Influenza Pneumonitis Research Articles

The impacts of bacterial co-infections and secondary bacterial infections on patients with severe influenza pneumonitis admitted to the intensive care units

PurposesThis study investigated the prevalence and clinical outcomes of pulmonary bacterial co-infections and secondary bacterial infections in patients with severe influenza pneumonitis. MethodsWe retrospectively analyzed the data of adult patients with severe influenza pneumonitis admitted to medical ICUs. Bacterial co-infections and secondary bacterial infections were identified. The risk factors of bacterial infection were evaluated. The outcomes of patients regarding co-infection or secondary bacterial infection were analyzed. ResultsWe identified 117 critically ill patients with laboratory-confirmed influenza pneumonitis admitted to the medical ICUs. Klebsiella pneumoniae (31.4%) and Staphylococcus aureus (22.8%) were the most identified bacteria in patients with bacterial co-infection. A high proportion of methicillin-resistant Staphylococcus aureus (17.1%) was noted. Liver cirrhosis and diabetes mellitus were the independent risk factors for bacterial co-infection. Acinetobacter baumannii (30.7%) and S. aureus (23.1%) were the most often identified bacteria in patients with secondary bacterial pneumonia. Patients with secondary bacterial infections had a longer duration of mechanical ventilation, and longer ICU and hospital stay. ConclusionsHigh rates of drug-resistant bacterial co-infections and secondary bacterial infections were identified in patients with severe influenza pneumonitis requiring ICU care and were associated with more morbidity in these patients.

Dysregulation of ion transport in the lung epithelium infected with SARS-CoV-2.

Dysregulation of ion transport in the lung epithelium infected with SARS-CoV-2.

Human genetics of life-threatening influenza pneumonitis.

Influenza viruses infect millions of people around the globe annually, usually causing self-limited upper respiratory tract infections. However, a small but non-negligible proportion of patients suffer from life-threatening pulmonary disease. Those affected include otherwise healthy individuals, and children with primary infections in particular. Much effort has been devoted to virological studies of influenza and vaccine development. By contrast, the enormous interindividual variability in susceptibility to influenza has received very little attention. One interesting hypothesis is that interindividual variability is driven largely by the genetic makeup of the infected patients. Unbiased genomic approaches have been used to search for genetic lesions in children with life-threatening pulmonary influenza. Four monogenic causes of severe influenza pneumonitis—deficiencies of GATA2, IRF7, IRF9, and TLR3—have provided evidence that severe influenza pneumonitis can be genetic and often in patients with no other severe infections. These deficiencies highlight the importance of human type I and III IFN-mediated immunity for host defense against influenza. Clinical penetrance is incomplete, and the underlying mechanisms are not yet understood. However, human genetic studies have clearly revealed that seemingly sporadic and isolated life-threatening influenza pneumonitis in otherwise healthy individuals can be genetic.

Human inborn errors of immunity to herpes viruses.

Infections with any of the nine human herpes viruses (HHV) can be asymptomatic or life-threatening. The study of patients with severe diseases caused by HHVs, in the absence of overt acquired immunodeficiency, has led to the discovery or diagnosis of various inborn errors of immunity. The related inborn errors of adaptive immunity disrupt α/β T-cell rather than B-cell immunity. Affected patients typically develop HHV infections in the context of other infectious diseases. However, this is not always the case, as illustrated by inborn errors of SAP-dependent T-cell immunity to EBV-infected B cells. The related inborn errors of innate immunity disrupt leukocytes other than T and B cells, non-hematopoietic cells, or both. Patients typically develop only a single type of infection due to HHV, although, again, this is not always the case, as illustrated by inborn errors of TLR3 immunity resulting in HSV1 encephalitis in some patients and influenza pneumonitis in others. Most severe HHV infections in otherwise healthy patients remains unexplained. The forward human genetic dissection of isolated and syndromic HHV-driven illnesses will establish the molecular and cellular basis of protective immunity to HHVs, paving the way for novel diagnosis and management strategies.

