Opioid use disorder and infectious complications in persons who inject drugs

To fully understand the modern opioid epidemic and the magnitude of the public health challenges that it encompasses, one has to first understand the scale of the crisis. Opioids have had a place in human usage for millennia and are one of the oldest known classes of drugs both medically and recreationally; there are references seen throughout ancient history alluding to their beneficial (and less desirable) properties. In the United States, there have been waves of addiction over time, notably as sequelae of medical prescribing. For example, in the 19th century, with widespread dissemination of morphine as a miracle drug, iatrogenic addiction drove a crisis peaking at roughly 4. 6 opioid-addicted individuals per 1000. 1 With advances in medical knowledge and more circumspect prescribing behavior, and efforts to limit sales, this epidemic abated. Further intermittent waves through the 20th century tended to arise from nonmedical use in urban areas, disproportionately impacting people of color. 1 The late 1980s through the early 2000s marked the nascent stages of the current epidemic. In brief, a myriad of factors—including the promotion of pain as the “fifth vital sign” by several prominent medical societies and the rise of new formulations of medications that had purportedly low addictive potential—led to aggressive opioid prescribing practices. 1 Both in acute and chronic settings, prescribing sky-rocketed. In the span of 15 years (1999-2011), consumption of oxycodone went up nearly 5-fold. 2 As has become apparent, the consequences of the exuberant opioid prescribing for expanded indications have been dire. Three separate waves of the current epidemic have been described: the first involving prescription opioids in the 1990s, the second beginning around 2010 as individuals transitioned to heroin in the wake of stricter prescribing, and the third beginning in 2013 as synthetic opioids (especially fentanyl) became more prevalent on the black market. 3 As it stands, per last available data in 2018, 2. 9 million individuals in the United States reported misuse of a prescription pain medication within the past month; 2. 0 million people had a concomitant DSM-IV diagnosis of opioid use disorder (OUD) or dependence in the past year; and 5. 1 million people have tried heroin in their lifetimes. 4 In 2014, as rates of opioid-related overdoses soared, 5 the Centers for Disease Control and Prevention (CDC) named the epidemic one of the top 5 public health challenges facing the United States. Much of the focus nationally has centered on overdose prevention, with good reason. Per last available data, there were roughly 47, 600 deaths directly attributable to opioid overdose in 2017, comprising 67. 8% of all drug overdose deaths in the country. 6 In context, opioid overdose alone therefore ranks among the top 10 causes of all-cause mortality in the United States. 7 The incidence of death has unfortunately increased broadly across age groups, racial/ethnic groups, and in both rural and urban areas with an overall increase of 9. 6% from 2016 to 2017, suggesting that the tide of overdose deaths has yet to turn. 1, 6 Overdose alone, however, does not adequately capture the scope of morbidity and mortality attributed to the current opioid epidemic. In recent years, there has been increasing alarm surrounding the infectious complications of OUD, especially as relates in persons who inject drugs (PWID). An estimated half-million to 1-million persons inject annually, and hospitalizations for injection drug use (IDU) -related infection have increased in the last several years. 8 Concern falls largely along 2 avenues: disease that is introduced from the environment (ie, bacterial and fungal infections) and disease that is transmitted between individuals ie, viral illnesses such as human immunodeficiency virus (HIV) and the hepatitides. In both scenarios, contamination of the drug product, injection equipment, and unsterile technique play a significant role. These infections have serious consequences, both for the individual and from a larger public health perspective. IDU is known to be a driver of HIV infection, currently representing 9% of new diagnoses per year; clusters and outbreaks of IDU-associated HIV have made national headlines in recent years. 9–11 Hepatitis C (HCV) continues to present a serious challenge as well—nationally, an over 2-fold increase in acute HCV infection over the past decade is attributed to increases in IDU. 12 Meanwhile, serious bacterial/fungal infections are on the uptrend. A recent study found that hospitalizations for infective endocarditis (IE), osteomyelitis (OM), septic arthritis, and/or spinal epidural abscess in individuals with known OUD doubled from 3421 annually to 6535 over the 2002-2012 period, whereas total hospitalizations remained constant; costs associated with these hospitalizations increased from 191 to 701 million. 13 With respect to hospitalizations for OUD without infection, individuals were more likely to die while inpatient during these stays, and stays were 4-fold more costly. 13 Even for comparatively less life-threatening infections, such as skin and soft tissue infection (SSTI), high burden of disease proves daunting; an estimated 44% of all PWID have had an SSTI during their lifetime, and other studies suggest even higher prevalence. 