Influenza A H5N1 and HIV co-infection: case report
© Fox et al; licensee BioMed Central Ltd. 2010
Received: 1 March 2010
Accepted: 14 June 2010
Published: 14 June 2010
The role of adaptive immunity in severe influenza is poorly understood. The occurrence of influenza A/H5N1 in a patient with HIV provided a rare opportunity to investigate this.
A 30-year-old male was admitted on day 4 of influenza-like-illness with tachycardia, tachypnea, hypoxemia and bilateral pulmonary infiltrates. Influenza A/H5N1 and HIV tests were positive and the patient was treated with Oseltamivir and broad-spectrum antibiotics. Initially his condition improved coinciding with virus clearance by day 6. He clinically deteriorated as of day 10 with fever recrudescence and increasing neutrophil counts and died on day 16. His admission CD4 count was 100/μl and decreased until virus was cleared. CD8 T cells shifted to a CD27+CD28- phenotype. Plasma chemokine and cytokine levels were similar to those found previously in fatal H5N1.
The course of H5N1 infection was not notably different from other cases. Virus was cleared despite profound CD4 T cell depletion and aberrant CD8 T cell activation but this may have increased susceptibility to a fatal secondary infection.
Influenza A/H5N1 infection is characterized by high viral loads, overproduction of pro-inflammatory cytokines and chemokines, direct lung tissue destruction, pulmonary oedema and extensive inflammatory infiltration [1–3]. The prevailing view is that alveolar damage is the primary pathology leading to acute respiratory distress, multiple organ dysfunction syndrome and death . Likewise, 2009 H1N1 infection can cause acute respiratory distress syndrome and death in previously healthy young adults very similar to the clinical syndrome seen in H5N1 .
It remains unclear whether lung pathology in severe influenza is a direct consequence of high viral loads and/or of ensuing inflammatory responses. The involvement of innate versus adaptive immunity in inflammation or controlling viremia is also poorly defined. Further understanding of the pathological processes is necessary to develop interventions that prevent severe lung disease. The occurrence of H5N1 infection in a patient with HIV infection offered a unique opportunity to study the pathological and immunological process when adaptive immunity is impaired.
Antibiotics and antifungals given
Days of illness
Laboratory tests for co-infection
negative after 5 days
smear and Ziehl-Neelsen stain
culture for bacteria and fungi
Mantoux/PPD skin test
negative after 5 days
culture for bacteria and fungi
negative after 5 days
smear for fungi
smear and Ziehl-Neelsen stain
culture for bacteria and fungi
Candida albicans Aspergillus fumigatus
Blood samples were available for immunological assessment until day 7 of illness. CD4 lymphopenia was marked (Figure 1) with a CD4 count of 100/μl and a CD4:CD8 ratio of 0.16 at admission, which is lower than previously reported for any H5N1 case . CD4 and CD8 counts decreased until virus was cleared (Figure 1). The percentage of CD8 T cells expressing activation markers including HLA-DR (Figure 1) increased to reach levels at least 10 times higher than normal . At admission 50% of CD8 T cells had a fully differentiated (CD27-CD28-) phenotype but this decreased with a concomitant increase in the percentage with an intermediate differentiation (CD27+CD28-) phenotype (Figure 1).
Chemokine and cytokine levels were measured using cytometric bead array kits (Becton Dickinson). MIG (CXCL9), IL-8 (Figure 1), IP-10 (CXCL10), MCP-1 (CCL2), IL-6 and IFN-γ (not shown) concentrations were increased to levels similar to those found previously in patients with fatal H5N1. IL-8, MCP-1 and IL-6 levels declined from day 5 to 7 whereas MIG and IP-10 increased.
To our knowledge only one other patient with documented HIV and H5N1 co-infection has been reported and details of the clinical course in this patient have not been published .
Patients with immune compromise including those with HIV are at higher risk of complications associated with seasonal influenza . This may not translate to highly pathogenic H5N1 which has been fatal in the majority of previously healthy patients. Although early clinical and laboratory findings were similar to those of other fatal H5N1 patients [2, 6, 8, 9], the patient showed a transient clinical improvement and a relatively delayed time to death, which was accompanied by signs of secondary pneumonia. In addition, viral loads were relatively low with no virus detection in plasma, unlike some fatal cases described previously [2, 6, 8, 9] suggesting that H5N1 viral clearance was not compromised by HIV co-infection. H5N1 can be cleared without antivirals and there is little benefit of Oseltamivir after day 6 of illness [9, 10]. However early control of viral load appears to be important because survival rates are highest in patients treated earliest . Thus, the contribution of Oseltamivir may have been negligible in this patient because viral loads were relatively low prior to administration. Lymphopenia is common in H5N1 patients [2, 6, 9] and low CD3 counts and CD4:CD8 ratios have been reported . We can not determine if immune compromise preceded influenza A/H5N1 infection in this patient. Investigation of AIDS defining illnesses was not exhaustive because the patient was reported to have been healthy and the presenting symptoms and rapid onset of illness were consistent with the confirmed diagnosis of H5N1. We can not exclude the possibility of P. jirovecci or mycobacterial co-infection. CD4 counts and CD4:CD8 ratios were lower than we have seen in other H5N1 patients (unpublished findings). This suggests that CD4 T cells may not be required for viral clearance consistent with findings that CD8 T cells are more important for survival from highly virulent influenza infection in mice . The patient maintained substantial numbers of peripheral CD8 T cells and a large fraction became activated, but the concomitant shift to a CD27+CD28- phenotype raises doubts about their antiviral function. This phenotype is associated with CD8 T cells that proliferate but lack cytotoxic function and accumulate in progressive HIV infection . Chemokine and cytokine levels were high as in other fatal H5N1 cases and may account for the severity of the early pneumonia. The prevailing view is that excessive cytokine and chemokine release are secondary to high viral loads , whereas viral loads were low in this patient. Although HIV infection is also associated with increased expression of proinflammatory cytokines [13, 14], levels tend to be lower than found here , even with co-presentation of pneumocystis pneumonia, bacterial pneumonia or mycobacteriosis, and IFN-γ expression is often decreased . Levels of IL-8, MCP-1, and IL-6 also decreased with H5N1 viral load indicting that they are primarily induced by H5N1 infection. There has been no conclusive report of secondary infection accompanying H5N1 whereas secondary pneumonia may have caused a considerable fraction of the deaths from the highly pathogenic 1918 H1N1 strain and the current H1N1 2009 strain . Findings in this patient including recrudescence of fever, rising CRP levels and neutrophilia were consistent with a secondary infection despite being treated with broad-spectrum antibiotics. A. fumigatus was detected in a tracheal aspirate suggestive of invasive pulmonary aspergillosis. Corticosteroid adminsitration may have contributed to the presumed development of invasive pulmonary aspergillosis , but there have been numerous reports of invasive pulmonary aspergillosis developing after influenza A infection in which T cell lymphopenia occurred [18, 19]. None these patients had HIV and few received corticosteroids indicating the influenza A associated immune suppression may be sufficient for the development of invasive pulmonary aspergillosis. In conclusion the course of H5N1 infection in this case was not notably different in the presence of HIV co-infection but it is possible that HIV co-infection and profound CD4 T cell depletion increase susceptibility to secondary infection. The findings suggest that CD4 T cells may not be required for H5N1 virus clearance.
The admitting hospital approved the use of patient samples and data and written informed consent was obtained from the next of kin for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
This work was funded by the Wellcome Trust UK Major Overseas Programme and The South East Asia Infectious Diseases Clinical Research Network. We thank Ngoc Nghiem My and Rogier Van Doorn for performing the HIV viral load determination.
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