Influence of aluminum salts on COVID-19 infected patients

Background/aim: Based on the antiviral and antibacterial properties of aluminum salts, we aimed to find out the influence of aluminum salts on COVID-19 infected patients. Materials and methods: We performed an observational retrospective cohort study which includes the patients diagnosed as COVID-19 and received aluminum salts in addition to actual treatments during hospitalization as the treatment group (Alum Group). Patients who received standard COVID-19 treatment protocols in the Infectious Diseases Clinics were included as the Control Group. Clinical findings, laboratory parameters, length of stay, survival, radiological follow-up, intensive care and mechanical ventilation needs, the presence of comorbidity, polymerase chain reaction (PCR) tests, symptoms, symptom recovery times, hospital stay times, treatment protocols, and clinical presence of pneumonia were examined in all patients. Advanced chemical composition analyzes of existing aluminum salts were also performed. Results: A total of 109 patients, 54 in the alum group and 55 in the control group, were included in the study. None of the patients in the aluminum group developed side effects due to the intake of aluminum salt. Survival status was significantly different between the two groups as there were 5 loss in the Control Group and none in the Alum Group (P = 0.023). The symptom recovery time was significantly shorter in the Alum Group; 2 (1­3) vs. 1 (1­2) days, P = 0.003. According to the paired samples analyses of the comparison between hospitalization and discharge, CRP levels significantly drops in the Alum Group (from 54.09 to 27, P = 0.001) but not in the Control Group. The drop was significantly same for the lactate dehydrogenase (LDH) and procalcitonin levels with P = 0.001. Conclusion: It has been observed that aluminum salts have beneficial effects in COVID-19 infected cases. Considering the low systemic toxicity of intermittent oral intake of aluminum salts as food supplements and the fact that pandemic control is still not achieved, the use of aluminum salts is promising.

Laparoscopic rectal tumor surgery after administration of a new sclerosing therapy (aluminum potassium sulfate and tannic acid injection) for internal hemorrhoids: A report of three cases.

Aluminum potassium sulfate and tannic acid (ALTA) injection is a new sclerosing therapy for internal hemorrhoids that has been gaining widespread use. However, there have been few reports about rectal cancer after ALTA injection. We performed laparoscopic surgery for three patients who had underwent ALTA therapy 6 months or 1 year earlier: (i) a 51-year-old man with neuroendocrine tumor; (ii) a 44-year-old woman with rectal cancer; and (iii) 77-year-old man with rectal cancer. All three patients had sclerosis of the resected rectal wall stump, making transection of the rectum difficult. Histological examination of the specimens also showed an inflammatory reaction and/or fibrosis of the resection stump. Although laparoscopic low anterior resection was planned for all three patients, we had to construct a diverting stoma for two patients and could not perform sphincter-preserving surgery for the other. We must be well prepared for laparoscopic rectal surgeries after ALTA therapy, and these cases suggest sigmoidoscopy before ALTA therapy should be recommended.

Risk of continuous bladder irrigation in the monoplace hyperbaric chamber: a cautionary tale.

We previously published our method of performing continuous bladder irrigation (CBI) in a monoplace hyperbaric chamber [1]. This method entailed the use of an IV pump to infuse saline into the monoplace chamber. The specter of causing iatrogenic rupture of the bladder was raised following such a case, reported herein, of a woman with hemorrhagic radiation cystitis leading to cystectomy. Due to the danger of bladder rupture while providing CBI with a pump, we retract ourpreviously reported method and encourage the use of either a gravity-fed system or delay in hyperbaric oxygen therapy treatment until CBI is no longer necessary.

Liver injury after aluminum potassium sulfate and tannic acid treatment of hemorrhoids.

