unAbstract

Although fungal infections contribute substantially to human morbidity

and mortality, the impact of these diseases on human health is not widely
appreciated. Moreover, despite the urgent need for efficient diagnostic
tests and safe and effective new drugs and vaccines, research into the
pathophysiology of human fungal infections lags behind that of diseases
caused by other pathogens. In this Review, we highlight the importance of
fungi as human pathogens and discuss the challenges we face in combating
the devastating invasive infections caused by these microorganisms, in
particular in immunocompromised individuals.gi infect billions of people
every year, yet their contribution to the global burden of disease is largely
unrecognized. Most are “relatively” minor infections, but millions contract
diseases that kill at least as many people as tuberculosis or malaria.
Although true mortality rates are unknown because of a lack of good
epidemiological data, the incidence of invasive fungal infections is rising as
a result of modern medical interventions and immunosuppressive
diseases, such as AIDS. Despite the high mortality rates of invasive fungal
infections, they remain understudied and underdiagnosed as compared
with other infectious diseases. What can be done to remedy this
unfortunate situation?

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Most important is to raise the general awareness of the problem. Over 600
different fungi have been reported to infect humans, ranging from
common to fatal infections, including those of the mucosa, skin, hair, and
nails, and other ailments including allergies. Even influential international
organizations, such as the World Health Organization and the Bill &
Melinda Gates Foundation, appear not to fully appreciate the burden
imposed by infection with fungi. Three issues require immediate attention.
Robust, rapid, simple, and cheap diagnostics are needed to allow quicker
implementation of antifungal therapeutics. Most diagnostics still suffer
from long assay times and poor specificity and/or sensitivity. These
problems, combined with subtle clinical presentations, often result in
missed or delayed diagnosis and compromise clinical care. Appropriate
diagnostics would immediately affect mortality and reduce morbidity.

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Safer and more effective antifungal drugs are also needed. Although
several classes of antifungal drugs are clinically available, they have had
only modest success in reducing the high mortality rates of invasive
mycoses such as candidiasis and cryptococcosis. Although this is due in
large part to delays in disease diagnosis and fungal identification,
antifungal drugs also suffer from restrictions in route of administration,
toxicity, a narrow spectrum of activity, detrimental drug interactions, the
development of drug resistance, and bioavailability in target tissues. These
factors, and the high cost of many antifungal therapies, exacerbate the
problem in resource-limited settings, where mortality rates are
consequently much higher. Although combinations of existing drugs may
yet prove to be more efficacious, new and cheaper drugs are needed that
are rapidly fungicidal and overcome the various deficiencies listed above.
Only a few drugs are currently in preclinical development, and it will be
years before any of them reach the clinic (if they do). We also need a
better understanding of who is at risk of infection, to facilitate targeted
preventative measures. Finally, fungal vaccines must be developed for
clinical use. There are currently no approved human vaccines for any
fungal pathogen, despite the advances in our understanding of antifungal
immunity. Although effective in animal models, few vaccines have reached
clinical trials, which is due in part to a lack of commercial interest. In
addition to preventing invasive infections, an effective vaccine could also
benefit those with fungal-related allergies and mucocutaneous infections,
such as vulvovaginal candidiasis.

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Accurate data on fungal disease burdens and their economic impact are
needed to raise scientific interest and increase global investments. The
major U.S. and UK funding agencies currently invest only about 2% of their
infectious disease budgets in fungal research. More private funding can be
generated through partnerships with academia and public health
institutions. The population at risk for life-threatening fungal infections is
growing worldwide, and tackling the challenges of these pathogens should
become a much higher priority.* Fungal infections throughout the world
appear to be increasing. This may in part be due to the increase in the
population of patients that are susceptible to otherwise rare fungal
infections resulting from the use of immune modulating procedures such
as hematopoietic stem cell transplants and drugs like tissue necrosis factor
antagonists. Histoplasma capsulatum, an endemic fungus throughout
North and South America, is reemerging among HIV+ patients in Central
and South America and among patients taking tissue necrosis factor
antagonists and …

