Julia Friend

Chronic granulomatous disease as a risk factor for autoimmune disease

Chronic granulomatous disease (CGD) is characterized by recurrent infections and granuloma formation. In addition, we have observed a number of diverse autoimmune conditions in our CGD population, suggesting that patients with CGD are at an elevated risk for development of autoimmune disorders. In this report, we describe antiphospholipid syndrome, recurrent pericardial effusion, juvenile idiopathic arthritis, IgA nephropathy, cutaneous lupus erythematosus, and autoimmune pulmonary disease in the setting of CGD. The presence and type of autoimmune disease have important treatment implications for patients with CGD.

Suppression of inflammation in ulcerative colitis by interferon-β-1a is accompanied by inhibition of IL-13 production

Objective Ulcerative colitis is associated with increased interleukin 13 (IL-13) production by natural killer T cells. Taking advantage of the inhibitory actions of interferon β on IL-13 expression, this proof-of-concept study aimed to show that decreasing IL-13 production is associated with clinical improvement of ulcerative colitis symptoms. Design Open-label interventional drug trial. Setting Outpatient clinical research hospital. Patients Adult patients with active ulcerative colitis (Short Clinical Colitis Activity Index (SCCAI)≥5). Interventions Treatment with 30 μg IM interferon-β-1a (Avonex) weekly for 12 weeks with 6 month follow-up. Main outcome measures Clinical response was defined as ≥3 point drop in the SCCAI for at least two consecutive monitoring visits, and cytokine production was measured in cultured peripheral blood and lamina propria mononuclear cells (LPMC) before and after treatment. Results 11 of 16 patients were clinical responders, and 4 were in remission (SCCAI ≤ 2) at the end of treatment. Rectal bleeding subscores improved dramatically by week 4 (38% with frank bleeding vs 87% pretreatment). Increased IL-13 production by LPMC T cells fell significantly in clinical responders (690±99 vs 297±58 pg/ml p=0.015) but was unchanged in non-responders (542±83 vs 510±39 pg/ml). In addition, non-responders had significantly higher production of IL-17 and IL-6 pre-treatment compared to responders. Conclusions Interferon-β-1a induces clinical response and remission in a large subset of patients with ulcerative colitis that is associated with significant inhibition of IL-13 production. In addition, increased IL-17 and IL-6 production is associated with no response to interferon-β. These data provide a proof-of-concept that IL-13 is an effector cytokine in ulcerative colitis and should be a target for novel therapies.

Sarcoidosis in Chronic Granulomatous Disease

In addition to increased susceptibility to infections in patients with chronic granulomatous disease (CGD), a higher incidence of sterile inflammatory disorders in these patients has been noted. However, sarcoidosis has not been reported previously in CGD. In this report, we describe two patients who have CGD and a disorder consistent with sarcoidosis on the basis of unequivocal clinical-radiographic presentations, their responses to treatment, and serum angiotensin-converting enzyme levels. Serum angiotensin-converting enzyme levels were measured in 26 other patients with CGD to establish an appropriate reference range. A possible relationship between CGD and sarcoidosis is discussed.

Successful granulocyte-colony stimulating factor treatment of Crohn's disease is associated with the appearance of circulating interleukin-10-producing T cells and increased lamina propria plasmacytoid dendritic cells

Granulocyte‐colony stimulating factor (G‐CSF) has proved to be a successful therapy for some patients with Crohns disease. Given the known ability of G‐CSF to exert anti‐T helper 1 effects and to induce interleukin (IL)‐10‐secreting regulatory T cells, we studied whether clinical benefit from G‐CSF therapy in active Crohns disease was associated with decreased inflammatory cytokine production and/or increased regulatory responses. Crohns patients were treated with G‐CSF (5 µg/kg/day subcutaneously) for 4 weeks and changes in cell phenotype, cytokine production and dendritic cell subsets were measured in the peripheral blood and colonic mucosal biopsies using flow cytometry, enzyme‐linked immunosorbent assay and immunocytochemistry. Crohns patients who achieved a clinical response or remission based on the decrease in the Crohns disease activity index differed from non‐responding patients in several important ways: at the end of treatment, responding patients had significantly more CD4+ memory T cells producing IL‐10 in the peripheral blood; they also had a greatly enhanced CD123+ plasmacytoid dendritic cell infiltration of the lamina propria. Interferon‐γ production capacity was not changed significantly except in non‐responders, where it increased. These data show that clinical benefit from G‐CSF treatment in Crohns disease is accompanied by significant induction of IL‐10 secreting T cells as well as increases in plasmacytoid dendritic cells in the lamina propria of the inflamed gut mucosa.