14 The significant impact of both life-altering medical conditions and cost to the medical system necessitates that the infectious complications of OUD receive particular attention as a crisis within the overarching epidemic of opioid use in this country. In this review, we will focus on infectious complications of OUD by examining mechanisms of transmission, further define the specific types of infection noted above, and detail the unique challenges posed by serious infection in the setting of OUD. Mechanisms of transmission Opioids can be taken in many ways, including ingestion, insufflation (“sniffing” or “snorting”), inhalation or smoking, injection into the soft tissues (“muscling” or “skin-popping”), and intravenous injection (mainlining). There can be non-negligible spread of infection due to sequela of the substance’s psychoactive effects and addictive potential, particularly in the case of sexually transmitted infections such as HIV and HCV. However, as noted above, primarily, infection is transmitted due to contamination during the multi-step process of injection, which will be the focus of our discussion. There are multiple pieces of equipment (works) that are common or necessary for injection. These include needles, syringes, “cookers” or “spoons, ” “cottons, ” and water. Typically, the syringe is used to draw up water, which is placed into the cooker or spoon with the substance. Common cookers include bottle caps or an actual spoon. Heat is applied from below to aid in the dissolving process, and a piece of the syringe may also be used to stir the solution. Citrus peels or juice (lemon or orange) may be added to help acidify the solution, which further aids in dissolving the substance. A “cotton” (frequently cotton from a Q-tip or cotton ball, but also possibly cigarette filters) acts as a filter—it is placed in the cooker, absorbing the solution. The syringe tip is then advanced into the cotton and retracted to resorb the solution. The area of the body that will be injected is then cleaned with alcohol, the needle is inserted, and the substance is injected. 15 As is evident, there are many aspects to the above process that are susceptible to contamination. Compounding risk attributed to IDU is the practice of needle and syringe sharing, or reuse; even if needles are not shared with other individuals, they are often reused multiple times. This not only contaminates the equipment but also dulls the needle, which may cause more trauma at the site of injection and predispose to infection. As a result, efforts at improving access to new needles have been on the rise. Still, the rest of the process raises high concern. Cookers, cottons, and water are all commonly shared between individuals and reused. Cookers can be cleaned with bleaching solutions, but how frequently this is performed is unclear. The water that is used to dissolve the solution typically is not sterile, and manipulation of the solution with other objects contaminates it regardless. Acidifying the solution with citrus, although more common with crack cocaine, is frequently done with brown heroin—this has been known to cause disseminated fungal infections. 16–18 The efficacy of filtering large particulate matter through cottons is unclear, but drawing a substance up through unsterile material also poses an infection risk; use of cigarette filters or pocket lint likely exacerbates this risk. As there is likely residual drug in the cotton after use, PWID also commonly save the used cotton to further extract any retained substance at a future date. This further exposes the individual to contamination. 15 Interestingly, the different forms of heroin specifically may be linked to increased risk for certain infections. Heroin comes primarily in 3 forms—white, black tar, and brown—which have differing degrees of solubility in water, necessitating the addition of acid (as above) or heat. White powder heroin is easily dissolvable, facilitating intravenous injection; black tar and brown are less so. As a result, HIV prevalence in PWID is higher in cities where white powder heroin is endemic compared with black tar. 19 In contrast, there is an association with SSTIs with both black tar and brown heroin, likely due to more difficulty with intravenous administration. 19, 20 Bacterial/fungal infections There are multiple hallmark bacterial/fungal infectious complications of IDU. These include bacteremia, IE, OM, spinal epidural abscess, septic arthritis, and SSTIs (Table 1). Table 1: Common bacterial infections and causative organisms in persons who inject opioids. Bacteremia/fungemia Bacteremia is an unsurprising complication of IDU, and frequently presents concomitantly with other infections. Causative organisms range from expected skin or oral species including Staphylococcus aureus, Streptococcus spp. , Candida spp. to more uncommon organisms such as Bacillus cereus. 21–24 It is noteworthy that one common phenomenon, “cotton fever, ” refers to a self-limited syndrome that produces a systemic inflammatory response syndrome-like response. Individuals who report utilization of cottons as a filter sometimes develop fever, myalgias, nausea, vomiting, etc. , within half an hour of injecting; they are also frequently found to have brief lab abnormalities including leukocytosis. However, infectious workup can be negative and the syndrome resolves within 12 hours. It is still unclear why this occurs, but the leading theory (the endotoxin theory) posits that a transient bacteremia occurs with Enterobacter agglomerans, which colonizes cotton and releases endotoxins. Alternate theories include an immunologic response (in some individuals who have preformed antibodies against cotton) or a pharmacologic response (pyrogenic substances within cotton may cause the reaction). 