Human Metapneumovirus
hMPV is a respiratory pathogen that causes infections ranging from colds to severe bronchiolitis and pneumonia. The first metapneumovirus associated with human infection, hMPV was discovered in 2001 when viruses that had been isolated from children presenting with RSV-like illnesses failed to be identified by standard techniques. After random-primer RT-PCR was used, the virus was identified as a new metapneumovirus related to turkey tracheitis virus. Serologic studies demonstrated that by 5 years of age, all children were seropositive and that sera originally collected in 1958 were also positive for hMPV antibodies.57 Two genetic clusters of hMPV that correspond to two different serotypes of hMPV have been recognized on every continent.
Epidemiology
Infections by hMPV occur worldwide and year-round, with a winter predominance. The season peaks between December and February in the northern hemisphere, with a longer season in temperate climates. hMPV can be isolated from 5.5% to 6.5% of children hospitalized with respiratory symptoms. The peak incidence is between 4 and 6 months of age, with most children being younger than 5 years. Coinfection with hMPV and RSV has been documented frequently, and several cases of concomitant hMPV and SARS-CoV infection have been documented.
Asymptomatic or mild illness appears to be much more common with hMPV. hMPV has been detected in 20% of ambulatory young children presenting with respiratory illness in whom no other cause was found. Most cases occurred between December and April.59 In infirm elderly patients, the incidence is 6.5%. The incidence of hMPV in general-community persons presenting with influenzalike illness is only 2%, whereas hMPV can be isolated from 3% to 6.6% of the general community with acute respiratory illnesses.
Diagnosis
Clinical features hMPV causes clinical syndromes indistinguishable from RSV, including bronchiolitis, croup, asthma exacerbation, and pneumonia. Studies attempting to differentiate hMPV from other respiratory viruses have found that hMPV infection appears to occur at a slightly older age and causes slightly milder symptoms than RSV. Infections in adults manifest as colds, influenzalike illness, bronchitis, exacerbations of underlying airway disease, or, uncommonly, pneumonia. hMPV infections in immunocompromised patients can be severe and have been associated with at least three deaths.
Laboratory tests RT-PCR has become the standard method of detecting hMPV in respiratory samples. Methods that use primers targeted at the polymerase (L) and fusion (F) protein genes have shown adequate sensitivities. The presence of antibodies is not diagnostic by itself, although seroconversion or a greater than fourfold rise in titer is indicative of recent infection. The virus can be grown in cell culture, but the cytopathic effect may not be seen for up to 14 days.
Treatment
In vitro data suggest that ribavirin has activity against hMPV similar to that against RSV. Likewise, neutralizing antibody titers against hMPV in IVIg are similar to titers against RSV. Clinical studies are required to determine the possible clinical efficacy of ribavirin and IVIg.60
Influenza Virus
Classification and Pathogenesis
Influenza viruses belong to the orthomyxovirus family and consist of types A, B, and C. These medium-sized (80 to 120 nm), enveloped, single-stranded RNA viruses contain eight gene segments (seven for influenza C). The segmented nature of the genome allows reassortment of RNA segments between two influenza viruses during dual infection and facilitates antigenic variation. Surface glycoprotein spikes possess either hemagglu-tinin or neuraminidase activity. Hemagglutinin mediates cell attachment and fusion of virus and cell membranes. By cleaving terminal sialic acid residues and destroying the receptors recognized by hemagglutinin, neuraminidase promotes release of virus from infected cells and spread within the respiratory tract.
Influenza A viruses are further classified into subtypes on the basis of their surface proteins (15 hemagglutinins and nine neur-aminidases are recognized in animal influenza viruses). Three A hemagglutinin subtypes (H1, H2, and H3) and two neuraminidases (N1, N2) have caused extensive human infections. Influenza C viruses have seven gene segments and lack a neur-aminidase. Influenza viruses are named by the type; location of isolation; isolate number; year of recovery; and, for influenza A type viruses, the subtype (e.g., A/Texas/36/91[H1N1]).
The surface glycoproteins induce host humoral and cellular immune responses and are responsible for the changing anti-genicity of influenza viruses. Two major types of antigenic change can occur: drift and shift. Antigenic drift refers to relatively minor changes in hemagglutinin and, less often, neur-aminidase antigenicity that occur frequently (usually every few years) and sequentially in the setting of selective immunologic pressure in the population. Drift results from point mutations of the corresponding RNA segment. Antigenic shift occurs only in influenza A viruses and results from acquisition of a new gene segment for hemagglutinin with or without one for neur-aminidase. This may occur through genetic reassortment during dual infections with human and animal influenza type A viruses; by the reintroduction of a virus that has not circulated recently in the human population; or by direct transmission to humans of an animal influenza virus that is capable of efficient human-to-human transmission.
