Impact of a Severe Rocky Mountain Spotted Fever Case on Treatment Practices at an Academic Institution within a Nonendemic Area

Abstract

Introduction:

Rocky Mountain spotted fever (RMSF) is a bacterial disease associated with morbidity and mortality when untreated. The primary study objectives are to describe clinician diagnostic and treatment practices in a nonendemic area after the occurrence of an unrecognized severe pediatric presumed RMSF case (index case). We hypothesized that inpatient diagnostic testing frequency and initiation of empiric treatment will increase after the index case.

Methods:

We performed a retrospective chart review of subjects aged less than 18 y evaluated for RMSF at Penn State Hershey Children’s Hospital between 2010 and 2019. We divided the study population into 2 groups (preindex and postindex) and evaluated for patient characteristics, RMSF testing completion, and doxycycline administration timing.

Results:

Fifty-four subjects (n%) [14 (26%) preindex and 40 (74%) postindex] were included. Age [median y, (25^th percentile, 75^th percentile)] decreased from 14.5 (8.6, 16) preindex to 8.3 (3.6, 14) postindex. Twelve (86%) preindex and 31 (78%) postindex patients received empiric doxycycline (P=0.70). Four y after the index case, a decrease in empiric as well as urgent initiation of doxycycline administration was noted. One case of severe RMSF was diagnosed 4 y after the index case.

Conclusions:

Our study found that inpatient RMSF testing increased after the index case, but not all patients received empiric treatment. This possibly represents an underappreciation of RMSF severity even after a recent devastating case. We suggest that when severe rare but possibly reversible diseases, such as RMSF occur, all clinicians are educated on the diagnostic and treatment approach to reduce the morbidity and mortality risk.

INTRODUCTION

Rocky Mountain spotted fever (RMSF) is a severe tickborne illness caused by the bacteria Rickettsia rickettssii¹. The common symptoms of this disease include fever, headache, myalgia, and various types of rashes (maculopapular to petechial)². These nonspecific symptoms, along with a rash that may not be present in all cases, can result in under recognition¹.

When RMSF is not promptly recognized and treated, it can result in multiorgan system failure including encephalopathy, acute respiratory failure due to acute respiratory distress syndrome, and septic shock^2–6. Multiple studies have demonstrated that if doxycycline administration did not occur within 5 d of onset of symptoms, patients were at high risk of these complications, including death^2,7 The standard of care is to initiate therapy early even if an alternative diagnosis is more likely or the classic findings of RMSF are absent^2,8. Thus, when a pediatrician works at an RMSF endemic area, a high index of suspicion is required and when suspected, testing and early treatment are necessary.

RMSF is commonly diagnosed in areas of southeastern and southcentral United States where climate and host availability are favorable to the various tick vectors that harbor Rickettsia^4,9. In recent years, however, there are concerns that these environmental risk factors may change due to climate change¹⁰. This has resulted in an increase in tick bites for not only RMSF but other tickborne illnesses as well^10,11. If climate change continues, the frequency of tick attacks will likely continue to rise in endemic areas and ticks may migrate northward placing nonendemic areas at risk^10,12.

If a severe case of RMSF occurs in a nonendemic area and it is unrecognized, its individual emotional impact can be profound especially if it resulted in patient harm¹³. This can include modifications in diagnostic approaches that are less risky¹³. It is unknown, however, how noninvolved clinicians react to similar cases and whether group knowledge of the event improves the care of future patients¹⁴. Understanding how clinicians react to these rare cases can influence the way a region prepares healthcare providers for the possibility of RMSF (and other rare diseases) and may potentially improve the quality of care of patients who present with signs and symptoms of suspected RMSF.

In 2014, a pediatric patient (referred herein as the index case) presented to our institution’s pediatric intensive care unit with severe presumed RMSF. Despite aggressive therapy, the patient succumbed to this illness. The primary objectives of this present study are to examine the diagnostic and treatment practices in a nonendemic area before and after a severe pediatric case of RMSF. We hypothesized that inpatient diagnostic testing frequency and initiation of empiric treatment will increase after the occurrence of a severe case of presumed RMSF.

