A retrospective study of clinical and laboratory features and treatment on cats highly suspected of feline infectious peritonitis in Wuhan, China

4.3.2021; Translation 16.4.2021
Yiya Yin, Ting Li, Chaohao Wang, Xiaoya Liu, Hehao Ouyang, Wanfeng Ji, Jiahao Liu, Xueyu Liao, Junyi Li, and Changmin Hu

Original article: A retrospective study of clinical and laboratory features and treatment on cats highly suspected of feline infectious peritonitis in Wuhan, China

Abstract

Feline infectious peritonitis (FIP) is a systemic, potentially fatal viral disease. The aim of this study was to investigate the clinical and laboratory characteristics and treatment of cats with highly suspected FIP in Wuhan, China. The clinical records of 127 cats with highly suspicious FIP were reviewed for history, clinical signs, physical findings, and diagnostic test results. Gender, castration status, breed, age and month of onset of the disease were compared with the characteristics of the clinical population. Age and castration status were significantly correlated with suspected FIP. Gender, breed and month of onset of symptoms were not related to FIP. Many more cases of suspected FIP have been reported in young cats or intact males. The effusion was observed in 85.8% cats suspected of having FIP. Elevations in serum amyloid A (SAA) and lymphopenia were common abnormalities in FIP cases. Furthermore, 91.7% cats with highly suspected FIP had an albumin / globulin (A / G) ratio <0.6, while 85.3% had an A / G ratio <0.5. Mortality for cats suspected of FIP was 67% and six cases were confirmed by FIP-specific immunohistochemistry. Of the 30 cats treated with GS-441524 and / or GC376, 29 were clinically cured. The study highlights the diversity of clinical manifestations in the diagnosis of this potentially fatal disease. The A / G ratio and SAA had a higher diagnostic value. GS-441524 and GC376 have been shown to be effective in treating cats suspected of having FIP.

Keywords: Zoology, Diagnosis of infectious diseases

Introduction

Infectious feline peritonitis (FIP) is a worldwide disease of domestic and feral cats. The pathogen of FIP is feline infectious peritonitis virus (FIPV), which was caused by a mutation in feline coronavirus (FCoV) ^1,2. Although extensive FIP research has been conducted, FIP remains one of the most widespread and deadly infectious diseases in cats.

In addition to non-specific clinical symptoms such as malaise, anorexia, fluctuating fever, and weight loss, the clinical picture of FIP is complex and variable. Different clinical signs may be the result of variations in the virus and the nature of the individual host's immune response. FIP can be divided into three types - effusive, non-effusive and mixed - depending on the different clinical features that occur, these types may change over time for each individual cat. Effusive (wet) FIP manifests itself mainly as ascites and / or pleural effusion, while non-effusive (dry) FIP manifests itself mainly by the formation of granulomas in the central nervous system, eyes and abdominal organs and does not produce effusion in the body cavity.³. If the symptoms of effusive and non-effusive form appear simultaneously, it is a mixed FIP⁴. To our knowledge, there are few studies on the clinical and laboratory properties of FIP in China.

Diagnosing FIP before death is a controversial and complicated issue. It is more difficult to diagnose FIP in vivo in non-exuding cats because the clinical signs and laboratory characteristics are relatively unclear. Immunofluorescence staining of FCoV antigen in macrophages is highly specific, but is difficult to detect due to the low number of macrophages in the effusion. Immunohistochemistry (IHC) is currently the gold standard for FIP diagnostics to identify FCoV antigens in affected tissues. However, this invasive method has low operability and requires professional detection equipment and personnel. At the same time, a negative IHC result does not rule out the diagnosis of FIP, which poses another challenge for the diagnosis of this disease.⁵. FIP has an extremely high mortality rate and until recently was considered a fatal disease. In recent years, a 3C protease inhibitor (GC376) and a nucleoside analogue (GS-441524) have been shown to have some therapeutic effect on FIP.^6-9. The purpose of this study is to determine the epidemiological properties and associated risk factors of FIP, to summarize common clinical signs and laboratory characteristics, and to evaluate the therapeutic effects of GS-441524 and GC376.