We are reporting a rare case of acute liver injury that developed after an internal hemorrhoid treatment with the aluminum potassium sulfate and tannic acid (ALTA) regimen. A 41-year-old man developed a fever and liver injury after undergoing internal hemorrhoid treatment with a submucosal injection of ALTA with lidocaine. The acute liver injury was classified clinically as hepatocellular and pathologically as cholestastic. We could not classify the mechanism of injury. High eosinophil and immunoglobulin E levels characterized the injury, and a drug lymphocyte stimulation test was negative on postoperative day 25. Fluid replacement for two weeks after hospitalization improved the liver injury. ALTA therapy involves injecting chemicals into the submucosa, from the rectum to the anus, and this is the first description of a case that developed a severe liver disorder after this treatment; hence, an analysis of future cases as they accumulate is desirable.

No pain no gain? Adjuvant effects of alum and monophosphoryl lipid A in pertussis and HPV vaccines.

Development of non-infectious subunit vaccines is hampered by a slow pipeline of new adjuvants to replace or enhance alum in part because expectations of safety are high. Transient vaccine side effects are not clinical priorities because they cause no lasting harm and vaccine development has appropriately been focused on avoidance of serious adverse events. As a result, surprisingly little is known about the extent to which side effects caused by a vaccine's reactogencicity are predictive of successful immunization outcomes. Recent clinical studies of pertussis and human papillomavirus vaccines adjuvanted with alum or the TLR4 agonist monophosphoryl lipid A can be used to advance understanding of the relationship between vaccine side effects and immunization outcomes.

Leukotriene receptor antagonist attenuated airway inflammation and hyperresponsiveness in a double-stranded RNA-induced asthma exacerbation model.

BACKGROUND: Viral infections are the most common triggers of asthma exacerbation, but the key molecules involved in this process have not been fully identified. Although cysteinyl leukotrienes (cysLTs) have been postulated as the key mediators, their precise roles remain largely unclear. To investigate the roles of cysLTs in virus-induced asthma exacerbation, we developed a murine model using a viral double-stranded RNA analog, polyinosinic-polycytidylic acid (poly I:C), and analyzed the effect of leukotriene receptor antagonist (LTRA) administration. METHODS: A/J mice were immunized with ovalbumin (OVA) + alum (days 0, 28, 42, and 49), followed by intranasal challenge with OVA (phase 1: days 50-52) and poly I:C (phase 2: days 53-55). Montelukast was administered during poly I:C challenge (phase 2) in the reliever model or throughout the OVA and poly I:C challenges (phases 1 and 2) in the controller model. Airway responsiveness to acetylcholine chloride was assessed, and bronchoalveolar lavage (BAL) was performed on day 56. RESULTS: Administration of poly I:C to OVA-sensitized and -challenged mice increased the number of eosinophils and levels of IL-13, IL-9, CCL3, and CXCL1 in BAL fluid (BALF) and tended to increase airway responsiveness. Montelukast significantly attenuated the poly I:C-induced increase in the number of eosinophils and levels of IL-13, IL-9, and CCL3 in BALF and airway hyperresponsiveness in both the reliever and controller models. CONCLUSIONS: This is the first report showing that LTRA functionally suppressed the pathophysiology of a virus-induced asthma exacerbation model, suggesting the importance of cysLTs as a potential treatment target.

Safety and efficacy of intravesical alum for intractable hemorrhagic cystitis: a contemporary evaluation

ABSTRACT Introduction: Hemorrhagic cystitis (HC) represents a challenging clinical entity. While various intravesical agents have been utilized in this setting, limited data exist regarding safety or efficacy. Herein, then, we evaluated the effectiveness and complications associated with intravesical alum instillation for HC in a contemporary cohort. Materials and Methods: We identified 40 patients treated with intravesical alum for HC between 1997-2014. All patients had failed previous continuous bladder irrigation with normal saline and clot evacuation. Treatment success was defined as requiring no additional therapy beyond normal saline irrigation after alum instillation. Results: Median patient age was 76.5 years (IQR 69, 83). Pelvic radiation was the most common etiology for HC (n=38, 95%). Alum use decreased patient's transfusion requirement, with 82% (32/39) receiving a transfusion within 30 days before alum instillation (median 4 units) versus 59% (23/39) within 30 days after completing alum (median 3 units) (p=0.05). In total, 24 patients (60%) required no additional therapy prior to hospital discharge. Moreover, at a median follow-up of 17 months (IQR 5, 38.5), 13 patients (32.5%) remained without additional treatment for HC. Adverse effects were reported in 15 patients (38%), with bladder spasms representing the most common event (14/40; 35%). No clinical evidence of clinically significant systemic absorption was detected. Conclusion: Intravesical alum therapy is well-tolerated, with resolution of HC in approximately 60% of patients, and a durable response in approximately one-third. Given its favorable safety/efficacy profile, intravesical alum may be considered as a first-line treatment option for patients with HC.

