Author: Amy L. Puchalski, MD, Assistant Professor of Emergency Medicine and Pediatrics, Medical College of Georgia, Augusta.
Peer Reviewer: Steven M. Winograd, MD, FACEP, Attending, Emergency Medicine, St. Joseph Medical Center, Yonkers, NY.
Petechial rashes represent a common finding among pediatric patients presenting to emergency departments (EDs). By definition, a petechial lesion is a reddish-purple macule that does not blanch when pressed.3 A petechia measures < 2 mm in diameter, a purpura is 2 mm to 1cm diameter, and an ecchymosis is larger than 1 cm.4
They are often the cause of great concern for clinicians, particularly in the setting of a febrile or ill-appearing child. One prospective study in a pediatric ED found 2.5% of patients presented to their facility with a petechial rash.1 Petechiae are a common finding among children evaluated for routine health maintenance visits, as well. Among 116 well infants presenting to a single outpatient clinic, 27.6% were found to have at least one petechial lesion on close physical examination.2 The number of diagnostic possibilities for a child with petechiae is sizeable. Coupled with the consideration that some of these rashes are sentinels of life-threatening conditions, the evaluation of a child with petechiae or purpura can often be challenging for clinicians.
Introduction / Pathophysiology
An understanding of hemostatic mechanisms is helpful in considering the causes of petechial rashes, as these lesions are a result of local areas of hemorrhage into the dermis. Normal hemostasis first requires constriction at the site of vascular injury or inflammation. In addition, von Willebrand factor and factor VIII are released from damaged endothelial cells, forming a complex which adheres to the exposed collagen matrix. The vWF –VIII complex helps platelets adhere to the damaged endothelium, promoting formation of the platelet plug. These platelets go on to release ADP and thromboxane A2 to continue the process of platelet aggregation and plug formation. This process constitutes primary hemostasis. The endothelial injury also initiates the coagulation cascade, resulting in the fibrin clot to stabilize the initial platelet plug, the process comprising secondary hemostasis.3,4,10 Derangements in any aspect of this process can result in petechial lesions, along with a variety of other clinical findings.
The primary pathophysiologic causes of petechial and purpuric lesions are thrombocytopenia, platelet dysfunction, disorders of coagulation, and loss of vascular integrity.3,4 Thrombocytopenia may be secondary to increased platelet destruction, decreased platelet production, sequestration, and platelet loss or consumption.5 Platelet dysfunction results from both congenital and acquired causes, as do disorders of coagulation. Vascular integrity can be altered by trauma, vascular inflammation, or congenital defects in connective tissues. Various clinical entities result in petechial lesions through multiple of these mechanisms. Infections, for example, can result in purpuric lesions via thrombocytopenia due to consumption during disseminated intravascular coagulation (DIC) or decreased production from marrow suppression; disruption of vascular integrity due to capillary leak or vessel inflammation; and consumption of coagulation factors in DIC.3 In hemolytic uremic syndrome, platelet sequestration, consumption in diffuse microthrombi and increased platelet destruction are all at work in the resultant thrombocytopenia and petechial rash.3
It is helpful to consider the differential diagnosis of petechial rashes in light of the various pathophysiologic mechanisms of petechiae and purpura formation mentioned previously. Table 1 summarizes some diagnostic considerations based on the mechanism of petechiae formation. (A more extensive list of the causes of petechial and purpuric rashes can be found on the Rapid Reference card inserted in this issue.)
Thrombocytopenia. Increased destruction of platelets is seen in conditions such as idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), neonatal alloimmune thrombocytopenia (NAIT), and hemolytic uremic syndrome (HUS). NAIT is akin to Rh hemolytic disease of the newborn in that it occurs in infants of mothers negative for human platelet antigen 1a who were sensitized during a prior pregnancy. Thrombocytopenia may begin in utero or the early neonatal period due to destruction of platelets by maternal antibodies. Petechiae, severe bleeding, intracranial hemorrhage, and resultant hydrocephalus can occur in utero and over the first few months of life. Diagnosis is confirmed by good response to transfusion of maternal platelets as opposed to destruction of transfused random donor platelets.5
Decreased production of platelets is characteristic of marrow infiltrative processes and bone marrow suppression. Marrow suppression is caused by multiple viral or bacterial infections, including Epstein-Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), varicella, mumps, and TORCH infections.5,6 Various drugs and toxins may cause marrow suppression, as well. Marrow infiltrative processes are seen with malignancies such as leukemia and neuroblastoma as well as storage diseases.4 Thrombocytopenia –absent radii syndrome (TAR) is an autosomal recessive disorder characterized by absence of megakaryocytes at birth, though they are often present by age 2-3 years. Fanconi anemia is characterized by short stature, skeletal anomalies, and café-au-lait spots, as well as pancytopenia.4
Platelet sequestration may occur in any condition causing splenomegaly. This may include chronic liver disease, viral infection, or portal vein thrombosis.3-5 Sequestration within a cavernous hemangioma is characteristic of Kasabach-Merritt syndrome and may be accompanied by DIC or high output congestive heart failure.3,4
Platelet Dysfunction. Congenital causes of platelet dysfunction are usually rare, recessive, inherited conditions that may present with petechial rashes. Wiscott-Aldrich is an X-linked recessive disease characterized by thrombocytopenia due to shortened platelet survival, immunodeficiency, and eczema.3,4 Glanzmann's thrombasthenia results from a platelet membrane glycoprotein IIb or IIIa deficiency, impairing platelet aggregation.3 Bernard-Soulier is another inherited platelet membrane glycoprotein deficiency resulting in platelet dysfunction. Storage pool disease and congenital amegakaryocytic thrombocytopenia are other rare inherited causes.3 Acquired platelet dysfunction may be present in patients with uremia or those exposed to drugs such as salicylates, lasix, heparin, or non-steroidal anti-inflammatory drugs (NSAIDs).3
