Bacterial Coinfection in Influenza a Grand Rounds Review Jama 309 275ã¢â‚¬â€œ282
Artículos originales
Effect of coinfection with influenza virus and bacteria on host damage
Efecto de la coinfección por virus de la flu y bacterias en el daño al hospedero
1 Universidad Nacional Autónoma de México, Kinesthesia of Medicine, Department of Public Wellness. Mexico City, Mexico
2 Laboratory of Virology, Instituto Nacional de Enfermedades Respiratorias. United mexican states City, Mexico
3 Universidad Nacional Autónoma de México, Faculty of Medicine, Section of Cell and Tissue Biological science. Mexico Metropolis, Mexico
Abstruse
Groundwork:
Flu virus infection is oftentimes complicated by a bacterial infection, with this coinfection causing astringent pneumonia. If not timely treated, the disease can cause decease.
Objective:
To demonstrate, in animal models, that coinfection with influenza virus and bacteria that affect the respiratory tract causes multisystemic harm.
Method:
6 groups of mice were formed: a control grouping, ane infected with the influenza virus, two infected with leaner: Haemophilus influenzae and Streptococcus pneumoniae, respectively; and two co-infected with influenza virus and Haemophilus influenzae or Streptococcus pneumoniae, respectively.
Results:
Of the half dozen groups of mice, simply the group co-infected with influenza virus and Streptococcus pneumoniae showed damage to thoracic and intestinal organs. A subtract in serum cytokine levels was found in all study groups, which was more pronounced in the co-infected mice.
Conclusions:
The groups of mice infected with Streptococcus pneumoniae or influenza virus solitary showed no harm, which indicates that coexistence of these infections caused the damage in the group of co-infected mice.
Fundamental WORDSInfluenza; Bacterial infection; Coinfection; Pro-inflammatory cytokines
Resumen
Antecedentes:
La infección por el virus de la influenza con frecuencia se complica con una infección bacteriana, coinfección que provoca cuadros graves de neumonía, la cual puede ocasionar la muerte si no es tratada en forma oportuna.
Objetivo:
Demostrar en modelos animales que la coinfección por el virus de la influenza y bacterias que afectan el tracto respiratorio ocasiona daño multisistémico.
Método:
Se formaron seis grupos de ratones: un grupo control, uno infectado de virus de la influenza, dos infectados de bacterias: Haemophilus influenzae y Streptococcus pneumoniae, respectivamente; y dos coinfectados de virus de la flu y Haemophilus influenzae y Streptococcus pneumoniae, respectivamente.
Resultados:
De los seis grupos de ratones, solo en el grupo coinfectado de virus de la influenza y Streptococcus pneumoniae se observó daño en órganos torácicos y abdominales. En todos los grupos se encontró disminución de los niveles séricos de las citocinas, mayor en los ratones coinfectados.
Conclusiones:
Los grupos de ratones infectados solo de Streptococcus pneumoniae o el virus de la influenza no presentaron daños, lo cual indica que la coexistencia de estas infecciones fue la que ocasionó el daño en el grupo de ratones coinfectados.
PALABRAS CLAVEInfluenza; Infección bacteriana; Coinfección; Citocinas proinflamatorias
Introduction
Viruses and leaner have been documented to be the main etiologic agents in customs-origin infections.1 Lower respiratory tract infections generally get-go with a viral infection (respiratory syncytial, influenza, parainfluenza viruses and adenovirus are the most mutual causative agents1); nonetheless, they are oftentimes complicated by bacterial infection, a combination that tin can trigger astringent pneumonia presentations. Amongst the leaner that near commonly crusade pneumonia, Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae), Staphylococcus aureus (S. aureus), and Streptococcus pyogenes (Due south. pyogenes) take been identified.
In 2016, the Earth Health Organization reported that pneumonia was the leading cause of children mortality in the globe. It has been estimated that, in 2015, it caused the decease of approximately 920,136 children younger than v years; i.eastward., it caused xv % of all deaths of children younger than 5 years worldwide.2 In Mexico, respiratory tract infections continue to stand for one of the acme 10 causes of morbidity and mortality in this population group.
