Overview of Hantavirus 

Hantavirus is a family of viruses that fall under the Bunyaviridae family of viruses, causing several severe diseases with resultant deaths among humans worldwide.1 They are a zoonotic pathogen transmitted by rodents to humans, which causes  Hantavirus Pulmonary Syndrome (HPS) or Hemorrhagic Fever with Renal Syndrome in humans.2  Hantavirus is so-called because initially they were isolated in the laboratory from the striped field mice collected near Korea's Hantaan River. For years, Hantaviruses have been known to be causative agents of diseases in Europe and Asia. Yet, in 1993, a new, recently recognised type of infection, which causes a sickness unlike other distinguished Hantavirus infections, was identified in the southwestern US. Since that flare-up, the infection has been identified in the greater part of states in the U.S., one case and death from Hantavirus were reported in Illinois in 1996, and another case reported in 2005 survived.³

More than 40 species of hantavirus have been identified, 22 of which have been regarded as a potential public health hazard.² 

Understanding co-infection dynamics

In coinfection, two different viruses infect one host either simultaneously or within a short time, Coinfections are challenging to diagnose. As PCR and serological tests, laboratory testing may become essential for diagnosing the coexistence of several pathogens and for proper treatment.¹⁰ When other zoonotic diseases are involved in co-infection, hantavirus is distinguished due to interactions involving the host immune system and ecological overlap (niche overlap).

Co-infection with Hantavirus and other zoonotic diseases provoked by leptospirosis, Lyme disease, or even vector-borne diseases such as tick-borne encephalitis may worsen symptoms or complicate diagnosis.¹³ This article will explore the coinfection of Hantavirus with other zoonotic pathogens.

Hantavirus transmission

Hantaviruses do not harm rats, they cause illness in humans. Humans become infected with a Hantavirus disease when they inhale dust contaminated with saliva, urine, or faeces of infected rodents, or else if they ingest water or food contaminated with urine, saliva, or faeces of infectious rodents. Contaminated material or dust, when it comes in contact with their skin either by entering through open cuts, broken skin, or through an opening of the mucus membrane like an eye, may be responsible for human infection. Also, when bitten by infected rodents could reason for transmission through infected rodents.

As for person-to-person transmission, no cases have been documented.³

Common hantavirus coinfection with other zoonotic pathogens

Coinfections of Hantavirus with other zoonotic pathogens are known to create considerable clinical challenges and affect disease outcomes. Probably, the most frequently encountered zoonotic coinfections with the Hantavirus include: Hantavirus and Leptospira spp

‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌Pathogens Hantavirus (for example, ortho hantavirus), as well as Leptospira spp, causing leptospirosis

‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌‌Common Reservoirs Hantavirus is known to be present as a reservoir in rodents, whereas Leptospira frequently dwells in water that is urine-contaminated from infected rodents.

Clinical implication: Coinfection can lead to potentially more severe side effects such as fever, myalgia, respiratory distress, and acute renal failure. This is based on the fact that these microbes cause febrile human infections with similar symptoms and disease progression. Overlapping symptoms can cause difficulty in diagnosis.

Prevalence of orthoheantavirus and leptospira infections in small mammals

This is a December 2022 prevalence study of the two important zoonotic pathogens, Orthohantavirus and Leptospira, in small mammals of the Gampaha district, Sri Lanka. Both Orthohantaviruses and Leptospira are zoonotic diseases due to the transfer of disease agents from animals to humans and may cause lethal health problems. The researcher examined rodents and shrews, which carry these pathogens, to estimate the prevalence of these infections in the local wildlife.

