Diagnosis and treatment of pulmonary cryptococcosis

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Cryptococcosis (cryptococcosis) is an acute, subacute or chronic fungal disease caused by Cryptococcus neoformans. In recent years, the inci

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Cryptococcosis (cryptococcosis) is an acute, subacute or chronic fungal disease caused by Cryptococcus neoformans. In recent years, the incidence of cryptococcosis has a tendency to increase, which can not only infect the host with strong immune function, but also can infect the host with immune dysfunction. Among them, cryptococcal meningitis is the most common, followed by lung and skin infections [1].

First, epidemiology

The disease is spread all over the world, in the normal host immune function, the annual incidence rate of pulmonary cryptococcosis is about 0.4/10 million ~0.9/10, and the immune function damage, especially HIV infection, the annual incidence rate is about 6%~10%. According to the data of the United States, the most common pathogens in 140 patients with pulmonary fungal infection in 1988-1997 were Aspergillus (57%), Cryptococcus neoformans (Candida albicans) and Candida (14%). China has seen cases reported in Shanghai, Jiangsu, Zhejiang, Heilongjiang, Jilin, Guangdong, Guangxi, Hunan, Hubei, Yunnan, Chongqing, more than 10 provinces. Peking Union Medical College Hospital investigation of pulmonary fungal infection in 1986-1998 pathogens, the incidence rate of pulmonary cryptococcosis after Candida (79.5%), (11.8%) Niger, Penicillium, Mucor (3.9%) (3.9%) after fifth, 0.78%. 2002-2006 years to investigate the pathogens of pulmonary fungal infection in 97 cases, clinical diagnosis and suspected patients, incidence rate were Aspergillus, Cryptococcus, Mucor, Candida, the incidence of pulmonary cryptococcal infection rate was 13.4%; if the calculation is only diagnosis and clinical diagnosis of patients, the incidence of pulmonary cryptococcosis the rate is 20.9%. The PLA General Hospital during 1955-1991 were 75 cases of deep fungal infection in autopsies, incidence rate were Niger (53.5%) (33.3%), Candida, Cryptococcus neoformans (6.9%) and (5.8%), and by major violations of the meninges and pulmonary cryptococcosis. In recent years, the incidence of cryptococcosis is getting higher and higher, and it has become one of the most common complications of AIDS in foreign countries, and is the leading cause of death in AIDS patients. According to reports, the annual incidence of normal immune function was 0.2%, while the annual incidence of AIDS patients was from 80% to 90%. Pulmonary cryptococcosis after pulmonary aspergillosis in the pulmonary fungal disease, accounting for about 20%. A small number of cryptococcosis can be primary, most of the secondary; there is no evidence of nosocomial outbreak of infection; no animal to human transmission, there are reports of human infection. Pulmonary cryptococcosis can occur at any age, children are rare, 40 to more than 60 years of age, more susceptible to infection, men and women, the proportion of men and women in the HIV negative is about 2: 1, HIV positive for the number of 5: 1 to 11.

Two, etiology

In 1894, Sanfelice was first isolated from a new kind of fungus in peach juice. It was not until 1950 that Benham eventually named it Cryptococcus neoformans (Cryptococcusneoformans). Cryptococcus genus has 37 species and 9 varieties, is a saprophytic yeast, widely distributed in the world, can be separated from soil, pigeon dung and fruit, but also can be separated from healthy human skin, mucosa and feces. Pigeon manure is the natural host of the new variant of Cryptococcus neoformans, and it is considered as the most important source of infection. The diameter of the aerosol particles formed by drying pigeon droppings is usually less than 2 m, which is easy to reach. Cryptococcus neoformans is round or oval yeast, diameter of 4 ~ 17 m; in the solid medium, most strains of mucous, not forming hyphae and spores, Lai budding, usually single bud, thick wall. Most strains have thick capsule wrapped by capsular glycosaminoglycan composition, thickness of 3 ~ 5 m. In HE stained tissue sections, Cryptococcus neoformans was pale red, not easy to see. PAS or silver staining was clearly visible. Cryptococcus neoformans has 3 variants, namely new variants (varneoformans), (vargattii) and Gutt variant (vargrubii) variants will ge lu. Var gattii is mainly distributed in tropical and subtropical regions of Shanghai, Shanghai variety from non immunosuppressed patients, but more than 90% of cryptococcosis caused by Cryptococcus neoformans var.neoformans. According to the antigenicity of cryptococcal capsular, divided into A, AD, D, B and C5 serotypes, in addition there are a few uncertain. Type A is widely distributed all over the world, B type and C type are mainly distributed in South Africa and the United States in the South California, D type is more common in Europe [2]. There are A, B, D and AD type in our country, most of which are A type, followed by type B and type D, have not yet found. Capsular antigen can be dissolved in the serum and urine, cerebrospinal fluid, available specific serum detection.

