North Manchester General Hospital

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Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Lung cancer is the leading cause of cancer-related death in the world. It is broadly divided into small cell (SCLC, approx. 15% cases) and non-small cell lung cancer (NSCLC, approx. 85% cases). The main histological subtypes of NSCLC are adenocarcinoma and squamous cell carcinoma, with the presence of specific DNA mutations allowing further molecular stratification. If identified at an early stage, surgical resection of NSCLC offers a favourable prognosis, with published case series reporting 5-year survival rates of up to 70% for small, localized tumours (stage I). However, most patients (approx. 75%) have advanced disease at the time of diagnosis (stage III/IV) and despite significant developments in the oncological management of late stage lung cancer over recent years, survival remains poor. In 2014, the UK Office for National Statistics reported that patients diagnosed with distant metastatic disease (stage IV) had a 1-year survival rate of just 15-19% compared with 81-85% for stage I.

The Tampa Scale for Kinesiophobia (TSK) is one of the most frequently employed measures for assessing pain-related fear in back pain patients. Despite its widespread use, there is relatively little data to support the psychometric properties of the English version of this scale. This study investigated the psychometric properties of the English version of the TSK in a sample of chronic low back pain patients. Item analysis revealed that four items possessed low item total correlations (4, 8, 12, 16) and four items had response trends that deviated from a pattern of normal distribution (4, 9, 12, 14). Consequently, we tested the psychometric properties of a shorter version of the TSK (TSK-11), having excluded the six psychometrically poor items. The psychometric properties of this measure were compared to those of the original TSK. Both measures demonstrated good internal consistency (TSK: alpha=0.76; TSK-11: alpha=0.79), test-retest reliability (TSK: ICC=0.82, SEM=3.16; TSK-11: ICC=0.81, SEM=2.54), responsiveness (TSK: SRM=-1.19; TSK-11: SRM=-1.11), concurrent validity and predictive validity. In respect of specific cut-off scores, a reduction of at least four points on both measures maximised the likelihood of correctly identifying an important reduction in fear of movement. Overall, the TSK-11 possessed similar psychometric properties to the original TSK and offered the advantage of brevity. Further research is warranted to investigate the utility of the new instrument and the cut-off scores in a wider group of chronic pain patients in different clinical settings.

To evaluate the efficacy and safety of voriconazole in acute invasive aspergillosis (IA), an open, noncomparative multicenter study was conducted. Immunocompromised patients with IA were treated with intravenously administered voriconazole 6 mg/kg twice a day (b.i.d.) twice and then 3 mg/kg b.i.d. for 6-27 days, followed by 200 mg b.i.d. administered orally for up to 24 weeks. Response was assessed by clinical and radiographic change. A total of 116 patients were assessable. IA was proven in 48 (41%) and probable in 68 patients. Voriconazole was given as primary therapy in 60 (52%). Good responses were seen in 56 (48%); 16 (14%) showed complete response and 40 (34%) partial response. A stable response was seen in 24 patients (21%), and 36 (31%) of the infections failed to respond to therapy. Good responses were seen in 60% of those with pulmonary or tracheobronchial IA (n=84), 16% with cerebral IA (n=19), 58% with hematologic disorders (n=67), and 26% of allogeneic stem cell transplant recipients (n=23). Voriconazole is efficacious in treating acute IA.

ABSTRACT Background Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death. Methods The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality. Results 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P<0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p<0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p<0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14). Conclusions In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support. Trial registrations The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov ( NCT04381936 ). Funding Medical Research Council and National Institute for Health Research (Grant ref: MC_PC_19056).

Prognostic factor research aims to identify factors associated with subsequent clinical outcome in people with a particular disease or health condition. In this article, the second in the PROGRESS series, the authors discuss the role of prognostic factors in current clinical practice, randomised trials, and developing new interventions, and explain why and how prognostic factor research should be improved.

