ARTICULO MEDICO:Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone.SIADH

Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone
secretion (SIADH)
Author
Richard H Sterns, MD
Section Editor
Michael Emmett, MD
Deputy Editor
John P Forman, MD, MSc
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jan 2013. | This topic last updated: nov 20, 2012.
INTRODUCTION — The syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
is a disorder of impaired water excretion caused by the inability to suppress the secretion of
antidiuretic hormone (ADH) [1]. If water intake exceeds the reduced urine output, the ensuing
water retention leads to the development of hyponatremia.
The SIADH should be suspected in any patient with hyponatremia, hypoosmolality, and a urine
osmolality above 100 mosmol/kg. In SIADH, the urine sodium concentration is usually above 40
meq/L, the serum potassium concentration is normal, there is no acid-base disturbance, and the
serum uric acid concentration is frequently low [1]. (See "Evaluation of the patient with
hyponatremia".)
The pathophysiology and etiology of SIADH will be reviewed here. The treatment of this
disorder is discussed separately. (See "Treatment of hyponatremia: Syndrome of inappropriate
antidiuretic hormone secretion (SIADH) and reset osmostat".)
PATHOPHYSIOLOGY
Pathogenesis of hyponatremia — The plasma sodium concentration (PNa) is a function of the
ratio of the body's content of exchangeable sodium and potassium (NaE and KE) and total body
water (TBW) as described by Edelman's classic equation:
PNa ≈ NaE + KE/Total body water
Antidiuretic hormone (ADH, arginine vasopressin) secretion results in a concentrated urine and
therefore a reduced urine volume. The higher the plasma ADH, the more concentrated the
urine. In most patients with the syndrome of inappropriate secretion of antidiuretic hormone
(SIADH), ingestion of water does not adequately suppress ADH, and the urine remains
concentrated. This leads to water retention, which increases TBW. This increase in TBW lowers
the plasma sodium concentration by dilution (see above equation) [1]. In addition, the increase
in TBW transiently expands the extracellular fluid volume and thereby triggers increased urinary
sodium excretion, which both returns the extracellular fluid volume toward normal and further
lowers the plasma sodium concentration.
Hyponatremia can occur in SIADH even if the only fluid given is isotonic saline [2]. The
mechanism by which this occurs and why isotonic saline administration can lower the plasma
sodium concentration in patients with SIADH and a highly concentrated urine is discussed
separately. (See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone
secretion (SIADH) and reset osmostat", section on 'Intravenous saline'.)
Patterns of ADH secretion — In normal individuals, plasma ADH levels are very low when the
plasma osmolality is below 280 mosmol /kg, thereby permitting the excretion of ingested water,
and ADH levels increase progressively as the plasma osmolality rises above 280 mosmol/kg
(figure 1).
ADH regulation is impaired in SIADH; four different patterns have been described [3,4]:
 Type A is characterized by erratic, unregulated release of ADH that varies widely
with no relation to the plasma osmolality. Plasma ADH levels are often above that
required for maximum antidiuresis, so the urine osmolality is typically very high.
 Type B is characterized by a modest and constant leak of ADH.
 Type C, characterized by downward resetting of the osmostat, is a variant of
SIADH in which the plasma sodium concentration is normally regulated (and is
therefore stable) at a lower level, typically between 125 and 135 meq/L.
Establishing the presence of this condition is important because, unlike other
forms of SIADH, there is no need to be concerned that the plasma sodium will
continue to fall without therapy. This disorder is discussed in detail elsewhere.
(See "Treatment of hyponatremia: Syndrome of inappropriate antidiuretic hormone
secretion (SIADH) and reset osmostat", section on 'Reset osmostat'.)
 Type D, the least common, is characterized by normal osmoregulation (ie, ADH
secretion varies appropriately with the plasma osmolality), but the urine is
concentrated even if ADH release is suppressed. At least one mechanism by
which this occurs is a germ cell mutation in which the V2 vasopressin receptor is
constituently activated [3]. Other potential mechanisms include production of an
antidiuretic compound other than immunoreactive arginine vasopressin and a
postreceptor defect in trafficking of aquaporin-2 water channels, which mediate
ADH-induced antidiuresis. (See 'Hereditary SIADH' below.)
Determinants of urine output — In addition to the persistent secretion of ADH, there are two
other potentially important determinants of the urine output in patients with SIADH: the rate of
solute excretion and partial escape from the effect of ADH.
Solute excretion — In normal subjects, the urine output is primarily determined by water
intake. Changes in water intake lead to alterations in the plasma osmolality that are sensed by
the osmoreceptors in the hypothalamus that regulate both ADH release and thirst. As an
example, an increase in water intake sequentially lowers the plasma osmolality, decreases ADH
secretion, and reduces collecting tubule permeability to water; the net effect is the rapid
excretion of the excess water in a dilute urine.
