Excipient Lung Disease and Fatal Outcome Among Young Adults: A Case Series on the Hidden Dangers of Intravenous Drug Abuse in India
Department of Forensic Medicine and Toxicology, Government Stanley Medical College, Chennai, Tamil Nadu, India
Department of Forensic Medicine and Toxicology, All India Institute of Medical Sciences, Kalyani, West Bengal, India
Department of Forensic Medicine and Toxicology, All India Institute of Medical Sciences, Madurai, Tamil Nadu, India
Address for correspondence: Dr. Venkatesh Janarthanan, Department of Forensic Medicine and Toxicology, All India Institute of Medical Sciences, Kalyani - 741 245, West Bengal, India. E-mail: venkijanas@gmail.comAbstract
Background:
Excipient lung disease (ELD) arises from the intravenous (IV) injection of crushed oral tablets, leading to acute or chronic pulmonary complications. Despite its significance, ELD is under-recognized, particularly in countries like India, where over-the-counter availability of pharmaceutical drugs contributes to rising abuse rates. This study investigates sudden deaths among young adults due to ELD, emphasizing the need for increased awareness and preventive measures.
Materials and Methods:
This case series examined 10 cases of sudden death in individuals aged 18–25 with a history of IV drug abuse. Data were collected from postmortem examinations, death scene investigations, and toxicological and histopathological analyses. The aim was to confirm ELD as the cause of death and understand its presentation.
Results:
Deaths in these cases were strongly associated with drug overdoses. Death scene investigations revealed signs of IV drug use, such as track marks and drug paraphernalia. External and internal examinations showed consistent pathological findings, including edematous lungs with frothy secretions, granulomatous reactions in the pulmonary vasculature, and right ventricular hypertrophy. Toxicological analyses detected substances such as tapentadol and tetrahydrocannabinol, with excipients linked to ELD found in histopathological examinations.
Conclusion:
When injected, excipients such as talc and microcrystalline cellulose lead to granulomatous reactions and pulmonary complications. The study highlights the prevalence of ELD among young adults in India and the challenges in diagnosing this condition due to its nonspecific presentation and lack of disclosure of drug abuse history. Effective public health measures and stricter regulation of prescription drugs are crucial in preventing ELD-related deaths. This study underscores the severe health risks associated with IV drug abuse of oral tablets, leading to ELD. The findings emphasize the need for enhanced awareness, accurate documentation, and preventive strategies to address the rising substance abuse among youth in India.
Résumé
Contexte:
La maladie pulmonaire excipiente (MPE) résulte de l’injection intraveineuse (IV) de comprimés oraux écrasés, entraînant des complications pulmonaires aiguës ou chroniques. Malgré son importance, la MPE est sous-estimée, en particulier dans des pays comme l’Inde, où la disponibilité en vente libre de médicaments pharmaceutiques contribue à l’augmentation des taux d’abus. Cette étude examine les décès subits chez les jeunes adultes dus à la MPE, soulignant la nécessité d’une sensibilisation accrue et de mesures préventives.
Matériel et méthodes:
Cette série de cas a examiné 10 cas de décès subit chez des personnes âgées de 18 à 25 ans ayant des antécédents d’abus de drogues par voie intraveineuse. Les données ont été recueillies à partir d’examens post-mortem, d’enquêtes sur les lieux du décès et d’analyses toxicologiques et histopathologiques. L’objectif était de confirmer la MPE comme cause du décès et de comprendre sa présentation.
Résultats:
Les décès dans ces cas étaient fortement associés à des surdoses de drogue. Les enquêtes sur les lieux du décès ont révélé des signes d’utilisation de drogues par voie intraveineuse, tels que des traces et du matériel de consommation de drogue. Les examens externes et internes ont montré des résultats pathologiques cohérents, notamment des poumons œdémateux avec des sécrétions mousseuses, des réactions granulomateuses dans la vascularisation pulmonaire et une hypertrophie ventriculaire droite. Les analyses toxicologiques ont détecté des substances telles que le tapentadol et le tétrahydrocannabinol, avec des excipients liés à l’ELD trouvés dans les examens histopathologiques.
