Viral infections of the lung, including influenza and emerging infections: histopathology Dr. Muehlenbachs has nothing to Disclose

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1 Viral infections of the lung, including influenza and emerging infections: histopathology Dr. Muehlenbachs has nothing to Disclose 3/13/2016 Binford Dammin Society Companion Meeting Atis Muehlenbachs, MD, PhD Infectious Diseases Pathology Branch Centers for Disease Control and Prevention Outline Viral taxonomy Overview: Viral taxonomy. Patterns of disease. Viruses you can see in the lung. Viral inclusions and mimics. Selected viruses you cannot see in the lung. Bronchiolitis and asthma exacerbations. Carriage versus disease. HR Gelderblom, Structure and Classification of Viruses, Med Micro 4 th ed. 1

2 Rhinoviruses EVD68 Viral taxonomy: Respiratory viruses Hantaviruses Rhinoviruses EVD68 Viral taxonomy: Lung infection Hantaviruses Coronaviruses (229E, HKU1, OC43, SARS, MERS) Influenza viruses Coronaviruses (229E, HKU1, OC43, SARS, MERS) Influenza viruses Bocavirus RSV Parainfluenza hmpv Nipah Measles Bocavirus RSV Parainfluenza hmpv Nipah Measles Adenoviruses Adenoviruses CMV HR Gelderblom, Structure and Classification of Viruses, Med Micro 4 th ed. CMV HR Gelderblom, Structure and Classification of Viruses, Med Micro 4 th ed. Interstitial Pneumonitis Bronchiolitis/bronchitis/tracheitis Parainfluenza Respiratory syncytial virus (RSV) Human metapneumovirus Influenza Cytomegalovirus Respiratory syncytial virus (RSV) Parainfluenza Influenza Rhinovirus Human metapneumovirus 2

3 Necrotizing inflammation Diffuse alveolar damage Adenovirus Herpesviruses 1 3 (HSV 1&2, VZV) Influenza (H1N1) SARS/MERS Hantavirus Other viruses after prolonged disease course Syncytial cells and inclusions Bacterial Bronchopneumonia Courtesy Jana Ritter/Kelly Keating, CDC RSV Parainfluenza Measles Nipah Influenza 3

4 Pulmonary edema Viral Inclusions Paracrystalline arrays of virions; these have light scattering properties. Arrays need to be large enough to be seen on an H&E stained slide. Hanta Dengue Enterovirus 71 (neurogenic) Courtesy Cynthia Goldsmith, CDC Viral taxonomy: inclusions RSV Parainfluenza Nipah Measles Case #1 21 year old woman with shortness of breath, chest pain and light headedness. Mid May. Emergency department: no pulmonary embolism, Lung imaging normal. Discharged and died. Autopsy: Pericarditis and pneumonia Adenoviruses CMV, HSV1&2, VZV HR Gelderblom, Structure and Classification of Viruses, Med Micro 4 th ed. 4

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6 Case #1 Circulating megakaryocytes What is the diagnosis? Degenerating cells Case #1 Diagnosis Adenovirus Lung: Negative adenovirus IHC and PCR Pericardium: Positive parvovirus B19 by PCR Courtesy Kelly Keating/Sherif Zaki, CDC 6

7 Adenovirus Adenovirus Difficult case Courtesy Kelly Keating/Sherif Zaki, CDC CMV effect described in 1904 Cytomegalovirus From Jesionek A, 1904, reprinted by: Ho, M, Med Microbiol Immunol, 2008 Courtesy Wun Ju Shieh/Sherif Zaki, CDC 7

8 Cytomegalovirus Difficult case Paramyxoviruses Pulmonary findings: Bronchiolitis, pneumonitis and pneumonia. Syncytial cells with viral inclusions, both cytoplasmic and intranuclear. Often not seen in positive cases of RSV and parainfluenza Viral fusion protein mediated fusion. Courtesy Kelly Keating/Sherif Zaki, CDC RSV Parainfluenza Courtesy Kelly Keating/Sherif Zaki, CDC Courtesy Sherif Zaki, CDC 8

