Hemorrhagic Varicella in Osteosarcoma: Case Report Is It Induced

by Chemotherapy Agent or Nature of the Disease?

Benny Nelson, Matahari Arsy Harum P., Vita Siphra, Eliza Miranda, Sri Linuwih Menaldi

Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia / Dr. Cipto Mangunkusumo

National General Hospital, Jakarta, Indonesia

Keywords: varicella, hemorrhagic, osteosarcoma, immunocompromised, thrombocytopenia

Abstract: Varicella is a result of primary varicella-zoster virus infection and can be found worldwide. Eventhough

varicella is a self-limiting disease, serious complications can occur in 2-6% cases, especially in neonatus,

adults, and immunocompromised patients. The uncommon hemorrhagic complication that occurs in these

patients could be the result of thrombocytopenia, increased capillary pressure secondary to cutaneous

hyperemia, or bacterial secondary infection. Thrombocytopenia state can be caused by the chemoterapy agent

and be worsen by the increasing antibody response to the platelets, interaction between the virus and the

platelets resulting early removal of platelets by the reticuloendothelial system, or the release of the

neuraminidase from the virus. Mortality rates of complicated varicella is 63%. We report 2 patients with

hemorrhagic varicela in osteosarcoma in the facial region and thrombocytopenia. Both patients were clinically

diagnosed with varicella and were given intravenous acyclovir 10 mg / kg bodyweight for 10 consecutive

days. During treatment, there were no new vesicles, last crop of vesicles had crusted. Thrombocytopenia state

was corrected with thrombocyte concentrate (TC) transfusion and fortunately no internal bleeding found.

1 INTRODUCTION

Varicella is primary infection of varicella-zoster virus

(VZV). Varicella cases are distributed worldwide, but

the incidence differs in climates and vaccination

status (Schmader & Oxman, 2012). The incidence is

expected to be 60 million cases every year (Gancheva

et al., 2014). Varicella is highly contagious and could

be endemic in subtropic countries and the lack of

vaccination. About 90% of varicella occurred in

children younger than 10 years old (Schmader &

Oxman, 2012). There were approximately 11.000

hospitalization and 100 deaths caused by varicella

each year before vaccination era in 2004 (Seward et

al., 2002).

Varicella patients starts to be infectious from 1-2

days before exanthem appears and for 4-5 days after

it appears. In immunocompromised patients, the

exanthem can last longer, which means the infectious

period is also prolonged. The incubation period of

varicella is 10-23 days, with the average of 14 days

(Schmader & Oxman, 2012; Marin et al., 2016). The

major route of infection is the respiratory tract and

direct contact (Schmader & Oxman, 2012;

Gancheva et al., 2014; Seward et al., 2002; Marin

et al., 2016).

Before exanthem appears, varicella is often

preceded by 2-3 days of prodromal symptoms, though

these prodromal symptoms are uncommon in young

children. After the prodromal symptoms,

erythematous macules appear firstly on the scalp and

face, then spread rapidly to the trunk. Progressively,

the macules turn into papules, vesicles, pustules, and

crusts that distributed centrally on the body

(Schmader & Oxman, 2012; Miller & Stephan, 1993).

Differential diagnosis includes vesicular viral

exanthem, insect bites, impetigo, contact dermatitis,

and disseminated herpes simplex (Schmader &

Oxman, 2012; Miller & Stephan, 1993). Varicella can

be diagnosed from the clinical appereance and

evolution of its characteristic rash, especially if

there’s a direct contact with other varicella patient 2-

3 weeks before (Schmader & Oxman, 2012). Tzanck

smear test from the base of the vesicles shows the

presence of a characteristic multinucleated giant cells

but can’t distinguish it from other viral infection

(Leung et al., 2010; Nahass et al., 1992).

Eventhough varicella is a self-limiting disease,

serious complications can occur in 2-6% cases,

especially in neonatus, adults, and

420

Nelson, B., Harum P., M., Siphra, V., Miranda, E. and Menaldi, S.

