Animal, especially avian, influenza A viruses occasionally infect humans and to date human cases of infection with H7N7, H7N3, H7N2, H9N2, H5N1, H1N1, H6N1 and, most recently, H7N9 viruses have been identified.1 One of them has caused a pandemic (H1N1/2009), whilst the others have so far remained zoonotic causing either rare sporadic cases (H7N3, H7N2, H9N2, H6N1) or larger numbers of cases sometimes with evidence of limited person to person transmission (H5N1, H7N7, H7N9).1-3
Each new finding of a novel influenza hemagglutinin (HA) or neuraminidase (NA) type that can infect humans changes our understanding of the diversity of influenza subtypes that pose a risk to humans, and for which surveillance is critical. These infections also add to our understanding of the genetic and phenotypic determinants of the ability of animal influenza viruses to infect humans and cause disease. Recently, one fatal case of human infection with a novel reassortment avian influenza A (H10N8) virus was reported in Nanchang, Jiangxi Province, China.4 The second and third cases of human infection with H10N8 virus were also occurred to date. Here we summarize the clinical characteristics of the three cases to improve the understanding of this novel avian virus resulting in infection.
METHODS
Clinical data of the three cases of human infection with H10N8 virus were collected from four hospitals in Nanchang, Jiangxi Province, China, including symptoms, signs, underlying diseases, laboratory tests, radiologic imaging, epidemiology, treatment and prognosis from November 30, 2013 to June 22, 2014.
RESULTS
Clinical data
Case 1
A 73-year-old female was admitted to Nanchang First Hospital, Nanchang, Jiangxi Province, on November 30, 2013 with a febrile respiratory illness. Three days prior to admission, she had a productive cough with white sputum and chest tightness, then developed a fever with a temperature of 38.6 °C. The patient had a history of hypertension and coronary heart disease for many years. In December 2012, she underwent a thymectomy for thymoma complicated with myasthenia gravis.
On admission, the patient had an axillary temperature of 38.4 °C, a pulse of 94 per minute, blood pressure of 150/80 mmHg and a respiratory rate of 24 per minute. Inspiratory crackles were heard in the left lower lobe, but no other abnormalities were noted. Laboratory tests revealed increased proportion of neutrophils, hyponatremia, raised serum glucose, and remarkable high C-reactive protein and procalcitonin (Table 1). The patient was hypoxic with a PaO2/FiO2 ratio of 114 and a chest computed tomography (CT) showed multiple ground glass opacities and consolidations in both lungs with a small pleural effusion, and chest radiography showed worsening bilateral pulmonary infiltrations (Figure 1).
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Table 1:
Laboratory results initially obtained in the course of illness
Figure 1.:
Chest radiologic imaging for case 1. A and B were computed tomography scan on December 1, 2013. On day 3 of admission, A showing consolidations and partial ground glass opacities in the right middle and lower lobes, and ground glass opacities in left lingular lobe at superior segment of right lower lobe level; B showing consolidations and partial ground glass opacities in the right middle and lower lobes, and left lower lobe at right pulmonary vein level. C showing portable chest radiographs on December 3, 2013. On day 5 of admission, bilateral opacities and consolidations deteriorated, especially in the right lung.
The patient was commenced on cefotaxime and levofloxacin, and prompt noninvasive ventilation with an FiO2 of 50% on day 1 of admission. However, she remained pyrexic (up to 40.0 °C) and her condition deteriorated. On day 3, the anti-infective regimen was changed to meropenem, vancomycin, moxifloxacin, and oseltamivir 75 mg b.i.d. Glucocorticoids were given from day 3, with dosage equivalent to methylprednisolone 107 mg to 160 mg daily. The patient continued to deteriorate and was intubated and mechanically ventilated on day 4. Her body temperature was still more than 39.0 °C. Her blood pressure decreased to 72/40 mmHg on day 5, but did not improve despite inotropic and vasopressor therapy. The patient died 6 days after admission with respiratory failure, renal failure and septic shock.
