2004;17:302-313.
- Robison RG, Singh AM. Controversies in allergy: food testing and dietary avoidance in atopic dermatitis. J Allergy Clin Immunol Pract. 2019;7:35-39.
- Sicherer SH, Morrow EH, Sampson HA. Dose-response in double-blind, placebo-controlled oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2000;105:582-586.
- Kelso JM. Unproven diagnostic tests for adverse reactions to foods. J Allergy Clin Immunol Pract. 2018;6:362-365.
- Heratizadeh A, Wichmann K, Werfel T. Food allergy and atopic dermatitis: how are they connected? Curr Allergy Asthma Rep. 2011;11:284-291.
- Breuer K, Heratizadeh A, Wulf A, et al. Late eczematous reactions to food in children with atopic dermatitis. Clin Exp Allergy. 2004;34:817-824.
- Roerdink EM, Flokstra-de Blok BMJ, Blok JL, et al. Association of food allergy and atopic dermatitis exacerbations. Ann Allergy Asthma Immunol. 2016;116:334-338.
- Fuglsang G, Madsen G, Halken S, et al. Adverse reactions to food additives in children with atopic symptoms. Allergy. 1994;49:31-37.
- Ehlers I, Worm M, Sterry W, et al. Sugar is not an aggravating factor in atopic dermatitis. Acta Derm Venereol. 2001;81:282-284.
- Staudacher HM, Irving PM, Lomer MCE, et al. The challenges of control groups, placebos and blinding in clinical trials of dietary interventions. Proc Nutr Soc. 2017;76:203-212.
- Masi A, Lampit A, Glozier N, et al. Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis. Transl Psychiatry. 2015;5:E640.
- Thompson MM, Hanifin JM. Effective therapy of childhood atopic dermatitis allays food allergy concerns. J Am Acad Dermatol. 2005;53(2 suppl 2):S214-S219.
- Meyer R, De Koker C, Dziubak R, et al. The impact of the elimination diet on growth and nutrient intake in children with food protein induced gastrointestinal allergies. Clin Transl Allergy. 2016;6:25.
- Webber SA, Graham-Brown RA, Hutchinson PE, et al. Dietary manipulation in childhood atopic dermatitis. Br J Dermatol. 1989;121:91-98.
- Chang A, Robison R, Cai M, et al. Natural history of food-triggered atopic dermatitis and development of immediate reactions in children. J Allergy Clin Immunol Pract. 2016;4:229-236.e1.
It is unsurprising that food frequently is thought to be the culprit behind an eczema flare, especially in infants. Indeed, it often is said that infants do only 3 things: eat, sleep, and poop.1 For those unfortunate enough to develop the signs and symptoms of atopic dermatitis (AD), food quickly emerges as a potential culprit from the tiny pool of suspects, which is against a cultural backdrop of unprecedented focus on foods and food reactions.2 The prevalence of food allergies in children, though admittedly fraught with methodological difficulties, is estimated to have more than doubled from 3.4% in 1999 to 7.6% in 2018.3 As expected, prevalence rates were higher among children with other atopic comorbidities including AD, with up to 50% of children with AD demonstrating convincing food allergy.4 It is easy to imagine a patient conflating these 2 entities and mistaking their correlation for causation. Thus, it follows that more than 90% of parents/guardians have reported that their children have had food-induced AD, and understandably—at least according to one study—75% of parents/guardians were found to have manipulated the diet in an attempt to manage the disease.5,6
Patients and parents/guardians are not the only ones who have suspected food as a driving force in AD. An article in the British Medical Journal from the 1800s beautifully encapsulated the depth and duration of this quandary: “There is probably no subject in which more deeply rooted convictions have been held, not only in the profession but by the laity, than the connection between diet and disease, both as regards the causation and treatment of the latter.”7 Herein, a wide range of food reactions is examined to highlight evidence for the role of diet in AD, which may contradict what patients—and even some clinicians—believe.
No Easy Answers
A definitive statement that food allergy is not the root cause of AD would put this issue to rest, but such simplicity does not reflect the complex reality. First, we must agree on definitions for certain terms. What do we mean by food allergy? A broader category—adverse food reactions—covers a wide range of entities, some immune mediated and some not, including lactose intolerance, irritant contact dermatitis around the mouth, and even dermatitis herpetiformis (the cutaneous manifestation of celiac disease).8 Although the term food allergy often is used synonymously with adverse food reactions, the exact definition of a food allergy is specific: “adverse immune responses to food proteins that result in typical clinical symptoms.”8 The fact that many patients and even health care practitioners seem to frequently misapply this term makes it even more confusing.
The current focus is on foods that could trigger a flare of AD, which clearly is a broader question than food allergy sensu stricto. It seems self-evident, for example, that if an infant with AD were to (messily) eat an acidic food such as an orange, a flare-up of AD around the mouth and on the cheeks and hands would be a forgone conclusion. Similar nonimmunologic scenarios unambiguously can occur with many foods, including citrus; corn; radish; mustard; garlic; onion; pineapple; and many spices, food additives, and preservatives.9 Clearly there are some scenarios whereby food could trigger an AD flare, and yet this more limited vignette generally is not what patients are referring to when suggesting that food is the root cause of their AD.
The Labyrinth of Testing for Food Allergies
Although there is no reliable method for testing for irritant dermatitis, understanding the other types of tests may help guide our thinking. Testing for IgE-mediated food allergies generally is done via an immunoenzymatic serum assay that can document sensitization to a food protein; however, this testing by itself is not sufficient to diagnose a clinical food allergy.10 Similarly, skin prick testing allows for intradermal administration of a food extract to evaluate for an urticarial reaction within 10 to 15 minutes. Although the sensitivity and specificity vary by age, population, and the specific allergen being tested, these are limited to immediate-type reactions and do not reflect the potential to drive an eczematous flare.
The gold standard, if there is one, is likely the double-blind, placebo-controlled food challenge (DBPCFC), ideally with a long enough observation period to capture later-occurring reactions such as an AD flare. However, given the nature of the test—having patients eat the foods of concern and then carefully following them for reactions—it remains time consuming, expensive, and labor intensive.11
To further complicate matters, several unvalidated tests exist such as IgG testing, atopy patch testing, kinesiology, and hair and gastric juice analysis, which remain investigational but continue to be used and may further confuse patients and clinicians.12
Classification of Food Allergies
It is useful to first separate out the classic IgE-mediated food allergy reactions that are common. In these immediate-type reactions, a person sensitized to a food protein will develop characteristic cutaneous and/or extracutaneous reactions such as urticaria, angioedema, and even anaphylaxis, usually within minutes of exposure. Although it is possible that an IgE-mediated reaction could trigger an AD flare—perhaps simply by causing pruritus, which could initiate the itch-scratch cycle—because of the near simultaneity with ingestion of the offending food and the often dramatic clinical presentations, such foods clearly do not represent “hidden” triggers for AD flares.3 The concept of food-triggered AD (FTAD) is crucial for thinking about foods that could result in true eczematous flares, which historically have been classified as early-type (<2 hours after food challenge) and late-type (≥2 hours after food challenge) reactions.13,14
A study of more than 1000 DBPCFCs performed in patients with AD was illustrative.15 Immediate reactions other than AD were fairly common and were observed in 40% of the food challenges compared to only 9% in the placebo group. These reactions included urticaria, angioedema, and gastrointestinal and respiratory tract symptoms. Immediate reactions of AD alone were exceedingly rare at only 0.7% and not significantly elevated compared to placebo. Just over 4% experienced both an immediate AD exacerbation along with other non-AD findings, which was significantly greater than placebo (P<.01). Although intermediate and late reactions manifesting as AD exacerbations did occur after food ingestion, they were rare (2.2% or less) and not significantly different from placebo. The authors concluded that an exacerbation of AD in the absence of other allergic symptoms in children was unlikely to be due to food,15 which is an important finding.
A recent retrospective review of 372 children with AD reported similar results.4 The authors defined FTAD in a different way; instead of showing a flare after a DBPCFC, they looked for “physician-noted sustained improvement in AD upon removal of a food (typically after 2–6-wk follow-up), to which the child was sensitized without any other changes in skin care.” Despite this fundamentally different approach, they similarly concluded that while food allergies were common, FTAD was relatively uncommon—found in 2% of those with mild AD, 6% of those with moderate AD, and 4% of those with severe AD.4
There are other ways that foods could contribute to disease flares, however, and one of the most compelling is that there may be broader concepts at play; perhaps some diets are not specifically driving the AD but rather are affecting inflammation in the body at large. Although somewhat speculative, there is evidence that some foods may simply be proinflammatory, working to exacerbate the disease outside of a specific mechanism, which has been seen in a variety of other conditions such as acne or rheumatoid arthritis.16,17 To speculate further, it is possible that there may be a threshold effect such that when the AD is poorly controlled, certain factors such as inflammatory foods could lead to a flare, while when under better control, these same factors may not cause an effect.
Finally, it is important to also consider the emotional and/or psychological aspects related to food and diet. The power of the placebo in dietary change has been documented in several diseases, though this certainly is not to be dismissive of the patient’s symptoms; it seems reasonable that the very act of changing such a fundamental aspect of daily life could result in a placebo effect.18,19 In the context of relapsing and remitting conditions such as AD, this effect may be magnified. A landmark study by Thompson and Hanifin20 illustrates this possibility. The authors found that in 80% of cases in which patients were convinced that food was a major contributing factor to their AD, such concerns diminished markedly once better control of the eczema was achieved.20
Navigating the Complexity of Dietary Restrictions
This brings us to what to do with an individual patient in the examination room. Because there is such widespread concern and discussion around this topic, it is important to at least briefly address it. If there are known food allergens that are being avoided, it is important to underscore the importance of continuing to avoid those foods, especially when there is actual evidence of true food allergy rather than sensitization alone. Historically, elimination diets often were recommended empirically, though more recent studies, meta-analyses, and guidance documents increasingly have recommended against them.3 In particular, there are major concerns for iatrogenic harm.
First, heavily restricted diets may result in nutritional and/or caloric deficiencies that can be dangerous and lead to poor growth.21 Practices such as drinking unpasteurized milk can expose children to dangerous infections, while feeding them exclusively rice milk can lead to severe malnutrition.22
Second, there is a dawning realization that children with AD placed on elimination diets may actually develop true IgE-mediated allergies, including fatal anaphylaxis, to the excluded foods. In fact, one retrospective review of 298 patients with a history of AD and no prior immediate reactions found that 19% of patients developed new immediate-type hypersensitivity reactions after starting an elimination diet, presumably due to the loss of tolerance to these foods. A striking one-third of these reactions were classified as anaphylaxis, with cow’s milk and egg being the most common offenders.23
It also is crucial to acknowledge that recommending sweeping lifestyle changes is not easy for patients, especially pediatric patients. Onerous dietary restrictions may add considerable stress, ironically a known trigger for AD itself.
Finally, dietary modifications can be a distraction from conventional therapy and may result in treatment delays while the patient continues to experience uncontrolled symptoms of AD.
Final Thoughts
Diet is intimately related to AD. Although the narrative continues to unfold in fascinating domains, such as the skin barrier and the microbiome, it is increasingly clear that these are intertwined and always have been. Despite the rarity of true food-triggered AD, the perception of dietary triggers is so widespread and addressing the topic is important and may help avoid unnecessary harm from unfounded extreme dietary changes. A recent multispecialty workgroup report on AD and food allergy succinctly summarized this as: “AD has many triggers and comorbidities, and food allergy is only one of the potential triggers and comorbid conditions. With regard to AD management, education and skin care are most important.”3 With proper testing, guidance, and both topical and systemic therapies, most AD can be brought under control, and for at least some patients, this may allay concerns about foods triggering their AD.
It is unsurprising that food frequently is thought to be the culprit behind an eczema flare, especially in infants. Indeed, it often is said that infants do only 3 things: eat, sleep, and poop.1 For those unfortunate enough to develop the signs and symptoms of atopic dermatitis (AD), food quickly emerges as a potential culprit from the tiny pool of suspects, which is against a cultural backdrop of unprecedented focus on foods and food reactions.2 The prevalence of food allergies in children, though admittedly fraught with methodological difficulties, is estimated to have more than doubled from 3.4% in 1999 to 7.6% in 2018.3 As expected, prevalence rates were higher among children with other atopic comorbidities including AD, with up to 50% of children with AD demonstrating convincing food allergy.4 It is easy to imagine a patient conflating these 2 entities and mistaking their correlation for causation. Thus, it follows that more than 90% of parents/guardians have reported that their children have had food-induced AD, and understandably—at least according to one study—75% of parents/guardians were found to have manipulated the diet in an attempt to manage the disease.5,6
Patients and parents/guardians are not the only ones who have suspected food as a driving force in AD. An article in the British Medical Journal from the 1800s beautifully encapsulated the depth and duration of this quandary: “There is probably no subject in which more deeply rooted convictions have been held, not only in the profession but by the laity, than the connection between diet and disease, both as regards the causation and treatment of the latter.”7 Herein, a wide range of food reactions is examined to highlight evidence for the role of diet in AD, which may contradict what patients—and even some clinicians—believe.
No Easy Answers
A definitive statement that food allergy is not the root cause of AD would put this issue to rest, but such simplicity does not reflect the complex reality. First, we must agree on definitions for certain terms. What do we mean by food allergy? A broader category—adverse food reactions—covers a wide range of entities, some immune mediated and some not, including lactose intolerance, irritant contact dermatitis around the mouth, and even dermatitis herpetiformis (the cutaneous manifestation of celiac disease).8 Although the term food allergy often is used synonymously with adverse food reactions, the exact definition of a food allergy is specific: “adverse immune responses to food proteins that result in typical clinical symptoms.”8 The fact that many patients and even health care practitioners seem to frequently misapply this term makes it even more confusing.
The current focus is on foods that could trigger a flare of AD, which clearly is a broader question than food allergy sensu stricto. It seems self-evident, for example, that if an infant with AD were to (messily) eat an acidic food such as an orange, a flare-up of AD around the mouth and on the cheeks and hands would be a forgone conclusion. Similar nonimmunologic scenarios unambiguously can occur with many foods, including citrus; corn; radish; mustard; garlic; onion; pineapple; and many spices, food additives, and preservatives.9 Clearly there are some scenarios whereby food could trigger an AD flare, and yet this more limited vignette generally is not what patients are referring to when suggesting that food is the root cause of their AD.
The Labyrinth of Testing for Food Allergies
Although there is no reliable method for testing for irritant dermatitis, understanding the other types of tests may help guide our thinking. Testing for IgE-mediated food allergies generally is done via an immunoenzymatic serum assay that can document sensitization to a food protein; however, this testing by itself is not sufficient to diagnose a clinical food allergy.10 Similarly, skin prick testing allows for intradermal administration of a food extract to evaluate for an urticarial reaction within 10 to 15 minutes. Although the sensitivity and specificity vary by age, population, and the specific allergen being tested, these are limited to immediate-type reactions and do not reflect the potential to drive an eczematous flare.
The gold standard, if there is one, is likely the double-blind, placebo-controlled food challenge (DBPCFC), ideally with a long enough observation period to capture later-occurring reactions such as an AD flare. However, given the nature of the test—having patients eat the foods of concern and then carefully following them for reactions—it remains time consuming, expensive, and labor intensive.11
To further complicate matters, several unvalidated tests exist such as IgG testing, atopy patch testing, kinesiology, and hair and gastric juice analysis, which remain investigational but continue to be used and may further confuse patients and clinicians.12
Classification of Food Allergies
It is useful to first separate out the classic IgE-mediated food allergy reactions that are common. In these immediate-type reactions, a person sensitized to a food protein will develop characteristic cutaneous and/or extracutaneous reactions such as urticaria, angioedema, and even anaphylaxis, usually within minutes of exposure. Although it is possible that an IgE-mediated reaction could trigger an AD flare—perhaps simply by causing pruritus, which could initiate the itch-scratch cycle—because of the near simultaneity with ingestion of the offending food and the often dramatic clinical presentations, such foods clearly do not represent “hidden” triggers for AD flares.3 The concept of food-triggered AD (FTAD) is crucial for thinking about foods that could result in true eczematous flares, which historically have been classified as early-type (<2 hours after food challenge) and late-type (≥2 hours after food challenge) reactions.13,14
A study of more than 1000 DBPCFCs performed in patients with AD was illustrative.15 Immediate reactions other than AD were fairly common and were observed in 40% of the food challenges compared to only 9% in the placebo group. These reactions included urticaria, angioedema, and gastrointestinal and respiratory tract symptoms. Immediate reactions of AD alone were exceedingly rare at only 0.7% and not significantly elevated compared to placebo. Just over 4% experienced both an immediate AD exacerbation along with other non-AD findings, which was significantly greater than placebo (P<.01). Although intermediate and late reactions manifesting as AD exacerbations did occur after food ingestion, they were rare (2.2% or less) and not significantly different from placebo. The authors concluded that an exacerbation of AD in the absence of other allergic symptoms in children was unlikely to be due to food,15 which is an important finding.
A recent retrospective review of 372 children with AD reported similar results.4 The authors defined FTAD in a different way; instead of showing a flare after a DBPCFC, they looked for “physician-noted sustained improvement in AD upon removal of a food (typically after 2–6-wk follow-up), to which the child was sensitized without any other changes in skin care.” Despite this fundamentally different approach, they similarly concluded that while food allergies were common, FTAD was relatively uncommon—found in 2% of those with mild AD, 6% of those with moderate AD, and 4% of those with severe AD.4
There are other ways that foods could contribute to disease flares, however, and one of the most compelling is that there may be broader concepts at play; perhaps some diets are not specifically driving the AD but rather are affecting inflammation in the body at large. Although somewhat speculative, there is evidence that some foods may simply be proinflammatory, working to exacerbate the disease outside of a specific mechanism, which has been seen in a variety of other conditions such as acne or rheumatoid arthritis.16,17 To speculate further, it is possible that there may be a threshold effect such that when the AD is poorly controlled, certain factors such as inflammatory foods could lead to a flare, while when under better control, these same factors may not cause an effect.
