Aspergillus-Associated Endophenotypes in Bronchiectasis

2021 ◽  
Vol 42 (04) ◽  
pp. 556-566
Author(s):  
Tavleen Kaur Jaggi ◽  
Soo Kai Ter ◽  
Micheál Mac Aogáin ◽  
Sanjay H. Chotirmall

AbstractBronchiectasis is a chronic condition of global relevance resulting in permanent and irreversible structural airway damage. Bacterial infection in bronchiectasis is well studied; however, recent molecular studies identify fungi as important pathogens, either independently or in association with bacteria. Aspergillus species are established fungal pathogens in cystic fibrosis and their role is now increasingly being recognized in noncystic fibrosis bronchiectasis. While the healthy airway is constantly exposed to ubiquitously present Aspergillus conidia in the environment, anatomically damaged airways appear more prone to colonization and subsequent infection by this fungal group. Aspergilli possess diverse immunopathological mechanistic capabilities and when coupled with innate immune defects in a susceptible host, such as that observed in bronchiectasis, it may promote a range of clinical manifestations including sensitization, allergic bronchopulmonary aspergillosis, Aspergillus bronchitis, and/or invasive aspergillosis. How such clinical states influence “endophenotypes” in bronchiectasis is therefore of importance, as each Aspergillus-associated disease state has overlapping features with bronchiectasis itself, and can evolve, depending on underlying host immunity from one type into another. Concurrent Aspergillus infection complicates the clinical course and exacerbations in bronchiectasis and therefore dedicated research to better understand the Aspergillus-host interaction in the bronchiectasis airway is now warranted.

2020 ◽  
Vol 21 (6-8) ◽  
pp. 409-419
Author(s):  
Irfan Hussain ◽  
Nashaiman Pervaiz ◽  
Abbas Khan ◽  
Shoaib Saleem ◽  
Huma Shireen ◽  
...  

AbstractThe outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading fast worldwide. There is a pressing need to understand how the virus counteracts host innate immune responses. Deleterious clinical manifestations of coronaviruses have been associated with virus-induced direct dysregulation of innate immune responses occurring via viral macrodomains located within nonstructural protein-3 (Nsp3). However, no substantial information is available concerning the relationship of macrodomains to the unusually high pathogenicity of SARS-CoV-2. Here, we show that structural evolution of macrodomains may impart a critical role to the unique pathogenicity of SARS-CoV-2. Using sequence, structural, and phylogenetic analysis, we identify a specific set of historical substitutions that recapitulate the evolution of the macrodomains that counteract host immune response. These evolutionary substitutions may alter and reposition the secondary structural elements to create new intra-protein contacts and, thereby, may enhance the ability of SARS-CoV-2 to inhibit host immunity. Further, we find that the unusual virulence of this virus is potentially the consequence of Darwinian selection‐driven epistasis in protein evolution. Our findings warrant further characterization of macrodomain-specific evolutionary substitutions in in vitro and in vivo models to determine their inhibitory effects on the host immune system.


2020 ◽  
Vol 10 (01) ◽  
pp. e137-e140
Author(s):  
Mosaad Abdel-Aziz ◽  
Nada M. Abdel-Aziz ◽  
Dina M. Abdel-Aziz ◽  
Noha Azab

AbstractThe clinical manifestations of novel coronavirus disease 2019 (COVID-19) vary from mild flu-like symptoms to severe fatal pneumonia. However, children with COVID-19 may be asymptomatic or may have mild clinical symptoms. The aim of this study was to investigate clinical features of pediatric COVID-19 and to search for the factors that may mitigate the disease course. We reviewed the literature to realize the clinical features, laboratory, and radiographic data that may be diagnostic for COVID-19 among children. Also, we studied the factors that may affect the clinical course of the disease. Fever, dry cough, and fatigue are the main symptoms of pediatric COVID-19, sometimes flu-like symptoms and/or gastrointestinal symptoms may be present. Although some infected children may be asymptomatic, a recent unusual hyperinflammatory reaction with overlapping features of Kawasaki's disease and toxic shock syndrome in pediatric COVID-19 has been occasionally reported. Severe acute respiratory syndrome-coronvirus-2 (SARS-CoV-2) nucleic acid testing is the corner-stone method for the diagnosis of COVID-19. Lymphocyte count and other inflammatory markers are not essentially diagnostic; however, chest computed tomography is highly specific. Factors that may mitigate the severity of pediatric COVID-19 are home confinement with limited children activity, trained immunity caused by compulsory vaccination, the response of the angiotensin-converting enzyme 2 receptors in children is not the same as in adults, and that children are less likely to have comorbidities. As infected children may be asymptomatic or may have only mild respiratory and/or gastrointestinal symptoms that might be missed, all children for families who have a member diagnosed with COVID-19 should be investigated.