Bacterial cultures from tracheal aspirates and blood were all negative. On December 9, 2013, influenza A(H10N8) was confirmed in the tracheal aspirates specimen by Chinese center for Disease control and prevention (CDC) as a new reassortment avian influenza virus A(H10N8) with A (H9N2) vitus.
Case 2
A 55-year-old female was admitted to Jiangxi Provincial People's Hospital, Nanchang, Jiangxi Province, on January 15, 2014, after developing a dry cough and dyspnea without fever for a week. No special management was given prior to admission. One day before admission, she developed a fever with a maximal temperature of 39.7°C. There was no recorded underlying disorder before.
On admission, the patient had an axillary temperature of 39.1 °C, a pulse of 127 per minute, blood pressure of 139/74 mmHg and a respiratory rate of 30 per minute. On examination inspiratory crackles were heard in both lower lobe without other abnormalities. Laboratory tests revealed increased proportion of neutrophils, hyponatremia, elevated C-reactive protein and elevated aspartate aminotransferase (Table 1). The patient was hypoxic with a PaO2/FiO2 ratio of 224 and a chest computed tomography CT taken on admission showed diffuse infiltrations and consolidations in both lungs, with a large mass (10 cm × 8 cm) in the left upper lobe (Figure 2).
Figure 2.:
Chest radiologic imaging for case 2. A and B were serial portable chest radiographs on January 17 and 24, 2014, respectively. A showing multiple diffused infiltrations in bilateral lungs; B showing deterioration in radiology. C and D were computed tomography scan on January 15, 2013. On day 1 of admission, C showing multiple diffused infiltrations and consolidations in bilateral lungs (lung window); D showed a large mass (10 cm × 8 cm) in the left upper lobe (mediastinal window). E, F, G and H were computed tomography scan taken respectively on February 11, February 27, March 21 and April 18, 2014, and show that partial infiltrations were absorbed gradually.
The patient was initially administrated with imipenem, moxifloxacin, and oseltamivir 75 mg b.i.d. on day 1 of admission. Due to deteriorating respiratory failure the patient was intubated and mechanically ventilated with an FiO2 of 80%, and immunoglobulin was also administrated intravenously from day 2 for five days. Methylprednisolone was intermittently administrated from day 2 with dosage ranging from 10 mg to 40 mg daily. Meanwhile the patient developed hypotension, and inotropic and vasopressor therapy was commenced on day 2. The dosage of oseltamivir was doubled on day 3 after confirmed un-subtypable influenza A virus infection. In view of her deteriorating clinical status, she was transferred to Nanchang University First Affiliated Hospital on day 4. The patient underwent percutaneous tracheostomy on day 12. Oseltamivir was withdrawn on day 17. Anti-infective regimen was adjusted for secondary bacterial and fungal infections according to pathogen species in cultures, susceptibility testing and drug toxicity. Chest CT taken on February 11, February 27, March 21 and April 18, 2014 showed that bilateral infiltrations were absorbed gradually, and the mass in the left upper lobe was suspected as a benign tumor (possibly teratoma) (Figure 2). The condition of this patient improved after transferal with gradually reduction of ventilation support requirements, and she was successfully withdrawn from the mechanical ventilation in the weaning process. Currently, the patient was wellrecovered and discharged from hospital.
Serial bacterial cultures from tracheal aspirates showed Serratia marcescens, Xanthomonas maltophilia, and Acinetobacter baumannii. Candida, Acinetobacter baumannii, and Burkholderia cepacia were detected in blood cultures respectively on day 7, 8 and 16. However, blood cultures were negative on day 9, 11, 14 and 20. On January 24, 2014, influenza A(H10N8) virus was confirmed in the tracheal aspirates specimen by Chinese CDC as a new reassortment avian influenza virus A (H10N8) with A(H9N2) virus. Regarding to the viral shedding, no more influenza A virus HA RNA was detected by Real-time (RT)-PCR in local CDC laboratory after January 24, 2014.