In SIADH, however, an increase in water intake does not produce an increase in water
excretion because ADH release is relatively fixed. Suppose that a patient has moderately
severe SIADH with a urine osmolality that cannot be reduced below 750 mosmol/kg (the normal
minimum urine osmolality is 40 to 100 mosmol/kg). In this patient, the urine output is determined
by the rate of excretion of solutes (primarily sodium and potassium salts and urea). Now
suppose this patient consumes a typical Western diet containing approximately 750 mosmol of
solute, all of which are excreted in the urine each day. With a fixed urine osmolarity of 750
mosmol/kg, the daily urine output will be only one liter (750 ÷ 750 = 1), and it will not increase in
response to increased water intake.
One way to increase water excretion in this hypothetical patient with SIADH is to prescribe a
high salt and protein diet without a increase in water ingestion. If, for example, the solute intake
and therefore solute excretion rose to 1200 mosmol/day, the urine output would increase to 1.6
L/day (1200 ÷ 750 = 1.6). The increase in water excretion would then tend to raise the plasma
sodium concentration toward normal.
Similar considerations concerning the role of solute intake apply when ADH effect is relatively
fixed at a low level in central or nephrogenic diabetes insipidus. (See "Urine output in diabetes
insipidus".)
Escape from the effect of ADH — Studies in experimental animals given ADH and water have
shown an initial phase of water retention and hyponatremia followed by partial escape from the
antidiuresis so that, despite persistently high levels of ADH, urine osmolality decreases. When
the urine osmolality falls, water excretion increases, matching water intake, and the plasma
sodium concentration tends to stabilize [5,6]. A similar response appears to occur in humans
[7,8].
This escape from ADH-induced antidiuresis appears to be mediated by decreased expression
of aquaporin-2, the ADH-sensitive water channel in the collecting tubules [9]. The regulation of
aquaporin-2 in this setting appears to be unrelated to plasma or tissue osmolality [10,11].
ETIOLOGY — One of the following causes of persistent antidiuretic hormone (ADH) release is
likely to be present in patients who fulfill the clinical criteria for the syndrome of inappropriate
secretion of antidiuretic hormone (SIADH) [1,12]:
CNS disturbances — Any CNS disorder, including stroke, hemorrhage, infection, trauma, and
psychosis, can enhance ADH release. A discussion of the disturbances in water balance that
may occur in patients with mental illness and a brief review of the antidiuretic action of
carbamazepine, a drug that can cause an SIADH picture, are found elsewhere. (See "Polydipsia
and hyponatremia in patients with mental illness".)
As in other causes of SIADH, hyponatremia associated with intracranial bleeding, as well as
other severe neurologic events, is due to ADH-mediated water retention and to urinary sodium
losses. However, with these severe neurological conditions, there is uncertainty as to whether
the sodium losses are a result of SIADH-induced expansion of the extracellular volume or
whether they are caused by salt wasting (ie, cerebral salt wasting), with release of ADH that is
secondary to a reduction in extracellular fluid volume. (See 'Cerebral salt wasting' below.)
Because of this uncertainty, therapy of hyponatremia in patients with CNS disorders usually
requires the administration of hypertonic saline, rather than fluid restriction or isotonic saline
(see 'Cerebral salt wasting' below).
Malignancies — Ectopic production of ADH by a tumor is most often due to a small cell
carcinoma of the lung and is rarely seen with other lung tumors [1,13]. Less common causes of
malignancy-associated SIADH include head and neck cancer, olfactory neuroblastoma
(esthesioneuroblastoma), and extrapulmonary small cell carcinomas [14-16].
Ectopic ADH secretion by tumor cells has been documented in vitro. In addition, some small cell
lung cancer cells increase ADH secretion in response to high osmolality, suggesting a degree of
regulation of the ectopic secretion [17]. This in vitro finding is compatible with the clinical
observation that some patients with tumor-induced SIADH show evidence of osmoregulation of
ADH release [4]. (See "Pathobiology and staging of small cell carcinoma of the lung".)
Drugs — Certain drugs can enhance ADH release or effect, including chlorpropamide,
carbamazepine, oxcarbazepine (a derivative of carbamazepine), high-dose intravenous
cyclophosphamide, and selective serotonin reuptake inhibitors [1,18-26]. Experimental studies
suggest that chlorpropamide may increase concentrating ability both by increasing sodium
chloride reabsorption in the loop of Henle (thereby enhancing the efficiency of countercurrent
exchange) and by augmenting collecting tubule permeability to water [19]. The latter effect may
be mediated by an increased number of ADH receptors in the collecting tubule cells.
Carbamazepine and oxcarbazepine also act at least in part by increasing the sensitivity to ADH
[20,21,24].