2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 414.2-415
Author(s):  
X. Huang ◽  
T. W. Li ◽  
J. Chen ◽  
Z. Huang ◽  
S. Chen ◽  
...  

Background:Ankylosing spondylitis (AS) is a type of common, chronic inflammatory disease that compromises the axial skeleton and sacroiliac joints, causing inflammatory low back pain and progressive spinal stiffness, over time some patients develop spinal immobility and ankylosis which can lead to a decrease in quality of life. The last few decades, evidence has clearly indicated that neutrophil also plays key roles in the progression of AS. However, the immunomodulatory roles and mechanisms of neutrophils in AS are poorly understood. T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3) has been reported as an important regulatory molecule, expressed and regulated on different innate immune cells, plays a pivotal role in several autoimmunity diseases. Recent study indicates that Tim3 is also expressed on neutrophils. However, the frequency and roles of Tim3-expressing neutrophils in AS was not clear.Objectives:In this study, we investigated the expression of Tim3 on neutrophils in AS patients and explored the correlation between the level of Tim3-expressing neutrophils and the disease activity and severity of AS.Methods:Patients with AS were recruited from Guangdong Second Provincial General Hospital (n=62). Age/sex-matched volunteers as Healthy controls (HC) (n=39). The medical history, clinical manifestations, physical examination, laboratory measurements were recorded. The expression of costimulatory molecules including programmed death 1 (PD-1), Tim-3 on neutrophils were determined by flow cytometry. The mRNA expression of PD-1 and Tim-3 was determined by real-time PCR. The levels of Tim3-expressing neutrophils in AS patients were further analyzed for their correlation with the markers of inflammation such as ESR,CRP,WBC and neutrophil count(NE), as well as disease activity and severity of AS. The expression of Tim3 on neutrophils was monitored during the course of treatment (4 weeks).Results:The expression of Tim3 on neutrophils in patients with AS was increased compared to the HC (Figure 1A). However, significant difference was observed in the frequency of PD-1-expressing neutrophils between AS patients and HC (Figure 1B). The expression analysis of Tim-3 mRNA, but not PD-1, confirmed the results obtained from flow cytometry (Figure 1C). The level of Tim3-expressing neutrophils in patients with AS showed an positive correlation with ESR, CRP and ASAS-endorsed disease activity score (ASDAS) (Figure 1D). Moreover, the frequency of Tim3-expressing neutrophils in active patients(ASDAS≥1.3) was increased as compare with the inactive patients (ASDAS<1.3) (Figure 1E). As shown in Figure 1F, the frequency of Tim3-expressing neutrophils decreased after the treatment.Conclusion:Increased Tim-3 expression on neutrophils may be a novel indicator to assess disease activity and severity in AS, which may serves as a negative feedback mechanism preventing potential tissue damage caused by excessive inflammatory responses in AS patients.References:[1]Han, G., Chen, G., Shen, B. & Li, Y., Tim-3: an activation marker and activation limiter of innate immune cells. FRONT IMMUNOL 4 449 (2013).[2]Vega-Carrascal, I. et al., Galectin-9 signaling through TIM-3 is involved in neutrophil-mediated Gram-negative bacterial killing: an effect abrogated within the cystic fibrosis lung. J IMMUNOL 192 2418 (2014).Figure 1.(A,B)The expression of Tim3 and PD-1 on neutrophils in AS and HC were determined by flow cytometry.(C) The expression of Tim3 and PD-1 on neutrophils in AS and HC were determined by RT-PCR.(D)The correction between Tim3-expressing neutrophils and ESR,CRP,ASDAS.(E) The expression of Tim3 on neutrophils in active and inactive patients.(F) Influence of treatment on the frequency of Tim3-expressing neutrophils.Disclosure of Interests:None declared


2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1424.3-1425
Author(s):  
I. Kirillova ◽  
D. Novikova ◽  
T. Popkova ◽  
Y. Gorbunova ◽  
E. Markelova ◽  
...  

