What Is Haemolytic Uremic Syndrome

Overview

Haemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by thrombocytopenia, acute renal impairment, and microangiopathic hemolytic anemia. It is a potentially life-threatening condition, especially in children, and requires prompt diagnosis and treatment. HUS is caused by the formation of small blood clots in tiny blood vessels, leading to platelet consumption, destruction of red blood cells, and kidney injury. Treatment involves supportive measures, such as maintaining fluid balance and addressing renal dysfunction, along with interventions like plasma exchange or dialysis in severe cases. Identification and management of the underlying cause, including bacterial infections or genetic predispositions, are important for improving outcomes. Early recognition and intervention play a crucial role in managing HUS and preventing complications.¹

Causes of haemolytic uremic syndrome

The majority of cases of haemolytic uremic syndrome (HUS) are associated with acute infections, particularly acute hemorrhagic colitis caused by Shiga toxin–producing bacteria. Approximately 90% of HUS cases are triggered by these bacteria, with Escherichia coli O157:H7 being the most commonly implicated strain. Additionally, certain strains of Shigella dysenteriae, a different bacteria, can also lead to HUS. These infections typically result from the consumption of contaminated food or water.

Less frequently, HUS can be caused by other types of infections. Pneumococcal infections, which are usually respiratory in nature, have been associated with HUS, although these cases are relatively rare. In extremely rare instances, HUS can be linked to HIV infection.

In a small minority of cases, HUS occurs without an infectious trigger and is instead related to dysregulation of the complement system. The complement system is a part of the immune system that helps identify and eliminate pathogens. Dysregulation of this system in HUS can occur due to genetic mutations affecting complement proteins or factors. These mutations can disrupt the normal functioning of the complement system and contribute to the development of HUS. In some cases, acquired autoantibodies from the bacterial infection, against certain complement factors can also lead to complement dysregulation and subsequent HUS. Furthermore, individuals with congenital complement disorders may have an increased risk of developing HUS following an infection.²

It is important to note that while acute infection and complement dysregulation are the main causes of HUS, there may be other rare or unidentified factors that can contribute to its development. The understanding of the causes of HUS continues to evolve as research progresses in this field.²

Signs and symptoms of haemolytic uremic syndrome

Preliminary phase: vomiting, abdominal pain, and bloody diarrhoea preceded by an infection (Shiga toxin exposure).

Pneumococcal-associated HUS: manifestations of pneumonia, meningitis, or sepsis without fever.

Haemolytic anaemia: signs of haemolytic anaemia, thrombocytopenia, and acute kidney injury appear approximately one week after the prodromal phase.

Neurological manifestations: weakness, confusion, and seizures were observed in about one-quarter of patients.

Kidney injury: hematuria, decreased urination or anuria, and hypertension.

Gastrointestinal involvement: hemorrhagic colitis with abdominal pain, nausea, vomiting, and bloody diarrhoea.

Potential cardiac involvement: development of arrhythmias.

Systemic nature: HUS affects multiple organ systems.

Early identification of signs and symptoms is crucial for the diagnosis and management of HUS. Timely management prevents further complications and improve outcomes.²

Management and treatment for haemolytic uremic syndrome

The management and treatment of HUS involve various approaches tailored to the individual patient's condition. Here is a summary of the key aspects:

Supportive therapy is the primary approach during the acute phase of HUS and includes maintaining fluid and electrolyte balance, controlling blood pressure, managing seizures if present, and optimising nutrition.

The use of antibiotics in HUS is controversial, and antibiotics targeting DNA synthesis should generally be avoided unless the patient is septic. Antibiotics that target the cell wall, transcription, or translation do not increase toxin production. Azithromycin has shown promise in reducing toxin levels without affecting bacterial viability.

Kidney transplantation is a viable option for children who progress to end-stage renal disease (ESRD), with a recurrence rate of HUS ranging from 0 to 10%.

Plasma exchange is the initial treatment of choice for atypical HUS, aiming to remove potentially harmful substances from the blood. Early initiation, preferably within 24 hours of presentation, has significantly reduced mortality rates.

