Chronic hepatitis B is a major cause of liver disease in China. One of the treatments currently recommended is interferon (IFN). Although uncommon, there have been some case reviews on patients with hepatitis C with pulmonary adverse effects following treatment with IFN. Our case report is of a patient who acquired organizing pneumonia after he was treated for hepatitis B with pegylated IFN alfa-2b. We aim to raise awareness of the pulmonary toxicity of interferon, especially as it is increasingly used to treat patients with chronic hepatitis B.

Pegylated interferon-alpha (PEG-IFN-α) is an antiviral medication used to treat chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. It may result in rare but severe side effects, such as undifferentiated connective tissue disease (UCTD) and excessive dynamic airway collapse (EDAC), which can occur as delayed complications of PEG-IFN-α-induced UCTD. In cases where these complications arise, entecavir, employed for treating HBV infection, may be considered. A 49-year-old female patient, monitored for nine years with HCV and a viral load of 1.5 million, genotype 3, and normal liver function tests (LFTs), possibly acquired the infection from her HCV-positive husband. The patient was initially treated with PEG-IFN-α (IFN-α-2b, 100 µg/week subcutaneously) and ribavirin (RBV, 500 mg/twice daily). Following the sixth injection, the patient exhibited symptoms, including shortness of breath and cough, leading to limited daily activities. Subsequent high-resolution computed tomography (HRCT) showed interstitial pneumonitis (IP) signs. She was given a high dose of steroids. Over the next two to four weeks, the patient experienced Raynaud's phenomenon, skin tightening, joint pains, and dryness of the eyes and mouth. The antinuclear antibody (ANA) test was negative, while the extractable nuclear antigen (ENA) test showed equivocal anti-Smith antibodies (6.38). Rheumatoid factor (RA) factors were mildly positive, and pulmonary function tests (PFTs) indicated a restrictive pattern. The patient was intolerant to hydroxychloroquine (HCQ) and azathioprine (Imuran) 500 mg, subsequently receiving mycophenolate mofetil 500 mg/thrice daily. Despite four years of treatment, UCTD due to PEG-IFN-α remained difficult to control; however, IP responded well to steroids. Rituximab pulse therapy was planned before the initiation; serological tests showed positive anti-HBs with a titer of 17.02, positive anti-HBc, but negative HBsAg and undetectable HBV viral load, indicating immunity to HBV due to natural infection. Given the potential for rituximab to cause immunosuppression and HBV reactivation, entecavir treatment was started and continued for 18 months. The patient was followed for another five years, during which her LFTs and viral markers showed stability. However, after nine years of PEG-IFN-α-induced UCTD disorder, she experienced a reoccurring cough but was unresponsive to steroids that were against her suspicion of a flare of IP. A subsequent dynamic CT scan detected a 75% trachea collapse while in a supine position, indicating a potential complication termed EDAC. This EDAC could not be linked to PEG-IFN-α-induced UCTD disorder or EDAC after the use of entecavir in a patient with PEG-IFN-α-induced UCTD disorder. Treatment of such complex patients requires flexible, specific treatment plans and continuous monitoring. This case emphasizes the need for caution in patients with a history of IFN-induced disease and the possibility of late effects and possible effects of the use of entecavir in a patient with PEG-IFN-α-induced UCTD. To the best of our knowledge, this is the first case reported as EDAC, a possible delayed complication of PEG-IFN-α plus ribavirin or entecavir in a patient with PEG-IFN-α-induced UCTD.

Quinoxalines, a class of N-heterocyclic compounds, are important biological agents, and a significant amount of research activity has been directed towards this class. They have several prominent pharmacological effects like antifungal, antibacterial, antiviral, and antimicrobial. Quinoxaline derivatives have diverse therapeutic uses and have become the crucial component in drugs used to treat cancerous cells, AIDS, plant viruses, schizophrenia, certifying them a great future in medicinal chemistry. Due to the current pandemic situation caused by SARS-COVID 19, it has become essential to synthesize drugs to combat deadly pathogens (bacteria, fungi, viruses) for now and near future. Since quinoxalines is an essential moiety to treat infectious diseases, numerous synthetic routes have been developed by researchers, with a prime focus on green chemistry and cost-effective methods. This review paper highlights the various synthetic routes to prepare quinoxaline and its derivatives, covering the literature for the last two decades. A total of 31 schemes have been explained using the green chemistry approach, cost-effective methods, and quinoxaline derivatives' therapeutic uses.

