Published online June 19, 2006
PEDIATRICS Vol. 118 No. 1 July 2006, pp. e216-e219 (doi:10.1542/peds.2005-1861)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mou, S. S.
Right arrow Articles by Shetty, A. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mou, S. S.
Right arrow Articles by Shetty, A. K.
Related Collections
Right arrow Infectious Disease & Immunity

EXPERIENCE AND REASON

Hemophagocytic Lymphohistiocytosis Complicating Influenza A Infection

Steven S. Mou, MDa,b, Thomas A. Nakagawa, MDa,b, Ellen C. Riemerc, Thomas W. McLean, MDb, Michael H. Hines, MDd and Avinash K. Shetty, MDb

a Anesthesiology
b Pediatrics
c Pathology
d Cardiothoracic Surgery, Wake Forest University School of Medicine and Brenner Children's Hospital, Winston-Salem, North Carolina


   ABSTRACT
TOP
 ABSTRACT
CASE REPORT
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
During the influenza A (H3N2) season of 2003–2004, several influenza-related complications and deaths were reported in children. Hemophagocytic lymphohistiocytosis complicating influenza A infection is very rare. We report a 3-year-old girl who presented with severe pneumonia and hemophagocytic lymphohistiocytosis associated with influenza A infection. Clinicians should be aware of hemophagocytic syndrome as a serious complication of influenza A infection.

Key Words: influenza A • hemophagocytic lymphohistiocytosis • pneumonia

Abbreviations: HLH, hemophagocytic lymphohistiocytosis • HPS, hemophagocytic syndrome • EBV, Epstein-Barr virus • VAHS, virus-associated hemophagocytic syndrome • WBC, white blood cell • LDH, lactate dehydrogenase • CSF, cerebrospinal fluid • BAL, bronchoalveolar lavage • IL, interleukin

Hemophagocytic lymphohistiocytosis (HLH), also called hemophagocytic syndrome (HPS), is a disorder of the mononuclear phagocytic system that is characterized by nonmalignant, generalized histiocyte proliferation with marked hemophagocytosis.1,2 The clinical presentation is characterized by fever, pancytopenia, hepatosplenomegaly, and hemophagocytosis in bone marrow, liver, or lymph nodes. In addition to the primary or familial form of the disorder,1,2 secondary HLH has been associated with a variety of infections, malignancy, and autoimmune disease.3,4

Described primarily in association with Epstein-Barr virus (EBV), virus-associated HPS (VAHS) has been linked to other viruses, including cytomegalovirus; herpes simplex virus; adenovirus; parvovirus B19; HIV; respiratory syncytial virus; parainfluenza III virus; enterovirus; and hepatitis A, B, and C viruses.3–8 Although HLH complicating influenza A infection has been reported, these have occurred largely in immunocompromised patients.9–11 We report a fatal case of influenza A–associated HLH in a previously immunocompetent child and review previously reported cases in the literature.


   CASE REPORT
TOP
 ABSTRACT
 CASE REPORT
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
A 3-year-old previously healthy, black girl was transferred to our PICU for treatment of severe pneumonia. She presented to a local emergency department with a 1-week history of fever, dry nonproductive cough, vomiting, and progressive dyspnea. On initial evaluation, she was febrile (temperature: 102.2°F) and, tachypneic with retractions and required 8 L of supplemental oxygen by face mask to maintain saturations >93%. Evaluation at the referring center revealed a nasopharyngeal swab that was positive for influenza A by rapid antigen testing. The patient had not been immunized against influenza A. Chest radiograph demonstrated consolidation of the right hemithorax, consistent with pneumonia. Blood cultures were obtained, and before transfer she received a dose of intravenous vancomycin (15 mg/kg) and ceftriaxone (50 mg/kg).

On arrival to our PICU, the patient was alert and interactive. Her vital signs included a temperature of 100.3°F, heart rate of 165 beats per minute, respiratory rate of 70 breaths per minute, and a blood pressure of 120/56 mm Hg. Moderate respiratory distress with intercostal retractions and intermittent grunting was noted. Her oxygen saturation was 93% on 8 L of 100% oxygen by face mask. Physical examination was notable for moderate dehydration and capillary refill of <3 seconds. Lung examination revealed no aeration in the right hemithorax. Hepatosplenomegaly was noted, with liver edge palpated at 4 cm below the right costal margin and spleen palpated at 3 cm below left costal margin. No lymphadenopathy or skin rash was present. The rest of the physical examination was normal.

