The pathological basis of dengue fever is systemic inflammation caused by dengue virus infection. With the development of dengue virus and its serotype detection technology, it is found that some serotypes of dengue virus are easy to cause severe dengue and multiple organ function damage [10]. In the past, it was thought that the lung was not the most common organ affected by dengue fever. Instead, attention paid to lung involvement was mainly on severe cases with pulmonary hemorrhage [11]. However, lung is the most vulnerable organ of systemic inflammatory response. With the increasing incidence of dengue fever and the popularity of imaging examination in recent years, the incidence of pulmonary involvement in dengue fever has increased significantly [12, 13].
In this study, the proportion of patients with SD was as high as 35.8% (212/592). There are several reasons for the high proportion of SD in the study. Firstly, recent dengue virus serotype infection prevalent in Guangdong Province was easy to cause severe cases [14, 15]. Secondly, our hospital is the designated unit for the management of SD. Lastly, those asymptomatic or mild dengue may not come to hospital or just went to clinics for treatment. The study found that the ratio of SD in DWLI group was particularly higher than that in DWOLI group. The general data of this study showed that dengue fever patients who were old, smoking population, accompanied by underlying diseases such as hepatobiliary disease, hypertension, diabetes, coronary heart disease were prone to have lung involvement. It is known that dengue virus causes more SD in the elderly and those with underlying diseases than otherwise. Lung involvement is probably one of the early manifestations and pathological mechanisms.
The incidence of cough and breathlessness in DWLI group was significantly higher than that in DWOLI group. Further analysis showed that the above symptoms were mainly in SD subgroup, implying that cough and breathlessness can be used as the observation index of SD with lung involvement, there were no studies before reporting the great value of cough and breathlessness in identifying SD. The lymphocyte count in DWLI group was significantly lower than that in DWOLI group, the cholinesterase was also significantly lower while the myoglobin increased. The pathological mechanism may be the intense inflammatory reaction induced by the high viral load, which caused numerous damage to lymphocyte, liver cells and muscle cells. The increase of C-reactive protein (CRP) and pro-calcitonin (PCT) reflected the increase of inflammatory response in DWLI patients. Imaging examination showed that pleural effusion and bilateral pneumonic exudation were associated with SD. Therefore, in areas with pandemic dengue fever, it is necessary to consider that lung involvement in dengue fever is one of the causes of pneumonia, and for these patients should be warned of SD.
In-depth study on the pathogenesis of dengue virus showed that in the early stage of virus infection, the organ-specific (Brain, lung, retina) tight junction of microvascular endothelial cells was destroyed, which would increase exudation [16]. NS1 was thought to be the intriguer [17]. Other study found that plasma leakage was caused by the decrease of plasma concentration of sphingosine-1-phosphate, which protected endothelial cell [18]. Since the lung is the organ most vulnerable to exudation and edema in inflammatory reaction, these mechanisms explained why clinical symptoms such as cough, breathlessness, pleural effusion emerged more often in DWLI patients. The advanced mechanism of lung involvement is mainly focused on endothelial cells and peripheral organs. High mobility group protein 1 (HMGB1) is an important regulator of inflammatory response. It was highly activated in the lungs and peripheral organs in patients died of dengue [19]. Lung and peripheral organ damage due to inflammatory reaction contributed to the same pathological mechanism of lung involvement and SD. Therefore, once lung involvement is present, more attention should be paid to the risk of SD or even MODS. In this study, it was found that there was a clear correlation between bilateral pneumonic exudation and SD. It was also found that patients with lung involvement were prone to acute liver, kidney damage and MODS.
In addition, the relationship between lung involvement and severity of dengue fever relies on two aspects, the pathogenicity of the virus itself and other complicated infections. Firstly, the high viral load or reinfection patients in the course of the disease can cause serious lung and multiple organ functional damage [20, 21]. Micro abscesses existed in heart, brain, lung and kidney of the reported dengue cases with MODS after autopsy [5]. Secondly, other complicated infections such as staphylococcus aureus, fungi or influenza A virus could aggravate the lung damage or even induce pulmonary cavity, acute respiratory distress syndrome (ARDS) and MODS [22–25]. Therefore, patients with lung involvement need more surveillance on their risk of more advanced disease. Active measures include timely discover of ARDS caused by dengue fever, early utilization of noninvasive mechanical ventilation [26, 27], timely cardiac ultrasound examination for dengue fever patients with respiratory distress, and monitoring of systemic hemodynamics such as cardiac output and blood volume [28, 29].
Most dengue fever patients with lung involvement can be relieved after active treatment. However, there are reports showing patients with large volume pleural effusions needed emergent puncture and drainage. There are also reports of acute lung injury after platelet transfusion of ordinary dengue patients, which indicates that the treatment of dengue fever patients with lung involvement should be active and cautious [30]. In this study, the proportion of anti-virus, anti-bacteria and the combination therapy in DWLI group were significantly higher than that in DWOLI group. Combined with the analysis of the increase of CRP and PCT in DWLI group, the results implied that these patients had more serious inflammatory reaction and higher incidence of secondary bacterial infection. The prognosis of patients with lung involvement was worse than those without lung involvement. In this study, 10 patients complicated with MODS were all in DWLI group, and 2 of them died. At present, there are few studies exploring how to prevent lung damage and progression to SD. The above mentioned NS1 may be one of the effective targets for prevention and treatment.
Though the present study gave some insight to the understanding of SD, it still had some limitations. Firstly, it was a single-center retrospective study, it may had selective bias since different types of patients may go to different hospitals for therapy. Secondly, it lacked the analyses of the influence of serotypes on the outcome of patients since many patients didn’t have it tested. Lastly, not all patients undergone CT scan due to the cost and radioactivity, and sensitivity of X-ray is much lower. Therefore, a more well-designed, multicenter, serotype involved prospective study is expected to demonstrate the value of lung involvement in dengue management.