H1N1 "Swine Flu" influenza, SARS and MERS

One finds this transient epidemic merited only one appearance among the CICM papers. Its use in Question 19 from the first paper of 2013 follows the 2009 pandemic by four years. One may also find a similar delay in the appearance of SARS in Question 13 from the second paper of 2004. Using this logic, the savvy trainees were able to anticipate an Ebola question in the second paper of 2015 (Question 22).  A MERS question cannot be far behind.

If one felt for whatever reason compelled to explore this pathogen in great depth, one may use this WHO (2009) clinical practice guideline statement as a starting point, and then move on to something like this article from Chest. It would be a mental exercise to satisfy one's curiosity, as H1N1 may never appear in the papers again; at least not until the next pandemic.

In summary:

Signs and symptoms of H1N1 influenza

  • Nothing too different to "uncomplicated" influenza:
    • Fever
    • cough
    • sore throat
    • malaise
    • myalgias
    • headache
    • diarrhoea or vomiting
  • No shortness of breath to begin with
  • Progressive disease is characterised by dysponea, progressive hypoxia, dehydration and multi-organ system failure. Progression can be rapid, over 24 hours.

Factors associated with severe disease and poor outcome

This is on the basis of a global pooled analysis of outcomes, available in 2011.

Overall, the risk factors were approximately the same as for the normal garden-variety seasonal influenza.

  • Age over 65(increasing age was associated with more severe disease)
  • One or more chronic condition
  • Asthma
  • Pregnancy (especially first trimester)
  • Obesity
  • Smoking
  • Chronic cardiovascular disease
  • Chronic respiratory disease (eg. COPD)
  • Immunosuppression

The WHO has also published a table of features which predict a more stormy course:

  • Cyanosis
  • Haemoptysis
  • Chest pain
  • Altered mental status
  • High fever persisting for longer than 72 hours
  • Features of shock
  • Dyspnoea with activity or at rest

Diagnosis of H1N1 influenza

Management of H1N1 influenza

  • ABC management - intubation and ventilation as needed, using lung-protective strategies
  • Oseltamivir - though it has recently come under fire, its use may still contribute to survival in patients at greatest risk of death. And it seems vaguely safe in pregnancy.
  • Isolation
  • Airborne precautions
  • Pregnant?
    • Consult O&G
    • Prepare the foetus for delivery with corticosteroids
  • Preparation for transfer to a large ICU, where ECMO is available

Innovative therapies

Complications associated with H1N1 influenza

There are significant differences between the H1N1 cohort and the seasonal influenza patients:

  • Pulmonary emboli
  • Bacterial superinfection:
    • S.aureus
    • H.influenzae
    • S.pneumoniae
    • S.pyogenes
  • Encephalitis
  • Renal failure
  • Hepatic dysfunction

A brief word about SARS and MERS

SARS appeared in Question 13 from the second paper of 2004. MERS is too new, and has not yet made an appearance. LITFL has an excellent summary page dedicated to these coronaviruses, which contains precisely enough information to revise this exotic topic, but not too much so as to waste the precious time of the fellowship exam candidates. Published literature dealing with these pathogens is extensive and widely available; so as not to inundate the reader with references, this author will recommends only Chen et al (2006) for SARS, and Sharif-Yakan et al (2014) for MERS.  These disease entities are lumped together with H1N1 in this revision chapter, owing to the following similaries:

  • Both are coronaviruses
  • Both cause severe ARDS
  • Neither have a satisfying specific treatment
  • All of these lifethreatening viral pneumonitis scenarios play out essentially the same.

Coronaviruses (and related toroviruses) are mainly respiratory pathogens. They are the largest known RNA viruses; the particle is a huge discoid lipid-enveloped positive-sensesingle-stranded RNA virus, with a code length of approximately 30 Kb. The group contains many animal-specific species, such as the porcine transmissible gastroenteritis virus, the porcine diarrhoea epidemic virus, the feline infectious peritonitis virus, the mouse hepatitis virus, and various others. Until SARS and MERS there were only two recognised human coronovirus species, which both caused a mild case of the snots and sniffles.