Finally, it is important to also consider the emotional and/or psychological aspects related to food and diet. The power of the placebo in dietary change has been documented in several diseases, though this certainly is not to be dismissive of the patient’s symptoms; it seems reasonable that the very act of changing such a fundamental aspect of daily life could result in a placebo effect.18,19 In the context of relapsing and remitting conditions such as AD, this effect may be magnified. A landmark study by Thompson and Hanifin20 illustrates this possibility. The authors found that in 80% of cases in which patients were convinced that food was a major contributing factor to their AD, such concerns diminished markedly once better control of the eczema was achieved.20
Navigating the Complexity of Dietary Restrictions
This brings us to what to do with an individual patient in the examination room. Because there is such widespread concern and discussion around this topic, it is important to at least briefly address it. If there are known food allergens that are being avoided, it is important to underscore the importance of continuing to avoid those foods, especially when there is actual evidence of true food allergy rather than sensitization alone. Historically, elimination diets often were recommended empirically, though more recent studies, meta-analyses, and guidance documents increasingly have recommended against them.3 In particular, there are major concerns for iatrogenic harm.
First, heavily restricted diets may result in nutritional and/or caloric deficiencies that can be dangerous and lead to poor growth.21 Practices such as drinking unpasteurized milk can expose children to dangerous infections, while feeding them exclusively rice milk can lead to severe malnutrition.22
Second, there is a dawning realization that children with AD placed on elimination diets may actually develop true IgE-mediated allergies, including fatal anaphylaxis, to the excluded foods. In fact, one retrospective review of 298 patients with a history of AD and no prior immediate reactions found that 19% of patients developed new immediate-type hypersensitivity reactions after starting an elimination diet, presumably due to the loss of tolerance to these foods. A striking one-third of these reactions were classified as anaphylaxis, with cow’s milk and egg being the most common offenders.23
It also is crucial to acknowledge that recommending sweeping lifestyle changes is not easy for patients, especially pediatric patients. Onerous dietary restrictions may add considerable stress, ironically a known trigger for AD itself.
Finally, dietary modifications can be a distraction from conventional therapy and may result in treatment delays while the patient continues to experience uncontrolled symptoms of AD.
Final Thoughts
Diet is intimately related to AD. Although the narrative continues to unfold in fascinating domains, such as the skin barrier and the microbiome, it is increasingly clear that these are intertwined and always have been. Despite the rarity of true food-triggered AD, the perception of dietary triggers is so widespread and addressing the topic is important and may help avoid unnecessary harm from unfounded extreme dietary changes. A recent multispecialty workgroup report on AD and food allergy succinctly summarized this as: “AD has many triggers and comorbidities, and food allergy is only one of the potential triggers and comorbid conditions. With regard to AD management, education and skin care are most important.”3 With proper testing, guidance, and both topical and systemic therapies, most AD can be brought under control, and for at least some patients, this may allay concerns about foods triggering their AD.
- Eat, sleep, poop—the top 3 things new parents need to know. John’s Hopkins All Children’s Hospital website. Published May 18, 2019. Accessed September 13, 2022. https://www.hopkinsallchildrens.org/ACH-News/General-News/Eat-Sleep-Poop-%E2%80%93-The-Top-3-Things-New-Parents-Ne
- Onyimba F, Crowe SE, Johnson S, et al. Food allergies and intolerances: a clinical approach to the diagnosis and management of adverse reactions to food. Clin Gastroenterol Hepatol. 2021;19:2230-2240.e1.
- Singh AM, Anvari S, Hauk P, et al. Atopic dermatitis and food allergy: best practices and knowledge gaps—a work group report from the AAAAI Allergic Skin Diseases Committee and Leadership Institute Project. J Allergy Clin Immunol Pract. 2022;10:697-706.
- Li JC, Arkin LM, Makhija MM, et al. Prevalence of food allergy diagnosis in pediatric patients with atopic dermatitis referred to allergy and/or dermatology subspecialty clinics. J Allergy Clin Immunol Pract. 2022;10:2469-2471.
- Thompson MM, Tofte SJ, Simpson EL, et al. Patterns of care and referral in children with atopic dermatitis and concern for food allergy. Dermatol Ther. 2006;19:91-96.
- Johnston GA, Bilbao RM, Graham-Brown RAC. The use of dietary manipulation by parents of children with atopic dermatitis. Br J Dermatol. 2004;150:1186-1189.
- Mackenzie S. The inaugural address on the advantages to be derived from the study of dermatology: delivered to the Reading Pathological Society. Br Med J. 1896;1:193-197.
- Anvari S, Miller J, Yeh CY, et al. IgE-mediated food allergy. Clin Rev Allergy Immunol. 2019;57:244-260.
- Brancaccio RR, Alvarez MS. Contact allergy to food. Dermatol Ther. 2004;17:302-313.
- Robison RG, Singh AM. Controversies in allergy: food testing and dietary avoidance in atopic dermatitis. J Allergy Clin Immunol Pract. 2019;7:35-39.
- Sicherer SH, Morrow EH, Sampson HA. Dose-response in double-blind, placebo-controlled oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2000;105:582-586.
- Kelso JM. Unproven diagnostic tests for adverse reactions to foods. J Allergy Clin Immunol Pract. 2018;6:362-365.
- Heratizadeh A, Wichmann K, Werfel T. Food allergy and atopic dermatitis: how are they connected? Curr Allergy Asthma Rep. 2011;11:284-291.
- Breuer K, Heratizadeh A, Wulf A, et al. Late eczematous reactions to food in children with atopic dermatitis. Clin Exp Allergy. 2004;34:817-824.
- Roerdink EM, Flokstra-de Blok BMJ, Blok JL, et al. Association of food allergy and atopic dermatitis exacerbations. Ann Allergy Asthma Immunol. 2016;116:334-338.
- Fuglsang G, Madsen G, Halken S, et al. Adverse reactions to food additives in children with atopic symptoms. Allergy. 1994;49:31-37.
- Ehlers I, Worm M, Sterry W, et al. Sugar is not an aggravating factor in atopic dermatitis. Acta Derm Venereol. 2001;81:282-284.
- Staudacher HM, Irving PM, Lomer MCE, et al. The challenges of control groups, placebos and blinding in clinical trials of dietary interventions. Proc Nutr Soc. 2017;76:203-212.
- Masi A, Lampit A, Glozier N, et al. Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis. Transl Psychiatry. 2015;5:E640.
- Thompson MM, Hanifin JM. Effective therapy of childhood atopic dermatitis allays food allergy concerns. J Am Acad Dermatol. 2005;53(2 suppl 2):S214-S219.
- Meyer R, De Koker C, Dziubak R, et al. The impact of the elimination diet on growth and nutrient intake in children with food protein induced gastrointestinal allergies. Clin Transl Allergy. 2016;6:25.
- Webber SA, Graham-Brown RA, Hutchinson PE, et al. Dietary manipulation in childhood atopic dermatitis. Br J Dermatol. 1989;121:91-98.
- Chang A, Robison R, Cai M, et al. Natural history of food-triggered atopic dermatitis and development of immediate reactions in children. J Allergy Clin Immunol Pract. 2016;4:229-236.e1.
- Eat, sleep, poop—the top 3 things new parents need to know. John’s Hopkins All Children’s Hospital website. Published May 18, 2019. Accessed September 13, 2022. https://www.hopkinsallchildrens.org/ACH-News/General-News/Eat-Sleep-Poop-%E2%80%93-The-Top-3-Things-New-Parents-Ne
- Onyimba F, Crowe SE, Johnson S, et al. Food allergies and intolerances: a clinical approach to the diagnosis and management of adverse reactions to food. Clin Gastroenterol Hepatol. 2021;19:2230-2240.e1.
- Singh AM, Anvari S, Hauk P, et al. Atopic dermatitis and food allergy: best practices and knowledge gaps—a work group report from the AAAAI Allergic Skin Diseases Committee and Leadership Institute Project. J Allergy Clin Immunol Pract. 2022;10:697-706.
- Li JC, Arkin LM, Makhija MM, et al. Prevalence of food allergy diagnosis in pediatric patients with atopic dermatitis referred to allergy and/or dermatology subspecialty clinics. J Allergy Clin Immunol Pract. 2022;10:2469-2471.
- Thompson MM, Tofte SJ, Simpson EL, et al. Patterns of care and referral in children with atopic dermatitis and concern for food allergy. Dermatol Ther. 2006;19:91-96.
- Johnston GA, Bilbao RM, Graham-Brown RAC. The use of dietary manipulation by parents of children with atopic dermatitis. Br J Dermatol. 2004;150:1186-1189.
- Mackenzie S. The inaugural address on the advantages to be derived from the study of dermatology: delivered to the Reading Pathological Society. Br Med J. 1896;1:193-197.
- Anvari S, Miller J, Yeh CY, et al. IgE-mediated food allergy. Clin Rev Allergy Immunol. 2019;57:244-260.
- Brancaccio RR, Alvarez MS. Contact allergy to food. Dermatol Ther. 2004;17:302-313.
- Robison RG, Singh AM. Controversies in allergy: food testing and dietary avoidance in atopic dermatitis. J Allergy Clin Immunol Pract. 2019;7:35-39.
- Sicherer SH, Morrow EH, Sampson HA. Dose-response in double-blind, placebo-controlled oral food challenges in children with atopic dermatitis. J Allergy Clin Immunol. 2000;105:582-586.
- Kelso JM. Unproven diagnostic tests for adverse reactions to foods. J Allergy Clin Immunol Pract. 2018;6:362-365.
- Heratizadeh A, Wichmann K, Werfel T. Food allergy and atopic dermatitis: how are they connected? Curr Allergy Asthma Rep. 2011;11:284-291.
- Breuer K, Heratizadeh A, Wulf A, et al. Late eczematous reactions to food in children with atopic dermatitis. Clin Exp Allergy. 2004;34:817-824.
- Roerdink EM, Flokstra-de Blok BMJ, Blok JL, et al. Association of food allergy and atopic dermatitis exacerbations. Ann Allergy Asthma Immunol. 2016;116:334-338.
- Fuglsang G, Madsen G, Halken S, et al. Adverse reactions to food additives in children with atopic symptoms. Allergy. 1994;49:31-37.
- Ehlers I, Worm M, Sterry W, et al. Sugar is not an aggravating factor in atopic dermatitis. Acta Derm Venereol. 2001;81:282-284.
- Staudacher HM, Irving PM, Lomer MCE, et al. The challenges of control groups, placebos and blinding in clinical trials of dietary interventions. Proc Nutr Soc. 2017;76:203-212.
- Masi A, Lampit A, Glozier N, et al. Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis. Transl Psychiatry. 2015;5:E640.
- Thompson MM, Hanifin JM. Effective therapy of childhood atopic dermatitis allays food allergy concerns. J Am Acad Dermatol. 2005;53(2 suppl 2):S214-S219.
- Meyer R, De Koker C, Dziubak R, et al. The impact of the elimination diet on growth and nutrient intake in children with food protein induced gastrointestinal allergies. Clin Transl Allergy. 2016;6:25.
- Webber SA, Graham-Brown RA, Hutchinson PE, et al. Dietary manipulation in childhood atopic dermatitis. Br J Dermatol. 1989;121:91-98.
- Chang A, Robison R, Cai M, et al. Natural history of food-triggered atopic dermatitis and development of immediate reactions in children. J Allergy Clin Immunol Pract. 2016;4:229-236.e1.
Practice Points
- The perception of dietary triggers is so entrenched and widespread that it should be addressed even when thought to be irrelevant.
- It is important not to dismiss food as a factor in atopic dermatitis (AD), as it can play a number of roles in the condition.
- On the other hand, education about the wide range of food reactions and the relative rarity of true food-driven AD along with the potential risks of dietary modification may enhance both rapport and understanding between the clinician and patient.
Patch Testing on Dupilumab: Reliable or Not?
In patients with persistent atopic dermatitis (AD) who are taking dupilumab, is there benefit of patch testing to determine if allergic contact dermatitis (ACD) also is contributing to their disease? Results of patch testing are likely be influenced by the immunomodulatory effects of dupilumab. Similar to the recommendation for patients to refrain from using topical or systemic corticosteroids for 1 week or more prior to patch testing to eliminate false negatives, we reviewed the literature to create practice guidelines for dermatologists regarding patch testing while a patient is taking dupilumab.
Pathophysiology and Pathomechanism
Dupilumab functions through the blockade of T helper 2 (TH2) cells; ACD is propagated through the T helper 1 (TH1) cellular pathway. However, patients with ACD that is unresponsive to allergen avoidance and traditional therapies, such as topical and oral corticosteroids, have responded to dupilumab. The more common reports of this responsiveness are with fragrances; multiple case series described patients with ACD to fragrance mix I1 and balsam of Peru1,2 who improved on dupilumab when other treatments failed. There also are reports of response when ACD was secondary to nickel,2,3p-phenylenediamine,1 Compositae,4 and non–formaldehyde-releasing preservatives (non-FRPs).5 Therefore, not all ACD is propagated through the TH1 cellular pathway.
As noted in these cases, ACD can be a response to an allergen whose pathogenesis involves the TH2 pathway or when patient characteristics favor a TH2 response. It has been suggested that AD patients are more susceptible to TH2-mediated contact sensitization to less-potent allergens, such as fragrances.6
Patch Test Results
Positive patch test results for allergens have been reported while patients are on dupilumab therapy, including a few studies in which results prior to starting dupilumab were compared with those while patients were on dupilumab therapy. In a retrospective chart review of 48 patients on dupilumab for AD with persistent disease, 23 patients were patch tested before and during dupilumab therapy. In these patients, the majority of contact allergies were persistent and only 10% (13/125) of patch test–positive results resolved on dupilumab therapy.7 Contact allergies that resolved included those to emulsifiers (propylene glycol, Amerchol L101 [lanolin-containing products found in cosmetics and other goods], dimethylaminopropylamine), fragrances (fragrance mix I, balsam of Peru), sunscreens (sulisobenzone, phenylbenzimidazole-5-sulfonic acid), and metals (vanadium chloride, phenylmercuric acetate).7 The following results observed in individual cases demonstrated conflicting findings: persistence of allergy to non-FRPs (methylisothiazolinone [MI]) but resolution of allergy to formaldehyde8; persistence of allergy to corticosteroids (budesonide and alclometasone)9; persistence of allergy to an antibiotic (neomycin sulfate) but resolution of allergies to a different antibiotic (bacitracin), glues (ethyl acrylate), bleach, and glutaraldehyde9; persistence of nickel allergy but resolution of allergies to fragrances (cinnamic aldehyde, balsam of Peru) and non-FRPs (methylchloroisothiazolinone or MI)10; and persistence of allergies to non-FRPs (MI) and FRPs (bronopol) but resolution of allergies to nickel, fragrances (hydroperoxides of linalool), and Compositae.11 Additional case reports of positive patch test results while on dupilumab but with no pretreatment results for comparison include allergies to rubber additives,12-14 nickel,14 textile dyes,14 cosmetic and hair care additives,12,14,15 corticosteroids,15 FRPs,15 fragrances,15,16 emulsifiers,16 and non-FRPs.17
An evident theme in the dupilumab patch-testing literature has been that results are variable and case specific: a given patient with ACD to an allergen will respond to dupilumab treatment and have subsequent negative patch testing, while another patient will not respond to dupilumab treatment and have persistent positive patch testing. This is likely because, in certain individuals, the allergen-immune system combination shifts ACD pathogenesis from a purely TH1 response to at least a partial TH2 response, thus allowing for benefit from dupilumab therapy. T helper 1 cell–mediated ACD should not be affected by dupilumab; therefore, reliable results can be elucidated from patch testing despite the drug.
Final Thoughts
We propose that AD patients with residual disease after taking dupilumab undergo patch testing. Positive results indicate allergens that are not inhibited by the drug. Patients will need to follow strict allergen avoidance to resolve this component of their disease; failure to improve might suggest the result was a nonrelevant positive.
If patch testing is negative, an alternative cause for residual disease must be sought. We do not recommend stopping dupilumab prior to patch testing to avoid a disease flare from AD or possible TH2-mediated ACD.
- Chipalkatti N, Lee N, Zancanaro P, et al. Dupilumab as a treatment for allergic contact dermatitis. Dermatitis. 2018;29:347-348. doi:10.1097/DER.0000000000000414
- Jacob SE, Sung CT, Machler BC. Dupilumab for systemic allergy syndrome with dermatitis. Dermatitis. 2019;30:164-167. doi:10.1097/DER.0000000000000446
- Joshi SR, Khan DA. Effective use of dupilumab in managing systemic allergic contact dermatitis. Dermatitis. 2018;29:282-284. doi:10.1097/DER.0000000000000409
- Ruge IF, Skov L, Zachariae C, et al. Dupilumab treatment in two patients with severe allergic contact dermatitis caused by sesquiterpene lactones. Contact Dermatitis. 2020:83;137-139. doi:10.1111/cod.13545
- Goldminz AM, Scheinman PL. A case series of dupilumab-treated allergic contact dermatitis patients. Dermatol Ther. 2018;31:e12701. doi:10.1111/dth.12701
- Kohli N, Nedorost S. Inflamed skin predisposes to sensitization to less potent allergens. J Am Acad Dermatol. 2016;75:312-317. doi:10.1016/j.jaad.2016.03.010
- Raffi J, Suresh R, Botto N, et al. The impact of dupilumab on patch testing and the prevalence of comorbid allergic contact dermatitis in recalcitrant atopic dermatitis: a retrospective chart review. J Am Acad Dermatol. 2020;82:132-138. doi:10.1016/j.jaad.2019.09.028
- Puza CJ, Atwater AR. Positive patch test reaction in a patient taking dupilumab. Dermatitis. 2018;29:89. doi:10.1097/DER.0000000000000346
- Suresh R, Murase JE. The role of expanded series patch testing in identifying causality of residual facial dermatitis following initiation of dupilumab therapy. JAAD Case Rep. 2018;4:899-904. doi:10.1016/j.jdcr.2018.08.027
- Stout M, Silverberg JI. Variable impact of dupilumab on patch testing results and allergic contact dermatitis in adults with atopic dermatitis. J Am Acad Dermatol. 2019;81:157-162. doi:10.1016/j.jaad.2019.03.020
- Raffi J, Botto N. Patch testing and allergen-specific inhibition in a patient taking dupilumab. JAMA Dermatol. 2019;155:120-121. doi:10.1001/jamadermatol.2018.4098
- Hoot JW, Douglas JD, Falo LD Jr. Patch testing in a patient on dupilumab. Dermatitis. 2018;29:164. doi:10.1097/DER.0000000000000357
- Crepy M-N, Nosbaum A, Bensefa-Colas L. Blocking type 2 inflammation by dupilumab does not control classic (type 1-driven) allergic contact dermatitis in chronic hand eczema. Contact Dermatitis. 2019;81:145-147. doi:10.1111/cod.13266
- Raffi J, Chen R, Botto N. Wide dye reactors. JAAD Case Rep. 2019;5:877-879. doi:10.1016/j.jdcr.2019.08.005
- Koblinski JE, Hamann D. Mixed occupational and iatrogenic allergic contact dermatitis in a hairdresser. Occup Med (Lond). 2020;70:523-526. doi:10.1093/occmed/kqaa152
- Raffi J, Suresh R, Fishman H, et al. Investigating the role of allergic contact dermatitis in residual ocular surface disease on dupilumab (ROSDD). Int J Womens Dermatol. 2019;5:308-313. doi:10.1016/j.ijwd.2019.10.001
- Zhu GA, Chen JK, Chiou A, et al. Repeat patch testing in a patient with allergic contact dermatitis improved on dupilumab. JAAD Case Rep. 2019;5:336-338. doi:10.1016/j.jdcr.2019.01.023
In patients with persistent atopic dermatitis (AD) who are taking dupilumab, is there benefit of patch testing to determine if allergic contact dermatitis (ACD) also is contributing to their disease? Results of patch testing are likely be influenced by the immunomodulatory effects of dupilumab. Similar to the recommendation for patients to refrain from using topical or systemic corticosteroids for 1 week or more prior to patch testing to eliminate false negatives, we reviewed the literature to create practice guidelines for dermatologists regarding patch testing while a patient is taking dupilumab.
