Rituximab Induced Interstitial Lung Disease Diagnosis, Treatment Outcome, and Risk’s Factor, a Place for Transbronchial Pulmonary Cryobiopsy

Rituximab (RTX) is a mouse/human chimeric anti-CD20 IgG1 monoclonal antibody, approved in late 1998 by the FDA. Effectively used as a single agent or combined with a chemotherapy regimen to treat lymphoma, RTX is a significant step forward in the arsenal treatment of idiopathic thrombocytopenic purpura, systemic lupus erythematous, rheumatoid arthritis, and autoimmune hemolytic anemia. Side effects of RTX are commonly seen during the first infusion in up to 50% of patients and include fever, chills, and rigors. These side effects are generally transient and related to the tumor burden, probably due to a greater degree of complement activation and proinflammatory cytokine release. Severe lung toxicity like cryptogenic organizing pneumonia, pneumonitis, and interstitial lung diseases are infrequent, with most of the knowledge coming from case reports.


Material and Methods
The objective of this article is to peculiarize the syndrome of rituximab-induced interstitial lung disease (R-ILD). We proposed a thorough description of R-ILD, How to cite this paper: Makenzi

Case One
A 67-year-old male Caucasian patient presented at the emergency department with a history of progressive dyspnea, fever, and dry cough. Two weeks before the onset of his symptoms, he received his second dose of rituximab (RTX-based regimen of 1 g followed 14 days later of another 1 g dose) in the setting of a P-ANCA granulomatosis with polyangiitis diagnoses by renal biopsy. At the beginning of his condition, the patient presented with isolated renal involvement such as acute kidney injury, strong sediment hematuria, and nephrotic syndrome, 3.5 g/24 hr. No other systemic presentations nor functional and radiological respiratory impairment were highlighted.
At the emergency department, his initial vital signs were as follows: temperature 36.9˚C, with a heart rate of 90 beats/min, blood pressure 140/80 mmHg, tachypnea with a respiratory rate of 20/min and oxygen saturation 86% on room air, 91% with 3 L of O 2 within a nasal canula. Physical examination was unremarkable except for bilateral scattered inspiratory crackles.
Laboratory examination revealed normocytic anemia, a mild inflammatory syndrome, stable CKD (chronic kidney disease) function. A whole review is then launched; because of the current context, during a viral pandemic at SARS CoV2, a nasopharyngeal smear is performed to search for SARS CoV2 by polymerase chain reaction (PCR) method, which returns negative twice. The extend of other laboratory tests searching for an infectious etiology was negative (Table 1). Computer tomography (CT-Scan) of the chest revealed diffuse bilateral ground-glass opacities, poorly defined centrilobular nodules, and mosaic attenuation ( Figure 1). Cardiac origin was excluded by a 2D echocardiogram that demonstrated an ejection fraction of 55% with no valvular abnormalities.

Differential Diagnosis
CT scan images finding, with a diffuse interstitial pathology aspect can be found on Nonspecific Interstitial Pneumonia (NSIP) and can either reflect extrinsic allergic alveolitis, interstitial hypersensitivity pneumonitis, toxic pneumonia, or diffuse infectious lung disease. Compared to the same review conducted for the GNSA's assessment, these lesions are new. Bronchoscopy with bronchoalveolar lavage (BBL) with transbronchial biopsy is mandatory to rule out an infection etiology, autoimmune features, or presences of malignancy cells. BBL was performed, with a negative result for the presence of SARS CoV2 or other infectious (Table 2), as such of atypic cells. A thorough review of the patient's   Therefore, in the absence of any counterindications, a TPC is performed. The histologic report revealed strongly suggestive images of nonspecific interstitial pneumonia with enlarging septa, discrete fibrosis, and inflammatory infiltrates ( Figure   2). All these findings support the diagnosis of interstitial lung disease (ILD).
Initially, pulse therapy, 250 mg/day of methylprednisolone for three to five days. The patient presented immediate signs of clinical improvements, followed by oral prednisone at a dose of 1 mg/kg per day (using ideal body weight). Subsequent tapering down over six months was conducted with an excellent clinical   (Table 3). But no sufficient material was obtained from the transbronchial biopsies to identify a histologic entity.

Case Two
A multidisciplinary consensus agrees to perform a (TLC) which showed desquamation of alveolar pneumocytes eosinophilic inflammation and macrophages with reactive changes consistent with alveolar damage interstitial fibrosis.
Drug induced pneumonitis was the most likely possible underlying etiology. The diagnosis of RTX-ILD was made on clinical, radiological, and histological bases.