Severe influenza pneumonitis in children with inherited TLR3 deficiency

Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN-mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.

Understanding the role of host response in influenza pneumonitis.

Understanding the role of host response in influenza pneumonitis.

Excessive Neutrophils and Neutrophil Extracellular Traps Contribute to Acute Lung Injury of Influenza Pneumonitis

Complications of acute respiratory distress syndrome (ARDS) are common among critically ill patients infected with highly pathogenic influenza viruses. Macrophages and neutrophils constitute the majority of cells recruited into infected lungs, and are associated with immunopathology in influenza pneumonia. We examined pathological manifestations in models of macrophage- or neutrophil-depleted mice challenged with sublethal doses of influenza A virus H1N1 strain PR8. Infected mice depleted of macrophages displayed excessive neutrophilic infiltration, alveolar damage, and increased viral load, later progressing into ARDS-like pathological signs with diffuse alveolar damage, pulmonary edema, hemorrhage, and hypoxemia. In contrast, neutrophil-depleted animals showed mild pathology in lungs. The brochoalveolar lavage fluid of infected macrophage-depleted mice exhibited elevated protein content, T1-α, thrombomodulin, matrix metalloproteinase-9, and myeloperoxidase activities indicating augmented alveolar-capillary damage, compared to neutrophil-depleted animals. We provide evidence for the formation of neutrophil extracellular traps (NETs), entangled with alveoli in areas of tissue injury, suggesting their potential link with lung damage. When co-incubated with infected alveolar epithelial cells in vitro, neutrophils from infected lungs strongly induced NETs generation, and augmented endothelial damage. NETs induction was abrogated by anti-myeloperoxidase antibody and an inhibitor of superoxide dismutase, thus implying that NETs generation is induced by redox enzymes in influenza pneumonia. These findings support the pathogenic effects of excessive neutrophils in acute lung injury of influenza pneumonia by instigating alveolar-capillary damage.

Delayed diagnosis of novel H1N1 influenza pneumonitis in a vaccinated heart transplant recipient

We report the case of a 36-year-old heart transplant recipient who presented with pyrexia, respiratory failure, and progressive chest X-ray infiltrates 74 days after orthotopic heart transplantation. Notably, this patient had been vaccinated against both seasonal and novel 2009 H1N1 influenza viruses. Nasopharyngeal aspirates tested negative for influenza viruses. Diagnosis of novel H1N1 influenza pneumonitis was made on a bronchiolar lavage sample 14 days after initial presentation. Treatment was successful with high-dose oseltamivir. Novel H1N1 influenza infection has been reported in vaccinated lung transplant candidates and recipients, although compliance with vaccination of only 20% was found in infected patients. With this report, we present a case of novel H1N1 influenza vaccine failure in a fully vaccinated heart transplant recipient. The efficacy of this vaccine in heart transplant recipients is unknown. Studies on seasonal influenza vaccination in heart transplant recipients suggest a diminished antibody response. Given the rapid spread of novel H1N1 influenza virus, transplant recipients may begin vaccination as soon as 1 month after transplantation. However, this case illustrates how the immune response to early vaccination may only be partially protective in heart transplant recipients and that assumed vaccine-afforded protection may result in a delayed diagnosis. (Table 1). The immunosuppressive regimen used in solid-organ transplant recipients may also contribute to the risk of vaccine failure. For example, mycophenolate mofetil (used in this patient) is associated with a lower serologic response to vaccination than other immunosuppressive drugs. Furthermore, in addition to chemotherapy and bone marrow transplantation for acute myeloid leukemia 5 years before heart transplantation, this patient’s medical history also included heparin-induced thrombocytopenia. This therefore suggests a previous history of immune dysfunction, which may also have contributed to vaccine failure. European surveillance data has reported cases of novel H1N1 influenza pneumonitis in vaccinated (non-immunocompromised) patients during this pandemic, indicating that immunosuppression alone may not account for vaccine failure.