Pathophysiology and Pathomechanism
Dupilumab functions through the blockade of T helper 2 (TH2) cells; ACD is propagated through the T helper 1 (TH1) cellular pathway. However, patients with ACD that is unresponsive to allergen avoidance and traditional therapies, such as topical and oral corticosteroids, have responded to dupilumab. The more common reports of this responsiveness are with fragrances; multiple case series described patients with ACD to fragrance mix I1 and balsam of Peru1,2 who improved on dupilumab when other treatments failed. There also are reports of response when ACD was secondary to nickel,2,3p-phenylenediamine,1 Compositae,4 and non–formaldehyde-releasing preservatives (non-FRPs).5 Therefore, not all ACD is propagated through the TH1 cellular pathway.
As noted in these cases, ACD can be a response to an allergen whose pathogenesis involves the TH2 pathway or when patient characteristics favor a TH2 response. It has been suggested that AD patients are more susceptible to TH2-mediated contact sensitization to less-potent allergens, such as fragrances.6
Patch Test Results
Positive patch test results for allergens have been reported while patients are on dupilumab therapy, including a few studies in which results prior to starting dupilumab were compared with those while patients were on dupilumab therapy. In a retrospective chart review of 48 patients on dupilumab for AD with persistent disease, 23 patients were patch tested before and during dupilumab therapy. In these patients, the majority of contact allergies were persistent and only 10% (13/125) of patch test–positive results resolved on dupilumab therapy.7 Contact allergies that resolved included those to emulsifiers (propylene glycol, Amerchol L101 [lanolin-containing products found in cosmetics and other goods], dimethylaminopropylamine), fragrances (fragrance mix I, balsam of Peru), sunscreens (sulisobenzone, phenylbenzimidazole-5-sulfonic acid), and metals (vanadium chloride, phenylmercuric acetate).7 The following results observed in individual cases demonstrated conflicting findings: persistence of allergy to non-FRPs (methylisothiazolinone [MI]) but resolution of allergy to formaldehyde8; persistence of allergy to corticosteroids (budesonide and alclometasone)9; persistence of allergy to an antibiotic (neomycin sulfate) but resolution of allergies to a different antibiotic (bacitracin), glues (ethyl acrylate), bleach, and glutaraldehyde9; persistence of nickel allergy but resolution of allergies to fragrances (cinnamic aldehyde, balsam of Peru) and non-FRPs (methylchloroisothiazolinone or MI)10; and persistence of allergies to non-FRPs (MI) and FRPs (bronopol) but resolution of allergies to nickel, fragrances (hydroperoxides of linalool), and Compositae.11 Additional case reports of positive patch test results while on dupilumab but with no pretreatment results for comparison include allergies to rubber additives,12-14 nickel,14 textile dyes,14 cosmetic and hair care additives,12,14,15 corticosteroids,15 FRPs,15 fragrances,15,16 emulsifiers,16 and non-FRPs.17
An evident theme in the dupilumab patch-testing literature has been that results are variable and case specific: a given patient with ACD to an allergen will respond to dupilumab treatment and have subsequent negative patch testing, while another patient will not respond to dupilumab treatment and have persistent positive patch testing. This is likely because, in certain individuals, the allergen-immune system combination shifts ACD pathogenesis from a purely TH1 response to at least a partial TH2 response, thus allowing for benefit from dupilumab therapy. T helper 1 cell–mediated ACD should not be affected by dupilumab; therefore, reliable results can be elucidated from patch testing despite the drug.
Final Thoughts
We propose that AD patients with residual disease after taking dupilumab undergo patch testing. Positive results indicate allergens that are not inhibited by the drug. Patients will need to follow strict allergen avoidance to resolve this component of their disease; failure to improve might suggest the result was a nonrelevant positive.
If patch testing is negative, an alternative cause for residual disease must be sought. We do not recommend stopping dupilumab prior to patch testing to avoid a disease flare from AD or possible TH2-mediated ACD.
In patients with persistent atopic dermatitis (AD) who are taking dupilumab, is there benefit of patch testing to determine if allergic contact dermatitis (ACD) also is contributing to their disease? Results of patch testing are likely be influenced by the immunomodulatory effects of dupilumab. Similar to the recommendation for patients to refrain from using topical or systemic corticosteroids for 1 week or more prior to patch testing to eliminate false negatives, we reviewed the literature to create practice guidelines for dermatologists regarding patch testing while a patient is taking dupilumab.
Pathophysiology and Pathomechanism
Dupilumab functions through the blockade of T helper 2 (TH2) cells; ACD is propagated through the T helper 1 (TH1) cellular pathway. However, patients with ACD that is unresponsive to allergen avoidance and traditional therapies, such as topical and oral corticosteroids, have responded to dupilumab. The more common reports of this responsiveness are with fragrances; multiple case series described patients with ACD to fragrance mix I1 and balsam of Peru1,2 who improved on dupilumab when other treatments failed. There also are reports of response when ACD was secondary to nickel,2,3p-phenylenediamine,1 Compositae,4 and non–formaldehyde-releasing preservatives (non-FRPs).5 Therefore, not all ACD is propagated through the TH1 cellular pathway.
As noted in these cases, ACD can be a response to an allergen whose pathogenesis involves the TH2 pathway or when patient characteristics favor a TH2 response. It has been suggested that AD patients are more susceptible to TH2-mediated contact sensitization to less-potent allergens, such as fragrances.6
Patch Test Results
Positive patch test results for allergens have been reported while patients are on dupilumab therapy, including a few studies in which results prior to starting dupilumab were compared with those while patients were on dupilumab therapy. In a retrospective chart review of 48 patients on dupilumab for AD with persistent disease, 23 patients were patch tested before and during dupilumab therapy. In these patients, the majority of contact allergies were persistent and only 10% (13/125) of patch test–positive results resolved on dupilumab therapy.7 Contact allergies that resolved included those to emulsifiers (propylene glycol, Amerchol L101 [lanolin-containing products found in cosmetics and other goods], dimethylaminopropylamine), fragrances (fragrance mix I, balsam of Peru), sunscreens (sulisobenzone, phenylbenzimidazole-5-sulfonic acid), and metals (vanadium chloride, phenylmercuric acetate).7 The following results observed in individual cases demonstrated conflicting findings: persistence of allergy to non-FRPs (methylisothiazolinone [MI]) but resolution of allergy to formaldehyde8; persistence of allergy to corticosteroids (budesonide and alclometasone)9; persistence of allergy to an antibiotic (neomycin sulfate) but resolution of allergies to a different antibiotic (bacitracin), glues (ethyl acrylate), bleach, and glutaraldehyde9; persistence of nickel allergy but resolution of allergies to fragrances (cinnamic aldehyde, balsam of Peru) and non-FRPs (methylchloroisothiazolinone or MI)10; and persistence of allergies to non-FRPs (MI) and FRPs (bronopol) but resolution of allergies to nickel, fragrances (hydroperoxides of linalool), and Compositae.11 Additional case reports of positive patch test results while on dupilumab but with no pretreatment results for comparison include allergies to rubber additives,12-14 nickel,14 textile dyes,14 cosmetic and hair care additives,12,14,15 corticosteroids,15 FRPs,15 fragrances,15,16 emulsifiers,16 and non-FRPs.17
An evident theme in the dupilumab patch-testing literature has been that results are variable and case specific: a given patient with ACD to an allergen will respond to dupilumab treatment and have subsequent negative patch testing, while another patient will not respond to dupilumab treatment and have persistent positive patch testing. This is likely because, in certain individuals, the allergen-immune system combination shifts ACD pathogenesis from a purely TH1 response to at least a partial TH2 response, thus allowing for benefit from dupilumab therapy. T helper 1 cell–mediated ACD should not be affected by dupilumab; therefore, reliable results can be elucidated from patch testing despite the drug.
Final Thoughts
We propose that AD patients with residual disease after taking dupilumab undergo patch testing. Positive results indicate allergens that are not inhibited by the drug. Patients will need to follow strict allergen avoidance to resolve this component of their disease; failure to improve might suggest the result was a nonrelevant positive.
If patch testing is negative, an alternative cause for residual disease must be sought. We do not recommend stopping dupilumab prior to patch testing to avoid a disease flare from AD or possible TH2-mediated ACD.
- Chipalkatti N, Lee N, Zancanaro P, et al. Dupilumab as a treatment for allergic contact dermatitis. Dermatitis. 2018;29:347-348. doi:10.1097/DER.0000000000000414
- Jacob SE, Sung CT, Machler BC. Dupilumab for systemic allergy syndrome with dermatitis. Dermatitis. 2019;30:164-167. doi:10.1097/DER.0000000000000446
- Joshi SR, Khan DA. Effective use of dupilumab in managing systemic allergic contact dermatitis. Dermatitis. 2018;29:282-284. doi:10.1097/DER.0000000000000409
- Ruge IF, Skov L, Zachariae C, et al. Dupilumab treatment in two patients with severe allergic contact dermatitis caused by sesquiterpene lactones. Contact Dermatitis. 2020:83;137-139. doi:10.1111/cod.13545
- Goldminz AM, Scheinman PL. A case series of dupilumab-treated allergic contact dermatitis patients. Dermatol Ther. 2018;31:e12701. doi:10.1111/dth.12701
- Kohli N, Nedorost S. Inflamed skin predisposes to sensitization to less potent allergens. J Am Acad Dermatol. 2016;75:312-317. doi:10.1016/j.jaad.2016.03.010
- Raffi J, Suresh R, Botto N, et al. The impact of dupilumab on patch testing and the prevalence of comorbid allergic contact dermatitis in recalcitrant atopic dermatitis: a retrospective chart review. J Am Acad Dermatol. 2020;82:132-138. doi:10.1016/j.jaad.2019.09.028
- Puza CJ, Atwater AR. Positive patch test reaction in a patient taking dupilumab. Dermatitis. 2018;29:89. doi:10.1097/DER.0000000000000346
- Suresh R, Murase JE. The role of expanded series patch testing in identifying causality of residual facial dermatitis following initiation of dupilumab therapy. JAAD Case Rep. 2018;4:899-904. doi:10.1016/j.jdcr.2018.08.027
- Stout M, Silverberg JI. Variable impact of dupilumab on patch testing results and allergic contact dermatitis in adults with atopic dermatitis. J Am Acad Dermatol. 2019;81:157-162. doi:10.1016/j.jaad.2019.03.020
- Raffi J, Botto N. Patch testing and allergen-specific inhibition in a patient taking dupilumab. JAMA Dermatol. 2019;155:120-121. doi:10.1001/jamadermatol.2018.4098
- Hoot JW, Douglas JD, Falo LD Jr. Patch testing in a patient on dupilumab. Dermatitis. 2018;29:164. doi:10.1097/DER.0000000000000357
- Crepy M-N, Nosbaum A, Bensefa-Colas L. Blocking type 2 inflammation by dupilumab does not control classic (type 1-driven) allergic contact dermatitis in chronic hand eczema. Contact Dermatitis. 2019;81:145-147. doi:10.1111/cod.13266
- Raffi J, Chen R, Botto N. Wide dye reactors. JAAD Case Rep. 2019;5:877-879. doi:10.1016/j.jdcr.2019.08.005
- Koblinski JE, Hamann D. Mixed occupational and iatrogenic allergic contact dermatitis in a hairdresser. Occup Med (Lond). 2020;70:523-526. doi:10.1093/occmed/kqaa152
- Raffi J, Suresh R, Fishman H, et al. Investigating the role of allergic contact dermatitis in residual ocular surface disease on dupilumab (ROSDD). Int J Womens Dermatol. 2019;5:308-313. doi:10.1016/j.ijwd.2019.10.001
- Zhu GA, Chen JK, Chiou A, et al. Repeat patch testing in a patient with allergic contact dermatitis improved on dupilumab. JAAD Case Rep. 2019;5:336-338. doi:10.1016/j.jdcr.2019.01.023
- Chipalkatti N, Lee N, Zancanaro P, et al. Dupilumab as a treatment for allergic contact dermatitis. Dermatitis. 2018;29:347-348. doi:10.1097/DER.0000000000000414
- Jacob SE, Sung CT, Machler BC. Dupilumab for systemic allergy syndrome with dermatitis. Dermatitis. 2019;30:164-167. doi:10.1097/DER.0000000000000446
- Joshi SR, Khan DA. Effective use of dupilumab in managing systemic allergic contact dermatitis. Dermatitis. 2018;29:282-284. doi:10.1097/DER.0000000000000409
- Ruge IF, Skov L, Zachariae C, et al. Dupilumab treatment in two patients with severe allergic contact dermatitis caused by sesquiterpene lactones. Contact Dermatitis. 2020:83;137-139. doi:10.1111/cod.13545
- Goldminz AM, Scheinman PL. A case series of dupilumab-treated allergic contact dermatitis patients. Dermatol Ther. 2018;31:e12701. doi:10.1111/dth.12701
- Kohli N, Nedorost S. Inflamed skin predisposes to sensitization to less potent allergens. J Am Acad Dermatol. 2016;75:312-317. doi:10.1016/j.jaad.2016.03.010
- Raffi J, Suresh R, Botto N, et al. The impact of dupilumab on patch testing and the prevalence of comorbid allergic contact dermatitis in recalcitrant atopic dermatitis: a retrospective chart review. J Am Acad Dermatol. 2020;82:132-138. doi:10.1016/j.jaad.2019.09.028
- Puza CJ, Atwater AR. Positive patch test reaction in a patient taking dupilumab. Dermatitis. 2018;29:89. doi:10.1097/DER.0000000000000346
- Suresh R, Murase JE. The role of expanded series patch testing in identifying causality of residual facial dermatitis following initiation of dupilumab therapy. JAAD Case Rep. 2018;4:899-904. doi:10.1016/j.jdcr.2018.08.027
- Stout M, Silverberg JI. Variable impact of dupilumab on patch testing results and allergic contact dermatitis in adults with atopic dermatitis. J Am Acad Dermatol. 2019;81:157-162. doi:10.1016/j.jaad.2019.03.020
- Raffi J, Botto N. Patch testing and allergen-specific inhibition in a patient taking dupilumab. JAMA Dermatol. 2019;155:120-121. doi:10.1001/jamadermatol.2018.4098
- Hoot JW, Douglas JD, Falo LD Jr. Patch testing in a patient on dupilumab. Dermatitis. 2018;29:164. doi:10.1097/DER.0000000000000357
- Crepy M-N, Nosbaum A, Bensefa-Colas L. Blocking type 2 inflammation by dupilumab does not control classic (type 1-driven) allergic contact dermatitis in chronic hand eczema. Contact Dermatitis. 2019;81:145-147. doi:10.1111/cod.13266
- Raffi J, Chen R, Botto N. Wide dye reactors. JAAD Case Rep. 2019;5:877-879. doi:10.1016/j.jdcr.2019.08.005
- Koblinski JE, Hamann D. Mixed occupational and iatrogenic allergic contact dermatitis in a hairdresser. Occup Med (Lond). 2020;70:523-526. doi:10.1093/occmed/kqaa152
- Raffi J, Suresh R, Fishman H, et al. Investigating the role of allergic contact dermatitis in residual ocular surface disease on dupilumab (ROSDD). Int J Womens Dermatol. 2019;5:308-313. doi:10.1016/j.ijwd.2019.10.001
- Zhu GA, Chen JK, Chiou A, et al. Repeat patch testing in a patient with allergic contact dermatitis improved on dupilumab. JAAD Case Rep. 2019;5:336-338. doi:10.1016/j.jdcr.2019.01.023
Practice Points
- Allergic contact dermatitis is an important diagnostic consideration in patients with refractory or persistent dermatitis.
- Patch testing is important to help determine a possible allergic contactant, but there is confusion about its accuracy in patients taking dupilumab.
- Patients with residual dermatitis while on dupilumab are likely to benefit from patch testing.
Atopic Dermatitis and Peanut Allergy Prevention: New Guidelines
Updated Guidelines on Peanut Allergy Prevention in Infants With Atopic Dermatitis
It has been said that “extraordinary claims require extraordinary evidence.”1 In the pursuit of evidence-based medicine, we are encouraged to follow a similar standard, with an emphasis on waiting for multiple studies with good-quality data and high levels of agreement before changing any aspect of our clinical practice. The ostensible purpose is that studies can be flawed, conclusions can be incorrect, or biases can be overlooked. In such cases, acting on questionable results could imperil patients. It is for this reason that so many review articles sometimes frustratingly seem to conclude that further evidence is needed.2
Based on this standard, recently published addendum guidelines from the National Institute of Allergy and Infectious Diseases for prevention of peanut allergy in the United States3 are somewhat striking in that they make fairly bold recommendations based on results from the 2015 Learning Early about Peanut Allergy (LEAP) study,4 a randomized trial evaluating early peanut introduction as a preventive strategy for peanut allergy. Of note, this study was not placebo controlled, was conducted at only 1 site in the United Kingdom, and only included 640 children, though the number of participants was admittedly large for this type of study.4 Arguably, the LEAP study alone does not provide enough evidence upon which to base what essentially amounts to an about-face in the official recommendations for prevention of peanut and other food allergies, which emphasized delayed introduction of high-risk foods, especially in high-risk individuals.5-7 To better understand this shift, we need to briefly explore the context of the addendum guidelines.