Three, pathogenesis

Cryptococcosis infection may have several ways: by inhalation of Cryptococcus spores in the air is the main way of cryptococcal infection; also through traumatic skin inoculation, or feed contaminated food enters the human body through the digestive tract caused by disease, or to become a carrier. Healthy people are not susceptible to Cryptococcus neoformans infection, only when the body's resistance to decline, the pathogen is easy to invade the host body, causing cryptococcosis. Pigeon dung is considered to be the most important source of infection, the bacteria animal are horses, cows, dogs, cats, mountain antelope, mink, pig, koalas, rat isolated. At the beginning of the spore deposition in the lungs and no inhalation capsule, invade the host after 24 hours to get the spore capsule, pathogenicity.

The lung is the first site of infection. Cryptococcus neoformans after lung has 3 forms: Cryptococcus colonization: can colonize in the airway or alveolar, no symptoms, no imaging changes in patients with common chronic lung disease; the cryptococcal aggregation: cell growth but does not cause inflammatory reaction of the body in the alveoli; the granuloma formation: the pathological changes in the early stage of visible yellow white or pink translucent gelatinous substance, late for granulomatous lesions of varying size, caseous necrosis and small holes, not formed around the calcification, no obvious capsule. No primary lung disease and pulmonary abnormalities and the formation of pulmonary cryptococcosis called primary cryptococcal pneumonia, about 50% occur in immunocompetent patients, most patients with pulmonary single organ of [3].

The host's immune function determines the clinical and radiological manifestations of cryptococcal infection. Risk factors of cryptococcal disease including chronic wasting disease, such as diabetes, cancer, leukemia, sarcoidosis, AIDS and organ transplantation patients. Normal people can cause pulmonary infection after inhaling Cryptococcus neoformans, but often only imaging abnormalities, few symptoms, often self-healing tendencies. For immunocompromised patients, after inhalation of fungal lesions formed in the lungs, and hematogenous spread to the whole body, and invasion into the central nervous system. The ability of HIV infected monocytes to decrease the immunity of Cryptococcus neoformans was decreased, while the cryptococcal antigen reduced the cell-mediated immune function, which made it easier to survive in the host [1].

Four, pathological changes

Almost all cryptococcosis is caused by Cryptococcus neoformans, causing chronic inflammation in tissues. The lesions were related to the early and late stages of the disease. The lesions were formed in the early stage. The inflammatory reaction was mild and the neutrophils were few. A large number of Cryptococcus neoformans were found in fresh and active lesions. Advanced lesions of granulomatous and fibrous tissue proliferation, during which a large number of macrophages and foreign body giant cells and lymphocytes, most cells may have cryptococcal lesions may, after surrounded by fibrous tissue or fibrous scar formation. The type of lesion and the immune state of patients with normal immunity, often non caseating granulomatous lesions, including Cryptococcus engulfed in macrophage cytoplasm; and immunocompromised persons is not easy to see granuloma formation in the alveolar space, will be full of Cryptococcus spore, inflammatory cell necrosis and cavitation rare rare. There are 3 kinds of common pathological types of pulmonary cryptococcosis: solitary granuloma type, miliary granuloma type and pneumonia type, two type mainly in immunocompromised or long-term immunosuppression, involving multiple lobes; solitary granuloma type is more common in patients with normal immunity, can be expressed as multiple lobar involvement. Central nervous system cryptococcosis mainly manifested as meningitis. Late granulomatous lesions can occur in the meninges, brain parenchyma and spinal cord [1].

