Hypersensitivity Pneumonitis Due to Metalworking Fluid Aerosols.

PURPOSE OF REVIEW: This review summarises the clinical knowledge of hypersensitivity pneumonitis in workers exposed to aerosols of metalworking fluid, reviewing published outbreaks and clinical cases. RECENT FINDINGS: Metalworking fluid exposure has become the commonest recognised cause of occupational hypersensitivity pneumonitis, having been rare before 2000. There are many possible agents in the metalworking fluid which may be the cause of disease including bacteria, mycobacteria, fungae, biocides, emulsifiers, reodorants and dissolved chrome and cobalt. Causes are likely to be different in different outbreaks. Mycobacteria growing in the metalworking fluid have generated immune responses in some workers, but their role in disease causation is not yet established. Many outbreaks have been identified in large workplaces using common sumps. It is not possible to prevent microbial contamination of metalworking fluids in use. Disease prevention should focus on stopping inhalation of aerosols, particularly by re-engineering to remove recirculation.

Chemical determinants of occupational hypersensitivity pneumonitis.

BACKGROUND: Workplace inhalational exposures to low molecular weight (LMW) chemicals cause hypersensitivity pneumonitis (HP) as well as the more common manifestation of respiratory hypersensitivity, occupational asthma (OA). AIMS: To explore whether chemical causation of HP is associated with different structural and physico-chemical determinants from OA. METHODS: Chemical causes of human cases of HP and OA were identified from searches of peer-reviewed literature up to the end of 2011. Each chemical was categorized according to whether or not it had been the attributed cause of at least one case of HP. The predicted asthma hazard was determined for each chemical using a previously developed quantitative structure-activity relationship (QSAR) model. The chemicals in both sets were independently and 'blindly' analysed by an expert in mech anistic chemistry for a qualitative prediction of protein cross-linking potential and determination of lipophilicity (log K ow). RESULTS: Ten HP-causing chemicals were identified and had a higher median QSAR predicted asthma hazard than the control group of 101 OA-causing chemicals (P < 0.01). Nine of 10 HP-causing chemicals were predicted to be protein cross-linkers compared with 24/92 controls (P < 0.001). The distributions of log K ow indicated higher values for the HP list (median 3.47) compared with controls (median 0.81) (P < 0.05). CONCLUSIONS: These findings suggest that chemicals capable of causing HP tend to have higher predicted asthma hazard, are more lipophilic and are more likely to be protein cross-linkers than those causing OA.

Exposure to low doses of formaldehyde during pregnancy suppresses the development of allergic lung inflammation in offspring.

Formaldehyde (FA) is an environmental and occupational pollutant, and its toxic effects on the immune system have been shown. Nevertheless, no data are available regarding the programming mechanisms after FA exposure and its repercussions for the immune systems of offspring. In this study, our objective was to investigate the effects of low-dose exposure of FA on pregnant rats and its repercussion for the development of allergic lung inflammation in offspring. Pregnant Wistar rats were assigned in 3 groups: P (rats exposed to FA (0.75 ppm, 1 h/day, 5 days/week, for 21 days)), C (rats exposed to vehicle of FA (distillated water)) and B (rats non-manipulated). After 30 days of age, the offspring was sensitised with ovalbumin (OVA)-alum and challenged with aerosolized OVA (1%, 15 min, 3 days). After 24 h the OVA challenge the parameters were evaluated. Our data showed that low-dose exposure to FA during pregnancy induced low birth weight and suppressed the development of allergic lung inflammation and tracheal hyperresponsiveness in offspring by mechanisms mediated by reduced anaphylactic antibodies synthesis, IL-6 and TNF-alpha secretion. Elevated levels of IL-10 were found. Any systemic alteration was detected in the exposed pregnant rats, although oxidative stress in the uterine environment was evident at the moment of the delivery based on elevated COX-1 expression and reduced cNOS and SOD-2 in the uterus. Therefore, we show the putative programming mechanisms induced by FA on the immune system for the first time and the mechanisms involved may be related to oxidative stress in the foetal microenvironment.

Inadequate access to diagnostic resources: a case of unrecognised hypersensitivity pneumonitis.