Severe Acute Respiratory Syndrome coronavirus (SARS-CoV)

The WHO criteria which acted as a definition of SARS, and which were mentioned in the college answer to Question 13 from the second paper of 2004:

  • fever (>38C)
  • cough or difficulty breathing
  • close contact with a person diagnosed as SARS, OR
  • travel/residence (within 10 days of symptoms) in an area with recent local transmission of SARS.

The CDC criteria adds radiographic findings in patients with respiratory illness without known aetiology. SARS has generally been a diagnosis of exclusion, because no satisfactory rapid bedside test was available through much of the epidemic.

SARS coronavirus has not been seen since 2003. Apparently, it had originated in the Chinese horseshoe bat, Rhinolophus sinicus.  The civet cat acted as an intermediate host. The first cases occurred in occurred in November 2002 in Foshan, Guangdong Province in southern China. Vietnam, Hing Kong and Canada followed, and ultimately cases were reported from 29 different countries. The epidemic ended in July 2003 with a total of 8098 cases, of whom 774 died. For those interested, WHO maintain a summary record of probable cases. Transmission occurred by a combination of direct contact, small droplets and aerosols. It did not help that the index case in Hong Kong (an elderly Chinese physician) received a nebulised bronchodilator in the overcrowded and poorly ventilated hospital ward, infecting one hundred and thirty eight other patients and healthcare workers. The peak infective period, when viral load is at its highest, is also the period of the most aggressive symtoms, when the patient is most likely to be hospitalised. This makes heathcare workers the most vulnerable group in terms of viral transmission, The greatest risk was to the ICU staff, particularly those who worked closely with intubated and NIV-ventilated SARS patients.

Clinically, the incubation period lasted 2-10 days. The following signs and symptoms were noted among the earlier victims:

  • persistent high fever, chills and rigor
  • malaise
  • myalgia
  • headache
  • dry cough
  • dyspnoea
  • diarrhoea

The patients did not report much sputum production, and were not complaining of sore throats or rhinorrhoea. Weirdly, children had a milder course of infection; only adults were hit with the full-scale ARDS. The case fatality rate for SARS was <1% for patients aged 24 years or younger, 6% for 25–44 years, 15% for 45–64 years, and >50% for patients aged 65 years or older.

Investigations typically revealed the following features:

  • Deranged LFTs, mainly ALT
  • Raised LDH
  • Raised CK
  • Lymphopenia
  • Features of DIC

Radiological features were boring ARDS-like peripheral pulmonary infiltrates. 20% of the patients fit the contemporary criteria for ARDS. The lungs were fragile; in spite of wide adoption of lung protective ventilation strategies 26% of the patients developed some sort of barotrauma.

Attempts at specific management consisted of ribavirin, ritonavir, lopinavir and pulsed methylprednisolone. Interferon and monoclonal antibodies were trialed. Of all these, nothing showed any sort of favourable effect on outcome. Steroids were even associated with an increased 30 day mortality.

Middle East respiratory syndrome coronavirus (MERS-CoV)

The index case of MERS was tracked retrospectively to a hospital in the city of Al-Zarqa in Jordan, in April 2012. The CDC has a regularly updated page dealing with the evolving situation. Their clinical definition of a MERS case includes fever and pneumonia or ARDS, as well as epidemiological risk factors (eg. recent travel to a country with an outbreak, or recent contact with a symptomatic traveller). Confirmation of a case requires PCR identification. 

Incubation period is around 2-14 days (median = 5). Again, bats are probably the native reservoir, and camels may be the intermediate host. Clinical signs and symptoms are very similar to SARS, and include the following:

  • fever, chills/rigors
  • headache
  • non-productive cough
  • dyspnea
  • myalgia.

Unlike SARS, sore throat and coryza are more common. There is usually also  nausea and vomiting, dizziness, sputum production, diarrhea, vomiting, and abdominal pain.