Some investigators find a deficiency in IFN production from airway epithelial cells infected with human rhinovirus in asthma, but whether this abnormality occurs with other respiratory viruses is uncertain.

To assess the effect of influenza A virus (IAV) and respiratory syncytial virus (RSV) infection on IFN production and viral level in human bronchial epithelial cells (hBECs) from subjects with and without asthma.

Primary-culture hBECs from subjects with mild to severe asthma (n = 11) and controls without asthma (hBECs; n = 7) were infected with live or ultraviolet-inactivated IAV (WS/33 strain), RSV (Long strain), or RSV (A/2001/2-20 strain) with multiplicity of infection 0.01 to 1. Levels of virus along with IFN-β and IFN-λ and IFN-stimulated gene expression (tracked by 2'-5'-oligoadenylate synthetase 1 and myxovirus (influenza virus) resistance 1 mRNA) were determined up to 72 hours postinoculation.

After IAV infection, viral levels were increased 2-fold in hBECs from asthmatic subjects compared with nonasthmatic control subjects (P < .05) and this increase occurred in concert with increased IFN-λ1 levels and no significant difference in IFNB1, 2'-5'-oligoadenylate synthetase 1, or myxovirus (influenza virus) resistance 1mRNA levels. After RSV infections, viral levels were not significantly increased in hBECs from asthmatic versus nonasthmatic subjects and the only significant difference between groups was a decrease in IFN-λ levels (P < .05) that correlated with a decrease in viral titer. All these differences were found only at isolated time points and were not sustained throughout the 72-hour infection period.

The results indicate that IAV and RSV control and IFN response to these viruses in airway epithelial cells is remarkably similar between subjects with and without asthma.

Globally, 500 million people are chronically infected with Hepatitis B virus (HBV) and Hepatitis C virus (HCV). While these viruses are notorious for their detrimental effect on the liver they are also known to affect multiple organs in the body including the lungs.

To investigate if exposure to HBV and HCV is associated with lung function and respiratory diseases.

Data from the Third National Health and Nutrition Examination Survey (NHANES III) was analysed using multiple linear regressions to investigate the association between exposure to HBV and HCV with the various measures of lung function, while multiple logistic regressions were used to evaluate the association with the respiratory diseases asthma and chronic obstructive pulmonary disease (COPD).

Exposure to HCV was significantly associated with an increase in Forced Expiratory Volume in 1 s, FEV1 (Coef: 97.94 ml, 95% CI: 38.87 to 157.01) and Full Vital Capacity, FVC (Coef: 90 ml, 95% CI: 14.50 to 166.24). Individuals who had been exposed to both HBV and HCV also had a significantly higher FEV1 (Coef: 145.82, CI: 60.68 to 230.94) and FVC (Coef: 195.09, CI: 78.91 to 311.26). There was also a significant association between exposure to HBV and asthma (OR: 1.28, 95% CI: 1.05 to 1.58). These associations were no longer significant after additionally adjusting for cocaine and marijuana use as well as poverty income ratio.

Our research implies that hepatotropic viruses may affect the respiratory system, but more work at a population level is needed to further explore these associations.

This is the report of a workshop organised by the European Centre for the Validation of Alternative Methods (ECVAM). ECVAM's main goal, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods that are of importance to the biosciences and which replace, reduce or refine the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures that would enable it to become well informed about the state-of-the-art of non-animal test development and validation, and the potential for the possible incorporation of alternative tests into regulatory procedures. It was decided that this would be best achieved by the organization of ECVAM workshops on specific topics, at which small groups of invited experts would review the current status of various types of in vitro tests and their potential uses, and make recommendations about the best ways forward (Anonymous, 1994). The workshop on "The use of in vitro systems for evaluating Immunotoxicity" was held at ECVAM (Ispra), Italy, on 24th-26th November 2003. The participants represented academia, national organizations, international regulatory bodies and industry. The aim of the workshop was to review the state-of-the-art in the field of in vitro immunotoxicology, and to develop strategies towards the replacement of in vivo testing. At the end of this report are listed the recommendations that should be considered for prevalidation and validation of relevant and reliable procedures, that could replace the use of animals in chemical and cosmetics toxicity testing.

Asthma is a chronic inflammatory airway disease influenced by genetic and environmental factors that affects ~300 million people worldwide, leading to ~250,000 deaths annually. Glucocorticoids (GCs) are well-known therapeutics that are used extensively to suppress airway inflammation in asthmatics. The airway epithelium plays an important role in the initiation and modulation of the inflammatory response. While the role of GCs in disease management is well understood, few studies have examined the holistic effects on the airway epithelium.

