Zygomycosis is a rare inflammatory disease caused by fungi of the subphylum Zygomycetes, which can invade the nasal cavity, sinuses, orbits, brain, lungs, gastrointestinal tract, skin, etc., and can also cause systemic dissemination; it is a fungal infection with rapid onset, rapid progression, and high mortality (more than 50%), and only a few manifest as chronic infection, so patients are rarely diagnosed during life It is a fungal infection with rapid onset, rapid progression and high mortality (more than 50%). Because of the different methods of classification of fungi, jointed mycosis is also known as mucormycosis, phycomycosis or hyphomycosis [1].
[Pathogenesis].
The causative organism of jointed fungal disease is a fungus in the subphylum Jointed Fungi, a ubiquitous saprophytic fungus divided into two phyla, namely Jointed Fungi and Trichophyton. In the traditional custom, most authors will be divided into three orders (or two orders of Trichoderma and Trichoderma) of Trichoderma, Entamoeba and Entamoeba. A variety of fungi in the subphylum Zygomycetes can cause zygomycosis, the vast majority of clinically referred to as zygomycosis are caused by the fungi in the subphylum Zygomycetes – Zygomycetes – Trichoderma, but clinically not easily separated, so the causative agent of zygomycosis can be collectively referred to as Zygomycete (Zygomycete) or Trichoderma ( Mucoraceae); the lesion caused by Trichoderma is called Trichoderma, and the lesion caused by Trichoderma and Entamoeba is called together as jointed mycosis. Trichoderma is the largest order in the class of jointed fungi, can cause jointed fungal disease pathogenic bacteria are Trichoderma, Rhizopus, Rhizopus, Platygomycetes, Bottle mold, small grams of silver Han mold, common head mold, spore mold, etc., but the most common pathogenic bacteria reported in the literature are four species (genus): Rhizopus, Trichoderma (Mucor), Platygomycetes (Absidia) and small grams of silver Han mold Silver Han mold genus (Cunninghamella). Trichoderma can grow in most of the media (such as agar medium, chocolate medium and Sabro dextrose agar medium) at temperatures of 25-55°C; the special structure of Trichoderma under the microscope is: broad mycelium (10-50um), uneven thickness, thin wall, almost no separation, accompanied by right-angle type of branching, the angle of mycelium branching from 45° to 90° [2]. Entomopathogenic fungi are mainly parasitic on insects, protozoa and nematodes, and there are few pathogenic bacteria that can cause jointing fungal disease, only otomycetes and frog fecal molds. Splicing fungi are very abundant in nature, almost universally present on any organic matter in contact with the air, such as growing on bread, fruits, vegetables, soil and fertilizers, and a few parasitic on decaying plants or animals. Splice bacteria can be isolated from the nasal cavity, stool and sputum of healthy people. However, the pathogenicity of Seizobium is weak and rarely causes human pathogenicity, even in patients with severe immune impairment or organ transplantation, and Seizobacterium disease is a very rare conditional pathogenic infectious disease [1].
[Epidemiology].
In 1855, the first case of pulmonary trichinosis was reported by Kurchenmeister, a German, as a case of pulmonary cancer in a patient with combined trichinosis infection. Clinically, pulmonary joint mycosis is not common, but the incidence has been on the rise in the last 20 years. The survey of Anderson Cancer Research Center, Texas, USA, showed that the infection rate of Trichophyton rubrum increased from 8/100,000 in 1989-1993 to 17/100,000 in 1994-1998, which more than doubled [3].Eucker et al [4] reported that Trichophyton rubrum ranked third among invasive fungal infections, except for Aspergillosis and candidiasis. In China, Peking Union Medical College Hospital investigated the pathogenic spectrum of pulmonary fungal infections from 1986 to 1998, and the incidence of pulmonary Trichophyton infection ranked 3rd after Candida and Aspergillus, at 3.9%. 2002-2006, the pathogenic spectrum of pulmonary fungal infections was investigated again, and among 97 confirmed, clinically diagnosed and proposed patients, the incidence was in the order of Aspergillus, Cryptococcus, Trichophyton and Candida, and the incidence rate was 5.2%; if only patients with confirmed and clinical diagnosis were counted, the incidence rate of pulmonary Trichophyton infection was 8.1% [5]. Of the 75 cases of deep fungal infections diagnosed by autopsy in the PLA General Hospital from 1955 to 1991, the incidence was in the order of Aspergillus (53.5%), Candida (33.3%), Cryptococcus neoformans (6.9%), and Trichoderma (5.8%), and Trichoderma mainly invaded the lungs. The overall incidence of trichinosis is 8.3-13% [2].
