2-Year-old Girl With Fever and Multiple Nodular Shadows on Chest Radiograph

CASE

History and Clinical Examination

A previously healthy 2-year-old girl was taken to her primary care physician on day 1 of symptom onset with a fever reaching 40 °C and mild diarrhea. On day 4, she was prescribed cefcapene pivoxil. She was referred to our hospital on day 8 with continued fever. There was no medical history of note, and her immunization history was up to date. There were no pets in the home, and she had no history of allergies. On admission, heart rate was 152 beats/min, respiratory rate was 28 breaths/min, blood pressure was 115/98 mm Hg, body temperature was 38.0 °C and oxygen saturation was 99% on room air. Capillary refill time was normal. On physical examination, her general condition was rather poor. No cough or nasal discharge was noted. There was no conjunctival hyperemia, strawberry tongue or lip redness. Her pharynx was slightly reddened, but no cervical lymphadenopathy was noted. On chest auscultation, breath sounds were normal with no pulmonary rales. No heart murmur was heard. The abdomen was soft on palpation, and bowel peristalsis was normal. There was no redness at the bacille Calmette-Guerin vaccination site. Three 3-mm papules were observed on the lower extremities and trunk.

Initial laboratory investigations revealed a white blood cell count of 12.7 × 10⁹/L (normal 4.0–11.9), with 71% granulocytes and 25% lymphocytes, hemoglobin of 9.5 g/dL (normal 10.9–14.2), platelet count of 313 × 10⁹/L (normal 180–460), C-reactive protein level of 73.0 mg/L (normal ≤3), erythrocyte sedimentation rate of 107 mm/60 min (normal), serum aspartate aminotransferase level of 29 U/L (normal 24–50), alanine aminotransferase 11 U/L (normal 9–34), lactate dehydrogenase level of 353 U/L (normal 195–400) and serum creatinine level of 0.25 mg/dL (normal 0.17–0.45). Antigen tests for respiratory syncytial virus, adenovirus, and group A streptococcus were negative. Findings on a chest radiograph (X-ray) are shown in Figure 1.

FIGURE 1.

Chest X-ray obtained on day 11 of the illness showing multiple nodular shadows in both lungs.

DENOUEMENT

Haemophilus influenzae and Moraxella catarrhalis were isolated from sputum culture. No Staphylococci were isolated. Fungal cultures were negative. No pathogens were isolated from 4 serial blood cultures. The culture of gastric fluid was negative, and tuberculosis-specific interferon-gamma was not detected. Serum antibodies for Mycoplasma pneumoniae, cytomegalovirus and HIV were negative. A polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 was also negative. Urinary Legionella antigen was negative. On admission, we administered ampicillin 150 mg/kg/day but her fever continued. Findings on a chest X-ray and her white blood cell count and C-reactive protein level were largely unchanged. Based on the sputum culture results, her antimicrobial therapy was changed to ceftriaxone and claruthromycin on day 11, but her fever persisted and the C-reactive protein level continued to increase. On day 13, she required temporary administration of oxygen during sleep. In view of the course of the illness, antimicrobial therapy was deemed to be ineffective and discontinued on day 14. No airway symptoms were observed throughout the clinical course.

Investigation of her immune profile did not reveal any abnormalities [IgG 552 mg/dL (normal 500–1280), IgA 48 mg/dL (normal19–136), IgM 105 mg/dL (normal 72–297), C3 157 mg/dL (normal 84–151) and C4 35 mg/dL (normal17–40)]. The CD4/CD8 ratio was 4.0 (normal 0.6–2.4). Her lymphocyte fraction was normal. Antiglomerular basement membrane antibody, myeloperoxidase antineutrophil cytoplasmic antibody and proteinase 3 antineutrophil cytoplasmic antibody tests were negative. Urinary vanillylmandelic acid and homovanillic acid levels were within the normal ranges.

