Emerging viral respiratory illnesses

Nandhitha Natesan MD

Rana B Hejal MD

Introduction

Respiratory tract infections remain a major cause of morbidity and mortality throughout the world. A number of viruses are known to infect the respiratory tract producing different clinical syndromes (Table 3.1). Recently, several previously unrecognized viruses have come to the forefront of both media and scientific attention as important causes of acute respiratory illnesses. In this chapter, we will focus on three of these newer agents; namely, severe acute respiratory syndrome-associated coronavirus (SARS-CoV), human metapneumovirus (hMPV) and a novel strain of avian influenza A (H5N1).

Table 3.1 Respiratory viral infections and corresponding clinical syndromes in the immunocompetent host

*Clinical syndromes*
*Virus*	*Common cold*	*Pharyngitis*	*Croup*	*Bronchiolitis*	*Pneumonia*
Adenoviruses	Rare	Uncommon	Rare	Uncommon	Uncommon
Coronaviruses
Group I-III	Common	Rare	Rare	Rare	Uncommon
SARS-CoV	Rare	Rare	Rare	Rare	Very common
Herpesviruses
Cytomegalovirus	Rare	Uncommon	Rare	Rare	Uncommon
Epstein-Barr virus	Rare	Common	Rare	Rare	Uncommon
Herpes simplex virus	Rare	Common	Rare	Rare	Uncommon
Varicella-zoster virus	Rare	Rare	Rare	Rare	Uncommon
Orthomyxoviruses
Influenza A, B, C	Uncommon	Common	Uncommon	Uncommon	Common
Paramyxoviruses
Measles	Rare	Rare	Rare	Rare	Uncommon
Parainfluenza 1,2,3	Uncommon	Common	Very common	Common	Rare
Respiratory syncytial virus	Rare	Uncommon	Common	Common	Common
Metapneumovirus	Rare	Uncommon	Common	Very common	Common
Picornovirus
Enterovirus	Uncommon	Rare	Rare	Rare	Rare
Rhinovirus	Very common	Common	Uncommon	Uncommon	Rare

Fig. 3.1 Summary of SARS cases (A) and deaths (B) by country. (Adapted from WHO data.)

Fig. 3.2 A: Structure of coronavirus virion. (Adapted from Holmes KV. SARS-associated coronavirus. N Engl J Med 2003; 348(20):1948-1951.) B: The negative stain electron micrograph of coronavirus. Coronaviruses have a halo, or crown-like (corona) appearance when viewed under electron microscopy. (Courtesy of CDC.)

SARS coronavirus

Background

In late 2002, an outbreak of severe, atypical pneumonia began in southern China. Within months, the illness named SARS had affected more than 8,000 patients in 29 countries, leading to more than 900 fatalities worldwide (Fig. 3.1). Led by the World Health Organization (WHO), a massive global collaboration was undertaken to identify the pathogen and clinical and epidemiologic spectrum of this syndrome in order to arrest the spread of a threatened pandemic.

Table 3.2 Spectrum of coronavirus species, hosts, and corresponding clinical syndromes

		*Host*	*Clinical syndrome*
Group I
Human respiratory coronavirus	HCoV-229E	Human	Colds, pneumonia
Human coronavirus-Netherlands	HCoV-NL	Human	Colds, pneumonia
Porcine transmissible gastroenteritis virus	TGEV/PRCoV	Pig	Enteric, pneumonia
Canine respiratory coronavirus	CCoV	Dog	Enteric
Feline enteric coronavirus	FECoV	Cat	Enteric
Feline infectious peritonitis virus	FICoV	Cat	Systemic, peritonitis
Rabbit coronavirus	RbCoV	Rabbit	Enteric
Group II
Human respiratory coronavirus	HCoV-OC43	Human	Colds, pneumonia
Bovine respiratory coronavirus	BCoV	Cow	Enteric, pneumonia
Hemagglutinating encephalitis virus	HEV	Pig	Respiratory, enteric, neurologic
Rat coronavirus	RCoV	Rat	Respiratory
Sialodacryoadenitis virus	SDAV	Rat	Neurologic
Murine hepatitis virus	MHV	Mouse	Hepatitis, encephalitis
Group III
Avian bronchitis virus	IBV	Chicken	Tracheitis, hepatitis, renal
Turkey respiratory coronavirus	TCoV	Turkey	Respiratory, enteric
?Group IV
Severe acute respiratory syndrome-associated coronavirus	SARS-CoV	Human	Pneumonia, enteric

