Wednesday, June 22, 2011

Human Anaplasmosis and Leprosy. A case report

Leprosy Mailing List –   May 21st, 2011
Ref:    Human Anaplasmosis and Leprosy.  A case report
From: M A Piras, Sassari, Italy

Dear Dr. Noto,
Tick-borne infection caused by Anaplasma phagocytophilum (formerly known as Erlichia granulocytica), has recently been emerging in Sardinia, where it has been reported in dogs, horses, ticks of the genus Ripicephalus (R.sanguineus and R.turanicus) (1-3) and  in two human beings (4).  Human Anaplasmosis is usually a benign flu-like disease but can be very severe and lead to renal failure in immune-depressed patients (5).  We report the case of a Nigerian immigrant with a severe Anaplasmosis infection and a protracted acute renal failure, who turned out to be suffering from borderline lepromatous (BL) leprosy as well.
Case report
A  Nigerian 26 year old man was admitted in our hospital with a 5-day history of mild remittent fever, headache and peripheral symmetric oedema of his hands and feet.  A migrant, who has been living in Europe for one year, homeless, spent daytime in a town park and the nights in a hospice.  He denied any stay in the countryside and/or contact with domestic or wild animal.  In his medical history he reported Malaria but denied other relevant diseases, particularly Tuberculosis.
Physical examination was significant for cutaneous dyschromia with  the presence of diffuse circular, smooth, hypopigmented spots on his trunk and limbs, small and non tender lymph nodes in the laterocervical and axillary regions, moderate splenomegaly and peripheral symmetrical  oedema of his hands, wrists, feet and ankles with functional impairment; he was underweight. Chest X ray and pulmonary HRCT scan were normal.
On admission, remarkable laboratory findings were: absence of  acute phase reactants with low ESR and normal C reactive protein, alfa2 globulin and fibrinogen, presence of severe leucopenia with normal differential count, mild anemia, high hypergammaglobulinemia, moderate hypoalbuminemia.  Glucose, renal function and urine examination were normal.  Serological tests were negative for Malaria antigens, Streptolysin O antibodies, HIV screening and viremia, Syphilis and HCV; he was immune for past infection to HBV, CMV, EBV, Parvovirus and Measles. TB Quantiferon test resulted negative.
Pending the unrevealing results of blood and urine cultures, empiric  therapy was established  with two consecutive, both ineffective, courses of piperacilline/tazobactam and cyprofloxacin  while fever assumed an intermittent pattern with climax of 39.6 °C.  Successively, pending serological investigation for tickborne diseases, a course of doxicicline 100 mg bid po for 2 weeks achieved  that hectic fever subsided into a slight persistent fever of 37.2-37.4°C.  Eventually, serology proved to be significant for Anaplasma phagocytophylum with indirect immunofluorescence titres of IgM 1/160 and IgG 1/40 followed by seroconversion with IgG 1/320 and disappearance of IgM.
Early in the doxicicline course, clinical chemistry parameters got worse with increase of ALT (6x), AST (5x), GGT (6x), alkaline phosphatase (7x), LDH (3x), CPK (4x), myoglobin (8x), beta2 microglobulin (8x).  Acute renal failure was detected on day 12 of doxicicline treatment and persisted throughout with a progressive decline of creatinine clearance.  In the meantime there was a worsening of anaemia to HB 7.1 g/dl with inadequate reticolocyte response, lymphocytopenia to 300/l with normal neutrophil and platelet counts.  Moderate signs of rhabdomyolis and increase of ESR occurred while C reactive protein, alfa2globulins and fibrinogen persisted in the normal range.  Judging the first course of treatment insufficient a second 2 week course of doxicicline was established without significant results apart from a change of cutaneous dyschromic spots that became prominent, scaling and erythematous.
Diagnostic procedures were performed on kidney, bone marrow and skin.  Renal biopsyshowed at glomerular level a mild increase of the matrix and mesangial cellularity with deposits of IgM and IgA, the tubules had aspects of granular degeneration.  At interstitial level there was a marked lymphocytic infiltration with rare polymorphonucleated cell and a few plasmacells, mild thickening of the vessel walls.  Osteomedullary histology showed normal representation and maturation of the three lineages without increase of lymphoid cells, normal representation of B and T cells and polyclonal plasmacells with mild increase of the reticolinic network and CD34 positive cells in the normal range.  Skin biopsy, taken without any definite suspicion at the center of a dyschromic lesion in the anterior chest, revealed in the superficial and middle dermis histiocytic infiltration with epitelioid cells organized in perivascular granulomatous structures without evident aspects of necrosis.  Histochemical investigations (Pas, Giemsa, Grocott, Ziehl-Neelsen) were negative.  Fite staining was not available.
The latter report, although inconclusive on a possible microbiological etiology, pointed to a possible diagnosis of Leprosy.  Actually, on active search we found bilateral hypertrophy of the great auricular and ulnar nerves (see figures 1, 2).  After consulting a Leprosy expert (who became one of the authors), the diagnosis of borderline borderline (BB) leprosy in reversal reaction (RR), as evolution of borderline lepromatous (BL) leprosy was made.  We considered the RR a consequence of the anaplasmosis and doxicicline treatment.  On that moment the patient revealed he had been thinking of having leprosy because he was aware of a few cases in his Nigerian village, but he had never consulted a physician nor had he been treated for leprosy.  A five day course of metil-prednisolone 30 mg daily was started when the result of the kidney biopsy became known.  This resulted in an improvement of renal function, anemia, leucopenia and reduction of the extremity edema.  After three months the patient was transferred to the regional centre for Hansen, disease where the diagnosis was confirmed.
