Cimetidine-induced fever.

Cimetidine is a rare cause of drug-induced fever. In a patient without evidence of hypersensitivity (the lymphocytes did not react to the drug in vitro) fever was the sole manifestation of an adverse reaction to cimetidine that was confirmed by challenge with the drug.     

Coxiella burnetii, the agent of Q fever in Brazil: its hidden role in seronegative arthritis and the importance of molecular diagnosis based on the repetitive element IS1111 associated with the transposase gene

Coxiella burnetii is the agent of Q fever , an emergent worldwide zoonosis of wide clinical spectrum. Although C. burnetii infection is typically associated with acute infection, atypical pneumonia and flu-like symptoms, endocarditis, osteoarticular manifestations and severe disease are possible, especially when the patient has a suppressed immune system; however, these severe complications are typically neglected. This study reports the sequencing of the repetitive element IS1111 of the transposase gene of C. burnetii from blood and bronchoalveolar lavage (BAL) samples from a patient with severe pneumonia following methotrexate therapy, resulting in the molecular diagnosis of Q fever in a patient who had been diagnosed with active seronegative polyarthritis two years earlier. To the best of our knowledge, this represents the first documented case of the isolation of C. burnetii DNA from a BAL sample.     

Diverse and atypical manifestations of Q fever in a metropolitan city hospital: Emerging role of next-generation sequencing for laboratory diagnosis of Coxiella burnetii

Although Q fever has been widely reported in the rural areas of China, there is a paucity of data on the epidemiology and clinical characteristics of this disease in large metropolitan cities. In this study, we profile the epidemiology and clinical manifestations of Q fever from a tertiary hospital in Shenzhen, a Southern Chinese metropolitan city with a large immigrant population from other parts of China. A total of 14 patients were confirmed to have Q fever during a nine-year-and-six-month period, five of whom were retrospectively diagnosed during case review or incidentally picked up because of another research project on unexplained fever without localizing features. Some patients had the typical exposure histories and clinical features, while a few other patients had rare manifestations of Q fever, including one with heart failure and diffuse intracapillary proliferative glomerulonephritis, a patient presenting with a spontaneous bacterial peritonitis-like syndrome, and another one with concomitant Q fever and brucellosis. Using a combination of clinical manifestation, inflammatory marker levels, echocardiographic findings and serological or molecular test results, nine, three and two patients were diagnosed to have acute, chronic and convalescent Q fever, respectively. Seven, five and two patients were diagnosed to have Q fever by serological test, nested real-time PCR and next-generation sequencing respectively. Diverse and atypical manifestations are associated with Q fever. The incidence of Q fever is likely to be underestimated. Next-generation sequencing is becoming an important diagnostic modality for culture-negative infections, particularly those that the physicians fail to recognize clinically, such as Q fever.     

Sarcoidosis and Polyarthritis

Polyarthritis is a well-recognized manifestation of sarcoidosis, but the various series of cases reported in the literature reveal considerable variation in its incidence as well as in its clinical manifestations. Three major types of sarcoid polyarthritis are defined, as distinguished by their clinical and pathological features. Two of these types are usually seen in conjunction with the subacute or transient form of sarcoidosis and, in most cases, are accompanied by erythema nodosum. They differ markedly in severity, but their prognosis is uniformly good. The third type, in contrast, is of a chronic nature and is often associated with permanent joint changes. Mild joint manifestations are a frequent finding in sarcoidosis, but more severe arthritis is relatively rare.Two cases of sarcoidosis, presenting with severe polyarthritis, are reported in detail, and cases seen in Halifax hospitals during the period 1954 to 1964 are reviewed.     

