When sarcoidosis mimics immunodeficiency

Abstract

Sarcoidosis is a granulomatous disease with a wide spectrum of clinical manifestations. A 28-year-old previously healthy woman presented with multifocal pneumonia, mediastinal lymphadenopathy which was thought to be caused by actinomyces infection. Despite antibiotics, she developed cavitary lung lesions and had worsening lymphadenopathy prompting evaluation for alternative aetiologies like malignancy, autoimmune or immunodeficiency disorders. Further workup also revealed low CD4, CD8 cell counts, elevated soluble interleukin-2 levels. Over the due course of time, she developed granulomatous pan-uveitis, classical skin lesions leading to the diagnosis of sarcoidosis. Our case highlights the rare manifestations of sarcoidosis which can mimic immunodeficiency disorders especially when these patients develop secondary infections. Our goal is to raise awareness among clinicians about these atypical presentations of sarcoidosis which can lead to substantial delay in diagnosis thus leading to progression of the disease in the absence of appropriate treatment.

Background

Sarcoidosis is a systemic granulomatous inflammatory disorder of unknown aetiology primarily affecting lungs but can virtually affect any organ in the body. It typically presents in third or fourth decades of life.¹ It is a diagnosis of exclusion after ruling out other granulomatous diseases like mycobacterial and fungal infections, malignancies especially lymphomas and immunodeficiency disorders like common variable immunodeficiency (CVID) and chronic granulomatous diseases (CGDs) which can have a similar presentation.² As a clinician it is crucial to consider sarcoidosis earlier in the disease course when patients present with symptoms of immunodeficiency disorder as it will significantly change the management approach.

Case presentation

A 28-year-old African American woman with no significant comorbidities presented to emergency room with chest pain, shortness of breath and low-grade fever. Chest radiography revealed multifocal pneumonia. She was discharged home with 1 week of oral antibiotics for community acquired pneumonia.

She was readmitted 1 month later with similar complaints. She did not have any current or previous history of arthralgias, muscle weakness, weight loss, oral or nasal ulceration or sicca symptoms. On initial evaluation, her vital signs were reported within normal limits. On auscultation, inspiratory crackles were heard in mid and lower lung fields bilaterally. Skin examination was notable for macular erythematous rash on eyelids, nose, cheeks and scaly plaques on neck, chest, buttocks.

Investigations

Laboratory studies revealed mild eosinophilia and lymphopaenia with normal white cell count (table 1). Other cell counts, renal and liver function tests were within normal range. Skin biopsy demonstrated perivascular dermatitis with scattered eosinophils and she received topical steroids for possible atopic dermatitis.

Table 1.

Relevant laboratory workup

Test	Results	Reference range
White cell count	7400	4800–10 800/μL
Eosinophils	400	100–300/μL
Lymphocytes	800	1000–4800/μL
CD3	37	65–80 cells/μL
CD4	219	677–1401 cells/μL
CD8	73	212–1007 cells/μL
CD4/CD8	3.01	>0.9
CD19	248	180–492 cells/μL
CD16 +56	256	97–421 cells/μL
ACE	>80	<50 U/L
Lysozyme level	26.2	5.0–11.0 μg/mL
IL-2 receptor (CD25), soluble	2089	<1033 pg/mL

IL2, interleukin-2.

CT scan of chest showed bilateral pulmonary opacities, mediastinal and hilar lymphadenopathy.

Differential diagnosis

A broad differential was considered at this time including infection, malignancy, systemic autoimmune conditions such as sarcoidosis, lupus, sjogren’s syndrome, vasculitis, metabolic disorders and postviral inflammatory syndrome.

A thorough infectious workup was done and was reported negative for tuberculosis, syphilis, bartonella, lyme, HIV, hepatitis B and C infections. Initial sputum cultures did not reveal bacterial, viral or fungal organisms. Autoimmune workup including antinuclear antibodies, extractable nuclear antigen panel and human leucocyte antigen B27 testing was negative. The vasculitis workup was reported negative for myeloperoxidase antibody and proteinase-3 antibody. She had elevated ACE level and lysozyme (muramidase) level (table 1) and it was thought to be non-specific.

