#54924: Animal-Related Health Risks

Parasites that can cause disease directly in the host (not just transmission of a zoonosis) are represented in five different phyla: the pentastomida, nematodes, trematodes, cestodes, and protozoa (Table 2)[10].

The pentastomida are very primitive, worm-like parasites that primarily infect the lungs of reptiles. Human infection is by the larval stage. The spleen, liver, and/or lungs may be infected, but fortunately, the disease is self-limiting and usually not significant. While no fatalities have been reported, because any parasite is a foreign protein, a hypersensitivity reaction is a possible outcome with any of the parasitic zoonoses.

Nematodes are commonly referred to as roundworms, with hookworm being a common example. There are many zoonotic forms of nematode infections. One example is trichinosis, which will be discussed in detail later in this course. In general, most nematode zoonoses are transmitted through ingestion of the egg stage of the organism [10]. When in the feces, the eggs will hatch into the infective larval stage after 24 hours in most species. Occasionally, the larval phase of the parasite will penetrate the skin, usually through the sole of the foot because an individual has walked barefoot where larval forms of the nematode are present. This form of infection is referred to as cutaneous larval migrans. It is one of the better reasons not to walk barefoot in a city park, an unfamiliar backyard, or a veterinarian's office.

Trematodes, commonly called flukes or flatworms, are usually transmitted via ingestion [10]. As with the nematodes, some species can penetrate the skin and migrate to various organs. Most hatch in the gastrointestinal tract and migrate to other areas of the body to cause infection, unless they penetrate the skin. The liver and lungs are the most commonly affected tissues in a human host by the adult form of the agent.

Cestodes or tapeworms are primarily gastrointestinal parasites, but one type (Taenia spp.) can encyst in organs and cause severe disease, with occasional associated fatalities in humans [13]. These parasites reproduce by shedding segments (proglottids), so some species can autoinfect the host via the fecal-oral route. Some transmit by biologic vectors that are ingested by other hosts.

Protozoa are well documented as gastrointestinal parasites and can cause serious levels of disease [10]. Being the smallest of the parasites, they can inhabit a number of different locations in a host, including red blood cells (e.g., malaria) and the mucosal cells of the intestines. Another example is Giardia, which inhabit the brush border of intestinal epithelial cells. They produce diarrhea, which can be mild to severe depending on the agent causing the disease, the parasite burden present, and the underlying state of health of the host. Most protozoa spread via the fecal-oral route. Unlike the larger intestinal parasites, which are identified using routine direct stool sampling techniques where the eggs are "floated" up out of the fecal material for identification, protozoa can be difficult to detect because of their very small size.

The range of zoonotic diseases from bacteria is wider than that from parasites, although the total number of agents is less. Cholera, tularemia, shigellosis, salmonellosis, plague, and cat scratch fever are examples of gram-negative bacteria that can cause serious zoonotic diseases (Table 3). Gram-positive bacterial zoonoses include botulism, anthrax, Hansen disease (leprosy), and listeriosis. Diseases caused by spirochetes (specific types of gram-negative bacteria) include Lyme disease and leptospirosis. Some of the rickettsial diseases (gram-negative) are Rocky Mountain spotted fever, Q fever, and psittacosis.

Bacteria can be transmitted via all of the routes discussed, and more than one avenue of transmission may occur with the same agent. For example, tularemia can be transmitted by a bite wound from an infected cat or rabbit or from an arthropod source [14]. Tuberculosis is primarily transmitted by inhalation but can also be transmitted by the ingestion of raw milk [14].

Most bacterial zoonoses are treatable with appropriate antibiotics, antitoxin where applicable (e.g., tetanus), and supportive care [14]. However, recognition of the disease in a timely fashion is critical for a positive outcome in some bacterial zoonoses that can be fatal if not treated promptly.

There are many viruses that may be transmitted from animals to humans (Table 4). Viral transmission can be through direct contact, bites, arthropods, airborne inhalants, and other vectors. Treatment and prevention are specific to each disease. Some, such as rabies, have vaccines available, but most must be managed by careful preventive measures and universal precautions rather than pre- or postexposure treatments.

Zoonotic DNA viruses of concern include herpes simian B and T virus. Simian B virus causes simian herpes in humans, which carries a 70% to 85% case fatality rate [15]. A bite wound from an infected monkey or contamination of broken skin with saliva is usually required for transmission; however, it is now known that infection can also occur though contamination of the mucous membranes or eyes [15]. Fortunately, people generally do not have direct contact with the species of monkeys that are carriers of herpes B unless they work in zoos or research facilities that house them.

Most zoonotic viruses are RNA viruses. Rabies, Ebola, yellow fever, and the hemorrhagic fevers are examples of RNA viruses with serious zoonotic potential. Other viral zoonoses are fairly common and include West Nile encephalopathy, avian influenza, and the hantavirus syndromes. These will be discussed in detail later in this course.

Humans can have varied and severe reactions to Lyme disease; most organ systems have the potential to be affected. B. burgdorferi has an affinity for cartilage cells and the transitional cells of the urinary bladder.

The first signs of Lyme disease are usually flu-like symptoms and joint pain. In an elderly person, pre-existing arthritis may complicate early diagnosis. Three distinct stages have been described in patients with untreated infections [27]. Stage 1 (early localized stage) occurs 3 to 30 days after the tick bite and is associated with the appearance of the characteristic "bull's-eye" skin lesion of erythema migrans. Various sources estimate that approximately 70% to 80% of the documented infections will have the characteristic expanding rash [18]. This initial stage may show the nonspecific clinical signs of malaise, headache, arthralgia, fever, myalgia, and regional lymphadenopathy. If they never see a rash, many patients will not consider Lyme disease as the source of their symptoms.

Stage 2 (early disseminated stage) develops through hematogenous spread and is evident after days to weeks post-tick bite [18,28]. Possible manifestations include subtle encephalitis with headache and cognitive difficulty, stiff neck, cranial neuropathy (with facial palsy being a common finding), cerebellar ataxia, motor and sensory radiculoneuritis, myelitis, and visual disturbances. This stage is associated with acute neuroborreliosis in a significant number of cases [18,28]. Most patients with neuroborreliosis are affected by meningitis, facial nerve palsy, and/or radiculitis, with only a limited number having parenchymal spinal cord or brain involvement [29].

Stage 3 (late disseminated stage) is the chronic phase, which may appear months to years after the initial infection [18]. Various names for this stage have been proposed and are currently used, including post-Lyme syndrome, post-Lyme disease syndrome, post-treatment chronic Lyme disease, or chronic Lyme disease [29]. One of the most common findings in this stage is oligoarthritis, with the knee being the most frequently affected joint, although other joints can become inflamed [18,28]. Pain is usually out of proportion to the swelling [18]. Musculoskeletal pain, spinal radiculopathy with paresthesias, encephalopathy, and the symptom complex of fibromyalgia or chronic fatigue syndrome may be present. This stage is associated with chronic borreliosis; consequently, cardiac arrhythmias, respiratory compromise, and spread to the entire nervous system are liable to occur. It is suspected that fibromyalgia may be a long-term sequela to chronic Lyme disease. If untreated, chronic expression results in potentially crippling arthritic changes as well as organ system involvement. The organism can establish itself in the bladder wall and reoccur with another exposure or stress from another illness [25].

Concurrent infection with other tickborne diseases occurs in approximately 4% of Lyme-positive patients [30]. The combination of Lyme disease and either Ehrlichia chaffeensis, or an as yet undefined Ehrlichia or babesiosis can cause overwhelming illness for some individuals. Those concurrently infected will have the additional discomfort of dealing with changes in their circulatory system, as erythrocytes or leukocytes are infected and cannot deal with the demands of mounting an immune response to Lyme disease. Ehrlichia infections usually produce a high fever in the initial infection period [31]. The rare patients who go on to develop acute respiratory distress syndrome have a high correlation of concurrent infection with Ehrlichia[32].

Many of the symptoms of Lyme disease are caused by the body's immune system. Because the spirochete infects the cartilage cells intracellularly, the neutrophils concentrate in the region, resulting in a pain similar to the pain of rheumatoid arthritis. Damage to the cartilage cell and subsequent pain is caused by neutrophils attacking both infected and healthy cells. The amount of discomfort and joint destruction varies among patients depending upon their individual immune response.

Clinical suspicion from history, signs, and symptoms is paramount in the diagnosis of Lyme disease [18]. Patients can present with a variety of clinical findings, and not all classic signs or symptoms are present in those with active Lyme disease. If patients have a rash and recognize it as visceral migrans, it may be too early for other symptoms to be noted or for testing to yield positive results. Additionally, early but inadequate antibiotic treatment may prevent full antibody development in patients who are still clinically ill [33]. Varying severity and expression can make Lyme disease difficult to diagnose in some patients. The criteria as set by the CDC do not always fit the signs, symptoms, and test results. This can be very frustrating for patients as well as medical professionals. A few good diagnostic procedures are available, although they require diligent interpretation.

The CDC recommends using diagnostic tests for Lyme disease that have been cleared or approved by the U.S. Food and Drug Administration (FDA) [34]. The CDC recommends sampling blood with a two-step process. Both steps are required and can be done using the same blood sample [35]. The first test should include either an enzyme-linked immunosorbent assay (ELISA) or, rarely, an indirect immunofluorescence assay (IFA); however, false positives occur with cross reactions to other spirochetes, such as syphilis, mononucleosis, some autoimmune diseases, and oral cavity flora. If the first step is positive or indeterminate (sometimes called "equivocal"), the second step should be performed. The overall result is considered positive only when the first test is positive (or equivocal) and the second test is positive (or, for some tests, equivocal) [35]. The second step, the Western blot test, identifies antibodies for the different spirochetes [18]. Western blot serology is both more sensitive and more specific than ELISA. Serologic assays for immunoglobulin G (IgG) and M (IgM) are frequently used blot tests but are not recommended without a previous ELISA [34]. In any serologic testing, a comparison test repeated after an interval of a few weeks should be performed. Antibody levels should be monitored over this period of time to determine if the disease is worsening or improving as determined by the immune system's reaction. The CDC recommends that ELISA or IFA should always be performed before immunoblot testing in order to decrease the likelihood of false positive results [18]. In 2019, the FDA cleared several Lyme disease serologic assays with new indications for use, allowing for an ELISA, rather than Western immunoblot assay, as the second test in the testing algorithm [36,37]. With this new paradigm, two ELISAs can be run either concurrently or sequentially, rather than the traditional two-step process [36,37]. According to the FDA, this new option is easier to interpret in a clinical laboratory due to the streamlined method of conducting the tests [37]. It is prudent to check the laboratory standards for what is deemed positive, as there is variability between individual testing laboratories. It is highly recommended that the laboratory report and specify the bands; many will just list the test as positive, equivocal, or negative. The CDC has published a list of laboratory tests and practices that are not recommended [34].

It is important to caution patients that exposure based on serology does not necessarily mean active disease. Many individuals have titers deemed positive without evidence of Lyme disease, and individuals may have evidence of disease without positive titers. The levels of IgG in the serum can remain high for many years [18].

The specific antibodies of importance appear as bands on the Western blot assay. The antibody bands are individual molecular weights of specific antibodies against B. burgdorferi antigens that give specific evidence of exposure to the agent. In reporting the bands, the designation kDa stands for kilo Daltons of molecular weight and Osp refers to the outer surface protein of the organism. The bands that are most specific to Lyme disease are 23-25 kDa (Osp C), 31kDa (Osp A), 34 kDa (Osp B), 39 kDa, 41 kDa and 83-93 kDa [38]. IgG and IgM Western blot assays have the same antibody band specificity. Ideally, both should be performed at the same time. IgM can be positive as early as one week after exposure, and the positive response can last for the first six to eight weeks. IgG takes longer to respond and has some varying levels of response.

The CDC requires that two of three bands (i.e., 23, 39, 41 kDa) on the IgM or five of ten bands (i.e., 18, 21, 28, 30, 39, 41, 45, 58, 66, 93 kDa) on the IgG be present to positively diagnose Lyme disease [18,39,40,41]. This can be an insurance issue for some patients. If the national standard criteria are not met in the testing procedure, some insurance companies may deny payment. In some cases, the IgM test will be slightly more reactive, and this will meet the CDC criteria. In cases that seem to be Lyme disease but for which standard testing is not yielding a positive answer, the IgM Western blot can be a very helpful tool.

The Lyme Urine Antigen Test (LUAT) was once used widely as a diagnostic tool and is still used by some laboratories [28]. However, because of unreliability and inconsistencies, the FDA has advised against the use of this test for the diagnosis of Lyme disease. In addition, the agency recommends that polymerase chain reaction (PCR) analysis on inappropriate tissues, such as blood or urine, not be accepted as diagnostic, and that Western blot tests only be interpreted according to validated criteria [34,40]. Like the CDC, the FDA advises initial testing be done by ELISA or IFA and specimens that are positive or equivocal be followed up with a standardized Western blot assay or a concurrent or sequential ELISA [37,40].

As noted, PCR technology is also available for testing. Appropriate sources most likely to contain the agent are serum, cerebrospinal fluid (CSF), and synovial fluid. The result is positive in approximately 30% of patients with active Lyme disease [41]. Disadvantages of PCR testing include the likelihood of false-negative results due to a sparsity of spirochetes in infected tissues. Inexperience with PCR also can yield false-positive results when care is not taken to prevent contamination and when incorrect primers are used to prepare the specimen. PCR may be useful in confirming persistent or recurrent disease, because a positive result is highly specific for exposure to B. burgdorferi. However, the test has not been standardized and is not currently used in routine testing [41]. In general, all of these tests can be negative or inconclusive, and the patient can still have Lyme disease as documented with electron microscopy, but this is not a practical test due to cost and time issues. At this time, there are no good imaging procedures to help in the diagnosis of Lyme disease, and there are certainly no definitive test procedures that warrant withholding or denying treatment [28]. Treatment is usually indicated even if all, or almost all, routine diagnostic procedures are negative when there is a strong clinical suspicion of Lyme disease based on history and physical findings.

For high-risk Ixodes spp. bites in all age groups, the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR) recommend the administration of a single dose of oral doxycycline within 72 hours of tick removal over observation.

(https://www.idsociety.org/practice-guideline/lyme-disease Last Accessed: April 28, 2023)

Strength of Recommendation/Level of Evidence: Strong recommendation, moderate-quality evidence

Prompt and complete treatment of early Lyme disease with antibiotics is important to prevent the development of chronic Lyme disease and/or chronic neuroborreliosis and their troublesome sequelae. The International Lyme and Associated Diseases Society (ILADS) suggests that Lyme disease should be treated with doxycycline as the antibiotic of choice for prophylaxis following an Ixodes tick bite with known feeding, irrespective of the amount of tick engorgement or the local tick population infection rate [41,42]. Where doxycycline is contraindicated, antibiotics known to be effective for treating Lyme disease, such as amoxicillin, azithromycin, or cefuroxime, may be substituted. The recommended adult dose and prophylactic regimen is 100–200 mg doxycycline twice daily for 20 days [42].

