Viral hemorrhagic fevers: neurologic complications
Aug. 17, 2021
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This article includes discussion of Rocky Mountain spotted fever, rickettsial disease, Rickettsiae rickettsii infection, Rickettsial spotted fever, RMSF, spotted fever group rickettsiosis, and spotted tick fever. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Rocky Mountain spotted fever is a tickborne illness that often has an initial clinical presentation similar to a viral “flu-like” syndrome. Despite a nonspecific presentation, a prompt clinical diagnosis and initiation of antimicrobial therapy are essential to prevent multiple organ system sequelae. Despite a long history of the disease and effective antibiotic treatment since the 1940s, early opportunities for intervention are often missed, resulting in increased morbidity and mortality. In this article, the author reviews the clinical manifestations, pathophysiology, diagnosis, and recommended treatment. The neurologic manifestations of the disease are emphasized.
• Rocky Mountain spotted fever is a tickborne illness due to infection with the gram-negative coccobacillus, Rickettsia rickettsii.
• The primary target of infection is endothelial cells of small and medium blood vessels in multiple organ systems, including the skin, lungs, CNS, and renal systems.
• Early symptoms are nonspecific, but Rocky Mountain spotted fever should be suspected in patients with high fever, headache, and a macular rash with a possible tick exposure.
• Neurologic symptoms of Rocky Mountain spotted fever are headache, seizures, and altered mental status.
• Doxycycline at 2.2 mg/kg BID (max 100 mg BID) is first-line treatment for adults and children of ALL ages and should be started while awaiting laboratory confirmation. Chloramphenicol is second-line therapy for those with hypersensitivity reactions and can be used in pregnant patients.
Rocky Mountain spotted fever as a specific clinical disease has been recognized in the United States for more than 130 years. Originally described in Montana and Idaho in the 1870s, Rocky Mountain spotted fever was described in the literature by Maxey in 1899. Following this work, Wilson and Chowning discovered that wood ticks transmitted the infection. The extensive investigative work of Dr. Howard Taylor Ricketts between 1906 and 1909 led to the isolation of the etiologic infective agent for Rocky Mountain spotted fever, Rickettsia rickettsii (83; 84). Unfortunately, Ricketts contracted typhus while studying it and died from typhus in 1910. In 1919, Wolbach published a report confirming that the bacterium responsible for Rocky Mountain spotted fever was carried by wood ticks, and it was an obligate intracellular species (108). He subsequently named the bacterium rickettsii in Ricketts’s memory. In 1921 the Public Health Service allocated ,000 to establish the Rocky Mountain Laboratory in Hamilton, Montana, for the purpose of studying the spread of Rocky Mountain spotted fever and developing effective eradication and prevention measures. The work done at the Rocky Mountain Laboratory during the subsequent 8 decades has provided basic information and understanding about not only Rocky Mountain spotted fever, but also all other rickettsial diseases that have been identified worldwide since the discovery of R rickettsii (78). In 2010, the reporting of Rocky Mountain spotted fever was changed to the broader spotted fever rickettsiosis (109). Studies have focused on the use of genetic analysis and genotyping to uncover different clades of the bacterium and its evolution (66; 77).
The infection of endothelial cells of small- and medium-sized blood vessels with R rickettsii leads to a variable multisystemic pattern of symptoms. An accurate early diagnosis of Rocky Mountain spotted fever is critical; however, early symptoms are often nonspecific and include fever, headache, malaise, and myalgias (45; 18). The classical triad of Rocky Mountain spotted fever is high fever of greater than 102 degrees Fahrenheit (38.9 degrees Celsius), headache, and macular rash beginning on the wrists and ankles; however, this triad is rarely present early in the clinical course (45; 64; 09; 18). The characteristic rash of Rocky Mountain spotted fever, which is more common in children, begins as pink, blanching or nonblanching macules on the wrists and ankles and progresses to a maculopapular rash on the torso (45; 67; 64; 70).
Examples of an early-stage rash in a Rocky Mountain spotted fever patient. (Used with permission from: Centers for Disease Control and Prevention. Available at: http://www.c...
However, this rash is typically absent early in the illness, present in 60% to 70% in the second week of illness, and may be completely absent in up to 10% of patients (92; 09; 18). The classical centripetal spread of the rash is typically rare as well (18). Thus, the early nonspecific signs of Rocky Mountain spotted fever and the delayed onset of rash present a clinical dilemma in terms of early recognition and initiation of treatment.
