Effectiveness of ivermectin-based multidrug therapy in severely hypoxic, ambulatory COVID-19 patients.

Aims: Ivermectin is a safe, inexpensive and effective early COVID-19 treatment validated in 20+ random, controlled trials. Having developed combination therapies for Helicobacter pylori, the authors present a highly effective COVID-19 therapeutic combination, stemming from clinical observations. Patients & methods: In 24 COVID-19 subjects refusing hospitalization with high-risk features, hypoxia and untreated moderate to severe symptoms averaging 9 days, the authors administered this novel combination of ivermectin, doxycycline, zinc and vitamins D and C. Results & conclusions: All subjects resolved symptoms (in 11 days on average), and oxygen saturation improved in 24 h (87.4% to 93.1%; p = 0.001). There were no hospitalizations or deaths, less than (p < 0.002 or 0.05, respectively) background-matched CDC database controls. Triple combination therapy is safe and effective even when used in outpatients with moderate to severe symptoms. Clinical Trial Registration: NCT04482686 (ClinicalTrial.gov).

Clinical and economic impact of "triple therapy" for Helicobacter pylori eradication on peptic ulcer disease in Australia.

BACKGROUND: Helicobacter pylori infection has had a major impact on the global health of billions of people. Triple therapy was extensively used in Australia by 1986 for H pylori eradication after its discovery in 1984 and was critical in reducing the morbidity and mortality associated with this infection. AIMS: This study analyzed hospital admission, mortality, and therapeutic data to determine the economic and clinical impact that antibiotic triple therapy had on peptic ulcer disease (PUD) in Australia. METHODS: An analysis of indirect and direct cost-savings in Australia between 1990 and 2015 associated with triple therapy and the impact on PUD mortality and hospital admissions. RESULTS: The direct and indirect impacts of PUD treated by triple therapy between 1990 and 2015 suggest that triple therapy is likely to have prevented 18 665 deaths, and saved 258 887 life years and 33 776 productive life years. The total savings, over the 26-year period, including direct and indirect costs, are calculated to be $10.03 billion, equating to an average annual saving of $393.419 million. CONCLUSIONS: This study highlights the enormous benefits to Australia's health care of the discovery of triple therapy, a relatively low-cost antibiotic regimen which brought considerable savings via the reduction in morbidity (hospital admissions) and mortality related to PUD. It is likely that benefits of similar scale occurred internationally.

An Oral Whole-Cell Killed Nontypeable Haemophilus influenzae Immunotherapeutic For The Prevention Of Acute Exacerbations Of Chronic Airway Disease.

In subjects with chronic bronchitis, protection against acute bronchitis following oral administration of a whole-cell killed nontypeable Haemophilus influenzae (NTHi) preparation was demonstrated in the mid-1980s. Subsequently, studies aiming to validate clinical efficacy of this oral treatment were complicated by a number of factors, including the modification of clinical definitions, the implications of which were not recognized at that time. The objective of this review is to integrate our pre-clinical and clinical research in this field conducted over the past 30 years to demonstrate the evolution of the idea of communication between mucosal surfaces through the common mucosal immune system and the development of an effective oral NTHi immunotherapy. Our earliest studies recruited subjects with chronic sputum production and high levels of culture-positive sputum for Gram-negative bacteria but by 2000, the clinical diagnostic focus had switched from "chronic bronchitis" to "chronic obstructive pulmonary disease" (COPD), which was functionally defined using spirometry. This change led to variable clinical trial results, confirming the importance of chronic sputum production and culture-positive sputum. Additional conditioning factors such as patient age and gender were influential in study populations with low culture-positive sputum production. Through this period, studies in human and in rodent models provided new insights into airway protection mechanisms and the pathogenesis of airway inflammation. Key findings were the importance of a dysbiosis within the airway microbiome, and the critical role of an interdependence between the bronchus and the gut, with a Peyer's patch-dependent extra-bronchus "loop" controlling the composition of the bronchus microbiome. Within this context, intercurrent virus infections initiate a microbiome-dependant hypersensitivity reaction involving Peyer's patch-derived Th17 cells. We conclude that whole-cell killed NTHi immunotherapy has consistent and significant benefits when examined in the context of changing clinical disease definitions, age and gender, and has the potential to change the natural history of chronic airway disease.

