Atypical felid alphaherpesvirus 1 dermatitis in a cat

Abstract

Feline herpesviral ulcerative dermatitis is associated with ulceration of the face and oral mucosa. Histologically, lesions consist of eosinophilic inflammation in the superficial dermis, with occasional eosinophilic intranuclear viral inclusion bodies in the epidermis, follicular epithelium, and associated glands. We describe a case of atypical felid alphaherpesvirus 1 (FeAHV1; family Orthoherpesviridae, taxon species Varicellovirus felidalpha1) dermatitis in a 6-y-old, castrated male, domestic shorthair cat in which lesions were located on the limbs and shoulder without facial or oral involvement. Histologic findings consisted of deep eosinophilic and plasmacytic dermatitis with vasculitis, thrombosis, and intranuclear viral inclusion bodies within macrophages. Immunohistochemistry (IHC) for FeAHV1 revealed viral antigen within macrophages in the deep dermis but not in epithelial cells. FeAHV1 was identified in the affected tissue via a consensus PCR assay targeting the DNA polymerase and the DNA packaging terminase subunit 1 for herpesviruses, followed by sequencing of the PCR amplicons. Similar lesions appeared on the right shoulder and right tarsal area ~7 mo after the first biopsy. Histologically, lesions were typical of feline ulcerative dermatitis and consisted of extensive areas of epidermal and follicular necrosis with ulceration and occasional intranuclear eosinophilic viral inclusion bodies in the epidermis and sebocytes. IHC in the second biopsy sample revealed FeAHV1 antigen within epithelial cells and macrophages near the ulcerated areas. Clinicians and pathologists should be aware of unusual manifestations of FeAHV1-associated ulcerative dermatitis in cats.

Felid alphaherpesvirus 1 (FeAHV1; family Orthoherpesviridae, taxon species Varicellovirus felidalpha1) is a DNA virus that has widespread geographic distribution and is considered one of the most important pathogens of domestic and wild cats.^4,8 Acute FeAHV1 infection causes feline viral rhinotracheitis, a primarily upper respiratory disease of cats. ⁸ Infection occurs via close contact with oronasal and ocular secretions, leading to primary viral replication in the nasal, oropharyngeal, and tracheal mucosa, tonsils, and retropharyngeal lymph nodes. ⁸ Clinical signs include fever, anorexia, sneezing, serous and mucopurulent nasal secretion, dyspnea, coughing, and drooling. ⁸ Oral ulcerations are uncommon but may occur, and pulmonary involvement with pneumonia is rare. ⁸ Infection of the conjunctival mucosa and cornea leads to conjunctivitis, ocular discharge, and corneal ulceration. ⁸

Feline herpesviral ulcerative dermatitis is an uncommon disease that leads to erythema, erosion, and ulceration on the face, particularly the muzzle, nasal plane, and periocular areas.^2,3 Cutaneous lesions can occur in cats with or without respiratory disease. ² Histologically, lesions consist of extensive ulceration and crusting with occasional intranuclear eosinophilic viral inclusion bodies in the epidermis, follicular epithelium, and sebaceous glands.^2,3 A prominent inflammatory cell infiltration by eosinophils with occasional collagenolysis (flame figures) occurs throughout the superficial and mid dermis.^2–4 Ulcerative lesions typically appear on the face and/or oral mucosa and only rarely affect other areas of the body.^1,5 Cutaneous lesions without facial or oral involvement are exceedingly rare and have the same histologic features as the facial lesions.^1,5,10

We describe the clinical signs and the pathology, immunohistochemistry (IHC), and PCR assay findings of a case of superficial and deep dermatitis in a 6-y-old, castrated male, domestic shorthair cat that was examined in October 2024 because of a cutaneous lesion on the right elbow over 2 wk. The ~5 × 2-cm lesion was alopecic, linear, swollen, and ulcerated. The patient was a rescued stray cat and tested negative for feline immunodeficiency virus antibodies, feline leukemia virus antigen, and heartworm antigen (SNAP feline triple test; Idexx). No other clinical signs or lesions (including plasma cell pododermatitis) were found during physical examination. Minimal improvement of the cutaneous lesion was seen with an injectable antibiotic (cefovecin, Convenia; Zoetis). A punch biopsy from the lesion was fixed in 10% neutral-buffered formalin and submitted to the Athens Veterinary Diagnostic Laboratory (AVDL; University of Georgia, Athens, GA, USA) for histologic evaluation. Tissue sections were processed routinely for histology, and slides were stained with H&E. Subcutaneous vaccination against feline rhinotracheitis, calicivirus, feline parvovirus, and Chlamydia psittaci (FVRCP, Purevax Feline 4; Boehringer Ingelheim) was administered in the upper left thoracic limb 14 d after the biopsy procedure.

