대한중환자의학회지：제 25 권 제 4 호 Vol. 25, No. 4, December, 2010 / DOI: 10.4266/kjccm.2010.25.4.271
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Diffuse Alveolar Hemorrhage Subsequently Developed after Recovery from Severe Acute Lung Injury Caused by H1N1 Influenza Infection A Case Report Kyung Ah Lim, M.D., Ye Rym Lee, M.D., Soo Yeon Cho, M.D., † ‡ Du Hwan Choe, M.D.*, Jae Soo Koh, M.D. , Byoung Jun Lee, M.D. , Hye-Ryoun Kim, M.D., Cheol Hyeon Kim, M.D. and Jae Cheol Lee, M.D. Departments of Internal Medicine, *Radiology and †Pathology, Korea Cancer Center Hospital, ‡ Department of Internal Medicine, Bohun Hospital, Seoul, Korea
Severe acute lung injury (ALI), leading to respiratory failure caused by H1N1 infection, developed in a 34-yearold man during a work-up for non-small cell lung cancer. Although he fully recovered through instant treatment with oseltamivir, mechanical ventilation was required again, 7 days later, due to subsequent diffuse alveolar hemorrhage (DAH). Finally, his condition improved and he was able to move out of the intensive care unit. However, multiple pulmonary metastatic nodules appeared over a period of one month, suggesting the aggressive nature of lung cancer. Although he was discharged after chemotherapy, his prognosis seemed poor, considering the rapidity of growth of the lung cancer. It is important to recognize that DAH can occur after acute lung injury caused by influenza virus. Key Words: acute lung injury, diffuse alveolar hemorrhage, influenza A virus H1N1 subtype.
or sepsis is poor.3) Bronchoalveolar lavage (BAL) is a neces-
Diffuse alveolar hemorrhage (DAH) is a syndrome consisting of hemoptysis, anemia, diffuse radiographic pulmonary in-
sary procedure for confirming alveolar hemorrhage.
filtrates, and hypoxemic respiratory failure. It manifests as al-
H1N1 infection autopsy studies showed that the main patho-
veolar infiltrates of acute onset by hemorrhage originated from
logical changes were consistent with exudative diffuse alveolar
the pulmonary microvasculature.1) Pathologic examination can
damage with or without alveolar hemorrhage and necrotizing
reveal pulmonary carpillaritis, bland pulmonary hemorrhage,
bronchitis.4,5) However, clinical presentations of H1N1 infection
diffuse alveolar damage, or other miscellaneous histology. DAH
as DAH are hard to be found as only one case was reported
may be caused by Wegener’s granulomatosis, Goodpasture syn-
in Japan.6) Our case presented here might be the first case,
drome, microscopic polyangitis, hematopoietic stem cell trans-
which DAH subsequently developed after full recovery of res-
plantation, chemotherapy for malignancy, thrombocytopenia,
piratory failure caused by H1N1 influenza infection.