Practical lessons from the first outbreaks: Clinical presentation, obstacles, and management strategies for severe pandemic (pH1N1) 2009 influenza pneumonitis

During the initial spring wave of novel influenza pH1N1 (2009), several North American cities experienced localized epidemics that served as a harbinger of the larger second Fall wave of infection. The city of Winnipeg, the capital of the province of Manitoba in central Canada, was one of the first in North America to deal with a rapid presentation of large numbers of patients requiring critical care services resulting from pandemic (pH1N1) 2009 influenza-associated respiratory failure. Mexico City, Orlando, FL, and Salt Lake City, UT, were other Northern Hemisphere sites of heavy disease activity during the spring wave of the pandemic. This article is written in a narrative format that allows the reader to understand the problems (both major and mundane, anticipated and unexpected) experienced by healthcare workers in these sites during this pandemic. Descriptions cover a range of issues and difficulties that caused significant stress to the operations of intensive care units in these cities. We hope to offer some insight into potential pitfalls and problems that may be experienced by other centers and provide some potential approaches to addressing these issues.

MCP-1 Antibody Treatment Enhances Damage and Impedes Repair of the Alveolar Epithelium in Influenza Pneumonitis

Recent studies have demonstrated an essential role of alveolar macrophages during influenza virus infection. Enhanced mortalities were observed in macrophage-depleted mice and pigs after influenza virus infection, but the basis for the enhanced pathogenesis is unclear. This study revealed that blocking macrophage recruitment into the lungs in a mouse model of influenza pneumonitis resulted in enhanced alveolar epithelial damage and apoptosis, as evaluated by histopathology, immunohistochemistry, Western blot, RT-PCR, and TUNEL assays. Abrogation of macrophage recruitment was achieved by treatment with monoclonal antibody against monocyte chemoattractant protein-1 (MCP-1) after sub-lethal challenge with mouse-adapted human influenza A/Aichi/2/68 virus. Interestingly, elevated levels of hepatocyte growth factor (HGF), a mitogen for alveolar epithelium, were detected in bronchoalveolar lavage samples and in lung homogenates of control untreated and nonimmune immunoglobulin (Ig)G-treated mice after infection compared with anti-MCP-1-treated infected mice. The lungs of control animals also displayed strongly positive HGF staining in alveolar macrophages as well as alveolar epithelial cell hyperplasia. Co-culture of influenza virus-infected alveolar epithelial cells with freshly isolated alveolar macrophages induced HGF production and phagocytic activity of macrophages. Recombinant HGF added to mouse lung explants after influenza virus infection resulted in enhanced BrdU labeling of alveolar type II epithelial cells, indicating their proliferation, in contrast with anti-HGF treatment showing significantly reduced epithelial regeneration. Our data indicate that inhibition of macrophage recruitment augmented alveolar epithelial damage and apoptosis during influenza pneumonitis, and that HGF produced by macrophages in response to influenza participates in the resolution of alveolar epithelium.

Detection of mouse-adapted human influenza virus in the olfactory bulbs of mice within hours after intranasal infection

Influenza pneumonitis causes severe systemic symptoms in mice, including hypothermia and excess sleep. The association of extrapulmonary virus, particularly virus in the brain, with the onset of such disease symptoms has not been investigated. Mature C57BL/6 male mice were infected intranasally with mouse-adapted human influenza viruses (PR8 or X-31) under inhalation, systemic, or no anesthesia. Core body temperatures were monitored continuously by radiotelemetry, and tissues (lung, brain, olfactory bulb, spleen, blood) were harvested at the time of onset of hypothermia (13 to 24 h post infection [PI]) or at 4 or 7 h PI. Whole RNA from all tissues was examined by one or more of three reverse transcriptase-polymerase chain reaction (RT-PCR) procedures using H1N1 nucleoprotein (NP) primers for minus polarity RNA (genomic or vRNA) or plus polarity RNA (replication intermediates). Selected cytokines were assayed at 4, 7, and 15 h in the olfactory bulb (OB). Minus and plus RNA strands were readily detected in OBs as early as 4 h PI by nested RT-PCR. Anesthesia was not required for viral invasion of the OB. Cytokine mRNAs were also significantly elevated in the OB at 7 and 15 h PI in infected mice. Controls receiving boiled virus expressed only input vRNA and that only in lung. Immunohistochemistry demonstrated localization of H1N1 and NP antigens in olfactory nerves and the glomerular layer of the OB. Therefore a mouse-adapted human influenza virus strain, not known to be neurotropic, was detected in the mouse OB within 4 h PI where it appeared to induce replication intermediates and cytokines.

