Recent highlights in the development of new antiviral drugs

Twenty antiviral drugs, that is about half of those that are currently approved, are formally licensed for clinical use in the treatment of human immunodeficiency virus infections (acquired immune deficiency syndrome). The others are used in the treatment of herpesvirus (e.g. herpes simplex virus, varicella zoster virus and cytomegalo virus), hepatitis B virus, hepatitis C virus or influenza virus infections. Recent endeavours have focussed on the development of improved antiviral therapies for virus infections that have already proved amenable to antiviral drug treatment, as well as for virus infections for which, at present, no antiviral drugs have been formally approved (i.e. human papilloma viruses, adenoviruses, human herpesvirus type 6, poxviruses, severe acute respiratory syndrome coronavirus and hemorrhagic fever viruses).     

Epidemiologic aspects of M. pneumoniae disease complications: a review

As early as the 1940s, erythema multiforme exudativum (Stevens-Johnson syndrome) and hemolytic anemia were associated with outbreaks of atypical pneumonia, a disease later found to be caused by Mycoplasma pneumoniae. Epidemiologic evidence has also associated neurological complications, especially aseptic meningitis and meningoencephalitis, with M. pneumoniae infections. Urticarial and morbilliform skin rashes often appear late in the course of M. pneumoniae pneumonia. A multitude of other complications have been ascribed to M. pneumoniae infections, often reported as case reports diagnosed by serologic antibody titers only. More systematic investigations are needed to assess the frequency of complications to M. pneumoniae infections. Isolation of the agent, not only serologic titer rises, should be required before a syndrome is attributed to M. pneumoniae infection.     

Idiopathic CD4 lymphocytopenia: a case of missing, wandering or ineffective T cells

Idiopathic CD4 lymphocytopenia (ICL) is a presumed heterogenous syndrome with key element low CD4 T-cell counts (below 300/mm³) without evidence of HIV infection or other known immunodeficiency. The etiology, pathogenesis, and management of ICL remain poorly understood and inadequately defined. The clinical presentation can range from serious opportunistic infections to incidentally diagnosed asymptomatic individuals. Cryptococcal and non-tuberculous mycobacterial infections and progressive multifocal leukoencephalopathy are the most significant presenting infections, although the spectrum of opportunistic diseases can be similar to that in patients with lymphopenia and HIV infection. Malignancy is common and related to opportunistic pathogens with an oncogenic potential. Autoimmune diseases are also seen in ICL with an increased incidence. The etiology of ICL is unknown. Mechanisms implicated in CD4 reduction may include decreased production, increased destruction, and tissue sequestration. New distinct genetic defects have been identified in certain patients with ICL, supporting the hypothesis of the lack of a common etiology in this syndrome. The management of ICL is focused on the treatment of opportunistic infections, appropriate prophylactic antibiotics, and close monitoring. In selected patients with life-threatening infections or profound immunodeficiency, strategies to increase T-cell counts or enhance immune function could be considered and have included interleukin-2, interferon-gamma, interleukin-7, and hematopoietic stem cell transplantation. The prognosis is influenced by the accompanying opportunistic infections and may be affected by publication bias of severe cases with unfavorable outcomes. As newer laboratory investigation techniques are being developed and targeted experimental treatments become available, our comprehension and prognosis of this rare syndrome could be significantly improved.Idiopathic CD4 lymphocytopenia (ICL) was described in 1992 as an immunodeficiency syndrome characterized by opportunistic infections and low CD4 T-cell counts in the absence of HIV infection. Despite the 20 years that have elapsed, the clinical spectrum, pathogenesis, and possible treatment for ICL remain obscure. Here, we attempt to summarize the salient features of this condition on the basis of the available literature to date.     

Recommendations for fungal opportunistic infections prevention in persons infected with human immunodeficiency virus

Fungal infections have become important causes of morbidity and mortality in immunocompromised hosts, including those with the acquired immune deficiency syndrome (AIDS). Although significant therapeutic advances are being made in the field of antiretroviral therapy, parallel advances must be attained in the management of secondary infections, including those due to fungi. As increasing numbers of people with HIV infection come in to medical attention, the problem of fungal infections will also increase, requiring innovative approaches toward understanding the pathogenesis of these infections and developing new diagnostic and therapeutic modalities. A better understanding is required for the immunopathogenesis of fungal infections. Improved understanding of new and established antifungal agents in conjunction with ART agents as well as immune modulators, should yield important advances in prevention, control and treatment of fungal infections of HIV infected people.     

