Aspergillosis (aspergillosis) is a series of infectious or non-infectious diseases caused by Aspergillus spp. fungi. Infectious diseases caused by Aspergillus include superficial and deep infections, almost any organ can occur Aspergillus infection, the lung is a common site for deep Aspergillus infection, invasive infection often spread to the brain, skin, eyes, heart and other organs. Aspergillus is a conditionally pathogenic fungus, generally not easy to cause disease in healthy people, the infectious diseases caused by the infection site plus “Aspergillus infection” to name, such as “pulmonary Aspergillus infection”. Now often “invasive Aspergillus infection” called “invasive Aspergillosis”, they have the same meaning, can be called each other. Because “invasive” contains Aspergillus in the tissue growth, reproduction, resulting in tissue destruction and inflammatory response, and the propensity to spread to other organs, invasive infection is a serious disease, often life-threatening. However, it is not appropriate to confuse “Aspergillus infection” and “Aspergillosis”, the latter contains both Aspergillus infection and some non-infectious diseases. In recent years, the clinical invasive Aspergillosis increasingly important, in fact, deep Aspergillus infection is not necessarily invasive, there can be local tissue non-invasive infection, but invasive and non-invasive infection how to define, how to distinguish clinically very difficult, there is no consensus. Aspergillus caused by non-infectious diseases are mainly Aspergillus antigen-induced metaplasia, Aspergillus globules and Aspergillus toxin-induced acute and chronic poisoning. This section focuses on invasive Aspergillus infection.
【Clinical manifestations
(A) pulmonary aspergillosis
Roughly divided into Aspergillus-induced allergic lung disease, parasitic pulmonary aspergillosis (pulmonary aspergillosis) and invasive pulmonary aspergillosis (IPA) three categories. Aspergillus-induced allergic reactions include bronchial asthma and allergic bronchopulmonary aspergillosis (ABPA), exogenous allergic alveolitis, etc. Invasive pulmonary aspergillosis is caused by the invasive growth of Aspergillus in the airway and lung parenchyma, and can be divided into three subtypes: ① acute invasive pulmonary aspergillosis (AIPA), or vascular invasive (angioinvasive) pulmonary aspergillosis; ② chronic necrotizing pulmonary aspergillosis (CNPA), or incomplete invasive (semi-invasive) pulmonary aspergillosis; ③ airway invasive Aspergillosis (airway-invasiveaspergillosis, AIA).
1.ABPA
ABPA is an allergic disease caused by Aspergillus, almost exclusively caused by Aspergillus, mainly manifested by recurrent asthma symptoms, chest imaging shows pulmonary infiltrates and peripheral blood eosinophilia, fever and sputum with brown spots or coughing up sputum. Patients with ABPA can go through three clinical stages: early hormone-sensitive asthma, mid-stage hormone-dependent asthma, and late stage pulmonary fibrosis and cellulite. Early and effective treatment can stop the progression of the disease.
The typical presentation on X-ray chest radiograph and chest CT is a transient pulmonary infiltrate, mainly in the upper lungs, which can be bilateral, often due to sputum plugs obstructing the bronchi and disappearing after coughing up the mucus plugs. The “ring sign” or “orbital sign” suggests bronchial inflammation. Bronchial lumen filled with mucus may form band shadows and finger-loop shadows. As the disease progresses, proximal bronchial dilatation may appear.
2, parasitic pulmonary aspergillosis (pulmonary aspergillosis)
Aspergillus, often also known as fungal ball, the vast majority occur in the original lung cavity, occasionally also seen in the chronic obstruction of the paranasal sinuses, occurring in the lung cavity called pulmonary aspergillosis, mainly caused by Aspergillus fumigatus. Aspergillus, Fusarium and other fungi can occasionally form a fungal ball very similar to Aspergillus, although Aspergillus is only one of the fungal ball, but because the fungal ball is mainly caused by Aspergillus, other fungi are very rare, in other words, most of the fungal ball is Aspergillus, so the fungal ball is usually referred to as Aspergillus. In the early 1950s, Aspergillus pulmonarius was the classic form of pulmonary aspergillosis. At present, pulmonary aspergillosis is still not uncommon, and foreign studies have found that about 10% to 15% of patients with chronic cavitary lung disease have a combination of pulmonary aspergillosis.