According to ILADS guidelines, the treatment of erythema migrans rash in adults is a four- to six-week regimen with recommended first-line antibiotics, including amoxicillin 1,500–2,000 mg daily in divided doses, cefuroxime 500 mg twice daily, or doxycycline 100 mg twice daily [42]. Studies in Europe have shown that a minimum of 21 days of azithromycin 250–500 mg daily is equally or more effective than these three agents and may be considered, particularly for patients that place a high value on minimizing the number of days taking antibiotics. The recommended pediatric regimen is also four- to six-weeks of treatment of amoxicillin 50 mg/kg/day in three divided doses (maximum daily dose: 1,500 mg), cefuroxime 20–30 mg/kg/day in two divided doses (maximum daily dose: 1,000 mg), and azithromycin 10 mg/kg on day 1 then 5–10 mg/kg daily (maximum daily dose: 500 mg) [42]. Doxycycline is an additional option for children 8 years of age and older at 4 mg/kg/day in two divided doses (maximum daily dose: 200 mg). Higher daily doses of the individual agents may be appropriate in adolescents [42]. Patients should be instructed regarding the importance of completing the entire course of antibiotics; if a dose is missed, the course should be continued at the next regularly scheduled time and the missed dose taken at the end. Studies have found no evidence that treatment regimens of longer duration than those recommended result in better outcomes for patients whose rash is resolved, but they do increase the chance for antibiotic-related adverse events [42].

Patients who have not fully recovered (i.e., erythema migrans rash still visible) at the end of initial treatment but who show a strong-to-moderate response should be continued on the same agent; a dosage increase of the same antibiotic or switch to another first-line agent (or tetracycline) is recommended for a moderate response [42]. Patients with minimal or absent response should be prescribed two first-line agents. Injectable penicillin G benzathine or intravenous ceftriaxone may be considered for these patients and also for those with disease progression or recurrence [42]. This aggressive treatment is required if neurologic symptoms are present in either the acute or chronic stages or if quality of life impairments are significant or rapidly progressive.

Treatment of neuroborreliosis and chronic Lyme disease has been addressed by the American Academy of Neurology in a guideline reaffirmed in 2014. Three major recommendations are made [29]:

Doxycycline (suggested dosage: 200 mg daily for 14 days) is the only recommended oral regimen for neuroborreliosis, as it has shown a response rate of 98.6% compared with parenteral penicillin or ceftriaxone in an aggregation of data from eight studies (i.e., statistically equivalent) [29]. Symptomatic treatment is recommended if therapy fails to resolve arthritis and if PCR results from synovial fluid or tissue are negative [43]. Treatments include nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular injections of corticosteroids, or disease modifying anti-rheumatic drugs, such as hydroxychloroquine; referral to a rheumatologist is also recommended.

Patients with Lyme disease can frequently be frustrated with the long-term nature of the treatment and will need support, especially to maintain the antibiotic regimens. The long-term effects can also be very discouraging for the unfortunate patients who eventually develop the syndrome, which mimics fibromyalgia or chronic fatigue syndrome. Fortunately, it appears that early treatment, and in most cases even late treatment, can prevent or eliminate these sequelae [18,25].

As with any disease, prevention is the best solution. Educating people about how the disease is transmitted and its early signs will help reduce the overall incidence and lessen the severity in those who receive early treatment. The following advice should be given to patients, family, and friends.

If walking where ticks might be present, wear clothing that provides protection from tick exposure. Bare legs should not be exposed, and socks should be pulled up over pant legs. Ticks are not able to get through clothing to exposed skin, but they can climb up socks and reach exposed skin if the pant legs are not inside the socks. Long-sleeve tops and having long hair under control will help as well. Clothing should be removed and washed on arrival home. A thorough tick check should be completed, especially in body creases such as the groin and the axilla (armpit) [18]. Many people have been fooled into thinking ticks were freckles and have not removed them before they became engorged. It is most important that embedded ticks be removed promptly. If the capitulum, or head, is broken off, it may cause a local reaction. Borrelia is actually in the body of the tick, so transmission likelihood will decrease the faster the body is removed. It takes at least 24 to 36 hours of contact by the tick for the disease to be transmitted.

Though the organism is shed in the urine of mammals, no transmission has been documented to have occurred from urine exposure. Pregnant women should be especially alert when in areas known to have ticks, as there appears to be placental transmission of Lyme disease [18]. Some question this, despite evidence that some infants have positive titers after maternal antibodies should have disappeared. For now, erring on the side of caution would seem prudent. Lyme disease, unlike its close relative syphilis, has not been shown to be a sexually transmitted infection.

Dogs and cats can bring ticks into the house. Usually, once on an animal, the tick will remain and not drop off unless the animal has been treated with repellents. Most products to repel ticks will prevent them from ever getting into the house, as they will not remain on the dog or cat long enough to get indoors. Some products are designed to kill the tick if it does succeed in embedding [18].

Public health strategies have included methods to curtail deer populations. This is one way to lower the incidence of Lyme disease in local human inhabitants, because without the definitive host for the tick, the tick population will decrease. It will take a few years after the reduction of the deer population to see a drop in the number of human cases. This is because the newer generation of ticks on the mice will remain at a higher level. In fact, ticks may seem more numerous for the first two to three years after lowering the deer population because of the lack of the correct definitive host.

Insecticides, such as permethrin, and insect repellents, especially n, n-diethyl-m toluamide (DEET) in a concentration of at least 20% to 30%, can be very useful if used properly. Permethrin kills ticks on contact and can be used in a backyard, around a house, or on clothing. DEET is a well-known repellent that can be applied to clothing or exposed skin [18,44]. Some have suggested placing pesticide applicators at deer feeding stations to kill ticks on the deer that come to feed. Of course, controlling the mouse population will also help to reduce the number of cases.

Finally, it is important to know how to properly remove ticks. Petroleum jelly, mineral oil, heat, nail polish, or other materials should not be applied to the tick or immediate area. Embedded ticks are best removed with fine-tipped tweezers. The tick should be grasped as close to the body as possible and removed with a gentle steady pull. Even if all of the mouth parts are not removed, the threat of Lyme disease is very unlikely because B. burgdorferi is usually located in only the midgut and salivary glands of the tick. The area where the tick was located can be washed and cleansed with an antiseptic [18].

The FDA approved the first vaccine for human use, LYMErix, in 1998 [25]. However, in 2002 the manufacturer announced that they were discontinuing production of the vaccine, citing low demand; it is no longer commercially available [25,45]. When available, the results of trials showed a 50% vaccine efficacy in the first year after vaccinations were given as two injections approximately two months apart. The effectiveness of the vaccine increased to 75% in the second year, after a single booster; however, those who were previously vaccinated are no longer protected [45]. Clinical trials of new vaccines are underway as of 2023 [45].

There are several classification systems for clinical tularemia. One such system categorizes tularemia as either ulceroglandular (occurring in the majority of patients) or typhoidal [49]. Ulceroglandular disease is characterized by lesions on the skin or mucous membranes (including conjunctiva), lymph nodes larger than 1 centimeter, or both. Typhoidal tularemia describes systemic manifestation of the disease without skin or mucous membrane lesions [46,49]. In addition to these two types, pneumonic tularemia, caused by inhalation and primarily manifesting as pleuropneumonic disease, also occurs [46,49]. Pneumonic tularemia is often considered a type of typhoidal tularemia.

Typhoidal Tularemia

As noted, typhoidal tularemia is an acute, nonspecific febrile illness and is not associated with prominent lymphadenopathy or skin lesions [46]. This type of tularemia is caused by inhalation or ingestion of bacilli and may involve significant gastrointestinal symptoms. It is believed that this type would be most prevalent during an act of bioterrorism [47,50].

The incubation period is usually 3 to 5 days (range: 1 to 21 days), although aerosol exposures have been shown to result in incapacitation in the first day [46,50]. Symptoms may include fever with chills, headache, myalgia, sore throat, anorexia, nausea, vomiting, diarrhea, abdominal pain, and cough [50]. Patients may develop tularemia sepsis and/or pneumonia, which can be fatal. This syndrome manifests with hypotension, respiratory distress syndrome, renal failure, disseminated intravascular coagulation, and shock [50].

Pneumonic tularemia results from inhalation of infected aerosols or spread of existing, untreated disease [50]. Hemorrhagic inflammation of the airways is an early sign [46]. Radiologic studies show pleuritis with adhesions and effusions and peribronchial infiltrates; hilar lymphadenopathy is also common [46,49]. These signs, however, are not always present. Patients may develop acute respiratory distress syndrome and require mechanical ventilation [49].

Ulceroglandular Tularemia

Ulceroglandular tularemia occurs in 70% to 80% of cases [49]. It is generally caused by an arthropod bite or by handling the carcass of an infected small mammal, such as a wild rabbit; transmission has also been reported from ingestion of or contact with contaminated water, exposure to contaminated mud or animal bites, and exposure to aerosolized water droplets or dust from contaminated soil or grains [46,49,51,52,53]. A local papule develops at the inoculation site, with progression to a pustule and ulceration within a few days. The ulcer may be covered by an eschar [46,49]. Lymphadenopathy may also occur [49]. The nodes are usually tender and may become fluctuant, rupture, or persist for months to years [49]. In most cases, there is a single ulcer with raised borders. Other symptoms include fever, chills, headache, and cough [49].

Ulceroglandular tularemia is characterized by the presence of a small, ulcerated papule at the site of a tick bite or other contaminated break in the skin, followed by tender regional adenopathy and fever. A variation of this syndrome is oropharyngeal tularemia, presenting with subacute to chronic exudative pharyngitis/tonsillitis, cervical adenopathy, low-grade fever, and malaise (easily confused with infectious mononucleosis). Oropharyngeal tularemia likely arises from direct transmission via the hands or by droplet nuclei or dust arising from handling the carcass or dressing out meat from an infected animal [49]. Finally, there is a well-described oculoglandular form of tularemia, whereby inadvertent direct inoculation of the eye, as from touching the face or eyebrow after handling a dead wild animal, results in a unilateral conjunctivitis and preauricular adenopathy [46,49].

Diagnosis of tularemia requires a high index of suspicion, as the disease often presents with nonspecific symptoms [49]. A history of tick bite or exposure to wild game (e.g., rabbit, deer) provides a clue. The diagnosis can be made by recovery of the organism from blood, ulcers, conjunctival exudates, sputum, pleural fluid, lymph nodes, gastric washings, or pharyngeal exudates. Because the organism is difficult to isolate and constitutes a potential danger to laboratory personnel, serologic evidence of infection in a patient with a compatible clinical syndrome is commonly used for diagnosis [49].

There are several biologic variants (biovars) or subspecies of F. tularensis. Type A is considered to be more virulent, while the European biovar, F. tularensis var. palaearctic, typically causes a milder form of the disease [46]. Both types can be identified with direct fluorescent antibody (dFA) analysis, which gives a presumptive diagnosis of tularemia. Direct examination with gram stain may not be helpful because F. tularensis is a weakly staining pleomorphic gram-negative coccobacillus that may be difficult to identify. F. tularensis can be grown in appropriate cultures but may not be identifiable for 48 hours. Antibody or other serologic tests and/or culture are necessary for confirmation of the diagnosis. The antibody detection assays include ELISA, tube, and microagglutination, but significant antibodies may not appear until 10 to 14 days after the onset of the illness [46]. A positive dFA test on a culture can confirm the diagnosis.

It should be reinforced that significant personal safety precautions be taken when handling tissues or other samples possibly containing F. tularensis, as it is among the top 10 most common causes of laboratory-associated infections in the United States [54].

All forms of tularemia may be treated with streptomycin or gentamicin [46,49,50]. Gentamicin may be more readily available and easier to administer [49]. Also, because streptomycin has been associated with ototoxicity in fetuses, gentamicin is the drug of choice for pregnant women [55]. Doxycycline or ciprofloxacin are also acceptable alternatives [46].

When using aminoglycosides parenterally, the dosage must be calibrated to the patient's renal function (as estimated by the creatinine clearance), taking into account the expected reduction in renal function associated with aging. For adults, the starting dosage of streptomycin is 1–2 g administered intramuscularly (IM) every 12 hours for 7 to 14 days [55]. In very sick patients, streptomycin may be given initially at 15 mg/kg IM every 12 hours, then adjusted downward once there is clinical improvement. This is also the common pediatric dose [55]. The usual adult starting dose for gentamicin is 3–5 mg/kg/day IV or IM once a day (or in three divided doses), to achieve a peak serum level of at least 5 mcg/ml and a trough level <2 mg/kg. This is continued for 7 to 14 days [55].

Doxycycline is a good alternative for patients who are not seriously ill; the dosage is 100 mg IV or orally twice daily at 12-hour intervals for 14 to 21 days; however, relapses are reported to occur more often than with aminoglycoside therapy. Unfortunately, fully virulent streptomycin-resistant organisms have been described. In these cases, ciprofloxacin may be used at a dose of 400 mg IV twice a day (may switch to 500 mg orally twice a day when indicated), although ciprofloxacin use for tularemia treatment is not FDA approved [55].

As with all tickborne diseases, prevention begins with wearing appropriate clothing while in areas where ticks may be present. Also, contact with animals that might harbor the disease should be avoided. If working with domestic animals, be aware of tick infestations and wear protective clothing if contact with possibly infected animals is necessary [49]. The use of tick repellents, such as DEET or the newer plant-derived agents, applied to the clothing or lightly on the skin can be helpful. Wearing light-colored clothing so that ticks can be spotted more easily and tucking pant legs into socks is also recommended. Ticks should be removed as soon as possible after being discovered on the body. Ulcers or wounds in patients with tularemia should be covered and contact isolation maintained as F. tularensis can be shed from such lesions for one month or longer. No licensed vaccine is available for protection against tularemia; however, a live vaccine strain (LVS) may be given to at-risk laboratory personnel as an investigational new drug (IND) [56]. This vaccine is not commonly available in the United States [57]. In lieu of vaccination, antibiotic prophylaxis with 14 days of oral doxycycline or ciprofloxacin is recommended after high-risk exposure (e.g., laboratory accident) [50]. An attenuated vaccine was used in the former Soviet Union to immunize tens of millions of people and was subsequently sold to the U.S. military in 1956. Testing of the vaccine in military personnel proved it to be safe and reasonably effective; however, the scarification technique (similar to smallpox inoculation) used to administer the vaccine is inconvenient and highly variable.

The classical presentation of RMSF includes the sudden onset of headache, fever, chills, and an erythremic exanthem that appears within the first few days after the symptoms. The lesions are first present on the palms, soles, wrists, forearms, and ankles. The rash then appears on the buttocks, axilla, trunk, face, and neck. The lesions are initially pink and macular and blanch with pressure but later become maculopapular and petechial [58]. Occasionally, the lesions coalesce and become regions of ecchymosis and ulceration.

Symptoms usually appear within 2 to 14 days after the tick bite and can also include malaise, myalgia, nausea, and vomiting [58]. In rare cases, severe respiratory distress, circulatory failure, and neurologic complications may occur; this is especially true for patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.

The tick bite is remembered by 50% to 70% of patients who develop a tickborne disease [48]. As with the other tick-disseminated zoonoses, this is a helpful clue in establishing a diagnosis. Other information, such as exposure to high grass and tick-infested areas, contact with dogs, similar illnesses in family members or pets, or history of recent travel to areas of high incidence also can help establish a diagnosis [58]. If a rash is present, a skin biopsy and PCR or immunohistochemical staining for Rickettsia can be used. These tests have good sensitivity (70%) when applied to tissue specimens collected during the acute phase of illness and before antibiotic treatment has been started [58].

