What Does A Covid-19 Index Case Really Mean?

By Dr Milton Lum | 24 September 2020

Genome analysis is required to identify a primary case, the individual who infects others; an index case is the patient in an outbreak who is first noticed by health authorities.

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Medical terms have found their way into common use in the Covid-19 pandemic, of which “epidemiology” and “index case” are particular terms.

The term epidemiology is derived from the Greek words — epi, meaning on or upon, demos, meaning people, and logos, meaning the study of.

There have been different definitions for “epidemiology” over the years. A useful one is “Epidemiology is the study of how often diseases occur in different groups of people and why. Epidemiological information is used to plan and evaluate strategies to prevent illness and as a guide to the management of patients in whom disease has already developed.” (Epidemiology for the uninitiated).

There is a difference between the terms “index case” and “primary case”, which is stated in the official publication of the International Epidemiological Association, “A dictionary of epidemiology, 6th edition 2016.” The term, index case, is the “first case in a family or other defined group to come to the attention of the investigator”. The term, primary case, is the “individual who introduces the disease into the family or group under study. Not necessarily the first diagnosed case in a family or group.”

This distinction and confusion are succinctly summarised in a 2014 Lancet article: “Scientists and journalists are increasingly using the term ‘index case’ when they actually mean ‘primary case’. Both terms are well defined for outbreaks, and should not be confused. The term ‘primary case’ can only apply to infectious diseases that spread from human to human, and refers to the person who first brings a disease into a group of people—a school class, community, or country. The ‘index case’, however, is the patient in an outbreak who is first noticed by the health authorities, and who makes them aware that an outbreak might be emerging.

“Even outbreaks of disease that is not spread from human to human, such as Legionnaire’s disease, might have an index case…In some instances, the primary case is also the index case, but often they are not the same. The first term is linked to the basic epidemiology of the outbreak, the second rather to the surveillance system and public health action. Both are quite straightforward, and they deserve not to be mixed up.”

Covid-19 Index Case(s)

Two aspects need to be considered in the identification of the origin of the SARS-CoV-2 virus which causes Covid-19 in any cluster or community, i.e:

  • To trace back to the time when the virus first appeared in the cluster or community;
  • To sequence the viral genomes to establish the root of the viral genetic family tree.

The lineage of a virus could be traced back, with genome analysis, through those it had infected. Health care workers would still have to depend on contact tracing (i.e. the identification and monitoring of individuals who may have had contact with an infectious person as a means of controlling the spread of the disease) to find those whose infections have gone undiagnosed.

Genome analysis and epidemiological studies would facilitate the identification of individuals who may have been the first persons to start spreading the disease in a cluster or community. Such identification can address important questions about how, when and why it started. It could then help prevent more infections now or in the future.

The identification of the index case is vital to establish the viral genetic structure and any changes to it with the passage of time as well as understand the transmission to others. This task is not easy and is compounded by the high percentage of asymptomatic cases of Covid-19.

The World Health Organization (“WHO”) China Country Office was informed, on 31 December 2019, of pneumonia-like infections of unknown cause in Wuhan city. Many of the initial cases were linked to the seafood and animal market in Wuhan, which was the epicentre of the outbreak in China.

The clinical features of the initial cohort of 41 cases diagnosed between 16 December 2019 and 2 January 2020 were reported in The Lancet. The first patient identified had symptom onset on 1 December 2019. None of his family members developed fever or any respiratory symptoms and there was no epidemiological link found between the first patient and later cases. However, the report stated that 27 (66%) of the 41 cases had direct exposure to the market.

Wu Wenjuan, one of the authors of the report, stated on the Wenjun British Broadcasting Corporation (“BBC”) Chinese service that the first patient identified was an elderly man with Alzheimer’s disease, who lived four or five bus stops from the market and did not go out as he was sick. She also stated that three other persons developed symptoms subsequently, two of whom had no exposure to the market.

The WHO hypothesis is that the outbreak started and spread in the Wuhan area and the virus could have been spread from animal to human prior to human-to-human spread.

In short, the health authorities in China and global experts still have not agreed about the origin of Covid-19 in China, much less who the index case is.

The first European Covid-19 cases were announced in France on 24 January 2020, two of whom had a travel history to Wuhan. Doctors at the Groupe Hospitalier Paris Seine did a retrospective analysis for SARS-CoV-2 in respiratory samples collected in their intensive care unit (ICU) between 2 December 2019 and 16 January 2020. They found one SARS-CoV-2 infected patient one month before the first reported cases in France.

The “absence of a link with China and the lack of recent foreign travel suggest that the disease was already spreading among the French population at the end of December 2019.”

The first reported cases in Italy, on 31 January 2020, were a Chinese couple who had arrived from Wuhan. However, genetic analysis of the origin of the Italian epidemic published in the Journal of Virology showed Italy’s index case to have travelled from Munich in late January. Massimo Galli, of the University of Milan explained “It’s very clear that the virus arrived in Italy in January and spread for 3 or 4 weeks undetected.”

