Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Address correspondence and reprint requests to Viroj Wiwanitkit, MD, Department of Laboratory Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand 10330. E-mail: email@example.com.
Abstract: Bird flu, H5N1, infection is a new emerging infectious viral disease. This H5N1 virus jumped the species barrier and caused severe disease with high mortality in humans in recent years. Most infected patients usually developed progressive pneumonia with acute respiratory distress syndrome and consequently died. The hematologic aberration in bird flu infection is noted. Here, the author performs a summative review to document the impact of bird flu infection on hematologic findings among reported infected patients. The main hematologic manifestation of this infection is lymphopenia with decreased lymphocyte/neutrophil ratio. Anemia can also be observed in this infection. The effects of this infection on platelet are still controversial.
Influenza is an infectious disease caused by a constantly varying RNA virus. Natural infections with influenza A viruses can be found in many animals including humans, pigs, horses, sea mammals, mustelids, and birds.1 Capua and Alexander1 said that, in the 20th century, the sudden emergence of antigenically different strains transmissible in humans, termed antigenic shift, had occurred on many occasions, 1918 (H1N1), 1957 (H2N2), and 1968 (H3N2), each time resulting in a pandemic. In 1997, an outbreak of a new potentially devastating influenza strain occurred in Hong Kong.2 The outbreak included 18 cases of avian influenza (bird flu) caused by a novel H5N1 virus and occurred in humans, resulting in 6 deaths.2 Webster3 noted that the separation of aquatic birds from other land-based domestic poultry in Hong Kong after the H5N1 bird flu incident indicated that animal husbandry practices could influence the interspecies transmission of influenza viruses.
In the past year (2004), the revisit of H5N1 infection occurs in Southeast Asia. Since January 2004, the bird flu has been detected in some poultry farms, and the Thai government has launched several attempts to control the infection. Until the present time, more than 100 cases of human infection, with approximately 50% fatal cases, are documented.4 The most recent cases are part of a family under investigation to determine whether human-to-human transmission may have occurred.5 The initial case was a girl in a rural province in northern Thailand who died of pneumonia and finally diagnosed to have H5N1 infection.5,6 Her aunt who resided with the patients has also been confirmed for infection.5,6 Both patients are known to have had contact with infective dead chickens.5,6
The suspected human-to-human transmission case was the mother of the girl, who went back from Bangkok to take care of her daughter in the hospital up to the time of the child's death.5,6 Then this patient went back to Bangkok, developed flu, and died 8 days later.5,6 Continuous attempts are made to proof this possible human-to-human transmission.5,6 Indeed, a similar episode was documented in Vietnam early this year, but final conclusion cannot be made because of lack of patients' specimen. Concerning the probability of the human-to-human transmission, the epidemiology as well as the molecular biology investigations might answer this question.
Kida said that recent outbreaks of highly pathogenic avian influenza in chickens and ducks that occurred in 9 Asian countries alarmed to realize that there was no border for infections and gave a rise to great concern for human health as well as for agriculture.7 Kida also noted that this H5N1 virus jumped the species barrier and caused severe disease with high mortality in humans in Vietnam and Thailand.7 Most infected patients usually developed progressive pneumonia with acute respiratory distress syndrome and consequently died.8
An important reason to have the information on hematologic manifestations of avian influenza is that this is a new disease, and clinicians need to be better able to recognize specific signs suggestive of avian influenza as well as better treat the infection. The hematologic aberration in bird flu infection is noted.
Here, the author performs a summative review to document the impact of bird flu infection on hematologic findings among reported infected patients. A literature review on the papers concerning recent human bird flu in Thailand and Vietnam was performed from database of the published works cited in the Index Medicus, Scopus and Science Citation Index, and in all 256 local Thai journals, which are not included in the international citation index. The hematologic findings on presentation, early in the course of illness, are reviewed. Reports that contained no complete data were excluded for further analysis.
