Publications by authors named "David W Denning"

317 Publications

Diagnostic dilemma in COVID-19-associated pulmonary aspergillosis.

Lancet Infect Dis 2021 Mar 1. Epub 2021 Mar 1.

Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

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http://dx.doi.org/10.1016/S1473-3099(21)00066-9DOI Listing
March 2021

The global incidence and diagnosis of fungal keratitis.

Lancet Infect Dis 2021 03 22;21(3):e49-e57. Epub 2020 Oct 22.

University of Manchester, Manchester, UK; National Aspergillosis Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester UK; Global Action Fund for Fungal Infections, Geneva, Switzerland. Electronic address:

Fungal keratitis is a severe corneal infection that often results in blindness and eye loss. The disease is most prevalent in tropical and subtropical climates, and infected individuals are frequently young agricultural workers of low socioeconomic status. Early diagnosis and treatment can preserve vision. Here, we discuss the fungal keratitis diagnostic literature and estimate the global burden through a complete systematic literature review from January, 1946 to July, 2019. An adapted GRADE score was used to evaluate incidence papers-116 studies provided the incidence of fungal keratitis as a proportion of microbial keratitis and 18 provided the incidence in a defined population. We calculated a minimum annual incidence estimate of 1 051 787 cases (736 251-1 367 323), with the highest rates in Asia and Africa. If all culture-negative cases are assumed to be fungal, the annual incidence would be 1 480 916 cases (1 036 641-1 925 191). In three case series, 8-11% of patients had to have the eye removed, which represents an annual loss of 84 143-115 697 eyes. As fungal keratitis probably affects over a million people annually, an inexpensive, simple diagnostic method and affordable treatment are needed in every country.
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http://dx.doi.org/10.1016/S1473-3099(20)30448-5DOI Listing
March 2021

Effect of patient immunodeficiencies on the diagnostic performance of serological assays to detect Aspergillus-specific antibodies in chronic pulmonary aspergillosis.

Respir Med 2021 Mar 12;178:106290. Epub 2021 Jan 12.

Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom. Electronic address:

Background: Prevalence of chronic pulmonary aspergillosis (CPA) is ~3 million patients worldwide, and detection of Aspergillus-specific antibody is a critical diagnostic component. Some patients with CPA have subtle immune deficits possibly contributing to poor Aspergillus antibody production and false negative results.

Materials/methods: We analyzed patient data from 167 cases of clinically confirmed CPA previously evaluated by ImmunoCAP Aspergillus-specific IgG EIA, Bordier ELISA and LDBio Aspergillus IgG/IgM ICT lateral flow assay, to identify deficiencies in: mannose binding lectin (MBL), IgG, IgA, IgM, IFN gamma, IL12 or IL17 production, and/or low cell marker counts (CD4, CD19, CD56). We defined patients as 'sero-negative' if ImmunoCAP Aspergillus IgG was consistently and repeatedly negative (<40 mg A/L). 'Sero-positive' was defined as all other CPA cases.

Results: We found the rate of false negatives by ImmunoCAP Aspergillus IgG EIA (n = 23) to be more prevalent in patients with immunodeficiency markers, especially multiple defects. MBL deficiency combined with low CD19 cells (p < 0.001), pneumococcal antibody levels (p = 0.043), IgM (p = 0.047) or three combined (p = 0.001-0.018) or all four together (p = 0.018) were significant. The performance LDBio Aspergillus IgG/IgM ICT appears to be relatively unaffected by immunodeficiency (92.7% of ImmunoCap sero-negatives were positive). The Bordier assay performed significantly better than the ImmunoCAP assay (P = 0.0016) for sero-negative CPA cases.

Conclusions: In select cases of CPA, ImmunoCAP EIA yields a false negative result, making serological diagnosis difficult. ImmunoCAP false negatives are more prevalent in patients with multiple immunological defects, who may still be positive with the LDBio Aspergillus ICT or Bordier EIA.
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http://dx.doi.org/10.1016/j.rmed.2020.106290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957343PMC
March 2021

Estimated Burden of Fungal Infections in Oman.

J Fungi (Basel) 2020 Dec 23;7(1). Epub 2020 Dec 23.

Manchester Fungal Infection Group, Manchester Academic Health Science Centre, The University of Manchester, Manchester M13 9PL, UK.

For many years, fungi have emerged as significant and frequent opportunistic pathogens and nosocomial infections in many different populations at risk. Fungal infections include disease that varies from superficial to disseminated infections which are often fatal. No fungal disease is reportable in Oman. Many cases are admitted with underlying pathology, and fungal infection is often not documented. The burden of fungal infections in Oman is still unknown. Using disease frequencies from heterogeneous and robust data sources, we provide an estimation of the incidence and prevalence of Oman's fungal diseases. An estimated 79,520 people in Oman are affected by a serious fungal infection each year, 1.7% of the population, not including fungal skin infections, chronic fungal rhinosinusitis or otitis externa. These figures are dominated by vaginal candidiasis, followed by allergic respiratory disease (fungal asthma). An estimated 244 patients develop invasive aspergillosis and at least 230 candidemia annually (5.4 and 5.0 per 100,000). Only culture and microscopy are currently available for diagnosis, so case detection is suboptimal. Uncertainty surrounds these figures that trigger the need for urgent local epidemiological studies with more sensitive diagnostics.
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http://dx.doi.org/10.3390/jof7010005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823708PMC
December 2020

The role of antifungals in the management of patients with severe asthma.