Conclusion:
Lorsqu’ils sont injectés, des excipients tels que le talc et la cellulose microcristalline entraînent des réactions granulomateuses et des complications pulmonaires. L’étude met en évidence la prévalence de l’ELD chez les jeunes adultes en Inde et les défis liés au diagnostic de cette maladie en raison de sa présentation non spécifique et du manque de divulgation des antécédents de toxicomanie. Des mesures de santé publique efficaces et une réglementation plus stricte des médicaments sur ordonnance sont essentielles pour prévenir les décès liés à l’ELD. Cette étude souligne les risques graves pour la santé associés à l’abus de médicaments IV sous forme de comprimés oraux, conduisant à l’ELD. Les résultats soulignent la nécessité d’une sensibilisation accrue, d’une documentation précise et de stratégies préventives pour lutter contre la toxicomanie croissante chez les jeunes en Inde.
INTRODUCTION
Excipient lung disease (ELD) refers to the acute or chronic lung complications that arise from the intravenous (IV) injection of crushed drugs designed for oral ingestion.[1] According to a 2018 survey on drug abuse by the general population conducted by the United Nations Office on Drugs and Crime, drug use is more prevalent among young people than older individuals. Adolescents aged 12–17 are particularly at risk for initiating drug habits, with usage peaking among those aged 18–25.[2] The Ministry of Social Justice and Empowerment’s “National Survey on Extent and Pattern of Substance Use in India 2019” estimates that approximately 850,000 people in India inject drugs. Commonly used substances include heroin, buprenorphine, pentazocine, and other sedatives. Recently, there has been an increase in the IV use of crushed oral sedatives and opioid analgesics, driven by their lower cost and easy over-the-counter availability in India. This form of drug abuse, which leads to ELD, is underreported in vital statistics due to its lack of recognition as a cause of death.[3] There is an urgent need for a population-based study to examine the incidence, awareness, and presentation of ELD, particularly about mortality.
ELD was initially linked to the IV injection of methadone by heroin abusers. Since then, a variety of other drugs have been associated with this condition, including hydrocodone, oxycodone, methylphenidate, amphetamine, and codeine. People with an addiction began injecting methadone tablets containing talc to enhance the drug’s effects.[4] In addition, various other analgesics, sedatives, and stimulants have been abused similarly. In some cases, antihistamines were used alongside the abused drugs to prevent nausea and vomiting.[5] Recent trends indicate a rise in the abuse of opioid analgesics such as oxycodone, tapentadol, and tramadol. However, opiate solutions intended for IV use do not cause ELD due to the absence of insoluble particulate matter.[6]
The clinical manifestations of ELD can include both acute and chronic complications, such as pulmonary hypertensive changes.[1] Patients often present with shortness of breath and centrilobular nodules in the lungs visible on a computed tomography scan, yet they frequently do not disclose their history of drug abuse, complicating diagnosis and treatment. Death in these patients can result from right heart failure, delayed hypersensitivity reactions, or respiratory failure due to pulmonary fibrosis. In some cases, drug intoxication may also cause death in individuals with ELD. Determining the exact cause of death remains challenging even when ELD is confirmed histopathological.[7]
To accurately ascertain the cause of death, it is crucial to consider the history of drug abuse, clinical and imaging findings, postmortem examination, the extent of pulmonary involvement in histopathology, and toxicological analysis to detect polysubstance abuse. This study focuses on cases of death among young adults due to drug abuse. The article aims to confirm the diagnosis of ELD resulting from the complications of intravenously injected crushed drugs intended for oral ingestion based on history, autopsy findings, histopathological features, and toxicological analysis, which are rarely reported in the medical literature.