Five, clinical manifestation

1. Pulmonary cryptococcosis: subacute or chronic visceral mycosis caused by Cryptococcus neoformans infection. Pulmonary cryptococcosis can exist alone, or with other parts of cryptococcosis. About 1/3 to half of the lung lesions showed pulmonary nodules, without any symptoms, often found in chest X-ray examinations, sometimes misdiagnosed as tuberculosis or lung cancer (asymptomatic). Some patients with occult onset, mild cough, cough a small amount of phlegm or blood sputum, chest pain, low fever, fatigue and weight loss (chronic). A few cases had acute pneumonia, manifested as high fever, shortness of breath, hypoxemia, can cause acute respiratory failure; occasional chest pain or pulmonary consolidation and pleural effusion signs (acute), this type is more common in patients with AIDS. When complicated with meningitis, the symptoms are obvious and serious. Often have moderate fever, even high fever can reach 40 degrees, and the symptoms and signs of meningoencephalitis [1]. Check the body besides shortness of breath and cyanosis, sometimes the lungs could be heard and fine rales, very few patients with pleural effusion and corresponding clinical signs.

The X-ray manifestations of pulmonary cryptococcosis: rare bilateral multiple lesions may be unilateral or confined to one lobe, the performance of various types. The solitary mass, diameter of about 2cm~7cm, found in primary pulmonary cryptococcosis; second, single or multiple nodules; the single or multiple patchy shadows, about 10% of the patients had cavity, often secondary pulmonary cryptococcosis; the diffuse miliary shadow; acute interstitial. This rare type of pneumonia type. Calcification and caseous necrosis were rare in all types, but there was also calcification and void formation. Some scholars believe that in patients with AIDS, common interstitial lung and hilar lymphadenopathy; while in non AIDS patients are massive shadow or opacities, and atelectasis, lymph node enlargement, pleural effusion and empyema is rare. Pulmonary cryptococcosis X-ray showed no specific changes, and lung cancer, metastatic tumor, tuberculosis, and other diseases confused Wegner granuloma. In particular, isolated large spherical foci and lung cancer is not easy to identify.

CT: CT is one of the most important methods for the diagnosis of pulmonary cryptococcosis. With the wide application of thin layer and high resolution CT, the CT manifestations of pulmonary cryptococcosis show some characteristics. The main manifestations are as follows: 1. The infiltration of the bronchus is solid, and most of them are limited infiltration. The lesions are of different sizes, different shapes, single or multiple invasive lesions. May be a small strip, patchy or single lobe, multi lobe lesion, fuzzy boundary, uneven density, visible "air bronchogram" or "bubble" sign, visible part of the necrotic cavities. The pulmonary mass or nodule, solitary nodules, or multiple nodules, nodules of varying size, diameter of 0.5 ~ 6cm, even more, the boundary is clear, irregular in shape, with lobulation, 40% lesions surrounding or adjacent lung ring like glass mold paste film, called "halo sign". Most lesions located in the lung periphery and pleura, with smooth edge of cavity formation and pleural involvement. Individual lesions may have burr and pleural indentation sign, not easy to identify with lung cancer. The mixed lesions showed diffuse, nodules, patches, clumps, lobar consolidation lesions diversified coexistence. In conclusion, CT manifestations of pulmonary cryptococcosis are various and nonspecific. The lesions were more common in the two lower lung, and the normal immune adults had multiple nodules, masses and patchy exudation, while the adults and children with immune impairment were more likely to be affected by the lesions. The diagnosis depends on the pathological examination [4].

