It is important to emphasize that all invasive forms of aspergillosis arise from the lungs, the initial site of fungal replication and more than one organ may be affected, especially in severely immunocompromised patients. The clinical presentation of IA depends on the site of infection and several types have been described in literature [1]:

• Invasive pulmonary aspergillosis (IPA) - The most common form of IA is characterized by dyspnea, chest pain, dry cough, fever (which may be absent in the setting of high corticosteroid use) and hemoptysis.
• Tracheobronchitis - Although this type may present with similar symptoms such as IPA, extensive ulcerative lesions caused by Aspergillus can cause unilateral wheezing or stridor, leading to potentially fatal airway obstruction.
• Sinusitis - Often caused due to the dissemination of fungi during IPA, infection of the sinuses manifests as epistaxis, fever, and headaches.
• Cerebral aspergillosis - Even though it is rare, central nervous system invasion of Aspergillus is almost always fatal. Nonspecific signs including focal neurological deficits, altered mental status and headaches (hallmarks of CNS infection) are reported.

• Fever

  However, the vast majority of IA cases are lung infections that manifest with a cough, chest pain, heavy breathing, and fever, although severe immunosuppressive therapy may prevent fever from occurring. [symptoma.com]

  An eleven-year-old boy presented with one month's history of fever and weight loss. He was diagnosed with Acute Mycloid Leukemia (AML-M2). [ncbi.nlm.nih.gov]

• Hypoxemia

  This decrease in surfactant, results in alveolar collapse, ventilation- perfusion mismatch, and hypoxemia. It was hosted by CloudFlare Inc. Tobradex ist der Markenname von der Kombination der Medikamente Tobramycin und Dexamethason. [ucugyboj.gq]

  […] opacities Silver stain and immunofluorescence on bronchoalveolar lavage (or lung biopsy if sputum is negative): disc shaped-yeasts Cannot be cultured High-dose TMP-SMX (treatment and prophylaxis) or clindamycin primaquine Prednisone (moderate to severe hypoxemia [amboss.com]

  […] weight loss Invasive aspergillosis Occurs in patients with prolonged neutropenia or immunosuppression Typically manifests as fever, cough, dyspnea, pleuritic chest pain, and, sometimes, hemoptysis Patients may be tachypneic and have rapidly progressive hypoxemia [emedicine.medscape.com]

• Fulminant Sepsis

  Due to fulminant sepsis it was not possible to perform the planned biopsy. The patient died a few days later of cardio-respiratory insufficiency. [ncbi.nlm.nih.gov]

• Cough

  We present the case of a 33-year-old immunocompetent woman who presented with a history of cough and severe breathlessness, and was diagnosed to have invasive aspergillosis. [ncbi.nlm.nih.gov]

  The patient again presented a month later with stridor, dysphagia, and cough. [cureus.com]

• Hemoptysis

  Patients with Aspergillus pneumonia present with fever, cough, chest pain and occasionally hemoptysis. [ncbi.nlm.nih.gov]

  Although some patients are asymptomatic, 75% of patients develop hemoptysis [10]. This hemoptysis may be massive and poorly controlled, as was the case for our patient. [academic.oup.com]

  Pleuritic chest pain and hemoptysis may also be present 1. Spores of a variety of Aspergillus spp are inhaled and begin to proliferate in the alveoli. The hyphae are able to invade pulmonary arteries resulting in pulmonary necrosis and hemorrhage 1. [radiopaedia.org]

• Dyspnea

  Infusion-related reactions including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia were reported during intravenous administration of CRESEMBA. Discontinue the infusion of CRESEMBA if these reactions occur. [newsroom.astellas.us]

  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]

  The clinical presentation of IA depends on the site of infection and several types have been described in literature: Invasive pulmonary aspergillosis (IPA) - The most common form of IA is characterized by dyspnea, chest pain, dry cough, fever (which [symptoma.com]

  After 1 year, the patient was admitted to the pulmonology ward, complaining of cough worsening, increase in sputum volume and purulence, dyspnea, bloody sputum and fever, which had evolved over 4 weeks. [journalpulmonology.org]

  […] increasingly being reported in AIDS patients (1-12%) and also a common complication of chronic granulomatous disease of 25-40%.6 The most common symptoms of invasive aspergillosis are non-specific and include: fever, chest pain, cough, malaise, weight loss and dyspnea [medcraveonline.com]

• Productive Cough

  A 46-year-old man presented with productive cough of 2 weeks' duration. Besides, several painless, fixed lymph nodes were palpated at his left neck. He had PG and MDS diagnosed in June 2004 with regular use of oral dapsone and prednisolone. [ncbi.nlm.nih.gov]

