Acute Lung Injury Accompanying Alveolar Hemorrhage Associated ...

□

CASE REPORT

□

Acute Lung Injury Accompanying Alveolar Hemorrhage Associated with Flu Vaccination in the Elderly Etsuko Satoh 1,2, Takahito Nei 2,3, Shinichi Kuzu 1,4, Kumi Chubachi 1, Daisuke Nojima 1, Namiko Taniuchi 1, Yoshimitsu Yamano 1 and Akihiko Gemma 2

Abstract Flu vaccinations are administered worldwide every winter for prevention. We herein describe a case of acute lung injury resulting from a pathologically confirmed alveolar hemorrhage, which may have been closely related to a preceding vaccination for pandemic influenza A of 2009/10. The present patient had been hospitalized with an acute lung injury after flu vaccination one year prior to the present hospitalization, however, he received another flu vaccination. We should consider a vaccine-related adverse reaction as a potential cause of pulmonary disease if patients present with this illness during the winter season. Key words: acute lung injury, alveolar hemorrhage, flu vaccination (Intern Med 54: 3193-3196, 2015) (DOI: 10.2169/internalmedicine.54.4894)

Introduction Vaccination is the primary form of prophylaxis against infectious diseases, however, severe adverse drug responses (ADR), which are reactions other than the desired immune response, do occur at a very low frequency. The environment surrounding influenza has markedly changed after the influenza A (H1N1) pandemic of 2009/10 (H1N1pdm). Sporadic ADR cases have been reported since the H1N1pdm vaccine was introduced in 2010 (1-10). We herein report a case in which we pathologically diagnosed a typical pulmonary alveolar hemorrhage attributable to the H1N1pdm flu vaccine.

Case Report An 82-year-old man with hypertension, angina pectoris, and paroxysmal atrial fibrillation was referred to our hospital for an evaluation of a fever, bloody sputum, and dyspnea several days after receiving antimicrobial agents for pneumonia. He had been hospitalized with an acute lung injury (ALI) one year previously (Fig. 1A-C), however, the cause of his ALI had not been identified despite diagnostic tests

being performed. He was treated for five months, starting at the disease onset, with systemic corticosteroids. His familial and medical histories were unremarkable. He neither smoked nor drank alcohol regularly. He had no history of caring for animals. Moreover, he had no history of allergies to drugs, foods, or inhaled substances. Chest roentgenography showed an infiltration shadow in the lower right lung field (Fig. 1D), and computed tomography (CT) revealed ground-glass opacities with diffuse expansion not only in the right lung but also in the left lung (Fig. 1E, F). Radiological findings suggested ALI, and the patient was emergently hospitalized with a diagnosis of recurrent acute respiratory failure. On admission, there were no remarkable blood examination findings. Biochemistry and serology analyses, including tests for myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA), were negative (Table). After this admission, the bronchoalveolar lavage (BAL) fluid was collected using optical bronchoscopy to investigate the possible causes of ALI. The BAL fluid was bloody and hemosiderin-laden macrophages were seen on microscopic reflected images. Lung tissue obtained by a transbronchial lung biopsy also revealed the presence of hemosiderin-laden

１

Department of Respiratory Medicine, Ebina General Hospital, Japan, ２Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Japan, ３Department of Infection Control and Prevention, Nippon Medical School Hospital, Japan and ４Department of Pulmonary Medicine/Medical Oncology, Tama-Nagayama Hospital, Japan Received for publication January 6, 2015; Accepted for publication May 18, 2015 Correspondence to Dr. Takahito Nei, [email protected]

3193

Intern Med 54: 3193-3196, 2015

DOI: 10.2169/internalmedicine.54.4894

A

B

C

D

E

F

Figure 1. Chest roentogenographs (A, D) and computed tomography (CT) scans (B, C, E and F) obtained at each admission. A, B and C were obtained during the former admission, and D, E and F during the present. Chest roentogenographs (both A and D) show the focal lung parenchymal density. The most remarkable finding is ground-glass opacities in the right middle and lower fields. All chest CT panels (B, C, E and F) equally show the same ground-glass opacity pattern in the right lung (S4S5).

