CONTENTS

• General properties of viral pneumonias
• Herpesviruses
  • ⍺-herpesviruses
    • HSV
    • VZV
  • β-herpesviruses
    • CMV
• Paramyxoviruses
  • RSV (respiratory syncytial virus)
  • Parainfluenza
  • Metapneumovirus
• Adenovirus
• Rhinovirus
• Hantavirus
• Questions & discussion

abbreviations used in the pulmonary section: 2

• ABPA: Allergic bronchopulmonary aspergillosis 📖
• AE-ILD: Acute exacerbation of ILD 📖
• AEP: Acute eosinophilic pneumonia 📖
• AFB: Acid Fast Bacilli
• AIP: Acute interstitial pneumonia (Hamman-Rich syndrome) 📖
• ANA: Antinuclear antibody 📖
• ANCA: Antineutrophil cytoplasmic antibodies 📖
• ARDS: Acute respiratory distress syndrome 📖
• ASS: Antisynthetase Syndrome 📖
• BAL: Bronchoalveolar lavage 📖
• BiPAP: Bilevel positive airway pressure 📖
• CEP: Chronic eosinophilic pneumonia 📖
• COP: Cryptogenic organizing pneumonia 📖
• CPAP: Continuous positive airway pressure 📖
• CPFE: Combined pulmonary fibrosis and emphysema 📖
• CTD-ILD: Connective tissue disease associated interstitial lung disease 📖
• CTEPH: Chronic thromboembolic pulmonary hypertension 📖
• DAD: Diffuse alveolar damage 📖
• DAH: Diffuse alveolar hemorrhage 📖
• DIP: Desquamative interstitial pneumonia 📖
• DLCO: Diffusing capacity for carbon monoxide 📖
• DRESS: Drug reaction with eosinophilia and systemic symptoms 📖
• EGPA: Eosinophilic granulomatosis with polyangiitis 📖
• FEV1: Forced expiratory volume in 1 second 📖
• FVC: Forced vital capacity 📖
• GGO: Ground glass opacity 📖
• GLILD: Granulomatous and lymphocytic interstitial lung disease 📖
• HFNC: High flow nasal cannula 📖
• HP: Hypersensitivity pneumonitis 📖
• IPAF: Interstitial pneumonia with autoimmune features 📖
• IPF: Idiopathic pulmonary fibrosis 📖
• IVIG: Intravenous immunoglobulin 📖
• LAM: Lymphangioleiomyomatosis 📖
• LIP: Lymphocytic interstitial pneumonia 📖
• MAC: Mycobacterium Avium complex 📖
• MCTD: Mixed connective tissue disease 📖
• NIV: Noninvasive ventilation (including CPAP or BiPAP) 📖
• NSIP: Nonspecific interstitial pneumonia 📖
• NTM: Non-tuberculous mycobacteria 📖
• OP: Organizing pneumonia 📖
• PAP: Pulmonary alveolar proteinosis 📖
• PE: Pulmonary embolism 📖
• PFT: Pulmonary function test 📖
• PLCH: Pulmonary Langerhans Cell Histiocytosis 📖
• PPFE: Pleuroparenchymal fibroelastosis 📖
• PPF: Progressive pulmonary fibrosis 📖
• PVOD/PCH Pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis 📖
• RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease 📖
• RP-ILD: Rapidly progressive interstitial lung disease 📖
• TNF: tumor necrosis factor
• UIP: Usual Interstitial Pneumonia 📖

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general properties of viral pneumonias

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getting started

• The predominant challenges with viral pneumonia are often:
  • (a) Discerning the difference between viral colonization (aka asymptomatic shedding) versus invasive infection.
  • (b) Determining whether there may be a bacterial superinfection.
• Clues that may be helpful:
  • Involvement of other organs (e.g., skin lesions caused by HSV or VZV).
  • Characteristic radiologic patterns.
  • Clinical syndromes that match the virus (e.g., upper respiratory tract involvement).
  • Level of immunosuppression:
    • Immunocompetent patients: viral pneumonia is generally due to influenza, RSV, parainfluenza, metapneumovirus, or adenovirus.
    • Immunocompromised patients: a broader range of viruses may be involved.

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laboratory clues to a viral etiology of pneumonia

inflammatory markers

• Viral infection may be associated with a normal or mildly elevated procalcitonin (PCT).
• Elevation of C-reactive protein (CRP) is similar between viral or bacterial pneumonia.
• A markedly elevated C-reactive protein with an unimpressive procalcitonin might suggest a viral or nonbacterial process. (31128571)

complete blood count

• Leukopenia is associated with several viral pneumonias.
• Thrombocytopenia is associated with several viral pneumonias.
• Atypical lymphocytes may be suggestive of a viral infection. 📖

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clinical syndromes 

Patients with viral or atypical pneumonia may often present with several sites of involvement. 

otitis media

• Parainfluenza virus.
• Mycoplasma (may cause bullous myringitis).