Astute respiratory infections initially bear on the upper respiratory tract, simply, depending on the pathogen and the host, they can spread to the lower respiratory tract and cause pneumonia. Influenza, whose etiologic agent is the flu virus, is a highly contagious acute respiratory affliction that affects all historic period groups and can be more than serious in children and in the elderly. The infection is transmitted from person to person through aerosols generated by coughing or sneezing of sick people, which infect respiratory tract epithelial cells. Despite the use of vaccines, the impact of winter epidemics continues to be important in the world population.
In the 2018 flu virus pandemic, the main cause of death was secondary bacterial infection;three retrospective studies indicated that fifty to 100 million individuals died, out of whom 70 % were positive for S. pneumoniae.4 A clear predisposition to coinfection with influenza virus and this bacterium has been demonstrated in subsequent pandemics, including the most recent ane, in 2009, with H1N1 flu virus; hospitalization rate ranged from 10 % to 55 % and mortality was due to S. pneumoniae.five
The influenza virus responsible for the 1918 pandemic was observed to cause astringent lung damage, typified by bronchitis, bronchiolitis, alveolitis, predominance of neutrophils and astute alveolar edema, also as presence of inflammatory cells and dead cells.half-dozen
Damage to the respiratory tract acquired by coinfection has been documented. Changes in the respiratory tract caused by the influenza virus –including epithelial impairment, respiratory function alterations and allowed arrangement receptors exposure– take been proposed to prepare the upper airway for secondary bacterial infection.7 Respiratory disease severity is increased by the conjunction of coinfection and alteration of the innate allowed response.5
Once S. pneumoniae enters the respiratory tract, the innate immune response is activated, with alveolar macrophages participating by releasing pro-inflammatory cytokines and chemokines, which attract and recruit polymorphonuclear and mononuclear cells in the alveoli and lung parenchyma,8 which in turn initiates the inflammatory process inherent to the disease. If the infection is not treated in a timely manner, it evolves until causing patient death due to multi-systemic failure, which tin can be accompanied past coagulation disorders, mainly mucosal haemorrhage, every bit shown by blood in carrion and urine.
During influenza pandemics prior to that of 2009, bacterial coinfections acquired by S. pneumoniae, H. influenzae, S. aureus, and grouping A streptococci significantly contributed to morbidity and mortality.nine,ten
H. influenzae is a small gram-negative bacillus that can be role of the respiratory tract normal microbiome. When the bacterial cell membrane breaks, lipopolysaccharide is released, which is a molecule that participates in the inflammatory process and that in serum binds to lipopolysaccharide-bounden proteins (LBP), a complex with loftier specificity to CD14.11 In patients with sepsis, LBP levels are loftier.12
S. pneumoniae is a gram-positive coccus, and several of its antigens take been characterized, among them substance C (teicoic acid), which when binding to a betaglobulin called C-reactive protein, present in patient serum, forms the substance C-C-reactive protein complex, which activates the complement pour and, consequently, the release of inflammatory mediators.xiii
Pneumococci produce pneumolysin, which is released during lysis. High concentrations of pneumolysin oligomers are deposited on host cell membranes, where they form pores and cause cell lysis. Pneumolysin destroys the cilia of respiratory epithelial cells, breaks down the monolayer of respiratory tract epithelial cells, and decreases neutrophil bactericidal action and migration; in addition, it activates the classical complement pathway. The acute inflammatory response is also triggered by different bacterial structures. The cell wall polysaccharide activates the complement alternating pathway and favors the production of anaphylatoxins C3a and C5a, which increase vascular permeability.13
For the enquiry nosotros present, six groups of mice were formed in social club to demonstrate that the bacterial infection secondary to infection caused by the influenza virus is the cause of respiratory affliction severity: a control group, i infected only with the pandemic H1N1 influenza virus, one just with H. influenzae and ane with Southward. pmeumoniae; also as two groups co-infected with the virus and each one of those bacteria, respectively. Damage to thoracic and abdominal organs was recorded, and the inflammatory process was assessed past determining serum pro-inflammatory cytokines.
Although secondary bacterial infections have been reported to crusade the majority of deaths during flu pandemics, little is known about the underlying mechanisms responsible for the synergy between flu virus and bacteria.
