Urticaria

Photosensitivity due to doxycycline

As the patient’s rash presented in sun-exposed areas with both skin and nail changes, our patient was diagnosed with a phototoxic reaction to doxycycline, the oral antibiotic used to treat his acne.

Photosensitive cutaneous drug eruptions are reactions that occur after exposure to a medication and subsequent exposure to UV radiation or visible light. Reactions can be classified into two ways based on their mechanism of action: phototoxic or photoallergic.¹ Phototoxic reactions are more common and are a result of direct keratinocyte damage and cellular necrosis. Many classes of medications may cause this adverse effect, but the tetracycline class of antibiotics is a common culprit.² Photoallergic reactions are less common and are a result of a type IV immune reaction to the offending agent.¹

Courtesy Dr. Catalina Matiz

Phototoxic reactions generally present shortly after sun or UV exposure with a photo-distributed eruption pattern.³ Commonly involved areas include the face, the neck, and the extensor surfaces of extremities, with sparing of relatively protected skin such as the upper eyelids and the skin folds.² Erythema may initially develop in the exposed skin areas, followed by appearance of edema, vesicles, or bullae.^1-3 The eruption may be painful and itchy, with some patients reporting severe pain.³

Courtesy Dr. Catalina Matiz

Doxycycline phototoxicity may also cause onycholysis of the nails.² The reaction is dose dependent, with higher doses of medication leading to a higher likelihood of symptoms.^1,2 It is also more prevalent in patients with Fitzpatrick skin type I and II. The usual UVA wavelength required to induce this reaction appears to be in the 320-400 nm range of the UV spectrum.⁴ By contrast, photoallergic reactions are dose independent, and require a sensitization period prior to the eruption.¹ An eczematous eruption is most commonly seen with photoallergic reactions.³

Treatment of drug-induced photosensitivity reactions requires proper identification of the diagnosis and the offending agent, followed by cessation of the medication. If cessation is not possible, then lowering the dose can help to minimize worsening of the condition. However, for photoallergic reactions, the reaction is dose independent so switching to another tolerated agent is likely required. For persistent symptoms following medication withdrawal, topical or systemic steroids and oral antihistamine can help with symptom management.¹ For patients with photo-onycholysis, treatment involves stopping the medication and waiting for the intact nail plate to grow.

Courtesy Dr. Catalina Matiz

Dermatomyositis

Dermatomyositis is an autoimmune condition that presents with skin lesions as well as systemic findings such as myositis. The cutaneous findings are variable, but pathognomonic findings include Gottron papules of the hands, Gottron’s sign on the elbows, knees, and ankles, and the heliotrope rash of the face. Eighty percent of patients have myopathy presenting as muscle weakness, and commonly have elevated creatine kinase, aspartate transaminase, and alanine transaminase values.⁵ Diagnosis may be confirmed through skin or muscle biopsy, though antibody studies can also play a helpful role in diagnosis. Treatment is generally with oral corticosteroids or other immunosuppressants as well as sun protection.⁶ The rash seen in our patient could have been seen in patients with dermatomyositis, though it was not in the typical location on the knuckles (Gottron papules) as it also affected the lateral sides of the fingers.

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune condition characterized by systemic and cutaneous manifestations. Systemic symptoms may include weight loss, fever, fatigue, arthralgia, or arthritis; patients are at risk of renal, cardiovascular, pulmonary, and neurologic complications of SLE.⁷ The most common cutaneous finding is malar rash, though there are myriad dermatologic manifestations that can occur associated with photosensitivity. Diagnosis is made based on history, physical, and laboratory testing. Treatment options include NSAIDs, oral glucocorticoids, antimalarial drugs, and immunosuppressants.⁷ Though our patient exhibited photosensitivity, he had none of the systemic findings associated with SLE, making this diagnosis unlikely.

Allergic contact dermatitis

Allergic contact dermatitis (ACD) is a type IV hypersensitivity reaction, and may present as acute, subacute, or chronic dermatitis. The clinical findings vary based on chronicity. Acute ACD presents as pruritic erythematous papules and vesicles or bullae, similar to how it occurred in our patient, though our patient’s lesions were more tender than pruritic. Chronic ACD presents with erythematous lesions with pruritis, lichenification, scaling, and/or fissuring. Observing shapes or sharp demarcation of lesions may help with diagnosis. Patch testing is also useful in the diagnosis of ACD.

Treatment generally involves avoiding the offending agent with topical corticosteroids for symptom management.⁸

Polymorphous light eruption

Polymorphous light eruption (PLE) is a delayed, type IV hypersensitivity reaction to UV-induced antigens, though these antigens are unknown. PLE presents hours to days following solar or UV exposure and presents only in sun-exposed areas. Itching and burning are always present, but lesion morphology varies from erythema and papules to vesico-papules and blisters. Notably, PLE must be distinguished from drug photosensitivity through history. Treatment generally involves symptom management with topical steroids and sun protective measures for prevention.⁹ While PLE may present similarly to drug photosensitivity reactions, our patient’s use of a known phototoxic agent makes PLE a less likely diagnosis.

Ms. Appiah is a pediatric dermatology research associate and medical student at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. Neither Dr. Matiz nor Ms. Appiah has any relevant financial disclosures.

References

1. Montgomery S et al. Clin Dermatol. 2022;40(1):57-63.

2. Blakely KM et al. Drug Saf. 2019;42(7):827-47.

3. Goetze S et al. Skin Pharmacol Physiol. 2017;30(2):76-80.

4. Odorici G et al. Dermatol Ther. 2021;34(4):e14978.

5. DeWane ME et al. J Am Acad Dermatol. 2020;82(2):267-81.

6. Waldman R et al. J Am Acad Dermatol. 2020;82(2):283-96.

7. Kiriakidou M et al. Ann Intern Med. 2020;172(11):ITC81-ITC96.

8. Nassau S et al. Med Clin North Am. 2020;104(1):61-76.

9. Guarrera M. Adv Exp Med Biol. 2017;996:61-70.

Photosensitivity due to doxycycline

As the patient’s rash presented in sun-exposed areas with both skin and nail changes, our patient was diagnosed with a phototoxic reaction to doxycycline, the oral antibiotic used to treat his acne.

Photosensitive cutaneous drug eruptions are reactions that occur after exposure to a medication and subsequent exposure to UV radiation or visible light. Reactions can be classified into two ways based on their mechanism of action: phototoxic or photoallergic.¹ Phototoxic reactions are more common and are a result of direct keratinocyte damage and cellular necrosis. Many classes of medications may cause this adverse effect, but the tetracycline class of antibiotics is a common culprit.² Photoallergic reactions are less common and are a result of a type IV immune reaction to the offending agent.¹

Courtesy Dr. Catalina Matiz

Phototoxic reactions generally present shortly after sun or UV exposure with a photo-distributed eruption pattern.³ Commonly involved areas include the face, the neck, and the extensor surfaces of extremities, with sparing of relatively protected skin such as the upper eyelids and the skin folds.² Erythema may initially develop in the exposed skin areas, followed by appearance of edema, vesicles, or bullae.^1-3 The eruption may be painful and itchy, with some patients reporting severe pain.³

Courtesy Dr. Catalina Matiz

Doxycycline phototoxicity may also cause onycholysis of the nails.² The reaction is dose dependent, with higher doses of medication leading to a higher likelihood of symptoms.^1,2 It is also more prevalent in patients with Fitzpatrick skin type I and II. The usual UVA wavelength required to induce this reaction appears to be in the 320-400 nm range of the UV spectrum.⁴ By contrast, photoallergic reactions are dose independent, and require a sensitization period prior to the eruption.¹ An eczematous eruption is most commonly seen with photoallergic reactions.³

Treatment of drug-induced photosensitivity reactions requires proper identification of the diagnosis and the offending agent, followed by cessation of the medication. If cessation is not possible, then lowering the dose can help to minimize worsening of the condition. However, for photoallergic reactions, the reaction is dose independent so switching to another tolerated agent is likely required. For persistent symptoms following medication withdrawal, topical or systemic steroids and oral antihistamine can help with symptom management.¹ For patients with photo-onycholysis, treatment involves stopping the medication and waiting for the intact nail plate to grow.

Courtesy Dr. Catalina Matiz

Dermatomyositis

Dermatomyositis is an autoimmune condition that presents with skin lesions as well as systemic findings such as myositis. The cutaneous findings are variable, but pathognomonic findings include Gottron papules of the hands, Gottron’s sign on the elbows, knees, and ankles, and the heliotrope rash of the face. Eighty percent of patients have myopathy presenting as muscle weakness, and commonly have elevated creatine kinase, aspartate transaminase, and alanine transaminase values.⁵ Diagnosis may be confirmed through skin or muscle biopsy, though antibody studies can also play a helpful role in diagnosis. Treatment is generally with oral corticosteroids or other immunosuppressants as well as sun protection.⁶ The rash seen in our patient could have been seen in patients with dermatomyositis, though it was not in the typical location on the knuckles (Gottron papules) as it also affected the lateral sides of the fingers.

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune condition characterized by systemic and cutaneous manifestations. Systemic symptoms may include weight loss, fever, fatigue, arthralgia, or arthritis; patients are at risk of renal, cardiovascular, pulmonary, and neurologic complications of SLE.⁷ The most common cutaneous finding is malar rash, though there are myriad dermatologic manifestations that can occur associated with photosensitivity. Diagnosis is made based on history, physical, and laboratory testing. Treatment options include NSAIDs, oral glucocorticoids, antimalarial drugs, and immunosuppressants.⁷ Though our patient exhibited photosensitivity, he had none of the systemic findings associated with SLE, making this diagnosis unlikely.

Allergic contact dermatitis

Allergic contact dermatitis (ACD) is a type IV hypersensitivity reaction, and may present as acute, subacute, or chronic dermatitis. The clinical findings vary based on chronicity. Acute ACD presents as pruritic erythematous papules and vesicles or bullae, similar to how it occurred in our patient, though our patient’s lesions were more tender than pruritic. Chronic ACD presents with erythematous lesions with pruritis, lichenification, scaling, and/or fissuring. Observing shapes or sharp demarcation of lesions may help with diagnosis. Patch testing is also useful in the diagnosis of ACD.

Treatment generally involves avoiding the offending agent with topical corticosteroids for symptom management.⁸

Polymorphous light eruption

Polymorphous light eruption (PLE) is a delayed, type IV hypersensitivity reaction to UV-induced antigens, though these antigens are unknown. PLE presents hours to days following solar or UV exposure and presents only in sun-exposed areas. Itching and burning are always present, but lesion morphology varies from erythema and papules to vesico-papules and blisters. Notably, PLE must be distinguished from drug photosensitivity through history. Treatment generally involves symptom management with topical steroids and sun protective measures for prevention.⁹ While PLE may present similarly to drug photosensitivity reactions, our patient’s use of a known phototoxic agent makes PLE a less likely diagnosis.

Ms. Appiah is a pediatric dermatology research associate and medical student at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. Neither Dr. Matiz nor Ms. Appiah has any relevant financial disclosures.

References

1. Montgomery S et al. Clin Dermatol. 2022;40(1):57-63.

2. Blakely KM et al. Drug Saf. 2019;42(7):827-47.

3. Goetze S et al. Skin Pharmacol Physiol. 2017;30(2):76-80.

4. Odorici G et al. Dermatol Ther. 2021;34(4):e14978.

5. DeWane ME et al. J Am Acad Dermatol. 2020;82(2):267-81.

6. Waldman R et al. J Am Acad Dermatol. 2020;82(2):283-96.

7. Kiriakidou M et al. Ann Intern Med. 2020;172(11):ITC81-ITC96.

8. Nassau S et al. Med Clin North Am. 2020;104(1):61-76.

9. Guarrera M. Adv Exp Med Biol. 2017;996:61-70.

Photosensitivity due to doxycycline

As the patient’s rash presented in sun-exposed areas with both skin and nail changes, our patient was diagnosed with a phototoxic reaction to doxycycline, the oral antibiotic used to treat his acne.

Photosensitive cutaneous drug eruptions are reactions that occur after exposure to a medication and subsequent exposure to UV radiation or visible light. Reactions can be classified into two ways based on their mechanism of action: phototoxic or photoallergic.¹ Phototoxic reactions are more common and are a result of direct keratinocyte damage and cellular necrosis. Many classes of medications may cause this adverse effect, but the tetracycline class of antibiotics is a common culprit.² Photoallergic reactions are less common and are a result of a type IV immune reaction to the offending agent.¹

Courtesy Dr. Catalina Matiz

Phototoxic reactions generally present shortly after sun or UV exposure with a photo-distributed eruption pattern.³ Commonly involved areas include the face, the neck, and the extensor surfaces of extremities, with sparing of relatively protected skin such as the upper eyelids and the skin folds.² Erythema may initially develop in the exposed skin areas, followed by appearance of edema, vesicles, or bullae.^1-3 The eruption may be painful and itchy, with some patients reporting severe pain.³

Courtesy Dr. Catalina Matiz

Doxycycline phototoxicity may also cause onycholysis of the nails.² The reaction is dose dependent, with higher doses of medication leading to a higher likelihood of symptoms.^1,2 It is also more prevalent in patients with Fitzpatrick skin type I and II. The usual UVA wavelength required to induce this reaction appears to be in the 320-400 nm range of the UV spectrum.⁴ By contrast, photoallergic reactions are dose independent, and require a sensitization period prior to the eruption.¹ An eczematous eruption is most commonly seen with photoallergic reactions.³

Treatment of drug-induced photosensitivity reactions requires proper identification of the diagnosis and the offending agent, followed by cessation of the medication. If cessation is not possible, then lowering the dose can help to minimize worsening of the condition. However, for photoallergic reactions, the reaction is dose independent so switching to another tolerated agent is likely required. For persistent symptoms following medication withdrawal, topical or systemic steroids and oral antihistamine can help with symptom management.¹ For patients with photo-onycholysis, treatment involves stopping the medication and waiting for the intact nail plate to grow.

Courtesy Dr. Catalina Matiz

Dermatomyositis

Dermatomyositis is an autoimmune condition that presents with skin lesions as well as systemic findings such as myositis. The cutaneous findings are variable, but pathognomonic findings include Gottron papules of the hands, Gottron’s sign on the elbows, knees, and ankles, and the heliotrope rash of the face. Eighty percent of patients have myopathy presenting as muscle weakness, and commonly have elevated creatine kinase, aspartate transaminase, and alanine transaminase values.⁵ Diagnosis may be confirmed through skin or muscle biopsy, though antibody studies can also play a helpful role in diagnosis. Treatment is generally with oral corticosteroids or other immunosuppressants as well as sun protection.⁶ The rash seen in our patient could have been seen in patients with dermatomyositis, though it was not in the typical location on the knuckles (Gottron papules) as it also affected the lateral sides of the fingers.

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune condition characterized by systemic and cutaneous manifestations. Systemic symptoms may include weight loss, fever, fatigue, arthralgia, or arthritis; patients are at risk of renal, cardiovascular, pulmonary, and neurologic complications of SLE.⁷ The most common cutaneous finding is malar rash, though there are myriad dermatologic manifestations that can occur associated with photosensitivity. Diagnosis is made based on history, physical, and laboratory testing. Treatment options include NSAIDs, oral glucocorticoids, antimalarial drugs, and immunosuppressants.⁷ Though our patient exhibited photosensitivity, he had none of the systemic findings associated with SLE, making this diagnosis unlikely.

Allergic contact dermatitis

Allergic contact dermatitis (ACD) is a type IV hypersensitivity reaction, and may present as acute, subacute, or chronic dermatitis. The clinical findings vary based on chronicity. Acute ACD presents as pruritic erythematous papules and vesicles or bullae, similar to how it occurred in our patient, though our patient’s lesions were more tender than pruritic. Chronic ACD presents with erythematous lesions with pruritis, lichenification, scaling, and/or fissuring. Observing shapes or sharp demarcation of lesions may help with diagnosis. Patch testing is also useful in the diagnosis of ACD.

Treatment generally involves avoiding the offending agent with topical corticosteroids for symptom management.⁸

Polymorphous light eruption

Polymorphous light eruption (PLE) is a delayed, type IV hypersensitivity reaction to UV-induced antigens, though these antigens are unknown. PLE presents hours to days following solar or UV exposure and presents only in sun-exposed areas. Itching and burning are always present, but lesion morphology varies from erythema and papules to vesico-papules and blisters. Notably, PLE must be distinguished from drug photosensitivity through history. Treatment generally involves symptom management with topical steroids and sun protective measures for prevention.⁹ While PLE may present similarly to drug photosensitivity reactions, our patient’s use of a known phototoxic agent makes PLE a less likely diagnosis.

Ms. Appiah is a pediatric dermatology research associate and medical student at the University of California, San Diego, and Rady Children’s Hospital, San Diego. Dr. Matiz is a pediatric dermatologist at Southern California Permanente Medical Group, San Diego. Neither Dr. Matiz nor Ms. Appiah has any relevant financial disclosures.

References

1. Montgomery S et al. Clin Dermatol. 2022;40(1):57-63.

2. Blakely KM et al. Drug Saf. 2019;42(7):827-47.

3. Goetze S et al. Skin Pharmacol Physiol. 2017;30(2):76-80.

4. Odorici G et al. Dermatol Ther. 2021;34(4):e14978.

5. DeWane ME et al. J Am Acad Dermatol. 2020;82(2):267-81.

6. Waldman R et al. J Am Acad Dermatol. 2020;82(2):283-96.

7. Kiriakidou M et al. Ann Intern Med. 2020;172(11):ITC81-ITC96.

8. Nassau S et al. Med Clin North Am. 2020;104(1):61-76.

9. Guarrera M. Adv Exp Med Biol. 2017;996:61-70.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive lymphoma arising from follicular T-helper cells that predominantly affects older adults and carries a 5-year overall survival rate of 32%.¹ Notably, as many as 50% of AITL patients present with a skin rash in addition to the more common but nonspecific acute-onset generalized lymphadenopathy, hepatosplenomegaly, and anemia.² At presentation, most AITL patients are already at an advanced (III/IV) stage of disease.

Formerly known as angioimmunoblastic lymphadenopathy with dysproteinemia, AITL was once considered a benign entity that carried a risk for malignant transformation. As more cases have been identified and explored, this entity has been recategorized as a frank lymphoma.³ Therefore, it is critical that AITL be diagnosed and treated as early as possible.

We present the case of a 65-year-old man with clinical features that resembled drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). After extensive workup, he was found to have AITL. This atypical case highlights the importance of maintaining a flexible differential diagnosis in patients with a persistent rash that does not improve with appropriate drug withdrawal and therapy.

Case Report

A 65-year-old Filipino man whose medical history was notable for hepatitis B that had been treated with entecavir for years without issue was admitted to the internal medicine service with fever of unknown origin and malaise of approximately 6 weeks’ duration. Six days prior to admission and 5 days after completing courses of the antiviral oseltamivir phosphate and amoxicillin for an upper respiratory tract infection and sinusitis, he developed worsening of an intermittently pruritic rash of approximately 1 month's duration. The dermatology department was consulted the day of hospital admission for evaluation of the rash. Chronic home medications included entecavir, lisinopril/hydrochlorothiazide, amlodipine, atorvastatin, metformin, salsalate, and over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) as needed.

Physical examination was notable for mild erythema and scale distributed across the entire face; mild facial edema; and a blanchable, nonconfluent, macular erythema distributed across the trunk and upper and proximal lower extremities (Figure). In addition, the patient displayed conjunctival injection, pitting edema of the hands, and bilateral cervical and inguinal lymphadenopathy.

Photographs courtesy of James Contestable, MD (Camp Lejeune, North Carolina).

Laboratory tests revealed mild leukocytosis (11.6×10⁹/L, [reference range, 4.0–10.5×10⁹/L]), anemia (hemoglobin, 125 g/L (reference range, 138–170 g/L); hematocrit, 36.9%, [reference range, 40.0%–50.0%)], eosinophilia (1.07×10⁹/L [reference range, 0.00–0.70×10⁹/L)], hyponatremia, hypokalemia, and a mildly elevated creatinine level. Computed tomography and full-body positron-emission tomography (PET) scans during admission demonstrated diffuse lymphadenopathy. A skin biopsy from the left chest and a left inguinal lymph node biopsy also were performed.

Despite the lack of a clear medication trigger within the usual timeline for severe cutaneous drug-induced hypersensitivity reactions, DRESS syndrome was high on the differential diagnosis at the time of the initial presentation given the diffuse morbilliform eruption with pruritus, facial edema, eosinophilia, and lymphadenopathy.

Home medications were discontinued except for amlodipine, atorvastatin, and entecavir. The patient was treated symptomatically with topical steroids because it was believed that, if the clinical presentation represented DRESS syndrome, it was a mild variant that could be treated topically.⁴ His case was considered mild because of a lack of confirmed organ dysfunction and a mild protracted course.

After discharge following a 3-day inpatient stay, the patient was followed in the clinic weekly for 3 weeks without considerable change in the skin or laboratory findings. Discontinuation of entecavir was discussed and approved by his hepatologist.

Posthospitalization analysis of the punch biopsy specimen from the chest performed during the patient’s hospital stay revealed a superficial and deep dermal lymphoid infiltrate comprising CD3-, CD5-, and programmed cell death protein 1–positive cells with cytologic atypia in a perivascular distribution. Analysis of the lymph node biopsy specimen performed during the hospitalization showed effacement of the nodal architecture, a polymorphous lymphoid cell population with irregular nuclear contour, and abundant clear cytoplasm associated with high endothelial venules (HEVs). Cells of interest were positive for CD3, CD4, CD2, CD5, and CD7, with a subset staining positive for programmed cell death protein 1, inducible costimulator, CD10, and chemokine (C-X-C motif) ligand (CXCL) 13. CD21 demonstrated an expanded follicular dendritic cell meshwork in association with HEVs. Polymerase chain reaction revealed a clonal T-cell population. These findings of the skin and lymph node biopsies were consistent with AITL. Subsequent bone marrow biopsy with flow cytometry showed a normal CD4:CD8 ratio in T cells and no increase in natural killer cells.

Cyclophosphamide–hydroxydaunorubicin–Oncovin–prednisone (CHOP) chemotherapy was initiated; the patient completed a total of 6 cycles. He has had near resolution of the skin findings and is considered in remission based on a PET scan performed approximately 7 months after the initial presentation.

Comment

Angioimmunoblastic T-cell lymphoma is a rare peripheral T-cell lymphoma, part of a group of aggressive neoplasms that constitute approximately 15% of peripheral T-cell lymphomas and approximately 2% of non-Hodgkin lymphomas in adults worldwide.⁵ Cutaneous involvement occurs in approximately half of AITL cases and can be the first manifestation of disease.² Skin findings are largely nonspecific, ranging from simple morbilliform rashes to erythroderma, at times manifesting with purpura.

Given this variability in the presentation of AITL, early diagnosis is challenging in the absence of more specific signs and symptoms.² It can conceivably be mistaken for common entities such as viral exanthems or drug eruptions, depending on the history and context. DRESS syndrome, a T cell-mediated, delayed type-IV hypersensitivity drug reaction can present in a manner highly similar to that of AITL, with cutaneous involvement (diffuse morbilliform rash, fever, facial edema, and generalized lymphadenopathy) and variable systemic involvement. Laboratory findings of eosinophilia, atypical lymphocytes, and thrombocytopenia also might be seen in both entities.⁶ Furthermore, the AITL in our patient was accompanied by electrolyte disturbances that were concerning for syndrome of inappropriate antidiuretic hormone secretion, a rare complication of patients with DRESS syndrome complicated by encephalitis.^7,8

Our patient met 4 RegiSCAR criteria for DRESS syndrome, warranting high clinical suspicion for an offending drug.⁹ DRESS syndrome can be caused by numerous medications—most commonly anticonvulsants, sulfonamides, antibiotics, allopurinol, and NSAIDs. A review of our patient’s medication list identified NSAIDs (including salsalate), entecavir, and amoxicillin, as possible culpable medications. Notably, the only new addition to the patient’s regimen was amoxicillin, which did not fit the typical 2- to 8-week timeline for a DRESS syndrome nidus.¹⁰ Our patient’s fever began well before the antibiotic was initiated, and skin findings appeared within 1 week after the course of amoxicillin was completed. Although there is documented variability in the latency of onset of DRESS syndrome following administration of a culprit medication,¹¹ it is critical to maintain a broad differential diagnosis to allow for further diagnostic information to be obtained, especially when the medication timeline does not align with the clinical presentation.

