Unraveling the mystery of fever of unknown origin: a remarkable journey towards the diagnosis of peripheral T-cell lymphoma-T follicular helper type: A rare case report.

INTRODUCTION: Fever of unknown origin (FUO) remains one of the most challenging clinical conditions. It demands an exhaustive diagnostic approach, considering its varied etiologies spanning infectious, autoimmune, inflammatory, and malignant causes. PATIENT CONCERNS: This report shows the journey of diagnosing a 28-year-old male who presented with persistent fever and lower-extremity weakness over 9 months. Despite seeking care at multiple hospitals, a definitive diagnosis remained elusive. DIAGNOSIS: The patient underwent a series of evaluations in various specialties, including gastroenterology, infectious diseases, rheumatology, hematology, and cardiology. Multiple tests and treatments were administered, including antiviral therapy for hepatitis B and antibiotics for suspected infections. INTERVENTIONS: After an initial misdiagnosis and unsuccessful treatments, a positron emission tomography-computed tomography scan and lymph node biopsy ultimately led to the diagnosis of peripheral T-cell lymphoma-T follicular helper type (PTCL-TFH) lymphoma. The patient was referred to the hematology clinic and initiated on CHOEP (cyclophosphamide, vincristine, etoposide, and prednisone) chemotherapy. OUTCOMES: The patient showed a positive response to CHOEP therapy, as indicated by a posttreatment positron emission tomography-computed tomography scan. He reported a significant improvement in his quality of life. Additional rounds of the same regimen were planned to further manage the lymphoma. CONCLUSION: This case emphasizes the importance of a comprehensive and persistent diagnostic approach in managing FUO. Initially, the focus on infectious causes led to extensive treatments, but the disease's progression and complications shifted attention to other specialties. The eventual diagnosis of PTCL-TFH lymphoma highlights the significance of advanced imaging techniques and multidisciplinary collaboration in uncovering elusive diagnoses. Thorough surveillance, timely reassessments, and repeated testing can uncover definitive changes critical for diagnosis. PTCL-TFH lymphoma, although rare, should be considered in the differential diagnosis of FUO, especially when initial evaluations are inconclusive.

Ombitasvir, paritaprevir, ritonavir, dasabuvir and ribavirin in cirrhosis after complete destruction of hepatocellular carcinoma.

We observed a sustained viral response (SVR) of ombitasvir/paritaprevir/ritonavir, dasabuvir and ribavirin therapy, for 12 wk, in two cases with compensated liver cirrhosis and fully destroyed early hepatocellular carcinoma (HCC). Patients were infected with hepatitis C virus (HCV) genotype 1b and were previous null responders/relapsers to interferon-alpha/ribavirin (IFN/RBV). There was a rapid suppression of HCV RNA to undetectable levels within the first two treatment weeks. SVR was achieved even after marked reduction of the RBV dose. The treatment was well tolerated. Both subjects experienced worsening of liver disease during therapy, in different patterns: severe, transient, predominantly direct hyperbilirubinemia without cytolysis (case 1) or progressive increase of aminotransferases (grade 4) without severe hyperbilirubinemia (case 2). Adverse events spontaneously resolved. The patients remained in a good clinical condition without hepatic decompensation. There was no re-occurrence of HCC. This is the first report for treatment of HCV cirrhosis after complete HCC destruction.

Effects of hepatic dysfunction on the single-dose pharmacokinetics of fesoterodine.

