Staphylococcus protein A and interferon dont work for felv

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Immunomodulation Therapy for Feline Leukemia Virus Infection

Dudley L. McCaw, DVM,Diplomate ACVIM; G. Daniel Boon, DVM, MS, Diplomate ACVP; Albert E. Jergens, DVM, MS, Diplomate ACVIM; Margaret R. Kern, DVM, Diplomate ACVIM; Mary H. Bowles, DVM, Diplomate ACVIM; Jane C. Johnson, MA
Journal of the American Animal Hospital Association
July 1, 2001



Keywords: Feline, Immunomodulation Therapy, Feline Leukemia Virus Infection, FeLV,Staphylococcus protein A, SPA, interferon alpha, IFN

Clinically ill feline leukemia virus (FeLV)-infected cats, treated with Staphylococcus protein A (SPA) or oral interferon alpha (IFN), or both, were compared with cats treated with saline (SAL). Nine cats received SPA/SAL, nine received SPA/IFN, 10 received SAL/IFN, and eight received SAL/SAL. Twelve cats survived and completed the 10-week therapy. Significantly more owners of cats treated with SPA/SAL thought their cat’s health improved during treatment compared to owners of cats treated with SAL/SAL (P=0.05, pair-wise comparison) or SPA/IFN (P=0.05, pair-wise comparison). No significant differences in body weight, temperature, hematocrit, red blood cell counts, mean corpuscular hemoglobin concentration, reticulocyte counts, white blood cell or neutrophil numbers, lymphocyte concentrations, bone-marrow cytopathology, FeLV status, survival time, activity, or appetite scores were observed. No significant differences in the owners’ subjective assessment of their cat’s health following treatment with SAL/IFN, SPA/IFN, or SAL/SAL were seen. Therapy with SPA as a single agent results in the owners’ subjective impression of improved health of their FeLV-infected cats. J Am Anim Hosp Assoc 2001;37:356—363.



From the Departments of Veterinary Medicine and Surgery (McCaw) and Veterinary Pathobiology (Boon),College of Veterinary Medicine, and the Department of Statistics (Johnson), College of Arts and Sciences, University of Missouri, 379 East Campus Drive, Columbia, Missouri 65211; the Department of Veterinary Clinical Sciences (Jergens), College of Veterinary Medicine, Iowa State University, Ames, Iowa 50011; the Animal Health Center (Kern), College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi 39762; and the Department of Veterinary Clinical Sciences (Bowles), College of Veterinary Medicine, Oklahoma State University, Stillwater, Oklahoma 74078.


This work was supported by the American Animal Hospital Foundation.


Address all correspondence to Dr. McCaw.


Doctor Boon’s current address is the Department of Biomedical Science and Pathobiology, Virginia Polytechnic Institute and State University, Virginia-Maryland Regional College of Veterinary Medicine, Blacksburg, Virginia 24061-0442.


Jane Johnson’s current address is Kirksville College of Osteopathic Medicine, 800 West Jefferson, Kirksville, Missouri 63501.




Introduction

Feline leukemia virus (FeLV) has been called the principal scourge of cats, because it causes more diseases and deaths in cats than any other single agent.1 Feline leukemia virus has been linked to feline neoplasia, most often lymphoma and leukemia. More common are diseases of a degenerative nature such as anemia, enteritis, hepatic degeneration, and immune complex glomerulonephritis. Immunosuppression caused by FeLV also contributes to clinical disease by permitting secondary bacterial, viral, and parasitic infections of a variety of organs. These secondary diseases account for most of the morbidity and mortality of FeLV-infected cats.1

Treatment for FeLV-infected cats has been mostly symptomatic and directed at resolution of the secondary infections. Therapy with the intent to stimulate the immune system has been reported to be successful.2 Among the agents that have been used are acemannan, Propionibacterium acnes, Staphylococcus protein A (SPA), and interferon (IFN). Objective data to support improvement is scarce, and all are uncontrolled studies.

storm phobia can adversely affect the owner-pet bond, with seriously afflicted dogs having to be placed in an alternate home or even euthanized in some instances.

