Locally acquired severe non-O1 and non-O139 Vibrio cholerae infection associated with ingestion of imported seafood

To the Editor: We report a case
of severe Vibrio cholerae infection acquired in Sydney, likely due to ingestion of imported seafood.

An 83-year-old man with Parkinson disease presented with
a 3-day history of vomiting, large-volume watery diarrhoea and acute renal impairment necessitating admission to the intensive care unit. Blood cultures grew curved gram-negative bacilli, and intravenous piperacillin–clavulanic acid was commenced. Subsequent microbiological testing of blood isolated V. cholerae, prompting testing and confirmation of V. cholerae in stool cultures. The strain was identified as non-O1 and non-O139 by serotyping, and toxin gene-negative by polymerase chain reaction testing.

The patient subsequently reported ingestion of imported seafood (a marinara mix containing mussels from Chile, prawns from Vietnam and squid from China), purchased from a local supermarket, although none of the suspected food was available for testing. He had no recent travel history or exposure to marine or brackish-water environments and no unwell contacts.

Antimicrobial therapy was changed to ciprofloxacin. The patient’s recovery was complicated by caecal pseudo-obstruction requiring endoscopic decompression. He was discharged after 2 weeks of antibiotic treatment.

Although rare, sporadic cases
of both epidemic (O1 and O139 serotypes) and non-epidemic
(non-O1 and non-O139 serotypes)
V. cholerae infection have been reported in Australia.1 Australian cases have been linked to ingestion
of imported seafood, with a notable outbreak in Sydney associated with imported whitebait.2 V. cholerae is known to be present in Australian estuaries, and some endemic cases have been associated with local aquatic exposure.3

While only O1 and O139 isolates are mandated for reporting to Australian public health units, non-epidemic strains of V. cholerae are associated with bacteraemia and a poor prognosis.4 Clinically suspected cases of V. cholerae infection should
be reported to public health units, pending microbiological confirmation. As identification of Vibrio species is not routinely done on stool cultures, a suspicion of Vibrio infection must be communicated to laboratories.

Under current Australian law, only imported cooked prawns are required to be tested for Vibrio species contamination, and there is no restriction on the geographical origin of seafood imported into Australia.5,6 This case highlights an ongoing risk of potentially severe V. cholerae infection from imported seafood, and it should be considered as a differential diagnosis for patients presenting with severe enteritis and a compatible exposure history.

Sevenfold rise in likelihood of pertussis test requests in a stable set of Australian general practice encounters, 2000–2011

Pertussis, commonly known as whooping cough, is caused by the small, gram-negative coccobacillus Bordetella pertussis. Classic whooping cough illness is characterised by intense paroxysmal coughing followed by an inspiratory “whoop”, especially in young children or those without prior immunity, followed by a protracted cough.1,2 It is now more widely understood that these characteristic symptoms are not always present during B. pertussis infection, and that individuals may only have symptoms similar to those of the common cold or a non-specific upper respiratory tract infection.2

In recent years, rates of pertussis notifications have increased dramatically across Australia and in many other parts of the world.3–6 The rise has been seen in all Australian states and territories, with the highest notification rates in children aged under 15 years.7 Although increased notifications may be due to a true increase in circulating B. pertussis, it is possible that the magnitude of the increase has been amplified by better recognition of disease and more frequent testing.8

Historically, the diagnostic gold standard for pertussis laboratory testing was bacterial culture from nasopharyngeal secretions during the early phases of infection (Weeks 1 and 2), and serological testing was used as an alternative diagnostic method during later phases of infection.2 However, even with ideal specimen collection, transport and handling, culture has low sensitivity and does not provide timely results. Although serological testing is more sensitive, sensitivity and specificity may be lowered depending on the timing of specimen collection and the patient’s infection and vaccination history.9 Polymerase chain reaction (PCR) testing has emerged as a key diagnostic method, and respiratory specimens are now commonly tested for pertussis using PCR in Australia and other countries.2,4,10 PCR testing provides more sensitive and rapid results than culture and serological testing. Also, PCR allows less invasive specimen collection — especially useful in younger age groups, in whom infection rates are high and serum collection may be challenging.1

The key datasets used to monitor pertussis incidence and epidemiology in Australia — pertussis notifications, and pertussis-coded hospitalisations and deaths — are populated by positive test results from laboratories and, as such, are not independent of changes in testing practices. Without negative test results or other denominator data to assess changes in testing behaviour, it is difficult to distinguish changes in recorded disease incidence that are due to the effect of increased testing from any true increase in disease.

To better understand the role testing behaviour has on current pertussis epidemiology in Australia, we investigated pertussis testing trends in a stable set of general practice encounters. We hypothesised that the likelihood of pertussis testing, in a stable set of encounters that were most likely to result in a pertussis test request, has increased over time and that this may have led to amplification of laboratory-confirmed pertussis identification in Australia.

Methods

We analysed data from the Bettering the Evaluation and Care of Health (BEACH) program and the National Notifiable Diseases Surveillance System (NNDSS).

The BEACH program is a continuous cross-sectional national study that began collecting details of Australian general practice encounters in April 1998. Study methods for the BEACH program have been described elsewhere11 and are summarised in Appendix 1.

Initially, all encounters for which a pertussis test (ICPC-2 [International Classification of Primary Care, Version 2] PLUS code R33007 [ICPC-2 PLUS label: Test;pertussis]12) was ordered in the period April 2009 – March 2011 were identified and examined. During this period, 30 BEACH problems resulted in a pertussis test request at some time, and nine problems accounted for 90.9% of all pertussis test requests in the dataset. Four other problems, for which a pertussis test request was made at more than 1% of general practice management occasions of that problem, were added (Appendix 2). The 13 selected problems accounted for 92.3% of pertussis tests ordered between April 2009 and March 2011. These were labelled “pertussis-related problems” (PRPs) and data for these problems at encounters recorded between April 2000 and March 2011 were extracted.

BEACH data were grouped into two pre-epidemic periods (before the start of the national pertussis outbreak in 2008) and three epidemic years. During the pre-epidemic periods (April 2000 – March 2004 and April 2004 – March 2008), testing proportions were constant. For each pre-epidemic period and epidemic year, the proportion of PRPs with a pertussis test ordered and the proportion of BEACH problems that were PRPs were calculated. The proportions of PRPs with a pertussis test ordered were grouped into clinically meaningful age groups: 0–4 years, 5–9 years, 10–19 years, 20–39 years, 40–59 years, and ≥ 60 years.

The NNDSS collates notifications of confirmed and probable pertussis cases received in each state and territory of Australia under appropriate public health legislation.13 Notified cases meet a pertussis case definition, which requires: laboratory definitive evidence; or laboratory suggestive evidence and clinical evidence; or clinical evidence and epidemiological evidence (Appendix 3).

To match the BEACH years, all Australian pertussis notifications between April 2000 and March 2011 were extracted from the NNDSS database, including data on age and laboratory testing method. Pertussis notifications were aggregated by month and year, by age group, and by laboratory test method (serological, PCR, culture or unknown). Notifications that had more than one testing modality reported were classified into a single test category using the following hierarchy: culture, PCR, serological, unknown. A total of 1318 notifications were coded only as “antigen detection”, “histopathology”, “microscopy”, “not done” or “other” (epidemiologically linked cases); these were excluded from the analysis as they accounted for only 0.9% of notifications over the study period. The rates of pertussis notifications per 100 000 population were then calculated for each pre-epidemic period and epidemic year.

Temporal changes in the proportions of PRPs with a pertussis test ordered and the rates of pertussis notifications were assessed with a non-parametric test for trend over the whole study period and by calculating odds ratios with robust 95% confidence intervals. Correlation coefficients were calculated to determine the relationship between BEACH and NNDSS datasets. The BEACH analyses incorporated an adjustment for the cluster sample design. Initial BEACH analyses were performed using SAS version 9.1.3 (SAS Institute). Subsequent BEACH and NNDSS analyses were performed using Microsoft Excel and Stata version 11 (StataCorp).

During the study period, the BEACH program had ethics approval from the University of Sydney Human Research Ethics Committee and the Australian Institute of Health and Welfare Ethics Committee. This particular study was approved by the University of Queensland Medical Research Ethics Committee.

Results

The PRPs captured an average of 90.7% of all BEACH problems with a pertussis test ordered each year (range, 87.7%–92.7%) between April 2000 and March 2011 (Box 1). During the study period, PRPs as a proportion of all BEACH problems remained stable, with an annual average of 8.0% (range, 7.7%–8.7%).

When the BEACH data were grouped into pre-epidemic periods and epidemic years, the proportion of PRPs with a pertussis test ordered increased about sevenfold — from 0.25% to 1.71% — when comparing April 2000 – March 2004 and April 2010 – March 2011(Box 2, Box 3). This increase was highly correlated with NNDSS pertussis notification rates (correlation coefficient [r], 0.99), which increased about fivefold during the same period (Box 3). A highly significant trend was detected for changes in BEACH pertussis test requests (P < 0.001) and NNDSS notification rates (P < 0.001) from April 2000 to March 2011.

In the age-specific analysis, there were significant increases in laboratory-confirmed pertussis notifications and in the likelihood of pertussis test requests across all age groups during the study period (Box 3). When comparing April 2000 – March 2004 and April 2010 – March 2011 pertussis testing rates, the largest increase was in 5–9-year-olds (odds ratio, 11.6; 95% CI, 4.2–36.7), followed by 0–4-year-olds, 40–59-year-olds and ≥ 60-year-olds. With the exception of 5–9-year-olds, the increase in pertussis testing exceeded notification changes in all age groups.

Numbers of NNDSS pertussis notifications fluctuated over the study period (Box 4). From 2008 onwards, there was a clear increase in the numbers of PCR-confirmed notifications. Before April 2008, most NNDSS notifications were confirmed by serological testing (66.0%–80.7% of all notifications annually). The proportion of notifications confirmed by PCR increased from 16.3% in April 2000 – March 2004 to 65.3% in April 2010 – March 2011 (Box 1). The proportion of notifications confirmed by culture did not change, and accounted for an average of 2.0% of all notifications over the study period.

Discussion

Consistent with experience in other developed countries,4,14–16 we found that rates of pertussis notifications in Australia increased dramatically in recent years, from an average annual rate of 34 per 100 000 population between April 2000 and March 2004 to 158 per 100 000 population between April 2010 and March 2011. Our results cast some light on the potential role that the increasing likelihood of a pertussis test request may have on this change.

