Multiple granulomatous lung lesions in a patient with Epstein-Barr-virus-induced mononucleosis and new-onset systemic lupus erythematosus: a case report
© Sakurai et al.; licensee BioMed Central Ltd. 2012
Received: 20 January 2012
Accepted: 9 July 2012
Published: 9 July 2012
Granulomatous lesions are commonly encountered abnormalities in pulmonary pathology, and often pose a diagnostic challenge. We report an unusual case of granulomatous lung disease with uncommon characteristics, which developed following Epstein-Barr-virus-induced mononucleosis and new-onset systemic lupus erythematosus. We aim to highlight a diagnostic approach for the condition and to raise awareness of the possibility of it being related to the immunological reaction caused by Epstein-Barr virus infection.
A 36-year-old Japanese man, who had been diagnosed with Epstein-Barr-virus-induced infectious mononucleosis, new-onset systemic lupus erythematosus, and secondary Sjögren’s syndrome three weeks previously, presented to our facility with fever and diffuse pulmonary infiltrates. A computed tomography scan of the chest revealed multiple small nodules in both lungs. Fiberoptic bronchoscopy with bronchoalveolar lavage revealed lymphocytosis with predominance of T lymphocytes. A histological examination of a lung biopsy taken during video-assisted thoracic surgery showed randomly distributed tiny granulomatous lesions with infiltration of eosinophils. The differential diagnoses included hypersensitivity pneumonitis, sarcoidosis, and pulmonary involvement of Crohn’s disease, systemic lupus erythematosus, and Sjögren’s syndrome, but the clinical and pathological findings were not consistent with any of these. Our patient’s condition did not improve; therefore, prednisolone therapy was started because of the possibility of specific immunological reactions associated with Epstein-Barr virus infection. After steroid treatment, our patient showed radiological and clinical improvement.
To the best of our knowledge, this is the first case of a patient developing randomly distributed multiple granulomatous lung lesions with eosinophilic infiltrates after Epstein-Barr virus infection and systemic lupus erythematosus. On the basis of our data, we hypothesize that Epstein-Barr virus infection altered the immune response of our predisposed patient and contributed to the pathogenesis of the lung lesions. Our patient’s clinical response to steroid treatment was excellent.
KeywordsCentrilobular micronodules Epstein-Barr virus Granulomatous lesions Lung Sjögren’s syndrome Systemic lupus erythematosus
Granulomatous lesions are commonly encountered abnormalities in pulmonary pathology. Most granulomas in the lung are caused by mycobacterial or fungal infections; however, if no organisms are detected, then it is necessary to consider non-infectious causes of granulomatous disease such as sarcoidosis, hypersensitivity pneumonitis, hot tub lung, Wegener’s granulomatosis, and Churg-Strauss syndrome .
We report an unusual case of granulomatous lung disease that differed from the above-mentioned entities, which developed following Epstein-Barr virus (EBV)-induced mononucleosis and new-onset systemic lupus erythematosus (SLE) in our patient.
EBV has been linked to SLE for 40 years, and a growing body of experimental evidence supports a possible role for EBV in the etiology of SLE [2, 3], but the clear mechanism of this linkage has not been elucidated. Although there have been several case reports linking EBV and SLE [4, 5], to the best of our knowledge this is the first case of a patient who developed multiple eosinophilic granulomatous lesions in the lung after the diagnosis of new-onset SLE following EBV-induced mononucleosis.
This case report highlights a diagnostic approach for granulomatous lung disease and aims to raise awareness of the possibility of the connection between granulomatous lung disease and immunological reaction caused by EBV.
A 36-year-old Japanese man, with a history of presumed Crohn’s disease at age 16 years, on the basis of peri-anal fistula with compatible histopathological features and spontaneous healing without medical intervention, presented to our facility with a 10-day history of fever (39°C to 40°C), malaise and generalized lymphadenopathy. He also had a history of photosensitivity and erythema on the cheeks and nose over the past five years, which had worsened over the previous two days. Our patient had no history of smoking or asbestos exposure. On examination, he was febrile and had tachypnea. He had a bilateral malar rash, tender cervical lymphadenopathy, swelling of parotid and submandibular glands, and arthritis affecting the bilateral metacarpophalangeal joints of the hands. He also had a dry mouth and dry eyes, which were confirmed by a positive Schirmer’s test (<5mm per five minutes, bilaterally). Auscultation of the heart and lungs was normal. His abdomen was remarkable for moderate hepatomegaly and splenomegaly.