Hemorrhagic Varicella in Osteosarcoma: Case Report Is It Induced by Chemotherapy Agent or Nature of the Disease?.

DOI: 10.5220/0008158804200423

In Proceedings of the 23rd Regional Conference of Dermatology (RCD 2018), pages 420-423

ISBN: 978-989-758-494-7

immunocompromised patients (Schmader & Oxman,

2012, Miller et al., 1993; Bonanni, 2009). The

complications can occur before, during, or after the

presence of rashes. Most complications of varicella

can be grouped into eight major categories: (1)

bacterial superinfection; (2) herpes zoster; (3)

varicella-associated Reye’s syndrome; (4) central

nervous system; (5) pulmonary; (6) hemorrhagic; (7)

therapeutic complications or exacerbation of

underlying illnesses; and (8) immunocompromised

patients (Miller et al., 1993). Hemorrhagic

complication that occurs in varicella is frequently

associated with secondary thrombocytopenia or

secondary infection. The states of thrombocytopenia

relate to increased capillary pressure secondary to

cutaneous hyperemia causes the clinical hemorrhagic

appeareance (Charkes, 1961). Mortality rates of

complicated varicella is as high as 63% (Miller et al.,

1993).

2 CASE

We report 2 cases of hemorrhagic varicella in

osteosarcoma patients. First patient was a 16 years old

girl, presented to Pediatric Emergency Unit of Cipto

Mangunkusumo General Hospital (RSCM) with dark

vesicles and bullous on her body from 10 days before

admission. It started with 3 erythematous vesicles on

the face and high fever. Within the same day, the

vesicles spread to the other part of her body and

turned dark. New dark vesicles still appeared 1 day

before admission on the soles of the feet. She also

suffered pain sensation all over her body, which made

her uncomfortable and hard to sleep. The patient had

not given any medication before admission, except

for the paracetamol she had been taking since her first

chemotherapy.

Two weeks before the first vesicles appeared,

patient held her nephew who was having varicella.

There was no history of applying anything before

vesicles appeared. There was no history of loss of

consciousness, dispnea, cough, blurred vision, or

upper abdomen pain. The patient was diagnosed with

nasal osteosarcoma and was on the third

chemotherapy and took paracetamol regularly to

reduce the pain. The patient never had varicella and

varicella vaccination before.

From the physical examination, the vital signs

were within normal limit. Her body weight was 60 kg

and her body height was 158 cm (BMI: 24,03). We

found multiple, circumscribed, discrete hemorrhagic

vesicle-bullous and some black crusts all over her

body. There was no lymph enlargement. Laboratories

studies obtained: hemoglobin was 9,59 g/dL;

leukocyte was 2,58 x 10

/μL; platelet count was 17 x

/μL; and albumin was 2,23 g/dL. Other

laboratories studies were within normal limit.

The patient was diagnosed with osteosarcoma

grade IV on third cycle chemotherapy and varicella

with pancytopenia and hypoalbuminemia state. The

patient was admitted to the isolation room and given

intravenous acyclovir 600 mg every 8 hours,

intravenous ampicillin-sulbactam 2 gram every 6

hours, oral paracetamol 500 mg every 8 hours,

albumin 20% transfusion 2 x 100 mL, thrombocyte

concentrate (TC) transfusion, and high protein diet

(1,5 g/kg body weight/day).

On the fifth day of IV acyclovir, the patient was

getting better, there were no new lesions, while some

of the vesicles had already crusted. On the 10

day,

the patient felt so much better and was excited to get

home. There was no new lesions, fever, and pain. The

patient was then discharged and oral acyclovir was

continued until the 14

day.

Second

patient was a 23 years old male. The

patient was on the 5

day treatment in the ward by the

Internal Medicine Department, RSCM and was

consulted with hemorrhagic vesicles since 3 days ago

along with fever. The patient didn’t feel any pain or

itch sensation. The vesicles started as red patch on the

face and within 1 day, the red patch became vesicles

and spread to other part of his body.

