Telomeres are repetitive nucleotide sequences at the ends of chromosomes that preserve genomic integrity. Defects in telomere maintenance mechanisms lead to premature telomere shortening, resulting in cellular senescence, apoptosis, and organ dysfunction, collectively termed telomere biology disorders (TBDs). Short telomere length is associated with an increased risk of end-stage fibrotic disease of the lung and/or liver, which may necessitate lung or liver transplantation. Beyond pulmonary and hepatic involvement, TBDs can also affect cardiac and renal function. Importantly, the bone marrow function is often also compromised, which can significantly influence transplant outcomes. Although evidence remains scarce, particularly in non-lung solid organ transplant recipients, post-transplant immunosuppressive therapy, typically including corticosteroids, calcineurin inhibitors, and cell cycle inhibitors, may exacerbate the underlying hematopoietic fragility in TBD patients. Hematological complications may result from both the intrinsic TBD and the additive myelotoxic effects of immunosuppressive agents (e.g., azathioprine, mycophenolate mofetil) or anti-infectious prophylaxis (e.g., trimethoprim-sulfamethoxazole, valganciclovir). Early recognition of TBDs prior to transplantation is essential. Assessment of telomere length and genetic testing should be considered in at-risk candidates, particularly those with early-onset pulmonary fibrosis, unexplained cytopenia, cryptogenic liver disease, or a family history suggestive of TBD. A multidisciplinary approach involving pulmonology, hepatology, hematology, and transplant specialists is crucial to optimize patient selection, perioperative management, and post-transplant care. This review summarizes current knowledge on hematological complications following solid organ transplantation in TBD patients and describes expert-opinion strategies for the pre-transplant evaluation and post-transplant management of these high-risk individuals.

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.

BackgroundTelomere dysfunction can underly the development of idiopathic pulmonary fibrosis (IPF), and recent work suggests that patients with telomere syndromes might benefit from treatment with androgens, such as danazol.MethodsThis was a prospective observational cohort study. 50 patients with IPF received off-label treatment with danazol after they showed progressive disease under treatment with pirfenidone or nintedanib. The primary outcome was the difference in yearly decline in forced vital capacity (FVC) prior to (pre) and after (post) start of treatment with danazol.ResultsThere was no significant difference in FVC-decline between 1 year pre and 1 year post start of danazol treatment (mean decline pre 395 mL (95% confidence interval (CI) 290–500) compared to post 461 mL (95% CI 259–712); p=0.46; paired t-test). 11 patients (22%) were still on danazol after 1 year, and 39 patients had stopped danazol, mainly because of side-effects (56%) or death (33%). In patients who were still using danazol after 1 year, FVC-decline significantly slowed down under danazol treatment (mean pre 512 mL (95% CI 308–716)versuspost 198 mL (95% CI 16–380); p=0.04). Median survival post danazol was 14.9 months (95% CI 11.0–18.8).ConclusionDanazol as a treatment of last resort in patients with IPF did not lead to slowing of lung function decline and was associated with significant side-effects. It remains to be determined if earlier treatment or treatment of specific patient subgroups is beneficial.

Interstitial lung diseases (ILD) are a heterogeneous group of disorders, of which many have the potential to lead to progressive pulmonary fibrosis. A distinction is usually made between primarily inflammatory ILD and primarily fibrotic ILD. As recent studies show that anti-fibrotic drugs can be beneficial in patients with primarily inflammatory ILD that is characterized by progressive pulmonary fibrosis, treatment decisions have become more complicated. In this perspective, we propose that the ‘treatable trait’ concept, which is based on the recognition of relevant exposures, various treatable phenotypes (disease manifestations) or endotypes (shared molecular mechanisms) within a group of diseases, can be applied to progressive pulmonary fibrosis. These targets for medical intervention can be identified through validated biomarkers and are not necessarily related to specific diagnostic labels. Proposed treatable traits are: cigarette smoking, occupational, allergen or drug exposures, excessive (profibrotic) auto- or alloimmunity, progressive pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea, tuberculosis, exercise intolerance, exertional hypoxia, and anxiety and depression. There are also several potential traits that have not been associated with relevant outcomes or for which no effective treatment is available at present: air pollution, mechanical stress, viral infections, bacterial burden in the lungs, surfactant-related pulmonary fibrosis, telomere-related pulmonary fibrosis, the rs35705950 MUC5B promoter polymorphism, acute exacerbations, gastro-esophageal reflux, dyspnea, and nocturnal hypoxia. The ‘treatable traits’ concept can be applied in new clinical trials for patients with progressive pulmonary fibrosis and could be used for developing new treatment strategies.

Abstract 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.

