Pediatric fungal pneumonia

　　First, the cause of the disease

　　1, Pathogen

　　The main deep fungal diseases include candidiasis, aspergillosis, histoplasmosis, coccidioidomycosis, sporotrichosis, phaeohyphomycosis, chromomycosis, cryptococcosis, and blastomycosis, among which candidiasis is the most common and has the strongest pathogenicity. In addition, community-acquired pulmonary fungal infections have become a very serious problem, especially when diagnosing community-acquired pneumonia, this disease should be considered. Aspergillus is widely present in nature and is the second most common opportunistic fungal infection in humans after Candida. The main route of infection for aspergillosis is the respiratory tract, and the lungs are the most common site of lesion. Conditionally pathogenic fungi occupy an important position.

　　2, Triggering factors

　　Fungi have roughly two ways of infecting the respiratory tract: one is primary inhalation infection; the other is opportunistic infection. Factors that promote the occurrence of candidiasis include:

　　(1) Premature infants, newborns, undernourished children, and weak children.

　　(2) Chronic consumptive diseases such as malignant tumors.

　　(3) Reticuloendothelial system diseases affecting immune function and blood diseases such as leukemia, agranulocytosis, aplastic anemia, and others.

　　(4) Metabolic disorders such as diabetes and renal failure.

　　（5）长期使用肾上腺皮质激素及其他免疫抑制药，引起机体免疫功能低下。

　　（6）先天性免疫功能缺陷。

　　（7）长期使用广谱抗生素，抑制了肠道内制止念珠菌繁殖的微生物，使菌群平衡失调。

　　（8）长期应用静脉高营养病人。

　　（9）医院内因污染的器械(如较长期留置的各种导管)而感染。

　　（10）获得性免疫缺陷病(艾滋病，AIDS)。全身播散性念珠菌病过去罕见。目前由于临床应用免疫抑制药和静脉高营养日益增多而较前常见。慢性黏膜念珠菌病可单独发生或见于甲状旁腺功能低下或艾迪生病人。

　　二、发病机制

　　真菌可寄生于正常人的皮肤、呼吸道和消化道，一般不致病，但在患儿菌群失调、免疫功能低下时，可因该菌大量繁殖而致病。感染方式多为内源性，以消化道为主要入侵途径，呼吸道次之。原发病灶多在口腔(如鹅口疮)，感染可自口、咽部向下蔓延而引起食管、胃及小肠病变，亦可引起呼吸道疾病，或可经血行播散而波及肺部；当体质衰弱、免疫力低下患儿吸入大量菌丝及孢子时，偶可致原发性肺真菌病。肺曲菌病主要继发于肺结核、支气管扩张、肺脓、肺炎、肺囊肿或肺癌的基础上，婴儿及儿童少见。临床上可见变态反应性肺曲菌病，组织侵蚀性肺曲菌病以及曲菌球。变态反应性肺曲菌病的发病机制属于Ⅰ型及Ⅱ型变态反应。多发生于具有特异反应性个体及慢性哮喘病患者，血清IgE及沉淀IgG抗体均增高。本菌存在于谷物、稻草、腐败的植物、土壤、家禽及牲畜的皮毛中，曲菌主要侵犯肺部。大多由呼吸道吸入含大量曲菌孢子的尘埃而引起。一般情况下，吸入曲菌孢子不一定致病，但在组织损伤，发炎或因慢性病，机体抵抗力下降或长期应用广谱抗生素、肾上腺皮质激素以及细胞毒药物等，常致发病，为近年来本病有明显增加的原因之一。曲霉菌可引起5种类型的下呼吸道病变：孢子过敏、过敏性肺疾病、非侵袭性腐生性疾病(曲霉菌病)、变态反应性支气管肺曲霉菌病以及侵袭性曲霉菌病。机体免疫功能正常的人长时间暴露于存在大量曲霉孢子的环境中，吸入孢子数超出人体防御系统的极限时，也可引起侵袭性肺部感染。侵袭性肺曲霉菌病则多见于各种原因造成的免疫功能低下的病人。感染可经气道侵入或经血管侵入。

　　1、皮肤

　　鹅口疮、真菌性皮肤感染。

　　2、呼吸系统

　　可有肺不张，可并发渗出性胸膜炎，可发生呼吸衰竭等。

　　3、神经系统

　　可发生中毒性脑病和脑水肿；

　　4. Cardiovascular system

　　Dysfunction, shock, prone to myocarditis, pericarditis; Often accompanied by Reye syndrome; and

　　5. Urinary system

　　Manifested as hematuria, proteinuria;

　　6. Bacterial infection

　　Common pathogenic bacteria include Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and hemolytic streptococcus. The lesions can be bronchopneumonia, lobar pneumonia, or lung abscess.