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Severe COVID-19 disease is associated with an increase in pro-
inflammatory markers, such as IL-1, IL-6, and tumor necrosis alpha, less
CD4 interferon-gamma expression, and fewer CD4 and CD8 cells, which
increase the susceptibility to bacterial and fungal infections. One such
opportunistic fungal infection is mucormycosis. Initially, it was debated
whether a person taking immunosuppressants, such as corticosteroids,
and monoclonal antibodies will be at higher risk for COVID-19 or whether
the immunosuppresive state would cause a more severe COVID-19
disease. However, immunosuppressants are currently continued unless the
patients are at greater risk of severe COVID-19 infection or are on high-
dose corticosteroids therapy. As understood so far, COVID-19 infection
may induce significant and persistent lymphopenia, which in turn increases
the risk of opportunistic infections. It is also noted that 85% of the COVID-
19 patients’ laboratory findings showed lymphopenia. This means that
patients with severe COVID-19 have markedly lower absolute number of T
lymphocytes, CD4+ T and CD8+ T cells and, since the lymphocytes play a
major role in maintaining the immune homeostasis, the patients with
COVID-19 are highly susceptible to fungal co-infections. This report is
intended to raise awareness of the importance of early detection and
treatment of mucormycosis and other fungal diseases, such as candidiasis,
SARS-CoV-2-associated pulmonary aspergillosis, pneumocystis pneumonia
and cryptococcal disease, in COVID-19 patients, to reduce the risk of
mortality.

Fungal infections: a growing threat.

Dennis M Dixon, Michael M McNeil, Mitchell L Cohen, Bruce G Gellin, John

R La Montagne

Public health reports 111 (3), 226, 1996

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THE EMERGENCE OF newly identified fungal pathogens and the
reemergence of previously uncommon fungal diseases is primarily related
to increases in the numbers of susceptible persons: people with HIV
infection, bone marrow and organ transplant recipients, cancer patients
being treated with chemotherapy, critically ill persons, and very low birth
weight (< or= 1500 g) infants. These immunocompromised populations are
at risk for infection not only with opportunistic pathogens (for example,
Pneumocystis, Candida, Cryptococcus, Trichosporon, Malassezia,
Aspergillus, Penicillium marneffei, and numerous other moulds or yeasts)
but also with fungal pathogens that usually infect otherwise healthy
persons not previously exposed to endemic fungi (for example,
Coccidioides immitis, Histoplasma capsulatum, and Blastomyces
dermatitidis) and Sporothrix schenckii. Morbidity, mortality, and health
care costs associated with fungal infections are high. Addressing the
emergence of fungal diseases will require increased surveillance coupled
with the availability of rapid, noninvasive diagnostic tests; monitoring the
development of resistance to antifungal agents; and research focused on
the understanding, prevention, and control of fungal infection.
Serious fungal infections in Pakistan

Kauser Jabeen, Joveria Farooqi, Sajjad Mirza, David Denning, Afia Zafar

European Journal of Clinical Microbiology & Infectious Diseases 36 (6), 949-

956, 2017

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The true burden of fungal infection in Pakistan is unknown. High-risk
populations for fungal infections [tuberculosis (TB), diabetes, chronic
respiratory diseases, asthma, cancer, transplant and human
immunodeficiency virus (HIV) infection] are numerous. Here, we estimate
the burden of fungal infections to highlight their public health significance.
Whole and at-risk population estimates were obtained from the WHO (TB),
BREATHE study (COPD), UNAIDS (HIV), GLOBOCAN (cancer) and Heartfile
(diabetes). Published data from Pakistan reporting fungal infections rates
in general and specific populations were reviewed and used when
applicable. Estimates were made for the whole population or specific
populations at risk, as previously described in the LIFE methodology. Of
the 184,500,000 people in Pakistan, an estimated 3,280,549 (1.78%) are
affected by a serious fungal infection, omitting all cutaneous infection, oral
candidiasis and allergic fungal sinusitis, which we could not estimate.
Compared with other countries, the rates of candidaemia (21/100,000)
and mucormycosis (14/100,000) are estimated to be very high, and are
based on data from India. Chronic pulmonary aspergillosis rates are
estimated to be high (39/100,000) because of the high TB burden. Invasive
aspergillosis was estimated to be around 5.9/100,000. Fungal keratitis is
also problematic in Pakistan, with an estimated rate of 44/100,000.
Pakistan probably has a high rate of certain life- or sight-threatening
fungal infections. Fungal infection but not type of bacterial infection is
associated with a high mortality in primary and secondary infected
pancreatic necrosis

