Case Reports

Case Report

A 79-year-old man with chronic lymphocytic leukemia (CLL) who was being treated with ibrutinib presented to the emergency department with a dry cough, ataxia and falls, and vision loss. Physical examination was remarkable for diffuse crackles heard throughout the right lung and bilateral lower extremity weakness. Additionally, he had 4 pink mobile nodules on the left side of the forehead, right side of the chin, left submental area, and left postauricular scalp, which arose approximately 2 weeks prior to presentation. The left postauricular lesion had been tender at times and had developed a crust. The cutaneous lesions were all smaller than 2 cm.

The patient had a history of squamous cell carcinoma of the skin and was under the care of a dermatologist as an outpatient. His dermatologist had described him as an active gardener; he was noted to have healing abrasions on the forearms due to gardening raspberry bushes.

Computed tomography of the head revealed a 14-mm, ring-enhancing lesion in the left paramedian posterior frontal lobe with surrounding white matter vasogenic edema (Figure 1). Computed tomography of the chest revealed a peripheral mass on the right upper lobe measuring 6.3 cm at its greatest dimension (Figure 2).

Clinically, the constellation of symptoms was thought to represent an infectious process or less likely metastatic malignancy. Biopsies of the nodule on the right side of the chin were performed and sent for culture and histologic examination. Sections from the anterior right chin showed compact orthokeratosis overlying a slightly spongiotic epidermis (Figure 3). Within the deep dermis, there was a dense mixed inflammatory infiltrate comprising predominantly neutrophils, with occasional eosinophils, lymphocytes, and histiocytes (Figure 4).

Gram stain revealed gram-variable, branching, bacterial organisms morphologically consistent with Nocardia. Grocott-Gomori methenamine-silver and periodic acid–Schiff stains also highlighted the bacterial organisms (Figure 5). An auramine-O stain was negative for acid-fast microorganisms. After 3 days on a blood agar plate, cultures of a specimen of the chin nodule grew branching filamentous bacterial organisms consistent with Nocardia.

Comment

Presentation and Diagnosis
Nocardiosis is an infrequently encountered opportunistic infection that typically targets skin, lungs, and the central nervous system (CNS). Nocardia species characteristically are gram-positive, thin rods that form beaded, right-angle, branching filaments.¹ More than 50 Nocardia species have been clinically isolated.²

Definitive diagnosis requires culture. Nocardia grows well on nonselective media, such as blood or Löwenstein-Jensen agar; growth can be enhanced with 10% CO₂. Growth can be slow, however, and takes from 48 hours to several weeks. Nocardia typically grows as buff or pigmented, waxy, cerebriform colonies at 3 to 5 days’ incubation.¹

Cause of Infection
Nocardia species are commonly found in the environment—soil, plant matter, water, and decomposing organic material—as well as in the gastrointestinal tract and skin of animals. Infection has been reported in cattle, dogs, horses, swine, birds, cats, foxes, and a few other animals.² A history of exposure, such as gardening or handling animals, should increase suspicion of Nocardia.³ Although infection is classically thought to affect immunocompromised patients, there are case reports of immunocompetent individuals developing disseminated infection.^4-7 However, infected immunocompetent individuals typically have localized cutaneous infection, which often includes cellulitis, abscesses, or sporotrichoid patterns.² Cutaneous infections typically are the result of direct inoculation of the skin through a penetrating injury.⁸

Disseminated nocardiosis can be caused by numerous species and generally is the result of primary pulmonary infection.⁹ In these cases, skin disease is present in approximately 10% of patients. Disseminated infection from cutaneous nocardiosis is uncommon; when it does occur, the most common site of dissemination is the CNS, resulting in abscess or cerebritis.¹⁰ Therefore, CNS involvement should always be ruled out on diagnosis in immunocompromised patients, even if neurologic symptoms are absent.⁹ Nearly 80% of patients with disseminated disease are, in fact, immunocompromised.⁸

Association With CLL
Chronic lymphocytic leukemia is associated with profound immunodeficiency caused by quantitative and qualitative aberrations in both innate and adaptive immunity. This perturbation of the immune system predisposes the patient to infection.^11,12 Early in the course of CLL, a patient develops neutropenia, which predisposes to bacterial infection; later, the patient develops a sustained B- and T-cell immunodeficiency that predisposes to opportunistic infection.¹³ Treatment-naïve patients with CLL are commonly diagnosed with respiratory and urinary tract infections.¹² Chronic lymphocytic leukemia patients treated with alemtuzumab or purine analogs have been reported to have the highest risk for major infection.¹⁴

Ibrutinib is a commonly used treatment of CLL because it induces apoptosis in B cells, which are abnormal in CLL. Ibrutinib functions by inhibiting the Bruton tyrosine kinase pathway, which is essential in B-cell production and maintenance.¹⁵ Studies have reported a high rate of infection in ibrutinib-treated CLL patients^14,16; salvage ibrutinib therapy has been associated with higher infection risk than primary ibrutinib therapy.^16,17 Long-term follow-up studies have shown a decreased rate of infection in ibrutinib-treated CLL after 2 years or longer of treatment, suggesting a reconstitution of normal B cells and humoral immunity with longer ibrutinib therapy.^16,17

Many infections have been identified in association with ibrutinib therapy, including invasive aspergillosis, disseminated fusariosis, cerebral mucormycosis, disseminated cryptococcosis, and Pneumocystis jirovecii pneumonia.^18-22 Disseminated nocardiosis has been reported in a few patients with CLL, though the treatment they received for CLL varied from case to case.^23-25

Identification and Treatment
Clinical and microscopic identification of Nocardia organisms can be exceedingly difficult. Primary cutaneous nocardiosis clinically presents as tumors or nodules that often have a sporotrichoid pattern along the lymphatics. In disease that disseminates to skin, nocardiosis presents as vesiculopustules or abscesses. The biopsy specimen most often shows a dense dermal and subcutaneous infiltrate of neutrophils with abscess formation. Long-standing lesions might show chronic inflammation and nonspecific granulomas.

The appearance of Nocardia organisms is quite subtle on hematoxylin and eosin staining and can be easily missed. Special stains, such as Gram and Grocott-Gomori methenamine-silver stains as well as stains for acid-fast organisms, can be invaluable in diagnosing this disease. Biopsy in immunocompromised patients when nocardiosis is part of the differential diagnosis requires extra attention because the organisms can be gram variable and only partially acid fast, as was the case in our patient. Organisms typically will be positive with silver stains.

Trimethoprim-sulfamethoxazole typically is the first-line treatment of nocardiosis. Although prognosis is excellent when disease is confined to skin, disseminated infection has 25% mortality.⁸ Diagnosticians should maintain a high index of suspicion for the disease, especially in immunocompromised patients, because clinical and imaging findings can be nonspecific.

Conclusion

Our patient’s primary risk factor for nocardiosis was his immunocompromised state. In addition, he was an avid gardener, which increased his risk for exposure to the microorganism. Given the timing of disease progression, our case most likely represents primary cutaneous nocardiosis with dissemination to brain, lungs, and other organs, leading to death, and serves as a reminder to dermatologists and pathologists to establish a broad differential diagnosis when dealing with an infectious process in immunocompromised patients.

Case Report

A 79-year-old man with chronic lymphocytic leukemia (CLL) who was being treated with ibrutinib presented to the emergency department with a dry cough, ataxia and falls, and vision loss. Physical examination was remarkable for diffuse crackles heard throughout the right lung and bilateral lower extremity weakness. Additionally, he had 4 pink mobile nodules on the left side of the forehead, right side of the chin, left submental area, and left postauricular scalp, which arose approximately 2 weeks prior to presentation. The left postauricular lesion had been tender at times and had developed a crust. The cutaneous lesions were all smaller than 2 cm.

The patient had a history of squamous cell carcinoma of the skin and was under the care of a dermatologist as an outpatient. His dermatologist had described him as an active gardener; he was noted to have healing abrasions on the forearms due to gardening raspberry bushes.

Computed tomography of the head revealed a 14-mm, ring-enhancing lesion in the left paramedian posterior frontal lobe with surrounding white matter vasogenic edema (Figure 1). Computed tomography of the chest revealed a peripheral mass on the right upper lobe measuring 6.3 cm at its greatest dimension (Figure 2).

Clinically, the constellation of symptoms was thought to represent an infectious process or less likely metastatic malignancy. Biopsies of the nodule on the right side of the chin were performed and sent for culture and histologic examination. Sections from the anterior right chin showed compact orthokeratosis overlying a slightly spongiotic epidermis (Figure 3). Within the deep dermis, there was a dense mixed inflammatory infiltrate comprising predominantly neutrophils, with occasional eosinophils, lymphocytes, and histiocytes (Figure 4).

Gram stain revealed gram-variable, branching, bacterial organisms morphologically consistent with Nocardia. Grocott-Gomori methenamine-silver and periodic acid–Schiff stains also highlighted the bacterial organisms (Figure 5). An auramine-O stain was negative for acid-fast microorganisms. After 3 days on a blood agar plate, cultures of a specimen of the chin nodule grew branching filamentous bacterial organisms consistent with Nocardia.

Comment

Presentation and Diagnosis
Nocardiosis is an infrequently encountered opportunistic infection that typically targets skin, lungs, and the central nervous system (CNS). Nocardia species characteristically are gram-positive, thin rods that form beaded, right-angle, branching filaments.¹ More than 50 Nocardia species have been clinically isolated.²

Definitive diagnosis requires culture. Nocardia grows well on nonselective media, such as blood or Löwenstein-Jensen agar; growth can be enhanced with 10% CO₂. Growth can be slow, however, and takes from 48 hours to several weeks. Nocardia typically grows as buff or pigmented, waxy, cerebriform colonies at 3 to 5 days’ incubation.¹

Cause of Infection
Nocardia species are commonly found in the environment—soil, plant matter, water, and decomposing organic material—as well as in the gastrointestinal tract and skin of animals. Infection has been reported in cattle, dogs, horses, swine, birds, cats, foxes, and a few other animals.² A history of exposure, such as gardening or handling animals, should increase suspicion of Nocardia.³ Although infection is classically thought to affect immunocompromised patients, there are case reports of immunocompetent individuals developing disseminated infection.^4-7 However, infected immunocompetent individuals typically have localized cutaneous infection, which often includes cellulitis, abscesses, or sporotrichoid patterns.² Cutaneous infections typically are the result of direct inoculation of the skin through a penetrating injury.⁸

Disseminated nocardiosis can be caused by numerous species and generally is the result of primary pulmonary infection.⁹ In these cases, skin disease is present in approximately 10% of patients. Disseminated infection from cutaneous nocardiosis is uncommon; when it does occur, the most common site of dissemination is the CNS, resulting in abscess or cerebritis.¹⁰ Therefore, CNS involvement should always be ruled out on diagnosis in immunocompromised patients, even if neurologic symptoms are absent.⁹ Nearly 80% of patients with disseminated disease are, in fact, immunocompromised.⁸

Association With CLL
Chronic lymphocytic leukemia is associated with profound immunodeficiency caused by quantitative and qualitative aberrations in both innate and adaptive immunity. This perturbation of the immune system predisposes the patient to infection.^11,12 Early in the course of CLL, a patient develops neutropenia, which predisposes to bacterial infection; later, the patient develops a sustained B- and T-cell immunodeficiency that predisposes to opportunistic infection.¹³ Treatment-naïve patients with CLL are commonly diagnosed with respiratory and urinary tract infections.¹² Chronic lymphocytic leukemia patients treated with alemtuzumab or purine analogs have been reported to have the highest risk for major infection.¹⁴

Ibrutinib is a commonly used treatment of CLL because it induces apoptosis in B cells, which are abnormal in CLL. Ibrutinib functions by inhibiting the Bruton tyrosine kinase pathway, which is essential in B-cell production and maintenance.¹⁵ Studies have reported a high rate of infection in ibrutinib-treated CLL patients^14,16; salvage ibrutinib therapy has been associated with higher infection risk than primary ibrutinib therapy.^16,17 Long-term follow-up studies have shown a decreased rate of infection in ibrutinib-treated CLL after 2 years or longer of treatment, suggesting a reconstitution of normal B cells and humoral immunity with longer ibrutinib therapy.^16,17

Many infections have been identified in association with ibrutinib therapy, including invasive aspergillosis, disseminated fusariosis, cerebral mucormycosis, disseminated cryptococcosis, and Pneumocystis jirovecii pneumonia.^18-22 Disseminated nocardiosis has been reported in a few patients with CLL, though the treatment they received for CLL varied from case to case.^23-25

Identification and Treatment
Clinical and microscopic identification of Nocardia organisms can be exceedingly difficult. Primary cutaneous nocardiosis clinically presents as tumors or nodules that often have a sporotrichoid pattern along the lymphatics. In disease that disseminates to skin, nocardiosis presents as vesiculopustules or abscesses. The biopsy specimen most often shows a dense dermal and subcutaneous infiltrate of neutrophils with abscess formation. Long-standing lesions might show chronic inflammation and nonspecific granulomas.

The appearance of Nocardia organisms is quite subtle on hematoxylin and eosin staining and can be easily missed. Special stains, such as Gram and Grocott-Gomori methenamine-silver stains as well as stains for acid-fast organisms, can be invaluable in diagnosing this disease. Biopsy in immunocompromised patients when nocardiosis is part of the differential diagnosis requires extra attention because the organisms can be gram variable and only partially acid fast, as was the case in our patient. Organisms typically will be positive with silver stains.

Trimethoprim-sulfamethoxazole typically is the first-line treatment of nocardiosis. Although prognosis is excellent when disease is confined to skin, disseminated infection has 25% mortality.⁸ Diagnosticians should maintain a high index of suspicion for the disease, especially in immunocompromised patients, because clinical and imaging findings can be nonspecific.

Conclusion

Our patient’s primary risk factor for nocardiosis was his immunocompromised state. In addition, he was an avid gardener, which increased his risk for exposure to the microorganism. Given the timing of disease progression, our case most likely represents primary cutaneous nocardiosis with dissemination to brain, lungs, and other organs, leading to death, and serves as a reminder to dermatologists and pathologists to establish a broad differential diagnosis when dealing with an infectious process in immunocompromised patients.

Case Report

A 79-year-old man with chronic lymphocytic leukemia (CLL) who was being treated with ibrutinib presented to the emergency department with a dry cough, ataxia and falls, and vision loss. Physical examination was remarkable for diffuse crackles heard throughout the right lung and bilateral lower extremity weakness. Additionally, he had 4 pink mobile nodules on the left side of the forehead, right side of the chin, left submental area, and left postauricular scalp, which arose approximately 2 weeks prior to presentation. The left postauricular lesion had been tender at times and had developed a crust. The cutaneous lesions were all smaller than 2 cm.

The patient had a history of squamous cell carcinoma of the skin and was under the care of a dermatologist as an outpatient. His dermatologist had described him as an active gardener; he was noted to have healing abrasions on the forearms due to gardening raspberry bushes.

Computed tomography of the head revealed a 14-mm, ring-enhancing lesion in the left paramedian posterior frontal lobe with surrounding white matter vasogenic edema (Figure 1). Computed tomography of the chest revealed a peripheral mass on the right upper lobe measuring 6.3 cm at its greatest dimension (Figure 2).

Clinically, the constellation of symptoms was thought to represent an infectious process or less likely metastatic malignancy. Biopsies of the nodule on the right side of the chin were performed and sent for culture and histologic examination. Sections from the anterior right chin showed compact orthokeratosis overlying a slightly spongiotic epidermis (Figure 3). Within the deep dermis, there was a dense mixed inflammatory infiltrate comprising predominantly neutrophils, with occasional eosinophils, lymphocytes, and histiocytes (Figure 4).

Gram stain revealed gram-variable, branching, bacterial organisms morphologically consistent with Nocardia. Grocott-Gomori methenamine-silver and periodic acid–Schiff stains also highlighted the bacterial organisms (Figure 5). An auramine-O stain was negative for acid-fast microorganisms. After 3 days on a blood agar plate, cultures of a specimen of the chin nodule grew branching filamentous bacterial organisms consistent with Nocardia.

Comment

Presentation and Diagnosis
Nocardiosis is an infrequently encountered opportunistic infection that typically targets skin, lungs, and the central nervous system (CNS). Nocardia species characteristically are gram-positive, thin rods that form beaded, right-angle, branching filaments.¹ More than 50 Nocardia species have been clinically isolated.²

Definitive diagnosis requires culture. Nocardia grows well on nonselective media, such as blood or Löwenstein-Jensen agar; growth can be enhanced with 10% CO₂. Growth can be slow, however, and takes from 48 hours to several weeks. Nocardia typically grows as buff or pigmented, waxy, cerebriform colonies at 3 to 5 days’ incubation.¹

Cause of Infection
Nocardia species are commonly found in the environment—soil, plant matter, water, and decomposing organic material—as well as in the gastrointestinal tract and skin of animals. Infection has been reported in cattle, dogs, horses, swine, birds, cats, foxes, and a few other animals.² A history of exposure, such as gardening or handling animals, should increase suspicion of Nocardia.³ Although infection is classically thought to affect immunocompromised patients, there are case reports of immunocompetent individuals developing disseminated infection.^4-7 However, infected immunocompetent individuals typically have localized cutaneous infection, which often includes cellulitis, abscesses, or sporotrichoid patterns.² Cutaneous infections typically are the result of direct inoculation of the skin through a penetrating injury.⁸

Disseminated nocardiosis can be caused by numerous species and generally is the result of primary pulmonary infection.⁹ In these cases, skin disease is present in approximately 10% of patients. Disseminated infection from cutaneous nocardiosis is uncommon; when it does occur, the most common site of dissemination is the CNS, resulting in abscess or cerebritis.¹⁰ Therefore, CNS involvement should always be ruled out on diagnosis in immunocompromised patients, even if neurologic symptoms are absent.⁹ Nearly 80% of patients with disseminated disease are, in fact, immunocompromised.⁸

Association With CLL
Chronic lymphocytic leukemia is associated with profound immunodeficiency caused by quantitative and qualitative aberrations in both innate and adaptive immunity. This perturbation of the immune system predisposes the patient to infection.^11,12 Early in the course of CLL, a patient develops neutropenia, which predisposes to bacterial infection; later, the patient develops a sustained B- and T-cell immunodeficiency that predisposes to opportunistic infection.¹³ Treatment-naïve patients with CLL are commonly diagnosed with respiratory and urinary tract infections.¹² Chronic lymphocytic leukemia patients treated with alemtuzumab or purine analogs have been reported to have the highest risk for major infection.¹⁴

Ibrutinib is a commonly used treatment of CLL because it induces apoptosis in B cells, which are abnormal in CLL. Ibrutinib functions by inhibiting the Bruton tyrosine kinase pathway, which is essential in B-cell production and maintenance.¹⁵ Studies have reported a high rate of infection in ibrutinib-treated CLL patients^14,16; salvage ibrutinib therapy has been associated with higher infection risk than primary ibrutinib therapy.^16,17 Long-term follow-up studies have shown a decreased rate of infection in ibrutinib-treated CLL after 2 years or longer of treatment, suggesting a reconstitution of normal B cells and humoral immunity with longer ibrutinib therapy.^16,17

Many infections have been identified in association with ibrutinib therapy, including invasive aspergillosis, disseminated fusariosis, cerebral mucormycosis, disseminated cryptococcosis, and Pneumocystis jirovecii pneumonia.^18-22 Disseminated nocardiosis has been reported in a few patients with CLL, though the treatment they received for CLL varied from case to case.^23-25

Identification and Treatment
Clinical and microscopic identification of Nocardia organisms can be exceedingly difficult. Primary cutaneous nocardiosis clinically presents as tumors or nodules that often have a sporotrichoid pattern along the lymphatics. In disease that disseminates to skin, nocardiosis presents as vesiculopustules or abscesses. The biopsy specimen most often shows a dense dermal and subcutaneous infiltrate of neutrophils with abscess formation. Long-standing lesions might show chronic inflammation and nonspecific granulomas.

The appearance of Nocardia organisms is quite subtle on hematoxylin and eosin staining and can be easily missed. Special stains, such as Gram and Grocott-Gomori methenamine-silver stains as well as stains for acid-fast organisms, can be invaluable in diagnosing this disease. Biopsy in immunocompromised patients when nocardiosis is part of the differential diagnosis requires extra attention because the organisms can be gram variable and only partially acid fast, as was the case in our patient. Organisms typically will be positive with silver stains.

Trimethoprim-sulfamethoxazole typically is the first-line treatment of nocardiosis. Although prognosis is excellent when disease is confined to skin, disseminated infection has 25% mortality.⁸ Diagnosticians should maintain a high index of suspicion for the disease, especially in immunocompromised patients, because clinical and imaging findings can be nonspecific.

Conclusion

Our patient’s primary risk factor for nocardiosis was his immunocompromised state. In addition, he was an avid gardener, which increased his risk for exposure to the microorganism. Given the timing of disease progression, our case most likely represents primary cutaneous nocardiosis with dissemination to brain, lungs, and other organs, leading to death, and serves as a reminder to dermatologists and pathologists to establish a broad differential diagnosis when dealing with an infectious process in immunocompromised patients.

Asthma attacks account for 1.8 million emergency department (ED) visits each year in the US and for 10 deaths daily.¹ Management of asthma attacks includes administration of inhaled ß₂ adrenergic agonists, inhaled anticholinergic agents, IV magnesium sulfate, and corticosteroids.² Status asthmaticus is an intense acute exacerbation of asthma that does not respond to repeated treatments of bronchodilators and corticosteroids.³ It is a medical emergency requiring immediate recognition and treatment. The decision to intubate a patient with status asthmaticus is a clinical decision based on work of breathing, respiratory acidosis, and failure to respond to medical interventions.

In refractory cases of status asthmaticus, intubation and mechanical ventilation are undertaken to provide oxygenation and ventilation until the bronchospasm resolves. However, mechanical ventilation is associated with significant risks, including high end-inspiratory pressures, barotrauma, and volutrauma.⁴ Rescue therapies include muscle relaxation, infusion of ketamine (central acting nonopioid analgesic with bronchodilatory properties), heliox, and general anesthesia.^2,4 We report a case of a patient with life-threatening asthma and status asthmaticus treated with sevoflurane general anesthesia.

Case Presentation

A 55-year-old woman whose medical history was notable for asthma, psoriasis, hypothyroidism, tobacco, and alcohol abuse, and posttraumatic stress disorder (PTSD) presented to the ED. The patient had rarely sought medical attention and had no prior ED visits or hospitalizations in the electronic health record. Her home regimen included an albuterol inhaler used as needed. Her family reported that they had found her in distress in bed in a tripod position, unable to speak and struggling to breath.

Emergency medical services found the patient cyanotic, apneic, and pulseless. She received cardiopulmonary resuscitation for 30 seconds and 1-mg IV epinephrine, and spontaneous circulation returned. The patient arrived in the ED with an oral airway in place receiving bag valve mask ventilation. The patient expelled the oral airway. She was unable to speak due to dyspnea, exhibited persistent cyanosis, fatigue due to work of breathing, and failed to respond to nebulized albuterol/ipratropium bromide, IV methylprednisolone, and magnesium sulfate. The patient met criteria for acute severe asthma, or status asthmaticus. Thus, the patient received rapid sequence induction with rocuronium and ketamine and was intubated.

According to her family, the patient had no previous intensive care unit (ICU) admissions or prior intubations. Her only asthma medication was an albuterol inhaler as needed. The patient worked as a supervisor at a window blind manufacturing company. She lived alone, smoked 2 packs of cigarettes a day for more than 30 years, had no pets, drank unknown quantities of beer, wine, and hard liquor daily, and had smoked marijuana for several years.

