The Host Response to Influenza A Virus Interferes with SARS-CoV-2 Replication during Coinfection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) represent two highly transmissible airborne pathogens with pandemic capabilities. Although these viruses belong to separate virus families-SARS-CoV-2 is a member of the family Coronaviridae, while IAV is a member of the family Orthomyxoviridae-both have shown zoonotic potential, with significant animal reservoirs in species in close contact with humans. The two viruses are similar in their capacity to infect human airways, and coinfections resulting in significant morbidity and mortality have been documented. Here, we investigate the interaction between SARS-CoV-2 USA-WA1/2020 and influenza H1N1 A/California/04/2009 virus during coinfection. Competition assays in vitro were performed in susceptible cells that were either interferon type I/III (IFN-I/-III) nonresponsive or IFN-I/-III responsive, in addition to an in vivo golden hamster model. We find that SARS-CoV-2 infection does not interfere with IAV biology in vivo, regardless of timing between the infections. In contrast, we observe a significant loss of SARS-CoV-2 replication following IAV infection. The latter phenotype correlates with increased levels of IFN-I/-III and immune priming that interferes with the kinetics of SARS-CoV-2 replication. Together, these data suggest that cocirculation of SARS-CoV-2 and IAV is unlikely to result in increased severity of disease. IMPORTANCE The human population now has two circulating respiratory RNA viruses with high pandemic potential, namely, SARS-CoV-2 and influenza A virus. As both viruses infect the airways and can result in significant morbidity and mortality, it is imperative that we also understand the consequences of getting coinfected. Here, we demonstrate that the host response to influenza A virus uniquely interferes with SARS-CoV-2 biology although the inverse relationship is not evident. Overall, we find that the host response to both viruses is comparable to that to SARS-CoV-2 infection alone.

Coinfection with SARS-CoV-2 and Influenza A Virus Increases Disease Severity and Impairs Neutralizing Antibody and CD4+ T Cell Responses.

Given the current coronavirus disease 2019 (COVID-19) pandemic, coinfection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) is a major concern for public health. However, the immunopathogenic events occurring with coinfections of SARS-CoV-2 and IAV remain unclear. Here, we report the pathogenic and immunological consequences of SARS-CoV-2 and IAV H1N1 coinfection in the K18-hACE2 transgenic mouse model. Compared with a single infection with SARS-CoV-2 or IAV, coinfections not only prolonged the primary virus infection period but also increased immune cell infiltration and inflammatory cytokine levels in bronchoalveolar lavage fluid leading to severe pneumonia and lung damage. Moreover, coinfections caused severe lymphopenia in peripheral blood, resulting in reduced total IgG, neutralizing antibody titers, and CD4+ T cell responses against each virus. This study sheds light on the immunopathogenesis of SARS-CoV-2 and IAV coinfection, which may guide the development of effective therapeutic strategies for the treatment of patients coinfected with these viruses. IMPORTANCE The cocirculation of influenza virus merging with the COVID-19 pandemic raises a potentially severe threat to public health. Recently, increasing numbers of SARS-CoV-2 and influenza virus coinfection have been reported from many countries. It is a worrisome issue that SARS-CoV-2 coinfection with other pathogens may worsen the clinical outcome and severity of COVID-19 and increase fatality. Here, we evaluated SARS-CoV-2 and IAV coinfection using the K18-hACE2 mouse model. Coinfected mice exhibited increased mortality with prolonged IAV shedding. Furthermore, coinfected mice showed a higher level of cytokines and chemokines than a single infection condition. Interestingly, our data show that coinfected mice showed significantly fewer virus-specific and neutralizing antibodies than the mice with a single infection. Overall, this study suggests that coinfection aggravates viral pathology by impaired neutralizing antibody response.

The COVID-19/Tuberculosis Syndemic and Potential Antibody Therapy for TB Based on the Lessons Learnt From the Pandemic.

