PLoS Genet. 2021 Jul 12;17(7):e1009634. doi: 10.1371/journal.pgen.1009634. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa produces serious chronic infections in hospitalized patients and immunocompromised individuals, including patients with cystic fibrosis. The molecular mechanisms by which P. aeruginosa responds to antibiotics and other stresses to promote persistent infections may provide new avenues for therapeutic intervention. Azithromycin (AZM), an antibiotic frequently used in cystic fibrosis treatment, is thought to improve clinical outcomes through a number of mechanisms including impaired biofilm growth and quorum sensing (QS). The mechanisms underlying the transcriptional response to AZM remain unclear. Here, we interrogated the P. aeruginosa transcriptional response to AZM using a fast, cost-effective genome-wide approach to quantitate RNA 3' ends (3pMap). We also identified hundreds of P. aeruginosa genes with high incidence of premature 3' end formation indicative of riboregulation in their transcript leaders using 3pMap. AZM treatment of planktonic and biofilm cultures alters the expression of hundreds of genes, including those involved in QS, biofilm formation, and virulence. Strikingly, most genes downregulated by AZM in biofilms had increased levels of intragenic 3' ends indicating premature transcription termination, transcriptional pausing, or accumulation of stable intermediates resulting from the action of nucleases. Reciprocally, AZM reduced premature intragenic 3' end termini in many upregulated genes. Most notably, reduced termination accompanied robust induction of obgE, a GTPase involved in persister formation in P. aeruginosa. Our results support a model in which AZM-induced changes in 3' end formation alter the expression of central regulators which in turn impairs the expression of QS, biofilm formation and stress response genes, while upregulating genes associated with persistence.

PMID:34252072 | DOI:10.1371/journal.pgen.1009634

Orv Hetil. 2021 Jul 11;162(28):1129-1136. doi: 10.1556/650.2021.32115.