OBJECTIVE: Hypersensitivity pneumonitis (HP) often goes unrecognized because of its relatively low incidence in the general population and it is frequently misdiagnosed as a respiratory infection or idiopathic interstitial lung disease. METHODS: Through the analysis of a paradigmatic case of hypersensitivity pneumonitis, in which only symptomatic diagnosis and treatment were proposed, we argue that limiting the clinical process to generic diagnosis, without detection of the etiologic agent, makes it impossible to avoid exposure, hinders compensation and severely worsens the evolution of the disease. RESULTS: In 1981, a previously healthy, 28-year-old female clerk developed respiratory symptoms. She was diagnosed as suffering from extrinsic bronchial asthma and was treated with steroids and broncho-dilators. Neither immunologic tests nor any environmental pathogen research were proposed until 2008, when precipitins analysis showed positivity to Thermoactynomyces vulgaris, which had presumably contaminated the centralized air-conditioning system. CONCLUSIONS: The diagnosis of HP is unlikely to be missed if in all clinical settings, occupational or environmental causes are routinely considered in the differential diagnosis of any patient with a respiratory problem. This approach could provide a better clinical management of the disease and more effective programmes of primary prevention. Implicit rationing of healthcare resources by limiting diagnostic tests that are not readily accessible reduces patient autonomy and the benefits of medical care.

Implementation of a quantitative real-time PCR assay for the detection of Mycobacterium immunogenum in metalworking fluids.

The bacterium Mycobacterium immunogenum has been implicated in causing the lung condition hypersensitivity pneumonitis (HP) in factory workers exposed to colonized metalworking fluids (MWFs). M. immunogenum-specific, real-time quantitative PCR detection technique (MiRT-qPCR) was implemented on a large scale to 363 MWFs of varying types, originating from the United States and Europe, that had been in use for between 30 days and 1 year. In MWFs that contained between 10(3) and 10(9) culturable general heterotrophs mL(-1) the technique detected between 5 and 2 × 10(6) mL(-1) M. immunogenum cell equivalents (CE) in 12.2% (23 of 189) of U.S. samples and between 8 and 6 × 10(5) mL(-1) CE in 39.1% (68 of 174) of samples from Europe. In contrast, only three cultured presumptive mycobacterial isolates across all samples were confirmed as M. immunogenum. Implementation of the assay demonstrated its practicality and further emphasized the limitations of using cultivation alone. Interestingly, no M. immunogenum were detected in mineral oil-based Bio-Concept MWFs from the United States, while it was more commonly detected in used MWFs based on formaldehyde-releasing biocides than in MWFs free of formaldehyde-depot biocides.

Schistosoma mansoni antigens modulate the allergic response in a murine model of ovalbumin-induced airway inflammation.

Schistosoma mansoni infection has been associated with protection against allergies. The mechanisms underlying this association may involve regulatory cells and cytokines. We evaluated the immune response induced by the S. mansoni antigens Sm22.6, PIII and Sm29 in a murine model of ovalbumin (OVA)-induced airway inflammation. BALB/c mice were sensitized with subcutaneously injected OVA-alum and challenged with aerolized OVA. Mice were given three doses of the different S. mansoni antigens. Lung histopathology, cellularity of bronchoalveolar lavage (BAL) and eosinophil peroxidase activity in lung were evaluated. Immunoglobulin (Ig)E levels in serum and cytokines in BAL were also measured. Additionally, we evaluated the frequency of CD4+forkhead box P3 (FoxP3)+ T cells in cultures stimulated with OVA and the expression of interleukin (IL)-10 by these cells. The number of total cells and eosinophils in BAL and the levels of OVA-specific IgE were reduced in the immunized mice. Also, the levels of IL-4 and IL-5 in the BAL of mice immunized with PIII and Sm22.6 were decreased, while the levels of IL-10 were higher in mice immunized with Sm22.6 compared to the non-immunized mice. The frequency of CD4+FoxP3+ T cells was higher in the groups of mice who received Sm22.6, Sm29 and PIII, being the expression of IL-10 by these cells only higher in mice immunized with Sm22.6. We concluded that the S. mansoni antigens used in this study are able to down-modulate allergic inflammatory mediators in a murine model of airway inflammation and that the CD4+FoxP3+ T cells, even in the absence of IL-10 expression, might play an important role in this process.

Prevention of baker's asthma.

PURPOSE OF REVIEW: Baker's allergy and asthma continue to represent an important contributor of occupational asthma globally. This review identified recent studies related to the prevention of baker's allergy and asthma. RECENT FINDINGS: Studies with respect to regulatory exposure standards, workplace control measures aimed at reduction of flour dust exposures, surveillance programmes (exposure monitoring, medical surveillance) and workplace information, education and training programmes were identified. SUMMARY: Detailed knowledge on risk factors and detection methods to assess exposure and early identification of high-risk workers exist, but workplace control measures remain sub-optimal because they are rarely multifaceted. This is compounded by the lack of health-based exposure standards globally. Exposure level monitoring and medical surveillance are integral to assessing effectiveness of preventive strategies. Triage systems for optimizing the efficiency of medical surveillance programmes show promise, but need replication in different contexts. Future studies need to focus on evaluating the relevance and quantification of peak exposures in increasing risk; developing standardized respiratory questionnaires for medical surveillance; and further exploration of serial fractional exhaled nitric oxide (FeNO) measurements as an adjunct to allergic sensitization for the early identification of baker's asthma and assessing the long-term impact of interventions.