2020 will be marked in history for the dreadful implications of the COVID-19 pandemic that shook the world globally. The pandemic has reshaped the normality of life and affected mankind in the aspects of mental and physical health, financial, economy, growth, and development. The focus shift to COVID-19 has indirectly impacted an existing air-borne disease, Tuberculosis. In addition to the decrease in TB diagnosis, the emergence of the TB/COVID-19 syndemic and its serious implications (possible reactivation of latent TB post-COVID-19, aggravation of an existing active TB condition, or escalation of the severity of a COVID-19 during TB-COVID-19 coinfection), serve as primary reasons to equally prioritize TB. On a different note, the valuable lessons learnt for the COVID-19 pandemic provide useful knowledge for enhancing TB diagnostics and therapeutics. In this review, the crucial need to focus on TB amid the COVID-19 pandemic has been discussed. Besides, a general comparison between COVID-19 and TB in the aspects of pathogenesis, diagnostics, symptoms, and treatment options with importance given to antibody therapy were presented. Lastly, the lessons learnt from the COVID-19 pandemic and how it is applicable to enhance the antibody-based immunotherapy for TB have been presented.

Sequential infections with rhinovirus and influenza modulate the replicative capacity of SARS-CoV-2 in the upper respiratory tract.

Although frequently reported since the beginning of the pandemic, questions remain regarding the impact of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) interaction with circulating respiratory viruses in coinfected patients. We here investigated dual infections involving early-pandemic SARS-CoV-2 and the Alpha variant and three of the most prevalent respiratory viruses, rhinovirus (RV) and Influenza A and B viruses (IAV and IBV), in reconstituted respiratory airway epithelial cells cultured at air-liquid interface. We found that SARS-CoV-2 replication was impaired by primary, but not secondary, rhino- and influenza virus infection. In contrast, SARS-CoV-2 had no effect on the replication of these seasonal respiratory viruses. Inhibition of SARS-CoV-2 correlated better with immune response triggered by RV, IAV and IBV than the virus entry. Using neutralizing antibody against type I and III interferons, SARS-CoV-2 blockade in dual infections could be partly prevented. Altogether, these data suggested that SARS-CoV-2 interaction with seasonal respiratory viruses would be modulated by interferon induction and could impact SARS-CoV-2 epidemiology when circulation of other respiratory viruses is restored.

Severe Adaptive Immune Suppression May Be Why Patients With Severe COVID-19 Cannot Be Discharged From the ICU Even After Negative Viral Tests.

During the COVID-19 pandemic, a phenomenon emerged in which some patients with severe disease were critically ill and could not be discharged from the ICU even though they exhibited negative viral tests. To explore the underlying mechanism, we collected blood samples from these patients and analyzed the gene expression profiles of peripheral immune cells. We found that all enrolled patients, regardless of changes in genes related to different symptoms and inflammatory responses, showed universally and severely decreased expression of adaptive immunity-related genes, especially those related to T/B cell arms and HLA molecules, and that these patients exhibited long-term secondary infections. In addition, no significant change was found in the expression of classic immunosuppression molecules including PD-1, PD-L1, and CTLA-4, suggesting that the adaptive immune suppression may not be due to the change of these genes. According to the published literatures and our data, this adaptive immunosuppression is likely to be caused by the "dysregulated host response" to severe infection, similar to the immunosuppression that exists in other severely infected patients with sepsis.

Viral infections amidst COVID-19 in Africa: Implications and recommendations.

Viral infections have been on the rise for the past decades. The impact of the viruses worsened amidst the pandemic burdening the already overwhelmed health care system in African countries. This article sheds light on how the coronavirus together with the already existing viral infections, some of which re-emerged, impacted the continent. The strategies in place such as immunization, education, will have to be strengthened in all African countries to reduce the burden. Furthermore, governments can further collaborate with other countries in creating guidelines to reduce co-infection of the diseases.

Immunological Characterization of HIV and SARS-CoV-2 Coinfected Young Individuals.

While the risk of SARS-CoV-2 infection and/or COVID-19 disease progression in the general population has been largely assessed, its impact on HIV-positive individuals remains unclear. We present clinical and immunological data collected in a cohort of HIV-infected young individuals during the first wave of COVID-19 pandemic. SARS-CoV-2 RNA, virus-specific antibodies, as well as the expression of factors involved in the anti-viral immune response were analyzed. Moreover, we set up an in vitro coinfection assay to study the mechanisms correlated to the coinfection process. Our results did not show any increased risk of severe COVID-19 in HIV-positive young individuals. In those subjects who contracted SARS-CoV-2 infection, an increase in IL-10 expression and production was observed. Furthermore, in the in vitro coinfection assay, we revealed a reduction in SARS-CoV-2 replication associated to an upregulation of IL-10. We speculate that IL-10 could play a crucial role in the course of SARS-CoV-2 infection in HIV-positive individuals. These results might help defining clinical management of HIV/SARS-CoV-2 co-infected young individuals, or putative indications for vaccination schedules in this population.

