どこにでもいるアスペルギルス・フミガーツスがワクチン接種者の天敵と化したかもしれない件

The deadly fungus that preys on coronavirus patients and could have killed thousands
By John Naish for the Daily Mail
Published: 17:16 EST, 27 December 2021 | Updated: 06:25 EST, 28 December 2021
Once a patient with severe suffocating Covid-19 is through the doors of a critical care unit, they should be in the safest place to receive life-saving help.
But a further danger may await — a fungus that experts warn is infecting the weakened lungs of one in three Covid patients in intensive care, and killing up to 70 per cent of those affected.
The fungus in question, Aspergillus fumigatus, is all around us — in the air, soil, food and in decaying organic material such as garden compost. It spreads via microscopic spores, although it can be visible as a grey, wrinkled cushion on damp walls. It has also been found in flower beds in hospital grounds.
Aspergillus fumigatus is an opportunistic fungus that preys on people whose immune systems are seriously weakened by illness.
When it invades humans, it causes a condition called aspergillosis, which primarily affects the lungs. There the fungus can grow into a lump up to the size of a tennis ball that can be extremely difficult to eradicate.
The infection can develop into invasive aspergillosis, where it spreads to the skin, brain, heart or kidneys.
Aspergillosis hit the news last month when the widow of a Scottish government official, who died after contracting Covid-19, called on the First Minister of Scotland to investigate the hospital where he was being treated.
Andrew Slorance, who led the Scottish government’s response and communications unit, died nearly six weeks after being admitted to Queen Elizabeth University Hospital, Glasgow, last year. He had gone in for cancer treatment, but then contracted Covid-19.
The hospital listed the cause of Mr Slorance’s death as Covid pneumonia. However, his widow, Louise, requested a copy of his medical notes and discovered her husband had also become infected with Aspergillus fumigatus at the hospital.
She believes this may have brought on his death and claims the hospital ‘never mentioned’ the aspergillus infection to her at the time despite the ‘many mentions of it in the medical records’.
The hospital has denied any ‘attempt to conceal information’. It has not, however, answered Good Health’s questions concerning the role of aspergillosis in Mr Slorance’s death.
Experts who have spoken to Good Health say countless Covid patients admitted to critical care units with severe breathing difficulties have then become infected by aspergillus.
Estimates vary over the exact number of critical care patients afflicted. A research press release by investigators at Exeter University in March puts it as high as one in three. An international study in the journal Emerging Infectious Diseases in October suggests one in six.
Why the disparity? According to one of Britain’s foremost experts, David Denning, a professor of infectious diseases at the University of Manchester, much depends on how good clinicians are at diagnosing severe fungal infection and their awareness of it.
‘If you don’t look for it, you don’t find it,’ he told Good Health. ‘There are probably lots of patients who have died in critical care with this who were never diagnosed.’
The standard treatment is with anti-fungal drugs called azoles.
‘If they are given in good time, these can cure 75 per cent of patients with aspergillus,’ says Professor Denning.
However, aspergillus fungus is developing resistance to these.
This is due primarily to the overuse of azoles both in medicine and agriculture. This has encouraged more virulent strains of the fungus to evolve that are resistant to even high doses of azoles, says Professor Denning.
Azole anti-fungal sprays are used on ornamental plants to keep them looking healthy in greenhouses and on stored bulbs.
In 2019 Matthew Fisher, a professor of fungal disease epidemiology at Imperial College London, searched for drug-resistant aspergillus strains in flower beds outside hospitals, in parks and gardens across southern England, where tulip bulbs are often grown.
Of the eight most worrying London soil samples he found, four were from flower beds outside the Royal Free Hospital and The Whittington Hospital.
All the samples had Aspergillus fumigatus strains that had evolved to resist at least one of three commonly used azole drugs.
‘Drug resistance is something to be very worried about,’ says Professor Denning. ‘Around 13 per cent of aspergillus infections in some areas of London now involve resistant strains.’
Professor Denning says NHS critical care staff must become ‘much more aware and much more careful’ about the threat.
‘With sick people coming into intensive care units (ICU), particularly with Covid, we need to be thinking about aspergillus, taking routine samples. We need a whole new level of vigilance. It is bad enough to be in ICU, but to have a fungus as well, it’s not good.’
Professor Adilia Warris, the co-director of the Medical Research Council Centre for Medical Mycology (the study of fungi), says specialists are trying to find precisely why aspergillus is potentially so lethal to Covid patients.
‘We don’t yet fully understand how the Covid virus interacts with the immune system and makes patients’ defences less able to fight the second hit of the fungal infection,’ she told Good Health.
‘I think coronavirus is damaging very sick patients’ lung structures and airways and doing something to patients’ immune defences. This makes them highly susceptible to acquiring aspergillus.’
One theory, suggested in the journal Microbial Ecology last month, is that both Covid-19 and Aspergillus fumigatus attack the same molecules inside our lungs. So when Covid has effectively breached those defences, aspergillus can come marching in.
‘If the aspergillus takes advantage of weakened patients and grows, then things get really messy,’ says Professor Warris. ‘Mortality rates are very high. Studies so far suggest that these infections can kill up to about 70 per cent of infected patients.’
But it is not only severe Covid that opens the way for aspergillus.
Up until very recently, invasive aspergillosis was seen only to afflict people whose defences were severely laid waste by, for example, chemotherapy, bone marrow transplantation or a disease of the immune system such as Aids.
But in 2019, evidence published in the journal Lancet Respiratory Medicine by Belgian and Dutch investigators revealed how aspergillus had evolved into a super-fungus that could afflict otherwise healthy people with heavy viral infections — particularly with flu.
‘We had not really seen this before,’ says Professor Warris. ‘It made us aware that we should be looking for such problems in people in ICU with severe lung infections.’
Professor Denning says the mortality rate among severe flu patients who contract aspergillus in the UK is around 85 per cent.
Yet aspergillus often goes undetected in intensive care units treating patients with Covid or flu, he says, because the diagnostic methods can be difficult and dangerous.
The main one, bronchoscopy, involves inserting a tube down the nose or mouth and into the airways to take lung samples.
‘This is especially tricky with an infectious virus, from which healthcare workers must protect themselves by taking strict precautions,’ Professor Denning explains. ‘Also, you are working with the lungs of someone who is already short of oxygen so you may cause them serious harm.’
Professor Warris adds: ‘Aspergillus is everywhere in the environment, so just finding some in a patient’s sputum does not mean that they have the disease. It is all very challenging.’
Dr Colin Brown, a consultant in infectious diseases at the UK Health Security Agency (UKHSA) told Good Health that a study of 200 critical-care Covid patients who had aspergillus isolated from lung-fluid samples showed only a quarter actually had been infected by the fungus; the rest had simply breathed in fungal spores from the atmosphere that had not become a problem.
One hope for faster, easier and more accurate diagnosis is being developed by an international team of scientists that includes Professor Chris Thornton, a fungal immunologist at the University of Exeter.
The new technique, revealed in March in the journal Nature Communications, involves injecting a specially engineered antibody that will bind to aspergillosis molecules in the lungs of infected people.
The antibody is painted with a radioactive material that can be spotted on lung scans. Professor Thornton hails the advance as a ‘step-change in the way we diagnose this devastating disease’.
It is however, only a diagnosis. There is still the fact that the infection is highly invasive and difficult to treat. Yet another good reason, then, to get fully vaccinated against Covid-19 — and the flu.
https://www.dailymail.co.uk/health/article-10348095/The-deadly-fungus-preys-coronavirus-patients-killed-thousands.html