Initial laboratory data included hemoglobin of 8.4 g/dL; hematocrit of 24.4%; platelet count of 135000/mm3, white blood cell (WBC) count of 2000/mm3 with 12% segmental forms, 30% band forms, 38% lymphocytes, 1% monocytes, and 18% metamyelocytes; and absolute neutrophil count of 840. The chemistry profile revealed sodium of 116 mEq/L, potassium of 3.5 mEq/L, chloride of 85 mEq/L, bicarbonate of 18 mEq/L, blood urea nitrogen of 15 mg/dL, creatinine of 0.8 mg/dL, glucose of 101 mg/dL, aspartate aminotransferase of 2425 U/L, alanine aminotransferase of 451 U/L, total bilirubin of 4.2 mg/dL, albumin of 1.9 g/dL, and total protein of 3.7g/dL. A chest radiograph revealed diffuse obliteration of the air spaces in the right lung with blunting of the right costophrenic angle. A computed tomography scan of the chest revealed right lung consolidation, consistent with necrotizing pneumonia, with small pleural effusion. Intravenous vancomycin (45 mg/kg per day divided every 8 hours) was continued, and clindamycin (30 mg/kg per day divided every 8 hours) was added to the antibiotic regimen. In addition, amantadine was started for treatment of influenza A infection.

On the second day of hospitalization, the patient worsened clinically with severe hypoxemia and respiratory failure that required ventilatory support. Repeat laboratory data showed a WBC count of 1500/mm3 (absolute neutrophil count: 900), worsening anemia (hemoglobin: 7.8 g/dL; hematocrit: 22.9%), and thrombocytopenia (platelet count: 51000/mm3).

Given the combination of fever, pancytopenia, elevated transaminases and lactate dehydrogenase (LDH), and hepatosplenomegaly, the diagnosis of HPS was considered. Laboratory evaluation revealed a ferritin level of 14908 ng/dL, LDH of 931 U/L, and triglyceride level of 380 mg/dL. Coagulation profile was normal: prothrombin time of 10.5 seconds, partial thromboplastin time of 20.2 seconds, international normalized ratio of 0.66 seconds, and fibrinogen of 894 mg/dL. A bone marrow aspirate and biopsy and a lumbar puncture were performed. The marrow revealed mature histiocytes with hemophagocytosis, suggesting a diagnosis of reactive HPS (Fig 1). It also showed mild myeloid and megakaryocytic hyperplasia and mild erythroid hypoplasia, findings that are consistent with VAHS. Cerebrospinal fluid (CSF) analysis revealed 1 WBC and 46 red blood cells with glucose 114 mg/dL and protein 16 mg/dL. A CSF cytospin revealed rare lymphocytes and neutrophils but no evidence of hemophagocytosis. CSF Gram-stain was negative for microorganisms, and culture was negative. Multiple blood and urine cultures were negative for bacteria and fungi. Titers for Rocky Mountain spotted fever, mycoplasma IgG and IgM, EBV polymerase chain reaction, viral capsid antigen IgG/IgM, and EBV nuclear antigen were negative.


Figure 1
View larger version (97K):
[in this window]
[in a new window]
  		FIGURE 1 Bone marrow with modified Wright staining showing hemophagocytosis of an erythrocyte and platelets.

 
Empiric treatment for HLH was initiated with a 5-day course of intravenous immunoglobulin 400 mg/kg per day and dexamethasone. She continued to deteriorate, with increasing alveolar-arterial gradient and progressively decreasing lung compliance despite maximal ventilator support, use of neuromuscular relaxants, and inhaled nitric oxide. The patient progressed to acute respiratory distress syndrome, with an oxygenation index of 56. By the fourth day of hospitalization, she was placed on venovenous extracorporeal membrane oxygenation. On the fifth day of hospitalization, a flexible bronchoscopy with bronchoalveolar lavage (BAL) was performed. A viral culture of the BAL fluid was positive for influenza A virus that was antigenically similar to the vaccine strain A/Panama Strain/2007/99-(H3N2)-like. BAL fluid cultures were negative for bacteria, mycobacterium, and fungi. Silver stains were negative for Pneumocystis jiroveci.

The patient's extracorporeal membrane oxygenation course was complicated by progressive worsening of pulmonary injury with ultimate opacification of both lungs by repeat computed tomography scan, renal failure that required renal replacement therapy, desaturation, hypoxia with elevated lactate and C-reactive protein, and seizures. She died on hospital day 12 as a result of bradycardiac arrest despite maximal cardiorespiratory support.


