Systemic Sarcoidosis and Red Dye Granulomatous Tattoo Inflammation after Influenza Vaccination: A Case Report and Review of Literature

A patient with bilateral granulomatous uveitis also had the simultaneous manifestation of granulomatous inflammation under red dye areas of a 10-year-old multicolored tattoo. The patient manifested secondary cystoid macular edema and uveitic glaucoma due to the chronic uveitis. Punch biopsy of the inflamed area of the tattooed dermis displayed a dense lichenoid granulomatous inflammation. Thoracic imaging revealed lymphadenopathy and pulmonary biopsy confirmed a diagnosis of sarcoidosis.

This case and review of literature demonstrates that tattoo inflammation, whether generalized or localized to a particular color, should be considered a potential sign of systemic sarcoidosis and patients should be carefully evaluated for systemic granulomatous inflammation.

Case Report

A 44-year-old African American male veteran presented with complaints of bilateral ocular pain, photophobia, and blurred vision. The 10-year-old tattoo on his left arm was “thick and scaly” for the same 2-month period. He had received a 0.5-mL IM influenza vaccination (Sanofi Pasteur) in his right deltoid 2 months prior to his initial clinical presentation and at the approximate time of the initiation of his symptoms. His medical history was positive for arthritis and mild chronic obstructive pulmonary disease (COPD) and he denied any previous ocular injuries or surgeries. He was not using any significant systemic medication and denied any drug allergies. He denied cigarette, alcohol, and illicit drug use. He reported his maternal grandmother had glaucoma. Review of systems was positive for chest pain and shortness of breath.

Best corrected visual acuities were 20/150 in the right eye (OD) and 20/150 in the left eye (OS). Slit-lamp evaluation revealed trace injection of the bulbar conjunctiva along with 4+ anterior chamber cells and 2+ flare in both eyes (OU) according to the SUN grading scheme. There were multiple keratic precipitates and a near complete posterior iris synechiae OU. Fundus examination revealed a healthy appearing optic nerve OD with a 0.35 cup-to-disc ratio without edema or pallor. The optic nerve OS had a glaucomatous appearance with a 0.75 cup-to disc-ratio without edema or pallor. Intraocular pressure (IOP) was 14 mmHg OD and 16 mmHg OS. The optic nerves and retinal nerve fiber layer were analyzed with a time-domain Stratus optical coherence tomography (OCT) revealing healthy, robust nerve tissue OD of average thickness 108.27μm, but thinning inferiorly and superiorly OS with average thickness 70.23 μm, indicative for probable glaucoma OS with more testing necessary.

An aggressive dosing of topical prednisolone acetate 1% and atropine 1% was prescribed and a standard granulomatous uveitis blood panel was ordered. All results returned unremarkable with the exception of an elevated angiotensin converting enzyme (ACE). A chest x-ray (CXR) followed by a more detailed thoracic computed tomography (TCT) was also performed to explore for pulmonary disease. A consultation was placed to both dermatology and pulmonology departments. The refractory ocular inflammation resulted in bilateral cystoid macular edema (CME) 6 months following the patient's initial presentation. The maculae were scanned with retinal time-domain Stratus OCT to reveal a foveal thickness of 514 μm OD and 409 μm OS. The patient was referred to the ophthalmology clinic for triamcinolone intraocular injections.

The tattoo on the patient's left brachium contained indurated plaques sharply limited to red dye of the tattoo while the black dye was completely uninvolved (Figure 1). An 8-mm punch biopsy of the tattoo revealed a “dense lichenoid granulomatous inflammation permeating the superficial, mid, and deep dermis along with eccrine units.” The inflammation consisted of foci of reddish brown pigment, histiocytes, and multinucleated giant cells (Figure 2). There was no evidence of infection or necrosis. Infrared spectroscopy confirmed large, red, birefringent particles within the dermis containing carbon and consistent with “an aromatic, organic, non-mercury-containing dye within the cytoplasm of the macrophages and multinucleated giant cells.” The aromatic dye could not be further specified among several hundred possible chemical sources, as the red dye spectra were not identical to previous cases or to the reference spectra of the department of environmental and toxicologic pathology, but was consistent with red dye tattoo ink. Unfortunately, the tattoo artist was also unable to be contacted in regard to the composition of the dye. Following the results of the cutaneous biopsy, the patient was given an intralesional injection of triamcinolone.

