# A case of chronic granuloma related to wild-type strain of rubella virus in an adult patient with ITK deficiency without primary immunosuppression and review of the literature

Caroline Bouvarel, Léa Luciani, Simon Sunder, Carine Motard, Sebastien

Barbarot, Antoine Nougairède, Christine Zandotti, Xavier de Lamballerie,

Valérie Delargue, Cassandre Crémadès, et al.

► To cite this version:

Caroline Bouvarel, Léa Luciani, Simon Sunder, Carine Motard, Sebastien Barbarot, et al. A case of chronic granuloma related to wild-type strain of rubella virus in an adult patient with ITK deficiency without primary immunosuppression and review of the literature. JEADV Clinical Practice, 2023, 3 (1), pp.283-292. 10.1002/jvc2.268. hal-04247968

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Submitted on 31 May 2024

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<figure><img src="image_1.png" /></figure>

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## CASE REPORT

<figure><img src="image_1.png" /></figure>

JEADV
CLINICAL PRACTICE

OPEN ACCESS
JOURNAL OF THE
EUROPEAN ACADEMY
OF DERMATOLOGY &
VENELOGY

# A case of chronic granuloma related to wild-type strain of rubella virus in an adult patient with ITK deficiency without primary immunosuppression and review of the literature

Caroline Bouvarel<fnref n="1" /> ID | Léa Luciani<fnref n="2" />,<fnref n="3" /> | Simon Sunder<fnref n="4" /> | Carine Motard<fnref n="5" /> |

Sebastien Barbarot<fnref n="6" /> ID | Antoine Nougairède<fnref n="2" />,<fnref n="3" /> | Christine Zandotti<fnref n="2" />,<fnref n="3" /> |

Xavier de Lamballerie<fnref n="2" />,<fnref n="3" /> | Valérie Delargue<fnref n="7" /> | Cassandre Crémadès<fnref n="8" /> |

Caroline-Jade Clerc<fnref n="1" /> | Ingrid Kupfer-Bessaguet<fnref n="1" />

## Correspondence

Caroline Bouvarel, Service de Dermatologie, Centre hospitalier de Niort, 40 Ave Charles de Gaule 79021 Niort, France.

Email: bouvarelcaroline@gmail.com

## Funding information

None

## Abstract

According to the review of the literature, rubella virus-related granuloma is an entity first described in 2014 mainly affecting children with primary immune deficiencies infected with the rubella vaccine strain. The development of rubella virus-associated granulomas seems to be related to a defect in cellular immunity and their severity varies from a simple cutaneous lesion to deep visceral involvement in some patients. Since then, this type of granuloma has been described in immunocompetent adults, including two cases involving a wild-type strain of the virus (genotype 2). We report the case of a 70-year-old man had suffered from a granuloma of the leg for almost 40 years, in the absence of immunodeficiency. The assessment of the skin granuloma revealed a positive polymerase chain reaction for a wild-type rubella virus genotype 1a. Genetic studies performed using whole exome sequencing suggest that the disease is due to a homozygous splice site mutation in the ITK gene.

## KEYWORDS

chronic granuloma, rubella, wild-type

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

© 2023 The Authors. JEADV Clinical Practice published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.

<figure><img src="image_2.png" /></figure>

<footnote n="1">¹Service de Dermatologie, Centre Hospitalier de Niort, Niort, France</footnote>

<footnote n="2">²Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207), Marseille, France</footnote>

<footnote n="3">³Laboratoire de virologie, Assistance Publique Hôpitaux de Marseille, Marseille, France</footnote>

<footnote n="4">⁴Service d'infectiologie, centre hospitalier de Niort, Niort, France</footnote>

<footnote n="5">⁵Service d'hématologie, centre hospitalier de Niort, Niort, France</footnote>

<footnote n="6">⁶Service de dermatologie, centre hospitalier universitaire de Nantes, Nantes, France</footnote>

<footnote n="7">⁷Aix Marseille Univ, Inserm, MMG, U 1251, Marseille, France</footnote>

<footnote n="8">⁸University of Paris, Imagine Institute, INSERM U1163, Paris, France</footnote>
<figure><img src="image_2.png" /></figure>

## CASE REPORT

# A case of chronic granuloma related to wild-type strain of rubella virus in an adult patient with ITK deficiency without primary immunosuppression and review of the literature

Caroline Bouvarel¹

<figure><img src="image_3.png" /></figure>

Léa Luciani²,³

Simon Sunder⁴

Carine Motard⁵

<figure><img src="image_4.png" /></figure>

Sebastien Barbarot⁶

<figure><img src="image_5.png" /></figure>

Antoine Nougairède²,³

Christine Zandotti²,³

Xavier de Lamballerie²,³

Valérie Delargue⁷

Cassandre Crémadès⁸

Caroline-Jade Clerc¹

Ingrid Kupfer-Bessaguet¹

¹Service de Dermatologie, Centre Hospitalier de Niort, Niort, France

²Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207), Marseille, France

³Laboratoire de virologie, Assistance Publique Hôpitaux de Marseille, Marseille, France

⁴Service d'infectiologie, centre hospitalier de Niort, Niort, France

⁵Service d'hématologie, centre hospitalier de Niort, Niort, France

⁶Service de dermatologie, centre hospitalier universitaire de Nantes, Nantes, France

⁷Aix Marseille Univ, Inserm, MMG, U 1251, Marseille, France

⁸University of Paris, Imagine Institute, INSERM U1163, Paris, France

### Correspondence

Caroline Bouvarel, Service de Dermatologie, Centre hospitalier de Niort, 40 Ave Charles de Gaule 79021 Niort, France.

Email: bouvarelcaroline@gmail.com

### Funding information

None

### Abstract

According to the review of the literature, rubella virus-related granuloma is an entity first described in 2014 mainly affecting children with primary immune deficiencies infected with the rubella vaccine strain. The development of rubella virus-associated granulomas seems to be related to a defect in cellular immunity and their severity varies from a simple cutaneous lesion to deep visceral involvement in some patients. Since then, this type of granuloma has been described in immunocompetent adults, including two cases involving a wild-type strain of the virus (genotype 2). We report the case of a 70-year-old man had suffered from a granuloma of the leg for almost 40 years, in the absence of immunodeficiency. The assessment of the skin granuloma revealed a positive polymerase chain reaction for a wild-type rubella virus genotype 1a. Genetic studies performed using whole exome sequencing suggest that the disease is due to a homozygous splice site mutation in the ITK gene.

### KEYWORDS

chronic granuloma, rubella, wild-type

This is an open access article under the terms of the [Creative Commons Attribution License](https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

© 2023 The Authors. *JEADV Clinical Practice* published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.

<figure><img src="image_6.png" /></figure>
## INTRODUCTION

Granuloma is a lesion defined as a polymorphic inflammatory infiltrate with a predominance of macrophages that could be caused by an infection. The majority of cases of rubella virus-associated granulomas described in the literature since the first report in 2014¹ involved children with primary immune deficiency infected with a vaccine.²⁻⁵ Indeed, since the generalization of the mumps-measles-rubella (MMR) vaccine, the natural circulation of rubella has dramatically decreased.⁶ The vaccine strain is a live attenuated virus and can therefore cause infectious complications in case of immune deficiency. However, a recent article reports four cases of rubella granuloma in immunocompetent adult patients, including one involving a wild-type strain.⁷ We propose a review of the literature of cases of rubella-associated cutaneous granuloma and we report a new case of wild-type rubella virus granuloma in an elderly patient without MMR vaccination. In search for genetic determinants, we sequenced the patient's exome and identified a new homozygous loss of function mutation of the *ITK* (interleukin-2-inducible T-cell kinase) probably leading to susceptibility to rubella infection in a patient with no previous history of immunodeficiency.

