Avian Influenza Disease Presentations and Pathology in Humans:
An Overview
Joseph P. Dudley
Science Applications International Corporation
Rockville, MD 20852
Introduction
The article by Ryabchkova and Getmanova in the August ASA Newsletter [ASA 07-4, August 2007] provides an excellent overview of the clinical pathology of avian influenza in birds and mammals and important insights into the complexity and variability of the physiological effects of H5N1 virus infections in birds and mammals. Because the disease pathology of H5N1 viruses in humans was not addressed in their paper, the following brief review of human H5N1 disease presentations and symptoms should be of interest to ASA readers.
The landscape of technical literature for avian influenza viruses in animals and humans has become increasing complex in recent years, as investments in avian influenza surveillance and research during the past five years have begun to reach fruition. Important new discoveries resulting from avian influenza research on birds and humans include:
- the discovery of a new avian influenza hemagglutinin subtype (the H16 subtype) in European gulls that has genetic differences in the PB2, NP, and NS genes that render it distinct from other influenza A virus subtypes (Fouchier et al. 2005)
- the identification of a single gene mutation in an H5N1 virus isolated from a human bird flu case in Vietnam capable of facilitating the establishment and proliferation of the virus within the upper respiratory tract of mammals, and which may be a prerequisite for efficient human-to-human transmission of the H5N1 virus (Hatta et al. 2007)
- the discovery of the in utero transmission of H5N1 virus from mother to fetus in a fatal H5N1 bird flu case from China (Gu et al. 2007)
Previous Human Avian Influenza Outbreaks
Prior to 1997 outbreak of H5N1 avian influenza in Hong Kong, all reported human cases of avian influenza had involved H7N7 viruses. Since 1997, however, confirmed human outbreaks have been reported involving H7N2, H7N3, H7N7, and H9N2 avian flu viruses.
Three cases of human H7N7 subtype avian influenza virus were reported prior to 1997 (Subbarao & Katz 2000, Robert Webster, personal communication Richard Webby, personal communication). In two of these cases, H7N7 was documented as the cause of clinical disease symptoms, and both involved conjunctivitis symptoms (Campbell et al. 1970; Taylor & Turner 1976; Kurtz et al. 1976; Subbarao & Katz 2000). A widespread outbreak during 2003 of a highly pathogenic H7N7 poultry virus on poultry farms in the Netherlands was associated with 89 confirmed human cases, including a single fatality. Most of the observed cases in the 2003 H7N7 outbreak had mild symptoms involving conjunctivitis or influenza-like illness, although the fatal case presented as pneumonia that progressed into a severe acute respiratory distress syndrome, and the patient had no conjunctival symptoms (Fouchier et al. 2004). A follow-up study by Bosman et al. (2005) estimated that there may have been more than one thousand human infections associated with this outbreak.
Conjunctivitis was also reported as the principal symptom of human H7N3 cases recorded in Canada during 2004 (Tweed et al. 2005) and in the United Kingdom in 2006 (Nguyen-Van-Tam et al. 2006), sometimes accompanied by mild respiratory illness. Non-fatal human infections from an H9N2 virus have been recorded in Hong Kong and mainland China on several occasions since 1999, and have involved patients with respiratory or influenza-like disease symptoms (Subbarao & Katz 2000). During May 2007, three patients in the United Kingdom exhibiting respiratory disease symptoms were later confirmed to be infected with an H7N2 avian influenza virus (DEFRA 2007).
Presentations and Pathology
The first recorded human H5N1 cases in China during 1997 in conjunction with outbreaks among poultry in Hong Kong. A total of 18 cases including six fatalities were diagnosed; clinical presentations ranged from asymptomatic infection to fatal pneumonia and multiple organ failure were recorded (Chan et al 2002). In H5N1 outbreaks since 2003, the most characteristic presentation of humans infected with highly pathogenic avian influenza H5N1 virus strains has been severe Acute Respiratory Disease Syndrome (ARDS), accompanied by hypercytokinemia involving the alveolar tissues resulting in catastrophic damage to lung tissues, and subsequent death (Chan et al 2005; de Jong et al 2006). This “cytokine storm” pathology frequently associated with the most severe ARDS presentations of H5N1 is similar to that associated with fatal human Severe Acute Respiratory Syndrome (SARS) virus infections (Nicholls et al. 2003); in fact, a suspected SARS case in China during November 2003 was later confirmed as a fatal H5N1 case (Zhu et al. 2006). Experiments with reconstructed 1918 virus suggest that this “cytokine storm” mechanism may have been responsible for the high levels of mortality observed among young adults during the 1918 Spanish Flu pandemic (Loo et al. 2007).
