Question 1 of 10

    Aspergillosis (Aspergilloses)

    Pulmonary aspergillosis (1) invasive type[1]

    Aspergillosis is a general term referring to the variety of infectious diseases caused by the genus of fungi Aspergillus. Lungs are the primary target if this type of infection.

    The disorder is triggered by the following process: infectious.

    Presentation

    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.

    Skin
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  • respiratoric
    Cough
    • Along with a persistent cough, breathlessness, tiredness and weight loss, coughing up blood is a common symptom.[nhs.uk]
    • In addition to blood, the coughing frequently brings up thick lumps of mucus.[wikihow.com]
    • […] breath Kidney or liver failure Shock 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 that can develop include wheezing, shortness of breath, chest pain, a chronic cough, fatigue, a cough that brings up blood (mild hemoptysis), and weight loss.[rarediseases.org]
    Hemoptysis
    Productive Cough
    • KGH Characteristic symptoms of allergic bronchopulmonary aspergillosis, seen especially in patients with chronic pulmonary diseases, include a chronic productive cough and purulent sputum occasionally tinged with blood and flecks of white or brownish[britannica.com]
    • This morning, he reports developing a productive cough overnight, and is concerned because he noted some blood in his sputum this morning.[medbullets.com]
    • Along with near constant productive coughing (mucus and blood), the aspergillus fungal infection of the lungs and airways also cause breathing difficulties, such as wheezing and shortness of breath. [4] The breathing is often labored and sounds like a[wikihow.com]
    • ., shortness of breath, wheezing) Productive cough with brown bronchial mucous casts Sinusitis without tissue infiltration Fungus ball in the paranasal sinuses with symptoms of chronic rhinosinusitis May progress in immunocompromised patients (see invasive[amboss.com]
    • Clinical presentation and diagnosis Patients frequently complain of constitutional symptoms such as fever, malaise, fatigue, and weight loss of 1–6 months' duration, in addition to chronic productive cough and haemoptysis, which varies from mild to severe[err.ersjournals.com]
    Chronic Cough
    • Eventually, the infected person will experience weight loss and chronic coughing, lethargy and a general “run down” feeling.[petcha.com]
    • Due to the chronic coughing, breathing difficulty and potential chest pain, many sufferers of aspergillosis have difficulty sleeping at night and become sleep deprived — which also contributes to the fatigue.[wikihow.com]
    • Symptoms that can develop include wheezing, shortness of breath, chest pain, a chronic cough, fatigue, a cough that brings up blood (mild hemoptysis), and weight loss.[rarediseases.org]
    • Weight loss, chronic cough, feeling rundown and tired are common symptoms later.[aspergillus.org.uk]
    • cough , hemoptysis Invasive aspergillosis : fever , cough , respiratory distress Endocarditis ABPA : eosinophilia , IgE , pulmonary infiltrates on chest x-ray or CT Pulmonary aspergilloma : x-ray or CT shows mobile fungus ball ; serology is positive[amboss.com]
    Chronic Productive Cough
    • KGH Characteristic symptoms of allergic bronchopulmonary aspergillosis, seen especially in patients with chronic pulmonary diseases, include a chronic productive cough and purulent sputum occasionally tinged with blood and flecks of white or brownish[britannica.com]
    • Clinical presentation and diagnosis Patients frequently complain of constitutional symptoms such as fever, malaise, fatigue, and weight loss of 1–6 months' duration, in addition to chronic productive cough and haemoptysis, which varies from mild to severe[err.ersjournals.com]
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  • Entire body system
    Chills
    • 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[medlineplus.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[mountsinai.org]
    • Part 2 Recognizing Advanced Symptoms of Invasive Aspergillosis 1 Look for fever and chills.[wikihow.com]
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  • Workup

    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 [16]. 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 [16], 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° [16].

    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 [17].

    Laboratory

    Serum
    Globulins Increased
    • In a study group dominated by psittacine species, the most common electrophoretic change is an increase in beta globulins (40%) followed by beta/gamma globulin increases (18%) and gamma globulin increases alone (9%).[cpl.med.miami.edu]
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  • Microbiology
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  • Imaging

    X-ray
    Pulmonary Infiltrate
    • Pulmonary infiltrates do not respond to conventional antibiotics.[patient.info]
    • infiltrates (seen on X-ray) If a patient has all eight of the above, diagnosis is certain.[physio-pedia.com]
    • Utility of fiberoptic bronchoscopy in neutropenic patients admitted to the intensive care unit with pulmonary infiltrates.[emedicine.medscape.com]
    • Initial treatment with 1-2 mg/kg per day should be followed by gradual reduction in dose, titrating with clinical condition and reduction in pulmonary infiltrates.[clinicaladvisor.com]
    Cavitary Lesion
    • lesions or cystic airspaces; and from the rare Aspergillus pneumonia, which occurs in patients who take low doses of prednisone long term (eg, patients with COPD).[physio-pedia.com]
    • CXR may show nodules, cavitary lesions or pulmonary infiltrates.[patient.info]
    • Imaging studies, such as chest radiograph and chest CT scan, usually show consolidation, pleural thickening and cavitary lesions in the upper lung lobes.[err.ersjournals.com]
    • Imaging study results in invasive aspergillosis are as follows: Chest radiographic features are variable, with solitary or multiple nodules, cavitary lesions, or alveolar infiltrates that are localized or bilateral and more diffuse as disease progresses[emedicine.medscape.com]
    • Subacute infection: necrotizing and cavitary lesions typically seen in patients with chronic structural lung diseases that also involve the airways (e.g. cystic fibrosis, bronchiectasis, sarcoidosis, emphysema).[hopkinsguides.com]
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  • Treatment

    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 [18].