Coagulation Factor Deficiency. The hemophilias or congenital coagulation factor deficiencies, most commonly factor VIII or IX, generally present with hemarthrosis, muscle bleeds, ecchymosis, or severe bleeding associated with trauma and minor procedures. Petechiae or purpura may be components, as well; the aforementioned symptoms are more typical.3,4 von Willebrand factor deficiency is more common than the hemophilias and is characterized by mucosal bleeding with minor trauma, menorrhagia, and prolonged bleeding from dental extractions or circumcision. Some patients are relatively asymptomatic. Petechial or purpuric rashes may be seen in addition to these bleeding tendencies.3 Acquired factor deficiencies are a component of DIC, liver disease, uremia, and vitamin K deficiency.3,4
Loss of Vascular Integrity. Trauma is one of the primary mechanisms responsible for petechiae and purpura due to disruption of vessel walls. This includes abusive trauma, self-inflicted trauma, and increased systemic venous pressure due to strangulation, suffocation, or persistent coughing and emesis.3,4 Many infectious processes as well as DIC disrupt capillary walls and result in petechiae. Vasculidities such as Henoch-Schonlein Purpura (HSP) or systemic lupus erythematosis (SLE) have petechial rash as a component of their clinical picture, as well. Various drugs and toxins, such as penicillins, corticosteroids, bismuth, and sulfonamides, can disrupt vascular integrity.3,4 Vitamin C deficiency can occur in patients on parenteral nutrition, infants fed evaporated milk as their main source of nutrition, and those with iron overload.3,7 Collagen synthesis is impaired, resulting in poor wound healing, petechial lesions, swollen gingiva, irritability in infants, and generalized bony tenderness.7 Pseudoparalysis results from diffuse tenderness, with young children assuming a frog-leg position for comfort.7 An infant with significant irritability and generalized tenderness due to scurvy can be confused with the septic or abused patient. Radiographs reveal bones with a ground-glass appearance and thin cortex.7 A congenital disease that impairs vessel wall integrity is Ehlers-Danlos. Several of the types of Ehlers-Danlos cause easy bruising and petechiae. Other manifestations of this disease include hypermobile joints, hyperelastic skin, vascular aneurysms or valvular insufficiency, and bowel perforation.3,4
General Approach to a Child with a Petechial Rash
Historical Findings. Given the wide array of diagnostic considerations when evaluating the child with a petechial or purpuric rash, the initial assessment is paramount to guiding subsequent investigations, therapy and disposition. Important historical data to obtain initially include the onset, duration and pattern of spread of the lesions. Acute onset and rapid spread of lesions may be concerning for more serious conditions such as meningococcemia or other invasive bacterial diseases. The previously well child with sudden onset of petechiae and bruising is a classic presentation of ITP. It is important to note whether there is a history of bleeding from other sites, including gingival bleeding, epistaxis, hematemesis, hemoptysis, melena, hematochezia, menorrhagia, hematuria, or hemarthrosis.5 Potential central nervous system bleeds may present with headaches, visual changes, behavioral or mental status changes, focal weakness or sensory changes. A history of fever, myalgias, recent upper respiratory symptoms or vomiting and diarrhea certainly lead in the direction of an infectious cause of petechiae, whether it be a viral exanthem, thrombocytopenia related to viral marrow suppression, or onset of DIC or purpura fulminans. A history of preceding upper respiratory or gastrointestinal illness is often elicited in children with ITP or HUS. All patients should be questioned about current or recent medication use, as many can cause thrombocytopenia, platelet dysfunction or vascular fragility. Constitutional symptoms such as fever, malaise, night sweats, bone pain, or weight loss should prompt consideration of a malignancy. Joint swelling or arthralgias along with a history of fevers can be consistent with a systemic vasculitis such as SLE. Children with a history of congenital heart disease, prosthetic heart valve or an indwelling central venous catheter are at risk for infective endocarditis, which may present with a petechial rash, as well.
The age of the patient can be helpful in narrowing the diagnoses under consideration. HSP, for example, is most common in children age 2 years to 5 years. The neonate with petechiae certainly should bring to mind concern for infection, whether bacterial, viral or a congenitally acquired TORCH infection. History of hearing loss, microcephaly, jaundice, poor weight gain or skeletal anomalies may be other symptoms of TORCH infections. Skeletal anomalies are also seen in patient with TAR syndrome and Fanconi anemia. Neonatal autoimmune thrombocytopenia or neonatal thrombocytopenias secondary to maternal ITP are considerations in this age group as well. Inherited disorders of platelet function often present in the neonatal period, and a family history of bleeding or bruising may be elicited in these disorders. Family history may also be helpful in the diagnosis of hemophilia, though some children may have new, spontaneous mutations.
Associated Physical Signs. Physical examination findings in the evaluation of children with petechial rash are as varied as the historical features which aid in diagnosis. The overall appearance of the child is the most important initial clinical assessment. The ill-appearing, irritable or lethargic child with petechiae, regardless of the presence of fever, should prompt immediate consideration of invasive infection. Children with malignancy, aplastic anemia, HUS, and TTP, as well as victims of physical abuse, may be ill-appearing. Vital signs give important clues to potential causes of petechial rashes along with overall appearance of the patient. Tachycardia is an early sign of shock in pediatric patients and should prompt evaluation for sepsis, invasive bacterial or rickettsial infection, DIC, anemia, or significant blood loss. Hypertension may be seen in children with renal disease associated with HUS, HSP, or SLE. The finding of hepatosplenomegaly may be seen with viral infections (EBV, CMV, TORCH), leukemia and other malignancies, chronic liver disease, or splenic sequestration of platelets. Lymphadenopathy is similarly present in children with malignancy and viral infections, as well as SLE. Pallor is another finding consistent with malignancy in addition to HUS, aplastic anemia, Evans syndrome or children with significant blood loss. As mentioned previously, skeletal anomalies are present in children with TAR syndrome, Fanconi anemia, and some TORCH infections. Arthritis is sometimes a finding in those with SLE, HSP, or meningococcal septic arthritis.