ALI/ARDS and some infectious diseases such as invasive aspergillosis, cytomegalovirus infection, legionellosis, herpes sim-
CASE REPORT
plex virus infection, mycoplasmosis, hantavirus infection and leptospirosis.2) Patients with an immunologic/idiopathic patho-
A 34-year-old man was referred for treatment of non-small
genic mechanism have a relatively good prognosis, whereas the
cell lung cancer which had been diagnosed by percutaneous
outcome in individuals with DAH secondary to cancer therapy
needle biopsy at another hospital. Chest radiograph showed a huge lung mass on the left upper lung field with pleural effu-
Received on October 6, 2010, Accepted on November 29, 2010 Correspondence to: Jae Cheol Lee, Department of Internal Medicine, Korea Cancer Center Hospital, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Korea Tel: 82-2-970-1206, Fax: 82-2-970-2438 E-mail:
[email protected]
sion (Fig. 1). Sudden fever of over 39oC and progressive diffuse haziness on both lung fields appeared on hospital day 4 leading to acute respiratory failure (Fig. 2A). It was just time that pandemic H1N1 virus infection spread all over the nation 271
272 대한중환자의학회지：제 25 권 제 4 호 2010
at highest attack rates. Antibiotics and oseltamivir (75 mg bid
person with suspicious symptoms or who had been diagnosed
for 5 days) were instantly started and he was transferred to
with H1N1 infection in the hospital at that time. He was fully
the intensive care unit (ICU) for mechanical ventilation. On ar-
recovered and transferred to the general wards 10 days after
rival at ICU, his vital sign was blood pressure of 145/75 mm
the diagnosis (Fig. 2B). However, diffuse haziness similar to
Hg, heart rate of 145 beats per minute (bpm), respiratory rate
that of the initial incident, accompanied by mild fever, devel-
of 45 bpm, and oxygen saturation of 89% under a mask with
oped 7 days later (Fig. 2C). At that time, his vital sign was
reservoir bag at 10 L/min. H1N1 infection was confirmed by
blood pressure of 110/70 mm Hg, heart rate of 144 bpm, res-
real-time RT-PCR of tracheal aspirates. He was presumed to
piratory rate of 42 bpm, and oxygen saturation of 89% under
have been infected before referral because there was no other
a mask with reservoir bag at 10 L/min, therefore mechanical ventilation was required again. White blood cell count, hemoglobin, and platelet counts were 9.56 × 103/μl, 8.2 g/dl, and 5.1 × 103/μl. Prothrombin time was 14.4 sec and bleeding diathesis was absent. His hemoglobin was 10.2 g/dl three days ago and 9.8 g/dl a day before applying the ventilator. Liver and renal function tests and urine analysis were normal. Repeated RT-PCR test for H1N1 virus was negative. No microbiologic
pathogens
were
identified
from
endotracheal
aspirates. Diagnostic bronchoscopy with bronchoalveolar lavage (BAL) was done to find out the etiology. Unexpectedly, retrieved BAL fluid was fresh bloody-colored (Fig. 3A) and it became denser in the second bottle suggestive of DAH. Hemosiderin-laden macrophages were also noted on the BAL fluid examination (Fig. 3B). Reactivation of H1N1 influenza virus did not seem to be the cause of diffuse haziness because the repeated test for the virus was negative and there had Fig. 1. A huge tumor occupying the left upper hemithorax with pleural effusion of small amount was found on the initial chest radiograph.
been no report of similar cases. There was no evidence of infection on microbiologic studies. Intravenous high-dose methylprednisolone pulse therapy was done with supportive care. His
Fig. 2. During the work-up for lung cancer, diffuse air-space opacity developed (A), which resolved completely 10 days after treatment for H1N1 infection (B). However, diffuse air-space opacity appeared again 7 days later (C).
Kyung Ah Lim, et al：Diffuse Alveolar Hemorrhage after H1N1 273
condition got improved again and was able to move out of the
lying cancer (Fig. 3C, 4). He received chemotherapy and was
ICU 9 days. However, multiple metastatic nodules appeared in
discharged. His prognosis seemed poor considering the rapidity
his right lung which implied the aggressive nature of under-
of growth of the lung cancer.
DISCUSSION A novel H1N1 influenza infection can cause serious illness 7)
and death.
Although all complicated cases did not report co-
existing conditions, underlying conditions seem to be important causes for hospitalization or death. Established risk factor for complications of seasonal influenza such as diabetes and chronic cardiopulmonary disease, pregnancy and obesity were also reported as risk factors of severe disease for H1N1 infection.8,9) Although the mechanisms of severe case of H1N1 infection are unclear, some observations explain that it could be related with the ability of the virus to cause severe viral pneumonitis in humans.10) One of the early findings is pulmonary vascular congestion which can evolve into extensive alveolar hemorrhage in some fatal cases.11,12) The mortality case studies showed that the histopathological findings associated with H1N1 infection were variable from degrees of diffuse alveolar damage with hyaline membranes and septal edema, tracheitis, and necrotizing bronchiolitis.4,5) Cases with rapid progression need early intubation within day 4 to 5 from disease presentation. Commonly observed radiologic findings are diffuse Fig. 3. BAL fluid was grossly blood-colored and denser in the second bottle (A). Hemosiderin-laden macrophages were noted in the cytology specimen (B, Prussian blue staining, ×400). Diffuse air-space opacity was improved again 9 days after steroid therapy although multiple pulmonary metastatic nodules appeared after the resolution of diffuse haziness (C).