conjunctivitis

• Adenovirus.
• Parainfluenza virus.
• Leptospirosis should also be considered.
• Mycoplasma pneumoniae.

common cold (coryza)

• Symptoms: nasal congestion, rhinorrhea, odynophagia.
• Causes:
  • Rhinovirus (~50%), adenovirus, RSV, influenza, parainfluenza, metapneumovirus, human coronaviruses. (36338246)
  • Chlamydia pneumoniae, mycoplasma pneumonia.

pharyngitis

• Symptoms:
  • Pharyngitis is classically characterized by the triad of odynophagia, fever, and pharyngeal inflammation.
  • Note that odynophagia alone may be a component of the common cold (above).
• Causes:
  • Adenovirus is most commonly identified. (36338246)
  • HSV-1 may cause pharyngitis and ulcerative stomatitis.
  • EBV may cause severe tonsillar edema that can threaten the airway. (36338246)
  • Chlamydia pneumoniae, mycoplasma pneumonia.
  • Group A streptococcal pharyngitis.
  • Tularemia.

acute laryngitis

• Symptoms include hoarseness and dysphonia. This usually follows an upper respiratory tract infection.
• Causes:
  • Nearly all major respiratory viruses can cause this. (36338246)
  • Chlamydia pneumoniae, mycoplasma pneumonia. Chlamydia pneumoniae in particular may be associated with prominent laryngitis. (33835878)

tracheitis/bronchitis

• Symptoms: cough, with or without sputum production.
• Causes:
  • Usually viral (including influenza, parainfluenza, human metapneumovirus, adenovirus).
  • <10% due to atypical bacteria (Mycoplasma pneumoniae, Chlamydia pneumoniae, Bordetella pertussis). (36338246)

bronchiolitis

• Symptoms: wheezing, dyspnea.
• Radiology: minimal abnormalities or a tree-in-bud pattern on CT scan.
• Causes:
  • Most often due to the trifecta of RSV, parainfluenza, and metapneumovirus.
  • Other causes include rhinovirus.

pneumonia

• Symptoms: cough, sputum production, tachypnea, hypoxemia.
• Radiology shows parenchymal infiltrates.
• Causes: Influenza, RSV, human metapneumovirus, parainfluenza, adenoviruses, human coronaviruses. (36338246)

multisystem dissemination

• Adenovirus.
• CMV, HSV, VZV.

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radiological patterns of viral pneumonia

Viral pneumonia often causes one of the four following patterns:

bronchopneumonia (~30%)

• Discussed in the chapter on community-acquired pneumonia here: 📖

multifocal airspace pattern (~25%)

• Radiological findings:
  • Multifocal ground-glass opacities and/or consolidation with intervening normal lung.
• Common causes include:
  • Adenovirus especially.
  • Influenza.
  • Hantavirus.
  • CMV
  • VZV.

unifocal airspace pattern (~5%)

• Radiological findings: Focal consolidation, ground-glass opacities, or tree-in-bud opacities.

diffuse airspace pattern (~2%)

• Radiological findings: Diffuse, uniform, bilateral ground-glass opacities or consolidation. (Walker 2019)
• Common causes include:
  • CMV, HSV, hantavirus, or Influenza H1N1 especially.
  • VZV.
  • Parainfluenza.
  • RSV.
  • Metapneumovirus.
  • Adenovirus.
  • Seasonal influenza.
• Further discussion of diffuse ground glass opacities: 📖

features that usually aren't caused by viral pneumonia:

• ⚠️ Lobar areas of consolidation (but note that smaller areas of consolidation may often occur with viral pneumonia).
• ⚠️ Lymphadenopathy.
• ⚠️ Pneumothorax.

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HSV pneumonia

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HSV epidemiology: largely restricted to several risk groups

• Transplant patients:
  • Usually in the first few months post transplantation.
  • Accounts for 1-10% of post-transplant pneumonia.
• Immunosuppressive medications.
• Chemotherapy, malignancy.
• HIV:
  • HSV is frequently cultured from respiratory secretions, but it's generally a contaminant. Lower respiratory tract HSV involvement in HIV is possible, but rare. (Murray 2022) 
  • HSV pneumonia might be associated with lower CD4 counts (e.g., <200/uL). 
• Critically ill patients on mechanical ventilation. (24394829) However, HSV may merely correlate with illness severity, rather than cause invasive infection. (25749257)

HSV clinical findings

• Pneumonia may cause dyspnea, fever, cough, tachypnea, wheeze, chest pain, and/or hemoptysis.
• Oral or genital ulcers may provide a clue to the presence of HSV (but their absence certainly doesn't exclude HSV).
• HSV may involve other organs (e.g., hepatitis, meningitis, encephalitis, keratoconjunctivitis).

HSV chest radiology

• (#1) Bilateral, symmetric ground glass opacities and airspace consolidation may be seen. This could reflect hematogenous HSV dissemination.
• (#2) Focal pneumonia can occur, possibly related to contiguous spread of HSV from necrotizing tracheobronchitis. (Murray 2022)
  • Pseudomembranes due to tracheal ulcers may cause upper airway obstruction. (Walker 2019)
  • Centrilobular nodules in a tree-in-bud pattern may be seen.
• Small pleural effusions are commonly encountered.