A history of a tick bite or potential tick exposure can help in making an early diagnosis; however, up to 40% of patients report no history of tick bite (64). Patients may not report tick exposure due to painless attachment and feeding and attachment to difficult-to-visualize areas. Following tick exposure and infection with R rickettsii, the incubation period varies from 2 to 14 days, with the typical length between 4 to 7 days (45; 09; 70; 56). Following incubation, the progression of illness from symptoms consistent with a viral syndrome, to rash development, to more serious complications occurs.
The most common neurologic symptoms are fever with severe headache and altered mental status, mimicking meningitis (68; 69; Massey et al 1985). The severe headache is more common in adults and is typically frontal in nature; however, meningismus with meningeal signs is also common. Photophobia may also be present (68; 69; 06). Altered mental status can range from irritability or lethargy to confusion, delirium, and coma if severe (06). Neurologic involvement, even at these early stages, is associated with increased mortality (22). Focal neurologic deficits present 6 to 8 days after the onset of fever if they develop (69). These deficits are usually transient, but can include unilateral facial weakness, gaze and cranial nerve palsies, cerebellar deficits, and hemiparesis (68; 69; 06). As the disease progresses, more severe symptoms may occur and become prominent in up to 25% to 35% of patients (05). These include tremor, rigidity, ataxia, deafness, blindness, pyramidal signs, seizures, and coma (Massey et al 1985). In patients treated early, permanent neurologic sequelae, including seizures and other focal neurologic signs, are uncommon. However, 5% to 10% of patients may have permanent, significant CNS complications, including learning deficits, delayed speech, proximal motor weakness, vestibular dysfunction, dysarthria, paresthesias, and cranial nerve palsies (Massey et al 1985; 05).
Respiratory and cardiovascular manifestations may be severe and fatal (Lees et al 1978; 27; 89; 45; 38; 51; 10). Pneumonitis, cardiac and noncardiac pulmonary edema, and impaired ventilation results in rapid respiratory failure and death in approximately 6% to 9% of patients (38; 10). Adult respiratory distress syndrome can also develop (54). Chest x-ray shows pleural effusion in 10% to 36% and pulmonary infiltrate in 12% to 42%. Damage to pulmonary vasculature typically results in an interstitial pattern; however, secondary consolidation can occur in severe cases (45; 10).
Rocky Mountain spotted fever is the only tickborne disease to directly cause congestive heart failure (54; 60). Additionally, cardiac conduction abnormalities may rarely be severe and life threatening. Fortunately, myocarditis and dysrhythmias, which may be present by ECG criteria in 15% to 30% of patients during acute illness, usually resolve as illness subsides (60; 61; 73). ECG abnormalities include first-degree block, right bundle branch block, conduction defects, and ST-T wave changes (61). In addition, the development of cardiac tamponade in a severe case of Rocky Mountain spotted fever has also been reported (73).
Impaired renal function has long been associated with Rocky Mountain spotted fever as a marker of disseminated disease, but has received relatively little study. A retrospective chart review found that 19% of patients developed acute renal failure, as defined by a rise in serum creatinine to above 2 mg/dL (22). Though less than 3% required hemodialysis, the development of acute renal failure had a significant association with subsequent mortality. Approximately 20% to 30% of patients develop nontender splenomegaly and hepatomegaly, without lymphadenopathy. Up to two-thirds of patients can develop gastrointestinal symptoms typically involving abdominal pain, nausea, and vomiting (69). Diarrhea is prominent in 10% to 20% of cases (74; 81).
Ophthalmologic involvement includes conjunctivitis, uveitis, retinal infarctions, retinal hemorrhages, retinal edema, and optic disc swelling, probably as a result of obstructed venous outflow. In cases of severe and untreated disease, the development of macular star figures has also been reported (101). Fluorescein angiography readily demonstrates focal regions of capillary nonperfusion and infarction (28).
The early recognition and treatment of Rocky Mountain spotted fever is essential to prevent permanent sequelae, clinical deterioration, and death. Effective early treatment generally results in recovery without incident in immunocompetent individuals; however, delay in treatment can lead to increased morbidity and mortality (52; 11; 46; 80). In patients who received appropriate antimicrobial therapy less than 5 days from onset of illness, case fatality was just 1.9%, compared to 6% for treatment at 5 days and beyond (46). In the same study, independent risk factors associated with a worse prognosis included older age (> 60), African-American race, and failure of treatment with tetracycline antimicrobials (46). Additional signs indicative of poor prognosis include changes on neuroimaging, need for inotropic support, and coma (Bonawitz et all 1997; 46; 09; 59).
