Hospital Medicine

Infectious hemolytic anemias

Infectious Hemolytic Anemias

I. Problem/Condition.

Hemolytic anemia is caused by the destruction of red blood cells that exceeds the ability of the bone marrow to replace them. The causes of hemolytic anemia may be either intrinsic, or extrinsic. Intrinsic causes of hemolytic anemia are specific problems of the red blood cell, and are typically hereditary. Extrinsic causes of hemolytic anemia are typically acquired, and may be caused by infection, medications, or other etiologies. The focus of this chapter will be on infectious causes of hemolytic anemias.

Infectious causes should be considered in all patients with hemolytic anemia that was preceded by or occurs concurrently with fever, and in patients with underlying immunodeficiency. In the absence of fever or immunodeficiency, a careful history and physical exam will be useful in determining the likelihood that the hemolytic anemia was caused by infection. A number of pathogens including viruses, bacteria, parasites and fungi may cause hemolytic anemias. In this chapter, we will focus on the pathogens that are more strongly associated with hemolytic anemias.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Infectious agents may cause hemolytic anemia through any of three pathophysiological mechanisms. These are immune hemolytic anemia, microangiopathic hemolytic anemia, and by direct destruction of the red blood cell by the pathogen. Defining the pathophysiologic mechanism of the hemolysis is important for guiding the differential diagnosis.

I. Immune hemolysis is subcategorized into three types based on pathophysiology of immune hemolysis: Autoimmune, immune complex deposition, and polyagglutination hemolysis.

  1. Autoimmune hemolysis is characterized by host immune-mediated destruction of red blood cells. Autoimmune hemolysis can be further divided into cold agglutinin-mediated, warm agglutinin-mediated, and paroxysmal cold hemoglobinuria.

    • Cold agglutinin-mediated hemolysis is mediated by IgM antibodies directed to polysaccharides on the red blood cell surface. The pathogens primarily responsible for cold agglutinin disease include Mycoplasma pneumoniae (M. pneumoniae) and infectious mononucleosis (EBV). Cold hemaglutinin disease has also been described in mumps, cytomegalovirus, Legionnaires’ disease, and visceral leishmaniasis.

    • Warm agglutinin disease accounts for the majority of autoimmune hemolytic anemia and is generally mediated by IgG antibodies to the Rh system of erythrocytes. Pathogens associated with warm agglutinin disease include, HIV, hepatitis C and infectious mononucleosis.

    • Paroxysmal cold hemoglobinuria is a self-limiting autoimmune hemolytic anemia mediated by IgG antibodies names Donath-Landsteiner antibodies directed against P antigen on erythrocytes. It generally occurs after upper respiratory tract infections, chickenpox, infectious mononucleosis, mumps, measles, measles immunization, and Mycoplasma pneumonia; it also has been described in secondary syphilis. Timing of hemolysis should give a clue to diagnosis. It presents as an acute illness manifesting with sudden onset of pallor, hemoglobinuria, icterus, and hepatosplenomegaly during the convalescent stage.

  2. Immune complex-mediated immune hemolysis is frequently demonstrated in children with systemic infection with Hamophilus influenza type B, African trypnosomiasis, and malaria. Erythrocytes act as innocent bystanders that bind to antigen – antibody complexes and fix complements which subsequently results in hemolysis.

  3. Polyagglutination. This phenomenon of immune hemolysis is demonstrated in young infants with bowel disorders, such as necrotizing enterocolitis. Polyagglutination occurs when T cryptoantigen within the erythrocyte membrane is exposed. Neurominidase produced by enteric bacteria unmasks, and exposes cryptogenic T antigen of RBC to naturally occurring anti-T antibody.

II. Microangiopathic hemolytic anemia (MAHA) is characterized by mechanical destruction of red blood cells. MAHA is caused by thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), disseminated intravascular coagulation (DIC), or shear force created by extremely turbulent blood flow. Infectious pathogens associated with TTP/HUS include Shiga toxin producing Escherichia coli (E. coli), Shigella species, and HIV. DIC may occur as result of sepsis secondary to bacterial, or fungal infections. Extreme turbulent blood flow exerting shear force on erythrocytes is seen in cases with valvular rheumatic heart disease affecting aortic valve, and prosthetic infectious endocarditis.

