In 1993, a mysterious outbreak unnerved residents and bewildered investigators in the Four Corners region of the southwest US. Late in the morning on May 14, paramedics rushed a 19-year-old Navajo man suffering from acute respiratory failure to the Indian Medical Center in Gallup, New Mexico. Paramedics and doctors alike were unable to resuscitate him. Postmortem X-rays revealed his lungs were filled with fluid. Even more puzzling was the fact that this young man was healthy and athletic. He was a track star with no history of illness except for mild flu-like symptoms a few days earlier. Because his death was unexplained, medical reports and his body were turned over to the Office of the Medical Investigator for further review and autopsy.

Almost immediately, the investigator realized he had seen a similar case about a month earlier. A 30-year-old woman presented with mild flu-like symptoms that quickly worsened in a similar fashion. She too was a member of the Navajo Nation. Then came another bombshell: the 19-year-old man was on his way to the funeral of his fiancée. She had died 5 days earlier and also exhibited similar symptoms. The fear that this was a contagious outbreak grew, and rightfully so. It was an extremely fast-acting pathogen. Patients initially presented with flu-like symptoms, and quickly progressed to acute respiratory distress syndrome, followed by death. By May 17, 5 deaths were attributed to this unknown pathogen. On May 22, the brother of the 19-year-old man presented with similar symptoms, followed by his wife 5 days later. The local newspapers printed the story on May 27. The national media picked up the story and branded it the “Navajo disease.” However, by this time, more cases were coming into emergency rooms from all over Four Corners. Although the majority of the cases were not associated with the Navajo Nation, that didn’t change the national media’s story line.

By Memorial Day, the CDC descended on Four Corners. They spread out across New Mexico, Arizona, Colorado, and Utah looking for clues. One by one, they ruled out several toxins, illnesses, and pathogens, such as pneumonic plague, pneumonias, leptospirosis, anthrax, Rickettsia, Legionnaires’ disease, meningococcemia, many foreign viruses, and a variety of acquired sepsis syndromes. Investigators believed a single pathogen was responsible based on similarities in the victims’ labs and clinical findings. The victims had exceedingly high white blood cell counts, low platelet counts, high creatinine concentrations, and elevated BUN, hematocrit, serum lactate dehydrogenase, and creatine kinase levels. The most interesting fact was that every victim who died suffered from pulmonary edema that was further complicated by severe hypotension. Pulmonary edema was also present in the surviving patients but none experienced hypotension. An immunohistochemical analysis revealed a widespread distribution of a previously unknown viral antigen. However, the antigen was similar to known hantaviruses, and they worked on that assumption. It was found in the lungs, kidneys, heart, pancreas, adrenal glands, and skeletal muscle.

They determined that the hypotension was not a result of hypoxia. Lung secretions revealed elevated levels of albumin, total proteins, and lactate dehydrogenase. These levels were virtually identical to what was seen in their blood plasma. They concluded that pulmonary edema was most likely due to an increased permeability of pulmonary capillaries. The exact mechanism of action is not fully understood and is believed to be similar to the critical phase in dengue fever. However, one thing was obvious: this New World hantavirus is a truly nasty disease with a lethal one-two punch. Simply put, the victims’ capillaries would begin to leak plasma into their lungs. While they struggle for air as they literally drown in their own fluids, their blood pressure would drop. As symptoms progressed, cardiac shock soon followed, resulting in a massive heart attack and death. A 1994 review of this outbreak reported an estimated mortality rate of about 76%.


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With a fair amount of evidence at hand, investigators set off to collect rodents and other possible carriers. Hantavirus is transmitted through the feces and urine of infected hosts. In general, every hantavirus strain has a specific host, and that strain is seen in far fewer numbers in other species. Infections typically occur when a victim inhales airborne feces or urine particulates. The virus also displays cyclical patterns based on climate. Clustering occurs in years when there have been warmer winters, greater rain fall, and/or floods that result in an overabundance of food and an explosion in the rodent/host population. After the collection of 1700 samples from suspected houses and surrounding areas, the deer mouse was found to be the main culprit. The specific strain for the newly discovered hantavirus was named sin nombre virus (SNV). Because this new hantavirus directly affected a victim’s lungs, unlike any previously known Old World hantaviruses, it was given the name hantavirus pulmonary syndrome (HPS).

