Clinical characteristics of disseminated cryptococcosis in previously healthy children in China.

BACKGROUND: Disseminated cryptococcosis is a rare and fatal disease, and limited data exist regarding it in children. This study aimed to investigate the clinical characteristics of disseminated cryptococcosis in previously healthy children in China. METHODS: Hospitalized patients with disseminated cryptococcosis were enrolled during January 1996 to December 2015 in Beijing Children's Hospital, Capital Medical University, China. Data on clinical manifestations, laboratory tests, treatment, and prognosis were evaluated. RESULTS: A total of 52 pediatric patients with no underlying disease were enrolled, including 38 boys and 14 girls. Only 10 cases had a history of exposure to pigeon droppings. Fever, cough, and hepatomegaly were 3 main manifestations of disseminated cryptococcosis. However, headache was more common in patients with central nervous system (CNS) invasion than in patients with non-CNS invasion (P < 0.05). Lung (96.2%, 50/52) was the most commonly invaded organ, but only 9.6% (5/52) of patients had respiratory signs. The most common findings on chest imaging were hilar or mediastinal lymphadenopathy (46.8%, 22/47), and nodules (44.7%, 21/47), including small nodules in a scattered distribution (57.1%, 12/21) or miliary distribution (42.9%, 9/25), especially localized in subpleural area. Subsequent invasion occurred in the CNS, abdomen lymph nodes, liver, spleen, peripheral lymph nodes, and skin. In all patients, 42.3% (22/52) and 51.9% (27/52) had elevated eosinophils or IgE, respectively. The positive rate of serum cryptococcal antigen was higher, especially in patients with CNS invasion (approximately 83.3%), than with other primary methods used for pathogen detection, including cerebrospinal fluid (CSF) cryptococcal antigen, cultures of blood, bone marrow, or CSF, and CSF ink staining. The overall mortality rate of pediatric patients in our study was 11.5% (6/52). Some cases had long-term sequela, including hydrocephalus, cirrhosis, or blindness. CONCLUSIONS: Disseminated cryptococcosis can occur in previously healthy or immunocompetent children in China. Lung and CNS were most commonly invaded by this disease. Furthermore, most cases usually showed no obvious or specific symptoms or signs, and therefore pediatricians should pay more careful attention to identify this disease.

[Clinical analysis of bronchial foreign bodies in 246 children].

OBJECTIVE: To analyze the characters of bronchial foreign bodies in children and the utilization of bronchoscope in the treatment of bronchial foreign bodies. METHODS: A total of 246 children were diagnosed with bronchial foreign bodies at our hospital during January 2000 until August 2009. Under local mucosal anesthesia, a bronchoscope was inserted through nasal cavity into bronchi. After identifying the site of foreign body, grasping forceps was guided through bronchoscope to remove the foreign body from airway. RESULTS: Among 246 cases, hard nut and skin of melon seed were found (n = 230, 93.5%). The most common site of foreign body was in right lower lobe bronchi (n = 98, 38.9%). The average operative frequency was 1.9 +/- 1.3 and one-time extraction ratio 58.5% (n = 144). The one-time extraction ratio of patients with foreign body obstructed in main bronchi (91.1%), right middle lobe (60.0%) and right lower lobe (55.1%) was higher than others. The operation frequency of using basket grasping forceps (1.4 +/- 0.9) was lower than those using tooth type forceps (2.1 +/- 1.4). And the difference was significant (P = 0.000). CONCLUSION: For bronchial foreign body in pediatric patients, hard nut and skin of melon seed are the most common foreign bodies. The right and left lower lobe bronchi are the predilection site. Foreign body in main bronchus is the easiest to be removed by grasping forceps. For massive foreign bodies, basket grasping forceps fares better than tooth grasping forceps.

[Clinical features of endogenous bronchial foreign bodies and application of bronchoscopy in children].

OBJECTIVE: To study the clinical features of endogenous bronchial foreign bodies and the value of bronchoscopy in children. METHODS: One hundred and six children who presented lobe or lung segment atelectasis by the chest X-ray and bronchial foreign body inhalation was excluded by bronchoscopy were enrolled. The original diseases included Mycoplasma pneumonia (n=62), endobronchial tuberculosis (n=24), bronchial pneumonia (n=16), nephrotic syndrome (n=2), laryngotracheal bronchitis (n=1) and bronchiolitis (n=1). On the basis of conventional treatment of the original diseases, bronchoscopy was performed in the children. Eighty children with bronchial foreign body inhalation severed as the control group. RESULTS: Bronchoscopy showed the properties of endogenous foreign bodies: mucus emboli in 77 cases, cheese substances in 24 cases, dendritic white membrane in 4 cases, thrombosis in 1 case, and flaky pseudomembrane in 1 case. Hyperplasia of granulation tissue was seen in 25 cases. Of the 25 cases, endobronchial tuberculosis as the original disease was found in 22 cases. Mediastinal emphysema and pneumothorax occurred in 4 cases in the control group, but none in the endogenous foreign bodies group. The number of bronchoalveolar lavage by bronchoscopy in the endogenous foreign bodies group was significantly higher than that in the control group. CONCLUSIONS: Bronchoscopy is valuable in the diagnosis and treatment of endogenous bronchial foreign bodies.

