Human intravenous immunoglobulin use for hematological immune-mediated disease in dogs

Briannan-Kym Kane Small Animal Internal Medicine, Queensland Veterinary Specialists, Brisbane, QLD, Australia

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 BVSc MANZCVS
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Ristan M. Greer Torus Research, Brisbane, QLD, Australia
Faculty of Medicine, Mader Research Institute, University of Queensland, Brisbane, QLD, Australia

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 PhD, MVSc, MANZCVS

Abstract

OBJECTIVE

To report on survival rates and risk factors in dogs with immune-mediated hemolytic anemia (IMHA) and immune-mediated thrombocytopenia (ITP) treated with human IV immunoglobulin (hIVIG; Privigen). We hypothesized that hIVIG could be used as a salvage treatment to improve survival and reduce the requirement for ongoing blood transfusion therapy in IMHA and ITP patients.

ANIMALS

52 client-owned dogs with IMHA or ITP were included, comprising 31 females (28 spayed and 3 entire) and 21 males (19 castrated and 2 entire). Miniature Schnauzers were the most common breed (5), with a further 24 different breeds identified.

PROCEDURES

A retrospective cohort study was conducted between January 2006 and January 2022 that assessed the survival rates, risk factors, and need for ongoing transfusion in dogs with IMHA and ITP treated with hIVIG compared with those not receiving hIVIG.

RESULTS

Of 36 dogs that did not receive hIVIG, 29 (80%) survived and 7 (24%) died, and of 16 dogs administered hIVIG, 11 (69%) survived and 5 (31%) died (P = .56). No effect of PCV at admission or age on the risk of death was detected (OR, 1.00; 95% CI, 0.94 to 1.08; P = .89; and OR, 1.10; 95% CI, 0.85 to 1.47; P = .47, respectively).

CLINICAL RELEVANCE

This was the largest study to date of dogs with hematological immune-mediated disease treated with hIVIG. There was no difference in survival rates for dogs that received hIVIG versus those treated with standard immunosuppression. The benefit of hIVIG as a salvage treatment appears limited.

Abstract

OBJECTIVE

To report on survival rates and risk factors in dogs with immune-mediated hemolytic anemia (IMHA) and immune-mediated thrombocytopenia (ITP) treated with human IV immunoglobulin (hIVIG; Privigen). We hypothesized that hIVIG could be used as a salvage treatment to improve survival and reduce the requirement for ongoing blood transfusion therapy in IMHA and ITP patients.

ANIMALS

52 client-owned dogs with IMHA or ITP were included, comprising 31 females (28 spayed and 3 entire) and 21 males (19 castrated and 2 entire). Miniature Schnauzers were the most common breed (5), with a further 24 different breeds identified.

PROCEDURES

A retrospective cohort study was conducted between January 2006 and January 2022 that assessed the survival rates, risk factors, and need for ongoing transfusion in dogs with IMHA and ITP treated with hIVIG compared with those not receiving hIVIG.

RESULTS

Of 36 dogs that did not receive hIVIG, 29 (80%) survived and 7 (24%) died, and of 16 dogs administered hIVIG, 11 (69%) survived and 5 (31%) died (P = .56). No effect of PCV at admission or age on the risk of death was detected (OR, 1.00; 95% CI, 0.94 to 1.08; P = .89; and OR, 1.10; 95% CI, 0.85 to 1.47; P = .47, respectively).

CLINICAL RELEVANCE

This was the largest study to date of dogs with hematological immune-mediated disease treated with hIVIG. There was no difference in survival rates for dogs that received hIVIG versus those treated with standard immunosuppression. The benefit of hIVIG as a salvage treatment appears limited.

Introduction

Human IV immunoglobulins (hIVIG) have historically been used in human medicine for various immunodeficiencies, with earliest reports dating back to 1981 in children with idiopathic thrombocytopenic purpura.1 Extracted from purified donor serum, the available commercial preparations contain variable concentrations of immunoglobulin IgG, IgM, IgA, and IgE; plasma proteins; and trace amounts of different cytokines, receptors, and stabilizing substances.2 However, IgG immunoglobulin constitutes up to 90% of the available formulations.2

The immunomodulatory effects of hIVIG are complex, with multiple mechanisms often working synergistically. These include the following: Fc receptor antagonism, autoantibody neutralization, complement inhibition, Fas-Fas ligand mediation, cytokine downregulation, and B and T cell modulation.3,4 Antagonism of Fc receptors reduces subsequent opsonization and phagocytosis by macrophages within the reticuloendothelial system. This achieves downregulation of thrombocyte or erythrocyte phagocytosis. Additionally to this mechanism, competitive binding of hIVIG to FcyRIII induces receptor saturation and subsequent antagonism of IgG multimer access, inhibition of dendritic cell maturation, downregulation of proinflammatory cytokines, and many other intricate immunomodulatory mechanisms.2

In veterinary medicine, available studies report on the use of hIVIG in various diseases, including IMHA,412 ITP,4,5,13,14 Evans syndrome,4,15 myasthenia gravis,4 drug-induced cutaneous and immunological reactions,4,1618 dermatological disease,4,19 and sudden acquired retinal degeneration.4,20 Use in veterinary IMHA and ITP has not been widely studied, and there is a lack of substantial up-to-date, evidence-based literature. Only a handful of small studies are available, with 1 study reporting on the effect of hIVIG in reducing blood transfusion requirements.9 The most recent American College of Veterinary Internal Medicine consensus statement for IMHA dictates the use of hIVIG as a salvage treatment for patients that have not responded to traditional therapy, required additional immunosuppressant therapy (≥ 2), received multiple (≥ 2) blood transfusions, or display uncontrolled disease after 7 days.21 Bestwick et al7 authored a recent paper on hIVIG (Pentaglobin) therapy in dogs with an earlier disease course of primary IMHA. The prospective study administered a high dosed M-enriched immunoglobulin to 11 dogs receiving hIVIG with 3 controls. This study found no specific benefit of such use in the early treatment and response of dogs with IMHA compared to prednisolone alone.7 Use in ITP has been investigated with a particular interest in reporting platelet recovery times compared to vincristine administration. Most studies found no significant difference between the administration of vincristine versus hIVIG, with the conclusion that vincristine is superior to IVIG in terms of cost, ease of administration, and reduced risk of adverse events.5,22,23

Human IVIG is an expensive treatment modality within veterinary medicine and is often financially equivalent to a standard blood product transfusion, if not more. The financial burden and limited availability of this resource often restrict patients that rely on continuous blood transfusion therapy for survival. Attending clinicians face the difficult clinical judgment of recommending ongoing blood product transfusion therapy versus salvage hIVIG treatment with the currently available guidelines. When hIVIG is used as a salvage treatment for IMHA and ITP, there is limited evidence-based literature to indicate dosage, efficacy, and patient outcomes to support hIVIG use in such critical clinical scenarios.

