A 9-month-old boy with prolonged fever and pancytopenia

Prepared by.........Shanika Kosarat M.D. (Pediatric resident)
Suree Lekawanvijit M.D.(Pathologist)
Pimlak Charoenkwan, M.D
Virat Sirisanthana, M.D
CC : High continuous fever for 10 days.
PI : The patient had high grade fever without localizing sign for 10 days (temperature chart-blue color)
> On the 3rd day of fever, his mother took him to community hospital where he was admitted. Physical examination revealed a febrile boy with injected pharynx and hepatomegaly. CBC showed: Hb 12.2 g/dl, Hct 36%, WBC 8,100 /mm3 (N 35%, L 65%) platelet 112,000/cumm,
> On the 4th day of fever CBC showed: Hb 10.5 g/dl, Hct 33%, WBC 9,600/ mm3 (N 5%, L 92%, atypical lymphocyte 3%) platelet 79,000/mm3.
> On the 5th day of fever, he had mucus stools 7-8 times per day. Stool examination revealed moderate amount of WBC, no RBC. His doctor started him on oral cotrimoxazole.
> On the 7th day of fever, his fever and mucus diarrhea persisted, so oral cotrimoxazole was switched to ceftriaxone and gentamicin intravenously. His diarrhea got better, he could eat and play as usual, but he still had high fever and looked jaundice. Laboratory investigations included CBC : Hb 9.6 g/dl, Hct 29 %, WBC 3,400/mm3 (N 4%, L 96%), ESR : 7 mm/60 min, LFT : albumin 2.8 g/dl, globulin 3.5 g/dl, alkaline phosphatase 422 U/L, SGOT 412 U/L, SGPT 986 U/L , total bilirubin 5.2 g/dl, direct bilirubin 1.01 g/dl, HbsAg: negative, anti Hbs: negative, and anti HIV: negative.
> On the 8th day of fever, there was erythematous rash on his face which then progressed to his neck, arms and legs. He continued to have high fever but could eat and play as normal. Additional investigations showed CBC : Hb 8.5 g/dl, Hct 26 %, WBC 2,600/ mm3 (N13%, L 87 %) platelet 121,000/mm3, Widal test: typhi O - negative, Typhi H - negative, and chest X-ray showed right pleural effusion (fig 1).
> On the 10th day of fever, he was referred to Chiang Mai University hospital.
Significant Past History: He was born at community hospital by normal labor. His birth weight was 2,950 gm. He had normal growth and development and had been vaccinated according to the schedule. At the age of 6 months, he had URI and was hospitalized for 2 days. There was no history of parental consanguinity.
Figure 1. Chest film showed right pleural effusion.
Significant PE

A febrile boy, no pallor, mild jaundice
T 39 C, PR 130-180/min, RR 56/min, BP 80/55 mmHg, weight 7,300 gm
Oxygen saturation at room air: 98%
HEENT : anterior fontanelle: 1x1 cm, not tense
Mild icteric sclera, no injected pharynx, no patch at pharynx and tonsil, no Koplik's spot
LN: cervical LN 0.5 cm in diameter, 3-4 nodes, bilaterally
Heart: regular rhythm, normal S1, S2, no murmur
Lung: decreased breath sound at right lung field
Abdomen: soft, mild distension, active bowel sound, liver 4 cm below right costal margin, spleen not enlarged, ascites +ve
Skin : erythematous maculopapular rash at face, upper eyelids (fig 2), back, upper trunk and arms
Desquamation of both inguinal area and scrotum (fig 3), no eschars seen
Extremities: edema at dorsum of both feet, no tenderness
Figure 2
Figure 3
Problem lists

1. Prolonged fever
2. Pancytopenia
3. Hepatomegaly and jaundice
4. Erythematous maculopapular rash
5. Right pleural effusion

