• Users Online: 248
  • Print this page
  • Email this page

 Table of Contents  
Year : 2021  |  Volume : 8  |  Issue : 6  |  Page : 295-298

Multiple opportunistic infection-associated hemophagocytic lymphohistiocytosis in nephrotic syndrome: A case report

Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India

Date of Submission30-Jul-2021
Date of Decision25-Sep-2021
Date of Acceptance06-Oct-2021
Date of Web Publication19-Nov-2021

Correspondence Address:
Dr. Jhuma Sankar
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi - 110 029
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpcc.jpcc_64_21

Rights and Permissions

Multiple opportunistic coinfections during corticosteroid therapy for the nephrotic syndrome are uncommon. Infection-associated hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially fatal multisystem disorder, manifesting as a state of hypercytokinemia in response to an infectious trigger. We describe a 4½-year-old boy with steroid-dependent nephrotic syndrome receiving high-dose steroids, who developed respiratory failure due to pulmonary tuberculosis, Cytomegalovirus, and Pneumocystis jirovecii coinfections; HLH complicated the course. Aggressive management of the underlying infections with antitubercular, antiviral, and antifungal therapy, prompt recognition of HLH, and immunomodulation with intravenous (IV) immunoglobulin and IV methylprednisolone enabled convalescence. This report emphasizes the serious risks of immunosuppression and the need for strict vigilance for rare opportunistic infections with multiple pathogens in patients receiving oral steroids for nephrotic syndrome. Clinical distinctions between severe sepsis and HLH may be ambiguous; a high level of suspicion is required for timely recognition and management.

Keywords: Corticosteroid, Cytomegalovirus, intravenous immunoglobulin, Pneumocystis jirovecii, tuberculosis

How to cite this article:
Varadaraju S, Khandelwal P, Sankar J, Hari P. Multiple opportunistic infection-associated hemophagocytic lymphohistiocytosis in nephrotic syndrome: A case report. J Pediatr Crit Care 2021;8:295-8

How to cite this URL:
Varadaraju S, Khandelwal P, Sankar J, Hari P. Multiple opportunistic infection-associated hemophagocytic lymphohistiocytosis in nephrotic syndrome: A case report. J Pediatr Crit Care [serial online] 2021 [cited 2021 Nov 27];8:295-8. Available from: http://www.jpcc.org.in/text.asp?2021/8/6/295/330728

  Introduction Top

Children with nephrotic syndrome requiring immunosuppression are at risk of infectious complications. While serious opportunistic infections are rare in patients receiving corticosteroids alone,[1] vigilance for the same is required. Infection-associated hemophagocytic lymphohistiocytosis (HLH) is a multisystem disorder with high mortality,[2] uncommon in nephrotic syndrome.[3],[4],[5] Its pathogenesis involves abnormal activation of cytotoxic T and natural killer (NK) cells causing macrophage activation, hypercytokinemia, hemophagocytosis, and multi-organ dysfunction.[2] Overlap of clinical and biochemical features with sepsis makes timely recognition a challenge.[6] We describe a child with steroid-dependent nephrotic syndrome on corticosteroids, who developed respiratory failure due to Cytomegalovirus (CMV), Pneumocystis jirovecii, and Mycobacterium tuberculosis (MTB) coinfection; and the course was further complicated by HLH.

  Case Report Top

A 4½-year-old boy with nephrotic syndrome presented with fever for 1½ months, cough, and diarrhea for 5 days. Therapy consisted of oral prednisolone (60 mg/m2/day for 6 weeks and 40 mg/m2/alternate day for 6 weeks, each) followed by high-dose daily steroids (0.7–1.5 mg/kg) for 15 months, inappropriately administered for the steroid-dependent course. He presented to our institute, in remission, 3 months later for the evaluation of fever. There was no contact with tuberculosis. On examination, he was cushingoid with respiratory rate 34/min, heart rate 110/min, oxygen saturation 95%, and blood pressure 130/90 mmHg (systolic blood pressure was at 95th centile for gender and height). Edema and lymphadenopathy were absent. The chest, abdominal, cardiovascular, and neurological examination was unremarkable. Investigations revealed hemoglobin of 7 g/dl, normocytic normochromic anemia, and total leukocyte count 17,400/mm3 with left shift (neutrophil 84.2%, lymphocyte 5.8%, and monocyte 10%), platelets 260,000/mm3, erythrocyte sedimentation rate 48 mm/h, and international normalized ratio 1.1. His total protein was 3.2 mg/dL and albumin was 1.4 mg/dL and total cholesterol was 312 mg/dL. Serum electrolytes, blood gas, renal, liver function tests, and urine examination were normal. Bacterial and fungal cultures were sterile and workup for enteric fever, malaria, acid-fast bacilli, P. jirovecii, CMV, Chlamydia, Mycoplasma, and Nocardia were noncontributory. Ultrasound abdomen and echocardiography were normal. Chest X-ray showed bilateral patchy infiltrates; high-resolution computed tomography showed noncalcified, noncavitating pulmonary nodules [Figure 1]b and [Figure 1]c; with corresponding nodular uptake by whole-body positron emission tomography. Bronchoscopy and bronchoalveolar lavage fluid microscopy were normal. Qualitative polymerase chain reaction on the bronchoalveolar lavage fluid was positive for Pneumocystis, CMV, and MTB. Assays for human immunodeficiency virus, serum immunoglobulin profile, and CD4, CD8 levels were normal.
Figure 1: Figure depicting clinical course and management of the patient over 2-months finally leading to defervescence and improvement in biochemical parameters (a). Radiological investigations showed bilateral patchy pulmonary infiltrates (Chest X-ray; [b] and noncalcified, noncavitating pulmonary nodules (high-resolution computed tomography; [c])