## CASE REPORT

A 70-year-old man, former fish farmer, was admitted to the hematology department for the discovery of a lymphocytic lymphoma (lymph node form of chronic lymphocytic leukemia, Stade C) with secondary hypogammaglobinemia. His medical history did not indicate any particularity, except for large maculopapular, violaceous and indurated plaques with fibrinous ulcers of the left leg (Figure 1a). These lesions had been slowly spreading for over 30 years. During many years, with no definite diagnosis, the patient received antibiotic therapy and topical corticosteroids without any benefit. A skin biopsy from an infiltrated area revealed a granulomatous inflammatory infiltrate over the entire dermis, composed of epithelioid and giganto-cellular granulomas, centered by altered neutrophils and a thick lymphocytic corona in the periphery (Figure 2). The immunohistochemical study showed small lymphocytes of normal phenotype, with a predominance of T cells. The various stains with P.A.S, Grocott, slow Giemsa

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**FIGURE 1** Chronic cutaneous granuloma caused by a wild strain of rubella in an immunocompetent adult. (a) Extensive cutaneous granuloma of the left leg only that presents with purple patches, skin atrophy, ochre dermatitis and fibrinous ulcer. At the edge of the lesions, large inflammatory, papular infiltrated areas which became yellowish when subject to in vitro are observed. (b) Partial improvement of the lesions after Nitazoxamide treatment. (c) Ulcers repair and disinfiltration after Ibrutinib and polyvalent immunoglobulins treatment.</figcaption></figure>

and Ziehl did not reveal any microorganism. Alcian blue staining did not identify accumulation of mucin. Cultures and polymerase chain reaction (PCR) tests for atypical mycobacteria and microorganisms usually responsible for granulomas (Leishmania, Anaplasma, Rickettsia, Coxiella, Francisella, Poxvirus, *Treponema pallidum* and mycobacteria) were negative. The diagnosis of rubella granuloma was established by the PCR positivity (cycle threshold 31) on the cutaneous biopsy collected in lesioned skin (rubella PCR performed on healthy skin was negative). Regarding serology, the patient presented no antirubella IgM but an IgG titer (2610 IU/mL) much higher than the average titer calculated from a panel of person randomly selected between 70 and 75 years
# INTRODUCTION

Granuloma is a lesion defined as a polymorphic inflammatory infiltrate with a predominance of macrophages that could be caused by an infection. The majority of cases of rubella virus-associated granulomas described in the literature since the first report in 2014¹ involved children with primary immune deficiency infected with a vaccine.²⁻⁵ Indeed, since the generalization of the mumps-measles-rubella (MMR) vaccine, the natural circulation of rubella has dramatically decreased.⁶ The vaccine strain is a live attenuated virus and can therefore cause infectious complications in case of immune deficiency. However, a recent article reports four cases of rubella granuloma in immunocompetent adult patients, including one involving a wild-type strain.⁷ We propose a review of the literature of cases of rubella-associated cutaneous granuloma and we report a new case of wild-type rubella virus granuloma in an elderly patient without MMR vaccination. In search for genetic determinants, we sequenced the patient's exome and identified a new homozygous loss of function mutation of the *ITK* (interleukin-2-inducible T-cell kinase) probably leading to susceptibility to rubella infection in a patient with no previous history of immunodeficiency.

# CASE REPORT

A 70-year-old man, former fish farmer, was admitted to the hematology department for the discovery of a lymphocytic lymphoma (lymph node form of chronic lymphocytic leukemia, Stade C) with secondary hypogammaglobinemia. His medical history did not indicate any particularity, except for large maculopapular, violaceous and indurated plaques with fibrinous ulcers of the left leg (Figure 1a). These lesions had been slowly spreading for over 30 years. During many years, with no definite diagnosis, the patient received antibiotic therapy and topical corticosteroids without any benefit. A skin biopsy from an infiltrated area revealed a granulomatous inflammatory infiltrate over the entire dermis, composed of epithelioid and giganto-cellular granulomas, centered by altered neutrophils and a thick lymphocytic corona in the periphery (Figure 2). The immunohistochemical study showed small lymphocytes of normal phenotype, with a predominance of T cells. The various stains with P.A.S, Grocott, slow Giemsa

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /><figcaption>**FIGURE 1** Chronic cutaneous granuloma caused by a wild strain of rubella in an immunocompetent adult. (a) Extensive cutaneous granuloma of the left leg only that presents with purple patches, skin atrophy, ochre dermatitis and fibrinous ulcer. At the edge of the lesions, large inflammatory, papular infiltrated areas which became yellowish when subject to in vitro are observed. (b) Partial improvement of the lesions after Nitazoxamide treatment. (c) Ulcers repair and disinfiltration after Ibrutinib and polyvalent immunoglobulins treatment.</figcaption></figure>

and Ziehl did not reveal any microorganism. Alcian blue staining did not identify accumulation of mucin. Cultures and polymerase chain reaction (PCR) tests for atypical mycobacteria and microorganisms usually responsible for granulomas (Leishmania, Anaplasma, Rickettsia, Coxiella, Francisella, Poxvirus, *Treponema pallidum* and mycobacteria) were negative. The diagnosis of rubella granuloma was established by the PCR positivity (cycle threshold 31) on the cutaneous biopsy collected in lesioned skin (rubella PCR performed on healthy skin was negative). Regarding serology, the patient presented no antirubella IgM but an IgG titer (2610 IU/mL) much higher than the average titer calculated from a panel of person randomly selected between 70 and 75 years
<figure><img src="image_6.png" /><figcaption>**FIGURE 2** Histology of a skin granuloma biopsy. (a) Haemato-Eosin-Safran (HES), ×5: Granulomatous inflammatory infiltrate spread over the entire height of the dermis. (b) HES, ×20: epithelioid and giganto-cellular granulomas, centered by altered neutrophils and thick lymphocytic corona in the periphery.</figcaption></figure>

old (115 IU/mL) (Figure 3a). A treatment with nitazoxanide (7 mg/kg/day)²,⁸ was first administered for 2 months. It allowed a slight decrease of viral load (PCR cycle threshold 36) and partial improvement

with disinfiltration of the lesions, which remained inflammatory (Figure 1b). A treatment of the lymphocytic lymphoma that combined Ibrutinib and infusions of polyvalent immunoglobulin (Table 1) was then administered leading to a significant improvement with healing of the ulcerations (Figure 1c).

We obtained 62% of the viral genome directly from a cutaneous biopsy (Figure 3) and phylogenetic trees reveal that the virus (i) belongs to the rubella genotype 1a (Figure 3b), (ii) is not a vaccine strain (Figure 3c) and (iii) is phylogenetically distant from the strains available in GenBank (Figure 3b,c). Whole exome sequencing using DNA extracted from patient's fibroblasts led to the identification of a new homozygous c.138+2T>C splice-site variant in the *ITK* gene (NM_005546). This mutation is disrupting intron 1 donor splice site and is therefore predicted to lead to the absence of the protein. Bi-allelic mutations in *ITK* are known to cause a lymphoproliferative syndrome (MIM 613011) associated to infections by EBV,⁹ or mycobacteria.¹⁰ This is the first description of *ITK* deficiency associated to susceptibility to rubella infection.

## DISCUSSION

A review of the literature reports 40 cases of rubella virus-related skin granuloma (Table 1). The majority of patients were children vaccinated against rubella virus with primary immune deficiency. For those who had a deficiency of cellular immunity and in the majority of cases profound hypogammaglobulinemia, it has been suggested that granuloma formation is triggered by a functional imbalance in cellular immunity.³ The time between vaccination and the onset of a granulomatous disease (from 3 months to 13 years) probably depends on the type of immune system dysfunction.²,⁴,⁵,⁷,¹¹,¹² For the recently reported adult cases,⁷ although clinically immunocompetent and not meeting standard thresholds for immunosuppression, all cases had isolated laboratory abnormalities of lymphocytes or immunoglobulins. These evolutionary immune defects could allow silent rubella virus to emerge from a persistent reservoir as bone marrow neutrophils⁷ and produce sufficient amounts of viral antigen to trigger granulomatous inflammation years after initial inoculation.