    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 [14].

    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 [19], like the previously mentioned Aspergillus fumigatus, the most common infecting species, which appears to be resistant to fluconazole [20]. Therefore, the antibiotic choice must be pondered with care.

    Prognosis

    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 [14].

    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 [15], a triazole antifungal medication recently become the standard of care in antifungal treatment.

    Complications

    Lung Abscess
    • Abscesses in the brain caused by Aspergillus spp. known as cerebral aspergillosis.[life-worldwide.org]
    • Aspergilloma is a growth (fungus ball) that develops in an area of past lung disease or lung scarring such as tuberculosis or lung abscess .[medlineplus.gov]
    • Aspergilloma is a growth (fungus ball) that develops in an area of past lung disease or lung scarring such as tuberculosis or lung abscess.[pennmedicine.org]
    • Aspergilloma pertains to a fungus ball-like growth in a lung area that has undergone a lung disease such as tuberculosis or lung abscess.[medicalook.com]
    Bronchiectasis
    • Predominantly it affects asthma patients but also cystic fibrosis and bronchiectasis patients. [2] Allergic Broncho-Pulmonary Aspergillosis is a condition for which there is as yet no complete cure, so it is managed using steroids and antifungals in order[physio-pedia.com]
    • […] immunocompetent person (i.e. a person with no known suppression of their immune system) where previous tissue damage has occurred - for instance heavily scarred pulmonary tissue associated with tuberculosis, chronic obstructive pulmonary disease or bronchiectasis[aspergillus.org.uk]
    • […] or other fungi ( Clin Dev Immunol 2011;2011:843763 ); patients have elevated IgE directed against aspergillus antigens, also thick mucus plugs; impacted mucus may form cast of airways (plastic bronchitis); over time, bronchi become dilated, causing bronchiectasis[pathologyoutlines.com]
    • Contrast enhanced CT chest showed mucoid impaction (HAM—High attenuation mucus) and central bronchiectasis in right upper lobe (Fig. 1 ).[aacijournal.biomedcentral.com]
    Eosinophilia
    • If the patient has asthma, eosinophilia and a history of infiltrates then ABPA should be considered as possible and the other tests can be done to attempt to confirm.[physio-pedia.com]
    • Elevated serum IgE levels and eosinophilia indicate a fungal infection.[amboss.com]
    • […] non-immunocompromised’ critically ill patients INVESTIGATIONS Serum galactomannan: screening test of a major component in the cell wall of Aspergillus Sputum: Aspergillus radioallergosorbent assay test and culture, sliver staining IgG or IgE for Aspergillus peripheral eosinophilia[lifeinthefastlane.com]
    • Allergic bronchopulmonary aspergillosis may also cause chest pain, a cough that brings up blood or brown-colored globs (plugs) of mucus, and an excess of certain white blood cells (eosinophilia).[rarediseases.org]
    • […] test to Aspergillus species Positive laboratory test (precipitin to Aspergillus fumigatus [ A. fumigatus ] or immunoglobulin G [IgG] antibody against A. fumigatus ) or abnormal chest X-ray or change from previous exam Blood work showing an elevation in eosinophilia[cff.org]

    Etiology

    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 [7]. These fungi are hydrophobic in nature, and this characteristic helps their aerosolization [7] [8] [9]. 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 [10].

    In rare occasions, the Aspergillus fungi might infiltrate the human body via direct cutaneous inoculation, a situation which especially occurs after a trauma [11].

    Causes

    Fungus

    Epidemiology

    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 [12]. 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 [12].

    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 [13]. According to the data coming from the US, mortality has increased by 357 % between 1980 and 1997 [14], 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.

    Sex distribution
    Age distribution

    Pathophysiology

    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.

    Prevention

    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 [21] [22] [23]. Careful cleaning of showers and water systems is also paramount for the reduction of fungi exposure [24].

    The subjects who have received solid organ transplants or allogeneic stem cell transplantations are recommended to take preventive antifungal drugs such as posaconazole [25], voriconazole and fluconazole [26], especially in the cases involving severely compromised immune systems.

    Summary

    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 [1] and chronic obstructive pulmonary disease (COPD), which can indirectly trigger fungal infection even if the immune system is healthy and fully operational [2]. 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 [1] [3] [4] [5] [6].

    Patient Information

    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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    References

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    2. Smith N, Denning DW. Underlying conditions in chronic pulmonary aspergillosis including simple aspergilloma. European Respiratory Journal 2011 37 (4): 865–872.
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    18. Kontoyiannis DP, Lionakis MS, Lewis RE, Chamilos G, Healy M, Perego C, Safdar A, Kantarjian H, Champlin R, Walsh TJ, Raad II. Zygomycosis in a Tertiary‐Care Cancer Center in the Era ofAspergillus‐Active Antifungal Therapy: A Case‐Control Observational Study of 27 Recent Cases. The Journal of Infectious Diseases 2005 191 (8): 1350–1360.
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    • Breakthrough Scedosporium apiospermum (Pseudallescheria boydii) brain abscess during therapy for invasive pulmonary aspergillosis following high‐risk allogeneic - A Safdar, EB Papadopoulos - Transplant infectious , 2002 - Wiley Online Library
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    • Chronic Eosinophilic Pneumonia and Allergic Bronchopulmonary Aspergillosis: Two eosinophilic lung diseases in one patient. - AF Miranda, G Lieberman - Agenda, 2011 - eradiology.bidmc.harvard.edu
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