Treatment of DIHS/DRESS syndrome with combined N-acetylcysteine, prednisone and valganciclovir--a hypothesis.

BACKGROUND: Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a rare and severe adverse drug reaction with an associated mortality of 10-20%. Clinical worsening despite discontinuation of the culprit drug is considered a characteristic feature of DIHS/DRESS. Besides the early recognition of the syndrome and discontinuation of its causative drug, the mainstay of treatment is systemic corticosteroids. Nevertheless, treatment of severe DIHS/DRESS is not well defined, as corticosteroids may sometimes not be effective, and decreasing the dose may be associated with flaring of the disease. CASE REPORT: A 38-year-old woman with high fever, malaise, abdominal pain, rash, and elevated liver enzymes received immediate high-dose N-acetylcysteine, because acetaminophen hepatotoxicity was suspected. N-acetylcysteine administration was associated with a significant clinical improvement. However, within the next week DIHS/DRESS syndrome was diagnosed, which explained all the symptoms, and which was subsequently treated with prednisone and valganciclovir. CONCLUSIONS: New options necessary to improve treatment of severe DIHD/DRESS have to consider its sequential pathogenetic mechanisms. N-acetylcysteine might neutralize the drug-derived reactive metabolites, which are responsible for protein adduct formation and specific T cell stimulation, and replete the glutathione stores that counterbalance oxidative stress. Prednisone might inhibit lymphoproliferation and valganciclovir might prevent complications related to HHV-6 reactivation. We therefore propose the unprecedented combination of N-acetylcysteine, prednisone and valganciclovir as a treatment option for DIHS/DRESS.

Sugar and the Mosaic of Autoimmunity.

BACKGROUND Recent discoveries in the field of immunometabolism, and on the role of the serine-threonine kinase mTOR as a sensor of nutrients, integrator of cellular signaling pathways, and regulator of metabolism, have widened our understanding of the connection between nutrition, health, and diseases. Epidemiological studies have shown that higher sugar-sweetened beverage consumption is associated with increased risk of developing chronic diseases, including cardiovascular disease, type 2 diabetes mellitus, obesity, non-alcoholic fatty liver disease, gout, and rheumatoid arthritis and to worse symptoms in some patients with rheumatoid arthritis. Anabolic metabolism has been demonstrated to favor the differentiation of proinflammatory T lymphocytes while katabolic metabolism to favor regulatory T lymphocyte differentiation. CASE REPORT In a 66-year old male, the onset of gonarthritis and enthesitis and worsening of these symptoms 3 months later were associated with excessive intake of desserts. Two weeks after starting strict avoidance of sugar containing nutrients and beverages symptoms disappeared. During the next 6 months, on 3 occasions, the exceptional consumption of a dessert was followed by a mild and transient recurrence of the symptoms. CONCLUSIONS The repeatedly observed recurrence of enthesitis/arthritis symptoms following sugar intake and its disappearance following avoidance of sugar, represents an extreme example of a link between metabolism and local inflammation in the reported individual. The rapid absorption of the monosaccharides glucose and fructose from the intestine, where they derive from hydrolysis of the disaccharide sucrose (sugar) might lead to overactivation of mTOR if not counterbalanced by other mTOR interfering mechanisms.

Severe hepatotoxicity after therapeutic doses of acetaminophen.

BACKGROUND: Acetaminophen overdose is a frequent cause of acute liver failure. Controversy exists over the rare association of severe hepatotoxicity or acute liver failure with therapeutic doses of acetaminophen. CASE SUMMARY: A 45-year-old white man weighing 85 kg with asymptomatic HIV, hepatitis B virus, and hepatitis C virus (HCV) infection presented with signs of severe hepatotoxicity: aspartate aminotransferase (AST), 8,581 IU/L; alanine aminotransferase (ALT), 5,433 IU/L; L-lactate dehydrogenase, 13,641 IU/L; and prothrombin international normalized ratio, 2.15. He reported taking acetaminophen 1,000 mg QID for the previous 4 days and 1,000 mg that morning because of a febrile illness. Immediate administration of continuous IV N-acetylcysteine 150 mg/kg for the first 90 minutes and then 50 mg/kg q4h for the next 3 days was followed by clinical improvement and a rapid decrease in AST and ALT. AST levels decreased from 8,581 to 42 IU/L within 11 days. Several potential risk factors for acetaminophen hepatotoxicity (ie, chronic alcohol, tobacco, and opiate consumption, malnutrition, illness-induced starvation, HIV infection, and HCV infection) were present in this patient. CONCLUSIONS: This patient with multiple risk factors and severe hepatotoxicity after therapeutic dosage of acetaminophen was successfully treated with N-acetylcysteine.

Intravascular large B-cell lymphoma associated with silicone breast implant, HLA-DRB1*11:01, and HLA-DQB1*03:01 manifesting as macrophage activation syndrome and with severe neurological symptoms: a case report.

