Injections are often a problem for owners. The technical term for the category of injectable medicinal products is subcutaneous medicationwhich means it is applied subcutaneously. Some subcutaneous drugs are simply administered under the skin, while other types of subcutaneous drugs must be administered intramuscularly (intramuscular injection), and the route of administration will depend on the desired injection site. Proper subcutaneous administration can help reduce stress levels and keep your cat happy and healthy.
Preparing the cat for injection
Make sure your cat is hydrated. If you are giving the cat subcutaneous injections, it is essential that the cat is hydrated before and after administration. If your cat is severely dehydrated, the medicines you give may not be completely absorbed. This should not be a problem for most healthy cats, but if you suspect that your cat may be dehydrated, you should consult a veterinarian on how to keep it well hydrated.
Decide where you want to inject. You may want to keep your cat in your lap to calm it down during the injection, but this increases the likelihood that your cat may scratch or injure you, and may cause you to associate staying in your lap with injections. If you decide to keep your cat in your lap, it is best to put on a rough towel to cover your feet. However, it is best to place the cat on a flat surface, such as a tabletop.
Select a suitable injection site. The injection site will vary depending on whether you are giving a single subcutaneous injection or an intramuscular injection. Too many applications in the same place can be a problem for your cat. This is because it takes the cat's body six to eight hours to fully absorb the injected fluids. If you apply too many medicines to one site before they are absorbed, it can cause fluid to build up called edema. This can be annoying for your cat and could prevent many of the medications you give from running in your cat's body.
You should be able to give about 10 to 20 ml of medicine per kilogram of body weight before you have to choose a new injection site.
Check your cat to make sure the injections are adequately absorbed. The area around the injection site should remain dry.
Wipe the injection site with an alcohol swab. Most cats will not need this step unless they have a compromised immune system. The bactericidal effect is only one of the advantages. By easing the coat, you can see the skin better when injecting.
Use food to distract attention. Just before the injection, give your cat a taste that really tastes good, such as your favorite can or tuna. As soon as it starts to eat, gently pinch the skin at the injection site. After about five seconds, you should stop beasting and take food. Return the food and this time pinch (pinch) more intensely. Repeat this until your cat is tolerant to biting and stays focused on food. This will help her prepare for the injection and reduce the pain and stress she experiences when injecting.
Subcutaneous injection
Find a place with loose skin. In general, the areas between the neck and the back of the cat are the freest and most flexible places. Gently squeeze and stretch the skin where it is loosest, hold it between your thumb and forefinger, and distract the cat with food. The resulting shape resembles a tent.
Insert the needle. When you have the skin fold firmly between your fingers, you should see a narrow strip of skin between your thumb and forefinger. Insert the needle into this area.
The needle should be kept parallel to the skin along your cat's back at all times. Tilting the needle could pierce the skin on the other side and the needle could stab you in the finger.
Do not hold your thumb over the plunger until you are sure the needle is inserted correctly. Holding the plunger when inserting the needle could cause premature injection if the cat jerks or if you have inserted the needle incorrectly.
Pull out the plunger before injecting. It is important that you pull the plunger slightly before injecting the medicine. This will make sure that you hit the injection site.
If blood enters the syringe after pulling the plunger, it means that you have hit a vessel. You will need to pull the needle out and try again in another place.
If air bubbles enter the syringe, it means that you have pierced through the skin fold and sucked in air from the other side. You will need to pull the needle out and try again.
If no blood or air bubbles have entered the syringe, you have hit an acceptable site and can continue to inject.
Inject the contents of the syringe. Make sure you inject all the medicine. Once the syringe is completely empty, carefully pull the needle out and follow the same path that you used to inject it.
Holding the syringe between your index finger and middle finger and thumb (same hand), push the plunger.
Check for bleeding or leakage. You must check the injection site after the injection. If you find that blood or medicine is leaking from the injection site, apply a clean cotton swab or tissue to the injection site until excretion stops. This should take about a minute, or longer if the cat is too restless.
Dispose of the used needle correctly. Do not dispose of the syringe in the household waste, as needles are considered to be biohazardous waste. Contact your veterinarian to see if they can dispose of needles. Never throw the exposed needle in the trash, as this could cause injury or infection to the waste collector or anyone else handling your waste.
Intramuscular injection
Find the injection site. Your veterinarian should give you specific instructions on where to take intramuscular medication and you should follow them carefully. In general, most veterinarians recommend intramuscular injections into the quadriceps (upper thigh) or lumbar spinal epaxial muscles (dorsal muscles along the spine).
Be sure when giving intramuscular injections extremely careful . A poorly inserted needle could cause serious damage to your cat's nerves. For this reason, it is best to follow all the veterinarian's instructions. If you are unsure about any part of your veterinarian's instructions, or if you do not find a recommended injection site at home, call or visit a veterinarian for more detailed instructions.
Insert the needle. The needle should be inserted at an angle of 45 to 90 degrees, depending on the site chosen for the injection. To prevent the cat from moving and for the needle to enter the muscle correctly, it can help to keep the muscle flat.
Make sure you insert the needle at the correct angle as shown by your veterinarian. Inserting the needle at too small an angle can prevent the injection from reaching the required depth and penetrating the muscle.
Do not hold your thumb over the plunger of the syringe until you are sure that the needle is inserted correctly. If you touch the plunger while inserting the needle, it may result in premature injection if the cat moves or you have inserted the needle incorrectly.
Pull the plunger before injecting. As with subcutaneous injection, pull the plunger slightly before injecting. Air bubbles should not be a problem with intramuscular injections, but if you see blood, you must pull the needle out and try again, as this may mean hitting the blood vessel.
Inject the contents of the syringe. It is important to ensure that the full dose of the medicine is given in the syringe. Once the syringe is completely empty, pull the needle out the same way you inserted it.
Holding the syringe between your index finger and middle finger and thumb (same hand), push the plunger down.
Check for bleeding or leakage. Check the injection site after the injection. If you notice signs of blood or leaked medicine, press a clean cotton swab or swab into the injection site. It only takes one minute for the bleeding or leak to stop at the correct pressure.
Dispose of the needle properly. Used syringes are considered to be biohazardous waste and as such should never be disposed of with household waste or left uncovered in waste. Ask your veterinarian if they dispose of used needles.
Feline infectious peritonitis (FIP) has fascinated me for the last 50 years. Although FIP is caused by a virus, it most closely resembles mycobacterial infections, which cause tuberculosis and leprosy in humans and cats. The disease revealed its secrets very reluctantly, and each new discovery led to further questions. As Robert Frost's famous poem puts it: "We dance around the ring and assume, but the secret sits in the middle and knows." I'm lucky to have reached the last milestone of my career when I identified safe and effective FIP treatment. We were able to reach this vase only thanks to hard work and great cooperation with teams of people in the USA from places like Kansas State and Wichita State University or Gilead Sciences.
We know that small molecules targeting specific proteins involved in RNA virus replication are able to safely treat various forms of FIP. These small molecules include the protease inhibitor GC376 and the nucleoside analog GS-441524. Both are based on drugs that are currently used to treat common human diseases, such as hepatitis C and HIV / AIDS, and are tested for exotic infections called MERS (Middle East Respiratory Syndrome), SARS (Severe Acute Respiratory Syndrome). and Ebola.
It is important to note that the small clinical trials we have completed and published are intended primarily to validate the concept, but unfortunately not to be quickly translated into approved and commercially available products. Some investigational drugs may be preferred (and thus delayed for veterinary use) in human medicine, and all will require a lengthy process to obtain final approval, even for animals. Private veterinary pharmaceutical companies will ultimately be responsible for their marketing. Is the demand for such medicines and the willingness of owners to bear the costs a sufficient incentive for these companies?
The FIP relinquished its secrets with great reluctance, and each new discovery led to further questions.
Figure 1. Bubba was originally found as an abandoned 3-week-old kitten by its owner in Florida, USA. He was diagnosed with dry abdominal FIP at the age of 7 and enrolled in treatment study GS-441524. (a) In May 2017, just before the start of treatment, Bubba weighed 6 kg (13.5 lb). In the first week of the 12-week treatment, his owner stated that he "ate alone, alert, energetic and playful." (b) Bubba, shown in January 2018, weighing 9.3 kg (20.5 lb). Acknowledgments: Adel Gastle
Unfortunately, initial reports of successful treatment only stimulated the desperate owners' efforts for immediate access to these drugs and created a growing black market. Therefore, I suspect that we will test our patience and ethics over the next few years. None of this should detract from the fact that, after more than 50 years of research, we have reached this important point. Much more is waiting to be discovered. How does virus replication in macrophages lead to immunity in many cats, while in unfortunate individuals it leads to disease? Can this knowledge finally lead to effective vaccines? What is the best way to care for kittens in kennels, shelters and deposits to minimize FIP losses? Are even better drugs awaiting their discovery? Can small molecule inhibitors act in synergy with each other in a completely different treatment modality?
I will leave these and other questions to my scientific colleagues in the field of FIP.
Niels C Pedersen DVM, PhD Center for Pet Health, School of Veterinary Medicine, University of California, Davis, USA
References
Pedersen, NC, Perron, M, Bannasch, M. Efficacy and safety of the nucleoside analog GS-441524 for the treatment of cats with naturally occurring feline infectious peritonitis. J Feline Med Surg 2019; 21: 271–281. Google Scholar | SAGE Journals | ISI
Summary: Carol Johnson DVM, PhD. A Heather Lorimer Ph.D. For clarification, additional information from literature articles by Dr. Pedersena.
