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Year : 2015  |  Volume : 58  |  Issue : 3  |  Page : 392-394
Chlamydia pneumoniae-related hemophagocytic lymphohistiocytosis in an adult patient with clonal karyotype abnormality

1 Department of Pathology, Division of Clinical Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
2 Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
3 Department of Medical, Division of Hematology and Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

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Date of Web Publication14-Aug-2015


Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening disease characterized by a severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and macrophages. Herein, we report a 58-year-old male who had Chlamydia pneumoniae-related pneumonia, followed by aggressive HLH. An abnormal cytogenetic profile was also detected. To our knowledge, this is the first report of an adult patient with C. pneumonia-associated HLH.

Keywords: Chlamydia pneumoniae, hemophagocytic lymphohistiocytosis, karyotype

How to cite this article:
Huang ZY, Chieuh TS, Hwang KS, Huang TC. Chlamydia pneumoniae-related hemophagocytic lymphohistiocytosis in an adult patient with clonal karyotype abnormality. Indian J Pathol Microbiol 2015;58:392-4

How to cite this URL:
Huang ZY, Chieuh TS, Hwang KS, Huang TC. Chlamydia pneumoniae-related hemophagocytic lymphohistiocytosis in an adult patient with clonal karyotype abnormality. Indian J Pathol Microbiol [serial online] 2015 [cited 2020 Jun 6];58:392-4. Available from: http://www.ijpmonline.org/text.asp?2015/58/3/392/162928

   Introduction Top

Hemophagocytic lymphohistiocytosis (HLH) is a rare, but potentially fatal disorder that is caused by the deregulation of natural killer T-cells (NK-cell), impaired cytotoxic effect, and significant immune activation, which leads to unexplained fever, cytopenia, hepatitis, and even neurologic abnormalities. [1],[2] HLH can be either primary with genetic defects or secondary, associated with malignancies, autoimmune diseases, or infections. Although 90% of primary HLH usually occur in infants or children younger than 2 years of age, there have been very few reports of proven genetic defects in adult. [1],[3],[4] Both primary and secondary HLH are often elicited by acute infections, especially by the Epstein-Barr virus (EBV), Cytomegalovirus (CMV), parvovirus, herpes simplex virus, varicella-zoster, measles, human herpes virus 8, and human immunodeficiency virus (HIV). [2],[5] Therefore, it is difficult and challenging to diagnose and promptly treat this disease. Chlamydia pneumoniae is an obligate intracellular pathogen that invades human respiratory tract and commonly causes pharyngitis, bronchitis, and atypical pneumonia. Herein, we report the case of an adult with aggressive HLH associated with C. pneumoniae infection.

   Case Report Top

A 54-year-old male was sent to our emergency department for shortness of breath, unclear consciousness, and intermittent high fever (around 39.0°C). The medical history included type II diabetes, hypertension, and coronary artery bypass graft for ischemic heart disease. No remarkable family, travel, or animal contact history was noted. A week prior to his admission to the emergency department, he was diagnosed with C. pneumoniae associated pneumonia over the bilateral lower lung lobes and treated for 17 days with fluoroquinolone. On his emergency admission, his complete blood count showed a white blood cell (WBC) count of 5150/mL with 50% neutrophil, hemoglobin (Hb) level of 9.4 g/dL, and a platelet count of 71 × 10 3 /mL. Biochemical studies revealed elevated serum ferritin (3302 ng/mL), aspartate aminotransferase (51 IU/L) and alanine aminotransferase (66 IU/L). Autoimmune tests were all negative as well as a series of pathogen investigations, including bacterial cultures of the blood, sputum, and urine, blood cryptococcal antigen, Mycoplasma pneumoniae antibody, viral studies (anti-HIV antibody, anti-HCV antibody, and anti-EBV), IgM antibody, and blood polymerase chain reaction tests for CMV. Abdominal sonography presented a newly developed splenomegaly with a size of 15.1 cm.

Initially, a broad-spectrum antibiotic was administered, but his high fever persisted, accompanied by a prominent pancytopenia with a WBC count of 270/μL, Hb level of 8.7 g/dL, and platelet count of 42 × 10 3 /μL on day 17. In addition, serum ferritin level increased to 25,139 ng/mL. A bone marrow biopsy was performed and showed hypocellularity and obvious hemophagocytosis [Figure 1]a and b. The cytogenetic study revealed various chromosomal defects in chromosome 1, 12, 14, 15, 17, and 18 [Figure 2]. No evidence of malignancy was noted by computed tomography of the chest and abdomen.
Figure 1: (a) Giemsa staining of a bone marrow sample showing hemophagocytosis in variable cells (b) CD68 (macrophage marker) staining by immunohistochemistry showing the presence of macrophages

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Figure 2: Cytogenetic study was performed by Giemsa-banded chromosomes from unstimulated bone marrow cell culture and showed various chromosomal defects in chromosome 1, 9, 12, 14, 15, 17, and 18

