Infection-associated skin bleeding pmc

Hemorrhagic skin lesions associated with infectionsThis article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.


A variety of bacterial, viral, or parasitic infectious diseases can present with hemorrhagic efflorescences. The constellation of symptoms fever and petechiae can be a harbinger of fulminant bacterial sepsis, which must be treated intensively and immediately. Much more often, however, the symptoms are due to a harmless self-limiting viral infection, so that one is faced with a dilemma with regard to the extent of the necessary diagnostics. This article gives an overview of the differential diagnoses and pathophysiology of infection-associated skin hemorrhages, and proposes a differential diagnostic algorithm for the diagnosis of fever plus petechiae.


A broad spectrum of bacterial, viral, and parasitic infections is associated with hemorrhagic skin lesions, typically petechiae. The most prominent underlying entity is fulminant bacterial sepsis, which requires urgent and intensive treatment. In most cases, however, a self-limiting viral disease is the underlying cause. Thus, the pediatrician frequently encounters a diagnostic dilemma between timely diagnosis of sepsis and unnecessary invasive diagnostics. This article reviews the broad differential diagnosis and pathophysiology of infection-associated hemorrhagic skin lesions and proposes a diagnostic algorithm for the combination of fever and petechiae.

The combination of fever and hemorrhagic efflorescences, usually petechiae, is alarming for any pediatrician, as it may be indicative of fulminant bacterial sepsis. In most cases, however, this combination of symptoms is due to a self-limiting viral infection. Accordingly, the dilemma between the potentially fatal consequences of a delayed diagnosis on the one hand and unnecessary invasive diagnostics on the other hand is great. In this article an overview of the pathogenesis and causes of various infection-associated skin hemorrhages in children is given and a differential diagnostic algorithm for diagnosis is proposed.

Introduction – Terminology

Hemorrhagic efflorescences are divided into

subdivided. The unifying feature of these efflorescences is the extravasation of erythrocytes, which can be clinically verified by the lack of fading on prere with a glass spatula.

Petechiae and Purpura

Petechiae are small flea-like skin hemorrhages. The term purpura is used in German for the generalized, exanthema-like occurrence of skin and mucous membrane bleeding. In contrast, in the English literature, "petechiae" usually refers to small (1 mm), whereas "purpura" refers to larger skin hemorrhages (2 or 3 mm or more in diameter).


This term is used to describe larger, patchy hemorrhages.


This is the term used for extensive, confluent bleeding of the skin or mucous membranes.

Hemorrhagic efflorescences of vasculitic etiology can present a colorful clinical picture. They usually present as palpable purpura, but may also appear as hemorrhagic vesicles or urticaria.

Pathophysiology and differential diagnosis of infection-associated skin hemorrhages

Regardless of their genesis, 3 major pathomechanisms are responsible for the development of skin and mucosal hemorrhages:

Disorders of plasmatic coagulation (coagulopathies),

numerical or functional alterations of platelets (thrombocytopenias and thrombocytopathies) or

Diseases of the vessels (vasopathies).

Clinically, disorders of the plasmatic coagulation system are usually manifested as ecchymoses or sugillations. Platelet disorders, on the other hand, are manifested as petechiae, mucosal hemorrhages (wet purpura) or, less commonly, CNS hemorrhages (CNS: central nervous system). Palpable purpura is a typical symptom of vasopathies [13].

Pathologic changes in coagulation factors, platelets, and vasculature can occur in isolation and in combination in the setting of infection. An example of an isolated disorder of platelet formation is connatal CMV infection (CMV: cytomegalovirus; [1]). A typical example of involvement of all 3 systems (plasmatic coagulation, platelets, vascular system) is disseminated intravascular coagulation [consumption coagulopathy, DIC ("disseminated intravascular coagulation")].

Disseminated intravascular coagulation

DIC is by no means pathognomonic for infections, but can also be caused by oncologic disease, trauma, burns, maltransfusion, or severe organ dysfunction, e.g. B. Liver failure and pancreatitis, are triggered. It represents the most severe manifestation of an infection-related coagulopathy. Underlying pathophysiology is complex. Only incompletely understood. Its overriding mechanism is the disturbance of the balance of pro- and anticoagulatory factors. Excessive coagulation activity with extensive intravascular fibrin deposits and disseminated (micro)thromboses in various organs and a bleeding tendency may be present at the same time.

