{'fraction_non_alphanumeric': 0.02735481113426297, 'fraction_numerical': 0.00689213014906235, 'mean_word_length': 5.549335199440168, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 1, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Section 3. Colombian consensus on the diagnosis and treatment of extrapulmonary aspergillosis in adult patients* Development of the Colombian Consensus on the Management of Invasive Fungal Disease

The clinical manifestations of Aspergillus spp. associated diseases are variable and depend on the interaction between the inoculating dose (which is not known and probably varies widely), the patient’s ability to resist infection at both local and systemic level, and the virulence of the etiologic agent. The major difficulty in establishing a clinical classification scheme lies in the existence of a broad and continuous spectrum of disease, associated with a complicated diagnosis and clinical management. An IA can present as a localized infection in one organ, or as part of a disseminated infection, which presents itself in a varied spectrum of clinical pictures. However, no clinical trials have been completed to evaluate the different specific therapeutic approaches according to the type of involvement in these patients. The most common clinical forms of invasive aspergillosis (IA) occur in the lung and paranasal sinuses, chronic pulmonary aspergillosis (CPA) can be complicated by spreading to contiguous structures such as the pleural space, pericardium, chest wall and mediastinal structures such as the esophagus and great vessels. It frequently spreads beyond the respiratory tract, and can affect the skin, CNS, eyes, liver, kidneys and other structures.


Introduction
The clinical manifestations of Aspergillus spp. associated diseases are variable and depend on the interaction between the inoculating dose (which is not known and probably varies widely), the patient's ability to resist infection at both local and systemic level, and the virulence of the etiologic agent. The major difficulty in establishing a clinical classification scheme lies in the existence of a broad and continuous spectrum of disease, associated with a complicated diagnosis and clinical management [1][2][3][4][5][6][7][8][9][10][11] . An invasive aspergillosis (IA) can present as a localized infection in one organ, or as part of a disseminated infection, which presents itself in a varied spectrum of clinical pictures. However, no clinical trials have been completed to evaluate the different specific therapeutic approaches according to the type of involvement in these patients 3,21,76 . The most common clinical forms of IA occur in the lung and paranasal sinuses 62,64,[116][117][118] , chronic pulmonary aspergillosis (CPA) can be complicated by spreading to contiguous structures such as the pleural space, pericardium, chest wall and mediastinal structures such as the esophagus and great vessels 3,49,69 . It frequently spreads beyond the respiratory tract, and can affect the skin, CNS, eyes, liver, kidneys and other structures 20,61,62,90,[118][119][120] .
Most definitions covering disseminated aspergillosis require the demonstration of Aspergillus spp. in two or more noncontiguous compromised sites, with the assumption of en-dovascular or bloodstream infection implicated in the pathogenesis 20,49,65,[119][120][121][122][123] , which must be differentiated from local dissemination or extension through tissue planes (e.g., sinus aspergillosis with direct extension to the meninges and brain) 61,63,90 , from multifocal disease within an organ, and from situations where there is more than one site of infection within the organ (e.g., IPA and tracheobronchial aspergillosis) 20,49 . However, infection at two primary sites where it is assumed that infection is initiated simultaneously (e.g., concomitant acute invasive sinusitis and IPA) should probably not be considered as disseminated disease 3,20,21,49 . Table 1. Scale for measuring the quality of evidence and strength of recommendations.

High (i)
The probability that the results will change is minimal.
Moderate (ii) Results may change over time, but will not change dramatically.

Low (i)
The results can definitely change over time.

Strong
It is recommended to implement this recommendation in daily clinical practice.