ABSTRACT

Összefoglaló. A cystás fibrosisban szenvedő betegek várható élettartama jelentősen megnőtt az utóbbi évtizedben, egyre több beteg képes saját gyermeket vállalni. Célunk a cystás fibrosisban szenvedő várandós nők perinatalis és anyai történéseinek felmérése saját eseteink és az irodalmi adatok alapján. 14, cystás fibrosisban szenvedő nő 16 várandósságáról számolunk be. Rögzítettük a várandósok életkorát, testtömegét, testmagasságát, testtömegindexét, légzésfunkciós értékeit a graviditás kezdetén és végén. Az anyai átlagéletkor szüléskor 21,6 (18-25) év volt. Az anyák graviditásának kezdetén a testmagasság átlaga 162 (150-175) cm, a testtömeg átlaga 57,6 (42-72) kg, a testtömegindex átlaga 21,4 (19,1-23,2) kg/m2 volt. A graviditás végén a testtömeg átlaga 62 (39-76) kg, a testtömegindex átlaga 23,6 (21,3-24,1) kg/m2 volt. A graviditás alatti súlygyarapodás átlaga 8 (1,5-21,5) kg volt. A légzésfunkciós értékek a graviditás kezdetén 2 betegnél voltak beszűkültek. A graviditás alatt még 2 beteg légzésfunkciós értékei csökkentek. A sikeres graviditások száma 13 volt. 1 anya kétszer szült. A koraszülések száma 1 volt. A várandósság átlagosan a 38. (34-40.) gestatiós hét után 7 esetben császármetszéssel, 6 esetben hüvelyi szüléssel fejeződött be. A vetélések száma 3 volt. Az Apgar-pontszám minden esetben normális volt. 13 gyermek közül 11-nél a verejtékteszt nem volt emelkedett. 2 gyermeknél magas verejtékértékek voltak, egyikük c.1521_1523delCTT-heterozigóta, a másiknál génmutációt nem tudtunk igazolni. A cystás fibrosisban szenvedő nők általában jól tolerálják a várandósságot az esetek többségében. A kórosan beszűkült tüdőfunkcióval, alacsony tápláltsági állapottal és cukorbetegséggel rendelkező nők nagyobb valószínűséggel számíthatnak káros következményekre. Az újszülöttek prognózisa általában jó, de számítani kell a koraszülés és a kis súllyal születés gyakoribb előfordulására. Ideális esetben a várandósságot előzetes tanácsadás útján kell megtervezni, és speciális cystás fibrosis csoportnak kell a várandósok ellátását figyelemmel kísérni, ideértve a cystás fibrosis kezelésében jártas szülészeket is. Kisszámú saját adatunk retrospektív elemzése megerősíti az irodalmi adatok tanúságait. Orv Hetil. 2021; 162(28): 1129-1136. Summary. The life expectancy of patients with cystic fibrosis has increased significantly in the last decade, with more and more patients being able to have their own children. The aim of our study was to assess the perinatal and maternal outcome of pregnant women with cystic fibrosis based on our own cases and literature data. We report 16 pregnancies in 14 women with cystic fibrosis. We recorded the age, body weight, height, body mass index, and respiratory function values of pregnant women at the beginning and end of pregnancy. The mean maternal age at childbirth was 21.6 (18-25) years. At the beginning of maternal pregnancy, the mean height was 162 (150-175) cm, the mean body weight was 57.6 (42-72) kg, and the mean body mass index was 21.4 (19.1-23.2) kg/m2. At the end of pregnancy, the mean body weight was 62 (39-76) kg and the mean body mass index was 23.6 (21.3-24.1) kg/m2. The weight gain under pregnancy was mean 8 (1.5-21.5) kg. The respiratory function values at the onset of pregnancy were narrowed in 2 patients. During pregnancy, the respiratory function values of 2 more patients decreased. The number of successful gestations was 13. A mother gave birth twice. The number of premature births was one. The pregnancy after the mean 38. (34-40.) gestational week was completed in 7 cases by cesarean section and in 6 cases by vaginal delivery. The number of miscarriages was 3. The Apgar score was normal in all cases. In 11 of 13 children, the sweat test was not elevated. 2 children had high sweat values, one of them is heterozygous with c.1521_1523delCTT, the other could not prove a gene mutation. Women with cystic fibrosis generally tolerate pregnancy well, in most cases. Women with poor lung function, low nutritional status, and diabetes are more likely to expect adverse consequences. The outcome of the newborns is good in general, but a common occurrence of premature birth and low birth weight is to be expected. Ideally, pregnancy should be planned through prior counseling and the care of pregnant women should be monitored by a specialized cystic fibrosis team, including obstetricians experienced in the treatment of cystic fibrosis. A retrospective analysis of our own small-number data confirms the evidence from the literature data. Orv Hetil. 2021; 162(28): 1129-1136.

PMID:34252045 | DOI:10.1556/650.2021.32115

Microb Cell. 2021 May 31;8(7):161-163. doi: 10.15698/mic2021.07.755. eCollection 2021 Jul 5.

ABSTRACT

Pseudomonas aeruginosa is a gram-negative opportunistic pathogen capable of causing both acute and chronic infections, particularly in individuals with compromised host defenses. The quorum sensing transcriptional activator LasR is widely recognized for its role in regulating the expression of acute virulence factors, notably several secreted proteases which cause direct host damage and subvert host immunity in acute infections. Paradoxically, lung infections caused by LasR-deficient variants, which are found in at least a third of cystic fibrosis (CF) patients with chronic P. aeruginosa infections, are associated with accelerated lung disease and increased markers of inflammation compared to infections caused by strains with a functional LasR system. While the loss of LasR function often (although not always) results in impaired production of LasR-controlled acute virulence factors, the implication of this pathoadaptation on host-pathogen interactions and chronic disease pathology is less well recognized. We recently observed that loss of LasR function in lasR variants, which results in impaired secreted protease production, led to increased expression of the membrane-bound surface adhesion molecule mICAM-1 in the airway epithelium, and increased neutrophilic inflammation. Specifically, human airway epithelial cells stimulated with lasR variants had higher mICAM-1 expression and greater neutrophil binding in vitro compared to stimulation with wild-type P. aeruginosa. In a subacute non-lethal P. aeruginosa lung infection model, lasR variant infection also induced higher mICAM-1 expression in the murine airway epithelium and was associated with increased neutrophilic pulmonary inflammation in vivo. Here, we discuss how (loss of) LasR function and LasR-regulated proteases affect host immunity, inflammation and tissue pathology in acute vs. chronic P. aeruginosa lung infection.