Feline Infectios Peritonitis (FIP) is one of the most complex infectious diseases and is undoubtedly one of the worst diseases imaginable. It is caused by an RNA virus from the coronavirus family Nidovirales. Other RNA viruses that the reader may be familiar with include the Ebola virus, influenza virus, AIDS, and rhinoviruses. Coronaviruses are named after protrusions that look like a crown (or corona) when viewed under an electron microscope. Coronaviruses can cause disease in almost every animal species, but as such, coronaviruses are species-specific: feline coronaviruses do not infect humans, dogs, or other animals.
Feline enteric coronavirus (FECV, also referred to in the literature as FCoV) usually remains in the intestinal tract and infects the upper layer of cells lining the small intestine before settling in the large intestine. FECV can cause mild diarrhea and vomiting, but is not considered a serious pathogen in the intestinal tract.
An FECV-infected cat can shed the virus in large quantities and excretion can continue for months. Cats are obligatory carnivores and, as a result, have a very short digestive tract. This may play a role in high virus shedding. Immunity to FECV is usually temporary and previously immune animals may be reinfected. This is one of the reasons why vaccination prevention is difficult, if not impossible.
FECV specific mutations they allow him to leave the intestinal tract, where he infects cells of the immune system called macrophages, which usually help fight infection. This mutated version of FECV is called FIPV (feline infectious peritonitis virus). Infected macrophages spread the disease in the cat's body in a similar way as tuberculosis (TB) bacteria spread in humans or animals. FIPV-associated mutations occur in three parts of the FECV genome, but a particular mutation may be unique to each cat. As many as 20% FECV infections can lead to subclinical macrophage infection, but relatively few cats develop FIP. Similarly, up to 40% of the world's human population is infected with tuberculosis bacteria, but few people have developed complete tuberculosis. Unlike TB, FIPV is not transmitted to other cats; the transmission takes place via an unmutated FECV.
FIP is a population-related disease high-density cats, where kittens are part of the equation. Kittens are most susceptible to developing FIP and are usually infected with FECV at about 9 weeks of age. In general, FIP can also occur in a dense urban or rural population of free-range cats. In the United States, FIP is more common in cats and kittens from conventional, high-density shelters and feline shelters or rescue stations where kittens may be exposed to large viral loads. Another source of FIP are kennels. Not only are a number of cats concentrated in farms, but there may also be genetic predispositions that may also play a role (up to 50% in some cases). Although the genetic risk is clear, genetic analysis shows that susceptibility to FIP is likely to involve a large number of genes. As a result, inbreeding is associated with susceptibility to FIP, but genetic testing for this susceptibility is not currently possible. Overall, FIP occurs in about 0.3% cats, but can occur in up to 1-5% (or more) cats in high-density sites, such as kennels or rescue stations.
The FIP is on the rise probably due to the increasing number of rescued cats in which kittens can be fed from bottles, weaned prematurely and exposed to large amounts of FECV.
There is a dry and wet form of FIP, but there may be combined forms and it is possible to change from one form to another. In general, the moist form, characterized by effusion, which leads to enlargement of the abdomen or fluid in the lungs, along with other symptoms, has a rapid course and can kill the cat very quickly (in this case, it is often death due to euthanasia). The dry form can last for months to about a year, sometimes longer.
Risk factors for FIP development they include the prevalence of cats that shed FECV, the intensity of virus shedding, the number of cats aged 4 to 29 months (most sensitive) and genetic predisposition (in bred cats). FIP often occurs in young cats after a stressful event, such as castration or sterilization. In these cases, the cat may already have FIPV-infected macrophages in the lymph nodes, and stress allows FIP to break out.
FIP can also develop in older cats. It typically happens that one (or more) cats in a multi-cat household die due to old age and the owner feels that the remaining cat needs a new friend, so he gets the kitten out of the shelter. The older cat has long since lost immunity to FECV and is now susceptible to infection. Due to older age, an older cat may have a worse immune response than a younger animal and is more likely to develop FIP.
Dr. Pedersen is of the opinion that FIP can usually be diagnosed relatively easily. Kittens or young cats with a viscous, slimy, yellow-colored fluid in the abdomen or thoracic cavity are likely to have FIP. The dry form of FIP may be more difficult to diagnose, but in young cats it is usually a combination of symptoms associated with chronic ill health, including weight loss, cyclic fever, characteristic blood count (anemia, decreased albumin, increased globulin, low albumin to globulin ratio, increase in absolute neutrophil count, decrease in absolute lymphocyte count, increase in bilirubin, etc.) and coronavirus titre ≥ 1: 3200, which helps to guide the diagnosis of FIP. Dry FIP may present with neurological symptoms such as convulsions or ocular lesions. Autopsy of most cases confirms characteristic lesions and leads to characteristic histological findings. Tissue or histological specimens can be further tested by various techniques, such as polymerase chain reaction (PCR), immunofluorescence (IFA) (frozen tissue only) or immunohistochemistry (IHC) (formalin-fixed tissue), but Dr. Pedersen considers these tests to be confirmatory. He believes that in almost all cases it is possible to diagnose FIP by routine examination. Some diagnostic tools lead to false negative results. For example, PCR, a commonly used diagnostic test, has about 30% false negative results.
Traditional treatment does not work. Immunosuppressants such as corticosteroids may make the cat feel better, but the course of the disease will not change. Biological agents do not work. Vaccines do not work because the kitten is usually infected with FECV before vaccination and because the immunity is only temporary. The most common cause of death in cats with FIP is euthanasia due to loss of quality of life as the disease progresses relentlessly. Although the wet form of FIP is often very fast, some cats may live longer with supportive care than one might think (weeks or months). Pulmonary fluid should be aspirated, but abdominal fluid should generally not be aspirated. Dry cats can stay alive for months or more. Spontaneous remissions may occur, but usually all cats eventually succumb to FIP.
Hope comes in the form of new antivirals. RNA viruses share many of the same types of genes and therefore present similar goals in drug development. This means that drugs designed to block one type of RNA virus may prove useful in the treatment of another type. Two potential drugs that may be effective in the treatment of FIP are protease inhibitors and nucleoside analogs (NUCs), which specifically target viral enzymes. RNA viruses often form one very large protein, which is cleaved by very specific proteases into the individual viral proteins needed to assemble new viruses. Drugs that inhibit specific proteases have been developed as antiviral drugs for various viruses. NUCs used to prevent HIV genome replication (reverse transcriptase inhibitors) in AIDS patients may also block RNA-dependent RNA polymerases that replicate the coronavirus genome. Cats, like all mammals, do not have an RNA-dependent RNA polymerase, so it is an enzyme specific for a given virus. Protease inhibitors act in the late phase of cell infection, while NUCs act in the early phase.
GC376, a protease inhibitor, was the first drug of its kind to be studied in cats. Dr. Pedersen worked with a team of veterinarians and chemists at Kansas and Wichita State Universities to treat cats experimentally infected with FIP, and later naturally infected cats. The treatment included 20 naturally infected symptomatic cats with FIP. Thirteen eventually died, some relapsing after remission and death due to neurological FIP. Seven cats survived and now appear to be free of disease, one to 1 year after treatment. A study in symptomatic, naturally infected cats determined a safe dose of drugs and determined an optimal treatment time of 12 weeks. However, treatment of cats with neurological symptoms was not successful, probably because the drug does not cross the blood-brain barrier. The drugs had few adverse effects; one of the most pronounced was the inhibition of adult tooth formation, which is a known side effect of this group of drugs. The limiting factor in the study was the final amount of drug produced.
EVO984 is a nucleoside analogue - reverse transcriptase inhibitor developed by Gilead Sciences. NUCs may have some advantage over protease inhibitors because they act in the early stages of virus infection of the cell. Gilead has provided several NUCs for which Dr. Pedersen tested their effectiveness against FIPV in vitro, followed by a pharmacokinetic study and finally a study in cats with artificially induced FIP. UC Davis needed to obtain extensive documentation and knowledge before treatment could be done on client pets with naturally developed FIP, and this study is underway right now. The drug appears to be safe, has been able to reverse the symptoms of FIP, including effusion, and some cats have successfully entered remission. Like GC376, EVO984 is not effective on neurological FIP because it does not cross the blood-brain barrier well. Although this study has only been running for a few months, it looks more promising than GC376. The test has only lasted 12 weeks, but all 24 cats that took part are currently alive.
Translator's note: EVO984 later became known under a new name, which is known to almost everyone who treated a cat with FIP. EVO984 is nothing but GS441524. In addition, GS441524 has been shown to cross the blood-brain barrier at increased doses and thus to treat neurological forms of FIP.
Next steps: While the studies appear promising, many unanswered questions remain. Dr. Pedersen believes that if his study is successful, it will likely need to be confirmed by a second group. It has been pointed out that additional funding may be needed through the Winn Feline Foundation’s Bria Fund, which has invited contributions for future FIP research. Gilead is excited about the preliminary results, but the company develops drugs for human use and does not have an animal health division. Gilead has indicated to Dr. Pedersen that if the results continue to be promising, they may pursue it or seek a partner that specializes in animal health products. However, given the overall prevalence of FIP worldwide, the drug may not be attractive enough for large pharmaceutical companies. However, Dr. Pedersen pointed out that there may be a way to find a way around it using provisions of the FDA’s Minor Use and Minor Species Animal Health Act of 2004.
