The Lanzhou Brucella Leak: The Largest Laboratory Accident in the History of Infectious Diseases? Free

Abstract

In November 2019, an initial cluster of brucellosis cases was observed in the Lanzhou Veterinary Research Institute, in the Lanzhou city of the Gansu province of northwest China. By December 2019, 181 individuals related to the Lanzhou Animal Research Institute were confirmed as Brucella antibody positive [1]. The subsequent epidemiological investigation concluded that the patients were exposed to aerosolized Brucella due to inadequate sanitation practices in a nearby biopharmaceutical factory, Lanzhou Biopharmaceutical Plant, part of the state-owned China Animal Husbandry Co Ltd, producing animal brucellosis vaccines. The factory used expired disinfectants and sanitizers, which resulted in incomplete sterilization of the waste gas from the production fermentation tanks. The waste gas contained the notoriously easy-to-aerosolize pathogen, which was then further carried by southeast winds toward the Veterinary Research Institute and nearby settlements. Although an immediate halt to the factory’s processes was implemented and its vaccine production license was revoked, the long-term effects of Brucella spread could not be contained: On 15 September 2020, the Health Commission of Lanzhou City announced the expanded results of the public health investigation, with 4646 individuals initially screened as positive and 3245 cases confirmed [2]. This number was further expanded to 10 528 cases of brucellosis among 68 571 individuals tested in the nearby region; testing included local residents, workers, and temporary residents of the Yanchang Road subdistrict in the city, the worst impacted area, as well as those who previously worked or lived there [3].

Chinese public health authorities established an extended medical network for treatment and follow-up of diagnosed patients, which, according to a news site, initially included 213 students and members of faculty of the Veterinary Research Institute, 8 individuals directly related to the biopharmaceutical plant, >2500 residents of neighboring areas, and 150 individuals located farther out (at least some of them had been occupied or studying in the Veterinary Institute during exposure period, in August 2019) [4]. Moreover, officials responsible for the leak have been identified and punished, and a compensation plan for all infected has been announced. It has been since reported, in a press conference by Chinese authorities, that the factory has been completely dismantled.

Human brucellosis is possibly the commonest zoonotic infection worldwide, accounting for significant long-term health consequences, despite its minimal mortality [5]. Osteoarticular, genitourinary, cardiovascular, and neurological complications may be incapacitating, and the disease furthermore displays a propensity for relapse, even years after initial infection or even an ill-defined chronic phase. Protracted combined antibiotic regimens are typically warranted. Usually transmitted from animals to humans through direct contact with infected tissues or consumption of unpasteurized dairy products or undercooked meat, it nevertheless can be transmitted through inhalation of aerosolized particles, a property augmented by its volatility and the extremely low minimal infectious dose (10–100 organisms). These properties have been evaluated in the past in the context of biological weapons’ study facilities [6]: Brucella species have traditionally been included in biodefense research lists, while Brucella suis was the first pathogen to be weaponized in 1952. The same properties are also responsible for its significant burden on laboratory-acquired infections [7, 8], numerous of which have been reported from China, even since 1936 [9, 10]. In endemic areas, clinicians are aware that microbiology laboratory personnel should be preemptively informed about the possibility of brucellosis when dealing with blood cultures of patients, and ideally these should be handled at Biosafety Level 3 (BSL-3), or, when not applicable, with extreme caution and appropriate personal protective equipment (PPE), at BSL-2. Brucella aerosols as the means of infection have also been reported in individuals employed in a kitchen waste disposal company [11]: in this case, the forceful dumping of the waste in a feeding inlet (prior to its 3-phase separation for production of biodiesel, etc), resulted in production of infectious liquid splashes and aerosols and subsequent exposure of workers who were not using appropriate PPE.

In the case of the Lanzhou leak, one has to take into account the environmental effect of the pathogen atmosphere release, since humans may not be the only ones affected: animal herds may also become infected and give rise to secondary brucellosis outbreaks (and moreover the need for extensive animal culling and profound local economic consequences), while the environmental stability of Brucella may also possess risk for long-term airborne transmission, secondary to soil pollution through everyday agricultural practices.