PMID:34250084 | PMC:PMC8246023 | DOI:10.15698/mic2021.07.755

Front Cell Infect Microbiol. 2021 Jun 24;11:694789. doi: 10.3389/fcimb.2021.694789. eCollection 2021.

ABSTRACT

Pseudomonas aeruginosa is a metabolically versatile opportunistic pathogen capable of infecting distinct niches of the human body, including skin wounds and the lungs of cystic fibrosis patients. Eradication of P. aeruginosa infection is becoming increasingly difficult due to the numerous resistance mechanisms it employs. Adaptive resistance is characterized by a transient state of decreased susceptibility to antibiotic therapy that is distinct from acquired or intrinsic resistance, can be triggered by various environmental stimuli and reverted by removal of the stimulus. Further, adaptive resistance is intrinsically linked to lifestyles such as swarming motility and biofilm formation, both of which are important in infections and lead to multi-drug adaptive resistance. Here, we demonstrated that NtrBC, the master of nitrogen control, had a selective role in host colonization and a substantial role in determining intrinsic resistance to ciprofloxacin. P. aeruginosa mutant strains (ΔntrB, ΔntrC and ΔntrBC) colonized the skin but not the respiratory tract of mice as well as WT and, unlike WT, could be reduced or eradicated from the skin by ciprofloxacin. We hypothesized that nutrient availability contributed to these phenomena and found that susceptibility to ciprofloxacin was impacted by nitrogen source in laboratory media. P. aeruginosa ΔntrB, ΔntrC and ΔntrBC also exhibited distinct host interactions, including modestly increased cytotoxicity toward human bronchial epithelial cells, reduced virulence factor production and 10-fold increased uptake by macrophages. These data might explain why NtrBC mutants were less adept at colonizing the upper respiratory tract of mice. Thus, NtrBC represents a link between nitrogen metabolism, adaptation and virulence of the pathogen P. aeruginosa, and could represent a target for eradication of recalcitrant infections in situ.

PMID:34249781 | PMC:PMC8264665 | DOI:10.3389/fcimb.2021.694789

Front Endocrinol (Lausanne). 2021 Jun 25;12:696768. doi: 10.3389/fendo.2021.696768. eCollection 2021.

NO ABSTRACT

PMID:34248852 | PMC:PMC8270671 | DOI:10.3389/fendo.2021.696768

Front Physiol. 2021 Jun 24;12:691227. doi: 10.3389/fphys.2021.691227. eCollection 2021.

ABSTRACT

Mucosal surfaces are lined by epithelial cells, which provide a complex and adaptive module that ensures first-line defense against external toxics, irritants, antigens, and pathogens. The underlying mechanisms of host protection encompass multiple physical, chemical, and immune pathways. In the lung, inhaled agents continually challenge the airway epithelial barrier, which is altered in chronic diseases such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, or pulmonary fibrosis. In this review, we describe the epithelial barrier abnormalities that are observed in such disorders and summarize current knowledge on the mechanisms driving impaired barrier function, which could represent targets of future therapeutic approaches.

PMID:34248677 | PMC:PMC8264588 | DOI:10.3389/fphys.2021.691227

Nihon Shokakibyo Gakkai Zasshi. 2021;118(7):686-697. doi: 10.11405/nisshoshi.118.686.

