Penicillin Allergy Label Is Associated With Worse Clinical Outcomes in Bacterial Pneumonia.

BACKGROUND: Penicillins (PCNs) are a first-line treatment option for bacterial pneumonia. PCN allergy label can delay antimicrobial treatment and result in the use of alternative antibiotic regimens risking an inadequate response to treatment and potentially increased adverse drug reactions. OBJECTIVE: To investigate the impact of PCN allergy label on clinical outcomes of bacterial pneumonia. METHODS: This retrospective cohort study used TriNetX, a web-based tool for population cohort research, to identify adult patients with and without PCN allergy label diagnosed with bacterial pneumonia. Cohorts were matched for baseline demographics and chronic medical conditions. The 30-day risks of hospitalization, acute respiratory failure, intubation, need for intensive level of care, and mortality were compared. Antibiotics used and their possible adverse reactions were explored. RESULTS: After matching, there were 68,748 patients in each cohort. Patients with bacterial pneumonia with PCN allergy label had higher risks of hospitalization (risk ratio [RR], 1.23; 95% confidence interval [CI], 1.22-1.24), acute respiratory failure (RR, 1.14; 95% CI, 1.12-1.15), intubation (RR, 1.18; 95% CI, 1.13-1.22), intensive level of care (RR, 1.11; 95% CI, 1.08-1.14), and mortality (RR, 1.08; 95% CI, 1.04-1.13) compared with patients without PCN allergy label. Patients with PCN allergy label had decreased use of PCNs and cephalosporins and increased utilization of other antibiotic classes compared with patients without PCN allergy label. PCN allergy label was also associated with increased risk of adverse drug reactions. CONCLUSION: PCN allergy label is associated with worse clinical outcomes in bacterial pneumonia, and risk mitigation strategies should be considered.

Myeloid liver kinase B1 contributes to lung inflammation induced by lipoteichoic acid but not by viable Streptococcus pneumoniae.

BACKGROUND: Liver kinase B1 (Lkb1, gene name Stk11) functions as a tumor suppressor in cancer. Myeloid cell Lkb1 potentiates lung inflammation induced by the Gram-negative bacterial cell wall component lipopolysaccharide and in host defense during Gram-negative pneumonia. Here, we sought to investigate the role of myeloid Lkb1 in lung inflammation elicited by the Gram-positive bacterial cell wall component lipoteichoic acid (LTA) and during pneumonia caused by the Gram-positive respiratory pathogen Streptococcus pneumoniae (Spneu). METHODS: Alveolar and bone marrow derived macrophages (AMs, BMDMs) harvested from myeloid-specific Lkb1 deficient (Stk11-ΔM) and littermate control mice were stimulated with LTA or Spneu in vitro. Stk11-ΔM and control mice were challenged via the airways with LTA or infected with Spneu in vivo. RESULTS: Lkb1 deficient AMs and BMDMs produced less tumor necrosis factor (TNF)α upon activation by LTA or Spneu. During LTA-induced lung inflammation, Stk11-ΔM mice had reduced numbers of AMs in the lungs, as well as diminished cytokine release and neutrophil recruitment into the airways. During pneumonia induced by either encapsulated or non-encapsulated Spneu, Stk11-ΔM and control mice had comparable bacterial loads and inflammatory responses in the lung, with the exception of lower TNFα levels in Stk11-ΔM mice after infection with the non-encapsulated strain. CONCLUSION: Myeloid Lkb1 contributes to LTA-induced lung inflammation, but is not important for host defense during pneumococcal pneumonia.

Electronic cigarette vapour increases virulence and inflammatory potential of respiratory pathogens.