There was no history of loss of consciousness,

dispnea, cough, blurred vision, or upper abdomen

pain. The patient never had varicella and varicella

vaccination before, nor contact with other varicella

patients. The patient was already diagnosed with

osteosarcoma on the mastoid region and was at the

second chemotherapy with anemia,

hypoalbuminemia, and thrombocytopenia states.

From the physical examination, the vital signs

were within normal limit. His body weight was 70 kg

and his body height was 168 cm (BMI: 24,80). We

found multiple, circumscribed, discrete black vesicle-

bullous on the skalp, neck, chest, stomach, back, both

arms and legs. No lymph enlargement was found.

Laboratories studies revealed: hemoglobin was 8

g/dL; leukocyte was 0,26 x 10

/μL; platelet count was

25 x 10

/μL; andn albumin was 3,21 g/dL. Other

laboratories studies were within normal limit.

We diagnosed the patient as varicella in

immunocompromised and thrombocytopenia state

and gave him intravenous acyclovir 700 mg every 8

hours, oral paracetamol 500 mg every 8 hours, oral

paracetamol 500 mg every 8 hours, intravenous

meropenem 1 g every 8 hours, TC transfusion, and

high protein diet (1,5 g/kg body weight/day). During

Hemorrhagic Varicella in Osteosarcoma: Case Report Is It Induced by Chemotherapy Agent or Nature of the Disease?

421

treatment, patient was getting better and there were

no new lesions since intravenous acyclovir had been

given. All the vesicles had already crusted on the 10

day of acyclovir.

3 DISCUSSION

Both patients were clinically diagnosed with varicella

because of the characteristic rash, which began as red

macules on the scalp and progressively turned into

papules, vesicles, pustules, and crusts that centrally

distributed. There were direct contacts with other

varicella patients in the first patient, which was her

nephew. The high fever and pain in the first patient

were the prodromal symptoms. Tzanck smear from

the base of vesicle might show multinucleated giant

cells in viral infection and although it’s not specific

for varicella, it might be helpful in confirming the

diagnosis of varicella (leung et al., 2010; Nahass et

al., 1992). We did not do Tzanck smear because the

diagnosis can already be made clinically. Usually the

treatment is limited to acetaminophen for fever and

pain, sometimes antipruritic for the itch, and

maintenance of general hygiene. Varicella patients

with immunocompromised are generally given

intravenous acyclovir for 10-14 days, which

dramatically reduces the risk of complications and

formation of new lesions (Miller et al., 1993). The

virus will then remain latent in sensory ganglia and

could reappears as herpes zoster in 10%-15%

individuals (Schmader & Oxman, 2012).

Coagulopathies are frequently associated with

varicella infection through a variety of etiological

mechanism. The uncommon hemorrhagic lesions in

both patients could be the result of thrombocytopenia

caused by the chemotherapy agent, increased

capillary pressure secondary to cutaneous hyperemia,

or bacterial secondary infection. Viral infection could

make the thrombocytopenia worse by several

mechanisms: an increased antibody response

(suggesting the possibility of an autoimmune

mechanism), interaction between the virus and the

platelets result in early removal of platelets by the

reticuloendothelial system, or the release of the

neuraminidase from the virus attacks sialic acid in the

platelet membrane. Patients with malignant or

progressive varicella with purpura, are unable to

terminate the viremia because of the changes in T-cell

subsets and maybe related to inadequate production

of interferon. Bleeding from the gastrointestinal tract,

genitourinary tract, and mucous membranes is

frequent and the mortality rate is greater than 70%

(Miller et al., 1993).

Fortunately both patients did not

have any evidence related to gastrointestinal or

genitourinary bleeding.

Varicella is highly contagious and could be

endemic with attack rates 60-100%,

10,11

and for that

reason, both patients were admitted to isolation room

(Varicella-Zoster Infections, 2009; Heininger et al.,

2006). The most common complication of varicella is

bacterial superinfection (Schmader & Oxman, 2012,

Miller et al., 1993; Bonanni, 2009). This

superinfection could lead to septic shock in

immunocompromised patients. Both patients were

given broad spectrum antibiotic for severe infections

(Nelson et al., 2016).

