key: cord-0036703-tmq8viu0 authors: Luna, C. M.; Valentini, R.; Rizzo, O. title: Life-threatening Respiratory Failure from H1N1 Influenza: Lessons from the Southern Cone Outbreak date: 2011-01-31 journal: Intensive Care Medicine DOI: 10.1007/978-1-4419-5562-3_20 sha: 370f596435a1640c3522536dc92da5cb43c511d6 doc_id: 36703 cord_uid: tmq8viu0 A sharp increase in the hospitalization rate for pneumonia, particularly among adults between 20 and 40 years old, and an unusual series of deaths, coincident with an increase in laboratory-confirmed influenza cases, were reported in the spring of 2009 in Mexico. This outbreak appeared after the end of influenza season, and was associated with mortality in a younger age-group than the pattern observed in temperate areas in the northern hemisphere [1]. The concurrent finding of a novel, swine-origin influenza A virus (so called pandemic influenza [H1Nl] 2009) from infected children in the United States [2] completed the picture. A sharp inerease in the hospitalization rate for pneumonia, particularly among adults between 20 and 40 years old, and an unusual series of deaths, coincident with an increase in laboratory-eonfirmed influenza eases, were reported in the spring of 2009 in Mexieo. This outbreak appeared after the end of influenza season, and was associated with mortality in a younger age-group than the pattern observed in ternperate areas in the northern hemisphere [1] . The coneurrent finding of a novel, swine-origin influenza A virus (so called pandemie influenza [HINl] 2009) from infeeted ehildren in the United States [2] eompleted the pieture. This outbreak evolved rapidly and in a few weeks the number of eases with the same epidemiologieal and clinical eharaeteristies inereased globally; in 30 to 40 days the virus began to be clearly more virulent in the Southern Cone (a geographie region eomposed of the southernmost areas of South America, south of the tropie of Capricorn) and, eonsequently, by the first half of August, Argentina beeame the country with the highest rate of fatalities from pandemie influenza HINI 2009 in relation to its population. During some weeks in Iune, the intensive eare units (lCUs) in Buenos Aires experieneed a sharp inerease in eases of severe aeute respiratory distress syndrome (ARDS) and these subjeets typieally beeame the predominant population of meehanieally ventilated patients in these lCUs. The aim of this ehapter is to overview the eharaeteristies of life-threatening respiratory failure from pandemie influenza HINI 2009, trying to refleet on some praetieal issues that arose during this outbreak, and summarizing some of the rieh experienees from Buenos Aires (Table 1) together with data retrieved from other recent international publications. Attaek rates from influenza have been highly variable from outbreak to outbreak but are most eommonly in the range of 5 to 10 % of the general population. During the pandemie of 1957, it was estimated that the attaek rate of clinical influenza exeeeded 50 %, but an additional 25 % or more of individuals were probably subclinically infeeted with influenza A virus [3] . Perhaps the coincidenee between the beginning of the winter season in the southern hemisphere and the high air-traffie between United States and Mexieo and the countries from the Southern Cone , espeeially Argentina [4] , produeed an unusual Influenza eomplieations during seasonal influenza oeeur most frequently in patients older than 64 years old, in those with ehronic dis orders, including eardiae or pulmonary diseases, diabetes mellitus, hemoglobinopathies, renal dysfunction, and immunosuppression. Pregnant women in the seeond or third trimester, partieularly in the 1918 and 1957 pandemics, had a higher risk of eomplieations, especially of primary influenza pneumonia, and higher hospitalization rates . Pneumonia is the most signifieant complieation of influenza. The presentation of pneumonia includes: 'Primary' influenza viral pneumonia seeondary baeterial pneumonia and mixed viral and baeterial pneumonia. Primary influenza viral pneumonia may be the least eommon of the pneumonie eomplieations but it is also the most severe. It presents as aeute influenza that does not resolve but instead progresses relentlessly, with persistent fever, dyspnea, and eventual eyanosis. Sputum produetion is generally scanty, but the sputum ean eontain blood. Few physical signs may be evident early in the illness . In more advaneed eases, diffuse rales may be VI noted, and ehest X-ray findings eonsistent with diffuse interstitial infiltrates