INTRODUCTION: Bacteria have been extensively implicated in the development of smoking related diseases, such as COPD, by either direct infection or bacteria-mediated inflammation. In response to the health risks associated with tobacco exposure, the use of electronic cigarettes (e-cigs) has increased. This study compared the effect of e-cig vapour (ECV) and cigarette smoke (CSE) on the virulence and inflammatory potential of key lung pathogens (Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus and Pseudomonas aeruginosa). METHODS: Biofilm formation, virulence in the Galleria mellonella infection model, antibiotic susceptibility and IL-8/TNF-α production in A549 cells, were compared between bacteria exposed to ECV, CSE and non-exposed bacteria. RESULTS: Statistically significant increases in biofilm and cytokine secretion were observed following bacterial exposure to either ECV or CSE, compared to non-exposed bacteria; the effect of exposure to ECV on bacterial phenotype and virulence was comparable, and in some cases greater, than that observed following CSE exposure. Treatment of A549 cells with cell signaling pathway inhibitors prior to infection, did not suggest that alternative signaling pathways were being activated following exposure of bacteria to either ECV or CSE. CONCLUSIONS: These findings therefore suggest that ECV and CSE can induce changes in phenotype and virulence of key lung pathogens, which may increase bacterial persistence and inflammatory potential.

Alcohol-dependent pulmonary inflammation: A role for HMGB-1.

Previous studies have demonstrated that acute alcohol intoxication significantly impairs lung immune responses, which can lead to the tissue being undefended from microbial infection and resulting disease. Data suggest that acute intoxication presents an axis where simultaneously suppressing early pro-inflammatory cytokines while inducing anti-inflammatory signals contributes to alcohol-dependent immune suppression in the lung, and thus undeterred microbial replication. Interestingly, alcoholics and those with alcohol use disorder present with increased pneumonia and acute respiratory diseases (ARDs), suggesting a more active priming of inflammatory responses in the lungs. There is current research evaluating the acute effects of binge ethanol consumption on adolescents, which is of grave concern, though long-term effects of adolescent ethanol binge exposure are less studied. We hypothesize that adolescent binge drinking may prime the individual to severe pulmonary distress, when later challenged by a microbial pathogen. Herein, we evaluate a model of adolescent intermittent ethanol (AIE) exposure to investigate pulmonary pathology after microbial challenge. Ethanol was administered to adolescent mice using a binge exposure schedule, and mice were then rested to early adulthood. These mice were then challenged with a sub-lethal intranasal inoculation of Klebsiella pneumoniae and evaluated for severity of disease. We find that AIE exposure initially activates inflammatory mediators within the lung, which resolves over time. However, when challenged with a microbial pathogen after this resolution period, these animals present with more severity of inflammation, pulmonary tissue damage, and mortality when challenged with a pulmonary microbial infection. Interestingly, our data suggest a role for alcohol-dependent release of the protein HMGB-1 from host cells, for both morbidity and mortality in our model of microbial-dependent pulmonary inflammation.

Legionella pneumophila pneumonia possibly due to ustekinumab therapy in a patient with Crohn's disease.

PURPOSE: A case report of Legionella pneumophila pneumonia associated with off-label use of ustekinumab in a patient with Crohn's disease (CD) is presented. SUMMARY: A 57-year-old man with longstanding CD was hospitalized with a four-day history of fever (38.5 °C), dyspnea, left pleuritic pain, and weight loss (more than 6 kg) about six weeks after beginning treatment with ustekinumab, a human monoclonal antibody approved in the United States for two indications (plaque psoriasis and psoriatic arthritis) and currently under investigation as a potential treatment for CD and other inflammatory disorders. During the preceding 25 years, the man had been treated for severe CD with a number of agents (e.g., infliximab, adalimumab, certolizumab); ultimately, off-label ustekinumab therapy (90 mg subcutaneously weekly) was initiated due to persistent severe CD symptoms. Chest x-ray studies at the time of admission demonstrated left upper lobar consolidation, and a urine antigen test was positive for L. pneumophila. The patient was treated with i.v. levofloxacin and methylprednisolone and discharged after two weeks. Ustekinumab was reintroduced (45 mg subcutaneously every two weeks), and the patient continued to receive the drug for 16 months, with clinical remission of CD symptoms and no further adverse events. A literature search identified two case reports of pneumonia associated with ustekinumab use, but neither case involved L. pneumophila. CONCLUSION: Pneumonia caused by L. pneumophila developed in a patient with CD treated with ustekinumab. Pneumonia symptoms resolved after ustekinumab was discontinued.