On admission, his laboratory test results showed: leukocytosis (white blood cells 13,090 cells/μL; lymphocytes 57.4%, atypical lymphocytes 10.0%); elevated liver enzymes (alanine aminotransferase 202U/L (normal range 10 to 40U/L), aspartate aminotransferase 172U/L (normal range 13 to 30U/L), alkaline phosphatase 1332IU/L (normal range 100 to 320IU/L), γ glutamyltranspeptidase 223IU/L (normal range 5 to 60IU/L), lactate dehydrogenase 561IU/L (normal range 110 to 210IU/L)); and normal renal function and urine analysis with serum angiotensin-converting enzyme 16.4U/L (normal range 7 to 25U/L). Serum serological tests were positive for anti-nuclear antibody 1:80 (normal value <1:40), double-stranded DNA (dsDNA) antibodies 22IU/mL (normal value <10IU/mL), and anti-Sjögren syndrome antigen A (SS-A)/Ro antibody >500 (normal value <10).
Virological test results for human immunodeficiency virus antibody, cytomegalovirus antigen and antibody, hepatitis B surface antigen and antibody, hepatitis C virus antibody were negative, but our patient was positive for IgG and IgM to EBV viral capsid antigen and IgG to EBV early antigen. Our patient was negative for IgG to Epstein-Barr nuclear antigen (EBNA). A chest X-ray was clear and computed tomography (CT) revealed a small amount of pleural effusion in addition to lymphadenopathy in bilateral cervical, mediastinal and peritoneal areas, and hepatosplenomegaly. A neck lymph node biopsy showed positive expression of EBV-encoded RNA by in situ hybridization, and the presence of serum EBV DNA was confirmed by polymerase chain reaction (PCR). Based on our patient’s clinical course, a diagnosis of EBV-associated infectious mononucleosis, SLE and secondary Sjögren’s syndrome was made, with a SLE Disease Activity Index (SLEDAI) score of 11.
His serum lactate dehydrogenase and alkaline phosphatase levels gradually improved after three weeks of hospitalization, with no treatment. Improvement was also shown on physical examination, and our patient was discharged on day 21.
HP was considered as a possible etiology of our patient’s symptoms. However, our patient was not known to have been exposed to any inhaled agents, nor did he show any clinical improvement during hospitalization. In addition, the histopathological features of the lung biopsy were not typical of those of HP. The other possibilities, such as sarcoidosis, pulmonary involvement of Crohn’s disease, SLE, and Sjögren’s syndrome were also considered to be unlikely based on clinical and pathological findings.
Our patient’s condition did not improve: he had continued daily high-grade fever, and there was no improvement in his radiological findings. Thus, prednisolone therapy was started at a dose of 0.5mg/kg/day, as a result of the possibility of specific immunological reactions associated with EBV infection. Our patient showed remarkable clinical and radiological improvement, and he was discharged on a tapering dose of prednisolone.
After one year of follow-up, our patient remained asymptomatic and had no relapse after discontinuation of prednisolone. Physical examination and chest X-ray/CT results were normal. Serological studies showed an absence of ANA and anti-dsDNA antibodies, and the presence of anti-SS-A/Ro antibodies, EBNA IgG, and anti-smooth muscle antigen antibodies.
Recent research has revealed that EBV is a strong candidate etiological agent for SLE, based on pleiotropic interactions with host immune responses, such as molecular mimicry, adjuvant or bystander effects, and interferon (IFN)α induction [2, 6, 7]. Our patient had photosensitivity and butterfly rash five years before the diagnosis of SLE and his symptoms of lupus, such as pleural fluid and arthritis, resolved spontaneously after the acute phase of EBV infection. Considering the clinical course, he might have had unrecognized subclinical SLE several years before the diagnosis, and EBV infection might have influenced his immune response and played a crucial role in the pathogenesis of SLE and the onset of clinical manifestations.
