A Young Girl Lost in the Storm

Vigneshvarprashanth Umapathy^1,*, G. Dominic Rodriguez^2,*, RM. Subbaiah³

¹Resident Internal Medicine, Kauvery Hospital, Tennur, Trichy, India

²HOD Internal Medicine, Kauvery Hospital, Tennur, Trichy, India

³Consultant Hemato-Oncologist, Kauvery Hospital, Trichy, India

*Correspondence: worldofuv@gmail.com (V. Umapathy), domappa1966@gmail.com (G. Dominic Rodriguez)

Abstract

It’s a story of an unfortunate young girl who presented with fever, gastrointestinal symptoms, and pancytopenia and later lost her battle due to uncontrolled immune responses in a short time.

Keywords: fever; pancytopenia; hemophagocytosis; immune system

Background

It’s about a 20 years young girl who was studying at a college in Tamil Nadu. She was happy living with her friends, staying at a hostel in Trichy, and going back to her home on the weekends. She was apparently healthy and had not been troubled much by infections or any illnesses throughout her childhood. She had dreams of a future in public service.

How it started

It started with a low-grade, intermittent fever, associated with chills & rigors which lasted for 7 days. She also had complaints of vomiting, loose stools, melena, arthralgia, myalgia, headache, giddiness, cough, and shortness of breath. She initially went to a nearby hospital where she was found to have thrombocytopenia and positive Dengue IgM. She was then referred here.

On examination, she was conscious, oriented, pale, icteric and dehydrated. She was tachypnoeic. Flaring of ala nasi was noted. Capillary refill time was delayed. Diffuse tenderness was noted on abdominal examination. ECG showed sinus tachycardia. No significant findings were noted in the chest x-ray.

Initial blood investigations revealed pancytopenia, elevated liver enzymes, raised INR and elevated urea and creatinine. Scrub Typhus IgM was negative.

Tropical fever and autoimmune causes were suspected initially. She received doxycycline and ceftriaxone, after sending blood culture. She continued to be tachypnoeic and required NIV support soon.

Her USG abdomen showed splenomegaly, and bilateral minimal pleural effusion. CT chest was unremarkable. Macrocytic anemia with severe leukopenia, neutropenia and thrombocytopenia were noted in the peripheral smear. Dengue NS1, IgM, IgG were negative. Direct coombs test was negative. ECHO showed Adequate LV function (EF – 55%). Procalcitonin was raised. CRP, CPK and LDH were elevated. C3 was low and C4 was normal. CT abdomen showed hepatosplenomegaly with bilateral enlarged kidneys; thickened and edematous large bowel loops and minimal ascites.

With the above clinical picture and lab results, we suspected infective etiology due to gram-negative sepsis, enteric fever, and tuberculosis. Antibiotics were escalated to meropenem and azithromycin empirically.

The storm

She continued to deteriorate despite higher antibiotics. Hematologist got involved in her care and provided more input. Hemophagocytic Lymphohistiocytosis (HLH) and Systemic Lupus Erythematosus (SLE) were suspected.

She started to become delirious, and disoriented, talking to her friends in imagination.

Ferritin was raised (>3000). Hypertriglyceridemia and hypofibrinogenemia were noted. Urgent bone marrow assessment and study were done by the hematologist and significant hemophagocytosis was noted in the bone marrow. She was started on dexamethasone.

Widal was positive (tube test at 1:480 dilution) for Salmonella Typhi O & H. Leptospira IgM was also positive (probably false positive). ANA was negative. Blood culture was sterile.

At this point in time, we could see the rapid worsening of her clinical condition in front of our eyes. Parents were counselled. Myocarditis, rapid left ventricular systolic dysfunction, and pulmonary edema set in.

Chest X-ray – (a) Day 1 – No significant findings; (b) Day 2 – Bilateral haziness; (c) Day 4 – Gross pulmonary edema

CT abdomen showing (a) Hepatomegaly and splenomegaly (b) bilateral enlarged kidneys; (c) thickened and edematous colon

Bone marrow aspiration (a) and trephine biopsy of the bone marrow (b) and (c) showing hemophagocytic foci

HLH – 2004 Diagnostic Criteria [1]

The diagnosis of HLH can be established if one of either 1 or 2 given below is fulfilled

(1) A molecular diagnosis consistent with HLH

(2) Diagnostic criteria for HLH fulfilled (five out of the eight criteria below)

No	Features	Presence in our patient
1	Fever	Yes
2	Splenomegaly	Yes
3	Cytopenia in at least 2 cell lines	Yes
4	Hypertriglyceridemia and/or hypofibrinogenemia	Yes
5	Hemophagocytosis in marrow or spleen or lymph nodes or liver	Yes
6	Low or absent NK cells activity
7	Ferritin >500 mcg/L	Yes
8	Soluble CD25 >2500 U/mL

(NK – Natural Killer)

HLH diagnosis is established with at least 5 out of 8 of the above being fulfilled and our patient did fulfil 6 out of 8 criteria. Hence a diagnosis of HLH was made which was likely triggered by a febrile illness of unknown etiology.