Histologically, the deep dermis was expanded by sheets of plasma cells with fewer eosinophils, macrophages, and lymphocytes (Figs. 1–3). The inflammation extended to the superficial and mid-dermis but was less intense. Inflammatory infiltrates were prominent around deep dermal arterioles. In these areas, vascular walls were expanded and infiltrated by eosinophils, macrophages, and lymphocytes, and the vascular lumen was occasionally occluded by recent thrombi (Figs. 4, 5). The perivascular tissues were occasionally necrotic, likely because of ischemia secondary to the vascular lesions. Within perivascular areas, occasional eosinophilic intranuclear viral inclusion bodies were present in macrophages (Fig. 6). An ulcer was covered with cell debris, fibrin, and neutrophils. The adjacent epidermis was hyperplastic and covered with ortho- and parakeratotic scale. No viral inclusions were observed in the epidermis, hair follicles, or adnexal glands.

Figures 1–7.

Deep dermatitis caused by felid alphaherpesvirus 1 (FeAHV1) in a cat. Figure 1. Ulceration with crusting (arrow) and a dense inflammatory infiltrate that effaces primarily the deep dermis (white asterisks) and fibrotic subcutaneous tissue (black asterisks). Discrete areas with vasculitis, evident at low magnification (circles), occasionally surrounded by extensive areas of subcutaneous necrosis (arrowhead). H&E. Figure 2. Dense inflammatory infiltrate (of primarily plasma cells) effaces the deep dermis and infiltrates an arteriolar wall (asterisk). H&E. Figure 3. Dense inflammation (of primarily eosinophils) effaces the deep dermis. H&E. Figure 4. An arteriolar wall is expanded and infiltrated by eosinophils, macrophages, and lymphocytes. H&E. Figure 5. Lumen of a deep dermal venule occluded by a thrombus. H&E. Figure 6. Eosinophilic intranuclear viral inclusion bodies (arrows) in macrophages, admixed with eosinophils (arrowheads) in the deep dermis and subcutaneous tissue. H&E. Figure 7. FeAHV1 antigen within macrophages in the deep dermis. Inset: a macrophage with membranous IBA1 immunolabeling and an intranuclear viral inclusion (arrow).

IHC for FeAHV1 was performed for diagnostic confirmation (Table 1). Viral antigen was present within macrophages in the deep dermis, predominantly around areas with vasculitis (Fig. 7). Additional IHC for pan-cytokeratin (AE1/3) and ionized calcium–binding adaptor molecule 1 (IBA1) was performed to confirm that viral inclusions were present in macrophages and not in epithelial cells. All cells with intranuclear viral inclusion bodies had cytoplasmic immunolabeling for IBA1 and no immunolabeling for AE1/3, consistent with macrophages.

Table 1.

Details of the immunohistochemistry performed in a case of dermatitis caused by felid alphaherpesvirus 1 (FeAHV1) in a cat.

Antibody	Host	Source, catalog no	Clone	Dilution	Antigen retrieval	Link	Label	Control
FeAHV1	Mouse	Chris Grant, NA	FHV7-5	1:500 for 60 min at 37°C	Proteinase K for 5 min at 110°C	Bio Mouse for 10 min ar RT	4+HRP for 10 min	Cell pellet
AE1/3	Mouse	Cell Marque, 313M-18	AE1/3	RTU for 30 min	Citrate 10× (BioGenex) for 15 min at 110°C	Bio Mouse for 10 min at RT	4+HRP for 10 min	Skin
IBA1	Rabbit	Wako, 019-19741	NA	1:8,000 for 60 min at RT	Citrate 10× (BioGenex) for 15 min at 110°C	Bio Rabbit for 10 min at RT	4+HRP for 10 min	Spinal cord

AE1/3 = pancytokeratin; IBA1 = ionized calcium binding adaptor molecule 1; NA = not applicable; RT = room temperature; RTU = ready to use. In all IHC protocols, the autostainer was IntelliPATH (Biocare), enzyme block was performed using 3% H₂O₂ for 5 min, protein block was performed using Power Block (BioGenex) for 5 min, and the chromogen was diaminobenzidine (DAB).

Consensus PCR assays targeting the DNA polymerase gene and the DNA packaging terminase subunit 1 gene were performed on tissue scrolls using formalin-fixed, paraffin-embedded skin tissue. DNA extraction and Sanger sequencing were performed as described previously by our group.^7,9 Sequence identity was confirmed by BLAST nucleotide analysis (http://www.ncbi.nlm.nih.gov/blast/Blast.cgi). The DNA polymerase gene sequence was 94% identical to sequences from FeAHV1, and no matches with other members of the Orthoherpesviridae family were found in the BLAST analysis.

The patient was re-evaluated ~7 mo after the first biopsy because of similar lesions on the right shoulder and right tarsal area. Excisional biopsies from these lesions were submitted for histologic evaluation at the AVDL. Histologically, lesions consisted of extensive areas of epidermal and follicular necrosis with ulceration and occasional intranuclear eosinophilic viral inclusion bodies in the epidermis and sebocytes (Suppl. Figs. 1–4). Ulcerated areas were covered with serocellular crusts. The dermis was infiltrated with numerous eosinophils admixed with neutrophils, macrophages, lymphocytes, and plasma cells.

