Fever with bleeding

Fever with bleeding is fever of 38.0 C or over with haemorrhage from skin (petechiae, purpura, ecchymoses), mucosa (gums, nose, conjunctiva, urine, vagina) or the gastrointestinal tract. It is an emergency.

Mechanisms of bleeding

• Thrombocytopenia from marrow suppression, consumption or immune destruction.
• Platelet dysfunction.
• Coagulopathy from liver injury, consumption (disseminated intravascular coagulation), vitamin K deficiency or anticoagulant exposure.
• Vascular injury and endothelial leak (dengue, haemorrhagic fevers, leptospirosis, rickettsial vasculitis).
• Thrombotic microangiopathy with microvascular thrombosis (thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome).

Classification by cause

• Viral haemorrhagic fevers: filoviruses (Ebola, Marburg), arenaviruses (Lassa), bunyaviruses (Crimean-Congo haemorrhagic fever, Rift Valley fever), flaviviruses (dengue, yellow fever, Kyasanur forest disease, Omsk haemorrhagic fever).
• Bacterial and rickettsial: meningococcaemia, sepsis with disseminated intravascular coagulation, leptospirosis, rickettsial disease, plague, anthrax and typhoid with intestinal bleeding.
• Parasitic: severe falciparum malaria.
• Haematological: acute leukaemia, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome, haemophagocytic lymphohistiocytosis, immune thrombocytopenia with infection, aplastic anaemia.
• Drug and toxin: anticoagulants, drug induced thrombocytopenia, heparin induced thrombocytopenia, chemotherapy, snake venom.

Severity. Bleeding with shock, platelets under 20 x 10^9/L, INR over 1.5, fibrinogen under 1.5 g/L, or haemoglobin fall over 2 g/dL indicates high risk.

Key distinctions. Fever with petechiae and normal platelets suggests vasculitis or bacterial infection. Fever with thrombocytopenia and fragmented red cells suggests thrombotic microangiopathy. Fever with bleeding after contact with a case or travel to an outbreak area suggests viral haemorrhagic fever. Sudden fever, jaundice and bleeding after exposure to freshwater suggests leptospirosis.

History

• Onset and course of fever and bleeding. Site and severity of bleeding (gums, nose, haematemesis, melaena, haematuria, menorrhagia, injection sites).
• Exposure in the 21 days before onset: travel to or residence in Africa, Asia, Middle East or South America, forest and cave visits, bats, bushmeat, rodents and livestock, tick bites, slaughtering animals, unpasteurised milk, mosquito bites, and floodwater.
• Contact with a sick person with bleeding, funerals, care of sick relatives, healthcare facilities with outbreaks, laboratory exposure, and sexual contact with a survivor.
• Vaccination (yellow fever, meningococcal), malaria chemoprophylaxis, and recent antibiotics.
• Drugs: warfarin, direct oral anticoagulants, heparin, antiplatelet agents, NSAIDs, quinine, valproate, linezolid, chemotherapy and herbal products.
• Previous bleeding tendency, family history of bleeding, liver disease, alcohol use, HIV, haematological disease, pregnancy and the postpartum state.
• Associated symptoms: severe headache, myalgia, retro-orbital pain, diarrhoea, jaundice, abdominal pain, cough, haemoptysis, confusion and reduced urine output.

Examination

• Vital signs, capillary refill, shock index (heart rate divided by systolic pressure, over 0.9 indicates shock), mental state, and urine output.
• Pattern of bleeding: petechiae (platelet disorder or vasculitis), purpura and ecchymoses, gum bleeding, epistaxis, conjunctival haemorrhage, subconjunctival suffusion, haematuria, haemoptysis, haematemesis and melaena, and bleeding at venepuncture or cannula sites.
• Rash type, pallor, jaundice, lymphadenopathy, hepatosplenomegaly, ascites, pleural effusion, hepatic tenderness and peripheral oedema.
• Neck stiffness, neurological signs and fundoscopy (retinal haemorrhages, papilloedema).
• Skin necrosis, limb ischaemia and gangrene (purpura fulminans).
• Signs of intravascular catheter infection, endocarditis and wounds.
• Tourniquet test in dengue (20 or more petechiae in 2.5 cm square after 5 minutes at the midpoint between systolic and diastolic pressure) has limited sensitivity.

