Randi Y. Leavitt

Surgical pathology of the lung in Wegener's granulomatosis: Review of 87 open lung biopsies from 67 patients

We report the pulmonary pathologic features in 87 open lung biopsies from 67 patients with Wegeners granulo-matosis (WG) who were treated at a single institution from 1968 to 1990. At the time of open lung biopsy, 48 patients (72%) had classical WG with renal involvement; 19 (28%) had limited WG without renal involvement. The pathologic features were divided into major and minor manifestations. In the 82 specimens demonstrating no infectious organism, the three major pathologic manifestations of classical WG observed were also useful diagnostic criteria and included: (a) parenchymal necrosis, (b) vasculitis, and (c) granulomatous inflammation accompanied by an inflammatory infiltrate composed of a mixture of neutrophils, lymphocytes, plasma cells, histiocytes, and eosinophils. Parenchymal necrosis was found in 84% of biopsy specimens either as neutrophilic microabscesses (65% of specimens) or as large (67%) or small (69%) areas of geographic necrosis. Areas of geographic necrosis were usually surrounded by palisading histiocytes and giant cells. Additional granulomatous lesions consisted of microabscesses surrounded by giant cells (69%), poorly formed granulomas (59%), and scattered giant cells (79%). Sarcoid-like granulomas were uncommon (4%), and in only one specimen (1%) appeared within an inflammatory lesion of WG. Vascular changes were identified in 94% of biopsy specimens. Vascular inflammation was classified as chronic (37% arterial, 64% venous), acute (37% arterial, 29% venous), nonnecrotizing granulomatous (22% arterial, 9% venous), and necrotizing granulomatous (22% arterial, 10% venous). Fibrinoid necrosis was relatively uncommon (11% arterial, 6% venous). Cicatricial changes were found in arteries in 41% of biopsy specimens and in veins in 16%. Capillaritis was present in 31% of specimens. Minor pathologic lesions were commonly observed in biopsy specimens associated with classical WG lesions, but they were usually inconspicuous and not useful diagnostic criteria. These included interstitial fibrosis (26%), alveolar hemorrhage (49%), tissue eosinophils (100%), organizing intraluminal fibrosis (70%), endogenous lipoid pneumonia (59%), lymphoid aggregates (37%), and a variety of bronchial/bronchiolar lesions including acute and chronic bronchiolitis (51% and 64%), follicular bronchiolitis (28%), and bronchiolitis obliterans (31%). These minor lesions were often found at the periphery of typical nodules of WG. However, in 15 specimens (18%) a minor pathologic feature represented the dominant or major finding: pulmonary fibrosis (six specimens, 7%), diffuse pulmonary hemorrhage (six specimens, 7%), lipoid pneumonia (one specimen, 1%), acute bronchopneumonia (one specimen, 1%), and chronic bronchiolitis, bronchiolitic obliterans with organizing pneumonia (BOOP), and bronchocentric granulomatosis (one specimen, 1%). Bronchial stenosis was found in three specimens (4%). In 10 specimens (12%) active vasculitis affecting veins or arteries could not be identified. Diffuse pulmonary hemorrhage associated with capillaritis was the primary finding in three of these specimens. Nodular interstitial fibrosis was the primary finding in six cases, and in three of these specimens cicatricial vascular changes were also present. In the 10th specimen, geographic necrosis, microabscesses, and scattered giant cells were present. This review illustrates the wide variation and broad spectrum of pathologic features that can occur in pulmonary WG and addresses the complicated differential diagnosis that can be encountered in the lung.

Interpretation of head and neck biopsies in Wegener's granulomatosis. A pathologic study of 126 biopsies in 70 patients

The majority of patients with classic Wegeners granulomatosis present with symptoms of head and neck disease; accordingly, accurate interpretation of biopsy specimens from these sites is essential. This report details the histo-logic findings in 126 head and neck biopsy specimens from 70 patients (36 male and 34 female). Tissues were obtained from the following sites: 60 nasal, 27 paranasal sinuses, 17 laryngeal, five periorbital, five oral, four middle ear, three mastoid, two external ear, and three salivary gland. Vasculitis, necrosis, and granulomatous inflammation together were seen in only 16% of all head and neck biopsy specimens. Both vasculitis and granulomatous inflammation were seen in 21% and vasculitis and necrosis in 23% of the biopsy specimens reviewed. We discuss the problems in differential diagnosis, particularly the importance of excluding granulomatous infectious processes, which can imitate the histopathologic features of Wegeners granulomatosis. Based on this study, we propose criteria for the diagnosis of Wegeners granulomatosis based on biopsy specimens from the head and neck region.

