Lianhuaqingwen capsule inhibits non-lethal doses of influenza virus-induced secondary Staphylococcus aureus infection in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Lianhuaqingwen capsule (LH-C) is a traditional Chinese medicine (TCM), consisting of two prescriptions, Ma-xing-shi-gan-tang (MXSGT) and Yinqiao San. It has been proven to have antiviral, antibacterial, and immunomodulatory effects in recent years. Clinically, it is commonly used in the treatment of respiratory tract infections. AIM OF THE STUDY: It was demonstrated in our previous studies that LH-C has an effect of antivirus and inhibits influenza virus-induced bacterial adhesion to respiratory epithelial cells through down-regulation of cell adhesion molecules in vitro. However, LH-C's effect against influenza-induced secondary bacterial infection in animal studies remains unclear. Therefore, in the present study, we established a mouse model of infection with non-lethal doses of influenza virus(H1N1) and secondary infection of Staphylococcus aureus (S. aureus), to investigate the potential effects of LH-C. METHODS: Experiments were carried out on BALB/c mice infecting non-lethal doses of H1N1 and non-lethal doses of S. aureus, and the viral, and bacterial doses were determined by observing and recording changes in the body weight, mortality, and pathological changes. Moreover, after LH-C treatment, the survival rate, body weight, lung index, viral titers, bacterial colonies, pathological changes, and the inflammatory cytokines in the mouse model have all been systematically determined. RESULTS: In the superinfection models of H1N1 and S. aureus, the mortality rate was 100% in groups of mice infected with 20 PFU/50 µL of H1N1 and 105 CFU/mL of S. aureus, 20 PFU/50 µL of H1N1 and 106 CFU/mL of S. aureus, 4 PFU/50 µL of H1N1 and 106 CFU/mL of S. aureus. The mortality rate was 50% in the group of mice infected with 4 PFU/50 µL of H1N1 and 105 CFU/mL of S. aureus. The mortality rate was 37.5% in the group of mice infected with 20 PFU/50 µL of H1N1 alone and in the group of mice infected with 2 PFU/50 µL of H1N1 and 106 CFU/mL of S. aureus. The mortality rate in the group of mice infected with 2 PFU/50 µL of H1N1 and 106 CFU/mL of S. aureus was 30%. The infected mice of 2 PFU/50 µL of H1N1 and 106 CFU/mL of S. aureus had a weight loss of nearly 10%. About the histopathological changes in the lung tissue of infection mice, severe lung lesions were found in the superinfection models. LH-C improved survival in the superinfected mice, significantly reduced lung index, lowered viral titers and bacterial loads, and alleviated lung damage. It reduced lung inflammation by down-regulating mRNA expression levels of inflammatory mediators like IL-6, IL-1ß, IL-10, TNF-α, IFN-ß, MCP-1, and RANTES. CONCLUSIONS: We found that superinfection from non-lethal doses of S. aureus following non-lethal doses of H1N1 was equally fatal in mice, confirming the severity of secondary infections. The ability of LH-C to alleviate lung injury resulting from secondary S. aureus infection induced by H1N1 was confirmed. These findings provided a further assessment of LH-C, suggesting that LH-C may have good therapeutic efficacy in influenza secondary bacterial infection disease.

Severe neonatal COVID-19: Challenges in management and therapeutic approach.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), may manifest as a life-threatening respiratory infection with systemic complications. Clinical manifestations among children are generally less severe than those seen in adults, but critical cases have increasingly been reported in infants less than 1 year of age. We report a severe case of neonatal COVID-19 requiring intensive care and mechanical ventilation, further complicated by a multidrug-resistant Enterobacter asburiae super-infection. Chest X-rays, lung ultrasound, and chest computed tomography revealed extensive interstitial pneumonia with multiple consolidations, associated with persistent increased work of breathing and feeding difficulties. SARS-CoV-2 RNA was detected in respiratory specimens and stools, but not in other biological samples, with a rapid clearance in stools. Serological tests demonstrated a specific SARS-CoV-2 antibody response mounted by the neonate and sustained over time. The therapeutic approach included the use of enoxaparin and steroids which may have contributed to the bacterial complication, underlying the challenges in managing neonatal COVID-19, where the balance between viral replication and immunomodulation maybe even more challenging than in older ages.