Fecal microbiota transplantation as a new therapy: from Clostridioides difficile infection to inflammatory bowel disease, irritable bowel syndrome, and colon cancer.

Fecal microbiota transplantation (FMT) represents the most effective means of therapeutically manipulating the gastrointestinal microbiome. Originally employed as a treatment of last-resort in patients with life-threatening Clostridioides difficile infection (CDI), FMT gained widespread acceptance during the CDI epidemic, where it achieved resolution rates approaching 100%. Following our newfound appreciation for the role of the gut microbiome in both health and disease and owing to FMT's unique mechanism/s of action, FMT is rapidly advancing as an effective treatment for a number of conditions in which the gastrointestinal microbiome is thought to play a role. We review the role of FMT from its beginnings in CDI to its expansion into inflammatory bowel disease, irritable bowel syndrome, and colon cancer.

Nontypeable Haemophilus influenzae and chronic obstructive pulmonary disease: a review for clinicians.

Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and mortality worldwide. In the lower airways of COPD patients, bacterial infection is a common phenomenon and Haemophilus influenzae is the most commonly identified bacteria. Haemophilus influenzae is divided into typeable and nontypeable (NTHi) strains based on the presence or absence of a polysaccharide capsule. While NTHi is a common commensal in the human nasopharynx, it is associated with considerable inflammation when it is present in the lower airways of COPD patients, resulting in morbidity due to worsening symptoms and increased frequency of COPD exacerbations. Treatment of lower airway NTHi infection with antibiotics, though successful in the short term, does not offer long-term protection against reinfection, nor does it change the course of the disease. Hence, there has been much interest in the development of an effective NTHi vaccine. This review will summarize the current literature concerning the role of NTHi infections in COPD patients and the consequences of using prophylactic antibiotics in patients with COPD. There is particular focus on the rationale, findings of clinical studies and possible future directions of NTHi vaccines in patients with COPD.

Haemophilus influenzae and smoking-related obstructive airways disease.

BACKGROUND: Intralumenal bacteria play a critical role in the pathogenesis of acute infective episodes and airway inflammation. Antigens from colonizing bacteria such as nontypeable Haemophilus influenzae (NTHi) may contribute to chronic lung disease through an immediate hypersensitivity response. The objective of this study was to determine the presence of specific NTHi-IgE antibodies in subjects with chronic bronchitis (CB) and COPD who had smoked. METHODS: Serum, sputum, and saliva samples were collected from subjects with CB and moderate-severe COPD and healthy aged-matched controls. Total IgE and specific NTHi IgE were measured by enzyme linked immmunosorbent assay. Throat swabs were examined for the presence of NTHi. RESULTS: THE RESULTS DEMONSTRATE THAT: i) specific NTHi IgE antibodies occur at a low level in healthy subjects; ii) those with both CB and moderate-severe COPD have elevated specific NTHi IgE antibody compared with healthy controls, with higher levels in those with most severe disease; iii) IgE levels are greater in those with moderate-severe COPD than in those with CB. They demonstrate specific NTHi IgE antibody is regularly found at higher than normal levels in COPD. CONCLUSION: The detection of IgE antibody to colonizing bacteria in all subjects with CB or moderate-severe COPD identifies a possible mechanism of bronchospasm in these subjects amenable to specific intervention therapy.

Acute exacerbations in COPD and their control with oral immunization with non-typeable haemophilus influenzae.

