Case Reports

Acrodermatitis enteropathica (AE) is a rare disorder of zinc metabolism that typically presents in infancy.¹ Although it is clinically characterized by acral and periorificial dermatitis, alopecia, and diarrhea, only 20% of cases present with this triad.² Zinc deficiency in AE can either be acquired or inborn (congenital). Acquired forms can occur from dietary inadequacy or malabsorption, whereas genetic causes are related to an autosomal-recessive disorder affecting zinc transporters.¹ We report a case of a 3-month-old female infant with acquired AE who was successfully treated with zinc supplementation over the course of 3 weeks.

Case Report

A 3-month-old female infant presented to the emergency department with a rash of 2 weeks’ duration. She was born full term with no birth complications. The patient’s mother reported that the rash started on the cheeks, then enlarged and spread to the neck, back, and perineum. The patient also had been having diarrhea during this time. She previously had received mupirocin and cephalexin with no response to treatment. Maternal history was negative for lupus, and the mother’s diet consisted of a variety of foods but not many vegetables. The patient was exclusively breastfed, and there was no pertinent history of similar rashes occurring in other family members.

Physical examination revealed the patient had annular and polycyclic, hyperkeratotic, crusted papules and plaques on the cheeks, neck, back, and axillae, as well as the perineum/groin and perianal regions (Figure 1). The differential diagnosis at the time included neonatal lupus, zinc deficiency, and syphilis. Relevant laboratory testing and a shave biopsy of the left axilla were obtained.

Comment

Etiology of AE—Acrodermatitis enteropathica was first identified in 1942 as an acral rash associated with diarrhea³; in 1973, Barnes and Moynahan⁴ discovered zinc deficiency as a causal agent for these findings. The causes of AE are further subclassified as either an acquired or inborn etiology. Congenital causes commonly are seen in infants within the first few months of life, whereas acquired forms are seen at any age. Acquired forms in infants can occur from failure of the mother to secrete zinc in breast milk, low maternal serum zinc levels, or other reasons causing low nutritional intake. A single mutation in the SLC30A2 gene has been found to markedly reduce zinc concentrations in breast milk, thus causing zinc deficiency in breastfed infants.⁵ Other acquired forms can be caused by malabsorption, sometimes after surgery such as intestinal bypass or from intravenous nutrition without sufficient zinc.¹ The congenital form of AE is an autosomal-recessive disorder occurring from mutations in the SLC39A4 gene located on band 8q24.3. Affected individuals have a decreased ability to absorb zinc in the small intestine because of defects in zinc transporters ZIP and ZnT.⁶ Based on our patient’s laboratory findings and history, it is believed that the zinc deficiency was acquired, as the condition normalized with repletion and has not required any supplementation in the year of follow-up. In addition, the absence of a pertinent family history supported an acquired diagnosis, which has various etiologies, whereas the congenital form primarily is a genetic disease.

Diagnosis of AE—The characteristic clinical features of AE include erythematous, dry, scaly papules and plaques that may evolve into crusted, erosive, pustular lesions. These lesions typically are distributed in a periorificial and acral pattern.^1,2 Although AE includes the clinical triad of acral and periorificial dermatitis, alopecia, and diarrhea, most cases present with only partial features of this syndrome, as seen in our patient, who presented with only 2 symptoms—dermatitis and diarrhea. The diagnosis of AE is based on clinical and laboratory abnormalities, especially a low serum zinc level. Low levels of zinc-dependent enzymes, such as alkaline phosphatase, may support the diagnosis, as seen in our patient. Histologic evaluation is characteristic but is not diagnostic, as the same findings can be seen in other nutritional disorders. Such findings include confluent parakeratosis associated with a reduced granular layer in early lesions and subsequent ballooning of subcorneal keratinocytes, upper epidermal pallor, and intraepidermal clefts. Late lesions exhibit psoriasiform hyperplasia of the epidermis with less epidermal pallor.⁷

Acrodermatitis enteropathica (AE) is a rare disorder of zinc metabolism that typically presents in infancy.¹ Although it is clinically characterized by acral and periorificial dermatitis, alopecia, and diarrhea, only 20% of cases present with this triad.² Zinc deficiency in AE can either be acquired or inborn (congenital). Acquired forms can occur from dietary inadequacy or malabsorption, whereas genetic causes are related to an autosomal-recessive disorder affecting zinc transporters.¹ We report a case of a 3-month-old female infant with acquired AE who was successfully treated with zinc supplementation over the course of 3 weeks.

Case Report

A 3-month-old female infant presented to the emergency department with a rash of 2 weeks’ duration. She was born full term with no birth complications. The patient’s mother reported that the rash started on the cheeks, then enlarged and spread to the neck, back, and perineum. The patient also had been having diarrhea during this time. She previously had received mupirocin and cephalexin with no response to treatment. Maternal history was negative for lupus, and the mother’s diet consisted of a variety of foods but not many vegetables. The patient was exclusively breastfed, and there was no pertinent history of similar rashes occurring in other family members.

Physical examination revealed the patient had annular and polycyclic, hyperkeratotic, crusted papules and plaques on the cheeks, neck, back, and axillae, as well as the perineum/groin and perianal regions (Figure 1). The differential diagnosis at the time included neonatal lupus, zinc deficiency, and syphilis. Relevant laboratory testing and a shave biopsy of the left axilla were obtained.

Comment

Etiology of AE—Acrodermatitis enteropathica was first identified in 1942 as an acral rash associated with diarrhea³; in 1973, Barnes and Moynahan⁴ discovered zinc deficiency as a causal agent for these findings. The causes of AE are further subclassified as either an acquired or inborn etiology. Congenital causes commonly are seen in infants within the first few months of life, whereas acquired forms are seen at any age. Acquired forms in infants can occur from failure of the mother to secrete zinc in breast milk, low maternal serum zinc levels, or other reasons causing low nutritional intake. A single mutation in the SLC30A2 gene has been found to markedly reduce zinc concentrations in breast milk, thus causing zinc deficiency in breastfed infants.⁵ Other acquired forms can be caused by malabsorption, sometimes after surgery such as intestinal bypass or from intravenous nutrition without sufficient zinc.¹ The congenital form of AE is an autosomal-recessive disorder occurring from mutations in the SLC39A4 gene located on band 8q24.3. Affected individuals have a decreased ability to absorb zinc in the small intestine because of defects in zinc transporters ZIP and ZnT.⁶ Based on our patient’s laboratory findings and history, it is believed that the zinc deficiency was acquired, as the condition normalized with repletion and has not required any supplementation in the year of follow-up. In addition, the absence of a pertinent family history supported an acquired diagnosis, which has various etiologies, whereas the congenital form primarily is a genetic disease.

Diagnosis of AE—The characteristic clinical features of AE include erythematous, dry, scaly papules and plaques that may evolve into crusted, erosive, pustular lesions. These lesions typically are distributed in a periorificial and acral pattern.^1,2 Although AE includes the clinical triad of acral and periorificial dermatitis, alopecia, and diarrhea, most cases present with only partial features of this syndrome, as seen in our patient, who presented with only 2 symptoms—dermatitis and diarrhea. The diagnosis of AE is based on clinical and laboratory abnormalities, especially a low serum zinc level. Low levels of zinc-dependent enzymes, such as alkaline phosphatase, may support the diagnosis, as seen in our patient. Histologic evaluation is characteristic but is not diagnostic, as the same findings can be seen in other nutritional disorders. Such findings include confluent parakeratosis associated with a reduced granular layer in early lesions and subsequent ballooning of subcorneal keratinocytes, upper epidermal pallor, and intraepidermal clefts. Late lesions exhibit psoriasiform hyperplasia of the epidermis with less epidermal pallor.⁷

Acrodermatitis enteropathica (AE) is a rare disorder of zinc metabolism that typically presents in infancy.¹ Although it is clinically characterized by acral and periorificial dermatitis, alopecia, and diarrhea, only 20% of cases present with this triad.² Zinc deficiency in AE can either be acquired or inborn (congenital). Acquired forms can occur from dietary inadequacy or malabsorption, whereas genetic causes are related to an autosomal-recessive disorder affecting zinc transporters.¹ We report a case of a 3-month-old female infant with acquired AE who was successfully treated with zinc supplementation over the course of 3 weeks.

Case Report

A 3-month-old female infant presented to the emergency department with a rash of 2 weeks’ duration. She was born full term with no birth complications. The patient’s mother reported that the rash started on the cheeks, then enlarged and spread to the neck, back, and perineum. The patient also had been having diarrhea during this time. She previously had received mupirocin and cephalexin with no response to treatment. Maternal history was negative for lupus, and the mother’s diet consisted of a variety of foods but not many vegetables. The patient was exclusively breastfed, and there was no pertinent history of similar rashes occurring in other family members.

Physical examination revealed the patient had annular and polycyclic, hyperkeratotic, crusted papules and plaques on the cheeks, neck, back, and axillae, as well as the perineum/groin and perianal regions (Figure 1). The differential diagnosis at the time included neonatal lupus, zinc deficiency, and syphilis. Relevant laboratory testing and a shave biopsy of the left axilla were obtained.

Comment

Etiology of AE—Acrodermatitis enteropathica was first identified in 1942 as an acral rash associated with diarrhea³; in 1973, Barnes and Moynahan⁴ discovered zinc deficiency as a causal agent for these findings. The causes of AE are further subclassified as either an acquired or inborn etiology. Congenital causes commonly are seen in infants within the first few months of life, whereas acquired forms are seen at any age. Acquired forms in infants can occur from failure of the mother to secrete zinc in breast milk, low maternal serum zinc levels, or other reasons causing low nutritional intake. A single mutation in the SLC30A2 gene has been found to markedly reduce zinc concentrations in breast milk, thus causing zinc deficiency in breastfed infants.⁵ Other acquired forms can be caused by malabsorption, sometimes after surgery such as intestinal bypass or from intravenous nutrition without sufficient zinc.¹ The congenital form of AE is an autosomal-recessive disorder occurring from mutations in the SLC39A4 gene located on band 8q24.3. Affected individuals have a decreased ability to absorb zinc in the small intestine because of defects in zinc transporters ZIP and ZnT.⁶ Based on our patient’s laboratory findings and history, it is believed that the zinc deficiency was acquired, as the condition normalized with repletion and has not required any supplementation in the year of follow-up. In addition, the absence of a pertinent family history supported an acquired diagnosis, which has various etiologies, whereas the congenital form primarily is a genetic disease.

Diagnosis of AE—The characteristic clinical features of AE include erythematous, dry, scaly papules and plaques that may evolve into crusted, erosive, pustular lesions. These lesions typically are distributed in a periorificial and acral pattern.^1,2 Although AE includes the clinical triad of acral and periorificial dermatitis, alopecia, and diarrhea, most cases present with only partial features of this syndrome, as seen in our patient, who presented with only 2 symptoms—dermatitis and diarrhea. The diagnosis of AE is based on clinical and laboratory abnormalities, especially a low serum zinc level. Low levels of zinc-dependent enzymes, such as alkaline phosphatase, may support the diagnosis, as seen in our patient. Histologic evaluation is characteristic but is not diagnostic, as the same findings can be seen in other nutritional disorders. Such findings include confluent parakeratosis associated with a reduced granular layer in early lesions and subsequent ballooning of subcorneal keratinocytes, upper epidermal pallor, and intraepidermal clefts. Late lesions exhibit psoriasiform hyperplasia of the epidermis with less epidermal pallor.⁷

Mycetoma is a chronic subcutaneous infection due to fungal (eumycetoma) or aerobic actinomycetes (actinomycetoma) organisms. Clinical lesions develop from a granulomatous infiltrate organizing around the infectious organism. Patients can present with extensive subcutaneous nodularity and draining sinuses that can lead to deformation of the affected extremity. These infections are rare in developed countries, and the prevalence and incidence remain unknown. It has been reported that actinomycetes represent 60% of mycetoma cases worldwide, with the majority of cases in Central America from Nocardia (86%) and Actinomadura madurae (10%). ¹Gordonia species are aerobic, partially acid-fast, gram-positive actinobacteria that may comprise a notable minority of actinomycete isolates. ² The species Gordonia bronchialis is of particular interest as a human pathogen because of increasing reports of nosocomial infections. ^3,4 We describe a case of a mycetomalike infection due to G bronchialis in an immunocompetent patient with complete resolution after 3 months of antibiotics.

Case Report

An 86-year-old man presented to the emergency department with a pruritic rash on the right forearm. He had a history of chronic kidney disease, hypertension, and inverse psoriasis complicated by steroid atrophy. He reported trauma to the right antecubital fossa approximately 1 to 2 months prior from a car door; he received wound care over several weeks at an outside hospital. The initial wound healed completely, but he subsequently noticed erythema spreading down the forearm. At the current presentation, he was empirically treated with mid-potency topical steroids and cefuroxime for 7 days. Initial laboratory results were notable for a white blood cell count of 5.7×10³ cells/μL (reference range,3.7–8.4×10³ cells/μL) and a creatinine level of 1.5 mg/dL (reference range, 0.57–1.25 mg/dL). The patient returned to the emergency department 2 weeks later with spreading of the initial rash and worsening pruritus. Dermatologic evaluation revealed the patient was afebrile and had violaceous papules and nodules that coalesced into plaques on the right arm, with the largest measuring approximately 15 cm. Areas of superficial erosion and crusting were noted (Figure 1A). The patient denied constitutional symptoms and had no axillary or cervical lymphadenopathy. The differential initially included an atypical infection vs a neoplasm. Two 5-mm punch biopsies were performed, which demonstrated a suppurative granulomatous infiltrate in the dermis with extension into the subcutis (Figure 2A). Focal vacuolations within the dermis demonstrated aggregates of gram-positive pseudofilamentous organisms (Figures 2B and 2C). Aerobic tissue cultures grew G bronchialis that was susceptible to all antibiotics tested and Staphylococcus epidermidis. Fungal and mycobacterial cultures were negative. The patient was placed on amoxicillin 875 mg–clavulanate 125 mg twice daily for 3 weeks. However, he demonstrated progression of the rash, with increased induration and confluence of plaques on the forearm (Figure 1B). A repeat excisional biopsy was performed, and a tissue sample was sent for 16S ribosomal RNA sequencing identification. However, neither conventional cultures nor sequencing demonstrated evidence of G bronchialis or any other pathogen. Additionally, bacterial, fungal, and mycobacterial blood cultures were negative. Amoxicillin-clavulanate was stopped, and he was placed on trimethoprim-sulfamethoxazole for 2 weeks, then changed to linezolid (600 mg twice daily) due to continued lack of improvement of the rash. After 2 weeks of linezolid, the rash was slightly improved, but the patient had notable side effects (eg, nausea, mucositis). Therefore, he was switched back to trimethoprim-sulfamethoxazole for another 6 weeks. Antibiotic therapy was discontinued after there was notable regression of indurated plaques (Figure 1C); he received more than 3 months of antibiotics in all. At 1 month after completion of antibiotic therapy, the patient had no evidence of recurrence.

Comment

Microbiology of Gordonia Species—Gordonia bronchialis originally was isolated in 1971 by Tsukamura et al⁵ from the sputum of patients with cavitary tuberculosis and bronchiectasis in Japan. Other Gordonia species (formerly Rhodococcus or Gordona) later were identified in soil, seawater, sediment, and wastewater. Gordonia bronchialis is a gram-positive aerobic actinomycete short rod that organizes in cordlike compact groups. It is weakly acid fast, nonmotile, and nonsporulating. Colonies exhibit pinkish-brown pigmentation. Our understanding of the clinical significance of this organism continues to evolve, and it is not always clearly pathogenic. Because Gordonia isolates may be dismissed as commensals or misidentified as Nocardia or Rhodococcus by routine biochemical tests, it is possible that infections may go undetected. Speciation requires gene sequencing; as our utilization of molecular methods has increased, the identification of clinically relevant aerobic actinomycetes, including Gordonia, has improved,⁶ and the following species have been recognized as pathogens: Gordonia araii, G bronchialis, Gordonia effusa, Gordonia otitidis, Gordonia polyisoprenivorans, Gordonia rubirpertincta, Gordonia sputi, and Gordonia terrae.⁷

Cases Reported in the Literature—A PubMed search of articles indexed for MEDLINE using the term Gordonia bronchialis yielded 35 previously reported human cases of G bronchialis infection, most often associated with medical devices or procedures.^8-31 Eighteen of these cases were sternal surgical site infections in patients with a history of cardiac surgery,^3,4,12-16,30 including 2 outbreaks following coronary artery bypass grafting that were thought to be related to intraoperative transmission from a nurse.^3,4 Of the remaining cases, 12 were linked to a procedure or an indwelling catheter: 4 cases of peritonitis in the setting of continuous ambulatory peritoneal dialysis^17,18,26,27; 3 cases of skin and soft tissue infection (1 at the site of a prior needle injection,¹⁰ 1 after acupuncture,¹¹ and 1 after breast reduction surgery²⁹); 1 case of ventriculitis in a premature neonate with an underlying intraventricular shunt¹⁹; 2 cases of pacemaker-induced endocarditis^20,28; 1 case of tibial osteomyelitis related to a bioresorbable polymer screw²¹; and 1 case of chronic endophthalmitis with underlying intraocular lens implants.²² The Table lists all cases of G bronchialis skin or surgical site infections encountered in our literature search as well as the treatment provided in each case.

Only 4 of these 35 cases of G bronchialis infections were skin and soft tissue infections. All 4 occurred in immunocompetent hosts, and 3 were associated with needle punctures or surgery. The fourth case involved a recurrent breast abscess that occurred in a patient without known risk factors or recent procedures.²³ Other Gordonia species have been associated with cutaneous infections, including Gordonia amicalis, G terrae, and recently Gordonia westfalica, with the latter 2 demonstrating actinomycetoma formation.^32-34 Our case is remarkable in that it represents actinomycetoma due to G bronchialis. Of note, our patient was immunocompetent and did not have any radiation or chronic lymphedema involving the affected extremity. However, his history of steroid-induced skin atrophy may have predisposed him to this rare infection.

Clinical Presentation—Classic mycetoma demonstrate organismal granules within the dermis, surrounded by a neutrophilic infiltrate, which is in turn surrounded by histiocytes and multinucleated giant cells. Periodic acid–Schiff and silver stains can identify fungal organisms, while Gram stain helps to elucidate bacterial etiologies.¹ In our patient, a biopsy revealed several dermal aggregates of pseudofilamentous gram-positive organisms surrounded by a neutrophilic and histiocytic infiltrate.⁸ Because this case presented over weeks to months rather than months to years, it progressed more rapidly than a classic mycetoma. However, the dermatologic and histologic features were consistent with mycetoma.

Management—General treatment of actinomycetoma requires identification of the causative organism and prolonged administration of antibiotics, typically in combination.^35-37 Most G bronchialis infections associated with surgical intervention or implants in the literature required surgical debridement and removal of contaminated material for clinical cure, with the exception of 3 cases of sternal wound infection and 1 case of peritonitis that recovered with antimicrobial therapy alone.^3,17 Combination therapy often was used, but monotherapy, particularly with a fluoroquinolone, has been reported. Susceptibility data are limited, but in general, Gordonia species appear susceptible to imipenem, ciprofloxacin, amikacin, gentamicin, and linezolid, with variable susceptibility to vancomycin (89% of isolates), third-generation cephalosporins (80%–90% of isolates), tetracyclines (≤85% of isolates), penicillin (≤70% of isolates), and trimethoprim-sulfamethoxazole (≤65% of isolates).^{7,10,19,38-40} Although there are no standardized recommendations for the treatment of these infections, the most commonly used drugs to treat Gordonia are carbapenems and fluoroquinolones, with or without an aminoglycoside, followed by third-generation cephalosporins and vancomycin, depending on susceptibilities. Additional antibiotics (alone or in combination) that have previously been used with favorable outcomes include amoxicillin or amoxicillin-clavulanate, piperacillin-tazobactam, rifampicin, trimethoprim-sulfamethoxazole, minocycline, doxycycline, and daptomycin.

Our patient received amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, and linezolid. We considered combination therapy but decided against it due to concern for toxicity, given his age and poor renal function. The antibiotic that was most important to his recovery was unclear; the patient insisted that his body, not antibiotics, deserved most of the credit for healing his arm. Although cultures and polymerase chain reaction assays were negative after 3 weeks of amoxicillin-clavulanate, the patient did not show clinical improvement—reasons could be because the antibiotic reduced but did not eliminate the bacterial burden, sampling error of the biopsy, or it takes much longer for the body to heal than it takes to kill the bacteria. Most likely a combination of factors was at play.

Conclusion

Gordonia bronchialis is an emerging cause of human infections typically occurring after trauma, inoculation, or surgery. Most infections are localized; however, the present case highlights the ability of this species to form a massive cutaneous infection. Treatment should be tailored to susceptibility, with close follow-up to ensure improvement and resolution. For clinicians encountering a similar case, we encourage biopsy prior to empiric antibiotics, as antibiotic therapy can decrease the yield of subsequent testing. Treatment should be guided by the clinical course and may need to last weeks to months. Combination therapy for Gordonia infections should be considered in severe cases, in cases presenting as actinomycetoma, in those not responding to therapy, or when the susceptibility profile is unknown or unreliable.

Acknowledgments—The authors thank this veteran for allowing us to participate in his care and to learn from his experience. He gave his consent for us to share his story and the photographs of the arm.

Mycetoma is a chronic subcutaneous infection due to fungal (eumycetoma) or aerobic actinomycetes (actinomycetoma) organisms. Clinical lesions develop from a granulomatous infiltrate organizing around the infectious organism. Patients can present with extensive subcutaneous nodularity and draining sinuses that can lead to deformation of the affected extremity. These infections are rare in developed countries, and the prevalence and incidence remain unknown. It has been reported that actinomycetes represent 60% of mycetoma cases worldwide, with the majority of cases in Central America from Nocardia (86%) and Actinomadura madurae (10%). ¹Gordonia species are aerobic, partially acid-fast, gram-positive actinobacteria that may comprise a notable minority of actinomycete isolates. ² The species Gordonia bronchialis is of particular interest as a human pathogen because of increasing reports of nosocomial infections. ^3,4 We describe a case of a mycetomalike infection due to G bronchialis in an immunocompetent patient with complete resolution after 3 months of antibiotics.