interstitial and alveolar infiltrates. Also, chest computed tomography presents multiple ground-glass opacities.10) Actually, pulmonary hemorrhage was one of the most feared complications from prior influenza outbreaks such as the 1918 “Spanish Flu” and H5N1 in China and Thailand.13,14) Although there was a
Fig. 4. CT scans obtained initially (A) and a month later (B) demonstrated rapid tumor growth and pulmonary metastases for the short interval of time suggesting the very aggressive nature of the tumor.
274 대한중환자의학회지：제 25 권 제 4 호 2010
report showing that cancer was one of the important preexist-
cause they often have similar manifestations with pneumonia.
ing conditions in patients who died of confirmed H1N1 in-
Furthermore, despite extensive microbiologic and serologic test-
fection,4) it is uncertain whether the extremely aggressive na-
ing, an infectious etiology can only be found in approximately
ture of the malignancy in our case may have contributed to
50% of patients presenting with what is considered to be a
severe acute lung injury by H1N1 infection.
community-acquired pneumonia.16) Schwarz et al. suggested that
Diffuse alveolar hemorrhage is often presented as acute res-
patients thought to have ALI/ARDS on the basis of pneumo-
piratory failure with bilateral diffuse haziness mimicking acute
nia, and those considered to have ALI/ARDS but without a
lung injury/acute respiratory distress syndrome (ALI/ARDS) and
defined predisposing condition, should undergo BAL and, de-
hemoptysis may initially be absent in up to one third of
pending on the findings, a lung biopsy, to exclude one of the
cases.1) A study of severe respiratory failure due to alveolar
acute noninfectious parenchymal lung diseases.15) We performed
hemorrhage showed that DAH was unexpectedly diagnosed,
BAL to explore the cause of the patient’s second ARDS and
and most patients did not present hemoptysis.3) Clinical pre-
found evidence of DAH. At that time, the patient had already
sentations of H1N1 infection vary from simple upper respira-
recovered from the initial ARDS caused by H1N1 infection
tory infection to severe and fatal viral pneumonia. Among
and did not receive any drugs that could lead to DAH. In ad-
them, DAH, caused by H1N1 infection, is extremely rare at
dition, there was no evidence of metastasis although multiple
present. We were able to find only one case of H1N1 influen-
metastatic nodules became evident after improvement from
za infection with DAH as initial presentation in a 40-year-old
DAH. The possibility that metastatic lung cancer could have
Japanese woman with morbid obesity.6) However, there could
been the cause of DAH seems very low considering the abrupt
be more cases considering that it is prone to be missed with-
and diffuse nature of the hemorrhage. Furthermore, hemorrhage
out suspicion because hemoptysis may initially be absent in up
did not appear again after recovery even though the cancer
1)
to 33%. Furthermore, hemoptysis in DAH was absent in 97%
was progressively growing.
of patients admitted to the ICU.3) Both the Japanese woman
In summary, H1N1 infection is a pandemic disease and can
and our patient did not show hemoptysis. BAL was performed
cause severe morbidity and mortality. Although DAH can be
to exclude bacterial infection but instead, it revealed signs of
an initial presentation of H1N1 infection, it can also be fol-
alveolar hemorrhage in both cases. After diagnosis, treatment
lowed by acute lung injury caused by the influenza virus.
of DAH is initiated from treatment of underlying cause. It is important to recognize that DAH can be virtually reversible in
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