Chronic obstructive pulmonary disease (COPD) a term based on the demonstration of irreversible airways obstruction, introduced to unify a range of chronic progressive diseases of the airways consequent upon inhalation of toxins. While disease is initiated and progressed by inhaled toxins, an additional pathway of damage has emerged, with particular relevance to acute exacerbations. Exacerbations of disease due to an increase in the level of intrabronchial inflammation have taken on a new significance as their role in determining both acute and chronic outcomes is better understood. This "second pathway" of disease is a consequence of bacterial colonization of damaged airways. Although bacteria have been linked to acute episodes in COPD over 50 years, only recently has quality data on antibiotic usage and the detection of "exacerbation isolates" of non-typeable Haemophilus influenzae (NTHi) provided strong argument in support of a pathogenic role. Yet a poor correlation between detection of colonizing bacteria and clinical status remained a concern in attempts to explain a role for bacteria in a classical infection model. This presentation discusses a hypothesis that acute exacerbations reflect a T cell-dependent hypersensitivity response to colonizing bacteria, with IL-17 dependent accumulation of neutrophils within the bronchus, as the main outcome measure. Critical protection against exacerbations following oral administration of NTHi, an immunotherapy that drives a TH17 T cell response from Peyer's patches, reduces the load of intrabronchial bacteria while preventing access of inhaled bacteria into small airways. Immunotherapy augments a physiological "loop" based on aspiration of bronchus content into the gut. A second "hypersensitivity" mechanism may cause bronchospasm - in both COPD and treatment-resistant asthma - due to specific IgE antibody directed against colonizing bacteria, as oral NTHi abrogates wheeze in subjects with recurrent "wheezy bronchitis."

Probiotics--industry myth or a practical reality?

Probiotics are "bacteria that are good for you' evolving out of the food industry, without quality data or a framework in which to function. This review asks three questions, the answers to which dictate the level of success that probiotics have had in moving into the medical model. How do they work? Evidence is summarised to show that (at least) certain bacteria activate Peyer's patch T cells to drive the common mucosal system via toll-like receptors on antigen presenting cells. They influence distant mucosal sites, promoting Th1 cytokine responses while downregulating Th2 responses. New data is included. Are all probiotics the same? They clearly are not - variation occurs between different isolates and importantly within isolates due to variable production/storage and poor quality control. These latter issues, together with poor clinical trials lacking surrogate markers of activation, have made clinical assessment very difficult. Do they have a role in man? Yes they do, but whether that is now or in the future largely depends on the quality of studies done. There is clear evidence in man that mucosal INF-gamma secretion is stimulated, indicating promotion of immune protection, downregulation of hypersensitivity disease and (yet to be demonstrated) enhanced apoptosis to reduce cancer risk. Preliminary evidence suggests that certain probiotics may regulate cytokine secretion around a mean, ensuring optimal protection without non-specific damage. Thus probiotics appear to restore defective immunity rather than stimulate, an observation relevant to restoration of Th1 immunity in infants.

Variation of salivary immunoglobulins in exercising and sedentary populations.

PURPOSE: This study examined the nature of the variability in salivary immunoglobulin and albumin concentrations within an individual, between individuals, and between populations with differing levels of habitual physical activity. METHODS: Fourteen elite swimmers, and 21 active and 18 sedentary individuals provided 12 saliva samples over a 30-d period. Group classifications were based on interviews, anthropometric measurements, and physical activity records. Symptoms of illness and physical activity data were recorded daily. Salivary IgA, IgG, and IgM were measured by ELISA, and albumin concentrations were measured by nephelometry. Variability was assessed using ANOVA procedures. RESULTS: Elite swimmers, compared with active and sedentary individuals, had higher concentrations of salivary IgA (geometric mean=65 vs 32 and 40 mg.L, P=0.002) and greater variability in salivary IgA concentrations as individuals (P=0.007) and as a group (P=0.03). Salivary IgG variability in swimmers was also twofold greater than the other two groups (P=0.008). Salivary IgM and albumin variability were not significantly different between groups, but individual variability differed for swimmers and active individuals. The intraclass correlations for salivary IgA and IgG (but not for IgM or albumin) were 50% lower for swimmers than the other two groups (ICC for IgA: 20% swimmers vs 54% active and 46% sedentary individuals; ICC for IgG: 36 vs 59 and 57%). CONCLUSION: The variability and fluctuation of salivary immunoglobulin concentrations were consistently greater in the elite swimmers, but multiple samples from individual swimmers were less correlated compared with participants with lower physical activity levels. These findings have implications for monitoring mucosal immune status within individuals and when comparing salivary immunoglobulin concentrations between groups with differing levels of physical fitness and activity.

Mucosal immune responses to infections in infants with acute life threatening events classified as 'near-miss' sudden infant death syndrome.