Case 3
A 75-year-old male was admitted to Nanchang University Fourth Affiliated Hospital, Nanchang, Jiangxi Province, on February 4, 2014. Two days prior to admission, he developed a fever with a temperature of 38.7°C, accompanying with dry cough, fatigue, and anorexia. He took cold medications by himself with no improvement. The chest radiography taken one day before admission showed infections of both lungs (Figure 3). He had a history of hypertension and benign prostatic hyperplasia for many years.
Figure 3.:
Serial chest radiographs for case 3. A showing multiple infiltrations of bilateral lungs one day before admission, especially in right lower lobe (February 3, 2014). B and C showing deterioration respectively on February 5 and 7, 2014.
On admission, the patient had an axillary temperature of 38.7°C, a pulse of 100 per minute, blood pressure of 166/100 mmHg and a respiratory rate of 22 per minute. No crackles were heard in both lungs and no other abnormalities were found on examination. Laboratory tests revealed increased proportion of neutrophils, elevated aminotransferase, and remarkable high C-reactive protein (Table 1). The patient was hypoxic with a PaO2/FiO2 ratio of 233.
The patient was initially commenced on piperacillintazobactam and noninvasive ventilation on day 1 of admission. He remained pyrexic (up to 39.2 °C) and hypoxia was unable to improve. Then, invasive mechanical ventilation was administrated with an FiO2 of 100% and a high PEEP. Anti-infective regimen was changed to imipenem, fusidic acid and oseltamivir 75 mg B.I.D on day 3. However, his condition continued to deteriorate, serial chest radiology showed deterioration on day 2 and day 4 of admission (Figure 3). He developed hypotension and inotropic and vasopressor therapy was given on day 4. Methylprednisolone 40 mg Q.D. and immunoglobulin were administrated and the dosage of oseltamivir was doubled on day 4 as well. The patient died 5 days after admission with respiratory failure, renal failure and septic shock.
Bacterial cultures from tracheal aspirates were negative on day 3, but revealed Pseudomonas Aeruginosa and Acinetobacter baumanni on day 4. Blood cultures were all negative. Serum influenza A antigen was negative on day 3 but turned positive on day 4. On February 13, 2014, influenza A(H10N8) virus was confirmed in the tracheal aspirates specimen by Chinese CDC as a new reassortment avian influenza virus A(H10N8) with A(H9N2) virus.
Etiologic diagnosis and epidemiology
The final etiologic diagnosis of the three cases were severe pneumonia and ARDS due to a novel avian influenza A(H10N8) virus infection. Retrospective epidemiologic investigation showed that case 1 bought a freshly slaughtered-chicken at a local live poultry market 4 days before onset of illness, case 2 visited a wet market 3 days before onset of illness but no other exposure to live poultry was reported, and case 3 had a contact history of live poultry one week before onset of illness. None of their close contacts developed influenza-like symptoms during 14 days of follow-up.
DISCUSSION
Clinical characteristics
Here we described three cases of a new reassortment avian influenza A(H10N8) virus, of which two were fatal cases (case 1 and case 3), and one was severe case (case 2). The patients presented with severe pneumonia that progressed to ARDS and intractable respiratory failure without obvious involvement of other organs, although case 1 and case 3 developed acute kidney injury in the course of illness, which might be due to hypoperfusion or medication toxicity. Also there was no sufficient evidence that the viral replication took place in non-respiratory organs which was proven in H5N1 patients by means of postmortem examinations.5 Case 2 showed signs of improvement and was eventually discharged from hospital, but case 1 and case 3 died from the infection. We could find that case 1 and case 3 were older than case 2, which implied that elderly people infected with H10N8 might have poorer prognosis. Case 1 had thymoma and possibly undiagnosed type 2 diabetes which could impair immunologic functions, and case 2 had a possibly benign lung tumor. The underlying disorders indicated that the host factors might also have contributed to both susceptibility to infection and disease severity.