Congenital tracheobronchomegaly, also known as Mounier Kuhn Syndrome (MKS) is a rare respiratory disorder characterized by dilatation of the trachea and bronchi. We report a case of a 28-year-old male of African descent in Zambia, who presented with a history of chronic productive cough and repeated chest infections since childhood. He had been treated numerous times for lower respiratory tract infections, and had received empiric tuberculosis (TB) treatment based on chest radiograph findings, despite negative sputum microscopy and molecular tests for TB. Investigations revealed normal baseline blood results and sputum results. He however, had markedly increased levels of serum immunoglobulin E, and spirometry showed an obstructive pattern with significant post bronchodilator improvement. High-resolution computed tomography scan revealed tracheal dilatation, extensive bilateral bronchiectasis and tracheal and bronchial diverticula. The latter were also seen on bronchoscopy, confirming the diagnosis of Mounier-Kuhn syndrome. The patient was treated with combined inhaled corticosteroids and bronchodilators, as well as chest physiotherapy for mucus clearance, which led to improvement in his symptoms. Our case highlights how in low-resource settings, chronic lung diseases, particularly bronchiectasis, are often clinically and radiologically mistaken for and presumptively treated as TB (or its sequelae). Mounier-Kuhn syndrome, albeit rare, should be considered in the differential diagnosis of patients with recurrent lower respiratory tract infections or bronchiectasis. Multidisciplinary team meetings can help in the diagnosis of rare lung diseases.

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-CoV2 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.

BackgroundCommunity-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 methodsThree-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.ResultsThe 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).ConclusionMycobacterium 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.

Lung transplant recipients are at an increased risk for severe coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccination against SARS-CoV-2 has been recommended,1 but an impaired response has been observed in solid organ transplant recipients.2 For lung transplant recipients, impaired response to vaccination might be an especially pressing issue, as they usually receive more intensive immunosuppressive therapy compared with other solid organ transplant recipients. However, lung transplant recipients only represented a small proportion of the solid organ transplant recipients in whom the response to SARS-CoV-2 vaccines has been studied. In this study, we analyzed the serologic response to 2 doses of an mRNA-based SARS-CoV-2 vaccine in our cohort of 91 lung transplant recipients who were vaccinated in April and May 2021 (BNT162b2 [n = 2] or mRNA-1273 [n = 89]). The median time since lung transplantation was 5.35 y (interquartile range, 1.87–9.71 y). SARS-CoV-2 spike S1/S2 protein-specific immunoglobulin G antibody levels were measured before, 4 wk after the first dose and 6 wk after the second dose on the Liaison platform (DiaSorin, Saluggia, Italy). All patients gave written informed consent for the use of their data in clinical research. The study was approved by the local ethics committee and was conducted in accordance with the Declaration of Helsinki. In patients without COVID-19 before vaccination, the serologic response rate after 2 vaccine doses was 27% (Figure 1). Notably, in patients who had COVID-19 before vaccination (n = 12), the response rate was significantly higher at 75% (P = 0.002). This confirms that immunological memory is induced during and after the infection even in this immunocompromised patient population. This would argue for repeated exposure to SARS-CoV-2 antigens as a method for obtaining an improved serologic response. Importantly, 2 recent studies showed a clear improvement in serologic responses after a third dose of a SARS-CoV-2 vaccine in solid organ transplant recipients.3,4 In contrast, there were 3 patients who had COVID-19 before vaccination but did not develop measurable antibodies after the vaccinations. Thus, even having had COVID-19 is not likely to be protective in all solid organ transplant patients. We have not witnessed breakthrough infections in our patients thus far, but these have been reported in other solid organ transplant recipients who had received a complete vaccination schedule.5FIGURE 1.: Grouped scatter plot showing anti-SARS-CoV-2 IgG antibodies in lung transplant recipients before vaccination with SARS-CoV-2 vaccine, 4 wk after the first vaccination and 6 wk after the second vaccination. Error bars represent the group median with 25th and 75th percentiles. All values below the lower detection limit of the assay were set to 0. After the second vaccination, antibody levels were significantly higher in patients who had had COVID-19 before vaccination (n = 12) compared with patients who had not had COVID-19 (n = 80; median 800 AU/mL [IQR, 63.25–800] vs 0.00 [0.00–16.30]; P < 0.001). The dashed line represents the 2.5th percentile value of anti-SARS-CoV-2 IgG antibodies after the first and second vaccination in 102 healthy volunteers, as provided by the manufacturer (after the first vaccination, the 2.5th percentile was 25 AU/mL, and the median value 138 AU/mL; after the second vaccination, the 2.5th percentile was 372 AU/mL and the median value 1706 AU/mL) (https://www.diasorin.com/sites/default/files/immagini/ese_infografica_vaccinated_indivuduals_m0870004414_lr.pdf). COVID-19, coronavirus disease 2019; IgG, immunoglobulin G; IQR, interquartile range; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.A positive serologic response was also associated with younger age (P = 0.002), not using tacrolimus as an immunosuppressant (P = 0.04), and a normal response to previous pneumococcal vaccination (P = 0.03). Serologic response was not associated with the dose of mycophenolate mofetil or prednisone. In a multivariate model, both age at vaccination and having had COVID-19 before vaccination retained statistical significance (P = 0.002 and P = 0.002, respectively). In conclusion, and important for clinical practice, the response to mRNA-based SARS-CoV-2 vaccines is poor in lung transplant recipients. Factors associated with a positive serologic response were younger age at vaccination, having had COVID-19 before vaccination, and not using tacrolimus as an immunosuppressant. Lung transplant recipients will likely remain at risk for severe COVID-19, even after SARS-CoV-2 vaccination. Future studies will have to determine the optimal vaccination schedule.

