Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disease caused by Aspergillus induced hypersensitivity. It usually occurs in immunocompetent but susceptible patients with bronchial asthma and cystic fibrosis. If ABPA goes undiagnosed and untreated, it may progress to bronchiectasis and/or pulmonary fibrosis with significant morbidity and mortality. ABPA is a well-recognized entity in adults; however, there is lack of literature in children. The aim of the present review is to summarize pathophysiology, diagnostic criteria, clinical features, and treatment of ABPA with emphasis on the pediatric population. A literature search was undertaken through PubMed till April 30, 2018, with keywords "ABPA or allergic bronchopulmonary aspergillosis" with limitation to "title." The relevant published articles related to ABPA in pediatric population were included for the review. The ABPA is very well studied in adults. Recently, it is increasingly being recognized in children. There is lack of separate diagnostic criteria of ABPA for children. Although there are no trials regarding treatment of ABPA in children, steroids and itraconazole are the mainstay of therapy based on studies in adults and observational studies in children. Omalizumab is upcoming therapy, especially in refractory ABPA cases. There is a need to develop the pediatric-specific cutoffs for diagnostic criteria in ABPA. Well-designed trials are required to determine appropriate treatment regimen in children.

Invasive pulmonary aspergillosis is growing in incidence, as patients at risk are growing in diversity. Outside the classical context of neutropenia, new risk factors are emerging or newly identified, such as new anticancer drugs, viral pneumonias and hepatic dysfunctions. Clinical signs remain unspecific in these populations and the diagnostic work-up has considerably expanded. Computed tomography is key to assess the pulmonary lesions of aspergillosis, whose various features must be acknowledged. Positron-emission tomography can bring additional information for diagnosis and follow-up. The mycological argument for diagnosis is rarely fully conclusive, as biopsy from a sterile site is challenging in most clinical contexts. In patients with a risk and suggestive radiological findings, probable invasive aspergillosis is diagnosed through blood and bronchoalveolar lavage fluid samples by detecting galactomannan or DNA, or by direct microscopy and culture for the latter. Diagnosis is considered possible with mold infection in lack of mycological criterion. Nevertheless, the therapeutic decision should not be hindered by these research-oriented categories, that have been completed by better adapted ones in specific settings. Survival has been improved over the past decades with the development of relevant antifungals, including lipid formulations of amphotericin B and new azoles. New antifungals, including first-in-class molecules, are awaited.

Invasive pulmonary aspergillosis (IPA) may be a rare cause of granulomatous pneumonia in horses. The mortality of IPA is almost 100%; direct diagnostic tools in horses are needed. Bronchoalveolar lavage fluid (BALF) and serum samples were collected from 18 horses, including individuals suffering from IPA (n = 1), equine asthma (EA, n = 12), and 5 healthy controls. Serum samples were collected from another 6 healthy controls. Samples of BALF (n = 18) were analyzed for Aspergillus spp. DNA, fungal galactomannan (GM), ferricrocin (Fc), triacetylfusarinin C (TafC), and gliotoxin (Gtx). Analysis of 24 serum samples for (1,3)-β-D-glucan (BDG) and GM was performed. Median serum BDG levels were 131 pg/mL in controls and 1142 pg/mL in IPA. Similar trends were observed in BALF samples for GM (Area under the Curve (AUC) = 0.941) and DNA (AUC = 0.941). The fungal secondary metabolite Gtx was detected in IPA BALF and lung tissue samples (86 ng/mL and 2.17 ng/mg, AUC = 1).

Due to the difficulty in the access to free-ranging birds, data regarding Aspergillus infections in wild avian species is rare compared to captive wild and domestic birds.

The association of invasive tracheobronchial aspergillosis (ITBA) with invasive pulmonary aspergillosis (IPA) is not well established. We aimed to compare clinical characteristics between patients who exhibited ITBA with IPA and those who exhibited isolated ITBA (iITBA). Additionally, the usefulness of serum or bronchial galactomannan (GM) tests in diagnosing ITBA was evaluated.