2, other parts of cryptococcosis: cryptococcal meningitis: the central nervous system infection with cryptococcal meningitis is the most common, accounting for more than 80% of cryptococcosis. According to a retrospective analysis about 37% HIV negative patients with cryptococcal cryptococcal meningitis, about 6% to 11% of patients with AIDS infection of cryptococcal meningitis. The mortality rate was higher (20%~30%). The skin and mucous membrane cryptococcosis: rare happen alone, often coexist with meningeal and pulmonary lesions, often occurs in the nasal septum, gums, tongue, palate, soft palate, tonsils, throat, chest, face and neck and back and limbs, skin, or acne early contagiosum like papules, nodules or abscess, and Central ulceration break out of a small amount of pus with mucoid, containing cryptococcus. Bone and joint cryptococcosis: rarely occur alone, the whole body bone can be involved, but the bone, skull and spine for more. The joints are rarely involved, each with secondary bone lesions. Slow progression. The visceral cryptococcosis: by the spread of cause, often can affect the heart, testis, prostate, eye, but does not affect the kidney, liver and spleen, lymph nodes and other parts. Infection of the gastrointestinal tract and urogenital system is similar to that of tuberculosis [1].

Six, diagnosis

1 etiology examination: is an important basis for the diagnosis of pulmonary cryptococcosis, the case should be as many times as possible to collect specimens for smear and culture.

The positive rate of sputum culture and smear examination is generally lower than 25%, and because of Cryptococcus neoformans can colonize the normal population, so even sputum tracheal washes produce Cryptococcus neoformans, should according to the specific clinical situation to determine whether the pulmonary cryptococcal infection. When AIDS patients with Cryptococcus neoformans should be highly vigilant.

In the case of suspected cryptococcal infection, a biopsy should be performed to allow for the detection of the pathogen when conditions permit. If the samples were taken from percutaneous lung biopsy or fine needle aspiration, or transbronchial antipolluted specimens, microscopy and (or) training of Cryptococcus neoformans has diagnostic value.

It is worth noting that the pulmonary cryptococcosis immune dysfunction were more prone to disseminated infection, especially in the central nervous system involvement rare, if such patients with pathologically diagnosed or treated by operation, the greater possibility of extrapulmonary dissemination. Therefore, cerebrospinal fluid examination should be carried out as soon as possible for those with suspected meningitis, and the positive rate of cerebrospinal fluid smear in early meningitis can reach more than 85%, and the positive rate is higher. At present, it is not clear whether or not the routine cerebrospinal fluid examination is necessary for patients with pulmonary cryptococcosis.

2: immunological test polysaccharide of Cryptococcus capsular thickness with specific antigenicity, approximately 90% of patients with cryptococcal meningitis serum or cerebrospinal fluid can be detected in the corresponding antibody or antigen. But due to the antibody test in serum of patients with not much, and the specificity is not strong, the false positive rate is high, so the clinical value of antibody detection is not high, is commonly used in clinical detection of antigen, namely the application of latex agglutination test for detection of cryptococcal capsular polysaccharide antigen, which is a simple, rapid, sensitive and specific strong detection method is important for early diagnosis. The positive rate of cerebrospinal fluid antigen was 92%, the positive rate of serum was about 75%, and the positive rate of non meningitis patients was from 20% to 50%. It can be used for the detection of serum, cerebrospinal fluid, pleural effusion and bronchoalveolar lavage fluid. The rise and fall of antigen titer may also indicate the efficacy, duration and prognosis. Such as the antigen titer had no change or rise, is the progression of the disease and prognosis of adverse reactions, such as antigen titer fluctuation, suggest that chronic diseases. After the disease is cured, if the serological test and multiple antigen, titer of 1: 8 or more, should consider the possibility of recurrence. It should be noted that the antigen positive rate was lower in immunocompetent subjects than in those with immunodeficiency, suggesting that if the normal subjects were positive, the results showed that [1].