DIC is the most severe form of infection-related coagulopathy

Excessive coagulation is mediated by 3 major inflammatory mechanisms [23]:

Most important factor is upregulation of procoagulant signaling pathways v. a. By cytokine-mediated induction of the tie factor (TF) signaling pathway. TF is expressed on the surface of endothelial cells, monocytes, dendritic cells and platelets. It activates coagulation factor VII. Triggers thrombin generation via the extrinsic coagulation cascade. The monocyte-macrophage system seems to play a central role in this process.

Anticoagulant factors, such as protein C, are inhibited and depleted.

Fibrinolysis, and thus the degradation of microthrombi, is inhibited.

Thrombotic vascular occlusion leads to skin necrosis and organ dysfunction of varying severity up to refractory multiple organ failure [MODS ("multiple organ dysfunction syndrome"), [30]]. In addition to thrombotic complications, diffuse bleeding develops in skin, mucous membranes, and a variety of other organs [14]. Triggered by decreased synthesis and increased consumption of clotting factors and platelets. Due to this parallel occurrence of thromboembolic. Hemorrhagic complications, the clinical picture of DIC is highly variable.

The disease is often associated with v. a. Gram-negative pathogens associated [15]. However, their incidence is comparably high in infections with Gram-positive pathogens [14]. DIC occurs in 25-50% of adults with sepsis [30]. In addition to bacterial pathogens, it can also be caused by infections by parasites [18] or viruses [25] ( Tab. 1 , tab. 2 , Tab. 3 ).

Hemorrhages also possible in mild courses of disease

Hemorrhages (v. a. in the case of connatal infection)

Mostly self-limiting purpura

Severe courses in newborns

Possibly. Cell culture or PCR

PCR (respiratory secretions, stool, skin biopsy)

"blueberry muffin baby" in connatal infection

Mild febrile exanthema

HSS preferentially in young adults

PCR (EDTA blood, serum, skin biopsy)

PCR (EDTA blood, serum)

PCR (stool, skin biopsy)

Antigen test (respiratory secretions)

PCR (respiratory secretions, skin biopsy)

CMV cytomegalovirus, EBV Epstein-Barr virus, EDTA ethylenediaminetetraacetic acid, HAV, HBV, HCV hepatitis A-/-B-/-C virus, HSS glove sock syndrome, HSV herpes simplex virus, PCR polymerase chain reaction, RSV "respiratory syncytial virus", VZV varicella zoster virus a petechiae, hemorrhages, ecchymoses

(South America, Panama, Africa)

Sudden high fever (2 spikes/day)

Serology from day 7 (special laboratory)

VHF with secondary disease

(Central, South America, Africa, Indian subcontinent, Southeast Asia)

Sudden high fever

Possibly. PCR (blood, first days only)

(Africa, Indian continent, Southeast Asia, Italy)

Serology from day 4 (special laboratory)

(Africa, Middle East)

Serology from day 6 (special laboratory)

(Africa, Southeastern Europe, Middle East, Central Asia, Indian subcontinent)

Capillary leakage with facial swelling, flushing

In the course encephalitis

Possibly. PCR (blood, synovial fluid)

(Northern Europe, China, Australia, South Africa)

Serology from day 5 (special laboratory)

PCR polymerase chain reaction, VHF viral hemorrhagic fever a petechiae, hemorrhages, ecchymoses

IKZ 5 days to mon.

Initially flu-like, high fever, chills, possibly. gastrointestinal symptoms

Multi-organ failure possible in the course of the disease

IKZ 10 days to 10 years

PCR (EDTA blood; bone marrow)

IKZ 10 to 23 days

Risk factors Immunosuppression, newborns

Hepatopathy with icterus, interstitial pneumonia, myocarditis, encephalitis, evtl. Chorioretinitis

IKZ 3 to 4 weeks

Differential diagnosis: carry-over of intestinal bacteria during larval migration

Microscopy (stool, duodenal fluid, biopsy)

ICZ 1 to 2 weeks

Splintery hemorrhages under the nails, muscle pain, eyelid and facial swelling, evtl. meningitis, myocarditis

Sepsis-associated purpura fulminans (also known as connatal infection)

Sepsis-associated purpura fulminans

Risk factors Immunosuppression (v. a. neutropenia)

Always rule out meningitis

EDTA ethylenediaminetetraacetic acid, ICZ incubation time, PCR polymerase chain reaction

Newborns and infants with DIC show a particularly high risk of bleeding compared with older children [29]. This is attributed to lower serum concentrations of vitamin K-dependent coagulation factors (X, IX, VII, II) and anticoagulants, reduced thrombin synthesis, and lower activability of platelets in neonates and infants ( Fig. 1 a).

