Letters to the Editor

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Rabies surveillance

I am writing in regard to the recently published report from the CDC on rabies surveillance in the United States during 2018.1 Table 6 in that report lists numbers of reported human and animal contacts with baits containing an oral rabies vaccine during 2018 and indicates that there was one adverse event reported following human contact with a bait containing the vaccinia-rabies glycoprotein recombinant vaccine. Although there was indeed a report, this event appeared to represent only a temporal association with the bait and not a true adverse event. Therefore, we wanted to provide additional details to avoid any potential harm to the reputation of Boehringer Ingelheim Animal Health USA Inc and our product and to prevent any unjustified public concern.

The vaccinia-rabies glycoprotein recombinant vaccine, RABORAL V-RG, is an oral rabies vaccine sold only to government agencies for use in wildlife rabies prevention programs.2 Because this is a veterinary vaccine licensed by the USDA Center for Veterinary Biologics, there is a requirement for agencies using it to report any adverse events in humans or animals to the manufacturer. However, no such report was made to us.

According to Ma et al,1 the adverse event was a “mild skin reaction” associated with human exposure to a bait containing the vaccinia-rabies glycoprotein recombinant vaccine. On contacting the authors and, subsequently, the state public health veterinarian who had submitted the report to the CDC, I learned that the person involved had consulted with a dermatologist before ever contacting the bait. The reason for the consultation was a rash on the hands that developed after cleaning a home. Thus, it seems likely that the mild skin reaction was not actually associated with contact with the oral rabies vaccine bait but was a preexisting condition. Because neither the dermatologist nor the patient consulted their local department of health a second time, the case was closed. These circumstances also help explain why an adverse event was not reported to the manufacturer.

The accurate reporting of adverse events associated with our products is critically important to Boehringer Ingelheim Animal Health. Anyone suspecting an adverse event or having questions about our products can contact Veterinary Technical Services at 1-888-637-4251.

Joanne Maki, dvm, phd

Technical Director, Veterinary Public Health, North America

Boehringer Ingelheim Animal Health Inc, Athens, Ga

The authors respond:

The authors thank Dr. Maki for her comments. Over nine million doses of oral rabies vaccine (ORV) targeting wildlife are distributed in the United States each year to protect human and animal health and reduce the economic impacts associated with rabies. The national rabies surveillance report is based primarily on rabies case data provided by state and territorial health departments and USDA Wildlife Services.1 Information regarding human and domestic animal contact with ORV baits was included for the first time in 2017. Unlike reporting of rabies virus infections in humans or animals, which must be laboratory confirmed, reports of adverse events (AEs) associated with ORV bait contact can be based on clinical or laboratory diagnosis. Information provided to the CDC is used to identify longitudinal trends and inform broad public health practices. Notifications are made annually and unless specifically requested, the CDC is not involved in the investigation or management of AEs. Jurisdictions participating in oral rabies vaccination programs often follow standard procedures for the immediate reporting of ORV bait contact and AEs to relevant stakeholders, which typically includes vaccine manufacturers. The annual, voluntary notification of vaccine AEs to the CDC does not supersede these agreements, and the information obtained is not intended to retrospectively confirm or refute reports.

The AE described in the 2018 report highlights the difficulties of assessing causality when limited, retrospective details are available and is a reminder of the importance of real-time investigation and laboratory confirmation. Although extremely rare, human infections resulting from contact with live virus contained in ORVs have occurred. In these cases, vesicular or pustular lesions consistent with Vaccinia virus infection developed at the site of vaccine exposure.2,3 However, Vaccinia virus infections can produce a wide spectrum of illness ranging from mild skin reactions to uncontrolled systemic viral replication resulting in death, depending on the patient's underlying comorbidities, smallpox vaccination history, and immune status.4 Thus, AEs to ORVs cannot be ruled out solely on the basis of severity. Previous laboratory-confirmed ORV-related vaccinia infections have involved disruptions to the dermal barrier that preceded ORV exposure, including abrasions and puncture wounds from a dog bite and abrasions from picking blackberries.2,3 For the event referenced in the 2018 report, the patient had a preexisting rash attributed to a home cleaning product. As seen in past cases, this preexisting disruption of the dermal barrier could predispose the individual to an ORV AE. On the basis of the available information, a mild AE to an ORV product, although unlikely, could not be definitively ruled out.