  In September 2000, the patient developed a productive cough, and a chest x-ray showed a right upper lung lobe cavitation. [scielo.br]

  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]

• Rales

  […] or bradycardia Transient myocardial dysfunction (eg, systolic blood pressure 100 mm Hg or overt hypotension, elevated jugular venous pressure, dyskinetic apex, reverse splitting of S2, presence of S3 or S4, new or worsening apical systolic murmur, or rales [emedicine.medscape.com]

  Patients in this stage may present with dyspnoea, cyanosis, rales, and cor pulmonale. Clubbing may be present. The serum IgE level and eosinophil count might be low or high. Fortunately, few patients progress to this stage. [err.ersjournals.com]

• Chest Pain

  Patients with Aspergillus pneumonia present with fever, cough, chest pain and occasionally hemoptysis. [ncbi.nlm.nih.gov]

  However, the vast majority of IA cases are lung infections that manifest with a cough, chest pain, heavy breathing, and fever, although severe immunosuppressive therapy may prevent fever from occurring. [symptoma.com]

  Pleuritic chest pain and hemoptysis may also be present 1. Spores of a variety of Aspergillus spp are inhaled and begin to proliferate in the alveoli. The hyphae are able to invade pulmonary arteries resulting in pulmonary necrosis and hemorrhage 1. [radiopaedia.org]

  The patients can present with a wide array of symptoms such as fever, chest pain, shortness of breath, cough, and hemoptysis. Immunocompromised patients, especially patients with severe neutropenia, can have a transbronchial invasion. [cureus.com]

  Symptoms may include fever, cough, difficulty breathing, chest pain, seizures, and focal neurological problems. [elsevier.com]

• Epistaxis

  Sinusitis - Often caused due to the dissemination of fungi during IPA, infection of the sinuses manifests as epistaxis, fever, and headaches. [symptoma.com]

  Symptoms Patients with acute invasive Aspergillus rhinosinusitis typically present with nasal congestion, fever, sinus pain, epistaxis (nose bleeds) and may also experience facial numbness and diplopia if the cranial nerves are involved[38],[39]. [pharmaceutical-journal.com]

• Headache

  Predominant symptoms associated with cranial fungal granuloma include headache, vomiting, proptosis, and visual disturbances. Common signs include papilledema, cranial neuropathy, hemiparesis, and meningismus. [ncbi.nlm.nih.gov]

  A sinus infection causes headaches, nose bleeds and fever, whereas central nervous system infections (also known as cerebral aspergillosis) give nonspecific symptoms such as headaches and altered consciousness. [symptoma.com]

  The most frequent adverse events for patients treated with CRESEMBA in clinical trials were: nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (17%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough [newsroom.astellas.us]

  ADVERSE REACTIONS The most frequently reported adverse reactions among CRESEMBA-treated patients were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (16%), hypokalemia (14%), constipation (13%), dyspnea (12% [cresemba.com]

  Fever, facial pain and headache may also occur. When to see a doctor If you have asthma or cystic fibrosis, see your doctor whenever you notice a change in your breathing. [mayoclinic.org]

• Confusion

  Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances False-positive results are reported to occur at rates of 8% to 14% with this [mayomedicallaboratories.com]

  On exam, the patient was confused, with left palpebral ptosis and oral candidiasis. [scielo.br]

  A clear transparent space is observed above the cataractous lens in both the scenarios and can lead to confusion when examined under diffuse illumination with a slit lamp. [eyewiki.aao.org]

  […] neoformans Risk factors: AIDS, exposure to pigeon droppings Infected patients often asymptomatic Isolated pneumonia is possible Extrapulmonary: cryptococcal meningoencephalitis or brain abscess: headache, fever, signs of increased intracranial pressure, confusion [amboss.com]

  Thus, the morphology of an infecting fungus may be confusing, indicating that morphological diagnosis has certain limitations. [kjim.org]

• Altered Mental Status

  Nonspecific signs including focal neurological deficits, altered mental status and headaches (hallmarks of CNS infection) are reported. [symptoma.com]

• Altered Mental Status

  Nonspecific signs including focal neurological deficits, altered mental status and headaches (hallmarks of CNS infection) are reported. [symptoma.com]

• Cranial Neuropathy

  Common signs include papilledema, cranial neuropathy, hemiparesis, and meningismus. [ncbi.nlm.nih.gov]