HSV diagnostic studies

• PCR of respiratory specimens may be positive for HSV, but this doesn't necessarily establish the presence of invasive pneumonia.
  • ~1-5% of normal people shed HSV in their saliva. (24394829)
  • ~20% of intubated patients are PCR-positive for HSV. (Murray 2022)
  • Up to 70% of ARDS patients are PCR-positive for HSV. (35534126)
• Bronchoscopy:
  • May reveal tracheitis, bronchitis, or punctate mucosal lesions.
  • Cytology demonstrating HSV-specific intranuclear inclusions support the diagnosis of pneumonia. (Murray 2022)
  • Tissue biopsy would be ideal (but is often impossible to safely obtain).
• (Serology doesn't sort out prior exposure versus active infection.)

HSV management

• Among immunocompetent ICU patients found to be HSV-positive, it is often unclear whether treatment is beneficial. HSV is frequently found in respiratory secretions of critically ill patients; most of these patients won't benefit from acyclovir. Treatment should probably be reserved for patients with more persuasive evidence of infection (e.g., positive cytology, lesions seen on bronchoscopy, CT scan suggestive of HSV). (33926298) Unfortunately, there are no evidence-based criteria to identify patients who would benefit from treatment.
• IV acyclovir is first-line treatment for severe disease:
  • For severe disease, 10 mg/kg q8hrs may be reasonable.
  • For milder disease in the absence of substantial immunosuppression, 5 mg/kg q8hr may be reasonable. (24394829)
  • More on acyclovir pharmacology here: 📖.

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VZV pneumonia

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VZV epidemiology

• Transmission is airborne or through direct contact.
• Pneumonia usually occurs as a component of primary infection (chickenpox). Primary infection among adults is uncommon, but may result from lack of prior vaccination or exposure. Risk factors for more severe disease include:
  • Pregnancy.
  • Older age.
  • Malignancy (especially leukemia or lymphoma).
  • Immunocompromise (e.g., steroid therapy, HIV, organ transplantation).
• Pneumonia rarely occurs within the context of reactivation of VZV (shingles). This is a rare complication that may occur in the context of disseminated disease due to impaired cell-mediated immunity.

VZV clinical findings

• (#1) Chicken pox rash:
  • Erythematous macules transform into papules, and subsequently vesicles.
  • Classically, lesions first occur on the trunk and then spreads to the face and extremities.
  • ⚠️ Immunosuppressed patients may lack classic skin lesions. (29680828) Persistent fever and recurrent crops of lesions may predict visceral dissemination. (Fishman 2023)
• (#2) Pneumonia occurs 1-6 days after rash begins:
  • Symptoms may include cough, fever, dyspnea, pleuritic chest pain, and hemoptysis.
  • There is a high rate of respiratory failure, with mortality ranging from 10-50%.
• (#3) Bacterial superinfection may complicate underlying viral infection.
• Multiorgan involvement with encephalitis and hepatitis may occur.

VZV chest radiology

• Acute phase:
  • The characteristic pattern is diffuse nodular (1-10 mm) opacities in a random (miliary) distribution. Nodules are often ill-defined, and surrounded by ground glass halos. In severe disease, nodules may coalesce into consolidation (especially near the hila and bases). (Walker 2019)
  • Hilar lymphadenopathy and pleural effusions can occur. (29757717)
  • Diaphragmatic paralysis may result from involvement of the dorsal nerve root. (Walker 2019)
• Chronic, healed phase: Multiple calcified nodules may be seen in the lung parenchyma.

VZV diagnostic studies

• Rash may be evaluated (e.g., with cytologic examination using a Tzanck smear and/or PCR).
• Viral culture or PCR from bronchoalveolar fluid may be positive.

VZV management

• Prophylaxis: VZV immune globulin may be considered for pregnant women who are susceptible to VZV, within 96 hours of exposure. (Murray 2022)
• Treatment:
  • Mortality may be as high as 18%, so aggressive therapy is warranted. (29680828)
  • Empiric therapy should be started for patients with bilateral reticulonodular infiltrates with a vesicular rash. (32561442)
  • Acyclovir is the front-line therapy (10-15 mg/kg q8hrs, with dose-adjustment for renal dysfunction). More on acyclovir pharmacology here: 📖.
  • Use of steroid as adjunctive treatment is controversial. (29680828)

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CMV pneumonia

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CMV basics

• CMV is the most common viral pathogen associated with life-threatening pneumonia in the immunocompromised host. (Walker 2019) Pneumonia is largely confined to immunocompromised patients. (35534126)
• CMV pneumonia represents a systemic infection that involves the lung secondarily. (Fishman 2023)