Questions and Answers:
The question was asked why more cats could not be treated in the study. The drugs are experimental and have limited supplies. Dr. Pedersen feels that he only needs about 20 cats to draw conclusions, as this is usually a deadly disease. He also said that the desperate owners sometimes offered him a large amount of money so that their cat could be included in the study. He said it was very sad, but strict criteria had to be followed to be included in the study and it was not possible to meet everyone.
Asked about the genetic predisposition and whether it is possible to select purebred cats resistant to FIP, Dr. Pedersen shared his experience with randomly selected breeding cats experimentally infected with the highly lethal FIPV laboratory strain. Despite infection, about 20% cats did not develop FIP. When these cats were housed together, their kittens did not develop FIP in only about 10%. When the second generation of surviving cats were bred together, FIP developed in all their offspring. Dr. Pedersen believes that these results support the concept that the most resistant cats are crossbred cats, where many immune system genes are heterozygous (having two different versions of each gene), so that a cat's immune system can respond and attack a wider range of pathogenic targets. He believes that when cats are bred, the cat's immune system becomes more homozygous (they have two copies of the same version of each gene), which reduces the variety of targets to which the immune system can respond. Because mutations that change FECV to FIPV vary, cats with a broader ability to respond to small viral changes are likely to be better protected. Breeders should minimize the use of males that have fathered kittens that have died of FIP. Why males? Because individual breeding males generally produce more offspring than breeding females, they therefore have a greater impact on the next generation of cats.
The aim of this study was to evaluate acute phase protein (APP) measurements as a diagnostic tool to distinguish between feline infectious peritonitis (FIP) and other diseases in cats with body cavity effusions.
Methods
Cats with pleural, abdominal or pericardial effusion have been included prospectively. Cats were classified as FIP positive or negative based on immunohistochemistry (if available) or a sophisticated statistical method using machine learning methodologies using concepts from game theory. FIP-free cats were further divided into three subgroups: heart disease, neoplasia and other diseases. Serum amyloid A (SAA), haptoglobin (Hp) and α1-acid glycoprotein (AGP) were measured in serum and exudate using previously validated tests in cats.
The results
Serum and effusion samples from 88 and 88, respectively, were available for APP measurement. 67 cats. Serum and effusion APP concentrations were significantly different in cats with and without FIP (P <0.001 for all three APPs). The best APP to distinguish between cats without FIP was AGP in effusion; the cut-off value of 1550 µg / ml had a sensitivity and specificity of 93% for the diagnosis of FIP.
Conclusions and significance
AGP has been found, especially when measured in effusion, to be useful in distinguishing between FIP and other diseases, while SAA and Hp are not. The concentration of all three APPs in some diseases (e.g. septic processes, disseminated neoplasia) was as high as in cats with FIP; so none of them can be recommended as a single diagnostic test for FIP.
Introduction
Feline infectious peritonitis (FIP) is a fatal infectious disease that can occur in two clinically distinct forms, the more common effluent (wet) form and the granulomatous (dry) form.1-3 Abdominal distension and dyspnoea are common in cats with effusive FIP. Ascites or pleural effusion caused by FIP is important to distinguish from other potential causes such as heart disease, neoplasia or septic effusion.4,5 Although several diagnostic tests have been developed for the diagnosis of FIP, differentiation between FIP and diseases with similar clinical manifestations remains a challenge. Although recent advances in the development of antiviral drugs may change the outcome of the disease in the future, 6 there is currently no widely available effective treatment for FIP (translator's note - as we know, treatment already exists - the article is from 2016). It is essential to make a correct diagnosis, as the consequences are currently fatal. In most cases, a combination of several diagnostic tests is necessary.3
Because FIP is an inflammatory condition, an increase in acute phase protein (APP) concentrations can be expected. APPs are produced by hepatocytes as part of an acute phase response, which is an early and non-specific but very complex response of the body to various injuries (infection, trauma, necrosis, malignant growth, etc.). 7-9 Depending on the extent of their response to triggers, APPs can be classified as major (10- to 100-fold increase), mean (two- to ten-fold increase), and minor (10- to 100-fold increase). <dvojnásobné zvýšenie). U mačky sú hlavnými APP sérový amyloid A (SAA) a α1-kyslý glykoproteín (AGP); haptoglobín (Hp) je priemerný APP.10
Several studies have examined the diagnostic potential of APP in the diagnosis of FIP, as well as the possible role of APP in the pathogenesis of FIP. 11–17 These researches had certain disadvantages that limited the implementation of the results in practice. First, APP in cats with FIP was compared with APP in healthy cats or cats exposed to feline coronavirus (FCoV) (based on FCoV positive titer) instead of comparison with cats potentially suffering from FIP, based on similar clinical manifestations.11,13 Second, it was not clear whether effusion or serum was used to measure APP.12 In addition, the sample size was too small to draw meaningful conclusions, as only four cats without FIP and eight cats with FIP were included in one study.
The aim of this study was to evaluate the ability of APP (measured in serum and effusion) to distinguish FIP from other diseases.
Materials and methods
The study prospectively included cats with pleural, abdominal, or pericardial effusions or a combination thereof, which were examined at a small animal clinic at Justus-Liebig University in Giessen, Germany, and Tierklinik Hofheim, Germany, for a period of two years. Abdomino, thora- or pericardiocentesis were performed as routine diagnostic procedures to examine the nature of the disease process in each cat. Cats from which less than 5 ml of effusion could be obtained were excluded from this study.
Routine serum hematology and biochemistry, tests for antibodies to feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) antigen (SNAP FIV / FeLV Combo Test; IDEXX Laboratories) as well as standard laboratory analysis (total content) were performed on all cats. protein, albumin and total number of nucleated cells) and cytological examination of the effusion. Residual serum and effluent samples were stored for up to 24 months at -80 ° C until APP was analyzed.
In connection with FIP, several diagnostic tests have been performed in other studies, namely the Rivalt effusion test, the anti-FCoV antibody test in serum and effusion, immunofluorescence staining of the FCoV antigen in effusion macrophages, PCR in EDTA blood and effusion. 18 The rival's test was performed in a central laboratory at a small animal clinic, as mentioned above.19 Direct and indirect detection of FCoV was performed at the Justus-Liebig University Institute of Veterinary Virology in Giessen, with the exception of immunofluorescence staining of FCoV antigen in effusion macrophages, which was performed in an external laboratory (Landesbetrieb Hessisches Landeslabor, Giessen). Anti-FCoV antibody titers were determined by indirect immunofluorescence assay using a methodology similar to the previous study.20 Embedded PCR with reverse transcriptase from EDTA blood and effusion was performed by the method of Herrewegh et al. 21 Immunofluorescence staining of FCoV antigen in effusion macrophages was performed by a method identical to that used by Parodi et al. 22 Additional diagnostic procedures (thoracic and / or abdominal radiography, abdominal ultrasonography, CT, echocardiography, cytology, histopathology, chest or abdomen surgical examination) were performed depending on the medical condition. Cats that died or were killed during hospitalization were subjected to a post-mortem inspection at the Justus-Liebig Institute for Veterinary Pathology, Giessen University, subject to the owner's consent. Pathohistological examination included immunohistochemistry as the gold standard for the diagnosis of FIP according to the method described by Kipar et al. 23
The final diagnosis (FIP vs. non-FIP) in the previous study was made based on the results of immunohistochemistry, if possible.18 The remaining cats, for which no immunohistochemistry was available, either because the cats were discharged from the clinic or the owners refused postmortem examination, were classified as FIP-positive or FIP-negative using a sophisticated statistical method.24 This method combines machine learning methodology with partial supervision using concepts from cooperative game theory using the results of several diagnostic tests in individuals whose actual state of health is unknown.24 The method takes into account the accuracy of diagnostics and the clinical significance of individual tests and their combinations for the determination of the final diagnosis. Briefly, 29/100 cats included in the previous study underwent post mortem examination (including immunohistochemistry).18 and 11/29 cats were diagnosed with FIP. Results of several diagnostic tests (Rivalta effusion test, anti-FCoV antibody test in serum and effusion, immunofluorescent staining of FCoV antigen in effluent macrophages, PCR in EDTA blood and effusion) from 16/29 cats for which FIP / non-FIP status was known on the basis of immunohistochemistry, were used to teach the device. The remaining 13/29 cats were used as test samples. Using this statistical method, the FIP / non-FIP status of the remaining 71 cats in the previous study was then evaluated.
Cats without FIP were further divided according to the results of all diagnostic tests into three subgroups: (1) heart disease - cats in which echocardiography diagnosed effusion cardiomyopathy; (2) neoplasia - cats in which it has been possible to diagnose a tumor causing effusion on the basis of cytological and / or histological examination; and (3) others - cats with effusion caused by a disease other than FIP, heart disease or tumor.
The cats included in this study represent a subset of the population from previous research.18 The classification of cats into the FIP / non-FIP category, as well as the further classification of cats without FIP into three subgroups (heart disease, neoplasia, etc.), was performed in the same manner as in this study.
Measurement of acute phase proteins
Serum and effluent samples were thawed at room temperature before measuring APP. The presence of hemolysis was assessed visually.