A thorough patient history that comprises determination of predisposing conditions that may serve as risk factors for IA and a thorough physical examination are key steps in making a presumptive diagnosis. Laboratory findings that reveal neutropenia in a patient with a respiratory infection due to an immunocompromised status are highly suggestive of fungal infection, especially if symptoms do not resolve after a course of antibiotic therapy for presumed bacterial infection [1]. In addition to clinical and laboratory findings, imaging studies including X-ray and CT may be of great use in establishing the underlying cause. In fact, criteria for the diagnosis of IPA is the identification of macronodules (> 1 cm in diameter) that are surrounded by a ground-glass opacity (known as the halo sign) [11], which is why CT is highly recommended when suspecting a fungal pulmonary infection. Finally, confirming Aspergillus species through microbiological studies may be performed from samples such as bronchoalveolar lavage (BAL), blood or cerebrospinal fluid and their subsequent cultivation, or identification of serum markers - (1-3)-β-d-glucan and galactomannan, polysaccharide components of the fungal cell wall [5] [12] [13]. Unfortunately, many false positives and poor sensitivity of these tests have been documented, possibly due to the nature of Aspergillus sp. acquisition. For this reason, the initiation of treatment commonly rests on clinical and imaging criteria.

• Atelectasis

  Many ICU patients have nonspecific interfering radiologic abnormalities associated with atelectasis or ARDS (figures 1–4 ). [academic.oup.com]

  Atelectasis. Bronchiectasis. Steroid dependence. Progressive pulmonary fibrosis in severe cases. [patient.info]

  Areas of atelectasis related to bronchial obstruction from mucoid impaction may be present. [emedicine.medscape.com]

Current guidelines suggest voriconazole as first-line therapy in the following regimen: 6 mg/kg IV q12h on the first day followed by either 4 mg/kg IV q12h or 200 mg PO q12h for > 40 kg of body weight [7] [14]. The goal of therapy is to achieve drug concentrations in serum between 1.0-5.5 mg/L, a range in which maximal efficacy has been observed, but voriconazole is a potent substrate for various cytochrome enzymes in the liver, most notably CYP3A4 and CYP2C9. For this reason, careful evaluation of drugs used by the patient prior to initiation of therapy must be made [7]. Liposomal amphotericin B is also a good therapeutic option, given in doses of 3-5 mg/kg IV q24h, while caspofungin 70 mg q24h, micafungin 100 mg q12h, or posaconazole 200 mg q6h followed by 400 mg q12h are considered as alternative regimens [7] [14].

Several factors have been determined as predictors of prognosis of patients with IA, such as presence of neutropenia, liver and kidney insufficiency, use of corticosteroids and early-onset IA [3] [8], but the early initiation of systemic antifungal therapy is detrimental to achieving good outcomes [6]. Despite all efforts to treat IA, mortality rates range from 40-90% [3], indicating that this infection can be severely life-threatening for the patient.

IA is a fungal infection caused by Aspergillus sp., a saprophytic fungus present in soil and decaying matter [1]. However, this fungal pathogen produces small conidia (asexual forms) that are hydrophobic in nature, facilitating their dispersion throughout air and enabling survival in various conditions [3]. More than 200 species of Aspergillus are currently recognized, but A. fumigatus is by far the most important species when it comes to IA and other human infections [1]. A. niger, A. flavus and A. terreus are other Aspergillus species known to cause IA, but in only a small number of cases [3].

Because IA is considered almost exclusively to be an opportunistic infection, certain risk factors that lower the capacity of the immune system to cope with fungal invasion are present in virtually all cases. Most common conditions that predispose individuals to IA are [6]:

• Hematologic malignancies - leukemia and chronic lymphoproliferative disorders [9].
• Solid-organ and hematopoietic stem cell transplantation (HSCT).
• Continuous corticosteroid therapy.
• Human immunodeficiency virus (HIV) and consequent acquired immunodeficiency syndrome (AIDS).
• Neutropenia, either caused by chemotherapy, immunosuppressive therapy (eg. cyclophosphamide) or some genetic condition (such as chronic granulomatous disease) [1].

The true frequency of IA in clinical practice is currently unknown, partly because of the fact that many patients often yield false-positive results due to the ubiquitous presence of the fungus in respiratory samples of human hosts, thus questioning their role in disease [6]. Reports from Italy show than 0.2% of all patients admitted to the intensive care unit (ICU) suffer from IA [6], whereas a large multicentric study in France determined an incidence rate of 0.27 per 1000 admissions [9].