Case Report

An 86-year-old man presented to the emergency department with a pruritic rash on the right forearm. He had a history of chronic kidney disease, hypertension, and inverse psoriasis complicated by steroid atrophy. He reported trauma to the right antecubital fossa approximately 1 to 2 months prior from a car door; he received wound care over several weeks at an outside hospital. The initial wound healed completely, but he subsequently noticed erythema spreading down the forearm. At the current presentation, he was empirically treated with mid-potency topical steroids and cefuroxime for 7 days. Initial laboratory results were notable for a white blood cell count of 5.7×10³ cells/μL (reference range,3.7–8.4×10³ cells/μL) and a creatinine level of 1.5 mg/dL (reference range, 0.57–1.25 mg/dL). The patient returned to the emergency department 2 weeks later with spreading of the initial rash and worsening pruritus. Dermatologic evaluation revealed the patient was afebrile and had violaceous papules and nodules that coalesced into plaques on the right arm, with the largest measuring approximately 15 cm. Areas of superficial erosion and crusting were noted (Figure 1A). The patient denied constitutional symptoms and had no axillary or cervical lymphadenopathy. The differential initially included an atypical infection vs a neoplasm. Two 5-mm punch biopsies were performed, which demonstrated a suppurative granulomatous infiltrate in the dermis with extension into the subcutis (Figure 2A). Focal vacuolations within the dermis demonstrated aggregates of gram-positive pseudofilamentous organisms (Figures 2B and 2C). Aerobic tissue cultures grew G bronchialis that was susceptible to all antibiotics tested and Staphylococcus epidermidis. Fungal and mycobacterial cultures were negative. The patient was placed on amoxicillin 875 mg–clavulanate 125 mg twice daily for 3 weeks. However, he demonstrated progression of the rash, with increased induration and confluence of plaques on the forearm (Figure 1B). A repeat excisional biopsy was performed, and a tissue sample was sent for 16S ribosomal RNA sequencing identification. However, neither conventional cultures nor sequencing demonstrated evidence of G bronchialis or any other pathogen. Additionally, bacterial, fungal, and mycobacterial blood cultures were negative. Amoxicillin-clavulanate was stopped, and he was placed on trimethoprim-sulfamethoxazole for 2 weeks, then changed to linezolid (600 mg twice daily) due to continued lack of improvement of the rash. After 2 weeks of linezolid, the rash was slightly improved, but the patient had notable side effects (eg, nausea, mucositis). Therefore, he was switched back to trimethoprim-sulfamethoxazole for another 6 weeks. Antibiotic therapy was discontinued after there was notable regression of indurated plaques (Figure 1C); he received more than 3 months of antibiotics in all. At 1 month after completion of antibiotic therapy, the patient had no evidence of recurrence.

Comment

Microbiology of Gordonia Species—Gordonia bronchialis originally was isolated in 1971 by Tsukamura et al⁵ from the sputum of patients with cavitary tuberculosis and bronchiectasis in Japan. Other Gordonia species (formerly Rhodococcus or Gordona) later were identified in soil, seawater, sediment, and wastewater. Gordonia bronchialis is a gram-positive aerobic actinomycete short rod that organizes in cordlike compact groups. It is weakly acid fast, nonmotile, and nonsporulating. Colonies exhibit pinkish-brown pigmentation. Our understanding of the clinical significance of this organism continues to evolve, and it is not always clearly pathogenic. Because Gordonia isolates may be dismissed as commensals or misidentified as Nocardia or Rhodococcus by routine biochemical tests, it is possible that infections may go undetected. Speciation requires gene sequencing; as our utilization of molecular methods has increased, the identification of clinically relevant aerobic actinomycetes, including Gordonia, has improved,⁶ and the following species have been recognized as pathogens: Gordonia araii, G bronchialis, Gordonia effusa, Gordonia otitidis, Gordonia polyisoprenivorans, Gordonia rubirpertincta, Gordonia sputi, and Gordonia terrae.⁷

Cases Reported in the Literature—A PubMed search of articles indexed for MEDLINE using the term Gordonia bronchialis yielded 35 previously reported human cases of G bronchialis infection, most often associated with medical devices or procedures.^8-31 Eighteen of these cases were sternal surgical site infections in patients with a history of cardiac surgery,^3,4,12-16,30 including 2 outbreaks following coronary artery bypass grafting that were thought to be related to intraoperative transmission from a nurse.^3,4 Of the remaining cases, 12 were linked to a procedure or an indwelling catheter: 4 cases of peritonitis in the setting of continuous ambulatory peritoneal dialysis^17,18,26,27; 3 cases of skin and soft tissue infection (1 at the site of a prior needle injection,¹⁰ 1 after acupuncture,¹¹ and 1 after breast reduction surgery²⁹); 1 case of ventriculitis in a premature neonate with an underlying intraventricular shunt¹⁹; 2 cases of pacemaker-induced endocarditis^20,28; 1 case of tibial osteomyelitis related to a bioresorbable polymer screw²¹; and 1 case of chronic endophthalmitis with underlying intraocular lens implants.²² The Table lists all cases of G bronchialis skin or surgical site infections encountered in our literature search as well as the treatment provided in each case.

Only 4 of these 35 cases of G bronchialis infections were skin and soft tissue infections. All 4 occurred in immunocompetent hosts, and 3 were associated with needle punctures or surgery. The fourth case involved a recurrent breast abscess that occurred in a patient without known risk factors or recent procedures.²³ Other Gordonia species have been associated with cutaneous infections, including Gordonia amicalis, G terrae, and recently Gordonia westfalica, with the latter 2 demonstrating actinomycetoma formation.^32-34 Our case is remarkable in that it represents actinomycetoma due to G bronchialis. Of note, our patient was immunocompetent and did not have any radiation or chronic lymphedema involving the affected extremity. However, his history of steroid-induced skin atrophy may have predisposed him to this rare infection.

Clinical Presentation—Classic mycetoma demonstrate organismal granules within the dermis, surrounded by a neutrophilic infiltrate, which is in turn surrounded by histiocytes and multinucleated giant cells. Periodic acid–Schiff and silver stains can identify fungal organisms, while Gram stain helps to elucidate bacterial etiologies.¹ In our patient, a biopsy revealed several dermal aggregates of pseudofilamentous gram-positive organisms surrounded by a neutrophilic and histiocytic infiltrate.⁸ Because this case presented over weeks to months rather than months to years, it progressed more rapidly than a classic mycetoma. However, the dermatologic and histologic features were consistent with mycetoma.

Management—General treatment of actinomycetoma requires identification of the causative organism and prolonged administration of antibiotics, typically in combination.^35-37 Most G bronchialis infections associated with surgical intervention or implants in the literature required surgical debridement and removal of contaminated material for clinical cure, with the exception of 3 cases of sternal wound infection and 1 case of peritonitis that recovered with antimicrobial therapy alone.^3,17 Combination therapy often was used, but monotherapy, particularly with a fluoroquinolone, has been reported. Susceptibility data are limited, but in general, Gordonia species appear susceptible to imipenem, ciprofloxacin, amikacin, gentamicin, and linezolid, with variable susceptibility to vancomycin (89% of isolates), third-generation cephalosporins (80%–90% of isolates), tetracyclines (≤85% of isolates), penicillin (≤70% of isolates), and trimethoprim-sulfamethoxazole (≤65% of isolates).^{7,10,19,38-40} Although there are no standardized recommendations for the treatment of these infections, the most commonly used drugs to treat Gordonia are carbapenems and fluoroquinolones, with or without an aminoglycoside, followed by third-generation cephalosporins and vancomycin, depending on susceptibilities. Additional antibiotics (alone or in combination) that have previously been used with favorable outcomes include amoxicillin or amoxicillin-clavulanate, piperacillin-tazobactam, rifampicin, trimethoprim-sulfamethoxazole, minocycline, doxycycline, and daptomycin.

Our patient received amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, and linezolid. We considered combination therapy but decided against it due to concern for toxicity, given his age and poor renal function. The antibiotic that was most important to his recovery was unclear; the patient insisted that his body, not antibiotics, deserved most of the credit for healing his arm. Although cultures and polymerase chain reaction assays were negative after 3 weeks of amoxicillin-clavulanate, the patient did not show clinical improvement—reasons could be because the antibiotic reduced but did not eliminate the bacterial burden, sampling error of the biopsy, or it takes much longer for the body to heal than it takes to kill the bacteria. Most likely a combination of factors was at play.

Conclusion

Gordonia bronchialis is an emerging cause of human infections typically occurring after trauma, inoculation, or surgery. Most infections are localized; however, the present case highlights the ability of this species to form a massive cutaneous infection. Treatment should be tailored to susceptibility, with close follow-up to ensure improvement and resolution. For clinicians encountering a similar case, we encourage biopsy prior to empiric antibiotics, as antibiotic therapy can decrease the yield of subsequent testing. Treatment should be guided by the clinical course and may need to last weeks to months. Combination therapy for Gordonia infections should be considered in severe cases, in cases presenting as actinomycetoma, in those not responding to therapy, or when the susceptibility profile is unknown or unreliable.

Acknowledgments—The authors thank this veteran for allowing us to participate in his care and to learn from his experience. He gave his consent for us to share his story and the photographs of the arm.

Mycetoma is a chronic subcutaneous infection due to fungal (eumycetoma) or aerobic actinomycetes (actinomycetoma) organisms. Clinical lesions develop from a granulomatous infiltrate organizing around the infectious organism. Patients can present with extensive subcutaneous nodularity and draining sinuses that can lead to deformation of the affected extremity. These infections are rare in developed countries, and the prevalence and incidence remain unknown. It has been reported that actinomycetes represent 60% of mycetoma cases worldwide, with the majority of cases in Central America from Nocardia (86%) and Actinomadura madurae (10%). ¹Gordonia species are aerobic, partially acid-fast, gram-positive actinobacteria that may comprise a notable minority of actinomycete isolates. ² The species Gordonia bronchialis is of particular interest as a human pathogen because of increasing reports of nosocomial infections. ^3,4 We describe a case of a mycetomalike infection due to G bronchialis in an immunocompetent patient with complete resolution after 3 months of antibiotics.

Case Report

An 86-year-old man presented to the emergency department with a pruritic rash on the right forearm. He had a history of chronic kidney disease, hypertension, and inverse psoriasis complicated by steroid atrophy. He reported trauma to the right antecubital fossa approximately 1 to 2 months prior from a car door; he received wound care over several weeks at an outside hospital. The initial wound healed completely, but he subsequently noticed erythema spreading down the forearm. At the current presentation, he was empirically treated with mid-potency topical steroids and cefuroxime for 7 days. Initial laboratory results were notable for a white blood cell count of 5.7×10³ cells/μL (reference range,3.7–8.4×10³ cells/μL) and a creatinine level of 1.5 mg/dL (reference range, 0.57–1.25 mg/dL). The patient returned to the emergency department 2 weeks later with spreading of the initial rash and worsening pruritus. Dermatologic evaluation revealed the patient was afebrile and had violaceous papules and nodules that coalesced into plaques on the right arm, with the largest measuring approximately 15 cm. Areas of superficial erosion and crusting were noted (Figure 1A). The patient denied constitutional symptoms and had no axillary or cervical lymphadenopathy. The differential initially included an atypical infection vs a neoplasm. Two 5-mm punch biopsies were performed, which demonstrated a suppurative granulomatous infiltrate in the dermis with extension into the subcutis (Figure 2A). Focal vacuolations within the dermis demonstrated aggregates of gram-positive pseudofilamentous organisms (Figures 2B and 2C). Aerobic tissue cultures grew G bronchialis that was susceptible to all antibiotics tested and Staphylococcus epidermidis. Fungal and mycobacterial cultures were negative. The patient was placed on amoxicillin 875 mg–clavulanate 125 mg twice daily for 3 weeks. However, he demonstrated progression of the rash, with increased induration and confluence of plaques on the forearm (Figure 1B). A repeat excisional biopsy was performed, and a tissue sample was sent for 16S ribosomal RNA sequencing identification. However, neither conventional cultures nor sequencing demonstrated evidence of G bronchialis or any other pathogen. Additionally, bacterial, fungal, and mycobacterial blood cultures were negative. Amoxicillin-clavulanate was stopped, and he was placed on trimethoprim-sulfamethoxazole for 2 weeks, then changed to linezolid (600 mg twice daily) due to continued lack of improvement of the rash. After 2 weeks of linezolid, the rash was slightly improved, but the patient had notable side effects (eg, nausea, mucositis). Therefore, he was switched back to trimethoprim-sulfamethoxazole for another 6 weeks. Antibiotic therapy was discontinued after there was notable regression of indurated plaques (Figure 1C); he received more than 3 months of antibiotics in all. At 1 month after completion of antibiotic therapy, the patient had no evidence of recurrence.

Comment

Microbiology of Gordonia Species—Gordonia bronchialis originally was isolated in 1971 by Tsukamura et al⁵ from the sputum of patients with cavitary tuberculosis and bronchiectasis in Japan. Other Gordonia species (formerly Rhodococcus or Gordona) later were identified in soil, seawater, sediment, and wastewater. Gordonia bronchialis is a gram-positive aerobic actinomycete short rod that organizes in cordlike compact groups. It is weakly acid fast, nonmotile, and nonsporulating. Colonies exhibit pinkish-brown pigmentation. Our understanding of the clinical significance of this organism continues to evolve, and it is not always clearly pathogenic. Because Gordonia isolates may be dismissed as commensals or misidentified as Nocardia or Rhodococcus by routine biochemical tests, it is possible that infections may go undetected. Speciation requires gene sequencing; as our utilization of molecular methods has increased, the identification of clinically relevant aerobic actinomycetes, including Gordonia, has improved,⁶ and the following species have been recognized as pathogens: Gordonia araii, G bronchialis, Gordonia effusa, Gordonia otitidis, Gordonia polyisoprenivorans, Gordonia rubirpertincta, Gordonia sputi, and Gordonia terrae.⁷

Cases Reported in the Literature—A PubMed search of articles indexed for MEDLINE using the term Gordonia bronchialis yielded 35 previously reported human cases of G bronchialis infection, most often associated with medical devices or procedures.^8-31 Eighteen of these cases were sternal surgical site infections in patients with a history of cardiac surgery,^3,4,12-16,30 including 2 outbreaks following coronary artery bypass grafting that were thought to be related to intraoperative transmission from a nurse.^3,4 Of the remaining cases, 12 were linked to a procedure or an indwelling catheter: 4 cases of peritonitis in the setting of continuous ambulatory peritoneal dialysis^17,18,26,27; 3 cases of skin and soft tissue infection (1 at the site of a prior needle injection,¹⁰ 1 after acupuncture,¹¹ and 1 after breast reduction surgery²⁹); 1 case of ventriculitis in a premature neonate with an underlying intraventricular shunt¹⁹; 2 cases of pacemaker-induced endocarditis^20,28; 1 case of tibial osteomyelitis related to a bioresorbable polymer screw²¹; and 1 case of chronic endophthalmitis with underlying intraocular lens implants.²² The Table lists all cases of G bronchialis skin or surgical site infections encountered in our literature search as well as the treatment provided in each case.

Only 4 of these 35 cases of G bronchialis infections were skin and soft tissue infections. All 4 occurred in immunocompetent hosts, and 3 were associated with needle punctures or surgery. The fourth case involved a recurrent breast abscess that occurred in a patient without known risk factors or recent procedures.²³ Other Gordonia species have been associated with cutaneous infections, including Gordonia amicalis, G terrae, and recently Gordonia westfalica, with the latter 2 demonstrating actinomycetoma formation.^32-34 Our case is remarkable in that it represents actinomycetoma due to G bronchialis. Of note, our patient was immunocompetent and did not have any radiation or chronic lymphedema involving the affected extremity. However, his history of steroid-induced skin atrophy may have predisposed him to this rare infection.

Clinical Presentation—Classic mycetoma demonstrate organismal granules within the dermis, surrounded by a neutrophilic infiltrate, which is in turn surrounded by histiocytes and multinucleated giant cells. Periodic acid–Schiff and silver stains can identify fungal organisms, while Gram stain helps to elucidate bacterial etiologies.¹ In our patient, a biopsy revealed several dermal aggregates of pseudofilamentous gram-positive organisms surrounded by a neutrophilic and histiocytic infiltrate.⁸ Because this case presented over weeks to months rather than months to years, it progressed more rapidly than a classic mycetoma. However, the dermatologic and histologic features were consistent with mycetoma.

Management—General treatment of actinomycetoma requires identification of the causative organism and prolonged administration of antibiotics, typically in combination.^35-37 Most G bronchialis infections associated with surgical intervention or implants in the literature required surgical debridement and removal of contaminated material for clinical cure, with the exception of 3 cases of sternal wound infection and 1 case of peritonitis that recovered with antimicrobial therapy alone.^3,17 Combination therapy often was used, but monotherapy, particularly with a fluoroquinolone, has been reported. Susceptibility data are limited, but in general, Gordonia species appear susceptible to imipenem, ciprofloxacin, amikacin, gentamicin, and linezolid, with variable susceptibility to vancomycin (89% of isolates), third-generation cephalosporins (80%–90% of isolates), tetracyclines (≤85% of isolates), penicillin (≤70% of isolates), and trimethoprim-sulfamethoxazole (≤65% of isolates).^{7,10,19,38-40} Although there are no standardized recommendations for the treatment of these infections, the most commonly used drugs to treat Gordonia are carbapenems and fluoroquinolones, with or without an aminoglycoside, followed by third-generation cephalosporins and vancomycin, depending on susceptibilities. Additional antibiotics (alone or in combination) that have previously been used with favorable outcomes include amoxicillin or amoxicillin-clavulanate, piperacillin-tazobactam, rifampicin, trimethoprim-sulfamethoxazole, minocycline, doxycycline, and daptomycin.

Our patient received amoxicillin-clavulanate, trimethoprim-sulfamethoxazole, and linezolid. We considered combination therapy but decided against it due to concern for toxicity, given his age and poor renal function. The antibiotic that was most important to his recovery was unclear; the patient insisted that his body, not antibiotics, deserved most of the credit for healing his arm. Although cultures and polymerase chain reaction assays were negative after 3 weeks of amoxicillin-clavulanate, the patient did not show clinical improvement—reasons could be because the antibiotic reduced but did not eliminate the bacterial burden, sampling error of the biopsy, or it takes much longer for the body to heal than it takes to kill the bacteria. Most likely a combination of factors was at play.

Conclusion

Gordonia bronchialis is an emerging cause of human infections typically occurring after trauma, inoculation, or surgery. Most infections are localized; however, the present case highlights the ability of this species to form a massive cutaneous infection. Treatment should be tailored to susceptibility, with close follow-up to ensure improvement and resolution. For clinicians encountering a similar case, we encourage biopsy prior to empiric antibiotics, as antibiotic therapy can decrease the yield of subsequent testing. Treatment should be guided by the clinical course and may need to last weeks to months. Combination therapy for Gordonia infections should be considered in severe cases, in cases presenting as actinomycetoma, in those not responding to therapy, or when the susceptibility profile is unknown or unreliable.

Acknowledgments—The authors thank this veteran for allowing us to participate in his care and to learn from his experience. He gave his consent for us to share his story and the photographs of the arm.

The role of micronutrients in the hair follicle cycle is not fully understood; thus deficiency and/or excess of certain micronutrients may be a modifiable risk factor associated with the development and/or treatment of some types of hair loss and therefore may be included in the workup during an alopecia consultation.

Hereditary hemochromatosis (HHC) is the most common genetic disorder identified in White individuals, with a worldwide prevalence of 1 in 220 to 1 in 250 individuals for a homozygous mutation. It most commonly affects individuals of Northern European descent.¹ Men usually present in the fourth to sixth decades of life, while women usually develop symptoms after menopause, as pregnancy and menstruation delay the onset of the disease.² Early symptoms of HHC include fatigue, joint pain, abdominal pain, and weight loss. Men are more likely to develop complications; in fact, 1 in 10 men with HHC will develop severe liver disease.³ As the disease progresses, affected individuals can present with cardiomyopathy (restrictive and dilated), cirrhosis, hypogonadism (usually hypogonadotrophic), arthropathy, diabetes mellitus, hepatomegaly, hepatic cirrhosis, and primary liver cancer (eg, hepatocellular carcinoma, cholangiocarcinoma).² Approximately 90% of patients with HHC present with hyperpigmentation at the time of diagnosis.⁴ Thinning or loss of hair is another finding in HHC, primarily reported in the axillae and pubic regions, and is ascribed to hepatotesticular insufficiency.⁵

Alopecia areata (AA) is the most common cause of autoimmune, inflammation-induced hair loss, with a calculated lifetime risk of 2%.⁶ This disease manifests as loss of hair in well-circumscribed patches of skin, most commonly on the scalp; AA also may affect other hair-bearing sites on the body. It is associated with an increased risk for other autoimmune disorders, such as psoriasis, thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and vitiligo.⁷

Alopecia areata is induced by an inflammatory infiltrate of CD4⁺ and CD8⁺ T lymphocytes around hair follicles in the anagen stage, the active growth phase.⁸ Although the diagnosis is clinical, some clinicians order laboratory thyroid studies to investigate conditions that may be associated with AA. Common treatments include topical, intralesional, and/or systemic corticosteroids; contact immunotherapy; topical and more recently oral minoxidil; phototherapy; and topical and systemic JAK inhibitors, including tofacitinib.^4,9

We reviewed the medical records of 533 patients who were seen in The University of Texas Southwestern (Dallas, Texas) dermatology clinic from January 2015 through January 2020 and were diagnosed with AA. We examined their demographic data and medical history. We sought to determine any relationship between various types of alopecia and certain micronutrient levels through laboratory test results. Ferritin and iron saturation studies were evaluated. We report 4 cases of HHC concurrent with AA, of which 2 HHC diagnoses were uncovered through iron studies as part of the alopecia evaluation.

Case Reports

Patient 1—A 55-year-old White woman presented to the clinic for an alopecia consultation. She had a medical history of hypothyroidism and AA that was treated unsuccessfully with triamcinolone acetonide steroid injections; topical minoxidil; topical steroids; and systemic steroids, specifically oral prednisone. Following evaluation, she successfully transitioned to treatment with oral tofacitinib and continued to do well on tofacitinib.

The patient’s alopecia workup revealed a ferritin level of 245 ng/mL (reference range, 13–150 ng/mL) and iron saturation of 60% (reference range, 20%–50%). She was referred to the hematology department for further evaluation and was diagnosed with HHC. Genetic testing revealed a heterozygous H63D mutation; therapeutic phlebotomy was recommended. Her sister also was recently diagnosed with HHC.

Patient 2—A 55-year-old White man was referred for evaluation and treatment of alopecia universalis. He had a medical history of skin cancer and vitiligo. He attempted contact immunotherapy with diphenylcyclopropenone scalp treatment but stopped due to intolerable inflammation. Intervention with a topical steroid and topical minoxidil was unsuccessful, but use of triamcinolone acetonide steroid injection on the scalp and topical bimatoprost 0.03% on the eyebrows produced satisfactory results.

The patient’s alopecia workup revealed a ferritin level of 422 ng/mL (reference range, 30–400 ng/mL), which prompted a hematology consultation for further evaluation. Notably, the patient ate red meat several times a week, used iron skillets, and denied receiving blood transfusions. His social habits included 3 alcoholic beverages a night, 5 days a week. Ultrasonography of the liver was recommended to assess potential damage from iron overload and alcohol consumption; the results suggested chronic liver disease, not definitive for cirrhosis, and no evidence of hepatocellular carcinoma. Genetic analysis later revealed the heterozygous H63D variant; therapeutic phlebotomy was recommended.

Patient 3—A 22-year-old White man presented with AA involving his facial beard. He had a medical history of vitiligo and psoriasis and a family history of AA as well as other autoimmune diseases including Hashimoto thyroiditis, psoriasis, eczema, and autoimmune hepatitis. Diphenylcyclopropenone treatment was not successful.