IFA with R. rickettsii antigen is the gold-standard serologic test for diagnosis of RMSF. The test is performed on two paired serum samples [60]. The first sample should preferably be taken in the first week of symptoms; the second sample should be taken two to four weeks later. In most cases, the first IgG titer is low or negative, and the second typically shows a fourfold increase in IgG antibody levels. IgM antibodies usually rise at the same time as IgG (i.e., near the end of the first week of illness), but they are less specific than IgG antibodies and more likely to result in a false positive [60]. Both IgM and IgG levels can remain elevated for months or longer after RMSF has resolved, and they can be detected in up to 10% of currently healthy people who were previously exposed to R. rickettsii or a similar organism. For these reasons, clinicians requesting IgM serologic titers should also request a concurrent IgG titer [58].

The treatment of RMSF should begin immediately when the disease is suspected and not be delayed until a firm diagnosis is made during the convalescent period. The recommended first-line treatment is doxycycline. The recommended dosage for adults is 100 mg every 12 hours. The recommended dosage for children who weigh less than 45 kg is 2.2 mg/kg body weight, twice daily [58]. Treatment is most effective at preventing death if doxycycline is started in the first five days of symptoms. If the patient is treated within the first five days of infection, fever generally subsides within 24 to 72 hours. The minimum duration of therapy is five to seven days, though doxycycline should be continued until the patient has been afebrile for at least three days. Severely ill patients may require longer periods of treatment before fever resolves [58].

Doxycycline to treat suspected RMSF in children is standard practice recommended by both the CDC and the American Academy of Pediatrics Committee on Infectious Diseases. For patients with life-threatening allergies to doxycycline and in some pregnant patients for whom the clinical course of RMSF appears mild, chloramphenicol may be considered as an alternative antibiotic. Oral formulations of chloramphenicol are not available in the United States, and use of this drug carries the potential for other adverse risks (e.g., aplastic anemia, grey baby syndrome, increased fatality risk) [55,58]. The standard treatment duration is 7 to 14 days [58]. The use of fluoroquinolones is not recommended at this time because their benefit has not been documented [48,59,60]. The preventive measures are the same as for the other tickborne diseases.

The clinical presentation of ehrlichiosis is very similar to that of RMSF, though the incidence of rash is less common. After an incubation period of one to two weeks, a patient with ehrlichiosis will typically present with acute onset of fever and one or more of the following symptoms or signs [31]:

Nausea, vomiting, and diarrhea also occur in some patients. A non-pruritic skin rash may also develop (in 60% of children, but less than 30% of adults), with appearance ranging from maculopapular to petechial [31]. In some patients, the rash may resemble that often seen with RMSF, making careful differential diagnosis vital.

Diagnosis can be difficult, particularly in the early stages of illness; early recognition and treatment based on clinical suspicion are important to prevent severe illness. Diagnosis is generally made based on clinical presentation and clinical evidence and confirmed by IFA, PCR, or isolation of E. chaffeensis in cell culture [63]. IFA using E. chaffeensis antigen, performed on paired serum samples, is the gold-standard serologic diagnostic test [63]. Any tests completed in the first week should be repeated after two to four weeks, as antibodies may not be present in sufficient quantities to be detected in the first week.

The CDC recommends that healthcare providers consider Heartland virus testing in patients who develop fever, leukopenia, and thrombocytopenia who have tested negative for Ehrlichia. Heartland virus was first isolated in Northwestern Missouri in 2009; since then, more than 50 cases of Heartland virus disease have been reported from states in the Midwestern and Southern United States [64]. The virus likely is transmitted through the Lone Star tick or other arthropods [65].

Doxycycline is the first-line treatment for adults and children of all ages and should be initiated immediately if ehrlichiosis is suspected [60,63]. The recommended regimen is 100 mg twice daily for adults or 2.2 mg/kg twice daily for children weighing less than 45.4 kg [60,63]. For patients with severe diseases or who are hospitalized, intravenous administration is preferred. Treatment should continue for at least three days after the fever subsides and until evidence of clinical improvement, usually at least five to seven days [60,63]. Prevention should focus on measures established for all tickborne diseases.

Many cases of babesiosis remain subclinical. In fact, some young patients may be asymptomatic carriers for years. Those individuals who become ill may experience influenza-like symptoms, with fever, headache, malaise, myalgia, and hemolytic anemia and hemoglobinuria of varying severity. These symptoms usually occur within one week; jaundice and renal failure may follow [48,66]. Risk factors for severe disease include asplenia, advanced age, and immunodeficiency states. As noted, the clinical presentation may resemble malaria. The disease can be fatal in patients who have a prior history of splenectomy [66]. Animals other than humans with babesiosis have a very similar course.

Diagnosis of human babesiosis requires a high index of suspicion because the clinical manifestations are nonspecific. Examination of a blood smear from a suspected individual with infection will reveal the characteristic red blood cell parasite inclusions that resemble a Maltese cross. Fluorescent antibody serology and PCR amplification are available for diagnosis when the evaluation of the smear is not conclusive [66].

All cases of active babesiosis require treatment with a combination of either atovaquone plus azithromycin or clindamycin plus quinine (for severely ill patients) [66]. The suggested doses for adults include 750 mg of atovaquone two times per day for 7 to 10 days plus an initial oral dose of 500–1,000 mg azithromycin (decreasing to 250–1,000 mg/day as appropriate). An alternative is clindamycin 600 mg orally three times per day or 300–600 mg IV four times per day plus quinine 650 mg orally three times per day [44,48,68].

In severely ill patients with high titers of parasitemia (greater than 10%), significant hemolysis, or renal, hepatic, or pulmonary compromise, a partial or complete red blood cell exchange transfusion may be lifesaving. Patients in hemolytic crisis should be treated for shock, with particular consideration for maintaining renal function to counteract the potential damage from hemoglobinuria. The medical regimen is aimed at preventing anemia from becoming severe [48,59].

Individuals who have previously undergone splenectomy should exercise extreme caution in Ixodes tick territory. A thorough tick check should be done after being in the woods. Insect repellent will provide deterrent but should not be relied upon for complete protection against any arthropod vector. Rodent control measures can help reduce the reservoir numbers around the home and yard [66].

Most (70% to 80%) human West Nile virus infections are subclinical and unapparent. Approximately 20% of those who contract the virus experience a mild febrile illness called West Nile fever [44,77]. Only about 1 out of 150, or less than 1%, of those infected will develop severe neurologic effects [44]. Among patients with neuroinvasive disease, the case fatality rate is approximately 11% [70]. Although the full spectrum of West Nile fever cases in the United States has not been determined, there are degrees of clinical involvement that can be noted [77,78].

The mild infection of West Nile fever appears after an incubation period of about 2 to 14 days and lasts for 2 to 6 days [44]. It is described as a febrile illness of sudden onset accompanied by malaise, anorexia, nausea, vomiting, headache, and myalgia. Some patients complain of eye pain and upper respiratory symptoms, and there may be a rash or lymphadenopathy [44]. Interestingly, the macular, papular, or morbilliform erythematous rash and lymphadenopathy seen in earlier outbreaks of the disease were not common in the more recent cases [69].

More severe infections have occurred in older patients and those with coexisting morbidities. The rate of severe neurologic disease was 10 times higher for patients 50 to 59 years of age and 43 times higher for those older than 80 years of age. This indicates that advanced age is the most significant factor involved in the development of severe disease [77]. In recent outbreaks, encephalitis was more common than meningitis. Hospitalized patients demonstrated significant fever, weakness, gastrointestinal symptoms, and cognitive changes. Several experienced muscle weakness and a flaccid paralysis with the more common neurologic findings being ataxia and extrapyramidal signs, myelitis, optic neuritis, seizures, polyradiculitis, and cranial nerve abnormalities. The constellation of findings is similar to other viral encephalitides and cannot be distinguished from them clinically [44].

The clinical signs of West Nile meningitis can include nuchal rigidity, Kernig or Brudzinski sign, and photophobia or phonophobia. A fever of 38 degrees C or more, or hypothermia of 35 degrees C or less, help to make the diagnosis. West Nile encephalitis can present with lethargy, an altered level of consciousness, or a personality change lasting more than 24 hours. There may also be focal neurologic deficits, seizures, and all of the usual findings seen with a viral encephalopathy [69,78].

The acute flaccid paralysis seen with West Nile virus infections usually presents as a limb weakness that progresses markedly over a 48-hour period. There is an absence of pain, but paresthesia, areflexia or hyporeflexia, and asymmetry are commonly seen. About one-half of the patients hospitalized with severe disease in the United States experience a significant degree of weakness, and approximately 10% of the New York patients had acute flaccid paralysis, including several patients who developed a paralysis that resembled Guillain-Barré syndrome without the usual nerve conduction findings [79].

There is still no firm data regarding the long-term effects of West Nile virus infections. In the New York outbreak in 2000, over one-half of those hospitalized had not returned to their functional level by discharge, and only one-third were fully ambulatory. The most persistent long-term symptoms included fatigue, memory loss, difficulty walking, weakness, and depression [69,77,78,79].

A high index of suspicion based on symptoms, time of year, history, and the presence of other known cases is paramount in diagnosing West Nile fever. Other arboviral diseases, such as St. Louis encephalitis, Kunjin virus, or other diseases caused by flaviviruses can have a similar initial presentation [44,80]. Fortunately, there is a specific neutralizing antibody to West Nile virus that can be used in serologic tests to help make the diagnosis. A fourfold rise in titer between acute and convalescent samples, determined by plaque-reduction neutralization assay, is confirmatory. A useful serologic test on serum or CSF is the assay for IgM using the antibody-capture ELISA procedure [44,80]. The finding of IgM in the CSF is a very good indication of meningoencephalitis if found within eight days of the onset of symptoms [44,69,81]. Some IFA tests have also been suggested as being helpful in the diagnosis [80].

Because the IgM and IgG ELISA tests can cross-react between flaviviruses (e.g., dengue, yellow fever), they should be viewed as screening tests only. For a case to be considered confirmed, serum samples that are antibody-positive on initial screening should be evaluated by a more specific test. The plaque reduction neutralization test (PRNT) is currently recommended for differentiating between flavivirus infections [80,81]. Additionally, in patients who report recent travel, specimens submitted for West Nile virus also should be tested by ELISA and PRNT against other arboviruses known to be active or present in the area or region where the patient traveled [80].

Peripheral blood samples are usually not helpful because the leukocyte count is often normal, although it can be elevated in some cases [81]. There can be a lymphocytopenia or even anemia. The CSF will frequently have an increase in cell count, with a predominance of lymphocytes and increased protein. CSF glucose is usually normal [81].

Imaging studies may be helpful after the development of meningoencephalitis to exclude other etiologies [81]. Computed tomography (CT) scans usually do not show evidence of acute disease, but about one-third of the magnetic resonance imaging (MRI) studies revealed changes in the leptomeninges or periventricular areas. MRI studies have also shown lesions in the basal ganglia and thalamus [69].

Culture of the organism is difficult, but an unambiguous diagnosis of West Nile fever can be made by virus isolation in cell culture, or in suckling mice by IFA analysis. In fatal encephalitis cases, the West Nile virus can be readily detected by immunohistochemistry or molecular amplification methods. Brain tissues at autopsy can be stained to show the viral antigens as well as the neuronal necrosis and microglial infiltrates caused by the disease.

The treatment of West Nile virus infections is supportive, with hospitalization of any patient who appears to have meningitis or encephalitis. Intravenous fluids and respiratory assistance are often required, and the prevention of secondary infections should be considered. Patients with severe neurologic findings will need a great deal of supportive care [82].

Interferon alpha-2b, IgG, and ribavirin in high doses have shown some activity against the virus in vitro, but there has been no confirming evidence of their usefulness in patients [82]. Other possible medications being tested are steroids, antiseizure drugs, and antiosmotic agents [77,79,81].

The most prudent means of protection against West Nile virus is to avoid mosquito bites by wearing long-sleeved shirts and pants and being aware of the usual biting times of early morning and evening. This is often not practical, so using the proper insect repellent is the next best means of protection [82]. The CDC recommends that consumers use repellent products that have been registered by the Environmental Protection Agency (EPA). These products include DEET, with a concentration of 20% to 30%, picaridin (KBR 3023), oil of lemon eucalyptus or para-menthane-3,8-diol (PMD), and IR3535 applied to the clothing and skin [18,44]. Compounds containing permethrin may also be used and are highly effective in repelling and killing ticks, mosquitoes, and other arthropods but should only be applied to clothing, netting, and gear and not to the skin [18,44]. Permethrin retains effectiveness on clothing even after laundering. Community-level mosquito control programs to reduce vector densities and screening of blood and organ donors also are useful preventive measures [82].

A vaccine for humans is not available at this time; however, the National Institutes of Health sponsored a trial of an inactivated vaccine developed by scientists at the Oregon National Primate Research Center in Portland [83]. The phase I trial including 50 adults was completed December 2016, and as of April 2023, no results have been published [84]. In mice, the vaccine protected against a lethal dose of West Nile virus, successfully eliciting neutralizing antibody responses and CD8+ T cells, which attack infected cells [83].

In epidemic settings, the majority of primary ZIKV infections are asymptomatic, and those who do become ill usually experience a self-limited, mild febrile illness with rash, conjunctivitis, myalgia, and arthralgia lasting three to six days. The incubation period for ZIKV is not well defined; it is considered to be similar to that of other mosquito-borne flaviviruses—usually less than one week and in the range of 3 to 10 days.

During the period from September 2015 through February 2016, 72 of 88 women enrolled in a study tested positive for acute ZIKV infection by RT-PCR on blood, urine, or both. All women had rash, as this was an inclusion criterion; the prevailing pattern was a descending macular or maculopapular exanthem accompanied by pruritus in 94% of patients. Arthralgia was reported in 65% of ZIKV-positive women, conjunctival injection was seen in 58%, and lymphadenopathy (generalized or regional) was present in 41%. Fever was documented in only one-third of patients and, when present, was low-grade and of short duration. Nausea and vomiting were reported in 21%, and respiratory findings were evident in 7% [95].

From these observations there emerges a distinctive, though nonspecific, clinical ZIKV syndrome: an acute onset descending maculopapular rash (often with pruritus), conjunctival injection, arthralgia, myalgia, and transient low-grade fever. Lymphadenopathy may be present, but respiratory symptoms and signs are conspicuously uncommon. ZIKV disease should be considered in patients with any combination of these symptoms who have traveled to areas with ongoing transmission in the two weeks preceding onset of illness. Rare manifestations of acute ZIKV infection, based on isolated case reports, include meningoencephalitis, myelitis, thrombocytopenic purpura, and ocular complications [94,96,97].

Because dengue and chikungunya viruses have the same vector of transmission and share a similar geographic distribution and clinical profile with ZIKV, patients with suspected ZIKV disease should be evaluated and managed for these possibilities as well. Other considerations in the differential diagnosis include malaria, rubella, measles, parvovirus, adenovirus, enterovirus, leptospirosis, rickettsiosis, and group A streptococcal infections [98].

The possibility of ZIKV disease should be considered in the patient with a compatible clinical syndrome (e.g., febrile rash illness with arthralgia and conjunctivitis) and epidemiologic risk factors, such as residence in or travel to an area of active ZIKV transmission within the previous two weeks, or sexual contact with a person known or suspected of recent ZIKV infection. Laboratory confirmation relies on molecular detection of the viral genome (via RT-PCR) in blood or body fluids and serologic assay for acute-phase ZIKV-specific IgM antibody.

