Low CD4 T cell count was the dominant predictor of infectious pulmonary diagnoses in multi-variable analyses, yet the association between marijuana smoking and infectious pulmonary diagnoses remained significant in adjusted analyses restricted to visits with CD4 ≥ 200 cells/μl, and sensitivity analyses with no CD4 restriction. Tobacco smoking, reported during follow-up for 44% of HIV+ participants, was a stronger risk factor for chronic bronchitis in HIV+ participants compared to marijuana smoking, while for infectious pulmonary diagnoses in HIV+ participants, the risk associated with ≥1/2 pack/day tobacco smoking was comparable to that of daily or weekly marijuana smoking.Strengths of this study included the large sample size, large number of diagnoses reported, and substantial length of follow-up.Men at risk for HIV are recruited by the MACS from four U.S. urban sites, and thus HIV-infected participants share similar demographic and lifestyle characteristics with uninfected participants. HIV+ and HIV− participants reported substantial daily or weekly marijuana smoking,which allowed assessments of both current and average exposures during follow-up. The sample size allowed for stricter control of tobacco smoking with large numbers of participants in stratified analyses,which may in part explain the lack of association between marijuana smoking and pulmonary disease among HIV− individuals found here compared to previous studies. Injection drug use is a possible risk factor for lung disease among HIV-infected persons, and poly drug use is common in HIV-infected individuals, and we therefore excluded heavy cocaine and heroin users from our analysis to reduce the potential for competing risks from multiple inhaled or injected substances. Limitations of this study include those inherent to longitudinal prospective cohort studies, including the potential for findings to be specific to MSM populations recruited by the MACS, and for nonrandom dropout and ascertainment biases.
Measures of cannabis grow tent intake were limited to self-report during follow-up, with limited detail regarding exposure prior to MACS enrollment or marijuana potency, source, or quantity. These concerns are mitigated in part by the use of three separate measures of marijuana smoking,all of which were associated with infectious pulmonary diagnoses and chronic bronchitis in models of HIV-infected participants. Furthermore, the proportion of daily or weekly HIV+ marijuana smokers here is comparable to reports from other U.S. cohorts of HIV-infected individuals.The use of self-reported pulmonary symptoms and diagnoses is an additional potential source of bias, and possible under-representation of specific non-infectious diagnoses in the MACS, particularly COPD and pulmonary hypertension, has been reported. Most diagnoses were not assessed from both self-report and ICD-coded sources. This limitation was mitigated in part because most diagnoses were obtained from ICD code data, which consists of more specific diagnosis classifications.Potential ambiguities regarding terminology for diagnoses, and discordance between highly prevalent pulmonary symptoms and low rate of pulmonary diagnostic testing among HIV-infected persons has been noted in other clinical settings, and is mitigated here in part by use of composite diagnoses. The number of diagnoses reported for several categories, including tuberculosis, lung cancers, and Pneumocystis pneumonia, was small and lacked statistical power to assess an adjusted association with marijuana or tobacco smoking. In summary, we found a significant association between long-term marijuana smoking and risk of infectious lung disease and chronic bronchitis in HIV-infected men on ART, independent of tobacco smoking and other risk factors.In contrast, we detected no association between marijuana smoking and lung disease among HIV-uninfected men while controlling for tobacco smoking and other demographic characteristics. These findings suggest that marijuana smoking is a modifiable risk factor that healthcare providers should consider when seeking to prevent or treat lung disease in people infected with HIV, particularly those with other known risk factors including heavy tobacco smoking, and low CD4 T cell count or advanced HIV disease.
Given increasing trends of regular marijuana smoking among HIV-infected people and other high-risk populations in the U.S. and other developed and developing countries, more studies are needed to evaluate potential merits of non-smoked rather than smoked forms of marijuana for medicinal and other purposes.Ms. A, a 48-year-old woman with a history of cholecystectomy complicated by bile duct stricture and multiple hepatic abscesses and liver failure was evaluated for an orthotopic liver transplant. She had a psychiatric history of depression and anxiety, with a brief inpatient hospitalization after cutting her wrists 6 months before her transplant. She then had 1 month of outpatient therapy. During a pretransplant psychiatric evaluation, she reported no illicit drug use. Outpatient medications included opioid analgesics and cyclobenzaprine for pain, as well as zolpidem for insomnia secondary to abdominal pain. Ms. A was admitted to the hospital and received a trisegmental orthotopic liver transplant. She was monitored postoperatively in the surgical intensive care unit and started on 2 agents for immunosuppression as well as broad spectrum antibiotics and anti-fungal agents. The pain management service was consulted for postoperative pain control given her dependence on opioid analgesia as an outpatient. Per their recommendations, she was started on a hydromorphone PCA.Her transaminases and coagulation studies were reassuring and she was stable enough to be transferred out of the intensive care unit on post-transplant day 3. That same day, she was started on tacrolimus at 2 mg q12 hours. A serum tacrolimus level taken the next morning was 7.7 ng/mL which was at goal. On post-transplant day 5, the transplant psychiatry service was consulted for agitation and deliriumspecifically, she was oriented only to herself, had disorganized speech, was observed to be responding to internal stimuli and was exhibiting psychomotor agitation in the form of purposeless shifting and fidgeting.