We report 2 patients with invasive aspergillosis after infection with pandemic (H1N1) 2009. Influenza viruses are known to cause immunologic defects and impair ciliary clearance. These defects, combined with high-dose corticosteroids prescribed during influenza-associated adult respiratory distress syndrome, may be novel risk factors predisposing otherwise immunocompetent patients to invasive aspergillosis.

Aspergillus viridinutans, a mold phenotypically resembling A. fumigatus, was identified by gene sequence analyses from 2 patients. Disease was distinct from typical aspergillosis, being chronic and spreading in a contiguous manner across anatomical planes. We emphasize the recognition of fumigati-mimetic molds as agents of chronic or refractory aspergillosis.

Africa has a high burden of tuberculosis, which is the most important risk factor for chronic pulmonary aspergillosis (CPA). Our goal was to systematically evaluate the burden of CPA in Africa and map it by country. We conducted an extensive literature search for publications on CPA in Africa using the online databases. We reviewed a total of 41 studies published between 1976 and 2021, including a total of 1247 CPA cases from 14 African countries. Most of the cases came from Morocco (n = 764, 62.3%), followed by South Africa (n = 122, 9.9%) and Senegal (n = 99, 8.1%). Seventeen (41.5%) studies were retrospective, 12 (29.3%) were case reports, 5 case series (12.2%), 5 prospective cohorts, and 2 cross-sectional studies. The majority of the cases (67.1%, n = 645) were diagnosed in men, with a median age of 41 years (interquartile range: 36-45). Active/previously treated pulmonary tuberculosis (n = 764, 61.3%), human immunodeficiency virus infection (n = 29, 2.3%), diabetes mellitus (n = 19, 1.5%), and chronic obstructive pulmonary disease (n = 10, 0.8%) were the common co-morbidities. Haemoptysis was the most frequent presenting symptom, reported in up to 717 (57%) cases. Smoking (n = 69, 5.5%), recurrent lung infections (n = 41, 3%) and bronchorrhea (n = 33, 3%) were noted. This study confirms that CPA is common in Africa, with pulmonary tuberculosis being the most important risk factor.

Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection.

Background.  Invasive aspergillosis may occur in the setting of severe influenza infections due to viral-induced respiratory epithelium disruption and impaired immune effects, but data are limited. Methods.  A retrospective study was conducted among severe influenza cases requiring medical intensive care unit (ICU) admission at an academic center during the 2015-2016 season. Data collected included respiratory cultures, medical conditions and immunosuppressants, laboratory and radiographic data, and outcomes. A systematic literature review of published cases in the English language of aspergillosis complicating influenza was conducted. Results.  Six (75%) of 8 ICU influenza cases had Aspergillus isolated; 5 were classified as invasive disease. No ICU patient testing negative for influenza infection developed aspergillosis during the study period. Among cases with invasive aspergillosis, influenza infection was type A (H1N1) (n = 2) and influenza B (n = 3). Published and current cases yielded n = 57 (European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria: 37% proven, 25% probable, and 39% possible cases). An increasing number of cases were reported since 2010. Sixty-five percent of cases lacked classic underlying conditions at admission for aspergillosis, 86% had lymphopenia, and 46% died. Conclusions.  Aspergillosis may occur in the setting of severe influenza infections even among immunocompetent hosts. Risks may include influenza A (H1N1) or B infections and viral-induced lymphopenia, although further studies are needed. Prompt diagnosis and antifungal therapy are recommended given high mortality rates.