CMV epidemiology

• Stem cell transplantation:
  • Pneumonia usually occurs within the first 1-3 months following transplantation. However, CMV prophylaxis may shift the onset towards later timepoints.
  • CMV causes the majority of viral infections (and in some series, the majority of all pneumonia). However, prophylaxis may decrease this considerably.
  • Incidence is ~10-40% overall.
  • Risk factors: seropositivity of donor or recipient, allogeneic stem cell transplantation, advanced age, acute graft-versus-host disease.
• Solid organ transplantation:
  • Pneumonia usually occurs between 1-6 months following transplantation (during which time CMV may be the most common cause of viral infection). However, CMV prophylaxis may shift this towards later timepoints, with an increased risk following discontinuation of prophylaxis.
  • Following lung transplantation, CMV is the 2nd most common infection (after bacterial lung infections). (34673023)
• HIV
  • CMV is frequently isolated from the lungs. However, the role of CMV in causing pulmonary disease in HIV-infected people is debated. (Murray 2022) CMV is not considered a significant pathogen in most cases. (Shepard 2019)
  • Clinical pneumonia and disseminated CMV are more common when CD4 counts are <50/uL. The presence of extrathoracic CMV infection also supports the possibility of a clinically relevant CMV pneumonia.
  • CMV in AIDS patients is usually a combination of pneumocystis plus CMV, with pneumocystis as the predominant pathogen (unlike in transplant patients, who manifest with a pure CMV pneumonia). CMV pneumonia may be a consideration among patients who deteriorate following treatment of pneumocystis.
  • CMV infection is associated with micronodules/macronodules and patchy ground glass opacities more often than pneumocystis (which usually causes more homogeneous ground glass opacities). (35534126)
• Other immunosuppressed patients.
  • Including chronic steroid therapy.

CMV clinical findings

• Clinical features of pneumonia are nonspecific:
  • Fever, malaise, myalgias.
  • Dry cough.
  • Dyspnea, hypoxemia, tachypnea.
• Other organ system involvement with CMV may be present, for example:
  • Colitis may lead to intractable diarrhea.
  • Esophagitis.
  • Meningoencephalitis or subacute encephalitis.
  • Hepatitis.
  • Retinitis (consider retinal examination by an ophthalmologist, even in the absence of ocular complaints). (Murray 2022)
  • Anemia, thrombocytopenia.

CMV chest radiology

• (1) Diffuse ground glass opacities are seen most often:(15671387)
  • The most common pattern is isolated, diffuse ground glass opacities.
  • Opacities may be more prominent in the outer third of the lungs (unlike pneumocytis).
  • Tend to involve the mid and lower lung fields. (Fishman 2023)
  • In more severe cases, this may progress to diffuse consolidation.
• (2) Miliary pattern may occur (with small lesions <4 mm). A miliary pattern may be correlated with a rapidly progressive and fatal pneumonia (whereas interstitial abnormalities often correlate with more insidious onset of pneumonia). (Murray 2022)
• Other patterns that may be seen:
  • Septal thickening. (29757717)
  • Tree-in-bud pattern.
  • Centrilobular nodules (may resemble hypersensitivity pneumonitis).
  • Pleural effusion.
  • Masses and masslike infiltrates (especially in HIV). (Shepard 2019, 29757717) 

CMV laboratory studies

• General labs which may be seen in disseminated CMV:
  • Leukopenia, thrombocytopenia, and atypical lymphocytosis.
  • Liver function test abnormalities.
• Quantitative plasma PCR:
  • If positive:
    • PCR-positive CMV in the blood is more suggestive of pathogenic infection (as compared to the sputum).
    • However, CMV reactivation is common in acute illness. Thus, CMV in the plasma doesn't necessarily indicate invasive disease. (32561442)
    • Higher levels of CMV viremia correlate with a higher likelihood of invasive infection. Unfortunately assays aren't necessarily comparable, so precise cutoff values may vary.
  • If negative, this argues strongly against CMV pneumonia. (Fishman 2023)
• (CMV antigen detection in blood has largely been replaced by PCR with viral load detection.)(Fishman 2023)

CMV: bronchoscopy

• In general: CMV isolation doesn't indicate invasive disease, but it does increase the risk of disease. Tissue diagnosis is needed to prove infection (although typical intracellular inclusions found on BAL fluid cytology may be strongly suggestive of invasive infection).
• Transplant patient:
  • Biopsy has a sensitivity of 60-90% following lung transplantation.
  • Cytology has a sensitivity of ~20% and specificity of 98% (if inclusion bodies are seen).
• HIV patient:
  • Detection of CMV in bronchoalveolar lavage is often not associated with lung disease. (Murray 2022)
  • Cytology revealing viral cytopathic effect (inclusion bodies) is more specific, but the precise significance of this still remains unclear.
  • Transbronchial biopsy is more specific for CMV pneumonitis, but lacks sensitivity due to the patchy nature of the pneumonia.