and/or ARDS may be present ( Fig. 1 ). Viral eultures of respiratory specimens, especially if year-old obese male with arterial hypertension secondary to Cushing's disease (hypophyseal adenoma) developed bilateral pneumonia and died from respiratory failure secondary to acute respiratory distress syndrome (ARDS) after 13 days on mechanieal ventilation, with multiple organ failure, including renal and hemodynamie compromise requiring high doses of vasopressors. His disease began as an influenza-Iike iIIness 5 days before admission; influenza A H1 N1 was confirmed with RT-PCRperformed on pharyngeal swab. Post-mortem mieroscopie histopathologie findings in the lung included extensive alveolar edema (small arrow) replacing up to 90% of the effective alveolar space, with hyaline membrane development (big arrow); alveolar cellular infiltrate and baeterial superinfection (arrowhead) were also observed (diffuse alveolar damage pattern) (panel a). There was also mild evidence of a fibroproliferative stage, mierothrombi (gray arrow), small areas with weil preserved pulmonary parenchyma (blue arrow), and hemorrhagie infarets (panel b). Suprarrenal hyperplasia and acute tubular necrosis were found. sarnples are taken early in illness, yield high titers of virus. In fatal eases of primary viral pneumonia, histopathologie examination reveals a marked inflammatory reaetion in the alveolar septa, with edema and infiltration by lymphoeytes, macrophages, oeeasional plasma eells, and variable numbers of neutrophils (Fig. 2) . Fibrin thrombi in alveolar eapillaries, along with neerosis and hemorrhage, have also been noted. Hyaline membranes ean be found lining alveoli and alveolar duets. Primary influenza viral pneumonia has a predileetion for individuals with eardiae disease , partieularly those with mitral stenosis, but has also been reported in otherwisehealthy young adults as well as in older individuals with ehronic pulmonary disorders. Seeondary baeterial pneumonia follows aeute influenza; in these eases typieally improvement in the pat ient's eondition over 2 to 3 days is followed by a reappearanee of fever along with clinical signs and symptoms of pneumonia, including eough, purulent sputum, and physical and X-ray signs of eonsolidation. The most eommon baeterial pathogens in thi s setting are Streptococcus pneumoniae, Staphylococcus aureus , and Haemophilus influenzae -usual nasopharynx eolonizers. Secondary baeterial pneumonia oeeurs most frequently in high -risk individuals with chronic pulmonary and cardiac disease and in elderly individuals. Patients with secondary bacterial pneumonia often respond to antibiotic therapy when it is instituted promptly. The risk factors for acquiring severe HINI 2009 primary influenza pneumonia include age (partieularly young children) and comorbidities; some series have observed a particular prevalence of overweight individuals in this group of patients [1, 6, 7] . Obesity has not previously been mentioned among the risk factors for complications in patients with influenza. Being overweight is associated with a chronie increase in pro-inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor (TNF)-a. In an experimental model of influenza A, Smith et al. described higher mortality rates in overweight patients than in lean controls related to minimally expressed interferon (IFN)-a and -ß and a delay in expression of the proinflammatory cytokines, IL-6 and TNF-a, which may lead to increased morbidity and mortality from viral infections [8] . In contrast to what happens with the usual annual seasonal influenza outbreak, in this outbreak of pandemic influenza HINI 2009, young adults are dying and between one quarter and one half of the deaths around the world have happened in patients who were previously in good health and without any specific risk factors. In one of the earlier case report publications during the beginning of the pandemic in Mexico, the authors observed that 87 % of deaths and 71 % of cases of severe pneumonia involved patients between the ages of 5 and 59 years, compared with average rates of 17 % and 32 %, respectively, in that age group during the reference periods [1] . Features of this epidemie were similar to those of past influenza pandemies in that circulation of the new influenza virus was associated with an off-season wave of disease affecting a younger population [1] . In the setting of a disease with very high mortality, with no available controlled human clinical data to guide clinicians, in which most patients present with severe disease, a number of