Safety and efficacy of intravesical alum for intractable hemorrhagic cystitis: A contemporary evaluation.

INTRODUCTION: Hemorrhagic cystitis (HC) represents a challenging clinical entity. While various intravesical agents have been utilized in this setting, limited data exist regard¬ing safety or efficacy. Herein, then, we evaluated the effectiveness and complications associated with intravesical alum instillation for HC in a contemporary cohort. MATERIALS AND METHODS: We identified 40 patients treated with intravesical alum for HC between 1997-2014. All patients had failed previous continuous bladder irrigation with normal saline and clot evacuation. Treatment success was defined as requiring no additional therapy beyond normal saline irrigation after alum instillation. RESULTS: Median patient age was 76.5 years (IQR 69, 83). Pelvic radiation was the most common etiology for HC (n=38, 95%). Alum use decreased patient's transfusion requirement, with 82% (32/39) receiving a transfusion within 30 days before alum instillation (median 4 units) versus 59% (23/39) within 30 days after completing alum (median 3 units) (p=0.05). In total, 24 patients (60%) required no additional therapy prior to hospital discharge. Moreover, at a median follow-up of 17 months (IQR 5, 38.5), 13 patients (32.5%) remained without additional treatment for HC. Adverse ef¬fects were reported in 15 patients (38%), with bladder spasms representing the most common event (14/40; 35%). No clinical evidence of clinically significant systemic absorption was detected. CONCLUSION: Intravesical alum therapy is well-tolerated, with resolution of HC in ap¬proximately 60% of patients, and a durable response in approximately one-third. Given its favorable safety/efficacy profile, intravesical alum may be considered as a first-line treatment option for patients with HC.

Salivary protein levels as a predictor of perceived astringency in model systems and solid foods.

Salivary protein difference value (SP D-value) is a quantitative measure of salivary protein replenishment, which reportedly relates to individual differences in perceived astringency. This in vitro measure is calculated as the difference in total salivary protein before (S1) and after (S2) stimulation with tannic acid, with a greater absolute value (S2-S1) indicating less protein replenishment. Others report that this measure predicts perceived astringency and liking of liquid model systems and beverages containing added polyphenols. Whether this relationship generalizes to astringent compounds other than polyphenols, or to solid foods is unknown. Here, the associations between SP D-values and perceived astringency and overall liking/disliking for alum and tannic acid (experiment 1) as well as solid chocolate-flavored compound coating with added tannic acid or grape seed extract (GSE) (experiment 2) were examined. In both experiments, participants (n=84 and 81, respectively) indicated perceived intensity of astringency, bitterness, sweetness, and sourness, and degree of liking of either aqueous solutions, or solid chocolate-flavored compound coating with added astringents. Data were analyzed via linear regression, and as discrete groups for comparison to prior work. Three discrete groups were formed based on first and third quartile splits of the SP D-value distribution: low (LR), medium (MR), and high responding (HR) individuals. In experiment 1, significantly higher mean astringency ratings were observed for the HR as compared to the LR/MR groups for alum and tannic acid, confirming and extending prior work. In experiment 2, significantly higher mean astringency ratings were also observed for HR as compared to LR groups in solid chocolate-flavored compound containing added tannic acid or GSE. Significant differences in liking were found between HR and LR groups for alum and tannic acid in water, but no significant differences in liking were observed for chocolate-flavored compound samples. A significant linear relationship between SP D-values and perceived astringency was observed for both alum and tannic acid (p's<0.001), although the variance explained was relatively low (R(2)=0.33 and 0.29, respectively). In the solid chocolate-flavored compound spiked with either tannic acid or GSE, the relationship was not significant (p=0.17 and 0.30; R(2)=0.03 and 0.02, respectively). Due to the weak associations overall, and the lack of significant differences in perception of astringency between the MR and LR groups, we conclude that SP D-values are not a strong predictor of astringency, especially in solid, high-fat foods. Additional research investigating alternative methods for quantifying individual differences in astringency, as well as exploring the underlying complexities of this percept appears warranted.