The diseases caused by the syncytial bacteria are mostly sporadic, without any limitation in terms of age, sex, race, or climate, and are not infectious. However, some authors report that pulmonary Trichoderma infection is more common in men, the ratio of men to women is about 2.3~3:1. Some researchers also believe that Trichoderma infection is related to the season, such as Japanese Funada and Matsuda reported 7 cases of pulmonary Trichoderma infection, 6 cases occurred between August and September, which may be related to the appropriate growth temperature of Trichoderma (25~55℃) [2].
[Pathogenesis].
The jointed bacterium is a conditional pathogen, and the common factors that can induce jointed bacteriosis clinically are as follows: ① metabolic diseases: diabetes mellitus, especially patients with ketoacidosis; ② use of immunosuppressive drugs; ③ long-term use of broad-spectrum antibacterial drugs; ④ gastric and duodenal ulcers; ⑤ malignant tumors; ⑥ congenital or acquired immunodeficiency. As well as severe burns, trauma, mechanical ventilation, various trauma consultations, hemodialysis, etc. In general, the occurrence of splinter disease is often the result of a combination of factors, and primary infection is rare [1].In 1999, Lee et al [6] investigated 87 patients with pulmonary trichinosis and found that 76 (87%) had underlying risk factors and only 11 (13%) had no underlying disease.Tedder et al [7] analyzed 255 cases of pulmonary trichinosis and found that malignant hematologic disease in 37% and diabetes in 32%, followed by chronic renal failure and organ transplantation; instead, patients with solid tumors rarely developed pulmonary trichomycosis secondary to the disease. Among organ transplant patients, the incidence of postoperative trichothecene infection is higher in liver transplant recipients.
The portal of invasion for respiratory (sinus, lung) splinter disease is the respiratory tract, and most patients become infected due to inhalation of airborne spores; inhaled spores are deposited in the nasal cavity causing nasal cerebral splinter disease and in the alveoli causing pulmonary splinter disease, while the chance of secondary infection of hematogenous origin is relatively low. In immunocompromised populations, the inability of phagocytes to engulf pathogenic bacteria and the reduced ability of T cells to kill target cells due to the body’s natural immunity as well as the inadequate acquired immune barrier make it easy for splanchomycetes to colonize the respiratory tract and cause inflammation [8]. An increase in serum free iron also favors the growth of splanchomycetes. Normal serum pH (pH 7.35-7.45) can inhibit the growth of S. spliceum. In diabetes, especially in ketoacidosis, serum pH decreases, the ability of ferritin to transport iron is inhibited, and serum free iron increases, which is necessary for the growth of S. spliceum, and S. spliceum can use free iron to promote its own growth. In addition, high sugar and acidic environment are also conducive to the growth and reproduction of S. spliceum, so patients with diabetic acidosis can easily progress to pulmonary septicemia after inhalation of S. spliceum spores [2].
The invasiveness of S. spliceum is very strong, once it invades the lung tissue of susceptible patients, it quickly sprouts and grows a large number of hyphae and spreads rapidly to the surrounding tissues; the ability of S. spliceum to invade blood vessels is strong, and the hyphae invade the blood vessel wall to form thrombus, causing ischemia, hypoxia and acidosis in the tissue distal to the infarct, resulting in local tissue hemorrhagic necrosis. The bacterium can also involve the brain and various organs of the body via bloodstream. The lesions often progress at an alarming rate and are not easily detected, so the mortality rate is high. Infiltration, thrombosis, and necrosis are the characteristic changes of spliceomycosis. Microscopically, the lesions show an acute inflammatory process with severe necrosis and septicization of the tissues, a large number of macrophages, as well as neutrophil and eosinophil infiltration, interstitial fibrous tissue hyperplasia, and capillary wall thickening. A large number of mycelia are present in the lesion area including necrotic areas, vessel walls, vessel lumens and thrombi, but rarely granulomas are seen, which is a characteristic change of the disease [1].
[Clinical manifestations].
In clinical practice, according to the site of the lesion and the clinical manifestations of the patient, splinter mycosis is broadly classified into six types: pulmonary splinter mycosis, nasal cerebral splinter mycosis, gastrointestinal splinter mycosis, disseminated splinter mycosis, cutaneous splinter mycosis, and primary central nervous system splinter mycosis.