diagnostic criteria: CMV syndrome in a solid organ transplant recipient

• Diagnostic criteria should never be applied rigidly, but they may help conceptualize an approach to diagnosis. CMV syndrome has been defined as criteria to support CMV disease in the context of CMV detection in the blood (yet without a tissue diagnosis). A diagnosis of probable CMV syndrome requires at least two of the following: (27682069, ERS handbook 3rd ed.)
• (1) Fever >38 C on at least two days.
• (2) New or increased malaise or fatigue.
• (3) Leukopenia or neutropenia on two separate measurements at least 24 hours apart:
  • WBC count <3500/uL if the WBC count was previously >4000/uL.
  • WBC decrease by >20% if the WBC count was previously <4000/uL.
• (4) >5% atypical lymphocytes.
• (5) Thrombocytopenia:
  • Platelet count <100,000/uL if the platelet count previously was >115,000/uL.
  • Platelet count decrease by >20% if the platelet count was previously <115,000/uL.
• (6) Elevation of aminotransferases to twice the upper limit of normal.

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CMV management

HIV patients: 

• Among patients with pneumocystis and CMV, most will improve clinically in response to treatment solely for pneumocystis. (Murray 2022) 
• Potential indications for treatment of CMV might include:
  • Histopathological evidence of invasive infection (e.g., cytology with inclusion bodies).
  • Concomitant involvement of other organs (e.g., CMV retinitis or colitis).
  • More profound immunosuppression (e.g., CD4 count <50/uL).
  • Failure of other medical therapies. 

transplantation:

• Empiric therapy is suggested for patients with bilateral interstitial pneumonia after a recent lung transplant or hematopoietic stem cell transplant. (32561442)
• Bone marrow transplant recipients: CMV pneumonia has a higher frequency and morbidity in this context. Isolation of CMV from bronchoalveolar lavage or blood may be sufficient evidence to initiate therapy. (Fishman 2023)

 how to treat:

• Ganciclovir 💊 is front line therapy for invasive CMV.
  • Usual dose is 5 mg/kg IV q12 hours for at least two weeks (with dose adjustment if GFR <70 ml/min).
  • Adverse events include nephrotoxicity and myelosuppression (anemia, thrombocytopenia, leukopenia).
• Immunosuppression should be reduced (as able).
• Peripheral blood viral load may be utilized to confirm response to therapy. (Murray 2022) Persistent or recurrent viremia may suggest drug resistance. 
  • For patients with lung transplantation, treatment should be continued until resolution of symptoms and viremia. (34673023)

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respiratory syncytial virus (RSV)

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RSV basics

• RSV is an enveloped, negative-sense, single-stranded RNA virus.
• RSV and parainfluenza may produce a necrotizing bronchiolitis, with exudates in the bronchiolar lumen. This may explain their tendency to cause airway obstruction. (Shah 2019)
• RSV and influenza both tend to lead to bacterial superinfections. If a patient with RSV deteriorates clinically, this possibility should be considered. (Murray 2022)

RSV epidemiology

• RSV is seasonal. In northern locales, it usually occurs between November-April, with a peak in January-February.
• Transmission may occur via fomites or aerosol droplets.
• RSV pneumonia usually occurs in the context of:
  • Older age or debilitation.
  • Chronic respiratory or cardiac disease.
  • Leukemia.
  • Transplantation. Risk may be especially high in the first few months after transplantation. Following lung transplantation, RSV is associated with reduced pulmonary function and bronchiolitis obliterans syndrome. (29680828)

RSV clinical manifestations include

• Upper respiratory tract infection (e.g., sore throat, rhinorrhea, nasal congestion).
• Bronchiolitis:
  • RSV may cause impressive wheezing and dyspnea in adults (who may not have comorbidities or previously hyperreactive airways).
  • RSV is the cause of ~5-10% of COPD exacerbations. (Murray 2022) These often take a long time to resolve (with a tendency to cause bounce-back readmissions to the ICU).
• Viral pneumonia:
  • Symptoms of pneumonia may include cough, sputum production, and dyspnea.
  • Overall, RSV leads to a comparable morbidity compared to influenza.
  • Bacterial superinfection may occur (similarly to influenza).

RSV chest radiology in RSV pneumonia

• (1) Chest radiography may be normal in patients with predominantly obstructive physiology.
• (2) Bronchopneumonia pattern is typically seen (with tree-in-bud opacities, bronchial wall thickening, and peribronchial consolidations). (36338246) Infiltrates are often small, patchy, and disproportional to the degree of hypoxemia.
• (3) Diffuse ground glass opacities may occur.
• Other findings: Pleural effusions occasionally occur in RSV (unlike parainfluenza or metapneumovirus). (35534126)

RSV diagnosis is based on PCR

• Nasopharyngeal PCR: The significance of a positive PCR may be unclear. Among COPD patients, some patients may carry RSV even when they are not acutely ill.
• Among intubated patients, lower respiratory secretions have a higher yield (tracheal aspirate or bronchoalveolar lavage).