Materials and methods

Case selection

This study retrospectively evaluated medical records in a database of 12 veterinary hospitals in Wuchan, China, from January 1, 2019 to January 1, 2020. Due to the limitations of diagnostic facilities in veterinary hospitals and the reluctance of cat owners to consent to invasive diagnostic procedures such as biopsy, most cases were not confirmed by the IHC. Therefore, based on previously published literature in this area, the following inclusion criteria have been established for the diagnosis of suspected FIP cases.^5-15. Highly suspected cases of FIP were defined as those that met at least four of the following characteristics: 1) Typical clinical signs of FIP effusion (pleural effusion and / or ascites) or typical clinical signs of non-fusive FIP (ocular and neurological symptoms); 2) Decreased albumin / globulin ratio (A / G <0.6); 3) Rival's test showing positive results in effusion; 4) Positive detection of FCoV RNA in reverse transcription polymerase chain reaction (RT-PCR) effusion; 5) Tissue samples taken at necropsy that show typical histological features of FIP, namely systemic vasculitis and pyogranulomatous lesions.

Of the 20,984 cats registered in 12 veterinary hospitals, 127 cases with a high suspicion of FIP were included according to the above criteria. Through the collection of background information, history, clinical signs, haematological and biochemical analyzes, diagnostic imaging, RT-PCR, Rivalt's test, exploratory laparotomy and histopathology, cases were comprehensively diagnosed and analyzed and detailed information and test results were recorded (see Supplemental Table S1 for FIP case record sheet). All information was collected with the consent and cooperation of veterinarians and cat owners. The protocol was approved by the Animal Management and Ethics Committee of the Center for Laboratory Animals at Huazhong Agricultural University (approval number: HZAUCA-2018-005).

Statistical analysis

Statistical analysis was performed using commercial software (SPSS version 21.0 [IBM]). Descriptive statistics were used for all variables evaluated. Categorical data were analyzed using Pearson's chi-square test (χ²). Fisher's exact two-tailed results were used in 2 × 2 contingency tables with expected cell values <5. The sex, castration, breed, age, and onset of symptoms of suspected FIP were compared to a feline clinical population (20,984 cats) presented from January 2019 to January 2020 from 12 veterinary hospitals to determine if these risk factors were associated with FIP.

The history, clinical signs, and laboratory results of FIP suspicions were retrospectively analyzed to summarize common clinical signs and laboratory abnormalities of the disease. Samples were randomly selected from cats undergoing a laparotomy and sent to LABOKLIN GMBH & CO. KG. KG (Bad Kissingen, Germany) to the IHC to verify that the inclusion criteria for FIP cases are correct and justified. In addition, the therapeutic effect of GS-441524 and GC376 was evaluated.

Ethical approval

All relevant international, national and institutional guidelines for the care and use of animals have been complied with. All procedures performed in animal studies were in accordance with the ethical standards of the institution in which the studies were performed.

The results

Risk factors

No significant correlation was found between FIP and gender (p = 0.083). However, FIP significantly correlated with castration status (p <0.001) and intact males were more susceptible to the disease. Regarding the breed, whether classified as crossbred or purebred (p = 0.069) or specific to each breed (p = 0.246), no correlation was found with the FIP. There was a significant correlation between age and FIP (p <0.001) and young cats were more susceptible. The age of cases of suspected FIP ranged from 1 month to 8 years and 2 months, with a mean age of 13.1 months and a median age of 8 months. In these cases, 40.2% was less than 6 months old, 67% was less than 1 year old, and 90.6% was less than 2 years old; in addition, the prevalence in older cats was significantly lower than the prevalence in young cats (Table 1). The correlation of the month of onset of the disease was studied for the first time and the number of cats suspected of having FIP and the clinic population were counted for each month. The results showed that the highest prevalence was 1% in May. The prevalence in January (0.95%), February (0.87%), September (0.66%) and November (0.77%) was higher than the overall prevalence and the lowest prevalence was 0.35% in July. However, in the statistical analysis, there was no correlation between FIP and month (p = 0.135; Table 1).

Table 1

Pre-diagnosis stress events were documented in 60/127 cats. Because some cats had more stressors, a total of 77 stressors were recorded. Of these events, environmental change was the most common factor leading to stress (40.3%), followed by new domestic pets that coexisted with other diseases, intimidation, and dietary changes (Fig. 1). In addition, information was collected on the density of domestic cats, of which 43 (51.8%) were single-cat households and 40 (48.2%) were single-cat households.

