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 Table of Contents  
Year : 2018  |  Volume : 6  |  Issue : 1  |  Page : 30-33

Community Acquired Pneumonia Associated Fatal Secondary Hemophagocytic Lymphohistiocytosis Syndrome

1 Department of Internal Medicine, Narayana Multispeciality Hospital, Jaipur, Rajasthan, India
2 MBBS Student, AIIMS, New Delhi, India

Date of Web Publication3-Jan-2018

Correspondence Address:
Arun Agarwal
Senior Consultant and Head, Department of Internal Medicine, Narayana Multispeciality Hospital, A-235, Shivanand Marg, Malviya Nagar, Jaipur 302017, Rajasthan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jacp.jacp_10_17

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The burden of community-acquired pneumonia (CAP) requiring hospitalization among adults is substantial and is a leading infectious cause of hospitalization and death. Severe CAP may rarely get complicated with secondary hemophagocytic lymphohistiocytosis (HLH). The term hemophagocytosis refers to the pathologic finding of activated macrophages engulfing erythrocytes, leukocytes, platelets, or their precursor cells in the bone marrow, liver, or lymph nodes; this being characteristic for hemophagocytic syndrome. HLH can be primary or secondary and has a high mortality if left untreated. We report a case of severe CAP with secondary HLH in a 26-year-old male, who presented with fever, pancytopenia, jaundice, and pneumonia due to polymicrobial infection. This case report is presented to enlighten clinicians about the clinical entity of HLH and to suspect and recognize this rare and fatal disease.

Keywords: Community-acquired pneumonia, etoposide, hemophagocyte, histiocyte, macrophage, natural killer cell

How to cite this article:
Agarwal A, Agarwal M. Community Acquired Pneumonia Associated Fatal Secondary Hemophagocytic Lymphohistiocytosis Syndrome. J Assoc Chest Physicians 2018;6:30-3

How to cite this URL:
Agarwal A, Agarwal M. Community Acquired Pneumonia Associated Fatal Secondary Hemophagocytic Lymphohistiocytosis Syndrome. J Assoc Chest Physicians [serial online] 2018 [cited 2020 Sep 28];6:30-3. Available from: http://www.jacpjournal.org/text.asp?2018/6/1/30/217312

  Introduction Top

Much has been learned about hemophagocytic lymphohistiocytosis (HLH) in the 75 years since it was first discovered and described by Scott and Robb-Smith in 1939.[1] A hallmark of HLH is the impaired or absent function of natural killer (NK) cells and cytotoxic T-cells.[2] It is an underdiagnosed hyperinflammatory syndrome, which is being diagnosed frequently nowadays.[3] In its most severe form, it leads to a sepsis-like condition and multiorgan failure. It covers a wide array of related diseases including HLH, autosomal recessive familial HLH (FHL), familial erythrophagocytic lymphohistiocytosis, viral-associated hemophagocytic syndrome, and autoimmune-associated macrophage activation syndrome. These disorders feature severe cytopenia due to uncontrolled hemophagocytosis. Other laboratory signs and clinical symptoms result from disordered immune regulation and cytokine storm.[4] The term primary HLH refers to an underlying genetic abnormality causing the disorder, whereas secondary HLH has been associated with a variety of viral, bacterial, fungal, and parasitic infections, as well as collagen vascular diseases and malignancies. It can rarely complicate community-acquired pneumonia (CAP) and can be fatal. The disease has high mortality if left untreated.

  Case Report Top

A 26-year-old Asian male was admitted with complaints of fever, cough, breathlessness, and backache, which lasted for the past 3–4 days. He was initially admitted at a local hospital for 3 days and then referred to us in view of the presence of bilateral CAP with persistent pancytopenia. He had no chronic comorbidities except for hypothyroidism. He was on indwelling catheter from outside, hemodynamically stable, had low SpO2 70%, low-grade fever, and bilateral basal coarse crackles. He was admitted in the medical intensive care unit and further evaluated. Investigations showed pancytopenia − moderate anemia (lowest hemoglobin 7.5 g/dl), grade 4 neutropenia, and severe thrombocytopenia (<20,000/cmm). He had raised C reactive protein (CRP), procalcitonin clinically insignificant <0.5 ng/ml, renal dysfunction (acute kidney injury), transaminitis, mild cholestatic jaundice, coagulopathy [raised Prothrombin time-International normalized ratio (PT-INR)], negative serology for dengue virus, scrub typhus, human immunodeficiency virus, and hepatitis B and C viruses. His abdominal ultrasound was normal. Nasopharyngeal wash was positive for Klebsiella pneumoniae, Pseudomonas aeruginosa, and  Escherichia More Details coli.