The FDA has issued an emergency use authorization for a number of diagnostic tools for ZIKV, including the Triplex Real-Time RT-PCR assay and the Zika MAC-ELISA for anti-ZIKV IgM [99,100]. These have been distributed to qualified laboratories that are certified to perform high-complexity tests in the United States. Clinicians should contact local and state health departments to facilitate diagnostic testing. The CDC provides updated guidance for the selection and timing of ZIKV diagnostic testing at https://www.cdc.gov/zika/hc-providers/testing-for-zika-virus.html.

There is no effective antiviral therapy for ZIKV infection; treatment is supportive and directed toward relief of symptoms. When the diagnosis is uncertain and dengue, or co-infection with dengue, is a possibility, the patient should be managed expectantly for each. In consideration of dengue, aspirin and NSAIDs should be avoided and the patient should be monitored for signs of progression to hemorrhagic fever or shock [101]. In managing ZIKV disease, patient education and secondary prevention are important, especially in regard to sexual transmission and risk reduction in pregnancy. All pregnant women with molecular or serologic evidence of recent ZIKV infection should be evaluated and managed (monitored) for adverse pregnancy outcomes.

Pregnant women who report symptoms or signs consistent with acute ZIKV disease and who have traveled to or who live in areas with active ZIKV transmission or who have had potential sexual exposure (i.e., sexual contact without barrier/condom method with a person who lives in or has traveled to an area with ZIKV) should be tested for ZIKV infection. Updated recommendations include concurrent ZIKV nucleic acid test (NAT) serum and urine and ZIKV IgM serologic testing as soon as possible through 12 weeks after symptom onset. A positive ZIKV NAT result confirms the diagnosis of recent maternal ZIKV infection. If IgM result is negative, further testing may be warranted [102]. Patients with a negative ZIKV NAT and negative or nonnegative IgM test result should receive PRNT. A ZIKV PRNT result <10 means there is no evidence of ZIKV infection. Type and duration of ZIKV exposure before and during current pregnancy might limit interpretation of ZIKV IgM results. ZIKV testing is not routinely recommended for pregnant women with previous diagnosis of laboratory-confirmed ZIKV infection by either NAT or serology (positive/equivocal ZIKV or dengue virus IgM and ZIKV PRNT ≥10 and dengue virus PRNT <10 results). Preliminary data suggest that NAT might remain positive for several weeks after symptom onset. ZIKV IgM antibodies are most likely to be detected within 12 weeks after infection; however, IgM antibodies might be detected for months after infection, limiting the ability to determine whether infection occurred before or during the current pregnancy. Dengue virus IgM antibody testing is recommended for symptomatic pregnant women [102].

The first signs and symptoms of dengue infection typically develop within 4 to 7 days of the infectious mosquito bite and last for 3 to 10 days [107]. The characteristic presentation of classic dengue fever includes a high fever (up to 105 degrees F), severe headache, retro-orbital pain, severe joint and muscle pain, nausea and vomiting, rash, hemorrhagic manifestation, and/or leukopenia [68,107]. The characteristic rash is macular or maculopapular and generalized and usually develops as the fever subsides. About one in four people infected with dengue will become symptomatic. For those who develop dengue illness, symptoms can be mild or severe. Severe dengue can be life-threatening within a few hours and often requires hospital care. About 1 in 20 people with dengue illness will develop severe dengue [68]. Individuals who are infected for a second time are at greater risk of severe disease [103,104].

Early clinical findings are nonspecific but require a high index of suspicion, because recognizing early signs of shock and promptly initiating intensive supportive therapy can reduce risk of death among patients with severe dengue to <0.5% [104]. The most clinically relevant sign of dengue hemorrhagic fever is vascular leakage, with all of the following criteria necessary for diagnosis: fever or recent history of fever, any hemorrhagic manifestation, thrombocytopenia (i.e., platelet count <100,000/mm3), and evidence of increased vascular permeability [108]. In a few patients, most commonly children experiencing their second dengue infection, dengue shock syndrome will develop [107,108]. Dengue shock syndrome is characterized by the presence of all of the criteria for dengue hemorrhagic fever with the addition of hypotension, narrow pulse pressure (≤20 mm Hg), or shock [108].

Clinicians should obtain a complete personal and travel history for all patients suspected of having dengue fever or hemorrhagic fever and who live in or recently traveled to a disease-endemic area in the two weeks before symptom onset. All patients with clinically suspected dengue should receive appropriate management to monitor for shock and reduce the risk of complications resulting from increased vascular permeability and plasma leakage and organ damage without waiting for diagnostic test results to be received [104]. For patients with suspected dengue, nucleic acid amplification tests (NAATs) are the preferred method of laboratory diagnosis. NAATs should be performed on serum specimens collected seven days or less after symptom onset. Cases can be laboratory confirmed with the use of RT-PCR or dengue nonstructural protein-1 (NS1) antigen by immunoassay [104]. IgM antibody testing can identify additional infections and is an important diagnostic tool. Interpreting results is complicated by cross-reactivity with other flaviviruses (e.g., ZIKV, West Nile), and determining the specific timing of infection can be difficult. PRNTs can resolve false-positive IgM antibody results caused by non-specific reactivity, and can help identify the infecting virus, in some cases. However, in areas with high prevalence of dengue and ZIKV neutralizing antibodies, PRNT may not confirm a significant proportion of IgM-positive results. PRNT testing is available through several state health departments and the CDC [104].

There are no approved treatments available for dengue, although a vaccine was approved for endemic areas (i.e., American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands) in 2019 [68; 103; 109; 110]. However, the vaccine manufacturer has announced that people who receive the vaccine and have not been previously infected with a dengue virus may be at risk of developing more severe manifestations of dengue. The Philippines suspended its dengue vaccine program, and other countries have specified that only people who have been infected with a dengue virus should receive the vaccine. Three other dengue vaccines are currently in phase 3 clinical trials [111]. However, the vaccine manufacturer has announced that people who receive the vaccine and have not been previously infected with a dengue virus may be at risk of developing more severe manifestations of dengue. The Philippines suspended its dengue vaccine program, and other countries have specified that only people who have been infected with a dengue virus should receive the vaccine. Three other dengue vaccines are currently in phase 3 clinical trials [111]. Supportive care, in the form of bed rest and adequate fluids to maintain hydration, is recommended [103,104]. In more severe cases, maintaining the patient's circulatory volume will be key. Antipyretics may be necessary to reduce fever, and the CDC recommends the use of acetaminophen [104]. Narcotics may be used to treat severe pain. Aspirin (and other salicylates) and NSAIDs should be avoided due to the risk of hemorrhage and, in children, Reye syndrome [104].

As with many zoonotic diseases, the best treatment for dengue fever is prevention. This includes vaccination (if indicated) and all measures necessary to prevent being bitten by an Aedes mosquito, such as bed nets, use of DEET-containing insect repellants, and wearing long-sleeved shirts and long pants [68,103,107]. Travelers should be advised to choose accommodations with air conditioning and window and door screens [68]. Because mosquitoes breed in standing water, eliminating these habitats (e.g., earthenware jars, metal drums, concrete cisterns used for domestic water storage, discarded plastic food containers, used automobile tires) in urban or residential areas has become a priority [68].

The clinical presentation often begins with a feeling of fatigue, malaise, and possible paresthesias near the site of inoculation. Most patients have a low-grade fever, but some remain afebrile in the early stages prior to developing a fever over the next few days. Nausea and vomiting can be present as well as lethargy and anorexia. The signs and symptoms of a central nervous system disease and encephalitis usually follow rapidly. Diplopia or other visual defects, unsteady gait, cranial nerve palsies, cognitive changes, photophobia, phonophobia, restlessness, and limb weakness are common findings. The neurologic condition of the patient rapidly declines, with increasing confusion, disorientation, tremors, twitching or myoclonic muscle movements, seizures, and increased pain sensations. Some patients develop laryngospasm when attempting to drink. Many patients eventually have pulmonary problems, leading to poor ventilation and respiratory failure. Autonomic system collapse and coma ensue, with death following regardless of supportive measures [112,119].

There are descriptions of two possible forms of disease presentation. One is called the paralytic form, whereby an ascending paralysis similar to Guillain-Barré syndrome predominates. The other, which is more common, is the encephalitic or "furious" form described above [118,119,121].

It is imperative to make the diagnosis of a rabies-prone exposure during the period prior to the development of symptoms. A delay in diagnosis and treatment can mean almost certain death for the patient [119]. Therefore, a history of suspicious animal bite or contact with a victim of the disease, especially the saliva of a victim, must lead to the performance of diagnostic tests.

Several tests are necessary to diagnose rabies in humans; no single test is sufficient [122]. Fortunately, there are several very good diagnostic procedures that can be performed fairly quickly on serum, saliva, CSF, or skin biopsies taken from the nuchal region of the neck. Antibody analysis can be performed on serum or CSF, and skin biopsy samples can be examined for rabies antigen in the cutaneous nerves at the base of the hair follicles [122]. Other laboratory tests include electron microscopy, virus culture, and immunohistochemistry. Laboratory analysis also allows for the determination of the type of animal involved and, in many cases, the locality from which the infection originated. There are many public health and other designated facilities available to perform these procedures. Neuroimaging procedures, including CT scans and MRIs, are usually normal initially but show signs of cerebral edema and other features of encephalitis as the disease progresses.

If possible, the suspected animal should be tested for rabies antigen. Tests on animals may require samples of their brain tissue from at least two locations in the brain, preferably the brain stem and cerebellum [122]. Because of its high sensitivity and specificity, the direct fluorescent antibody (DFA) test is considered the gold-standard diagnostic method for rabies determination in animals in the United States [122]. The presence of Negri bodies, characteristic intracytoplasmic inclusion nodules within neurons, is confirmatory evidence of the disease. The rapid determination of whether an animal is rabid can save a potential victim from psychologic trauma and an expensive treatment regimen [122].

Any wound from an animal should be intensively cleaned with soap and water. Antiviral compounds (e.g., povidone iodine) should be used if available; thorough wound cleansing has been shown to markedly decrease the risk of bacterial infection[123]. As discussed, postexposure treatment can prevent the disease if given early and prior to the onset of symptoms.

In non-immunized individuals, treatment consists of the use of immune globulins and vaccine[123]. A human rabies immunoglobulin (HRIG) is available in the United States and most other developed countries. Historically, equine rabies immunoglobulin (ERIG) was used and regimens included a series of painful and sometimes dangerous injections. The currently available ERIG is highly purified and is considered safe by the WHO[124]. According to the WHO, there are no scientific grounds for performing a skin sensitivity test prior to administration of ERIG. However, the treating physician should be prepared to manage anaphylaxis, which, while rare, can occur at any stage of ERIG administration [124]. The safer HRIG is expensive, but requires only an intragluteal injection, usually with a dose of 20 IU/kg[124]. The WHO advises that HRIG, like ERIG, also be administered in the vicinity of the bite wound[124].

In addition, rabies vaccine must also be started. According to the CDC Advisory Committee on Immunization Practices (ACIP), the vaccine should be injected IM at a site distant from the HRIG injection site, possibly the deltoid. The ACIP recommends giving four doses of human diploid cell vaccine or purified chick embryo cell vaccine, 1.0 mL (at days 0, 3, 7, and 14) for immunocompetent individuals and the usual five-dose regimen for immunocompromised individuals[123,125].

When symptoms appear, diligent supportive measures are required, including induced coma for patients with involuntary muscle movements and severe pain[119,126]. Additional treatment regimens have included IV ribavirin and other antiviral agents under investigative drug protocols; however, there are very few reports of recovery[119,127]. The experimental Milwaukee protocol is associated with significantly longer survival than conventional treatments for symptomatic rabies, but has been tested on an exceedingly small number of patients and "excellent and adaptive medical intensive care and careful avoidance of mistakes and complications of intensive care may prove to be essential to positive outcomes" with this treatment regimen[126]. The probability of treatment failure, even with this protocol, is extremely high[119].

Individuals who had been previously adequately vaccinated for rabies are treated differently. The ACIP suggests that these patients receive rabies vaccine IM immediately or as soon as practical with a second injection three days later[123,125]. The recommended site is the deltoid muscle. They do not advise giving HRIG to previously immunized patients[123,125].

In the United States, every state has some type of requirement that household dogs and cats be vaccinated for rabies. Although the vaccine is commercially available, almost all vaccinations of domestic animals are performed by veterinarians. Some states or municipalities also impose quarantines of varying periods to help reduce the possible spread of rabies[128].

The CDC and the WHO suggest that individuals who might have a higher risk of coming in contact with a rabid animal be vaccinated. This pre-exposure prophylaxis includes occupations such as veterinarians, laboratory workers, animal control officers, animal handlers, and those who travel to parts of the world where rabies is common and access to medical care is limited. In May 2022, the ACIP updated rabies vaccine recommendations for persons at high risk (Table 5) [129]:

The recommended vaccine is a cell culture vaccine (CCV)[130]. It is also recommended that the production and use of nerve-cell vaccines cease.

The WHO suggests that an intradermal administration of CCV 0.1 mL be used in three doses at day 0, 7, and then between 21 and 28 days or, alternately, intramuscular administration of 0.5 to 1 mL, depending on the type of vaccine, on the same three-day schedule[130]. However, rabies vaccine adsorbed is no longer available in the United States and therefore intradermal administration is no longer recommended[120]. Intramuscular vaccinations should be administered in the deltoid area of the arm for adults and the anterolateral area of the thigh for children younger than 2 years of age; the vaccine should not be administered in the gluteal area. Serologic analyses should be performed every six months for those at high risk and every two years for those at lower risk; a booster injection is not recommended unless rabies-virus neutralizing antibody titers fall below 0.5 IU/mL[130]. Booster injections are not recommended for individuals travelling to high-risk areas if they have previously completed pre-exposure or post-exposure prophylaxis.

The hemagglutinin antigens that historically have caused human influenza are H1, H2, and H3. Although all known hemagglutinin subtypes occur in birds, H5, H7, and H9 have been implicated more in recent outbreaks. Various combinations with the neuraminidase antigens occur. All of these AI viruses are type A, as B and C do not infect birds. Some of the cases focused on in the past two decades have included the following [143,144]:

Fortunately, although in some of these outbreaks bird-to-human transmission did occur, human-to-human transmission has been extremely rare. Limited transmission possibly did occur between humans in the Netherlands, but no sustainable transmission occurred, so an epidemic or pandemic did not follow. There were 14 cases and 12 deaths (11 children) from H5N1 virus in Vietnam. The viruses isolated from those who expired in Vietnam were mostly resistant to amantadine and rimantadine. Studies are continuing as to the effectiveness of oseltamivir and zanamivir against H5N1 viruses. There is some evidence that H5N1 is sensitive to oseltamivir; however, some evidence of resistance to oseltamivir has been reported in highly pathogenic avian influenza H5N1 viruses isolated from human cases [141,144]. Most of the H5N1 outbreaks were controlled by veterinarian officials or spontaneously died out. However, H1N1 continues to fulminate in poultry in Egypt [145].

Most cases of AI in humans have resulted from contact with infected poultry or contaminated surfaces. It is also possible for the virus to become aerosolized and then land on exposed surfaces of the mouth, nose, or eyes. Aerosolized virus could also be inhaled directly into the lungs. Eating poultry products has not been associated with the development of AI. Influenza viruses are destroyed by adequate heat.