Fever plus petechiae as a warning sign of meningococcal sepsis

Patients with fever and petechiae present a diagnostic and therapeutic challenge. While in full-blown meningococcal sepsis (Waterhouse-Friderichsen syndrome, s. below) the intensive medical aspects are in the foreground of the therapy, the far more frequent patients with petechiae, fever and good general condition cause the greater difficulties in the differential diagnosis. There is no generally accepted consensus on the procedure for the latter. A survey of over 800 pediatricians revealed notable differences in diagnostic and therapeutic approach [19].

The prevalence of meningococcal disease in the constellation of fever plus petechiae ranged from 5 to 15% in pro- and retrospective studies. Overall, invasive bacterial disease has been detected in 8-20% of patients with these clinical symptoms [2, 6, 20, 27]. A prospective study of the risk of invasive meningococcal infection in children younger than 16 years with petechiae found confirmed or probable meningococcal disease in 13% of cases [28]. Interestingly, in this study, 5 of 24 children (20%) were afebrile at diagnosis, and another 20% had a body temperature< 38,6°C.

Fever and petechiae in children are most often due to viral infections

The most common underlying cause in children with fever and petechiae is self-limiting viral infections caused by, for example, echovirus, coxsackie virus, or adenovirus ( Tab. 1 ). Especially at the beginning of the disease, there are no reliable clinical signs or laboratory parameters that reliably distinguish between an invasive bacterial and a viral infection. A recent retrospective analysis of more than 400 children with meningococcal infections found that 49% of patients were discharged home after initial physician contact [26]. In Tab. 4 summarizes common problems that lead to incorrect or delayed diagnosis of meningococcal disease.

a Depending on their frequency

Invasive meningococcal infection typically progresses as sepsis with or without involvement of the meninges [21]. Rare are purely meningitic courses that do not meet the criteria for systemic inflammation (SIRS: "systemic inflammatory response syndrome") and thus do not meet the diagnostic criteria for sepsis; the diagnostic criteria are described in Tab. 5 shown.

Mean heart rate> 2 standard deviations above age norm, in newborns also bradycardia in the sense of a mean heart rate< 10. Age percentiles

Not applicable in case of vitium cordis or drug influence

Mean respiratory rate>2 standard deviations above age norm or mechanical ventilation

Not applicable in case of underlying neuromuscular disease or general anesthesia

ARDS "acute respiratory distress syndrome", SIRS "systemic inflammatory response syndrome"

The occurrence of meningitis is of prognostic importance: The more frequent sepsis courses without meningitis are associated with an up to 4-fold increased lethality (up to 40%) compared to meningitic courses. The most dramatic form of meningococcal sepsis with fulminant circulatory failure. Uncontrolled progressive disseminated intravascular coagulation is called purpura fulminans or Waterhouse-Friderichsen syndrome ( Fig. 1 b). In this case, the time interval between symptom onset and lethal outcome is z. T. Only a few hours.

The nonspecific prodromes of invasive meningococcal infection are fever, nausea, vomiting, and lethargy. Meningococcal meningitis also typically presents with headache, photophobia, decreased vigilance, and meningeal irritation signs. Early symptoms of the septic course are pain in the limbs, increasing apathy, and the onset of circulatory centralization, manifested by a striking pale or grayish skin color, cold extremities, and delayed recapillarization.

Hemorrhagic exanthem appears relatively early in the course of the disease. In a prospective epidemiological study, all meningococcal disease cases in the Netherlands from 2002-2005 were investigated, with a median appearance of efflorescences 11 h after onset of first symptoms [9]. Thus, this is often the first specific symptom of disease. The reason for the child's presentation to a physician by the parents.

In hemorrhagic efflorescences, histology usually demonstrates leukocytoclastic vasculitis with microthromboses [10]. Since meningococci are also found in endothelial cells and local leukocytes, biopsy of fresh skin lesions can be used to detect the bacteria.