The patient’s physical examination was notable for diffuse expiratory wheezes. Laboratory analysis revealed white blood cell count of 13.7 k/mcL, sodium 140 mmol/L, potassium 4.9 mmol/L, chloride 105 mmol/L, CO₂ 17 mmol/L, creatinine 0.98 mg/dL, troponin 0.03 ng/mL, lactate 7.2 mmol/L. Her chest X-ray showed hyperinflation but no focal opacities, pneumothorax, or pulmonary edema. Her endotracheal tube was in good position (Figure 1). A computed tomography pulmonary angiogram showed no pulmonary embolus or emphysema. There were atelectatic changes in the dependent portion of the right lower lobe, central bronchial wall thickening, and no stigmata of air trapping (Figure 2). An echocardiogram revealed a left ventricular ejection fraction of 45%, normal right ventricle and right ventricular size and function with an estimated right ventricular systolic pressure of 40 mm Hg.

The patient was admitted to the ICU and started on continuous infusion cisatracurium for paralysis and deep sedation to improve ventilatory synchrony and decrease auto positive end-expiratory pressure (PEEP). Mechanical ventilation was initiated with volume-cycled assist control ventilation, 6 mL/kg/ideal body weight (IBW) at 5-cm H₂O PEEP, and 1 minute ventilation of 10 liters. The patient had severe air trapping and high airway pressures. The dynamic PEEP was 22-cm H₂O (normal PEEP of 5-cm H₂O), peak airway pressure (PAP) 41-cm H₂O, and plateau pressure 31-cm H₂O. In addition, the arterial blood gas (ABG) showed severe hypercapnic respiratory acidosis without significant hypoxemia with pH 7.15, PaCO₂ 90 mm Hg, and PaO₂ 150 mm Hg.

Pressure controlled ventilation was attempted unsuccessfully due to high airway resistance. Ultimately, the patient was set on volume control with low tidal volume, 6 mL/kg/IBW, high flow 90 L/min, PEEP 0 cm of H₂O, and a low respiratory rate of 10 to achieve an inspiratory to expiratory (I:E) ratio of 1:7. Managing the ventilator to avoid dynamic hyperinflation and auto-PEEP, she remained relatively stable and improved.

By day 4 the patient’s ventilator was set to volume assist control with respiratory rate of 16, tidal volume, 6 mL/kg/IBW, PEEP 5-cm H₂O with auto PEEP of 3-cm H₂O, and fraction of inspired ABG O₂ (FiO₂) 0.35 with PAP of 46-cm H₂O and plateau pressure of 17-cm H₂O. The ABG was pH 7.32, PaCO₂ 65 mm Hg, and PaO₂ 74 mm Hg. However, on hospital day 5, she developed worsening PAP 60 to 77-cm H₂O, plateau pressures 17-cm H₂O, and a dynamic PEEP 16-cm H₂O and was unresponsive to ventilator maneuvers to lower airway pressures and improve ventilation.

The patient had been receiving continuous albuterol and ipratropium nebulizer treatments. Ketamine infusion was considered fraught with potential for a dissociative reaction due to the patient’s significant PTSD. The patient’s family requested avoidance of ketamine infusion since the patient was paralyzed and psychiatric effects could not be monitored. Heliox 80/20 mixture was considered; however, it is incompatible with the ventilator that was being used since it could not account for the density of the helium gas flow in the tidal volumes. Extracorporeal membrane oxygenation (ECMO) was not available at our facility, and the patient was not a candidate for the regional ECMO center.

On hospital day 8, the patient developed worsening respiratory acidosis. The patient’s PAP increased to > 77-cm H₂O, and her ABG revealed pH 7.22, PaCO₂ 90 mm Hg, and PaO₂ 77 mm Hg with FiO₂ 0.4. A chest X-ray demonstrated a new left lower lobe infiltrate. Fiber optic bronchoscopy was notable for scattered thick secretions throughout both lungs without obstructing mucus plug. Removal of airway secretions did not improve airway pressures or dynamic hyperinflation.

After consultation and discussion with the chief of anesthesia, the patient was placed on an anesthesia ventilator and started on sevoflurane 1.5% in the ICU. Anesthesiology was available 24 hours a day, and the anesthesiologist rounded with the intensivist frequently for this patient. The anesthesia technician worked closely with respiratory therapy regarding ventilator setting and changing the anesthesia gas scavenging charcoal canister. Within 4 hours, her gas exchange normalized (Table). The patient’s ABG was pH 7.44, PaCO₂ 52 mm Hg, and PaO₂ 69 mm Hg on FiO₂ 0.4. On volume cycled ventilation with a rate of 12, flow rate of 40 L/min, and tidal volume 6 mL/kg/IBW, the PAP decreased to 41-cm H₂O.

Within 24 hours bronchospasm improved as evidenced by decreased airway pressures, resolution of wheezing, and decreased CO₂ retention. The sevoflurane was easily weaned over the next 48 hours by decreasing the dose by 25% every 12-hour shift without rebound bronchospasm. Airway pressures and ABGs were frequently monitored during the weaning process. The patient resumed conventional mechanical ventilation, cisatracurium was discontinued, and she underwent a percutaneous tracheostomy for critical illness polymyopathy. Her respiratory muscle strength recovered more robustly than anticipated. Prior to discharge to a skilled nursing facility for continued rehabilitation, she was removed from mechanical ventilation and decannulated.

Discussion

This case illustrates the successful treatment of a patient with extreme status asthmaticus given inhalational anesthesia as supportive care while the bronchospasm and status asthmaticus abated. This is an unusual treatment in an ominous situation. Inhalational anesthetics are potent bronchodilators and have been successfully used in the management of status asthmaticus refractory to conventional therapy.⁴ Inhalational anesthetics have been shown to decrease airway resistance, dynamic hyperinflation, and intrinsic PEEP.⁵ These agents result in rapid bronchodilation by relaxing the smooth muscle and are associated with early liberation from mechanical ventilation.^5,6 Although there are no guidelines regarding which inhalational agent is best, specific dosing, duration, or titration, case reports in the literature regarding the successful use of inhalational agents in life-threatening status asthmaticus exist.^2,5,7

Caveats regarding the use of inhalational anesthetics in status asthmaticus include proarrhythmias, severe hepatic and renal toxicity. Although isoflurane is less likely to cause arrhythmia, both isoflurane and sevoflurane can cause dose-dependent hypotension by peripheral vasodilatation.⁷ Ourpatient did not manifest any adverse effects.

Additional challenges regarding the use of inhalational anesthetics for status asthmaticus include differences in ventilators and occupational hazards.⁸ Anesthesia or operating room ventilators differ from ICU ventilators in flow and pressure capabilities.⁷ The anesthesia ventilator is not capable of generating inspiratory pressures sufficient to ventilate patients with severely elevated airway resistance. Thus, the decrease inspiratory flow that occurs with increasing airway pressure limits the tidal volume delivered and consequently the minute volume. Although newer anesthesia ventilators have increased flow capabilities, they require a fully trained staff.⁸

Potential occupational exposure to these volatile anesthetic gases occurs as patients being treated may exhale considerable amounts of volatile anesthetics.⁸ An anesthesia gas scavenging device, such as a charcoal canister, must be attached to the ventilator to capture the exhaled anesthetic gases and should be changed every 12 hours.⁸ Finally, there is a potential for rebound bronchospasm as the anesthetic agent is tapered.^6,7,9-11

Conclusion

Inhalational anesthetics are an option as rescue therapy for severe life-threatening asthma when all other therapies have failed. Use of inhalational anesthetics in status asthmaticus consists of case reports of which half are in children.^2,5,7 Our patient contributes to the literature of case reports regarding using sevoflurane in refractory status asthmaticus. A decision to choose them must be a collaborative team approach with anesthesiology, pulmonary/critical care medicine, respiratory therapy, and ICU nurses, and the risks and benefits should be discussed with decision-making family members. Since there are no specific guidelines for the use of inhalational agents in status asthmaticus, close attention to inspiratory flows, gas scavenging devices, and clinical response is required. Additionally, the team must be comfortable with the plan to use an anesthesia ventilator and trained on its limitations.

Asthma attacks account for 1.8 million emergency department (ED) visits each year in the US and for 10 deaths daily.¹ Management of asthma attacks includes administration of inhaled ß₂ adrenergic agonists, inhaled anticholinergic agents, IV magnesium sulfate, and corticosteroids.² Status asthmaticus is an intense acute exacerbation of asthma that does not respond to repeated treatments of bronchodilators and corticosteroids.³ It is a medical emergency requiring immediate recognition and treatment. The decision to intubate a patient with status asthmaticus is a clinical decision based on work of breathing, respiratory acidosis, and failure to respond to medical interventions.

In refractory cases of status asthmaticus, intubation and mechanical ventilation are undertaken to provide oxygenation and ventilation until the bronchospasm resolves. However, mechanical ventilation is associated with significant risks, including high end-inspiratory pressures, barotrauma, and volutrauma.⁴ Rescue therapies include muscle relaxation, infusion of ketamine (central acting nonopioid analgesic with bronchodilatory properties), heliox, and general anesthesia.^2,4 We report a case of a patient with life-threatening asthma and status asthmaticus treated with sevoflurane general anesthesia.

Case Presentation

A 55-year-old woman whose medical history was notable for asthma, psoriasis, hypothyroidism, tobacco, and alcohol abuse, and posttraumatic stress disorder (PTSD) presented to the ED. The patient had rarely sought medical attention and had no prior ED visits or hospitalizations in the electronic health record. Her home regimen included an albuterol inhaler used as needed. Her family reported that they had found her in distress in bed in a tripod position, unable to speak and struggling to breath.

Emergency medical services found the patient cyanotic, apneic, and pulseless. She received cardiopulmonary resuscitation for 30 seconds and 1-mg IV epinephrine, and spontaneous circulation returned. The patient arrived in the ED with an oral airway in place receiving bag valve mask ventilation. The patient expelled the oral airway. She was unable to speak due to dyspnea, exhibited persistent cyanosis, fatigue due to work of breathing, and failed to respond to nebulized albuterol/ipratropium bromide, IV methylprednisolone, and magnesium sulfate. The patient met criteria for acute severe asthma, or status asthmaticus. Thus, the patient received rapid sequence induction with rocuronium and ketamine and was intubated.

According to her family, the patient had no previous intensive care unit (ICU) admissions or prior intubations. Her only asthma medication was an albuterol inhaler as needed. The patient worked as a supervisor at a window blind manufacturing company. She lived alone, smoked 2 packs of cigarettes a day for more than 30 years, had no pets, drank unknown quantities of beer, wine, and hard liquor daily, and had smoked marijuana for several years.

The patient’s physical examination was notable for diffuse expiratory wheezes. Laboratory analysis revealed white blood cell count of 13.7 k/mcL, sodium 140 mmol/L, potassium 4.9 mmol/L, chloride 105 mmol/L, CO₂ 17 mmol/L, creatinine 0.98 mg/dL, troponin 0.03 ng/mL, lactate 7.2 mmol/L. Her chest X-ray showed hyperinflation but no focal opacities, pneumothorax, or pulmonary edema. Her endotracheal tube was in good position (Figure 1). A computed tomography pulmonary angiogram showed no pulmonary embolus or emphysema. There were atelectatic changes in the dependent portion of the right lower lobe, central bronchial wall thickening, and no stigmata of air trapping (Figure 2). An echocardiogram revealed a left ventricular ejection fraction of 45%, normal right ventricle and right ventricular size and function with an estimated right ventricular systolic pressure of 40 mm Hg.

The patient was admitted to the ICU and started on continuous infusion cisatracurium for paralysis and deep sedation to improve ventilatory synchrony and decrease auto positive end-expiratory pressure (PEEP). Mechanical ventilation was initiated with volume-cycled assist control ventilation, 6 mL/kg/ideal body weight (IBW) at 5-cm H₂O PEEP, and 1 minute ventilation of 10 liters. The patient had severe air trapping and high airway pressures. The dynamic PEEP was 22-cm H₂O (normal PEEP of 5-cm H₂O), peak airway pressure (PAP) 41-cm H₂O, and plateau pressure 31-cm H₂O. In addition, the arterial blood gas (ABG) showed severe hypercapnic respiratory acidosis without significant hypoxemia with pH 7.15, PaCO₂ 90 mm Hg, and PaO₂ 150 mm Hg.

Pressure controlled ventilation was attempted unsuccessfully due to high airway resistance. Ultimately, the patient was set on volume control with low tidal volume, 6 mL/kg/IBW, high flow 90 L/min, PEEP 0 cm of H₂O, and a low respiratory rate of 10 to achieve an inspiratory to expiratory (I:E) ratio of 1:7. Managing the ventilator to avoid dynamic hyperinflation and auto-PEEP, she remained relatively stable and improved.

By day 4 the patient’s ventilator was set to volume assist control with respiratory rate of 16, tidal volume, 6 mL/kg/IBW, PEEP 5-cm H₂O with auto PEEP of 3-cm H₂O, and fraction of inspired ABG O₂ (FiO₂) 0.35 with PAP of 46-cm H₂O and plateau pressure of 17-cm H₂O. The ABG was pH 7.32, PaCO₂ 65 mm Hg, and PaO₂ 74 mm Hg. However, on hospital day 5, she developed worsening PAP 60 to 77-cm H₂O, plateau pressures 17-cm H₂O, and a dynamic PEEP 16-cm H₂O and was unresponsive to ventilator maneuvers to lower airway pressures and improve ventilation.

The patient had been receiving continuous albuterol and ipratropium nebulizer treatments. Ketamine infusion was considered fraught with potential for a dissociative reaction due to the patient’s significant PTSD. The patient’s family requested avoidance of ketamine infusion since the patient was paralyzed and psychiatric effects could not be monitored. Heliox 80/20 mixture was considered; however, it is incompatible with the ventilator that was being used since it could not account for the density of the helium gas flow in the tidal volumes. Extracorporeal membrane oxygenation (ECMO) was not available at our facility, and the patient was not a candidate for the regional ECMO center.

On hospital day 8, the patient developed worsening respiratory acidosis. The patient’s PAP increased to > 77-cm H₂O, and her ABG revealed pH 7.22, PaCO₂ 90 mm Hg, and PaO₂ 77 mm Hg with FiO₂ 0.4. A chest X-ray demonstrated a new left lower lobe infiltrate. Fiber optic bronchoscopy was notable for scattered thick secretions throughout both lungs without obstructing mucus plug. Removal of airway secretions did not improve airway pressures or dynamic hyperinflation.

After consultation and discussion with the chief of anesthesia, the patient was placed on an anesthesia ventilator and started on sevoflurane 1.5% in the ICU. Anesthesiology was available 24 hours a day, and the anesthesiologist rounded with the intensivist frequently for this patient. The anesthesia technician worked closely with respiratory therapy regarding ventilator setting and changing the anesthesia gas scavenging charcoal canister. Within 4 hours, her gas exchange normalized (Table). The patient’s ABG was pH 7.44, PaCO₂ 52 mm Hg, and PaO₂ 69 mm Hg on FiO₂ 0.4. On volume cycled ventilation with a rate of 12, flow rate of 40 L/min, and tidal volume 6 mL/kg/IBW, the PAP decreased to 41-cm H₂O.

Within 24 hours bronchospasm improved as evidenced by decreased airway pressures, resolution of wheezing, and decreased CO₂ retention. The sevoflurane was easily weaned over the next 48 hours by decreasing the dose by 25% every 12-hour shift without rebound bronchospasm. Airway pressures and ABGs were frequently monitored during the weaning process. The patient resumed conventional mechanical ventilation, cisatracurium was discontinued, and she underwent a percutaneous tracheostomy for critical illness polymyopathy. Her respiratory muscle strength recovered more robustly than anticipated. Prior to discharge to a skilled nursing facility for continued rehabilitation, she was removed from mechanical ventilation and decannulated.

Discussion

This case illustrates the successful treatment of a patient with extreme status asthmaticus given inhalational anesthesia as supportive care while the bronchospasm and status asthmaticus abated. This is an unusual treatment in an ominous situation. Inhalational anesthetics are potent bronchodilators and have been successfully used in the management of status asthmaticus refractory to conventional therapy.⁴ Inhalational anesthetics have been shown to decrease airway resistance, dynamic hyperinflation, and intrinsic PEEP.⁵ These agents result in rapid bronchodilation by relaxing the smooth muscle and are associated with early liberation from mechanical ventilation.^5,6 Although there are no guidelines regarding which inhalational agent is best, specific dosing, duration, or titration, case reports in the literature regarding the successful use of inhalational agents in life-threatening status asthmaticus exist.^2,5,7

Caveats regarding the use of inhalational anesthetics in status asthmaticus include proarrhythmias, severe hepatic and renal toxicity. Although isoflurane is less likely to cause arrhythmia, both isoflurane and sevoflurane can cause dose-dependent hypotension by peripheral vasodilatation.⁷ Ourpatient did not manifest any adverse effects.

Additional challenges regarding the use of inhalational anesthetics for status asthmaticus include differences in ventilators and occupational hazards.⁸ Anesthesia or operating room ventilators differ from ICU ventilators in flow and pressure capabilities.⁷ The anesthesia ventilator is not capable of generating inspiratory pressures sufficient to ventilate patients with severely elevated airway resistance. Thus, the decrease inspiratory flow that occurs with increasing airway pressure limits the tidal volume delivered and consequently the minute volume. Although newer anesthesia ventilators have increased flow capabilities, they require a fully trained staff.⁸

Potential occupational exposure to these volatile anesthetic gases occurs as patients being treated may exhale considerable amounts of volatile anesthetics.⁸ An anesthesia gas scavenging device, such as a charcoal canister, must be attached to the ventilator to capture the exhaled anesthetic gases and should be changed every 12 hours.⁸ Finally, there is a potential for rebound bronchospasm as the anesthetic agent is tapered.^6,7,9-11

Conclusion

Inhalational anesthetics are an option as rescue therapy for severe life-threatening asthma when all other therapies have failed. Use of inhalational anesthetics in status asthmaticus consists of case reports of which half are in children.^2,5,7 Our patient contributes to the literature of case reports regarding using sevoflurane in refractory status asthmaticus. A decision to choose them must be a collaborative team approach with anesthesiology, pulmonary/critical care medicine, respiratory therapy, and ICU nurses, and the risks and benefits should be discussed with decision-making family members. Since there are no specific guidelines for the use of inhalational agents in status asthmaticus, close attention to inspiratory flows, gas scavenging devices, and clinical response is required. Additionally, the team must be comfortable with the plan to use an anesthesia ventilator and trained on its limitations.

Asthma attacks account for 1.8 million emergency department (ED) visits each year in the US and for 10 deaths daily.¹ Management of asthma attacks includes administration of inhaled ß₂ adrenergic agonists, inhaled anticholinergic agents, IV magnesium sulfate, and corticosteroids.² Status asthmaticus is an intense acute exacerbation of asthma that does not respond to repeated treatments of bronchodilators and corticosteroids.³ It is a medical emergency requiring immediate recognition and treatment. The decision to intubate a patient with status asthmaticus is a clinical decision based on work of breathing, respiratory acidosis, and failure to respond to medical interventions.

In refractory cases of status asthmaticus, intubation and mechanical ventilation are undertaken to provide oxygenation and ventilation until the bronchospasm resolves. However, mechanical ventilation is associated with significant risks, including high end-inspiratory pressures, barotrauma, and volutrauma.⁴ Rescue therapies include muscle relaxation, infusion of ketamine (central acting nonopioid analgesic with bronchodilatory properties), heliox, and general anesthesia.^2,4 We report a case of a patient with life-threatening asthma and status asthmaticus treated with sevoflurane general anesthesia.

Case Presentation

A 55-year-old woman whose medical history was notable for asthma, psoriasis, hypothyroidism, tobacco, and alcohol abuse, and posttraumatic stress disorder (PTSD) presented to the ED. The patient had rarely sought medical attention and had no prior ED visits or hospitalizations in the electronic health record. Her home regimen included an albuterol inhaler used as needed. Her family reported that they had found her in distress in bed in a tripod position, unable to speak and struggling to breath.

Emergency medical services found the patient cyanotic, apneic, and pulseless. She received cardiopulmonary resuscitation for 30 seconds and 1-mg IV epinephrine, and spontaneous circulation returned. The patient arrived in the ED with an oral airway in place receiving bag valve mask ventilation. The patient expelled the oral airway. She was unable to speak due to dyspnea, exhibited persistent cyanosis, fatigue due to work of breathing, and failed to respond to nebulized albuterol/ipratropium bromide, IV methylprednisolone, and magnesium sulfate. The patient met criteria for acute severe asthma, or status asthmaticus. Thus, the patient received rapid sequence induction with rocuronium and ketamine and was intubated.

According to her family, the patient had no previous intensive care unit (ICU) admissions or prior intubations. Her only asthma medication was an albuterol inhaler as needed. The patient worked as a supervisor at a window blind manufacturing company. She lived alone, smoked 2 packs of cigarettes a day for more than 30 years, had no pets, drank unknown quantities of beer, wine, and hard liquor daily, and had smoked marijuana for several years.

The patient’s physical examination was notable for diffuse expiratory wheezes. Laboratory analysis revealed white blood cell count of 13.7 k/mcL, sodium 140 mmol/L, potassium 4.9 mmol/L, chloride 105 mmol/L, CO₂ 17 mmol/L, creatinine 0.98 mg/dL, troponin 0.03 ng/mL, lactate 7.2 mmol/L. Her chest X-ray showed hyperinflation but no focal opacities, pneumothorax, or pulmonary edema. Her endotracheal tube was in good position (Figure 1). A computed tomography pulmonary angiogram showed no pulmonary embolus or emphysema. There were atelectatic changes in the dependent portion of the right lower lobe, central bronchial wall thickening, and no stigmata of air trapping (Figure 2). An echocardiogram revealed a left ventricular ejection fraction of 45%, normal right ventricle and right ventricular size and function with an estimated right ventricular systolic pressure of 40 mm Hg.

The patient was admitted to the ICU and started on continuous infusion cisatracurium for paralysis and deep sedation to improve ventilatory synchrony and decrease auto positive end-expiratory pressure (PEEP). Mechanical ventilation was initiated with volume-cycled assist control ventilation, 6 mL/kg/ideal body weight (IBW) at 5-cm H₂O PEEP, and 1 minute ventilation of 10 liters. The patient had severe air trapping and high airway pressures. The dynamic PEEP was 22-cm H₂O (normal PEEP of 5-cm H₂O), peak airway pressure (PAP) 41-cm H₂O, and plateau pressure 31-cm H₂O. In addition, the arterial blood gas (ABG) showed severe hypercapnic respiratory acidosis without significant hypoxemia with pH 7.15, PaCO₂ 90 mm Hg, and PaO₂ 150 mm Hg.

Pressure controlled ventilation was attempted unsuccessfully due to high airway resistance. Ultimately, the patient was set on volume control with low tidal volume, 6 mL/kg/IBW, high flow 90 L/min, PEEP 0 cm of H₂O, and a low respiratory rate of 10 to achieve an inspiratory to expiratory (I:E) ratio of 1:7. Managing the ventilator to avoid dynamic hyperinflation and auto-PEEP, she remained relatively stable and improved.

By day 4 the patient’s ventilator was set to volume assist control with respiratory rate of 16, tidal volume, 6 mL/kg/IBW, PEEP 5-cm H₂O with auto PEEP of 3-cm H₂O, and fraction of inspired ABG O₂ (FiO₂) 0.35 with PAP of 46-cm H₂O and plateau pressure of 17-cm H₂O. The ABG was pH 7.32, PaCO₂ 65 mm Hg, and PaO₂ 74 mm Hg. However, on hospital day 5, she developed worsening PAP 60 to 77-cm H₂O, plateau pressures 17-cm H₂O, and a dynamic PEEP 16-cm H₂O and was unresponsive to ventilator maneuvers to lower airway pressures and improve ventilation.

The patient had been receiving continuous albuterol and ipratropium nebulizer treatments. Ketamine infusion was considered fraught with potential for a dissociative reaction due to the patient’s significant PTSD. The patient’s family requested avoidance of ketamine infusion since the patient was paralyzed and psychiatric effects could not be monitored. Heliox 80/20 mixture was considered; however, it is incompatible with the ventilator that was being used since it could not account for the density of the helium gas flow in the tidal volumes. Extracorporeal membrane oxygenation (ECMO) was not available at our facility, and the patient was not a candidate for the regional ECMO center.