[Pneumonia in immunosuppressed patients]. / Pneumonien bei immunsupprimierten Patienten.

CLINICAL/METHODICAL ISSUE: Pulmonary infections are a common complication in immunosuppressed patients with a frequently fatal prognosis despite modern prophylactic therapy. An early and correct diagnosis is important for initiation of the appropriate therapy. STANDARD RADIOLOGICAL METHODS: Chest radiography is the preferred initial imaging examination but is not accurate enough for the detection of pulmonary infections in immunosuppressed patients. METHODICAL INNOVATIONS: Pneumonia is caused by a broad spectrum of pathogens in immunocompromised patients. In addition to imaging, the clinical history and epidemiology also play an important role in the diagnostics. PERFORMANCE: Using epidemiological and anamnestic information, computed tomography (CT) shows a significantly better sensitivity and specificity particularly for the diagnosis of atypical forms of pneumonia. Due to the exact imaging of the different infiltration patterns CT provides an increased sensitivity with respect to the etiological classification of pulmonary infections. PRACTICAL RECOMMENDATIONS: This article reviews in particular the radiological findings of commonly occurring pulmonary infections in immunosuppressed patients.

Differential Toll-Like Receptor-Signalling of Burkholderia pseudomallei Lipopolysaccharide in Murine and Human Models.

The Gram-negative bacterium Burkholderia pseudomallei causes melioidosis and is a CDC category B bioterrorism agent. Toll-like receptor (TLR)-2 impairs host defense during pulmonary B.pseudomallei infection while TLR4 only has limited impact. We investigated the role of TLRs in B.pseudomallei-lipopolysaccharide (LPS) induced inflammation. Purified B.pseudomallei-LPS activated only TLR2-transfected-HEK-cells during short stimulation but both HEK-TLR2 and HEK-TLR4-cells after 24 h. In human blood, an additive effect of TLR2 on TLR4-mediated signalling induced by B.pseudomallei-LPS was observed. In contrast, murine peritoneal macrophages recognized B.pseudomallei-LPS solely through TLR4. Intranasal inoculation of B.pseudomallei-LPS showed that both TLR4-knockout(-/-) and TLR2x4-/-, but not TLR2-/- mice, displayed diminished cytokine responses and neutrophil influx compared to wild-type controls. These data suggest that B.pseudomallei-LPS signalling occurs solely through murine TLR4, while in human models TLR2 plays an additional role, highlighting important differences between specificity of human and murine models that may have important consequences for B.pseudomallei-LPS sensing by TLRs and subsequent susceptibility to melioidosis.

Acute exposure to silica nanoparticles enhances mortality and increases lung permeability in a mouse model of Pseudomonas aeruginosa pneumonia.

BACKGROUND: The lung epithelium constitutes the first barrier against invading pathogens and also a major surface potentially exposed to nanoparticles. In order to ensure and preserve lung epithelial barrier function, the alveolar compartment possesses local defence mechanisms that are able to control bacterial infection. For instance, alveolar macrophages are professional phagocytic cells that engulf bacteria and environmental contaminants (including nanoparticles) and secrete pro-inflammatory cytokines to effectively eliminate the invading bacteria/contaminants. The consequences of nanoparticle exposure in the context of lung infection have not been studied in detail. Previous reports have shown that sequential lung exposure to nanoparticles and bacteria may impair bacterial clearance resulting in increased lung bacterial loads, associated with a reduction in the phagocytic capacity of alveolar macrophages. RESULTS: Here we have studied the consequences of SiO2 nanoparticle exposure on Pseudomonas aeruginosa clearance, Pseudomonas aeruginosa-induced inflammation and lung injury in a mouse model of acute pneumonia. We observed that pre-exposure to SiO2 nanoparticles increased mice susceptibility to lethal pneumonia but did not modify lung clearance of a bioluminescent Pseudomonas aeruginosa strain. Furthermore, internalisation of SiO2 nanoparticles by primary alveolar macrophages did not reduce the capacity of the cells to clear Pseudomonas aeruginosa. In our murine model, SiO2 nanoparticle pre-exposure preferentially enhanced Pseudomonas aeruginosa-induced lung permeability (the latter assessed by the measurement of alveolar albumin and IgM concentrations) rather than contributing to Pseudomonas aeruginosa-induced lung inflammation (as measured by leukocyte recruitment and cytokine concentration in the alveolar compartment). CONCLUSIONS: We show that pre-exposure to SiO2 nanoparticles increases mice susceptibility to lethal pneumonia but independently of macrophage phagocytic function. The deleterious effects of SiO2 nanoparticle exposure during Pseudomonas aeruginosa-induced pneumonia are related to alterations of the alveolar-capillary barrier rather than to modulation of the inflammatory responses.