Pattern, Location, and Type of Lesion. The type of petechial lesions as well as sites of associated bleeding can provide clues to the pathophysiologic mechanism responsible for the rash. Coagulation factor deficiencies are characterized by ecchymoses, hemarthrosis, or muscle bleeds. Vasculitidies are often characterized by palpable purpura. Disorders of platelet number or function typically cause mucosal bleeding, petechiae, and occasionally central nervous system (CNS) bleeding.3 In cases of thrombocytopenia, the types of bleeding vary with the platelet count. Hemostasis is generally not impaired until the platelet value is < 75 x 103 / µL. Spontaneous bleeding, such as mucosal bleeding or petechiae, begins at levels < 50 x 103 / µL. Patients are at risk for clinically significant bleeding when platelets drop below 20 x 103 / µL, and spontaneous CNS hemorrhage is of concern with platelet counts < 10 x 103 / µL.5
The significance of the location of petechial lesions is often a topic of discussion, particularly related to its role in determining the severity of the underlying disease. Conventionally, petechial lesions above the nipple line, or in the distribution of the superior vena cava, are felt to be potentially less concerning and likely due to increased venous pressure from crying, coughing, or vomiting. Study data has given mixed results regarding this clinical assumption.8 One study prospectively enrolling 190 children presenting to a pediatric ED with fever and petechiae found that no children with petechiae limited to above the nipple line had invasive bacterial disease.9 A more recent study of 233 children presenting prospectively with a non-blanching rash to the ED found none with petechiae confined to the region of the SVC had meningococcal disease.10 No invasive bacteria other than Neisseria meningiditis were cultured from participants in this study. Contradictory to these two studies, however, a third that retrospectively evaluated children admitted with fever and petechiae reported that 25% of subjects with invasive bacterial disease had petechiae confined to above the nipple line.11 Clearly, the distribution of petechiae alone cannot rule out significant illness such as invasive bacterial disease, but must be taken within the entire clinical context. This specific pattern itself may in fact be associated with significant events such as strangulation or suffocation.
The specific type of lesion has been studied with regard to its ability to predict invasive bacterial disease. A retrospective review of children with documented meningococcal disease at 10 different centers failed to show significant difference in the number of patients with petechial lesions (< 2 mm diameter) versus purpuric lesions (> 2 mm diameter).12 The previously mentioned prospective study of 233 children with non-blanching rash, however, reported those with purpuric as opposed to petechial lesions were more likely to have meningococcal disease.1 As mentioned regarding location of petechial lesions, the size of the lesions is perhaps another observation that must be placed in the context of the patient's overall clinical picture.
Various patterns of petechial lesions can be helpful in diagnosis, particularly in the case of some infectious etiologies. The rash of Rocky Mountain Spotted Fever (RMSF) typically begins on day 4 of illness, initially consisting of blanching macules on the wrists and ankles before it becomes petechial in the next day or two. It spreads from the extremities centripetally to involve the trunk and proximal extremities. Involvement of the scrotum or labia may be a diagnostic clue for RMSF.13 The rash of measles may have petechial or purpuric components, and it classically spreads head to toe and centrally to peripherally. It resolves in the same order it appeared, usually by day 10 of illness. The classic symptoms of cough, coryza, and conjunctivitis accompany the rash as well as fever and ill-appearance.14 Rubella, or German measles, typically has milder symptoms. Classically, the rash consists of rose-pink macules and papules and may have a petechial or purpuric component. Neonates with congenitally acquired infection during the first trimester may develop petechiae or purpura, as well.14 Parvovirus B19 can occasionally cause the "purpuric gloves and socks syndrome" with petechial or purpuric lesions limited to the palms, soles, and distal extremities. This rash is more commonly manifested in adolescents and has been documented with EBV, CMV, and human herpes virus 6 infection, as well.14,15 Rapidly progressive lesions in number and or size can be consistent with meningococcemia, DIC, or purpura fulminans due to other invasive bacteria. Several folk remedies involve repeated trauma to the skin that result in petechial lesions in specific patterns.16 Inflicted or abusive injuries may also result in petechiae or purpura that either resemble an object used to deliver the blows or are in unusual locations, such as the pinna or helix of the ear.16 Finally, the purpuric rash of Henoch-Schonlein purpura classically involves the lower extremities, buttocks, and extensor surfaces of the arms.
Laboratory Evaluation. A myriad of additional studies may be considered in the child with a petechial rash to assist with diagnosis and evaluation. The well-appearing, afebrile child with a few scattered petechiae around an area of known accidental trauma clearly would not benefit from further study. The ill-appearing child with fever, hepatosplenomegaly, lymphadenopathy, or progressive rash, on the other hand will certainly undergo laboratory and diagnostic evaluation. As with the evaluation of many chief complaints in the pediatric population, the initial history and physical exam are paramount to decisions about likely diagnosis and further evaluation.
CBC with Differential. Initially, the complete blood count (CBC) with differential and PT/PTT can usually provide the most helpful information. The presence of thrombocytopenia, defined as a platelet count less than 150 x 103 / µL, is a helpful first distinction to make, and as noted previously, thrombocytopenia is seen in many diagnoses. (See Table 1.) The mean platelet volume (MPV), which normally ranges from 7-9 fL, can provide some valuable clinical information. An elevated MPV on the order of 10-15 fL may be indicative of ITP, while a low MPV is seen with marrow suppression or ineffective hematopoesis, such as aplastic anemia, Wiskott-Aldrich, or TAR syndrome.3,5 It is also important to note abnormalities in the other two bone marrow lineages. Anemia accompanying thrombocytopenia may indicate blood loss, hemolysis, or bone marrow suppression, failure, or infiltration. Infectious processes, DIC, HUS, aplastic anemia, malignancy, SLE, or Evans syndrome present with anemia and thrombocytopenia. Leukopenia, lymphopenia, or neutropenia in addition are potential findings in malignancy, infection, DIC, aplastic anemia, or SLE.3-5 Other specific findings on the differential may be helpful, as well. Neutrophilia or bandemia may be present with infection, though not universally. The presence of atypical lymphocytes can indicate infection with EBV or CMV, while blasts on the peripheral smear diagnose leukemia or lymphoma. Schistocytes are noted on the peripheral blood smear of patients with HUS, DIC, or TTP.