　　It often occurs secondary to infantile pneumonia, diarrhea, tuberculosis, and hematological diseases. The clinical manifestations of Candida albicans pneumonia include low fever, cough, dyspnea, cyanosis, listlessness, or restlessness. Older children may cough up colorless jelly-like sputum, occasionally with blood streaks. Chest signs include dullness on percussion and increased respiratory sounds on auscultation. There may be tubular breathing sounds and small and medium-sized bubble sounds. X-ray examination shows dot-like shadows, which may resemble miliary tuberculosis, and there are large areas of consolidation. A few cases have pleural effusion and pericardial effusion. At the same time, there may be candidiasis in the oral cavity, skin, or gastrointestinal tract. In the lungs, this bacterium can also coexist with drug-resistant Staphylococcus aureus or Escherichia coli. The clinical symptoms of Candida albicans pneumonia and invasive aspergillosis are similar, both with fever, cough, and progressive dyspnea. The typical sign of vascular invasive aspergillosis on CT is a hazy halo, which is hemorrhagic necrosis in pathology. However, invasive airway aspergillosis does not have specific features, similar to bacterial, mycoplasmal, viral bronchitis, or bronchopneumonia, and should be differentiated. Vascular invasive pulmonary aspergillosis may have atelectasis.

　　1. Strictly control the indications, time, and dosage of broad-spectrum antibiotics, corticosteroids, cytotoxic drugs, immunosuppressants, and antimetabolite drugs.

　　2. Early detection and treatment of focal fungal infections.

　　3. Detailed physical examination of suspected cases should be performed, and fungal cultures of throat swabs, urine, feces, and blood may be performed if necessary.

　　6. Long-term intravenous infusion, venous catheterization, high-nutrition fluid infusion, tracheal intubation, and other procedures should be strictly performed under sterile conditions.

　　1. Pathogenic examination

　　1. Culturing and smearing of sputum or bronchial secretions for fungi

　　About 10% to 20% of normal people's sputum can also detect this bacterium. It is necessary to distinguish whether it is a parasitic bacterium or a pathogenic bacterium. Candida albicans can form pseudohyphae when侵入mucosa and cause disease, so the detection of Candida spores and pseudohyphae in sputum smear is helpful for diagnosis. Culturing sputum Candida on Sabouraud glucose agar medium, incubated at 37℃ in an incubator or at room temperature for 3 to 5 days, can produce milky white, moist, glossy, round or oval colonies with a special yeast smell. If the number of colonies exceeds 50%, it has diagnostic significance. When transferred to corn medium, it can be seen that the characteristic of this bacterium is branching hyphae and thick-walled spores. In glucose agar medium, incubated at 37℃ or room temperature, milky yellow or brown yellow colonies can be obtained. Animal experiments have confirmed that Cryptococcus is pathogenic to white mice. The detection of Cryptococcus in sputum or bronchial secretions, combined with clinical findings, can make a diagnosis of pulmonary cryptococcosis.

　　2. Fungi detected in cerebrospinal fluid

　　In patients with meningitis manifestations, cerebrospinal fluid can be used for smears, India ink staining, and culture to detect Cryptococcus neoformans. After diagnosis of cryptococcal meningitis, the primary lung focus should be checked at the same time. 50% of patients with cryptococcal meningitis can have Cryptococcus detected in the cerebrospinal fluid using India ink staining.

　　3. Blood culture

　　Especially in patients with low immune function, repeated blood cultures with fungi are helpful for the diagnosis of disseminated cryptococcal disease. Generally, positive blood cultures are rare, but if positive, it suggests severe infection. For patients with superficial candidiasis or candidal enteritis, early and repeated blood cultures should be sent, and the culture time should not be less than 4 weeks. Positive results have diagnostic value.

　　4. Lung biopsy

　　It also helps in diagnosis. In severe cases with large areas of fused lung lesions, lung biopsy can be performed. The lung biopsy fluid can be cultured and directly smeared, and the detection of pathogenic bacteria has diagnostic significance.

　　5. Vaginal secretions

　　For newborn patients, it should be checked whether the mother has candidiasis of the vagina, as the newborn may be infected by swallowing or inhaling contaminated amniotic fluid through the birth canal.

　　6. Enzyme-linked immunosorbent assay (ELISA)

　　Enzyme-linked immunosorbent assay (ELISA) for detecting Candida antigens in blood is helpful for diagnosis. The use of gas-liquid chromatography to detect Candida albicans has high sensitivity and can quickly obtain results.

　　7. Skin tests and animal tests

　　Fungal antigen skin tests, serological tests, and animal inoculation can assist in diagnosis.