Fesoterodine, a new antimuscarinic for the treatment of overactive bladder, is rapidly and extensively hydrolyzed by nonspecific esterases to its principal active moiety, 5-hydroxymethyl tolterodine (5-HMT). The elimination of 5-HMT involves metabolism and renal excretion. The plasma and urinary pharmacokinetics of 5-HMT and its inactive carboxy (SPM 5509), N-desisopropyl (SPM 7789), and carboxy-N-desisopropyl (SPM 7790) metabolites were investigated after a single oral dose of 8 mg of fesoterodine in 8 male subjects with moderate hepatic cirrhosis (Child-Turcotte-Pugh class B) and 8 matched healthy controls. The estimated mean ratios (95% confidence interval) of the area under the curve extrapolated to infinity after dosing (AUC(0-∞)), cumulative urinary excretion up to 48 hours after dosing (Ae(0-48)), maximum observed concentration (C(max)), and apparent terminal disposition half-life (t(1/2)) of 5-HMT for cirrhotic and healthy subjects were 2.2 (1.5-3.1), 2.5 (1.7-3.8), 1.4 (1.0-1.9), and 1.1 (0.8-1.3), respectively. In subjects with hepatic cirrhosis, AUC(0-∞) and Ae(0-48) of 5-HMT increased approximately 2-fold; the increase in C(max) was smaller, and t(1/2) was unaffected. AUC and C(max) of the inactive carboxy metabolites, SPM 5509 and SPM 7790, were reduced reciprocally by about 50%, whereas exposure to the dealkylated metabolite, SPM 7789, increased about 2-fold. Fesoterodine 8 mg was equally well tolerated in both groups. The results indicate that moderate hepatic cirrhosis reduces 5-HMT clearance, with an apparent effect on the carboxylation pathway and not on dealkylation.

Prospective randomized open-label multicenter phase I/II dose escalation trial of visilizumab (HuM291) in severe steroid-refractory ulcerative colitis.

BACKGROUND: Visilizumab is a humanized IgG(2) monoclonal anti-CD3 antibody. We evaluated its safety and dose response in severe intravenous steroid-refractory ulcerative colitis (UC). METHODS: In all, 104 patients were treated. In Stage I, 73 patients were randomly assigned to receive intravenous visilizumab 5, 7.5, 10, or 12.5 microg/kg/day for 2 consecutive days. In Stage II, 33 patients received visilizumab at the optimal clinical dose (OCD) of 5 microg/kg/day for 2 days. Symptomatic response and remission were defined by the modified Truelove-Witts severity index. Clinical response and remission were defined by the Mayo score. RESULTS: The rates of symptomatic response at day 15 in the 5, 7.5, 10, or 12.5 microg/kg dose groups were 71%, 70%, 50%, and 61%, respectively, in Stage I and in 54% in Stage II. The symptomatic remission rates were 35%, 5%, 22%, and 11% in Stage I and 18% in Stage II. The rates of clinical response at day 30 in the 5, 7.5, 10, or 12.5 microg/kg dose groups were 71%, 65%, 50%, and 67%, respectively, in Stage I and 55% in Stage II. The clinical remission rates were 6%, 5%, 0%, and 11% in Stage I and 6% in Stage II. All patients experienced adverse events. Serious adverse events included abdominal abscess, cytomegalovirus infection, atrial fibrillation, herpes zoster, and esophageal candidiasis. CONCLUSIONS: Treatment with visilizumab induced symptomatic response and clinical response. Results with 5 microg/kg/day were similar to those observed with higher doses.

Isoprinosine affects serum cytokine levels in healthy adults.

Isoprinosine is a synthetic purine derivative with immunomodulatory and antiviral properties, which result from an apparent in vivo enhancement of host immune responses. To evaluate the serum levels of certain cytokines during and after isoprinosine treatment, we assigned 10 healthy volunteers to receive isoprinosine 1 g, 3 times daily, 5 consecutive days weekly. Both treatment and follow-up phase last 3 weeks. Interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-10, and tumor necrosis factor-alpha (TNF-alpha) were measured in serum using commercial ELISA kits at baseline, 7th, 10th, 14th, 21st, 28th, 35th, and 42nd day. We observed an increase in serum levels of all measured cytokines at 7th to 10th day. The levels of IL-2 had another raise at 42nd day after drop to initial values (P < 0.05; P < 0.001, respectively). Those of IL-10 held up enhanced from 7th to 28th day of measurement (P < 0.01). There was a nearly flat line of values of TNF-alpha after initial slight increase at 10th day. We found a moderate negative correlation between IFN-gamma and IL-2, IL-10, and TNF-alpha (Spearman's r: -0.63, -0.62, -0.63; P < 0.05, respectively). We have demonstrated the immunomodulating properties of isoprinosine in healthy adults. It suggests resumption of the research with up-to-date methods to elucidate the mechanisms of action of inosine pranobex and maybe the other inosine compounds in different clinical settings.

