Reversible Rituximab-Induced Bronchiectasis: A Pediatric Case Report and Literature Review

Introduction

Rituximab is a monoclonal antibody targeting the antigen CD20 and causing depletion of CD20+ B cells [1,2]. This medication has a broad spectrum of indications, including post-transplant complications, malignancy, immunodeficiency, and autoimmune disease [3]. One of the recognized uses of rituximab is treatment of nephrotic syndrome, as it has a well-established role in refractory, steroid-dependent, and steroid-resistant forms [4].

However, rituximab is also associated with many adverse effects, including immunosuppression, exemplified in hypogammaglobinemia. Pulmonary complications are a result of rituximab-induced immunosuppression, include organizing pneumonia (OP), along with bronchiectasis, pulmonary fibrosis, and recurrent infections [2].

The clinical syndrome of recurrent or persistent wet/productive cough, airway infection and inflammation, and abnormal bronchial dilatation on chest computed tomography (CT) scans is known as bronchiectasis, which is a chronic pulmonary disorder. If identified early, it can be reversible over time with effective therapy [5].

According to the International Paediatric Bronchiectasis Registry (Child-BEAR-Net Registry), bronchiectasis is no longer considered rare in children and adolescents. The registry described the common causes of the condition over 4 years. The most common identified underlying causes were post-infection, followed by primary and secondary immunodeficiencies, and known genetic disorders. Other common comorbidities included asthma, otorhinolaryngology disorders, and congenital major airway malformation [6].

The pathophysiology of bronchiectasis is complex and poorly understood, but it likely involves airway infection causing inflammation, impaired mucociliary clearance, and airway destruction, which in turn predisposes the damaged airway to further infection [5,7]. Early identification during childhood and treatment of bronchiectasis can be reversible, particularly in mild cases [5]. Australian data indicate that >60% of adults with bronchiectasis have symptoms beginning in childhood [8].

In this report, we present a pediatric case of steroid-dependent nephrotic syndrome with rituximab-induced bronchiectasis, who recovered fully after discontinuing use of the medication, along with airway clearance therapy. This is an unusual and novel scenario where bronchiectasis can be fully reversed. Early recognition of pediatric respiratory symptoms indicating bronchiectasis with any etiology is important, as rituximab can prevent permanent lung damage.

Case Report

We present the case of a 12-year-old girl with steroid-dependent minimal change disease (MCD) nephrotic syndrome, characterized by frequent relapses since diagnosis at age 6. Despite maintenance treatment with prednisolone 60 mg once daily and trials of cyclosporin and tacrolimus for 4 years, she continued to relapse until rituximab was introduced at age 10 years. After 5 doses, she achieved complete remission; therefore, rituximab was stopped and IVIG was started for hypogammaglobulinemia.

There was no clinical or radiological evidence of severe and prolonged respiratory infections or bronchiectatic changes before starting rituximab. Approximately 1 year into the therapy, she developed a chronic, productive cough with yellow-green sputum, worse in the mornings and with positional changes. The initial chest X-ray showed mild hilar infiltrates, and she was treated for pneumonia. However, the symptoms recurred, prompting further hospital admissions. Viral multiplex testing revealed adenovirus and rhinovirus, and antibiotics were adjusted accordingly.

Pulmonology evaluation was initiated due to persistent symptoms. She had coarse crackles and reduced breath sounds over the left middle zone. High-resolution computed tomography (HRCT) (Figures 1, 2) demonstrated segmental and subsegmental atelectasis in the right middle and left lower lobes, with associated bronchiectatic changes, mucus plugging, and peribranchial thickening. Sputum culture grew multidrug-resistant Haemophiles influenzae. Immunologic workup showed markedly reduced CD19 counts and persistent hypogammaglobulinemia (low IgA/IgM/IgG) before rituximab treatment) consistent with rituximab-induced B-cell suppression.

The patient was diagnosed with chronic suppurative lung disease, likely secondary to repeated infections in the context of humoral immunosuppression. Testing for nontuberculous mycobacteria (NTM) and aspergillus was not done. Results of pseudomonas, acid-fast bacilli, and fungal testing were all negative. Rituximab was discontinued, and azithromycin was initiated 3 times weekly for its anti-inflammatory properties. Airway clearance therapy was advised. IVIG was started to treat the hypogammaglobulinemia. Pulmonary function tests showed no obstructive or restrictive defects, with mild air trapping. Genetic testing ruled out primary immunodeficiency.