The novel H10N8 infected cases were all sporadic cases with no evidence of human-to-human transmission. The epidemiological contact history indicated that the incubation period might range from three to seven days. The treatment for fatal avian influenza virus infection is always intractable. The effect of antiviral treatment in clinical practice was limited for the delayed delivery beyond 48 hours after onset of illness (five to seven days in H10N8 cases), although there was evidence that H10N8 virus is sensitive to neuraminidase inhibitors (oseltamivir and zanamivir).4 Extracorporeal membrane oxygenation (ECMO) improved survival for certain patients with severe respiratory failure,6 and was previously used in H1N1, H5N1 and H7N9 patients, which may be a choice for refractory hypoxia in H10N8 patients as well.
Comparison with other high pathogenic avian influenza virus
H5N1 and H7N9 viruses are the other two common high pathogenic avian influenza viruses, which have some differences with the novel H10N8 virus. Similar with H5N1 and H7N9, H10N8 infection showed common symptoms of fever and cough, bilateral infiltrations in radiography, lymphopenia, and elevated C-reactive protein. Case 2 and case 3 showed elevated creatine kinase and lactate dehydrogenase that could also be found in H5N1 and H7N9 patients.7 The differences between H10N8 patients with H5N1 and H7N9 patients were summarized in Table 2. All of the three patients showed normal or mild increased leukocytes as well as increased proportion of neutrophils on the early stage of illness, which is unusual since leukopenia and neutropenia is a feature of other avian influenza infections.7,8 Some H5N1 and H7N9 patients developed anemia and thrombocytopenia, which were not showed in H10N8 patients. Elevated aminotransferase was found in the initial laboratory tests of case 2 and case 3, which could be found in H5N1 and H7N9 patients as well. However, it was hard to draw the conclusion that liver injury was directly related to H10N8 virus, since the medication usage before admission and hypoxia might play a role. Because of the limited number of H10N8 patients, the precise clinical picture of the novel virus is difficult to draw.
Table 2:
Differences between the novel H10N8 with H5N1 and H7N9
Viral characteristics
Influenza A(H10N8) virus is a low pathogenic avian influenza (LPAI) virus that was first detected in Europe in 1995.9 It circulates both in wild avian populations in wetlands and has been detected in live poultry and the associated market environment in the South of China.10,11 However, the recent cases were infected by a novel reassortment avian influenza A(H10N8) with A(H9N2), not previously detected in wild or domestic birds. Human infections with avian influenza viruses may cause a severe viral pneumonia with diffuse alveolar damage, presumably due to the affinity of the HA of avian viruses for glycans terminating in a sialic acid linked to galactose in an α2-3 configuration, which are present in the lower respiratory tract of humans. Severe pneumonia associated with avian influenza virus infections is also often accompanied by an exuberant inflammatory response, probably secondary to a failure to control viral replication. Although H10N8 is LPAI, existing H10N8 viruses can replicate efficiently in the murine lung without prior adaptation and its virulence in mice can also increase rapidly during infection.10 It raises the possibility that this novel reassortment influenza A(H10N8) may also be adaptable to mammalian hosts.
Pandemic influenza is one of the greatest threats to global health, and assessing the pandemic potential of the diverse range of avian influenza viruses requires continued vigilance and a fuller understanding of what currently constrains the ability of animal influenza viruses to infect and transmit between humans, and the mechanisms of pathogenesis. Here we summarized the clinical characteristics of the first three cases of human infection with the novel reassortment avian influenza A(H10N8) virus. This novel virus which can lead to fatal human infection should be concerned in clinical practice to avert a potentially broader transmission.
(Received April 29, 2014)
Edited by Chen Limin
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