Skin ulcers and disseminated abscesses are characteristic of Serratia marcescens infection in older patients with chronic granulomatous disease

To the Editor: Chronic Granulomatous Disease (CGD) is a primary immune deficiency resulting from mutations in any of four subunits of phagocytic cell NADPH oxidase. CGD patients are at risk for infections with catalase-positive bacteria and fungi [1-3]. Serratia marcescens infection of bone and soft tissue is a common presentation of CGD in infancy [4-6]. In older children and adults with CGD, infection with Staphylococcus aureus, Burkholderia cepacia and Nocardia species, or fungi such as Aspergillus make up the majority of infections [3,4]. Our experience indicates S. marcescens remains a significant cause of infection in older children and adults with CGD. These infections have a pattern different from that seen in CGD infants. Osteomyelitis is less common, skin infections form poorly healing ulcers [7], and infections frequently occur at multiple sites. We describe 16 episodes of S. marcescens infections in 15 patients 8–39 years of age with CGD followed between 1999–2008 at the National Institutes of Health (Table 1). Only patients with culture documented S. marcescens were included in this report. All patients were participants in an IRB approved study of the natural history of CGD. Written informed consent specifically allowed study of infections and other complications of CGD. Table 1 CGD mutation, age at diagnosis of infection, clinical sites of infection and length of antibiotic therapy in patients presenting with S. marcescens infections Three patients had additional documented S. marcescens infection at some time prior to the index period under review for this report. One of these three patients had a history of two previous S. marcescens lung infections. Each of these prior infections antedate the index review period by at least four years. We did not include these older episodes of infection, as detailed information about those infections was deemed less reliable. During the review period, some patients had one or more infections characteristic of CGD with organisms other than S. marcescens. Only one (Patient #13, Table 1) developed two episodes of infection with S. marcescens. We conclude that they are distinct Serratia infections and not relapse of the first infection, because those two infections were three years apart. This assumption is consistent with a previous report noting that for most infections in CGD, re-infection is more common than persistent infection [8]. Sites of infection included lung parenchyma (6), vertebrae (1), lymph nodes (3), deep intra-abdominal or pelvic abscess (4), deep soft tissue abscess of limb (6), and superficial infection of skin (2). Seven patients were found to have metastatic infection at multiple sites (Table 1). None of the 6 patients presenting with pneumonia had clinically apparent secondary sites of S. marcescens infection. Conversely, 7 of the 10 episodes of S. marcescens infection that did not involve pneumonia presented with widely metastatic dissemination. The characteristics of this dissemination included more than one non-contiguous site of skin abscess, deep muscle abscess in limbs and/or abscess in internal organs. A particularly informative example was Patient #9 (Table 1) who presented with skin and soft tissue abscesses (Figure 1). Epididymitis, apparent on physical examination, prompted pelvic Magnetic Resonance Imaging that revealed a prostate abscess (Figure 2). Figures 1A-C Photograph of skin ulcers resulting from S. marcescens infection in Patient #9. Figure 2 Magnetic resonance image of the pelvis of patient #9. The two bright confluent round objects in the center of this image represent a large abscess in the prostate. Mixed infection in the same biopsy sample (S. aureus or S. anginosis in addition to the Serratia) was identified in four patients, but in all cases the predominant organism by colony count appeared to be S. marcescens. Although the significance and relative impact of these additional organisms on the clinical course was unknown, antibiotic coverage was adjusted as necessary to include coverage for treatment of these additional organisms. In all cases, the S. marcescens isolate was sensitive to a broad range of antibiotic classes including carbapenems, quinolones, cephalosporins, aminoglycosides, extended-spectrum beta-lactams and trimethoprim-sulfamethoxazole. There was a tendency to include or use a quinolone as primary treatment in most cases. If a second antibiotic was used it tended to be either an intravenous carbapenem or intravenous high dose trimethoprim-sulfamethoxazole. In all of the cases these Serratia infections occurred in a setting where standard long term infection prophylaxis had included trimethoprim-sulfamethoxazole. Compliance with this long term prophylaxis was variable. Notably, 10 of 16 of the Serratia isolates were sensitive to this agent. The majority of patients received intravenous antibiotic therapy with two agents for at least a portion of the treatment period. One patient was treated with three intravenous antibiotics and one patient was treated with only one intravenous antibiotic (levofloxacin). Two patients received oral quinolone (ciprofloxacin or levofloxacin) therapy only (lymph node infection in one case and superficial abscess in the other; both without metastatic infection). Duration of therapy varied according to severity of the infection (range 14–180 days; mean 81 days; median 55 days). All infections were successfully eradicated; and all patients survived his or her infection. Our current report represents the largest aggregate detailed description of Serratia infections in older children and adults with CGD. Previous reports describe either single patients or small case series [4-7], primarily in infants and young children. In other publications, the incidence of Serratia infection is reported incidental to an overall report of a registry of CGD patients without detailed description of the characteristics of the Serratia infections [3]. The important findings of our study reporting the details of 16 episodes of S. marcescens infections in 15 older children and adults with CGD are: 1. Serratia osteomyelitis was uncommon compared to that reported in infants with CGD; 2. Serratia infections of skin form large poorly healing ulcers; 3. Serratia pneumonia in our series was not associated with clinically apparent infection to extrapulmonary sites; 4. Seven of the ten (70%) non-pulmonary infections with Serratia in our series were associated with metastatic spread of infection to multiple sites. As clinically indicated by history, exam or laboratory findings, this group of patients often may require additional imaging studies (CT, MRI or PET scan) to demonstrate the presence of cryptic sites of infection. Finally, we note that all the infections in our series were eventually eradicated; indicating that full recovery from Serratia infection in CGD is an expected outcome with recognition of the variable presentation of this disease and with proper management.