25 Infective endocarditis IE can present somewhat differently in PWID compared with the general population. Although it has been recently noted that there is an increasing proportion of PWID who develop left-sided IE (or involvement of multiple valves), classically, right-sided heart valves are more frequently involved. 26, 27 Ninety percent of right-sided IE occurs in PWID, whereas this group only comprises 20% of left-sided IE. 27 There are several hypotheses for why this may occur—adulterants in substances (eg, talc) may cause endothelial damage to the tricuspid valve predisposing to infection, and repetitive IDU itself may cause subclinical damage. Right-sided IE leads to a higher rate of septic pulmonary emboli. The peripheral emboli and immunologic vascular phenomena typically associated with left-sided IE are seen less frequently. In addition, acute IE generally evolves too quickly for these phenomena to develop regardless; the most common symptoms are nonspecific constitutional ones. 28 As a result, high for IE even in the of the IDU itself as a the high risk. It is noteworthy that although with a may large the for IE is only advances in if a negative the Common in PWID with IE include aureus, and that skin introduced through an unsterile injection infections can be as can organisms from the environment including including Candida the less of peripheral the high of for and symptoms of infection at other such as the (eg, (eg, or and (especially As with IE in other groups, IE intravenous and of infections may be to with a alone, but a of is to oral has not yet been area of PWID who valve for an of the and of OUD, IDU can predispose to valve As a result, there is a for medical alone, but be in with heart due to tricuspid infection with or over pulmonary septic emboli medical or general of response to medical is over valve for osteomyelitis generally occurs through spread and is typically is the although are found in roughly of In PWID, this and and can as of the occurs with or taken from more such as of any associated may be in less half of the are the as a with a likely as noted above can the for however, these are frequently to increase be is if the is of the a of of is of certain oral are not for the be in who have of disease medical alone, with new associated with of OM, or actual due to or or epidural abscess for infection, are frequently in these however, there are data to epidural abscess epidural abscess with OM, with mechanisms of is as with comprising from to of organisms include and is more common in In to OM, early or of the is in In one of only with medical had or In with there is less to while as alone will likely not the of an of is also compared with OM, with a of to if there is OM, however, of be as have not been presents primarily due to as during IDU is and are especially are also more in PWID, although to a in the above and is necessary for and for on the this may be by needle or possibly the has not been but a of if the individual not have concomitant bacteremia and a oral is available for the it is to a to of the with oral and soft tissue infection SSTI the from and abscess, to infection. to in the setting of injection into the tissue due to in a or with or less other infections above, they are one in found that of PWID had had an abscess and of individuals had an SSTI noted on at the of study in noted that of PWID who were for an infectious were for is due to aureus, which is the causative in up to of However, they can be such as and are also frequently seen in PWID, as needles are sometimes There have been case of spp. and is typically for although if there is for more systemic infection or a of is is typically by Streptococcus or group A and such as can help between or and these SSTI may become by infections, such as In one involving PWID half of all of over 15 there were significant in compared with infections Hepatitis A Hepatitis A is an infection that through Although outbreaks have been attributable to recent outbreaks associated with drug use and a in the of this As all people who use drugs be for Hepatitis Hepatitis is a infection that through and there are million PWID estimated to be with In the United States, as the overall incidence of virus in the United States has due to the of the the proportion of incidence attributable to drug use has with outbreaks in particularly marked in with access to OUD and such as needle and syringe people who use drugs be for and if Individuals with be per the Hepatitis C Hepatitis C is a chronic infection, which through and As of C virus (HCV) is for more deaths in the United States the other nationally infectious of PWID are HCV with IDU representing the of HCV transmission in the United HCV incidence in the United States has the opioid with a increase in acute HCV among to between and 2014, with an increase in for injection of prescription opioids and a increase in for heroin In addition, there has been an increase in HCV prevalence among of with a increase in the rate of HCV infection among Although there is to HCV infection, of opioid the incidence of in in with syringe The recent of oral HCV with effects in over of with an to of of HCV in people with OUD have high rates of in people on and with recent IDU, with rates not by drug use at the of In addition, of to HCV has been associated with rates of HCV and risk in people with OUD and Although the rate of HCV is around among people with recent drug of and of access to HCV for people with OUD further prevalence and in this receive HCV at with in individuals with risk individuals with HCV be HCV and without on drug HIV HIV infection linked to IDU typically occurs in of 10 new infections. 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