Clin Transl Allergy 2020 Nov 6;10(1):46. Epub 2020 Nov 6.

Manchester Fungal Infection Group (MFIG), Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, M13 9PL, UK.

In patients with asthma, the inhalation of elevated amounts of fungal spores and hyphae may precipitate the onset of asthma or worsen control to the extent of being life-threatening. Sensitisation to fungi, especially Aspergillus fumigatus, is found in 15% to 48% of asthmatics in secondary care and is linked to worse asthma control, hospitalisation, bronchiectasis and fixed airflow obstruction, irrespective of whether allergic bronchopulmonary aspergillosis (ABPA) is diagnosed. ABPA represents a florid response to the presence of Aspergillus spp. but up to 70% of patients with severe asthma exhibit sensitisation to different fungi without meeting the diagnostic criteria for ABPA. The presence of persistent endobronchial colonisation with fungi, especially A. fumigatus, is linked to significantly higher rates of radiological abnormalities, lower post-bronchodilator FEV1 and significantly less reversibility to short acting bronchodilators. The therapeutic benefit for antifungal intervention in severe asthma is based on the assumption that reductions in airway fungal burden may result in improvements in asthma control, lung function and symptoms (especially cough). This contention is supported by several prospective studies which demonstrate the effectiveness of antifungals for the treatment of ABPA. Significantly, these studies confirm lower toxicity of treatment with azoles versus high dose oral corticosteroid dosing regimens for ABPA. Here we review recent evidence for the role of fungi in the progression of severe asthma and provide recommendations for the use of antifungal agents in patients with severe asthma, airways fungal infection (mycosis) and fungal colonisation. Documenting fungal airways colonisation and sensitisation in those with severe asthma opens up alternative therapy options of antifungal therapy, which may be particularly valuable in low resource settings.
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http://dx.doi.org/10.1186/s13601-020-00353-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646070PMC
November 2020

Ending deaths from HIV-related cryptococcal meningitis by 2030.

Lancet Infect Dis 2021 01 30;21(1):16-18. Epub 2020 Nov 30.

Centre for Infectious Disease Epidemiology and Research, University of Cape Town, Cape Town, South Africa; Southern Africa Medical Unit, Doctors Without Borders Southern Africa, Cape Town, South Africa.

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http://dx.doi.org/10.1016/S1473-3099(20)30909-9DOI Listing
January 2021

Human Fungal Infections in Kuwait-Burden and Diagnostic Gaps.

J Fungi (Basel) 2020 Nov 21;6(4). Epub 2020 Nov 21.

Manchester Fungal Infection Group, The University of Manchester and the Manchester Academic Health Science Centre, Manchester M13 9PL, UK.

Fungal infections are an increasingly important public health issue, yet accurate statistics on fungal burden worldwide and in Kuwait are scarce. Here we estimate the incidence and prevalence of fungal infections in Kuwait. Population statistics from 2018 collected by the Public Authority for Civil Information were used, as well as data from the Ministry of Health. A literature search for Kuwait data on mycotic diseases and population at risk (chronic obstructive pulmonary disease, HIV infection/AIDS, cancer, and transplant patients) was conducted. The population in 2018 was estimated at 4,226,920 million people: 1,303,246 million Kuwaitis and 2,923,674 million expatriates. We determined the annual burden of serious fungal infections number (per 100,000) from high to low based on earlier reported fungal rates for populations at risk: recurrent vaginitis 54,842 (2595); severe asthma with fungal sensitisation 10,411 (246); allergic bronchopulmonary aspergillosis, 7887 (187); chronic pulmonary aspergillosis 995 (21.3); invasive aspergillosis 704 (16.7); fungal keratitis 654 (15.5); candidaemia 288 (6.8); peritonitis 63 (3.5) and oesophageal candidiasis in HIV 33 (0.8). Besides identifying rising new risk groups and expanding reports on antifungal resistance, surveillance programs and further epidemiological studies are needed to achieve more precise assessments of fungal disease epidemiology and correlated morbidity and mortality.
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http://dx.doi.org/10.3390/jof6040306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711545PMC
November 2020

Non-infectious status indicated by detectable IgG antibody to SARS-CoV-2.

Br Dent J 2020 10 23;229(8):521-524. Epub 2020 Oct 23.

Postgraduate Dental Studies, School of Health and Society, University of Salford, Greater Manchester, UK; ICE Postgraduate Dental Institute & Hospital, Salford Quays, Salford, M50 3XZ, UK.

A key tenet of protection from infection for dentists is to know who is not infectious. The evidence base regarding protection from respiratory pathogens in dentistry is poor. Those with a positive SARS-CoV-2 IgG antibody are non-infectious (>99% certainty) and can be safely treated with good universal precautions, even for aerosol generating procedures. Viral infectivity with SARS-CoV-2 lasts eight days, unlike viral polymerase chain reaction (PCR) swab tests which can persist for as long as seven weeks. SARS-CoV-2 IgG antibody becomes detectable from 11 days after infection. SARS-CoV-2 IgG antibodies are usually neutralising against the virus and their direct antiviral activity was partially demonstrated in 33,000 patients with COVID-19 treated with convalescent plasma in the USA. So, a positive SARS-CoV-2 IgG antibody is a much more accurate determination of infectiousness than a repeat PCR which is only 70% sensitive. It remains to be seen whether SARS-Cov-2 vaccine responses include protective IgG titres and, once vaccines become widespread, can be used to assist decision-making on appropriate personal protective equipment (PPE) in dentistry.
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http://dx.doi.org/10.1038/s41415-020-2228-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582419PMC
October 2020

Attainment of therapeutic posaconazole serum levels during co-administration with rifampicin.