combined strategies should be considered for therapy. These include pharmacologieal strategies (antiviral treatment) and non-pharmacologieal strategies (standardization of optimal ventilator and fluid managernent, especially for ARDS, and management of other complications) necessarily given empirically, as diagnostic confirrnation using real time reverse-transcriptase polymerase chain reaction (RT-peR), can take from several hours to days. VI C.M. Luna, R. Valentini, and o. RizzG Ventilatory settings Most of these patients have ARDS, and in these patients, ventilatory support should follow the concepts of protective ventilation, with a tidal volum e (VT) of 6 mllkg of predicted body weight [9] . ARDS is usually severe, with Pa0 2/Fi02 < than 150 and positive end-expiratory pressure (PEEP) should be high and optimized according to a mechanical basis. In our experience, we initially select PEEP according to the methods used in the ExPress trial where PEEP was adjusted based on airway pressure and was kept as high as possible without increasing the maximal inspiratory plateau pressure above 28 to 30 cmH 20 [10] . In more severe respiratory failure, we also set PEEP according to the transpulmonary press ure, by using esophageal-pressure measurements. In secondary, but also in primary ARDS the lungs can suffer substantial effects of ehest wall elastance and may be effectively compressed by high pleural pressures with their alveoli collapsed at the end of expiration, even though moderate or high PEEP levels are applied. Therefore, PEEP is set at a level necessary to obtain a positive end-expiratory transpulmonary-pressure to improve the oxygenation, an end -inspiratory transpulmonary-presure less than 20 cmH 20 to minimize stress-inducing ventilator lung injury, and a pulmonary driving pressure (end-inspiratory transpulmonary pressure less end-expiratory transpulmonary pressure)~10 cmH 20 to avoid straininducing ventilator lung injury (Fig. 3 ). Using these premises, the mean PEEP applied in patients with severe influenza HINI 2009 and ARDS was 20 cmH 20 . Interestingly, in contrast to other etiologies of ARDS, in primary influenza pneumonia, high PEEP levels were necessary for many days . In a group of 23 patients 20 . At these PEEP levels, the end-inspiratory transpulmonary pressure (EITP) was less than 20cmH 20, the end-expiratory transpulmonary pressure (EETP) was positive, and the transpulmonary driving pressure (Pulm Driv Pr = EITP -EETP) was less than 10cmH 20 . EETP became negative at PEEP less than 11 cmH 20 (arrow). Dead space ventilation (VoNT) was high (range 0.79-0.88). VoNTwas lowest at a PEEP of about 15cmH 20. Pplat: plateau pressure; Cstat: static lung compliance. . At the beginning of this outbreak, we decreased the PEEP level after a few days of mechanical ventilation, based on improvement in oxygenation levels; however, this produced a dramatic worsening of the PaOzlFiO z ratio. Because of this observation, it was decided that, in patients with severe ARDS, high PEEP levels should be maintained for at least two weeks regardless of the oxygenation levels (Fig. 4) . Most of the patients with severe influenza pneumonia responded to recruitment maneuvers. A recruitment maneuver in pressure controlled ventilation (PCV) with a PEEP of 25 -30 cmHzO and an inspiratory pressure of 25 cml-l.O (peak pressure 50-55 cmHzO) was performed in patients with a PaOz/FiO z < 200 mmHg. Many of these patients were young, healthy and had good cardia c performance and tolerance of high ventilatory pressures during the recruitment maneuver with adequate intravascular volume repletion. Several trials have demonstrated no survival benefit in ARDS patients managed in the prone position. However, these trials did not select the most severe patients. Many of our patients had severe ARDS with PaOzlFiO z < 100 mmHg despite PEEP optimization and recruitment maneuvers. In this setting, prone ventilation was used and, if PaOzlFiO z did not reach > 200 mmHg, a recruitment maneuver was applied in the prone position. Prone ventilation was used in 22 % of the patients with ARDS and in 50 % of patients with severe ARDS, and was associated with improved oxygenation and reduced distending pressures. We su ggest the use of adjunctive th erapies when plateau pressure is high er than 35 cmH 20 , despite a V r of 6 -8 mllkg predicted weight, severe hypercapnic acidosis, and refractory hypoxemia (defined as a PaO/Fi0 2 ratio< 100 mmHg after optimization of PEEP, recruitment maneuvers, prone position, and recruitment maneuvers in the prone