Prevention of influenza pneumonitis by sialic Acid-conjugated dendritic polymers.

Influenza A viral infection begins by hemagglutinin glycoproteins on the viral envelope binding to cell membrane sialic acid (SA). Free SA monomers cannot block hemagglutinin adhesion in vivo because of toxicity. Polyvalent, generation 4 (G4) SA-conjugated polyamidoamine (PAMAM) dendrimer (G4-SA) was evaluated as a means of preventing adhesion of 3 influenza A subtypes (H1N1, H2N2, and H3N2). In hemagglutination-inhibition assays, G4-SA was found to inhibit all H3N2 and 3 of 5 H1N1 influenza subtype strains at concentrations 32-170 times lower than those of SA monomers. In contrast, G4-SA had no ability to inhibit hemagglutination with H2N2 subtypes or 2 of 5 H1N1 subtype strains. In vivo experiments showed that G4-SA completely prevented infection by a H3N2 subtype in a murine influenza pneumonitis model but was not effective in preventing pneumonitis caused by an H2N2 subtype. Polyvalent binding inhibitors have potential as antiviral therapeutics, but issues related to strain specificity must be resolved.

Rapid interferon gamma-dependent clearance of influenza A virus and protection from consolidating pneumonitis in nitric oxide synthase 2-deficient mice.

Viral infection often activates the interferon (IFN)-gamma-inducible gene, nitric oxide synthase 2 (NOS2). Expression of NOS2 can limit viral growth but may also suppress the immune system and damage tissue. This study assessed each of these effects in genetically deficient NOS2(-/-) mice after infection with influenza A, a virus against which IFN-gamma has no known activity. At inocula sufficient to cause consolidating pneumonitis and death in wild-type control mice, NOS2(-/-) hosts survived with little histopathologic evidence of pneumonitis. Moreover, they cleared influenza A virus from their lungs by an IFN-gamma-dependent mechanism that was not evident in wild-type mice. Even when the IFN-gamma-mediated antiviral activity was blocked in NOS2(-/-) mice with anti-IFN-gamma mAb, such mice failed to succumb to disease. Further evidence that this protection was independent of viral load was provided by treating NOS2(+/+) mice with the NOS inhibitor, Nomega-methyl-L-arginine (L-NMA). L-NMA prevented mortality without affecting viral growth. Thus, host NOS2 seems to contribute more significantly to the development of influenza pneumonitis in mice than the cytopathic effects of viral replication. Although NOS2 mediates some antiviral effects of IFN-gamma, during influenza infection it can suppress another IFN-gamma-dependent antiviral mechanism. This mechanism was observed only in the complete absence of NOS2 activity and appeared sufficient to control influenza A virus growth in the absence of changes in cytotoxic T lymphocyte activity.

Sickness behavior in mice deficient in interleukin-6 during turpentine abscess and influenza pneumonitis.