Investigations

CBC : Hb 8.7 g/dl, Hct 29.7%, WBC 4,590/mm3 (N 6%, L 92%, band 2%) platelet 90,000/mm3
PBS : normochromic normocytic RBC, no toxic granululation, no vacuolization, band form 2%, platelets - adequate
U/A : brown, slightly cloudy, pH 6.5, sp.gr. 1.025, albumin 2+, sugar - negative, WBC 2-5/HPF, no RBC, epithelium 2-5 /HPF
Blood chemistry: BUN 7, Cr 0.5 Na 126 mmol/L, K 4.3 mmol/L , Cl 107 mmol/L, TCO2 12 mmol/L
LFT : albumin 2.6 g/dl, globulin 1.7 g/dl, alkaline phophatase 251 U/L, cholesterol 133 , AST 2673 U/L, ALT 599 U/L, TB 9.99 mg/dl, DB 6.57 mg/dl
ESR : 17 mm/60 min
Reticulocyte count : 2.0 %
BM aspiration: diluted spcimen, M:E ratio= 1:3, no hemophagocytosis, no blast cells seen
Chest X-ray (figure 4) :persistent of Rt. pleural effusion

Figure 4. Chest X-ray shows right pleural effusion.
Provisional diagnosis: Fever with muti-organ involvement, caused?
Differential diagnosis :

1. Infection
- Viral infection : hepatitis, dengue hemorrhagic fever
- Bacterial infection
- Rickettsial infection
2. Connective tissue disease
3. Kawasaki disease
4. Malignancy
- Acute leukemia
- Lymphoma
5. Childhood histiocytoses (Class II)
Course at CMU hospital :
  • On the 12th day of fever (day 2 of admission), he had septic shock and respiratory failure. He received fluid therapy including blood transfusion and was intubated and put on mechanical ventilator. He was empirically treated with imipenem and amikacin intravenously. Further investigations included CRP: 17.9 (0-5), CMV titer: IgG - negative, IgM - negative, and echocardiography: no structural heart abnormality, EF 69%, normal LV function, no coronary dilatation
  • On the 13th - 21th day of fever, he gradually deteriorated and went into comatose condition
  • On the 22th day of fever, although the repeated BM aspiration revealed diluted BM without evidence of hemophagocytosis, the infectious associated hemophagocytic syndrome (IAHS) was suspected and methylprednisolone was started.
He also developed dark-red discoloration of skin at his nose and right upper eyelid and swelling of his right eye suspected of naso-orbital cellulitis from fungal infection. Amphotericin B was added intravenously.
  • On the 24th day of fever, he had generalized tonic-clonic seizures. Laboratory investigations revealed: blood sugar 140 mg/dl, Na 155mmol/L, K 2.8 mmol/L, Cl 116 mmol/L, TCO2 17 mmol/L. He was given diazepam and IV dilantin load to stop seizure.
CT brain: no intracerebral hemorrhage, there were hypodensity lesions at both frontal regions
  • On the 25th day of fever, his he had another episode of generalized tonic clonic seizures. He expired on the 25th day of illness.
Culture reports:

Blood culture: no growth
Blood cuture for fungus: no growth for 2 weeks
Urine culture: non-significant (less than 1000 colonies/ml)
Urine culture for fungus: no growth for 2 weeks
Sputum culture: moderate yeast (Candida parapsilosis), Moderate coagulase negative Staphyllococci
Pus culture: no growth
Heart blood culture: no growth
Bone marrow culture: no growth

Autopsy : Gross:
1. Lymphadenopathy and hepatomegaly.
2. Ecthyma gangrenosum involving the right eye, medial side of the left eye, nose and upper lip.
3. Necrosis of ethmoidal, frontal and cavernous sinuses.
Microscopic examination:
1. Evidence of hemophagocytosis, in the bone marrow, and lymph nodes(fig 5-6)
2. Mucormycosis of the orbits, sinuses, and frontal lobes of the brain (fig 7-8).
Figure 5 Histiocytes with evident hemophagocytosis in bone marrow
Figure 6 Histiocyte with evident hemophagocytosis in abdominal lymph node
   