Using BEACH data, we found that individuals presenting to an Australian general practitioner between April 2010 and March 2011 were seven times more likely to have been tested for pertussis than 10 years earlier. This finding was within a set of general practice problems that remained stable as a proportion of all problems. This increased likelihood of pertussis testing, most evident in the epidemic years from April 2008 onwards, reached a maximum in the period April 2010 – March 2011, when pertussis tests were ordered in 1.71% of PRPs. A particular strength of our findings is that we used a data source that does not rely on laboratory testing, unlike most other datasets used to monitor pertussis in Australia and elsewhere.4,7,10,13

The increased likelihood of testing in general practice coincided with an increasing proportion of NNDSS pertussis notifications being confirmed by PCR, from 16.3% between April 2000 and March 2004 to 65.3% between April 2010 and March 2011. A review of pertussis cases in New South Wales during the period 2008–2009 also showed a shift away from serological testing (the predominant method before 2008) to PCR testing from 2008 onwards.10

Pertussis notification rates and the likelihood of testing varied considerably across age groups. There was a dramatic increase in notification rates in 0–4-year-olds and 5–9-year-olds from the 2004–2008 pre-epidemic period to the 2008–2009 epidemic year, compared with a moderate increase in testing, which indicates that there probably was a true increase in disease for these groups during this period. It is possible that a real increase in 0–4-year-olds and 5–9-year-olds early on prompted increased disease awareness among GPs, leading to widespread increases in testing across all ages. A positive feedback loop due to increased testing — leading to increased disease detection and awareness, leading to increased testing, and so on — may have been established. This interpretation is supported by the observation that although testing continued to increase from the epidemic year 2008–2009 to the epidemic year 2009–2010, there was little change in notifications, suggesting an increase in testing during that period rather than an increase in disease. In the other age groups, an increase in testing appeared to be responsible for magnified pertussis notifications. A study of pertussis resurgence in Toronto, Canada, also described this phenomenon and concluded that, although there had been true increase in local disease activity, the apparent size of the increase had been magnified by an increase in the use of pertussis testing and improvements in test sensitivity.4

In Australia, public funding for pathology laboratories to use PCR to test specimens for pertussis (and other pathogens) commenced under the Medicare Benefits Schedule (MBS) in November 2005.17 This specific reimbursement for PCR testing (MBS item 69494) — a Medicare fee of $28.65 compared with $22.00 for culture (MBS item 69303) and $15.65 for serological testing (MBS item 69384)17 — may have been an incentive for laboratories across Australia to implement PCR testing more routinely. In addition, during the 2009 H1N1 influenza pandemic, public funding was allocated for the purchase of laboratory equipment (notably PCR suites), but much of the funding was not received by laboratories until after the demand for pandemic influenza testing had subsided.18 New PCR capacity may have provided an increased opportunity for laboratories to conduct PCR testing for other pathogens, such as B. pertussis.

Several factors may have contributed to an increase in disease during the study period. Pertussis laboratory testing methods have been documented to vary between children and adults. While, historically, culture would have been preferred to serological tests for the very young,19 children now are more likely to be tested using PCR, and adults are predominantly tested using serological tests.10 The variation in testing and notification rates across age groups may be due to differences in susceptibility and immunity.20 Pertussis vaccination does not provide lifelong immunity against infection, with protection waning between booster doses.21 Waning immunity may partially explain differences in pertussis incidence between age groups, with older individuals having lower immunity due to longer periods since vaccination.20 Furthermore, there is evidence to suggest that whole-cell pertussis vaccine formulations used in Australia and overseas before the late 1990s were more protective against B. pertussis infection than currently used acellular pertussis vaccines,14,22–24 resulting in immunity levels waning faster in some age cohorts due to changes in vaccination schedules.25 In addition, a recent analysis of B. pertussis isolates collected in Australia between 2008 and 2010 indicates that there has been increasing circulation of vaccine-mismatched strains, hypothesised to be due to the selective pressure of vaccine-induced immunity.26

While these or other factors may have led to a true increase in disease during the study period, our data suggest that increased testing, most likely due to expanding use of PCR during the study period, has almost certainly amplified the magnitude of notified pertussis activity in Australia. This increase in testing might have led to identification of illness that would have otherwise gone undetected among age groups in which pertussis circulates widely or age groups in which pertussis had previously been largely left as a clinical diagnosis.

Our findings have global implications, particularly for countries with high or expanding PCR availability. They highlight the critical importance of analysing changes in infectious diseases using a range of surveillance systems. By monitoring changes in laboratory testing and using surveillance datasets that do not rely on laboratory test results, it is possible to determine whether increases in notifications for diseases such as pertussis are due to a true increase in disease, an increase in testing, or a combination of both.

1 PRPs as a proportion of all BEACH problems with a pertussis test ordered and as a proportion of all BEACH problems, and NNDSS PCR tests as a proportion of all NNDSS pertussis notifications, April 2000 to March 2011

Period (April – March)	PRPs as a proportion of all BEACH problems with a pertussis test ordered (total no. of pertussis tests)	PRPs as a proportion of all BEACH problems (total no. of PRPs)	NNDSS PCR tests as a proportion of all NNDSS pertussis notifications (total no. of pertussis notifications)

2000–2004	89.4% (141)	8.7% (51 396)	16.3% (16 983)
2004–2008	92.1% (216)	7.9% (45 872)	11.3% (31 559)
2008–2009	87.7% (114)	7.9% (12 551)	55.4% (17 945)
2009–2010	92.7% (164)	7.8% (12 228)	55.8% (22 754)
2010–2011	91.7% (216)	7.7% (11 557)	65.3% (33 641)
PRP = pertussis-related problem. BEACH = Bettering the Evaluation and Care of Health. NNDSS = National Notifiable Diseases Surveillance System. PCR = polymerase chain reaction.

2 Proportions of BEACH PRPs with a pertussis test ordered, and NNDSS pertussis notification rates, April 2000 to March 2011

BEACH = Bettering the Evaluation and Care of Health. PRP = pertussis-related problem.
NNDSS = National Notifiable Diseases Surveillance System. * Data for 2000–2004 and 2004–2008 are averaged annual rates, and data for 2008–2009, 2009–2010 and 2010–2011 are annual rates.

3 Proportions of BEACH PRPs with a pertussis test ordered, and NNDSS pertussis notification rates per 100 000 population, by age group, April 2000 to March 2011

		Period (April – March)					Odds ratio (95% CI)‡	Correlation coefficient (r)§
		Pre-epidemic period*		Epidemic year†
Age group	Dataset	2000–2004	2004–2008	2008–2009	2009–2010	2010–2011

0–4 years	BEACH	0.16%	0.12%	0.48%	0.89%	1.31%	8.0 (3.9–17.2)	0.89
0–4 years	NNDSS	44.97	35.78	244.23	225.60	299.17	4.7 (4.3–5.2)	0.89
5–9 years	BEACH	0.16%	0.22%	0.78%	2.61%	1.87%	11.6 (4.2–36.7)	0.75
5–9 years	NNDSS	29.68	17.55	202.17	260.06	507.62	14.2 (12.8–15.7)	0.75
10–19 years	BEACH	0.36%	0.36%	1.27%	1.95%	2.05%	5.7 (2.8–11.4)	0.88
10–19 years	NNDSS	82.29	38.24	126.87	134.15	226.45	2.2 (2.1–2.3)	0.88
20–39 years	BEACH	0.33%	0.54%	0.92%	1.10%	1.76%	5.4 (3.5–8.5)	0.98
20–39 years	NNDSS	22.58	34.51	64.41	84.42	105.60	2.8 (2.6–3.0)	0.98
40–59 years	BEACH	0.25%	0.65%	1.05%	1.50%	2.09%	8.5 (5.2–14.0)	0.99
40–59 years	NNDSS	29.17	54.60	82.12	113.33	153.61	3.2 (3.0–3.4)	0.99
≥ 60 years	BEACH	0.19%	0.41%	0.50%	0.54%	1.43%	7.6 (4.3–13.7)	0.90
≥ 60 years	NNDSS	16.12	50.15	76.57	103.49	142.84	5.6 (5.1–6.2)	0.90
All ages	BEACH	0.25%	0.43%	0.80%	1.24%	1.71%	7.0 (5.5–8.8)	0.99
All ages	NNDSS	33.73	42.31	88.86	108.56	158.42	3.2 (3.2–3.3)	0.99

BEACH = Bettering the Evaluation and Care of Health. PRP = pertussis-related problem. NNDSS = National Notifiable Diseases Surveillance System. * NNDSS data are average notifications per 100 000 population per year. † NNDSS data are notifications per 100 000 population per year. ‡ Comparison of 2000–2004 and 2010–2011 data. § Correlation between BEACH and NNDSS data.

4 NNDSS pertussis notifications by laboratory test method, April 2000 to March 2011

NNDSS = National Notifiable Diseases Surveillance System. PCR = polymerase chain reaction.

The drama of zoonoses

MY CAREER choice was based on non-fiction reading as a teenager. Starting with American journalist Berton Roueché, who adapted material from the terse Morbidity and Mortality Weekly Report covering investigations by the US Centers for Disease Control, I have been reading popular accounts of epidemics for a while.

And epidemics fascinated the earliest writers: pestilence as one of the horsemen of the Apocalypse in the Bible; Daniel DeFoe’s experimental Journal of the plague year, mistaken for reality by 18th century readers; 20th century disease “biographies”, with Hans Zinsser’s Rats, lice and history (on typhus), and countless others since. Australia has contributed to this literature, of course; Frank Bowden’s Gone viral is a recent example.

For such books, short words are preferred in the title — certainly not “epidemiology”. There is Robin Cook’s Vector, or the current entry into this crowded field, David Quammen’s Spillover, which was nominated for a 2013 Pulitzer Prize.

For me, popular epidemiology in a bookshop is always worth perusing, but is only purchased when necessary. What moved me from perusal to purchase in this case? I had to find out if Quammen had done justice to the story and memory of Brisbane horse trainer Vic Rail. And, indeed, the second paragraph of the opening chapter started thus: “The emergence of Hendra virus didn’t seem very dire or newsworthy unless you happened to live in eastern Australia.” In 1994, the disease killed Rail and his horse, and captured the attention of the Australian press, and students of communicable disease. Linda Selvey, then working as an epidemiologist in Queensland, investigated bats as a host of this disease. Years later, Quammen reconstructed the story, with careful interviews, and presents the “spillover”, from bats, with amplification in horses, and then to humans.

Spillover focuses on the passage of pathogens from one species to another. It is a book about emergence of animal disease and human disease as “strands of one braided cord” (p 13). Here, Quammen is not afraid of technical detail, explaining, for example, the Anderson and May model of parasite-host interactions (p 305), how the evolutionary success of a bug is directly related to its lethality, the rate of recovery from it, and the normal death rate from all other causes.