ventilatory position). The adjunctive therapies developed to reduce the stress of mechanical ventilation on the already damaged lungs include: Nitric oxide (NO) , extracorporeal membrane oxygenation (ECMO), arterial venous carbon dioxid e removal, high-frequency oscillatory vent ilation, and liquid ventilation. We prefer to use NO because of its availability and easy impl ementation and we have observed better improvement in oxygenation combining this therapy with prone ventilation, as previously described [12] . Non-invasive positive pressure ventilation (NPPV): NPPV has been used in respiratory failure due to viral pneumonia, even in cases of high transmission r isk like in the epidemic of severe acute respiratory syndrome (SARS) in Hong Kong [13] . In one study, the efficacy in SARS pneumonia with mild acute lung injury (ALl) was high an d no cases of healthworker infection were observed. However, appli cation of NPPV to patients with HINI influenza has not been well evaluated and it is not indicated for impending respiratory failure. In mild cases or in patients with chronic obstructive pulmonary disease (COPD) or chronic respiratory restriction, NPPV could be useful to support the resp iratory system, but it should be applied in healthcare facilities where staff have been adequately trained and with strict enforcement of personal protection measures; use of expiratory viral and bacterial filters are necessary to provide safer ventilation. Pharmacologic Therapy Antivirals Most of the patients with influenza HINI 2009 will recover without any antiviral therapy. Antivirals are indicated to prevent the rapid spread of the disease in a specific population, to prevent the pneumonia syndrome in susceptible patients, or to treat patients with influenza pneumonia. For critically ill influenza patients, antiviral treatment options are limited because no parenteral drug is available and no drug has been proved to be effective once life-threatening disease occurs. Currently, four antiviral drugs are available for the treatment of influenza: Amantadine, rimantadine (both cannot be used for the treatment of HINI influenza due to resistance), oseltamivir, available only for oral administration, and zanamivir, available as an inhalation agent; the two latter drugs are both sialic acid analogs that inhibit viral neuraminidases by competitively binding with the active enzyme site of influenza A and B viruses. The neuraminidase is critical for viral release from infected cells after replication. The earlier the administration of these agents, and the shorter the duration of fever, the greater the benefit of drug intervention [14, 15] . Oseltamivir has also been shown to reduce lower respiratory tract complications such as bronchitis and pneumonia [16] . In a prospective case control study, multivariate analysis suggested that treatment with oseltamivir decreased the likelihood of death (odds ratio 0.21 [confidence interval 0.06-0.80, p = 0.02]) [17] . Immunosuppressed patients (leukemia, organ transplantation, and hematopoietic stern cell transplantation) have a higher rate of viral pneumonia and higher attributable mortality [18] ; viral shedding is also prolonged in these patients to an average of 11 days [19] , which is associated with the development of resistance [20] . A standard dose and duration of antivirals may not be adequate in this population; for these reasons, some authors have advocated a higher dose of oseltamivir (300 mg daily) in these patients [18] . During the pandemie, the therapeutic strategy proposed by the Argentinean Health Authority for mechanica11y ventilated patients with presumptive primary influenza pneumonia was to use oseltamivir at a dose of 300 mg daily during an extended period of time, typiea11y until the patient was weaned from mechanieal ventilation. The most frequent reported adverse effect seen with oseltamivir is nausea and vomiting, but this leads to medication interruption in only a sma11 number of cases. Neuropsychiatrie disorders (seizure, confusion or hyper-excitation of the nervous system) and severe skin reactions (e.g., toxie epidermal necrolysis) are more severe adverse events that have been observed in some cases during the pandemie. These unusual events have been related to a single nucleotide polymorphism in a gene located near the enzymatie active site of human cytosolic sialidase, a homolog of the virus neuraminidase that is the target of oseltamivir. This polymorphism has been found to occur in 9.3 % of the Asian population [21] . Antibacterial antimicrobials