METHODS

This was a retrospective study of pediatric patients aged less than 18 y of age seen in the emergency department or admitted to an inpatient service in Penn State Hershey Children’s Hospital who were tested for RMSF. Penn State Hershey Children’s Hospital is a tertiary care facility located in the central Pennsylvania area. Using the Cerner hospital database, we identified and included the following subjects: 1) pediatric patients aged less than 18 y of age; 2) patients serologically tested for RMSF via indirect immunofluorescence (IFA) (our primary mode of diagnostic testing); and 3) were admitted to the Penn State Hershey Children’s Hospital or seen in our emergency department. After we obtained this list of patients, we utilized our electronic health record to perform a chart review of each case. Data collected included demographics (age, sex, race), timing of RMSF testing, presence of RMSF diagnosis, timing of doxycycline administration (with appropriate administration considered within 3 h upon suspicion of RMSF), patient outcome, length of stay, primary clinical setting during evaluation (inpatient or emergency department), and identification, timing, and description of a severe case of confirmed RMSF¹⁵. Retrospective review of the patient’s medical records was completed between January 1st, 2011 and December 31st, 2019. We divided the study population into 2 groups: preindex and postindex. Preindex was defined as cases where patients were evaluated for RMSF prior to and including the day of August 15^th, 2014, the day of a severe pediatric case of presumed RMSF where the patient did not survive. Postindex was defined as the cases after, but not including, this event. The study was reviewed by the Penn State College of Medicine institutional review board and determined to be exempt from institutional review board oversight (STUDY00013124). . Summary statistics using median, interquartile range or proportions were reported for clinical and demographic characteristics of the preindex and postindex patients who were tested for RMSF.Fisher’s exact test was applied to compare the proportions before and after index case periods. Wilcoxon rank sum test with continuity correction was applied to compare the annual incidences between periods of preindex and postindex case. Analysis was performed using R v4.0.0. P values of less than 0.05 were regarded as statistically significant.

RESULTS

During the study period, an average of 8829 ± 2138 pediatric patients (aged 0 to 18 y) were seen in the emergency department per year. A total of 54 patients were included in this study. The preindex age [median age, (25th percentile, 75th percentile)] of patients evaluated was 14.5 (8.6, 16) and 8.3 (3.6, 14) postindex. Seven patients (50%) were male preindex and 27 (68%) were male postindex. Other patient characteristics were similar. [Table 1]

Table 1:

Demographics

Patient characteristics	Preindex case (including index case)	Postindex case
Age [median age (y), 25th, 75th percentile]	14.5 (8.6, 16)	8.3 (3.6, 14)
Race (n, %)
White	12 (86%)	27 (68%)
Asian	1 (7%)	1 (3.0%)
African American	1 (7%)	3 (8.0%)
Other	0 (0%)	9 (23%)
Sex (n, %)
Male	7 (50%)	27 (68%)
Female	7 (50%)	13 (33%)
Length of stay [median (d), 25th, 75th percentile]	4.2 (1.7, 12)	5.0 (2.8, 9.6)
Outcome (n, %)
Survived	13 (93%)	40 (100%)
Died	1 (7%)	0 (0%)
RMSF diagnosed (n, %)	1 (7%)	1 (3%)
RMSF died	1 (100%)	0 (0%)
Location (n, %)
Inpatient	12 (86%)	36 (90%)
Emergency	2 (14%)	4 (10%)

The index case patient was a 3 y old female who presented to an outside hospital with nonspecific upper respiratory infection symptoms, rash, and encephalopathy during the summer months of 2014. There was no history of travel, but there was a history of a dog tick bite. She was transferred to our institution’s pediatric intensive care unit where the patient was empirically started on broad spectrum antibiotics including doxycycline within 95 min. The patient developed progressive encephalopathy, acute respiratory failure secondary to acute respiratory distress syndrome, and profound shock. RMSF testing performed indicated there was no significant level of Rickettsia rickettsii IgG antibody detected. Based on the findings of fever, generalized rash that begun on the wrists and ankles then spread centrally to involve the legs, buttocks, trunk, and face (with later stages becoming petechial) as well as pediatric infectious diseases consultation, the patient’s condition was determined to be consistent with RMSF. After 3 d in the hospital, the patient subsequently expired due to presumed RMSF. Upon review of the electronic health record, the patient was evaluated 4 d prior to presentation for a diffuse rash on her feet and fever, diagnosed as a viral exanthem. This was the only case of pediatric RMSF (albeit presumed) to our knowledge that expired during the study period.

Fourteen patients were evaluated for RMSF before the index case. More patients (n=40) were evaluated annually for RMSF after the index case (P<0.05). Twelve (86%) preindex patients received empiric doxycycline during testing compared to 31 (78%) postindex patients, but this was not statistically significant (P=0.70). Seven (50%) preindex patients were administered doxycycline within 3 h compared to 21 (53%) postindex patients, but this was also not statistically significant (P=1.0). [Table 2].