HEMATOLOGIC MANIFESTATION OF H5N1 INFECTION
Effects on White Blood Cell
In 2000, Katz et al said that, in addition to a lethal outcome, H5N1 viruses with a high pathogenicity phenotype exhibited additional features that include rapid and uncontrolled replication in the lungs of infected mice, dissemination and replication of the virus in other organs, and depletion of peripheral blood leukocytes.9 Concerning the leukocyte abnormality in bird flu infection, Tran et al10 reported 10 cases of bird flu infections in Vietnam and showed that all patients had clinically significant lymphopenia (average lymphocyte count, 700 cells/μL; Table 1). Grose and Chokephaibulkit8 also mentioned that lymphopenia was common in the patients infected with bird flu. This can support the finding of Katz et al9 for the lymphocyte suppression effect of H5N1 virus. Concerning 7 reports8,10-15 covering 22 Thai and Vietnamese patients with a firm diagnosis of bird flu, the lymphopenia is common. Indeed, Tam16 summarized the 18 infected cases of H5N1 in Hong Kong and found that all severe cases presented with lower respiratory tract infection and lymphopenia.
The immunohematologic aspect of this viral infection has not been well documented. Of interest, the reported ratios in Thai and Vietnamese patients8,11-15 are varied implying the variability in cellular response to the infection. Generally, viral infection usually induced increased lymphocyte/neutrophil ratio. However, some viral infections such as HIV infection directly attack the lymphocyte and cause decreased lymphocyte/neutrophil ratio. Concerning the average and mean of reported lymphocyte/neutrophil ratios in bird flu cases, the trend of normal to decreased ratio can be seen.8,11-15
Because the absolute neutrophil count is usually within reference range,8,11-15 the change of ratio should be due to the decrease in lymphocyte count. Considering the CD4+ count, the trend of normal level can be seen in the report of Tran et al.10
Effects on Red Blood Cell
There are only a little limited knowledge on the effect of H5N1 infection on red blood cell. According to the retrospective study of Wiwanitkit on 22 Thai and Vietnamese patients with a firm diagnosis of bird flu, the reported hemoglobin ranged from 10.0 to 17.6 g/dL with an average value equal to 13.0 ± 1.7 g/dL (median, 12.9 g/dL).17 Of the 22 cases, 5 cases or 22.7 % according to World Health Organization criteria (hemoglobin, ≤12 g/dL).17 Wiwanitkit17 noted that anemia might be an important manifestation of human bird flu infection, and H5N1 itself might cause red blood cell pathology leading to anemia. However, the conclusion cannot be made from this study because there are many contributing factors that can lead to anemia in the studied patients. Furthermore, there is no report of anisocytosis or poikilocytosis or evidence of disseminated intravascular coagulation on examination of red blood cell, which might be clues as to the etiology of the anemia.
Effects on Platelet
Concerning the platelet change in human bird flu infection, there are only a few reports on this topic. The median of platelet count in cases series in the report of Tran et al10 is low (median, 75,000/μL). Tran et al noted that severe thrombocytopenia was common and could be an important manifestation of H5N1 infection. However, Wiwanitkit18 recently studied the data on 6 Thai cases with H5N1 infection and found that the median of platelet count is within reference range (median, 167,500/μL). According to both studies, the wide range of platelet count can be seen. Further studies to get the conclusion are needed.
Bird flu, H5N1, infection is a new emerging infectious viral disease. The main hematologic manifestation of this infection is lymphopenia with decreased lymphocyte/neutrophil ratio. Anemia can also be observed in this infection. The effects of this infection on platelet are still controversial. Probably, the hematologic abnormalities seen in peripheral blood are the consequences of loss of control of hematopoiesis in individuals infected by bird flu virus as seen in other viral infection. However, some limitations of the analysis in this study should be mentioned. Bacterial coinfection with sepsis could cloud the picture, as could the timing of blood collection of the samples from which the blood cell counts are reported. Sometimes, it is difficult to determine these factors when it is a summarization of other people's reports rather than looking at all patient charts first hand.
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