Latently KSHV-Infected Cells Promote Further Establishment of Latency upon Superinfection with KSHV.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a cancer-related virus which engages in two forms of infection: latent and lytic. Latent infection allows the virus to establish long-term persistent infection, whereas the lytic cycle is needed for the maintenance of the viral reservoir and for virus spread. By using recombinant KSHV viruses encoding mNeonGreen and mCherry fluorescent proteins, we show that various cell types that are latently-infected with KSHV can be superinfected, and that the new incoming viruses establish latent infection. Moreover, we show that latency establishment is enhanced in superinfected cells compared to primary infected ones. Further analysis revealed that cells that ectopically express the major latency protein of KSHV, LANA-1, prior to and during infection exhibit enhanced establishment of latency, but not cells expressing LANA-1 fragments. This observation supports the notion that the expression level of LANA-1 following infection determines the efficiency of latency establishment and avoids loss of viral genomes. These findings imply that a host can be infected with more than a single viral genome and that superinfection may support the maintenance of long-term latency.

An unexpected intracerebral lesion - case report of a superinfected aspergillosis mimicking a brain metastasis.

BACKGROUND: Invasive aspergillosis of the central nervous system is a rare but increasingly prevalent disease. We present the unusual case of an immunosuppressed patient suffering from unexpected superinfected invasive aspergillosis with cerebral, pulmonal, and adrenal manifestations, mimicking a metastasized bronchial carcinoma. This report reveals the importance of including aspergillosis in the differential diagnosis of a cerebral mass lesion in the light of unspecific clinical findings. CASE PRESENTATION: A 58-year-old immunocompromised female presented to our emergency department with a single tonic-clonic seizure. Imaging showed a ring enhancing cerebral mass with perifocal edema and evidence of two smaller additional hemorrhagic cerebral lesions. In the setting of a mass lesion in the lung, and additional nodular lesions in the left adrenal gland the diagnosis of a metastasized bronchus carcinoma was suspected and the cerebral mass resected. However, histology did not reveal any evidence for a neoplastic lesion but septate hyphae consistent with aspergillus instead and microbiological cultures confirmed concomitant staphylococcal infection. CONCLUSIONS: A high index of suspicion for aspergillus infection should be maintained in the setting of immunosuppression. Clinical and radiological findings are often unspecific and even misleading. Definite confirmation usually relies on tissue diagnosis with histochemical stains. Surgical resection is crucial for establishing the diagnosis and guiding therapy with targeted antifungal medications.

Role of Pneumococcal NanC in the Severe Disease of Streptococcus pneumoniae Superinfection with Influenza.

Bacterial superinfection aggravates the disease of influenza. Streptococcus pneumoniae is the most common bacterial pathogen. Synergistic virulence has been demonstrated between influenza neuraminidase and pneumococcal NanA and NanB. NanC, the other pneumococcal neuraminidase infrequently present in clinical isolates, is not well characterized. In this study, we report that superinfection with a NanC-negative pneumococcus strain suppresses anti-influenza immunity and impairs viral clearance with higher TGF-ß activation in mice. Bacterial load in the lungs also increases as the host immunity is suppressed. NanC-positive isogenic mutant reverses wild type S. pneumoniae-mediated immune suppression and facilitates virus clearance. However, it causes more severe disease as the augmented inflammation causes collateral damage. Both virus-mediated damage and immune response-mediated inflammation are important for pathogenesis of severe influenza. Inflammation may be more critical than virus-mediated damage in influenza with bacterial superinfection.

Surgical Resections of Superinfected Pneumatoceles in a COVID-19 Patient.