Background:Objectives:to evaluate the effect of antirheumatic therapy according to the “treat to target” strategy on the course of chronic heart failure (CHF) in patients with early RA.Methods:The study included 22 patients CHF with valid diagnosis of RA (criteria ACR / EULAR, 2010), 17 (77%) of women, median (Me) age - 60 years, Me disease duration - 7 months; IgM seropositive for rheumatoid factor 10 (45%) and / or antibodies to the cyclic citrulline peptide 22 (100%), DAS28-5.6 [4,8;6,5]. CHF verified in accordance the recommendations for the diagnosis and treatment of CHF Society of Specialists in Heart Failure (2013). The concentration of NT-proBNP was determined by electrochemiluminescence. For all patients was started methotrexate (MT) therapy with a rapid increase in the dose to 30 mg per week subcutaneously. If the MT was not effective enough, after 3 months a biological Disease-Modifying Anti-Rheumatic Drug (bDMARDs) was added to the therapy, predominantly TNF-alpha inhibitors. After 18 months, 10 (45%) patients were in remission and low disease activity, 6 (60%) of patients underwent MT therapy in combination with bDMARDs.Results:In baseline CHF with preserved EF was revealed in 21 (95%) patients, in 1 patient - CHF with reduced EF. After 18 months there was a positive dynamics of improvement of clinical symptoms, echocardiographic indicators (decrease the size of the left atrium (LА) and the index of end-systolic volume of LА, IVRT, E’ LV), diastolic function of the left ventricle (LV). There was no decompensation of CHF. LV diastolic function normalized in 7 (32%) patients who reached the target level of blood pressure, remission (n = 5) and low (n = 2) disease activity, mainly in the treatment of MT and bDMARDs. In patients with RA and CHF, the level of NT-proBNP decreased from 192.2 [151.4; 266.4] to 114.0 [90.4; 163.4] pg / ml (p <0.001), normalized in 16 of 22 (73%) patients (p <0.001) with remission or low RA activity. In 5 (22%) patients, the clinical manifestations of CHF regressed, LV diastolic function and NT-proBNP level normalized.Conclusion:In patients with early RA and CHF anti-rheumatic therapy improves the clinical course of CHF. There were an improvement in the clinical course of CHF, diastolic function of the left ventricle and a decrease in NT-proBNP.Disclosure of Interests:None declared


2020 ◽  
pp. 72-79
Author(s):  
I. V. Аndrusovich

The longer the COVID−19 coronavirus pandemic lasts, the more information about its clinical manifestations is accumulated. The incubation period of COVID−19 ranges from 2 to 14 days, rarely up to 3 weeks, but in a significant number of cases an infection is not accompanied with the appearance of clinical symptoms. Currently, the following variants of the clinical course of COVID−19 can be identified as follows: viral load; subclinical; slight; uncomplicated with damage to only the upper respiratory tract; mild pneumonia, severe pneumonia, acute respiratory distress syndrome, etc. The clinical course of COVID−19 depends on the severity, the criteria of which are the intoxication manifestation, the degree of fever and the dominant syndrome. Mild / moderate forms are manifested by frequent increase in body temperature up to 38 ° C, respiratory symptoms, headache, myalgias, palpitations and general malaise. Patients stop distinguishing smells and feel the taste of food. Approximately from the 7th to the 9th days of the disease there are problems with breathing, which indicates the impairment of the lower respiratory tract and the beginning of the second phase of the disease, and its course is regarded as severe. Severe forms of the disease can also be manifested by impaired coordination of movements, slurred speech. In 1 to 4 % of patients there is developed the psychosis in the form of hallucinations. In the elderly, COVID−19 may be accompanied by delirium, lowering blood pressure. The risks of adverse disease are associated with somatic diseases: cardiovascular and nervous systems, respiratory tract, hormonal disorders, etc. Otitis, sinusitis, sepsis, bronchopulmonary infection, thrombosis, myocarditis etc. can be the complications of COVID−19. Computer tomography is an instrumental test that demonstrates the damage of lungs with coronavirus and allows to assess its severity. Key words: coronavirus infection, COVID−19, clinical variants, severity, pneumonia, acute respiratory distress syndrome.


2018 ◽  
Vol 3 (3) ◽  
pp. 104 ◽  
Author(s):  
Valentine Erulu ◽  
Mitchel Okumu ◽  
Francis Ochola ◽  
Joseph Gikunju