Multicenter Study of Trimethoprim/Sulfamethoxazole-Related Hepatotoxicity: Incidence and Associated Factors among HIV-Infected Patients Treated for Pneumocystis jirovecii Pneumonia

The incidence of hepatotoxicity related to trimethoprim/sulfamethoxazole (TMP/SMX) administered at a therapeutic dose may vary among study populations of different ethnicities and hepatotoxic metabolites of TMP/SMX may be decreased by drug-drug interaction with fluconazole. We aimed to investigate the incidence of hepatotoxicity and the role of concomitant use of fluconazole in HIV-infected patients receiving TMP/SMX for Pneumocystis jirovecii pneumonia. We reviewed medical records to collect clinical characteristics and laboratory data of HIV-infected patients who received TMP/SMX for treatment of P. jirovecii pneumonia at 6 hospitals around Taiwan between September 2009 and February 2013. Hepatotoxicity was defined as 2-fold or greater increase of aminotransferase or total bilirubin level from baselines. Roussel UCLAF Causality Assessment Method (RUCAM) was used to analyze the causality of drug-induced liver injuries. NAT1 and NAT2 acetylator types were determined with the use of polymerase-chain-reaction (PCR) restriction fragment length polymorphism to differentiate common single-nucleotide polymorphisms (SNPs) predictive of the acetylator phenotypes in a subgroup of patients. During the study period, 286 courses of TMP/SMX treatment administered to 284 patients were analyzed. One hundred and fifty-two patients (53.1%) developed hepatotoxicity, and TMP/SMX was considered causative in 47 (16.4%) who had a RUCAM score of 6 or greater. In multivariate analysis, concomitant use of fluconazole for candidiasis was the only factor associated with reduced risk for hepatotoxicity (adjusted odds ratio, 0.372; 95% confidence interval, 0.145–0.957), while serostatus of hepatitis B or C virus, NAT1 and NAT2 acetylator types, or receipt of combination antiretroviral therapy was not. The incidence of hepatotoxicity decreased with an increasing daily dose of fluconazole up to 4.0 mg/kg. We conclude that the incidence of TMP/SMX-related hepatotoxicity was 16.4% in HIV-infected Taiwanese patients who received TMP/SMX for pneumocystosis. Concomitant use of fluconazole was associated with decreased risk for TMP/SMX-related hepatotoxicity.     

The Role of Complement Activation in Hypersensitivity to Pegylated Liposomal Doxorubicin (Doxil®)

Abstract

Liposomal formulations of some drugs, most importantly pegylated liposomal doxorubicin (Doxil®), have been reported to cause immediate hypersensitivity reactions that cannot be explained with the conventional paradigm of IgE-mediated (type I) allergy. Here we present a rationale and experimental evidence for the concept that these reactions represent a novel type of drug-induced hypersensitivity that can be called complement (C) activation-related pseudoallergy (CARPA). The theoretical foundation includes the facts that 1) some liposomes have been known to activate C, 2) most of the clinical symptoms of liposome-induced reactions coincide with those caused by C activation by other activators, and 3) the C mechanism explains those manifestations which are atypical for type 1 reactions. The experimental evidence includes the observations that 1) Doxil caused massive C activation in a high ratio (4/10) of normal human sera, 2) high dose IgG attenuated Doxil-induced C activation in serum and prevented further C activation by amplification, and 3) intravenous injection of therapeutically relevant doses of Doxil in pigs caused significant pulmonary hypertension with consequent systemic hypotension and decline of cardiac output, which changes mimicked the cardiovascular manifestations of the human reaction and were shown to be triggered by C activation. As for the question how Doxil, a long-circulating “stealth” liposome formulation, avoids phagocytic uptake by macrophages despite its potential opsonization by C3b, we demonstrated efficient inactivation of Doxil-bound and free C3b to iC3b in human serum. Thus, it is unlikely that PEG would interfere with CD11b/CD18-mediated phagocytosis by inhibiting the formation of its main ligand, iC3b.     

Hepatitis C Virus Co-Infection Increases the Risk of Anti-Tuberculosis Drug-Induced Hepatotoxicity among Patients with Pulmonary Tuberculosis

Background

The country of Georgia has a high prevalence of tuberculosis (TB) and hepatitis C virus (HCV) infection.