Table 2:

Inpatient Rocky Mountain spotted fever (RMSF) diagnostic and empiric treatment practices

	Preindex casea	Postindex case	P value
Amount of RMSF Testing (n)	14	40	0.04*
Frequency of empiric doxycycline administration (n, %)	12 (86%)	31 (78%)	0.70
Frequency of empiric doxycycline administration within 6 h in suspected RMSF cases (n, %)	10 (71%)	28 (70%)	1.00
Frequency of empiric doxycycline administration within 3 h in suspected RMSF cases (n, %)	7 (50%)	21 (53%)	1.00

^*P-value <0.05, based on 2-sided Wilcoxon rank sum test with continuity correction comparing the annual incidences in periods of preindex and postindex case

^aIncludes index case

Three preindex children who were tested for RMSF were less than 8 y of age and all (100%) received empiric doxycycline treatment. Twenty postindex children were less than 8 y of age and 16 (80%) received empiric doxycycline treatment (P=1.0).

Four y after the index case, in 2019, a decrease in empiric as well as urgent initiation of doxycycline administration was noted in patients tested for RMSF. [Figure 1, Table 3]. One case of severe RMSF was diagnosed 4 y after the index case, doxycycline was administered within 3 h after RMSF testing was sent, and the patient survived.

Figure 1:

Count of testing and frequency of doxycycline administration (total and within 3 h) in suspected Rocky Mountain spotted fever (RMSF) patients. ^a represents counts of total doxycycline administration and administration within 3 h were equal.

Table 3:

Inpatient Rocky Mountain spotted fever (RMSF) diagnostic and empiric treatment practices divided by y

	RMSF testing (n)	Frequency of doxycycline administration in suspected RMSF (n, %)	Frequency of doxycycline administration within 6 h in suspected RMSF (n, %)	Frequency of doxycycline administration within 3 h in suspected RMSF (n, %)
2010	1	1 (100%)	1 (100%)	1 (100%)
2011	0	0 (0%)	0 (0%)	0 (0%)
2012	1	1 (100%)	1 (100%)	1 (100%)
2013	6	6 (100%)	2 (33%)	2 (33%)
Preindex Case 2014a	6	4 (67%)	4 (67%)	3 (50%)
Postindex Case 2014	2	0 (0%)	0 (0%)	0 (0%)
2015	7	5 (71%)	5 (71%)	3 (43%)
2016	2	1 (50%)	1 (50%)	0 (0%)
2017	13	12 (92%)	12 (92%)	7 (54%)
2018	7	7 (100%)	7 (100%)	7 (100%)
2019	9	6 (67%)	5 (56%)	4 (44%)

^aIncludes index case

DISCUSSION

This study found that after a severe case of RMSF in an area currently considered nonendemic, diagnostic testing for RMSF appropriately increased. Not all patients after this case, however, received empiric treatment during RMSF testing. In cases where empiric treatment was initiated, there was no difference in the frequency of doxycycline administration within the 3 hour time window between the preindex and postindex patients. Our findings possibly represent an underappreciation of RMSF severity and may have implications in the approach to diagnostic and treatment practices nonendemic RMSF areas.

RMSF is a vector borne illness². Therefore, it depends on the presence of ticks and how favorable the environment is to allow it thrive¹⁶. Warmer weather allows the tick to reproduce as well as facilitate the presence of human hosts¹⁶. This may contribute to tick bites and spread of RMSF, even if it is only present in a small population of ticks^10,11. As temperatures rise across the United States, including Pennsylvania, institutions such as ours need to be prepared to recognize the potential presence of this severe illness, diagnose it, and initiate early treatment to avoid the severe consequences of the disease.¹⁷

In order to avoid the morbidity and mortality associated with RMSF, empiric treatment with doxycycline is recommended^2,7. In pediatric patients, doxycyline is associated with adverse effects, particularly dental staining¹⁸. Recent American Academy of Pediatric (AAP) guidelines, however, strongly recommend that the risks of this outweigh the benefits of treatment¹⁸. Thus, in cases where RMSF is suspected, the patient should be tested, started on doxycycline within 5 d of symptoms and should be continued until the results return.

Our study found that despite AAP recommendations, not all patients received empiric treatment, including patients less than 8 y of age after the index case. This is consistent with previous studies examining RMSF therapeutic practices. Even though a majority of providers identified doxycycline as the appropriate antimicrobial through a survey, only 35% chose this antibiotic in children less than 8 y of age¹⁹. In Tennessee, an endemic area, it was reported that a high proportion of survey participants were unaware that doxycycline is the treatment of choice for children less than 8 y of age²⁰. Another study reported that treatment delay may be due to a likely decreased awareness of RMSF and reluctance to use doxycycline in children²¹. Our study confirms that this provider based issue continues to occur presently. In addition, this study highlights that education efforts are needed to enhance provider awareness that their clinical decision making process could contribute to a rare, but preventable cause of pediatric mortality.