The aim of this study was to report survival rates and associated risk factors in dogs with IMHA and ITP treated with hIVIG. The hypothesis was that hIVIG used as a salvage treatment would reduce mortality and the requirement for ongoing blood transfusion therapy in both IMHA and ITP patients.

Materials and Methods

This was a retrospective cohort study conducted at Veterinary Specialist Services, a private practice specialist referral hospital located in South East Queensland. Medical records between January 1, 2006, and January 1, 2022, from the 3 separate sites were reviewed, and results were pooled. Veterinary practice management software was utilized (ezyVet version 35.4; IDEXX). Search terms included immune-mediated hemolytic anemia, hemolytic anemia, immune-mediated thrombocytopenia, immune thrombocytopenia, primary thrombocytopenia, thrombocytopenic disorder, thrombocytopenia, IVIG, and Privigen.

The inclusion criteria were no prior IVIG administration, complete medical records with a documented diagnosis of IMHA or ITP (as determined by the attending clinician), hematological and biochemistry profiles, PCV, and total protein results. Dogs were excluded if they were administered hIVIG for disease processes not attributable to IMHA or ITP, had incomplete medical records, or had no diagnosis recorded. Diagnosis of IMHA and ITP was based on consistent hematological and cytological findings reported by a veterinary clinical pathologist (QML Pathology). Specific characteristics for IMHA included spherocytosis, microagglutination and macroagglutination, severe regenerative anemia (PCV < 35%), hemolysis, icteric serum, and positive direct Coombs test; specific characteristics for ITP included severe or absolute thrombocytopenia (< 200 X 109/L), regenerative anemia, clinical signs of petechiae, ecchymoses, melaena, and hematuria. A primary or secondary diagnosis of either IMHA or ITP was extracted from the available clinical records by the attending clinician (small animal internal medicine specialist, registrar, or supervised resident). Dogs were allocated to groups according to whether they had been treated with hIVIG. As many more dogs were not treated with hIVIG than treated, a non–hIVIG-treated control group was selected on the basis of signalment, breed, weight, and primary diagnoses to best match each of the dogs included in the hIVIG group. The author selected between 2 and 3 control cases per each case within the hIVIG group.

Data recorded for both groups included age, weight, sex, neuter status, date of diagnosis, date of admission to Veterinary Specialist Services, immunosuppressant medications administered, PCV/total protein on admission and recorded if available daily, blood transfusion type and number received during hospitalization, date hIVIG administered, the dose of hIVIG, subsequent transfusions required, any adverse reactions associated with transfusion reactions, the reason for hIVIG administration, and survival status (alive at hospital discharge or died). Weight was dichotomized to ≤ 13.0 kg (kg) or > 13 kg due to the large breed variation found within the study. No long-term follow-up data were obtained from the included cases, and the end point was survival to discharge.

Statistical analysis

Continuous variables were assessed for normality. Normally distributed continuous variables are described as mean (SD, SD) and nonnormally distributed continuous data as median (IQR) unless otherwise stated, with groups compared using a t test or Wilcoxon rank sum test, as appropriate, or Wilcoxon signed rank test for paired data. Categorical variables are described as n/N (%) and groups compared using a Pearson χ2 test or Fisher exact test if the expected cell frequency was < 5. Odds ratios (reported as OR; 95% CI) for death were estimated using logistic regression in uni- and multivariable models. Survived was coded as 0 and died as 1, with survival as the reference category. Data was collated and summarized using Excel 2019 (Microsoft Corp). Statistical software (R version 4.2.1; The R Foundation) was used for all statistical analyses. Significance was set at P ≤ 0.05, and all tests were 2-sided.

Results

Fifty-two client-owned dogs with IMHA or ITP were included. Seventeen out of 52 (32.69%) dogs had primary IMHA, 2 (2/52 [3.85%]) had secondary IMHA, 29 (29/52 [55.77%]) had primary ITP, and 4 (4/52 [7.69%]) had secondary ITP. The mean (range) age was 6.8 years (1 to 14 years). Sixteen dogs had been treated with hIVIG, and the control group comprised 36 control dogs, 13 diagnosed with IMHA and 23 diagnosed with ITP. There were 26 breeds recognized within the study. Of these, the most common breeds were Miniature Schnauzer (n = 5) and Border Collie (5). There were 31 females (31/52; 28 spayed and 3 entire) and 21 males (21/52; 19 castrated and 2 entire). In the control group, 12 of the 36 dogs had a primary diagnosis of IMHA, 1 had secondary IMHA, 20 of the 36 had a primary diagnosis of ITP, and 3 had secondary ITP. In the hIVIG group, 5 dogs of the 16 had a primary diagnosis of IMHA, 1 of the 16 dogs was diagnosed with secondary IMHA, 8 of the 16 dogs had a primary diagnosis of ITP, and 2 of the 16 dogs were diagnosed with secondary ITP. The secondary causes reported for IMHA included infectious disease (1/52) and suspected neoplasia (1/52). The secondary causes reported for ITP included heat stress (1/52), neoplasia (1/52), drug induced (1/52), and estrous (1/52). No difference was detected between groups in age at diagnosis, weight, sex, primary diagnosis, serum PCV, Hct, or total protein (Table 1).

Table 1

Patient characteristics including hematological values and primary diagnosis.

