Methotrexate Induced Lung Toxicity- A Case Report

 

Sandhya Lekshmi. S¹, Remya Antony, Neeraj Sidharthan², Gireesh Kammath², Anila. K. N¹*

¹Department of Pharmacy Practice, Amrita School of Pharmacy, Kochi Amrita Vishwa Vidyapeetham,

Amrita  University, India.

²Dept of Medical Oncology and Haemotology. Dept of Medical Oncology, Amrita Vishwa Vidyapeetham, Amrita University, Kochi, Kerala- 682030. India

 

ABSTRACT:

Methotrexate (MTX) belongs to a class of antimetabolites. It may cause serious side effects like lung problems, lung infections. Methotrexate-induced lung disease, as well as acute or chronic interstitial pneumonitis, is a potentially risky sore, which can happen intensely whenever, amid treatment and has been accounted for at low doses. The diagnosis of drug-induced pulmonary toxicity is generally settled in light of clinical discoveries. The present report describes a case of methotrexate-induced lung toxicity. Biopsy that had done reported as relapsed lymphoma. Then he got admitted for high dose methotrexate and rituximab followed by folinic acid rescue. He tolerated 2 chemotherapies well, without any major complications. He developed fever, cough with expectoration and breathlessness. In view of persisting high grade fever, associated with cough and breathing difficulty, pulmonology consultation was sought and CT done. In medication-induced lung toxicity, the radiologic patterns seen are exceeding factor and rely upon the kind of unfavorable response the patient is experiencing. One possibility in the clinical setting is methotrexate induced lung changes. Differential diagnosis (DD) is alveolitis due to infection. In view of suspected methotrexate induced lung toxicity, planned to withhold next dose of Methotrexate. He was started on high dose steroids. The patient symptomatically improved, fever subsided, counts improved. Prompt diagnosis is vital in light of the fact that early medication actuated lung harm will regularly relapse with cessation of treatment. It was found that the severity of the methotrexate induced lung toxicity is a probable adverse drug reaction (ADR) with Naranjo score of 7.

 

 

 

INTRODUCTION:

Methotrexate (MTX) comes under antimetabolites class of drug. It acts on cancerous cells by abating or halting its growth and by the suppression of immune system. Along these lines, this drug ought to be utilized just to treat malignancy or serious infections brought on by an overactive immune system like psoriasis, rheumatoid joint pain. It may cause serious side effects like lung problems, lung infections. (Pneumocystis jiroveci pneumonia).  Methotrexate may causes reactions because of the fast decimation of malignancy cells (tumor lysis syndrome), when it is used for the treatment of tumors.

 

 

In light of the therapeutic condition and response to treatment, its dosage and frequency of use can be determined. Especially for cancer treatment, MTX have many different dosing schedules.

 

Methotrexate-induced lung disease, as well as acute or chronic interstitial pneumonitis, is a potentially risky sore, which can happen intensely whenever, amid treatment. At low doses this has been accounted. This reaction isn’t completely reversible. Pneumonic manifestations particularly a nonproductive, dry cough may require intrusion of therapy and cautious examination. Pneumonic indications may happen whenever amid treatment and at any dosage. Other potential manifestations include fever, dyspnea, hypoxemia, or aspiratory invade.

 

 

CASE HISTORY:

A 50 year old male who was a diabetic, hypertensive, had presented with left testicular swelling. Fine-needle aspiration cytology (FNAC) showed Lymphoma. He underwent inguinal orchidectomy done in August 2014. Computed tomography (CT) imaging done showed isolated testicular lesion. Histopathology showed Non Hodgkin Lymphoma -Diffuse Large B Cell Lymphoma. He received 6 cycles of chemotherapy with R CHOP regimen followed by he completed external beam radiation therapy with a dose of 2400cGy in 12 fractions. Patient was asymptomatic for 3 years. Patient had a history of involuntary movements of left lower limb in a sitting position and had a fall while trying to get up and lost consciousness. MRI brain revealed two lesions- dural based around 1 cm in the left parietal region. Afterwards the patient was asymptomatic. Then he underwent awake minicraniotomy and navigation guided tumor decompression and biopsy. Biopsy reported as relapsed lymphoma. Then he got admitted for high dose methotrexate and rituximab followed by folinic acid rescue. Had received 1st cycle without major complaints. His MTX level was 0.1 umol/L on 14/01/2017. As 1st cycle was uneventful, it was decided to increase dose to 5gm/m2 in next cycle. His MTX level is 0.1 umol/L on 29/01/2017. He tolerated chemotherapy well, without any major complications. After discharge he had a fall early morning next day in his premises at home. He had a swollen bruised left knee – knee flexion is restricted. He was seen in Orthopedics Dept, they advised surgery for knee cap and planned for tension band wiring left patella. He underwent tension band wiring- left patella on 9/2/2017. Post surgery patient had developed fever, cough with expectoration and breathlessness. He was started on empirical antibiotics, growth factors and other supportive measures. Blood and urine cultures were sent for investigation. Chest X-Ray showed bilateral (B/L) diffuse ground glass opacities and B/L lower zone consolidation. Gram smear, KOH Acid- Fast Bacilli (AFB) sputum was negative. His cultures were sterile. In view of persisting high grade fever, associated with cough and breathing difficulty, pulmonology consultation was sought. He was started on high flow oxygen and advised for CT chest with contrast. CT chest showed Diffuse ground glassing in bilateral upper lobe predominantly involving apical segment, right middle, left lingular and mild in bilateral lower lobe with traction bronchiectasis and sub pleural sparing. One possibility in the clinical setting is methotrexate induced lung changes. Differential diagnosis (DD) is alveolitis due to infection. Gene Xpert MTB-RIF test is an automated diagnostic test. It is used to identify the resistance to rifampicin (RIF) and to identify the Mycobacterium tuberculosis (MTB) DNA based on the principle nucleic acid amplification test (NAAT) and this was found to be negative. Then he was planned for Trans Bronchial Biopsy, which was done shows lymphocytic infiltrate with suspicious area of loose Granuloma. Bronchoalveolar lavage (BAL) culture was negative. BAL Cell Block showed no organisms/atypical/ malignant cells noted. In view of suspected methotrexate induced lung toxicity, planned to withhold next dose of Methotrexate. He was started on high dose steroids (Tab. Prednisolone, 60 mg, OD) and on Pneumocystis pneumonia (PCP) prophylaxis the patient symptomatically improved, fever subsided, counts improved. Repeat Chest X Ray (CXR) showed good improvement. Orthopedics consultation sought and sutures removed on 23/2/2017. Patient was also planned for Dexa scan during next visit and now he is symptomatically better.

 

CASE DISCUSSION:

There is no tests to confirm MTX-induced lung toxicity, all the other relevant clinical investigations were helpful in ruling out possible etiologies. The analysis of medication-induced pulmonary toxicity is usually established in view of clinical discoveries. For the purpose of characterizing the radiographic variations from the norm, when compared with chest radiography, the high-resolution computed tomography (CT) examination is more effective.[1]

 

In patients with medication-induced lung toxicity, the radiologic patterns are highly variable and it rely upon the sort of antagonistic response the patient is experiencing. Since the vast majority of the medication prompted lung toxicities like the interstitial infiltrates, parenchyma may might be exhibited on radiographs. If the pulmonary vasculature or airways is being influenced, then the radiograph might be normal or negligibly irregular. It was found that there is a restrictive lung disease pattern on lung function tests (LFTs), due to the harmfulness from most medications, which results in declines in the total lung capacity (TLC). Forced expiratory volume in 1 second (FEV₁) /forced vital capacity (FVC) ratio might be typical or expanded. There is a decline in diffusion capacity of the lung (DLCO). The first thing to be lessened is the measure of lung function. If the medication-induced lung toxicity causes airway obstruction, then the FEV₁/FVC ratio is reduced hereby the FEV₁ will be decreased. There is an increase in residual volume to total lung capacity (RV/TLC) ratio.

 

Bronchoscopy along with transbronchial biopsy is typically unrewarding in building up the determination of medication incited lung poisonous quality. Bronchoalveolar lavage (BAL) can add to the normal clinicopathologic pattern of a given medication-induced lung infection for example, recognizing eosinophils in a drug-induced eosinophilic pneumonia. In addition, BAL is useful in the differential finding, principally by barring an infective etiology to the pulmonary infiltrates.

Drug-induced pulmonary diseases haven’t any pathognomonic clinical, lab, physical, radiographic, or histologic discoveries. Also it is generally viewed as a diagnosis of exclusion (eg, after eliminating infectious and other causes).[2]

 

The diagnosis of methotrexate-induced pulmonary toxicity must be made on the premise of the clinical manifestations, clinical setting, radiographic variations from the norm, and BAL reports. Once in a while, lung histopathology is important.