ABSTRACT

A 9-year-old Japanese girl was found to have persistently elevated hepatic enzymes, chronic bronchitis, chronic sinusitis, and poor weight gain beginning at 5 months of age. Chest computed tomography (CT) revealed diffuse bronchial wall thickening and peripheral bronchiectasis. Abdominal CT showed pancreatic atrophy, liver cirrhosis, a dilated splenic vein, and splenomegaly. Her sweat chloride concentration was 117mmol/l (normal, <60mmol/l). CFTR gene analysis revealed the presence of the Y517H variant on one allele and the 1540del10 variant one the other allele. These findings established a definitive diagnosis of cystic fibrosis (CF). While CF is the most common autosomal recessive genetic disorder among Europeans, it is quite rare in Southeast Asia including Japan. It is important that CF be considered in the work-up of children with chronic hepatic and respiratory disorders even if it is uncommon among children of a similar background.

PMID:34248082 | DOI:10.11405/nisshoshi.118.686

Bioorg Med Chem Lett. 2021 Jul 8:128243. doi: 10.1016/j.bmcl.2021.128243. Online ahead of print.

ABSTRACT

A growing number of diseases are linked to the misfolding of integral membrane proteins, and many of these proteins are targeted for ubiquitin-proteasome-dependent degradation. One such substrate is a mutant form of the Cystic Fibrosis Transmembrane Conductance Regulator (F508del-CFTR). Protein folding "correctors" that repair the F508del-CFTR folding defect have entered the clinic, but they are unlikely to protect the entire protein from degradation. To increase the pool of F508del-CFTR protein that is available for correction by existing treatments, we determined a structure-activity relationship to improve the efficacy and reduce the toxicity of an inhibitor of the E1 ubiquitin activating enzyme that facilitates F508del-CFTR maturation. A resulting lead compound lacked measurable toxicity and improved the ability of an FDA-approved corrector to augment F508del-CFTR folding, transport the protein to the plasma membrane, and maintain its activity. These data support a proof-of-concept that modest inhibition of substrate ubiquitination improves the activity of small molecule correctors to treat CF and potentially other protein conformational disorders.

PMID:34246753 | DOI:10.1016/j.bmcl.2021.128243

J Cyst Fibros. 2021 Jul 7:S1569-1993(21)01295-9. doi: 10.1016/j.jcf.2021.06.011. Online ahead of print.

ABSTRACT

BACKGROUND: Chronic infection with Pseudomonas aeruginosa (P. aeruginosa) is a leading cause of death in patients with cystic fibrosis (CF). Immunobiology of P. aeruginosa infection is complex and not well understood. Chronically infected CF patients generate high levels of antibodies to P. aeruginosa, but this response does not lead to clinical improvement. Therefore, additional studies aimed at identification and understanding of the host factors that influence naturally occurring immune responses to P. aeruginosa are needed. In this investigation, we evaluated the contribution of immunoglobulin GM (γ marker) and KM (κ marker) allotypes to the antibody responses to P. aeruginosa lipopolysaccharide (LPS) O1, O6, O11, and alginate antigens and the broadly-conserved surface polysaccharide expressed by many microbial pathogens, poly-N-acetyl-D-glucosamine (PNAG), in 58 chronically infected CF patients.

METHODS: IgG1 markers GM 3 and 17 and IgG2 markers GM 23- and 23+ were determined by a pre-designed TaqMan® genotyping assay. The κ chain determinants KM 1 and 3 were characterized by PCR-RFLP. Antibodies to the LPS O antigens, alginate, and PNAG were measured by an ELISA.

RESULTS: Several significant associations were noted with KM alleles. Particular KM 1/3 genotypes were individually and epistatically (with GM 3/17) associated with the level of IgG antibodies to O1, O11, alginate, and PNAG antigens.