BACKGROUND: Silicone implants have been successfully used for breast augmentation and reconstruction in millions of women worldwide. The reaction to the silicone implant is highly variable; it can lead to local inflammatory symptoms, and sometimes to systemic symptoms and disease. Over 80 cases of anaplastic lymphoma kinase-negative anaplastic large cell lymphoma have been reported in patients with silicone breast implants and have been accepted as a new clinical entity. To the best of our knowledge, an intravascular large B-cell lymphoma associated with a silicone breast implant has not been reported previously. CASE PRESENTATION: A 48-year-old Caucasian woman who presented with high fever was found to have splenomegaly on physical examination. A laboratory diagnosis revealed pancytopenia, hypertriglyceridemia, and hyperferritinemia. She developed signs of altered sensorium, hemiparesis, aphasia, and cauda equina syndrome. On further evaluation, she fulfilled the necessary five out of eight criteria for diagnosis of macrophage activation syndrome/hemophagocytic lymphohistiocytosis. Dexamethasone administration was followed by prompt improvement; however, 3 days later she again manifested high fever, which persisted despite administration of immunoglobulin and cyclosporine A. Her silicone breast implant was considered a possible contributor to her macrophage activation syndrome and was therefore removed. A histological examination of the capsule tissue showed an extensive lymphohistiocytic/giant cell foreign body reaction suggestive of autoimmune/inflammatory syndrome induced by adjuvants. However, the histological examination unexpectedly also revealed an intravascular large B-cell lymphoma. CONCLUSIONS: The genetic background of our patient with silicone breast implants might have predisposed her to three rare and difficult to diagnose syndromes/diseases: macrophage activation syndrome/hemophagocytic lymphohistiocytosis, autoimmune/inflammatory syndrome induced by adjuvants, and intravascular large B-cell lymphoma. The simultaneous manifestation of all three syndromes suggests causal interrelationships. Human leukocyte antigen testing in all women who undergo silicon breast implantation could in the future enable us to better evaluate the risk of potential side effects.

Increased IL-17, a Pathogenic Link between Hepatosplenic Schistosomiasis and Amyotrophic Lateral Sclerosis: A Hypothesis.

The immune system protects the organism from foreign invaders and foreign substances and is involved in physiological functions that range from tissue repair to neurocognition. However, an excessive or dysregulated immune response can cause immunopathology and disease. A 39-year-old man was affected by severe hepatosplenic schistosomiasis mansoni and by amyotrophic lateral sclerosis. One question that arose was, whether there was a relation between the parasitic and the neurodegenerative disease. IL-17, a proinflammatory cytokine, is produced mainly by T helper-17 CD4 cells, a recently discovered new lineage of effector CD4 T cells. Experimental mouse models of schistosomiasis have shown that IL-17 is a key player in the immunopathology of schistosomiasis. There are also reports that suggest that IL-17 might have an important role in the pathogenesis of amyotrophic lateral sclerosis. It is hypothesized that the factors that might have led to increased IL-17 in the hepatosplenic schistosomiasis mansoni might also have contributed to the development of amyotrophic lateral sclerosis in the described patient. A multitude of environmental factors, including infections, xenobiotic substances, intestinal microbiota, and vitamin D deficiency, that are able to induce a proinflammatory immune response polarization, might favor the development of amyotrophic lateral sclerosis in predisposed individuals.

Fatal lactic acidosis precipitated by nifedipine in a patient treated with disulfiram and antiretrovirals.

A 43 year old man with HIV and HCV infection and liver cirrhosis developed fatal lactic acidosis within five days from starting nifedipine for arterial hypertension. Multiple drug interactions, current and accumulated drug toxicities and the reduced liver function, might in combination have led to the acute lactic acidosis.

Mycobacterium marinum, a further infectious agent associated with sarcoidosis: the polyetiology hypothesis.

A 39-y-old male had a diagnosis of sarcoidosis and corticosteroid therapy was started. Surprisingly, following his discharge from hospital, Mycobacterium marinum was isolated in 1 of 3 sputum samples taken 7 weeks earlier on admission. After this, Mycobacterium marinum-DNA was identified in the stored lung biopsies by the PCR-RFLP of the hsp65 gene.

Induction of oral tolerance as treatment or prevention of chronic diseases associated with Chlamydia pneumoniae infection--hypothesis.

BACKGROUND: Chlamydia pneumoniae infection is associated with chronic diseases such as asthma, reactive arthritis, and atherosclerosis. Several investigations and experimental results indicate an excessive immune response to heat shock protein (hsp) 60 as a possible common pathogenetic link between Chlamydia pneumoniae infection and the associated chronic diseases. CASE REPORT: A 46-year old woman with persistent C. pneumoniae infection and Reiter's syndrome had been treated for three years with antibiotics and nonsteroidal anti-inflammatory drugs without success. However, she was repeatedly free of complaints for several months following two-week cycles taking oral dilutions of Chlamydia trachomatis daily. CONCLUSIONS: The placebo effect does not seem sufficient to explain the clinical benefits obtained repeatedly by drinking dilutions of C. trachomatis. Induction of oral tolerance (immune modulation) to hsp60 may have occurred, leading to the clinical benefits. The known risk factors for atherosclerosis do not account for all cases of atherosclerosis. If autoimmunity to hsp60 is involved in the pathogenesis of atherosclerosis, so natural acquisition of oral tolerance to hsp60 may contribute to the geographical differences in atherosclerosis prevalence.

Soft tissue infection and bacteremia caused by Shewanella putrefaciens.

Shewanella putrefaciens is as yet rarely responsible for clinical syndromes in humans. However, a case involving multiple organs in an elderly male under treatment with appropriate steroids confirms that attention should be devoted to unusual pathogens.