Laboratory studies revealed mildly elevated transaminase and ferritin levels. The patient also presented to the gastroenterologist for evaluation of abdominal pain. Subsequent hematology evaluation confirmed the presence of compound heterozygous C282Y and H63D mutations in the HFE gene, and the patient’s mother was later determined to be homozygous for the C282Y mutation with no elevated ferritin level. The patient’s ferritin level at diagnosis was approximately 500 ng/mL (reference range, 22–322 ng/mL); he required a modest number of therapeutic phlebotomies to normalize his ferritin level.

Patient 4—A 62-year-old White woman presented for evaluation and treatment of patchy hair loss on the scalp of 7 months’ duration. She was subsequently diagnosed with AA. After unsuccessful treatment with a triamcinolone acetonide steroid injection, topical immunotherapy with diphenylcyclopropenone was recommended. The patient achieved full hair regrowth after 35 treatments administered at 3-week intervals.

The patient had a medical history of HHC, including homozygosity for the C282Y mutation, and a family history of HHC in 1 sister. Treatment was therapeutic phlebotomy.

Comment

HHC in the Setting of AA—We presented 4 White patients with both HHC and AA. A PubMed search of articles indexed for MEDLINE using the terms HHC and AA yielded only 1 other reported case of newly identified HHC in a 56-year-old man who presented with pigmented purpuric dermatitis and AA that affected the beard.¹⁰ Because HHC is the most common genetic disorder identified in White individuals and has a varied clinical presentation, the documentation of AA may be an important cutaneous clue to help clinicians diagnose HHC early.

Iron Overload in Patients With HHC—The genetic association between HHC and AA, if any, is unknown. What is known is that iron overload can catalyze reactive oxygen species, which can overwhelm cellular antioxidant capacities at particular levels and cause injury to its constituents.¹¹ Data show that the levels of oxidative stress are elevated in the scalp of patients with AA compared to controls and increased 2-fold during the early phase of disease vs late-phase disease.¹² Thus, it is possible that increased iron levels in HHC may contribute to AA in genetically susceptible individuals by direct toxicity that ultimately results in the AA hair disorder that is CD8⁺ T-cell mediated.

Data show that 78% (31/40) of men and 36% (14/39) of women identified with homozygous C282Y mutations determined from family genetic analyses exhibited iron overload.¹³ In general, a normal life expectancy is possible for patients promptly treated with appropriate therapeutic phlebotomies.¹⁴ Thus, early diagnosis and appropriate therapy can prevent consequences of iron overload, which include cirrhosis, diabetes mellitus, and cardiomyopathy.¹³Iron Screening in the Alopecia Workup—Our cases illustrate how iron screening tests as part of the alopecia workup identified a cohort of White patients with iron overload and subsequently led to an early diagnosis of HHC. The calculated 2% lifetime risk for developing AA highlights the importance of evaluating iron status as part of the AA workup, particularly for White men, and the potential health benefit from early diagnosis of HHC. Limitations of this case series included its retrospective nature and small patient number.

The role of micronutrients in the hair follicle cycle is not fully understood; thus deficiency and/or excess of certain micronutrients may be a modifiable risk factor associated with the development and/or treatment of some types of hair loss and therefore may be included in the workup during an alopecia consultation.

Hereditary hemochromatosis (HHC) is the most common genetic disorder identified in White individuals, with a worldwide prevalence of 1 in 220 to 1 in 250 individuals for a homozygous mutation. It most commonly affects individuals of Northern European descent.¹ Men usually present in the fourth to sixth decades of life, while women usually develop symptoms after menopause, as pregnancy and menstruation delay the onset of the disease.² Early symptoms of HHC include fatigue, joint pain, abdominal pain, and weight loss. Men are more likely to develop complications; in fact, 1 in 10 men with HHC will develop severe liver disease.³ As the disease progresses, affected individuals can present with cardiomyopathy (restrictive and dilated), cirrhosis, hypogonadism (usually hypogonadotrophic), arthropathy, diabetes mellitus, hepatomegaly, hepatic cirrhosis, and primary liver cancer (eg, hepatocellular carcinoma, cholangiocarcinoma).² Approximately 90% of patients with HHC present with hyperpigmentation at the time of diagnosis.⁴ Thinning or loss of hair is another finding in HHC, primarily reported in the axillae and pubic regions, and is ascribed to hepatotesticular insufficiency.⁵

Alopecia areata (AA) is the most common cause of autoimmune, inflammation-induced hair loss, with a calculated lifetime risk of 2%.⁶ This disease manifests as loss of hair in well-circumscribed patches of skin, most commonly on the scalp; AA also may affect other hair-bearing sites on the body. It is associated with an increased risk for other autoimmune disorders, such as psoriasis, thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and vitiligo.⁷

Alopecia areata is induced by an inflammatory infiltrate of CD4⁺ and CD8⁺ T lymphocytes around hair follicles in the anagen stage, the active growth phase.⁸ Although the diagnosis is clinical, some clinicians order laboratory thyroid studies to investigate conditions that may be associated with AA. Common treatments include topical, intralesional, and/or systemic corticosteroids; contact immunotherapy; topical and more recently oral minoxidil; phototherapy; and topical and systemic JAK inhibitors, including tofacitinib.^4,9

We reviewed the medical records of 533 patients who were seen in The University of Texas Southwestern (Dallas, Texas) dermatology clinic from January 2015 through January 2020 and were diagnosed with AA. We examined their demographic data and medical history. We sought to determine any relationship between various types of alopecia and certain micronutrient levels through laboratory test results. Ferritin and iron saturation studies were evaluated. We report 4 cases of HHC concurrent with AA, of which 2 HHC diagnoses were uncovered through iron studies as part of the alopecia evaluation.

Case Reports

Patient 1—A 55-year-old White woman presented to the clinic for an alopecia consultation. She had a medical history of hypothyroidism and AA that was treated unsuccessfully with triamcinolone acetonide steroid injections; topical minoxidil; topical steroids; and systemic steroids, specifically oral prednisone. Following evaluation, she successfully transitioned to treatment with oral tofacitinib and continued to do well on tofacitinib.

The patient’s alopecia workup revealed a ferritin level of 245 ng/mL (reference range, 13–150 ng/mL) and iron saturation of 60% (reference range, 20%–50%). She was referred to the hematology department for further evaluation and was diagnosed with HHC. Genetic testing revealed a heterozygous H63D mutation; therapeutic phlebotomy was recommended. Her sister also was recently diagnosed with HHC.

Patient 2—A 55-year-old White man was referred for evaluation and treatment of alopecia universalis. He had a medical history of skin cancer and vitiligo. He attempted contact immunotherapy with diphenylcyclopropenone scalp treatment but stopped due to intolerable inflammation. Intervention with a topical steroid and topical minoxidil was unsuccessful, but use of triamcinolone acetonide steroid injection on the scalp and topical bimatoprost 0.03% on the eyebrows produced satisfactory results.

The patient’s alopecia workup revealed a ferritin level of 422 ng/mL (reference range, 30–400 ng/mL), which prompted a hematology consultation for further evaluation. Notably, the patient ate red meat several times a week, used iron skillets, and denied receiving blood transfusions. His social habits included 3 alcoholic beverages a night, 5 days a week. Ultrasonography of the liver was recommended to assess potential damage from iron overload and alcohol consumption; the results suggested chronic liver disease, not definitive for cirrhosis, and no evidence of hepatocellular carcinoma. Genetic analysis later revealed the heterozygous H63D variant; therapeutic phlebotomy was recommended.

Patient 3—A 22-year-old White man presented with AA involving his facial beard. He had a medical history of vitiligo and psoriasis and a family history of AA as well as other autoimmune diseases including Hashimoto thyroiditis, psoriasis, eczema, and autoimmune hepatitis. Diphenylcyclopropenone treatment was not successful.

Laboratory studies revealed mildly elevated transaminase and ferritin levels. The patient also presented to the gastroenterologist for evaluation of abdominal pain. Subsequent hematology evaluation confirmed the presence of compound heterozygous C282Y and H63D mutations in the HFE gene, and the patient’s mother was later determined to be homozygous for the C282Y mutation with no elevated ferritin level. The patient’s ferritin level at diagnosis was approximately 500 ng/mL (reference range, 22–322 ng/mL); he required a modest number of therapeutic phlebotomies to normalize his ferritin level.

Patient 4—A 62-year-old White woman presented for evaluation and treatment of patchy hair loss on the scalp of 7 months’ duration. She was subsequently diagnosed with AA. After unsuccessful treatment with a triamcinolone acetonide steroid injection, topical immunotherapy with diphenylcyclopropenone was recommended. The patient achieved full hair regrowth after 35 treatments administered at 3-week intervals.

The patient had a medical history of HHC, including homozygosity for the C282Y mutation, and a family history of HHC in 1 sister. Treatment was therapeutic phlebotomy.

Comment

HHC in the Setting of AA—We presented 4 White patients with both HHC and AA. A PubMed search of articles indexed for MEDLINE using the terms HHC and AA yielded only 1 other reported case of newly identified HHC in a 56-year-old man who presented with pigmented purpuric dermatitis and AA that affected the beard.¹⁰ Because HHC is the most common genetic disorder identified in White individuals and has a varied clinical presentation, the documentation of AA may be an important cutaneous clue to help clinicians diagnose HHC early.

Iron Overload in Patients With HHC—The genetic association between HHC and AA, if any, is unknown. What is known is that iron overload can catalyze reactive oxygen species, which can overwhelm cellular antioxidant capacities at particular levels and cause injury to its constituents.¹¹ Data show that the levels of oxidative stress are elevated in the scalp of patients with AA compared to controls and increased 2-fold during the early phase of disease vs late-phase disease.¹² Thus, it is possible that increased iron levels in HHC may contribute to AA in genetically susceptible individuals by direct toxicity that ultimately results in the AA hair disorder that is CD8⁺ T-cell mediated.

Data show that 78% (31/40) of men and 36% (14/39) of women identified with homozygous C282Y mutations determined from family genetic analyses exhibited iron overload.¹³ In general, a normal life expectancy is possible for patients promptly treated with appropriate therapeutic phlebotomies.¹⁴ Thus, early diagnosis and appropriate therapy can prevent consequences of iron overload, which include cirrhosis, diabetes mellitus, and cardiomyopathy.¹³Iron Screening in the Alopecia Workup—Our cases illustrate how iron screening tests as part of the alopecia workup identified a cohort of White patients with iron overload and subsequently led to an early diagnosis of HHC. The calculated 2% lifetime risk for developing AA highlights the importance of evaluating iron status as part of the AA workup, particularly for White men, and the potential health benefit from early diagnosis of HHC. Limitations of this case series included its retrospective nature and small patient number.

The role of micronutrients in the hair follicle cycle is not fully understood; thus deficiency and/or excess of certain micronutrients may be a modifiable risk factor associated with the development and/or treatment of some types of hair loss and therefore may be included in the workup during an alopecia consultation.

Hereditary hemochromatosis (HHC) is the most common genetic disorder identified in White individuals, with a worldwide prevalence of 1 in 220 to 1 in 250 individuals for a homozygous mutation. It most commonly affects individuals of Northern European descent.¹ Men usually present in the fourth to sixth decades of life, while women usually develop symptoms after menopause, as pregnancy and menstruation delay the onset of the disease.² Early symptoms of HHC include fatigue, joint pain, abdominal pain, and weight loss. Men are more likely to develop complications; in fact, 1 in 10 men with HHC will develop severe liver disease.³ As the disease progresses, affected individuals can present with cardiomyopathy (restrictive and dilated), cirrhosis, hypogonadism (usually hypogonadotrophic), arthropathy, diabetes mellitus, hepatomegaly, hepatic cirrhosis, and primary liver cancer (eg, hepatocellular carcinoma, cholangiocarcinoma).² Approximately 90% of patients with HHC present with hyperpigmentation at the time of diagnosis.⁴ Thinning or loss of hair is another finding in HHC, primarily reported in the axillae and pubic regions, and is ascribed to hepatotesticular insufficiency.⁵

Alopecia areata (AA) is the most common cause of autoimmune, inflammation-induced hair loss, with a calculated lifetime risk of 2%.⁶ This disease manifests as loss of hair in well-circumscribed patches of skin, most commonly on the scalp; AA also may affect other hair-bearing sites on the body. It is associated with an increased risk for other autoimmune disorders, such as psoriasis, thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and vitiligo.⁷

Alopecia areata is induced by an inflammatory infiltrate of CD4⁺ and CD8⁺ T lymphocytes around hair follicles in the anagen stage, the active growth phase.⁸ Although the diagnosis is clinical, some clinicians order laboratory thyroid studies to investigate conditions that may be associated with AA. Common treatments include topical, intralesional, and/or systemic corticosteroids; contact immunotherapy; topical and more recently oral minoxidil; phototherapy; and topical and systemic JAK inhibitors, including tofacitinib.^4,9

We reviewed the medical records of 533 patients who were seen in The University of Texas Southwestern (Dallas, Texas) dermatology clinic from January 2015 through January 2020 and were diagnosed with AA. We examined their demographic data and medical history. We sought to determine any relationship between various types of alopecia and certain micronutrient levels through laboratory test results. Ferritin and iron saturation studies were evaluated. We report 4 cases of HHC concurrent with AA, of which 2 HHC diagnoses were uncovered through iron studies as part of the alopecia evaluation.

Case Reports

Patient 1—A 55-year-old White woman presented to the clinic for an alopecia consultation. She had a medical history of hypothyroidism and AA that was treated unsuccessfully with triamcinolone acetonide steroid injections; topical minoxidil; topical steroids; and systemic steroids, specifically oral prednisone. Following evaluation, she successfully transitioned to treatment with oral tofacitinib and continued to do well on tofacitinib.

The patient’s alopecia workup revealed a ferritin level of 245 ng/mL (reference range, 13–150 ng/mL) and iron saturation of 60% (reference range, 20%–50%). She was referred to the hematology department for further evaluation and was diagnosed with HHC. Genetic testing revealed a heterozygous H63D mutation; therapeutic phlebotomy was recommended. Her sister also was recently diagnosed with HHC.

Patient 2—A 55-year-old White man was referred for evaluation and treatment of alopecia universalis. He had a medical history of skin cancer and vitiligo. He attempted contact immunotherapy with diphenylcyclopropenone scalp treatment but stopped due to intolerable inflammation. Intervention with a topical steroid and topical minoxidil was unsuccessful, but use of triamcinolone acetonide steroid injection on the scalp and topical bimatoprost 0.03% on the eyebrows produced satisfactory results.

The patient’s alopecia workup revealed a ferritin level of 422 ng/mL (reference range, 30–400 ng/mL), which prompted a hematology consultation for further evaluation. Notably, the patient ate red meat several times a week, used iron skillets, and denied receiving blood transfusions. His social habits included 3 alcoholic beverages a night, 5 days a week. Ultrasonography of the liver was recommended to assess potential damage from iron overload and alcohol consumption; the results suggested chronic liver disease, not definitive for cirrhosis, and no evidence of hepatocellular carcinoma. Genetic analysis later revealed the heterozygous H63D variant; therapeutic phlebotomy was recommended.

Patient 3—A 22-year-old White man presented with AA involving his facial beard. He had a medical history of vitiligo and psoriasis and a family history of AA as well as other autoimmune diseases including Hashimoto thyroiditis, psoriasis, eczema, and autoimmune hepatitis. Diphenylcyclopropenone treatment was not successful.

Laboratory studies revealed mildly elevated transaminase and ferritin levels. The patient also presented to the gastroenterologist for evaluation of abdominal pain. Subsequent hematology evaluation confirmed the presence of compound heterozygous C282Y and H63D mutations in the HFE gene, and the patient’s mother was later determined to be homozygous for the C282Y mutation with no elevated ferritin level. The patient’s ferritin level at diagnosis was approximately 500 ng/mL (reference range, 22–322 ng/mL); he required a modest number of therapeutic phlebotomies to normalize his ferritin level.

Patient 4—A 62-year-old White woman presented for evaluation and treatment of patchy hair loss on the scalp of 7 months’ duration. She was subsequently diagnosed with AA. After unsuccessful treatment with a triamcinolone acetonide steroid injection, topical immunotherapy with diphenylcyclopropenone was recommended. The patient achieved full hair regrowth after 35 treatments administered at 3-week intervals.

The patient had a medical history of HHC, including homozygosity for the C282Y mutation, and a family history of HHC in 1 sister. Treatment was therapeutic phlebotomy.

Comment

HHC in the Setting of AA—We presented 4 White patients with both HHC and AA. A PubMed search of articles indexed for MEDLINE using the terms HHC and AA yielded only 1 other reported case of newly identified HHC in a 56-year-old man who presented with pigmented purpuric dermatitis and AA that affected the beard.¹⁰ Because HHC is the most common genetic disorder identified in White individuals and has a varied clinical presentation, the documentation of AA may be an important cutaneous clue to help clinicians diagnose HHC early.

Iron Overload in Patients With HHC—The genetic association between HHC and AA, if any, is unknown. What is known is that iron overload can catalyze reactive oxygen species, which can overwhelm cellular antioxidant capacities at particular levels and cause injury to its constituents.¹¹ Data show that the levels of oxidative stress are elevated in the scalp of patients with AA compared to controls and increased 2-fold during the early phase of disease vs late-phase disease.¹² Thus, it is possible that increased iron levels in HHC may contribute to AA in genetically susceptible individuals by direct toxicity that ultimately results in the AA hair disorder that is CD8⁺ T-cell mediated.

Data show that 78% (31/40) of men and 36% (14/39) of women identified with homozygous C282Y mutations determined from family genetic analyses exhibited iron overload.¹³ In general, a normal life expectancy is possible for patients promptly treated with appropriate therapeutic phlebotomies.¹⁴ Thus, early diagnosis and appropriate therapy can prevent consequences of iron overload, which include cirrhosis, diabetes mellitus, and cardiomyopathy.¹³Iron Screening in the Alopecia Workup—Our cases illustrate how iron screening tests as part of the alopecia workup identified a cohort of White patients with iron overload and subsequently led to an early diagnosis of HHC. The calculated 2% lifetime risk for developing AA highlights the importance of evaluating iron status as part of the AA workup, particularly for White men, and the potential health benefit from early diagnosis of HHC. Limitations of this case series included its retrospective nature and small patient number.

Case Report

A 47-year-old man presented with a sudden-onset rash consisting of red bumps on the abdomen and legs that had been ongoing for several days. He had known psoriasis and psoriatic arthritis that had been well controlled with adalimumab for the last 18 months. He reported concurrent onset of nausea but denied fevers, chills, night sweats, unintentional weight loss, abdominal pain, and pruritus. He endorsed prior cutaneous infections of methicillin-resistant Staphylococcus aureus (MRSA). His medical history also included diabetes mellitus, hypertension, and obesity. His other medications included oral losartan-hydrochlorothiazide, amlodipine, naproxen, and atorvastatin.

Physical examination revealed numerous thin purpuric papules—some with adherent scale—distributed on the lower legs, extensor forearms, and abdomen. Abdominal lesions were confined to weight-related striae (Figure 1). The palms, soles, oral mucosa, and face were spared. Three punch biopsies were performed, including 1 for direct immunofluorescence (DIF), and the patient was instructed to apply clobetasol to the affected areas twice daily until further notice.

Pathology showed perivascular extravasation of erythrocytes, neutrophils, eosinophils, and leukocytoclasis surrounding blood vessels associated with fibrin (Figure 2). Direct immunofluorescence showed granular deposition of IgA, complement component 3, and fibrinogen in a superficial dermal vascular pattern (Figure 3). These results were consistent with IgA small-vessel vasculitis. One specimen was consistent with the patient’s known psoriasis.  

Urinalysis revealed moderate hemoglobinuria, and urine microscopy showed 174 red blood cells per high-power field. Creatinine was high at 1.87 mg/dL (reference range, <1.34 mg/dL; patient’s baseline, 0.81 mg/dL) and glomerular filtration rate was low (42 mL/min, patient’s baseline, >60 mL/min [reference range, 90–120 mL/min]). Erythrocyte sedimentation rate (21 mm/h [reference range, 0–22 mm/h]) and C-reactive protein were elevated (2.2 mg/dL [reference range, 0.3–1.0 mg/dL]). Given his history of cutaneous MRSA infections, a bacterial culture swab was collected from the skin surface to check for colonization, which showed moderate growth of MRSA. Naproxen was discontinued over concern of worsening the patient’s renal status. The patient was instructed to rest at home with his legs elevated, wear compression socks when ambulatory, use chlorhexidine antiseptic daily as a body wash when showering, and apply mupirocin three times daily to the biopsy sites. He was referred to urology for his microhematuria, where cystoscopy revealed no abnormalities.A month passed with no improvement of the patient’s cutaneous vasculitis, and his psoriatic arthritis worsened without his usual use of naproxen. He developed abdominal pain and loss of appetite. A prednisone taper was ordered starting at 40 mg/d (28.8 mg/kg), which provided relief of the skin and joint symptoms only until the course was completed 12 days later. 

Five weeks after the initial presentation, the patient returned with a more severe eruption consisting of innumerable purpuric papules that coalesced in plaques on the abdomen, arms, and legs. He also had erythematous facial pustules and mild palmar petechiae (Figure 4). Three biopsies were performed, including 1 for DIF and 1 from a pustule on the forehead. Histology and DIF were again consistent with IgA small-vessel vasculitis. The forehead biopsy was compatible with steroid acne (attributed to recent prednisone use) and psoriasis.   

Rheumatology was consulted, and adalimumab was discontinued 6 weeks after the initial presentation out of concern for drug-induced cutaneous vasculitis. Vasculitis work-up was unremarkable, including antineutrophil cytoplasmic antibodies, rheumatoid factor, cyclic citrullinated peptide, and serum protein electrophoresis. Oral dapsone was started at 100 mg/d, with the tentative plan of starting secukinumab if cutaneous symptoms improved. For 3 weeks, the patient’s cutaneous symptoms steadily improved.

Nine weeks after initial presentation to dermatology (3 weeks after discontinuing adalimumab) the patient self-administered his first dose of secukinumab at home. Several hours later, he reported sudden reappearance of vasculitis. He denied diarrhea, abdominal pain, bowel movement urgency, fevers, fatigue, and unintentional weight loss. Antistreptolysin O and hepatitis A antibodies were negative. He was instructed to hold secukinumab indefinitely.

Four weeks after his only secukinumab injection, the patient reported another episode of acute worsening cutaneous symptoms. A 4-week prednisone taper starting at 40 mg/d was ordered. Computed tomography of the chest, abdomen, and pelvis to rule out internal malignancy was unremarkable. Around this time, the patient reported major emotional distress related to an unexpected death in his family, which added to a gradual increase in his stress level related to the COVID-19 pandemic. 

Three weeks later, dapsone was increased to 100 mg twice daily on account of the patient’s adiposity and lack of cutaneous improvement on the lower dose. Subsequently, the vasculitis rapidly improved for 2 weeks. The patient then reported symptoms of headache, dizziness, and chills. He was tested for COVID-19 and was negative. Six weeks after increasing the dapsone dose (5 months after initial presentation), the skin was normalizing, showing only faintly hyperpigmented macules confined to areas of resolved vasculitis (forearms, abdomen, legs). 

