A Rare Case of Inhalational Paraquat Lung Injury Leading to Progressive Pulmonary Fibrosis
Corresponding Author: Surabhi Jaggi, Department of Tuberculosis and Respiratory Diseases, Government Medical College & Hospital, Chandigarh, India, Phone: +91 8968634206, e-mail: email@example.com
Received on: 03 March 2023; Accepted on: 30 July 2023; Published on: 30 October 2023
Introduction: Poisoning with various synthetic chemicals used in farming is a public health problem of considerable importance worldwide, particularly in developing countries. One of them is paraquat (PQ), which is an extensively used synthetic, nonselective, contact herbicide in the Indian agriculture industry. Although fatalities due to accidental or suicidal oral ingestion of PQ are common, inhalational injury due to this poison is very rare and often difficult to diagnose without a proper specific history, since the presenting symptoms are usually nonspecific.Case presentation and progress: Here, we report a case of a 35-year-old male, who had an accidental inhalation of Paraquat that led to lung injury and further complications. Initially, the patient had mild flu-like respiratory symptoms, but later symptoms worsened and he progressed into pulmonary fibrosis within a span of 2–3 weeks. Treatment and outcome: The patient was admitted and managed in respiratory intensive care unit (ICU). He was managed with steroids, prophylactic antibiotic therapy, and other supportive measures. During the treatment course, he developed bilateral secondary spontaneous pneumothorax. Initially, he responded to the steroid pulse therapy, but later the pulmonary fibrosis progressed further and the patient succumbed after 1 month of ICU admission.Discussion and conclusion: Paraquat is a bipyridylium quaternary ammonium compound that will cause direct harm to the cellular structures by the production of various reactive oxygen species (ROS) and other free radicals. The lungs and kidneys are the most affected organs. The treatment of PQ intoxication is not well set out. Prompt supportive medical treatment is essential to minimize the damage and improve the chances of recovery.
How to cite this article: S VN, Tomar S, Jaggi S, et al. A Rare Case of Inhalational Paraquat Lung Injury Leading to Progressive Pulmonary Fibrosis. Indian J Respir Care 2023;12(3):266–271.
Source of support: Nil
Conflict of interest: None
Patient consent statement: The author(s) have obtained written informed consent from the patient for publication of the case report details and related images.
Keywords: Bilateral pneumothorax, Case report, Inhalational lung injury, Organizing pneumonia, Paraquat poisoning, Progressive pulmonary fibrosis
Poisoning with herbicides and pesticides is a serious issue worldwide, especially in developing countries where agriculture is the primary source of income.1 Paraquat (PQ) is one of the bipyridylium quaternary ammonium compounds widely used as an herbicide in the Indian agriculture industry, usually available in the Indian market in the name of Gramoxone.2,3 Even though PQ can cause systemic effects, its toxicity mainly affects the lungs because of the presence of a special active uptake of the compound by the pneumocytes (type 1 and type 2 cells in alveoli) through the polyamine uptake route.4,5 In these cells, the compound goes through a complex series of oxidation-reduction reactions which involves several steps and produces free radicals, causing oxidative and free radical injury to the cells, further leading to inflammation and fibrosis. The effects of PQ are local as well as systemic, predominantly affecting the kidney, liver, and lung if ingested via oral route. Injury due to inhalational exposure is very rare and there is isolated lung involvement without systemic toxicity.6,7 The purpose of this study is to raise awareness regarding PQ-associated pulmonary symptoms, their progression, and complications. This case report puts emphasis on the gravity of recognizing the classical radiological and clinical progression of post-PQ poisoning, which might assist in early diagnosis in case the offending chemical is unknown. We must also suspect PQ poisoning as one of the primary diagnoses for cases reported especially from rural areas, where PQ is readily available for agricultural activities. Herein, we will see a case of lung injury following PQ inhalation.
This study reports a 35-year-old healthy male who is a manual laborer and a smoker with 10 pack years. He has no comorbidities. His symptoms started after an episode of accidental inhalation of herbicide spray (PQ) while he was working on his farmland. A strong wind was blowing in his direction, which led to inhalation of the substance and unfortunately, he was not wearing any facemask or personal protective measures while spraying the poison. After a few breaths, he covered his nose and mouth with a handkerchief. He had mild flu-like symptoms of dry cough, nasal congestion, and tightness of chest immediately after the exposure which he ignored and continued the work. The next day he developed dyspnea along with a dry cough, which gradually progressed over the next 2 days. He consulted a nearby clinic where he was managed conservatively.
