Aspergillosis has 4 main forms which differ in their general clinical manifestations: Allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, chronic necrotizing pulmonary aspergillosis (CNPA), and invasive aspergillosis.
ABPA is especially frequent in those affected by asthma and cystic fibrosis, which after a certain period of time result in a hypersensitivity reaction to fungi colonization. Its typical signs include cough, mucous plugs, fever and pulmonary infiltrates, which appear to be unresponsive to antibacterial therapy. ABPA frequently occurs in conjunction with allergic fungal sinusitis, which shows symptoms like chronic sinusitis with the related purulent sinus drainage.
The major sign of aspergilloma is undoubtedly hemopotysis, experienced by 40-60% of the patients affected by this form of aspergillosis, which might sometime be large in size and life threatening. Less common, but nevertheless typical of aspergilloma, are also cough and fever.
CNPA, instead, usually manifests itself with a subacute pneumonia, which also proves to be unresponsive to antibiotic therapy. This, then, while slowly progressing over the following weeks, is soon followed by the other classical signs such as fever, cough, and sometime night sweats and weight loss. CNPA is generally accompanied by underlying diseases or conditions, the most frequent of which are steroid-dependent chronic obstructive pulmonary disease and alcoholism.
To conclude, invasive aspergillosis usually presents itself in patients who have undergone prolonged neutropenia or immunosuppression, and manifests itself with the classical signs of fever, cough and hemoptysis, together with pleuritic chest pain and dyspnea. This form of aspergillosis is very frequent in those subjects who have received a solid organ transplant, particularly lung transplant which more likely shows aspergillosis-related complications. Invasive aspergillosis is also frequent in patients affected by chronic obstructive pulmonary disease, as serious adverse side effect.
Entire Body System
The most common symptoms in the CPA patients were cough (92.8%), hemoptysis (63.8%), chronic sputum (23.2%), and fever (17.4%). [ncbi.nlm.nih.gov]
[…] can cause massive bleeding from the lung Mucus plugs in the airways Permanent airway blockage Respiratory failure Call your provider if you develop symptoms of aspergillosis or if you have a weakened immune system and develop a fever. [nlm.nih.gov]
Fever Fever may be low grade, it may be high grade if bronchopneumonia develops. Low grade evening pyrexia may be associated with night sweats in the chronic granulomatous form giving the same picture as in tuberculosis. [medicaljoyworks.com]
Sometimes a slower course of disease progression may occur, leading to chronic cough, coughing up blood, and slight fever. Below are the sites involved with associated symptoms: Sinuses: congestion of the nose, fever, facial pain and around the eye. [healthengine.com.au]
However, the symptoms of invasive aspergillosis in the lungs include: Fever Chest pain Cough Coughing up blood Shortness of breath Other symptoms can develop if the infection spreads from the lungs to other parts of the body. [cdc.gov]
Health problems from the disease or treatment include: Amphotericin B can cause kidney damage and unpleasant side effects such as fever and chills Bronchiectasis (permanent scarring and enlargement of the small sacs in the lungs) Invasive lung disease [nlm.nih.gov]
Possible Complications Health problems from the disease or treatment include: Amphotericin B can cause kidney damage and unpleasant side effects such as fever and chills Bronchiectasis (permanent scarring and enlargement of the small sacs in the lungs [ufhealth.org]
Aspergillus necrotizing bronchitis may be seen at CT as an endobronchial mass, obstructive pneumonitis or collapse, or a hilar mass. [pubs.rsna.org]
Complications Pulmonary cavitation Pneumothorax Segmental or lobar collapse Progressive respiratory failure Differential diagnosis of pulmonary aspergillosis The differentials of the various clinical syndromes are wide, depending on the presenting symptoms [patient.info]
Boyd et al associated some adverse events to high concentrations, ie confusion, collapse with low blood pressure, electrolyte disturbances, abnormal liver function tests, arrhythmia and hypoglycaemia. [aspergillus.org.uk]
Weight loss, chronic cough, feeling rundown and tired are common symptoms later. Coughing of blood (haemoptysis) can occur in up to 50-80% of affected people. [aspergillus.org.uk]
However, the symptoms of invasive aspergillosis in the lungs include: Fever Chest pain Cough Coughing up blood Shortness of breath Other symptoms can develop if the infection spreads from the lungs to other parts of the body. [cdc.gov]