Retrospective analyses showed that 60-90% of all children with meningococcal meningitis develop exanthema during the course [16, 26].

However, the maculopapular-appearing efflorescences at the onset of meningococcal sepsis can sometimes make it impossible to differentiate it from viral exanthema [11]. However, in the setting of coagulopathy secondary to systemic inflammation, the exanthema progresses rapidly through the sequence of petechiae, larger purpura with eventual dark liver discoloration, and ultimately hemorrhagic necrosis [7]. However, it is of practical importance that besides meningococci other bacterial, viral or parasitic pathogens can cause hemorrhagic exanthema up to purpura fulminans ( Tab. 1 , Tab. 2 , Tab. 3 , Tab. 6 ). For this reason, initial antibiotic therapy must be chosen broadly if microscopy of the CSF does not reveal definite findings for meningococci.

Look for meningitistrias: Fever – Headache – Meningismus

Occurring mainly in young children

Culture (blood, CSF, pleural fluid, skin florescence)

PCR in cerebrospinal fluid, pleural fluid, urine

Occurring primarily in infancy and early childhood

Culture (blood, CSF, skin florescence)

Petechiae in endocarditis

Search for ports of entry

Vitium cordis risk factor

Zoonosis with petechiae

Culture (blood, skin florescence – Streptobacillus moniliformis)

Microscopy (blood, skin efflorescence – Spirillum minus)

Only in connatal infection

Mucopurulent ophthalmia neonatorum

Culture (blood, skin florescence, stool)

Risk factors Immunosuppression, endocarditis, homeless alcoholic

Culture (blood, skin florescence; only in special laboratories)

Often presents with thrombocytopenia, leukocytopenia, and left shift

Mostly imported cases

Risk factor unpasteurized milk products, direct animal contact

Culture (blood, skin biopsy, bone marrow)

Especially in icteric form of progression

Usually with interstitial nephritis

Culture (blood, only in the 1. Week)

Serology (from the end of the 1. to 2. Week)

Carrier Ticks (mostly non-European, but also in Southern Europe)

"Tache noir" at the bite site

Complication Myocarditis (with poor prognosis)

PCR (skin biopsy; possibly. blood)

a Petechiae, hemorrhages, ecchymoses

Differential diagnosis of hemorrhagic efflorescences

In distinction to infections with cutaneous manifestations, there are many noninfectious causes of skin bleeding, which can be divided into coagulopathies, thrombocytopathies and thrombocytopenias, and vasopathies as listed above. Examples are immune thrombocytopenic purpura (ITP) as the most frequent cause of infantile thrombocytopenia and Schonlein-Henoch purpura (Fig. 1 c) mentioned as the most frequent vasculitis in childhood.

Based on history and a thorough clinical examination, the broad differential diagnosis of skin hemorrhages can be narrowed down considerably. In addition to general aspects (age, sex, previous illnesses and medication), the central elements of the anamnesis are the recording of the temporal dynamics and localization of the efflorescences, the occurrence of accompanying symptoms, in particular fever or B symptoms, and indications of a bleeding tendency. Nutrition may also be important, as severe malnutrition can lead to both coagulopathy (deficiency of vitamin K-dependent clotting factors) and vasopathy (scurvy).

If there is evidence of an underlying infection in a patient with hemorrhagic efflorescences, a decision must be made quickly as to whether the infection is self-limiting, usually viral, or invasive bacterial. The overall clinical impression of the experienced pediatrician is an indispensable pillar of any diagnostic and therapeutic algorithm, because no laboratory parameter has sufficient negative predictive value – this also applies to CSF diagnostics.

Differential diagnostic algorithm

Fig. 2 summarizes the differential diagnostic algorithm in the presence of hemorrhagic efflorescences. In case of hemorrhagic exanthema, fever and clinical signs of sepsis, supportive therapy in the sense of an extended "early goal-directed therapy" (hemodynamic stabilization, ensuring adequate oxygen supply and metabolic balance) and antibiotic treatment must be initiated immediately. For a detailed overview of sepsis therapy, please refer to current literature [5]. Before the first administration of antibiotics, CSF diagnostics must be performed in addition to taking blood cultures, unless contraindications exist (thrombocytopenia< 30.000 G/l, advanced DIC, pronounced circulatory instability, focal neurological signs, incipient symptoms of entrapment) against a lumbar puncture.

infection-associated skin hemorrhages pmc

As a general rule, diagnostics, including lumbar puncture, should not significantly delay the necessary therapy.