Gene expression data were used to generate a co-transcriptional network, which was interrogated to identify modules of functionally related genes. In parallel, expression data were mapped to the human protein-protein interaction (PPI) network in order to identify modules with differentially expressed genes. A common pathways approach was applied to highlight genes and pathways functionally relevant and significantly altered following GC treatment.

Co-transcriptional network analysis identified pathways involved in inflammatory processes in the epithelium of asthmatics, including the Toll-like receptor (TLR) and PPAR signaling pathways. Analysis of the PPI network identified RXRA, PPARGC1A, STAT1 and IRF9, among others genes, as differentially expressed. Common pathways analysis highlighted TLR and PPAR signaling pathways, providing a link between general inflammatory processes and the actions of GCs. Promoter analysis identified genes regulated by the glucocorticoid receptor (GCR) and PPAR pathways as well as highlighted the interferon pathway as a target of GCs.

Network analyses identified known genes and pathways associated with inflammatory processes in the airway epithelium of asthmatics. This workflow illustrated a hypothesis generating experimental design that integrated multiple analysis methods to produce a weight-of-evidence based approach upon which future focused studies can be designed. In this case, results suggested a mechanism whereby GCs repress TLR-mediated interferon production via upregulation of the PPAR signaling pathway. These results highlight the role of interferons in asthma and their potential as targets of future therapeutic efforts.

Human rhinoviruses (HRV) are the leading cause of upper respiratory infections and have been postulated to trigger asthma exacerbations. However, whether HRV are detected during crises because upper respiratory infections often accompany asthma attacks, or because they specifically elicit exacerbations, is unclear. Moreover, although several hypotheses have been advanced to explain virus-induced exacerbations, their mechanism remains unclear.

To determine the role of HRV in pediatric asthma exacerbations and the mechanisms mediating wheezing.

We prospectively studied 409 children with asthma presenting with upper respiratory infection in the presence or absence of wheezing. Candidate viral and immune mediators of illness were compared among children with asthma with different degrees of severity of acute asthma.

HRV infections specifically associated with asthma exacerbations, even after adjusting for relevant demographic and clinical variables defined a priori (odds ratio, 1.90; 95% confidence interval, 1.21-2.99; P = 0.005). No difference in virus titers, HRV species, and inflammatory or allergic molecules was observed between wheezing and nonwheezing children infected with HRV. Type III IFN-λ(1) levels were higher in wheezing children infected with HRV compared with nonwheezing (P < 0.001) and increased with worsening symptoms (P < 0.001). Moreover, after adjusting for IFN-λ(1), children with asthma infected with HRV were no longer more likely to wheeze than those who were HRV-negative (odds ratio, 1.18; 95% confidence interval, 0.57-2.46; P = 0.66).

Our findings suggest that HRV infections in children with asthma are specifically associated with acute wheezing, and that type III IFN-λ(1) responses mediate exacerbations caused by HRV. Modulation of IFN- λ(1) should be studied as a therapeutic target for exacerbations caused by HRV.

After 4-months of alpha interferon (IFN-α), a 64-year old woman with chronic hepatitis C developed a cough and dyspnea and showed diffuse infiltrative opacities on her chest X-ray. Her symptoms persisted after stopping the IFN-α therapy. Pulmonary function testing revealed a reduced forced vital capacity. High-resolution computed tomography of the lung showed peripheral and peribronchovascular ground glass attenuation and consolidation associated with reticulation. Bronchoalveolar lavage was performed for further evaluation and showed a lymphocyte level of 8.2%, an uncommon finding in IFN-α-induced interstitial pneumonitis. We performed a lung biopsy to diagnose her disease and it suggested interstitial pneumonitis. This was considered to be due to the immunomodulatory effects of INF-α. Although rare, any sign of significant pulmonary involvement should be evaluated.

Combination of pegylated interferon and ribavirin has been the standard program for hepatitis C virus (HCV) infection. Pulmonary complications, although uncommon, have been reported in association with the use of interferon, and pleural effusion is rare. We report the second case of pleural effusion and interstitial pneumonitis in a patient treated with pegylated interferon and ribavirin for chronic HCV infection. The respiratory symptoms of our patient continued to progress even though the treatment with pegylated interferon had been withdrawn, but the symptoms improved dramatically following treatment with steroids.