Bloody cough or massive bleeding from the lungs. Allergic bronchopulmonary aspergillosis may cause: Coughing accompanied by mucus or blood. Wheezing or worsening of asthma. Fever. Increased mucus or sputum secretions. [my.clevelandclinic.org]
Symptoms of an aspergilloma: The associated symptoms are a cough, hemoptysis (coughing up blood), and shortness of breath. [news-medical.net]
Chronic pulmonary aspergillosis is a major cause of life-threatening hemoptysis. In symptomatic patients with simple aspergillomas, surgery is the main therapeutic method for preventing or treating life-threatening hemoptysis. [ncbi.nlm.nih.gov]
Aspergillomas are usually asymptomatic, although it may cause mild cough and occasionally hemoptysis. [msdmanuals.com]
In such cases surgical resection is indicated if significant hemoptysis occurs. [aacijournal.biomedcentral.com]
[…] if pulmonary function is adequate Bronchial artery embolization may be used for life-threatening hemoptysis in patients unlikely to tolerate surgery or in patients with recurrent hemoptysis (eg, patients with CF in whom hemoptysis may be related to underlying [emedicine.medscape.com]
Infusion-Related Reactions including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur. [cresemba.com]
We herein report a case of slowly progressing chronic multiple nodular pulmonary aspergillosis in a 59-year-old man with rheumatoid arthritis, dyspnea, and fatigue. One nodule was surgically resected. [ncbi.nlm.nih.gov]
A 67-year-old man with granulomatous polyangiitis (Wegener granulomatosis) complicated by end-stage renal disease requiring hemodialysis and mild pulmonary fibrosis, was hospitalized with a 2-week history of worsening dyspnea and dry cough. [jamanetwork.com]
[…] hemoptysis Invasive aspergillosis: IV voriconazole Coccidioidomycosis (Valley fever) Pathogen: Coccidioides immitis Risk factors: travel to Southwestern United States, California Often asymptomatic Acute pneumonia: fever, chest pain, cough, arthralgia, dyspnea [amboss.com]
Co-aspiration of adiponectin with chitin significantly reduced eosinophil accumulation in the lungs, and airway eosinophil recruitment in adiponectin-deficient mice was increased with chitin aspiration. [jimmunol.org]
Clinico-radiological impression was left breast carcinoma with secondary skin involvement. fine-needle aspiration cytology (FNAC) from the swelling showed inflammatory cells, necrosis, epitheloid cell granulomas, and giant cells along with branching hyphae [ncbi.nlm.nih.gov]
Clinical material: Sputum, bronchial washings and tracheal aspirates from patients with pulmonary disease and tissue biopsies from patients with disseminated disease. 2. [web.archive.org]
Initial treatment with anti-fungals and percutaneous aspiration failed to clear the abscess necessitating splenectomy, despite the risks of surgical complications and further compromise of immunity. [bmcinfectdis.biomedcentral.com]
Severe bilateral chronic pulmonary aspergillosis with the left upper lobe replaced by one large and several smaller cavities and a fluid level (which on aspiration grew a pure growth of Aspergillus fumigatus). [life-worldwide.org]
- Productive Cough
cough and purulent sputum occasionally tinged with blood and flecks of white or brownish mycelium (fungus material). [britannica.com]
There is productive cough with large amounts of thick green sputum and it might produce thick yellow mucus plugs. Cough with mucous plugs Inhalation of aspergillus spores produces type 1 hypersensitivity reaction in the bronchial wall. [medicaljoyworks.com]
Overall, 109 (52.4%) had documented TB, 140 (67.3%) had a productive cough and 50 had haemoptysis. CPA prevalence was 8.7%; 10 (6.5%) had HIV infection and 8 (14.5%) were HIV-negative (Fisher's exact P = 0.092). [ncbi.nlm.nih.gov]
He was admitted for fever and productive cough, after receiving inhaled colistin for one month for multidrug-resistant Pseudomonas aeruginosa respiratory tract colonization. We decided to suspend chemotherapy and started a diagnostic study. [archbronconeumol.org]
Common symptoms are fatigue, weight loss breathlessness, productive cough and haemoptysis (coughing up blood). The disease is often mistaken for pulmonary tuberculosis and both diseases can co-exist. [life-worldwide.org]
The main diagnostic tool to diagnose aspergillosis is optical microscopy. When using silver staining, aspergillosis fungi appear as elongated hyphae with walls neatly marked in gray-black color . The hyphae appear septate and have a diameter ranging from 2.5 to 4.5 µm. These structures are not always clear and apparent, and they can be frequently mistaken with the members of Zygomycota , another phylum of terrestrial fungi which mainly live as parasites of animals and plants and sometime in symbiotic relationships with them. The peculiar characteristic of these hyphae is their progressive branching patter, which tends to form acute angles of 45° .