CONCLUSIONS: Immunoglobulin GM and KM genotypes influence the magnitude of humoral immunity to LPS O, alginate, and PNAG antigens. These results, if confirmed in a larger study population, will be helpful in devising novel immunotherapeutic approaches against P. aeruginosa.

PMID:34246573 | DOI:10.1016/j.jcf.2021.06.011

J Allergy Clin Immunol Pract. 2021 Jul;9(7):2562-2566. doi: 10.1016/j.jaip.2021.04.025. Epub 2021 May 4.

NO ABSTRACT

PMID:34246432 | DOI:10.1016/j.jaip.2021.04.025

Chest. 2021 Jul;160(1):e25-e28. doi: 10.1016/j.chest.2021.01.042.

ABSTRACT

A 19-year-old woman presented to pulmonary clinic with recurrent episodes of fevers and productive cough over the last 2 years. She was diagnosed with several episodes of respiratory infection that required antibiotic therapy. Her symptoms improved transiently after antibiotic therapy. However, symptoms continued to recur every 1 to 2 months. She denied any close TB contacts or travel outside the United States. She was a nonsmoker and had no history of immunodeficiency. There was no history of cystic fibrosis or any foreign body aspiration.

PMID:34246384 | DOI:10.1016/j.chest.2021.01.042

Lancet. 2021 Jul 10;398(10295):156. doi: 10.1016/S0140-6736(21)01048-5.

NO ABSTRACT

PMID:34246348 | DOI:10.1016/S0140-6736(21)01048-5

Pediatr Pulmonol. 2021 Jul 10. doi: 10.1002/ppul.25572. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis-related diabetes (CFRD) is a risk factor for adverse clinical outcomes including poor nutritional status, deterioration in lung functions, and increased mortality. The association between nutritional status between 5 and 10 years of age and later diagnosis of CFRD is not known.

METHODS: A retrospective chart review was performed for our patients with CF between 10 to18 years. Data was collected at age 5 and 10 years. Comparison made between patients with and without CFRD.

RESULTS: Two groups were comparable for age and sex. At age 5, groups had no differences in weight, height, and BMI. At age 10, the CFRD group had a lower body mass index (40.2 ± 24.7 vs. 61.5 ± 22.5 percentile, p=0.02). Spirometry was similar between groups at 5 and 10 years. Patients with CFRD had lower growth velocity (5 ± 0.9 vs. 5.7 ± 0.9 cm/yr, p=0.03) and reduced weight gain rate (2.2 ± 0.9 vs. 3.2 ± 1.2 kg/yr, p=0.03) compared to patients without CFRD between 5 and 10 years. Patients with a weight gain less than 2.5 kg/year between 5 and 10 years were nine times more likely to develop CFRD in adolescence (Unadjusted Odds Ratio: 8.9; 95% CI:1.4, 47.2; p=0.01).

CONCLUSION: Patients who later developed CFRD had significantly lower weight gain rate and height growth between 5 and 10 years of age than those without diabetes. Close monitoring of nutritional status in before age 10 years may help identify CF patients at-risk of developing CFRD. This article is protected by copyright. All rights reserved.

PMID:34245493 | DOI:10.1002/ppul.25572

Hum Mol Genet. 2021 Jul 10:ddab191. doi: 10.1093/hmg/ddab191. Online ahead of print.

ABSTRACT

The causative gene in cystic fibrosis was identified in 1989, three years before the publication of the first issue of Human Molecular Genetics. CFTR was among the first genes underlying a common inherited disorder to be cloned, and hence its subsequent utilization towards a cure for CF provides a roadmap for other monogenic diseases. Over the past 30 years the advances that built upon knowledge of the gene and the CFTR protein to develop effective therapeutics have been remarkable, and yet the setbacks have also been challenging. Technological progress in other fields has often circumvented the barriers. This review focuses on key aspects of CF diagnostics and current approaches to develop new therapies for all CFTR mutations. It also highlights the major research advances that underpinned progress towards treatments, and considers the remaining obstacles.