The underlying diseases of pulmonary aspergillosis are mainly cavitary tuberculosis, large alveolar emphysema, pulmonary fibrosis, nodular disease or histoplasmosis, etc. Even in the dilated bronchi of ABPA patients can also form aspergillosis, cavitary tuberculosis is the most common in China. Pulmonary aspergillosis is usually a benign putrefactive parasitic state of Aspergillus in the lung, but can develop on this basis into invasive pulmonary aspergillosis or other types of aspergillosis.
Patients with pulmonary aspergillosis are generally asymptomatic and are often detected by other lung diseases or physical examination X-ray chest radiographs. The main symptom is hemoptysis, and life-threatening hemoptysis occurs in a few patients. Sometimes it can be accompanied by fever, cough and other symptoms of Aspergillus allergic reaction, which needs to be differentiated from secondary infection or invasive pulmonary aspergillosis. Chest X-ray examination has diagnostic value, typical manifestations are: the formation of spherical solid masses in the original cavity of the lung, watery density, can move; masses of fast and cavity wall between the air cavity separation; located in the outer zone of the lung, there is often pleural thickening, long-term follow-up pleural thickness can change. There may be elevated titers of antibodies against Aspergillus antigen.
Invasive pulmonary aspergillosis with varicellosis often occurs in immunosuppressed patients in the process of neutrophil recovery, the formation of cavities and varicellosis at the site of invasive lesions without significant pleural thickening, there may be an increase in antibody titers. For this type of Aspergillus, CT chest examination is more sensitive than plain X-ray chest radiographs. For convenience, this section will be accompanied by invasive pulmonary aspergillosis Aspergillus called “secondary pulmonary Aspergillus”, and the “classic” Aspergillus called “primary pulmonary Aspergillus”.
3.Invasive pulmonary aspergillosis
Different types of invasive pulmonary aspergillosis have different clinical and pathological features, acute invasive pulmonary aspergillosis Aspergillus invade the lung tissue, small pulmonary arteries, can lead to pulmonary infarction, the disease is serious, often disseminated, rapid progress. Chronic necrotizing pulmonary aspergillosis is characterized by the formation of necrotizing granulomas in the lung tissue, no vascular invasion, no dissemination to distant organs, so also known as incomplete invasive pulmonary aspergillosis, usually progresses slowly (months to years), the prognosis is relatively good. Airway invasive aspergillosis is less common and does not involve the lung parenchyma.
The clinical manifestations and the rate of progression of invasive pulmonary aspergillosis are closely related to the patient’s immune status, and it is generally believed that in those with severe immunosuppression, the disease progresses rapidly while the inflammatory response is mild and the symptoms of infection are not obvious, and respiratory failure can occur early. If the degree of immunosuppression is light, the disease progresses relatively slowly while the inflammatory response is more intense, more obvious symptoms of infection and toxicity can occur, and respiratory failure can occur later.
Signs and symptoms of invasive pulmonary aspergillosis are often non-characteristic, and 1/3 of patients can be asymptomatic. Early symptoms may include cough, fever, chest pain and hemoptysis, and general malaise, weight loss, etc. Acute invasive pulmonary aspergillosis is often associated with shortness of breath and hypoxemia. The chest imaging manifestations of invasive aspergillosis are varied, and some patients may present with relatively characteristic manifestations that may suggest a diagnosis, but imaging has no confirmatory value because other infectious or non-infectious diseases can sometimes have similar manifestations. The risk factors and imaging manifestations of different types of invasive pulmonary aspergillosis are different, but the diagnostic principles and treatment methods are basically the same.
(1) Acute invasive pulmonary aspergillosis
The risk factors for acute aggressive pulmonary aspergillosis are neutropenia or neutrophil and/or macrophage dysfunction, cytotoxic drug chemotherapy, long-term hormone therapy, bone marrow or solid organ transplantation, congenital or acquired immunodeficiency, etc. Some patients do not have these risk factors, but often have underlying diseases, such as chronic obstructive pulmonary disease (COPD), diabetes mellitus, chronic kidney disease, mechanical ventilation in the ICU, and malnutrition; among these patients, COPD combined with long-term corticosteroid therapy is the most common. There is also a proportion of patients without clear risk factors.