Because of the high frequency of bacterial co-infection, antibiotic administration is recommended for a11 patients with pandemie HINl 2009 influenza infection who require admission to a critical care unit. In immunocompetent patients, without recent antibiotic exposure, combination therapy with a beta-lactam plus a macrolide or arespiratory fluorquinolone, is recommended [22] . Corticosteroid therapy Corticosteroids may be used to treat airflow obstruction due to asthma or COPD, to maintain immunosuppression in transplant patients, and when adrenal dysfunction is suspected because of refractory vasodilatory shock. Corticosteroids are not indicated for ALl; prolonged or high-dose corticosteroid therapy can result in serious adverse events, including opportunistie infections. In patients with H5Nl pulmonary infection, corticosteroids were not effective and in one series mortality was 59 % in 29 recipients of corticosteroids, compared with 24 % in 38 patients who did not receive corticosteroids [231. One exception to this is cryptogenic organizing pneumonia (COP) described below under 'complications'. In addition to primary viral pneumonia, viral and bacterial co-infection and secondary bacterial pneumonia are frequent. Co-infection with S. pneumoniae, S. aureus, and Mycoplasma pnemoniae has been detected in some of the reported series from Argentina: this co-infection occurs after several days of influenza infection and occurs more frequently in the elderly and in patients with chronic pulmonary diseases [24] . It has been observed in one series that 9 % of hospitalized patients with communityacquired pneumonia had dual infection with arespiratory virus and a bacterial pathogen, influenza being the most common viral agent [25] . Proposed theories for the high incidence of superimposed bacterial infections in influenza pneumonia emphasize the synergistic effects of viral and bacterial pathogens in producing lung injury. Studies suggested that influenza virus can directly damage the respiratory epithelium, allowing free access to invading bacteria. It has also been demonstrated that some Staphylococcus and Streptococcus strains may inerease viral replieation and pathogenicity, eontributing to influenza viral pneumonia [26) . Pulmonary embolism ha s not been reeognized as a eommon eomplieation of severe influenza with ARDS. However, in aseries of 10 patients with pandemie influenza HINI 2009 infeetion and ARDS at a tertiary-eare ICU in Miehigan, five had pulmonary emboli [6] . Influenza infeetions have been associated with proeoagulant changes [27] . Pathologie fibrin deposition also occurs in the vaseulature in ARDS and pulmonary artery thrombi are found, implying an anatomic mechanism for the occurrence of increased pulmonary vascular resistance in ARDS [28] . It remains unknown whether these cases were secondary to some of the several risk faetors that these bed-ridden severely ill patients had, or whether it was a direct consequenee of a particular risk in influenza patients. Meanwhile, c1inicians should periodieally search for thrombosis and if necessary use ehest multislice spiral eomputed tomography (CT) to eonfirm pulmonary embolism. Influenza virus does not replieate in the alveoli or tissues beyond the respiratory tract. Histopathological analyses revealed that no virus was detected in the liver, spleen, kidney, or brain of animals inoculated with influenza HINI 2009 virus at 3 or 7 days after inoculation [29) . However, myocarditis and periearditis have been described in association with influenza infection and it has been suggested that influenza-associated myocarditis can take two forms: Immediate, associated with fulminating disease, and delayed, occurring during late convalescence [30) . Renal failure has been described in a number of influenza patients [7, 31) . It is usually the consequenee of shoek and multiorgan dysfunction. We recommend adequate fluid replaeement and, in patients with severe ARDS, fluid infusion should not be restrictive and diuretic use should be avoided to prevent the progression of renal dysfunction [11) . Using this strategy in our patients, the positive fluid balance at the 7 th day was 10,000 ml and hemodialysis was necessary in only 18 % of patients [11] . Oecasionally, rhabdomyolysis may facilitate the development of renal failure; in fact, high levels of serum creatine phosphokinase have been described in reports of HIN 1 infection [31) . This condition, occasionally associated with influenza, is characterized by progressive respiratory failure after 1 week of