Background and objective Idiopathic pulmonary fibrosis (IPF) is a heterogenous disease with a median survival of 3-4 years. Patients with mutations in telomere-related genes exhibit extrapulmonary signs and symptoms. These patients represent a distinct phenotype of IPF with worse survival. As genetic analyses are not available for most patients with IPF, we sought to determine the predictive value of extrapulmonary signs and symptoms of a telomere syndrome in patients with IPF. Methods We retrospectively studied 409 patients with IPF. Clinical characteristics, laboratory results and family history suggestive of a telomere syndrome were related to leukocyte telomere length measured by quantitative PCR and patient outcomes. Results The cohort included 293 patients with sporadic IPF and 116 patients with a background of familial pulmonary fibrosis. Any or a combination of a clinical history (haematological disease, liver disease, early greying of hair, nail dystrophy, skin abnormalities), a family history or haematological laboratory abnormalities (macrocytosis, anaemia, thrombopenia or leukopenia) suggestive of a telomere syndrome was present in 27% of IPF patients and associated with shorter leukocyte telomere length and shorter survival (p = 0.002 in a multivariate model). In sporadic IPF, having either a clinical history, family history or haematological laboratory abnormalities was not significantly associated with decreased survival (p = 0.07 in a multivariate model). Conclusion Taking a careful clinical and family history focused on extrapulmonary manifestations of a telomere syndrome can provide important prognostic information in patients with IPF, as this is associated with shorter survival.

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.

Introduction Lung transplant patients are immunocompromised because of the medication they receive to prevent rejection, and as a consequence are susceptible to (respiratory) infections. Adequate vaccination strategies, including COVID-19 vaccination, are therefore needed to minimize infection risks.Areas covered The international vaccination guidelines for lung transplant patients are reviewed, including the data on immunogenicity and effectivity of the vaccines. The impact on response to vaccination of the various categories of immunosuppressive drugs, used in the posttransplant period, on response to vaccination is described. A number of immunosuppressive and/or anti-inflammatory drugs also is used for controlling the immunopathology of severe COVID-19. Current available COVID-19 vaccines, both mRNA or adenovirus based are recommended for lung transplant patients.Expert opinion In order to improve survival and quality of life, infections of lung transplant patients should be prevented by vaccination. When possible, vaccination should start already during the pre-transplantation period when the patient is on the waiting list. Booster vaccinations should be given post-transplantation, but only when immunosuppression has been tapered. Vaccine design based on mRNA technology could allow the design of an array of vaccines against other respiratory viruses, offering a better protection for lung transplant patients.

Background. The Netherlands was the third country to adopt the lung allocation score (LAS) for national allocation of donor lungs in April 2014. Evaluations of the introduction of the LAS in the United States and Germany showed mainly beneficial effects, including increased survival after transplantation. Methods. Data for transplant candidates from 2010 to 2019 were retrieved from the Dutch Transplant Foundation database. Diagnosis categories and outcomes were compared between the periods before and after the introduction of the LAS. Time-dependent Cox regression and Fine-Gray analyses were performed to compare the chance for transplantation before and after introduction of the LAS. Results. The cohort comprised 1276 patients. After introduction of the LAS, the annual number of transplantations and waiting list mortality did not change. The proportion of patients on the waiting list and transplanted patients with pulmonary fibrosis increased (25%–37%, P < 0.001; 22%–39%, P < 0.001). The chance of transplantation increased significantly for patients with pulmonary fibrosis after introduction of the LAS (hazard ratio 1.9 [95% confidence interval 1.4-2.9]). Patients who died on the waiting list had an increased LAS compared to the time of placement on the waiting list, reflecting clinical deterioration. This was not the case in patients with chronic obstructive pulmonary disease (P < 0.001). Overall survival was similar after introduction of the LAS (5-y survival 68%, compared to 74% [P = 0.171]). Conclusions. After the introduction of the LAS in The Netherlands, an increased proportion of transplantations was performed for patients with pulmonary fibrosis. Overall survival after transplantation did not change.