SIADH due to high-dose intravenous cyclophosphamide may be a particular problem since
patients receiving this regimen are often fluid loaded to prevent hemorrhagic cystitis [25,26]. As
a result, marked water retention and potentially fatal hyponatremia may ensue in selected cases
[25]. This complication has been primarily described with doses in the range of 30 to 50 mg/kg
used to treat malignancy, or 6 g/m2 as given in the STAMP protocol in preparation for bone
marrow rescue [26]. Although less common, hyponatremia can also occur with the lower doses
(10 to 15 mg/kg) that are given as pulse therapy in autoimmune diseases such as lupus
nephritis. Chemotherapy-induced nausea may play a contributory role since nausea is a potent
stimulus to ADH release. (See "Chapter 6B: Antidiuretic hormone and water balance", section
on 'Other factors affecting ADH secretion'.) The fall in the plasma sodium concentration in this
setting can be minimized by using isotonic saline rather than free water to maintain a high urine
output.
SIADH is also associated with the selective serotonin reuptake inhibitors (eg, fluoxetine,
sertraline) [27-31]. The exact prevalence is unknown; patients above age 65 years may be more
susceptible to the complication [31].
Many other drugs have been associated with the SIADH. These include vincristine, vinblastine,
vinorelbine, cisplatin, thiothixene, thioridazine, haloperidol, amitriptyline, monoamine oxidase
inhibitors, melphalan, ifosfamide, methotrexate, opiates, nonsteroidal antiinflammatory agents,
interferon-alpha, interferon-gamma, sodium valproate, bromocriptine, lorcainide, amiodarone,
ciprofloxacin, high-dose imatinib, and "ecstasy" (methylenedioxymethamphetamine), a drug of
abuse that may also be associated with excessive water intake [1,27,32-36].
Surgery — Surgical procedures are often associated with hypersecretion of ADH, a response
that is probably mediated by pain afferents [37-39]. In addition, hyponatremia may develop after
other types of interventional procedures, such as cardiac catheterization [40].
Hyponatremia is also a common late complication of transsphenoidal pituitary surgery,
occurring in 21 to 35 percent of cases [41,42]. Although relative cortisol deficiency may
contribute, the major cause is inappropriate ADH release from the injured posterior pituitary
gland. The fall in the plasma sodium concentration is most severe on the sixth to seventh
postoperative day. This form of isolated hyponatremia (or isolated second phase) appears to be
a subset of the classic triphasic cycle in which initial polyuria is followed by transient SIADH
and then either recovery or, in severe cases, a third phase of permanent central diabetes
insipidus. (See "Clinical manifestations and causes of central diabetes insipidus", section on
'Neurosurgery or trauma'.)
Rarely, hyponatremia after pituitary surgery is due to cerebral salt wasting (see 'Cerebral salt
wasting' below).
Pulmonary disease — Pulmonary diseases, particularly pneumonia (viral, bacterial,
tuberculous), can lead to the SIADH, although the mechanism by which this occurs is not clear
[38]. A similar response may infrequently be seen with asthma, atelectasis, acute respiratory
failure, and pneumothorax [1,38].
Hormone deficiency — Both hypopituitarism and hypothyroidism may be associated with
hyponatremia and an SIADH picture that can be corrected by hormone replacement. (See
"Hyponatremia and hyperkalemia in adrenal insufficiency" and "Causes of hyponatremia",
section on 'Hypothyroidism'.)
Hormone administration — The SIADH can by induced by exogenous hormone
administration, as with vasopressin (to control gastrointestinal bleeding),
desmopressin (dDAVP, to treat von Willebrand disease or hemophilia or platelet dysfunction), or
oxytocin (to induce labor) [43-46]. As with vasopressin and desmopressin, oxytocin acts by
increasing the activity of the V2 (antidiuretic) vasopressin receptor [47].
HIV infection — A common cause of hyponatremia is symptomatic HIV infection, either the
acquired immune deficiency syndrome (AIDS) or early symptomatic HIV infection [48]. Although
volume depletion (due, for example, to gastrointestinal losses) or adrenal insufficiency may be
responsible, many patients have the SIADH. Pneumonia, due to Pneumocystis carinii or other
organisms, central nervous system infections, and malignant disease, are most often
responsible in this setting [48]. (See "Electrolyte disturbances with HIV infection".)
Hereditary SIADH — The clinical picture of SIADH may result from genetic disorders that result
in antidiuresis. At least two genetic abnormalities have been identified, one affecting the gene
for the renal vasopressin-2 (V2) receptor, which some investigators have named nephrogenic
syndrome of inappropriate antidiuresis, and one affecting osmolality sensing in the
hypothalamus.
In the initial description of the nephrogenic syndrome, two male infants were described who
presented with hyponatremia, hypoosmolality, increased urine osmolality, and a high urine
sodium concentration consistent with SIADH, but with no detectable circulating ADH [49,50].