III. Direct destruction of red blood cells may be mediated by the pathogen itself, or a toxin produced by the pathogen. Malaria, Babesia, and Bartonella bacilliformis (B. bacilliformis) directly destroy red blood cells. Clostridium perfringens (C. perfringens) causes toxin mediated destruction of red blood cells.

B. Describe a diagnostic approach/method to the patient with this problem.

Figure 1 gives a good outline for how to approach these patients. A diagnosis of anemia is typically made by the detection of a low hemoglobin. Once this diagnosis has been made, the clinician must then determine the pathophysiology of the anemia.

Figure 1

General approach for Anemia

Anemia may be due to blood loss, decreased production or increased destruction (hemolysis). A careful history/physical exam revealing a source of bleeding combined with the finding of iron deficiency anemia is suggestive of blood loss as the cause of anemia. A peripheral smear showing a low reticulocyte percentage or count in the setting of anemia is suggestive of decreased production as the etiology of anemia. A peripheral smear showing schistocytes, spherocytes as well laboratory findings of an elevated LDH, and a low haptoglobin suggest increased destruction, or hemolysis as the cause of anemia.

If hemolysis is suggested by early laboratory studies, a careful history would help determine if the hemolysis is due to intrinsic red blood cell defects, or extrinsic factors. Intrinsic red blood cell defects (such as hereditary spherocytosis, sickle cell disease, pyruvate kinase deficiency, glucose-6-phosphate deficiency) are typically hereditary, manifest early in life, and are associated with recurrences. In adults with evidence of hemolytic anemia and no prior history of intrinsic red blood cell defects, extrinsic causes of hemolysis must be evaluated.

If extrinsic causes of hemolysis are considered, an attempt must be made to determine if the underlying pathophysiology is autoimmune, microangiopathic, or direct pathogen-mediated destruction. Table 1 gives a breakdown on how to approach these patients. A positive direct Coombs test is suggestive of autoimmune hemolytic anemia. A peripheral smear showing schistocytes is suggestive of microangiopathic hemolytic anemia (MAHA).

Table 1.

MAHA may be due to TTP/HUS or DIC. Differentiating between the two is important as different infectious pathogens may be associated with each. TTP/HUS is typically characterized by platelet activation/consumption with sparing of clotting factors. Hence, while there is thrombocytopenia in TTP/HUS, the INR, PT, aPTT, fibrin, and fibrinogen are normal. DIC, on the other hand, is characterized by diffuse utilization of clotting factors. In addition to thrombocytopenia, there is also high INR, PT, aPTT, and low fibrinogen in patients with DIC.

I. Historical information important in the diagnosis of this problem.

In patients suspected of having an extrinsic cause of hemolysis, infection should be considered in the differential for all those who are immunocompromised and those with associated fever. For non-immunocompromised patients, a careful history will help raise or lower the likelihood of infection as the cause. The history should focus on three main groups of questions.

  1. Host-specific factors that predispose the patient to infection or infection-induced treatment-related hemolysis. A history of host immune status such as HIV, solid organ transplant, stem cell transplant, or other evidence of immunodeficiency is important. A history of splenectomy may predispose the patient to infection with babesia. A history of underlying hemoglobinopathies such as sickle cell anemia, Bart hemoglobin, hemoglobin Koln, etc. and a history of inherent deficiency of reductive enzymes implicated in repair of oxidative damage, e.g., G6PD deficiency, is essential to obtain. The presence of such inherent disorders render erythrocytes susceptible to hemolysis when exposed to oxidative stressors like infections, or oxidative drugs used in the treatment of infections.

  2. Additional symptoms associated with the hemolytic anemia. Symptoms such as fever are prominent among infections such as malaria, babesiosis, C. perfringens and B. bacilliformis (Oroya fever). Diarrhea that preceded or is concurrent with hemolytic anemia may be suggestive E. coli or Shigella associated HUS. A history of dark colored urine may be associated with malaria or oroya fever caused by B. bacilliformis infection, or any other severe intravascular hemolytic process. Concurrent or recent symptoms of respiratory infection may be suggestive of Mycoplasma pneumonia infection.

  3. Disease exposures. These questions should be focused on three main areas:

    • High risk behavior or exposures,

    • Local infectious disease epidemiology,

    • Travel to areas that are endemic for specific infectious pathogens.

