Cryptococcosis: It is a fungal infectious disease caused by Cryptococcus neoformans and can involve the meninges, brain, lungs, skin, central nervous system or other internal organs. Since the first case of cryptococcosis was reported in China in 1946, it has been found almost everywhere, and the incidence has been on the rise in recent years. Cryptococcus neoformans is the only pathogenic bacteria of this disease, the transmission route of this disease has not been elucidated, when the body’s immunity is reduced, the pathogenic bacteria can directly invade and cause blood transmission, so long-term use of immunosuppressive drugs or glucocorticoids and other patients susceptible to this disease. Clinical manifestations can be divided into pulmonary cryptococcosis, central nervous system cryptococcosis, skin mucosal cryptococcosis, bone cryptococcosis and visceral cryptococcosis. Early diagnosis mainly relies on high vigilance of clinicians. Treatment is based on the systematic application of antifungal drugs. Causes: Cryptococcus neoformans is the sole pathogen of the disease. The fungus is widely distributed in nature and can be found in human skin, soil, dust, and pigeon droppings. In large cities, pigeon droppings dropped on windowsills are often the source of infection. The genus Cryptococcus includes 17 species and 18 variants, of which only Cryptococcus neoformans and its variants are pathogenic. Cryptococcus neoformans is a round, yeast-shaped bacterium surrounded by a broad pod, called a thick pod. The diameter of the bacterium is 4-20um, the width of the pods is 3-5um, and there are one or more reflective particles in the bacterium, which are nuclear structures. Part of the bacterium can be seen sprouting, but does not form pseudomycelium. Non-pathogenic cryptococci do not have pods. Cryptococcus neoformans can grow at 25℃ and 37℃ on Sabo medium and blood agar medium, while non-pathogenic Cryptococcus cannot grow at 37℃. Culture a few days to form yeast-type colonies, the surface is sticky, initially creamy white, and then turn orange. This bacteria can decompose urea, can be distinguished from pseudofilamentous yeast. Both humans and animals can be infected. Pathogenesis: The pathway of transmission of this disease has not been elucidated, when the body’s immunity is reduced, the pathogenic bacteria can directly invade and cause blood transmission, so long-term use of immunosuppressive drugs or glucocorticoids, AIDS, leukemia and other patients susceptible to this disease. Almost all Cryptococcus neoformans infect the body through pulmonary invasion, 90% of the lesions are confined to the lungs, and 10% can spread to other organs through blood transmission. The central nervous system and the skin are the most common sites of secondary infection, and the susceptibility of the bacterium to invade the central nervous system may be related to the presence of aspartame and creatinine in the cerebrospinal fluid, which contribute to the growth of the bacterium. Pathophysiology: There are two basic pathological changes in this disease: diffuse infiltrative exudative changes in the early stage and granuloma formation in the late stage. In the early stage, there is a large number of new cryptococci clustered in the tissue of the lesion, because the bacterium is surrounded by gel-like pods, so that there is no direct contact between the bacterium and the tissue, so the tissue inflammatory response is not obvious. Granuloma formation is often seen several months after infection, with proliferation of giant cells, macrophages and fibroblasts, lymphocyte and plasma cell infiltration, and occasional necrotic foci and small cavity formation. Small amounts of lymphocytic infiltration, granuloma formation, and extensive fibrosis are seen in pulmonary lesions. Brain tissue is more prone to small cavity formation than other tissues, with thickened meninges and granuloma formation, with the most severe involvement of the basal ganglia and gray matter of the cortex. Cutaneous mucococcal cryptococcosis has two types of damage lesions: (1) colloid damage: small tissue reaction, with a large number of local bacterial aggregates; (2) granulomatous damage: there can be a significant tissue reaction, including histiocytes, macrophages, lymphocytes and fibroblasts infiltration, there may be necrotic areas. Clinical manifestations: 1. Multiple groups: When the body’s immunity is reduced, the pathogenic bacteria can directly invade and cause blood transmission, so patients with long-term use of immunosuppressive drugs or glucocorticoids, leukemia, AIDS are susceptible to this disease. 