This study examined the hypothesis that dysregulation of mucosal immune responses to respiratory infections is a critical event, which could be causal in respiratory arrest of some previously healthy infants. To examine this hypothesis, a prospective study was undertaken of infants presenting to the emergency department of a major teaching hospital with acute life threatening events (ALTE) of unknown cause and classified as "near-miss" SIDS. Salivary immunoglobulin concentrations were measured on admission and again after 14 days. The salivary immunoglobulins were compared with three control groups: infants with a mild upper respiratory tract infection (URTI); bronchiolitis; and healthy age-matched infants. The salivary IgA and IgM concentrations in the ALTE infants at presentation to hospital indicated a significant mucosal immune response had already occurred, with nearly 60% of the IgA concentrations significantly above the population-based reference ranges. The hyper-immune response was most evident in the ALTE infants with pathology evidence of an infection; 87% of these infants had salivary IgA concentrations on average 10 times higher that the age-related median concentration. The most prevalent pathogen identified in the ALTE infants was respiratory syncytial virus (RSV) (64%). RSV was also identified in all subjects with bronchiolitis. Risk factors for SIDS were assessed in each group. The data indicated that the ALTE infants diagnosed as 'near-miss' SIDS were a relatively homogeneous group, and most likely these ALTE infants and SIDS represent associated clinical outcomes. The study identified exposure to cigarette smoke and elevated salivary IgA concentrations as predictors of an ALTE. The study findings support the hypothesis of mucosal immune dysregulation in response to a respiratory infection in some infants with an ALTE. They provide a plausible explanation for certain SIDS risk factors. The underlying patho-physiological mechanism of proinflammatory responses to infections during a critical developmental period might be a critical factor in infants who have life-threatening apnoea or succumb to SIDS. The study raises the possibility of using salivary IgA to test infants who present with mild respiratory infections to identify a substantial number of infants at risk of developing an ALTE or SIDS, thus enabling intervention management to prevent such outcomes.

Valtrex therapy for Epstein-Barr virus reactivation and upper respiratory symptoms in elite runners.

PURPOSE: The aim of the study was to examine the effectiveness of prophylactic administration of the antiviral agent Valtrex for control of Epstein-Barr virus (EBV) reactivation and upper respiratory symptoms in elite distance runners. METHODS: Twenty elite male distance runners were randomized into a 4-month double-blind, placebo-controlled cross-over trial. Saliva samples were collected weekly and mucosal immune status assessed by measurement of secretory IgA (SIgA) using an enzyme-linked immunosorbent assay (ELISA). EBV reactivation was monitored at the same time by detection of EBV in saliva using a quantitative real-time polymerase chain reaction. The initial EBV status of the runners was determined by detecting EBV antibodies in serum using an ELISA. Upper respiratory symptoms were recorded using self-reporting illness logs. RESULTS: There was no evidence of any marked change in maximal oxygen uptake (P = 0.86), training volume (P = 0.30), or mucosal immunity (P = 0.21) over the study period. Valtrex treatment resulted in an 82% reduction in the detectable EBV load in saliva for EBV seropositive runners compared with the placebo treatment (P = 0.04). The incidence of upper respiratory symptoms was not reduced by Valtrex treatment. CONCLUSIONS: The prophylactic administration of Valtrex reduced EBV reactivation but was not an effective intervention strategy for limiting upper respiratory symptoms in this cohort of elite distance runners. The upper respiratory symptoms in the distance runners could not be directly attributed to infection and may be of a noninfectious inflammatory nature.

Innate versus adaptive immunity in Candida albicans infection.

Candida albicans is a common opportunistic pathogen, causing both superficial and systemic infection. Clinical observations indicate that mucocutaneous infections are commonly associated with defective cell-mediated immune responses, whereas systemic infection is more frequently seen in patients with deficiencies in neutrophil number or function. Analysis of mechanisms of host resistance against gastrointestinal and oral infection in mouse models has demonstrated an absolute dependence on CD4(+) T cells, although clearance also involves phagocytic cells. Both IL-12 and TNF-alpha appear to be important mediators, but mouse strain-dependent variations in susceptibility to infection may be related to T-cell enhancement of production of phagocytic cells by the bone marrow. In murine systemic infection, the role of innate and adaptive responses is less well defined. Studies in immunodeficient and T-cell-depleted mice suggest that clearance of the yeast may be predominantly a function of the innate response, whereas the adaptive response may either limit tissue damage or have the potential to cause immunopathology, depending on the host genetic context in which the infection takes place.