DRESS syndrome is far more common than AITL. Similarities in their clinical presentation pose a substantial challenge and often cause a delay in the diagnosis of AITL, which is made by excisional tissue biopsy, most commonly of a lymph node, with assessment of morphology and immunophenotyping. Histologic assessment of tissue reveals a polymorphous infiltrate of variably sized atypical lymphocytes with prominent arborizing HEVs as well as expanded populations of follicular dendritic cells that can be detected by CD21 staining. Cells express CD3 and CD4, variably express BCL6 (B-cell lymphoma 6 antigen) and CD10, and also may have partial or complete loss of expression of a subset of pan T-cell antigens (CD2, CD3, CD5, and CD7).^12-18

The treatment approach to AITL mirrors that of other nodal peripheral T-cell lymphomas, including chemotherapy and consideration of autologous stem-cell transplantation. Recent prospective trials of CHOP and CHOP-like chemotherapy have reported 3-year event-free survival and overall survival rates of 50% and 68%, respectively.¹⁹ Novel chemotherapeutic targets and gene-expression profiling are being investigated as potential therapeutic avenues.²⁰

Conclusion

DRESS syndrome and AITL can have near-identical presentations. Clinicians should maintain a high index of suspicion for AITL in patients with presumed DRESS syndrome whose rash does not improve with appropriate drug withdrawal and steroid therapy or who lack a strong offending medication history. In such cases, skin and lymph node biopsies should be performed as early as possible to evaluate for AITL and so that appropriate therapy can be initiated.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive lymphoma arising from follicular T-helper cells that predominantly affects older adults and carries a 5-year overall survival rate of 32%.¹ Notably, as many as 50% of AITL patients present with a skin rash in addition to the more common but nonspecific acute-onset generalized lymphadenopathy, hepatosplenomegaly, and anemia.² At presentation, most AITL patients are already at an advanced (III/IV) stage of disease.

Formerly known as angioimmunoblastic lymphadenopathy with dysproteinemia, AITL was once considered a benign entity that carried a risk for malignant transformation. As more cases have been identified and explored, this entity has been recategorized as a frank lymphoma.³ Therefore, it is critical that AITL be diagnosed and treated as early as possible.

We present the case of a 65-year-old man with clinical features that resembled drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). After extensive workup, he was found to have AITL. This atypical case highlights the importance of maintaining a flexible differential diagnosis in patients with a persistent rash that does not improve with appropriate drug withdrawal and therapy.

Case Report

A 65-year-old Filipino man whose medical history was notable for hepatitis B that had been treated with entecavir for years without issue was admitted to the internal medicine service with fever of unknown origin and malaise of approximately 6 weeks’ duration. Six days prior to admission and 5 days after completing courses of the antiviral oseltamivir phosphate and amoxicillin for an upper respiratory tract infection and sinusitis, he developed worsening of an intermittently pruritic rash of approximately 1 month's duration. The dermatology department was consulted the day of hospital admission for evaluation of the rash. Chronic home medications included entecavir, lisinopril/hydrochlorothiazide, amlodipine, atorvastatin, metformin, salsalate, and over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) as needed.

Physical examination was notable for mild erythema and scale distributed across the entire face; mild facial edema; and a blanchable, nonconfluent, macular erythema distributed across the trunk and upper and proximal lower extremities (Figure). In addition, the patient displayed conjunctival injection, pitting edema of the hands, and bilateral cervical and inguinal lymphadenopathy.

Photographs courtesy of James Contestable, MD (Camp Lejeune, North Carolina).

Laboratory tests revealed mild leukocytosis (11.6×10⁹/L, [reference range, 4.0–10.5×10⁹/L]), anemia (hemoglobin, 125 g/L (reference range, 138–170 g/L); hematocrit, 36.9%, [reference range, 40.0%–50.0%)], eosinophilia (1.07×10⁹/L [reference range, 0.00–0.70×10⁹/L)], hyponatremia, hypokalemia, and a mildly elevated creatinine level. Computed tomography and full-body positron-emission tomography (PET) scans during admission demonstrated diffuse lymphadenopathy. A skin biopsy from the left chest and a left inguinal lymph node biopsy also were performed.

Despite the lack of a clear medication trigger within the usual timeline for severe cutaneous drug-induced hypersensitivity reactions, DRESS syndrome was high on the differential diagnosis at the time of the initial presentation given the diffuse morbilliform eruption with pruritus, facial edema, eosinophilia, and lymphadenopathy.

Home medications were discontinued except for amlodipine, atorvastatin, and entecavir. The patient was treated symptomatically with topical steroids because it was believed that, if the clinical presentation represented DRESS syndrome, it was a mild variant that could be treated topically.⁴ His case was considered mild because of a lack of confirmed organ dysfunction and a mild protracted course.

After discharge following a 3-day inpatient stay, the patient was followed in the clinic weekly for 3 weeks without considerable change in the skin or laboratory findings. Discontinuation of entecavir was discussed and approved by his hepatologist.

Posthospitalization analysis of the punch biopsy specimen from the chest performed during the patient’s hospital stay revealed a superficial and deep dermal lymphoid infiltrate comprising CD3-, CD5-, and programmed cell death protein 1–positive cells with cytologic atypia in a perivascular distribution. Analysis of the lymph node biopsy specimen performed during the hospitalization showed effacement of the nodal architecture, a polymorphous lymphoid cell population with irregular nuclear contour, and abundant clear cytoplasm associated with high endothelial venules (HEVs). Cells of interest were positive for CD3, CD4, CD2, CD5, and CD7, with a subset staining positive for programmed cell death protein 1, inducible costimulator, CD10, and chemokine (C-X-C motif) ligand (CXCL) 13. CD21 demonstrated an expanded follicular dendritic cell meshwork in association with HEVs. Polymerase chain reaction revealed a clonal T-cell population. These findings of the skin and lymph node biopsies were consistent with AITL. Subsequent bone marrow biopsy with flow cytometry showed a normal CD4:CD8 ratio in T cells and no increase in natural killer cells.

Cyclophosphamide–hydroxydaunorubicin–Oncovin–prednisone (CHOP) chemotherapy was initiated; the patient completed a total of 6 cycles. He has had near resolution of the skin findings and is considered in remission based on a PET scan performed approximately 7 months after the initial presentation.

Comment

Angioimmunoblastic T-cell lymphoma is a rare peripheral T-cell lymphoma, part of a group of aggressive neoplasms that constitute approximately 15% of peripheral T-cell lymphomas and approximately 2% of non-Hodgkin lymphomas in adults worldwide.⁵ Cutaneous involvement occurs in approximately half of AITL cases and can be the first manifestation of disease.² Skin findings are largely nonspecific, ranging from simple morbilliform rashes to erythroderma, at times manifesting with purpura.

Given this variability in the presentation of AITL, early diagnosis is challenging in the absence of more specific signs and symptoms.² It can conceivably be mistaken for common entities such as viral exanthems or drug eruptions, depending on the history and context. DRESS syndrome, a T cell-mediated, delayed type-IV hypersensitivity drug reaction can present in a manner highly similar to that of AITL, with cutaneous involvement (diffuse morbilliform rash, fever, facial edema, and generalized lymphadenopathy) and variable systemic involvement. Laboratory findings of eosinophilia, atypical lymphocytes, and thrombocytopenia also might be seen in both entities.⁶ Furthermore, the AITL in our patient was accompanied by electrolyte disturbances that were concerning for syndrome of inappropriate antidiuretic hormone secretion, a rare complication of patients with DRESS syndrome complicated by encephalitis.^7,8

Our patient met 4 RegiSCAR criteria for DRESS syndrome, warranting high clinical suspicion for an offending drug.⁹ DRESS syndrome can be caused by numerous medications—most commonly anticonvulsants, sulfonamides, antibiotics, allopurinol, and NSAIDs. A review of our patient’s medication list identified NSAIDs (including salsalate), entecavir, and amoxicillin, as possible culpable medications. Notably, the only new addition to the patient’s regimen was amoxicillin, which did not fit the typical 2- to 8-week timeline for a DRESS syndrome nidus.¹⁰ Our patient’s fever began well before the antibiotic was initiated, and skin findings appeared within 1 week after the course of amoxicillin was completed. Although there is documented variability in the latency of onset of DRESS syndrome following administration of a culprit medication,¹¹ it is critical to maintain a broad differential diagnosis to allow for further diagnostic information to be obtained, especially when the medication timeline does not align with the clinical presentation.

DRESS syndrome is far more common than AITL. Similarities in their clinical presentation pose a substantial challenge and often cause a delay in the diagnosis of AITL, which is made by excisional tissue biopsy, most commonly of a lymph node, with assessment of morphology and immunophenotyping. Histologic assessment of tissue reveals a polymorphous infiltrate of variably sized atypical lymphocytes with prominent arborizing HEVs as well as expanded populations of follicular dendritic cells that can be detected by CD21 staining. Cells express CD3 and CD4, variably express BCL6 (B-cell lymphoma 6 antigen) and CD10, and also may have partial or complete loss of expression of a subset of pan T-cell antigens (CD2, CD3, CD5, and CD7).^12-18

The treatment approach to AITL mirrors that of other nodal peripheral T-cell lymphomas, including chemotherapy and consideration of autologous stem-cell transplantation. Recent prospective trials of CHOP and CHOP-like chemotherapy have reported 3-year event-free survival and overall survival rates of 50% and 68%, respectively.¹⁹ Novel chemotherapeutic targets and gene-expression profiling are being investigated as potential therapeutic avenues.²⁰

Conclusion

DRESS syndrome and AITL can have near-identical presentations. Clinicians should maintain a high index of suspicion for AITL in patients with presumed DRESS syndrome whose rash does not improve with appropriate drug withdrawal and steroid therapy or who lack a strong offending medication history. In such cases, skin and lymph node biopsies should be performed as early as possible to evaluate for AITL and so that appropriate therapy can be initiated.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive lymphoma arising from follicular T-helper cells that predominantly affects older adults and carries a 5-year overall survival rate of 32%.¹ Notably, as many as 50% of AITL patients present with a skin rash in addition to the more common but nonspecific acute-onset generalized lymphadenopathy, hepatosplenomegaly, and anemia.² At presentation, most AITL patients are already at an advanced (III/IV) stage of disease.

Formerly known as angioimmunoblastic lymphadenopathy with dysproteinemia, AITL was once considered a benign entity that carried a risk for malignant transformation. As more cases have been identified and explored, this entity has been recategorized as a frank lymphoma.³ Therefore, it is critical that AITL be diagnosed and treated as early as possible.

We present the case of a 65-year-old man with clinical features that resembled drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). After extensive workup, he was found to have AITL. This atypical case highlights the importance of maintaining a flexible differential diagnosis in patients with a persistent rash that does not improve with appropriate drug withdrawal and therapy.

Case Report

A 65-year-old Filipino man whose medical history was notable for hepatitis B that had been treated with entecavir for years without issue was admitted to the internal medicine service with fever of unknown origin and malaise of approximately 6 weeks’ duration. Six days prior to admission and 5 days after completing courses of the antiviral oseltamivir phosphate and amoxicillin for an upper respiratory tract infection and sinusitis, he developed worsening of an intermittently pruritic rash of approximately 1 month's duration. The dermatology department was consulted the day of hospital admission for evaluation of the rash. Chronic home medications included entecavir, lisinopril/hydrochlorothiazide, amlodipine, atorvastatin, metformin, salsalate, and over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) as needed.

Physical examination was notable for mild erythema and scale distributed across the entire face; mild facial edema; and a blanchable, nonconfluent, macular erythema distributed across the trunk and upper and proximal lower extremities (Figure). In addition, the patient displayed conjunctival injection, pitting edema of the hands, and bilateral cervical and inguinal lymphadenopathy.

Photographs courtesy of James Contestable, MD (Camp Lejeune, North Carolina).

Laboratory tests revealed mild leukocytosis (11.6×10⁹/L, [reference range, 4.0–10.5×10⁹/L]), anemia (hemoglobin, 125 g/L (reference range, 138–170 g/L); hematocrit, 36.9%, [reference range, 40.0%–50.0%)], eosinophilia (1.07×10⁹/L [reference range, 0.00–0.70×10⁹/L)], hyponatremia, hypokalemia, and a mildly elevated creatinine level. Computed tomography and full-body positron-emission tomography (PET) scans during admission demonstrated diffuse lymphadenopathy. A skin biopsy from the left chest and a left inguinal lymph node biopsy also were performed.

Despite the lack of a clear medication trigger within the usual timeline for severe cutaneous drug-induced hypersensitivity reactions, DRESS syndrome was high on the differential diagnosis at the time of the initial presentation given the diffuse morbilliform eruption with pruritus, facial edema, eosinophilia, and lymphadenopathy.

Home medications were discontinued except for amlodipine, atorvastatin, and entecavir. The patient was treated symptomatically with topical steroids because it was believed that, if the clinical presentation represented DRESS syndrome, it was a mild variant that could be treated topically.⁴ His case was considered mild because of a lack of confirmed organ dysfunction and a mild protracted course.

After discharge following a 3-day inpatient stay, the patient was followed in the clinic weekly for 3 weeks without considerable change in the skin or laboratory findings. Discontinuation of entecavir was discussed and approved by his hepatologist.

Posthospitalization analysis of the punch biopsy specimen from the chest performed during the patient’s hospital stay revealed a superficial and deep dermal lymphoid infiltrate comprising CD3-, CD5-, and programmed cell death protein 1–positive cells with cytologic atypia in a perivascular distribution. Analysis of the lymph node biopsy specimen performed during the hospitalization showed effacement of the nodal architecture, a polymorphous lymphoid cell population with irregular nuclear contour, and abundant clear cytoplasm associated with high endothelial venules (HEVs). Cells of interest were positive for CD3, CD4, CD2, CD5, and CD7, with a subset staining positive for programmed cell death protein 1, inducible costimulator, CD10, and chemokine (C-X-C motif) ligand (CXCL) 13. CD21 demonstrated an expanded follicular dendritic cell meshwork in association with HEVs. Polymerase chain reaction revealed a clonal T-cell population. These findings of the skin and lymph node biopsies were consistent with AITL. Subsequent bone marrow biopsy with flow cytometry showed a normal CD4:CD8 ratio in T cells and no increase in natural killer cells.

Cyclophosphamide–hydroxydaunorubicin–Oncovin–prednisone (CHOP) chemotherapy was initiated; the patient completed a total of 6 cycles. He has had near resolution of the skin findings and is considered in remission based on a PET scan performed approximately 7 months after the initial presentation.

Comment

Angioimmunoblastic T-cell lymphoma is a rare peripheral T-cell lymphoma, part of a group of aggressive neoplasms that constitute approximately 15% of peripheral T-cell lymphomas and approximately 2% of non-Hodgkin lymphomas in adults worldwide.⁵ Cutaneous involvement occurs in approximately half of AITL cases and can be the first manifestation of disease.² Skin findings are largely nonspecific, ranging from simple morbilliform rashes to erythroderma, at times manifesting with purpura.

Given this variability in the presentation of AITL, early diagnosis is challenging in the absence of more specific signs and symptoms.² It can conceivably be mistaken for common entities such as viral exanthems or drug eruptions, depending on the history and context. DRESS syndrome, a T cell-mediated, delayed type-IV hypersensitivity drug reaction can present in a manner highly similar to that of AITL, with cutaneous involvement (diffuse morbilliform rash, fever, facial edema, and generalized lymphadenopathy) and variable systemic involvement. Laboratory findings of eosinophilia, atypical lymphocytes, and thrombocytopenia also might be seen in both entities.⁶ Furthermore, the AITL in our patient was accompanied by electrolyte disturbances that were concerning for syndrome of inappropriate antidiuretic hormone secretion, a rare complication of patients with DRESS syndrome complicated by encephalitis.^7,8

Our patient met 4 RegiSCAR criteria for DRESS syndrome, warranting high clinical suspicion for an offending drug.⁹ DRESS syndrome can be caused by numerous medications—most commonly anticonvulsants, sulfonamides, antibiotics, allopurinol, and NSAIDs. A review of our patient’s medication list identified NSAIDs (including salsalate), entecavir, and amoxicillin, as possible culpable medications. Notably, the only new addition to the patient’s regimen was amoxicillin, which did not fit the typical 2- to 8-week timeline for a DRESS syndrome nidus.¹⁰ Our patient’s fever began well before the antibiotic was initiated, and skin findings appeared within 1 week after the course of amoxicillin was completed. Although there is documented variability in the latency of onset of DRESS syndrome following administration of a culprit medication,¹¹ it is critical to maintain a broad differential diagnosis to allow for further diagnostic information to be obtained, especially when the medication timeline does not align with the clinical presentation.

DRESS syndrome is far more common than AITL. Similarities in their clinical presentation pose a substantial challenge and often cause a delay in the diagnosis of AITL, which is made by excisional tissue biopsy, most commonly of a lymph node, with assessment of morphology and immunophenotyping. Histologic assessment of tissue reveals a polymorphous infiltrate of variably sized atypical lymphocytes with prominent arborizing HEVs as well as expanded populations of follicular dendritic cells that can be detected by CD21 staining. Cells express CD3 and CD4, variably express BCL6 (B-cell lymphoma 6 antigen) and CD10, and also may have partial or complete loss of expression of a subset of pan T-cell antigens (CD2, CD3, CD5, and CD7).^12-18

The treatment approach to AITL mirrors that of other nodal peripheral T-cell lymphomas, including chemotherapy and consideration of autologous stem-cell transplantation. Recent prospective trials of CHOP and CHOP-like chemotherapy have reported 3-year event-free survival and overall survival rates of 50% and 68%, respectively.¹⁹ Novel chemotherapeutic targets and gene-expression profiling are being investigated as potential therapeutic avenues.²⁰

Conclusion

DRESS syndrome and AITL can have near-identical presentations. Clinicians should maintain a high index of suspicion for AITL in patients with presumed DRESS syndrome whose rash does not improve with appropriate drug withdrawal and steroid therapy or who lack a strong offending medication history. In such cases, skin and lymph node biopsies should be performed as early as possible to evaluate for AITL and so that appropriate therapy can be initiated.

Incidence and Characteristics

Mosquitoes are insects categorized into the order of Diptera and family of Culicidae, and more than 3500 different species have been identified.¹ In the United States, the most common genus of mosquitoes is Aedes, with other common genera including Culex, Anopheles, Culiseta, and Coquillettidia. Most bites are performed by female rather than male mosquitoes, as it serves to complete their life cycle (Figure 1).¹

There are a variety of possible reactions to mosquito bites. Severe local reactions that are large (papules >30 mm in diameter) or are accompanied by systemic manifestations are referred to as hypersensitivity to mosquito bites (HMB).² These hypersensitivity reactions vary according to multiple factors, including comorbid conditions, genetic predisposition, and geographic location. The majority of the world’s population will exhibit local reactions to mosquito bites at some point during life, with the median age of onset of the first bite at 2 years of age.³ In a study by Arias-Cruz et al,⁴ the incidence of patient-reported large local reactions was 2.5%. Hypersensitivity to mosquito bites, perhaps the most rare reaction, is more common among Asian and Central American children.⁵ The median age of diagnosis for HMB is 7 years, and most reactions occur during the first 2 decades of life.^6,7

Clinical Presentation

Mosquitoes bite vertebrates in an attempt to feed and thus must locate the host’s blood vessels through a process known as probing, which often necessitates changing the bite site several times. Once the vessel is located and lacerated, the mosquito feeds either from the vessel directly or the hematoma around it. Not only does the bite cause trauma to the skin, but a cutaneous reaction also may occur in response to salivary gland secretions that concurrently are deposited in the host tissue.⁸ Mosquitoes’ salivary gland components are the primary cause of cutaneous reactions, as one study showed that bites from mosquitoes lacking salivary gland ducts were not associated with these reactions.⁹ Mosquito saliva contains a large number of compounds with biologic activities, including lysozymes, antibacterial glucosidases, anticoagulants, antiplatelet aggregating factors, and vasodilators, as well as a potentially large number of unknown allergenic proteins. As of 2016, 70 mosquito-derived allergens have been identified, but this number continues to grow.² After a bite from a mosquito, these compounds may result in host sensitization over time, though interestingly, sensitization to mosquito bites from a species different from the original offender does not occur due to lack of cross-reactivity between species.¹ 

Because mosquitoes reproduce by laying their eggs directly on or near water, people who live near bodies of water or wetlands are at the highest risk for mosquito bites. Patient factors that have been found to lead to increased rates of mosquito bites include lower microbial diversity on the skin, the presence of sweat or body odor, pregnancy, increased body temperature, type O blood, dark clothing, and perfumes.² Exaggerated bite reactions are associated with Epstein-Barr virus (EBV) infection and hematologic malignancies.¹⁰ 

Immediate hypersensitivity is mediated by a specific IgE antibody and is characterized by erythema and a wheal at the bite site that peaks within minutes of the bite. In contrast, delayed hypersensitivity is lymphocyte mediated; occurs 24 hours after the bite; and causes an indurated, pruritic, and erythematous 2- to 10-mm papule that may blister.¹¹ Although the evidence of immediate hypersensitivity disappears within hours, symptoms of delayed hypersensitivity may last days to weeks. Accompanying symptoms may include local swelling, pain, and warmth. The itch that often is experienced in conjunction with erythema and papule formation is elicited in 3 main ways: direct induction utilizing classic pruritic pathways, IgE-mediated hypersensitivity reaction to salivary components, and IgE-independent host immune response to salivary antigens. Papular urticaria is a common additional finding in children with mosquito bites.¹ As an individual is repeatedly bitten, they may undergo 5 stages of sensitization: stage I (neither immediate nor delayed reaction), stage II (delayed reaction), stage III (immediate and delayed reaction), stage IV (immediate reaction), and stage V (neither immediate or delayed reaction).¹¹

Although most mosquito bites cause common local reactions, patients rarely demonstrate systemic reactions that can be much more severe. Skeeter syndrome is a milder systemic response characterized by large local reactions (papules >30 mm in diameter) developing hours after a bite with accompanying fever.¹² The reaction typically peaks over days to weeks.² Although the reaction may resemble cellulitis clinically, a history of a preceding mosquito bite can help make the distinction.¹³ 

A more severe systemic reaction is HMB, which is characterized by intense local skin findings as well as generalized systemic symptoms. Initially, indurated, clear, or hemorrhagic bullae appear at the bite site (Figure 2). Later, there is progression to swelling, necrosis, and ulceration.¹⁰ Biopsies from the skin lesions associated with HMB reveal necrosis, interstitial and perivascular eosinophilic and lymphocytic infiltrates, and small vessels with fibrinoid necrosis.⁷ Systemically, high fever, general malaise, liver dysfunction, proteinuria, hematuria, hepatosplenomegaly, and lymph node enlargement may occur. Patients typically experience these severe symptoms each time they are bitten.¹⁰

The mechanism of the HMB reaction is complex but has a close association with natural killer (NK) cell lymphoproliferative disorder and EBV infection (Figure 3). In fact, it is not uncommon for HMB patients to develop malignant lymphomas during their clinical course, even those unrelated to EBV.¹⁴ Epstein-Barr virus, one of the human herpesviruses, produces latent infection in NK cells. It is hypothesized that after a mosquito bite, EBV may be reactivated within these cells by induced expression of the viral lytic-cycle transactivator gene BamHI Z fragment leftward open reading frame 1, BZLF1.⁶ In response to mosquito salivary gland components, CD4⁺ T cells proliferate and induce expression of the EBV oncogene latent membrane protein 1, LMP1, on NK cells, which then infiltrate the bite site.¹⁵ These EBV-infected NK cells also overexpress the Fas ligand, thus contributing to organ and tissue damage.⁶ In addition to activating oncogene expression on NK cells, T cells also activate the basophils and mast cells carrying mosquito-specific IgE, both of which also add to the severe skin reaction of HMB.¹⁵ The particular triad of HMB, chronic active EBV infection, and NK cell lymphoproliferative disorder commonly is known as HMB-EBV-NK or HEN disease.¹ Patients with HMB should be monitored for malignancy. The mortality of HMB is increased in patients in whom onset occurs when they are older than 9 years and with BZLF1 messenger RNA in skin lesions.⁶ 

Other rare reactions to mosquito bites include Wells syndrome, anaphylaxis, and superficial lymphangitis. Wells syndrome (also known as eosinophilic cellulitis) is characterized by erythematous or violaceous plaques and pruritic blisters. Although its etiology has not been defined, it is thought to be evoked or exacerbated by insect bites, with CD4⁺ T cells playing a primary role.¹ Anaphylaxis (angioedema, urticaria, and wheezing) rarely may occur due to mosquito salivary gland components but typically is caused by other stinging insects. Superficial lymphangitis, often misdiagnosed as an infection of the lymphatic system, presents within minutes as nontender pink streaks originating from the bite site. A biopsy with eosinophil and mast cell infiltrates consistent with an allergic-type reaction confirms the absence of infection. Patients respond well to glucocorticoid treatment.