Gain-of-function mutations were found in the gene encoding the V2 receptor that mediates the
antidiuretic response to ADH; persistent activation of the receptor was responsible for the
persistent antidiuretic state [51]. The gene for the V2 receptor is located on the X chromosome,
and loss-of-function mutations of the gene are responsible for X-linked nephrogenic diabetes
insipidus. (See "Clinical manifestations and causes of nephrogenic diabetes insipidus", section
on 'Hereditary nephrogenic DI'.)
The nephrogenic syndrome of inappropriate antidiuresis has also been found in adult men and
women. In one study, a 74-year-old man with an initial diagnosis of SIADH was unresponsive to
oral inhibitors of the V2 receptor; he was subsequently discovered to have a gain-of-function
mutation of the gene for this receptor [52]. After screening of family members, two additional
hemizygous males and four heterozygous females were identified. Spontaneous episodes of
hyponatremia and/or an abnormal water-load test were observed in all but one woman with the
genetic defect, who had preferential inactivation of the X chromosome harboring the mutated
allele.
The hereditary hypothalamic syndrome is due to a mutation in the transient receptor potential
vanilloid type 4 (TRPV4) gene, which encodes a component of the central osmolality-sensing
mechanism in the hypothalamus [53]. A loss-of-function polymorphism in this gene interferes
with sensing of hypoosmolality and therefore interferes with appropriate suppression of ADH
release in the presence of hypoosmolality. Thus, affected individuals behave as if they have a
reset osmostat, as the serum sodium is modestly reduced (mean 136 meq/L in this family) and
regulated normally around that value. Thus, in the absence of a superimposed disease, there is
no risk of progressive hyponatremia. (See "Treatment of hyponatremia: Syndrome of
inappropriate antidiuretic hormone secretion (SIADH) and reset osmostat", section on 'Reset
osmostat'.)
Idiopathic — Idiopathic SIADH has been described primarily in elderly patients [54-57].
However, some cases of apparently idiopathic disease were later found to be caused by an
occult tumor (most often small cell carcinoma or olfactory neuroblastoma) and, in older patients,
giant cell (temporal) arteritis [1,55,58,59].
CEREBRAL SALT WASTING — A rare syndrome has been described in patients with cerebral
disease (particularly subarachnoid hemorrhage) that mimics all of the findings in the syndrome
of inappropriate secretion of antidiuretic hormone (SIADH) except that salt wasting is thought to
be the primary defect, with the ensuing volume depletion causing a secondary rise in
antidiuretic hormone (ADH) release. This distinction is not always easy to make since the true
volume status of the patient is sometimes difficult to ascertain. The pathogenesis,
manifestations, and treatment of cerebral salt wasting are discussed separately. (See "Cerebral
salt-wasting".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials,
“The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain
language, at the 5th to 6th grade reading level, and they answer the four or five key questions a
patient might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics patient
education pieces are longer, more sophisticated, and more detailed. These articles are written
at the 10th to 12th grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on “patient info” and the keyword(s) of interest.)
 Basics topic (see "Patient information: Syndrome of inappropriate antidiuretic
hormone secretion (SIADH) (The Basics)")
SUMMARY
 The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a
disorder of impaired water excretion caused by the inability to suppress the
secretion of antidiuretic hormone (ADH). (See 'Introduction' above.)
 SIADH should be suspected in any patient with hyponatremia, hypoosmolality, and
a urine osmolality above 100 mosmol/kg. In SIADH, the urine sodium
concentration is usually above 40 meq/L, the serum potassium concentration is
normal, there is no acid-base disturbance, and the serum uric acid concentration is
frequently low. (See 'Introduction' above.)
 ADH secretion results in a concentrated urine and therefore a reduced urine
volume. In most patients with SIADH, ingestion of water does not adequately
suppress ADH, and the urine remains concentrated. This leads to water retention,
which increases total body water (TBW). This increase in TBW lowers the plasma
sodium concentration by dilution. In addition, the increase in TBW transiently
expands the extracellular fluid volume and thereby triggers increased urinary
sodium excretion, which both returns the extracellular fluid volume toward normal
and further lowers the plasma sodium concentration. (See
'Pathophysiology' above.)
 One of the following causes of persistent ADH release is likely to be present in
patients who fulfill the clinical criteria for the SIADH (see 'Etiology' above):
 Any CNS disorder, including stroke, hemorrhage, infection, trauma, and
psychosis can enhance ADH release. There is uncertainty as to whether
hyponatremia in patients with severe neurologic disorders (such as
hemorrhage or trauma) is due to SIADH or salt wasting (ie, cerebral salt
wasting). (See 'CNS disturbances' above and 'Cerebral salt wasting' above.)