J Glob Antimicrob Resist 2020 12 20;23:284-285. Epub 2020 Oct 20.

National Aspergillosis Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Southmoor Road, Manchester M23 9LT, UK; Division of Infection, Inflammation and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PL, UK.

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http://dx.doi.org/10.1016/j.jgar.2020.09.029DOI Listing
December 2020

Evaluation of the LDBio Aspergillus ICT lateral flow assay for serodiagnosis of allergic bronchopulmonary aspergillosis.

PLoS One 2020 25;15(9):e0238855. Epub 2020 Sep 25.

Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom.

Background: Early recognition and diagnosis of allergic bronchopulmonary aspergillosis (ABPA) is critical to improve patient symptoms, and antifungal therapy may prevent or delay progression of bronchiectasis and development of chronic pulmonary aspergillosis.

Objective: A recently commercialized lateral flow assay (Aspergillus ICT) (LDBio Diagnostics, Lyons, France) detects Aspergillus-specific antibodies in <30 minutes, requiring minimal laboratory equipment. We evaluated this assay for diagnosis of ABPA compared to diseased (asthma and/or bronchiectasis) controls.

Methods: ABPA and control sera collected at the National Aspergillosis Centre (Manchester, UK) and/or from the Manchester Allergy, Respiratory and Thoracic Surgery research biobank were evaluated using the Aspergillus ICT assay. Results were read both visually and digitally (using a lateral flow reader). Serological Aspergillus-specific IgG and IgE, and total IgE titres were measured by ImmunoCAP.

Results: For 106 cases of ABPA versus all diseased controls, sensitivity and specificity for the Aspergillus ICT were 90.6% and 87.2%, respectively. Sensitivity for 'proven' ABPA alone (n = 96) was 89.8%, and 94.4% for 'presumed' ABPA (n = 18). 'Asthma only' controls (no bronchiectasis) and 'bronchiectasis controls' exhibited 91.4% and 81.7% specificity, respectively. Comparison of Aspergillus ICT result with Aspergillus-specific IgG and IgE titres showed no evident immunoglobulin isotype bias. Digital measurements displayed no correlation between ImmunoCAP Aspergillus-specific IgE level and ICT test line intensity.

Conclusions: The Aspergillus ICT assay exhibits good sensitivity for ABPA serological screening. It is easy to perform and interpret, using minimal equipment and resources; and provides a valuable simple screening resource to rapidly distinguish more serious respiratory conditions from Aspergillus sensitization alone.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238855PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518618PMC
November 2020

The global distribution of actinomycetoma and eumycetoma.

PLoS Negl Trop Dis 2020 09 24;14(9):e0008397. Epub 2020 Sep 24.

The University of Manchester, National Aspergillosis Centre, Wythenshawe Hospital, Manchester Academic Health Science Centre, United Kingdom.

Background: Mycetoma, a chronic infection of the skin and underlying structures, affects those with a close relationship to the land, often in resource-poor areas of the world. Whether caused by any one of a variety of fungus or bacteria, mycetoma causes significant disability and mortality. Acknowledged as a neglected tropical disease (NTD) by the World Health Organization (WHO) in 2016, mycetoma is susceptible to being misunderstood, misdiagnosed, and mismanaged. In an effort to shift the balance in favor of recognition and effective treatment, sound epidemiological understanding is required.

Methods And Findings: In this paper, a literature review of case reports and series (332 papers in total) is presented as three maps. We identified 19,494 cases dating from 1876 to 2019, with cases contracted in 102 countries. The first map shows where mycetoma has ever been reported, the second shows how many cases have been reported, and the third shows the ratio of eumycetoma (fungal) to actinomycetoma (bacterial). Most cases are found in Mexico, India, and Sudan, where mycetoma is studied rigorously. We identified emergence of new geographical loci, including the United States, Venezuela, Italy, China, and Australia. Notably, mycetoma is reported far outside the tropics. In the Americas, bacterial forms dominate, whereas, in Africa and Asia, the picture is more varied.

Conclusions: With better understanding of the epidemiology of mycetoma, more can be done to direct education, preventive measures, and treatment to at-risk areas, enabling a reduction in disease burden.
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http://dx.doi.org/10.1371/journal.pntd.0008397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7514014PMC
September 2020

The global impact of Aspergillus infection on COPD.

BMC Pulm Med 2020 Sep 11;20(1):241. Epub 2020 Sep 11.

Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester and Manchester Academic Health Science Centre, Manchester, UK.

Background: Advanced chronic obstructive pulmonary disease (COPD) often leads to hospitalisation and invasive aspergillosis (IA) is a serious complication. Aspergillus sensitisation may worsen symptoms in COPD.

Methods: We identified published papers between January 2000 and May 2019 with > 50 subjects and GOLD criteria for grade II, III or IV (FEV1/FVC < 70% and FEV1 < 80%) using standardised criteria in multiple countries, to re-estimate the prevalence of COPD. Hospitalised COPD patients develop IA in 1.3-3.9%, based on positive cultures of Aspergillus spp. and radiological findings. Given limited data on per-patient annual hospitalisation rates, we assumed a conservative 10.5% estimate. Annual IA mortality in COPD was estimated using the literature rates of 43-72%. A separate literature search assessed the impact of Aspergillus sensitisation on severity of COPD (by FEV1).