In terms of long-term sequelae, the most common sequelae tend to be neurologic, occurring in 5% to 10% of patients (68; 05; 06). Neurologic sequelae can include hearing loss, peripheral neuropathy, paraparesis, bladder and bowel incontinence, cerebellar and vestibular dysfunction, cranial nerve palsies, and seizures (68; 40; 03). Focal deficits, such as cranial nerve palsies, tend to be associated with correlated anatomical defects on imaging (03; 06; 23; 59). Thus, it is important to perform a thorough neurologic exam on initial presentation and during follow-up of recovery (03). Many of the focal deficits occurring during acute illness resolve (68).
Although microinfarctions occur in the CNS, large areas of infarction and clinical stroke are rare. Occasionally cranial neuropathies, transverse myelitis, and peripheral mononeuropathies result from small-vessel occlusions and persist for protracted periods after the patient has generally recovered. Two case reports have associated Rocky Mountain spotted fever with postinfectious complications, namely acute disseminated encephalomyelitis and Guillain Barré syndrome (98; 106).
Complications during acute illness include hypovolemia, shock, thrombocytopenia, coagulopathy, renal failure, hepatic dysfunction, pulmonary edema, pneumonitis, diarrhea, and cardiac conduction defects. Hyponatremia and thrombocytopenia may be a clue to the diagnosis, but are considered nonspecific. Elevations in blood urea nitrogen and transaminases, reflecting renal and liver involvement, are found in a small percentage of patients. In some patients, the skin rash becomes necrotic and regions of gangrene develop.
One afternoon in late June, a previously healthy 9-year-old male from North Carolina was brought to his family physician by his mother due to fever of 102.2 degrees Fahrenheit and headache. The patient had returned from an outdoor summer camp several days before presentation. The patient’s mother reported the fever had increased over the past 2 days to the highest of 102.2 degrees Fahrenheit that morning; the patient was also complaining of muscle aches and general fatigue. The primary care physician believed the patient contracted a virus, possibly influenza, due to the close quarters of camp and recommended supportive care and rest for the patient at home. At home, the patient continued to complain of myalgias, malaise, and eventually headache that night. The following morning the patient’s temperature was 103.5 degrees Fahrenheit, and his mother felt he was behaving oddly and seemed confused. She decided to bring him to the emergency room.
On arrival, the patient complained he was having pain in his abdomen and felt nauseated. Labs were drawn and showed a mild leukocytosis, mild thrombocytopenia, and mild hyponatremia. The patient’s mother noted he had not been drinking fluids well over the past several days. The patient denied having any sick contacts at camp and stated he only drank the bottled water provided while there. His mother stated he did not complain of any history of tick bite, but was outdoors in wooded areas regularly. In the emergency room, the patient began to have respiratory difficulty. He was started on ceftriaxone, and the decision was made to admit the patient. A neurologic examination revealed the patient was confused with some mild dysarthria, but no focal deficits were found.
Later in the day, a faint rash on the patient’s ankles was noticed by his nurse. Ceftriaxone was stopped, and the patient was put on broad spectrum antibiotics. Overnight, the patient’s respiratory status declined further, and he eventually required intubation. He also became hypotensive and required pressor support.
It was felt that the patient was septic from an unknown cause, so blood, urine, and sputum cultures were sent off, broad spectrum antibiotics were continued, and a neurologic consultation was obtained. The consulting team suggested sending tests for tickborne illnesses, including Rocky Mountain spotted fever. They also started the patient empirically on chloramphenicol in addition to his broad spectrum antibiotics. After literature review, the decision was made to switch the patient to doxycycline given the superior results of the antibiotic, broader coverage of tickborne illnesses, and updated treatment protocols.
Two days later, the patient improved, with decreasing requirement for pressor and ventilatory support. His rash had spread proximally to his knees and to his elbows. Three days later, he was completely off pressors and the ventilator. His mental status and speech returned to baseline. Supportive care was continued a few more days, and then the patient was discharged. The patient was continued on doxycycline for an additional 3 days as he had just become afebrile at discharge. A week later, his Rocky Mountain spotted fever serology returned positive with an IgG titer of 1:512. On follow-up, the patient’s rash had resolved; a neurologic examination revealed no focal deficits with baseline cognitive functioning. His mother reported he had been active with his friends over the past week.