   DISCUSSION
TOP
 ABSTRACT
 CASE REPORT
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
HLH is an unusual disorder that is characterized by uncontrolled proliferation of mature histiocytes, hemophagocytosis, and upregulation of inflammatory cytokines.1,2 The proposed diagnostic criteria for HLH include fever; splenomegaly; cytopenia in ≥2 cell lines; hypertriglyceridemia and/or hypofibrinogenemia; and hemophagocytosis on bone marrow, spleen, or lymph nodes without evidence of malignancy.1 Secondary, reactive forms of HLH, such as VAHS, has been reported to be distinguished by a characteristically mature, cytologically normal histiocytic invasion of marrow or node samples with a predominance of erythrophagocytosis.5

Influenza A (H3N2)–associated HLH has been reported previously in immunosuppressed individuals,9–11 but the association is very unusual in previously healthy hosts.4,12 To the best of our knowledge, our patient represents the first report in an immunocompetent, previously healthy child of HLH related to influenza A infection that meets all of the clinicopathologic diagnostic criteria for HLH as defined by the Histiocyte Society.1 Bone marrow specimen showed only mature histiocytes invading the marrow with no evidence of malignancy. The absence of hypertriglyceridemia and hypofibrinogenemia is consistent with previous reports.1,7,8,13 Two consistent laboratory findings are elevated levels of LDH and ferritin, which also may have prognostic value.7,13 Other supportive laboratory derangements that were noted in our case include elevated transaminases, hypoproteinemia, and hyponatremia.1,7 There is only 1 other report of influenza A–associated HPS in a previously healthy child, who presented with altered mental status and seizures12; however, the diagnosis of VAHS was made solely on postmortem examination, which revealed erythrophagocytosis in the bone marrow, spleen, and lymph nodes, and additional supportive evidence1 to confirm the diagnosis of HPS was not available.

In the absence of pertinent family history and parental consanguinity, distinguishing infection-associated HLH from the familial form can be difficult. There are reports that familial HLH can be triggered by infection,14 although, to date, no such reports have been associated with influenza A. In the absence of an evaluation of natural killer cell activity or perforin expression,15 it is impossible to distinguish firmly primary from secondary HLH in this case. Although, given the presence of documented influenza A infection, the negative family history and that 80% of familial cases occur in the first year of life,13,16 we believe that our case is consistent with a diagnosis of infection-associated HLH.

HLH can be confused easily with other diagnoses, including fever of unknown origin, hepatitis, and child abuse.7,17 Early diagnosis and treatment of HLH is crucial because the disease often is associated with high mortality and morbidity.1 In case series of HLH (combining both familial and reactive forms), mortality occurs in 50% to 63% of patients.7,18 Many patients require mechanical ventilation and vasopressor support,7,18 with multiple organ failure as a prominent feature in fatal cases.18 Secondary HPS seems to have a more favorable outcome. Some report that supportive care and treatment of the underlying causative agent are associated with recovery in ~60% of cases.19

Therapy for VAHS should be directed at treating the underlying infection. An immunosuppressive regimen that consists of dexamethasone, etoposide, and cyclosporin A (and bone marrow/stem cell transplantation, in many cases) has significantly improved the prognosis for patients with familial HLH.20,21 This also is the case for children and adolescents with severe virus-associated HLH, at least with regard to EBV infection. An improved survival has been observed when early implementation of etoposide is used, preferably in conjunction with cyclosporin A, in children with EBV-associated HLH.22 This chemotherapeutic regimen should be administered under the supervision of a hematology-oncology specialist. The role of immunoglobulin and plasmapheresis in the treatment of HLH is anecdotal.23

The pathogenesis of VAHS still is unclear, but it is hypothesized to be caused by abnormal immune regulation resulting in hypercytokinemia.12,13,24–26 In models of familial HLH, natural killer cell activity is impaired,1,16,27 and it is postulated that this immunodeficiency facilitates an uncontrolled T-lymphocyte activation that results in increased T-helper 1 cytokines such as interferon-{gamma}, interleukin 12 (IL-12), and IL-18 that promotes macrophage activation. It has been shown that avian influenza (H5N1) can infect macrophages and elicit a marked elevation of IL-1, IL-6, and tumor necrosis factor {alpha}.24,28,29 In the reported 1997 outbreak of avian influenza A (H5N1) in Hong Kong, reactive HLH was a characteristic pathologic finding in postmortem examinations,24,30 suggesting that the pathogenesis of fatal cases of avian influenza may be driven by such a profound inflammatory state.