[ORGANIZED PNEUMONIA IN A PATIENT WITH ULCERATIVE COLITIS].

The article presents a case of organized pneumonia development in 44-year-old patient with ulcerative colitis, successfully permitted on the background of treatment with high doses of systemic steroids. The authors consider the case as extra-intestinal IBD-associated pulmonary disease.

Mycobacterium abscessus pulmonary infection during hepatitis C treatment with telaprevir, peginterferon and ribavirin.

The first generation protease inhibitors has been the mainstay of hepatitis C treatment for the last couple of years, showing marked improvement in sustained virological response, but also increased side effects. Infection has emerged as a common complication of telaprevir and boceprevir in combination with peginterferon and ribavirin, usually caused by common pathogens. We present the case of a 65 years old man who developed a Mycobacterium abscessus pulmonary infection during treatment with telaprevir, peginterferon and ribavirin. The patient was successfully treated with amikacin, imipenem and chlarithromycin. The present case is relevant for increasing awareness for recognition of opportunistic infections and particularly nontuberculous mycobacterial infections in patients receiving triple therapy for chronic hepatitis C, especially in cirrhotic subjects who develop significant lymphopenia.

Cigarette smoke exposure exacerbates lung inflammation and compromises immunity to bacterial infection.

The detrimental impact of tobacco on human health is clearly recognized, and despite aggressive efforts to prevent smoking, close to one billion individuals worldwide continue to smoke. People with chronic obstructive pulmonary disease are susceptible to recurrent respiratory infections with pathogens, including nontypeable Haemophilus influenzae (NTHI), yet the reasons for this increased susceptibility are poorly understood. Because mortality rapidly increases with multiple exacerbations, development of protective immunity is critical to improving patient survival. Acute NTHI infection has been studied in the context of cigarette smoke exposure, but this is the first study, to our knowledge, to investigate chronic infection and the generation of adaptive immune responses to NTHI after chronic smoke exposure. After chronic NTHI infection, mice that had previously been exposed to cigarette smoke developed increased lung inflammation and compromised adaptive immunity relative to air-exposed controls. Importantly, NTHI-specific T cells from mice exposed to cigarette smoke produced lower levels of IFN-γ and IL-4, and B cells produced reduced levels of Abs against outer-membrane lipoprotein P6, with impaired IgG1, IgG2a, and IgA class switching. However, production of IL-17, which is associated with neutrophilic inflammation, was enhanced. Interestingly, cigarette smoke-exposed mice exhibited a similar defect in the generation of adaptive immunity after immunization with P6. Our study has conclusively demonstrated that cigarette smoke exposure has a profound suppressive effect on the generation of adaptive immune responses to NTHI and suggests the mechanism by which prior cigarette smoke exposure predisposes chronic obstructive pulmonary disease patients to recurrent infections, leading to exacerbations and contributing to mortality.

An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor.

We report a case of Cryptococcus neoformans pneumonia in a patient taking ruxolitinib, a janus kinase 1,2 inhibitor approved for the treatment of myelofibrosis. We hypothesize that ruxolitinib contributed to this infection through its effects on cell-mediated immunity. Clinicians should be aware of the potential for intracellular or opportunistic infections associated with this novel drug class.

Confounding in the association of proton pump inhibitor use with risk of community-acquired pneumonia.