Key discoveries                                               

1. Animals Tested There were sampled 43 small mammals, including the following species of rat, i.e Rattus rattus, Rattus tanezumi, Rattus norvegicus, and mice (Mus musculus).
2. Screening for Infections Evaluation for Contamination. Assessed samples of lung tissues and blood from the animals for the presence of Leptospira and Orthohantavirus. However, 72% of the rats had antibodies against Orthohantaviruses. This means rats had eventually been exposed to the virus. Furthermore, 92% of the rodents possessed antibodies for Leptospira. It indicated their similar exposure to the virus  3. Coinfection. Interestingly, 67% of the rats had antibodies for both Orthohantavirus and Leptospira, meaning that they would probably be exposed to both pathogens

Conclusion: The study reveals that rats in Sri Lanka, especially in this region, are generally exposed to both Orthohantavirus and Leptospira. This poses huge risks to humans, especially those working closely with these animals.⁴ 

Hantavirus and lyme disease (Borrelia burgdorferi)

Pathogens: Hantavirus and Borrelia burgdorferi,causes Lyme disease

Common Reservoirs Rodents are the typical reservoirs of hantavirus, while Borrelia is primarily transmitted by ticks (Ixodes spp)

Clinical Implications: Patients may exhibit overlapping symptoms such as fever and weakness. A combination of both infections may lead to a challenge when clinically implicated. 

Prevalence of hantavirus and borrelia burgdorferi coinfections 

This study aimed to establish the presence of three pathogens, namely, Borrelia (BOR), Rickettsia (RICK), and Hantavirus (HANT), in the rural zones of North Vietnam. These pathogens may be transferred to humans through either vectors like ticks or by being carried by animals, like rodents. 

Key discoveries 

1. Animals tested 121 residents of the country region Tà Xùa and 220 of the rural area Mama Ly Pho in North Vietnam. The characteristics of most participants were female, aged about 40 years. Of those: 61% in Ma Ly Pho, 58% in Tà Xùa
2. Screening and testing for infection: They tested the sera of residents' blood for antibodies against Rickettsia, Hantavirus, and Borrelia using different kits. The investigators also conducted interviews to get more information about their contact with animals such as rodents and bats, and their exposure to ticks. Most of the interviewees are rural workers and have seen rodents near their houses most often. Plenty of interviewees (38% in Ma Ly Pho and 37% in Tà Xùa) self-reported catching, killing, or preparing rodents or rats for eating. Tick bites were less common, as reported by 8% and 3% of the interviewees
3. Coinfection: By blood tests, IgM antibodies to Hantavirus, Rickettsia, and Borrelia were detected, and more frequent cases were reported in MaLy Pho compared to Tà Xùa. IgG antibodies to the same pathogens in both areas

Conclusion: 

The rural population of North Vietnam had a high likelihood of contact with animals and vectors- the ticks-carrying disease pathogens. The percentage of antibodies related to Hantavirus, Rickettsia, and Borrelia is also relatively high, showing exposure to these diseases.⁵

Hantavirus and rickettsia spp

Pathogens: Hantavirus and Rickettsia spp. causing various rickettsial diseases.

Common Reservoirs Rodents are the potential reservoirs of Hantavirus, while the disease Rickettsia is usually transmitted through tick bites.

Clinical Implications: Patients can present with signs such as fever, rash, and other systemic signs and symptoms, which makes diagnosis and treatment challenging because the diseases share clinical features. This study, conducted in Croatia, focused on rodent- and tick-borne diseases, hantaviruses, TBEV, and Rickettsia species. These agents are of public health significance because they can be potentially transmitted from animals to humans. The study was conducted in two regions: the mountain and the lowland, in Croatia, by carrying out sampling of small wild rodents for signs of infections. Genes are of particular relevance to public health because of the potential for transmission from animals to humans. 

Key discoveries                                     

Animals tested Rodents examined: 170 rodents were sampled with a focus on the following species: Apodemus flavicollis, yellow-necked mouse; Apodemus agrarius, striped field mouse; Myodes glareolus, bank vole.

Detection of Hantavirus

Around 25.5 per cent of the rodents in mountainous areas were positive for hantaviruses. Therefore, they were infected with the viruses. PUUV or DOBV was found through PCR tests in the mountainous region (21.3 %), and in the lowland region, it was estimated to be 29.0%.

Detection of Tick-borne Encephalitis Virus (TBEV)

No rodent samples were positive for TBEV, and evidence of this virus was found in the animals tested.

Detection of Rickettsia Infection

In the mountainous region, 4.3% had antibodies to Rickettsia, and 3.2% tested positive for Rickettsia DNA. No rodents were positive for Rickettsia from the lowland region.

