Five-year-old female ragdoll mix cat (Felis catus).The cat was
found dead at home in January 2014, after one day of anorexia, open-mouth
breathing, and hiding. The cat had lived with two littermates and had no
outdoor access. On the day before this cats death, a littermate from the same
home had developed severe respiratory distress and been euthanized but not
necropsied. The third littermate never became ill and is still alive 2.5 years
later at the time of submission.
necropsy, both lungs were diffusely consolidated and edematous. Formalinfixed
slabs of lung had prominent, grossly visible, pale cuffs around bronchioles.
There were no other gross abnormalities in any organ system.
In most bronchioles, the lining epithelium is segmentally to completely
sloughed or attenuated, with occasional attempts at regeneration. The lumens of
affected bronchioles frequently contain adherent strands of fibrin and cellular
debris composed of macrophages, sloughed epithelial cells, and free red blood
Diffusely, alveolar airspaces contain moderate numbers of cells, predominantly macrophages and lymphocytes, with fewer non-degenerate neutrophils and red blood cells. In addition, alveolar airspaces contain abundant eosinophilic beaded to fibrillar material (fibrin). Numerous peribronchiolar alveoli are lined by markedly hypertrophied cuboidal epithelial cells with large nuclei and prominent nucleoli (type II pneumocyte hyperplasia). Multinucleate pneumocytes are occasionally seen.
Around larger pulmonary vessels, connective tissue is moderately expanded by clear space (perivascular edema). Throughout all sections, muscular pulmonary arteries and arterioles have moderately thickened walls (smooth muscle hyperplasia).
Lung: Severe, diffuse, acute to subacute,
multifocal to coalescing, necrotizing bronchointerstitial pneumonia with
alveolar edema and marked peribronchiolar type II pneumocyte hyperplasia.
of lung were submitted to a commercial diagnostic laboratory for a feline upper
respiratory disease panel. This panel was negative by real-time PCR for all
agents tested: feline calicivirus, Chlamydophila felis, feline
herpesvirus 1, Bordetella bronchiseptica, Mycoplasma felis and H1N1
cat died from severe bronchointerstitial pneumonia, which is most frequently
caused by feline herpesvirus or feline calicivirus infection.4 Lung
samples were submitted to a commercial diagnostic laboratory and no viral or
bacterial sequences were detected using real time PCR. However, because this
cats gross and histologic lesions were nearly identical to those described
previously in two cats that died of influenza A(H1N1)pdm09 virus infection
(so-called pandemic influenza),8 we submitted samples to a
provincial diagnostic laboratory, which detected this virus. This is, to our
knowledge, the first confirmed case of influenza A(H1N1)pdm09 infection in a
Influenza A viruses are RNA viruses in the family Orthomyxoviridae that can infect multiple species of mammals and birds, although different viral subtypes tend to be host-specific.17 These viruses have caused multiple epidemics and pandemics in human populations,11 as well as epizootics and panzootics in animal species.12,16 Rapid mutation and gene reassortment of influenza A viruses lead to a high diversity of viral subtypes, and this genetic flexibility results in a propensity for between-species and cross-class transmission.18 The so-called pandemic strain of the H1N1 influenza virus isolated in 2009 (influenza A(H1N1)pdm09) contained a novel combination of genetic segments from influenza viruses affecting humans, pigs, and birds.6
Cats are susceptible to infection by multiple influenza A virus subtypes;1 however, reports of clinical disease in cats resulting from natural infection with A(H1N1)pdm09 are relatively scarce.3,5,8,10,13 The source of this particular cats infection could not be determined. The owner lived alone, had received a seasonal influenza vaccination in October of 2013, and had never become sick. However, she had hosted two house guests for a three day period after Christmas 2013, approximately 10 days before the deaths of her two cats in early January, 2014. One guest had flu-like symptoms and remained indoors for the majority of the visit. Although the cause of this guests illness was never known, the 20132014 influenza season was intensive in Alberta; there were 35% more lab-confirmed cases of human influenza infection than the previous year and the predominant circulating strain was influenza A(H1N1)pdm09.14 Thus, the sick guest could not be ruled out as the source of this cats, and/or her littermates, infection.