Quammen’s survey results from years of travel and interviews, and extensive reading of the original literature, and in general seems to fairly consider many old papers; this book does not derive from the latest multi-author textbooks. But would you be in safer hands turning to those modern texts? With the availability of collaborative online resources now, how many books like this one, the result of so much individual effort, will appear in the future?

The book is in the style of National Geographic, to which the author has contributed for many years. Alongside moments of drama, Quammen also takes the time to examine competing theories. The book’s subtitle points to the Next Big One — after a detailed examination of SARS, and a bit less on influenza — but there is so much more here. Good for a holiday read, Spillover will also be a valuable companion to anyone with a professional interest in zoonoses. Students needing the salient facts in a concise summary will start elsewhere, however.

Gambling is always a big subject, and currently more prominent with betting on Australian sports, while the flu season has many of us reassessing our disease risk, with or without this year’s vaccine. In the United States, there has been extravagant praise for Spillover, but I lost my bet that it would win a Pulitzer Prize.

A pilgrim’s progress: severe Rickettsia conorii infection complicated by gangrene

This challenging case of acute febrile illness and rapidly evolving petechial rash and digital gangrene in a traveller who returned from North India and highlights the need for a high index of suspicion for rickettsial infection in returned travellers.

Clinical record

A 47-year-old Australian man of Vietnamese origin presented to hospital 3 days after returning from a 2-week pilgrimage to and in January 2012 with a 10-day history of fever and myalgia. He had developed high-grade fever with chills and rigors associated with myalgia 7 days after arriving in . Two days later, he developed nausea and vomiting. He had been vaccinated for hepatitis B and cholera before travel. He was not taking prophylactic antibiotics. He travelled with a group of 10 others who remained well. He recalled receiving a few mosquito bites, and noted rodent infestation and stray dogs in some of the temples he visited. A doctor in the group treated him empirically with oseltamivir after his initial symptoms began. A rash developed 2 days before his admission and 9 days after the onset of symptoms.

The main findings of an examination on admission were a high fever (40°C), a macular erythematous rash over his trunk and extremities sparing his palms and soles, and facial flushing. There were no eschars.

Laboratory investigations on admission showed a platelet count of 44 × 109/L (reference interval [RI], 150–450 × 109/L), white cell count of 14 × 109/L (RI, 4–11 × 109/L; 88% neutrophils), and haemoglobin concentration of 124 g/L (RI, 135–175 g/L). Biochemical tests and liver function tests showed the following levels (with RIs in parentheses): sodium, 124 mmol/L (137–145 mmol/L); urea, 6.1 mmol/L (2.7–8.0 mmol/L); creatinine, 74 µmol/L (50–120 µmol/L); albumin, 21 g/L (34–48 g/L); lactate dehydrogenase, 478 U/L (110–230 U/L); bilirubin, 31 µmol/L (2–24 µmol/L); γ-glutamyl transferase, 242 U/L (< 60 U/L); alkaline phosphatase, 243 U/L (30–110 U/L); alanine aminotransferase, 136 U/L (< 55 U/L); and aspartate aminotransferase, 159 U/L (< 45 U/L). The international normalised ratio was 1.2 (0.9–1.2). Laboratory features of disseminated intravascular coagulation such as elevated D-dimer and low fibrinogen concentrations were not present. There was no evidence of glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Differential diagnoses included leptospirosis, enteric fever, dengue fever, chikungunya, malaria, rickettsiosis and influenza. Results of initial investigations were suggestive of dengue fever (IgM-positive, IgG-negative, although a test for dengue virus NS-1 antigen was negative). Blood cultures and serological tests for leptospirosis and rickettsia at admission were negative. Because of the broad differential diagnosis, and despite the initial positive serological test for dengue virus, the patient was treated empirically with ceftriaxone and doxycycline and nursed in a side room with infection control droplet precautions.

Over the next 48 hours, the patient developed increasing thigh pain, conjunctival injection, and his rash evolved into a petechial/haemorrhagic rash, particularly over the legs. He developed bilateral leg oedema. His fingertips and toes became dusky and swollen with poor capillary refill (Box 1). His oxygen requirement increased and he was transferred to the intensive care unit. Compartment syndrome was ruled out.

A skin biopsy showed epidermal necrosis, fibrin thrombi and associated vascular necrosis with variable inflammatory infiltrates including focal leukocytoclasis. A vasculitic component was reported, though not prominent. The result of a test for autoimmune vasculitis was negative. Therapy with doxycycline and ceftriaxone was continued. The patient’s fever persisted and the digital ischaemia progressed. A ketamine infusion was initiated to control pain from the digital ischaemia. The white cell count increased to 34.3 × 109/L; the platelet count had recovered (539 × 109/L). Rheumatologist and vascular surgeon opinions were sought. Therapy with heparin (infused) and prostacyclin was commenced to improve microvascular perfusion. Methylprednisolone was given for 3 days, followed by prednisolone at a dose of 1 mg/kg, after which there was marginal improvement in the digital ischaemia.

The patient developed hypotension 48 hours later. This was associated with abdominal distension and a drop in the concentration of haemoglobin to 63 g/L. Computed tomography angiography of the abdomen showed a large retroperitoneal bleed with multiple sites of venous ooze. Prostacyclin and heparin infusions were ceased and the patient’s haemodynamic status stabilised after transfusion of 9 units of blood. Repeat serological tests were performed 2 weeks after admission to hospital. The results for dengue IgM, IgG and NS-1 antigen were negative, suggesting an initial false-positive result. Repeat serological tests for rickettsia (indirect microimmunofluorescence assay detecting IgG and IgM antibody) were performed at the Australian Rickettsial Reference Laboratory using an inhouse assay for a range of rickettsia from the spotted fever group and typhus group. No antibody was detected in the patient’s serum on presentation (titres all < 128). However, the following titres were found in his convalescent serum:

Spotted fever group — R. australis (Queensland tick typhus), 4096; R. honei (Flinders Island spotted fever), 1024; R. conorii (Mediterranean spotted fever), 8192; R. sibirica (North Asian tick typhus), 2048; R. rickettsii (Rocky Mountain spotted fever), 4096; R. akari (Rickettsial pox), 4096; and
Typhus group — R. prowazekii (epidemic typhus), 256; R. typhi (Murine typhus), 1024.

These findings demonstrate seroconversion to rickettsia, and the high titre for R. conorii (8192) suggests that this may have been the infecting pathogen.

A real-time polymerase chain reaction targeting the citrate synthase gene was performed retrospectively on serum obtained on the day of admission. The result was positive, indicating rickettsia of the spotted fever group or typhus group, but further DNA amplification for species identification was unsuccessful. The patient completed 21 days of therapy with doxycycline. His fever resolved within 20 days of symptom onset and 10 days after the initiation of antibiotic therapy. Blurring of vision was noted 2 weeks into his hospital admission and fundoscopy showed retinal haemorrhages with focal thrombosis and mild papilloedema.

The patient underwent multiple surgical debridement procedures and amputations of gangrenous digits, and is currently undergoing rehabilitation. Twelve months later, he is still receiving ongoing treatment for chronic osteomyelitis of the calcaneum, but is otherwise well although unable to work. Osteomyelitis developed because of chronically exposed bone and ischaemic necrosis. Magnetic resonance imaging revealed multifocal osteonecrosis involving the marrow of the tibia, fibula and bones of the foot, most prominently the calcaneus (Box 2). The causative organism was Escherichia coli resistant to most β-lactam antibiotics (extended-spectrum β-lactamase-producing) and quinolones. As a result, the patient required a prolonged period of therapy with meropenem.

Discussion

Rickettsiae are small, obligate intracellular gram-negative bacteria. Rickettsial infections fall into three groups: the spotted fever group, the typhus group and the scrub typhus group. The vectors are invertebrates, whose habitats determine the geographical and temporal distribution of rickettsiae. Clinical manifestations vary between regions and hosts.1

The rickettsial species in this case — R. conorii — belongs to the spotted fever group, which is distributed worldwide.1 Three known spotted fever group rickettsiae are recognised in Australia: R. australis, occurring down the east coast of Australia and transmitted by mammalian ticks; R. honei, occurring in South Australia, Victoria and Tasmania and transmitted by reptile ticks; and R. felis in Victoria and Western Australia transmitted by cat fleas.2 This is the first report of severe R. conorii infection in a traveller returning to Australia.

R. conorii infection occurs mostly in regions adjacent to the Mediterranean Sea as well as in sub-Saharan Africa, India and countries adjacent to the Black Sea, including Turkey, Bulgaria and Ukraine. Mediterranean spotted fever rickettsia (a subspecies of R. conorii, known as Rickettsia conorii subsp. indica) is known to occur in the Indian subcontinent, although there are no reported cases from Nepal in the literature.3 A case of R. honei infection has been reported from Nepal.3

R. conorii is transmitted to humans by bites of the tick species Rhipicephalus sanguineus, typically carried by dogs. R. conorii is able to adapt to different environments (ie, physiological conditions and nutrient changes) between hosts. Cases of R. conorii infection occur mainly in warmer months. On transmission to a human, R. conorii invades host cells, where it begins to replicate. The incubation period ranges from 3 to 15 days, depending on the route of pathogen entry and the pathogen load.

The common triad of clinical manifestations include fever, headache and maculopapular rash (seen in 97% of patients) with or without an eschar, which is pathognomonic and seen in over 70% of cases. The diagnostic feature of the eschar was first described by Boinet and Pieri in Marseille in 1925 and represents the site of inoculation, usually localised to the legs, arms or trunk. It has been identified on the scrotum in 2% of cases and found on scalp and retroauricular areas in children.4,5 Petechial rash occurs in less than 10% of cases. Patients often have myalgia. Laboratory investigations often show neutropenia or lymphopenia, thrombocytopenia and elevation of liver transaminase levels. Hyponatraemia is commonly described.

Fulminant infection and death occur in 1.4%–5.6% of hospitalised patients, which is higher than the rate for most spotted fevers other than Rocky Mountain spotted fever, which has a mortality of 5%–7%. The severity of infection is related to the virulence of the pathogen, older age, male sex, G6PD deficiency, alcohol consumption, African American race, presence of pulmonary infiltrates and delayed administration of doxycycline, with a 20% increase in major organ dysfunction with each day of delay.6,7 Doxycycline is the treatment of choice, although other antimicrobials such as macrolides have been reported to be effective.8 The severity of disease in our patient was probably a result of his delayed presentation, as well as the virulence of the infecting rickettsial species.

