Nitrofurantoin-Induced Pulmonary Eosinophilia

Abbreviations

NTF- Nitrofurantoin Antibiotic
UTIS- Urinary Tract Infections
NIPE- Nitrofurantoin Induced Pulmonary Eosinophilia
URIT- Upper Respiratory Tract Infection
DM TYPE 2- Diabetes Mellitus Type 2
 CKD- Chronic Kidney Disease
COPD- Chronic Obstructive Pulmonary Disease
ADE- Adverse Effect
PE- Pulmonary Eosinophilia
DILD- Drug Induced Lung Disease

Introduction

Pulmonary eosinophilia (PE) is a lung disorder characterized by an abnormal accumulation of eosinophils in the respiratory tract. Eosinophils that are normally involved in the immune response against allergens and parasites in PE, however, the aberrant ac- cumulation of eosinophils within the airways and alveolar spac- es triggers an inflammatory cascade leading to tissue damage and dysfunction [1].
 
PE can be broadly classified into two main categories (1) Primary Eosinophilia -a group of idiopathic disorders where the under- lying cause of the increased eosinophils remains unknown, and the pathogenesis is thought to involve an autoimmune process. Ex: Idiopathic Hyper-eosinophilic Syndrome (HES). (2) Sec- ondary Pulmonary Eosinophilia - It is caused by an identifiable underlying condition, such as: drugs, environmental exposures, other clinical conditions [2].
The diagnosis of PE is based upon the combination of clinical presentation, chest imaging findings, peripheral blood eosinophil- ia, and bronchoalveolar lavage (BAL) with a characteristic eosin- ophilic infiltrate (usually > 3% of the total differential cell count) [3]. The mainstay of treatment for PE depends on the etiology. For primary eosinophilia corticosteroids are the main drug of choice and in secondary eosinophilia discontinuation of the offending drug and allergen avoidance or specific medications for allergic causes helps in better patient care. This case report describes an old male patient who developed NIPE following treatment with nitrofurantoin [4,5].

While generally well-tolerated, nitrofurantoin can cause a variety of pulmonary complications. One rare but serious adverse effect is nitrofurantoin-induced pulmonary eosinophilia. It is usually given in doses from 25mg, 50mg,100mg IV and 100mg PO on discharge and usually prescribed for not >7 days.

Measures in such cases included withdrawal of nitrofurantoin, bronchodilators, corticosteroids; management of underlying dis- orders such as diabetes, CKD; and supportive therapy refer to patient response to treatment (e.g., improvement in respiratory symptoms, resolution of eosinophilia) and the prolonged impact of NIPE on the patient's pulmonary function, where available.

 Pathophysiology of Developing NIPE

Nitrofurantoin is well-absorbed orally, primarily metabolized in the liver, and excreted mainly through the kidneys. Its mecha- nism of action involves interfering with bacterial cell wall and protein synthesis.

After metabolism of the drug in liver to form reactive metab- olites. Whether the parent drug itself or the metabolites acts as haptens (small molecules that binds to proteins in the body) and forms antigenic complexes which triggers an immune response.
 
In susceptible patient, after administration it activates the immune system, particularly T lymphocytes that releases cy- tokines and chemokines, recruiting inflammatory cells to the lungs. Eosinophils that are involved in allergic reactions are recruited to lungs in response to inflammatory signals where they migrate from bloodstream to lung tissue further releasing various mediators such as chemokines, cytokines causing tis- sue damage and inflammation.

Adverse effects include gastrointestinal symptoms, rare hemato- logic abnormalities, pulmonary toxicity, neuropathy, and hep- atotoxicity. It's generally safe in pregnancy but excreted in breast milk. Dosage adjustments are needed in renal impair- ment. Drug interactions and monitoring parameters, like renal function and hematologic parameters, should be considered [6-8].

Case Report

Patient Details
A 60-year-old male patient presented with symptoms of fever, chills, rigors, vomiting, headache and anorexia in the past 5 days. He had a medical record of DM TYPE 2 and recently diagnosed with typhoid 15 days back. His medication his- tory includes Tab. Voglibose (0.2mg) +Metformin (500mg) +Glimepiride (2mg) for DM TYPE 2 and for typhoid he was on 5days treatment with Tab. Azithromycin (250mg) + Omeprazole (20mg) and again for 10 days he was on Tab. Cefuroxime (250mg) + Tab. Omeprazole + Domperidone (40mg/10mg). His social and occupational history shows that he is a farmer who works part-time at a mill and consumes both vegetarian and non-vegetarian foods, with alcohol con- sumption occurring once every six months.

