Introduction

Individuals worldwide receive the influenza vaccine because it decreases the incidence of influenza and the risk of more serious influenza-related complications (1,2). Although the safety and efficacy of this vaccine is well known, interstitial pneumonia can occasionally occur as a complication. We herein describe two cases of interstitial pneumonia secondary to the 2014-2015 seasonal influenza vaccine, which contained the A(H1N1)pdm09-like antigen, and present a review of similar reported cases.

Patient 1

In December 2014, a 71-year-old Japanese woman presented with severe, dry cough and left chest pain. She had received the seasonal influenza vaccine at another clinic 36 days before visiting our clinic, and the local injection site reaction was mild. She developed a dry cough the following day, and it gradually worsened. Two days before the first visit, she developed left chest pain. Her medical history revealed well-controlled diabetes mellitus and dyslipidemia. She had undergone right nephrectomy for renal tuberculosis 37 years ago and had been prescribed rosuvastatin and linagliptin for the past 12 months.

At the first visit, all her vital signs and physical features were normal. A complete blood count revealed mild leukocytosis (white blood cell count, 11,400/mm3) with normal white blood cell differentiation. Blood chemistry showed no abnormalities, including a normal lactate dehydrogenase (LDH) level. Serological tests revealed the following: C-reactive protein (CRP), 5.54 mg/dL; soluble interleukin-2 receptor (sIL-2R), 1,086 U/mL; and surfactant protein-D, 178.2 ng/mL. Her serum surfactant protein-A (SP-A) and Krebs von den Lungen-6 (KL-6) levels were normal. Chest roentgenography (Fig. 1A) and computed tomography (Fig. 1B) showed patchy, peribronchial consolidations with air bronchograms and ground-glass opacities without pleural effusion in both lungs. Electrocardiogram and ultrasonic echocardiogram were normal. The severe cough followed by musculoskeletal chest pain precluded pulmonary function tests. Bronchoalveolar lavage fluid (BALF) examination revealed 65% lymphocytes, 15% eosinophils, 19% macrophages, and 1% neutrophils, with no infectious organisms or malignant cells. The CD4+/CD8+ ratio was 2.1. Transbronchial lung biopsy revealed lymphocytic alveolitis and granulation tissue plugs within airspaces, suggesting organizing pneumonia (Fig. 1C). A drug lymphocyte stimulation test (DLST) performed using peripheral lymphocytes showed a positive reaction to the influenza vaccine, with a stimulation index of 190% (normal, <180%).

Oral prednisolone at 35 mg (0.8 mg/kg/day) was administered daily, and within a week, our patient's symptoms and abnormal radiography and laboratory findings began resolving. We then performed pulmonary function tests and found a forced vital capacity (FVC) of 2.07 L (normal, 79.6% predicted), forced expiratory volume in 1 s (FEV1) of 1.68 L (normal, 88.0% predicted), and an FEV1/FVC ratio of 81.1%. Oral steroid therapy was tapered on an outpatient basis. Ten months after the treatment, her prednisolone dose was tapered. The patient remains healthy with no further symptoms or radiographic abnormalities (Fig. 1D), and she did not receive the annual influenza vaccine the following year.

Patient 2

In November 2014, a previously healthy 67-year-old Japanese man presented with a dry cough and dyspnea on exertion. He had received the seasonal influenza vaccine at another clinic 41 days prior to visiting our clinic, and the local injection site reaction was mild. Six days later, he developed a low-grade fever, general fatigue, and a dry cough, which gradually worsened. Nine days before admission, he visited an outpatient clinic with a severe, progressively worsening cough. Chest roentgenogram revealed patchy airspace infiltrations in both his lungs. Clarithromycin administered at 400 mg/day for 5 days was ineffective. His dyspnea on exertion gradually worsened, and he was referred to our outpatient clinic for further evaluation.

His medical history was unremarkable, and a chest roentgenogram obtained during a routine annual health check-up 7 months ago showed normal findings. On admission, his oxygen saturation was 93% in room air, and the other vital signs were normal. A physical examination revealed inspiratory fine crackles at both lung bases. A complete blood count revealed no abnormalities. Blood chemistry showed normal renal and liver function tests and an LDH level of 302 IU/L. Serological tests revealed the following: CRP, 2.95 mg/dL; ferritin, 701.1 ng/mL; sIL-2R, 670 U/mL; KL-6, 2,276 U/mL; SP-D, 160.6 ng/mL; and SP-A, 152.9 ng/mL. Chest roentgenography (Fig. 2A) and computed tomography (Fig. 2B) showed peripheral, predominantly basilar, and partially subpleural ground-glass opacities and consolidations without honeycomb changes in both lungs. The severe cough precluded carrying out pulmonary function tests. BALF examination revealed 49.3% lymphocytes, 15.5% eosinophils, 34.2% macrophages, and 1% neutrophils, without infectious organisms or malignant cells. The CD4+/CD8+ ratio was 0.7. Transbronchial lung biopsy confirmed lymphocytic alveolitis and scattered granulation tissue plugs within airspaces (Fig. 2C), with alveolar epithelial shedding and regenerative hyperplastic epithelia, suggesting organizing pneumonia with alveolar epithelial injury. A DLST performed using peripheral lymphocytes showed a positive reaction to the influenza vaccine, with a stimulation index of 330%.

Intravenous methylprednisolone was administered at 1,000 mg daily for 3 days, followed by oral prednisolone at 40 mg (0.6 mg/kg/day) daily. His symptoms and radiographic and laboratory abnormalities gradually resolved, and oral steroid therapy was tapered on an outpatient basis. Thirteen months after treatment, his steroid dose was tapered off. The patient remains healthy with no further symptoms or radiographic abnormalities (Fig. 2D), and he did not get the annual influenza vaccine the following year.

Conclusions

Our findings suggest that clinicians should be aware of the possibility of interstitial pneumonia as a complication of the influenza vaccine, ask closed questions about vaccination in medical interviews, and educate patients about this complication, as these will facilitate early detection and treatment. Although the safety of this vaccine has been confirmed, relatively newer drugs warrant further investigation to confirm their association with interstitial pneumonia.