He was diagnosed to have CAP [Figure 1] with Type 1 respiratory failure with multiorgan dysfunction syndrome. In the view of persistent pancytopenia, bone marrow aspiration was performed, and it showed the presence of histiocytes with hemophagocytosis [Figure 2]. He was further evaluated for HLH syndrome, and his serum ferritin was estimated, which was reported to be high (2414.5 ng/ml).
Figure 1: X-ray chest taken on December 31, 2014

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Figure 2: The bone marrow showing histiocyte with hemophagocytosis

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He was managed with oseltamivir, imipenem + cilastin, moxifloxacin, colistin, insulin, Bilevel positive airway pressure (BIPAP) (later mechanically ventilated), filgrastim [granulocyte colony stimulating factor (G-CSF) analog], thyroxin, and other supportive treatment. He received a total of 32 units of random donar platelets, 1 unit of single donar platelets, and 2 units of packed red cells. Later, his fasting triglycerides were also reported to be high (274.2 mg/dl), and nasopharyngeal swab for influenza panel was reported as negative. By now, he was confirmed to have secondary HLH syndrome because of the presence of fever, cytopenia (all three lines reduced), hypertriglyceridemia, hemophagocytosis, and increased ferritin (fulfilling five of the nine clinical criteria for HLH). His NK cell panel was sent for examination. The panel showed very low (1%) NK cell activity (normal levels are >10% activity by flow cytometry assays). He was initiated on dexamethasone in the dosage 10 mg/sqm intravenously. In the absence of significant response and the presence of persistent pancytopenia, definitive treatment was started with etoposide, and dexamethasone continued as per the HLH-94 treatment protocol.[5] He was given etoposide 150 mg/sqm and also started on fluconazole, clarithromycin, and cotrimoxazole prophylactically. On the 10th day of his hospital stay, he developed surgical emphysema, mild pneumothorax, and pneumomediastinum secondary to minor tracheal tear at D4/D5 levels (likely traumatic) and widespread heterogeneous pulmonary infiltration [[Figure 3]a and [Figure 3]b]. Endotracheal tube (ET) secretions showed the presence of fluconazole-resistant Candida albicans. Fluconazole was changed to voriconazole. However, he succumbed to his disease.
Figure 3: (A) CECT chest taken on January 09, 2015 showing a tear in the posterolateral tracheal wall ATD4-5 levels and surgical emphysema. (B) CECT chest taken on January 09, 2015 showing consolidation, bilateral bronchopneumonia, surgical emphysema, pneumomediastinum, and small pneumothorax. CECT, contrast enhanced computed tomography

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  Discussion Top

The burden of CAP requiring hospitalization among adults is substantial and is a leading infectious cause of hospitalization and death. In a recent study with radiographic evidence of pneumonia, 21% of the patients required intensive care and 2% died.[6] Rarely, this gets complicated with HLH, which, if not thought of, can be fatal.

HLH is a syndrome of pathologic immune activation, occurring as either a familial disorder or a sporadic condition in association with a variety of triggers. The diagnosis of FHL or secondary HLH is based on a number of clinical signs and laboratory findings. The diagnosis of HLH, established by the Histiocyte Society, is based on fulfilling one or both of the following criteria:
  1. A molecular diagnosis consistent with HLH.
  2. Five out of the following eight diagnostic criteria for HLH: fever (>38.5°C), splenomegaly, cytopenia (affecting two or more of three lineages in the peripheral blood), hypertriglyceridemia (fasting >265 mg/dl) and/or hypofibrinogenemia (<150 mg/dl), elevated ferritin levels (>500 ng/ml), hemophagocytosis in the bone marrow/spleen/lymph nodes, low or absent NK cell activity (<10% activity by flow cytometric assays), or elevated soluble CD25 (interleukin-2 receptor) levels.[3],[7],[8],[9]

Our patient fulfilled six of these criteria. Ironically, despite the fact that hemophagocytosis is prominently featured in the name of this disease, it is rarely found at presentation in secondary cases and may not be visible until late in disease progression. We could demonstrate the presence of hemophagocytosis in the bone marrow on day 3, thereby confirming HLH syndrome in our patient. He had 1% NK-cell activity.