Rocky Mountain spotted fever is caused by infection with Rickettsia rickettsii, a small (0.2 to 2.0 µm) gram-negative coccobacillus in the spotted fever group of Rickettsiaceae. R rickettsii is an obligate intracellular organism with a tropism for mammalian endothelial cells of small- and medium-sized blood vessels. At the molecular level, there is an interaction between the host receptor Ku70 present on endothelial cells and rickettsial outer membrane protein B (rOmpB) (62; 15). Additional adhesion to endothelial cells is mediated via rOmpA and Sca1 proteins, but these play a far lesser role (55; Chan et al 2010; 85). Although it was previously believed that OmpA played a critical role in virulence, a knockout model of the gene in the virulent Sheila Smith strain did not effect the clinical phenotype of infected guinea pigs (75). It is still believed OmpA plays a role in attachment/transmission. On rOmpB-Ku70 binding, Ku70 becomes ubiquitinated and a number of intracellular pathways become activated, leading to actin polymerization and rearrangement, along with clathrin and caveolin recruitment to the site of binding where endocytosis can then take place (15). Studies examining Ku70-deficient cell lines showed a 50% reduction in cell penetrance by rickettsial species, illustrating the receptor’s importance in bacterial entry and a potential vaccine target (62). Additionally, it is believed the rickettsial protein RickA also plays a role in the actin polymerization process during cell entry (43).
Within the cell, Rickettsiae have developed a number of adaptations to survive and reproduce. In terms of movement, organisms move via an actin-based movement both within cells and intercellularly (44). The rickettsial protein Sca2 serves to organize and polymerize actin tails for actin-based movement, which may also become a future vaccine target (Chan et al 2010; 43; 53). For metabolism, R rickettsii relies on using host cell substrates as it has few of its own metabolic enzymes (Fuxelius et al 2007; 82). Rickettsia harvest energy from the host cell via an ADP-ATP translocase that pumps ADP out of the organism in exchange for host ATP from the cytosol (42; 82). This allows Rickettsia to obtain energy efficiently without having to carry all metabolic genes for ATP production (82).
R rickettsii is transmitted to humans only by the bite of ticks in the family Ixodidae (hard ticks), which are the natural hosts of this organism (04). Ticks can become infected by feeding on the blood of an infected animal. Male ticks can infect females through mating, and infected female ticks can pass the infection on to their offspring. The major tick vectors in the United States include Dermacentor andersoni (Rocky Mountain wood tick), distributed throughout the western United States and Canada; Dermacentor variabilis (American dog tick) in the eastern half of the country; Amblyommaamericanum (Lone Star tick) in the southwest; Amblyommacajenneuse (Cayenne Tick) in Texas and Central America; and the discovered vector of Rhipicephalussanguineus in eastern Arizona and Mexico (24; 99). This last vector was previously known as a Rickettsial vector in Mexico and was subsequently the cause of an outbreak in Arizona in the early 2000s due to infestation of local dogs (24). Although R sanguineus is present in Mexico and Arizona, the Arizona species and the R rickettsii it transmits were found to be genetically distinct from those in Mexico (99). Studies have illustrated that the R sanguineus tick has increased aggressiveness and propensity for attack in higher temperatures, such as those of Arizona and Mexico (66). Unlike the deer ticks famous for transmitting Lyme disease, these ticks are generally easily visible to the naked eye, ranging in size from 1 to 5 mm.
The transmission of R rickettsii infection is by tick bite. The organisms are maintained within the tick vector’s saliva in an avirulent state, and ticks need to feed on a human host for approximately 6 to 10 hours before the transmission of organisms is complete (06). This large window of time required for transmission provides ample opportunity to search common areas of attachment such as the scalp, axillae, groin and perineum, buttocks, and legs and remove the tick (18). It was demonstrated that in response to blood feeding by host ticks, the transcriptome of R rickettsii is altered to increase gene production of antioxidant enzymes, type IV secretion systems, and a number of proteins involved in attachment and invasion of mammalian cells (37). The total bacterial load in ticks was also increased in response to a blood meal, and a dose-response study concluded the R rickettsii ID50 for humans to be 23 organisms (Tamrakar and Haas 2011; 37). On entering the epidermis, the organism is transported via lymphatics and eventually to the bloodstream where the organisms bind and enter endothelial cells of small- and medium-sized blood vessels in various tissues, including the skin, brain, lungs, spleen, and heart (105; 110). With endothelial cell infection, the integrity of the layer becomes increasingly compromised, both through oxidative injury and immune response of the host (87; 86; Rydkina et al 2010; 105; 110). Endothelial infection results in accumulation of lymphocytes and macrophages in a perivascular infiltrate—the end result of which is a lymphohistiocytic vasculitis (18). This vasculitis and its accompanying complications are the predominant pathologic feature of Rocky Mountain spotted fever.
The damage of endothelial cells results in a procoagulant state with platelet activation and consumption resulting in thrombocytopenia, thrombin generation, increased fibrinolysis, and subsequent consumption of anticoagulant proteins (31; 18; 109). Although this procoagulant state may induce microinfarctions in tissue, overt disseminated intravascular coagulation is rare (31; 105; 18).