Targeting the mTOR pathway in Chromophobe Kidney Cancer

Chromophobe kidney cancer accounts for approximately 5% of cases of renal cell carcinoma (RCC). While the genetics of clear cell RCC has been a major focus of research, little is known about the biology of chromophobe tumors. There is ample preclinical rationale for the use of targeted therapy in clear cell tumors, and agents targeting the VHL/HIF pathway are now widely used in clinical practice. However, there is limited experience with targeted agents in non-clear cell tumors. Recently, a few case reports have emerged which report the use of mTOR inhibitors in chromophobe tumors. Here, we report our experience with targeted therapy in a patient with advanced chromophobe RCC who had a durable partial response to temsirolimus. We also include a literature review summarizing the published experience with targeted therapeutic approaches in chromophobe RCC. Additionally, the preclinical rationale for the use of mTOR inhibitors in this population based on our characterization of the hereditary form of chromophobe kidney cancer, Birt-Hogg-Dube syndrome, is discussed.

Determinants and prognostic implications of malignant ascites in metastatic papillary renal cancer

OBJECTIVE To describe the incidence of ascites in metastatic papillary renal cell cancer (pRCC), identify the factors associated with its development and evaluate its prognostic effect on the survival of these patients. METHODS A retrospective evaluation of the medical records of patients with metastatic pRCC seen at National Cancer Institute (2000-2014) was undertaken. Logistic regression to identify predictors of the development of malignant ascites and Kaplan-Meier analysis to estimate survival was done. RESULTS Overall, 106 consecutive patients with metastatic pRCC were identified; sufficient data were available in 100 patients to enable assessment of ascites. Further, 20% had evidence of malignant ascites. Median age at diagnosis of ascites was 48.0 years (26.1-76.6 years) and median time to development of ascites from initial diagnosis of metastatic disease was 16.0 (0-73.3) months. There was no significant difference in the incidence of ascites between patients with hereditary and sporadic pRCC (P = 0.803) or among patients with different subtypes of pRCC (P = 0.456). Elevated platelet-lymphocyte ratio predicted development of malignant ascites in our cohort (P = 0.009). Median overall survival was shorter for patients who developed ascites [25.0 (10.2-39.8) months] compared with patients who did not develop this complication [42.5 (30.5-54.4) months, P = 0.041]. CONCLUSION To our knowledge, this is the first systematic evaluation of the incidence, predictors, and prognostic effect of ascites in metastatic pRCC. Malignant ascites is a common manifestation of metastatic pRCC and is associated with a shorter overall survival. An elevated platelet-lymphocyte ratio predicts a higher risk of developing malignant ascites.