The One Health Zoonotic Disease Prioritization workshop, organized jointly by the United States Centers for Disease Control and Prevention (CDC), US Department of Agriculture, and US Department for the Interior, recently reported a list of 8 top zoonotic diseases of national concern.1 These endemic and emerging diseases were ranked according to epidemic and pandemic potential, risk for introduction or increase in transmission within the US, severity of disease in humans, and potential for bioterrorism. The workshop highlighted the requirement for a coordinated multisector response with input from human, animal, and environmental sectors.

In light of this report, Infectious Disease Advisor presents a series of clinical updates for each identified zoonosis.

Zoonotic Influenza

The influenza virus is divided into 3 types (A, B, and C), with only influenza A having an animal reservoir that significantly influences its epidemiology. Influenza A leads to both seasonal epidemics and sporadic pandemics. Subtypes are defined antigenically by 2 surface glycoproteins: neuraminidase and hemagglutinin. Annual recurrence of susceptibility to influenza is a result of antigenic drift, a continuous process of point mutation of the genes encoding the 2 surface glycoproteins that allows repeated evasion of the protective immunity from exposure or vaccination in preceding seasons. Antigenic shift, conversely, gives rise to novel strains after genetic re-assortment with animal viruses.

Zoonotic infections occur when influenza strains that normally circulate in mammal or avian populations are transmitted to humans. These sporadic events are rare, but may present a significant risk, particularly to individuals working with livestock, with some strains (eg H5N1, H7N9) known to cause severe disease with very high case fatality rates. However, the greater concern regarding the zoonotic transmission of so-called variant influenza viruses is the potential for a new influenza pandemic. Such an event is more likely to occur in animals susceptible to influenza co-infections. It is then possible that viral re-assortment may produce a virus to which human populations are immune-naive. The pandemic H1N1 swine flu outbreak in 2009 is an example of such an occurrence with a triple re-assortment of swine-, avian-, and human-origin viruses.2 This led to significant rise in mortality, and H1N1 has since become one of the dominant circulating seasonal influenza strains.

The CDC classified the 2018 to 2019 influenza season as moderate in severity across all age groups, estimating that there were approximately 37.4 to 42.9 million cases of influenza resulting in half a million hospitalizations and between 36,000 and 61,000 deaths.3 Two different influenza A viruses, (H1N1)pdm09 and H3N2, caused the majority of cases, peaking in February and March, respectively, and a small proportion caused by influenza B.

The World Health Organization and the US Food and Drug Administration (FDA) Vaccines and Related Biological Products Committee have announced that vaccine viruses selected for the 2019 to 2020 northern hemisphere vaccine include a A/Kansas/14/2017-like virus for the H3N2 component and an A/Brisbane/02/2018 (H1N1)pdm09-like virus for the H1N1 component. Antigens from the dominant circulated influenza B lineage (Victoria) and from both (Victoria and Yamagata) for the quadrivalent vaccine are also included.

Guidelines updated at the end of 2018 from the Infectious Diseases Society of America (IDSA) recommended that clinicians should aim to employ influenza testing, particularly during the seasonal influenza period.4 In the outpatient setting, this includes all individuals presenting with acute-onset respiratory symptoms who are high risk for influenza complications or those for whom the results will influence antibiotic or antiviral treatment decisions. In hospitalized patients, all those with acute respiratory illness including pneumonia require testing. Outside of the influenza season, this applies only to those with an epidemiological link to an influenza case or outbreak. Testing should be performed on nasopharyngeal specimens collected with a flocked swab as soon as possible after illness onset. Rapid molecular assays such as nucleic acid amplification tests (NAATs) or reverse-transcriptase polymerase chain reaction as single or multiplex assays are preferred over antigen-based rapid diagnostics. This is a result of rapid turnaround time, detection of both influenza A and B, and superior sensitivity while maintaining specificity.

For antiviral treatment, neuraminidase inhibitors such as oral oseltamivir and inhaled zanamivir have been the mainstay of treatment for many years. Controversy remains concerning questionable support from randomized controlled trials for neuraminidase inhibitor use in preventing influenza complications; however, considerable observational data, evaluated in a 2014 meta-analysis,5 indicate a reduction in mortality that is highly dependent on time to initiation. This evidence, albeit imperfect, is reflected in international guidelines, with the IDSA recommending early use for hospitalized patients and outpatients with chronic medical conditions or immunocompromise. Other groups at increased risk that should also be treated include children younger than age 2 years, adults age >65 years, and pregnant women <2 weeks postpartum.

In October 2018, the FDA approved baloxavir marboxil, a cap-dependent endonuclease inhibitor of influenza polymerase, for patients aged >12 years with uncomplicated influenza A or B infection who have been symptomatic for 48 hours or less. A long half-life allows this medication to be administered as a single oral dose, avoiding issues of adherence. Evidence of efficacy, to date, is a reduction in time to symptom improvement of 26.5 hours compared with placebo (P <.001), but no significant difference from oseltamivir.6 This phase 3 trial also highlighted concern that emergence of polymerase variants with reduced susceptibility to baloxavir was apparent in 9.7% of participants receiving the drug, and the effect on hospitalized and severe or complicated influenza is yet to be demonstrated.

