A 40-Year-Old Man With a Nodular Lung Disease and Skin RashA Case of Nodular Lung Disease and Skin Rash FREE TO VIEW

A 40-year-old black man was referred to pulmonary clinic for evaluation of pulmonary nodules. He reported a recent one time incident of right lower quadrant abdominal pain for which he was seen in the ED where an abdominal CT scan and a chest radiograph revealed a right lower lobe lung nodular opacity. On further review of systems, he reported occasional right-sided pleuritic chest pain, mild malaise, mild exertional dyspnea, and extensive nonpruritic skin rash on his left shin that had developed about 3 months before his current presentation. The rash had worsened despite the efforts of his primary care providers to treat it. He denied cough, fever, chills, night sweats, hemoptysis, arthralgias, or weight loss. Additional medical problems included poorly controlled hypertension. His family history was significant for diabetes in his mother and two siblings, chronic anemia in his sister, and lung cancer in his uncle. He lived in northwest Louisiana and worked as a roofer most of his adult life but had recently worked in landscaping. No significant environmental exposure to chemicals, dust, or asbestos was indicated. He reported a 15 pack-year smoking history, but no alcohol or illicit drugs. Six years before his current presentation, he was incarcerated for a period of 8 months. He also reported sexual activity with a male partner in the past but no recent sexual activity.

Physical examination at the time first seen was as follows: BP, 146/90 mm Hg; heart rate, 80 beats/min; and respiratory rate, 14 breaths/min. His temperature was 37°C, and his oxygen saturation was 97% on room air. Breath sounds were normal without wheezing, crepitations, or localized decrease in breath sounds. His abdomen was soft and nontender, with normal bowel sounds and no organomegaly. Extremities were without clubbing, cyanosis, or edema. His left lower extremity had a large (20×15 cm) area skin with raised, dark, nontender nodules and plaques with some overlying scales (Fig 1). No lymphadenopathy was found in his neck, supraclavicular, axillary, or inguinal areas.

Initial chest radiograph showed right lower lung field nodular opacity (Fig 2A). A dedicated contrast-enhanced CT scan of the chest confirmed the presence of a cluster of three subpleural nodular opacities in the right middle lobe (Fig 2B), as well as smaller lower lobe subpleural nodules without evidence of pleural effusion, mediastinal lymphadenopathy, or pulmonary emboli. Ultrasound echocardiography revealed concentric left ventricular hypertrophy and was otherwise unremarkable.

CBC count with differential and comprehensive metabolic panel with transaminases were all within normal limits (no eosinophilia noted on CBC count). C-reactive protein was mildly elevated. HIV serology was nonreactive. Fungal serology was negative for all fungi tested (including coccidiomycosis, blastomycosis, and histoplasmosis). Angiotensin-converting enzyme level was within normal limits. The TB purified protein derivative skin test was negative as was the quantiferon test. The hepatitis panel showed immunity against hepatitis B and nonreactive otherwise. A screening venereal disease research laboratory was positive. Cytoplasmic-antineutrophil cytoplasmic antibodies, perinuclear-antineutrophil cytoplasmic antibodies, antinuclear antibodies screen, rheumatoid factor, and myeloperoxidase antibodies were tested later and confirmed negative.

A skin biopsy of the involved area was obtained and revealed a plasma cell-rich perivascular infiltration and psoriasiform dermatitis. Whole-body (18)F-fluorodeoxyglucose (FDG) PET/CT scan was obtained and showed intense uptake in the described lung nodules (Fig 3). A CT imaging-guided lung biopsy was then obtained and was negative for malignancy, but showed fibrotic tissue with dense lymphoplasmacytic infiltrate (Fig 4).

A follow-up noncontrast CT scan of his chest 3 months later revealed an increase in number and location of the lung nodules necessitating further interventions. Bronchoscopy with BAL, transbronchial lung biopsies of the right middle and lower lobes, and cultures were then performed. Biopsies showed findings similar to the earlier biopsy obtained by CT-imaging guidance with fibrinoid thickening of the vessels seen on the specimen, suggesting a possible vasculitic process. Periodic acid-Schiff, Grocott methenamine silver, acid-fast bacilli, and Warthin-Starry stains were all negative for microorganisms and all cultures obtained returned negative.

The differential diagnosis of multiple lung nodules in this patient can be limited to infectious and noninfectious etiologies. Fungal and mycobacterial infections as well as nocardia, and septic emboli were all excluded in the absence of positive cultures from bronchoscopies and biopsies as well as negative serological tests and echocardiography. Noninfectious etiologies such as rheumatoid nodules, and carcinoid, vasculitic lesions such as granulomatosis with polyangiitis (Wegener) and sarcoidosis, were all excluded by the serologic and pathologic work-up. Sarcoidosis was very high on the list given the patient’s ethnic background and the appearance of skin lesions. The lack of adenopathy and absence of radiographic features of sarcoidosis, lack of the typical pathologic appearance of the noncaseating granulomas and presence of perivascular plasma cell infiltrates on biopsies, the normal angiotensin-converting enzyme level, and rapid response to the specific antibiotics eliminated sarcoidosis as the first diagnosis. Malignancy, primary and metastatic, remained a concern despite the repeatedly negative biopsies. However, negative biopsies (from two bronchoscopies and one CT imaging-guided biopsy) along with the clinical course over 17 months and rapid response to antibiotics excluded this possibility.