3 molecular biology detection: since 1990, PCR technology has been used in the detection and research of fungi. It is considered to be one of the best methods to detect fungi because of its good specificity and sensitivity. But the PCR technology can only determine whether the presence of fungi samples, you can not determine pathogens or contaminated bacteria, bacteria or dead bacteria, also can not determine whether the drug resistance, therefore it cannot serve as a curative effect evaluation and completely replace the traditional fungal culture method. Therefore, it is best to do fungal culture and PCR at the same time, and if the results are consistent, the diagnosis can be repeated. The most important advantage of PCR is that it can be used to identify the species of bacteria and drug sensitivity test, and then select the most effective antifungal drugs.

4 diagnosis: the key to the diagnosis of this disease is to improve the vigilance of the clinician. The diagnosis was based on the results of surgical resection of the specimen, and all kinds of invasive biopsy to obtain the histopathological evidence. The blood and the sterile cavity fluid (such as pleural effusion and cerebrospinal fluid) were directly examined or cultured positive. The clinical diagnosis: evidence based on the history, respiratory symptoms and chest imaging, and qualified sputum or bronchoalveolar lavage fluid direct microscopy or culture of Cryptococcus neoformans positive, or blood, pleural fluid specimens of cryptococcal capsular polysaccharide antigen; because the cryptococcal cell wall without 1-3-ß -D glucan antigen, the level of serum G test negative in cryptococcal infection at. If only the host risk factors without clinical symptoms and pathogenic examination support, for the case of [5].

Seven, treatment

1 drug treatment: treatment of cryptococcal disease and drug selection often have to be different according to the state of the immune function of patients with different preferred amphotericin B. The general is the use of combination therapy, does not recommend the use of flucytosine alone. Drug treatment is mainly amphotericin B and flucytosine 5-, or other antifungal drug combination therapy.

The treatment of pulmonary cryptococcosis often varies according to the severity of the symptoms and the state of immune function, as shown in table 1. Not only if the immune compromised patients, focal pulmonary involvement, to confirm the normal cerebrospinal fluid parameters, cerebrospinal fluid and urine culture were negative, no other extrapulmonary lesions, and asymptomatic, without treatment, but must close observation of changes. In the absence of meningitis and respiratory symptoms, depending on the severity of the symptoms of different treatment options. Kidney and blood function must be checked regularly before and during treatment. In patients with severe pulmonary cryptococcosis should adopt the method of treatment of cryptococcal meningitis, initial combination therapy (amphotericin B+5- and flucytosine) method using fluconazole maintenance therapy than single drug treatment has obvious advantages. Our formulation of the principle of diagnosis and treatment of invasive pulmonary fungal infection, recommended disseminated pulmonary cryptococcosis with two amphotericin B and flucytosine or fluconazole or itraconazole; non AIDS patients without meningitis. Refractory pulmonary cryptococcosis can use of voriconazole in the treatment of [6].

Treatment response in patients with AIDS is often poor. It is recommended that the initial treatment with amphotericin B and flucytosine, and maintained at least 2 weeks, then oral fluconazole (200 ~ 400mg/d). Patients with cryptococcosis in patients with AIDS, the start of treatment with fluconazole, the time of death than the use of amphotericin B to early. After treatment, most of the disease recurrence, so the need for long-term suppression treatment, preferably with fluconazole 200 ~ 400mg/d oral. Weekly intravenous injections of amphotericin B can prevent recurrence. A larger dose of fluconazole is being tested and may have a better effect. In principle, the non AIDS patients should be in culture negative after remain at least another 2 Zhou Fang can stop treatment.