[Measurement of pulmonary function with body plethysmograph in infants].

OBJECTIVE: To observe the alterations of pulmonary function in infants with respiratory diseases. METHODS: A total of 900 infants with respiratory diseases were recruited and pulmonary function measured in 30 healthy infants. The tests were performed in the sleeping infants with sedation. Tidal breathing flow-volume (TBFV) loops were recorded when infants were breathing quietly. Passive flow-volume technique was used to obtain static respiratory system compliance and resistance. Functional residual capacity was measured by body plethysmograph. RESULTS: The TBFV loop showed proximate round or oval curve in healthy infants. The shape and parameters of TBFV loop had significant differences in infants with respiratory diseases as compared with healthy controls. The TBFV loop displayed a concave expiratory curve and ratio of time to reach tidal peak flow to total expiratory time, the expiratory volume till peak flow divided by the total expiratory volume significantly decreased in infants with small airway obstruction. The expiratory or inspiratory curve showed a plateau and the ratio of mid-expiratory to mid-inspiratory flow was less than 60% or over 150% in infants with upper airway obstruction. The TBFV loop turned narrow and lung volume decreased in infants with restrictive diseases. CONCLUSION: The TBFV loop show proximate round or oval curve in healthy infants. Pulmonary function has significant differences between healthy controls and infants with respiratory diseases. Pulmonary function test is useful in the assessment of respiratory diseases.

[Association of NRAMP1 gene polymorphisms with the susceptibility to tuberculosis in ethnic Han Chinese children].

OBJECTIVE: Tuberculosis is still a public health problem. Host genetic factors, such as polymorphisms in NRAMP1 gene, may play a role in the development of tuberculosis. To clarify the effect of NRAMP1 gene polymorphisms on the development of childhood tuberculosis, the association of NRAMP1 gene polymorphisms with susceptibility to tuberculosis in the ethnic Han Chinese children was investigated. METHODS: From January 2005 to March 2008, 130 ethnic Han children with tuberculosis (TB group) were enrolled. Three hundred and ninety hospitalized ethnic Han children for physical examination in the surgery department were used as the control group. The controls were matched with tuberculosis children by age, sex and area. PCR-RFLP analysis was performed on DNA samples to identify allele genotypes of INT4 and D543N in NRAMP1 gene. Genotype frequency differences between tuberculosis patients and controls were analyzed using x2 test. RESULTS: No statistical difference was found in the genotype frequency of variants G/C and C/C at the INT4 locus between the TB and the control groups. At the D543N locus, the frequency of genotype variants (G/A and A/A) was significantly higher in the TB group (34/130) than that in the control group (66/390) (x2=5.349, P<0.05; OR=1.74, 95%CI=1.08-2.79). When stratified by sex, differences in the genotype distribution were observed only in females at the D543N locus, which the variant genotypes were higher in the TB group (16/52) than in the control group (21/155) (x2=7.866, P<0.05; OR=2.84, 95%CI=1.34-5.99). For males, there was no difference between the TB and the control groups. At the INT4 locus, no difference was observed between the two groups in boys and girls. CONCLUSIONS: Genotypic variation at the D543N locus in NRAMP1 gene may be associated with susceptibility to tuberculosis in ethnic Han Chinese children. Variant genotypes in NRAMP1 gene (G/A and A/A) may be susceptible genotypes to tuberculosis in ethnic Han Chinese children. Girls with variant genotypes were more susceptible to tuberculosis.

Characteristics and clinical role of bronchoscopy in diagnosis of childhood endobronchial tuberculosis.