Emerging studies on radiologic findings in patients with coronavirus disease 2019 (COVID-19) report a high incidence of bilateral lung involvement, with ground-glass opacities imaging being the most common pattern on computed tomography. Cystic lesions, such as pneumatoceles, are rare, although they may occur in 10% of cases. Cyst formation may be explained by a focal pulmonary trauma caused by mechanical ventilation or infection-related damage to the alveolar walls leading to pneumatoceles. The superinfection of pneumatoceles is a potential life-threatening condition for which no standardized therapeutic algorithm has been accepted. We report a case of a COVID-19 patient successfully treated by lung resections for infected pneumatoceles.

Distinct Chronic Post-Viral Lung Diseases upon Infection with Influenza or Parainfluenza Viruses Differentially Impact Superinfection Outcome.

Chronic obstructive pulmonary disease (COPD) and asthma remain prevalent human lung diseases. Variability in epithelial and inflammatory components that results in pathologic heterogeneity complicates the development of treatments for these diseases. Early childhood infection with parainfluenza virus or respiratory syncytial virus is strongly associated with the development of asthma and COPD later in life, and exacerbations of these diseases correlate with the presence of viral RNA in the lung. Well-characterized animal models of postviral chronic lung diseases are necessary to study the underlying mechanisms of viral-related COPD and asthma and to develop appropriate therapies. In this study, we cross-analyzed chronic lung disease caused by infection with Sendai virus (SeV) or influenza A virus in mice. Differences were observed in lesion composition and inflammatory profiles between SeV- and influenza A virus-induced long-term lung disease. In addition, a primary SeV infection led to worsened pathologic findings on secondary heterologous viral challenge, whereas the reversed infection scheme protected against disease in response to a secondary viral challenge >1 month after the primary infection. These data demonstrate the differential effect of primary viral infections in the susceptibility to disease exacerbation in response to a different secondary viral infection and highlight the usefulness of these viral models as tools to understand the underlying mechanisms that mediate distinct chronic postviral lung diseases.

Vegetable fibre in an infected ovarian dermoid cyst.

Tubo-ovarian abscesses (TOAs) are inflammatory masses involving the fallopian tube, ovary and occasionally other adjacent pelvic organs. A 32-year-old woman with no significant medical history presented with a chief complaint of lower abdominal pain. Initial CT of the abdomen was suggestive of a colon abscess; however, a repeat CT suggested a TOA. The left ovary was densely adherent to the left pelvic sidewall and the rectosigmoid colon. The content of the ovary was consistent with a dermoid and suspected of superinfection. Pathological examination of the tissue revealed normal ovarian cortical tissue, hair cells, melanin, and epidermal and neural tissue, as well as evidence of a foreign object resembling vegetable matter. The vegetable fibre found in this patient's biopsy was of an unclear aetiology, but probably indicates a perforation of the bowel. Any cause of bowel perforation adjacent to the adnexa can lead to TOA, therefore providing a rational speculation for this case.

A unique presentation of superinfected pseudomyxoma peritonei secondary to a low-grade appendiceal mucinous neoplasm.

BACKGROUND: Pseudomyxoma peritonei (PMP) is an uncommon condition characterized by diffuse mucinous material in the abdomen and pelvis, generally arising from a perforated epithelial neoplasm. Typically, the disease presents as suspected acute appendicitis, ovarian mass, abdominal distension, or ventral hernia. Our case represents a very rare presentation of superinfected PMP. CASE PRESENTATION: A 46-year-old female with a past medical history notable for depression, asthma, and uterine leiomyomas presented to an urgent care with 5 days of progressive abdominal pain, bloating, nausea, and subjective fevers. The patient had a diffusely tender abdomen, without peritonitis, was mildly tachycardic, and had a white blood cell count of 15 K. A CT of the abdomen/pelvis was consistent with PMP with a ruptured appendiceal mucocele versus PMP secondary to an adnexal ovarian neoplastic pathology with an infectious component. The patient initially improved on antibiotics but ultimately required two surgeries, the first of which controlled intraabdominal sepsis while the second permitted definitive management of PMP with cytoreductive surgery (CRS) and HIPEC. CONCLUSION: Superinfected PMP is a rare entity with very few documented cases. A staged approach that incorporates clearing the peritoneal infection, with or without resection of the primary tumor, followed by rehabilitation and definitive surgery appears to be a safe and effective management strategy.

