Via PlosONE.org a paper detailing the case presentations of the 26 human H5N1 infections in China. It is always of interest when we receive clinical case data on human infections, and again we find that a delay in seeking medical treatment does not bode well for survival.
Clinical Characteristics of 26 Human Cases of Highly Pathogenic Avian Influenza A (H5N1) Virus Infection in China Hongjie Yu et al. [here]
Background
While human cases of highly pathogenic avian influenza A (H5N1) virus infection continue to increase globally, available clinical data on H5N1 cases are limited. We conducted a retrospective study of 26 confirmed human H5N1 cases identified through surveillance in China from October 2005 through April 2008.
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Discussion
Our findings suggest that H5N1 disease in Chinese patients generally begins with fever, cough, and sputum production, and progresses rapidly to lower respiratory disease. Upper respiratory symptoms of rhinorrhea and sore throat were less common in China than observed in Hong Kong SAR, China, Thailand [13], Turkey [21], Azerbaijan [18], and Egypt [2]. Studies suggest that the lower respiratory tract is the major site for H5N1 viral replication, although initial infection may occur in either the upper or lower respiratory tract [30]–[33].
Diarrhea was present in only two H5N1 cases at admission, but developed in a quarter of cases during hospitalization. Diarrhea was a common presenting symptom among H5N1 cases in Vietnam [11], [12] and Thailand [13], but was reported infrequently among cases in Hong Kong SAR, China [9], [10], and Indonesia[4], [16]. H5N1 virus and viral RNA have been detected in feces and intestines of human H5N1 cases [12],[17], [30], [33]. Whether the gastrointestinal tract is a primary site for H5N1 virus infection is currently unknown.
Disease course in Chinese H5N1 cases was rapidly progressive; the median time from illness onset to death in our case series is consistent with WHO findings [2]. All H5N1 cases presented with pulmonary infiltrates, and all cases progressed rapidly to bilateral disease. Many cases experienced respiratory failure, ARDS, and multi-organ failure, with hepatic dysfunction and cardiac failure. Leukopenia and lymphopenia were also common. A recent molecular pathology study on two cases documented that in addition to the lungs, H5N1 virus infects the trachea and disseminates to other organs including the brain [30]. Our findings are consistent with other reports [11]–[20]. The pathogenesis of some clinical complications could be immunologically mediated, as suggested by high levels of proinflammatory cytokines and chemokines in vitro and cytokine dysregulation in fatal cases in observational studies [10], [33], [34].
Five H5N1 cases were younger than 10 years old and one was aged 16-years, in contrast to other case series [16], [19]–[20] and the WHO finding that the highest frequency of cases was aged 10–19 years old[35]. The age profile of Chinese H5N1 cases may reflect exposure differences due to traditional social and cultural behaviours. Visiting wet poultry markets in urban areas and exposure to sick or dead backyard poultry in rural areas before illness onset are H5N1 risk factors in China (unpublished data, China CDC). Paediatric cases lived in rural areas of China, and likely had more exposures to sick/dead backyard poultry than children in urban areas. In rural areas, young Chinese children are much more likely to play with backyard poultry than older children. Adults are much more likely to visit poultry markets in urban areas of China than children and all urban adult H5N1 cases had visited a wet poultry market prior to illness onset (unpublished data, China CDC).
In contrast to the WHO finding that cases aged 10–19 years old had the highest case-fatality [2], mortality of H5N1 cases in China was not associated with median age, sex or underlying medical conditions in the bivariate analysis. Isolates from 24 cases in southern China were characterized as H5N1 clade 2.3.4 viruses with consistent genetic and antigenic properties from 2005 through 2008 (unpublished data, China CDC). There were no significant differences in case-fatality ratios between years during 2005–2008 or between cases with clade 2.2 and clade 2.3.4 H5N1 virus infection. However, fatal outcomes were associated with decreased platelet counts, increased LDH, ARDS, cardiac failure, and lack of antiviral treatment in the bivariate analyses. In Thailand [13] and Hong Kong SAR [9], mortality was associated with late presentation, lower admission leukocyte, platelet, and lymphocyte counts, bilateral pulmonary findings on chest X-ray, and development of ARDS. Decreased leukocyte and lymphocyte counts, and increased d-dimer levels were associated with fatal outcomes in other studies [4], [17], [20], [33].