Aspergillosis can also be diagnosed with chest X-ray and CT scan, with which the colonies of hyphae appear as halo signs that later progressive in air crescent signs .
- Pulmonary Infiltrate
Allergic bronchopulmonary aspergillosis is characterized by eosinophilic pulmonary infiltrates, bronchiectasis and bronchial mucus plugs, and can progress to chronic pulmonary fibrosis. [ajronline.org]
The authors report on 4 patients with acute leukemia and invasive aspergillosis whose radiographs demonstrated a distinctive feature of one or more air crescents within an area of pulmonary infiltrate. [ncbi.nlm.nih.gov]
Because it is uncommon, CNPA often remains unrecognized for weeks or months and can cause a progressive cavitary pulmonary infiltrate. [emedicine.medscape.com]
- Cavitary Lesion
lesions aspergilloma well-formed cavitary lesion, often mobile (changes as the patient changes position) Monad sign air surrounding soft tissue mass, indicating pre-existing cavity ABPA bronchiectasis Bronchoscopy indication to obtain sample for culture [medbullets.com]
A movable fungus ball within a cavitary lesion is characteristic on both, although most lesions are focal and solid. Sometimes imaging detects a halo sign (a hazy shadow surrounding a nodule) or cavitation within a necrotic lesion. [msdmanuals.com]
(b) Photograph of an autopsy specimen from the left upper lobe shows an irregular cavitary lesion with regular margins and a dark brown appearance caused by necrotic material and Aspergillus infection. Figure 9b. [pubs.rsna.org]
‘Of these, one case with pulmonary aspergillosis and one case with atelectasis (due to acute hemorrhage) were confirmed.’ [en.oxforddictionaries.com]
[…] in blood Positive sputum culture for Aspergillus species (or, rarely, other fungi) IgE levels The diagnosis is suspected in patients with asthma with recurrent asthma exacerbations, migratory or nonresolving infiltrates on chest x-ray (often due to atelectasis [msdmanuals.com]
Atelectasis. Bronchiectasis. Steroid dependence. Progressive pulmonary fibrosis in severe cases. [patient.info]
Occasionally, isolated lobar or segmental atelectasis may occur. [pubs.rsna.org]
- Pleural Mass
CT scan of the chest demonstrated bilateral pulmonary infiltrates, pleural masses ( Figure 1a, arrows) and a lytic lesion of the left fourth rib ( Figure 1b, arrow). [nature.com]
Empyema or pleural masses are rare.(6) In a small observational cohort study conducted in Spain, investigators identified 19 of 1,605 HIV-infected individuals with invasive pulmonary aspergillosis, yielding an incidence rate of 1.12%.(16) Ninety-five [hivinsite.ucsf.edu]
- X-Ray Abnormal
A chest x-ray may be abnormal and may look the same as the chest x-ray of someone with ‘pneumonia’ (but pneumonia is a different condition due to infection of the lung with other bugs). Often these x-ray changes can be ‘fleeting’ or come and go. [lungfoundation.com.au]
For the most aggressive forms of aspergillosis the medical treatments currently deployed are based on the combined use of two important antifungal agents, voriconazole and liposomal amphotericin B. In the most severe cases these two agents might not be sufficient, and their use should be coupled with the removal of the affected tissue, so that the healing of the remaining healthy part of the organ can be improved .