　　8. PCR detection

　　The sensitivity of PCR detection of highly conservative and specific rDNA fragments of fungi is higher than that of inulin determination and latex agglutination test. In addition, some people use biostyrenes such as Calcofluor white, Blankophor, and IJvitex as fluorescent agents for fungal staining of body fluids, tissue sections, smears, and dandruff and hair, causing the samples to emit blue-white or yellow-white light under ultraviolet light, which can improve the sensitivity of microscopy and the detection rate (up to 95%).

　　9. Others

　　Finding fungal spores and (or) hyphae in smears, cultures, and tissue examinations of urine, feces, secretions, pleural effusion, cerebrospinal fluid, pus, etc., is an important basis for diagnosis. Typical hyphae and positive fungal cultures indicate fungal culture medium, with a higher fungal yield than standard bacterial culture medium. 2. Inulin is a polysaccharide antigen of Aspergillus, which can be used for early diagnosis in high-risk populations. Serum (1→3)-β-D-glucan is an important component of the fungal cell wall, which can not only be used for early diagnosis of deep fungal infections but also for monitoring the change of its plasma content to indicate the patient's response to antifungal drug treatment.

　　Secondly, Imaging examination

　　X-ray examination

　　The chest X-ray shows spots of shadow, which may resemble sputum granuloma tuberculosis, with large areas of consolidation, and a small number have pleural effusion and pericardial effusion. The lung lesions are mainly distributed in the middle and lower fields, especially in the lower part, generally not invading the lung apex. The classification of lung X-ray manifestations includes 6 types:

　　(1) Pneumonia type: It presents as large, dense shadows that can affect multiple lung segments or lobes, with a few cases showing segmental changes.

　　(2) Bronchopneumonia type: It presents as diffused spotted and cotton-like shadows along the bronchi, which are more common in the lower lungs.

　　(3) Lung abscess type.

　　(4) Inflammatory mass type.

　　(5) The X-ray changes of aspergilloma are characteristic.

　　(6) Pleurisy type: A few children may develop exudative pleurisy, and the shadow changes greatly in a short period of time. One lung field shadow diminishes, while another shadow may increase. In cases of acute hematic disseminated inflammatory fungal disease, X-ray examination may show granular shadows, disseminated nodular shadows, or multiple small abscesses. CT, B-ultrasound, and electrocardiogram examinations may be performed if necessary.

　　1. Keep the respiratory tract unobstructed. When children have pneumonia, the gas exchange in the alveoli is restricted, and there is varying degrees of hypoxia in the body. If the nasal passages are blocked or there is a large amount of sputum in the trachea and bronchi, it will affect the intake of air and worsen hypoxia. Therefore, parents should timely remove nasal secretions and aspirate sputum to keep the respiratory tract unobstructed. The room should maintain a certain level of humidity to avoid dry air, which is conducive to expectoration of sputum.

　　2. Take medication and injections on time to avoid affecting the efficacy. Due to the poor resistance to disease in children, especially in young infants, the condition is prone to recurrence. When parents find that the child breathes quickly, has difficulty breathing, the lips around the mouth turn blue, or the complexion is pale or cyanotic, it indicates that the child is hypoxic and needs to be rescued early.

　　3. The diet should mainly consist of liquid foods, and the diet should be light and non-greasy. Do not eat moldy food.

　　1. Treatment

　　1. Antifungal therapy

　　Early, adequate, and full-course treatment is necessary. Common antifungal drugs include:

　　(1) Amphotericin B (AmB): A broad-spectrum antifungal drug, it is the only polyene antibiotic currently used for systemic fungal infections and is widely recognized as the first-line antifungal drug. It significantly improves the survival rate of patients with various fungal diseases. Its pharmacological action is to alter the permeability of the fungal cell membrane, causing substances in the cytoplasm and potassium ions to leak out, leading to the dissolution of the bacterial body and achieving its therapeutic effect. It cannot be absorbed orally and must be administered intravenously. Initially, it is 0.1mg/kg per day, increasing by 0.1mg/kg each day until reaching 1mg/kg per day or every other day, with a course of 6 to 12 weeks. The dose for pulmonary aspergillosis and pulmonary mucormycosis can reach 1.5mg/kg. Before infusion, the required amount of the drug is first dissolved in 10ml of sterile water, then diluted with 5% to 10% glucose solution to a concentration of 0.1mg/ml, infused in the dark for 4 to 8 hours, and shaken every 15 to 30 minutes to prevent precipitation. Prophylactic measures include premedication with promethazine intramuscularly or indomethacin (an anti-inflammatory pain reliever) orally, or concurrent infusion of hydrocortisone (0.5 to 1mg/kg per dose) or dexamethasone (0.5 to 1mg per dose). Common side effects include chills, high fever, nausea, and vomiting, followed by hypokalemia, liver and kidney damage, etc. Overdosage or rapid infusion can cause arrhythmia. Those who have been off medication for more than a week should restart with a low dose.

