Human granulocytic plasmosis – causes, symptoms and treatment

Human granulocytic plasmosis is an acute bacterial fever, tick-borne anthroposoonosis caused by infection with Anaplasma phagocytophilum.

The occurrence of human granulocytic plasmosis

Disease-causing bacteria known today as Anaplasma phagocytophilum, formerly Ehrlichia, were considered animal pathogens. A. phagocytophilum infection was discovered almost simultaneously in Scotland, by conducting research on sheep’s disease, and in the USA – in Pennsylvania voles in the 30s. Human infection was detected in an 80-year-old man in Arkansas (USA) in 1990 and published in 1994 (Bakken et al.). The first Polish patients with human granulocytic plasmosis were described in Białystok in 2001.

The vector of the infection are ticks from the Ixodes persulcatus complex; in Poland – the common tick (Ixodes ricinus). Small and medium-sized mammals and cervids are of major importance in the circulation of A. phagocytophilum in nature. Symptomatic animal infections are known as pasture fever or goat, sheep and cattle tick fever in the UK, the Netherlands, Scandinavia, Spain, France, Germany and Switzerland; Canine and equine granulocytic ehrlichiosis – in many US states as well as Canada, Brazil, Venezuela and Northern Europe.

How do we get infected?

Human infection occurs through the skin when ticks are feeding. Perinatal infection is also possible when exposed to infected blood. Human granulocytic plasmosis has been diagnosed and reported in over 2960 people in the US. In Europe, a dozen or so cases have been described, mainly in:

1. Slovenia,
2. Sweden
3. Austria,
4. Poland,
5. France,
6. Spain,
7. Italy,
8. The Netherlands,
9. Norway
10. Lithuania,
11. Latvia.

The total number of cases diagnosed in Europe does not exceed 100. However, seroepidemiological data show that we may be dealing with asymptomatic infections and / or undetectable infections due to the lack of pathognomic symptoms and limited knowledge of practitioners and access to diagnostics.

Human granulocytic plasmosis – causes

It is an etiological factor Anaplasma phagocytophilum, Gram-negative, obligate intracellular bacterium of the Anaplasmataceae family, Rickettsiales order, alpha-proteobacteria class. This species was created in 2001 on the basis of molecular studies (mainly 16S rRNA and groESL genes) and antigenic and biological characteristics, combining three bacteria – Ehrlichia equi, Ehrlichia phagocytophila and human granulocytic erlichiosis (HGE) factor, considered as separate species.

The bacterium A. phagocytophilum infects mainly neutrophils; after entering the cell, it multiplies and forms clusters in endoplasmic vacuoles, called morulas due to the similarity to the mulberry fruit.

The mechanism of infection with human granulocytic plasmosis

A. phagocytophilum penetrates the skin together with the secretions and saliva of the attacking tick. Then the neutrophils become infected and the infection spreads. A. phagocytophilum modifies the phenotype and functions of infected host cells by:

1) inactivation of antimicrobial mechanisms, both directly (superoxide dismutase) and indirectly (suppression of antimicrobial genes CYBB and RAC2);

2) it inhibits apoptosis;

3) modifies the expression of surface adhesive particles;

4) inhibits phagocytosis;

5) enhances the degranulation of metalloproteinases and chemokines.

During infection, complex cytokine production was observed, with a predominance of Th1 response – an increase in INF-gamma and low levels of IL-10. These complex mechanisms allow bacteria to survive and reproduce in the extremely hostile environment inside the neutrophil and lead to immunosuppression that predisposes them to opportunistic infections.

Pathological changes in human granulocytic plasmosis

In anatomopathological studies of infected animals and humans, the most frequently observed changes were:

1. slight lymphocytic infiltrates perosinus and intramedullary in the liver,
2. sporadically – apoptosis of hepatocytes,
3. atrophy of the white pulp with a decrease in the number of lymphocytes,
4. erythrophagocytosis in the spleen,
5. parabolic hyperplasia in the lymph nodes.

However, there is no necrosis, abscess formation or granulomas in the course of A. phagocytophilum infection.

Human granulocytic plasmosis – symptoms

Main symptoms

Symptoms of human granulocytic anaplasmosis are non-specific. Most often it is a sudden onset fever with headache, chills, malaise and muscle aches. They can be so severe that patients report feeling “beaten” or “run over by a truck”. It is less common:

1. decreased appetite,
2. nausea,
3. vomiting,
4. stomach pain,
5. diarrhea,
6. cough,
7. entanglement.