Click here to view

Therapy of Pneumocystis, MTB, and CMV with intravenous (IV) cotrimoxazole (20 mg/kg/d of trimethoprim), IV ganciclovir (5 mg/kg/d), and antitubercular therapy (ATT) were initiated. However, respiratory failure occurred with hemodynamic instability requiring inotropic agents (epinephrine and dobutamine) and mechanical ventilation for 10 days. Platelet (45,000/mm3) and leukocyte count (8900/mm3) dropped concomitant with elevation in serum aspartate and alanine transaminases [859 and 692 IU/L, respectively, [Figure 1]a]. IV cotrimoxazole was changed to IV clindamycin and primaquine for possible drug-induced hepatitis and first-line ATT (isoniazid 10 mg/kg, rifampicin 15 mg/kg, pyrazinamide 30 mg/kg, and ethambutol 20 mg/kg) were gradually introduced once liver functions had recovered. Neurological manifestations including seizures, tremors, hallucinations, and irritability developed; brain magnetic resonance imaging revealed thin meningeal enhancement of prepontine and interpeduncular region. Fever persisted and pancytopenia appeared (hemoglobin 6.3 g/dl, leukocyte 3900/mm3, and platelets 30,000/mm3). Although serum triglycerides (360 mg/dl), serum ferritin (380 ng/ml), and fibrinogen (420 mg/dl) were modestly elevated and NK cell activity was normal, secondary HLH was considered after demonstration of hemophagocytes in bone marrow aspiration. IV methylprednisolone (IVMP), (pulse methylprednisolone 30 mg/kg/day for 5 days) IV immunoglobulin (IVIG) and IV dexamethasone, and cyclosporine (empirically administered due to prominent neurological manifestations) were administered following which respiratory status and blood count improved and the child became afebrile and was subsequently shifted out of the intensive care unit [Figure 1]a.

  Discussion Top

We describe a child with nephrotic syndrome administered prolonged high-dose steroids with consequent multiple opportunistic infections with P. jirovecii, MTB, and CMV causing respiratory failure and infection-associated HLH, thus demonstrating the risks of excessive and inappropriate immunosuppression. Tuberculosis is common in Indian children with nephrotic syndrome with higher cumulative doses of steroids related to increased susceptibility.[7] Pneumocystis pneumonia (PCP) and CMV pneumonitis are uncommon in children[8],[9] or adults[1],[10] with nephrotic syndrome since steroids with concomitant additional immunosuppression generally predispose for these infections. However, adult guidelines advocating prophylaxis for Pneumocystis during high-dose steroids,[11] emerging reports of immunocompetent patients on steroids developing CMV pneumonitis, PCP,[12],[13] and mixed infections with these organisms[1],[14] indicate that even low-dose steroids may predispose to opportunistic infections.

HLH is associated with tuberculosis,[15] PCP[16] and CMV infections;[3],[5] nephrotic syndrome rarely antedates occurrence of HLH in children[3] and adults.[4] The diagnostic criteria of HLH include five of the following: Fever, splenomegaly, bicytopenia, increased fasting triglycerides/low fibrinogen levels, raised serum ferritin, hemophagocytosis in bone marrow aspirates, low/absent NK cell activity, and increased soluble CD25 levels.[17] However, the distinction between infection-associated HLH, severe sepsis, and systemic inflammatory response syndrome (SIRS) is ambiguous by the above criteria and these entities are considered intermediate phenotypes of the same inflammatory process.[6] Similarly, the distinction between HLH and SIRS due to disseminated tuberculosis was unclear in our patient; persistence of symptoms despite prolonged therapy of underlying infections prompted consideration of HLH. Treatment of infection-associated HLH by a pathogen-directed therapy alone is usually not sufficient and additional immunomodulators/immunosuppression is required. While, standard therapy of HLH involves chemotherapy and dexamethasone achieving a 40%–89% survival rate,[17] recently children with hyperferritinemic sepsis/SIRS/HLH treated with IVMP, IVIG, and plasma exchange had 100% survival.[18] We initially administered IVIG and IVMP, following stabilization and due to prominent neurological manifestations, dexamethasone which crosses the blood–brain barrier, was empirically administered along with cyclosporine.