Aquatic fowl are the main reservoir for influenza A viruses in nature, although some subtypes also infect other species, including swine, horses, and marine mammals. Swine are susceptible to infection with viruses from both birds and humans and may serve as a so-called mixing vessel, providing an opportunity for the generation of new pathogenic viruses.
Epidemiology and Transmission
Influenza viruses A and B cause annual outbreaks of illness affecting approximately 5% to 10% of adults, with higher rates in children. In the United States, influenza causes an average of over 36,000 deaths61 and 130,000 to 170,000 hospitalizations during each epidemic.21 The appearance of a new strain for which most of the population lacks immunity can result in worldwide outbreaks, or pandemics. Pandemic strains are associated with global spread over months and with high attack rates. Three such pandemics occurred during the 20th century; the most severe was the Spanish influenza pandemic in 1918 and 1919, which caused 20 to 40 million deaths worldwide and over 500,000 deaths in the United States.
Epidemic influenza occurs annually in temperate areas, typically between the months of December and March in the Northern Hemisphere, and follows the reintroduction of virus each year. Influenza activity usually occurs in May through August in the Southern Hemisphere and can be year-round in the tropics. Regional outbreaks caused by a particular strain are usually short (6 to 8 weeks), although successive waves of infection by different influenza viruses can occur. Influenza activity in the community is marked by increased medical contacts for febrile respiratory illness, increased absenteeism from school and the workplace, subsequent increased hospitalizations for pneumonia and other cardiopulmonary disorders, and increased mortality. Pneumonia hospitalizations increase by two to five times in high-risk patients. Persons 65 years of age and older constitute nearly 50% of excess hospitalizations and over 85% of deaths from influenza.
Influenza viruses are transmitted principally via large and small aerosolized particles. Direct transmission of influenza A virus to humans from animals has been documented.63 Although animal-to-human transmission has typically been from swine, direct transmission from birds caused an epizootic of avian influenza A H5N1 subtype virus in Hong Kong and Southeast Asia, with several dozen human infections, many of which were fatal.64,65 In the cluster of H5N1 avian virus in Hong Kong,66 the source was domestic poultry, although human-to-human transmission may have occurred in several cases. Additionally, avian H9N2 influenza virus infection has been documented in several children, and a large outbreak of H7N7 avian influenza A virus in the Netherlands was associated with at least one death.67 H7 subtype viruses have also caused an outbreak, predominantly of conjunctivitis, in British Columbia, Canada,67 and infected an immunocompromised man in New York. Influenza H5N1 or other avian viruses may pose a reemerging pandemic threat in the future.
Diagnosis
Clinical features The incubation period for influenza virus is short, averaging 2 days (range, 1 to 4 days). Classic influenza is distinguished by abrupt onset of prominent systemic symptoms, including fever, chills, headache, myalgia, malaise, and anorexia. Fever usually lasts for an average of 3 days in adults. Sore throat, dry cough, photophobia, and pain on eye movement occur frequently early in the illness. Mild conjunctivitis, clear nasal discharge, pharyngeal injection, and small, tender cervical lymph nodes are also common. As systemic illness abates, respiratory symptoms become more apparent. The most troubling respiratory symptom is protracted cough, which results from viral tracheobronchitis. Airway hyperactivity and abnormalities in pulmonary function may last from weeks to several months in previously healthy persons. Exacerbations of asthma and other types of preexisting airway disease are often severe. Infections may be subclinical or cause milder illness, including colds.
Primary influenza virus pneumonia is a heterogeneous condition, ranging from mild disease with patchy infiltrates to rapidly fatal infection. Severe pneumonia generally accounts for 2% of influenza-associated pneumonia, but during pandemics, it can account for up to 20%; influenza A viruses cause more than 90% of cases.69 As many as 40% of patients with influenza pneumonia have no prior underlying disease. Pneumonia usually begins with typical influenza, followed within 1 to 3 days by rapidly progressive dyspnea, cyanosis, diffuse rales, and wheezing. Pleuritic chest pain and blood-tinged sputum or frank hemoptysis occurs. Patients with influenza virus pneumonia have a high mortality.
Laboratory tests Multiple rapid assays are commercially available in the United States to detect influenza A and B antigens or neuraminidase activity; some of these assays differentiate between influenza A and B, and several can be performed by clinical personnel at the point of care [see Table 2]. The specificity of these assays is good to excellent, but the sensitivity varies between approximately 60% and 90%, depending on the sample type, the age of the patient, and the duration of the illness.68,70 Diagnosis can also be made by viral culture or by RT-PCR. When viral pneumonia is present, Gram stain of sputum shows few to many polymorphonuclear leukocytes, but only rarely does it show bacteria. The chest radiograph shows bilateral infiltrates that may be in the form of diffuse interstitial infiltrates, perihilar pulmonary edema, or dense opacifications. On blood counts, leukocytosis with a left shift is variably present.