    Malaria is endemic in sub-Saharan Africa, Southeast Asia and the Indian Subcontinent, Central America, parts of South America, and in Haiti. Babesia is transmitted by ticks and infections may be seen in the Northeast and Upper Midwest of the United States of America. B. bacilliformis infections cause Oroya fever which is marked by hemolytic anemia and dark colored urine. Transmission of B. bacilliformis is by the sandfly, and cases are seen in Peru, Ecuador and Colombia.

  4. Management of infections. Multiple drugs used to treat infections are implicated in causing hemolysis via immune mechanism or oxidative hemolysis. Drug-induced hemolysis can be seen with acetaminophen, amoxicillin, cephalosporin, isoniazid, quinidine, rifampin, salicylic acid, streptomycin, sulphonamide, tetracycline, and α-methyldopa. Mechanisms of drug-induced hemolytic anemia is beyond the scope of this topic. Several antimicrobial drugs cause oxidative-induced hemolysis in G6PD-deficient patients. These drugs include nalidixic acid, niridazole, nitrofurantoin, pamaquine, primaquine, sulfacetamide, sulfamethoxasole, sulphanilamide, sulfapyridine, thiazolsulfone, and dapsone.

  5. History of blood transfusions can also clue into the diagnosis of infectious causes of hemolytic anemia. Some infections that are incriminated in hemolytic anemia and that can be transmission via blood transfusions include: hepatitis, CMV, EBV, HTLV-1, malaria, Rickettsia, Treponema, Brucella, Trypanosoma, Babesia, etc.

  6. Procedural history. Recent history of septic abortion, acute cholecystitis, amniocentesis makes Clostridium perfringes likely cause of hemolytic anemia. Severe sepsis and gas gangrene are the most common presenting features of Clostridium perfringes infection.

II. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

  1. Vital signs should be checked and particular attention should be placed on determining if there are any signs of sepsis.

  2. A thorough skin exam should be performed to look for any evidence of purpura or petechiae which may suggest MAHA. Also check for jaundice, or scleral icterus.

  3. Cervical, axillary and inguinal lymphadenopathy may be present. Lymphadenopathy may be prominent features in EBV, and HIV infections.

  4. An abdominal exam should focus on determining if there is splenomegaly. This may be seen in autoimmune hemolytic anemias, malaria infection, and B. bacilliformis infection as well.

III. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

In addition to the lab tests outlined in section IIb, the following tests may also help in the diagnostic work-up.

Autoimmune Hemolytic Anemia

  • HIV test

  • Blood cultures

  • Hepatitis C antibody if the history is suggestive

  • Acute and convalescent sera for mycoplasma pneumonia

  • EBV serologies (Viral Capsid Antigen IgG and IgM, Early Antigen IgG, Nuclear Antigen IgG)

  • Peripheral blood smear to look for atypical lymphocytes

MAHA

  • HIV test

  • Blood cultures

Hemolytic anemia not consistent with MAHA or Autoimmune hemolytic anemia

  • Peripheral blood smear with Giemsa stain for malaria, Babesia, and Bartonella bacilliformis if the history is suggestive.

  • If malaria is suspected, Thick blood film should be obtained at least three days after symptom to allow parasitemia to reach detectable level.

  • In infections due to Babesia, Geimsa thin blood film reveals dark-stained rings within blue cytoplasm or occasionally classic Maltese cross tetrads.

  • In patients with infection from Bartonella bacilliformis, Geimsa stain demonstrates red violet rods on erythrocytes.

  • Serology for Bartonella bacilliformis if history is suggestive. Immunofluoresent test for babesia antibodies and PCR for diagnostic confirmation, and monitoring response to therapy are available.

  • Blood cultures for Clostridium perfringes. Astriking dissociation between blood hemoglobin and hematocrit, marked hemoglobinuria, hemoglobinemia, and dark mahogany-colored urine should clue in to diagnosis of Clostridium perfringes.

C. Criteria for Each Diagnosis in the Method Above.

  1. HIV - Positive screening ELIZA with positive confirmatory Western Blot.

  2. Hepatitis C - Positive antibody test with positive confirmatory viral load.

  3. EBV - Positive Viral Capsid Antigen IgM/IgG as well as positive early antigen IgG are suggestive of acute infection.

  4. Malaria - The combination of fever and a peripheral smear demonstrating malaria parasites is diagnostic. Rapid diagnostic tests are also available at most clinical labs as well.