Virology

Coronaviruses are large enveloped, single stranded, positivesense ribonucleic acid (RNA) viruses that cause the ‘common cold’ in humans as well as a variety of illnesses in other species (Table 3.2). They have been divided into three groups based on serologic cross-reactivity, but more recently on genomic sequence homology. When the SARS-CoV genome was identified, it appeared similar to other coronaviruses in its organization, but quite different in phylogenic analysis and sequence comparisons, making it likely the representative of a new fourth group of coronaviruses (Fig. 3.2). In fact the sequence analysis suggested that this new virus is an animal virus that has gained the ability to cross the species barrier. The SARS-CoV has four major proteins: the envelope (E), membrane (M), spike (S), and nucleocapsid protein (N). It is the S protein that binds to a species-specific host cell and along with the host’s immune responses determines the virulence of the organism. Several antigenically diverse strains were identified in China; however, only one went on to be responsible for the major outbreak and global spread of SARS.

Fig. 3.3 Exotic animals regarded as a delicacy in Guangdong, China believed to harbor SARS-CoV. A: Masked palm civets (Paguma larvata). B: Raccoon dog (Nyctereutes procyonoides).

Epidemiology

The SARS-CoV is believed to be of animal origin, and to have spread from animals to humans in crowded, open air, live animal markets, which are common in east Asia. Precursors of this virus with 99% homology have been identified in several species of exotic animals sold at these markets, including civets and raccoon dogs (Fig. 3.3). It remains unclear whether these animals represent the natural reservoirs of this virus, or serve as amplifiers. The principle mode of transmission is thought to be close person-to-person contact with exposure to infected body secretions, including respiratory droplets, infected fomites, feces, and other bodily fluids.

SARS emerged in the Guangdong province of China in November 2002. By January 2003, multiple independent outbreaks had occurred within this province. A physician who had been in the Guangdong province, caring for SARS patients, returned to Hong Kong where he seeded at least 17 guests at a hotel (Fig. 3.4). Many of these guests traveled out of the country in the following days, and were responsible for the spread of this virus to Vietnam, Singapore, and Canada.

The unexplained respiratory illness was first reported to the WHO in February of 2003. Standard public health measures, along with advanced screening and communication measures, were quickly implemented. A virtual network was established, with daily teleconferences enabling real time sharing and application of information. In addition, global health alerts and travel advisories were issued and updated regularly. Many countries implemented screening for elevated body temperatures and quarantines in airports. In late March, three independent labs identified a novel coronavirus from patients with SARS from different countries. The identified virus fulfilled the six Koch’s postulates, as modified by Rivers for pathogenic viruses (Table 3.3). On April 16, 2003 WHO announced this new virus to be the definitive cause of SARS. By July of 2003, human-to-human spread of this virus was under control leading to the successful averting of the threatened pandemic.

SARS-CoV largely affects adults. A disproportionate number of cases were in health care workers (greater than 40% of cases in China and Canada). The global average case fatality rate was just over 10% (Fig. 3.5); however, for patients requiring intensive care and/or mechanical ventilation, fatality rates greater than 50% were reached. Predictors of mortality include increasing age, presence of comorbidities, atypical initial symptoms, and some abnormal laboratory findings (Table 3.4).

Fig. 3.4 Effect of travel and missed cases on the SARS epidemic. Spread from Hotel M, Hong Kong. Case A from Guangdong Province, China and two hotel guests who became ill, cases H and J, started outbreaks of SARS in three Hong Kong hospitals involving at least 95 health care workers (HCW) and more than 100 contacts. (Adapted from CDC data.)

Table 3.3 Koch’s postulates as modified by Rivers for viruses

•	Isolation of the virus from each of the suspected cases
•	Cultivation of the virus in host cell
•	Proof of filterability
•	Production of a comparable disease in related species
•	Re-isolation of the same organism
•	Detection of specific host immune response to the virus

Fig. 3.5 The evolution of the people probably infected, by main countries (moving average of 7 days) and the mortality rates for the last 2 weeks. People probably infected = cumulative case x number of deaths x number of people discharged. Mortality rate = deaths / (deaths + discharged). (Adapted from WHO data.)