Figure 7 Mucormycosis involving blood vessle
Figure 8 Mucormycosis involving retina

Final Diagnosis :
1. Childhood histiocytoses .......most likely Class II....Familial erythrophagocytic lymphohistiocytosis.
2. Rhinocerebral mucormycosis
Discussion: Childhood histiocytoses .......most likely Class II....Familial erythrophagocytic lymphohistiocytosis (FEL)

With:
1. The histologic findings of the post mortem specimens of BM and lymph nodes revealed histiocytes with evident hemophagocytosis, particularly erythrophagocytosis, and
2. Diverse clinical findings and laboratory investigations (fever, pancytopenia, hepatomegaly and jaundice, erythematous maculopapular rash, pleural effusion) that could explain the involvement of several organs, particularly reticuloendothelial system.
3. Age at occurence (less than 2-year-old) and rapid course of the disease.
The most likely diagnosis of this child is familial erythrophagocytic lymphohistiocytosis (FEL). Although the evidence of hemophagocytosis was not found in the first and second bone marrow aspirates, the diagnosis of Class II histiocytosis could not be excluded. In the large European review, only 22 of the 65 patients had verified hemophagocytosis in the initial bone marrow. Serial marrow aspirates or biopsy from other organs such as liver, lymph nodes or spleen is suggested (ref 2).
Summary from reference 1. The childhood histiocytoses constitute a diverse group of disorders, which, although rare in occurrence, may be severe in their clinical expression. These disorders are grouped together because they have in common a prominent proliferation/accumulation of cells of the monocyte-macrophage system of bone marrow origin. A systematic classification of the childhood histiocytoses is in the below table.
Discussion: Mucormycosis

At the end of the course of the illness, there is an additional disease... "Mucormycosis". The neutropenia, prolonged use of antibiotics and the underlying familial erythrophagocytic lymphohistiocytosis were the risk factors for mucormycosis in this child.
The clinical presentation of the child is compatible with rhinocerebral mucormycosis.

Mucormycosis is the common name given to several different diseases caused by fungi of the order Mucorales. Many species have been implicated as etiologic agents of similar clinical syndromes. Rhizopus species are the most commonly isolated agents of mucormycosis.

The most common entity is the rhinocerebral mucormycosis. The fungus gains entry to the body through the respiratory tract. The spores presumably are deposited in the nasal turbinates and may be inhaled into the pulmonary alveoli. Once the fungus begins to grow, the hyphae invade tissue and have a special affinity for blood vessels. Direct penetration and growth through the blood vessel wall explain the propensity for thrombosis and tissue necrosis, two major hallmarks of the histopathology of mucormycosis

Rhinocerebral mucormycosis is most often found in patients with diabetes mellitus, particularly in the presence of acidosis, and in patients with leukemia who have been neutropenic for long periods and who have been receiving broad-spectrum antibacterial drugs.

Signs and symptoms includes facial pain, headache, fever, orbital cellulitis, loss of extraocular muscle function, proptosis. As the disease progresses, marked swelling of the conjunctiva, loss of vision, ptosis, pupillary dilatation can occur. Other complications are cerebral abscess, cavernous sinus and internal carotid artery thrombosis. The end result of such progression is death.

Therapy includes:
1. Correct the underlying disease
2. Treatment with amphotericin B
3. Aggressive surgical debridement of necrotic tissue

References and suggested further readings
1. Ladisch S. Histiocytosis Syndrome of Childhood. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia: WB Saunders, 2000:1570-2.
2. Henter J, Arico M, Elinder G, Imashuku S, Janka G. Familial hemophagocytic lymphohistiocytosis. Hematology/Oncology Clinics of North America. 1998:12;417-33.
3. Sugar AM. Agent of mucormycosis and related species. In Mandell GL, Bennett JE and Dorin R, eds. Principles and practice of infectious diseases, 5th ed. Philadelphia: Churchill Livingston; 2000:2685-2695.

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