Some patients might become concerned about contaminated poultry products from other countries entering our food supply. Some countries will not permit poultry to be imported from countries in which there were confirmed human cases of AI, such as China's ban of U.S. chicken in 2015. However, the risk of AI spreading through the global chicken industry is low because most chickens on the international market are killed and frozen or chilled. All documented transmission to date has been from live birds [144,146].

Humans have no immunity to AI viruses, so illness tends to be severe and the fatality rate is high. Prevention is difficult because the viruses tend to be highly contagious. Because of the mobile nature of people and efficient, rapid transport, any virus can spread quickly around the world. The current manufacturing process of influenza vaccine requires several months. The elements are all in place for a pandemic.

In August 2007, a team of scientists at the National Institute of Allergy and Infectious Diseases reported that it had developed a way to generate vaccines and therapeutic antibodies that could target constantly mutating influenza viruses, such as H5N1. The team focused on mutations that enable H5N1 hemagglutinin protein to better recognize and enter human cells and those mutations that will elicit antibodies. This information will enable researchers to consider how to design potential vaccines that will protect people from future emerging AI virus mutants, possibly helping to contain a pandemic in its early stages [147].

In order to understand how influenza viruses mutate, researchers have been working to synthesize the hemagglutinin responsible for the 1918 influenza ("Spanish flu") pandemic. The success of this endeavor was reported in 2004, and scientists have since discovered how subtle alterations enabled the virus to move from birds to people [148].

The H5N2 avian influenza virus continues to be monitored around the world by scientists. It is highly virulent but has not been transmitted person-to-person yet [136,149]. In 2015, H5N2 avian influenza virus (along with H5N8 and H5N1) were found in more than 200 bird samples, indicating the likelihood that 40 million farm and backyard birds have been infected in 20 states [150].

As noted, humans have no immunity to avian influenza A viruses, so illness tends to be severe and the fatality rate is high. The symptom complex can range from the typical influenza findings of fever, headache, myalgia, sore throat, and cough to severe respiratory distress. Many humans develop conjunctivitis, which can be the initial complaint. This usually includes red, itching, and tearing eyes with associated photophobia and purulent discharge. The severe form progresses to pneumonia, which can be fulminant and followed by multiorgan failure and death. Although the very young and very old are most at risk for the viral pneumonia, fatalities have occurred among previously healthy adults [151].

Laboratory testing is required to diagnose avian viral disease; it cannot be determined by clinical signs and symptoms alone [151]. Diagnosis is initially based on the history from a patient with the symptoms of influenza who has had contact with birds, poultry, or an endemic area. A complaint of eye irritation, which on examination appears to be conjunctivitis, is another clue to the presence of the disease. The available laboratory tests include viral culture and reverse transcriptase PCR (RT-PCR). The CDC recommends testing by RT-PCR [151]. These can be performed on samples of eye exudate, tears, or throat swabs. Analyses are most useful if obtained within four days of the onset of symptoms, and eye swabs are more likely to be positive than throat culture [152].

As in other viral diseases, supportive treatment is a mainstay in avian viral infections. Over the past few years, several regimens have been attempted in the treatment of avian viral disease. The antiviral medications amantadine, rimantadine, oseltamivir, and zanamivir have been used in cases of human influenza in the United States. However, amantadine and rimantadine were shown to be ineffective against the H5N1 strain of avian influenza in humans during the outbreaks in Asia in 2004 and 2005 [153]. The CDC and the WHO recommend oseltamivir, peramivir, zanamivir, or baloxavir marboxil for treatment and prevention of human infection with avian influenza A viruses; however, as noted, some evidence of resistance to oseltamivir has been reported in viruses isolated from some human cases [68,151]. The suggested adult dose for the treatment of influenza is 75 mg twice per day, starting within two days of symptoms and continuing for five days. Results are best if the drug is started within two days after contact with an infected individual or fowl. For prophylaxis, the dose is also 75 mg twice a day, but taken for 10 days [55].

A major step to limiting disease and transmission among domesticated fowl is to destroy all diseased birds and their flock mates. Because the virus appears to be carried by people and machines, possibly on shoes and tires to surrounding areas, the recommendation is that all fowl in a 2-mile (3-kilometer) radius of the diseased flock be culled. Obviously, no shipping of live poultry from the infected areas should occur.

During the outbreaks of avian influenza in poultry in Asia during 2003–2004, people were not restricted from traveling to outbreak areas because of the limited transmission to humans. However, the following recommendations were sent to embassies and Americans living abroad [68,154]:

The CDC has also developed guidelines for airline personnel dealing with a suspected case of avian influenza on board an international flight originating in an area in which avian influenza has been reported [155]:

Influenza viruses are destroyed by adequate heat. Because the pathogen is found in poultry, all individuals should be reminded to cook poultry, including eggs, thoroughly. Chicken should be cooked until the internal temperature reaches 180 degrees F. All utensils and surfaces that have come in contact with raw poultry should be washed well with soap and water immediately following use. A separate cutting board should be used to cut raw poultry. In order to retard bacterial or viral replication, all poultry products should be defrosted in the refrigerator, not at room temperature.

Some patients might become concerned about contaminated poultry products from other countries entering our food supply. Some countries will not permit imported poultry from countries in which there were confirmed human cases of avian influenza. However, the risk of avian influenza spreading through the global chicken industry is low because most chickens on the international market are killed and frozen or well chilled. All documented transmission to date has been from live birds [146].

As with the development of all vaccines, the first step is to isolate the organism. In the case of AI, various research centers and companies around the world are working to make a vaccine. The first step is to isolate the virus (e.g., the H5N1 influenza A virus in 2004). Next, the virus is dismantled so the most virulent elements can be excluded. Then the virus is reassembled without those virulent elements, and attempts are made to produce it [146]. As noted, the virus has been isolated and the virulent elements have been identified to allow vaccine development to proceed. In 2006, a new recombinant H5N1 virus became available for distribution to companies interested in pandemic vaccine development [156]. In 2007, GlaxoSmithKline received a contract from the U.S. Department of Health and Human Services to manufacture 22.5 million doses of AI vaccine in addition to the 5 million doses ordered in 2006 [157]. Research to find novel media or methods (rather than using eggs) is ongoing [158].

In April 2007, the FDA approved the first human vaccine for the AI virus H5N1 [159]. This vaccine is intended for individuals 18 to 64 years of age who could be at an increased risk of exposure to the H5N1 influenza virus. The vaccine is not available commercially, but rather has been purchased by the federal government to be distributed if necessary [160]. The vaccine consists of two 90-mcg IM doses given 28 days apart. There is thimerosal, a preservative, in this vaccine [55,159]. Because this vaccine has been approved by the FDA and found to be safe and effective, it is no longer considered experimental. Therefore, it can be used during a pandemic without the time-consuming protocol and signed informed consent necessary for an experimental drug or vaccine [159]. Data from trials being conducted on ACAM-FLU-A show that the vaccine generates a robust antibody response against H5N1 avian influenza [161]. The WHO provides a summary of ongoing H5N1 vaccine development [162].

Like all flu viruses, 2009 H1N1 is mainly spread among people by coughing, sneezing, talking, and occasionally via fomites. It is not spread by food or by eating pork or pork products. There have been no cases acquired from influenza-contaminated drinking water. Chlorine treatment of drinking water has been shown to inactivate the highly pathogenic H5N1 virus, and H1N1 would be similarly affected. A documented case of influenza from any water exposure (drinking or recreational) has not occurred.

Pets, such as dogs, cats, and ferrets, can be infected with H1N1 from close contact with a sick human. All available information indicates that H1N1-infected dogs, cats, and ferrets do not transmit the illness to humans. So far, there is no H1N1 vaccine for animals. Most recover with supportive care [166].

When a swine influenza virus does become a source of widespread human illness, the transmission patterns change. Instead of being mainly limited to swine contact, the virus will spread by human-to-human contact. According to the CDC, available data indicate that the 2009 H1N1 virus is transmitted in ways similar to other influenza viruses, primarily large-particle respiratory droplet transmission [171]. Because humans have little to no immunity to influenza viruses of swine origin, transmission may be common.

H1N1 survives on surfaces, including kitchen counters, doorknobs, desktops, and other fomites, for two to eight hours. Individuals can pick up the virus when they touch contaminated objects and unconsciously then touch their eyes, mouth, or nose. Thus, it is vital for people to learn to keep their hands away from their mouths, eyes, and nose and to frequently wash their hands well with soap and water or use an alcohol-based hand sanitizer. An alcohol-based product, bleach solution, or hot, soapy water can be used to clean surfaces [172]. One positive result of the H1N1 pandemic, as indicated in a study conducted in Hong Kong, is that people are washing their hands more frequently and wearing face masks when having influenza-like illness or when in public areas [173].

A major transmission concern with 2009 H1N1 was regarding newborns whose mothers had the virus. The CDC and State Health Departments strongly recommended the 2009 H1N1 vaccine for this population because of demonstrated risks to both infants and pregnant women. However, many disregarded the recommendation. It was then decided that infant and mother should be separated until the mother had been on antivirals for at least 48 hours, was afebrile for 24 hours without antipyretics, and could control her cough and respiratory secretions. Before visiting the infant, the mother was instructed to clean her hands well with soap and water or an alcohol-based hand sanitizer, wear a face mask, and observe respiratory/cough etiquette. If her gown had been contaminated with byproducts of coughing or sneezing, she was instructed to change to a fresh gown. Following these guidelines, the mother was then permitted to hold, feed, and care for the infant [174].

Like seasonal influenza, vaccination is the most important preventive measure. Other common-sense preventive steps (e.g., appropriate cough cover, correct disposal of used tissues, adequate rest, good fluid intake, staying home when ill) should be practiced. No vaccine specifically targeted against variant viruses is available at this time. Immunization with seasonal influenza vaccine does not provide protection against infection with variant viruses. Persons who are at high risk for influenza complications should avoid exposure to swine and to ill persons with swine exposure [175].

The CDC identified five groups who were given first priority 2009 H1N1 vaccination [176]:

These patients were vaccinated as soon as the vaccine was available. As with seasonal influenza vaccine, it is also important to note that two doses of the vaccine are necessary for previously unvaccinated children younger than 9 years of age, as they typically have had limited exposure to influenza viruses and are not immunologically primed [176,177]. For the 2016–2017 flu season, the ACIP recommended that children 6 months through 8 years of age not previously immunized be given two doses at least four weeks apart [177]. At least one study has shown that a single injection is adequate when vaccinating pregnant women [177].

Similar to seasonal flu, H1N1 symptoms include chills, fever, myalgia, fatigue, headache, cough, sore throat, and rhinitis. But unlike seasonal flu, there may be vomiting and diarrhea in some people. Others may have respiratory symptoms without fever [175].

Unless it becomes a pandemic, swine influenza infection in humans generally goes undistinguished from typical human influenza as a result of the overlapping flu seasons and the relatively mild clinical presentation. Clinicians should obtain a nasopharyngeal swab or aspirate (or a combined nasal swab and throat swab) collected in the first four to five days of illness, when an individual is most likely to be shedding the virus [175]. A new test for 2009 H1N1 was authorized by the FDA in June 2010 to be used on upper or lower respiratory secretions. The CDC Influenza 2009 A (H1N1) pdm Real-Time RT-PCR panel (IVD) replaced the test authorized in April 2009 [178].

The CDC currently recommends antigen detection tests, (e.g., rapid influenza diagnostic tests [RIDTs], immunofluorescence assays), which may detect variant viruses (e.g., H1N1v) in respiratory specimens [175]. Some RIDTs may not detect these viruses, producing a false-negative result. (A false-negative result also can occur with other influenza viruses.) While some variant virus infections have tested positive by RIDTs, other confirmed variant virus infections have tested negative by RIDTs. There also are a variety of commercially available molecular assays, including RT-PCR assays, that can detect influenza viruses. All of the available assays are likely to detect influenza A virus infection and, in general, are more sensitive and specific than RIDTs. However, commercially available molecular assays cannot differentiate variant viruses from seasonal influenza A viruses, and the sensitivity and specificity of molecular assays to detect variant viruses are not known. Some medical center laboratories may use non-commercially available molecular assays for influenza ("home brews"); the sensitivity and specificity of home-brew molecular assays to detect variant viruses are not known [175].

Because variant virus infection cannot be distinguished by clinical features from seasonal influenza virus infection, or from infection with other respiratory viruses that can cause influenza-like illness, the key to suspecting variant virus infection in an ill patient is to elicit an epidemiologic link to recent swine exposure in the week prior to illness onset. Exposure can be defined as follows [175]:

For any ill person with an exposure as defined above, respiratory samples should be taken for testing [175].

While most swine influenza cases were sufficiently mild to resolve spontaneously, antiviral medications were used if treatment was indicated. The specifically recommended agents were determined based on clinical and epidemiologic assessment of the virus. For example, in the case of the 2009 H1N1 outbreak in North America, the virus's susceptibility profile indicated that the preferred antivirals would be oseltamivir or zanamivir (or peramivir in case of severe illness requiring hospitalization) [163,165].

During the 2009 H1N1 pandemic, the CDC recommended antiviral treatment for all persons with suspected or confirmed influenza requiring hospitalization [167]. For the 2022–2023 influenza season, antiviral treatment is recommended as soon as possible for any patient with suspected or confirmed influenza who is hospitalized; has severe, complicated, or progressive illness; or is at higher risk for influenza complications, including [179]:

Four antiviral medications are FDA-approved for treatment of influenza: oral oseltamivir, inhaled zanamivir, intravenous peramivir, and oral baloxavir marboxil (endonuclease inhibitor) (Table 6)[179]. Use of these agents is not contraindicated during pregnancy [55].

For hospitalized patients with suspected or confirmed influenza, initiation of antiviral treatment with oral or enterically-administered oseltamivir is recommended as soon as possible. For outpatients with complications or progressive disease and suspected or confirmed influenza (e.g., pneumonia, exacerbation of underlying chronic medical conditions), initiation of antiviral treatment with oral oseltamivir is recommended as soon as possible. For outpatients with suspected or confirmed uncomplicated influenza, oral oseltamivir, inhaled zanamivir, intravenous peramivir, or oral baloxavirmay be used for treatment, depending upon approved age groups and contraindications [179].

Laboratory testing has found the H1N1 influenza A virus susceptible to both oseltamivir and zanamivir, with a few exceptions. Those resistant to oseltamivir have been sensitive to zanamivir. Sporadic oseltamivir-resistant 2009 H1N1 virus infections have been identified, but the public health impact has been limited[181]. As of October 2012, no evidence existed of ongoing transmission of oseltamivir-resistant 2009 H1N1 virus strains worldwide[181].

The use of antiviral treatments in combination for influenza is of interest. One potential benefit of this treatment strategy is that the combination of drugs with different mechanisms of action may lower the selection of resistance due to treatment. In addition, combination therapy may become an important treatment option to improve patient outcomes in those with severe illness due to influenza or those that are immunocompromised. Clinical trials increasingly evaluate drug combinations in a range of patient cohorts. Combination treatment regimens should be carefully evaluated to determine whether they provide an added benefit relative to effectiveness of monotherapy and in a variety of patient cohorts, particularly, if there is a greater chance of an adverse outcome. Safe and effective treatment of influenza is important not only for seasonal influenza infection, but also in the event a pandemic strain was to emerge [182].