This unique case of association of anaplasmosis with leprosy can be regarded as an interesting natural experiment of immunological perturbation that caused a prolonged and difficult to decipher disease presentation.  Let us examine separately the most interesting points of the two infections.
Anaplasmosis: on an epidemiological point of view, it was not immediately clear if our patient had been exposed to tick infested in rural areas or had been in contact with pets or wild animals. Nevertheless, his stay in town parks and night cohabitation with homeless people could well have exposed him to ticks. The absence of acute phase reactants in a highly febrile patient was another intriguing point.  Actually, Anaplasma phagocytophylum has as virulence factor the escape from neutrophil phagocytosis, through the inhibition of phagolysosome fusion.  Although it is a potent inducer of -- INF, at the same time it behaves as an inhibitor suppressing the expression of -- INF membrane receptors and inhibiting the proinflammatory action in favour of bacterial multiplication withi n neutrophils (5- 6).  The apparent failure of the appropriate treatment for anaplasmosis was another point of doubt since, despite the abatement of fever, the clinical course tended toward a greater severity.  Limited rabdomyolisis with increased levels of creatinphosphokinase and myoglobin did not seem high enough to justify the persistence of moderate renal failure in comparison with similar data reported in the literature (7).  Other findings like anaemia, ineffective reticulocyte response, leucopenia and hypergammaglobulinemia suggested an anergy inducing disease that was searched in vain among lymphoproliferative disorders or miliary tuberculosis.  Furthermore, while renal insufficiency persisted, the second doxicicline course produced a variation of the skin lesions that, together with renal failure and nerve hypertrophy, were later interpreted as reversal reaction in BL leprosy.
Leprosy:  autochthonous leprosy has not disappeared in Europe, even if no case has been reported in WHO weekly epidemiological records in recent years.  In Italy, between 1970 and 2006, local data report a decreasing (autochthonous) incidence but with increasing percentage of imported cases.  These were 16% of 102 new cases in 1970-79 and 80% of 61 new cases in 2000-06 (8). In 2010 only one case of autochthonous leprosy was reported in Italy.  Thus, with the great migration of people from endemic countries we are coping with in the last decades, we should expect more than one opportunity to encounter a leprosy patient than we used to think.  Among Africa countries, Nigeria is afflicted by high Leprosy burden that has remained grossly stable between 2003 and 2009 when 88% of 4219 new cases were multibacillary forms (9).
Although our patient had an impressive dyschromic skin with  several circular hypopigmented spots we didn’t think of leprosy and passively accepted a trivial dermatologic diagnosis until the change of their appearance prompted new diagnostic procedures.  Unfortunately, the skin biopsy was taken from the centre of the lesion instead of the periphery, as prescribed for leprosy, so diminishing the chance to find mycobacteria in the histologic smear in spite of the multibacillary form of the disease.  Yet, the finding of a granulomatous lesion was the key to the final diagnosis.  Reversal reaction occurs mainly in the instable forms of leprosy, very rarely in polar forms, and is characterized by an upgrading of cell mediated immunity toward the mycobacterial antigens.  It implies oedematous alterations of the limb extremities, increase of inflammation in skin lesions with dermis oedema, nerve alterations with hypertrophy, neuritis and functional impairment.  Type 2 leprosy reaction is most frequent in lepromatous leprosy and is characterized by deposition of immune complexes causing erythema nodosum and glomerulonephritis. RR is controlled by steroid treatment (10).
In our case we hypothesize that the extremity peripheral oedema, for long ascribed to anaplasmosis, was already giving shape to a reversal reaction.  It could be triggered bygamma INF induced by Anaplasma phagocytophylum infection, with doxicicline treatment (which has an antibacterial effect against M. Leprae), contributing to the evolution of BL leprosy towards BB leprosy.  The small enlargement of latero-cervical and axillary lymph nodes that remained unchanged through the disease in a very thin patient were not considered of clinical significance.  Complicated Anaplasmosis is the most likely explanation for renal insufficiency.  Renal disease is not a feature of RR in instable forms of leprosy.  Serendipitously, steroid treatment, aimed to control renal insufficiency, turned out to be useful for the RR in our patient.
Best regards,
Maria Adriana Piras
MD, Clinic of Infectious Diseases, University of Sassari, Italy
Coauthors: Are R, Figoni M, Salis MT, Caddeo A, Fiori ML, Manconi GG
Figures: (attached)
  1. Skin lesions on the chest figure 1figure 2
  2. Great auricular nerves
  3. Table