Facilities for sCD25 assay and genetic testing for mutations associated with HLH were limited and histopathology of the lung was not done, and it is possible that pulmonary involvement due to HLH was further aggravated by superadded infection. Microscopic evidence of cytomegalic inclusion bodies was not demonstrated; therefore CMV may have been colonization rather than true infection. Despite these limitations, this report emphasizes strict vigilance for opportunistic infections and the need for further research on whether children with nephrotic syndrome receiving immunosuppression would benefit from preventive chemoprophylaxis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient's legal guardian has given the consent for images and other clinical information to be reported in the journal. The patient's legal guardian understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Lin TY, Ni YH, Chang FY, Wang NC. Cytomegalovirus pneumonitis in a patient with nephrotic syndrome receiving low-dose prednisolone and pulmonary tuberculosis. Am J Med Sci 2007;334:393-5.  Back to cited text no. 1
Rosado FG, Kim AS. Hemophagocytic lymphohistiocytosis: An update on diagnosis and pathogenesis. Am J Clin Pathol 2013;139:713-27.  Back to cited text no. 2
Landau D, Gurevich E, Kapelushnik J, Tamary H, Shelef I, Lazar I. Association between childhood nephrotic syndrome and hemophagocytic lymphohistiocytosis. Pediatr Nephrol 2013;28:2389-92.  Back to cited text no. 3
Chang CC, Hsiao PJ, Chiu CC, Chen YC, Lin SH, Wu CC, et al. Catastrophic hemophagocytic lymphohistiocytosis in a young man with nephrotic syndrome. Clin Chim Acta 2015;439:168-71.  Back to cited text no. 4
Poyrazoglu HM, Dursun I, Bastug F, Gunduz Z, Akyildiz BN, Tulpar S. Cytomegalovirus infection and haemophagocytosis in a patient with congenital nephrotic syndrome. Pediatr Nephrol 2009;24:2257-9.  Back to cited text no. 5
Carcillo JA, Simon DW, Podd BS. How we manage hyperferritinemic sepsis-related multiple organ dysfunction syndrome/macrophage activation syndrome/secondary hemophagocytic lymphohistiocytosis histiocytosis. Pediatr Crit Care Med 2015;16:598-600.  Back to cited text no. 6
Gulati S, Kher V, Gulati K, Arora P, Gujral R. Tuberculosis in childhood nephrotic syndrome in India. Pediatr Nephrol 1997;11:695-8.  Back to cited text no. 7
Sato M, Ito S, Ogura M, Kamei K, Miyairi I, Miyata I, et al. Atypical Pneumocystis jiroveci pneumonia with multiple nodular granulomas after rituximab for refractory nephrotic syndrome. Pediatr Nephrol 2013;28:145-9.  Back to cited text no. 8
Czarniak P, Załuska-Leśniewska I, Zagożdżon I, Zurowska A. Difficulties in diagnosing severe Pneumocystis jiroveci pneumonia after rituximab therapy for steroid-dependent nephrotic syndrome. Pediatr Nephrol 2013;28:987-8.  Back to cited text no. 9
Plakke MJ, Jalota L, Lloyd BJ. Pneumocystis pneumonia in a non-HIV patient on chronic corticosteroid therapy: A question of prophylaxis. BMJ Case Rep 2013;2013:bcr2012007912.  Back to cited text no. 10
Limper AH, Knox KS, Sarosi GA, Ampel NM, Bennett JE, Catanzaro A, et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-128.  Back to cited text no. 11
Troselj-Vukic B, Milotic I. Low-dose corticosteroid therapy increases the risk of cytomegalovirus reactivation. Biomed Pharmacother 2009;63:72-3.  Back to cited text no. 12
Guillemot N, Blanchon S, Nathan N, Corvol H, Fauroux B, Aubertin G, et al. Pneumocystis jiroveci pneumonia during prolonged corticosteroid therapy in an immunocompetent infant. Rev Pneumol Clin 2008;64:225-8.  Back to cited text no. 13
Filoche P, Adoun M, Caron F, Godet C, Robert R, Meurice JC. Co-infection with Mycobacterium tuberculosis and Pneumocystis jiroveci in a patient without HIV infection. Rev Mal Respir 2006;23:83-7.  Back to cited text no. 14
Brastianos PK, Swanson JW, Torbenson M, Sperati J, Karakousis PC. Tuberculosis-associated haemophagocytic syndrome. Lancet Infect Dis 2006;6:447-54.  Back to cited text no. 15
Pasic S, Jankovic I, Rosic R, Ognjanovic M. Pneumocystis carinii pneumonitis in haemophagocytic lymphohistiocytosis. Acta Paediatr 2001;90:1480-2.  Back to cited text no. 16
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. 17
Demirkol D, Yildizdas D, Bayrakci B, Karapinar B, Kendirli T, Koroglu TF, et al. Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: What is the treatment? Crit Care 2012;16:R52.  Back to cited text no. 18


  [Figure 1]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Case Report
Article Figures

 Article Access Statistics
    PDF Downloaded10    
    Comments [Add]    

Recommend this journal