Aspergillosis comprises a variety of manifestations of infection. These guidelines are directed to 3 principal entities: invasive aspergillosis, involving several organ systems (particularly pulmonary disease); pulmonary aspergilloma; and allergic bronchopulmonary aspergillosis. The recommendations are distilled in this summary, but the reader is encouraged to review the more extensive discussions in subsequent sections, which show the strength of the recommendations and the quality of the evidence, and the original publications cited in detail. Invasive aspergillosis. Because it is highly lethal in the immunocompromised host, even in the face of therapy, work-up must be prompt and aggressive, and therapy may need to be initiated upon suspicion of the diagnosis, without definitive proof (BIII). Intravenous therapy should be used initially in rapidly progressing disease (BIII). The largest therapeutic experience is with amphotericin B deoxycholate, which should be given at maximum tolerated doses (e.g., 1–1.5 mg/kg/d) and should be continued, despite modest increases in serum creatinine levels (BIII). Lipid formulations of amphotericin are indicated for the patient who has impaired renal function or who develops nephrotoxicity while receiving deoxycholate amphotericin (AII). Oral itraconazole is an alternative for patients who can take oral medication, are likely to be adherent, can be demonstrated (by serum level monitoring) to absorb the drug, and lack the potential for interaction with other drugs (BII). Oral itraconazole is attractive for continuing therapy in the patient who responds to initial iv therapy (CIII). Therapy should be prolonged beyond resolution of disease and reversible underlying predispositions (BIII). Adjunctive therapy (particularly surgery and combination chemotherapy, also immunotherapy), may be useful in certain situations (CIII). Aspergilloma. The optimal treatment strategy for aspergilloma is unknown. Therapy is predominantly directed at preventing life-threatening hemoptysis. Surgical removal of aspergilloma is definitive treatment, but because of significant morbidity and mortality it should be reserved for high-risk patients such as those with episodes of life-threatening hemoptysis, and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). Surgical candidates would need to have adequate pulmonary function to undergo the operation. Bronchial artery embolization rarely produces a permanent success, but may be useful as a temporizing procedure in patients with life-threatening hemoptysis. Endobronchial and intracavitary instillation of antifungals or oral itraconazole may be useful for this condition. Since the majority of aspergillomas do not cause life-threatening hemoptysis, the morbidity and cost of treatment must be weighed against the clinical benefit. Allergic bronchopulmonary aspergillosis (APBA). Although no well-designed studies have been carried out, the available data support the use of corticosteroids for acute exacerbations of ABPA (AII). Neither the optimal corticosteroid dose nor the duration of therapy has been standardized, but limited data suggest the starting dose should be ∼0.5 mg/kg/d of prednisone. The decision to taper corticosteroids should be made on an individual basis, depending on the clinical course (BIII). The available data suggest that clinical symptoms alone are inadequate to make such decisions, since significant lung damage may occur in asymptomatic patients. Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids should be used (BII). Multiple asthmatic exacerbations in a patient with ABPA suggest that chronic corticosteroid therapy should be used (BIII). Itraconazole appears useful as a corticosteroid sparing agent (BII). Although the frequency of these diseases is on the rise, there is a paucity of randomized comparative trials involving these entities; therefore, the recommendations represent a compromise and consensus among students of these diseases (i.e., the authors). They have synthesized the recommendations from published and personal experience, including case series, open trials, and any comparative trials, as indicated. Aspergillus species are saprophytic molds found worldwide. Diseases caused by Aspergillus species are most commonly caused by Aspergillus fumigatus, with Aspergillus flavus the second most frequently isolated pathogen. Other species reported to cause disease include Aspergillus amstelodami, Aspergillus avenaceus, Aspergillus candidus, Aspergillus carneus, Aspergillus caesiellus, Aspergillus clavatus, Aspergillus glaucus, Aspergillus granulosus, Aspergillus nidulans, Aspergillus niger, Aspergillus oryzae, Aspergillus quadrilineatus, Aspergillus restrictus, Aspergillus sydowi, Aspergillus terreus, Aspergillus ustus, and Aspergillus versicolor. The frequency and relative importance of these infections are on the rise in all developed countries, which is possibly related to increased numbers of immunocompromised patients, owing to improved survival from AIDS, malignancies and more intensive cytotoxic therapy, more transplantation (with immunosuppression) for organ dysfunctions, and better therapy and prophylaxis for candidal infections. These guidelines are drafted to ensure appropriate and successful therapy for 3 main diseases caused by Aspergillus species. They include invasive aspergillosis, ABPA, and aspergilloma. The guidelines proposed initially are general and are followed by modifications for individual clinical settings. The guidelines are based on scientific publications and peer-reviewed information (this documentation is provided), and are largely concerned with therapy. The guidelines are not intended to be a comprehensive treatise on pathogenesis or diagnosis. The categories of ranking of the strength of the recommendation and the quality of the evidence are given in tables 1 and 2. Guidelines for prophylaxis and empirical therapy for invasive aspergillosis in neutropenic hosts have recently been published [1] and will not be discussed here. Categories reflecting the strength of each recommendation for or against the use of therapy for diseases caused by Aspergillus species. Categories indicating the quality of evidence for recommendations for antifungal therapy in diseases caused by Aspergillus species. General and specific commentary on antifungal drugs has been provided in a previous guideline in this series. The drugs available to treat aspergillosis presently include amphotericin B in deoxycholate [2–4], a familiar drug with 40 years' clinical experience; 3 lipid-based preparations of amphotericin B [5–12]; and itraconazole, an oral and iv triazole [13–18]. In general, the largest databases for therapy in aspergillosis concern amphotericin B deoxycholate and various surgical modalities. There is thus some concern about the efficacy of the newer in patients with rapidly invasive Itraconazole has drug which are in patients at of aspergillosis, because such patients are receiving other drugs for a variety of These patients also have as a of these therefore, oral itraconazole is serum should be to ensure adequate (BII). should be given to the oral of itraconazole in such patients, because is to that with itraconazole iv has been but there is information available about that any drug used for invasive disease be given at for 1–1.5 mg/kg/d of amphotericin B deoxycholate, mg/kg/d of formulations of and of itraconazole (BIII). in serum creatinine level with amphotericin B deoxycholate is and with amphotericin use are to the dose because of a modest of and have against Aspergillus species and are or clinical oral triazole and 3 and are also in of clinical Invasive aspergillosis is a that patients with or cytotoxic chemotherapy, corticosteroid therapy, or organ or or in patients at and prompt of antifungal therapy may be for patient survival (BIII). The are the most of invasive disease it in frequency in some The is the most of invasive most of the in this are on invasive pulmonary The of this disease and to therapy in to the and to to for clinical trials have and will to as clinical trials such as the of and Diseases the for and of and and to of previous trials and the and to a evidence of in and Aspergillus species from by from the from a and rarely Aspergillus species. The of Aspergillus are by and and it would be to include these in the initial invasive disease is Aspergillus are to from those of of and some other Aspergillus species from of the (e.g., and are a of in the but may invasive disease in the immunocompromised The may be as as in patients with or studies may include such as or on on include the of a lung initially by or an the the of a lung caused by of These studies may and the of in neutropenic patients, but the are not because other infections and may The have been in neutropenic commonly chest the more specific and chest should be considered in patients with a infection. resolution or may an with of the by has and for