Superinfection and cell regeneration can lead to chronic viral coinfections.

Molecular diagnostic techniques have revealed that approximately 43% of the patients hospitalized with influenza-like illness are infected by more than one viral pathogen, sometimes leading to long-lasting infections. It is not clear how the heterologous viruses interact within the respiratory tract of the infected host to lengthen the duration of what are usually short, self-limiting infections. We develop a mathematical model which allows for single cells to be infected simultaneously with two different respiratory viruses (superinfection) to investigate the possibility of chronic coinfections. We find that a model with superinfection and cell regeneration has a stable chronic coinfection fixed point, while superinfection without cell regeneration produces only acute infections. This analysis suggests that both superinfection and cell regeneration are required to sustain chronic coinfection via this mechanism since coinfection is maintained by superinfected cells that allow slow-growing infections a chance to infect cells and continue replicating. This model provides a possible mechanism for chronic coinfection independent of any viral interactions via the immune response.

Superinfection of mature ovarian cystic teratoma in a child: An unusual presentation.

Mature cystic teratoma is the most common type of ovarian germ cell tumor. The presentation ranges from its asymptomatic nature to various complications such as torsion, rupture, and malignant change. The present case summarizes the rarest complication in the form of superinfection in a young girl without preexisting risk factors.

The Streptococcus pyogenes fibronectin/tenascin-binding protein PrtF.2 contributes to virulence in an influenza superinfection.

Influenza A virus (IAV) and Streptococcus pyogenes (the group A Streptococcus; GAS) are important contributors to viral-bacterial superinfections, which result from incompletely defined mechanisms. We identified changes in gene expression following IAV infection of A549 cells. Changes included an increase in transcripts encoding proteins with fibronectin-type III (FnIII) domains, such as fibronectin (Fn), tenascin N (TNN), and tenascin C (TNC). We tested the idea that increased expression of TNC may affect the outcome of an IAV-GAS superinfection. To do so, we created a GAS strain that lacked the Fn-binding protein PrtF.2. We found that the wild-type GAS strain, but not the mutant, co-localized with TNC and bound to purified TNC. In addition, adherence of the wild-type strain to IAV-infected A549 cells was greater compared to the prtF.2 mutant. The wild-type strain was also more abundant in the lungs of mice 24 hours after superinfection compared to the mutant strain. Finally, all mice infected with IAV and the prtF.2 mutant strain survived superinfection compared to only 42% infected with IAV and the parental GAS strain, indicating that PrtF.2 contributes to virulence in a murine model of IAV-GAS superinfection.

The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice.

Secondary bacterial respiratory infections are commonly associated with both acute and chronic lung injury. Influenza complicated by bacterial pneumonia is an effective model to study host defense during pulmonary superinfection due to its clinical relevance. Multiprotein inflammasomes are responsible for IL-1ß production in response to infection and drive tissue inflammation. In this study, we examined the role of the inflammasome during viral/bacterial superinfection. We demonstrate that ASC-/- mice are protected from bacterial superinfection and produce sufficient quantities of IL-1ß through an apoptosis-associated speck-like protein containing CARD (ASC) inflammasome-independent mechanism. Despite the production of IL-1ß by ASC-/- mice in response to bacterial superinfection, these mice display decreased lung inflammation. A neutrophil elastase inhibitor blocked ASC inflammasome-independent production of IL-1ß and the IL-1 receptor antagonist, anakinra, confirmed that IL-1 remains crucial to the clearance of bacteria during superinfection. Delayed inhibition of NLRP3 during influenza infection by MCC950 decreases bacterial burden during superinfection and leads to decreased inflammatory cytokine production. Collectively, our results demonstrate that ASC augments the clearance of bacteria, but can also contribute to inflammation and mortality. ASC should be considered as a therapeutic target to decrease morbidity and mortality during bacterial superinfection.