Monoclonal antibodies, a protein which binds to a specific target in the body, such as eculizumab and ravulizumab, are approved for the treatment of atypical HUS. They inhibit excessive generation of complement proteins, a crucial process in HUS development. However, they carry the risk of meningococcal infection, necessitating vaccination prior to treatment.

Other treatments, including plasma therapy, intravenous immunoglobulin (IgG), fibrinolytic agents, antiplatelet agents, corticosteroids, and antioxidants, have not proven to be effective in controlled clinical trials during the acute phase of the disease.³

Diagnosis of haemolytic uremic syndrome

Clinical presentation: HUS is suspected in patients with suggestive symptoms, such as abdominal pain, bloody diarrhoea, and decreased urine output. Signs of acute kidney injury, thrombocytopenia (low platelet count), and microangiopathic anaemia are also indicative of HUS.

Laboratory tests: various laboratory tests aid in confirming the diagnosis of HUS. These include a complete blood count (CBC) with platelets, peripheral blood smear examination, and measurements of serum markers such as lactic dehydrogenase (LDH), haptoglobin, and bilirubin.

Ruling out other conditions: exclusion of other thrombocytopenic disorders is important in the diagnosis of HUS. This is done through the evaluation of clinical features, laboratory findings, and specific tests, such as the direct antiglobulin (Coombs) test.

ADAMTS13 activity: testing for ADAMTS13 enzyme activity levels may be helpful in differentiating HUS from thrombotic thrombocytopenic purpura (TTP). While ADAMTS13 deficiency is associated with TTP, it is typically normal or only mildly decreased in HUS cases.

Stool testing: stool testing, such as Shiga toxin enzyme-linked immunosorbent assay or specific culture media, may be conducted in patients with a history of diarrhoea, particularly if bloody diarrhoea was an early symptom. This helps identify the presence of Escherichia coli O157:H7, a bacterium commonly associated with HUS.

Genetic testing: in atypical cases of HUS, testing for complement factor gene mutations is recommended to identify underlying genetic factors contributing to the disease.

Comprehensive evaluation: a comprehensive assessment combining clinical presentation, laboratory findings, and specific tests is essential to establish a definitive diagnosis of HUS and differentiate it from other similar conditions.

By considering these key factors and conducting the necessary tests, healthcare professionals can accurately diagnose HUS and determine the most appropriate treatment strategy for the patient.²

Risk factors

Rural populations: HUS is more prevalent in rural populations compared to urban populations.

Warmer summer months: cases of HUS tend to increase during the warmer months, specifically from June to September.

Young age: children between 6 months and 5 years old are at a higher risk of developing HUS.

Older people or immunocompromised individuals: older individuals or those with altered immune responses are more susceptible to HUS.

Contact with farm animals: exposure to farm animals increases the risk of developing HUS.

E. coli O157 enteritis: children with E. coli O157 enteritis should refrain from attending school or nursery until they receive two negative tests.

Post-symptomatic shedding: even after symptoms subside, individuals can continue to shed the bacteria, potentially leading to transmission.

Highest transmissibility: the acute diarrheal phase is believed to be the period of highest transmission for HUS.⁴

Complications

Gastrointestinal complications: HUS may give rise to a range of gastrointestinal issues, such as intestinal strictures and perforations, intussusception (where a portion of the intestine folds into another section), rectal prolapse, pancreatitis (inflammation of the pancreas), and severe colitis (inflammation of the colon).

Neurological complications: this can result in complications like altered mental status, cerebrovascular accidents (CVAs) or strokes, and seizures. These ailments may arise due to diminished blood flow and oxygen supply to the brain.

Renal complications: the hallmark of HUS lies in its renal involvement. Renal system complications can include acute kidney injury (sudden loss of kidney function), chronic kidney disease (long-term kidney damage), hematuria (presence of blood in the urine), hypertension (high blood pressure), and proteinuria (excessive protein in the urine).⁴

FAQs

How can I prevent haemolytic uremic syndrome?