Secondary syphilis with pulmonary involvement is rare and has received little attention in the literature, possibly because of the long-held belief that pulmonary syphilitic involvement is part of advanced-stage disease (tertiary syphilis) where gummas can affect any organ, including the lung. It is likely that the availability of effective treatment and the ability to diagnose syphilis in the early stages has also led to a decreased recognition of pulmonary involvement. Pulmonary syphilis was reported in the literature in the pre-HIV and post-HIV eras. To our knowledge, there are 11 reported cases of secondary syphilis with pulmonary involvement in the English language literature.^1–11 Most of the HIV-era cases were reported in patients who were infected with HIV.^1,7,10 In a series of 1,500 cases with secondary syphilis studied between 1939 and 1944 on patients screened prior to arsenic therapy, none showed radiographic evidence of pulmonary involvement (S. Landry, quoted in Biro et al¹ and Coleman et al³). The advances in radiographic techniques and development of newer modalities, namely high-quality CT scans, may have resulted in more pulmonary syphilis cases reported after the 1980s despite the decrease in prevalence of the disease. Because of the rarity of the disease, Coleman et al³ proposed five diagnostic criteria for pulmonary syphilis: (1) historical and physical findings typical of secondary syphilis; (2) serologic test results positive for syphilis; (3) pulmonary abnormalities seen radiographically with or without associated pulmonary symptoms or signs; (4) exclusion of other forms of pulmonary disease when possible by findings of serologic tests, sputum smears and cultures, and sputum cytology examination; and (5) therapeutic response of radiologic findings to antisyphilitic therapy. All of these criteria were eventually met in this case.

In this case, most of the nodules appeared subpleural and increased in number and size with disease progression (Figs 2B, 5); lesions were PET scan-positive (Fig 3). The patient had no immune compromise; this appears to have influenced his course and may have limited his nodules to a small size compared with larger ones noted in some reported HIV-positive cases.^2,7,10 This patient’s radiographic presentation is not typical for any form of sarcoidosis, including the milliary and nodular forms. In addition, there was no mediastinal adenopathy noted during the follow-up period.

The pathology specimens obtained from lung biopsies showed perivascular plasmacytic infiltrate and fibrotic changes in blood vessels (Fig 4). Biopy specimens did not reveal clear granulomatous formation and were repeatedly negative for malignancy. The skin biopsy specimens were more revealing with more prominent plasma cell infiltrate in the perivascular space with the presence of some psoriasiform and granulomatous changes. These changes were typical for syphilis and not for sarcoidosis. No organism identified with the Grocott methenamine silver, acid- fast bacilli, and Warthin-Starry stains performed on all specimens obtained from lung and skin biopsies.

Identification of Treponema pallidum from lung or skin biopsies failed in all reported cases except one⁹ where the organism was seen on the Warthin-Starry-stained skin biopsy specimen. In another recent case,¹⁰ polymerase chain reaction was performed on BAL and was positive. Although this test may be helpful, mucosal fluids can be positive in this stage of disease regardless of the presence of lung nodules and thus it is less specific than immunohistochemical (IHC) staining performed on tissue biopsies. We were unable to obtain IHC staining on the biopsy specimens due to the age of the specimens by the time the diagnosis was considered.

After missing several follow-up appointments, the patient returned to clinic for follow-up 6 months later. He reported that his skin lesions were getting worse despite two courses of antibiotics and steroid creams prescribed by his primary provider and urgent care centers. Skin biopsy was repeated and revealed superficial and deep plasma-rich perivascular infiltrate and nonnecrotizing granulomas in the superficial dermis, suggestive of syphilis, autoimmune vascular disease, or sarcoidosis (Fig 6). Complete syphilis serology (antitreponemal IgG and rapid plasma reagin) was obtained. The rapid plasma reagin was positive at 1:64 dilutions and syphilis IgG was positive. Repeat HIV serology was again nonreactive. A repeat CT scan of the chest was obtained and showed new nodules in both lung fields (Fig 5). Upon further questioning, he reported a mild skin rash on his palms and soles that had resolved spontaneously without treatment several months previous to his first presentation, and an episode of epididymitis treated a few months later with ceftriaxon and doxycycline. He also reported unprotected sex with a male partner about a year previously (about 2-3 months before his initial presentation). He described a small painless penile sore appearing shortly after his exposure which resolved without treatment in 2 weeks. Efforts to trace his partner failed. The epididymitis incident was confirmed in his records in the urology clinic as well as the negative cultures from penile secretions obtained by his treating physician at that time.

A lumbar puncture was obtained which documented negative cerebrospinal fluid-venereal disease research laboratory with normal cell count and protein level. The patient then received 2.4 million units of benzathine penicillin every week for 3 consecutive weeks for treatment of secondary syphilis. Repeat CT scan 4 weeks after completion of treatment showed near complete resolution of the lung nodules. Four months later, his CT scan showed almost clear lung fields without lung nodules (Fig 7A). Six months after completion of treatment, his chest radiograph remains clear (Fig 7B). His skin rash improved significantly (Fig 8) with only residual postinflammatory changes. He reported feeling better in general with more energy, no chest pain, and no new symptoms.

Syphilitic lung involvement is rare but should be suspected in highly endemic areas presenting with pulmonary nodules and skin rash, especially when work-up of pulmonary nodules returns negative for other infectious, malignancy, vasculitic illnesses, and sarcoidosis. Detailed history, serological tests for syphilis, and biopsies of skin and lung lesions may be needed to confirm the diagnosis.

Based on our observations in this case and review of the previously reported cases, in addition to Coleman’s criteria, we suggest that the following clinical and radiographic observations of secondary syphilitic lung involvement be considered in future suspected cases:

This case is unique in its demonstration of the natural history of pulmonary syphilis in a patient who is HIV-negative from an area of the United States with a very high syphilis incidence rate.¹² Syphilis has been known for a long time as “The Great Imitator,” and our case proves the lung is no exception.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: This case and all related work-up was done at Louisiana State University Health Sciences Center, Shreveport, LA.