Over the next few years, the patient’s B-cell function recovered, although immunoglobulin levels remained low. She received a total of 8 cycles of IVIG. Follow-up HRCT (Figures 3, 4) after 4 years showed complete resolution of bronchiectasis and atelectasis, with only minimal linear scarring in the previously affected lobes. Pulmonary function test results normalized, and the patient remained asymptomatic. To date, she is in full remission, with a plan to resume cyclosporin if she relapses.

This case, summarized in (Table 1), illustrates a rare but reversible pulmonary complication of rituximab therapy in a pediatric patient. It underscores the importance of early recognition of respiratory symptoms in immunosuppressed individuals and the value of multidisciplinary management. Discontinuation of rituximab and supportive pulmonary care led to full radiological and clinical recovery.

Discussion

Rituximab is an established therapy in children with idiopathic nephrotic syndrome, used to sustain short- to medium-term disease remission and avoid steroid toxicities [4]. Our patient was administered it as a corticosteroid-sparing agent.

Rituximab therapy for pulmonary complications such as Izanagi organizing pneumonia, interstitial lung disease, anaphylactic reactions is more commonly prescribed for adults than for children. Our patient’s recurrent infections due to B-cell dysfunction could explain the bronchiectasis changes found on imaging [9].

The time to onset of pulmonary complications after rituximab therapy is very important. Hyperacute and acute onset of respiratory symptoms can manifest as acute respiratory distress syndrome (ARDS) and hypoxemic organizing pneumonia. Delayed onset of symptoms is associated with occurrence of infections leading to bronchiectasis changes, as shown in the present case was demonstrated clinically, radiographically, and microbiologically via bronchoalveolar lavage samples [5].

Bronchiectasis is classically characterized by recurrent infections, airway inflammation, and subsequent decline in lung function. Much recent research has sought to determine the relationship between airway inflammation and bronchiectasis. Regarding airway inflammation, there are some similarities between bronchiectasis and other long-term respiratory conditions, such as cystic fibrosis [10].

An evolving variant known as the “vicious vortex” is based on the original cycle idea of repeated infections impairing airway integrity. According to this view, a dysregulated cytokine network can cause airway inflammation. Similar to this, rituximab’s adverse effects include immunological dysregulation that results in cytokine imbalance and B-cell depletion that causes hypogammaglobulinemia and an increased risk of infection [6]. In our patient, we think that immunomodulation and recurrent bacterial infections worked altogether to generate bronchiectasis in response to rituximab [2].

Effective treatment must interrupt the infection/inflammation cycle as soon as possible to reverse and/or stop the progression of bronchiectasis and further lung damage.

To illustrate the importance of prompt recognition and treatment in decreasing the burden of bronchiectasis, a cohort study demonstrated significant morbidity and mortality while examining 2 groups of patients: 42 patients had undergone post-allogeneic hematopoietic cell transplantation and 63 patients had chronic lymphocytic leukemia. Morbidity and mortality were related to hematology–respiratory-specific complications, including bronchiolitis obliterans (BO) and recurrent pneumonia. While both groups experienced an overall decline in pulmonary function, the minority of patients (14%) who received specialized pulmonology follow-up – including airway clearance therapy and inhaler optimization – demonstrated significantly better clinical outcomes than those without subspecialty care [11]. In our case, the gradual cessation of rituximab, combined with aggressive airway clearance and immunoglobulin replacement, led to the complete radiological resolution of bronchiectasis. To the best of our knowledge, such a reversible course of rituximab-induced chronic suppurative lung disease has not been previously documented in the pediatric literature.

Conclusions

Although rituximab-induced pulmonary complications are more common in adults, this case underscores the critical need to recognize and consider rituximab as a potential causative agent in pediatric patients presenting with respiratory symptoms, especially after prolonged use for various medical indications. Early identification and timely intervention are paramount in mitigating the risk of further lung injury and can even facilitate a complete recovery. Pediatricians and healthcare providers are strongly encouraged to maintain a high index of suspicion for rituximab-associated pulmonary complications, particularly in patients with previously unaffected or “naive” lungs. Hence, guided by our example, early and prompt recognition of bronchiectasis can successfully reduce and even fully reverse its negative effects. Based on our experience, an understanding of how rituximab immunological mechanisms work and close multidisciplinary team follow-up are 2 key factors in recovery. By remaining vigilant and proactive in monitoring for such adverse effects, clinicians can optimize the clinical course and tailor treatment strategies to improve outcomes for pediatric patients undergoing rituximab therapy.