Haptoglobin and SAA were measured with an ABX Pentra 400 automated analyzer (Axon Lab) using reagents from the Phase Range Haptoglobin kit (second generation) (Tridelta Development) and the LZ Test 'Eiken' SAA (Eiken Chemical). Both tests were used to measure APP in cats. 11,25,26 AGP was measured by the manual method using reagents from the SRID Assay Kit (Phidel Feline α1 Acid Glycoprotein) (Tridelta Development). This test has also been validated and used in cats. 13,14
Statistical analysis
The data were tested for normality using the D'Agostino and Pearson summary normality test and found not to be normally distributed. Numeric values are therefore given as median and range. APPs in cats with and without FIP were compared using the Mann-Whitney U-test, while the four groups (depending on the final diagnosis) were compared using the Kruskal-Wallis test, followed by Dunn's comparison. Receiver operating characteristic curves (ROC) and area under the curve (AUC) were calculated for each parameter tested. Statistical analysis was performed using commercial software (GraphPad Prism version 6). Statistical significance was defined as P ⩽0.05.
The results
Serum samples were available for APP measurement from 88 cats. In 67/88 cats, APP was also measured in effusion. The median age of the 88 cats was 8.3 years (range 0.3-17.9 years); the age of the four cats was unknown. Thirty (34%) cats were females (four intact, 26 sterilized) and 57 (65%) males (seven intact, 50 neutered); in one (1%) cat, gender was not recorded. The most common breed was the domestic shorthair (63 cats [72%]); Another 11 breeds were recorded. Thirty-seven (42%) cats had ascites, 44 (50%) cats had pleural effusion, five (6%) cats had ascites and pleural effusion, and two (2%) cats had pericardial effusion. Of the 88 cats, 20 (23%) cats had FIP (nine cats confirmed this by immunohistochemistry; the remaining 11 cats were found statistically) and 68 (77%) cats had other diseases (16 cats were diagnosed by histopathology). Of these, 22 (25%) cats had heart disease, 24 (27%) had tumor and 22 (25%) cats had other diseases. In the second group, the diagnosis was made in all but two cats. Cats were diagnosed with one of the following diseases: septic peritonitis or pyothorax (n = 10), sepsis (with chest effusion classified as transudate based on cell number and total protein; n = 1), idiopathic chylothorax (n = 3), kidney disease ( n = 2), hepatic amyloidosis (n = 1), cholangiohepatitis (n = 1), permethrin intoxication (n = 1) and trauma (n = 1).
Two cats were positive for FIV, two for FeLV and one was positive for both FIV and FeLV. The underlying diseases responsible for effusion in these cats were FIP, septic peritonitis, carcinoma, lymphoma and trauma.
Three serum samples and 12 effusion samples were markedly hemolytic.
Serum and effusion concentrations of the three APPs were significantly different in cats with and without FIP (P <0.001 for all three APPs) (Table 1).
FIP
Non-FIP
P value
Serum
Hp (mg / ml)
2.0 (2.0-9.0)
1.8 (0-2.0)
<0.001
AGP (μg / ml)
2900 (960-5040)
690 (120-4500)
<0.001
SAA (μg / ml)
98.5(1.3-163.4)
7.6(0.1-163.8)
<0.001
Effusion
Hp (mg / ml)
2.2(0.1-9.3)
0.8(0.1-2.5)
<0.001
AGP (μg / ml)
2570(1300-5760)
480 (190-3800)
<0.001
SAA (μg / ml)
80.4(0.1-207.4)
0.1 (0.1-182.7)
<0.001
Table 1 Serum haptoglobin (Hp), α1-acid glycoprotein (AGP) and serum amyloid A (SAA) concentrations (20 cats with FIP and 68 cats without FIP) and effusion (14 cats with FIP and 53 cats without FIP)
There was a significant difference in serum and effusive concentrations of all three APP concentrations between cats with FIP, heart disease, neoplasias, and others (Figures 1a – ca 2a, b), with the sole exception of serum SAA, which did not differ between cats with FIP and other diseases (Figure 2c).
Figure 1 (a) Haptoglobin, (b) α1-acid glycoprotein (AGP) and (c) serum amyloid A (SAA) concentration in the fusion of cats with feline infectious peritonitis (FIP; n = 14), heart disease (n = 17)), neoplasia (n = 21) and other diseases (n = 15). The boxes represent the 25th and 75th quartiles, the horizontal line represents the median. The protrusions represent the range of data. Asterisks represent levels of significance (*** P <0.001, ** P <0.01, * P <0.05) when comparing the group with heart disease, neoplasia and other diseases with the FIP group
Figure 2 (a) Haptoglobin, (b) α1-acid glycoprotein (AGP) and (c) serum amyloid A (SAA) in the serum of cats with feline infectious peritonitis (FIP; n = 20), heart disease (n = 22)), neoplasia (n = 24) and other diseases (n = 22). The boxes represent the 25th and 75th quartiles, the median is expressed by a horizontal line. The protrusions represent the range of data. Asterisks represent levels of significance (*** P <0.001, ** P <0.01, * P <0.05) when comparing the group with heart disease, neoplasia and other diseases with the FIP group
The ROC curves for the three APPs in the diagnosis of FIP are shown for the serum in Figure 3 and for the effusion in Figure 4.
Figure 3 Curves of the operating characteristics of the acceptor of three acute phase proteins, haptoglobin (Hp), α1-acid glycoprotein (AGP) and serum amyloid A (SAA) in the serum of cats with infectious peritonitis in cats (FIP; n = 20) and cats without FIP (n = 68) )
Figure 4 Curves of the operating characteristics of the receiver of the three acute phase proteins haptoglobin (Hp), α1-acid glycoprotein (AGP) and serum amyloid A (SAA) from the effusion of cats with infectious peritonitis in cats (FIP; n = 14) and cats without FIP (n = 53)
Table 2 shows the AUC for each APP, including the best cut-off values based on the ratio of the best probability to its sensitivity and specificity.
AUC
Cut-off
Sensitivity (%)
Specificity (%)
Serum
Hp
0.777
2.0 mg / ml
55
82
AGP
0.899
2260 μg / ml
85
90
SAA
0.800
97.3 μg / ml
55
87
Effusion
Hp
0.870
2.1 mg / ml
79
87
AGP
0.950
1550 μg / ml
93
93
SAA
0.885
43.6 μg / ml
71
91
Table 2 Area under the curve (AUC), optimal cut-off values and sensitivity and specificity of the three acute phase proteins in serum and effusion
AGP in effusion has been shown to be the best marker for distinguishing FIP from other diseases; the cut-off value of 1550 μg / ml had a sensitivity and specificity of 93% for the diagnosis of FIP.
Discussion
This is the first study to evaluate all three important APPs in cats, measured in serum and effusion, as a diagnostic tool to distinguish FIP from other diseases. The best APP to distinguish cats with or without FIP was AGP in effusion. The AUC of the ROC curve for this analyte was 0.95; the cut-off value of 1550 μg / ml had a sensitivity and specificity of 93% for the diagnosis of FIP. The cut-off values for the tested parameters were chosen preferentially to obtain high specificity, as a false positive result could be potentially fatal for the cat. In the present study, only four cats with non-FIP diseases had effusion AGP concentrations higher than 1550 μg / ml and would therefore be falsely diagnosed with FIP. Of these cats, three had septic effusion and one had metastatic pancreatic carcinoma, endocarditis, and purulent bronchopneumonia. This cat had ascites, and although no tumor cells were found on cytology, the cause was most likely metastatic pancreatic cancer and the cat was classified as a "tumor group." However, this cat also tested positive for FIV and FeLV, which may have affected APP levels. As FIV or FeLV contributed to APP concentrations in the remaining four cats with FIV and / or FeLV, it is not possible to determine using current methods.
In all APPs tested in serum and effusion, some cats with septic processes and several cats with disseminated neoplasms had APP levels as high as cats with FIP. However, cats with heart disease had low APP, with the sole exception of one cat with endocarditis with an AGP concentration at an effusion of 1500 μg / ml. This cat also showed signs of bronchopneumonia at post-mortem examination, which probably contributed to the high concentration of AGP. However, this cat was classified as a "heart disease" because AGP was measured in ascites, which was considered a secondary consequence of heart failure based on post-mortem and cytological findings (modified transudate). Interestingly, in all APPs when measuring APP in effusion, there was less overlap between cats with FIP and cats with septic or neoplasia. The cause of this finding is currently unknown.
Based on these findings, a proposed diagnostic algorithm could be useful in clinical practice. In cats with body effusions, AGP in effusions should be determined. If AGP levels are high, FIP or septic or disseminated neoplastic disease should be considered. Septic effusion can be easily identified by the results of hematology and cytological examination of the effusion. If there is no evidence of a septic process, additional FIP diagnostic tests should be performed. The main disadvantage of this diagnostic algorithm is the poor availability of AGP testing compared to other methods, including PCR. However, this could be improved in the future by introducing tests that can be used with automated analyzers.27
Several studies have found elevated APP levels in cats with FIP; 11–14, however, high levels of APP have also been reported in a variety of other inflammatory and non-inflammatory conditions, such as neoplasia. 25,26,28–30 Two studies in cats with FIP evaluated only AGP, 13,14 and one study evaluated both AGP and Hp.12 All three APPs have also been the subject of other research; however, the results were only compared with those in healthy cats.11 In one study, the ROC curve for serum AGP showed an AUC of 0.850,13, which is similar to the value found in the current research (0.899). However, clinically healthy cats were used to calculate the ROC in this study, which prevented direct comparison of results.13 For sensitivity AGP, excellent sensitivity and specificity have been reported for the diagnosis of FIP, each with 100% specificity using a cut-off value of 1.5 mg / ml (ie 1500 /g / ml).14 However, only eight cats with FIP and four cats with other diseases were included and these results should be interpreted with caution. Using the same cut-off value, AGP had a sensitivity of 85% and a specificity of 100% in another study.12 This excellent specificity can be attributed to the fact that no cats with septic effusion were included.12 Septic cats, according to this study, have AGP values as high as cats with FIP, which reduces the specificity of this parameter.
