Heart Gray

The opioid epidemic is cutting a wide swath through American life and culture as individuals struggle not only with their dependence on and abuse of painkillers but also experience financial, social, and emotional fallout from their conditions. Added to these challenges is a growing health menace: drug use-associated (DUA) infectious diseases, which are on the rise across a range of disorders. For example, acute hepatitis C virus infections in the United States more than doubled between 2004 and 2014, with more than 75% of patients reporting injection drug use in recent years. In addition, 2015 was the first year in more than 2 decades in which the number of HIV diagnoses attributed to injection drug use grew.

DUA hepatitis and HIV infections are not the only ones increasing. A less well-known type of DUA infection also is on the uptick: infective endocarditis (IE). A recent study conducted in North Carolina found that annual hospitalizations for DUA IE in that state rose roughly twelvefold between 2007 and 2017 (Ann Intern Med 2019;170:31-40). Similarly, researchers at the University of Virginia in Charlottesville noted a “dramatic increase” from 2000 to 2016 in DUA-IE-related hospitalizations at that institution (BMC Infect Dis 2018;18:532).

“The rise in endocarditis is making it clear that overdoses are not the only public health concern related to drug use,” said Asher Schranz, MD, an infectious disease specialist at the University of North Carolina in Chapel Hill and lead author of the North Carolina study. Based on their findings he and his colleagues averred, “[DUA]-IE is a critical, emerging public health issue that is affecting the lives of young persons, burdening health systems and public insurance payers, and fundamentally reshaping the epidemiology and management of endocarditis.”

A New Patient Profile

Patients with DUA IE have a strikingly different profile from patients with IE that is not associated with drug use. First, patients with DUA IE are typically decades younger. In addition, Staphylococcus aureus is more often the cause of their IE, and this pathogen results in particularly severe infections and worse post-surgical outcomes. This may help explain the longer, more expensive hospital stays of patients with DUA IE. Finally, patients with DUA IE may require multiple heart valve surgeries, either because of recurrent IE due to continued drug use or because of normal deterioration of the prosthetic valves they have received to repair the damage to their hearts.

Changing Patterns of Drug Use Driving Cases

In Canada, researchers have found that the increase in DUA IE cases has paralleled the use of hydromorphone; these controlled-release pills are more difficult to dissolve and inject than the opioid formulations that came before them (CMAJ 2019;191:E93-9). “Cookers and filters used to prepare the drug are frequently contaminated with S. aureus,” said Mike Silverman, MD, chief of infectious diseases at St. Joseph’s Hospital and London Health Sciences Centre in Ontario, and senior author of the article describing that research. “The contamination seems to be related to the complex method used to prepare the drug, as well as drug excipients that keep S. aureus viable longer.”

The growth in cases in the United States may result from different patterns of drug use. “There was more injection of prescription narcotics and heroin earlier in the epidemic,” said Sandra Springer, MD, associate professor of medicine at Yale School of Medicine in New Haven, Connecticut. “Now, the spike in infectious diseases related to injection drug use is due to a surge in illicit fentanyl analogs, alone and mixed with other drugs—in particular, methamphetamine.” Springer served on the planning committee for a 2018 National Academies of Sciences, Engineering, and Medicine workshop on integrating treatment for opioid use disorder and infectious diseases and co-authored a call for action on this issue (Ann Intern Med 2018;169:335-6).

The Diagnostic Workup for DUA IE

Clinical labs may be the first to learn that a patient has IE, and their support is crucial for ensuring that patients receive timely and effective treatment, according to experts. To diagnose IE, labs rely on blood cultures. They may need to help educate clinicians on best practices for gathering samples, said Rachael Liesman, PhD, director of microbiology at Kansas University Medical Center in Kansas City. “Blood should be collected via two venipuncture sites across four to six blood culture bottles—10 mL per bottle. Underfilling bottles results in lower sensitivity.”