Purpose

To determine whether HCV co-infection increases the risk of incident drug-induced hepatitis among patients on first-line anti-TB drug therapy.

Methods

Prospective cohort study; HCV serology was obtained on all study subjects at the time of TB diagnosis; hepatic enzyme tests (serum alanine aminotransferase [ALT] activity) were obtained at baseline and monthly during treatment.

Results

Among 326 study patients with culture-confirmed TB, 68 (21%) were HCV co-infected, 14 (4.3%) had chronic hepatitis B virus (HBV) infection (hepatitis B virus surface antigen positive [HBsAg+]), and 6 (1.8%) were HIV co-infected. Overall, 19% of TB patients developed mild to moderate incident hepatotoxicity. In multi-variable analysis, HCV co-infection (adjusted Hazards Ratio [aHR]=3.2, 95% CI=1.6-6.5) was found to be an independent risk factor for incident anti-TB drug-induced hepatotoxicity. Survival analysis showed that HCV co-infected patients developed hepatitis more quickly compared to HCV seronegative patients with TB.

Conclusion

A high prevalence of HCV co-infection was found among patients with TB in Georgia. Drug-induced hepatotoxicity was significantly associated with HCV co-infection but severe drug-induced hepatotoxicity (WHO grade III or IV) was rare.     

Drug-specific T cells derived from patients with drug-induced allergic hepatitis.

Drug-induced allergic hepatitis is a tissue-specific inflammatory disease caused by hypersensitivity to a particular drug. Although the frequency of drug-induced allergic hepatitis appears to increase in proportion to the medicine, the mechanism by which tissue specificity is determined is still to be elucidated. In this study, we established CD4+ T cell clones specific for particular drugs from patients with drug-induced allergic hepatitis accompanied with mild blood eosinophilia and analyzed the possible role of liver protein as a directing factor of liver-specific inflammatory reactions. All CD4+ T cell clones obtained from two patients with this disease proliferated in response to a combination of the particular drug plus liver specific protein (LSP), which consists of over 30 proteins. Some T cell clones were responsive to an antigenic conformation consisting of the 200-kDa glycoprotein (partly purified LSP), a component of LSP, plus the causal drug. In contrast, all CD4+ T cell clones from a patient with simple drug-induced eosinophilia responded to the causal drug in the absence of LSP and partly purified LSP. These data suggested that LSP or partly purified LSP of the appropriate Ag is the target that leads to liver-specific inflammation in drug-induced allergic hepatitis. Furthermore, T cell lines derived from patients with drug-induced allergic hepatitis and simple drug-induced eosinophilia produced large amounts of IL-5 after the appropriate antigenic stimulation, whereas CD4+ T cell clones from donors with a normal amount of peripheral blood eosinophils secreted a much less IL-5. Taken together, these results indicate that overproduction of IL-5 by the allergen-sensitized T cells may result in blood eosinophilia.     

The T mu- and T gamma-lymphocyte count and their ratio in patients with brucellosis of various focal natures

The content of T mu- and T gamma-lymphocytes and their ratio in patients having subacute and chronic brucellosis with different foci of infection have been studied. The relationship between the decrease in the levels of T mu- and T gamma-cells and the clinical form of the disease and its clinical manifestations, such as polyarthritis, has been established. Manifestations of disturbances in the T mu-cell/T gamma-cell ratio were more pronounced in patients with subacute brucellosis in whom the lesions of the osteoarticular system prevailed. The detected changes in the counts of immunoregulatory cells in brucellosis are assumed to be of pathogenetic importance.     

An outbreak of Q fever in the Basque country.

The main clinical manifestations of 42 cases of Q fever occurring in an outbreak in Valmaseda, Spain during March, April and May 1982 are described in this paper. The benign character of the acute disease is emphasized. Further epidemiologic studies must be done to determine the incidence of Q fever in the Basque country.     