Her last breath

After being intubated and ventilated for a brief moment she opened her eyes and made eye contact with her father. But on the same night, she went into cardiogenic shock, and despite resuscitation efforts, we lost her on the 5th day of hospitalization.

Her genetic study revealed normal karyotype.

Laboratory investigations from Day 1 to Day 5

	Day 1	Day 2	Day 3	Day 4	Day 5
Hemoglobin	9.3	8.6	8.2	7.8	9.1
Total WBC Count	1000	1100	1000	1600	3200
Platelets	14000	15000	15000	20000	22000
ESR	22
INR	2.30				1.95
Urea	108		78.7	62.4	106
Creatinine	2.04		1.08	0.89	1.44
Uric acid		5.54			10.9
Sodium	137.9			151	155
Potassium	3.09			3.89
Bilirubin	2.97				3.94
SGOT	975			995	905
SGPT	144			159	177
Urine pus cells	6-8				2-4
Urine RBCs	8-10				15-20
Urine albumin	1+				1+
Calcium		7.11
Phosphorus		1.49
LDH		5050
Procalcitonin		14.4
CRP		202
CPK		8357
C3		47.8 (low)
C4		26.2
Ferritin		>3000
Triglycerides		279
Fibrinogen		0.825 (low)
T3					0.45
T4					4.15
TSH					0.18

Discussion

Though bone marrow study was done immediately on suspicion of HLH, a bone marrow culture was not sent. But blood culture was negative for Salmonella Typhi. As such high titre Widal positivity was unexpected at the end of the first week along with probable false positive Leptospira IgM, an anamnestic response was considered. Yet antibiotic cover for enteric fever was given. We could not confirm the response by repeat titre after one week since she succumbed to the illness. As Epstein-Barr virus (EBV) is a well-known trigger for HLH, EBV serology was requested. However, she succumbed before the sample was sent.

Pancytopenia

Pancytopenia is a hematologic condition characterized by a decrease in all three peripheral blood cell lines. It is characterized by a hemoglobin value of less than 12 g/dL in women and 13 g/dL in men, platelets of less than 150,000 per mcL, and leukocytes of less than 4000 per ml (or absolute neutrophil count of less than 1800 per ml) [3].

Pancytopenia can be congenital or acquired [4]

CONGENITAL
Wiskott Aldrich syndrome
Fanconi anemia
Dyskeratosis congenital/telomere biology disorders
Shwachman-Diamond syndrome
GATA2 deficiency
Hemophagocytic lymphohistiocytosis (HLH)

ACQUIRED
Bone marrow infiltration/ replacement	Malignant	Acute leukemias
		Chronic leukemias/myeloproliferative neoplasms (MPN)
		Myelodysplastic syndromes (MDS)
		Multiple myeloma
		Metastatic cancer
	Non-malignant	Myelofibrosis
		Infectious (eg, fungal, tuberculous)
		Storage diseases
Bone marrow failure	Immune destruction/ suppression	Aplastic anemia/paroxysmal nocturnal hemoglobinuria
		Drugs
		Large granular lymphocyte leukemia
		Autoimmune disorders (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis [RA], sarcoidosis)
		Hemophagocytic lymphohistiocytosis (HLH)
	Nutritional	Megaloblastic (vitamin B12, folate deficiency)
		Excessive alcohol
		Other (eg, copper deficiency, zinc toxicity)
		Malnutrition/anorexia nervosa with gelatinous degeneration
	Marrow suppression	Viral infection (eg, HIV, hepatitis, Epstein-Barr virus [EBV])
	Ineffective hematopoiesis (eg, MDS, nutritional)
Destruction/ sequestration/ redistribution	Consumption	Disseminated intravascular coagulation (eg, associated with sepsis, acute promyelocytic leukemia)
	Splenomegaly	Portal hypertension/cirrhosis
		Infections (eg, EBV)
		Autoimmune disorders (eg, SLE, RA/Felty syndrome)
		Malignancies (eg, lymphomas, MPN)
		Myelofibrosis with myeloid metaplasia
		Storage diseases (eg, Gaucher)

Approach to pancytopenia

Fig. 1. Approach to diagnose the cause of pancytopenia [5].