Thrombotic complications are seen mostly in infections with R. rickettsii and R. conorii, and are due to disseminated endothelial injury, release of procoagulant factors, and activation of the coagulation cascade.6 However, contrary to what is frequently described in case reports, disseminated intravascular coagulopathy is rare.6 There is little in the literature on the treatment of this condition. Prednisolone has not been shown to confer additional benefit.9 Multifocal osteonecrosis, as seen in our patient, has not been reported in the literature, but is probably caused by microvascular occlusion as seen in skin and other organs such as the eye.

Massive skin and tissue necrosis, and consequent gangrene requiring digit amputations of a magnitude similar to that seen in this case have been reported in a 54-year-old woman with R. australis infection complicated by type 1 diabetes in Queensland in 2009, and in an 8-year-old girl with Rocky Mountain spotted fever in 1978.10 Both patients had an initial presentation of fever and rash which progressed rapidly to widespread dermal necrosis requiring significant debridement of eschar, skin grafting, amputation and challenging wound care, as for our patient.

Diagnosis of spotted fevers is based on molecular and, more commonly, serological techniques. The use of polymerase chain reaction to detect the citrate synthase (glt) gene from serum or tissue is useful in detecting early infection. Serological tests for rickettsia, preferably on paired sera, are a useful diagnostic tool in the later stages, especially in the third week of illness. Indirect fluorescent antibody assay is the best method of serological testing. Enzyme-linked immunosorbent assay, latex agglutination and western blot may also be used. There is significant cross-reactivity between rickettsia of the spotted fever and typhus groups. The infecting rickettsiae usually produce the highest titre, but sometimes the end points for multiple species are the same. Laboratories should test both local and “overseas” rickettsial antigens to indicate the causative organism. Shell-vial cultures are not routinely performed and require a physical containment level 3 laboratory.

This case highlights that rickettsial infection should be considered and empirically treated in returned travellers with rash, even in the absence of classical features such as presence of eschar or headache, particularly when they have travelled to areas where rickettsial disease is endemic (including parts of Australia), as severe complications may occur in patients in whom treatment is delayed. It is important to note that serological tests for rickettsia may be negative until the third week of clinical illness, so a high level of clinical suspicion should be maintained, and molecular testing is required to obtain an early diagnosis. Thrombotic complications of infection, while rare, are related to infections with specific rickettsial species (R. rickettsii and R. conorii), delayed treatment and specific host factors. Early therapy with doxycycline and supportive care remains the most effective treatment for this condition.

References

1 Images of the patient’s rash and developing symptoms at 12 days and 40 days after symptom onset



Day 12.		Day 40.

2 Magnetic resonance image showing osteonecrosis of the marrow of the patient’s tibia, fibula and bones of the foot

Prevention of peripheral intravenous catheter-related bloodstream infections: the need for a new focus

Careful insertion and maintenance technique on every occasion is important — not routine replacement

Intravascular access device-related bloodstream infections, including Staphylococcus aureus bacteraemias (SABs), cause substantial clinical harm and waste scarce health care resources. And yet, many, if not most, are preventable. We are belatedly realising that to eliminate these complications we must conduct research, implement evidence-based interventions and reduce the clinical practice variation that leads to their occurrence. Public reporting and the financial disincentives associated with apparent poor performance are also pulling us along this path. In this issue of the Journal, Stuart and colleagues provide yet another wake-up call by describing a case series of 137 peripheral intravenous catheter (PIVC)-associated SABs.1 They highlight some important failings in our processes for managing PIVCs that allow devastating complications to occur and which require our urgent attention.

Infections can occur at any time after PIVC insertion, but early infections typically reflect the insertion procedure.2 More than half of the SAB episodes in Stuart et al’s study (55%) occurred within 96 hours of insertion, suggesting suboptimal practice. Aseptic insertion is difficult in emergency situations, and SAB episodes were predominantly associated with insertion by the ambulance service or in the emergency department (ED) (21% and 40% of SABs, respectively). In addition, ambulance or ED insertions accounted for 61% of early infections (up to 96 hours). PIVCs inserted in the ED have been reported to have a sixfold higher incidence of SAB than lines inserted in wards.3 Hospital-wide data including PIVC insertions that did not result in SAB were not available, but Stuart and colleagues’ series suggests institutional reliance on the prehospital and ED settings for PIVC insertion as well as increased SAB risk associated with these settings.

Treating all PIVCs inserted by the ambulance service and in the ED as “guilty” of non-aseptic insertion is one avenue for potentially avoiding complications. At our hospitals, we try to remove such PIVCs within 24 hours. This may explain why we found just two PIVC-associated SABs in our study — only 10% of 5907 PIVCs were inserted in the ED.4 However, “routine replacement” of PIVCs inserted by the ambulance service or in the ED increases workload in the wards, compromises vessel health and fails to address the root cause of the problem — non-aseptic insertion technique. It would be preferable to get it right the first, and every, time we perform an insertion. Achieving consistent aseptic insertion across the prehospital, emergency and inpatient spectrum, in addition to flagging and removing PIVCs inserted in true emergencies, requires a coordinated, disciplined approach, but we should demand nothing less.

Not all PIVC-related infections will be prevented with a focus on catheters inserted in prehospital and ED settings; indeed, Stuart et al found that most PIVC-associated SAB episodes (65%) occurring within 72 hours of insertion were among patients whose PIVCs were inserted in a ward. This rate demands close attention be paid to practices throughout the hospital; specifically, preinsertion skin preparation with alcoholic chlorhexidine ≥ 0.5%, hand hygiene and aseptic, non-touch technique using a sterile field and clean or sterile gloves. Correct insertion will prevent many infections — but not all, unless clean, intact dressings and aseptic technique when accessing the PIVC are also used. Careful daily assessment is required; of need, and for inflammation or infection, with prompt removal of clinically suspect or redundant lines. Amazingly, we do a poor job at identifying PIVCs that have no purpose and should be removed. New strategies to reduce complications could include chlorhexidine-impregnated dressings and bundles of care, both of which have been shown to be effective in reducing infections associated with central venous catheters (CVCs) and potentially also with PIVCs.5,6 Our hospitals have moved from using “IV teams” to perform insertions to leadership by key individuals who champion policies and drive change to ensure PIVC care is evidence-based and standardised.

Stuart and colleagues found 24% of SABs (137/583) to be PIVC-associated, which was higher than the 4% (24/544) found in a recent US study.3 Further, they found more SABs were associated with PIVCs than with CVCs (24% compared with 18%). In contrast, a review of 491 bloodstream infections, of which 31% were SABs, found many more were CVC-associated (38%) than PIVC-associated (7%).7 Stuart et al’s definition of PIVC-associated SAB allowed for up to 7 days between the presence of a PIVC and a positive blood culture for SAB, which is likely to have increased PIVC-associated SAB incidence; a more restrictive 48-hour time frame is more common.8 This incidence rate may also have been increased by the use of site symptoms (redness, tenderness, phlebitis or induration) as confirmation of the PIVC source, rather than microbiological catheter-tip or site cultures. We observed that PIVCs frequently developed site symptoms, and these had poor positive predictive value for bloodstream infections.4 Regardless of definitions, the overall incidence of PIVC-related bloodstream infection is very low — < 1 in 1000 patients;4,9 randomised controlled trials of interventions would require logistically impossible sample sizes to prove efficacy using this end point.

The SAB episodes described by Stuart and colleagues occurred despite institutional policies already being in place for PIVC removal in 96 hours or less. Dwell times for episodes of PIVC-associated SAB averaged 3.5 days — within the recommended time frame — further suggesting that dwell time was not a factor. Some SABs occurred up to 9 days after insertion, but it is often impossible to resite catheters routinely, owing to patients’ poor veins or clinical condition, or staff unavailability.10 Undoubtedly, microbes increase over time, and longer overall dwell time holds greater risk than a shorter period, but strong data have indicated that two 3-day PIVCs hold the same risk as a PIVC with a dwell time of 6 days.4,11

Stuart et al’s data confirm that SAB remains a problem with PIVCs and that, rather than relying on the “3 day rule” to prevent complications, strict attention to insertion and maintenance practice is required. This complements the message from our recent large trial published in The Lancet — PIVCs can be safely used beyond 96 hours, but they must also be aseptically inserted, carefully maintained, assessed daily and removed as soon as possible.4 It is time to stop watching the clock and instead focus on our own practices — for our patients’ benefit.

Immigration screening for latent tuberculosis infection

Epidemiologist Justin Denholm advocates universal screening of migrants from high-incidence countries

In Australia, 1222 cases of tuberculosis (TB) were notified in 2011, which represents an annual incidence of six cases per 100 000 population.1 Despite this relatively low incidence by global standards, TB disease continues to cause significant morbidity and mortality, and has a substantial impact on the health and wellbeing of affected individuals and communities.2 In addition to the direct clinical impact, effective management of TB imposes a substantial burden on health care systems and public health programs. Opportunities to reduce TB incidence further in Australia, therefore, would be welcome and should be actively pursued.

Over the past decade, 80%–90% of people who developed TB in Australia were born overseas, with by far the most common clinical pathway to presentation being reactivation of previously latent TB infection (LTBI).3 People migrating to Australia from countries with high TB incidence are at significant risk of developing TB disease, even decades after arrival.4 In 2012, the National Tuberculosis Advisory Committee highlighted the importance of migrants in their strategic plan for control of TB in Australia, identifying overseas-born people in general, and overseas-born students in particular, as priority populations in the plan to reduce TB risk.5 Effective therapy for preventing reactivation is available, but most people who have LTBI have not been diagnosed and are unaware of their risk of developing active TB disease. Practical approaches to diagnosing LTBI among groups who are at high risk of TB disease are required, particularly close to the time of arrival in Australia because this is when diagnosis of LTBI would be most effective in preventing subsequent disease. While a variety of different strategies might accomplish this aim, perhaps the most efficient would be incorporating a screening program for LTBI into the existing immigration process.

Currently, TB screening in immigrants consists of a chest x-ray and a clinical examination before entry, to identify those with active disease. This program, combined with postmigration follow-up (the TB Health Undertaking) is effective in identifying migrants who have active TB infection.6 However, no testing for LTBI — with tests such as the tuberculin skin test or the interferon-γ release assay (eg, the QuantiFERON-TB Gold In-Tube assay [Cellestis], which is in use in Australia) — is performed routinely, apart from the testing done in accordance with recommendations to screen refugees and asylum seekers. Thus, the opportunity to systematically identify those at highest risk of progression to active TB is missed, as is the chance to intervene and prevent TB disease.