Variable Treated with hIVIG (n = 16) Control animals (n = 36) Total in study (n = 52) P value (not treated with hIVIG vs treated)
Age at diagnosis (mean, SD) 6.2 (3.1) 7.1 (3.1) 6.8 (3.1) .39
Weight in kg at diagnosis (median, IQR) 8.9 (6.0–14.3) 10.2 (7.3–18.8) 10.1 (6.6–16.7) .40**
Sex .23†
   Entire female 1 (6.2) 3 (8.3) 4 (7.7)
   Spayed female 8 (50.0) 18 (50.0) 26 (50.0)
   Entire male 2 (12.5) 0 (0.0) 2 (3.8)
   Neutered male 5 (31.2) 15 (41.7) 38 (5)
PCV at diagnosis (%; mean, SD) 25.2 (10.8) 29.8 (12.1) 28.3 (11.7) .23
Hct at diagnosis (%; mean, SD) 29.0 (11.0) 33.9 (14.0) 32.6 (13.2) .35
TP at diagnosis (g/L; median, IQR) 63.5 (52.5–70.5) 64.5 (52.0–76.0) 64.0 (52.0–76.0) .81
Primary diagnosis (n/N, %) .87
   Primary IMHA 5 (31.2) 12 (33.3) 17 (32.7)
   Secondary IMHA 1 (6.2) 1 (2.8) 2 (3.8)
   Primary ITP 9 (56.2) 20 (55.5) 29 (55.8)
   Secondary ITP 1 (6.2) 3 (8.3) 4 (7.7)
Breed (n/N, %) < .001
   Miniature Schnauzer 4 (25.0) 2 (5.5) 6 (11.5)
   Border Collie 3 (18.7) 2 (5.5) 5 (9.6)
   Maltese and Maltese mix 8 (50.0) 3 (8.3) 11 (21.1)
   Cocker Spaniel 0 4 (11.1) 4 (7.6)
   Other 1 (6.2) 25 (69.4) 26 (50.0)

hIVIG = Human IV immunoglobulin. IMHA = Immune-mediated hemolytic anemia. ITP = Immune-mediated thrombocytopenia. TP = Total protein.

†Fisher exact test. **Wilcoxon rank sum test.

Survival

Five of the 16 (31.2%) dogs in the hIVIG group died, compared with 7 of 36 (19.4%) in the control group (P = .35). From the univariable logistic regression, there was no evidence that the administration of hIVIG improved survival (OR, 1.88; 95% CI, 0.47 to 7.23; P = .35). Similarly, there was no detected effect of PCV at admission on the risk of death (OR, 0.99; 95% CI, 0.93 to 1.06; P = .86) nor of age at admission (OR, 1.15; 95% CI, 0.93 to 1.46; P = .19), weight ≤ 13 kg (OR, 0.5; 95% CI, 0.10 to 1.98), or total protein at admission (OR 0.96; 95% CI, 0.90 to 1.03; P = .25). Multivariable regression was consistent with these results, with no detected modifying effect of age, weight, or PCV at admission on the risk of death (Table 2).

Table 2

Multivariable model for risk of death. In the multivariable model there was no evidence of effect of treatment, PCV at admission, or age at diagnosis on risk of death.

Risk factor Adjusted OR (95% CI) P value
Treatment (hIVIG vs no hIVIG) 2.17 (0.44–10.76) .33
Age at diagnosis (y) 1.10 (0.85–1.47) .47
PCV at admission 1.00 (0.93–1.08) .89

hIVIG = Human IV immunoglobulin.

Blood transfusions

Twenty one of the 52 (40.4%) dogs had at least 1 blood transfusion, of which 11 received hIVIG and 10 did not receive hIVIG (Figure 1). Ten of the 36 (27.7%) dogs in the control group received at least 1 transfusion, compared with 11 of 16 (68.7%) in the hIVIG group. The median (range) number of transfusions in the control group was 0 (0 to 5) compared with 4.5 (0 to 9) in the hIVIG group (P < .001; Figure 2).

Figure 1
Figure 1

Number of transfusions in dogs receiving or not receiving human IV immunoglobulin (hIVIG). P values indicate comparisons for number of transfusions between the respective boxes. †Median (range) number of transfusions.

Citation: Journal of the American Veterinary Medical Association 261, 7; 10.2460/javma.23.01.0043

Figure 2
Figure 2

Twenty one of the 52 dogs had at least 1 blood transfusion, of which 11 received hIVIG and 10 did not receive hIVIG. The median (range) number of transfusions in the hIVIG group was 4.5 (0 to 9), compared with 0 (0 to 5) in the group that did not receive hIVIG (P < .001).

Citation: Journal of the American Veterinary Medical Association 261, 7; 10.2460/javma.23.01.0043

hIVIG group—number of transfusions before and after hIVIG administration

Of all the 16 dogs that received hIVIG, the median (range) number of transfusions prior to hIVIG was 2.5 (0 to 9), and the median (range) number of transfusions following hIVIG administration was 0 (0 to 4; P = .02; Figure 1). This data must be interpreted with caution, as 1 dog (case 39) received both hIVIG and a transfusion the day after admission and was euthanized the following day, 1 dog (case 43) received both hIVIG and a transfusion on the day of admission and was discharged alive 2 days later, and 1 dog (case 40) received 9 transfusions prior to hIVIG on the eleventh day and subsequently was euthanized 4 days later.

Days in hospital

The median (range) days in hospital for the hIVIG group preadministration was 3 (0 to 10), and the median (range) days in hospital postadministration of hIVIG was 3.5 (1 to 14; P = .05; Figure 3). For cases that died, the median (range) days in hospital prior to hIVIG administration was 3 (1 to 10) and after hIVIG administration was 3 (1 to 14; P = 1.0). In dogs that survived to discharge, the median (range) days in hospital prior to hIVIG was 2 (0 to 4) and after hIVIG was 4 (2 to 8; P = .02; Figure 4). The median (range) days in hospital for the control dogs was 4 (1 to 11).

Figure 3
Figure 3

Dogs that received hIVIG spent a median (range) 3.0 days (0 to 10 days) in hospital before and 3.5 days (1 to 14 days) in hospital following hIVIG administration (P = .05). The median (range) increase in days in hospital following hIVIG administration was 1.5 days (–5 to 10 days).