On admission he was provisionally diagnosed with Dengue with Dengue IgG positive in k/c/o DM TYPE 2 and CKD Grade 4 with significant lab reports attached in Table 2.1.1

                                                                Table 1: Lab Investigations
                       a.    Green color highlights increased count and red color highlights decreased count
                        b.    Other relevant results not reported were within normal limits 

The patient was prescribed with dosage regimen mentioned below in Table 2.1.2

                                                           Table 2: Treatment Chart

USG abdomen showed fatty liver grade 1 with early changes of renal parenchymal tissue. His eGFR calculated was 29ml/ min/1.73m2 indicating CKD stage 4 (severe kidney damage). Urinalysis showed presence of bacteria, pus cells, RBCs and epithelial cells confirming urinary tract infection for which he was treated with Tab. Nitrofurantoin 100mg B.D for 10 days. His final diagnosis upon discharge from the hospital following a 15-day stay was iron deficiency anaemia, diabetic nephropathy, non-alcoholic fatty liver grade 1, COPD, UTI, CKD stage 2, and asthma in k/c/o DM type 2.

Clinical Evidence

PFE due to nitrofurantoin is a very rare occurrence. NTF-in- duced pulmonary toxicity typically appears as fever, cough, pleuritis, dyspnea, and diffuse parenchymal opacities, with iso- lated pleural effusion being unusual. On 10th day of the treat- ment with nitrofurantoin, the patient experienced symptoms of cough, cold and chest tightness confirming ADE of NTF through lab investigation showing increased IgE antibodies in urine and increased Abs. eosinophil counts. Current Infectious Disease Society of America guidelines recommend nitrofuran- toin monohydrate/macrocrystals as a first-line antibiotic for uncomplicated urinary tract infections and the prescribed days for nitrofurantoin are only 7 days or a week, although the patient was prescribed nitrofurantoin 100mg B.D. for more than 7 days i.e.10 days.

Discussion

The patient’s clinical symptoms were suggestive for drug re- lated event. As the laboratory reports and objective evidence showcased only after treatment with Nitrofurantoin more than prescribed days there was a suspected adverse drug reaction [9]. His symptoms improved upon with appropriate treatment for eosinophilic pneumonia. Nitrofurantoin-induced pulmonary eosinophilia, though uncommon, can mimic other respiratory illnesses. Elevated blood eosinophil levels supported the di- agnosis of NIPE.

The ADR was neither predictable nor preventable due to its rarity. No De-challenge nor Re-challenge was performed WHO- Causality Assessment Scale gave probable causality term as the event had a reasonable laboratory investigations abnormality and time relationship with drug intake and was unlikely attributed to other drugs or disease. The Naranjo Scale (Table 3.1) gave a score of 6 i.e. Probable.
 

                                                                                Table 3: 1 Naranjo Scale

This case presentation aligns with previously reported cases with similar symptoms like cough, dyspnea, and chest infiltrates are consistent. While nitrofurantoin is widely used, some reports emphasize the rarity of pulmonary eosinophilia, making this case and awareness of this potential complication even more important [10-18].

Conclusion

Pinning down the exact prevalence of nitrofurantoin-induced pulmonary eosinophilia (NIPE) is a formidable task NIPE as a side effect itself makes accumulating large-scale data challeng- ing. Additionally, NIPE symptoms can be mistaken for other lung conditions, potentially leading to underdiagnosis and in- accurate prevalence figures. PE is a rare but serious complica- tion associated with nitrofurantoin. Studies suggest that older age, pre-existing lung issues, and prolonged nitrofurantoin use might increase the risk of NIPE, offering clues for further investigation. This report discusses a case of interstitial lung illness linked to the usage of Nitrofurantoin and the potential pathways of lung harm. Clinicians should be mindful of the plausible side effects of Nitrofurantoin when administering it to patients over time. DIILDs may be caused by a variety of medicines and substances. Medication reconciliation and medication history have a crucial role in determining the main cause of interstitial lung disease. The first step in managing DIILD is to identify the causative medicine and discontinue it promptly. Patients on Nitrofurantoin should be regularly examined for potential lung damage.

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