1, Pulmonary seizure bacteriosis: The lung is the second most affected organ after the brain, but the prevalence is much lower than that of rhinocerebral seizure bacteriosis. In recent years, the prevalence is gradually increasing with the popularity of ICU. The symptoms of pulmonary joint bacteriosis are not specific, usually acute or subacute, the disease is usually serious, clinical manifestations include cough, coughing, dyspnea and fever (mostly persistent hyperthermia), sometimes the temperature can rise suddenly. Chronic onset (symptoms for more than 30 days) is less common. Almost all patients have thrombosis and infarction of the blood vessels at the site of the lesion, so hemoptysis and relatively severe chest pain are often present. Lee et al [6] summarized the clinical manifestations of 87 cases of pulmonary Trichophyton infection, and the common symptoms were fever (63%), cough (61%), chest pain (37%), dyspnea (29%), and hemoptysis (26%). The clinical manifestations reported in China were cough (89%), fever (85%), hemoptysis (63%), chest pain (26%), and shortness of breath (26%). Those with underlying pathology account for 70% of cases and 63% of mortality [2]. Diabetic patients rarely develop pulmonary sequestration disease and have a poor prognosis when they do. In addition, patients with fulminant pulmonary splinter disease are susceptible to hematogenous dissemination, which commonly occurs in the central nervous system, gastrointestinal tract, spleen, kidneys, heart, and liver, and is almost always lethal, with patients usually dying within 2 weeks.
Chest imaging (especially chest CT) may show single or multiple infiltrative or nodular shadows, sometimes with wedge-shaped changes, with the predilection for the upper lobe, which may involve both lungs simultaneously, and less commonly the lower lobe. Some patients have interstitial pneumonia or mass-like changes, single or multiple, with halo sign (halo sign), crescent sign, and cavitation, with marginal enhancement after contrast injection, and occasional pleural effusion. Hypoxemia can occur if the lung lesion is extensive.
2, Other types of spliceomycosis: ① disseminated spliceomycosis: It is an infection that occurs in two or more distant tissue systems, most commonly the lung and central nervous system. There is little hope of survival because of the difficulty of diagnosis. (②Nasal cerebral splinter disease: It is the most common clinical type, accounting for more than 75% of all splinter diseases. It has an acute onset, progresses rapidly, and is very aggressive. The pathogenic bacteria invade the paranasal sinuses and epiglottis through the nasal cavity and then spread peripherally to the ipsilateral orbits, eyeballs, intraorbital soft tissues, blood vessels and nerves, eventually causing central nervous system lesions. (iii) Gastrointestinal splinter disease: extremely rare, mostly occurring in patients with severe malnutrition and gastrointestinal abnormalities, probably due to swallowing food contaminated with fungal spores during feeding. The main manifestations are abdominal pain and fever, followed by diarrhea, vomiting blood, blood in the stool, and gastric and duodenal ulcers. ④Dermal splinter fungal disease: It is the mildest type, relatively uncommon, often secondary to nosocomial infection after burns and blunt force trauma, and can also originate from other sites of dissemination. The clinical presentation is a progressively enlarging nodular erythema with redness and pain at the site of the lesion with varying degrees of central necrosis, which can form scabs or develop into necrotizing cellulitis. ⑤ Primary CNS splinter disease: extremely rare, mainly seen in intravenous drug users with infections caused by the blood. Patients first present with hemiparesis and fever, followed by symptoms of rash, encephalitis, and meningitis [1].
[Diagnosis].
Due to the seriousness of the patient’s condition, the non-specificity of clinical symptoms and signs, as well as the lack of laboratory test support, it is difficult to make a diagnosis based on clinical experience alone. Fungal antigen tests such as serum 1-3 ß-D glucan antigen (G test) carried out in recent years are negative in the case of Trichophyton infection. Therefore, the diagnosis of Trichophyton infection can only be confirmed by mycological and pathological histological examination. The diagnosis is confirmed once the splice organism is found in a lesion scraping or culture, or when mycelium is found in a tissue section that has invaded the vessel wall. Respiratory secretions or abnormal tissue smears are not very reliable, sputum cultures are often negative, and blood cultures are even less positive than sputum cultures. In the literature, it has been reported that only 50% of patients with positive sputum culture were finally confirmed by fibrinoscopic biopsy to have pulmonary Trichophyton infection, and only 32% were confirmed by open-chest biopsy [2]. Thus, sputum culture can lead to false positives and therefore is usually considered as a contaminating organism when Trichoderma is detected in clinical specimens, but it should be taken seriously when Trichoderma is detected simultaneously in different specimen sources from the same patient or when Trichoderma is cultured several times in the same specimen. For those patients who cannot confirm the diagnosis often need to use invasive tests to clarify the diagnosis, such as transbronchoscopic lung biopsy (including bronchoalveolar lavage), percutaneous pulmonary puncture biopsy or open lung biopsy.