 Ectopic production of ADH by a tumor is most often due to a small cell
carcinoma of the lung and is rarely seen with other lung tumors. Less common
causes of malignancy-associated SIADH include head and neck cancer,
olfactory neuroblastoma (esthesioneuroblastoma), and extrapulmonary small
cell carcinomas. (See 'Malignancies' above.)
 Certain drugs can enhance ADH release or effect, including chlorpropamide,
carbamazepine, oxcarbazepine (a derivative of carbamazepine), high-dose
intravenous cyclophosphamide, and selective serotonin reuptake inhibitors.
Many other drugs have been associated with the SIADH. These include
vincristine, vinblastine, vinorelbine, cisplatin, thiothixene, thioridazine,
haloperidol, amitriptyline, monoamine oxidase inhibitors, melphalan,
ifosfamide, methotrexate, opiates, nonsteroidal antiinflammatory agents,
interferon-alpha, interferon-gamma, sodium valproate, bromocriptine,
lorcainide, amiodarone, ciprofloxacin, and high-dose imatinib. "Ecstasy"
(methylenedioxymethamphetamine) is a drug of abuse that may also be
associated with both SIADH and excessive water intake. (See 'Drugs' above.)
 Surgical procedures are often associated with hypersecretion of ADH, a
response that is probably mediated by pain afferents. In addition,
hyponatremia may develop after other interventional medical procedures, such
as cardiac catheterization. (See 'Surgery' above.)
 Pulmonary diseases, particularly pneumonia (viral, bacterial, tuberculous), can
lead to the SIADH, although the mechanism by which this occurs is not clear.
A similar response may infrequently be seen with asthma, atelectasis, acute
respiratory failure, and pneumothorax. (See 'Pulmonary disease' above.)
 Both hypopituitarism and hypothyroidism may be associated with
hyponatremia and clinical findings identical to SIADH, but these abnormalities
are corrected by hormone replacement. (See 'Hormone deficiency' above.)
 SIADH can by induced by exogenous administration of hormones: vasopressin
(to control gastrointestinal bleeding); ADH analogs, such as
desmopressin (dDAVP, to treat von Willebrand disease, hemophilia, other
forms of platelet dysfunction, or enuresis); or other hormones with antidiuretic
effects, such as oxytocin (to induce labor). (See 'Hormone
administration' above.)
 Symptomatic HIV infection is associated with SIADH. (See 'HIV
infection' above.)
 The clinical picture of SIADH may result from genetic disorders that result in
antidiuresis. (See 'Hereditary SIADH' above.)

ARTICULO MEDICO: MANIFESTACIONES CLINICAS Y DX DE LA FIEBRE MANCHADA DE LAS MONTAÑAS ROCOSAS

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Clinical manifestations and diagnosis of Rocky Mountain spotted fever
Author
Daniel J Sexton, MD
Section Editors
Stephen B Calderwood, MD
Sheldon L Kaplan, MD
Deputy Editor
Elinor L Baron, MD, DTMH
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Jan 2013. | This topic last updated: mar 16, 2011.
INTRODUCTION — Rocky Mountain spotted fever (RMSF) is a potentially lethal but usually curable tick-borne disease. It is the most common rickettsial infection in the United States. The etiologic agent, Rickettsia rickettsii, is a gram-negative, obligate intracellular bacterium with tropism for human endothelial cells. The clinical spectrum of human infection with R. rickettsii ranges from mild to fulminant. The epidemiology, clinical manifestations, and diagnosis of RMSF will be reviewed here.
The basic biology of R. rickettsii infection, the mechanisms of disease, and the treatment of
this disorder are discussed separately. (See "Biology of Rickettsia rickettsii infection" and "Treatment of Rocky Mountain spotted fever".)

EPIDEMIOLOGY
Geography — RMSF occurs throughout the United States, in Canada, Mexico, Central America,
and in parts of South America (Bolivia, Argentina, Brazil, and Colombia). In the United States,
RMSF is most prevalent in the southeastern and south central states. In 2007, there were 2221
cases of RMSF reported to the Centers for Disease Control and Prevention (CDC); this represented
an increase from the 1130 cases reported in 2003 [1]. The estimated national average annual
incidence of RMSF was 2.2 cases per million persons in 2003, but incidence varied by geographic
area from 1 to >15/100,000 persons (figure 1) [1,2]. However, epidemiologic studies that attempt to assess the frequency of RMSF have been hampered by the fact that serologic assays that do not distinguish RMSF from other spotted fever group rickettsiae species and by imprecise case
definitions [3,4].
An outbreak of RMSF in 16 patients from 2002 through 2004 was reported from rural eastern
Arizona, a state that had previously only rarely reported the disease (three cases from 1981 through
2001) [5]. Of these patients, 13 (81 percent) were children ≤12 years of age; all had contact with
tick-infested dogs (see 'Transmission' below).