Figure 1. Tattoo inflammation.

Figure 2. Dermatological pathology.

CXR and TCT revealed lymphadenopathy of the middle mediastinum along with both right and left hila. Pulmonary function testing (PFT) was performed and compared to measurements from 2 years prior revealing mild restriction. An endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) and bronchoalveolar lavage (BAL) were performed. The specimen from the biopsy of the patient's right lower lobe lymph node contained mononuclear cells along with a trace amount of squamous cells and polymorphonuclear leukocytes (PMNs). There were small, well-formed granulomas with accompanying lymphocytes. Acid-fast bacillus and periodic acid Schiff stains failed to reveal any acid-fast or fungal organism and there was no evidence of tissue necrosis. Flow cytometry revealed no distinct CD34⁺ population. Approximately 74% of the cells were within the lymphoid gate, 48% of which were T cells and 45% of which were B cells, the high lymphocyte percentage being indicative of sarcoidosis. There was no aberrant T-cell antigen or light chain restriction. There was no abnormal CD19/5⁺, CD19/10⁺, or CD38/138⁺ populations identified, where mutations may be indicative of severe immunodepression. No features were diagnostic for malignancy. Importantly, no birefringent tattoo particles were found within the specimen. The EBUS-TNA and BAL results confirmed a diagnosis of sarcoidosis, and 20 mg daily oral prednisolone was prescribed and eventually tapered. His ongoing pulmonary symptoms are now managed only with steroidal and bronchodilator inhalers.

The timeline of the inflammatory reaction following the patient's influenza vaccination raised suspicion of an activation of his immune system from allergy of the injected material. The Sanofi Pasteur influenza vaccination the patient received was preserved with thimerosal. Thimerosal is a mercury-containing preservative and is frequently an ingredient of red tattoo dye, especially at the time of application of the patient's tattoo. As a precaution, mercury-containing substances were added to the patient's allergy list and the patient was warned of a potential thimerosal allergy.

Comment

Scar sarcoidosis is a granulomatous infiltration and elevation of previously flat scars. In addition to previous injury sites, scar sarcoidosis has been documented in tattoos and in sites of previous intramuscular injections, blood donation, and herpes zoster.1 The first case of tattoo sarcoidosis was mentioned by Madden2 in 1939. Granulomatous inflammation under scars is believed to occur due to systemic or local diseases as a result of being sites of lower resistence.3 Scar sarcoidosis is an example of the well-known Koebner phenomenon, which is defined as skin lesions appearing on lines of trauma. The Koebner phenomenon was first mentioned in 1877 as psoriatic lesions appearing on scars and no other location in psoriatic patients.4

Immunological granulomatous reactions are often indistinguishable from foreign body granulomatous reactions, with the exception of the presence of the foreign matter. Although foreign body granulomas are generally, by definition, isolated to the offending foreign body, there have been documented cases of foreign matter resulting in systemic granulomatous inflammation.5 Many studies have found incidental birefrigent material within the cutaneous biopsies of patients with known systemic sarcoidosis.5–6 Foreign bodies have also been found in granulomatous systemic lesions. These studies demonstrate that foreign bodies may be a stimulus for granuloma formation in some cases of sarcoidosis.

There have been a number of documented cases of granulomatous tattoo inflammation confined to a specific color dye in cases of sarcoidosis with only a cutaneous component. There are far fewer reports of tattoo reaction confined to a particular color dye along with systemic inflammation (Table 1). Inflammation restricted to a particular color dye is evidence that a local hypersensitivity is the origin to a broad, sarcoid-like systemic inflammation. Sensitization in delayed hypersensitivity inflammation can actually occur at any point during the existence of the foreign body antigen. Therefore, tattoo reactions may occur weeks to years following placement of the tattoo.

Table 1. Review of literature.