  1. Alberti A, Addis MF, Sparagano O, Zobba R, Chessa B, Cubeddu T, Pinna Parpaglia ML, Ardu M, Pittau M. Anaplasma phagocytophylum, Sardinia, Italy. Emerg Infect Dis 2005;11:1322-24
  2. Alberti A, Zobba R, Chessa B, Addis MF, Sparagano O, Pinna Parpaglia ML, Cubeddu T, Pintori G, Pittau M. Equine and canine Anaplasma phagocytophylum strains isolated on the island of Sardinia (Italy) are phylogenetically related to pathogenic strains from the United States. Appl Environ Microbiol 2005;71:6418-22
  3. Satta G, Chisu V, Cabras P, Fois F, Masala G. Pathogens and symbionts in ticks: a survey on tick species distribution and presence of tick-transmitted micro-organisms in Sardinia, Italy. J Med Microbiol 2010 Sept 30 [Epub ahead of print]
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  6. Bussmeyer U, Sarkar A, Broszat K, Ludemann T,Moller S, van Zandbergen G, Bogdan C, Behnen M, Dumler JS, von Loewenich F, Solbach W, Laskay T. Impairment of gamma interferon signalling in human neutrophilsa infected with Anaplasma phagocytophylum. Infect Immun 2010;78:358-63
  7. Boateng F, Ohene-adijei R, Amoateng-Adjepong Y.  Rhabdomyolysis and acute renal failure associated with human granulocytic Anaplasmosis. Mayo Clin Proc 2007;82:250-53
  8. Deepak s, Voltolini G. La lebbra oggi in Italia: malattia dimenticata? Giorn It Mal Tor 2007;61:413-416
  9. WHO. Global leprosy situation 2010.  WHO Week Epidem Rec 2010;85:337-348
  10. Walker SL, Lockwood DNJ. Leprosy Tipe 1 (reversal) reactions and their management. Lepr Rev 2008;79:372-86

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