Weak
It is recommended that before implementing this recommendation, the risks and benefits to the patient, as well as the costs or utilization of health resources, be evaluated.
Adapted from: Andrews JC et al. 12 From a practical point of view, the diagnosis of extrapulmonary aspergillosis poses a number of difficulties related to the use of diagnostic tools, since the revised EORTC/MSG (European Organization for Research and Treatment of Cancer/ Mycoses Study Group) criteria 65 , specifically state that, in the case of suspected disease, the site from which clinical samples should be taken should be related to the region of tissue damage (defined clinically and radiologically), but that this is not feasible in many cases (e.g., CNS aspergillosis) 21,69,76 .
Finally, proven disseminated aspergillosis has been defined as proven/probable IA at two noncontiguous involved sites (e.g., pulmonary and cutaneous disease), and probable disseminated aspergillosis has been defined as a proven/probable IA at one involved site, but with evidence of tissue damage at a noncontiguous (usually sterile) site, that is compatible with an IA (with evidence of invasive disease), but without diagnostic evidence for the involved site 3,21,45,49, .
A detailed description of the background, methods and potential conflicts of interest can be found in the Section 1 "Colombian Consensus on the Diagnosis and Follow-Up of Invasive Aspergillosis and Aspergillus Disease in Adult and Pediatric Patients". Summarized below are the recommendations for the diagnosis and treatment of extrapulmonary aspergillosis. To assess the quality of the evidence and the strength of the recommendations, the modified GRADE methodology 12,13 was used. It assigns each recommendation with separate ratings for the underlying quality of the evidence supporting the recommendation, and for the strength with which the recommendation is made, establishing the following levels of evidence: LOW (III): results may definitely change over time; MODERATE (II): results may change over time, but will not change dramatically; HIGH (I): the likelihood that the results will change is minimal. The strength of the recommendation (STRONG OR WEAK) was evaluated taking into account the balance between benefits and risks, quality of evidence, patient values and preferences, and cost or resource utilization (Table 1)   Evidence of tissue plane disruption and vascular invasion by adhesion of surface components of fungal structures (including vascular wall components, basement membrane, extracellular matrix, and cellular constituents), associated with coagulative necrosis and hemorrhagic infarction. Fungal lesion (or fungal sequestration) and areas of distal wedge-shaped pulmonary infarction are manifestations of angioinvasion.
Imaging findings depend on the patient's characteristics, and a wide variety of nonspecific radiographic patterns may be present. X-ray may show peripheral opacities (ill-defined, 1-3 cm, gradually merging into larger opacities) with or without cavitation. The opacities may increase in size and become necrotic in their central part, which reduces their density and favors air trapping, producing the "air-crescent sign"; such cavitation occurs after neutrophil recovery, which is a sign of good prognosis. An early but non-specific finding on CT is the presence of nodular opacities with a groundglass border "halo sign" (reflecting hemorrhage and edema surrounding the lesion), also the presence of peripheral opacities by complete alveolar occupation, wedge-shaped with a base towards the pleura which, in the appropriate clinical setting, are highly suggestive of angioinvasive aspergillosis.
On multislice CT, a budding tree pattern can be seen. Pleural effusion and mediastinal adenopathies are rare. Invasion of the chest wall or mediastinal pleura may occur.

IPA (non-angioinvasive)
There is no evidence of vascular invasion by the fungal structures, with the presence of a pyogranulomatous inflammatory infiltrate, inflammatory necrosis or cavitation (occasionally a mixed histologic picture may be observed).
Almost any radiologic pattern may be present. Nonspecific abnormalities may be evident, including airspace disease, single or multiple nodular infiltrates (with or without halo sign), segmental or subsegmental consolidation, diffuse ground-glass opacities or cavitation. CT allows a better definition of halo and crescent signs.

ABI
It is an invasive disease that mainly affects the large airways, (bronchoscopically accessible Generally, imaging findings are normal, although X-ray and CT scan may show airway wall thickening, presence of patchy opacities or centrolobular nodules, atelectasis and/or lobar collapse.