invasive aspergillosis in immunocompromised patients (BII). or are (CIII). of have been useful such are Because of the of the a definitive of disease caused by Aspergillus is The use of against Aspergillus to invasive aspergillosis has in are frequently or more isolated but specific recommendations about frequency of have not been have been developed to Aspergillus in and by and These more and with an available in for of Aspergillus reported of and of largely among in in some studies with that case to be has been in some studies with In some more among the and more in are for use in the In that use have been reported to the of Aspergillus species the in the of Aspergillus species and a in the of and may more of these have been with in trials of invasive aspergillosis, and must be There is also in such as or for of invasive are with some but not evidence of invasive pulmonary and treatment may need to be initiated at that in the more immunocompromised or to or the should in such an empirical treatment The optimal duration of therapy is and on the of invasive aspergillosis, the to therapy, and the underlying or course would be to therapy to treat clinical and are can be are and reversible underlying predispositions have (BIII). of therapy should be by clinical any of antifungal therapy chemotherapy, or of antifungal therapy in patients with who are about to chemotherapy, is of The of these patients to antifungal therapy is largely related to such as the resolution of and the of and the of function from a or organ as as the of aspergillosis Intravenous therapy may be at in patients who are because drug is certain (BIII). B has been the of treatment in invasive aspergillosis, for life-threatening and infections. In patients, the has been to all because of underlying of resolution of or underlying of duration of and other with in made in other a is more likely with in The lipid-based formulations are indicated for patients with invasive aspergillosis who nephrotoxicity while receiving amphotericin B (AII). The lipid-based preparations may be as initial therapy in patients with renal function or in patients receiving other The studies on the preparations have been or with amphotericin B comparative clinical trials amphotericin B and a specific lipid-based for invasive aspergillosis, or specific doses of to be or have been thus Although most studies have that doses of the preparations are to therapeutic to deoxycholate a has the doses are Itraconazole has been as therapy for invasive aspergillosis in studies which found of and These are of has been reported in may be among the immunocompromised The oral is an alternative to amphotericin in patients who are likely to to therapy, to have with and who are not receiving drugs that with itraconazole or which be and attractive would be to use iv therapy (e.g., amphotericin at disease is and with oral therapy for prolonged treatment (CIII). has been used in an of invasive aspergillosis with in studies has been that a triazole with any amphotericin B for invasive aspergillosis. therapy that amphotericin B with or has in and in has also been in and in has with limited in case but the of or efficacy of such has not been in invasive aspergillosis. In may in patients with and levels may be amphotericin is owing to the to function of the of may have significant drug owing to in who are receiving or and this also the of itraconazole use for Surgical has been successful for some of pulmonary prompt surgery as a for the the because of the of pulmonary such as such as or are for prophylaxis or therapy, in the neutropenic or immunocompromised host, but are not for therapeutic use (CIII). of increased survival has not been demonstrated with any of these modalities. to Aspergillus species at other are pulmonary and treatment trials are with most reported treatment In this the therapeutic recommendations are based on of or series, in to from the of infections at more such as lung infections. Aspergillus infections may or may not be invasive and can a or an course The disease manifestations and the subsequent treatment may also depending on the of of the invasive is the of aspergillosis that in the immunocompromised These infections are by with and of in to is from in patients with in who are therapy, to to in patients with or those transplantation of suspicion is in immunocompromised patients. Although are of or limited should be considered in these patients. is and the of new such as a in a host, or an should to including of the and subsequent of are not to but also to Aspergillus infections from those caused by other such as those to or species of by corticosteroid or resolution of the most that should with surgical (BIII). Although surgical alone may be in it may mortality among patients with surgery has been used for in which an is in an to with as as is more extensive surgery is indicated there is of the or or or is (BIII). amphotericin B or has been used by some invasive infections occur in hosts in with levels of such as the and other or and in patients with in other flavus is the most agent of these in to the of from of in immunocompromised These infections have a clinical course to with of the the and subsequent and with acute invasive infections in treatment of surgical and which is in the majority of (BIII). The of antifungal therapy is (CIII). this are Aspergillus infections may also as a or These to a for to with and no invasive surgical removal of the to ensure adequate antifungal therapy has no in these infections (CIII). The is Aspergillus species are a cause of allergic which in with a of allergic from is in of in the of the and is surgical with as for (BIII). antifungal therapy is not used there is evidence of or (CIII). corticosteroids and may be used for There may be a potential for corticosteroids with allergic in to surgery and in the there is a in corticosteroid use is because of corticosteroid of and of the and The of of Aspergillus of the have been reported in immunocompromised such as patients with or AIDS, organ or patients receiving chronic corticosteroid therapy that has commonly been limited to the has been in and lung or have been in patients who with and to this has rarely been reported antifungal therapy has been the of treatment in these Although amphotericin B may have a as therapy In the several reported of surgical or has been for a successful in to antifungal therapy. in the of Aspergillus with the of a in the removal of the by procedure may be given the of antifungals the infections. invasive and infections have been Aspergillus species may the in the with no infection. invasive of the has been in patients with and in patients with acute Aspergillus may Aspergillus In immunocompromised patients, antifungal therapy appears (BIII). infections of or those that occur in patients may be with including removal (BIII). variety of such therapeutic has been which amphotericin B and In these prolonged therapy may be infections. Aspergillus may occur by several including by surgical such as or by which is most commonly in immunocompromised patients, drug or patients with Aspergillus in these and of of amphotericin B and itraconazole the and is inadequate and treatment is Because of amphotericin B may be of in are that of serum experience with this agent in infections is may be for the and of these in with amphotericin B or amphotericin B (BIII). Other manifestations of Aspergillus infections are may be with surgery and amphotericin B it is not antifungal therapy is in these have been used for including the of with amphotericin B amphotericin B amphotericin B or Oral itraconazole may also a in these more since this agent the is there is while the patient is receiving therapy or there is a of Surgical include of a a to the from or or to or may be infections. Aspergillus infections of the may as or an or a The published that mortality in occur as a of with subsequent of and of these is to Aspergillus infections from those caused by other such as or which may of antifungal therapy has been reported to be in some surgical for of the agent with removal of which may not be by antifungals for have also been used Although surgery alone may be in the of in immunocompromised patients, antifungal therapy is also used in the majority of (BIII). in with amphotericin may have a because of There are of with itraconazole, or may be Aspergillus is are reported in drug or or patients on prolonged corticosteroid therapy. may as an of as a of therapy or in the surgery and rarely in patients with no underlying Aspergillus may be in the and may be used for of the course of therapy and (e.g., an amphotericin B has been used for the treatment of these infections as has itraconazole and of may be caused by Aspergillus are to a of such as in a Surgical with therapy is indicated for these infections (BIII). infections. The for Aspergillus infections is by by a surgical or in patients with the those with chronic