Circulating L-lymphocytes in brucellosis patients

The content of L-lymphocytes in patients with different clinical forms of brucellosis has been studied. The degree of a decrease in the level of these cells has been found to depend on the activity of the infectious process and its clinical manifestations in the form of polyarthritis. The severity of the course of acute and subacute brucellosis has been found to produce no essential influence on the level of L-cells. These cells are supposed to participate in the processes of pathogenesis and the elimination of the pathogen in brucellosis.     

Effect of levamisole and etimisole on the development of experimental allergic encephalomeylitis

A single subcutaneous inoculation with 0.02 mg of heterologous myelin basic protein (MBP) in combination with Freund's complete adjuvant resulted in clinical and histological manifestations of experimental allergic encephalomyelitis (EAE) in 80-90% of treated guinea pigs. Daily parenteral administration of levamisole and etimisole during the latent period produced a suppressive effect on EAE development, reducing morbidity and mortality rates and preventing pathomorphological changes in the CNS. Animals receiving the drugs had decreased delayed hypersensitivity reactions to MBP in vitro. Etimisole brought about a moderate decline in the formation of circulating anti-MBP antibodies, while levamisole did not affect the strength of the humoral response, something which confirmed the primary role of cell-mediated immune reactions in the CNS demyelinization process. The reported findings may be significant in developing therapeutic strategies with respect to demyelinization diseases.     

Cutaneous and Ocular Reactions to Practolol

A total of 21 patients suffering from drug-induced rashes from practolol have been seen over the past two years. The clinical manifestations varied, with the morphological appearances of the rash resembling those of eczema, lupus erythematosus, lichen planus, and a highly characteristic toxic erythematous psoriasiform eruption. Persistent ocular damage was a feature in three cases.     

A new category of autoinflammatory disease associated with NOD2 gene mutations

Introduction

Autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high titers of autoantibodies or antigen-specific T cells, and derive from genetic variants of the innate immune system. This study characterized a cohort of patients with similar phenotypes and nucleotide oligomerization domain 2 (NOD2) gene mutations.

Methods

Diagnostically challenging patients with the following clinical and genetic characteristics were prospectively studied between January 2009 and April 2011: periodic fever, dermatitis, polyarthritis, serositis, negative serum autoantibodies and additional positive NOD2 IVS8⁺¹⁵⁸ gene mutation. Genetic testing for gene mutations of NOD2, tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) and familial Mediterranean fever (FMF) was performed.

Results

All seven patients with the disease were Caucasians, with four being male. The mean age at disease onset was 40.7 years and disease duration was 3.2 years. These patients characteristically presented with periodic fever, dermatitis and inflammatory polyarthritis. There were gastrointestinal symptoms in three patients, granulomas of the skin and gut in two, and recurrent chest pain in two, with one having pleuritis and pericarditis. Three patients had sicca-like symptoms. Five patients had increased acute phase reactants. All seven patients had negative tests for autoantibodies but carried the NOD2 gene mutation IVS8⁺¹⁵⁸ with four having concurrent R702W mutation.

Conclusions

Our cohort may represent a new disease category of autoinflammatory disease with characteristic clinical phenotypes and genotypes. It may somewhat resemble pediatric Blau's syndrome.     