A definitive diagnosis of influenza can have a significant impact on medical management. In a pediatric population, detection of influenza A antigen resulted in a decrease in antibiotic use, a decrease in duration of antibiotic use in hospitalized patients, and an increase in antiviral use.
Complications
Secondary bacterial pneumonia should be suspected when fever, increasing cough, and sputum production develop after several days of improvement. Streptococcus pneumoniae is the most common bacterial pathogen, but Staphylococcus aureus, including community-acquired methicillin-resistant strains, causes up to 25% of cases and is associated with high mortality. S. au-reus and certain other bacteria produce proteolytic enzymes that activate influenza hemagglutinin and enhance viral replication. Haemophilus influenzae and Streptococcus pyogenes are also recognized as causes of bacterial complications. Bacterial infections of the sinuses and ears are frequent. Toxic-shock syndrome and invasive meningococcal disease have also been known to complicate influenza.
Uncommon complications are myositis with rhabdomyolysis, renal failure, disseminated intravascular coagulopathy, myocarditis, pericarditis, myelitis, Guillain-Barre syndrome, and Reye syndrome. Neurologic complications, including encephalopathy or encephalitis, are unusual and occur mainly in children.63,72
Treatment
A variety of antiviral agents are available for treatment of influenza [see Table 3]. The M2 inhibitors amantadine and rimanta-dine are active against influenza A only, although recent human isolates of avian H5N1 viruses are resistant.31,68 Oral amantadine and rimantadine reduce the duration of fever and symptoms of uncomplicated influenza A virus infection by 1 to 2 days and provide more rapid overall functional recovery. Effectiveness in preventing complications or treating severe illness in hospitalized patients is uncertain. Resistant virus may arise during treatment and be transmissible on close contact.
The neuraminidase inhibitors, zanamivir and oseltamivir, are active against influenza A and B viruses.32 Zanamivir is administered by inhalation and may, in rare cases, cause bronchospasm, which can be severe. Oseltamivir is administered orally and is associated with self-limited GI upset in about 10% to 15% of treated patients; this can be reduced by taking the medication with food. Treatment of acute uncomplicated influenza in adults with inhaled zanamivir or oral oseltamivir provides symptomatic relief, reduces time to functional recovery, and decreases the likelihood of lower respiratory tract complications leading to antibiotic use.22,23 In children 1 to 12 years of age, oseltamivir provides symptomatic relief and also reduces the likelihood of otitis media.21 Oseltamivir treatment has been associated with reduced risk of hospitalization in both previously healthy and high-risk or elderly adults.74 Emergence of resistance appears to be very uncommon.
Influenza pneumonia Treatment of influenza virus pneumonia is primarily supportive. Improvements in assisted ventilation techniques have raised the survival rate above 50%, although pulmonary fibrosis develops in some patients. M2 inhibitors, NA inhibitors, and aerosolized or I.V. ribavirin, which is active against influenza A and B viruses, have been used with uncertain benefit. Combination therapies (e.g., an M2 inhibitor plus a neuraminidase inhibitor for influenza A) show enhanced activity in animal models. Although unstudied, the use of neur-aminidase inhibitors, either alone or in combination with other agents, seems reasonable in the treatment of influenza virus pneumonia.
Prevention
Chemoprophylaxis Antiviral chemoprophylaxis with aman-tadine or rimantadine is about 70% to 90% effective in preventing illness caused by influenza A virus. Chemoprophylaxis can provide several weeks’ protection to patients immunized after influenza A activity has begun, can be given throughout the season to those who cannot receive influenza vaccine (e.g., those with egg allergy) or who are unlikely to respond to the vaccine, or can be used for protection of high-risk persons when the epidemic strain diverges significantly from the vaccine antigens. Side effects of amantadine are GI upset and minor, reversible central nervous system symptoms (e.g., insomnia, dizziness, and difficulty with concentration). Rimantadine appears to be equally effective as amantadine and is associated with a lower risk of CNS side effects.