Although RMSF is more common in rural and suburban locations, it also may occasionally occur in
residents of urban areas. For example, cases of RMSF have been described in New York City in
patients who presumably acquired the infection from tick bites in urban parks [6]. The ease and
frequency of interstate travel means that patients with RMSF acquired in endemic areas may
present to physicians practicing in locations where RMSF is uncommon or unknown. In addition,
family clusters of infection are a well-recognized feature of RMSF because of shared residence and
risks for vector exposure [7,8].
An investigation of clusters of cases in Tennessee and North Carolina concluded that significant
geographic differences in disease severity were present [9]. Similar clusters of severe disease have
been reported in several locations in South America [10].
Seasonal variation — Most cases of RMSF occur in the spring and early summer, when outdoor
activity is most frequent. However, rare cases are seen in the cold weather months in residents of
the southern United States [11]. Whether these "out of season" cases are due to infection with R.
rickettsii or other more benign spotted fever group rickettsiae has recently been questioned [3].
Risk factors — The frequency of reported cases of RMSF is highest among males. Although
previous studies found that the highest incidence of RMSF occurred in children <10 p="" years="">surveillance during 2003 demonstrated the highest age-specific incidence was among persons
aged 40 and 64 years [12]. Individuals with frequent exposure to dogs and who reside near wooded
areas or areas with high grass are probably also at increased risk for infection.
A retrospective study utilizing a national surveillance database found that the incidence of RMSF
among American Indians was 16.8/100,000 during the period from 2000 to 2005. In contrast, the
incidence among whites and blacks was 4.2 and 2.6/100,000, respectively [13].
TRANSMISSION
Route — RMSF is usually transmitted via a tick bite; tick bites are painless and many occur in body
areas obscured by hair or skin folds. Thus it is not surprising that up to one-third of patients with
proven RMSF do not recall a recent tick bite or recent tick contact [14,15]. Transmission rarely
occurs from infective tick tissues or feces by conjunctival contamination, transcutaneous
transmission, or inhalation (eg, after crushing blood-engorged ticks).
Vectors — The principal vector of RMSF in the eastern and south central United States is
Dermacentor variabilis (the American dog tick) (picture 1). In contrast, Dermacentor andersoni (the
Rocky Mountain wood tick) (picture 2) is the primary vector in the mountain states west of the
Mississippi River.
Rhipicephalus sanguineus, the common brown dog tick (picture 3), is also a vector for RMSF in
some areas of the United States [5]. This tick was implicated in the outbreak of RMSF in rural
eastern Arizona, noted above. R. sanguineus ticks in all life-stages of growth were abundantly found in and around many of the patients' homes and R. rickettsii was detected on polymerase chain reaction (PCR) and cultured from engorged and nonengorged ticks. Neither of the primary vectors for RMSF in the United States, D. variabilis nor D. andersonii ticks, was recovered from the homesites. Although the ecology of rural eastern Arizona that allowed the infestation of R.
sanguineous ticks may not be generalizable to other regions of the United States, the R.
sanguineus tick is widely distributed across North America, and should be considered as a potential
vector. The Cayenne tick (Amblyomma cajennense) is a vector for R. rickettsii transmission in
Central and South America. The yellow dog tick (Amblyomma aureolatum) has also been implicated as a vector in Brazil [16].
Incubation period — Infected patients become symptomatic 2 to 14 days after being bitten by an
infected tick, with most cases occurring between five and seven days after exposure.

CLINICAL MANIFESTATIONS
Early nonspecific symptoms — In the early phases of illness, most patients have nonspecific
signs and symptoms such as fever (in virtually all cases), headache (often severe), malaise,
myalgias, arthralgias, and nausea with or without vomiting (each in about 60 percent) [17]. Some
patients, especially children, may also have prominent abdominal pain that may be severe and may
lead to erroneous diagnoses such as acute appendicitis, cholecystitis, and even bowel obstruction
[18,19]. A small number of patients in the early phases of RMSF have been admitted to surgical
services and some have undergone laparotomy.
Rash — Most patients with RMSF develop a rash between the third and fifth days of illness (picture4) [8,17].

PICTURE 4: Rocky mountain spotted fever rash

Child with Rocky Mountain spotted fever has the rash that is characteristic but typically does not appear until several days after fever onset.

From: Fatal Cases of Rocky Mountain Spotted Fever in Family Clusters --- Three States, 2003. MMWR Morb Mortal Wkly Rep 2004; 53(19):407. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5319a1.htm.

 However, only 14 percent of patients have rash on the first day, and less than one-half
develop a rash in the first 72 hours of illness [20]. As a result, rash is often absent when patients
first contact a physician [20,21]. In a small percentage of patients, the rash is delayed in onset past
five days and/or is atypical (eg, confined to one body region).
