Background
The first human avian influenza H7N9 cases were reported in March of 2013 in China. Most of these cases had a history of recent exposure to poultry. Associated with severe and fatal respiratory disease, avian influenza A (H7N9) virus was so fatal that many persons with confirmed H7N9 virus infection were critically ill, almost 100% of cases were hospitalized, and 34% of them died. [
1] Apart from the occurrence of acute respiratory distress syndrome (ARDS) and multi-organ failure, additional atypical clinical manifestations, such as neurological presentations, were associated with fatal avian influenza infection. Additional manifestations include seizures, encephalopathy and Guillan-Barré syndrome (GBS) [
2], among which GBS is usually triggered by viral or bacterial infection and characterized by acute progressive symmetric limb weakness and areflexia. GBS has been reported to result from H1N1 infection [
3‐
5]. Considering the severe conditions of H7N9 patients, 63% [
1] of whom were transferred to the intensive care unit, it is necessary to mention another neurological complication, intensive care unit-acquired weakness (ICUAW) [
6‐
8], that frequently occurred in ICU patients. Additional neurological complications include critical illness polyneuropathy (CIP) and myopathy (CIM), the paralysis of which is typically symmetrical and affects predominantly proximal limb muscles and respiratory muscles, sparing facial and ocular muscles. In this study, we report the cases of patients infected with H7N9 who developed muscle weakness and were diagnosed with ICUAW, although we could not tell if it was CIP or GBS due to various factors.
Discussion
Antiviral treatment was associated with a reduction of viral load and death rate. In this report, case 1 presented a sustained viral shedding time of 28 days, while the median has been reported to be approximately 19 days after anti-viral treatment [
9,
10]. The main reason may be the late prescription of oseltamivir on day 8 in combination with peramivir on day 26 after the onset of illness, even though it has been reported that no obvious advantage is observed from antiviral treatment to viral-negative in oseltamivir-peramivir combination therapy comparing to oseltamivir monotherapy [
11]. Another factor maybe associated is the application of corticosteroids, which could affect the viral shedding time on H7N9 patients [
12] and may cause antiviral resistance in A/H7N9 viruses [
13]. In these two cases, we prescribed methylprednisolone as 40 mg daily for 13 days and cut off to half. More solid evidence, such as randomized controlled trials, on the effect of adjuvant corticosteroids administration on viral shedding time need to be conducted on H7N9 patients.
Among 167 H7N9 infected patients admitted in our hospital centre, 89 had a severe infection and were admitted in ICU with a mean duration of mechanical ventilation of 26.3 days. Two patients, reported herein, presented a muscle weakness when we tried to withdraw mechanical ventilation, at day 28 in case 1 and at day 20 in case 2. These two patients presented bilateral and relatively symmetric flaccid weakness of the limbs with the involvement of respiratory without paralyzed cranial nerve-innervated muscles and developed decreased deep tendon reflexes, absence of an alternative diagnosis for weakness, which are consistent with Brighton Working Group clinical case definitions for GBS in level 3 certainty [
14]. The diagnosis of ICUAW could be established according to the diagnosing standards [
7], since features of these two critically ill patients almost matched all of risky factors of ICUAW reported before, including female, immobility, sepsis, persistent systemic inflammation, multi-organ system failure, hyperglycaemia, glucocorticoids, neuromuscular blocking agent, and bed rest [
6,
15].
Furthermore, the values of CK remained in the normal range, except that upon admission, the electrophysiological examination result showed that both sensory and motor nerves were injured. This finding is more similar to CIP than CIM in ICUAW. However, electrophysiological examination enabled a diagnosis of GBS at level 1 certainty or CIP, since they both include axonal motor and sensory injury, polyneuropathy in electrophysiological feathers as part of definition. Furthermore, the condition of being on a sedative for a long time made it more difficult for observing a complete course. In addition, there are about 4 to 7 cases of influenza related GBS per 100,000 cases of influenza [
16] and it has been reported that H1N1 influenza is more likely to be associated with heightened neurological complications comparing to seasonal influenza [
17]. Therefore, we cannot exclude the possibility of the H7N9 virus itself contributing and resulting in paralysis roughly.
In conclusion, it is surprising, though educational, that these two mechanically ventilated patients were hospitalized for more than two months, 90 and 77 days for each, since they both experienced ARDS, severe bacterium and fungal infection, and respiratory muscle weakness. These complications resulted in ventilatory failure and, in turn, increased the possibility of VAP, which is the most common nosocomial infection in mechanically ventilated patients. There are many aspects that we can improve. Throughout the whole disease course, a series of prevention methods, such as intensive insulin therapy and passive roll over, are needed daily, as well as prevention of VAP [
18].
Even though early investigation of muscle weakness is challenging, since mechanically ventilated patients are always sedated, physical examinations, especially neurological, for critically ill patients [
19] are needed several times per day and should be recorded in detail. As patients gradually become alert, muscle strength should be tested in functional limb muscle groups using the Medical Research Council scale [
20] or handheld dynamometry [
21] to estimate the severity of force-generating impairments. This estimation is particularly important in patients with immune-mediated polyneuropathies [
22], including GBS. To further differentiate between GBS and CIP, several procedures are important such as lumbar puncture, blood testing including tests for anti-GM1 antibodies, and anti-GQ1b and anti-GD1a IgG antibodies, and muscle and nerve biopsies.