On hospital day 8, the patient developed worsening respiratory acidosis. The patient’s PAP increased to > 77-cm H₂O, and her ABG revealed pH 7.22, PaCO₂ 90 mm Hg, and PaO₂ 77 mm Hg with FiO₂ 0.4. A chest X-ray demonstrated a new left lower lobe infiltrate. Fiber optic bronchoscopy was notable for scattered thick secretions throughout both lungs without obstructing mucus plug. Removal of airway secretions did not improve airway pressures or dynamic hyperinflation.

After consultation and discussion with the chief of anesthesia, the patient was placed on an anesthesia ventilator and started on sevoflurane 1.5% in the ICU. Anesthesiology was available 24 hours a day, and the anesthesiologist rounded with the intensivist frequently for this patient. The anesthesia technician worked closely with respiratory therapy regarding ventilator setting and changing the anesthesia gas scavenging charcoal canister. Within 4 hours, her gas exchange normalized (Table). The patient’s ABG was pH 7.44, PaCO₂ 52 mm Hg, and PaO₂ 69 mm Hg on FiO₂ 0.4. On volume cycled ventilation with a rate of 12, flow rate of 40 L/min, and tidal volume 6 mL/kg/IBW, the PAP decreased to 41-cm H₂O.

Within 24 hours bronchospasm improved as evidenced by decreased airway pressures, resolution of wheezing, and decreased CO₂ retention. The sevoflurane was easily weaned over the next 48 hours by decreasing the dose by 25% every 12-hour shift without rebound bronchospasm. Airway pressures and ABGs were frequently monitored during the weaning process. The patient resumed conventional mechanical ventilation, cisatracurium was discontinued, and she underwent a percutaneous tracheostomy for critical illness polymyopathy. Her respiratory muscle strength recovered more robustly than anticipated. Prior to discharge to a skilled nursing facility for continued rehabilitation, she was removed from mechanical ventilation and decannulated.

Discussion

This case illustrates the successful treatment of a patient with extreme status asthmaticus given inhalational anesthesia as supportive care while the bronchospasm and status asthmaticus abated. This is an unusual treatment in an ominous situation. Inhalational anesthetics are potent bronchodilators and have been successfully used in the management of status asthmaticus refractory to conventional therapy.⁴ Inhalational anesthetics have been shown to decrease airway resistance, dynamic hyperinflation, and intrinsic PEEP.⁵ These agents result in rapid bronchodilation by relaxing the smooth muscle and are associated with early liberation from mechanical ventilation.^5,6 Although there are no guidelines regarding which inhalational agent is best, specific dosing, duration, or titration, case reports in the literature regarding the successful use of inhalational agents in life-threatening status asthmaticus exist.^2,5,7

Caveats regarding the use of inhalational anesthetics in status asthmaticus include proarrhythmias, severe hepatic and renal toxicity. Although isoflurane is less likely to cause arrhythmia, both isoflurane and sevoflurane can cause dose-dependent hypotension by peripheral vasodilatation.⁷ Ourpatient did not manifest any adverse effects.

Additional challenges regarding the use of inhalational anesthetics for status asthmaticus include differences in ventilators and occupational hazards.⁸ Anesthesia or operating room ventilators differ from ICU ventilators in flow and pressure capabilities.⁷ The anesthesia ventilator is not capable of generating inspiratory pressures sufficient to ventilate patients with severely elevated airway resistance. Thus, the decrease inspiratory flow that occurs with increasing airway pressure limits the tidal volume delivered and consequently the minute volume. Although newer anesthesia ventilators have increased flow capabilities, they require a fully trained staff.⁸

Potential occupational exposure to these volatile anesthetic gases occurs as patients being treated may exhale considerable amounts of volatile anesthetics.⁸ An anesthesia gas scavenging device, such as a charcoal canister, must be attached to the ventilator to capture the exhaled anesthetic gases and should be changed every 12 hours.⁸ Finally, there is a potential for rebound bronchospasm as the anesthetic agent is tapered.^6,7,9-11

Conclusion

Inhalational anesthetics are an option as rescue therapy for severe life-threatening asthma when all other therapies have failed. Use of inhalational anesthetics in status asthmaticus consists of case reports of which half are in children.^2,5,7 Our patient contributes to the literature of case reports regarding using sevoflurane in refractory status asthmaticus. A decision to choose them must be a collaborative team approach with anesthesiology, pulmonary/critical care medicine, respiratory therapy, and ICU nurses, and the risks and benefits should be discussed with decision-making family members. Since there are no specific guidelines for the use of inhalational agents in status asthmaticus, close attention to inspiratory flows, gas scavenging devices, and clinical response is required. Additionally, the team must be comfortable with the plan to use an anesthesia ventilator and trained on its limitations.

Although solar radiation is the most commonly recognized source of UV radiation (UVR), occupational exposures can contribute due to the intensity and chronicity of exposure. Arc welding is a process whereby metal is fused together by heat produced from an electric arc. The electric arc that forms between the electrode and the base metal emits radiation in the full UV spectrum including UVA (400–315 nm), UVB (315–290 nm), and UVC (290–100 nm) wavelengths. Welders, therefore, have an increased risk for broad-spectrum, intense exposure to UVR, which may play a notable role in UV-related skin disease without proper protection. We report 3 welders with skin disease attributed to occupational exposure to UVR.

Case Reports

Patient 1
A 41-year-old man presented for evaluation of treatment-resistant cutaneous lupus. During the 10-year disease course, the patient was treated by both dermatologists and rheumatologists with frequent exacerbations and poor disease control. At the time of presentation, treatment with hydroxychloroquine 200 mg twice daily, azathioprine 50 mg twice daily, intramuscular methylprednisolone acetateinjectable suspension 40 mg, and prednisone 20 mg daily was failing. Physical examination revealed polycyclic erythematous plaques typical of subacute cutaneous lupus erythematosus. A skin biopsy confirmed the diagnosis. Upon further discussion of exacerbating risk factors, the patient noted UVR exposure while working as a welder. Although he had been previously told to avoid sunlight, he did not realize that this recommendation included all forms of UV light. Once this work exposure was eliminated, he was restarted on hydroxychloroquine 200 mg twice daily and topical steroids, and he responded with complete and sustained clearance of disease. When he returned to welding, utilization of sunscreen and sun-protective clothing enabled him to maintain control of his subacute cutaneous lupus erythematosus on oral hydroxychloroquine 200 mg twice daily and topical steroids.

Patient 2
A 55-year-old man presented with numerous actinic keratoses and persistent erythema in a well-demarcated area involving the forehead, temples, and lateral cheeks but sparing the periorbital area. The patient also experienced UVR exposure from welding (up to 4 to 5 times per week during his career spanning more than 20 years). He cited frequent burns in areas where his protective equipment did not cover his skin. He also reported that he often forgoes wearing protective equipment, even though it is available, and only uses safety goggles due to the extreme heat of the working environment as well as the awkwardness of wearing full protective gear while performing certain aspects of the job.

Patient 3
A 63-year-old man presented with a growth on the left side of the upper forehead. A biopsy revealed a squamous cell carcinoma, keratoacanthoma type. He worked as a welder for 40 years until retiring 1 year prior to presentation. He welded daily and always wore a tall face shield. Although the face shield covered most of his face, the scalp and some parts of the upper face were not well protected. In addition to the keratoacanthoma, which presented just outside of the area protected by the face shield, the patient had numerous actinic keratoses on the scalp.

Comment

Welding and UVR Exposure
Arc welders endure large amounts of UVR exposure, which is substantial enough to have notable health effects. The duration of exposure, electrical current used, angle of exposure, amount of ventilation, and the distance from the welding arc play a role in overall UVR exposure.^1,2 Maximum permissible exposure (MPE) limits to UVR have been set by the International Commission on Non-Ionizing Radiation Protection and the National Institute for Occupational Safety and Health.^3,4 The quantity of radiation produced by the arc allows for an exposure time of only a few seconds to minutes before surpassing MPE to UV light.^1,5 Welders are exposed to total-body UVR doses up to 3000 times the MPE, and mean cumulative exposure calculated over an 8-hour workday can reach 9795 mJ/cm².⁶

Workers in close proximity to welders also receive large UVR doses and may not be aware of its hazardous effects. Nearby nonwelders can be exposed to 13 times the MPE of UVR.⁶ At distances up to 10 m from the arc, the irradiance is large enough to reach MPE to UVR in less than 3 hours.¹

Skin and Eye Damage From Welding
Exposure to UVR produced by the welding arc may lead to acute skin or eye reactions, chronic skin or eye disorders, or exacerbation of photosensitive diseases. Common acute problems are photokeratoconjunctivitis (welder’s flash) and skin erythema.^7,8

Actinic elastosis, actinic keratoses, ocular melanoma, and photosensitive diseases represent a spectrum of disorders that can present from chronic UV exposure in welders. In a study by Emmett et al⁷ of 152 welders and 58 controls, actinic elastosis was found to be more frequent in welders than controls. Cases of basal cell carcinoma and squamous cell carcinoma also have been reported in welders.^9,10 However, in the study by Emmett et al,⁷ a statistically significant correlation between welding and skin cancer was not documented. There were limitations in the study, such as small sample size and a young average age of welders.⁷ Future studies may be needed to further clarify the risk for skin cancer in welders.

Although there is no clear association with skin cancer, an increased risk of ocular melanoma in welders is more clearly established. A meta-analysis of 5 studies found that welding was a significant risk factor for ocular melanoma, with an odds ratio of 2.05 (95% confidence interval, 1.20-3.51).¹¹ Other reported eye damage from chronic UVR exposure includes cataracts, chronic conjunctivitis, and retinal damage.^12,13

Case reports of the following photosensitive diseases have been reported to be exacerbated or caused by UV light exposure in welders: discoid lupus erythematosus¹⁴; photodermatitis¹⁵; broadband photosensitivity with decreased minimal erythema dose to UVA, UVB, and UVC¹⁶; UVC-exacerbated atopic dermatitis¹⁷; polymorphous light eruption–like skin eruption¹⁸; and UVA-induced photoallergy to hydrochlorothiazide and ramipril.¹⁹

Prevention of Occupational Exposure to UVR
Occupational Safety and Health Administration guidelines protect workers from excessive exposure to UVR with personal protective equipment (PPE). In addition to UVR protection, PPE needs to protect welders from other risks including trauma from welding debris (slag), fires, electrical burns, and fumes. Online resources from the National Ag Safety Database,²⁰ the American Welding Society,²¹ and Occupational Safety and Health Administration^22,23 are available. These resources advise welders to work in ventilated areas with respirators specific for the metal being welded and to wear clothing and gloves that are not only fire retardant but also UV resistant.^20-23 Additional PPE should protect the head, face, and eyes.

Unfortunately, even workers well trained in prevention guidelines may not adequately protect themselves. Some welders forego PPE due to heat, thus exposing themselves to UVR damage in areas that are normally covered. Welders also may forego equipment when working on jobs requiring more detailed welds where clothing, masks, and glasses may be overly bulky and inhibit the worker’s precision. Nontraditional welders, such as artisans or handymen, may not have workplace safety education to be aware of UVR emitted from welding and may not have readily available PPE.

The Figure portrays an amateur welder working without full PPE. Although he is wearing a face shield, he is not wearing fire-retardant clothing, lacks full protective garments, and has no ventilation system.

Conclusion

It is important to recognize welding as an occupation with notable exposure to UVR. Personal protective equipment should be the mainstay of prevention. Sunscreen is a useful adjunct but does not cover UVC that is emitted in the welding arc. Screens and welding blankets can be placed around welders to contain UVR and limit nonwelder exposure. Although UVR hazards should be regulated in the workplace as part of regular safety reviews, the clinician can play a role in recognizing this source of UVR in skin disease and in encouraging the use of PPE.

Although solar radiation is the most commonly recognized source of UV radiation (UVR), occupational exposures can contribute due to the intensity and chronicity of exposure. Arc welding is a process whereby metal is fused together by heat produced from an electric arc. The electric arc that forms between the electrode and the base metal emits radiation in the full UV spectrum including UVA (400–315 nm), UVB (315–290 nm), and UVC (290–100 nm) wavelengths. Welders, therefore, have an increased risk for broad-spectrum, intense exposure to UVR, which may play a notable role in UV-related skin disease without proper protection. We report 3 welders with skin disease attributed to occupational exposure to UVR.

Case Reports

Patient 1
A 41-year-old man presented for evaluation of treatment-resistant cutaneous lupus. During the 10-year disease course, the patient was treated by both dermatologists and rheumatologists with frequent exacerbations and poor disease control. At the time of presentation, treatment with hydroxychloroquine 200 mg twice daily, azathioprine 50 mg twice daily, intramuscular methylprednisolone acetateinjectable suspension 40 mg, and prednisone 20 mg daily was failing. Physical examination revealed polycyclic erythematous plaques typical of subacute cutaneous lupus erythematosus. A skin biopsy confirmed the diagnosis. Upon further discussion of exacerbating risk factors, the patient noted UVR exposure while working as a welder. Although he had been previously told to avoid sunlight, he did not realize that this recommendation included all forms of UV light. Once this work exposure was eliminated, he was restarted on hydroxychloroquine 200 mg twice daily and topical steroids, and he responded with complete and sustained clearance of disease. When he returned to welding, utilization of sunscreen and sun-protective clothing enabled him to maintain control of his subacute cutaneous lupus erythematosus on oral hydroxychloroquine 200 mg twice daily and topical steroids.

Patient 2
A 55-year-old man presented with numerous actinic keratoses and persistent erythema in a well-demarcated area involving the forehead, temples, and lateral cheeks but sparing the periorbital area. The patient also experienced UVR exposure from welding (up to 4 to 5 times per week during his career spanning more than 20 years). He cited frequent burns in areas where his protective equipment did not cover his skin. He also reported that he often forgoes wearing protective equipment, even though it is available, and only uses safety goggles due to the extreme heat of the working environment as well as the awkwardness of wearing full protective gear while performing certain aspects of the job.

Patient 3
A 63-year-old man presented with a growth on the left side of the upper forehead. A biopsy revealed a squamous cell carcinoma, keratoacanthoma type. He worked as a welder for 40 years until retiring 1 year prior to presentation. He welded daily and always wore a tall face shield. Although the face shield covered most of his face, the scalp and some parts of the upper face were not well protected. In addition to the keratoacanthoma, which presented just outside of the area protected by the face shield, the patient had numerous actinic keratoses on the scalp.

Comment

Welding and UVR Exposure
Arc welders endure large amounts of UVR exposure, which is substantial enough to have notable health effects. The duration of exposure, electrical current used, angle of exposure, amount of ventilation, and the distance from the welding arc play a role in overall UVR exposure.^1,2 Maximum permissible exposure (MPE) limits to UVR have been set by the International Commission on Non-Ionizing Radiation Protection and the National Institute for Occupational Safety and Health.^3,4 The quantity of radiation produced by the arc allows for an exposure time of only a few seconds to minutes before surpassing MPE to UV light.^1,5 Welders are exposed to total-body UVR doses up to 3000 times the MPE, and mean cumulative exposure calculated over an 8-hour workday can reach 9795 mJ/cm².⁶

Workers in close proximity to welders also receive large UVR doses and may not be aware of its hazardous effects. Nearby nonwelders can be exposed to 13 times the MPE of UVR.⁶ At distances up to 10 m from the arc, the irradiance is large enough to reach MPE to UVR in less than 3 hours.¹

Skin and Eye Damage From Welding
Exposure to UVR produced by the welding arc may lead to acute skin or eye reactions, chronic skin or eye disorders, or exacerbation of photosensitive diseases. Common acute problems are photokeratoconjunctivitis (welder’s flash) and skin erythema.^7,8

Actinic elastosis, actinic keratoses, ocular melanoma, and photosensitive diseases represent a spectrum of disorders that can present from chronic UV exposure in welders. In a study by Emmett et al⁷ of 152 welders and 58 controls, actinic elastosis was found to be more frequent in welders than controls. Cases of basal cell carcinoma and squamous cell carcinoma also have been reported in welders.^9,10 However, in the study by Emmett et al,⁷ a statistically significant correlation between welding and skin cancer was not documented. There were limitations in the study, such as small sample size and a young average age of welders.⁷ Future studies may be needed to further clarify the risk for skin cancer in welders.

Although there is no clear association with skin cancer, an increased risk of ocular melanoma in welders is more clearly established. A meta-analysis of 5 studies found that welding was a significant risk factor for ocular melanoma, with an odds ratio of 2.05 (95% confidence interval, 1.20-3.51).¹¹ Other reported eye damage from chronic UVR exposure includes cataracts, chronic conjunctivitis, and retinal damage.^12,13

Case reports of the following photosensitive diseases have been reported to be exacerbated or caused by UV light exposure in welders: discoid lupus erythematosus¹⁴; photodermatitis¹⁵; broadband photosensitivity with decreased minimal erythema dose to UVA, UVB, and UVC¹⁶; UVC-exacerbated atopic dermatitis¹⁷; polymorphous light eruption–like skin eruption¹⁸; and UVA-induced photoallergy to hydrochlorothiazide and ramipril.¹⁹

Prevention of Occupational Exposure to UVR
Occupational Safety and Health Administration guidelines protect workers from excessive exposure to UVR with personal protective equipment (PPE). In addition to UVR protection, PPE needs to protect welders from other risks including trauma from welding debris (slag), fires, electrical burns, and fumes. Online resources from the National Ag Safety Database,²⁰ the American Welding Society,²¹ and Occupational Safety and Health Administration^22,23 are available. These resources advise welders to work in ventilated areas with respirators specific for the metal being welded and to wear clothing and gloves that are not only fire retardant but also UV resistant.^20-23 Additional PPE should protect the head, face, and eyes.

Unfortunately, even workers well trained in prevention guidelines may not adequately protect themselves. Some welders forego PPE due to heat, thus exposing themselves to UVR damage in areas that are normally covered. Welders also may forego equipment when working on jobs requiring more detailed welds where clothing, masks, and glasses may be overly bulky and inhibit the worker’s precision. Nontraditional welders, such as artisans or handymen, may not have workplace safety education to be aware of UVR emitted from welding and may not have readily available PPE.

The Figure portrays an amateur welder working without full PPE. Although he is wearing a face shield, he is not wearing fire-retardant clothing, lacks full protective garments, and has no ventilation system.

Conclusion

It is important to recognize welding as an occupation with notable exposure to UVR. Personal protective equipment should be the mainstay of prevention. Sunscreen is a useful adjunct but does not cover UVC that is emitted in the welding arc. Screens and welding blankets can be placed around welders to contain UVR and limit nonwelder exposure. Although UVR hazards should be regulated in the workplace as part of regular safety reviews, the clinician can play a role in recognizing this source of UVR in skin disease and in encouraging the use of PPE.

Although solar radiation is the most commonly recognized source of UV radiation (UVR), occupational exposures can contribute due to the intensity and chronicity of exposure. Arc welding is a process whereby metal is fused together by heat produced from an electric arc. The electric arc that forms between the electrode and the base metal emits radiation in the full UV spectrum including UVA (400–315 nm), UVB (315–290 nm), and UVC (290–100 nm) wavelengths. Welders, therefore, have an increased risk for broad-spectrum, intense exposure to UVR, which may play a notable role in UV-related skin disease without proper protection. We report 3 welders with skin disease attributed to occupational exposure to UVR.

Case Reports

Patient 1
A 41-year-old man presented for evaluation of treatment-resistant cutaneous lupus. During the 10-year disease course, the patient was treated by both dermatologists and rheumatologists with frequent exacerbations and poor disease control. At the time of presentation, treatment with hydroxychloroquine 200 mg twice daily, azathioprine 50 mg twice daily, intramuscular methylprednisolone acetateinjectable suspension 40 mg, and prednisone 20 mg daily was failing. Physical examination revealed polycyclic erythematous plaques typical of subacute cutaneous lupus erythematosus. A skin biopsy confirmed the diagnosis. Upon further discussion of exacerbating risk factors, the patient noted UVR exposure while working as a welder. Although he had been previously told to avoid sunlight, he did not realize that this recommendation included all forms of UV light. Once this work exposure was eliminated, he was restarted on hydroxychloroquine 200 mg twice daily and topical steroids, and he responded with complete and sustained clearance of disease. When he returned to welding, utilization of sunscreen and sun-protective clothing enabled him to maintain control of his subacute cutaneous lupus erythematosus on oral hydroxychloroquine 200 mg twice daily and topical steroids.

Patient 2
A 55-year-old man presented with numerous actinic keratoses and persistent erythema in a well-demarcated area involving the forehead, temples, and lateral cheeks but sparing the periorbital area. The patient also experienced UVR exposure from welding (up to 4 to 5 times per week during his career spanning more than 20 years). He cited frequent burns in areas where his protective equipment did not cover his skin. He also reported that he often forgoes wearing protective equipment, even though it is available, and only uses safety goggles due to the extreme heat of the working environment as well as the awkwardness of wearing full protective gear while performing certain aspects of the job.

Patient 3
A 63-year-old man presented with a growth on the left side of the upper forehead. A biopsy revealed a squamous cell carcinoma, keratoacanthoma type. He worked as a welder for 40 years until retiring 1 year prior to presentation. He welded daily and always wore a tall face shield. Although the face shield covered most of his face, the scalp and some parts of the upper face were not well protected. In addition to the keratoacanthoma, which presented just outside of the area protected by the face shield, the patient had numerous actinic keratoses on the scalp.

Comment

Welding and UVR Exposure
Arc welders endure large amounts of UVR exposure, which is substantial enough to have notable health effects. The duration of exposure, electrical current used, angle of exposure, amount of ventilation, and the distance from the welding arc play a role in overall UVR exposure.^1,2 Maximum permissible exposure (MPE) limits to UVR have been set by the International Commission on Non-Ionizing Radiation Protection and the National Institute for Occupational Safety and Health.^3,4 The quantity of radiation produced by the arc allows for an exposure time of only a few seconds to minutes before surpassing MPE to UV light.^1,5 Welders are exposed to total-body UVR doses up to 3000 times the MPE, and mean cumulative exposure calculated over an 8-hour workday can reach 9795 mJ/cm².⁶

Workers in close proximity to welders also receive large UVR doses and may not be aware of its hazardous effects. Nearby nonwelders can be exposed to 13 times the MPE of UVR.⁶ At distances up to 10 m from the arc, the irradiance is large enough to reach MPE to UVR in less than 3 hours.¹

Skin and Eye Damage From Welding
Exposure to UVR produced by the welding arc may lead to acute skin or eye reactions, chronic skin or eye disorders, or exacerbation of photosensitive diseases. Common acute problems are photokeratoconjunctivitis (welder’s flash) and skin erythema.^7,8

Actinic elastosis, actinic keratoses, ocular melanoma, and photosensitive diseases represent a spectrum of disorders that can present from chronic UV exposure in welders. In a study by Emmett et al⁷ of 152 welders and 58 controls, actinic elastosis was found to be more frequent in welders than controls. Cases of basal cell carcinoma and squamous cell carcinoma also have been reported in welders.^9,10 However, in the study by Emmett et al,⁷ a statistically significant correlation between welding and skin cancer was not documented. There were limitations in the study, such as small sample size and a young average age of welders.⁷ Future studies may be needed to further clarify the risk for skin cancer in welders.

Although there is no clear association with skin cancer, an increased risk of ocular melanoma in welders is more clearly established. A meta-analysis of 5 studies found that welding was a significant risk factor for ocular melanoma, with an odds ratio of 2.05 (95% confidence interval, 1.20-3.51).¹¹ Other reported eye damage from chronic UVR exposure includes cataracts, chronic conjunctivitis, and retinal damage.^12,13

Case reports of the following photosensitive diseases have been reported to be exacerbated or caused by UV light exposure in welders: discoid lupus erythematosus¹⁴; photodermatitis¹⁵; broadband photosensitivity with decreased minimal erythema dose to UVA, UVB, and UVC¹⁶; UVC-exacerbated atopic dermatitis¹⁷; polymorphous light eruption–like skin eruption¹⁸; and UVA-induced photoallergy to hydrochlorothiazide and ramipril.¹⁹

Prevention of Occupational Exposure to UVR
Occupational Safety and Health Administration guidelines protect workers from excessive exposure to UVR with personal protective equipment (PPE). In addition to UVR protection, PPE needs to protect welders from other risks including trauma from welding debris (slag), fires, electrical burns, and fumes. Online resources from the National Ag Safety Database,²⁰ the American Welding Society,²¹ and Occupational Safety and Health Administration^22,23 are available. These resources advise welders to work in ventilated areas with respirators specific for the metal being welded and to wear clothing and gloves that are not only fire retardant but also UV resistant.^20-23 Additional PPE should protect the head, face, and eyes.