A number of conditions are associated with secondary HLH. By prevalence, these include viral infections (29%), other infections (20%), malignancies (27%), rheumatologic disorders (7%), and immune deficiency syndromes (6%).[10] We postulate his HLH to be associated with acute CAP. The pathophysiology of HLH requires a potent stimulus of the immune system, followed by an inability to cease the consequent response. Regardless of the cause, physiologically, HLH is characterized by defective cytotoxic cell function along with uncontrolled macrophage activity, leading to excessive cytokine production, subsequent immune dysregulation, and tissue damage. Left untreated, the dysregulated inflammatory response causes severe neutropenia, and patients often die from bacterial or fungal infections. Our patient succumbed to probably fungal bronchopneumonia. The syndrome is associated with high morbidity and mortality.[7] The median survival without treatment is estimated at 2 months.[7],[8] Prior to the use of modern treatment regimens, survival with HLH was close to 0%.[4] In general, the treatment of HLH involves immunosuppressive and modulatory agents, bio­logical response modifiers, the treatment of the inciting illness if secondary, and subsequent stem cell transplantation. Therapy is directed at suppressing the hyperinflammatory state and immune dysregulation. It is also important to kill infected antigen-presenting cells to remove the stimulus for ongoing immune activation. The treatment of HLH may vary according to the cause.[4]

Most cases of infection-related HLH should be treated aggressively with standard HLH protocols.[4],[7] HLH-specific therapy based on the HLH-94 protocol, HLH-2004 protocol, or enrollment in a clinical trial has been suggested. Until the results of the HLH-2004 study are published, the current practice is to treat patients who are not enrolled in a clinical study with a strategy based on HLH-94.[11] If the patient is not critically or severely ill, the triggering condition must be treated with the addition of corticosteroids and observed for a response before initiating chemotherapy. If the patient shows clinical improvement upon treatment of the triggering condition, chemotherapy may be avoided (although this is a rare exception rather than the rule). We treated our patient with dexamethasone and etoposide in the recommended dosage; however, he succumbed to the deadly infections. Autopsy was not performed. There are sporadic case reports in literature regarding hemophagocytic syndrome in association with CAP; therefore, it should be thought of as a possible cause in refractory cases.[12],[13]

  Conclusion Top

This case is presented to enlighten clinicians about the clinical entity of secondary HLH. HLH should be suspected when patients present with an underlying infection (CAP in the case presented) and have fever unresponsive to antibiotics, organomegaly, pancytopenia of unknown origin, liver dysfunction, and elevated ferritin levels. HLH is associated with high morbidity and mortality, and timely clinical suspicion is essential for its management.


The authors acknowledge Dr. Vivek Bhargava (Critical Care), Dr. Pallavi Maheshwari (Blood Bank), Dr. Vijay Sharma (Radiodiagnosis), and MICU residents and staff for their help and support in the management of this patient.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Scott RB, Robb-Smith AH. Histiocytic medullary reticulosis. Lancet 1939;234:194-8.  Back to cited text no. 1
Janka GE, Schneider EM. Modern management of children with haemophagocytic lymphohistiocytosis. Br J Haematol 2004;124:4-14.  Back to cited text no. 2
Agarwal A, Agarwal A. Infection associated secondary hemophagocytic lymphohistiocytosis in sepsis syndromes – A tip of an iceberg. J Assoc Physicians India 2016;64:44-50.  Back to cited text no. 3
George MR. Hemophagocytic lymphohistiocytosis: Review of etiologies and management. J Blood Med 2014;5:69-86.  Back to cited text no. 4
Trottestam H, Horne A, Arico M, Egeler RM, Filipovich AH, Gadner H et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: Long-term results of the HLH-94 treatment protocol. Blood 2011;118:4577-84.  Back to cited text no. 5
Jain S, Self WH, Wunderink RG, Fakhran S, Balk R, Bramley AM et al. Community-acquired pneumonia requiring hospitalization among U.S. adults. N Engl J Med 2015;373:415-27.  Back to cited text no. 6
Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr 1983;140:221-30.  Back to cited text no. 7
Henter JI, Horne A, Arico 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. 8
Weitzman S. Approach to hemophagocytic syndromes. Hematology Am Soc Hematol Educ Program 2011;2011:178-83.  Back to cited text no. 9
Dhote R, Simon J, Papo T, Detournay B, Sailler L, Andre MH et al. Reactive hemophagocytic syndrome in adult systemic disease: Report of twenty-six cases and literature review. Arthritis Rheum 2003;49:633-9.  Back to cited text no. 10
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. 11
Ku YH, Yu WL. Extensive community-acquired pneumonia with hemophagocytic syndrome caused by Aeromonas veronii in an immunocompetent patient. J Microbiol Immunol Infect 2015. doi: 10.1016/j.jmii.2015.06.007.  Back to cited text no. 12
García-Astudillo LA, Fontalba A, Mazorra F, Marín MJ, Castellanos A, Fernández S et al. Severe course of community-acquired pneumonia in an adult patient who is heterozygous for Q481P in the perforin gene: Are carriers of the mutation free of risk? J Investig Allergol Clin Immunol 2009;19:311-6.  Back to cited text no. 13


  [Figure 1], [Figure 2], [Figure 3]


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