RSV management

• Bronchodilators may be helpful among patients with wheezing.
• Noninvasive or invasive ventilation may be required.
• Steroid is indicated among patients with underlying airway disease (e.g., exacerbation of asthma or COPD).
• Ribavirin 💊 may be considered among patients with severe immunocompromise (especially bone marrow or solid organ transplantation).
  • Oral ribavirin is preferable to aerosolized ribavirin, based on evidence that oral ribavirin is more effective in reducing mortality and the development of bronchiolitis obliterans. (29680828) Oral ribavirin is also logistically more feasible to deliver. 
  • Ribavirin is teratogenic and contraindicated by pregnancy.
  • The primary side effect is hemolytic anemia. 

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parainfluenza

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parainfluenza basics

• Parainfluenza virus is a negative-sense, single-stranded, enveloped RNA virus in the Paramyxoviridae family. There are four serotypes of parainfluenza:
  • Parainfluenza-1 and Parainfluenza-2 replicate in upper airway epithelium, usually causing an upper respiratory tract infection.
  • Parainfluenza-3 and Parainfluenza-4 replicate in the lower respiratory tract, so it's the most common serotype to cause pneumonia.
• Pathophysiology:
  • RSV and parainfluenza may produce a necrotizing bronchiolitis, with exudates in the bronchiolar lumen. This may explain their tendency to cause airway obstruction. (Shah 2019)
  • Among immunocompromised patients, parainfluenza may cause a giant cell pneumonia with DAD (diffuse alveolar damage). (Shah 2019)

parainfluenza epidemiology

• Transmission likely occurs predominantly via respiratory droplets.
• Parainfluenza usually causes only mild illness among adults.
• Seasonal:
  • Parainfluenza-1 and Parainfluenza-2 are more frequent in the fall.
  • Parainfluenza-3 has the greatest rates between April and June. (29680828) 
  • Parainfluenza-4 has no seasonality.
• Parainfluenza pneumonia is most likely among patients with: (29680828)
  • Older age.
  • Steroid use.
  • Immunocompromise (e.g., transplantation, hematological malignancy).
    • Lung transplantation: Parainfluenza is a common cause of lower respiratory tract infection, potentially predisposing to bronchiolitis obliterans. (32629492)
    • Mortality may be ~10% among patients with hematologic malignancy or status post transplantation. (32629492)

parainfluenza clinical manifestations

• Incubation is ~2-6 days.
• Manifestations range the gamut from otitis media, conjunctivitis, pharyngitis, acute bronchitis, bronchiolitis, to pneumonia. (29757717) Unsurprisingly, parainfluenza may also lead to exacerbations of COPD or asthma.
• Pneumonia: Compared to other causes of pneumonia, parainfluenza is more likely to cause wheezing (somewhat similar to RSV, as discussed above). (29680828)

parainfluenza chest radiology

• RSV, parainfluenza, and metapneumovirus tend to cause airway-centered infection (e.g., tree-in-bud pattern, bronchial wall thickening, and sometimes lobular consolidation or lobular ground glass opacities). (35534126)
• Parainfluenza may be more likely than RSV to cause patchy basilar multifocal consolidation. (35534126) Predilection for the lower lobes may help differentiate parainfluenza from other viral infections (e.g., influenza or RSV). (33485125)

parainfluenza diagnostic studies

• Parainfluenza is generally identified by multiplex PCR performed on nasopharyngeal swabs.

parainfluenza management

• Treatment is supportive.
• Bacterial or fungal co-infection is common, so these should be excluded. (36338246)
• Ribavirin has antiviral activity, but its clinical benefit is unclear. Available evidence suggests that ribavirin isn't effective. (32629492)

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metapneumovirus

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metapneumovirus basics

• Metapneumovirus is closely related to RSV.
• Metapneumovirus is a negative-sense, nonsegmented, single-stranded RNA virus.

metapneumovirus epidemiology

• Metapneumovirus is thought to be transmitted via droplets, contaminated secretions, large particle aerosol, or fomites. (Murray 2022)
• Seasonal distribution is similar to influenza and RSV (with peak activity in the late winter and early spring). Outbreaks may occur (e.g., in nursing homes). (Murray 2022) 
• Immunity is transient, with reinfection occurring throughout life.
• Risk factors for pneumonia and severe disease: (29680828)
  • Elderly.
  • Underlying lung disease (e.g., COPD).
  • Immunocompromise:
    • Transplantation.
    • HIV.
    • Hematologic malignancy.
    • Chronic steroid therapy.
    • Low lymphocyte count. (32629492)

metapneumovirus clinical findings

• Incubation is ~3-9 days.
• Symptoms commonly include cough, rhinorrhea, and sore throat.
• Fever is less common as compared to RSV or influenza.
• Bronchiolitis:
  • High rates of wheezing have been noted, which approach the incidence of bronchospasm found with RSV. (32629492)
  • Metapneumovirus often causes COPD or asthma exacerbations.
• Severe pneumonia can occur.
• Metapneumovirus carries a similar risk of ICU admission, as compared to RSV and influenza.