The possibility of anthroponotic transmission of influenza A(H1N1)pdm09 to cats is supported by two earlier reports. The first describes an indoor-only cat that was infected with influenza A(H1N1)pdm09 after exposure to human family members with a non-diagnosed flu-like illness.13 The second shows that pet cats are nearly three times more likely to be seropositive for influenza A(H1N1)pdm09 than free-roaming cats.18 Cat-to-cat transmission of influenza A(H1N1)pdm09 has also been documented, both experimentally15 and in an outbreak in cats with little human contact living in a cat colony in Italy.5 Zoonotic transmission of influenza viruses from cats to humans may also occur, and the role that cats may play in the epidemiology of human influenza infections needs further investigation.1
The cat described here died from severe pneumonia caused by pandemic influenza A virus infection. This virus was not detected in samples sent to a commercial laboratory, but was detected in samples sent to a second laboratory. Therefore, if clinical signs, history (exposure to people or animals infected with influenza virus), gross lesions, and histologic findings are suggestive of influenza virus infection, it is reasonable to test samples in a second laboratory should a first laboratory provide a negative result for influenza virus infection. This case highlights the importance of including influenza virus infection in the differential diagnosis for respiratory disease in cats. It also further demonstrates the importance of investigating any discrepancy between histologic findings and expected laboratory results.
Lung: Pneumonia, bronchointerstitial,
necrotizing, multifocal to coalescing, severe with marked peri-bronchiolar type
II pneumocyte hyperplasia, ragdoll mix cat, Felis catus.
The diagnosis of
bronchointerstitial pneumonia was the subject of much debate among conference
participants. It is usually reserved for cases where there is microscopic
evidence of viral targeting of both the bronchiolar and alveolar epithelium,
which is the typical behavior of aerogenous viral infections or inhaled toxins.4
Damage to the airway epithelium and alveolar septa causes epithelial necrosis
and hyperplasia of type II pneumoncytes.4 This case is an excellent
example of bronchointerstitial pneumonia with profound multifocal
bronchiolar-centric type II pneumocyte hyperplasia, nicely highlighted by
pancytokeratin immuno-histochemical stain run by the Joint Pathology Center
prior to the conference. Interestingly, marked type II pneumocyte hyperplasia
can occur as early as two days after initial insult to the respiratory
epithelium and alveolar septum, coinciding with the acute onset reported in the
history of this case.7,8 Conference participants discussed other
differential diagnoses for bronchointerstitial pneumonia in cats, such as
feline herpesvirus-1 and feline calicivirus.4,7,8
The conference moderator also noted that in this case the virus appears to exhibit a tropism for terminal airways with relative sparing of the larger bronchi. The specific anatomic location of lesions associated with influenza virus has been reported to correlate with the distribution of sialic acid molecules on the cell surface of the host.8,9 In human pandemic H1N1 influenza A, these sialic acids are distributed in the trachea and larger airways, resulting in necrotizing tracheitis and bronchitis in severely affected human patients. In pathogenic avian influenza H5N1, the virus binds to sialic acids present mainly on terminal bronchioles and pneumocytes.8,9 Interestingly, the distribution of lesions in this case differs from the typical presentation of human H1N1 influenza A, and resembles binding of avian influenza viral particles. This distribution pattern has been reported in other cases of H1N1 infection in cats.8
Influenza viruses are RNA viruses of the Orthomyxovridiae family, and are able to rapidly mutate through antigenic drift and genetic reassortment.1,7,8,9 This leads to a high degree of viral diversity and genetic flexibility, thus allowing the virus to quickly adapt and infect multiple different species.7,8 In addition to human origin H1N1, presented in this case, cats are also susceptible to highly pathogenic avian influenza H5N1 and H7N2 viruses.4 Cats have been reported to be infected with H1N1 by interaction with infected humans, as is suspected in this case, and then transmit the disease horizontally to other felids. There are currently no reports of transmission from cat to human with H1N1 virus.7,8 Infection with highly pathogenic avian influenza in cats is thought to be secondary to both inhalation of aerosolized virus and consumption of infected birds.4
In December 2016, there was an outbreak of H7N2 avian influenza in almost 400 shelter cats in New York City.2 A shelter veterinarian who had prolonged and unprotected exposure to affected cats was also infected with the virus. This is the first documented case of cat to human transmission of influenza and only the third case of human H7N2 avian influenza infection in the United States.2 Given their close relationship with humans and susceptibility to both human and avian influenza strains, cats have the potential to be important reservoirs for infection.2,7,8 Feline co-infection with human and avian strains may allow genetic reassortment and antigenic shift creating a novel influenza A subtype and provide the basis for a new influenza pandemic.7 As a result, influenza virus should be carefully considered as a differential diagnosis for respiratory disease in cats.