Subclinical form of the American visceral leishmaniasis

The subclinical form of visceral leishmaniasis (VL) shows nonspecific clinical manifestations, with difficulties being frequently met in its clinical characterization and diagnostic confirmation. Thus, the objective of the present study was to define the clinical-laboratory profile of this clinical form. A cohort study was conducted in the state of Maranh?o, Brazil, from January/1998 to December/2000, with monthly follow-up of 784 children aged 0-5 years. Based on the clinical-laboratory parameters reported in the literature, four categories were established, with the children being classified (according to their clinical-evolutive behavior) as asymptomatic (N = 144), as having the subclinical form (N = 33) or the acute form (N = 12) or as subjects "without VL" (N = 595). Multiple discriminant analysis demonstrated that the combination of fever, hepatomegaly, hyperglobulinemia, and increased blood sedimentation rate (BSR) can predict the subclinical form of VL as long as it is not associated with splenomegaly or leukopenia. Subjects with the subclinical form did not show prolonged or intermittent evolution or progression to the acute form of VL. Subclinical cases have a profile differing from the remaining clinical forms of VL, being best characterized by the combination of fever, hepatomegaly, hyperglobulinemia, and increased BSR.     

Extracardiac Manifestations of Bacterial Endocarditis

Bacterial endocarditis is an elusive disease that challenges clinicians'' diagnostic capabilities. Because it can present with various combinations of extravalvular signs and symptoms, the underlying primary disease can go unnoticed.A review of the various extracardiac manifestations of bacterial endocarditis suggests three main patterns by which the valvular infection can be obscured. (1) A major clinical event may be so dramatic that subtle evidence of endocarditis is overlooked. The rupture of a mycotic aneurysm may simulate a subarachnoid hemorrhage from a congenital aneurysm. (2) The symptoms of bacterial endocarditis may be constitutional complaints easily attributable to a routine, trivial illness. Symptoms of low-grade fever, myalgias, back pain and anorexia may mimic a viral syndrome. (3) Endocarditis poses a difficult diagnostic dilemma when it generates constellations of findings that are classic for other disorders. Complaints of arthritis and arthralgias accompanied by hematuria and antinuclear antibody may suggest systemic lupus erythematosus; a renal biopsy study showing diffuse proliferative glomerulonephritis may support this diagnosis. The combination of fever, petechiae, altered mental status, thrombocytopenia, azotemia and anemia may promote the diagnosis of thrombotic thrombocytopenic purpura.When the protean guises of bacterial endocarditis create these clinical difficulties, errors in diagnosis occur and appropriate therapy is delayed. Keen awareness of the varied disease presentations will improve success in managing endocarditis by fostering rapid diagnosis and prompt therapy.     

Role of cognitive parameters in dengue hemorrhagic fever and dengue shock syndrome

Dengue is becoming recognized as one of the most important vector-borne human diseases. It is predominant in tropical and subtropical zones but its geographical distribution is progressively expanding, making it an escalating global health problem of today. Dengue presents with spectrum of clinical manifestations, ranging from asymptomatic, undifferentiated mild fever, dengue fever (DF), to dengue hemorrhagic fever (DHF) with or without shock (DSS), a life-threatening illness characterized by plasma leakage due to increased vascular permeability. Currently, there are no antiviral modalities or vaccines available to treat and prevent dengue. Supportive care with close monitoring is the standard clinical practice. The mechanisms leading to DHF/DSS remains poorly understood. Multiple factors have been attributed to the pathological mechanism, but only a couple of these hypotheses are popular in scientific circles. The current discussion focuses on underappreciated factors, temperature, natural IgM, and endotoxin, which may be critical components playing roles in dengue pathogenesis.     

Arthritis and Hepatitis

The evidence relating four clinically distinct rheumatologic syndromes to infection by the hepatitis B virus is reviewed. Acute hepatitis B is not infrequently heralded by a prodromal rash and rheumatoidlike polyarthritis. Chronic active hepatitis B more rarely is associated with transient arthritis or arthralgias. Polyarteritis nodosa may be a manifestation of hepatitis B infection in as many as 40 percent of cases, and recently the syndrome of “essential” mixed cryoglobulinemia has also been linked to infection with this virus. The finding of immune complexes of varying composition, sometimes with the viral antigen or its antibody (or both) contained in both the serum and synovial fluid suggests that these four syndromes are clinical manifestations of immune complex disease resulting from hepatitis B infection.