Mosquitoes are vectors for many blood-borne diseases, including dengue hemorrhagic fever, malaria, Chikungunya virus, La Crosse encephalitis, St. Louis encephalitis, West Nile virus, and yellow fever.¹⁶ Additionally, scratching the bites may lead to superinfection and scarring.¹

Prevention and Treatment

Patients with known mosquito sensitivity should avoid areas of stagnant water and utilize preventative measures such as wearing protective clothing and using mosquito repellent containing DEET (N,N-diethyl-meta-toluamide), IR3535 (ethyl butylacetylaminopropionate), picaridin, or 2-undecanone (methyl nonyl ketone or IBI-246) when outdoors. Essential oils such as lemon, eucalyptus, citronella, and garlic are somewhat effective.¹ Additionally, prophylactic dosing of antihistamines may prevent milder reactions.

Although often supportive, treatment and management of mosquito bites depends on the extent of the reaction. For common local reactions, symptomatic management with topical anesthetics, calamine lotion, or corticosteroid creams is appropriate. If superinfection from scratching is a concern, antibiotics may be appropriate.

Management of more severe and systemic reactions such as HMB also is supportive, and the addition of oral corticosteroids to decrease inflammation is required.⁷ Severe HMB also has been treated with immunosuppressive and anticancer drugs, though the efficacy is limited. Venom immunotherapy is a preventative option for patients with mosquito-specific IgE antibodies, and hematopoietic stem cell transplant may be required in patients with HMB.^14,16

Conclusion

Mosquito allergens can cause a variety of reactions, ranging from those limited to the skin to those characterized by severe systemic effects. Although common local reactions can be symptomatically treated with topical medication, more severe reactions such as HMB require more involved clinical management. Hypersensitivity to mosquito bites is an important condition to recognize, as it is related to multiple organ impairment as well as later development of malignancy. Patients should be closely monitored during the entire clinical course and in the years following.

Incidence and Characteristics

Mosquitoes are insects categorized into the order of Diptera and family of Culicidae, and more than 3500 different species have been identified.¹ In the United States, the most common genus of mosquitoes is Aedes, with other common genera including Culex, Anopheles, Culiseta, and Coquillettidia. Most bites are performed by female rather than male mosquitoes, as it serves to complete their life cycle (Figure 1).¹

There are a variety of possible reactions to mosquito bites. Severe local reactions that are large (papules >30 mm in diameter) or are accompanied by systemic manifestations are referred to as hypersensitivity to mosquito bites (HMB).² These hypersensitivity reactions vary according to multiple factors, including comorbid conditions, genetic predisposition, and geographic location. The majority of the world’s population will exhibit local reactions to mosquito bites at some point during life, with the median age of onset of the first bite at 2 years of age.³ In a study by Arias-Cruz et al,⁴ the incidence of patient-reported large local reactions was 2.5%. Hypersensitivity to mosquito bites, perhaps the most rare reaction, is more common among Asian and Central American children.⁵ The median age of diagnosis for HMB is 7 years, and most reactions occur during the first 2 decades of life.^6,7

Clinical Presentation

Mosquitoes bite vertebrates in an attempt to feed and thus must locate the host’s blood vessels through a process known as probing, which often necessitates changing the bite site several times. Once the vessel is located and lacerated, the mosquito feeds either from the vessel directly or the hematoma around it. Not only does the bite cause trauma to the skin, but a cutaneous reaction also may occur in response to salivary gland secretions that concurrently are deposited in the host tissue.⁸ Mosquitoes’ salivary gland components are the primary cause of cutaneous reactions, as one study showed that bites from mosquitoes lacking salivary gland ducts were not associated with these reactions.⁹ Mosquito saliva contains a large number of compounds with biologic activities, including lysozymes, antibacterial glucosidases, anticoagulants, antiplatelet aggregating factors, and vasodilators, as well as a potentially large number of unknown allergenic proteins. As of 2016, 70 mosquito-derived allergens have been identified, but this number continues to grow.² After a bite from a mosquito, these compounds may result in host sensitization over time, though interestingly, sensitization to mosquito bites from a species different from the original offender does not occur due to lack of cross-reactivity between species.¹ 

Because mosquitoes reproduce by laying their eggs directly on or near water, people who live near bodies of water or wetlands are at the highest risk for mosquito bites. Patient factors that have been found to lead to increased rates of mosquito bites include lower microbial diversity on the skin, the presence of sweat or body odor, pregnancy, increased body temperature, type O blood, dark clothing, and perfumes.² Exaggerated bite reactions are associated with Epstein-Barr virus (EBV) infection and hematologic malignancies.¹⁰ 

Immediate hypersensitivity is mediated by a specific IgE antibody and is characterized by erythema and a wheal at the bite site that peaks within minutes of the bite. In contrast, delayed hypersensitivity is lymphocyte mediated; occurs 24 hours after the bite; and causes an indurated, pruritic, and erythematous 2- to 10-mm papule that may blister.¹¹ Although the evidence of immediate hypersensitivity disappears within hours, symptoms of delayed hypersensitivity may last days to weeks. Accompanying symptoms may include local swelling, pain, and warmth. The itch that often is experienced in conjunction with erythema and papule formation is elicited in 3 main ways: direct induction utilizing classic pruritic pathways, IgE-mediated hypersensitivity reaction to salivary components, and IgE-independent host immune response to salivary antigens. Papular urticaria is a common additional finding in children with mosquito bites.¹ As an individual is repeatedly bitten, they may undergo 5 stages of sensitization: stage I (neither immediate nor delayed reaction), stage II (delayed reaction), stage III (immediate and delayed reaction), stage IV (immediate reaction), and stage V (neither immediate or delayed reaction).¹¹

Although most mosquito bites cause common local reactions, patients rarely demonstrate systemic reactions that can be much more severe. Skeeter syndrome is a milder systemic response characterized by large local reactions (papules >30 mm in diameter) developing hours after a bite with accompanying fever.¹² The reaction typically peaks over days to weeks.² Although the reaction may resemble cellulitis clinically, a history of a preceding mosquito bite can help make the distinction.¹³ 

A more severe systemic reaction is HMB, which is characterized by intense local skin findings as well as generalized systemic symptoms. Initially, indurated, clear, or hemorrhagic bullae appear at the bite site (Figure 2). Later, there is progression to swelling, necrosis, and ulceration.¹⁰ Biopsies from the skin lesions associated with HMB reveal necrosis, interstitial and perivascular eosinophilic and lymphocytic infiltrates, and small vessels with fibrinoid necrosis.⁷ Systemically, high fever, general malaise, liver dysfunction, proteinuria, hematuria, hepatosplenomegaly, and lymph node enlargement may occur. Patients typically experience these severe symptoms each time they are bitten.¹⁰

The mechanism of the HMB reaction is complex but has a close association with natural killer (NK) cell lymphoproliferative disorder and EBV infection (Figure 3). In fact, it is not uncommon for HMB patients to develop malignant lymphomas during their clinical course, even those unrelated to EBV.¹⁴ Epstein-Barr virus, one of the human herpesviruses, produces latent infection in NK cells. It is hypothesized that after a mosquito bite, EBV may be reactivated within these cells by induced expression of the viral lytic-cycle transactivator gene BamHI Z fragment leftward open reading frame 1, BZLF1.⁶ In response to mosquito salivary gland components, CD4⁺ T cells proliferate and induce expression of the EBV oncogene latent membrane protein 1, LMP1, on NK cells, which then infiltrate the bite site.¹⁵ These EBV-infected NK cells also overexpress the Fas ligand, thus contributing to organ and tissue damage.⁶ In addition to activating oncogene expression on NK cells, T cells also activate the basophils and mast cells carrying mosquito-specific IgE, both of which also add to the severe skin reaction of HMB.¹⁵ The particular triad of HMB, chronic active EBV infection, and NK cell lymphoproliferative disorder commonly is known as HMB-EBV-NK or HEN disease.¹ Patients with HMB should be monitored for malignancy. The mortality of HMB is increased in patients in whom onset occurs when they are older than 9 years and with BZLF1 messenger RNA in skin lesions.⁶ 

Other rare reactions to mosquito bites include Wells syndrome, anaphylaxis, and superficial lymphangitis. Wells syndrome (also known as eosinophilic cellulitis) is characterized by erythematous or violaceous plaques and pruritic blisters. Although its etiology has not been defined, it is thought to be evoked or exacerbated by insect bites, with CD4⁺ T cells playing a primary role.¹ Anaphylaxis (angioedema, urticaria, and wheezing) rarely may occur due to mosquito salivary gland components but typically is caused by other stinging insects. Superficial lymphangitis, often misdiagnosed as an infection of the lymphatic system, presents within minutes as nontender pink streaks originating from the bite site. A biopsy with eosinophil and mast cell infiltrates consistent with an allergic-type reaction confirms the absence of infection. Patients respond well to glucocorticoid treatment.

Mosquitoes are vectors for many blood-borne diseases, including dengue hemorrhagic fever, malaria, Chikungunya virus, La Crosse encephalitis, St. Louis encephalitis, West Nile virus, and yellow fever.¹⁶ Additionally, scratching the bites may lead to superinfection and scarring.¹

Prevention and Treatment

Patients with known mosquito sensitivity should avoid areas of stagnant water and utilize preventative measures such as wearing protective clothing and using mosquito repellent containing DEET (N,N-diethyl-meta-toluamide), IR3535 (ethyl butylacetylaminopropionate), picaridin, or 2-undecanone (methyl nonyl ketone or IBI-246) when outdoors. Essential oils such as lemon, eucalyptus, citronella, and garlic are somewhat effective.¹ Additionally, prophylactic dosing of antihistamines may prevent milder reactions.

Although often supportive, treatment and management of mosquito bites depends on the extent of the reaction. For common local reactions, symptomatic management with topical anesthetics, calamine lotion, or corticosteroid creams is appropriate. If superinfection from scratching is a concern, antibiotics may be appropriate.

Management of more severe and systemic reactions such as HMB also is supportive, and the addition of oral corticosteroids to decrease inflammation is required.⁷ Severe HMB also has been treated with immunosuppressive and anticancer drugs, though the efficacy is limited. Venom immunotherapy is a preventative option for patients with mosquito-specific IgE antibodies, and hematopoietic stem cell transplant may be required in patients with HMB.^14,16

Conclusion

Mosquito allergens can cause a variety of reactions, ranging from those limited to the skin to those characterized by severe systemic effects. Although common local reactions can be symptomatically treated with topical medication, more severe reactions such as HMB require more involved clinical management. Hypersensitivity to mosquito bites is an important condition to recognize, as it is related to multiple organ impairment as well as later development of malignancy. Patients should be closely monitored during the entire clinical course and in the years following.

Incidence and Characteristics

Mosquitoes are insects categorized into the order of Diptera and family of Culicidae, and more than 3500 different species have been identified.¹ In the United States, the most common genus of mosquitoes is Aedes, with other common genera including Culex, Anopheles, Culiseta, and Coquillettidia. Most bites are performed by female rather than male mosquitoes, as it serves to complete their life cycle (Figure 1).¹

There are a variety of possible reactions to mosquito bites. Severe local reactions that are large (papules >30 mm in diameter) or are accompanied by systemic manifestations are referred to as hypersensitivity to mosquito bites (HMB).² These hypersensitivity reactions vary according to multiple factors, including comorbid conditions, genetic predisposition, and geographic location. The majority of the world’s population will exhibit local reactions to mosquito bites at some point during life, with the median age of onset of the first bite at 2 years of age.³ In a study by Arias-Cruz et al,⁴ the incidence of patient-reported large local reactions was 2.5%. Hypersensitivity to mosquito bites, perhaps the most rare reaction, is more common among Asian and Central American children.⁵ The median age of diagnosis for HMB is 7 years, and most reactions occur during the first 2 decades of life.^6,7

Clinical Presentation

Mosquitoes bite vertebrates in an attempt to feed and thus must locate the host’s blood vessels through a process known as probing, which often necessitates changing the bite site several times. Once the vessel is located and lacerated, the mosquito feeds either from the vessel directly or the hematoma around it. Not only does the bite cause trauma to the skin, but a cutaneous reaction also may occur in response to salivary gland secretions that concurrently are deposited in the host tissue.⁸ Mosquitoes’ salivary gland components are the primary cause of cutaneous reactions, as one study showed that bites from mosquitoes lacking salivary gland ducts were not associated with these reactions.⁹ Mosquito saliva contains a large number of compounds with biologic activities, including lysozymes, antibacterial glucosidases, anticoagulants, antiplatelet aggregating factors, and vasodilators, as well as a potentially large number of unknown allergenic proteins. As of 2016, 70 mosquito-derived allergens have been identified, but this number continues to grow.² After a bite from a mosquito, these compounds may result in host sensitization over time, though interestingly, sensitization to mosquito bites from a species different from the original offender does not occur due to lack of cross-reactivity between species.¹ 

Because mosquitoes reproduce by laying their eggs directly on or near water, people who live near bodies of water or wetlands are at the highest risk for mosquito bites. Patient factors that have been found to lead to increased rates of mosquito bites include lower microbial diversity on the skin, the presence of sweat or body odor, pregnancy, increased body temperature, type O blood, dark clothing, and perfumes.² Exaggerated bite reactions are associated with Epstein-Barr virus (EBV) infection and hematologic malignancies.¹⁰ 

Immediate hypersensitivity is mediated by a specific IgE antibody and is characterized by erythema and a wheal at the bite site that peaks within minutes of the bite. In contrast, delayed hypersensitivity is lymphocyte mediated; occurs 24 hours after the bite; and causes an indurated, pruritic, and erythematous 2- to 10-mm papule that may blister.¹¹ Although the evidence of immediate hypersensitivity disappears within hours, symptoms of delayed hypersensitivity may last days to weeks. Accompanying symptoms may include local swelling, pain, and warmth. The itch that often is experienced in conjunction with erythema and papule formation is elicited in 3 main ways: direct induction utilizing classic pruritic pathways, IgE-mediated hypersensitivity reaction to salivary components, and IgE-independent host immune response to salivary antigens. Papular urticaria is a common additional finding in children with mosquito bites.¹ As an individual is repeatedly bitten, they may undergo 5 stages of sensitization: stage I (neither immediate nor delayed reaction), stage II (delayed reaction), stage III (immediate and delayed reaction), stage IV (immediate reaction), and stage V (neither immediate or delayed reaction).¹¹

Although most mosquito bites cause common local reactions, patients rarely demonstrate systemic reactions that can be much more severe. Skeeter syndrome is a milder systemic response characterized by large local reactions (papules >30 mm in diameter) developing hours after a bite with accompanying fever.¹² The reaction typically peaks over days to weeks.² Although the reaction may resemble cellulitis clinically, a history of a preceding mosquito bite can help make the distinction.¹³ 

A more severe systemic reaction is HMB, which is characterized by intense local skin findings as well as generalized systemic symptoms. Initially, indurated, clear, or hemorrhagic bullae appear at the bite site (Figure 2). Later, there is progression to swelling, necrosis, and ulceration.¹⁰ Biopsies from the skin lesions associated with HMB reveal necrosis, interstitial and perivascular eosinophilic and lymphocytic infiltrates, and small vessels with fibrinoid necrosis.⁷ Systemically, high fever, general malaise, liver dysfunction, proteinuria, hematuria, hepatosplenomegaly, and lymph node enlargement may occur. Patients typically experience these severe symptoms each time they are bitten.¹⁰

The mechanism of the HMB reaction is complex but has a close association with natural killer (NK) cell lymphoproliferative disorder and EBV infection (Figure 3). In fact, it is not uncommon for HMB patients to develop malignant lymphomas during their clinical course, even those unrelated to EBV.¹⁴ Epstein-Barr virus, one of the human herpesviruses, produces latent infection in NK cells. It is hypothesized that after a mosquito bite, EBV may be reactivated within these cells by induced expression of the viral lytic-cycle transactivator gene BamHI Z fragment leftward open reading frame 1, BZLF1.⁶ In response to mosquito salivary gland components, CD4⁺ T cells proliferate and induce expression of the EBV oncogene latent membrane protein 1, LMP1, on NK cells, which then infiltrate the bite site.¹⁵ These EBV-infected NK cells also overexpress the Fas ligand, thus contributing to organ and tissue damage.⁶ In addition to activating oncogene expression on NK cells, T cells also activate the basophils and mast cells carrying mosquito-specific IgE, both of which also add to the severe skin reaction of HMB.¹⁵ The particular triad of HMB, chronic active EBV infection, and NK cell lymphoproliferative disorder commonly is known as HMB-EBV-NK or HEN disease.¹ Patients with HMB should be monitored for malignancy. The mortality of HMB is increased in patients in whom onset occurs when they are older than 9 years and with BZLF1 messenger RNA in skin lesions.⁶ 

Other rare reactions to mosquito bites include Wells syndrome, anaphylaxis, and superficial lymphangitis. Wells syndrome (also known as eosinophilic cellulitis) is characterized by erythematous or violaceous plaques and pruritic blisters. Although its etiology has not been defined, it is thought to be evoked or exacerbated by insect bites, with CD4⁺ T cells playing a primary role.¹ Anaphylaxis (angioedema, urticaria, and wheezing) rarely may occur due to mosquito salivary gland components but typically is caused by other stinging insects. Superficial lymphangitis, often misdiagnosed as an infection of the lymphatic system, presents within minutes as nontender pink streaks originating from the bite site. A biopsy with eosinophil and mast cell infiltrates consistent with an allergic-type reaction confirms the absence of infection. Patients respond well to glucocorticoid treatment.

Mosquitoes are vectors for many blood-borne diseases, including dengue hemorrhagic fever, malaria, Chikungunya virus, La Crosse encephalitis, St. Louis encephalitis, West Nile virus, and yellow fever.¹⁶ Additionally, scratching the bites may lead to superinfection and scarring.¹

Prevention and Treatment

Patients with known mosquito sensitivity should avoid areas of stagnant water and utilize preventative measures such as wearing protective clothing and using mosquito repellent containing DEET (N,N-diethyl-meta-toluamide), IR3535 (ethyl butylacetylaminopropionate), picaridin, or 2-undecanone (methyl nonyl ketone or IBI-246) when outdoors. Essential oils such as lemon, eucalyptus, citronella, and garlic are somewhat effective.¹ Additionally, prophylactic dosing of antihistamines may prevent milder reactions.

Although often supportive, treatment and management of mosquito bites depends on the extent of the reaction. For common local reactions, symptomatic management with topical anesthetics, calamine lotion, or corticosteroid creams is appropriate. If superinfection from scratching is a concern, antibiotics may be appropriate.

Management of more severe and systemic reactions such as HMB also is supportive, and the addition of oral corticosteroids to decrease inflammation is required.⁷ Severe HMB also has been treated with immunosuppressive and anticancer drugs, though the efficacy is limited. Venom immunotherapy is a preventative option for patients with mosquito-specific IgE antibodies, and hematopoietic stem cell transplant may be required in patients with HMB.^14,16

Conclusion

Mosquito allergens can cause a variety of reactions, ranging from those limited to the skin to those characterized by severe systemic effects. Although common local reactions can be symptomatically treated with topical medication, more severe reactions such as HMB require more involved clinical management. Hypersensitivity to mosquito bites is an important condition to recognize, as it is related to multiple organ impairment as well as later development of malignancy. Patients should be closely monitored during the entire clinical course and in the years following.

In the clinical experience of Adam Friedman, MD, when patients present with acute urticaria, the culprit is usually food, a drug, or a bug.

But in some cases, the trigger remains elusive. “We don’t always find the source, but don’t beat yourself up about it,” Dr. Friedman, professor and chair of dermatology at George Washington University, Washington, said at the ODAC Dermatology, Aesthetic, and Surgical Conference. “The basic rule is to treat patients to clearance and keep them clear.”

Chronic urticaria is characterized by plaques with a burning/itch sensation that often “move” to different locations on the body over minutes to hours, and they typically last for less than 24 hours. The plaques are often oval, round, or irregular in shape and they typically leave no postinflammatory pigmentary alteration or scarring other than from scratching.

Urticaria affects an estimated 20% of the population, Dr. Friedman said, and is more common in females than males. More than two-thirds of cases are self-limiting but 10% can persist longer than 5 years. Acute episodes are more likely to have an identifiable trigger, while chronic episodes, which last more than six weeks, typically do not. The longer the duration, the lower the chance of identifying the root cause. The foods/food products most commonly affecting children with acute urticaria include milk, egg, peanut, wheat, and soy, while the common culprits in adults are tree nuts, peanuts, and shellfish. Other triggers include the yellow food dye annatto, the red food dye carmine, contact with raw fruits or vegetables, animal saliva, and certain detergents or perfume.

“When you have no idea what the cause is for acute urticaria, I think about viral or bacterial infections, especially in children,” Dr. Friedman said, particularly mycoplasma, adenovirus, enterovirus, rotavirus, respiratory syncytial virus, Epstein-Barr virus, and cytomegalovirus. COVID-19 has also been a new etiologic source for a recent rise in acute urticaria cases.

Other causes include certain medications such as antibiotics, opiates, muscle relaxants, salicylates, and NSAIDs; stinging insects; and exposure to latex products, which can cross react with passion fruit, banana, avocado, chestnut, and kiwi. Alcohol consumption can also trigger urticaria.

“Ask patients if they have joint discomfort or pain,” Dr. Friedman advised, referring to urticaria arthritis syndrome that is typically seen more often in women than in men. “It’s rare but important, because that may distinguish for you what is needed to get those patients under control.”

Chronic urticaria develops in 20%-45% of patients who present with acute urticaria. One form of chronic urticaria is inducible urticaria, which spontaneously occurs after an exposure to an external force. “The distinguishing feature here is that it doesn’t last long – 30 minutes or so – and is typically unresponsive to corticosteroids,” Dr. Friedman said. “It comes on quickly but disappears quickly whereas with chronic spontaneous urticaria, someone might be getting those wheals of flare for hours and hours.”

The most common form of physical urticaria is dermatographism, while other examples include physical urticaria resulting from exposure to cholinergic agents, heat, exercise, cold, water, sunlight, and pressure on the skin.

