Prolonged Disease Course of COVID-19 in a Patient with CTLA-4 Haploinsufficiency.

Patients with primary immunodeficiencies are especially vulnerable to developing severe coronavirus disease 2019 (COVID-19) after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an important regulator of immune responses, and patients who suffer from CTLA4 haploinsufficiency have hyperactivation of effector T cells and infiltration of various organs. Overexpression of CTLA4 has been associated with a more severe disease course in patients with COVID-19, but there have only been a few reports on the disease course of COVID-19 in patients with CTLA4 haploinsufficiency. We report on a 33-year-old female with a history of immune thrombocytopenia, autoimmune haemolytic anaemia, granulomatous-lymphocytic interstitial lung disease, and common variable immunodeficiency who developed COVID-19. She was admitted and discharged from the hospital several times in the months thereafter and remained symptomatic and had a positive SARS-CoV-2 PCR for up to 137 days after the first symptoms. No SARS-CoV-2 antibodies were identified in the patients' serum. The disease was finally controlled after repeated infusions of convalescent plasma and treatment of concurrent bacterial and fungal infections. Genetic analysis revealed a likely pathogenic variant in CTLA4, and CTLA4 expression on regulatory T-cells was low. This case illustrates that patients with primary immunodeficiencies who have a protracted disease course of COVID-19 could benefit from convalescent plasma therapy.

Potential interstitial lung abnormalities on chest X-rays prior to symptoms of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) often has significant diagnostic delay. At present it is not well-known what factors associate with time to diagnosis and if this is associated with survival after the diagnosis. There has also been increasing attention for interstitial lung abnormalities on chest CT-scans. In this study we assessed what factors associate with time to diagnosis in patients with IPF, and whether early stages of pulmonary fibrosis can be seen on chest X-rays prior to the start of symptoms. METHODS: In this retrospective study, 409 Dutch patients with IPF were included. Clinical characteristics, including patient demographics, medical history, time of start of symptoms, time of first visit to pulmonologist, and any previous radiographic imaging reports were collected from patient records. RESULTS: In 96 patients (23%) a chest X-ray was available that had been made prior to the start of symptoms (median of 50.5 months (IQR 26.3-83.3 months)), and this showed potential interstitial lung abnormalities in 56 patients (58%). The median time from the start of symptoms to the final diagnosis was 24.0 months (interquartile range 9.0-48.0 months). In a multivariate model that corrected for diffusion capacity of the lung for carbon monoxide, forced vital capacity, sex, and age at diagnosis, time to diagnosis did not associate with survival (hazard ratio 1.051 (95% CI 0.800-1.380; p = 0.72)). CONCLUSIONS: There is a significant diagnostic delay for patients with IPF, but longer time to diagnosis did not associate with survival. Interstitial lung abnormalities were seen in more than half of the patients in whom a chest X-ray had been made prior to the start of symptoms. This illustrates that a computed tomography scan should be strongly considered for analysis of unexplained abnormalities on a chest X-ray. This could facilitate early detection and possibly prevention of disease progression for patients with pulmonary fibrosis.

Aetiology and prognosis of community-acquired pneumonia at the Adult University Teaching Hospital in Zambia.