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Based on the HLH diagnosis, we applied the HLH-2004 protocol [6] with intravenous administration of etoposide, cyclosporine, and dexamethasone from the 21 th to 51 th day of hospitalization. Fever gradually subsided, and meanwhile, apparent improvement of dyspnea, appetite, and spirit were noted. The level of ferritin decreased to 4002 ng/μL, and WBC count increased to 7820 cells/μL (neutrophil 90%). Recurrent episodes of high fever, elevated ferritin reaching 6027 ng/μL, and pancytopenia occurred on day 43. Workups on infectious pathogens were negative, except for the positive result of sputum chlamydia antigen on day 48 (IMAGEN™ Chlamydia). Despite aggressive immunosuppressive therapy, blood transfusions, and anti-microorganism treatment (4 th generation cephalosporin and clarithromycin), pancytopenia still progressed and the ferritin level increased again to 16,635 ng/mL. The patient died 4 weeks later.

   Discussion Top

Although NK-cell function and soluble CD25 test were not available in our institute, the clinical manifestations such as unexplained high fever, pancytopenia, hyperferritinemia higher than 10,000 ng/mL, splenomegaly, and hemophagocytosis in the bone marrow aspirates fulfilled the Histiocyte Society diagnostic criteria (2004) for HLH. [6] It was reasonable to assume that the etiology was related to the C. pneumoniae infection and underlying genetic defects because of the following evidence. First, HLH can be induced by a variety of infections. Although the pathogens are more frequently viruses, various bacterial infection ( Brucella More Details, Gram-negative bacilli, and tuberculosis), parasites (Leishmania), and fungal organisms have been reported in rare cases. Yagi et al. reported that a 3-year-old boy suffered C. pneumoniae related HLH and acute encephalitis with poliomyelitis-like flaccid paralysis. [7] In our case, pancytopenia occurred about 1-week after the C. pneumoniae infection [Table 1]. Secondly, C. pneumoniae may trigger HLH by infecting monocytes and macrophages and replicating, which arouse cellular secretion of various pro-inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1beta (IL-1b), IL-4, IL-6, and IL-8 and lead to a significant immune activation. [5],[8] Thirdly, the disease progression corresponded with the second C. pneumoniae infection on day 48. Finally, various cytogenetic abnormalities were observed on chromosome 1, 15, and 17 in this patient, which may be associated with gene mutations related to primary or familial HLH such as those observed in LYST (1q42.1-42.2), RAB27A (15q21), and UNC13D (17q25) genes. [3] Several reported atypical mutations do not have an important molecular function and cannot induce HLH under normal conditions. This finding likely explains why the disease onset was delayed in this case. [1] To date, the HLH-2004 protocol followed by hematopoietic stem cell transplantation is considered as the standard treatment for HLH patients with genetic defects, familial inheritance, and refractoriness to steroids. However, high treatment-related mortality is also noted due to profound immunosuppression and sequential occurrence of infections. [1]
Table 1: Literature review for Chlamydia pneumoniae-associated HLH

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From the analysis of this case, a particular attention should be paid to individuals infected with C. pneumoniae, especially patients presenting unexplained fever and persistent cytopenia. Once HLH is highly suspected, a bone marrow biopsy, cytogenetic studies, early administration of antibiotics, and immunosuppressive agents could be crucial for these patients.

   References Top

Jordan MB, Allen CE, Weitzman S, Filipovich AH, McClain KL. How I treat hemophagocytic lymphohistiocytosis. Blood 2011;118:4041-52.  Back to cited text no. 1
Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis 2007;7:814-22.  Back to cited text no. 2
Wang Y, Wang Z, Chen H, Wang X. Adult onset of primary hemophagocytic syndrome in subjects carrying PRF1 mutations. Ann Hematol 2012;91:1489-90.  Back to cited text no. 3
Janka G, zur Stadt U. Familial and acquired hemophagocytic lymphohistiocytosis. Hematology Am Soc Hematol Educ Program 2005;1:82-8.  Back to cited text no. 4
Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis 2000;6:601-8.  Back to cited text no. 5
Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124-31.  Back to cited text no. 6
Yagi K, Kano G, Shibata M, Sakamoto I, Matsui H, Imashuku S. Chlamydia pneumoniae infection-related hemophagocytic lymphohistiocytosis and acute encephalitis and poliomyelitis-like flaccid paralysis. Pediatr Blood Cancer 2011;56:853-5.  Back to cited text no. 7
Cho YS, Kim TB, Lee TH, Moon KA, Lee J, Kim YK, et al. Chlamydia pneumoniae infection enhances cellular proliferation and reduces steroid responsiveness of human peripheral blood mononuclear cells via a tumor necrosis factor-alpha-dependent pathway. Clin Exp Allergy 2005;35:1625-31.  Back to cited text no. 8

Correspondence Address:
Tzu-Chuan Huang
Tri-Service General Hospital, 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan
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Source of Support: This study was supported by grants TSGH-C104-185 from the Department of Defense and Tri-Service General Hospital, Taiwan, Republic of China, Conflict of Interest: None

DOI: 10.4103/0377-4929.162928

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