Results: We re-estimated the global prevalence of COPD GOLD stages II-IV at 552,300,599 people (7.39% of the population) with 339,206,893 (8.58%) in Asia, 85,278,783 (8.52%) in the Americas, 64,298,051 (5.37%) in Africa, 59,484,329 (7.77%) in Europe and 4,032,543 (10.86%) in Oceania. An estimated 57,991,563 (10.5%) people with COPD are admitted to hospital annually and of these 753,073 (1.3%) - 2,272,322 (3.9%) develop IA and 540,451-977,082 deaths are predicted annually. Aspergillus sensitisation prevalence in COPD was 13.6% (7.0-18.3%) and not related to lower predicted FEV1% (P > 0.05).

Conclusions: The prevalence of COPD is much higher than previously estimated. Overall COPD mortality may be higher than estimated and IA probably contributes to many deaths. Improved rapid diagnosis of IA using culture and non-culture based techniques is required in COPD hospital admissions to reduce mortality.
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http://dx.doi.org/10.1186/s12890-020-01259-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488557PMC
September 2020

Deciphering Aspergillus fumigatus cyp51A-mediated triazole resistance by pyrosequencing of respiratory specimens.

J Antimicrob Chemother 2020 12;75(12):3501-3509

Mycology Reference Centre Manchester, ECMM Centre of Excellence, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Wythenshawe Hospital, Manchester, UK.

Background: Infections caused by triazole drug-resistant Aspergillus fumigatus are an increasing problem. The sensitivity of standard culture is poor, abrogating susceptibility testing. Early detection of resistance can improve patient outcomes, yet tools for this purpose are limited.

Objectives: To develop and validate a pyrosequencing technique to detect resistance-conferring cyp51A polymorphisms from clinical respiratory specimens and A. fumigatus isolates.

Methods: Method validation was performed by Sanger sequencing and pyrosequencing of 50 A. fumigatus isolates with a spectrum of triazole susceptibility patterns. Then, 326 Aspergillus quantitative PCR (qPCR)-positive respiratory samples collected over a 27 month period (January 2017-March 2019) from 160 patients at the UK National Aspergillosis Centre were assessed by cyp51A pyrosequencing. The Sanger sequencing and pyrosequencing results were compared with those from high-volume culture and standard susceptibility testing.

Results: The cyp51A genotypes of the 50 isolates analysed by pyrosequencing and Sanger sequencing matched. Of the 326 Aspergillus qPCR-positive respiratory specimens, 71.2% were reported with no A. fumigatus growth. Of these, 56.9% (132/232) demonstrated a WT cyp51A genotype and 31.5% (73/232) a resistant genotype by pyrosequencing. Pyrosequencing identified the environmental TR34/L98H mutation in 18.7% (61/326) of the samples in contrast to 6.4% (21/326) pan-azole resistance detected by culture. Importantly, pyrosequencing detected resistance earlier than culture in 23.3% of specimens.

Conclusions: The pyrosequencing assay described could detect a wide range of cyp51A polymorphisms associated with triazole resistance, including those not identified by commercial assays. This method allowed prompt recognition of resistance and the selection of appropriate antifungal treatment when culture was negative.
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http://dx.doi.org/10.1093/jac/dkaa357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662182PMC
December 2020

The incidence of cutaneous squamous cell carcinoma in patients receiving voriconazole therapy for chronic pulmonary aspergillosis.

Naunyn Schmiedebergs Arch Pharmacol 2020 11 21;393(11):2233-2237. Epub 2020 Aug 21.

Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Voriconazole has been associated with cutaneous squamous cell carcinoma (cSCC) in transplant patients but less is known about the risk in less severely immunosuppressed patients. Our aim was to estimate the incidence of cSCC after voriconazole exposure in patients with chronic pulmonary aspergillosis on a background of chronic lung disease. The notes of patients seen at a tertiary referral centre from 2009 to 2019 with chronic pulmonary aspergillosis were reviewed for the diagnosis of cSCC and voriconazole use documented. Among 1111 patients, 668 (60.1%) received voriconazole for longer than 28 days. Twelve patients received a diagnosis of cSCC; nine had used voriconazole. Mean duration of voriconazole use was 36.7 months. The crude incidence rate was 4.88 in 1000 person/years in those who had voriconazole and 2.79 in 1000 patient/years in those who did not receive voriconazole for longer than 28 days. On Cox regression, age (HR 1.09, 95% CI 1.02-1.16, p = 0.01) and male gender (HR 3.97, 95% CI 0.84-18.90, p = 0.082) were associated with cSCC. Voriconazole use was associated with a slightly increased risk, which was not significant (HR 1.35, 95% CI 0.35-5.20, p = 0.659). Voriconazole use beyond 28 days did not lead to a significantly increased risk of cSCC in a large cohort of patients with chronic pulmonary aspergillosis.
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http://dx.doi.org/10.1007/s00210-020-01950-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578142PMC
November 2020

Risk-Based Estimate of Human Fungal Disease Burden, China.