The incubation time from contact with the virus until the onset of symptoms is thought to be about one to eight weeks. Almost everyone who develops the disease will have fatigue, fever greater than 38.3 degrees C, and myalgia, usually in the large muscles of the back, thighs, and shoulders. There is usually hypotension, tachypnea, and tachycardia. About one-half of patients experience nausea and vomiting, headache, dizziness, and abdominal pain [184,187]. After 4 to 10 days, the late symptoms of HPS appear with the onset of coughing, shortness of breath, increasing pulmonary distress, and pulmonary edema [184]. HPS appears to resemble acute respiratory distress syndrome in patients with advanced disease. In some patients, renal impairment may also develop, but this is more common in illness caused by hantaviruses other than the Sin Nombre virus.

Chest x-ray shows bilateral interstitial edema, which becomes progressively worse and develops into alveolar edema as the patient deteriorates. Differentiation from acute respiratory distress syndrome can usually be made based on clinical findings; however, good laboratory tests are also available. Laboratory diagnosis can be made by the detection of hantavirus-specific IgM or rising titers of hantavirus-specific IgG. PCR analysis of clinical specimens is also useful. In addition, blood samples can be analyzed for hantavirus antigen by immunochemistry. Patients with HPS often have a left-shifted increase in neutrophils, which helps to differentiate the early symptoms from other viral infections [184,186,187].

No treatment has proven to be useful for HPS, with the exception of supportive care. Ribavirin, which has helped in some hantavirus infections in Europe, is not recommended for treatment of HPS [187,188]. In most cases, admission to an intensive care unit is necessary, and oxygen is required as the patient becomes hypoxic. Broad-spectrum antibiotics are suggested to help combat secondary bacterial infections. Analgesics and antipyretics provide comfort, but fluids should be carefully monitored due to possible capillary leakage [187,188]. Mechanical ventilation and cardiopulmonary support should be available in the event of a sudden onset of pulmonary failure.

As noted, even with treatment, about 33% of patients have died from the disease [184]. This makes prevention an important factor in decreasing the morbidity and mortality associated with HPS. Educating the public in the proper handling of rodents and their excrement is the primary method of prevention. Avoiding contact with rodents is an obvious rule, but this is not always possible. Using latex or other protective gloves is suggested if contact with a dead rodent or its excrement is necessary. Because aerosolizing of the excretory products is documented to cause the disease, it is advised to "wet down" dead rodents or any areas where rodents have been present before attempting to clean the region. An enclosed area should be left open to air out before entry, if possible [184].

Attempt to rodent-proof the home and outbuildings by sealing off the possible points of entry and removing foodstuffs from kitchen counters and tables, especially at night. Garbage cans and other refuse containers should have tight lids. Trapping rodents or using traps and baits to decrease their numbers has been shown to reduce the number of cases in a local area [184]. The virus is inactivated by alcohol and chlorine preparations, which can be used as disinfectants in indoor and outdoor areas. Complete drenching with a 10% bleach solution is recommended [184]. Sunlight can also kill the virus. The use of respirators is only suggested for workers in regions of high rodent population or where the disease is known to be present but is a sensible precaution when working in enclosed areas with limited ventilation [184].

Rodents infected with LCM virus show little sign of illness. Serologic testing of the rodents has not been very reliable, and the animals can shed virus for the duration of their lives without appearing to be ill [190]. In humans, LCM is characterized by a flu-like illness lasting only a few days. A few cases will relapse afterward, and these rare cases may develop meningeal inflammation signs, beginning with nuchal rigidity, headache, fever, malaise, and muscular pain. A limited number of cases progress to meningoencephalitis with paralysis and coma. Most will recover, although severe cases may have a protracted recovery time [190,191]. If a pregnant woman contracts the disease in the first or second trimester, there can be serious consequences for the fetus. Case fatalities are rare, except in immunocompromised patients. LCM can be isolated from the blood of febrile patients or from CSF in patients with meningitis; however, laboratory diagnosis in a patient suspected of having LCM is usually made by CSF PCR or by serologic studies (IgM and IgG antibody titers) on acute and convalescent serum.

Treatment of LCM is based on symptom management. Prevention of the disease involves care in cleaning and disinfecting cages and regions of wild mouse activity. Pregnant women should avoid handling possibly infected rodents. Wholesale and retail merchants should be aware of outbreaks and keep groups of rodents isolated from each other to prevent cross contamination [190].

It is difficult to document the disease agent when it is non-antigenic, as the body does not mount any immune response, making tests such as standard antibody titers useless. Diagnosis of vCJD therefore tends to be based on signs and symptoms with confirmation by examining brain tissue.

This makes the differentiation of vCJD from other progressive, neurodegenerative processes difficult, especially in older patients. The diagnosis is also hampered by the very long incubation period of vCJD, which can be many years between contact with the organism and the development of symptoms [203]. Usual symptoms can include progressive dementia, myoclonus, visual changes, cerebellar dysfunction, pyramidal or extrapyramidal signs, and akinetic mutism. Pain is experienced by about one-half of the patients [204].

When the more common causes are eliminated and a spongiform encephalopathy is suspected, there are several ways to distinguish between "classic" CJD and vCJD. The most obvious is age; classic CJD causes death at a mean age of 68 years following a rapid course with a duration of illness of only four to five months [192]. Variant CJD is a disease of young people, with death at a mean age of 28 years following a more prolonged course, usually over a year. Classic CJD presents with early neurologic signs and dementia, but patients with vCJD often have early behavioral or psychiatric symptoms and painful dysesthesias, with delayed neurologic findings [192,203].

The American College of Radiology notes diffusion-weighted imaging can help identify and characterize Creutzfeldt-Jakob disease.

(https://acsearch.acr.org/docs/69477/Narrative Last Accessed: April 28, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

MRI has been used successfully to diagnose vCJD. An unusual appearance of the thalamus or a specific increase in intensity in the posterior portion of the thalamus, the pulvinar region, has been found in neurologically confirmed cases of vCJD [203]. This finding, called "the pulvinar sign" has not been observed in classic CJD [203,204].

As noted, the firm diagnosis of vCJD is made with either a brain biopsy during life or examining pathology material at autopsy; however, Western blot analysis of lymph node specimens has shown the presence of prion material in patients with the disease. Florid plaques have been described in brain sections of patients with vCJD but not in those with classic CJD. The vacuolation (spongiform change) has been seen in many portions of examined brains, with most disease found in the occipital cortex and cerebellum [194,205].

There is no treatment for this disease in any species mentioned. This makes prevention and radical public health measures essential to control BSE, vCJD, and scrapie. All are reportable diseases. Compulsory slaughter has been practiced to eradicate herds with BSE-positive cattle; this was obviously done at huge costs to the public, farmer, and government. The United States has a scrapie eradication program to eliminate scrapie from the sheep herds in the country. The United States and other countries had barred blood donations from people who have lived in the United Kingdom or continental Europe for a cumulative three months or more between the years 1980 to 1996 as a precautionary measure against the spread of vCJD [206]. However, the FDA removed the recommendation for this deferral in a guidance document published in 2022 [193].

The best way to protect ourselves and educate patients is to have the correct information and to practice safe consumption. Due to the nature of the prion proteinase resistance and probably its small size, the agent is not destroyed with ultraviolet light, freezing or thawing, boiling for 30 minutes, or formaldehyde. In other words, there is no way to safely cook the agent out of a brain or render a tissue absolutely free of the agent. In 2006, the European Union ban on British beef was lifted due to enhanced BSE testing and control measures (e.g., the banning of feeding cow proteins, including brains, to other cows) [205]. Travelers to the United Kingdom, Ireland, or certain other European countries (France, Greece, and Poland) should be advised that if they are concerned about contracting vCJD, avoiding beef products altogether is the only certain option, but that eating whole muscle meat, rather than ground meat or foods made with brains, carries an "exceedingly low risk" of infection [205]. Aside from the European countries listed above, the risk posed by BSE in other European countries is similar to that from U.S. beef. The risk status of Canadian beef is an estimated 18 to 48 times higher than that of U.S. beef and is considered to have similar risk as United Kingdom beef. Cow milk and milk products from all countries are believed to be safe [205].

Because there is no cure or vaccine for the TSEs, treatment is generally confined to supportive measures and symptomatic therapies. It has been suggested that phenothiazines may inhibit prion production, but this has not been confirmed in a series of studies [207]. Anticonvulsants are used to manage seizures and violent outbursts [203]. Experimental therapies include the antimalarial quinacrine and the antipsychotic chlorpromazine to prevent abnormal prion protein conversion. One patient has been treated with pentosan polysulphate and had no evidence of disease progression for 23 months [203]. The agent inhibits prion protein production, replication, and cell toxicity associated with vCJD. Unfortunately, the treatment must be initiated soon after infection to prevent disease onset, which, outside of experiments, is likely impractical.

The clinical manifestations of infection in humans are similar to the flu or mononucleosis. As noted, the concern is greatest for pregnant women and HIV-positive individuals. In the first trimester of pregnancy, spontaneous abortions, retinochoroiditis, hydrocephalus, microencephaly, and psychomotor retardation of the fetus are the most common sequelae to exposure [208,212]. In an immunocompromised host, toxoplasmosis can be life-threatening. These individuals are more prone to a disseminating version that can lead to hemorrhagic lesions in the brain. Myocarditis, hepatitis, meningoencephalitis, chorioretinitis, and internal organ involvement have also been reported [212].

Diagnosis of toxoplasmosis is usually made with serologic testing. Indirect IFAs of IgG and IgM are positive within a few days after infection [208]. Imaging studies and PCR analysis of CSF are useful in immunocompromised patients with signs of encephalitis or focal mass lesions within the brain. In such patients, a brain biopsy may be considered for definitive diagnosis and to exclude other diagnostic possibilities (e.g., brain abscess, lymphoma, metastatic carcinoma). In many cases, the history of the consumption of undercooked or raw meat aids in making the diagnosis [211].

In order to prevent Toxoplasma gondii infection, the American Academy of Pediatrics recommends that pregnant women avoid contact with material/soil potentially contaminated with cat feces, especially handling of cat litters or gardening.

(https://publications.aap.org/pediatrics/article/139/2/e20163860/59988/Diagnosis-Treatment-and-Prevention-of-Congenital Last Accessed: April 28, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

Treatment is rarely necessary in people with normal immune systems as most recover without treatment. Suspected cases in persons who are ill may be treated with the combination of pyrimethamine and sulfadiazine, plus folinic acid (leucovorin) for a period of three to four weeks. Clindamycin may be substituted for sulfadiazine in patients sensitive to sulfa drugs [208]. For encephalitis, the treatment is continued for four to six weeks. Patients with HIV/AIDS who are toxoplasma-seropositive and who have CD4 counts <100 cells/mcL should receive prophylaxis against toxoplasmosis. This can be accomplished with trimethoprim/sulfamethoxazole (TMP-SMX) double-strength daily dose or alternately, TMP-SMX double-strength three times weekly [213]. The recommended therapy for acquired toxoplasmosis in HIV-infected children is sulfadiazine plus pyrimethamine and leucovorin [214].

It is very important to educate immunocompromised individuals and pregnant women in prevention techniques. All meat should be thoroughly cooked. Not coming in contact with cat feces or contaminated soil is very important, as is handwashing after gardening or yard work. If there is a sandbox in the backyard, it should be covered. If possible, limit a household cat's ability to consume rodents, which would best be accomplished by keeping the cat indoors, and only feed commercial pet food [208]. Oocysts hatch about 24 hours after being shed in the feces and are not infective before hatching. If the litter box is changed daily, exposure risk will be reduced. Encourage others in the household to participate in the cat's care, and ask them to change the litter box to protect the family members who are at risk. If the at-risk person must change the box, gloves, dust mask (to prevent swallowing or inhaling oocysts), and diligent emptying of the box daily are recommended. If you are working with a woman in early prenatal screening who owns a cat or who comes in contact with them, recommend having a titer if exposure must be documented and explain the importance of handwashing after handling cats or raw meat. Because of the potential seriousness of this zoonosis for certain populations, research is being conducted on a vaccine. At this time, there is no approved vaccine available [208].

The majority of patients present with an insidious onset of diarrhea. This usually consists of frequent loose stools that do not contain blood or mucus. Watery diarrhea and malodorous soft or greasy stools can be interspersed with episodes of constipation. The gastrointestinal symptoms are often exacerbated by eating and may be associated with mid abdominal pain and cramping. Nausea, gastroesophageal reflux, malaise, fatigue, lactose intolerance, and weight loss are common. Adult patients with long-term disease may develop malabsorption syndrome, while children can demonstrate the findings of failure to thrive [215,217].

Physical examination is usually normal, with the exception of possible abdominal tenderness upon palpation. In extreme cases, there may be dehydration and wasting. Laboratory studies should include stool examination with at least three samples taken at two-day intervals [215,218]. Because antibiotics, laxatives, or barium may mask the presence of the organism in the stool, the samples may need to be obtained after a 5- to 10-day hiatus. There are ELISA and IFA tests available for stool samples that have excellent sensitivity and specificity [218]. Microscopy with direct fluorescent antibody testing is considered the test of choice for diagnosis of giardiasis, because it provides increased sensitivity over nonfluorescent microscopy techniques [215]. Cultures are useful primarily to detect other causes of diarrhea, because Giardia is not easily grown from stool samples. The most useful serum study is IgM analysis, but only for the determination of acute versus chronic infections [218]. Endoscopy, with duodenal aspiration or biopsy, may also be used to obtain a diagnosis.

The World Gastroenterology Organisation asserts that nitazoxanide is an effective antiprotozoal in the treatment of diarrhea caused by Giardia intestinalis.

(https://www.worldgastroenterology.org/guidelines/global-guidelines/acute-diarrhea/acute-diarrhea-english Last Accessed: April 28, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

Several drugs can be used to treat Giardia infection, including metronidazole, tinidazole, and nitazoxanide. Other medications include paromomycin, quinacrine, and furazolidone. Some of these drugs may not be readily available in the United States [215]. Metronidazole is the most commonly prescribed antibiotic for this condition. However, metronidazole use has been associated with significant failure rates in clearing parasites from the gut and with poor patient compliance. In addition, an increasing incidence of nitroimidazole-refractory giardiasis has been reported, particularly in travelers from India and other regions in Asia. An optimal treatment strategy for refractory giardiasis remains to be determined, and no standard treatment regimen for nitroimidazole-refractory giardiasis exists to date [218]. The usual adult dose of metronidazole is 500 mg orally twice daily for five to seven days [55]. Tinidazole can be administered in a single oral dose of 2 grams, taken with food. For children older than 3 years of age, the recommended dose is 50 mg/kg [55]. For women in the first trimester of pregnancy, for whom metronidazole and tinidazole are contraindicated, paromomycin 25–35 mg/kg/day in three divided doses should be used for 5 to 10 days [55]. Paromomycin has been recommended for use in pregnancy because systemic absorption is low, but the cure rate is lower than with other agents [218]. Quinacrine is commonly used outside the United States. It achieves a cure rate of 90% to 95% but is available in the United States only as an orphan drug [218]. Other antibiotics and antiparasitic agents, such as nitazoxanide, have also been used to effectively treat the disease [55,215]. Some authorities feel that asymptomatic cases of diagnosed giardiasis infection, especially in children, should be left untreated. However, if untreated, an individual can shed the organisms for weeks to months. In rare cases, hospitalization is required for fluid and nutritional replacement, but most cases will resolve with minimal treatment.