Table 3.4 Risk factors for death or admission to an Intensive Care Unit

Risk factor	Relative riskor odds ratio	95% CI	Author
Age >60 years	1.8	1.16-2.81	Lee N, et al., 2003
	28	3.1-253.3	Peiris J, et al. (A), 2003
	3.5	1.2-10.2	Chan JWM, et al., 2003
	1.57	1.26-1.95	Tsui PT, et al., 2003
	19.9	11.7-33.8	Leung GM, et al., 2004
Diabetes mellitus	3.1	1.4-7.2	Booth CM, et al., 2003
	9.1	2.8-29.1	Chan JWM, et al., 2003
Comorbid illness	2.5	1.1-5.8	Booth CM, et al., 2003
	5.2	1.4-19.7	Chan JWM, et al., 2003
Increased neutrophil count	1.6	1.03-2.50	Lee N, et al., 2003
	1.28	1.13-1.46	Tsui PT, et al., 2003
Increased lactate dehydrogenase	2.09	1.28-3.42	Booth CM, et al., 2003
	1.35	1.11-1.64	Tsui PT, et al., 2003
	2.3	1.4-3.8	Leung GM, et al., 2004

Clinical features

The vast majority of patients pass through three phases in this illness: exposure, early prodrome, and late respiratory phase (Fig. 3.6). The incubation period varies between 2 and 10 days. Unlike many of the common viral respiratory pathogens, evidence suggests that there are rather few asymptomatic or mild illnesses associated with SARS-CoV, except for children, in whom the disease is uncommon, generally mild, and self limited. Typical adult illness begins with a prodrome of non-specific symptoms including high-grade fever, chills/rigors, myalgias, headache, and diarrhea (Fig. 3.7). Upper respiratory tract symptoms are less common. The clinical course tends to be insidious, and patients frequently improve transiently prior to developing lower respiratory symptoms in the second week of illness, with non-productive cough, dyspnea, and hypoxia. In 10-20% of hospitalized patients, symptoms progress to respiratory failure requiring intubation and mechanical ventilation. It is unclear whether this clinical deterioration is due to ongoing viral replication or uncontrolled immune response mediated by host defenses.

Fig. 3.6 The clinical phases of SARS.

Lymphocytopenia at presentation is common. Patients often go on to develop leukopenia and thrombocytopenia with the onset of respiratory symptoms. Elevated amino-transferases, creatinine kinase, and lactate dehydrogenase are also reported (Fig. 3.8). Moreover, these variables tend to worsen at different time points over the disease course (Fig. 3.9).

Fig. 3.7 SARS clinical symptoms at presentation. (Data from almost 2000 patients are compiled from several series, including Avendano M, et al., 2003; Booth CM, et al., 2003; Chan PK, et al., 2003; Donnelly CA, et al., 2003; Hsu LY, et al., 2003; Lee N, et al., 2003; Peiris JS, et al., (B), 2003; Poutanen SM, et al., 2003; Rainer TH, et al., 2003; Tsang KW, et al., 2003; Zhong NS, et al., 2003.)

Fig. 3.8 Initial laboratory abnormalities in patients with SARS. (Data from close to 500 patients are compiled from several series, including Booth CM, et al., 2003; Hsu LY, et al., 2003; Lee N, et al., 2003; Peiris JS, et al. (B), 2003; Poutanen SM, et al., 2003; Tsang KW, et al., 2003; Zhao, Z, et al., 2003.) (LDH: serum lactate dehydrogenase level; ALT: serum alanine aminotransferase.)

Fig. 3.9 The time relationships between the time points of defervescence, initiation of steroid, and when chest radiographic finding, as well as various laboratory parameters became most severe. Mean and standard deviation (days) are presented. (CXR: chest radiography; ALT: alanine aminotransferase; LDH: lactate dehydrogenase; AST: aspartate aminotransferase; CRP: C-reactive protein; CK: creatine kinase.) (Adapted from CDC data.)

Chest radiographs in SARS are usually abnormal (Table 3.5). Approximately 50% of patients present with unilateral focal consolidation. Lower lobe predominance is rather common. While patients presenting early can have a normal film initially, they uniformly develop some abnormality by the seventh day of their illness. In the setting of high clinical suspicion and normal chest X-ray, high resolution chest computed tomography (HRCT) may identify early parenchymal abnormalities and should be considered. Illustrative cases are shown in Figs. 3.10, 3.11 and 3.12.

Table 3.5 Radiographic features of severe acute respiratory syndrome

Chest radiograph			High resolution computed tomography
•	Normal, only early in course		•	Ill-defined ground-glass opacification
•	Peripheral alveolar infiltrates (most common):		•	Reticulation
	–	Basilar predilection	•	Irregular interlobular septal thickening
	–	Often multifocal	•	Subpleural reticulation
	–	Nodular infiltrate (early)	•	Late manifestations (patients surviving respiratory failure):
•	Non-cardiogenic pulmonary edema
•	Pleural effusion rarely			–	Bronchiectasis
•	Pneumomediastinum			–	Honey-combing and fibrosis
•	Absence of:
	–	Adenopathy
	–	Cavitation