This present study set a time point of 3 h after doxycycline administration as appropriate empiric treatment.. This may be considered overly conservative, especially since patients with RMSF have a time window of 5 d². But, when this time point was expanded to 6 hours (to evaluate if any clinicians recognized the possibility of RMSF later), there were still patients that did not receive empiric treatment. In endemic areas, due to its nonspecific symptomology, treatment is often initiated even if an alternative diagnosis is more likely². In our area, however, RMSF is nonendemic, thus it may not even be considered as a high priority diagnosis. Nevertheless, because of the severity of RMSF, we argue that if a clinician considers this as a diagnosis, there likely was a delay in its consideration and thus this conservative approach should be taken to avoid the potential complications. In addition, despite studies showing that treatment for RMSF should be initiated within 5 d of onset of symptoms, it is supported to initiate treatment as soon as possible when this disease is suspected².

This study is unique in that we report how our practices changed after the RMSF index case. Because our institution is in an academic center, this case did undergo routine morbidity and mortality conference review focusing on inpatient care (not outpatient care) and due to how rare this diagnosis, it was presented in resident academic conferences. This index case provided a real life example of the lethality of RMSF, the ease in which this diagnosis was overlooked, and appropriately should have resulted in a change in practice (even in noninvolved clinicians). The only significant practice change that was noted, however, was an increase in testing (with only 1 year where all patients tested received empiric treatment). RMSF IFA testing costs approximately $27.05.²² At our institution, however, the test is analyzed externally and the turnaround time can be 2–3 days.²³ Thus, while the index of suspicion appropriately increased, the definitive action to prevent harm was not undertaken as the results are not immediately available and because diagnostic testing depends on the host’s antibody response (a negative test does not necessarily mean the patient does not have RMSF)⁷. Various reasons likely contributed to the approach our clinicians took to suspected RMSF patients. First, the AAP guidelines for doxycycline administration in suspected RMSF are relatively recent, thus not all clinicians may be aware of this new recommendation especially since clinicians are taught early in their training to avoid doxycycline use in children less than 8. Because RMSF is rare in our region, even if clinicians did consider RMSF, it may have been considered unlikely, thus decreasing the priority of the timeliness of doxycycline administration. Clinicians may have collected a thorough history and determined that even though the patient has symptoms similar to RMSF, the risk factors were likely lower (ie the patient did not have any recent travel history, tick bites, or frequented any wooded regions). Finally, most of these children presented in a nonacute fashion (ie were not in shock, respiratory failure, or encephalopathic like our index case). Thus, the relatively well condition of the patient impacted how a clinician ordered the medication (urgently versus not). Based on our study findings, known microbiology testing limitations, and the potential for patient harm in an unrecognized case, we recommend that if a provider suspects and/or tests for RMSF, empiric doxycycline should be administered.

It is unclear why there was only 1 y (2018) where all patients tested for RMSF received empiric treatment with a potential decreasing trend in RMSF testing the y thereafter. Possibilities for this include faculty and resident turnover, where the clinicians involved in the case no longer are present within the institution (thereby resulting in a collective decrease in the index of suspicion). The personal impact of the event may have diminished due to the passage of time. There may be less experienced clinicians. Finally, this case may no longer be discussed within the residency education curriculum.

There were various limitations in this study. This was a single center retrospective study with a small sample size. Due to limitations in data retrieval from our electronic health record, variation in provider documentation practices, and potential for omitted data, we focused only on patients who were tested for RMSF rather than subjects that should have been considered. Thus, we did not review patients who may have been empirically treated for RMSF without testing or who may have symptoms possibly associated with RMSF. We did not determine if sepsis associated organ dysfunction was present. The index case was seen initially in the outpatient setting. Therefore, it is unknown if a peer review discussion took place after this case or if there was an impact on diagnostic and/or treatment practices in the outpatient setting. Finally, it is unknown if the practice changes that we described were truly in response to the index case or from the rise in RMSF cases noted nationwide.

CONCLUSION

Our study found that inpatient testing for RMSF increased after the index case, but not all patients received empiric treatment. This possibly represents an underappreciation of RMSF severity even with a devastating case that should have triggered a change in practice, even with noninvolved clinicians. We suggest that when severe rare but possible reversible diseases, such as RMSF occur, all clinicians are educated on the diagnostic and treatment approach to reduce the risk of morbidity and mortality.