MATERIALS AND METHODS
This case series involves 10 cases of sudden death in individuals aged 18–25 years of age, all with a history of IV drug abuse [Table 1]. Consent was obtained from a legally authorized relative and the investigating officer before performing the autopsies. The identities of the deceased individuals were kept confidential. Postmortem examinations in these medicolegal cases were conducted at the Department of Forensic Medicine and Toxicology, Government Stanley Medical College, Chennai, India. The study did not interfere with any autopsy findings or medicolegal procedures. The data were collected from the history of cases, autopsy findings, death scene investigation, external examination, internal examination, and histopathological and toxicological screening to confirm the diagnosis of ELD arising as a complication of the case of intravenously injected crushed drugs intended for oral ingestion.
| Case number | Age (years) and gender of deceased | Symptoms were present before the arrival at the hospital and brought dead at the emergency department with a known case of IV drug abuse |
|---|---|---|
| Case number 1 | 23 and male | Vomiting and loss of consciousness on sudden onset |
| Case number 2 | 23 and male | Stomach pain for the last 2 weeks and aggravated on the day of death of a patient |
| Case number 3 | 23 and male | Stomach pain, vomiting, and weight loss for the last 2 months |
| Case number 4 | 25 and male | Fever for 2 days |
| Case number 5 | 18 and male | Headache for the last 3 months |
| Case number 6 | 19 and male | Presence of seizure episode |
| Case number 7 | 25 and male | Presence of seizure episode |
| Case number 8 | 23 and male | Stomach pain and fatigue for the last 1 month |
| Case number 9 | 24 and male | Sudden loss of consciousness following IV drug intake |
| Case number 10 | 23 and male | Sudden loss of consciousness following IV drug intake |
RESULTS
This case series analyses 10 instances of sudden death, all strongly suspected to be caused by drug overdoses. The investigations included death scene examinations, external inspections, and internal autopsies to identify consistent patterns and underlying causes.
Death scene investigation
In most instances, the individuals were discovered unconscious or deceased either in or close to their homes, with several scenes showing evidence of IV drug use, such as empty drug blisters and indications of shared usage with friends: Cases 1, 3, 4, and 5 were found at their residences; Cases 6, 7, 8, and 9 were near their homes, with some being taken to the hospital postmortem; and Cases 2 and 9 were found in public or unusual locations, specifically on a terrace and on the road, respectively, Table 2.
| Case number | Death scene investigation | External examination | Internal examination |
|---|---|---|---|
| 1 | He was found unconscious at his residence. An empty blister of drugs was found | Track marks were present over both the right and left elbow [Figure 1a] | Thickening of cubital veins and blood extravasation were noted underlying the track marks [Figure 2a]. Lungs were found edematous, with frothy secretions from the congested cut surface |
| 2 | He was found dead on a terrace in his house; there is no evidence of IV drug usage | Thin built; nicotine stains over teeth; track marks were present over both right and left elbow [Figure 1b] | Thickening of cubital veins and blood extravasation were noted underlying the track marks [Figure 2b]. The lungs were found edematous, with frothy secretions from the congested cut surface |
| 3 | Found dead at this house; no evidence of IV drug usage | Thin built; multiple tattoo marks all over the body; track marks were present over both right and left forearm [Figure 1c] | Thickening of veins along with extravasation of blood was noted underlying the track marks; lungs were found edematous with frothy secretions oozing out from the congested cut surface. Diffuse small nodules were noted in lung parenchyma |
| 4 | He fainted at this home and was brought dead to the hospital | Moderately built with multiple old healed linear scars on both elbow | Partial occlusion of left anterior descending and circumflex arteries; multiple raised atheromatous plaques in the root of the aorta |
| 5 | Alleged history of IV drug use on the day of death at home; found unconscious in his room | No significant findings | Lungs were found edematous with frothy secretions oozing out from the congested cut surface |
| 6 | Found dead in a ditch near the house | Thin built with multiple tattoo marks all over the body; track marks were present over both right and left arm [Figure 1d] | Underlying the track marks, vein thickening, and blood extravasation were noted. The lungs were found edematous, with frothy secretions from the congested cut surface. Diffuse small nodules were pointed out in the lung parenchyma. Right ventricular hypertrophy was seen |