Citation: Journal of the American Veterinary Medical Association 261, 7; 10.2460/javma.23.01.0043

Figure 4
Figure 4

In the hIVIG group, those that died spent a median (range) 3 days (1 to 10 days) in hospital before and 3 (1 to 14) days in hospital following hIVIG administration (P = 1.0). Those that survived spent a median (range) 2 days (0 to 4 days) in hospital before and 4 days (2 to 8 days) in hospital following hIVIG administration (P = .02).

Citation: Journal of the American Veterinary Medical Association 261, 7; 10.2460/javma.23.01.0043

Of the 16 dogs administered hIVIG, all received hIVIG at a dose of 0.5 g/kg, administered as a continuous rate infusion (CRI) over 4 to 8 hours with standard blood product transfusion monitoring. Fourteen of the 16 (87.5%) dogs received 1 dose of hIVIG, 1 case received 2 doses (1/16), and 1 case received 3 doses (1/16). Dogs administered multiple doses received each dose at least 12 hours apart. Only 1 case reported an adverse reaction to hIVIG characterized by a type 1 hypersensitivity reaction, most notably presenting as pyrexia. This occurred during the first dose of IVIG. Resolution of the pyrexia with slowing the transfusion was reported. This patient was diagnosed with secondary IMHA, had received up to 9 blood product transfusions (packed RBCs) prior to administration of hIVIG, and subsequently went on to have a splenectomy.

All dogs that did not survive within this study were humanely euthanized. Owners elected euthanasia due to persistent clinical signs associated with transfusion triggers, tachypnea, tachycardia, dull mentation, pale mucous membranes, hypothermia, reduced PCV, and financial constraints to continue treatment with ongoing blood product transfusion therapy.

Discussion

Administration of hIVIG did not improve survival rates in dogs with either IMHA or ITP within this study compared to a control population that did not receive hIVIG. The reported mortality rate within the hIVIG group was 31.2% (5/16) compared to 19.4% (7/36) within the control group. No pharmacokinetic studies have been published on hIVIG therapy in dogs, leading to an unknown half-life of hIVIG in dogs. Extrapolating from human studies, the half-life of IgG is 5 to 7 days, with a reported response rate (time to platelet recovery) in adult ITP of 24 to 48 hours.24,25 Therefore, applying this information to the current study, dogs that received hIVIG had an adequate amount of time to respond with a median (range) number of days in hospital following hIVIG administration of 3 (1 to 14), thus ensuring adequate time (24 to 48 hours) for patients to respond to the administered hIVIG. All dogs euthanized following hIVIG administration were given at least 1 day (≥ 24 hours) to respond before euthanasia. Therefore, all cases within this study were given adequate time to respond to hIVIG administration; however, no improvement in survival rate was identified in the hIVIG compared to the control group. This finding could be explained by selection bias; the most severely affected patients were selected to receive hIVIG as a salvage treatment, consequently conferring a negative outcome. Based on the current guidelines for use in IMHA in particular, hIVIG is currently recommended as a salvage treatment.21

In our study, hIVIG was associated with a reduction in ongoing blood transfusion requirements, in which dogs after hIVIG administration required 1 less blood transfusion than prior administration of hIVIG. However, multiple patients (n = 5) were humanely euthanized after hIVIG administration due to ongoing blood transfusion requirements, which invertedly skewed this result. Two dogs were diagnosed with primary ITP, 2 with primary IMHA, and 1 with secondary IMHA. All of the patients that did not survive in this study were humanely euthanized due to ongoing blood transfusion requirements and the financial limitation of continuing treatment. Our results agreed with those of Bestwick et al,7 which demonstrated no benefit in using an M-enriched human immunoglobulin, Pentaglobin, in early treatment for patients with primary IMHA. That study7 administered hIVIG at a dose of 1 g/kg, a higher dose than the present study, and instituted therapy in an early stage of the disease. However, that study7 contained limited case and control numbers, thus potentially contributing to an insufficient statistical analysis. In the present study, hIVIG was administered to 6 IMHA cases (5 primary IMHA and 1 secondary IMHA), of which 42.8% (n = 3) died. The merit of previous studies supports future endeavors to utilize hIVIG at a dose range of 1 g/kg or above, given the human documentation of a dose-dependent result.

Furthermore, there are limited data in the present study on additional dosages of hIVIG administered as consecutive continuous rate infusions. Two cases received more than 1 dose, 1 case received 2 doses (0.5 g/kg) 12 hours apart, and another received 3 doses (0.5 g/kg) 12 hours apart. The case receiving 3 doses was euthanized, whereas the case receiving 2 doses survived to discharge. Extrapolating dosage protocols from human medicine, dosages of 0.4 g/kg over 3 to 5 days to reach a total dose of 2 g/kg might be of benefit for such patients. However, future prospective studies are required. In human literature, the dosage of hIVIG varies from reported low doses of 0.4 g/kg once monthly to high doses of 2 g/kg divided over 3 to 5 consecutive days.2,26 In childhood or adult ITP, the effect of hIVIG has been reported as dose dependent in many papers, with one reporting that higher doses of 1 to 2 g/kg, compared to traditional 0.5 g/kg, were more effective in platelet response rates (67% vs 24% on day 4),27 leading to dosing guidelines of 1 g/kg hIVIG as an initial single dose and repeated as required.28 In veterinary medicine, dosages of 0.28 to 1.5 g/kg have been reported for use in primary ITP cases, with most receiving a mean dose of 0.5 g/kg.5,13,14 Administration was given as a CRI and as a single dose. In early disease, hIVIG has been demonstrated to be equally successful in mean platelet recovery times with inclusion of vincristine therapy (2.5 days), with the conclusion of vincristine being superior to hIVIG in terms of cost, ease of administration, and reduced risk of adverse effects.5,14 To the authors’ knowledge, this study was the only one that has looked at hIVIG use as a salvage treatment for ITP cases. When used at 0.5 g/kg, this study found no clinical benefit in survival rate or reduced transfusion requirements for patients with severe disease. This finding could be explained by bias selection, whereby the cases selected were the most severely affected, received multiple blood transfusions, and had already conferred a negative outcome. However, with knowledge of previous studies and human literature, increased dosages of 1 to 2 g/kg as a single CRI should be considered for severe ITP patients, given the demonstration of a dose-dependent mechanism within human literature. The likelihood of prescribing lower dosages in the veterinary literature is presumed on the basis of insufficient evidence-based support, risk of adverse reactions, and financial prohibition.