Chest X-ray may show wedge-shaped shadow, patchy infiltrative shadow, isolated or multiple nodular shadow, etc. Cavities may be formed within the lesion, and pleural effusion is rare. In some patients, CT examination of the chest can reveal certain characteristic changes, and CT abnormalities of the chest often precede the X-ray plain film, which can suggest the diagnosis at an early stage. In the early stage of the disease (within about 1 week), the halo sign (halosign) can be seen on CT, which is a glassy ring-like shadow surrounding the lesion due to edema or hemorrhage around the lesion; later (about 1 week), a wedge-shaped shadow with the bottom edge adjacent to the pleura and the tip toward the lung door can appear, similar to the pulmonary infarction caused by pulmonary thromboembolism. The air crescent sign (crescentsign) appears later (around 2-3 weeks) as a crescent-shaped hypointense translucent area in the original lesion, more commonly seen in immunosuppressed patients during neutrophil recovery, due to contraction of the infarcted foci. In later stages, varicoceles may form within the lesion. It is worth mentioning that in recent years, clinical attention has been paid to the phenomenon of “halo sign”, and studies have shown that early initiation of antifungal therapy according to the manifestation of “halo sign” can significantly improve the survival rate of patients, but “halo sign The “halo sign” is not unique to invasive pulmonary aspergillosis, but can also be seen in fungal infections such as Aspergillus and Fusarium, as well as alveolar cell carcinoma, Kaposi’s sarcoma, Wegener’s granuloma and pulmonary hemorrhagic metastases. It has even been found that the halo sign is also seen in invasive pulmonary Candida infections. The rapid progression of acute invasive pulmonary aspergillosis, with a significant increase in the number of lesions usually within a few days, is one of its imaging features.
In fact, most of the cases seen clinically do not have these typical imaging features. We analyzed 8 cases confirmed by pathological examination and/or culture of lung tissue specimens and found that chest imaging mainly showed diffuse irregular infiltrative shadows, multiple nodular shadows or isolated spherical (or hemispherical) lesions with rapid lesion progression, and more than half of them showed round cavities with no fluid level in the cavity; only 2 cases showed the halo sign and 1 case showed the crescent sign.
(2) Chronic necrotizing pulmonary aspergillosis
Chronic necrotizing pulmonary aspergillosis is common in middle-aged and elderly people, and the main symptoms include cough, sputum, hemoptysis and weight loss, etc. The disease is relatively mild and often progresses slowly over several months to years. Patients also have a relatively better underlying immune status than patients with acute invasive pulmonary aspergillosis. Risk factors include: (i) chronic lung diseases: such as COPD, bronchial asthma, cystic pulmonary fibrosis, pulmonary tuberculosis, post partial lung resection, nodular disease, pneumoconiosis, etc.; (ii) systemic diseases: such as diabetes, rheumatoid arthritis, malnutrition and other diseases, as well as patients on long-term low-dose glucocorticoid therapy.
Chest imaging reveals unilateral or bilateral pulmonary infiltrative lesions or nodular shadows, often with irregular borders, mostly in the upper and lower lobe dorsal segments, with or without cavitation, with 50% of those with cavitation appearing as varicose spheres, often with adjacent pleural thickening.
(3) Airway invasive pulmonary aspergillosis is mainly seen in patients with neutropenia and AIDS.
Clinical and imaging can be manifested as follows: ① acute tracheobronchitis: X-rays are mostly normal, occasionally with increased lung texture; ② fine bronchitis: HRCT shows lobular central nodules and “tree-in-bud” (tree-in-bud) sign; ③ bronchopneumonia: small solid shadow in the distribution area of the peripheral fine bronchus; ④ obstructive Bronchopulmonary aspergillosis: Aspergillus is growing in the lumen in the form of masses, CT performance is similar to ABPA, which is more likely to occur in the lower lobe, there can be bronchial dilatation on both sides, a large amount of mucus embedding, and bronchial obstruction can lead to pulmonary atelectasis.
(B) Extrapulmonary varicose infection
Aspergillus infection of extra-pulmonary organs and tissues can be primary infection, but also secondary infection caused by invasive Aspergillus hematogenous dissemination or direct spread of infection from adjacent organs. In addition to the lungs, Aspergillus infections also occur more frequently in the paranasal sinuses, central nervous system, bones, skin, heart, and eyes. In fact, in invasive Aspergillosis, it can spread hematologically to any organ and tissue, including the thyroid, kidney, liver, spleen, gastrointestinal tract, etc., often multiple organs are involved at the same time.
1.Sinus Aspergillus infection
(1) Acute invasive Aspergillus sinusitis
It can be accompanied by pulmonary infection or exist alone, mostly in neutropenic patients, and is not very rare in solid organ transplant patients, and its actual incidence may be underestimated. The main symptoms include fever, orbital swelling, facial neuralgia, and nasal congestion. CT is more sensitive than conventional radiography, showing high-density shadowing of the paranasal sinuses, sometimes accompanied by bone destruction or adjacent tissue invasion.