Emerg Infect Dis 2020 09;26(9):2137-2147

We conducted a systematic literature review to obtain risk population-based fungal disease incidence or prevalence data from China. Data were categorized by risk factors and extrapolated by using most recent demographic figures. A total of 71,316,101 cases (5.0% of the population) were attributed to 12 risk factors and 17 fungal diseases. Excluding recurrent Candida vaginitis (4,057/100,000 women) and onychomycosis (2,600/100,000 persons), aspergillosis (317/100,000 persons) was the most common problem; prevalence exceeded that in most other countries. Cryptococcal meningitis, an opportunistic infection, occurs in immunocompetent persons almost twice as often as AIDS. The pattern of fungal infections also varies geographically; Talaromyces marneffei is distributed mainly in the Pearl River Basin, and the Yangtze River bears the greatest histoplasmosis burden. New host populations, new endemic patterns, and high fungal burdens in China, which caused a huge impact on public health, underscore the urgent need for building diagnostic and therapeutic capacity.
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http://dx.doi.org/10.3201/eid2609.200016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454105PMC
September 2020

Optimising the cut-off of the Bordier Aspergillus IgG ELISA for the diagnosis of chronic pulmonary aspergillosis.

J Microbiol Methods 2020 09 12;176:106021. Epub 2020 Aug 12.

Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom; National Aspergillosis Centre, Manchester University NHS Foundation Trust, Manchester, United Kingdom. Electronic address:

Aspergillus IgG detection is an essential tool in the diagnosis and treatment of chronic pulmonary aspergillosis (CPA), and is often positive in allergic bronchopulmonary aspergillosis and Aspergillus bronchitis. The Bordier ELISA had an 83.3% sensitivity (identical to ImmunoCap at a cut-off of 40mgA/L) and 97.3% specificity using a cut-off of 0.9 and a diagnostic accuracy of 90.9%.
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http://dx.doi.org/10.1016/j.mimet.2020.106021DOI Listing
September 2020

Evaluation and comparison of automated and manual ELISA for diagnosis of chronic pulmonary aspergillosis (CPA) in Indonesia.

Diagn Microbiol Infect Dis 2020 Nov 4;98(3):115124. Epub 2020 Jul 4.

Faculty Biology, Medicine and Health, The University of Manchester and Manchester Academic Health Science Centre, Manchester, United Kingdom; National Aspergillosis Centre, Wythenshawe Hospital, Manchester, United Kingdom.

Pulmonary tuberculosis (TB) is one of the common risk factors for chronic pulmonary aspergillosis (CPA). A positive Aspergillus IgG is a key element of the diagnosis of CPA but this has not been studied in Indonesia. We conducted studies with patients at the end of TB therapy in Indonesia. We performed receiver operating curve (ROC) analysis to determine the optimum cutoff of the Aspergillus-specific IgG level (Immulite and Dynamiker ELISA) in those patients who met criteria of CPA in relation to control groups. In 203 TB patients, 26 (13%) patients had clinical and radiological features of CPA. We derived optimum cutoffs for Immulite Aspergillus-specific IgG of 11.5 mg/L and Dynamiker anti-galactomannan IgG of 106.8 AU/mL (sensitivity 89% and 83%, specificity 78% and 51%, respectively). The currently accepted Aspergillus-specific IgG cutoff of Immulite and Dynamiker assays for CPA diagnosis may require slight adjustment for the Indonesian population.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.115124DOI Listing
November 2020

Comparative performance of the laboratory assays used by a Diagnostic Laboratory Hub for opportunistic infections in people living with HIV.

AIDS 2020 09;34(11):1625-1632

Global Action Fund for Fungal Infections, Geneva, Switzerland.

Objectives: We evaluated the comparative performance of different assays used in a Diagnostic Laboratory Hub that linked 13 HIV healthcare facilities for the diagnosis of tuberculosis (TB), histoplasmosis, and cryptococcosis, and describing its functions in Guatemala compared with other National Reference Laboratories.

Methods: The following diagnostic techniques were analyzed in 24 months (2017-2018) in a cohort of patients with HIV: smear microscopy, mycobacterial and fungal cultures, isolator blood culture, PCR assays, and antigen detection tests.

Results: A total of 4245 patients were included, 716 (16.2%) had an opportunistic infection: 249 (34.7%) TB, 40 (5.6%) nontuberculous mycobacteria, 227 (31.7%) histoplasmosis, 138 (19.3%) cryptococcosis, and 62 (8.6%) had multiple opportunistic infections. Two hundred sixty-three [92.6%; 95% confidence interval (CI), 89-95.1] of TB cases were diagnosed by PCR. Urine antigen assay detected 94% (95% CI, 89-96) of the disseminated histoplasmosis cases. A lateral flow assay to detect cryptococcal antigen diagnosed 97% (95% CI, 93.3-98.7%) of the cryptococcal cases. In 85 patients (51.5%) with a cerobrospinal fluid sample, cryptococcal meningitis was diagnosed in 55 (64.7%), of which 18 (32.7%) were only detected by cryptococcal antigen.

Conclusion: Validated commercial antigen tests, as used in this program, should be the new gold standard for histoplasmosis and cryptococcosis diagnosis. In their absence, 35% of disseminated histoplasmosis and 32.7% of cryptococcal meningitis cases would have been missed. Patients with multiple opportunistic infections were frequently diagnosed and strategies should be designed to screen patients irrespective of their clinical presentation. In low resource settings, Diagnostic Laboratory Hubs can deliver quality diagnostics services in record time at affordable prices.
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http://dx.doi.org/10.1097/QAD.0000000000002631DOI Listing
September 2020

Tackling cryptococcal meningitis in Nigeria, one-step at a time; the impact of training.

