Babesiosis - "Malaria of the North" - chronic infection that is underestimated in its frequency but also in its severity

From Dr. Wolfgang Klemann, internist, Pforzheim

Presentation on the occasion of the autumn conference 2017 of the German Borreliose Society in Giessen.

introduction

“I came up with the topic of babesiosis after Babesia DNA was detected in several patients in my practice using PCR from whole blood.
Those affected became seriously ill after tick bites that had occurred 30 years ago in one case and 15 years in another. After there was an urgent suspicion of Lyme disease, conventional antibiosis was initially applied, which, however, did not bring any improvement; Rather, this only occurred after the additional use of anti-malaria agents.

The following presentation corresponds to excerpts from "Human Babesiosis" (1), a literature review by Edouard Vannier et al. from 2008

Viktor Babes, a Hungarian pathologist who investigated the cause of febrile hemoglobinuria in cattle grazed in the Danube basin of Romania, was the first to document a microorganism living in red blood cells. Shortly thereafter, Smith and Kilborne identified a similar organism in cattle in Texas. [3] Named Pyrosoma bigeminum after its pear shape, the protozoon was later recognized as Babesia bigemina.

The first human case of babesiosis was identified near Zagreb, Croatia, in 1957. [4] A young farmer raised cattle on tick-infested pastures and developed fever, anemia, and hemoglobinuria. He was asplenic and died of renal failure during the second week of the illness. First reported as Babesia bovis, the causative agent was most likely Babesia divergens,
Originally only diagnosed in Europe and North America, human babesiosis is now reported from around the world.

transmission

B. microti is the leading cause of human babesiosis. The primary vector of this species is Ixodes scapularis. [10]

The primary reservoir for B. microti in eastern North America is the white-footed mouse (Peromyscus leucopus). [7, 10] Up to two thirds of the mice are parasitic in endemic areas. [10] These mice can also be infected with Borrelia burgdorferi, the etiological agent of Lyme disease, and Anaplasma phagocytophilum, the cause of human granulocytic anaplasmosis. I. scapularis can acquire B. microti, B. burgdorferi and / or A. phagocytophilum during a blood meal and then transmit these pathogens [10, 21].

Symptoms

Most babesiosis cases are mild to moderate in severity, characterized by fatigue and tiredness followed by intermittent fever and one or more of the following:

• chills
• Sweats
• a headache
• Arthralgia
• Myalgia
• Anorexia and
• Cough (Table 1). [21, 47-49]

Less known are sore throats, abdominal pain, nausea, vomiting, weight loss, conjunctival injection, photophobia, pallor, emotional lability, depression and hyperesthesia. [50, 51] [21, 48]
Mild splenomegaly, hepatomegaly, or both are occasionally observed. [48, 52] Minor pharyngeal erythema, jaundice, and retinopathy with splinter hemorrhage and retinal infarction have also been reported. [53, 54] Rash is rarely seen, although ecchymoses and petechiae have been reported in severe cases. [51]

The disease usually lasts for several weeks to months, sometimes with protracted convalescence that can last longer than a year. [21, 48, 55, 56]
The parasitemia can persist even after the patient has largely recovered and can occasionally persist for more than two years after the onset of the disease. [56]

Severe course of the disease

Severe courses occur in people with underlying immunosuppressive conditions, including HIV coinfection, [57-59] malignancy, [55] immunosuppressive drugs [55, 60] and splenectomy. [55, 61, 62] Patients with more than one of these immunosuppressive conditions showed a prolonged course of the disease, also characterized by recurrences, which sometimes lasted for over a year. [55] Despite several treatment cycles of antibabesial therapy, one fifth of these patients died. [47, 49]

Babesiosis complications are often found and included in more severe courses

• acute respiratory failure
• DIC (disseminated intravascular coagulation)
• congestive heart failure
• Liver and kidney failure and
• Splenic infarction (Table 2).

Asymptomatic parasitemia

Patients who develop babesiosis notice subclinical infection in the first few weeks after being bitten by an infected tick. Asymptomatic parasitemia can persist for months or years after symptoms are resolved. [56] It is well known that many people infected with B. microti never experience any symptoms, as indicated by the inequality between seroprevalence and the number of regionally reported cases. [48]

Pathogenesis

The pathogenesis of babesiosis is based on two essential processes: the change in red blood cells caused by the pathogen and the host's immune response to the pathogen.

Changes in red blood cells

The only cells produced by Babesia spp. Erythrocytes are affected.
As the infection progresses, hemolytic anemia develops, which can be accompanied by tissue hypoxia.

As with Plasmodium spp., Babesia spp. Proteins built into the red blood cell membrane.
Like the P. falciparum erythrocyte membrane protein 1 (PfEMP1), the variant erythrocyte antigen 1 (VESA1) from B. bovis appears to be encoded by a highly polymorphic gene. [69]
It is believed that cytoadherence facilitates persistent infection, for example by reducing the access of immune defense cells of the host or by preventing the removal of infected erythrocytes in the spleen. [73]
In B. bovis and B. duncani infections, excessive cytoadherence and sequestration lead to microvascular obstruction and tissue hypoxia. [74-76]

Host immune response

The host's immune response is required to control and eliminate Babesia infected red blood cells, but it can also cause symptoms of disease. Cytokines are important for both aspects of the immune response.
It is believed that expression of the pro-inflammatory cytokines IL-12 and IFN-γ precedes expression of the anti-inflammatory cytokines IL-4 and IL-10 in order to achieve protective immunity. [79, 80]

………… Since a stronger inflammatory response is required to prevent a more severe infection, the inflammatory response can spread to the systemic compartment, creating a sepsis-like syndrome or causing adult respiratory distress syndrome.
The pulmonary inflammation is microti infection who are suffering the most common complication in people with a severe example of up to 20% of patients in non-cardiac pulmonary edema. [47]

Clinical diagnosis

The diagnosis of "babesiosis" should be urgently considered if there is a clinical suspicion, as the symptoms of babesial infection can overlap with those of several other diseases. There are no pathognomonic signs on physical examination.

