Disseminated Histoplasmosis and Miliary Tuberculosis Imitating Colon Cancer in Patient with HIV Who Refuses to Antirretroviral Treatment

Simultaneous infection with histoplasmosis and miliary tuberculosis is rare and mainly affects people with severe immunosuppression, they can present very diverse clinical forms, similar to other infectious and neoplastic pathologies. We present the case of a 27-year-old woman diagnosed with HIV infection for 08 years who refuses to receive antiretroviral treatment (ART) and conceals her diagnosis, comes to the Hospital for pain, abdominal distension and ulcer in the oral cavity. The patient was diagnosed with likely cancer by presenting irregular intestinal thickening with homogeneous gray pattern in colon tomography and signs of intestinal obstruction, that after hemicolectomy was evidenced histoplasmosis in the pathological study, during the treatment with amphotericin B deoxycholate and improvement of the oral ulcer, the patient presented dyspnea, micronodular pattern on the chest radiograph that had not previously existed and the lipoarabinomanan antigen in the urine was positive for tuberculosis. In immunosuppressed patients, intestinal histoplasma infection may have clinical and tomographic characteristics similar to colon cáncer.

     

LPS-Binding Protein and IL-6 Mark Paradoxical Tuberculosis Immune Reconstitution Inflammatory Syndrome in HIV Patients

Background

Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) remains a poorly understood complication in HIV-TB co-infected patients initiating antiretroviral therapy (ART). The role of the innate immune system in TB-IRIS is becoming increasingly apparent, however the potential involvement in TB-IRIS of a leaky gut and proteins that interfere with TLR stimulation by binding PAMPs has not been investigated before. Here we aimed to investigate the innate nature of the cytokine response in TB-IRIS and to identify novel potential biomarkers.

Methods

From a large prospective cohort of HIV-TB co-infected patients receiving TB treatment, we compared 40 patients who developed TB-IRIS during the first month of ART with 40 patients matched for age, sex and baseline CD4 count who did not. We analyzed plasma levels of lipopolysaccharide (LPS)-binding protein (LBP), LPS, sCD14, endotoxin-core antibody, intestinal fatty acid-binding protein (I-FABP) and 18 pro-and anti-inflammatory cytokines before and during ART.

Results

We observed lower baseline levels of IL-6 (p = 0.041), GCSF (p = 0.036) and LBP (p = 0.016) in TB-IRIS patients. At IRIS event, we detected higher levels of LBP, IL-1RA, IL-4, IL-6, IL-7, IL-8, G-CSF (p ≤ 0.032) and lower I-FABP levels (p = 0.013) compared to HIV-TB co-infected controls. Only IL-6 showed an independent effect in multivariate models containing significant cytokines from pre-ART (p = 0.039) and during TB-IRIS (p = 0.034).

Conclusion

We report pre-ART IL-6 and LBP levels as well as IL-6, LBP and I-FABP levels during IRIS-event as potential biomarkers in TB-IRIS. Our results show no evidence of the possible contribution of a leaky gut to TB-IRIS and indicate that IL-6 holds a distinct role in the disturbed innate cytokine profile before and during TB-IRIS. Future clinical studies should investigate the importance and clinical relevance of these markers for the diagnosis and treatment of TB-IRIS.     

Risk Factors for Disseminated Histoplasmosis in a Cohort of HIV-Infected Patients in French Guiana

Disseminated histoplasmosis is the first AIDS-defining infection in French Guiana. A retrospective cohort study studied predictive factors of disseminated histoplasmosis in HIV-infected patients between 1996 and 2008. Cox proportional hazards models were used. The variables studied were age, sex, last CD4/CD8 count, CD4 nadir, herpes or pneumocystosis, cotrimoxazole and fluconazole use, antiretroviral treatment and the notion of recent initiation of HAART. A total of 1404 patients were followed for 6833 person-years. The variables independently associated with increased incidence of disseminated histoplasmosis were CD4 count<50 per mm3, CD4 count between 50 and 200 per mm3, a CD4 nadir <50 per mm3, CD8 count in the lowest quartile, herpes infection, and recent antiretroviral treatment initiation (less than 6 months). The variables associated with decreased incidence of histoplasmosis were antiretroviral treatment for more than 6 months, fluconazole treatment, and pneumocystosis. There were 13.5% of deaths at 1 month, 17.5% at 3 months, and 22.5% at 6 months after the date of diagnosis of histoplasmosis. The most important predictive factors for death within 6 months of diagnosis were CD4 counts and antiretroviral treatment. The present study did not study environmental/occupational factors but provides predictive factors for disseminated histoplasmosis and its outcome in HIV patients in an Amazonian environment during the HAART era.     