Atypical response to bacterial coinfection and persistent neutrophilic bronchoalveolar inflammation distinguish critical COVID-19 from influenza.

Neutrophils are recognized as important circulating effector cells in the pathophysiology of severe coronavirus disease 2019 (COVID-19). However, their role within the inflamed lungs is incompletely understood. Here, we collected bronchoalveolar lavage (BAL) fluids and parallel blood samples of critically ill COVID-19 patients requiring invasive mechanical ventilation and compared BAL fluid parameters with those of mechanically ventilated patients with influenza, as a non-COVID-19 viral pneumonia cohort. Compared with those of patients with influenza, BAL fluids of patients with COVID-19 contained increased numbers of hyperactivated degranulating neutrophils and elevated concentrations of the cytokines IL-1ß, IL-1RA, IL-17A, TNF-α, and G-CSF; the chemokines CCL7, CXCL1, CXCL8, CXCL11, and CXCL12α; and the protease inhibitors elafin, secretory leukocyte protease inhibitor, and tissue inhibitor of metalloproteinases 1. In contrast, α-1 antitrypsin levels and net proteolytic activity were comparable in COVID-19 and influenza BAL fluids. During antibiotic treatment for bacterial coinfections, increased BAL fluid levels of several activating and chemotactic factors for monocytes, lymphocytes, and NK cells were detected in patients with COVID-19 whereas concentrations tended to decrease in patients with influenza, highlighting the persistent immunological response to coinfections in COVID-19. Finally, the high proteolytic activity in COVID-19 lungs suggests considering protease inhibitors as a treatment option.

Increased lethality in influenza and SARS-CoV-2 coinfection is prevented by influenza immunity but not SARS-CoV-2 immunity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. The continued spread of SARS-CoV-2 increases the probability of influenza/SARS-CoV-2 coinfection, which may result in severe disease. In this study, we examine the disease outcome of influenza A virus (IAV) and SARS-CoV-2 coinfection in K18-hACE2 mice. Our data indicate enhance susceptibility of IAV-infected mice to developing severe disease upon coinfection with SARS-CoV-2 two days later. In contrast to nonfatal influenza and lower mortality rates due to SARS-CoV-2 alone, this coinfection results in severe morbidity and nearly complete mortality. Coinfection is associated with elevated influenza viral loads in respiratory organs. Remarkably, prior immunity to influenza, but not to SARS-CoV-2, prevents severe disease and mortality. This protection is antibody-dependent. These data experimentally support the necessity of seasonal influenza vaccination for reducing the risk of severe influenza/COVID-19 comorbidity during the COVID-19 pandemic.

SARS-CoV-2-induced immunodysregulation and the need for higher clinical suspicion for co-infection and secondary infection in COVID-19 patients.

Cases of co-infection and secondary infection emerging during the current Coronavirus Disease-19 (COVID-19) pandemic are a major public health concern. Such cases may result from immunodysregulation induced by the SARS-CoV-2 virus. Pandemic preparedness must include identification of disease natural history and common secondary infections to implement clinical solutions.

Relationship of SARS-CoV-2-specific CD4 response to COVID-19 severity and impact of HIV-1 and tuberculosis coinfection.

T cells are involved in control of coronavirus disease 2019 (COVID-19), but limited knowledge is available on the relationship between antigen-specific T cell response and disease severity. Here, we used flow cytometry to assess the magnitude, function, and phenotype of SARS coronavirus 2-specific (SARS-CoV-2-specific) CD4+ T cells in 95 hospitalized COVID-19 patients, 38 of them being HIV-1 and/or tuberculosis (TB) coinfected, and 38 non-COVID-19 patients. We showed that SARS-CoV-2-specific CD4+ T cell attributes, rather than magnitude, were associated with disease severity, with severe disease being characterized by poor polyfunctional potential, reduced proliferation capacity, and enhanced HLA-DR expression. Moreover, HIV-1 and TB coinfection skewed the SARS-CoV-2 T cell response. HIV-1-mediated CD4+ T cell depletion associated with suboptimal T cell and humoral immune responses to SARS-CoV-2, and a decrease in the polyfunctional capacity of SARS-CoV-2-specific CD4+ T cells was observed in COVID-19 patients with active TB. Our results also revealed that COVID-19 patients displayed reduced frequency of Mycobacterium tuberculosis-specific CD4+ T cells, with possible implications for TB disease progression. These results corroborate the important role of SARS-CoV-2-specific T cells in COVID-19 pathogenesis and support the concept of altered T cell functions in patients with severe disease.