Her vital signs were significant for tachycardia and absence of fever. Laboratory testing revealed a significant increase in her tacrolimus level to 17.2 ng/mL despite no changes in dosing. Labs were otherwise stable.Ms. A’s encephalopathy was felt to be secondary to tacrolimus toxicity, though the reason for the change in the tacrolimus level was initially unclear. Her tacrolimus was held and the psychiatry team recommended low-dose quetiapine as needed for agitation to avoid use of restraints and to mitigate the risk of decannulation or removal of other lines. Later that night, Ms. A’s tachycardia, disorientation, and confusion worsened, and she required 2 doses of IV haloperidol. By post-transplant day 7, her encephalopathy began to resolve, with improving orientation and less psychomotor agitation. Her serum tacrolimus level was downtrending to 7.3 ng/mL and she was restarted at a dose of 1 mg q12 hours. At this time, Ms. A’s family mentioned that as her preoperative pain was poorly controlled by various opioids, she had sought pain management from a medical marijuana clinic in a neighboring state where medical marijuana was legalized. A urine drug screen confirmed her use of cannabinoids. Ms. A produced a bottle of medical marijuana lozenges from her purse at the bedside. The bottle indicated that each lozenge contained 10 mg of tetrahydrocannabinol and 1 mg cannabidiol. She had filled the bottle 10 days before admission, and reported taking 24 lozenges per day up until her transplant, though she denied taking any during admission. She denied any other previous marijuana use. On post-transplant day 9, her level was stable at 3.4 ng/mL and her dose was titrated to 2 mg q12 hours. Ms. A was advised to discontinue cannabis usage due to concern for drug-drug interactions. Her postoperative care was uncomplicated by subsequent mental status issues. Her tacrolimus dosage remained stable at 3 mg po q12 and her level remained at goal, most recently 7.4 mg/mL.Marijuana is the most commonly used illicit substance in the US. In the past decade alternative formulations of its active ingredients have been adopted in many states for the treatment of various medical conditions, including chronic pain.In this case, our patient was seen in a medical marijuana clinic by a pain specialist who was registered with the New Jersey Medical Marijuana Treatment Program.
Under this program, patients must be found to have an “approved debilitating medical condition” that has either been demonstrated to be treatable by cannabis or has not responded to conventional treatment. Our patient met criteria for “chronic pain of visceral origin.” She was able to obtain the lozenges at a licensed dispensary affiliated with her doctor’s office. Anecdotal reports of marijuana use leading to decreased reliance on opioid pain medications have led to new investigations into its analgesic effects. One case study from 2016 described the use of marijuana to wean opioid use in a patient who had received an orthotopic liver transplant.Additionally, while many proponents of marijuana’s analgesic properties distinguish between the potential therapeutic effects of its 2 major ingredients, tetrahydrocannabinol and cannabidiol, it is unclear whether their pharmacokinetics differ meaningfully.In vitro studies have demonstrated tetrahydrocannabinol and cannabidiol to be CYP 3A4 substrates and there is some evidence that they act as inhibitors as well.A case report from 2006 described myocardial infarction in an otherwise healthy 41-year-old man after concomitant use of sildenafil and grow lights for marijuana, thought to be due to 3A4 inhibition.Additionally, constituents in marijuana have been shown both to inhibit or induce P-glycoprotein, which could then interfere with the absorption and distribution of medications like tacrolimus.As mentioned above, the resultant variability in tacrolimus levels not only leaves the potential for neurotoxicity, but it is also associated with worse graft survival.The evaluation and treatment of encephalopathy in post-transplant patients are similar those for delirium in the general postoperative patient, with the additional consideration of immunosuppression as a unique factor. While haloperidol and quetiapine are 3A4 substrates, they are not known to interfere with the metabolism of tacrolimus, and their metabolism is not impaired in patients with poor liver function when used conservatively. There is a case report of QT interval prolongation leading to arrhythmia in a patient receiving both tacrolimus and haloperidol, though tacrolimus is less likely to prolong QT independently when compared to other immuno suppressants.
The increased prevalence of both recreational and medical marijuana use represent challenges to safe immunosuppression in post-transplant patients. Since medical marijuana is not consistently monitored between states and is not thought of universally as a legal medication, it can easily be overlooked as part of medication reconciliation. Additionally, as medical marijuana therapy remains a controversial topic among providers, there is significant stigma attached to its use.In one study, 10.4% of transplant candidates used cannabis, and were found to be less likely to receive a transplant despite similar survival rates to those who did not.The perception that disclosing marijuana use could hurt her chances at receiving a transplant was likely a factor in our patient not disclosing it to her transplant team. Emerging research on cannabinoids suggest that they offer immunosuppressive effects independently which further complicates their use in patients where tightly controlled immunosuppression is necessary for healthy recovery.Marijuana use is widespread and increasing. In the 2015 National Survey on Drug Use and Health, 8.3% of respondents said that they had used marijuana in the past month. As of April 2018, 30 states, the District of Columbia, Guam and Puerto Rico had passed medical marijuana laws permitting programs public medical marijuana. The total number of medical marijuana patients is unknown but estimates place the number at greater than 2 million patients in the United States. Marijuana refers to the dried leaves and flowers of the Cannabis sativa plant, which are rich in phytocannabinoids. The plant is grown either indoors or outdoors before it is harvested, cured, and dried. Molds may be present and can multiply under conditions of high moisture as with inappropriate watering, humidity or ventilation or inadequate drying and curing. Mold spores may survive the drying and curing process even under ideal conditions.Marijuana obtained from medical dispensaries does not differ significantly with regards to microflora when compared to illicit marijuana. One analysis of twenty marijuana samples obtained from dispensaries in northern California showed the presence of 20 fungal genera including Aspergillus, Cryptococcus, and Mucor as well as several bacterial pathogens such as Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Previous case reports have documented cases of pulmonary aspergillosis associated with marijuana smoking in immunocompromised patients.