The pathogenesis of IA starts with the introduction of conidia into the upper respiratory tract of human hosts, specifically the bronchioles and alveolar spaces [3]. If individuals are immunocompetent, conidia will be either expelled from the lungs by the action of the cilia on the respiratory epithelium or degraded by alveolar macrophages, whereas neutrophils, the complement system, and numerous inflammatory cytokines are activated if necessary [1]. If patients suffer from a disease that makes the immune system unable to resolve the fungal threat, or if iatrogenic factors such as corticosteroid or chemotherapy cause severe neutropenia, Aspergillus is able to survive and further proliferate in the pulmonary system [3]. As the fungus transforms into hyphae and replicates, it eventually spreads both via hematogenous routes and by direct invasion into the surrounding tissues, ultimately causing an invasive infection in one or more organs [10].

Although risk factors and the mode of infection in the case of IA are well-known, prevention in severely immunocompromised patients may be difficult, especially for those in whom prolonged immunosuppression is evident (eg. transplant recipients or effects of chemotherapy). Adequate management of the underlying disease that predisposes individuals to IA is the single most important preventive strategy, whereas long-term prophylaxis with azole agents such as posaconazole in high-risk patients has shown good results [1].

Invasive aspergillosis (IA) encompasses a range of infections caused by Aspergillus species, one of the most common fungi encountered in clinical practice [1]. IA is almost exclusively an opportunistic infection, meaning that an immunocompromised status is considered to be a crucial risk factor [2]. Patients suffering from malignancies, human immunodeficiency virus (HIV) infection, severe neutropenia, and also transplant and stem cell recipients are in a state of severe immunosuppression [2]. A weakened immune system is used by the fungi to gain entry into the human host and establish an infection. Aspergillus sp. are ubiquitous, as they are found in soil, decaying matter and air [3]. The pathogenesis of IA starts with the colonization of the upper respiratory tract by Aspergillus fumigatus (species most frequently diagnosed in IA) and under physiological circumstances, fungi are either expelled by the ciliary respiratory epithelium or destroyed by local macrophages [1]. In the setting of reduced ability of the immune system to neutralize the invading fungi, however, Aspergillus is able to proliferate in the respiratory tract, initially causing a local infection. IA occurs as a result of the hematogenous or local dissemination of fungal hyphae and in the majority of cases, a diffuse pulmonary infection is the most common form of IA [1]. Hemoptysis, chest pain, dyspnea, and fever are some of the signs of invasive pulmonary aspergillosis (IPA), whereas other forms include tracheobronchitis [4], sinusitis, osteomyelitis and cerebral aspergillosis, which is rare but almost always fatal [1]. The initial diagnosis can be made by obtaining a thorough patient history that reveals an immunosuppressed status, together with a meticulous physical examination. Imaging studies such as computed tomography (CT) and plain radiography are highly useful in the setting of a pulmonary, sinus and skeletal infection, but microbiological confirmation should be attained whenever possible. Cultivation of samples from infected tissue on standard fungal media, determination of (1-3)-β-d-glucan and galactomannan - polysaccharides found on the fungal cell wall, as well as a biopsy of the affected tissue, may be performed [1] [5]. Unfortunately, confirmation of Aspergillus as the culprit is often difficult to obtain [6], as serum markers and blood cultures are often negative, whereas biopsy may be contraindicated in patients because of their underlying conditions which may predispose them to adverse events during or after the procedure. For these reasons, clinical and imaging criteria should serve as a primary source of information when initiating antifungal therapy, the mainstay in IA. Various regimens exist, but voriconazole and liposomal amphotericin B are considered as first-line drugs. Alternatives include caspofungin, micafungin, itraconazole or posaconazole. It is important to mention, however, that some agents may have deleterious effects when interacting with other drugs used by patients for their underlying condition (eg. protease inhibitors for HIV+ patients), which is why careful evaluation should be performed prior to selecting therapy [7]. The prognosis of IA depends on the severity of the underlying condition and the overall status of the patient [8], but even though certain reports suggest that IA is not that commonly seen in critically ill patients (<1% of all cases) [2], mortality rates are 40-90% [1] [3]; an effort to make an early diagnosis is essential.