Unfortunately, even workers well trained in prevention guidelines may not adequately protect themselves. Some welders forego PPE due to heat, thus exposing themselves to UVR damage in areas that are normally covered. Welders also may forego equipment when working on jobs requiring more detailed welds where clothing, masks, and glasses may be overly bulky and inhibit the worker’s precision. Nontraditional welders, such as artisans or handymen, may not have workplace safety education to be aware of UVR emitted from welding and may not have readily available PPE.

The Figure portrays an amateur welder working without full PPE. Although he is wearing a face shield, he is not wearing fire-retardant clothing, lacks full protective garments, and has no ventilation system.

Conclusion

It is important to recognize welding as an occupation with notable exposure to UVR. Personal protective equipment should be the mainstay of prevention. Sunscreen is a useful adjunct but does not cover UVC that is emitted in the welding arc. Screens and welding blankets can be placed around welders to contain UVR and limit nonwelder exposure. Although UVR hazards should be regulated in the workplace as part of regular safety reviews, the clinician can play a role in recognizing this source of UVR in skin disease and in encouraging the use of PPE.

The expanded use of targeted anticancer agents such as sorafenib has revealed a growing spectrum of adverse cutaneous eruptions. We describe 3 patients with sorafenib-induced psoriasiform dermatitis and review the literature of only 10 other similar reported cases based on a search of PubMed, Web of Science, and American Society of Clinical Oncology abstracts using the terms psoriasis or psoriasiform dermatitis and sorafenib.^1-10 We seek to increase awareness of this particular drug eruption in response to sorafenib and to describe potential effective treatment options, especially when sorafenib cannot be discontinued.

Case Reports

Patient 1
A 68-year-old man with chronic hepatitis B infection and hepatocellular carcinoma (HCC) was started on sorafenib 400 mg daily. After 2 months of treatment, he developed painful hyperkeratotic lesions on the bilateral palms and soles with formation of calluses and superficial blisters on an erythematous base that was consistent with hand-foot skin reaction (HFSR). He also had numerous erythematous thin papules and plaques with adherent white scale and yellow crust on the bilateral thighs, lower legs, forearms, dorsal hands, abdomen, back, and buttocks (Figure 1). He had no personal or family history of psoriasis, and blood tests were unremarkable. Histologic analysis of punch biopsies from the buttocks and right leg revealed focal parakeratosis with neutrophils and serous crust, acanthosis, mild spongiosis, and lymphocytes at the dermoepidermal junction and surrounding dermal vessels, consistent with psoriasiform dermatitis (Figure 2). Sorafenib was discontinued and the eruption began to resolve within a week. A lower dose of sorafenib (200 mg daily) was attempted and the psoriasiform eruption recurred.

Patient 2
An 82-year-old man with chronic hepatitis B infection and HCC with lung metastasis was treated with sorafenib 400 mg daily. One week after treatment, he developed painful, thick, erythematous lesions on acral surfaces, consistent with HFSR. The sorafenib dose was decreased to 200 mg daily and HFSR resolved. Four months later, he developed well-demarcated, erythematous, scaly plaques with peripheral pustules on the right thigh (Figure 3) and right shin. He had no personal or family history of psoriasis, and blood tests were unremarkable. Samples from the pustules were taken for bacterial culture and fungal stain, but both were negative. Histologic analysis of a punch biopsy from the right thigh revealed necrotic parakeratosis, spongiform pustules, mild acanthosis, and a perivascular lymphocytic infiltrate with many neutrophils in the dermis. These findings suggested a diagnosis of pustular psoriasis, pustular drug eruption, or acute generalized exanthematous pustulosis. Treatment was initiated with mometasone cream. The patient subsequently developed hemoptysis and ascites from sorafenib. Sorafenib was discontinued and his skin eruption gradually resolved.

Comment

Sorafenib is an oral tyrosine kinase inhibitor that blocks tumor cell proliferation and angiogenesis due to its activity against vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, stem cell growth factor receptor, and rapidly accelerated fibrosarcoma kinases.¹¹ It is primarily used for the treatment of solid tumors, such as advanced renal cell carcinoma, unresectable HCC, and thyroid carcinoma, and more recently has been expanded for treatment of AML due to potential inhibition of FMS-like tyrosine kinase 3 receptor. Although dermatologic toxicity is a common adverse event during treatment with sorafenib,¹¹ reports of psoriasiform drug eruptions are rare.

Review of Cases
Based on our literature search, there are 10 previously reported cases of psoriasiform drug eruption secondary to sorafenib. Of the 13 total cases (including the 3 patients in this report), 7 patients had a history of psoriasis; most were middle-aged men; and the treatment with sorafenib was for solid tumors, primarily HCC with the exception of patient 3 from the current report who was treated for AML (Table). In all cases, the dose of sorafenib ranged from 200 to 800 mg daily. In 5 cases, HFSR preceded (as with patient 2 in the current report) or presented concurrently (as with patient 1 in the current report) with the onset of psoriasiform rash.^1,3,5

Vascular endothelial growth factor is overexpressed on psoriatic keratinocytes, contributes to epidermal hyperplasia, and induces angiogenesis in the dermis.¹² The development of psoriasiform eruptions in patients treated with sorafenib seems paradoxical, as this drug has been considered as potential therapy for psoriasis due to its ability to block VEGF receptor signaling. Indeed, an improvement of psoriasis has been reported in 1 case of a patient treated with sorafenib¹³ and in multiple patients with psoriasis treated with other VEGF antagonists (eg, bevacizumab).¹⁴ The underlying mechanisms by which sorafenib induced or exacerbated psoriasis are not entirely clear. Palmoplantar hyperkeratosis, keratosis pilaris–like eruption, multiple cysts, eruptive keratoacanthomas, and squamous cell carcinoma have been described in patients treated with sorafenib, supporting the hypothesis that treatment with sorafenib alters keratinocyte proliferation and differentiation.¹⁵ In addition, B-Raf inhibitors such as imatinib are known to induce or exacerbate psoriasiform dermatitis.¹⁶ The activity of sorafenib resulting in psoriasis may be specific to RAF kinase inhibition, as there are no reports in the literature that describe psoriasiform dermatitis with agents that preferentially block other sorafenib targets such as VEGF receptor, stem cell growth factor receptor, or platelet-derived growth factor receptor. Future studies are needed to fully elucidate the underlying mechanisms by which sorafenib induces or exacerbates psoriasiform dermatitis and whether the severity of the drug eruption correlates with the antitumor efficacy of sorafenib.

Conclusion

Although psoriasiform drug eruptions secondary to sorafenib are not life-threatening, they impact quality of life with associated pain, pruritus, infection, and limitation of daily activities. Dose reduction or discontinuation of sorafenib resulted in resolution of the psoriasiform dermatitis; however, as demonstrated in 3 cases (including patient 3),^1,2 psoriasiform dermatitis can be managed while maintaining the patient on sorafenib so that treatment of the malignancy is not compromised.

The expanded use of targeted anticancer agents such as sorafenib has revealed a growing spectrum of adverse cutaneous eruptions. We describe 3 patients with sorafenib-induced psoriasiform dermatitis and review the literature of only 10 other similar reported cases based on a search of PubMed, Web of Science, and American Society of Clinical Oncology abstracts using the terms psoriasis or psoriasiform dermatitis and sorafenib.^1-10 We seek to increase awareness of this particular drug eruption in response to sorafenib and to describe potential effective treatment options, especially when sorafenib cannot be discontinued.

Case Reports

Patient 1
A 68-year-old man with chronic hepatitis B infection and hepatocellular carcinoma (HCC) was started on sorafenib 400 mg daily. After 2 months of treatment, he developed painful hyperkeratotic lesions on the bilateral palms and soles with formation of calluses and superficial blisters on an erythematous base that was consistent with hand-foot skin reaction (HFSR). He also had numerous erythematous thin papules and plaques with adherent white scale and yellow crust on the bilateral thighs, lower legs, forearms, dorsal hands, abdomen, back, and buttocks (Figure 1). He had no personal or family history of psoriasis, and blood tests were unremarkable. Histologic analysis of punch biopsies from the buttocks and right leg revealed focal parakeratosis with neutrophils and serous crust, acanthosis, mild spongiosis, and lymphocytes at the dermoepidermal junction and surrounding dermal vessels, consistent with psoriasiform dermatitis (Figure 2). Sorafenib was discontinued and the eruption began to resolve within a week. A lower dose of sorafenib (200 mg daily) was attempted and the psoriasiform eruption recurred.

Patient 2
An 82-year-old man with chronic hepatitis B infection and HCC with lung metastasis was treated with sorafenib 400 mg daily. One week after treatment, he developed painful, thick, erythematous lesions on acral surfaces, consistent with HFSR. The sorafenib dose was decreased to 200 mg daily and HFSR resolved. Four months later, he developed well-demarcated, erythematous, scaly plaques with peripheral pustules on the right thigh (Figure 3) and right shin. He had no personal or family history of psoriasis, and blood tests were unremarkable. Samples from the pustules were taken for bacterial culture and fungal stain, but both were negative. Histologic analysis of a punch biopsy from the right thigh revealed necrotic parakeratosis, spongiform pustules, mild acanthosis, and a perivascular lymphocytic infiltrate with many neutrophils in the dermis. These findings suggested a diagnosis of pustular psoriasis, pustular drug eruption, or acute generalized exanthematous pustulosis. Treatment was initiated with mometasone cream. The patient subsequently developed hemoptysis and ascites from sorafenib. Sorafenib was discontinued and his skin eruption gradually resolved.

Comment

Sorafenib is an oral tyrosine kinase inhibitor that blocks tumor cell proliferation and angiogenesis due to its activity against vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, stem cell growth factor receptor, and rapidly accelerated fibrosarcoma kinases.¹¹ It is primarily used for the treatment of solid tumors, such as advanced renal cell carcinoma, unresectable HCC, and thyroid carcinoma, and more recently has been expanded for treatment of AML due to potential inhibition of FMS-like tyrosine kinase 3 receptor. Although dermatologic toxicity is a common adverse event during treatment with sorafenib,¹¹ reports of psoriasiform drug eruptions are rare.

Review of Cases
Based on our literature search, there are 10 previously reported cases of psoriasiform drug eruption secondary to sorafenib. Of the 13 total cases (including the 3 patients in this report), 7 patients had a history of psoriasis; most were middle-aged men; and the treatment with sorafenib was for solid tumors, primarily HCC with the exception of patient 3 from the current report who was treated for AML (Table). In all cases, the dose of sorafenib ranged from 200 to 800 mg daily. In 5 cases, HFSR preceded (as with patient 2 in the current report) or presented concurrently (as with patient 1 in the current report) with the onset of psoriasiform rash.^1,3,5

Vascular endothelial growth factor is overexpressed on psoriatic keratinocytes, contributes to epidermal hyperplasia, and induces angiogenesis in the dermis.¹² The development of psoriasiform eruptions in patients treated with sorafenib seems paradoxical, as this drug has been considered as potential therapy for psoriasis due to its ability to block VEGF receptor signaling. Indeed, an improvement of psoriasis has been reported in 1 case of a patient treated with sorafenib¹³ and in multiple patients with psoriasis treated with other VEGF antagonists (eg, bevacizumab).¹⁴ The underlying mechanisms by which sorafenib induced or exacerbated psoriasis are not entirely clear. Palmoplantar hyperkeratosis, keratosis pilaris–like eruption, multiple cysts, eruptive keratoacanthomas, and squamous cell carcinoma have been described in patients treated with sorafenib, supporting the hypothesis that treatment with sorafenib alters keratinocyte proliferation and differentiation.¹⁵ In addition, B-Raf inhibitors such as imatinib are known to induce or exacerbate psoriasiform dermatitis.¹⁶ The activity of sorafenib resulting in psoriasis may be specific to RAF kinase inhibition, as there are no reports in the literature that describe psoriasiform dermatitis with agents that preferentially block other sorafenib targets such as VEGF receptor, stem cell growth factor receptor, or platelet-derived growth factor receptor. Future studies are needed to fully elucidate the underlying mechanisms by which sorafenib induces or exacerbates psoriasiform dermatitis and whether the severity of the drug eruption correlates with the antitumor efficacy of sorafenib.

Conclusion

Although psoriasiform drug eruptions secondary to sorafenib are not life-threatening, they impact quality of life with associated pain, pruritus, infection, and limitation of daily activities. Dose reduction or discontinuation of sorafenib resulted in resolution of the psoriasiform dermatitis; however, as demonstrated in 3 cases (including patient 3),^1,2 psoriasiform dermatitis can be managed while maintaining the patient on sorafenib so that treatment of the malignancy is not compromised.

The expanded use of targeted anticancer agents such as sorafenib has revealed a growing spectrum of adverse cutaneous eruptions. We describe 3 patients with sorafenib-induced psoriasiform dermatitis and review the literature of only 10 other similar reported cases based on a search of PubMed, Web of Science, and American Society of Clinical Oncology abstracts using the terms psoriasis or psoriasiform dermatitis and sorafenib.^1-10 We seek to increase awareness of this particular drug eruption in response to sorafenib and to describe potential effective treatment options, especially when sorafenib cannot be discontinued.

Case Reports

Patient 1
A 68-year-old man with chronic hepatitis B infection and hepatocellular carcinoma (HCC) was started on sorafenib 400 mg daily. After 2 months of treatment, he developed painful hyperkeratotic lesions on the bilateral palms and soles with formation of calluses and superficial blisters on an erythematous base that was consistent with hand-foot skin reaction (HFSR). He also had numerous erythematous thin papules and plaques with adherent white scale and yellow crust on the bilateral thighs, lower legs, forearms, dorsal hands, abdomen, back, and buttocks (Figure 1). He had no personal or family history of psoriasis, and blood tests were unremarkable. Histologic analysis of punch biopsies from the buttocks and right leg revealed focal parakeratosis with neutrophils and serous crust, acanthosis, mild spongiosis, and lymphocytes at the dermoepidermal junction and surrounding dermal vessels, consistent with psoriasiform dermatitis (Figure 2). Sorafenib was discontinued and the eruption began to resolve within a week. A lower dose of sorafenib (200 mg daily) was attempted and the psoriasiform eruption recurred.

Patient 2
An 82-year-old man with chronic hepatitis B infection and HCC with lung metastasis was treated with sorafenib 400 mg daily. One week after treatment, he developed painful, thick, erythematous lesions on acral surfaces, consistent with HFSR. The sorafenib dose was decreased to 200 mg daily and HFSR resolved. Four months later, he developed well-demarcated, erythematous, scaly plaques with peripheral pustules on the right thigh (Figure 3) and right shin. He had no personal or family history of psoriasis, and blood tests were unremarkable. Samples from the pustules were taken for bacterial culture and fungal stain, but both were negative. Histologic analysis of a punch biopsy from the right thigh revealed necrotic parakeratosis, spongiform pustules, mild acanthosis, and a perivascular lymphocytic infiltrate with many neutrophils in the dermis. These findings suggested a diagnosis of pustular psoriasis, pustular drug eruption, or acute generalized exanthematous pustulosis. Treatment was initiated with mometasone cream. The patient subsequently developed hemoptysis and ascites from sorafenib. Sorafenib was discontinued and his skin eruption gradually resolved.

Comment

Sorafenib is an oral tyrosine kinase inhibitor that blocks tumor cell proliferation and angiogenesis due to its activity against vascular endothelial growth factor (VEGF) receptor, platelet-derived growth factor receptor, stem cell growth factor receptor, and rapidly accelerated fibrosarcoma kinases.¹¹ It is primarily used for the treatment of solid tumors, such as advanced renal cell carcinoma, unresectable HCC, and thyroid carcinoma, and more recently has been expanded for treatment of AML due to potential inhibition of FMS-like tyrosine kinase 3 receptor. Although dermatologic toxicity is a common adverse event during treatment with sorafenib,¹¹ reports of psoriasiform drug eruptions are rare.

Review of Cases
Based on our literature search, there are 10 previously reported cases of psoriasiform drug eruption secondary to sorafenib. Of the 13 total cases (including the 3 patients in this report), 7 patients had a history of psoriasis; most were middle-aged men; and the treatment with sorafenib was for solid tumors, primarily HCC with the exception of patient 3 from the current report who was treated for AML (Table). In all cases, the dose of sorafenib ranged from 200 to 800 mg daily. In 5 cases, HFSR preceded (as with patient 2 in the current report) or presented concurrently (as with patient 1 in the current report) with the onset of psoriasiform rash.^1,3,5

Vascular endothelial growth factor is overexpressed on psoriatic keratinocytes, contributes to epidermal hyperplasia, and induces angiogenesis in the dermis.¹² The development of psoriasiform eruptions in patients treated with sorafenib seems paradoxical, as this drug has been considered as potential therapy for psoriasis due to its ability to block VEGF receptor signaling. Indeed, an improvement of psoriasis has been reported in 1 case of a patient treated with sorafenib¹³ and in multiple patients with psoriasis treated with other VEGF antagonists (eg, bevacizumab).¹⁴ The underlying mechanisms by which sorafenib induced or exacerbated psoriasis are not entirely clear. Palmoplantar hyperkeratosis, keratosis pilaris–like eruption, multiple cysts, eruptive keratoacanthomas, and squamous cell carcinoma have been described in patients treated with sorafenib, supporting the hypothesis that treatment with sorafenib alters keratinocyte proliferation and differentiation.¹⁵ In addition, B-Raf inhibitors such as imatinib are known to induce or exacerbate psoriasiform dermatitis.¹⁶ The activity of sorafenib resulting in psoriasis may be specific to RAF kinase inhibition, as there are no reports in the literature that describe psoriasiform dermatitis with agents that preferentially block other sorafenib targets such as VEGF receptor, stem cell growth factor receptor, or platelet-derived growth factor receptor. Future studies are needed to fully elucidate the underlying mechanisms by which sorafenib induces or exacerbates psoriasiform dermatitis and whether the severity of the drug eruption correlates with the antitumor efficacy of sorafenib.

Conclusion

Although psoriasiform drug eruptions secondary to sorafenib are not life-threatening, they impact quality of life with associated pain, pruritus, infection, and limitation of daily activities. Dose reduction or discontinuation of sorafenib resulted in resolution of the psoriasiform dermatitis; however, as demonstrated in 3 cases (including patient 3),^1,2 psoriasiform dermatitis can be managed while maintaining the patient on sorafenib so that treatment of the malignancy is not compromised.

Spindle cell sarcomas are part of a rare, heterogeneous family of connective tissue tumors. These tumors are primarily treated with surgery and have a high risk of recurrence and distant metastasis with elevated mortality rates.¹ Other than the evidence for first-line therapy with doxorubicin in advanced soft tissue sarcoma, little evidence exists to point to an optimal second-line therapy. This is due to the diversity of soft tissue sarcomas, which encompass approximately 70 different histologic subtypes that can each respond differently to treatment.² As such, newer strategies, including immunotherapy and targeted molecular drugs, are being developed.

Quiescent in most adult tissues, the Hedgehog signaling pathway, when inappropriately activated, has been implicated in the development of multiple types of cancers, including basal cell, breast, prostate, hepatocellular, pancreatic, and brain cancer.³ The Hedgehog signaling pathway is an important regulator of cell growth and differentiation in early development, but when inappropriately activated can lead to cell proliferation and increased angiogenic factors, decreased apoptosis, and breakdown of tight junctions promoting cancer growth and metastasis.⁴ Recent data reveal that the Hedgehog pathway plays a specific role in activation of satellite cells, proliferation of myoblasts, and differentiation of skeletal muscle.⁵ Activation of this embryonic pathway has been implicated in embryonal rhabdoymyosarcoma, osteosarcoma, and chondrosarcoma.^5-7

This pathway has recently been recognized as a therapeutic target, with the development of vismodegib, a targeted Hedgehog pathway inhibitor. This novel agent is in active use for treatment of advanced basal cell carcinoma and is currently undergoing trials for various other malignancies. Recently, a phase 2a basket study, called MyPathway, evaluated the use of targeted therapies in 35 different advanced refractory solid tumors harboring specific molecular alterations. Out of 21 patients with mutations in the Hedgehog pathway, 3 had a partial response to vismodegib—one had an unknown primary tumor, another a squamous skin cancer, and the third a salivary gland cancer.⁸ Vismodegib (GDC-0449) was also evaluated in a phase 2 multicenter clinical trial in patients with progressive advanced chondrosarcoma.7 Although the study did not meet its primary endpoint, the proportion of patients with non-progressive disease was 25.6% at 6 months. Investigators observed that the benefit occurred in the subset of patients with overexpression of the Hedgehog ligand. Genomic studies for mutations in SMO and PTCH genes were available for only 28 and 26 patients, respectively, of the 45 patients enrolled on the trial. While there were no mutations identified, expression data revealed that overexpression of the Hedgehog ligand was present in 65% of cases tested (13 out of 20 patients). In patients with stable disease at 6 months, all had overexpression of the Hedgehog ligand.⁷ These studies point to the potential use of vismodegib in both bone and soft tissue sarcomas, and more specifically, to the importance of genomic testing in these cases.

Case Presentation and Summary

This report describes the novel use of vismodegib, an oral Hedgehog signaling pathway inhibitor, in the treatment of a patient with metastatic soft tissue sarcoma.

An 18-year-old female with no particular previous illnesses was initially diagnosed with superficial soft tissue sarcoma overlying the right hip in 2013. Due to the complexity of pathology, a second opinion was requested and revealed atypical cellular spindle and epithelioid cells, morphologically and immunohistochemically suggestive of spindle cell sarcoma, not otherwise specified. She underwent negative-margin resection in January 2014. Her course was complicated by two recurrences in the right inguinal lymph nodes in July 2014 and July 2015. She was treated with lymph node dissection in 2014, followed by numerous right lymph node dissections and adjuvant radiation in 2015.

A routine computerized tomography (CT) scan of the thorax-abdomen and pelvis in August 2016 revealed recurrence of disease, with multiple lung nodules as well as metastases in the retroperitoneum. She received 6 cycles of gemcitabine and docetaxel with stability of disease. The patient was then started on a PI3K inhibitor as part of a clinical trial, as genotypic analysis of the tumor revealed an activating mutation of the PI3K gene. The patient’s course was complicated by acute obstructive renal failure requiring a double J stent for right-sided hydronephrosis.

Repeat imaging revealed disease progression, and the patient was then switched to liposomal doxorubicin alone for 4 months and then in combination with olaratumab. She received the combined treatment for a total of 3 months, which was then stopped when she was found to have new peritoneal implants and worsening ascites. At this time, tissue was sent for FoundationOne® next generation sequencing (NGS)-based genomic testing, and the patient received one dose of nivolumab.

In January 2018, 2 days after receiving her first dose of nivolumab, the patient required admission for worsening abdominal pain secondary to progression of her disease (FIGURE 1). She was found to have acute kidney injury on top of chronic kidney disease due to hydronephrosis requiring a left-sided double J stent. She also had transaminitis resulting from a common bile duct stricture treated with a biliary stent and worsening ascites requiring regular paracentesis. This was all in the context of new or growing metastatic implants.

At this time, the result of the FoundationOne genomic testing revealed PTCH1 loss of exons 1-24 and CDKN2A/B loss. Mutation of tumor suppressor gene PTCH1 leads to Hedgehog pathway activation and therefore the patient was started on vismodegib on January 22, 2018. She was discharged from the hospital in stable condition a day later, on January 23.