Of interest, the strain implicated in the leak was that of the B. suis S2 vaccine, one of the lesser-studied strains (and vaccines). The S2 vaccine is widely used in China, inducing animal protection against infection by heterologous Brucella species [12], and is considered of low virulence: A previous cluster of cases in animal epidemic prevention controllers exposed to the S2 vaccine reported an excellent outcome in all 54 infected individuals [13]. A description of the clinical course of the initial Lanzhou patients reported fatigue and sweat in the majority of them, while a significant percentage, approaching 10%, reported orchitis, one of the commonest and most troublesome brucellosis complications [1]. Another recent study mentions that 96 of the initially exposed individuals seroconverted but were asymptomatic, yet offers limited information on their details and follow-up (there is no mention of the number of overall patients, and instead the study attempts to synthesize available literature knowledge on brucellosis-asymptomatic individuals) [14].

On the other hand, human brucellosis worldwide is typically associated with Brucella melitensis and, to a lesser extent, Brucella abortus, with B. suis infections extremely rarely observed, usually in secluded communities with a cultural preponderance for swine husbandry [15]. China has been increasingly reporting brucellosis cases, with an incidence rise during the last 25 years, a shift toward southern regions [10, 16], and published case series of thousands of patients [17].

One may support that many of these cases could be attributed elsewhere and not to the laboratory leak. Diagnosis based on serology may diagnose previously exposed individuals who remain asymptomatic [18]. Yet, these cases have been attributed to the laboratory accident by official sources (presumably through diagnostics focusing on the particular B. suis strain), while the overall increase in China’s brucellosis cases in 2020, compared to 2019, has also been attributed, in relevant scientific publications, to the Lanzhou incident [19].

Moreover, taking into account the available literature on disease seroprevalence and annual cases in the district of Lanzhou, the increase is massive. Lanzhou is an urban area of the Gansu province, a province that has exhibited a steady brucellosis incidence in recent years—a considerable one belonging to the provinces targeted by the National Brucellosis Prevention and Control Plan (2016–2020) of the Chinese authorities, but far below the incidence observed in endemic regions like Inner Mongolia; an average annual incidence of 6.32 cases per 100 000 population was reported for the period 2016–2019 for the whole Gansu region, extrapolated to an average of 1500–1600 annual cases [20]. But these cases were recorded in the whole region, and a study focusing on the spatial distribution of brucellosis cases in Gansu showed that Lanzhou district was never the epicenter of brucellar endemicity in the 2013–2018 period [21]. Furthermore, a recent study on brucellosis seroprevalence in high-risk individuals in endemic Chinese provinces demonstrated low percentages of positivity that could not support an extended, asymptomatic, undetected, preexisting seroprevalence in Lanzhou [22]. Thus, the sudden massive increase in cases could not have been attributed to enhanced surveillance.

What is still missing is an extended clinical description of the cases and of the incident itself from Chinese researchers. The incident has been consistently mentioned in recent publications of Chinese origin, even of irrelevant nature (eg, a recent study on micro-RNA in brucellosis [23] or an overview of infectious diseases of Chinese cattle [24]), and questions have been raised in the press about the diagnostic and therapeutic effectiveness of the authorities' response [25].

The Lanzhou event is actually the largest documented laboratory-leak outbreak known in infectious disease history. Experts have suggested that the 1977 H1N1 influenza reemergence can be considered such an incident, undoubtedly an unsurpassable precedent [26], and admittedly other events were related to pathogens with more significant mortality, as in the anthrax 1979 Sverdlovsk leak [27]. The current incident, though, can serve as a useful reminder of the need of enhanced vigilance on all aspects of biosafety (even gaining a mention in the recent Athena Agenda report of the Bipartisan Commission on Biodefense [28]), particularly in our times of expanded BSL-4 development. The majority of BSL-4 laboratories currently in action emerged in the recent decade and are located in big cities (meaning that the effect of an accident might be disproportionate, similar to what was observed in Lanzhou in different settings), while the countries hosting them do not have, in their majority, high scores in biosafety and biosecurity (according to the Nuclear Threat Initiative) and do not possess specific dual-use legislature [29, 30]. At the moment, there is no international organization supervising these BSL-4 laboratories (or, moreover, BSL-3 laboratories as the ones theoretically necessary for Brucella research), although there exists an International Organization for Standardization description of the standards on bio-risk management for such laboratories. An inspection role could be undertaken by World Health Organization officials, but transparency would be needed: Imagine the aftermath of an accident similar to the Lanzhou one, but concerning a more virulent pathogen.

Further data of the investigation and the long-term follow-up of the patients involved will definitely offer useful information. At present though, the event per se underlines the need for safety vigilance in biopharmaceutical facilities; the hazards imposed by aggressive agricultural and husbandry expansion programs, the rhythms of which cannot be matched by regulatory authorities; and the need for a renewed evaluation of the continuing significance of Brucella species [31].

References

Author notes