The major sequelae of Rocky Mountain spotted fever are primarily the result of vascular insufficiency, which results in decreased intravascular fluid volume, hypovolemia, and increased interstitial fluid. Research has shown that during the early stages of infection, Rickettsiae induce the phosphorylation of vascular endothelial-cadherin, which impacts inter-endothelial connections and significantly increases microvascular permeability within 48 hours (39). Rickettsial infection can also induce the endothelial cyclooxygenase-2 system, which, in turn, upregulates synthesis of vasoactive prostaglandins, which may influence the vascular permeability changes seen in the clinical disease (86).
In the nervous system, the pathologic changes found in Rocky Mountain spotted fever are the same as those found in other tissues. The vascular changes in the brain can lead to cerebral edema, increased intracranial pressure, and potential death. Rickettsial infection can lead to increased production of IL-8 and monocyte chemoattractant protein-1, the latter of which has been shown to affect the tight junctions of the blood-brain barrier through internalization of the zonulae occludens-1 and occludin proteins (Song and Pachter 2004; 21). Microinfarctions have been shown throughout the CNS, including the brain, brainstem, and spinal cord, with focal deficits often corresponding to these areas (68; 69). Pathologic specimens have shown the accumulation of microglia, astrocytes, and macrophages adjacent to damaged blood vessels (68; 69).
A number of studies over the last 10 to 15 years have illustrated that the human immune response, while necessary to clear Rickettsial organisms, also contributes to its pathogenesis. Numerous cytokines and chemokines are upregulated by rickettsial infection, including IL-1 alpha, CXCL9, and CXCL10 (94; 100). These signals target infected cells for destruction by T cells, eliminating the infection, but also heavily contribute to the pathologic vascular damage. The critical immune response involving the cytokines TNFα, IFN-γ, and IL-1β leading to production of rickettsicidal nitric oxide has been well documented (35; 104). There has also been a case report of Rocky Mountain spotted fever in a patient taking TNFα inhibitors (65). However, in addition to upregulating transcription of NO-producing enzymes, IL-1β and TNFα have been shown to significantly increase the permeability of endothelial membranes during rickettsial infection (110). This immune response is another way in which vascular permeability is increased relatively early during infection with Rickettsiae species.
Oxidative stress also plays a significant role in the cellular injury caused by rickettsial infection, and several antioxidant proteins are upregulated in response (26; 34; 87; 33). Rickettsial species can cause oxidative damage through the activity of various enzymes, including proteases, phospholipases, and free radical production (105; 88). In fact, the ability of various subgroups of Rickettsia rickettsii to cause oxidative damage may be directly related to their ability to cause significant clinical disease (32).
Finally, much work has demonstrated that rickettsial infection activates nuclear factor-kappaB, which, in turn, suppresses host cell apoptosis through signaling cascades, mediated by the caspase and Bcl-2 families (95; 20; 91; 90; 93; 48; 49). The ability to suppress apoptosis is likely an important, adaptive survival mechanism for the rickettsial organism.
Rocky Mountain spotted fever is the most commonly reported rickettsial disease encountered in the United States, and it has been a reportable disease since the 1920s. The incidence of the disease increased steadily during the 2000s. The incidence increased from 1.7 cases per million people from 2000 to 2007 to a peak of just over 8 cases per million in 2008 (2563 cases), an all-time high (76; 56). In 2010, the incidence decreased to just over 6 cases per million (13). The increased incidence was particularly prominent in the Native American population, where the incidence was 33 cases per million in 2005 (46). During this same time period, the case fatality rate decreased from 2.2% to 0.5%, an all-time low; however, amongst Native Americans and children (5 to 9 years old) the rate was 2.2% and 2.6%, respectively (46; 76). A study examined the outbreak of Rocky Mountain spotted fever in Native American tribes of Arizona during the first decade of the 2000s (99). The study illustrated that tribes in Arizona had exposure to a novel vector in the United States, R sanguineus, which had infested local dogs and was believed to be the reason that 50% of the infected cases were in children under 10 years of age (99). The mean age of infection in these Native American populations was 19.8, compared to 46 across the general United States population and 33 in other Native American populations (99). The authors hypothesized that children would have greater interaction with local dogs and, subsequently, the tick vector.
The name Rocky Mountain spotted fever is actually a misnomer as less than 1.5% of cases in 2002 were reported from the Rocky Mountain geographic area. Just 5 states—Oklahoma, North Carolina, Tennessee, Arkansas, and Missouri—accounted for 64% of the Rocky Mountain spotted fever cases from 2000 to 2007 (76). The incidence in these states is much higher than the rest of the continental United States. In 2010, the incidence was zero in Nevada, South Dakota, Kansas, West Virginia, Massachusetts, Connecticut, and Vermont (13).