The patient’s clinical status subsequently improved, with significant reduction in her chronic abdominal pain and very minimal side effects. Clinically, the patient’s acute kidney injury resolved (from a creatinine of 272 μmol/L at discharge to 85 μmol/L after a week of treatment) and her liver enzymes normalized (from an alkaline phosphatase of 301 U/L to 83 U/L, and alanine transaminase of 111 U/L to 38 U/L). CT scan of her chest and abdomen, which was performed 1 month post treatment, revealed stability of disease with absence of ascites (FIGURE 2). The patient continued to have a good response to treatment for 6 months, with no recurrence of pain or ascites.

Six months later, in July 2018, the patient developed increasing pain and a CT scan revealed worsening of abdominopelvic carcinomatosis. In this context, vismodegib was discontinued on July 17. In the next 5 months, she went on to receive carboplatin and paclitaxel, gemcitabine, and nivolumab consecutively with no response. She was admitted to hospital on December 30 for a pain crisis. She passed away on January 9, 2019, from fecal peritonitis.

Discussion

To the best of our knowledge, this is the first patient with metastatic sarcoma to receive vismodegib, a Hedgehog signaling pathway inhibitor. She achieved an excellent clinical response with progression- free disease for approximately 6 months after starting treatment.

There is no current standard second- line treatment for metastatic soft tissue sarcoma. The choice of systemic therapy is histology-driven and therefore treatment is individualized for each patient. The future of oncology is heading towards an even more personalized approach with molecular profiling. Our case report highlights the relevance of genomic testing and targeted therapies, especially in cases of diverse clinical and biological disease behavior.

Molecular targeting is even more necessary in patients with advanced cancer who have failed multiple lines of treatment. As in our study, these patients can obtain a significant response with meaningful improvement in their quality of life. Future research is currently focusing on identifying new molecular targets in patients with advanced refractory cancers. Further studies will need to be done to determine whether these molecular targeting agents, such as vismodegib, lead to significant outcome changes in these patients.

Spindle cell sarcomas are part of a rare, heterogeneous family of connective tissue tumors. These tumors are primarily treated with surgery and have a high risk of recurrence and distant metastasis with elevated mortality rates.¹ Other than the evidence for first-line therapy with doxorubicin in advanced soft tissue sarcoma, little evidence exists to point to an optimal second-line therapy. This is due to the diversity of soft tissue sarcomas, which encompass approximately 70 different histologic subtypes that can each respond differently to treatment.² As such, newer strategies, including immunotherapy and targeted molecular drugs, are being developed.

Quiescent in most adult tissues, the Hedgehog signaling pathway, when inappropriately activated, has been implicated in the development of multiple types of cancers, including basal cell, breast, prostate, hepatocellular, pancreatic, and brain cancer.³ The Hedgehog signaling pathway is an important regulator of cell growth and differentiation in early development, but when inappropriately activated can lead to cell proliferation and increased angiogenic factors, decreased apoptosis, and breakdown of tight junctions promoting cancer growth and metastasis.⁴ Recent data reveal that the Hedgehog pathway plays a specific role in activation of satellite cells, proliferation of myoblasts, and differentiation of skeletal muscle.⁵ Activation of this embryonic pathway has been implicated in embryonal rhabdoymyosarcoma, osteosarcoma, and chondrosarcoma.^5-7

This pathway has recently been recognized as a therapeutic target, with the development of vismodegib, a targeted Hedgehog pathway inhibitor. This novel agent is in active use for treatment of advanced basal cell carcinoma and is currently undergoing trials for various other malignancies. Recently, a phase 2a basket study, called MyPathway, evaluated the use of targeted therapies in 35 different advanced refractory solid tumors harboring specific molecular alterations. Out of 21 patients with mutations in the Hedgehog pathway, 3 had a partial response to vismodegib—one had an unknown primary tumor, another a squamous skin cancer, and the third a salivary gland cancer.⁸ Vismodegib (GDC-0449) was also evaluated in a phase 2 multicenter clinical trial in patients with progressive advanced chondrosarcoma.7 Although the study did not meet its primary endpoint, the proportion of patients with non-progressive disease was 25.6% at 6 months. Investigators observed that the benefit occurred in the subset of patients with overexpression of the Hedgehog ligand. Genomic studies for mutations in SMO and PTCH genes were available for only 28 and 26 patients, respectively, of the 45 patients enrolled on the trial. While there were no mutations identified, expression data revealed that overexpression of the Hedgehog ligand was present in 65% of cases tested (13 out of 20 patients). In patients with stable disease at 6 months, all had overexpression of the Hedgehog ligand.⁷ These studies point to the potential use of vismodegib in both bone and soft tissue sarcomas, and more specifically, to the importance of genomic testing in these cases.

Case Presentation and Summary

This report describes the novel use of vismodegib, an oral Hedgehog signaling pathway inhibitor, in the treatment of a patient with metastatic soft tissue sarcoma.

An 18-year-old female with no particular previous illnesses was initially diagnosed with superficial soft tissue sarcoma overlying the right hip in 2013. Due to the complexity of pathology, a second opinion was requested and revealed atypical cellular spindle and epithelioid cells, morphologically and immunohistochemically suggestive of spindle cell sarcoma, not otherwise specified. She underwent negative-margin resection in January 2014. Her course was complicated by two recurrences in the right inguinal lymph nodes in July 2014 and July 2015. She was treated with lymph node dissection in 2014, followed by numerous right lymph node dissections and adjuvant radiation in 2015.

A routine computerized tomography (CT) scan of the thorax-abdomen and pelvis in August 2016 revealed recurrence of disease, with multiple lung nodules as well as metastases in the retroperitoneum. She received 6 cycles of gemcitabine and docetaxel with stability of disease. The patient was then started on a PI3K inhibitor as part of a clinical trial, as genotypic analysis of the tumor revealed an activating mutation of the PI3K gene. The patient’s course was complicated by acute obstructive renal failure requiring a double J stent for right-sided hydronephrosis.

Repeat imaging revealed disease progression, and the patient was then switched to liposomal doxorubicin alone for 4 months and then in combination with olaratumab. She received the combined treatment for a total of 3 months, which was then stopped when she was found to have new peritoneal implants and worsening ascites. At this time, tissue was sent for FoundationOne® next generation sequencing (NGS)-based genomic testing, and the patient received one dose of nivolumab.

In January 2018, 2 days after receiving her first dose of nivolumab, the patient required admission for worsening abdominal pain secondary to progression of her disease (FIGURE 1). She was found to have acute kidney injury on top of chronic kidney disease due to hydronephrosis requiring a left-sided double J stent. She also had transaminitis resulting from a common bile duct stricture treated with a biliary stent and worsening ascites requiring regular paracentesis. This was all in the context of new or growing metastatic implants.

At this time, the result of the FoundationOne genomic testing revealed PTCH1 loss of exons 1-24 and CDKN2A/B loss. Mutation of tumor suppressor gene PTCH1 leads to Hedgehog pathway activation and therefore the patient was started on vismodegib on January 22, 2018. She was discharged from the hospital in stable condition a day later, on January 23.

The patient’s clinical status subsequently improved, with significant reduction in her chronic abdominal pain and very minimal side effects. Clinically, the patient’s acute kidney injury resolved (from a creatinine of 272 μmol/L at discharge to 85 μmol/L after a week of treatment) and her liver enzymes normalized (from an alkaline phosphatase of 301 U/L to 83 U/L, and alanine transaminase of 111 U/L to 38 U/L). CT scan of her chest and abdomen, which was performed 1 month post treatment, revealed stability of disease with absence of ascites (FIGURE 2). The patient continued to have a good response to treatment for 6 months, with no recurrence of pain or ascites.

Six months later, in July 2018, the patient developed increasing pain and a CT scan revealed worsening of abdominopelvic carcinomatosis. In this context, vismodegib was discontinued on July 17. In the next 5 months, she went on to receive carboplatin and paclitaxel, gemcitabine, and nivolumab consecutively with no response. She was admitted to hospital on December 30 for a pain crisis. She passed away on January 9, 2019, from fecal peritonitis.

Discussion

To the best of our knowledge, this is the first patient with metastatic sarcoma to receive vismodegib, a Hedgehog signaling pathway inhibitor. She achieved an excellent clinical response with progression- free disease for approximately 6 months after starting treatment.

There is no current standard second- line treatment for metastatic soft tissue sarcoma. The choice of systemic therapy is histology-driven and therefore treatment is individualized for each patient. The future of oncology is heading towards an even more personalized approach with molecular profiling. Our case report highlights the relevance of genomic testing and targeted therapies, especially in cases of diverse clinical and biological disease behavior.

Molecular targeting is even more necessary in patients with advanced cancer who have failed multiple lines of treatment. As in our study, these patients can obtain a significant response with meaningful improvement in their quality of life. Future research is currently focusing on identifying new molecular targets in patients with advanced refractory cancers. Further studies will need to be done to determine whether these molecular targeting agents, such as vismodegib, lead to significant outcome changes in these patients.

Spindle cell sarcomas are part of a rare, heterogeneous family of connective tissue tumors. These tumors are primarily treated with surgery and have a high risk of recurrence and distant metastasis with elevated mortality rates.¹ Other than the evidence for first-line therapy with doxorubicin in advanced soft tissue sarcoma, little evidence exists to point to an optimal second-line therapy. This is due to the diversity of soft tissue sarcomas, which encompass approximately 70 different histologic subtypes that can each respond differently to treatment.² As such, newer strategies, including immunotherapy and targeted molecular drugs, are being developed.

Quiescent in most adult tissues, the Hedgehog signaling pathway, when inappropriately activated, has been implicated in the development of multiple types of cancers, including basal cell, breast, prostate, hepatocellular, pancreatic, and brain cancer.³ The Hedgehog signaling pathway is an important regulator of cell growth and differentiation in early development, but when inappropriately activated can lead to cell proliferation and increased angiogenic factors, decreased apoptosis, and breakdown of tight junctions promoting cancer growth and metastasis.⁴ Recent data reveal that the Hedgehog pathway plays a specific role in activation of satellite cells, proliferation of myoblasts, and differentiation of skeletal muscle.⁵ Activation of this embryonic pathway has been implicated in embryonal rhabdoymyosarcoma, osteosarcoma, and chondrosarcoma.^5-7

This pathway has recently been recognized as a therapeutic target, with the development of vismodegib, a targeted Hedgehog pathway inhibitor. This novel agent is in active use for treatment of advanced basal cell carcinoma and is currently undergoing trials for various other malignancies. Recently, a phase 2a basket study, called MyPathway, evaluated the use of targeted therapies in 35 different advanced refractory solid tumors harboring specific molecular alterations. Out of 21 patients with mutations in the Hedgehog pathway, 3 had a partial response to vismodegib—one had an unknown primary tumor, another a squamous skin cancer, and the third a salivary gland cancer.⁸ Vismodegib (GDC-0449) was also evaluated in a phase 2 multicenter clinical trial in patients with progressive advanced chondrosarcoma.7 Although the study did not meet its primary endpoint, the proportion of patients with non-progressive disease was 25.6% at 6 months. Investigators observed that the benefit occurred in the subset of patients with overexpression of the Hedgehog ligand. Genomic studies for mutations in SMO and PTCH genes were available for only 28 and 26 patients, respectively, of the 45 patients enrolled on the trial. While there were no mutations identified, expression data revealed that overexpression of the Hedgehog ligand was present in 65% of cases tested (13 out of 20 patients). In patients with stable disease at 6 months, all had overexpression of the Hedgehog ligand.⁷ These studies point to the potential use of vismodegib in both bone and soft tissue sarcomas, and more specifically, to the importance of genomic testing in these cases.

Case Presentation and Summary

This report describes the novel use of vismodegib, an oral Hedgehog signaling pathway inhibitor, in the treatment of a patient with metastatic soft tissue sarcoma.

An 18-year-old female with no particular previous illnesses was initially diagnosed with superficial soft tissue sarcoma overlying the right hip in 2013. Due to the complexity of pathology, a second opinion was requested and revealed atypical cellular spindle and epithelioid cells, morphologically and immunohistochemically suggestive of spindle cell sarcoma, not otherwise specified. She underwent negative-margin resection in January 2014. Her course was complicated by two recurrences in the right inguinal lymph nodes in July 2014 and July 2015. She was treated with lymph node dissection in 2014, followed by numerous right lymph node dissections and adjuvant radiation in 2015.

A routine computerized tomography (CT) scan of the thorax-abdomen and pelvis in August 2016 revealed recurrence of disease, with multiple lung nodules as well as metastases in the retroperitoneum. She received 6 cycles of gemcitabine and docetaxel with stability of disease. The patient was then started on a PI3K inhibitor as part of a clinical trial, as genotypic analysis of the tumor revealed an activating mutation of the PI3K gene. The patient’s course was complicated by acute obstructive renal failure requiring a double J stent for right-sided hydronephrosis.

Repeat imaging revealed disease progression, and the patient was then switched to liposomal doxorubicin alone for 4 months and then in combination with olaratumab. She received the combined treatment for a total of 3 months, which was then stopped when she was found to have new peritoneal implants and worsening ascites. At this time, tissue was sent for FoundationOne® next generation sequencing (NGS)-based genomic testing, and the patient received one dose of nivolumab.

In January 2018, 2 days after receiving her first dose of nivolumab, the patient required admission for worsening abdominal pain secondary to progression of her disease (FIGURE 1). She was found to have acute kidney injury on top of chronic kidney disease due to hydronephrosis requiring a left-sided double J stent. She also had transaminitis resulting from a common bile duct stricture treated with a biliary stent and worsening ascites requiring regular paracentesis. This was all in the context of new or growing metastatic implants.

At this time, the result of the FoundationOne genomic testing revealed PTCH1 loss of exons 1-24 and CDKN2A/B loss. Mutation of tumor suppressor gene PTCH1 leads to Hedgehog pathway activation and therefore the patient was started on vismodegib on January 22, 2018. She was discharged from the hospital in stable condition a day later, on January 23.

The patient’s clinical status subsequently improved, with significant reduction in her chronic abdominal pain and very minimal side effects. Clinically, the patient’s acute kidney injury resolved (from a creatinine of 272 μmol/L at discharge to 85 μmol/L after a week of treatment) and her liver enzymes normalized (from an alkaline phosphatase of 301 U/L to 83 U/L, and alanine transaminase of 111 U/L to 38 U/L). CT scan of her chest and abdomen, which was performed 1 month post treatment, revealed stability of disease with absence of ascites (FIGURE 2). The patient continued to have a good response to treatment for 6 months, with no recurrence of pain or ascites.

Six months later, in July 2018, the patient developed increasing pain and a CT scan revealed worsening of abdominopelvic carcinomatosis. In this context, vismodegib was discontinued on July 17. In the next 5 months, she went on to receive carboplatin and paclitaxel, gemcitabine, and nivolumab consecutively with no response. She was admitted to hospital on December 30 for a pain crisis. She passed away on January 9, 2019, from fecal peritonitis.

Discussion

To the best of our knowledge, this is the first patient with metastatic sarcoma to receive vismodegib, a Hedgehog signaling pathway inhibitor. She achieved an excellent clinical response with progression- free disease for approximately 6 months after starting treatment.

There is no current standard second- line treatment for metastatic soft tissue sarcoma. The choice of systemic therapy is histology-driven and therefore treatment is individualized for each patient. The future of oncology is heading towards an even more personalized approach with molecular profiling. Our case report highlights the relevance of genomic testing and targeted therapies, especially in cases of diverse clinical and biological disease behavior.

Molecular targeting is even more necessary in patients with advanced cancer who have failed multiple lines of treatment. As in our study, these patients can obtain a significant response with meaningful improvement in their quality of life. Future research is currently focusing on identifying new molecular targets in patients with advanced refractory cancers. Further studies will need to be done to determine whether these molecular targeting agents, such as vismodegib, lead to significant outcome changes in these patients.

THE CASE

A 49-year-old woman presented to our clinic with concerns about the changing appearance of her tongue over the past 2 to 3 weeks. She had been given a diagnosis of celiac disease by her gastroenterologist approximately 5 years earlier. At the time of that diagnosis, she had smooth patches on the surface of her tongue with missing papillae and slightly raised borders. (This gave her tongue a map-like appearance, consistent with geographic tongue [GT].) The patient’s symptoms improved after she started a gluten-free diet, but she reported occasional noncompliance over the past year.

At the current presentation, the patient noted that new lesions on the tongue had started as diffuse shiny red patches surrounded by clearly delineated white borders, ultimately progressing to structural changes. She denied any burning of the tongue or other oral symptoms but reported feelings of anxiety, a “foggy mind,” and diffuse arthralgia for the past several weeks. The patient’s list of medications included vitamin D and magnesium supplements, a multivitamin, and probiotics.

On physical examination, her tongue showed areas of shiny erythematous mucosa and deep central grooves with small radiating furrows giving a wrinkled appearance ­(FIGURE). A review of systems revealed nonspecific abdominal pain including bloating, cramping, and gas for the previous few months. An examination of her throat and oral cavity was unremarkable, and the remainder of the physical examination was normal.

THE DIAGNOSIS

A diagnosis of fissured tongue (FT) was suspected based on the clinical appearance of the patient’s tongue. Laboratory studies including a complete blood count; antinuclear antibody test; rheumatoid factor test; anticyclic citrullinated peptide test; a comprehensive metabolic panel; and thyroid-stimulating hormone, 25-hydroxyvitamin D, and vitamin B₁₂ level tests were performed based on her symptoms and current medications to rule out any other potential diagnoses. All laboratory results were normal, and a tissue transglutaminase IgA test was not repeated because it was positive when previously tested by the gastroenterologist at the time of her celiac disease diagnosis. A diagnosis of FT due to incompletely treated celiac disease was confirmed.

DISCUSSION

Clinical presentation. FT commonly presents in association with GT,^1,2 with some cases of GT naturally progressing to FT.^3,4 In most cases, FT is asymptomatic unless debris becomes entrapped in the fissures. Rarely, patients may complain of a burning sensation on the tongue. The clinical appearance of the tongue includes deep grooves with possible malodor or halitosis along with discoloration if trapping of debris and subsequent inflammation occurs.¹

Etiology. FT has been linked to celiac disease; systemic conditions such as arthritis, iron deficiency, depression, anxiety, and neuropathy; and poor oral hygiene. Genetics also may play a role, as some cases of FT may be inherited. Getting to the source requires a careful history to uncover signs and symptoms (that may not have been reported until now) and to determine if other family members also have FT. A careful examination of the oral cavity, with an eye toward the patient’s oral hygiene, is also instructive (TABLE).^5-8 In general, FT is believed to be a normal tongue variant in less than 10% of the general population.^5,6 Additionally, local factors such as ill-fitting prosthesis, infection, parafunctional habits, allergic reaction, xerostomia, and galvanism have been implicated in the etiology of FT.⁵

In most cases, fissured tongue is asymptomatic unless debris becomes entrapped in the fissures.

In our patient, progression of GT to FT was caused by incompletely treated celiac disease. Both FT and GT may represent different reaction patterns caused by the same hematologic and immunologic diseases.³ In fact, the appearance of the tongue may aid in the diagnosis of celiac disease, which has been observed in 15% of patients with GT.⁷ Fissured tongue also may indicate an inability of the gastrointestinal mucosa to absorb nutrients; therefore, close nutrition monitoring is recommended.⁹

Continue to: Other oral and dental manifestations...

Other oral and dental manifestations of celiac disease include enamel defects, delayed tooth eruption, recurrent aphthous ulcers, cheilosis, oral lichen planus, and atrophic glossitis.¹⁰ Our patient also reported anxiety, “foggy mind,” diffuse arthralgia, and abdominal pain, which are symptoms of uncontrolled celiac disease. There is no known etiology of tongue manifestations in patients with incompletely treated celiac disease.

Treatment. FT generally does not require specific therapy other than the treatment of the underlying inflammatory condition. It is important to maintain proper oral and dental care, such as brushing the top surface of the tongue to clean and remove food debris. Bacteria and plaque can collect in the fissures, leading to bad breath and an increased potential for tooth decay.

Our patient was referred to a dietitian to assist with adherence to the gluten-free diet. At follow-up 3 months later, the appearance of her tongue had improved and fewer fissures were visible. The majority of her other symptoms also had resolved.

THE TAKEAWAY

FT may be a normal variant of the tongue in some patients or may be associated with poor oral hygiene. Additionally, FT often is associated with an underlying medical or inherited condition and may serve as a marker for an untreated or partially treated condition such as celiac disease, as was the case with our patient. When other signs or symptoms of systemic disease are present, further laboratory and endoscopic workup is necessary to rule out other causes and to diagnose celiac disease, if present.

As FT has been reported to be a natural progression from GT, the appearance of FT may indicate partial treatment of the underlying disease process and therefore more intensive therapy and follow-up would be needed. In this case, more intensive dietary guidance was provided with subsequent improvement of symptoms.

CORRESPONDENCE
Peter J. Carek, MD, MS, Department of Community Health and Family Medicine, College of Medicine, University of Florida, P.O. Box 100237, Gainesville, FL 32610-0237; [email protected]

THE CASE

A 49-year-old woman presented to our clinic with concerns about the changing appearance of her tongue over the past 2 to 3 weeks. She had been given a diagnosis of celiac disease by her gastroenterologist approximately 5 years earlier. At the time of that diagnosis, she had smooth patches on the surface of her tongue with missing papillae and slightly raised borders. (This gave her tongue a map-like appearance, consistent with geographic tongue [GT].) The patient’s symptoms improved after she started a gluten-free diet, but she reported occasional noncompliance over the past year.

At the current presentation, the patient noted that new lesions on the tongue had started as diffuse shiny red patches surrounded by clearly delineated white borders, ultimately progressing to structural changes. She denied any burning of the tongue or other oral symptoms but reported feelings of anxiety, a “foggy mind,” and diffuse arthralgia for the past several weeks. The patient’s list of medications included vitamin D and magnesium supplements, a multivitamin, and probiotics.

On physical examination, her tongue showed areas of shiny erythematous mucosa and deep central grooves with small radiating furrows giving a wrinkled appearance ­(FIGURE). A review of systems revealed nonspecific abdominal pain including bloating, cramping, and gas for the previous few months. An examination of her throat and oral cavity was unremarkable, and the remainder of the physical examination was normal.

THE DIAGNOSIS

A diagnosis of fissured tongue (FT) was suspected based on the clinical appearance of the patient’s tongue. Laboratory studies including a complete blood count; antinuclear antibody test; rheumatoid factor test; anticyclic citrullinated peptide test; a comprehensive metabolic panel; and thyroid-stimulating hormone, 25-hydroxyvitamin D, and vitamin B₁₂ level tests were performed based on her symptoms and current medications to rule out any other potential diagnoses. All laboratory results were normal, and a tissue transglutaminase IgA test was not repeated because it was positive when previously tested by the gastroenterologist at the time of her celiac disease diagnosis. A diagnosis of FT due to incompletely treated celiac disease was confirmed.

DISCUSSION

Clinical presentation. FT commonly presents in association with GT,^1,2 with some cases of GT naturally progressing to FT.^3,4 In most cases, FT is asymptomatic unless debris becomes entrapped in the fissures. Rarely, patients may complain of a burning sensation on the tongue. The clinical appearance of the tongue includes deep grooves with possible malodor or halitosis along with discoloration if trapping of debris and subsequent inflammation occurs.¹

Etiology. FT has been linked to celiac disease; systemic conditions such as arthritis, iron deficiency, depression, anxiety, and neuropathy; and poor oral hygiene. Genetics also may play a role, as some cases of FT may be inherited. Getting to the source requires a careful history to uncover signs and symptoms (that may not have been reported until now) and to determine if other family members also have FT. A careful examination of the oral cavity, with an eye toward the patient’s oral hygiene, is also instructive (TABLE).^5-8 In general, FT is believed to be a normal tongue variant in less than 10% of the general population.^5,6 Additionally, local factors such as ill-fitting prosthesis, infection, parafunctional habits, allergic reaction, xerostomia, and galvanism have been implicated in the etiology of FT.⁵

In most cases, fissured tongue is asymptomatic unless debris becomes entrapped in the fissures.