There are several limitations in this study. First, immunohistochemistry, the gold standard method for diagnosing FIP, could only be performed in 11 cats for confirmation and in 18 cats for FIP exclusion (cats suffering from diseases other than FIP) because post-mortem examination was performed only in this subgroup of cats.18 However, in the latest comprehensive review of FIP diagnosis, histological examination and immunohistochemistry were not considered necessary requirements for FIP diagnosis.31 Instead, the typical characteristics, anamnesis, and clinical signs of FIP have proven to be important diagnostic tools. However, the limitations of every laboratory method, including immunohistochemistry, have also emerged.31 Other authors based the diagnosis of FIP on the findings of cytological examination of the effusion in combination with other laboratory parameters and a typical history for cases where histology was not available.32,33 To overcome the problem of the absence of post-mortem examinations, a highly reliable and sophisticated statistical method combining the results of several tests was used to classify FIP positive or FIP negative cats.24
The assays used to measure APP were not specifically designed to measure these analytes in effusion. However, according to the manufacturer's instructions, the AGP tests in this study can be used to determine the concentration of AGP in feline serum or other samples. A similar test was previously used to measure AGP in effusion.12 Long-term storage may have affected APP concentrations in our samples, as some were stored for up to 2 years at -80 ° C prior to analysis.
It is known that some laboratory methods are affected by the presence of hemolysis, lipemia and bilirubinemia in the analyzed samples. We still do not have much information about the effect of these substances on the measurement of APP in dogs and cats.10 To our knowledge, no specific measures have been published for the immunoturbidimetric assay used to measure the concentration of SAA or single radial immunodiffusion used to measure the concentration of AGP in cats in this study. When measuring the Hp concentration, haemolysis could be of concern, as free hemoglobin could bind to haptoglobin in the sample, which in turn could lead to falsely reduced Hp concentrations. 34 Because hemolytic samples were not excluded from the analysis, their use could affect the results and could be responsible for the limited usefulness of Hp in the diagnosis of FIP.
In conclusion, it is important to emphasize that the findings of this study are only applicable to cats with effusions in body cavities, which may suffer from the effusive (wet) form of FIP. Further studies are needed to evaluate APP in cats with granulomatous (dry) FIP.
Conclusions
Although AGP has been found to be a useful diagnostic tool for distinguishing between FIP and other diseases causing effusion, the contribution of SAA and Hp has not been sufficient in this regard. Measurement of AGP in effusion provided the highest diagnostic benefit among APPs tested in both serum and effusion. However, because some AGP overlap has been found in cats with FIP and septic disease or disseminated neoplasia, AGP cannot be used as the sole test for FIP.
Thanks
We would like to thank Sabina Zielinska for technical support and all colleagues from the Clinic of Small Animals and Dr. Christiane Stengel from Tierklinik Hofheim, Germany, for sampling.
Conflict of interests The authors did not indicate any potential conflict of interest in connection with the research, authorship or publication of this article.
Financing The authors have not received any financial support for the research, authorship and / or publication of this article.
Part of this study was presented as an oral abstract presentation at the 22nd Annual ECVIM-CA Congress in 2012 in Maastricht, the Netherlands.
Received: June 16, 2016
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I would like to summarize the research that Hsieh and his colleagues did in the article.1 The researchers hypothesized that interferon-gamma is involved in protecting against FIP, a reasonable assumption based on previous research by other scientists. They sequenced the feline interferon-gamma gene (fIFNG) and identified differences between cats (i.e., genetic polymorphisms) at three different positions, which they designated 401, 408, and 428B. These polymorphisms included a single nucleotide polymorphism (SNP) at each of these positions. These SNPs were not located in the parts of the genes that code for the fIFNG protein (i.e., exons) but rather in the regions that surround the exons (i.e., introns). Intron regions are known to contain both nonsense sequences and genetic elements that regulate the level of protein expression by the gene. They then collected DNA from 66 healthy cats and 60 cats with FIP. They found no relationship between the differences in SNPs at positions +401 and +408, but there was a relationship with disease status for the SNP at position +428B. I quote their work – “of all SNPs tested; only fIFNG + 428C/T was shown to be significantly associated with infection outcome. At position +428, there was a higher frequency of the CT genotype in asymptomatic control cats (19.5 %) than in cats with FIP (6.3 %) and the data showed a significant correlation with disease resistance (p = 0.03) (Table 2).” It is noteworthy that among the 66 healthy and 60 cats with FIP, only cats that had CC or CT were present; no cats that had TT were present in either population. The table showing the relevant findings is given below:
Healthy cats
FIP cats
+428 SNPs
(% of cats)
(% of cats)
CC
66 (80.5)
60 (93.8)
CT
16 (19.5)
4 (6.3)
TT
0 (0.0)
0 (0.0)
The authors concluded that the difference between 16 healthy cats with CT (19.5 % healthy cats) was significantly different from the 4 FIP cats with CT (6.3 % cats with FIP). Using the odds ratio (OR), they calculated that the odds of CC in FIP cats were 3.6 times higher than in CT cats, and concluded that the T SNP is dominant over C. There were two problems with this conclusion, however. First, no cat in their study was TT, and given the fact that 20 cats in both populations carried the T SNP (20/126=15.8 %), one would expect 9 % (0.158 x 0.158=.092), or 11 cats out of 126 cats to be TT. This suggests that either TT is embryonic lethal or, more likely, the populations studied were not a random representation of all cats. Statistical comparisons are only valid when the populations are randomly selected, and special care should be taken when the significance level approaches the minimum P value of P ≤ 0.05 and the number of cases and controls is small. The null value for TT cats in the population also made it impossible to assess whether cats containing two copies of the “protective allele” also had significantly higher resistance than cats that were CC. One would expect that if T is dominant and CT is protective, TT would also be protective. Knowledge of the incidence of cats that are TT at +428 is crucial to the use of the test, because the only way to breed to the CT genotype, if it is the only genotype associated with resistance to FIP, is to maintain CC cats in the population. If TT cats are shown to have a similar degree of resistance to FIP as CT cats, then it is theoretically possible to breed for the T allele alone (CT and TT) assuming that the T allele is indeed associated with resistance. Therefore, the value of the test depends on the prevalence of the CC, CT and TT genotypes in the populations in which it will be used. It is likely that some breeds will be homozygous for the common C allele and therefore will not be covered by the test. Although unlikely, some breeds may have a high prevalence of T and again assuming that both CT and TT are protective, testing may not be cost-effective. If the prevalence of T is low, positive selection for T carries a risk of inbreeding (see discussion below). The bottom line is that breeders should not pay for this test until they have the information they need to use it properly in their breeding programs.
The authors had the biggest problem explaining the biological significance of the T SNP polymorphism. Most significant genetic mutations are found in exons (protein coding regions) and not in introns (non-protein coding regions). To provide biological relevance, the authors had to demonstrate that an intron mutation caused an increase in fIFNG production. The usual way to do this would be to isolate a normal gene with a CC SNP and an alternative gene with a CT SNP and show that there was a difference in the expression level of fIFNG between the two genes in a test system (ie in-vitro). The simplest test would be to identify a large group of cats that are CC, CT or TT, isolate their blood lymphocytes, stimulate them to produce IFNG, and then compare the levels of either specific RNA (by qRT-PCR) or the actual protein by ELISA or other assay. If their observations are correct, cat lymphocytes that are CT or TT should express more fIFNG than cats that are CC. Instead of this complex experiment, the authors decided to only measure fIFNG levels in the plasma of cats with FIP, arguing that cats with FIP and CT SNPs would have higher plasma levels of fIFNG than cats with FIP and CC SNPs. They found that 12/12 cats with FIP with CC SNP had very low levels of fIFNG, while all three cats with FIP with CT mutation had high levels. The conclusion was that the CT mutation allows for higher expression of fIFNG. There are several serious problems with this conclusion. First, it is paradoxical to conclude that a CT mutation confers resistance to FIP and that this resistance is associated with increased fIFNG expression, but then to prove this using plasma from CT cats that have suffered from FIP. The second problem is that there were only three cats in the CT group and 12 cats in the CC group, which makes any statistical comparison irrelevant. Finally, there is no good evidence that cats develop FIP because they are unable to produce sufficient levels of fIFNG. Several FIP studies have measured cytokine expression in cats with FIP.3 These studies were more concise when they showed an increase in FIFNG in the serum of cats with FIP and an increased production of blood lymphocytes in cats with FIP after stimulation. In fact, the general conclusion is that IFNG is stimulated rather than inhibited in cats with FIP.