Human IVIG dosed at 0.5 g/kg did appear to be safe at this current dose in combination with multiple other blood product transfusions with only 1 reported adverse reaction, characterized by a type 1 hypersensitivity reaction. The patient developed a pyrexia during administration that resolved by slowing the continuous rate infusion. It was difficult to determine whether this reaction was directly linked to hIVIG, as this patient had received up to 9 packed RBC transfusions before hIVIG administration. A delayed transfusion reaction cannot be excluded. However, given the resolution of the pyrexia with slowing the CRI, this was likely attributable. The reported prevalence of adverse reactions to hIVIG in veterinary patients is low in comparison to human literature, which reports adverse events ranging from 2.5% up to 87.5%.26 The most commonly reported veterinary adverse reactions to hIVIG are immediate, type 1 hypersensitivity reactions.29 Anaphylaxis, hypercoagulation, renal failure, hypotension, pseudohyponatremia, aseptic meningitis, and volume overload are other reported side effects in human literature,26 none of which were encountered in the current study. Despite this finding, veterinary patients are at risk of all listed side effects, with the most significant risk of anaphylaxis and delayed transfusion reactions from introduced xenoproteins. Premedication with antihistamines or glucocorticoids is not routinely performed. Compared to human medicine, people are premedicated with various medications, including hydrocortisone, paracetamol, and diphenhydramine, prior to hIVIG administration.30 In veterinary medicine, premedication may not be required, as most if not all cases of IMHA and ITP are concurrently treated with a glucocorticoid, a first-line immunosuppressant, prednisolone. There are reports of premedication using diphenhydramine (0.5 mg/kg, IV)13; however, the benefit is unknown as there is lacking supportive evidence.

Three of the 16 (0.18%) cases within the hIVIG group were diagnosed with secondary immune-mediated disease. One of the 3 dogs (case 40) had a presumptive diagnosis of an infectious disease inducing a secondary IMHA. The diagnosis was extrapolated from the attending clinicians’ medical records; however, no definitive diagnosis was achieved. This patient received up to 9 blood transfusions prior to hIVIG, progressed onto splenectomy following hIVIG administration, and ultimately was euthanized on day 15 in hospital. There are multiple documented reports of infectious agents implicated in canine immune-mediated disease. The most widely documented agents within Australia include vector-borne agents such as Babesiosis and Rickettsial diseases and Leptospirosis.3133

Two of the 3 cases were diagnosed with secondary ITP. The first (case 46) was attributed to a heat stress event, and the second (case 49) was presumed from a large animal long-acting penicillin injection. Both cases were treated with 1 dose of hIVIG, survived to discharge, and did not require additional blood transfusions. Heat stress–induced thrombocytopenia is a well-recognized complication with multiple documented theories reported in the veterinary literature, including a type II hypersensitivity autoantibody response, direct heat damage to megakaryocytes or platelets and disseminated intravascular coagulation (DIC).31 The prompt response of this case after hIVIG administration is supportive of autoantibody production against platelet surface glycoproteins. Furthermore, penicillin antibiotics have been implicated in drug-induced ITP in human literature. The specific mechanisms of action are complex and, as a brief summary, involve hapten-induced antibody production whereby the drug forms a covalent linkage to platelet membrane glycoproteins and acts as a hapten to induce a drug-dependent antibody response.32 The case included in this study was treated with a large animal long-acting penicillin injection following ovariohysterectomy approximately 7 days prior to presentation and, therefore, was believed to be linked.

The main limitations of the present study included the retrospective nature of data collection and limited case number. Although this was the largest study reporting on hIVIG use as a salvage treatment, future prospective studies including large case numbers would be of benefit. Case selection bias was present, given the current guidelines for the use of hIVIG is as a salvage treatment. Therefore, as stated earlier, all cases within the study administered hIVIG were the most severely affected patients that had received multiple blood product transfusions before administration and had already conferred a negative outcome. We tried to minimize bias by adjusting the risk of death for baseline disease severity using PCV at admission as a proxy; however, baseline PCV may not reflect the overall disease process. A randomized controlled trial is required to more accurately assess any benefit of hIVIG, but these are notoriously challenging to conduct in the setting of veterinary practice.

In conclusion, there was no detectable difference in survival rates for dogs that were administered hIVIG versus those that did not receive hIVIG in this study. Administration of IVIG was a risk factor of death as 31.2% of cases that received IVIG died in the study. Administration did statistically reduce the need for ongoing blood transfusion requirements for either IMHA or ITP. However, multiple patients were humanely euthanized following administration for ongoing transfusion requirements and therefore have produced a false result. In summary, as concluded via earlier studies, the benefit of hIVIG, particularly Privigen formulation at a dose of 0.5 g/kg, appears limited for both IMHA and ITP in dogs, and therefore its use as a salvage treatment appears limited.

Acknowledgments

No third-party funding or support was received in connection with this study or the writing or publication of the manuscript. The authors declare that there were no conflicts of interest.

The authors thank Veterinary Specialist Services and Animal Emergency Services for access to all medical records.

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  • 7.

    Bestwick JP, Sharman M, Whitley NT, et al. The use of high-dose immunoglobulin M-enriched human immunoglobulin in dogs with immune-mediated hemolytic anemia. J Vet Intern Med. 2022;36(1):7885. doi:10.1111/jvim.16315

    • Search Google Scholar
    • Export Citation
  • 8.

    Brunori L, Romero-Fernandez N. Immune-mediated haemolytic anaemia, part 1: pathophysiology and diagnosis. Companion Anim. 2021;26(4):111. doi:10.12968/coan.2020.0072

    • Search Google Scholar
    • Export Citation
  • 9.

    Gerber B, Steger A, Hässig M, Glaus TM. Immunglobulin bei Hunden mit Anämie Einleitung. Schweiz Arch Tierheilkd. 2002;144(4):180185. doi:10.1024/0036-7281.144.4.180

    • Search Google Scholar
    • Export Citation
  • 10.

    Kellerman DL, Bruyette DS. Intravenous human immunoglobulin for the treatment of immune-mediated hemolytic anemia in 13 dogs. J Vet Intern Med. 1997;11(6):327332. doi:10.1111/j.1939-1676.1997.tb00475.x

    • Search Google Scholar
    • Export Citation
  • 11.