As many as one-third of pediatric patients with atopic dermatitis (AD) have food allergies, thus diet often is invoked by patients and providers alike as an underlying cause of the disease.8 Many patients in my practice are so focused on potential food allergies that actual treatment of the affected skin is marginalized and often dismissed as a stopgap that does not address the root of the problem. A 2004 study of 100 children with AD found that diet was manipulated by the parents in 75% of patients in an attempt to manage the disease.9
Patients are not the only ones who consider food allergies to be a driving force in AD. The medical literature indicates that this theory has existed for centuries; for instance, with regard to the relationship between diet and AD, the author of an article from 1830 quipped, “There is probably no subject in which more deeply rooted convictions have been held . . . than the connection between diet and disease, both as regards the causation and treatment of the latter . . .”10 More apropos perhaps is a statement from the 2010 National Institute of Allergy and Infectious Diseases guidelines on food allergy management, which noted that while the expert group “does not mean to imply that AD results from [food allergies], the role of [food allergies] in the pathogenesis and severity of this condition remains controversial.”11
Prior to the LEAP study, food allergy recommendations for clinical practice in the United Kingdom in 199812 and the United States in 200013 recommended excluding allergenic foods (eg, peanuts, tree nuts, soy, milk, eggs) from the diet in infants with a family history of atopy until 3 years of age. However, those recommendations did not seem to be working, when in fact just the opposite was happening. From 1997 until the LEAP study was conducted in 2015, the prevalence of peanut allergy more than quadrupled and became the leading cause of anaphylaxis and death related to food allergy.14 Additionally, study after study concluded that elimination diets did not seem to help most patients with AD.15 As is required in good scientific thinking, when a hypothesis is proven false, other approaches must be considered.
The idea arose that perhaps delaying introduction of allergenic foods was the opposite of the answer.4 The LEAP study tested the notion that peanut allergies are rare in countries where peanuts are introduced early and if telling families to delay introduction of peanuts in infants might actually be causing development of a peanut allergy, and the tests bore fruit. It was found that giving infants peanut-containing foods resulted in a more than 80% reduction in peanut allergy at 5 years of age (P<.001).4 What was perhaps even more interesting was the connection between AD and peanut allergy. An important idea articulated in the LEAP study is in some ways revolutionary: Rather than foods causing AD, it could be that “early environmental exposure (through the skin) to peanut may account for early sensitization, whereas early oral exposure may lead to immune tolerance.”4 This concept—that impaired eczematous skin may actually lead to the development of food allergies—turns the whole thing upside down.
What do these updated guidelines actually suggest? The first guideline focuses on infants with severe AD, egg allergy, or both, who therefore are thought to be at the highest risk for developing peanut allergy.3 Because of the higher baseline risk in this subgroup, measurement of the peanut-specific IgE (peanut sIgE) level, skin prick testing (SPT), or both is strongly recommended before introducing peanut protein into the diet. This testing can be performed by qualified providers as a screening measure, but if positive (≥0.35 kUA/L for peanut sIgE or >2 mm on the peanut SPT), referral to an allergy specialist is warranted. If these studies are negative, it is thought the likelihood of peanut allergy is low, and it is recommended that caregivers introduce age-appropriate peanut-containing foods (eg, peanut butter snack puffs, diluted peanut butter) as early as 4 to 6 months of age. The second guideline recommends that peanut-containing foods should be introduced into the diets of infants with mild or moderate AD at approximately 6 months of age without the need for prior screening via peanut sIgE or SPT. Lastly, the third guideline recommends that caregivers freely introduce peanut-containing foods together with other solid foods in infants without AD or food allergies in accordance with family preference.3
The results of the LEAP study are certainly exciting, and although the theoretical basis makes good scientific sense and the updated guidelines truly address an important and growing problem, there are several issues with this update that are worth considering. Given the constraints of the LEAP study, it certainly seems possible that the results will not be applicable to all populations or foods. More research is needed to ensure that this robust finding applies to other children and to explore the introduction of other allergenic foods, which the LEAP study investigators also emphasized.4
In fairness, the updated guidelines clearly state the quality of evidence of their recommendations and make it clear that expert opinion is playing a large role.3 For the first guideline regarding recommendations for those with severe AD and/or egg allergy, the quality of evidence is deemed moderate, while the contribution of expert opinion is listed as significant. For the second and third guidelines regarding recommendations for mild to moderate AD and those without AD, respectively, the quality of evidence is low and expert opinion is again listed as significant.3
Importantly, delineating severe AD from moderate disease—which is necessary because only severe AD warrants evaluation with peanut sIgE and/or SPT—can be difficult, as the distinction relies on a degree of subjectivity that may vary between specialists. Indeed, 2 publications suggest extending the definition of severe AD to include infants with early-onset AD (<3 months of age) and those with moderate AD not responding to treatment.16,17
Despite these reservations, the updated guidelines represent a breakthrough in understanding in an area truly in need of advancement. Although the evidence may not be exactly extraordinary, the context for these developments and our deeper understanding suggest that we do indeed live in extraordinary times.
- Encyclopaedia Galactica [television transcript]. Cosmos: A Personal Voyage. Public Broadcasting Service. December 14, 1980.
- Ezzo J, Bausell B, Moerman DE, et al. Reviewing the reviews: how strong is the evidence? how clear are the conclusions? Int J Technol Assess Health Care. 2001;17:457-466.
- Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases–sponsored expert panel.J Allergy Clin Immunol. 2017;139:29-44.
- Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372:803-813.
- Høst A, Koletzko B, Dreborg S, et al. Dietary products used in infants for treatment and prevention of food allergy. joint statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child. 1999;81:80-84.
- American Academy of Pediatrics. Committee on Nutrition. hypoallergenic infant formulas. Pediatrics. 2000;106(2, pt 1):346-349.
- Fiocchi A, Assa’ad A, Bahna S; Adverse Reactions to Foods Committee; American College of Allergy, Asthma and Immunology. Food allergy and the introduction of solid foods to infants: a consensus document. Ann Allergy Asthma Immunol. 2006;97:10-20.
- Thompson MM, Hanifin JM. Effective therapy of childhood atopic dermatitis allays food allergy concerns. J Am Acad Dermatol. 2005;53(2 suppl 2):S214-S219.
- Johnston GA, Bilbao RM, Graham-Brown RA. The use of dietary manipulation by parents of children with atopic dermatitis. Br J Dermatol. 2004;150:1186-1189.
- Mackenzie S. The inaugural address on the advantages to be derived from the study of dermatology. BMJ. 1830;1:193-197.
- Boyce JA, Assa’ad A, Burks AW, et al; NIAID-Sponsored Expert Panel. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126(6 suppl):S1-S58.
- Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment. Peanut Allergy. London, England: Department of Health; 1998.
- American Academy of Pediatrics Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics. 2000;106(2, pt 1):346-349.
- Gruchalla RS, Sampson HA. Preventing peanut allergy through early consumption—ready for prime time? N Engl J Med. 2015;372:875-877.
- Lim NR, Lohman ME, Lio PA. The role of elimination diets in atopic dermatitis: a comprehensive review. Pediatr Dermatol. 2017;34:516-527.
- Wong CC, Allen KJ, Orchard D. Changes to infant feeding guidelines: relevance to dermatologists. Australas J Dermatol. 2017;58:e171-e175.
- Martin PE, Eckert JK, Koplin JJ, et al. Which infants with eczema are at risk of food allergy? results from a population-based cohort. Clin Exp Allergy. 2015;45:255-264.
It has been said that “extraordinary claims require extraordinary evidence.”1 In the pursuit of evidence-based medicine, we are encouraged to follow a similar standard, with an emphasis on waiting for multiple studies with good-quality data and high levels of agreement before changing any aspect of our clinical practice. The ostensible purpose is that studies can be flawed, conclusions can be incorrect, or biases can be overlooked. In such cases, acting on questionable results could imperil patients. It is for this reason that so many review articles sometimes frustratingly seem to conclude that further evidence is needed.2
Based on this standard, recently published addendum guidelines from the National Institute of Allergy and Infectious Diseases for prevention of peanut allergy in the United States3 are somewhat striking in that they make fairly bold recommendations based on results from the 2015 Learning Early about Peanut Allergy (LEAP) study,4 a randomized trial evaluating early peanut introduction as a preventive strategy for peanut allergy. Of note, this study was not placebo controlled, was conducted at only 1 site in the United Kingdom, and only included 640 children, though the number of participants was admittedly large for this type of study.4 Arguably, the LEAP study alone does not provide enough evidence upon which to base what essentially amounts to an about-face in the official recommendations for prevention of peanut and other food allergies, which emphasized delayed introduction of high-risk foods, especially in high-risk individuals.5-7 To better understand this shift, we need to briefly explore the context of the addendum guidelines.
As many as one-third of pediatric patients with atopic dermatitis (AD) have food allergies, thus diet often is invoked by patients and providers alike as an underlying cause of the disease.8 Many patients in my practice are so focused on potential food allergies that actual treatment of the affected skin is marginalized and often dismissed as a stopgap that does not address the root of the problem. A 2004 study of 100 children with AD found that diet was manipulated by the parents in 75% of patients in an attempt to manage the disease.9
Patients are not the only ones who consider food allergies to be a driving force in AD. The medical literature indicates that this theory has existed for centuries; for instance, with regard to the relationship between diet and AD, the author of an article from 1830 quipped, “There is probably no subject in which more deeply rooted convictions have been held . . . than the connection between diet and disease, both as regards the causation and treatment of the latter . . .”10 More apropos perhaps is a statement from the 2010 National Institute of Allergy and Infectious Diseases guidelines on food allergy management, which noted that while the expert group “does not mean to imply that AD results from [food allergies], the role of [food allergies] in the pathogenesis and severity of this condition remains controversial.”11
Prior to the LEAP study, food allergy recommendations for clinical practice in the United Kingdom in 199812 and the United States in 200013 recommended excluding allergenic foods (eg, peanuts, tree nuts, soy, milk, eggs) from the diet in infants with a family history of atopy until 3 years of age. However, those recommendations did not seem to be working, when in fact just the opposite was happening. From 1997 until the LEAP study was conducted in 2015, the prevalence of peanut allergy more than quadrupled and became the leading cause of anaphylaxis and death related to food allergy.14 Additionally, study after study concluded that elimination diets did not seem to help most patients with AD.15 As is required in good scientific thinking, when a hypothesis is proven false, other approaches must be considered.
The idea arose that perhaps delaying introduction of allergenic foods was the opposite of the answer.4 The LEAP study tested the notion that peanut allergies are rare in countries where peanuts are introduced early and if telling families to delay introduction of peanuts in infants might actually be causing development of a peanut allergy, and the tests bore fruit. It was found that giving infants peanut-containing foods resulted in a more than 80% reduction in peanut allergy at 5 years of age (P<.001).4 What was perhaps even more interesting was the connection between AD and peanut allergy. An important idea articulated in the LEAP study is in some ways revolutionary: Rather than foods causing AD, it could be that “early environmental exposure (through the skin) to peanut may account for early sensitization, whereas early oral exposure may lead to immune tolerance.”4 This concept—that impaired eczematous skin may actually lead to the development of food allergies—turns the whole thing upside down.
What do these updated guidelines actually suggest? The first guideline focuses on infants with severe AD, egg allergy, or both, who therefore are thought to be at the highest risk for developing peanut allergy.3 Because of the higher baseline risk in this subgroup, measurement of the peanut-specific IgE (peanut sIgE) level, skin prick testing (SPT), or both is strongly recommended before introducing peanut protein into the diet. This testing can be performed by qualified providers as a screening measure, but if positive (≥0.35 kUA/L for peanut sIgE or >2 mm on the peanut SPT), referral to an allergy specialist is warranted. If these studies are negative, it is thought the likelihood of peanut allergy is low, and it is recommended that caregivers introduce age-appropriate peanut-containing foods (eg, peanut butter snack puffs, diluted peanut butter) as early as 4 to 6 months of age. The second guideline recommends that peanut-containing foods should be introduced into the diets of infants with mild or moderate AD at approximately 6 months of age without the need for prior screening via peanut sIgE or SPT. Lastly, the third guideline recommends that caregivers freely introduce peanut-containing foods together with other solid foods in infants without AD or food allergies in accordance with family preference.3
The results of the LEAP study are certainly exciting, and although the theoretical basis makes good scientific sense and the updated guidelines truly address an important and growing problem, there are several issues with this update that are worth considering. Given the constraints of the LEAP study, it certainly seems possible that the results will not be applicable to all populations or foods. More research is needed to ensure that this robust finding applies to other children and to explore the introduction of other allergenic foods, which the LEAP study investigators also emphasized.4
In fairness, the updated guidelines clearly state the quality of evidence of their recommendations and make it clear that expert opinion is playing a large role.3 For the first guideline regarding recommendations for those with severe AD and/or egg allergy, the quality of evidence is deemed moderate, while the contribution of expert opinion is listed as significant. For the second and third guidelines regarding recommendations for mild to moderate AD and those without AD, respectively, the quality of evidence is low and expert opinion is again listed as significant.3
Importantly, delineating severe AD from moderate disease—which is necessary because only severe AD warrants evaluation with peanut sIgE and/or SPT—can be difficult, as the distinction relies on a degree of subjectivity that may vary between specialists. Indeed, 2 publications suggest extending the definition of severe AD to include infants with early-onset AD (<3 months of age) and those with moderate AD not responding to treatment.16,17
Despite these reservations, the updated guidelines represent a breakthrough in understanding in an area truly in need of advancement. Although the evidence may not be exactly extraordinary, the context for these developments and our deeper understanding suggest that we do indeed live in extraordinary times.
It has been said that “extraordinary claims require extraordinary evidence.”1 In the pursuit of evidence-based medicine, we are encouraged to follow a similar standard, with an emphasis on waiting for multiple studies with good-quality data and high levels of agreement before changing any aspect of our clinical practice. The ostensible purpose is that studies can be flawed, conclusions can be incorrect, or biases can be overlooked. In such cases, acting on questionable results could imperil patients. It is for this reason that so many review articles sometimes frustratingly seem to conclude that further evidence is needed.2
Based on this standard, recently published addendum guidelines from the National Institute of Allergy and Infectious Diseases for prevention of peanut allergy in the United States3 are somewhat striking in that they make fairly bold recommendations based on results from the 2015 Learning Early about Peanut Allergy (LEAP) study,4 a randomized trial evaluating early peanut introduction as a preventive strategy for peanut allergy. Of note, this study was not placebo controlled, was conducted at only 1 site in the United Kingdom, and only included 640 children, though the number of participants was admittedly large for this type of study.4 Arguably, the LEAP study alone does not provide enough evidence upon which to base what essentially amounts to an about-face in the official recommendations for prevention of peanut and other food allergies, which emphasized delayed introduction of high-risk foods, especially in high-risk individuals.5-7 To better understand this shift, we need to briefly explore the context of the addendum guidelines.
As many as one-third of pediatric patients with atopic dermatitis (AD) have food allergies, thus diet often is invoked by patients and providers alike as an underlying cause of the disease.8 Many patients in my practice are so focused on potential food allergies that actual treatment of the affected skin is marginalized and often dismissed as a stopgap that does not address the root of the problem. A 2004 study of 100 children with AD found that diet was manipulated by the parents in 75% of patients in an attempt to manage the disease.9
Patients are not the only ones who consider food allergies to be a driving force in AD. The medical literature indicates that this theory has existed for centuries; for instance, with regard to the relationship between diet and AD, the author of an article from 1830 quipped, “There is probably no subject in which more deeply rooted convictions have been held . . . than the connection between diet and disease, both as regards the causation and treatment of the latter . . .”10 More apropos perhaps is a statement from the 2010 National Institute of Allergy and Infectious Diseases guidelines on food allergy management, which noted that while the expert group “does not mean to imply that AD results from [food allergies], the role of [food allergies] in the pathogenesis and severity of this condition remains controversial.”11
Prior to the LEAP study, food allergy recommendations for clinical practice in the United Kingdom in 199812 and the United States in 200013 recommended excluding allergenic foods (eg, peanuts, tree nuts, soy, milk, eggs) from the diet in infants with a family history of atopy until 3 years of age. However, those recommendations did not seem to be working, when in fact just the opposite was happening. From 1997 until the LEAP study was conducted in 2015, the prevalence of peanut allergy more than quadrupled and became the leading cause of anaphylaxis and death related to food allergy.14 Additionally, study after study concluded that elimination diets did not seem to help most patients with AD.15 As is required in good scientific thinking, when a hypothesis is proven false, other approaches must be considered.
The idea arose that perhaps delaying introduction of allergenic foods was the opposite of the answer.4 The LEAP study tested the notion that peanut allergies are rare in countries where peanuts are introduced early and if telling families to delay introduction of peanuts in infants might actually be causing development of a peanut allergy, and the tests bore fruit. It was found that giving infants peanut-containing foods resulted in a more than 80% reduction in peanut allergy at 5 years of age (P<.001).4 What was perhaps even more interesting was the connection between AD and peanut allergy. An important idea articulated in the LEAP study is in some ways revolutionary: Rather than foods causing AD, it could be that “early environmental exposure (through the skin) to peanut may account for early sensitization, whereas early oral exposure may lead to immune tolerance.”4 This concept—that impaired eczematous skin may actually lead to the development of food allergies—turns the whole thing upside down.