A, Daniels JB, Zhang Y, Rodriguez-Palacios A, Hayes-Ozello K, Mathes L, Lee
C-W. Pandemic and seasonal human influenza virus infections in domestic cats:
Prevalence, association with respiratory disease, and seasonality patterns. J
Clin Microbiol. 2001; 49:4101-4105
influenza A (H7N2) in cats in animal shelters in NY; one human infection.
Centers for Disease Control and Prevention website. https://www.cdc.gov/flu/spotlights/avian-influenza-cats.htm. Updated
January 4, 2017. Accessed February 16, 2017.
ER, Rankin JT, Daverio SA, Hunt EA, Lute JR, Tewari D, Acland HM, Ostrowski SR,
Moll ME, Urdaneta VV, Ostroff SM. Fatal pandemic (H1N1) 2009 influenza A virus
infection in a Pennsylvania domestic cat. Zoonoses Public Health. 2011 58:500-507
4. Caswell JL, Williams KJ. Respiratory system. In: Maxie MG ed. Jubb,
Kennedy and Palmer's Pathology of Domestic Animals. Vol 2. 6th ed. St.
Louis, MO: Elsevier; 2016:511,587-591.
L, Taddei R, Moreno A, Gelmetti D, Barbieri I, De Marco MA, Tosi G, Cordioli P,
Massi P: Influenza A pandemic (H1N1) 2009 virus outbreak in a cat colony in
Italy. Zoonoses Public Health. 2011; 58:573-581
RJ, Davis CT, Russell CA, Shu B, Lindstrom S, Balish A, Sessions WM, Xu XY,
Skepner E, Deyde V, Okomo-Adhiambo M, Gubareva L, Barnes J, Smith CB, Emery SL,
Hillman MJ, Rivailler P, Smagala J, de Graaf M, Burke DF, Fouchier RAM, Pappas
C, Alpuche-Aranda CM, Lopez-Gatell H, Olivera H, Lopez I, Myers CA, Faix D,
Blair PJ, Yu C, Keene KM, Dotson PD, Boxrud D, Sambol AR, Abid SH, George KS,
Bannerman T, Moore AL, Stringer DJ, Blevins P, Demmler-Harrison GJ, Ginsberg M,
Kriner P, Waterman S, Smole S, Guevara HF, Belongia EA, Clark PA, Beatrice ST,
Donis R, Katz J, Finelli L, Bridges CB, Shaw M, Jernigan DB, Uyeki TM, Smith
DJ, Klimov AI, Cox NJ. Antigenic and genetic characteristics of swine-origin
2009 A(H1N1) influenza viruses circulating in humans. Science. 2009;
CG, Davies JL, Joseph T, Ondrich S, Rosa BV. Pandemic H1N1 influenza virus
infection in a Canadian cat. Can Vet J. 2016; 57(5):497-500.
CV, DeBess EE, Baker RJ, Hiett SL, Hoffman KA, Murdoch VJ, Fischer KA,
Mulrooney DM, Selman RL, Hammill-Black WM. Pathology and viral antigen
distribution of lethal pneumonia in domestic cats due to pandemic (H1N1) 2009
influenza A virus. Vet Pathol. 2010; 47:378-386
J, Hartmann K. Avian influenza A H5N1 infections in cats. J Fel Med Surg.
AM, Haak CE, Breshears MA, Linklater AKJ. Acute bronchointerstitial pneumonia
in two indoor cats exposed to the H1N1 influenza virus. J Vet Emerg Crit
Care. 2014; 24:715-723
S. Overview of influenza viruses. In: Richt JA, ed. Current Topics in
Microbiology and Immunology: Swine Influenza. Webby RJ: Springer-Verlag,
S, Olsen CW, Easterday BC. History of swine influenza. In: Richt JA, ed. Current
Topics in Microbiology and Immunology: Swine Influenza. Webby RJ:
Springer-Verlag, Berlin; 2013:21-28