The pathological changes in NP include inflammatory infiltration of lung tissue, liquefaction and necrosis of lung parenchyma, and formation of multiple cavities after necrotic tissue clearance [11]. In this study, lung abscess was also included in the NP group for retrospective analysis. In NP, chest CT showed that there were multiple thin-walled cavities or vesicles in the lung consolidation area, which could fuse into a large cavity, some accompanied with liquid level and gas surface. Chest-enhanced CT showed no enhancement at the edge of the cavity, whereas the lung abscess was observed as a single thick wall cavity[10].
At present, the causes and mechanisms of NP are mainly believed to be related to the following two factors: (1) it may be related to various host susceptibility and bacterial virulence factors, and the virus bacteria interaction may also play a role. Some scholars believe that most children with NP have been healthy, which may be an independent risk factor for pulmonary necrosis [12]. (2) Pulmonary capillaries in the necrotic area are blocked by thrombus, which can cause pulmonary parenchymal ischemia and necrosis under the action of inflammatory factors [13].
In recent years, there are several studies on NP in children[13–15]; however, there are few reports on NP caused by different pathogens. Streptococcus pneumoniae and Staphylococcus aureus are the most common pathogens that cause NP in children, and MPNP has been reported mostly in China in the last few years. Considering the high infection rate of MP in China, it may be associated with the increasing number of refractory Mycoplasma Pneumoniae pneumonia and severe Mycoplasma pneumoniae pneumonia cases, decreasing number of severe cases of polyvalent pneumonia vaccination, and the low positive rate of bacterial culture caused by extensive use of antibiotics in the early stage of pneumonia. In this study, 10 cases of N-MPNP were most commonly caused by Streptococcus pneumoniae pneumonia, followed by Staphylococcus aureus pneumonia (four cases), including methicillin-resistant Staphylococcus aureus (two cases) and Acinetobacter baumannii infection (2 cases). In the past, Staphylococcus aureus was considered the typical pathogen of NP. In the past few years, the reports of Streptococcus pneumoniae increased. This study is typically consistent with the reports. Streptococcus pneumoniae is a type of bacteria normally colonized in the human nasopharynx. When the immunity is reduced, Streptococcus pneumoniae causes respiratory tract infection. It is the main pathogen that causes lobar pneumonia. Hsieh YC and other studies have found that the age of more than three years was associated with pulmonary necrosis of Streptococcus pneumoniae pneumonia; however, it is not a confirmed risk factor for NP [12]. In this study, because of the small sample size, NP bacterial pathogen groups, and age were not compared. Moreover, two children who gave up treatment died of Acinetobacter baumannii infection, which did not exclude the possibility of infection during invasive ventilator treatment in the hospital. However, one of them was infected with H5N9, which did not exclude the death due to respiratory failure caused by the virulence of the virus; the other patient died of Acinetobacter baumannii combined with Streptococcus pneumoniae and filamentous fungi infection. Considering the possibility of multiple pathogen infections, it is more lethal; however, further prospective studies are needed to confirm this. In addition, the age of children in the MPNP group was significantly older than those in the N-MPNP group, which may be associated with the strong systemic immune response of MP infection in older children.
In terms of clinical characteristics, this retrospective study found that all children with NP had a fever, cough of different degrees, poor spirit, and other manifestations, and the duration of fever lasted for more than ten days in them; however, no statistical difference was observed between the two groups, and no report exists on the difference of fever time. Moreover, the proportion of patients with dyspnea and the need for oxygen therapy were significantly higher in the N-MPNP group than that in the MPNP group (P < 0.05). It may be because of the release of inflammatory factors after bacteria mainly infect the lung parenchyma, resulting in inflammatory infiltration and exudation in the alveolar cavity; thus, reducing alveolar ventilation function [16]. In terms of extrapulmonary complications, severe Steven-Johnson syndrome and central nervous system infection occurred in the N-MPNP group. However, the sample size was extremely small in this study to prove that the extrapulmonary manifestations of the N-MPNP group were severe compared with those of the MPNP group; thus, a prospective study, including large sample size, is needed.
In terms of laboratory examination, LDH levels in the MPNP and N-MPNP groups were increased to varying degrees; however, the median LDH level in the MPNP group (805.0 [423.7–1029.5] U/L) was significantly higher than that in the N-MPNP group (414.0 [299.9–540.6] U/L). LDH mainly consists of five isozymes. LDH1 and LDH2 are commonly found in the human heart, kidney, and red blood cells, and LDH3 levels are higher in the lungs [17]. Studies have shown that the body produces excessive immune inflammatory response after MP infection and the release of inflammatory factors causes tissue cell damage; thus, the serum LDH level of patients is significantly increased [18]. Therefore, the serum LDH level in children with NP caused by MP infection was higher. In addition, the results showed that the levels of FIB and DD were significantly increased. DD > 1367 ng/mL (OR = 8.501) is a risk factor for NP [13]; however, DD between MPNP and N-MPNP groups was not statistically significant, and no case of pulmonary embolism was observed in this study. In addition, the WBC count was significantly higher in the N-MPNP group than that in the MPNP group. Considering that N-MPNP was mainly caused by bacterial infections, the WBC count was primarily increased. Among inflammatory indexes such as N%, CRP, PCT, and ESR, different degrees of increase were noted, but no significant difference was observed between the two groups. Some studies reported that WBC, N%, CRP, and PCT of children with bacterial NP were significantly higher than that of children with MPNP [19]. However, no significant statistical difference was found in this retrospective study, except for WBC, which may be associated with the long-time use of antibiotics before admission, small sample size, and longer duration of sample collection.
