The clinical presentation of patients is characterized by a nonspecific appearance of symptoms that indicate lung pathology. Dyspnea, dry cough, pleuritic chest pain and hemoptysis are most commonly reported, while fever despite antibiotic therapy (which is often administered empirically due to bacterial respiratory tract infection) and increased respiratory secretions may be present as well [6] [10]. In patients with severe immunodeficiency, symptoms may be mild or even absent due to the inability of the immune system to mount an appropriate inflammatory reaction [6].

• Fever

  The patients with SFTS-associated IPA first presented with fever, gastrointestinal symptoms, thrombocytopenia, leukopenia, and multiple organ failure. [ncbi.nlm.nih.gov]

• Unconsciousness

  Here, we report a case of a 56 yr old previously healthy woman who was found unconscious at home and admitted to the emergency room with mild respiratory insufficiency. [ncbi.nlm.nih.gov]

• Cough

  We present a 45-year-old male heart transplant recipient who developed fever, progressive worsening of dyspnea, and productive cough without response to antibiotics. [ncbi.nlm.nih.gov]

  – you may cough up blood or lumps of mucus wheezing (a whistling sound when breathing) a high temperature of 38C or above weight loss If you already have a lung condition, your existing symptoms may get worse. a cough for more than 3 weeks a lung condition [nhs.uk]

• Hemoptysis

  Massive hemoptysis (MH) with blood loss more than 300-600 ml in 24 hours is a rare (5-10% of IA patients) but frequently fatal complication. [ncbi.nlm.nih.gov]

  Cough, hemoptysis, dyspnea and poor general condition are most commonly observed. Imaging studies and levels of galactomannan are used for the diagnosis. Voriconazole and other antifungal agents are the mainstays of therapy. [symptoma.com]

• Dyspnea

  We present a 45-year-old male heart transplant recipient who developed fever, progressive worsening of dyspnea, and productive cough without response to antibiotics. [ncbi.nlm.nih.gov]

  Cough, hemoptysis, dyspnea and poor general condition are most commonly observed. Imaging studies and levels of galactomannan are used for the diagnosis. Voriconazole and other antifungal agents are the mainstays of therapy. [symptoma.com]

• Productive Cough

  We present a 45-year-old male heart transplant recipient who developed fever, progressive worsening of dyspnea, and productive cough without response to antibiotics. [ncbi.nlm.nih.gov]

  On day 17 sputum culture done for a productive cough revealed Aspergillus spp. and voriconazole was immediately started per oral. At this point, chest X-ray was normal and the blood cultures for bacteria and fungi were negative. [austinpublishinggroup.com]

  Symptoms are nonspecific and usually mimic bronchopneumonia: fever unresponsive to antibiotics, cough, sputum production and dyspnoea. [err.ersjournals.com]

• Rales

  After 1-2 weeks, the patients developed mild polypnea and wheezing rales, and quickly developed dyspnea and respiratory failure. [ncbi.nlm.nih.gov]

  She had bilateral rales on lung auscultation. Complete blood count showed white blood cells of 6,900/mm 3, a hemoglobin level of 10.5 mg/dl, and a platelet count of 405,000/mm 3. [ispub.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]

• Stroke

  Brain imaging was consistent with a large right parieto-occipital ischemic stroke, leading to a limitation of treatment, and the patient eventually died. [rc.rcjournal.com]

Making the diagnosis of IPA, or fungal respiratory infection, in general, may be significantly prolonged if clinical suspicion is not made early on, especially in susceptible patients. For these reasons, diagnostic criteria were created based on clinical, laboratory, imaging and histopathological findings [12] [13]:

• A presumptive diagnosis can be made if 1) Lower respiratory tract culture yields Aspergillus species; 2) Signs and symptoms such as pleuritic chest pain, dyspnea, and hemoptysis, together with worsening respiratory function and recurrent fever despite antibiotic therapy; 3) Abnormal findings on either plain radiography or chest CT; and 4) Predisposing host factors such as neutropenia, presence of malignancy, corticosteroid therapy, and AIDS, or positive semiquantitative Aspergillus culture of bronchoalveolar fluid with a cytological smear showing branching hyphae.
• Criteria for establishing a probable diagnosis include 1) Presence of host factors (one of the following), such as neutropenia for more than 110 days, status of an allogeneic stem cell transplant recipient, prolonged use of corticosteroids, treatment with T-cell immunosuppressants and inherited severe immunodeficiency; 2) One of the following findings on CT - Air-crescent sign, well-circumscribed lesion(s) with or without a halo sign (reflecting lung infarction and necrosis surrounded by blood and interstitial fluid), or cavitation; 3) Microbiological confirmation by either positive direct tests (such as direct microscopy, cytology or culture) in respiratory secretions or detection of galactomannan.
• A definite diagnosis is made after histopathological confirmation from specimens obtained by needle aspiration of bronchoalveolar fluid or bronchoscopy.