Incidence,Clinical Spectrum,Risk Factors and Impact of HIV-Associated Immune Reconstitution Inflammatory Syndrome in South Africa

Background

Immune reconstitution inflammatory syndrome (IRIS) is a widely recognised complication of antiretroviral therapy (ART), but there are still limited data from resource-limited settings. Our objective was to characterize the incidence, clinical spectrum, risk factors and contribution to mortality of IRIS in two urban ART clinics in South Africa.

Methods and Findings

498 adults initiating ART in Durban, South Africa were followed prospectively for 24 weeks. IRIS diagnosis was based on consensus expert opinion, and classified by mode of presentation (paradoxical worsening of known opportunistic infection [OI] or unmasking of subclinical disease). 114 patients (22.9%) developed IRIS (36% paradoxical, 64% unmasking). Mucocutaneous conditions accounted for 68% of IRIS events, mainly folliculitis, warts, genital ulcers and herpes zoster. Tuberculosis (TB) accounted for 25% of IRIS events. 18/135 (13.3%) patients with major pre-ART OIs (e.g. TB, cryptococcosis) developed paradoxical IRIS related to the same OI. Risk factors for this type of IRIS were baseline viral load >5.5 vs. <4.5 log₁₀ (adjusted hazard ratio 7.23; 95% confidence interval 1.35–38.76) and ≤30 vs. >30 days of OI treatment prior to ART (2.66; 1.16–6.09). Unmasking IRIS related to major OIs occurred in 25/498 patients (5.0%), and risk factors for this type of IRIS were baseline C-reactive protein ≥25 vs. <25 mg/L (2.77; 1.31–5.85), haemoglobin <10 vs. >12 g/dL (3.36; 1.32–8.52), ≥10% vs. <10% weight loss prior to ART (2.31; 1.05–5.11) and mediastinal lymphadenopathy on pre-ART chest x-ray (9.15; 4.10–20.42). IRIS accounted for 6/25 (24%) deaths, 13/65 (20%) hospitalizations and 10/35 (29%) ART interruptions or discontinuations.

Conclusion

IRIS occurred in almost one quarter of patients initiating ART, and accounted for one quarter of deaths in the first 6 months. Priority strategies to reduce IRIS-associated morbidity and mortality in ART programmes include earlier ART initiation before onset of advanced immunodeficiency, improved pre-ART screening for TB and cryptococcal infection, optimization of OI therapy prior to ART initiation, more intensive clinical monitoring in initial weeks of ART, and education of health care workers and patients about IRIS.     

Cerebrospinal Fluid Cytokine Profiles Predict Risk of Early Mortality and Immune Reconstitution Inflammatory Syndrome in HIV-Associated Cryptococcal Meningitis

Understanding the host immune response during cryptococcal meningitis (CM) is of critical importance for the development of immunomodulatory therapies. We profiled the cerebrospinal fluid (CSF) immune-response in ninety patients with HIV-associated CM, and examined associations between immune phenotype and clinical outcome. CSF cytokine, chemokine, and macrophage activation marker concentrations were assayed at disease presentation, and associations between these parameters and microbiological and clinical outcomes were examined using principal component analysis (PCA). PCA demonstrated a co-correlated CSF cytokine and chemokine response consisting primarily of Th1, Th2, and Th17-type cytokines. The presence of this CSF cytokine response was associated with evidence of increased macrophage activation, more rapid clearance of Cryptococci from CSF, and survival at 2 weeks. The key components of this protective immune-response were interleukin (IL)-6 and interferon-γ, IL-4, IL-10 and IL-17 levels also made a modest positive contribution to the PC1 score. A second component of co-correlated chemokines was identified by PCA, consisting primarily of monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). High CSF chemokine concentrations were associated with low peripheral CD4 cell counts and CSF lymphocyte counts and were predictive of immune reconstitution inflammatory syndrome (IRIS). In conclusion CSF cytokine and chemokine profiles predict risk of early mortality and IRIS in HIV-associated CM. We speculate that the presence of even minimal Cryptococcus-specific Th1-type CD4+ T-cell responses lead to increased recruitment of circulating lymphocytes and monocytes into the central nervous system (CNS), more effective activation of CNS macrophages and microglial cells, and faster organism clearance; while high CNS chemokine levels may predispose to over recruitment or inappropriate recruitment of immune cells to the CNS and IRIS following peripheral immune reconstitution with ART. These results provide a rational basis for future studies of immune modulation in CM, and demonstrate the potential of baseline immune profiling to identify CM patients most at risk of mortality and subsequent IRIS.     

Risk Factor Analyses for Immune Reconstitution Inflammatory Syndrome in a Randomized Study of Early vs. Deferred ART during an Opportunistic Infection

Background

Immune reconstitution inflammatory syndrome (IRIS) is reported widely in patients initiating antiretroviral therapy (ART). However, few studies are prospective, and no study has evaluated the impact of the timing of ART when allocated randomly during an acute opportunistic infection (OI).