macrophages in alveolar areas (Fig. 2), however, evidence of vasculitis was minimal. He was administered steroids and his condition gradually improved. Steroid therapy was continued for approximately five months, with gradual tapering. A review of the patient’s medical problems revealed that he had been regularly given medications for cardiac disease (amlodipine, aspirin, losartan, bepridil, and cilostazol) and an antimicrobial agent (sulbactam-ampicillin). Interestingly, he had received an influenza vaccination before each hospitalization. He had been given an influenza vaccination 10 days prior to the ALI diagnosis at the first admission one year previously. At the first admission, we had not suspected ADR developing after vaccination against H1N1pdm. The next year, he had also been vaccinated for the second time by chance; two weeks later, he began to suffer from bloody sputum. This strongly supported our assumption that ALI with alveolar hemorrhage in this case was associated with influenza vaccination. We therefore diagnosed the patient with ALI due to influenza vaccination and administered steroid (methylprednisolone) treatment. We were able to control the disease activity and steroid therapy was continued for approximately six months, with gradual tapering of the dosage.

Discussion The 2009 H1N1 influenza virus was first detected in the United States (US) in April 2009 (H1N1pdm) (11-14), and the outbreak occurred not only in the US and Mexico, but also Europe and Japan. As soon as the pandemic was recognized, the vaccine for H1N1pdm was developed and used in many countries worldwide. In the US, reports documented by the Vaccine Adverse Event Reporting System (VAERS, https://v aers.hhs.gov/index) of ADR with flu vaccination totaled 10,085 cases, 7.2% of which were severe. There were 48 fatalities, of which two were caused by respiratory ADRs, however, the details of the causative factors of drug-related pulmonary disorders were not reported (1, 2). On the other hand, there were 7 reports of severe cases in Spain, 4 of which had respiratory ADRs (3). These included respiratory distress syndrome in a 6-year-old boy and pneumonia in a 94-year-old man. In Korea, 178 vaccine-related severe ADR cases including Guillain-Barré syndrome, neurologic abnormalities such as acute disseminated encephalomyelitis and anaphylactic disorders were reported. However, none of the Korean cases had respiratory ADRs (4). In Italy, a casecontrol study was conducted to show the effectiveness and safety of H1N1pdm vaccination for children, and only one case of vasculitis was reported (5). Thus, there are very few

3194

Intern Med 54: 3193-3196, 2015


Table. Laboratory Data for the Present Admission. Blood cell counts white blood cells red blood cells hemoglobin platelets Biochemical parameters aspartate aminotransaminase alanine aminotransferase lactose dehydrogenase sodium potassium chloride blood urea nitrogen creatinin total protein albumin

9,310 /ȝ/ 399×104 /ȝ/ 10.8 g/d/ 34.8×104/ȝ/ 22 IU// 19 IU// 265 IU// 141 mEq// 4.1 mEq// 104 mEq// 22.6 mg/d/ 1.17 mg/d/ 7.3 g/d/ 3.4 g/d/

Serologies C reactive protein antinuclear antibody anti-neutrophil cytoplasmic antibody against myeloperoxidase against protease-3

negeative negeative

Other markers surfactant protein D K/-6

241.6 ng/m/ 343 U/m/

Figure 2. Microscopic findings of a transbronchial lung biopsy specimen obtained from the right lung. The specimen is stained with Berlin blue. There are numerous hemosiderinladen macrophages (black arrows), however, signs of vasculitis are indistinct.