Red flags

• Shock, hypotension, mean arterial pressure under 65 mmHg, lactate over 2 mmol/L, oliguria, or altered consciousness.
• Active bleeding from several sites, haematemesis, melaena or intracranial bleeding signs.
• Platelets under 20 x 10^9/L, INR over 1.5, fibrinogen under 1.5 g/L, or haemoglobin under 7 g/dL.
• Rapidly spreading purpura or skin necrosis.
• Fever with bleeding and travel to or contact with an outbreak area, or contact with a person with haemorrhagic illness.
• Fever with jaundice, anuria and haemoptysis (leptospirosis).
• Fragmented red cells, renal failure and neurological signs (thrombotic microangiopathy).
• Pancytopenia with blasts, or abnormal white cell count (acute leukaemia).
• Pregnancy, postpartum state, neonates, immunosuppression and anticoagulant use.

Special groups

• Pregnancy: haemorrhagic fevers (Ebola, Lassa, Crimean-Congo haemorrhagic fever, Rift Valley fever) have very high maternal and foetal mortality. Severe malaria, HELLP syndrome, abruption, sepsis and acute fatty liver of pregnancy cause bleeding with fever.
• Children and neonates need age specific assessment and doses.
• Kidney and liver impairment: adjust doses of antibiotics, ribavirin and tranexamic acid.
• Healthcare workers and laboratory staff: exposure review and monitoring for 21 days after contact.
• Region specific: dengue, yellow fever, Ebola and Marburg, Lassa fever, Crimean-Congo haemorrhagic fever, Rift Valley fever, Kyasanur forest disease, hantavirus infection, leptospirosis, rickettsial disease, plague and severe malaria.

Viral haemorrhagic fevers and flaviviruses

• Ebola virus disease and Marburg virus disease.
• Lassa fever.
• Crimean-Congo haemorrhagic fever.
• Rift Valley fever.
• Yellow fever.
• Dengue haemorrhagic fever and dengue shock syndrome.
• Hantavirus infection (haemorrhagic fever with renal syndrome).
• Kyasanur forest disease and Omsk haemorrhagic fever.
• Chikungunya with bleeding, rare.
• Severe acute viral infection with disseminated intravascular coagulation (influenza, measles, varicella in immunocompromised).

Bacterial and rickettsial

• Meningococcal sepsis with purpura fulminans.
• Gram negative sepsis and pneumococcal sepsis in asplenia (overwhelming post splenectomy infection).
• Staphylococcal and streptococcal toxic shock syndrome.
• Leptospirosis.
• Rickettsial disease (African tick bite fever, spotted fever group, epidemic typhus, scrub typhus).
• Typhoid fever with intestinal haemorrhage.
• Plague (septicaemic, pneumonic).
• Anthrax.
• Infective endocarditis with embolic and vasculitic bleeding.
• Capnocytophaga and Clostridium sepsis.
• Relapsing fever.

Parasitic

• Severe falciparum malaria with coagulopathy and blackwater fever.
• Visceral leishmaniasis with thrombocytopenia.

Haematological and immune

• Acute leukaemia, including acute promyelocytic leukaemia.
• Thrombotic thrombocytopenic purpura.
• Haemolytic uraemic syndrome (Shiga toxin producing Escherichia coli, atypical).
• Haemophagocytic lymphohistiocytosis.
• Immune thrombocytopenia with intercurrent infection.
• Aplastic anaemia and myelodysplastic syndromes with infection.
• Systemic vasculitis (IgA vasculitis, ANCA associated vasculitis, polyarteritis nodosa, cryoglobulinaemia).
• Catastrophic antiphospholipid syndrome.
• Systemic lupus erythematosus with thrombocytopenia.
• Heparin induced thrombocytopenia.

Drug, toxin and other

• Anticoagulant and antiplatelet toxicity with fever from another cause.
• Drug induced thrombocytopenia (quinine, vancomycin, linezolid, beta lactams, valproate).
• Snake envenoming with coagulopathy.
• Acute liver failure of any cause.
• Heat stroke with disseminated intravascular coagulation.
• Pregnancy related: HELLP syndrome, placental abruption, amniotic fluid embolism and septic abortion.
• Peptic ulcer or variceal bleeding with fever from aspiration or sepsis.

Step 1. Infection control and triage. If viral haemorrhagic fever is possible (compatible exposure within 21 days plus fever and bleeding or compatible illness), isolate the patient in a single room with a dedicated toilet. Limit staff to those with full protective equipment. Notify public health at once. Contact the reference laboratory before taking viral samples. Use routine infection control precautions for all other patients, with blood and body fluid care.

Step 2. Resuscitation first. Check airway, breathing, circulation, glucose and lactate, and place intravenous or intraosseous access. Do not delay antibiotics and antimalarials for confirmatory tests.