In addition, our patient developed multiple tiny, well-formed granulomatous lesions in the lung three weeks after the diagnosis of primary EBV-induced infectious mononucleosis, new-onset SLE, and Sjögren’s syndrome. Infectious causes, such as tuberculosis, atypical mycobacterial infection, and fungi, were excluded based on histochemical staining, cultures, and PCR. Drug-induced pneumonitis was also excluded.
Classification of non-infectious granulomatous lung diseases according to the distribution and the presence of necrosis
Distribution of granuloma
Presence of necrosis
Hypersensitivity pneumonitis, lymphocytic interstitial pneumonia, talcosis
Sarcoidosis, chronic beryllium disease
Wegener’s granulomatosis, lymphomatoid granulomatosis
HP, which is a diffuse granulomatous interstitial lung disease caused by inhalation of various agents, was considered based on our patient’s radiological and histopathological findings. Although the diagnosis of HP is often difficult to make , in our patient HP was unlikely given the lack of a history of exposure to occupational and domestic agents, and the fact that the lung biopsy lacked the characteristic features of HP, such as alveolitis with significant lymphocytic infiltrates within the interstitium, even in areas where no granulomas are present, and poorly formed interstitial granulomas . Furthermore, our patient failed to respond to removal from antigen exposure by hospitalization. Serological study results were negative for precipitating antibodies to fungal antigens, such as Aspergillus sp. and Trichosporon cutaneum.
Another possibility that we considered was sarcoidosis. Histologically, sarcoidosis is characterized by well-formed interstitial, non-caseating granulomas, which show lymphangitic distribution . In our patient, the distribution was different from that of sarcoidosis, and his serum angiotensin-converting enzyme level was normal.
Crohn’s disease, which shares pathological and immunological features with sarcoidosis  and can develop granulomatous lung disease as extra-intestinal involvement , was also considered to be unlikely, because the evidence of gastrointestinal involvement of Crohn’s disease was not confirmed by upper endoscopy and colonoscopy.
Furthermore, we raised the possibility that the pulmonary manifestation was associated with SLE and Sjögren’s syndrome. Pulmonary involvement is frequently seen in SLE , and there is a case report of acute granulomatous lupus pneumonitis . Sjögren’s syndrome, which shares similar clinical and radiographic features with sarcoidosis , is also known to demonstrate various types of pulmonary manifestations, including granulomatous infiltrations . Even though SLE and Sjögren’s syndrome seemed to be in a dormant state when our patient developed pulmonary manifestations, and granulomatous lesions are not typical findings of these conditions, we cannot exclude the possibility that these lesions were attributable to SLE and Sjögren’s syndrome.
Lastly, EBV was considered as a possible etiological agent. Lymphomatoid granulomatosis, which is a rare EBV-associated lymphoproliferative disorder, was excluded histopathologically, and there have been no reports to suggest involvement of EBV in granulomatous reactions in the lung, which can be seen in the spleen, bone marrow and liver [17, 18]. However, considering the fact that EBV is known to cause pleiotropic interactions with host inflammatory responses, and in the present case, played a crucial role in the development of SLE clinically, we hypothesize that EBV infection might have altered the immune response and contributed to the pathogenesis of the lung lesions through aberrant T cell responses, dysregulated IFN and other cytokines responses, and dysfunctional CD8 responses [2, 3, 6, 7]. Rapid improvement in the symptoms by administration of prednisolone also supports an immunological process.
We describe the case of a patient who developed randomly distributed multiple granulomatous lung lesions with eosinophilic infiltrates, following EBV infection and new-onset SLE. Although we cannot fully explain the linkage between these conditions, we think that the immunological reaction induced by EBV contributed to the pathogenesis of the lung lesions, as well as the onset of SLE. His clinical and radiological response to prednisolone was excellent.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
We would like to thank our patient for allowing us to report his unusual case to the medical community.
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