The 2003–2004 influenza season in the Unites States was very unusual for a variety of reasons, including early onset of disease, vaccine strains that did not corresponding fully to circulating community strains, several reports of severe complications including deaths among previously healthy children, increased vaccine demands and subsequent shortages, and outbreaks of avian influenza A (H5N1) in poultry flocks in Southeast Asia.31 The Centers for Disease Control and Prevention reported >152 cases of influenza-associated deaths in children, most of whom previously were healthy.32 Causes of death included encephalopathy, seizures, dehydration with severe hypotension, respiratory failure that required mechanical ventilation, and secondary bacterial pneumonia.33 Approximately 91% of the influenza A (H3N2) isolates were A/Fujian/411/2002-like or A/Korea/770/2002-like strain.34 Our patient was infected by the A/Panama/2007/99 (H3N2) strain, which was contained in the 2002–2004 vaccine. Among 111 children with known immunization status, 18 (16%) had received at least 1 dose of vaccine during the 2003–2004 season,34 whereas 84%, like our patient, received no immunization at all, underscoring the importance of vaccination.35 The American Academy of Pediatrics Committee on Infectious Diseases recently published guidelines for routine use of influenza vaccine in children.35


   CONCLUSIONS
TOP
 ABSTRACT
 CASE REPORT
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
We have described a previously healthy child with HLH in association with a documented influenza A infection. Physicians who care for children should be aware of HLH as an unusual but potentially severe and life-threatening complication of influenza in previously healthy children.


   ACKNOWLEDGMENTS
 
We thank the Centers for Disease Control and Prevention (Atlanta, GA) and Peggy Bentley (North Carolina Public Health Department, Raleigh, NC).


   FOOTNOTES
 
Accepted Jan 17, 2006.