In general, HPS is a more lethal form of the disease than the Old World strains, which are collectively known as hemorrhagic fever with renal syndrome (HFRS). HPS has an average mortality rate of about 40%. Presently, HPS is found solely in the Americas, and currently, 17 strains have been identified. SNV is the most common strain in the US and Canada. HFRS can be found throughout Europe and Asia, and serological tests indicate its presence in Africa. Both HPS and HFRS are characterized by capillary leakage. However, HFRS primarily affects capillaries in the kidneys and other organs, whereas HPS involves pulmonary capillaries to a greater extent. There are 7 infectious HFRS strains, and in general, they have a shorter incubation period than HPS. Initial symptoms are similar to HPS, with patients displaying fever, chills, nausea, headaches, abdominal or muscle pains, as well as other flu-like symptoms. Low blood pressure has also been noted. However, polyuria and acute shock are more often associated with patients with HFRS. This population is also prone to severe protein loss via urine (proteinuria) and renal failure. Depending on the strain, other symptoms include neurological features such as encephalomyelitis and hypopituitarism, and, similar to HPS, there may be pulmonary impairment and cardiac shock. The most lethal strains of HFRS are Seoul virus (SEOV) and the Hantaan virus (HTNV), with mortality rates that range around 3% to 12%. An interesting aspect of both HPS and HFRS is that evidence suggests an immunopathology rather than a direct viral cytopathology may be responsible for their pathogenesis.

There is no cure for either HPS or HFRS. When hantavirus is suspected, supportive measures are often taken, such as maintaining fluids, monitoring kidney function, hemodialysis, placing patients on ventilators, and oxygenating blood. Cortical steroids are not the standard of care but have been used in severe cases. Ribavirin has been used in China to treat HFRS, and clinical trials have shown a marked reduction in HFRS mortalities. There are a few other experimental therapies for HFRS involving the use of multiple antivirals. However, prevention, precaution, and monitoring host populations are perhaps the best ways to reduce exposure.

Was English Sweating Sickness Actually a Hantavirus?

Hantaviruses are nothing new. Some of the earliest hantavirus descriptions date back to 900 AD in China. It has also been suggested as a cause of “war nephritis” during the American Civil War. With respect to the Four Corners outbreak, tissue samples taken from a 38 year old who died of respiratory failure in 1959 tested positive for the SNV strain. Navajo oral medical traditions also recall mouse-borne illnesses that occurred in 1918, 1933, and again in 1934. Over the years and particularly after the 1993 outbreak, researchers have suggested that a hantavirus was the cause of English sweating sickness, although this theory does have its detractors.

English sweating sickness, also known as the English sweat and sometimes referred to as the sweat, has been a medical mystery for over 500 years. From 1485 to 1551, 5 separate outbreaks ravaged England and parts of Europe. The disease was not caused by plague or typhus. Influenza was also ruled out due in part to how and when the infection spread. Unlike influenza, the English sweat traveled in an opposite direction. It would start in the west and travel east. It would appear in late June and disappear around October or November. Late fall and early winter is typically when the plague and influenza would become dangerous and highly infectious. Also, during that time, influenza and the plague would return year after year but the sweat only emerged in 1485, 1508, 1517, 1528, and 1551.

Ergot poisoning has also been suggested and also largely dismissed. Ergot is a fungus that grows on wheat and rye under certain seasonal conditions. Ergot poisoning occurs when the grains are harvested and baked into bread or other food products and consumed. However, rye and wheat cultivation were virtually nonexistent in England around that time. Also, in cases of ergot poisoning, hallucinations are common effects, yet records do not indicate hallucinations as a common symptom of the English sweat.