Helicobacter pylori in intensive care: why we should be interested.

Helicobacter pylori is estimated to infect over 50% of the world's population, the majority of whom are asymptomatic. Although most research to date has focused on local gastroduodenal disease manifestations, the potential impact of H. pylori infection and the associated chronic active inflammation on systemic disease processes is now being explored. This review addresses three aspects of emerging importance regarding H. pylori in intensive care medicine: acute gastric stress ulceration, nosocomial infection, and the potential modulatory effect on the systemic stress response. The role of H. pylori in acute stress ulceration remains uncertain, but it is unlikely to have the same major aetiological role as in peptic ulcer disease. The pathogenesis of both acute stress ulceration and H. pylori gastritis suggest overlapping mechanisms of gastric mucosal damage and H. pylori may augment stress ulceration incidence and severity. Nosocomial infection of both staff and patients with H. pylori has been suggested by serological studies, and increased H. pylori infection has been reported in intensive care staff. This has significant short- and long-term health implications and also raises questions regarding the efficacy and implementation of routine infection control precautions in intensive care. Finally, H. pylori infection has been linked with the pathogenesis of many extra-intestinal diseases, but the evidence is weak and the relationship between H. pylori and systemic diseases remains controversial. However, the potential for H. pylori to modulate systemic disease processes, particularly the systemic stress response in critical illness, is both theoretically plausible and therapeutically tantalising and requires further investigation.

Trends in mucosal immunity in Antarctica during six Australian winter expeditions.

The mucosal immune status of Australian Antarctic personnel was monitored during six wintering expeditions at two Australian Antarctic Research Stations, Casey in 1992, 1993, 1994, and Mawson in 1992, 1995, 1996. Salivary immunoglobulin and albumin levels were examined for differences between stations and expeditions, and for monthly changes over the expedition year. Salivary IgA and IgM concentrations were on average higher for the 1993 Casey expeditioners, and all salivary protein levels were lower for 1996 Mawson expeditioners compared to levels of the other expeditions. The change in salivary IgA and IgM concentrations over the 1-year period revealed a consistent pattern between expeditions. Salivary IgA levels were lower in March, April and May compared to other months of the year (P = 0.0002). Salivary IgM levels were lowest in the first 4 months of the year, with peak levels in June and July (P < 0.0001). There were no changes in salivary IgG and albumin concentrations over the expedition year. Though the cause of the changes in salivary IgA and IgM levels over the year is unknown, the changes could reflect alterations in mucosal immunity in response to stressors associated with isolation.

Epstein-Barr virus reactivation and upper-respiratory illness in elite swimmers.

PURPOSE: The aim of this study was to investigate the relationships between latent viral shedding of Epstein-Barr virus (EBV) in saliva, upper-respiratory illness, and mucosal immune suppression in a cohort of highly trained swimmers undertaking intensive training. METHODS: Saliva was collected before selected training sessions from 14 elite male swimmers during a 30-d period of intensive training. Prior infection with EBV was determined by EBV antibody serology. Salivary IgA concentrations were measured by enzyme linked immunosorbent assay (ELISA), and EBV viral shedding (EBV-DNA) was detected by polymerase chain reaction (PCR). Symptoms of upper-respiratory illness were recorded daily. RESULTS: Eleven swimmers (79%) were seropositive for prior EBV infection. Seven EBV seropositive swimmers (64%) had EBV-DNA detected during the study period. Upper-respiratory symptoms (URS) were reported in six of seven swimmers in whom EBV-DNA was detected and in three of four swimmers with no EBV-DNA detection. No URS were reported in the EBV seronegative swimmers. There was a statistically significant relationship between EBV serology status and URS (P = 0.027). EBV-DNA was detected in saliva before the appearance of URS. Salivary IgA levels were significantly lower immediately before the URS (P = 0.01) compared with subsequent peak IgA levels and declined to pre-URS levels on average 11 d after the first appearance of URS. CONCLUSIONS: The time course of appearance of EBV-DNA in relation to URS suggests latent viral EBV shedding may be a contributing factor in the URS. The low levels of salivary IgA detected before the URS indicated transient mucosal immune suppression in the study cohort. The viral shedding may alternatively be a reflection of the altered immune control mechanisms that occur in response to intensive exercise and unrelated to the URS.