The fever continued after discontinuation of antimicrobial therapy, and whole-body magnetic resonance imaging performed on day 16 to search for a neoplasm revealed multiple nodules in both lungs and a high signal on diffusion-weighted images, as did computed tomography (Fig. 2A). Findings in the liver were the same as those in the lungs (Fig. 2B). On day 17, the fever resolved spontaneously, and clinical data showed a trend toward improvement. However, the possibility of malignancy could not be completely ruled out, so a lung biopsy was performed on day 21.

FIGURE 2.

A: Computed tomography scan of the chest obtained on day 12 of the illness showing multiple well-defined nodules measuring 3–8 mm in both lungs and in all lung fields. B: Magnetic resonance imaging in diffusion-weighted b-1000 mode acquired on day 16 showing multiple nodules in liver, similar to findings in the lung. C: Thoracoscopic observation. The arrows indicate multiple white nodules on the surface of the lungs seen on gross examination. D: Hematoxylin & eosin (HE)-stained section of the lung tissue on low power magnification. Arrows show the epithelioid granulomas with central necrosis. E: Microphotograph of HE-stained section. Epithelioid cells surrounded necrosis (left upper). F: Immunohistochemistry of Propionibacterium Acnes. The cytoplasm of macrophage shows positivity.

On thoracoscopic gross examination, multiple white nodules measuring several millimeters in size were observed on the surface of the lungs (Fig. 2C). Microscopic observation revealed multiple epithelioid granulomas with central necrosis on low-power magnification of the lung tissue (Fig. 2D). Necrotic tissue was surrounded by epithelioid cells without obvious multinucleated giant cells (Fig. 2E). Macrophages accumulated around the blood vessels in the area adjacent to the granuloma, indicating vasculitis. Ziehl-Neelsen staining failed to detect acid-fast bacterium. Immunohistochemically, the sections were stained with a primary antibody against Propionibacterium acnes (PAB antibody), a so-called acne bacillus that has recently been shown to be highly prevalent in sarcoidosis. The cytoplasm of macrophages was positive for P. acnes (Fig. 2F). Finally, a diagnosis of necrotizing sarcoid granulomatosis (NSG) was made based on nonsarcoid granuloma (sarcoid-like granuloma), diffuse vasculitis, various degrees of necrotic lesions, and PAB antibody-positive cells.

The patient was discharged from the hospital in good general condition without fever 1 week after the biopsy. Six months later, there was a complete resolution of the nodular shadows on chest radiography, and there has been no recurrence of symptoms in the 3 years since her discharge from the hospital.

NSG is a rare disease that is included in the concept of pulmonary angiitis and granulomatosis proposed by Liebow in 1973.¹ Histologically, NSG presents with epithelioid cell granulomas similar to those of sarcoidosis but is characterized by more extensive necrosis and granulomatous vasculitis than typical sarcoidosis.^2–4 There have been scattered reports of sarcoidosis from various countries, but few pediatric cases have been reported, with the youngest case described being 8 years old.³ In recent years, as for sarcoidosis, it has become clear that P. acnes DNA is present in large amounts in NSG lesions; immunostaining with PAB antibodies has a high positivity rate, suggesting that NSG is a type of sarcoidosis.^3,4

Cough, dyspnea, chest pain, fever, general malaise, and weight loss have been reported, but about 25% of patients are asymptomatic.² Therefore, the disease is often discovered incidentally during a medical examination for another purpose. It has been reported that more than 80% of patients have extrapulmonary symptoms (skin, nerve and eye symptoms or liver dysfunction). In the present case, fever was present but there were no airway symptoms, and the diagnosis was based on findings on a chest X-ray obtained for investigation of fever of unknown origin. The disease resolved spontaneously, and although there have been reports of recurrence, the prognosis is reported to be good.

In summary, this report describes a child who presented to our hospital with an 8-day history of fever of unknown origin and was finally diagnosed as having NSG by endoscopic lung biopsy. To our knowledge, this case is the youngest to be reported anywhere in the world, and we anticipate that it will be educational for pediatricians.