A potential diagnostic problem is that rash never occurs in up to 10 percent of patients. These cases
of "spotless" RMSF may be severe and end fatally [22]. In addition, the rash can be easily
overlooked in dark-skinned individuals. These observations are important clinically because a delay
in the institution of antimicrobial therapy beyond five days is associated with an increased mortality
rate (22.9 versus 6.5 percent in those treated earlier in one report) [21]. (See "Treatment of Rocky
Mountain spotted fever".)
The typical rash of RMSF begins on the ankles and wrists and spreads both centrally and to the
palms and soles. The evolution of skin rash may vary among patients. Although the rash commonly
begins as a maculopapular eruption and then becomes petechial, some patients may suddenly
develop a petechial rash without a prior maculopapular eruption. Urticaria and pruritus are not
characteristic of RMSF and their presence makes the diagnosis unlikely.
Other symptoms — In addition to early nonspecific symptoms, abdominal pain, and rash, cough,
bleeding, edema (especially in children), confusion, focal neurologic signs, and seizures may also
be present [18]. Conjunctivitis, retinal abnormalities, and electrocardiographic abnormalities may
also rarely occur and lead to diagnostic confusion. The presence or absence of individual clinical
manifestations is in part dependent upon the duration of illness. As an example, physicians in
referral centers often see patients late in the course and are more likely to observe symptoms such
as abnormal mentation, seizures, and focal neurologic deficits such as cranial nerve palsies or
transient deafness. Gangrene of the digits, ears, and scrotum can also occur in severe cases, as
can widespread organ dysfunction [23,24].
Mortality — An estimated 612 deaths were attributable to RMSF in the United States between
1983 and 1998 [25]. The case-fatality rate was highest in the very young (≤4 years, 3 to 4 percent)
and elderly persons (≥60 years, 4 to 9 percent) (figure 2) [26].
DIFFERENTIAL DIAGNOSIS — In view of the protean clinical features of RMSF, it is not surprising
that this disorder is often confused with a wide array of other conditions.
· RMSF is commonly mistaken for an undifferentiated viral illness during the first few days of
illness. If penicillin or a cephalosporin is administered empirically during this phase of
illness, the subsequent rash may then be incorrectly diagnosed as a drug eruption.
· RMSF has been confused with measles, meningococcemia, infectious mononucleosis, viral
hepatitis, leptospirosis, streptococcal infection, parvovirus infection (Fifth disease), roseola,
enteroviral infection, and viral meningitis. In tropical areas typhoid fever, leptospirosis, and
even dengue may be confused with RMSF.
· The clinical features of RMSF overlap with those of both monocytic ehrlichiosis and
granulocytic anaplasmosis. Distinguishing between RMSF and ehrlichiosis on the basis of
clinical features may be impossible, although the presence of leukopenia and the absence
of rash are more typical of ehrlichiosis (table 1). The preferred treatment of
ehrlichiosis, doxycycline, is the same as that of RMSF. (See"Human ehrlichiosis and
anaplasmosis" and "Treatment of Rocky Mountain spotted fever".)
· One study reported that a proposed new rickettsial species (Rickettsia amblyommii) present
in the tick Ambylomma americanum may be in fact responsible for some illnesses in North
Carolina that are identical in their clinical presentation to infection with R. rickettsii [27]. At
present this report remains unconfirmed and of unknown significance.

DIAGNOSIS — The diagnosis of RMSF is based upon the probability that individual clinical features represent RMSF in the appropriate epidemiologic setting, as with suggestive symptoms in an endemic area in the spring or early summer [28]. There is no completely reliable diagnostic test in the early phases of illness when therapy should be begun. Later, the diagnosis can be made by skin biopsy and confirmed serologically. Rickettsial blood cultures are highly sensitive and specific but are only available in research centers with specialized laboratories.
Laboratory studies — Most patients with RMSF have a normal white blood cell count at
presentation. However, the white blood cell count may be low, normal, or elevated in individual
patients and is therefore not diagnostically helpful. As the illness progresses, thrombocytopenia
becomes more prevalent and may be severe; it is thought to result from increased destruction at
sites of rickettsia-mediated vascular injury [20]. The low platelet count may be accompanied by a
reduced fibrinogen concentration and elevated fibrin split products; however, true disseminated
intravascular coagulation is rare.
Other findings that are common in advanced cases include hyponatremia, elevations in serum
aminotransferases and bilirubin, azotemia, and prolongation of the partial thromboplastin and
prothrombin times [18]. In a small number of cases, jaundice and renal failure dominate and
confuse the clinical presentation [24,29].
In a review of 114 patients from our hospital, 19 percent developed acute renal failure (defined as
an elevation in the serum creatinine concentration above 2 mg/dL [177 micromol/L]) [29]. A variety of mechanisms may contribute to this complication, including hypotension-induced acute tubular necrosis, intravascular thrombosis, and interstitial vascular inflammation due to direct infection of the endothelial cells by R. rickettsii. (See "Biology of Rickettsia rickettsii infection".)