About half of patients with chronic urticaria are disease free within 1 year, but 20% continue to experience episodes for more than 10 years. One study found that patients with chronic spontaneous urticaria who were diagnosed at a younger age trended toward a longer disease course, and rates were higher in women, compared with men. “Perceived stress can make this worse,” Dr. Friedman added.

According to Dr. Friedman, it’s more important to ask patients targeted questions during office visits than it is to do a full workup. “I ask patients to keep a diary, which can help them identify triggers if there are any,” he said. “I also ask them to take a picture of the papules with their smartphone. There can be a genetic association, so it’s important to ask if anyone else in the family has urticaria. No routine lab tests are required unless there’s something in the history that suggests it’s worthwhile. Let the patient guide the diagnostic workup; don’t just order a million tests.”

That said, known comorbidities associated with urticaria include autoimmune disease, atopy, infections, metabolic conditions, and neoplastic disorders. “Biopsies are typically useless because this is an invisible dermatosis,” he said. “They’re useful when it’s urticarial, not urticaria, when you’re trying to figure out what it is.”

According to recently published international guidelines on urticaria, published in September 2021, the recommended first line of treatment for urticaria is with second-generation nonsedating antihistamines such as cetirizine and loratadine, up to four times the recommended dose.

Second-generation derivatives include desloratadine, levocetirizine, and fexofenadine. “I like using fexofenadine in the morning for folks who don’t tolerate cetirizine, then I’ll recommend something a little more sedating at night,” Dr. Friedman said. “We max out [the dose] by week 4. If it works, great. If not, we move on to something else.”

In late 2021, the British Association of Dermatologists also published guidelines on the treatment of chronic urticaria.

As for markers of treatment success, a study of 240 children with chronic spontaneous urticaria found that risk factors for a poor response included longer duration of disease, higher treatment step until initial disease control, and food sensitization.

Vitamin D supplementation may also add some benefit. One study of 42 adults with urticaria found that low and high doses of vitamin D added to antihistamine therapy can boost effectiveness. “This may be because vitamin D could be a marker of severity,” Dr. Friedman said. “The reality is, however, that a lot of patients don’t do well.”

Data from the large, prospective study known as AWARE (A World-Wide Antihistamine-Refractory Chronic Urticaria Patient Evaluation) found that 23% patients treated with nonsedating H1-antihistamines and 42% patients treated with up-dosed nonsedating H1-antihistamines had uncontrolled chronic spontaneous urticaria at month 24.

A second-line treatment option for patients aged 6 and older is the anti-IgE antibody omalizumab, 150-300 mg by subcutaneous injection every 4 weeks. Dr. Friedman typically uses only the 300-mg dose. “You do not need to take pretreatment serum IgE levels,” he said. “The most significant adverse event is anaphylaxis, which only affects 0.2% of patients.”

A third-line option is cyclosporine A. A dose of 3-5mg/kg per day appears to benefit about two-thirds of patients with antihistamine recalcitrant chronic urticaria. “It works fast but you can’t keep patients on it for very long,” he said.

Another third-line option is mycophenolate mofetil, which may work by inhibiting the production of autoantibodies to the high-affinity IgE receptor and/or IgE. “It does work well, especially in conjunction with antihistamines; it’s kind of a softer immunosuppressant,” he said. Methotrexate can also be used as an add-on therapy to H1 antihistamine therapy in difficult-to-treat cases.

“It’s great we have [a Food and Drug Administration]–approved biologic therapy in omalizumab and access to over-the-counter antihistamines, but there is a high unmet need for treatment,” and a need for new therapies, Dr. Friedman said. “Only about 39% achieve symptomatic control with conventional dosing of antihistamines, and 63% of nonresponders achieve symptom control with a fourfold increased dosing of antihistamines.” In addition, about 20% of patients will not respond to either standard or increased doses of antihistamines and are eligible for treatment with omalizumab. However, more than 50% of such patients experience a delay or lack of response to omalizumab. “We need innovation; we need to understand the disease better,” he said.

Dr. Friedman disclosed that he serves as a consultant and/or adviser for Loreal, La Roche Posay, Cerave, Galderma, Aveeno, Microcures, Pfizer, Novartis, Dermira, Brickell Biotech, Incyte, UCB, Janssen, Pfizer, Bristol-Myers Squibb, Almirall, Zylo Therapeutics, Hoth Therapeutics, Corbus, Greenway Therapeutics, TruPotency, and Dermavant. He is a speaker for Regeneron/Sanofi, AbbVie, Janssen, Brickell Biotech, and Incyte, and has received grants from Pfizer, the Dermatology Foundation, Incyte, and Galderma.

In the clinical experience of Adam Friedman, MD, when patients present with acute urticaria, the culprit is usually food, a drug, or a bug.

But in some cases, the trigger remains elusive. “We don’t always find the source, but don’t beat yourself up about it,” Dr. Friedman, professor and chair of dermatology at George Washington University, Washington, said at the ODAC Dermatology, Aesthetic, and Surgical Conference. “The basic rule is to treat patients to clearance and keep them clear.”

Chronic urticaria is characterized by plaques with a burning/itch sensation that often “move” to different locations on the body over minutes to hours, and they typically last for less than 24 hours. The plaques are often oval, round, or irregular in shape and they typically leave no postinflammatory pigmentary alteration or scarring other than from scratching.

Urticaria affects an estimated 20% of the population, Dr. Friedman said, and is more common in females than males. More than two-thirds of cases are self-limiting but 10% can persist longer than 5 years. Acute episodes are more likely to have an identifiable trigger, while chronic episodes, which last more than six weeks, typically do not. The longer the duration, the lower the chance of identifying the root cause. The foods/food products most commonly affecting children with acute urticaria include milk, egg, peanut, wheat, and soy, while the common culprits in adults are tree nuts, peanuts, and shellfish. Other triggers include the yellow food dye annatto, the red food dye carmine, contact with raw fruits or vegetables, animal saliva, and certain detergents or perfume.

“When you have no idea what the cause is for acute urticaria, I think about viral or bacterial infections, especially in children,” Dr. Friedman said, particularly mycoplasma, adenovirus, enterovirus, rotavirus, respiratory syncytial virus, Epstein-Barr virus, and cytomegalovirus. COVID-19 has also been a new etiologic source for a recent rise in acute urticaria cases.

Other causes include certain medications such as antibiotics, opiates, muscle relaxants, salicylates, and NSAIDs; stinging insects; and exposure to latex products, which can cross react with passion fruit, banana, avocado, chestnut, and kiwi. Alcohol consumption can also trigger urticaria.

“Ask patients if they have joint discomfort or pain,” Dr. Friedman advised, referring to urticaria arthritis syndrome that is typically seen more often in women than in men. “It’s rare but important, because that may distinguish for you what is needed to get those patients under control.”

Chronic urticaria develops in 20%-45% of patients who present with acute urticaria. One form of chronic urticaria is inducible urticaria, which spontaneously occurs after an exposure to an external force. “The distinguishing feature here is that it doesn’t last long – 30 minutes or so – and is typically unresponsive to corticosteroids,” Dr. Friedman said. “It comes on quickly but disappears quickly whereas with chronic spontaneous urticaria, someone might be getting those wheals of flare for hours and hours.”

The most common form of physical urticaria is dermatographism, while other examples include physical urticaria resulting from exposure to cholinergic agents, heat, exercise, cold, water, sunlight, and pressure on the skin.

About half of patients with chronic urticaria are disease free within 1 year, but 20% continue to experience episodes for more than 10 years. One study found that patients with chronic spontaneous urticaria who were diagnosed at a younger age trended toward a longer disease course, and rates were higher in women, compared with men. “Perceived stress can make this worse,” Dr. Friedman added.

According to Dr. Friedman, it’s more important to ask patients targeted questions during office visits than it is to do a full workup. “I ask patients to keep a diary, which can help them identify triggers if there are any,” he said. “I also ask them to take a picture of the papules with their smartphone. There can be a genetic association, so it’s important to ask if anyone else in the family has urticaria. No routine lab tests are required unless there’s something in the history that suggests it’s worthwhile. Let the patient guide the diagnostic workup; don’t just order a million tests.”

That said, known comorbidities associated with urticaria include autoimmune disease, atopy, infections, metabolic conditions, and neoplastic disorders. “Biopsies are typically useless because this is an invisible dermatosis,” he said. “They’re useful when it’s urticarial, not urticaria, when you’re trying to figure out what it is.”

According to recently published international guidelines on urticaria, published in September 2021, the recommended first line of treatment for urticaria is with second-generation nonsedating antihistamines such as cetirizine and loratadine, up to four times the recommended dose.

Second-generation derivatives include desloratadine, levocetirizine, and fexofenadine. “I like using fexofenadine in the morning for folks who don’t tolerate cetirizine, then I’ll recommend something a little more sedating at night,” Dr. Friedman said. “We max out [the dose] by week 4. If it works, great. If not, we move on to something else.”

In late 2021, the British Association of Dermatologists also published guidelines on the treatment of chronic urticaria.

As for markers of treatment success, a study of 240 children with chronic spontaneous urticaria found that risk factors for a poor response included longer duration of disease, higher treatment step until initial disease control, and food sensitization.

Vitamin D supplementation may also add some benefit. One study of 42 adults with urticaria found that low and high doses of vitamin D added to antihistamine therapy can boost effectiveness. “This may be because vitamin D could be a marker of severity,” Dr. Friedman said. “The reality is, however, that a lot of patients don’t do well.”

Data from the large, prospective study known as AWARE (A World-Wide Antihistamine-Refractory Chronic Urticaria Patient Evaluation) found that 23% patients treated with nonsedating H1-antihistamines and 42% patients treated with up-dosed nonsedating H1-antihistamines had uncontrolled chronic spontaneous urticaria at month 24.

A second-line treatment option for patients aged 6 and older is the anti-IgE antibody omalizumab, 150-300 mg by subcutaneous injection every 4 weeks. Dr. Friedman typically uses only the 300-mg dose. “You do not need to take pretreatment serum IgE levels,” he said. “The most significant adverse event is anaphylaxis, which only affects 0.2% of patients.”

A third-line option is cyclosporine A. A dose of 3-5mg/kg per day appears to benefit about two-thirds of patients with antihistamine recalcitrant chronic urticaria. “It works fast but you can’t keep patients on it for very long,” he said.

Another third-line option is mycophenolate mofetil, which may work by inhibiting the production of autoantibodies to the high-affinity IgE receptor and/or IgE. “It does work well, especially in conjunction with antihistamines; it’s kind of a softer immunosuppressant,” he said. Methotrexate can also be used as an add-on therapy to H1 antihistamine therapy in difficult-to-treat cases.

“It’s great we have [a Food and Drug Administration]–approved biologic therapy in omalizumab and access to over-the-counter antihistamines, but there is a high unmet need for treatment,” and a need for new therapies, Dr. Friedman said. “Only about 39% achieve symptomatic control with conventional dosing of antihistamines, and 63% of nonresponders achieve symptom control with a fourfold increased dosing of antihistamines.” In addition, about 20% of patients will not respond to either standard or increased doses of antihistamines and are eligible for treatment with omalizumab. However, more than 50% of such patients experience a delay or lack of response to omalizumab. “We need innovation; we need to understand the disease better,” he said.

Dr. Friedman disclosed that he serves as a consultant and/or adviser for Loreal, La Roche Posay, Cerave, Galderma, Aveeno, Microcures, Pfizer, Novartis, Dermira, Brickell Biotech, Incyte, UCB, Janssen, Pfizer, Bristol-Myers Squibb, Almirall, Zylo Therapeutics, Hoth Therapeutics, Corbus, Greenway Therapeutics, TruPotency, and Dermavant. He is a speaker for Regeneron/Sanofi, AbbVie, Janssen, Brickell Biotech, and Incyte, and has received grants from Pfizer, the Dermatology Foundation, Incyte, and Galderma.

In the clinical experience of Adam Friedman, MD, when patients present with acute urticaria, the culprit is usually food, a drug, or a bug.

But in some cases, the trigger remains elusive. “We don’t always find the source, but don’t beat yourself up about it,” Dr. Friedman, professor and chair of dermatology at George Washington University, Washington, said at the ODAC Dermatology, Aesthetic, and Surgical Conference. “The basic rule is to treat patients to clearance and keep them clear.”

Chronic urticaria is characterized by plaques with a burning/itch sensation that often “move” to different locations on the body over minutes to hours, and they typically last for less than 24 hours. The plaques are often oval, round, or irregular in shape and they typically leave no postinflammatory pigmentary alteration or scarring other than from scratching.

Urticaria affects an estimated 20% of the population, Dr. Friedman said, and is more common in females than males. More than two-thirds of cases are self-limiting but 10% can persist longer than 5 years. Acute episodes are more likely to have an identifiable trigger, while chronic episodes, which last more than six weeks, typically do not. The longer the duration, the lower the chance of identifying the root cause. The foods/food products most commonly affecting children with acute urticaria include milk, egg, peanut, wheat, and soy, while the common culprits in adults are tree nuts, peanuts, and shellfish. Other triggers include the yellow food dye annatto, the red food dye carmine, contact with raw fruits or vegetables, animal saliva, and certain detergents or perfume.

“When you have no idea what the cause is for acute urticaria, I think about viral or bacterial infections, especially in children,” Dr. Friedman said, particularly mycoplasma, adenovirus, enterovirus, rotavirus, respiratory syncytial virus, Epstein-Barr virus, and cytomegalovirus. COVID-19 has also been a new etiologic source for a recent rise in acute urticaria cases.

Other causes include certain medications such as antibiotics, opiates, muscle relaxants, salicylates, and NSAIDs; stinging insects; and exposure to latex products, which can cross react with passion fruit, banana, avocado, chestnut, and kiwi. Alcohol consumption can also trigger urticaria.

“Ask patients if they have joint discomfort or pain,” Dr. Friedman advised, referring to urticaria arthritis syndrome that is typically seen more often in women than in men. “It’s rare but important, because that may distinguish for you what is needed to get those patients under control.”

Chronic urticaria develops in 20%-45% of patients who present with acute urticaria. One form of chronic urticaria is inducible urticaria, which spontaneously occurs after an exposure to an external force. “The distinguishing feature here is that it doesn’t last long – 30 minutes or so – and is typically unresponsive to corticosteroids,” Dr. Friedman said. “It comes on quickly but disappears quickly whereas with chronic spontaneous urticaria, someone might be getting those wheals of flare for hours and hours.”

The most common form of physical urticaria is dermatographism, while other examples include physical urticaria resulting from exposure to cholinergic agents, heat, exercise, cold, water, sunlight, and pressure on the skin.

About half of patients with chronic urticaria are disease free within 1 year, but 20% continue to experience episodes for more than 10 years. One study found that patients with chronic spontaneous urticaria who were diagnosed at a younger age trended toward a longer disease course, and rates were higher in women, compared with men. “Perceived stress can make this worse,” Dr. Friedman added.

According to Dr. Friedman, it’s more important to ask patients targeted questions during office visits than it is to do a full workup. “I ask patients to keep a diary, which can help them identify triggers if there are any,” he said. “I also ask them to take a picture of the papules with their smartphone. There can be a genetic association, so it’s important to ask if anyone else in the family has urticaria. No routine lab tests are required unless there’s something in the history that suggests it’s worthwhile. Let the patient guide the diagnostic workup; don’t just order a million tests.”

That said, known comorbidities associated with urticaria include autoimmune disease, atopy, infections, metabolic conditions, and neoplastic disorders. “Biopsies are typically useless because this is an invisible dermatosis,” he said. “They’re useful when it’s urticarial, not urticaria, when you’re trying to figure out what it is.”

According to recently published international guidelines on urticaria, published in September 2021, the recommended first line of treatment for urticaria is with second-generation nonsedating antihistamines such as cetirizine and loratadine, up to four times the recommended dose.

Second-generation derivatives include desloratadine, levocetirizine, and fexofenadine. “I like using fexofenadine in the morning for folks who don’t tolerate cetirizine, then I’ll recommend something a little more sedating at night,” Dr. Friedman said. “We max out [the dose] by week 4. If it works, great. If not, we move on to something else.”

In late 2021, the British Association of Dermatologists also published guidelines on the treatment of chronic urticaria.

As for markers of treatment success, a study of 240 children with chronic spontaneous urticaria found that risk factors for a poor response included longer duration of disease, higher treatment step until initial disease control, and food sensitization.

Vitamin D supplementation may also add some benefit. One study of 42 adults with urticaria found that low and high doses of vitamin D added to antihistamine therapy can boost effectiveness. “This may be because vitamin D could be a marker of severity,” Dr. Friedman said. “The reality is, however, that a lot of patients don’t do well.”

Data from the large, prospective study known as AWARE (A World-Wide Antihistamine-Refractory Chronic Urticaria Patient Evaluation) found that 23% patients treated with nonsedating H1-antihistamines and 42% patients treated with up-dosed nonsedating H1-antihistamines had uncontrolled chronic spontaneous urticaria at month 24.

A second-line treatment option for patients aged 6 and older is the anti-IgE antibody omalizumab, 150-300 mg by subcutaneous injection every 4 weeks. Dr. Friedman typically uses only the 300-mg dose. “You do not need to take pretreatment serum IgE levels,” he said. “The most significant adverse event is anaphylaxis, which only affects 0.2% of patients.”

A third-line option is cyclosporine A. A dose of 3-5mg/kg per day appears to benefit about two-thirds of patients with antihistamine recalcitrant chronic urticaria. “It works fast but you can’t keep patients on it for very long,” he said.

Another third-line option is mycophenolate mofetil, which may work by inhibiting the production of autoantibodies to the high-affinity IgE receptor and/or IgE. “It does work well, especially in conjunction with antihistamines; it’s kind of a softer immunosuppressant,” he said. Methotrexate can also be used as an add-on therapy to H1 antihistamine therapy in difficult-to-treat cases.

“It’s great we have [a Food and Drug Administration]–approved biologic therapy in omalizumab and access to over-the-counter antihistamines, but there is a high unmet need for treatment,” and a need for new therapies, Dr. Friedman said. “Only about 39% achieve symptomatic control with conventional dosing of antihistamines, and 63% of nonresponders achieve symptom control with a fourfold increased dosing of antihistamines.” In addition, about 20% of patients will not respond to either standard or increased doses of antihistamines and are eligible for treatment with omalizumab. However, more than 50% of such patients experience a delay or lack of response to omalizumab. “We need innovation; we need to understand the disease better,” he said.

Dr. Friedman disclosed that he serves as a consultant and/or adviser for Loreal, La Roche Posay, Cerave, Galderma, Aveeno, Microcures, Pfizer, Novartis, Dermira, Brickell Biotech, Incyte, UCB, Janssen, Pfizer, Bristol-Myers Squibb, Almirall, Zylo Therapeutics, Hoth Therapeutics, Corbus, Greenway Therapeutics, TruPotency, and Dermavant. He is a speaker for Regeneron/Sanofi, AbbVie, Janssen, Brickell Biotech, and Incyte, and has received grants from Pfizer, the Dermatology Foundation, Incyte, and Galderma.

The Diagnosis: Pemphigoid Gestationis

A lesional biopsy showed a subepidermal split with eosinophils and neutrophils. Perilesional biopsy for direct immunofluorescence (DIF) showed linear deposition of 3+ C3 along the basement membrane zone. The clinical, histopathologic, and immunofluorescent findings were consistent with pemphigoid gestationis (PG). Prednisone 1 mg/kg daily was initiated. Her condition continued to worsen, and cyclosporine 250 mg daily was added while prednisone was tapered, with remission of disease.

Pemphigoid gestationis is an autoimmune bullous dermatosis that occurs in the second or third trimester of pregnancy, with an incidence of 1 in 50,000 to 60,000 pregnancies.¹ In terms of pathogenesis, aberrant expression of major histocompatibility complex class II molecules on placental tissues causes the loss of immune tolerance of the placenta, which leads to the production of antibodies against the placental protein bullous pemphigoid 180.² Bullous pemphigoid 180 also is a hemidesmosomal protein found in the skin of the mother; therefore, the presence of the circulating antibodies leads to separation at the dermoepidermal junction and vesiculation.

Pemphigoid gestationis is characterized by the sudden eruption of intensely pruritic urticarial papules and plaques, classically with periumbilical involvement. Tense vesicles and bullae can develop. Women with PG have an increased risk for development of Graves disease. Histopathology shows subepidermal vesiculation with a predominance of eosinophils. Direct immunofluorescence classically shows linear deposition of C3 along the basement membrane zone. Fetal complications include prematurity and small size for gestational age. Additionally, blisters can be seen in 5% to 10% of neonates due to placental transmission of autoantibodies.³

Frequently PG flares shortly postpartum. Pemphigoid gestationis resolves within 6 months postdelivery but frequently reoccurs in subsequent pregnancies. Mild disease can be treated with mid- to high-potency topical corticosteroids. Severe disease is managed with oral corticosteroids, most commonly prednisone. Refractory disease is managed with azathioprine, cyclosporine, intravenous immunoglobulin, or plasmapheresis.

The differential diagnosis of PG includes other pregnancy-associated dermatoses such as atopic eruption of pregnancy, impetigo herpetiformis, intrahepatic cholestasis of pregnancy, and polymorphous eruption of pregnancy. Atopic eruption of pregnancy is the most common dermatosis of pregnancy and is characterized by an eczematous eruption in patients with an atopic history, typically in the first trimester. Blisters are not seen, and DIF is negative. Impetigo herpetiformis, or pustular psoriasis of pregnancy, is a variant of generalized pustular psoriasis that occurs during pregnancy. Diffuse erythematous patches studded with pustules, rather than vesicles, are seen; DIF is negative. Intrahepatic cholestasis of pregnancy presents without primary skin findings and severe pruritus predominantly on the palms and soles, often with secondary excoriations. Polymorphous eruption of pregnancy presents as a polymorphous eruption of urticarial to erythematous papules and plaques commonly originating in striae. In contrast to PG, there is periumbilical sparing, vesiculation is rare, and DIF is negative.

The Diagnosis: Pemphigoid Gestationis

A lesional biopsy showed a subepidermal split with eosinophils and neutrophils. Perilesional biopsy for direct immunofluorescence (DIF) showed linear deposition of 3+ C3 along the basement membrane zone. The clinical, histopathologic, and immunofluorescent findings were consistent with pemphigoid gestationis (PG). Prednisone 1 mg/kg daily was initiated. Her condition continued to worsen, and cyclosporine 250 mg daily was added while prednisone was tapered, with remission of disease.

Pemphigoid gestationis is an autoimmune bullous dermatosis that occurs in the second or third trimester of pregnancy, with an incidence of 1 in 50,000 to 60,000 pregnancies.¹ In terms of pathogenesis, aberrant expression of major histocompatibility complex class II molecules on placental tissues causes the loss of immune tolerance of the placenta, which leads to the production of antibodies against the placental protein bullous pemphigoid 180.² Bullous pemphigoid 180 also is a hemidesmosomal protein found in the skin of the mother; therefore, the presence of the circulating antibodies leads to separation at the dermoepidermal junction and vesiculation.

Pemphigoid gestationis is characterized by the sudden eruption of intensely pruritic urticarial papules and plaques, classically with periumbilical involvement. Tense vesicles and bullae can develop. Women with PG have an increased risk for development of Graves disease. Histopathology shows subepidermal vesiculation with a predominance of eosinophils. Direct immunofluorescence classically shows linear deposition of C3 along the basement membrane zone. Fetal complications include prematurity and small size for gestational age. Additionally, blisters can be seen in 5% to 10% of neonates due to placental transmission of autoantibodies.³

Frequently PG flares shortly postpartum. Pemphigoid gestationis resolves within 6 months postdelivery but frequently reoccurs in subsequent pregnancies. Mild disease can be treated with mid- to high-potency topical corticosteroids. Severe disease is managed with oral corticosteroids, most commonly prednisone. Refractory disease is managed with azathioprine, cyclosporine, intravenous immunoglobulin, or plasmapheresis.