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Salmonellosis (nontyphoidal)

Salmonella (enterica subspecies) is one of the leading foodborne pathogens with an estimated 1.2 million infections, 23,000 hospitalizations, and 450 deaths annually.7 Although cases are estimated to be fewer than viral causes of infectious diarrhea (eg norovirus, rotavirus, sapovirus), the numbers of hospitalizations and deaths are greater.7 In the United States, S enteritidis, S typhimurium, and S newport are the predominant etiologic serotypes. Transmission occurs through ingestion of contaminated agricultural products and animal contact, and there is rare human-to-human spread documented in occasional case reports. Undercooked poultry and egg consumption are most commonly associated with salmonellosis, with transovarial spread leading to normal-appearing infected eggs. Outbreaks have also been associated with milk, fresh meat, raw tuna, fruit, spices, water, and both liquid and powered infant formula. Contact with both pets and live poultry has been implicated, and in particular, reptiles and amphibians. For this reason, the CDC recommends against contact with reptiles for infants and the immunocompromised who are at high risk for invasive Salmonella disease.

Clinically, gastroenteritis caused by Salmonella spp infection should be considered in people with acute diarrhea with the presence of blood, fever, and abdominal pain or cramping. Although, as features are nonspecific, diagnosis relies on isolation of the bacillus with stool testing, which should include other enteropathogens (Shigella, Campylobacter, Shiga toxin-producing Escherichia coli). For diagnosis, the IDSA recommends stool culture and advises caution with the interpretation of multipathogen nucleic acid amplification tests, as these do not confirm viability of identified pathogens. Further, positive results from these tests require follow-up culture to meet public health reporting rules, determine antimicrobial susceptibilities, and identify serotype for outbreak surveillance.8

Nonsevere Salmonella gastroenteritis should be managed with supportive care only. A Cochrane meta-analysis of randomized controlled trials found no evidence for benefit from antibiotic treatment in otherwise healthy people, and a slightly higher number of adverse events.9 Moreover, risk for long-term asymptomatic carriage appears to be increased, as shown by excretion of the same Salmonella serovar in stool 1 month after treatment (relative risk, 1.96; 95% CI, 1.29-2.98). Antibiotic therapy is reserved for severe illness (>9 stools per day, persistent/high fever or requirement for hospitalization) or those considered at risk for invasive disease independent of disease severity.

Risk groups include infants aged <12 months, adults aged >50 years, individuals with HIV, and those with other immunocompromise (eg chronic use of steroids or other immunosuppressive agents). Given the risk for suppurative endovascular and osseous complications after bacteremia, those with pre-existing cardiac valvular pathology, arteriopathy, or prosthetic joints are also considered high risk. In bacteremic patients, focal metastatic infection can develop in multiple sites. These extra-intestinal infections include pneumonia, often with cavitary disease, osteomyelitis, endocarditis, aortitis (more common with underlying atherosclerosis), meningitis, pyomyositis, and visceral or soft tissue abscesses.

The recommendations for treatment, when appropriate, are for fluoroquinolones or third-generation cephalosporins with alternatives options such as trimethoprim-sulfamethoxazole, ampicillin, or azithromycin. The rate of antimicrobial resistance remains low and is rare for both fluoroquinolones and cephalosporins together. Extended-spectrum beta-lactamases, however, are increasingly present in many Salmonella serotypes such that the Clinical Laboratory Standards Institute breakpoints have been altered to account for this with antimicrobial susceptibility reporting of cephalosporins.

The IDSA also recommends evaluation for postinfectious complications. After salmonellosis, these are frequent and include reactive arthritis, erythema nodosum, and irritable bowel syndrome. Importantly, these may be presenting conditions in subclinical cases of gastroenteritis, allowing late diagnosis of Salmonella and assisting public health surveillance.

References

1. Centers for Disease Control and Prevention. U.S. one health zoonotic disease prioritization. https://www.cdc.gov/onehealth/domestic-activities/us-ohzdp.html. Accessed October 9, 2019.

2. Smith GJD, Vijaykrishna D, Bahl J, et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature. 2009;459(7250):1122-1125. 

3. Centers for Disease Control and Prevention. Influenza surveillance update. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-06/flu-2-Brammer-508.pdf. Accessed October 9, 2019.

4. Uyeki TM, Bernstein HH, Bradley JS, et al. Clinical practice guidelines by the Infectious Diseases Society of America: 2018 update on diagnosis, treatment, chemoprophylaxis, and institutional outbreak management of seasonal influenza. Clin Inf Dis. 2019;68(6):e1-e47.

5. Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: A meta-analysis of individual participant data. Lancet Respiratory Med. 2014;2(5):395-404.

6. Hayden FG, Sugaya N, Hirotsu N, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med. 2018;379:913-923.

7. Scallan E, Hoekstra RM, Angulo FJ, Tauxe RV, Widdowson MA, Roy SL, et al. Foodborne illness acquired in the United States major pathogens. Emerg Infect Dis. 2011;17(1):7-15.

8. Shane AL, Mody RK, Crump JA, et al. 2017 Infectious Diseases Society of America clinical practice guidelines for the diagnosis and management of infectious diarrhea. Clin Infect Dis. 2017;65(12):e45-e80.

9. Onwuezobe IA, Oshun PO, Odigwe CC. Antimicrobials for treating symptomatic non-typhoidal Salmonella infection [published online November 14, 2012]. Cochrane Database Syst Rev. doi:10.1002/14651858.CD001167.pub2

This article originally appeared on Infectious Disease Advisor