ABSTRACT
We describe emergomycosis in a patient in Uganda with HIV infection. We tested a formalin-fixed, paraffin-embedded skin biopsy to identify Emergomyces pasteurianus or a closely related pathogen by sequencing broad-range fungal PCR amplicons. Results suggest that emergomycosis is more widespread and genetically diverse than previously documented. PCR on tissue blocks may help clarify emergomycosis epidemiology.
Subject(s)
Chrysosporium/isolation & purification , HIV Infections , Mycoses/diagnosis , Adult , Antifungal Agents/therapeutic use , Chrysosporium/genetics , Diagnosis, Differential , Female , Humans , Itraconazole/therapeutic use , Mycoses/drug therapy , Mycoses/microbiology , Polymerase Chain Reaction , UgandaABSTRACT
OBJECTIVES: Immune checkpoint inhibitors can cause severe immune-related adverse events, with immune-related diarrhea and colitis (irColitis) being among the most frequent ones. While the majority of patients with irColitis respond well to corticosteroid treatment ± other immunomodulatory drugs such as infliximab, some patients do not show resolution of their symptoms. In the present study, we analysed the frequency of therapy-refractory irColitis, the underlying cause, and useful diagnostic approaches. METHODS: Between 2006 and 2016, 370 patients with metastatic malignant melanoma were treated with checkpoint inhibitors at the Department of Dermatology at the University Hospital Essen. All patients were identified for whom diarrhea and/or colitis was documented in the digital patient records. Patients who did not respond to standard immunosuppressive therapy within 2 weeks were classified as refractory. Demographic and clinical data of all patients were collected. RESULTS: We identified 41 patients with irColitis, the majority occurring during treatment with ipilimumab. Amongst these, 5 (12.2%) were refractory to standard immunomodulatory treatment with corticosteroids and infliximab. Therapy-refractory cases tended to show more severe inflammation in colonic biopsies (p = 0.04). In all therapy-refractory cases cytomegalovirus (CMV) was detectable. CMV-DNA in colonic biopsies and in plasma was significantly more often detectable in therapy-refractory cases (in colonic biopsies p = 0.005, in plasma: p = 0.002). Presence of serum CMV IgM and positive immunohistochemical stainings of colon biopsies for CMV were also associated with refractory colitis (p=0.021; p = 0.053). CONCLUSIONS: This report on CMV reactivation during management of checkpoint inhibitor-induced colitis emphasises the need for repetitive diagnostic measures in treatment-refractory irColitis.
Subject(s)
Antineoplastic Agents, Immunological/adverse effects , Colitis/virology , Cytomegalovirus Infections/virology , Cytomegalovirus/pathogenicity , Melanoma/drug therapy , Opportunistic Infections/virology , Skin Neoplasms/drug therapy , Virus Activation , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Viral/blood , Antiviral Agents/therapeutic use , Colitis/chemically induced , Colitis/drug therapy , Colitis/immunology , Cytomegalovirus/drug effects , Cytomegalovirus/genetics , Cytomegalovirus/immunology , Cytomegalovirus Infections/chemically induced , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/immunology , DNA, Viral/genetics , Female , Ganciclovir/therapeutic use , Germany , Hospitals, University , Host-Pathogen Interactions , Humans , Immunocompromised Host , Immunosuppressive Agents/therapeutic use , Male , Melanoma/immunology , Melanoma/secondary , Middle Aged , Opportunistic Infections/chemically induced , Opportunistic Infections/drug therapy , Opportunistic Infections/immunology , Predictive Value of Tests , Risk Factors , Skin Neoplasms/immunology , Skin Neoplasms/pathology , Time Factors , Treatment Outcome , Virus Activation/drug effects , Young AdultABSTRACT
INTRODUCTION: Apart from neutrophils, other immune cells may play a significant pathogenetic role in cutaneous leukocytoclastic vasculitis (CLV). AIM: To investigate lymphocytes and related immunological factors in patients with CLV requiring systemic glucocorticosteroid treatment. MATERIAL AND METHODS: Fourteen patients with severe idiopathic CLV were treated with systemic prednisolone in a tapered dose regimen. Ten healthy individuals served as controls. At baseline and post-treatment, we studied inducer/helper and suppressor/cytotoxic T lymphocytes, B lymphocytes, natural killer cells, CD4+CD25++CD127- cells, CD4+CD25+CD39+ cells and FOXP3, transforming growth factor ß1 (TGF-ß1) and interleukin-10 (IL-10) mRNA levels in the blood using flow cytometry and real time polymerase chain reaction (RT-PCR), respectively. On immunohistochemistry, we studied CD4, CD8, granzyme B, TGF-ß1, and IL-10. RESULTS: Flow cytometry did not show significant differences. The RT-PCR revealed that TGF-ß1 mRNA expression was significantly higher after therapy when compared to baseline and controls. On immunohistology, baseline CLV lesions showed significantly more CD4+ lymphocytes than post-treated CLV and controls. CD8+ expression was significantly higher after therapy when compared to baseline and controls. Baseline granzyme B was significantly increased when compared to treated CLV and controls. The IL-10 expression of treated CLV was significantly increased when compared to baseline CLV and; baseline CLV IL-10 expression was significantly increased as compared to controls. CONCLUSIONS: Circulating T regulatory cells do not play a significant role in the pathogenesis of CLV. T helper cells and granzyme B seem to be involved in the inflammatory cutaneous process of CLV. A resolution of CLV observed after glucocorticosteroid treatment may be mediated via up-regulation of TGF-ß1 and IL-10 in different compartments.