BACKGROUND: Community-acquired pneumonia (CAP) is a frequent cause of death worldwide, and in sub-Saharan Africa particularly. Human immunodeficiency virus infection (HIV) and tuberculosis (TB) influence pathogen distribution in patients with CAP. Previous studies in sub-Saharan Africa have shown different frequencies of respiratory pathogens and antibiotic susceptibility compared to studies outside Africa. This study aimed to investigate the aetiology, presentation, and treatment outcomes of community-acquired pneumonia in adults at the University Teaching Hospital in Lusaka, Zambia. MATERIALS AND METHODS: Three-hundred-and-twenty-seven patients were enrolled at the University Teaching Hospital in Lusaka between March 2018 and December 2018. Clinical characteristics and laboratory data were collected. Sputum samples were tested by microscopy, other TB diagnostics, and bacterial cultures. RESULTS: The commonest presenting complaint was cough (96%), followed by chest pain (60.6%), fever (59.3%), and breathlessness (58.4%). The most common finding on auscultation of the lungs was chest crackles (51.7%). Seventy percent of the study participants had complaints lasting at least a week before enrolment. The prevalence of HIV was 71%. Sputum samples were tested for 286 patients. The diagnostic yield was 59%. The most common isolate was Mycobacterium tuberculosis (20%), followed by Candida species (18%), Klebsiella pneumoniae (12%), and Pseudomonas aeruginosa (7%). Streptococcus pneumoniae was isolated in only four patients. There were no statistically significant differences between the rates of specific pathogens identified in HIV-infected patients compared with the HIV-uninfected. Thirty-day mortality was 30%. Patients with TB had higher 30-day mortality than patients without TB (p = 0.047). CONCLUSION: Mycobacterium tuberculosis was the most common cause of CAP isolated in adults at the University Teaching Hospital in Lusaka, Zambia. Gram-negative organisms were frequently isolated. A high mortality rate was observed, as 30% of the followed-up study population had died after 30 days.

Serologic response to a third dose of an mRNA-based SARS-CoV-2 vaccine in lung transplant recipients.

Lung transplant recipients have an increased risk for severe coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A third dose of a SARS-CoV-2 vaccine has been recommended for all solid organ transplant recipients, but data from lung transplant recipients specifically are scarce. In this study, the serologic response to a third dose of an mRNA-based SARS-CoV-2 vaccine was measured in 78 lung transplant recipients. Sixty-two percent (n = 48) had a serological response to vaccination, which was significantly higher than after the second vaccine dose (27 patients (35%); p = 0.0013). A positive serologic response was associated with having had COVID-19 (p = 0.01), and higher serum IgG level and complement mannose binding lectin pathway activity prior to vaccination (p = 0.04 and p = 0.03, respectively). Serologic response was not associated with the dose of mycophenolate mofetil or prednisone or other immune status parameters. Eleven patients (14%) developed COVID-19 after the second or third vaccine dose, but this did not associate with serologic response after the second vaccine dose (9% in patients who developed COVID-19 versus 39% in patients who did not develop COVID-19 (p = 0.09)), or with serologic response above cut-off values associated with clinical protection in previous studies. In conclusion, the response to mRNA-based SARS-CoV-2 vaccines in lung transplant recipients improves significantly after a third vaccine dose. Factors associated with a positive serologic response are having had COVID-19 prior to vaccination, and serum IgG and complement mannose binding lectin pathway activity prior to vaccination. Serologic response did not associate with clinical protection against COVID-19 in this study.

Humoral Immune Status in Relation to Outcomes in Patients with Idiopathic Pulmonary Fibrosis.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a severe fibrotic lung disease, in which inflammation is thought to only play a secondary role. Several factors associated with acute exacerbations of IPF (AE-IPF) have been identified, including infections. This study investigated whether humoral immunodeficiency or increased inflammatory markers at diagnosis were associated with AE-IPF and survival. METHODS: Four-hundred-and-nine patients diagnosed with IPF between 2011 and 2017 were retrospectively included. Immune status investigations at diagnosis included measurement of serum immunoglobulins (available in 38%), leukocyte and lymphocyte subsets in blood and bronchoalveolar lavage (BAL) fluid (available in 58%), as well as response to pneumococcal vaccination (available in 64%). RESULTS: Serum immunoglobulins or IgG subclass levels were below the lower limit of normal in 6%. The response to pneumococcal vaccination was severely impaired in 1%. Thirteen percent of patients developed an AE-IPF (4.7% per year). AE-IPF were associated with elevated lymphocytes in BAL fluid at diagnosis (p = 0.03). Higher serum IgA and IgG at diagnosis were associated with worse survival (p = 0.01; and p = 0.04), as were an increased BAL lymphocyte percentage (p = 0.005), and higher blood leukocytes and neutrophils (p = 0.01; and p = 0.0005). In a multivariate model, only BAL lymphocyte count retained statistical significance (p = 0.007). CONCLUSION: The prevalence of humoral immunodeficiencies was low in patients with IPF and not associated with AE-IPF or survival. Elevated lymphocytes in BAL were associated with the development of AE-IPF and worse survival. Higher serum immunoglobulins and immune cells in blood were also associated with worse survival. The local immune response in the lungs may be a target for future therapies.