BACKGROUND: Endobronchial tuberculosis (EBTB) is the most frequent complication of primary pulmonary tuberculosis (PTB) in children. The aim of the study was to analyze characteristics and clinical role of bronchoscopy in diagnosis of childhood EBTB. METHODS: A retrospective, descriptive study was undertaken in 157 children with EBTB undergone flexible bronchoscopy (FB) between January 2006 and June 2014. RESULTS: The median age of the enrolled patients was 3.4 years, with 73.2% of patients under five years old. The most common subtype was tumorous type (145/157, 92.4%). If only involved bronchus were considered, the common affected sites were right middle lobe bronchus (49/228, 21.5%), left upper lobe bronchus (41/228, 18.0%), right upper lobe bronchus (41/228, 18.0%), right main bronchus (35/228, 15.4%), respectively. Children younger than five years old were at higher risk to have multiple endobronchial lesions (P=0.044), with an odds ratio of 2.313 (95% confidence interval: 1.009-5.299). Before the bronchoscopy, only 16 (10.2%) patients were highly suspected of EBTB, while the others were diagnosed as PTB without EBTB (69.4%), or misdiagnosed as pneumonia or foreign body aspiration (20.4%) on admission. CONCLUSIONS: The patients under five years old are at high risk to progress to EBTB and have multiple endobronchial lesions. The most frequent subtype of EBTB in children is tumorous type. The lesions are seen in the right bronchial system more frequently. FB should be performed to detect the endobronchial lesions in suspected patients as soon as possible.

Rapid diagnosis of childhood pulmonary tuberculosis by Xpert MTB/RIF assay using bronchoalveolar lavage fluid.

In order to evaluate the diagnostic accuracy of the Xpert MTB/RIF assay on childhood pulmonary tuberculosis (PTB) using bronchoalveolar lavage fluid (BALF), we evaluated the sensitivity, specificity, positive predictive value, and negative predictive value of Xpert MTB/RIF assay using BALF in comparison with acid-fast bacilli (AFB) microscopy and Mycobacterium tuberculosis (MTB) culture for diagnosing childhood PTB using Chinese "composite clinical reference standard" (CCRS) as reference standard. Two hundred fifty-five children with suspected PTB were enrolled at Beijing Children's Hospital from September 2010 to July 2013. Compared with Chinese CCRS, the sensitivity of AFB microscopy, MTB culture, and Xpert MTB/RIF assay was 8.4%, 28.9%, and 53.0%, respectively. The specificity of three assays was all 100%. Xpert MTB/RIF assay could detect 33.9% of cases with negative MTB culture, and 48.7% of cases with negative AFB microscopy. Younger age (<3 years), absence of BCG scar, and contact with TB patient were found significantly associated with a positive result of Xpert MTB/RIF assay. In conclusion, Xpert MTB/RIF assay using BALF can assist in diagnosing childhood PTB much faster when fiberoptic bronchoscopy is necessary according to the chest radiograph.

Impact of glutathione S-transferase M1 and T1 on anti-tuberculosis drug-induced hepatotoxicity in Chinese pediatric patients.

BACKGROUND: Anti-tuberculosis drug induced hepatotoxicity (ATDH) is a major adverse drug reaction associated for anti-tuberculosis therapy. The glutathione S-transferases (GST) plays a crucial role in the detoxification of hepatotoxic metabolites of anti-tuberculosis drugs.An association between GSTM1/GSTT1 null mutations and increased risk of ATDH has been demonstrated in adults. Given the ethnic differences and developmental changes, our study aims to investigate the potential impacts of GSTM1/GSTT1 genotypes on the development of ATDH in Han Chinese children treated with anti-tuberculosis therapy. METHODS: Children receiving anti-tuberculosis therapy with or without evidence of ATDH were considered as the cases or controls, respectively. The GSTM1 and GSTT1 genotyping were performed using the polymerase chain reaction. RESULTS: One hundred sixty-three children (20 cases and 143 controls) with a mean age of 4.7 years (range: 2 months-14.1 years) were included. For the GSTM1, 14 (70.0%) cases and 96 (67.1%) controls had homozygous null mutations. For the GSTT1, 13 (65.0%) cases and 97 (67.8%) controls had homozygous null mutations. Neither the GSTM1, nor the GSTT1 polymorphism was significantly correlated with the occurrence of ATHD. CONCLUSION: Our results did not support the GSTM1 and GSTT1 polymorphisms as the predictors of ADTH in Chinese Han children treated with anti-tuberculosis drugs. An age-related association between pharmacogenetics and ATHD need to be confirmed in the further study.

Pediatric tuberculosis at Beijing Children's Hospital: 2002-2010.

OBJECTIVE: Our aim was to describe the patient characteristics, clinical-epidemiological profile, and treatment outcome of childhood tuberculosis (TB). METHODS: A retrospective, descriptive study was undertaken of 1212 children aged 0 to 18 years admitted to Beijing Children's Hospital for the treatment of TB from January 2002 to December 2010. Statistical significance of category variables was evaluated by using Fisher's exact test. RESULTS: Fifty-four percent of patients had extrapulmonary tuberculosis (EPTB), 38.8% had tuberculous meningitis, and 31.3% had disseminated TB. The last 2 types were defined as severe TB. Most patients with TB (81.6%) were cured or completed treatment. There were more patients aged <5 years and from rural areas with EPTB than with pulmonary tuberculosis. More severe cases of TB were found in patients aged <1 year than other less severe types of TB. Patients with no bacille Calmette-Guérin vaccination and a contact history at home had a significantly risk of contracting severe TB. Children aged <1 year and those with severe TB were more likely to have poor treatment outcomes (failed to improve or died). Among those with EPTB, only 61.3% and 61.1% had positive results on the purified protein derivative tuberculin skin test and chest radiograph, respectively. CONCLUSIONS: In this referral hospital setting, more pediatric EPTB and severe TB patients were found among children aged <1 year. Age <1 year and having severe TB were risk factors for treatment failure. Thus, prevention and health care in pediatric TB should focus on both EPTB and severe TB.

