In May 2021 a suspected outbreak of feline pancytopenia of unknown cause was recognised in the United Kingdom. A relatively high frequency of cases was recognised in the small animal veterinary community in both referral hospitals and first opinion practices. To gather further information about cases an on-line survey was set up on May 24th 2021 which allowed any veterinary practitioner to submit information about cases of feline pancytopenia they had seen. Five hundred seventy (570) pancytopenic cats from 368 veterinary practices in the UK were registered between 26th February 2021 and 2nd September 2021. The clinical pathological findings of the cats were most consistent with an aplastic pancytopenia, which is characterised by cytopenias of erythrocytes, leukocytes, and platelets in the blood combined with a hypo- or a-cellular bone marrow with the marrow space replaced by adipose tissue (Weiss 2003). Aplastic pancytopenia is a rare disorder in cats which can be caused by destruction of bone marrow stem cells, genetic mutations causing inadequate stem cell function or haemopoietic microenvironment disorders (Weiss 2003). Idiopathic aplastic pancytopenia is described in humans but this has not been reported in cats (Weiss 2003). Reported toxic causes of feline aplastic pancytopenia include phenobarbitone (Lyraki, Wilson 2020), griseofulvin, trimethoprim/sulphonamide and various chemotherapeutic agents (Weiss 2003). Infectious causes include feline leukaemia virus, feline immunodeficiency virus, Erlichia spp. and parvovirus (Weiss 2003). Cobalamin deficiency has also been reported to cause feline aplastic pancytopenia (Stanley, Eatroff 2017).
Overall, 362 (63.5%) affected cats died, whilst 204 (35.8%) cats were alive at time of follow-up, with this information unknown in 4 (0.7%) cats. There was no recognised infectious cause for this outbreak and no obvious link to medication or vaccination detected in the data gathered, but 3 different brands of cat food (which were found to all be made at the same factory) were noted as being fed to a large majority (86.8%) of the affected cats. This led to a voluntary removal of one of the brands from shops on 11th June 2021 and a product recall of all 3 brands on 15th June 2021.
The association with feed suggested either a feed deficiency or intoxication. Diagnostic tests in individual cats showed no evidence of vitamin deficiency or heavy metal intoxication so further investigations into other possible causes were carried out including assessment for the presence of trichothecene mycotoxins. The group A tricothecene mycotoxins T-2 and HT-2 (a metabolite of T-2), produced by Fusarium spp. fungi, cause alimentary toxic aleukia in humans in which pancytopenia and bleeding due to bone marrow toxicity are seen (Pitt, Miller 2017; Smith, McGinnis 2009; Joffe 1971). Experimental studies have shown that the T-2 and HT-2 trichothecene mycotoxins are fatal when administered enterally and parenterally to cats, with clinical signs prior to death including lethargy, anorexia, bloody diarrhoea, and weight loss (Lutsky et al. 1978; Lutsy, Mor 1981; Sato et al. 1975) consistent with the clinical signs seen in the affected cats in this outbreak.
Although strict controls are in place for maximum levels of trichothecene contamination of human foodstuffs (Open Government License 2006) there is no legal limit for pet foods. Due to lack of data on the feline-specific biotransformation and toxicodynamics there are no ‘no observed adverse effect level’ (NOAEL) or ‘lowest observed adverse effect level’ (LOAEL) for trichothecenes in cats. There is European Union guidance for a maximum combined T-2 and HT-2 level of 50 µg/kg in dry cat food, however, which is based on experimental studies (Lutsky et al. 1978; Lutsy, Mor 1981; Sato et al. 1975). This level is lower than that for other animal feeds as it is recognised that cats are extremely susceptible to T-2 toxin induced haemotoxicity compared to other species which is postulated to be due to their decreased ability to form glucuronide conjugates.
Combined T-2 and HT-2 levels over 50 µg/kg were found in several samples of recalled cat food but no samples of control brands. The trichothecene diacetoxyscirpenol (DAS) was also detected in all food samples of the recalled foods but none of the control brands. DAS is another group A trichothecene with a similar structure to T-2 (Hoerr et al. 1981), but data regarding its effect in cats are lacking. In chickens it has been shown that bone marrow, lymphoid, hepatic, and intestinal tissue necrosis induced by DAS is similar to that induced by T-2, but that it is less severe for equivalent µg/kg dosing (Hoerr et al. 1981). There is no data describing the levels of DAS found in cat food, but estimated exposure levels based concentrations in cereal grains and their relative proportions in diets suggest 95th percentile diet concentration of 13 µg/kg in dry cat food (Knutsen et al. 2018) and this is, therefore, thought to be a safe level. The levels of DAS detected in the recalled foods were higher than this 95th percentile.
Although there is a clear association between the ingestion of the recalled food brands and the pancytopenia outbreak, they cannot be definitively stated to be the cause in this situation as they were not shown to be deficient in any essential minerals or vitamins and toxin contamination can be proved as there is no LOAEL for T-2, HT-2, and DAS in cats. However, given the high proportion of affected cats known to be consuming the 3 brands, their common manufacturing source, the detection of T-2 and HT-2 in the feeds at levels much higher than those previously reported in cats (and above that recommended by the European Union), the consistency between the clinical signs seen with intoxication with these trichothecenes in various species including cats and those seen in this outbreak and the decreased severity of clinical signs and eventual resolution of the outbreak when the 3 brands were withdrawn from the market, trichothecene contamination of the recalled food brands should be strongly considered as a possible cause of this feline pancytopenia outbreak.
Acknowledgements
Barbara Glanemann organised the survey for collection of data and was integral in the investigation into this outbreak working in partnership with me. The data in these notes was produced with the great help of Barbara Glanemann and Camilla Pegram. The Small Animal Medicine Society provided funds for trichothecene analysis. Many veterinary surgeons in many practices helped by providing data, information, and their services, we thank them all.
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