  5. Babesiosis - Peripheral blood smear and Giemsa stain that shows characteristic forms of Babesia parasites in a patient with consistent exposure history.

  6. E. coli and Shigella - Positive blood cultures and or stool cultures.

  7. C. perfringens - Positive blood cultures.

  8. B. bacilliformis - blood cultures may need to be incubated for up to 6 weeks. Acute and convalescent sera is also helpful in making the diagnosis.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Infectious Hemolytic Anemias.

Management of these patients should be focused on three key areas:

1) Management of Anemia and symptoms related to anemia

2) Management targeted at the underlying pathogenesis of the anemia (autoimmune, MAHA)

3) Treatment of the infectious agent causing the hemolytic anemia.

When addressing each of these three areas, care should be taken to address issues that may be life threatening.

1. Management of anemia: Symptoms of severe anemia include, hypotension/shock, weakness/fatigue, shortness of breath, dizziness, and chest pain. Patients with underlying coronary artery disease should be transfused to maintain a hemoglobin of 10 g/dL. Transfusion should also be considered for all patients who are symptomatic.

In patients with autoimmune hemolytic anemia, the blood bank should be notified of the patient's diagnosis prior to transfusion. A hematologist should be consulted to assist with management and with blood transfusion. The patient's blood will need to be tested for the presence of auto antibodies and allo-antibodies. The presence of allo-antibodies may lead to significant transfusion reactions.

2. Management directed at underlying pathogenesis of hemolytic anemia:

a. Management of TTP/HUS must be initiated emergently if this diagnosis is suspected to prevent adverse outcomes. Treatment of TTP/HUS involves plasma exchange. Avoid platelet transfusions as this may lead to exacerbation of symptoms. A hematologist should be consulted to assist with management.

b. Management of autoimmune hemolytic anemia typically requires steroids and/or other immunosuppressive agents. In severe cases that are refractory to steroids, splenectomy may be considered. A hematologist should be consulted to assist with management.

c. Management of DIC is typically directed at the underlying cause. If the underlying cause is suspected to be infection, broad spectrum antibiotics should be initiated and later narrowed based on culture information. Transfusion of platelets and fresh frozen plasma should be considered in patients with active bleeding. A hematologist should be consulted to assist with management.

3. Treatment of the infectious agent causing hemolytic anemia: Target antimicrobial therapy toward the pathogenic agent causing the hemolytic anemia. Table 2 outlines antimicrobial options for common infectious causes of hemolytic anemia. If malaria or babesiosis is suspected, therapy should be initiated immediately and infectious diseases consulted. Antibiotic treatment of E. coli/Shigella-associated HUS/TTP has not been shown to improve the outcome of HUS/TTP. Antibiotics may actually lead to increased toxicity related to HUS/TTP. Treatment of HIV and hepatitis C should be done in consultation with an infectious disease specialist. There is no antimicrobial therapy for EBV infections.

Table 2.

Medications:

IV quinidine gluconate 6.25mg base/kg load then 0.0125mg base/kg for at least 24hrs

IV artesunate 2.4mg/kg 1st those then 2.4mg/kg at 12hrs and at 24hrs. Then 2.4mg/kg once a day.

Atovoquone-proguanil 250/100, 4 tabs po once a day

Atovoquone 750mg po twice daily

Azithromycin 500-1000mg po for 1 dose and then 250mg po for 7 days

Clindamycin 600mg po three times a day

Doxycycline 100mg po twice a day

Penicillin G 3-4 million units every 4 hours

Ampicillin 2 grams IV every 4 hours

Erythromicin 500mg 4 times a day

Levofloxacin 500mg po once a day

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

N/A

IV. What's the evidence?

Williams Hematology – Eighth edition

Berkowitz, Frank E.. "Hemolysis and infection: categories and Mechanisms of Their interrelationship". Oxford journals. 1991;13 (Nov-Dec).

Dhaliwal, G, Cornett, P, Tierney, L.. "Hemolytic anemia". Am Fam Physician. vol. 69. 2004. pp. 2599-2607.

**The original Author for this chapter was Dr. Obinna Nnedu. The chapter was revised by Dr. Juvvigunta Vasthala.

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