(2) Chronic invasive sinus varices
There are often manifestations of chronic paranasal sinusitis, which may be accompanied by headache, loss of smell and diplopia. The disease progresses slowly and often recurs repeatedly. Chronic varicose infection of the septal sinus can erode the bone affecting the orbit and cavernous sinus, and is most often seen in patients on systemic hormone therapy, HIV infection, and diabetes mellitus.
(3) Primary paranasal sinus granuloma
Most often seen in patients with relatively normal immune function, mainly due to Aspergillus flavus, lesions are more limited, invasion of the paranasal sinuses can form non-caseating granulomas, local symptoms are more severe, can also spread to the orbit, dura mater and brain tissue.
(4) Allergic aspergillosis paranasal sinusitis
It may manifest as chronic intractable paranasal sinusitis and nasal polyps (without invasive bone), asthma, eczema or allergic rhinitis with elevated IgE levels and increased isolation of Aspergillus, but no manifestation of invasive disease on CT scan.
2, central nervous system Aspergillus infection
The central nervous system is also one of the common sites of infection of invasive Aspergillosis. It is often caused by hematogenous spread of invasive Aspergillus infection in the lungs and other sites, paranasal sinus infection can also spread directly into the skull, and occasionally intracranial Aspergillus infection can occur after brain surgery. Symptoms and signs are often insidious, not easy to find, there can be headache, fever, seizures and other manifestations, occasionally cerebral hemorrhage can occur. Cranial CT or MRI examination can be seen intracranial single or multiple occupying lesions, the center of the lesion easy to appear cavity.
3, ocular Aspergillus infection Aspergillus is a common pathogenic bacteria leading to post-traumatic keratitis. Endophthalmitis can occur during systemic disseminated infection or after ocular surgery, and periorbital infection is often the result of paranasal sinus infection invasion.
4, bone Aspergillus infection
Bone Aspergillus infection is rare, to the end of the last century, only 70 cases reported internationally. Other parts of the invasive infection hematogenous dissemination can cause Aspergillus infection, commonly in immunosuppressed patients. Paranasal sinus and body surface Aspergillus infection can spread directly to the adjacent bone, open trauma or bone surgery can also cause Aspergillus infection. Nanjing Military General Hospital had admitted a middle-aged female patient with vertebral aspergillosis infection, the diagnosis was confirmed by pathological examination and culture of surgical specimens. The patient is not immunosuppressed, no other sites of Aspergillus infection, no special contact history, no history of surgery and trauma, the infection pathway and mechanism is not clear.
5.Dermal Aspergillosis
Aspergillosis of skin and soft tissue can be the skin manifestation of disseminated infection, or primary skin infection, mostly seen in immunosuppressed patients, or occur in postoperative or post-traumatic wound infection, burn infection. Crust-like skin lesions are common, and lesions such as ulcers, subcutaneous granulomas or abscesses can also form. Neutropenic patients can occur gangrenous deep pustulosis. Aspergillus flavus causes skin damage more commonly than Aspergillus fumigatus, Aspergillus niger may be associated with otitis externa.
6, heart and vascular Aspergillus infection
Aspergillus has been reported to cause endocarditis, myocarditis, pericarditis, mediastinitis, septic thrombophlebitis and aortic graft infection. Most occur in solid organ transplant patients, but can also occur in immunocompetent individuals. The clinical manifestations are usually insidious, with a high mortality rate and are not easily detected during life.
Aspergillus endocarditis, pericarditis and myocarditis are mainly due to hematogenous spread of invasive infections from other sites. Aspergillus endocarditis can also be seen after cardiac surgery, cardiac interventions and can occasionally recur. Septic thrombophlebitis is seen in neutropenic patients and is associated with long-term indwelling central venous catheters, and histological examination may reveal varicoceles invading the venous wall. Aortic graft varicose infection is rare, and skeletal involvement has been reported in about half of patients.
(7) Gastrointestinal infection
Aspergillus infection caused by direct inoculation of the gastrointestinal tract is rare, mainly due to hematogenous dissemination. CT scan shows multiple small translucent areas in the liver.