or drug or is the most caused by Aspergillus with infections Surgical is for these infections. Although an case may be by surgical antifungal therapy is used in B levels in are which may the of drugs that have such as or Itraconazole and has also been used infections. infections caused by Aspergillus species are commonly a of from a of most the which in highly immunocompromised patients. These may be or may not be and occur most commonly on the They as and a with an that is by a Although this is of Aspergillus the is not and a with is indicated to other infections that may in a The majority of infections are caused by fumigatus, or terreus, more Aspergillus has been reported to cause which and in invasive infections to Aspergillus species have been reported in with for which are with Aspergillus These to of of may may also by Aspergillus species. may be caused by Aspergillus species. The of of for a definitive has been antifungal therapy is the of therapy and the are Surgical may be the be in the neutropenic In removal of the in to antifungal therapy is indicated aspergillosis and infections are by surgical in to therapy. Oral itraconazole, with or without therapy, such as is used for infections and Aspergillus species have been reported as a cause of and which is a of aspergillosis. The is rarely isolated from The are and and a of Because of the of amphotericin B the in to the of surgical with is in the of amphotericin B appears case has been with amphotericin B and alone is a of may from of a or from the with or of the may useful in diagnosis. of patients with or have been of antifungal therapy and including appropriate may be as an isolated or with infections. infections are a of that the renal are more in immunocompromised such as patients with or chronic or drug and patients with are at for infections that the renal The of a renal with or without a also occur antifungal therapy is used for of and surgical removal may be indicated. Therapy is by the in by itraconazole or or disease has been with amphotericin B or preparations the of may be since this agent in the with amphotericin B has also been used for and renal infections. infections. antifungal therapy is for aspergillosis The of this with amphotericin B therapy has been this amphotericin or itraconazole, of which in should be Aspergillus has as a of chronic removal is for these infections therapy should be used in and amphotericin B have been as has itraconazole organ with Aspergillus species most in the of infection. The is the most of in the the and in these may in or therapy is but the is infections. Aspergillus species may cause of In to antifungal therapy, surgical of the may be to the infection. aspergilloma. aspergilloma can be as a a pulmonary or of Aspergillus with and have underlying pulmonary disease such as sarcoidosis, or or lung disease The of aspergilloma is made without a lung and the chest are of importance in the diagnosis. pulmonary aspergilloma appears as a of a or and from the of the by an of and is The of an aspergilloma is made the are found in a patient with serum that are for an Aspergillus a with for aspergilloma some patients who corticosteroids may be Although aspergillomas are of as saprophytic of the lung with the manifestations of Aspergillus lung disease with a and Invasive pulmonary aspergillosis may from an aspergilloma and is chronic of Aspergillus has been in which symptoms (e.g., and are an aspergilloma is on chest radiograph, and evidence of is found on of lung is a of aspergilloma and may in is the cause of in to of patients with aspergilloma that aspergilloma on preventing life-threatening hemoptysis, patients with symptoms are candidates for therapy. have been that suggest a with aspergilloma. These include the of the underlying lung increasing or of aspergillomas on chest increasing Aspergillus-specific IgG titers underlying and Although not it that patients who have an of would be at of a life-threatening There is no consensus the treatment of aspergilloma. or randomized trials have been treatment have been from trials and case The decision in the of aspergilloma is therapy is Since life-threatening in a of patients, it may be to all patients with aspergilloma to therapy, since therapy is with significant morbidity and treatment for aspergilloma is surgical surgery has been with a morbidity and mortality is owing to the of and the of of the mortality is and such as and are that to the surgical of is that aspergillomas to in with pulmonary function in patients, surgery is because of underlying pulmonary has been that surgical of aspergilloma be to patients with and adequate pulmonary function and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). The course of the in the of surgery about surgical Bronchial artery embolization has been used to the that the in patients from aspergilloma other are in and can be is or and a patient who can for from the pulmonary and to the will not be successful should be considered as a temporizing procedure in a patient with life-threatening hemoptysis, who be for more definitive therapy the (BIII). for aspergillomas have therapy intracavitary or instillation of antifungal antifungals and antifungals symptoms (e.g., or are may be related in to with agent or to allergic has been in patients with evidence of (e.g., IgE and given corticosteroid therapy such therapy the of to invasive or disease of an infection. of these studies Intravenous amphotericin B for aspergilloma provided no pulmonary that used or intracavitary instillation of amphotericin B for aspergilloma of patients resolution or clinical is more in the patient with pulmonary The use of itraconazole for aspergilloma has been reported in several studies of these studies and not a the dose and duration of itraconazole therapy not the of these studies suggest that itraconazole may be in the treatment of aspergilloma (BIII). is a disease of the caused by initially as a disease by pulmonary and and or for ABPA proposed to Aspergillus to Aspergillus serum of pulmonary or and The of ABPA likely the and the of all made the certain of Aspergillus in by use of a of of or specific IgE directed against Aspergillus to Aspergillus and on with ABPA has been reported to be in of patients with in the patients with have with Aspergillus and ABPA these patients may be at for invasive aspergillosis lung transplantation is the chest in ABPA of that in the and may be These are commonly caused by with The with may a or a These are a of the disease and may be by a or may be on chest The of ABPA should be considered in a asthmatic or an asthmatic with any of the ABPA may clinical of acute to to lung disease with lung Therapy in ABPA is directed at acute asthmatic exacerbations and of Although corticosteroid therapy is the of therapy for ABPA, there is a paucity of data The studies of corticosteroids for ABPA have numbers of patients and have been nor and the corticosteroid dose has despite these data support the of corticosteroids in the of acute ABPA (AII). ABPA patients with mg/kg/d of for 1 followed by other made to The symptoms of and rapidly with this the dose of most patients developed symptoms of that with corticosteroids in most IgE levels with disease since with a clinical to corticosteroids and increased exacerbations of There have been studies that the treatment of chronic ABPA with and all have been ABPA patients for and found that patients a chronic course by pulmonary with in lung not a to as several asymptomatic patients developed and lung that in chronic lung doses in episodes of patients with pulmonary of ABPA patients given chronic corticosteroid therapy likely to those given These found that of for an to the of pulmonary the clinical course of patients with ABPA a of of with at a dose of There no significant in spirometry the These data are since pulmonary function not the a would be to the by a in a Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids are (BII). Multiple asthmatic exacerbations in an ABPA patient suggest that corticosteroid therapy should be at a dose of of (BIII). The decision to the of corticosteroids should be made on an individual basis, depending on the clinical course (BIII). to the treatment of ABPA is to Aspergillus species from the and oral are not in preventing In a Aspergillus-specific IgG and symptoms in ABPA patients. subsequent of an that not randomized no from trials have indicated that itraconazole is useful as therapy in ABPA, because the corticosteroid dose can be pulmonary function is and IgE levels recently for ABPA that itraconazole, for in significant in to as by the in corticosteroid dose and IgE and the in and in pulmonary Itraconazole may be useful as a agent (BII). corticosteroids not to be for ABPA some this may be a useful in some patients and suggest doses may be in to with exacerbations of ABPA there have been no studies of to ABPA, and the of such therapy therapy or of in the have not been