For the less aggressive forms of aspergillosis, like allergic bronchopulmonary aspergillosis, the medical treatment is largely based on the use of oral steroids for a prolonged period of time, usually ranging from 6 to 9 months. The treatment can be integrated with itracozanole, another triazole antifungal agent frequently prescribed for its “steroid sparing” effect which makes steroids’ action much more effective .
Other drugs used against aspergillosis include caspofungin, flucytosine, or the already mentioned itracozanole, many of them belonging to the class of compounds called triazoles, for the presence in their molecular structure of the triazole ring, a pentameric aromatic structure with two atoms of carbons and three atoms of nitrogen. It should be remembered that there is a growing portion of infections which turn out to be resistant to triazoles , like the previously mentioned Aspergillus fumigatus, the most common infecting species, which appears to be resistant to fluconazole . Therefore, the antibiotic choice must be pondered with care.
The prognosis of aspergillosis is generally good provided that treatment is strictly followed, and clinical symptoms should begin to improve quickly after a few days from therapy initiation. The successful outcome of the treatment heavily depends on early diagnosis, early and effective antifungal therapy initiation, and immunological restoration. The outlook has very much improved over the last few decades, thanks to the availability of advanced tools for early diagnosis (e.g., high-resolution CT scan or fungal biomarkers) and increasingly better antifungal drugs which prove to be more effective than amphotericin B .
Aspergillosis tends to remain quiescent or dormant until another factor or event restarts immunosuppression, for example when immunotherapy, for whatever reason, is reintroduced. Therefore, the risk of relapse is quite high and cannot be underestimated. For instance, in subjects with prior history of aspergillosis and undergoing myeloablative chemotherapy, the risk of relapse is around 20%, a figure which does not allow to dismiss the reoccurrence of aspergillosis. As a rule, as way of secondary prophylaxis specialists tend to use voriconazole , a triazole antifungal medication recently become the standard of care in antifungal treatment.
The fungi of the genus Aspergillus are ubiquitous and very common molds of the soil, which usually grow in organic matter as mycelium and hyphal stalks . These fungi are hydrophobic in nature, and this characteristic helps their aerosolization   . There are approximately 180 species of Aspergillus known to cause aspergillosis. Among these, the most common is undoubtedly Aspergillus fumigatus, accounting for 50% to 70% of the aspergillus diseases, especially aspergilloma that is almost exclusively caused by this species. Instead, one of the most dangerous fungi is Aspergillus terreus, which is resistant to amphotericin B and the patients affected by it always have a very poor prognosis .
Aspergillosis is found all over the world, regardless the geographic region concerned, where it especially affects individuals with compromised immune systems due to malignancies and organ transplants, as well as the occurrence of major illnesses like AIDS and pulmonary disease.
The incidence of aspergillosis at 12 months varies according to the underlying condition which has triggered it. At 12 months after stem cell transplantation, the incidence of aspergillosis is 0.05% in autologous recipients, 2.3% in allogeneic recipients with HLA-matched related donors, and 3.9% in patients with a related donors . At 12 months after solid organ transplantation, instead, the incidence is 2.4% for lung transplants, 0.8% for heart transplants, 0.3% for liver transplants, and 0.1% for kidney transplants .
Mortality at 1 year after stem cell transplantation has gradually decreased in these last few decades, but it still remains very high, stable in the range going from 50% to 80%. Mortality is even higher when aspergillosis affects the brain and the infection begins to spread throughout the body . According to the data coming from the US, mortality has increased by 357 % between 1980 and 1997 , even though this is attributed to social phenomena, like the increased number of individuals at risk due to advances of medicine or simply the wider portion of the aging population.