Clinical signs

Of the 127 cats with highly suspicious FIP, 12 (9.4%) developed dry FIP and 109 (85.8%) developed effusive FIP, of which 92 exhibited ascites (84.4%), 11 had pleural effusion (10.1%). and 6 with ascites and pleural effusion (5.5%). In addition, 6 cats (4.7%) had mixed FIP. Some first developed dry FIP, followed by ascites and the development of effusive FIP. Some cats initially showed effusive FIP and developed neurological symptoms several days before death.

The clinical signs of cats with a high suspicion of FIP are listed in Table 2. The most common non-specific signs were weight loss (93.8%), malaise (86.2%) and anorexia (86%). In more than half of the cases, jaundice and 59.4% and 52.9% fever, respectively, were present. Of the 85 cats with highly suspected FIP for whom the temperature was documented on physical examination, 52.9% had a temperature above 39.5 ℃, 36.5% had a temperature above 40 ℃ and 10.6% had a temperature above 40.5 ℃ (see Additional Figure S1.). As a result, the 41.3% cats had a palpable mass on abdominal palpation, which could be either an enlargement of the mesenteric lymph nodes or an increase in the intestinal wall. Diarrhea was less common and occurred in only 17.6%, while dyspnoea occurred in 35.2% and was most common in cats with pleural effusion. In addition, ocular and neurological symptoms generally occurred only in dry or mixed forms of FIP.

Table 2

Hematology and serum biochemistry

As shown in Table 3, hematocrit (HCT) decreased in 40.2% cats, but only in 15.9% cats there was a decrease in red blood cell (RBC) counts. Half of the cats developed lymphocytopenia, 33.9% had an increase in white blood cell (WBC) count, and 34.3% had an increase in neutrophil count (NEU).

Table 3

In serum biochemistry, total protein (TP) levels were mostly normal (75.2%); several (14,7%) cats had elevated levels and very little had decreased levels. More than half of the cats with highly suspected FIP showed hypoalbuminemia (58.7%). Although albumin (ALB) levels in the remaining cats were normal, they were also close to the lower end of the reference range. Hyperglobulinemia was also common in cats with a high suspicion of FIP (57.8%) and the rest of the cats had normal globulin levels (GLOB). The A / G ratio ranged from 0.137 to 0.767, with a mean of 0.399 and a median of 0.385. Among the results, 91.7% was less than 0.6, 85.3% was less than 0.5, and 54.1% was less than 0.4 (see Additional Figure S2). An increase in total bilirubin (TBIL) was observed in almost half of the cats with highly suspected FIP (48.7%) and alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were mostly normal. Creatinine (CRE) decreased in 47.9% cats, while urea decreased in 60.7% cats and rarely increased. Amylase (AMYL) and lipase (LIPA) were mostly negative and positive in only a small number of cats. In addition, feline serum amyloid A (SAA) increased in all cats (Table 3).

Imaging and molecular biology

Of the 127 cats, 90 were examined by ultrasound, which showed varying degrees of ascites, and several cats showed loss of corticomedullar resolution in the kidneys. Radiography was performed on 21 cats that showed pleural effusion and / or ascites (Fig. 2). Of the 109 cats with exudate, 98 exuded the exudate. We then detected FCoV RNA in 98 effusions by RT-PCR, with 83 cats (84.7%) showing FCoV positivity. The FCoV mutation was detected in 34 FCoV-positive effusions with 12 successfully sequenced and obtained partial sequences of the S gene, all of which had M1058L or S1060A mutations. In addition, Rivalta's tests were performed in 85 cases with a positivity rate of 100%; FCoV antibody tests were performed in 12 cases and all were positive. Microscopic examination of swabs from 25 cat effusions showed many pink protein granules and an increase in inflammatory cells.

Histopathology and immunohistochemistry

13 cats underwent an exploratory laparotomy and histopathological diagnosis was performed on 9 cats (for details on 13 cats, see Additional Table S2). After exploratory laparotomy, the samples were subjected to histopathological examination and we found typical pathological changes of FIP, namely systemic vasculitis and pyogranulomatous lesions (Fig. 2). Tissue samples from six cats were randomly sent to LABOKLIN GMBH & CO. KG. KG for IHC. This testing revealed that tissue macrophages showed positive staining for FCoV antigen, confirming the diagnosis of FIP (see Additional Figure S3-S8).