The neuraminidase inhibitors are also effective for prophylaxis of influenza A and B infections. Both inhaled zanamivir75,76 and oral oseltamivir77,78 prevent influenza when used for seasonal prophylaxis or after exposure (e.g., for family or nursing home contacts), but only oseltamivir has been approved by the Food and Drug Administration for this indication. Oseltamivir has been found to be safe for treatment of children as young as 1 year79; inhaled zanamivir has been found to be safe in children as young as 5 years. Of note, both the M2 and the neur-aminidase inhibitors may reduce the efficacy of live attenuated influenza vaccine, if the vaccine and the antiviral agent are given together.
Immunization Influenza vaccines are available in two forms: (1) an intramuscular preparation containing formalin-inactivated virus and purified surface antigen and (2) an in-tranasal spray containing live attenuated viruses.21 Both are made from egg-grown virus. Vaccine composition is reviewed annually and adjusted to reflect changes in antigenicity and anticipated circulation of viral strains; current vaccines contain one influenza B and two influenza A (H1 and H3 subtypes) anti-gens.21 The efficacy of these vaccines is approximately 70% to 90% in young adults, especially when the vaccine antigen and the circulating strain are closely matched. Immunization in healthy working adults is associated with fewer upper respiratory illnesses and fewer visits to physicians’ offices.80,81 The in-tranasal vaccine is currently approved only for healthy persons 5 to 49 years of age; it appears to be less effective in the elderly but possibly superior to inactivated vaccine in young children. Immunization with inactivated vaccine reduces influenza-related hospitalizations, including acute cardiovascular events and COPD exacerbations,82 and reduces mortality in ambulatory elderly patients by 40% to 60%.83 Wide-scale immunization of schoolchildren may reduce influenza-related mortality in older adults.84 Although inactivated vaccine is less effective in infirm elderly patients, it provides partial protection against pneumonia and death.
Table 3 Agents Used to Prevent and Treat Influenza111112
|
|
Adult Dosage |
Efficacy for Documented Influenza |
Dosage Adjustment |
|||
|
Drug |
Prophylaxis* |
Treatment1 |
Prophylaxis |
Treatment |
State |
Dosage |
|
Amantadine |
100 mg b.i.d. |
100 mg b.i.d. |
63% efficacy95 |
Shorter duration of fever and symptoms |
CCr 30-50 CCr 15-30 CCr < 15 Hemodialysis Elderly |
100 mg q.d 100 mg q.o.d. 100 mg q. wk. 100 mg q. wk. s 100 mg q.d. |
|
Rimantadine |
100 mg b.i.d. or 200 mg q.d. |
100 mg b.i.d. or 200 mg q.d. |
72%-83% efficacy95 |
Shorter duration of fever and symptoms |
Severe hepatic dysfunction Elderly CCr < 10 |
100 mg q.d. 100 mg q.d. 100 mg q.d. |
|
Zanamivir |
2 puffs q.d.’ |
2 puffs b.i.d. |
67%-84% efficacy96 |
1 day faster recovery from illness (up to 2.5 day improvement in high-risk patients) |
— |
No dosage adjustments |
|
Reduction in severity of illness, number of nights of disturbed sleep, and use of relief medications |
||||||
|
Reduction in complications that require antibiotic treatment |
||||||
|
More rapid return to normal function |
||||||
|
Oseltamivir |
75 mg q.d. |
75 mg b.i.d. |
87% efficacy96 |
24 to 36 hr faster recovery from illness |
||
|
Reduction in severity of illness, number of nights of disturbed sleep, and use of relief medications |
CCr < 30 |
Treatment, 75 mg q.d. Prophylaxis, |
||||
|
Reduction in complications that require antibiotic treatment, hospitalization |
75 mg q.o.d. |
|||||
^Duration of prophylaxis depends on the clinical circumstances: 7-10 days after close contact for postexposure prophylaxis; 2 wk after immunization of an adult; 4-6 wk after a community outbreak; and at least 1 wk (preferably 2 wk) after the last case in outbreak control.
+First dose should be given within 48 hr of the onset of illness to be effective. Therapy should be continued for 5 days.
t The Food and Drug Administration has not approved zanamivir for this indication.
CCr—creatinine clearance
The highest priority for vaccination should be given to persons at increased risk for influenza-related complications and their contacts [see Table 4]. Administration of the inactivated vaccine is associated with soreness at the injection site in as many as one third of recipients, but fever or systemic reactions are uncommon in adults. Influenza vaccination does not adversely affect CD4+ T cell counts or accelerate progression to AIDS or death in HIV-infected patients.85
The intranasal vaccine causes transient coryza and sore throat. Vaccine viruses are recoverable from nasal samples in low titers for up to 1 week in adults and are genetically stable. Although viral transmission is rare between children and has not been documented in adults to date, vaccine recipients should avoid close contact with highly immunocompromised hosts (e.g., stem cell transplant recipients) for 1 week after immunization.