Laboratory tests
(A) Pathogenic examination
1. Smear microscopy
Take sputum, airway aspirate, bronchoalveolar lavage fluid or brush specimen by fibrinoscopy, pus, stool, urine, scab and other specimens on a slide, add 1 drop of 10%-20% potassium hydroxide solution, and add a coverslip. Microscopically, separated mycelium, conidia, sometimes visible conidial peduncle, apical capsule and small peduncle. Sexual stage Aspergillus infection can be seen in the closed capsule and ascospores. The advantage of direct microscopic examination is simple and rapid, the disadvantage is that the positive rate is low.
2. Culture
Specimens used for culture can have sputum, tracheal aspirate, brush examination by fibrinoscopy, bronchial lavage or bronchoalveolar lavage fluid, pus, pleural fluid and lesion tissue. After inoculation of various specimens placed at room temperature to 37 ℃ culture, most Aspergillus fast growth, 48h
can have more mycelium and conidia appear. Percutaneous lung puncture biopsy or other methods to obtain larger pieces of tissue specimens should be cut or homogenized under aseptic operation to improve the positive rate of culture.
Specimens from normal sterile sites (such as cerebrospinal fluid, thoracoabdominal fluid, pericardial fluid, deep tissue puncture aspirate) with positive culture combined with clinical manifestations can confirm the diagnosis of Aspergillus infection, and can distinguish between strains. Distinguish Aspergillus species has some significance in guiding treatment, common Aspergillus is usually sensitive to dicloxacillin B, new azoles and echinocandins antifungal drugs, but Aspergillus terreus has poor sensitivity to dicloxacillin B. It is generally believed that blood, bone marrow culture rarely grow Aspergillus, if the culture is positive may be contaminating bacteria, can not be used as a basis for diagnosis.
Sputum, nasal secretions, airway aspirates or bronchoalveolar lavage fluid, urine and other non-sterile specimens with positive culture, can not be used as a basis for diagnosis, may be infected, may also be Aspergillus colonization. Repeated cultures of the same species of Aspergillus in immunosuppressed hosts should be alert to the possibility of invasive infection. The sensitivity and specificity of specimens obtained by fibrinoscopy, including brush examination, bronchoalveolar lavage or aspirate specimen smear, culture are not high.
Aspergillus drug sensitivity test has not been commonly carried out, drug sensitivity test methods, sensitivity folding point, etc. is still under study, the current clinical application is of little value.
(B) histopathological examination
Histopathological examination is important for the diagnosis and typing of invasive Aspergillosis, is the “gold standard” for the diagnosis of deep fungal infections, including fiberoptic bronchoscopic lung biopsy, transthoracic skin lung puncture biopsy or open lung biopsy. However, because of the need to obtain specimens by invasive means, its clinical application is somewhat limited in severe cases. Conventional HE staining can better show Aspergillus mycelium, mycelium separation and conidia, but easy to miss the diagnosis. It is best to PAS staining or silverophilic staining, which can more clearly show the fungal cells. But histopathological examination can not distinguish Aspergillus species.
Aspergillus mycelium, spores in tissue sections, HE staining is blue-gray slightly red, PAS is red, silver staining is black or brown. Aspergillus conidia are sometimes seen in the lesion. Aspergillus mycelium vary in length, but more uniform in diameter, about 3 to 5 μm, clearly separated, branching about 45 °, arranged in a radial and coral-like. Mycelium cross-section is very similar to spores, but the spores are more dense groups, slightly smaller than the diameter of the mycelium. Aspergillus mycelium should be mainly identified with Candida, Trichoderma mycelium. Candida mycelium is thin, often with pseudomycelium, branching irregular; Trichoderma mycelium is thicker, is 2 to 3 times the diameter of Aspergillus and uneven, not separated, right angle branching.
(C) trichothecene skin test trichothecene skin test is one of the basis for the diagnosis of ABPA, but has no value for the diagnosis of invasive Aspergillosis.
(iv) Serological test
Serum antibody test is helpful in the diagnosis of ABPA, guiding glucocorticoid treatment and disease follow-up, and also helps to determine whether the patient with pulmonary aspergillosis is accompanied by allergic reaction to Aspergillus and chronic Aspergillus infection. For the diagnosis of invasive aspergillosis is basically worthless, because of the late production of antibodies, not early diagnosis, and immunosuppressed patients with impaired antigen-presenting function and lymphocyte function, even if there is a serious Aspergillus infection may not be able to effectively produce antibodies, or produce a low titer of antibodies, difficult to detect; in addition, antibody testing because of cross-reactivity also has a certain rate of false positives.