Wegener granulomatosis in children and adolescents: Clinical presentation and outcome

We prospectively studied and compared clinical features, treatment, course of illness, and long-term morbidity and mortality rates for Wegener granulomatosis in 23 childhood-onset patients with those of 135 adult-onset patients who were studied concurrently. Treatment was usually provided with glucocorticoids and cyclophosphamide. The mean follow-up period was 8.7 years for childhood-onset and 7.6 years for adult-onset Wegener granulomatosis. Most aspects of Wegener granulomatosis were similar in childhood-onset and adult-onset patients. Permanent morbidity from disease occurred in 86% of both groups. However, some features were significantly different. Wegener granulomatosis in childhood-onset patients was complicated five times more often by subglottic stenosis and twice as often by nasal deformity. Treatment-related permanent morbidity occurred in 22% of childhood-onset patients and 45% of adult-onset patients. After similar periods of cyclophosphamide therapy and follow-up, cyclophosphamide-related malignancies were less likely (0% vs 11%) to have developed in childhood-onset patients. Although 89% of patients treated with glucocorticoids and cyclophosphamide had remission, prolonged delay in achieving remission and relapses led in both patient groups to freedom from active disease for approximately 50% of the total patient-years. As a result, morbidity was substantial and has led to comparative studies of alternative therapies.

Relationship of the genes for Chediak-Higashi syndrome (beige) and the T-cell receptor [gamma] chain in mouse and man

The genetic linkage of Chediak-Higashi syndrome and its murine analog, beige (bg), to the T-cell receptor (TCR-gamma) gamma chain gene is further defined. Previous studies using recombinant inbred strains of mice demonstrated that the murine bg gene is genetically linked to a murine TCR-gamma gene. We report that in the mouse the frequency of recombination between these two markers is 0.025. Further, we tested the hypothesis that these two genes are linked in the human genome by analyzing restriction fragment length polymorphisms (RFLPs) in five families with children afflicted with Chediak-Higashi syndrome. In three families, RFLPs in TCR-gamma genes were inherited discordantly from Chediak-Higashi syndrome, demonstrating nonlinkage. We postulate that there is an evolutionary chromosomal breakpoint between the bg gene and the TCR-gamma gene.

Buerger's disease in a young woman

Buergers disease or thromboangiitis obliterans is characterized by peripheral arterial occlusions in young male cigarette smokers. It is rarely considered in the differential diagnosis of vascular disease in women, although there have been several well-documented cases in the literature. This report presents a young woman with both angiographic and histopathologic evidence for Buergers disease who was initially treated with daily corticosteroids for presumed vasculitis. This case emphasizes the fact that Buergers disease can present in a fashion similar to both vasculitis and collagen vascular disease.

A Phase III Comparative Study of the Efficacy and Tolerability of Three Non-Nucleoside Reverse Transcriptase Inhibitor-Sparing Antiretroviral Regimens for Treatment-Naïve HIV-1-Infected Volunteers: A Randomized, Controlled Trial

Background Non-nucleoside reverse transcriptase (NNRTI) inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.BACKGROUND Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. OBJECTIVE To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability. DESIGN A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954). SETTING 57 sites in the United States and Puerto Rico. PATIENTS Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors. INTERVENTION Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d. MEASUREMENTS Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability. RESULTS Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir. LIMITATION The trial was open-label, and ritonavir was not provided. CONCLUSION Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen. PRIMARY FUNDING SOURCE National Institute of Allergy and Infectious Diseases.

Efficacy and Tolerability of 3 Nonnucleoside Reverse Transcriptase Inhibitor–Sparing Antiretroviral Regimens for Treatment-Naive Volunteers Infected With HIV-1A Randomized, Controlled Equivalence TrialNNRTI-Sparing Antiretroviral Regimens for Treatment-Naive Volunteers Infected With HIV-1

Background Non-nucleoside reverse transcriptase (NNRTI) inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons.BACKGROUND Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons. OBJECTIVE To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability. DESIGN A phase 3, open-label study randomized in a 1:1:1 ratio with follow-up for at least 96 weeks. (ClinicalTrials.gov: NCT00811954). SETTING 57 sites in the United States and Puerto Rico. PATIENTS Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors. INTERVENTION Atazanavir, 300 mg/d, with ritonavir, 100 mg/d; raltegravir, 400 mg twice daily; or darunavir, 800 mg/d, with ritonavir, 100 mg/d, plus combination emtricitabine, 200 mg/d, and tenofovir disoproxil fumarate, 300 mg/d. MEASUREMENTS Virologic failure, defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks, and tolerability failure, defined as discontinuation of atazanavir, raltegravir, or darunavir for toxicity. A secondary end point was a combination of virologic efficacy and tolerability. RESULTS Among 1809 participants, all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10% to 10%. Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability, whereas ritonavir-boosted atazanavir resulted in a 12.7% and 9.2% higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir, respectively, primarily because of hyperbilirubinemia. For combined virologic efficacy and tolerability, ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir, and raltegravir was superior to both protease inhibitors. Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir. LIMITATION The trial was open-label, and ritonavir was not provided. CONCLUSION Over 2 years, all 3 regimens attained high and equivalent rates of virologic control. Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen. PRIMARY FUNDING SOURCE National Institute of Allergy and Infectious Diseases.