アスペルギルス・フミガーツス、アスペルギルス・フミガタス(Aspergillus fumigatus)は、コウジカビ属（アスペルギルス属）に属するカビの一種である^[1]。アスペルギルス症の最も一般的な原因菌である^[1]。

アスペルギルス症 (英: aspergillosis) とはアスペルギルス属の真菌を原因とする種々の真菌症疾病の総称で胞子の吸入と体内での増殖が原因の日和見感染症。アスペルギルス属の胞子は環境中に広く存在することから、ほとんどのヒトが毎日吸入しており、免疫に障害のあるヒトや家畜ではアスペルギルス症に進行する事がある。一般的な原因菌はアスペルギルス・フミガタス(Aspergillus fumigatus)であるが、A.flavusやA. nigerでも発生することがある。発症には、原因菌により生産されるマイコトキシンの一種のグリオトキシンが関与していると考えられる^[1]。
原因菌は病院内では観葉植物（鉢内の堆肥や土）、生花やドライフラワーの表面、花瓶の水、エアコンまたはヒーターの吹出し口、浮遊粉塵などから高頻度で検出される。特に、病院改築や改装の際、院内の空気中に増加することが報告されているが、この事は医療関係者の間でも周知されていない現状があるため、免疫力が落ちている者への予防が大切である。

最も一般的な型はアレルギー性気管支肺アスペルギルス症、アスペルギルス腫、侵襲性アスペルギルス症である。免疫不全者や免疫力が低下している際に起こりやすいことから症状の進行は速く、全身に感染するため症状は多岐に渡る。治療が遅れた場合の致死性は高い。