Bronchoalveolar lavage (BAL) was done and transbronchial biopsies obtained from hilar/subcarinal lymph nodes and right middle lobe showed confluent non-necrotising granulomas with some scant necrosis.

CD4/CD8 ratio in BAL fluid was 5.09. BAL cultures were positive for actinomyces turicensis. The patient had multiple risk factors for actinomyces infection including history of heavy alcohol use, smoking and dental caries. But dental caries was thought be the major predisposing factor in her case. She was treated with antibiotics for 6 months.

However, post-treatment CT of chest showed worsening of cervical, mediastinal and axillary lymphadenopathy and interval development of internal cavitation in areas of lung consolidations (figure 1). A repeat lymph node biopsy showed granulomatous lymphadenitis and a subset of granulomas showed central necrosis.

Figure 1.

CT scan of the lungs done 6 months apart showing interval development of cavitary lesions (white arrows).

As the patient was young with no comorbidities, and had recent actinomyces turicensis pulmonary infection in the setting of lymphopaenia with low CD3, CD4 and CD8 counts (table 1), it raised concern for an underlying immunodeficiency disorder. A thorough workup for CVID was negative with no evidence of hypogammaglobulinaemia, normal IgG subclasses (table 2) and normal immune response to vaccinations. She had a normal oxidative burst test and henceforth ruling out CGD. Cytokine panel was normal apart from elevated soluble interleukin-2 receptor (sIL-2) (CD25) (table 1).

Table 2.

Immunoglobulin levels

Test	Results	Reference range (mg/dL)
IgA	569	60–400
IgM	213	50–300
IgG (total)	2420	700–1600
IgG1	1559*	382–929
IgG2	633	241–700
IgG3	177	22–178
IgG4	49	4–86

*Total Immunoglobulin

A few months later, she presented to the ophthalmology clinic with left eye redness, pain associated with photophobia and was diagnosed with granulomatous pan-uveitis of left eye. At that time, she was also noted to have skin lesions for which she was referred to dermatology. Dermatology evaluation revealed skin lesions with three different morphologies (figure 2A–C) suggestive of sarcoidosis and skin biopsy revealed granulomatous dermatitis.

Figure 2.

Three types of sarcoid skin lesions. (A) Hypopigmented sarcoidosis, (B) Tatto infiltration (C) Plaque sarcoidosis.

After multidisciplinary discussion between allergy/immunology, infectious disease, pulmonary, pathology and rheumatology, sarcoidosis was thought to be the unifying diagnosis given pulmonary findings, panuveitis, skin manifestations with mild eosinophilia, lymphopaenia, low CD4 and CD8 counts and a high sIL2 levels.

Outcome and follow-up

She was started on prednisone 1 mg/kg body weight orally once a day. There was marked improvement of skin lesions, uveitis and lymphadenopathy within few weeks. Later methotrexate was added as a steroid sparing agent with good clinical response.

Discussion

Sarcoidosis is an inflammatory disorder typically characterised by presence of non-caseating epithelioid granulomas. The presence of necrotising granulomas can sometimes pose a diagnostic challenge as seen in our case.² Our patient had some of the rare manifestations of sarcoidosis in the form of cavitary lung lesions, necrotising granulomas which along with actinomyces turicensis infection made us suspect an immunodeficiency disorder like CVID, CGD masking the underlying diagnosis of sarcoidosis.