Treatment and results

The results of 88 cats were recorded. Of these, 59 eventually died with a mortality rate of 67%. Thirty-two cats were directly euthanized. Twenty-six cats underwent no treatment or were treated only for symptoms and eventually died naturally. Only one dry FIP was treated with GS-441524 for 4 weeks. After the disease subsided, the owner decided to stop the treatment and the cat eventually relapsed and was killed. In addition, 29 cats (25 wet, 3 dry and 1 mixed) were treated with GS-441524 (2-4 mg / kg, once daily for at least 4 weeks) or GC-376 (6-8 mg / kg) once daily after for at least 4 weeks) with a success rate of 33%. The most visible signs were rapid loss of ascites and / or pleural effusion (within 1 week), recovery of psyche and appetite, and weight gain. The cat with a wet FIP, which was diagnosed on January 1, 2019 and survived for more than a year, survived the longest.

Discussion

In the past, FIP was considered a deadly disease by scientists. In addition, it is difficult to apply the IHC gold standard in FIP diagnostics in China. With the development of research, breakthroughs have gradually been made in the treatment of FIP, such as studies on GS-441524 and GC376 ^6-9.16. However, the side effects of the two medicines are not clear and cannot be used immediately for clinical treatment. Therefore, the establishment of a more accurate diagnostic system is essential for the FIP in China. This paper examined 127 cases of FIP in Wuhan, China, and studied the diagnostic methods of several hospitals. He focused on clinicians' clinical practices in diagnosing the disease and improving the FIP diagnostic system.

This study collected data from 127 cases with highly suspected FIP, where 13 cats underwent exploratory laparotomy, 9 samples from cats with high suspicion of FIP underwent histopathology, and 6 samples underwent IHC, all of which were finally confirmed as FIP. Therefore, the inclusion criteria for the cases in this study were justified. Many studies and studies have been conducted on FIP based on the analysis of highly suspicious cases, which could not be diagnosed by gold standard (IHC) methods, but still provided a high reference value for the diagnosis and treatment of FIP.^17–22. In addition, the implementation of invasive diagnostic methods has been difficult in clinical practice. Even owners of cats who chose euthanasia were not willing to accept the autopsy after death. Thus, if the IHC is not available, a more accurate diagnosis of a case of suspected FIP is a problem that veterinarians are currently paying close attention to.

In this study, the prevalence of cats with highly suspected FIP was 0.61%. Riemer's research in Germany showed that the prevalence of FIP was 1.42% ¹⁴. Previous studies have also shown that the prevalence of FIP in households with one cat or with two cats was 0.02%, while the prevalence in shelters was 5-10%. ^23,24. No correlation was found between gender and FIP. However, some studies have suggested that males are more susceptible to FIP²⁵. The prevalence of intact males was significantly higher than that of other groups and the prevalence of neutered cats was lower, consistent with Rohrbach's findings.²⁶. This may be because sex hormones, especially androgens, have a negative effect on the immune system and increase the risk of viruses spreading and mutating.²⁷. As mentioned above, this study showed that FIP is significantly associated with age, so young cats are more susceptible, probably because the immature immune system and various stressors have often led to a high viral load in young cats. It is possible that the increased rate of uncastrated cats may have been partly due to the young age of the infected cats, which means that the disease occurred before the age of castration. Purebred cats were previously considered more susceptible to FIP. However, a growing number of studies, including this study, showed that the proportion of purebred cats compared to the clinic population did not deviate from the average.¹⁴. This study also examined the regularity of the FIP outbreak month, which was not considered in other FIP-related epidemiological surveys, and ultimately found no significant difference in FIP prevalence by month. This study reported stressors in 60 cats, the most common of which was environmental change. There is no doubt that stress can inhibit immune function and increase the susceptibility of viruses to mutations and multiplication.¹⁰. Housing density was also considered to be one of the main risk factors for FIP, and overcrowding could lead to virus mutations and disease development.¹⁴. In any case, several cats with a high suspicion of FIP in this study came from single-cat households. This may be because these cats were exposed to FCoV when they lived in a multi-cat household as a child and then moved to a single cat household before developing FIP.