Method
Male mice of the BALB/C strain, eight to 12 weeks old, were used, distributed in six groups, a command grouping and five groups in which influenza virus, H. influenzae or S. Pneumoniae, or the virus and ane of the leaner were intranasally inoculated. The microorganisms were diluted in phosphate-buffered saline (PBS):
-
– Grouping 1 or control: but received PBS.
-
– Grouping ii: inoculated with pandemic H1N1 influenza virus, 1 ten 105/50 μL of PBS.
-
– Group 3: inoculated with S. pneumoniae ATCC 49614, 1 ten ten7/500 μL of PBS.
-
– Group iv: inoculated with H. influenzae ATCC 49766, 1 ten xvii/500 μL of PBS.
-
– Group 5: inoculated with influenza virus and S. pneumoniae, ane ten 107/500 μL of PBS.
-
– Group 6: inoculated with influenza virus and H. influenzae, i x 107/500 μL of PBS.
The number of colony forming units (CFU) of the bacteria was confirmed; S. pneumoniae was grown in blood agar and H. influenzae in chocolate agar. The real dose ranged from 1.2 x 10seven CFU to one.4 x 10vii CFU.
The groups were infected at the beginning of the project: Groups 5 and 6 were first infected with influenza virus and, at 72 hours, with S. pneumoniae and H. influenzae, respectively.
The study went on for 4 weeks; 3 mice from each group were sacrificed every four days.
Each mouse's weight of was recorded daily, and concrete activeness, hair and eye characteristics were assessed.
The mice were anesthetized with an injectable solution (Sedalpharma®, Pet'due south Pharma, Mexico). Afterward, claret was obtained from the heart, which was conventionally processed to obtain serum, which was stored at -xx °C.
Serum pro-inflammatory cytokines were adamant. Detection and quantification of proinflammatory cytokines interleukin (IL) 1β, IL-6 and tumor necrosis cistron alpha (TNFα,) were carried out by enzyme-linked immunosorbent assay (ELISA); PeproTech brand equipment was used and the manufacturer'due south instructions were followed.
Results
On the second post-coinfection day, the mice co-infected with influenza virus and Southward. pneumoniae had bristling pilus. On the 4th day after coinfection, the sign of the hair was accentuated in co-infected groups 5 and 6, in improver to presenting eye infections. On the sixth post-coinfection twenty-four hours, in addition to the above data, a mouse coinfected with influenza virus and S. pneumoniae showed respiratory distress. On seventh twenty-four hour period mail service-coinfection, the signs continued and 3 mice with influenza virus and S. pneumoniae exhibited respiratory distress. The mice with the greatest coinfection effects were euthanized on the eighth day mail-coinfection. On day 12 post-coinfection, some mice continued to take centre infection and bristling pilus. The above signs progressively decreased in the remaining mice, which were finally sacrificed.
Mice infected with influenza H1N1 virus, S. pneumoniae, or H. influenzae alone had no information consequent with infection in thoracic or intestinal cavity organs.
In the exam of the sacrificed mice, different alterations were identified depending on the fourth dimension after coinfection with influenza virus and South. pneumoniae:
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– At 4 days, pleural fluid was identified in one mouse; in one, collapse of the lung; in some other, ileal hemorrhage.
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– At eight days, 1 mouse had bloody pleural fluid, pulmonary hemorrhage and whitish nodules in the lung (Fig. one); in another, thoracoabdominal hemorrhage and abdominal bleeding (melena) were observed; and in one more, abdominal vasodilation (Fig. 2);
-
– At 12 days, one mouse exhibited pulmonary hemorrhage, and some other, small hemorrhages in both lungs and intestinal vasodilation (Fig. 1).
Effigy 1 Findings in a mouse eight days after co-infection with influenza virus and Southward. pneumoniae. A) Whitish nodules in the lung. B) Thoracoabdominal hemorrhage and hepatosplenomegaly.
Figure two Findings in a mouse viii days after coinfection with influenza virus and S. pneumoniae. A) Thoracoabdominal hemorrhage. B) Intestinal hemorrhage (melena). C) Abdominal vasodilation.
Serum cytokines IL-1β, IL-6 and TNFα concentrations were determined four days later infection; decreased cytokines were plant, both in mice with H1N1 virus, H. influenzae, and Southward. pneumoniae infection, and in control mice. The decrease was greater in the co-infected mice blood samples (Fig. three).