Step 3. Tests in every patient

• Malaria rapid test and thick and thin films, repeated every 12 to 24 hours for 3 sets if negative and suspicion remains.
• Full blood count with differential and blood film (schistocytes over 1% suggest thrombotic microangiopathy, blasts suggest leukaemia, atypical lymphocytes suggest viral infection, parasites).
• Coagulation: prothrombin time, INR, activated partial thromboplastin time, fibrinogen, D dimer and thrombin time. Platelet function is not usually tested acutely.
• Urea, creatinine, electrolytes, liver tests, LDH, bilirubin, haptoglobin, creatine kinase, glucose, lactate and blood gas.
• Group and crossmatch.
• Blood cultures, two sets before antibiotics.
• Urinalysis (blood, protein) and pregnancy test.
• HIV test and syphilis serology.
• Chest radiograph and abdominal ultrasound (ascites, gallbladder wall thickening, pleural effusion, hepatosplenomegaly, liver abscess).

Step 4. Disseminated intravascular coagulation score. Assign points as follows. Platelets (over 100 x 10^9/L 0, 50 to 100 1, under 50 2). D dimer (normal 0, moderate rise 2, strong rise 3). Prolonged prothrombin time (under 3 seconds 0, 3 to 6 seconds 1, over 6 seconds 2). Fibrinogen (over 1 g/L 0, 1 g/L or under 1). A total of 5 or more indicates overt disseminated intravascular coagulation.

Step 5. Targeted tests

• Viral haemorrhagic fever: PCR for Ebola, Marburg, Lassa, Crimean-Congo haemorrhagic fever and Rift Valley fever on blood after public health approval (PCR can be negative in the first 72 hours, so repeat). Yellow fever and dengue RT PCR and IgM. Hantavirus serology.
• Dengue: NS1 antigen or RT PCR on days 1 to 5, IgM from day 5, with haematocrit trend. Platelets under 100 x 10^9/L with a rise in haematocrit of 20% or more indicates plasma leakage.
• Leptospirosis: PCR of blood in the first 10 days, then microscopic agglutination test or IgM.
• Rickettsial disease: PCR of eschar swab or blood. Treat before confirmation.
• Meningococcal PCR of blood, skin lesion aspirate for Gram stain, and lumbar puncture only after coagulopathy is corrected and shock is controlled.
• Thrombotic thrombocytopenic purpura: ADAMTS13 activity before plasma exchange (under 10% confirms) with a pretest score based on platelets under 30 x 10^9/L, creatinine under 200 micromol/L, no active cancer, and haemolysis. Shiga toxin PCR on stool for haemolytic uraemic syndrome.
• Acute leukaemia: urgent blood film review, flow cytometry, and bone marrow aspirate with trephine. Acute promyelocytic leukaemia is suggested by coagulopathy with abnormal promyelocytes.
• Haemophagocytic lymphohistiocytosis: ferritin over 10,000 micrograms/L, triglycerides over 3 mmol/L, fibrinogen under 1.5 g/L, cytopenias, splenomegaly and bone marrow haemophagocytosis.
• Heparin induced thrombocytopenia: 4T score and immunoassay for platelet factor 4 antibodies.
• Autoimmune tests: ANA, anti dsDNA, complement, ANCA, antiphospholipid antibodies, cryoglobulins.
• Stool testing for occult blood and endoscopy for gastrointestinal bleeding after resuscitation.
• CT head for severe headache, focal signs or altered consciousness (intracranial haemorrhage).

Interpretation. Thrombocytopenia is common in many infections, and a low platelet count without bleeding does not signal haemorrhagic fever. Prolonged INR with low fibrinogen and raised D dimer indicates disseminated intravascular coagulation, which occurs in sepsis, malaria, haemorrhagic fever, acute promyelocytic leukaemia and obstetric emergencies. Normal INR and fibrinogen with isolated thrombocytopenia and fragmented red cells point to thrombotic microangiopathy.

Limits. Early PCR for viral haemorrhagic fever can be negative. A single negative malaria film does not exclude malaria. ADAMTS13 results can take several days, so treat on clinical probability. Serological cross reaction occurs between flaviviruses.