Interstitial pneumonitis (IP) is an uncommon pulmonary complication associated with interferon (IFN) therapy for chronic hepatitis C virus (HCV) infection. Pneumonitis can occur at any stage of HCV treatment, ranging from 2 to 48 wk, usually in the first 12 wk. Its most common symptoms are dyspnoea, dry cough, fever, fatigue, arthralgia or myalgia, and anorexia, which are reversible in most cases after cessation of IFN therapy with a mean subsequent recovery time of 7.5 wk. Bronchoalveolar lavage in combination with chest high resolution computed tomography has a high diagnostic value. Prompt discontinuation of medication is the cornerstone, and corticosteroid therapy may not be essential for patients with mild-moderate pulmonary functional impairment. The severity of pulmonary injury is associated with the rapid development of IP. We suggest that methylprednisolone pulse therapy followed by low dose prednisolone for a short term is necessary to minimize the risk of fatal pulmonary damage if signs of significant pulmonary toxicity occur in earlier stage. Clinicians should be aware of the potential pulmonary complication related to the drug, so that an early and opportune diagnosis can be made.

The interferons are a complex group of virally induced proteins produced by activated macrophages and lymphocytes, which have become the mainstay of therapy for hepatitis C infection. Sustained viral response (SVR) rates in noncirrhotic patients vary from 40-80% with interferon-based therapy. This, along with transplantation, has drastically changed the course of hepatitis C virus (HCV) infection over the last two decades. Numerous side effects associated with interferon therapy have been reported. These range from transient flu-like symptoms to serious effects such as cardiac arrhythmias, cardiomyopathy, renal and liver failure, polyneuropathy, and myelosuppression. Pulmonary side effects including pneumonitis, pulmonary fibrosis, and reversible pulmonary hypertension have been reported. Herein, we present four cases in which irreversible pulmonary hypertension was diagnosed after prolonged treatment with interferon alpha. In each case, other causes of pulmonary hypertension were systematically eliminated. Pulmonary artery hypertension, which may be irreversible, should be considered in patients being treated with interferon alpha who present with exertional dyspnea and do not have a readily identifiable inflammatory or thromboembolic cause.

New 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines were synthesized with high yields using bromoethylisatin and 6-(2-bromoethyl)-6H-indolo[2,3-b]quinoxaline as intermediates. These compounds were screened for the cytotoxicity, antiviral activity and interferon inducing ability. It was shown, that tested 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines are low toxic potent interferon inducers and antivirals. Morpholine and 4-methyl-piperidine derivatives appeared as the most active antivirals and the least cytotoxic in the investigated series.

Pulmonary manifestations of interferon (IFN) use are a rare but well known complication seen with both standard and pegylated interferon alpha-2b (pegIFNalpha-2b) forms of the agent. These are generally of modest intensity and reversible. We report the first case of fulminant adult respiratory distress syndrome (ARDS) associated with pegylated interferon alpha-2a (pegIFNalpha-2a) and ribavirin use for hepatitis C, complicated by subsequent and ultimately fatal sepsis and multiorgan failure. Practicing gastroenterologists and intensivists alike need to be aware of the potential for serious pulmonary sequelae with the use of combination therapy for chronic hepatitis C viral (CHCV) infections.

A 53-year-old man with a history of blood transfusion at the age of 20 was admitted to our hospital because of liver dysfunction. He had bronchial asthma when he was 18 years old, which naturally resolved within 2 years. However, his bronchial asthma recurred at the age of 45 and was treated with oral theophylline. He was diagnosed as having chronic hepatitis C based on the histological and clinical findings, and then interferon (IFN) therapy was administered. The frequency of bronchial asthma attack was gradually decreasing after IFN therapy with marked improvement of hypereosinophilia. He achieved sustained viral response (SVR) and his bronchial asthma did not worsen even after the cessation of IFN. Hepatitis C virus (HCV) infection and IFN therapy were considered in the remission of asthma in this case. HCV infection could be the cause of bronchial asthma, especially in patients with late appearance of asthma.

Hepatitis C virus (HCV) infection is a chronic blood-borne disease that affects > 4,000,000 individuals in the United States. The majority of individuals with HVC infection acquire a chronic hepatitis that predisposes them to the complications of cirrhosis and hepatoma. Chronic HCV infection is, however, associated with multiple extrahepatic manifestations as well, including recently recognized effects on the lung. These include primary effects on lung function, as well as secondary effects in the settings of progressive liver disease and drug treatment for HCV. In this article, we discuss the emerging clinical data that support a role for HCV infection in lung disease, describe the multiple pulmonary manifestations of this viral infection, and outline the therapies available for specific pulmonary complications of chronic HCV infection.