| 7 | He fainted near his home after injecting crushed travel and tidal tablets with his friend; he was brought to the hospital in an unconscious state and died in 2 h | Moderately built; old healed punctured wounds over both forearms and legs; needle puncture marks noted on the elbow [Figure 1e] multiple tattoo marks all over the body | Extravasation of blood was noted underlying the puncture mark. Lungs were found edematous, with frothy secretions from the congested cut surface. Right ventricular hypertrophy was seen |
| 8 | He fainted near his home after injecting drugs with his friend and was brought dead to the hospital | Moderately built with multiple old healed linear scars on the left forearm. Track marks with puncture marls were noted over the right and left elbow | Extravasation of blood was noted underlying the puncture mark. Lungs were found edematous, with frothy secretions from the congested cut surface |
| 9 | Found unconscious in the road; brought dead to hospital | Moderately built; track marks were noted over the right forearm, elbow, wrist, right and left knees, ankles, and foot | Thickening of blood vessels noted underlying the track marks. Right ventricular hypertrophy was seen |
| 10 | Found dead at this home | Thin built; thick, dark, and palpable vessel noted over the left elbow [Figure 3] | Thickening of underlying blood vessels noted |
External examination
Common findings across most cases include track marks from IV drug use, multiple tattoos, and nicotine stains: track marks were observed in Cases 1, 2, 3, 6, 8, and 9, indicating repeated IV drug use; multiple tattoos were noted in Cases 3, 6, and 7, possibly suggesting a lifestyle associated with high-risk behaviors; and nicotine stains were present in Case 2, indicating chronic smoking [Table 2].
Internal examination
The consistent findings from internal examinations revealed significant pathological changes, particularly in the lungs and cardiovascular system: edematous lungs with frothy secretions from the congested cut surface were common in nearly all cases (1, 2, 3, 5, 6, 7, 8), with diffuse small nodules in the lung parenchyma noted in Cases 3 and 6; thickening of veins with blood extravasation was observed at the sites of track marks in Cases 1, 2, 3, 6, 7, 8, and 9; right ventricular hypertrophy was present in Cases 6, 7, and 9, and Case 4 showed partial occlusion of major arteries and multiple raised atheromatous plaques in the root of the aorta [Table 2].
Histopathological findings
The positive findings of IV drug abuse in all cases and its interpretation are mentioned in Table 3.
| Case number | Histopathological findings and its interpretation | Toxicological interpretation | Cause of death |
|---|---|---|---|
| 1 | Foreign-body granulomatous reactions in both lung parenchyma and pulmonary vasculature along with features of pulmonary edema [Figure 3a]. Sections from both cubital veins showed features of thrombophlebitis with foreign-body granuloma. The granuloma in both lung and cubital veins contained basophilic material | Tapentadol was detected in the blood, liver, and kidney, and ethyl alcohol in the stomach, intestine, liver, kidney, and blood | IV injection of particulate substances, which led to granulomatous inflammation in the lungs and vascular complications, contributing to the overall toxic effects and resulting in sudden death |
| 2 | Angiocentric granulomas filled with basophilic material in lungs-ELD | They detected tetrahydrocannabinol in blood, urine, liver, and kidney | Injection of drugs with excipients that caused localized inflammatory reactions in the lungs, leading to severe pulmonary complication |
| 3 | Foreign-body granulomatous reaction filled with basophilic material in lungs and pulmonary vasculature [Figure 3b]; basophilic material surrounded by foreign-body giant cell reaction and mononuclear inflammatory infiltrates in the vein from arm; gastric mucosa showed erosions | Negative | IV drug use, which led to systemic granulomatous inflammation |
| 4 | Pulmonary edema with foreign-body granulomatous reaction filled with pale gray material in both parenchyma and vasculature | Negative | Severe pulmonary inflammation and edema, likely due to the IV injection of foreign substances |
| 5 | Foreign-body granulomatous reaction filled with lung and pulmonary vasculature basophilic material and emphysematous changes [Figure 3c] Foreign-body granulomatous reaction in a vessel of the left forearm [Figure 2c] | Detected tapentadol in the liver, kidney, and blood | Extensive granulomatous inflammation and lung damage resulting from IV drug use |