Previous research has indicated that contact with ORV baits occurs infrequently.5 Nonetheless, surveillance of AEs related to the widespread distribution of ORV baits is critical for regulatory compliance and to assist in monitoring product safety. Comprehensive monitoring of bait contacts can also inform rabies management strategies to further reduce the likelihood of unintended bait exposures. Early identification of AEs provides an opportunity to intervene with available treatment, when indicated.6 Individuals who have contact with ORV baits or suspect AEs are encouraged to contact their state or local public health authorities to ensure appropriate investigation, triage, management, and reporting. The CDC and USDA will continue to collaborate with relevant stakeholders to evaluate the adequacy of current ORV AE notification policies and revise such policies in an evidence-based manner.

Brett W. Petersen, md

Ryan M. Wallace, dvm

Xiaoyue Ma, mph

Lillian A. Orciari, ms

Victoria Olson, phd

Poxvirus and Rabies Branch Division of High-Consequence Pathogens and Pathology

National Center for Emerging and Zoonotic Infectious Diseases

CDC

Atlanta, Ga

Jordona D. Kirby, ms

Richard B. Chipman, ms

Wildlife Services APHIS, USDA Concord, NH

Christine Fehlner-Gardiner, phd

Centre of Expertise for Rabies Ottawa Laboratory-Fallowfield Canadian Food Inspection Agency Ottawa, Canada

Veronica Gutiérrez Cedillo, phd

Centro Nacional de Programas Preventivos y Control de Enfermedades

Secretaria de Salud de Mexico Ciudad de Mexico, Mexico

  • 1. Ma X, Monroe BP, Cleaton JM, et al. Rabies surveillance in the United States during 2018. J Am Vet Med Assoc 2020;256:195208.

  • 2. Rupprecht CE, Blass L, Smith K, et al. Human infection due to recombinant vaccinia-rabies glycoprotein virus. N Engl J Med 2001;345:582586.

  • 3. CDC. Human vaccinia infection after contact with a raccoon rabies vaccine bait – Pennsylvania, 2009. MMWR Morb Mortal Wkly Rep 2009;58:12041207.

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  • 4. Cono J, Casey CG, Bell DM. Smallpox vaccination and adverse reactions. Guidance for clinicians. MMWR Recomm Rep 2003;52:128.

  • 5. Roess AA, Rea N, Lederman E, et al. National surveillance for human and pet contact with oral rabies vaccine baits, 2001–2009. J Am Vet Med Assoc 2012;240:163168.

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  • 6. CDC. Medical management of adverse reactions. Available at: www.cdc.gov/smallpox/clinicians/vaccine-medical-management6.html. Accessed Apr 8, 2020.

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Toxoplasmosis in a squirrel monkey

I read with interest the recent Pathology in Practice article regarding a squirrel monkey with toxoplasmosis.1 However, I am confused by the final sentence, which states that “ [t]here is no specific treatment for T gondii infection in exposed animals,” because treatment with sulfonamides with or without pyrimethamine or trimethoprim has been reported to be successful in experimentally infected squirrel monkeys.2 Is it that the peracute nature of naturally occurring toxoplasmosis in this species causes death prior to antemortem diagnosis, negating the opportunity for treatment?

Kimberly Coyner, dvm

Dermatology Clinic for Animals Lacey, Wash

  • 1. Long ME, Kirejczyk SGM, Howerth E. Pathology in Practice: disseminated toxoplasmosis in a captive squirrel monkey. J Am Vet Med Assoc 2020;256:661663.

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  • 2. Harper JS, London WT, Sever JL. Five drug regimens for treatment of acute toxoplasmosis in squirrel monkeys. Am J Trop Med Hyg 1985;34:5057.