BACKGROUND: Use of proton pump inhibitors (PPIs) is associated with community-acquired pneumonia (CAP), an association which may be confounded by unobserved patient and prescriber characteristics. OBJECTIVE: We assessed for confounding in the association between PPI use and CAP by using a 'falsification approach,' which estimated whether PPI use is also implausibly associated with other common medical conditions for which no known pathophysiologic link exists. DESIGN: Retrospective claims-based cohort study. SETTING: Six private U.S. health plans. SUBJECTS: Individuals who filled at least one prescription for a PPI (N = 26,436) and those who never did (N = 28,054) over 11 years. INTERVENTIONS: Multivariate linear regression of the association between a filled prescription for a PPI and a diagnosis of CAP in each 3-month quarter. In falsification analyses, we tested for implausible associations between PPI use in each quarter and rates of osteoarthritis, chest pain, urinary tract infection (UTI), deep venous thrombosis (DVT), skin infection, and rheumatoid arthritis. Independent variables included an indicator for whether a prescription for a PPI was filled in a given quarter, and quarterly indicators for various co-morbidities, age, income, geographic location, and marital status. KEY RESULTS: Compared to nonusers, those ever using a PPI had higher adjusted rates of CAP in quarters in which no prescription was filled (68 vs. 61 cases per 10,000 persons, p < 0.001). Similar associations were noted for all conditions (e.g. chest pain, 336 vs. 282 cases, p < 0.001; UTI, 151 vs. 139 cases, p < 0.001). Among those ever using a PPI, quarters in which a prescription was filled were associated with higher adjusted rates of CAP (111 vs. 68 cases per 10,000, p < 0.001) and all other conditions (e.g. chest pain, 597 vs. 336 cases, p < 0.001; UTI, 186 vs. 151 cases, p < 0.001), compared to quarters in which no prescription was filled. CONCLUSION: PPI use is associated with CAP, but also implausibly associated with common medical conditions. Observed associations between PPI use and CAP may be confounded.

Proton pump inhibitors: bacterial pneumonia.

After two decades of widespread use, proton pump inhibitors are considered to have a very well-documented and acceptable adverse effect profile in the short-term. Yet adverse effects continue to emerge. In particular, epidemiological studies conducted over the past 10-12 years showed an increased incidence of fractures. New data now point to an increased risk of bacterial pneumonia. A Korean meta-analysis published in 2011 showed a statistically significant increase in the risk of bacterial pneumonia in patients taking proton pump inhibitors, with an odds ratio of 1.27 (95% confidence interval (95% CI): 1.11 to 1.46). The increase in community-acquired pneumonia was also statistically significant, with an odds ratio of 1.34 (95% CI: 1.14 to 1.57). This is consistent with the results of a meta-analysis published in 2010, which gave an odds ratio of 1.36 (95% CI: 1.12 to 1.65). The increase in the frequency of bacterial pneumonia was highest during the first week of treatment, with an odds ratio of 3.95 (95% CI: 2.86 to 5.45). Subsequent studies have provided conflicting results. Possible mechanisms include bacterial passage into the lungs after colonisation of the upper gastrointestinal tract resulting from the reduction in gastric acidity; bacterial overgrowth in the lungs due to a change in the pH of respiratory secretions; and impaired neutrophil phagocytic function. The available data suggest that proton pump inhibitors play a role in the increased frequency of bacterial pneumonia in treated patients. Similar data implicating H2 receptor antagonists and the proposed mechanism (acid suppression) imply that there are no alternative acid-suppressive medications. This risk of pneumonia is yet another reason not to trivialise the use of proton pump inhibitors. These drugs should only be used when the likely benefits clearly outweigh the potential harms.

[Unclear tetraparesis under immunosupression]. / Unklare Tetraparese unter Immunsuppression.

We report a case of a 69-year-old man who developed tetraparesis and muscular pain under the therapy of prednisolone for several months. Diagnosis was sepsis due to pyomyositis with multiple septic pulmonary staphylococcus aureus abscesses. Antibiotic therapy with piperacillin and tazobactam resulted in a decrease of the inflammatory factors and improvement of the tetraparesis. Pyomyositis, common in tropical areas, is a suppurative infection of striated muscle. Immunodeficiency has been implicated in the development of pyomyositis in temperate climates.