Survival was significantly higher in cases that received any antiviral treatment than in untreated cases, and 5 of 8 adult cases that received standard oseltamivir treatment survived even though all were treated late in their illnesses. However, it should be noted that treatment was uncontrolled and our findings lack sequential virological data on antiviral susceptibilities or quantitative H5N1 viral shedding, and favorable outcomes and clinical courses of some H5N1 cases cannot be attributed definitively to antiviral treatment. In contrast to clade 1 H5N1 viruses isolated in Vietnam and clade 2.1 viruses in Indonesia [2], the clade 2.3.4 and clade 2.2 H5N1 viruses isolated from cases in China were susceptible to both M2 inhibitors and neuraminidase inhibitors (unpublished data, China CDC). These findings suggest roles for either class of antiviral drugs as well as combination antiviral therapy for H5N1 cases in China [36], [37].
Very few Chinese H5N1 cases received early antiviral treatment because only one patient was admitted within two days of illness onset, and no patients received outpatient antiviral treatment. Antivirals were not administrated to most Chinese H5N1 cases until they were hospitalized with pneumonia. Oseltamivir was not available in some hospitals for treatment of some cases that died. Therefore, education of health-care providers about the epidemiological risk factors and clinical characteristics of H5N1 patients, and wider availability of antiviral drugs could help facilitate earlier detection and treatment of H5N1 cases in China. Although little data on early versus late oseltamivir treatment for H5N1 patients are available, current WHO guidance recommends initiating oseltamivir treatment as early as possible, including consideration of higher dosing for severe disease and longer treatment duration because of prolonged viral replication [37].
Although antiviral therapy is the primary treatment, most clinical management of H5N1 disease is supportive. For severely ill Chinese H5N1 patients with ARDS or multiorgan failure, management has focused on appropriate mechanical ventilation, correction of hypoxemia, fluid management, and treatment of other complications such as DIC. Corticosteroids were administered empirically to most H5N1 cases in China. A reduction in the proportion of cases reporting with fever from illness onset (92%) to hospital admission (69%) may reflect an early use of corticosteroids or non steroidal anti-inflammatory drugs. Compared to fatal cases, nonfatal cases in China had a longer duration of corticosteroid treatment. However, we cannot conclude that corticosteroid therapy resulted in survival and such treatment has not been shown to be effective in H5N1 patients [2]. Furthermore, prolonged or high-dose corticosteroid therapy may result in serious adverse events, including infection with opportunistic pathogens. Recent WHO H5N1 treatment guidance recommends against routine use of corticosteroid treatment [37].
Two cases with ARDS survived after receiving passive immunotherapy with transfused convalescent plasma from surviving H5N1 cases. This is compelling, but since passive immunotherapy and other treatments were administered in an uncontrolled manner, no definitive conclusions can be made about the benefit of such treatment [38]. A third Chinese H5N1 case survived after receiving post-vaccination plasma from an H5N1 vaccine clinical trial participant and combination antiviral treatment [5]. A meta-analysis of studies of convalescent plasma treatment during the 1918 influenza pandemic [39], evidence from animal experiments [40]–[42], and the limited experience in three Chinese H5N1 cases suggest that passive immunotherapy may be a viable option for the treatment of H5N1. Further research is needed to investigate the efficacy and effectiveness of passive immunotherapy with H5N1 convalescent plasma treatment for H5N1 patients, including cases with severe complications such as ARDS.
Our study was limited to available data for H5N1 cases identified through surveillance during the study period. Due to the small number of H5N1 cases, the study was too underpowered to compare differences between fatal and nonfatal cases. National surveillance and laboratory testing might not have identified all H5N1 cases that occurred, especially if the cases were clinically mild. Clinical management was uncontrolled, H5N1 viral shedding data, immunological and pathological data were not available, and any differences in outcomes cannot be interpreted to be due to the use of antiviral drugs, corticosteroids, or other uncontrolled treatments.
To improve clinical management of H5N1 patients in China, physicians should be educated about the natural history of H5N1 disease and epidemiological risk factors, and therapy should be standardized based upon current knowledge [37]. Early antiviral treatment and expanded testing should be considered for suspected H5N1 patients, with wider availability of antiviral medications at all health care facilities. In the absence of any definitive treatment for H5N1, preventive education to reduce risk behaviours for H5N1 exposures (e.g. avoiding direct contact with sick or dead poultry) must be emphasized more strongly.