A review of Covid-19 cases in Europe from 24 January to 21 February 2020 reported that as at 21 February 2020, there were 47 cases in nine countries i.e. Belgium (1), Finland (1), France (12), Germany (16), Italy (3), Russia (2), Spain (2), Sweden (1) and United Kingdom (9). Of the 38 cases studied, 14 were infected in China and 21 were linked to two clusters in Germany and France, of which, 14 were linked to a cluster in Bavaria, Germany, and seven to a cluster in Haute-Savoie, France.

“Cases from the Bavarian cluster were reported from Germany and Spain, whereas cases from the Haute-Savoie cluster were reported from France and Spain. Cases linked to the Haute Savoie cluster were also detected in the UK, including the index case of this cluster, who was infected in Singapore before travelling to France. The index cases for the cluster in Bavaria was reported to be infected in China.”

The first laboratory confirmed case in the United States was reported on 23 January 2020 in a woman who returned from China in mid-January 2020. Her husband, who did not travel but had close contact with her, tested positive eight days later. The first cases of non-travel related cases were confirmed on 26 and 28 February 2020.

Evidence from syndromic and viral surveillance, genomic analysis and retrospectively identified cases “suggest that limited U.S. community transmission likely began in late January or early February 2020, after a single importation from China, followed by multiple importations from Europe. Until late February, Covid-19 incidence was too low to be detected by emergency department syndromic surveillance for Covid-19–like illness.”

Previous Outbreaks

Mary Mallon, an Irish emigrant to the United States, was well known as one of the earliest super-spreaders of disease. She worked in a variety of domestic positions for wealthy families in New York. Mary was a healthy carrier of typhoid which had a mortality rate of 10% at that time. Many family members of whoever she worked for developed the disease. This led to her nickname “Typhoid Mary” which was synonymous with the typhoid outbreak in New York in 1906.

The term “patient zero” is the colloquial term for an index case. It is, however, loaded with stigma and discrimination.

Gaetan Dugas, a Canadian, was once regarded as patient zero of the HIV epidemic in the United States in the 1980s. In the report of eight cases to the Centres for Disease Control (“CDC”), cases were labelled according to the city they lived, for example, those who lived in Los Angeles were labelled LA1, LA2 etc. Dugas, who was labelled “Patient O, the Outside-of-California case”, died in 1984.

The 1987 book on the start of the HIV epidemic, “And The Band Played On” written by Randy Shilts, a reporter in San Francisco, included Dugas’ story. It moved Dugas from Patient O to Patient Zero. Dugas was lodged in the public mind as Patient Zero i.e. the source of HIV in North America. He was vilified, for years, as the mass spreader of HIV and even perceived as the source of HIV in North America.

It was only in 2016 that Dugas’ name was cleared. While testing for hepatitis B in blood collected from gay men in 1978 and 1979, genetic analysis of the blood for HIV showed that the HIV virus arrived from Africa through the Caribbean around 1970. Analysis of Dugas’ own blood showed that the HIV strain that killed him did not match the others.

“The history of diseases has always been, in part, that someone needs to be blamed.”

Anthony Fauci, director of the United States’ National Institute of Allergy and Infectious Diseases

The Ebola virus was discovered in 1976. According to the WHO, the 2014-2016 outbreak in West Africa infected more than 28,000 people and killed more than 11,000 people i.e. a mortality rate of almost 40%. Ebola cases were not only reported in Africa but also in Italy, Spain, United Kingdom and United States. The Ebola outbreak was due to a new strain of the Ebola virus.

The index case of the Ebola outbreak was traced to a two-year-old boy in Meliandou, Guinea, who used to play in and around a hollow tree that housed a colony of insectivorous bats, which led to massive exposure to the bats that were carriers of the virus. The methods which the researchers used involved a combination of informal discussions, formal interviews and direct observations with hunters, their families and bush meat sellers.

Use Correct Terminology

The task of identification of the Covid-19 index case(s) is compounded by substantial numbers of asymptomatic cases, shortcomings in information from contact tracing and lack of compliance by positive cases.

The Health Ministry has used the term “index case” in its daily statements. The impression from the Health Ministry’s graphics is that the person labelled as the “index case” had spread the infection to others in the cluster. This gives rise to a mistaken perception of an index case.

The question is whether the first cases detected in the cluster(s) were a primary case or an index case. In determining this, genome analysis is essential. Whether this was done is a pertinent question.

The University of Malaya has reported on the genome analysis of the SARS-CoV-2 virus collected from patients between 14 and 22 March 2020.

Whilst identification of the Covid-19 index case(s) is important, it should not lead to stigmatisation and/or victimisation of the person(s) as well as disinformation about the disease. As such, usage of correct terminology is vital.

Dr Milton Lum is a past President of the Federation of Private Medical Practitioners Associations, Malaysia and the Malaysian Medical Association. This article is not intended to replace, dictate or define evaluation by a qualified doctor. The views expressed do not represent that of any organization the writer is associated with.

  • This is the personal opinion of the writer or publication and does not necessarily represent the views of CodeBlue.
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