After 3 days, symptoms progressed further and he was taken to a nearby hospital. On evaluation he had a mild fever, and routine investigations were within normal limits except for mild leukocytosis. His chest radiograph showed bilateral patchy reticulonodular shadows (Fig. 1). Non-contrast computed tomography (NCCT) chest showed bilateral patchy consolidation with surrounding ground glass opacities (GGOs) (Fig. 2). He was started on intravenous (IV) antibiotics (azithromycin and amoxicillin/Clavulanic acid), antihistamines and antitussives. However, he did not respond to the treatment given, symptoms progressed further, and hence was referred to a higher center. About 12 days after the initial exposure to the poison, he was brought to our emergency department with complaints of severe dyspnea. He was febrile (99.8°) and his vitals were SpO2—76% under room air, blood pressure—146/82 mm Hg, heart rate—112/minute, and respiratory rate—30/minute. Auscultation revealed bilateral crepitations. Routine investigations showed leukocytosis (18000 cells/uL), and arterial blood gas (ABG) was suggestive of type 1 respiratory failure. Serum electrolytes, renal function tests, liver function tests, and inflammatory markers such as C-reactive protein, D-dimer, and serum procalcitonin were within normal limits. Covid reverse transcription–polymerase chain reaction was negative. Chest X-ray showed bilateral reticulonodular patches (Fig. 3) and high-resolution computed tomography (HRCT) chest revealed multiple ill-defined confluents patches of consolidation in bilateral lung fields, more toward the periphery and lower zones. There were bilateral extensive reticulations in the form of inter and intralobular septal thickening, peri-broncho-vascular interstitial thickening and tractional bronchiectasis (Figs 4 and 5).
Since the oxygen requirement increased, he was started on noninvasive ventilation. During the treatment course, he developed a right secondary spontaneous pneumothorax, for which an intercostal drainage tube was inserted. Despite the empirical IV antibiotic therapy, the patient deteriorated further, both clinically as well as radiologically. On day 5 of admission, the patient was intubated due to an increase in respiratory distress and was started on invasive ventilation (Fig. 6). He was managed with a lung-protective ventilation strategy. His tracheal aspirate was sent for culture and cytology. The culture was sterile with no fungal elements and cytology was also inconclusive. Since he was not responding to the IV antibiotic therapy and after ruling out other infective causes, he was clinically diagnosed as a case of secondary organizing pneumonia with progressive fibrosis based on the exposure history, the pattern of disease progression, and clinical-radiological findings. Thus, he was given a pulse therapy of systemic steroids (injection methylprednisolone 1 g × 3 days), followed by tapering to oral steroid therapy, following which there was clinical as well as radiological improvement (Fig. 7). The patient underwent tracheostomy later in view of the need for prolonged mechanical ventilation.
After steroid pulse therapy, his oxygen demand decreased and his serial chest X-rays started to show mild improvement. He was gradually weaned off from the ventilator and stepped down from the controlled mode of ventilation to pressure support mode. However, the improvement in steroid therapy was short-lived. After 12 days of pulse therapy, he developed secondary spontaneous pneumothorax on the left side too, following which the patient deteriorated (Fig. 8). Pneumothorax was managed with intercostal drain (ICD) insertion and antibiotics were upgraded (meropenem and vancomycin). Cultures were sent to rule out the septic cause of deterioration.
Despite ICD insertion both the lungs were nonexpanding and had persistent free air leaks, pointing toward the presence of bilateral bronchopleural fistula (Fig. 9). Regardless of all measures, the pulmonary fibrosis progressed further, thereby increasing oxygen requirement and support of invasive ventilation. Serial cultures of blood, urine, and tracheal aspirate were done and sepsis was ruled out. Day by day, the patient deteriorated further with increasing oxygen demand. Later patient developed hospital-acquired pneumonia which progressed into sepsis and sepsis-induced kidney injury. The patient’s condition worsened abruptly and finally, despite all measures patient succumbed to death after 1 month of hospital admission, due to refractory shock.