The differential diagnosis of PG includes other pregnancy-associated dermatoses such as atopic eruption of pregnancy, impetigo herpetiformis, intrahepatic cholestasis of pregnancy, and polymorphous eruption of pregnancy. Atopic eruption of pregnancy is the most common dermatosis of pregnancy and is characterized by an eczematous eruption in patients with an atopic history, typically in the first trimester. Blisters are not seen, and DIF is negative. Impetigo herpetiformis, or pustular psoriasis of pregnancy, is a variant of generalized pustular psoriasis that occurs during pregnancy. Diffuse erythematous patches studded with pustules, rather than vesicles, are seen; DIF is negative. Intrahepatic cholestasis of pregnancy presents without primary skin findings and severe pruritus predominantly on the palms and soles, often with secondary excoriations. Polymorphous eruption of pregnancy presents as a polymorphous eruption of urticarial to erythematous papules and plaques commonly originating in striae. In contrast to PG, there is periumbilical sparing, vesiculation is rare, and DIF is negative.

The Diagnosis: Pemphigoid Gestationis

A lesional biopsy showed a subepidermal split with eosinophils and neutrophils. Perilesional biopsy for direct immunofluorescence (DIF) showed linear deposition of 3+ C3 along the basement membrane zone. The clinical, histopathologic, and immunofluorescent findings were consistent with pemphigoid gestationis (PG). Prednisone 1 mg/kg daily was initiated. Her condition continued to worsen, and cyclosporine 250 mg daily was added while prednisone was tapered, with remission of disease.

Pemphigoid gestationis is an autoimmune bullous dermatosis that occurs in the second or third trimester of pregnancy, with an incidence of 1 in 50,000 to 60,000 pregnancies.¹ In terms of pathogenesis, aberrant expression of major histocompatibility complex class II molecules on placental tissues causes the loss of immune tolerance of the placenta, which leads to the production of antibodies against the placental protein bullous pemphigoid 180.² Bullous pemphigoid 180 also is a hemidesmosomal protein found in the skin of the mother; therefore, the presence of the circulating antibodies leads to separation at the dermoepidermal junction and vesiculation.

Pemphigoid gestationis is characterized by the sudden eruption of intensely pruritic urticarial papules and plaques, classically with periumbilical involvement. Tense vesicles and bullae can develop. Women with PG have an increased risk for development of Graves disease. Histopathology shows subepidermal vesiculation with a predominance of eosinophils. Direct immunofluorescence classically shows linear deposition of C3 along the basement membrane zone. Fetal complications include prematurity and small size for gestational age. Additionally, blisters can be seen in 5% to 10% of neonates due to placental transmission of autoantibodies.³

Frequently PG flares shortly postpartum. Pemphigoid gestationis resolves within 6 months postdelivery but frequently reoccurs in subsequent pregnancies. Mild disease can be treated with mid- to high-potency topical corticosteroids. Severe disease is managed with oral corticosteroids, most commonly prednisone. Refractory disease is managed with azathioprine, cyclosporine, intravenous immunoglobulin, or plasmapheresis.

The differential diagnosis of PG includes other pregnancy-associated dermatoses such as atopic eruption of pregnancy, impetigo herpetiformis, intrahepatic cholestasis of pregnancy, and polymorphous eruption of pregnancy. Atopic eruption of pregnancy is the most common dermatosis of pregnancy and is characterized by an eczematous eruption in patients with an atopic history, typically in the first trimester. Blisters are not seen, and DIF is negative. Impetigo herpetiformis, or pustular psoriasis of pregnancy, is a variant of generalized pustular psoriasis that occurs during pregnancy. Diffuse erythematous patches studded with pustules, rather than vesicles, are seen; DIF is negative. Intrahepatic cholestasis of pregnancy presents without primary skin findings and severe pruritus predominantly on the palms and soles, often with secondary excoriations. Polymorphous eruption of pregnancy presents as a polymorphous eruption of urticarial to erythematous papules and plaques commonly originating in striae. In contrast to PG, there is periumbilical sparing, vesiculation is rare, and DIF is negative.

The Diagnosis: Gamasoidosis

An entomologist confirmed the specimen as an avian mite in either the Dermanyssus or Ornithonyssus genera (quiz image [bottom]). The patient was asked whether any bird had nested around her bedroom, and she affirmed that a woodpecker had nested outside her bedroom closet that spring. She subsequently discovered it had burrowed a hole into her closet wall. She and her husband removed the nest, and within 4 weeks, the eruption permanently cleared.

Gamasoidosis, or avian mite dermatitis, often is an overlooked, difficult-to-make diagnosis that is increasing in prevalence.¹ Bird mites are ectoparasitic arthropods that are 0.3 to 1 mm in length. They have egg-shaped bodies with 4 pairs of legs; they are a translucent brown color before feeding and red after feeding.² Although most avian mites cannot subsist off human blood, if the mites are without an avian host, such as after affected birds abandon their nests, the mites will bite humans.³ Studies have discovered the presence of mammalian erythrocytes in the digestive tracts of one species of bird mite, Dermanyssus gallinae, suggesting that at least one form of avian mite may feed off humans but typically cannot reproduce without an avian blood meal.⁴ Individuals with gamasoidosis often are exposed to avian mites by owning birds as pets, rearing chickens or messenger pigeons, or having bird’s nests around their bedrooms or air conditioning units.¹

Most people who develop avian mite dermatitis are the only affected member of the family to develop pruritus and papules since the reaction requires both bites and hypersensitivity to them; however, there are cases of nuclear families all reacting to avian mite bites.^2,4 As in this case, hypersensitivity to avian mite bites causes exquisitely pruritic 2- to 5-mm papules, vesicles, or urticarial lesions that may be diagnosed as papular urticaria or misdiagnosed as scabies. Although bird mites may carry bacteria such as Salmonella, Spirochaete, Rickettsia, and Pasteurella, they have not demonstrated an ability to pass these on to human vectors.^5,6

Bird mites will spend most of their lives on avian hosts but can spread to humans through direct contact or through air.⁷ Mites can go through floors, walls, ceilings, or most commonly through ventilation or air conditioning units. Increasing urbanization, especially in warmer climates where avian mites thrive, has increased the prevalence of gamasoidosis.¹

Avian mite dermatitis commonly can be mistaken for scabies, but the mites can be seen with the naked eye and cannot form burrows, unlike scabies.^4,8 Avian mites usually are not found on human skin since they leave the host after feeding and move with surprising speed.⁸ Pediculosis corporis (body lice) results from an infestation of Pediculus humanus corporis. At 2- to 4-mm long, this louse is much larger than a bird mite. Body lice rarely are found on the skin but rather live and lay eggs on clothing, particularly along the seams. The body louse has an elongated body with 3 segments and short antennae. Pthirus pubis (pubic lice) measure 1.5 to 2.0 mm in adulthood and have wider, more crablike bodies compared to body or hair lice or avian mites. Lice, being insects, have 6 legs as opposed to mites, being arachnids, having 8 legs. Cheyletiella are 0.5-mm long, nonburrowing mites commonly found on cats, dogs, and rabbits. Cheyletiella blakei affects cats. They look somewhat similar to bird mites but have hooklike palps extending from their heads instead of antennae.

Antihistamines and topical corticosteroids may reduce discomfort from avian bites but are not curative.^2,9 The most efficient way to treat gamasoidosis is to remove any affected birds or nearby bird’s nests, as the mites cannot survive more than a few weeks to months without feeding on an avian host.⁸ It also may be necessary to fumigate infested rooms.¹⁰

The diagnosis of avian mite dermatitis often is missed to the frustration of the patient and clinician alike. Becoming familiar with this bite reaction will help clinicians diagnose this dermatologic conundrum.

The Diagnosis: Gamasoidosis

An entomologist confirmed the specimen as an avian mite in either the Dermanyssus or Ornithonyssus genera (quiz image [bottom]). The patient was asked whether any bird had nested around her bedroom, and she affirmed that a woodpecker had nested outside her bedroom closet that spring. She subsequently discovered it had burrowed a hole into her closet wall. She and her husband removed the nest, and within 4 weeks, the eruption permanently cleared.

Gamasoidosis, or avian mite dermatitis, often is an overlooked, difficult-to-make diagnosis that is increasing in prevalence.¹ Bird mites are ectoparasitic arthropods that are 0.3 to 1 mm in length. They have egg-shaped bodies with 4 pairs of legs; they are a translucent brown color before feeding and red after feeding.² Although most avian mites cannot subsist off human blood, if the mites are without an avian host, such as after affected birds abandon their nests, the mites will bite humans.³ Studies have discovered the presence of mammalian erythrocytes in the digestive tracts of one species of bird mite, Dermanyssus gallinae, suggesting that at least one form of avian mite may feed off humans but typically cannot reproduce without an avian blood meal.⁴ Individuals with gamasoidosis often are exposed to avian mites by owning birds as pets, rearing chickens or messenger pigeons, or having bird’s nests around their bedrooms or air conditioning units.¹

Most people who develop avian mite dermatitis are the only affected member of the family to develop pruritus and papules since the reaction requires both bites and hypersensitivity to them; however, there are cases of nuclear families all reacting to avian mite bites.^2,4 As in this case, hypersensitivity to avian mite bites causes exquisitely pruritic 2- to 5-mm papules, vesicles, or urticarial lesions that may be diagnosed as papular urticaria or misdiagnosed as scabies. Although bird mites may carry bacteria such as Salmonella, Spirochaete, Rickettsia, and Pasteurella, they have not demonstrated an ability to pass these on to human vectors.^5,6

Bird mites will spend most of their lives on avian hosts but can spread to humans through direct contact or through air.⁷ Mites can go through floors, walls, ceilings, or most commonly through ventilation or air conditioning units. Increasing urbanization, especially in warmer climates where avian mites thrive, has increased the prevalence of gamasoidosis.¹

Avian mite dermatitis commonly can be mistaken for scabies, but the mites can be seen with the naked eye and cannot form burrows, unlike scabies.^4,8 Avian mites usually are not found on human skin since they leave the host after feeding and move with surprising speed.⁸ Pediculosis corporis (body lice) results from an infestation of Pediculus humanus corporis. At 2- to 4-mm long, this louse is much larger than a bird mite. Body lice rarely are found on the skin but rather live and lay eggs on clothing, particularly along the seams. The body louse has an elongated body with 3 segments and short antennae. Pthirus pubis (pubic lice) measure 1.5 to 2.0 mm in adulthood and have wider, more crablike bodies compared to body or hair lice or avian mites. Lice, being insects, have 6 legs as opposed to mites, being arachnids, having 8 legs. Cheyletiella are 0.5-mm long, nonburrowing mites commonly found on cats, dogs, and rabbits. Cheyletiella blakei affects cats. They look somewhat similar to bird mites but have hooklike palps extending from their heads instead of antennae.

Antihistamines and topical corticosteroids may reduce discomfort from avian bites but are not curative.^2,9 The most efficient way to treat gamasoidosis is to remove any affected birds or nearby bird’s nests, as the mites cannot survive more than a few weeks to months without feeding on an avian host.⁸ It also may be necessary to fumigate infested rooms.¹⁰

The diagnosis of avian mite dermatitis often is missed to the frustration of the patient and clinician alike. Becoming familiar with this bite reaction will help clinicians diagnose this dermatologic conundrum.

The Diagnosis: Gamasoidosis

An entomologist confirmed the specimen as an avian mite in either the Dermanyssus or Ornithonyssus genera (quiz image [bottom]). The patient was asked whether any bird had nested around her bedroom, and she affirmed that a woodpecker had nested outside her bedroom closet that spring. She subsequently discovered it had burrowed a hole into her closet wall. She and her husband removed the nest, and within 4 weeks, the eruption permanently cleared.

Gamasoidosis, or avian mite dermatitis, often is an overlooked, difficult-to-make diagnosis that is increasing in prevalence.¹ Bird mites are ectoparasitic arthropods that are 0.3 to 1 mm in length. They have egg-shaped bodies with 4 pairs of legs; they are a translucent brown color before feeding and red after feeding.² Although most avian mites cannot subsist off human blood, if the mites are without an avian host, such as after affected birds abandon their nests, the mites will bite humans.³ Studies have discovered the presence of mammalian erythrocytes in the digestive tracts of one species of bird mite, Dermanyssus gallinae, suggesting that at least one form of avian mite may feed off humans but typically cannot reproduce without an avian blood meal.⁴ Individuals with gamasoidosis often are exposed to avian mites by owning birds as pets, rearing chickens or messenger pigeons, or having bird’s nests around their bedrooms or air conditioning units.¹

Most people who develop avian mite dermatitis are the only affected member of the family to develop pruritus and papules since the reaction requires both bites and hypersensitivity to them; however, there are cases of nuclear families all reacting to avian mite bites.^2,4 As in this case, hypersensitivity to avian mite bites causes exquisitely pruritic 2- to 5-mm papules, vesicles, or urticarial lesions that may be diagnosed as papular urticaria or misdiagnosed as scabies. Although bird mites may carry bacteria such as Salmonella, Spirochaete, Rickettsia, and Pasteurella, they have not demonstrated an ability to pass these on to human vectors.^5,6

Bird mites will spend most of their lives on avian hosts but can spread to humans through direct contact or through air.⁷ Mites can go through floors, walls, ceilings, or most commonly through ventilation or air conditioning units. Increasing urbanization, especially in warmer climates where avian mites thrive, has increased the prevalence of gamasoidosis.¹

Avian mite dermatitis commonly can be mistaken for scabies, but the mites can be seen with the naked eye and cannot form burrows, unlike scabies.^4,8 Avian mites usually are not found on human skin since they leave the host after feeding and move with surprising speed.⁸ Pediculosis corporis (body lice) results from an infestation of Pediculus humanus corporis. At 2- to 4-mm long, this louse is much larger than a bird mite. Body lice rarely are found on the skin but rather live and lay eggs on clothing, particularly along the seams. The body louse has an elongated body with 3 segments and short antennae. Pthirus pubis (pubic lice) measure 1.5 to 2.0 mm in adulthood and have wider, more crablike bodies compared to body or hair lice or avian mites. Lice, being insects, have 6 legs as opposed to mites, being arachnids, having 8 legs. Cheyletiella are 0.5-mm long, nonburrowing mites commonly found on cats, dogs, and rabbits. Cheyletiella blakei affects cats. They look somewhat similar to bird mites but have hooklike palps extending from their heads instead of antennae.

Antihistamines and topical corticosteroids may reduce discomfort from avian bites but are not curative.^2,9 The most efficient way to treat gamasoidosis is to remove any affected birds or nearby bird’s nests, as the mites cannot survive more than a few weeks to months without feeding on an avian host.⁸ It also may be necessary to fumigate infested rooms.¹⁰

The diagnosis of avian mite dermatitis often is missed to the frustration of the patient and clinician alike. Becoming familiar with this bite reaction will help clinicians diagnose this dermatologic conundrum.

To the Editor:

Minocycline is a commonly prescribed semisynthetic tetracycline derivative used for long-term treatment of acne vulgaris.¹ Given the continued popularity of minocycline and other tetracyclines in treating acne, more adverse side effects are being reported. We report a patient who experienced acute severe urticaria with angioedema from minocycline.

A 35-year-old woman with a history of acne vulgaris presented to the emergency department with urticaria and associated angioedema. Fifteen days after starting minocycline, she awoke with diffuse hives sparing only the abdomen that resolved with diphenhydramine. Later that day, she developed generalized pruritus, hives, and lip swelling. She received intravenous methylprednisolone, diphenhydramine, and famotidine in the emergency department. She returned to the emergency department the next day due to facial and lip swelling, diffuse urticaria that was most pronounced on the arms, and throat irritation. Intramuscular epinephrine was administered first followed by methylprednisolone, famotidine, and cetirizine. She was discharged and advised to start daily prednisone 50 mg and cetirizine 20 mg every evening.

She returned to the emergency department the following morning due to worsening generalized urticaria and angioedema of the lips. She denied any associated respiratory, joint, or gastrointestinal tract symptoms. She had several urticarial plaques on the scalp, face, and body (Figure), only sparing the abdomen. Her hives were erythematous, raised, pruritic, and blanching. There was no residual purpura, ecchymosis, or hyperpigmentation associated with the urticaria, and each lesion was present for less than 24 hours. There was no swelling on examination. Additionally, she was afebrile. The C4 level was 18 mg/dL (reference range, 15–45 mg/dL). She did not develop eosinophilia (absolute eosinophil count, 0/µL [reference range, 50–500/µL]), lymphocytosis (absolute lymphocyte count, 1300/µL [reference range, 1000–4800/µL]), or abnormal liver or renal function. She was hospitalized for 3 days with severe urticaria and required 7 days of prednisone 40 to 50 mg, fexofenadine 360 mg, and cetirizine 20 mg. A viral infection was considered as a possible etiology; however, she had no supporting signs or symptoms of an upper respiratory illness or other viral illness.

The patient’s minocycline use was considered the most likely etiology, as an oral contraceptive was the only other medication. She was labelled allergic to minocycline and discharged with intramuscular epinephrine. She was evaluated in the outpatient allergy immunology clinic 9 days later, and all her symptoms had resolved. Due to the severity of our patient’s reaction and the possibility of further severe reactions, an oral challenge was not carried out. Our patient was not interested in pursuing any further minocycline or other tetracycline-based therapy for her acne. She also was not interested in pursuing any minocycline skin-prick testing or oral challenge. One limitation to this case is our patient declining a confirmatory drug challenge; however, given the severity of the symptoms, the physicians involved agreed the patient's safety outweighed the benefits of confirmatory testing.

A PubMed search of articles indexed for MEDLINE and a Google Scholar search using the terms minocycline, drug hypersensitivity, urticaria, anaphylaxis, minocycline allergy, and angioedema yielded only 16 articles and correspondences. Reported adverse effects of minocycline included drug-induced lupus erythematosus, vasculitis, nausea, photosensitivity, and DRESS-like (drug reaction with eosinophilia and systemic symptoms syndrome) conditions. Three case reports of anaphylaxis/anaphylactoid reactions have been published,^2-4 but cases of urticaria attributable to minocycline appear to be exceedingly rare.^2,3 Reports of serum sickness in patients aged 15 to 62 years were rare. Women were noted to experience a higher frequency of adverse effects compared to men.⁵ Symptoms typically presented 3 to 28 days after initiation of minocycline. Data currently suggest that the pathogenesis of hypersensitivity reactions to minocycline remains unknown⁶; however, one hypothesis is that minocycline or its metabolites act as a superantigen, resulting in lymphocyte overactivation and massive cytokine release.⁷

Minocycline generally is well tolerated by patients. Physicians should be aware that minocycline is a possible causative agent of allergic drug reactions. Our patient’s presentation of severe acute urticaria with angioedema of the face and lips is a rarity.

To the Editor:

Minocycline is a commonly prescribed semisynthetic tetracycline derivative used for long-term treatment of acne vulgaris.¹ Given the continued popularity of minocycline and other tetracyclines in treating acne, more adverse side effects are being reported. We report a patient who experienced acute severe urticaria with angioedema from minocycline.

A 35-year-old woman with a history of acne vulgaris presented to the emergency department with urticaria and associated angioedema. Fifteen days after starting minocycline, she awoke with diffuse hives sparing only the abdomen that resolved with diphenhydramine. Later that day, she developed generalized pruritus, hives, and lip swelling. She received intravenous methylprednisolone, diphenhydramine, and famotidine in the emergency department. She returned to the emergency department the next day due to facial and lip swelling, diffuse urticaria that was most pronounced on the arms, and throat irritation. Intramuscular epinephrine was administered first followed by methylprednisolone, famotidine, and cetirizine. She was discharged and advised to start daily prednisone 50 mg and cetirizine 20 mg every evening.

She returned to the emergency department the following morning due to worsening generalized urticaria and angioedema of the lips. She denied any associated respiratory, joint, or gastrointestinal tract symptoms. She had several urticarial plaques on the scalp, face, and body (Figure), only sparing the abdomen. Her hives were erythematous, raised, pruritic, and blanching. There was no residual purpura, ecchymosis, or hyperpigmentation associated with the urticaria, and each lesion was present for less than 24 hours. There was no swelling on examination. Additionally, she was afebrile. The C4 level was 18 mg/dL (reference range, 15–45 mg/dL). She did not develop eosinophilia (absolute eosinophil count, 0/µL [reference range, 50–500/µL]), lymphocytosis (absolute lymphocyte count, 1300/µL [reference range, 1000–4800/µL]), or abnormal liver or renal function. She was hospitalized for 3 days with severe urticaria and required 7 days of prednisone 40 to 50 mg, fexofenadine 360 mg, and cetirizine 20 mg. A viral infection was considered as a possible etiology; however, she had no supporting signs or symptoms of an upper respiratory illness or other viral illness.

The patient’s minocycline use was considered the most likely etiology, as an oral contraceptive was the only other medication. She was labelled allergic to minocycline and discharged with intramuscular epinephrine. She was evaluated in the outpatient allergy immunology clinic 9 days later, and all her symptoms had resolved. Due to the severity of our patient’s reaction and the possibility of further severe reactions, an oral challenge was not carried out. Our patient was not interested in pursuing any further minocycline or other tetracycline-based therapy for her acne. She also was not interested in pursuing any minocycline skin-prick testing or oral challenge. One limitation to this case is our patient declining a confirmatory drug challenge; however, given the severity of the symptoms, the physicians involved agreed the patient's safety outweighed the benefits of confirmatory testing.

A PubMed search of articles indexed for MEDLINE and a Google Scholar search using the terms minocycline, drug hypersensitivity, urticaria, anaphylaxis, minocycline allergy, and angioedema yielded only 16 articles and correspondences. Reported adverse effects of minocycline included drug-induced lupus erythematosus, vasculitis, nausea, photosensitivity, and DRESS-like (drug reaction with eosinophilia and systemic symptoms syndrome) conditions. Three case reports of anaphylaxis/anaphylactoid reactions have been published,^2-4 but cases of urticaria attributable to minocycline appear to be exceedingly rare.^2,3 Reports of serum sickness in patients aged 15 to 62 years were rare. Women were noted to experience a higher frequency of adverse effects compared to men.⁵ Symptoms typically presented 3 to 28 days after initiation of minocycline. Data currently suggest that the pathogenesis of hypersensitivity reactions to minocycline remains unknown⁶; however, one hypothesis is that minocycline or its metabolites act as a superantigen, resulting in lymphocyte overactivation and massive cytokine release.⁷

Minocycline generally is well tolerated by patients. Physicians should be aware that minocycline is a possible causative agent of allergic drug reactions. Our patient’s presentation of severe acute urticaria with angioedema of the face and lips is a rarity.

To the Editor:

Minocycline is a commonly prescribed semisynthetic tetracycline derivative used for long-term treatment of acne vulgaris.¹ Given the continued popularity of minocycline and other tetracyclines in treating acne, more adverse side effects are being reported. We report a patient who experienced acute severe urticaria with angioedema from minocycline.

A 35-year-old woman with a history of acne vulgaris presented to the emergency department with urticaria and associated angioedema. Fifteen days after starting minocycline, she awoke with diffuse hives sparing only the abdomen that resolved with diphenhydramine. Later that day, she developed generalized pruritus, hives, and lip swelling. She received intravenous methylprednisolone, diphenhydramine, and famotidine in the emergency department. She returned to the emergency department the next day due to facial and lip swelling, diffuse urticaria that was most pronounced on the arms, and throat irritation. Intramuscular epinephrine was administered first followed by methylprednisolone, famotidine, and cetirizine. She was discharged and advised to start daily prednisone 50 mg and cetirizine 20 mg every evening.