Up to this point, I assume that this research is justified and that further research is needed. The problem is to make a huge leap from some weak research findings to practical applications. There is already ample evidence that FIP resistance cannot be attributed to a single polymorphism in a single gene. Our attempts to find the only gene responsible for FIP resistance in field studies with Burmese cats4 and randomly bred cats in our own experimental breeding program5 did not allow us to identify a single genetic marker of FIP resistance / susceptibility that we would consider significant. In fact, the only genetic risk factor we were able to identify for FIP resistance was kinship crossing itself.6 Breeding resistant cats with resistant cats did not increase the resistance of their offspring, but rather made them even more susceptible. This is exactly what you would expect from a genetic trait that includes many different genes and gene pathways. The more you try to select a single resistance factor, the more you inadvertently limit the role of multiple genes and gene pathways. Interestingly, the current recommendation is still the best, ie to avoid inbreeding and not keep cats that have fathered kittens with FIP. This recommendation is based on the theory that such cats carry a greater proportion of susceptibility factors than cats that do not produce kittens that have developed FIP and will produce kittens with an even higher proportion of risk factors when bred together. Based on these findings, selection for resistance to FIP using a single genetic marker is more likely to favor inbreeding and, in fact, increase the incidence of FIP. Finally, it should be recalled that heredity explains only 50 % susceptibilities to FIP, 7 the remainder being attributed to epigenetic (genetic changes that occur after birth) and environmental factors.
Although a simple genetic test that would significantly reduce the risk of FIP does not seem realistic, there is reason to continue to look for genetic explanations for why some cats may appear to be resistant to FIP and others succumb to it, and why some cats develop a wet form of FIP and in others a chronic dry form. These studies should focus on farms where FIP exists, where pedigrees are known and where genetic traits can be easily traced. However, the cost of such research should not be at the expense of breeders who order the test. The normal procedure for placing a genetic test for a disease trait on the market is to verify it before it is offered to the public. I don't think this test has been sufficiently researched.
Cited literature
Hsieh LE, Chueh LL. Identification and genotyping of feline infectious peritonitis-associated single nucleotide polymorphisms in the feline interferon-γ gene. Vet Res. 2014, 45:57.
Pedersen NC. A review of feline infectious peritonitis virus infection: 1963-2008. J Feline Med Surg. 2009, 11 (4): 225-58.
Pedersen NC. An update on feline infectious peritonitis: virology and immunopathogenesis. Vet J. 2014, 201 (2): 123-32
Golovko L, Lyons LA, Liu H, Sørensen A, Wehnert S, Pedersen NC. Genetic susceptibility to feline infectious peritonitis in Birman cats. Virus Res. 2013, 175 (1): 58-63.
Pedersen NC, Liu H, Gandolfi B, Lyons LA. The influence of age and genetics onnatural resistance to experimentally induced feline infectious peritonitis. Vet Immunol Immunopathol. 2014, 162 (1-2): 33-40.
Pedersen NC, et al. Immunity to feline infectious peritonitis virus infection is diminished rather than enhanced by positive selection for a resistant phenotype over three generations.Manuscript in preparation.
Foley JE, Pedersen NC: Inheritance of susceptibility of feline infectious peritonitis in purebred catteries. Feline Practice, 1996, 24 (1): 14-22
I was born in 1943. My father was a Danish emigrant and my mother was the daughter of Danish emigrants. However, I learned that I also have Swedish roots after my father's line. I spent the first 14 years of my life in Southern California (Azusa and San Dimas), where my parents rented and then owned several family poultry farms. Although wholesale and retail eggs were their main business, they also raised ducks, geese and turkeys for the holidays. My father liked cats, but not pets. He always kept a large number of them on the farm to keep the rodent population low and their diet was supplemented by blood eggs. I loved all sorts of animals and bred pigeons, pheasants, wild ducks. As a pet, I even had a goat and a rabbit. However, my greatest love was the cats.
My first feline companion was a white, short-haired female with brownish ears, called MoMo (the mother of a cat in my child's tongue). She lived with me for 14 years and regularly and later irregularly gave me kittens. I also befriended many wild cats and one of my tasks was to sit with a box of kittens when customers came to buy eggs. I found homes for many kittens and once in a while I got 25 or 50 cents. I got to know the character and personality of cats more than anyone else. My life changed in 1956, when a huge summer fire in the hills around our San Dimas farm caused the temperature around the chickens to rise to more than 53 ° C and we lost all the water used to cool them. Sixty thousand chickens died within a week as a result of the sunburn. This unfortunate incident was, in fact, a blessing, as small family poultry farms in Southern California were rapidly becoming unprofitable, and this event forced my father to leave poultry after 30 years. He monetized all the property, which had some value, and exchanged it for a small warm spring resort in southern Nevada, and since then my family has been a real middle class. The resort was located in a valley called Upper Muddy, which also housed a large cattle ranch. The high school was 20 miles from Overton and the school started by 6:30. I started high school as a freshman with great tremor and on the first day of school I immediately fell in love with my future wife (Gerie). A small high school and living in a Mormon farming community have given me all sorts of experiences I wouldn't have had if I attended a much larger high school in Southern California. Every capable boy competed in sports and there were many interesting courses and extracurricular activities. Each student had to participate in several activities. My greatest high school experience was with Future Farmers of America, and I eventually became an FFA civil servant.
In 1961, I was accepted to the University of Nevada in Rene for scholarships from the Union Pacific Railroad and the Max E. Fleishman Foundation with the intention of becoming a teacher of professional agriculture. I soon realized that this was probably not the best career choice, but I had no idea about anything else. At the end of the first year, however, I switched to Animal Sciences and in the second year I began to attend much more demanding subjects in preparation for a possible Ph.D. in this field. My life changed again when I enrolled in a veterinary course led by one of the two veterinarians who were responsible for the small veterinary program at UNR. I have never had any direct experience with veterinarians before. Dr. Marble started my interest in veterinary medicine and even allowed me to help him with some of his experimental operations. I was immediately caught up in it and at the last minute I applied to three veterinary schools, UC Davis, WSU and CSU. I was accepted to all three schools, but I decided to go to UC Davis, California, which was closer to my home. I'm a native Californian (and an adapted Nevada). I was also fortunate that my tuition was paid by the state of Nevada under the Western Interstate Compact for Higher Education (WICHE).
I entered veterinary school in September 1963 with the intention of becoming a general practitioner for cattle (my second and third loves are cows and poultry). I worked on several science projects over the weekends and holidays, and I fell even more in love with research. In August 1964, I married my high school love Gerie. In my spare time, I worked with one of the graduate pathology students on a new feline disease called feline peritonitis and co-authored my first scientific article on FIP in 1964. I was horrified by a lack of knowledge about cats and their diseases, but that didn't stop me. After graduating from veterinary school, I graduated in internal medicine for small animals and surgery at Colorado State University, which significantly affected my future life and career. Once again, I realized how little we knew about cat diseases, and I became even more aware of my lifelong affinity and understanding with this species. Prior to my internship in 1967, I was accepted as a graduate student at the John Curtin School of Medical Research (JCSMR), Australian National University, Canberra, ACT, Australia. Australia has fascinated me all my life and JCSMR has given me not only a great research experience, but also my first experience with this vast and beautiful country. After graduating, I worked briefly as a celebrity practitioner in Hollywood to earn money to get my family (I already had a daughter) to Australia. Studying research at the Department of Experimental Pathology at JCSMR was unmatched, but not entirely related to my future career. But I learned about experimental methods. In 1972 I received my Ph.D. from experimental pathology and immunology with honors in. My love for Australia, which I cultivated in books as a child, became a lifelong passion. My hobby is identifying and photographing Western Australian plants. At our house in Winters, California, I have a large collection of photos of the flowering shrubs of Western Australia.
Dr. As longtime director of the Center for Pet Health (CCAH), Pedersen led a team that raised money and designed his current home. The CCAH building was completed in 2006 at a cost of $ 16 million, all of which was obtained from private sources. It is considered one of the most beautiful and functional buildings in the complex and is home to five clinical services and four major research programs.
In early 1972, I returned to the United States for a research position at the School of Veterinary Medicine at UC Davis, where I studied animal cancer associated with retroviruses. This was my first experience with the feline leukemia virus, which we saw during my studies in many cats, but whose cause was unknown at the time. My first year in research did not go well for me and I was considering moving to a postdoctoral position in transplant immunology at the University of Washington. Before formalizing this position, however, the dean of the Veterinary School called me and asked me if I would consider accepting a position at an internal medicine clinic for small animals. Dean Pritchard was tired of hiring doctors with rich clinical experience but weak scientific skills. He decided to try to admit to the clinic people with great research experience and good clinical potential. I became the first of a large number of employees at UC Davis with a professional background of this kind. It turned out to be a very wise decision, as the clinical program at UC Davis soon became world famous not only for its high clinical level but also high level of research.
I have worked at UC Davis since 1972 and retired in October 2013 as Professor Emeritus. I spent the first 17 years in clinics, teaching and working in research. For the rest of my time at Davis, my career was much more about administration and research. After serving as chair of the department, I became the founder and director of the Center for Pet Health and a few years later the director of the Laboratory for Veterinary Genetics. This latter function has rekindled my interest in the role of genetics in disease. Research into infectious and immunological diseases in cats and dogs has accompanied me throughout my career. I am still working and continuing my first love, research. I have no plans to retire if my health allows it, because for me, retirement in research is much better than retirement.