metapneumovirus chest radiology

• RSV, parainfluenza, and metapneumovirus tend to cause airway-centered infection (e.g., tree-in-bud pattern, bronchial wall thickening, and sometimes lobular consolidation or lobular ground glass opacities). (35534126)
• A large series found the following features to be most common:(30560776)
  • Bronchial wall thickening (88%).
  • Ground glass opacities (79%).
  • Centrilobular nodules (69%).
  • Macronodules (45%) – nodular consolidation can occur.
  • Consolidations (43%).
  • Mediastinal lymphadenopathy (27%).
  • Pleural effusions (22%).
• Bilateral involvement was seen in most patients (76%).

metapneumovirus diagnostic studies

• General labs may reveal lymphopenia, neutropenia, and/or elevated transaminases.
• Specific: Unlike influenza or RSV, asymptomatic metapneumovirus is common in adults. Thus, interpretation of a positive PCR result may be confusing. (Murray 2022)

metapneumovirus management

• Management is supportive.
• Secondary bacterial pneumonia may occur following metapneumovirus, which could require antibiotics. (35649569)

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adenovirus

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adenovirus basics

• Adenoviruses are non-enveloped, double-stranded DNA viruses.
• Different types of adenovirus may have different clinical manifestations.

adenovirus epidemiology

• Uncommonly seen in adults.
• Infections occur without seasonality. (36338246)
• Some serotypes are associated with outbreaks (e.g., among military recruits, long-term care facilities, hospital wards, boarding schools, prisons). (Murray 2022)
• Transmission may occur via droplets, contact, fomites, or fecal-oral transmission.
• Risk factors for severe disease include:
  • Organ transplantation (latent disease may become reactivated). (Murray 2022)
  • HIV infection.

adenovirus clinical findings

• Pertussis-like illness can occur with prominent coughing.
• Upper respiratory tract illness may occur, with manifestations including:
  • Fever, pharyngitis, and pharyngeal exudate.
  • Laryngotracheitis.
  • Bronchiolitis.
  • Conjunctivitis (this may be a useful clue, since this is not a feature of other major respiratory viruses). (Murray 2022)
• Pneumonia:
  • Immunocompetent patients may develop pneumonia due to some types of adenovirus. This may resemble mycoplasma pneumonia.
  • In severe cases, disseminated intravascular coagulation and septic shock may occur. (Murray 2022) Mortality rates may be high (~25%), even among immunocompetent patients. (29680828) 
  • Bacterial superinfection may occur, especially with Neisseria meningitidis. (Fishman 2023)
• Disseminated adenovirus infection may occur in immunocompromised patients (especially bone marrow transplantation). This may involve:
  • Pneumonia.
  • Hepatitis.
  • Gastroenteritis, colitis.
  • Hemorrhagic cystitis, nephritis.
  • Encephalitis, meningitis, retinitis.
  • Myocarditis.

adenovirus chest radiology

• Imaging is variable, but the most common patterns appear to be:
• (#1) Ground glass opacities:
  • Typically there are bilateral and multifocal ground glass opacities.
  • There may be superimposed septal thickening, which creates a crazy-paving pattern.
• (#2) Consolidation is the most common finding:
  • Consolidation is generally patchy, involving lobules or segments of the lung. (Walker 2019)
  • The overall distribution is typically subpleural or peribronchovascular. (32629492)
  • Consolidation may be unilateral or bilateral. (35534126)
  • Dense consolidation can mimic a bacterial pneumonia. Adenovirus is the only virus known to cause focal or lobar consolidation resembling bacterial pneumonia. (33485125)
• Other findings:
  • Small pleural effusions are commonly seen on CT scan. (35534126)

adenovirus diagnostic studies

• General laboratory studies:
  • Leukopenia and/or thrombocytopenia may be seen.
  • Disseminated adenovirus may cause abnormal liver function tests.
• Specific diagnosis:
  • Diagnosis is usually based on multiplex PCR performed on nasopharyngeal swabs. Unfortunately, distinguishing invasive infection from asymptomatic viral shedding may be difficult.
  • Serum PCR for adenovirus may be utilized to evaluate for disseminated adenovirus.

adenovirus management

• Supportive care is the most important intervention.
• If possible, the level of immunosuppression should be reduced.
• Cidofovir 💊 may be used for patients with severe infection, especially within the context of immunocompromise. (29680828) 
  • No randomized controlled trial has been performed.
  • The usual dose is 5 mg/kg IV weekly, until symptoms resolve. Probenecid is utilized to reduce nephrotoxicity (2 grams 3 hours prior to infusion, then 1 gram at 2 hours and 8 hours after completion of the infusion). Intravenous hydration should also be administered. (29680828) 
  • Nephrotoxicity is the major adverse effect. Cidofovir is contraindicated among patients with baseline GFR <55 ml/min. (29680828) Myelosuppression may also occur, causing neutropenia. 
• Brincidofovir is a lipid conjugate of cidofovir that is associated with less nephrotoxicity. This may be an attractive option, if available. (29320657)