The patient had been on dapsone 100 mg twice daily for 3 months when he was started on ustekinumab (90 mg at weeks 0 and 4, with planned doses every 12 weeks) for psoriatic arthritis in hopes of withdrawing dapsone. His cutaneous symptoms have remained well controlled on this regimen for 18 months. Lowering of dapsone below 100 mg daily has resulted in recurrent mild vasculitis symptoms; he now maintains the once-daily dosing without negative side effects.

Comment

IgA vasculitis is a form of cutaneous small-vessel leukocytoclastic vasculitis (LCV) characterized by episodes of palpable purpura on the extensor surfaces of the arms and legs that may be associated with arthritis, abdominal pain, and/or hematuria. Although vasculitis is a known potential adverse effect of anti–tumor necrosis factor (TNF) α therapy, cases of adalimumab-induced IgA vasculitis are uncommon. As use of more targeted therapies for psoriasis and psoriatic arthritis, such as the IL-17 inhibitor secukinumab, increases so do reports of associated adverse events. Of 6 previously reported cases of secukinumab-associated vasculitis, at least 4 were IgA vasculitis (Table).^1-6 Another case described one patient with rheumatoid arthritis undergoing secukinumab treatment who experienced necrotizing glomerulonephritis; however, the authors concluded secukinumab likely was not causative in that case, as serologies and urinalyses suggested gradual onset of the process prior to initiating the medication.⁷

The exact pathogenesis of IgA vasculitis is unclear, but a prevailing theory involves the dysregulation of IgA synthesis and metabolism. Other than increased serum levels of transforming growth factor β, which is a major stimulating factor for IgA production, it also has been hypothesized that the presence of aberrantly hypoglycosylated IgA exposes an autoepitope for recognition by other pathogenic IgG and IgA, leading to the formation of large immune complexes that can readily deposit in postcapillary venules. The deposition of IgA immune complexes in postcapillary venules and the subsequent activation of the complement system causes direct damage to the endothelial cells of vessel walls. This complement activation is evidenced by vascular complement component 3 deposition on DIF (a nonspecific feature of LCV). Chemotaxis of neutrophils ensues, followed by their firm adherence and transendothelial migration (mediated by monocyte chemoattractant protein 1 [MCP-1]). Neutrophil degranulation releases reactive oxygen species and cytokines, which in turn recruit additional leukocytes to the area of inflammation, subsequently undergoing degeneration (leukocytoclasis). Microvascular permeability also is enhanced by MCP-1, allowing exudation of serum, erythrocytes, and fibrin. In the setting of elevated circulating TNF and IL-1, endothelium is stimulated to activate the intrinsic and extrinsic coagulation pathways. This decreases endothelial fibrinolytic activity, leading to thrombosis. The high venous pressure and low fibrinolytic activity in the lower legs explains why vasculitic lesions often are confined to or begin in this distribution.^1,8-10

There also are noteworthy roles for cytokines in LCV. Circulating transforming growth factor β and IL-6—which are necessary for development of T helper 17 (T_H17) cells and production of IL-17—are higher in patients with LCV compared to controls. Peripheral blood monocytes in patients with LCV demonstrate higher production of IL-17. Once T_H17 cells develop, their survival and phenotype are maintained by IL-23 (considered the master regulator of T_H17 differentiation). IL-17 is a potent chemoattractant of IL-8 (CXCL8) and MCP-1, both of which promote neutrophil-mediated perivascular inflammation. The IL-23 and IL-17 pathways implicated in the pathogenesis of psoriasis also cause neutrophil activation and upregulate transcription of proinflammatory cytokines (IL-1, IL-6, IL-8, and TNF-α), which overlap with those implicated in LCV. Autoimmune disease generally entails some positive feedback loop of progressively severe self-recognition and tissue destruction by the immune system. These shared cytokinetic processes may explain how the internal environment of psoriasis could perpetuate IgA vasculitis.^1,2,8,10-12

The mechanisms underlying vasculitis associated with adalimumab are unclear, but hypotheses involve direct toxicity on vessels, capillary deposition of anti-TNF/TNF immune complexes, or an inflammatory process resulting in autoantibodies. Similar hypotheses are posited for secukinumab-associated vasculitis, including deposition of secukinumab–IL-17 complexes. Anti–TNF-α medications may increase T_H17 cell numbers, leading to increased production of IL-22 and a resultant immunologic microenvironment conducive to vasculitis. All 6 published cases of secukinumab-associated vasculitis that we found had received prior treatment with a TNF-α blocker, but only 1 had occurrence of vasculitis during that treatment.^1-6,10

In the 6 cases we reviewed, the time from starting secukinumab to onset of vasculitis ranged from 1 to 18 months. Our patient’s same-day re-emergence of vasculitis after his first secukinumab dose was so acute that we were skeptical of secukinumab as a potential trigger; this may simply have been coincident to the natural waxing and waning of the vasculitis (although onset of IgA vasculitis within 1 day of starting anti–TNF-α therapy has been reported).^1-6,13  

Specific associations of IgA vasculitis are many and can include bacterial organisms such as Helicobacter pylori, streptococci, and staphylococci. Although internal mucous membrane infections are considered more linked because of the surveillance role of IgA predominantly in mucosal tissues, it is possible that our patient with cutaneous MRSA harbored the same within the nasal mucosa. Our patient also received multiple vaccinations outside our department throughout his clinical course (2 hepatitis B and 1 pneumococcal conjugate), which are known potential triggers for vasculitis. Psychological stress is a known trigger for psoriasis, and given the cytokinetic relationship of psoriasis to vasculitis described previously, it may have indirectly contributed to vasculitis in our case. The anxiety associated with being immunosuppressed during the COVID-19 pandemic and bereavement of losing a family member may have contributed to the refractory nature of our patient’s condition. Renal involvement is relatively common in adults with IgA vasculitis and so should be ruled out, as should occult internal malignancy.^8,10,14

It is unclear which of the above factors was causative in our case, but a multifactorial process is likely. Treatment of monoclonal antibody–associated vasculitis entails investigating for triggers and systemic involvement, removing the most likely culprit, quelling the vasculitis acutely, avoiding known potential exacerbators, and introducing an alternative long-term immunomodulant. In all 6 reported similar cases, discontinuation of secukinumab and initiation of prednisone or colchicine led to resolution.^1-6 Dapsone also is acceptable for acute control of IgA vasculitis, although this medication is highly lipid soluble and penetrates well into various tissues.¹⁵ Thus, lower doses may prove ineffective for obese patients, as was demonstrated in our case. Given the known potential of vaccinations, infections, and other factors (eg, alcohol, penicillin) to trigger IgA vasculitis, these should be avoided.¹⁰

Blockade of IL-23 with ustekinumab has been suggested by other authors encountering secukinumab-associated vasculitis, as IL-23 is the main driver and sustainer of T_H17 cell differentiation.⁸ Although 6 previously reported cases of secukinumab-associated vasculitis achieved resolution without long-term recurrence, none did so using an IL-23 inhibitor (nor had any of the described patients received IL-23 inhibitors previously).^1-6 Given the established safety of IL-23 inhibitors and that they theoretically are well suited for this unique circumstance (by ceasing the main causative cytokine cascades “upstream”) and were efficacious in quickly resolving our patient’s vasculitis, we suggest that ustekinumab may represent an ideal treatment option for patients in whom adalimumab- or secukinumab-associated vasculitis is suspected. Further research is needed given the complex interplay of so many variables and the increasingly common reports of adverse cutaneous events associated with these drugs.^1-6,10 

Case Report

A 47-year-old man presented with a sudden-onset rash consisting of red bumps on the abdomen and legs that had been ongoing for several days. He had known psoriasis and psoriatic arthritis that had been well controlled with adalimumab for the last 18 months. He reported concurrent onset of nausea but denied fevers, chills, night sweats, unintentional weight loss, abdominal pain, and pruritus. He endorsed prior cutaneous infections of methicillin-resistant Staphylococcus aureus (MRSA). His medical history also included diabetes mellitus, hypertension, and obesity. His other medications included oral losartan-hydrochlorothiazide, amlodipine, naproxen, and atorvastatin.

Physical examination revealed numerous thin purpuric papules—some with adherent scale—distributed on the lower legs, extensor forearms, and abdomen. Abdominal lesions were confined to weight-related striae (Figure 1). The palms, soles, oral mucosa, and face were spared. Three punch biopsies were performed, including 1 for direct immunofluorescence (DIF), and the patient was instructed to apply clobetasol to the affected areas twice daily until further notice.

Pathology showed perivascular extravasation of erythrocytes, neutrophils, eosinophils, and leukocytoclasis surrounding blood vessels associated with fibrin (Figure 2). Direct immunofluorescence showed granular deposition of IgA, complement component 3, and fibrinogen in a superficial dermal vascular pattern (Figure 3). These results were consistent with IgA small-vessel vasculitis. One specimen was consistent with the patient’s known psoriasis.  

Urinalysis revealed moderate hemoglobinuria, and urine microscopy showed 174 red blood cells per high-power field. Creatinine was high at 1.87 mg/dL (reference range, <1.34 mg/dL; patient’s baseline, 0.81 mg/dL) and glomerular filtration rate was low (42 mL/min, patient’s baseline, >60 mL/min [reference range, 90–120 mL/min]). Erythrocyte sedimentation rate (21 mm/h [reference range, 0–22 mm/h]) and C-reactive protein were elevated (2.2 mg/dL [reference range, 0.3–1.0 mg/dL]). Given his history of cutaneous MRSA infections, a bacterial culture swab was collected from the skin surface to check for colonization, which showed moderate growth of MRSA. Naproxen was discontinued over concern of worsening the patient’s renal status. The patient was instructed to rest at home with his legs elevated, wear compression socks when ambulatory, use chlorhexidine antiseptic daily as a body wash when showering, and apply mupirocin three times daily to the biopsy sites. He was referred to urology for his microhematuria, where cystoscopy revealed no abnormalities.A month passed with no improvement of the patient’s cutaneous vasculitis, and his psoriatic arthritis worsened without his usual use of naproxen. He developed abdominal pain and loss of appetite. A prednisone taper was ordered starting at 40 mg/d (28.8 mg/kg), which provided relief of the skin and joint symptoms only until the course was completed 12 days later. 

Five weeks after the initial presentation, the patient returned with a more severe eruption consisting of innumerable purpuric papules that coalesced in plaques on the abdomen, arms, and legs. He also had erythematous facial pustules and mild palmar petechiae (Figure 4). Three biopsies were performed, including 1 for DIF and 1 from a pustule on the forehead. Histology and DIF were again consistent with IgA small-vessel vasculitis. The forehead biopsy was compatible with steroid acne (attributed to recent prednisone use) and psoriasis.   

Rheumatology was consulted, and adalimumab was discontinued 6 weeks after the initial presentation out of concern for drug-induced cutaneous vasculitis. Vasculitis work-up was unremarkable, including antineutrophil cytoplasmic antibodies, rheumatoid factor, cyclic citrullinated peptide, and serum protein electrophoresis. Oral dapsone was started at 100 mg/d, with the tentative plan of starting secukinumab if cutaneous symptoms improved. For 3 weeks, the patient’s cutaneous symptoms steadily improved.

Nine weeks after initial presentation to dermatology (3 weeks after discontinuing adalimumab) the patient self-administered his first dose of secukinumab at home. Several hours later, he reported sudden reappearance of vasculitis. He denied diarrhea, abdominal pain, bowel movement urgency, fevers, fatigue, and unintentional weight loss. Antistreptolysin O and hepatitis A antibodies were negative. He was instructed to hold secukinumab indefinitely.

Four weeks after his only secukinumab injection, the patient reported another episode of acute worsening cutaneous symptoms. A 4-week prednisone taper starting at 40 mg/d was ordered. Computed tomography of the chest, abdomen, and pelvis to rule out internal malignancy was unremarkable. Around this time, the patient reported major emotional distress related to an unexpected death in his family, which added to a gradual increase in his stress level related to the COVID-19 pandemic. 

Three weeks later, dapsone was increased to 100 mg twice daily on account of the patient’s adiposity and lack of cutaneous improvement on the lower dose. Subsequently, the vasculitis rapidly improved for 2 weeks. The patient then reported symptoms of headache, dizziness, and chills. He was tested for COVID-19 and was negative. Six weeks after increasing the dapsone dose (5 months after initial presentation), the skin was normalizing, showing only faintly hyperpigmented macules confined to areas of resolved vasculitis (forearms, abdomen, legs). 

The patient had been on dapsone 100 mg twice daily for 3 months when he was started on ustekinumab (90 mg at weeks 0 and 4, with planned doses every 12 weeks) for psoriatic arthritis in hopes of withdrawing dapsone. His cutaneous symptoms have remained well controlled on this regimen for 18 months. Lowering of dapsone below 100 mg daily has resulted in recurrent mild vasculitis symptoms; he now maintains the once-daily dosing without negative side effects.

Comment

IgA vasculitis is a form of cutaneous small-vessel leukocytoclastic vasculitis (LCV) characterized by episodes of palpable purpura on the extensor surfaces of the arms and legs that may be associated with arthritis, abdominal pain, and/or hematuria. Although vasculitis is a known potential adverse effect of anti–tumor necrosis factor (TNF) α therapy, cases of adalimumab-induced IgA vasculitis are uncommon. As use of more targeted therapies for psoriasis and psoriatic arthritis, such as the IL-17 inhibitor secukinumab, increases so do reports of associated adverse events. Of 6 previously reported cases of secukinumab-associated vasculitis, at least 4 were IgA vasculitis (Table).^1-6 Another case described one patient with rheumatoid arthritis undergoing secukinumab treatment who experienced necrotizing glomerulonephritis; however, the authors concluded secukinumab likely was not causative in that case, as serologies and urinalyses suggested gradual onset of the process prior to initiating the medication.⁷

The exact pathogenesis of IgA vasculitis is unclear, but a prevailing theory involves the dysregulation of IgA synthesis and metabolism. Other than increased serum levels of transforming growth factor β, which is a major stimulating factor for IgA production, it also has been hypothesized that the presence of aberrantly hypoglycosylated IgA exposes an autoepitope for recognition by other pathogenic IgG and IgA, leading to the formation of large immune complexes that can readily deposit in postcapillary venules. The deposition of IgA immune complexes in postcapillary venules and the subsequent activation of the complement system causes direct damage to the endothelial cells of vessel walls. This complement activation is evidenced by vascular complement component 3 deposition on DIF (a nonspecific feature of LCV). Chemotaxis of neutrophils ensues, followed by their firm adherence and transendothelial migration (mediated by monocyte chemoattractant protein 1 [MCP-1]). Neutrophil degranulation releases reactive oxygen species and cytokines, which in turn recruit additional leukocytes to the area of inflammation, subsequently undergoing degeneration (leukocytoclasis). Microvascular permeability also is enhanced by MCP-1, allowing exudation of serum, erythrocytes, and fibrin. In the setting of elevated circulating TNF and IL-1, endothelium is stimulated to activate the intrinsic and extrinsic coagulation pathways. This decreases endothelial fibrinolytic activity, leading to thrombosis. The high venous pressure and low fibrinolytic activity in the lower legs explains why vasculitic lesions often are confined to or begin in this distribution.^1,8-10

There also are noteworthy roles for cytokines in LCV. Circulating transforming growth factor β and IL-6—which are necessary for development of T helper 17 (T_H17) cells and production of IL-17—are higher in patients with LCV compared to controls. Peripheral blood monocytes in patients with LCV demonstrate higher production of IL-17. Once T_H17 cells develop, their survival and phenotype are maintained by IL-23 (considered the master regulator of T_H17 differentiation). IL-17 is a potent chemoattractant of IL-8 (CXCL8) and MCP-1, both of which promote neutrophil-mediated perivascular inflammation. The IL-23 and IL-17 pathways implicated in the pathogenesis of psoriasis also cause neutrophil activation and upregulate transcription of proinflammatory cytokines (IL-1, IL-6, IL-8, and TNF-α), which overlap with those implicated in LCV. Autoimmune disease generally entails some positive feedback loop of progressively severe self-recognition and tissue destruction by the immune system. These shared cytokinetic processes may explain how the internal environment of psoriasis could perpetuate IgA vasculitis.^1,2,8,10-12

The mechanisms underlying vasculitis associated with adalimumab are unclear, but hypotheses involve direct toxicity on vessels, capillary deposition of anti-TNF/TNF immune complexes, or an inflammatory process resulting in autoantibodies. Similar hypotheses are posited for secukinumab-associated vasculitis, including deposition of secukinumab–IL-17 complexes. Anti–TNF-α medications may increase T_H17 cell numbers, leading to increased production of IL-22 and a resultant immunologic microenvironment conducive to vasculitis. All 6 published cases of secukinumab-associated vasculitis that we found had received prior treatment with a TNF-α blocker, but only 1 had occurrence of vasculitis during that treatment.^1-6,10

In the 6 cases we reviewed, the time from starting secukinumab to onset of vasculitis ranged from 1 to 18 months. Our patient’s same-day re-emergence of vasculitis after his first secukinumab dose was so acute that we were skeptical of secukinumab as a potential trigger; this may simply have been coincident to the natural waxing and waning of the vasculitis (although onset of IgA vasculitis within 1 day of starting anti–TNF-α therapy has been reported).^1-6,13  

Specific associations of IgA vasculitis are many and can include bacterial organisms such as Helicobacter pylori, streptococci, and staphylococci. Although internal mucous membrane infections are considered more linked because of the surveillance role of IgA predominantly in mucosal tissues, it is possible that our patient with cutaneous MRSA harbored the same within the nasal mucosa. Our patient also received multiple vaccinations outside our department throughout his clinical course (2 hepatitis B and 1 pneumococcal conjugate), which are known potential triggers for vasculitis. Psychological stress is a known trigger for psoriasis, and given the cytokinetic relationship of psoriasis to vasculitis described previously, it may have indirectly contributed to vasculitis in our case. The anxiety associated with being immunosuppressed during the COVID-19 pandemic and bereavement of losing a family member may have contributed to the refractory nature of our patient’s condition. Renal involvement is relatively common in adults with IgA vasculitis and so should be ruled out, as should occult internal malignancy.^8,10,14

It is unclear which of the above factors was causative in our case, but a multifactorial process is likely. Treatment of monoclonal antibody–associated vasculitis entails investigating for triggers and systemic involvement, removing the most likely culprit, quelling the vasculitis acutely, avoiding known potential exacerbators, and introducing an alternative long-term immunomodulant. In all 6 reported similar cases, discontinuation of secukinumab and initiation of prednisone or colchicine led to resolution.^1-6 Dapsone also is acceptable for acute control of IgA vasculitis, although this medication is highly lipid soluble and penetrates well into various tissues.¹⁵ Thus, lower doses may prove ineffective for obese patients, as was demonstrated in our case. Given the known potential of vaccinations, infections, and other factors (eg, alcohol, penicillin) to trigger IgA vasculitis, these should be avoided.¹⁰

Blockade of IL-23 with ustekinumab has been suggested by other authors encountering secukinumab-associated vasculitis, as IL-23 is the main driver and sustainer of T_H17 cell differentiation.⁸ Although 6 previously reported cases of secukinumab-associated vasculitis achieved resolution without long-term recurrence, none did so using an IL-23 inhibitor (nor had any of the described patients received IL-23 inhibitors previously).^1-6 Given the established safety of IL-23 inhibitors and that they theoretically are well suited for this unique circumstance (by ceasing the main causative cytokine cascades “upstream”) and were efficacious in quickly resolving our patient’s vasculitis, we suggest that ustekinumab may represent an ideal treatment option for patients in whom adalimumab- or secukinumab-associated vasculitis is suspected. Further research is needed given the complex interplay of so many variables and the increasingly common reports of adverse cutaneous events associated with these drugs.^1-6,10 

Case Report

A 47-year-old man presented with a sudden-onset rash consisting of red bumps on the abdomen and legs that had been ongoing for several days. He had known psoriasis and psoriatic arthritis that had been well controlled with adalimumab for the last 18 months. He reported concurrent onset of nausea but denied fevers, chills, night sweats, unintentional weight loss, abdominal pain, and pruritus. He endorsed prior cutaneous infections of methicillin-resistant Staphylococcus aureus (MRSA). His medical history also included diabetes mellitus, hypertension, and obesity. His other medications included oral losartan-hydrochlorothiazide, amlodipine, naproxen, and atorvastatin.

Physical examination revealed numerous thin purpuric papules—some with adherent scale—distributed on the lower legs, extensor forearms, and abdomen. Abdominal lesions were confined to weight-related striae (Figure 1). The palms, soles, oral mucosa, and face were spared. Three punch biopsies were performed, including 1 for direct immunofluorescence (DIF), and the patient was instructed to apply clobetasol to the affected areas twice daily until further notice.

Pathology showed perivascular extravasation of erythrocytes, neutrophils, eosinophils, and leukocytoclasis surrounding blood vessels associated with fibrin (Figure 2). Direct immunofluorescence showed granular deposition of IgA, complement component 3, and fibrinogen in a superficial dermal vascular pattern (Figure 3). These results were consistent with IgA small-vessel vasculitis. One specimen was consistent with the patient’s known psoriasis.  

Urinalysis revealed moderate hemoglobinuria, and urine microscopy showed 174 red blood cells per high-power field. Creatinine was high at 1.87 mg/dL (reference range, <1.34 mg/dL; patient’s baseline, 0.81 mg/dL) and glomerular filtration rate was low (42 mL/min, patient’s baseline, >60 mL/min [reference range, 90–120 mL/min]). Erythrocyte sedimentation rate (21 mm/h [reference range, 0–22 mm/h]) and C-reactive protein were elevated (2.2 mg/dL [reference range, 0.3–1.0 mg/dL]). Given his history of cutaneous MRSA infections, a bacterial culture swab was collected from the skin surface to check for colonization, which showed moderate growth of MRSA. Naproxen was discontinued over concern of worsening the patient’s renal status. The patient was instructed to rest at home with his legs elevated, wear compression socks when ambulatory, use chlorhexidine antiseptic daily as a body wash when showering, and apply mupirocin three times daily to the biopsy sites. He was referred to urology for his microhematuria, where cystoscopy revealed no abnormalities.A month passed with no improvement of the patient’s cutaneous vasculitis, and his psoriatic arthritis worsened without his usual use of naproxen. He developed abdominal pain and loss of appetite. A prednisone taper was ordered starting at 40 mg/d (28.8 mg/kg), which provided relief of the skin and joint symptoms only until the course was completed 12 days later. 

Five weeks after the initial presentation, the patient returned with a more severe eruption consisting of innumerable purpuric papules that coalesced in plaques on the abdomen, arms, and legs. He also had erythematous facial pustules and mild palmar petechiae (Figure 4). Three biopsies were performed, including 1 for DIF and 1 from a pustule on the forehead. Histology and DIF were again consistent with IgA small-vessel vasculitis. The forehead biopsy was compatible with steroid acne (attributed to recent prednisone use) and psoriasis.   