Management of acute neurologic syndromes in infants and children

Neurological problems in the pediatric intensive care unit all too frequently seem to be among the most mysterious of disorders. This review provides a framework to diagnose and treat four frequently observed neurological syndromes: coma, status epilepticus, central nervous system infections, and post-infectious polyneuropathy (Guillain-Barré syndrome). An emphasis is placed on the diagnosis of coma due to metabolic disorders, the most common cause of coma, and coma as a result of supratentorial lesions. This differentiation can be effected by an easily performed assessment (Glasgow Scale) supplemented by a limited number of tests of brain stem function (pupillary responses, oculocephalic, and oculovestibular responses). Preserved pupillary responses are characteristic of the metabolic coma while an orderly rostral-caudal deterioration, termed the central syndrome, is characteristic of coma resulting from an enlarging supratentorial mass. If confusion exists, the CT scan may be helpful. The approach to emergency management emphasizes the establishment and maintenance of airway and circulation. Management of status epilepticus emphasizes the role of pharmacotherapy, particularly the use of diazepam and phenytoin in combination. The management of infections details antibiotic therapy of bacterial infections and new antiviral therapy for herpesvirus infections. The section on Guillain-Barré syndrome emphasizes good supportive care.     

Citrullination of fibronectin modulates synovial fibroblast behavior

The hyper-IgE syndromes (HIES; originally named Job's syndrome) are a collection of primary immunodeficiency syndromes resulting in elevated serum IgE levels and typified by recurrent staphylococcal skin abscesses, eczema and pulmonary infections. The disorder has autosomal dominant and recessive forms. Autosomal dominant HIES has been shown to be mainly due to STAT3 mutations and additionally results in connective tissue, skeletal, vascular and dental abnormalities. Autosomal recessive HIES has been shown to be mainly due to mutations in DOCK8; these patients are more prone to viral skin infections instead. This review article discusses the common clinical features of the syndrome, the genetic mutations responsible and the pathogenesis of the disease, as well as treatments currently used.     

Opportunistic infections and acquired cellular immune deficiency among Haitian immigrants in Montreal.

Eight Haitian immigrants (five with acquired immune deficiency syndrome [AIDS] and three with the signs and symptoms of AIDS but without opportunistic infections or malignant diseases) are described. All had malaise, weight loss, fever and generalized lymphadenopathy. All five of those with opportunistic infections died from the infections, which were multiple in four cases. Septic shock due to Escherichia coli or Klebsiella pneumoniae developed in two patients. Evidence of immune deficiency in the AIDS patients included anergy, lymphocytopenia (in all but two), polyclonal hypergamma-globulinemia and abnormal sizes of the subsets of circulating T lymphocytes. Autopsies revealed no recognizable causes for immune deficiency; the lymph nodes showed follicular hyperplasia in four cases and lymphocyte depletion in one case. Except for the absence of opportunistic infections, the illness in the three patients not classed as having AIDS was indistinguishable from that in the other five, which suggests that this syndrome is AIDS-related, like the persistent generalized lymphadenopathy that occurs in homosexual men and patients with hemophilia.     

Effect of experimental viral infection in thymectomized rodents

Neonatally thymectomized rodents present an increased susceptibility to experimental viral infections leading to a severe growth depression. In thymectomized mice, viral infections significantly enhance the appearance of the wasting syndrome. These data suggest that viral infections may contribute to the development of wasting syndrome.     

