Monday, August 25, 2008

Clinical Case Review Of 26 Chinese H5N1 Patients



#  2254




First, my thanks to SophiaZoe for posting this PLoS One study on her Blog, A Pandemic Chronicle.   



There is a good deal here to absorb, and many will want to read the entire study (always recommended), but I will try to hit the high spots of this overview of the clinical outcomes of 26 human H5N1 infections from China.



The study:


Clinical Characteristics of 26 Human Cases of Highly Pathogenic Avian Influenza A (H5N1) Virus Infection in China

Hongjie Yu1#, Zhancheng Gao2#*, Zijian Feng1#, Yuelong Shu3#, Nijuan Xiang1, Lei Zhou1, Yang Huai1, Luzhao Feng1, Zhibin Peng1, Zhongjie Li1, Cuiling Xu3, Junhua Li4, Chengping Hu5, Qun Li6, Xiaoling Xu7, Xuecheng Liu8, Zigui Liu9, Longshan Xu10, Yusheng Chen11, Huiming Luo12, Liping Wei13, Xianfeng Zhang14, Jianbao Xin15, Junqiao Guo16, Qiuyue Wang17, Zhengan Yuan18, Longnv Zhou19, Kunzhao Zhang20, Wei Zhang21, Jinye Yang22, Xiaoning Zhong23, Shichang Xia24, Lanjuan Li25, Jinquan Cheng26, Erdang Ma27, Pingping He28, Shui Shan Lee29, Yu Wang1, Timothy M. Uyeki30, Weizhong Yang1*




This study follows 26 (of 30)  reported human H5N1 cases treated in China between October, 2005 and April of 2008. 



The median age was 28, and 58% of these patients were female.



Out of 26 patients in this study, 17 (65%) died.



Interestingly, the average age of cases in this study was more than 10 years higher than we've seen from other countries, where the highest incidence of infection has been in the 10-19 year-old range.  



It is suggested in the study that  "The age profile of Chinese H5N1 cases may reflect exposure differences due to traditional social and cultural behaviours".



The good news (if it can be called that), at least for nations that have stockpiled antivirals, is the following:



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.





Even cases that received the antiviral late, tended to survive, although it is noted that this is an anecdotal observation, and is not backed up with `virological data on antiviral susceptibilities or quantitative H5N1 viral shedding'.




Of the 14 patients who did not receive antivirals, only 1 (7%) survived.




And not only was oseltamivir (Tamiflu) effective, so apparently were the older (M2 Inhibitor) antivirals like Amantadine and Rimantadine.



. . .  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.




Late hospital treatment was the norm among these Chinese patients, with some never receiving antivirals, even once hospitalized. 



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.



While antiviral therapy was the primary treatment, patients also routinely received broad spectrum antibiotics ceftriaxone (n = 6), moxifloxacin (n = 8) and azithromycin (n = 15).    


Most (88%) received high-dose corticosteroids (despite the WHO's admonition against their use).   


Out of 26 patients, 23 required ventilatory support (88%) and ARDS developed in 21 cases (81%) at a median of 8 days post-onset of the the illness.


Perhaps the most remarkable statistic of all is this:



Nine (35%) nonfatal cases were discharged at a median of 41 days (IQR 31.5–64.0) after illness onset.



In other words, the average hospital stay (among survivors) was just under 6 weeks.    



Two patients also received experimental blood plasma from previously infected survivors of the H5N1 virus.   It should be noted that these patients also received antivirals as well.



Experimental Treatment


Two critically ill adult H5N1 cases (31-year-old male, 44-year-old female) with ARDS were treated with convalescent plasma obtained from one of two fully recovered H5N1 adult donor cases.


Plasma was obtained 129 days after illness onset from an adult female case and 81 days after illness onset from an adult male case. Both donors' convalescent plasma tested negative for hepatitis B, hepatitis C, and HIV, and were separated and heat-inactivated at 56°C for 10 h before transfusion.


The male ARDS case received three units (200 mL/unit) of transfused convalescent plasma from the female donor for 2 days, beginning on illness day 13. His H5N1 viral titre in bronchial-alveolar lavage fluid declined substantially and was undetectable for the next 3 consecutive days after receipt of the third convalescent plasma dose.


The female ARDS case, who had a history of bronchiectasis, received one unit (200 mL) of transfused convalescent plasma from the male donor once daily for 3 days, starting on illness day 13. Further virological testing has not been done for this case. Both cases also received oseltamivir (75 mg po BID) on illness days 10–14 and days 8–12, respectively.


Both cases recovered fully and were discharged home.



Of the 17 fatalities (2 children, 1 adolescent, 14 adults), the average death occurred 10 days post-onset of the illness. 



The authors of the study describe the course of illness this way:


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




Of interest is the different presentation of patients from various parts of the world (and presumably due to different clades of the virus).   Chinese patients not only tended to be older than average, they showed fewer upper respiratory symptoms.



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 [9], 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.




The incidence of diarrhea reported post-hospitalization in these patients could be due to other factors than just the virus.  The administration of antibiotics, for example, can often cause this side effect.   




Twenty-six cases, with only 9 survivors, is a fairly small sample to draw firm conclusions from.   Late treatment (or no treatment with antivirals), also clouds the clinical picture considerably.



Since no autopsy results were included (likely not done due to cultural and religious objections), we don't have definitive answers as to the cause of deaths in these 17 fatalities.  



ARDS is often cited, but is this due to the virus?  Or due to a secondary bacterial pneumonia?  



The timing, 8 days into the illness, is suggestive of a secondary bacterial pneumonia, but tissue cultures would have been very useful in confirming that.  



While this study doesn't answer all of our questions, it does give us more insight into the clinical picture of H5N1 infection than we've had up till now.   



It also provides us with a pretty good indication that antivirals are at least partially effective in increasing survivability from the virus, even when administered late in the illness.