In episode 14 we take a look at hyperpyrexia, covert duplication of clinical trial data, norovirus as the perfect human pathogen, smallpox, fulminant liver disease, and more.


Fever over 41.1º centigrade aka 106ºF. Hyperpyrexia as a term supposedly originated in the 1970s, except … I found the article below from 1951. It references the, “Committee on Hyperpyrexia in Rheumatic Fever 1882” report. So this term has been around a while.

“Hyperpyrexia with cerebellar damage in acute rheumatism.” Lancet. 1951. [PubMed]

“That afternoon at 4.15 P.M. the patient got out of bed and stood waving his arms about and talking incoherently. He was put back to bed and lay smiling, grimacing, and screwing up his eyes. There was occasional rhythmical twitching of his arms, lasting a few minutes. The axillary temperature was 106ºF and rectal temperature 110ºF.”

  • The 1951 Lancet article summarizes several other cases from the literature. For example:

“Seventeen days after admission signs of severe chorea with maniacal outbursts developed. The temperature was 103-106ºF and later rose to 108.4ºF when the patient became comatose and cyanotic. The cerebrospinal fluid was under slightly increased pressure and contained an increased amount of globulin and 70 cells per, 80% of which were lymphocytes. Signs of diffuse brain damage with maximal involvement of the basal ganglia appeared thereafter. These gradually disappeared, and eight weeks after the onset no abnormality was demonstrable in the nervous system.”

Does hyperpyrexia predict anything inherently “bad”? (aka: should we worry more about 106º than 102º?)

  • SBI is reported as more common in some papers I found… but…
    • “SBI” often defined to include bacteremia → which can simply be positive urine as surrogate marker
    • True SBI (ie meningitis) doesn’t seem to have a difference, but this is hard to study (rare)

“Case-control study of hyperpyrexia in children.” Pediatr Infect Dis J. 1990. [PubMed]

  • Retrospective case-control study.
  • 76 hyperpyrexic children (+76 control cases) with temperatures of 39.1-40ºC and 40.1-41.0ºC
  • A significantly larger number of diagnostic procedures including blood cultures, urine cultures, chest x-rays and white blood cell counts were performed in the hyperpyrexic children (P < 0.05).
  • The frequency of serious bacterial infections and bacteremia did not differ among the groups (P > 0.05).
  • “Hyperpyrexic children need to be evaluated as thoroughly and carefully as any other febrile child but do not merit special consideration.”

“Hyperpyrexia among infants younger than 3 months.” Pediatr Emerg Care. 2005. [PubMed]

  • 5279 infants (age < 3mos) with fever → (1.7%) had triage temperature ≥ 40ºC rectally
  • No difference in bacterial meningitis prevalence between the groups

“Association of hyperpyrexia with serious disease in children.” Clin Pediatr (Phila). 1994. [PubMed]

  • 1 in 3000 urban pediatric emergency department visits was hyperpyrexia
  • 7 year study, looked at 300k ED visits (to find 105 hyperpyrexic kiddos)
  • “Pneumonia (33 lobar, three interstitial, two clinical) was the most common diagnosis (36.2%), followed by probable viral illness in 20 (19.0%) of the patients. Bacteremia (6.7%) and bacterial meningitis (5.7%) were less commonly found. Four (3.8%) patients died. The admission rate was 62.9%. Eighteen patients (17.1%) also had seizures.”
    • “Sensitive indicators to help distinguish those with serious illness, with the exception of clinical appearance, were not found.”

“Relationship of fever magnitude to rate of serious bacterial infections in neonates.” Bonadio, et al. 1990. [JPeds]

  • Another “UTI = SBI” article

Takeaway? If a person looks sick, probably they are sick. Sometimes people who are sick don’t look sick, but it doesn’t seem that there is some population of people who have occult toxicity yet are also hyperpyrexic.

The 1935 JAMA article, “FEVER THERAPY FOR GONOCOCCIC INFECTIONS” is just one of many I found from the pre-antibiotic era, where medically-induced hyperthermia was used to treat infection. In all cases I’ve found, there is no mention of harm to subjects related to the temperature (ie some were not cured). Here is a quote detailing the therapy used in this JAMA article:

“At the outset, it was arbitrarily decided to raise the temperature to between 41.1 C. (106 F.) and 41.7 C. (107 F.) and to maintain it at this level for five consecutive hours. On the average it requires from sixty to ninety minutes, and in some cases even longer, to bring a patient’s temperature to 41 C. (105.8 F.), and at the end of a session of fever at this level it requires approximately the same length of time for the temperature to return to normal.”