In our patient, progression of GT to FT was caused by incompletely treated celiac disease. Both FT and GT may represent different reaction patterns caused by the same hematologic and immunologic diseases.³ In fact, the appearance of the tongue may aid in the diagnosis of celiac disease, which has been observed in 15% of patients with GT.⁷ Fissured tongue also may indicate an inability of the gastrointestinal mucosa to absorb nutrients; therefore, close nutrition monitoring is recommended.⁹

Continue to: Other oral and dental manifestations...

Other oral and dental manifestations of celiac disease include enamel defects, delayed tooth eruption, recurrent aphthous ulcers, cheilosis, oral lichen planus, and atrophic glossitis.¹⁰ Our patient also reported anxiety, “foggy mind,” diffuse arthralgia, and abdominal pain, which are symptoms of uncontrolled celiac disease. There is no known etiology of tongue manifestations in patients with incompletely treated celiac disease.

Treatment. FT generally does not require specific therapy other than the treatment of the underlying inflammatory condition. It is important to maintain proper oral and dental care, such as brushing the top surface of the tongue to clean and remove food debris. Bacteria and plaque can collect in the fissures, leading to bad breath and an increased potential for tooth decay.

Our patient was referred to a dietitian to assist with adherence to the gluten-free diet. At follow-up 3 months later, the appearance of her tongue had improved and fewer fissures were visible. The majority of her other symptoms also had resolved.

THE TAKEAWAY

FT may be a normal variant of the tongue in some patients or may be associated with poor oral hygiene. Additionally, FT often is associated with an underlying medical or inherited condition and may serve as a marker for an untreated or partially treated condition such as celiac disease, as was the case with our patient. When other signs or symptoms of systemic disease are present, further laboratory and endoscopic workup is necessary to rule out other causes and to diagnose celiac disease, if present.

As FT has been reported to be a natural progression from GT, the appearance of FT may indicate partial treatment of the underlying disease process and therefore more intensive therapy and follow-up would be needed. In this case, more intensive dietary guidance was provided with subsequent improvement of symptoms.

CORRESPONDENCE
Peter J. Carek, MD, MS, Department of Community Health and Family Medicine, College of Medicine, University of Florida, P.O. Box 100237, Gainesville, FL 32610-0237; [email protected]

THE CASE

A 49-year-old woman presented to our clinic with concerns about the changing appearance of her tongue over the past 2 to 3 weeks. She had been given a diagnosis of celiac disease by her gastroenterologist approximately 5 years earlier. At the time of that diagnosis, she had smooth patches on the surface of her tongue with missing papillae and slightly raised borders. (This gave her tongue a map-like appearance, consistent with geographic tongue [GT].) The patient’s symptoms improved after she started a gluten-free diet, but she reported occasional noncompliance over the past year.

At the current presentation, the patient noted that new lesions on the tongue had started as diffuse shiny red patches surrounded by clearly delineated white borders, ultimately progressing to structural changes. She denied any burning of the tongue or other oral symptoms but reported feelings of anxiety, a “foggy mind,” and diffuse arthralgia for the past several weeks. The patient’s list of medications included vitamin D and magnesium supplements, a multivitamin, and probiotics.

On physical examination, her tongue showed areas of shiny erythematous mucosa and deep central grooves with small radiating furrows giving a wrinkled appearance ­(FIGURE). A review of systems revealed nonspecific abdominal pain including bloating, cramping, and gas for the previous few months. An examination of her throat and oral cavity was unremarkable, and the remainder of the physical examination was normal.

THE DIAGNOSIS

A diagnosis of fissured tongue (FT) was suspected based on the clinical appearance of the patient’s tongue. Laboratory studies including a complete blood count; antinuclear antibody test; rheumatoid factor test; anticyclic citrullinated peptide test; a comprehensive metabolic panel; and thyroid-stimulating hormone, 25-hydroxyvitamin D, and vitamin B₁₂ level tests were performed based on her symptoms and current medications to rule out any other potential diagnoses. All laboratory results were normal, and a tissue transglutaminase IgA test was not repeated because it was positive when previously tested by the gastroenterologist at the time of her celiac disease diagnosis. A diagnosis of FT due to incompletely treated celiac disease was confirmed.

DISCUSSION

Clinical presentation. FT commonly presents in association with GT,^1,2 with some cases of GT naturally progressing to FT.^3,4 In most cases, FT is asymptomatic unless debris becomes entrapped in the fissures. Rarely, patients may complain of a burning sensation on the tongue. The clinical appearance of the tongue includes deep grooves with possible malodor or halitosis along with discoloration if trapping of debris and subsequent inflammation occurs.¹

Etiology. FT has been linked to celiac disease; systemic conditions such as arthritis, iron deficiency, depression, anxiety, and neuropathy; and poor oral hygiene. Genetics also may play a role, as some cases of FT may be inherited. Getting to the source requires a careful history to uncover signs and symptoms (that may not have been reported until now) and to determine if other family members also have FT. A careful examination of the oral cavity, with an eye toward the patient’s oral hygiene, is also instructive (TABLE).^5-8 In general, FT is believed to be a normal tongue variant in less than 10% of the general population.^5,6 Additionally, local factors such as ill-fitting prosthesis, infection, parafunctional habits, allergic reaction, xerostomia, and galvanism have been implicated in the etiology of FT.⁵

In most cases, fissured tongue is asymptomatic unless debris becomes entrapped in the fissures.

In our patient, progression of GT to FT was caused by incompletely treated celiac disease. Both FT and GT may represent different reaction patterns caused by the same hematologic and immunologic diseases.³ In fact, the appearance of the tongue may aid in the diagnosis of celiac disease, which has been observed in 15% of patients with GT.⁷ Fissured tongue also may indicate an inability of the gastrointestinal mucosa to absorb nutrients; therefore, close nutrition monitoring is recommended.⁹

Continue to: Other oral and dental manifestations...

Other oral and dental manifestations of celiac disease include enamel defects, delayed tooth eruption, recurrent aphthous ulcers, cheilosis, oral lichen planus, and atrophic glossitis.¹⁰ Our patient also reported anxiety, “foggy mind,” diffuse arthralgia, and abdominal pain, which are symptoms of uncontrolled celiac disease. There is no known etiology of tongue manifestations in patients with incompletely treated celiac disease.

Treatment. FT generally does not require specific therapy other than the treatment of the underlying inflammatory condition. It is important to maintain proper oral and dental care, such as brushing the top surface of the tongue to clean and remove food debris. Bacteria and plaque can collect in the fissures, leading to bad breath and an increased potential for tooth decay.

Our patient was referred to a dietitian to assist with adherence to the gluten-free diet. At follow-up 3 months later, the appearance of her tongue had improved and fewer fissures were visible. The majority of her other symptoms also had resolved.

THE TAKEAWAY

FT may be a normal variant of the tongue in some patients or may be associated with poor oral hygiene. Additionally, FT often is associated with an underlying medical or inherited condition and may serve as a marker for an untreated or partially treated condition such as celiac disease, as was the case with our patient. When other signs or symptoms of systemic disease are present, further laboratory and endoscopic workup is necessary to rule out other causes and to diagnose celiac disease, if present.

As FT has been reported to be a natural progression from GT, the appearance of FT may indicate partial treatment of the underlying disease process and therefore more intensive therapy and follow-up would be needed. In this case, more intensive dietary guidance was provided with subsequent improvement of symptoms.

CORRESPONDENCE
Peter J. Carek, MD, MS, Department of Community Health and Family Medicine, College of Medicine, University of Florida, P.O. Box 100237, Gainesville, FL 32610-0237; [email protected]

THE CASE

An 8-year-old boy presented to his family physician (FP) with pharyngitis, nasal drainage, and a dry cough of 3 days’ duration. He denied any fever, chills, vomiting, or diarrhea. He had no sick contacts or prior history of streptococcal pharyngitis, but a rapid strep test was positive. No throat culture was performed at this time. The patient was started on amoxicillin 250 mg 3 times daily for 10 days.

On Day 7 of symptoms, the patient presented to the emergency department with elbow and knee pain, as well as mild swelling and purpura of his legs of 3 days’ duration. He was normotensive and reported no abdominal pain. A laboratory workup, including a complete blood cell count and differential, prothrombin time, partial thromboplastin time, comprehensive metabolic panel, creatinine kinase test, urinalysis, and chest radiograph, was normal, but his erythrocyte sedimentation rate (ESR) was mildly elevated at 22 mm/h (reference range, 0–20 mm/h). The patient was discharged on acetaminophen 15 mg/kg every 4 hours as needed for pain.

THE DIAGNOSIS

Based on the distinctive palpable purpura on the legs, arthralgia, upper respiratory infection, and lack of thrombocytopenia and coagulopathy, a presumptive diagnosis of Henoch-Schönlein purpura (HSP) was made.

On Day 9 of symptoms, the patient returned to his FP’s office because the arthralgia persisted in his ankles, knees, and hips. He had developed lower back pain, but the pharyngitis and upper respiratory symptoms had resolved. On physical examination, he was normotensive with a normal abdominal exam. The patient reported that it hurt to move his wrists, hands, elbows, shoulders, knees, and ankles. He also had mild swelling in his left wrist, hand, and ankle. The paraspinal muscles in the lower thoracic and lumbar back were mildly tender to palpation. A complete metabolic panel and urinalysis were normal. Dermatologic examination revealed discrete purpuric lesions ranging from 1 to 8 mm in diameter on the child’s shins, thighs, and buttocks. Urinalysis, blood urea nitrogen, and creatinine kinase were normal. His ESR remained mildly elevated at 24 mm/h. Since there was no evidence of glomerulonephritis, ibuprofen 10 mg/kg every 8 hours as needed was added for pain management.

The child was brought back to his FP on Day 18 for a scheduled follow-up visit. The parents reported that his arthralgia was improved during the day, but by the evening, his knees and ankles hurt so much that they had to carry him to the bathroom. On physical examination, he still had palpable purpura of the legs. There was no swelling, but his joints were still tender to palpation. His parents were reminded to give him ibuprofen after school to control evening pain. Over the next 2 weeks, the patient showed gradual improvement, and by Day 33 the rash and all of the associated symptoms had resolved.

DISCUSSION

Clinical presentation. HSP is an IgA immune complex vasculitis in which abnormal glycosylation of IgA creates large immune complexes that are deposited in the walls of the skin capillaries and arterioles. The primary clinical finding in HSP is a distinctive nonthrombocytopenic purpuric rash that is not associated with coagulopathy and is characterized by reddish purple macules that progress to palpable purpura with petechiae (Figure). Lesions generally are distributed on the legs or buttocks but also may appear on the torso or arms. Flu-like symptoms, such as fever, runny nose, and cough, are common.

A preceding upper respiratory infection has been found in 37% of patients,¹ and in patients with renal complications, 20% to 50% have been found to have a group A Streptococcus infection.² Other associations include food allergies, cold exposure, insect bites, and drug allergies.

Continue to: HSP vasculitis causes...

HSP vasculitis causes abdominal pain in 50% to 75% of patients due to proximal small-bowel submucosal hemorrhage and bowel wall edema.³ In children with HSP, 20% to 55% have been shown to develop renal disease,⁴ which can range in severity from microscopic hematuria to nephrotic syndrome.³ To ensure prompt treatment of renal manifestations, renal function should be monitored regularly via blood pressure and urinalysis during the course of HSP and after resolution. Renal disease associated with HSP can be acute or chronic.

This case was different because our patient did not exhibit all elements of the classic tetrad of HSP, which includes the characteristic rash, abdominal pain, renal involvement, and arthralgia.

Incidence. HSP is more common in children than adults, with average annual incidence rates of 20/100,000 and 70/100,000 in children in the United States and Asia, respectively.⁵ While 90% of HSP cases occur in children < 10 years, the peak incidence is at 6 years of age.⁶ Complications from HSP are more common in adults than in children.⁷ Caucasian and Asian populations have a 3- to 4-times higher prevalence of HSP than black populations. The male-to-female ratio is 2 to 1.⁶

The diagnosis of HSP is usually made clinically, based on the distinctive rash, which typically is symmetrical, involving the buttocks, lower legs, elbows, and/or knees. HSP also can be confirmed via skin biopsy and/or direct immunofluorescence, which can identify the presence of IgA in the vessel walls.

The presence of 3 or more of the following criteria also suggests HSP: palpable purpura, bowel angina, gastrointestinal (GI) bleeding, hematuria, ≤ 20 years of age at onset, and no medications prior to presentation of symptoms (87% of cases correctly classified). Fewer than 3 of these factors favor hypersensitivity vasculitis (74% of cases correctly classified).⁸

Continue to: The differential diagnosis

The differential diagnosis for HSP includes polyarteritis nodosa, a vasculitis with a different characteristic rash; acute abdomen, distinguished by the absence of purpura or arthralgia; meningococcemia, in which fever and meningeal signs may occur; hypersensitivity vasculitis, which arises due to prior exposure to medications or food allergens; and thrombocytopenic purpura, which is characterized by low platelet count.⁹

Treatment focuses on pain management

In the absence of renal disease, HSP commonly is treated with naproxen for pain management (dosage for children < 2 years of age: 5-7 mg/kg orally every 8-12 hours; dosage for children ≥ 2 years of age, adolescents, and adults: 10-20 mg/kg/d divided into 2 doses; maximum adolescent and adult dose is 1500 mg/d for 3 days followed by a maximum of 1000 mg/d thereafter).

For patients of all ages with severe pain and those with GI effects limiting oral intake of medication, use oral prednisone (1-2 mg/kg/d [maximum dose, 60-80 mg/d]) or intravenous methylprednisolone (0.8-1.6 mg/kg/d [maximum dose, 64 mg/d). Glucocorticoids may then be tapered slowly over 4 to 8 weeks to avoid rebound since they help with inflammation but do not shorten the course of disease. Steroids can ease GI and joint symptoms in HSP but will not improve the rash.

THE TAKEAWAY

The classic tetrad of HSP includes the characteristic rash, abdominal pain, renal involvement, and arthralgia. Diagnosis usually is made clinically, but skin biopsy and direct immunofluorescence can confirm small vessel vasculitis with IgA deposits. More severe manifestations of HSP such as renal disease, hemorrhage, severe anemia, signs of intestinal obstruction, or peritonitis require rapid subspecialty referral.

CORRESPONDENCE
Rachel Bramson, MD, Department of Primary Care, Baylor Scott and White Health, University Clinic, 1700 University Drive, College Station, TX 77840; [email protected]

THE CASE

An 8-year-old boy presented to his family physician (FP) with pharyngitis, nasal drainage, and a dry cough of 3 days’ duration. He denied any fever, chills, vomiting, or diarrhea. He had no sick contacts or prior history of streptococcal pharyngitis, but a rapid strep test was positive. No throat culture was performed at this time. The patient was started on amoxicillin 250 mg 3 times daily for 10 days.

On Day 7 of symptoms, the patient presented to the emergency department with elbow and knee pain, as well as mild swelling and purpura of his legs of 3 days’ duration. He was normotensive and reported no abdominal pain. A laboratory workup, including a complete blood cell count and differential, prothrombin time, partial thromboplastin time, comprehensive metabolic panel, creatinine kinase test, urinalysis, and chest radiograph, was normal, but his erythrocyte sedimentation rate (ESR) was mildly elevated at 22 mm/h (reference range, 0–20 mm/h). The patient was discharged on acetaminophen 15 mg/kg every 4 hours as needed for pain.

THE DIAGNOSIS

Based on the distinctive palpable purpura on the legs, arthralgia, upper respiratory infection, and lack of thrombocytopenia and coagulopathy, a presumptive diagnosis of Henoch-Schönlein purpura (HSP) was made.

On Day 9 of symptoms, the patient returned to his FP’s office because the arthralgia persisted in his ankles, knees, and hips. He had developed lower back pain, but the pharyngitis and upper respiratory symptoms had resolved. On physical examination, he was normotensive with a normal abdominal exam. The patient reported that it hurt to move his wrists, hands, elbows, shoulders, knees, and ankles. He also had mild swelling in his left wrist, hand, and ankle. The paraspinal muscles in the lower thoracic and lumbar back were mildly tender to palpation. A complete metabolic panel and urinalysis were normal. Dermatologic examination revealed discrete purpuric lesions ranging from 1 to 8 mm in diameter on the child’s shins, thighs, and buttocks. Urinalysis, blood urea nitrogen, and creatinine kinase were normal. His ESR remained mildly elevated at 24 mm/h. Since there was no evidence of glomerulonephritis, ibuprofen 10 mg/kg every 8 hours as needed was added for pain management.

The child was brought back to his FP on Day 18 for a scheduled follow-up visit. The parents reported that his arthralgia was improved during the day, but by the evening, his knees and ankles hurt so much that they had to carry him to the bathroom. On physical examination, he still had palpable purpura of the legs. There was no swelling, but his joints were still tender to palpation. His parents were reminded to give him ibuprofen after school to control evening pain. Over the next 2 weeks, the patient showed gradual improvement, and by Day 33 the rash and all of the associated symptoms had resolved.

DISCUSSION

Clinical presentation. HSP is an IgA immune complex vasculitis in which abnormal glycosylation of IgA creates large immune complexes that are deposited in the walls of the skin capillaries and arterioles. The primary clinical finding in HSP is a distinctive nonthrombocytopenic purpuric rash that is not associated with coagulopathy and is characterized by reddish purple macules that progress to palpable purpura with petechiae (Figure). Lesions generally are distributed on the legs or buttocks but also may appear on the torso or arms. Flu-like symptoms, such as fever, runny nose, and cough, are common.

A preceding upper respiratory infection has been found in 37% of patients,¹ and in patients with renal complications, 20% to 50% have been found to have a group A Streptococcus infection.² Other associations include food allergies, cold exposure, insect bites, and drug allergies.

Continue to: HSP vasculitis causes...

HSP vasculitis causes abdominal pain in 50% to 75% of patients due to proximal small-bowel submucosal hemorrhage and bowel wall edema.³ In children with HSP, 20% to 55% have been shown to develop renal disease,⁴ which can range in severity from microscopic hematuria to nephrotic syndrome.³ To ensure prompt treatment of renal manifestations, renal function should be monitored regularly via blood pressure and urinalysis during the course of HSP and after resolution. Renal disease associated with HSP can be acute or chronic.

This case was different because our patient did not exhibit all elements of the classic tetrad of HSP, which includes the characteristic rash, abdominal pain, renal involvement, and arthralgia.

Incidence. HSP is more common in children than adults, with average annual incidence rates of 20/100,000 and 70/100,000 in children in the United States and Asia, respectively.⁵ While 90% of HSP cases occur in children < 10 years, the peak incidence is at 6 years of age.⁶ Complications from HSP are more common in adults than in children.⁷ Caucasian and Asian populations have a 3- to 4-times higher prevalence of HSP than black populations. The male-to-female ratio is 2 to 1.⁶

The diagnosis of HSP is usually made clinically, based on the distinctive rash, which typically is symmetrical, involving the buttocks, lower legs, elbows, and/or knees. HSP also can be confirmed via skin biopsy and/or direct immunofluorescence, which can identify the presence of IgA in the vessel walls.

The presence of 3 or more of the following criteria also suggests HSP: palpable purpura, bowel angina, gastrointestinal (GI) bleeding, hematuria, ≤ 20 years of age at onset, and no medications prior to presentation of symptoms (87% of cases correctly classified). Fewer than 3 of these factors favor hypersensitivity vasculitis (74% of cases correctly classified).⁸

Continue to: The differential diagnosis

The differential diagnosis for HSP includes polyarteritis nodosa, a vasculitis with a different characteristic rash; acute abdomen, distinguished by the absence of purpura or arthralgia; meningococcemia, in which fever and meningeal signs may occur; hypersensitivity vasculitis, which arises due to prior exposure to medications or food allergens; and thrombocytopenic purpura, which is characterized by low platelet count.⁹

Treatment focuses on pain management

In the absence of renal disease, HSP commonly is treated with naproxen for pain management (dosage for children < 2 years of age: 5-7 mg/kg orally every 8-12 hours; dosage for children ≥ 2 years of age, adolescents, and adults: 10-20 mg/kg/d divided into 2 doses; maximum adolescent and adult dose is 1500 mg/d for 3 days followed by a maximum of 1000 mg/d thereafter).

For patients of all ages with severe pain and those with GI effects limiting oral intake of medication, use oral prednisone (1-2 mg/kg/d [maximum dose, 60-80 mg/d]) or intravenous methylprednisolone (0.8-1.6 mg/kg/d [maximum dose, 64 mg/d). Glucocorticoids may then be tapered slowly over 4 to 8 weeks to avoid rebound since they help with inflammation but do not shorten the course of disease. Steroids can ease GI and joint symptoms in HSP but will not improve the rash.

THE TAKEAWAY

The classic tetrad of HSP includes the characteristic rash, abdominal pain, renal involvement, and arthralgia. Diagnosis usually is made clinically, but skin biopsy and direct immunofluorescence can confirm small vessel vasculitis with IgA deposits. More severe manifestations of HSP such as renal disease, hemorrhage, severe anemia, signs of intestinal obstruction, or peritonitis require rapid subspecialty referral.

CORRESPONDENCE
Rachel Bramson, MD, Department of Primary Care, Baylor Scott and White Health, University Clinic, 1700 University Drive, College Station, TX 77840; [email protected]

THE CASE

An 8-year-old boy presented to his family physician (FP) with pharyngitis, nasal drainage, and a dry cough of 3 days’ duration. He denied any fever, chills, vomiting, or diarrhea. He had no sick contacts or prior history of streptococcal pharyngitis, but a rapid strep test was positive. No throat culture was performed at this time. The patient was started on amoxicillin 250 mg 3 times daily for 10 days.

On Day 7 of symptoms, the patient presented to the emergency department with elbow and knee pain, as well as mild swelling and purpura of his legs of 3 days’ duration. He was normotensive and reported no abdominal pain. A laboratory workup, including a complete blood cell count and differential, prothrombin time, partial thromboplastin time, comprehensive metabolic panel, creatinine kinase test, urinalysis, and chest radiograph, was normal, but his erythrocyte sedimentation rate (ESR) was mildly elevated at 22 mm/h (reference range, 0–20 mm/h). The patient was discharged on acetaminophen 15 mg/kg every 4 hours as needed for pain.

THE DIAGNOSIS

Based on the distinctive palpable purpura on the legs, arthralgia, upper respiratory infection, and lack of thrombocytopenia and coagulopathy, a presumptive diagnosis of Henoch-Schönlein purpura (HSP) was made.

On Day 9 of symptoms, the patient returned to his FP’s office because the arthralgia persisted in his ankles, knees, and hips. He had developed lower back pain, but the pharyngitis and upper respiratory symptoms had resolved. On physical examination, he was normotensive with a normal abdominal exam. The patient reported that it hurt to move his wrists, hands, elbows, shoulders, knees, and ankles. He also had mild swelling in his left wrist, hand, and ankle. The paraspinal muscles in the lower thoracic and lumbar back were mildly tender to palpation. A complete metabolic panel and urinalysis were normal. Dermatologic examination revealed discrete purpuric lesions ranging from 1 to 8 mm in diameter on the child’s shins, thighs, and buttocks. Urinalysis, blood urea nitrogen, and creatinine kinase were normal. His ESR remained mildly elevated at 24 mm/h. Since there was no evidence of glomerulonephritis, ibuprofen 10 mg/kg every 8 hours as needed was added for pain management.

The child was brought back to his FP on Day 18 for a scheduled follow-up visit. The parents reported that his arthralgia was improved during the day, but by the evening, his knees and ankles hurt so much that they had to carry him to the bathroom. On physical examination, he still had palpable purpura of the legs. There was no swelling, but his joints were still tender to palpation. His parents were reminded to give him ibuprofen after school to control evening pain. Over the next 2 weeks, the patient showed gradual improvement, and by Day 33 the rash and all of the associated symptoms had resolved.

DISCUSSION

Clinical presentation. HSP is an IgA immune complex vasculitis in which abnormal glycosylation of IgA creates large immune complexes that are deposited in the walls of the skin capillaries and arterioles. The primary clinical finding in HSP is a distinctive nonthrombocytopenic purpuric rash that is not associated with coagulopathy and is characterized by reddish purple macules that progress to palpable purpura with petechiae (Figure). Lesions generally are distributed on the legs or buttocks but also may appear on the torso or arms. Flu-like symptoms, such as fever, runny nose, and cough, are common.