Rheumatology was consulted, and adalimumab was discontinued 6 weeks after the initial presentation out of concern for drug-induced cutaneous vasculitis. Vasculitis work-up was unremarkable, including antineutrophil cytoplasmic antibodies, rheumatoid factor, cyclic citrullinated peptide, and serum protein electrophoresis. Oral dapsone was started at 100 mg/d, with the tentative plan of starting secukinumab if cutaneous symptoms improved. For 3 weeks, the patient’s cutaneous symptoms steadily improved.

Nine weeks after initial presentation to dermatology (3 weeks after discontinuing adalimumab) the patient self-administered his first dose of secukinumab at home. Several hours later, he reported sudden reappearance of vasculitis. He denied diarrhea, abdominal pain, bowel movement urgency, fevers, fatigue, and unintentional weight loss. Antistreptolysin O and hepatitis A antibodies were negative. He was instructed to hold secukinumab indefinitely.

Four weeks after his only secukinumab injection, the patient reported another episode of acute worsening cutaneous symptoms. A 4-week prednisone taper starting at 40 mg/d was ordered. Computed tomography of the chest, abdomen, and pelvis to rule out internal malignancy was unremarkable. Around this time, the patient reported major emotional distress related to an unexpected death in his family, which added to a gradual increase in his stress level related to the COVID-19 pandemic. 

Three weeks later, dapsone was increased to 100 mg twice daily on account of the patient’s adiposity and lack of cutaneous improvement on the lower dose. Subsequently, the vasculitis rapidly improved for 2 weeks. The patient then reported symptoms of headache, dizziness, and chills. He was tested for COVID-19 and was negative. Six weeks after increasing the dapsone dose (5 months after initial presentation), the skin was normalizing, showing only faintly hyperpigmented macules confined to areas of resolved vasculitis (forearms, abdomen, legs). 

The patient had been on dapsone 100 mg twice daily for 3 months when he was started on ustekinumab (90 mg at weeks 0 and 4, with planned doses every 12 weeks) for psoriatic arthritis in hopes of withdrawing dapsone. His cutaneous symptoms have remained well controlled on this regimen for 18 months. Lowering of dapsone below 100 mg daily has resulted in recurrent mild vasculitis symptoms; he now maintains the once-daily dosing without negative side effects.

Comment

IgA vasculitis is a form of cutaneous small-vessel leukocytoclastic vasculitis (LCV) characterized by episodes of palpable purpura on the extensor surfaces of the arms and legs that may be associated with arthritis, abdominal pain, and/or hematuria. Although vasculitis is a known potential adverse effect of anti–tumor necrosis factor (TNF) α therapy, cases of adalimumab-induced IgA vasculitis are uncommon. As use of more targeted therapies for psoriasis and psoriatic arthritis, such as the IL-17 inhibitor secukinumab, increases so do reports of associated adverse events. Of 6 previously reported cases of secukinumab-associated vasculitis, at least 4 were IgA vasculitis (Table).^1-6 Another case described one patient with rheumatoid arthritis undergoing secukinumab treatment who experienced necrotizing glomerulonephritis; however, the authors concluded secukinumab likely was not causative in that case, as serologies and urinalyses suggested gradual onset of the process prior to initiating the medication.⁷

The exact pathogenesis of IgA vasculitis is unclear, but a prevailing theory involves the dysregulation of IgA synthesis and metabolism. Other than increased serum levels of transforming growth factor β, which is a major stimulating factor for IgA production, it also has been hypothesized that the presence of aberrantly hypoglycosylated IgA exposes an autoepitope for recognition by other pathogenic IgG and IgA, leading to the formation of large immune complexes that can readily deposit in postcapillary venules. The deposition of IgA immune complexes in postcapillary venules and the subsequent activation of the complement system causes direct damage to the endothelial cells of vessel walls. This complement activation is evidenced by vascular complement component 3 deposition on DIF (a nonspecific feature of LCV). Chemotaxis of neutrophils ensues, followed by their firm adherence and transendothelial migration (mediated by monocyte chemoattractant protein 1 [MCP-1]). Neutrophil degranulation releases reactive oxygen species and cytokines, which in turn recruit additional leukocytes to the area of inflammation, subsequently undergoing degeneration (leukocytoclasis). Microvascular permeability also is enhanced by MCP-1, allowing exudation of serum, erythrocytes, and fibrin. In the setting of elevated circulating TNF and IL-1, endothelium is stimulated to activate the intrinsic and extrinsic coagulation pathways. This decreases endothelial fibrinolytic activity, leading to thrombosis. The high venous pressure and low fibrinolytic activity in the lower legs explains why vasculitic lesions often are confined to or begin in this distribution.^1,8-10

There also are noteworthy roles for cytokines in LCV. Circulating transforming growth factor β and IL-6—which are necessary for development of T helper 17 (T_H17) cells and production of IL-17—are higher in patients with LCV compared to controls. Peripheral blood monocytes in patients with LCV demonstrate higher production of IL-17. Once T_H17 cells develop, their survival and phenotype are maintained by IL-23 (considered the master regulator of T_H17 differentiation). IL-17 is a potent chemoattractant of IL-8 (CXCL8) and MCP-1, both of which promote neutrophil-mediated perivascular inflammation. The IL-23 and IL-17 pathways implicated in the pathogenesis of psoriasis also cause neutrophil activation and upregulate transcription of proinflammatory cytokines (IL-1, IL-6, IL-8, and TNF-α), which overlap with those implicated in LCV. Autoimmune disease generally entails some positive feedback loop of progressively severe self-recognition and tissue destruction by the immune system. These shared cytokinetic processes may explain how the internal environment of psoriasis could perpetuate IgA vasculitis.^1,2,8,10-12

The mechanisms underlying vasculitis associated with adalimumab are unclear, but hypotheses involve direct toxicity on vessels, capillary deposition of anti-TNF/TNF immune complexes, or an inflammatory process resulting in autoantibodies. Similar hypotheses are posited for secukinumab-associated vasculitis, including deposition of secukinumab–IL-17 complexes. Anti–TNF-α medications may increase T_H17 cell numbers, leading to increased production of IL-22 and a resultant immunologic microenvironment conducive to vasculitis. All 6 published cases of secukinumab-associated vasculitis that we found had received prior treatment with a TNF-α blocker, but only 1 had occurrence of vasculitis during that treatment.^1-6,10

In the 6 cases we reviewed, the time from starting secukinumab to onset of vasculitis ranged from 1 to 18 months. Our patient’s same-day re-emergence of vasculitis after his first secukinumab dose was so acute that we were skeptical of secukinumab as a potential trigger; this may simply have been coincident to the natural waxing and waning of the vasculitis (although onset of IgA vasculitis within 1 day of starting anti–TNF-α therapy has been reported).^1-6,13  

Specific associations of IgA vasculitis are many and can include bacterial organisms such as Helicobacter pylori, streptococci, and staphylococci. Although internal mucous membrane infections are considered more linked because of the surveillance role of IgA predominantly in mucosal tissues, it is possible that our patient with cutaneous MRSA harbored the same within the nasal mucosa. Our patient also received multiple vaccinations outside our department throughout his clinical course (2 hepatitis B and 1 pneumococcal conjugate), which are known potential triggers for vasculitis. Psychological stress is a known trigger for psoriasis, and given the cytokinetic relationship of psoriasis to vasculitis described previously, it may have indirectly contributed to vasculitis in our case. The anxiety associated with being immunosuppressed during the COVID-19 pandemic and bereavement of losing a family member may have contributed to the refractory nature of our patient’s condition. Renal involvement is relatively common in adults with IgA vasculitis and so should be ruled out, as should occult internal malignancy.^8,10,14

It is unclear which of the above factors was causative in our case, but a multifactorial process is likely. Treatment of monoclonal antibody–associated vasculitis entails investigating for triggers and systemic involvement, removing the most likely culprit, quelling the vasculitis acutely, avoiding known potential exacerbators, and introducing an alternative long-term immunomodulant. In all 6 reported similar cases, discontinuation of secukinumab and initiation of prednisone or colchicine led to resolution.^1-6 Dapsone also is acceptable for acute control of IgA vasculitis, although this medication is highly lipid soluble and penetrates well into various tissues.¹⁵ Thus, lower doses may prove ineffective for obese patients, as was demonstrated in our case. Given the known potential of vaccinations, infections, and other factors (eg, alcohol, penicillin) to trigger IgA vasculitis, these should be avoided.¹⁰

Blockade of IL-23 with ustekinumab has been suggested by other authors encountering secukinumab-associated vasculitis, as IL-23 is the main driver and sustainer of T_H17 cell differentiation.⁸ Although 6 previously reported cases of secukinumab-associated vasculitis achieved resolution without long-term recurrence, none did so using an IL-23 inhibitor (nor had any of the described patients received IL-23 inhibitors previously).^1-6 Given the established safety of IL-23 inhibitors and that they theoretically are well suited for this unique circumstance (by ceasing the main causative cytokine cascades “upstream”) and were efficacious in quickly resolving our patient’s vasculitis, we suggest that ustekinumab may represent an ideal treatment option for patients in whom adalimumab- or secukinumab-associated vasculitis is suspected. Further research is needed given the complex interplay of so many variables and the increasingly common reports of adverse cutaneous events associated with these drugs.^1-6,10 

Herpes simplex keratitis (HSK) is a common yet potentially blinding condition caused by a primary or reactivated herpetic infection of the cornea.¹ The Herpetic Eye Disease Study established the standard of care in HSK management.² Treatments range from oral antivirals and artificial tears to topical antibiotics, amniotic membranes, and corneal transplantation.³ Patients with immune stromal keratitis (ISK) may experience low-grade chronic keratitis for years.⁴ ISK is classified by a cellular and neovascularization infiltration of the cornea.⁵ We present a case of a patient with recurrent ISK and review its presentation, diagnosis, and management.

Case Presentation

A 52-year-old man presented to the eye clinic with a watery and itchy right eye with mildly blurred vision. His ocular history was unremarkable. His medical history was notable for hepatitis C, hypertension, alcohol and drug dependence, homelessness, and a COVID-19–induced coma. His medications included trazodone, nifedipine, clonidine HCl, and buprenorphine/naloxone.

On clinical examination, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left. Corneal sensitivity was absent in the right eye and intact in the left. Anterior segment findings in the right eye included 360-degree superficial corneal neovascularization, deep neovascularization temporally, scattered patches of corneal haze, epithelial irregularity, and 2+ diffuse bulbar conjunctival injection (Figure 1). The anterior segment of the left eye and the posterior segments of both eyes were unremarkable. The differential diagnosis included HSK, syphilis, Cogan syndrome, varicella-zoster virus keratitis, Epstein-Barr virus keratitis, and Lyme disease. With consultation from a corneal specialist, the patient was given the presumptive diagnosis of ISK in the right eye based on unilateral corneal presentation and lack of corneal sensitivity. He was treated with 1-g oral valacyclovir HCl 3 times daily and 1 drop of prednisolone acetate 1% suspension 3 times daily in the right eye.

The patient followed up 2 weeks later. He reported good adherence to the ISK medication regimen. His symptoms had resolved, and his visual acuity returned to 20/20 in the right eye. Slit-lamp examination showed improvement in injection, and the superficial corneal neovascularization had cleared. A trace ghost vessel was seen temporally at a site of deep neovascularization (Figure 2). He was instructed to continue valacyclovir once daily and prednisolone drops once daily in the right eye and to follow up in 1 month.

At the 1-month follow-up, the patient’s signs and symptoms had reverted to his original presentation. The patient reported poor adherence to the medication regimen, having missed multiple doses of prednisolone drops as well as valacyclovir. The patient was counseled again on the ISK regimen, and the prednisolone drops and 1-g oral valacyclovir were refilled. A follow-up visit was scheduled for 2 weeks. Additional follow-up revealed a resolved corneal appearance and bimonthly follow-ups were scheduled thereafter.

Discussion

HSK is the most common infectious cause of unilateral blindness and vision impairment in the world.² This case highlights the diagnosis and management of a patient with ISK, a type of HSK characterized by decreased corneal sensitivity and unilateral stromal opacification or neovascularization.⁶

ISK is caused by the herpes simplex virus (HSV), a double-stranded enveloped DNA virus that occurs worldwide with little variation, replicates in many types of cells, has rapid growth, and is cytolytic, causing necrosis of nearby cells. Transmission is via direct contact and there is a lifelong latency period in the trigeminal ganglia. Both primary and reactivation infections of HSK can affect a broad array of ocular structures, from the lids to the retina. Infectious epithelial keratitis, also known as dendritic keratitis, is the reactivation of the live virus and is the most common presentation of HSK. ISK is responsible for 20% to 48% of recurrent HSV disease and is the leading cause of vision loss. ISK is the result of an immune-mediated inflammatory response due to a retained viral antigen within the stromal tissue.⁷ Inflammation in the corneal stroma leads to corneal haze and eventually focal or diffuse scarring, reducing the visual potential.⁷ This presentation may occur days to years after the initial epithelial episode and may persist for years. Although this patient did not present with infectious epithelial keratitis, it is possible he had a previous episode not mentioned as a history was difficult to obtain, and it can be subtle or innocuous, like pink eye.

Symptoms of ISK include unilateral redness, photophobia, tearing, eye pain, and blurred vision, as described by this patient. On examination, initial manifestations of ISK include corneal haze, edema, scarring, and neovascularization.⁷ Again, this patient presented with edema and neovascularization. These signs may improve with prompt diagnosis and treatment. More frequent reactivated disease leads to a higher propensity of corneal scarring and irregular astigmatism, reducing the visual outcome.

The standard of care established by the Herpetic Eye Disease Study recommends that a patient with presumed ISK should be started on oral antiviral therapy and, in the absence of epithelial disease, topical steroids. Oral antivirals, such as acyclovir and valacyclovir, have good ocular penetration, a good safety profile, a low susceptibility of resistance, and are well tolerated with long-term treatment.^2,8 There were no known interactions between any of the patient’s medications and valacyclovir. Oral antivirals should be used in the initial presentation and for maintenance therapy to help reduce the chance of recurrent disease. Initial treatment for ISK is 1-g valacyclovir 3 times daily. When the eye becomes quiet, that dosage can be tapered to 1 g twice daily, to 1 g once daily, and eventually to a maintenance dose of 500 mg daily. Topical steroids block the inflammatory cascade, therefore reducing the corneal inflammation and potential scarring, further reducing the risk of visual impairment.⁹ Initial treatment is 1 drop 3 times daily, then can be tapered at the same schedule as the oral acyclovir to help simplify adherence for the patient. After 1 drop once daily, steroids may be discontinued while the oral antiviral maintenance dosage continues. Follow-ups should be performed on a monthly to bimonthly basis to evaluate intraocular pressure, ensuring there is no steroid response.

As seen in this patient, adherence with a treatment regimen and awareness of factors, such as a complex psychosocial history that may impact this adherence, are of utmost importance.⁷

Conclusions

ISK presents unilaterally with decreased or absent corneal sensitivity and nonspecific symptoms. It should be at the top of the list in the differential diagnosis in any patient with unilateral corneal edema, opacification, or neovascularization, and the patient should be started on oral antiviral therapy.

Herpes simplex keratitis (HSK) is a common yet potentially blinding condition caused by a primary or reactivated herpetic infection of the cornea.¹ The Herpetic Eye Disease Study established the standard of care in HSK management.² Treatments range from oral antivirals and artificial tears to topical antibiotics, amniotic membranes, and corneal transplantation.³ Patients with immune stromal keratitis (ISK) may experience low-grade chronic keratitis for years.⁴ ISK is classified by a cellular and neovascularization infiltration of the cornea.⁵ We present a case of a patient with recurrent ISK and review its presentation, diagnosis, and management.

Case Presentation

A 52-year-old man presented to the eye clinic with a watery and itchy right eye with mildly blurred vision. His ocular history was unremarkable. His medical history was notable for hepatitis C, hypertension, alcohol and drug dependence, homelessness, and a COVID-19–induced coma. His medications included trazodone, nifedipine, clonidine HCl, and buprenorphine/naloxone.

On clinical examination, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left. Corneal sensitivity was absent in the right eye and intact in the left. Anterior segment findings in the right eye included 360-degree superficial corneal neovascularization, deep neovascularization temporally, scattered patches of corneal haze, epithelial irregularity, and 2+ diffuse bulbar conjunctival injection (Figure 1). The anterior segment of the left eye and the posterior segments of both eyes were unremarkable. The differential diagnosis included HSK, syphilis, Cogan syndrome, varicella-zoster virus keratitis, Epstein-Barr virus keratitis, and Lyme disease. With consultation from a corneal specialist, the patient was given the presumptive diagnosis of ISK in the right eye based on unilateral corneal presentation and lack of corneal sensitivity. He was treated with 1-g oral valacyclovir HCl 3 times daily and 1 drop of prednisolone acetate 1% suspension 3 times daily in the right eye.

The patient followed up 2 weeks later. He reported good adherence to the ISK medication regimen. His symptoms had resolved, and his visual acuity returned to 20/20 in the right eye. Slit-lamp examination showed improvement in injection, and the superficial corneal neovascularization had cleared. A trace ghost vessel was seen temporally at a site of deep neovascularization (Figure 2). He was instructed to continue valacyclovir once daily and prednisolone drops once daily in the right eye and to follow up in 1 month.

At the 1-month follow-up, the patient’s signs and symptoms had reverted to his original presentation. The patient reported poor adherence to the medication regimen, having missed multiple doses of prednisolone drops as well as valacyclovir. The patient was counseled again on the ISK regimen, and the prednisolone drops and 1-g oral valacyclovir were refilled. A follow-up visit was scheduled for 2 weeks. Additional follow-up revealed a resolved corneal appearance and bimonthly follow-ups were scheduled thereafter.

Discussion

HSK is the most common infectious cause of unilateral blindness and vision impairment in the world.² This case highlights the diagnosis and management of a patient with ISK, a type of HSK characterized by decreased corneal sensitivity and unilateral stromal opacification or neovascularization.⁶

ISK is caused by the herpes simplex virus (HSV), a double-stranded enveloped DNA virus that occurs worldwide with little variation, replicates in many types of cells, has rapid growth, and is cytolytic, causing necrosis of nearby cells. Transmission is via direct contact and there is a lifelong latency period in the trigeminal ganglia. Both primary and reactivation infections of HSK can affect a broad array of ocular structures, from the lids to the retina. Infectious epithelial keratitis, also known as dendritic keratitis, is the reactivation of the live virus and is the most common presentation of HSK. ISK is responsible for 20% to 48% of recurrent HSV disease and is the leading cause of vision loss. ISK is the result of an immune-mediated inflammatory response due to a retained viral antigen within the stromal tissue.⁷ Inflammation in the corneal stroma leads to corneal haze and eventually focal or diffuse scarring, reducing the visual potential.⁷ This presentation may occur days to years after the initial epithelial episode and may persist for years. Although this patient did not present with infectious epithelial keratitis, it is possible he had a previous episode not mentioned as a history was difficult to obtain, and it can be subtle or innocuous, like pink eye.

Symptoms of ISK include unilateral redness, photophobia, tearing, eye pain, and blurred vision, as described by this patient. On examination, initial manifestations of ISK include corneal haze, edema, scarring, and neovascularization.⁷ Again, this patient presented with edema and neovascularization. These signs may improve with prompt diagnosis and treatment. More frequent reactivated disease leads to a higher propensity of corneal scarring and irregular astigmatism, reducing the visual outcome.

The standard of care established by the Herpetic Eye Disease Study recommends that a patient with presumed ISK should be started on oral antiviral therapy and, in the absence of epithelial disease, topical steroids. Oral antivirals, such as acyclovir and valacyclovir, have good ocular penetration, a good safety profile, a low susceptibility of resistance, and are well tolerated with long-term treatment.^2,8 There were no known interactions between any of the patient’s medications and valacyclovir. Oral antivirals should be used in the initial presentation and for maintenance therapy to help reduce the chance of recurrent disease. Initial treatment for ISK is 1-g valacyclovir 3 times daily. When the eye becomes quiet, that dosage can be tapered to 1 g twice daily, to 1 g once daily, and eventually to a maintenance dose of 500 mg daily. Topical steroids block the inflammatory cascade, therefore reducing the corneal inflammation and potential scarring, further reducing the risk of visual impairment.⁹ Initial treatment is 1 drop 3 times daily, then can be tapered at the same schedule as the oral acyclovir to help simplify adherence for the patient. After 1 drop once daily, steroids may be discontinued while the oral antiviral maintenance dosage continues. Follow-ups should be performed on a monthly to bimonthly basis to evaluate intraocular pressure, ensuring there is no steroid response.

As seen in this patient, adherence with a treatment regimen and awareness of factors, such as a complex psychosocial history that may impact this adherence, are of utmost importance.⁷

Conclusions

ISK presents unilaterally with decreased or absent corneal sensitivity and nonspecific symptoms. It should be at the top of the list in the differential diagnosis in any patient with unilateral corneal edema, opacification, or neovascularization, and the patient should be started on oral antiviral therapy.

Herpes simplex keratitis (HSK) is a common yet potentially blinding condition caused by a primary or reactivated herpetic infection of the cornea.¹ The Herpetic Eye Disease Study established the standard of care in HSK management.² Treatments range from oral antivirals and artificial tears to topical antibiotics, amniotic membranes, and corneal transplantation.³ Patients with immune stromal keratitis (ISK) may experience low-grade chronic keratitis for years.⁴ ISK is classified by a cellular and neovascularization infiltration of the cornea.⁵ We present a case of a patient with recurrent ISK and review its presentation, diagnosis, and management.

Case Presentation

A 52-year-old man presented to the eye clinic with a watery and itchy right eye with mildly blurred vision. His ocular history was unremarkable. His medical history was notable for hepatitis C, hypertension, alcohol and drug dependence, homelessness, and a COVID-19–induced coma. His medications included trazodone, nifedipine, clonidine HCl, and buprenorphine/naloxone.

On clinical examination, the patient’s best-corrected visual acuity was 20/40 in the right eye and 20/20 in the left. Corneal sensitivity was absent in the right eye and intact in the left. Anterior segment findings in the right eye included 360-degree superficial corneal neovascularization, deep neovascularization temporally, scattered patches of corneal haze, epithelial irregularity, and 2+ diffuse bulbar conjunctival injection (Figure 1). The anterior segment of the left eye and the posterior segments of both eyes were unremarkable. The differential diagnosis included HSK, syphilis, Cogan syndrome, varicella-zoster virus keratitis, Epstein-Barr virus keratitis, and Lyme disease. With consultation from a corneal specialist, the patient was given the presumptive diagnosis of ISK in the right eye based on unilateral corneal presentation and lack of corneal sensitivity. He was treated with 1-g oral valacyclovir HCl 3 times daily and 1 drop of prednisolone acetate 1% suspension 3 times daily in the right eye.

The patient followed up 2 weeks later. He reported good adherence to the ISK medication regimen. His symptoms had resolved, and his visual acuity returned to 20/20 in the right eye. Slit-lamp examination showed improvement in injection, and the superficial corneal neovascularization had cleared. A trace ghost vessel was seen temporally at a site of deep neovascularization (Figure 2). He was instructed to continue valacyclovir once daily and prednisolone drops once daily in the right eye and to follow up in 1 month.