    Park SY, Kim H, Kang BT, Kang JH, Yang MP. Prognostic factors and efficacy of human intravenous immunoglobulin G in dogs with idiopathic immune-mediated hemolytic anemia: a retrospective study. Korean J Vet Res. 2016;56(3):139145. doi:10.14405/kjvr.2016.56.3.139

    • Search Google Scholar
    • Export Citation
  • 12.

    Scott-Moncrieff JC, Reagan WJ, Snyder PW, Glickman LT. Intravenous administration of human immune globulin in dogs with immune-mediated hemolytic anemia. J Am Vet Med Assoc. 1997;210(11):16231627.

    • Search Google Scholar
    • Export Citation
  • 13.

    Bianco D, Armstrong PJ, Washabau RJ. Treatment of severe immune-mediated thrombocytopenia with human IV immunoglobulin in 5 dogs. J Vet Intern Med. 2007;21(4):694699. doi:10.1892/0891-6640(2007)21[694:tositw]2.0.co;2

    • Search Google Scholar
    • Export Citation
  • 14.

    Bianco D, Armstrong PJ, Washabau RJ. A prospective, randomized, double-blinded, placebo-controlled study of human intravenous immunoglobulin for the acute management of presumptive primary immune-mediated thrombocytopenia in dogs. J Vet Intern Med. 2009;23(5):10711078. doi:10.1111/j.1939-1676.2009.0358.x

    • Search Google Scholar
    • Export Citation
  • 15.

    Bianco D, Hardy RM. Treatment of Evans’ syndrome with human intravenous immunoglobulin and leflunomide in a diabetic dog. J Am Anim Hosp Assoc. 2009;45(3):147150. doi:10.5326/0450147

    • Search Google Scholar
    • Export Citation
  • 16.

    Reagan WJ, Scott-Moncrieff C, Christian J, Snyder P, Kelly K, Glickman L. Effects of human intravenous immunoglobulin on canine monocytes and lymphocytes. Am J Vet Res. 1998;59(12):15681574.

    • Search Google Scholar
    • Export Citation
  • 17.

    Trotman TK, Phillips H, Fordyce H, King LG, Morris DO, Giger U. Treatment of severe adverse cutaneous drug reactions with human intravenous immunoglobulin in two dogs. J Am Anim Hosp Assoc. 2006;42(4):312320. doi:10.5326/0420312

    • Search Google Scholar
    • Export Citation
  • 18.

    Nuttall TJ, Malham T. Successful intravenous human immunoglobulin treatment of drug-induced Stevens-Johnson syndrome in a dog. J Small Anim Pract. 2004;45(7):357361. doi:10.1111/j.1748-5827.2004.tb00248.x

    • Search Google Scholar
    • Export Citation
  • 19.

    Rahilly LJ, Keating JH, O’Toole TE. The use of intravenous human immunoglobulin in treatment of severe pemphigus foliaceus in a dog. J Vet Intern Med. 2006;20(6):14831486. doi:10.1892/0891-6640(2006)20[1483:tuoihi]2.0.co;2

    • Search Google Scholar
    • Export Citation
  • 20.

    Grozdanic SD, Harper MM, Kecova H. Antibody-mediated retinopathies in canine patients: mechanism, diagnosis, and treatment modalities. Vet Clin North Am Small Anim Pract. 2008;38(2):361387, vii. doi:10.1016/j.cvsm.2007.12.003

    • Search Google Scholar
    • Export Citation
  • 21.

    Swann JW, Garden OA, Fellman CL, et al. ACVIM consensus statement on the treatment of immune-mediated hemolytic anemia in dogs. J Vet Intern Med. 2019;33(3):11411172. doi:10.1111/jvim.15463

    • Search Google Scholar
    • Export Citation
  • 22.

    Rozanski EA, Callan MB, Hughes D, Sanders N, Giger U. Comparison of platelet count recovery with use of vincristine and prednisone or prednisone alone for treatment for severe immune-mediated thrombocytopenia in dogs. J Am Vet Med Assoc. 2002;220(4):477481. doi:10.2460/javma.2002.220.477

    • Search Google Scholar
    • Export Citation
  • 23.

    Whelan MF, O’Toole TE, Chan DL, et al. Use of human immunoglobulin in addition to glucocorticoids for the initial treatment of dogs with immune-mediated hemolytic anemia. J Vet Emerg Crit Care (San Antonio). 2009;19(2):158164. doi:10.1111/j.1476-4431.2009.00403.x

    • Search Google Scholar
    • Export Citation
  • 24.

    Mahmood I, Tegenge MA, Golding B. Considerations for optimizing dosing of immunoglobulins based on pharmacokinetic evidence. Antibodies (Basel). 2020;9(2):24. doi:10.3390/antib9020024

    • Search Google Scholar
    • Export Citation
  • 25.

    Almizraq RJ, Branch DR. Efficacy and mechanism of intravenous immunoglobulin treatment for immune thrombocytopenia in adults. Ann Blood. 2021;6:2. doi:10.21037/aob-20-87

    • Search Google Scholar
    • Export Citation
  • 26.

    Guo Y, Tian X, Wang X, Xiao Z. Adverse effects of immunoglobulin therapy. Front Immunol. 2018;9:1299. doi:10.3389/fimmu.2018.01299

  • 27.

    Godeau B, Caulier MT, Decuypere L, Rose C, Schaeffer A, Bierling P. Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 0.5 and 1 g/kg b.w. Br J Haematol. 1999;107(4):716719. doi:10.1046/j.1365-2141.1999.01766.x

    • Search Google Scholar
    • Export Citation
  • 28.

    Arbach O, Taumberger AB, Wietek S, Cervinek L, Salama A. Efficacy and safety of a new intravenous immunoglobulin (Panzyga®) in chronic immune thrombocytopenia. Transfus Med. 2019;29(1):4854. doi:10.1111/tme.12573

    • Search Google Scholar
    • Export Citation
  • 29.