2, disease symptoms: the disease according to the clinical manifestations can be divided into five types of pulmonary cryptococcosis, central nervous system cryptococcosis, skin mucosal cryptococcosis, bone cryptococcosis and visceral cryptococcosis. (1) Pulmonary cryptococcosis: Cryptococcus neoformans present in the environment is less than 10 μm in diameter, and once it is deposited in the human body through the respiratory tract, under the influence of higher carbon dioxide concentration, it forms an obvious protective layer of polysaccharide pods to antagonize the host’s defense mechanism. In most healthy individuals, the infection resolves spontaneously or the lesion is confined to the lungs. In immunocompromised patients, Cryptococcus is capable of progressive activity and can cause severe pulmonary infection or even systemic dissemination via hematogenous routes. The symptoms include cough, chest pain, malaise, fever, weight loss, etc. There is often a small amount of mucus sputum or blood sputum, and the pathogenic bacteria can be found in the sputum. x-ray manifestations: the lesions are usually bilateral in the middle and lower lungs, but can be unilateral or confined to one lobe, and may appear as isolated large spherical foci or several nodular lesions with no obvious surrounding reaction, resembling tumors; or diffuse corn-like shadows; or lamellar infiltrative shadows. About 10% of patients have cavity formation. (2) Cryptococcosis of the central nervous system: Patients often complain of pain in the forehead, both temporal or behind the eyes, with intermittent episodes and gradual increase in pain, mostly accompanied by fever and signs of meningeal irritation such as cervical tonicity and positive cervical elevation test. If limited granuloma of the brain parenchyma occurs and simple occupying lesions appear, symptoms such as nausea, vomiting, mental retardation, coma, hemiparesis, blurred vision, vertigo, ophthalmoplegia, nystagmus, diplopia, etc. may occur. Mental disturbances can be significant. Epileptiform seizures may also occur. This disease often occurs in patients with AIDS and is a common cause of death. (3) Cutaneous mucococcal cryptococcosis: Skin infection with cryptococci is most often seen in the head and neck, often caused by the spread of the primary focus, seen in 10-15% of patients. The rash presents as papules, acne-like pustules or abscesses that easily ulcerate. Infectious molluscum contagiosum-like lesions will occur in approximately 50% of HIV-infected patients. Primary skin lesions are rare, presenting as isolated whitlow, and the diagnosis must be confirmed by a clear history of implantation and culture of Cryptococcus in the suspected implant. In 2/3 of patients, nodular, granulomatous, or ulcerative lesions may also be present due to mucosal involvement. (4) Bone cryptococcosis: It occurs in the skull and spine, but often does not involve the joints. The bone damage is often chronic, multiple, scattered destructive lesions, without periosteal hyperplasia, may have swelling and pain. (5) Visceral cryptococcosis: disseminated cryptococcosis can first manifest on many organs or systems, and it has been reported that sensitis, osteomyelitis, prostatitis, pyelonephritis, and peritonitis can be the first manifestation of cryptococcosis. Infections of the gastrointestinal tract and genitourinary system are similar to those of tuberculosis. Individual cases may invade the heart and cause endocarditis. Diagnostic differentiation: 1. Auxiliary examination: (1) Pathogenic examination ① Ink staining method: It is a rapid, easy and reliable method. Take fresh specimens to be examined according to different damaged parts, such as cerebrospinal fluid, sputum, focal tissue or exudate, place them on a slide, add 1 drop of ink, cover with a coverslip, and look for cryptococci in the dark field of the microscope. reflective spores, but no mycelium. Repeatedly find high positive rate, cerebrospinal fluid should be centrifuged to take precipitate smear. ②Fungal culture: take a small amount of specimens placed in the sand medium, at room temperature or 37 ℃ culture 3-4 days visible colonies grow. (2) Serological examination Because there are not many antibodies measurable in the patient’s serum, the positive rate of antibody detection is not high and the specificity is not strong, only for counselling diagnosis. Usually the detection of novel Cryptococcus podococcal polysaccharide antigen is inspired and specific by latex agglutination test, and it is useful for estimating prognosis and efficacy. (3) Pathological examination: varies depending on the stage of disease and the organ involved. There may be no tissue reaction in the brain tissue and only gelatinous mucinous edema is seen. The meninges show a chronic, nonspecific septic inflammatory reaction with a large infiltration of lymphocytes and plasma cells. Tuberculous granuloma-like manifestations are seen in chronic lesions. Mycobacteria are seen in the tissues. There are two types of lesions in cutaneous mucocutaneous cryptococcosis: (1) colloid lesions: small tissue reaction with large local accumulation of mycobacteria; (2) granulomatous lesions: significant tissue reaction, including histiocytes, macrophages, lymphocytes and fibroblasts infiltration, and necrotic areas may be present. 