While most confirmed human H5N1 cases have been associated with ARDS symptoms, pneumonia, coughing and fever, it is important to recognize that fatal H5N1 infections have been confirmed in patients with atypical presentations involving fever with encephalitis and/or gastroenteritis syndromes (Apisarnthanarak et al. 2004; de Jong et al. 2005). Serological studies have identified asymptomatic infections from H5N1 in health care workers, poultry workers, and the relatives of fatal H5N1 cases (Bridges at al. 2000; Bridges et al 2002, Anonymous 2005; Dudley 2007). Positive serological studies have shown the presence of the H5N1 virus in lung tissues of patients infected during the 1997 Hong Kong outbreaks (To et al. 2001), and subsequently, in multiple body tissues: lung, brain, large intestine, small intestine, cerebrospinal fluid, kidney, spleen, liver, pharynx, and blood. (de Jong et al. 2006, Ng & To 2007). A case of the in-utero transmission of H5N1 from mother to fetus has also been reported recently (Gu et al. 2007).
The pathology and clinical presentations of H5N1 cases associated with ARDS, and that of a fatal H7N7 case from the Netherlands in 2003 resemble that which has been described for many of the fatalities from the 1918 H1N1 “Spanish Flu” pandemic. Although official epidemiological reports on the human H7N2 outbreak in the United Kingdom during 2007 are pending, media reports indicate that, of the four laboratory-confirmed human H7N2 cases in the United Kingdom in May 2007, one patient exhibited non-respiratory symptoms including nausea, headaches, and fever similar to those reported from atypical H5N1 cases in Thailand and Vietnam. This UK patient’s domestic partner was also confirmed with an H7N2 infection, but exhibited respiratory symptoms and high fever.
Conclusions
The existence of documented laboratory-confirmed atypical human H5N1 cases is critical, because the current official World Health Organization (WHO) case definition for H5N1 is categorically restricted to presentations involving respiratory symptoms (WHO 2006). As a result, the official H5N1 bird flu case counts issued by WHO exclude human H5N1 infections that are not associated with respiratory symptoms or syndromes -- even in cases with severe or fatal atypical disease syndromes (e.g., encephalitis, gastroenteritis) where the virus has been confirmed through laboratory.
While atypical human H5N1 cases involving gastroenteritis syndromes in the absence of respiratory symptoms are believed to occur only infrequently, it is important to note that diarrhea and other gastrointestinal presentations have been reported at high frequencies (40-70%) in confirmed H5N1 cases in Vietnam and Thailand (Tran et al. 2004, Areechokchai et al. 2006; de Jong & Hein 2006). This phenomenon is significant from an epidemiological perspective because viable H5N1 virus has been recovered from the feces of infected patients; fecal contamination represents a potential non-respiratory transmission route for people in developing country settings lacking sufficient public sanitation and/or wastewater treatment facilities (de Jong et al. 2005).
A comprehensive understanding of the full range of possible clinical presentations of avian influenza viruses in humans is essential for the design and implementation of effective avian flu disease surveillance and response programs. The continuing uncertainty about the role of atypical presentations in human avian influenza cases is an obstacle that must be overcome to achieve a comprehensive understanding of the significance of these viruses for human populations.
Acknowledgments
This activity was performed under the auspices of the Center for Innovative Technology's Institute for Defense and Homeland Security (www.idhs.org) in support of the Department of Defense and Air Force Research Laboratory.
Barbara Price, Col. Richard Price, Laura Peitersen, and Jeanne Marin provided helpful comments and inputs. I am grateful Robert Webster and Richard Webby for the identifications of avian influenza subtypes not provided in the original literature.
References
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Ed. Note: We want to thank Dr. Joe Dudley for his in-depth contribution to our understanding of the disease pathology of H5N1 viruses in humans and his analysis and review of human disease presentations and symptoms of avian influenza types in both animal and human. We are hoping Dr. Dudley will be able to join us at CBMTS VII with a presentation on "Zoonotic and Emerging Diseases Surveillance: A Global Public Health and Biosecurity Imperative". And with Dr. Erna Tresnaningsih's Update: Indonesia, Dr. Elena Ryabchikova's Pathology of AI in Birds and Animals, and Dr. Brian Davey's UN Preparations for Pandemic - we would have a truly super effort in this area.
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