What do these updated guidelines actually suggest? The first guideline focuses on infants with severe AD, egg allergy, or both, who therefore are thought to be at the highest risk for developing peanut allergy.3 Because of the higher baseline risk in this subgroup, measurement of the peanut-specific IgE (peanut sIgE) level, skin prick testing (SPT), or both is strongly recommended before introducing peanut protein into the diet. This testing can be performed by qualified providers as a screening measure, but if positive (≥0.35 kUA/L for peanut sIgE or >2 mm on the peanut SPT), referral to an allergy specialist is warranted. If these studies are negative, it is thought the likelihood of peanut allergy is low, and it is recommended that caregivers introduce age-appropriate peanut-containing foods (eg, peanut butter snack puffs, diluted peanut butter) as early as 4 to 6 months of age. The second guideline recommends that peanut-containing foods should be introduced into the diets of infants with mild or moderate AD at approximately 6 months of age without the need for prior screening via peanut sIgE or SPT. Lastly, the third guideline recommends that caregivers freely introduce peanut-containing foods together with other solid foods in infants without AD or food allergies in accordance with family preference.3
The results of the LEAP study are certainly exciting, and although the theoretical basis makes good scientific sense and the updated guidelines truly address an important and growing problem, there are several issues with this update that are worth considering. Given the constraints of the LEAP study, it certainly seems possible that the results will not be applicable to all populations or foods. More research is needed to ensure that this robust finding applies to other children and to explore the introduction of other allergenic foods, which the LEAP study investigators also emphasized.4
In fairness, the updated guidelines clearly state the quality of evidence of their recommendations and make it clear that expert opinion is playing a large role.3 For the first guideline regarding recommendations for those with severe AD and/or egg allergy, the quality of evidence is deemed moderate, while the contribution of expert opinion is listed as significant. For the second and third guidelines regarding recommendations for mild to moderate AD and those without AD, respectively, the quality of evidence is low and expert opinion is again listed as significant.3
Importantly, delineating severe AD from moderate disease—which is necessary because only severe AD warrants evaluation with peanut sIgE and/or SPT—can be difficult, as the distinction relies on a degree of subjectivity that may vary between specialists. Indeed, 2 publications suggest extending the definition of severe AD to include infants with early-onset AD (<3 months of age) and those with moderate AD not responding to treatment.16,17
Despite these reservations, the updated guidelines represent a breakthrough in understanding in an area truly in need of advancement. Although the evidence may not be exactly extraordinary, the context for these developments and our deeper understanding suggest that we do indeed live in extraordinary times.
- Encyclopaedia Galactica [television transcript]. Cosmos: A Personal Voyage. Public Broadcasting Service. December 14, 1980.
- Ezzo J, Bausell B, Moerman DE, et al. Reviewing the reviews: how strong is the evidence? how clear are the conclusions? Int J Technol Assess Health Care. 2001;17:457-466.
- Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases–sponsored expert panel.J Allergy Clin Immunol. 2017;139:29-44.
- Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372:803-813.
- Høst A, Koletzko B, Dreborg S, et al. Dietary products used in infants for treatment and prevention of food allergy. joint statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child. 1999;81:80-84.
- American Academy of Pediatrics. Committee on Nutrition. hypoallergenic infant formulas. Pediatrics. 2000;106(2, pt 1):346-349.
- Fiocchi A, Assa’ad A, Bahna S; Adverse Reactions to Foods Committee; American College of Allergy, Asthma and Immunology. Food allergy and the introduction of solid foods to infants: a consensus document. Ann Allergy Asthma Immunol. 2006;97:10-20.
- Thompson MM, Hanifin JM. Effective therapy of childhood atopic dermatitis allays food allergy concerns. J Am Acad Dermatol. 2005;53(2 suppl 2):S214-S219.
- Johnston GA, Bilbao RM, Graham-Brown RA. The use of dietary manipulation by parents of children with atopic dermatitis. Br J Dermatol. 2004;150:1186-1189.
- Mackenzie S. The inaugural address on the advantages to be derived from the study of dermatology. BMJ. 1830;1:193-197.
- Boyce JA, Assa’ad A, Burks AW, et al; NIAID-Sponsored Expert Panel. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126(6 suppl):S1-S58.
- Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment. Peanut Allergy. London, England: Department of Health; 1998.
- American Academy of Pediatrics Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics. 2000;106(2, pt 1):346-349.
- Gruchalla RS, Sampson HA. Preventing peanut allergy through early consumption—ready for prime time? N Engl J Med. 2015;372:875-877.
- Lim NR, Lohman ME, Lio PA. The role of elimination diets in atopic dermatitis: a comprehensive review. Pediatr Dermatol. 2017;34:516-527.
- Wong CC, Allen KJ, Orchard D. Changes to infant feeding guidelines: relevance to dermatologists. Australas J Dermatol. 2017;58:e171-e175.
- Martin PE, Eckert JK, Koplin JJ, et al. Which infants with eczema are at risk of food allergy? results from a population-based cohort. Clin Exp Allergy. 2015;45:255-264.
- Encyclopaedia Galactica [television transcript]. Cosmos: A Personal Voyage. Public Broadcasting Service. December 14, 1980.
- Ezzo J, Bausell B, Moerman DE, et al. Reviewing the reviews: how strong is the evidence? how clear are the conclusions? Int J Technol Assess Health Care. 2001;17:457-466.
- Togias A, Cooper SF, Acebal ML, et al. Addendum guidelines for the prevention of peanut allergy in the United States: report of the National Institute of Allergy and Infectious Diseases–sponsored expert panel.J Allergy Clin Immunol. 2017;139:29-44.
- Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372:803-813.
- Høst A, Koletzko B, Dreborg S, et al. Dietary products used in infants for treatment and prevention of food allergy. joint statement of the European Society for Paediatric Allergology and Clinical Immunology (ESPACI) Committee on Hypoallergenic Formulas and the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Committee on Nutrition. Arch Dis Child. 1999;81:80-84.
- American Academy of Pediatrics. Committee on Nutrition. hypoallergenic infant formulas. Pediatrics. 2000;106(2, pt 1):346-349.
- Fiocchi A, Assa’ad A, Bahna S; Adverse Reactions to Foods Committee; American College of Allergy, Asthma and Immunology. Food allergy and the introduction of solid foods to infants: a consensus document. Ann Allergy Asthma Immunol. 2006;97:10-20.
- Thompson MM, Hanifin JM. Effective therapy of childhood atopic dermatitis allays food allergy concerns. J Am Acad Dermatol. 2005;53(2 suppl 2):S214-S219.
- Johnston GA, Bilbao RM, Graham-Brown RA. The use of dietary manipulation by parents of children with atopic dermatitis. Br J Dermatol. 2004;150:1186-1189.
- Mackenzie S. The inaugural address on the advantages to be derived from the study of dermatology. BMJ. 1830;1:193-197.
- Boyce JA, Assa’ad A, Burks AW, et al; NIAID-Sponsored Expert Panel. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126(6 suppl):S1-S58.
- Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment. Peanut Allergy. London, England: Department of Health; 1998.
- American Academy of Pediatrics Committee on Nutrition. Hypoallergenic infant formulas. Pediatrics. 2000;106(2, pt 1):346-349.
- Gruchalla RS, Sampson HA. Preventing peanut allergy through early consumption—ready for prime time? N Engl J Med. 2015;372:875-877.
- Lim NR, Lohman ME, Lio PA. The role of elimination diets in atopic dermatitis: a comprehensive review. Pediatr Dermatol. 2017;34:516-527.
- Wong CC, Allen KJ, Orchard D. Changes to infant feeding guidelines: relevance to dermatologists. Australas J Dermatol. 2017;58:e171-e175.
- Martin PE, Eckert JK, Koplin JJ, et al. Which infants with eczema are at risk of food allergy? results from a population-based cohort. Clin Exp Allergy. 2015;45:255-264.
Identification of Cutaneous Warts: Cryotherapy-Induced Acetowhitelike Epithelium
To the Editor:
Cutaneous warts are benign proliferations of the epidermis that occur secondary to human papillomavirus (HPV) infection. The diagnosis of cutaneous warts is generally based on clinical appearance. Occasionally subtle lesions, particularly those of verruca plana, escape clinical identification leading to incomplete treatment and spreading. The acetic acid test (sometimes called the acetic acid visual inspection) causes epithelial whitening of HPV-infected areas after application of a 3% to 5% aqueous solution of acetic acid and has been used to detect subclinical HPV infection.1 Although the acetic acid test can support the diagnosis of cutaneous warts, it is more effective at detecting hyperplastic rather than flat warts and may be cumbersome to use routinely.2 We describe a simple clinical maneuver to help confirm the presence of subtle warts using gentle liquid nitrogen cryotherapy to induce epithelial whitening in areas of HPV infection.
A 22-year-old man presented for evaluation of a 5-mm verrucous papule on the right wrist. He was diagnosed with verruca vulgaris. During treatment, small satellite verrucous papules were visualized by differential whitening from the surrounding uninfected skin (Figure). A brief light spray of liquid nitrogen cryotherapy (-196°C) was applied over areas containing suspicious lesions for confirmation. This acetowhitelike change from indirect collateral cryotherapy allowed for identification and treatment of these subtle warts.
Cutaneous warts represent foci of epithelial proliferation, and acetowhite changes are thought to occur from extravasation of intracellular water with subsequent tissue whitening in areas of high nuclear density.3 Acetowhite epithelium also has been reported after other ablative wart therapies.4 Similarly, acetowhitelike changes after cryotherapy may be secondary to cellular dehydration from ice crystal formation,5 with HPV-infected areas demonstrating increased susceptibility to freezing because of increased cellular water content in areas of hyperkeratosis. In addition, it has been demonstrated that cryotherapy alters the composition of the epithelium by destroying neutral and acidic mucopolysaccharides, which may subsequently induce the characteristic acetowhitelike changes in the epithelium of cutaneous warts.6
We propose that gentle painless sprays of liquid nitrogen to areas with suspicious lesions can help confirm the presence of subtle warts through cryotherapy-induced epithelial whitening. Although this test is a valuable diagnostic pearl, it should be noted that cryotherapy may accentuate an area of hyperkeratosis from causes other than an HPV infection. As such, clinical judgment is required.
1. Allan BM. Acetowhite epithelium. Gynecol Oncol. 2004;95:691-694.
2. Kumar B, Gupta S. The acetowhite test in genital human papillomavirus infection in men: what does it add? J Eur Acad Dermatol Venereol. 2001;15:27-29.
3. O’Connor DM. A tissue basis for colposcopic findings. Obstet Gynecol Clin North Am. 2008;35:565-582.
4. MacLean AB. Healing of the cervical epithelium after laser treatment of cervical intraepithelial neoplasia. Br J Obstet Gynaecol. 1984;91:697-706.
5. Gage AA, Baust J. Mechanisms of tissue injury in cryosurgery. Cryobiology. 1998;37:171-186.
6. Ciecierski L. Histochemical studies on acid and neutral mucopolysaccharides in the acanthotic epidermis of warts before and after cryotherapy with liquid nitrogen. Przegl Dermatol. 1970;57:11-15.
To the Editor:
Cutaneous warts are benign proliferations of the epidermis that occur secondary to human papillomavirus (HPV) infection. The diagnosis of cutaneous warts is generally based on clinical appearance. Occasionally subtle lesions, particularly those of verruca plana, escape clinical identification leading to incomplete treatment and spreading. The acetic acid test (sometimes called the acetic acid visual inspection) causes epithelial whitening of HPV-infected areas after application of a 3% to 5% aqueous solution of acetic acid and has been used to detect subclinical HPV infection.1 Although the acetic acid test can support the diagnosis of cutaneous warts, it is more effective at detecting hyperplastic rather than flat warts and may be cumbersome to use routinely.2 We describe a simple clinical maneuver to help confirm the presence of subtle warts using gentle liquid nitrogen cryotherapy to induce epithelial whitening in areas of HPV infection.
A 22-year-old man presented for evaluation of a 5-mm verrucous papule on the right wrist. He was diagnosed with verruca vulgaris. During treatment, small satellite verrucous papules were visualized by differential whitening from the surrounding uninfected skin (Figure). A brief light spray of liquid nitrogen cryotherapy (-196°C) was applied over areas containing suspicious lesions for confirmation. This acetowhitelike change from indirect collateral cryotherapy allowed for identification and treatment of these subtle warts.
Cutaneous warts represent foci of epithelial proliferation, and acetowhite changes are thought to occur from extravasation of intracellular water with subsequent tissue whitening in areas of high nuclear density.3 Acetowhite epithelium also has been reported after other ablative wart therapies.4 Similarly, acetowhitelike changes after cryotherapy may be secondary to cellular dehydration from ice crystal formation,5 with HPV-infected areas demonstrating increased susceptibility to freezing because of increased cellular water content in areas of hyperkeratosis. In addition, it has been demonstrated that cryotherapy alters the composition of the epithelium by destroying neutral and acidic mucopolysaccharides, which may subsequently induce the characteristic acetowhitelike changes in the epithelium of cutaneous warts.6
We propose that gentle painless sprays of liquid nitrogen to areas with suspicious lesions can help confirm the presence of subtle warts through cryotherapy-induced epithelial whitening. Although this test is a valuable diagnostic pearl, it should be noted that cryotherapy may accentuate an area of hyperkeratosis from causes other than an HPV infection. As such, clinical judgment is required.
To the Editor:
Cutaneous warts are benign proliferations of the epidermis that occur secondary to human papillomavirus (HPV) infection. The diagnosis of cutaneous warts is generally based on clinical appearance. Occasionally subtle lesions, particularly those of verruca plana, escape clinical identification leading to incomplete treatment and spreading. The acetic acid test (sometimes called the acetic acid visual inspection) causes epithelial whitening of HPV-infected areas after application of a 3% to 5% aqueous solution of acetic acid and has been used to detect subclinical HPV infection.1 Although the acetic acid test can support the diagnosis of cutaneous warts, it is more effective at detecting hyperplastic rather than flat warts and may be cumbersome to use routinely.2 We describe a simple clinical maneuver to help confirm the presence of subtle warts using gentle liquid nitrogen cryotherapy to induce epithelial whitening in areas of HPV infection.
A 22-year-old man presented for evaluation of a 5-mm verrucous papule on the right wrist. He was diagnosed with verruca vulgaris. During treatment, small satellite verrucous papules were visualized by differential whitening from the surrounding uninfected skin (Figure). A brief light spray of liquid nitrogen cryotherapy (-196°C) was applied over areas containing suspicious lesions for confirmation. This acetowhitelike change from indirect collateral cryotherapy allowed for identification and treatment of these subtle warts.
Cutaneous warts represent foci of epithelial proliferation, and acetowhite changes are thought to occur from extravasation of intracellular water with subsequent tissue whitening in areas of high nuclear density.3 Acetowhite epithelium also has been reported after other ablative wart therapies.4 Similarly, acetowhitelike changes after cryotherapy may be secondary to cellular dehydration from ice crystal formation,5 with HPV-infected areas demonstrating increased susceptibility to freezing because of increased cellular water content in areas of hyperkeratosis. In addition, it has been demonstrated that cryotherapy alters the composition of the epithelium by destroying neutral and acidic mucopolysaccharides, which may subsequently induce the characteristic acetowhitelike changes in the epithelium of cutaneous warts.6
We propose that gentle painless sprays of liquid nitrogen to areas with suspicious lesions can help confirm the presence of subtle warts through cryotherapy-induced epithelial whitening. Although this test is a valuable diagnostic pearl, it should be noted that cryotherapy may accentuate an area of hyperkeratosis from causes other than an HPV infection. As such, clinical judgment is required.
1. Allan BM. Acetowhite epithelium. Gynecol Oncol. 2004;95:691-694.
2. Kumar B, Gupta S. The acetowhite test in genital human papillomavirus infection in men: what does it add? J Eur Acad Dermatol Venereol. 2001;15:27-29.
3. O’Connor DM. A tissue basis for colposcopic findings. Obstet Gynecol Clin North Am. 2008;35:565-582.
4. MacLean AB. Healing of the cervical epithelium after laser treatment of cervical intraepithelial neoplasia. Br J Obstet Gynaecol. 1984;91:697-706.
5. Gage AA, Baust J. Mechanisms of tissue injury in cryosurgery. Cryobiology. 1998;37:171-186.
6. Ciecierski L. Histochemical studies on acid and neutral mucopolysaccharides in the acanthotic epidermis of warts before and after cryotherapy with liquid nitrogen. Przegl Dermatol. 1970;57:11-15.
1. Allan BM. Acetowhite epithelium. Gynecol Oncol. 2004;95:691-694.
2. Kumar B, Gupta S. The acetowhite test in genital human papillomavirus infection in men: what does it add? J Eur Acad Dermatol Venereol. 2001;15:27-29.
3. O’Connor DM. A tissue basis for colposcopic findings. Obstet Gynecol Clin North Am. 2008;35:565-582.
4. MacLean AB. Healing of the cervical epithelium after laser treatment of cervical intraepithelial neoplasia. Br J Obstet Gynaecol. 1984;91:697-706.
5. Gage AA, Baust J. Mechanisms of tissue injury in cryosurgery. Cryobiology. 1998;37:171-186.
6. Ciecierski L. Histochemical studies on acid and neutral mucopolysaccharides in the acanthotic epidermis of warts before and after cryotherapy with liquid nitrogen. Przegl Dermatol. 1970;57:11-15.
In-Office Diagnosis of Cutaneous Mycosis: A Comparison of Potassium Hydroxide, Swartz-Lamkins, and Chlorazol Black E Fungal Stains
Derm emergencies— detecting early signs of trouble
• Consider starting a course of systemic corticosteroids for a patient with erythroderma, fever, and multiorgan involvement when you strongly suspect a drug reaction is the cause—and have ruled out infection. C
• Suspect Stevens– Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in a patient with widespread and rapidly progressive desquamation, fever, hypotension, and end-organ involvement. C
• In assessing the severity of skin pain, consider the location; involvement of the eyes, perineum, and hands are associated with greater morbidity. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
The usual approach to dermatologic conditions—honed pattern recognition, a deliberate differential diagnosis, and empiric treatment with longer follow-up—runs counter to the response that dermatologic red flags require. Because patients with signs and symptoms associated with dermatologic emergencies have the potential for rapid clinical deterioration, urgent action is paramount.
With this in mind, we’ve focused on 4 red flags—erythroderma, desquamation, skin pain, and petechiae/purpura—as a starting point, rather than presenting a list of dermatologic emergencies and discussing each diagnosis in turn. The text, tables, and images on the pages that follow will increase your awareness of dermatologic presentations that require an immediate response and help you differentiate between signs and symptoms of serious skin disorders and benign findings that might be described as red flag mimics (TABLE 1).
