Bacillus anthracis is a spore-forming, gram–positive zoonosis which causes infection in humans through contact with contaminated animals or animal products (10). It occurs naturally in soil and mainly affects hoofed animals including goats, cattle, and sheep that ingest endospores (11–13). B. anthracis endospores are hardy and resistant to drying, heat, ultraviolet light, and many disinfectants, and can lie dormant in soil for many years (10). The endospores can be ingested, inhaled, or enter through skin abrasions after which they are phagocytosed by macrophages, where they germinate, resulting in activation and recruitment of other immune cells (10,11). In some cases, the bacteria are not destroyed and can activate a program of antigen-presenting cells and migrate toward lymph nodes (11); replication in the lymphatic system can then lead to septicemia. B. anthracis secretes 3 polypeptides called protective antigen, lethal factor, and edema factor, which combine to form exotoxins (10,11). These toxins have numerous effects on phagocytes, including impairment of maturation, impairment of chemotaxis of different phagocytes, and inhibition of phagocyte function (11). Edema toxin (protective antigen and edema factor) inhibits neutrophil function and lethal toxin (protective antigen and lethal factor) stimulates macrophages to release tumor necrosis factor α and interleukin-1α (10). It is possible that the host immune response contributes to the virulence of the pathogen, stimulating greater inflammatory cytokine release and recruitment of cells, including neutrophils, which have an essential role in controlling anthrax infection (11).

Typically, infection occurs through entry of the spores through the skin, by ingestion of contaminated meat, or by inhalation; contamination via these routes commonly results in cutaneous, gastrointestinal, or pulmonary anthrax, or may manifest as hemorrhagic meningitis (10,12,13). The intravenous route of exposure has added a new complexity to the immunopathogenic picture and has resulted in novel, severe, and highly variable patterns of manifestation which are described in the clinical cases section of this article. Anthrax has been used as a biowarfare select agent, and there is concern regarding potential future use. In 2001, the greater New York City metropolitan area in the United States was the scene of an attack (14) which resulted in at least 22 cases of anthrax, leading to 5 deaths. These cases resulted from a mix of inhalational and cutaneous exposures, affecting mainly persons who had contact with contaminated items sent through mail. This was a deliberate bioterrorist attack in which envelopes containing anthrax spores were delivered to victims. Early recognition of the first case resulted in a prompt public health response and epidemiologic investigations in the United States and internationally (15).

Afghanistan is now the largest exporter of heroin, accounting for 93% of the world’s supply (16). The United Kingdom National Anthrax Outbreak Control Team hypothesized that the heroin responsible for the 2009 outbreak had been contaminated at its likely source in Afghanistan or entered the supply chain by introduction of cutting or dissolving agents or through animal hides used for transport (17).

Phylogeographic analysis demonstrated that the anthrax strains responsible for the 2009–2010 outbreak in Scotland were closely related to strains from Turkey and not to prior isolates from Scotland or Afghanistan (18). Anthrax is endemic in Turkey, and heroin passing through Turkey may have been contaminated while being transported in contaminated goatskins (18). Isolates from the 2009–2010 and 2012–2013 outbreaks and the isolate from the case-patient from Norway in 2000 were subjected to comparative molecular typing by using a 31-marker multilocus variable number tandem repeat analysis and a broad single-nucleotide-polymorphism analysis. Results demonstrated that these strains were almost identical (8).

Here we give a firsthand account of 3 persons with anthrax associated with subcutaneous or intraarterial injection of heroin who sought care at different hospitals in the National Hospital Service trust. These cases highlight the spectrum of disease, specific management challenges, and the importance of serologic testing.

The manifestations of disease, treatments, and outcomes are summarized in the Table. Patient 1 manifested extensive, painless edema in the left thigh at the subcutaneous injection site. (Figure 1, panels A and B.) Despite remaining lucid and appearing comfortable, she was hemodynamically unstable and initially managed for severe soft tissue infection with septicemia; B. anthracis was identified from blood cultures the next day. Patient 2 also had extensive tissue involvement at the site of subcutaneous injection to the right buttock; he required extensive tissue debridement (Figure 2, panels A and B). Patient 3 had a pseudoaneurysm of the femoral artery after he injected heroin into that vessel; he was systemically well, although febrile, on arrival to the acute care facility. Samples taken at debridement and cultured were negative for anthrax; however, positive serology indicated recent infection.

These cases demonstrate the range of clinical manifestations, from relative hemodynamic stability (patient 3) to multiorgan failure requiring intensive care support (patients 1 and 2.) Clinical features of anthrax-associated soft tissue infection that differentiate it from that caused by other bacteria include the degree of edema affecting surrounding tissue (18,19), the excessive bleeding at the time of surgery, and the lack of a clear demarcation between affected and unaffected tissue.