The role of humoral immunity remains unclear. On the one hand, the literature shows that immunoglobulin supplementation tried in 12 patients was unsuccessful,²,⁴,¹² whereas our patient actually improved with this treatment. On the other hand, no
<figure><img src="image_10.png" /><figcaption>**FIGURE 2** Histology of a skin granuloma biopsy. (a) Haemato-Eosin-Safran (HES), ×5: Granulomatous inflammatory infiltrate spread over the entire height of the dermis. (b) HES, ×20: epithelioid and giganto-cellular granulomas, centered by altered neutrophils and thick lymphocytic corona in the periphery.</figcaption></figure>

old (115 IU/mL) (Figure 3a). A treatment with nitazoxanide (7 mg/kg/day)²,⁸ was first administered for 2 months. It allowed a slight decrease of viral load (PCR cycle threshold 36) and partial improvement

with disinfiltration of the lesions, which remained inflammatory (Figure 1b). A treatment of the lymphocytic lymphoma that combined Ibrutinib and infusions of polyvalent immunoglobulin (Table 1) was then administered leading to a significant improvement with healing of the ulcerations (Figure 1c).

We obtained 62% of the viral genome directly from a cutaneous biopsy (Figure 3) and phylogenetic trees reveal that the virus (i) belongs to the rubella genotype 1a (Figure 3b), (ii) is not a vaccine strain (Figure 3c) and (iii) is phylogenetically distant from the strains available in GenBank (Figure 3b,c). Whole exome sequencing using DNA extracted from patient's fibroblasts led to the identification of a new homozygous c.138+2T>C splice-site variant in the *ITK* gene (NM_005546). This mutation is disrupting intron 1 donor splice site and is therefore predicted to lead to the absence of the protein. Bi-allelic mutations in *ITK* are known to cause a lymphoproliferative syndrome (MIM 613011) associated to infections by EBV,⁹ or mycobacteria.¹⁰ This is the first description of *ITK* deficiency associated to susceptibility to rubella infection.

DISCUSSION

A review of the literature reports 40 cases of rubella virus-related skin granuloma (Table 1). The majority of patients were children vaccinated against rubella virus with primary immune deficiency. For those who had a deficiency of cellular immunity and in the majority of cases profound hypogammaglobulinemia, it has been suggested that granuloma formation is triggered by a functional imbalance in cellular immunity.³ The time between vaccination and the onset of a granulomatous disease (from 3 months to 13 years) probably depends on the type of immune system dysfunction.²,⁴,⁵,⁷,¹¹,¹² For the recently reported adult cases,⁷ although clinically immunocompetent and not meeting standard thresholds for immunosuppression, all cases had isolated laboratory abnormalities of lymphocytes or immunoglobulins. These evolutionary immune defects could allow silent rubella virus to emerge from a persistent reservoir as bone marrow neutrophils⁷ and produce sufficient amounts of viral antigen to trigger granulomatous inflammation years after initial inoculation.

The role of humoral immunity remains unclear. On the one hand, the literature shows that immunoglobulin supplementation tried in 12 patients was unsuccessful,²,⁴,¹² whereas our patient actually improved with this treatment. On the other hand, no
<figure><img src="image_7.png" /><figcaption>**FIGURE 3** Patient serological titers and phylogenetic analysis of the rubella genome obtained directly from the skin lesion. (a) Graph showing that the presented case's antirubella IgG titer (orange dot) is about 20 times higher than the average titer of a panel of 31 randomly selected persons between 70 and 75 years old (blue dots). The phylogenetic trees presented in (b and c) were made based on the 62% (including the coding area for the E1 envelope protein enabling rubella genotyping) of the genomic sequence obtained using Maximum Likelihood method complete deletion, Tamura-Nei model. Numbers represent bootstrap values for each node calculated with 1000 replicates. Bootstraps lower than 80% are not shown. Phylogenetic analysis of a panel of wild reference strains (b) showing that the presented case strain belongs to genotype 1a. Phylogenetic analysis of a panel of genotype 1a strains including vaccine and laboratory strains (c) showing that the presented case strain is not vaccine-related.</figcaption></figure>

case of rubella-associated granuloma has been described in patients suffering from isolated agamaglobulinemia,⁴ yet our patient had very high levels of antirubella IgG, without recovering for almost 30 years.

Skin damages could be explained by the persistence of the virus in M2 macrophages and in keratinocytes, which can lead to a deregulation of the architecture of the epidermis.¹³,¹⁴ In addition to the skin, the viral antigen can be found in granulomas in several visceral organs or bones.²⁻⁵,¹¹ No visceral

involvement was diagnosed in immunocompetent adults and in our patient. Regarding the phylogeny of the virus, the cases reported so far involving a wild-type strain of virus belong to genotype 2 in contrast to our patient who has a 1a-derived strain that circulated in the 1960s.¹⁵ It seems that, independently of the genotype, intra-host genetic drift occurs during chronic infection.

The number of cases described is still insufficient to understand the mechanisms of these atypical and chronic rubella infections. We describe for the first
<figure><img src="image_11.png" /><figcaption>**FIGURE 3** Patient serological titers and phylogenetic analysis of the rubella genome obtained directly from the skin lesion. (a) Graph showing that the presented case's antirubella IgG titer (orange dot) is about 20 times higher than the average titer of a panel of 31 randomly selected persons between 70 and 75 years old (blue dots). The phylogenetic trees presented in (b and c) were made based on the 62% (including the coding area for the E1 envelope protein enabling rubella genotyping) of the genomic sequence obtained using Maximum Likelihood method complete deletion, Tamura-Nei model. Numbers represent bootstrap values for each node calculated with 1000 replicates. Bootstraps lower than 80% are not shown. Phylogenetic analysis of a panel of wild reference strains (b) showing that the presented case strain belongs to genotype 1a. Phylogenetic analysis of a panel of genotype 1a strains including vaccine and laboratory strains (c) showing that the presented case strain is not vaccine-related.</figcaption></figure>

case of rubella-associated granuloma has been described in patients suffering from isolated agamaglobulinemia,⁴ yet our patient had very high levels of antirubella IgG, without recovering for almost 30 years.

Skin damages could be explained by the persistence of the virus in M2 macrophages and in keratinocytes, which can lead to a deregulation of the architecture of the epidermis.¹³,¹⁴ In addition to the skin, the viral antigen can be found in granulomas in several visceral organs or bones.²⁻⁵,¹¹ No visceral

involvement was diagnosed in immunocompetent adults and in our patient. Regarding the phylogeny of the virus, the cases reported so far involving a wild-type strain of virus belong to genotype 2 in contrast to our patient who has a 1a-derived strain that circulated in the 1960s.¹⁵ It seems that, independently of the genotype, intra-host genetic drift occurs during chronic infection.