Methodology/Principal Findings

A5164 randomized 282 subjects with AIDS-related OIs (tuberculosis excluded), to early or deferred ART. IRIS was identified prospectively using pre-defined criteria. We evaluated associations between IRIS and baseline variables in subjects with follow-up on ART using Wilcoxon and Fisher''s exact tests, logistic regression, and Cox models with time-varying covariates. Twenty of 262 (7.6%) subjects developed IRIS after a median of 33 days on ART. Subjects with fungal infections (other than pneumocystis) developed IRIS somewhat more frequently (OR = 2.7; 95% CI: 1.02, 7.2; p-value = 0.06 (using Fisher''s exact test)). In Cox models, lower baseline and higher on-treatment CD4+ T-cell counts and percentage were associated with IRIS. Additionally, higher baseline and lower on-treatment HIV RNA levels were associated with IRIS. Corticosteroids during OI management and the timing of ART were not associated with the development of IRIS.

Implications

In patients with advanced immunosuppression and non-tuberculous OIs, the presence of a fungal infection, lower CD4+ T-cell counts and higher HIV RNA levels at baseline, and higher CD4+ T-cell counts and lower HIV RNA levels on treatment are associated with IRIS. Early initiation of ART does not increase the incidence of IRIS, and concern about IRIS should not prompt deferral of ART.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00055120","term_id":"NCT00055120"}}NCT00055120     

Isolated Oral Histoplasmosis Presenting as Fever of Unknown Origin in a Portuguese Hemodialysis Patient

The authors report a clinical case of an isolated oral histoplasmosis in a hemodialysis patient that presented with fever of unknown origin and had an unremarkable physical examination. During the investigation, a Gallium scan showed uptake in the oral cavity and soon after the oral cavity examination revealed a granulomatous lesion on the tooth 26. Histopathologic findings were compatible with histoplasmosis. The treatment regimen included liposomal amphotericin B followed by itraconazole consolidation therapy, and side effects did not occur. Both clinical evolution and outcome were favorable. Oral histoplasmosis in a non-immunosuppressed patient is extremely rare.     

Cowchock Syndrome Is Associated with a Mutation in Apoptosis-Inducing Factor

Cowchock syndrome (CMTX4) is a slowly progressive X-linked recessive disorder with axonal neuropathy, deafness, and cognitive impairment. The disease locus was previously mapped to an 11 cM region at chromosome X: q24-q26. Exome sequencing of an affected individual from the originally described family identified a missense change c.1478A>T (p.Glu493Val) in AIFM1, the gene encoding apoptosis-inducing factor (AIF) mitochondrion-associated 1. The change is at a highly conserved residue and cosegregated with the phenotype in the family. AIF is an FAD-dependent NADH oxidase that is imported into mitochondria. With apoptotic insults, a N-terminal transmembrane linker is cleaved off, producing a soluble fragment that is released into the cytosol and then transported into the nucleus, where it triggers caspase-independent apoptosis. Another AIFM1 mutation that predicts p.Arg201del has recently been associated with severe mitochondrial encephalomyopathy in two infants by impairing oxidative phosphorylation. The c.1478A>T (p.Glu493Val) mutation found in the family reported here alters the redox properties of the AIF protein and results in increased cell death via apoptosis, without affecting the activity of the respiratory chain complexes. Our findings expand the spectrum of AIF-related disease and provide insight into the effects of AIFM1 mutations.     

Orbital Inflammatory Disease in A Patient Treated with Zoledronate

ObjectiveTo increase awareness of orbital inflammatory disease as a rare adverse effect of bisphosphonates.MethodsWe present a case report and a review of the relevant literature.ResultsA 57-year-old woman with history of esophageal, breast, and lung cancers was diagnosed with postmenopausal osteoporosis. She initially received intravenous ibandronate for a total of 6 infusions. Later, she was changed to zoledronate infusion because of its yearly dosing schedule. Several hours after her initial infusion of zoledronate, she developed a painfully swollen left eye with photophobia. Ophthalmologic exam showed edema of the left upper lid. No exophthalmos was noted. Slitlamp exam showed conjunctival injection in the left eye with an elevated intraocular pressure. An orbital computed tomographic scan showed inflammation of the left orbital, preseptal, and retroseptal spaces. She was started on 2 methylprednisolone dose packs and the swelling and erythema disappeared completely in 2 weeks. Subsequent orbital magnetic resonance imaging showed no mass within either the left or right orbit, and no abnormal enhancement following contrast administration.ConclusionPhysicians should be aware of this rare complication of zoledronate. It should be used with caution in patients with a history of inflammatory eye disease or mild ocular symptoms following use of a bisphosphonate. (Endocr Pract. 2011;17:e101-e103)     