Racotumomab-alum vaccine for the treatment of non-small-cell lung cancer.

Racotumomab-alum vaccine is an anti-idiotypic vaccine able to mimic the tumor-associated antigen NeuGcGM3. Different Phase I clinical trials and compassionate use studies demonstrated its low toxicity and capacity to induce a strong anti-NeuGcGM3 response, able to bind and directly kill tumor cells expressing the antigen. A Phase II/III randomized double-blind clinical trial in advanced non-small cell lung cancer patients showed a significant improvement in overall survival and progression-free survival for racotumomab-alum versus placebo. Patients who developed anti-NeuGcGM3 antibodies capable of binding and killing NeuGcGM3 expressing tumor cells showed significantly longer median survival times. The impact of using racotumomab-alum as switch maintenance followed by second-line therapy is currently being explored in a new randomized, multinational Phase III study.

G Protein signaling modulator-3 inhibits the inflammasome activity of NLRP3.

Inflammasomes are multi-protein complexes that regulate maturation of the interleukin 1ß-related cytokines IL-1ß and IL-18 through activation of the cysteine proteinase caspase-1. NOD-like receptor family, pyrin domain containing 3 (NLRP3) protein is a key component of inflammasomes that assemble in response to a wide variety of endogenous and pathogen-derived danger signals. Activation of the NLRP3-inflammasome and subsequent secretion of IL-1ß is highly regulated by at least three processes: transcriptional activation of both NLRP3 and pro-IL-1ß genes, non-transcriptional priming of NLRP3, and final activation of NLRP3. NLRP3 is predominantly expressed in cells of the hematopoietic lineage. Using a yeast two-hybrid screen, we identified the hematopoietic-restricted protein, G protein signaling modulator-3 (GPSM3), as a NLRP3-interacting protein and a negative regulator of IL-1ß production triggered by NLRP3-dependent inflammasome activators. In monocytes, GPSM3 associates with the C-terminal leucine-rich repeat domain of NLRP3. Bone marrow-derived macrophages lacking GPSM3 expression exhibit an increase in NLRP3-dependent IL-1ß, but not TNF-α, secretion. Furthermore, GPSM3-null mice have enhanced serum and peritoneal IL-1ß production following Alum-induced peritonitis. Our findings suggest that GPSM3 acts as a direct negative regulator of NLRP3 function.

Serum aluminum levels in dialysis patients after sclerotherapy of internal hemorrhoids with aluminum potassium sulfate and tannic acid.

PURPOSE: Aluminum potassium sulfate and tannic acid (ALTA) is an effective sclerosing agent for internal hemorrhoids. However, it is contraindicated for patients with chronic renal failure on dialysis, because the aluminum in ALTA can cause aluminum encephalopathy when it is not excreted effectively. We conducted this study to measure the serum aluminum concentrations and observe for symptoms relating to aluminum encephalopathy in dialysis patients after ALTA therapy. METHODS: Ten dialysis patients underwent ALTA therapy for hemorrhoids. We measured their serum aluminum concentrations and observed them for possible symptoms of aluminum encephalopathy. RESULTS: The total injection volume of ALTA solution was 31 mL (24-37). The median serum aluminum concentration before ALTA therapy was 9 µg/L, which increased to 741, 377, and 103 µg/L, respectively, 1 h, 1 day, and 1 week after ALTA therapy. These levels decreased rapidly, to 33 µg/L by 1 month and 11 µg/L by 3 months after ALTA therapy. No patient suffered symptoms related to aluminum encephalopathy. CONCLUSIONS: Although the aluminum concentrations increased temporarily after ALTA therapy, dialysis patients with levels below 150 µg/L by 1 week and thereafter are considered to be at low risk of the development of aluminum encephalopathy.

