Wednesday, February 13, 2013

American Hemorrhagic Fevers

This week we cover the American hemorrhagic fevers, which are a group of hemorrhagic fevers occurring primarily in different parts of South America. These are all caused by arenaviruses and will constitute the final installment of the extended series on hemorrhagic fevers.

The Pathogen. We are going to focus on the four major American hemorrhagic fevers (AHF): Bolivian hemorrhagic fever (BoHF), Argentinian hemorrhagic fever (ArHF), Venezuelan hemorrhagic fever (VHF), and Brazilian hemorrhagic fever (BrHF). BoHF is caused by Machupo virus, ArHF is caused by Junin virus, VHF is caused by Guanarito virus, and BrHF is caused by Sabia virus. All of these viruses are members of the Tacaribe (New World) serocomplex in the Arenaviridae family. They are enveloped viruses approximately 110 to 130 nanometers in diameter with single-stranded, ambisense RNA genomes in two segments:

Macrophages are the primary target cells for these AHF-causing arenaviruses. A membrane-bound glycoprotein (GP1) binds to the host receptor, and the virus enters the cell by endocytosis. Replication occurs in the cytoplasm of the host cell.

There is typically strong upregulation of pro-inflammatory cytokines and altered coagulation following dramatic increases in thrombopoietin and decreases in erythropoietin. Unlike some other hemorrhagic fevers, the endothelium typically experiences only minor damage in AHF.

The Reservoir. Rodents are the natural reservoirs for each of the viruses causing the four AHF. The reservoir for Machupo virus is Calomys callosus, commonly known as the large vesper mouse:

Calomys callosus

There are several important reservoirs for Junin virus. These are Calomys musculinus (drylands vesper mouse), Calomys laucha (small vesper mouse). Akodon azarae (Azara's grass mouse), and Mus musculus (house mouse).

Calomys musculinus

The reservoirs for Guanarito virus are Zygodontomys brevicauda, the cane mouse, and Sigmodon alstoni, the cotton rat:

Zygodontomys brevicauda

Sigmodon alstoni

The reservoir for Sabia virus is currently unknown but is strongly suspected to be another rodent species.

The Disease. The four AHF discussed here are similar to each other in presentation. Early symptoms include fever, headache, fatigue, myalgia, pharyngitis, and lymphadenopathy. Petechial and erythematous rash, vomiting and diarrhea are also common and can present early or late. Vascular complications begin to emerge later in the disease course. Thrombocytopenia can be extensive and typically leads to focal hemorrhage and potential necrosis in several organs systems, with the liver and spleen commonly affected. Bleeding from the nose and gums and hematemesis can be common later in the disease course, and gastrointestinal bleeding can be quite severe. Low blood pressure due to extensive bleeding and increased vascular permeability and subsequent leakage can lead to shock. Pulmonary, renal, and neurologic complications can also present. These can include pneumonia following pulmonary edema and secondary bacterial infection, frank proteinuria, and tremor, ataxia, convulsions, and coma. Recovery begins 1 to 2 weeks after the onset of symptoms and may require a month of convalescence. Those who recover do not typically suffer chronic disability. Nevertheless, the mortality attributable to AHF can be quite high. The mortality associated with BoHF is approximately 30%; ArHF ranges between 25% and 35%; VHF is approximately 34%; and BrHF is 33%, though this last estimate is based on very few cases.

The Epidemiology and the Landscape. The primary mode of transmission for the Tacaribe serocomplex is from infected rodents to humans via the airborne route. The virus is shed in the stool, urine, and saliva of the rodent reservoirs. As the excreta dry out, the virus remains viable in dust. If the the dust is disturbed, particularly by human activity, the virus particles can be inhaled as they are introduced into the air. Transmission through a common vehicle, such as contaminated food, has been documented for BoHF, but is not common. Person to person transmission is also possible for BoHF, but has not been documented for the other AHF. As such, nosocomial infection can be an important source of additional cases of BoHF particularly in an outbreak setting.

Most cases of AHF occur in rural settings in either agricultural landscapes or at the intersection of agricultural and residential landscapes. These spaces are most clearly delineated in ArHF, which follows a clear seasonal transmission cycle corresponding to the autumnal corn harvest in landscapes intersected by human maize agriculture and the drylands vesper mouse habitat. While there are several reservoir species for ArHF, the drylands vesper mouse is the  most important for transmission to humans because of its extensive exploitation of agriculturally modified landscapes. Venezuelan HF also occupies a similar landscape at the intersection of cane and cotton agriculture and cane mouse and cotton rat habitats, respectively, across five states of the central plains in Venezuela. The physical processes of harvesting, whether manual or automated, are directly relevant to transmission as these create large amounts of dust, which can contain the dried excreta of infected rodent reservoirs and subsequently enter the respiratory tract of the agricultural laborers.

