Publications by authors named "I Ferrarotti"

72 Publications

The Importance of N186 in the Alpha-1-Antitrypsin Shutter Region Is Revealed by the Novel Bologna Deficiency Variant.

Int J Mol Sci 2021 May 26;22(11). Epub 2021 May 26.

Department of Molecular and Translational Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.

Alpha-1-antitrypsin (AAT) deficiency causes pulmonary disease due to decreased levels of circulating AAT and consequently unbalanced protease activity in the lungs. Deposition of specific AAT variants, such as the common Z AAT, within hepatocytes may also result in liver disease. These deposits are comprised of ordered polymers of AAT formed by an inter-molecular domain swap. The discovery and characterization of rare variants of AAT and other serpins have historically played a crucial role in the dissection of the structural mechanisms leading to AAT polymer formation. Here, we report a severely deficient shutter region variant, Bologna AAT (N186Y), which was identified in five unrelated subjects with different geographical origins. We characterized the new variant by expression in cellular models in comparison with known polymerogenic AAT variants. Bologna AAT showed secretion deficiency and intracellular accumulation as detergent-insoluble polymers. Extracellular polymers were detected in both the culture media of cells expressing Bologna AAT and in the plasma of a patient homozygous for this variant. Structural modelling revealed that the mutation disrupts the hydrogen bonding network in the AAT shutter region. These data support a crucial coordinating role for asparagine 186 and the importance of this network in promoting formation of the native structure.
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http://dx.doi.org/10.3390/ijms22115668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198886PMC
May 2021

Mesenchymal Stromal Cell Secretome for Post-COVID-19 Pulmonary Fibrosis: A New Therapy to Treat the Long-Term Lung Sequelae?

Cells 2021 05 14;10(5). Epub 2021 May 14.

Center for Diagnosis of Inherited Alpha1-Antitrypsin Deficiency, Department of Internal Medicine and Therapeutics, Pneumology Unit IRCCS San Matteo Hospital Foundation, University of Pavia, 27100 Pavia, Italy.

To date, more than 100 million people worldwide have recovered from COVID-19. Unfortunately, although the virus is eradicated in such patients, fibrotic irreversible interstitial lung disease (pulmonary fibrosis, PF) is clinically evident. Given the vast numbers of individuals affected, it is urgent to design a strategy to prevent a second wave of late mortality associated with COVID-19 PF as a long-term consequence of such a devastating pandemic. Available antifibrotic therapies, namely nintedanib and pirfenidone, might have a role in attenuating profibrotic pathways in SARS-CoV-2 infection but are not economically sustainable by national health systems and have critical adverse effects. It is our opinion that the mesenchymal stem cell secretome could offer a new therapeutic approach in treating COVID-19 fibrotic lungs through its anti-inflammatory and antifibrotic factors.
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http://dx.doi.org/10.3390/cells10051203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155949PMC
May 2021

COVID-19 infection in severe Alpha 1-antitrypsin deficiency: Looking for a rationale.

Respir Med 2021 07 30;183:106440. Epub 2021 Apr 30.

Centre for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Laboratory of Biochemistry and Genetics, Institute for Respiratory Disease, Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

The clinical manifestations of COVID-19 are heterogeneous: 46.4% of patients admitted into hospital reported to have at least one comorbidity. Comorbidities such as COPD, diabetes, hypertension and malignancy predispose patients with Covid-19 to adverse clinical outcomes. Alpha 1-antitrypsin deficiency (AATD) is a genetic disorder caused by pathological mutation(s) in the SERPINA1 gene resulting in an imbalance in proteinase activity which may lead to premature emphysema and COPD. Our aim was to investigate whether people with severe AAT deficiency (AATD) have an increased risk of (severe) COVID-19 infection. We collected data on COVID-19 symptoms, laboratory-confirmed infection, hospitalization and treatment by means of a telephone survey, directly administered to Italian severe AATD subjects in May 2020. We then compared our findings with data collected by the Istituto Superiore di Sanità on the total population in Italy during the same period. We found an higher frequency of SARS-CoV-2 infection in our cohort (3.8%) compared to national data regarding infection, thus giving severe AATD a relative risk of 8. 8 (95%CI 5.1-20,0; p<0.0001) for symptomatic SARS-CoV-2 infection. Moreover, the relative risk (RR) was higher in AATD patients with pre-existing lung diseases (RR 13.9; 95%CI 8.0-33.6; p<0.001), but with a similar death rate (1 in 8, 12.5%) compared to the general population (13.9%; RR 0.9). These preliminary findings highlight the importance of close surveillance in the spread of COVID-19 in patients with severe AATD and underlines the need for further studies into the role of the antiprotease shield in preventing SARS-Cov-2 infection.
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http://dx.doi.org/10.1016/j.rmed.2021.106440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086383PMC
July 2021

Alpha-1 Antitrypsin Screening in a Selected Cohort of Patients Affected by Chronic Pulmonary Diseases in Naples, Italy.