Hypersensitivity pneumonitis caused by occupational exposure to phytase.

A 43-yr-old male presented with a 6-month history of episodes of coughing, shortness of breath and fever. He suffered from dyspnoea on minor exertion. The patient worked in a cattle feed factory and noticed that he had more complaints after his working hours. His symptoms could be ascribed to hypersensitivity pneumonitis due to contact with phytase, an enzyme added to cattle feed to strengthen bone and diminish phosphorus excretion. The diagnosis was supported by bibasal lung crackles on physical examination, restrictive ventilatory defect (with decreased diffusion capacity for carbon monoxide), typical radiographical findings, lymphocytosis in bronchoalveolar lavage fluid and a positive exposure test performed at the workplace. Blood examination showed high immunoglobulin G levels to phytase. After treatment and cessation of phytase contact the patient became symptom free and lung function normalised. Phytase should be considered as a cause of occupational hypersensitivity pneumonitis in the animal feed industry.

[Allergic alveolitis after influenza vaccination]. / Allergische Alveolitis nach Grippeschutzimpfung.

Allergic alveolitis as a side effect of vaccination is very rare. We report a life-threatening complication in a female patient after influenza vaccination. The causative antigen was the influenza virus itself. Our Patient has suffered from exogen-allergic alveolitis for 12 years. Because of the guidelines of regular administration of influenza vaccination in patients with chronic pulmonary disease further research in patients with known exogen-allergic alveolitis is vitally important for the pharmaceutical drug safety.

Detection of Mycobacterium immunogenum by real-time quantitative Taqman PCR.

A quantitative real-time 5'-nuclease (Taqman) PCR technique was developed to specifically detect Mycobacterium immunogenum. rpoB-specific primers and Taqman probe were evaluated for detection of M. immunogenum DNA extracted from pure cultures and from industrial metal working fluids (MWFs). Specificity was confirmed and the sensitivity of detection of M. immunogenum genomic DNA was shown to be approximately 9 fg (2 cell equivalents). When tested on industrial metal working fluids from the UK and USA from which no M. immunogenum CFU were recovered, the assay detected between 3.4x10(1) and 1.9x10(4) cell equivalents (CE) per ml, and increased the detection rate over culture to 37.5% (12 of 32 samples). This assay provides a specific, sensitive and rapid method for the detection of M. immunogenum and is applicable within industry for the early detection of this human pathogen and to the possible prevention of hypersensitivity pneumonitis (HP) in workers.

Treatment of water-based metalworking fluids to prevent hypersensitivity pneumonitis associated with Mycobacterium spp.

AIM: To prevent further outbreaks of hypersensitivity pneumonitis (HP), biocides are required which are capable of protecting water-based coolants from proliferating mycobacteria. The aim of this study was therefore, to test different biocide preparations on their mycobactericidal activity. METHODS AND RESULTS: Minimal inhibitory concentration values were determined for Mycobacterium chelonae and Mycobacterium immunogenum for triazine-based, methyloxazolidine-based, N/O-formal-based biocidal formulations. All biocides were effective already at a low dosage (<0.05%) irrespective of the presence or absence of organic soiling, except for one N/O-formal-based formulation containing Kathon 886 (CMI). Quenching of CMI in the presence of organic soiling was found to account for loss in efficacy as determined by high-performance liquid chromatography measurement. Preservation tests were carried out to investigate the efficacy of the biocidal preparations under practical conditions. CONCLUSIONS: Results indicate that methyloxazolidine-based biocidal preparations were most effective to prevent coolants from microbial contamination including rapidly growing mycobacteria. Furthermore, it could be demonstrated that common dipslides can be used to easily monitor coolants for contamination by mycobacteria. SIGNIFICANCE AND IMPACT OF THE STUDY: Our data does not support the hypothesis that mycobacterial proliferation is enhanced by the reduction of competitive microbial population by biocides such as triazines as described earlier but rather suggests a protective effect of biocides regarding mycobacteria in the presence of competitive microbial flora, thereby preventing further outbreaks of HP.