[Biopersistence and systemic distribution of intramuscularly injected particles: what impact on long-term tolerability of alum adjuvants?]. / Bio-persistance et distribution systémique des particules injectées par voie intra-musculaire: quelle incidence sur la tolérance à long terme des adjuvants aluminiques?

Aluminium oxyhydroxide (alum), a nanocrystalline compound that forms agglomerates, has been widely used as a vaccine adjuvant since 1927, but the mechanisms by which it stimulates immune responses remain poorly understood. Although generally well tolerated, alum may occasionally cause chronic health problems in presumably susceptible individuals. Some individuals may rarely develop delayed-onset diffuse myalgia, chronic exhaustion and cognitive dysfunction, associated with long-term persistence (up to 12 years) of alum-loaded macrophages at site of i.m. immunization, defining so-called macrophagic myofasciitis (MMF). Symptoms are consistent with the chronic fatigue/myalgic encephalomyelitis (CFS/ME) syndrome, and have been used as a paradigm of the "autoimmune/inflammatory syndrome induced by adjuvants" (ASIA). Cognitive dysfunction is reminiscent of that described in workers exposed to inhaled Al particles. Individual susceptibility may influence both alum biopersistence and difusion away from injection sites. Biopersistent particles such as fluorescent alum-coated nanohybrids, when injected into mouse muscle, are captured by monocyte-lineage cells and then carried to distant organs, draining lymph nodes and blood, probably via the thoracic duct, with delayed and accumulative translocation to the brain (microglial cells). Brain penetration occurs at extremely low levels in normal conditions, possibly explaining the good tolerance of alum despite its high neurotoxic potential. However, systemic diffusion is considerably enhanced by the potentiating effect of MCP-1, the main monocyte chemoattractant factor, the production of which is subject to marked variations linked to age and to genetic and environmental factors. Selective MCP-1 elevation is the only known circulating biomarker of MMF.

Responses to multiple injections with alum alone compared to injections with alum adsorbed to proteins in mice.

New effects and mechanisms of alum on innate immunity have emerged in recent years. A number of cellular and molecular mechanisms induced by aluminum adjuvant have been reported, while the role of NALP3 and inflammasome in the cellular pathway induced by alum is still controversial. The effect of injection of alum alone without vaccine antigen into human has not been reported so far. Recently, in a phase IIIa double-blinded placebo controlled clinical trial testing the therapeutic HBsAg-anti-HBs vaccine formulated with alum against chronic viral hepatitis B patients, the placebo group receiving alum only showed substantial therapeutic effects. To explore possible underlying therapeutic mechanisms, mice were treated either with multiple injections of alum alone or with alum adsorbed to proteins (HBsAg-anti-HBs). After 4 injections Gr1(+)/CD11b(+) cells in the spleen were increased in both alum alone and alum adsorbed in proteins groups. Increased Gr1(+)/CD11b(+) cells in spleens remained consistently high in the alum alone treated group, while Gr1(+)/CD11b(+)cells decreased in the alum adsorbed to proteins group after 6 injections. Both treatments triggered increased levels of TNF-alpha measured in the plasma, but only the alum alone treated mice showed increased levels of IL-10. Histology of the liver tissues revealed a higher number of spotty necrotic foci in the alum alone immunized group. Taken together, potent inflammatory responses were induced in the alum alone immunized mice, which suggests that the substantial therapeutic effects observed in chronic hepatitis B patients immunized with alum alone might be attributed to inflammatory responses.

Macrophagic myofasciitis: characterization and pathophysiology.