呼吸器系への感染では、血性痰、喘息、肺炎、副鼻腔炎など。

血管内に進入した場合、口蓋または歯肉の潰瘍化、血栓や出血性壊死など。

皮膚感染は手術創に発生することが殆どで、急速な組織壊死を起こす。

中枢神経系感染は脳膿瘍を呈し、全身播種性感染の部分症である。副鼻腔からの直接感染は少ない。

診断

画像検査、組織病理検査（生検）、検体の染色および培養等による。

治療

アスペルギルス症の疑いがある場合には、確定診断を待たず適応菌種が広い抗真菌薬を投与する。病変部位が局所的な場合には、外科手術が行われる場合がある。

家畜

ウシに於いても、アスペルギルス症を発症することがある。

詳細は「牛アスペルギルス症」を参照

Aspergillus fumigatus is a species of fungus in the genus Aspergillus, and is one of the most common Aspergillus species to cause disease in individuals with an immunodeficiency.
Aspergillus fumigatus, a saprotroph widespread in nature, is typically found in soil and decaying organic matter, such as compost heaps, where it plays an essential role in carbon and nitrogen recycling.^[1] Colonies of the fungus produce from conidiophores; thousands of minute grey-green conidia (2–3 μm) which readily become airborne. For many years, A. fumigatus was thought to only reproduce asexually, as neither mating nor meiosis had ever been observed. In 2008, A. fumigatus was shown to possess a fully functional sexual reproductive cycle, 145 years after its original description by Fresenius.^[2] Although A. fumigatus occurs in areas with widely different climates and environments, it displays low genetic variation and a lack of population genetic differentiation on a global scale.^[3] Thus, the capability for sex is maintained, though little genetic variation is produced.
The fungus is capable of growth at 37 °C or 99 °F (normal human body temperature), and can grow at temperatures up to 50 °C or 122 °F, with conidia surviving at 70 °C or 158 °F—conditions it regularly encounters in self-heating compost heaps. Its spores are ubiquitous in the atmosphere, and everybody inhales an estimated several hundred spores each day; typically, these are quickly eliminated by the immune system in healthy individuals. In immunocompromised individuals, such as organ transplant recipients and people with AIDS or leukemia, the fungus is more likely to become pathogenic, over-running the host's weakened defenses and causing a range of diseases generally termed aspergillosis. Due to the recent increase in the use of immunosuppressants to treat human illnesses, it is estimated that A. fumigatus may be responsible for over 600,000 deaths annually with a mortality rate between 25 and 90%.^[4] Several virulence factors have been postulated to explain this opportunistic behaviour.^[5]
When the fermentation broth of A. fumigatus was screened, a number of indolic alkaloids with antimitotic properties were discovered.^[6] The compounds of interest have been of a class known as tryprostatins, with spirotryprostatin B being of special interest as an anticancer drug.
Aspergillus fumigatus grown on certain building materials can produce genotoxic and cytotoxic mycotoxins, such as gliotoxin.^[7]

Genome
Aspergillus fumigatus has a stable haploid genome of 29.4 million base pairs. The genome sequences of three Aspergillus species—Aspergillus fumigatus, Aspergillus nidulans, and Aspergillus oryzae—were published in Nature in December 2005.^[8]^[9]^[10]

Pathogenesis
Aspergillus fumigatus is the most frequent cause of invasive fungal infection in immunosuppressed individuals, which include patients receiving immunosuppressive therapy for autoimmune or neoplastic disease, organ transplant recipients, and AIDS patients.^[11] A. fumigatus primarily causes invasive infection in the lung and represents a major cause of morbidity and mortality in these individuals.^[12] Additionally, A. fumigatus can cause chronic pulmonary infections, allergic bronchopulmonary aspergillosis, or allergic disease in immunocompetent hosts.^[13]

Innate immune response
Inhalational exposure to airborne conidia is continuous due to their ubiquitous distribution in the environment. However, in healthy individuals, the innate immune system is an efficacious barrier to A. fumigatus infection.^[13] A large portion of inhaled conidia are cleared by the mucociliary action of the respiratory epithelium.^[13] Due to the small size of conidia, many of them deposit in alveoli, where they interact with epithelial and innate effector cells.^[11]^[13] Alveolar macrophages phagocytize and destroy conidia within their phagosomes.^[11]^[13] Epithelial cells, specifically type II pneumocytes, also internalize conidia which traffic to the lysosome where ingested conidia are destroyed.^[11]^[13]^[14] First line immune cells also serve to recruit neutrophils and other inflammatory cells through release of cytokines and chemokines induced by ligation of specific fungal motifs to pathogen recognition receptors.^[13] Neutrophils are essential for aspergillosis resistance, as demonstrated in neutropenic individuals, and are capable of sequestering both conidia and hyphae through distinct, non-phagocytic mechanisms.^[11]^[12]^[13] Hyphae are too large for cell-mediated internalization, and thus neutrophil-mediated NADPH-oxidase induced damage represents the dominant host defense against hyphae.^[11]^[13] In addition to these cell-mediated mechanisms of elimination, antimicrobial peptides secreted by the airway epithelium contribute to host defense.^[11] The fungus and its polysaccharides have ability to regulate the functions of dendritic cells by Wnt-β-Catenin signaling pathway to induce PD-L1 and to promote regulatory T cell responses^[15]^[16]