TABLE 1
Conditions that mimic dermatologic emergencies
Red skin | |
Diagnosis | Key discriminating features |
Allergic contact dermatitis | Itchy, rather than painful |
Red man syndrome | History of vancomycin infusion |
Stasis dermatitis | Stasis dermatitis location (lower extremities), pruritus |
Sunburn | History, sun-exposed areas |
Desquamation | |
Diagnosis | Key discriminating features |
Bullous impetigo | Localized; no systemic manifestations |
Postinfectious desquamation | Subungual location common; occurs during convalescent phase of illness |
Petechiae and purpura | |
Diagnosis | Key discriminating features |
Local trauma | History and location |
Pigmented purpuric dermatosis | History and healthy appearance |
Viral exanthema | Healthy appearance |
Erythroderma: Red skin that’s life-threatening
From an etymological perspective, “erythroderma” simply means red skin. Clinically, however, it is defined as extensive erythema, typically covering ≥90% of the skin surface (FIGURE 1). True erythroderma can be life-threatening and must always be considered a dermatologic emergency.1,2
Diligent monitoring of the speed of progression and the presence of fever, systemic symptoms, and multiorgan dysfunction is essential. In a case review of 56 children who presented to an emergency department with fever and erythroderma, 45% progressed to shock.3 Some common causes of erythroderma are psoriasis; contact, atopic, and seborrheic dermatitis; pityriasis rubra pilaris; cutaneous T-cell lymphoma; drug reaction; and toxic shock syndrome (TSS).4
Is it a drug reaction? Erythroderma, fever, and evidence of multiorgan involvement in a patient taking any medication—not just a new one—prompts consideration of a drug reaction. Antiepileptics, dapsone, and sulfonamides are the most frequent offenders.5
DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) is characterized by fever, lymphadenopathy, elevated liver enzymes, and leukocytosis with eosinophilia, as well as erythroderma. The rash may be urticarial or morbilliform in appearance; petechiae, purpura, and blisters may be present, as well.
Because fever, leukocytosis, and transaminitis are also suggestive of an infectious etiology, DRESS syndrome is frequently overlooked. As a result, its true incidence is unknown. Estimates range from about one in 1000 to one in 10,000 drug exposures.6
In addition to discontinuing the medication, treatment for DRESS calls for systemic corticosteroids—which may actually be harmful when infection, rather than a drug reaction, is the cause. Thus, it is necessary to maintain a high index of suspicion and to thoroughly review the medication history of
any patient who presents with erythroderma and systemic symptoms.
When to suspect toxic shock syndrome. Consider TSS in any patient with erythroderma and hypotension, as well as laboratory evidence of end-organ involvement (including transaminitis, elevated creatinine, anemia, thrombocytopenia, and elevated creatinine kinase). Diagnostic criteria are detailed in FIGURE 2.7 Group A Streptococcus and Staphylococcus aureus are the classic infectious causes, but other bacteria have been implicated, as well. In most cases, the responsible bacterium is not known initially.
Because the toxins produced by these streptococcal and staphylococcal strains act as superantigens that fuel the immune response and worsen the shock, patients with a presumptive diagnosis of TSS should begin empiric treatment with an antimicrobial agent that inhibits toxin synthesis, such as clindamycin, immediately.8,9
FIGURE 1
Erythema covering the chest and arms
This patient was given a diagnosis of erythrodermic psoriasis.
FIGURE 2
Diagnostic criteria for toxic shock syndrome
ARDS, acute respiratory distress syndrome; BUN, blood urea nitrogen; CNS, central nervous system; CPK, creatinine phosphokinase; DIC, disseminated intravascular coagulation; GAS, group A Streptococcus; GI, gastrointestinal; RMSF, Rocky Mountain spotted fever.
Adapted from: Pickering LK, et al, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 2009.7
Desquamation/blistering: Act quickly when it’s widespread
Although desquamation can be seen in benign skin conditions, widespread desquamation with or without bullae requires careful evaluation and a rapid response. Separation, either at the dermal-epidermal junction or intraepidermally, raises the specter of 2 emergent conditions: the Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) spectrum and staphylococcal scalded skin syndrome (SSSS). Mucosal involvement is another red flag, if the patient appears ill and the desquamation is progressing rapidly. Conjunctival involvement, in particular, is associated with greater morbidity, and a consult with an ophthalmologist is prude
Rapid progression is a hallmark of SJS/TEN. Desquamation that’s widespread and rapidly progressive in a patient with fever, hypotension, and end-organ involvement is suggestive of SJS/TEN (FIGURE 3). Medications, including allopurinol, antimicrobials, and antiepileptics, are frequent culprits.10,11
Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been linked to SJS/TEN.10 Given their widespread use (1-2 per million users per week), however, the likelihood of NSAIDs leading to SJS/TEN is exceedingly low.12
Signs and symptoms of SJS/TEN may include target lesions with dusky centers, erythroderma, or significant pain without any visible skin abnormality, typically accompanied by fever and malaise. Widespread sloughing of the skin may be seen within several hours.11
Admission to an intensive care unit—preferably a burn unit—is suggested for aggressive fluid resuscitation and management of shock and end-organ dysfunction. Intravenous immunoglobulin G (IVIG) and steroids are often used, although there is little consensus as to the most effective treatment.13 Mortality from TEN approaches 50%.13
SSSS can present at any age. Newborns often present with SSSS during their first week of life: Widespread erythema is quickly followed by fragile blisters, which may have already ruptured by the time the infant receives medical attention. Mucosal surfaces are not typically involved. Nikolsky’s sign (separation of the upper epidermis with gentle pressure) is a classic finding.
Infants with SSSS are frequently irritable, suggesting that the skin may be painful. Cultures from unruptured bullae will be negative as the blisters represent a cutaneous reaction to an infection, rather than a skin infection, but blood, urine, and nasopharynx cultures may be positive. Systemic treatment with nafcillin or oxacillin should be initiated, and supportive skin care provided.14,15 Clindamycin or vancomycin should be used in parts of the country in which methicillin-resistant Staphylococcus aureus is prevalent. In very young infants, the outcome of SSSS is generally favorable. Not so with adults.
Because mature kidneys have a greater ability to excrete exfoliative toxins, SSSS primarily affects adults with significant comorbidities—and has a much poorer prognosis.16 You may also see chronic autoimmune bullous diseases, such as bullous pemphigoid and pemphigus vulgaris, with widespread desquamation and blistering, in the adult population. Untreated, the secondary infection and electrolyte disturbances from fluid loss associated with pemphigus vulgaris can be fatal.
Desquamation is a late finding in Kawasaki disease. Desquamation is often cited as a potential skin finding in children with Kawasaki disease (KD) (FIGURE 4), but usually not until the convalescent stage.17 (Desquamation may also appear during the recovery period of several other infections, including scarlet fever and TSS.) IVIG can prevent coronary aneurysm, the major complication of KD, but only if it is administered during the acute phase of the illness. Therefore, early diagnosis of KD (TABLE 2)18—before desquamation occurs—is critical.19
FIGURE 3
Desquamation, full-thickness epidermal necrosis on the upper back
Erythroderma and widespread denudation on the upper back of a patient who was given a diagnosis of toxic epidermal necrolysis.
FIGURE 4
Desquamation on a young patient
Desquamation associated with Kawasaki disease (shown on the hand of a child) usually occurs during the convalescent stage.
TABLE 2
Diagnostic criteria for Kawasaki disease
Fever for ≥5 days, and 4 out of 5 criteria (required): |
---|
|
Supporting findings: |
|
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate. Source: Kawasaki Disease Research Committee. Pediatr Int. 2005.18 |
Skin pain is always a red flag
Widespread skin pain should always be taken seriously, as it is rarely associated with minor dermatoses.20 Infectious cellulitis is the most likely diagnosis of a painful erythematous skin lesion. Patients with cellulitis do not usually have erythroderma, as the affected area tends to be very localized.
Cellulitis may be over- or undertreated. Once cellulitis has been diagnosed, the next thing to consider is severity. A recent retrospective study found that misclassification of skin and soft-tissue infections may result in both significant overtreatment of mild soft-tissue infections and dangerous undertreatment of severe infections, with consequent morbidity.21
Location is a key consideration, as cellulitis in certain locations—including the eye, perineum, and hand—carries an increased risk of morbidity. Orbital cellulitis—which may be characterized by proptosis, ophthalmoplegia, and pain with extraocular movements—most often results from initial sinusitis, and can lead to vision loss, intracranial infection, and significant invasive disease. Prompt antimicrobial therapy and urgent ophthalmologic consultation are essential, as operative drainage may be required.22,23
When the perineum is involved, a careful exam must be performed to determine the limits of the affected area. Although Fournier’s gangrene is uncommon, it is a life-threatening infection. In one small retrospective study, more than half of the patients presented with a perianal abscess.24
Similarly, the hand is vulnerable to significant infection, particularly if it is inoculated with bacteria from human mouth flora (the well-described “fight bite”). In a review of 100 cases of human fight bites, 18 patients ultimately required amputation.25
Early necrotizing fasciitis is often missed. Clinicians generally expect painful lesions to also have erythema, swelling, and increased warmth—the cardinal signs of inflammation. As a result, early necrotizing fasciitis, which initially presents with pain out of proportion to other dermatologic findings, may be overlooked. In fact, pain can precede significant skin findings by 24 to 48 hours; prior to that, only mild erythema or swelling (with minimal pain, in some cases) may be evident.26,27
The general pattern, however, is for a site with exquisite tenderness to evolve into a smooth, swollen area, then to develop dusky plaques and late-stage full thickness necrosis with hemorrhagic bullae.26 At that point, necrosis can render the skin insensate. Case reviews have found necrotizing fasciitis to be protean, with only 3 findings—erythema, edema, and tenderness beyond the expected lesion borders—present in most patients.27 Assiduous attention to skin pain in the presence of any other skin manifestation is the key to early diagnosis and rapid treatment.
Petechiae/purpura may be severe or benign
Petechiae are flat, pinpoint, nonblanching spots caused by intradermal hemorrhage associated with a wide variety of conditions, ranging from benign (local trauma) to severe (eg, disseminated intravascular coagulation [DIC] and sepsis). Similarly, purpura—larger lesions that may be palpable—can accompany less severe diseases, such as Henoch-Schönlein purpura (HSP), or life-threatening conditions like sepsis and DIC (FIGURE 5). Here, as in many other dermatologic conditions, the key differentiating features are location (local vs diffuse), speed of progression, and signs and symptoms of systemic illness.
FIGURE 5
Signs of a life-threatening condition
Hemorrhagic bullae with surrounding erythema on the lateral thigh of a patient with purpura fulminans from bacterial sepsis.
Localized petechiae are common with direct trauma, as well as barotrauma associated with coughing, vomiting, or even asphyxiation. Location is an important clue. Periorbital petechiae and petechiae on the chest above the nipple line suggest that the lesions were caused by the force of the barotrauma, rather than systemic disease.28 A careful history and physical exam are needed to rule out serious underlying conditions, such as pneumonia, dehydration, and abdominal obstruction.
Petechiae out of proportion to the force applied may be an indication of an underlying bleeding diathesis, including thrombocytopenia, coagulation defects, and some fulminant infections. Idiopathic thrombocytopenic purpura (ITP) and HSP may present with more widespread petechiae/purpura, but without fever or systemic symptoms. ITP can develop spontaneously, after a viral infection or after a child’s inoculation with the measles-mumps-rubella vaccine.29 ITP typically presents as easy bruising and petechiae out of proportion to the condition that caused it. These patients, as a rule, will have a healthy appearance.
Treatment (with steroids, IVIG, or anti-D immunoglobulin) is generally not required for children with ITP unless they have bleeding that is mucosal or substantial, as spontaneous remission is expected. Adults, who are more likely to develop chronic ITP, may benefit from treatment.30
HSP occurs most commonly in children, who may have palpable purpura, typically in the lower extremities, as well as arthritis or arthralgia, abdominal pain, and renal involvement that can progress from microscopic hematuria or proteinuria to renal insufficiency.31 Typically, children whose disease is in the acute phase do not appear to be sick, with an important exception: Those who develop hemorrhage and edema in the bowel wall, resulting in intussusception, have significant abdominal pain and are more likely to need surgical reduction.32
Diffuse petechiae in the absence of any trauma, accompanied by significant signs of systemic illness, may be an indication of fulminant infection, including meningococcemia, DIC, and Rocky Mountain spotted fever (RMSF). (Fever and diffuse petechiae can also be seen in viral exanthema, but patients usually look well and the rash often has both blanching and petechial components.33)
When a returning traveler presents with a rash and systemic symptoms, it is important to take a thorough history and to consider infections endemic to the area visited. RMSF may initially be localized to the wrists and progress to widespread petechiae over hours to days. Because the cutaneous findings may not be as fulminant—and up to 10% of patients with RMSF have no rash at all34—attention to the noncutaneous features is important. Fever, headache, neurologic symptoms, joint complaints, and abdominal pain (or only a few of these manifestations) in the context of potential tick bite exposure should prompt consideration of RMSF.35
Keep in mind, too, that in cases of fulminant infections such as meningococcemia and DIC, the hallmark purpura fulminans may not be present initially.36 Although the initial cutaneous findings may be subtle, however, such patients will appear quite ill, and their condition will deteriorate rapidly. Because prompt antibiotic therapy can save life and limb, a high index of suspicion should be maintained for any patient who presents with a rash in the setting of fever and hypotension or other evidence of shock.
1. Botella-Estrada R, Sanmartin O, Oliver V, et al. Erythroderma. A clinicopathological study of 56 cases. Arch Dermatol. 1994;130:1503-1507.
2. King LE, Jr, Dufresne RG, Jr, Lovett GL, et al. Erythroderma: review of 82 cases. South Med J. 1986;79:1210-1215.
3. Byer RL, Bachur RG. Clinical deterioration among patients with fever and erythroderma. Pediatrics. 2006;118:2450-2460.
4. Yuan XY, Guo JY, Dang YP, et al. Erythroderma: a clinical-etiological study of 82 cases. Eur J Dermatol. 2010;20:373-377.
5. Walsh SA, Creamer D. Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking. Clin Exp Dermatol. 2010;36:6-11.
6. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124:588-597.
7. Pickering LK, Baker CJ, Kimberlin DW, et al. eds Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 2009.
8. Silversides JA, Lappin E, Ferguson AJ. Staphylococcal toxic shock syndrome: mechanisms and management. Curr Infect Dis Rep. 2011;12:392-400.
9. Lappin E, Ferguson AJ. Gram-positive toxic shock syndromes. Lancet Infect Dis. 2009;9:281-290.
10. Sanmarkan AD, Sori T, Thappa DM, et al. Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis over a period of 10 years. Indian J Dermatol. 2011;56:25-29.
11. Fritsch PO, Sidoroff A. Drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Am J Clin Dermatol. 2000;1:349-360.
12. Ward KE, Archambault R, Mersfelder TL. Severe adverse skin reactions to nonsteroidal antiinflammatory drugs: a review of the literature. Am J Health Syst Pharm. 2010;67:206-213.
13. Worswick S, Cotliar J. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of treatment options. Dermatol Ther. 2011;24:207-218.
14. Patel GK, Finlay AY. Staphylococcal scalded skin syndrome: diagnosis and management. Am J Clin Dermatol. 2003;4:165-175.
15. Berk DR, Bayliss SJ. MRSA, staphylococcal scalded skin syndrome, and other cutaneous bacterial emergencies. Pediatr Ann. 2010;39:627-633.
16. Dobson CM, King CM. Adult staphylococcal scalded skin syndrome: histological pitfalls and new diagnostic perspectives. Br J Dermatol. 2003;148:1068-1069.
17. Wang S, Best BM, Burns JC. Periungual desquamation in patients with Kawasaki disease. Pediatr Infect Dis J. 2009;28:538-539.
18. Kawasaki Disease Research Committee. Revision of diagnostic guidelines for Kawasaki disease (the 5th rev ed). Pediatr Int. 2005;47:232-234.
19. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2747-2771.
20. Lio PA. The many faces of cellulitis. Arch Dis Child Educ Pract Ed. 2009;94:50-54.
21. Koerner R, Johnson AP. Changes in the classification and management of skin and soft tissue infections. J Antimicrob Chemother. 2010;66:232-234.
22. Botting AM, McIntosh D, Mahadevan M. Paediatric pre- and post-septal periorbital infections are different diseases. A retrospective review of 262 cases. Int J Pediatr Otorhinolaryngol. 2008;72:377-383.
23. Liu IT, Kao SC, Wang AG, et al. Preseptal and orbital cellulitis: a 10-year review of hospitalized patients. J Chin Med Assoc. 2006;69:415-422.
24. Koukouras D, Kallidonis P, Panagoloulos C, et al. Fournier’s gangrene, a urologic and surgical emergency: presentation of a multi-institutional experience with 45 cases. Urol Int. 2011;86:167-172.
25. Mennen U, Howells CJ. Human fight-bite injuries of the hand. A study of 100 cases within 18 months. J Hand Surg Br. 1991;16:431-435.
26. Morgan MS. Diagnosis and management of necrotising fasciitis: a multiparametric approach. J Hosp Infect. 2010;75:249-257.
27. Sarani B, Strong M, Pascual J, et al. Necrotizing fasciitis: current concepts and review of the literature. J Am Coll Surg. 2009;208:279-288.
28. Baker RC, Seguin JH, Leslie N, Gilchrist MJ, Myers MG. Fever and petechiae in children. Pediatrics. 1989;84:1051-1055.
29. Mantadakis E, Farmaki E, Buchanan GR. Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management. J Pediatr. 2010;156:623-628.
30. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117:4190-4207.
31. Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, et al. Henoch-Schönlein purpura in adulthood and childhood: two different expressions of the same syndrome. Arthritis Rheum. 1997;40:859-864.
32. Choong CK, Beasley SW. Intra-abdominal manifestations of Henoch-Schönlein purpura. J Paediatr Child Health. 1998;34:405-409.
33. Klinkhammer MD, Colletti JE. Pediatric myth: fever and petechiae. CJEM. 2008;10:479-482.
34. Sexton DJ, Kaye KS. Rocky Mountain spotted fever. Med Clin North Am. 2002;86:351-360, vii-viii.
35. Elston DM. Tick bites and skin rashes. Curr Opin Infect Dis. 2010;23:132-138.
36. Milonovich LM. Meningococcemia: epidemiology, pathophysiology, and management. J Pediatr Health Care. 2007;21:75-80.
CORRESPONDENCE Stephen A. Martin, MD, EdM, Barre Family Health Center, 151 Worcester Road, Barre, MA 01005; stephen.martin@umassmemorial.org
• Consider starting a course of systemic corticosteroids for a patient with erythroderma, fever, and multiorgan involvement when you strongly suspect a drug reaction is the cause—and have ruled out infection. C
• Suspect Stevens– Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in a patient with widespread and rapidly progressive desquamation, fever, hypotension, and end-organ involvement. C
• In assessing the severity of skin pain, consider the location; involvement of the eyes, perineum, and hands are associated with greater morbidity. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
The usual approach to dermatologic conditions—honed pattern recognition, a deliberate differential diagnosis, and empiric treatment with longer follow-up—runs counter to the response that dermatologic red flags require. Because patients with signs and symptoms associated with dermatologic emergencies have the potential for rapid clinical deterioration, urgent action is paramount.