The imaging manifestations of children with NP were generally serious; most of them were complicated with pleural effusion, atelectasis, and pleural thickening. The incidence of pleural effusion in the N-MPNP group was 95%, which was higher than that in the MPNP group (54.55%). A statistical significance was observed between the two groups. The incidence of pleural effusion separation was higher in the N-MPNP group than that in the MPNP group, which may be associated with the activation of coagulation promoting mechanism by the bacterial cell wall.
In this study, the average time of pulmonary necrosis was 18.8 ± 6.3 days of the disease course, and the duration of pulmonary necrosis in the MPNP group was longer than that in the N-MPNP group, which may be associated with the older age of children with MPNP, the ignorance of clinicians on NP occurrence, and the delay of lung CT examination. Therefore, in clinical practice, for children with persistent fever, significantly increased WBC, CRP, PCT, LDH and other inflammatory indicators, as well as chest X-ray with large high-density shadow and pleural effusion, it is necessary to be alert to the occurrence of NP and conduct chest CT examination in time.
Treatment
because of the long duration of fever, high fever peak, and severe illness, all the children in the study were treated with antibacterial drugs (one or more of β-lactam antibiotics, macrolides, meropenem, vancomycin, or linezolid; one patient infected with Sparganum mansoni was treated with praziquantel), and the children with fungal infection were given carbamazepine. The course of treatment was longer. As inflammatory indexes such as WBC, CRP, LDH, and DD increased and pleural effusion was formed, and there may be excessive immune inflammatory reaction mediated by cytokines, most children were given different doses of glucocorticoids at the same time. If an appropriate dose of hormone therapy is given on the basis of anti-infection, it can inhibit the progress of NP or shorten the course of the disease; however, a large sample randomized controlled study is still needed to further verify this.
Intravenous immunoglobulin (IVIG) was given to 13 children with NP. IVIG can neutralize the toxin, reduce the damage to the lung parenchyma, and inhibit the systemic inflammatory response. There is no consensus on the application of glucocorticoid and IVIG in NP. In addition to drug therapy, the clinical application of bronchofibroscopic lavage is highly increased. When children’s airway is blocked by sputum, pulmonary consolidation compresses pulmonary vessels and reduces blood flow; thus, not allowing antibiotics to reach the peak value in the blood, which is required by the pathological site. Alveolar lavage can significantly reduce the number of bacteria and the content of virulence factors; improve the bronchial ventilation function by clearing secretions, and promote the dissolution, absorption, and dissipation of lung consolidation. This study also found that the proportion of children who received BAL two or more times in the MPNP group was significantly higher than those in the N-MPNP group, which may be associated with MP infection, causing atelectasis and requiring bronchoscopy lavage treatment. With the development of fiberoptic bronchoscopy and lavage treatment technology, the operation probability of children with NP was greatly reduced. In this study, only one patient with pleural adhesion thickening and chest collapse underwent pleural fiberboard peeling. In addition, pleural effusion often leads to high fever, shortness of breath, and prolonged course of the disease. To relieve pleural effusion, three children underwent thoracentesis, and nine underwent closed drainage.
Although the onset of children with NP is acute and serious, and the course of the disease is prolonged, compared with NP in adults, most children with NP recover well [1, 4]. All the patients in this study, except for two (both in the N-MPNP group) whose family members gave up treatment, which lead to their death, the rest 29 patients were improved and discharged, and no one underwent pneumonectomy. In the follow-up of 17 children, most of them recovered within half a year. In addition, seven patients had sequelae, four had pleural thickening, three had bronchiectasis, five had pulmonary fibrosis, and several cases had the above-mentioned two or more sequelae, which were consistent with previous reports [20]. Because of the small number of samples in this study and a few follow-up cases, the difference in the proportion of sequelae between the two groups was not evident; therefore, further research is needed.
This study may have the following limitations: (1) this study was a retrospective study, and there may be some bias in case selection; (2) the sample size was small, and the duration of collecting samples was longer, which may have affected the statistical results; and (3) the use of antibiotics, glucocorticoids, and other drugs before admission and the time of chest imaging to find necrosis may have affected the statistical results. Therefore, it is necessary to accumulate more clinical data and further conduct prospective, large-scale, multicenter studies in clinical practice.