Extreme fear of thunderstorms is just one of many inanimate fears dogs may develop. Some observers believe the phobia is simply the result of an innate fear of loud noises4 and that it may be a genetic trait.3 It has been observed that many dogs that have thunderstorm phobia also fear other sharp, percussive noises.2 Others believe that thunderstorm phobia is a composite fear that has various acquired elements, as dogs with thunderstorm phobia appear to react to a number of components of storms, including the sound of thunder, lightning, and changes in the level of illumination.3 In addition, it has been suggested that dogs may be able to sense atmospheric changes imperceptible to humans, such as changes in barometric pressure, ionization, static field, and even odors.2,3,5 It is not known which, if any, of these features are truly involved in thunderstorm phobia. Some storm-phobic dogs display a low-level fear response well before the owner is aware of the storm,3 supporting the belief that dogs may react to features of storms that are not apparent to humans. It is not known why certain dogs develop thunderstorm phobia while others do not. Some blame lack of early habituation,4 while others believe the problem is exacerbated by unintentional reinforcement of fearful responses by owners.2 Thunderstorm phobia may develop gradually but can also occur precipitously during a violent storm.6

In this study, the authors surveyed owners of dogs with thunderstorm phobia in order to gain a better understanding of the etiology of thunderstorm phobia and underlying temperament of thunderstorm-phobic dogs. Pet owners are generally accurate when labeling a pet’s behavior as fearful,3 and they tend to be aware of the situations that evoke a fearful response and the specific reactions of their pet. For this reason, the authors were confident that an owner-based survey would produce valid information. The histories and owner-reported behaviors of dogs suffering from thunderstorm phobia were evaluated to see if any common trends could be elucidated. Several factors that might contribute to the development of thunderstorm phobia were examined, including breed, age, origin, early life history, temperament, and concurrent behavioral problems of the affected dogs. Owners were also asked to describe treatments they had used and the effectiveness of these treatments.

Among the agents that have been used are acemannan, Propionibacterium acnes, Staphylococcus protein A (SPA), and interferon (IFN). Objective data to support improvement is scarce, and all are uncontrolled studies.

Staphylococcus protein A is a cell wall component of Staphylococcus aureus Cowan Strain I. Feline leukemia virus-infected cats have been treated with SPA using either extracorporeal perfusion of plasma through columns containing SPA or intraperitoneal (IP) injection of SPA.3 Improved survival, remission of lymphoma and leukemia, reversal of FeLV positive status, and general improvement in the overall condition of treated cats have been reported.3 Human interferon alpha has been shown to reduce FeLV replication in cell culture4 and to reduce FeLV p27 levels in asymptomatic cats. When human IFN is administered parenterally, antibodies directed against human IFN develop and limit the duration of response.5 To reduce the development of antibodies, lower doses of IFN have been administered orally.6 Seroconversion to FeLV negative status, prolonged survival, and subjective improvement in the quality of life have been reported with the use of oral human IFN.6

This study was undertaken to evaluate the objective and subjective responses of two agents, SPA and IFN, in naturally infected, client-owned, FeLV-positive cats that were clinically ill. The agents were used alone and in combination. Responses were compared to responses of cats being treated with placebo.

Materials and Methods

Animals

Thirty-six client-owned cats that were brought to the participating teaching hospitals were enrolled into the study. To be eligible for the study, the cats had to be negative for feline immunodeficiency virus (FIV) antibody based upon enzyme-linked immunosorbent assay (ELISA) methodology, have positive test results for FeLV antigen with both ELISA and immunofluorescence assay (IFA) methods, and be clinically ill. Cats with lymphoma or other tumors detected by physical examination were excluded. The owners were informed of the nature of the study, including the fact that their cat might receive a placebo.

Therapeutic Agents

The agents were prepared and used as previously described.7 The SPA was prepared by dissolving a 5-mg vial of lyophilized SPAa in 500 mL sterile saline to give a final concentration of 10 mcg/mL. The SPA was frozen at -20ûC in 4 mL aliquots. Saline used as a placebo was frozen and stored in a similar manner. The dose of both solutions was 1 mL/kg IP twice weekly with at least 3 days between treatments.