9 Measles Nipah virus Courtesy Jana Ritter/Kelly Keating, CDC Courtesy Wun Ju Shieh/Sherif Zaki, CDC Vasculitis Case #2 7 year old girl with a history of asthma presented to Emergency department with difficulty breathing, chest pain, fever and coughing. Early April. Diagnosed as asthma exacerbation, received albuterol and supportive care. Improved and was sent home. Next morning had similar complaints, collapsed and resuscitation was unsuccessful 9

10 PCR: Influenza A H3 IHC: influenza A Case #2 Diagnosis: Influenza A(H3) seasonal flu infection in the setting of asthma. Respiratory viruses and asthma Respiratory viral infections are clinically associated with asthma exacerbation and hospitalization. By NP swab, rhinovirus is most commonly detected, followed by RSV and influenza. Busse WW et al, Lancet 2010 Question of carriage versus disease: Many respiratory viruses can be present in upper airways but not lower airways. Immunohistochemistry can localize viral antigen to bronchioles. 10

11 Case #3 8 month old infant, previously well, discovered unresponsive on recliner. December. Resuscitation resulted in hypoxic ischemic encephalopathy. Following a negative septic, genetic and metabolic work up, life support was withdrawn, and died 2 days after admission. NP swab was negative. Bronchiolitis PCR: Influenza A &B, RSV, Paraflu and Mycoplasma Negative PCR: Rhinovirus Positive IHC using a cross reactive enterovirus antibody Rhinoviruses and bronchiolitis Following RSV (50 80%), rhinoviruses are second most detected viruses (5 25%) in NP swabs from children hospitalized with bronchiolitis. Meissner, NEJM, 2010 Peak activity in autumn and spring. Severe disease seen largely in age less than 2 years (clinical immunity rapidly gained due to high exposure). Severe episodes associated with asthma later in life. Often thought to be restricted to upper airways, involvement of lower airways demonstrated by pre and post inoculation bronchial biopsies of human volunteers. Papadopoulos NG et al JID Question of carriage versus disease: Prevalence of rhinovirus can be as high as 50% in asymptomatic populations. Immunohistochemistry can localize viral antigen to bronchioles. 11

12 Bronchiolitis: RSV IHC Case #4 4 year old girl, near absent medical care, and on no medication. Cough, wheezing, shortness of breath noted late august She died two days later without medical care. Autopsy: asthma. Courtesy Wun Ju Shieh/Sherif Zaki, CDC 12

13 Case #4 Enterovirus IHC Post mortem NP swab: Flu A/B, RSV, paraflu, adeno PCR NEGATIVE Both rhinovirus and enterovirus PCR POSITIVE PCR from formalin fixed paraffin embedded tissues: Positive for EV D68 Picornavirus like particles by TEM Enterovirus D68 Bronchiolar basement membrane Cilia Bronchiolar Lumen Outbreak in ,153 people in 49 states had respiratory illness caused by EV D68. Almost all of the confirmed cases were children, many whom had asthma or a history of wheezing. Likely millions of asymptomatic or minimally symptomatic cases. 14 confirmed deaths. Courtesy Maureen Metcalfe, CDC polio enterovirus/about/ev d68.html 13

14 Conclusions: Respiratory viruses, bronchiolitis and asthma Respiratory viruses can cause bronchiolitis and asthma exacerbations. Significant cause of morbidity and hospitalization in the U.S. Limitations in understanding pathogenesis because detection is largely based on nasopharyngeal secretions. Carriage versus disease. Upper versus lower airways. Pathologic studies, including immunohistochemistry to localize antigen, can provide insight to pathogenesis. Acknowledgements Infectious Diseases Pathology Branch, CDC Wun Ju Shieh Sherif Zaki Amy Denison Kelly Keating Jana Ritter Herpesvirus 14

Influenza Surveillance Weekly Report CDC MMWR Week 16: Apr 17 to 23, 2016

Office of Surveillance & Public Health Preparedness Program of Public Health Informatics Influenza Surveillance Weekly Report CDC MMWR Week 16: Apr 17 to 23, 2016 Influenza Activity by County, State, and