Literature	Affected pigment	Tattoo histology	Diagnostic workup	Pulmonary inflammation	Ocular inflammation	Timing of tattoo placement
Moschos et al.32	Multiple pigments	Not specified	Labs normal. No chest imaging performed	None detected	Bilateral retinal vasculitis, macular edema	6 years prior and progressively completed
McElvanney et al.36	Multiple pigments	Granulomatous	CXR–normal	None detected	Bilateral anterior uveitis remitted with tattoo excision	“Long-standing”
Lubeck et al.3	Multiple pigments	Granulomatous	CXR–abnormal	BHL	Bilateral anterior uveitis, secondary glaucoma	20 years prior
Post et al.31	Multiple pigments	Granulomatous	ACE–elevated hypercalcemia TCT–abnormal	Increased interstitial markings on thoracic CT	Bilateral anterior uveitis	Not specified
Yoong et al.22	Blue pigment	Granulomatous	Labs–normal CXR–normal TCT–normal	None detected	None detected	6 months prior
Wollina et al.11	Red pigment of red and black tattoo	Tattoo biopsy revealed pigment mostly within macrophages. Dense granulomatous inflammation with foreign body-type giant cells in all layers	ESR–elevated CRP–elevated ACE–normal IgM–elevated IgG–elevated CXR–normal Lymph node ultrasound–enlarged inguinal nodules without sign of neoplastic or metastatic disease	None detected	None detected	Days following tattoo placement
Lowenthal et al.19	Green pigment	Skin biopsy demonstrated sarcoid-like granulomas along with lymphocytic and giant cell infiltration as well as foreign body-type giant cells with foreign particles in the cytoplasm	Patch test to potassium dichromate– strongly positive Patch test to moistened Portland cement–negative Patch test to chromic acid–positive Patch test to chromium sulfate–negative Patch test to chromic chloride–negative	None detected	None detected	20 years prior
Verdich et al.12	Red pigment	Punch biopsy of tattoo revealed granulomatous infiltrates of lymphocytes and histiocytes. No epithelioid or foreign body type giant cells. Pigment particles seen intra- and extracellularly	None performed	None detected	None detected	2 weeks prior
Cruz et al.9	Red pigment	Lichenoid dermatitis	None performed	None detected	None detected	3 years
Mortimer et al.10	2 cases red pigment (one confirmed cinnabar dye)	Lichenoid basal damage without granuloma in both cases	None performed	None detected	None detected	Once case 18 months following tattoo placement. Another case 2 weeks following placement
Haddad et al.23	Blue pigment	Granulomatous	None performed	None detected	None detected	13 years
Kluger et al.13	Red pigment	Granuloma annulare	None performed	None detected	None detected	10 years
Jones et al.37	Rose-colored cosmetic lip liner	Granulomatous	None performed	None detected	None detected	4 years
Bachmeyer et al.24	Isolated to blue dye of multicolored tattoo	Granulomatous	None performed	None detected	None detected	20 years (1 month after initiating enterecept therapy)
Morales-Callaghan et al.30	Isolated to black dye of multicolored tattoo	Granulomatous	Labs–normal CXR–normal	None detected	None detected	10 months prior
Bagley et al.15	Red pigment	Granulomatous	None performed	None detected	None detected	1 year prior
Tope et al.16	Restricted to red and black areas of multicolored tattoo	Granulomatous	None performed	None detected	None detected	10 years prior
McFadden et al.17	Isolated to violet areas of multicolored tattoo	Granulomatous	Labs–normal No mention of ACE testing CXR–normal	None detected	None detected	4 weeks prior
Schwartz et al.18	Isolated to purple areas of multicolored tattoo	Granulomatous	None performed	None detected	None detected	3 weeks prior
Sowden at al.8	Red pigment	Granulomatous, analysis of skin biopsy by energy Dispersive analysis of x-rays revealed iron as only inorganic element of red pigment	CXR–positive Kveim–positive	BHL	None detected	Not specified
Baumgartner et al.26	Black pigment of multicolored tattoo	Granulomatous	Thrombocytosis, All other labs normal CXR–abnormal TCT–abnormal	Stage I pulmonary sarcoidosis	None detected	10 years prior
Jones et al.27	Black pigment	Granulomatous	ACE–elevated CXR–abnormal	Hilar, periaortic, and mediastinal adenopathy	None detected	15 years prior
Ali et al.25	Brown pigment	Granulomatous	ACE–elevated CXR–abnormal Mediastinoscopy and hilar and mediastinal lymph node biopsy–confirmed sarcoidosis	Mediastinoscopy and hilar and mediastinal lymph node biopsy confirmed pulmonary sarcoidosis 6 years prior to tattoo inflammation	None detected	13 years prior
Toulemonde et al.38	Labial nodules on permanent monochromatic tattoo during low-dose interferon therapy	Granulomatous	TCT–positive	Pulmonary infiltrate on CT Nodules disappeared following interferon therapy	None detected	Not specified
Collins et al.21	Navy blue pigment	Granulomatous	CXR–positive Pulmonary biopsy–negative	Bilateral pulmonary shadowing on thoracic x-ray	None detected	Not specified
Atluri et al.39	Red pigment	Granulomatous	ACE–mildly elevated	On pegylated IFN and ribavirin treatment for chronic Hep C	None detected	Not specified
Hanada et al.7	Red pigment	Granulomatous	Labs–normal Patch test of mercuric sulfide–negative Patch test of tattoo pigments in petrolatum album–negative	Mercury, aluminum, and silicon in pulmonary biopsy sample. Electron microscopic evaluation of lung tissue on deparaffinized sections revealed very fine pigment granules similar to red pigment analyzed from tattoo.	Bilateral panuveitis	Not specified
Rorsman et al.20	3 cases of blue pigment	Granulomatous	CXR–normal	None detected	Bilateral uveitis	Case 1—6 months prior Case 2—18 months prior Case 3—6 months prior
Anolik et al.29	Black pigment in monochromatic tattoo	Granulomatous	ACE–elevated IgM–elevated IgG–elevated IgE–elevated CXR–normal Thoracic CT–normal	None detected	Bilateral uveitis	Not specified
Saliba et al.28	Black pigment in monochromatic tattoo	Granulomatous	ACE–normal CXR–normal Thoracic CT–normal	None detected	Panuveitis with bilateral cystoid macular edema	Not specified
Barbasi et al.14	Red pigment in monochromatic tattoo	Granulomatous	CXR–normal Thoracic CT–normal	None detected	Bilateral panuveitis	Ocular symptoms began 3 days after tattoo placement