Prevention includes the avoidance of potentially contaminated water and foodstuffs. Drinking water from a stream, shallow well, or other unfiltered source can lead to ingestion of the cysts. The cysts can live for extended periods of time in an outdoor environment. However, they are inactivated by chlorine and can be eliminated from a water source by filters of less than 1 micron (e.g., National Safety Foundation [NSF] Standard 53 or NSF Standard 58 for cyst and oocyst reduction) [215].

Giardiasis cannot be transmitted by blood products, but any possible fecal contact can be a source of infection, which includes accidentally swallowing water in a recreational pool or pond. Peeling or washing fruits and vegetables in clean water is also recommended [14,215]. When traveling to countries with an unsafe water supply, only drink water that has been boiled for more than one minute or bottled water labeled as reverse osmosis treated, distilled, filtered through an absolute 1 micron or smaller filter, or "1 micron absolute" [215]. Additionally, ice should not be used [215].

Prompt and accurate diagnosis of malaria is a cornerstone of the treatment process. Identification not only of the presence of the disease but also of the causative agent is necessary in order to implement appropriate and effective treatment. This can be difficult, as the initial signs and symptoms of malaria are nonspecific and may be confused for other systemic viral infections. After infection, there is typically a 7- to 30-day incubation period, or longer if antiviral medications have been taken prophylactically. The classically described malaria attack (cold, hot, and sweating stages) is rarely observed [223]. More often, the first symptoms are a combination of headache, weakness, fatigue, abdominal discomfort, and/or muscle and joint aches, followed by fever, chills, perspiration, anorexia, vomiting, and/or worsening malaise [223,224]. Possible signs include elevated temperature, enlarged spleen, and perspiration. If the disease is limited to this stage, it is considered uncomplicated, and treatment is often successful. Relapse of malaria can occur after two to four symptom-free years in persons infected with P. vivax and P. ovale species [221].

If the disease is caused by the P. falciparum species, it can progress to severe malaria. Severe malaria is complicated by serious organ failures or abnormalities in the patient's blood or metabolism. Advanced severe malaria can result in [221,223]:

Other conditions that should raise concern in malarial patients are acute kidney failure, hyperparasitemia, metabolic acidosis, and hypoglycemia [223]. In patients for whom the malaria infection reaches the severe stage, the mortality rate is 15% to 20% [224].

In addition to the clinical diagnosis, there are three main tests used in the parasitologic confirmation of the diagnosis of malaria: light microscopy, rapid diagnostic tests, and PCR. Light microscopy remains the standard test for detection of malarial parasites [225]. The test is conducted by staining a blood smear, usually with the Giemsa stain, and examining the specimen by microscope. There are also several rapid tests available that utilize antigen detection. These tests provide results quickly (within 2 to 15 minutes), but their use is restricted by limited accuracy and higher costs [225]. When they are used, it is usually as an adjunct to microscopy or as the main test if microscopic analysis is not available, particularly because early treatment is so vital for positive clinical outcomes. The limitations of the rapid tests have shifted attention to PCR-based molecular diagnosis. Although the PCR tests available for malaria are more accurate than either the microscopy or antigen detection systems, the prohibitive costs and need for specialized equipment have made this option less useful [225,226]. IFA and ELISA tests are available to test for past exposure to the disease [225].

Treatment for uncomplicated malaria varies based on the region in which the disease was acquired and the infective species (Table 7). Some areas have been particularly identified as sensitive to chloroquine, the traditional drug of choice for malaria. Because resistance to chloroquine has increased significantly, it is now generally used only for malaria known to originate from Central America (west of the Panama Canal), Haiti, the Dominican Republic, and most of the Middle East[227]. In all other areas, the organisms are considered to be resistant to the drug, and other agents are used. It is also recommended that, when possible, in vivo assessment of therapeutic efficacy, in vitro studies of parasite susceptibility to drugs in culture, or molecular genotyping be used to establish sensitivity of the parasite to the drug regimen[224].

Patients with any manifestations of severe malaria (e.g., impaired consciousness/coma, acute kidney injury, circulatory collapse/shock) should be treated promptly and aggressively with IV artesunate, regardless of infecting species. When IV artesunate is not in stock, consider interim treatment with an effective oral antimalarial while obtaining IV artesunate emergently from a commercial source. If the patient is unable to tolerate oral medications, consider alternative ways to administer oral medications while awaiting IV artesunate. The preferred interim oral treatment is artemether-lumefantrine because of its fast onset of action. Other oral options include atovaquone-proguanil, quinine, and mefloquine. IV or oral clindamycin and tetracyclines (e.g., doxycycline) are not adequate for interim treatment. These drugs are slow-acting and would not take effect until well after 24 hours. They also are not effective for treatment of severe malaria when used alone. As for any malaria treatment, the interim regimen should not include the medication used for chemoprophylaxis, if possible. When IV artesunate arrives, immediately discontinue the oral medication and start parenteral treatment. Artesunate is dosed at 2.4 mg/kg at 0, 12, and 24 hours. The weight-based dosing applies to both adults and children [55,227]. Assess parasite density at least four hours after last dose and proceed with therapy based on results [55].

Malaria in pregnant women is associated with high risk of both maternal and perinatal morbidity and mortality. Pregnant women of all gestational ages diagnosed with uncomplicated malaria acquired in areas with chloroquine-resistant P. falciparum can be treated with artemether-lumefantrine, mefloquine, or a combination of quinine sulfate and clindamycin. Quinine treatment should continue for seven days for P. falciparum infections acquired in Southeast Asia and for three days for infections acquired elsewhere; clindamycin treatment should continue for seven days regardless of where the infection was acquired [227]. Promptly treat uncomplicated malaria caused by P. malariae, P. ovale, chloroquine-sensitive P. vivax, or chloroquine-sensitive P. falciparum infection, with chloroquine or hydroxychloroquine. Treat chloroquine-resistant P. vivax infections with artemether-lumefantrine, quinine plus clindamycin, or mefloquine [227].

Pregnant patients with P. vivax or P. ovale infections should be maintained on chloroquine chemoprophylaxis (300 mg base [500 mg salt] orally, once per week) for the duration of their pregnancy. After delivery, for pregnant patients with normal glucose-6-phosphate-dehydrogenase (G6PD) activity, subsequent treatment with primaquine phosphate or tafenoquine is needed but will depend on breastfeeding. If not breastfeeding, either drug can be used depending on the regimen used to treat the acute malaria episode. For women who are breastfeeding, infants should be tested for G6PD deficiency and if found to have normal activity, oral primaquine phosphate can be given to the mother. Tafenoquine is not recommended during breastfeeding. Women who after delivery cannot take primaquine or tafenoquine should be maintained on weekly chloroquine chemoprophylaxis for a total of one year after the acute malaria episode [227].

Doxycycline and tetracycline are generally not indicated for use in pregnant patients. However, in rare instances, doxycycline or tetracycline can be used in combination with quinine if other treatment options are not available or are not being tolerated and the benefit of adding doxycycline or tetracycline is judged to outweigh the risks. Atovaquone-proguanil is not indicated for use in pregnant patients because of the lack of data on its safety in this population. However, for pregnant patients diagnosed with uncomplicated malaria caused by chloroquine-resistant P. falciparum infection, atovaquone-proguanil may be used if other treatment options are not available or are not being tolerated, and if the potential benefit is judged to outweigh the potential risks [227].

CDC clinicians are on call at the Malaria Hotline 24 hours per day, seven days per week, to provide advice to healthcare providers on the diagnosis and treatment of malaria. They may reached during business hours 9 a.m. to 5 p.m. Monday through Friday) at (770) 488-7788 or (885) 856-4713. During off hours, weekends, and federal holidays, call (770) 488-7100 and ask to have the malaria clinician on call paged.

Individuals that are known to be traveling to malaria-endemic areas, and areas of resistance in particular, should be counseled regarding antimosquito measures and malarial symptoms prior to departure [229]. Chemoprophylaxis with the most appropriate antimalarial agents should be provided.

Cutaneous anthrax skin infection begins as a raised pruritic lesion or papule that resembles an insect bite. Within one to two days, the lesion develops into a fluid-filled vesicle, which ruptures to form a painless ulcer 1–3 cm in diameter with a necrotic area in the center. Pronounced edema is often associated with the lesions because of the release of an edema-producing toxin by the bacteria. The lymph nodes in the area may become involved and enlarged.

The incubation period in humans is usually 1 to 10 days but can be prolonged to almost two weeks [231,234]. To describe the lesion in more detail, picture a painless macular eruption that appears within two to five days, most commonly on an exposed portion of the body. The lesion progresses from a red macule to a pruritic papule, then to a single or ring of vesicles. This is followed by a depressed ulcer and finally a black necrotic eschar that falls off within 7 to 10 days. There is edema associated with the eschar but usually no permanent scarring of the affected area. The symptoms of purely cutaneous anthrax infection can include fever, headache, regional lymph node involvement, and myalgia. The cutaneous form of anthrax may progress to systemic disease, with a fatality rate of up to 20% if untreated [234].

Gastrointestinal anthrax is characterized by an acute inflammation of the intestinal tract. Initial signs of nausea, loss of appetite, vomiting, and fever are followed by abdominal pain, vomiting of blood, and severe diarrhea [231,232].

The first sign of inhalation anthrax is the acute onset of a flu-like illness. If inhalation anthrax progresses to the pneumonic form, the initial symptoms are often followed by a short period of improvement. Next, there is an abrupt development of severe respiratory distress with dyspnea, diaphoresis, stridor, and cyanosis. Shock and death usually occur within 24 to 36 hours after the onset of respiratory distress [230,234]. In the later stages, mortality approaches 100% despite aggressive treatment. Physical findings can be nonspecific. The chest x-ray is usually disease-specific, revealing a widened mediastinum with pleural effusions, but typically without infiltrates [232]. Thoracic trauma can have similar signs, but often with infiltrates. A hemorrhagic mediastinitis often develops.

Laboratory tests of blood products are usually normal if the disease is not disseminated. The B. anthracis organism can be obtained for culture or gram stain; however, analysis beyond simple cultures should only be performed in a specialized laboratory environment [235]. On gram stain, the organism can be recognized as a large, rod-shaped, gram-positive, spore-forming bacillus [230]. More positive identification requires lysis by gamma phage and dFA, or most positively by immunohistochemical staining. There is an ELISA test available, but generally only at reference laboratories. A negative culture does not rule out cutaneous anthrax, especially if obtained after antibiotics are started [230].

Most B. anthracis strains are sensitive to a broad range of antibiotics. Either ciprofloxacin or doxycycline is usually recommended for the treatment of anthrax. In the past, penicillin was a first-line treatment, but due to concerns regarding resistance, it is no longer recommended by the CDC or the U.S. military [230]. To be truly effective, antibiotic treatment should be initiated as early as possible. If left untreated, the disease is highly fatal. Immediate prophylaxis with ciprofloxacin 500 mg (off-label) or doxycycline 100 mg orally twice daily is commonly recommended for cutaneous anthrax [55,236,237]. Treatment should continue for 60 days or longer; if the source in known to be from livestock or its products, a 7- to 10-day course is sufficient. If an individual has not been previously vaccinated, a three-dose series of vaccine should also be given subcutaneously at diagnosis and two and four weeks later [232,237]. For inhalation anthrax treatment in adults, intravenous medications are suggested as the initial treatment and should be combined with one or two other effective agents [235,237].

In some cases, other antibiotics may be considered, such as the other fluoroquinolones, including levofloxacin, clindamycin, and moxifloxacin. Clindamycin and moxifloxacin are not currently approved for this use by the FDA; however, the CDC indicates that these agents are effective, acceptable alternatives for postexposure prophylaxis or for treatment of systemic anthrax [55,236,238]. Rifampin and linezolid have been suggested as an adjunct treatment, and high-dose penicillins (e.g., amoxicillin, penicillin VK) may be tried if no other antibacterials are available and the strain is susceptible. In general, the cephalosporins are not useful in treating anthrax because the organism produces an enzyme that neutralizes them [236]. The monoclonal antibodies obiltoxaximab and raxibacumab (in combination with antimicrobial therapy) are indicated for postexposure prophylaxis of inhalation anthrax due to B. anthracis when alternative therapies are not available or are not appropriate [55,232]. Supportive therapy for shock, fluid volume deficit, and adequacy of the airway may be needed.

In 2013, a new antibiotic with significant activity against B. anthracis, anthracimycin, was discovered [239]. Although it is not yet FDA-approved, it may have a place in the treatment of anthrax in the future.

Human-derived anthrax immune globulin (AIG) was used to successfully treat a naturally occurring inhalation anthrax case in Pennsylvania in 2006 [240]. In 2015, the FDA approved AIG for the treatment of inhalation anthrax [55,241]. Immune globulin administration may be considered in combination with appropriate antibiotics when multiple organ systems are involved or following lack of response to standard therapy.

Vaccination for anthrax can prevent the disease if given prior to contact with the bacillus. However, it can also be used postexposure to help minimize the patient's reaction to the organism. Anthrax Vaccine Adsorbed (AVA) is the only licensed human anthrax vaccine in the United States [232]. For pre-exposure prophylaxis, the vaccination schedule consists of three injections of 0.5 mL of the vaccine administered subcutaneously in the deltoid region at 0, 1, and 6 months with boosters at 6 and 12 months after completion of the primary series and at 12-month intervals thereafter. For postexposure prophylaxis for adults 18 to 65 years of age, the dosage is 0.5 mL administered subcutaneously at 0, 2, and 4 weeks [232]. The vaccine is approved only for healthy, nonpregnant adults, although it will be made available under appropriate emergency use regulatory provisions [232]. The ACIP recommends that a booster dose of AVA for pre-exposure prophylaxis be given every three years to persons who are not at high risk for exposure to B. anthracis and who have previously completed the three-dose primary and the initial two-dose boosters AVA series and want to maintain protection. For persons at high risk for exposure to B. anthracis, booster doses at 12 and 18 months and annually thereafter are recommended [232]. There is an adverse reaction incidence of approximately 6% for local inflammation and 2% to 3% for systemic symptoms [55].

There is no data to suggest patient-to-patient transmission of anthrax; therefore, only standard barrier isolation precautions are recommended for hospitalized patients with all forms of anthrax [237]. There is no need to immunize or provide prophylaxis to patient contacts unless a determination is made that they, like the patient, were exposed to the organism. Standard disinfectants used for hospital infection control are effective in cleaning surfaces contaminated with infected bodily fluids [231].

Proper burial or cremation of humans and animals that have died because of anthrax infection is essential to prevent further transmission of the disease. Serious consideration must be given to cremation. Embalming of bodies could be associated with special risks.

Some cases of cholera are asymptomatic or only produce a mild diarrhea. A major Vibrio infection is characterized by a sudden onset of severe enteritis with diarrhea, vomiting, and leg cramps. The usual incubation period is 0.5 to 5 days [243]. Marked dehydration can occur, especially in the instance where reinfection is occurring from a point source. There may be accompanying fever. If the bacteria infect a wound, the site can become necrotic and cellulitis can spread until the infection is no longer localized. Once septicemia occurs, the case fatality rate can be as high as 50%; it may be as high as 25% in wound infection cases [14]. Laboratory diagnosis can be made with gram stain or by culture of the organism.