The number of cases described is still insufficient to understand the mechanisms of these atypical and chronic rubella infections. We describe for the first
<table><caption>TABLE 1 Literature review of rubella virus-related granulomas.</caption><thead><tr><th></th><th>Immune deficiency</th><th>Age of rubella vaccination</th><th>Age of granuloma onset</th><th>Chronic inflammation site</th><th>Viral diagnosis</th><th>Treatments</th><th>Intravenous immunoglobulin</th><th>Nitazoxanide efficacy</th><th>Follow-up</th></tr></thead><tbody><tr><td></td><td>NC</td><td>Unvaccinated</td><td>35 years</td><td>Skin</td><td>PCR</td><td>Ibrutinib (for Lymphoma, 140 mg per day, for 23 months)<br/>Nitazoxanide<br/>Antibiotics<br/>Topical corticosteroids</td><td>Yes 20 g/month<br/>Still ongoing</td><td>7 mg/kg/day<br/>2 months<br/>Skin improvement<br/>Positives PCR control</td><td></td></tr><tr><td>Perelygina et al.<sup>2</sup></td><td>LIG4 Syndrome</td><td>12 months</td><td>15 months</td><td>Skin, liver, bowel</td><td>PCR</td><td>Topical steroids.<br/>Nitazoxanide</td><td>Yes</td><td>32 mg/kg/24 h.<br/>5 weeks (norvirus treatment)<br/>No improvement</td><td>Bone marrow transplant, improvement of lesions then death.</td></tr><tr><td>Perelygina et al.<sup>2</sup></td><td>Ataxia-telangiectasia</td><td>24 months</td><td>30 months</td><td>Skin</td><td>PCR</td><td>Cryotherapy, Erythromycin, Nitazoxanide, Imiquimod, topical tacrolimus, hydroxychloroquine, topical steroids</td><td>Yes</td><td>7 mg/kg/24 h<br/>1 year<br/>No improvement</td><td>Granuloma progression<br/>PCR + on repeated biopsies</td></tr><tr><td>Perelygina et al.<sup>2</sup></td><td>Ataxia-telangiectasia</td><td>12 and 17 months</td><td>39 months</td><td>Skin</td><td>PCR</td><td>Topical steroids, NSAIDS, Nitazoxanide</td><td>Yes</td><td>11 mg/kg/24 h<br/>5 months<br/>No improvement</td><td>Bone marrow transplant Improvement of lesions.</td></tr><tr><td>Perelygina et al.<sup>2</sup></td><td>Ataxia-telangiectasia</td><td>18 months</td><td>10 years</td><td>Skin</td><td>PCR</td><td>Abatacept<br/>Nitazoxanide</td><td>Yes</td><td>22 mg/kg/24 h<br/>Slowdown of the cutaneous progression and negative PCR control but underlying bone involvement.</td><td>Alive</td></tr><tr><td>Perelygina et al.<sup>2</sup></td><td>Congenital immunodeficiency</td><td>5 and 9 years</td><td>13 years</td><td>Skin</td><td>PCR</td><td>Linezolid, Nitazoxanide<br/>Chlorthromycin, Rifampicin, Isoniazid, Ethambutol, Voriconazole, Posaconazole, Interferon Amputation</td><td>Yes</td><td>16 mg/kg/24 h<br/>5 month<br/>No clinical improvement but virus undetectable in immunohistochemistry.</td><td>PML Death</td></tr><tr><td>Perelygina et al.<sup>2</sup></td><td>Severe combined immune deficiency</td><td>3 and 5 years</td><td>13 years</td><td>Skin and underlying bone</td><td>PCR</td><td>Nitazoxanide Cotrimoxazole, Azithromycin, Fluconazole, Amocixillin clavulanic acid, Ciprofloxacin, Surgery</td><td>Yes</td><td>25 mg/kg/24 h<br/>4 month<br/>No improvement</td><td>Alive</td></tr></tbody></table>

(Continues)
<table><caption>TABLE 1 Literature review of rubella virus-related granulomas.</caption><thead><tr><th></th><th>Immune deficiency</th><th>Age of rubella vaccination</th><th>Age of granuloma onset</th><th>Chronic inflammation site</th><th>Viral diagnosis</th><th>Treatments</th><th>Intravenous immunoglobulin</th><th>Nitazoxanide efficacy</th><th>Follow-up</th></tr></thead><tbody><tr><td></td><td>NC</td><td>Unvaccinated</td><td>35 years</td><td>Skin</td><td>PCR</td><td>Ibrutinib (for Lymphoma, 140 mg per day, for 23 months)<br/>Nitazoxanide<br/>Antibiotics<br/>Topical corticosteroids</td><td>Yes 20 g/month<br/>Still ongoing</td><td>7 mg/kg/day<br/>2 months<br/>Skin improvement<br/>Positives PCR control</td><td></td></tr><tr><td>Perelygina et al.<sup>2</sup></td><td>LIG4 Syndrome</td><td>12 months</td><td>15 months</td><td>Skin, liver, bowel</td><td>PCR</td><td>Topical steroids.<br/>Nitazoxanide</td><td>Yes</td><td>32 mg/kg/24 h.<br/>5 weeks (norvirus treatment)<br/>No improvement</td><td>Bone marrow transplant, improvement of lesions then death.</td></tr><tr><td>Perelygina et al.<sup>2</sup></td><td>Ataxia-telangiectasia</td><td>24 months</td><td>30 months</td><td>Skin</td><td>PCR</td><td>Cryotherapy, Erythromycin, Nitazoxanide, Imiquimod, topical tacrolimus, hydroxychloroquine, topical steroids</td><td>Yes</td><td>7 mg/kg/24 h<br/>1 year<br/>No improvement</td><td>Granuloma progression<br/>PCR + on repeated biopsies</td></tr><tr><td>Perelygina et al.<sup>2</sup></td><td>Ataxia-telangiectasia</td><td>12 and 17 months</td><td>39 months</td><td>Skin</td><td>PCR</td><td>Topical steroids, NSAIDS, Nitazoxanide</td><td>Yes</td><td>11 mg/kg/24 h<br/>5 months<br/>No improvement</td><td>Bone marrow transplant Improvement of lesions.</td></tr><tr><td>Perelygina et al.<sup>2</sup></td><td>Ataxia-telangiectasia</td><td>18 months</td><td>10 years</td><td>Skin</td><td>PCR</td><td>Abatacept<br/>Nitazoxanide</td><td>Yes</td><td>22 mg/kg/24 h<br/>Slowdown of the cutaneous progression and negative PCR control but underlying bone involvement.</td><td>Alive</td></tr><tr><td>Perelygina et al.<sup>2</sup></td><td>Congenital immunodeficiency</td><td>5 and 9 years</td><td>13 years</td><td>Skin</td><td>PCR</td><td>Linezolid, Nitazoxanide<br/>Chlorthromycin, Rifampicin, Isoniazid, Ethambutol, Voriconazole, Posaconazole, Interferon Amputation</td><td>Yes</td><td>16 mg/kg/24 h<br/>5 month<br/>No clinical improvement but virus undetectable in immunohistochemistry.</td><td>PML Death</td></tr><tr><td>Perelygina et al.<sup>2</sup></td><td>Severe combined immune deficiency</td><td>3 and 5 years</td><td>13 years</td><td>Skin and underlying bone</td><td>PCR</td><td>Nitazoxanide Cotrimoxazole, Azithromycin, Fluconazole, Amocixillin clavulanic acid, Ciprofloxacin, Surgery</td><td>Yes</td><td>25 mg/kg/24 h<br/>4 month<br/>No improvement</td><td>Alive</td></tr></tbody></table>

