A Diagnostic Dilemma of a Case of Granulomatosis With Polyangiitis (GPA) Presenting With Thrombotic Vasculopathy.

Granulomatosis with polyangiitis (GPA) is a rare disease with a prevalence of about three in 100,000 persons in the United States. GPA is an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis affecting predominantly small-sized vessels. It can present with localized or systemic symptoms with multiple organ involvement, thus making diagnosis challenging. Common skin lesions in GPA are palpable purpura, petechiae, ulcers, and livedo reticularis. These lesions usually have underlying vasculitis with or without granuloma on histology findings. To date, there have been no previous reports about thrombotic vasculopathy in GPA before. We present a case of a 25-year-old female who presented with intermittent joint pain for weeks, purpuric rash, and mild hemoptysis for a few days. A review of systems was notable for a 15-pound weight loss in one year. Physical examination was significant for a purpuric rash on the left elbow and toe, and left knee swelling and erythema. Presenting laboratory results were notable for anemia, indirect hyperbilirubinemia, mildly elevated D-dimers, and microscopic hematuria. Chest radiograph revealed confluent airspace disease. Extensive infectious workup was negative. A skin biopsy of her left toe revealed dermal intravascular thrombi without evidence of vasculitis. The thrombotic vasculopathy did not favor vasculitis but raised concern for a hypercoagulable state. However, extensive hematologic workup was negative. Bronchoscopy findings were consistent with diffuse alveolar hemorrhage. Later, cytoplasmic ANCA (c-ANCA) and anti-proteinase 3 (PR3) antibody titers were positive. Her diagnosis was unclear since both skin biopsy and bronchoscopy were nonspecific and inconsistent with her positive antibody results. The patient eventually underwent a kidney biopsy, which showed pauci-immune necrotizing and crescentic glomerulonephritis. Finally, a diagnosis of granulomatosis with polyangiitis was made based on the kidney biopsy and positive c-ANCA. The patient was treated with steroids and IV rituximab and discharged home with outpatient rheumatology follow-up. Due to multiple signs and symptoms including thrombotic vasculopathy, there was a diagnostic dilemma requiring a multidisciplinary approach. This case highlights the importance of pattern recognition for the diagnostic framework of rare disease entities and the multidisciplinary collaborative efforts required to reach the final diagnosis.

A wolf in sheep's clothing: Dogs confer an unrecognized risk for their immunocompromised master.

Bordetella bronchiseptica is a pleomorphic gram-negative coccobacillus that commonly causes respiratory tract infections in canines, felines, and swine. Human infections are rare. We report a case of Bordetella bronchiseptica pneumonia in a 67-year-old immunocompromised host. His past medical history included multiple myeloma treated with autologous bone marrow transplant followed by a chimeric antigen receptor cell therapy for relapse. He was admitted with unrelenting diarrhea due to HHV-6 pancolitis. During the hospital course he developed high-grade fever (102.3°F), cough and respiratory failure requiring mechanical ventilation. Chest imaging demonstrated bilateral opacities most pronounced at lung bases and worsening mediastinal lymphadenopathy. Bronchoalveolar lavage cultures grew Bordetella bronchiseptica. He was treated with piperacillin/tazobactam, but developed progressive multiorgan failure, transitioned to comfort care, and expired in the hospital. Bordetella bronchiseptica is an organism that do not cause serious infection in immunocompetent persons but can sometimes cause serious illness in immunocompromised populations. It causes "kennel cough" in dogs and spready by respiratory droplets. Dogs and cats are not uniformly vaccinated against this pathogen. Therefore, transmission through animal contact is becoming increasingly common. Realize that unlike other Bordetella spp, this pathogen is not typically responsive to erythromycin and is often resistant to ampicillin and cephalosporins so the typical neutropenic fever coverage with an antipseudomonal cephalosporin and azithromycin might not be effective. Given the increasing recognition of this zoonosis as a threat to the immunocompromised, it is essential to educate immunocompromised patients to minimize zoonotic exposure, as immunization of pets might not confer protection to humans.

Ketoconazole-Associated Liver Injury in Drug-Drug Interaction Studies in Healthy Volunteers.

Ketoconazole is a potent CYP3A inhibitor in vivo, and frequently serves as an index CYP3A inhibitor in drug-drug interaction (DDI) studies with healthy volunteers. Limitations restricting the use of systemic ketoconazole in such studies have been recently imposed by regulatory agencies in the United States, the European Union, and elsewhere. A risk of ketoconazole-associated liver injury in the context of DDI studies was cited as the primary justification for these measures. To evaluate the basis for these restrictions, we analyzed a series of published DDI studies identified from a review of existing literature. The study set consisted of 53 DDI studies, and included 971 healthy volunteers with systemic ketoconazole exposure in addition to the victim drug under study. Ketoconazole-associated abnormalities in serum chemistry values indicative of liver injury were observed in 4 subjects, representing a prevalence of 0.41% within the study population. There were no major adverse reactions or instances of hepatic failure. All abnormalities indicative of liver injury resolved upon discontinuation of ketoconazole treatment. The findings from this review do not support restriction of ketoconazole as an index CYP3A inhibitor in DDI studies involving healthy volunteers.