Arguably, the most appropriate approach to identifying LTBI in immigrants would be a requirement for LTBI testing to be performed on those arriving from countries with a high incidence of tuberculosis, followed by provision of effective LTBI therapy after arrival. For such a strategy to be justifiable, it should screen immigrants with an appropriately large risk of LTBI, using a test with high specificity, and positive test results should not be used to restrict migration.7 Data from LTBI screening programs in the United Kingdom suggest that the use of an interferon-γ release assay for screening immigrants from high-incidence countries would have a high yield of positive results — a positive test result is seen in 20% and 28% of migrants from the Indian subcontinent and sub-Saharan Africa, respectively.8 These programs are cost-effective when used to screen those younger than 35 years from countries with TB incidence of more than 40 cases per 100 000 population per year, with optimal efficiency for country thresholds of about 150 cases per 100 000 population per year.8 While an optimal threshold for the Australian context remains to be established, it is likely to be broadly comparable with the UK experience, suggesting that an efficient and cost-effective immigration screening program is a realistic consideration.

TB rates in Australia are likely to continue to rise due to the ongoing arrival of migrants with LTBI. While international efforts to control TB disease in high-incidence countries are critical for reducing transmission, prevention of LTBI reactivation is very important in terms of eradicating TB as a global public health issue. An immigration screening program for LTBI would be an effective and practical way to improve the health of new Australians through prevention of TB, reduce TB incidence and risk of secondary transmission in the Australian community, and further strengthen TB control programs in the Asia–Pacific region.

Peripheral intravenous catheter-associated Staphylococcus aureus bacteraemia: more than 5 years of prospective data from two tertiary health services

Staphylococcus aureus bacteraemia (SAB) is an important hospital-acquired infection often associated with indwelling devices.1–3 The risk of a peripheral intravenous catheter (PIVC) leading to SAB is low, estimated to occur in about 0.1% of lines.4 However, up to 80% of hospitalised patients have a PIVC in situ at some time during their acute stay,5,6 so absolute numbers of PIVC-associated SAB may be a more pressing issue than has been previously recognised.1,3,5

Debate over the need for routine PIVC replacement is ongoing. In 1996, the United States Centers for Disease Control and Prevention recommended that PIVC sites should be rotated at intervals of 48–72 hours.7 Later guidelines suggested that routine PIVC changes were not required more frequently than 72–96 hours in adults.8 In 1998, researchers reported that the hazard for PIVC complications (thrombophlebitis, infection) did not appear to increase during prolonged catheterisation and recommended that routine replacement was unnecessary.9 These findings have been recently echoed in a multicentre randomised trial involving over 3200 patients but remain controversial.10

We sought to review 5 years of PIVC-associated SAB in two tertiary referral health services to define the frequency, mortality and associated risk factors for this health care-associated complication.

Methods

Two tertiary referral health services in Melbourne (Monash Health and Austin Health, with 2150 and 840 beds, respectively) were included in our analysis. Both services prospectively used the same data collection tool to collect data on every episode of SAB that occurred within each facility. The data for this study included all health care-associated SAB episodes occurring in adults aged > 17 years at each site from January 2007 to July 2012.

Every positive blood culture for S. aureus was investigated by infection control and classified as health care or community associated. Health care-associated SAB was defined as isolation of S. aureus from one or more blood cultures taken:

during hospitalisation, 48 hours or more after admission; or
within 48 hours of admission in a patient with an indwelling medical device; or
within the last 30 days in a patient who has had surgery and the SAB is deemed to be related to the procedure; or
within 48 hours of an invasive procedure.

Data collected for each health care-associated SAB episode included patient demographics, place of acquisition (community or hospital), likely source of infection, primary clinical manifestation and outcomes at 7 and 30 days. Neither service has a dedicated peripheral-line management team.

For SAB deemed to be device-related, details of device type, place of insertion (ambulance, emergency department [ED], ward) and device dwell time (days before the SAB was identified) were collected. A case of PIVC-associated SAB was defined as a health care-associated SAB in a patient:

with a PIVC in situ or removed within the 7 days before the positive blood culture; and
with no other source of SAB identified and either a physician or nurse documenting the PIVC as the source of the SAB in the medical record; and/or
with physical findings suggesting a PIVC as the source (erythema, induration, phlebitis, tenderness).

To estimate the PIVC-associated SAB rate we used occupied bed-days (OBD) for all overnight stays as the denominator.

This study was approved at both hospitals by their respective ethics committees as a quality study.

Results

There were 583 health care-associated SAB episodes across the two health services, with 137 (23.5%) deemed to be PIVC-associated SAB (Box 1). The total number of episodes of PIVC-associated SAB exceeded that of SAB associated with central intravenous lines (102 [17.5%]).

Over the period of the study there were 5 235 560 total OBDs across both sites and an overall rate of PIVC-associated SAB of 0.261/10 000 OBD (Box 2). Of the patients with PIVC-associated SAB, 95 (69%) were men and mean age was 71 years (range, 18–95 years).

Dwell time could be ascertained in 124 of the 137 episodes of PIVC-associated SAB. Of these, the mean PIVC dwell time was 3.5 days (median, 3 days; range, 0.25–9 days). Fifty-six PIVC-associated SAB episodes (45.2%) occurred in PIVCs with dwell times greater than or equal to 4 days (Box 2).

There were 44 PIVCs (39.6%) inserted in the ED, 44 (39.6%) in the ward and 23 (20.8%) by the ambulance service (Box 2). Of 68 PIVC-associated SAB episodes occurring within 3 days of insertion, 24 (35.3%) were inserted in the ED or by the ambulance service. This increased to 61% (48 of 79 SAB episodes) for dwell times of ≤ 4 days.

PIVC-associated SAB episodes were associated with a 30-day all-cause mortality rate of 26.5%.

Discussion

Data collected over more than 5 years in two tertiary health services showed a high incidence of SAB episodes associated with PIVCs inserted in emergency locations and with prolonged (≥ 4 days) dwell times.

SAB is a major cause of morbidity and mortality. Similar to our finding of 26.5%, a 30-day all-cause mortality rate of 20.6% has been reported previously in a study of 1994 episodes of SAB.3

Each PIVC-associated SAB episode also has a significant financial cost. Financial data for SAB in Australia are scarce, and measuring the economic costs were beyond the scope of this study. Assumed additional costs of $20 000 per episode have been previously quoted.2 This would equate to $29 500 on average, adjusted for the consumer price index, and give an estimated total cost of PIVC-associated SAB at our two institutions for the study period of $4.04 million.

Reducing PIVC-associated SAB is therefore paramount. Prevention strategies include not inserting PIVCs unless needed, ensuring aseptic technique on insertion and early removal when the line is no longer required or when it is inserted during emergency situations. Additionally, reduction of SAB may also be possible by routine replacement of PIVCs.7,8 A multicentre, randomised, non-blinded equivalence trial among adults with a PIVC of expected use longer than 4 days was reported recently. Researchers compared rates of thrombophlebitis, during catheterisation or within 48 hours of removal, between patients who had PIVCs routinely replaced on Day 3 and those having a PIVC replaced only if clinically indicated (completion of therapy, thrombophlebitis, inflammation, occlusion, suspected infection). While the study was powered for phlebitis, they only noted one PIVC-associated SAB (in the routine-change arm) in 3283 patients and out of 5907 catheters.10

Our study design was based on investigation of each incident case of SAB, not following two arms of a randomised cohort. We believe our data suggest that timely removal of PIVCs is important for reducing risk of SAB, particularly when inserted in suboptimal circumstances. The likely explanation for the different finding of the equivalence trial is that the true incidence of PIVC-associated SAB was below the level of detection allowed by its design, and that phlebitis is not a reliable predictor of SAB.

Other factors that might have influenced the results of the equivalence study include non-blinding of the research nurses, the daily presence of research nurses on the wards and up to 40% of PIVC being placed by a specialised team dedicated to inserting intravenous catheters.10 Our study, on the other hand, shows rates of PIVC-associated SAB in a real-life situation, where PIVCs were inserted in EDs and wards.

From our study, we cannot confirm whether PIVC replacement at 72–96 hours is appropriate or whether only clinically indicated replacement is warranted. However, about 45% of PIVC-associated SAB were potentially preventable by removal before the 4-day cut-off.

Strengths of our study include the large numbers of cases across two sites and the prospective nature of data collection. Limitations include the fact that the rate of PIVC-associated SAB we have defined is a crude rate. To adequately define relative risks associated with longer dwell times we would need data on PIVC days among this population. Additionally, although to our knowledge these data are the largest series of PIVC-associated SAB episodes reported, the results may not be generalisable to all health services.

Our study highlights the significant issue of PIVC-associated SAB. Further studies powered for the outcome of SAB to solve the issue of whether routine PIVC replacement reduces SAB are required, as are studies investigating the cost of SAB. In the meantime, protocols for PIVC removal at ≤ 4 days will remain at our two hospitals. National standards for PIVC insertion and maintenance are needed.

1 Sources of health care-associated Staphylococcus aureus bacteraemia (SAB) in two tertiary health services, January 2007 to July 2012

	SAB episodes, no. (%)
Source	Monash Health	Austin Health	Total

Device-associated	267 (67.6%)	107 (56.9%)	374 (64.2%)
PIVC	96 (24.3%)	41 (21.8%)	137 (23.5%)
Central line	78 (19.7%)	24 (12.8%)	102 (17.5%)
PICC	47 (11.7%)	12 (6.4%)	59 (10.1%)
Haemodialysis	27 (6.8%)	15 (8.0%)	42 (7.2%)
Urinary device	9 (2.3%)	3 (1.6%)	12 (2%)
Orthopaedic device	3 (0.8%)	6 (3.2%)	9 (1.5%)
Other device	7 (1.8%)	6 (3.2%)	13 (2.2%)
Not device-associated	128 (32.4%)	81 (43.1%)	209 (35.9%)
Total	395	188	583

PIVC = peripheral intravenous catheter. PICC = peripherally inserted central catheter.

2 Details of PIVC-associated Staphylococcus aureus bacteraemia in two tertiary health services, January 2007 to July 2012*

Variable

Monash Health

Austin Health

Total

Rate per 10 000 OBD

0.288

0.280

0.261

MRSA episodes

18/96 (18.8%)

14/41 (34.1%)

32/137 (23.4%)

Location where insertion took place

Ambulance

20/77 (26.0%)

3/34 (8.8%)

23/111 (20.8%)

28/77 (36.4%)

16/34 (47.1%)

44/111 (39.6%)

Ward

29/77 (37.7%)

15/34 (44.1%)

44/111 (39.6%)

Mean dwell time, days (range)

3.5 (1–9)

3.5 (0.25–9)

Dwell time ≥ 4 days

43/90 (47.8%)

13/34 (38.2%)

56/124 (45.2%)

Alive at 7 days

89/96 (92.7%)

38/41 (92.7%)

127/137 (92.7%)

Alive at 30 days

48/61 (78.7%)

27/41 (65.9%)

75/102 (73.5%)

OBD = occupied bed-days. MRSA = methicillin-resistant S. aureus. ED = emergency department. * Values are no. of episodes/total PIVC-associated SAB episodes (%) unless otherwise indicated. Denominators vary according to the total number of episodes that could be ascertained for each variable.