A review of series of > or = 4 cases of invasive aspergillosis (total, 1,223 cases) was undertaken to establish the crude mortality and rate of response to therapy with amphotericin B in the major at-risk host groups. In association with pulmonary, sinus, and cerebral aspergillosis in immunocompromised patients, the crude mortality rates were 86%, 66%, and 99%, respectively. No untreated patient survived. Among 84 patients treated for 1-13 days, only one survived. Among those with invasive pulmonary aspergillosis treated for > or = 14 days, the response rates to amphotericin B deoxycholate were 83% (in cases of heart and renal transplantation), 54% (leukemia), 33% (bone marrow transplantation) and 20% (liver transplantation). Patients with AIDS mostly received both amphotericin B and itraconazole, and 37% of those treated for > or = 14 days responded to therapy. Substantial variation in outcome from series to series was related to underlying disease status, site of disease, and management. Invasive aspergillosis remains a devastating opportunistic infection despite current treatment.

OBJECTIVES: To evaluate the risk of serious infections (SIs) in patients with RA treated with anti-TNF therapy with emphasis on the risk across different ages. METHODS: Using data from the British Society for Rheumatology Biologics Register, a prospective observational study, we compared the risk of SI between 11 798 anti-TNF-treated patients and 3598 non-biologic DMARD (nbDMARD)-treated patients. RESULTS: A total of 1808 patients had at least one SI (anti-TNF: 1512; nbDMARD: 296). Incidence rates were: anti-TNF 42/1000 patient-years of follow-up (95% CI 40, 44) and nbDMARD 32/1000 patient-years of follow-up (95% CI 28, 36). The adjusted hazard ratio (adjHR) for SI in the anti-TNF cohort was 1.2 (95% CI 1.1, 1.5). The risk did not differ significantly between the three agents adalimumab, etanercept and infliximab. The risk was highest during the first 6 months of therapy [adjHR 1.8 (95% CI 1.3, 2.6)]. Although increasing age was an independent risk factor for SI in both cohorts, there was no difference in relative risk of infection in patients on anti-TNF therapy in the older population. There was no difference in hospital stay for SI between cohorts. Mortality within 30 days of SI was 50% lower in the anti-TNF cohort [odds ratio 0.5 (95% CI 0.3, 0.8)]. CONCLUSIONS: These data add to currently available evidence suggesting that anti-TNF therapy is associated with a small but significant overall risk of SI. This must be balanced against the risks associated with poor disease control or alternative treatments.