Annual reported incidence (cases per million population) of Rocky Mountain spotted fever in the United States in 2010. (Used with permission from: Centers for Disease Control and Prevention.)
A study of 10,000 serum samples from ethnically and geographically diverse individuals, though mostly young males, found seropositivity for spotted fever group Rickettsiae to be 6% by ELISA for R rickettsii (41). Approximately 90% of all cases occur between early April and the end of September, when there is the greatest number of adult and nymphal Dermacentor ticks. Within this time period, a peak number of cases are typically reported in June and July (46; 76). The populations at highest risk of acquiring infection are children between 5 and 9 years old and Native Americans; however, elderly patients are also at risk (46; 17; 76). About two-thirds of cases occur in people less than 15 years old. The ratio of males to females with Rocky Mountain spotted fever is approximately 2 to 1. Caucasians, dog owners, and those who live near woods or tall grass fields are also at increased risk. These demographic risk factors probably correlate with exposure risk; a history of tick bite or exposure to a tick habitat can be elicited in only 60% of cases (09; 13).
The mortality rate for patients older than 30 years is 6 to 7 times greater than for patients less than 30 (8.2% vs. 1.3%). Factors that increase mortality risk include age older than 15 years, male gender, absence of known tick exposure, absence of classic symptoms, delay in correct diagnosis, delay in beginning appropriate antibiotic therapy, black race, and presence of glucose-6-phosphate dehydrogenase deficiency (46; 11; 19).
Rickettsia rickettsii infection has been documented throughout North, Central, and South America. Other antigenically related tickborne spotted fevers are reported globally from diverse regions, including Mediterranean countries, the Middle East, continental Europe, China, Japan, Southeast Asia, Africa, India, Russia, Mongolia, and Australia (66).
Although there are currently a number of promising vaccine targets, including outer membrane proteins and motility proteins, no effective vaccine is currently available (62; 43; 53). Prevention is best achieved through avoidance of heavily populated tick areas, especially during the months of May to September; permethrin-coated clothing; and DEET spray (96; 18; 109). Community based projects in Arizona Native American reservations targeted the brown dog tick (R sanguineus) vector, which was highly prevalent in the communities and contributed to significant morbidity and mortality over the last decade (29). The projects used tick collars and acaricides to drastically reduce tick infestations and subsequent human transmission over a 2-year period (29).
Secondly, due to the long attachment time required for rickettsial infection, checking one’s skin, scalp, and hair-covered areas after exposure to tick areas provides ample opportunity for identification and removal of ticks (06; 37). Proper removal technique involves the use of tweezers, grabbing the tick close to the skin and pulling straight out of skin, with no twisting (72; 12). Fingers should not be used for removal as transmission via the tick hemolymph is possible if the tick is crushed between the fingers (18). If ticks are identified and removed, patients should be aware and monitor for signs of infection such as fever, severe headache, myalgias, etc.
The primary considerations in the differential diagnosis of Rocky Mountain spotted fever are other tickborne illnesses and severe causes of sepsis, such as meningococcemia. If a patient presents with a history of tick bite, several tickborne diseases should be considered, including anaplasmosis, ehrlichiosis, tularemia, Lyme disease, Colorado tick fever, babesiosis, and tick paralysis (47; 16). The geographic location of the patient, type of tick involved (if known), progression of symptoms, and results of laboratory studies can usually be relied on for diagnosis. However, the need for a definitive diagnosis amongst these conditions is not necessary to initiate treatment as doxycycline is the first-line therapy for all of them (11; 16).
Up to 40% of patients who are eventually proven to have Rocky Mountain spotted fever have no known tick exposure. In these cases, several other infections usually receive strong consideration, such as meningococcemia, measles, enterovirus, typhoid fever, HHV6, parvovirus, secondary syphilis, Mycoplasma pneumoniae, and murine typhus (109). The combination of fever and rash, together with other systemic signs, can also raise the concern for noninfectious inflammatory disorders, including Kawasaki disease, rheumatoid arthritis, systemic lupus erythematosus, and Henoch-Schonlein purpura. Given the rapidly progressive nature of meningococcemia, patients with high fever and rash should be started on a third-generation cephalosporin empirically if the history of tick exposure is unclear (70).
Any patient who lives in or near a wooded area and has unexplained fever, headache, and mental status changes should be suspected of having Rocky Mountain spotted fever. When Rocky Mountain spotted fever is a possibility, doxycycline must be started immediately and healthcare practitioners should never await laboratory confirmation (11; 46). Such a delay in therapy is likely to allow the disease to progress and greatly increases the patient’s morbidity and mortality risk (11).