Coagulation Studies. An elevated prothrombin time indicates low levels of factor II, V, VII, X, or fibrinogen.3,4 DIC, liver disease, renal disease, vitamin K deficiency, and congenital heart disease may have a prolonged PT.3 A prolongation of the activated partial thromboplastin time occurs with decreased factor II, V, VIII, IX, X, XI, XII, and fibrinogen.3,4 Hemophilia, von Willebrand disease (vWD), DIC, liver disease, heparin therapy, or vitamin K deficiency may prolong this time.3 As for specific factor deficiencies, once there is less than 40% of the factor activity level, the coagulation studies will show an abnormality. Healthy infants may have prolongation of PT/PTT up to 3 or 4 months of age due to hepatic immaturity.3 One interesting study showed a trend toward prolonged PTT among children presenting for evaluation of fever and petechial rash who ultimately did not have bacteremia or sepsis. Two-hundred seventy-three prospectively identified pediatric patients at a single pediatric ED who had a PT/PTT as part of their evaluation for fever and petechial rash were retrospectively compared with controls without fever or petechiae. Significantly more case patients had a prolonged PTT as compared to the controls. The PT values did not differ, and, interestingly, the white blood cell count was similar among the groups. The case patients also had lower platelet counts than the controls (273,000 vs. 347,000).17 The authors point out that an isolated prolonged PTT in a febrile child with petechiae may not itself be an indicator of invasive bacterial disease. A bleeding time or studies of platelet aggregation may be considered in a patient with suspected vWD or inherited disorders of platelet function, though this study would be done on an outpatient basis and not during the ED visit.3,4
Other Studies. Blood cultures and specific viral or RMSF titers are certainly indicated to evaluate for sepsis, meningococcemia, and DIC. Fibrinogen and fibrin split products are also helpful in evaluating and treating the patient with suspected DIC. Children suspected of having a malignancy need electrolytes, BUN, creatinine, uric acid, and lactate dehydrogenase (LDH) levels to assess for tumor burden and possible tumor lysis syndrome. A urinalysis with dipstick and microscopy are helpful in any patient suspected of having associated hemolysis, tumor lysis, or renal involvement, such as those with HSP, HUS, or SLE. Rheumatoid factor and anti-nuclear antibodies may be of use in a child with associated arthritis or malar rash in whom SLE or other vasculitis is suspected. Children with severe factor deficiencies or thrombocytopenia, particularly < 10 x 103 µL, and focal neurologic findings, seizures, or altered mental status require urgent computerized tomography of the head to evaluate for intracranial hemorrhage. Neonates with lesser degrees of thrombocytopenia are at risk for spontaneous intracranial hemorrhage, and may manifest only non-specific clinical symptoms such as poor feeding or fussiness, if any at all. A small portion of children require bone marrow aspiration for diagnosis of their condition, particularly if two or three cell lineages are abnormal on the CBC. This decision is made in consultation with a hematologist.3,4,6 (See the Rapid Reference card in this issue for a table showing diagnostic considerations for various historical, examination, and laboratory findings.)
The issue of management of a child with a petechial or purpuric rash depends primarily on the suspected diagnosis and clinical presentation. Subsequent sections will address more specifically the management of patients with some of the more common or life-threatening etiologies of petechial rashes. One particularly challenging general scenario is that of the febrile or ill-appearing child who presents with a petechial rash.
Fever and Petechiae. The presentation of fever and petechial rash in a child is often a source of great concern and anxiety for clinicians. Petechiae are not an uncommon finding in febrile children. One study documented 1.8% of children presenting to an ED with fever and rash had petechiae, as well.18 Likewise, viral symptoms are frequently found in children with petechial rashes. In a study of babies presenting to a clinic for routine health maintenance visits, 22.5% of those reporting recent viral symptoms had one or more petechiae identified on physical examination.2 In another study, the most common diagnosis among 190 study patients admitted to the hospital with fever and petechiae was viral upper respiratory infection or documentation of a specific viral infection.9 Many viral etiologies have been associated with petechiae, including enteroviruses, respiratory syncitial virus, adenovirus, parvovirus, echovirus, CMV, and EBV, as well as multiple viral hemorrhagic fevers.9,19 The challenge comes in sorting out which patient may in fact have invasive bacterial or rickettsial disease as opposed to a viral syndrome.
The incidence of invasive bacterial disease or clinical sepsis in children with fever and petechiae has varied in the literature. In one prospective cohort of 411 patients evaluated in the ED for fever and petechiae, 1.9% had either sepsis or a bacterial pathogen cultured from blood. Over half the patients with bacteremia or sepsis were 3 –36 months old.18 Another prospective study of 264 patients admitted for fever and petechial rash reported 15% had meningococcemia and 2% had other bacterial pathogens cultured from blood.20 This study was conducted prior to the introduction of meningococcal vaccination into the schedule of routine childhood vaccinations. Two other studies in hospitalized children with fever and petechial rash report incidences of 7% and 11% of patients with meningococcemia.9,11 The studies of hospitalized patients with fever and petechiae would be expected to report higher rates of invasive bacterial disease than the study of ED patients due to selection bias.
The aforementioned studies sought to establish risk factors or criteria to aid in predicting which children with fever and petechiae have invasive bacterial disease. In the cohort of children evaluated in the ED, none who were documented as being well-appearing had bacteremia or sepsis.18 The two patients with meningococcemia from this study both had purpuric lesions as opposed to only petechial ones.18 The prospective study of 264 hospitalized children with fever and petechiae established five variables in their population, which helped to predict which patients had invasive bacterial disease. These included ill appearance, nuchal rigidity, widely distributed petechiae, at least one purpuric lesion (diameter > 2 mm), and appearance of petechial lesions consistent with ones previously seen in meningococcal disease. Presence of at least two of these five variables gave a 97% probability of correctly identifying children with meningococcal disease, with only a 12% false positive rate.20 These predictors were not helpful in identifying patients with bacteremia or sepsis due to organisms other than N. meningiditis. The prospective study of 190 hospitalized children found those with invasive bacterial disease were more often ill-appearing, had petechiae on the lower extremities and had meningismus.9
Laboratory investigations are sometimes helpful in predicting which children have invasive bacterial disease, though not always reliably. The study by Baker and colleagues of hospitalized febrile children with petechiae did not identify any single test that could detect all patients with invasive bacterial disease.9 There was a trend toward increased risk in those with elevated CSF WBC (> 7 cells), elevated WBC (> 15,000), or elevated peripheral band count (> 500). The presence of any one of these abnormalities in a child with fever and petechiae had a sensitivity of 93%, specificity of 62%, and positive predictive value of 48% for invasive bacterial disease.9 The study also reported a trend toward decreased risk of invasive disease in those who were well-appearing and had normal labs, or the population of children over age three years with pharyngitis. The study by Nguyen, et al of admitted patients with fever and petechiae similarly found no children with invasive bacterial disease with the combination of fever < 40º C and normal WBC, ANC, absolute band count, and CSF studies. No single test in this study predicted all patients with invasive disease.11 (See Table 2.)