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<table><caption>TABLE 1 (Continued)</caption><thead><tr><th></th><th>Immune deficiency</th><th>Age of rubella vaccination</th><th>Age of granuloma onset</th><th>Chronic inflammation site</th><th>Viral diagnosis</th><th>Treatments</th><th>Intravenous immunoglobulin</th><th>Nitazoxanide efficacy</th><th>Follow-up</th></tr></thead><tbody><tr><td>Perelygina et al.<sup>2</sup></td><td>Metaphyseal chondrodysplasia</td><td>1 year</td><td>15 years</td><td>Skin, liver, kidney, larynx, palate, bone marrow</td><td>PCR</td><td>Azithromycin Azathioprine, MMF Ciclosporin and steroids</td><td>Yes</td><td>20 mg/kg/24 h<br>Improvement after 2 months of treatment, no recurrence until death.</td><td>PML Death</td></tr><tr><td>Leclerc-Mercier et al.<sup>3</sup></td><td>Ataxia-telangiectasia</td><td>NC</td><td>1 year</td><td>Skin</td><td>PCR and/or immuno-histochemistry</td><td>NC</td><td>NC</td><td>NA</td><td>NC</td></tr><tr><td>Leclerc-Mercier et al.<sup>3</sup></td><td>Ataxia-telangiectasia</td><td>NC</td><td>6 years</td><td>Skin</td><td>PCR and/or immuno-histochemistry</td><td>NC</td><td>NC</td><td>NA</td><td>NC</td></tr><tr><td>Leclerc-Mercier et al.<sup>3</sup></td><td>Severe combined immune deficiency</td><td>NC</td><td>1 year</td><td>Skin</td><td>PCR and/or immuno-histochemistry</td><td>NC</td><td>NC</td><td>NA</td><td>NC</td></tr><tr><td>Leclerc-Mercier et al.<sup>3</sup></td><td>IgG2 deficiencies</td><td>NC</td><td>1 year</td><td>Skin</td><td>PCR and/or immuno-histochemistry</td><td>NC</td><td>NC</td><td>NA</td><td>NC</td></tr><tr><td>Leclerc-Mercier et al.<sup>3</sup></td><td>Simpson-Golabi-Behmel Syndrome</td><td>NC</td><td>10 years</td><td>Skin, lymph nodes, spleen</td><td>PCR and/or immuno-histochemistry</td><td>NC</td><td>NC</td><td>NA</td><td>NC</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Nijmegen Syndrome</td><td>13 months</td><td>2 years</td><td>Skin</td><td>PCR</td><td>Antibiotics<br>Topical steroids<br>Bone marrow transplantation</td><td>None</td><td>NC</td><td>Alive after bone marrow transplantation</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Nijmegen Syndrome</td><td>16 months</td><td>14 years</td><td>Skin</td><td>PCR</td><td>Bone marrow transplantation</td><td>None</td><td>NC</td><td>Alive after bone marrow transplantation</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Nijmegen Syndrome</td><td>14 months</td><td>10 years</td><td>Skin</td><td>PCR</td><td>Antibiotics<br>Topical steroids</td><td>None</td><td>NC</td><td>Death</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Nijmegen Syndrome</td><td>13 months</td><td>NC</td><td>Skin</td><td>PCR</td><td>Permetrin, Ivermectin<br>Cefalotin<br>Minocycline<br>Topical metronidazole</td><td>None</td><td>NC</td><td>Alive</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>12 months</td><td>5 years</td><td>Skin</td><td>PCR</td><td>Antibiotics<br>Topical steroids</td><td>None</td><td>NC</td><td>Death</td></tr></tbody></table>
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th></th><th>Immune deficiency</th><th>Age of rubella vaccination</th><th>Age of granuloma onset</th><th>Chronic inflammation site</th><th>Viral diagnosis</th><th>Treatments</th><th>Intravenous immunoglobulin</th><th>Nitazoxanide efficacy</th><th>Follow-up</th></tr></thead><tbody><tr><td>Perelygina et al.<sup>2</sup></td><td>Metaphyseal chondrodysplasia</td><td>1 year</td><td>15 years</td><td>Skin, liver, kidney, larynx, palate, bone marrow</td><td>PCR</td><td>Azithromycin Azathioprine, MMF Ciclosporin and steroids</td><td>Yes</td><td>20 mg/kg/24 h Improvement after 2 months of treatment, no recurrence until death.</td><td>PML Death</td></tr><tr><td>Leclerc-Mercier et al.<sup>3</sup></td><td>Ataxia-telangiectasia</td><td>NC</td><td>1 year</td><td>Skin</td><td>PCR and/or immuno-histochemistry</td><td>NC</td><td>NC</td><td>NA</td><td>NC</td></tr><tr><td>Leclerc-Mercier et al.<sup>3</sup></td><td>Ataxia-telangiectasia</td><td>NC</td><td>6 years</td><td>Skin</td><td>PCR and/or immuno-histochemistry</td><td>NC</td><td>NC</td><td>NA</td><td>NC</td></tr><tr><td>Leclerc-Mercier et al.<sup>3</sup></td><td>Severe combined immune deficiency</td><td>NC</td><td>1 year</td><td>Skin</td><td>PCR and/or immuno-histochemistry</td><td>NC</td><td>NC</td><td>NA</td><td>NC</td></tr><tr><td>Leclerc-Mercier et al.<sup>3</sup></td><td>IgG2 deficiencies</td><td>NC</td><td>1 year</td><td>Skin</td><td>PCR and/or immuno-histochemistry</td><td>NC</td><td>NC</td><td>NA</td><td>NC</td></tr><tr><td>Leclerc-Mercier et al.<sup>3</sup></td><td>Simpson-Golabi-Behmel Syndrome</td><td>NC</td><td>10 years</td><td>Skin, lymph nodes, spleen</td><td>PCR and/or immuno-histochemistry</td><td>NC</td><td>NC</td><td>NA</td><td>NC</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Nijmegen Syndrome</td><td>13 months</td><td>2 years</td><td>Skin</td><td>PCR</td><td>Antibiotics, Topical steroids, Bone marrow transplantation</td><td>None</td><td>NC</td><td>Alive after bone marrow transplantation</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Nijmegen Syndrome</td><td>16 months</td><td>14 years</td><td>Skin</td><td>PCR</td><td>Bone marrow transplantation</td><td>None</td><td>NC</td><td>Alive after bone marrow transplantation</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Nijmegen Syndrome</td><td>14 months</td><td>10 years</td><td>Skin</td><td>PCR</td><td>Antibiotics, Topical steroids</td><td>None</td><td>NC</td><td>Death</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Nijmegen Syndrome</td><td>13 months</td><td>NC</td><td>Skin</td><td>PCR</td><td>Permetrin, Ivermectin, Cefalotin, Minocycline, Topical metronidazole</td><td>None</td><td>NC</td><td>Alive</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>12 months</td><td>5 years</td><td>Skin</td><td>PCR</td><td>Antibiotics, Topical steroids</td><td>None</td><td>NC</td><td>Death</td></tr></tbody></table>
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th></th><th>Immune deficiency</th><th>Age of rubella vaccination</th><th>Age of granuloma onset</th><th>Chronic inflammation site</th><th>Viral diagnosis</th><th>Treatments</th><th>Intravenous immunoglobulin</th><th>Nitazoxanide efficacy</th><th>Follow-up</th></tr></thead><tbody><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>16 months</td><td>9 years</td><td>Skin</td><td>PCR</td><td>Nitazoxanide</td><td>Yes</td><td>NC</td><td>Alive</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>13 months</td><td>2 years</td><td>Skin</td><td>NC</td><td>Interferon α</td><td>Yes</td><td>NC</td><td>Alive</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>13 months</td><td>3 years</td><td>Skin</td><td>PCR and immuno-histochemistry</td><td>Nitazoxanide</td><td>None</td><td>NC</td><td>Alive after bone marrow transplantation</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>NC</td><td>NC</td><td>Skin</td><td>immuno-histochemistry</td><td>Antibiotics<br/>Topical steroids</td><td>None</td><td>NC</td><td>Death</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>12 months</td><td>NC</td><td>Skin</td><td>immuno-histochemistry</td><td>Topical steroids<br/>Nutrition</td><td>None</td><td>NC</td><td>Death</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>NC</td><td>NC</td><td>Skin</td><td>immuno-histochemistry</td><td>Topical steroids and steroids</td><td>None</td><td>NC</td><td>Death</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>NC</td><td>4 years</td><td>Skin</td><td>immuno-histochemistry</td><td>Surgery, emollients<br/>Topical steroids<br/>Etanercept<br/>Nitazoxanide</td><td>None</td><td>NC</td><td>Alive</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>NC</td><td>NC</td><td>Skin</td><td>Immunohistochimie</td><td>Topical steroids and steroids</td><td>None</td><td>NC</td><td>Alive</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Severe combined immunodeficiency due to DCLRE1C deficiency</td><td>12 months</td><td>7 years</td><td>Skin</td><td>Immunohistochimie</td><td>Cotrimoxazole<br/>Topical steroids<br/>Bone marrow transplantation</td><td>Yes</td><td>NC</td><td>Alive after bone marrow transplantation</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>LIG4 Syndrome</td><td>12 months</td><td>14 months</td><td>Skin</td><td>Immunohistochimie</td><td>Nitazoxanide<br/>Topical steroids<br/>Bone marrow transplantation</td><td>Yes</td><td>No improvement</td><td>Death after bone marrow transplantation</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Caltillage-Hair Hypoplasia</td><td>18 years</td><td>27 years</td><td>Skin</td><td>PCR</td><td>Ciclosporin<br/>Steroids</td><td>None</td><td>NC</td><td>Progressive disease</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>MHC class II deficiency</td><td>9 months</td><td>2 years</td><td>Skin</td><td>PCR</td><td>none</td><td>None</td><td>NC</td><td>Alive after bone marrow transplantation and improvement</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>WHIM Syndrome</td><td>NC</td><td>16 years</td><td>Skin</td><td>PCR</td><td>Topical Steroids<br/>Anti-TNF</td><td>None</td><td>NC</td><td>Stable</td></tr></tbody></table>