CoInfection: One rodent from the mountainous region tested positive for both Puumala virus (PUUV) and Rickettsia, which established the multi-infection capability of the animals.

This is the first report of Rickettsia species determined in small rodents in Croatia.

The above-described Coinfections with Hantavirus can significantly complicate clinical presentations by overlapping symptoms and increase the risk of severe disease. Understanding the interactions between Hantavirus and other zoonotic pathogens is crucial for effective diagnosis, treatment, and public health interventions. Awareness of these potential coinfections is essential, especially in regions where these pathogens are prevalent and rodent populations are abundant.⁶

Diagnosis and treatment challenges of hantavirus coinfections

Coinfection with other zoonotic pathogens may cause difficulty in diagnosing and managing of these diseases. Here is a general overview of the approach toward diagnosis and treatment:           

1. Clinical presentation symptoms of hantavirus infection are often nonspecific, such as fever, muscle aches, and fatigue. Coinfection with other zoonotic pathogens (e.g., leptospirosis, Lyme disease, or rickettsial infections) may present with overlapping symptoms, including fever, malaise, and respiratory or renal involvement.

Consider the patient's history of exposure, such as rodent exposure, and outdoor activities.

• Laboratory Tests
  • Serology:  In serology, ELISA or immunofluorescence assays are used to detect hantavirus-specific IgM and IgG antibodies
  • PCR: The presence of Hantavirus RNA in blood or tissue samples, usually during the first week, is confirmed by PCR, therefore assuring the diagnosis⁷

Testing for Other Pathogens is based on clinical suspicion. Tests for other zoonotic infections, e.g., PCR for leptospirosis.⁸

Serology used for Lyme disease should be performed in parallel to detect potential coinfections.⁹ 

• Imaging and Organ Function Tests
  • Chest X-ray: Often shows bilateral infiltrates in HPS
  • Renal Function Tests Monitor for renal impairment, especially in HFRS, and potential coinfections that may affect the kidneys (e.g., leptospirosis)⁸

How to treat hantavirus coinfection?

There is no specific treatment for hantavirus infection. A suspected patient having HPS should receive emergency medical care in the intensive care unit even before diagnosis takes place. Suspected patients of HPS should receive proper broad-spectrum antibiotic therapy. Care should also include pain relievers and fever reducers. Intensive medical care at an early stage is very important because patients who have sudden acute disease may rapidly become severely sick and die.

1. Supportive Care
   • Respiratory Support: The patient would require mechanical ventilation for serious cases, as the lungs are mostly involved in HPS patients.
   • Fluid Management Fluid balance needs to be closely monitored as it can lead to pulmonary oedema (HPS) or worsening of renal function(HFRS).
2.  Antiviral Therapy

There is no specific antiviral treatment for hantavirus, Ribavirin has been observed to offer some benefit in HFRS if given early.

In the absence of adequate treatment, major mortalities can be seen in patients with HPS. Within 24 to 48 hours after initiation of the cardiopulmonary phase.⁷

Management of coinfection

Leptospirosis

Leptospirosis may be treated with antibiotics, such as doxycycline or penicillin. Early antibiotics should be given if our healthcare professional thinks we may have leptospirosis. IV antibiotics may be necessary in more seriously ill patients.

Lyme disease

The antibiotics most commonly used, Doxycycline, amoxicillin, or cefuroxime axetil, should be administered for the treatment of Lyme disease.

Early diagnosis and complete antibiotic treatment of Lyme disease can prevent more severe disease.¹¹

Rickettsial infections

Treatment is usually with the drug of choice, which is tetracycline antibiotic doxycycline, that reduces the duration and severity of infection.¹²

Summary 

Coinfection with other zoonotic pathogens may play a highly significant role in hantavirus, potentially complicating outcomes for the disease. When a host is coinfected, the host's immune system will often become impaired or compromised such that it cannot help control an outbreak adequately. Coinfections with pathogens like those for leptospirosis, Rickettsial, or Lyme diseases lead to increased diagnostic challenges, complicated treatment, and even an increased fatal outcome. Understanding these interactions is extremely important to develop improved public health responses and disease management