 

The diagnostic criteria proposed by Searles and McKendry for MTX-induced toxicity comprises of the accompanying major and minor criteria.[3]

 Major criteria are as follows:

·        Hypersensitivity pneumonitis in view of histopathology, without confirmation of pathogenic organisms

·        Radiologic evidence of alveolar or pulmonary interstitial infiltrates.

·        Negative blood cultures (if febrile) and initial sputum cultures (if sputum is produced)

 

Minor criteria are as follows:

·        Cough that are non-productive

·        Shortness of breath for <  2 months

·        During initial evaluation, Oxygen saturation ≤ 90% on room air.

·        DLCO ≤ 70% of predicted

·        ≤ 15,000 cells/µL of leukocyte count

 

There are very few studies in similar occurrence. A study reported by Ayushi Sikka et al showed fifty-one-year-old lady being treated with methotrexate for leucocytoclastic vasculitis, developed respiratory symptoms and signs. These improved on drug withdrawal and with four weeks of steroid treatment.[4]

 

A study conducted by M R Hargreaves et al showed that  a patient was treated with 10 doses of intrathecal methotrexate (MTX) directed at interims of 2 days. Taking after these medications she developed fever, hypoxemia, and bilateral pulmonary infiltrates without recorded pulmonary infection. Post-mortem discoveries were predictable with the pneumonitis that has been related with intermittent oral, intramuscular, and intravenous MTX therapy. Serum MTX levels most likely surpassed 10-8M during the entire 20-day course of treatment, thus exposing the pulmonary parenchyma to significant drug concentrations for a prolonged interval.[5] Five patients having low dose methotrexate treatment developed acute pneumonitis. In all cases methotrexate was discontinued and high dose corticosteroids started, with rapid clinical and radiological improvement. After withdrawal of steroid both clinical and radiological resolution was maintained at follow up.[6] It was found that the severity of the methotrexate induced lung toxicity is a probable ADR with a NARANJO score of seven.[7] Overall, the etiology for lung diseases are many. With the correct diagnostic parameters and treatment certain conditions can be completely cured.[8]

 

CONCLUSION:

Lung harm is an expanding reason for morbidity and mortality in patients treated with cytotoxic and non cytotoxic medications. In this case study, patient showed better clinical presentation after the cessation of the culprit, high dose methotrexate, Prompt diagnosis is vital in cases like above, in light of the fact that early medication-induced lung damage will frequently relapse with the end of treatment.

 

REFERENCES:

1.     Tamura M, Saraya T, Fujiwara M, Hiraoka S, Yokoyama T, Yano K, et al. High-resolution computed tomography findings for patients with drug-induced pulmonary toxicity, with special reference to hypersensitivity pneumonitis-like patterns in gemcitabine-induced cases. Oncologist. 2013; 18(4):454-9.

2.     Irey NS. Teaching monograph. Tissue reactions to drugs. Am J Pathol. 1976; 82:613-47

3.     Searles G, McKendry RJ. Methotrexate pneumonitis in rheumatoid arthritis: potential risk factors. Four case reports and a review of the literature. J Rheumatol. 1987:14(6);1164-71.

4.     Ayushi Sikka, Methotrexate-induced Pulmonary Toxicity. J Indian Acad Clin Med 2006;7(4):365-7

5.     Gutin PH, Green MR, Bleyer WA, Bauer VL, Wiernik PH, Walker MD. Methotrexate Pneumonitis Induced by Intrathecal Methotrexate therapy A Case Report with Pharmacokinetic Data. Cancer 1976;38:1529-1534,

6.     Hargreaves MR¹, Mowat AG, Benson MK. Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis: report of five cases and review of published reports: Thorax. 1992;47(8):628-33.

7.     Naranjo CA et al. A method for estimating the probability of adverse drug reactions. Clin. Pharmacol. Ther. 1981; 30:239-245.

8.     Karakkattu, J., Roshni, P.R. Etiology for liver diseases in pediatric population, Asian J Pharm Clin Res 2017;10:91-4.

 

Accepted on 07.07.2017        © RJPT All right reserved

Research J. Pharm. and Tech 2017; 10(10):3458-3460.