The black mamba (Dendroaspis polylepis) ranks consistently as one of the most revered snakes in sub-Saharan Africa. It has potent neurotoxic venom, and envenomation results in rapid onset and severe clinical manifestations. This report describes the clinical course and reversal of effects of black mamba envenomation in a 13-year-old boy in the Jimba area of Malindi. The victim presented to Watamu Hospital, a low resource health facility with labored breathing, frothing at the mouth, severe ptosis and pupils non-responsive to light. His blood pressure was unrecordable, heart rate was 100 beats per minute but thready, his temperature was 35.5 °C, and oxygen saturation was 83%. Management involved suction to clear salivary secretions, several hours of mechanical ventilation via ambu-bagging, oxygen saturation monitoring, and the use of South African Vaccine Producers (SAVP) polyvalent antivenom. Subcutaneous adrenaline was used to stave off anaphylaxis. The victim went into cardiac arrest on two occasions and chest compressions lasting 3–5 min was used to complement artificial ventilation. Hemodynamic instability was corrected using IV infusion of ringers lactate and normal saline (three liters over 24 h). Adequate mechanical ventilation and the use of specific antivenom remain key in the management of black mamba envenomation.


2020 ◽  
Author(s):  
Shouyong Ju ◽  
Hanqiao Chen ◽  
Shaoying Wang ◽  
Jian Lin ◽  
Raffi V Aroian ◽  
...  

AbstractPathogen recognition and triggering pattern of host innate immune system is critical to understanding pathogen-host interaction. It is generally accepted that the microbial infection can be recognized by host via pattern-triggered immunity (PTI) or effector-triggered immunity (ETI) responses. Recently, non-PRR-mediated cellular surveillance systems have been reported as an important supplement strategy to PTI and ETI responses. However, the mechanism of how surveillance systems sense pathogens and trigger innate immune responses is largely unknown. In the present study, using Bacillus thuringiensis-Caenorhabditis elegans as a model, we found a new approach for surveillance systems to sense the pathogens through no-PPRs patterns. We reported C. elegans can monitor intracellular energy status through the mitochondrial surveillance system to triggered innate immune responses against pathogenic attack via AMP-activated protein kinase (AMPK). Consider that the mitochondria surveillance systems and AMPK are conserved components from worms to mammals, our study suggests that disrupting mitochondrial homeostasis to activate the immune system through AMPK-dependent pathways may widely existing in animals.


Author(s):  
О.Г. Новоселова ◽  
Е.И. Кондратьева ◽  
Н.В. Петрова ◽  
В.Д. Шерман ◽  
А.Ю. Воронкова ◽  
...  

Тяжесть клинических проявлений муковисцидоза может быть обусловлена действием генов-модификаторов. Выяснение причин неэффективности терапии и нежелательных побочных реакций, определение факторов риска позволит улучшить прогноз для данной категории больных. Исследованы ассоциации 18 полиморфных вариантов 10 генов ферментов первой и второй фазы биотрансформации ксенобиотиков: CYP2C9 (c.430C>T, c.1075A> C), CYP2C19 (c.681G>A), CYP2D6 (1846G>A), CYP3A4 (c-392C>T), GSTT1 (del), GSTM1 (del), GSTP1 (c.313A>C), GCLC (TVR GAG, c.-129C>T), GCLM (c.-588C>T), NAT2 (c.282C>T, c.341T>C, c.434A>C, c.481C>T, c.590G>A, c.845A>C, c.857G>A) с тяжестью клинических проявлений муковисцидоза. CF clinical variability could be associated with interaction of modifier genes. Сlarification of the causes of treatment failure and adverse reactions, prediction of risk factors could improve the outcome of therapy. Association of 18 polymorphic variants of 10 genes of xenobiotic biotransformation: CYP2C9 (c.430C>T, c.1075A> C), CYP2C19 (c.681G>A), CYP2D6 (1846G>A), CYP3A4 (c-392C>T), GSTT1 (del), GSTM1 (del), GSTP1 (c.313A>C), GCLC (TVR GAG, c.-129C>T), GCLM (c.-588C>T), NAT2 (c.282C>T, c.341T>C, c.434A>C, c.481C>T, c.590G>A, c.845A>C, c.857G>A) with severity of clinical manifestations were analyzed in 333 CF patients.


1979 ◽  
Vol 88 (4) ◽  
pp. 486-494 ◽  
Author(s):  
Michael Setzen ◽  
Steven Sobol ◽  
James M. Toomey

The clinical manifestations of 29 recently encountered sarcomas of the head and neck were analyzed in an attempt to define more accurately the diagnostic characteristics and therapeutic responses of these unusual tumors. The host factors of age, sex distribution, race, habits and associated features differ sufficiently to distinguish the sarcoma from the carcinoma population. In addition, the clinical course of sarcoma patients as monitored by mode of presentation, site of involvement, tumor histology, diagnostic features and certain elements of management and outcome, further indicates that these tumors can be defined and managed as a distinct group of lesions. A review of the recent literature supports the major conclusions of this study.


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