    Spurlock NK, Prittie JE. A review of current indications, adverse effects, and administration recommendations for intravenous immunoglobulin. J Vet Emerg Crit Care (San Antonio). 2011;21(5):471483. doi:10.1111/j.1476-4431.2011.00676.x

    • Search Google Scholar
    • Export Citation
  • 30.

    Elajez R, Ezzeldin A, Gaber H. Safety evaluation of intravenous immunoglobulin in pediatric patients: a retrospective, 1-year observational study. Ther Adv Drug Saf. 2019;10:2042098619876736. doi:10.1177/2042098619876736

    • Search Google Scholar
    • Export Citation
  • 31.

    Romanucci M, Salda LD. Pathophysiology and pathological findings of heatstroke in dogs. Vet Med (Auckl). 2013;4:19. doi:10.2147/VMRR.S29978

    • Search Google Scholar
    • Export Citation
  • 32.

    George JN, Aster RH. Drug-induced thrombocytopenia: pathogenesis, evaluation, and management. Hematology Am Soc Hematol Educ Program. 2009:153158. doi:10.1182/asheducation-2009.1.153

    • Search Google Scholar
    • Export Citation
  • 33.

    Griebsch C, Kirkwood N, Ward MP, et al. Emerging leptospirosis in urban Sydney dogs: a case series (2017-2020). Aust Vet J. 2022;100(5):190200. doi:10.1111/avj.13148

    • Search Google Scholar
    • Export Citation
  • Figure 1

    Number of transfusions in dogs receiving or not receiving human IV immunoglobulin (hIVIG). P values indicate comparisons for number of transfusions between the respective boxes. †Median (range) number of transfusions.

  • Figure 2

    Twenty one of the 52 dogs had at least 1 blood transfusion, of which 11 received hIVIG and 10 did not receive hIVIG. The median (range) number of transfusions in the hIVIG group was 4.5 (0 to 9), compared with 0 (0 to 5) in the group that did not receive hIVIG (P < .001).

  • Figure 3

    Dogs that received hIVIG spent a median (range) 3.0 days (0 to 10 days) in hospital before and 3.5 days (1 to 14 days) in hospital following hIVIG administration (P = .05). The median (range) increase in days in hospital following hIVIG administration was 1.5 days (–5 to 10 days).

  • Figure 4

    In the hIVIG group, those that died spent a median (range) 3 days (1 to 10 days) in hospital before and 3 (1 to 14) days in hospital following hIVIG administration (P = 1.0). Those that survived spent a median (range) 2 days (0 to 4 days) in hospital before and 4 days (2 to 8 days) in hospital following hIVIG administration (P = .02).

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    Shock A, Humphreys D, Nimmerjahn F. Dissecting the mechanism of action of intravenous immunoglobulin in human autoimmune disease: lessons from therapeutic modalities targeting Fcγ receptors. J Allergy Clin Immunol. 2020;146(3):492500. doi:10.1016/j.jaci.2020.06.036

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    Spurlock N, Prittie J. Use of human intravenous immunoglobulin in veterinary clinical practice. Vet Clin North Am Small Anim Pract. 2020;50(6):13711383. doi:10.1016/j.cvsm.2020.07.015

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  • 5.

    Balog K, Huang AA, Sum SO, Moore GE, Thompson C, Scott-Moncrieff JC. A prospective randomized clinical trial of vincristine versus human intravenous immunoglobulin for acute adjunctive management of presumptive primary immune-mediated thrombocytopenia in dogs. J Vet Intern Med. 2013;27(3):536541. doi:10.1111/jvim.12066

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    Ballow M. The IgG molecule as a biological immune response modifier: mechanisms of action of intravenous immune serum globulin in autoimmune and inflammatory disorders. J Allergy Clin Immunol. 2011;127(2):315323. doi:10.1016/j.jaci.2010.10.030

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  • 7.

    Bestwick JP, Sharman M, Whitley NT, et al. The use of high-dose immunoglobulin M-enriched human immunoglobulin in dogs with immune-mediated hemolytic anemia. J Vet Intern Med. 2022;36(1):7885. doi:10.1111/jvim.16315

    • Search Google Scholar
    • Export Citation
  • 8.

    Brunori L, Romero-Fernandez N. Immune-mediated haemolytic anaemia, part 1: pathophysiology and diagnosis. Companion Anim. 2021;26(4):111. doi:10.12968/coan.2020.0072

    • Search Google Scholar
    • Export Citation
  • 9.

    Gerber B, Steger A, Hässig M, Glaus TM. Immunglobulin bei Hunden mit Anämie Einleitung. Schweiz Arch Tierheilkd. 2002;144(4):180185. doi:10.1024/0036-7281.144.4.180

    • Search Google Scholar
    • Export Citation
  • 10.

    Kellerman DL, Bruyette DS. Intravenous human immunoglobulin for the treatment of immune-mediated hemolytic anemia in 13 dogs. J Vet Intern Med. 1997;11(6):327332. doi:10.1111/j.1939-1676.1997.tb00475.x

    • Search Google Scholar
    • Export Citation
  • 11.

    Park SY, Kim H, Kang BT, Kang JH, Yang MP. Prognostic factors and efficacy of human intravenous immunoglobulin G in dogs with idiopathic immune-mediated hemolytic anemia: a retrospective study. Korean J Vet Res. 2016;56(3):139145. doi:10.14405/kjvr.2016.56.3.139

    • Search Google Scholar
    • Export Citation
  • 12.

    Scott-Moncrieff JC, Reagan WJ, Snyder PW, Glickman LT. Intravenous administration of human immune globulin in dogs with immune-mediated hemolytic anemia. J Am Vet Med Assoc. 1997;210(11):16231627.

    • Search Google Scholar
    • Export Citation
  • 13.

    Bianco D, Armstrong PJ, Washabau RJ. Treatment of severe immune-mediated thrombocytopenia with human IV immunoglobulin in 5 dogs. J Vet Intern Med. 2007;21(4):694699. doi:10.1892/0891-6640(2007)21[694:tositw]2.0.co;2

    • Search Google Scholar
    • Export Citation
  • 14.

    Bianco D, Armstrong PJ, Washabau RJ. A prospective, randomized, double-blinded, placebo-controlled study of human intravenous immunoglobulin for the acute management of presumptive primary immune-mediated thrombocytopenia in dogs. J Vet Intern Med. 2009;23(5):10711078. doi:10.1111/j.1939-1676.2009.0358.x

    • Search Google Scholar
    • Export Citation
  • 15.