Figure 1. First patient with hemorrhagic varicella

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422

Figure 2. Second patient with hemorrhagic varicella

4 CONCLUSION

Serious complications can occur in varicella,

especially those with immunocompromised state,

including hemorrhagic lesions. These hemorrhagic

lesions can be the result of thrombocytopenia caused

by the chemotherapy agent and increased capillary

pressure secondary to cutaneous hyperemia. The

thrombocytopenia is worsen by several mechanism,

which is the nature of the disease itself.

REFERENCES

Bonanni, P., Breuer, J., Gershon, A., Gershon, M.,

Hryniewicz, W., Papaevangelou, V., Rentier, B.,

Rümke, H., Sadzot-Delvaux, C., Senterre, J., Weil-

Olivier, C. & Wutzler, P., 2009. Varicella Vaccination

in Europe – Taking the Practical Approach, BMC

Medicine, 7(1), 26. doi: 10.1186/1741-7015-726.

Charkes, N. D., 1961. Purpuric chickenpox: report of a

case, review of the literature, and classification by

clinical features. Annals of internal medicine, 54(4), pp.

745-759.

Gancheva, G. I., Doichinova, T. G., & Lukanov, T. C.,

2014. Complications of Varicella–Report of Case with

Hemorrhagic-Necrotic Rash and Cerebellar Ataxia,

JMED Research, Article ID: 589754.

Heininger, U., & Seward, J. F., 2006. Varicella. The

Lancet, 368(9544), pp. 1365-1376.

Leung, J., Harpaz, R., Baughman, A. L., Heath, K.,

Loparev, V., Vázquez, M., Watson, B. M., & Schmid,

D. S., 2010. Evaluation of laboratory methods for

diagnosis of varicella. Clinical infectious

diseases, 51(1), pp. 23-32.

Marin, M., Marti, M., Kambhampati, A., Jeram, S. M., &

Seward, J. F., 2016. Global varicella vaccine

effectiveness: a meta-analysis. Pediatrics, 137(3),

e20153741.

Miller, H. C., & Stephan, M., 1993. Hemorrhagic varicella:

a case report and review of the complications of

varicella in children. The American journal of

emergency medicine, 11(6) ,pp. 633-638.

Nahass, G. T., Goldstein, B. A., Zhu, W. Y., Serfling, U.,

Penneys, N. S., & Leonardi, C. L., 1992. Comparison

of Tzanck smear, viral culture, and DNA diagnostic

methods in detection of herpes simplex and varicella-

zoster infection. Jama, 268(18), pp. 2541-2544.

Nelson, J. D., Bradley, J.S., Barnett, E.D., Cantey, J.B.,

Kimberlin, D.W., Palumbo, P.E., Sauberan, J., et al.,

2016. Nelson’s Pediatric Antimicrobial Therapy. 22

ed. Elk Groove Village: AAP.

Schmader, K.E., & Oxman, M.N., 2012. Varicella and

Herpes Zoster. In: Goldsmith LA, Katz SI, Gilchrest

BA, Paller AS, Leffel JD, Wolff K, editor. Fitzpatrick’s

dermatology in general medicine. 8

Edition. New

York: McGraw-Hill, pp. 2383-2401

Seward, J. F., Watson, B. M., Peterson, C. L., Mascola, L.,

Pelosi, J. W., Zhang, J. X., Maupin, J.T., Goldman

S,G., Tabony J.L., Brodovich G.K., Jumaan, A. O., &

Melinda, W., 2002. Varicella disease after introduction

of varicella vaccine in the United States, 1995-

2000. Jama, 287(5), pp. 606-611.

Varicella-Zoster Infections., 2009. in: Report of the

Committee on Infectious Diseases. American Academy

of Pediatrics (Red Book), pp. 714.

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