IFN-γ release assay: a diagnostic assistance tool of tuberculin skin test in pediatric tuberculosis in China.

BACKGROUND: Prompt diagnosis of Mycobacterium tuberculosis (MTB) infection is an essential step in tuberculosis control and elimination. However, it is often difficult to accurately diagnose pediatric tuberculosis (TB). The tuberculin test (TST) may have a low specificity because of cross-reactivity with antigens present in Mycobacterium bovis bacillus Calmette-Guerin (BCG) and other mycobacteria, especially in China with a predominantly BCG-vaccinated population. Early-secreted antigenic target 6-kDa protein (ESAT-6) and culture filtrate protein 10 (CFP-10), stand out as suitable antigens that induce an interferon-gamma (IFN-γ) secreting, T-cell-mediated immune response to infection. While, considered the higher costs and complexity of the IFN-γ release assay (TSPOT), we aimed to evaluate the TSPOT and TST test in the clinical diagnosis of pediatric tuberculosis and to establish a diagnostic process suitable for China. METHODS: The sensitivity and specificity of the assay were evaluated in total seventy four children with active tuberculosis and fifty one nontuberculous children with other disease, and then the results were compared with TST. Logistic regression models were used to identify variables that were associated with positive results for each assay. The independent variables included sex, age, birth place, vaccination history, close contract with an active TB patient. RESULTS: The sensitivity of TSPOT was higher than TST in active TB children with or without BCG vaccination, as well as in children with culture-confirmed TB. But the difference was not significant statistically. Combining results of the TSPOT and TST improved the sensitivity to 94.6%. Agreement of the TST and TSPOT was low (77.0%, κ = 0.203) in active TB patients. The difference in specificity between TSPOT and TST test was statistically significant (94.1% vs. 70.6%, P = 0.006). Specificity of the two tests in patients without prior BCG vaccination history was similar (80.0% vs. 60.0%). The concordance between the two tests results in BCG vaccinated subjects was low (71.7%, κ = 0.063). For TSPOT, none of the included risk factors was significantly associated with positive results. For TST, BCG vaccination (OR: 1.78; 95%CI: 1.30 - 2.00) was significantly associated with positive results. CONCLUSIONS: Although IFN-γ release assay had relatively high sensitivity and specificity, we also should consider the higher costs and complexity of this test. Therefore, TSPOT could be used as the complementary tool of TST in circumstances when a suspected patient with negative TST results, or to exclude a positive TST result caused by BCG vaccination.

[Diffuse panbronchiolitis in a child: case report and literature review].

OBJECTIVE: Diffuse panbronchiolitis (DPB) is a chronic progressive disease of the lower respiratory tract, which is prevalent in Asian population. So far, many DPB cases have been found in adults in China. To our knowledge, no pediatric DPB case has ever been reported in China. We describe the first pediatric DPB case in Chinese literature and the second case in the English-language literature. METHOD: The clinical manifestations, characteristic imaging and histological features of this DPB case were summarized. RESULTS: The patient was a 13-year old girl complained of chronic productive cough with wheezing. Chest auscultation revealed fine moist rales and wheezing over both lung fields. The chest X-ray showed small nodules and reticular opacities in left lower lobe. High-resolution thorax computerized tomography (HRCT) demonstrated bilateral diffuse small centrilobuler nodules and bronchial wall thickening or bronchiectasis in some parts of the lungs. Histopathological examination of transbronchial biopsy specimen revealed lymphocytes and foamy histocytes infiltrated in the walls of bronchi, respiratory bronchioles and adjacent alveoli. Lymphoid follicles were present around some bronchi. Sinus radiographs revealed sinusitis. Lung function studies showed obstruction and restriction. PaO2 was 65 mm Hg. The diagnosis of DPB was made according to the current diagnostic criteria. Low-dose erythromycin [5 - 10 mg/(kg.d)] was effective. CONCLUSION: DPB could occur in children in China. The major diagnostic clues may include the following: (1) persistent cough, sputum, and dyspnea; (2) coexistent chronic sinusitis; (3) bilateral diffuse small nodular opacities on HRCT. Low-dose erythromycin was effective in treatment of the case with DPB.