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<table><caption>TABLE 1 (Continued)</caption><thead><tr><th></th><th>Immune deficiency</th><th>Age of rubella vaccination</th><th>Age of granuloma onset</th><th>Chronic inflammation site</th><th>Viral diagnosis</th><th>Treatments</th><th>Intravenous immunoglobulin</th><th>Nitazoxanide efficacy</th><th>Follow-up</th></tr></thead><tbody><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>16 months</td><td>9 years</td><td>Skin</td><td>PCR</td><td>Nitazoxanide</td><td>Yes</td><td>NC</td><td>Alive</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>13 months</td><td>2 years</td><td>Skin</td><td>NC</td><td>Interferon α</td><td>Yes</td><td>NC</td><td>Alive</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>13 months</td><td>3 years</td><td>Skin</td><td>PCR and immuno-histochemistry</td><td>Nitazoxanide</td><td>None</td><td>NC</td><td>Alive after bone marrow transplantation</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>NC</td><td>NC</td><td>Skin</td><td>immuno-histochemistry</td><td>Antibiotics<br/>Topical steroids</td><td>None</td><td>NC</td><td>Death</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>12 months</td><td>NC</td><td>Skin</td><td>immuno-histochemistry</td><td>Topical steroids<br/>Nutrition</td><td>None</td><td>NC</td><td>Death</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>NC</td><td>NC</td><td>Skin</td><td>immuno-histochemistry</td><td>Topical steroids and steroids</td><td>None</td><td>NC</td><td>Death</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>NC</td><td>4 years</td><td>Skin</td><td>immuno-histochemistry</td><td>Surgery, emollients<br/>Topical steroids<br/>Etanercept<br/>Nitazoxanide</td><td>None</td><td>NC</td><td>Alive</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Ataxia-telangiectasia</td><td>NC</td><td>NC</td><td>Skin</td><td>Immunohistochimie</td><td>Topical steroids and steroids</td><td>None</td><td>NC</td><td>Alive</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Severe combined immunodeficiency due to DCLRE1C deficiency</td><td>12 months</td><td>7 years</td><td>Skin</td><td>Immunohistochimie</td><td>Cotrimoxazole<br/>Topical steroids<br/>Bone marrow transplantation</td><td>Yes</td><td>NC</td><td>Alive after bone marrow transplantation</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>LIG4 Syndrome</td><td>12 months</td><td>14 months</td><td>Skin</td><td>Immunohistochimie</td><td>Nitazoxanide<br/>Topical steroids<br/>Bone marrow transplantation</td><td>Yes</td><td>No improvement</td><td>Death after bone marrow transplantation</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Caltillage-Hair Hypoplasia</td><td>18 years</td><td>27 years</td><td>Skin</td><td>PCR</td><td>Ciclosporin<br/>Steroids</td><td>None</td><td>NC</td><td>Progressive disease</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>MHC class II deficiency</td><td>9 months</td><td>2 years</td><td>Skin</td><td>PCR</td><td>none</td><td>None</td><td>NC</td><td>Alive after bone marrow transplantation and improvement</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>WHIM Syndrome</td><td>NC</td><td>16 years</td><td>Skin</td><td>PCR</td><td>Topical Steroids<br/>Anti-TNF</td><td>None</td><td>NC</td><td>Stable</td></tr></tbody></table>

(Continues)
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th></th><th>Immune deficiency</th><th>Age of rubella vaccination</th><th>Age of granuloma onset</th><th>Chronic inflammation site</th><th>Viral diagnosis</th><th>Treatments</th><th>Intravenous immunoglobulin</th><th>Nitazoxanide efficacy</th><th>Follow-up</th></tr></thead><tbody><tr><td>Buchbinder et al.<sup>4</sup></td><td>Severe combined immune deficiency CORO 1</td><td>NC</td><td>13 years</td><td>Skin</td><td>PCR</td><td>Antibiotics. Topical steroids Surgery</td><td>None</td><td>NC</td><td>Stable</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>X-linked severe combined immunodeficiency</td><td>2 years</td><td>10 years</td><td>Skin</td><td>Immunohistochimie</td><td>None</td><td>Yes</td><td>NC</td><td>Stable</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Combined immune deficiency</td><td>12 months</td><td>12 years</td><td>Skin</td><td>PCR</td><td>Chloroquine<br/>Chlaritromycin<br/>Doxycycline<br/>Ciprofloxacin<br/>Nitazoxanide<br/>Topical steroids Tacrolimus<br/>Steroids<br/>Methotrexate<br/>Bone marrow transplant</td><td>None</td><td>Improvement</td><td>Alive after bone marrow transplantation and improvement</td></tr><tr><td>Dhossche et al.<sup>5</sup></td><td>Nijmegen Syndrome</td><td>1 and 5 years</td><td>10 years</td><td>Skin</td><td>PCR et immunohistochimie</td><td>None</td><td>NC</td><td>NC</td><td>Alive, without treatment</td></tr><tr><td>Dhossche et al.<sup>5</sup></td><td>NOD mutation</td><td>12 months</td><td>18 months</td><td>Skin</td><td>Immunohistochimie</td><td>NC</td><td>NC</td><td>NC</td><td>Alive</td></tr><tr><td>Shields et al.<sup>12</sup></td><td>Common variable immunodeficiency</td><td>Unvaccinated</td><td>61 years</td><td>Skin</td><td>PCR</td><td>Hydroxychloroquine, minocycline, doxycycline, oral corticosteroids, and methotrexate<br/>Ribavirine</td><td>Yes</td><td>Improvement</td><td>NC</td></tr><tr><td>Wanat et al.<sup>7</sup></td><td>NC</td><td>43 years</td><td>45 years</td><td>Skin (upper left arm)</td><td>PCR</td><td>Methotrexate, bexarotene, hydroxychloroquine, topical imiquimod</td><td>None</td><td>NC</td><td>NC</td></tr><tr><td>Wanat et al.<sup>7</sup></td><td>NC</td><td>38 years</td><td>45 years</td><td>Skin (upper left arm)</td><td>PCR</td><td>Hydroxychloroquine</td><td>None</td><td>NC</td><td>NC</td></tr><tr><td>Wanat et al.<sup>7</sup></td><td>NC</td><td>42 years</td><td>55 years</td><td>Skin (upper left arm)</td><td>PCR</td><td>Surgical excision, intralesional triamcinolone and hydroxychloroquine</td><td>None</td><td>NC</td><td>NC</td></tr><tr><td>Wanat et al.<sup>7</sup></td><td>NC</td><td>Unvaccinated</td><td>56 years</td><td>Skin (upper left arm)</td><td>PCR</td><td>Minocycline and hydroxychloroquine</td><td>None</td><td>NC</td><td>NC</td></tr></tbody></table>
<table><caption>TABLE 1 (Continued)</caption><thead><tr><th></th><th>Immune deficiency</th><th>Age of rubella vaccination</th><th>Age of granuloma onset</th><th>Chronic inflammation site</th><th>Viral diagnosis</th><th>Treatments</th><th>Intravenous immunoglobulin</th><th>Nitazoxanide efficacy</th><th>Follow-up</th></tr></thead><tbody><tr><td>Buchbinder et al.<sup>4</sup></td><td>Severe combined immune deficiency CORO 1</td><td>NC</td><td>13 years</td><td>Skin</td><td>PCR</td><td>Antibiotics. Topical steroids Surgery</td><td>None</td><td>NC</td><td>Stable</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>X-linked severe combined immunodeficiency</td><td>2 years</td><td>10 years</td><td>Skin</td><td>Immunohistochimie</td><td>None</td><td>Yes</td><td>NC</td><td>Stable</td></tr><tr><td>Buchbinder et al.<sup>4</sup></td><td>Combined immune deficiency</td><td>12 months</td><td>12 years</td><td>Skin</td><td>PCR</td><td>Chloroquine<br/>Chlaritromycin<br/>Doxycycline<br/>Ciprofloxacin<br/>Nitazoxanide<br/>Topical steroids Tacrolimus<br/>Steroids<br/>Methotrexate<br/>Bone marrow transplant</td><td>None</td><td>Improvement</td><td>Alive after bone marrow transplantation and improvement</td></tr><tr><td>Dhossche et al.<sup>5</sup></td><td>Nijmegen Syndrome</td><td>1 and 5 years</td><td>10 years</td><td>Skin</td><td>PCR et immunohistochimie</td><td>None</td><td>NC</td><td>NC</td><td>Alive, without treatment</td></tr><tr><td>Dhossche et al.<sup>5</sup></td><td>NOD mutation</td><td>12 months</td><td>18 months</td><td>Skin</td><td>Immunohistochimie</td><td>NC</td><td>NC</td><td>NC</td><td>Alive</td></tr><tr><td>Shields et al.<sup>12</sup></td><td>Common variable immunodeficiency</td><td>Unvaccinated</td><td>61 years</td><td>Skin</td><td>PCR</td><td>Hydroxychloroquine, minocycline, doxycycline, oral corticosteroids, and methotrexate<br/>Ribavirine</td><td>Yes</td><td>Improvement</td><td>NC</td></tr><tr><td>Wanat et al.<sup>7</sup></td><td>NC</td><td>43 years</td><td>45 years</td><td>Skin (upper left arm)</td><td>PCR</td><td>Methotrexate, bexarotene, hydroxychloroquine, topical imiquimod</td><td>None</td><td>NC</td><td>NC</td></tr><tr><td>Wanat et al.<sup>7</sup></td><td>NC</td><td>38 years</td><td>45 years</td><td>Skin (upper left arm)</td><td>PCR</td><td>Hydroxychloroquine</td><td>None</td><td>NC</td><td>NC</td></tr><tr><td>Wanat et al.<sup>7</sup></td><td>NC</td><td>42 years</td><td>55 years</td><td>Skin (upper left arm)</td><td>PCR</td><td>Surgical excision, intralesional triamcinolone and hydroxychloroquine</td><td>None</td><td>NC</td><td>NC</td></tr><tr><td>Wanat et al.<sup>7</sup></td><td>NC</td><td>Unvaccinated</td><td>56 years</td><td>Skin (upper left arm)</td><td>PCR</td><td>Minocycline and hydroxychloroquine</td><td>None</td><td>NC</td><td>NC</td></tr></tbody></table>
time, mendelian susceptibility to rubella infection, due to ITK deficiency, in a patient without overt immunodeficiency.