Aspergillus causes a variety of diseases, like hypersensitivity reactions, chronic necrotizing infections, or progressive angioinvasion, many of which result in death. Aspergillus always occurs in subjects with compromised immune systems due to underlying conditions, like the occurrence of a lung disease, the implementation of an immunosuppressive drug therapy, or an immunodeficiency acquired from a disease such as AIDS.
Aspergillus fumigatus is the most frequent pathogen responsible for this infection in humans, which has the ability of this species to grow and thrive in the environmental conditions found within the human body. In any case, many species manage to overcome the immune system defenses by producing toxic metabolites that inhibit the action of macrophages and neutrophils. These immune cells are also largely neutralized in immunosuppressive conditions, like the already mentioned occurrence of HIV or under pharmacogenetic immunosuppression.
The prevention of aspergillosis is largely based on the reduction to mold and spore exposure, which should be implemented by taking proper environmental preventive measures. In particular, special care has to be given to the hospital setting, which should be equipped with proper elements such as high-efficient particulate air filters and positive-pressure ventilation and air exchange systems   . Careful cleaning of showers and water systems is also paramount for the reduction of fungi exposure .
The subjects who have received solid organ transplants or allogeneic stem cell transplantations are recommended to take preventive antifungal drugs such as posaconazole , voriconazole and fluconazole , especially in the cases involving severely compromised immune systems.
Aspergillosis is a classical example of opportunistic infection, which takes advantage of the moment of weakness of the immune system due to the occurrence of other diseases and conditions. This is the reason why aspergillosis is particularly frequent in patients affected by AIDS, or in those undergoing hematopoietic stem cell transplantation or chemotherapy for leukemia. Aspergillosis is also frequent in patients with underlying diseases affecting the respiratory system, in particular tuberculosis  and chronic obstructive pulmonary disease (COPD), which can indirectly trigger fungal infection even if the immune system is healthy and fully operational . This can be explained by remembering that the species of the Aspergillus genus are ubiquitous organisms, capable of living under the most stressful environmental conditions, and people inhale thousands of spores every day without no sign of infection. When the immune system fails, the fungal cells can enter the bloodstream via the lungs and disseminate throughout the body, infecting major organs such as heart and kidneys.
The most common forms of aspergillosis are chronic pulmonary aspergillosis (CPA), aspergilloma, and allergic bronchopulmonary aspergillosis (ABPA), which frequently occur in intertwined forms. Taking together in all their forms, chronic, invasive and allergic, they cause around 600.000 deaths every year all around the world     .
Aspergillosis is a general term referring to the variety of infectious diseases caused by the genus of fungi Aspergillus, whose primary target is the lungs. Aspergillosis is a classical example of opportunistic infection, which takes advantage of a moment of weakness of the immune system due to the occurrence of other diseases and conditions. It is particularly frequent in patients affected by AIDS, or in those undergoing stem cell transplantation or chemotherapy for leukemia. Aspergillosis is also common in patients with underlying diseases affecting the respiratory system, in particular tuberculosis and chronic obstructive pulmonary disease.
Aspergillosis has 4 main forms which differ in their signs and symptoms: Allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, chronic necrotizing pulmonary aspergillosis (CNPA), and invasive aspergillosis. Common symptoms are cough, fever, malaise, coughing up blood or mucus plugs, chest pain and shortness of breath.
For the most aggressive forms of aspergillosis, the medical treatments currently deployed are based on the combined use of two drugs, voriconazole and liposomal amphotericin B. In the most severe cases these two agents might not be enough, and their use should be coupled with the removal of the affected tissue, so that the healing of the remaining healthy part of the organ can be improved. For the less aggressive forms of aspergillosis, the medical treatment is largely based on the use of oral steroids for prolonged periods of time.
The prognosis of aspergillosis is generally good provided that treatment is strictly followed, and clinical symptoms should begin to improve quickly after a few days from therapy initiation. The successful outcome of the treatment heavily depends on early diagnosis, early and effective antifungal therapy initiation, and immunological restoration. The outlook has very much improved over the last few decades, thanks to the availability of advanced tools for early diagnosis and increasingly better antifungal drugs.
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