Invasive aspergillosis (IA) is a medical term that denotes a severe form of infection caused by a fungus called Aspergillus, one of the most common fungi encountered in medical practice. Today, more than 200 species of Aspergillus have been described in medical literature, but the species that are responsible for the majority of human diseases are Aspergillus fumigatus, which can be isolated from moist soil and decaying matter. More importantly, it can also travel through air particles and the principal mode of acquisition is through inhalation of fungi and their subsequent entry into the upper respiratory tract. Under physiological circumstances, human hosts are able to fend off this microorganism through normal activity of the respiratory epithelium and cells of the immune system inside the lungs. However, in the setting of immunosuppression that may occur due to numerous illnesses and conditions (cancer, severe immunosuppressive therapy in the form of corticosteroids or chemotherapy, human immunodeficiency virus infection - HIV, but also genetic diseases), the fungi are able to establish an infection in the respiratory tract. For this reason, IA is considered to be an opportunistic infection, meaning that it can only cause a disease in hosts who have some defect in their immune response. As the fungus replicates in the lungs, it can spread through the direct invasion of local tissues or through blood vessels. Eventually, the lungs, but also the bones, the sinuses, and the central nervous system can be affected, either as isolated infections or in combination. However, the vast majority of IA cases are lung infections that manifest with a cough, chest pain, heavy breathing, and fever, although severe immunosuppressive therapy may prevent fever from occurring. A sinus infection causes headaches, nose bleeds and fever, whereas central nervous system infections (also known as cerebral aspergillosis) give nonspecific symptoms such as headaches and altered consciousness. To make the diagnosis, the physician must conduct a thorough physical examination and obtain a detailed patient history that may identify underlying conditions or factor that predisposes individuals to IA. Laboratory studies may reveal a decreased number of a specific subset of white blood cells, neutrophils, whereas computed tomography (CT) and plain X-ray is recommended for all forms of IA, especially in the setting of pulmonary infection. Although several tests for confirmation of Aspergillus as the underlying cause of symptoms exist (cultivation of obtained samples, determination of various fungal cell wall components in blood, or even biopsy), their accuracy has not been satisfactory, which is why clinical findings and results from imaging studies are used for treatment initiation. Antifungal therapy is the mainstay of treating IA patients and voriconazole and liposomal amphotericin B are considered as first-line agents against this microbial organism. A good prognosis may be expected when the diagnosis is made early on, but the outcome depends on the severity of the infection, but of the underlying condition as well and mortality rates range from 40-90%. Because it poses a life-threatening risk, these findings suggest that physician must consider Aspergillus as a potential cause of infection in an immunocompromised host who does not respond to standard therapy.

1. Mandell GL, Bennett JE, Dolin R. Mandel, Douglas and Bennett's Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, Pennsylvania: Churchill Livingstone; 2015.
2. Taccone FS, Van den Abeele A-M, Bulpa P, et al. Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes. Crit Care. 2015;19(1):7.
3. Dagenais TRT, Keller NP. Pathogenesis of Aspergillus fumigatus in Invasive Aspergillosis. Clin Microbiol Rev. 2009;22(3):447-465.
4. He H, Jiang S, Zhang L, et al. Aspergillus tracheobronchitis in critically ill patients with chronic obstructive pulmonary diseases. Mycoses. 2014;57(8):473–482.
5. Angebault C, Lanternier F, Dalle F, et al. Prospective Evaluation of Serum β-Glucan Testing in Patients With Probable or Proven Fungal Diseases. Open Forum Infect Dis. 2016;3(3):ofw128.
6. Maschmeyer G, Haas A, Cornely OA. Invasive aspergillosis: epidemiology, diagnosis and management in immunocompromised patients. Drugs. 2007;67(11):1567-601.
7. Gilbert DN, Chambers HF, Eliopoulos GN, Saag MS. The Sanford Guide to Antimicrobial Therapy 2015. 45th ed. Antimicrobial Therapy, Inc, Sperryville, VA; 2015.
8. Baddley JW, Andes DR, Marr KA, et al. Factors associated with mortality in transplant patients with invasive aspergillosis. Clin Infect Dis. 2010;50(12):1559–1567.
9. Lortholary O, Gangneux JP, Sitbon K, et al. French Mycosis Study Group. Epidemiological trends in invasive aspergillosis in France: the SAIF network (2005–2007). Clin Microbiol Infect 2011;17(12):1882–1889.
10. Hope WW, Walsh TJ, Denning DW. The invasive and saprophytic syndromes due to Aspergillus spp. Med Mycol. 2005;43(Suppl 1): S207–S238.
11. Greene RE, Schlamm HT, Oestmann JW, et al. Imaging findings in acute invasive pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis. 2007;44(3):373–379.
12. Hope WW, Walsh TJ, Denning DW. Laboratory diagnosis of invasive aspergillosis. Lancet Infect Dis. 2005;5(10):609-622.
13. Zhang S, Wang S, Wan Z, Li R, Yu J. The Diagnosis of Invasive and Noninvasive Pulmonary Aspergillosis by Serum and Bronchoalveolar Lavage Fluid Galactomannan Assay. BioMed Research International. 2015;2015:943691.
14. Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3):327-360.