4.87 mg/d/ negeative

BA/ fluid analysis (obtained from right-sided B4) cell counts 12.5×105/m/ macrophages 69% neutrophils 1% lymphocytes 27% eosinophils 3% CD4/CD8 ratio 0.26 Abbreviations: K/-6: Krebs von /ungen 6, BA/: bronchoalveolar lavage, CD: cluster of differentiation

descriptions of vaccine-related vasculitis or pulmonary injury. In Japan, the Ministry of Health, Labour and Welfare reported ADRs to the H1N1pdm vaccine (from October 2009 to March 2010) and the seasonal flu vaccine (from April 2007 to March 2010) (6). ADRs to the former vaccine included five interstitial pneumonia cases, four which experienced exacerbation and one with allergic purpura. The latter vaccine resulted in two cases of interstitial pneumonia (one case with exacerbation), nine with thrombocytopenia purpura, and five with allergic purpura (6). In addition, several Japanese reports have described flu vaccine-related interstitial pneumonia (15-17). Moreover, there are reports of cases with systemic vasculitis (18-20), two of which had positive serum MPO-ANCA results (18, 19). These vasculitis cases raise the possibility of an association with flu vaccination (21). However, vaccine-related interstitial pneumonia or systemic vasculitis appears to be rare. Watanabe et al. reported a 7-year-old girl who developed H1N1 pdm vaccination-related Henoch-Schönlein purpura (HSP), despite having previously received an inoculation against the seasonal influenza annually (22). There are additives in the H1N1pdm vaccine, but not in the seasonal flu vac-

cine. Certain additives have, in fact, been suggested to be associated with the onset of HSP. However, the causative associations between HSP onset and these additives were unclear (23). Generally, additives are included in vaccine preparations. For instance, squalene, a naturally occurring substance found in plants, animals, and humans, is added to vaccines as an adjuvant, and thimerosal, a well-established antiseptic and antifungal agent, is also included in most vaccine formulations (24). Mild erythema, muscular pain, fatigue, and severe lassitude are the reported side effects of these additives, however, there have been no reports of serious ADRs (25). To the best of our knowledge, this is the first reported case of ALI with pathologically confirmed pulmonary alveolar hemorrhage developing after vaccination against H1N1pdm. Furthermore, the history of the previous H1N1pdm vaccinations, despite several seasonal flu vaccinations before the pulmonary events, is clinically significant. In conclusion, we herein experienced a case of pathologically confirmed pulmonary alveolar hemorrhage associated with H1N1pdm flu vaccination. Our present case strongly suggests that physicians should be aware of the potential of this serious ADR developing after vaccination against H1N1pdm but not seasonal flu. Therefore, pulmonary injury or alveolar hemorrhage in the influenza season should always prompt physicians to consider the possibility of flu vaccinationrelated ADR. The authors state that they have no Conflict of Interest (COI). Acknowledgement We thank Bierta Barfod for editing the manuscript and Hiromi Watanabe for secretarial assistance.

References

3195

1. Vellozzi C, Broder KR, Haber P, et al. Adverse events following

Intern Med 54: 3193-3196, 2015

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.


influenza A (H1N1) 2009 monovalent vaccines reported to the Vaccine Adverse Event Reporting System, United States, October 1, 2009-January 31, 2010. Vaccine 28: 7248-7255, 2010. Centers for Disease Control and Prevention (CDC). Safety of influenza A (H1N1) 2009 monovalent vaccines-United States, October 1-November 24, 2009. MMWR Morb Mortal Wkly Rep 58: 1351-1356, 2009. Carvajal A, Ortega PG, Sáinz M, et al. Adverse events associated with pandemic influenza vaccines: comparison of the results of a follow-up study with those coming from spontaneous reporting. Vaccine 29: 519-522, 2011. Kim JH, Cho HY, Hennessey KA, Lee HJ, Bae GR, Kim HC. Adverse events following immunization (AEFI) with the novel influenza a (H1N1) 2009 vaccine: findings from the national registry of all vaccine recipients and AEFI and the passive surveillance system in South Korea. Jpn J Infect Dis 65: 99-104, 2012. Italian Multicenter Study Group for Drug and Vaccine Safety in Children. Effectiveness and safety of the A-H1N1 vaccine in children: a hospital-based case-control study. BMJ Open 1: e000167, 2011. Pharmaceutical and Food Safety Bureau，Ministry of Health, Labor and Welfare. Iyakuhin, Iryokikito Anzenseijoho (Pharmaceuticals and Medical Devices Safety Information) 273: 11-22, 2010 (in Japanese). Yih WK, Lee GM, Lieu TA, et al. Surveillance for adverse events following receipt of pandemic 2009 H1N1 vaccine in the PostLicensure Rapid Immunization Safety Monitoring (PRISM) System, 2009-2010. Am J Epidemiol 175: 1120-1128, 2012. McCarthy NL, Gee J, Lin ND, et al. Evaluating the safety of influenza vaccine using a claims-based health system. Vaccine 31: 5975-5982, 2013. Pahud BA, Williams SE, Dekker CL, et al. Clinical assessment of serious adverse events in children receiving 2009 H1N1 vaccination. Pediatr Infect Dis J 32: 163-168, 2013. Liang XF, Li L, Liu DW, et al. Safety of influenza A (H1N1) vaccine in postmarketing surveillance in China. N Engl J Med 364: 638-647, 2011. Echevarría-Zuno S, Mejía-Aranguré JM, Mar-Obeso AJ, et al. Infection and death from influenza A H1N1 virus in Mexico: a retrospective analysis. Lancet 374: 2072-2079, 2009. Perez-Padilla R, de la Rosa-Zamboni D, Ponce de Leon S, et al. Pneumonia and respiratory failure from swine-origin influenza A