| 6 | Foreign-body granulomatous reaction filled with basophilic material in lungs and its vasculature; hemosiderin-laden macrophages and pulmonary arteriole dilatation also seen; granuloma with similar morphological features as in lungs [Figure 2d] and chronic inflammatory cells in vessels from arm along with features of thrombophlebitis | Detected tapentadol is in the blood, stomach, intestine, liver, and kidneys | Chronic IV drug use leads to persistent inflammatory responses and vascular changes |
| 7 | Foreign-body granulomatous reaction filled with basophilic material in lungs and its vasculature; hemosiderin-laden macrophages and pulmonary arteriole dilatation also seen; granuloma with similar morphological features as in lungs and chronic inflammatory cells in vessels from arm along with features of thrombophlebitis | Detected tapentadol in the blood, brain, liver, and kidneys | Chronic IV drug use leads to persistent inflammatory responses and vascular changes |
| 8 | Angiocentric granulomas filled with pale gray material in lungs-ELD [Figure 2e and f]; cubital veins showed features of thrombophlebitis | Detected tapentadol in blood, liver, and kidneys; ethyl alcohol in stomach, intestine, liver, kidneys, and blood | We have localized inflammatory responses to injected excipients and associated vascular inflammation |
| 9 | Angiocentric granulomas filled with basophilic material in lungs-ELD; hemosiderin-laden macrophages also seen. Cubital veins showed features of thrombophlebitis | Detected tapentadol in the blood, brain, liver, and kidneys | IV drug use leads to pulmonary and vascular inflammation |
| 10 | The cubital vein showed features of thrombophlebitis | Detected tapentadol in blood, brain, liver, and kidneys | IV drug use leading to pulmonary and vascular inflammation |
Toxicology investigations
The toxicological analyses revealed the presence of various substances correlating with the histopathological findings: tapentadol was detected in multiple cases (1, 5, 6, 7, 8, 9, 10), indicating widespread use among the deceased and suggesting IV injection of substances with excipients that can lead to granulomatous reactions; ethyl alcohol was found in Cases 1 and 8, indicating concurrent alcohol consumption that may have exacerbated the toxic effects of other substances; and tetrahydrocannabinol was detected in Case 2 suggesting marijuana use, which might have contributed to or interacted with different health conditions [Table 3].
DISCUSSION
Excipients are insoluble, inert substances used as fillers and binders in oral tablets to shape, protect active ingredients, and aid disintegration. Examples of excipients include talc, starch, microcrystalline cellulose, and crospovidone.[8] When these excipients are crushed and injected, they enter the pulmonary circulation and due to their size (ranging from 5 to 200 μ), become filtered and deposited in arterioles and capillaries.[9] These micro-emboli can provoke a foreign-body giant cell reaction and granuloma formation in intravascular and perivascular areas. Over time, these granulomas can lead to pulmonary hypertension and cor pulmonale, resulting in sudden death.[5] Additional complications may include pulmonary fibrosis and delayed hypersensitivity reactions.
ELD generally affects men in their 40s.[4] However, a study by Hossein-Zadeh et al. found that three out of five affected individuals were female, with the remaining two cases being male.[1] In our study, all reported cases were males aged 18–25. This condition is often seen in patients with chronic illnesses such as malignancy, seizures, or psychiatric disorders due to easy access to drugs that can lead to dependence and addiction.[9] In our series, two cases involved individuals with seizure disorders who were undergoing treatment.
More often, the history of drug abuse is not disclosed by relatives in cases of death at a young age. In this study, out of 10 cases, six had a known history of IV drug abuse. Five cases exhibited multiple tattoo marks on their bodies, a common practice among IV drug users to conceal track marks. Track marks in IV drug abusers are typically found on the upper and lower limbs and result from sclerosis of the underlying blood vessels due to thrombophlebitis from repeated injections. These marks usually appear black, with discoloration caused by postinflammatory hyperpigmentation.[10] In this study, six cases displayed typical track marks; one had a thickened and darkened vessel in the elbow, one had old healed puncture marks, and two had no notable external findings. All seven cases with track marks showed blood extravasation beneath the marks, suggesting recent IV use. In addition, five cases had foreign-body granulomas in the vessels beneath the track marks, and six cases showed features of thrombophlebitis in those vessels.