Paraquat (PQ) (1,1’-dimethyl-4,4’-bipyridylium dichloride) is a bipyridylium quaternary ammonium compound (contains two pyridine rings and a quaternary ammonium group) that will cause direct harm to the cellular structures by the production of various reactive oxygen species (ROS) and other free radicals.6 Invariably lungs and kidneys are the most commonly affected, showing the highest aggregation of the chemical, irrespective of its route of entry into the body. The compound’s elevated accumulation in the kidneys occurs due to the fact that it is primarily removed from the system via the renal excretory route and hence kidney failure is the most frequent way of presentation in systemic intake of PQ.6 PQ has preferential absorption in the cells of the lung. In the pulmonary system, this toxin selectively accumulates in type 1 and type 2 pneumocytes of the lung. This occurs due to the presence of a special mechanism of active uptake of the toxin via the polyamine pathway present in these cells. After gaining entry into the cells, the PQ undergoes a complex process known as redox cycling. One of the mechanisms by which PQ causes toxicity is via redox cycling. Redox cycling refers to the repeated cycling of a molecule between its oxidized and reduced forms, which generates various ROS including superoxide and hydrogen peroxide. PQ is an excellent substrate for redox cycling because it readily accepts an electron from reducing agents such as nicotinamide adenine dinucleotide phosphate and flavoenzymes.8 As the first step PQ is reduced by various enzymes of cytochrome P450 enzyme system. The cytochromes P450 enzyme system is responsible for the metabolism of various drugs and chemicals in the body. Once PQ accepts an electron, it becomes reduced to form the PQ anion, which in the next step transfers the electron to oxygen to generate superoxide free radicals, which can then be processed to other ROS such as hydrogen peroxide, hydroxyl radicals, and singlet oxygen via a cascade of chemical reactions. These oxygen free radicals subsequently lead to oxidative damage to various cell elements such as deoxyribonucleic acid, lipids, proteins, etc. The generation of ROS through redox cycling is thought to be a crucial contributor to PQ toxicity. ROS can damage cellular structures and disrupt cellular signaling pathways, leading to cell death. They cause cell membrane damage by extracting hydrogen from membrane-associated polyunsaturated fatty acids leading to lipid peroxidation.8
While further looking into the pathophysiology of lung damage, it is characterized by two separate stages of the inflammatory process—the destructive phase and the proliferative phase. These phases occur concurrently with the early and late clinical stages respectively. During the destructive phase, PQ causes damage to the alveolar cells. If the PQ was ingested systemically it affects several organs in this phase, including the liver, renal system, cardiac system, and lungs.3 This damage leads to inflammation with infiltration of the walls of alveoli by inflammatory cells mainly neutrophils and lymphocytes, followed by macrophages. These occur within the first few days of the ingestion of the toxin.7 Patients who get through this point might show a brief span of amelioration of symptoms. The next phase is characterized by diffuse and intense pulmonary fibrosis. This fibrosis is in response to the inflammation of the initial stage and acts as a repair mechanism. The patients develop an increase in respiratory symptoms and further clinical deterioration occurs. Extensive fibrosis can lead to death due to respiratory failure. Severe fibrosis affects the diffusion capacity of the lungs leading to serious hypoxia, as the gases are unable to diffuse across the damaged respiratory epithelium.7
Although PQ poisoning and related lung injury is common, the majority of the route of exposure to the poison is via oral route. Also in such cases apart from a lung injury, damage also occurs to the gastrointestinal system as well as the renal system. Here in our case scenario, the exposure to poison occurred as accidental inhalation of spray/fumes, which is rare. Also, unlike other routine PQ poisoning cases gastrointestinal and renal injury were absent, the patient had isolated lung injury without other systemic involvement, where it looked like a case of atypical viral pneumonia.
Paraquat (PQ) is a highly lethal herbicide and its intoxication has very high mortality because there is no known antidote to this compound till date.2,6,8-11 According to many case reports of PQ ingestion, the mortality rate ranges from 60 to 90%.3,6,8,9 If there is concurrent occurrence of pneumomediastinum, mortality rises to almost 100%. Currently, there is no proven effective treatment for PQ lung toxicity and treatment typically focuses on managing symptoms and preventing further damage to the body.3,12 Controlled oxygen support, and prompt anti-inflammatory therapy, can improve outcomes in some patients but need further extensive studies on this aspect.7 Therapy with reduction of oxygen supply (hypo-oxygenation) has been tried based on the evidence of studies in animals which show a relationship between the FiO2 (fraction of inspired oxygen) delivered during treatment and the severity of the pulmonary damage that follows. The hypothesis is that although the oxygen was given for the treatment of hypoxia, it might act as a villain to cause further lung damage by providing additional substrate for free radical formation, thus causing indirect harm during the treatment process.8,13 Moreover, the role of various anti-oxidants and free radical neutralizers such as vitamin C, N-acetyl cysteine, vitamin E, glutathione, etc. were studied but has no proven role in the suppression of the pathological process of PQ associated inflammation. Although steroid pulse therapy has shown some promise in reducing PQ-related mortality, there is no gripping evidence of its clinical utility and efficiency. Steroids are expected to be effective as they have a role in contracting inflammatory processes that otherwise might progress further and be complicated by pulmonary fibrosis.12,14
In conclusion, the treatment of PQ intoxication is not well set out. Prompt supportive medical treatment is essential to minimize the damage and improve the chances of recovery. To date, most of the studies are performed in vitro or in animal models. Further research is needed to focus on finding efficient treatment options that can alter patient outcomes. Our case points out a few more factors which have led to the unfavorable outcome. Inappropriate initial diagnosis, delay in starting steroids, and time wasted in the periphery before reporting to the tertiary care center are all contributing factors. The patient initially did not give a history of episode of exposure, until it was specifically asked for multiple times. Extensive history taking, quick diagnosis, and prompt initiation of steroid therapy would have changed the course of the disease. Additionally, our goal is to raise public awareness about the significance of employing personal protective measures when using PQ spray.
Vishnu N S https://orcid.org/0009-0000-7468-4626
Siddharth Tomar https://orcid.org/0009-0007-2176-1510
Surabhi Jaggi https://orcid.org/0000-0003-2060-5990
Saloni R Kumar https://orcid.org/0009-0002-4186-772X
Mandeep K Sodhi https://orcid.org/0000-0003-2813-9437
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