Treatment of cryptococcal meningitis is shown in table 2. The optimal dosage and course of fluconazole in the treatment of cryptococcal meningitis in patients without AIDS remains to be determined. But also the use of itraconazole in 200 ~ 400mg/d, with more than 2 months successfully for maintenance treatment or therapy for cryptococcal meningitis. On the central nervous system cryptococcosis, such as serious illness, or poor efficacy of intravenous injection, using intrathecal or intracisternal administration of amphotericin B, first dose of 0.05mg ~ 0.1mg, 2 ~ 5mg plus dexamethasone. Injection diluted with cerebrospinal fluid repeatedly, so as not to cause serious consequences such as limb paralysis caused by drug stimulation. Increase the dose gradually to the high limit of 1mg. Intrathecal drug delivery can be the next day to 1 times or 2 times a week, the total should be 20mg. Intrathecal administration should be used with caution in patients with elevated intracranial pressure and optic disc edema [1].

Table 1 treatment of pulmonary cryptococcosis

Immune state

Symptom severity

medicine

Course of treatment

HIV negative

Asymptomatic person

Observe the change of the disease or choose the light treatment program

Mild to moderate

Fluconazole, itraconazole or 200mg~400mg/d

6 to 12 months

Critically ill

Meningitis treatment

HIV positive

Mild to moderate symptoms

Fluconazole 200mg~400mg/d

lifelong

Critically ill

Meningitis treatment

Table 2 treatment programs for cryptococcal meningitis

Immune state

Treatment period

medicine

Course of treatment

HIV negative

induction period

AmB0.7~1.0mg/ (kg.d, 5-) combined with flucytosine (kg.d) 100mg/

2 weeks

Consolidation phase

Fluconazole 400mg/ day

10 weeks

HIV positive

induction period

AmB0.7~1.0mg/ (kg.d, 5-) combined with flucytosine (kg.D) 100~150mg/

2 weeks

Consolidation phase

Fluconazole 400mg/d

10 weeks

Strengthening phase

Fluconazole 200~400mg/d

lifelong

2 other therapies:

(1) surgical therapy: the localized lesion such as skin, chest granuloma and abscess or granuloma of lung and cavity, in the central nervous system of cryptococcal disease unmerging with cases, surgery should be considered. The main surgical procedures were standard thoracotomy and video-assisted thoracoscopic surgery. Before and after the operation must use amphotericin B drug or fluconazole therapy to control cryptococcal infection. Has confirmed that thoracic lesions were excised (partial or complete resection of lung) can effectively cure pulmonary nodules. At present, surgical treatment is not recommended except for neoplastic lesions. It has been reported in the literature that the patients with pulmonary cryptococcosis after surgery were not treated with antifungal therapy, 1 years later. Therefore, for pulmonary cryptococcosis, after surgery should be given adequate doses and courses of systemic antifungal therapy, so as not to translate into cryptococcal meningitis [1]. Fluconazole 200mg/d, intravenous drip, course of treatment 7d; fluconazole 200 ~ 400mg/d, oral for 6 to 12 months.

(2): two other drugs besides hydroxyl amidine hairpin, cycloheximide (Actidione, Cycloheximide) and can be used for the treatment of visceral cryptococcosis. Sulfanilamide and potassium iodide can be used as adjuvant therapy.

Reference

Cao Ehong 1. Pulmonary cryptococcosis. Zhao Beilei, Shi Yi, mulberry red ed. modern pulmonary fungal diseases. Beijing: People's Medical Publishing House, 2004:134-143.

2.JarvisJN, HarrisonTS.Pulmonarycryptococcosis, SeminRespirCritCareMed, 2008,29 (2): 141-150.

3.HungMS, TsaiYH, LeeCH, etal.Pulmonarycryptococcosis:Clinical, radiographicalandserologicalmarkersofdissemination.Respirology, 2008,13:247-251.

4.KishiK, HommaS, KurosakiA, etal.Clinicalfeaturesandhigh-resolutionCTfindingsofpulmonarycryptococcosisinnon-AIDSpatients.RespirMed, 2006100:807-812.

5.WuB, LiuH, HuangJ, etal.Pulmonarycryptococcosisinnon-AIDSpatients.

ClinInvestMed, 2009,32:E70-77.

6.PasqualottoAC, DenningDW.Newandemergingtreatmentsforfungalinfections.JAntimicrobChemother, 2008,61:i19-i30.

 

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