Acute invasive sinusitis
There is evidence of an acute and relatively sparse inflammatory infiltrate, with tissue infiltration by hyphal elements, angioinvasion and coagulative necrosis. It is locally more invasive, causes bone destruction, spreads to adjacent soft tissues and invades the pterygopalatine fossa, cavernous sinus and intracranial cavity. With vascular invasion and hematogenous dissemination.
Initially, noncontrast CT shows low-density mucosal thickening or soft tissue attenuation within the paranasal cavity, with a predilection for unilateral involvement of the ethmoid and the sphenoid cell. Aggressive bone destruction of the sinus walls can be rapid, and is associated with intracranial and intra-orbital extension. Bone erosion and mucosal thickening is sometimes subtle, as these fungi tend to extend along the vessels; extension beyond the sinuses may occur with intact bone walls. Intracranial extension of the disease from the sphenoid sinus leads to thrombosis of the cavernous sinus and even invasion Severe unilateral thickening of the soft tissues of the nasal cavity is the earliest finding and the most consistent, although nonspecific, sign seen on CT. More extensive changes, such as inflammation of the periantral fat, erosion, and orbital or intracranial invasion are more specific but late and infrequent features. MRI is the imaging of choice to evaluate intracranial and intra-orbital extension, as it better characterizes inflammatory changes in the orbital fat, extraocular muscles and proptosis resulting from intra-orbital invasion. Obliteration of periantral fat is a subtle sign of such extension, and should be looked for in patients at risk. Leptomeningeal enhancement with intracranial invasion may be seen, which is subtle in the early stages of infection.
With the progression of infection there may be adjacent cerebritis, granulomas and brain abscess formation. Intracranial granulomas are hypointense in T1 and T2, with minimal enhancement in the contrasted T1 sequence.

Chronic invasive sinusitis
Presence of a mass composed of friable, necrotic or purulent material, associated with a mixed cellular infiltrate, inflammatory necrosis and invasion of contiguous structures, such as the skull base, orbit and brain.
Noncontrast CT shows a pseudomass with hyper-attenuated (dense) soft tissue in one or more of the paranasal sinuses, with an infiltrative appearance (mimicking cancer) and destruction of the sinus walls, with extension beyond the paranasal cavities.
MRI is preferred to evaluate the associated intracranial extension, which behaves isointense on T1 and hypointense on T2 and FLAIR, without diffusion restriction, with mottled appearance in the bone tissue due to irregular bone destruction.
Sinus aspergilloma Presence of a fungus ball composed of cheesy and friable material and a conglomerate of hyphal elements in concentric circles. The antral mucosa is well preserved, with chronic non-granulomatous inflammatory response, and no evidence of bone erosion.
There is evidence of sinus opacification with one or more oval or rounded soft tissue dense images, called foreign bodies, concretions or antroliths, found centrally or towards the orifice of the antrum, without evidence of tissue invasion; there may be thickening or sclerosis of the sinus wall due to pressure, which may lead to necrosis. Echocardiographic findings are non-specific, and include compromised mechanical valve function and seating, paravalvular leak and paravalvular abscess formation.

Pericardial aspergillosis
It may arise by contiguous dissemination from the pleura or myocardium. There is evidence of fibrinous or exudative pericarditis, or contiguous IPA, or myocardial aspergillosis.
Postmortem findings demonstrate patchy, diffuse pericarditis, or the presence of multiple raised nodules or plaques on one or both pericardial surfaces.
Pericardial aspergillosis is not a frequent ante mortem diagnosis, but should be suspected when a patient with IPA develops pericardial effusion (suspected clinically or seen on imaging), or there is other evidence of pericardial disease. There is echocardiographic evidence of pericardial disease, including pericardial effusion and signs of pericardial tamponade, with a widened cardiac silhouette on chest X-ray. CT or MRI shows single or multiple space-occupying lesions showing ring enhancement, mass effect or cerebral edema.

Brain granuloma
There is evidence of a firm, rubbery or gritty mass, without suppuration, with florid granulomatous inflammation and fibrinous tissue interspersed with hyphal elements.
CT shows a space-occupying lesion. The MRI characteristic of Aspergillus granulomas, shows to be extremely hypointense on T2, and hypointense or isointense on T1.
Fungal cerebral aneurysm There is evidence of aneurysm formation in the intracranial artery, and invasion of the vessel wall by hyphal elements. The aneurysm may rupture or leak, which usually manifests as hemorrhage into the subarachnoid space.
In catheter angiographies and CT and MRI angiographies, aneurysms are usually fusiform, most often involving the proximal vasculature, such as internal carotid arteries and vessels forming the polygon of Willis. Intracranial hemorrhage may be a complication of vasculitis or fungal aneurysm formation, which appears hyperdense on non-contrast CT.