Pulmonary Mucormycosis due to Lichtheimia ramosa in a Patient with HIV Infection

Mucormycosis is increasingly common in patients with risk factors such as diabetes mellitus, neutropenia, and corticosteroid therapy. However, mucormycosis seems to be less common in patients with human immunodeficiency virus (HIV) infection compared to patients with other risk factors. Despite their lower virulence, Lichtheimia species should be regarded as emerging pathogens among Mucoralean fungi. We report a fatal case of pulmonary mucormycosis due to Lichtheimia ramosa in a 52-year-old man with an end-stage HIV infection. He had a cachectic appearance and his CD4 count was 8 cells/mm³. The fungal infection was diagnosed based on a positive sputum culture with histopathologic confirmation. The fungus was resistant to caspofungin, anidulafungin, and voriconazole [minimum inhibitory concentration (MCI) >32 µg/ml], whereas the E test MIC values of itraconazole, posaconazole, and amphotericin B were 0.38, 0.38, and 0.5 µg/ml, respectively. Although intravenous drug use is the main risk factor for the development of mucormycosis in HIV-infected patients, it may also develop in patients with low CD4 count, opportunistic infections and/or additional diseases, such as Kaposi’s sarcoma or severe immunodeficiency, as in our case.     

Cytomegalovirus Infection in Inflammatory Bowel Disease Is Not Associated with Worsening of Intestinal Inflammatory Activity

Background

Cytomegalovirus is highly prevalent virus and usually occurs in immunocompromised patients. The pathophysiology and treatment of inflammatory bowel disease often induce a state of immunosuppression. Because this, there are still doubts and controversies about the relationship between inflammatory bowel disease and cytomegalovirus.

Aim

Evaluate the frequency of cytomegalovirus in patients with inflammatory bowel disease and identify correlations.

Methods

Patients with inflammatory bowel disease underwent an interview, review of records and collection of blood and fecal samples. The search for cytomegalovirus was performed by IgG and IgM blood serology, by real-time PCR in the blood and by qualitative PCR in feces. Results were correlated with red blood cell levels, C-reactive protein levels, erythrocyte sedimentation rates and fecal calprotectin levels for each patient.

Results

Among the 400 eligible patients, 249 had Crohn''s disease, and 151 had ulcerative colitis. In the group of Crohn''s disease, 67 of the patients had moderate or severe disease, but 126 patients presented with active disease, based on the evaluation of the fecal calprotectin. In patients with ulcerative colitis, only 21 patients had moderate disease, but 76 patients presented with active disease, based on the evaluation of the fecal calprotectin. A large majority of patients had positive CMV IgG. Overall, 10 patients had positive CMV IgM, and 9 patients had a positive qualitative detection of CMV DNA by PCR in the feces. All 400 patients returned negative results after the quantitative detection of CMV DNA in blood by real-time PCR. Analyzing the 19 patients with active infections, we only found that such an association occurred with the use of combined therapy (anti-TNF-alpha + azathioprine)

Conclusion

The findings show that latent cytomegalovirus infections are frequent and active cytomegalovirus infection is rare. We did not find any association between an active infection of CMV and inflammatory bowel disease activity.     

Fenofibrate Increases Serum Creatinine in a Patient with Familial Nephropathy Associated to Hyperuricemia

Background: Kidney function progressively deteriorates in patients with familial juvenile hyperuricemiac nephropathy (FJHN, OMIN 162000) and chronic renal disease is commonly associated to dyslipidemia. We report for the first time abrupt renal insufficiency in a patient with FJHN and hypertrygliceridemia following fenofibrate administration.Case report: A 53-year-old man was diagnosed clinically with FJHN at age 24 years which was subsequently confirmed by genotypic analysis of the UMOD gene at age 40 years. His mother and two brothers suffered the disease. At that time, renal size and function were normal, as was his blood pressure and serum lipids. At age 34 years, serum urate was 8.5 mg/dL and creatinine 1.7 mg/dL (GFR, 58 mL/min/1.73 m²). He was treated with allopurinol, losartan, and lovastatin. Serum TG levels ranged between 150 and 250 mg/dL. At age 52 years, serum urate was 4.1 mg/dL, creatinine 3.2 mg/dL, LDLc 99 mg/dL (atorvastatin 40 mg/d), and TG 275 mg/dL. Fenofibrate (160 mg/d) was added. One month later, serum creatinine increased to 4.2 mg/dL and TG decreased to 125 mg/dL. He did not complain of muscle pain, weakness, or changes in urinary frequency or color and rabdomyolysis was discarded. Fenofibrate was withheld and three months later serum creatinine decreased to baseline levels (3.2 mg/dL) and TG increased to 197 mg/dL.Conclusion: To our knowledge, this is the first patient with FJHN in whom fenofibrate administration was associated to a further impairment in renal function not attributable to rabdomyolysis.