PLoS One 2020 6;15(7):e0235577. Epub 2020 Jul 6.

Mycotic Diseases Branch, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, United States of America.

Background: Nigeria is estimated to have 25,000 cases of cryptococcal antigenemia (CrAg) annually. CrAg screening with pre-emptive fluconazole treatment is recommended but not yet implemented in Nigeria. Trainings were conducted to improve health-care provider (HCP) awareness and clinical skills in the management and prevention of cryptococcal meningitis (CM).

Methods: HCPs providing care for people living with HIV were targeted for training at 13 sites from April to November 2018 Course content was adapted from CDC Cryptococcal Screening Program Training Manual and LIFE-website. "Hands-on" training on CrAg testing and lumbar puncture was included. A 14-point pre and post-test assessment instrument was designed to capture the impact of the training and focus group discussions (FGDs) were conducted.

Results: A total of 761 HCPs were trained. 519 HCPs completed the pre-test evaluation while 470 (90.6%) took part in the post-test evaluation. Post-training, HCPs were significantly more likely to respond correctly to all 14 assessment items, with the mean percentage score rising to 91.0% from a pre-training value of 60.0%. FGDs revealed that many of the HCPs were not aware of the CrAg screening and pre-emptive treatment recommendations in Nigerian guidelines, and reported not having seen or managed a case of CM. Also, they highlighted challenges with routine CrAg screening due to a lack of access to CD4 testing, CrAg test kits, antifungal drugs, as well as the need for similar trainings across all tiers of care in Nigeria.

Conclusion: Training significantly improved HCPs' understanding of Nigerian policy on CrAg screening, CM diagnosis and best management practices. This training could be included in routine capacity building efforts for HCPs involved in HIV care in Nigeria.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235577PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7337344PMC
September 2020

Integration of fungal diseases into health systems in Latin America.

Lancet Infect Dis 2020 08 30;20(8):890-892. Epub 2020 Jun 30.

Global Action Fund for Fungal Infections, 1208 Geneva, Switzerland; The National Aspergillosis Centre, Wythenshawe Hospital, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(20)30469-2DOI Listing
August 2020

Skin prick reactivity among asthmatics in East Africa.

World Allergy Organ J 2020 Jun 23;13(6):100130. Epub 2020 Jun 23.

Makerere University Lung Institute, College of Health Sciences, Makerere University, Kampala, Uganda.

Background: The burden of asthma in Africa is high, and yet the disease is not universally prioritised. Data on allergic asthma and its impact on asthma morbidity are limited in Africa. Our aim was to describe the distribution of skin prick positivity among asthmatics in Eastern Africa.

Methods: From August 2016 to May 2018, 1671 asthmatic patients were enrolled from Uganda, Kenya, and Ethiopia as part of the African Severe Asthma Program clinical study. Skin prick testing was performed at baseline using a panel of 12 allergens, and factors associated with skin prick reactivity determined.

Results: Of the 1, 671 patients recruited, 71% were female with a median age of 40 years, 93.6% were aged >15 years and the patterns of asthma symptom frequency was intermittent in 2.9%, mild persistent in 19.9%, moderate persistent in 42.6% and severe persistent in 34.6% at baseline. Self-reported triggers, were dust (92%), cold weather (89%), upper respiratory infections (84%), strong smells (79%) and exposure to tobacco (78%). The majority (90%) of the participants had at least 1 positive allergen reaction, with 0.9% participants reacting to all the 12 allergens. Participants commonly reacted to house dust mites (66%), (62%), and the German cockroach (52%). Patients sensitized to more allergens (>2) had significantly reduced lung function (FEV ≤ 80%; p = 0.001) and were more likely to visit the emergency department due to asthma (p = 0.012). There was no significant relationship between number of allergens and measures of asthma control, quality of life, and other clinical outcomes. Only the country of origin was independently associated with atopy among African asthmatics.

Conclusion: There is a high prevalence of skin prick positivity among East African patients with asthma, with the commonest allergen being house dust mite. Skin reactivity did not correlate well with asthma severity and poor asthma control. The relation between atopy, measured through skin prick testing, and measures of asthma control among asthma patients in Eastern Africa is unclear and needs further study.

Trial Registration: The ASAP study was registered prospectively. ClinicalTrials.gov Identifier: NCT03065920; Registration date: February 28, 2017; Last verified: February 28, 2017.
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http://dx.doi.org/10.1016/j.waojou.2020.100130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322185PMC
June 2020

Pulmonary Aspergillosis in Patients with Suspected Ventilator-associated Pneumonia in UK ICUs.