Although reactions to red,7–16 purple,17–18 green,19 blue,20–24 brown,25 and black16,26–28 have been reported, mercuric sulfide (red pigment) is the most common irritant in tattoo hypersensitivity.2,7–10 Modern red pigment alternatives such as cadmium selenide (cadmium red), ferric hydrate (sienna/red ochre), and organic vegetable dyes such as brazilwood and sandalwood are still causing red dye hypersensitivities.2,10 Documented reactions to red tattoo dye include dermatitis of granulomatous, lichenoid, and pseudolymphomatous types (Table 1).

There have been a number of documented cases of uveitis associated with a granulomatous tattoo reaction (Table 1). Saliba et al.28 reported a case of bilateral panuveitis and CME associated with a non-color-specific tattoo reaction and a cutaneous biopsy that revealed noncaseating granulomas. The patient was diagnosed as having delayed tattoo hypersensitivity on account of serum ACE, chest x-ray, and CT scan all being normal. No pulmonary biopsy was performed on account of the normal imaging; however, the patient was symptomatic with a chronic cough and had a history positive for asthma. The patient was successfully treated with systemic immunosuppressive agents.

Hanada et al.7 documented 3 cases of bilateral uveitis, BHL, and red dye-specific tattoo noncaseating granulomatous inflammation. However, aluminum, mercury, and silicon were found within the bronchial biopsy specimen. Lubeck et al.3 described a case of BHL, polyarthralgia, a nonspecific red, blue, and green tattoo nonnecrotizing granulomatous inflammation with simultaneous bilateral uveitis, which increased in severity and led to bilateral glaucoma. The patient was treated with systemic corticosteroids, which suppressed the inflammation. Post et al.31 described a case of granulomatous inflammation in a monochromatic tattoo, bilateral uveitis with suggestive pulmonary changes. The patient in the Post et al.31 case was given a diagnosis of sarcoidosis, but pulmonary biopsy was not performed.