Without the aid of a single way to predict which children have invasive bacterial disease when presenting with fever and petechial rashes, clinicians are left to take all aspects of history, physical exam, and laboratory evaluation into account on a case by case basis to determine the best management strategy. In general, many clinicians will obtain a blood culture, CBC, and often PT/PTT as screening for this patient population. A rash pattern classic for a specific virus or documentation of a positive rapid strep test, for example, may make even these laboratory evaluations unnecessary. Social support and access to medical care need to be taken into account when making decisions about possible outpatient treatment of well-appearing febrile children with petechial rash and normal laboratory values. The challenge of the ill-appearing child is not the decision of whether or not to begin empiric antibiotic therapy or embark on a laboratory evaluation, but on rapid recognition of symptoms and institution of supportive care. In the case of an ill-appearing child with a petechial rash, with or without a fever, clinicians should consider life threatening infections, in particular RMSF, meningococcemia, and invasive Staphylococcus aureus or Streptococcus pneumoniae.8,21 Concerning findings such as a generalized rash, delayed capillary refill, and abnormal CBC, CRP, or other labs should prompt rapid administration of empiric antibiotics.8 Obtaining a blood culture prior to antibiotic administration is ideal, but difficulty or inability to do this should not delay antibiotic administration. Similarly, antibiotic administration should not be delayed to obtain a lumbar puncture in the ill-appearing or septic child. Ceftriaxone at a dose of 100 mg/kg/day in one or two divided doses will cover N. meningiditis as well as possible gram-negative organisms and some S. pneumoniae strains.8 S. pneumoniae is a documented cause of purpura fulminans and petechial rash.6,9,11,21 The addition of vancomycin will provide coverage for resistant strains of S. pneumoniae and S. aureus. Finally, doxycycline should be included as the treatment of choice for RMSF.
Selected Etiologies of Petechial Rash
Meningococcal Disease. Epidemiology. In 2008, there were 1,172 cases of meningococcal disease reported to the Centers for Disease Control and Prevention (CDC) in the United States.22 Approximately 98% of cases in recent years have been sporadic, though outbreaks may occur in close quarters such as dorms or barracks.23-25 Disease is most common among infants < 1 year of age and in adolescents and young adults, with the highest attack rates occurring in young children.12,25,26 As discussed previously, meningococcal disease is not an uncommon etiology of fever and petechial rash in children. Studies of patients in the ED have been more widely discrepant, with one documenting 0.5% and another 11% of patients with petechial rash in the ED ultimately having meningococcal disease.1,18 Among non-toxic appearing febrile children age 3 –36 months, one database of 6,649 subjects documented 0.03% had a positive blood culture for meningococcus.26 The high mortality rate of this relatively uncommon infection makes it widely known and feared by clinicians. The disease carries an 8% –15% mortality rate, and 10% –19% of survivors may have long term sequelae, such as hearing loss, neurodevelopmental problems, seizures, cognitive deficits, amputations or skin grafting.12,21,23,27,28 Mortality may decrease to 5% with early recognition of the disease symptoms and prompt transfer to a pediatric intensive care unit.21
Pathophysiology. N. meningiditis is an encapsulated gram-negative diplococcus which causes a clinical spectrum ranging from asymptomatic nasopharyngeal carriage to meningitis and purpura fulminans.29 Up to 5% –20% of people in non-endemic areas may have nasopharyngeal colonization.13,29 Transmission occurs via droplet transfer by direct or close contact. Symptom onset occurs within 14 days of exposure.18.29 Upper respiratory tract infections and passive smoke exposure increase meningococcal disease susceptibility as do a history of asplenia and terminal complement or properidin deficiency.29,30 Serotypes B and C predominate in the United States, while serotype A predominates worldwide.12,29
Clinical Presentation. N. meningiditis classically presents with fever, headache, rash, and myalgias, and most commonly causes sepsis, meningitis, or both. Meningitis occurs in 50% –85% of patients with meningococcal disease, sepsis alone is seen in 10% –20%, and a mixed picture of sepsis and meningitis in 40% –60%.12,21,25,29 Meningococcus can also cause septic arthritis, osteomyelitis, conjunctivitis, endophthalmitis, pharyngitis, and pericarditis.25,28 Rash is one of the most common presenting features of this disease process, though it is not always present and not always petechial. In a study of 336 patients with known positive cultures for N. meningiditis, 69% had a petechial rash.26 Another observational study of patients with meningococcal disease found 80% had a petechial/purpuric rash, 13% had a blanching maculopapular rash, and 7% had no rash at all.31 It is important to recognize that the rash of meningococcal disease may initially be blanching and macular before progressing to petechial or purpuric. As the rash progresses into palpable purpura, it may take on a characteristic "gunmetal gray" discoloration with a necrotic center.13 Likewise, the absence of fever on presentation should not exclude the diagnosis of invasive meningococcal disease. In the study by Wells and colleagues, 20% of children who ultimately had meningococcal disease were not febrile at presentation.10 Another early clinical symptom is extremity pain. A review of 274 children with invasive meningococcal disease showed 16% had a history or physical exam that documented extremity pain or refusal to walk.32 Close attention should be given to signs of shock, including tachycardia, cool extremities, delayed capillary refill, altered mental status, tachypnea, and hypoxia.21,29