Human papillomavirus vaccine in boys: background rates of potential adverse events

Cervical cancer is the most common cancer affecting women in developing countries. It is caused by persistent infection with specific types of human papillomavirus (HPV).1 Quadrivalent human papillomavirus (4vHPV) vaccine is a recombinant vaccine administered as a three-dose course to provide protection against four types of HPV (6, 11, 16 and 18).2 The vaccine is highly efficacious for the four included types, of which 16 and 18 are reported to cause 70% of cervical cancers and 6 and 11 cause anogenital warts.1,3 4vHPV vaccination was introduced under the Australian National Immunisation Program (NIP) in April 2007 for adolescent girls, with an initial catch-up program including women up to 26 years of age. The current ongoing funded program is only for girls in the first year of high school (aged 12–13 years). Recent data suggest that the 4vHPV vaccination program has caused a rapid decline in genital wart presentations in females,4,5 and there are early indications of a reduction in high-grade cervical dysplasias.6

Following advice from the Australian Technical Advisory Group on Immunisation, vaccination of males was recommended as a cost-effective intervention by the Pharmaceutical Benefits Advisory Committee in November 2011.7 Accordingly, 4vHPV vaccination for boys has been added to the Australian NIP, commencing in 2013 and targeting boys aged 12–13 years in a school-based program, with a catch-up program over 2 years for boys aged 14–16 years.7,8 The program aims to reduce the incidence of HPV disease in males, such as anogenital warts and anal intraepithelial neoplasia,9 and reduce sexual pathways of virus transmission. Australia will be the first nation to implement HPV vaccination for boys in a national program.

Vaccines, as with any medicine, have potential adverse reactions varying from mild and expected to rare and/or serious events. Vaccination may cause such events — the nature of adverse events following immunisation (AEFI) and the timing of onset after vaccination are important factors when assessing causation. Adverse events may also coincide temporally with vaccine administration by chance. To interpret postlicensure surveillance data, it is useful to know the background rates of common and rare potential adverse events before introduction of the vaccine.10,11 With this understanding, increases above background rates can be rapidly identified, which can assist with the evaluation and reporting of potential vaccine-associated adverse event rates.

The mass school-based introduction of female 4vHPV vaccination raised a number of well publicised initial safety concerns, including “scares” regarding potential episodes of anaphylaxis and multiple sclerosis after vaccination.12–14 In addition, a mass psychogenic reaction was seen in a Melbourne school vaccination environment,15 with syncope and syncopal seizures occurring in response to the vaccination process.16 Such spurious events may arise from the psychological impact of the vaccination process, particularly when using mass vaccination strategies in a school-based teenaged population.

Release of the 4vHPV vaccine to boys has the advantage of adverse event information from prelicensure clinical trials and postlicensure surveillance of adverse events arising from administration to adolescent girls. However, additional information on the background rates of potential adverse events in teenaged boys is critical for assessing the safety of this vaccination program.

Our aim was to explore the use of routinely collected information for estimating potential adverse event rates. We used population-level health outcome administration data to describe the background rates of potential AEFI before the introduction of 4vHPV vaccination for boys into the NIP in Australia, and to estimate numbers of a range of neurological, allergic and other events that can be expected following vaccination, assuming temporal association with administration of vaccine but no other association.

Methods

Two statewide Victorian datasets were accessed — the Victorian Admitted Episodes Dataset (VAED; hospital discharge data) and the Victorian Emergency Minimum Dataset (VEMD; emergency department visit data) — both of which include International Classification of Diseases 10th revision Australian modification (ICD-10-AM) codes. The data included a unique identifier that enabled linking of individuals across the datasets, but were otherwise non-identifying, according to Victorian Department of Health data linkage protocols.17 Ethics approval for the study was provided by the VAED and VEMD data custodians.

Multiple records of the same event within a dataset or across datasets — for example, a person presenting at emergency who is subsequently admitted, or a person admitted to hospital who is then discharged to a different hospital or to home and who later returns with continuation of the same episode (with each presentation recorded as a separate event) — were linked via the unique identifier. All events occurring within 28 days of a previous event were combined into a single episode.

The data that we analysed comprised all episodes that occurred in boys aged 12 to < 16 years and were recorded in the VAED and/or VEMD with one of the ICD-10-AM codes listed in Box 1 and an admission or presentation date from 1 July 2004 to 30 June 2009.18 Conditions selected for inclusion are rare adverse events, conditions that patients are likely to present to hospitals with after vaccination, and conditions that have previously been raised as potential sources of concern in Australia and overseas.10,19

Age was taken to be the youngest age at which an episode occurred, and records were excluded from the analysis if sex was recorded inconsistently among records with the same unique identifier. Some records had more than one ICD-10-AM code, and these were preserved. Events with an interstate or overseas postcode were excluded, but those with “unknown” (8888 and 9988) and “of no fixed abode” (1000) postcodes were preserved under the assumption that these occurred in Victoria. Episodes that were ongoing from the 3 months before the study period, the washout period (31 March to 30 June 2004), were also excluded.

Events were described as the number of episodes and the number of first events. An episode was considered a discrete event if it occurred more than 28 days after a prior event in the same individual, as patients were deemed to still be “at risk” of the same event during their recovery from an acute condition. First events were defined as the first time a condition was diagnosed in each patient during the study period. First events are more relevant for chronic conditions and episodes are more relevant for acute conditions.

We calculated background annual incidence rates as the number of events during the 5-year study period divided by the population at risk during this period, using Australian Bureau of Statistics 2006 mid-year resident population data for males.20

The analysis was restricted to boys aged 12 to < 16 years — the target age range for vaccination. We used these background rates to estimate the number of events expected within 1 day, 1 week and 6 weeks of vaccination per 100 000 vaccinees. We then estimated the expected number of events for each condition 1 day, 1 week and 6 weeks after vaccination across Australia following the introduction of 4vHVP into the NIP, assuming there is no association (other than temporal) with the vaccine.

Seasonal variation was analysed by graphing the number of first events or episodes by month of presentation. As the numbers of chronic neurological presentations in the study group were small, they were combined and compared with numbers of all-age presentations in males for individual neurological conditions. For multiple sclerosis, data were also presented omitting presentations in the first 12 months of the study period to assess the effectiveness of the study’s 3-month washout period.

Results

The numbers of and incidence rates for potential AEFI in boys aged 12 to < 16 years are shown in Box 2, and the estimated numbers of cases of potential AEFI per 100 000 adolescent boys that would occur, even in the absence of vaccine, are shown in Box 3. Assuming an 80% vaccination rate with three doses per person — which equates to about 480 000 boys vaccinated and a total of 1 440 000 doses administered nationally per year in the first 2 years of the program — about 2.4 episodes of Guillain-Barré syndrome would be expected to occur within 6 weeks of vaccination. In addition, about 3.9 seizures and 6.5 acute allergy presentations would be expected to occur within 1 day of vaccination, including 0.3 episodes of anaphylaxis.

There was minimal seasonal variation in the occurrence of potential AEFI (Box 4, Box 5). However, repeating this analysis with a larger number of neurological presentations (using data for all age groups) revealed a notable peak in the number of multiple sclerosis presentations in July. This peak was reduced but not eliminated when the washout period was increased to 15 months (Box 4).

Discussion

Using statewide morbidity data, we estimated background rates of neurological and allergic events in adolescent boys in Victoria to be 252.9 and 175.2 per 100 000 person-years, respectively. Such adverse events may be mistakenly assumed to be caused by vaccination, owing to temporal association, when the 4vHPV vaccination program is expanded to include adolescent boys.10 Postlicensure safety assessments of 4vHPV vaccine programs in adolescent girls have shown little evidence of increased risk of neurological and allergic adverse events after vaccination.3,21,22

Expected rates of potential AEFI in recent studies vary widely, but direct comparisons are restricted because of differences in methods, health care systems and data collection and analyses.10,11,23 In particular, caution is required when using emergency presentation databases as these may record preliminary diagnoses, rather than final diagnoses. Studies limited to analysis of ICD-10 coded data, such as ours, lack the rigour of diagnosis verification and conformity to standardised case definitions, although coding standards are maintained. Our study identified higher reporting rates for anaphylaxis compared with similar studies.10,11 While data aberrations are possible, marked increases in anaphylaxis rates Australia and the United States over the past two decades may play a part.24,25

Background rates of potential AEFI and consequent thresholds for safety flags should not be informed merely using data on adolescent girls because sex-related differences could cause misinterpretation of potential signals.10,11 For example, the rate of adolescent boys presenting with a first multiple sclerosis event in the 6 weeks following vaccination would be expected to be one-third of the rate seen for adolescent girls assuming no relationship with vaccine other than temporal.26

In our study, we used a 3-month washout period to attempt to remove the risk of categorising events as incident cases when they were part of a pre-existing illness than was ongoing from before the study period. However, the 3-month washout period did not remove this issue for multiple sclerosis. While our study showed little seasonal variation in potential AEFI, school-based vaccination programs are conducted in blocks (as convenient to the vaccine schedule and the school year), which may give rise to false signal detection. Specific investigation of appropriate washout periods, as well as seasonal variation in the occurrence potential AEFI and implementation of the vaccine program, must therefore be explored before conducting in-depth analyses for specific conditions or extrapolating data to other jurisdictions.

In Victoria, first-dose 4vHPV vaccine coverage for adolescent girls has reached 80%,27 but challenges of uptake and course completion by males may be anticipated.28 If coverage for boys is less than 80%, the expected rates in our study should be recalculated to avoid erroneous alert thresholds.

The background rates of potential AEFI that we have estimated can be used to inform surveillance systems, health care providers and the community regarding health care events that may be temporally related to vaccination. In mass vaccination programs, where vaccine exposure is a common event in the target group, many incident acute health conditions will occur following vaccination, irrespective of causal association. While current passive surveillance system reporting is likely to underascertain postvaccination events, prior knowledge of expected numbers of events are valuable in helping determine whether reports or clusters of reports represent real safety flags that require urgent investigation.26

Our data highlight the value of statewide and nationwide health datasets in providing information that can improve public safety. In addition to establishing background rates of diseases, international systems such as those in Denmark and the US, have been used to link vaccination databases to health care event databases, enabling direct investigation of potential associations with adverse events.29–31 These methods, conducted in accordance with state and federal privacy protections, offer a promising future for further improving vaccine safety in Australia.32

Routinely collected state health outcome data can enable informed postlicensure safety surveillance of conditions that may be perceived as AEFI. When the 4vHPV vaccine program is expanded to adolescent boys, such data can be used for targeted active surveillance of potential vaccine safety flags.