The importance of power and sample size estimation for study design and analysis.

PURPOSE: In patients with neutropenia, thoracic computed tomography (CT) halo and air-crescent signs are recognized as major indicators of invasive pulmonary aspergillosis (IPA). Nevertheless, the exact timing of CT images is not well known. PATIENTS AND METHODS: Seventy-one thoracic CT scans were analyzed in 25 patients with neutropenia with surgically proven IPA. RESULTS: On the first day of IPA diagnosis with early CT scan (d0), a typical CT halo sign was observed in 24 of 25 patients. At that time, the median number of thoracic lesions was two (range, one to six), and pulmonary involvement was bilateral in 12 cases. The halo sign was present in 68%, 22%, and 19% of cases on d3, d7, and d14, respectively. Similarly, the air-crescent sign was seen in 8%, 28%, and 63% of cases on the same days. Otherwise, a nonspecific air-space consolidation aspect was seen in 31%, 50%, and 18% of cases on the same days. The analysis of calculated aspergillary volumes on CT showed that, despite antifungal treatment, the median volume of lesions increased four-fold from d0 to d7, whereas it remained stable from d7 to d14. Overall, 21 patients (84%) were cured by the medical-surgical approach. CONCLUSION: In patients with neutropenia, CT halo sign is a highly effective modality for IPA diagnosis. The duration of the halo sign is short, and it demonstrates the value of early CT. The increase of the aspergillosis size on CT in the first days after IPA diagnosis is not correlated with a pejorative immediate outcome when using a combined medical-surgical approach.