She returned to the emergency department the following morning due to worsening generalized urticaria and angioedema of the lips. She denied any associated respiratory, joint, or gastrointestinal tract symptoms. She had several urticarial plaques on the scalp, face, and body (Figure), only sparing the abdomen. Her hives were erythematous, raised, pruritic, and blanching. There was no residual purpura, ecchymosis, or hyperpigmentation associated with the urticaria, and each lesion was present for less than 24 hours. There was no swelling on examination. Additionally, she was afebrile. The C4 level was 18 mg/dL (reference range, 15–45 mg/dL). She did not develop eosinophilia (absolute eosinophil count, 0/µL [reference range, 50–500/µL]), lymphocytosis (absolute lymphocyte count, 1300/µL [reference range, 1000–4800/µL]), or abnormal liver or renal function. She was hospitalized for 3 days with severe urticaria and required 7 days of prednisone 40 to 50 mg, fexofenadine 360 mg, and cetirizine 20 mg. A viral infection was considered as a possible etiology; however, she had no supporting signs or symptoms of an upper respiratory illness or other viral illness.

The patient’s minocycline use was considered the most likely etiology, as an oral contraceptive was the only other medication. She was labelled allergic to minocycline and discharged with intramuscular epinephrine. She was evaluated in the outpatient allergy immunology clinic 9 days later, and all her symptoms had resolved. Due to the severity of our patient’s reaction and the possibility of further severe reactions, an oral challenge was not carried out. Our patient was not interested in pursuing any further minocycline or other tetracycline-based therapy for her acne. She also was not interested in pursuing any minocycline skin-prick testing or oral challenge. One limitation to this case is our patient declining a confirmatory drug challenge; however, given the severity of the symptoms, the physicians involved agreed the patient's safety outweighed the benefits of confirmatory testing.

A PubMed search of articles indexed for MEDLINE and a Google Scholar search using the terms minocycline, drug hypersensitivity, urticaria, anaphylaxis, minocycline allergy, and angioedema yielded only 16 articles and correspondences. Reported adverse effects of minocycline included drug-induced lupus erythematosus, vasculitis, nausea, photosensitivity, and DRESS-like (drug reaction with eosinophilia and systemic symptoms syndrome) conditions. Three case reports of anaphylaxis/anaphylactoid reactions have been published,^2-4 but cases of urticaria attributable to minocycline appear to be exceedingly rare.^2,3 Reports of serum sickness in patients aged 15 to 62 years were rare. Women were noted to experience a higher frequency of adverse effects compared to men.⁵ Symptoms typically presented 3 to 28 days after initiation of minocycline. Data currently suggest that the pathogenesis of hypersensitivity reactions to minocycline remains unknown⁶; however, one hypothesis is that minocycline or its metabolites act as a superantigen, resulting in lymphocyte overactivation and massive cytokine release.⁷

Minocycline generally is well tolerated by patients. Physicians should be aware that minocycline is a possible causative agent of allergic drug reactions. Our patient’s presentation of severe acute urticaria with angioedema of the face and lips is a rarity.

Kowtoniuk RA, Liu YE, Jeter JP. Cutaneous cold weather injuries in the US Military. Cutis. 2021;108:181-184, 202. doi:10.12788/cutis.0363

In the article above from the October 2021 issue, an author’s name was spelled incorrectly. The correct byline appears below. The article has been corrected online at www.mdedge.com/dermatology. We apologize for the error.

Robert A. Kowtoniuk, DO; Yizhen E. Liu, MD; Jonathan P. Jeter, MD

Kowtoniuk RA, Liu YE, Jeter JP. Cutaneous cold weather injuries in the US Military. Cutis. 2021;108:181-184, 202. doi:10.12788/cutis.0363

In the article above from the October 2021 issue, an author’s name was spelled incorrectly. The correct byline appears below. The article has been corrected online at www.mdedge.com/dermatology. We apologize for the error.

Robert A. Kowtoniuk, DO; Yizhen E. Liu, MD; Jonathan P. Jeter, MD

Kowtoniuk RA, Liu YE, Jeter JP. Cutaneous cold weather injuries in the US Military. Cutis. 2021;108:181-184, 202. doi:10.12788/cutis.0363

In the article above from the October 2021 issue, an author’s name was spelled incorrectly. The correct byline appears below. The article has been corrected online at www.mdedge.com/dermatology. We apologize for the error.

Robert A. Kowtoniuk, DO; Yizhen E. Liu, MD; Jonathan P. Jeter, MD

The US Department of Defense maintains a presence in several cold weather environments such as North Dakota, Alaska, and South Korea. Although much is known about preventing and caring for cold weather injuries, many of these ailments continue to occur. Therefore, it is vital that both military and civilian physicians who care for patients who are exposed to cold weather conditions have a thorough understanding of the prevention, clinical presentation, and treatment of cold weather injuries.

Although the focus of this article is on cutaneous cold weather injuries that occur in military service, these types of injuries are not limited to this population. Civilians who live, work, or seek recreation in cold climates also may experience these injuries. Classically, cold injuries are classified as freezing and nonfreezing injuries. For the purpose of this article, we also consider a third category: dermatologic conditions that flare upon cold exposure. Specifically, we discuss frostbite, cold-weather immersion foot, pernio, Raynaud phenomenon (RP), and cold urticaria. We also present a case of pernio in an active-duty military service member.

Frostbite

For centuries, frostbite has been well documented as a cold weather injury in military history.¹ Napoleon’s catastrophic invasion of Russia in 1812 started with 612,000 troops and ended with fewer than 10,000 effective soldiers; while many factors contributed to this attrition, exposure to cold weather and frostbite is thought to have been a major factor. The muddy trench warfare of World War I was no kinder to the poorly equipped soldiers across the European theater. Decades later during World War II, frostbite was a serious source of noncombat injuries, as battles were fought in frigid European winters. From 1942 to 1945, there were 13,196 reported cases of frostbite in the European theater, with most of these injuries occurring in 1945.¹

Despite advancements in cold weather clothing and increased knowledge about the causes of and preventative measures for frostbite, cold weather injuries continue to be a relevant topic in today’s military. From 2015 to 2020, there were 1120 reported cases of frostbite in the US military.² When skin is exposed to cold temperatures, the body peripherally vasoconstricts to reduce core heat loss. This autoregulatory vasoconstriction is part of a normal physiologic response that preserves the core body temperature, often at the expense of the extremities; for instance, the hands and feet are equipped with arteriovenous shunts, known as glomus bodies, which consist of vascular smooth muscle centers that control the flow of blood in response to changing external temperatures.³ This is partially mitigated by cold-induced vasodilation of the digits, also known as the Hunting reaction, which generally occurs 5 to 10 minutes after the start of local cold exposure.⁴ Additionally, discomfort from cold exposure warrants behavioral modifications such as going indoors, putting on warmer clothing, or building a fire. If an individual is unable to seek shelter in the face of cold exposure, the cold will inevitably cause injury.

Frostbite is caused by both direct and indirect cellular injury. Direct injury results from the crystallization of intracellular and interstitial fluids, cellular dehydration, and electrolyte disturbances. Indirect cellular injury is the result of a progressive microvascular insult and is caused by microvascular thrombosis, endothelial damage, intravascular sludging, inflammatory mediators, free radicals, and reperfusion injury.⁵

Frostnip is a more superficial injury that does not involve freezing of the skin or underlying tissue and typically does not leave any long-term damage. As severity of injury increases, frostbite is characterized by the depth of injury, presence of tissue loss, and radiotracer uptake on bone scan. There are 2 main classification systems for frostbite: one is based on the severity of the injury outcome, categorized by 4 degrees (1–4), and the other is designed as a predictive model, categorized by 4 grades (1–4).⁶ The first classification system is similar to the system for the severity of burns and ranges from partial-thickness injury (first degree) to full-thickness skin, subcutaneous tissue, muscle, tendon, and bone (fourth degree). The latter classification system uses the presence and characteristics of blisters after rewarming on days 0 and 2 and radiotracer uptake on bone scan on day 2. Severity ranges from no blistering, no indicated bone scan, and no long-term sequelae in grade 1 to hemorrhagic blisters overlying the carpal or tarsal bones and absence of radiotracer uptake with predicted extensive amputation, risk for thrombosis or sepsis, and long-term functional sequelae in grade 4.⁶

Male sex and African descent are associated with increased risk for sustaining frostbite. The ethnic predisposition may be explained by a less robust Hunting reaction in individuals of African descent.^4,7 Other risk factors include alcohol use, smoking, homelessness, history of cold-related injury, use of beta-blockers, and working with equipment that uses nitrogen dioxide or CO₂.⁵ Additionally, a history of systemic lupus erythematosus has been reported as a risk factor for frostbite.⁸

Clinically, frostbite initially may appear pale, blue, or erythematous, and patients may report skin numbness. In severe cases, necrosis can be seen.⁹ The most commonly affected anatomic locations include the fingers, toes, ears, and nose. Prevention is key for frostbite injuries. Steps to avoid injury include wearing appropriate clothing, minimizing the duration of time the skin is exposed to cold temperatures, avoiding alcohol consumption, and avoiding physical exhaustion in cold weather. These steps can help mitigate the effects of wind chill and low temperatures and decrease the risk of frostbite.¹⁰

Management of this condition includes prevention, early diagnosis, prehospital management, hospital management, and long-term sequelae management. Leadership and medical personnel for military units assigned to cold climates should be vigilant in looking for symptoms of frostbite. If any one individual is found to have frostbite or any other cold injury, all other team members should be evaluated.⁵

After identification of frostbite, seeking shelter and evacuation to a treatment facility are vital next steps. Constrictive clothing or jewelry should be removed. Depending on the situation, rewarming can be attempted in the prehospital setting, but it is imperative to avoid refreezing, as this may further damage the affected tissue due to intracellular ice formation with extensive cell destruction.⁶ Gentle warming can be attempted by placing the affected extremity in another person’s armpit or groin for up to 10 minutes or by immersing the affected limb in water that is 37° C to 39° C (98.6° F to 102.2° F). Rubbing the affected area and dry heat should be avoided. It should be noted that the decision to thaw in the field introduces the challenge of dealing with the severe pain associated with thawing in a remote or hostile environment. Ibuprofen (400 mg) can be given as an anti-inflammatory and analgesic agent in the prehospital setting.⁵ Once safely evacuated to the hospital, treatment options expand dramatically, including warming without concern of refreezing, wound care, thrombolytic therapy, and surgical intervention. If local frostbite expertise is not available, there are telemedicine services available.^5,6

Frostbite outcomes range from complete recovery to amputation. Previously frostbitten tissue has increased cold sensitivity and is more susceptible to similar injury in the future. Additionally, there can be functional loss, chronic pain, chronic ulceration, and arthritis.^5,6 As such, a history of frostbite can be disqualifying for military service and requires a medical waiver.¹¹ If a service member experiences frostbite and does not have any residual effects, they can expect to continue their military service, but if there are sequelae, it may prove to be career limiting.^12-14

Immersion Foot

Although frostbite represents a freezing injury, immersion foot (or trench foot) represents a nonfreezing cold injury. It should be noted that in addition to immersion foot associated with cold water exposure, there also are warm-water and tropical variants. For the purpose of this article, we are referring to immersion foot associated with exposure to cold water. Trench foot was described for the first time during Napoleon’s invasion of Russia in 1812 but came to prominence during World War I, where it is thought to have contributed to the deaths of 75,000 British soldiers. During World War II, there were 25,016 cases of immersion foot reported in the US military.¹ More recently, 590 cases of immersion foot were reported in the US military from 2015 to 2020.²

Classically, this condition was seen in individuals whose feet were immersed in cold but not freezing water or mud in trenches or on boats, hence the terms immersion foot and trench foot. The pathogenesis is thought to be related to overhydration of the stratum corneum and repetitive cycles of cold-induced, thermoprotective vasoconstriction, leading to cyclical hypoxic and reperfusion injuries, which eventually damage nerves, muscle, subcutaneous fat, and blood vessels.^9,15

A recent case series of 100 military service members in the United Kingdom showed that cold-induced extremity numbness for more than 30 minutes and painful rewarming after cold exposure were highly correlated with the development of immersion foot. Additionally, this case series showed that patients with repeated cycles of cooling and rewarming were more likely to have long-term symptoms.¹⁶ As with frostbite, prior cold injury and African descent increases the risk for developing immersion foot, possibly due to a less-pronounced Hunting reaction.^4,7

Early reports suggested prehyperemic, hyperemic, and posthyperemic stages. The prehyperemic stage lasts from hours to days and is characterized by cold extremities, discoloration, edema, stocking- or glove-distributed anesthesia, blisters, necrosis, and potential loss of palpable pulses.¹⁷ Of note, in Kuht et al’s¹⁶ more recent case series, edema was not seen as frequently as in prior reports. The hyperemic stage can last for 6 to 10 weeks and is characterized by vascular disturbances. In addition, the affected extremity typically remains warm and red even when exposed to cold temperatures. Sensory disturbances such as paresthesia and hyperalgesia may be seen, as well as motor disturbances, anhidrosis, blisters, ulcers, and gangrene. The posthyperemic stage can last from months to years and is characterized by cold sensitivity, possible digital blanching, edema, hyperhidrosis, and persistent peripheral neuropathy.¹⁶

Prevention is the most important treatment for immersion foot. The first step in preventing this injury is avoiding prolonged cold exposure. When this is not possible due to the demands of training or actual combat conditions, regular hand and foot inspections, frequent sock changes, and regularly rotating out of cold wet conditions can help prevent this injury.¹⁵ Vasodilators also have been considered as a possible treatment modality. Iloprost and nicotinyl alcohol tartrate showed some improvement, while aminophylline and papaverine were ineffective.¹⁵

As with frostbite, a history of immersion foot may be disqualifying for military service.¹¹ If it occurs during military service and there are no residual effects that limit the service member’s capabilities, they may expect to continue their career; however, if there are residual effects that limit activity or deployment, medical retirement may be indicated.

Pernio

Pernio is another important condition that is related to cold exposure; however, unlike the previous 2 conditions, it is not necessarily caused by cold exposure but rather flares with cold exposure.

Case Presentation—A 39-year-old active-duty male service member presented to the dermatology clinic for intermittent painful blistering on the toes of both feet lasting approximately 10 to 14 days about 3 to 4 times per year for the last several years. The patient reported that his symptoms started after spending 2 days in the snow with wet nonwinterized boots while stationed in Germany 10 years prior. He reported cold weather as his only associated trigger and denied other associated symptoms. Physical examination revealed mildly cyanotic toes containing scattered bullae, with the dorsal lesions appearing more superficial compared to the deeper plantar bullae (Figure 1). A complete blood cell count, serum protein electrophoresis, and antinuclear and autoimmune antibodies were within reference range. A punch biopsy was obtained from a lesion on the right dorsal great toe. Hematoxylin and eosin–stained sections revealed lichenoid and vacuolar dermatitis with scattered dyskeratosis and subtle papillary edema (Figure 2). Minimal interstitial mucin was seen on Alcian blue–stained sections. The histologic and clinical findings were most compatible with a diagnosis of chronic pernio. Nifedipine 20 mg once daily was initiated, and he had minimal improvement after a few months of treatment. His condition continued to limit his functionality in cold conditions due to pain. Without improvement of the symptoms, the patient likely will require medical separation from military service, as this condition limits the performance of his duties and his deployability.

Clinical Discussion—Pernio, also known as chilblains, is characterized by cold-induced erythematous patches and plaques, pain, and pruritus on the affected skin.¹⁸ Bullae and ulceration can be seen in more severe and chronic cases.¹⁹ Pernio most commonly is seen in young women but also can be seen in children, men, and older adults. It usually occurs on the tips of toes but also may affect the fingers, nose, and ears. It typically is observed in cold and damp conditions and is thought to be caused by an inflammatory response to vasospasms in the setting of nonfreezing cold. Acute pernio typically resolves after a few weeks; however, it also can persist in a chronic form after repeated cold exposure.¹⁸

Predisposing factors include excessive cold exposure, connective tissue disease, hematologic malignancy, antiphospholipid antibodies in adults, and anorexia nervosa in children.^18,20,21 More recently, perniolike lesions have been associated with prior SARS-CoV-2 infection.²² Histologically, pernio is characterized by a perivascular lymphocytic infiltrate and dermal edema.²³ Cold avoidance, warming, drying, and smoking cessation are primary treatments, while vasodilating medications such as nifedipine have been used with success in more resistant cases.^20,24

Although the prognosis generally is excellent, this condition also can be career limiting for military service members. If it resolves with no residual effects, patients can expect to continue their service; however, if it persists and limits their activity or ability to deploy, a medical retirement may be indicated.^11-14

Raynaud Phenomenon

Raynaud phenomenon (also known as Raynaud’s) is characterized by cold-induced extremity triphasic color changes—initial blanching and pallor that transitions to cyanosis and finally erythema with associated pain during the recovery stage. The fingers are the most commonly involved appendages and can have a symmetric distribution, but RP also has been observed on the feet, lips, nose, and ears. In severe cases, it can cause ulceration.²⁵ The prevalence of RP may be as high as 5% in the general population.²⁶ It more commonly is primary or idiopathic with no underlying cause or secondary with an associated underlying systemic disease.

Cold-induced vasoconstriction is a normal physiologic response, but in RP, the response becomes a vasospasm and is pathological. Autoimmune and connective tissue diseases often are associated with secondary RP. Other risk factors include female sex, smoking, family history in a first-degree relative, and certain medications.²⁵ A study in northern Sweden also identified a history of frostbite as a risk factor for the development of RP.²⁷ This condition can notably restrict mobility and deployability of affected service members as well as the types of manual tasks that they may be required to perform. As such, this condition can be disqualifying for military service.¹¹

Many patients improve with conservative treatment consisting of cold avoidance, smoking cessation, and avoidance of medications that worsen the vasospasm; however, some patients develop pain and chronic disease, which can become so severe and ischemic that digital loss is threatened.²⁵ When needed, calcium channel blockers commonly are used for treatment and can be used prophylactically to reduce flare rates and severity of disease. If this class of medications is ineffective or is not tolerated, there are other medications and treatments to consider, which are beyond the scope of this article.²⁵

Cold Urticaria

Cold urticaria is a subset of physical urticaria in which symptoms occur in response to a cutaneous cold stimulus. It can be primary or secondary, with potential underlying causes including cryoglobulinemia, infections, and some medications. Systemic involvement is possible with extensive cold contact and can include severe anaphylaxis. This condition is diagnosed using a cold stimulation test. Cold exposure avoidance and second-generation antihistamines are considered first-line treatment. Because anaphylaxis is possible, patients should be given an epinephrine pen and should be instructed to avoid swimming in cold water.²⁸ Cold urticaria is disqualifying for military service.¹¹

A 2013 case report described a 29-year-old woman on active duty in the US Air Force whose presenting symptoms included urticaria on the exposed skin on the arms when doing physical training in the rain.²⁹ In this case, secondary causes were eliminated, and she was diagnosed with primary acquired cold urticaria. This patient was eventually medically discharged from the air force because management with antihistamines failed, and her symptoms limited her ability to function in even mildly cold environments.²⁹

Final Thoughts

An understanding of cold weather injuries and other dermatologic conditions that may be flared by cold exposure is important for a medically ready military force, as there are implications for accession, training, and combat operations. Although the focus of this article has been on the military, these conditions also are seen in civilian medicine in patient populations routinely exposed to cold weather. This becomes especially pertinent in high-risk patients such as extreme athletes, homeless individuals, or those who have other predisposing characteristics such as chronic alcohol use. Appropriate cold weather gear, training, and deliberate mission or activity planning are important interventions in preventing cutaneous cold weather injuries within the military.

The US Department of Defense maintains a presence in several cold weather environments such as North Dakota, Alaska, and South Korea. Although much is known about preventing and caring for cold weather injuries, many of these ailments continue to occur. Therefore, it is vital that both military and civilian physicians who care for patients who are exposed to cold weather conditions have a thorough understanding of the prevention, clinical presentation, and treatment of cold weather injuries.

Although the focus of this article is on cutaneous cold weather injuries that occur in military service, these types of injuries are not limited to this population. Civilians who live, work, or seek recreation in cold climates also may experience these injuries. Classically, cold injuries are classified as freezing and nonfreezing injuries. For the purpose of this article, we also consider a third category: dermatologic conditions that flare upon cold exposure. Specifically, we discuss frostbite, cold-weather immersion foot, pernio, Raynaud phenomenon (RP), and cold urticaria. We also present a case of pernio in an active-duty military service member.

Frostbite

For centuries, frostbite has been well documented as a cold weather injury in military history.¹ Napoleon’s catastrophic invasion of Russia in 1812 started with 612,000 troops and ended with fewer than 10,000 effective soldiers; while many factors contributed to this attrition, exposure to cold weather and frostbite is thought to have been a major factor. The muddy trench warfare of World War I was no kinder to the poorly equipped soldiers across the European theater. Decades later during World War II, frostbite was a serious source of noncombat injuries, as battles were fought in frigid European winters. From 1942 to 1945, there were 13,196 reported cases of frostbite in the European theater, with most of these injuries occurring in 1945.¹

Despite advancements in cold weather clothing and increased knowledge about the causes of and preventative measures for frostbite, cold weather injuries continue to be a relevant topic in today’s military. From 2015 to 2020, there were 1120 reported cases of frostbite in the US military.² When skin is exposed to cold temperatures, the body peripherally vasoconstricts to reduce core heat loss. This autoregulatory vasoconstriction is part of a normal physiologic response that preserves the core body temperature, often at the expense of the extremities; for instance, the hands and feet are equipped with arteriovenous shunts, known as glomus bodies, which consist of vascular smooth muscle centers that control the flow of blood in response to changing external temperatures.³ This is partially mitigated by cold-induced vasodilation of the digits, also known as the Hunting reaction, which generally occurs 5 to 10 minutes after the start of local cold exposure.⁴ Additionally, discomfort from cold exposure warrants behavioral modifications such as going indoors, putting on warmer clothing, or building a fire. If an individual is unable to seek shelter in the face of cold exposure, the cold will inevitably cause injury.