The first antibiotic should be administered within 30-60 min after the suspected diagnosis has been made.

In the more frequent case of a child with fever and hemorrhagic efflorescences, but with little or no impairment of the general condition, the differential diagnosis is much more difficult. Several studies addressed the question of which parameters argue against the presence of meningococcal disease in these cases [9, 20, 21, 26, 28]. Petechiae no more than 1 mm in diameter and limitation of efflorescences to the catchment area of the superior vena cava are clinical signs atypical of bacterial sepsis. If there is no clear mechanical explanation for the efflorescences-such as the appearance of congestive petechiae after recurrent vomiting ( Fig. 1 d) – a blood sample must always be taken in order to better assess the severity of an infectious event. Helpful laboratory parameters that are more indicative of a self-limiting viral event are normal values for CRP (C-reactive protein), leukocyte and platelet counts, and coagulation parameters. If the patient's general condition is unimpaired and there are no or only few pathological changes in laboratory parameters, a lumbar puncture can initially be dispensed with. However, reevaluation of the clinical course must be ensured in these patients. As simple thresholds beyond the 3. In these cases, CRP values of 20 mg/l or 40 mg/l, which have a negative predictive value of 99 and 95%, respectively, can serve as an indicator of the presence of fever during the first month of life [24]. A CRP> 100 mg/l is suspicious of meningitis until proven otherwise, if no other clear cause can be identified. Because of the dynamics of systemic bacterial infections, all laboratory parameters may still be unsuspicious in the early stage and must be collected repeatedly in case of doubt (including CSF cell count and microbiology). If lumbar puncture is initially omitted in ambivalent cases, inpatient observation with repeated reevaluation (clinic and laboratory) is an important measure.

Empirical antibiotic therapy without a clear focus must be strongly discouraged. This procedure carries the risk of inadequately treated meningitis with considerable morbidity.

Special features in newborns and infants

The listed differential diagnostic algorithm ( Fig. 2 ) is only applicable to infants with restrictions, it is not valid in the neonatal period. Because of the nonspecific clinical signs of sepsis and meningitis in the first 12, but especially in the first 3 months of life, the indication for lumbar puncture should be generous.

In neonates with hemorrhagic efflorescences, a comprehensive diagnosis is obligatory

In neonates with hemorrhagic efflorescences, the differential diagnosis differs from that in other age groups. Since a serious underlying disease is likely, a comprehensive diagnosis must be made. First of all, sepsis and meningitis should be ruled out, as indicated. If necessary. treated empirically. In the case of connatal purpura, extramedullary hematopoiesis must also be considered as a differential diagnosis. In this case, the efflorescences appear as dark blue-livid indurated papules that cannot be pushed away and occur disseminated over the entire body (so-called meningitis). "blueberry muffin baby," Ill. 1 e). Until the introduction of universal vaccination, the clinical picture was mostly an expression of connatal rubella. Today, intrauterine CMV infection represents the most common infectious cause. In addition, intrauterine infections with parvovirus B19 or coxsackieviruses can cause a similar clinical picture in newborns [3]. In addition, non-infectious causes such as rhesus incompatibility or anemia due to fetofetal transfusion syndrome can lead to extramedullary erythropoiesis with the clinical aspect of a "blueberry muffin baby".

Conclusion for practice

A variety of bacterial, viral, or parasitic infectious diseases may present with hemorrhagic efflorescences. The most important differential diagnosis in the presence of fever. petechiae is fulminant bacterial sepsis. However, the most common underlying cause in this constellation of symptoms is self-limiting viral infections.

Clinical parameters that speak against the presence of bacterial sepsis are purely petechial efflorescences of a maximum diameter of 1 mm and the limitation of the petechiae to the catchment area of the superior vena cava. The search for petechiae must therefore always include the lower extremities.

Ultimately, there are no clinical signs or laboratory parameters that can rule out invasive bacterial infection with certainty in the presence of petechiae. Therefore, in cases of doubt, comprehensive diagnostics including lumbar puncture must always be performed.

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