The lung has significant susceptibility to injury from a variety of chemotherapeutic agents. The clinician must be familiar with classic chemotherapeutic agents with well-described pulmonary toxicities and must also be vigilant about a host of new agents that may exert adverse effects on lung function. The diagnosis of chemotherapy-associated lung disease remains an exclusionary process, particularly with respect to considering usual and atypical infections, as well as recurrence of the underlying neoplastic process in these immune compromised patients. In many instances, chemotherapy-associated lung disease may respond to withdrawal of the offending agent and to the judicious application of corticosteroid therapy.

A 49-year-old man with cirrhosis due to hepatitis C virus developed interstitial pneumonitis documented by surgical lung biopsy specimen evaluation after two weekly doses of pegylated interferon-alpha(2)b in combination with ribavirin. He developed ARDS and died after 26 days of hospitalization from multisystem organ failure. This case suggests that interstitial pulmonary disease can occur with pegylated interferon-alpha(2)b therapy.

The current arsenal of antiviral agents available to the practitioner is expanding rapidly, such that by the time this article goes to press, new drugs may have already been added. Although the majority of approved drugs have been developed for use in only a few viral infections (eg, HIV, herpesviruses, and papillomavirus), discoveries made in the development of these drugs may lead to antiviral agents effective against other viruses. In addition, new uses for the currently available drugs are under evaluation. This review of antiviral agents discusses the treatments available for viral infections such as herpes simplex virus, varicella zoster virus, cytomegalovirus, human papillomavirus, chronic viral hepatitis, and others.

The aim of this study was to analyze the clinical presentation and outcomes of significant pulmonary toxicity associated with interferon and ribavirin.

We conducted a retrospective review of patients enrolled in four clinical trials at three sites, two academic medical centers and one community practice, and reviewed the literature.

Four patients, while on therapy with interferon a and ribavirin for chronic hepatitis C, developed significant pulmonary signs and symptoms. Further workup, which included lung biopsy in three, revealed bronchiolitis obliterans organizing pneumonia in two, and interstitial pneumonitis in two other cases. There were no other predisposing factors for lung disease identified. Resolution of symptoms occurred in all patients upon discontinuation of interferon and ribavirin, with or without corticosteroid therapy. One of the patients developed pulmonary complications while on a clinical trial of pegylated interferon and represents the first reported case associated with the use of long-acting interferon in chronic hepatitis C infection.

A spectrum of significant pulmonary toxicity, including bronchiolitis obliterans organizing pneumonia and interstitial pneumonitis, can occur with interferon or pegylated interferon in combination with ribavirin. Though pulmonary toxicity of interferon is well known, these cases represent the first cases reported in the literature with combination therapy. It is likely that pulmonary toxicity may not be investigated in patients on combination therapy because of the frequent pulmonary symptoms with ribavirin. Though usually reversible, at least one case has required long-term steroids with inadequate resolution. Though pulmonary toxicity is rare, symptoms which are more than mild or progressive in nature should likely be investigated.

Oromucosal (o.m.) administration of interferon-alpha (IFN-alpha) during either allergic sensitization (days 0-6) or the hypersensitive response (days 11 and 12) or both periods caused a dose-dependent reduction in allergen-specific IgE production and allergen-induced eosinophil recruitment in mice sensitized to ragweed pollen, a common allergen in humans. Treatment during the hypersensitive response period alone appeared to be most effective. Oromucosal treatment was as effective as intraperitoneal (i.p.) treatment, with maximum inhibition of both allergen-specific IgE production and allergen-induced eosinophil recruitment observed at a dose of a 1000 IU IFN-alpha. Treatment of animals with up to 10(5) IU murine IFN-alpha/beta (MuIFN-alpha/beta) by either the om. or i.p. route did not inhibit significantly allergen-specific IgG production, which may even have been increased at certain doses of IFN. Treatment of animals with up to 10(5) IU MuIFN-alpha/beta by either the o.m. or i.p. route did not affect significantly total serum IgE or IgG levels. Oromucosal administration of IFN-alpha reduced allergen-specific IgE production and allergen-induced eosinophil recruitment in the absence of detectable toxicity, the induction of H(2) antigen expression, and 2',5'-oligoadenylate synthetase activity associated with parenteral administration of IFN-alpha and thus may find application for the treatment of asthma and associated viral infections.