Here’s a quote from a review paper of the era, detailing another example of hyperthermic treatment:

“These same authors have treated 118 patients in addition to the 11 listed above, 64 females and 54 males, with varying periods of hyperpyrexia at 106.7°F. lasting from 5 to 17 hours.”


Tramèr. “Impact of covert duplicate publication on meta-analysis: a case study.” BMJ. 1997. [BMJ]

“By searching systematically we found 17% of published full reports of randomised trials and 28% of the patient data were duplicated. Trials reporting greater treatment effect were significantly more likely to be duplicated. Inclusion of duplicated data in meta-analysis led to a 23% overestimation of ondansetron’s antiemetic efficacy.”

Norovirus — the perfect human pathogen?

Norovirus basic reproduction number [PubMed].

“Noroviruses are perhaps the perfect human pathogens. These viruses possess essentially all of the attributes of an ideal infectious agent: highly contagious, rapidly and prolifically shed, constantly evolving, and evoking limited immunity…” [Journal of Infectious Disease, 2012]

  • Unique among enteric pathogens, norovirus can be spread by aerosol
  • As few as ~10 virions are needed for infectious dose
  • Chemical, heat, cold resistant. Can persist on fomites for 2 weeks.
  • No animal reservoir and not culturable = difficult to study
  • Up to 30% of Pt’s are asymptomatic
  • Viral shedding can continue for weeks after symptoms subside
  • High rate of mutation and number of strains = little acquired protection
  • Associated with shellfish (in addition to cruise ships)
  • Known colloquially sometimes as “Winter vomiting disease” (hint at seasonality)


“…virus shed in vomitus, and perhaps even feces, became aerosolized in a bathroom where the index case was actively symptomatic. These aerosolized particles then settled on a reusable shopping bag that contained lunch items to be consumed the following day. The authors note that neither the bag nor its contents were ever actually touched by the index case, who left to return home early the next morning before the lunch items were consumed. After handling the food items in this bag and consuming their contents, 7 of 11 individuals (64%) exposed in this manner became ill.” [Journal of Infectious Disease, 2012]


“Recurring Norovirus Transmission on an Airplane” Thornley, et al. Clinical Infectious Diseases. 2011. [link]

On 18 October 2009, an airline medical team became aware that multiple flight attendants working in different teams had become unwell with gastroenteritis since 14 October. All these teams had worked on a single airplane over successive flight sectors. The airline medical staff notified the disease investigation team at Auckland Regional Public Health Service on 19 October, and an outbreak investigation commenced.

The supervisor for the 13 October flight reported that an unidentified male passenger seated in the economy section of the airplane had vomited and soiled carpet next to his seat. This was cleaned during the flight by one of the flight attendants. Waste from the clean-up was deposited in a waste disposal unit in a passenger restroom at the rear of the aircraft.

Sixty-three of 77 flight attendants who worked on the airplane during 13–18 October provided information, and 27 (43%) met the case definition. The attack rate among flight attendants decreased significantly over successive flight sectors from 13 October onward (P < .001). Working or having meals in the economy section was associated with illness in univariate analysis. In multivariate analysis, flight attendants in supervisory roles were more likely to develop gastroenteritis than were others (OR 5.8). Supervisors tend to move more widely through the airplane cabin rather than staying in one section and may have, therefore, increased their exposure to virus present on airplane surfaces. Norovirus genotype GI.6 was detected in stool samples from 2 case patients who worked on different flight sectors.


NV retains infectivity following:

  1. exposure to pH 2.7 for 3 hours at room temperature
  2. treatment with 20% ether at 4°C for 24 hours, or
  3. after incubation at 60°C for 30 minutes.

Norovirus studies have shown retained infectivity after freezing. Contaminated surfaces can be disinfected using dilute bleach solution.


In the early studies, approximately 13 to 40% of volunteers never became infected, and only 50% developed illness. Further investigations showed that susceptibility to norovirus infection, and possibly rotavirus infection, depends on the presence of histocompatibility-blood group antigen (HBGA) receptors in the gut of hosts. HBGAs are carbohydrates expressed on mucosal epithelia, which are recognized as receptors allowing norovirus attachment and cellular entry.

In the studies mentioned above, when volunteers were challenged with norovirus twice, at intervals of two to three years, those who had contracted gastroenteritis on the first occasion and had developed an antibody response were the very ones who became sick on a second occasion. This suggested that (1) prior infection confers no significant long-term immunity, and (2) genetic or physiological factors may predispose certain individuals but not others to gastroenteritis following exposure to virus.

— Episode credits —

Hosted by Addie, Kim, and Alex. Audio production and editing by Addie. Show notes written by Addie. Theme music (Too Cool, and Laserpack) by Kevin MacLeod of, licensed under Creative Commons: By Attribution 3.0 License.