1 Conditions included in the study

ICD-10-AM codes

Neurological

Guillain-Barré syndrome*

G61.0

Transverse myelitis*

G37.3

Multiple sclerosis*

G35

Optic neuritis*

H46, G36.0

ADEM

G04.0

Bell’s palsy

G51.0

Syncope

R55

Seizures

R56, R56.0, R56.8

Allergic

Anaphylaxis

T78.2, T88.6

Urticaria

L50.0, L50.1, L50.9

Serum sickness

T80.6

Adverse effect of drug or medication†

T88.7

Other

Adverse events

T78.8, T78.9, T88.1, T78.3

ICD-10-AM = International Classification of Diseases 10th revision Australian modification. ADEM = acute disseminated encephalomyelitis. * Conditions considered chronic. † Not otherwise specified.

2 Numbers of and incidence rates for potential AEFI in boys aged 12 to < 16 years (Victoria, July
2004 – June 2009)

First events

Episodes

No. of events

Incidence rate (95% CI) per 100 000 person-years

No. of events

Incidence rate (95% CI) per 100 000 person-years

Neurological

Guillain-Barré syndrome

1.46 (0.56 to 2.37)

1.61 (0.66 to 2.56)

Transverse myelitis

0.29 (− 0.11 to 0.70)

0.44 (− 0.06 to 0.94)

Multiple sclerosis

0.29 (− 0.11 to 0.70)

Optic neuritis

0.59 (0.01 to 1.16)

0.88 (0.18 to 1.58)

ADEM

0.17 (0.45 to 1.90)

1.61 (0.66 to 2.56)

Bell’s palsy

8.78 (6.56 to 11.00)

Syncope

807

118.0 (109.9 to 126.2)

831

121.5 (113.3 to 129.8)

Seizures

666

97.4 (90.0 to 104.8)

830

121.4 (113.1 to 129.7)

Total

1516

221.7 (210.6 to 232.9)

1729

252.9 (241.0 to 264.8)

Allergic

Anaphylaxis

7.17 (5.16 to 9.17)

7.46 (5.41 to 9.51)

Urticaria

620

90.7 (83.6 to 97.8)

647

94.6 (87.3 to 101.9)

Serum sickness

3.4 (2.0 to 4.7)

Allergic reaction

495

72.4 (66.0 to 78.8)

517

75.6 (69.1 to 82.1)

Total

1125

164.6 (154.9 to 174.2)

1198

175.2 (165.3 to 185.1)

Other

Total

1.02 (0.27 to 1.78)

AEFI = adverse events following immunisation. ADEM = acute disseminated encephalomyelitis.

3 Estimated numbers of cases of potential AEFI in vaccinated boys aged 12 to < 16 years, assuming no relationship with vaccine*

No. of first events per 100 000 population

No. of episodes per 100 000 population

1 day

1 week

6 weeks

1 day

1 week

6 weeks

Neurological

Guillain-Barré syndrome

0 (0.00–0.01)

0.03 (0.01–0.05)

0.17 (0.06–0.27)

0 (0.00–0.01)

0.03 (0.01–0.05)

0.19 (0.08–0.29)

Transverse myelitis

0 (0.00–0.00)

0.01 (0.00–0.01)

0.03 (0.00–0.08)

0 (0.00–0.00)

0.01 (0.00–0.02)

0.05 (0.00–0.11)

Multiple sclerosis

0 (0.00–0.00)

0.01 (0.00–0.01)

0.03 (0.00–0.08)

0 (0.00–0.00)

0.01 (0.00–0.01)

0.03 (0.00–0.08)

Optic neuritis

0 (0.00–0.00)

0.01 (0.00–0.02)

0.07 (0.00–0.13)

0 (0.00–0.00)

0.02 (0.00–0.03)

0.10 (0.02–0.18)

ADEM

0 (0.00–0.01)

0.02 (0.01–0.04)

0.15 (0.05–0.25)

0 (0.00–0.01)

0.03 (0.01–0.05)

0.19 (0.08–0.29)

Bell’s palsy

0.02 (0.02–0.03)

0.17 (0.13–0.21)

1.01 (0.75–1.26)

0.02 (0.02–0.03)

0.17 (0.13–0.21)

1.01 (0.75–1.26)

Syncope

0.32 (0.30–0.35)

2.26 (2.11–2.42)

13.57 (12.64–14.51)

0.33 (0.31–0.36)

2.33 (2.17–2.49)

13.98 (13.03–14.93)

Seizures

0.27 (0.25–0.29)

1.87 (1.73–2.01)

11.20 (10.35–12.05)

0.33 (0.31–0.35)

2.33 (2.17–2.48)

13.96 (13.01–14.91)

Total

0.61 (0.58–0.64)

4.25 (4.04–4.46)

25.50 (24.22–26.78)

0.69 (0.66–0.72)

4.85 (4.62–5.07)

29.08 (27.71–30.45)

Allergic

Anaphylaxis

0.02 (0.01–0.03)

0.14 (0.10–0.18)

0.82 (0.59–1.05)

0.02 (0.01–0.03)

0.14 (0.10–0.18)

0.86 (0.62–1.09)

Urticaria

0.25 (0.23–0.27)

1.74 (1.60–1.87)

10.43 (9.61–11.25)

0.26 (0.24–0.28)

1.81 (1.67–1.95)

10.88 (10.04–11.72)

Serum sickness

0.01 (0.01–0.01)

0.06 (0.04–0.09)

0.39 (0.23–0.54)

0.01 (0.01–0.01)

0.06 (0.04–0.09)

0.39 (0.23–0.54)

Allergic reaction

0.20 (0.18–0.22)

1.39 (1.27–1.51)

8.33 (7.59–9.06)

0.21 (0.19–0.22)

1.45 (1.32–1.57)

8.70 (7.95–9.44)

Total

0.45 (0.42–0.48)

3.15 (2.97–3.34)

18.92 (17.82–20.03)

0.48 (0.45–0.51)

3.36 (3.17–3.55)

20.15 (19.01–21.29)

Other

Total

0 (0.00–0.00)

0.02 (0.01–0.03)

0.12 (0.03–0.20)

0 (0.00–0.00)

0.02 (0.01–0.03)

0.12 (0.03–0.20)

AEFI = adverse events following immunisation. ADEM = acute disseminated encephalomyelitis. * Data are based on one dose of vaccine per vaccinee.

4 Numbers of first events of chronic conditions, by month (Victoria, July 2004 – June 2009)

* Data are numbers of first events for chronic neurological conditions analysed in boys aged 12 to
< 16 years and numbers of presentations for individual neurological conditions in males of all ages.
† Conditions included were Guillain-Barré syndrome, transverse myelitis, multiple sclerosis and
optic neuritis.

5 Number of episodes of acute conditions by month in boys aged 12 to < 16 years (Victoria, July 2004 – June 2009)

ADEM = acute disseminated encephalomyelitis.

Steroids control paradoxical worsening of Mycobacterium ulcerans infection following initiation of antibiotic therapy

Clinical record

A 19-year-old man with a 3-month history of a non-healing ulcer of the right knee and indurated oedema involving the entire lower leg (Box 1) presented after not responding to multiple courses of antibiotics. A punch biopsy showed necrosis of the dermis and subcutaneous tissues, and extensive infiltration with extracellular acid-fast bacilli on auramine–rhodamine staining. Polymerase chain reaction (PCR) testing for the IS2404 insertion sequence of Mycobacterium ulcerans was positive,1 and M. ulcerans was isolated from culture at 6 weeks. The patient reported holidaying on the Bellarine Peninsula, an endemic area for M. ulcerans, 6 months before the development of the lesion. Surgical intervention was deferred due to the extensive area involved and World Health Organization guidelines suggesting antibiotics as first-line treatment for extensive oedematous disease.2

He commenced oral daily rifampicin (600 mg) and moxifloxacin (400 mg) and, within a week, noted a marked decrease in exudate and improvement in the painful oedematous disease of the lower leg. Therapy was well tolerated and the ulcer remained stable with only one small area of new skin loss lateral to the primary lesion.

Four weeks later, there was a rapid deterioration in clinical condition, with fevers, sweats, anorexia and a recurrence of lower limb oedema and pain. Significant skin breakdown occurred around the ulcer and distally on the leg, with copious serous exudate (Box 2). Full blood examination showed a neutrophilia (neutrophil count, 14.9 × 109/L [reference interval, 1.9–8.0 × 109/L]) and a raised C-reactive protein level (69.8 mg/L [reference interval, < 3 mg/L]). Prednisolone 50 mg daily and

intravenous piperacillin–tazobactam 4.5 g three times daily was commenced. An ultrasound of the limb showed extensive liquefaction of the subcutaneous fat, and swabs were PCR-positive for M. ulcerans but culture-negative following prolonged incubation.

Within 12 hours of commencing prednisolone therapy (combined with broad-spectrum antibiotics), the patient became afebrile, with neutrophil and C-reactive protein levels within reference intervals on full blood examination and an improvement in ulcer appearance. He was discharged on a 25 mg maintenance dose of prednisolone while continuing rifampicin and moxifloxacin. Increasing areas of skin loss and exudate developed when prednisolone was decreased to 12.5 mg daily, and thus he underwent a limited debridement of the lateral knee and negative-pressure wound therapy (VAC GranuFoam dressing, KCI Medical), followed by successful split skin grafting. Heat therapy (Bair Hugger, 3M Arizant Healthcare) was used to maintain skin temperature
at 39°C.

Prednisolone was continued for 2 weeks postoperatively (15 mg daily) and then stopped without further deterioration in the patient’s condition. The patient completed a 3-month course of antimycobacterial antibiotics, at which time there was no sign of ongoing infection. Two skin sites subsequently discharged a small amount of culture-negative material but, at 12 months, there was no evidence of microbiological relapse.

Mycobacterium ulcerans infection is a geographically restricted infection often referred to by its local name as Daintree, Buruli or Bairnsdale ulcer (BU). The disease occurs in sub-Saharan Africa and within discrete regions of Australia, predominantly coastal Victoria and northern Queensland. Significant diagnostic delays, which place patients at risk of more extensive disease, are common. A recent review identified a mean duration of 42 days of symptoms before diagnosis (range, 2–270 days).3 These delays often occur when patients present outside endemic areas, a factor affected by the long incubation period of 4–7 months.4

BU is characterised by slowly progressive skin lesions with local necrosis, destruction of lipocytes and surprisingly little systemic inflammation. This unusual pattern of infection is the result of its unique virulence factor mycolactone, an immunomodulatory toxin that induces necrosis of host tissues and can limit initiation of immune responses and the recruitment of inflammatory cells.5 Following the increased use of antibiotics in BU, there have been descriptions of worsening clinical condition after an initial response to therapy.6 Such deteriorations (referred to as paradoxical reactions) are most common in patients with extensive disease and can take a variety of forms including increased ulcer size, ulceration of previously non-ulcerative papules or the development of new lesions not detectable before antibiotics.7 It is particularly important that paradoxical reactions are not misinterpreted as antibiotic failure, as the vast majority of lesions will resolve without a change in antibiotic regimen.