Distinct clinical and immunological profiles of patients with evidence of SARS-CoV-2 infection in sub-Saharan Africa.

Although the COVID-19 pandemic has left no country untouched there has been limited research to understand clinical and immunological responses in African populations. Here we characterise patients hospitalised with suspected (PCR-negative/IgG-positive) or confirmed (PCR-positive) COVID-19, and healthy community controls (PCR-negative/IgG-negative). PCR-positive COVID-19 participants were more likely to receive dexamethasone and a beta-lactam antibiotic, and survive to hospital discharge than PCR-negative/IgG-positive and PCR-negative/IgG-negative participants. PCR-negative/IgG-positive participants exhibited a nasal and systemic cytokine signature analogous to PCR-positive COVID-19 participants, predominated by chemokines and neutrophils and distinct from PCR-negative/IgG-negative participants. PCR-negative/IgG-positive participants had increased propensity for Staphylococcus aureus and Streptococcus pneumoniae colonisation. PCR-negative/IgG-positive individuals with high COVID-19 clinical suspicion had inflammatory profiles analogous to PCR-confirmed disease and potentially represent a target population for COVID-19 treatment strategies.

Sequential infection with H1N1 and SARS-CoV-2 aggravated COVID-19 pathogenesis in a mammalian model, and co-vaccination as an effective method of prevention of COVID-19 and influenza.

Influenza A virus may circulate simultaneously with the SARS-CoV-2 virus, leading to more serious respiratory diseases during this winter. However, the influence of these viruses on disease outcome when both influenza A and SARS-CoV-2 are present in the host remains unclear. Using a mammalian model, sequential infection was performed in ferrets and in K18-hACE2 mice, with SARS-CoV-2 infection following H1N1. We found that co-infection with H1N1 and SARS-CoV-2 extended the duration of clinical manifestation of COVID-19, and enhanced pulmonary damage, but reduced viral shedding of throat swabs and viral loads in the lungs of ferrets. Moreover, mortality was increased in sequentially infected mice compared with single-infection mice. Compared with single-vaccine inoculation, co-inoculation of PiCoVacc (a SARS-CoV-2 vaccine) and the flu vaccine showed no significant differences in neutralizing antibody titers or virus-specific immune responses. Combined immunization effectively protected K18-hACE2 mice against both H1N1 and SARS-CoV-2 infection. Our findings indicated the development of systematic models of co-infection of H1N1 and SARS-CoV-2, which together notably enhanced pneumonia in ferrets and mice, as well as demonstrated that simultaneous vaccination against H1N1 and SARS-CoV-2 may be an effective prevention strategy for the coming winter.

COVID-19 and HIV infection co-pandemics and their impact: a review of the literature.

Coronavirus disease 2019 (COVID-19) was first detected in December 2019. In March 2020, the World Health Organization declared COVID-19 a pandemic. People with underlying medical conditions may be at greater risk of infection and experience complications from COVID-19. COVID-19 has the potential to affect People living with HIV (PLWH) in various ways, including be increased risk of COVID-19 acquisition and interruptions of HIV treatment and care. The purpose of this review article is to evaluate the impact of COVID-19 among PLWH. The contents focus on 4 topics: (1) the pathophysiology and host immune response of people infected with both SARS-CoV-2 and HIV, (2) present the clinical manifestations and treatment outcomes of persons with co-infection, (3) assess the impact of antiretroviral HIV drugs among PLWH infected with COVID-19 and (4) evaluate the impact of the COVID-19 pandemic on HIV services.

Association of mortality and recent Mycoplasma pneumoniae infection in COVID-19 patients.

To compare characteristics and outcomes of patients who had COVID-19 with Mycoplasma pneumoniae immunoglobulin M (IgM) antibodies to those without M. pneumoniae antibodies. We retrospectively reviewed cases admitted over a 4-week period between 17 March 2020 and 14 April 2020 to the Hoboken University Medical Center, NJ, USA. We compared the outcomes of COVID-19 patients who were positive for M. pneumoniae IgM with those who were negative for M. pneumoniae IgM. The primary outcome was mortality. The adjusted odds ratio was calculated after controlling for baseline differences. Of 139 patients admitted with COVID-19, 79 were positive for M. pneumoniae IgM. The mortality among those who were M. pneumoniae IgM positive was significantly higher (adjusted odds ratio: 2.28, 95% confidence interval: 1.03 to 5.03) compared with those who were M. pneumoniae IgM negative. Patients with coinfection (COVID-19 and mycoplasma) have higher mortality compared with patients with just COVID-19 disease.