The authors respond:

Thank you for your letter regarding our recent Pathology in Practice article describing toxoplasmosis in a squirrel monkey and for astutely pointing out that Harper et al1 described successful treatment of experimentally induced toxoplasmosis in squirrel monkeys with sulfonamides. We are unaware of any reports describing the diagnosis and treatment of naturally acquired toxoplasmosis in squirrel monkeys or other New World monkeys, which can have fulminant disease, making antemortem diagnosis extremely difficult because of the abrupt onset.2–4 Therefore, the final sentence in our paper could be rephrased as “there is no reported treatment for naturally acquired T gondii infection in exposed animals…,” given the abrupt onset in New World monkeys, which often precludes timely diagnosis and treatment of these animals.

Elizabeth W. Howerth, dvm, phd

Department of Pathology College of Veterinary Medicine University of Georgia Athens, Ga

Mackenzie E. Long, dvm

Department of Veterinary Biosciences College of Veterinary Medicine The Ohio State University Columbus, Ohio

Shannon G. M. Kirejczyk, dvm, mph

Yerkes National Primate Research Center

Emory University Atlanta, Ga

  • 1. Harper JS, London WT, Sever JL. Five drug regimens for treatment of acute toxoplasmosis in squirrel monkeys. Am J Trop Med Hyg 1985;34:5057.

  • 2. Epiphanio S, Sinhorini IL, Catão-Dias JL. Pathology of toxoplasmosis in captive new world primates. J Comp Pathol 2003;129:196204.

  • 3. Gyimesi ZS, Lappin MR, Dubey JP. Application of assays for the diagnosis of toxoplasmosis in a colony of woolly monkeys (Lagothrix lagotricha). J Zoo Wildl Med 2006;37:27680.

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  • 4. Pardini L, Dellarupe A, Bacigalupe D, et al. Isolation and molecular characterization of Toxoplasma gondii in a colony of captive black-capped squirrel monkeys (Saimiri boliviensis). Parasitol Int 2015;64:58790.

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Fecal shedding of SARS-CoV-2 in COVID-19 patients: insights from animal coronaviruses

Although the primary clinical signs in human patients with COVID-19 are related to the respiratory tract, shedding of intact virus in the feces can also occur.1,2 This raises questions about routes of transmission of SARS-CoV-2 and the mechanisms by which the virus can be found in both respiratory secretions and feces. Importantly, enteric infection with coronaviruses and subsequent fecal shedding are common in a wide range of animal species, including pigs, cattle, dogs, and cats.3–6 In many cases, both respiratory and enteric infection and shedding can occur.7 The range of disease symptoms for COVID-19 patients and the severe nature of clinical signs for a subset of individuals infected with SARS-CoV-2 draw parallels with feline infectious peritonitis in cats. Feline infectious peritonitis is believed to be caused by an internal mutation of an enteric feline coronavirus commonly found in cats. This virus, although conventionally considered an enteric pathogen, does not have a rigid tissue tropism8 and likely spreads systemically, including in the respiratory tract. In early studies9 of cats with feline coronavirus, the virus could easily be recovered from the oropharynx within just a few days after inoculation, preceding shedding in the feces in some cases. It is not uncommon for cats infected with feline coronavirus to show a range of clinical signs, including diarrhea and upper respiratory tract signs such as sneezing.10 Likewise, in calves infected with bovine coronavirus, the virus can be detected in respiratory samples before it is detected in fecal samples; however, both respiratory and fecal shedding has been observed for nearly a month in some instances.11 In rhesus macaques infected with SARS-CoV-2, pulmonary disease has been observed, but viral RNA has also been detected in rectal swabs by means of a quantitative reverse transcription PCR assay.12

Gastrointestinal signs have been reported in human patients infected with SARS-CoV-2, alone or in combination with respiratory signs. These gastrointestinal signs vary with respect to time of onset and severity, but can include nausea, loss of appetite, vomiting, diarrhea, and abdominal pain. In one retrospective study,13 16% of patients presented solely with gastrointestinal signs. Importantly, a recent study14 of SARS-CoV-2 infection in people showed prolonged fecal shedding, with and without shedding from the respiratory system. However, the presence of SARS-CoV-2 RNA in fecal samples was not significantly associated with the presence of gastrointestinal signs, and an extended duration of shedding was not significantly associated with severity of the disease. In that study,14 fecal samples from 41 of 74 (55%) patients were positive for SARS-CoV-2 RNA, and fecal samples were positive for the virus for a longer time (mean ± SD, 27.9 ± 10.7 days) than respiratory samples were (16.7 ± 6.7 days).

