*3.2.4 Primary immunodeficiency*

As in severely immunosuppressed patients (transplant patients, advanced HIV, etc.), cases of primary immunodeficiencies and systemic

**163**

**4. Diagnostic approach**

*Granulomatous Diseases Mimicking Sarcoidosis DOI: http://dx.doi.org/10.5772/intechopen.92233*

*3.2.5 Interstitial granulomatous dermatitis*

infections, may appear.

prognosis.

sepsis [8].

granulomatous complications, either primary or following opportunistic

Common variable immunodeficiency comprises a heterogeneous group of diseases characterized by a significant hypogammaglobulinemia of unknown cause, failure to produce specific antibodies after immunization, and susceptibility to bacterial infections, but others develop complications, like granulomas or autoimmune diseases. Sarcoid-like granulomas are also well described in the liver, spleen, and lung in patients with common variable immunodeficiency [8]. This involvement is usually associated with other autoimmune manifestations and has a worse

Chronic granulomatous disease is a rare primary immunodeficiency caused by an inherited defect in the genes encoding any of the NADPH oxidase components responsible for the respiratory burst of phagocytic leukocytes. The NADPH oxidase is responsible for the production of reactive oxygen species (ROS) in the activated phagocyte ("respiratory burst"). When present, mutations on the NAPDH oxidase genes do not allow ROS production, making the neutrophils of these patients incapable of destroying pathogens. These patients are especially susceptible to infections by staphylococcus, fungi and some gram-negative bacteria. The main clinical manifestations include recurrent life-threatening episodes of lymphadenitis, abscess, pneumonias, osteomyelitis, granuloma formation, and

It is important to recognize interstitial granulomatous dermatitis, because although it can sometimes occur as an isolated skin disease, it is often associated with a systemic disease, which marks the prognosis of the patient; thus an active study should be carried out [4]. Ackerman first described this rare type of dermatitis in 1993. Although the original manifestation has been described as subcutaneous linear nodules (also known as rope sign), later reports showed a quite heterogeneous clinical spectrum ranging from hyperpigmented, erythematous papules, subcutaneous plaques, and annular lesions to firm red purplish nodules. The lesions are usually asymptomatic, but can be slightly pruritic or painful. The histopathological examination confirms the diagnosis and is characterized by a dense and diffuse interstitial infiltrate in the reticular dermis, composed of histiocytes in a palisade arrangement, sometimes with necrobiosis of collagen and neutrophils and eosinophils. Interstitial granulomatous dermatitis has been associated with various systemic diseases, including autoimmune diseases such as rheumatoid arthritis (the most common), systemic sclerosis, or lupus erythematosus. Recently, a case has been reported in association with primary biliary cholangitis. However, other etiologies have been described in isolated cases including malignancy or drugs (angiotensin-converting enzyme inhibitors, calcium channel

blockers, beta blockers, diuretics, TNF-α blockers, etc.) [1, 4].

granulomas with potentially serious diseases (**Table 3**).

The diagnostic approach must be structured, and the analytical, microbiological, or radiological tests must be adapted to the epidemiological factors of the patient's clinical history, as well as to the results of the physical examination. Obtaining a biopsy, both for histological and microbiological studies, is fundamental. In cases of uncertain etiology, close monitoring should be carried out, given the association of

#### *Granulomatous Diseases Mimicking Sarcoidosis DOI: http://dx.doi.org/10.5772/intechopen.92233*

*Sarcoidosis and Granulomatosis - Diagnosis and Management*

*3.2.1 Chronic gastrointestinal and chronic biliary diseases*

involving the hepatobiliary tree by the disease.

*3.2.2 Vasculitis and collagen vascular diseases*

granulomas [6].

non-necrotizing.

allergic angiitis.

*3.2.3 Adverse drug reaction*

suggests drug-associated liver injury [7].

*3.2.4 Primary immunodeficiency*

addressed in this chapter. Not all immune-mediated systemic processes should be assimilated as diseases capable of producing granulomas. For example, in the disease related to IgG4, although cases of pulmonary lymphomatoid granulomatosis associated with it have been described, two findings are extraordinary and practically discard it, namely, the presence of granulomas and the presence of a neutrophilic infiltrate [4, 5]. In this same sense we must refer to the diseases included in the so-called xanthogranulomatous diseases (Langerhans cell histiocytosis, Erdheim-Chester disease, Rosai-Dorfman disease, hemophagocytic lymphohistiocytosis, and juvenile xanthogranuloma) where space-occupying lesions can be seen in imaging techniques and a histiocytic infiltrate in biopsies, but rarely

Granulomas have been reported in a small minority of patients with ulcerative colitis, Crohn's disease, and idiopathic eosinophilic gastroenteritis. It is unclear whether the granulomas associated with chronic idiopathic inflammatory bowel disease could be due to diseases such as primary sclerosing cholangitis or an adverse drug reaction. Granulomas may also be a feature of idiopathic eosinophilic enteritis