Immediate: resuscitation and control of bleeding

• Oxygen to saturation 94 to 98%, large bore access, blood cultures and glucose. Treat hypoglycaemia (under 4 mmol/L) with dextrose 25 g intravenously.
• Shock: crystalloid boluses of 250 to 500 mL with reassessment (up to 30 mL/kg in 3 hours when clearly hypovolaemic). In dengue and severe malaria give smaller boluses with frequent review of lung fields and haematocrit because of leakage and the risk of pulmonary oedema. Start noradrenaline to keep mean arterial pressure at 65 mmHg or over if hypotension persists.
• Major bleeding: activate the major haemorrhage plan. Give red cells (target haemoglobin 7 to 9 g/dL) and plasma, platelets and cryoprecipitate as directed by clotting tests (thresholds are in the next bullet).
• Use tranexamic acid 1 g intravenously over 10 minutes then 1 g over 8 hours for major bleeding without established thrombosis. In disseminated intravascular coagulation with thrombosis or purpura fulminans, specialist haematology advice is needed before antifibrinolytics.
• Blood product thresholds: platelets under 10 x 10^9/L, or under 50 x 10^9/L with active bleeding (give 1 adult dose of apheresis platelets or 4 to 6 pooled units; avoid in thrombotic thrombocytopenic purpura and heparin induced thrombocytopenia unless life threatening bleeding).
• Fresh frozen plasma 15 mL/kg for INR over 1.5 with bleeding.
• Cryoprecipitate 2 pools (about 10 units) when fibrinogen is under 1.5 g/L with bleeding.
• Vitamin K: phytomenadione 10 mg intravenously slowly once daily for 3 days when INR is raised in malnutrition, liver disease or antibiotic exposure.
• Anticoagulant reversal when relevant: warfarin with major bleeding needs prothrombin complex concentrate 25 to 50 units/kg with vitamin K 5 to 10 mg intravenously. Direct oral anticoagulants need specific reversal agents or prothrombin complex concentrate 50 units/kg under haematology direction.
• Empirical antimicrobial treatment started within 1 hour: ceftriaxone 2 g intravenously (every 12 hours when meningitis is possible). Doxycycline 100 mg orally or intravenously twice daily for rickettsial disease and leptospirosis. Give artesunate 2.4 mg/kg intravenously for suspected severe malaria in an endemic or travel setting.
• Avoid aspirin, NSAIDs, intramuscular injections, unnecessary venepuncture and invasive procedures.