Laboratory Evaluation. Initial laboratory evaluation for meningococcal disease ideally includes a blood culture, CBC, PT/PTT, CRP, lumbar puncture if there are signs of meningitis, and a type and screen to prepare for a possible clinical deterioration. When presented with an ill-appearing or critically ill child, the diagnostic evaluation should not delay administration of antibiotics. Similarly, an LP should never be performed on a clinically unstable patient or before verification of a normal platelet count and coagulation studies when the child has a petechial rash. Blood and CSF PCR and serology can still provide confirmation of the diagnosis even after administration of antibiotics. Laboratory data may not always be confirmatory of clinically suspected disease, especially early in the course of the illness.21 Wells and colleagues found among children presenting with petechial rashes who were ultimately diagnosed with invasive meningococcal disease, 42% had a normal WBC (4,000 –11,000), 75% had a normal platelet count (> 150,000), 92% a normal PTT and 42% a normal PT.1 The one laboratory value that was predictive of disease in this study was an elevated CRP. No child with a CRP < 6.0 mg/L had meningococcal disease.1
Management. The most important component of the management of children with suspected meningococcal disease is early recognition and treatment. Clinical suspicion should prompt early administration of parenteral antibiotics.21,28,29 If a blood culture can be obtained prior to giving antibiotics, that is ideal, but the primary goal is to begin antimicrobial therapy as quickly as possible. Most strains of meningococcus are sensitive to penicillin, but in the early stages of therapy before an actual pathogen is cultured and sensitivities obtained, ceftriaxone or cefotaxime are the antibiotics of choice.21 As gram-negative rods and S. pneumoniae are also possible etiologic agents in sepsis or purpura fulminans, third-generation cephalosporins provide the necessary breadth of coverage.51 Intravenous access should be obtained rapidly, often times necessitating placement of an intraosseous needle. Early fluid resuscitation with crystalloid has been shown to increase survival from meningococcemia.34 Many children will go on to require ionotropic support after several boluses of crystalloid. In shock refractory to fluids and ionotropes, the administration of hydrocortisone should be considered to treat possible adrenal insufficiency due to shock or Waterhouse-Friedrichson syndrome. Anemia, thrombocytopenia, hypoglycemia, and abnormalities of electrolytes or coagulation should be closely monitored and corrected. Fluid resuscitation, ionotropic support, and sepsis often result in capillary leak, pulmonary edema, and the need for mechanical ventilation.21 As mentioned previously, early transfer to a pediatric intensive care unit can optimize the patient's outcome.29
Prophylaxis must be administered to close household contacts and those in close proximity to the patient's respiratory droplets. Ceftriaxone, rifampin, and azithromycin are options for prophylaxis.27
In summary, suspect meningococcal disease in patients who are ill-appearing with fever and rash; patients with meningismus, fever, and prolonged capillary refill; or patients with a progressive petechial rash. Treat clinically suspected cases early and aggressively.29
Rocky Mountain Spotted Fever. Epidemiology. In 2008, 2,563 cases of RMSF were reported to the CDC, of which 2,367 were probable cases and only 190 confirmed.22 The disease is most commonly seen in the spring and summer, with 90% occurring from April to October over the 10-year period from 1994 to 2003.34,35 Despite its name, most cases occur in the south Atlantic, southeastern, and south central United States.34,35 An estimated 2/3 of cases occur in children, with a peak in the 5- to 9-year-old age group.35 Unfortunately this age group also carries the highest mortality rate, sometimes approaching 15% –20%.8,34 Mortality is also greater in those who are untreated or have significant delay in treatment, as well as those without a known history of a tick bite, likely a risk factor for delayed therapy.35 Only about 50% –60% of patients have a known history of tick exposure.30,34 Early antimicrobial therapy may reduce mortality to 5%.8
Pathophysiology. Rickettsia rickettsii is an obligate gram-negative intracellular organism with predilection for endothelial cells.30,35 It is transmitted to humans via bite or exposure to crushed tissue from the wood tick, dog tick, or lone star tick.30 Tick attachment of 12 –24 hours is necessary to allow sufficient transfer of fluids containing the pathogen, and the incubation period is 2 –14 days.30,34,35 The organisms infect and multiply in small vessel endothelial cells, leading to thrombosis and red cell leakage through the vessel wall.34
Clinical Manifestations. RMSF often presents with the triad of fever, headache, and rash, similar to meningococcal disease.34 Patients first have a prodrome of fever, headache, nausea, vomiting, malaise, anorexia, abdominal pain and myalgias, particularly of the calves.34 The rash begins around day 4 of illness, initially characterized by reddish-pink blanching macules on the palms, soles, wrists and ankles.13 The rash spreads centripetally over the next hours to days to involve the proximal extremities and trunk.13,35 Petechiae are apparent a day or two after the rash begins.30,34,35 Ten percent to 20% of patients never develop a rash at all, making the diagnosis even more challenging.13,35,36 Additional clinical symptoms that appear after the prodrome may include meningismus, seizure, coma, 6th-nerve palsy, joint pain, diarrhea, deafness, and blindness.34 Some may develop pneumonia, myocarditis, arrhythmias, congestive heart failure, jaundice, and heptosplenomegaly, as well, though these are less common.34
Laboratory Evaluation. Laboratory confirmation of suspected cases of RMSF is often difficult. Acute and convalescent serologies are the standard method to confirm the diagnosis of RMSF.34,35 A four-fold or greater increase in IgG-specific antibodies drawn 2 –3 weeks apart constitutes a positive test.35 PCR, culture methods, and stainings of skin biopsies are available as well and may help confirm a case. A single IgG titer of 1:64 or greater defines a probable case.35 Laboratory abnormalities may include hyponatremia, seen in about 20% of patients, thrombocytopenia, seen in 33% of patients, anemia, elevated transaminases, and mononuclear CSF pleocytosis.34
Management. Clinical suspicious for RMSF should prompt empiric therapy with doxycycline in all age groups.34,35 Consider a diagnosis of RMSF in any patient who is ill-appearing presenting with fever and petechial rash, and initiate prompt empiric treatment with doxycycline, along with therapy for other potential bacterial pathogens.8 As with invasive meningococcal disease, aggressive supportive therapy for shock, respiratory failure and electrolyte imbalances is vital to optimizing the child's clinical outcome.