The gastroenteritis form of Vibrio infection can usually be managed supportively in previously healthy individuals with intravenous followed by oral fluid and electrolyte replacement. It is the very young, the elderly, and patients with chronic disease, who may have a harder time dealing with vibriosis and require antibiotics. Antibiotic use for moderately and severely ill patients has been shown to reduce the volume of stool output, the duration of diarrhea, and the duration of positive stool cultures [244]. Doxycycline is recommended for adults, and azithromycin is recommended as first-line treatment for children and pregnant women [244].

Care must be taken with cooked shellfish to ensure that handling does not recontaminate the food product just before consumption. As noted, Vibrio spp. are relatively tolerant of wide temperature ranges and, consequently, can exist on a food preparation surface for a considerable time.

In 2016, the FDA approved the first cholera vaccine, Vaxchora. This one-dose oral vaccine is approved for adults 18 to 64 years of age traveling to cholera-affected areas. The vaccine should be administered at least 10 days prior to potential exposure [55,245]. Other preventative measures recommended by the CDC include only drinking safe water, frequently washing hands with soap (or scrubbing hands with ash or sand) and safe water, cooking all foods and eating them hot, and only consuming raw fruits and vegetables that have been peeled recently by oneself.

Following an incubation period of 2 hours to 8 days, depending on the dose (typically 12 to 72 hours), the early signs and symptoms of diplopia, blurred vision, dry mouth, ptosis, and photophobia appear. This is followed by skeletal muscle weakness and paralysis, which is typified by a descending, symmetrical pattern, ending in respiratory difficulty and eventually respiratory failure. Interestingly, the patient usually remains alert and afebrile, although there may be dysarthria, dysphagia, and dysphonia. The pupils may be dilated and fixed, the gag reflex may be absent, and deep tendon reflexes are diminished or absent. The patient may develop hypotension, cyanosis, and evidence of carbon dioxide retention. In foodborne botulism, all of these findings may be evident in patients within 24 hours of the ingestion of the tainted items [246,249].

Some cases of botulism may be confused with disorders such as Guillain-Barré syndrome or myasthenia gravis (MG). It has been suggested that the edrophonium (Tensilon) test may be used to differentiate it from MG, but because it may be transiently positive in botulism, its actual usefulness is in doubt [250]. The edrophonium test requires that the patient have a sign, such as ptosis, that can be reversed with an intravenous injection of a cholinesterase agent like edrophonium.

Very limited information can be obtained from laboratory tests. Survivors usually do not develop an antibody response to the toxin because of the subimmunogenic amount of material required to produce major symptoms. In cases of ingested botulinum toxin, culture of the serum or stool may be useful [246]. An ELISA test might possibly detect the toxin on nasal mucous membranes for 24 hours in cases of inhalation.

The recommended test for confirmation of botulism is the mouse neutralization bioassay [246,249]. This assay can detect as little as 0.03 ng of botulinum toxin within one to four days after exposure.

There are good antitoxins available; however, they only halt the progression of future symptoms and do not reverse the existing clinical presentation. A licensed heptavalent antitoxin for all known types of botulinum (A, B, C, D, E, F, and G) has been approved by the FDA and is recommended for all cases of botulism in patients other than infants [180,246]. The antitoxin is of equine origin, which means that skin testing must be performed to help prevent serum sickness or anaphylaxis in susceptible individuals [251]. Intravenous human botulism immune globulin (BIG-IV, BabyBIG) is available for the treatment of patients younger than 1 year of age with infant botulism caused by toxin type A or B. In cases of suspected infant botulism, for consultation, and to obtain BabyBIG, physicians should call (510) 231-7600 [252]. Antibiotics (i.e., penicillin G, chloramphenicol, clindamycin) are useful in wound botulism, but not in foodborne botulism [246].

For patients with symptoms of botulism, the prompt administration of botulinum antitoxin and supportive care can markedly reduce the mortality rate. Supportive care may include ventilatory assistance for several weeks or even months. Treatment is the same for children and adults [246].

Botulism poisoning is not an infection. It is not transmitted from person to person, and only standard precautions are required to control its spread. Because botulism poisoning is not transmittable, patients do not need to be isolated. The CDC recommends that contaminated objects or surfaces be cleaned with 0.1% hypochlorite bleach solution if they cannot be avoided for the hours to days required for natural degradation [253].

The common presentation of salmonellosis is gastroenteritis with fever, abdominal cramping, vomiting, diarrhea that is often bloody, chills, and weight loss [254,255]. There is often a history of ingesting a possibly contaminated food product within the past few days, but in many cases a full epidemiologic investigation is necessary to find the source of infection. The symptoms usually appear within 12 to 72 hours after ingestion of the infective organism.

Serum is useful in testing for the enteric fever form S. typhi only. Culturing the feces is usually needed to verify the disease [257]. The samples can be serotyped, in most cases, to help identify the exact source of an infection.

Antimicrobial therapy is not recommended for the usual case of uncomplicated salmonella gastroenteritis, as this tends to be self-limited, lasting about four to seven days; antibiotic treatment does not shorten the duration and may prolong the carrier state, which could have adverse public health consequences if the patient is in close contact with others or is a food handler [255,257]. Patients with enteric fever presentation or signs of disseminated foci of salmonella infection do require antibiotic treatment. Careful attention to antimicrobial sensitivity testing of the infecting strain is important, as some salmonella strains are multidrug-resistant [254,257,258]. Choices for antibiotic therapy for severe infections include fluoroquinolones, third-generation cephalosporins, and ampicillin (for susceptible infections) [257]. Third-generation cephalosporins, which must be given by injection, are widely used in children with serious infections because the quinolones are not generally recommended for this age group. The drugs commonly used in the past, chloramphenicol, ampicillin, amoxicillin, and trimethoprim-sulfamethoxazole, are occasionally used as alternatives [255]. For cases in which a carrier state is identified, it is important to treat the individual who is the carrier. It is also especially important to identify sources of drug-resistant strains to avoid outbreaks similar to those in northern California during spring 1997 related to the home production of Mexican-style cheese [259].

According to the World Gastroenterology Organisation, two typhoid vaccines (with limited cost-efficiency) are approved for clinical use to prevent diarrhea associated with Salmonella typhi infection.

(https://www.worldgastroenterology.org/guidelines/global-guidelines/acute-diarrhea/acute-diarrhea-english Last Accessed: April 28, 2023)

Level of Evidence: Expert Opinion/Consensus Statement

In managing clusters of salmonellosis among livestock, fecal samples should be tested and the animal cleared of carrier status only after a series of samples are determined to be free of the bacteria. In the case of infection coming from a food handler, tracking the source will be hastened if the initial case is reported in a timely fashion to allow public health officials to investigate as quickly as possible.

Common sense (e.g., hand washing after handling raw foods or animals/animal feces) prevails in the prevention of these diseases. Avoiding raw eggs, unpasteurized dairy products, and other questionable food products will prevent most cases, as will proper cooking of poultry and meats [254,256,257].

The brucellae are a group of gram-negative cocci bacillary organisms. The most common way to become infected is by drinking or eating unpasteurized milk or cheese products derived from sheep, goats, or cows. Meat packing and laboratory worker infections suggest that Brucella is highly infectious via direct contact with carcasses or by inhalation aerosol route [263]. It is estimated that inhalation of only 10–100 bacteria is sufficient to cause disease in humans. The incubation period is 5 to 60 days, and many infections are asymptomatic under natural conditions. Large aerosol doses may shorten the incubation period and increase the clinical attack rate. Brucellosis infection has a low mortality rate (2% to 5% of untreated cases), with most deaths caused by endocarditis or meningitis. It is an incapacitating disease in its natural form [237,263].

Acute brucellosis presents as a flu-like illness, with fever, headache, joint pain, sweats, chills, and general weakness as common complaints. Cough and pleuritic chest pain may be present but may not correlate with radiographic results. Chest x-rays may show lung abscesses, single or miliary nodules, and pleural effusions. Gastrointestinal symptoms, such as anorexia, nausea, vomiting, diarrhea, and constipation, colitis, or an infiltrative hepatitis occur in up to 70% of adult cases and less frequently in children. Hepatomegaly and splenomegaly can occur in as many as 20% to 30% of cases. Peripheral joint involvement may vary from pain on range of motion to joint immobility and effusion, usually involving the hips and sacroiliac joints [264]. Meningitis occurs in less than 5% of brucellosis cases and may be an acute presenting illness of a chronic syndrome, occurring late in the course of a persistent infection [264]. Behavioral disturbances in children and psychoses may occur in the meningoencephalitic form of the disease.

Laboratory studies for Brucella spp. are most productive if accomplished early in the course of the disease. The organism is slow-growing and should be incubated for about three weeks before a negative result can be reported. Cultures can be obtained from blood, urine, CSF, or even bone marrow. Serologic testing is the most common diagnostic procedure, with rising titers or an agglutination titer of ≥1:160 is presumptive of brucellosis diagnosis [264].

Many other procedures have been utilized, including IFA, ELISA, and counter immunoelectrophoresis. The micro-agglutination test is still considered to be the gold standard test. This test allows for the differentiation of an acute (predominately IgM) infection versus a relapse (predominately IgG). Identification is made by culturing Brucella spp. from blood or bone marrow [237,262]. Evidence of Brucella antibodies by nonagglutination-based tests does not meet the current CDC case definition for a presumptive diagnosis of brucellosis. However, any quantitative test can be used for confirmation if there is a four-fold or greater rise in Brucella antibody titer [264].

Brucellosis is treatable with antibiotics, but due to the intracellular nature of the infectious process, treatment usually requires combination therapy over a long duration. Optimal antibiotic therapy for brucellosis has been studied; however, recommendations differ [262]. Doxycycline (200 mg daily) plus rifampin (600–1,200 mg daily) for six weeks may be appropriate for uncomplicated disease in adults [264]. Fluoroquinolones (e.g., ciprofloxacin) have been used as monotherapy but carry a high relapse rate; adding these agents to doxycycline offers no specific advantages over other combination regimens but may be preferred in areas where resistance to rifampin is high [262]. The CDC guidelines for treatment of brucellosis recommend [264]:

Arthritis may occur in recurrent cases.

A 2012 Cochrane review found that a regimen consisting of doxycycline for six weeks plus streptomycin for two to three weeks was more effective than one consisting of doxycycline plus rifampicin for six weeks [265]. The investigators also found that a regimen consisting of a fluoroquinolone plus rifampicin for six weeks was as effective overall as doxycycline plus rifampin (based on low-quality evidence) and was slightly better tolerated.

Prevention is largely limited to those occupations for which brucellosis is a risk, as naturally occurring forms of the disease have been drastically limited in the United States through the use of animal vaccines. However, food and animal products imported from other countries can pose a risk. Avoidance of high-risk food products, particularly unpasteurized dairy products, is an important step in avoiding the disease [263]. For those in direct contact with Brucella spp. cultures, prophylaxis is recommended [264].

The symptoms of infection are initially diarrhea, vomiting, fever, and abdominal distress. This is followed by flu-like symptoms from the muscle infection. In this stage, patients may have headaches, chills, cough, arthralgia, and myalgia. In severe infections, there can be myocarditis, paresis, central nervous system involvement, and respiratory distress. There have been fatalities from the disease [267].

The initial symptoms usually appear one to two days after ingesting the contaminated food product, with the later signs and symptoms showing up after about two to eight weeks. A detailed patient history is very helpful in identifying this zoonosis, and cases frequently present in an isolated small group or family.

Some of the Trichinella larvae may be passed in the feces, which can assist in diagnosis. Laboratory analysis includes antibody detection, muscle biopsy, and microscopy. The patient may have a pronounced eosinophilia [267].

Treatment should begin as soon as possible once the diagnosis is suggested. The CDC suggests the anthelmintics mebendazole and albendazole as possible therapeutic medications, although they are not FDA approved for this purpose. Steroids may be required for severe symptoms [55,267,268].

Adequate cooking of meat products will kill the organisms. This usually means obtaining an internal temperature of 170 degrees F. Pork can also be frozen for 20 days at 5 degrees F (if less than 6 inches thick) to assure safety. Thorough cooking of wild game meats will provide protection, but the freezing regimen is not always effective. In addition, curing by salting, smoking, or drying does not always kill the nematodes or cysts. Interestingly, microwaving does not consistently inactivate the organism, but ionizing irradiation has been used successfully to provide protection [267].

The symptoms of infestation with T. saginata are minimal, with mild abdominal pain being the most common finding. The clinical presentation of T. solium is even more minimal. It is usually the discovery of proglottids in the stool that signals the presence of the infestation [13]. Infrequently, the pork tapeworm progresses to cysticercosis, which can cause central nervous system symptoms if it invades the brain.

Dipylidiasis is typically asymptomatic; however, a severe worm burden can cause local pruritus, abdominal pain, allergic manifestations, and intestinal obstruction. The disease is often identified by the parent noting "rice stools" in a child's diaper [13,270].

Microscopic identification of the eggs and proglottids in the feces is diagnostic. This may not be possible until three months after infection because the adult tapeworm must first be present. Repeated examinations may be necessary to find the organisms, especially in light infestations. Antibody detection methods can be useful in the early stages of the disease, before the presence of proglottids in the stool. The differentiation of the species of Taenia requires more detailed analysis, with examination of the gravid proglottids or the scolex of the organism [13,270].

Treatment with antiparasitic medication is usually very effective. The CDC recommends praziquantel, although it is not yet approved for this use by the FDA [13,55]. The usual anthelmintics (i.e., albendazole or praziquantel) have been used for the treatment of neurocysticercosis [271]. Treatment of dipylidiasis in adults and children can be with praziquantel or albendazole (off-label use) [55].

Prevention of dipylidiasis in pets and humans is aided by the control of fleas with pet medications or flea collars. Good hygiene and refraining from sleeping with or kissing the animal will also help prevent the infestation. Good sanitary practices are also the best way to prevent taeniasis [269].

Patients may suffer a marked allergic response, including urticaria, angioedema, bronchospasm, and anaphylaxis, within 24 hours of eating raw or undercooked fish [272]. The latency of the reaction ranges from 15 minutes to 26 hours, with 5 hours after consumption being the mean [273]. Gastrointestinal symptoms of abdominal pain, diarrhea, fullness, nausea, and vomiting are often mild, although the vomiting may be violent enough to expel some of the larvae [272]. If the organisms lodge in the bowel, they can produce a granulomatous response, mimicking Crohn disease, after about one to two weeks [273]. They can also be found in organs or areas outside the gastrointestinal tract, such as the peritoneum and liver [274].

Diagnosis can be made by endoscopy, during which the 2-cm larvae can be seen and removed. The organisms can also be seen on biopsy specimens obtained during the endoscopic procedure or surgery [272].

The treatment of choice is removal of the organisms during fiberoptic endoscopy or surgery [272,273]. Successful treatment of anisakiasis with albendazole 400 mg orally twice daily for 6 to 21 days has been reported in cases with a strong presumptive diagnosis based on history and/or serology [272]. Prevention is almost absolute if raw or uncooked fish is avoided. However, this is not practical in many parts of the world, including the United States. Fortunately, most chefs trained in handling and preparing raw fish can spot tainted fish. Freezing at negative 4 degrees F for at least seven days will kill the larvae, as will "blast-freezing" at negative 31 degrees F for 15 hours [272]. Irradiation of fish can also kill the organisms as will the cooking of thawed or fresh fish. Salting, in high concentration, and smoking may provide some prevention but not enough to assure a safe product [275]. When smoking, the flesh must reach 65 degrees C to kill the parasites.