With this in mind, we’ve focused on 4 red flags—erythroderma, desquamation, skin pain, and petechiae/purpura—as a starting point, rather than presenting a list of dermatologic emergencies and discussing each diagnosis in turn. The text, tables, and images on the pages that follow will increase your awareness of dermatologic presentations that require an immediate response and help you differentiate between signs and symptoms of serious skin disorders and benign findings that might be described as red flag mimics (TABLE 1).
TABLE 1
Conditions that mimic dermatologic emergencies
Red skin | |
Diagnosis | Key discriminating features |
Allergic contact dermatitis | Itchy, rather than painful |
Red man syndrome | History of vancomycin infusion |
Stasis dermatitis | Stasis dermatitis location (lower extremities), pruritus |
Sunburn | History, sun-exposed areas |
Desquamation | |
Diagnosis | Key discriminating features |
Bullous impetigo | Localized; no systemic manifestations |
Postinfectious desquamation | Subungual location common; occurs during convalescent phase of illness |
Petechiae and purpura | |
Diagnosis | Key discriminating features |
Local trauma | History and location |
Pigmented purpuric dermatosis | History and healthy appearance |
Viral exanthema | Healthy appearance |
Erythroderma: Red skin that’s life-threatening
From an etymological perspective, “erythroderma” simply means red skin. Clinically, however, it is defined as extensive erythema, typically covering ≥90% of the skin surface (FIGURE 1). True erythroderma can be life-threatening and must always be considered a dermatologic emergency.1,2
Diligent monitoring of the speed of progression and the presence of fever, systemic symptoms, and multiorgan dysfunction is essential. In a case review of 56 children who presented to an emergency department with fever and erythroderma, 45% progressed to shock.3 Some common causes of erythroderma are psoriasis; contact, atopic, and seborrheic dermatitis; pityriasis rubra pilaris; cutaneous T-cell lymphoma; drug reaction; and toxic shock syndrome (TSS).4
Is it a drug reaction? Erythroderma, fever, and evidence of multiorgan involvement in a patient taking any medication—not just a new one—prompts consideration of a drug reaction. Antiepileptics, dapsone, and sulfonamides are the most frequent offenders.5
DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) is characterized by fever, lymphadenopathy, elevated liver enzymes, and leukocytosis with eosinophilia, as well as erythroderma. The rash may be urticarial or morbilliform in appearance; petechiae, purpura, and blisters may be present, as well.
Because fever, leukocytosis, and transaminitis are also suggestive of an infectious etiology, DRESS syndrome is frequently overlooked. As a result, its true incidence is unknown. Estimates range from about one in 1000 to one in 10,000 drug exposures.6
In addition to discontinuing the medication, treatment for DRESS calls for systemic corticosteroids—which may actually be harmful when infection, rather than a drug reaction, is the cause. Thus, it is necessary to maintain a high index of suspicion and to thoroughly review the medication history of
any patient who presents with erythroderma and systemic symptoms.
When to suspect toxic shock syndrome. Consider TSS in any patient with erythroderma and hypotension, as well as laboratory evidence of end-organ involvement (including transaminitis, elevated creatinine, anemia, thrombocytopenia, and elevated creatinine kinase). Diagnostic criteria are detailed in FIGURE 2.7 Group A Streptococcus and Staphylococcus aureus are the classic infectious causes, but other bacteria have been implicated, as well. In most cases, the responsible bacterium is not known initially.
Because the toxins produced by these streptococcal and staphylococcal strains act as superantigens that fuel the immune response and worsen the shock, patients with a presumptive diagnosis of TSS should begin empiric treatment with an antimicrobial agent that inhibits toxin synthesis, such as clindamycin, immediately.8,9
FIGURE 1
Erythema covering the chest and arms
This patient was given a diagnosis of erythrodermic psoriasis.
FIGURE 2
Diagnostic criteria for toxic shock syndrome
ARDS, acute respiratory distress syndrome; BUN, blood urea nitrogen; CNS, central nervous system; CPK, creatinine phosphokinase; DIC, disseminated intravascular coagulation; GAS, group A Streptococcus; GI, gastrointestinal; RMSF, Rocky Mountain spotted fever.
Adapted from: Pickering LK, et al, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 2009.7
Desquamation/blistering: Act quickly when it’s widespread
Although desquamation can be seen in benign skin conditions, widespread desquamation with or without bullae requires careful evaluation and a rapid response. Separation, either at the dermal-epidermal junction or intraepidermally, raises the specter of 2 emergent conditions: the Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) spectrum and staphylococcal scalded skin syndrome (SSSS). Mucosal involvement is another red flag, if the patient appears ill and the desquamation is progressing rapidly. Conjunctival involvement, in particular, is associated with greater morbidity, and a consult with an ophthalmologist is prude
Rapid progression is a hallmark of SJS/TEN. Desquamation that’s widespread and rapidly progressive in a patient with fever, hypotension, and end-organ involvement is suggestive of SJS/TEN (FIGURE 3). Medications, including allopurinol, antimicrobials, and antiepileptics, are frequent culprits.10,11
Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been linked to SJS/TEN.10 Given their widespread use (1-2 per million users per week), however, the likelihood of NSAIDs leading to SJS/TEN is exceedingly low.12
Signs and symptoms of SJS/TEN may include target lesions with dusky centers, erythroderma, or significant pain without any visible skin abnormality, typically accompanied by fever and malaise. Widespread sloughing of the skin may be seen within several hours.11
Admission to an intensive care unit—preferably a burn unit—is suggested for aggressive fluid resuscitation and management of shock and end-organ dysfunction. Intravenous immunoglobulin G (IVIG) and steroids are often used, although there is little consensus as to the most effective treatment.13 Mortality from TEN approaches 50%.13
SSSS can present at any age. Newborns often present with SSSS during their first week of life: Widespread erythema is quickly followed by fragile blisters, which may have already ruptured by the time the infant receives medical attention. Mucosal surfaces are not typically involved. Nikolsky’s sign (separation of the upper epidermis with gentle pressure) is a classic finding.
Infants with SSSS are frequently irritable, suggesting that the skin may be painful. Cultures from unruptured bullae will be negative as the blisters represent a cutaneous reaction to an infection, rather than a skin infection, but blood, urine, and nasopharynx cultures may be positive. Systemic treatment with nafcillin or oxacillin should be initiated, and supportive skin care provided.14,15 Clindamycin or vancomycin should be used in parts of the country in which methicillin-resistant Staphylococcus aureus is prevalent. In very young infants, the outcome of SSSS is generally favorable. Not so with adults.
Because mature kidneys have a greater ability to excrete exfoliative toxins, SSSS primarily affects adults with significant comorbidities—and has a much poorer prognosis.16 You may also see chronic autoimmune bullous diseases, such as bullous pemphigoid and pemphigus vulgaris, with widespread desquamation and blistering, in the adult population. Untreated, the secondary infection and electrolyte disturbances from fluid loss associated with pemphigus vulgaris can be fatal.
Desquamation is a late finding in Kawasaki disease. Desquamation is often cited as a potential skin finding in children with Kawasaki disease (KD) (FIGURE 4), but usually not until the convalescent stage.17 (Desquamation may also appear during the recovery period of several other infections, including scarlet fever and TSS.) IVIG can prevent coronary aneurysm, the major complication of KD, but only if it is administered during the acute phase of the illness. Therefore, early diagnosis of KD (TABLE 2)18—before desquamation occurs—is critical.19
FIGURE 3
Desquamation, full-thickness epidermal necrosis on the upper back
Erythroderma and widespread denudation on the upper back of a patient who was given a diagnosis of toxic epidermal necrolysis.
FIGURE 4
Desquamation on a young patient
Desquamation associated with Kawasaki disease (shown on the hand of a child) usually occurs during the convalescent stage.
TABLE 2
Diagnostic criteria for Kawasaki disease
Fever for ≥5 days, and 4 out of 5 criteria (required): |
---|
|
Supporting findings: |
|
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate. Source: Kawasaki Disease Research Committee. Pediatr Int. 2005.18 |
Skin pain is always a red flag
Widespread skin pain should always be taken seriously, as it is rarely associated with minor dermatoses.20 Infectious cellulitis is the most likely diagnosis of a painful erythematous skin lesion. Patients with cellulitis do not usually have erythroderma, as the affected area tends to be very localized.
Cellulitis may be over- or undertreated. Once cellulitis has been diagnosed, the next thing to consider is severity. A recent retrospective study found that misclassification of skin and soft-tissue infections may result in both significant overtreatment of mild soft-tissue infections and dangerous undertreatment of severe infections, with consequent morbidity.21
Location is a key consideration, as cellulitis in certain locations—including the eye, perineum, and hand—carries an increased risk of morbidity. Orbital cellulitis—which may be characterized by proptosis, ophthalmoplegia, and pain with extraocular movements—most often results from initial sinusitis, and can lead to vision loss, intracranial infection, and significant invasive disease. Prompt antimicrobial therapy and urgent ophthalmologic consultation are essential, as operative drainage may be required.22,23
When the perineum is involved, a careful exam must be performed to determine the limits of the affected area. Although Fournier’s gangrene is uncommon, it is a life-threatening infection. In one small retrospective study, more than half of the patients presented with a perianal abscess.24
Similarly, the hand is vulnerable to significant infection, particularly if it is inoculated with bacteria from human mouth flora (the well-described “fight bite”). In a review of 100 cases of human fight bites, 18 patients ultimately required amputation.25
Early necrotizing fasciitis is often missed. Clinicians generally expect painful lesions to also have erythema, swelling, and increased warmth—the cardinal signs of inflammation. As a result, early necrotizing fasciitis, which initially presents with pain out of proportion to other dermatologic findings, may be overlooked. In fact, pain can precede significant skin findings by 24 to 48 hours; prior to that, only mild erythema or swelling (with minimal pain, in some cases) may be evident.26,27
The general pattern, however, is for a site with exquisite tenderness to evolve into a smooth, swollen area, then to develop dusky plaques and late-stage full thickness necrosis with hemorrhagic bullae.26 At that point, necrosis can render the skin insensate. Case reviews have found necrotizing fasciitis to be protean, with only 3 findings—erythema, edema, and tenderness beyond the expected lesion borders—present in most patients.27 Assiduous attention to skin pain in the presence of any other skin manifestation is the key to early diagnosis and rapid treatment.
Petechiae/purpura may be severe or benign
Petechiae are flat, pinpoint, nonblanching spots caused by intradermal hemorrhage associated with a wide variety of conditions, ranging from benign (local trauma) to severe (eg, disseminated intravascular coagulation [DIC] and sepsis). Similarly, purpura—larger lesions that may be palpable—can accompany less severe diseases, such as Henoch-Schönlein purpura (HSP), or life-threatening conditions like sepsis and DIC (FIGURE 5). Here, as in many other dermatologic conditions, the key differentiating features are location (local vs diffuse), speed of progression, and signs and symptoms of systemic illness.
FIGURE 5
Signs of a life-threatening condition
Hemorrhagic bullae with surrounding erythema on the lateral thigh of a patient with purpura fulminans from bacterial sepsis.
Localized petechiae are common with direct trauma, as well as barotrauma associated with coughing, vomiting, or even asphyxiation. Location is an important clue. Periorbital petechiae and petechiae on the chest above the nipple line suggest that the lesions were caused by the force of the barotrauma, rather than systemic disease.28 A careful history and physical exam are needed to rule out serious underlying conditions, such as pneumonia, dehydration, and abdominal obstruction.
Petechiae out of proportion to the force applied may be an indication of an underlying bleeding diathesis, including thrombocytopenia, coagulation defects, and some fulminant infections. Idiopathic thrombocytopenic purpura (ITP) and HSP may present with more widespread petechiae/purpura, but without fever or systemic symptoms. ITP can develop spontaneously, after a viral infection or after a child’s inoculation with the measles-mumps-rubella vaccine.29 ITP typically presents as easy bruising and petechiae out of proportion to the condition that caused it. These patients, as a rule, will have a healthy appearance.
Treatment (with steroids, IVIG, or anti-D immunoglobulin) is generally not required for children with ITP unless they have bleeding that is mucosal or substantial, as spontaneous remission is expected. Adults, who are more likely to develop chronic ITP, may benefit from treatment.30
HSP occurs most commonly in children, who may have palpable purpura, typically in the lower extremities, as well as arthritis or arthralgia, abdominal pain, and renal involvement that can progress from microscopic hematuria or proteinuria to renal insufficiency.31 Typically, children whose disease is in the acute phase do not appear to be sick, with an important exception: Those who develop hemorrhage and edema in the bowel wall, resulting in intussusception, have significant abdominal pain and are more likely to need surgical reduction.32
Diffuse petechiae in the absence of any trauma, accompanied by significant signs of systemic illness, may be an indication of fulminant infection, including meningococcemia, DIC, and Rocky Mountain spotted fever (RMSF). (Fever and diffuse petechiae can also be seen in viral exanthema, but patients usually look well and the rash often has both blanching and petechial components.33)
When a returning traveler presents with a rash and systemic symptoms, it is important to take a thorough history and to consider infections endemic to the area visited. RMSF may initially be localized to the wrists and progress to widespread petechiae over hours to days. Because the cutaneous findings may not be as fulminant—and up to 10% of patients with RMSF have no rash at all34—attention to the noncutaneous features is important. Fever, headache, neurologic symptoms, joint complaints, and abdominal pain (or only a few of these manifestations) in the context of potential tick bite exposure should prompt consideration of RMSF.35
Keep in mind, too, that in cases of fulminant infections such as meningococcemia and DIC, the hallmark purpura fulminans may not be present initially.36 Although the initial cutaneous findings may be subtle, however, such patients will appear quite ill, and their condition will deteriorate rapidly. Because prompt antibiotic therapy can save life and limb, a high index of suspicion should be maintained for any patient who presents with a rash in the setting of fever and hypotension or other evidence of shock.
• Consider starting a course of systemic corticosteroids for a patient with erythroderma, fever, and multiorgan involvement when you strongly suspect a drug reaction is the cause—and have ruled out infection. C
• Suspect Stevens– Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in a patient with widespread and rapidly progressive desquamation, fever, hypotension, and end-organ involvement. C
• In assessing the severity of skin pain, consider the location; involvement of the eyes, perineum, and hands are associated with greater morbidity. C
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
The usual approach to dermatologic conditions—honed pattern recognition, a deliberate differential diagnosis, and empiric treatment with longer follow-up—runs counter to the response that dermatologic red flags require. Because patients with signs and symptoms associated with dermatologic emergencies have the potential for rapid clinical deterioration, urgent action is paramount.
With this in mind, we’ve focused on 4 red flags—erythroderma, desquamation, skin pain, and petechiae/purpura—as a starting point, rather than presenting a list of dermatologic emergencies and discussing each diagnosis in turn. The text, tables, and images on the pages that follow will increase your awareness of dermatologic presentations that require an immediate response and help you differentiate between signs and symptoms of serious skin disorders and benign findings that might be described as red flag mimics (TABLE 1).
TABLE 1
Conditions that mimic dermatologic emergencies
Red skin | |
Diagnosis | Key discriminating features |
Allergic contact dermatitis | Itchy, rather than painful |
Red man syndrome | History of vancomycin infusion |
Stasis dermatitis | Stasis dermatitis location (lower extremities), pruritus |
Sunburn | History, sun-exposed areas |
Desquamation | |
Diagnosis | Key discriminating features |
Bullous impetigo | Localized; no systemic manifestations |
Postinfectious desquamation | Subungual location common; occurs during convalescent phase of illness |
Petechiae and purpura | |
Diagnosis | Key discriminating features |
Local trauma | History and location |
Pigmented purpuric dermatosis | History and healthy appearance |
Viral exanthema | Healthy appearance |
Erythroderma: Red skin that’s life-threatening
From an etymological perspective, “erythroderma” simply means red skin. Clinically, however, it is defined as extensive erythema, typically covering ≥90% of the skin surface (FIGURE 1). True erythroderma can be life-threatening and must always be considered a dermatologic emergency.1,2
Diligent monitoring of the speed of progression and the presence of fever, systemic symptoms, and multiorgan dysfunction is essential. In a case review of 56 children who presented to an emergency department with fever and erythroderma, 45% progressed to shock.3 Some common causes of erythroderma are psoriasis; contact, atopic, and seborrheic dermatitis; pityriasis rubra pilaris; cutaneous T-cell lymphoma; drug reaction; and toxic shock syndrome (TSS).4
Is it a drug reaction? Erythroderma, fever, and evidence of multiorgan involvement in a patient taking any medication—not just a new one—prompts consideration of a drug reaction. Antiepileptics, dapsone, and sulfonamides are the most frequent offenders.5
DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) is characterized by fever, lymphadenopathy, elevated liver enzymes, and leukocytosis with eosinophilia, as well as erythroderma. The rash may be urticarial or morbilliform in appearance; petechiae, purpura, and blisters may be present, as well.
Because fever, leukocytosis, and transaminitis are also suggestive of an infectious etiology, DRESS syndrome is frequently overlooked. As a result, its true incidence is unknown. Estimates range from about one in 1000 to one in 10,000 drug exposures.6
In addition to discontinuing the medication, treatment for DRESS calls for systemic corticosteroids—which may actually be harmful when infection, rather than a drug reaction, is the cause. Thus, it is necessary to maintain a high index of suspicion and to thoroughly review the medication history of
any patient who presents with erythroderma and systemic symptoms.
When to suspect toxic shock syndrome. Consider TSS in any patient with erythroderma and hypotension, as well as laboratory evidence of end-organ involvement (including transaminitis, elevated creatinine, anemia, thrombocytopenia, and elevated creatinine kinase). Diagnostic criteria are detailed in FIGURE 2.7 Group A Streptococcus and Staphylococcus aureus are the classic infectious causes, but other bacteria have been implicated, as well. In most cases, the responsible bacterium is not known initially.