The diseases were described as atypical pneumonia or Sweet’s dermatological syndrome. Infections with human granulocytic plasmosis appear to be milder in Europe than in North America. In about 30% of patients on the old continent, they coexist with tick-borne encephalitis or Lyme disease.

The physical examination of human plasmosis is often not abnormal; however, conjunctivitis, cervical lymphadenopathy, slight splenomegaly and hepatomegaly have been reported. Laboratory abnormalities are most often related to thrombocytopenia, leukopenia, and a left shift in the leukogram during the first week of human granulocytic plasmosis, and a slight or moderate increase in hepatic transaminases and C-reactive white levels.

How does human granulocytic plasmosis work?

The hatching period of human granulocytic plasmosis is about 9 days and in most patients the disease is mild to moderately severe. Most often, recovery occurs, even without the use of appropriate antibiotic therapy.

The prognosis of the disease worsens:

1. older age of patients,
2. chronic comorbidities (cancer, immunosuppression),
3. delayed use of appropriate antibiotics.

Clinical improvement and fever reduction occurring 24-48 hours after taking doxycycline are evidence of correct diagnosis. When the patient’s condition does not improve during this time, another cause should be sought.

About half of the patients in the USA required hospitalization, and about 7% of patients – treatment in intensive care units. In severe human granulocytic anaplasmosis, the following has been observed:

1. rhabdomyolysis,
2. septic shock-like syndrome,
3. shoulder plexus damage,
4. demyelinating polyneuropathy.
5. myocarditis,
6. adult respiratory distress syndrome,
7. muscle inflammation,
8. disseminated intravascular coagulation,
9. shock,
10. kidney failure or neurological syndromes.

In most fatal cases of human granulocytic anaplasmosis, opportunistic infections such as disseminated candidiasis, cryptococcosis, invasive pulmonary aspergillosis, herpes necrotizing oesophagitis and others have been observed.

How is human granulocytic plasmosis diagnosed?

The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) working group (Table 35.3) has defined the definition of the case of human granulocytic plasmosis in force in Europe. The diagnosis is based on the results:

1. Epidemiological history – bite or exposure to ticks; however, failure to contact does not rule out A. phagocytophilum infection.
2. Biochemical tests – possible deviations from the norm are: leukopenia, thrombocytopenia, a slight increase in the activity of transaminases and the concentration of C-reactive protein.
3. Leukogram with detection of morula in neutrophils of peripheral blood (or bone marrow) in classic smears stained with the May-Grünwald-Giemsa (Pappenheim) method. A very fast staining method can also be used, using the commercial Diff-Quick kit (Dade Bering, Switzerland).
4. Serological testing of seroconversion or a fourfold increase or decrease in antibody titer.
5. Molecular tests involving the detection of DNA in the peripheral blood or in the “buffy coat” by PCR techniques, including sequencing of the reaction product (used most often).
6. In cell culture, HL60 (promyelocytic HL60 leukemia cell line – ATCCCL240) lines are typically used; using this method limits the availability of the laboratory with the third level of biological protection and the time (min. 2-3 weeks) of waiting for the test result.

In the diagnosis of human granulocytic plasmosis, it is also important to differentiate the disease from other ailments. Consider:

1. Other tick-borne diseases: Lyme borreliosis, tick-borne encephalitis, babesiosis, Rocky Mountain fever (North America), monocytic ehrlichiosis (North America), Ehrlichia ewingii infection, other rickettsial diseases [e.g. tick-borne lymphadenopathy (TeBoLa) = Dermacentor-borne necrosis erythemalymphadenopathy (Debonel) – Rickettsia slovaka infection, Rickettsia helvetica).
2. Viral infections, including the flu.
3. Sepsis.
4. Pneumonia, including atypical ones.
5. Gastrointestinal infections (viral and bacterial) and viral hepatitis.

Human granulocytic plasmosis – treatment

The drug of choice is the drug of choice in the treatment of human granulocytic plasmosis doxycycline used in adults at a dose of 0,1 g twice a day for 2-7 days or at least 10-3 days after fever.

Children over 8 years of age and with severe infections, regardless of age, should also be treated with doxycycline in the dose depending on weight (4,4 mg / kg / 24 hours, in two doses, not more than 0,1 g per dose). ). Alternatively, children younger than 8 years of age with mild infections and pregnant women may be treated rifampicin.