Am J Respir Crit Care Med 2020 10;202(8):1125-1132

Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom.

infection in patients with suspected ventilator-associated pneumonia remains uncharacterized because of the absence of a disease definition and limited access to sensitive diagnostic tests. To estimate the prevalence and outcomes of infection in adults with suspected ventilator-associated pneumonia. Two prospective UK studies recruited 360 critically ill adults with new or worsening alveolar shadowing on chest X-ray and clinical/hematological parameters supporting suspected ventilator-associated pneumonia. Stored serum and BAL fluid were available from 194 nonneutropenic patients and underwent mycological testing. Patients were categorized as having probable infection using a definition comprising clinical, radiological, and mycological criteria. Mycological criteria included positive histology or microscopy, positive BAL fluid culture, galactomannan optical index of 1 or more in BAL fluid or 0.5 or more in serum. Of 194 patients evaluated, 24 met the definition of probable infection, giving an estimated prevalence of 12.4% (95% confidence interval, 8.1-17.8). All 24 patients had positive galactomannan in serum ( = 4), BAL fluid ( = 16), or both ( = 4); three patients cultured sp. in BAL fluid. Patients with probable infection had a significantly longer median duration of critical care stay (25.5 vs. 15.5 d,  = 0.02). ICU mortality was numerically higher in this group, although this was not statistically significant (33.3% vs. 22.8%;  = 0.23). The estimated prevalence for probable infection in this geographically dispersed multicenter UK cohort indicates that this condition should be considered when investigating patients with suspected ventilator-associated pneumonia, including patient groups not previously recognized to be at high risk of aspergillosis.
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http://dx.doi.org/10.1164/rccm.202002-0355OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560800PMC
October 2020

Intravenous therapy for chronic pulmonary aspergillosis: A systematic review and meta-analysis.

Mycoses 2020 Sep 1;63(9):921-927. Epub 2020 Jul 1.

The National Aspergillosis Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK.

Chronic pulmonary aspergillosis (CPA) is a potentially life-threatening debilitating lung disease necessitating long-term oral antifungal treatment. However, development of antifungal-resistant isolates of Aspergillus and major toxicities requiring discontinuation of treatment limits their use. Intravenous (IV) antifungals are an option in this group of patients. We comprehensively evaluate the response rates to IV antifungals in the management of CPA. We searched Medline and Embase databases to select clinical studies providing information about IV amphotericin B or an echinocandin for the treatment of CPA from inception to May 2020. Reviews, single-case reports and case series reporting <10 patients were excluded. We evaluated 12 eligible studies. A total of 380 patients received amphotericin B (n = 143) or an echinocandin (n = 237) and were included in the meta-analysis. In a pooled analysis, overall response to IV antifungals was 61% ((95% confidence interval (CI): 52%-70%; I  = 73.3%; P < .001), to amphotericin B was 58% (95% CI: 36%-80%; I  = 86.6%; P < .001) and to echinocandins was 62% (95% CI: 53%-72%; I  = 63.6%; P < .001). Amphotericin B courses were usually doses at slightly <1 mg/Kg (deoxycholate) or 3 mg/Kg (liposomal) for 2-3 weeks. Micafungin doses varied from 12.5 to 300 mg (frequently, 150 mg) daily for at least 3 weeks, and sometimes much longer. Liposomal amphotericin B was well tolerated, but led to renal function loss in 25% of patients. Adverse events were observed in 5-35.3% of patients receiving echinocandins, none of which was considered major. Intravenous antifungals have a place in the management of CPA. A head-to-head comparison of amphotericin B and echinocandins is lacking, and future studies should look at evaluating short- and longer-term outcomes of these agents.
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http://dx.doi.org/10.1111/myc.13131DOI Listing
September 2020

Chronic Pulmonary Aspergillosis: Notes for a Clinician in a Resource-Limited Setting Where There Is No Mycologist.

J Fungi (Basel) 2020 Jun 2;6(2). Epub 2020 Jun 2.

The National Aspergillosis Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester M23 9LT, UK.

Chronic pulmonary aspergillosis (CPA) is a spectrum of several progressive disease manifestations caused by species in patients with underlying structural lung diseases. Duration of symptoms longer than three months distinguishes CPA from acute and subacute invasive pulmonary aspergillosis. CPA affects over 3 million individuals worldwide. Its diagnostic approach requires a thorough Clinical, Radiological, Immunological and Mycological (CRIM) assessment. The diagnosis of CPA requires (1) demonstration of one or more cavities with or without a fungal ball present or nodules on chest imaging, (2) direct evidence of infection or an immunological response to species and (3) exclusion of alternative diagnoses, although CPA and mycobacterial disease can be synchronous. antibody is elevated in over 90% of patients and is the cornerstone for CPA diagnosis. Long-term oral antifungal therapy improves quality of life, arrests haemoptysis and prevents disease progression. Itraconazole and voriconazole are alternative first-line agents; voriconazole is preferred for patients with contra-indications to itraconazole and in those with severe disease (including large aspergilloma). In patients co-infected with tuberculosis (TB), it is not possible to treat TB with rifampicin and concurrently administer azoles, because of profound drug interactions. In those with pan-azole resistance or intolerance or progressive disease while on oral triazoles, short-term courses of intravenous liposomal amphotericin B or micafungin is used. Surgery benefits patients with well-circumscribed simple aspergillomas and should be offered earlier in low-resource settings.
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http://dx.doi.org/10.3390/jof6020075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345130PMC
June 2020

Chronic Pulmonary Histoplasmosis-A Scoping Literature Review.

Open Forum Infect Dis 2020 May 6;7(5):ofaa119. Epub 2020 Apr 6.

The University of Manchester and the Manchester Academic Health Service Centre, Manchester, UK.