Pulmonary cavitary lesions in sarcoidosis are uncommon with overall prevalence between 2% and 3% and are usually associated with active, severe sarcoidosis and often run an unpredictable course. The aetiopathogenesis of formation of these lung cavities is not clear, tumour necrosis factor alpha is thought to play role.³ Another hypothesis suggests that perivascular granulomas cause mechanical obstruction to blood flow leading to ischaemic necrosis and formation of cavitary lesions.⁴ This entity can be easily confused with other disorders like granulomatosis with polyangiitis and necrotising sarcoid granulomatosis.^{5 6} Pulmonary cavitary lesions are associated with high risk of complications including haemoptysis, aspergilloma, pneumothorax and other infections.³ So far, to our knowledge, this is the first reported case of pulmonary cavitary sarcoidosis with Actinomyces secondary infection.

Cutaneous manifestations in sarcoidosis can manifest as erythema nodosum, lupus pernio, macular sarcoidosis, plaque sarcoidosis, annular sarcoidosis, hypopigmented lesions, scar and tatto infiltration.⁷ Sarcoidosis patients can exhibit koebnerisation phenomenon as seen in our patient and it is thought to be the result of immune dysregulation favouring Th-1 response after trauma/pigment exposure.⁸ Initially, when patient had macular erythematous scaly plaques, biopsy was non-diagnostic. As the disease evolved, she developed classical lesions with three different morphologies.

Lymphopaenia is observed in around 50% of patients with sarcoidosis. A low CD4, CD8 and CD19 counts is associated with severe organ system involvement and poor prognosis. This finding may suggest that lymphocytes are depleted in peripheral blood due to increased infiltration of target organs.⁹ Dental caries was thought to be possible source of actinomyces infection in this patient. In sarcoidosis, there is thought to be dysregulation of adaptive immunity (cellular and humoral) predisposing patients to infection. Also, there are ongoing studies looking at possible role of environmental or infectious triggers in formation of sarcoid granulomas but no clear association has been proven so far.¹⁰ So, it is unclear if sarcoidosis predisposed this patient to Actinomyces infection or vice-versa.

Eosinophilia is seen in about 35%–40% of the patients with Sarcoidosis.¹¹ In this case, the patient had mild eosinophilia on initial presentation and also intermittently during her clinical course and even her initial skin biopsy reported presence of eosinophils.¹²

Another interesting fact that we wanted to highlight is that our patient had markedly elevated sIL-2R levels which was ordered as part of immunodeficiency work up. A cohort study showed that sensitivity and specificity of sIL-2R levels to diagnose sarcoidosis is 88% and 85%, respectively.¹³ Another Japanese study analysed data from 72 patients and found that sIL-2R was much more sensitive (52.8%) in diagnosing sarcoidosis compared with ACE (29%) and lysozyme (26.4%).

Additionally, the sIL-2R level was significantly higher in patients with multiple organ involvement and parenchymal infiltration.^{13 14}

This case is unique as the patient had multiple signs and symptoms of sarcoidosis that manifested over the due course of time, with evolution of the disease process. She had both the classical findings which included hilar lymphadenopathy, uveitis, skin lesions as well as rare findings in the form of necrotising granulomas, cavitary lung lesions, eosinophilia, lymphopaenia, low CD4, low CD8 counts offering a comprehensive review to the readers about what can be expected in patients of sarcoidosis with multiorgan involvement.

Infection, immunodeficiency disorders and sarcoidosis can have similar presentations and it is crucial to differentiate from one from the other as the treatment is entirely different for each entity.

Learning points.

• This case highlights both common and rare findings of sarcoidosis providing comprehensive review to the readers.

• Infection, immunodeficiency disorders and sarcoidosis can have similar presentations and it is crucial to differentiate from one from the other as the treatment is entirely different for each entity.

• Lymphopaenia especially presenting during early adulthood should raise suspicion for autoimmune diseases like lupus, sarcoidosis after ruling out infections like HIV.

• Another important point that we want to stress on is that soluble interleukin-2 receptor levels might be superior to ACE levels in diagnosing sarcoidosis.

Ethics statements

Patient consent for publication

Obtained.