Epidemiology
The incidence rate of RTX-ILD is unknown but rare; early reports indicated meager incidence rates at 0.010.03% [1]. Nevertheless, much higher incidence rates were reported in post-marketing case series ranging from 3.7% to 10% [2].
Those discrepancies might be attributed to the difference in the target population between clinical trials and daily clinical practice. Besides, some cases of RTX-ILD might be regarded as lower respiratory tract infections because of the overlap between the signs and symptoms of these complications.

Clinical Settings, Timing and Images Characteristics
Details of RTX-ILD have been described in a systematic review [3], and the most common symptoms are dry cough, exertional dyspnea, and fever. Nonspecific symptoms are less common and included fatigue, rigors, wheeze, hemoptysis, skin rash, and pleuritic chest pain. Hadjinicolaou AV and al; in a case series, found that around 20% of patients were asymptomatic at the time of diagnosis, with the disease being detected either by CT or LFT. Three clinical presentations were identified based on symptoms onset: Early onset hyperacute forms (less than 7 days) after infusion. Acute/Subacute (7 to 21 days), Chronic (over 30 days) [4].
In a multivariate analysis, poor Eastern Cooperative Oncology Group (ECOG) performance status (odds ratio 10.8% and 95% confidence interval 1.6 -74.8, p = 0.016) and age (odds ratio 1.1% and 95% confidence interval 0.0 -1.2, p = 0.048) were significant risk factors for rituximab-induced ILD. The most common form on CT scan is an organizing pneumonia pattern or/and diffuse interstitial pattern (ground-glass opacities, alveolitis, and diffuse infiltrate); diffuse or patchy bilateral consolidation in some cases had been described, with the addition of centrilobular nodules which can indicate the presence of alveolitis. Pleural effusion is uncommon; its presence a co-existing infection should be excluded. Hypersensitivity pneumonitis, ARDS, interstitial pneumonitis, organizing pneumonia, also had been reported [5]. Our findings are consistent with the reported cases in the literature in which alveolitis, fibrosis [6].

Risks Factors
The majority of patients had a diagnosis of NHL (75%), and Hadjinicolaou et al. [1] suggested that the elderly is at the most significant risk of rituximab-associated IL D were elderly (average age 65). In the same multivariate analysis, poor East-

Treatment Strategy
Conventionally the treatment of RTX-ILD follows the general principles of drug-induced pulmonary toxicity: 1) discontinuation of the offensive agent, 2)

Discussion
Rituximab-induced interstitial lung disease is a rare but known complication. Its low incidence may be attributed to a failure to recognize the complication or due to it spontaneously resolution after discontinuing the medication or after a steroid course [7].
The definite causal relationship is difficult to prove, but chronological association together with the described clinical and radiological features make a probable diagnosis of RTX-ILD. Another challenge in the diagnosis is the use of concomitant drugs or chemotherapeutic agents particularly in the treatment of lymphoma. For this dilemma some authors used Drug lymphocyte stimulation test, a result strongly positive for rituximab with elevated Levels of TNF-a, interferon g, and interleukin 4 but negative for others immunosuppressive or chemotherapeutic agents (such as cyclophosphamide and vincristine) can be a useful tool to discriminate [8].
Bronchoalveolar lavage findings may support the likelihood of certain lung diseases; however, the information is not specific, and to obtain a definitive diagnosis, further investigations are required such as Transbronchial biopsy. Other alternative to enhance the diagnostic sensitivity in case of transbronchial biopsy failure could be the realization of a Transbronchial Pulmonary cryobiopsy. This relatively new technic has proved to be reasonably safe and useful as an evaluable tool in the pathological assessment of ILDs [9] [10].

Conclusions
Rituximab-induced interstitial lung disease is a rare pathology and often misdiagnosed. Clinical, laboratory and radiological findings can be inconstant, which can make its diagnosis quite challenging. Strong suspicions, clinic presentation, and well-trained clinicians can help an early diagnostic establish a corticotherapy regimen to prevent life-threatening complications.
TPC realization can be considered, this procedure has been proved to be a safe alternative to surgical lung biopsy in ILD diagnosis. Although this technique may not be applied to all ILD cases, it needs to be included in the armamentarium of techniques available for sampling lung tissue when deemed indicated.

Statements
This work was not supported by any grant or funding. We did not receive any contributions fees. There are no competing interests for any other participants (such as board membership, consultancy, employment, expert testimony grant, contract research, lectures/other education events). We do not require and exclusive license for this article publication. This article does not involve human participants neither any drugs trial.