Transmission of virus for all AHF also can occur commonly in the home, particularly among agricultural communities where residential spaces may overlap or exist in close proximity to subsistence farming spaces. In these latter landscapes, some reservoir rodents may occupy both the agricultural and residential spaces.

Control and Prevention. Because the reservoir host is ubiquitous in endemic areas, elimination of the reservoir is not possible. However, rodent control is still an important strategy to control human infection with the Machupo, Junin, Guanarito, and Sabia viruses. Taking precautions to eliminate safe spaces for rodents in the home or other structures of human habitation or occupation can reduce effective human to rodent contact and thus block this important mode of transmission.

In order to eliminate safe spaces for mice the following steps can be employed:

Remove all food sources: Food and garbage should always be kept in well-sealed containers that cannot be breached by rodents. In addition, pet food and/or garden fruit and vegetables left unattended outside will often attract rodents.

Household maintenance: Good maintenance both inside and outside the home can be very important in eliminating rodent habitat. On the outside, overgrown plants and shrubs, unattended woodpiles or debris, and unattended outdoor structures can all serve as welcome homes for rodents, and should be regularly maintained. On the inside, poorly sealed foundations, roofing, vents, and other household structures can provide easy access to the interior of the house and thus provide good rodent habitat. As such, it is very important to maintain good structural integrity of the house to keep the rodents out.

Occupational exposure: Given the particular risk associated with occupational exposure in the agricultural setting, providing personal protective equipment for workers may mitigate exposure and reduce infections. For example, the use of fitted respirators may effectively block the inhalation of infectious virions as dust is generated during farm work. Nevertheless, there are little data providing solid evidence that the respirators reduce the incidence of AHF and, moreover, such protective equipment may be cost prohibitive especially among subsistence farmers. 

Candid #1 Vaccine: This vaccine was developed to prevent ArHF. It is a live attenuated vaccine based on the XJ strain of the Junin virus. It has demonstrated remarkably high efficacy, ranging between 95% and 98% with good long-term (9-10 years) immunity. The vaccine is also cross-protective against BoHF. While this vaccine has demonstrated good protection, there can still be disparities in accessibility, with poorer individuals living and working in more remote areas of Argentina missing opportunities for vaccination. 

While person to person transmission of Machupo virus is not common, during outbreaks of BoHF, or in any BoHF endemic health care setting, blocking nosocomial transmission by employing good barrier protection and patient isolation can also be important in preventing Machupo virus spread from infected patients to health care personnel and/or other non-infected patients.


  1. I decided to read about a disease I knew nothing about. I found it interesting (and disgusting) that the most common mode of transmission was the inhalation of dried out feces mixed in dust. This sounds like a very serious, but preventable disease.

    1. Colee, I also thought the most common mode of transmission was interesting. It made me think of areas, like my home country, where rodents are prevalent in agricultural areas. Therefore, transmission is considerably easy which is alarming since the mortality rates for these types of fevers are so high

  2. It is quite interesting that leptospirosis can exist as a free living organism in water or in moist soil.
    Leptospirosis seems to be a disease that affects people who come in contact with animals, such as farmers and sewer workers. Prevention measures include: rodent control, sanitation and use of gloves and other protective gear.
    Some countries such as Italy and Spain carry out immunizations for those who are at occupational risk of developing leptospirosis.

    1. Being from Italy and having family that still resides here I found your comment very interesting. The fact that Italy carries out immunizations against those who are at risk for leptotspirosis in an occupational setting is a great idea. I decided to research this further and came across this article on pubmed that investigates the vaccination efficency called ‘Comparative tests with formolized and irradicated vaccines against leptospirosis’ ( This articles questions how effective the vaccine is through testing on guinea pigs.

  3. Like the commentators before me, the mode of transmission caught me off guard. I'm curious how long the virus is viable in the dust. It seems the virus could potentially be very pervasive, depending in its life span.

    Furthermore, many of the prevention tips listed may not be feasible for some of the residents in the poorer countries. What could be a possible solution for those who cannot afford well sealed containers, or properly maintain an already hazardous living arrangement?