The present case suggests that patients with NS may have a higher risk of developing PB, which is a life-threatening disease. Therefore, the respiratory status of a patient with simultaneous NS and influenza should be monitored closely.
In airway diseases that are risk factors for PB, bronchial narrowing due to bronchospasm and post-inflammatory fibrosis, increased secretions, and acute and chronic inflammation of the airway mucosa contribute to mucus formation. After cardiac surgery for congenital heart lesions, damage to the peribronchial lymphatic channels, pleural adhesions, and increased venous pressure are thought to be involved in the formation of mucus plugs. It has been surmised that PB and protein-losing enteropathy (PLE) after Fontan surgery have similar mechanisms of lymphatic leakage to the bronchi and intestinal tract, and the activation of the immune and inflammatory systems may trigger the development of PB [4,5]. During relapse of NS, the lung interstitium might be edematous due to hypoproteinemia, and the exudate is likely to easily leak into the bronchi. In the present case, no wheezing was heard, although the patient had a history of atopy. PSL (60 mg/day; 2 mg/kg) was administered for possible bronchial asthma. The dose was reduced to 30 mg/day (1 mg/kg) after improvement of hypoproteinemia to lower the risk of steroid psychosis.
Several cases of pediatric PB and underlying NS have been reported [6-10]. A Japanese boy who developed PB during relapse of NS was reported to be infected with the influenza B virus. He was unvaccinated . The patient developed oliguria during the course of the illness and required renal replacement therapy. In a report of 14 cases of PB due to influenza A and B at a single center in China, one patient had NS and developed renal dysfunction that required renal replacement therapy during the course of the disease . In a report of pediatric cases of severe influenza A from another center in China, two of the 15 patients had NS, one of whom died after development of PB .
Seear et al. classified the pathological findings of mucus plugs into two categories . Type I is an inflammatory type formed by inflammatory cells, mainly eosinophils, and fibrin. Type II is an acellular type formed by mucin and mononuclear cells, which often occurs after Fontan surgery. The mucus plug in our case showed numerous neutrophils and eosinophils and was classified as type I. The mucus plugs in the cases of Oonoki et al. and in the Chinese patients also displayed a type I pathology [6,9]. In contrast, in a study comprising 21 children with PB at a single center, one child had NS and presented with a type II mucus plug . Therefore, we speculated that patients with NS can have either types of mucous plugs.
Further, children with NS have often been reported to have allergic disease . Our patient had atopy and possibly the complication of bronchial asthma. We hypothesized that the pathophysiology of PB was as follows: a lower airway viral influenza infection caused increased secretion and infiltration of inflammatory cells into the airway. Relapse of NS led to hypoproteinemia and leakage of fluid into the subcutaneous tissue and airways. Subsequently, the decrease in circulating blood volume caused the bronchial secretions to become viscous causing cast formation. The infection in our patient might have been more severe due to oral immunosuppressive medications; nevertheless, we found no case report of PB in post-transplant or immunocompromised pediatric patients caused by an influenza virus. Additionally, hypoglobulinemia associated with NS may contribute to disease severity. Children with frequently relapsing NS who developed PB while not experiencing relapse of NS, although they had a low level of immunoglobulin G (IgG; 311 mg/dL) at the time of onset . In addition, in the case of PLE and PB after Fontan surgery, regular supplementation of albumin and IgG was provided because of low IgG level (342 mg/dL) at onset . At onset, our patient’s IgG level (775 mg/dL) was in the lower normal range. Children with NS may be at a higher risk of developing PB with the potential for severe disease due to the following two factors: the patient’s predisposition to complications of allergic diseases and the pathophysiology of protein loss during a relapse.
Patients with NS are known to have a higher risk of thrombus formation from intravascular condensation due to hypoproteinemia and leakage of anticlotting factors . Furthermore, the patient in the present case might have been prone to thrombus formation from hypercytokinemia associated with infection and catheter placement. However, details of the pathophysiology have not yet been proven.
In summary, PB may be life-threatening; therefore, pediatric patients with NS should be followed-up more carefully, especially during the influenza epidemic period, as protein leakage may be exacerbated by an infection.