Human IFN alpha was diluted by adding a 3 million-unit vial of human IFN alphab into 1,000 mL sterile saline. One mL aliquots of this mixture were frozen in 100-mL vials. One mL aliquots of saline (i.e., placebo) were frozen in a similar manner. As needed, the vials of IFN or saline were thawed and diluted with 99 mL of sterile saline. This resulted in a final IFN concentration of 30 U/mL. When the solution was dispensed, the owners were instructed to keep it refrigerated. One mL was to be given daily orally for 7 days; then no oral medication was to be given for 7 days. The cycle of alternate-week therapy was continued for the treatment period.

Treatment

The cats were randomized into four treatment groups. All cats received IP and oral medications. The IP medications were administered twice weekly for 10 weeks or until the cat was removed from the study. The oral medications were given daily on weeks 1, 3, 5, 7, and 9 or until the cat was removed from the study. Eight cats received saline IP and oral saline (SAL/SAL); 10 cats received saline IP and oral IFN (SAL/IFN); nine cats received SPA IP and oral saline (SPA/SAL); and nine cats received SPA IP and oral IFN (SPA/IFN). The solutions were labeled A, B, C, and D so the owners and the person administering the medication were blinded as to the treatment group. The treatment period was 10 weeks. Unless deemed necessary, other medications were not given.

Animal Evaluation

Prior to treatment, a history, physical examination, determination of body weight, complete blood count (CBC), reticulocyte count (aggregate form) if the hematocrit was <24%, examination of a blood smear for Haemobartonella felis, bone-marrow cytopathology, FIV (ELISA), and FeLV testing (ELISA and IFA) were performed. All these except the FIV testing and blood smear examination for parasites were repeated at the end of the 10-week treatment period. For those cats that did not complete the treatment period, the above parameters were not reevaluated.

Objective Evaluation

Temperature, body weight, red blood cell (RBC) count, white blood cell (WBC) count, hematocrit (Hct), hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, absolute neutrophil, and lymphocyte counts of cats in the four treatment groups were compared prior to therapy and at the end of the 10-week treatment period. The groups were also compared for survival time. For those cats that completed the full 10-week therapy, the survival time was 70 days, and the actual survival time was used for the cats that died. Cats that were removed from the study at the owner’s request were censored, with the time of removal from the study used in the statistical comparison.

Subjective Evaluation

Bone-marrow smears obtained by aspiration were evaluated by one investigator (Boon) without knowledge of the treatment. Subjective evaluations of the smears were used, and no cell counts were performed. The erythroid, granulocytic, and megakaryocytic cell lines were numerically scored with a range of 0 to 3. If the cell line appeared to be represented in near-normal numbers, it was scored as 0; if a cell line was not observed, a score of 3 was assigned. A cell line that was assessed to be about 25% to 75% of normal was scored as 1, and a score of 2 was given if the cell line was thought to be present in numbers <25% of expected cells. The bone marrow was also examined for neoplastic-appearing cells. A score of 0 was assigned if no neoplastic-appearing cells were seen. If neoplastic-appearing cells were present but appeared to be <5% of the cells, a score of 1 was assigned. If 5% to 50% of the cells were thought to be neoplastic-appearing, the bone marrow was scored as 2; if neoplastic-appearing cells appeared to comprise >50% of the cells, a score of 3 was assigned. The scores from each cell line and a total of scores were compared between groups. Inadequate sample collection resulted in bone-marrow evaluation not being interpretable for four cats before treatment and for two cats after treatment.

The activity and appetite were subjectively evaluated and scored before and after treatment, from information obtained from the owner by a person who had no knowledge of the treatments. The appetite was subjectively evaluated and scored as normal, 0; decreased, 1; or not eating, 2. The appetite was considered decreased if the owner described the cat as eating less than normal but still eating without being force fed. Those cats that had to be force fed were classified as not eating. The activity was scored as normal, 0; mild lethargy, 1; and severe lethargy, 2. Lethargy was determined to be mild if the owners reported that the cat was sleeping more and was not as sociable; lethargy was classified as severe if the cat no longer wanted interaction with the owner or would actively avoid the owner.

At the posttreatment evaluation, the owners were asked by someone blinded to the treatment group if they thought their cat’s health had improved on the medication.