Comprehensive Characterization of Humoral Correlates of Human Immunodeficiency Virus 1 Superinfection Acquisition in High-risk Kenyan Women.

HIV-1 superinfection, in which an infected individual acquires a second HIV-1 infection from a different partner, is one of the only settings in which HIV acquisition occurs in the context of a pre-existing immune response to natural HIV infection. There is evidence that initial infection provides some protection from superinfection, particularly after 6months of initial infection, when development of broad immunity occurs. Comparison of the immune response of superinfected individuals at the time of superinfection acquisition to that of individuals who remain singly infected despite continued exposure can shed light on immune correlates of HIV acquisition to inform prophylactic vaccine design. We evaluated a panel of humoral immune responses in the largest published group of superinfected individuals (n=21), compared to a set of 3:1 matched singly infected controls from the same cohort. The immune functions studied included plasma neutralization, plasma and cervical antibody-dependent cellular cytotoxicity, and plasma IgG and IgA binding to a panel of 18 envelope antigens, including correlates of HIV acquisition in the RV144 vaccine trial, IgG binding to V1V2 and IgA binding to gp140. Association between each immune function and HIV superinfection was evaluated using conditional logistic regression. No significant associations were detected between any of the immune functions and superinfection acquisition. This study constitutes the most comprehensive and detailed characterization of multiple immune correlates of superinfection to date. The results suggest that immune responses not commonly measured in current HIV studies may be important in protection from HIV infection, and these or a more robust humoral response than that seen in naturally infected women may be needed for a protective vaccine.

EGFR inhibitor-induced skin reactions: differentiating acneiform rash from superimposed bacterial infections.

PURPOSE: Epidermal growth factor receptor (EGFR) inhibitors are approved for use as targeted chemotherapeutic agents against multiple solid-organ malignancies. The most common side effect associated with EGFR inhibitor therapy is a papulopustular eruption, which can easily be confused with bacterial folliculitis. In this study, we examine the relative timing and location of the EGFR-induced papulopustular eruption compared to the associated bacterial superinfections. METHODS: In this retrospective chart review, patients enrolled in our institution's IRB-approved prospective registry of cutaneous reactions to chemotherapy were screened for inclusion. All patients who received an EGFR inhibitor and developed either a papulopustular eruption or bacterial superinfection at some point during treatment were included. RESULTS: Of the 157 patients who met inclusion criteria, 36 (23 %) developed bacterial superinfections at some point during EGFR therapy. Papulopustular eruptions developed in a highly predictable time course, with a mean time to onset of 1.5 weeks and mean duration of 9.4 weeks. Bacterial superinfections occurred at widely variable time points during therapy with a mean time to onset of 27.7 weeks. Papulopustular eruptions much more frequently affected the face (97 %), chest (75 %), and back (61 %), while bacterial superinfections occurred more commonly on the upper extremity (64 %), lower extremity (47 %), and abdomen (39 %). CONCLUSIONS: The EGFR inhibitor-induced papulopustular eruption has a stereotypical time course and occurs in a characteristic distribution affecting the central face, upper chest, and back. Bacterial superinfections more frequently affect the extremities, abdomen, and groin and may occur at any point during EGFR therapy.

[Morphological diagnosis of tuberculosis under present-day conditions].

The paper presents general statistical data on morbidity and mortality rates of tuberculosis, which show positive trends in recent years, with exception of those of its concurrence with HIV infection. The tasks of the morphological diagnosis of tuberculosis are divided into 4 groups: 1) to refine approaches to detecting mycobacteria in tissues; 2) to optimize the postmortem diagnosis of tuberculosis; 3) to optimize the lifetime differential diagnosis of tuberculosis and to develop methods for predicting its course; 4) to study the pathogenesis of tuberculosis from the standpoint of modern views on an infectious process. The data suggesting that the tissue forms of mycobacteria, the types of inflammatory responses, and the specific features of the pathogenesis of tuberculosis call for further investigations are given. To establish the real role of nontuberculous mycobacteria, to study the likelihood that the patient will be superinfected with other M. tuberculosis genotypes, and to elaborate a uniform (clinical, pathogenetic, and morphological) classification of tuberculosis should be also regarded as the most important tasks in its morphological examination.