J Clin Med 2021 Apr 7;10(8). Epub 2021 Apr 7.

Unit of Respiratory Physiopathology, Department of Critic Area, Monaldi Hospital, 80131 Naples, Italy.

Introduction: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition associated with several respiratory diseases in patients with severe protein deficiency. AATD is often late diagnosed or underdiagnosed. Diagnosis frequently occurs in patients with chronic obstructive pulmonary disease and emphysema characterized by frequent exacerbations and over ten years' duration. The purpose of this study was to evaluate the incidence of alpha-1 antitrypsin deficiency in patients with the chronic pulmonary disease after a thorough screening in the city of Naples in southern Italy.

Materials And Methods: Two hundred patients suffering from respiratory pathology (chronic obstructive pulmonary disease (COPD), emphysema, asthma, or bronchiectasis) were examined and evaluated in our outpatients' clinic and tested for serum levels of AAT. Patients who had a respiratory disease suspected of AATD and/or serum AAT < 120 mg/dL underwent genetic testing. Genetic screening was performed on samples from 141 patients.

Results: A total of 36 patients had an intermediate deficiency of AAT levels. Among them, 8 were PI*MZ, 6 were PI*MS and 22 had rare pathological mutations. Five patients had a severe AATD, all were composite heterozygous with S or Z allele, while the other allele had a rare pathological mutation.

Conclusions: The incidence of genetic defects as AATD in the population of patients affected by chronic respiratory disorders is always a matter of discussion because of the frequent interaction between genes and environmental causes. In our series, numerous rare variants and compound heterozygosity have been described. No homozygous patients have been described. The present is one of few studies available on the incidence of rare variants in the geographic area of the city of Naples. So, our results could be considered interesting not only to know the incidence of AATD and its related rare mutations but also to support early diagnosis and treatments for patients with chronic pulmonary disease and frequent exacerbation and to fight the association with environmental causes of pulmonary damages as smoking.
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http://dx.doi.org/10.3390/jcm10081546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067626PMC
April 2021

Comparison of different algorithms in laboratory diagnosis of Alpha1-antitrypsin deficiency.

Clin Chem Lab Med 2021 Mar 5. Epub 2021 Mar 5.

Centre for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Laboratory of Biochemistry and Genetics, Institute for Respiratory Disease, Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.

Objectives: Alpha1-antitrypsin deficiency (AATD) is an inherited condition that predisposes individuals to an increased risk of developing lung and liver disease. Even though AATD is one of the most widespread inherited diseases in Caucasian populations, only a minority of affected individuals has been detected. Whereas methods have been validated for AATD testing, there is no universally-established algorithm for the detection and diagnosis of the disorder. In order to compare different methods for diagnosing AATD, we carried out a systematic review of the literature on AATD diagnostic algorithms.

Methods: Complete biochemical and molecular analyses of 5,352 samples processed in our laboratory were retrospectively studied using each of the selected algorithms.

Results: When applying the diagnostic algorithms to the same samples, the frequency of False Negatives varied from 1.94 to 12.9%, the frequency of True Negatives was 62.91% for each algorithm and the frequency of True Positives ranged from 24.19 to 35.15%. We, therefore, highlighted some differences among Negative Predictive Values, ranging from 0.83 to 0.97. Accordingly, the sensitivity of each algorithm ranged between 0.61 and 0.95. We also postulated 1.108 g/L as optimal AAT cut-off value, in absence of inflammatory status, which points to the possible presence of genetic AATD.

Conclusions: The choice of the diagnostic algorithm has a significant impact on the correct diagnosis of AATD, which is essential for appropriate treatment and medical care. The fairly large number of possible false negative diagnoses revealed by the present paper should also warn clinicians of negative results in patients with clinically-suspected AATD.
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http://dx.doi.org/10.1515/cclm-2020-1881DOI Listing
March 2021