Although I have studied many infectious diseases of cats, FIP remains my first love, if the term can be called a disease that is still so widespread and almost always fatal. I learned to look at the FIP as a "worthy adversary." It is undoubtedly one of the most complex and challenging infectious diseases in existence, and trying to find prevention and treatment is what drives me the most. I realize that the answers don't just come. It's not like researching human diseases that have no problems with funding, whether from individuals or organizations that have a personal interest in discovering treatments. I hope that I will continue to strive to keep the disease at the center of attention, and I can say that I am not alone. I have recently reviewed more than 100 clinical and scientific publications on FIP submitted by research groups around the world since 2008. No other cat disease has received so much attention.
I enclose a more detailed biography of my career with an emphasis on FIP research, which still engulfs me. My biggest career achievements have been in the field of feline infectious diseases such as FeLV, FIV, FCV, FECV and FIPV. My textbook on diseases in a multi-cat environment, which has become a classic today, is perhaps my best creative work. However, my wife, three daughters, a son and 7 (soon to be 8) grandchildren, all successful so far, are my greatest legacy. But I hope that at least for a while, my "paw prints" will remain visible through the literature on cat diseases. And something like pets I've always had cats - always only two and always males.
–Niels C. Pedersen
Note: When Dr. Pedersen mentions a more detailed career CV, meaning mainly a number of published articles that you will find in scientific journals.
This is a 1991 photo when I received the first Jean Holzworth Cat Research Award. Dr. Holzworth was for me the best feline medicine expert he had ever lived. She graduated from DVM at Cornell University and spent her entire life at Angell Memorial Animal Hospital in Boston. She wrote the first modern textbook on cat diseases and I considered her a good friend and inspiration. She convinced me of something I've always believed in - you can't be a great veterinarian for cats without deep and confidential knowledge of this species, including everything from anatomy and physiology to behavior. -DR. P.
Wife of Dr. Pedersen Gerie with the newest members of the SOCK FIP family - recently adopted two brothers Piper (right) and Frodo (left). Frodo and Piper are among the many former experimental cats that the Pedersen have adopted over the past 40 years.
Ascitic feline coronavirus (FCoV) RNA was examined in 854 cats suspected of having feline infectious peritonitis (FIP) by RT-PCR. Positivity was significantly higher in purebreds (62.2%) than in hybrids (34.8%) (P <0.0001). Among purebred breeds, the positives of the Norwegian Forest Cat (92.3%) and the Scottish Fold cat (77.6%) were significantly higher than the average of purebred breeds (P = 0.0274 and 0.0251, respectively). Positivity was significantly higher in males (51.5%) than in cats (35.7%) (P <0.0001), whereas the prevalence of anti-FCoV antibodies generally showed no gender difference, suggesting that FIP in males infected with FCoV is more common, so males are more likely to break FIP. Genotyping was performed on 377 gene positive samples. Type I (83.3%) was detected much more frequently than type II (10.6%) (P <0.0001), similar to previous serological and genetic surveys.
See for more information original article. Among other things, it is mentioned that the incidence of FIP shows seasonal changes, and most often occurs in the autumn and winter months, while in summer the incidence is significantly lower.
Probably the oldest recorded case of FIP (Utrecht State Veterinary School, 1912/13); retrospective diagnosis is likely from the description of chronic exudative peritonitis, dyspnoea (pleurisy?), fever and eye symptoms. (Jacob, 1914).
The sudden occurrence of FIP in the late 1950s has been documented in long-term and thorough autopsy records at the hospital. Angell Memorial Animal Hospital in Boston. Therefore, the existence of FIP as a major disease before this time is questionable. The mention of a cat with a disease reminiscent of the FIP was published half a century earlier (1914 Jakob-Groot and Horzinek), but whether it was really the FIP is uncertain given the absence of reports of a similar disease in the following decades. The incidence of the disease has steadily increased since the 1960s and is currently one of the leading infectious causes of death in young cats from shelters and kennels. The reason for the sudden onset of FIP is unknown, but there are at least three possible explanations. First, coronaviruses may have specialized in cats over the last half century. Remarkably, FIP emerged ten years after the first mentions of porcine gastroenteritis (TGE) in North America. The causative FIP virus is closely related to porcine TGE virus and CCV (Canine Corona Virus), although they are still genetically distinguishable. However, recombinants are known to occur between these three viruses. At least one CCV strain can cause mild enteritis in cats and exacerbate subsequent FIPV infection, suggesting a strong resemblance to feline coronaviruses. Therefore, in this scenario, CCV may be a more likely precursor to FECV. Recombinant events are favored by the ease with which transcription units (RNAs) can be gained or lost during the divergent development of coronaviruses. Second, the FIP mutation may be selective for the FECV variant that emerged in the 1950s. This variant could also arise due to intraspecific and interspecific mutability of coronaviruses in general, and in this case FCoV in particular. The third explanation may include changes in the understanding of cats as pets and their breeding in this modern age. After World War II, there was a dramatic shift when cats began to behave like pets. The numbers of domestic cats have increased significantly, the breeding of purebred animals and cat breeding has become more popular, and more and more cats, especially kittens, have found themselves in shelters. These large, multi-cat enclosures are known to be a breeding ground for feline enteric coronavirus (FECV) and FIP infection. Interestingly, feline leukemia virus infection also spread among domestic cats during this period. FeLV infection was an important cofactor for FIP until it was pushed back into the wild in the 1970s and 1980s by testing, elimination / isolation, and possible vaccination.
Genetic relationships between different genotypes of feline and canine coronaviruses (FCoV and CCoV). Feline sequences are colored blue, canine sequences are colored orange, and porcine sequences are colored purple. Arrows indicate predicted recombination sites. Genes encoding polymerase polyprotein (Pol), structural peak (S), envelope (E), membrane (M) and nucleocapsid (N) proteins are indicated. Genes encoding helper proteins are indicated by numbers.
Loretta D. Pesteanu-Somogyi, DVM †, Christina Radzai, DVM Bar, Barrak M. Pressler, DVM, DACVIM
Abstract
Although purebred cats are known to be more likely to develop feline infectious peritonitis (FIP), previous studies have not examined the prevalence of the disease in individual breeds. During 16 years, all cats diagnosed with FIP were identified at the University Veterinary Hospital. The breed, sex and reproductive status of the affected cats were compared with the general cat population and with mixed cat breeds evaluated during the same period. As in previous studies, sexually intact cats and purebred cats were significantly more likely to be diagnosed with FIP; the prevalence of the disease was also higher in males and young cats. Abesian, Bengal, Burmese, Himalayan, Ragdoll and Rex cats showed a significantly higher risk, while Burmese, Exotic Shorthair, Manx, Persian, Russian Blue and Siamese cats did not show an increased risk of developing FIP. Although other factors undoubtedly affect the relative prevalence of FIP, this study provides further guidance in prioritizing differential diagnoses in sick purebred cats.
Feline infectious peritonitis (FIP) is a progressive systemic disease with a wide range of clinical symptoms and high mortality (Hartmann 2005). It is caused by a mutation in feline enteric coronavirus, a common feline pathogen that may not cause any clinical signs or only transient diarrhea (Pedersen 1995; McReynolds and Macy 1997; Hartmann 2005). The mutated FIP virus spreads through the monocyte phagocytic system, and variations in the immune response of individual cats cause one of two recognized forms of the disease (Pedersen 1995, McReynolds and Macy 1997, Hartmann 2005). The "wet" form of FIP, which is observed in approximately 75% cases, is caused by complement-mediated vasculitis initiated by deposition of the immune complex in the vessel walls and usually leads to effusions in the body cavity (Pedersen 1995; McReynolds and Macy 1997, Hartmann 2005.). The "dry" form of FIP, identified in other cases, arises when a cell-mediated immune response dominates and granulomas form in various organs (Pedersen 1995; McReynolds and Macy 1997; Hartmann 2005).
Epidemiological studies of cats with FIP have identified several risk factors for developing the disease. The highest prevalence is in young cats (aged 3 months to 3 years), with most cases (75%) being in an environment with numerous cats (Kass and Dent 1995, Pedersen 1995, Foley et al. 1997a, McReynolds and Macy 1997, Rohrbach et al., 2001). Males and sexually intact cats are also at increased risk of developing FIP (Robison et al. 1971; Rohrbach et al. 2001). Other factors that are mentioned less frequently, associated with an increased prevalence of the disease, include seasonal (more cases are usually diagnosed in winter) FeLV infection, increased factors associated with "stress", high titers of coronavirus antibodies, regular feeding of new cats. to kennels and increased coronavirus excretion (Kass and Dent 1995, Pedersen 1995, McReynolds and Macy 1997, Foley et al. 1997a, Rohrbach et al. 2001).
Two studies report that FIP is more common in purebred cats (Robison et al. 1971; Rohrbach et al. 2001). Although the relative prevalence of FIP in different breeds of cats has been the subject of at least one study, statistical differences have not been calculated (Scott 1991). Therefore, to the authors' knowledge, it has never been thoroughly examined whether there is a specific predisposition to FIP depending on the breed. The purpose of this study was to determine whether such a preference for the cat breed actually exists. The sex and age of the affected cats were also examined to allow some comparison between the current population in the study and the populations from previous studies.
Materials and methods
The final diagnosis was checked for all cats entered into the computer database of patients at North Carolina State University College of Veterinary Medicine (NCSU-CVM) between December 22, 1986 and December 22, 2002. Cats with FIP were identified using coding terms. "Feline infectious peritonitis" or "FIP". In all cases, the final diagnosis was made by the attending physician; diagnostic criteria and the results of anti-mortem or post-mortem diagnostic test results have not been reviewed.