Unfortunately, there is no rapid, widely available confirmatory laboratory test for Rocky Mountain spotted fever with early recognition and initiation of treatment based largely on clinical suspicion. It is crucial to initiate treatment as soon as possible and before any subsequent laboratory confirmation (11). The current mainstays of confirmatory testing include serologic immunofluorescent antibody (IFA) assays and skin biopsy immunohistochemical staining (14). For serologic analysis, IFA measures IgG and IgM antibodies to rickettsial antigens, which typically become detectable during the second week of the illness (109; 14). A paired serological sample is recommended with the first sample during the first week of illness at the time of presentation and the second sample 2 to 4 weeks after onset of illness; a 4-fold or greater rise in antibodies is confirmatory of R rickettsii infection (16). If a paired sample is not obtained, a single IFA titer equal or greater than 1:64 or latex agglutination 1:128 or greater is suggestive of infection with clinical correlation (16; 109). Although this test is the current gold standard, titers may be elevated in 10% of people in high-prevalence areas, and crossreactivity with other Rickettsia is possible (79; 16). Additionally, evidence from North Carolina has shown that patients with clinical syndromes indicative of Rocky Mountain spotted fever may be seropositive for other spotted fever group rickettsiae, including R parkeri and R amblyommii (102). Perhaps a rickettsial panel in future serological studies would ensure a negative R rickettsii titer does not impact treatment.
Skin biopsy is another method for confirmatory testing; however, it is unavailable in many areas and often requires sending of samples to large centers or the Centers for Disease Control and Prevention (14). Biopsy of a rash site can be tested with immunohistochemical staining with 70% sensitivity and 100% specificity (30; 107). A study looked at the use of a multiplex RT-PCR assay of skin biopsies and was able to effectively diagnose and distinguish R rickettsii, R parkeri, and R akari (25). This multiplex assay was also able to establish a diagnosis in under 3 hours, compared to 8-plus hours of conventional nested polymerase chain reaction (25). Although it offers a possible future method of rapid diagnosis, it is currently not widely available.
Outside of observing clinical manifestations and patient history, several laboratory findings may point toward a diagnosis of Rocky Mountain spotted fever. Thrombocytopenia due to platelet activation and sequestration, along with hyponatremia and decreased albumin due to increased endothelial permeability, are potential but nonspecific markers of Rocky Mountain spotted fever (09; 18; 109). CSF analysis is normal in up to two-thirds of patients, with one-third showing a pleocytosis that is typically mononuclear in predominance (06; 09; 109). Mild protein concentration elevation is also noted in approximately 50%, with glucose concentration abnormalities being rare (06; 09). In terms of EEG findings, a generalized slowing is most commonly detected if any abnormality is present at all (18).
Neuroimaging abnormalities are usually nonspecific and show signs of white matter changes and cerebral edema. On CT scan, sulcal effacement due to cerebral edema, focal hypodensities due to microinfarctions, and white matter changes are the abnormalities seen (07; 109). On MRI, multifocal T2 hyperintensities can be seen throughout the white and deep gray matter, along with perivascular patterns of inflammation on diffusion-weighted imaging (07; 23; 59). When abnormalities are present on neuroimaging, they are associated with increased mortality and long-term sequelae (07).
The prompt treatment of Rocky Mountain spotted fever with effective antibiotics is crucial to preventing progression of the illness. Although doxycycline and chloramphenicol were considered equally effective in treatment in the past, emerging evidence has shown increased morbidity and mortality in patients treated with chloramphenicol (50; 02; 36; 51; 111; Spach et al 1993; 46; 16; 109). This trend was especially true in pediatric populations where the case fatality rate for children treated with chloramphenicol was nearly 5 times higher than those treated with doxycycline (46). This has shifted the treatment protocol to doxycycline as a first-line therapy, with severe hypersensitivity reactions and early pregnancy the only contraindications (18; 70; 01; 109; 08). Thus, for all pediatric and adult patients, doxycycline is administered at 2.2 mg/kg (max 100 mg) every 12 hours for an average of 5 to 10 days or for 3 days after defervescence. Treatment should be started as soon as possible, and physicians should not wait for lab confirmation (11; 08).
The second-line therapy for Rocky Mountain spotted fever remains chloramphenicol. It should be used in patients with a history of life-threatening hypersensitivity reaction to doxycycline and during the first and second trimester of pregnancy (18). Administration of chloramphenicol oral or IV 100 mg/kg per day, maximum dose of 4 g, divided into 4 doses is recommended for these patients. Patients should be made aware of the risk of agranulocytosis and gray baby syndrome in pregnant patients, although the risk of this is minimized in the first 2 trimesters (18).