2, differential diagnosis: early diagnosis of the disease is particularly important for prognosis and reducing or avoiding sequelae. Early mainly rely on the clinician’s high vigilance, suspected encephalopathy should be promptly performed cerebrospinal fluid examination such as direct ink pictures to check whether there are thick pods of bacteria, while performing cerebrospinal fluid culture. Central nervous system cryptococcosis must be differentiated from tuberculous meningitis, intracranial occupying lesions and other intracranial diseases. Treatment: General treatment: 1. Actively treat the primary cause and remove the cause. 2.Strictly grasp the indications of antibiotics, glucocorticoids and immunosuppressive drugs. 3, strengthen nursing and supportive therapy. Antifungal treatment: fluconazole, itraconazole, flucytosine, amphotericin B and its liposomes can be used. For severe patients, the standard treatment of intravenous amphotericin B followed by oral fluconazole is given. In mildly ill patients without AIDS, fluconazole at 400-600 mg/d orally for 8-10 weeks may be effective. When other antifungals are not effective, voriconazole has some therapeutic benefit. Caspofungin has limited effect on this disease. For skin mucosal cryptococcosis out of systemic drugs, should be supplemented with local treatment. 1, dictyostatin B is a polyene antibiotic, combined with steroids on the fungal cell membrane, changing the permeability of the membrane, so that the fungal body destruction, fungicidal effect. It is the drug of choice for the treatment of cryptococcosis, histoplasmosis and systemic candidiasis, with poor effect on trichothecene fungal disease. (1) Intravenous drip: start with a small amount of 0.1mg/kg per day, and gradually increase to 1-1.5mg/kg per day if there is no adverse reaction, for a period of 1-3 months. Dilute with 5% glucose solution, the concentration should not exceed 0.05-0.1mg/ml, slowly drip intravenously, each dose should be finished in not less than 6 hours. Too high a concentration is likely to cause phlebitis, and too fast a drip can cause convulsions, irregular heart rhythm, sudden drop in blood pressure, and even cardiac arrest. (2) Intrathecal injection or intracerebroventricular injection: limited to the treatment of cryptococcal membranes in cases of severe disease or failure of intravenous drip. For intrathecal injection in children, the first 0.1mg should be diluted with distilled water (without 0.9% sodium chloride solution) at a concentration of not more than 0.25mg/ml (dilute is appropriate) or the drug should be injected slowly after mixing with 3-5md of cerebrospinal fluid drained during lumbar puncture. The course of treatment is generally about 30 times, if there are side effects can be reduced or suspended, too much drug in the cerebrospinal fluid can cause arachnoiditis and cerebrospinal fluid cell increase, temporary neuritis, loss of sensation, urinary retention, and even paralysis, convulsions, such as early stop yell five, most can be relieved. (3) The side effects of diclofenac: nausea, vomiting, abdominal pain, fever, chills, headache, dizziness, anemia, thrombophlebitis, thrombophlebitis, etc., to inflammation, kidney, hematopoietic system has some toxicity. To reduce side effects, aspirin can be given half an hour before and 3 hours after treatment, and in severe cases, intravenous hydrocortisone or dexamethasone can be used. During the medication period, blood and urine routine and liver and kidney function should be checked every 3-7 days, serum creatinine >2.5mg/dl should be reduced, urea nitrogen >40mg/d should be discontinued, 2-5 weeks to restore normal, and then start from small dose, injection site is prone to thrombophlebitis, the initial infusion site should start from the limbs The initial infusion site should start from the small distal veins. 2.5-Fluorocytosine is an oral systemic antifungal chemical drug, which has food inhibiting effect on Cryptococcus and Candida albicans. It can be used in combination with diphenomycin B for the treatment of systemic cryptococcosis at a dose of 50-150 mg/kg/day, divided into 4 oral doses, for 4-6 weeks. The dose for infants should be reduced. Oral absorption is good, serum concentration is high, cerebrospinal fluid concentration can reach 64-88% of the serum, easy to produce resistance, side effects include nausea, vomiting, rash, neutrophil nuclear platelet reduction, liver and kidney damage, when combined with dicloxacillin B can reduce resistance, the dose can be slightly reduced, toxic reactions can be reduced, and the course of treatment can be shortened. 3, Fluconazole (Fluconazol) double triazole antifungal drugs, mechanism of action and antibacterial spectrum and ketoconazole similar, in vivo antifungal activity than ketoconazole strong, high bioavailability, oral absorption is good, on Candida, Cryptococcus and other inhibitory effect, can reach effective therapeutic concentration in the cerebrospinal fluid > 3 years old 3-6mg/kg per day, once orally or intravenously. Side effects include gastrointestinal reactions, skin rash, and occasionally abnormal liver function.