Babesiosis should be considered when patients complain of virus-like symptoms and have recently been in a babesial endemic area during the summer or early fall months.

Babesiosis should also be considered in patients with Lyme disease or human granulocytic anaplasmosis, as all three infections can be transmitted through I. scapularis at the same time. [45]

Babesiosis should be considered in patients who develop a virus-like disease within 2 months of a blood transfusion, unless (further) alternative diagnosis is available.

Laboratory examination

Nonspecific laboratory findings of babesiosis reflect the lysis of the erythrocytes. These can include normocytic hemolytic anemia, hyperbilirubinemia and an increased indirect bilirubin fraction, increased serum lactate dehydrogenase (LDH) and decreased serum haptoglobin. Increased reticulocyte counts and thrombocytopenia are commonly observed. [45] White blood cell counts are generally normal to slightly decreased, with a left shift. Elevated transaminase and alkaline phosphatase are found in about half of the patients. [49] Proteinuria, elevated blood urea, and creatinine can also occur in severe cases. Urinalysis may also reflect hemolysis with hemoglobinuria.

The final diagnosis of babesial infection is generally made by microscopic identification of the organism (Fig. 2) from thick and thin blood smears stained Giemsa or Wright. [98] Babesia species can appear as round, oval or pear-shaped shapes, with blue cytoplasm and red chromatin. Several parasites can be present in infected red blood cells. The ring shape is the most common and is similar to that of P. falciparum.

Differentiating features of babesiosis in the smear are the presence of extra-erythrocytic forms in severe cases and the absence of pigment deposits (hemozoin), which are typically observed in older ring stages of P. falciparum. Tetrads of merozoites arranged in a 'Maltese cross' are pathognomonic for babesiosis, but are rarely seen. [98] The percentage of infected erythrocytes varies over the course of the infection. Often less than 1% of the erythrocytes become parasitized in the course of the disease. Several blood smears over several days may thus be necessary to identify parasite forms.

If babesiosis is still suspected despite negative smears, babesial DNA can be amplified from blood samples using the polymerase chain reaction (PCR). [99, 100] The PCR provides a highly sensitive and specific, albeit expensive test for the detection of babesial DNA in the blood. [99, 100] Babesian DNA can be amplified for months after initial infection despite standard treatment and resolution of clinical symptoms. [56]

Serology is also useful in confirming the babesial diagnosis. Anti-babesial IgM and IgG antibodies can be detected using an indirect immunofluorescence test (IFA) [101-103].

In rare cases, when conventional tests are negative, but babesiosis dd remains to be considered, the diagnosis can be confirmed by injecting patient's blood into a test animal (hamster), as this very susceptible test animal experiences intense parasitaemia 2 to 4 weeks after the inoculation will develop. [104]

therapy

Patients with symptomatic babesiosis should receive antimicrobial therapy after the diagnosis is confirmed by blood smear or PCR. [52, 105, 106] Two commonly used antimicrobial therapies are highly effective: the combination of atovaquone and azithromycin and the combination of clindamycin and quinine

(Table 3).

Mild to moderate illness

Atovaquone and azithromycin for 7 to 10 days is the regimen of choice for mild to moderate babesiosis.
Alternatively, clindamycin and quinine can be given, however adverse effects associated with this combination occur at a relatively high frequency during the treatment of babesiosis. In particular, tinnitus and gastroenteritis limit the ability of many patients to tolerate this regimen.

While these drug combinations were similarly effective in eliminating parasitemia and symptom relief, side effects were reported in 15% of those given atovaquone and azithromycin, but the rate of side effects was 72% in those given clindamycin and quinine.
In addition, about a third of the patients taking clindamycin and quinine had side effects that were severe enough to require dose reduction or drug discontinuation. In contrast, only 2% of patients taking atovaquone and azithromycin had such severe drug reactions.

severe Babesia disease

In patients with severe Babesia disease, the combination of clindamycin (administered intravenously) and quinine for 7 to 10 days is the treatment of choice (Table 3). [52, 106]

The combination of pentamidine and trimethoprim-sulfamethoxazole has been used successfully to treat a case of B. divergens infection. [108]

B. divergens infections are consistently described as life threatening, and clindamycin and quinine should be used in all of these cases, in addition to blood transfusions. [64]
Exchange blood transfusion is indicated for all babesiosis patients with severe parasitaemia (≥ 10%) or with significant pulmonary, renal or hepatic complications. [47, 109-111] The partial or complete transfusion reduces the parasite load quickly and removes toxic substances of the babesial infection.

Despite standard combination antimicrobial therapy, persistent recurrent babesial infection can develop in people with significant immunosuppression. [55]

In a recent case-control study of chronic babesiosis in 14 highly immunocompromised patients, not a single antimicrobial combination was effective; the infection could not be eliminated [55].