Thomas C. Mahl

Pneumocystis jiroveci (carinii) pneumonia after infliximab therapy: a review of 84 cases.

Anti-tumor necrosis factor-α therapy, infliximab, has become an established effective therapy for Crohns disease and rheumatoid arthritis. However, infliximab has been associated with various opportunistic pathogens such as tuberculosis, histoplasmosis, listeriosis, aspergillosis, and Pneumocystis jiroveci (carinii) pneumonia. We reviewed the FDA Adverse Event Reporting System for cases of Pneumocystis associated with infliximab use from January 1998 through December 2003. The database revealed 84 cases of PCP following infliximab therapy. Concomitant immunosuppressive medications included methotrexate, prednisone, azathioprine, 6-mercaptopurine, and cyclosporine. Mean time between infliximab infusion and onset of symptoms of pneumonia, when reported, was 21 days (±18 days; n=40). Twenty-three of the 84 (27%) patients died. The use of infliximab is associated with PCP infection. Further, the mortality rate for Pneumocystis following the use of infliximab is significant. The potential for severe disease, mortality, and often subtle presentation of these infections warrant close follow-up and careful monitoring after therapy.

Primary biliary cirrhosis: survival of a large cohort of symptomatic and asymptomatic patients followed for 24 years.

We extended by 10 years, a follow-up study of 279 patients with primary biliary cirrhosis initially evaluated at the Yale Liver Study Unit between 1955 and 1979. Thirty-six patients (13%) were asymptomatic at the time of diagnosis. Accurate follow-up survival data were available for 247 patients (89%), ranging up to 24 years after the original diagnosis. Median predicted survival of patients in this study from the time of diagnosis is twice as long for patients who present without symptoms compared to symptomatic patients (16 vs 7.5 years, p < 0.0001). However, overall survival of those asymptomatic patients is shorter than that predicted for an age- and gender-matched control population (p < 0.0001), a difference that became apparent only after 11 years of follow up. With a median follow up of 12.1 years, 33% of the asymptomatic patients remained free of symptoms of liver disease, However, once symptoms develop, their survival is similar to those presenting with symptoms. Independent predictors of diminished survival include: elevated bilirubin, increasing age, ascites, advanced fibrosis and the degree of portal bile stasis on liver biopsy. It was not possible to predict which asymptomatic patients would remain symptom free.

Regression of Fibrosis in Chronic Hepatitis C After Therapy with Interferon and Ribavirin

Interferon and ribavirin decrease necroinflammation in chronic hepatitis C with or without virological clearance; however, reversibility of fibrosis remains to be established. We evaluated the effect of combination therapy on virological and liver histopathological outcomes in 52 naïve patients and 79 patients unresponsive to interferon monotherapy with predominantly genotype 1 chronic hepatitis C. One hundred four patients completed interferon and ribavirin treatment after 24–48 weeks. Fifty-six paired liver biopsies (mean biopsy interval 28 months) were assessed by the Ishak score. Sustained virological responses were 37% in naïve patients and 22% in re-treated patients. In virological responders and nonresponders, fibrosis and necroinflammation scores decreased by −0.91 (P =0.04) and −0.5 (P =0.02) and by −2.8 (P =0.001) and −0.66 (P =0.06), respectively. Interferon and ribavirin had greater benefit on fibrosis when associated with clearance of HCV RNA. Treatment strategies in virological nonresponders who show fibrosis regression should include consideration of maintenance therapy, if such treatment eventually proves to benefit histological outcomes.

Pathophysiology of Portal Hypertension and Variceal Bleeding

Portal hypertension results from an interaction of abnormal intrahepatic resistance and increases in portal blood flow. Intrahepatic resistance is probably multifactorial in nature and may include compression of hepatic veins by regenerating nodules, collagen deposition in sinusoids and venules, hepatocyte enlargement, and constriction of sinusoids by contractile myofibroblasts. The increase in splanchnic blood flow observed is incompletely understood, but it may involve circulating vasodilators and alteration in volume and sodium balance. The end result of these interactions is the development of increased portal pressure and portosystemic collaterals, the most important of which are esophageal varices. The rupture of esophageal varices is a devastating complication of portal hypertension. Increased portal pressure is necessary for the development and rupture of varices but apparently not sufficient, because many patients with elevated portal pressures never bleed. Presumably, local factors must be involved. Variceal wall tension is probably the best single descriptor of risk from variceal hemorrhage. The wall-tension formula unites the contributions of portal pressure, varix size, and wall thickness to variceal rupture. Lowering portal pressure, reducing varix size, and supporting varices in scar tissue may all lower the risk of hemorrhage.

Pneumocystis carinii pneumonia with oral candidiasis after infliximab therapy for crohn's disease

Anti-tumor necrosis factor-α antibody, infliximab, has become an established effective therapy for Crohn’s disease and rheumatoid arthritis. In each disease, this medication is usually reserved for patients who fail to respond to conventional therapy (1). The use of infliximab as a therapy for other autoimmune diseases including sarcoidosis, psoriasis, ankylosing spondylitis, and arthritis has been suggested (2). While this therapy is helpful to many who suffer from inflammatory disease, it is not without hazard. Infliximab has been associated with invasive aspergillosis (3), histoplasmosis (4), cytomegalovirus (5), listeriosis (6, 7), and tuberculosis reactivation (8). There have been reports of drug-induced lupus secondary to infliximab therapy (9). Retinal vein thrombosis and new-onset heart failure have also been reported in association with this medication (10, 11). In 2002, Tai et al. reported a case of Pneumocystis carinii pneumonia (PCP) in a patient receiving infliximab for rheumatoid arthritis (12); the U.S. Food and Drug Administration has 10 reports on file of patients developing PCP after infliximab infusion (13). Although PCP after infliximab therapy for Crohn’s disease has been mentioned in reviews (14), no formal cases have yet been reported. Here we report a case of PCP with oral candidiasis after a second infusion of infliximab for Crohn’s disease.