At the 1-month follow-up, the patient’s signs and symptoms had reverted to his original presentation. The patient reported poor adherence to the medication regimen, having missed multiple doses of prednisolone drops as well as valacyclovir. The patient was counseled again on the ISK regimen, and the prednisolone drops and 1-g oral valacyclovir were refilled. A follow-up visit was scheduled for 2 weeks. Additional follow-up revealed a resolved corneal appearance and bimonthly follow-ups were scheduled thereafter.

Discussion

HSK is the most common infectious cause of unilateral blindness and vision impairment in the world.² This case highlights the diagnosis and management of a patient with ISK, a type of HSK characterized by decreased corneal sensitivity and unilateral stromal opacification or neovascularization.⁶

ISK is caused by the herpes simplex virus (HSV), a double-stranded enveloped DNA virus that occurs worldwide with little variation, replicates in many types of cells, has rapid growth, and is cytolytic, causing necrosis of nearby cells. Transmission is via direct contact and there is a lifelong latency period in the trigeminal ganglia. Both primary and reactivation infections of HSK can affect a broad array of ocular structures, from the lids to the retina. Infectious epithelial keratitis, also known as dendritic keratitis, is the reactivation of the live virus and is the most common presentation of HSK. ISK is responsible for 20% to 48% of recurrent HSV disease and is the leading cause of vision loss. ISK is the result of an immune-mediated inflammatory response due to a retained viral antigen within the stromal tissue.⁷ Inflammation in the corneal stroma leads to corneal haze and eventually focal or diffuse scarring, reducing the visual potential.⁷ This presentation may occur days to years after the initial epithelial episode and may persist for years. Although this patient did not present with infectious epithelial keratitis, it is possible he had a previous episode not mentioned as a history was difficult to obtain, and it can be subtle or innocuous, like pink eye.

Symptoms of ISK include unilateral redness, photophobia, tearing, eye pain, and blurred vision, as described by this patient. On examination, initial manifestations of ISK include corneal haze, edema, scarring, and neovascularization.⁷ Again, this patient presented with edema and neovascularization. These signs may improve with prompt diagnosis and treatment. More frequent reactivated disease leads to a higher propensity of corneal scarring and irregular astigmatism, reducing the visual outcome.

The standard of care established by the Herpetic Eye Disease Study recommends that a patient with presumed ISK should be started on oral antiviral therapy and, in the absence of epithelial disease, topical steroids. Oral antivirals, such as acyclovir and valacyclovir, have good ocular penetration, a good safety profile, a low susceptibility of resistance, and are well tolerated with long-term treatment.^2,8 There were no known interactions between any of the patient’s medications and valacyclovir. Oral antivirals should be used in the initial presentation and for maintenance therapy to help reduce the chance of recurrent disease. Initial treatment for ISK is 1-g valacyclovir 3 times daily. When the eye becomes quiet, that dosage can be tapered to 1 g twice daily, to 1 g once daily, and eventually to a maintenance dose of 500 mg daily. Topical steroids block the inflammatory cascade, therefore reducing the corneal inflammation and potential scarring, further reducing the risk of visual impairment.⁹ Initial treatment is 1 drop 3 times daily, then can be tapered at the same schedule as the oral acyclovir to help simplify adherence for the patient. After 1 drop once daily, steroids may be discontinued while the oral antiviral maintenance dosage continues. Follow-ups should be performed on a monthly to bimonthly basis to evaluate intraocular pressure, ensuring there is no steroid response.

As seen in this patient, adherence with a treatment regimen and awareness of factors, such as a complex psychosocial history that may impact this adherence, are of utmost importance.⁷

Conclusions

ISK presents unilaterally with decreased or absent corneal sensitivity and nonspecific symptoms. It should be at the top of the list in the differential diagnosis in any patient with unilateral corneal edema, opacification, or neovascularization, and the patient should be started on oral antiviral therapy.

THE CASE

A 57-year-old man with type 2 diabetes, hyperlipidemia, and obesity presented to the emergency department (ED) for bilateral foot blisters, both of which appeared 1 day prior to evaluation. The patient’s history also included right-side Charcot foot diagnosed 4 years earlier and right foot osteomyelitis diagnosed 2 years prior. He had ongoing neuropathy in both feet but denied any significant pain.

The patient wore orthotics daily and he’d had new orthotics made 6 months prior; however, a recent COVID-19 diagnosis and prolonged hospital stay resulted in a 30-pound weight loss and decreased swelling in his ankles. He acquired new shoes 2 weeks prior to ED presentation.

Physical examination revealed large blisters along the medial aspect of the patient’s feet, with both hemorrhagic and serous fluid-filled bullae. The lesions were flaccid but intact, without drainage or surrounding erythema, warmth, or tenderness. The blister on the left foot measured 8 x 5 cm and extended from the great toe to mid-arch (FIGURE), while the one on the right foot measured 8 x 3 cm and extended from the great toe to the base of the proximal arch. Sensation was decreased in the bilateral first and second digits but unchanged from prior documented exams. Bilateral dorsalis pedis pulses were normal.

Work-up included imaging and lab work. The patient’s complete blood count was normal, as were his erythrocyte sedimentation rate and C-reactive protein level. Radiographs of the right foot were normal, but those of the left foot were concerning, although inconclusive, for osteomyelitis. Further evaluation with magnetic resonance imaging of his left foot revealed a deformity of the first digit with some subchondral signal change that was thought to be posttraumatic or degenerative, but unlikely osteomyelitis.

THE DIAGNOSIS

Podiatry was consulted for blister management. Based on atraumatic history, rapid appearance, location of blisters, unremarkable lab work and imaging, and concurrent diabetes, the patient received a diagnosis of bilateral bullous diabeticorum (BD).

DISCUSSION

Roughly one-third of patients with diabetes will experience some cutaneous adverse effect because of the disease.¹ Common iterations include acanthosis nigricans, rash, or even infection.² BD is a rare bullous skin lesion that occurs in patients with diabetes; it has a reported annual incidence of 0.16% and may be underdiagnosed.¹

Although A1C values do not correlate with blister formation, patients with hypoglycemic episodes and highly varying blood glucose values seem to have higher rates of bullous diabeticorum occurrence.

Cases of BD have been described both in patients with longstanding diabetes and in those newly diagnosed, although the former group is more often affected.¹ BD is reported more frequently in males than females, at a ratio of 2:1.^1,3 Patients ages 17 to 80 years (average age, 55 years) have received a diagnosis of BD.¹ Most affected patients will have a concomitant peripheral neuropathy and sometimes nephropathy or retinopathy.¹

Continue to: The etiology of BD...

The etiology of BD is unclear but appears to be multifactorial. Hypotheses suggest that there’s a link to neuropathy/nephropathy, excessive exposure to ultraviolet light, or a vascular cause secondary to hyaline deposition in the capillary walls.^4,5

What you’ll see at presentation

The typical manifestation of BD is the rapid appearance of tense blisters, which may occur overnight or even within hours.¹ They are usually painless; common locations include the feet, distal legs, hands, and forearms.^1,5 The bullae can be serous or hemorrhagic.¹

Most notable in the patient’s history will be a lack of trauma or injury to the area.¹ Although A1C values do not correlate with blister formation, patients with hypoglycemic episodes and highly varying blood glucose values seem to have higher rates of occurrence.¹

Other sources of blistering must be ruled out

The diagnosis of BD is clinical and based on history, exam, and exclusion of other bullous diagnoses.⁶ A key clue in the history is the spontaneous and rapid onset without associated trauma in a patient with diabetes.⁶ Direct immunofluorescence, although nonspecific, can be helpful to rule out other disorders (such as porphyria cutanea tarda and bullous pemphigoid) if the history and exam are inconclusive. Direct and indirect immunofluorescence is typically negative in BD.^4,6

The differential diagnosis includes other conditions that involve bullae—such as frictional bullae, bullous pemphigoid, and bullous systemic lupus erythematosus—as well as porphyria, erythema multiforme, insect bites, or even fixed drug eruption.^2,7

Continue to: Porphyria

Porphyria tends to develop on the hands, whereas BD most commonly occurs on the feet.⁵

Erythema multiforme typically includes inflammatory skin changes.⁵

Trauma or fixed drug eruption as a cause of blistering lesions would be revealed during history taking.

Considerations for treatment and follow-up

Without treatment, blisters often self-resolve in 2 to 6 weeks, but there is high likelihood of recurrence.^6,8 There is no consensus on treatment, although a typical course of action is to deroof the blister and examine the area to rule out infection.⁶ The wound is then covered with wet-to-dry gauze that is changed regularly. If there is suspicion for or signs of underlying infection, such as an ulcer or skin necrosis, antibiotics should be included in the treatment plan.⁷

Additional considerations. Patients will often need therapeutic footwear if the blisters are located on the feet. Given the higher prevalence of microvascular complications in patients with diabetes who develop BD, routine ophthalmologic examination and renal function testing to monitor for microalbuminuria are recommended.⁵

Our patient underwent bedside incision and drainage and was discharged home with appropriate wound care and follow-up. 

THE TAKEAWAY

BD cases may be underdiagnosed in clinical practice, perhaps due to patients not seeking help for a seemingly nonthreatening condition or lack of clinician recognition that bullae are related to a patient’s diabetes status. Prompt recognition and proper wound care are important to prevent poor outcomes, such as ulceration or necrosis.

CORRESPONDENCE
Kathleen S. Kinderwater, MD, 101 Heart Drive, Greenville, NC 27834; [email protected]

THE CASE

A 57-year-old man with type 2 diabetes, hyperlipidemia, and obesity presented to the emergency department (ED) for bilateral foot blisters, both of which appeared 1 day prior to evaluation. The patient’s history also included right-side Charcot foot diagnosed 4 years earlier and right foot osteomyelitis diagnosed 2 years prior. He had ongoing neuropathy in both feet but denied any significant pain.

The patient wore orthotics daily and he’d had new orthotics made 6 months prior; however, a recent COVID-19 diagnosis and prolonged hospital stay resulted in a 30-pound weight loss and decreased swelling in his ankles. He acquired new shoes 2 weeks prior to ED presentation.

Physical examination revealed large blisters along the medial aspect of the patient’s feet, with both hemorrhagic and serous fluid-filled bullae. The lesions were flaccid but intact, without drainage or surrounding erythema, warmth, or tenderness. The blister on the left foot measured 8 x 5 cm and extended from the great toe to mid-arch (FIGURE), while the one on the right foot measured 8 x 3 cm and extended from the great toe to the base of the proximal arch. Sensation was decreased in the bilateral first and second digits but unchanged from prior documented exams. Bilateral dorsalis pedis pulses were normal.

Work-up included imaging and lab work. The patient’s complete blood count was normal, as were his erythrocyte sedimentation rate and C-reactive protein level. Radiographs of the right foot were normal, but those of the left foot were concerning, although inconclusive, for osteomyelitis. Further evaluation with magnetic resonance imaging of his left foot revealed a deformity of the first digit with some subchondral signal change that was thought to be posttraumatic or degenerative, but unlikely osteomyelitis.

THE DIAGNOSIS

Podiatry was consulted for blister management. Based on atraumatic history, rapid appearance, location of blisters, unremarkable lab work and imaging, and concurrent diabetes, the patient received a diagnosis of bilateral bullous diabeticorum (BD).

DISCUSSION

Roughly one-third of patients with diabetes will experience some cutaneous adverse effect because of the disease.¹ Common iterations include acanthosis nigricans, rash, or even infection.² BD is a rare bullous skin lesion that occurs in patients with diabetes; it has a reported annual incidence of 0.16% and may be underdiagnosed.¹

Although A1C values do not correlate with blister formation, patients with hypoglycemic episodes and highly varying blood glucose values seem to have higher rates of bullous diabeticorum occurrence.

Cases of BD have been described both in patients with longstanding diabetes and in those newly diagnosed, although the former group is more often affected.¹ BD is reported more frequently in males than females, at a ratio of 2:1.^1,3 Patients ages 17 to 80 years (average age, 55 years) have received a diagnosis of BD.¹ Most affected patients will have a concomitant peripheral neuropathy and sometimes nephropathy or retinopathy.¹

Continue to: The etiology of BD...

The etiology of BD is unclear but appears to be multifactorial. Hypotheses suggest that there’s a link to neuropathy/nephropathy, excessive exposure to ultraviolet light, or a vascular cause secondary to hyaline deposition in the capillary walls.^4,5

What you’ll see at presentation

The typical manifestation of BD is the rapid appearance of tense blisters, which may occur overnight or even within hours.¹ They are usually painless; common locations include the feet, distal legs, hands, and forearms.^1,5 The bullae can be serous or hemorrhagic.¹

Most notable in the patient’s history will be a lack of trauma or injury to the area.¹ Although A1C values do not correlate with blister formation, patients with hypoglycemic episodes and highly varying blood glucose values seem to have higher rates of occurrence.¹

Other sources of blistering must be ruled out

The diagnosis of BD is clinical and based on history, exam, and exclusion of other bullous diagnoses.⁶ A key clue in the history is the spontaneous and rapid onset without associated trauma in a patient with diabetes.⁶ Direct immunofluorescence, although nonspecific, can be helpful to rule out other disorders (such as porphyria cutanea tarda and bullous pemphigoid) if the history and exam are inconclusive. Direct and indirect immunofluorescence is typically negative in BD.^4,6

The differential diagnosis includes other conditions that involve bullae—such as frictional bullae, bullous pemphigoid, and bullous systemic lupus erythematosus—as well as porphyria, erythema multiforme, insect bites, or even fixed drug eruption.^2,7

Continue to: Porphyria

Porphyria tends to develop on the hands, whereas BD most commonly occurs on the feet.⁵

Erythema multiforme typically includes inflammatory skin changes.⁵

Trauma or fixed drug eruption as a cause of blistering lesions would be revealed during history taking.

Considerations for treatment and follow-up

Without treatment, blisters often self-resolve in 2 to 6 weeks, but there is high likelihood of recurrence.^6,8 There is no consensus on treatment, although a typical course of action is to deroof the blister and examine the area to rule out infection.⁶ The wound is then covered with wet-to-dry gauze that is changed regularly. If there is suspicion for or signs of underlying infection, such as an ulcer or skin necrosis, antibiotics should be included in the treatment plan.⁷

Additional considerations. Patients will often need therapeutic footwear if the blisters are located on the feet. Given the higher prevalence of microvascular complications in patients with diabetes who develop BD, routine ophthalmologic examination and renal function testing to monitor for microalbuminuria are recommended.⁵

Our patient underwent bedside incision and drainage and was discharged home with appropriate wound care and follow-up. 

THE TAKEAWAY

BD cases may be underdiagnosed in clinical practice, perhaps due to patients not seeking help for a seemingly nonthreatening condition or lack of clinician recognition that bullae are related to a patient’s diabetes status. Prompt recognition and proper wound care are important to prevent poor outcomes, such as ulceration or necrosis.

CORRESPONDENCE
Kathleen S. Kinderwater, MD, 101 Heart Drive, Greenville, NC 27834; [email protected]

THE CASE

A 57-year-old man with type 2 diabetes, hyperlipidemia, and obesity presented to the emergency department (ED) for bilateral foot blisters, both of which appeared 1 day prior to evaluation. The patient’s history also included right-side Charcot foot diagnosed 4 years earlier and right foot osteomyelitis diagnosed 2 years prior. He had ongoing neuropathy in both feet but denied any significant pain.

The patient wore orthotics daily and he’d had new orthotics made 6 months prior; however, a recent COVID-19 diagnosis and prolonged hospital stay resulted in a 30-pound weight loss and decreased swelling in his ankles. He acquired new shoes 2 weeks prior to ED presentation.

Physical examination revealed large blisters along the medial aspect of the patient’s feet, with both hemorrhagic and serous fluid-filled bullae. The lesions were flaccid but intact, without drainage or surrounding erythema, warmth, or tenderness. The blister on the left foot measured 8 x 5 cm and extended from the great toe to mid-arch (FIGURE), while the one on the right foot measured 8 x 3 cm and extended from the great toe to the base of the proximal arch. Sensation was decreased in the bilateral first and second digits but unchanged from prior documented exams. Bilateral dorsalis pedis pulses were normal.

Work-up included imaging and lab work. The patient’s complete blood count was normal, as were his erythrocyte sedimentation rate and C-reactive protein level. Radiographs of the right foot were normal, but those of the left foot were concerning, although inconclusive, for osteomyelitis. Further evaluation with magnetic resonance imaging of his left foot revealed a deformity of the first digit with some subchondral signal change that was thought to be posttraumatic or degenerative, but unlikely osteomyelitis.

THE DIAGNOSIS

Podiatry was consulted for blister management. Based on atraumatic history, rapid appearance, location of blisters, unremarkable lab work and imaging, and concurrent diabetes, the patient received a diagnosis of bilateral bullous diabeticorum (BD).

DISCUSSION

Roughly one-third of patients with diabetes will experience some cutaneous adverse effect because of the disease.¹ Common iterations include acanthosis nigricans, rash, or even infection.² BD is a rare bullous skin lesion that occurs in patients with diabetes; it has a reported annual incidence of 0.16% and may be underdiagnosed.¹

Although A1C values do not correlate with blister formation, patients with hypoglycemic episodes and highly varying blood glucose values seem to have higher rates of bullous diabeticorum occurrence.

Cases of BD have been described both in patients with longstanding diabetes and in those newly diagnosed, although the former group is more often affected.¹ BD is reported more frequently in males than females, at a ratio of 2:1.^1,3 Patients ages 17 to 80 years (average age, 55 years) have received a diagnosis of BD.¹ Most affected patients will have a concomitant peripheral neuropathy and sometimes nephropathy or retinopathy.¹

Continue to: The etiology of BD...

The etiology of BD is unclear but appears to be multifactorial. Hypotheses suggest that there’s a link to neuropathy/nephropathy, excessive exposure to ultraviolet light, or a vascular cause secondary to hyaline deposition in the capillary walls.^4,5

What you’ll see at presentation

The typical manifestation of BD is the rapid appearance of tense blisters, which may occur overnight or even within hours.¹ They are usually painless; common locations include the feet, distal legs, hands, and forearms.^1,5 The bullae can be serous or hemorrhagic.¹

Most notable in the patient’s history will be a lack of trauma or injury to the area.¹ Although A1C values do not correlate with blister formation, patients with hypoglycemic episodes and highly varying blood glucose values seem to have higher rates of occurrence.¹

Other sources of blistering must be ruled out

The diagnosis of BD is clinical and based on history, exam, and exclusion of other bullous diagnoses.⁶ A key clue in the history is the spontaneous and rapid onset without associated trauma in a patient with diabetes.⁶ Direct immunofluorescence, although nonspecific, can be helpful to rule out other disorders (such as porphyria cutanea tarda and bullous pemphigoid) if the history and exam are inconclusive. Direct and indirect immunofluorescence is typically negative in BD.^4,6

The differential diagnosis includes other conditions that involve bullae—such as frictional bullae, bullous pemphigoid, and bullous systemic lupus erythematosus—as well as porphyria, erythema multiforme, insect bites, or even fixed drug eruption.^2,7

Continue to: Porphyria

Porphyria tends to develop on the hands, whereas BD most commonly occurs on the feet.⁵

Erythema multiforme typically includes inflammatory skin changes.⁵

Trauma or fixed drug eruption as a cause of blistering lesions would be revealed during history taking.

Considerations for treatment and follow-up

Without treatment, blisters often self-resolve in 2 to 6 weeks, but there is high likelihood of recurrence.^6,8 There is no consensus on treatment, although a typical course of action is to deroof the blister and examine the area to rule out infection.⁶ The wound is then covered with wet-to-dry gauze that is changed regularly. If there is suspicion for or signs of underlying infection, such as an ulcer or skin necrosis, antibiotics should be included in the treatment plan.⁷

Additional considerations. Patients will often need therapeutic footwear if the blisters are located on the feet. Given the higher prevalence of microvascular complications in patients with diabetes who develop BD, routine ophthalmologic examination and renal function testing to monitor for microalbuminuria are recommended.⁵

Our patient underwent bedside incision and drainage and was discharged home with appropriate wound care and follow-up. 

THE TAKEAWAY

BD cases may be underdiagnosed in clinical practice, perhaps due to patients not seeking help for a seemingly nonthreatening condition or lack of clinician recognition that bullae are related to a patient’s diabetes status. Prompt recognition and proper wound care are important to prevent poor outcomes, such as ulceration or necrosis.

CORRESPONDENCE
Kathleen S. Kinderwater, MD, 101 Heart Drive, Greenville, NC 27834; [email protected]

Shrapnel injuries are commonly encountered in war zones.¹ Shrapnel injuries can remain asymptomatic or become systemic, with health effects of the retained foreign body ranging from local to systemic toxicities depending on the patient’s reaction to the chemical composition and corrosiveness of the fragments in vivo.² We present a case of a reactivating shrapnel injury in the form of a retroperitoneal infection and subsequent iliopsoas abscess. A collaborative procedure was performed between surgery and interventional radiology to snare and remove the infected fragment and drain the abscess.

Case Presentation

While serving in Vietnam, a soldier sustained a fragment injury to his left lower abdomen. He underwent a laparotomy, small bowel resection, and a temporary ileostomy at the time of the injury. Nearly 50 years later, the patient presented with chronic left lower quadrant pain and a low-grade fever. He was diagnosed clinically in the emergency department (ED) with diverticulitis and treated with antibiotics. The patient initially responded to treatment but returned 6 months later with similar symptoms, low-grade fever, and mild leukocytosis. A computed tomography (CT) scan during that encounter without IV contrast revealed a few scattered colonic diverticula without definite diverticulitis as well as a metallic fragment embedded in the left iliopsoas with increased soft tissue density.

The patient was diagnosed with a pelvic/abdominal wall hematoma and was discharged with pain medication. The patient reported recurrent attacks of left lower quadrant pain, fever, and changes in bowel habits, prompting gastrointestinal consultation and a colonoscopy that was unremarkable. Ten months later, the patient again presented to the ED, with recurrent symptoms, a fever of 102 °F, and leukocytosis with a white blood cell count of 11.7 × 10⁹/L. CT scan with IV contrast revealed a large left iliopsoas abscess associated with an approximately 1-cm metallic fragment (Figure 1). A drainage catheter was placed under CT guidance and approximately 270 mL of purulent fluid was drained. Culture of the fluid was positive for Escherichia coli (E coli). Two days after drain placement, the fragment was removed as a joint procedure with interventional radiology and surgery. Using the drainage catheter tract as a point of entry, multiple attempts were made to retrieve the fragment with Olympus EndoJaw endoscopic forceps without success.