Statistical Methods

For comparison of the groups prior to therapy, Fisher’s exact test was used for gender.8 The Kruskal-Wallis test was used for age, weight, temperature, CBC results, and the subjective scores of activity, appetite, and bone-marrow evaluation. The previous parameters (except age and gender) were evaluated for change at the end of the treatment period, except for the SAL/SAL group, which had only one cat complete the therapy. A paired t-test was used to determine significance in those groups with less than five cats, and the Wilcoxon’s signed rank test was used in groups with five or more cats being compared after therapy. Fisher’s exact test was used to compare the owner’s impression of improvement of the cat’s health. Log rank test was used to compare survival time. When significance between groups was shown, a pair-wise comparison procedure was used to determine which groups were different. Significance was determined if P was ²0.05.

Results

Lethargy and decreased appetite were the most common presenting signs, occurring in 29 (81%) of the 36 cats. Weight loss was also common, occurring in 22 (61%) of the 36 cats. Less common were clinical signs of upper or lower respiratory disease, or both, in seven (19%) cats. The blood smear examinations for Haemobartonella felis were negative in all cats.

Prior to therapy, there were no differences between the groups regarding gender, age, weight, body temperature, CBC parameters, bone-marrow scores [Table 1], appetite scores, and activity scores. No changes were observed at the end of therapy in these parameters.

Twelve of the 36 cats finished the 10-week protocol; six cats were censored, and 18 cats died [Table 2]. In group SAL/SAL, one (13%) cat survived, one (13%) cat was censored at 36 days, and six (74%) cats died at 6, 10, 11, 14, 14, and 16 days. Three (30%) cats survived in group SAL/IFN, two (20%) cats were censored at 7 and 28 days, and five (50%) cats died at 7, 10, 14, 17, and 54 days. Six (67%) cats survived, one (11%) cat was censored at 59 days, and two (22%) died at 13 and 49 days in group SPA/SAL. Two (22%) cats survived in group SPA/IFN, two (22%) cats were censored at 32 and 42 days, and five (56%) cats died at 9, 10, 19, 24, and 35 days. There was no significance in survival based upon treatment group. The only difference between groups occurred with the subjective opinion of the owners. Improvement by treatment group was: SAL/SAL 1/8 (13%), SAL/IFN 3/10 (30%), SPA/SAL 6/9 (67%), and SPA/IFN 1/9 (11%) [Table 2]. Significantly more cats treated with SPA/SAL were subjectively reported by owners to have improved health compared to cats treated with SAL/SAL (P=0.05, pair-wise comparison) and SPA/IFN (P=0.05, pair-wise comparison). The FeLV status of only one cat changed after therapy. A cat in group SAL/IFN was negative for FeLV by IFA after treatment, but it remained positive by ELISA.

Deviations From Protocol

Five cats were transfused; one was in the SAL/SAL group, three were in the SAL/IFN group, and one was in the SPA/IFN group. The only cat to receive a transfusion and survive was the cat in the SPA/IFN group, and it did not show improvement.

Three cats received antibiotics; two were in the SPA/SAL group and one was in the SAL/SAL group. Both cats in the SPA/SAL group were receiving antibiotics prior to examination. One cat continued to receive antibiotics for 2 weeks after the start of immunotherapy, at which time they were discontinued. The cat survived and was considered by the owner to improve. The other cat received antibiotics until it was censored at 59 days. A cat in the SAL/SAL group was administered antibiotics at the initial examination because a fever was present. The antibiotics were continued until the cat died at 14 days.

Discussion

Interferons were first discovered as secreted factors, produced by chicken-egg chorioallantoic membrane, that were able to transfer a viral-resistant state and thus interfere with subsequent influenza virus replication.9 In addition to antiviral properties, IFNs also play a role in resistance to tumors, in the control of cell growth and differentiation, in the expression of cell surface molecules, and in immune system and lymphocyte proliferation, maturation, and circulation.10 Interferon alpha has biological activities that cross species lines, and because human recombinant IFN alpha is readily available, its use in cats is practical.6 Although IFNs are proteins and destroyed by trypsin and other proteolytic enzymes found in the gastrointestinal tract, use of IFN orally has been shown to modulate diseases;11,12 the proposed mechanism is action of IFN upon the lymphoid tissue in the oropharynx.12 The dose of IFN is critical, in that low doses are immunostimulatory while larger doses are immunosuppressive.13 At low doses, a direct antiviral effect is unlikely.6