The "return" of hepatitis B.

There has been a significant advance in the treatment of chronic Hepatitis B virus (HBV) infection and the following drugs were approved for therapy: Conventional interferon (IFN), pegylated interferon alfa-2a (PEG IFN alpha2a), lamivudine, adefovir and entecavir. Compared to nucleoside analogues IFN induces higher rates of sustained remission and HBsAg loss. Conventional IFN in lower doses (1, 5-3 MIU) tiw for 4-6 mo has similar efficacy in comparison to "standard IFN therapy". Longer IFN treatment is a significant factor for long-term remission in HBeAg-negative CHB, but the higher actual IFN dose is not such a factor. PEG IFN is superior to conventional IFN. There is no significant difference between PEG IFN alpha2a at doses 90 mcg/wk and 180 mcg/wk in HBeAg-positive patients. These results provide a rational for further clinical trials with lower doses PEG IFN alpha2a given in prolonged course as maintenance or intermittent treatment. Serious new problems arose after the introduction of nucleoside/nucleotide analogues in clinical practice. The most important ones are drug-resistance and the high rates of relapse after treatment discontinuation. Therapy should only be recommended if the expected benefit exceeds significantly the abstain from treatment. The choice of therapy should take into account the patient's age, co-morbidity, severity of liver disease and the risk of drug-resistance. New antivirals significantly suppress HBV-replication, but have no effect on cccDNA in hepatocytes, and after the treatment discontinuation viral relapses occurs. At the present level of knowledge it is impossible "to eradicate the virus" The realistic treatment goal is to achieve durable response by clearance of HBeAg, sustained decrease of serum HBV DNA levels, normalization of ALT, improvement of liver histology and stopping of liver fibrogenesis. The competition between IFN based therapy and nucleoside or nucleotide analogues still remains. IFN can cure the liver disease while nucleotide analogues only suppress the viral replication during therapy and can reduce the liver fibrosis. Treatment should be prolonged for 24-mo or longer by using maintenance or intermittent treatment course with the lowest effective IFN and PEG IFN doses. Nucleoside/nucleotide analogues are a promising treatment option, but additional data for treatment duration and long-term post-treatment outcome are necessary.

Chronic Epstein-Barr virus-related hepatitis in immunocompetent patients.

AIM: To investigate reactivated Epstein-Barr virus (EBV) infection as a cause for chronic hepatitis. METHODS: Patients with occasionally established elevated serum aminotransferases were studied. HIV, HBV and HCV-infections were excluded as well as any other immunosuppressive factors, metabolic or toxic disorders. EBV viral capsid antigen (VCA) IgG and IgM, EA-R and EA-D IgG and Epstein-Barr nuclear antigen (EBNA) were measured using IFA kits. Immunophenotyping of whole blood was performed by multicolor flow cytometry. CD8(+) T cell responses to EBV and PHA were determined according to the intracellular expression of IFN-gamma. RESULTS: The mean alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGTP) values exceeded twice the upper normal limit, AST/ALT ratio < 1. Serology tests showed reactivated EBV infection in all patients. Absolute number and percentages of T, B and NK cells were within the reference ranges. Fine subset analysis, in comparison to EBV(+) healthy carriers, revealed a significant decrease of naive T cells (P < 0.001), accompanied by increased percentage of CD45RA(-) (P < 0.0001), and terminally differentiated CD28(-)CD27(-)CD8(+) T cells (P < 0.01). Moderately elevated numbers of CD38 molecules on CD8(+) T cells (P < 0.05) proposed a low viral burden. A significantly increased percentage of CD8(+) T cells expressing IFN-gamma in response to EBV and PHA stimulation was registered in patients, as compared to controls (P < 0.05). Liver biopsy specimens from 5 patients revealed nonspecific features of low-grade hepatitis. CONCLUSION: Chronic hepatitis might be a manifestation of chronic EBV infection in the lack of detectable immune deficiency; the expansion of CD28(-)CD27(-) and increase of functional EBV-specific CD8(+) T cells being the only surrogate markers of viral activity.