TINF2 Gene Mutation in a Patient with Pulmonary Fibrosis.

Pulmonary fibrosis is a frequent manifestation of telomere syndromes. Telomere gene mutations are found in up to 25% and 3% of patients with familial disease and sporadic disease, respectively. The telomere gene TINF2 encodes an eponymous protein that is part of the shelterin complex, a complex involved in telomere protection and maintenance. A TINF2 gene mutation was recently reported in a family with pulmonary fibrosis. We identified a heterozygous Ser245Tyr mutation in the TINF2 gene of previously healthy female patient that presented with progressive cough due to pulmonary fibrosis as well as panhypogammaglobulinemia at age 52. Retrospective multidisciplinary evaluation classified her as a case of possible idiopathic pulmonary fibrosis. Telomere length-measurement indicated normal telomere length in the peripheral blood compartment. This is the first report of a TINF2 mutation in a patient with sporadic pulmonary fibrosis, which represents another association between TINF2 mutations and this disease. Furthermore, this case underlines the importance of telomere dysfunction and not telomere length alone in telomere syndromes and draws attention to hypogammaglobulinemia as a manifestation of telomere syndromes.

Response to pneumococcal vaccination in mannose-binding lectin-deficient adults with recurrent respiratory tract infections.

Mannose-binding lectin (MBL)-deficiency is associated with an increased susceptibility to pneumococcal infections and other forms of disease. Pneumococcal vaccination is recommended in MBL-deficient patients with recurrent respiratory tract infections (RRTI). The response to pneumococcal vaccination in MBL-deficient individuals has not yet been studied in detail. An impaired response to pneumococcal polysaccharides in MBL-deficient patients might explain the association between MBL deficiency and pneumococcal infections. This study investigates the antibody response to pneumococcal vaccination in MBL-deficient adult patients with RRTI. Furthermore, we investigated whether there was a difference in clinical presentation between MBL-deficient and -sufficient patients with RRTI. Eighteen MBL-deficient and 63 MBL-sufficient adult patients with RRTI were all vaccinated with the 23-valent pneumococcal polysaccharide vaccine and antibodies to 14 pneumococcal serotypes were measured on a Luminex platform. There were no differences observed in the response to pneumococcal vaccination between MBL-sufficient and -deficient patients. Forty-three MBL-sufficient patients could be classified as responders to pneumococcal vaccination and 20 as low responders, compared to 15 responders and three low responders in the MBL-deficient patients. We found no clear difference in clinical, radiological, lung function and medication parameters between MBL-sufficient and -deficient patients. In conclusion, our study suggests that MBL-deficient adults with RRTI have a response to a pneumococcal capsular polysaccharide vaccine comparable with MBL-sufficient patients. Moreover, we did not find a clear clinical role of MBL deficiency in adults with RRTI. As MBL deficiency is associated with an increased susceptibility to pneumococcal infections, pneumococcal vaccination might be protective in MBL-deficient patients with RRTI.

National Beef Quality Audit-2005: survey of targeted cattle and carcass characteristics related to quality, quantity, and value of fed steers and heifers.