Frostbite is caused by both direct and indirect cellular injury. Direct injury results from the crystallization of intracellular and interstitial fluids, cellular dehydration, and electrolyte disturbances. Indirect cellular injury is the result of a progressive microvascular insult and is caused by microvascular thrombosis, endothelial damage, intravascular sludging, inflammatory mediators, free radicals, and reperfusion injury.⁵

Frostnip is a more superficial injury that does not involve freezing of the skin or underlying tissue and typically does not leave any long-term damage. As severity of injury increases, frostbite is characterized by the depth of injury, presence of tissue loss, and radiotracer uptake on bone scan. There are 2 main classification systems for frostbite: one is based on the severity of the injury outcome, categorized by 4 degrees (1–4), and the other is designed as a predictive model, categorized by 4 grades (1–4).⁶ The first classification system is similar to the system for the severity of burns and ranges from partial-thickness injury (first degree) to full-thickness skin, subcutaneous tissue, muscle, tendon, and bone (fourth degree). The latter classification system uses the presence and characteristics of blisters after rewarming on days 0 and 2 and radiotracer uptake on bone scan on day 2. Severity ranges from no blistering, no indicated bone scan, and no long-term sequelae in grade 1 to hemorrhagic blisters overlying the carpal or tarsal bones and absence of radiotracer uptake with predicted extensive amputation, risk for thrombosis or sepsis, and long-term functional sequelae in grade 4.⁶

Male sex and African descent are associated with increased risk for sustaining frostbite. The ethnic predisposition may be explained by a less robust Hunting reaction in individuals of African descent.^4,7 Other risk factors include alcohol use, smoking, homelessness, history of cold-related injury, use of beta-blockers, and working with equipment that uses nitrogen dioxide or CO₂.⁵ Additionally, a history of systemic lupus erythematosus has been reported as a risk factor for frostbite.⁸

Clinically, frostbite initially may appear pale, blue, or erythematous, and patients may report skin numbness. In severe cases, necrosis can be seen.⁹ The most commonly affected anatomic locations include the fingers, toes, ears, and nose. Prevention is key for frostbite injuries. Steps to avoid injury include wearing appropriate clothing, minimizing the duration of time the skin is exposed to cold temperatures, avoiding alcohol consumption, and avoiding physical exhaustion in cold weather. These steps can help mitigate the effects of wind chill and low temperatures and decrease the risk of frostbite.¹⁰

Management of this condition includes prevention, early diagnosis, prehospital management, hospital management, and long-term sequelae management. Leadership and medical personnel for military units assigned to cold climates should be vigilant in looking for symptoms of frostbite. If any one individual is found to have frostbite or any other cold injury, all other team members should be evaluated.⁵

After identification of frostbite, seeking shelter and evacuation to a treatment facility are vital next steps. Constrictive clothing or jewelry should be removed. Depending on the situation, rewarming can be attempted in the prehospital setting, but it is imperative to avoid refreezing, as this may further damage the affected tissue due to intracellular ice formation with extensive cell destruction.⁶ Gentle warming can be attempted by placing the affected extremity in another person’s armpit or groin for up to 10 minutes or by immersing the affected limb in water that is 37° C to 39° C (98.6° F to 102.2° F). Rubbing the affected area and dry heat should be avoided. It should be noted that the decision to thaw in the field introduces the challenge of dealing with the severe pain associated with thawing in a remote or hostile environment. Ibuprofen (400 mg) can be given as an anti-inflammatory and analgesic agent in the prehospital setting.⁵ Once safely evacuated to the hospital, treatment options expand dramatically, including warming without concern of refreezing, wound care, thrombolytic therapy, and surgical intervention. If local frostbite expertise is not available, there are telemedicine services available.^5,6

Frostbite outcomes range from complete recovery to amputation. Previously frostbitten tissue has increased cold sensitivity and is more susceptible to similar injury in the future. Additionally, there can be functional loss, chronic pain, chronic ulceration, and arthritis.^5,6 As such, a history of frostbite can be disqualifying for military service and requires a medical waiver.¹¹ If a service member experiences frostbite and does not have any residual effects, they can expect to continue their military service, but if there are sequelae, it may prove to be career limiting.^12-14

Immersion Foot

Although frostbite represents a freezing injury, immersion foot (or trench foot) represents a nonfreezing cold injury. It should be noted that in addition to immersion foot associated with cold water exposure, there also are warm-water and tropical variants. For the purpose of this article, we are referring to immersion foot associated with exposure to cold water. Trench foot was described for the first time during Napoleon’s invasion of Russia in 1812 but came to prominence during World War I, where it is thought to have contributed to the deaths of 75,000 British soldiers. During World War II, there were 25,016 cases of immersion foot reported in the US military.¹ More recently, 590 cases of immersion foot were reported in the US military from 2015 to 2020.²

Classically, this condition was seen in individuals whose feet were immersed in cold but not freezing water or mud in trenches or on boats, hence the terms immersion foot and trench foot. The pathogenesis is thought to be related to overhydration of the stratum corneum and repetitive cycles of cold-induced, thermoprotective vasoconstriction, leading to cyclical hypoxic and reperfusion injuries, which eventually damage nerves, muscle, subcutaneous fat, and blood vessels.^9,15

A recent case series of 100 military service members in the United Kingdom showed that cold-induced extremity numbness for more than 30 minutes and painful rewarming after cold exposure were highly correlated with the development of immersion foot. Additionally, this case series showed that patients with repeated cycles of cooling and rewarming were more likely to have long-term symptoms.¹⁶ As with frostbite, prior cold injury and African descent increases the risk for developing immersion foot, possibly due to a less-pronounced Hunting reaction.^4,7

Early reports suggested prehyperemic, hyperemic, and posthyperemic stages. The prehyperemic stage lasts from hours to days and is characterized by cold extremities, discoloration, edema, stocking- or glove-distributed anesthesia, blisters, necrosis, and potential loss of palpable pulses.¹⁷ Of note, in Kuht et al’s¹⁶ more recent case series, edema was not seen as frequently as in prior reports. The hyperemic stage can last for 6 to 10 weeks and is characterized by vascular disturbances. In addition, the affected extremity typically remains warm and red even when exposed to cold temperatures. Sensory disturbances such as paresthesia and hyperalgesia may be seen, as well as motor disturbances, anhidrosis, blisters, ulcers, and gangrene. The posthyperemic stage can last from months to years and is characterized by cold sensitivity, possible digital blanching, edema, hyperhidrosis, and persistent peripheral neuropathy.¹⁶

Prevention is the most important treatment for immersion foot. The first step in preventing this injury is avoiding prolonged cold exposure. When this is not possible due to the demands of training or actual combat conditions, regular hand and foot inspections, frequent sock changes, and regularly rotating out of cold wet conditions can help prevent this injury.¹⁵ Vasodilators also have been considered as a possible treatment modality. Iloprost and nicotinyl alcohol tartrate showed some improvement, while aminophylline and papaverine were ineffective.¹⁵

As with frostbite, a history of immersion foot may be disqualifying for military service.¹¹ If it occurs during military service and there are no residual effects that limit the service member’s capabilities, they may expect to continue their career; however, if there are residual effects that limit activity or deployment, medical retirement may be indicated.

Pernio

Pernio is another important condition that is related to cold exposure; however, unlike the previous 2 conditions, it is not necessarily caused by cold exposure but rather flares with cold exposure.

Case Presentation—A 39-year-old active-duty male service member presented to the dermatology clinic for intermittent painful blistering on the toes of both feet lasting approximately 10 to 14 days about 3 to 4 times per year for the last several years. The patient reported that his symptoms started after spending 2 days in the snow with wet nonwinterized boots while stationed in Germany 10 years prior. He reported cold weather as his only associated trigger and denied other associated symptoms. Physical examination revealed mildly cyanotic toes containing scattered bullae, with the dorsal lesions appearing more superficial compared to the deeper plantar bullae (Figure 1). A complete blood cell count, serum protein electrophoresis, and antinuclear and autoimmune antibodies were within reference range. A punch biopsy was obtained from a lesion on the right dorsal great toe. Hematoxylin and eosin–stained sections revealed lichenoid and vacuolar dermatitis with scattered dyskeratosis and subtle papillary edema (Figure 2). Minimal interstitial mucin was seen on Alcian blue–stained sections. The histologic and clinical findings were most compatible with a diagnosis of chronic pernio. Nifedipine 20 mg once daily was initiated, and he had minimal improvement after a few months of treatment. His condition continued to limit his functionality in cold conditions due to pain. Without improvement of the symptoms, the patient likely will require medical separation from military service, as this condition limits the performance of his duties and his deployability.

Clinical Discussion—Pernio, also known as chilblains, is characterized by cold-induced erythematous patches and plaques, pain, and pruritus on the affected skin.¹⁸ Bullae and ulceration can be seen in more severe and chronic cases.¹⁹ Pernio most commonly is seen in young women but also can be seen in children, men, and older adults. It usually occurs on the tips of toes but also may affect the fingers, nose, and ears. It typically is observed in cold and damp conditions and is thought to be caused by an inflammatory response to vasospasms in the setting of nonfreezing cold. Acute pernio typically resolves after a few weeks; however, it also can persist in a chronic form after repeated cold exposure.¹⁸

Predisposing factors include excessive cold exposure, connective tissue disease, hematologic malignancy, antiphospholipid antibodies in adults, and anorexia nervosa in children.^18,20,21 More recently, perniolike lesions have been associated with prior SARS-CoV-2 infection.²² Histologically, pernio is characterized by a perivascular lymphocytic infiltrate and dermal edema.²³ Cold avoidance, warming, drying, and smoking cessation are primary treatments, while vasodilating medications such as nifedipine have been used with success in more resistant cases.^20,24

Although the prognosis generally is excellent, this condition also can be career limiting for military service members. If it resolves with no residual effects, patients can expect to continue their service; however, if it persists and limits their activity or ability to deploy, a medical retirement may be indicated.^11-14

Raynaud Phenomenon

Raynaud phenomenon (also known as Raynaud’s) is characterized by cold-induced extremity triphasic color changes—initial blanching and pallor that transitions to cyanosis and finally erythema with associated pain during the recovery stage. The fingers are the most commonly involved appendages and can have a symmetric distribution, but RP also has been observed on the feet, lips, nose, and ears. In severe cases, it can cause ulceration.²⁵ The prevalence of RP may be as high as 5% in the general population.²⁶ It more commonly is primary or idiopathic with no underlying cause or secondary with an associated underlying systemic disease.

Cold-induced vasoconstriction is a normal physiologic response, but in RP, the response becomes a vasospasm and is pathological. Autoimmune and connective tissue diseases often are associated with secondary RP. Other risk factors include female sex, smoking, family history in a first-degree relative, and certain medications.²⁵ A study in northern Sweden also identified a history of frostbite as a risk factor for the development of RP.²⁷ This condition can notably restrict mobility and deployability of affected service members as well as the types of manual tasks that they may be required to perform. As such, this condition can be disqualifying for military service.¹¹

Many patients improve with conservative treatment consisting of cold avoidance, smoking cessation, and avoidance of medications that worsen the vasospasm; however, some patients develop pain and chronic disease, which can become so severe and ischemic that digital loss is threatened.²⁵ When needed, calcium channel blockers commonly are used for treatment and can be used prophylactically to reduce flare rates and severity of disease. If this class of medications is ineffective or is not tolerated, there are other medications and treatments to consider, which are beyond the scope of this article.²⁵

Cold Urticaria

Cold urticaria is a subset of physical urticaria in which symptoms occur in response to a cutaneous cold stimulus. It can be primary or secondary, with potential underlying causes including cryoglobulinemia, infections, and some medications. Systemic involvement is possible with extensive cold contact and can include severe anaphylaxis. This condition is diagnosed using a cold stimulation test. Cold exposure avoidance and second-generation antihistamines are considered first-line treatment. Because anaphylaxis is possible, patients should be given an epinephrine pen and should be instructed to avoid swimming in cold water.²⁸ Cold urticaria is disqualifying for military service.¹¹

A 2013 case report described a 29-year-old woman on active duty in the US Air Force whose presenting symptoms included urticaria on the exposed skin on the arms when doing physical training in the rain.²⁹ In this case, secondary causes were eliminated, and she was diagnosed with primary acquired cold urticaria. This patient was eventually medically discharged from the air force because management with antihistamines failed, and her symptoms limited her ability to function in even mildly cold environments.²⁹

Final Thoughts

An understanding of cold weather injuries and other dermatologic conditions that may be flared by cold exposure is important for a medically ready military force, as there are implications for accession, training, and combat operations. Although the focus of this article has been on the military, these conditions also are seen in civilian medicine in patient populations routinely exposed to cold weather. This becomes especially pertinent in high-risk patients such as extreme athletes, homeless individuals, or those who have other predisposing characteristics such as chronic alcohol use. Appropriate cold weather gear, training, and deliberate mission or activity planning are important interventions in preventing cutaneous cold weather injuries within the military.

The US Department of Defense maintains a presence in several cold weather environments such as North Dakota, Alaska, and South Korea. Although much is known about preventing and caring for cold weather injuries, many of these ailments continue to occur. Therefore, it is vital that both military and civilian physicians who care for patients who are exposed to cold weather conditions have a thorough understanding of the prevention, clinical presentation, and treatment of cold weather injuries.

Although the focus of this article is on cutaneous cold weather injuries that occur in military service, these types of injuries are not limited to this population. Civilians who live, work, or seek recreation in cold climates also may experience these injuries. Classically, cold injuries are classified as freezing and nonfreezing injuries. For the purpose of this article, we also consider a third category: dermatologic conditions that flare upon cold exposure. Specifically, we discuss frostbite, cold-weather immersion foot, pernio, Raynaud phenomenon (RP), and cold urticaria. We also present a case of pernio in an active-duty military service member.

Frostbite

For centuries, frostbite has been well documented as a cold weather injury in military history.¹ Napoleon’s catastrophic invasion of Russia in 1812 started with 612,000 troops and ended with fewer than 10,000 effective soldiers; while many factors contributed to this attrition, exposure to cold weather and frostbite is thought to have been a major factor. The muddy trench warfare of World War I was no kinder to the poorly equipped soldiers across the European theater. Decades later during World War II, frostbite was a serious source of noncombat injuries, as battles were fought in frigid European winters. From 1942 to 1945, there were 13,196 reported cases of frostbite in the European theater, with most of these injuries occurring in 1945.¹

Despite advancements in cold weather clothing and increased knowledge about the causes of and preventative measures for frostbite, cold weather injuries continue to be a relevant topic in today’s military. From 2015 to 2020, there were 1120 reported cases of frostbite in the US military.² When skin is exposed to cold temperatures, the body peripherally vasoconstricts to reduce core heat loss. This autoregulatory vasoconstriction is part of a normal physiologic response that preserves the core body temperature, often at the expense of the extremities; for instance, the hands and feet are equipped with arteriovenous shunts, known as glomus bodies, which consist of vascular smooth muscle centers that control the flow of blood in response to changing external temperatures.³ This is partially mitigated by cold-induced vasodilation of the digits, also known as the Hunting reaction, which generally occurs 5 to 10 minutes after the start of local cold exposure.⁴ Additionally, discomfort from cold exposure warrants behavioral modifications such as going indoors, putting on warmer clothing, or building a fire. If an individual is unable to seek shelter in the face of cold exposure, the cold will inevitably cause injury.

Frostbite is caused by both direct and indirect cellular injury. Direct injury results from the crystallization of intracellular and interstitial fluids, cellular dehydration, and electrolyte disturbances. Indirect cellular injury is the result of a progressive microvascular insult and is caused by microvascular thrombosis, endothelial damage, intravascular sludging, inflammatory mediators, free radicals, and reperfusion injury.⁵

Frostnip is a more superficial injury that does not involve freezing of the skin or underlying tissue and typically does not leave any long-term damage. As severity of injury increases, frostbite is characterized by the depth of injury, presence of tissue loss, and radiotracer uptake on bone scan. There are 2 main classification systems for frostbite: one is based on the severity of the injury outcome, categorized by 4 degrees (1–4), and the other is designed as a predictive model, categorized by 4 grades (1–4).⁶ The first classification system is similar to the system for the severity of burns and ranges from partial-thickness injury (first degree) to full-thickness skin, subcutaneous tissue, muscle, tendon, and bone (fourth degree). The latter classification system uses the presence and characteristics of blisters after rewarming on days 0 and 2 and radiotracer uptake on bone scan on day 2. Severity ranges from no blistering, no indicated bone scan, and no long-term sequelae in grade 1 to hemorrhagic blisters overlying the carpal or tarsal bones and absence of radiotracer uptake with predicted extensive amputation, risk for thrombosis or sepsis, and long-term functional sequelae in grade 4.⁶

Male sex and African descent are associated with increased risk for sustaining frostbite. The ethnic predisposition may be explained by a less robust Hunting reaction in individuals of African descent.^4,7 Other risk factors include alcohol use, smoking, homelessness, history of cold-related injury, use of beta-blockers, and working with equipment that uses nitrogen dioxide or CO₂.⁵ Additionally, a history of systemic lupus erythematosus has been reported as a risk factor for frostbite.⁸

Clinically, frostbite initially may appear pale, blue, or erythematous, and patients may report skin numbness. In severe cases, necrosis can be seen.⁹ The most commonly affected anatomic locations include the fingers, toes, ears, and nose. Prevention is key for frostbite injuries. Steps to avoid injury include wearing appropriate clothing, minimizing the duration of time the skin is exposed to cold temperatures, avoiding alcohol consumption, and avoiding physical exhaustion in cold weather. These steps can help mitigate the effects of wind chill and low temperatures and decrease the risk of frostbite.¹⁰

Management of this condition includes prevention, early diagnosis, prehospital management, hospital management, and long-term sequelae management. Leadership and medical personnel for military units assigned to cold climates should be vigilant in looking for symptoms of frostbite. If any one individual is found to have frostbite or any other cold injury, all other team members should be evaluated.⁵

After identification of frostbite, seeking shelter and evacuation to a treatment facility are vital next steps. Constrictive clothing or jewelry should be removed. Depending on the situation, rewarming can be attempted in the prehospital setting, but it is imperative to avoid refreezing, as this may further damage the affected tissue due to intracellular ice formation with extensive cell destruction.⁶ Gentle warming can be attempted by placing the affected extremity in another person’s armpit or groin for up to 10 minutes or by immersing the affected limb in water that is 37° C to 39° C (98.6° F to 102.2° F). Rubbing the affected area and dry heat should be avoided. It should be noted that the decision to thaw in the field introduces the challenge of dealing with the severe pain associated with thawing in a remote or hostile environment. Ibuprofen (400 mg) can be given as an anti-inflammatory and analgesic agent in the prehospital setting.⁵ Once safely evacuated to the hospital, treatment options expand dramatically, including warming without concern of refreezing, wound care, thrombolytic therapy, and surgical intervention. If local frostbite expertise is not available, there are telemedicine services available.^5,6

Frostbite outcomes range from complete recovery to amputation. Previously frostbitten tissue has increased cold sensitivity and is more susceptible to similar injury in the future. Additionally, there can be functional loss, chronic pain, chronic ulceration, and arthritis.^5,6 As such, a history of frostbite can be disqualifying for military service and requires a medical waiver.¹¹ If a service member experiences frostbite and does not have any residual effects, they can expect to continue their military service, but if there are sequelae, it may prove to be career limiting.^12-14

Immersion Foot

Although frostbite represents a freezing injury, immersion foot (or trench foot) represents a nonfreezing cold injury. It should be noted that in addition to immersion foot associated with cold water exposure, there also are warm-water and tropical variants. For the purpose of this article, we are referring to immersion foot associated with exposure to cold water. Trench foot was described for the first time during Napoleon’s invasion of Russia in 1812 but came to prominence during World War I, where it is thought to have contributed to the deaths of 75,000 British soldiers. During World War II, there were 25,016 cases of immersion foot reported in the US military.¹ More recently, 590 cases of immersion foot were reported in the US military from 2015 to 2020.²

Classically, this condition was seen in individuals whose feet were immersed in cold but not freezing water or mud in trenches or on boats, hence the terms immersion foot and trench foot. The pathogenesis is thought to be related to overhydration of the stratum corneum and repetitive cycles of cold-induced, thermoprotective vasoconstriction, leading to cyclical hypoxic and reperfusion injuries, which eventually damage nerves, muscle, subcutaneous fat, and blood vessels.^9,15

A recent case series of 100 military service members in the United Kingdom showed that cold-induced extremity numbness for more than 30 minutes and painful rewarming after cold exposure were highly correlated with the development of immersion foot. Additionally, this case series showed that patients with repeated cycles of cooling and rewarming were more likely to have long-term symptoms.¹⁶ As with frostbite, prior cold injury and African descent increases the risk for developing immersion foot, possibly due to a less-pronounced Hunting reaction.^4,7

Early reports suggested prehyperemic, hyperemic, and posthyperemic stages. The prehyperemic stage lasts from hours to days and is characterized by cold extremities, discoloration, edema, stocking- or glove-distributed anesthesia, blisters, necrosis, and potential loss of palpable pulses.¹⁷ Of note, in Kuht et al’s¹⁶ more recent case series, edema was not seen as frequently as in prior reports. The hyperemic stage can last for 6 to 10 weeks and is characterized by vascular disturbances. In addition, the affected extremity typically remains warm and red even when exposed to cold temperatures. Sensory disturbances such as paresthesia and hyperalgesia may be seen, as well as motor disturbances, anhidrosis, blisters, ulcers, and gangrene. The posthyperemic stage can last from months to years and is characterized by cold sensitivity, possible digital blanching, edema, hyperhidrosis, and persistent peripheral neuropathy.¹⁶

Prevention is the most important treatment for immersion foot. The first step in preventing this injury is avoiding prolonged cold exposure. When this is not possible due to the demands of training or actual combat conditions, regular hand and foot inspections, frequent sock changes, and regularly rotating out of cold wet conditions can help prevent this injury.¹⁵ Vasodilators also have been considered as a possible treatment modality. Iloprost and nicotinyl alcohol tartrate showed some improvement, while aminophylline and papaverine were ineffective.¹⁵

As with frostbite, a history of immersion foot may be disqualifying for military service.¹¹ If it occurs during military service and there are no residual effects that limit the service member’s capabilities, they may expect to continue their career; however, if there are residual effects that limit activity or deployment, medical retirement may be indicated.

Pernio

Pernio is another important condition that is related to cold exposure; however, unlike the previous 2 conditions, it is not necessarily caused by cold exposure but rather flares with cold exposure.

Case Presentation—A 39-year-old active-duty male service member presented to the dermatology clinic for intermittent painful blistering on the toes of both feet lasting approximately 10 to 14 days about 3 to 4 times per year for the last several years. The patient reported that his symptoms started after spending 2 days in the snow with wet nonwinterized boots while stationed in Germany 10 years prior. He reported cold weather as his only associated trigger and denied other associated symptoms. Physical examination revealed mildly cyanotic toes containing scattered bullae, with the dorsal lesions appearing more superficial compared to the deeper plantar bullae (Figure 1). A complete blood cell count, serum protein electrophoresis, and antinuclear and autoimmune antibodies were within reference range. A punch biopsy was obtained from a lesion on the right dorsal great toe. Hematoxylin and eosin–stained sections revealed lichenoid and vacuolar dermatitis with scattered dyskeratosis and subtle papillary edema (Figure 2). Minimal interstitial mucin was seen on Alcian blue–stained sections. The histologic and clinical findings were most compatible with a diagnosis of chronic pernio. Nifedipine 20 mg once daily was initiated, and he had minimal improvement after a few months of treatment. His condition continued to limit his functionality in cold conditions due to pain. Without improvement of the symptoms, the patient likely will require medical separation from military service, as this condition limits the performance of his duties and his deployability.

Clinical Discussion—Pernio, also known as chilblains, is characterized by cold-induced erythematous patches and plaques, pain, and pruritus on the affected skin.¹⁸ Bullae and ulceration can be seen in more severe and chronic cases.¹⁹ Pernio most commonly is seen in young women but also can be seen in children, men, and older adults. It usually occurs on the tips of toes but also may affect the fingers, nose, and ears. It typically is observed in cold and damp conditions and is thought to be caused by an inflammatory response to vasospasms in the setting of nonfreezing cold. Acute pernio typically resolves after a few weeks; however, it also can persist in a chronic form after repeated cold exposure.¹⁸

Predisposing factors include excessive cold exposure, connective tissue disease, hematologic malignancy, antiphospholipid antibodies in adults, and anorexia nervosa in children.^18,20,21 More recently, perniolike lesions have been associated with prior SARS-CoV-2 infection.²² Histologically, pernio is characterized by a perivascular lymphocytic infiltrate and dermal edema.²³ Cold avoidance, warming, drying, and smoking cessation are primary treatments, while vasodilating medications such as nifedipine have been used with success in more resistant cases.^20,24

Although the prognosis generally is excellent, this condition also can be career limiting for military service members. If it resolves with no residual effects, patients can expect to continue their service; however, if it persists and limits their activity or ability to deploy, a medical retirement may be indicated.^11-14

Raynaud Phenomenon

Raynaud phenomenon (also known as Raynaud’s) is characterized by cold-induced extremity triphasic color changes—initial blanching and pallor that transitions to cyanosis and finally erythema with associated pain during the recovery stage. The fingers are the most commonly involved appendages and can have a symmetric distribution, but RP also has been observed on the feet, lips, nose, and ears. In severe cases, it can cause ulceration.²⁵ The prevalence of RP may be as high as 5% in the general population.²⁶ It more commonly is primary or idiopathic with no underlying cause or secondary with an associated underlying systemic disease.