Arginine deficiency, hyperammonemia and Reye's syndrome in ferrets

Young male ferrets developed hyperammonemia and encephalopathy shortly after eating a diet lacking in arginine. The dietary supplementation of arginine or intraperitoneal injection of ornithine prevented hyperammonemia and shortened the duration of encephalopathy. Therefore, young ferrets were assumed to be unable to meet their ornithine needs from sources other than arginine. Adult ferrets did not develop hyperammonemia and encephalopathy after eating arginine-free diet. Because young ferrets are also susceptible to human influenza infections, they were further tested as animal model of Reye's syndrome. Reye's syndrome is a serious childhood disorder that develops following influenza infections and is characterized in part by an encephalopathy, hyperammonemia and elevated serum transaminases. In young ferrets, concurrent administration of aspirin with human influenza inoculation and an arginine-free diet produced symptoms similar to those seen in humans with Reye's syndrome. The ferret model appears to be useful for studying the roles of various etiologic agents and their interactions in producing Reye's syndrome-like disorders. The ammonia metabolism in ferrets is reviewed and the ferret model for Reye's syndrome and its applications for the better understanding of this disorder in humans are discussed.     

Neurology of AIDS virus infection: a clinical classification

Infection with the AIDS virus itself (HIV, HTLV-III, LAV, ARV) is associated with a full spectrum of neurological disorders. The application of diagnostic studies for HTLV-III infection has demonstrated that these neurologic disorders can be the first manifestation of AIDS or occur in the absence of AIDS. The most common conditions associated with HTLV-III infection alone are a subacute encephalopathy (AIDS dementia) and peripheral neuropathy; however, vacuolar myelopathy and both acute and chronic aseptic meningitis are also common. Congenital (or neonatal) transmission of the virus can result in a mental retardation syndrome of delayed onset. The AIDS virus is neurotropic as well as targeting T-helper lymphocytes. The virus has been readily identified in neural tissues and cerebrospinal fluid, including instances in which other central nervous system infections, such as toxoplasmosis, coexist. Hence, recognition of an appropriate syndrome, neurodiagnostic studies, and exclusion (or treatment) of other infections, as well as evidence for HTLV-III infection are required for diagnosis. The development of successful therapy will require agents which cross the blood-brain barrier.     

Immune Dysfunction in Children with CHARGE Syndrome: A Cross-Sectional Study

CHARGE syndrome is a variable, multiple congenital malformation syndrome. Patients with CHARGE syndrome have frequent infections that are presumed to be due to anatomical anomalies of the craniofacial region and upper airway, and cranial nerve problems resulting in swallowing difficulties and aspiration. The possible contribution of immunological abnormalities to these infections has not been systematically studied even though immune deficiencies have been described in patients with 22q11.2 deletion syndrome, a condition which shares remarkable clinical overlap with CHARGE syndrome. We assessed the frequency and nature of immune dysfunction in 24 children with genetically proven CHARGE syndrome. All patients, or their parents, completed a questionnaire on infectious history. Their immune system was extensively assessed through full blood counts, immunoglobulin levels, lymphocyte subpopulations, peripheral B- and T-cell differentiation, T-receptor excision circle (TREC) analysis, T-cell function, and vaccination responses. All CHARGE patients had a history of infections (often frequent), mainly otitis media and pneumonia, leading to frequent use of antibiotics and to hospital admissions. Decreased T-cell numbers were found in 12 (50%) patients, presumably caused by insufficient thymic output since TREC amounts were also diminished in CHARGE patients. Despite normal peripheral B-cell differentiation and immunoglobulin production in all patients, 83% of patients had insufficient antibody titers to one or more early childhood vaccinations. Based on our results, we recommend immunological evaluation of CHARGE patients with recurrent infections.     

Centromeric heterochromatin instability of chromosomes 1, 9, and 16 in variable immunodeficiency syndrome — a virus-induced phenomenon?

Summary Centromeric instability of chromosomes 1, 9, and 16 has been described in eight patients with variable immunodeficiency. Although the pathogenetic relationship of these cytogenetic abnormalities with the clinical symptoms are unclear, it has nevertheless been proposed that they are a hallmark of this syndrome. Based on the clinical, immunological and cytogenetic data from the literature, a model is presented suggesting that the cytogenetic changes are not causatively involved in the immunodeficiency syndrome, but result from specific virus infections occurring as a consequence of the immunodeficiency in genetically predisposed individuals.     