Idiopathic Thrombocytopenic Purpura. Epidemiology and Pathophysiology. ITP is the most common cause of isolated thrombocytopenia in childhood, affecting approximately 5/100,000 children annually.5 Most children with ITP are younger than 10 years old, with the highest incidence among 3- to 5-year-olds.6 The disease occurs when anti-platelet antibodies form, bind to the patient's own platelets, and result in enhanced uptake and phagocytosis in the spleen.5 At least 50% of cases are known to occur after a viral infection such as gastroenteritis or an upper respiratory infection.5 ITP is also seen in association with viral infections such as CMV, HSV, and HIV.3 Approximately 10% of patient with SLE have ITP, and it may be the presenting sign of SLE in some adolescent patients.3,4 Drug-induced ITP may be caused by penicillin, valproic acid, quinidine, heparin, and sulfonamides.3
Clinical Course. ITP classically presents with the sudden onset of a petechial rash and easy bruising in an otherwise healthy, well-appearing child.5,37 About 30% will present with hemorrhage as well, such as epistaxis, hematochezia, or hematuria.5 Physical exam is generally significant only for petechiae, purpura. and bruising. It is important to look for signs of anemia secondary to acute blood loss on exam, such as tachycardia, tachypnea, pallor, or delayed capillary refill. Patients generally do not have hepatosplenomegaly, lymphadenopathy, fever, malaise, bony pain, rash, fatigue, weight loss, or jaundice.5,6,37 Presence of these or any other concerning symptoms warrants consideration of other diagnoses, such as leukemia, lymphoproliferative disorders, common variable immunodeficiency, SLE, inherited causes of thrombocytopenia, or child abuse.5,37 When adolescents present with ITP, consider evaluation for HIV, SLE, or other underlying autoimmune disorders.4 Less than 1% of children with ITP will develop intracranial hemorrhages during their illness.5,6 ITP is an acute disease in the majority of children; however, 10% –20% develop chronic ITP, defined as symptoms lasting for more than 6 months.5,6,37 Evaluation for an underlying autoimmune disorder should be considered in patients with chronic ITP.3
Diagnosis and Treatment. ITP is usually suspected based on the initial history and physical exam. The CBC generally helps to confirm the diagnosis by revealing thrombocytopenia with platelets less than 20,000, an elevated MPV of 10 –15 fL, and normal hemoglobin, WBC, and MCV.5 Patients with chronic ITP, atypical physical examination or laboratory findings, or poor response to therapy may require a bone marrow aspirate to make the diagnosis and exclude alternatives, such as leukemia.37 Treatment of ITP is supportive unless platelet counts fall below 10 –20 x 103/ µL. At this level, risk of spontaneous hemorrhage is significant and several different therapies are available to temporarily decrease platelet destruction. Intravenous immunoglobulins (IVIG), corticosteroids and anti- immunoglobulin are the more common treatment modalities, and the decision to use one is generally made in conjunction with a hematologist.5 In very rare instances of life-threatening bleeding that does not improve with any of these interventions, splenectomy may be considered as this removes the site of uptake and phagocytosis of platelets.5,6 Children with ITP may not participate in contact sports or activities that put them at risk for falls, and they should not take any medications containing aspirin or NSAIDs.5
Henoch-Schonlein Purpura. Epidemiology and Pathophysiology. HSP is the most common vasculitis in the pediatric population.3-5 It primarily affects younger children, with 75% of cases occurring in 2- to 11-year-olds, and occurs in boys twice as often as girls.4,37 Nephritis and gastrointestinal bleeding occur more often in children under 4 years of age, and 3% of children progress to end stage renal disease.39,40 HSP is a small vessel IgA-mediated vasculitis that is often preceded by a viral upper respiratory infection, hepatitis, Group A streptococcal infection or viral gastroenteritis.3,40 Immuncomplexes containing IgA deposit on vessel basement membranes to cause vasculitis.41
Clinical Course. The vasculitis primarily affects the blood vessels of the skin, gastrointestinal tract, kidneys and synovium, and yields the classic symptoms of purpuric rash, abdominal pain, joint pain and renal symptoms.41,42 The rash has a classic appearance, and often the diagnosis is based on this physical exam finding. It consists of petechiae and purpura primarily of the lower extremities and buttocks. Some boys will have scrotal involvement as well. Lesions may be present on the extensor surface of the arms, and in children under two, facial lesions may be present as well.41,43 In one case series, 100% of patients had the petechial rash, 75% had GI symptoms, 47% had renal symptoms, and 43% had arthritis or arthralgias.44 Gastrointestinal symptoms may include abdominal pain, hematochezia, and, rarely, intussusception. Renal symptoms and findings include proteinuria, hematuria, edema, nephritic syndrome, hypertension or even renal insufficiency and failure.42 Significant proteinuria may be a poor prognostic indicator for development of chronic or end-stage renal disease.45 Laboratory evaluation for children with suspected HSP includes a CBC, PT/PTT, urinalysis with microscopy, electrolytes, BUN, and creatinine. The CBC and coagulation studies are normal in HSP, though a child who has significant GI bleeding may be anemic.43
Treatment. The therapy for HSP is mainly supportive. NSAIDs may offer some relief from abdominal and joint pain. Occasionally, children require anti-hypertensive medications, and this is usually decided in conjunction with a pediatric nephrologist. The role of immunosuppressive therapy for HSP is controversial. One randomized, placebo-controlled study looking at the use of prednisone early in the course of disease showed a significant decrease in abdominal pain and joint pain. There was no difference in the number of children developing renal symptoms; however, in those who had renal symptoms and were randomized to prednisone, there was a reduction in the severity of symptoms.42 Another randomized trial evaluating cyclophosphamide failed to show any difference between the placebo and treatment group.39 In summary, children with nephritis, proteinuria, severe joint pain, or severe abdominal pain may get symptomatic relief from prednisone, but it will not alter the eventual outcome of their disease.46 Patients need close follow-up with their primary care physician or a nephrologist to continue screening for hypertension, the development of proteinuria or hematuria, or worsening joint or abdominal pain. Clinicians should consult a pediatric nephrologist when a child with HSP presents with hematuria, proteinuria or an abnormal BUN or creatinine. Parents must know signs of renal insufficiency, hypertension, and intussusception as well as have a plan for close follow-up when being discharged from the ED.