The pathology findings (particularly in the second set of biopsies) associated with the IHC and PCR results in our case were supportive of the diagnosis of herpesviral ulcerative dermatitis. FeAHV1 dermatitis is a well-documented disease of cats and is associated primarily with ulcerative facial lesions. ³ Clinicians and pathologists should be aware of unusual manifestations of FeAHV1 dermatitis in cats. Our case is atypical because of the anatomic location of the lesions (limbs and shoulder without facial or oral involvement) and the histologic findings on the first biopsy submission, which consisted of deep dermatitis with vasculitis and thrombosis, as well as intranuclear viral inclusion bodies within macrophages. A search on 2025 Aug 8 of Google, PubMed, CAB Direct, Web of Science, and Scopus for herpesviral infection in cats associated with vasculitis and viral inclusions in macrophages retrieved no results, confirming that these atypical features of feline herpesviral ulcerative dermatitis have not been reported previously.

Although primarily facial, feline herpesviral ulcerative dermatitis may affect other locations, such as the thorax, flank, abdomen, back, and limbs.^1,5 Lesions typically occur concomitantly with the facial and/or oral lesions,^1,5 but rarely occur without facial or oral involvement.^1,5,10 Direct contact of infected secretion or crusts from affected parts of the body (particularly distal limbs) with the face and/or saliva during grooming has been proposed as a mechanism for the development of lesions in these atypical sites. ³ In our case, lesions were located on the right elbow and subsequently on the right shoulder and right tarsal area. No facial or oral lesions were observed during physical examination at the time of the first submission or during the second biopsy procedure, which does not support this form of self-infection. ³ Unusual skin lesions at or near vaccination sites after administration of modified live virus vaccines is thought to be associated with reactivation of attenuated vaccine virus. ¹⁰ Although the cat in our case received a dose of FVRCP vaccine, it was administered on the left thoracic limb, rendering this possibility unlikely. The appearance of subsequent lesions at distant sites also does not support a potential vaccine-associated infection. Environmental or physiologic stressors such as changes in housing or lactation or administration of corticosteroids can trigger viral reactivation from latency. FeAHV1 lifelong latency occurs mainly in the trigeminal ganglia, but latency can also occur in other ganglia throughout the body.^8,10 Viral reactivation can be either subclinical or associated with clinical signs that are similar to, but usually milder than, those during acute infection. ⁸ The immune status of our patient was not known, but that could have played a role in the reactivation of a latent infection and the development of the cutaneous lesions.

Regardless of the anatomic location of lesions, the histologic hallmarks of feline herpesviral dermatitis are epidermal and follicular necrosis with ulceration, exudation, crusting, and prominent superficial-to-mid dermal eosinophilic or neutrophilic inflammation.^1,3–5,8 Although histologic changes in the original biopsy submission consisted of ulceration and eosinophilic inflammation, inflammatory infiltrates were predominantly plasmacytic and located mainly in the deep dermis. The cause of the vasculitis in our case remains undetermined, but it may have occurred secondarily to the extensive ulceration and necrosis. Although infection of macrophages could have led to viremia, ⁸ the absence of systemic disease did not favor this possibility.

Because FeAHV1 is an epitheliotropic virus, intranuclear viral inclusion bodies occur in epithelial cells of the epidermis, hair follicles, and sebaceous glands.^3,4 Macrophages are not a primary target cell for FeAHV1 infection. However, viral inclusions in our first biopsy sample were observed within macrophages in the deep dermis, with no inclusions in epithelial cells.^2–4 Infection of subsets of macrophages has been reported for other alphaherpesviruses, such as human alphaherpesvirus 1. ⁶ Although M1 (pro-inflammatory) macrophages are less permissive of infection, M2 (anti-inflammatory) macrophages were shown to allow higher levels of viral infection and replication. These differences may be associated with the fact that M1 macrophages produce abundant antiviral cytokines and chemokines that create a hostile intracellular environment for viral replication, whereas M2 macrophages may lack intrinsic antiviral activity. ⁶

The histologic findings in our first biopsy substantially differ from previously documented cases of FeAHV1 dermatitis in cats and could have precluded the etiologic diagnosis had the biopsies been more superficial. Herpesviral dermatitis in cats may be misdiagnosed histologically as hypersensitivity, including mosquito bite hypersensitivity and feline eosinophilic granuloma complex.^2,10 Feline eosinophilic granuloma was initially suspected in our case. However, rare viral inclusions sufficed for the suspicion of herpesviral infection, which was confirmed by IHC and PCR. Our IHC findings confirmed that clusters of viral antigen were concentrated within inflammatory cells mainly around areas with vasculitis in the deep dermis and subcutaneous tissue, with no immunolabeling in the remaining epidermis or adnexal structures, mirroring the distribution of the viral inclusions. These findings suggest that although primarily epitheliotropic, FeAHV1 can also replicate in macrophages, similar to the tropism that has been occasionally documented for other alphaherpesviruses. ⁶ The histologic changes and the distribution of viral antigen in the second set of biopsies were typical of feline herpesviral dermatitis, indicating that lesions may have different histologic features even when diagnosed in the same patient.