Interleukin-6 (IL-6), among other cytokines, is thought to be involved in the regulation of sickness behavior (e.g., anorexia, cachexia, fever, and lethargy) induced by infections bacterial and viral origin) and sterile tissue necrosis (burns and surgical traumas). Mice deficient in IL-6 (IL-6 KO) were generated by gene targeting. Homozygous IL-6 KO male and female mice and their appropriate controls were implanted with biotelemeters to monitor body temperature (Tb) and motor activity (Act). Normal circadian rhythms in Tb and Act as well as rates of food intake and weight gain did not differ significantly between sex-matched IL-6 KO and control groups at 30 degrees C in a 12:12-h light-dark cycle. Sterile tissue damage was induced in mice by subcutaneous injection of turpentine (0.1 ml, left hindlimb). Influenza pneumonitis was induced by intranasal inoculation of mouse-adapted influenza A virus (17.5 plaque-forming units). Lack of IL-6 completely prevented fever, anorexia, and cachexia because of turpentine abscess in both sexes. It did not prevent lethargy, although IL-6 KO mice recovered to normal Act significantly sooner than wild-type mice. Symptoms of sickness were only slightly modified during influenza virus infection in IL-6 KO mice. Attenuation of sickness behavior was more pronounced in IL-6 KO female than in male mice. We conclude that, although IL-6 is induced during both turpentine abscess and influenza infection, this cytokine appears to be more critical in induction of the symptoms of sickness behavior during sterile tissue abscess than during influenza infection.

Maternal-infant transfer of influenza-specific immunity in the mouse.

The effects of maternal-infant transfer of influenza-specific antibody on influenza infection in the infant mouse were studied by following mortality, hemagglutination inhibition antibody, virus shedding from the nose and lung, and pathology of the upper and lower airway. By cross-fostering infants, influenza-specific antibody was shown to be acquired mainly by breast-feeding. Mice acquiring specific antibody survived lethal influenza infection (p less than 0.001) and had no evidence of influenza pneumonitis. There was variable suppression of nasal virus shedding and tracheal desquamation. Infected infants that initially acquired high levels of serum antibody also showed no evidence for serum antibody 10 wk later. Infant mice surviving initial influenza infection were lethally rechallenged 10 wk later. Rechallenged mice had a higher survival rate when compared to control mice (p less than 0.001) in spite of the absence of anti-influenza antibody and the presence of high lung virus titers in both groups 1 day after rechallenge. Rechallenged mice showed evidence for both significantly lower nasal virus titers (p less than 0.001) and a secondary serum antibody response with associated decline in lung virus titer. These results suggest maternal influenza-specific antibody a) is transferred to the infant mouse; b) is transferred mainly by breast-feeding; c) is life saving and lowers lung virus titers in the infant; and d) suppresses the infant's serum antibody production after challenge without affecting local immunity or the ability to mount a secondary antibody response.

A Comparative Roentgen Study of Primary Atypical and Bacterial Pneumonia

Numerous articles have appeared in the literature concerning the bacteriologic and clinical aspects of primary atypical pneumonia, and sporadic attempts have been made to establish roentgenologic criteria for its differentiation from bacterial pneumonia. As Rigler (1) put it, “in the case of acute lung conditions the roentgenogram presents an autopsia in vivo, requiring only adequate and intelligent interpretation to make it the most valuable adjunct in the diagnosis and study of pneumonia.” Bowen (2), in 1935, was one of the first to describe the clinical syndrome now designated as “primary atypical pneumonia,” which he called “acute influenza pneumonitis.” His description of the characteristic roentgen appearances of this syndrome has remained fairly constant throughout the literature. The roentgen shadow is usually described as extending outward from the hilum well into the parenchyma, occasionally reaching the periphery, presenting the appearance of a confluent mottled fan-shaped or rounded area, usually of homogeneous density in the central portion, with the borders fading into the normal lung. In 1940, Kornblum and Reimann (3) called attention to the “great variability in the type of lesion produced.” One of the characteristic lesions they describe as “a fairly well localized area of increased density situated in various portions of the lung but occurring predominantly in the lower lobes. The areas while variable in size were never very large, thus differing from the consolidations encountered in lobar pneumonia. Although the inflammatory reaction was localized, it was not sharply defined, the opacity tending to merge imperceptibly with the surrounding pulmonary tissues. The areas of involvement varied considerably in density. Again, they were never as dense as the consolidations of lobar pneumonia.” Dingle and Finland (4) suggested similar characteristic findings for the roentgen diagnosis of primary atypical pneumonia, including an increase in size of one or both hilar shadows, followed by an infiltration, extending outward from the hilum toward the periphery of the lung fields, often in the shape of a fan or wedge, fading out gradually into the normal lung parenchyma. The density was described as usually soft, either mottled or homogeneous, more dense near the hilum, but rarely so dense and circumscribed as that in pneumococcal pneumonia and seldom occupying more than a portion of the lobe. In January 1943, Seeds and Mazer (5), on the basis of 221 cases, established criteria for the roentgen diagnosis of primary atypical pneumonia, which they considered characteristic and fairly constant for the syndrome.

