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.

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.

Anti-ETAR and anti-AT1R autoantibodies are elevated in patients with endstage cystic fibrosis.

Autoantibodies against endothelin-1 type A receptor (ETAR) are present in systemic sclerosis complicated by lung fibrosis and pulmonary hypertension. As increased serum levels and local overproduction of endothelin-1 in the airways are reported in cystic fibrosis (CF) patients, we reasoned that anti-ETAR antibodies could be prevalent in endstage CF patients prior to lung transplantation (LTx). Also, ETAR autoantibodies are frequently associated with autoantibodies against the angiotensin II type 1 receptor (AT1R). We analyzed the presence of anti-ETAR and anti-AT1R autoantibodies in 43 LTx patients (chronic obstructive pulmonary disease (COPD), n=20; CF, n=13; interstitial lung disease (ILD), n=1). We observed overall higher anti-ETAR and anti-AT1R autoantibody titers in sera taken prior to LTx in the CF patient group as compared to COPD. No difference was found in autoantibody levels between patients with CF versus ILD. In sera taken post-LTx we found the same difference in anti-ETAR and anti-AT1R autoantibody titers between patients with CF versus COPD. No difference was found in antibody titers between sera taken prior to or 6 months after LTx. There was no association between autoantibody levels and other relevant demographic parameters, and we found no association between autoantibody titers and the development of the bronchiolitis obliterans syndrome. Both autoantibody titers were strongly correlated. We hypothesize that due to prolonged exposure to bacterial infection, increased levels of AT1R and ETAR result in a deregulated immune response causing autoantibody formation. Further research is expedient to elucidate the occurrence of autoantibodies against ETAR and AT1R and their role in disease progression.

Diabetes before and after lung transplantation in patients with cystic fibrosis and other lung diseases.

AIMS: The aims of the study are to investigate the prevalence of diabetes in patients with cystic fibrosis compared with patients without cystic fibrosis, and its impact on the outcome after lung transplantation. METHODS: Data were reviewed from 77 lung transplantation recipients in our centre between 2001 and 2010; 43 patients had cystic fibrosis and 34 patients had other lung diseases (no cystic fibrosis). To define diabetes, we used the American Diabetes Association definition. RESULTS: Before lung transplantation, diabetes was diagnosed in 63% of patients with cystic fibrosis and 6% of patients without cystic fibrosis (P<0.001). In both groups, approximately 60% of the patients at risk developed new-onset diabetes after transplantation. The mortality in patients with cystic fibrosis was higher in patients with diabetes diagnosed before lung transplantation compared with those without (44 vs. 6%, P=0.04). Diabetes remained an independent factor in multivariate analyses. CONCLUSIONS: Diabetes diagnosed before lung transplantation has a negative effect on survival after lung transplantation in patients with cystic fibrosis. Pre-existing diabetes is common in patients with cystic fibrosis, in contrast to patients without cystic fibrosis. Development of new-onset diabetes after transplantation is similar in both groups.

Effective Prolonged Therapy with Voriconazole in a Lung Transplant Recipient with Spondylodiscitis Induced by Scedosporium apiospermum.

Scedosporium/Pseudallescheria species are frequently seen in cystic fibrosis patients. However, disseminated forms after lung transplantation in these patients are rarely seen, but often with poor outcome. In this case report we describe a lung transplant recipient with cystic fibrosis who developed a spondylodiscitis that was caused by Scedosporium apiospermum. The patient was treated with anti-fungal treatment by voriconazole for over three years with a clinical good response and without the need for surgical intervention. To our opinion this is the first anti-fungal treated case of invasive disease caused by Scedosporium/Pseudallescheria in a cystic fibrosis (CF) patient who underwent lung transplantation that survived.

Impaired pneumococcal antibody response in bronchiectasis of unknown aetiology.

As a defective anti-polysaccharide response can exist in the absence of an immunoglobulin deficiency, a series of 26 patients with bronchiectasis of unknown aetiology was vaccinated with a 23-valent pneumococcal polysaccharide vaccine. All patients suffered from recurrent respiratory tract infections. When measuring total antibody levels to pneumococcal serotypes 3, 4 and 9, a normal polysaccharide antibody response was found in 22 patients. However, only 11 of these subjects showed a normal pneumococcal antibody response within the IgA and/or IgG2 subclass, and thus could be classified as true responders, while 15 patients did not respond in either the IgA class or in the IgG2 subclass. When analysing differences between the responder (n = 11) and nonresponder (n = 15) groups, the latter demonstrated higher frequencies of respiratory tract infections and more severe lung pathology, as revealed by the presence of more bronchi visualised in the peripheral third of the lung by high-resolution computed tomography scanning. Moreover, nonresponders needed extensive lung surgery more often in order to control their disease (number of resected segments eight versus five). In conclusion, an important fraction of patients presenting with idiopathic bronchiectasis is associated with a selective anti-polysaccharide response deficiency and this subgroup appears to represent a more severe clinical phenotype. Therefore, it can be regarded as a separate clinical entity with possible therapeutic targets. In order to identify IgA and IgG2 anti-polysaccharide nonresponders, all patients presenting with bronchiectasis of unknown aetiology should be immunised with a pneumococcal polysaccharide vaccine, and IgA and IgG2 isotype responses should be evaluated as well as the total antibody response.