We describe 18 nonimmunocompromised patients with chronic pulmonary aspergillosis. Duration of the disease ranged from several months to >12 years. All 18 patients had prior pulmonary disease. Weight loss, chronic cough (often with hemoptysis and shortness of breath), fatigue, and chest pain were the most common symptoms. All 18 patients had cavities, usually multiple and in 1 or both upper lobes of the lung, that expanded over time, with or without intraluminal fungal balls. All had detectable Aspergillus precipitins and inflammatory markers. Elevated levels of total immunoglobulin E were seen in 78% of patients and of Aspergillus-specific immunoglobulin E in 64%. Directed lung biopsies showed chronic inflammation, necrosis, or granulomas without hyphal invasion. Antifungal therapy with itraconazole resulted in 71% of patients improved or stabilized, with relapse common. Interferon-gamma treatment was useful in 3 patients. In azole nonresponders, modest responses to intravenous amphotericin B (80%) followed by itraconazole were seen. Surgery removed disease but postoperative pleural aspergillosis was inevitable. Indicators of good long-term medical outcomes were mild symptoms, thin-walled quiescent cavities, residual pleural fibrosis, and normal inflammatory markers.

Invasive aspergillosis is an increasingly frequent opportunistic infection in immunocompromised patients. Only two agents, amphotericin B and itraconazole, are licensed for therapy. Itraconazole acts through inhibition of a P-450 enzyme undertaking sterol 14alpha demethylation. In vitro resistance in Aspergillus fumigatus to itraconazole correlated with in vivo outcome has not been previously described. For three isolates (AF72, AF90, and AF91) of A. fumigatus from two patients with invasive aspergillosis itraconazole MICs were elevated. A neutropenic murine model was used to establish the validity of the MICs. The isolates were typed by random amplification of polymorphic DNA. Analysis of sterols, inhibition of cell-free sterol biosynthesis from [14C] mevalonate, quantitation of P-450 content, and [3H]itraconazole concentration in mycelial pellets were used to determine the mechanisms of resistance. The MICs for the three resistant isolates were >16 microg/ml. In vitro resistance was confirmed in vivo for all three isolates. Molecular typing showed the isolates from the two patients to be genetically distinct. Compared to the susceptible isolate from patient 1, AF72 had a reduced ergosterol content, greater quantities of sterol intermediates, a similar susceptibility to itraconazole in cell-free ergosterol biosynthesis, and a reduced intracellular [3H]itraconazole concentration. In contrast, AF91 and AF92 had slightly higher ergosterol and lower intermediate sterol concentrations, fivefold increased resistance in cell-free systems to the effect of itraconazole on sterol 14alpha demethylation, and intracellular [3H] itraconazole concentrations found in susceptible isolates. Resistance to itraconazole in A. fumigatus is detectable in vitro and is present in wild-type isolates, and at least two mechanisms of resistance are responsible.

BACKGROUND: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population. METHODS: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure, web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19 outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within 28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN, number 30448031. FINDINGS: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone, and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33). There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir. INTERPRETATION: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community. FUNDING: UK National Institute for Health and Care Research.