influenza symptoms with ehest computerized axial tomography demonstrating multiple, bilateral, patchy alveolar opacities [11) . If identified, this complication must be treated with high doses of corticosteroids [32) . Ho et al. performed a study to define the prognostie factors for fatal adult influenza pneumonia [33] . Univariate analysis demonstrated that, compared with survivors of septic shock, arespiratory rate 2: 25 breaths per min, an arterial pH < 7.35, a Pa0 2 / Fi0 2 ratio< 150 mmHg, a creatinine value 2: 2 mg/dl, a pneumonia severity index (PSI) of IV or V, and an APACHE II score 2: 20 were all associated with decreased survival. Adjustments were made for septie shock, respiratory rate, arterial pH, creatinine and PSI in the Cox proportional hazard model. The multivariate analysis demonstrate that only the Pa0 2/Fi02 ratio< 150 mmHg (p = 0.024) and an APACHE II score 2: 20 (p = 0.017) remained associated with death. In another study, the development of ARDS and a history of immunosuppression were independent risk factors for hospital mortality in critically ill patients with confirmed influenza virus infection [34] . The emergence of an antigenieally novel influenza virus to whieh little or no antibody was present in a community, resulted in an extensive outbreak; the absence of antibody is worldwide, and for that reason there has been a pandemie. Independent of this antigenieally new virus, questions regarding the potential effectiveness of vaccination for seasonal influenza arises. In one interim analysis of the pandemie in Australia, the authors found that there was no evidence of significant protection from seasonal vaccine against pandemic influenza virus infection in any age group [35] . A new vaccine has been developed, but there have been concerns based on the experience during the 1976 -77 flu season, during whieh a swine flu outbreak at Fort Dix, New Jersey led the federal government to expedite vaccine production. Some 40 million people had been vaccinated by the time Guillain-Barre syndrome was identified as a side effect. However, with the pandemic as a reality, it is considered that the benefit of the vaccine far outweighs the risks, Pandemics provide the most dramatie evidence of the impact of influenza. The morbidity and mortality caused by this first influenza pandemie in the 21st century, characterized by an unusual increase in the number of cases of primary viral severe community-acquired pneumonia requiring mechanieal ventilation, has been substantial. Interestingly this high er incidence of severe cases appeared in a younger age group than that usually involved in the annual seasonal flu outbreak. The percentage of the population that acquired influenza during this pandemie has not yet been estimated but certainly it was much higher than during seasonal influenza; this higher incidence may explain the high number of cases of severe primary pneumonia observed in the Southern Cone. The apparently less aggressive nature of the infection and the younger population affected may explain an estimated mortality rate of 0.05 -0.1 %, lower than that observed in seasonal influenza, as complications and mortality in seasonal flu are more frequent among patients 2: 65 years old and in those with chronic disorders, including cardiac or pulmonary diseases, diabetes mellitus, hemoglobinopathies, renal dysfunction, and imrnunosuppression, also usually associated with older age. lmproved and standardized optimal leu care for patients with influenza HIN I 2009, including young and immunocompetent patients, with or without comorbidities, should lead to lower mortality than that previously observed for influenza pneumonia when mechanical support is required. The pandemie HINI 2009 influenza has resulted in tremendous press ures on the critical care system. The unexpected and rapid influx of such a large number of patients to emergency room and critical care services has highlighted not only a shortage of critical care capacity but also an inadequate supply of critical care resources. The extreme severity of ARDS in these patients has necessitated a change in the usual approach to the management of these patients to improve success rates. The health system must be prepared to reallocate resources in response to demand. Therefore, early recognition of probable viral pneumonia is crucial in order to implement early infection-control strategies and to redu ce transmission to health-care workers who are at high risk for exposure to these pathogens. 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