The breed, sex, and reproductive status of all cats examined at NCSU-CVM during the 16-year study period were assessed; all cats of unknown breed were excluded. Mixed breeds of cats of all coat lengths (domestic short-haired, medium and long-haired) were considered as a single breed (called "mixed breed") for data analysis purposes. Descriptive statistics were calculated for each variable studied for the FIP population and for the total cat population. Descriptive statistics on the age of cats at the time of evaluation were calculated only for cats affected by the FIP. Differences in breed, sex, and reproductive status were compared using Fisher's exact test; P values less than or equal to 0.05 were considered significant. The odds ratio (OR) and 95% confidence interval (CI) were also calculated for each variable.
The results
During the 16-year study period, 11,535 cats of known breeds were examined at the NCSU-CVM. The cats studied included mixed breeds of cats (9511 cats) and 36 different purebred breeds (2024 cats). Sixty cats (0.52%) had a definitive diagnosis of FIP; the breed was intended for all affected cats. Gender and reproductive status information was available for 57 of the 60 FIP cats and 11303 of the 11475 FIP negative cats. Age information was available for 58 of the 60 FIP cats.
Cats diagnosed with FIP included mixed breeds of cats (33 cats) and 13 different purebred breeds (27 cats). The prevalence of FIP in the mixed cat breed population was 0.35% versus 1.3% in the purebred cat population (Fig. 1). Purebred cats showed a significantly higher probability of developing FIP than mixed breeds (OR 4.5, CI 2.7-7.5; P <0.001). Breeds with a FIP prevalence significantly higher than that of mixed cat breeds included the Abyssinian, Bengal, Birman, Himalayan, Ragdoll and Rex breeds (including Cornish and Devon varieties) (Table 1, Figure 2). The prevalence of FIP in Burmese, exotic shorthair, Manx, Persian, Russian blue and Siamese cats did not differ significantly from mixed breed cats. Although two Havana cats evaluated at NCSU-VTH during the study period were diagnosed as FIP positive, this small number precluded statistical analysis.
Figure 1: Prevalence of FIP by group of cats
Figure 2: Prevalence of feline infectious peritonitis (FIP) in mixed breeds of cats and in breeds with a prevalence of FIP significantly different (P <0.05) from mixed breeds of cats.
Tribeand
Cats diagnosed with FIP / total number of cats (% affected by FIP)
Odds ratio
Confidence interval
P value (Fisher's exact test)
Abesín cat
3/99 (3.0%)
8.98
2.71-29.77
0.006
Bengal cat
1/8 (12.5%)
41.03
4.91-342.85
0.028
Burma
4/18 (22.2%)
82.06
26.66-262.44
<0.001
Burmese cat
1/37 (2.7%)
7.98
1.06-59.91
0.124
Exotic shorthair cat
1/62 (1.6%)
4.71
0.63-34.98
0.199
Havana cat
2/2 (100%)
_b
_b
_b
Himalayan cat
4/364 (1.1%)
3.19
1.12-9.06
0.046
Manx
1/67 (1.5%)
4.35
0.59-32.29
0.213
Persian cat
4/481 (0.5%)
2.41
0.85-6.83
0.101
Ragdoll
2/13 (15.3%)
52.22
11.14-244.79
0.001
Rex (Cornish and Devon)
2/17 (11.7%)
38.29
8.42-174.15
0.002
Russian blue
1/39 (2.6%)
7.56
1.01-56.68
0.130
Siamese cat
1/536 (0.2%)
0.54
0.07-3.93
1.00
Table 1: Prevalence, odds ratios and confidence intervals in purebred cats with FIP and Breeds with 0.0% prevalence of feline infectious peritonitis are not listed. b Insufficient number of cats for statistical calculations.
The prevalence of FIP was zero in 23 cat breeds. These included Angora (11 cats evaluated during the study period), Balinese (25 cats), Belgian (two cats), Bombay (four cats), British Blue (two cats), British Shorthair (three cats), Carthusian (four cats) , Colorpoint Shorthair (one cat), Egyptian Mau (one cat), Japanese bobtail (six cats), Korat (five cats), Maine Coon (151 cats), Maltese (two cats), Norwegian Forest (five cats), Ocicat ( 16 cats), Ragamuffin (one cat), Scottish Fold (15 cats), Siberian (one cat), Snowshoe (two cats), Somali (three cats), Sphinx (one cat), Tonkin (18 cats) and Turkish Van ( two cats). Unfortunately, the low prevalence of FIP in the population of mixed cat breeds has prevented the determination of significance or relative risk in these purebred cat varieties.
FIP was significantly more likely in sexually intact cats compared to the general cat population, regardless of gender (intact male versus neutered male, P <0.001; intact female versus neutered female, P = 0.002; all intact cats versus all neutered cats, P < 0.001, the prevalence of intact cats in the general population was 15.8%, compared to 45.6% in the FIP population). Although FIP was more numerous in males than in females, the difference in prevalence was not statistically significant (P = 0.425; 53.6% from the total cat population were males, compared to 59.6% from the FIP population). At the time of the last evaluation, the median age of cats with FIP was 0.96 years (25th percentile 0.5 years, 75th percentile 2.0 years). 67% cats with FIP were less than 2 years old.
Discussion
Although an increased prevalence of FIP in purebred cats has been reported previously, this is the first time that the predisposition of specific breeds to disease development has been investigated (Robison et al. 1971; Rohrbach et al. 2001). Our results show that some breeds may in fact be more likely to develop FIP, especially Biri, Ragdoll, Bengal, Rex, Abesian and Himalayan breeds. Other cat breeds, Burmese, Exotic Shorthair, Manx, Persian, Russian Blue and Siamese, do not appear to be at increased risk compared to mixed cats. Our results regarding the effect of gender, reproductive status, and age on the relative prevalence of FIP are similar, although not identical, to previous studies (Robison et al. 1971, Horzinek and Osterhaus 1979; Kass and Dent 1995; Rohrbach et al. 2001).
Previous evidence supports the influence of host genetics on the mutation of feline enteric coronavirus or on susceptibility to FIP. Cheetahs, whose genomes have become more homozygous with minimal allelic diversity due to evolutionary narrowing, have a very high prevalence of FIP (O'Brien et al. 1985). Similarly, the increased prevalence we found in some purebred variations could be due to the concentration of inherited factors through breeding or small founder populations. Given the shared environment and virus strain, Foley and Pedersen (1995) calculated that slightly more than 50% of the susceptibility to FIP in purebred cats from six breeds could be attributed to inherited differences between individuals. Interestingly, in this study, one of the kennels with numerous closely related cats suffering from FIP was the Biriem kennel (Foley and Pedersen 1995). In this study, Birmans were by far the most commonly affected, and therefore we may not be the first to point out an increased susceptibility to FIP in this breed.
Other researchers have questioned whether the increased prevalence of FIP in purebred cats could not actually be due to misleading factors. Purebred cats are bred more frequently in kennels, which can be inherently more stressful due to the environment with numerous cats, the regular arrival of new cats and frequent breeding (Kass and Dent 1995, Pedersen 1995). In addition, kennel cats are likely to face higher exposure to feline enteric coronavirus (a condition for FIP development) due to increased population density (Foley et al. 1997a, 1997b, McReynolds and Macy 1997). Finally, the possible increased willingness of owners of expensive purebred cats to perform advanced diagnosis and supportive care at a recommended veterinary facility, such as NCSU-VTH, may skew the apparent prevalence of the disease. However, these factors are expected to falsely increase the prevalence of FIP in all purebred cats, and not only in those breeds that we report have an increased risk of developing the disease.
We have decided to include in this report cases based on the final diagnosis entered in our computerized medical database, and not on the control of records and histopathological reports. As a result, we must recognize that future investigations, which will be limited to cases with a confirmed diagnosis, may yield different results. However, because the pre-death diagnosis of FIP in our tertiary care hospital is expected to be similar to the diagnostic algorithms proposed by other authors, we feel that our results, especially in breeds with more or a particularly strong association with the disease, are unlikely to conflict with future studies. (Sparkes et al. 1991, Rohrer et al. 1993, Addie and Jarrett 1998).
A multivariate analysis of the variables studied here would further define the susceptibility of a specific breed to FIP. For example, it is not known whether breeds with an increased FIP prevalence actually had a higher number of intact cats, which affected our calculations. Furthermore, very few individuals were examined in some breeds and the large CI reflected inaccuracy in risk determination. We doubt that the absence of cats diagnosed with FIP in 23 breeds indicates absolute disease resistance, although it is possible that some of these breeds (such as the Maine Coon cat, which were observed in relatively large numbers at NCSU-VTH) have unrecognized protective factors. which affect susceptibility to FIP. Unfortunately, due to the low prevalence of FIP in all cats, a much larger population will need to be examined to determine if the low incidence of the disease in these breeds is statistically significant.
The predisposition of certain breeds to the development of FIP demonstrated here requires further research. Our results suggest that in some sick purebred cats, the suspected FIP index is likely to increase. A multicenter study, which includes cases from both primary and recommended facilities with multivariate analysis, is probably necessary to definitively answer the question of the sensitivity of individual breeds to FIP.
Thanks
We thank Cavell Brownie, PhD (Department of Statistics, State University of North Carolina) for performing statistical analyzes, and Malcolm Roberts, BVSc, PhD, MPH, FRCVS, FACVSc (Department of Clinical Sciences, State University of North Carolina) for reviewing the manuscript.
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