Early Virus Clearance and Delayed Antibody Response in a Case of Coronavirus Disease 2019 (COVID-19) With a History of Coinfection With Human Immunodeficiency Virus Type 1 and Hepatitis C Virus.

The effect of host immune status on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unknown. Here, we report the first case of coronavirus disease 2019 (COVID-19) with human immunodeficiency virus type 1 (HIV-1)/hepatitis C virus coinfection, who showed a persistently negative SARS-CoV-2 RNA test but delayed antibody response in the plasma. This case highlights the influence of HIV-1-induced immune dysfunction on early SARS-CoV-2 clearance.

Interaction between hepatitis B virus and SARS-CoV-2 infections.

Coronavirus disease 2019 (COVID-19) has become a global pandemic and garnered international attention. The causative pathogen of COVID-19 is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel, highly contagious coronavirus. Numerous studies have reported that liver injury is quite common in patients with COVID-19. Hepatitis B has a worldwide distribution as well as in China. At present, hepatitis B virus (HBV) remains a leading cause of cirrhosis, liver failure, and hepatocellular carcinoma. Because both viruses challenge liver physiology, it raises questions as to how coinfection with HBV and SARS-CoV-2 affect disease progression and mortality. Is there an increased risk of COVID-19 in patients with HBV infection? In this review, we summarize the current reports of SARS-CoV-2 and HBV coinfection and elaborate the interaction of the two diseases. The emphasis was placed on evaluating the impact of HBV infection on disease severity and clinical outcomes in patients with COVID-19 and discussing the potential mechanism behind this effect.

COVID-19, HHV6 and MOG antibody: A perfect storm.

BACKGROUND: Serious neurological complications of SARS-CoV-2 are increasingly being recognized. CASE: We report a novel case of HHV6 myelitis with parainfectious MOG-IgG in the setting of COVID-19-induced lymphopenia and hypogammaglobulinemia. The patient experienced complete neurological recovery with gancyclovir, high dose corticosteroids, and plasma exchange. To our knowledge, this is the first case of HHV6 reactivation in the central nervous system in the setting of COVID19 infection and the first case of MOG-IgG myelitis in the setting of SARS-CoV-2 and HHV6 coinfection. CONCLUSION: Patients with neurological manifestations in the setting of COVID19-related immunodeficiency should be tested for opportunistic infections including HHV6. Viral infection is a known trigger for MOG-IgG and therefore this antibody should be checked in patients with SARS-CoV-2 associated demyelination.

Clinical characteristics and outcomes of people living with HIV hospitalized with COVID-19: a nationwide experience.

In this prospective, multicentric, observational study, we describe the clinical characteristics and outcomes of people living with HIV (PLHIV) requiring hospitalization due to COVID-19 in Chile and compare them with Chilean general population admitted with SARS-CoV-2. Consecutive PLHIV admitted with COVID-19 in 23 hospitals, between 16 April and 23 June 2020, were included. Data of a temporally matched-hospitalized general population were used to compare demography, comorbidities, COVID-19 symptoms, and major outcomes. In total, 36 PLHIV subjects were enrolled; 92% were male and mean age was 44 years. Most patients (83%) were on antiretroviral therapy; mean CD4 count was 557 cells/mm3. Suppressed HIV viremia was found in 68% and 56% had, at least, one comorbidity. Severe COVID-19 occurred in 44.4%, intensive care was required in 22.2%, and five patients died (13.9%). No differences were seen between recovered and deceased patients in CD4 count, HIV viral load, or time since HIV diagnosis. Hypertension and cardiovascular disease were associated with a higher risk of death (p = 0.02 and 0.006, respectively). Compared with general population, the HIV cohort had significantly more men (OR 0.15; IC 95% 0.07-0.31) and younger age (OR 8.68; IC 95% 2.66-28.31). In PLHIV, we found more intensive care unit admission (OR 2.31; IC 95% 1.05-5.07) but no differences in the need for mechanical ventilation or death. In this cohort of PLHIV hospitalized with COVID-19, hypertension and cardiovascular comorbidities, but not current HIV viro-immunologic status, were the most important risk factors for mortality. No differences were found between PLHIV and general population in the need for mechanical ventilation and death.