PRIMARY ATYPICAL PNEUMONIA

They do certainly give very strange and new-fangled names to diseases. —Plato. An increasing number of reports in the literature indicates the presence of a pulmonary condition known by many names but called chiefly virus pneumonia or primary atypical pneumonia. Modern interest in the condition dates from the report of Bowen, 1 who called it acute influenza pneumonitis, feeling that it was a mild variant of pandemic influenza. In 1936, one year after Bowen's paper, Allen 2 reported 50 cases of the disease and emphasized, as had Bowen, the paucity of physical findings as compared with roentgen films of the chest. Beginning in 1938, Reimann, with various co-workers, has published a number of reports of the disease. 3 It has been Reimann's impression that the infection is caused by a filtrable virus, though he admits the absence of conclusive proof. However, this work has served to emphasize the etiologic problem,

The Probable Incidence and Clinical Features of “Virus” Pneumonia

There can be no doubt that an unusual type of atypical primary bronchopneumonia has become much more prevalent in widely separated districts of the United States in the past two years. Many good clinical descriptions of the outbreaks of the disease, which has been given a variety of names, are quite similar in all of their essential features. While the term “virus pneumonia” seems justified on the basis of several excellent studies, we have no knowledge of the number of viruses involved. Few clinicians have the facilities for determining whether or not a virus is present at all. Hence, in the present state of our knowledge, it is probably wiser to use the term “primary atypical bronchopneumonia, etiology un-determined” in describing the pneumonias which apparently fall into this group, as recommended by the War Department (1). Other names by which the disease has been called are: acute influenza pneumonitis (Bowen, 2); acute pneumonitis (Allen, 3); disseminated focal pneumonia (Scad-ding, 4); atypical pne...

Atypical Pneumonia of Probable Virus Origin

Evidence of infective non-bacterial primary bronchopneumonia in man has become sufficient to establish its recognition as a clinical entity. Many reports of this type of disease have appeared in the literature in the past seven years. Epidemics, both small and great, have been reported from several sections of this country, England, France, Spain, and Hawaii. Most of these have occurred in schools, among hospital personnel, or in military groups. An epidemic among the white troops stationed in Hawaii in 1933 was described as “acute influenza pneumonitis” by Major Albert Bowen, Medical Corps, U. S. Army, and reported in the American Journal of Roentgenology in August 1935 (3). Major Bowen pointed out that the condition occurred particularly during influenza epidemics and spoke of it as being more or less benign. He recognized it as a bronchopneumonia, but with certain features which characterized it as a distinct clinical entity. Most of the literature on the subject has appeared to carry this conception a...

AN EPIDEMIC DISEASE OF THE RESPIRATORY TRACT

In the past few years numerous clinicians have described isolated cases and epidemics of infection of the respiratory tract especially associated with pulmonary involvement. The disease in most instances resembled epidemic influenza so closely that clinical differentiation could not be made, and in only one or two studies were attempts made to differentiate the disease from influenza by serologic or other laboratory methods. Definite diagnoses in this group of infections of the respiratory tract cannot be made, of course, until the etiologic agents in the different diseases become known. Various names have been given to the diseases described, such as acute pneumonitis,1acute influenza pneumonitis,2acute interstitial pneumonitis,3atypical pneumonia,4bronchopneumonia,5pseudolobarbronchopneumonia,6benign circumscribed pneumonia,7disseminated focal pneumonia,8acute diffuse bronchiolitis9and capillary pneumonia. These terms may be fairly descriptive of the underlying pathoanatomic changes, but beyond this they serve no useful purpose. Furthermore, in our recent experience with a