Paradoxical reactions may be the result of antibiotic-induced suppression of mycolactone synthesis, leading to decreased mycolactone concentrations and thus a reversal of macrophage and neutrophil dysfunction with renewed immune surveillance and response.7 There are many parallels to the paradoxical reactions described with Mycobacterium tuberculosis in HIV co-infected patients who initiate antiretroviral therapy. In that setting, the reaction likely represents an increased inflammatory response secondary to antiretroviral-induced immune reconstitution. As with M. tuberculosis, paradoxical reactions to BU commonly occur 4–8 weeks after therapy commences.7

In our case, the deterioration 4 weeks into therapy at the time that mycobacterial cultures became sterile indicates that this was not a failure of antibiotics but an unmasked immune phenomenon. Although our patient did receive a short course of intravenous antibiotics at the time of initiation of steroid therapy, the rapidity of his response and lack of identification of a new bacterial pathogen suggests that the steroid therapy itself was responsible for his improvement. This is supported by the fact that his condition deteriorated when his prednisolone dose was weaned.

It has been shown in animal models that corticosteroids do not adversely affect the outcome of antibiotic therapy in BU,8 and Friedman and colleagues reported a marked improvement in the appearance of lesions when steroids were used for paradoxical reactions in this setting.9 Established dosing guidelines are available for the management of paradoxical reactions to M. tuberculosis (most popularly, 1 mg/kg/day until improvement, followed by a 2-week wean),10 yet the degree of applicability of these guidelines to BU management is unknown.

As treatment evolves from a purely surgical approach to an adjunctive or primary antibiotic focus, optimal management remains controversial. In patients with extensive and oedematous disease, pre-emptive steroid therapy may have a role in preventing paradoxical deteriorations, although to date there is no randomised evidence to support its use in this way.

Lessons from practice

Mycobacterium ulcerans should be considered in patients who present with non-healing chronic ulcers or atypical cellulitis that do not respond to standard treatment.
It is common for M. ulcerans infections to worsen following the initiation of antibiotics; these paradoxical reactions are likely due to an enhanced immune response directed at dead and dying bacteria and do not reflect a failure of antibiotic therapy.
Antibiotics should be continued unchanged when a paradoxical reaction occurs.
Steroids may play a role in diminishing skin loss and systemic symptoms associated with paradoxical reactions.

1 Appearance of the ulcer and proximal leg before antibiotic therapy

The lesion had been present and undiagnosed for 3 months. Swabs of the ulcer base were positive for acid-fast bacilli (auramine–rhodamine stain) and for Mycobacterium ulcerans: IS2404 polymerase chain reaction test and culture (inoculation on Lowenstein–Jensen media at 30°C).

2 Appearance of the ulcer 4 weeks into antibiotic therapy, at the time of paradoxical reaction

New areas of breakdown were appearing daily with liquefied fatty tissue protruding from the wound and associated with new onset of fevers and a marked increase in pain.

Direct-to-consumer genetic testing — where should we focus the policy debate?

What are the implications for health systems, children and informed public debate?

Until recently, human genetic tests were usually performed in clinical genetics centres. In this context, tests are provided under specific protocols that often include medical supervision, counselling and quality assurance schemes that assess the value of the genetic testing services. Direct-to-consumer (DTC) genetic testing companies operate outside such schemes, as noted by Trent in this issue of the Journal.1 While the uptake of DTC genetic testing has been relatively modest, the number of DTC genetic testing services continues to grow.2 Although the market continues to evolve,3 it seems likely that the DTC genetic testing industry is here to stay.

This reality has led to calls for regulation, with some jurisdictions going so far as to ban public access to genetic tests outside the clinical setting.4,5 In Australia, as Nicol and Hagger observe, the regulatory situation is still ambiguous;6 regulation is further complicated by the activity of internet-accessible companies that lie outside Australia’s jurisdiction. In general, the numerous policy documents that have emanated from governments and scientific and professional organisations cast DTC services in a negative light, seeing more harms than benefits, and, in some jurisdictions, governments have tried to regulate their services and products accordingly.7,8 Policy debates have focused on the possibility that DTC tests could lead to anxiety and inappropriate health decisions due to misinterpretation of the results. But are these concerns justified? Might they be driven by the hype that has surrounded the field of genetics in general. If so, what policy measures are actually needed and appropriate?

Time for a hype-free assessment of the issues?

Driven in part by the scientific excitement associated with the Human Genome Project, high expectations and a degree of popular culture hype have attracted both public research funds and venture capital to support the development of disease risk-prediction tests.3 This hype — which, to be fair, is created by a range of complex social and commercial forces9 — likely contributed to both the initial interest in the clinical potential of genetic testing and the initial concerns about possible harms. Both are tied to the perceived — and largely exaggerated — predictive power of genetic risk information, especially in the context of common diseases. There are numerous ironies to this state of affairs, including the fact that the call for tight regulation of genetic testing services may have been the result, at least in part, of the hype created by the both the research community and the private sector around the utility of genetic technologies.9 This enthusiasm helped to create a perception that genetic information is unique, powerful and highly sensitive, and specifically that, as a result, the genetic testing market warrants careful oversight.

Now that research on both the impact and utility of genetic information is starting to emerge, a more dispassionate assessment can be made about risks and the need for regulation. Are the concerns commonly found in policy reports justified? Where should we direct our policymaking energy?

It may be true that consumers of genetic information — and, for that matter, physicians — have difficulty understanding probabilistic risk information. However, the currently available evidence does not show that the information received from DTC companies causes significant individual harm, such as increased anxiety or worry.10,11 In addition, there is little empirical support for the idea that genetic susceptibility information results in unhealthy behavioural changes (eg, the adoption of a fatalistic attitude).5

The concerns about consumer anxiety and unhealthy behaviour change have driven much of the policy discussion surrounding DTC testing. As such, the research could be interpreted as suggesting that there is no need for regulation or further ethical analysis. This is not the case. We suggest that the emerging research invites us to focus our policy attention on issues that reach beyond the potential harms to the individual adult consumer — where, one could argue, there seems to be little empirical evidence to support the idea that the individual choice to use DTC testing should be curtailed — to consideration of the implications of DTC testing for health systems, children and informed public debate.

Health system costs

Although genetic testing is often promoted as a way of making health care more efficient and effective by enabling personalised medical treatment, it has been suggested that the growth in genetic testing will increase health system costs. A recent survey of 1254 United States physicians reported that 56% believed new genetic tests will increase overall health care spending.12

Will DTC testing exacerbate these health system issues by increasing costs and, perhaps, the incidence of iatrogenic injuries due to unnecessary follow-up? This seems a reasonable concern given that studies have consistently shown that DTC consumers view the provided data as health information that should be brought to a physician for interpretation. One study, for example, found that 87% of the general public would seek more information about test results from their doctor.13 The degree to which these stated intentions translate into actual physician visits is unclear. But for health systems striving to contain costs, even a small increase in use is a potential health policy issue, particularly given the questionable clinical utility of most tests offered by DTC companies. It seems likely that there will be an increase in costs with limited offsetting health benefits — although more research is needed on both these possible outcomes.

Compounding the health system concerns is the fact that few primary care physicians are equipped to respond to inquiries about DTC tests. A recent US study found that only 38% of the surveyed physicians were aware of DTC testing and even fewer (15%) felt prepared to answer questions.14 As Trent notes, even specialists can encounter difficulties in interpreting DTC genetic tests.1 This raises interesting questions about how primary care physicians will react to DTC test results. Will they, for example, order unnecessary follow-up tests or referrals, thus amplifying the concerns about the impact of DTC testing on costs?

Testing of children

While there is currently little evidence of harm caused by DTC genetic testing, most of the research has been done in the context of the adult population. The issues associated with the testing of minors are more complicated, involving children’s individual autonomy and their right to control information about themselves. Many DTC genetic testing companies include tests for adult-onset diseases or carrier status. Testing children for such traits contravenes professional guidelines. Nevertheless, research indicates that only a few DTC companies have addressed this concern. A study of 29 DTC companies found that 13 did not have policies on the issue and eight allowed testing if requested by a parent.15 While it is hard to prevent parents from submitting samples from minors to genetic testing companies, this calls for an important policy debate on whether there are limits on parental rights to access the genetic information of their children. Current paediatric genetic guidelines recommend delaying testing in minors unless it is in their best interests, but these are not enforceable and not actively monitored.16

In addition, unique policy challenges remain with regard to the submission of DNA samples in a DTC setting. It is difficult for DTC companies to check whether the sample received is from the person claiming to be the sample donor. Policymakers should consider strategies, such as sanctions, that eliminate the ordering of tests without the consent of the tested person.

Truth in advertising

The DTC industry is largely based on reaching consumers via the internet. Research has shown that the company websites — which, in many ways, represent the face of the industry — contain a range of untrue or exaggerated claims of value.17 Advertisements for tests that have no or limited clinical value have a higher risk of misleading consumers, because the claims needed to promote these services are likely to be exaggerated. It is no surprise that stopping the dissemination of false or misleading statements about the predictive power of genetics has emerged as one of the most agreed policy priorities.8 While evidence of actual harm caused by this trend is far from robust, it is hard to argue against the development of policies that encourage truth in advertising and the promotion of more informed consumers. Moreover, the claims found on these websites may add to the general misinformation about value and risks associated with genetic information that now permeates popular culture. Taking steps to correct this phenomenon is likely to help public debate and policy deliberations. For example, this might include a coordinated and international push by national consumer protection agencies to ensure that, at a minimum, the information provided by DTC companies is accurate.18

Conclusion

These are not the only social and ethical issues associated with DTC genetic testing. Others, like the use of DTC data for research and the implications of cheap whole genome sequencing, also need to be considered. But they stand as examples of issues worthy of immediate policy attention, regardless of what the evidence says about a lack of harm to individual adult users. We must seek policies that, on the one hand, allow legitimate commercial development in genomics and, on the other, achieve appropriate and evidence-based consumer protection. In finding this balance, we should not be distracted by hype or unsupported assertions of either harm or benefit.