Avoid unsanitary swimming areas: it is important to avoid swimming in areas where water quality and sanitation are below standard, as it can be a potential source of E. coli contamination.

Avoid swimming if you have diarrhoea: if you are experiencing diarrhoea, you should not go swimming to prevent the spread of E. coli bacteria.

Avoid drinking unpasteurized drinks: unpasteurized drinks such as milk, cider, and juice can be a source of E. coli contamination. Pasteurised forms of these beverages are recommended.

Regularly cleaning: kitchen utensils (knives, spatulas, tongs, spoons, etc.) and food surfaces (cutting boards, countertops, plates, etc.) should be kept clean to prevent cross-contamination and the spread of E. coli bacteria.

Properly-cook meat: ensure that meat is cooked thoroughly, reaching a temperature of at least 160 °F (71 °C) to kill any potential E. coli bacteria present.

Defrost meat properly: defrost meat in a microwave or refrigerator rather than on a food surface or in warm water to prevent E. coli growth.

Separate raw and cooked foods: properly separate raw foods from cooked foods during storage, preparation, and cooking to prevent cross-contamination.

Wash hands before eating: thoroughly wash your hands with soap and water before eating to eliminate any potential E. coli bacteria present on your hands.

Wash hands after specific activities: it is important to wash hands after changing diapers, using the restroom, and after petting farm animals to reduce the risk of E. coli contamination.

By following these preventive measures, individuals can limit their risk of E. coli O157 infection and subsequently reduce the chances of developing HUS.⁵

How common is haemolytic uremic syndrome?

HUS primarily affects children, particularly those under the age of 10, with the majority of cases occurring in children younger than 5 years old. Shiga toxin-producing Escherichia coli (STEC) is responsible for over 90% of typical HUS cases. The annual incidence of typical HUS is approximately 3 cases per 100,000 individuals. In the United States, typical HUS cases are more common in rural communities during the summer and autumn seasons.

Atypical HUS, on the other hand, occurs less frequently and in a more sporadic manner. It is estimated to have an incidence rate of 10 cases per 1,000,000 individuals in the U.S. and around 7 per 1,000,000 individuals in Europe. About 40% of atypical HUS cases are associated with Streptococcus pneumoniae.

The fatality rate for both typical and atypical HUS is relatively low, with an estimated rate below 5%. However, it is important to note that HUS can still lead to serious complications, and prompt medical attention is essential for early diagnosis and appropriate management.⁵

When should I see a doctor?

It is important to seek medical attention from your healthcare provider if you experience any of the following symptoms associated with HUS:

• Presence of bloody diarrhoea
• Diarrhoea that persists for more than three days
• Decreased urine output or low amounts of pee when you urinate
• Swelling in various parts of the body
• Easy bruising of the skin
• Persistent fatigue or feeling excessively tired
• If you notice any of these signs, it is advisable to promptly contact your healthcare provider for evaluation and appropriate management. Early detection and intervention can help prevent potential complications and improve outcomes in cases of HUS⁶

Summary

HUS is an uncommon disorder characterised by a triad of hemolytic anaemia, thrombocytopenia, and acute kidney injury. It primarily affects young children, especially those below the age of 5. It is frequently caused by infection with STEC. HUS can also manifest in rare variants with diverse underlying causes.

Signs and symptoms of HUS encompass bloody diarrhoea, abdominal pain, vomiting, and indications of renal dysfunction. Swift medical attention is crucial to prevent complications and effectively manage the condition. Treatment primarily revolves around supportive care, maintaining optimal fluid and electrolyte balance, and addressing potential complications. In severe cases, interventions such as plasma exchange and the administration of monoclonal antibodies may be warranted.

Although the mortality rate is generally low, HUS can lead to long-term renal impairment and additional complications. Preventive measures involve practising meticulous hygiene, avoiding consumption of contaminated food and water sources, and exercising caution when engaging in activities like swimming or interacting with animals.