Aluminium oxyhydroxide (alum), a nanocrystalline compound forming agglomerates, has been used in vaccines for its immunological adjuvant effect since 1927. Alum is the most commonly used adjuvant in human and veterinary vaccines, but the mechanisms by which it stimulates immune responses remain incompletely understood. Although generally well tolerated, alum may occasionally cause disabling health problems in presumably susceptible individuals. A small proportion of vaccinated people present with delayed onset of diffuse myalgia, chronic fatigue and cognitive dysfunction, and exhibit very long-term persistence of alum-loaded macrophages at the site of previous intramuscular (i.m.) immunization, forming a granulomatous lesion called macrophagic myofasciitis (MMF). Clinical symptoms associated with MMF are paradigmatic of the recently delineated 'autoimmune/inflammatory syndrome induced by adjuvants' (ASIA). The stereotyped cognitive dysfunction is reminiscent of cognitive deficits described in foundry workers exposed to inhaled Al particles. Alum safety concerns will largely depend on whether the compound remains localized at the site of injection or diffuses and accumulates in distant organs. Animal experiments indicate that biopersistent nanomaterials taken up by monocyte-lineage cells in tissues, such as fluorescent alum surrogates, can first translocate to draining lymph nodes, and thereafter circulate in blood within phagocytes and reach the spleen, and, eventually, slowly accumulate in the brain.

Do aluminum vaccine adjuvants contribute to the rising prevalence of autism?

Autism spectrum disorders (ASD) are serious multisystem developmental disorders and an urgent global public health concern. Dysfunctional immunity and impaired brain function are core deficits in ASD. Aluminum (Al), the most commonly used vaccine adjuvant, is a demonstrated neurotoxin and a strong immune stimulator. Hence, adjuvant Al has the potential to induce neuroimmune disorders. When assessing adjuvant toxicity in children, two key points ought to be considered: (i) children should not be viewed as "small adults" as their unique physiology makes them much more vulnerable to toxic insults; and (ii) if exposure to Al from only few vaccines can lead to cognitive impairment and autoimmunity in adults, is it unreasonable to question whether the current pediatric schedules, often containing 18 Al adjuvanted vaccines, are safe for children? By applying Hill's criteria for establishing causality between exposure and outcome we investigated whether exposure to Al from vaccines could be contributing to the rise in ASD prevalence in the Western world. Our results show that: (i) children from countries with the highest ASD prevalence appear to have the highest exposure to Al from vaccines; (ii) the increase in exposure to Al adjuvants significantly correlates with the increase in ASD prevalence in the United States observed over the last two decades (Pearson r=0.92, p<0.0001); and (iii) a significant correlation exists between the amounts of Al administered to preschool children and the current prevalence of ASD in seven Western countries, particularly at 3-4 months of age (Pearson r=0.89-0.94, p=0.0018-0.0248). The application of the Hill's criteria to these data indicates that the correlation between Al in vaccines and ASD may be causal. Because children represent a fraction of the population most at risk for complications following exposure to Al, a more rigorous evaluation of Al adjuvant safety seems warranted.

Macrophagic myofaciitis a vaccine (alum) autoimmune-related disease.

Macrophagic myofasciitis (MMF) is an immune-mediated condition first reported in 1998. MMF is characterized by post-vaccination systemic manifestations as well as local-stereotyped and immunologically active lesion in the site of inoculation (deltoid muscle). MMF systemic symptoms included myalgias, arthralgias, marked asthenia, muscle weakness, chronic fatigue, and fever. Recently, studies demonstrated that the local lesion is due to persistence for years at site of injection of an aluminum (Al(OH)3) adjuvant commonly used in human vaccines. Time elapsed from last immunization with an Al(OH)3-containing vaccine to muscle biopsy range from 3 months to 8 years; in rare cases, MMF may be diagnosed even 10 years post-vaccination. The discrepancy between the wide applications of aluminum hydroxide-containing vaccines and the very limited number of MMF cases reported may be resolved by observations suggesting that aluminum-containing vaccinations may trigger MMF in genetically susceptible subjects carrying the HLA-DRB1*01. Thus, MMF may be defined as an emerging novel condition that may be triggered by exposure to alum-containing vaccines, in patients with a specific genetic background, and this temporal association may be exhibited from a few months up to 10 years.