Pneumonia caused by severe acute respiratory syndrome coronavirus 2 emerged in China at the end of 2019. Because of the severe immunomodulation and lymphocyte depletion caused by this virus and the subsequent administration of drugs directed at the immune system, we anticipated that patients might experience fungal superinfection. We collected data from 186 patients who had coronavirus disease-associated pulmonary aspergillosis (CAPA) worldwide during March-August 2020. Overall, 182 patients were admitted to the intensive care unit (ICU), including 180 with acute respiratory distress syndrome and 175 who received mechanical ventilation. CAPA was diagnosed a median of 10 days after coronavirus disease diagnosis. Aspergillus fumigatus was identified in 80.3% of patient cultures, 4 of which were azole-resistant. Most (52.7%) patients received voriconazole. In total, 52.2% of patients died; of the deaths, 33.0% were attributed to CAPA. We found that the cumulative incidence of CAPA in the ICU ranged from 1.0% to 39.1%.

Aspergillus spp. are ubiquitous and cause severe infections in immunocompromised patients. Less is known about its incidence and prognosis in patients with HIV/AIDS. We reviewed the mortality of invasive aspergillosis in HIV/AIDS patients. Pubmed, Embase and Medline databases were used to search for articles. Studies were excluded if they contained other aspergillosis risk factors, no original or patient survival data or were not in English. From 747 articles published, 54 studies and case reports were identified following reading, published between 1985 and 2021, with 54% papers prior to 2000 reporting 853 patients from 16 countries, none from Africa. 707 (83%) patients died with an average time from diagnosis to death of 77.5 days. Postmortem diagnosis was seen in 21% of deaths recorded. A national series from France of 242 cases of invasive aspergillosis diagnosed in life recorded a 3 month mortality of 68% pre-ART, falling to 31% after introduction of ART and voriconazole. CD4 count was recorded in 39 studies and ranged from 2 to >1000 cells/mm3; only 8 patients (1.8%) had a CD4 > 100 cells/mm3. Aspergillosis occurs in patients with HIV/AIDS and associated with high mortality but its slow progression should allow diagnosis and treatment with improved outcome.

We noted a cluster of 4 cases of infection or colonization by Emericella spp., identified by sequence-based analysis as E. quadrilineata. Sequence-based analysis of an international collection of 33 Emericella isolates identified 12 as E. nidulans, all 12 of which had previously been identified by morphologic methods as E. nidulans. For 12 isolates classified as E. quadrilineata, only 6 had been previously identified accordingly. E. nidulans was less susceptible than E. quadrilineata to amphotericin B (median MICs 2.5 and 0.5 mg/L, respectively, p<0.05); E. quadrilineata was less susceptible than E. nidulans to caspofungin (median MICs, 1.83 and 0.32 mg/L, respectively, p<0.05). These data indicate that sequence-based identification is more accurate than morphologic examination for identifying Emericella spp. and that correct species demarcation and in vitro susceptibility testing may affect patient management.

The airborne fungus Aspergillus fumigatus poses a serious health threat to humans by causing numerous invasive infections and a notable mortality in humans, especially in immunocompromised patients. Mould-active azoles are the frontline therapeutics employed to treat aspergillosis. The global emergence of azole-resistant A. fumigatus isolates in clinic and environment, however, notoriously limits the therapeutic options of mould-active antifungals and potentially can be attributed to a mortality rate reaching up to 100 %. Although specific mutations in CYP 51A are the main cause of azole resistance, there is a new wave of azole-resistant isolates with wild-type CYP 51A genotype challenging the efficacy of the current diagnostic tools. Therefore, applications of whole-genome sequencing are increasingly gaining popularity to overcome such challenges. Prominent echinocandin tolerance, as well as liver and kidney toxicity posed by amphotericin B, necessitate a continuous quest for novel antifungal drugs to combat emerging azole-resistant A. fumigatus isolates. Animal models and the tools used for genetic engineering require further refinement to facilitate a better understanding about the resistance mechanisms, virulence, and immune reactions orchestrated against A. fumigatus. This review paper comprehensively discusses the current clinical challenges caused by A. fumigatus and provides insights on how to address them.