Introduction: This review analyzes the efficacy of pneumococcal vaccinations in lung transplant patients before and after transplantation.Areas covered: This review addresses the risk for respiratory infections, in particular pneumococcal infections, in lung transplantation patients in the context of immunodeficiency and immunosuppressive medication. Vaccination is recommended to counteract the increased risk of pneumococcal infection, and the relevant guidelines are discussed in this review. The design of specific vaccination schedules is required because of the impaired antibody response in specific patient categories.Expert opinion: Lung transplantation candidates should be vaccinated with pneumococcal vaccines prior to transplantation. Currently, the 23-valent pneumococcal polysaccharide vaccine offers the broadest coverage, but the antibody response should be monitored. New generation pneumococcal conjugate vaccines with equally broad serotype coverage could be used in the future. During the post-transplantation period, the immune status of the patients should be monitored regularly, and vaccination should be repeated when indicated.

Introduction: This review analyzes the efficacy of pneumococcal vaccinations in lung transplant patients before and after transplantation. Areas covered: This review addresses the risk for respiratory infections, in particular pneumococcal infections, in lung transplantation patients in the context of immunodeficiency and immunosuppressive medication. Vaccination is recommended to counteract the increased risk of pneumococcal infection, and the relevant guidelines are discussed in this review. The design of specific vaccination schedules is required because of the impaired antibody response in specific patient categories. Expert opinion: Lung transplantation candidates should be vaccinated with pneumococcal vaccines prior to transplantation. Currently, the 23-valent pneumococcal polysaccharide vaccine offers the broadest coverage, but the antibody response should be monitored. New generation pneumococcal conjugate vaccines with equally broad serotype coverage could be used in the future. During the post-transplantation period, the immune status of the patients should be monitored regularly, and vaccination should be repeated when indicated.

Background. Pneumococcal conjugate vaccination as well as pneumococcal polysaccharide vaccination are recommended for lung transplant candidates and recipients, but the combination of these vaccines has not been extensively studied in these specific populations. Methods. Lung transplant candidates and recipients were vaccinated with a 13-valent pneumococcal conjugate vaccine, followed 8 weeks later by a pneumococcal polysaccharide vaccine. Pneumococcal antibody levels against 13 pneumococcal serotypes were measured and followed up after 1 year in the transplant recipients. These values were compared with a historical control group vaccinated with the polysaccharide vaccine alone. Results. Twenty-five lung transplant candidates and 23 lung transplant recipients were included. For the majority of serotypes, there was no significant increase in antibody levels after additional vaccination with the polysaccharide vaccine in both patient groups. When compared with the historical control group, the antibody response in lung transplant recipients 1 year after vaccination did not seem to have improved by vaccination with both vaccines instead of the polysaccharide vaccine alone. Conclusions. Serologic vaccination responses in lung transplant candidates and recipients were not improved by giving a 23-valent pneumococcal polysaccharide vaccine after a 13-valent pneumococcal conjugate vaccine. The benefit of this vaccination schedule in lung transplant recipients seems to differ from other immunocompromised populations. The optimal vaccination schedule for lung transplant candidates and recipients remains to be determined.

Pulmonary fibrosis is associated with mutations in the ACD gene, encoding the telomere protein TPP1. Potentially disease-causing variants were found in 5% of a cohort of 60 unrelated patients with pulmonary fibrosis who were referred for genetic screening.http://bit.ly/2Mw9Cn0

Fibrotic interstitial pneumonias are a group of rare diseases characterised by distortion of lung interstitium. Patients with mutations in surfactant-processing genes, such as surfactant protein C (SFTPC), surfactant protein A1 and A2 (SFTPA1 and A2), ATP binding cassette A3 (ABCA3) and Hermansky-Pudlak syndrome (HPS1, 2 and 4), develop progressive pulmonary fibrosis, often culminating in fatal respiratory insufficiency. Although many mutations have been described, little is known about the optimal treatment strategy for fibrotic interstitial pneumonia patients with surfactant-processing mutations. We performed a systematic literature review of studies that described a drug effect in patients, cell or mouse models with a surfactant-processing mutation. In total, 73 articles were selected, consisting of 55 interstitial lung disease case reports/series, two clinical trials and 16 cell or mouse studies. Clinical effect parameters included lung function, radiological characteristics and clinical symptoms, while experimental outcome parameters included chemokine/cytokine expression, surfactant trafficking, necrosis and apoptosis. SP600125, a c-jun N-terminal kinase (JNK) inhibitor, hydroxychloroquine and 4-phenylbutyric acid were most frequently studied in disease models and lead to variable outcomes, suggesting that outcome is mutation dependent. This systematic review summarises effect parameters for future studies on surfactant-processing disorders in disease models and provides directions for future trials in affected patients.