• Atelectasis

  A severe obstructive pattern with impossibility of ventilation because of bilateral atelectasis was observed, requiring emergent venovenous extracorporeal membrane oxygenator device insertion. [ncbi.nlm.nih.gov]

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

  Other radiographic findings have been described, especially bilateral lower lobes atelectasis and consolidations ( 44 ), and mycetoma formation in patients with pre-existing cavities due to tuberculosis or pneumocystis ( 45 ). [ispub.com]

Early initiation of antifungal therapy is essential and various regimens exist [9]:

• Voriconazole is currently considered as first-line therapy and is administered in the following manner: 6 mg/kg IV q12 on the first day, followed by 4 mg/kg, with the goal of reaching blood levels of 1.0-5.5 mg/L. At these concentrations, both increased efficacy and reduced rate of adverse effects occur [10]. Voriconazole is a potent inhibitor of several cytochromal enzymes, including CYP3A4 and should be cautiously administered together with other CYP3A4 metabolizing drugs, such as protease inhibitors [9].
• Itraconazole, administered 600 mg q24h PO for 3 days followed by 400 q24h is considered to be an alternative regimen, but like voriconazole, it is a potent CYP3A4 inhibitor and causes significant drug interactions.
• Amphotericin B is considered to be an alternative drug, but only in lipid forms (both liposomal and lipid complex) and is given 3-5 mg/kg IV q24h. Much better effects are observed with liposomal than lipid complex Ampho B.
• Caspofungin and micafungin have somewhat different mechanisms of action compared to azoles and they are usually indicated in patients who do not respond to first or second-line therapy. Their efficacy, however, is limited compared to agents such as voriconazole. 70 mg q24h followed by 50 mg q24h is the recommended dose for caspofungin, while micafungin is given 100 mg q12h [9].

Despite advances in antifungal therapy, as well as intensive care monitoring, the mortality rate is very high in patients suffering from this condition and range between 30%-70% across different studies [3], which is why an early diagnosis is detrimental in achieving better patient outcomes. The severity of immune deficiency, site, and extent of infection, as well as choice and effectiveness of therapy are main factors that determine survival rates [3].

IPA is a fungal infection caused by Aspergillus sp, a ubiquitous fungal pathogen that exists as a saprophyte in nature [3]. In almost all cases, A. fumigatus is responsible for IPA, while other species such as A. flavus, A. terreus and A. niger are less frequently encountered [2]. Aspergillus is a filamentous (branching) mould that grows on most standard media when exposed to air [1]. This fungus causes various forms of both lower and upper respiratory tract, including sinusitis, allergic bronchopulmonary aspergillosis, and development of aspergillomas, whereas invasive and disseminated aspergillosis, are most severe complications of respiratory colonization [1].

It is important to mention that IPA is almost exclusively seen in patients with an underlying immunocompromising disease. According to recent epidemiological reports, between 8%-15% of patients undergoing stem cell transplantation and 5%-15% of organ-transplant recipients develop this infection [8]. Severe and prolonged neutropenia is shown to be the most important risk factor for IPA, together with high-dose corticosteroid use. Advanced AIDS, hematopoietic stem cell and solid organ transplantation and chronic granulomatous diseases [5]. Respiratory comorbidities are becoming increasingly important in the pathogenesis of IPA and are present in approximately 9% [10]. COPD is observed in up to 2% of all fatalities, while certain studies have estimated that more than 20% of patients suffering from severe forms of H1N1 infection develop IPA in the intensive care unit [10] [11].

The pathogenesis of IPA starts with inhalation and colonization of the upper respiratory tract by asexual spores of Aspergillus (known as conidia) and their subsequent deposition in bronchioles or alveolar spaces [3]. In immunocompetent individuals, several barriers against fungal infection exist, such as the mucociliary barrier and both innate and adaptive immune factors. When conidia reach the lower respiratory tract, alveolar macrophages are responsible for the destruction of Aspergillus conidia through the release of reactive oxygen species, but also through recruitment of neutrophils and initiation of a pro-inflammatory response [3]. In immunocompromised individuals, however, various pathological mechanisms lead to immune system dysfunction, thus allowing Aspergillus to proliferate and invade the vascular system. Corticosteroids possess strong inhibitory effects on the phagocytic system and overall immune response [3], while patients with advanced stages of AIDS lack adequate T-cell responses [6]. In the case of COPD and other lung diseases, profound structural changes, such as impairment of ciliary function, repeated infections with resultant scarring and frequent use of antimicrobial therapy that disrupts normal flora, are shown to promote fungal proliferation [10].