Some historians suggest that the sweat was instrumental in Henry Tudor’s victory over King Richard III, thus ending the Wars of the Roses. However, that point is suspect. What is not suspect is the fact that shortly after his victory, a strange sickness quickly swept across London, killed 15,000, and mysteriously vanished in late October. The disease had a rapid onset like other hantaviruses; symptoms included fever, chills, tremors, weakness, perspiration, and a rash. Polyuria was also noted, and according to most accounts, it primarily infected the affluent and the healthy. Unlike many other communicable diseases that target immune-compromised individuals, the English sweat and hantavirus seemingly target the healthy. The mortality rate was estimated to have been around 30% to 50%, similar to HPS. There is one glaring difference between hantaviruses and the English sweat, and that is the mode of transmission. Medical literature suggests person-to-person transmission of the English sweat, and based on historical records detailing epidemiological patterns, many researchers agree.

About 150 years after the last known case in England, a similar epidemic called Picardy sweat emerged in France. Picardy sweat, also called military fever, was responsible for 196 outbreaks from 1718 to 1861. Some scholars believe that Mozart died from a severe case of military fever. Medical literature suggests that the mode of transmission was rodent-to-human, with a vole (small mouse-like creature) as the main culprit. The Picardy sweat was not as severe as the English sweat but there is some consensus that the 2 diseases are related.

In a review published in a recent edition of Viruses, the authors make a compelling argument that a hantavirus was the underlying cause of the English sweat. They tracked weather patterns, winter severity, seasonal rain falls, and flooding. Those patterns coincided with outbreaks of the English sweat. These same weather patterns are highly correlated to modern-day hantavirus clustering. However, the largest hurdle, with regard to the English sweat, is route of transmission. The authors tackled this with a logical and compelling argument about food storage. Unlike today, one would have to store enough food to last through the winter. Essentially, these storage facilities were prime targets for infestations. They were dry, relatively warm, and had plenty of food for any host species. To feed armies, especially during a war, one would need a moving food supply. As these armies moved, so did the host species, all the while multiplying and spreading disease.

Symptoms of the English sweat, as well as the incubation period and mortality rates, closely resemble HPS. Of course, a New World hantavirus did not exist in 14th century England. However, a severe HFRS variant that affects pulmonary capillaries to a greater extent may have, something similar to SEOV or HTNV. It is easy to say that this is only academic and that the English sweat is gone, never to be seen again. That’s not entirely correct. During World War II, the English sweat reemerged. An outbreak of sudor anglicus (Latin for English sweat) was reported in occupied France. It happened in the southernmost region where recent hantavirus outbreaks have been reported.

Opponents of the hantavirus origin theory will always point to human-to-human transmission as an intrinsic feature only present in the English sweat. It is difficult to reconcile the differences in mode of transmission between the English sweat and hantaviruses. However, there is evidence indicating person-to-person hantavirus infections. In 1996, a highly virulent and transmissible outbreak occurred in southern Argentina. This new hantavirus strain was named Andes virus. The outbreak stretched across 3 cities, lasting over 11 weeks. Primary infections were tracked back to a host species but there were clusters of secondary infections. Each secondary infected patient had proven contact with an infected primary patient. Further evidence identified identical viral nucleotide sequences in primary patients and secondary patients. In one case, strong evidence linked an infection in a health care worker to his patient. There were other clinical features unique to this HPS. It demonstrated more hemorrhagic, renal, hepatic, and muscular involvement than the SNV outbreak in 1993.

The exact route of transmission is still unclear. It is believed that airborne exposure may contribute to secondary infections. Saliva and respiratory secretions may harbor a sufficient viral load to pass from person to person via cough, as may an exchange of other bodily fluids. It is suggested that when the disease has reached the cardiopulmonary phase, health care workers should use precautions. Hantavirus infections may be more prevalent than previously thought. Seroprevalence rates from around the world range from 1% to 12% of the total population. Essentially, hundreds of millions of people test positive for viral antigens that never become clinically significant. One may also come to the conclusion that millions of people are misdiagnosed. In the US, there are approximately 50,000 unexplained respiratory illnesses yearly. How many other cases of bronchitis, flu, or other upper respiratory infections are actually a less-severe form of hantavirus?

Was the English sweat a hantavirus? There is a fair amount of evidence indicating that it was. However, is that the question we should be asking? Around the world, we are seeing extreme weather patterns unlike anything in recent history. The question should be: how long do we have until the English sweat reemerges? Or more importantly, how long until an unidentified strain with characteristics of both SNV and Andes strikes: a strain that is highly virulent, with a high mortality rate and person-to-person transmission?

Reference

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