[Feeding during the first months of life and prevention of allergy]. / Alimentation des premiers mois de vie et prévention de l'allergie.

Allergy consists in the different manifestations resulting from immune reactions triggered by food or respiratory allergens. Both its frequency and severity are increasing. The easiest intervention process for allergy prevention is the reduction of the allergenic load which, for a major allergen such as peanuts, has to begin in utero. The primary prevention strategy relies first on the detection of at risk newborns, i.e. with allergic first degree relatives. In this targeted population, as well as for the general population, exclusive breastfeeding is recommended until the age of 6 months. The elimination from the mother's diet of major food allergens potentially transmitted via breast milk may be indicated on an individual basis, except for peanut, which is systematically retrieved. In the absence of breastfeeding, prevention consists in feeding at-risk newborns until the age of 6 months with a hypoallergenic formula, provided that its efficiency has been demonstrated by well-designed clinical trials. Soy based formulae are not recommended for allergy prevention. Complementary feeding should not be started before the age of 6 months. Introduction of egg and fish into the diet can be made after 6 months but the introduction of potent food allergens (kiwi, celery, crustaceans, seafood, nuts, especially tree nuts and peanuts) should be delayed after 1 year. This preventive policy seems partially efficacious on early manifestations of allergy but does not restrain the allergic march, especially in its respiratory manifestations. Probiotics, prebiotics as well as n-3 fatty polyunsaturated acids have not yet demonstrated any definitive protective effect.

[Drug-induced alveolitis associated with infliximab/azathioprine therapy]. / Medikamenten-induzierte Alveolitis unterInfliximab-/Azathioprin-Therapie.

BACKGROUND: TNF-alpha is known to play a decisive role as a pro-inflammatory cytokine in several autoimmune conditions. Its neutralisation by TNF-alpha antagonists such as infliximab (Remicade), a chimeric monoclonal anti-TNF-alpha antibody, may be beneficial in patients with active disease. These anticytokine drugs have been approved and are being increasingly used in the therapy of rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriatic arthropathy and generalised psoriasis after established treatments have failed. Whenever therapy options are few, TNF-alpha antagonists are regarded as an effective, relatively safe and generally well-tolerated alternative, even if there is no detailed knowledge of their safety profile and possible long-term adverse events. In the respiratory tract an increased risk of viral, (myco-)bacterial, fungal and opportunistic infections has been observed. Furthermore, rare cases of severe fibrosing alveolitis in patients with concomitant immunosuppressant therapy or underlying lung disease have been reviewed recently. CASE: We present a case of drug-induced alveolitis following infliximab and azathioprine for the treatment of severe, generalised psoriasis and atopic eczema without pre-existing lung disease. Withdrawal of both drugs achieved clinical and functional stabilisation, and the addition of prednisolone resulted in a rapid improvement. CONCLUSION: As the pathophysiology of the pulmonary insult is unknown and since there are potentially serious adverse effects, we advise caution and close screening before and after initiation of TNF-alpha blockade, especially in patients with an underlying lung disease or with a combination of pneumotoxic agents.

[Actualities in extrinsic allergic alveolities or hypersensitivity pneumonitis]. / Actualités sur les alvéolites allergiques extrinsèques ou pneumopathies d'hypersensibilité.

Significant advances have been noticed in the pathogenesis and the diagnosis of extrinsic allergic alveolitis during the last few years. Indeed the immune mechanism and the enabling conditions have been more precisely defined, the clinical stages and the diagnosis criterias clearly defined, new antigens incriminated and some etiological agents have been reclassified. The present pathogenic explanation insists on the type IV hypersensitivity reaction with sensitization of T lymphocytes, activation macrophages, the formation of IgG type antibodies and immune complexes, activation of complement and secretion of cytokines. The involvement of certain HLA classes (HLA2, DR3, DRB1, DQB1), interaction of genetics and environments factors, the role of infections agents and smoking have been demonstrated in several studies. The development of news clinical and biological diagnosis criteria have led the discovery of new extrinsic allergic alveolitis in the work places, a better knowledge of the prognostic elements and an appropriate adaptation of prevention measures.

Temporal variation of airborne fungi concentrations and related factors in subway stations in Seoul, Korea.