Sharif-Yakan et al (2014) report 707 cases, from three continents. The current case fatality rate approaches 35%. Of the patients that end up requiring ICU admission, this mortality statistic approaches 60%, with a median ICU stay of around 30 days. Again, no effective therapy or prophylaxis for MERS-CoV exists. Fortunately, several Hajj seasons have now passed without a fearsome worldwide outbreak, which may mean that this virus may ultimately retreat into the realm of virological pub trivia.

Nonspecific management of a mysterious and deadly respiratory viral illness

  • Isolation facilities
  • Strict droplet and contact precautions (hand hygiene, gown, gloves, N95 masks and eye protection) for healthcare workers
  • Avoidance of nebulisers on general wards
  • Contact tracing and quarantine isolation for close contacts


Vasoo, Shawn, Jane Stevens, and Kamaljit Singh. "Rapid antigen tests for diagnosis of pandemic (Swine) influenza A/H1N1." Clinical infectious diseases49.7 (2009): 1090-1093.

Balish, A., et al. "Evaluation of rapid influenza diagnostic tests for detection of novel influenza A (H1N1) virus-United States, 2009." Morbidity and Mortality Weekly Report 58.30 (2009): 826-829.

Gerrard, John, et al. "Clinical diagnostic criteria for isolating patients admitted to hospital with suspected pandemic influenza." The Lancet 374.9702 (2009): 1673.

Dunstan, H. J., et al. "Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza A/H1N1 pandemic: a national prospective surveillance study." BJOG: An International Journal of Obstetrics & Gynaecology 121.7 (2014): 901-906.

Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments. BMJ 2014; 348: g2545

World Health Organization (WHO. "Clinical management of human infection with pandemic (H1N1) 2009: revised guidance." Clinical management of human infection with pandemic (H1N1) 2009: revised guidance. World Health Organization (WHO), 2009.

Baden, Lindsey R., et al. "H1N1 influenza A disease—information for health professionals." New England Journal of Medicine 360.25 (2009): 2666-2667.

Hui, David S., Nelson Lee, and Paul KS Chan. "Clinical management of pandemic 2009 influenza A (H1N1) infection." Chest Journal 137.4 (2010): 916-925.

Harada, Daisuke, et al. "Reliability of a rapid test for the clinical diagnosis of influenza A/H1N1 2009." Scandinavian journal of infectious diseases 44.10 (2012): 776-781.

Van Kerkhove, Maria D., et al. "Risk factors for severe outcomes following 2009 influenza A (H1N1) infection: a global pooled analysis." PLoS medicine8.7 (2011): e1001053.

Liu, Zeyu, et al. "Evaluation of the efficacy and safety of a statin/caffeine combination against H5N1, H3N2 and H1N1 virus infection in BALB/c mice."European Journal of Pharmaceutical Sciences 38.3 (2009): 215-223.

Yuen, K. Y., et al. "Clinical features and rapid viral diagnosis of human disease associated with avian influenza A H5N1 virus." The Lancet 351.9101 (1998): 467-471.

Han, Sung Nim, and Simin Nikbin Meydani. "Antioxidants, cytokines, and influenza infection in aged mice and elderly humans." Journal of Infectious Diseases 182.Supplement 1 (2000): S74-S80.

Lee, Nelson, et al. "Complications and outcomes of pandemic 2009 influenza A (H1N1) virus infection in hospitalized adults: how do they differ from those in seasonal influenza?.Journal of Infectious Diseases 203.12 (2011): 1739-1747.

Centers for Disease Control and Prevention (CDC. "Outbreak of severe acute respiratory syndrome--worldwide, 2003." MMWR. Morbidity and mortality weekly report 52.11 (2003): 226.

Li, Wendong, et al. "Bats are natural reservoirs of SARS-like coronaviruses." Science 310.5748 (2005): 676-679.

Chan, Paul, Julian Tang, and David Hui. "SARS: clinical presentation, transmission, pathogenesis and treatment options." Clinical Science 110 (2006): 193-204.

Sharif-Yakan, Ahmad, and Souha S. Kanj. "Emergence of MERS-CoV in the Middle East: origins, transmission, treatment, and perspectives." PLoS pathogens 10.12 (2014): e1004457.