Staphylococcus protein A is a cell-wall constituent of Staphylococcus aureus Cowan I. Staphylococcus protein A has antitumor and immunoenhancing properties.13 Increased macrophage activity has also been reported.14 The proposed mechanism of action in treating FeLV-positive cats has included enhanced antibody to gp70,15 increased IFN,16 and removal of circulating immune complexes.17 These effects are probably mediated through the ability of SPA to bind the Fc portion of antibodies.18 The dose of SPA appears to be critical, with lower doses being more immunoenhancing than higher doses.13

Feline leukemia virus infection has been linked to neoplasia, anemia, enteritis, hepatic degeneration, immune complex glomerulonephritis, and immune suppression.1 This study did not address the diagnosis of secondary conditions, and necropsies were not performed; therefore, exact cause of death or termination of treatment is not known. Lymphoma was an exclusion criterion for entering the study; therefore, no cats had lymphoma that involved the peripheral lymph nodes. During the course of the treatment, no cat developed peripheral lymph node enlargement such that lymphoma was diagnosed; therefore, this was not a factor in death or euthanasia. Several cats had neoplastic cells identified on bone-marrow examination; those cats were classified as having leukemia or myeloproliferative disease. These cancers would be the most likely cause of death in some of those cats. Lethargy and decreased appetite were the most common clinical signs that prompted clients to seek veterinary care. Although the reason for euthanasia or withdrawal from the study was not recorded, the failure to increase the energy level and appetite in the censored cats was common and probably prompted action by the owners. This is not surprising, as most owners relate these signs to quality of life in their pets.

The treatment of FeLV-positive cats with IFN and SPA in this study did not produce the same results as previous studies. Increased neutrophils,19 increased RBCs,20 and resolution of abnormal cells in the bone marrow20 have been the results using SPA. Interferon has been reported to stimulate appetite.6 Both agents have resulted in conversion to negative FeLV status.6,20 No significant differences in any objective responses measured in this study, including increased weight, decreased body temperature, and increased survival, were observed among treatment groups. In previous studies, FeLV-infected cats with dysplastic or neoplastic cells present in the bone marrow were treated with SPA either IP or by filtering blood over a column containing SPA. The treatment resulted in 80% of cats having bone marrows void of dysplastic cells after treatment.20 In this study, there was no difference in the subjective bone-marrow scores before and after treatment. Of the eight cats in either the SPA/SAL or SPA/IFN treatment groups that had neoplastic-appearing cells observed prior to treatment, three survived. Two had slight improvement in the subjective bone-marrow evaluation, and the bone-marrow aspirate on the other cat was insufficient for interpretation. One cat that had <5% neoplastic-appearing cells estimated on the pretreatment evaluation had no neoplastic-appearing cells observed on the posttreatment evaluation. The second cat’s bone marrow that was subjectively thought to contain >50% neoplastic-appearing cells before treatment was estimated to contain 5% to 50% after treatment.

Little change in Hct and neutrophil counts was seen in this study. Historically, 50% of anemic cats treated with SPA had an increased Hct.20 Seven cats in groups SPA/SAL and SPA/IFN were anemic (i.e., Hct <24%; reference range, 24% to 45%) at the initial evaluation. Two of those cats finished the 10-week treatment and were reevaluated. Both had a Hct less than the initial evaluation. Staphylococcus protein A has been reported to increase neutrophil counts by inducing bone-marrow production.19 Eight cats in groups SPA/SAL and SPA/IFN had both pre- and posttreatment WBCs. Four cats had more neutrophils posttreatment than pretreatment, while four cats had fewer.

Interferon has been reported to increase appetite.6 The mechanism may be through central nervous system effects, similar to effects of endorphine peptides.21 Fifteen cats treated with IFN (groups SAL/IFN and SPA/IFN) were described by the owners as not eating or having decreased appetite on initial evaluation. Improvement of appetite during therapy occurred in three of those cats.