This study was performed to assess the levels of fungi concentration in subway stations in Seoul, Korea, and to investigate factors contributing to these concentrations. Ninety air samples were collected hourly over the course of a day from five different subway stations. In addition, five settled dust samples and 12 stagnant water samples were collected to investigate these as potential sources of fungi contamination. The number of passengers and frequency of passing trains were also determined during the sampling periods, as they were considered potential factors influencing the airborne fungi concentrations at a given time during the day. The airborne fungi concentrations, as a function of time, were log-normally distributed. The airborne fungi concentrations measured during the morning and evening commute hours (during which the number of passengers and frequency of passing trains was highest) were significantly higher than those measured during non-commute hours. High concentrations of fungi were found in the settled dust samples, suggesting that the settled dust may have been the main source of airborne fungi concentration. The air movement generated mainly by passengers and additionally by trains might have played a role in suspending the fungi from the settled dust. It was also found that stagnant water might be a potential source of airborne fungi.

Hypersensitivity Pneumonitis.

Chronic exposure to a broad array of antigens after workers inhale aerosolized organic dust particles from mold, animal dander, bird droppings, and chemicals, especially pesticides or herbicides, increases risk for hypersensitivity pneumonitis. Several demographic characteristics of immigrant workers in farming, poultry processing, construction, and landscaping increase this worker population's risk.

Protective effects of inhibitors of nitric oxide synthase in immune complex-induced vasculitis.

1. The ability of analogues of L-arginine (N-iminoethyl-L-ornithine (L-NIO), NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine methyl ester (L-NAME) and NG-nitro-L-arginine (L-NNA)) to protect against inflammatory injury induced by activated neutrophils was investigated in rats following intradermal or intrapulmonary deposition of immune complexes. 2. The descending order of potency for protective effects of these analogues was: L-NIO > L-NMMA > L-NNA = L-NAME. The approximate IC50 value for L-NIO in the dermal vasculitis model was 65 microM. For all other compounds, the IC50 values were > 5 mM. 3. The protective effect of L-NIO in the skin was reversed in a dose-dependent manner by the presence of L-arginine, but not by D-arginine. L-Arginine also reversed the protective effects of L-NIO in immune complex-induced lung injury. 4. The protective effects of L-NIO were not associated with reductions in neutrophil accumulation, as measured by extraction from tissues of myeloperoxidase. 5. These data demonstrate that L-NIO has the most potent protective effects against immune complex-induced vascular injury induced by activated macrophages. Furthermore, they indicate that this injury is dependent upon the generation of nitric oxide.

Respiratory symptoms and farming practices in farmers associated with an acute febrile illness after organic dust exposure.

STUDY OBJECTIVE: To conduct a preliminary study of occupational respiratory complaints in farmers who have experienced organic dust toxic syndrome (ODTS) symptoms. DESIGN: Cross-sectional. SETTING: An agricultural trade show. INTERVENTION: None. MEASUREMENT AND RESULTS: Two hundred ninety-seven people (204 men, 93 women) completed a questionnaire about agricultural practices, respiratory health (including history of febrile episodes while handling grain), and use of respirators. Spirometry was also performed. ODTS symptoms were described by 107 of the people (36%). A strong significant association was found between ODTS and cough or chest tightness after handling grain (odds ratio [OR], 7.5; 95% confidence ratio [CI], 4.2 to 13.5). People who experienced cough or chest tightness after handling grain were more likely to report handling grain sorghum than people who had not experienced cough or chest tightening after handling grain (OR, 2.1; 95% CI, 1.3 to 3.5). The strong association seen between ODTS and frequent use of a respirator while working in grain bins (OR, 3.9; 95% CI, 1.6 to 9.4) may indicate that farmers began using respirators after respiratory symptoms developed. CONCLUSIONS: Having a history consistent with ODTS exposure was very common in the farmers surveyed. Farmers who had a history consistent with ODTS were more likely to report cough or chest tightness with handling grain. Exposure to grain sorghum was more likely to be associated with respiratory symptoms than was exposure to other types of grain. There is a need for additional studies to further examine the relationship between ODTS and respiratory symptoms with grain dust exposure in farmers.

Effect of air pollution in asthma and respiratory allergy.

Epidemiologic and controlled exposure studies of human volunteers have shown that exposure to a variety of pollutants induces asthma exacerbations. Interestingly, in the case of ozone, recent evidence suggests that this pollutant acts to enhance the effect of inhaled allergen in persons with asthma. These and other data also suggest that pollutants may influence lung function in persons with asthma by increasing airway inflammation. The interaction of pollutants and inhaled allergens and the effect of pollutant exposure on baseline airway inflammation may be a key mechanism of pollutant-induced exacerbation of asthma. Further study of this interaction, as well as interactions of multiple pollutants, will be crucial for rational development of intervention and regulatory strategies.