　　(2) Globorubrumycin: A seven-membered antifungal drug created in China. Its efficacy is similar to that of AmB, but it has lower toxicity. It cannot be absorbed by oral administration and must be administered intravenously. The initial dose is 0.2 mg/kg, and the dose is gradually increased by 0.2 to 0.4 mg/kg each time, until it reaches 2 to 4 mg/kg per day, with a slow infusion rate, attention to the points and reactions, and the treatment method is the same as that of AmB. The side effects on the kidneys and other organs are lower than those of AmB.

　　(3) 5-Fluorocytosine (5-fluorocytosine, 5Fc): An antimetabolite drug that selectively acts on the ribonucleic acid of pathogenic fungi, thereby affecting the protein synthesis of fungi. Its antibacterial spectrum is narrow, and it is only effective against a few strains of Candida, Cryptococcus, and Aspergillus. The efficacy is lower than that of amphotericin B, and it is often used in combination with amphotericin B in clinical practice. It is prone to produce drug resistance. It is well absorbed by oral administration, with a dose of 50 to 150 mg/kg per day, administered once every 6 hours, and the course of treatment is 1 to 3 months. Some patients may have side effects such as anorexia, nausea, diarrhea, rash, fever, leukopenia, thrombocytopenia, and liver and kidney damage. Therefore, regular blood tests, liver, and kidney function tests should be conducted during the medication period.

　　(4) Clotrimazole: A broad-spectrum antifungal drug, it has good antibacterial effects against Candida, Cryptococcus, Aspergillus, and Capsulatum haemolyticus. It is not easy to produce drug resistance. Its pharmacological action is to selectively combine with the plasma membrane lipids, thereby affecting the structure and function of fungal cells. It is absorbed quickly by oral administration, reaching a peak blood drug concentration in about 4 hours, and is widely distributed to the heart, lungs, kidneys, and other tissues. The dose is 50 to 100 mg/kg per day, once every 8 hours. The side effects are mild, mainly gastrointestinal reactions such as nausea, loss of appetite, vomiting, abdominal pain, and diarrhea. A few cases have leukopenia, elevated transaminases, and other conditions.

　　(5) Mocazolone: An imidazole derivative, a new antifungal drug, with broad-spectrum antifungal and antibacterial activity. The drug acts by destroying the permeability of the fungal cell membrane, causing leakage of the cytoplasm. It has synergistic effects when used with AmB. The general intravenous dose is 20-40mg/kg per day. The side effects include nausea, vomiting, rash, phlebitis, liver function damage, and others.

　　(6) Ketoconazole: A relatively new imidazole derivative with broad-spectrum antifungal activity. It has antibacterial effects against Candida, Cryptococcus neoformans, Capsulatum histolyticum, and Coccidioides. It mainly acts on the fungal cell membrane, alters its permeability, and interferes with the synthesis of ergosterol in the cell. It has good absorption, low toxicity, good efficacy, does not damage kidney function, and can increase the杀菌 ability when used with AmB. This drug cannot pass through the blood-brain barrier. The dose is 200mg for adults, taken orally 1-2 times a day. It is used for visceral fungal disease for 2-4 weeks. It is used for histoplasmosis for 2-4 months. The side effects are rare, and occasional nausea, vomiting, decreased appetite, dizziness, nervousness, rash, itching, diarrhea, constipation, increased transaminases, and other symptoms may occur.

　　(7) Allicin: Currently, most artificial synthetic products are used. The side effects are small, with a dose of 10-40ml/d for children, and it should be diluted with more than 4 times of 5% glucose when infused to reduce its irritability to the vascular wall. The course of treatment is generally 2-4 months.

　　(8) Traditional Chinese medicine: Coptis, Phellodendron, Scutellaria, Polygonatum, Sophora flavescens, Radix et rhizoma Stephaniae, Rhizoma et radix Dictamni, and other herbs have antifungal effects.

　　2. Adjunctive therapy

　　Treat the primary disease, increase nutrition, and take a moderate amount of various vitamins. Blood transfusion or plasma, immunoglobulin, transfer factor, thymosin, and other drugs should be applied according to the condition.

　　3. Surgical resection

　　For patients with pulmonary空洞-type aspergillus ball disease and repeated hemoptysis, surgical resection can be performed.

　　II. Prognosis

　　The mortality rate is relatively high for patients with hospital-acquired infections or those with concurrent respiratory failure.