A preceding upper respiratory infection has been found in 37% of patients,¹ and in patients with renal complications, 20% to 50% have been found to have a group A Streptococcus infection.² Other associations include food allergies, cold exposure, insect bites, and drug allergies.

Continue to: HSP vasculitis causes...

HSP vasculitis causes abdominal pain in 50% to 75% of patients due to proximal small-bowel submucosal hemorrhage and bowel wall edema.³ In children with HSP, 20% to 55% have been shown to develop renal disease,⁴ which can range in severity from microscopic hematuria to nephrotic syndrome.³ To ensure prompt treatment of renal manifestations, renal function should be monitored regularly via blood pressure and urinalysis during the course of HSP and after resolution. Renal disease associated with HSP can be acute or chronic.

This case was different because our patient did not exhibit all elements of the classic tetrad of HSP, which includes the characteristic rash, abdominal pain, renal involvement, and arthralgia.

Incidence. HSP is more common in children than adults, with average annual incidence rates of 20/100,000 and 70/100,000 in children in the United States and Asia, respectively.⁵ While 90% of HSP cases occur in children < 10 years, the peak incidence is at 6 years of age.⁶ Complications from HSP are more common in adults than in children.⁷ Caucasian and Asian populations have a 3- to 4-times higher prevalence of HSP than black populations. The male-to-female ratio is 2 to 1.⁶

The diagnosis of HSP is usually made clinically, based on the distinctive rash, which typically is symmetrical, involving the buttocks, lower legs, elbows, and/or knees. HSP also can be confirmed via skin biopsy and/or direct immunofluorescence, which can identify the presence of IgA in the vessel walls.

The presence of 3 or more of the following criteria also suggests HSP: palpable purpura, bowel angina, gastrointestinal (GI) bleeding, hematuria, ≤ 20 years of age at onset, and no medications prior to presentation of symptoms (87% of cases correctly classified). Fewer than 3 of these factors favor hypersensitivity vasculitis (74% of cases correctly classified).⁸

Continue to: The differential diagnosis

The differential diagnosis for HSP includes polyarteritis nodosa, a vasculitis with a different characteristic rash; acute abdomen, distinguished by the absence of purpura or arthralgia; meningococcemia, in which fever and meningeal signs may occur; hypersensitivity vasculitis, which arises due to prior exposure to medications or food allergens; and thrombocytopenic purpura, which is characterized by low platelet count.⁹

Treatment focuses on pain management

In the absence of renal disease, HSP commonly is treated with naproxen for pain management (dosage for children < 2 years of age: 5-7 mg/kg orally every 8-12 hours; dosage for children ≥ 2 years of age, adolescents, and adults: 10-20 mg/kg/d divided into 2 doses; maximum adolescent and adult dose is 1500 mg/d for 3 days followed by a maximum of 1000 mg/d thereafter).

For patients of all ages with severe pain and those with GI effects limiting oral intake of medication, use oral prednisone (1-2 mg/kg/d [maximum dose, 60-80 mg/d]) or intravenous methylprednisolone (0.8-1.6 mg/kg/d [maximum dose, 64 mg/d). Glucocorticoids may then be tapered slowly over 4 to 8 weeks to avoid rebound since they help with inflammation but do not shorten the course of disease. Steroids can ease GI and joint symptoms in HSP but will not improve the rash.

THE TAKEAWAY

The classic tetrad of HSP includes the characteristic rash, abdominal pain, renal involvement, and arthralgia. Diagnosis usually is made clinically, but skin biopsy and direct immunofluorescence can confirm small vessel vasculitis with IgA deposits. More severe manifestations of HSP such as renal disease, hemorrhage, severe anemia, signs of intestinal obstruction, or peritonitis require rapid subspecialty referral.

CORRESPONDENCE
Rachel Bramson, MD, Department of Primary Care, Baylor Scott and White Health, University Clinic, 1700 University Drive, College Station, TX 77840; [email protected]

Sorbitan sesquioleate (SSO), sorbitan monooleate (SMO), and related compounds are increasingly recognized contact allergens. Sorbitan sesquioleate and SMO are nonionic emulsifying agents derived from sorbitol.¹

Sorbitan sesquioleate, SMO, and other sorbitol derivatives are used as emulsifiers and dispersing agents in cosmetics, topical medications, topical emollients, produce, and other commercial products. Related compounds also are found in foods such as apples, berries, cherries, and sucrose-free cakes and cookies.¹ We present a case of allergic contact dermatitis (ACD) with positive patch testing to sorbitans and clinical correlation with beer and bread exposure.

Case Report

A 62-year-old man presented with a persistent pruritic rash of 6 months’ duration. Erythematous eczematous papules and plaques were observed on the face, neck, chest, abdomen, back, and upper and lower extremities, affecting approximately 60% of the body surface area. His current list of medications was reviewed and included a multivitamin, fish oil, and vitamin C. A punch biopsy revealed spongiotic dermatitis with eosinophils. Patch testing using the North American Contact Dermatitis Group Standard Series with supplemental allergens found in toiletries revealed a positive reaction to SSO and SMO that was persistent at 48 and 96 hours. Notably, patch testing for sodium benzoate, nickel, potassium dichromate, and balsam of Peru were negative. Investigation into the personal care products the patient used identified the presence of sorbitol solution in Vanicream bar soap and Vanicream moisturizing cream (Pharmaceutical Specialties Inc). These products were started after the development of the rash and were discontinued after positive patch testing, but the patient continued to experience the eruption with no improvement.

Retrospectively, the patient was able to correlate exacerbations with drinking beer and eating sandwiches. He habitually ate a sandwich on the same type of bread every single day and enjoyed the same brand of beer 2 to 4 times per week without much variation. To limit allergens, the patient gave up the daily sandwich and avoided bread altogether, noting remarkable clinical improvement over a few weeks. Later, he described even more improvement while on a trip where he did not have access to his usual beer. The eruption recurred when he returned home and excessively indulged in his favorite beer. He also noted recurrence with exposure to certain breads. No new lesions developed with avoidance of beer and bread, and he had less than 1% body surface area involvement at 2-month follow-up and 0% involvement at 1 year. For educational purposes, follow-up patch testing was performed using Vanicream sorbitol solution and the specific beer and bread the patient consumed. The Vanicream solution was obtained from the manufacturer. The beer was placed directly onto a test disc. The bread was moistened with a drop of saline and then placed directly onto a test disc. All were negative at 48 and 96 hours.

Comment

Sorbitol Ingredients
We report a case of systemic ACD with a positive patch test to sorbitans that was exacerbated with consumption of beer and bread and resolved with avoidance of these products. Although it was determined that the patient used personal care products containing a sorbitol solution, discontinuation did not result in clinical improvement. Sorbitol, sorbitans, and sorbitol derivatives are not commonly reported in the ingredient lists of foods such as beer and bread. Both beer and bread are created with the addition of yeast cultures, for fermentation in beer and for leavening in bread. Sorbitol is used as an osmotic stabilizer in the preparation of yeast strains² and also is a by-product of fermentation by certain bacteria³ found in beer. Additionally, review of commercially available preparations of baker’s and brewer’s yeasts, such as Fleischmann’s and Red Star, list sorbitan monostearate in the ingredients.^4-7 We propose that trace amounts are present in the yeast preparations for brewing and baking.

In this case, the offending beer and bread were locally made products (Abita Beer, Covington, Louisiana; Leidenheimer Bread, New Orleans, Louisiana). Both companies were unable to share their yeast sources, limiting our ability to confirm the use of sorbitol in their preparation. We hypothesize that if sorbitol is commonly used in yeast culture preparation and can be a by-product of fermentation, then it is present in trace amounts in many beers and breads and is not specific to these two products.

Contact Allergy
There are few prior reports of ACD due to beer. A case series in 1969 described 4 patients with positive patch testing to ethanol and alcohol by-products and clinical resolution with avoidance of alcohol.⁸ Another case from 1985 described ACD to beer where patch testing was positive to the beer itself.⁹ Other published cases of cutaneous reactions to beer demonstrated immediate-type hypersensitivity resulting from both ingestion and skin contact, which is thought to be caused by IgE antibodies to malt and barley proteins.^10,11

It is important to distinguish between systemic ACD and oral allergy syndrome (OAS). Although the defining features and criteria for diagnosing OAS have not been officially established, OAS is an IgE-mediated immune reaction commonly described as itching, tingling, or swelling, usually confined to the oral cavity after recent consumption of foods such as raw fruits, vegetables, and nuts.¹² Oral allergy syndrome is treated with antihistamines and avoidance of known food allergens. In comparison, ACD is a type IV hypersensitivity, delayed cell-mediated reaction, commonly presenting with widespread rash.

Occupational contact dermatitis is common in bakers and food handlers and is more often irritant than allergic. Several relevant allergens have been identified in these groups^13,14 and do not include sorbitans; our patient tested positive to both SSO and SMO. Sorbitan sesquioleate and SMO have been increasingly recognized as contact allergens over the last several years, both as standalone allergens and as potential cross-reactors.¹ Sorbitan sesquioleate, SMO, and other sorbitol derivatives are found in cosmetics, topical and oral medications, topical emollients, produce, and other commercial products, including but not limited to topical clindamycin, topical metronidazole, topical ketoconazole, tazarotene cream 0.05% and 0.1%, toothpastes, acetaminophen maximum strength liquid, apples, berries, and sucrose-free cakes and cookies.^1,15,16

In 2014, a study evaluated 12 oral antihistamines as potential sources for systemic contact allergens; 55% of these 12 oral antihistamine preparations included at least 1 of 10 allergen groups specifically identified. The sorbitans and sorbitol derivatives group ranked highest among the group of allergens found listed in these oral medications.¹⁷

Most patients found to have a contact allergy to the products containing SSO, SMO, or sorbitol derivatives reported notable improvement with discontinuation and change to sorbitol-free product use.^1,18 It should be noted that SSO is added as an emulsifier to many of the fragrances used for patch testing. A positive patch test to fragrance mix without concomitant sorbitan testing may incorrectly diagnose the allergen.¹⁹

Patients with atopic dermatitis, particularly those with a filaggrin mutation, are at increased risk for ACD to sorbitans due to a compromised skin barrier and frequent use of topical steroids. In one study, 75% of patients (n=12) with a positive patch test to SSO were using a topical steroid emulsified with sorbitol or sorbitan derivatives.¹⁹

Conclusion

Sorbitan sesquioleate and SMO are increasingly relevant contact allergens. Sorbitol and related substances have been identified in numerous products and may be present in yeast-fermented and leavened goods. When patch testing is positive to SSO and SMO, the dermatologist should inquire about dietary habits with specific attention to beer and bread, in addition to inventorying other dietary preferences, prescription and over-the-counter medications, and personal care products. We suggest dietary considerations only if topical exposures have been eliminated and the rash has not improved.

Sorbitan sesquioleate (SSO), sorbitan monooleate (SMO), and related compounds are increasingly recognized contact allergens. Sorbitan sesquioleate and SMO are nonionic emulsifying agents derived from sorbitol.¹

Sorbitan sesquioleate, SMO, and other sorbitol derivatives are used as emulsifiers and dispersing agents in cosmetics, topical medications, topical emollients, produce, and other commercial products. Related compounds also are found in foods such as apples, berries, cherries, and sucrose-free cakes and cookies.¹ We present a case of allergic contact dermatitis (ACD) with positive patch testing to sorbitans and clinical correlation with beer and bread exposure.

Case Report

A 62-year-old man presented with a persistent pruritic rash of 6 months’ duration. Erythematous eczematous papules and plaques were observed on the face, neck, chest, abdomen, back, and upper and lower extremities, affecting approximately 60% of the body surface area. His current list of medications was reviewed and included a multivitamin, fish oil, and vitamin C. A punch biopsy revealed spongiotic dermatitis with eosinophils. Patch testing using the North American Contact Dermatitis Group Standard Series with supplemental allergens found in toiletries revealed a positive reaction to SSO and SMO that was persistent at 48 and 96 hours. Notably, patch testing for sodium benzoate, nickel, potassium dichromate, and balsam of Peru were negative. Investigation into the personal care products the patient used identified the presence of sorbitol solution in Vanicream bar soap and Vanicream moisturizing cream (Pharmaceutical Specialties Inc). These products were started after the development of the rash and were discontinued after positive patch testing, but the patient continued to experience the eruption with no improvement.

Retrospectively, the patient was able to correlate exacerbations with drinking beer and eating sandwiches. He habitually ate a sandwich on the same type of bread every single day and enjoyed the same brand of beer 2 to 4 times per week without much variation. To limit allergens, the patient gave up the daily sandwich and avoided bread altogether, noting remarkable clinical improvement over a few weeks. Later, he described even more improvement while on a trip where he did not have access to his usual beer. The eruption recurred when he returned home and excessively indulged in his favorite beer. He also noted recurrence with exposure to certain breads. No new lesions developed with avoidance of beer and bread, and he had less than 1% body surface area involvement at 2-month follow-up and 0% involvement at 1 year. For educational purposes, follow-up patch testing was performed using Vanicream sorbitol solution and the specific beer and bread the patient consumed. The Vanicream solution was obtained from the manufacturer. The beer was placed directly onto a test disc. The bread was moistened with a drop of saline and then placed directly onto a test disc. All were negative at 48 and 96 hours.

Comment

Sorbitol Ingredients
We report a case of systemic ACD with a positive patch test to sorbitans that was exacerbated with consumption of beer and bread and resolved with avoidance of these products. Although it was determined that the patient used personal care products containing a sorbitol solution, discontinuation did not result in clinical improvement. Sorbitol, sorbitans, and sorbitol derivatives are not commonly reported in the ingredient lists of foods such as beer and bread. Both beer and bread are created with the addition of yeast cultures, for fermentation in beer and for leavening in bread. Sorbitol is used as an osmotic stabilizer in the preparation of yeast strains² and also is a by-product of fermentation by certain bacteria³ found in beer. Additionally, review of commercially available preparations of baker’s and brewer’s yeasts, such as Fleischmann’s and Red Star, list sorbitan monostearate in the ingredients.^4-7 We propose that trace amounts are present in the yeast preparations for brewing and baking.

In this case, the offending beer and bread were locally made products (Abita Beer, Covington, Louisiana; Leidenheimer Bread, New Orleans, Louisiana). Both companies were unable to share their yeast sources, limiting our ability to confirm the use of sorbitol in their preparation. We hypothesize that if sorbitol is commonly used in yeast culture preparation and can be a by-product of fermentation, then it is present in trace amounts in many beers and breads and is not specific to these two products.

Contact Allergy
There are few prior reports of ACD due to beer. A case series in 1969 described 4 patients with positive patch testing to ethanol and alcohol by-products and clinical resolution with avoidance of alcohol.⁸ Another case from 1985 described ACD to beer where patch testing was positive to the beer itself.⁹ Other published cases of cutaneous reactions to beer demonstrated immediate-type hypersensitivity resulting from both ingestion and skin contact, which is thought to be caused by IgE antibodies to malt and barley proteins.^10,11

It is important to distinguish between systemic ACD and oral allergy syndrome (OAS). Although the defining features and criteria for diagnosing OAS have not been officially established, OAS is an IgE-mediated immune reaction commonly described as itching, tingling, or swelling, usually confined to the oral cavity after recent consumption of foods such as raw fruits, vegetables, and nuts.¹² Oral allergy syndrome is treated with antihistamines and avoidance of known food allergens. In comparison, ACD is a type IV hypersensitivity, delayed cell-mediated reaction, commonly presenting with widespread rash.

Occupational contact dermatitis is common in bakers and food handlers and is more often irritant than allergic. Several relevant allergens have been identified in these groups^13,14 and do not include sorbitans; our patient tested positive to both SSO and SMO. Sorbitan sesquioleate and SMO have been increasingly recognized as contact allergens over the last several years, both as standalone allergens and as potential cross-reactors.¹ Sorbitan sesquioleate, SMO, and other sorbitol derivatives are found in cosmetics, topical and oral medications, topical emollients, produce, and other commercial products, including but not limited to topical clindamycin, topical metronidazole, topical ketoconazole, tazarotene cream 0.05% and 0.1%, toothpastes, acetaminophen maximum strength liquid, apples, berries, and sucrose-free cakes and cookies.^1,15,16

In 2014, a study evaluated 12 oral antihistamines as potential sources for systemic contact allergens; 55% of these 12 oral antihistamine preparations included at least 1 of 10 allergen groups specifically identified. The sorbitans and sorbitol derivatives group ranked highest among the group of allergens found listed in these oral medications.¹⁷

Most patients found to have a contact allergy to the products containing SSO, SMO, or sorbitol derivatives reported notable improvement with discontinuation and change to sorbitol-free product use.^1,18 It should be noted that SSO is added as an emulsifier to many of the fragrances used for patch testing. A positive patch test to fragrance mix without concomitant sorbitan testing may incorrectly diagnose the allergen.¹⁹

Patients with atopic dermatitis, particularly those with a filaggrin mutation, are at increased risk for ACD to sorbitans due to a compromised skin barrier and frequent use of topical steroids. In one study, 75% of patients (n=12) with a positive patch test to SSO were using a topical steroid emulsified with sorbitol or sorbitan derivatives.¹⁹

Conclusion

Sorbitan sesquioleate and SMO are increasingly relevant contact allergens. Sorbitol and related substances have been identified in numerous products and may be present in yeast-fermented and leavened goods. When patch testing is positive to SSO and SMO, the dermatologist should inquire about dietary habits with specific attention to beer and bread, in addition to inventorying other dietary preferences, prescription and over-the-counter medications, and personal care products. We suggest dietary considerations only if topical exposures have been eliminated and the rash has not improved.

Sorbitan sesquioleate (SSO), sorbitan monooleate (SMO), and related compounds are increasingly recognized contact allergens. Sorbitan sesquioleate and SMO are nonionic emulsifying agents derived from sorbitol.¹

Sorbitan sesquioleate, SMO, and other sorbitol derivatives are used as emulsifiers and dispersing agents in cosmetics, topical medications, topical emollients, produce, and other commercial products. Related compounds also are found in foods such as apples, berries, cherries, and sucrose-free cakes and cookies.¹ We present a case of allergic contact dermatitis (ACD) with positive patch testing to sorbitans and clinical correlation with beer and bread exposure.

Case Report

A 62-year-old man presented with a persistent pruritic rash of 6 months’ duration. Erythematous eczematous papules and plaques were observed on the face, neck, chest, abdomen, back, and upper and lower extremities, affecting approximately 60% of the body surface area. His current list of medications was reviewed and included a multivitamin, fish oil, and vitamin C. A punch biopsy revealed spongiotic dermatitis with eosinophils. Patch testing using the North American Contact Dermatitis Group Standard Series with supplemental allergens found in toiletries revealed a positive reaction to SSO and SMO that was persistent at 48 and 96 hours. Notably, patch testing for sodium benzoate, nickel, potassium dichromate, and balsam of Peru were negative. Investigation into the personal care products the patient used identified the presence of sorbitol solution in Vanicream bar soap and Vanicream moisturizing cream (Pharmaceutical Specialties Inc). These products were started after the development of the rash and were discontinued after positive patch testing, but the patient continued to experience the eruption with no improvement.

Retrospectively, the patient was able to correlate exacerbations with drinking beer and eating sandwiches. He habitually ate a sandwich on the same type of bread every single day and enjoyed the same brand of beer 2 to 4 times per week without much variation. To limit allergens, the patient gave up the daily sandwich and avoided bread altogether, noting remarkable clinical improvement over a few weeks. Later, he described even more improvement while on a trip where he did not have access to his usual beer. The eruption recurred when he returned home and excessively indulged in his favorite beer. He also noted recurrence with exposure to certain breads. No new lesions developed with avoidance of beer and bread, and he had less than 1% body surface area involvement at 2-month follow-up and 0% involvement at 1 year. For educational purposes, follow-up patch testing was performed using Vanicream sorbitol solution and the specific beer and bread the patient consumed. The Vanicream solution was obtained from the manufacturer. The beer was placed directly onto a test disc. The bread was moistened with a drop of saline and then placed directly onto a test disc. All were negative at 48 and 96 hours.

Comment

Sorbitol Ingredients
We report a case of systemic ACD with a positive patch test to sorbitans that was exacerbated with consumption of beer and bread and resolved with avoidance of these products. Although it was determined that the patient used personal care products containing a sorbitol solution, discontinuation did not result in clinical improvement. Sorbitol, sorbitans, and sorbitol derivatives are not commonly reported in the ingredient lists of foods such as beer and bread. Both beer and bread are created with the addition of yeast cultures, for fermentation in beer and for leavening in bread. Sorbitol is used as an osmotic stabilizer in the preparation of yeast strains² and also is a by-product of fermentation by certain bacteria³ found in beer. Additionally, review of commercially available preparations of baker’s and brewer’s yeasts, such as Fleischmann’s and Red Star, list sorbitan monostearate in the ingredients.^4-7 We propose that trace amounts are present in the yeast preparations for brewing and baking.

In this case, the offending beer and bread were locally made products (Abita Beer, Covington, Louisiana; Leidenheimer Bread, New Orleans, Louisiana). Both companies were unable to share their yeast sources, limiting our ability to confirm the use of sorbitol in their preparation. We hypothesize that if sorbitol is commonly used in yeast culture preparation and can be a by-product of fermentation, then it is present in trace amounts in many beers and breads and is not specific to these two products.

Contact Allergy
There are few prior reports of ACD due to beer. A case series in 1969 described 4 patients with positive patch testing to ethanol and alcohol by-products and clinical resolution with avoidance of alcohol.⁸ Another case from 1985 described ACD to beer where patch testing was positive to the beer itself.⁹ Other published cases of cutaneous reactions to beer demonstrated immediate-type hypersensitivity resulting from both ingestion and skin contact, which is thought to be caused by IgE antibodies to malt and barley proteins.^10,11

It is important to distinguish between systemic ACD and oral allergy syndrome (OAS). Although the defining features and criteria for diagnosing OAS have not been officially established, OAS is an IgE-mediated immune reaction commonly described as itching, tingling, or swelling, usually confined to the oral cavity after recent consumption of foods such as raw fruits, vegetables, and nuts.¹² Oral allergy syndrome is treated with antihistamines and avoidance of known food allergens. In comparison, ACD is a type IV hypersensitivity, delayed cell-mediated reaction, commonly presenting with widespread rash.

Occupational contact dermatitis is common in bakers and food handlers and is more often irritant than allergic. Several relevant allergens have been identified in these groups^13,14 and do not include sorbitans; our patient tested positive to both SSO and SMO. Sorbitan sesquioleate and SMO have been increasingly recognized as contact allergens over the last several years, both as standalone allergens and as potential cross-reactors.¹ Sorbitan sesquioleate, SMO, and other sorbitol derivatives are found in cosmetics, topical and oral medications, topical emollients, produce, and other commercial products, including but not limited to topical clindamycin, topical metronidazole, topical ketoconazole, tazarotene cream 0.05% and 0.1%, toothpastes, acetaminophen maximum strength liquid, apples, berries, and sucrose-free cakes and cookies.^1,15,16

In 2014, a study evaluated 12 oral antihistamines as potential sources for systemic contact allergens; 55% of these 12 oral antihistamine preparations included at least 1 of 10 allergen groups specifically identified. The sorbitans and sorbitol derivatives group ranked highest among the group of allergens found listed in these oral medications.¹⁷

Most patients found to have a contact allergy to the products containing SSO, SMO, or sorbitol derivatives reported notable improvement with discontinuation and change to sorbitol-free product use.^1,18 It should be noted that SSO is added as an emulsifier to many of the fragrances used for patch testing. A positive patch test to fragrance mix without concomitant sorbitan testing may incorrectly diagnose the allergen.¹⁹

Patients with atopic dermatitis, particularly those with a filaggrin mutation, are at increased risk for ACD to sorbitans due to a compromised skin barrier and frequent use of topical steroids. In one study, 75% of patients (n=12) with a positive patch test to SSO were using a topical steroid emulsified with sorbitol or sorbitan derivatives.¹⁹

Conclusion

Sorbitan sesquioleate and SMO are increasingly relevant contact allergens. Sorbitol and related substances have been identified in numerous products and may be present in yeast-fermented and leavened goods. When patch testing is positive to SSO and SMO, the dermatologist should inquire about dietary habits with specific attention to beer and bread, in addition to inventorying other dietary preferences, prescription and over-the-counter medications, and personal care products. We suggest dietary considerations only if topical exposures have been eliminated and the rash has not improved.