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rhinovirus

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rhinovirus basics

• Rhinoviruses are single-stranded, positive-sense RNA viruses.
• Rhinovirus by itself has no cytopathic effect on respiratory epithelium. However, it may increase vascular permeability and stimulate mucus production. (33485125)

rhinovirus epidemiology

• Rhinovirus infections occur year-round, with peaks in early fall and again in the spring. (Murray 2022)
• Transmission may occur via aerosols, direct contact, or fomites.
• Risk factors for progression to pneumonia include:
  • Hematopoietic stem cell transplantation.
  • Lung transplantation. (32629492)

rhinovirus clinical findings

• Rhinovirus is a frequent cause of the common cold among adults.
• Exacerbations of COPD or asthma may occur.
• Pneumonia:
  • Among younger and immunocompetent patients, it's dubious whether rhinovirus is truly able to cause pneumonia as a sole causative pathogen. (36338246, 29757717)
  • Among substantially immunosuppressed patients, progression to pneumonia seems more likely. (32629492)

rhinovirus chest radiology

• Relatively few studies describe the findings of rhinovirus pneumonia (perhaps due to its rarity).
• CT scan may show multiple ill-defined patchy areas of ground glass opacity with interlobular septal thickening. (29757717) Peribronchial nodules may also occur. (35534126)

rhinovirus diagnostic studies

• Diagnosis is generally based on multiplex PCR of nasopharyngeal secretions, tracheal or bronchial aspiration, or bronchoalveolar lavage. (36338246)
• Only ~60% of infections cause overt illness, so detection of rhinovirus doesn't necessarily correlate with clinical infection. (Murray 2022) 
  • ⚠️ Detection of rhinovirus is of uncertain clinical importance, especially among immunocompetent patients. (35534126)

rhinovirus management

• For patients with severe parenchymal pneumonia, consider the possibility that rhinovirus is merely one co-pathogen, in the presence of additional pathogens. For example, rhinovirus has been associated with co-infection with Streptococcus pneumoniae. (33485125)

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hantavirus

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hantavirus epidemiology

• Acquisition:
  • Usually via inhalation of rodent droppings (especially deer mice).
  • Rarely by direct inoculation via mouse bite.
• Geography:
  • Most cases occur in the southwest United States, but the virus is widely distributed.
  • Hantavirus may be more common in rural areas.
• Cases usually occur in the spring and summer.

hantavirus clinical findings

• Incubation (usually 2-3 weeks, up to 6 weeks).
• Prodrome (~3-6 days):
  • Fever, chills, myalgia.
  • Headache, neck pain.
  • Cough.
  • Gastrointestinal symptoms (nausea/vomiting, abdominal pain, occasional diarrhea).
  • Unlike other viruses, hantavirus usually doesn't cause rhinitis, sore throat, or conjunctival symptoms.
• Cardiopulmonary phase (~5-7 days):
  • ARDS with profound capillary leak syndrome.
    • Bronchorrhea may occur, with production of copious proteinaceous fluid.
    • Diffuse alveolar hemorrhage may occur.
    • Intubation is frequently required (but not always).
  • Shock may occur, which may involve:
    • Reduced intravascular volume.
    • Reduced ejection fraction.
    • Sinus bradycardia or malignant ventricular arrhythmias may occur.
  • Oliguria often occurs.
• Diuretic phase (2-3 days)
  • Symptoms improve.
  • Diuresis occurs.

hantavirus radiology tends to mimic heart failure 

• Common findings:(28670025)
  • Bilateral ground glass opacities (often in a central distribution most prominent in the mid-lung zones, sometimes with sparing of the periphery).
  • Smooth septal thickening (which may generate a crazy-paving pattern).
  • Bilateral pleural effusions (which may be either transudative or exudative).
• Other features may include:
  • Bronchial wall thickening.
  • Small nodules.

hantavirus diagnostic studies

• General laboratory studies:
  • Thrombocytopenia is seen in ~98% of patients.
  • Hemoconcentration occurs in about half of patients.
  • Leukocytosis (which may be accompanied by circulating immunoblasts, bandemia, and/or atypical lymphocytosis). Usually there is an absence of toxic granulations in neutrophils. (27502993)
• Serological evaluation for IgM and IgG seems to be utilized most often.
  • Symptomatic patients should be uniformly IgM-positive (especially critically ill patients in a cardiopulmonary phase). In low-prevalence areas, a positive IgM strongly supports the diagnosis. (Murray 2022)
  • IgG is often present soon after the onset of clinical illness, so if IgG is detected this may be consistent with acute illness. Rising IgG titers may be used to confirm active disease. (32294350)
• PCR evaluation for hantavirus in the blood may also be available at some hospitals. However, blood levels of virus decrease rapidly following the onset of symptoms, so PCR may be negative later on in the disease course. (32294350)

hantavirus management

• Management is mainly supportive.
• Patients can decompensate very quickly, so early ICU-level monitoring may be beneficial.
• Bacterial superinfection is common, so there should be a low threshold to treat for this.

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questions & discussion

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