Hemolytic Uremic Syndrome. Epidemiology. HUS is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure.47,43 It is the most common cause of acute renal failure in children under age 5 years.47,49 The majority of cases occur in this age group, as well.43 In 2008, 330 cases of post-diarrheal cases were reported in the United States.22
Pathogenesis. Most pediatric cases of HUS are post-diarrheal. Escherichia coli O157:H7 is the causative organism in about 75% of HUS, and other cases have been associated with Shigella, Salmonella, Campylobacter, and enterohemorrhagic E. coli.43,47,48 Infection occurs either by exposure to contaminated animal products such as undercooked meat and unpasturized milk, or spread from contaminated vegetables, petting zoos, or other people with diarrheal illness.43,47
Clinical Course. HUS presents 2-14 days after the onset of diarrheal illness. Symptoms of anemia and thrombocytopenia are seen first, followed a few days later by diminished urine output, renal insufficiency and edema.47 Various specific clinical signs of disease include pallor and jaundice due to hemolysis, petechiae or purpura, tachycardia, hypertension, peripheral edema, CHF due to severe anemia, mucosal or genitourinary bleeding, altered mental status, seizures, and rarely, complications such as cerebral infarcts, hepatitis, myocarditis, and pancreatitis. It can be difficult to differentiate HUS from thrombotic thrombocytopenic purpura when neurologic symptoms predominate, a disease seen more often in adolescents and adults.47,48 Half of children develop hypertension, 50% have anuria for at least some part of their illness, and 20% –30% will have neurologic symptoms, most often seizures.47 The overall survival rate from HUS is 90%, with 65% –85% of children recovering completely over 1-2 weeks.47 Ten percent to 15% have long-term sequelae such as persistent hypertension or end-stage renal disease, and 5% may require long-term dialysis or renal transplant.47
Management. Early recognition of HUS and supportive care are the mainstays of therapy. Laboratory assessment for suspected HUS should include a CBC with differential, PT/PTT, Coombs test, electrolytes, BUN and creatinine, liver enzymes, and type and screen. The average hemoglobin of these patients is 8 gm/µL and average platelets are 50,000/µL, though half of children have > 100,000 platelets/µL at presentation.47 Coagulation studies are generally normal, and the direct coombs test is negative. Fluid and electrolyte imbalances must be corrected and monitored to determine need for dialysis in the case of worsening renal insufficiency. Some children require antihypertensive medications. Transfusion with packed red blood cells should be considered for symptomatic anemia, though platelet transfusions should be avoided as they may potentially contribute to increased microvascular thrombi.47,48 Platelet transfusions may be indicated prior to surgical procedures or catheter placement for dialysis.47 Plasmapheresis usually is not helpful in diarrhea-associated HUS, although it may be indicated in cases with severe renal disease, significant neurologic symptoms, or sporadic or non-diarrheal cases of HUS.47,48 All children with diagnosed or suspected HUS should be admitted to the hospital.
Malignancy. The leukemias and lymphomas are the most common childhood cancers, with acute lymphoblastic leukemia (ALL) being the most common and accounting for 25% of malignancy in children younger than age 15 years.49 The peak age of presentation for ALL is 2-5 years.49 Acute myeloid leukemia accounts for 4% of childhood cancer, and is seen in children who have undergone previous chemotherapy or radiation therapy. Children with certain underlying medical conditions are at greater risk for malignancies, specifically those with trisomy,21 Fanconi anemia, Klinefelter syndrome, neurofibromatosis, and Shwachman-Diamond syndrome.49 Thrombocytopenia and resultant petechial rashes are a common physical finding in children presenting with any malignancy that may infiltrate the bone marrow, including leukemia, lymphoma, neuroblastoma, rhabdomyosarcoma, and others. Up to 45% of patients with ALL present with petechiae or purpura, and 30% have a platelet level less than 20,000/ µL at diagnosis.49 Other symptoms include fever, pallor, weight loss, malaise, bone pain, lymphadenopathy, and hepatosplenomegaly. A child with bulky mediastinal disease may present with respiratory distress, facial edema or difficulty swallowing. A child with an extremely elevated WBC, greater than 100 x 103/ µL for example, is at risk for hyperviscosity syndrome and associated respiratory distress or neurologic impairment.
Laboratory evaluation for a child with suspected malignancy includes a CBC with differential, PT/PTT, type and screen, LFTs, electrolytes, BUN and creatinine, uric acid, lactate dehydrogenase (LDH) and chest radiograph. Children my have either leukocytosis or leucopenia at presentation, and up to half of young children presenting with ALL have a WBC less than 10 x 103/ µL.49,50 It is important to check the differential for evidence of neutropenia, lymphopenia or abnormal cell such as blasts. When a child presents to the ED with suspected malignancy, it is important to evaluate for tumor lysis syndrome when drawing lab work, as well. ED care of the child with suspected malignancy consists of obtaining diagnostic studies and providing supportive care. This may include packed red blood cells, platelets, or fresh frozen plasma transfusions; intravenous hydration to treat tumor lysis; correction of electrolyte abnormalities; or respiratory support for children with airway compromise.
Child Abuse. Petechiae, purpura, and bruising in specific patterns or on areas of the body not normally prone to trauma should raise the clinician's suspicion for non-accidental trauma. The presence of multiple other injuries, injuries in different stages of healing, injuries without an explanation consistent with the child's developmental stage or consistent with the proposed mechanism should also be concerning for potential abuse. Bruising or petechiae to the pinna or external helix, for example, is concerning for pinching or a sharp blow to the side of the head.16 Prominent facial and upper chest petechiae, while often caused by coughing or vomiting, may also be seen with intentional strangulation or suffocation. A child hit with an open hand may have lines of petechiae coinciding with the areas where skin was compressed between two adjacent fingers. Any suspicion of abuse or neglect in the ED must be referred to child protective services. Further evaluation may include a skeletal survey, ophthalmologic exam for retinal hemorrhages, or neuroimaging for intracranial hemorrhages.
Several folk remedies involve repeated trauma to the skin that results in specific patterns of petechiae and bruising. Coining, or Cao gio, is a remedy for fever, headache, and chills practiced in areas of Southeast Asia. A coin is used to vigorously rub a child's back repeatedly in a linear fashion, causing a linear pattern of petechiae covering the back, chest, and shoulders. Cupping involves warming the edge of a cup, placing it on a child's back to create a vacuum, and then pulling the cup off. Round ecchymotic and petechial lesions covering the back are seen after this practice, which is performed in Mexico and Eastern Europe to relieve febrile illnesses. Finally, spooning, or quat sha, is a Chinese remedy for headache that utilizes a spoon to rub the back in much the same way as coining.16 These practices are generally not considered to be abusive, and it is important to be aware of them as a potential cause of patterned petechial lesions.
Petechiae are a common physical exam finding among children evaluated in the ED. The most common causes of petechial rashes include viral illness, minor trauma, and increased venous pressure from coughing or vomiting. Petechia may also be a sign of serious underlying illnesses, including invasive bacterial disease, malignancy, DIC, HUS, child abuse, coagulopathy, or thrombocytopenia. Clinicians must rely on a thorough history and physical examination to narrow the differential diagnosis and determine further evaluation. The complete blood count and coagulation studies are helpful tools in determining the etiology of petechiae when further work up is warranted. Children with petechial rashes who are ill-appearing or febrile are particularly concerning and should always prompt consideration of evaluation and treatment for invasive bacterial illness.
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