Close monitoring of patients and appropriate management of underlying disorders that may predispose patients to this infection is vital in terms of prevention. Because of the ubiquitous nature of the fungus and its widespread distribution in air, however, prevention may be hardly achieved in these patients and the most important step in reducing mortality rates is an early diagnosis.

Invasive pulmonary aspergillosis (IPA) is a severe form of infection caused by Aspergillus sp, ubiquitous fungi that can be found in soil, air and decaying matter [1]. Aspergillus fumigatus is the causative agent in the vast majority of cases, whereas A. flavus, A. terreus and A. niger are less common causes [2]. Aspergillus species are contracted by inhalation of air that contains this fungus and under physiological conditions, both mechanical and immune barriers can successfully eradicate this microorganism. In the setting of immunosuppression, however, the fungi can replicate in the upper and lower respiratory tract, spread via the pulmonary vasculature and cause severe infection. As a result, immunosuppressive states, such as the use of high-dose corticosteroids, organ transplant recipients and severe neutropenia that is often seen in patients with hematological malignancies [3] are predisposing factors; while chronic obstructive pulmonary disease (COPD) has shown to be an important comorbidity in IPA [4]. Patients in advanced stages of acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV) infection and those with chronic granulomatous diseases are also shown to be at increased risk for this type of infection [5]. The clinical presentation of patient invariably includes respiratory complaints such as dyspnea, chest pain, and cough, while severe cases include hemoptysis, development of pleural effusions and pneumothorax [6]. Initial suspicion of a fungal respiratory infection can be made in immunocompromised patients who do not respond to initial antimicrobial therapy and in whom pulmonary infiltrates are detected on X-ray [6]. To confirm the presence of Aspergillus, imaging studies and a microbiological investigation is necessary. Either bronchoalveolar aspirate or bronchoscopy is rapid and successful method of obtaining viable samples for cultivation and microscopic evaluation, as Aspergillus sp. are rarely detected in blood [1]. Computed tomography (CT) may provide a better view into the lung parenchyma. A halo sign is described in these patients when CT is utilized, which represents lung infarction and coagulation necrosis surrounded by edema and blood [7]. Although it is not shown to be highly specific and sensitive, identification of galactomannan, a constituent of the Aspergillus cell wall, in serum, blood or bronchoalveolar aspirate can be performed as well [8]. Early antifungal therapy is vital in reducing mortality rates that were shown to be up to 80% in the last few decades [7]. Voriconazole, liposomal amphotericin B, caspofungin, and itraconazole are recommended in different regimens [9].

Invasive pulmonary aspergillosis (IPA) is one of the most severe infections caused by Aspergillus, a ubiquitously present fungus that causes a variety of clinical syndromes. This infection is almost exclusively seen in patients who have some form of immunosuppression. Patients with cancer, acquired immunodeficiency syndrome (AIDS) caused by human immunodeficiency virus (HIV) infection, those receiving high-dose corticosteroids and organ-transplant recipients are conditions that predispose individuals to this fungal infection. Lung diseases such as chronic obstructive pulmonary disease (COPD) and influenza infection are also shown to be important risk factors. Severe neutropenia (defined as a low neutrophil count, which comprises approximately 60% of all white blood cells), however, is the most significant risk factor, as neutrophils are one of the most important cells when it comes to defenses against fungi. Aspergillus is found in damp soil and air and inhalation is the way this microorganism is acquired. Under physiological circumstances, the fungus should be killed by host defenses once it reaches the respiratory tract, but because of various impairments of the immune system that are seen, the fungus is able to proliferate and spread throughout the lungs. As a result, a life-threatening infection develops and presents with symptoms such as a dry cough, chest pain, and breathing difficulties. Expectoration of blood may be seen, together with fever, but symptoms may often be mild or even absent, as the immune system is not able to create an adequate response to the harmful fungus. To make the diagnosis, a high index of clinical suspicion is necessary, especially in patients with underlying immunosuppression and symptoms that indicate the lungs as the site of infection. Computed tomography (CT scan) and chest X-ray is used to confirm the presence of lung disease, while microbiological inspection of samples obtained by either aspiration of bronchial fluid or biopsy is necessary for confirming the diagnosis. Treatment includes administration of antifungal agents such as voriconazole, itraconazole, liposomal amphotericin B, and caspofungin. Despite available therapy and advances in the care of critically ill patients, however, mortality rates are up to 90% in certain patient groups, which is why an early diagnosis is detrimental and often life-saving. Appropriate management of malignancies and other disorders that may predispose patients to this infection can significantly aid in reducing the number of patients suffering from invasive pulmonary aspergillosis.

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