Safety and Preliminary Clinical Activity of a Novel Pancreatic Enzyme Preparation in Pancreatic Insufficient Cystic Fibrosis Patients

Objectives: Currently available pancreatic enzyme products are crude porcine products with few data available regarding their efficacy, safety, and manufacture. We conducted a phase 1 study of a novel pancreatic enzyme product, TheraCLEC-Total (TCT), a proprietary formulation of microbial-derived lipase, protease, and amylase, to determine its safety and preliminary efficacy in cystic fibrosis. Methods: We conducted an open-label, dose-ranging study in 23 subjects diagnosed with pancreatic insufficiency with cystic fibrosis. The subjects received TCT containing lipase dose of 100, 500, 1000, 2500, or 5000 USP U/kg per meal with each meal or snack for 3 days. The clinical and laboratory parameters and adverse events (AEs) were monitored. Results: There were no serious AEs. Most AEs were mild, although gastrointestinal complaints were common. TCT increased the coefficient of fat and nitrogen absorption in all groups except in the low-dose group. At the other dosing levels, the mean coefficient of fat and nitrogen absorption increases were 19.1% ± 24.9% and 17.8% ± 13.6%, respectively, whereas the mean stool weight decreased by 517 ± 362 g. Conclusions: TCT was well tolerated in this short-term exposure study. The preliminary efficacy data demonstrate lipase and protease activity with little difference seen with lipase doses greater than 500 USP U/kg per meal. These data support a larger randomized phase 2 trial.

Postmenarchal development of chylous ascites in acrocephalosyndactyly with congenital lymphatic dysplasia

Background Acrocephalosyndactyly is a syndrome characterized by congenital malformation of the skull with craniosynostosis, midface hypoplasia, and symmetrical webbed fusion of the fingers and toes. We describe a possible pathophysiologic mechanism for chylous ascites that developed several months after menarche in a woman with acrocephalosyndactyly and congenital lymphatic dysplasia. Case A 25-year-old nulligravid woman with acrocephalosyndactyly, at 18 months after menarche, developed persistent abdominal distension at age 18 years. Laparoscopy at age 25 years revealed chylous ascites with marked chronic peritoneal inflammation, and lymphatic dysplasia with lymphocysts. With hormone manipulation, the chylous ascites fluctuated. Conclusion After menarche in a woman with acrocephalosyndactyly, ovarian steroid hormones might have increased lymph production and hydrostatic pressure, causing rupture of congenitally dysplastic lymph vessels resulting in chylous ascites.

Rizatriptan-Induced Colonic Ischemia: A Case Report and Literature Review

vomiting, and sensitivity to light and sound ( 1 ). Although triptans are the standard of care for the treatment of migraines and are considered to be at low risk for complications, they have been implicated in serious adverse reactions, which have reportedly resulted in death. Cases of serious adverse events, including ischemic colitis (IC) ( 2–4 ) are thought to occur as a result of systemic eff ects of the medication, causing peripheral vasoconstriction and ischemia of vital organs. Here we report a 52-year-old caucasian male with a history of migraines treated prophylactically with propranolol and managed acutely with dose adjusted rizatriptan. On presentation, the patient reported stabbing right lower quadrant abdominal pain, which gradually worsened, becoming constant. Th e patient’s pain was associated with chills, constipation, anorexia, and nausea without vomiting. He reported no fever, diarrhea, hematochezia, melena, dizziness, or syncope. He reported no use of alcohol, tobacco products, supplements, or recreational drugs, and did not exceed the maximum recommended dose of rizatriptan. Physical examination revealed right lower quadrant tenderness with mild rebound and voluntary guarding. Although initial vital signs and laboratory tests were essentially normal, an abdominal and pelvic computed tomography angiogram showed abnormal mucosal thickening, pneumatosis, and pericolonic fat stranding of the cecum and proximal ascending colon as well as portal venous air in the right hepatic lobe. Th e patient underwent an emergent laparotomy with a right hemicolectomy 5. Casella G , Villanacci V , Di Bella C et al. Pulmonary diseases associated with infl ammatory bowel diseases . J Crohns Colitis 2010 ; 4 : 384 – 9 . 6. Bonniere P , Wallaert B , Cortot A et al. Latent pulmonary involvement in Crohn’s disease: biological, functional, bronchoalveolar lavage and scintigraphic studies . Gut 1986 ; 27 : 919 – 25 . 7. Colombel JF , Sands BE , Rutgeerts P et al. Th e safety of vedolizumab for ulcerative colitis and Crohn’s disease . Gut 2017 ; 66 : 839 – 51 .

Spontaneous perforation of zenkers diverticulum presenting as massive upper gastrointestinal and mediastinal bleeding: first report of a case

Spontaneous perforation of zenkers diverticulum presenting as massive upper gastrointestinal and mediastinal bleeding: first report of a case