Discussion

Foreign body injuries can be benign or debilitating depending on the initial damage, anatomical location of the foreign body, composition of the foreign body, and the patient’s response to it. Retained shrapnel deep within the muscle tissue rarely causes complications. Although many times embedded objects can be asymptomatic and require no further management, migration of the foreign body or the formation of a fistula is possible, causing symptoms and requiring surgical intervention.¹ One case involved the formation of a purulent fistula appearing a year after an explosive wound to the lumbosacral spine, which was treated with antimicrobials. Recurrence of the fistula several times after treatment led to surgical removal of the shrapnel along with antibiotic treatment of the osteomyelitis.³ Although uncommon, lead exposure that occurs due to retained foreign body fragments from gunshot or military-related injuries can cause systemic lead toxicity. Symptoms may range from abdominal pain, nausea, and constipation to jaundice and hepatitis.⁴ The severity has also been stated to correlate with the surface area of the lead exposed for dissolution.⁵ Migration of foreign bodies and shrapnel to other sites in the body, such as movement from soft tissues into distantly located body cavities, have been reported as well. Such a case involved the spontaneous onset of knee synovitis due to an intra-articular metallic object that was introduced via a blast injury to the upper third of the ipsilateral thigh.¹

In this patient’s case, a large intramuscular abscess had formed nearly 50 years after the initial combat injury, requiring drainage of the abscess and removal of the fragment. By snaring the foreign body to a more superficial site, the surgical removal only required a minor incision, decreasing recovery time and the likelihood of postoperative complications that would have been associated with a large retroperitoneal dissection. While loop snare is often the first-line technique for the removal of intravascular foreign bodies, its use in soft tissue retained materials is scarcely reported.⁶ The more typical uses involve the removal of intraluminal materials, such as partially fractured venous catheters, guide wires, stents, and vena cava filters. The same report mentioned that in all 16 cases of percutaneous foreign body retrieval, no surgical intervention was required.⁷ In the case of most nonvascular foreign bodies, however, surgical retrieval is usually performed.⁸

Surgical removal of foreign bodies can be difficult in cases where a foreign body is anatomically located next to vital structures.⁹ An additional challenge with a sole surgical approach to foreign body retrieval is when it is small in size and lies deep within the soft tissue, as was the case for our patient. In such cases, the surgical procedure can be time consuming and lead to more trauma to the surrounding tissues.¹⁰ These factors alone necessitate consideration of postoperative morbidity and mortality.

Conclusions

This case demonstrates a multidisciplinary approach to transforming an otherwise large retroperitoneal dissection to a minimally invasive and technically efficient abscess drainage and foreign body retrieval.

Shrapnel injuries are commonly encountered in war zones.¹ Shrapnel injuries can remain asymptomatic or become systemic, with health effects of the retained foreign body ranging from local to systemic toxicities depending on the patient’s reaction to the chemical composition and corrosiveness of the fragments in vivo.² We present a case of a reactivating shrapnel injury in the form of a retroperitoneal infection and subsequent iliopsoas abscess. A collaborative procedure was performed between surgery and interventional radiology to snare and remove the infected fragment and drain the abscess.

Case Presentation

While serving in Vietnam, a soldier sustained a fragment injury to his left lower abdomen. He underwent a laparotomy, small bowel resection, and a temporary ileostomy at the time of the injury. Nearly 50 years later, the patient presented with chronic left lower quadrant pain and a low-grade fever. He was diagnosed clinically in the emergency department (ED) with diverticulitis and treated with antibiotics. The patient initially responded to treatment but returned 6 months later with similar symptoms, low-grade fever, and mild leukocytosis. A computed tomography (CT) scan during that encounter without IV contrast revealed a few scattered colonic diverticula without definite diverticulitis as well as a metallic fragment embedded in the left iliopsoas with increased soft tissue density.

The patient was diagnosed with a pelvic/abdominal wall hematoma and was discharged with pain medication. The patient reported recurrent attacks of left lower quadrant pain, fever, and changes in bowel habits, prompting gastrointestinal consultation and a colonoscopy that was unremarkable. Ten months later, the patient again presented to the ED, with recurrent symptoms, a fever of 102 °F, and leukocytosis with a white blood cell count of 11.7 × 10⁹/L. CT scan with IV contrast revealed a large left iliopsoas abscess associated with an approximately 1-cm metallic fragment (Figure 1). A drainage catheter was placed under CT guidance and approximately 270 mL of purulent fluid was drained. Culture of the fluid was positive for Escherichia coli (E coli). Two days after drain placement, the fragment was removed as a joint procedure with interventional radiology and surgery. Using the drainage catheter tract as a point of entry, multiple attempts were made to retrieve the fragment with Olympus EndoJaw endoscopic forceps without success.

Discussion

Foreign body injuries can be benign or debilitating depending on the initial damage, anatomical location of the foreign body, composition of the foreign body, and the patient’s response to it. Retained shrapnel deep within the muscle tissue rarely causes complications. Although many times embedded objects can be asymptomatic and require no further management, migration of the foreign body or the formation of a fistula is possible, causing symptoms and requiring surgical intervention.¹ One case involved the formation of a purulent fistula appearing a year after an explosive wound to the lumbosacral spine, which was treated with antimicrobials. Recurrence of the fistula several times after treatment led to surgical removal of the shrapnel along with antibiotic treatment of the osteomyelitis.³ Although uncommon, lead exposure that occurs due to retained foreign body fragments from gunshot or military-related injuries can cause systemic lead toxicity. Symptoms may range from abdominal pain, nausea, and constipation to jaundice and hepatitis.⁴ The severity has also been stated to correlate with the surface area of the lead exposed for dissolution.⁵ Migration of foreign bodies and shrapnel to other sites in the body, such as movement from soft tissues into distantly located body cavities, have been reported as well. Such a case involved the spontaneous onset of knee synovitis due to an intra-articular metallic object that was introduced via a blast injury to the upper third of the ipsilateral thigh.¹

In this patient’s case, a large intramuscular abscess had formed nearly 50 years after the initial combat injury, requiring drainage of the abscess and removal of the fragment. By snaring the foreign body to a more superficial site, the surgical removal only required a minor incision, decreasing recovery time and the likelihood of postoperative complications that would have been associated with a large retroperitoneal dissection. While loop snare is often the first-line technique for the removal of intravascular foreign bodies, its use in soft tissue retained materials is scarcely reported.⁶ The more typical uses involve the removal of intraluminal materials, such as partially fractured venous catheters, guide wires, stents, and vena cava filters. The same report mentioned that in all 16 cases of percutaneous foreign body retrieval, no surgical intervention was required.⁷ In the case of most nonvascular foreign bodies, however, surgical retrieval is usually performed.⁸

Surgical removal of foreign bodies can be difficult in cases where a foreign body is anatomically located next to vital structures.⁹ An additional challenge with a sole surgical approach to foreign body retrieval is when it is small in size and lies deep within the soft tissue, as was the case for our patient. In such cases, the surgical procedure can be time consuming and lead to more trauma to the surrounding tissues.¹⁰ These factors alone necessitate consideration of postoperative morbidity and mortality.

Conclusions

This case demonstrates a multidisciplinary approach to transforming an otherwise large retroperitoneal dissection to a minimally invasive and technically efficient abscess drainage and foreign body retrieval.

Shrapnel injuries are commonly encountered in war zones.¹ Shrapnel injuries can remain asymptomatic or become systemic, with health effects of the retained foreign body ranging from local to systemic toxicities depending on the patient’s reaction to the chemical composition and corrosiveness of the fragments in vivo.² We present a case of a reactivating shrapnel injury in the form of a retroperitoneal infection and subsequent iliopsoas abscess. A collaborative procedure was performed between surgery and interventional radiology to snare and remove the infected fragment and drain the abscess.

Case Presentation

While serving in Vietnam, a soldier sustained a fragment injury to his left lower abdomen. He underwent a laparotomy, small bowel resection, and a temporary ileostomy at the time of the injury. Nearly 50 years later, the patient presented with chronic left lower quadrant pain and a low-grade fever. He was diagnosed clinically in the emergency department (ED) with diverticulitis and treated with antibiotics. The patient initially responded to treatment but returned 6 months later with similar symptoms, low-grade fever, and mild leukocytosis. A computed tomography (CT) scan during that encounter without IV contrast revealed a few scattered colonic diverticula without definite diverticulitis as well as a metallic fragment embedded in the left iliopsoas with increased soft tissue density.

The patient was diagnosed with a pelvic/abdominal wall hematoma and was discharged with pain medication. The patient reported recurrent attacks of left lower quadrant pain, fever, and changes in bowel habits, prompting gastrointestinal consultation and a colonoscopy that was unremarkable. Ten months later, the patient again presented to the ED, with recurrent symptoms, a fever of 102 °F, and leukocytosis with a white blood cell count of 11.7 × 10⁹/L. CT scan with IV contrast revealed a large left iliopsoas abscess associated with an approximately 1-cm metallic fragment (Figure 1). A drainage catheter was placed under CT guidance and approximately 270 mL of purulent fluid was drained. Culture of the fluid was positive for Escherichia coli (E coli). Two days after drain placement, the fragment was removed as a joint procedure with interventional radiology and surgery. Using the drainage catheter tract as a point of entry, multiple attempts were made to retrieve the fragment with Olympus EndoJaw endoscopic forceps without success.

Discussion

Foreign body injuries can be benign or debilitating depending on the initial damage, anatomical location of the foreign body, composition of the foreign body, and the patient’s response to it. Retained shrapnel deep within the muscle tissue rarely causes complications. Although many times embedded objects can be asymptomatic and require no further management, migration of the foreign body or the formation of a fistula is possible, causing symptoms and requiring surgical intervention.¹ One case involved the formation of a purulent fistula appearing a year after an explosive wound to the lumbosacral spine, which was treated with antimicrobials. Recurrence of the fistula several times after treatment led to surgical removal of the shrapnel along with antibiotic treatment of the osteomyelitis.³ Although uncommon, lead exposure that occurs due to retained foreign body fragments from gunshot or military-related injuries can cause systemic lead toxicity. Symptoms may range from abdominal pain, nausea, and constipation to jaundice and hepatitis.⁴ The severity has also been stated to correlate with the surface area of the lead exposed for dissolution.⁵ Migration of foreign bodies and shrapnel to other sites in the body, such as movement from soft tissues into distantly located body cavities, have been reported as well. Such a case involved the spontaneous onset of knee synovitis due to an intra-articular metallic object that was introduced via a blast injury to the upper third of the ipsilateral thigh.¹

In this patient’s case, a large intramuscular abscess had formed nearly 50 years after the initial combat injury, requiring drainage of the abscess and removal of the fragment. By snaring the foreign body to a more superficial site, the surgical removal only required a minor incision, decreasing recovery time and the likelihood of postoperative complications that would have been associated with a large retroperitoneal dissection. While loop snare is often the first-line technique for the removal of intravascular foreign bodies, its use in soft tissue retained materials is scarcely reported.⁶ The more typical uses involve the removal of intraluminal materials, such as partially fractured venous catheters, guide wires, stents, and vena cava filters. The same report mentioned that in all 16 cases of percutaneous foreign body retrieval, no surgical intervention was required.⁷ In the case of most nonvascular foreign bodies, however, surgical retrieval is usually performed.⁸

Surgical removal of foreign bodies can be difficult in cases where a foreign body is anatomically located next to vital structures.⁹ An additional challenge with a sole surgical approach to foreign body retrieval is when it is small in size and lies deep within the soft tissue, as was the case for our patient. In such cases, the surgical procedure can be time consuming and lead to more trauma to the surrounding tissues.¹⁰ These factors alone necessitate consideration of postoperative morbidity and mortality.

Conclusions

This case demonstrates a multidisciplinary approach to transforming an otherwise large retroperitoneal dissection to a minimally invasive and technically efficient abscess drainage and foreign body retrieval.

Hereditary angioedema (HAE) is a rare genetic disorder affecting about 1 in 67,000 individuals and may lead to increased morbidity and mortality.^1,2 HAE is characterized by recurring episodes of subcutaneous and/or submucosal edema without urticaria due to an excess of bradykinin.^2,3 Autosomal dominant inheritance is present in 75% of patients with HAE and is classified into 2 main types.² Type I HAE is caused by deficiency of C1 esterase inhibitor, accounting for 85% of cases.² Type II HAE is marked by normal to elevated levels of C1 esterase inhibitor but with reduced activity.²

Cutaneous and abdominal angioedema attacks are the most common presentation.¹ However, any location may be affected, including the face, oropharynx, and larynx.¹ Only 0.9% of all HAE attacks cause laryngeal edema, but 50% of HAE patients have experienced a laryngeal attack, which may be lethal.¹ An angioedema attack can range in severity, depending on the location and degree of edema.³ In addition, patients with HAE often are diagnosed with anxiety and depression secondary to their poor quality of life.⁴ Thus, long-term prophylaxis of attacks is crucial to reduce the physical and psychological implications.

Previously, HAE was treated with antifibrinolytic agents and attenuated androgens for short- and long-term prophylaxis.¹ These treatment modalities are now considered second-line since the development of novel medications with improved efficacy and limited adverse effects (AEs).¹ For long-term prophylaxis, subcutaneous and IV C1 esterase inhibitor has been proven effective in both types I and II HAE.¹ Another option, lanadelumab, a subcutaneously delivered monoclonal antibody inhibitor of plasma kallikrein, has been proven to decrease the frequency of HAE attacks without significant AEs.⁵ Lanadelumab works by binding to the active site of plasma kallikrein, which reduces its activity and slows the production of bradykinin.⁶ This results in decreasing vascular permeability and swelling episodes in patients with HAE.⁷ Data, however, are limited, specifically regarding patients with type II HAE and patients aged ≥ 65 years.⁵ This article reports on an older male with type II HAE successfully treated with lanadelumab.

Case Presentation

An 81-year-old male patient with hypertension, hypertriglyceridemia, and aortic aneurysm had recurrent, frequent episodes of severe abdominal pain with a remote history of extremity and scrotal swelling since adolescence. He was misdiagnosed for years and was eventually determined to have HAE at age 75 years after his niece was diagnosed, prompting him to be reevaluated for his frequent bouts of abdominal pain. His laboratory findings were consistent with HAE type II with low C4 (7.8 mg/dL), normal C1 esterase inhibitor levels (24 mg/dL), and low levels of C1 esterase inhibitor activity (28% of normal).

Initially, he described having weekly attacks of abdominal pain that could last 1 to several days. At worst, these attacks would last up to a month, causing a decrease in appetite and weight loss. At age 77 years, he began an on-demand treatment, icatibant, a bradykinin receptor blocker. After initiating icatibant during an acute attack, the pain would diminish within 1 to 2 hours, and within several hours, he would be pain free. Previously, pain relief would take several days to weeks. He continued to use icatibant on-demand, typically requiring treatment every 1 to 2 months for only the more severe attacks.

After an increasing frequency of abdominal pain attacks, prophylactic medication was recommended. Therefore, subcutaneous lanadelumab 300 mg every 2 weeks was initiated for long-term prophylaxis. The patient went from requiring on-demand treatment 2 to 3 times per month to once in 6 months after starting lanadelumab. In addition, he tolerated the medication well without any AEs.

Discussion

According to the international WAO/EAACI 2021 guidelines, HAE treatment goals are “to achieve complete control of the disease and to normalize patients’ lives.”⁸ On-demand treatment options include C1 esterase inhibitor, icatibant, or ecallantide (a kallikrein inhibitor).⁸ Long-term prophylaxis in HAE should be considered, accounting for disease activity, burden, control, and patient preference. Five medications have been used for long-term prophylaxis: antifibrinolytic agents (not recommended), attenuated androgens (considered second-line), C1 esterase inhibitor, berotralstat, and lanadelumab.⁸

Antifibrinolytics are no longer recommended for long-term prophylactic treatment as their efficacy is poor and was not considered for our patient. Attenuated androgens, such as danazol, have a history of prophylactic use in patients with HAE due to their good efficacy but are suboptimal due to their significant AE profile and many drug-drug interactions.⁸ In addition, androgens have many contraindications, including hypertension and hypertriglyceridemia, which were both present in our patient. Consequently, danazol was not an advised treatment for our patient. C1 esterase inhibitor is often used to prevent HAE attacks and can be given intravenously or subcutaneously, typically administered biweekly. A potential AE of C1 esterase inhibitor is thrombosis.Therefore, C1 esterase inhibitor was not a preferred choice in our older patient with a history of hypercoagulability. Berotralstat, a plasma kallikrein inhibitor, is an oral treatment option that also has shown efficacy in long-term prophylaxis. The most common AEs of berotralstat tend to be gastrointestinal symptoms, and the medication requires dose adjustment for patients with hepatic impairment.⁸ Berotralstat was not considered because it was not an approved treatment option at the time of this patient’s treatment. Lanadelumab is a human monoclonal antibody against plasma kallikrein, which decreases bradykinin production in patients with HAE, thus preventing angioedema attacks.⁵ Data regarding the use of lanadelumab in patients with type II HAE are limited, but because HAE with normal C1 esterase inhibitor levels involves the production of bradykinin via kallikrein, lanadelumab should still be effective.¹ Lanadelumab was chosen for our patient because of its minimal AEs and is not known to increase the risk of thrombosis.

Lanadelumab is a novel medication, recently approved in 2018 by the US Food and Drug Administration for the treatment of type I and type 2 HAE in patients aged ≥ 12 years.⁷ The phase 3 Hereditary Angioedema Long-term Prophylaxis (HELP) study concluded that treatment with subcutaneous lanadelumab for 26 weeks significantly decreased the frequency of angioedema attacks compared with placebo.⁵ However, 113 (90.4%) of patients in the phase III HELP study had type I HAE.⁵ Of the 125 patients that completed this randomized, double-blind study, only 12 had type II HAE.⁵ In addition, this study only included 5 patients aged ≥ 65 years.⁵ Also, no patients aged ≥ 65 years were part of the treatment arms that included a lanadelumab dose of 300 mg.⁵ In a case series of 12 patients in Canada, treatment with lanadelumab decreased angioedema attacks by 72%.⁹ However, the series only included 1 patient with type II HAE who was aged 36 years.⁹ Therefore, our case demonstrates the efficacy of lanadelumab in a patient aged ≥ 65 years with type II HAE.

Conclusions

HAE is a rare and potentially fatal disease characterized by recurrent, unpredictable attacks of edema throughout the body. The disease burden adversely affects a patient’s quality of life. Therefore, long-term prophylaxis is critical to managing patients with HAE. Lanadelumab has been proven as an effective long-term prophylactic treatment option for HAE attacks. This case supports the use of lanadelumab in patients with type II HAE and patients aged ≥ 65 years.

Acknowledgments

The patient was initially written up based on his delayed diagnosis as a case report.³ An earlier version of this article was presented by Samuel Weiss, MD, and Derek Smith, MD, as a poster at the American Academy of Allergy, Asthma, and Immunology virtual conference February 26 to March 1, 2021.

Hereditary angioedema (HAE) is a rare genetic disorder affecting about 1 in 67,000 individuals and may lead to increased morbidity and mortality.^1,2 HAE is characterized by recurring episodes of subcutaneous and/or submucosal edema without urticaria due to an excess of bradykinin.^2,3 Autosomal dominant inheritance is present in 75% of patients with HAE and is classified into 2 main types.² Type I HAE is caused by deficiency of C1 esterase inhibitor, accounting for 85% of cases.² Type II HAE is marked by normal to elevated levels of C1 esterase inhibitor but with reduced activity.²

Cutaneous and abdominal angioedema attacks are the most common presentation.¹ However, any location may be affected, including the face, oropharynx, and larynx.¹ Only 0.9% of all HAE attacks cause laryngeal edema, but 50% of HAE patients have experienced a laryngeal attack, which may be lethal.¹ An angioedema attack can range in severity, depending on the location and degree of edema.³ In addition, patients with HAE often are diagnosed with anxiety and depression secondary to their poor quality of life.⁴ Thus, long-term prophylaxis of attacks is crucial to reduce the physical and psychological implications.

Previously, HAE was treated with antifibrinolytic agents and attenuated androgens for short- and long-term prophylaxis.¹ These treatment modalities are now considered second-line since the development of novel medications with improved efficacy and limited adverse effects (AEs).¹ For long-term prophylaxis, subcutaneous and IV C1 esterase inhibitor has been proven effective in both types I and II HAE.¹ Another option, lanadelumab, a subcutaneously delivered monoclonal antibody inhibitor of plasma kallikrein, has been proven to decrease the frequency of HAE attacks without significant AEs.⁵ Lanadelumab works by binding to the active site of plasma kallikrein, which reduces its activity and slows the production of bradykinin.⁶ This results in decreasing vascular permeability and swelling episodes in patients with HAE.⁷ Data, however, are limited, specifically regarding patients with type II HAE and patients aged ≥ 65 years.⁵ This article reports on an older male with type II HAE successfully treated with lanadelumab.

Case Presentation

An 81-year-old male patient with hypertension, hypertriglyceridemia, and aortic aneurysm had recurrent, frequent episodes of severe abdominal pain with a remote history of extremity and scrotal swelling since adolescence. He was misdiagnosed for years and was eventually determined to have HAE at age 75 years after his niece was diagnosed, prompting him to be reevaluated for his frequent bouts of abdominal pain. His laboratory findings were consistent with HAE type II with low C4 (7.8 mg/dL), normal C1 esterase inhibitor levels (24 mg/dL), and low levels of C1 esterase inhibitor activity (28% of normal).

Initially, he described having weekly attacks of abdominal pain that could last 1 to several days. At worst, these attacks would last up to a month, causing a decrease in appetite and weight loss. At age 77 years, he began an on-demand treatment, icatibant, a bradykinin receptor blocker. After initiating icatibant during an acute attack, the pain would diminish within 1 to 2 hours, and within several hours, he would be pain free. Previously, pain relief would take several days to weeks. He continued to use icatibant on-demand, typically requiring treatment every 1 to 2 months for only the more severe attacks.

After an increasing frequency of abdominal pain attacks, prophylactic medication was recommended. Therefore, subcutaneous lanadelumab 300 mg every 2 weeks was initiated for long-term prophylaxis. The patient went from requiring on-demand treatment 2 to 3 times per month to once in 6 months after starting lanadelumab. In addition, he tolerated the medication well without any AEs.

Discussion

According to the international WAO/EAACI 2021 guidelines, HAE treatment goals are “to achieve complete control of the disease and to normalize patients’ lives.”⁸ On-demand treatment options include C1 esterase inhibitor, icatibant, or ecallantide (a kallikrein inhibitor).⁸ Long-term prophylaxis in HAE should be considered, accounting for disease activity, burden, control, and patient preference. Five medications have been used for long-term prophylaxis: antifibrinolytic agents (not recommended), attenuated androgens (considered second-line), C1 esterase inhibitor, berotralstat, and lanadelumab.⁸

Antifibrinolytics are no longer recommended for long-term prophylactic treatment as their efficacy is poor and was not considered for our patient. Attenuated androgens, such as danazol, have a history of prophylactic use in patients with HAE due to their good efficacy but are suboptimal due to their significant AE profile and many drug-drug interactions.⁸ In addition, androgens have many contraindications, including hypertension and hypertriglyceridemia, which were both present in our patient. Consequently, danazol was not an advised treatment for our patient. C1 esterase inhibitor is often used to prevent HAE attacks and can be given intravenously or subcutaneously, typically administered biweekly. A potential AE of C1 esterase inhibitor is thrombosis.Therefore, C1 esterase inhibitor was not a preferred choice in our older patient with a history of hypercoagulability. Berotralstat, a plasma kallikrein inhibitor, is an oral treatment option that also has shown efficacy in long-term prophylaxis. The most common AEs of berotralstat tend to be gastrointestinal symptoms, and the medication requires dose adjustment for patients with hepatic impairment.⁸ Berotralstat was not considered because it was not an approved treatment option at the time of this patient’s treatment. Lanadelumab is a human monoclonal antibody against plasma kallikrein, which decreases bradykinin production in patients with HAE, thus preventing angioedema attacks.⁵ Data regarding the use of lanadelumab in patients with type II HAE are limited, but because HAE with normal C1 esterase inhibitor levels involves the production of bradykinin via kallikrein, lanadelumab should still be effective.¹ Lanadelumab was chosen for our patient because of its minimal AEs and is not known to increase the risk of thrombosis.