If a lumbar puncture is performed in a patient with RMSF, cerebrospinal fluid (CSF) analysis usually shows a white blood count (WBC) of <100 a="" cells="" either="" microl="" or="" p="" per="" polymorphonuclear="" with="">lymphocytic predominance [18]. Moderately elevated protein (100 to 200 mg/dL) and a normal glucose level are common [30,31]. These findings may not help distinguish RMSF from meningococcal disease.
Skin biopsy — Biopsy of a skin lesion obtained with a 3 mm punch biopsy can establish the
diagnosis of RMSF. Fresh or formaldehyde-fixed tissue should be examined for rickettsiae using
direct immunofluorescence or immunoenzyme methods [32]. Direct immunofluorescence staining
can provide an answer in a few hours if the necessary conjugates are available locally. If local
facilities are not able to do direct immunofluorescence, reference laboratories can perform
immunoperoxidase stains on fixed tissue specimens. However, the delay in obtaining results makes
this technique of little or no use for initial patient management.
The sensitivity of detecting R. rickettsii in skin biopsies by direct immunofluorescence staining is
approximately 70 percent with a specificity of 100 percent; however, the sensitivity rapidly declines
after antirickettsial therapy is begun [32]. It is therefore not useful to obtain a skin biopsy in patients
who have received a tetracycline (usually doxycycline) or chloramphenicol for more than 48 hours.
Serologic testing — The diagnosis of RMSF is best confirmed serologically using the indirect
fluorescent antibody (IFA) test [33]. IFA testing is available through all state health departments and through several large reference laboratories. Antibodies typically appear 7 to 10 days after the onset of the illness, and the optimal time to obtain a convalescent antibody titer is at 14 to 21 days after the onset of symptoms. The minimum diagnostic titer in most laboratories is 1:64.
The overall sensitivity of the IFA test is approximately 95 percent. However, there are two settings in which false negative results are more likely:
· Serologic testing is usually not helpful during the first five days of symptoms, when therapy
should be initiated, because the antibody response is not yet detectable [21].
· A small percentage of patients who are treated within the first 48 hours after symptoms
have begun may not develop convalescent antibodies [33].
Although the IFA is sensitive, serologic assays are insufficient to identify conclusively the specific
rickettsial agent responsible for the infection. A study of 15 serum specimens with antibodies
reactive with R. rickettsii from the CDC examined the specimens by microimmunofluorescence and
Western blot assays against antigens of R. rickettsii and R. parkeri [34]. Four patients had higher
titers of antibody to R. rickettsii, five had higher titers to R. parkeri, and in six patients titers were
equivalent to both rickettsial pathogens. Thus, spotted fever group rickettsiae, other than R.
rickettsii, may be responsible for cases of tick-borne rickettsiosis in the United States.
Other serologic tests that may be employed include enzyme immunoassay (EIA), complement
fixation (CF) and latex agglutination (LA), indirect hemagglutination (IHA) or microagglutination (MA) assays. A probable diagnosis of RMSF may be established with a titer of 1:128 or greater by LA, IHA, or MA.
The Weil-Felix test, which detects crossreacting antibodies against Proteus vulgaris antigens (OX2
and OX19), lacks sensitivity and specificity and its use is no longer recommended [17,33].

SUMARY AND RECOMMENDATIONS
· Rocky Mountain spotted fever (RMSF) is a potentially lethal but usually curable tick-borne
disease. (See 'Introduction' above.)
· RMSF occurs throughout the United States, Canada, Mexico, Central America, and in parts
of South America (Bolivia, Argentina, Brazil, and Colombia). (See 'Geography' above.)
· Most cases of RMSF occur in the spring and early summer, when outdoor activity is most
frequent. (See 'Seasonal variation' above.)
· RMSF is usually transmitted via a tick bite, although up to one-third of patients with proven
RMSF do not recall a recent tick bite or recent tick contact. (See 'Transmission' above.)
· In the early phases of illness, most patients have nonspecific signs and symptoms such as
fever, headache, malaise, myalgias, arthralgias, and nausea with or without vomiting.
Children may also have prominent abdominal pain that may be mistaken for other
intraabdominal processes, like appendicitis. Most patients with RMSF develop a rash
between the third and fifth days of illness. (See 'Clinical manifestations' above.)
· The diagnosis of RMSF is a clinical one based on a constellation of symptoms that is
consistent with the clinical presentation in an appropriate epidemiologic setting (eg, an
endemic area in the spring or early summer). There is no completely reliable diagnostic test
in the early phases of illness when therapy should be initiated. (See 'Diagnosis' above.)
· In later illness, the diagnosis can be made by skin biopsy and confirmed serologically.
(See 'Diagnosis' above.)
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REFERENCES