This consensus report of the EGILS (European Gastro-Intestinal Lymphoma Study) group includes recommendations on the management of gastric extranodal marginal zone B-cell lymphoma of MALT. They are based on data from the literature and on intensive discussions and votings of the experts during their annual meetings.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

RATIONALE: Some patients with severe asthma are immunologically sensitized to one or more fungi, a clinical entity categorized as severe asthma with fungal sensitization (SAFS). It is not known whether SAFS responds to antifungal therapy. OBJECTIVES: To evaluate the response of SAFS to oral itraconazole. METHODS: Patients with severe asthma sensitized to at least one of seven fungi by skin prick or specific IgE testing were recruited. All had total IgE less than 1,000 IU/ml and negative Aspergillus precipitins. They were treated with oral itraconazole (200 mg twice daily) or placebo for 32 weeks, with follow-up for 16 weeks. MEASUREMENTS AND MAIN RESULTS: The primary end point was change in the Asthma Quality of Life Questionnaire (AQLQ) score, with rhinitis score, total IgE, and respiratory function as secondary end points. Fifty-eight patients were enrolled, of whom 41% had been hospitalized in the previous year. Baseline mean AQLQ score was 4.13 (range, 1-7). At 32 weeks, the improvement (95% confidence interval) in AQLQ score was +0.85 (0.28, 1.41) in the antifungal group, compared with a -0.01 (-0.43, 0.42) change in the placebo group (P = 0.014). Rhinitis score improved (-0.43) in the antifungal, and deteriorated (+0.17) in the placebo group (P = 0.013). Morning peak flow improved (20.8 L/minute, P = 0.028) in the antifungal group. Total serum IgE decreased in the antifungal group (-51 IU/ml) but increased in placebo group (+30 IU/ml) (P = 0.001). No severe adverse events were observed, but seven patients developed adverse events requiring discontinuation, five in the antifungal group. CONCLUSIONS: SAFS responds to oral antifungal therapy as judged by large improvements in quality of life in about 60% of patients.

The Joint British Diabetes Societies guidelines for the management of diabetic ketoacidosis (these do not cover Hyperosmolar Hyperglycaemic Syndrome) are available in full at: (i) http://www.diabetes.org.uk/About_us/Our_Views/Care_recommendations/The-Management-of-Diabetic-Ketoacidosis-in-Adults; (ii) http://www.diabetes.nhs.uk/publications_and_resources/reports_and_guidance; (iii) http://www.diabetologists-abcd.org.uk/JBDS_DKA_Management.pdf. This article summarizes the main changes from previous guidelines and discusses the rationale for the new recommendations. The key points are: Monitoring of the response to treatment (i) The method of choice for monitoring the response to treatment is bedside measurement of capillary blood ketones using a ketone meter. (ii) If blood ketone measurement is not available, venous pH and bicarbonate should be used in conjunction with bedside blood glucose monitoring to assess treatment response. (iii) Venous blood should be used rather than arterial (unless respiratory problems dictate otherwise) in blood gas analysers. (iv) Intermittent laboratory confirmation of pH, bicarbonate and electrolytes only. Insulin administration (i) Insulin should be infused intravenously at a weight-based fixed rate until the ketosis has resolved. (ii) When the blood glucose falls below 14 mmol/l, 10% glucose should be added to allow the fixed-rate insulin to be continued. (iii) If already taking, long-acting insulin analogues such as insulin glargine (Lantus(®), Sanofi Aventis, Guildford, Surry, UK) or insulin detemir (Levemir(®), Novo Nordisk, Crawley, West Sussex, UK.) should be continued in usual doses. Delivery of care (i) The diabetes specialist team should be involved as soon as possible. (ii) Patients should be nursed in areas where staff are experienced in the management of ketoacidosis.

BACKGROUND: This study sought to establish the long-term effects of Covid-19 following hospitalisation. METHODS: 327 hospitalised participants, with SARS-CoV-2 infection were recruited into a prospective multicentre cohort study at least 3 months post-discharge. The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, disability (Washington group short scale), breathlessness (MRC Dyspnoea scale) and quality of life (EQ5D-5L). FINDINGS: 55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse following acute illness (median difference 0.1 points on a scale of 0 to 1, IQR: -0.2 to 0.0). Females under the age of 50 years were five times less likely to report feeling recovered (adjusted OR 5.09, 95% CI 1.64 to 15.74), were more likely to have greater disability (adjusted OR 4.22, 95% CI 1.12 to 15.94), twice as likely to report worse fatigue (adjusted OR 2.06, 95% CI 0.81 to 3.31) and seven times more likely to become more breathless (adjusted OR 7.15, 95% CI 2.24 to 22.83) than men of the same age. INTERPRETATION: Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females. FUNDING: National Institute for Health Research, UK Medical Research Council, Wellcome Trust, Department for International Development and the Bill and Melinda Gates Foundation.