Most of the FIP cases presented were effusive (up to 85.8%), most of which were ascites. FIP can affect systemic organs, most commonly abdominal organs, including the intestine, mesenteric lymph nodes, liver, kidney, and spleen. Neurological and ocular symptoms were typical features of dry FIP. A retrospective study of 286 cats with neurological disease showed that FIP was one of the main causes of neurological diseases in cats²⁸. In this study, 52.9% infected cats had a temperature greater than 39.5 ° C and 36.5% had a temperature greater than 40 ° C. Another study showed that the proportion of cats with fever was higher, where 82% cats had a temperature higher than 39.5 ℃ and 39% had a temperature higher than 40 ℃; Fever has also been found to be more common in effusive FIP¹⁴. Cases of pericardial effusion, swelling of the scrotum or skin papules, which are not common but could not be ignored during routine examination, have not been reported. The clinical signs of FIP always change over time (for example, gradual effusion and changes in fundus), so repeated clinical examination was very important to avoid delays in diagnosis and treatment.

Changes in serum hematology and biochemistry could only increase or decrease the suspicion of FIP, but could not be used as a definitive diagnostic method. In this study, there were no apparent signs of haematological changes in the diagnosis of FIP cases, with a decrease in HCT in 40,2% cats and LYM in 50% cats. However, many studies have shown that lymphocytopenia is the most common haematological abnormality of FIP caused by natural or experimental infection.^29,30caused by virus-induced T-cell apoptosis³¹. In this study, we hypothesize that protein testing plays an important role in the diagnosis of FIP cases. ALB decreased in 58.7% cats and GLOB increased in 57.8% cats, so when both occurred simultaneously, TP often remained within the normal range. Therefore, only 14.7% cats showed an increase in TP. Both hyperglobulinemia and hypoalbuminemia may have increased the suspicion of FIP, but the most important serum biochemical abnormality was the A / G ratio. The A / G ratio decreased in almost all cases of FIP. Different studies have yielded different results regarding the effective critical value of the A / G ratio³². According to the A / G ratios in this study (91.7% <0.6, 85.3% <0.5 and 54.1% <0.4), a ratio of 0.5 can be considered a critical value. When the A / G ratio was> 0.8, the probability of FIP was very small; when the ratio was 0.5³³. Therefore, we hypothesize that an increase in SAA may help diagnose FIP.

Compared to serum detection, detection and analysis of body effusion has a better predictive value in cats.³². The positivity rate of the Rivalt test in this study was 100%. The study indicated that the sensitivity of the Rivalt test was 91.3%, the specificity was 65.5%, the positive predictive value was 58.4%, and the negative predictive value was 93.4%. ³⁴. Rival's test is a cheap and fast detection method that does not require expensive instruments and is easy to handle. In view of good sensitivity and negative predictive value, the Rivalt test should be included in the diagnosis of each fed cat.¹⁵. The positive rate of FCoV RNA detected by RT-PCR was 84.7%. However, all coronaviruses, including FCoV, often mutate and recombine, so RT-PCR designed for specific sequences could not amplify all FCoV³⁵ and positive results only represented the presence of FCoV, but not exact FIPV.

In this study, a total of 24 cats were treated with GS-441524, of which 23 were cured. Only one cat relapsed after 4 weeks of treatment and was eventually sacrificed. GS-441524 treatment for more than 8 weeks has been shown to be highly effective. Treatment with GC376 alone or in combination with GS-441524 was also effective. In fact, most of the terminal deaths were due to absence of treatment, purely symptomatic treatment, or euthanasia. In addition, Pruijssers and Denison have suggested that the combination of strong broad-spectrum anti-coronavirus drugs may increase efficacy and reduce the incidence of drug resistance.³⁶.

In conclusion, it can be stated that the FIP did not correlate with gender, breed or month, but significantly correlated with age and castration status. FIP was significantly more common in young cats or intact males. Wet FIP was the most common clinical form. Decreased A / G ratio, increased SAA and lymphopenia were common laboratory abnormalities. GS-441524 and GC376 have been shown to be effective in treating cats with suspected FIP.

Additional information

Complementary pictures. ^{(5.0 million Docx)}

Thanks

The authors would like to thank the veterinarians and owners of the cats, without whose help this study would not have been possible. The study was funded by the National Key Research and Development Plan (No. 2020YFC08845600) and Huazhong Agricultural University. The study was performed in accordance with ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines (https://arriveguidelines.org).

Author's contributions

Study concept and design: CH and Y.Yin. Data collection: YY, HO, WJ, JL, XL and JL Data analysis: YY, TL, CW and XL Manuscript: YY and CH All authors reviewed the manuscript.

Data availability

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Conflict of interests

The authors are not aware of any conflict of interest.

Footnotes

Publisher Note

Springer Nature remains neutral in terms of jurisdictional claims in published maps and institutional links.

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