Effigy iii Cytokine concentration in serum of mice with H1N1 influenza virus or with S. pneumoniae and H. influenzae leaner, and of mice co-infected with H1N1 influenza virus and S. pneumoniae or H1N1 influenza virus and H. influenzae. A) Interleukin 1β. B) Interleukin half dozen. C) Tumor necrosis factor α(TNF-(α).
Although the levels of all three cytokines did subtract in control mice, they remained constant throughout all iv weeks, with only slight variations. H. flu-infected mice showed the highest values of all three cytokines, and those infected with the H1N1 influenza virus, the lowest. The concentrations of all three cytokines were lower four days after coinfection; notwithstanding, they were re-established in the H1N1 and H. flu-co-infected mice, unlike the H1N1 and S. pneumoniae-co-infected animals (Fig. 3).
Give-and-take
During the 1918 pandemic, bacterial coinfection was implicated in almost all deaths of people infected with the influenza virus. The aforementioned happened in the 2009 pandemic: bacterial coinfection was observed in up to 34 % of patients with pandemic flu A (H1N1) treated in intensive care units. Pathogens that colonize the nasopharynx (including South. aureus, S. pneumoniae and South. pyogenes) were near often isolated.14
Numerous articles have documented that type A influenza virus causes inflammation and necrosis in the respiratory tract epithelium. In different animal models, Wu et al.fifteen establish that coinfection affected the adaptive allowed response: compared to mice infected with influenza virus lonely, mice coinfected with influenza virus and pneumococcus had significant body weight loss; IgG, IgM and IgA levels were decreased in the lung, equally well as the number of plasma CD4 and B cells. Lethal coinfection reduced the size and weight of the spleen, as well as the number of B cells. In mediastinal lymph nodes, lethal coinfection decreased germ center B cells, follicular T-helper cells, and plasma cells.
Walters et al.16 found that co-infected mice showed histopathological changes in more than one-half the alveolar parenchyma, with alveolar air spaces filled with inflammatory infiltrate, extensive acute suppurative pleuritis, generalized necrosis, bronchiolitis, and abundant fibrin thrombi in veins, venules, and capillaries. The in a higher place findings were similar to those observed in our research: mice co-infected with H1N1 flu virus and Southward. pneumoniae showed bloody fluid in the pleura, hemorrhage and whitish nodules in the lung. Walters et al. documented an increased expression of genes that inhibit platelet office and coagulation but in co-infected mice, which are data that are consequent with those observed in our research.
In the mice that we studied, nosotros detected thoracic and abdominal hemorrhages, likewise as digested claret in the intestine (melena), which suggests that hemorrhages are due to an increase in clotting time, probably related to higher expression in the inhibition of genes involved in platelet function and coagulation, as demonstrated past Walters et al.
Patients with flu virus infection who die are likely to accept had bacterial coinfection; S. pneumoniae might have caused changes in clotting time, bleeding and fluid loss and, consequently, poor claret supply to the organs, multi-systemic failure, hypovolemic daze and death.
In a murine model coinfected with H1N1 influenza virus and S. pneumoniae, Wu et al.15 demonstrated a subtract in the levels of specific IgG, IgA and IgM, as well as in the number of B cells, TCD4 cells and plasma cells in the lung and lymphoid organs. In our research, the concentration of pro-inflammatory cytokines showed a subtract in all mice groups; this decrease could be attributed to a decrease in the number of cells that produce these cytokines, as demonstrated by Wu et al.
Conclusions
In our study, the inflammation and necrosis caused by the flu virus could probably have been exacerbated by S. pneumoniae and evolved into bleeding and clotting time alterations, both in thoracic organs and abdominal cavity, particularly in the grouping of mice with thoracic and abdominal damage.
On the other paw, viral and bacterial virulence factors, as well as those of the host, also contribute to the pathogenesis of coinfection; therefore, the decrease in morbidity and mortality will depend on prevention with vaccines, too as on early diagnosis and handling.
Acknowledgements
This research was supported by the Kinesthesia of Medicine of the National Democratic Academy of United mexican states.
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