Cold-induced vasoconstriction is a normal physiologic response, but in RP, the response becomes a vasospasm and is pathological. Autoimmune and connective tissue diseases often are associated with secondary RP. Other risk factors include female sex, smoking, family history in a first-degree relative, and certain medications.²⁵ A study in northern Sweden also identified a history of frostbite as a risk factor for the development of RP.²⁷ This condition can notably restrict mobility and deployability of affected service members as well as the types of manual tasks that they may be required to perform. As such, this condition can be disqualifying for military service.¹¹

Many patients improve with conservative treatment consisting of cold avoidance, smoking cessation, and avoidance of medications that worsen the vasospasm; however, some patients develop pain and chronic disease, which can become so severe and ischemic that digital loss is threatened.²⁵ When needed, calcium channel blockers commonly are used for treatment and can be used prophylactically to reduce flare rates and severity of disease. If this class of medications is ineffective or is not tolerated, there are other medications and treatments to consider, which are beyond the scope of this article.²⁵

Cold Urticaria

Cold urticaria is a subset of physical urticaria in which symptoms occur in response to a cutaneous cold stimulus. It can be primary or secondary, with potential underlying causes including cryoglobulinemia, infections, and some medications. Systemic involvement is possible with extensive cold contact and can include severe anaphylaxis. This condition is diagnosed using a cold stimulation test. Cold exposure avoidance and second-generation antihistamines are considered first-line treatment. Because anaphylaxis is possible, patients should be given an epinephrine pen and should be instructed to avoid swimming in cold water.²⁸ Cold urticaria is disqualifying for military service.¹¹

A 2013 case report described a 29-year-old woman on active duty in the US Air Force whose presenting symptoms included urticaria on the exposed skin on the arms when doing physical training in the rain.²⁹ In this case, secondary causes were eliminated, and she was diagnosed with primary acquired cold urticaria. This patient was eventually medically discharged from the air force because management with antihistamines failed, and her symptoms limited her ability to function in even mildly cold environments.²⁹

Final Thoughts

An understanding of cold weather injuries and other dermatologic conditions that may be flared by cold exposure is important for a medically ready military force, as there are implications for accession, training, and combat operations. Although the focus of this article has been on the military, these conditions also are seen in civilian medicine in patient populations routinely exposed to cold weather. This becomes especially pertinent in high-risk patients such as extreme athletes, homeless individuals, or those who have other predisposing characteristics such as chronic alcohol use. Appropriate cold weather gear, training, and deliberate mission or activity planning are important interventions in preventing cutaneous cold weather injuries within the military.

Rashes that develop during pregnancy often result in considerable anxiety or concern for patients and their families. Recognizing these pregnancy-specific dermatoses is important in identifying fetal risks as well as providing appropriate management and expert guidance for patients regarding future pregnancies. Managing cutaneous manifestations of pregnancy-related disorders is challenging and requires knowledge of potential side effects of therapy for both the mother and fetus. It also is important to appreciate the physiologic cutaneous changes of pregnancy along with their clinical significance and management.

In 2006, Ambrose-Rudolph et al¹ proposed reclassification of pregnancy-specific dermatoses, which has since been widely accepted by the academic dermatology community. The 4 most prominent disorders include intrahepatic cholestasis of pregnancy (ICP); pemphigoid gestationis (PG); polymorphic eruption of pregnancy (PEP), also known as pruritic urticarial papules and plaques of pregnancy; and atopic eruption of pregnancy.² It is important to recognize these pregnancy-specific disorders and to understand their clinical significance. The morphology of the eruption as well as the location and timing of the onset of the rash are important clues in making an accurate diagnosis.³

Clinical Presentation

Intrahepatic cholestasis of pregnancy presents with severe generalized pruritus, usually with involvement of the palms and soles, in the late second or third trimester. Pemphigoid gestationis presents with urticarial papules and/or bullae, often in the second or third trimester or postpartum. An important diagnostic clue for PG is involvement near the umbilicus. Polymorphic eruption of pregnancy presents with urticarial papules and plaques; onset occurs in the third trimester or postpartum and initially involves the striae while sparing the umbilicus, unlike in PG. Atopic eruption of pregnancy has an earlier onset than the other pregnancy-specific dermatoses, often in the first or second trimester, and presents with widespread eczematous lesions.³

Diagnosis

The pregnancy dermatoses with the greatest potential for fetal risks are ICP and PG; therefore, it is critical for health care providers to diagnose these dermatoses in a timely manner and initiate appropriate management. Intrahepatic cholestasis of pregnancy is confirmed by elevated serum bile acids (ie, >10 µmol/L), often during the third trimester. The risk of fetal morbidity is high in ICP with increased bile acids crossing the placenta causing placental anoxia and impaired cardiomyocyte function.⁴ Fetal risks, including preterm delivery, meconium-stained amniotic fluid, and stillbirth, correlate with the level of bile acids in the serum.⁵ Maternal prognosis is favorable, but there is an increased association with hepatitis C and hepatobiliary disease.⁶

Diagnosis of PG is confirmed by classic biopsy results and direct immunofluorescence revealing C3 with or without IgG in a linear band along the basement membrane zone. Additionally, complement indirect immunofluorescence reveals circulating IgG anti–basement membrane zone antibodies. Pemphigoid gestationis is associated with increased fetal risks of preterm labor and intrauterine growth retardation.⁷ Clinical findings of PG may present in the fetus upon delivery due to transmission of autoantibodies across the placenta. The symptoms usually are mild.⁸ An increased risk of Graves disease has been reported in mothers with PG.

In most cases, diagnosis of PEP is based on history and morphology, but if the presentation is not classic, skin biopsy must be used to differentiate it from PG as well as more common dermatologic conditions such as contact dermatitis, drug and viral eruptions, and urticaria.

Atopic eruption of pregnancy manifests as widespread eczematous excoriated papules and plaques. Lesions of prurigo nodularis are common.

Comorbidities

It is important to be aware of specific clinical associations related to pregnancy-specific dermatoses. Pemphigoid gestationis has been associated with gestational trophoblastic tumors including hydatiform mole and choriocarcinoma.⁴ An increased risk for Graves disease has been reported in patients with PG.⁹ Patients who develop ICP have a higher incidence of hepatitis C, postpartum cholecystitis, gallstones, and nonalcoholic cirrhosis.⁸ Polymorphic eruption of pregnancy is associated with a notably higher incidence in multiple gestation pregnancies.²

Treatment and Management

Management of ICP requires an accurate and timely diagnosis, and advanced neonatal-obstetric management is critical.³ Ursodeoxycholic acid is the treatment of choice and reduces pruritus, prolongs pregnancy, and reduces fetal risk.⁴ Most stillbirths cluster at the 38th week of pregnancy, and patients with ICP and highly elevated serum bile acids (>40 µmol/L) should be considered for delivery at 37 weeks or earlier.⁵

Management of the other cutaneous disorders of pregnancy can be challenging for health care providers based on safety concerns for the fetus. Although it is important to minimize risks to the fetus, it also is important to adequately treat the mother’s cutaneous disease, which requires a solid knowledge of drug safety during pregnancy. The former US Food and Drug Administration classification system using A, B, C, D, and X pregnancy categories was replaced by the Pregnancy Lactation Label Final Rule, which provides counseling on medication safety during pregnancy.¹⁰ In 2014, Murase et al¹¹ published a review of dermatologic medication safety during pregnancy, which serves as an excellent guide.

Before instituting treatment, the therapeutic plan should be discussed with the physician managing the patient’s pregnancy. In general, topical steroids are considered safe during pregnancy, and low-potency to moderate-potency topical steroids are preferred. If possible, use of topical steroids should be limited to less than 300 g for the duration of the pregnancy. Fluticasone propionate should be avoided during pregnancy because it is not metabolized by the placenta. When systemic steroids are considered appropriate for management during pregnancy, nonhalogenated corticosteroids such as prednisone and prednisolone are preferred because they are enzymatically inactivated by the placenta, which results in a favorable maternal-fetal gradient.¹² There has been concern expressed in the medical literature that systemic steroids during the first trimester may increase the risk of cleft lip and cleft palate.^3,12 When managing pregnancy dermatoses, consideration should be given to keep prednisone exposure below 20 mg/d, and try to limit prolonged use to 7.5 mg/d. However, this may not be possible in PG.³ Vitamin D and calcium supplementation may be appropriate when patients are on prolonged systemic steroids to control disease.

Antihistamines can be used to control pruritus complicating pregnancy-associated dermatoses. First-generation antihistamines such as chlorpheniramine and diphenhydramine are preferred due to long-term safety data.^3,11,12 Loratadine is the first choice and cetirizine is the second choice if a second-generation antihistamine is preferred.³ Loratadine is preferred during breastfeeding due to less sedation.¹² High-dose antihistamines prior to delivery may cause concerns for potential side effects in the newborn, including tremulousness, irritability, and poor feeding.

Recurrence

Women with pregnancy dermatoses often are concerned about recurrence with future pregnancies. Pemphigoid gestationis may flare with subsequent pregnancies, subsequent menses, or with oral contraceptive use.³ Recurrence of PEP in subsequent pregnancies is rare and usually is less severe than the primary eruption.⁸ Often, the rare recurrent eruption of PEP is associated with multigestational pregnancies.² Mothers can anticipate a recurrence of ICP in up to 60% to 70% of future pregnancies. Patients with AEP have an underlying atopic diathesis, and recurrence in future pregnancies is not uncommon.⁸

Final Thoughts

In summary, it is important for health care providers to recognize the specific cutaneous disorders of pregnancy and their potential fetal complications. The anatomical location of onset of the dermatosis and timing of onset during pregnancy can give important clues. Appropriate management, especially with ICP, can minimize fetal complications. A fundamental knowledge of medication safety and management during pregnancy is essential. Rashes during pregnancy can cause anxiety in the mother and family and require support, comfort, and guidance.

Rashes that develop during pregnancy often result in considerable anxiety or concern for patients and their families. Recognizing these pregnancy-specific dermatoses is important in identifying fetal risks as well as providing appropriate management and expert guidance for patients regarding future pregnancies. Managing cutaneous manifestations of pregnancy-related disorders is challenging and requires knowledge of potential side effects of therapy for both the mother and fetus. It also is important to appreciate the physiologic cutaneous changes of pregnancy along with their clinical significance and management.

In 2006, Ambrose-Rudolph et al¹ proposed reclassification of pregnancy-specific dermatoses, which has since been widely accepted by the academic dermatology community. The 4 most prominent disorders include intrahepatic cholestasis of pregnancy (ICP); pemphigoid gestationis (PG); polymorphic eruption of pregnancy (PEP), also known as pruritic urticarial papules and plaques of pregnancy; and atopic eruption of pregnancy.² It is important to recognize these pregnancy-specific disorders and to understand their clinical significance. The morphology of the eruption as well as the location and timing of the onset of the rash are important clues in making an accurate diagnosis.³

Clinical Presentation

Intrahepatic cholestasis of pregnancy presents with severe generalized pruritus, usually with involvement of the palms and soles, in the late second or third trimester. Pemphigoid gestationis presents with urticarial papules and/or bullae, often in the second or third trimester or postpartum. An important diagnostic clue for PG is involvement near the umbilicus. Polymorphic eruption of pregnancy presents with urticarial papules and plaques; onset occurs in the third trimester or postpartum and initially involves the striae while sparing the umbilicus, unlike in PG. Atopic eruption of pregnancy has an earlier onset than the other pregnancy-specific dermatoses, often in the first or second trimester, and presents with widespread eczematous lesions.³

Diagnosis

The pregnancy dermatoses with the greatest potential for fetal risks are ICP and PG; therefore, it is critical for health care providers to diagnose these dermatoses in a timely manner and initiate appropriate management. Intrahepatic cholestasis of pregnancy is confirmed by elevated serum bile acids (ie, >10 µmol/L), often during the third trimester. The risk of fetal morbidity is high in ICP with increased bile acids crossing the placenta causing placental anoxia and impaired cardiomyocyte function.⁴ Fetal risks, including preterm delivery, meconium-stained amniotic fluid, and stillbirth, correlate with the level of bile acids in the serum.⁵ Maternal prognosis is favorable, but there is an increased association with hepatitis C and hepatobiliary disease.⁶

Diagnosis of PG is confirmed by classic biopsy results and direct immunofluorescence revealing C3 with or without IgG in a linear band along the basement membrane zone. Additionally, complement indirect immunofluorescence reveals circulating IgG anti–basement membrane zone antibodies. Pemphigoid gestationis is associated with increased fetal risks of preterm labor and intrauterine growth retardation.⁷ Clinical findings of PG may present in the fetus upon delivery due to transmission of autoantibodies across the placenta. The symptoms usually are mild.⁸ An increased risk of Graves disease has been reported in mothers with PG.

In most cases, diagnosis of PEP is based on history and morphology, but if the presentation is not classic, skin biopsy must be used to differentiate it from PG as well as more common dermatologic conditions such as contact dermatitis, drug and viral eruptions, and urticaria.

Atopic eruption of pregnancy manifests as widespread eczematous excoriated papules and plaques. Lesions of prurigo nodularis are common.

Comorbidities

It is important to be aware of specific clinical associations related to pregnancy-specific dermatoses. Pemphigoid gestationis has been associated with gestational trophoblastic tumors including hydatiform mole and choriocarcinoma.⁴ An increased risk for Graves disease has been reported in patients with PG.⁹ Patients who develop ICP have a higher incidence of hepatitis C, postpartum cholecystitis, gallstones, and nonalcoholic cirrhosis.⁸ Polymorphic eruption of pregnancy is associated with a notably higher incidence in multiple gestation pregnancies.²

Treatment and Management

Management of ICP requires an accurate and timely diagnosis, and advanced neonatal-obstetric management is critical.³ Ursodeoxycholic acid is the treatment of choice and reduces pruritus, prolongs pregnancy, and reduces fetal risk.⁴ Most stillbirths cluster at the 38th week of pregnancy, and patients with ICP and highly elevated serum bile acids (>40 µmol/L) should be considered for delivery at 37 weeks or earlier.⁵

Management of the other cutaneous disorders of pregnancy can be challenging for health care providers based on safety concerns for the fetus. Although it is important to minimize risks to the fetus, it also is important to adequately treat the mother’s cutaneous disease, which requires a solid knowledge of drug safety during pregnancy. The former US Food and Drug Administration classification system using A, B, C, D, and X pregnancy categories was replaced by the Pregnancy Lactation Label Final Rule, which provides counseling on medication safety during pregnancy.¹⁰ In 2014, Murase et al¹¹ published a review of dermatologic medication safety during pregnancy, which serves as an excellent guide.

Before instituting treatment, the therapeutic plan should be discussed with the physician managing the patient’s pregnancy. In general, topical steroids are considered safe during pregnancy, and low-potency to moderate-potency topical steroids are preferred. If possible, use of topical steroids should be limited to less than 300 g for the duration of the pregnancy. Fluticasone propionate should be avoided during pregnancy because it is not metabolized by the placenta. When systemic steroids are considered appropriate for management during pregnancy, nonhalogenated corticosteroids such as prednisone and prednisolone are preferred because they are enzymatically inactivated by the placenta, which results in a favorable maternal-fetal gradient.¹² There has been concern expressed in the medical literature that systemic steroids during the first trimester may increase the risk of cleft lip and cleft palate.^3,12 When managing pregnancy dermatoses, consideration should be given to keep prednisone exposure below 20 mg/d, and try to limit prolonged use to 7.5 mg/d. However, this may not be possible in PG.³ Vitamin D and calcium supplementation may be appropriate when patients are on prolonged systemic steroids to control disease.

Antihistamines can be used to control pruritus complicating pregnancy-associated dermatoses. First-generation antihistamines such as chlorpheniramine and diphenhydramine are preferred due to long-term safety data.^3,11,12 Loratadine is the first choice and cetirizine is the second choice if a second-generation antihistamine is preferred.³ Loratadine is preferred during breastfeeding due to less sedation.¹² High-dose antihistamines prior to delivery may cause concerns for potential side effects in the newborn, including tremulousness, irritability, and poor feeding.

Recurrence

Women with pregnancy dermatoses often are concerned about recurrence with future pregnancies. Pemphigoid gestationis may flare with subsequent pregnancies, subsequent menses, or with oral contraceptive use.³ Recurrence of PEP in subsequent pregnancies is rare and usually is less severe than the primary eruption.⁸ Often, the rare recurrent eruption of PEP is associated with multigestational pregnancies.² Mothers can anticipate a recurrence of ICP in up to 60% to 70% of future pregnancies. Patients with AEP have an underlying atopic diathesis, and recurrence in future pregnancies is not uncommon.⁸

Final Thoughts

In summary, it is important for health care providers to recognize the specific cutaneous disorders of pregnancy and their potential fetal complications. The anatomical location of onset of the dermatosis and timing of onset during pregnancy can give important clues. Appropriate management, especially with ICP, can minimize fetal complications. A fundamental knowledge of medication safety and management during pregnancy is essential. Rashes during pregnancy can cause anxiety in the mother and family and require support, comfort, and guidance.

Rashes that develop during pregnancy often result in considerable anxiety or concern for patients and their families. Recognizing these pregnancy-specific dermatoses is important in identifying fetal risks as well as providing appropriate management and expert guidance for patients regarding future pregnancies. Managing cutaneous manifestations of pregnancy-related disorders is challenging and requires knowledge of potential side effects of therapy for both the mother and fetus. It also is important to appreciate the physiologic cutaneous changes of pregnancy along with their clinical significance and management.

In 2006, Ambrose-Rudolph et al¹ proposed reclassification of pregnancy-specific dermatoses, which has since been widely accepted by the academic dermatology community. The 4 most prominent disorders include intrahepatic cholestasis of pregnancy (ICP); pemphigoid gestationis (PG); polymorphic eruption of pregnancy (PEP), also known as pruritic urticarial papules and plaques of pregnancy; and atopic eruption of pregnancy.² It is important to recognize these pregnancy-specific disorders and to understand their clinical significance. The morphology of the eruption as well as the location and timing of the onset of the rash are important clues in making an accurate diagnosis.³

Clinical Presentation

Intrahepatic cholestasis of pregnancy presents with severe generalized pruritus, usually with involvement of the palms and soles, in the late second or third trimester. Pemphigoid gestationis presents with urticarial papules and/or bullae, often in the second or third trimester or postpartum. An important diagnostic clue for PG is involvement near the umbilicus. Polymorphic eruption of pregnancy presents with urticarial papules and plaques; onset occurs in the third trimester or postpartum and initially involves the striae while sparing the umbilicus, unlike in PG. Atopic eruption of pregnancy has an earlier onset than the other pregnancy-specific dermatoses, often in the first or second trimester, and presents with widespread eczematous lesions.³

Diagnosis

The pregnancy dermatoses with the greatest potential for fetal risks are ICP and PG; therefore, it is critical for health care providers to diagnose these dermatoses in a timely manner and initiate appropriate management. Intrahepatic cholestasis of pregnancy is confirmed by elevated serum bile acids (ie, >10 µmol/L), often during the third trimester. The risk of fetal morbidity is high in ICP with increased bile acids crossing the placenta causing placental anoxia and impaired cardiomyocyte function.⁴ Fetal risks, including preterm delivery, meconium-stained amniotic fluid, and stillbirth, correlate with the level of bile acids in the serum.⁵ Maternal prognosis is favorable, but there is an increased association with hepatitis C and hepatobiliary disease.⁶

Diagnosis of PG is confirmed by classic biopsy results and direct immunofluorescence revealing C3 with or without IgG in a linear band along the basement membrane zone. Additionally, complement indirect immunofluorescence reveals circulating IgG anti–basement membrane zone antibodies. Pemphigoid gestationis is associated with increased fetal risks of preterm labor and intrauterine growth retardation.⁷ Clinical findings of PG may present in the fetus upon delivery due to transmission of autoantibodies across the placenta. The symptoms usually are mild.⁸ An increased risk of Graves disease has been reported in mothers with PG.

In most cases, diagnosis of PEP is based on history and morphology, but if the presentation is not classic, skin biopsy must be used to differentiate it from PG as well as more common dermatologic conditions such as contact dermatitis, drug and viral eruptions, and urticaria.

Atopic eruption of pregnancy manifests as widespread eczematous excoriated papules and plaques. Lesions of prurigo nodularis are common.

Comorbidities

It is important to be aware of specific clinical associations related to pregnancy-specific dermatoses. Pemphigoid gestationis has been associated with gestational trophoblastic tumors including hydatiform mole and choriocarcinoma.⁴ An increased risk for Graves disease has been reported in patients with PG.⁹ Patients who develop ICP have a higher incidence of hepatitis C, postpartum cholecystitis, gallstones, and nonalcoholic cirrhosis.⁸ Polymorphic eruption of pregnancy is associated with a notably higher incidence in multiple gestation pregnancies.²

Treatment and Management

Management of ICP requires an accurate and timely diagnosis, and advanced neonatal-obstetric management is critical.³ Ursodeoxycholic acid is the treatment of choice and reduces pruritus, prolongs pregnancy, and reduces fetal risk.⁴ Most stillbirths cluster at the 38th week of pregnancy, and patients with ICP and highly elevated serum bile acids (>40 µmol/L) should be considered for delivery at 37 weeks or earlier.⁵

Management of the other cutaneous disorders of pregnancy can be challenging for health care providers based on safety concerns for the fetus. Although it is important to minimize risks to the fetus, it also is important to adequately treat the mother’s cutaneous disease, which requires a solid knowledge of drug safety during pregnancy. The former US Food and Drug Administration classification system using A, B, C, D, and X pregnancy categories was replaced by the Pregnancy Lactation Label Final Rule, which provides counseling on medication safety during pregnancy.¹⁰ In 2014, Murase et al¹¹ published a review of dermatologic medication safety during pregnancy, which serves as an excellent guide.

Before instituting treatment, the therapeutic plan should be discussed with the physician managing the patient’s pregnancy. In general, topical steroids are considered safe during pregnancy, and low-potency to moderate-potency topical steroids are preferred. If possible, use of topical steroids should be limited to less than 300 g for the duration of the pregnancy. Fluticasone propionate should be avoided during pregnancy because it is not metabolized by the placenta. When systemic steroids are considered appropriate for management during pregnancy, nonhalogenated corticosteroids such as prednisone and prednisolone are preferred because they are enzymatically inactivated by the placenta, which results in a favorable maternal-fetal gradient.¹² There has been concern expressed in the medical literature that systemic steroids during the first trimester may increase the risk of cleft lip and cleft palate.^3,12 When managing pregnancy dermatoses, consideration should be given to keep prednisone exposure below 20 mg/d, and try to limit prolonged use to 7.5 mg/d. However, this may not be possible in PG.³ Vitamin D and calcium supplementation may be appropriate when patients are on prolonged systemic steroids to control disease.

Antihistamines can be used to control pruritus complicating pregnancy-associated dermatoses. First-generation antihistamines such as chlorpheniramine and diphenhydramine are preferred due to long-term safety data.^3,11,12 Loratadine is the first choice and cetirizine is the second choice if a second-generation antihistamine is preferred.³ Loratadine is preferred during breastfeeding due to less sedation.¹² High-dose antihistamines prior to delivery may cause concerns for potential side effects in the newborn, including tremulousness, irritability, and poor feeding.

Recurrence

Women with pregnancy dermatoses often are concerned about recurrence with future pregnancies. Pemphigoid gestationis may flare with subsequent pregnancies, subsequent menses, or with oral contraceptive use.³ Recurrence of PEP in subsequent pregnancies is rare and usually is less severe than the primary eruption.⁸ Often, the rare recurrent eruption of PEP is associated with multigestational pregnancies.² Mothers can anticipate a recurrence of ICP in up to 60% to 70% of future pregnancies. Patients with AEP have an underlying atopic diathesis, and recurrence in future pregnancies is not uncommon.⁸

Final Thoughts

In summary, it is important for health care providers to recognize the specific cutaneous disorders of pregnancy and their potential fetal complications. The anatomical location of onset of the dermatosis and timing of onset during pregnancy can give important clues. Appropriate management, especially with ICP, can minimize fetal complications. A fundamental knowledge of medication safety and management during pregnancy is essential. Rashes during pregnancy can cause anxiety in the mother and family and require support, comfort, and guidance.