Because the toxins produced by these streptococcal and staphylococcal strains act as superantigens that fuel the immune response and worsen the shock, patients with a presumptive diagnosis of TSS should begin empiric treatment with an antimicrobial agent that inhibits toxin synthesis, such as clindamycin, immediately.8,9
FIGURE 1
Erythema covering the chest and arms
This patient was given a diagnosis of erythrodermic psoriasis.
FIGURE 2
Diagnostic criteria for toxic shock syndrome
ARDS, acute respiratory distress syndrome; BUN, blood urea nitrogen; CNS, central nervous system; CPK, creatinine phosphokinase; DIC, disseminated intravascular coagulation; GAS, group A Streptococcus; GI, gastrointestinal; RMSF, Rocky Mountain spotted fever.
Adapted from: Pickering LK, et al, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 2009.7
Desquamation/blistering: Act quickly when it’s widespread
Although desquamation can be seen in benign skin conditions, widespread desquamation with or without bullae requires careful evaluation and a rapid response. Separation, either at the dermal-epidermal junction or intraepidermally, raises the specter of 2 emergent conditions: the Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) spectrum and staphylococcal scalded skin syndrome (SSSS). Mucosal involvement is another red flag, if the patient appears ill and the desquamation is progressing rapidly. Conjunctival involvement, in particular, is associated with greater morbidity, and a consult with an ophthalmologist is prude
Rapid progression is a hallmark of SJS/TEN. Desquamation that’s widespread and rapidly progressive in a patient with fever, hypotension, and end-organ involvement is suggestive of SJS/TEN (FIGURE 3). Medications, including allopurinol, antimicrobials, and antiepileptics, are frequent culprits.10,11
Nonsteroidal anti-inflammatory drugs (NSAIDs) have also been linked to SJS/TEN.10 Given their widespread use (1-2 per million users per week), however, the likelihood of NSAIDs leading to SJS/TEN is exceedingly low.12
Signs and symptoms of SJS/TEN may include target lesions with dusky centers, erythroderma, or significant pain without any visible skin abnormality, typically accompanied by fever and malaise. Widespread sloughing of the skin may be seen within several hours.11
Admission to an intensive care unit—preferably a burn unit—is suggested for aggressive fluid resuscitation and management of shock and end-organ dysfunction. Intravenous immunoglobulin G (IVIG) and steroids are often used, although there is little consensus as to the most effective treatment.13 Mortality from TEN approaches 50%.13
SSSS can present at any age. Newborns often present with SSSS during their first week of life: Widespread erythema is quickly followed by fragile blisters, which may have already ruptured by the time the infant receives medical attention. Mucosal surfaces are not typically involved. Nikolsky’s sign (separation of the upper epidermis with gentle pressure) is a classic finding.
Infants with SSSS are frequently irritable, suggesting that the skin may be painful. Cultures from unruptured bullae will be negative as the blisters represent a cutaneous reaction to an infection, rather than a skin infection, but blood, urine, and nasopharynx cultures may be positive. Systemic treatment with nafcillin or oxacillin should be initiated, and supportive skin care provided.14,15 Clindamycin or vancomycin should be used in parts of the country in which methicillin-resistant Staphylococcus aureus is prevalent. In very young infants, the outcome of SSSS is generally favorable. Not so with adults.
Because mature kidneys have a greater ability to excrete exfoliative toxins, SSSS primarily affects adults with significant comorbidities—and has a much poorer prognosis.16 You may also see chronic autoimmune bullous diseases, such as bullous pemphigoid and pemphigus vulgaris, with widespread desquamation and blistering, in the adult population. Untreated, the secondary infection and electrolyte disturbances from fluid loss associated with pemphigus vulgaris can be fatal.
Desquamation is a late finding in Kawasaki disease. Desquamation is often cited as a potential skin finding in children with Kawasaki disease (KD) (FIGURE 4), but usually not until the convalescent stage.17 (Desquamation may also appear during the recovery period of several other infections, including scarlet fever and TSS.) IVIG can prevent coronary aneurysm, the major complication of KD, but only if it is administered during the acute phase of the illness. Therefore, early diagnosis of KD (TABLE 2)18—before desquamation occurs—is critical.19
FIGURE 3
Desquamation, full-thickness epidermal necrosis on the upper back
Erythroderma and widespread denudation on the upper back of a patient who was given a diagnosis of toxic epidermal necrolysis.
FIGURE 4
Desquamation on a young patient
Desquamation associated with Kawasaki disease (shown on the hand of a child) usually occurs during the convalescent stage.
TABLE 2
Diagnostic criteria for Kawasaki disease
Fever for ≥5 days, and 4 out of 5 criteria (required): |
---|
|
Supporting findings: |
|
CRP, C-reactive protein; ESR, erythrocyte sedimentation rate. Source: Kawasaki Disease Research Committee. Pediatr Int. 2005.18 |
Skin pain is always a red flag
Widespread skin pain should always be taken seriously, as it is rarely associated with minor dermatoses.20 Infectious cellulitis is the most likely diagnosis of a painful erythematous skin lesion. Patients with cellulitis do not usually have erythroderma, as the affected area tends to be very localized.
Cellulitis may be over- or undertreated. Once cellulitis has been diagnosed, the next thing to consider is severity. A recent retrospective study found that misclassification of skin and soft-tissue infections may result in both significant overtreatment of mild soft-tissue infections and dangerous undertreatment of severe infections, with consequent morbidity.21
Location is a key consideration, as cellulitis in certain locations—including the eye, perineum, and hand—carries an increased risk of morbidity. Orbital cellulitis—which may be characterized by proptosis, ophthalmoplegia, and pain with extraocular movements—most often results from initial sinusitis, and can lead to vision loss, intracranial infection, and significant invasive disease. Prompt antimicrobial therapy and urgent ophthalmologic consultation are essential, as operative drainage may be required.22,23
When the perineum is involved, a careful exam must be performed to determine the limits of the affected area. Although Fournier’s gangrene is uncommon, it is a life-threatening infection. In one small retrospective study, more than half of the patients presented with a perianal abscess.24
Similarly, the hand is vulnerable to significant infection, particularly if it is inoculated with bacteria from human mouth flora (the well-described “fight bite”). In a review of 100 cases of human fight bites, 18 patients ultimately required amputation.25
Early necrotizing fasciitis is often missed. Clinicians generally expect painful lesions to also have erythema, swelling, and increased warmth—the cardinal signs of inflammation. As a result, early necrotizing fasciitis, which initially presents with pain out of proportion to other dermatologic findings, may be overlooked. In fact, pain can precede significant skin findings by 24 to 48 hours; prior to that, only mild erythema or swelling (with minimal pain, in some cases) may be evident.26,27
The general pattern, however, is for a site with exquisite tenderness to evolve into a smooth, swollen area, then to develop dusky plaques and late-stage full thickness necrosis with hemorrhagic bullae.26 At that point, necrosis can render the skin insensate. Case reviews have found necrotizing fasciitis to be protean, with only 3 findings—erythema, edema, and tenderness beyond the expected lesion borders—present in most patients.27 Assiduous attention to skin pain in the presence of any other skin manifestation is the key to early diagnosis and rapid treatment.
Petechiae/purpura may be severe or benign
Petechiae are flat, pinpoint, nonblanching spots caused by intradermal hemorrhage associated with a wide variety of conditions, ranging from benign (local trauma) to severe (eg, disseminated intravascular coagulation [DIC] and sepsis). Similarly, purpura—larger lesions that may be palpable—can accompany less severe diseases, such as Henoch-Schönlein purpura (HSP), or life-threatening conditions like sepsis and DIC (FIGURE 5). Here, as in many other dermatologic conditions, the key differentiating features are location (local vs diffuse), speed of progression, and signs and symptoms of systemic illness.
FIGURE 5
Signs of a life-threatening condition
Hemorrhagic bullae with surrounding erythema on the lateral thigh of a patient with purpura fulminans from bacterial sepsis.
Localized petechiae are common with direct trauma, as well as barotrauma associated with coughing, vomiting, or even asphyxiation. Location is an important clue. Periorbital petechiae and petechiae on the chest above the nipple line suggest that the lesions were caused by the force of the barotrauma, rather than systemic disease.28 A careful history and physical exam are needed to rule out serious underlying conditions, such as pneumonia, dehydration, and abdominal obstruction.
Petechiae out of proportion to the force applied may be an indication of an underlying bleeding diathesis, including thrombocytopenia, coagulation defects, and some fulminant infections. Idiopathic thrombocytopenic purpura (ITP) and HSP may present with more widespread petechiae/purpura, but without fever or systemic symptoms. ITP can develop spontaneously, after a viral infection or after a child’s inoculation with the measles-mumps-rubella vaccine.29 ITP typically presents as easy bruising and petechiae out of proportion to the condition that caused it. These patients, as a rule, will have a healthy appearance.
Treatment (with steroids, IVIG, or anti-D immunoglobulin) is generally not required for children with ITP unless they have bleeding that is mucosal or substantial, as spontaneous remission is expected. Adults, who are more likely to develop chronic ITP, may benefit from treatment.30
HSP occurs most commonly in children, who may have palpable purpura, typically in the lower extremities, as well as arthritis or arthralgia, abdominal pain, and renal involvement that can progress from microscopic hematuria or proteinuria to renal insufficiency.31 Typically, children whose disease is in the acute phase do not appear to be sick, with an important exception: Those who develop hemorrhage and edema in the bowel wall, resulting in intussusception, have significant abdominal pain and are more likely to need surgical reduction.32
Diffuse petechiae in the absence of any trauma, accompanied by significant signs of systemic illness, may be an indication of fulminant infection, including meningococcemia, DIC, and Rocky Mountain spotted fever (RMSF). (Fever and diffuse petechiae can also be seen in viral exanthema, but patients usually look well and the rash often has both blanching and petechial components.33)
When a returning traveler presents with a rash and systemic symptoms, it is important to take a thorough history and to consider infections endemic to the area visited. RMSF may initially be localized to the wrists and progress to widespread petechiae over hours to days. Because the cutaneous findings may not be as fulminant—and up to 10% of patients with RMSF have no rash at all34—attention to the noncutaneous features is important. Fever, headache, neurologic symptoms, joint complaints, and abdominal pain (or only a few of these manifestations) in the context of potential tick bite exposure should prompt consideration of RMSF.35
Keep in mind, too, that in cases of fulminant infections such as meningococcemia and DIC, the hallmark purpura fulminans may not be present initially.36 Although the initial cutaneous findings may be subtle, however, such patients will appear quite ill, and their condition will deteriorate rapidly. Because prompt antibiotic therapy can save life and limb, a high index of suspicion should be maintained for any patient who presents with a rash in the setting of fever and hypotension or other evidence of shock.
1. Botella-Estrada R, Sanmartin O, Oliver V, et al. Erythroderma. A clinicopathological study of 56 cases. Arch Dermatol. 1994;130:1503-1507.
2. King LE, Jr, Dufresne RG, Jr, Lovett GL, et al. Erythroderma: review of 82 cases. South Med J. 1986;79:1210-1215.
3. Byer RL, Bachur RG. Clinical deterioration among patients with fever and erythroderma. Pediatrics. 2006;118:2450-2460.
4. Yuan XY, Guo JY, Dang YP, et al. Erythroderma: a clinical-etiological study of 82 cases. Eur J Dermatol. 2010;20:373-377.
5. Walsh SA, Creamer D. Drug reaction with eosinophilia and systemic symptoms (DRESS): a clinical update and review of current thinking. Clin Exp Dermatol. 2010;36:6-11.
6. Cacoub P, Musette P, Descamps V, et al. The DRESS syndrome: a literature review. Am J Med. 2011;124:588-597.
7. Pickering LK, Baker CJ, Kimberlin DW, et al. eds Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, Ill: American Academy of Pediatrics; 2009.
8. Silversides JA, Lappin E, Ferguson AJ. Staphylococcal toxic shock syndrome: mechanisms and management. Curr Infect Dis Rep. 2011;12:392-400.
9. Lappin E, Ferguson AJ. Gram-positive toxic shock syndromes. Lancet Infect Dis. 2009;9:281-290.
10. Sanmarkan AD, Sori T, Thappa DM, et al. Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis over a period of 10 years. Indian J Dermatol. 2011;56:25-29.
11. Fritsch PO, Sidoroff A. Drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Am J Clin Dermatol. 2000;1:349-360.
12. Ward KE, Archambault R, Mersfelder TL. Severe adverse skin reactions to nonsteroidal antiinflammatory drugs: a review of the literature. Am J Health Syst Pharm. 2010;67:206-213.
13. Worswick S, Cotliar J. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of treatment options. Dermatol Ther. 2011;24:207-218.
14. Patel GK, Finlay AY. Staphylococcal scalded skin syndrome: diagnosis and management. Am J Clin Dermatol. 2003;4:165-175.
15. Berk DR, Bayliss SJ. MRSA, staphylococcal scalded skin syndrome, and other cutaneous bacterial emergencies. Pediatr Ann. 2010;39:627-633.
16. Dobson CM, King CM. Adult staphylococcal scalded skin syndrome: histological pitfalls and new diagnostic perspectives. Br J Dermatol. 2003;148:1068-1069.
17. Wang S, Best BM, Burns JC. Periungual desquamation in patients with Kawasaki disease. Pediatr Infect Dis J. 2009;28:538-539.
18. Kawasaki Disease Research Committee. Revision of diagnostic guidelines for Kawasaki disease (the 5th rev ed). Pediatr Int. 2005;47:232-234.
19. Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110:2747-2771.
20. Lio PA. The many faces of cellulitis. Arch Dis Child Educ Pract Ed. 2009;94:50-54.
21. Koerner R, Johnson AP. Changes in the classification and management of skin and soft tissue infections. J Antimicrob Chemother. 2010;66:232-234.
22. Botting AM, McIntosh D, Mahadevan M. Paediatric pre- and post-septal periorbital infections are different diseases. A retrospective review of 262 cases. Int J Pediatr Otorhinolaryngol. 2008;72:377-383.
23. Liu IT, Kao SC, Wang AG, et al. Preseptal and orbital cellulitis: a 10-year review of hospitalized patients. J Chin Med Assoc. 2006;69:415-422.
24. Koukouras D, Kallidonis P, Panagoloulos C, et al. Fournier’s gangrene, a urologic and surgical emergency: presentation of a multi-institutional experience with 45 cases. Urol Int. 2011;86:167-172.
25. Mennen U, Howells CJ. Human fight-bite injuries of the hand. A study of 100 cases within 18 months. J Hand Surg Br. 1991;16:431-435.
26. Morgan MS. Diagnosis and management of necrotising fasciitis: a multiparametric approach. J Hosp Infect. 2010;75:249-257.
27. Sarani B, Strong M, Pascual J, et al. Necrotizing fasciitis: current concepts and review of the literature. J Am Coll Surg. 2009;208:279-288.
28. Baker RC, Seguin JH, Leslie N, Gilchrist MJ, Myers MG. Fever and petechiae in children. Pediatrics. 1989;84:1051-1055.
29. Mantadakis E, Farmaki E, Buchanan GR. Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management. J Pediatr. 2010;156:623-628.
30. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117:4190-4207.
31. Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, et al. Henoch-Schönlein purpura in adulthood and childhood: two different expressions of the same syndrome. Arthritis Rheum. 1997;40:859-864.
32. Choong CK, Beasley SW. Intra-abdominal manifestations of Henoch-Schönlein purpura. J Paediatr Child Health. 1998;34:405-409.
33. Klinkhammer MD, Colletti JE. Pediatric myth: fever and petechiae. CJEM. 2008;10:479-482.
34. Sexton DJ, Kaye KS. Rocky Mountain spotted fever. Med Clin North Am. 2002;86:351-360, vii-viii.
35. Elston DM. Tick bites and skin rashes. Curr Opin Infect Dis. 2010;23:132-138.
36. Milonovich LM. Meningococcemia: epidemiology, pathophysiology, and management. J Pediatr Health Care. 2007;21:75-80.
CORRESPONDENCE Stephen A. Martin, MD, EdM, Barre Family Health Center, 151 Worcester Road, Barre, MA 01005; stephen.martin@umassmemorial.org
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24. Koukouras D, Kallidonis P, Panagoloulos C, et al. Fournier’s gangrene, a urologic and surgical emergency: presentation of a multi-institutional experience with 45 cases. Urol Int. 2011;86:167-172.
25. Mennen U, Howells CJ. Human fight-bite injuries of the hand. A study of 100 cases within 18 months. J Hand Surg Br. 1991;16:431-435.
26. Morgan MS. Diagnosis and management of necrotising fasciitis: a multiparametric approach. J Hosp Infect. 2010;75:249-257.
27. Sarani B, Strong M, Pascual J, et al. Necrotizing fasciitis: current concepts and review of the literature. J Am Coll Surg. 2009;208:279-288.
28. Baker RC, Seguin JH, Leslie N, Gilchrist MJ, Myers MG. Fever and petechiae in children. Pediatrics. 1989;84:1051-1055.
29. Mantadakis E, Farmaki E, Buchanan GR. Thrombocytopenic purpura after measles-mumps-rubella vaccination: a systematic review of the literature and guidance for management. J Pediatr. 2010;156:623-628.
30. Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117:4190-4207.
31. Blanco R, Martinez-Taboada VM, Rodriguez-Valverde V, et al. Henoch-Schönlein purpura in adulthood and childhood: two different expressions of the same syndrome. Arthritis Rheum. 1997;40:859-864.
32. Choong CK, Beasley SW. Intra-abdominal manifestations of Henoch-Schönlein purpura. J Paediatr Child Health. 1998;34:405-409.
33. Klinkhammer MD, Colletti JE. Pediatric myth: fever and petechiae. CJEM. 2008;10:479-482.
34. Sexton DJ, Kaye KS. Rocky Mountain spotted fever. Med Clin North Am. 2002;86:351-360, vii-viii.
35. Elston DM. Tick bites and skin rashes. Curr Opin Infect Dis. 2010;23:132-138.
36. Milonovich LM. Meningococcemia: epidemiology, pathophysiology, and management. J Pediatr Health Care. 2007;21:75-80.
CORRESPONDENCE Stephen A. Martin, MD, EdM, Barre Family Health Center, 151 Worcester Road, Barre, MA 01005; stephen.martin@umassmemorial.org