PMID:34245257 | DOI:10.1093/hmg/ddab191

Eur Respir J. 2021 Jul 8;58(1):2100236. doi: 10.1183/13993003.00236-2021. Print 2021 Jul.

NO ABSTRACT

PMID:34244301 | DOI:10.1183/13993003.00236-2021

PLoS One. 2021 Jul 9;16(7):e0254353. doi: 10.1371/journal.pone.0254353. eCollection 2021.

ABSTRACT

Neutrophils are recognized for their role in host defense against pathogens as well as inflammatory conditions mediated through many mechanisms including neutrophil extracellular trap (NET) formation and generation of reactive oxygen species (ROS). NETs are increasingly appreciated as a major contributor in autoimmune and inflammatory diseases such as cystic fibrosis. Myeloperoxidase (MPO), a key neutrophil granule enzyme mediates generation of hypochlorous acid which, when extracellular, can cause host tissue damage. To better understand the role played by neutrophils in inflammatory diseases, we measured and modulated myeloperoxidase activity and NETs in vivo, utilizing a rat peritonitis model. RLS-0071 is a 15 amino acid peptide that has been shown to inhibit myeloperoxidase activity and NET formation in vitro. The rat model of inflammatory peritonitis was induced with intraperitoneal injection of either P. aeruginosa supernatant or immune-complexes. After euthanasia, a peritoneal wash was performed and measured for myeloperoxidase activity and free DNA as a surrogate for measurement of NETs. P. aeruginosa supernatant caused a 2-fold increase in MPO activity and free DNA when injected IP. Immune-complexes injected IP increased myeloperoxidase activity and free DNA 2- fold. RLS-0071 injection decreased myeloperoxidase activity and NETs in the peritoneal fluid generally to baseline levels in the presence of P. aeruginosa supernatant or immune-complexes. Taken together, RLS-0071 demonstrated the ability to inhibit myeloperoxidase activity and NET formation in vivo when initiated by different inflammatory stimuli including shed or secreted bacterial constituents as well as immune-complexes.

PMID:34242348 | DOI:10.1371/journal.pone.0254353

Pediatr Pulmonol. 2021 Jul 9. doi: 10.1002/ppul.25569. Online ahead of print.

ABSTRACT

OBJECTIVES: The primary objective of this study was to compare the therapeutic predictive value of area under the curve (AUC24 ) versus maximum concentration (Cmax ) in cystic fibrosis (CF) patients receiving intravenous (IV) tobramycin for a Pseudomonas aeruginosa (PsA) acute pulmonary exacerbation (APE). Acute kidney injury (AKI) incidence and the relationship between time undetectable and efficacy were also assessed.

METHODS: A retrospective review was conducted in patients aged at least one month with a diagnosis of CF receiving IV tobramycin for treatment of a PsA APE and admitted to the University of Kentucky between August 2015 and August 2019. Patients were excluded if they had no growth of PsA on sputum culture or if two post-dose tobramycin levels were not obtained following a dose adjustment of ≥20%.

RESULTS: A total of 44 pediatric and 107 adult patient encounters met inclusion criteria. In patients with therapeutic success (n=91), 75.8% had an AUC24 ≥80 and 80.3% had a Cmax ≥8 times the highest PsA minimal inhibitory concentration (MIC). There was a significant correlation between AUC24 and Cmax (r[149] =0.727; p<0.001). AKI incidence was significantly higher in patients receiving IV tobramycin dosed multiple times daily versus at least every 24 hours (χ2 [1,151] =3.9; p=0.047).

CONCLUSIONS: The results of this study indicate that both AUC24 and Cmax serve as relatively accurate predictors of tobramycin efficacy. Additionally, given the significant increase in incidence of AKI, multi-daily dosing of IV tobramycin should be avoided in pediatric and adult patients with CF. This article is protected by copyright. All rights reserved.