In sum, although COVID-19 is primarily associated with respiratory signs in people, the observation of numerous other clinical signs in some patients requires evaluating the systemic nature of the disease. We suggest that detection of SARS-CoV-2 in the feces of patients does not merely represent the passage of virus from consumed respiratory secretions but may, in fact, reflect shedding resulting from active replication in enteric tissues. We consider it prudent, therefore, to consider the results of studies of animal coronaviruses when trying to understand the human disease. In the public health battle to contain COVID-19, it is important to consider multiple transmission routes and to take into account commonalties between SARS-CoV-2 in people and animal coronaviruses in their natural hosts.

Nicole M. Andre, bs

Alison E. Stout, dvm

Gary R. Whittaker, phd

Department of Microbiology and Immunology

College of Veterinary Medicine Cornell University Ithaca, NY

  • 1. Peng L, Liu J, Xu W, et al. 2019 novel coronavirus can be detected in urine, blood, anal swabs and oropharyngeal swabs samples [published online ahead of print Feb 25, 2020]. MedRXiv doi: 10.1101/2020.02.21.20026179.

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  • 2. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens [published online ahead of print Mar 11, 2020]. JAMA doi: 10.1001/jama.2020.3786.

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  • 3. Chasey D, Cartwright SF. Virus-like particles associated with porcine epidemic diarrhoea. Res Vet Sci 1978;25:255256.

  • 4. Clark MA. Bovine coronavirus. Br Vet J 1993;149:5170.

  • 5. Buonavoglia C, Decaro N, Martella V, et al. Canine coronavirus highly pathogenic for dogs. Emerg Infect Dis 2006;12:492494.

  • 6. Pedersen NC. Morphologic and physical characteristics of feline infectious peritonitis virus and its growth in autochthonous peritoneal cell cultures. Am J Vet Res 1976;37:567572.

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  • 7. Saif LJ. Animal coronaviruses: what can they teach us about the severe acute respiratory syndrome? Rev Sci Tech OIE 2004;23:643660.

  • 8. Porter E, Tasker S, Day MJ, et al. Amino acid changes in the spike protein of feline coronavirus correlate with systemic spread of virus from the intestine and not with feline infectious peritonitis. Vet Res 2014;45:49.

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  • 9. Stoddart ME, Gaskell RM, Harbour DA, et al. The sites of early viral replication in feline infectious peritonitis. Vet Microbiol 1988;18:259271.

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  • 10. Addie DD, Jarrett O. A study of naturally occurring feline coronavirus infections in kittens. Vet Rec 1992;130:133137.

  • 11. Oma VS, Tråvén M, Alenius S, et al. Bovine coronavirus in naturally and experimentally exposed calves; viral shedding and the potential for transmission. Virol J 2016;13:100.

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  • 12. Munster VJ, Feldmann F, Williamson BN, et al. Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2 [published online ahead of print Mar 21, 2020]. Microbiology doi: 10.1101/2020.03.21.001628.

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  • 13. Luo S, Zhang X, Xu H. Don't overlook digestive symptoms in patients with 2019 novel coronavirus disease (COVID-19) [published online ahead of print Mar 20, 2020]. Clin Gastroenterol Hepatol doi: 10.1016/j.cgh.2020.03.043.

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  • 14. Wu Y, Guo C, Tang L, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples [published online ahead of print Mar 19, 2020]. Lancet Gastroenterol Hepatol doi: 10.1016/S2468-1253(20)300832.

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