(H1N1) in Mexico. N Engl J Med 361: 680-689, 2009. 13. Dawood FS, Jain S, Finelli L, et al. Emergence of a novel swineorigin influenza A (H1N1) virus in humans. N Engl J Med 360: 2605-2615, 2009. 14. Bautista E, Chotpitayasunondh T, Gao Z, et al. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med 362: 1708-1719, 2010. 15. Kanemitsu Y, Kita H, Fuseya Y, et al. Interstitial pneumonitis caused by seasonal influenza vaccine. Nihon Kokyuki Gakkai Zasshi 48: 739-742, 2010 (in Japanese, Abstract in English). 16. Kumamoto T, Mitsuyama H, Hamasaki T. [Case report; Drug induced lung injury caused by 2009 pandemic H1N1 vaccine]. Nihon Naika Gakkai Zasshi (Journal of the Japanese Society of Internal Medicine) 100: 3034-3037, 2011 (in Japanese). 17. Umeda Y, Morikawa M, Anzai M, et al. Acute exacerbation of idiopathic pulmonary fibrosis after pandemic influenza A (H1N1) vaccination. Intern Med 49: 2333-2336, 2010. 18. Konishi M, Koarada S, Yamaguchi K, et al. Case of microscopic polyangiitis and giant cell arteritis after influenza vaccination. Nihon Rinsho Meneki Gakkai Kaishi (Japanese Journal of Clinical Immunology) 34: 154-161, 2011 (in Japanese, Abstract in English). 19. Uji M, Matsushita H, Iwata S. Microscopic polyangiitis after influenza vaccination. Intern Med 44: 892-896, 2005. 20. Liu PY, Shi ZY, Lee CH. Cutaneous vasculitis following influenza vaccination. Intern Med 49: 2187-2188, 2010. 21. Birck R, Kaelsch I, Schnuelle P, Flores-Suárez LF, Nowack R. ANCA-associated vasculitis following influenza vaccination: causal association or mere coincidence? J Clin Rheumatol 15: 289-291, 2009. 22. Watanabe T. Henoch-Schönlein purpura following influenza vaccinations during the pandemic of influenza A (H1N1). Pediatr Nephrol 26: 795-798, 2011. 23. Zafrir Y, Agmon-Levin N, Shoenfeld Y. Post-influenza vaccination vasculitides: a possible new entity. J Clin Rheumatol 15: 269-270, 2009. 24. Montana M, Verhaeghe P, Ducros C, Terme T, Vanelle P, Rathelot P. Safety review: squalene and thimerosal in vaccines. Therapie 65: 533-541, 2010. 25. Fox CB, Haensler J. An update on safety and immunogenicity of vaccines containing emulsion-based adjuvants. Expert Rev Vaccines 12: 747-758, 2013.

Ⓒ 2015 The Japanese Society of Internal Medicine http://www.naika.or.jp/imonline/index.html

3196