The National Beef Quality Audit-2005 assessed the current status of quality and consistency of US fed steers and heifers. Hide colors or breed type were black (56.3%), red (18.6%), Holstein (7.9%), gray (6.0%), yellow (4.9%), brown (3.0%), white (2.3%), and brindle (1.0%). Identification method and frequency were lot visual tags (63.2%), individual visual tags (38.7%), metal-clip tags (11.8%), electronic tags (3.5%), bar-coded tags (0.3%), by other means (2.5%), and without identification (9.7%). Brand frequencies were no (61.3%), 1 (35.1%), and 2 or more (3.6%), and brands were located on the butt (26.5%), side (7.4%), and shoulder (1.2%). There were 22.3% of cattle without horns, and the majority of those with horns (52.2%) were between 2.54 and 12.7 cm in length. Percentages of animals with mud or manure on specific body locations were none (25.8%), legs (61.4%), belly (55.9%), side (22.6%), and top-line (10.0%). Permanent incisor number and occurrence were zero (82.2%), 1 (5.2%), 2 (9.9%), 3 (0.4%), 4 (1.2%), 5 (0.1%), 6 (0.3%), 7 (0.0%), and 8 (0.7%). Most carcasses (64.8%) were not bruised, 25.8% had one bruise, and 9.4% had multiple bruises. Bruise location and incidence were round (10.6%), loin (32.6%), rib (19.5%), chuck (27.0%), and brisket, flank, and plate (10.3%). Condemnation item and incidence were liver (24.7%), lungs (11.5%), tripe (11.6%), heads (6.0%), tongues (9.7%), and carcasses (0.0%). Carcass evaluation revealed these traits and frequencies: steer (63.7%), heifer (36.2%), bullock (0.05%), and cow (0.04%) sex classes; dark-cutters (1.9%); A (97.1%), B (1.7%), and C or older (1.2%) overall maturities; and native (90.9%), dairy-type (8.3%), and Bos indicus (0.8%) estimated breed types. Mean USDA yield grade (YG) traits were USDA YG (2.9), HCW (359.9 kg), adjusted fat thickness (1.3 cm), LM area (86.4 cm(2)), and KPH (2.3%). The USDA YG were YG 1 (16.5%), YG 2 (36.3%), YG 3 (33.1%), YG 4 (11.8%), and YG 5 (2.3%). Mean USDA quality grade traits were USDA quality grade (Select(90)), marbling score (Small(32)), overall maturity (A(64)), lean maturity (A(57)), and skeletal maturity (A(68)). Marbling score distribution was Slightly Abundant or greater (2.7%), Moderate (4.3%), Modest (14.4%), Small (34.5%), Slight (41.2%), and Traces or less (2.9%). This information helps the beef industry measure progress and provides a benchmark for future educational and research activities.

Estimated compliance for removal of specified risk materials from 18 U.S. beef packing plants.

The removal of 18,345 specified risk materials was observed during audits of 18 U.S. beef processing facilities that, in total, account for over 90% of total U.S. beef slaughtered. Audited plants varied in capacity (280 to 6,000 head per day) and processed both "fed (young cattle)" and "nonfed (mature cows/bulls)" cattle. When all observations for removal of specified risk materials were combined from plants and adjusted for type of cattle processed, overall compliance with specified risk material removal regulations was 98.08%. A 100% compliance rate for removal of brains and distal ileums was recorded based on a total of 600 observations for removal of brains and a total of 2,400 observations for removal of distal ileums. Observations for removal of dorsal root ganglia were collected from 16 of the 18 plants, and overall compliance for dorsal root ganglia removal was 99.6% (4,783 of 4,800). Fifteen of the 16 plants were 100% compliant. For tonsils, data from 18 plants were collected, and tonsils were correctly removed from 92.8% (4,777 of 5,145) of tongues and heads. Data for spinal cord removal were collected from 18 plants, and the spinal cord was removed completely in line with U.S. Department of Agriculture-Food Safety and Inspection Service regulations for 99.43% of the observations. Based on the results of this study, packing plants have demonstrated that they are complying with regulations for removal of specified risk materials from beef meat products intended for human consumption greater than 98% of the time. To continue to assure food safety and consumer confidence, continued vigilance and provision of training programs for plant workers are essential.