Candida albicans (C albicans) is a normal commensal in the human gastrointestinal (GI) tract. In addition to localized infections in healthy human beings, dissemination with fatal outcome can occur in immunocompromised individuals.¹

Invasive candidiasis (IC) due to C albicans is the most common nosocomial mycosis in the world and has 2 forms, candidemia and deep-seated tissue candidiasis, which can lead to multisystem organ failure.² The deep-seated form may originate from nonhematogenous routes, such as introduction through a peritoneal catheter or ascending infection from cystitis.² In addition, about 50% of primary candidemia cases lead to secondary deep-seated candidiasis; however, only about 40% of these cases show positive blood cultures. Since the window of opportunity for a positive culture is narrow, active candidemia may be missed.^3,4

Once developed, the prognosis for IC is grim: Mortality is 40% regardless of therapy.² IC typically occurs in immunocompromised hosts; IC in immunocompetent persons has rarely been reported.^5,6 It is challenging to diagnose IC in the immunocompetent patients as 50% to 70% of the general population is naturally colonized by this organism, and when found, it is assumed to be mostly innocuous. Neutrophil-driven cell-mediated immunity associated with IL-1 and IL-17 response prevent fungal growth and dissemination, protecting the immunocompetent host.⁷

We report on a patient who showed no neutropenia or leukocytopenia but developed disseminated candidiasis. This report is one of the rare cases of full-blown disseminated candidiasis with lesions related to C albicans found in almost all of the important organs.

Case Presentation

A 67-year-old male patient with a history of hypertension, peripheral vascular disease, daily heavy alcohol consumption, and a 50-pack-year history of smoking developed gangrene of the left fifth toe. He underwent vascular surgery consultation with an aortogram/left lower extremity angiography that showed occlusion of the left external iliac artery as well as the left common femoral artery. It was decided to improve inflow in the common iliac artery by placing a bare metal stent and subsequent balloon dilatation before a right to left femoral to femoral artery bypass. The patient tolerated the procedure well and was discharged home.

Two days later, the patient was admitted to a US Department of Veterans Affairs (VA) complexity level 1a hospital with weakness and worsening pain in the left lower extremities. Examination revealed chronic ischemic changes in the feet bilaterally and evidence of dry gangrene in the left fifth toe requiring femoral bypass surgery. But poor nutritional status and cardiac status prevented pursuing a permanent solution.

Following completion of a stress echocardiogram, the patient developed shock with systolic blood pressure of 60 mm Hg, and atrial fibrillation (AF) with rapid ventricular rate (RVR). He was initially treated with IV fluid supplementation, vasopressor therapy, synchronized cardioversion, and IV amiodarone/anticoagulation therapy, due to his persistent AF with RVR. The patient was transferred to a tertiary care center for persistent hypothermia and received treatment with warm saline. After initial recovery with warm saline resuscitation, he had a prolonged, complicated hospital course in which he developed progressive respiratory failure requiring intubation and critical care support. He developed a right internal jugular deep venous thrombosis, heparin-induced thrombocytopenia, lower GI bleeding requiring emergent embolization by interventional radiology, inferior vena cava filter placement, renal failure requiring dialysis, small bowel obstruction secondary to right lower quadrant phlegmon and perforation requiring small bowel resection and end ileostomy. His antibiotic regimen included therapy with vancomycin and piperacillin-tazobactam.

He eventually recovered and was extubated and subsequently transferred back to the VA hospital where cefepime was initiated because of suspicion of a urinary tract infection and septicemia (urine cultures eventually grew C albicans). Over the subsequent 3 days, the patient’s renal output and hyperkalemia worsened, he also developed increased anion gap metabolic acidosis and was intubated again and placed on full mechanical ventilatory support. His blood cultures were negative, and sputum cultures revealed normal respiratory flora and 1+ C albicans. Infectious diseases consultation recommended an abdominal ultrasound, which revealed nonspecific findings. The antibiotic regimen was changed to daptomycin and piperacillin-tazobactam. A follow-up chest X-ray revealed a developing right lower lobe pneumonia and hilar prominence suggestive of lymphadenopathy. The patient’s clinical condition deteriorated, and he subsequently developed cardiac arrest; resuscitation was not successful and he expired.

Outcome and Follow-up

An autopsy disclosed the cause of death to be bilateral candida pneumonia, part of a disseminated (invasive) candidiasis, in a patient rendered vulnerable to such infection by peripheral vascular disease and renal insufficiency. Purulent inflammation was noted at the site of disarticulation of the left foot and confluent consolidation of the lower lobes of both lungs as well as focal consolidation of the middle lobe of the right lung. Examination of histologic sections, with staining both by routine method (hematoxylin and eosin) and the Grocott-Gömöri methenamine silver method for fungus, disclosed fungal forms (yeast and filamentous) in most tissues, including the lungs (Figure 1 A and B) and kidneys (Figure 1 C and D). The pulmonary sections in addition to massive inflammation showed macrophages with engulfed yeast (Figure 2 A) and a lymphatic channel, stuffed with yeast in an alveolar septum (Figure 2 B). These findings confirmed the antemortem presence of the fungus and the body’s response to it. Inflammation was noted around glomeruli overgrown by candida (Figure 1 C and D); fungi also were seen in capsular regions (not depicted). C albicans was present in the myocardium (Figure 1 E and F), brain, thyroid, and adrenal glands (Figure 3); the only organ without C albicans was the liver, either because invasion was truly absent here or because sampling had not managed to retrieve it.

Paraffin-embedded blocks of lung tissue, sent to the University of Washington Molecular Diagnosis Microbiology Laboratory for broad-range polymerase chain reaction (PCR) identification, were positive for C albicans after extraction of gDNA and conduction of PCR using internal transcribed spacer 1 and 2 specific primers.

Discussion

IC is rare among immunocompetent individuals, but C albicans can evolve into a fatal disseminated infection. We report an atypical case of IC, with profound pulmonary infection in a patient who died 1 month after hospitalization for lower extremity pain.

Cell-mediated immunity involving neutrophils and macrophages plays a major role in protection against candidiasis, while cytokines and chemokines involve regulating balanced immunity.^1,2 A series of recent studies show that alcohol impairs neutrophil-mediated killing and phagocytic-mediated uptake of a pathogen in this process.^8,9 As the patient chronically misused alcohol, his immune system may have experienced a subclinical immunosuppression, which would have become clinically relevant once C albicans was introduced systemically. Recent studies of bacterial pathogenesis and alcoholism strongly support this hypothesis.^10,11

Most patients with the unusual diagnosis of candida pneumonia have had a background of malignancy or immunosuppressive factors (eg, administration of corticosteroids).¹² In a series of 20 cases, 14 had sputum cultures positive for the organism, 6 had positive urine cultures, and 6 had positive blood cultures. Chest radiographs usually showed confluent bronchopneumonia. Five patients were diagnosed antemortem and treated with amphotericin B, but none survived.¹³ In the literature a positive blood culture or demonstration of yeast within pulmonary histiocytes has been considered proof of the pathogenicity of the fungus, as opposed to noninvasive colonization of the airways, a common occurrence in patients receiving mechanical ventilation.²

The C albicans in this case may have been introduced hematogenously from the amputation site or through an ascending cystitis, or possibly have been derived from commensal flora in the GI tract. The iron supplementation provided to the patient may have promoted the growth and virulence of the candida; studies have shown that the kidneys assimilate increased levels of iron during disseminated candidiasis thus providing a more favorable site for colonization.¹⁷The presence of C albicans in a single collection of sputum or urine does not ordinarily indicate infection in an immunocompetent individual. Estimation of serum procalcitonin, a biomarker for bacterial infection and sepsis, might be useful if negative, for turning attention to a nonbacterial (such as, candida) source as the causative agent.¹⁸

Conclusion

C albicans can rarely cause disseminated disease in nonimmunocompromised critically ill patients. Low serum procalcitonin levels in a septic patient might indicate nonbacterial cause such as candidiasis. Even with disseminated candidiasis, blood cultures may remain negative.

Candida albicans (C albicans) is a normal commensal in the human gastrointestinal (GI) tract. In addition to localized infections in healthy human beings, dissemination with fatal outcome can occur in immunocompromised individuals.¹

Invasive candidiasis (IC) due to C albicans is the most common nosocomial mycosis in the world and has 2 forms, candidemia and deep-seated tissue candidiasis, which can lead to multisystem organ failure.² The deep-seated form may originate from nonhematogenous routes, such as introduction through a peritoneal catheter or ascending infection from cystitis.² In addition, about 50% of primary candidemia cases lead to secondary deep-seated candidiasis; however, only about 40% of these cases show positive blood cultures. Since the window of opportunity for a positive culture is narrow, active candidemia may be missed.^3,4

Once developed, the prognosis for IC is grim: Mortality is 40% regardless of therapy.² IC typically occurs in immunocompromised hosts; IC in immunocompetent persons has rarely been reported.^5,6 It is challenging to diagnose IC in the immunocompetent patients as 50% to 70% of the general population is naturally colonized by this organism, and when found, it is assumed to be mostly innocuous. Neutrophil-driven cell-mediated immunity associated with IL-1 and IL-17 response prevent fungal growth and dissemination, protecting the immunocompetent host.⁷

We report on a patient who showed no neutropenia or leukocytopenia but developed disseminated candidiasis. This report is one of the rare cases of full-blown disseminated candidiasis with lesions related to C albicans found in almost all of the important organs.

Case Presentation

A 67-year-old male patient with a history of hypertension, peripheral vascular disease, daily heavy alcohol consumption, and a 50-pack-year history of smoking developed gangrene of the left fifth toe. He underwent vascular surgery consultation with an aortogram/left lower extremity angiography that showed occlusion of the left external iliac artery as well as the left common femoral artery. It was decided to improve inflow in the common iliac artery by placing a bare metal stent and subsequent balloon dilatation before a right to left femoral to femoral artery bypass. The patient tolerated the procedure well and was discharged home.

Two days later, the patient was admitted to a US Department of Veterans Affairs (VA) complexity level 1a hospital with weakness and worsening pain in the left lower extremities. Examination revealed chronic ischemic changes in the feet bilaterally and evidence of dry gangrene in the left fifth toe requiring femoral bypass surgery. But poor nutritional status and cardiac status prevented pursuing a permanent solution.

Following completion of a stress echocardiogram, the patient developed shock with systolic blood pressure of 60 mm Hg, and atrial fibrillation (AF) with rapid ventricular rate (RVR). He was initially treated with IV fluid supplementation, vasopressor therapy, synchronized cardioversion, and IV amiodarone/anticoagulation therapy, due to his persistent AF with RVR. The patient was transferred to a tertiary care center for persistent hypothermia and received treatment with warm saline. After initial recovery with warm saline resuscitation, he had a prolonged, complicated hospital course in which he developed progressive respiratory failure requiring intubation and critical care support. He developed a right internal jugular deep venous thrombosis, heparin-induced thrombocytopenia, lower GI bleeding requiring emergent embolization by interventional radiology, inferior vena cava filter placement, renal failure requiring dialysis, small bowel obstruction secondary to right lower quadrant phlegmon and perforation requiring small bowel resection and end ileostomy. His antibiotic regimen included therapy with vancomycin and piperacillin-tazobactam.

He eventually recovered and was extubated and subsequently transferred back to the VA hospital where cefepime was initiated because of suspicion of a urinary tract infection and septicemia (urine cultures eventually grew C albicans). Over the subsequent 3 days, the patient’s renal output and hyperkalemia worsened, he also developed increased anion gap metabolic acidosis and was intubated again and placed on full mechanical ventilatory support. His blood cultures were negative, and sputum cultures revealed normal respiratory flora and 1+ C albicans. Infectious diseases consultation recommended an abdominal ultrasound, which revealed nonspecific findings. The antibiotic regimen was changed to daptomycin and piperacillin-tazobactam. A follow-up chest X-ray revealed a developing right lower lobe pneumonia and hilar prominence suggestive of lymphadenopathy. The patient’s clinical condition deteriorated, and he subsequently developed cardiac arrest; resuscitation was not successful and he expired.

Outcome and Follow-up

An autopsy disclosed the cause of death to be bilateral candida pneumonia, part of a disseminated (invasive) candidiasis, in a patient rendered vulnerable to such infection by peripheral vascular disease and renal insufficiency. Purulent inflammation was noted at the site of disarticulation of the left foot and confluent consolidation of the lower lobes of both lungs as well as focal consolidation of the middle lobe of the right lung. Examination of histologic sections, with staining both by routine method (hematoxylin and eosin) and the Grocott-Gömöri methenamine silver method for fungus, disclosed fungal forms (yeast and filamentous) in most tissues, including the lungs (Figure 1 A and B) and kidneys (Figure 1 C and D). The pulmonary sections in addition to massive inflammation showed macrophages with engulfed yeast (Figure 2 A) and a lymphatic channel, stuffed with yeast in an alveolar septum (Figure 2 B). These findings confirmed the antemortem presence of the fungus and the body’s response to it. Inflammation was noted around glomeruli overgrown by candida (Figure 1 C and D); fungi also were seen in capsular regions (not depicted). C albicans was present in the myocardium (Figure 1 E and F), brain, thyroid, and adrenal glands (Figure 3); the only organ without C albicans was the liver, either because invasion was truly absent here or because sampling had not managed to retrieve it.

Paraffin-embedded blocks of lung tissue, sent to the University of Washington Molecular Diagnosis Microbiology Laboratory for broad-range polymerase chain reaction (PCR) identification, were positive for C albicans after extraction of gDNA and conduction of PCR using internal transcribed spacer 1 and 2 specific primers.

Discussion

IC is rare among immunocompetent individuals, but C albicans can evolve into a fatal disseminated infection. We report an atypical case of IC, with profound pulmonary infection in a patient who died 1 month after hospitalization for lower extremity pain.

Cell-mediated immunity involving neutrophils and macrophages plays a major role in protection against candidiasis, while cytokines and chemokines involve regulating balanced immunity.^1,2 A series of recent studies show that alcohol impairs neutrophil-mediated killing and phagocytic-mediated uptake of a pathogen in this process.^8,9 As the patient chronically misused alcohol, his immune system may have experienced a subclinical immunosuppression, which would have become clinically relevant once C albicans was introduced systemically. Recent studies of bacterial pathogenesis and alcoholism strongly support this hypothesis.^10,11

Most patients with the unusual diagnosis of candida pneumonia have had a background of malignancy or immunosuppressive factors (eg, administration of corticosteroids).¹² In a series of 20 cases, 14 had sputum cultures positive for the organism, 6 had positive urine cultures, and 6 had positive blood cultures. Chest radiographs usually showed confluent bronchopneumonia. Five patients were diagnosed antemortem and treated with amphotericin B, but none survived.¹³ In the literature a positive blood culture or demonstration of yeast within pulmonary histiocytes has been considered proof of the pathogenicity of the fungus, as opposed to noninvasive colonization of the airways, a common occurrence in patients receiving mechanical ventilation.²

The C albicans in this case may have been introduced hematogenously from the amputation site or through an ascending cystitis, or possibly have been derived from commensal flora in the GI tract. The iron supplementation provided to the patient may have promoted the growth and virulence of the candida; studies have shown that the kidneys assimilate increased levels of iron during disseminated candidiasis thus providing a more favorable site for colonization.¹⁷The presence of C albicans in a single collection of sputum or urine does not ordinarily indicate infection in an immunocompetent individual. Estimation of serum procalcitonin, a biomarker for bacterial infection and sepsis, might be useful if negative, for turning attention to a nonbacterial (such as, candida) source as the causative agent.¹⁸

Conclusion

C albicans can rarely cause disseminated disease in nonimmunocompromised critically ill patients. Low serum procalcitonin levels in a septic patient might indicate nonbacterial cause such as candidiasis. Even with disseminated candidiasis, blood cultures may remain negative.

Candida albicans (C albicans) is a normal commensal in the human gastrointestinal (GI) tract. In addition to localized infections in healthy human beings, dissemination with fatal outcome can occur in immunocompromised individuals.¹

Invasive candidiasis (IC) due to C albicans is the most common nosocomial mycosis in the world and has 2 forms, candidemia and deep-seated tissue candidiasis, which can lead to multisystem organ failure.² The deep-seated form may originate from nonhematogenous routes, such as introduction through a peritoneal catheter or ascending infection from cystitis.² In addition, about 50% of primary candidemia cases lead to secondary deep-seated candidiasis; however, only about 40% of these cases show positive blood cultures. Since the window of opportunity for a positive culture is narrow, active candidemia may be missed.^3,4

Once developed, the prognosis for IC is grim: Mortality is 40% regardless of therapy.² IC typically occurs in immunocompromised hosts; IC in immunocompetent persons has rarely been reported.^5,6 It is challenging to diagnose IC in the immunocompetent patients as 50% to 70% of the general population is naturally colonized by this organism, and when found, it is assumed to be mostly innocuous. Neutrophil-driven cell-mediated immunity associated with IL-1 and IL-17 response prevent fungal growth and dissemination, protecting the immunocompetent host.⁷

We report on a patient who showed no neutropenia or leukocytopenia but developed disseminated candidiasis. This report is one of the rare cases of full-blown disseminated candidiasis with lesions related to C albicans found in almost all of the important organs.

Case Presentation

A 67-year-old male patient with a history of hypertension, peripheral vascular disease, daily heavy alcohol consumption, and a 50-pack-year history of smoking developed gangrene of the left fifth toe. He underwent vascular surgery consultation with an aortogram/left lower extremity angiography that showed occlusion of the left external iliac artery as well as the left common femoral artery. It was decided to improve inflow in the common iliac artery by placing a bare metal stent and subsequent balloon dilatation before a right to left femoral to femoral artery bypass. The patient tolerated the procedure well and was discharged home.

Two days later, the patient was admitted to a US Department of Veterans Affairs (VA) complexity level 1a hospital with weakness and worsening pain in the left lower extremities. Examination revealed chronic ischemic changes in the feet bilaterally and evidence of dry gangrene in the left fifth toe requiring femoral bypass surgery. But poor nutritional status and cardiac status prevented pursuing a permanent solution.

Following completion of a stress echocardiogram, the patient developed shock with systolic blood pressure of 60 mm Hg, and atrial fibrillation (AF) with rapid ventricular rate (RVR). He was initially treated with IV fluid supplementation, vasopressor therapy, synchronized cardioversion, and IV amiodarone/anticoagulation therapy, due to his persistent AF with RVR. The patient was transferred to a tertiary care center for persistent hypothermia and received treatment with warm saline. After initial recovery with warm saline resuscitation, he had a prolonged, complicated hospital course in which he developed progressive respiratory failure requiring intubation and critical care support. He developed a right internal jugular deep venous thrombosis, heparin-induced thrombocytopenia, lower GI bleeding requiring emergent embolization by interventional radiology, inferior vena cava filter placement, renal failure requiring dialysis, small bowel obstruction secondary to right lower quadrant phlegmon and perforation requiring small bowel resection and end ileostomy. His antibiotic regimen included therapy with vancomycin and piperacillin-tazobactam.

He eventually recovered and was extubated and subsequently transferred back to the VA hospital where cefepime was initiated because of suspicion of a urinary tract infection and septicemia (urine cultures eventually grew C albicans). Over the subsequent 3 days, the patient’s renal output and hyperkalemia worsened, he also developed increased anion gap metabolic acidosis and was intubated again and placed on full mechanical ventilatory support. His blood cultures were negative, and sputum cultures revealed normal respiratory flora and 1+ C albicans. Infectious diseases consultation recommended an abdominal ultrasound, which revealed nonspecific findings. The antibiotic regimen was changed to daptomycin and piperacillin-tazobactam. A follow-up chest X-ray revealed a developing right lower lobe pneumonia and hilar prominence suggestive of lymphadenopathy. The patient’s clinical condition deteriorated, and he subsequently developed cardiac arrest; resuscitation was not successful and he expired.

Outcome and Follow-up

An autopsy disclosed the cause of death to be bilateral candida pneumonia, part of a disseminated (invasive) candidiasis, in a patient rendered vulnerable to such infection by peripheral vascular disease and renal insufficiency. Purulent inflammation was noted at the site of disarticulation of the left foot and confluent consolidation of the lower lobes of both lungs as well as focal consolidation of the middle lobe of the right lung. Examination of histologic sections, with staining both by routine method (hematoxylin and eosin) and the Grocott-Gömöri methenamine silver method for fungus, disclosed fungal forms (yeast and filamentous) in most tissues, including the lungs (Figure 1 A and B) and kidneys (Figure 1 C and D). The pulmonary sections in addition to massive inflammation showed macrophages with engulfed yeast (Figure 2 A) and a lymphatic channel, stuffed with yeast in an alveolar septum (Figure 2 B). These findings confirmed the antemortem presence of the fungus and the body’s response to it. Inflammation was noted around glomeruli overgrown by candida (Figure 1 C and D); fungi also were seen in capsular regions (not depicted). C albicans was present in the myocardium (Figure 1 E and F), brain, thyroid, and adrenal glands (Figure 3); the only organ without C albicans was the liver, either because invasion was truly absent here or because sampling had not managed to retrieve it.

Paraffin-embedded blocks of lung tissue, sent to the University of Washington Molecular Diagnosis Microbiology Laboratory for broad-range polymerase chain reaction (PCR) identification, were positive for C albicans after extraction of gDNA and conduction of PCR using internal transcribed spacer 1 and 2 specific primers.

Discussion

IC is rare among immunocompetent individuals, but C albicans can evolve into a fatal disseminated infection. We report an atypical case of IC, with profound pulmonary infection in a patient who died 1 month after hospitalization for lower extremity pain.

Cell-mediated immunity involving neutrophils and macrophages plays a major role in protection against candidiasis, while cytokines and chemokines involve regulating balanced immunity.^1,2 A series of recent studies show that alcohol impairs neutrophil-mediated killing and phagocytic-mediated uptake of a pathogen in this process.^8,9 As the patient chronically misused alcohol, his immune system may have experienced a subclinical immunosuppression, which would have become clinically relevant once C albicans was introduced systemically. Recent studies of bacterial pathogenesis and alcoholism strongly support this hypothesis.^10,11

Most patients with the unusual diagnosis of candida pneumonia have had a background of malignancy or immunosuppressive factors (eg, administration of corticosteroids).¹² In a series of 20 cases, 14 had sputum cultures positive for the organism, 6 had positive urine cultures, and 6 had positive blood cultures. Chest radiographs usually showed confluent bronchopneumonia. Five patients were diagnosed antemortem and treated with amphotericin B, but none survived.¹³ In the literature a positive blood culture or demonstration of yeast within pulmonary histiocytes has been considered proof of the pathogenicity of the fungus, as opposed to noninvasive colonization of the airways, a common occurrence in patients receiving mechanical ventilation.²

The C albicans in this case may have been introduced hematogenously from the amputation site or through an ascending cystitis, or possibly have been derived from commensal flora in the GI tract. The iron supplementation provided to the patient may have promoted the growth and virulence of the candida; studies have shown that the kidneys assimilate increased levels of iron during disseminated candidiasis thus providing a more favorable site for colonization.¹⁷The presence of C albicans in a single collection of sputum or urine does not ordinarily indicate infection in an immunocompetent individual. Estimation of serum procalcitonin, a biomarker for bacterial infection and sepsis, might be useful if negative, for turning attention to a nonbacterial (such as, candida) source as the causative agent.¹⁸

Conclusion

C albicans can rarely cause disseminated disease in nonimmunocompromised critically ill patients. Low serum procalcitonin levels in a septic patient might indicate nonbacterial cause such as candidiasis. Even with disseminated candidiasis, blood cultures may remain negative.