Chronic pulmonary histoplasmosis (CPH) is an uncommon manifestation of infection with features similar to pulmonary tuberculosis (TB). In endemic areas, it may be misdiagnosed as smear-negative pulmonary TB. Historical case series mainly from patients with presumed TB described a high frequency of cavitation and poor prognosis, likely resulting from delayed presentation. More recent reports suggest that CPH can present with nodules, lymphadenopathy, or infiltrates, with cavities being a less common feature. Emphysema is the main risk factor for cavitary CPH. CPH is therefore an umbrella term, with chronic cavitary pulmonary histoplasmosis and nodules being the main long-term manifestations in nonimmunocompromised individuals. Diagnosis relies on a high index of suspicion, use of fungal culture of respiratory samples, antibody testing, and compatible radiological picture. Treatment with itraconazole for at least 12 months is recommended. Morbidity from CPH results from slow progression of cavities and gradual loss of lung function, especially if not recognized and treated. Studies on the epidemiology of CPH are needed in order to improve understanding of the disease.
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http://dx.doi.org/10.1093/ofid/ofaa119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210804PMC
May 2020

The antiseptic Miramistin: a review of its comparative in vitro and clinical activity.

FEMS Microbiol Rev 2020 07;44(4):399-417

Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Miramistin is a topical antiseptic with broad antimicrobial action, including activity against biofilms and a clinical profile showing good tolerability. Miramistin was developed within a framework of the Soviet Union Cold War Space Program. It is available for clinical use in several prior Soviet bloc countries, but barely known outside of these countries and there is almost no mention of miramistin in the English literature. However, considering emerging antimicrobial resistance, the significant potential of miramistin justifies its re-evaluation for use in other geographical areas and conditions. The review consists of two parts: (i) a review of the existing literature on miramistin in English, Russian and Ukrainian languages; (ii) a summary of most commonly used antiseptics as comparators of miramistin. The oral LD50 was 1200 mg/kg, 1000 mg/kg and 100 g/L in rats, mice and fish, respectively. Based on the results of the review, we suggest possible applications of miramistin and potential benefits over currently used agents. Miramistin offers a novel, low toxicity antiseptic with many potential clinical uses that need better study which could address some of the negative impact of antimicrobial, antiseptic and disinfectant resistance.
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http://dx.doi.org/10.1093/femsre/fuaa012DOI Listing
July 2020

Clinical outcomes of patients with chronic pulmonary aspergillosis managed surgically.

Eur J Cardiothorac Surg 2020 11;58(5):997-1003

Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK.

Objectives: Surgical resection is one treatment modality for chronic pulmonary aspergillosis (CPA), and sometimes a preoperative presumption of lung cancer turns out to be CPA. We have audited our surgical experience with regard to risk factors for relapse, and the value of postoperative monitoring of Aspergillus-immunogolubulin G (IgG) titres.

Methods: All patients with CPA surgically treated at National Aspergillosis Centre (NAC), Manchester, UK (2007-2018), were retrospectively evaluated. Surgical procedures, underlying disorders, Aspergillus-IgG titres (ImmunoCap) and antifungal therapy were evaluated for symptom control, operative complications, CPA relapse and mortality.

Results: A total of 61 patients with CPA (28 males, 33 females) were operated on primarily for antifungal therapy failure (51%, n = 31) and presumed lung malignancies (38%, n = 23). Procedures included lobectomy (64%, n = 39), wedge resection (28%, n = 17), segmentectomy (n = 3), pneumonectomy (n = 3) and decortication (n = 2). Overall, 25 (41%) patients relapsed, 26 months (standard deviation: 24.8 months) after surgery. Antifungal therapy before surgery (P = 0.002) or both before and after surgery (P = 0.005) were protective for relapse. The relapse rate within 3 years after surgery (33%, n = 20) was higher than the 3-10 years after surgery (8%, n = 5). At the end of follow-up, the median Aspergillus-IgG titre was lower than at relapse in 12 patients (67 vs 126 mg/l) (P = 0.016).

Conclusions: Surgery in these selected patients with CPA resulted in favourable outcomes. Relapse is common after surgical treatment of CPA but can be minimized with antifungal therapy, emphasizing the importance of an accurate diagnosis prior to surgery.
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http://dx.doi.org/10.1093/ejcts/ezaa137DOI Listing
November 2020

Threats Posed by the Fungal Kingdom to Humans, Wildlife, and Agriculture.

mBio 2020 05 5;11(3). Epub 2020 May 5.

Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

The fungal kingdom includes at least 6 million eukaryotic species and is remarkable with respect to its profound impact on global health, biodiversity, ecology, agriculture, manufacturing, and biomedical research. Approximately 625 fungal species have been reported to infect vertebrates, 200 of which can be human associated, either as commensals and members of our microbiome or as pathogens that cause infectious diseases. These organisms pose a growing threat to human health with the global increase in the incidence of invasive fungal infections, prevalence of fungal allergy, and the evolution of fungal pathogens resistant to some or all current classes of antifungals. More broadly, there has been an unprecedented and worldwide emergence of fungal pathogens affecting animal and plant biodiversity. Approximately 8,000 species of fungi and Oomycetes are associated with plant disease. Indeed, across agriculture, such fungal diseases of plants include new devastating epidemics of trees and jeopardize food security worldwide by causing epidemics in staple and commodity crops that feed billions. Further, ingestion of mycotoxins contributes to ill health and causes cancer. Coordinated international research efforts, enhanced technology translation, and greater policy outreach by scientists are needed to more fully understand the biology and drivers that underlie the emergence of fungal diseases and to mitigate against their impacts. Here, we focus on poignant examples of emerging fungal threats in each of three areas: human health, wildlife biodiversity, and food security.
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http://dx.doi.org/10.1128/mBio.00449-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403777PMC
May 2020