## AUTHOR CONTRIBUTIONS

Caroline Bouvarel followed the patient, obtained the patient's consent, and wrote the manuscript. Léa Luciani performed the virological laboratory experiments and wrote the manuscript. Valérie Delargue and Christine Zandotti carried out the patient's genetic analysis. Simon Sunder, Carine Motard and Ingrid Kupfer-Bessaguet followed the patient and corrected the manuscript. Antoine Nougairède, Christine Zandotti and Xavier de Lamballerie corrected the manuscript and provided virological expertise. Caroline-Jade Clerc and Sebastien Barbarot corrected the manuscript and provided dermatological expertise.

## ACKNOWLEDGEMENTS

We are grateful to the Genomics and Bioinformatics Core Facility from U1251/Marseille Medical Genetics (Marseille, France).

## CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

## DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

## ETHICS STATEMENT

All patients in this manuscript have given written informed consent for participation in the study and the use of their deidentified, anonymized, aggregated data and their case details (including photographs) for publication. Ethical Approval: not applicable.

## ORCID

Caroline Bouvarel ID http://orcid.org/0000-0001-5879-8885

Sebastien Barbarot ID http://orcid.org/0000-0002-6629-9100

## REFERENCES

1. Bodemer C, Sauvage V, Mahlaoui N, Cheval J, Couderc T, Leclerc-Mercier S, et al. Live rubella virus vaccine long-term persistence as an antigenic trigger of cutaneous granulomas in patients with primary immunodeficiency. Clin Microbiol Infect. 2014;20: O656-63. https://doi.org/10.1111/1469-0691.12573

2. Perelygina L, Buchbinder D, Dorsey MJ, Eloit M, Hauck F, Hautala T, et al. Outcomes for nitazoxanide treatment in a case series of patients with primary immunodeficiencies and rubella virus-sssociated granuloma. J Clin Immunol. 2019;39: 112-7. https://doi.org/10.1007/s10875-019-0589-0

3. Leclerc-Mercier S, Moshous D, Neven B, Mahlaoui N, Martin L, Pellier I, et al. Cutaneous granulomas with primary immunodeficiency in children: a report of 17 new patients and a review of the literature. J Eur Acad Dermatol Venereol. 2019;33:1412-20. https://doi.org/10.1111/jdv.15568

4. Buchbinder D, Hauck F, Albert MH, Rack A, Bakhtiar S, Shcherbina A, et al. Rubella virus-associated cutaneous granulomatous disease: a unique complication in immune-deficient patients, not limited to DNA repair disorders. J Clin Immunol. 2019;39:81-9. https://doi.org/10.1007/s10875-018-0581-0

5. Dhossche J, Johnson L, White K, Funk T, Leitenberger S, Perelygina L, et al. Cutaneous granulomatous disease with presence of rubella virus in lesions. JAMA Dermatol. 2019;155: 859-61. https://doi.org/10.1001/jamadermatol.2019.0814

6. Papania MJ, Wallace GS, Rota PA, Icenogle JP, Fiebelkorn AP, Armstrong GL, et al. Elimination of endemic measles, rubella, and congenital rubella syndrome from the Western hemisphere: the US experience. JAMA Pediatrics. 2014;168:148-55. https://doi.org/10.1001/jamapediatrics.2013.4342

7. Wanat KA, Perelygina L, Chen M, Hao L, Abernathy E, Bender NR, et al. Association of persistent rubella virus with idiopathic skin granulomas in clinically immunocompetent adults. JAMA Dermatol. 2022;158:626-33. https://doi.org/10.1001/jamadermatol.2022.0828

8. Perelygina L, Hautala T, Seppänen M, Adebayo A, Sullivan KE, Icenogle J. Inhibition of rubella virus replication by the broad-spectrum drug nitazoxanide in cell culture and in a patient with a primary immune deficiency. Antiviral Res. 2017;147:58-66. https://doi.org/10.1016/j.antiviral.2017.09.019

9. Ghosh S, Bienemann K, Boztug K, Borkhardt A. Interleukin-2-inducible T-cell kinase (ITK) deficiency—clinical and molecular aspects. J Clin Immunol. 2014;34:892-9. https://doi.org/10.1007/s10875-014-0110-8

10. Ogishi M, Yang R, Rodriguez R, Golec DP, Martin E, Philippot Q, et al. Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis. J Exp Med. 2023;220:e20220484. https://doi.org/10.1084/jem.20220484

11. Perelygina L, Icenogle J, Sullivan KE. Rubella virus-associated chronic inflammation in primary immunodeficiency diseases. Cur Opin Allergy Clin Immunol. 2020;20:574-81. https://doi.org/10.1097/ACI.0000000000000694

12. Shields BE, Perelygina L, Samimi S, Haun P, Leung T, Abernathy E, et al. Granulomatous dermatitis associated with rubella virus infection in an adult with immunodeficiency. JAMA Dermatol. 2021;157:842-7. https://doi.org/10.1001/jamadermatol.2021.1577

13. Perelygina L, Plotkin S, Russo P, Hautala T, Bonilla F, Ochs HD, et al. Rubella persistence in epidermal keratinocytes and granuloma M2 macrophages in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2016;138: 1436-1439.e11. https://doi.org/10.1016/j.jaci.2016.06.030

14. Bender NR, Cardwell LA, Siegel D, Sokumbi O. Rubella vaccine persistence within cutaneous granulomas in common variable immunodeficiency disorder. Am J Dermatopathol. 2020;42:455-7. https://doi.org/10.1097/DAD.0000000000001598
time, mendelian susceptibility to rubella infection, due to ITK deficiency, in a patient without overt immunodeficiency.