In patients that have predominantly soft tissue manifestations, there is a notable absence of the eschar that is typical of cutaneous anthrax, marking this manifestation as a distinct form. Despite extensive tissue involvement as seen in patients 1 and 2, the degree of discomfort displayed by the patients was markedly less than would be expected, and they appeared deceptively comfortable despite the clinical features and laboratory tests that indicated severe infection. Both of these patients were coagulopathic with substantial renal failure requiring hemofiltration. The leukocyte count and C-reactive protein level were not as elevated as might be expected, given the degree of tissue involvement and the degree of organ failure evident; this was particularly evident in patient 2.

Patients 1 and 2, as seen in the Scottish anthrax case-patients, exhibited a biphasic illness with an initial recovery, then further deterioration (20,21,22). Radiologic features of pulmonary anthrax include pleural effusions, mediastinal widening, paratracheal or hilar fullness, and parenchymal infiltrates. Patients 1 and 2 showed chest x-ray evidence of severe pulmonary edema shortly after arrival.

Patients 1 and 2 were managed by a multidisciplinary team that included plastic surgeons, a gynecologist (for patient 1), intensive care specialists, microbiologists, and infectious diseases physicians. Patient 1 was the first case documented in London; the team drew on experience from the US Centers for Disease Control and Prevention, Health Protection Scotland, and the Rare and Imported Pathogens Laboratory at Porton Down, England. Anthrax Immune Globulin Intravenous (Human) (AIGIV) was approved for patient 1, but was not given because she had improved by the time of its arrival. Patient 2 received AIGIV within 24 hours of arrival at the hospital.

The death rate early in the 2009–2010 anthrax outbreak in Scotland was ≈50% and dropped to 28% toward the end of the outbreak (23). These results are likely to be a reflection of increased vigilance, earlier identification of cases, and an increase in experience in managing the cases. There is speculation that, rather than destroying the contaminated heroin, dealers in Scotland may have “cut,” or diluted, the batch with other supplies; this may have resulted in a reduction in the size of the inoculum. The death rate was also high in the 2012–2013 outbreak, although this outbreak was more limited in extent than the one in 2009–2010.

This outbreak reinforces the importance of vigilance in the early identification of emerging infections to ensure rapid identification of cases, containment of an outbreak, and effective management. Early cooperation and dissemination of information to at-risk groups and health care professionals are also vital.

The case-patients in the 2009–2010 outbreak most commonly sought treatment with localized abscesses or inflammatory lesions at the site of injection or skin popping with a breadth of presentation from subclinical to hemorrhagic meningitis and peritonitis (12,20,25–27). The novelty of this outbreak is the mode of transmission with endospores injected (in most cases) directly into the blood supply, resulting in novel soft tissue manifestations and severe systemic manifestations. The recurrence of cases in 2012–2013 has reinforced the awareness that vigilance should continue to be exercised in medical practice, looking for links among cases with early reporting and automatic collating of cases so that outbreaks can be identified early.

Here we describe 3 cases from the 2009–2010 outbreak of heroin-associated anthrax in the United Kingdom. Our interest lies in the way that the anthrax spores were introduced into the body, their novel effects, and breadth of manifestation. Lessons learned from the detection and management of these cases is of renewed interest given the cases seen during June 2012.

Clinicians may not consider anthrax in the differential diagnoses of sepsis and soft tissue infection among PWIDs, leading to an underestimate of the incidence of anthrax in this novel manifestation. The reemergence of anthrax makes a strong argument for serologic surveillance to determine the prevalence of anthrax exposure in PWIDs and to further our understanding of the nature of anthrax immunity and pathogenesis in this cohort. Results of this surveillance would have major implications for health policy in managing an infection for which there is heightened public concern.

Outbreaks among heroin users occur intermittently (34), hence vigilance should be exercised for these patients. Ongoing cases in Europe suggest that affected batches of heroin remain in circulation, therefore efficient reporting and noting the association between heroin use and illness are vital in ensuring early awareness of outbreaks.

The possibility that there may be a reservoir of undiagnosed disease, particularly in those with subclinical or mild symptoms, makes a strong case for serologic surveillance among PWIDs seeking treatment for sepsis or soft tissue infections. This will help determine the serologic prevalence in the community and may confirm the possibility that some heroin users possess immunity to anthrax through prior low-level exposure to contaminated drugs. Greater understanding of the nature of anthrax immunity and pathogenesis in this cohort is necessary for the development of health policies targeting this infection for which there is heightened public concern.