Immunocompromised patients are highly susceptible to invasive aspergillosis. Herein, we identified a homozygous deletion mutation (507 del C) resulting in a frameshift (N170I) and early stop codon in the fungal binding Dectin-2 receptor, in an immunocompromised patient. The mutated form of Dectin-2 was weakly expressed, did not form clusters at/near the cell surface and was functionally defective. Peripheral blood mononuclear cells from this patient were unable to mount a cytokine (tumor necrosis factor, interleukin 6) response to Aspergillus fumigatus, and this first identified Dectin-2-deficient patient died of complications of invasive aspergillosis.

Aspergillus species are the major life threatening fungal pathogens in transplant patients. Germination of inhaled fungal spores initiates infection, causes severe pneumonia, and has a mortality of >50%. This is leading to the consideration of pre-exposure prophylaxis to prevent infection. We made a very low MWt amphotericin B-polymethacrylic acid nanoparticle. It was not toxic to lung epithelial cells or monocyte-derived-macrophages in-vitro, or in an in-vivo transplant immuno-suppression mouse model of life threatening invasive aspergillosis. Three days of nebuliser based prophylaxis delivered the nanoparticle effectively to lung and prevented both fungal growth and lung inflammation. Protection from disease was associated with >99% killing of the Aspergillus and a 90% reduction in lung TNF-α; the primary driver of tissue destructive immuno-pathology. This study provides in-vivo proof-of-principle that very small and cost-effective nanoparticles can be made simply, and delivered safely and effectively to lung by the aerosol route to prevent fungal infections.

Early evidence suggests the efficacy of voriconazole for chronic pulmonary aspergillosis (CPA). We conducted a prospective, open, multicenter trial to evaluate the efficacy and safety of voriconazole for proven CPA in minimally or non-immunocompromised patients. Patients had CPA confirmed by chest computed tomography (CT) and/or endoscopy, positive Aspergillus culture from a respiratory sample, and positive serologic test for Aspergillus precipitins. Patients received voriconazole (200 mg twice daily) for a period of 6-12 months and were followed for 6 months after the end of therapy (EOT). The primary endpoint was global success at 6 months, defined as complete or partial (≥50 % improvement) radiological response and mycological eradication. Forty-one patients with confirmed CPA were enrolled. All patients had A. fumigatus as the etiologic agent. By EOT, five patients had died from comorbidities and seven had discontinued voriconazole due to toxicity. The global success rate at 6 months was 13/41 (32 %): 10/19 (53 %) for chronic necrotizing aspergillosis and 3/22 (14 %) for chronic cavitary aspergillosis (p = 0.01). The respective success rates at EOT were 58 and 32 %. Clinical symptoms and quality of life also improved during treatment. Voriconazole is effective for CPA, with acceptable toxicity. The response rate is higher and obtained more rapidly in necrotizing than cavitary forms.

Allergic bronchopulmonary aspergillosis (ABPA) is a pulmonary disorder that often occurs in patients with asthma or cystic fibrosis (CF) and is characterized by a hypersensitivity response to the allergens of the fungus Aspergillus fumigatus. In patients with CF, growth of A. fumigatus hyphae within the bronchial lumen triggers an immunoglobulin E (IgE)-mediated hypersensitivity response that results in airway inflammation, bronchospasm, and bronchiectasis. In most published studies, the prevalence of ABPA is about 8.9% in patients with CF. Since the clinical features of this condition overlap significantly with that of CF, ABPA is challenging to diagnose and remains underdiagnosed in many patients. Diagnosis of ABPA in CF patients should be sought in those with evidence of clinical and radiologic deterioration that is not attributable to another etiology, a markedly elevated total serum IgE level (while off steroid therapy) and evidence of A. fumigatus sensitization. Management of ABPA involves the use of systemic steroids to reduce inflammation and modulate the immune response. In patients who do not respond to steroids or cannot tolerate them, antifungal agents should be used to reduce the burden of A. fumigatus allergens. Recent studies suggest that omalizumab may be an effective option to reduce the frequency of ABPA exacerbations in patients with CF. Further randomized controlled trials are needed to better establish the efficacy of omalizumab in managing patients with CF and ABPA.