Lanadelumab is a novel medication, recently approved in 2018 by the US Food and Drug Administration for the treatment of type I and type 2 HAE in patients aged ≥ 12 years.⁷ The phase 3 Hereditary Angioedema Long-term Prophylaxis (HELP) study concluded that treatment with subcutaneous lanadelumab for 26 weeks significantly decreased the frequency of angioedema attacks compared with placebo.⁵ However, 113 (90.4%) of patients in the phase III HELP study had type I HAE.⁵ Of the 125 patients that completed this randomized, double-blind study, only 12 had type II HAE.⁵ In addition, this study only included 5 patients aged ≥ 65 years.⁵ Also, no patients aged ≥ 65 years were part of the treatment arms that included a lanadelumab dose of 300 mg.⁵ In a case series of 12 patients in Canada, treatment with lanadelumab decreased angioedema attacks by 72%.⁹ However, the series only included 1 patient with type II HAE who was aged 36 years.⁹ Therefore, our case demonstrates the efficacy of lanadelumab in a patient aged ≥ 65 years with type II HAE.

Conclusions

HAE is a rare and potentially fatal disease characterized by recurrent, unpredictable attacks of edema throughout the body. The disease burden adversely affects a patient’s quality of life. Therefore, long-term prophylaxis is critical to managing patients with HAE. Lanadelumab has been proven as an effective long-term prophylactic treatment option for HAE attacks. This case supports the use of lanadelumab in patients with type II HAE and patients aged ≥ 65 years.

Acknowledgments

The patient was initially written up based on his delayed diagnosis as a case report.³ An earlier version of this article was presented by Samuel Weiss, MD, and Derek Smith, MD, as a poster at the American Academy of Allergy, Asthma, and Immunology virtual conference February 26 to March 1, 2021.

Hereditary angioedema (HAE) is a rare genetic disorder affecting about 1 in 67,000 individuals and may lead to increased morbidity and mortality.^1,2 HAE is characterized by recurring episodes of subcutaneous and/or submucosal edema without urticaria due to an excess of bradykinin.^2,3 Autosomal dominant inheritance is present in 75% of patients with HAE and is classified into 2 main types.² Type I HAE is caused by deficiency of C1 esterase inhibitor, accounting for 85% of cases.² Type II HAE is marked by normal to elevated levels of C1 esterase inhibitor but with reduced activity.²

Cutaneous and abdominal angioedema attacks are the most common presentation.¹ However, any location may be affected, including the face, oropharynx, and larynx.¹ Only 0.9% of all HAE attacks cause laryngeal edema, but 50% of HAE patients have experienced a laryngeal attack, which may be lethal.¹ An angioedema attack can range in severity, depending on the location and degree of edema.³ In addition, patients with HAE often are diagnosed with anxiety and depression secondary to their poor quality of life.⁴ Thus, long-term prophylaxis of attacks is crucial to reduce the physical and psychological implications.

Previously, HAE was treated with antifibrinolytic agents and attenuated androgens for short- and long-term prophylaxis.¹ These treatment modalities are now considered second-line since the development of novel medications with improved efficacy and limited adverse effects (AEs).¹ For long-term prophylaxis, subcutaneous and IV C1 esterase inhibitor has been proven effective in both types I and II HAE.¹ Another option, lanadelumab, a subcutaneously delivered monoclonal antibody inhibitor of plasma kallikrein, has been proven to decrease the frequency of HAE attacks without significant AEs.⁵ Lanadelumab works by binding to the active site of plasma kallikrein, which reduces its activity and slows the production of bradykinin.⁶ This results in decreasing vascular permeability and swelling episodes in patients with HAE.⁷ Data, however, are limited, specifically regarding patients with type II HAE and patients aged ≥ 65 years.⁵ This article reports on an older male with type II HAE successfully treated with lanadelumab.

Case Presentation

An 81-year-old male patient with hypertension, hypertriglyceridemia, and aortic aneurysm had recurrent, frequent episodes of severe abdominal pain with a remote history of extremity and scrotal swelling since adolescence. He was misdiagnosed for years and was eventually determined to have HAE at age 75 years after his niece was diagnosed, prompting him to be reevaluated for his frequent bouts of abdominal pain. His laboratory findings were consistent with HAE type II with low C4 (7.8 mg/dL), normal C1 esterase inhibitor levels (24 mg/dL), and low levels of C1 esterase inhibitor activity (28% of normal).

Initially, he described having weekly attacks of abdominal pain that could last 1 to several days. At worst, these attacks would last up to a month, causing a decrease in appetite and weight loss. At age 77 years, he began an on-demand treatment, icatibant, a bradykinin receptor blocker. After initiating icatibant during an acute attack, the pain would diminish within 1 to 2 hours, and within several hours, he would be pain free. Previously, pain relief would take several days to weeks. He continued to use icatibant on-demand, typically requiring treatment every 1 to 2 months for only the more severe attacks.

After an increasing frequency of abdominal pain attacks, prophylactic medication was recommended. Therefore, subcutaneous lanadelumab 300 mg every 2 weeks was initiated for long-term prophylaxis. The patient went from requiring on-demand treatment 2 to 3 times per month to once in 6 months after starting lanadelumab. In addition, he tolerated the medication well without any AEs.

Discussion

According to the international WAO/EAACI 2021 guidelines, HAE treatment goals are “to achieve complete control of the disease and to normalize patients’ lives.”⁸ On-demand treatment options include C1 esterase inhibitor, icatibant, or ecallantide (a kallikrein inhibitor).⁸ Long-term prophylaxis in HAE should be considered, accounting for disease activity, burden, control, and patient preference. Five medications have been used for long-term prophylaxis: antifibrinolytic agents (not recommended), attenuated androgens (considered second-line), C1 esterase inhibitor, berotralstat, and lanadelumab.⁸

Antifibrinolytics are no longer recommended for long-term prophylactic treatment as their efficacy is poor and was not considered for our patient. Attenuated androgens, such as danazol, have a history of prophylactic use in patients with HAE due to their good efficacy but are suboptimal due to their significant AE profile and many drug-drug interactions.⁸ In addition, androgens have many contraindications, including hypertension and hypertriglyceridemia, which were both present in our patient. Consequently, danazol was not an advised treatment for our patient. C1 esterase inhibitor is often used to prevent HAE attacks and can be given intravenously or subcutaneously, typically administered biweekly. A potential AE of C1 esterase inhibitor is thrombosis.Therefore, C1 esterase inhibitor was not a preferred choice in our older patient with a history of hypercoagulability. Berotralstat, a plasma kallikrein inhibitor, is an oral treatment option that also has shown efficacy in long-term prophylaxis. The most common AEs of berotralstat tend to be gastrointestinal symptoms, and the medication requires dose adjustment for patients with hepatic impairment.⁸ Berotralstat was not considered because it was not an approved treatment option at the time of this patient’s treatment. Lanadelumab is a human monoclonal antibody against plasma kallikrein, which decreases bradykinin production in patients with HAE, thus preventing angioedema attacks.⁵ Data regarding the use of lanadelumab in patients with type II HAE are limited, but because HAE with normal C1 esterase inhibitor levels involves the production of bradykinin via kallikrein, lanadelumab should still be effective.¹ Lanadelumab was chosen for our patient because of its minimal AEs and is not known to increase the risk of thrombosis.

Lanadelumab is a novel medication, recently approved in 2018 by the US Food and Drug Administration for the treatment of type I and type 2 HAE in patients aged ≥ 12 years.⁷ The phase 3 Hereditary Angioedema Long-term Prophylaxis (HELP) study concluded that treatment with subcutaneous lanadelumab for 26 weeks significantly decreased the frequency of angioedema attacks compared with placebo.⁵ However, 113 (90.4%) of patients in the phase III HELP study had type I HAE.⁵ Of the 125 patients that completed this randomized, double-blind study, only 12 had type II HAE.⁵ In addition, this study only included 5 patients aged ≥ 65 years.⁵ Also, no patients aged ≥ 65 years were part of the treatment arms that included a lanadelumab dose of 300 mg.⁵ In a case series of 12 patients in Canada, treatment with lanadelumab decreased angioedema attacks by 72%.⁹ However, the series only included 1 patient with type II HAE who was aged 36 years.⁹ Therefore, our case demonstrates the efficacy of lanadelumab in a patient aged ≥ 65 years with type II HAE.

Conclusions

HAE is a rare and potentially fatal disease characterized by recurrent, unpredictable attacks of edema throughout the body. The disease burden adversely affects a patient’s quality of life. Therefore, long-term prophylaxis is critical to managing patients with HAE. Lanadelumab has been proven as an effective long-term prophylactic treatment option for HAE attacks. This case supports the use of lanadelumab in patients with type II HAE and patients aged ≥ 65 years.

Acknowledgments

The patient was initially written up based on his delayed diagnosis as a case report.³ An earlier version of this article was presented by Samuel Weiss, MD, and Derek Smith, MD, as a poster at the American Academy of Allergy, Asthma, and Immunology virtual conference February 26 to March 1, 2021.

THE CASE

A 56-year-old physician (CUL) visited a local seafood restaurant, after having fasted since the prior evening. He had a history of hypertension that was well controlled with lisinopril/hydrochlorothiazide.

The physician and his party were seated outside, where the temperature was in the mid-70s. The group ordered oysters on the half shell accompanied by mignonette sauce, cocktail sauce, and horseradish. The physician ate an olive-size amount of horseradish with an oyster. He immediately complained of a sharp burning sensation in his stomach and remarked that the horseradish was significantly stronger than what he was accustomed to. Within 30 seconds, he noted an increased heart rate, weakness, and intense sweating. There was no increase in nasal secretions. Observers noted that he was very pale.

About 5 minutes after eating the horseradish, the physician leaned his head back and briefly lost consciousness. His wife, while supporting his head and checking his pulse, instructed other diners to call for emergency services, at which point the physician regained consciousness and the dispatcher was told that an ambulance was no longer necessary. Within a matter of minutes, all symptoms had abated, except for some mild weakness.

THE DIAGNOSIS

Ten minutes after the event, the physician identified his symptoms as a horseradish-­induced vasovagal syncope (VVS), based on a case report published in JAMA in 1988, which his wife found after he asked her to do an Internet search of his symptoms.¹

THE DISCUSSION

Horseradish’s active component is isothiocyanate. Horseradish-induced syncope is also called Seder syncope after the Jewish Passover holiday dinner at which observant Jews are required to eat “bitter herbs.”^1,2 This type of syncope is thought to occur when horseradish vapors directly irritate the gastric or respiratory tract mucosa.

VVS commonly manifests for the first time at around age 13 years; however, the timing of that first occurrence can vary significantly among individuals (as in this case).³ The afferent aspect of a VVS episode is poorly understood, while the efferent aspect has been elucidated. A transient inhibition of the sympathetic nervous system results in vasodilatation, hypotension, and a temporary increase in vagal tone with bradycardia,^4-7 which leads to cerebral underperfusion and loss of consciousness.

The loss of consciousness may be caused by an emotional trigger (eg, sight of blood, cast removal,⁸ blood or platelet donations^9,10), a painful event (eg, an injection¹¹), an orthostatic trigger¹² (eg, prolonged standing), or visceral reflexes such as swallowing.¹³ In approximately 30% of cases, loss of consciousness is associated with memory loss.¹⁴ Loss of consciousness with VVS may be associated with injury in 33% of cases.¹⁵

Continue to: The recovery with awareness

The recovery with awareness of time, place, and person may be a feature of VVS, which would differentiate it from seizures and brainstem vascular events. Autonomic prodromal symptoms—including abdominal discomfort, pallor, sweating, and nausea—may precede the loss of consciousness.⁸

An evolutionary response?

VVS may have developed as a trait through evolution, although modern medicine treats it as a disease. Many potential explanations for VVS as a body defense mechanism have been proposed. Examples include fainting at the sight of blood, which developed during the Old Stone Age—a period with extreme human-to-human violence—or acting like a “possum playing dead” as a tactic designed to confuse an attacker.¹⁶

Vasovagal syncope may have developed as a trait through evolution, although modern medicine treats it as a disease.

Another theory involves clot production and suggests that VVS-induced hypotension is a defense against bleeding by improving clot formation.¹⁷

A psychological defense theory maintains that the fainting and memory loss are designed to prevent a painful or overwhelming experience from being remembered. None of these theories, however, explain orthostatic VVS.¹⁸

The brain defense theory could explain all forms of VVS. It postulates that hypotension causes decreased cerebral perfusion, which leads to syncope resulting in the body returning to a more orthostatic position with increased cerebral profusion.¹⁹

Continue to: The patient

The patient in this case was able to leave the restaurant on his own volition 30 minutes after the event and resume normal activities. Ten days later, an electrocardiogram was performed, with negative results. In this case, the use of a potassium-wasting diuretic exacerbated the risk of a fluid-deprived state, hypokalemia, and hypotension, possibly contributing to the syncope. The patient has since “gotten back on the horseradish” without ill effect.

THE TAKEAWAY

Consumers and health care providers should be aware of the risks associated with consumption of fresh horseradish and should allow it to rest prior to ingestion to allow some evaporation of its active ingredient. An old case report saved the patient from an unnecessary (and costly) emergency department visit.

ACKNOWLEDGEMENTS
The authors would like to thank Terry J. Hannan, MBBS, FRACP, FACHI, FACMI for his critical review of the manuscript.

CORRESPONDENCE
Christoph U. Lehmann, MD, Clinical Informatics Center, 5323 Harry Hines Boulevard, Dallas, TX 75390; [email protected]

THE CASE

A 56-year-old physician (CUL) visited a local seafood restaurant, after having fasted since the prior evening. He had a history of hypertension that was well controlled with lisinopril/hydrochlorothiazide.

The physician and his party were seated outside, where the temperature was in the mid-70s. The group ordered oysters on the half shell accompanied by mignonette sauce, cocktail sauce, and horseradish. The physician ate an olive-size amount of horseradish with an oyster. He immediately complained of a sharp burning sensation in his stomach and remarked that the horseradish was significantly stronger than what he was accustomed to. Within 30 seconds, he noted an increased heart rate, weakness, and intense sweating. There was no increase in nasal secretions. Observers noted that he was very pale.

About 5 minutes after eating the horseradish, the physician leaned his head back and briefly lost consciousness. His wife, while supporting his head and checking his pulse, instructed other diners to call for emergency services, at which point the physician regained consciousness and the dispatcher was told that an ambulance was no longer necessary. Within a matter of minutes, all symptoms had abated, except for some mild weakness.

THE DIAGNOSIS

Ten minutes after the event, the physician identified his symptoms as a horseradish-­induced vasovagal syncope (VVS), based on a case report published in JAMA in 1988, which his wife found after he asked her to do an Internet search of his symptoms.¹

THE DISCUSSION

Horseradish’s active component is isothiocyanate. Horseradish-induced syncope is also called Seder syncope after the Jewish Passover holiday dinner at which observant Jews are required to eat “bitter herbs.”^1,2 This type of syncope is thought to occur when horseradish vapors directly irritate the gastric or respiratory tract mucosa.

VVS commonly manifests for the first time at around age 13 years; however, the timing of that first occurrence can vary significantly among individuals (as in this case).³ The afferent aspect of a VVS episode is poorly understood, while the efferent aspect has been elucidated. A transient inhibition of the sympathetic nervous system results in vasodilatation, hypotension, and a temporary increase in vagal tone with bradycardia,^4-7 which leads to cerebral underperfusion and loss of consciousness.

The loss of consciousness may be caused by an emotional trigger (eg, sight of blood, cast removal,⁸ blood or platelet donations^9,10), a painful event (eg, an injection¹¹), an orthostatic trigger¹² (eg, prolonged standing), or visceral reflexes such as swallowing.¹³ In approximately 30% of cases, loss of consciousness is associated with memory loss.¹⁴ Loss of consciousness with VVS may be associated with injury in 33% of cases.¹⁵

Continue to: The recovery with awareness

The recovery with awareness of time, place, and person may be a feature of VVS, which would differentiate it from seizures and brainstem vascular events. Autonomic prodromal symptoms—including abdominal discomfort, pallor, sweating, and nausea—may precede the loss of consciousness.⁸

An evolutionary response?

VVS may have developed as a trait through evolution, although modern medicine treats it as a disease. Many potential explanations for VVS as a body defense mechanism have been proposed. Examples include fainting at the sight of blood, which developed during the Old Stone Age—a period with extreme human-to-human violence—or acting like a “possum playing dead” as a tactic designed to confuse an attacker.¹⁶

Vasovagal syncope may have developed as a trait through evolution, although modern medicine treats it as a disease.

Another theory involves clot production and suggests that VVS-induced hypotension is a defense against bleeding by improving clot formation.¹⁷

A psychological defense theory maintains that the fainting and memory loss are designed to prevent a painful or overwhelming experience from being remembered. None of these theories, however, explain orthostatic VVS.¹⁸

The brain defense theory could explain all forms of VVS. It postulates that hypotension causes decreased cerebral perfusion, which leads to syncope resulting in the body returning to a more orthostatic position with increased cerebral profusion.¹⁹

Continue to: The patient

The patient in this case was able to leave the restaurant on his own volition 30 minutes after the event and resume normal activities. Ten days later, an electrocardiogram was performed, with negative results. In this case, the use of a potassium-wasting diuretic exacerbated the risk of a fluid-deprived state, hypokalemia, and hypotension, possibly contributing to the syncope. The patient has since “gotten back on the horseradish” without ill effect.

THE TAKEAWAY

Consumers and health care providers should be aware of the risks associated with consumption of fresh horseradish and should allow it to rest prior to ingestion to allow some evaporation of its active ingredient. An old case report saved the patient from an unnecessary (and costly) emergency department visit.

ACKNOWLEDGEMENTS
The authors would like to thank Terry J. Hannan, MBBS, FRACP, FACHI, FACMI for his critical review of the manuscript.

CORRESPONDENCE
Christoph U. Lehmann, MD, Clinical Informatics Center, 5323 Harry Hines Boulevard, Dallas, TX 75390; [email protected]

THE CASE

A 56-year-old physician (CUL) visited a local seafood restaurant, after having fasted since the prior evening. He had a history of hypertension that was well controlled with lisinopril/hydrochlorothiazide.

The physician and his party were seated outside, where the temperature was in the mid-70s. The group ordered oysters on the half shell accompanied by mignonette sauce, cocktail sauce, and horseradish. The physician ate an olive-size amount of horseradish with an oyster. He immediately complained of a sharp burning sensation in his stomach and remarked that the horseradish was significantly stronger than what he was accustomed to. Within 30 seconds, he noted an increased heart rate, weakness, and intense sweating. There was no increase in nasal secretions. Observers noted that he was very pale.

About 5 minutes after eating the horseradish, the physician leaned his head back and briefly lost consciousness. His wife, while supporting his head and checking his pulse, instructed other diners to call for emergency services, at which point the physician regained consciousness and the dispatcher was told that an ambulance was no longer necessary. Within a matter of minutes, all symptoms had abated, except for some mild weakness.

THE DIAGNOSIS

Ten minutes after the event, the physician identified his symptoms as a horseradish-­induced vasovagal syncope (VVS), based on a case report published in JAMA in 1988, which his wife found after he asked her to do an Internet search of his symptoms.¹

THE DISCUSSION

Horseradish’s active component is isothiocyanate. Horseradish-induced syncope is also called Seder syncope after the Jewish Passover holiday dinner at which observant Jews are required to eat “bitter herbs.”^1,2 This type of syncope is thought to occur when horseradish vapors directly irritate the gastric or respiratory tract mucosa.

VVS commonly manifests for the first time at around age 13 years; however, the timing of that first occurrence can vary significantly among individuals (as in this case).³ The afferent aspect of a VVS episode is poorly understood, while the efferent aspect has been elucidated. A transient inhibition of the sympathetic nervous system results in vasodilatation, hypotension, and a temporary increase in vagal tone with bradycardia,^4-7 which leads to cerebral underperfusion and loss of consciousness.

The loss of consciousness may be caused by an emotional trigger (eg, sight of blood, cast removal,⁸ blood or platelet donations^9,10), a painful event (eg, an injection¹¹), an orthostatic trigger¹² (eg, prolonged standing), or visceral reflexes such as swallowing.¹³ In approximately 30% of cases, loss of consciousness is associated with memory loss.¹⁴ Loss of consciousness with VVS may be associated with injury in 33% of cases.¹⁵

Continue to: The recovery with awareness

The recovery with awareness of time, place, and person may be a feature of VVS, which would differentiate it from seizures and brainstem vascular events. Autonomic prodromal symptoms—including abdominal discomfort, pallor, sweating, and nausea—may precede the loss of consciousness.⁸

An evolutionary response?

VVS may have developed as a trait through evolution, although modern medicine treats it as a disease. Many potential explanations for VVS as a body defense mechanism have been proposed. Examples include fainting at the sight of blood, which developed during the Old Stone Age—a period with extreme human-to-human violence—or acting like a “possum playing dead” as a tactic designed to confuse an attacker.¹⁶

Vasovagal syncope may have developed as a trait through evolution, although modern medicine treats it as a disease.

Another theory involves clot production and suggests that VVS-induced hypotension is a defense against bleeding by improving clot formation.¹⁷

A psychological defense theory maintains that the fainting and memory loss are designed to prevent a painful or overwhelming experience from being remembered. None of these theories, however, explain orthostatic VVS.¹⁸

The brain defense theory could explain all forms of VVS. It postulates that hypotension causes decreased cerebral perfusion, which leads to syncope resulting in the body returning to a more orthostatic position with increased cerebral profusion.¹⁹

Continue to: The patient

The patient in this case was able to leave the restaurant on his own volition 30 minutes after the event and resume normal activities. Ten days later, an electrocardiogram was performed, with negative results. In this case, the use of a potassium-wasting diuretic exacerbated the risk of a fluid-deprived state, hypokalemia, and hypotension, possibly contributing to the syncope. The patient has since “gotten back on the horseradish” without ill effect.

THE TAKEAWAY

Consumers and health care providers should be aware of the risks associated with consumption of fresh horseradish and should allow it to rest prior to ingestion to allow some evaporation of its active ingredient. An old case report saved the patient from an unnecessary (and costly) emergency department visit.

ACKNOWLEDGEMENTS
The authors would like to thank Terry J. Hannan, MBBS, FRACP, FACHI, FACMI for his critical review of the manuscript.

CORRESPONDENCE
Christoph U. Lehmann, MD, Clinical Informatics Center, 5323 Harry Hines Boulevard, Dallas, TX 75390; [email protected]