PMID:34241975 | DOI:10.1002/ppul.25569

Elife. 2021 Jul 9;10:e65355. doi: 10.7554/eLife.65355. Online ahead of print.

ABSTRACT

Bacteriophages can be trapped in the matrix of bacterial biofilms, such that the cells inside them are protected. It is not known whether these phages are still infectious and whether they pose a threat to newly arriving bacteria. Here we address these questions using Escherichia coli and its lytic phage T7. Prior work has demonstrated that T7 phages are bound in the outermost curli polymer layers of the E. coli biofilm matrix. We show that these phages do remain viable and can kill colonizing cells that are T7-susceptible. If cells colonize a resident biofilm before phages do, we find that they can still be killed by phage exposure if it occurs soon thereafter. However, if colonizing cells are present on the biofilm long enough before phage exposure, they gain phage protection via envelopment within curli-producing clusters of the resident biofilm cells.

PMID:34240700 | DOI:10.7554/eLife.65355

Pulm Med. 2021 Jun 18;2021:5488591. doi: 10.1155/2021/5488591. eCollection 2021.

ABSTRACT

The S100 protein family consists of over 20 members in humans that are involved in many intracellular and extracellular processes, including proliferation, differentiation, apoptosis, Ca2 + homeostasis, energy metabolism, inflammation, tissue repair, and migration/invasion. Although there are structural similarities between each member, they are not functionally interchangeable. The S100 proteins function both as intracellular Ca2+ sensors and as extracellular factors. Dysregulated responses of multiple members of the S100 family are observed in several diseases, including the lungs (asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, cystic fibrosis, pulmonary hypertension, and lung cancer). To this degree, extensive research was undertaken to identify their roles in pulmonary disease pathogenesis and the identification of inhibitors for several S100 family members that have progressed to clinical trials in patients for nonpulmonary conditions. This review outlines the potential role of each S100 protein in pulmonary diseases, details the possible mechanisms observed in diseases, and outlines potential therapeutic strategies for treatment.

PMID:34239729 | PMC:PMC8214497 | DOI:10.1155/2021/5488591

Front Immunol. 2021 Jun 22;12:695954. doi: 10.3389/fimmu.2021.695954. eCollection 2021.

ABSTRACT

Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder caused by hypersensitivity to Aspergillus which colonizes the airways of patients with asthma and cystic fibrosis. Its diagnosis could be difficult in some cases due to atypical presentations especially when there is no medical history of asthma. Treatment of ABPA is frequently associated to side effects but cumulated drug toxicity due to different molecules is rarely reported. An accurate choice among the different available molecules and effective on ABPA is crucial. We report a case of ABPA in a woman without a known history of asthma. She presented an acute bronchitis with wheezing dyspnea leading to an acute respiratory failure. She was hospitalized in the intensive care unit. The bronchoscopy revealed a complete obstruction of the left primary bronchus by a sticky greenish material. The culture of this material isolated Aspergillus fumigatus and that of bronchial aspiration fluid isolated Pseudomonas aeruginosa. The diagnosis of ABPA was based on elevated eosinophil count, the presence of specific IgE and IgG against Aspergillus fumigatus and left segmental collapse on chest computed tomography. The patient received an inhaled treatment for her asthma and a high dose of oral corticosteroids for ABPA. Her symptoms improved but during the decrease of corticosteroids, the patient presented a relapse. She received itraconazole in addition to corticosteroids. Four months later, she presented a drug-induced hepatitis due to itraconazole which was immediately stopped. During the monitoring of her asthma which was partially controlled, the patient presented an aseptic osteonecrosis of both femoral heads that required surgery. Nine months after itraconazole discontinuation, she presented a second relapse of her ABPA. She received voriconazole for nine months associated with a low dose of systemic corticosteroid therapy with an improvement of her symptoms. After discontinuation of antifungal treatment, there was no relapse for one year follow-up.

PMID:34239516 | PMC:PMC8259593 | DOI:10.3389/fimmu.2021.695954