PCR techniques have also been used for the diagnosis of Trichophyton infection, but have not been accepted as a basis for confirming the diagnosis due to the problems of false positives and false negatives. However, PCR techniques can distinguish clinical specimens from Rhizopus spp., Plasmodium spp., and S. graminearum, as well as some Trichoderma spp. [9,10].
The basic features of syncytial mycosis are as follows, which can be used as a reference in the diagnosis: ① there is a causative agent or primary disease that causes the body’s resistance to decline; ② there are fever and other corresponding clinical symptoms and signs, but not specific; ③ conventional laboratory tests have no diagnostic value; ④ there are no specific antigens or antibodies that can determine the diagnosis; ⑤ biopsy or scraping can see a large number of fungi, and culture does not grow; ⑥ mycelium is coarse, no or very little separation, and (6) irregular branching angle; (7) very easy to invade the walls of large and small arteries, leading to infarction and tissue necrosis [1].
Treatment]
Pulmonary sequestrum disease has a high mortality rate; therefore, early diagnosis using invasive methods, immediate correction and control of the cause of sequestrum disease, aggressive surgical debridement and early systemic treatment with diclofenac are essential to improve survival.
After the diagnosis of pulmonary splinter disease is confirmed, the first step should be to immediately control diabetes mellitus and correct underlying diseases such as ketoacidosis and metabolic disorders; avoid the use of broad-spectrum antibacterial drugs as much as possible; reduce the drugs to the minimum dose for patients receiving immunosuppressive therapy, especially glucocorticoids; and intensify adjuvant therapy (such as hyperbaric oxygen therapy and application of colony-stimulating factor) and systemic supportive therapy.
To date, dicentrin B remains the only antifungal drug with proven clinical efficacy, and patients should be treated with high-dose dicentrin B as soon as possible once diagnosed. The conventional dosing method is 1-5mg of dicitomycin B, added to 100-250ml of 5% glucose solution intravenously. If the patient can tolerate it, the dose is increased by 5mg daily or every other day until the therapeutic dose of 1-1.5mg/(kg.d) and maintained for at least 6-10 weeks, and can be changed to every other day when the patient’s condition stabilizes or improves significantly. The length of treatment depends on the patient’s clinical condition, and the total dose is usually 2-5 g. Recently, Lehrer et al. used the rapid incremental method to apply disulfiramycin B, first using 1 mg intravenously, then 10-15 mg intravenously a few hours later, and then increasing the dose every 12 hours until the therapeutic dose. Liposomal disulfiramycin B is less toxic to the kidneys and can be used in patients who cannot tolerate disulfiramycin B or have some impairment of renal function at a dose of 3-5 mg/kg. combination therapy, usually disulfiramycin B + flucytosine, can be considered in severely ill patients. There are also combinations of disulfiramycin + caspofungin, which can improve the survival rate of patients (50%) [2,7]. Authors have also reported the use of voriconazole, itraconazole, and fluconazole for the treatment of trichothecene infections, and the efficacy remains to be further investigated. However, it has been reported in the literature that the new triazole drug posaconazole is much more effective than voriconazole and fluconazole [11,12].
Because of the vascular obstruction caused by Trichoderma, it is difficult to penetrate the lesions with drugs for pulmonary trichoderma treatment, so the treatment with antifungal drugs alone is ineffective. Therefore, surgical lobectomy is mostly advocated for lesions that are confined to the lung. It has been reported in the literature that the mortality rate of pulmonary trichinosis treated with drugs alone is 50%-55%, while the mortality rate decreases to 9.4%-27% with surgery + drugs [2,7]. The excision can be of a lobe or a lung segment and is treated with diphenhydramine B preoperatively and postoperatively. Nasal cerebral splinter disease generally requires aggressive debridement, including removal of the eye and debridement of necrotic tissue from the sinuses and orbit. Some patients may need to undergo serial debridement, which may improve patient survival. Cutaneous splinter disease also requires aggressive debridement, and deep tissue infections of the extremities usually require amputation.
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