Pancytopenia may present with the following emergencies [3]:

Neutropenia (new diagnosis or associated with fever/infection)
Metabolic emergencies (e.g., symptomatic hyperkalemia, hypercalcemia, tumor lysis syndrome)
Disseminated intravascular coagulation (DIC)
Hemophagocytic lymphohistiocytosis (HLH)
Abnormal peripheral blood smear (e.g., microangiopathy, blasts)
Severe aplastic anemia
Symptomatic anemia (e.g., cardiac ischemia, hemodynamic instability, worsening congestive heart failure)
Thrombocytopenia (platelets <10,000/microL, or <50,000/microL associated with bleeding)

Hemophagocytic lymphohistiocytosis (HLH) – a brief overview

HLH is an aggressive and life-threatening syndrome of excessive immune activation. It most frequently affects infants from birth to 18 months of age, but the disease is also observed in children and adults of all ages. HLH can occur as a familial or sporadic disorder, and it can be triggered by a variety of events that disrupt immune homeostasis [2]. Genetic testing is important when HLH is suspected. The important associated genes are PRF1, UNC13D, STX11, STXBP2. [2]

Infection is a common trigger both in those with a genetic predisposition and in sporadic cases [2]. Viral infections such as Epstein-Barr virus, Cytomegalovirus, Parvovirus, Herpes simplex, Varicella-zoster, measles, HHV-8, HIV, bacterial infections like brucella, gram negative bacteria, rickettsia, leptospira, tuberculosis, malaria, leishmania and fungal infections could cause HLH [6].

If the patient is not severely ill, it may be possible to treat the triggering condition with the addition of corticosteroids, and to observe the patient for a response prior to initiating chemotherapy. For those who show clinical improvement upon treatment of the triggering condition, it may be possible to avoid chemotherapy, although this is the rare exception rather than the rule [7].

Therapy based on the HLH-94 protocol consists of eight weeks of induction therapy with etoposide and dexamethasone, with intrathecal therapy with methotrexate for those with CNS involvement [7].

Liver biopsy in a HLH patient showing hemophagocytosis (a) by the activated macrophage, as stained by CD68 (b) [8]

Conclusion

The immune system which was supposed to fight off the infections ran amok and took away the young girl’s life.

One has to be wary in evaluating a patient with fever and pancytopenia. Making an early diagnosis of diseases like HLH could help initiate appropriate therapy and save the patient. However, this girl had an unusual acute presentation that cost her precious life, despite making an early diagnosis.

HLH is not only debilitating for the patient but also poses a great challenge for the treating clinician especially if it takes an aggressive and unpredictable course.

Learning points

- Once pancytopenia is confirmed, extensive workup has to be done to diagnose the cause of pancytopenia.
- Bone marrow assessment is pivotal in arriving at a diagnosis in consultation with a hematologist.
- Identifying whether the pancytopenia is caused by a production disorder or a consumption disorder or a combination of both is a key step in both diagnosing the cause and for management of the patient [5].

Once a diagnosis of HLH is established, treatment with etoposide, dexamethasone and methotrexate can be done depending on the severity.

Making relatives understand the nature of illness (HLH) with clear documentation and fulfilment of criteria is essential.

References

Henter JI, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatric Blood Cancer. 2007;48(2):124-31.
McClain KL, et al. Clinical features and diagnosis of hemophagocytic lymphohistiocytosis. UpToDate. 2018.
Chiravuri S, De Jesus O. Pancytopenia. [Updated 2022 Nov 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available at: https://www.ncbi.nlm.nih.gov/books/NBK563146/
Berliner N. Approach to the adult with pancytopenia. Available at: https://www.uptodate.com/contents/approach-to-the-adult-with-pancytopenia#H1287772966
Gnanaraj J, et al. Approach to pancytopenia: Diagnostic algorithm for clinical hematologists. Blood reviews. 2018;32(5):361-7.
Gosh JB, et al. Infection associated with hemophagocytic lymphohisticytosis triggered by nosocomial infection. Oman Med J. 2009;24(3):223.
McClain KL, et al. Treatment and prognosis of hemophagocytic lymphohistiocytosis. UpToDate, Waltham, MA. 2014.
Tiong IS, et al. A case of hemophagocytic lymphohistiocytosis in a patient with chronic lymphocytic leukemia after treatment with fludarabine, cyclophosphamide, and rituximab chemotherapy, with autopsy findings. Case Rep Hematol. 2012;2012.

Dr. Vigneshvarprashanth Umapathy

Resident Internal Medicine

Dr. G. Dominic Rodriguez

HOD Internal Medicine

Dr. R. M. Subbaih

Consultant Hemato-Oncologist