We evaluated the expression of biomarkers of innate and adaptive immune response in correlation with underlying conditions in 144 patients with chronic pulmonary aspergillosis (CPA). Patients with complete medical and radiological records, white cell counts, and a complete panel of CD3, CD4, CD8, CD19, and CD56 lymphocyte subsets were included. Eighty-four (58%) patients had lymphopenia. Six (4%) patients had lymphopenia in all five CD variables. There were 62 (43%) patients with low CD56 and 62 (43%) patients with low CD19. Ten (7%) patients had isolated CD19 lymphopenia, 18 (13%) had isolated CD56 lymphopenia, and 15 (10%) had combined CD19 and CD56 lymphopenia only. Forty-eight (33%) patients had low CD3 and 46 (32%) had low CD8 counts. Twenty-five (17%) patients had low CD4, 15 (10%) of whom had absolute CD4 counts <200/μL. Multivariable logistic regression showed associations between: low CD19 and pulmonary sarcoidosis (Odds Ratio (OR), 5.53; 95% Confidence Interval (CI), 1.43-21.33; p = 0.013), and emphysema (OR, 4.58; 95% CI; 1.36-15.38; p = 0.014), low CD56 and no bronchiectasis (OR, 0.27; 95% CI, 0.10-0.77; p = 0.014), low CD3 and both multicavitary CPA disease (OR, 2.95; 95% CI, 1.30-6.72; p = 0.010) and pulmonary sarcoidosis (OR, 4.94; 95% CI, 1.39-17.57; p = 0.014). Several subtle immune defects are found in CPA.

Despite best available therapy, cerebral aspergillosis is an often-lethal complication of disseminated aspergillosis. There is an urgent need to expand the currently limited therapeutic options. In this study, we assessed cerebral drug exposure and efficacy of caspofungin (CAS) using a lethal infant rat model of cerebral aspergillosis. Eleven-day-old Wistar rats were infected by intracisternal injection of Aspergillus fumigatus conidia. Treatment started after 22 h and was continued for 10 days. Regimens were CAS 1 mg/kg/day intraperitoneally (i.p.), liposomal amphotericin B (L-AmB) 5 mg/kg/day i.p., and both drugs combined at the same dose i.p. Infected controls were given NaCl 0.85% i.p. Primary endpoints assessed were survival, cerebral fungal burden, galactomannan index, and drug concentrations in brain homogenate at 2, 3, 5, and 11 days after infection. Compared to those of controls (4.4 ± 2.7 days), survival times were increased by treatment with CAS alone (10.3 ± 1.7 days; P < 0.0001) and CAS combined with L-AmB (9.3 ± 2.8 days; P < 0.0001). In contrast, survival time of L-AmB-treated animals (4.3 ± 3.1 days) was not different from that of controls. Cerebral fungal burden and galactomannan index declined in all animals over time, without significant differences between controls and treated animals. CAS trough levels in brain tissue were between 0.84 and 1.4 μg/g, concentrations we show to be associated with efficacy. AmB trough levels in brain tissue were higher than the MIC of the A. fumigatus isolate. In summary, CAS concentrations in brain tissue suggest it may be therapeutically relevant and it significantly improved survival in this lethal model of cerebral aspergillosis in nonneutropenic rats. The clinical efficacy of CAS treatment for cerebral aspergillosis merits further study. IMPORTANCE Treatment options for cerebral aspergillosis, an often-lethal disease, are limited. The echinocandins (caspofungin is one of them) are not recommended treatment because their brain tissue penetration is often considered insufficient. In a nursing rat model of cerebral aspergillosis that mimics human disease, we found potentially therapeutically relevant concentrations of caspofungin in brain tissue and prolonged survival of caspofungin-treated animals. The efficacy of caspofungin in the treatment of cerebral aspergillosis documented here, if confirmed in other animal models (especially immunosuppressed murine models) and by using additional Aspergillus isolates across a range of CAS minimal effective concentrations (MECs), would suggest that caspofungin merits further study as a treatment option for patients suffering from aspergillosis disseminated to the brain.