The effectiveness of the above therapy is confirmed not only by clinical data, but also by in vitro studies of North American strains of A. phagocytophilum. Antibiotic susceptibility tests based on the real-time PCR method showed high efficacy of doxycycline and rifampicin with variable susceptibility to fluoroquinolones. Beta-lactam antibiotics, co-trimoxazole, macrolides and telithromycin showed no activity against A. phagocytophilum. In case of suspected simultaneous Borrelia burgdorferi infection, doxycycline should be used for at least 14 days.

What’s the prognosis?

The prognosis for human granulocytic plasmosis is good. Mortality is about 0,7%. There are no data on chronic A. phagocytophilum infection.

Summary of information about the disease

1. Human granulocytic plasmosis is an anthropozoonosis transmitted by ticks, in Europe it is the common tick (Ixodes ricinus). This disease is caused by Anaplasma phagocytophilum, a gram-negative obligate intracellular bacterium that infects neutrophils.

2. The incubation period of human granulocytic plasmosis – 9 days.

3. Symptomatic infections include sudden onset fever, headaches, muscle aches and malaise. There were no pathognomic symptoms in the physical examination. The most common laboratory abnormalities are neutropenia, thrombocytopenia, and mild increases in transaminases.

4. The prognosis in human granulocytic plasmosis is good (mortality is about 0,7%).

5. The etiology of infection can be confirmed by detecting bacterial clusters in neutrophils – morule (peripheral blood leukogram), seroconversion or> = 4-fold increase / decrease in antibody titre or bacterial DNA by PCR with sequencing of the product. A. phagocytophilum does not grow on cell-free media.

6. The drug of choice is doxycycline 0,2 / day. Rifampicin can be used as an alternative in pregnant women and young children in mild infections.

Literature

1. Bakken JS, Dumler JS, Chen SM i wsp.: Human granulocytic ehrlichiosis in the upper midwest United States: a new species emerging? JAMA 1994; 272: 212-218

2. Buczek A .: Parasitic diseases. Epidemiology, diagnostics and symptoms, Wydawnictwo Drukarnia Liber, Lublin 2003.

3. Brouqui P., Bacellar F., Baranton G. i wsp.: Guidelines for the diagnosis of tick-borne bacterial diseases in Europe, Clin Microbiol Infect 2004; 10: 1108-1132.

4. Dumler J.S., Barbet A.F., Bekker C.P.J. i wsp.: Reorganization of genera in the families Rickettsiaceae and Anaplasmataceae in the order Rickettsiales; unification of some species of Ehrlichia with Anapalsma, Cowdria with Ehrlichia and Ehrlichia with Neorickettsia; description of five new species combinations; and designation of Ehrlichia equi and HGE agent as subjective synonyms of Ehrlichia phagocytophila, Int J Syst Evol Microbiol 2001; 51: 2145-2165.

5. Grzeszczuk A., Stańczak J., Kubica-Bierant B. i wsp.: First seroepidemiological evidence of human granulocytic ehrlichiosis (HGE) in Poland. Preliminary results. VIII European Multicolloquium of Parasitology (EMOP) Poznań, Poland 2000, Acta Parasitol 2000; 45: 219.

6. Grzeszczuk A., Ziarko S., Kovalchuk O., Stańczak J.: Etiology of tick-borne febrile illnesses in adult residents of north-eastern Poland. Report from a prospective clinical study, Int J Med Microbiol 2006, 296, Suppl 1, 242-249.

7. Grzeszczuk A., Barrat NC, Bakken SJ, Dumler JS: Anaplasmosis in humans, [w:] Raoult D., Parola P. (eds.): Rickettsial diseases, New York, Informa Healthcare 2007, 223-236.

8. Strle F.: Human granulocytic ehrlichiosis in Europe, Int J Med Microbiol 2004; 293, Suppl 37: 27-35.

9. Lotrič-Furlan S., Petrovec M., Avsic-Zupanc T., Strle F.: Human granulocytic ehrlichiosis in Slovenia, Ann NY Acad Sci 2003; 990: 279-284.

10. Thomas R.J., Dumler J.S., Carlyon J.A.: Current management of human granulocytic anaplasmosis, human monocytic ehrlichiosis and Ehrlichia ewingii ehrlichiosis, Expert Rev Anti Infect Ther 2009 Aug; 7(6): 709-722.

11. Tylewska-Wierzbanowska S., Chmielewski T. et al .: First cases of acute human granulocytic ehrlichiosis in Poland, Eur J Clin Microbiol Infect Dis 2001; 20: 196-198.

Source: J. Cianciara, J. Juszczyk, Infectious and parasitic diseases; Czelej Publishing House