Identifying the responsible pathogen(s) and performing antimicrobial susceptibility testing “will generally take anywhere from 2 to 5 days, depending on how fast the organisms grow in blood culture,” said Peter Gilligan, PhD, director emeritus of the clinical microbiology-pathology laboratories at the University of North Carolina Hospitals in Chapel Hill. As Liesman noted in a minireview she co-authored, documenting two or more blood cultures that are positive for a microorganism capable of causing IE is a major diagnostic criterion for the condition (J Clin Microbiol 2017;55:2599–608).

In 2% to 40% of cases of IE, blood cultures are negative; the most common cause of this is a patient receiving antibiotics prior to the collection of blood cultures. If a patient undergoes valve surgery for her IE, the excised valve can be subjected to 16S ribosomal sequencing to identify the pathogen responsible. However, “in patients for whom surgery is not an option, diagnostic options remain inadequate,” said Liesman. “No published molecular or diagnostic assay has demonstrated acceptable clinical sensitivity.”

Many patients with DUA IE have other infections that require treatment as well. For that reason, patients with DUA IE should be tested and treated for common blood-borne infections. “Because this patient population is generally [intravenous] drug users, they should be tested for HIV, hepatitis C virus, hepatitis B virus, and hepatitis A virus,” said Gilligan.

“They should also be offered immunization for hepatitis B and hepatitis A virus, if they are not already immune,” added Schranz. “Persons who inject drugs may be candidates for preexposure prophylaxis for HIV as well.”

Tracking Opiate Use

Performing tests to help document and monitor a patient’s drug use is another way that clinical labs help support the treatment of patients with DUA IE. “If patients’ underlying opioid use disorder is not identified, and thus not treated, then they are often unable to get or complete effective treatment for their infections,” said Springer. “Surgeons may not operate on a patient who is unable to stop using drugs due to untreated addiction, or patients may be readmitted multiple times for poorly or untreated infections.”

Thus, “when persons are hospitalized with DUA IE, or other infections related to injecting drugs, it should be viewed as an opportunity to intervene to help reduce further harms and to offer them substance use disorder treatment services,” said Schranz.

Drug screens for opiates are typically performed via immunoassay of urine samples, said Kevin Foley, PhD, director of clinical pathology at Kaiser Permanente Northwest in Portland, Oregon. With their rapid turnaround times, immunoassays allow labs to provide results quickly to clinicians. More resource-intensive liquid chromatography tandem mass spectrometry (LC-MS/MS) assays are typically used to confirm drug use, due to their superior sensitivity and specificity, as well as their ability to produce quantitative information about drug concentrations in a patient’s urine. However, Foley noted that LC-MS/MS testing may be difficult to justify for smaller institutions. “To give a sense of scale, we currently have four LC-MS/MS instruments that serve a patient population of about 600,000,” he said.

Laboratorians also play an important role in helping clinicians interpret the results of these tests. “Clinicians use concentrations to monitor compliance,” Foley explained. “A quantitative result can give useful insights into questions such as ‘Is it likely the morphine detected is from poppy seeds?’ Or ‘Does it appear that this patient stopped using drugs since we last tested him two weeks ago, or is he continuing to use’?”

Labs Support Integrated Care

The growing number of patients with DUA IE is just one highly visible manifestation of the much larger problem of DUA infections. “Infections associated with opioid use are one of the most serious infectious disease problems in the United States since AIDS,” said Gilligan. “Since the people who are infected are [intravenous] drug users, often on the fringes of society, this problem has not gotten the attention it deserves.”

Because the opioid epidemic shows no sign of abating soon, clinical labs will continue to play a key role in addressing IE and other DUA infections, said experts. By supplying healthcare teams with essential information for diagnosing and managing DUA, labs help ensure that patients are offered prompt and effective treatment for their current health problems and also given the support they need to avoid future problems. To improve the ability of labs to play this role, lab directors and other researchers have been discussing DUA IE data at infectious disease conferences, said Schranz.

“Integrating treatment for opioid use disorder and infectious diseases is critical to ending these coalescing epidemics,” said Springer, and clinical labs can provide the testing to help make this type of integration a reality.

Kristin Harper is a freelance writer in Seattle. +Email: kristin.nicole.harper@gmail.com