Both IFN and SPA have resulted in seroconversion to FeLV negative status in other studies.6,20 The results of the FeLV tests changed at the end of the study in only one cat. This was a discordant result, with the IFA methodology being negative while the ELISA was still positive. The authors’ interpretation is that true seroconversion did not occur.

The randomization occurred before the study commenced, and stratification based upon severity of clinical signs did not occur. A natural concern is whether the groups were randomized equally. Prior to therapy there was no difference in gender, age, weight, temperature, or CBC results between the groups. The scores of the subjective evaluations of activity, appetite, and bone-marrow evaluation likewise did not indicate differences between the groups. Looking subjectively at the data, however, suggests that perhaps the SPA/IFN group might have contained sicker cats than the other groups. The subjective parameters that would be directly related to the degree of illness are neoplastic cells in the bone marrow, attitude, and appetite. Neoplastic cells were observed in the bone marrow of three of eight (38%) cats in the SAL/SAL group, three of 10 (30%) cats in the SAL/IFN group, three of nine (33%) cats in the SPA/SAL group, and five of nine (55%) cats in the SPA/IFN group. Lethargy was noted in seven of eight (88%) cats in the SAL/SAL group, six of 10 (60%) cats in the SAL/IFN group, five of nine (56%) cats in the SPA/SAL group, and eight of nine (88%) cats in the SPA/IFN group. Decreased appetite was noted in six of eight (75%) cats in the SAL/SAL group, six of 10 (60%) cats in the SAL/IFN group, five of nine (56%) cats in the SPA/SAL group, and nine of nine (100%) cats in the SPA/IFN group. Significant differences in objective and subjective data between groups were not observed. However, at the start of the study, higher percentages of cats had lethargy and decreased appetite, respectively, in the SAL/SAL (88%, 75%) and SPA/IFN (88%, 100%) groups than cats in the SAL/IFN (60%, 60%) and SPA/SAL (56%, 56%) groups. In addition, more cats in the SPA/IFN (55%) group had neoplastic cells detected in bone marrow. The SPA/IFN group contained eight (88%) cats that had both lethargy and decreased appetite.

A surprising finding in this study was the failure of cats in the SAL/IFN group to perform better than cats given the placebo. Interferon has been reported to subjectively improve the clinical signs.6 Another unexpected finding was the apparent lack of efficacy of SPA/IFN. The combination of the two drugs performed worse than SPA alone. As discussed above, the cats in this group subjectively appeared more debilitated than cats in the other groups.

Previous studies using immunomodulating therapy for treatment of FeLV-infected cats suggest a positive effect from treatment. Most results were subjective, and the studies were uncontrolled.2,3,6 This controlled study showed no difference in the objective parameters evaluated. A trend for cats in the SPA/SAL group to live longer than those in the SAL/SAL and SPA/IFN groups (P=0.08, log rank test) was present. In addition, significantly more cats in the SPA/SAL group were evaluated by the owners as having improved health when compared to cats in the SAL/SAL group (P=0.05, pair-wise comparison) and cats in the SPA/IFN group (P=0.05, pair-wise comparison); however, as this is subjective data, caution is warranted in its interpretation. The question of improved health was posed to the owners as a yes/no question. They were not queried as to the reason for the response. The authors’ perceptions would be that appetite and activity would be factors that would influence the owners as to quality of life. Some owners believed their cat had improved health even though these parameters did not change as they were recorded. However, given the definitions applied to appetite and activity, there could be considerable improvement in what the owners observed but not enough improvement for the investigator to place the response in a higher category. The authors believe SPA as a single immunomodulating agent has a role in the treatment of ill FeLV-infected cats. Although supportive care (e.g., antibiotics and transfusion) was discouraged in this study, use of supportive care along with immunostimulation with SPA may be the desired treatment for FeLV-infected cats.




a Product Number 17-0872-05; Amersham Pharmacia/Biotech, Piscataway, NJ (800-526-3593)

b Roferan; Hoffman LaRoche, Nutley, NJ



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16. Liu WT, Good RA, Trang LQ, Engelman RW, Day NK. Remission of leukemia and loss of feline leukemia virus in cats injected with Staphylococcus protein A: association with increased circulating interferon and complement-dependent cytotoxic antibody. Proc Natl Acad Sci USA 1984;81:6471-6475.

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