Cause directed

• Severe malaria: artesunate 2.4 mg/kg intravenously at 0, 12 and 24 hours then once daily, followed by oral artemether with lumefantrine (4 tablets of 20 mg/120 mg at 0, 8, 24, 36, 48 and 60 hours for 35 kg or over, with fatty food).
• Monitor glucose every 4 to 6 hours. Transfuse for haemoglobin under 7 g/dL. Give ceftriaxone 2 g daily for possible bacteraemia. Avoid corticosteroids.
• Meningococcal and other bacterial sepsis: ceftriaxone 2 g intravenously every 12 hours for 5 to 7 days (longer for other organisms), source control, vasopressors, and intensive care.
• Prophylaxis for meningococcal contacts: ciprofloxacin 500 mg orally once, or rifampicin 600 mg orally twice daily for 2 days, or ceftriaxone 250 mg intramuscularly once in pregnancy. Purpura fulminans needs specialist haematology and intensive care.
• Leptospirosis: benzylpenicillin 1.5 million units intravenously every 6 hours, or ceftriaxone 1 g intravenously once daily, for 7 days. Expect a Jarisch-Herxheimer reaction. Early dialysis for renal failure and ventilatory support for pulmonary haemorrhage.
• Rickettsial disease: doxycycline 100 mg orally or intravenously twice daily for 5 to 7 days and for at least 3 days after fever settles. Children under 45 kg: 2.2 mg/kg twice daily, maximum 100 mg each dose.
• Dengue: oral fluids and paracetamol for no warning signs.
• Warning signs (abdominal pain, persistent vomiting, mucosal bleeding, lethargy, liver enlargement over 2 cm, rising haematocrit with falling platelets): admit and give isotonic crystalloid 5 to 7 mL/kg/h for 1 to 2 hours, then 3 to 5 mL/kg/h adjusted to haematocrit and clinical response.
• For shock give 10 to 20 mL/kg over 15 to 30 minutes, with red cells for suspected major bleeding when haematocrit falls with unstable circulation. Avoid prophylactic platelet transfusion.
• Lassa fever: ribavirin 30 mg/kg intravenously (maximum 2 g) as a loading dose, then 16 mg/kg every 6 hours for 4 days, then 8 mg/kg every 8 hours for 6 days, started as early as possible. Ribavirin is teratogenic and causes haemolysis, so monitor haemoglobin; use in pregnancy only when the maternal risk justifies it.
• Crimean-Congo haemorrhagic fever: supportive care; ribavirin 30 mg/kg intravenously loading then 15 mg/kg every 6 hours for 4 days, then 7.5 mg/kg every 8 hours for 6 days, under specialist direction. Evidence of benefit is limited.
• Ebola virus disease (Zaire species): supportive care with fluid and electrolyte correction, plus a monoclonal antibody given intravenously as a single infusion (ansuvimab 50 mg/kg, or the combination of atoltivimab, maftivimab and odesivimab 50 mg/kg of each antibody) through a designated treatment centre. Marburg disease: supportive care and experimental therapy under specialist direction.
• Rift Valley fever, yellow fever, hantavirus and other haemorrhagic fevers: supportive care only. Treat associated hypoglycaemia, hypocalcaemia, acidosis and renal failure.
• Thrombotic thrombocytopenic purpura: admit to a haematology service the same day. Start daily plasma exchange (1 to 1.5 plasma volumes) with prednisolone 1 mg/kg orally daily (or methylprednisolone 1 g intravenously for 3 days), caplacizumab 10 mg intravenously then 10 mg subcutaneously once daily, and rituximab 375 mg/m2 weekly for 4 doses. Avoid platelet transfusion unless life threatening bleeding.
• Haemolytic uraemic syndrome: fluid management, early dialysis, blood pressure control and transfusion as needed. Antibiotics are avoided in Shiga toxin producing Escherichia coli. Atypical haemolytic uraemic syndrome needs complement inhibitor therapy (eculizumab 900 mg intravenously weekly for 4 weeks then 1200 mg every 2 weeks) at a specialist centre.
• Acute promyelocytic leukaemia: start all-trans retinoic acid 45 mg/m2 orally daily in 2 divided doses as soon as the diagnosis is suspected, and arsenic trioxide 0.15 mg/kg intravenously daily under haematology direction. Maintain platelets over 30 to 50 x 10^9/L and fibrinogen over 1.5 g/L.
• Haemophagocytic lymphohistiocytosis: dexamethasone 10 mg/m2 daily with etoposide under haematology direction, and treat the trigger.
• Immune thrombocytopenia: prednisolone 1 mg/kg orally daily (maximum 80 mg) for 2 to 4 weeks, with intravenous immunoglobulin 1 g/kg once or twice for severe bleeding.
• Heparin induced thrombocytopenia: stop all heparin, start a nonheparin anticoagulant (argatroban 2 micrograms/kg/min intravenously, reduce in liver impairment; or fondaparinux), and avoid platelet transfusion.
• Snake envenoming with coagulopathy: antivenom as directed by the regional product and the 20 minute whole blood clotting test.
• Disseminated intravascular coagulation: treat the cause. Replace products only for bleeding or procedures, and consider prophylactic low molecular weight heparin when there is no bleeding and platelets are over 30 x 10^9/L.
• Vasculitis and lupus: prednisolone 1 mg/kg daily with rheumatology review.

Contacts and healthcare workers. After contact with a suspected viral haemorrhagic fever case, record the exposure, monitor temperature twice daily for 21 days, and ring vaccination or post exposure treatment under public health direction.

Monitoring. Vital signs every 15 minutes during resuscitation, then hourly. Urine output hourly. Repeat haemoglobin, platelets, INR, fibrinogen, creatinine, lactate and glucose every 4 to 6 hours initially. Haematocrit every 4 to 6 hours in dengue. Repeat malaria films every 12 to 24 hours. Neurological observations when intracranial bleeding is possible.

Referral and escalation. Intensive care for shock, respiratory failure and active bleeding. Haematology urgently for thrombotic microangiopathy, leukaemia, haemophagocytic lymphohistiocytosis and disseminated intravascular coagulation. Infectious diseases and public health for suspected viral haemorrhagic fever. Obstetrics and anaesthesia for pregnancy related bleeding. Surgery or endoscopy for gastrointestinal haemorrhage and intracranial bleeding.

Admission criteria. All patients with fever and bleeding. Patients with possible viral haemorrhagic fever are admitted to an isolation unit.

Discharge and follow up. Discharge only after fever resolves, platelets recover and are rising, bleeding stops, haemoglobin is stable and the cause is established. Repeat count and coagulation tests at 48 to 72 hours. Survivors of viral haemorrhagic fever need counselling about persistence of virus in body fluids. Safety net advice: return for new bleeding, black stools, vomiting blood, severe headache, drowsiness, severe abdominal pain, breathlessness, or reduced urine.