## AUTHOR CONTRIBUTIONS

Caroline Bouvarel followed the patient, obtained the patient's consent, and wrote the manuscript. Léa Luciani performed the virological laboratory experiments and wrote the manuscript. Valérie Delargue and Christine Zandotti carried out the patient's genetic analysis. Simon Sunder, Carine Motard and Ingrid Kupfer-Bessaguet followed the patient and corrected the manuscript. Antoine Nougairède, Christine Zandotti and Xavier de Lamballerie corrected the manuscript and provided virological expertise. Caroline-Jade Clerc and Sebastien Barbarot corrected the manuscript and provided dermatological expertise.

## ACKNOWLEDGEMENTS

We are grateful to the Genomics and Bioinformatics Core Facility from U1251/Marseille Medical Genetics (Marseille, France).

## CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

## DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.

## ETHICS STATEMENT

All patients in this manuscript have given written informed consent for participation in the study and the use of their deidentified, anonymized, aggregated data and their case details (including photographs) for publication. Ethical Approval: not applicable.

## ORCID

Caroline Bouvarel ID http://orcid.org/0000-0001-5879-8885

Sebastien Barbarot ID http://orcid.org/0000-0002-6629-9100

## REFERENCES

1. Bodemer C, Sauvage V, Mahlaoui N, Cheval J, Couderc T, Leclerc-Mercier S, et al. Live rubella virus vaccine long-term persistence as an antigenic trigger of cutaneous granulomas in patients with primary immunodeficiency. Clin Microbiol Infect. 2014;20: O656-63. https://doi.org/10.1111/1469-0691.12573

2. Perelygina L, Buchbinder D, Dorsey MJ, Eloit M, Hauck F, Hautala T, et al. Outcomes for nitazoxanide treatment in a case series of patients with primary immunodeficiencies and rubella virus-sssociated granuloma. J Clin Immunol. 2019;39: 112-7. https://doi.org/10.1007/s10875-019-0589-0

3. Leclerc-Mercier S, Moshous D, Neven B, Mahlaoui N, Martin L, Pellier I, et al. Cutaneous granulomas with primary immunodeficiency in children: a report of 17 new patients and a review of the literature. J Eur Acad Dermatol Venereol. 2019;33:1412-20. https://doi.org/10.1111/jdv.15568

4. Buchbinder D, Hauck F, Albert MH, Rack A, Bakhtiar S, Shcherbina A, et al. Rubella virus-associated cutaneous granulomatous disease: a unique complication in immune-deficient patients, not limited to DNA repair disorders. J Clin Immunol. 2019;39:81-9. https://doi.org/10.1007/s10875-018-0581-0

5. Dhossche J, Johnson L, White K, Funk T, Leitenberger S, Perelygina L, et al. Cutaneous granulomatous disease with presence of rubella virus in lesions. JAMA Dermatol. 2019;155: 859-61. https://doi.org/10.1001/jamadermatol.2019.0814

6. Papania MJ, Wallace GS, Rota PA, Icenogle JP, Fiebelkorn AP, Armstrong GL, et al. Elimination of endemic measles, rubella, and congenital rubella syndrome from the Western hemisphere: the US experience. JAMA Pediatrics. 2014;168:148-55. https://doi.org/10.1001/jamapediatrics.2013.4342

7. Wanat KA, Perelygina L, Chen M, Hao L, Abernathy E, Bender NR, et al. Association of persistent rubella virus with idiopathic skin granulomas in clinically immunocompetent adults. JAMA Dermatol. 2022;158:626-33. https://doi.org/10.1001/jamadermatol.2022.0828

8. Perelygina L, Hautala T, Seppänen M, Adebayo A, Sullivan KE, Icenogle J. Inhibition of rubella virus replication by the broad-spectrum drug nitazoxanide in cell culture and in a patient with a primary immune deficiency. Antiviral Res. 2017;147:58-66. https://doi.org/10.1016/j.antiviral.2017.09.019

9. Ghosh S, Bienemann K, Boztug K, Borkhardt A. Interleukin-2-inducible T-cell kinase (ITK) deficiency—clinical and molecular aspects. J Clin Immunol. 2014;34:892-9. https://doi.org/10.1007/s10875-014-0110-8

10. Ogishi M, Yang R, Rodriguez R, Golec DP, Martin E, Philippot Q, et al. Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis. J Exp Med. 2023;220:e20220484. https://doi.org/10.1084/jem.20220484

11. Perelygina L, Icenogle J, Sullivan KE. Rubella virus-associated chronic inflammation in primary immunodeficiency diseases. Cur Opin Allergy Clin Immunol. 2020;20:574-81. https://doi.org/10.1097/ACI.0000000000000694

12. Shields BE, Perelygina L, Samimi S, Haun P, Leung T, Abernathy E, et al. Granulomatous dermatitis associated with rubella virus infection in an adult with immunodeficiency. JAMA Dermatol. 2021;157:842-7. https://doi.org/10.1001/jamadermatol.2021.1577

13. Perelygina L, Plotkin S, Russo P, Hautala T, Bonilla F, Ochs HD, et al. Rubella persistence in epidermal keratinocytes and granuloma M2 macrophages in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2016;138: 1436-1439.e11. https://doi.org/10.1016/j.jaci.2016.06.030

14. Bender NR, Cardwell LA, Siegel D, Sokumbi O. Rubella vaccine persistence within cutaneous granulomas in common variable immunodeficiency disorder. Am J Dermatopathol. 2020;42:455-7. https://doi.org/10.1097/DAD.0000000000001598
15. Abernathy E, Chen M, Bera J, Shrivastava S, Kirkness E, Zheng Q, et al. Analysis of whole genome sequences of 16 strains of rubella virus from the United States, 1961–2009. Virol J. 2013;10:32. https://doi.org/10.1186/1743-422X-10-32

## SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

**How to cite this article:** Bouvarel C, Luciani L, Sunder S, Motard C, Barbarot S, Nougairède A, et al. A case of chronic granuloma related to wild-type strain of rubella virus in an adult patient with ITK deficiency without primary immunosuppression and review of the literature. JEADV Clin Pract. 2024;3:283–292. https://doi.org/10.1002/jvc2.268
15. Abernathy E, Chen M, Bera J, Shrivastava S, Kirkness E, Zheng Q, et al. Analysis of whole genome sequences of 16 strains of rubella virus from the United States, 1961–2009. Virol J. 2013;10:32. https://doi.org/10.1186/1743-422X-10-32

## SUPPORTING INFORMATION

Additional supporting information can be found online in the Supporting Information section at the end of this article.

**How to cite this article:** Bouvarel C, Luciani L, Sunder S, Motard C, Barbarot S, Nougairède A, et al. A case of chronic granuloma related to wild-type strain of rubella virus in an adult patient with ITK deficiency without primary immunosuppression and review of the literature. JEADV Clin Pract. 2024;3:283–292. https://doi.org/10.1002/jvc2.268