Another consideration in management is the possibility of meningococcal infection, which may be difficult to distinguish from Rocky Mountain spotted fever with nonspecific early symptoms of high fever, meningeal signs, and petechial rash. In patients at increased risk, it is recommended that they be started empirically on a third or fourth generation cephalosporin, such as ceftriaxone, pending the results of blood cultures (18; 109).
Administration of steroids, along with doxycycline, may theoretically be beneficial by reducing pathologically damaging inflammation. Several case reports have described the use of steroids in human disease, but such therapy has not been studied systematically, and, therefore, any benefit that it may have remains unproven (57; 50).
Meticulous supportive care, including intensive care monitoring, is also important in severe cases. Such care involves rapid treatment of cardiorespiratory failure, shock, fluid imbalance, and electrolyte disturbances. Severe thrombocytopenia may need correction with platelet transfusions. When evidence of prolonged clotting time develops, administration of vitamin K may help reverse this abnormality. Transfusions may be indicated for patients who become anemic. Maintaining good nutritional support with a high-protein diet is also an important aspect of general supportive care. Because Rocky Mountain spotted fever is not transmitted person-to-person, strict isolation of infected patients is not necessary.
The pregnant patient who contracts Rocky Mountain spotted fever presents a clinical dilemma for the treating practitioner. Historically chloramphenicol has been the treatment of choice in the pregnant patient, and although it still has its role, doxycycline may have a role in certain patients. In a pregnant patient in the first and second trimester, chloramphenicol remains the treatment of choice as the risk of gray baby syndrome is decreased at this time, and the adverse effects of doxycycline are more pronounced (18). In the third trimester, however, doxycycline is likely to be of increased benefit as the risk to teeth and bone are decreased (18). Doxycycline also remains the treatment of choice in severe cases in which the pregnant patient’s life is in jeopardy and her survival is the focus of treatment. During periods of lactation, doxycycline is again the antimicrobial of choice due to the high concentration of chloramphenicol in breast milk (71).
Additionally, the initial nonspecific symptoms of Rocky Mountain spotted fever may mimic several conditions of pregnancy (HELLP), complicating a physician’s ability to make the diagnosis and start antibiotics as rapidly as desired (96). Vertical transmission of Rickettsia rickettsii or typhus group Rickettsia has not been documented in humans, and there is no known effect of the infection itself on the developing baby (96).
Prevention of infection through avoidance of exposure and the use of repellants such as DEET or permethrin-treated clothing is recommended (96). The maximal recommended concentration of DEET is 35%.
The pediatric population afflicted with Rocky Mountain spotted fever continues to have one of the highest case fatality rates of any group (46). In the past, the treatment of pediatric patients was divided based on age, with those younger than 8 years old receiving chloramphenicol and those over 8 receiving doxycycline. The adverse effects of doxycycline on bone and teeth were the main reason for this division. However, the present standard of care is to treat ALL pediatric patients with doxycycline oral or IV at 2.2 mg/kg every 12 hours for 2 to 4 days after defervescence (18; 70; 01; 109; 08).
Despite this new standard of care, a survey of healthcare practitioners across the United States revealed that only 35% identified doxycycline as the first-line therapy for pediatric patients under 8 years of age (112). It is speculated that historical concerns of tetracycline-induced tooth staining and impact on bone development contributed to this apprehension in using doxycycline in children under 8 years of age. However, there is mounting evidence that this concern is unwarranted for short courses of doxycycline, such as those for Rocky Mountain spotted fever (58; 103; 112; 97). A randomized control study of children 4 to 5 years of age treated with a 10-day course of doxycycline did not reveal evidence of enamel staining in any of the study participants (103). Additionally, evaluation of children on a Native American reservation exposed to doxycycline before 8 years of age did not reveal any staining, enamel hypoplasia, or change in tooth color measured with a spectrophotometer (97). It is believed that up to 4 10-day courses of doxycycline can be administered without concern for enamel staining (103). This being said, parents should still be informed that a theoretical risk does exist in the interest of full disclosure. The improper choice of antimicrobial by many healthcare practitioners in pediatric populations shows the need for increased education on this updated treatment protocol.
Additionally, the pediatric population can present in atypical ways that can delay the early identification and treatment of Rocky Mountain spotted fever. Young patients may be unable to identify history of a tick bite and describe their symptoms, which could further cloud the clinical picture (109).
Scott Speelziek MS
Dr. Speelziek of Mayo Clinic, Rochester has no relevant financial relationships to disclose.See Profile
Karen L Roos MD FAAN
Dr. Roos of Indiana University School of Medicine has no relevant financial relationships to disclose.See Profile
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