Studies by Chute et al. reported that the lungs exhibited diffuse small nodules throughout the parenchyma, giving a sandpaper-like texture.[11] In this case series, two cases displayed similar features. The diagnosis of ELD is confirmed by identifying intravascular and perivascular granuloma formation and determining the type of exogenous material involved.[12] All 10 cases in this series showed foreign-body granulomas filled with basophilic material in both the pulmonary vasculature and parenchyma surrounding the vessels. In addition, four cases exhibited right ventricular hypertrophy and hemosiderin-laden macrophages, indicating right heart failure and pulmonary hypertension. Sudden and unexpected deaths due to pulmonary hypertension and right ventricular failure have been documented in ELD.[13] Pulmonary arteriole dilatation was also observed in three cases, further suggesting pulmonary hypertension.
Common excipients include talc, starch, crospovidone, and microcrystalline cellulose. Historically, talc was the most frequently implicated excipient in ELD, but with the advent of newer oral narcotic tablets, microcrystalline cellulose has become more prevalent.[8] Each excipient has distinct characteristics, such as size, histochemical features, and polarization,[59] summarized in Table 2.
The intensity of the angiogranulomatous reaction and the distribution of excipient particles to various organs depending on their size. Talc tends to migrate to the perivascular tissue through macrophage engulfment or increased hydrostatic pressure, resulting in higher concentrations in the perivascular region rather than the intravascular region.[14] Due to their smaller size, talc particles can pass through capillaries into the pulmonary veins and deposit in other organs. Starch is rapidly removed from the lungs and shows minimal granulomatous reaction, so its presence in biopsy samples typically indicates a recent drug injection.[15] Microcrystalline cellulose and crospovidone are more significant and less likely to migrate from the lungs to other organs.[1617] While histochemical analysis is generally adequate for identifying excipients due to its accessibility, lower cost, and efficiency, different techniques such as polarization microscopy and infrared spectroscopy can be used but are more expensive and time-consuming.[918] In our case series, eight cases showed basophilic material suggestive of crospovidone, whereas two instances exhibited pale gray material indicative of microcrystalline cellulose in the angiogranulomas. Further studies with special stains and polarization microscopy are needed to precisely identify the excipients in each case.
In this study, tapentadol, an opioid analgesic, was found in six cases, and tetrahydrocannabinol in one case. Routine quantitative analysis of these drugs is not conducted in our facility. While the presence of drugs is identified through toxicological analyses, establishing acute drug toxicity as the cause of death requires correlating blood drug concentrations with the deceased’s tolerance levels. Thus, identifying ELD through histopathological examination assists forensic experts in attributing death to chronic drug abuse. The investigation of these 10 cases reveals a strong association with IV drug use, as evidenced by track marks, thickened veins, and blood extravasation. The consistent finding of edematous lungs with frothy secretions indicates acute pulmonary edema, likely due to overdose. In addition, right ventricular hypertrophy, in several cases, suggests chronic cardiac strain, potentially from repeated drug use. These findings underscore the severe health consequences of IV drug use and highlight the critical need for effective public health strategies to address substance abuse and provide support to those at risk.
CONCLUSION
This study highlights the risks associated with IV drug abuse involving oral tablets, leading to ELD. While cardiac pathology often accounts for common deaths among young adults, this series reveals cases where ELD, an under-recognized and overlooked issue, was the cause of death. This condition poses a challenge for clinicians due to its nonspecific symptoms and incomplete medical histories. Forensic pathologists also struggle to determine the cause of death without considering ELD as a potential factor.
In India, where pharmaceutical drugs like analgesics are readily available over the counter compared to other countries with stricter regulations, there is a need for rigorous monitoring of prescription drug distribution to prevent deaths related to ELD. Toxicological analyses may fail to detect drugs due to their low doses and timing of intake. In such cases, histopathological examination of pulmonary vasculature can be crucial for identifying excipients and determining the cause of death. Reporting ELD as a cause of death is vital to raise awareness, especially given the rising substance abuse among children and adolescents in India.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest
There are no conflicts of interest.