Murine gammaherpesvirus 68: a model for the study of Epstein-Barr virus infections and related diseases

Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus (GHV) that causes acute infection and establishes life-long latency. EBV is associated with the development of B-cell lymphoproliferative disorders, several malignant cancers, the syndrome of infectious mononucleosis, and chronic interstitial lung disease. Although the molecular biology of EBV has been characterized extensively, the associated disease conditions and their pathogenesis are difficult to study in human populations because of variation in human environments and genetics, the well-documented effect of stressors on pathogenesis, and the chronic and latent properties of the virus. GHV are highly species-specific, and suitable animal models for EBV are not available. However, in 1980, a murine gammaherpesvirus (MuGHV, also known as MHV68 and gammaHV68) was identified as a natural pathogen of bank voles and wood mice. Experimental MuGHV infections in laboratory mice share many features of EBV infections in humans, including facets of the clinical human syndrome known as infectious mononucleosis. These features make MuGHV a valuable experimental model for studying the pathophysiology of a GHV in a natural host.     

New insights on the development of fungal vaccines: from immunity to recent challenges

Fungal infections are emerging as a major problem in part due to high mortality associated with systemic infections, especially in the case of immunocompromised patients. With the development of new treatments for diseases such as cancer and the acquired immune deficiency syndrome pandemic, the number of immunosuppressed patients has increased and, as a consequence, also the number of invasive fungal infections has increased. Several studies have proposed new strategies for the development of effective fungal vaccines. In addition, better understanding of how the immune system works against fungal pathogens has improved the further development of these new vaccination strategies. As a result, some fungal vaccines have advanced through clinical trials. However, there are still many challenges that prevent the clinical development of fungal vaccines that can efficiently immunise subjects at risk of developing invasive fungal infections. In this review, we will discuss these new vaccination strategies and the challenges that they present. In the future with proper investments, fungal vaccines may soon become a reality.     

New infections: myths and reality

New contemporary data about new infectious diseases of XXI century are presented. Data on morbidity and mortality from severe acute respiratory syndrome (SARS, atypical pneumonia) and avian influenza are analyzed and compared with World Health Organization data on human influenza. Biologic characteristics of avian influenza virus A/H5N1 are discussed as well as possibility of its human-to-human transmission. Principles of SARS and avian influenza infections transmission as zoonoses are described as well as mechanisms of transmission impeding their ability to infect humans. It has been argued that SARS should be regarded as contagious infection, whereas avian influenza - as non-contagious. Features of all stages of epidemic process of these infections are analyzed.     

TLR2 signalling: At the crossroads of commensalism,invasive infections and toxic shock syndrome by Staphylococcus aureus

Although up to 60% of the population at any one time carry Staphylococcus aureus (S. aureus) without significant clinical consequences, infections by S. aureus are a major health care threat in the Western world. The underlying mechanisms that determine this two-sided interaction between S. aureus and the human immune system are unknown. Work on the pathogenesis of S. aureus infections and toxic shock syndrome may provide unexpected clues to understand the duality of such an interaction. Recent evidence suggests that the cell wall of S. aureus contains peptidoglycan-embedded TLR2 ligands that not only act as pathogen-associated molecular patterns, which trigger pro-inflammatory innate immune responses, but also can act as anti-inflammatory modulators of the pathogenicity by this microbe and its toxins. Here, we discuss this theme in the context of staphylococcal toxic shock syndrome and explore its implications on the development of therapeutic strategies to prevent and treat S. aureus infections.     

Hantaviruses: an emerging public health threat in India? A review

The emerging viral diseases haemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS) are a cause of global concern as they are increasingly reported from newer regions of the world. The hantavirus species causing HFRS include Hantaan virus, Seoul virus, Puumala virus, and Dobrava-Belgrade virus while Sin Nombre virus was responsible for the 1993 outbreak of HCPS in the Four Corners Region of the US. Humans are accidental hosts and get infected by aerosols generated from contaminated urine, feces and saliva of infected rodents. Rodents are the natural hosts of these viruses and develop persistent infection. Human to human infections are rare and the evolution of the virus depends largely on that of the rodent host. The first hantavirus isolate to be cultured, Thottapalayam virus, is the only indigenous isolate from India, isolated from an insectivore in 1964 in Vellore, South India. Research on hantaviruses in India has been slow but steady since 2005. Serological investigation of patients with pyrexic illness revealed presence of anti-hantavirus IgM antibodies in 14.7% of them. The seropositivity of hantavirus infections in the general population is about 4% and people who live and work in close proximity with rodents have a greater risk of acquiring hantavirus infections. Molecular and serological evidence of hantavirus infections in rodents and man has also been documented in this country. The present review on hantaviruses is to increase awareness of these emerging pathogens and the threats they pose to the public health system.     