Meningitis
Presence of a thick grayish-white membrane covering the brain, in cases of dissemination from sinuses; or of focal and contiguous meningitis in cases of cerebrovascular aspergillosis, with the formation of a cerebral abscess, meninges infiltrated by hyphal elements and inflammatory infiltrate. CSF shows neutrophil pleocytosis, elevated protein and low to normal glucose.
Radiologic abnormalities within the meninges are usually absent. MRI shows thick meningeal enhancement on T1-weighted images, particularly at the skull base. The presence of leptomeningeal enhancement is nonspecific, but nodularity may be more specific of a fungal infection. Ocular ultrasound may reveal intraocular abnormalities.

Scleritis
Infiltration of the sclera by hyphal elements is more common in the setting of recent surgery, accidental or traumatic injury, or may be due to hematogenous seeding. Fungal lesions can be seen on simple X-ray, CT and MRI, and may be helpful in stratifying and guiding needle biopsy of the lesion. The imaging features of infections are often nonspecific and difficult to differentiate from findings due to pyogenic infections or other causes of inflammatory arthropathy. CT findings include bone destruction, mixed lytic and sclerotic foci, cortical thickening and joint space narrowing.

Septic arthritis
It may be the result of hematogenous seeding, or direct inoculation after joint instrumentation.
CT and MRI findings are nonspecific. The most common findings are bone erosion, joint space narrowing, synovitis and joint effusions.

Pathological findings Imaging findings
Renal aspergillosis This entity is the result of hematogenous seeding, and is usually an incidental finding in the context of disseminated disease.
Several different pathological processes are observed, ranging from vascular involvement with tissue infarction to renal abscess formation. Involvement of the renal vasculature results in multiple areas of renal infarction and ischemic and papillary necrosis. The renal vein may also be involved with complications including renal vein thrombosis and renal infarction.
CT reveals typically heterogeneous focal abscesses; these appear as hypoattenuating collections, which replace the renal parenchyma, with or without associated hydronephrosis. Advanced infection can lead to renal infarction and necrosis, which appears on contrast-enhanced MRI and on CT as a hypointense image, rarely progressing to emphysematous pyelonephritis.

Renal aspergilloma
Similar to formation of aspergillomas of pulmonary or sinus origin; the renal pelvis is the most common site of involvement.
Aspergilloma is composed of gray or brown cheesy material that completely fills and occludes the pelvis and other components of the collecting system. The renal parenchyma is not involved, although there may be an ascending infection.
The presence of an aspergilloma occupying the renal collecting system, appearing as a heterogeneous hypoechoic mass within the dilated calyces, can be seen by ultrasound. On CT they appear as soft tissue dense masses within the collecting system.

ITZ
• To improve efficacy in patients (immunocompromised or not) receiving ITZ, in prophylaxis or for treatment of an IFD or an allergic fungal disease: • When there are drug interactions, when starting or stopping therapy (either by inhibiting absorption or affecting its metabolism) • In co-medications (with Cytochrome P450 inducers). • In case of suspicion of non-adherence to oral therapy.

Involved organ Recommended approach
Lesions close to great vessels and/ or pericardium.

Pericardial involvement Pericardiectomy
Chest wall invasion due to pulmonary lesion Resection of thoracic lung and wall lesion (possibility of subsequent reconstruction).

Empyema
Chest tube drainage, consider surgical drainage and thoracotomy (in case of fibrinopurulent or organized empyema).

Hemoptysis secondary to lung injury
Cavity resection or embolization Skin and soft tissue involvement Debridement and resection with wide margins

Infected vascular catheters and prostheses
Removal of devices

Endocarditis
Removal of the device, excision of the vegetation and resection of the infected valves.

Osteomyelitis
Debridement and cleaning of the affected tissue, if possible, with subsequent reconstruction (musculoskeletal grafts, bone grafts).

Sinusitis
Cleaning, curettage and resection of affected tissues CNS involvement Resection and removal of affected tissue and space-occupying lesions.