Plastic Bronchitis Associated With Inuenza a Virus in a Child With Nephrotic Syndrome

Background Plastic bronchitis (PB) combined with nephrotic syndrome (NS) is rare, and the pathophysiological relationship between PB and NS has not been elucidated. We report a case of an 8-year-old boy with life-threatening PB caused by an inuenza infection during a relapse of NS.


Abstract Background
Plastic bronchitis (PB) combined with nephrotic syndrome (NS) is rare, and the pathophysiological relationship between PB and NS has not been elucidated. We report a case of an 8-year-old boy with lifethreatening PB caused by an in uenza infection during a relapse of NS.

Case presentation
The patient was on immunosuppressive drugs for NS. He developed fever due to an in uenza A virus infection, followed by respiratory distress and frequent vomiting. Prednisolone was administered for possible bronchial asthma and NS. His respiratory status deteriorated rapidly, which required ventilator management. A large mucus plug was aspirated using bronchoscopy. He was then diagnosed with PB caused by the in uenza A virus. Increased lower airway secretion and uid leakage into the airways by relapse of NS were considered the causes of mucus plug formation. Besides, the decreased circulating blood volume might have made the bronchial secretions viscous with cast formation.

Conclusions
Pediatric patients with NS may be at a higher risk of developing PB. As PB is a life-threatening condition, patients with NS should be closely monitored when simultaneously infected with in uenza virus.

Background
Plastic bronchitis (PB) is a potentially life-threatening acute respiratory disease that can cause bronchial obstruction due to a cast-like mucus plug. The following causes of PB have been reported: atopy, bronchial asthma, airway diseases such as cystic brosis, and postoperative congenital heart disease [1][2][3]. Although few cases associated with nephrotic syndrome (NS) have been reported, these studies did not elucidate the association between the pathophysiology of NS and PB. The combination of NS and PB is a rare condition, and such cases should be evaluated because NS may be a risk factor for PB. Here, we present a case of pediatric PB during a relapse of NS.

Case Presentation
An 8-year-old boy experienced frequently relapsing NS since the age of 2 years despite being on immunosuppressive drugs (tacrolimus and mizoribine) for approximately 1 year prior to the current hospitalization. One month before admission, he experienced an episode of relapse and his prednisolone (PSL) dose was tapered off. He developed proteinuria and eyelid edema few days before admission, indicative of yet another relapse episode.
One day before admission, he developed fever, followed by respiratory distress and frequent vomiting.
He appeared pale, with cold extremities, and dry lips and skin. He had hyperventilation, see-saw breathing, and decreased breath sounds in the right lung. His hemoglobin level (18.3 g/dL), and urine protein level (6,933 mg/dL) and speci c gravity (1.050) were elevated, whereas the serum albumin level was reduced (2.5 g/dL). Chest radiography showed reduced permeability of the lower lobe of the right lung with no air bronchograms. The rapid in uenza antigen test was positive for in uenza A virus; however, viral isolation did not detect H1N1. The patient had not been vaccinated against in uenza.
The patient was in hypovolemic shock, which was thought to be indicative of decreased circulating blood volume due to reduced oncotic pressure from NS-induced hypoproteinemia. We administered 12.5 g of albumin at frequent intervals, in addition to massive infusions of isotonic solution to increase extracellular uid, 20 mL/kg rapid administration, and catecholamine support with adrenaline and dobutamine. Fluid infusion was closely monitored to avoid overhydration. To treat the infection, we used a combination of meropenem and vancomycin and peramivir, an anti-in uenza drug. In addition, because of his atopy, PSL (60 mg/day; 2 mg/kg/day) was administered for possible bronchial asthma and NS. However, his respiratory status worsened, and a few hours after admission, ventilatory management was initiated. Bronchoscopy revealed a large mucus plug embolizing the right bronchus, which was aspirated ( Fig. 1). Based on these ndings, he was diagnosed with PB caused by the in uenza A virus. His respiratory status gradually improved, and he was extubated on the 5 th day of admission.
On the 10 th day of admission, the patient developed pulmonary arterial thromboembolism caused by a thrombus in the right internal jugular vein, where a central venous catheter had been placed, and he underwent anticoagulation therapy with heparin and warfarin. The intrapulmonary arterial thrombus decreased in size and resolved on the 25 th day, leading to an increase in blood ow to the right internal jugular vein.
The proteinuria gradually decreased and completely cleared on the 14 th day of admission. Treatment with a combination of tacrolimus and mizoribine was resumed, and rituximab was restarted from the 23 rd day. The patient was discharged at 30 days after admission. He remained in remission for 6 months after discharge from our hospital.

Discussion And Conclusions
The present case suggests that patients with NS may have a higher risk of developing PB, which is a lifethreatening disease. Therefore, the respiratory status of a patient with simultaneous NS and in uenza should be monitored closely.
In airway diseases that are risk factors for PB, bronchial narrowing due to bronchospasm and postin ammatory brosis, increased secretions, and acute and chronic in ammation 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 in ammatory 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 in uenza B virus. He was unvaccinated [7]. 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 in uenza 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 [8]. In a report of pediatric cases of severe in uenza A from another center in China, two of the 15 patients had NS, one of whom died after development of PB [9].
Seear et al. classi ed the pathological ndings of mucus plugs into two categories [10]. Type I is an in ammatory type formed by in ammatory cells, mainly eosinophils, and brin. 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 classi ed 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 [11]. 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 [12]. 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 in uenza infection caused increased secretion and in ltration of in ammatory cells into the airway. Relapse of NS led to hypoproteinemia and leakage of uid 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 in uenza 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 [6]. 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 [13]. 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 [14]. 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 in uenza epidemic period, as protein leakage may be exacerbated by an Availability of data and materials: Not applicable.
Code availability: Not applicable.
Author contributions: MK and MK took primary responsibility for writing the paper. JT, SL, and YK were responsible for the clinical management and provided helpful discussions for the completion of the work.
Ethics approval: This article does not contain any studies with human participants or animals performed by any of the authors.
Consent to participate: This is not an experimental case report. Therefore, consent to participate was not required.
Consent for publication: Informed consent was obtained from the patient's guardian for the publication of this case report.  Figure 1 Mucus plug from the right bronchus