Post-streptococcal antibodies are associated with metabolic syndrome in a population-based cohort

Background

Streptococcal infections are known to trigger autoimmune disorders, affecting millions worldwide. Recently, we found an association between post-streptococcal autoantibodies against Protein Disulphide Isomerase (PDI), an enzyme involved in insulin degradation and insulin resistance. This led us to evaluate associations between post-streptococcal antibodies and metabolic syndrome, as defined by the updated National Cholesterol Education Program definition, 2005.

Methods and Findings

Metabolic data (HDL, triglycerides, fasting glucose, blood pressure, waist circumference, BMI, smoking), post-streptococcal antibodies (anti-Streptolysin O (ASO) and anti-PDI), and C-reactive protein (CRP, as a general inflammatory marker), were assessed in 1156 participants of the Wisconsin Sleep Cohort Study. Anti-PDI antibodies were found in 308 participants (26.6%), ASO≥100 in 258 (22.3%), and 482 (41.7%) met diagnostic criteria for metabolic syndrome. Anti-PDI antibodies but not ASO were significantly associated with metabolic syndrome [n = 1156, OR 1.463 (95% CI 1.114, 1.920), p = 0.0062; adjusted for age, gender, education, smoking]. Importantly, the anti-PDI - metabolic syndrome association remained significant after adjusting for CRP and fasting insulin.

Conclusions

Post-streptococcal anti-PDI antibodies are associated with metabolic syndrome regardless of fasting insulin and CRP levels. Whereas these data are in line with a growing body of evidence linking infections, immunity and metabolism, additional studies are necessary to establish the post-streptococcal – metabolic syndrome association.     

Coronavirus and co-infections: A Saudi Arabian perspective

Mortality due to infectious diseases continues to rise globally, despite advances in antimicrobial therapy and supportive care. This is evident with the occurrence of coronavirus disease 2019 (COVID-19) pandemic, instigated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Saudi Arabia, an eminent country within the Arab region, has had significant impact during global pandemics, concomitant with the fact that millions of Muslims travel to Saudi Arabia for pilgrimages every year. Herein, we discuss the significance of SARS-CoV-1, SARS-CoV-2, as well as the Middle East respiratory syndrome coronavirus (MERS-CoV) in Saudi Arabia with particular reference to global transmission and/or emergence of new variants due to genetic mixing of different strains. Furthermore, we also discuss the role of Saudi Arabia with reference to novel emerging infectious diseases and re-emerging infections, such as Ebola, zika, and monkeypox, as well as in the context on coinfections. Future strategies to limit the spread of viral infections and the pivotal role of Saudi Arabia, are deliberated upon.     

The microbial environment and intestinal nematode infections of Heligmosomoides polygyrus in laboratory mice

The difficulty of establishing primary infections of Heligmosomoides polygyrus (= Nematospiroides dubius) in ASH/CSI mice in the Laboratory Animal House at Royal Holloway and Bedford New College during a recent autumn and spring period was associated with a syndrome of worm distortion, together with zero or low worm establishment and reduced fecundity (eggs/female worm). The eggs produced were non-viable and the egg capsule comprised a rumpled lipid and ruptured chitin layer. The egg size and peaks of egg production were also reduced and the total egg output ceased entirely by day 28 post-infection in male mice. The syndrome was repeated when control LACA mice harbouring 'normal' infections of H. polygyrus were housed on the same source of peat bedding material as the ASH/CSI mice. An increase in H. polygyrus egg production in ASH/CSI mice, removed from the peat or treated with 0.04% oxytetracycline hydrochloride suggested that the cause of the syndrome was microbial in origin. A microbiological assay of the peat, which was the common denominator of all syndrome infections, revealed an abundance of chitinase secreting species of bacteria (Bacillaceae). Bacterial chitinase was therefore likely to rupture the chitin layer of the egg capsule producing nonviable eggs and either abnormal or no larvae. Preliminary in vitro studies using chitinase from Streptomyces griseus indicated that the hatching success of eggs of H. polygyrus was reduced as the concentration of chitinase increased.