S Connor, N Alexakis, T Neal, M Raraty, P Ghaneh, J Evans, M Hughes, P

Rowlands, CJ Garvey, R Sutton, JP Neoptolemos

Digestive Surgery 21 (4), 297-304, 2004

Introduction:

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Knowledge of microbiology in the prognosis of patients with necrotizing
pancreatitis is incomplete.

Aim:

This study compared outcomes based on primary and secondary infection

after surgery for pancreatic necrosis.

Method:

From a limited prospective database of pancreatic necrosectomy, a

retrospective case note review was performed (October 1996 to April
2003).

Results:

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55 of 73 patients had infected pancreatic necrosis at the first
necrosectomy. 25 of 47 patients had resistant bacteria to prophylactic
antibiotics (n= 21) or did not receive prophylactic antibiotics (n= 4), but
this was not associated with a higher mortality (9 of 25) compared to those
with sensitive organisms (4 of 22). Patients with fungal infection (n= 6) had
a higher initial median (95% CI) APACHE II score compared to those
without (11 (9–13) verus 8.5 (7–10), p= 0.027). Five of six patients with
fungal infection died compared to 13 of 47 who did not (p= 0.014). With
the inclusion of secondary infections 21 (32%) of 66 patients had fungal
infection with 10 (48%) deaths compared to 11 (24%) of 45 patients
without fungal infection (p= 0.047).

Conclusion:

Whether associated with primary or secondary infected pancreatic

necrosis, fungal but not bacterial infection was associated with a high
mortality. Fungal endocarditis: evidence in the world literature, 1965–1995

ME Ellis, H Al-Abdely, A Sandridge, W Greer, W Ventura

Clinical Infectious Diseases 32 (1), 50-62, 2001

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We analyzed 270 cases of fungal endocarditis (FE) that occurred over 30
years. Vascular lines, non-cardiac surgery, immunocompromise and
injection drug abuse are increasing risk factors. Delayed or mistaken
diagnosis (82% of patients), long duration of symptoms before
hospitalization (mean ± standard deviation, 32 ± 39 days) and extracardiac
manifestations were characteristic. From 1988 onwards, 72% of patients
were diagnosed preoperatively, compared with 43% before 1988 (P
= .0001). The fungi most commonly isolated were Candida albicans (24% of
patients), non-albicans species of Candida (24%), Apergillus species (24%),
and Histoplasma species (6%); recently-emerged fungi accounted for 25%
of cases. The mortality rate was 72%. Survival rates were better among
patients who received combined surgical-antifungal treatment, were
infected with Candida, and had univalvular involvement. Improvement in
the survival rate (from <20% before 1974 to 41% currently) coincided with
the introduction of echocardiography and with improved diagnostic
acumen. Fungal endocarditis recurs in 30% of survivors. It is recommended
that fungal endocarditis be diagnosed early through heightened diagnostic
acumen; that patients be treated with combined lipid-based amphotericin
B and early surgery; and that patients be followed up for ⩾4 years while on
prophylactic antifungal therapy. The consequences of
our changing environment on life threatening and debilitating fungal
diseases in humans

Norman van Rhijn, Michael Bromley

Journal of Fungi 7 (5), 367, 2021

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Human activities have significantly impacted the environment and are
changing our climate in ways that will have major consequences for
ourselves, and endanger animal, plant and microbial life on Earth. Rising
global temperatures and pollution have been highlighted as potential
drivers for increases in infectious diseases. Although infrequently
highlighted, fungi are amongst the leading causes of infectious disease
mortality, resulting in more than 1.5 million deaths every year. In this
review we evaluate the evidence linking anthropomorphic impacts with
changing epidemiology of fungal disease. We highlight how the geographic
footprint of endemic mycosis has expanded, how populations susceptible
to fungal infection and fungal allergy may increase and how climate
change may select for pathogenic traits and indirectly contribute to the
emergence of drug resistance.

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