Granulomas are reported very frequently (more than 50% in many series) in primary biliary cirrhosis cases. They may be portal or lobular, but are often associated with duct lesions. However, granulomas are also seen in a minority of cases in primary sclerosing cholangitis, in which they are usually well formed and

Granulomas may involve the vasculature in collagen vascular diseases, like lupus erythematosus systemic, or more usually in vasculitic diseases including systemic necrotizing vasculitis and giant cell arteritis. Systemic necrotizing vasculitis is a group of heterogeneous diseases characterized clinically by a greater presentation and histologically by the presence of fibrinoid necrosis more intense than that seen in in other forms of vasculitis. Panarteritis nodosa is a vasculitis that characteristically affects the arteries of medium and small sizes. Vasculitis associated with antineutrophil cytoplasmic antibodies include granulomatosis accompanied by polyangiitis, microscopic polyarteritis, and granulomatous

After the skin, the liver is a frequent focus of granulomas secondary to drugs. Granulomas associated with adverse drug reactions may be well or poorly formed,

associated inflammatory infiltrate that may include lymphocytes, plasma cells, and eosinophils. There may be associated duct and/or vascular injury. The combination of granulomatous inflammation with significant hepatocellular injury strongly

but necrosis is very rare. Giant cells may be present, and there is a variable

As in severely immunosuppressed patients (transplant patients, advanced HIV, etc.), cases of primary immunodeficiencies and systemic

**162**

granulomatous complications, either primary or following opportunistic infections, may appear.

Common variable immunodeficiency comprises a heterogeneous group of diseases characterized by a significant hypogammaglobulinemia of unknown cause, failure to produce specific antibodies after immunization, and susceptibility to bacterial infections, but others develop complications, like granulomas or autoimmune diseases. Sarcoid-like granulomas are also well described in the liver, spleen, and lung in patients with common variable immunodeficiency [8]. This involvement is usually associated with other autoimmune manifestations and has a worse prognosis.

Chronic granulomatous disease is a rare primary immunodeficiency caused by an inherited defect in the genes encoding any of the NADPH oxidase components responsible for the respiratory burst of phagocytic leukocytes. The NADPH oxidase is responsible for the production of reactive oxygen species (ROS) in the activated phagocyte ("respiratory burst"). When present, mutations on the NAPDH oxidase genes do not allow ROS production, making the neutrophils of these patients incapable of destroying pathogens. These patients are especially susceptible to infections by staphylococcus, fungi and some gram-negative bacteria. The main clinical manifestations include recurrent life-threatening episodes of lymphadenitis, abscess, pneumonias, osteomyelitis, granuloma formation, and sepsis [8].

### *3.2.5 Interstitial granulomatous dermatitis*

It is important to recognize interstitial granulomatous dermatitis, because although it can sometimes occur as an isolated skin disease, it is often associated with a systemic disease, which marks the prognosis of the patient; thus an active study should be carried out [4]. Ackerman first described this rare type of dermatitis in 1993. Although the original manifestation has been described as subcutaneous linear nodules (also known as rope sign), later reports showed a quite heterogeneous clinical spectrum ranging from hyperpigmented, erythematous papules, subcutaneous plaques, and annular lesions to firm red purplish nodules. The lesions are usually asymptomatic, but can be slightly pruritic or painful. The histopathological examination confirms the diagnosis and is characterized by a dense and diffuse interstitial infiltrate in the reticular dermis, composed of histiocytes in a palisade arrangement, sometimes with necrobiosis of collagen and neutrophils and eosinophils. Interstitial granulomatous dermatitis has been associated with various systemic diseases, including autoimmune diseases such as rheumatoid arthritis (the most common), systemic sclerosis, or lupus erythematosus. Recently, a case has been reported in association with primary biliary cholangitis. However, other etiologies have been described in isolated cases including malignancy or drugs (angiotensin-converting enzyme inhibitors, calcium channel blockers, beta blockers, diuretics, TNF-α blockers, etc.) [1, 4].

### **4. Diagnostic approach**

The diagnostic approach must be structured, and the analytical, microbiological, or radiological tests must be adapted to the epidemiological factors of the patient's clinical history, as well as to the results of the physical examination. Obtaining a biopsy, both for histological and microbiological studies, is fundamental. In cases of uncertain etiology, close monitoring should be carried out, given the association of granulomas with potentially serious diseases (**Table 3**).

```
Medical history
```

Physical examination: Clinical sign-associated diseases

Biopsy (depending on the affected organ and accessibility)

	- ◯ Culture (bacteria, mycobacteria)
	- ◯ PCR (mycobacteria, parasites, etc.)

Laboratory testing


Mantoux or interferon gamma release assays for TB

Radiological tests


#### **Table 3.**

*Diagnostic approach to granulomatous diseases.*