Moschos et al.32 reported a case of severe posterior uveitis with retinal vasculitis and CME following tattoo placement, which resolved after systemic immunosuppressive therapy. Their systemic workup ruled out an infectious or autoimmune cause and the severe vasculitis was concluded to be the result of severe tattoo hypersensitivity. Mansour et al.33 described a case of chronic bilateral uveitis with recurrent simultaneous swelling of various tattoo sites preceding the ocular inflammation by 1 week. Results of laboratory, imaging, and lung biopsies were repeatedly negative. The high B-lymphocyte and macrophage ratio with an equal number of T-helper and T-suppressor cells was demonstrative of a delayed hypersensitivity reaction and not of a typical sarcoidosis histology. An elevation T-helper cells is typical in traditional sarcoidal inflammation.

Our case is unique on account of the confinement of the inflammation only within the red dye tattoo areas in the multicolored tattoo in addition to the other multisystem involvement. The limitation to the red areas indicates that this is more than the previously described Koebner phenomenon. If our case were simply a case of severe delayed tattoo dye hypersensitivity as in the Hanada et al.7 cases, then we would expect foreign birefringent particles to be present not only in the cutaneous punch biopsy, but also in EBUS-TNA and BAL specimens. We suspect that the sarcoidal reaction in this case was the result of an immunologic cascade to the foreign red-dye tattoo antigen. Since the specific red dye was not recognizable or reproducible in our case, patch testing was not performed, although the majority of patch tests previously performed on red dye tattoo hypersensitivity have been inconclusive. Due to the 10-year delay between the placement of the tattoo and the initiation of symptoms, we believe an immunological trigger set off the systemic inflammation. As previously mentioned, the patient in our case received his influenza vaccine 2 months prior to his first presentation in our clinic and the approximate time his tattoo signs appeared. His triggering event may very well have been his viral vaccination leading to the stimulation of his immune system. Our patient was injected with 0.5 mL im influenza vaccination (Sanofi Pasteur) preserved with thimerosal, an organomercury compound.

Handler et al.34 reported a case of granulomatous inflammation confined to the blue areas of a patient's tattoo 1 week following injection of an H1N1 vaccine containing 0.01% thimerosal preservative. The injection was administered directly superior to the tattoo on the right deltoid, which was placed 8 years prior. The patient underwent a sarcoidosis workup that was unremarkable with exception of a moderate restrictive lung defect on PFT. Handler et al.34 theorized the release of the tattoo pigment into extracellular space during the patient's immunization initiated the granulomatous reaction. The Handler et al.34 case differs from our case because our patient received his vaccination in the arm contralateral to the tattooed arm. Therefore, the theory of Handler et al. of the release of the tattoo pigment would not apply to our case. We believe our patient developed a hypersensitivity to mercury and the injection of the vaccination with the mercuric compound caused a systemic hypersensitivity simply by the injection of the organomercury compound.

In our case, there were no signs of mercury in the birefringence investigation of the biopsied tattoo pigment. However, we strongly believe there was mercury contained in the original red compound, on account of the popularity of the ingredient in red tattoo dye, even though the tattoo biopsy was negative for mercury within the pigment granules in the inflammatory cells' cytoplasm. Taaffee and Wyatt35 reported a case of a lichenoid reaction confined to red areas of a 14-year-old tattoo in a metallurgy extraction process worker. Although no mercury was identified in the biopsy of the patient's tattoo, the authors believed mercury was in fact used in the red dye as mercury was commonly used when the patient's tattoo was applied.

To our knowledge, this is the first documented case of bronchoscopy-confirmed systemic sarcoidosis presenting with an aggressive bilateral granulomatous uveitis and resulting subsequent CME and glaucoma, BHL, and color-specific granulomatous tattoo inflammation. The finding of a granulomatous tattoo inflammation restricted to a specific color dye should not be assumed to be strictly a localized hypersensitivity reaction and warrants an extensive workup for systemic sarcoidosis, including chest imaging and possible bronchoscopy confirmation, a comprehensive ophthalmological examination, and close monitoring if tests fail to reveal the disease. Tissue samples should also be carefully examined with stains for bacterial, fungal, and mycobacterial infection, while malignancy must also be ruled out as a cause of the inflammation. The isolation of inflammation to a particular tattoo color in the presence of systemic sarcoidosis supports the theory of an exogenous antigen releasing an inflammatory cascade leading to the disease. Risk of secondary multisystem sarcoidosis should be included in possible side effects of tattooing and there should be an increase in public awareness. This case demonstrates that widespread sarcoidal inflammation may result from a hypersensitivity to an identifiable antigen.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.