Address correspondence to Steven S. Mou, MD, Department of Anesthesiology, Section on Pediatric Critical Care Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009. E-mail: smou{at}wfubmc.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
TOP
 ABSTRACT
 CASE REPORT
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991;18 :29 –33[ISI][Medline]
  2. Loy TS, Diaz-Arias AA, Perry MC. Familial erythrophagocytic lymphohistiocytosis. Semin Oncol. 1991;18 :34 –38[ISI][Medline]
  3. Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis. 2000;6 :601 –608[ISI][Medline]
  4. Imashuku S. Differential diagnosis of hemophagocytic syndrome: underlying disorders and selection of the most effective treatment. Int J Hematol. 1997;66 :135 –151[CrossRef][ISI][Medline]
  5. Risdall RJ, McKenna RW, Nesbit ME, et al. Virus-associated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer. 1979;44 :993 –1002[CrossRef][ISI][Medline]
  6. Close P, Friedman D, Uri A. Viral-associated hemophagocytic syndrome. Med Pediatr Oncol. 1990;18 :119 –122[ISI][Medline]
  7. Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome in children: an important diagnostic consideration in fever of unknown origin. Clin Infect Dis. 2003;36 :306 –312[CrossRef][ISI][Medline]
  8. Chen CJ, Huang YC, Jaing TH, et al. Hemophagocytic syndrome: a review of 18 pediatric cases. J Microbiol Immunol Infect. 2004;37 :157 –163[Medline]
  9. Potter MN, Foot AB, Oakhill A. Influenza A and the virus associated haemophagocytic syndrome: cluster of three cases in children with acute leukaemia. J Clin Pathol. 1991;44 :297 –299[Abstract/Free Full Text]
  10. Klein A, Corazza F, Demulder A, Van Beers D, Ferster A. Recurrent viral associated hemophagocytic syndrome in a child with Langerhans cell histiocytosis. J Pediatr Hematol Oncol. 1999;21 :554 –556[CrossRef][ISI][Medline]
  11. Cunney RJ, Bialachowski A, Thornley D, Smaill FM, Pennie RA. An outbreak of influenza A in a neonatal intensive care unit. Infect Control Hosp Epidemiol. 2000;21 :449 –454[CrossRef][ISI][Medline]
  12. Watanabe T, Okazaki E, Shibuya H. Influenza A virus-associated encephalopathy with haemophagocytic syndrome. Eur J Pediatr. 2003;162 :799 –800[CrossRef][ISI][Medline]
  13. Imashuku S, Hibi S, Todo S. Hemophagocytic lymphohistiocytosis in infancy and childhood. J Pediatr. 1997;130 :352 –357[CrossRef][ISI][Medline]
  14. Henter J, Ehrnst A, Andersson J, Elinder G. Familial hemophagocytic lymphohistiocytosis and viral infections. Acta Paediatr. 1993;82 :369 –372[ISI][Medline]
  15. Ueda I, Ishii E, Morimoto A, Ohga S, Sako M, Imashuku S. Correlation between phenotypic heterogeneity and gene mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL). Pediatr Blood Cancer. 2006;46 :482 –488[CrossRef][ISI][Medline]
  16. Aricò M, Janka G, Fischer A, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. 1996;10 :197 –203[ISI][Medline]
  17. Rooms L, Fitzgerald N, McClain KL. Hemophagocytic lymphohistiocytosis masquerading as child abuse: presentation of three cases and review of central nervous system findings in hemophagocytic lymphohistiocytosis. Pediatrics. 2003;111 (5). Available at: www.pediatrics.org/cgi/content/full/111/5/e636
  18. Nahum E, Ben-Ari J, Stain J, Schonfeld T. Hemophagocytic lymphohistiocytic syndrome: unrecognized cause of multiple organ failure. Pediatr Crit Care Med. 2000;1 :51 –54[CrossRef][Medline]
  19. Reiner AP, Spivak JL. Hematophagic histiocytosis. A report of 23 new patients and a review of the literature. Medicine (Baltimore). 1988;67 :369 –388[Medline]
  20. Henter JI, Arico M, Egeler RM, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH study Group of the Histiocyte Society. Med Pediatr Oncol. 1997;28 :342 –347[CrossRef][ISI][Medline]
  21. Henter JI, Samuelsson-Horne A, Aricò M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood. 2002;100 :2367 –2373[Abstract/Free Full Text]
  22. Imashuku S, Kuriyama K, Teramura T, et al. Requirement for etoposide in the treatment of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. J Clin Oncol. 2001;19 :2665 –2673[Abstract/Free Full Text]
  23. Goulder P, Seward D, Hatton C. Intravenous immunoglobulin in virus associated haemophagocytic syndrome. Arch Dis Child. 1990;65 :1275 –1277[Abstract]
  24. To KF, Chan PK, Chan KF, et al. Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol. 2001;63 :242 –246[CrossRef][ISI][Medline]
  25. Broxmeyer HE, Williams DE, Lu L, et al. The suppressive influences of human tumor necrosis factors on bone marrow hematopoietic progenitor cells from normal donors and patients with leukemia: synergism of tumor necrosis factor and interferon-gamma. J Immunol. 1986;136 :4487 –4495[Abstract]
  26. Mamus SW, Beck-Schroeder S, Zanjani ED. Suppression of normal human erythropoiesis by gamma interferon in vitro. Role of monocytes and T lymphocytes. J Clin Invest. 1985;75 :1496 –1503[ISI][Medline]
  27. Perez N, Virelizier JL, Arenzana-Seisdedos F, Fischer A, Griscelli C. Impaired natural killer activity in lymphohistiocytosis syndrome. J Pediatr. 1984;104 :569 –573[ISI][Medline]
  28. Lehmann C, Sprenger H, Nain M, Bacher M, Gemsa D. Infection of macrophages by influenza A virus: characteristics of tumour necrosis factor-alpha (TNF alpha) gene expression. Res Virol. 1996;147 :123 –130[CrossRef][ISI][Medline]
  29. Peschke T, Bender A, Nain M, Gemsa D. Role of macrophage cytokines in influenza A virus infections. Immunobiology. 1993;189 :340 –355[ISI][Medline]
  30. Chan PK. Outbreak of avian influenza A(H5N1) virus infection in Hong Kong in 1997. Clin Infect Dis. 2002;34 (suppl 2):S58–S64
  31. Meissner CH, Rennels MB. Unpredictable patterns of viral respiratory disease in children. Pediatrics. 2004;113 :1814 –1816[Free Full Text]
  32. Centers for Disease Control and Prevention (CDC). Update: influenza activity—United States, January 11–17, 2004. MMWR Morb Mortal Wkly Rep. 2004;53 :35 –37[Medline]
  33. Centers for Disease Control and Prevention (CDC). Update: influenza activity—United States, January 18–24, 2004. MMWR Morb Mortal Wkly Rep. 2004;53 :63 –65[Medline]
  34. Bhat N, Wright JG, Broder KR, et al. Influenza-associated deaths among children in the United States, 2003–2004. N Engl J Med. 2005;353 :2559 –2567[Abstract/Free Full Text]
  35. American Academy of Pediatrics Committee on Infectious Diseases. Recommendations for influenza immunization of children. Pediatrics. 2004;113 :1441 –1447[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Mou, S. S.
Right arrow Articles by Shetty, A. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Mou, S. S.
Right arrow Articles by Shetty, A. K.
Related Collections
Right arrow Infectious Disease & Immunity