PHiD-CV induces anti-Protein D antibodies but does not augment pulmonary clearance of nontypeable Haemophilus influenzae in mice.

BACKGROUND: A recently-licensed 10-valent pneumococcal conjugate vaccine (PHiD-CV; Synflorix, GSK) uses Protein D from Haemophilus influenzae as a carrier protein. PHiD-CV therefore has the potential to provide additional protection against nontypeable H. influenzae (NTHi). NTHi frequently causes respiratory tract infections and is associated with significant morbidity and mortality worldwide and there is currently no vaccine. METHODS: We developed mouse models of NTHi infection and influenza/NTHi superinfection. Mice were immunized with PHiD-CV, heat-killed NTHi, or a 13-valent pneumococcal conjugate vaccine that did not contain Protein D (PCV13; Prevenar, Pfizer) and then infected intranasally with NTHi. RESULTS: Infection with NTHi resulted in weight loss, inflammation and airway neutrophilia. In a superinfection model, prior infection with pandemic H1N1 influenza virus (strain A/England/195/2009) augmented NTHi infection severity, even with a lower bacterial challenge dose. Immunization with PHiD-CV produced high levels of antibodies that were specific against Protein D, but not heat-killed NTHi. Immunization with PHiD-CV led to a slight reduction in bacterial load, but no change in disease outcome. CONCLUSIONS: PHiD-CV induced high levels of Protein D-specific antibodies, but did not augment pulmonary clearance of NTHi. We found no evidence to suggest that PHiD-CV will offer added benefit by preventing NTHi lung infection.

Uropathogenic Escherichia coli superinfection enhances the severity of mouse bladder infection.

Urinary tract infections (UTIs) afflict over 9 million women in America every year, often necessitating long-term prophylactic antibiotics. One risk factor for UTI is frequent sexual intercourse, which dramatically increases the risk of UTI. The mechanism behind this increased risk is unknown; however, bacteriuria increases immediately after sexual intercourse episodes, suggesting that physical manipulation introduces periurethral flora into the urinary tract. In this paper, we investigated whether superinfection (repeat introduction of bacteria) resulted in increased risk of severe UTI, manifesting as persistent bacteriuria, high titer bladder bacterial burdens and chronic inflammation, an outcome referred to as chronic cystitis. Chronic cystitis represents unchecked luminal bacterial replication and is defined histologically by urothelial hyperplasia and submucosal lymphoid aggregates, a histological pattern similar to that seen in humans suffering chronic UTI. C57BL/6J mice are resistant to chronic cystitis after a single infection; however, they developed persistent bacteriuria and chronic cystitis when superinfected 24 hours apart. Elevated levels of interleukin-6 (IL-6), keratinocyte cytokine (KC/CXCL1), and granulocyte colony-stimulating factor (G-CSF) in the serum of C57BL/6J mice prior to the second infection predicted the development of chronic cystitis. These same cytokines have been found to precede chronic cystitis in singly infected C3H/HeN mice. Furthermore, inoculating C3H/HeN mice twice within a six-hour period doubled the proportion of mice that developed chronic cystitis. Intracellular bacterial replication, regulated hemolysin (HlyA) expression, and caspase 1/11 activation were essential for this increase. Microarrays conducted at four weeks post inoculation in both mouse strains revealed upregulation of IL-1 and antimicrobial peptides during chronic cystitis. These data suggest a mechanism by which caspase-1/11 activation and IL-1 secretion could predispose certain women to recurrent UTI after frequent intercourse, a predisposition predictable by several serum biomarkers in two murine models.