    Bianco D, Hardy RM. Treatment of Evans’ syndrome with human intravenous immunoglobulin and leflunomide in a diabetic dog. J Am Anim Hosp Assoc. 2009;45(3):147150. doi:10.5326/0450147

    • Search Google Scholar
    • Export Citation
  • 16.

    Reagan WJ, Scott-Moncrieff C, Christian J, Snyder P, Kelly K, Glickman L. Effects of human intravenous immunoglobulin on canine monocytes and lymphocytes. Am J Vet Res. 1998;59(12):15681574.

    • Search Google Scholar
    • Export Citation
  • 17.

    Trotman TK, Phillips H, Fordyce H, King LG, Morris DO, Giger U. Treatment of severe adverse cutaneous drug reactions with human intravenous immunoglobulin in two dogs. J Am Anim Hosp Assoc. 2006;42(4):312320. doi:10.5326/0420312

    • Search Google Scholar
    • Export Citation
  • 18.

    Nuttall TJ, Malham T. Successful intravenous human immunoglobulin treatment of drug-induced Stevens-Johnson syndrome in a dog. J Small Anim Pract. 2004;45(7):357361. doi:10.1111/j.1748-5827.2004.tb00248.x

    • Search Google Scholar
    • Export Citation
  • 19.

    Rahilly LJ, Keating JH, O’Toole TE. The use of intravenous human immunoglobulin in treatment of severe pemphigus foliaceus in a dog. J Vet Intern Med. 2006;20(6):14831486. doi:10.1892/0891-6640(2006)20[1483:tuoihi]2.0.co;2

    • Search Google Scholar
    • Export Citation
  • 20.

    Grozdanic SD, Harper MM, Kecova H. Antibody-mediated retinopathies in canine patients: mechanism, diagnosis, and treatment modalities. Vet Clin North Am Small Anim Pract. 2008;38(2):361387, vii. doi:10.1016/j.cvsm.2007.12.003

    • Search Google Scholar
    • Export Citation
  • 21.

    Swann JW, Garden OA, Fellman CL, et al. ACVIM consensus statement on the treatment of immune-mediated hemolytic anemia in dogs. J Vet Intern Med. 2019;33(3):11411172. doi:10.1111/jvim.15463

    • Search Google Scholar
    • Export Citation
  • 22.

    Rozanski EA, Callan MB, Hughes D, Sanders N, Giger U. Comparison of platelet count recovery with use of vincristine and prednisone or prednisone alone for treatment for severe immune-mediated thrombocytopenia in dogs. J Am Vet Med Assoc. 2002;220(4):477481. doi:10.2460/javma.2002.220.477

    • Search Google Scholar
    • Export Citation
  • 23.

    Whelan MF, O’Toole TE, Chan DL, et al. Use of human immunoglobulin in addition to glucocorticoids for the initial treatment of dogs with immune-mediated hemolytic anemia. J Vet Emerg Crit Care (San Antonio). 2009;19(2):158164. doi:10.1111/j.1476-4431.2009.00403.x

    • Search Google Scholar
    • Export Citation
  • 24.

    Mahmood I, Tegenge MA, Golding B. Considerations for optimizing dosing of immunoglobulins based on pharmacokinetic evidence. Antibodies (Basel). 2020;9(2):24. doi:10.3390/antib9020024

    • Search Google Scholar
    • Export Citation
  • 25.

    Almizraq RJ, Branch DR. Efficacy and mechanism of intravenous immunoglobulin treatment for immune thrombocytopenia in adults. Ann Blood. 2021;6:2. doi:10.21037/aob-20-87

    • Search Google Scholar
    • Export Citation
  • 26.

    Guo Y, Tian X, Wang X, Xiao Z. Adverse effects of immunoglobulin therapy. Front Immunol. 2018;9:1299. doi:10.3389/fimmu.2018.01299

  • 27.

    Godeau B, Caulier MT, Decuypere L, Rose C, Schaeffer A, Bierling P. Intravenous immunoglobulin for adults with autoimmune thrombocytopenic purpura: results of a randomized trial comparing 0.5 and 1 g/kg b.w. Br J Haematol. 1999;107(4):716719. doi:10.1046/j.1365-2141.1999.01766.x

    • Search Google Scholar
    • Export Citation
  • 28.

    Arbach O, Taumberger AB, Wietek S, Cervinek L, Salama A. Efficacy and safety of a new intravenous immunoglobulin (Panzyga®) in chronic immune thrombocytopenia. Transfus Med. 2019;29(1):4854. doi:10.1111/tme.12573

    • Search Google Scholar
    • Export Citation
  • 29.

    Spurlock NK, Prittie JE. A review of current indications, adverse effects, and administration recommendations for intravenous immunoglobulin. J Vet Emerg Crit Care (San Antonio). 2011;21(5):471483. doi:10.1111/j.1476-4431.2011.00676.x

    • Search Google Scholar
    • Export Citation
  • 30.

    Elajez R, Ezzeldin A, Gaber H. Safety evaluation of intravenous immunoglobulin in pediatric patients: a retrospective, 1-year observational study. Ther Adv Drug Saf. 2019;10:2042098619876736. doi:10.1177/2042098619876736

    • Search Google Scholar
    • Export Citation
  • 31.

    Romanucci M, Salda LD. Pathophysiology and pathological findings of heatstroke in dogs. Vet Med (Auckl). 2013;4:19. doi:10.2147/VMRR.S29978

    • Search Google Scholar
    • Export Citation
  • 32.

    George JN, Aster RH. Drug-induced thrombocytopenia: pathogenesis, evaluation, and management. Hematology Am Soc Hematol Educ Program. 2009:153158. doi:10.1182/asheducation-2009.1.153

    • Search Google Scholar
    • Export Citation
  • 33.

    Griebsch C, Kirkwood N, Ward MP, et al. Emerging leptospirosis in urban Sydney dogs: a case series (2017-2020). Aust Vet J. 2022;100(5):190200. doi:10.1111/avj.13148

    • Search Google Scholar
    • Export Citation

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